RU2826004C2 - Amatoxin antibody-drug conjugates and use thereof - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to amatoxins of general formula (An), where n is 2, 3, 4, 5, 6, 7, 8 or 9. Invention also relates to an antibody-drug conjugate (ADC) consisting of an antibody conjugated to amatoxin through a linker, wherein the ADC has structural formula (Ia), where Q is S; L is -(CH₂)_n, wherein n is integer from 1 to 6; Z is a maleimide group; and Ab is an antibody which specifically binds to Her2 or PSMA. Invention also relates to an antibody-drug conjugate (ADC), wherein the antibody specifically binds to human PSMA and contains heavy and light chain amino acid sequences and which is conjugated with HDP30.2867 compound. Invention also relates to the use of ADC for treating cancer. (HDP30.2867).

EFFECT: providing amatoxins which can be used in antibody-drug conjugates (ADC) for delivering amatoxin to a target cell, which have high plasma stability and tolerance in vivo.

16 cl, 15 tbl, 48 dwg, 22 ex

Description

Field of technology to which the present invention relates

The present invention relates to amatoxins, antibody drug conjugates (ADCs) comprising an amatoxin, compositions comprising such ADCs, and methods of using the same.

Prior art of the present invention

Monoclonal antibodies (mAbs) can be conjugated to a therapeutic agent to form an antibody drug conjugate (ADC). ADCs can exhibit increased potency compared to unconjugated antibody. The binding of the antibody to the drug can be direct or indirect via a linker. An important aspect of successful therapeutic ADCs is that the ADC is not only efficacious but also well tolerated. Often, a cytotoxin affects both potency and tolerability.

ADCs have been proposed as therapeutic agents for the treatment of cancer. The use of ADCs for local delivery of cytotoxic or cytostatic agents, i.e., drugs to kill or inhibit tumor cells in the treatment of cancer, theoretically allows targeted delivery of the drug moiety to tumors and intracellular accumulation in them, where systemic administration of these unconjugated drugs would result in unacceptable levels of toxicity, including for normal cells.

ADCs have also been proposed as a therapeutic regimen to prepare patients for transplantation and stem cell therapy. By conditioning a patient with a cell-specific ADC, stem cells or immune cells can be selectively depleted while leaving the rest of the patient's immune system largely intact. For example, Palchaudhuri et al. (2016) Nat. Biotechnol. 34, 738–745 described the use of a single dose of anti-CD45 ADC, in which the anti-CD45 antibody was conjugated to saporin, and its ability to promote donor cell engraftment and application to a sickle cell disease model. Unlike radiotherapy, CD45-SAP ADC was reported to avoid neutropenia and anemia and provide rapid T- and B-cell reconstitution with minimal systemic toxicity. There remains a need for toxins that can be used for non-genotoxic targeted ADC conditioning, where the toxin is potent for target cells while minimizing side effects for the patient.

Brief summary of the present invention

The present invention relates to amatoxins that can be used in antibody drug conjugates (ADCs), for example, to deliver amatoxin to a target cell. The present invention also relates to specific modifications of antibodies that can be used in antibody drug conjugates to deliver amatoxin to a target cell. The present invention also relates to combinations of said amatoxins and antibodies that have increased potency, increased in vivo tolerability, and therefore favorable therapeutic windows.

Brief description of the figures

Figure 1 depicts the structures of formulas IV (Figure 1A), VI (Figure 1B), and Ha (Figure 1C). "Ab" in Figures 1A-1C represents an antibody. Figures 1A, 1B, and 1C depict conjugates A, B, and C, respectively, mentioned in the examples. Conjugates A, B, and C are also referred to as ADC A, ADC B, and ADC C.

Figure 2 graphically shows the results of in vitro cytotoxicity assays using Kasumi-1 cells in the presence of ADC with pre-incubation of ADC in medium (A) or 50% human serum (B) to assess the stability of the conjugates in serum.

Figure 3 graphically shows the results of in vitro cytotoxicity assays using Kasumi-1 cells in the presence of ADC with repeated incubation times with titrated ADC samples to assess differences in cytotoxicity kinetics between cleavable and non-cleavable conjugates.

Figure 4 graphically shows the results of two in vitro cell killing assays using Kasumi-1 cells (4A) and CD34+ cells (4B). The ADC tested was anti-CD117 ADC C.

Figure 5 graphically depicts the ability of anti-CD117 ADC C to potently deplete human CD34+ in the bone marrow of humanized NSG mice.

Figure 6 presents Kaplan-Meier plots showing the survival of humanized NSG mice implanted with Kasumi-1 that were treated with the indicated doses of conjugates or controls.

Figure 7 graphically depicts the potency of conjugate C assessed in male cynomolgus monkeys. Dose 2.0 mg/kg (LALA). Issues with lot 30.2867 may have resulted in decreased HSC sensitivity.

Figure 8 graphically depicts the tolerability of ADCs containing either conjugate A or conjugate C in male cynomolgus macaques.

Figure 9 graphically depicts the pharmacokinetic analysis of conjugate A and conjugate C administered to male cynomolgus macaques.

Figure 10 graphically shows that ADC C against CD2 and CD5 are capable of depleting T cells.

Figure 11 graphically shows that although anti-CD2 ADCs A and C reach saturation by day 5, some cells still express CD5.

Figures 12A and 12B graphically represent the results showing ADC against CD45 A or C (Figure 14A) or ADC against CD45 A or B (Figure 14B) in in vitro cell killing assays.

Figure 13 graphically shows the results showing ADC A or C against CD45 in in vitro cell killing assays.

Figure 14 graphically shows the results of ADC A or C against CD45 in in vivo cell depletion experiments.

Figure 15 graphically shows the results of administration of anti-CD45 ADC A or C to mice at different doses. The levels of peripheral lymphocytes, HSCs, and lymphocytes are shown. All ADCs were administered at a dose of 1 mg/kg.

Figure 16 graphically presents the results showing ADC A and C against CD137 in the T cell killing assay.

Figure 17 graphically depicts the serum stability of ADC A and C cell lines against CD137 over 48 hours.

Figure 18 shows the structures of amanitin-linker constructs HDP30.2867, 30.0880, 30.2371, and 30.1699, respectively.

Figure 19 shows the structures of the amanitin-linker constructs HDP30.2115, 30.2060, and 30.2347, respectively.

Figure 20 graphically depicts the in vitro cytotoxic activity of ADC compounds T-D265C-30.2867 and T-D265C-30.0880, respectively, on (A) SKBR-3, (B) NCI-N87, (C) BT474, and (D) JIMT-1 cell lines in the 96P-BrdU assay.

Figure 21 graphically shows the results of the stability analysis of the ADC compounds T-D265C-30.2867 and T-D265C-30.0880 by SDS-PAGE/Western blot after incubation for 0, 4, and 10 days, respectively, in (A) human, (B) mouse, (C) cynomolgus monkey, and (D) PBS (control) plasma, respectively.

Figure 22 graphically depicts the in vitro cytotoxic activity of the ADC T-D265C-30.2867 on SBR-3 cells after incubation for 0, 4 and 10 days, respectively, in (A) human, (B) mouse, (C) cynomolgus monkey plasma and (D) PBS (control), respectively.

Figure 23 graphically depicts the in vitro cytotoxic activity of the ADC T-D265C-30.2867 on NCI-N87 cells after incubation for 0, 4 and 10 days, respectively, in (A) human, (B) mouse, (C) cynomolgus monkey plasma and (D) PBS (control), respectively.

Figure 24 graphically depicts the in vitro cytotoxic activity of the ADC T-D265C-30.2867 on JIMT-1 cells after incubation for 0, 4 and 10 days, respectively, in (A) human, (B) mouse, (C) cynomolgus monkey plasma and (D) PBS (control), respectively.

Figure 25 graphically shows the results of the cytotoxic efficacy analysis of anti-Her2 ADCs in in vivo JIMT-1 cell xenograft mouse tumor models using the ADC compounds T-D265C-30.2867, T-D265C-30.0880, and T-D265C-30.1699.

Figure 26 graphically shows the results of the cytotoxic efficacy analysis of anti-Her2 ADCs in NCI-N87 cell xenograft mouse tumor models in vivo using ADC compounds T-D265C-30.2867, T-D265C-30.0880, and T-D265C-30.1699.

Figure 27 graphically depicts the in vitro cytotoxic activity of the ADC compounds h3/F11-D265C-Var16-30.2867 and h3/F11-D265C-Var16-30.0880 on (A) LNCap, (B) 22RV1, and (C) PC3 cell lines, respectively, in the 96h-BrdU assay.

Figure 28 graphically shows the results of the cytotoxic efficacy analysis of ADCs against PSMA in LNCap cell xenograft mouse tumor models in vivo using the ADC compounds h3/F11-D265C-Var16-30.2867, h3/F11-D265C-Var-16-30.0880, and h3/F11-D265C-Var16-30.2060.

Figure 29 graphically presents the results of a tolerance study in monkeys using the anti-digoxigenin ADC compound DIG-D265C-30.2867 at various doses from 1 mg/kg to 20 mg/kg. The results of the assessment of LDH, AST, and ALT indices are presented.

Figure 30 graphically presents the results of a tolerability study in monkeys using DIG-D265C-30.2867. Pharmacokinetic data for the ADC in serum are shown.

Figure 31 graphically presents the results of a tolerability study in monkeys using DIG-D265C-30.2867. Pharmacokinetic data for amatoxin in serum are shown.

Figure 32 graphically depicts the in vitro cytotoxic activity of ADC compounds containing an anti-Her2 antibody with the D265C mutation (T-D265C) conjugated to structurally distinct amanitin derivatives on JIMT-1 cells (A, B).

Figure 33 graphically depicts the in vitro cytotoxic activity of ADC compounds containing the Her2 antibody with the D265C mutation (T-D265C) conjugated to structurally distinct amanitin derivatives on NCI-N87 cells (A, B).

Figure 34 graphically depicts the in vitro cytotoxic activity of ADC compounds containing an anti-Her2 antibody with the D265C mutation (T-D265C) conjugated to structurally distinct amanitin derivatives on SKBR-3 cells (A, B).

Figure 35 graphically depicts the in vitro cytotoxic activity of ADC compounds containing an anti-PSMA antibody with the D265C mutation (h3/F11-D265C-Var16) conjugated to structurally distinct amanitin derivatives on LNCap cells (A, B).

Figure 36 graphically depicts the in vitro cytotoxic activity of ADC compounds containing an anti-PSMA antibody with the D265C mutation (h3/F11-D265C-Var16) conjugated to structurally distinct amanitin derivatives on 22RV1 cells (A, B).

Figure 37 graphically presents the results of the cytotoxic efficacy analysis of various anti-PSMA ADCs containing structurally different amanitin derivatives in an in vivo mouse LNCap cell xenograft tumor model. Mean values +/- SEM for all groups are shown at And maximum tolerated dose (MTD).

Figure 38 graphically presents the results of the cytotoxic efficacy analysis of various anti-PSMA ADCs containing structurally different amanitin derivatives in an in vivo mouse LNCap cell xenograft tumor model. Mean values +/- SEM for all groups are shown. maximum tolerated dose (MTD).

Figure 39 graphically presents the results of the cytotoxic efficacy analysis of various anti-PSMA ADCs containing structurally different amanitin derivatives in an in vivo mouse LNCap cell xenograft tumor model. Mean values +/- SEM for all groups are shown. maximum tolerated dose (MTD).

Figure 40 graphically depicts the results of cytotoxic efficacy analysis of various anti-PSMA ADCs containing structurally different amanitin derivatives in an in vivo mouse LNCap cell xenograft tumor model. Shown are the mean values +/- SEM for ADCs with a linker attached to amino acid 1 of amatoxin at And maximum tolerated dose (MTD).

Figure 41 graphically presents the results of cytotoxic efficacy analysis of various anti-PSMA ADCs containing structurally different amanitin derivatives in an in vivo mouse LNCap cell xenograft tumor model. Shown are the mean values +/- SEM for ADCs with a linker attached to amino acid 4 of amatoxin at And maximum tolerated dose (MTD).

Figure 42 graphically shows the results of cytotoxic efficacy analysis of various anti-PSMA ADCs containing structurally different amanitin derivatives in an in vivo mouse LNCap cell xenograft tumor model. Shown are mean values +/- SEM for ADCs with cleavable linkers at maximum tolerated dose (MTD).

Figure 43 graphically shows the results of the cytotoxic efficacy analysis of Her2 ADCs containing the L234A/L235A/D265C triple mutations and the toxoid-linker construct HDP30.2060 and HDP30.2867, respectively (T-LALA-D265C-30.2060, T-LALA-D265C-30.2867, respectively) on Her2-positive NCI-N87 cells in a CDX mouse model.

Figure 44 graphically shows the results of the cytotoxic efficacy analysis of ADCs against PSMA containing the L234A/L235A/D265C triple mutations and the amatoxin-linker construct HDP30.2060 and HDP30.2867, respectively (h3/F11-LALA-D265C-Var-30.2060, h3/F11-LALA-D265C-Var-30.2867, respectively) on PSMA-positive LNCap cells in a mouse CDX model.

Figure 45 graphically shows the results of a 96-hour BrdU assay to evaluate the in vitro cytotoxic potential of Her2-specific ADCs containing an antibody carrying the L234A/L235A mutations and/or the D265C mutation, or control mutations, on Her2-positive SKBR-3 cells (A, B, C, D).

Figure 46 graphically shows the results of a 96-hour CTG assay to evaluate the in vitro cytotoxic potential of Her2-specific ADCs containing an antibody carrying the L234A/L235A mutations and/or the D265C mutation, or control mutations on Her2-negative THP-1 cells (A, B, C, D).

Figure 47 graphically shows the results of a 120-hour CTG assay to evaluate the in vitro cytotoxic potential of Her2-specific ADCs containing an antibody carrying the L234A/L235A mutations and/or the D265C mutation, or control mutations, on Her2-negative THP-1 cells (A, B, C, D).

Detailed disclosure of the present invention

For clarity of the present disclosure, and not for purposes of limitation, the detailed disclosure of the present invention is divided into the following subsections.

The present invention relates to a camatoxin or a derivative or analogue thereof comprising a structure of formula (An) or formula (Bn)

Formula (An)

Formula (Bn)

where n is 2, 3, 4, 5, 6, 7, 8 or 9,

According to one embodiment, the present invention relates to an amatoxin or a derivative or analogue thereof comprising a structure of formula (A)

or its enantiomer or diastereomer.

According to a further embodiment, the present invention relates to an amatoxin or a derivative or analogue thereof; comprising a structure of formula (B)

or its enantiomer or diastereomer.

The amatoxins mentioned or their derivatives or analogs can be used in the preparation of antibody drug conjugate (ADC).

The present inventors have shown that the ADCs according to the present invention have particularly high stability and tolerability in plasma and, therefore, an improved therapeutic window.

The present invention also relates to an antibody drug conjugate (ADC) comprising an antibody or antigen-binding fragment thereof conjugated to an amatoxin via a linker, wherein the ADC is characterized by a structure of formula (I):

or its stereoisomer;

Where:

Q represents S or a sulfoxide group;

L is a non-cleavable linker;

Z is a chemical moiety formed by a coupling reaction between a reactive substituent present on L and a reactive substituent present in the antibody or antigen-binding fragment thereof; and

Ab is an antibody or its antigen-binding fragment.

The said ADC may be characterized by the structure of formula (Ia):

The said ADC may also be characterized by the structure of formula (Ib):

In said ADCs, L may comprise one or more of the following: a bond, -(C=O)-, a -C(O)NH- group, an -OC(O)NH- group, _C1 - _C6 alkylene, _C1 - _C6 heteroalkylene, _{C2 - C6} alkenylene, C2- _C6 heteroalkenylene, _C2 - _C6 alkynylene, _C2 - _C6 heteroalkynylene, _C3 - _C6 cycloalkylene, heterocycloalkylene, arylene, _{heteroarylene} , a -( _CH2CH2O ) _p- group, where p is an integer from 1 to 6, or a solubility-enhancing group;

wherein each C ₁ -C ₆ alkylene, C ₁ -C ₆ heteroalkylene, C ₂ -C ₆ alkenylene, C 2 -C ₆ heteroalkenylene, C ₂ -C ₆ alkynylene, C ₂ -C ₆ heteroalkynylene, C _{3 -C 6} cycloalkylene, heterocycloalkylene, arylene or heteroarylene may be optionally substituted with 1 to 5 substituents independently selected for each occurrence from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkaryl, alkylheteroaryl, amino, ammonium, acyl, acyloxy, acylamino, aminocarbonyl, alkoxycarbonyl, ureido, carbamate, aryl, heteroaryl, sulfinyl, sulfonyl, hydroxyl, alkoxy, sulfanyl, helogen, carboxy, trihalomethyl, cyano, hydroxy, mercapto and nitro;

or each _C1 - _C6 alkylene, _C1 - _C6 heteroalkylene, _C2 - _{C6 alkenylene} , C2- _C6 heteroalkenylene, _C2 - _C6 alkynylene, _C2 - _C6 heteroalkynylene, _C3 - _C6 cycloalkylene, heterocycloalkylene, arylene or heteroarylene may optionally be interrupted by one or more heteroatoms selected from O, S and N.

The said solubility enhancing group can be characterized by the formula -O _a -C(O)NH-SO ₂ -NR ¹ -, where:

a is 0 or 1; and

R ¹ is selected from the group consisting of: hydrogen, C ₁ -C ₂₄ alkyl groups, C ₃ -C ₂₄ cycloalkyl groups, C ₂ -C ₂₄ (hetero)aryl groups, C ₃ -C ₂₄ alkyl(hetero)aryl groups and C ₃ -C ₂₄ (hetero)arylalkyl groups, each of which may be optionally substituted or optionally interrupted by one or more heteroatoms selected from O, S and NR ³ , wherein R ³ is independently selected from the group consisting of hydrogen and C ₁ -C ₄ alkyl.

In the said ADCs, L may comprise a unit -( _CH2 ) _n- , where n is an integer of 2-6. Preferably, L is -( _CH2 ) _n- , where n is 6.

In the above ADCs, Ab, Z and L, taken together as Ab-Z-L, can be represented by the formula:

where S represents the sulfur atom of a cysteine residue present in the antibody or antigen-binding fragment thereof.

According to one embodiment, the present invention relates to an antibody drug conjugate (ADC) comprising an antibody or antigen-binding fragment thereof conjugated to an amatoxin via a linker, wherein the ADC is characterized by a structure of formula (I):

or its stereoisomer;

Where:

Q represents S or a sulfoxide group;

L is a cleavable linker;

Z is a chemical moiety formed by a coupling reaction between a reactive substituent present on L and a reactive substituent present in the antibody or antigen-binding fragment thereof; and

Ab is an antibody or its antigen-binding fragment.

The said ADC may be characterized by the structure of formula (Ia):

The said ADC may be characterized by the structure of formula (Ib):

In said ADCs, L comprises one or more of the following: hydrazine, disulfide, thioether, amino acid, peptide consisting of up to 10 amino acids, para-aminobenzyl (PAB) group, heterocyclic self-cleaving group, _C1 - _C6 alkyl, _C1 - _{C6 heteroalkyl, C2-C6 alkenyl , C2} - _C6 , heteroalkenyl, _C2 - _C6 , _alkynyl , _C2 -C6 , heteroalkynyl, _C3 - _C6 cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -(C=O)- group, -C(O)NH- group, -OC(O)NH- group, -( _CH2CH2O ) _p- group, where p is an integer from 1 to 6, or a solubility _- enhancing group;

wherein each C ₁ -C ₆ alkyl, C ₁ -C ₆ heteroalkyl, C ₂ -C ₆ alkenyl, C _{2 -C 6 heteroalkenyl, C 2 -C 6 alkynyl} , C ₂ -C ₆ heteroalkynyl, C ₃ -C ₆ cycloalkyl, heterocycloalkyl, aryl or heteroaryl group may be optionally substituted with from 1 to 5 substituents independently selected for each occurrence from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkaryl, alkyl heteroaryl, amino, ammonium, acyl, acyloxy, acylamino, aminocarbonyl, alkoxycarbonyl, ureido, carbamate, aryl, heteroaryl, sulfinyl, sulfonyl, hydroxyl, alkoxy, sulfanyl, helogen, carboxy, trihalomethyl, cyano, hydroxy, mercapto and nitro;

or each _C1 - _C6 alkyl, _C1 - _C6 heteroalkyl, _C2 - _C6 alkenyl, _C2 - _C6 heteroalkenyl, _C2 - _C6 alkynyl, _C2 - _C6 heteroalkynyl, _C3 - _C6 cycloalkyl, heterocycloalkyl, aryl or heteroaryl group may optionally be interrupted by one or more heteroatoms selected from O, S and N.

The said solubility enhancing group can be characterized by the formula -O _a -C(O)NH-SO ₂ -NR ¹ -, where:

a is 0 or 1; and

R ¹ is selected from the group consisting of: hydrogen, C ₁ -C ₂₄ alkyl groups, C ₃ -C ₂₄ cycloalkyl groups, C ₂ -C ₂₄ (hetero)aryl groups, C ₃ -C ₂₄ alkyl(hetero)aryl groups and C ₃ -C ₂₄ (hetero)arylalkyl groups, each of which may be optionally substituted or optionally interrupted by one or more heteroatoms selected from O, S and NR ³ , wherein R ³ is independently selected from the group consisting of hydrogen and C ₁ -C ₄ alkyl.

According to one embodiment of the present invention, L comprises a peptide selected from the group consisting of Phe-Lys, Val-Lys, Phe-Ala, Phe-Cit, Val-Ala, Val-Cit and Val-Arg. L may further comprise a PAB group.

According to one embodiment, L is represented by the formula:

According to a preferred embodiment, the present invention relates to an ADC comprising an antibody conjugated to an amatoxin, wherein the ADC is characterized by a structure of formula (II):

or its stereoisomer.

The specified ADC may be characterized by the structure of formula (IIa):

The said ADC may be characterized by the structure of formula (IIb):

According to a preferred embodiment of the present invention, the antibody or antigen-binding fragment thereof specifically binds to an antigen expressed on the cell surface of a human cancer cell or stem cell, in particular a hematopoietic stem cell (HSC), or T cell.

According to a further preferred embodiment of the present invention, the antibody or antigen-binding fragment thereof specifically binds to human Her2, PSMA, CD37 or CD123.

According to another preferred embodiment of the present invention, the antibody or antigen-binding fragment thereof comprises an Fc region comprising at least one mutation selected from the group consisting of D265C, D265A, A118C, H435A, L234A or L235A (according to the EU index).

According to another preferred embodiment of the present invention, the antibody or antigen-binding fragment thereof specifically binds to PSMA and comprises CDRH1 according to SEQ ID NO: 378, CDRH2 according to SEQ ID NO: 379, CDRH3 according to SEQ ID NO: 380, CDRL1 according to SEQ ID NO: 381, CDRL2 according to SEQ ID NO: 382 and CDRL3 according to SEQ ID NO: 383.

According to another preferred embodiment of the present invention, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region according to SEQ ID NO: 375 and a light chain variable region according to SEQ ID NO: 377.

According to another preferred embodiment of the present invention, said antibody comprises a heavy chain according to SEQ ID NO: 371, SEQ ID NO: 372, SEQ ID NO: 373 or SEQ ID NO: 374 and a light chain according to SEQ ID NO: 376 or an antigen-binding fragment thereof.

The present invention further relates to an antibody drug conjugate (ADC) comprising an antibody or antigen binding fragment thereof conjugated to an amatoxin or a derivative or analogue thereof via a linker, wherein the antibody or antigen binding fragment thereof comprises an Fc region comprising at least two mutations consisting of L234A and L235A (according to the EU index).

According to a particularly preferred embodiment, said Fc region further comprises a mutation consisting of D265C (according to the EU index).

According to a preferred embodiment of the present invention, said antibody or antigen-binding fragment thereof specifically binds to an antigen expressed on the cell surface of a cancer cell, preferably a human cancer cell.

According to another preferred embodiment of the present invention, said antibody or antigen-binding fragment thereof specifically binds to prostate-specific membrane antigen (PSMA), preferably human PSMA, or to the Her2, CD37 or CD123 antigen.

A preferred embodiment relates to an antibody drug conjugate (ADC), wherein said antibody or antigen binding fragment thereof specifically binds to PSMA and comprises CDRH1 according to SEQ ID NO: 378, CDRH2 according to SEQ ID NO: 379, CDRH3 according to SEQ ID NO: 380, CDRL1 according to SEQ ID NO: 381, CDRL2 according to SEQ ID NO: 382 and CDRL3 according to SEQ ID NO: 383.

According to a preferred embodiment of the present invention, said antibody that specifically binds to PSMA, or an antigen-binding fragment thereof, comprises a heavy chain variable region according to SEQ ID NO: 375 and a light chain variable region according to SEQ ID NO: 377.

According to another preferred embodiment of the present invention, said antibody comprises a heavy chain according to SEQ ID NO: 372, SEQ ID NO: 373 or SEQ ID NO: 374 and a light chain according to SEQ ID NO: 376 or an antigen-binding fragment thereof.

According to further preferred embodiments, the antibody drug conjugate (ADC) comprises an antibody or antigen-binding fragment thereof that is conjugated to any compound selected from the group consisting of HDP30.2060, HDP30.2115, HDP30.2347, HDP30.1699, HDP30.2371, HDP30.0880 and HDP30.2867.

The present invention further relates to an antibody drug conjugate (ADC) comprising an antibody or an antigen-binding fragment thereof that specifically binds to human PSMA and comprises a heavy chain with an amino acid sequence according to SEQ ID NO: 374 and a light chain with an amino acid sequence according to SEQ ID NO: 376, and which is conjugated to the compound HDP30.2060. Most preferably, in said ADC, the compound HDP30.2060 is directly linked to the sulfur atom of cysteine D265C of said antibody (EU numbering).

The present invention further relates to an antibody drug conjugate (ADC) comprising an antibody or antigen-binding fragment thereof that specifically binds to human PSMA and comprises a heavy chain with an amino acid sequence according to SEQ ID NO: 374 and a light chain with an amino acid sequence according to SEQ ID NO: 376, and which is conjugated to the compound HDP30.2115. Most preferably, in said ADC, the compound HDP30.2115 is directly linked to the sulfur atom of cysteine D265C of said antibody.

The present invention further relates to an antibody drug conjugate (ADC) comprising an antibody or antigen binding fragment thereof that specifically binds to human PSMA and comprises a heavy chain with an amino acid sequence according to SEQ ID NO: 374 and a light chain with an amino acid sequence according to SEQ ID NO: 376, and which is conjugated to the compound HDP30.2347. Most preferably, in said ADC, the compound HDP30.2347 is directly linked to the sulfur atom of cysteine D265C of said antibody.

The present invention further relates to an antibody drug conjugate (ADC) comprising an antibody or antigen-binding fragment thereof that specifically binds to human PSMA and comprises a heavy chain with an amino acid sequence according to SEQ ID NO: 374 and a light chain with an amino acid sequence according to SEQ ID NO: 376, and which is conjugated to the compound HDP30.1699. Most preferably, in said ADC, the compound HDP30.1699 is directly linked to the sulfur atom of cysteine D265C of said antibody.

The present invention further relates to an antibody drug conjugate (ADC) comprising an antibody or antigen-binding fragment thereof that specifically binds to human PSMA and comprises a heavy chain with an amino acid sequence according to SEQ ID NO: 374 and a light chain with an amino acid sequence according to SEQ ID NO: 376, and which is conjugated to the compound HDP30.2371. Most preferably, in said ADC, the compound HDP30.2371 is directly linked to the sulfur atom of cysteine D265C of said antibody.

The present invention further relates to an antibody drug conjugate (ADC) comprising an antibody or antigen-binding fragment thereof that specifically binds to human PSMA and comprises a heavy chain with an amino acid sequence according to SEQ ID NO: 374 and a light chain with an amino acid sequence according to SEQ ID NO: 376, and which is conjugated to the compound HDP30.0880. Most preferably, in said ADC, the compound HDP30.0880 is directly linked to the sulfur atom of cysteine D265C of said antibody.

The present invention further relates to an antibody drug conjugate (ADC) comprising an antibody or antigen-binding fragment thereof that specifically binds to human PSMA and comprises a heavy chain with an amino acid sequence according to SEQ ID NO: 374 and a light chain with an amino acid sequence according to SEQ ID NO: 376, and which is conjugated to the HDP30.2867 compound. Most preferably, in said ADC, the HDP30.2867 compound is directly linked to the sulfur atom of cysteine D265C of said antibody.

In the antibody drug conjugates (ADC) of the present invention, the drug to antibody ratio (DAR) is about 1, 2, 3 or 4, preferably the DAR is 2.

An additional aspect of the present invention relates to said ADCs for use in the treatment of cancer in a patient, in particular wherein the cancer is selected from the group consisting of: breast cancer, pancreatic cancer, cholangiocarcinoma, colorectal cancer, lung cancer, prostate cancer, ovarian cancer, prostate cancer, gastric cancer, renal cancer, malignant melanoma, hematological malignancy, leukemia and malignant lymphoma.

The present invention further relates to the use of any of said ADCs for treating cancer in a patient, in particular, wherein the cancer is selected from the group consisting of the following: breast cancer, pancreatic cancer, cholangiocarcinoma, colorectal cancer, lung cancer, prostate cancer, ovarian cancer, prostate cancer, gastric cancer, renal cancer, malignant melanoma, hematological malignancy, leukemia, and malignant lymphoma.

According to another preferred embodiment of the present invention, said antibody drug conjugate (ADC) comprises an antibody or antigen-binding fragment thereof that specifically binds to an antigen expressed on the cell surface of a hematopoietic stem cell (HSC), preferably a human HSC.

An additional embodiment of the present invention relates to a method of depleting a cell population in a human subject, said method comprising administering said ADC to the subject, wherein the ADC comprises an antibody or antigen-binding fragment thereof that specifically binds to an extracellular antigen expressed by cells in the cell population.

An additional embodiment of the present invention relates to a method of conditioning a human subject for cell transplantation, said method comprising administering said ADC to the human subject such that endogenous stem or endogenous immune cells in the human subject are depleted, wherein the ADC specifically binds to an extracellular antigen expressed by the endogenous stem or endogenous immune cells.

A further embodiment of the present invention relates to the said method, further comprising administering to the human subject allogeneic stem cells or allogeneic immune cells.

A further embodiment of the present invention relates to the said method, wherein the ADC specifically binds to an extracellular antigen expressed on an immune cell, and wherein the subject is characterized by having or is at risk of developing a graft-versus-host disease (GVHD).

The present invention further relates to a pharmaceutical composition comprising any of the said ADCs or combinations thereof and at least a pharmaceutically acceptable carrier.

Definitions

Unless otherwise specified, the following terms and phrases used in this document have the following meanings.

As used herein, the term "acyl" refers to the following: -C(=O)R, where R is hydrogen ("aldehyde"), _C1 - _C12 alkyl, _C2 - _C12 alkenyl, _C2 - _C12 alkynyl, _C3 - _C7 carbocyclyl, _C6 - _C20 aryl, 5-10 membered heteroaryl, or 5-10 membered heterocyclyl, as defined herein. Non-limiting examples include formyl, acetyl, propanoyl, benzoyl, and acryloyl.

As used herein, the term " _C1 - _C12 alkyl" refers to a straight or branched chain saturated hydrocarbon containing 1-12 carbon atoms. Typical _C1 - _C12 alkyl groups include, but are not limited to, -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, and -n-hexyl; while branched _C1 - _C12 alkyls include, but are not limited to, -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, and 2-methylbutyl. A _C1 - _C12 alkyl group may be unsubstituted or substituted.

As used herein, the term "alkenyl" refers to a _C2 - _C12 hydrocarbon containing normal, secondary or tertiary carbon atoms with at least one site of unsaturation, i.e., a carbon-carbon double bond, ^sp2 . Examples include, but are not limited to: ethylene or vinyl, -allyl, -1-butenyl, -2-butenyl, -isobutylenyl, -1-pentenyl, -2-pentenyl, -3-methyl-1-butenyl, -2-methyl-2-butenyl, -2,3-dimethyl-2-butenyl, and the like. The alkenyl group may be unsubstituted or substituted.

As used herein, "alkynyl" refers to a _C2 - _C12 hydrocarbon containing normal, secondary, or tertiary carbon atoms with at least one site of unsaturation, i.e., a carbon-carbon triple bond sp. Examples include, but are not limited to, acetylene and propargyl. An alkynyl group may be unsubstituted or substituted.

As used herein, "aryl" refers to a _C6 - _C20 carbocyclic aromatic group. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, and anthracenyl. An aryl group may be unsubstituted or substituted.

As used herein, "arylalkyl" refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or ^sp3 carbon atom, is replaced with an aryl radical. Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-1-yl, 2-phenylethen-1-yl, naphthylmethyl, 2-naphthylethan-1-yl, 2-naphthylethen-1-yl, naphthobenzyl, 2-naphthophenylethan-1-yl, and the like. An arylalkyl group contains from 6 to 20 carbon atoms, for example, the alkyl moiety, including alkanyl, alkenyl, or alkynyl groups, of an arylalkyl group contains from 1 to 6 carbon atoms and the aryl moiety contains from 5 to 14 carbon atoms. The alkaryl group may be unsubstituted or substituted.

As used herein, the term "cycloalkyl" refers to a saturated carbocyclic radical that may be mono- or bicyclic. Cycloalkyl groups include a ring containing from 3 to 7 carbon atoms as a monocycle or from 7 to 12 carbon atoms as a bicycle. Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. A cycloalkyl group may be unsubstituted or substituted.

As used herein, the term "cycloalkenyl" refers to an unsaturated carbocyclic radical that may be mono- or bicyclic. Cycloalkenyl groups include a ring containing from 3 to 6 carbon atoms as a monocycle or from 7 to 12 carbon atoms as a bicycle. Examples of monocyclic cycloalkenyl groups include 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl and 1-cyclohex-3-enyl. The cycloalkenyl group may be unsubstituted or substituted.

As used herein, the term "heteroarylalkyl" refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or ^sp3 carbon atom, is replaced by a heteroaryl radical. Typical heteroarylalkyl groups include, but are not limited to, 2-benzimidazolylmethyl, 2-furylethyl, and the like. The heteroarylalkyl group contains 6-20 carbon atoms, for example, the alkyl moiety, including alkanyl, alkenyl or alkynyl groups, of the heteroarylalkyl group contains 1-6 carbon atoms, and the heteroaryl moiety contains 5-14 carbon atoms and 1-3 heteroatoms selected from N, O, P and S. The heteroaryl moiety of the heteroarylalkyl group can be a monocycle containing 3-7 ring members (2-6 carbon atoms) or a bicycle containing 7-10 ring members (4-9 carbon atoms and 1 to 3 heteroatoms selected from N, O, P and S), for example: bicyclo[4,5], [5,5], [5,6] or [6,6] system.

As used herein, the terms "heteroaryl" and "heterocycloalkyl" refer to an aromatic or non-aromatic ring system, respectively, in which one or more ring atoms is a heteroatom, such as nitrogen, oxygen and sulfur. A heteroaryl or heterocycloalkyl radical contains 2-20 carbon atoms and 1-3 heteroatoms selected from N, O, P and S. A heteroaryl or heterocycloalkyl may be a monocycle containing 3-7 ring members (2-6 carbon atoms and 1-3 heteroatoms selected from N, O, P and S) or a bicycle containing 7-10 ring members (4-9 carbon atoms and 1-3 heteroatoms selected from N, O, P and S), such as a bicyclo[4,5], [5,5], [5,6] or [6,6] system. Heteroaryl and heterocycloalkyl may be unsubstituted or substituted.

Heteroaryl and heterocycloalkyl groups are described in Paquette, Leo A.; "Principles of Modern Heterocyclic Chemistry" (W. A. Benjamin, New York, 1968), especially chapters 1, 3, 4, 6, 7, and 9; "The Chemistry of Heterocyclic Compounds, A series of Monographs" (John Wiley & Sons, New York, 1950 to present), especially volumes 13, 14, 16, 19, and 28; and J. Am. Chem. Soc. (1960) 82:5566.

Examples of heteroaryl groups include, by way of example, but are not limited to, pyridyl, thiazolyl, tetrahydrothiophenyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, isoxazolyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, 1H-indazolyl, purinyl, 4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, furazanil, phenoxazinyl, isochromanil, chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, benzotriazolyl, benzisoxazolyl and isatinoyl.

Examples of heterocycloalkyl include, by way of example, but are not limited to, dihydropyridyl, tetrahydropyridyl (piperidyl), tetrahydrothiophenyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, tetrahydrofuranyl, tetrahydropyranyl, bis-tetrahydropyranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroisoquinolinyl, piperazinyl, quinuclidinyl, and morpholinyl.

By way of example, but not limitation, carbon-linked heteroaryls and heterocycloalkyls are linked at position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5, or 6 of a pyridazine, position 2, 4, 5, or 6 of a pyrimidine, position 2, 3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan, tetrahydrofuran, thiofuran, thiophene, pyrrole, or tetrahydropyrrole, position 2, 4, or 5 of an oxazole, imidazole, or thiazole, position 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of an aziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6, 7, or 8 of a quinoline, or position 1, 3, 4, 5, 6, 7, or 8 isoquinoline. Even more typically, carbon-linked heterocycles include 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, or 5-thiazolyl.

By way of example, and not limitation, nitrogen-linked heteroaryls and heterocycloalkyls are linked at position 1 of aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, 1H-indazole, position 2 of isoindole or isoindoline, position 4 of morpholine, and position 9 of carbazole or beta-carboline. Even more typically nitrogen-linked heterocycles include 1-aziridyl, 1-azetedyl, 1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl, and 1-piperidinyl.

"Substituted" as used herein and with respect to any of the above alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, heteroaryl, heterocyclyl, etc. means that one or more hydrogen atoms are independently replaced with a substituent. Unless otherwise limited by the definition of an individual substituent, the above chemical moieties such as "alkyl,""alkylene,""heteroalkyl,""heteroalkylene,""alkenylene,""heteroalkenyl,""heteroalkenylene,""alkynyl,""alkynylene,""heteroalkynyl,""heteroalkynylene,""cycloalkyl,""cycloalkylene,""heterocycloalkyl,"heterocycloalkylene,""aryl,""arylene,""heteroaryl," and "heteroarylene" groups may be optionally substituted. Typical substituents include, but are not limited to, -X, -R, -OH, -OR, -SH, -SR, NH ₂ , -NHR, -N(R) ₂ , -N ⁺ (R) ₃ , -CX ₃ , -CN, -OCN, -SCN, -NCO, -NCS, -NO, -NO ₂ , -N ₃ , -NC(=O)H, -NC(=O)R, -C(=O)H, -C(=O)R, -C(=O)NH ₂ , -C(=O)N(R) ₂ , -SO ₃ -, -SO ₃ H, -S(=O) ₂ R, -OS(=O) ₂ OR, -S(=O) ₂ NH ₂ , -S(=O) ₂ N(R) ₂ , -S(=O)R, -OP(=O)(OH) ₂ , -OP(=O)(OR) ₂ , -P(=O)(OR) ₂ , _-PO3 , _{-PO3H2 ,} -C(=O) _X , -C(=S)R, -CO2H _, -CO2R _, -CO2-, -C(=S)OR, -C(=O)SR, -C(=S)SR, -C(=O)NH2, -C(=O) _N (R) ₂ , -C _{(=S)NH2, -C(=S)N(R)2 ,} -C(=NH) _NH2 , and -C(=NR)N(R) ₂ ; where each X is independently selected for each occurrence from F, Cl, Br, and I; and each R is independently selected for each occurrence from the following: _C1 - _C12 alkyl, _C6 - _C20 aryl, _C3 - _C14 heterocycloalkyl or heteroaryl, a protecting group, and a prodrug moiety. Wherever a group is described as "optionally substituted," that group may be substituted with one or more of the above substituents, independently for each occurrence.

It should be understood that some radical naming conventions may include either a monoradical or a diradical, depending on the context. For example, if a substituent requires two points of attachment to the rest of the molecule, it is clear that the substituent is a diradical. For example, a substituent identified as alkyl, which requires two points of attachment, includes diradicals such as -CH ₂ -, -CH ₂ CH ₂ -, -CH ₂ CH(CH ₃ )CH ₂ -, etc. Other radical naming conventions clearly indicate that the radical is a diradical, such as "alkylene", "alkenylene", "arylene", "heterocycloalkylene", etc.

Wherever a substituent is depicted as a diradical (i.e. has two points of attachment to the rest of the molecule), it should be understood that the substituent may be attached in any directional configuration unless otherwise noted.

"Isomerism" refers to compounds that have identical molecular formulas but differ in the order in which their atoms are bonded or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are called "stereoisomers." Stereoisomers that are not mirror images of each other are called "diastereoisomers," and stereoisomers that are not superimposable mirror images of each other are called "enantiomers" or sometimes "optical isomers."

A carbon atom bonded to four non-identical substituents is called a "chiral center". A "chiral isomer" means a compound with at least one chiral center. Compounds with more than one chiral center may exist either as an individual diastereoisomer or as a mixture of diastereoisomers, called a "diastereomeric mixture". When one chiral center is present, the stereoisomer can be characterized by the absolute configuration (R or S) of that chiral center. The absolute configuration refers to the spatial arrangement of the substituents attached to the chiral center. The substituents attached to the chiral center in question are ranked according to the Cahn, Ingold, and Prelog sequence rule. (Cahn et al., Angew. Chem. Inter. Edit. 1966, 5, 385; corrigenda 511; Cahn et al., Angew. Chem. 1966, 78, 413; Cahn and Ingold, J. Chem. Soc. 1951 (London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J. Chem. Educ. 1964, 41, 116). A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is called a "racemic mixture."

The compounds disclosed in the present specification and claims may contain one or more asymmetric centers, and there may be different diastereoisomers and/or enantiomers of each of the compounds. The description of any compound in this specification and claims is intended to include all enantiomers, diastereoisomers, and mixtures thereof, unless otherwise indicated. Furthermore, the description of any compound in the present specification and claims is intended to include both individual enantiomers and any mixture, racemic or otherwise, of enantiomers, unless otherwise indicated. When the structure of a compound is depicted as a particular enantiomer, it is to be understood that the present invention of the present application is not limited to that particular enantiomer. Accordingly, enantiomers, optical isomers, and diastereoisomers of each of the structural formulas of the present disclosure are provided herein. In the present description, the structural formula of a compound represents a specific isomer for convenience in some cases, but the present disclosure includes all isomers, such as geometric isomers, optical isomers based on asymmetric carbon, stereoisomers, tautomers and the like, while it is understood that not all isomers may have the same level of activity. Compounds can exist in various tautomeric forms. It is understood that the compounds of the present disclosure include all tautomeric forms, unless otherwise indicated. When the structure of a compound is depicted as a specific tautomer, it is to be understood that the present invention of the present application is not limited to that specific tautomer.

Compounds of any formula described herein include the compounds themselves, as well as their salts and solvates, if applicable. A salt, for example, can be formed between an anion and a positively charged group (e.g., an amino group) in a compound according to the present disclosure. Suitable anions include chloride, bromide, iodide, sulfate, bisulfate, sulfamate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, glutamate, glucuronate, glutarate, malate, maleate, succinate, fumarate, tartrate, tosylate, salicylate, lactate, naphthalenesulfonate, and acetate (e.g., trifluoroacetate). The term "pharmaceutically acceptable anion" refers to an anion suitable for forming a pharmaceutically acceptable salt. Similarly, a salt can also be formed between a cation and a negatively charged group (e.g., a carboxylate) in a compound according to the present disclosure. Suitable cations include a sodium ion, a potassium ion, a magnesium ion, a calcium ion, and an ammonium cation such as a tetramethylammonium ion. Examples of some suitable substituted ammonium ions are those derived from: ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, as well as amino acids such as lysine and arginine.

The compounds of the present disclosure also include salts containing quaternary nitrogen atoms.

Examples of suitable inorganic anions include, but are not limited to, anions derived from the following inorganic acids: hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfurous, nitric, nitrous, phosphoric, and phosphorous. Examples of suitable organic anions include, but are not limited to, those derived from the following organic acids: 2-acetyloxybenzoic, acetic, ascorbic, aspartic, benzoic, camphorsulfonic, cinnamic, citric, ethylenediaminetetraacetic acid, ethanedisulfonic, ethanesulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, hydroxymaleic, hydroxynaphthalenecarboxylic, isethionic, lactic, lactobionic, lauric, maleic, malic, methanesulfonic, mucinous, oleic, oxalic, palmitic, pamoic, pantothenic, phenylacetic, phenylsulfonic, propionic, pyruvic, salicylic, stearic, succinic, sulfanilic, tartaric, toluenesulfonic and valerianic. Examples of suitable polymeric organic anions include, but are not limited to, anions derived from the following polymeric acids: tannic acid, carboxymethylcellulose.

In addition, the compounds of the present disclosure, such as salts of the compounds, may exist in either hydrated or non-hydrated (anhydrous) form or as solvates with other solvent molecules. Non-limiting examples of hydrates include monohydrates, dihydrates, etc. Non-limiting examples of solvates include ethanol solvates, acetone solvates, etc. "Solvate" means solvent addition forms that contain stoichiometric or non-stoichiometric amounts of solvent. Some compounds tend to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thereby forming a solvate. If the solvent is water, the resulting solvate is a hydrate; and if the solvent is an alcohol, the resulting solvate is an alcoholate. Hydrates are formed by the combination of one or more water molecules with one molecule of a substance in which the water retains its molecular state as _H2O . Hydrate refers to, for example, monohydrate, dihydrate, trihydrate, etc.

In addition, crystalline polymorphism may be present for the compounds or salts thereof represented by the formulas disclosed herein. It should be noted that any crystalline form, mixture of crystalline forms, or anhydride or hydrate thereof is included within the scope of the present disclosure.

As used herein, the term "about" refers to a value that is within 10% above or below the value being described. For example, the term "about 5 nM" refers to a range of 4.5 to 5.5 nM.

As used herein, the term "amatoxin" refers to a member of the amatoxin family of peptides produced by the mushroom Amanita phalloides, or a variant or derivative thereof, such as a variant or derivative thereof capable of inhibiting RNA polymerase II activity. Suitable amatoxins and derivatives thereof are further described herein below. As described herein, amatoxins can be conjugated to an antibody or antigen-binding fragment thereof, such as via a linker moiety (L) (thus forming a conjugate (i.e., ADC)). Examples of amatoxin conjugation methods and linkers useful for such processes are described below.

In the context of the present invention, the term "amatoxin" includes all cyclic peptides consisting of 8 amino acids isolated from the genus Amanita and described in Wieland, T. and Faulstich H. (Wieland T, Faulstich H., CRC Crit Rev Biochem. 5 (1978) 185-260), as well as all chemical derivatives thereof;

additionally all its semi-synthetic analogues; additionally all their synthetic analogues constructed from elementary units in accordance with the basic structure of natural compounds (cyclic, 8 amino acids), additionally all synthetic or semi-synthetic analogues containing non-hydroxylated amino acids instead of hydroxylated amino acids, additionally all synthetic or semi-synthetic analogues in which the sulfoxide moiety is replaced by a sulfone, thioether or atoms other than sulfur, for example a carbon atom, as in the carbon analogue of amanitin.

As used herein, the term "derivative" of a compound refers to a species that has a chemical structure similar to the compound, but contains at least one chemical group that is not present in the compound and/or lacks at least one chemical group that is present in the compound. The compound to which a derivative is compared is known as the "parent" compound. Typically, a "derivative" can be prepared from the parent compound by one or more chemical reaction steps.

As used herein, an "analogue" of a compound is structurally related to, but not identical to, the compound and exhibits at least one activity of the compound. The compound to which an analogue is compared is known as the "parent" compound. The above-mentioned activities include, but are not limited to: binding activity to another compound; inhibitory activity, such as enzyme inhibitory activity; toxic effects; activating activity, such as enzyme activating activity. It is not required that an analogue exhibit such activity to the same extent as the parent compound. A compound is considered to be an analogue in the context of the present application if it exhibits the relevant activity to an extent of at least 1% (more preferably at least 5%, more preferably at least 10%, more preferably at least 20%, more preferably at least 30%, more preferably at least 40% and more preferably at least 50%) of the activity of the parent compound. Thus, "amatoxin analog" as used herein refers to a compound that is structurally related to any of the following: α-amanitin, β-amanitin, γ-amanitin, ε-amanitin, amanin, amaninamide, amanullin and amanullinic acid, and that exhibits at least 1% (more preferably at least 5%, more preferably at least 10%, more preferably at least 20%, more preferably at least 30%, more preferably at least 40% and more preferably at least 50%) inhibitory activity against mammalian RNA polymerase II compared to at least one of α-amanitin, β-amanitin, γ-amanitin, ε-amanitin, amanin, amaninamide, amanullin and amanullinic acid. An "amatoxin analog" suitable for use in the present invention may even exhibit higher inhibitory activity against mammalian RNA polymerase II than any of α-amanitin, β-amanitin, γ-amanitin, ε-amanitin, amanin, amaninamide, amanullin or amanullinic acid. The inhibitory activity can be measured by determining the concentration at which 50% inhibition occurs (IC ₅₀ value). The inhibitory activity against mammalian RNA polymerase II can be determined indirectly by measuring the inhibitory activity against cell proliferation.

"Semi-synthetic analogue" refers to an analogue that has been obtained by chemical synthesis using compounds from natural sources (e.g., plant materials, bacterial cultures, fungal cultures, or cell cultures) as starting material. Typically, the "semi-synthetic analogue" of the present invention is synthesized using a compound isolated from fungi of the Amanitaceae family as starting material. In contrast, "synthetic analogue" refers to an analogue synthesized by so-called total synthesis from small (usually petrochemical) building blocks. Typically, this total synthesis is accomplished without the aid of biological processes.

According to some embodiments of the present invention, the amatoxin may be selected from the group consisting of α-amanitin, β-amanitin, amanin, amaninamide, and analogs, derivatives, and salts thereof.

Functionally, amatoxins are defined as peptides or depsipeptides that inhibit mammalian RNA polymerase II. Preferred amatoxins are those that have a functional group (e.g., a carboxyl group, an amino group, a hydroxy group, a thiol group, or a thiol trapping group) that can react with linker molecules or target-binding moieties, as defined below.

In the context of the present invention, the term "amanitins" refers in particular to a bicyclic structure which is based on an aspartic acid or asparagine residue in position 1, a proline residue, in particular a hydroxyproline residue in position 2, an isoleucine, hydroxyisoleucine or dihydroxyisoleucine residue in position 3, a tryptophan or hydroxytryptophan residue in position 4, glycine residues in positions 5 and 7, an isoleucine residue in position 6 and a cysteine residue in position 8, in particular a cysteine derivative which is oxidized to a sulfoxide or a sulfone derivative (for numbering and representative examples of amanitins, see Fig. 1) and further comprises all chemical derivatives thereof; additionally all semi-synthetic analogues thereof; additionally all its synthetic analogues constructed from elementary units in accordance with the basic structure of natural compounds (cyclic, 8 amino acids), additionally all synthetic or semi-synthetic analogues containing non-hydroxylated amino acids instead of hydroxylated amino acids, additionally all synthetic or semi-synthetic analogues, in each case in which any such derivative or analogue is functionally active by inhibiting mammalian RNA polymerase II.

As used herein, the term "antibody" refers to an immunoglobulin molecule that specifically binds to or immunologically reacts with a particular antigen, and includes monoclonal, genetically engineered, and otherwise modified forms of antibodies, including, but not limited to, chimeric antibodies, humanized antibodies, heteroconjugate antibodies (e.g., bi-, tri-, and quadri-specific antibodies, diabodies, triabodies, and tetrabodies), and antigen-binding fragments of antibodies, including, for example, Fab', F(ab') ₂ , Fab, Fv, rIgG, and scFv fragments. Unless otherwise specified, the term "monoclonal antibody" (mAb) is intended to include both intact molecules and fragments of antibodies (including, for example, Fab and F(ab') ₂ fragments) that are capable of specifically binding to a target protein. As used herein, Fab and F(ab') ₂ fragments refer to antibody fragments that lack the Fc portion of an intact antibody. Examples of these antibody fragments are described herein.

As used herein, the term "monoclonal antibody" refers to an antibody that is obtained from a single clone, including any eukaryotic, prokaryotic or phage clone, and not to the method by which it is obtained.

Antibodies of the present invention are typically isolated or recombinant. As used herein, the term "isolated" refers to a polypeptide, such as an antibody, that has been separated and/or recovered from the cell or cell culture from which it was expressed. Thus, an "isolated antibody" refers to an antibody that is substantially free of other antibodies having different antigen specificities. For example, an isolated antibody that specifically binds to CD117 is substantially free of antibodies that specifically bind antigens other than CD117.

As used herein, the term "antigen-binding fragment" refers to a fragment of an antibody that retains the ability to specifically bind to a target antigen. The antigen-binding function of an antibody can be performed by fragments of a full-length antibody. The antibody fragment can be, for example, a Fab, F(ab') ₂ , scFv, diabody, triabody, affibody, nanobody, aptamer, or domain antibody. Examples of binding fragments encompassed within the term "antigen-binding fragment" of an antibody include, but are not limited to: (i) a Fab fragment, a monovalent fragment consisting of the V _L , v _h , _{CL ,} and _CH 1 domains; (ii) an F(ab') ₂ fragment, a divalent fragment comprising two Fab fragments linked by a disulfide bridge in the hinge region; (iii) an Fd fragment consisting of the v _h and _CH 1 domains; (iv) an Fv fragment consisting of the V _L and v _h domains of one arm of an antibody, (v) a dAb including both the v _h and V _L domains; (vi) a dAb fragment that consists of a v _h domain (see, e.g., Ward et al., Nature 341:544-546, 1989); (vii) a dAb that consists of either a v _h or V _L domain; (viii) an isolated complementarity determining region (CDR); and (ix) a combination of two or more (e.g., two, three, four, five, or six) isolated CDRs, which may optionally be joined by a synthetic linker. Furthermore, although the two domains of the Fv fragment, V _L and v _h , are encoded by separate genes, they can be joined by recombinant techniques using a linker that allows them to be produced as a single protein chain in which the v _L and v _h regions are paired to form monovalent molecules (known as single-chain Fv (scFv); see, e.g., Bird et al., Science 242:423-426, 1988 and Huston et al., Proc. Natl. Acad. Sci. USA 85:5879-5883, 1988). Antibody fragments can be prepared using conventional techniques known to those skilled in the art, and the fragments can be tested for suitability in the same manner as intact antibodies. Antigen-binding fragments may be produced by recombinant DNA techniques, enzymatic or chemical cleavage of intact immunoglobulins, or, in certain cases, by chemical peptide synthesis techniques known in the art.

As used herein, the term "anti-CD117 antibody" or "antibody that binds to CD117" refers to an antibody that is capable of binding CD117, such as human CD117, with sufficient affinity such that the antibody is useful as a diagnostic and/or therapeutic agent targeting CD117. The amino acid sequences of the two major isoforms of human CD117 are set forth in SEQ ID NO: 145 (isoform 1) and SEQ ID NO: 146 (isoform 2). "ADC against CD117" refers to adc, wherein the antibody is the KCD117 antibody.

As used herein, the term "anti-CD45 antibody" or "antibody that binds to CD45" refers to an antibody that is capable of binding CD45, such as human CD45, with sufficient affinity such that the antibody can be used as a diagnostic and/or therapeutic agent targeting CD45. "Anti-CD45 ADC" refers to an ADC wherein the antibody is an antibody to CD45.

As used herein, the term "anti-CD137 antibody" or "antibody that binds to CD137" refers to an antibody that is capable of binding CD137, such as human CD137, with sufficient affinity such that the antibody can be used as a diagnostic and/or therapeutic agent targeting CD137. "Anti-CD137 ADC" refers to an ADC wherein the antibody is an anti-CD137 antibody.

As used herein, the term "anti-CD2 antibody" or "antibody that binds to CD2" refers to an antibody that is capable of binding CD2, such as human CD2, with sufficient affinity such that the antibody can be used as a diagnostic and/or therapeutic agent targeting CD2. "Anti-CD2 ADC" refers to an ADC wherein the antibody is an antibody to CD2.

As used herein, the term "anti-CD5 antibody" or "antibody that binds to CD5" refers to an antibody that is capable of binding CD5, such as human CD5, with sufficient affinity such that the antibody can be used as a diagnostic and/or therapeutic agent targeting CD5. "Anti-CD5 ADC" refers to an ADC wherein the antibody is an antibody to CD5.

As used herein, the term "bispecific antibody" refers to, for example, a monoclonal, often human or humanized antibody that is capable of binding at least two different antigens. For example, one of the binding specificities may be directed to the hematopoietic stem cell surface antigen, CD117 (e.g., GNNK+ CD117), and the other may specifically bind to another hematopoietic stem cell surface antigen or another cell surface protein, such as a receptor or receptor subunit involved in a signal transduction pathway that, among other things, potentiates cell growth.

As used herein, the term "complementarity determining region" (CDR) refers to the hypervariable region found in both the light chain variable domains and the heavy chain variable domains of an antibody. The more highly conserved portions of the variable domains are referred to as framework regions (FRs). The amino acid positions that define the hypervariable region of an antibody may vary depending on the context and various definitions known in the art. Some positions in a variable domain may be considered hybrid hypervariable positions in the sense that these positions may be considered to be within the hypervariable region according to one set of criteria, while they may be considered to be outside the hypervariable region according to another set of criteria. One or more of these positions may also be found in extended hypervariable regions. The antibodies described herein may contain modifications at these hybrid hypervariable positions. Each of the variable domains of native heavy and light chains contains four framework regions that generally adopt a β-sheet configuration connected by three CDRs that form loops that connect, and in some cases form part of, the β-sheet structure. The CDRs in each chain are held together in close proximity by the framework regions in the order FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4 and, together with the CDRs from other chains of the antibody, contribute to the formation of the target antibody binding site (see Kabat et al., Sequences of Proteins of Immunological Interest, National Institute of Health, Bethesda, MD, 1987). In certain embodiments, the numbering of immunoglobulin amino acid residues is performed in accordance with the immunoglobulin amino acid residue numbering system of Kabat et al., unless otherwise indicated (although any antibody numbering scheme may be used, including but not limited to IMGT and Chothia).

As used herein, the terms "condition" and "conditioning" refer to processes by which a patient is prepared to receive a transplant, such as a transplant containing hematopoietic stem cells. Such procedures promote hematopoietic stem cell engraftment (e.g., as evidenced by a sustained increase in the number of viable hematopoietic stem cells in a blood sample isolated from the patient following a conditioning procedure and subsequent hematopoietic stem cell transplantation. Using the methods described herein, a patient can be prepared for hematopoietic stem cell transplantation therapy by administering to the patient an ADC capable of binding an antigen expressed by hematopoietic stem cells, such as CD117 (e.g., GNNK+ CD117). Administration of an ADC capable of binding an HSC antigen to a patient in need of hematopoietic stem cell transplantation therapy can promote hematopoietic stem cell engraftment, e.g., by selectively depleting endogenous hematopoietic stem cells, thereby creating a vacancy that can be filled by a transplant of exogenous hematopoietic stem cells.

As used herein, the term "conjugate" refers to a compound formed by chemically linking a reactive functional group of one molecule, such as an antibody or antigen-binding fragment thereof, to a correspondingly reactive functional group of another molecule, such as a cytotoxin described herein. Conjugates may include a linker between the two molecules linked to each other. Examples of linkers that can be used to form a conjugate include peptide-containing linkers, such as linkers that contain naturally occurring or non-naturally occurring amino acids, such as D-amino acids. Linkers can be prepared using a variety of strategies described herein and known in the art. Depending on the reactive components contained therein, the linker can be cleaved, for example, by enzymatic hydrolysis, photolysis, acidic hydrolysis, basic hydrolysis, oxidation, disulfide reduction, nucleophilic cleavage, or organometallic cleavage (see, for example, Leriche et al., Bioorg. Med. Chem., 20:571-582, 2012). Notably, the term "conjugate" (when referring to a compound) is also referred to herein interchangeably as a "drug conjugate," "antibody drug conjugate," or "ADC."

As used herein, the term "coupling reaction" refers to a chemical reaction in which two or more substituents suitable for reaction with each other react to form a chemical moiety that joins (e.g., covalently) the molecular moieties linked to each substituent. Coupling reactions include reactions in which a reactive substituent linked to a moiety that is a cytotoxin, such as a cytotoxin known in the art or described herein, reacts with a suitable reactive substituent linked to a moiety that is an antibody or antigen-binding fragment thereof, such as an antibody, antigen-binding fragment thereof, or a CD117-specific antibody that binds CD117 (such as GNNK+ CD117), known in the art or described herein. Examples of suitable reactive substituents include a nucleophile/electrophile pair (e.g., a thiol/haloalkyl pair, an amine/carbonyl pair, or a thiol/α,β-unsaturated carbonyl pair, among others), a diene/dienophile pair (e.g., an azide/alkyne pair, among others), and the like. Coupling reactions include, but are not limited to, thiol alkylation, hydroxyl alkylation, amine alkylation, amine condensation, amidation, esterification, disulfide formation, cycloaddition (e.g., [4+2] Diels-Alder cycloaddition, [3+2] Huisgen cycloaddition, among others), nucleophilic aromatic substitution, electrophilic aromatic substitution, and other reaction methods known in the art or described herein.

As used herein, the term "CRU (competitive repopulating unit)" refers to a unit of measurement of long-term engraftable stem cells that can be detected after transplantation in vivo.

As used herein, the term "donor" refers to a human or animal from which one or more cells are isolated prior to the introduction of the cells or their progeny into a recipient. The one or more cells may be, for example, a population of hematopoietic stem cells.

As used herein, the term "diabody" refers to a bivalent antibody comprising two polypeptide chains in which each polypeptide chain comprises v _h and v _l domains connected by a linker that is too short (e.g., a linker consisting of five amino acids) to allow intramolecular association of the v _h and v _l domains on the same peptide chain. This configuration forces each domain to pair with a complementary domain on another polypeptide chain to form a homodimeric structure. Accordingly, the term "triabody" refers to trivalent antibodies comprising three peptide chains, each comprising one v _h domain and one v _l domain, connected by an extremely short linker (e.g., a linker consisting of 1-2 amino acids) to allow intramolecular association of the v _h and v _l domains within the same peptide chain. To fold into their native structures, peptides configured in this way typically trimerize in a manner that positions the v _h and v _l domains of adjacent peptide chains spatially proximal to each other (see, e.g., Holliger et al., Proc. Natl. Acad. Sci. USA 90:6444–48, 1993).

As used herein, the term "drug-to-antibody ratio" or "DAR" refers to the amount of drug, such as amatoxin, attached to the antibody in a conjugate. The DAR of an ADC can range from 1 to 8, although higher loadings are possible depending on the number of binding sites on the antibody. In some embodiments, the conjugate has a DAR of 1, 2, 3, 4, 5, 6, 7, or 8.

As used herein, the term "endogenous" describes a substance, such as a molecule, cell, tissue, or organ (e.g., a hematopoietic stem cell or a cell of hematopoietic origin such as a megakaryocyte, platelet, red blood cell, mast cell, myeloblast, basophil, neutrophil, eosinophil, microglial cell, granulocyte, monocyte, osteoclast, antigen-presenting cell, macrophage, dendritic cell, natural killer cell, T lymphocyte, or B lymphocyte) that occurs naturally in a particular organism, such as a human patient.

As used herein, the term "engraftment potential" is used to refer to the ability of hematopoietic stem and progenitor cells to repopulate tissue, whether such cells are circulating naturally or obtained by transplantation. The term encompasses all events associated with or leading to engraftment, such as homing of cells to tissue and colonization of cells within the tissue of interest. Engraftment efficiency or engraftment rate may be assessed or quantified using any clinically acceptable parameter known to those skilled in the art and may include, for example, an assessment of competitive repopulating units (CRUs); marker incorporation or expression in the tissue(s) into which the stem cells have homed, colonized, or engrafted; or by assessing the progress of a subject through disease progression, the survival of the hematopoietic stem and progenitor cells, or the survival of the recipient. Engraftment can also be determined by measuring the white blood cell count in the peripheral blood in the post-transplant period. Engraftment can also be assessed by measuring the reconstitution of bone marrow cells by donor cells in a bone marrow aspirate sample.

As used herein, the term "exogenous" describes a substance, such as a molecule, cell, tissue, or organ (e.g., a hematopoietic stem cell or a cell of hematopoietic origin such as a megakaryocyte, platelet, red blood cell, mast cell, myeloblast, basophil, neutrophil, eosinophil, microglial cell, granulocyte, monocyte, osteoclast, antigen-presenting cell, macrophage, dendritic cell, natural killer cell, T lymphocyte, or B lymphocyte) that is not naturally occurring in a particular organism, such as a human patient. Exogenous substances include substances that are introduced from an external source into the body or cultured substances that are extracted from the body.

As used herein, the terms "Fc", "Fc region" and "Fc domain" refer to the portion of an IgG antibody that correlates with the crystallizable fragment obtained by treating the IgG molecule with papain. The Fc region comprises the C-terminal half of the two heavy chains of the IgG molecule, which are linked by disulfide bonds. It has no antigen-binding activity, but contains a carbohydrate moiety and binding sites for complement and Fc receptors, including the FcRn receptor. The Fc region comprises a second CH2 constant domain (e.g., residues at positions EU 231-340 of IgG1) and a third CH3 constant domain (e.g., residues at positions EU 341-447 of human IgG1). As used herein, the term Fc region includes the "lower hinge region" (e.g., residues at positions EU 233-239 of IgG1). Fc may refer to this region alone or to this region in the context of an antibody, antibody fragment, or Fc fusion protein. Polymorphisms have been observed at a number of positions in the Fc domains, including but not limited to positions EU 270, 272, 312, 315, 356, and 358, and thus there may be minor differences between the sequences provided herein and sequences known in the art. Thus, a "wild-type IgG Fc domain" or "WT IgG Fc domain" refers to any naturally occurring IgG Fc region (i.e., any allele). The heavy chain sequences of human IgG1, IgG2, IgG3 and IgG4 can be found in a number of sequence databases, such as the Uniprot database (www.uniprot.org) under accession numbers P01857 (IGHG1_JHUMAN), P01859 (IGHG2_JHUMAN), P01860 (IGHG3_JHUMAN) and P01861 (IGHG1_HUMAN), respectively. An example of a "WT" Fc region is shown in SEQ ID NO: 122 (which represents the heavy chain constant region containing the Fc region).

As used herein, the terms “modified Fc region” or “variant Fc region” refer to an Fc domain of an IgG comprising one or more amino acid substitutions, deletions, insertions, or modifications introduced at any position within the Fc region.

The terms "full-length antibody" and "intact antibody" are used interchangeably herein to refer to an antibody in its substantially intact form, rather than an antibody fragment as defined herein. In one embodiment, an ADC described herein comprises an intact antibody. Thus, for an IgG antibody, an intact antibody comprises two heavy chains, each comprising a variable region, a constant region, and an Fc region, and two light chains, each comprising a variable region and a constant region. More specifically, an intact IgG comprises two light chains, each comprising a light chain variable region (VL) and a light chain constant region (CL), and comprises two heavy chains, each comprising a heavy chain variable region (VH) and three heavy chain constant regions (CH1, CH2, and CH3). CH2 and CH3 represent the Fc region of the heavy chain.

As used herein, the term "framework region" or "FW region" includes amino acid residues that are adjacent to the CDR of an antibody or antigen-binding fragment thereof. FW region residues may be present, for example, in human antibodies, humanized antibodies, monoclonal antibodies, antibody fragments, Fab fragments, single-chain antibody fragments, scFv fragments, antibody domains, and bispecific antibodies, among others.

As used herein, the term "hematopoietic stem cells" ("HSCs") refers to immature blood cells that have the capacity to self-renew and differentiate into mature blood cells of various lineages, including, but not limited to, granulocytes (e.g., promyelocytes, neutrophils, eosinophils, basophils), red blood cells (e.g., reticulocytes, erythrocytes), platelets (e.g., megakaryoblasts, platelet-producing megakaryocytes, thrombocytes), monocytes (e.g., monocytes, macrophages), dendritic cells, microglia, osteoclasts, and lymphocytes (e.g., NK cells, B cells, and T cells). Such cells may include CD34+ cells. CD34+ cells are immature cells that express the surface marker CD34. In humans, CD34+ cells are considered to comprise a subpopulation of cells with stem cell properties defined above, whereas in mice, HSCs are CD34-. In addition, HSCs also include long-term repopulating HSCs (LT-HSCs) and short-term repopulating HSCs (ST-HSCs). LT-HSCs and ST-HSCs differentiate based on functional potential and expression of cell surface markers. For example, human HSCs are CD34+, CD38-, CD45RA-, CD90+, CD49F+, and lin- (negative for mature lineage markers including CD2, CD3, CD4, CD7, CD8, CD10, CD11B, CD19, CD20, CD56, CD235A). In mice, bone marrow LT-HSCs are CD34-, SCA-1+, C-kit+, CD135-, Slamfl/CD150+, CD48-, and lin- (negative for mature lineage markers including Ter119, CD11b, Gr1, CD3, CD4, CD8, B220, IL7ra), whereas ST-HSCs are CD34+, SCA-1+, C-kit+, CD135-, Slamfl/CD150+, and lin- (negative for mature lineage markers including Ter119, CD11b, Gr1, CD3, CD4, CD8, B220, IL7ra). Furthermore, ST-HSCs are less immobile and more proliferative than LT-HSCs under homeostatic conditions. However, LT-HSCs have a high self-renewal potential (i.e., they survive throughout adult life and can be serially transplanted into successive recipients), whereas ST-HSCs have limited self-renewal (i.e., they survive only for a limited period of time and do not have the potential for serial transplantation). Either of these HSCs can be used in the methods described herein. ST-HSCs are particularly useful because they are highly proliferative and can thus more quickly give rise to differentiated progeny.

As used herein, the term "hematopoietic stem cell functional potential" refers to functional properties of hematopoietic stem cells that include the following: 1) multipotency (which refers to the ability to differentiate into multiple different blood cell lineages, including but not limited to granulocytes (e.g., promyelocytes, neutrophils, eosinophils, basophils), red blood cells (e.g., reticulocytes, erythrocytes), platelets (e.g., megakaryoblasts, platelet-producing megakaryocytes, thrombocytes), monocytes (e.g., monocytes, macrophages), dendritic cells, microglia, osteoclasts, and lymphocytes (e.g., NK cells, B cells, and T cells), 2) self-renewal (which refers to the ability of hematopoietic stem cells to give rise to daughter cells that have the same potential as the mother cell, and furthermore, this ability can (i) be repeated throughout a person's life without depletion) and 3) the ability of hematopoietic stem cells or their progeny to be reintroduced into a transplant recipient, after which they hom to the hematopoietic stem cell niche and restore productive and stable hematopoiesis.

As used herein, the term "human antibody" is intended to include antibodies that contain variable and constant regions derived from human germline immunoglobulin sequences. A human antibody may include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro, or during gene rearrangement, or by somatic mutation in vivo). However, as used herein, the term "human antibody" is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences. A human antibody may be produced in a human cell (e.g., by recombinant expression) or by a non-human animal or prokaryotic or eukaryotic cell that is capable of expressing functionally rearranged human immunoglobulin genes (such as heavy chain and/or light chain genes). When a human antibody is a single-chain antibody, it may include a linker peptide that is not found in native human antibodies. For example, Fv may include a linker peptide, such as two to about eight glycine or other amino acid residues, that connects the variable region of the heavy chain and the variable region of the light chain. Such linker peptides are believed to be of human origin. Human antibodies can be produced by a variety of methods known in the art, including phage display techniques using antibody libraries derived from human immunoglobulin sequences. Human antibodies can also be produced using transgenic mice that are incapable of expressing functional endogenous immunoglobulins, but which can express human immunoglobulin genes (see, e.g., PCT Publication Nos. WO 1998/24893; WO 1992/01047; WO 1996/34096; WO 1996/33735; U.S. Patent Nos. 5,413,923; 5,625,126; 5,633,425; 5,569,825; 5,661,016; 5,545,806; 5,814,318; 5,885,793; 5,916,771; and 5,939,598).

A "humanized" antibody refers to an antibody that contains minimal sequences derived from a non-human immunoglobulin. Thus, "humanized" forms of non-human (e.g., murine) antibodies are chimeric antibodies that contain minimal sequence derived from a non-human antibody. All or substantially all of the FW regions may also be regions from a human immunoglobulin sequence. A humanized antibody may also contain at least a portion of an immunoglobulin constant region (Fc), typically a portion of a human immunoglobulin consensus sequence. Methods for humanizing antibodies are known in the art and are described, for example, in P Jechmann et al., Nature 332:323-7, 1988; U.S. Patent Nos. 5,530,101; 5,585,089; 5,693,761; 5,693,762; and 6180370.

As used herein, the term "antibody-like protein" refers to a protein that has been engineered (e.g., by mutagenesis of Ig loops) to specifically bind to a target molecule. Typically, such an antibody-like protein comprises at least one variable peptide loop attached at both ends to a protein scaffold. This dual structural constraint significantly increases the binding affinity of the antibody-like protein to levels comparable to that of an antibody. The variable peptide loop is typically 10 to 20 amino acids in length. The scaffold protein can be any protein that has good solubility properties. Preferably, the scaffold protein is a small globular protein. Antibody-like proteins include, but are not limited to, affibodies, anticalins, and engineered ankyrin repeat proteins (Binz et al., 2005). Antibody-like proteins can be generated from large libraries of mutants, for example by panning from large phage display libraries, and can be isolated in analogy to conventional antibodies. In addition, antibody-like binding proteins can be generated by combinatorial mutagenesis of surface-exposed residues in globular proteins.

As used herein, the term "Fab" refers to a fragment of IgG containing an antigen-binding region, wherein said fragment consists of one constant and one variable domain from each of the heavy and light chains of the antibody.

As used herein, the term “F(ab)2” refers to an IgG fragment consisting of two Fab fragments linked to each other by disulfide bonds.

As used herein, the term "scFv" refers to a single-chain variable fragment that is a fusion of the variable regions of the heavy and light chains of immunoglobulins linked together by a short linker, typically comprising serine (S) and/or glycine (G) residues. This chimeric molecule retains the specificity of the parent immunoglobulin despite the removal of the constant regions and the introduction of a linker peptide.

According to one aspect of the present invention, the present invention relates to said conjugate or pharmaceutical composition as described, for use in the treatment of cancer.

According to one aspect of the present invention, the present invention relates to said conjugate or pharmaceutical composition as described for use in the treatment of malignancies associated with B-lymphocytes or autoimmune diseases mediated by B-cells, in particular for use in the treatment of the following: non-Hodgkin's lymphoma, follicular lymphoma, diffuse large cell non-Hodgkin's lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis, granulomatosis with polyangiitis and microscopic polyangiitis and pemphigus vulgaris.

For the purposes of this document, patients who are "in need" of hematopoietic stem cell transplantation include patients who have a defect or deficiency of one or more types of blood cells, as well as patients who have a stem cell disorder, autoimmune disease, cancer, or other pathology described herein. Hematopoietic stem cells typically exhibit the following: 1) multipotency, and thus can differentiate into several different blood cell lineages, including but not limited to granulocytes (e.g., promyelocytes, neutrophils, eosinophils, basophils), red blood cells (e.g., reticulocytes, erythrocytes), platelets (e.g., megakaryoblasts, platelet-producing megakaryocytes, thrombocytes), monocytes (e.g., monocytes, macrophages), dendritic cells, microglia, osteoclasts, and lymphocytes (e.g., NK cells, B cells, and T cells), 2) self-renewal, and thus can give rise to daughter cells that have the same potential as the mother cell, and 3) the ability to be reintroduced into a transplant recipient, whereupon they hom to the hematopoietic stem cell niche and restore productive and robust hematopoiesis. Thus, hematopoietic stem cells can be administered to a patient with a defect or deficiency in one or more cell types of the hematopoietic lineage to reconstitute the defective or deficient cell population in vivo. For example, the patient may have cancer and the deficiency may be caused by administration of a chemotherapeutic agent or other drug that selectively or non-specifically depletes the cancer cell population. Additionally or alternatively, the patient may have a hemoglobinopathy (e.g., a non-malignant hemoglobinopathy) such as sickle cell anemia, thalassemia, Fanconi anemia, aplastic anemia, and Wiskott-Aldrich syndrome. The subject may be a subject suffering from adenosine deaminase severe combined immunodeficiency (ADA SCID), HIV/AIDS, metachromatic leukodystrophy, Diamond-Blackfan anemia, and Shwachman-Diamond syndrome. The subject may have or may be affected by an inherited blood disorder (e.g., sickle cell anemia) or an autoimmune disease. Additionally or alternatively, the subject may have or may be affected by a malignancy, such as a neuroblastoma or a hematological cancer. For example, the subject may have leukemia, lymphoma, or myeloma. In some embodiments, the subject has acute myeloid leukemia, acute lymphoid leukemia, chronic myeloid leukemia, chronic lymphoid leukemia, multiple myeloma, diffuse large B-cell lymphoma, or non-Hodgkin's lymphoma. In some embodiments, the subject is characterized by having myelodysplastic syndrome. In some embodiments, the subject is characterized by having an autoimmune disease, such as scleroderma, multiple sclerosis, ulcerative colitis, Crohn's disease, type 1 diabetes, or another autoimmune pathology described herein. In some embodiments, the subject is in need of chimeric antigen receptor T-cell (CART) therapy. In some embodiments, the subject is characterized by having or is otherwise affected by a metabolic storage disorder. The subject may suffer from or may be otherwise afflicted with a metabolic disorder selected from the group consisting of glycogen storage diseases, mucopolysaccharidoses, Gaucher disease, Hurler disease, sphingolipidoses, metachromatic leukodystrophy, or any other diseases or disorders that may benefit from the treatments and therapies described herein, and including, without limitation, severe combined immunodeficiency, Wiskott-Aldrich syndrome, hyperimmunoglobulin M syndrome (IgM), Chediak-Higashi disease, hereditary lymphohistiocytosis, osteopetrosis, osteogenesis imperfecta, storage diseases, thalassemia major, sickle cell anemia, systemic sclerosis, systemic lupus erythematosus, multiple sclerosis, juvenile rheumatoid arthritis, and those diseases or disorders described in "Bone Marrow Transplantation for Non-Malignant Disease," ASH Education Book, 1:319-338 (2000), the disclosure of which is incorporated herein by reference in its entirety because it pertains to pathologies that can be treated by the administration of hematopoietic stem cell transplantation therapy. Additionally or alternatively, a patient "in need" of a hematopoietic stem cell transplant may be a patient who does or does not have one of the above-mentioned pathologies but nevertheless exhibits a reduced level (e.g., compared to that of an otherwise healthy subject) of one or more types of endogenous cells within the hematopoietic lineage, such as megakaryocytes, platelets, red blood cells, mast cells, myeloblasts, basophils, neutrophils, eosinophils, microglia, granulocytes, monocytes, osteoclasts, antigen-presenting cells, macrophages, dendritic cells, natural killer cells, T lymphocytes, and B lymphocytes. One skilled in the art can readily determine whether a patient has reduced levels of one or more of the above cell types or another blood cell type compared to an otherwise healthy subject, such as by flow cytometry and fluorescence-activated sorting (FACS) techniques, among other procedures known in the art.

As used herein, the term "neutral antibody" refers to an antibody or antigen-binding fragment thereof that is incapable of substantially neutralizing, blocking, inhibiting, abolishing, reducing, or interfering with the activity of a specified or indicated target (e.g., CD117), including receptor-ligand binding or enzyme-substrate interactions. In one embodiment, a neutral anti-CD117 antibody or fragment thereof is an anti-CD117 antibody that does not substantially inhibit SCF-dependent cell proliferation and does not cross-block SCF binding to CD117. An example of a neutral antibody is Ab67 (or an antibody comprising Ab67 binding regions). In contrast, an "antagonist" anti-CD117 antibody inhibits SCF-dependent proliferation and is capable of cross-blocking SCF binding to CD117. An example of an antagonist antibody is Ab55 (or an antibody containing Ab55 binding regions).

As used herein, the term "recipient" refers to a patient who receives a transplant, such as a transplant containing a population of hematopoietic stem cells. The transplanted cells administered to the recipient may be, for example, autologous, syngeneic, or allogeneic cells.

As used herein, the term "specimen" refers to a sample (e.g., blood, a blood component (e.g., serum or plasma), urine, saliva, amniotic fluid, cerebrospinal fluid, tissue (e.g., placental or dermal), pancreatic fluid, chorionic villus sample, and cells) collected from a subject.

As used herein, the term "scFv" refers to a single-chain Fv antibody in which the variable domains of the heavy chain and light chain of the antibody are joined to form a single chain. scFv fragments comprise a single polypeptide chain that includes an antibody light chain variable region (V _L ) (e.g., CDR-L1, CDR-L2 and/or CDR-L3) and an antibody heavy chain variable region (V _H ) (e.g., CDR-H1, CDR-H2 and/or CDR-H3), separated by a linker. The linker that joins the V _L and V _H regions of the scFv fragment may be a peptide linker consisting of proteinogenic amino acids. Alternative linkers can be used to increase the resistance of the scFv fragment to proteolytic degradation (e.g., linkers containing D-amino acids), to increase the solubility of the scFv fragment (e.g., hydrophilic linkers such as polyethylene glycol-containing linkers or polypeptides containing repeating glycine and serine residues), to improve the biophysical stability of the molecule (e.g., a linker containing cysteine residues that form intramolecular or intermolecular disulfide bonds), or to reduce the immunogenicity of the scFv fragment (e.g., linkers containing glycosylation sites). One of skill in the art will also appreciate that the variable regions of the scFv molecules described herein can be modified so that they differ in amino acid sequence from the antibody molecule from which they were derived. For example, nucleotide or amino acid substitutions resulting in conservative substitutions or changes in amino acid residues (e.g., in CDR and/or framework region residues) can be made to maintain or enhance the ability of the scFv to bind to an antigen recognized by the corresponding antibody.

As used herein, the terms "specific binding" or "specifically binding" refer to the ability of an antibody to recognize and bind to a specific protein structure (epitope), rather than to proteins in general. If an antibody is specific for epitope "A", the presence of a molecule containing epitope A (or free unlabeled A) in a reaction medium containing labeled "A" and antibody will reduce the amount of labeled A bound to the antibody. For example, an antibody "specifically binds" to a target if the antibody, when labeled, can be eliminated from competition with its target by the corresponding unlabeled antibody. According to one embodiment, an antibody specifically binds to a target, such as CD117, CD45, CD2, CD5, CD137, CD134, or CD252, if the antibody has a K _D value for the target of at least about 10 ^-4 M, 10 ^-5 M, 10 ^-6 M, 10 ^-7 M, 10 ^-8 M, 10 ^-9 M, 10 ^-10 M, 10 ^-11 M, 10 ^-12 M, or less (less means a number that is less than 10 ^-12 , such as 10 ^-13 ). In one embodiment, the term "specific binding to CD117" or "specifically binds to CD117" as used herein refers to an antibody that binds to CD117 and has a dissociation constant (K _D ) of 1.0 x 107 M or less, as determined by surface plasmon resonance. In one embodiment, K _D (M) is determined by standard biolayer interferometry (BLI). In one embodiment, K _off (1/s) is determined by standard biolayer interferometry (BLI). However, it should be understood that an antibody may be capable of specifically binding to two or more antigens that are bound to each other sequentially. For example, in one embodiment, the antibody can specifically bind to human and non-human (e.g., mouse or non-human primate) orthologs of CD117, CD45, CD2, CD5, CD137, CD134, or CD252.

As used herein, the terms "subject" and "patient" refer to an organism, such as a human, who is receiving treatment for a particular disease or condition as described herein. For example, a patient, such as a human patient, may receive treatment prior to hematopoietic stem cell transplantation therapy to promote engraftment of exogenous hematopoietic stem cells.

As used herein, the phrase "substantially cleared from the blood" refers to a time after administration of a therapeutic agent, such as an ADC comprising an amatoxin, to a patient, when the concentration of the therapeutic agent in a blood sample isolated from the patient is such that the therapeutic agent cannot be detected by conventional means (e.g., such that the therapeutic agent is not detected above the noise threshold of the device or assay used to detect the therapeutic agent). Various methods known in the art can be used to detect antibodies or antibody fragments, such as ELISA-based detection assays known in the art or described herein. Additional assays that can be used to detect antibodies or antibody fragments include, but are not limited to, immunoprecipitation and immunoblotting methods known in the art.

As used herein, the phrase "stem cell disorder" broadly refers to any disease, disorder, or condition that can be treated or cured by conditioning the target tissues of a subject and/or by removing the endogenous stem cell population in the target tissue (e.g., removing the endogenous hematopoietic stem cell or progenitor cell population from the bone marrow tissue of a subject) and/or by engraftment or transplantation of stem cells into the target tissues of a subject. For example, type 1 diabetes has been shown to be curable by hematopoietic stem cell transplantation and can benefit from conditioning in accordance with the compositions and methods described herein. Additional disorders that can be treated using the compositions and methods described herein include, but are not limited to, sickle cell anemia, thalassemias, Fanconi anemia, aplastic anemia, Wiskott-Aldrich syndrome, ADA SCID, HIV/AIDS, metachromatic leukodystrophy, Diamond-Blackfan anemia, and Shwachman-Diamond syndrome. Additional diseases that can be treated using the patient conditioning and/or hematopoietic stem cell transplantation methods described herein include inherited blood disorders (e.g., sickle cell anemia) and autoimmune disorders such as scleroderma, multiple sclerosis, ulcerative colitis, and Crohn's disease. Additional diseases that can be treated using the conditioning and/or transplantation methods described herein include malignancies such as neuroblastoma, or hematological malignancies such as leukemia, lymphoma, and myeloma.

For example, the cancer may be acute myeloid leukemia, acute lymphoid leukemia, chronic myeloid leukemia, chronic lymphoid leukemia, multiple myeloma, diffuse large B-cell lymphoma, or non-Hodgkin's lymphoma. Additional diseases treatable using the conditioning and/or transplantation methods described herein include myelodysplastic syndrome. In some embodiments, the subject is characterized by having or is otherwise affected by a metabolic storage disorder. For example, the subject may suffer from or may otherwise be afflicted with a metabolic disorder selected from the group consisting of glycogen storage diseases, mucopolysaccharidoses, Gaucher disease, Hurler disease, sphingolipidoses, metachromatic leukodystrophy, or any other diseases or disorders that may benefit from the treatments and therapies disclosed herein, and including, but not limited to, severe combined immunodeficiency, Wiskott-Aldrich syndrome, hyperimmunoglobulin M syndrome (IgM), Chediak-Higashi disease, hereditary lymphohistiocytosis, osteopetrosis, osteogenesis imperfecta, storage diseases, thalassemia major, sickle cell anemia, systemic sclerosis, systemic lupus erythematosus, multiple sclerosis, juvenile rheumatoid arthritis, and those diseases or disorders described in "Bone Marrow Transplantation for Non-Malignant Disease," ASH Education Book, 1:319-338 (2000), the disclosure of which is incorporated herein by reference in its entirety because it pertains to conditions that can be treated with hematopoietic stem cell transplantation.

As used herein, the term "transfection" refers to any of a wide variety of methods commonly used to introduce exogenous DNA into a prokaryotic or eukaryotic host cell, such as electroporation, lipofection, calcium phosphate precipitation, DEAE-dextran transfection, etc.

As used herein, the terms "treat" or "treatment" refer to reducing the severity and/or frequency of disease symptoms, eliminating disease symptoms and/or the underlying cause of said symptoms, reducing the frequency or likelihood of disease symptoms and/or their underlying cause, and ameliorating or eliminating damage directly or indirectly caused by the disease. Beneficial or desired clinical outcomes include, but are not limited to, promoting engraftment of exogenous hematopoietic cells in a patient following conditioning antibody therapy as described herein and subsequent hematopoietic stem cell transplantation therapy. Additional beneficial outcomes include increasing the cell count or relative concentration of hematopoietic stem cells in a patient in need of hematopoietic stem cell transplantation following conditioning therapy and subsequent administration of an exogenous hematopoietic stem cell graft to the patient. Beneficial results of the therapy described herein may also include an increase in the number of cells or the relative concentration of one or more cells of hematopoietic origin, such as a megakaryocyte, platelet, red blood cell, mast cell, myeloblast, basophil, neutrophil, eosinophil, microglial cell, granulocyte, monocyte, osteoclast, antigen-presenting cell, macrophage, dendritic cell, natural killer cell, T lymphocyte, or B lymphocyte after conditioning therapy and subsequent hematopoietic stem cell transplantation therapy. Additional beneficial results may include a decrease in the number of a disease-causing cell population, such as a cancer cell population (e.g., CD117+ leukemia cells) or autoimmune cells (e.g., CD117+ autoimmune lymphocytes, such as CD117+ T lymphocytes that express a T cell receptor that cross-reacts with an autoantigen). Since the methods of the present invention are directed to preventing disorders, it is understood that the term "prevent" does not require the complete prevention of the disease state. Rather, as used herein, the term "prevention" refers to the ability of a skilled artisan to identify a population susceptible to the disorder so that administration of the compounds of the present invention can occur before the onset of the disease. This term does not mean that the disease state is completely avoided.

As used herein, the terms "variant" and "derivative" are used interchangeably and refer to naturally occurring, synthetic, and semi-synthetic analogs of a compound, peptide, protein, or other substance described herein. A variant or derivative of a compound, peptide, protein, or other substance described herein may retain or improve the biological activity of the starting material.

As used herein, the term "vector" includes a nucleic acid vector such as a plasmid, a DNA vector, a plasmid, an RNA vector, a virus, or another suitable replicon. The expression vectors described herein may contain a polynucleotide sequence as well as, for example, additional sequence elements used to express proteins and/or integrate these polynucleotide sequences into the genome of a mammalian cell. Some vectors that can be used to express the antibodies and antibody fragments of the present invention include plasmids that contain regulatory sequences, such as promoter and enhancer regions, that direct gene transcription. Other useful vectors for expressing antibodies and antibody fragments contain polynucleotide sequences that increase the rate of translation of these genes or improve the stability or nuclear export of mRNA that results from gene transcription. These sequence elements may include, for example, 5' and 3' untranslated regions and a polyadenylation signal site to direct efficient transcription of a gene carried in the expression vector. The expression vectors described herein may also contain a polynucleotide encoding a marker for selecting cells that contain such a vector. Examples of suitable markers include genes encoding resistance to antibiotics such as ampicillin, chloramphenicol, kanamycin, and norepinephrine.

Antibody drug conjugates (ADCs)

Antibodies and antigen-binding fragments thereof, as described herein, may be conjugated (linked) to a cytotoxic molecule (i.e., a cytotoxin), thereby forming an antibody drug conjugate (ADC). As used herein, the terms "cytotoxin," "cytotoxic moiety," and "drug" are used interchangeably.

In particular, the ADCs described herein include an antibody (including an antigen-binding fragment thereof) conjugated to an amatoxin, such as an amatoxin as shown in formula (V), wherein the cytotoxic moiety, when not conjugated to the antibody, has a cytotoxic or cytostatic effect. In various embodiments, the cytotoxic moiety exhibits reduced or no cytotoxicity when linked in a conjugate, but regains cytotoxicity upon cleavage from the linker. In various embodiments, the cytotoxic moiety retains cytotoxicity without cleavage from the linker. In some embodiments, the cytotoxic molecule is conjugated to a cell-internalizing antibody or antigen-binding fragment thereof as disclosed herein such that upon cellular uptake of the antibody or fragment thereof, the cytotoxin can reach its intracellular target and, for example, mediate hematopoietic cell death. Therefore, ADCs according to the present disclosure may be characterized by the general formula

Ab-(ZL-Cy) _n ,

wherein the antibody or its antigen-binding fragment (Ab) is conjugated (covalently linked) to a linker (L) via a chemical moiety (Z) with a cytotoxic moiety (Cy).

Accordingly, the antibody or antigen-binding fragment thereof can be conjugated to a number of drug moieties, as indicated by an integer n, which represents the average number of cytotoxins per antibody, which can range, for example, from about 1 to about 20. Any number of cytotoxins can be conjugated to the antibody, for example, 1, 2, 3, 4, 5, 6, 7 or 8. In some embodiments, n is from 1 to 4. In some embodiments, n is 1. The average number of drug moieties per antibody in ADC preparations from conjugation reactions can be characterized by conventional methods, such as mass spectroscopy, ELISA analysis and HPLC. It is also possible to determine the quantitative distribution of the ADC by n. In some cases, separation, purification, and characterization of homogeneous ADC, where n is a specific value, from ADCs with other drug loadings, can be achieved by means such as reversed-phase HPLC or electrophoresis.

For some antibody-drug conjugates, n may be limited by the number of attachment sites on the antibody. For example, if the attachment is a cysteine thiol, the antibody may contain only one or more cysteine thiol groups or may have only one or more sufficiently reactive thiol groups through which a linker can be attached. Typically, antibodies do not contain many free and reactive cysteine thiol groups that can be linked to a drug moiety; primarily, cysteine thiol residues in antibodies exist as disulfide bridges. In certain embodiments, the antibody can be reduced with a reducing agent such as dithiothreitol (DTT) or tricarbonylethylphosphine (TCEP) under partial or complete reducing conditions to form reactive cysteine thiol groups. In certain embodiments, higher drug loading, such as n>5, may cause aggregation, insolubility, toxicity, or loss of cellular permeability of some antibody-drug conjugates.

In certain embodiments, less than a theoretical maximum of drug moieties are conjugated to the antibody during the conjugation reaction. The antibody may contain, for example, lysine residues that do not react with the drug-linker intermediate or linker reagent, as discussed below. Only the most reactive lysine groups may react with the amino-reactive linker reagent. In certain embodiments, the antibody is subjected to denaturing conditions to expose reactive nucleophilic groups such as lysine or cysteine.

The loading (drug/antibody ratio) of the ADC can be controlled in a variety of ways, such as: (i) limiting the molar excess of the drug-linker intermediate or linker reagent relative to the antibody, (ii) limiting the conjugation reaction time or temperature, (iii) partial or limiting reducing conditions for modification of the cysteine thiol, (iv) recombinantly engineering the amino acid sequence of the antibody such that the number and position of cysteine residues is varied to control the number and/or position of drug-linker attachments.

Cytotoxins

The cytotoxin of the antibody drug conjugates described herein is amatoxin or a derivative thereof.

Amatoxins are potent and selective inhibitors of RNA polymerase II and thus also inhibit transcription and protein biosynthesis of infected cells. As used herein, the term "amatoxin" refers to a member of the amatoxin family of peptides produced by the mushroom Amanita phalloides, or a variant or derivative thereof, such as a variant or derivative thereof capable of inhibiting RNA polymerase II activity. Amatoxins are rigid bicyclic octapeptides characterized by the backbone sequence Ile-Trp-Gly-Ile-Gly-Cys-Asn (or Asp)-Pro, cross-linked by the attachment of the Cys sulfur to position 2 of the indole ring of Trp, forming tryptathionine. Depending on the specific amatoxin, certain amino acid substituents are changed by post-translational modification (e.g., Pro to Hyp; Ile to DHIle; and Trp to 5-OH Trp).

Amatoxins can be isolated from various species of fungi (e.g., Amanita phalloides, Galerina marginata, Lepiota brunneo-incarnata) or can be produced semisynthetically or synthetically. Different species of fungi contain varying amounts of different members of the amatoxin family. A member of this family, α-amanitin, is known to be an extremely potent inhibitor of eukaryotic RNA polymerase II and, to a lesser extent, RNA polymerase III, thereby inhibiting transcription and protein biosynthesis. Wieland, Int. J. Pept. Protein Res. 1983, 22(3):257-276.

The structures of various naturally occurring amatoxins are shown in formula (III) and in the accompanying Table 1 and are disclosed, for example, in Zanotti et al., Int. J. Peptide Protein Res. 30, 1987, 450-459, which is incorporated herein by reference in its entirety.

Antibodies or antigen binding fragments thereof that recognize and bind to an antigen expressed on the cell surface of a human stem cell or T cell can be conjugated to an amatoxin such as α-amanitin or a derivative thereof, as described in, for example, U.S. Patent Nos. 9,233,173 and 9,399,681 and U.S. Patent Application Publication Nos. 2016/0089450, 2016/0002298, 2015/0218220, 2014/0294865, the disclosure of each of which is incorporated herein by reference as it relates to, for example, amatoxins such as α-amanitin, as well as covalent linkers that can be used for covalent conjugation. Described herein are exemplary methods for conjugating amatoxin and linkers useful for such methods. Examples of linker-containing amatoxins useful for conjugation to an antibody or antigen binding fragment, in accordance with the compositions and methods, are also described herein.

As used herein, the term "amatoxin derivative" or "amanitin derivative" refers to an amatoxin that has been chemically modified at one or more positions relative to a naturally occurring amatoxin, such as α-amanitin, β-amanitin, γ-amanitin, ε-amanitin, amanin, amaninamide, amanullin, amanullinic acid, or proamanullin. In each case, the derivative may be prepared by chemical modification of a naturally occurring compound ("semi-synthetic") or may be obtained from a fully synthetic source. Synthetic routes for various amatoxin derivatives are disclosed, for example, in U.S. Patent No. 9,676,702 and in Perrin et al., J. Am. Chem. Soc. 2018, 140, p. 6513-6517, each of which is incorporated herein by reference in its entirety, with respect to synthetic methods for producing and derivatizing amatoxins.

According to some embodiments, the amatoxin or derivative thereof is represented by formula (V):

or its enantiomer or diastereomer.

In some embodiments, Q is S. In some embodiments, Q is a sulfoxide group.

According to one embodiment, the amatoxin or derivative thereof is represented by formula (Va):

In some embodiments, Q is S. In some embodiments, Q is a sulfoxide group.

According to this particular embodiment, the amatoxin or derivative thereof is represented by formula (Vb):

In some embodiments, Q is S. In some embodiments, Q is a sulfoxide group.

Additional amatoxins that can be used for conjugation with an antibody or antigen-binding fragment thereof in accordance with the compositions and methods described herein are described, for example, in WO 2016/142049; WO 2016/071856; WO 2017/149077; WO 2018/115466; and WO 2017/046658, the disclosures of which are incorporated herein by reference in their entirety.

Linkers

As used herein, the term "linker" means a divalent chemical moiety containing a covalent bond or chain of atoms that covalently attaches an antibody or fragment thereof (Ab) to an amatoxin as described herein, such as an amatoxin of formula (IV), (IVa), (IVb), (V), (Va), or (Vb), to form an antibody drug conjugate (ADC).

Covalent attachment of antibody and amatoxin requires that the linker have two reactive functional groups, i.e., divalency in the reactive sense. Divalent linker reagents that can be used to attach two or more functional or biologically active moieties such as peptides, nucleic acids, drugs, toxins, antibodies, haptens, and reporter groups are known, and methods for preparing their conjugates have been described (Hermanson, G. T. (1996) Bioconjugate Techniques; Academic Press: New York, p. 234-242).

Accordingly, the linkers of the present invention are characterized by two reactive ends, one for conjugation with an antibody and the other for conjugation with an amatoxin. The reactive end of the linker for conjugation with an antibody (the reactive moiety, defined herein as Z') is typically a chemical moiety that is capable of conjugation with an antibody, for example, via a cysteine thiol or lysine amino group on the antibody, and therefore is typically the following: a thiol-reactive group such as a Michael acceptor (as in maleimide), a leaving group such as chlorine, bromine, iodine, or an R-sulfanyl group, or an amine-reactive group such as a carboxyl group. Conjugation of a linker with an antibody is described more fully herein below.

The reactive end of the linker for conjugation with amatoxin is typically a chemical moiety that is capable of conjugation with amatoxin by forming a bond with a reactive substituent in the amatoxin molecule. Non-limiting examples include, for example, the formation of an amide bond with a basic amine or carboxyl group on amatoxin via a carboxyl or basic amino group on the linker, respectively, or the formation of an ether or the like by alkylation of an OH group on amatoxin, for example via a leaving group on the linker.

When the term "linker" is used to describe a linker in conjugated form, one or both reactive ends will be missing (e.g., a reactive moiety Z' converted to a chemical moiety Z as described herein below) or incomplete (e.g., being only a carbonyl of a carboxylic acid) due to the formation of bonds between the linker and/or amatoxin, and between the linker and/or the antibody or antigen-binding fragment thereof. Such conjugation reactions are further described herein below.

Various linkers can be used to conjugate the disclosed antibodies, antigen-binding fragments and ligands to a cytotoxic molecule. Typically, linkers suitable for the present disclosure may be substantially stable in the bloodstream, but allow the release of amatoxin within or in close proximity to target cells. According to some embodiments, certain linkers suitable for the present disclosure can be classified as "cleavable" or "non-cleavable". Typically, cleavable linkers contain one or more functional groups that are cleaved in response to the physiological environment. For example, a cleavable linker may comprise an enzymatic substrate (e.g., valine-alanine) that is degraded in the presence of an intracellular enzyme (e.g., cathepsin B), an acid-cleavable group (e.g., a hydrozone) that is degraded in the acidic environment of a cellular compartment, or a reducing group (e.g., a disulfide) that is degraded in an intracellular reducing environment. In contrast, non-cleavable linkers are typically released from the ADC during degradation (e.g., lysosomal degradation) of the antibody-ADC fragment within the target cell.

Non-cleavable linkers

Non-cleavable linkers suitable for use herein may further include one or more groups selected from the following: a bond, -(C=O)-, _C1 - _C6 alkylene, C1-C6 heteroalkylene, _C2 - _C6 alkenylene, _C2 - _C6 heteroalkenylene _{, C2-C6 alkynylene, C2-C6 heteroalkynylene, C3-C6 cycloalkylene , heterocycloalkylene , arylene , heteroarylene} , and combinations thereof, each of which may be optionally substituted and/or may include one or more heteroatoms (e.g., S, N, or O) in place of one or more carbon atoms. Non-limiting examples of such groups include ( _CH2 ) _p , (C=O)( _CH2 ) _p , and _{polyethyleneglycol} (PEG; ( _CH2CH2O ) _p ) units, where p is an integer from 1 to 6, independently selected for each instance.

According to some embodiments, the linker L comprises one or more of the following: a bond, -(C=O)-, a -C(O)NH- group, an -OC(O)NH- group, _C1 - _C6 alkylene, _{C1 - C6} heteroalkylene, C2- _C6 alkenylene, _C2 - _C6 heteroalkenylene, _C2 - _C6 alkynylene, _C2 - _C6 heteroalkynylene, _C3 - _C6 cycloalkylene, heterocycloalkylene, arylene, _{heteroarylene} , a -( _CH2CH2O ) _p- group, where p is an integer from 1 to 6, or a solubility-enhancing group;

wherein each C ₁ -C ₆ alkylene, C ₁ -C ₆ heteroalkylene, _{C 2} -C ₆ alkenylene, C 2 -C 6 heteroalkenylene, C ₂ -C ₆ alkynylene, C ₂ -C ₆ heteroalkynylene, C _{3 -C 6} cycloalkylene, heterocycloalkylene, arylene or heteroarylene may be optionally substituted with 1 to 5 substituents independently selected for each occurrence from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkaryl, alkyl heteroaryl, amino, ammonium, acyl, acyloxy, acylamino, aminocarbonyl, alkoxycarbonyl, ureido, carbamate, aryl, heteroaryl, sulfinyl, sulfonyl, hydroxyl, alkoxy, sulfanyl, helogen, carboxy, trihalomethyl, cyano, hydroxy, mercapto and nitro;

According to some embodiments, each _C1 - _C6 alkylene, _C1 - _C6 heteroalkylene, _C2 - _C6 alkenylene, C2- _C6 heteroalkenylene, _C2 - _C6 alkynylene, _C2 - _C6 heteroalkynylene, _{C3 - C6} cycloalkylene, heterocycloalkylene, arylene, or heteroarylene may optionally be interrupted by one or more heteroatoms selected from O, S, and N.

According to some embodiments, each C ₁ -C ₆ alkylene, C ₁ -C ₆ heteroalkylene, C ₂ -C ₆ alkenylene, C ₂ -C ₆ heteroalkenylene, C ₂ -C ₆ alkynylene, C ₂ -C ₆ heteroalkynylene, C ₃ -C ₆ cycloalkylene, heterocycloalkylene, arylene, or heteroarylene may be optionally interrupted by one or more heteroatoms selected from O, S, and N, and may be optionally substituted with 1 to 5 substituents independently selected for each occurrence from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkaryl, alkyl heteroaryl, amino, ammonium, acyl, acyloxy, acylamino, aminocarbonyl, alkoxycarbonyl, ureido, carbamate, aryl, heteroaryl, sulfinyl, sulfonyl, hydroxyl, alkoxy, sulfanyl, halogen, carboxy, trihalomethyl, cyano, hydroxy, mercapto and nitro.

According to some embodiments, the linker L comprises a solubility-enhancing group according to the formula -O _a -C(O)NH-SO ₂ -N(R ₁ )-, where:

a is 0 or 1;

R ¹ is selected from the group consisting of hydrogen, C ₁ -C ₂₄ alkyl groups, C ₃ -C ₂₄ cycloalkyl groups, C ₂ -C ₂₄ (hetero) aryl groups, C ₃ -C ₂₄ alkyl (hetero) aryl groups, and C ₃ -C ₂₄ (hetero) aryl alkyl groups, each of which may be optionally substituted or optionally interrupted by one or more heteroatoms selected from O, S, and NR ³ , wherein R ³ is independently selected from the group consisting of hydrogen and C ₁ -C ₄ alkyl. Such solubility-enhancing groups are described, for example, in U.S. Patent No. 9,636,421 and U.S. Patent Application Publication No. 2017/0298145, the disclosures of each being incorporated herein by reference in their entirety.

According to some embodiments, the solubility-enhancing group according to the formula -O _a -C(O)NH-SO ₂ -N(R ₁ )- further comprises a C ₁ -C ₆ alkylene or a -(CH ₂ CH ₂ O) _p - group, where p is an integer from 1 to 6. Non-limiting examples of such solubility-enhancing groups include the groups presented in Table 2 below.

In some embodiments, the non-cleavable linker comprises a -(CH ₂ ) _n - unit, wherein n is an integer of 2-12, such as 2-6. In some embodiments, the non-cleavable linker comprises -(CH ₂ ) _n -, wherein n is 1, 2, 3, 4, 5, or 6. In some embodiments, the non-cleavable linker is a -(CH ₂ ) _n - unit, wherein n is 6, represented by the formula:

Cleavable linkers

According to some embodiments, a linker conjugated to an antibody or antigen-binding fragment thereof and an amatoxin is cleavable under intracellular conditions such that cleavage of the linker releases the drug moiety from the antibody in the intracellular environment. Cleavable linkers are designed to exploit differences in local environments, such as extracellular and intracellular environments, including, for example, pH, reducing potential, or enzyme concentration, to trigger the release of amatoxin in a target cell. Typically, cleavable linkers are relatively stable in the bloodstream, but are particularly susceptible to cleavage in the intracellular environment by one or more mechanisms (e.g., including, but not limited to, protease, peptidase, and glucuronidase activity). The cleavable linkers used herein are substantially stable in circulating plasma and/or outside the target cell and can be cleaved at some effective rate within the target cell or in close proximity to the target cell.

Suitable cleavable linkers include those that are cleavable by, for example, enzymatic hydrolysis, photolysis, acidic hydrolysis, basic hydrolysis, oxidation, disulfide reduction, nucleophilic cleavage, or organometallic cleavage (see, for example, Leriche et al., Bioorg. Med. Chem., 20:571-582, 2012, the disclosure of which is incorporated herein by reference as it relates to linkers suitable for covalent conjugation). Suitable cleavable linkers can include, for example, chemical moieties such as a hydrazine, a disulfide, a thioether, or a dipeptide.

Linkers that are hydrolyzed under acidic conditions include, for example, hydrazones, semicarbazones, thiosemicarbazones, cis-aconitic amides, orthoesters, acetals, ketals, etc. (See, e.g., U.S. Patent Nos. 5,122,368; 5,824,805; 5,622,929; Dubowchik and Walker, 1999, Pharm. Therapeutics 83:67-123; Neville et al., 1989, Biol. Chem. 264:14653-14661, the disclosures of each of which are incorporated herein by reference in their entireties as they relate to linkers suitable for covalent conjugation. Such linkers are relatively stable under neutral pH conditions, such as in blood, but are unstable at pH below 5.5 or 5.0, the approximate pH of the lysosome.

Linkers that are cleavable under reducing conditions include, for example, disulfide. Various disulfide linkers are known in the art, including, for example, those that can be formed using SATA N-succinimidyl-S-acetylthioacetate), SPDP (N-succinimidyl-3-(2-pyridyldithio)propionate), SPDB N-succinimidyl-3-(2-pyridyldithio)butyrate), and SMPT (N-succinimidyloxycarbonyl-alpha-methyl-alpha-(2-pyridyldithio)toluene), SPDB and SMPT (see, for example, Thorpe et al., 1987, Cancer Res. 47:5924-5931; Wawrzynczak et al., in Immunoconjugates: Antibody Conjugates in Radioimagery and Therapy of Cancer (C. W. Vogel ed., Oxford U. Press, 1987). See also U.S. Patent No. 4,880,935, the disclosure of each of which is incorporated herein by reference in its entirety as it relates to clinkers suitable for covalent conjugation.

Linkers sensitive to enzymatic hydrolysis can be, for example, a peptide-containing linker that is cleaved by an intracellular peptidase or protease enzyme, including but not limited to a lysosomal or endosomal protease. One advantage of using intracellular proteolytic release of a therapeutic agent is that the agent is typically attenuated upon conjugation, and the stability of the conjugates in serum is typically high. According to some embodiments, the peptidyl linker consists of at least two amino acids or at least three amino acids. Exemplary amino acid linkers include a dipeptide, tripeptide, tetrapeptide, or pentapeptide. Examples of suitable peptides include peptides containing amino acids such as valine, alanine, citrulline (Cit), phenylalanine, lysine, leucine, and glycine. Amino acid residues that comprise an amino acid linker component include naturally occurring as well as minor amino acids and non-naturally occurring amino acid analogs such as citrulline. Exemplary dipeptides include valine-citrulline (vc or val-cit) and alanine-phenylalanine (af or ala-phe). Exemplary tripeptides include glycine-valine-citrulline (gly-val-cit) and glycine-glycine-glycine (gly-gly-gly). In some embodiments, the linker includes a dipeptide such as Val-Cit, Ala-Val, or Phe-Lys, Val-Lys, Ala-Lys, Phe-Cit, Leu-Cit, Ile-Cit, Phe-Arg, or Trp-Cit. Linkers comprising dipeptides such as Val-Cit or Phe-Lys are disclosed, for example, in U.S. Patent No. 6,214,345, the disclosure of which is incorporated herein by reference in its entirety as it relates to linkers suitable for covalent conjugation. In some embodiments, the linker comprises a dipeptide selected from Val-Ala and Val-Cit.

Linkers suitable for conjugating antibodies, antigen-binding fragments described herein to a cytotoxic molecule include linkers capable of releasing amatoxin via a 1,6-elimination process. Chemical moieties capable of this elimination process include a p-aminobenzyl (PAB) group, 6-maleimidohexanoic acid, pH-sensitive carbonates, and other reagents as described in Jain et al., Pharm. Res. 32:3526-3540, 2015, the disclosure of which is incorporated herein by reference in its entirety as it relates to linkers suitable for covalent conjugation.

In some embodiments, the linker includes a "self-cleaving" group, such as the above-mentioned PAB or PABC (para-aminobenzyloxycarbonyl), which are disclosed in, for example, Carl et al., J. Med. Chem. (1981) 24:479-480; Chakravarty et al (1983) J. Med. Chem. 26:638-644; US6214345; US20030130189; US20030096743; US6759509; US20040052793; US6218519; US6835807; US6268488; US20040018194; W098/13059; US20040052793; US6677435; US5621002; US20040121940; W02004/032828). Other such chemical moieties capable of this process ("self-cleaving linkers") include methylene carbamates and heteroaryl groups such as aminothiazoles, aminoimidazoles, aminopyrimidines, and the like. Linkers containing such heterocyclic self-cleaving groups are disclosed, for example, in US Patent Publication Nos. 20160303254 and 20150079114 and US Pat. No. 7754681; Hay et al. (1999) Bioorg. Med. Chem. Lett. 9:2237; US 2005/0256030; de Groot et al (2001) J. Org. Chem. 66:8815-8830; and U.S. Patent No. 7,223,837. In some embodiments, the dipeptide is used in combination with a self-cleaving linker.

According to some embodiments, the linker L comprises one or more of the following: hydrazine, a disulfide, a thioether, an amino acid, a peptide consisting of up to 10 amino acids, a p-aminobenzyl (PAB) group, a heterocyclic self-cleaving group, C ₁ -C ₆ alkyl, C ₁ -C ₆ heteroalkyl, C ₂ -C 6 alkenyl, C _{2 -C 6 heteroalkenyl, C 2 -C 6 alkynyl} , C ₂ -C ₆ heteroalkynyl, C _{3 -C 6 cycloalkyl} , heterocycloalkyl, aryl, heteroaryl, a -(C=O)- group, a -C(O)NH- group, a -OC(O)NH- group, a -(CH ₂ CH ₂ O) _p - group, where p is an integer from 1 to 6, or a solubility-enhancing group;

wherein each C ₁ -C ₆ alkyl, C ₁ -C ₆ heteroalkyl, C ₂ -C ₆ alkenyl, C _{2 -C 6 heteroalkenyl, C 2 -C 6 alkynyl} , C ₂ -C ₆ heteroalkynyl, C ₃ -C ₆ cycloalkyl, heterocycloalkyl, aryl or heteroaryl group may be optionally substituted with from 1 to 5 substituents independently selected for each occurrence from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkaryl, alkyl heteroaryl, amino, ammonium, acyl, acyloxy, acylamino, aminocarbonyl, alkoxycarbonyl, ureido, carbamate, aryl, heteroaryl, sulfinyl, sulfonyl, hydroxyl, alkoxy, sulfanyl, helogen, carboxy, trihalomethyl, cyano, hydroxy, mercapto and nitro.

According to some embodiments, each _C1 - _C6 alkyl, _C1 - _C6 heteroalkyl, _C2 - _C6 alkenyl, _C2 - _C6 heteroalkenyl, _C2 - _C6 alkynyl, _C2 - _C6 heteroalkynyl, _C3 - _C6 cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group may optionally be interrupted by one or more heteroatoms selected from O, S, and N.

According to some embodiments, each C ₁ -C ₆ alkyl, C ₁ -C ₆ heteroalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ heteroalkenyl, C ₂ -C ₆ alkynyl, C ₂ -C ₆ heteroalkynyl, C ₃ -C ₆ cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group may be optionally interrupted by one or more heteroatoms selected from O, S, and N and may be optionally substituted with 1 to 5 substituents independently selected for each occurrence from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkaryl, alkyl heteroaryl, amino, ammonium, acyl, acyloxy, acylamino, aminocarbonyl, alkoxycarbonyl, ureido, carbamate, aryl, heteroaryl, sulfinyl, sulfonyl, hydroxyl, alkoxy, sulfanyl, heloyl, carboxy, trihalomethyl, cyano, hydroxy, mercapto and nitro.

It will be understood by one skilled in the art that one or more of the listed groups may be present in the form of divalent (biradical) compounds, for example, C ₁ -C ₆ alkylene, etc.

According to some embodiments, the linker L comprises a solubility-enhancing group according to the formula -O _a -C(O)NH-SO ₂ -N(R ₁ )-, where:

a is 0 or 1;

R ¹ is selected from the group consisting of hydrogen, C ₁ -C ₂₄ alkyl groups, C ₃ -C ₂₄ cycloalkyl groups, C ₂ -C ₂₄ (hetero) aryl groups, C ₃ -C ₂₄ alkyl (hetero) aryl groups, and C ₃ -C ₂₄ (hetero) aryl alkyl groups, each of which may be optionally substituted or optionally interrupted by one or more heteroatoms selected from O, S, and NR ³ , wherein R ³ is independently selected from the group consisting of hydrogen and C ₁ -C ₄ alkyl. Such solubility-enhancing groups are described, for example, in U.S. Patent No. 9,636,421 and U.S. Patent Application Publication No. 2017/0298145, the disclosures of each of which are incorporated herein by reference in their entireties.

According to some embodiments, the solubility-enhancing group according to the formula -O _a -C(O)NH-SO ₂ -N(R ₁ )- further comprises a C ₁ -C ₆ alkylene or a -(CH ₂ CH ₂ O) _p - group, where p is an integer from 1 to 6. Non-limiting examples of such solubility-enhancing groups include those groups presented in Table 2, above.

In some embodiments, the linker includes a p-aminobenzyl group (PAB). In one embodiment, the p-aminobenzyl group is located between the cytotoxic drug and the protease cleavage site in the linker. In one embodiment, the p-aminobenzyl group is part of a p-aminobenzyloxycarbonyl unit. In one embodiment, the p-aminobenzyl group is part of a p-aminobenzylamido unit.

In some embodiments, the linker comprises a dipeptide selected from the group consisting of Phe-Lys, Val-Lys, Phe-Ala, Phe-Cit, Val-Ala, Val-Cit, and Val-Arg. In some embodiments, the linker comprises one or more of PAB, Val-Cit-PAB, Val-Ala-PAB, Val-Lys(Ac)-PAB, Phe-Lys-PAB, Phe-Lys(Ac)-PAB, D-Val-Leu-Lys, Gly-Gly-Arg, Ala-Ala-Asn-PAB, or Ala-PAB.

According to some embodiments, the linker comprises a combination of one or more of a peptide, an oligosaccharide, -( _CH2 ) _p- , - _{( CH2CH2O} ) _p , PAB, Val-Cit-PAB, Val-Ala-PAB, Val-Lys(Ac)-PAB, Phe-Lys-PAB, Phe-Lys(Ac)-PAB, D-Val-Leu-Lys, Gly-Gly-Arg, Ala-Ala-Asn-PAB, or Ala-PAB.

According to some embodiments, the linker comprises a unit -(C=O)( _CH2 ) _p- , where p is an integer from 1 to 6.

According to some embodiments, the linker comprises PAB-Ala-Val-propionyl represented by the formula:

According to some embodiments, the linker comprises PAB-Cit-Val-propionyl represented by the formula:

Such PAB-dipeptide-propionyl linkers are disclosed, for example, in International Patent Application Publication No. WO2017/149077, which is incorporated herein by reference in its entirety. In addition, the cytotoxins disclosed in WO2017/149077 are incorporated herein by reference.

One skilled in the art will appreciate that any one or more of the chemical groups, moieties, and features disclosed herein can be combined in a variety of ways to form linkers useful for conjugating antibodies and amatoxins as disclosed herein. Additional linkers useful in combination with the compositions and methods described herein are described, for example, in U.S. Patent Application Publication No. 2015/0218220, the disclosure of which is incorporated herein by reference in its entirety.

Linker-amatoxin and linker-antibody conjugation

In certain embodiments, the linker reacts with an amatoxin or a derivative thereof according to any of formulae (V), (Va), or (Vb) under appropriate conditions to form a linker-amatoxin conjugate. In certain embodiments, reactive groups are used on the amatoxin or the linker to form a covalent bond.

The amatoxin-linker conjugate is subsequently reacted with the antibody, derivatized antibody, or antigen-binding fragment thereof under appropriate conditions to form an ADC. Alternatively, the linker may first react with the antibody, derivatized antibody, or antigen-binding fragment thereof to form a linker-antibody conjugate and then react with amatoxin to form an ADC. Such conjugation reactions will now be described more fully.

A number of different reactions are available for covalently attaching linkers or amatoxin-linker conjugates to an antibody or antigen-binding fragment thereof. Suitable attachment points on the antibody molecule include, but are not limited to, amino groups of lysine, free carboxylic acid groups of glutamic acid and aspartic acid, sulfhydryl groups of cysteine, and various aromatic amino acid moieties. For example, non-specific covalent attachment can be accomplished using a carbodiimide reaction to couple a carboxy (or amino) group on a linker to an amino (or carboxy) group on an antibody fragment. In addition, bifunctional agents such as dialdehydes or imidoesters can also be used to couple an amino group of a linker to an amino group of an antibody fragment. In addition, the Schiff base reaction is available for attaching amatoxins to antibody fragments. This method involves periodate oxidation of a glycol or hydroxy group on an antibody or linker to thereby form an aldehyde, which is then reacted with the linker or antibody, respectively. The covalent bond is formed through the formation of a Schiff base between the aldehyde and the amino group. Isothiocyanates can also be used as coupling agents for covalently attaching amatoxins or antibody fragments to linkers. Other techniques are known to those skilled in the art and are within the scope of the present disclosure.

Linkers used for conjugation with antibodies or antigen-binding fragments as described herein include, but are not limited to, linkers comprising a chemical moiety Z formed by a coupling reaction between an antibody and a reactive chemical moiety (referred to herein as a reactive substituent, Z') on the linker, as shown in Table 3 below. The wavy lines represent attachment points to the antibody or antigen-binding fragment and the cytotoxic molecule, respectively.

One skilled in the art will appreciate that a reactive substituent Z' attached to a linker and a reactive substituent on the antibody or antigen-binding fragment thereof are involved in a covalent coupling reaction to form a chemical moiety Z, and will be able to recognize the reactive substituent Z'. Accordingly, antibody drug conjugates useful in combination with the methods described herein can be formed by reacting an antibody or antigen-binding fragment thereof with a linker or an amatoxin-linker conjugate as described herein, a linker or an amatoxin-linker conjugate comprising a reactive substituent Z' suitable for reaction with a reactive substituent on the antibody or antigen-binding fragment thereof to form a chemical moiety Z.

As shown in Table 3, examples of suitable reactive substituents Z' on the linker and reactive substituents on the antibody or antigen-binding fragment thereof include a nucleophile/electrophile pair (e.g., a thiol/haloalkyl pair, an amine/carbonyl pair, or a thiol/α,β-unsaturated carbonyl pair, etc.), a diene/dienophile pair (e.g., an azide/alkyne pair or a diene/-α,β-unsaturated carbonyl pair, among others), etc. Coupling reactions between reactive substituents to form a chemical moiety Z include, but are not limited to, thiol alkylation, hydroxyl alkylation, amine alkylation, amine or hydroxylamine condensation, hydrazine formation, amidation, esterification, disulfide formation, cycloaddition (e.g., [4+2] Diels-Alder cycloaddition, [3+2] Huisgen cycloaddition, among others), nucleophilic aromatic substitution, electrophilic aromatic substitution, and other reaction methods known in the art or described herein. In some embodiments, the reactive substituent Z' is an electrophilic functional group suitable for reaction with a nucleophilic functional group on the antibody or antigen-binding fragment thereof.

Reactive substituents that may be present in an antibody or antigen-binding fragment thereof as disclosed herein include, but are not limited to, nucleophilic groups such as (i) N-terminal amino groups, (ii) side chain amino groups, such as lysine, (iii) side chain thiol groups, such as cysteine, and (iv) hydroxyl or amino groups of a sugar where the antibody is glycosylated. Reactive substituents that may be present in an antibody or antigen-binding fragment thereof as disclosed herein include, but are not limited to, hydroxyl moieties of serine, threonine, and tyrosine residues; amino moieties of lysine residues; carboxyl moieties of aspartic acid and glutamic acid residues; and thiol moieties of cysteine residues, as well as propargyl, azido, haloaryl (e.g., fluoroaryl), haloheteroaryl (e.g., fluoroheteroaryl), haloalkyl, and haloheteroalkyl moieties of unnatural amino acids. In some embodiments, the reactive substituents present in an antibody or antigen-binding fragment thereof as disclosed herein include amine or thiol moieties. Some antibodies contain reducible interchain disulfides, i.e., cysteine bridges. Antibodies can be rendered reactive for conjugation with linker reagents by treatment with a reducing agent, such as DTT (dithiothreitol). Thus, each cysteine bridge theoretically forms two reactive thiol nucleophiles. Additional nucleophilic groups can be introduced into antibodies by reacting lysines with 2-iminothiolane (Traut's reagent), resulting in the conversion of the amine to a thiol. Reactive thiol groups can be introduced into an antibody (or fragment thereof) by introducing one, two, three, four or more cysteine residues (e.g., producing mutant antibodies containing one or more non-native cysteine amino acid residues). U.S. Patent No. 7,521,541 describes the construction of antibodies by introducing reactive amino acids - cysteine.

In some embodiments, the reactive substituent Z' attached to the clinker is a nucleophilic group that reacts with an electrophilic group present on the antibody. Useful electrophilic groups on the antibody include, but are not limited to, aldehyde and ketone carbonyl groups. The nucleophilic group (e.g., a heteroatom thereof) can react with an electrophilic group on the antibody and form a covalent bond with the antibody. Useful nucleophilic groups include, but are not limited to, hydrazide, oxime, amino, hydroxyl, hydrazine, thiosemicarbazone, hydrazine carboxylate, and aryl hydrazide.

In some embodiments, the chemical moiety Z is a reaction product between reactive nucleophilic substituents present in antibodies or antigen binding moieties thereof, such as amine and thiol moieties, and a reactive electrophilic substituent Z' attached to a linker. For example, Z' can be, among others, a Michael acceptor (e.g., maleimide), an activated ester, an electron-deficient carbonyl compound, or an aldehyde.

Several representative and non-limiting examples of reactive substituents Z' and the resulting chemical moieties Z are presented in Table 4.

For example, linkers suitable for synthesizing linker-antibody conjugates and ADCs include, but are not limited to, reactive substituents Z' attached to the linker, such as a maleimide or haloalkyl group. They can be attached to the linker, for example, using reagents such as succinimidyl 4-(N-maleimidomethyl)-cyclohexane-L-carboxylate (SMCC), N-succinimidyl iodoacetate (SIA), sulfo-SMCC, m-maleimidobenzoyl-1N-hydroxysuccinimidyl ester (MBS), sulfo-MBS and succinimidyl iodoacetate, among others, described, for example, in Liu et al., 18:690-697, 1979, the disclosure of which is incorporated herein by reference as it relates to linkers for chemical conjugation.

In some embodiments, the reactive substituent Z' attached to the linker L is a maleimide, azide, or alkyne. An example of a maleimide-containing linker is a non-cleavable maleimidocaproyl-based linker, which is particularly useful for conjugating microtubule-disrupting agents such as auristatins. Such linkers are described by Doronina et al., Bioconjugate Chem. 17:14-24, 2006, the disclosure of which is incorporated herein by reference as it relates to linkers for chemical conjugation.

In some embodiments, the reactive substituent Z' is -(C=O)- or -NH(C=O)-, such that the linker can be attached to the antibody or antigen-binding fragment thereof via an amide or urea moiety, respectively, resulting from the reaction of the -(C=O)- or -NH(C=O)- group with an amino group of the antibody or antigen-binding fragment thereof.

According to some embodiments, the reactive substituent Z' is an N-maleimidyl group, a halogenated N-alkylamido group, a sulfonyloxy-N-alkylamido group, a carbonate group, a sulfonyl halide group, a thiol group or a derivative thereof, an alkynyl group containing an internal carbon-carbon triple bond, a (hetero)cycloalkynyl group, a bicyclo[6.1.0]non-4-yn-9-yl group, an alkenyl group containing an internal carbon-carbon double bond, a cycloalkenyl group, a tetrazinyl group, an azido group, a phosphine group, a nitrile oxide group, a nitrone group, a nitrilimine group, a diazo group, a ketone group, an (O-alkyl)hydroxylamino group, a hydrazine group, a halogenated N-maleimidyl group, 1,1-bis(sulfonylmethyl)methylcarbonyl group or their elimination derivatives, carbonyl halide group or allenamide group, each of which may be optionally substituted. According to some embodiments, the reactive substituent comprises a cycloalkene group, a cycloalkyne group or an optionally substituted (hetero)cycloalkynyl group.

In some embodiments, the chemical moiety Z is selected from Table 3 or Table 4. In some embodiments, the chemical moiety Z is:

where S is a sulfur atom that represents a reactive substituent present in the antibody or antigen-binding fragment thereof that specifically binds to an antigen expressed on the cell surface of a human stem cell or T cell (e.g., from the -SH group of a cysteine residue).

According to some embodiments, the linker-reactive substituent group, taken together as L-Z', prior to conjugation with the antibody or antigen-binding fragment thereof, is characterized by the structure:

where the wavy line indicates the point of attachment to the substituent on amatoxin. This linker-reactive substituent group L-Z' may alternatively be referred to as N-beta-maleimidopropyl-Val-Ala-para-aminobenzyl (BMP-Val-Ala-PAB). The wavy line at the end of the linker indicates the point of attachment to amatoxin. In some embodiments, the linker L and the chemical moiety Z, after conjugation to the antibody, taken together as L-Z-Ab, are characterized by the structure:

where S is a sulfur atom that is a reactive substituent present in the antibody or antigen-binding fragment thereof that specifically binds to an antigen expressed on the cell surface of a human stem cell or T cell (e.g., from the -SH group of a cysteine residue). The wavy line at the end of the linker indicates the point of attachment to amatoxin.

According to some embodiments, the linker-reactive substituent group, taken together as L-Z', prior to conjugation with the antibody or antigen-binding fragment thereof, is characterized by the structure:

This linker-reactive substituent group may alternatively be called 1-n-hexylmaleimide, which is a non-cleavable linker. The wavy line at the end of the linker indicates the point of attachment to amatoxin.

According to some embodiments, the linker L and the chemical moiety Z, after conjugation with the antibody, taken together as L-Z-Ab, are characterized by the structure:

where S is a sulfur atom, which is a reactive substituent present in the antibody or antigen-binding fragment thereof, which specifically binds to an antigen expressed on the cell surface of a cell, for example, a tumor cell or a stem cell or a human T cell (for example, from the -SH group of a cysteine residue). The wavy line at the end of the linker indicates the point of attachment to the amatoxin. It will be understood by one skilled in the art that, according to this embodiment, the structure of the linker-reactive substituent group L-Z' before conjugation with the antibody or antigen-binding fragment thereof includes maleimide as the Z' group. The above-mentioned linker moieties and amatoxin-linker conjugates, among others, useful in combination with the compositions and methods described herein, are described, for example, in U.S. Patent Application Publication No. 2015/0218220 and Patent Application Publication No. WO 2017/149077, the disclosure of each of which is incorporated herein by reference in its entirety.

In one aspect, the cytotoxin in the ADC as disclosed herein is an amatoxin or derivative thereof represented by any of formula (V), (Va), or (Vb). One skilled in the art will appreciate that such amatoxins provide a variety of possibilities for attachment points to the linker.

In some embodiments, the amatoxin has a structure of formula (V), and the linker is attached via an ether bond to the OH group of the hydroxyltryptophan residue. In such embodiments, the ADC may be represented by formula (I):

or its stereoisomer;

Where:

Q represents S;

L is a linker;

Z is a chemical moiety formed by a coupling reaction between a reactive substituent present on L and a reactive substituent present in the antibody or antigen-binding fragment thereof; and

Ab is an antibody,

each is as disclosed herein.

In some embodiments, the amatoxin has a structure of formula (Va), and the linker is attached via an ether bond to the OH group of the hydroxyltryptophan residue. In such embodiments, the ADC may be represented by formula (Ia):

In some embodiments, the amatoxin has a structure of formula (Vb), and the linker is attached via an ether bond to the OH group of the hydroxyltryptophan residue. In such embodiments, the ADC may be represented by formula (Ib):

In some embodiments, the linker L in the ADC of formula (I), (Ia), or (Ib) is a non-cleavable linker. In some embodiments, the non-cleavable linker L comprises one or more of the following: a bond, -(C=O)-, a -C(O)NH- group, an -OC(O)NH- group, a _C1 - _C6 alkylene, a _C1 - _C6 heteroalkylene, a _C2 - _C6 alkenylene, a _C1 -C6 heteroalkenylene, a _{C1 - C6} alkynylene, a _C1 - _C6 heteroalkynylene, a _C3 - _C6 cycloalkylene, a heterocycloalkylene, an arylene, a _{heteroarylene} , a -( _CH2CH2O ) _p- group, wherein p is an integer from 1 to 6, or a solubility enhancing group;

wherein each C ₁ -C ₆ alkylene, C ₁ -C ₆ heteroalkylene, C ₂ -C ₆ alkenylene, C 2 -C ₆ heteroalkenylene, C ₂ -C ₆ alkynylene, C ₂ -C ₆ heteroalkynylene, C _{3 -C 6} cycloalkylene, heterocycloalkylene, arylene or heteroarylene may be optionally substituted with from 1 to 5 substituents independently selected for each occurrence from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkaryl, alkyl heteroaryl, amino, ammonium, acyl, acyloxy, acylamino, aminocarbonyl, alkoxycarbonyl, ureido, carbamate, aryl, heteroaryl, sulfinyl, sulfonyl, hydroxyl, alkoxy, sulfanyl, helogen, carboxy, trihalomethyl, cyano, hydroxy, mercapto and nitro; or

each _C1 - _C6 alkylene, _C1 - _C6 heteroalkylene, _C2 - _C6 alkenylene _, C2- _C6 heteroalkenylene, _C2 - _C6 alkynylene, _C2 - _C6 heteroalkynylene, _C3 - _C6 cycloalkylene, heterocycloalkylene, arylene or heteroarylene may optionally be interrupted by one or more heteroatoms selected from O, S and N.

According to some embodiments, the non-cleavable linker L comprises a solubility-enhancing group according to the formula -O _a -C(O)NH-SO ₂ -NR ¹ -, where:

a is 0 or 1; and

R ¹ is selected from the group consisting of: hydrogen, C ₁ -C ₂₄ alkyl groups, C ₃ -C ₂₄ cycloalkyl groups, C ₂ -C ₂₄ (hetero) aryl groups, C ₃ -C ₂₄ alkyl (hetero) aryl groups and C ₃ -C ₂₄ (hetero) aryl alkyl groups, each of which may be optionally substituted, optionally interrupted, or both substituted and interrupted by one or more heteroatoms selected from O, S and NR ³ , wherein R ³ is independently selected from the group consisting of hydrogen and C ₁ -C ₄ alkyl.

According to some embodiments, the non-cleavable linker L comprises a unit -( _CH2 ) _n- , where n is an integer from 2 to 6.

In some embodiments, the non-cleavable linker L is -( _CH2 ) _n- , where n is 6.

According to some embodiments, Ab, Z, and the non-cleavable linker L, taken together as Ab-Z-L, are represented by the formula:

where S is a sulfur atom which is a reactive substituent present in the antibody or antigen-binding fragment thereof which specifically binds to an antigen expressed on a cell, such as the surface of a human stem cell or T cell (e.g. from the -SH group of a cysteine residue). The wavy line at the end of the linker indicates the point of attachment to amatoxin.

According to some embodiments, the ADC according to formula (I) is represented by formula (II):

its stereoisomer or its pharmaceutically acceptable salt.

According to some embodiments, the ADC according to formula (II) is represented by formula (IIa):

its stereoisomer or its pharmaceutically acceptable salt.

According to some embodiments, the ADC according to formula (II) is represented by formula (IIb):

its stereoisomer or its pharmaceutically acceptable salt.

Surprisingly, according to the present disclosure, it has been found that ADCs comprising an amatoxin and a non-cleavable linker conjugating the amatoxin to an antibody fragment of the ADC have improved tolerability compared to an ADC comprising an amatoxin and a cleavable linker. For example, in some embodiments, improved tolerability can be an increased therapeutic index. In some embodiments, improved tolerability can be a smaller increase or no increase in one or more liver enzymes in the blood (e.g., AST, ALT, ADH, or total bilirubin) at a particular dose of an ADC comprising a non-cleavable linker compared to an ADC comprising a cleavable linker.

In some embodiments, the linker L in an ADC of formula (I), (Ia), or (Ib) is a cleavable linker. According to some embodiments, the cleavable linker L comprises one or more of the following: hydrazine, a disulfide, a thioether, an amino acid, a peptide consisting of up to 10 amino acids, a p-aminobenzyl (PAB) group, a heterocyclic self-cleaving group, C ₁ -C ₆ alkyl, C ₁ -C ₆ heteroalkyl, C ₂ -C 6 alkenyl, C _{2 -C 6 heteroalkenyl, C 2 -C 6 alkynyl , C 2} -C ₆ heteroalkynyl, C _{3 -C 6} cycloalkyl, heterocycloalkyl, aryl, heteroaryl, a -(C=O)- group, a -C(O)NH- group, a -OC(O)NH- group, a -(CH ₂ CH ₂ O) _p - group, where p is an integer from 1 to 6, or a solubility-enhancing group;

wherein each C ₁ -C ₆ alkyl, C ₁ -C ₆ heteroalkyl, C ₂ -C ₆ alkenyl, C _{2 -C 6 heteroalkenyl, C 2 -C 6 alkynyl} , C ₂ -C ₆ heteroalkynyl, C ₃ -C ₆ cycloalkyl, heterocycloalkyl, aryl or heteroaryl group may be optionally substituted with from 1 to 5 substituents independently selected for each occurrence from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkaryl, alkyl heteroaryl, amino, ammonium, acyl, acyloxy, acylamino, aminocarbonyl, alkoxycarbonyl, ureido, carbamate, aryl, heteroaryl, sulfinyl, sulfonyl, hydroxyl, alkoxy, sulfanyl, helogen, carboxy, trihalomethyl, cyano, hydroxy, mercapto and nitro;

or each _C1 - _C6 alkyl, _C1 - _C6 heteroalkyl, _C2 - _C6 alkenyl, _C2 - _C6 heteroalkenyl, _C2 - _C6 alkynyl, _C2 - _C6 heteroalkynyl, _C3 - _C6 cycloalkyl, heterocycloalkyl, aryl or heteroaryl group may optionally be interrupted by one or more heteroatoms selected from O, S and N.

According to some embodiments, the cleavable linker L comprises a solubility-enhancing group according to the formula -O _a -C(O)NH-SO ₂ -NR ¹ -, where:

a is 0 or 1; and

R ¹ is selected from the group consisting of: hydrogen, C ₁ -C ₂₄ alkyl groups, C ₃ -C ₂₄ cycloalkyl groups, C ₂ -C ₂₄ (hetero) aryl groups, C ₃ -C ₂₄ alkyl (hetero) aryl groups and C ₃ -C ₂₄ (hetero) aryl alkyl groups, each of which may be optionally substituted or optionally interrupted by one or more heteroatoms selected from O, S and NR ³ , wherein R ³ is independently selected from the group consisting of hydrogen and C ₁ -C ₄ alkyl.

According to some embodiments, the cleavable linker L comprises a peptide selected from the group consisting of Phe-Lys, Val-Lys, Phe-Ala, Phe-Cit, Val-Ala, Val-Cit, and Val-Arg.

According to some embodiments, the cleavable linker L further comprises a PAB group.

According to some embodiments, the cleavable linker L is represented by the formula:

Preparation of antibody-drug conjugates

In an ADC of formula Ab-(ZL-Cy) _n as disclosed herein, such as an ADC of any of formulae (I), (Ia), or (Ib), (II), (IIa), or (IIb), an antibody or antigen-binding fragment thereof (Ab) is conjugated to one or more cytotoxic drug moieties (Cy; e.g., amatoxin), e.g., about 1 to about 20 cytotoxic moieties per antibody, via a linker L and a chemical moiety Z, each of which are disclosed herein. In some embodiments, n is 1. In some embodiments, n is about 1 to about 5, about 1 to about 4, about 1 to about 3, or about 3 to about 5. In some embodiments, n is about 1, about 2, about 3, or about 4.

The ADCs of the present disclosure can be prepared by several methods using organic chemistry reactions, conditions, and reagents known to those skilled in the art, including the following: (1) reacting a reactive substituent of an antibody or antigen-binding fragment thereof with a divalent linker reagent to form Ab-ZL, as described herein above, followed by reaction with a cytotoxic moiety Cy; or (2) reacting a reactive substituent of a cytotoxic moiety with a divalent linker reagent to form Cy-LZ', followed by reaction with a reactive substituent of an antibody or antigen-binding fragment thereof, as described herein above, to form an ADC of the formula Ab-(ZL-Cy) _n . Additional methods for preparing ADCs are described herein.

In one embodiment, the antibody or antigen-binding fragment thereof may comprise one or more carbohydrate moieties that may be chemically modified to comprise one or more sulfhydryl groups. The ADC is then formed by conjugation via the sulfur atom of the sulfhydryl group, as described herein above.

In another embodiment, the antibody may comprise one or more carbohydrate moieties that can be oxidized to form an aldehyde group (-CHO) (see, e.g., Laguzza, et al., J. Med. Chem. 1989, 32(3), 548-55). The ADC is then formed by conjugation via the appropriate aldehyde as described herein above. Other protocols for modifying proteins for the attachment or association of cytotoxins are described in Coligan et al., Current Protocols in Protein Science, vol. 2, John Wiley & Sons (2002), incorporated herein by reference.

Methods for conjugating linker moieties of a drug to cell-targeting proteins such as antibodies, immunoglobulins, or fragments thereof can be found, for example, in U.S. Patent No. 5,208,020; U.S. Patent No. 6,441,163; WO 2005037992; WO 2005081711; and WO 2006/034488, all of which are incorporated herein by reference in their entireties.

Alternatively, a fusion protein comprising an antibody and a cytotoxic agent may be produced, for example, by recombinant methods or peptide synthesis. The length of DNA may include the corresponding regions encoding the two parts of the conjugate, either adjacent to each other or separated by a region encoding a linker peptide that does not interfere with the desired properties of the conjugate.

In some embodiments, an ADC according to formula (IIa) can be prepared by conjugating a thiol group on an antibody to an amatoxin-linker conjugate Cy-L-Z' represented by the structure:

This amatoxin-linker conjugate can be prepared according to Schemes 1-3, starting from commercially available 6-hydroxytryptophan (1). Compound 1 can be protected with tert-butyloxycarbonyl anhydride ((BOC) _2O ). Hexahydropyrroloindole 3 can be obtained as a mixture of cis- and trans-isomers by irradiating protected hydroxytryptophan 2 in the presence of oxygen and a sensitizer (rose bengal). The preparation of compound 3 (as well as the procedure for preparing compounds 2 through Va) is described in International Patent Application Publication No. WO 2019/030173, the disclosure of which is incorporated herein by reference in its entirety. Commercial 9-fluorenylmethoxycarbonyl (FMOC)-protected 4-hydroxyproline (4) can be alkylated with allyl bromide and subsequently coupled to a tetrahydropyranyl (THP)-polystyrene resin under mild acidic conditions (pyridinium para-toluenesulfonate; PPTS) to afford resin-bound allyl ester 5, which can be deprotected with tetrakistriphenylphosphine palladium and dimethylbarbituric acid to afford intermediate 6. Protected amino acid 7 can be prepared according to the method described in International Patent Application Publication No. WO 2014/009025, the disclosure of which is incorporated herein in its entirety. Protected amine 7 can then be coupled with resin-bound hydroxyproline 6 to afford peptide 8.

Peptide 8 can then be subjected to multiple coupling and deprotection reactions to afford the monocyclic intermediate 9 (Scheme 2). The amino acids FmocAsn(Trt)OH, FmocCys(OTrt)OH, FmocGlyOH, FmodleOH, FmocGlyOH, and hexahydropyrroloindole 3 can be used in sequential solid-phase coupling reactions to afford intermediate 9. Each amino acid can be coupled using PyBOP/HOBT in dichloromethane and dimethylformamide (DMF) in the presence of diisopropylethylamine (DIEA). Deprotection can be accomplished with 20% piperidine in DMF.

After the final coupling reaction, intermediate 9 can be cleaved from the solid phase resin support with trifluoroacetic acid in the presence of triisopropylsilane to afford peptide 10. Treatment of 10 with diphenylphosphoryl azide (DPPA) and DIEA-induced macrocyclization and deprotection with ammoniacal methanol afforded the amatoxin a derivative 11 (i.e., formula Va, where Q=S).

Maleimideshexyl-amatoxin conjugate 14 can be prepared from compound 11 according to Scheme 3. Diels-Alder adduct 12 can be prepared from maleimide and 2,5-dimethylfuran and then alkylated with 1,6-dibromohexane to provide protected linker 13. Compound 11 can be alkylated with compound 13 in dimethyl sulfoxide (DMSO) in the presence of sodium hydroxide, followed by heating to 100 °C in DMSO to provide amatoxin-linker conjugate 14. The procedures for the preparation of compounds 12 and 13, as well as the O-alkylation of the related amatoxin (α-amanitin), are previously described in U.S. Patent Application Publication No. 2018/0043033, the disclosure of which is incorporated herein by reference in its entirety.

Antibodies

The ADC compositions and methods disclosed herein comprise an agent for facilitating selective delivery of such ADCs to a population of cells in target tissues (e.g., cancer or tumor cells or hematopoietic stem cells of the bone marrow stem cell niche). The specificity of the ADC for a cellular target is determined by an antigen binding protein, such as an antibody or an antigen-binding portion thereof.

According to one embodiment, the present invention includes ADCs comprising antibodies and antigen binding fragments thereof that specifically bind to the following: human CD45, CD49d (VLA-4), CD49f (VLA-6), CD51, CD84, CD90, CD117, CD133, CD134, CD184 (CXCR4), HLA-DR, CD11a, CD18, CD34, CD41/61, CD43, CD58, CD71, CD97, CD162, CD 166, CD205 and CD361, CD13, CD33, CD34, CD44, CD 4, CD59, CD84/CD150, CD90Ahyl, CD93, CD105/endoglin, CD123/IL-3R, CD126/IL-6R, CD133, receptor CD135/Flt3, CD166/ALCAM, prominin 2, erythropoietin R, selective endothelial cell adhesion molecule, CD244, Tie1, Tie2, MPL, G-CSFR, CSF3R, IL-1R, gp130, leukemia inhibitory factor receptor, oncostatin M receptor, embigin, and IL-18R. Other examples of antigens that can be bound by the ADCs disclosed herein include, but are not limited to, CD7, CDw12, CD13, CD15, CD19, CD21, CD22, CD29, CD30, CD33, CD34, CD36, CD38, CD40, CD41, CD42a, CD42b, CD42c, CD42d, CD43, CD45RA, CD45RB, CD45RC, CD45RO, CD48, CD49b, CD49d, CD49e, CD49f, CD50, CD53, CD55, CD64a, CD68, CD71, CD72, CD73, CD81, CD82, CD85A, CD85K, CD90, CD99, CD104, CD105, CD109, CD110, CD111, CD112, CD114, CD115, CD123, , CD126, CD127, CD130, CD131, CD133, CD135, CD138, CD151, CD157, CD162, CD164, CD168, CD172a, CD173, CD174, CD175, CD175s, CD176, CD183, CD191, CD200, CD201, CD205, CD217, CD220, CD221, CD222, CD223, CD224, CD225, CD226, CD227, CD228, CD229, CD230, CD235a, CD235b, CD236, CD236R, CD238, CD240, CD242, CD243, CD277, CD292, CDw293, CD298, , CD309, CD318, CD324, CD325, CD338, CD344, CD349 or CD350. Other examples of antigens that can be bound by the ADCs disclosed herein include, but are not limited to, CD11a, CD18, CD37, CD47, CD52, CD58, CD62L, CD69, CD74, CD97, CD103, CD132, CD156a, CD179a, CD79b, CD184, CD232, CD244, CD252, CD302, CD305, CD317, and CD361.

In certain embodiments, the antibody or antigen-binding fragment thereof in the ADC described herein has a particular off-rate that is particularly advantageous when used as part of a conjugate. For example, in certain embodiments, the anti-CD117 antibody has a off-rate constant (Koff) for human CD117 and/or rhesus CD117 of 1×10 ^-2 - 1×10 ^-3 , 1×10 ^-3 - 1×10 ^-4 , 1×10 ^-5 - 1×10 ^-6 , 1×10 ^-6 - 1×10 ^-7 , or 1×10 ^-7 - 1×10 ^-8 , as measured by biolayer interferometry (BLI). In some embodiments, the antibody or antigen-binding fragment thereof binds a cell surface antigen (e.g., human CD117 and/or rhesus monkey CD117) with a K _D of about 100 nM or less, about 90 nM or less, about 80 nM or less, about 70 nM or less, about 60 nM or less, about 50 nM or less, about 40 nM or less, about 30 nM or less, about 20 nM or less, about 10 nM or less, about 8 nM or less, about 6 nM or less, about 4 nM or less, about 2 nM or less, about 1 nM or less, as determined by a biolayer interferometry (BLI) assay.

Antibodies to CD117

In one embodiment, the present invention provides ADCs comprising antibodies and antigen-binding fragments thereof that specifically bind to CD117, such as GNNK+ CD117. Such ADCs can be used as therapeutic agents, for example, (i) for the treatment of cancer and autoimmune diseases characterized by CD117+ cells, and (ii) for promoting engraftment of transplanted hematopoietic stem cells in a patient in need of transplant therapy. These therapeutic activities can be caused, for example, by the binding of isolated anti-CD117 antibodies, antigen-binding fragments thereof that bind to CD117 (e.g., GNNK+ CD117), expressed on the surface of a cell, such as a cancer cell, an autoimmune cell, or a hematopoietic stem cell, and subsequently causing cell death. Depletion of endogenous hematopoietic stem cells can provide a niche into which transplanted hematopoietic stem cells can enter and subsequently establish productive hematopoiesis. Thus, transplanted hematopoietic stem cells can successfully engraft in a patient, such as a human patient suffering from a stem cell disease described herein.

Antibodies and antigen-binding fragments capable of binding human CD117 (also referred to as c-Kit, NCBI mRNA reference sequence: NM_000222.2, NCBI protein reference sequence: NP_000213.1), including those capable of binding GNNK+ CD117, can be used in combination with the compositions and methods described herein to prepare a patient for hematopoietic stem cell transplantation therapy. Polymorphisms affecting the coding region or extracellular domain of CD117 in a significant percentage of the population are currently poorly known in non-oncologic indications. At least four isoforms of CD117 have been identified, with the potential for additional isoforms to be expressed in tumor cells. Two isoforms of CD117 are located in the intracellular domain of the protein, and two are present in the outer membrane adjacent region. Two extracellular isoforms, GNNK+ and GNNK-, differ in the presence (GNNK+) or absence (GNNK-) of a 4 amino acid sequence. These isoforms are reported to have similar affinity for ligand (SCF), but ligand binding to the GNNK- isoform is reported to increase internalization and degradation. The GNNK+ isoform can be used as an immunogen to generate antibodies capable of binding CD117, since antibodies generated against this isoform will span both GNNK+ and GNNK- proteins. The amino acid sequences of human CD117 isoforms 1 and 2 are described in SEQ ID NOs: 145 and 146, respectively. In certain embodiments, the anti-human CD117 (hCD117) antibodies disclosed herein are capable of binding to both isoform 1 and isoform 2 of human CD117.

As described below, a yeast library of human antibodies was screened to identify novel anti-CD117 antibodies and fragments thereof with diagnostic and therapeutic utility. Antibody 54 (Ab54), antibody 55 (Ab5), antibody 56 (Ab56), antibody 57 (Ab57), antibody 58 (Ab58), antibody 61 (Ab61), antibody 66 (Ab66), antibody 67 (Ab67), antibody 68 (Ab68), and antibody 69 (Ab69) were the human antibodies that were identified in this screen. These antibodies cross-react with human CD117 and rhesus macaque CD117. In addition, the antibodies described herein are capable of binding to both human CD117 isoforms, i.e., isoform 1 (SEQ ID NO: 145) and isoform 2 (SEQ ID NO: 146).

The amino acid sequences for the various binding regions of the CD117 antibodies, including Ab54, Ab55, Ab56, Ab57, Ab58, Ab61, Ab66, Ab67, Ab68, and Ab69, are described in the sequence table below. Included in the present invention are ADCs comprising human CD117 antibodies comprising CDRs as set forth in the sequence table below, as well as human CD117 antibodies comprising variable regions as set forth in the sequence table below.

According to one embodiment, the present invention relates to an ADC comprising an anti-CD117 antibody or antigen-binding fragment thereof comprising binding regions, e.g., CDRs, variable regions, corresponding to those of antibody 55. The amino acid sequence of the heavy chain variable region (VH) of antibody 55 (i.e., Ab55) is set forth in SEQ ID NO: 19 (see Sequence Table). The amino acid sequences of the VH CDR domain of antibody 55 are set forth in SEQ ID NO: 21 (VH CDR1); SEQ ID NO: 22 (VH CDR2) and SEQ ID NO: 23 (VH CDR3). The amino acid sequence of the light chain variable region (VL) of antibody 55 is described in SEQ ID NO: 20 (see Sequence Table). The amino acid sequences of the VL CDR domain of antibody 55 are shown in SEQ ID NO: 24 (VL CDR1); SEQ ID NO: 25 (VL CDR2) and SEQ ID NO: 26 (VL CDR3). The heavy chain constant region of antibody 55 is shown in SEQ ID NO: 122. The light chain constant region of antibody 55 is shown in SEQ ID NO: 121. Thus, in certain embodiments, the anti-CD117 antibody or antigen-binding portion thereof comprises a set of heavy chain variable region CDRs (CDR1, CDR2, and CDR3) as shown in SEQ ID NOs: 21, 22, and 23, and a set of light chain variable region CDRs as shown in SEQ ID NOs: 24, 25, and 26. In other embodiments, the anti-CD117 antibody or antigen-binding portion thereof comprises a light chain variable region comprising the amino acid residues shown in SEQ ID NO: 20 and a heavy chain variable region as shown in SEQ ID NO: 19.

According to one embodiment, the present invention relates to an ADC comprising an anti-CD117 antibody or antigen-binding fragment thereof comprising binding regions, e.g., CDRs, variable regions, corresponding to those of antibody 54. The amino acid sequence of the heavy chain variable region (VH) of antibody 54 (i.e., Ab54) is set forth in SEQ ID NO: 29 (see sequence table). The amino acid sequences of the VH CDR domain of antibody 54 are set forth in SEQ ID NO: 31 (VH CDR1); SEQ ID NO: 32 (VH CDR2) and SEQ ID NO: 33 (VH CDR3). The amino acid sequence of the light chain variable region (VL) of antibody 54 is described in SEQ ID NO: 30 (see sequence table). The amino acid sequences of the VL CDR domain of antibody 54 are shown in SEQ ID NO: 34 (VL CDR1); SEQ ID NO: 35 (VL CDR2) and SEQ ID NO: 36 (VL CDR3). The heavy chain constant region of antibody 54 is shown in SEQ ID NO: 122. The light chain constant region of antibody 54 is shown in SEQ ID NO: 121. Thus, in certain embodiments, the anti-CD117 antibody or antigen-binding portion thereof comprises a set of heavy chain variable CDRs (CDR1, CDR2, and CDR3) as shown in SEQ ID NOs: 31, 32, and 33, and a set of light chain variable CDRs as shown in SEQ ID NOs: 34, 35, and 36. In other embodiments, the anti-CD117 antibody or antigen-binding portion thereof comprises a light chain variable region comprising the amino acid residues shown in SEQ ID NO: 30 and a heavy chain variable region as shown in SEQ ID NO: 29.

According to one embodiment, the present invention relates to an ADC comprising an anti-CD117 antibody or antigen-binding fragment thereof comprising binding regions, e.g., CDRs, variable regions, corresponding to those of antibody 56. The amino acid sequence of the heavy chain variable region (VH) of antibody 56 (i.e., Ab56) is set forth in SEQ ID NO: 39 (see Sequence Table). The amino acid sequences of the VH CDR domain of antibody 56 are set forth in SEQ ID NO: 41 (VH CDR1); SEQ ID NO: 42 (VH CDR2) and SEQ ID NO: 43 (VH CDR3). The amino acid sequence of the light chain variable region (VL) of antibody 56 is described in SEQ ID NO: 40 (see Sequence Table). The amino acid sequences of the VL CDR domain of antibody 56 are shown in SEQ ID NO: 44 (VL CDR1); SEQ ID NO: 45 (VL CDR2) and SEQ ID NO: 46 (VL CDR3). The heavy chain constant region of antibody 56 is shown in SEQ ID NO: 122. The light chain constant region of antibody 56 is shown in SEQ ID NO: 121. Thus, in certain embodiments, the anti-CD117 antibody or antigen-binding portion thereof comprises a set of heavy chain variable region CDRs (CDR1, CDR2, and CDR3) as shown in SEQ ID NOs: 41, 42, and 43, and a set of light chain variable region CDRs as shown in SEQ ID NOs: 44, 45, and 46. In other embodiments, the anti-CD117 antibody or antigen-binding portion thereof comprises a light chain variable region comprising the amino acid residues shown in SEQ ID NO: 40 and a heavy chain variable region as shown in SEQ ID NO: 39.

According to one embodiment, the present invention relates to an ADC comprising an anti-CD117 antibody or antigen-binding fragment thereof comprising binding regions, e.g., CDRs, variable regions, corresponding to those of antibody 57. The amino acid sequence of the heavy chain variable region (VH) of antibody 57 (i.e., Ab57) is set forth in SEQ ID NO: 49 (see sequence table). The amino acid sequences of the VH CDR domain of antibody 57 are set forth in SEQ ID NO: 51 (VH CDR1); SEQ ID NO: 52 (VH CDR2) and SEQ ID NO: 53 (VH CDR3). The amino acid sequence of the light chain variable region (VL) of antibody 57 is described in SEQ ID NO: 50 (see sequence table). The amino acid sequences of the VL CDR domain of antibody 57 are shown in SEQ ID NO: 54 (VL CDR1); SEQ ID NO: 55 (VL CDR2) and SEQ ID NO: 56 (VL CDR3). The heavy chain constant region of antibody 57 is shown in SEQ ID NO: 122. The light chain constant region of antibody 57 is shown in SEQ ID NO: 121. Thus, in certain embodiments, the anti-CD117 antibody or antigen-binding portion thereof comprises a set of heavy chain variable region CDRs (CDR1, CDR2, and CDR3) as shown in SEQ ID NOs: 51, 52, and 53, and a set of light chain variable region CDRs as shown in SEQ ID NOs: 54, 55, and 56. In other embodiments, the anti-CD117 antibody or antigen-binding portion thereof comprises a light chain variable region comprising the amino acid residues shown in SEQ ID NO: 50 and a heavy chain variable region as shown in SEQ ID NO: 49.

According to one embodiment, the present invention relates to an ADC comprising an anti-CD117 antibody or antigen-binding fragment thereof comprising binding regions, e.g., CDRs, variable regions, corresponding to those of antibody 58. The amino acid sequence of the heavy chain variable region (VH) of antibody 58 (i.e., Ab58) is set forth in SEQ ID NO: 59 (see sequence table). The amino acid sequences of the VH CDR domain of antibody 58 are set forth in SEQ ID NO: 61 (VH CDR1); SEQ ID NO: 62 (VH CDR2) and SEQ ID NO: 63 (VH CDR3). The amino acid sequence of the light chain variable region (VL) of antibody 58 is described in SEQ ID NO: 60 (see sequence table). The amino acid sequences of the VL CDR domain of antibody 58 are shown in SEQ ID NO: 64 (VL CDR1); SEQ ID NO: 65 (VL CDR2) and SEQ ID NO: 66 (VL CDR3). The heavy chain constant region of antibody 58 is shown in SEQ ID NO: 122. The light chain constant region of antibody 58 is shown in SEQ ID NO: 121. Thus, in certain embodiments, the anti-CD117 antibody or antigen-binding portion thereof comprises a set of heavy chain variable region CDRs (CDR1, CDR2, and CDR3) as shown in SEQ ID NOs: 61, 62, and 63, and a set of light chain variable region CDRs as shown in SEQ ID NOs: 64, 65, and 66. In other embodiments, the anti-CD117 antibody or antigen-binding portion thereof comprises a light chain variable region comprising the amino acid residues shown in SEQ ID NO: 60 and a heavy chain variable region as shown in SEQ ID NO: 59.

According to one embodiment, the present invention relates to an ADC comprising an anti-CD117 antibody or antigen-binding fragment thereof comprising binding regions, e.g., CDRs, variable regions, corresponding to those of antibody 61. The amino acid sequence of the heavy chain variable region (VH) of antibody 61 (i.e., Ab61) is set forth in SEQ ID NO: 69 (see Sequence Table). The amino acid sequences of the VH CDR domain of antibody 61 are set forth in SEQ ID NO: 71 (VH CDR1); SEQ ID NO: 72 (VH CDR2) and SEQ ID NO: 73 (VH CDR3). The amino acid sequence of the light chain variable region (VL) of antibody 61 is described in SEQ ID NO: 70 (see Sequence Table). The amino acid sequences of the VL CDR domain of antibody 61 are shown in SEQ ID NO: 74 (VL CDR1); SEQ ID NO: 75 (VL CDR2) and SEQ ID NO: 76 (VL CDR3). The heavy chain constant region of antibody 61 is shown in SEQ ID NO: 122. The light chain constant region of antibody 61 is shown in SEQ ID NO: 121. Thus, in certain embodiments, the anti-CD117 antibody or antigen-binding portion thereof comprises a set of heavy chain variable region CDRs (CDR1, CDR2, and CDR3) as shown in SEQ ID NOs: 71, 72, and 73, and a set of light chain variable region CDRs as shown in SEQ ID NOs: 74, 75, and 76. In other embodiments, the anti-CD117 antibody or antigen-binding portion thereof comprises a light chain variable region comprising the amino acid residues shown in SEQ ID NO: 70 and a heavy chain variable region as shown in SEQ ID NO: 69.

According to one embodiment, the present invention relates to an ADC comprising an anti-CD117 antibody or antigen-binding fragment thereof comprising binding regions, e.g., CDRs, variable regions, corresponding to those of antibody 66. The amino acid sequence of the heavy chain variable region (VH) of antibody 66 (i.e., Ab66) is set forth in SEQ ID NO: 79 (see Sequence Table). The amino acid sequences of the VH CDR domain of antibody 66 are set forth in SEQ ID NO: 81 (VH CDR1); SEQ ID NO: 82 (VH CDR2) and SEQ ID NO: 83 (VH CDR3). The amino acid sequence of the light chain variable region (VL) of antibody 66 is described in SEQ ID NO: 80 (see Sequence Table). The amino acid sequences of the VL CDR domain of antibody 66 are shown in SEQ ID NO: 84 (VL CDR1); SEQ ID NO: 85 (VL CDR2) and SEQ ID NO: 86 (VL CDR3). The heavy chain constant region of antibody 66 is shown in SEQ ID NO: 122. The light chain constant region of antibody 66 is shown in SEQ ID NO: 121. Thus, in certain embodiments, the anti-CD117 antibody or antigen-binding portion thereof comprises a set of heavy chain variable region CDRs (CDR1, CDR2, and CDR3) as shown in SEQ ID NOs: 81, 82, and 83, and a set of light chain variable region CDRs as shown in SEQ ID NOs: 84, 85, and 86. In other embodiments, the anti-CD117 antibody or antigen-binding portion thereof comprises a light chain variable region comprising the amino acid residues shown in SEQ ID NO: 80 and a heavy chain variable region as shown in SEQ ID NO: 79.

According to one embodiment, the present invention relates to an ADC comprising an anti-CD117 antibody or antigen-binding fragment thereof comprising binding regions, e.g., CDRs, variable regions, corresponding to those of antibody 67. The amino acid sequence of the heavy chain variable region (VH) of antibody 67 is shown in SEQ ID NO: 9 (see Table 2). The amino acid sequences of the VH CDR domain of antibody 67 are shown in SEQ ID NO: 11 (VH CDR1); SEQ ID NO: 12 (VH CDR2) and SEQ ID NO: 13 (VH CDR3). The amino acid sequence of the light chain variable region (VL) of antibody 67 is described in SEQ ID NO: 10 (see Table 2). The amino acid sequences of the VL CDR domain of antibody 67 are shown in SEQ ID NO: 14 (VL CDR1); SEQ ID NO: 15 (VL CDR2) and SEQ ID NO: 16 (VL CDR3). The full-length heavy chain (HC) of antibody 67 is shown in SEQ ID NO: 110, and the constant region of the full-length heavy chain of antibody 67 is shown in SEQ ID NO: 122. The light chain (LC) of antibody 67 is shown in SEQ ID NO: 109. The constant region of the light chain of antibody 67 is shown in SEQ ID NO: 121. Thus, in certain embodiments, the anti-CD117 antibody or antigen-binding portion thereof comprises a set of heavy chain variable CDRs (CDR1, CDR2, and CDR3) as shown in SEQ ID NOs: 11, 12, and 13, and a set of light chain variable CDRs as shown in SEQ ID NOs: 14, 15, and 16. In other embodiments, the anti-CD117 antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising the amino acid residues shown in SEQ ID NO: 9, and a light chain variable region as depicted in SEQ ID NO: 10. According to additional embodiments, the anti-CD117 antibody comprises a heavy chain comprising SEQ ID NO: 110 and a light chain comprising SEQ ID NO: 109.

According to one embodiment, the present invention relates to an ADC comprising an anti-CD117 antibody or antigen-binding fragment thereof comprising binding regions, e.g., CDRs, variable regions, corresponding to those of antibody 68. The amino acid sequence of the heavy chain variable region (VH) of antibody 68 (i.e., Ab68) is set forth in SEQ ID NO: 89 (see sequence table). The amino acid sequences of the VH CDR domain of antibody 68 are set forth in SEQ ID NO: 91 (VH CDR1); SEQ ID NO: 92 (VH CDR2) and SEQ ID NO: 93 (VH CDR3). The amino acid sequence of the light chain variable region (VL) of antibody 68 is described in SEQ ID NO: 90 (see sequence table). The amino acid sequences of the VL CDR domain of antibody 68 are shown in SEQ ID NO: 94 (VL CDR1); SEQ ID NO: 95 (VL CDR2) and SEQ ID NO: 96 (VL CDR3). The heavy chain constant region of antibody 68 is shown in SEQ ID NO: 122. The light chain constant region of antibody 68 is shown in SEQ ID NO: 121. Thus, in certain embodiments, the anti-CD117 antibody or antigen-binding portion thereof comprises a set of heavy chain variable region CDRs (CDR1, CDR2, and CDR3) as shown in SEQ ID NOs: 91, 92, and 93, and a set of light chain variable region CDRs as shown in SEQ ID NOs: 94, 95, and 96. In other embodiments, the anti-CD117 antibody or antigen-binding portion thereof comprises a light chain variable region comprising the amino acid residues shown in SEQ ID NO: 90 and a heavy chain variable region as shown in SEQ ID NO: 89.

According to one embodiment, the present invention relates to an ADC comprising an anti-CD117 antibody or antigen-binding fragment thereof comprising binding regions, e.g., CDRs, variable regions, corresponding to those of antibody 69. The amino acid sequence of the heavy chain variable region (VH) of antibody 69 (i.e., Ab69) is set forth in SEQ ID NO: 99 (see sequence table). The amino acid sequences of the VH CDR domain of antibody 69 are set forth in SEQ ID NO: 101 (VH CDR1); SEQ ID NO: 102 (VH CDR2) and SEQ ID NO: 103 (VH CDR3). The amino acid sequence of the light chain variable region (VL) of antibody 69 is described in SEQ ID NO: 100 (see sequence table). The amino acid sequences of the VL CDR domain of antibody 69 are shown in SEQ ID NO: 104 (VL CDR1); SEQ ID NO: 105 (VL CDR2) and SEQ ID NO: 106 (VL CDR3). The heavy chain constant region of antibody 69 is shown in SEQ ID NO: 122. The light chain constant region of antibody 69 is shown in SEQ ID NO: 121. Thus, in certain embodiments, the anti-CD117 antibody or antigen-binding portion thereof comprises a set of heavy chain variable region CDRs (CDR1, CDR2, and CDR3) as shown in SEQ ID NOs: 101, 102, and 103, and a set of light chain variable region CDRs as shown in SEQ ID NOs: 104, 105, and 106. In other embodiments, the anti-CD117 antibody or antigen-binding portion thereof comprises a light chain variable region comprising the amino acid residues shown in SEQ ID NO: 100 and a heavy chain variable region as shown in SEQ ID NO: 99.

In addition, the amino acid sequences for the various binding regions of the CD117 antibodies Ab77, Ab79, Ab81, Ab85, Ab86, Ab87, Ab88, and Ab89 are described in the sequence table provided below. Anti-CD117 antibodies characterized by these sequences can also be used in the ADCs described herein.

According to one embodiment, the present invention relates to an ADC comprising an anti-CD117 antibody or antigen-binding fragment thereof comprising binding regions, e.g., CDRs, variable regions, corresponding to those of antibody 77. The amino acid sequence of the heavy chain variable region (VH) of antibody 77 (i.e., Ab77) is set forth in SEQ ID NO: 147 (see Sequence Table). The amino acid sequences of the VH CDR domain of antibody 77 are set forth in SEQ ID NO: 263 (VH CDR1); SEQ ID NO: 2 (VH CDR2) and SEQ ID NO: 3 (VH CDR3). The amino acid sequence of the light chain variable region (VL) of antibody 77 is described in SEQ ID NO: 231 (see Sequence Table). The amino acid sequences of the VL CDR domain of antibody 77 are shown in SEQ ID NO: 264 (VL CDR1); SEQ ID NO: 265 (VL CDR2) and SEQ ID NO: 266 (VL CDR3). The heavy chain constant region of antibody 77 is shown in SEQ ID NO: 269. The light chain constant region of antibody 77 is shown in SEQ ID NO: 283. Thus, in certain embodiments, the anti-CD117 antibody or antigen-binding portion thereof comprises a set of heavy chain variable region CDRs (CDR1, CDR2, and CDR3) as shown in SEQ ID NOs: 263, 2, and 3, and a set of light chain variable region CDRs as shown in SEQ ID NOs: 264, 265, and 266. In other embodiments, the anti-CD117 antibody or antigen-binding portion thereof comprises a light chain variable region comprising the amino acid residues shown in SEQ ID NO: 231 and a heavy chain variable region as shown in SEQ ID NO: 147.

According to one embodiment, the present invention relates to an ADC comprising an anti-CD117 antibody or antigen-binding fragment thereof comprising binding regions, e.g., CDRs, variable regions, corresponding to those of antibody 79. The amino acid sequence of the heavy chain variable region (VH) of antibody 79 (i.e., Ab79) is set forth in SEQ ID NO: 147 (see Sequence Table). The amino acid sequences of the VH CDR domain of antibody 79 are set forth in SEQ ID NO: 263 (VH CDR1); SEQ ID NO: 2 (VH CDR2) and SEQ ID NO: 3 (VH CDR3). The amino acid sequence of the light chain variable region (VL) of antibody 79 is described in SEQ ID NO: 233 (see Sequence Table). The amino acid sequences of the VL CDR domain of antibody 79 are shown in SEQ ID NO: 267 (VL CDR1); SEQ ID NO: 265 (VL CDR2) and SEQ ID NO: 266 (VL CDR3). The heavy chain constant region of antibody 79 is shown in SEQ ID NO: 269. The light chain constant region of antibody 79 is shown in SEQ ID NO: 283. Thus, in certain embodiments, the anti-CD117 antibody or antigen-binding portion thereof comprises a set of heavy chain variable region CDRs (CDR1, CDR2, and CDR3) as shown in SEQ ID NOs: 263, 2, and 3, and a set of light chain variable region CDRs as shown in SEQ ID NOs: 267, 265, and 266. In other embodiments, the anti-CD117 antibody or antigen-binding portion thereof comprises a light chain variable region comprising the amino acid residues shown in SEQ ID NO: 233 and a heavy chain variable region as shown in SEQ ID NO: 147.

According to one embodiment, the present invention relates to an ADC comprising an anti-CD117 antibody or antigen-binding fragment thereof comprising binding regions, e.g., CDRs, variable regions, corresponding to those of antibody 81. The amino acid sequence of the heavy chain variable region (VH) of antibody 81 (i.e., Ab81) is set forth in SEQ ID NO: 147 (see Sequence Table). The amino acid sequences of the VH CDR domain of antibody 81 are set forth in SEQ ID NO: 263 (VH CDR1); SEQ ID NO: 2 (VH CDR2) and SEQ ID NO: 3 (VH CDR3). The amino acid sequence of the light chain variable region (VL) of antibody 81 is described in SEQ ID NO: 235 (see Sequence Table). The amino acid sequences of the VL CDR domain of antibody 81 are shown in SEQ ID NO: 264 (VL CDR1); SEQ ID NO: 268 (VL CDR2) and SEQ ID NO: 266 (VL CDR3). The heavy chain constant region of antibody 81 is shown in SEQ ID NO: 269. The light chain constant region of antibody 81 is shown in SEQ ID NO: 283. Thus, in certain embodiments, the anti-CD117 antibody or antigen-binding portion thereof comprises a set of heavy chain variable region CDRs (CDR1, CDR2, and CDR3) as shown in SEQ ID NOs: 263, 2, and 3, and a set of light chain variable region CDRs as shown in SEQ ID NOs: 264, 268, and 266. In other embodiments, the anti-CD117 antibody or antigen-binding portion thereof comprises a light chain variable region comprising the amino acid residues shown in SEQ ID NO: 235 and a heavy chain variable region as shown in SEQ ID NO: 147.

In one embodiment, the present invention relates to an ADC comprising an anti-CD117 antibody or antigen-binding fragment thereof comprising binding regions, e.g., CDRs, variable regions, corresponding to those of antibody 85. The amino acid sequence of the heavy chain variable region (VH) of antibody 85 (i.e., Ab86) is set forth in SEQ ID NO: 243 (see Sequence Table). The amino acid sequences of the VH CDR domain of antibody 85 are set forth in SEQ ID NO: 245 (VH CDR1); SEQ ID NO: 246 (VH CDR2) and SEQ ID NO: 247 (VH CDR3). The amino acid sequence of the light chain variable region (VL) of antibody 85 is described in SEQ ID NO: 242 (see Sequence Table). The amino acid sequences of the VL CDR domain of antibody 85 are shown in SEQ ID NO: 248 (VL CDR1); SEQ ID NO: 249 (VL CDR2) and SEQ ID NO: 250 (VL CDR3). The heavy chain constant region of antibody 85 is shown in SEQ ID NO: 269. The light chain constant region of antibody 85 is shown in SEQ ID NO: 283. Thus, in certain embodiments, the anti-CD117 antibody or antigen-binding portion thereof comprises a set of heavy chain variable region CDRs (CDR1, CDR2, and CDR3) as shown in SEQ ID NOs: 245, 246, and 247, and a set of light chain variable region CDRs as shown in SEQ ID NOs: 248, 249, and 250. In other embodiments, the anti-CD117 antibody or antigen-binding portion thereof comprises a light chain variable region comprising the amino acid residues shown in SEQ ID NO: 244 and a heavy chain variable region as shown in SEQ ID NO: 243.

In one embodiment, the present invention relates to an ADC comprising an anti-CD117 antibody or antigen-binding fragment thereof comprising binding regions, e.g., CDRs, variable regions, corresponding to those of antibody 86. The amino acid sequence of the heavy chain variable region (VH) of antibody 86 (i.e., Ab86) is set forth in SEQ ID NO: 251 (see Sequence Table). The amino acid sequences of the VH CDR domain of antibody 86 are set forth in SEQ ID NO: 245 (VH CDR1); SEQ ID NO: 253 (VH CDR2) and SEQ ID NO: 3 (VH CDR3). The amino acid sequence of the light chain variable region (VL) of antibody 86 is described in SEQ ID NO: 252 (see Sequence Table). The amino acid sequences of the VL CDR domain of antibody 86 are shown in SEQ ID NO: 254 (VL CDR1); SEQ ID NO: 249 (VL CDR2) and SEQ ID NO: 255 (VL CDR3). The heavy chain constant region of antibody 86 is shown in SEQ ID NO: 269. The light chain constant region of antibody 86 is shown in SEQ ID NO: 283. Thus, in certain embodiments, the anti-CD117 antibody or antigen-binding portion thereof comprises a set of heavy chain variable region CDRs (CDR1, CDR2, and CDR3) as shown in SEQ ID NOs: 245, 253, and 3, and a set of light chain variable region CDRs as shown in SEQ ID NOs: 254, 249, and 255. In other embodiments, the anti-CD117 antibody or antigen-binding portion thereof comprises a light chain variable region comprising the amino acid residues shown in SEQ ID NO: 252 and a heavy chain variable region as shown in SEQ ID NO: 251.

According to one embodiment, the present invention relates to an ADC comprising an anti-CD117 antibody or antigen-binding fragment thereof comprising binding regions, e.g., CDRs, variable regions, corresponding to those of antibody 87. The amino acid sequence of the heavy chain variable region (VH) of antibody 87 (i.e., Ab87) is set forth in SEQ ID NO: 243 (see Sequence Table). The amino acid sequences of the VH CDR domain of antibody 87 are set forth in SEQ ID NO: 245 (VH CDR1); SEQ ID NO: 246 (VH CDR2) and SEQ ID NO: 247 (VH CDR3). The amino acid sequence of the light chain variable region (VL) of antibody 87 is described in SEQ ID NO: 256 (see Sequence Table). The amino acid sequences of the VL CDR domain of antibody 87 are shown in SEQ ID NO: 257 (VL CDR1); SEQ ID NO: 5 (VL CDR2) and SEQ ID NO: 255 (VL CDR3). The heavy chain constant region of antibody 87 is shown in SEQ ID NO: 269. The light chain constant region of antibody 87 is shown in SEQ ID NO: 283. Thus, in certain embodiments, the anti-CD117 antibody or antigen-binding portion thereof comprises a set of heavy chain variable region CDRs (CDR1, CDR2, and CDR3) as shown in SEQ ID NOs: 245, 246, and 247, and a set of light chain variable region CDRs as shown in SEQ ID NOs: 257, 5, and 255. In other embodiments, the anti-CD117 antibody or antigen-binding portion thereof comprises a light chain variable region comprising the amino acid residues shown in SEQ ID NO: 256 and a heavy chain variable region as shown in SEQ ID NO: 243.

According to one embodiment, the present invention relates to an ADC comprising an anti-CD117 antibody or antigen-binding fragment thereof comprising binding regions, e.g., CDRs, variable regions, corresponding to those of antibody 88. The amino acid sequence of the heavy chain variable region (VH) of antibody 88 (i.e., Ab88) is set forth in SEQ ID NO: 258 (see Sequence Table). The amino acid sequences of the VH CDR domain of antibody 88 are set forth in SEQ ID NO: 245 (VH CDR1); SEQ ID NO: 259 (VH CDR2) and SEQ ID NO: 3 (VH CDR3). The amino acid sequence of the light chain variable region (VL) of antibody 88 is described in SEQ ID NO: 256 (see Sequence Table). The amino acid sequences of the VL CDR domain of antibody 88 are shown in SEQ ID NO: 257 (VL CDR1); SEQ ID NO: 5 (VL CDR2) and SEQ ID NO: 255 (VL CDR3). The heavy chain constant region of antibody 88 is shown in SEQ ID NO: 269. The light chain constant region of antibody 88 is shown in SEQ ID NO: 283. Thus, in certain embodiments, the anti-CD117 antibody or antigen-binding portion thereof comprises a set of heavy chain variable region CDRs (CDR1, CDR2, and CDR3) as shown in SEQ ID NOs: 245, 259, and 3, and a set of light chain variable region CDRs as shown in SEQ ID NOs: 257, 5, and 255. In other embodiments, the anti-CD117 antibody or antigen-binding portion thereof comprises a light chain variable region comprising the amino acid residues shown in SEQ ID NO: 256 and a heavy chain variable region as shown in SEQ ID NO: 258.

According to one embodiment, the present invention relates to an ADC comprising an anti-CD117 antibody or antigen-binding fragment thereof comprising binding regions, e.g., CDRs, variable regions, corresponding to those of antibody 89. The amino acid sequence of the heavy chain variable region (VH) of antibody 89 (i.e., Ab89) is set forth in SEQ ID NO: 260 (see Sequence Table). The amino acid sequences of the VH CDR domain of antibody 89 are set forth in SEQ ID NO: 245 (VH CDR1); SEQ ID NO: 2 (VH CDR2) and SEQ ID NO: 3 (VH CDR3). The amino acid sequence of the light chain variable region (VL) of antibody 89 is described in SEQ ID NO: 252 (see Sequence Table). The amino acid sequences of the VL CDR domain of antibody 89 are shown in SEQ ID NO: 254 (VL CDR1); SEQ ID NO: 249 (VL CDR2) and SEQ ID NO: 255 (VL CDR3). The heavy chain constant region of antibody 89 is shown in SEQ ID NO: 269. The light chain constant region of antibody 89 is shown in SEQ ID NO: 283. Thus, in certain embodiments, the anti-CD117 antibody or antigen-binding portion thereof comprises a set of heavy chain variable region CDRs (CDR1, CDR2, and CDR3) as shown in SEQ ID NOs: 245, 2, and 3, and a set of light chain variable region CDRs as shown in SEQ ID NOs: 254, 249, and 255. In other embodiments, the anti-CD117 antibody or antigen-binding portion thereof comprises a light chain variable region comprising the amino acid residues shown in SEQ ID NO: 252 and a heavy chain variable region as shown in SEQ ID NO: 260.

According to one embodiment, the present invention relates to an ADC comprising an anti-CD117 antibody or antigen-binding fragment thereof comprising binding regions, e.g., CDRs, variable regions, corresponding to those of antibody 249. The amino acid sequence of the heavy chain variable region (VH) of antibody 249 (i.e., Ab249) is set forth in SEQ ID NO: 238 (see Sequence Table). The amino acid sequences of the VH CDR domain of antibody 249 are set forth in SEQ ID NO: 286 (VH CDR1); SEQ ID NO: 2 (VH CDR2) and SEQ ID NO: 287 (VH CDR3). The amino acid sequence of the light chain variable region (VL) of antibody 249 is described in SEQ ID NO: 242 (see Sequence Table). The amino acid sequences of the VL CDR domain of antibody 249 are shown in SEQ ID NO: 288 (VL CDR1); SEQ ID NO: 249 (VL CDR2) and SEQ ID NO: 289 (VL CDR3). The heavy chain constant region of antibody 249 is shown in SEQ ID NO: 269. The light chain constant region of antibody 249 is shown in SEQ ID NO: 283. Thus, in certain embodiments, the anti-CD117 antibody or antigen-binding portion thereof comprises a set of heavy chain variable region CDRs (CDR1, CDR2, and CDR3) as shown in SEQ ID NOs: 286, 2, and 287, and a set of light chain variable region CDRs as shown in SEQ ID NOs: 288, 249, and 289. In other embodiments, the anti-CD117 antibody or antigen-binding portion thereof comprises a light chain variable region comprising the amino acid residues shown in SEQ ID NO: 242 and a heavy chain variable region as shown in SEQ ID NO: 238.

Also included in the present disclosure are anti-CD117 antibody drug conjugates (ADCs) comprising binding regions (heavy and light chain CDRs, or variable regions) as depicted in SEQ ID NOs: 147-168. In one embodiment, the anti-CD117 antibody or antigen-binding portion thereof comprises a heavy chain variable region as depicted in the amino acid sequence of SEQ ID NO: 147 and a light chain variable region as depicted in the amino acid sequence of SEQ ID NO: 148. In one embodiment, the anti-CD117 antibody or antigen-binding portion thereof comprises a heavy chain variable region as depicted in the amino acid sequence of SEQ ID NO: 147 and a light chain variable region as depicted in the amino acid sequence of SEQ ID NO: 149. In one embodiment, the anti-CD117 antibody or antigen-binding portion thereof comprises a heavy chain variable region as shown in the amino acid sequence of SEQ ID NO: 147, and a light chain variable region as shown in the amino acid sequence of SEQ ID NO: 150. In one embodiment, the anti-CD117 antibody or antigen-binding portion thereof comprises a heavy chain variable region as shown in the amino acid sequence of SEQ ID NO: 147 and a light chain variable region as shown in the amino acid sequence of SEQ ID NO: 151. In one embodiment, the anti-CD117 antibody or antigen-binding portion thereof comprises a heavy chain variable region as shown in the amino acid sequence of SEQ ID NO: 147 and a light chain variable region as shown in the amino acid sequence of SEQ ID NO: 152. In one embodiment, the anti-CD117 antibody or antigen-binding portion thereof comprises a heavy chain variable region as shown in the amino acid sequence of the amino acid sequence of SEQ ID NO: 147, and a light chain variable region as shown in the amino acid sequence of SEQ ID NO: 153. In one embodiment, the anti-CD117 antibody or antigen-binding portion thereof comprises a heavy chain variable region as shown in the amino acid sequence of SEQ ID NO: 147, and a light chain variable region as shown in the amino acid sequence of SEQ ID NO: 154. In one embodiment, the anti-CD117 antibody or antigen-binding portion thereof comprises a heavy chain variable region as shown in the amino acid sequence of SEQ ID NO: 147, and a light chain variable region as shown in the amino acid sequence of SEQ ID NO: 155. In one embodiment, the anti-CD117 antibody or antigen-binding portion thereof comprises a heavy chain variable region as shown in the amino acid sequence of SEQ ID NO: 147, and a light chain variable region as shown in the amino acid sequence of SEQ ID NO: 156. In one embodiment, the anti-CD117 antibody or antigen-binding portion thereof comprises a heavy chain variable region as shown in the amino acid sequence of SEQ ID NO: 147 and a light chain variable region as shown in the amino acid sequence of SEQ ID NO: 157. In one embodiment, the anti-CD117 antibody or antigen-binding portion thereof comprises a heavy chain variable region as shown in the amino acid sequence of SEQ ID NO: 147 and a light chain variable region as shown in the amino acid sequence of SEQ ID NO: 158. In one embodiment, the anti-CD117 antibody or antigen-binding portion thereof comprises a heavy chain variable region as shown in the amino acid sequence of SEQ ID NO: 147 and a light chain variable region as shown in the amino acid sequence of SEQ ID NO: sequence according to SEQ ID NO: 159. In one embodiment, the anti-CD117 antibody or antigen-binding portion thereof comprises a heavy chain variable region as shown in the amino acid sequence according to SEQ ID NO: 147 and a light chain variable region as shown in the amino acid sequence according to SEQ ID NO: 160. In one embodiment, the anti-CD117 antibody or antigen-binding portion thereof comprises a heavy chain variable region as shown in the amino acid sequence according to SEQ ID NO: 147 and a light chain variable region as shown in the amino acid sequence according to SEQ ID NO: 161. In one embodiment, the anti-CD117 antibody or antigen-binding portion thereof comprises a heavy chain variable region as shown in the amino acid sequence according to SEQ ID NO: 147 and a light chain variable region as shown in the amino acid sequence according to SEQ ID NO: 162. In one embodiment, the anti-CD117 antibody or antigen-binding portion thereof comprises a heavy chain variable region as shown in the amino acid sequence according to SEQ ID NO: 147 and a light chain variable region as shown in the amino acid sequence according to SEQ ID NO: 162. In one embodiment, the anti-CD117 antibody or antigen-binding portion thereof comprises a heavy chain variable region as shown in the amino acid sequence of SEQ ID NO: 147 and a light chain variable region as shown in the amino acid sequence of SEQ ID NO: 163. In one embodiment, the anti-CD117 antibody or antigen-binding portion thereof comprises a heavy chain variable region as shown in the amino acid sequence of SEQ ID NO: 164 and a light chain variable region as shown in the amino acid sequence of SEQ ID NO: 165. In one embodiment, the anti-CD117 antibody or antigen-binding portion thereof comprises a heavy chain variable region as shown in the amino acid sequence of SEQ ID NO: 166 and a light chain variable region as shown in the amino acid sequence of SEQ ID NO: 167. In one embodiment, the anti-CD117 antibody or antigen-binding portion thereof comprises a heavy chain variable region as shown in the amino acid sequence of SEQ ID NO: 167. the antigen-binding portion comprises a heavy chain variable region as shown in the amino acid sequence of SEQ ID NO: 168 and a light chain variable region as shown in the amino acid sequence of SEQ ID NO: 169. In one embodiment, the anti-CD117 antibody or antigen-binding portion thereof comprises a heavy chain variable region as shown in the amino acid sequence of SEQ ID NO: 170 and a light chain variable region as shown in the amino acid sequence of SEQ ID NO: 171. In one embodiment, the anti-CD117 antibody or antigen-binding portion thereof comprises a heavy chain variable region as shown in the amino acid sequence of SEQ ID NO: 172 and a light chain variable region as shown in the amino acid sequence of SEQ ID NO: 173. In one embodiment, the anti-CD117 antibody or antigen-binding portion thereof comprises a heavy chain variable region, as shown in the amino acid sequence of SEQ ID NO: 174, and a light chain variable region as shown in the amino acid sequence of SEQ ID NO: 175. In one embodiment, the anti-CD117 antibody or antigen-binding portion thereof comprises a heavy chain variable region as shown in the amino acid sequence of SEQ ID NO: 176 and a light chain variable region as shown in the amino acid sequence of SEQ ID NO: 177. In one embodiment, the anti-CD117 antibody or antigen-binding portion thereof comprises a heavy chain variable region as shown in the amino acid sequence of SEQ ID NO: 178 and a light chain variable region as shown in the amino acid sequence of SEQ ID NO: 179. In one embodiment, the anti-CD117 antibody or antigen-binding portion thereof comprises a heavy chain variable region as shown in the amino acid sequence of SEQ ID NO: 180, and a light chain variable region as shown in the amino acid sequence according to SEQ ID NO: 181. According to one embodiment, the anti-CD117 antibody or antigen-binding portion thereof comprises a heavy chain variable region as shown in the amino acid sequence according to SEQ ID NO: 172, and a light chain variable region as shown in the amino acid sequence according to SEQ ID NO: 182. According to one embodiment, the anti-CD117 antibody or antigen-binding portion thereof comprises a heavy chain variable region as shown in the amino acid sequence according to SEQ ID NO: 183, and a light chain variable region as shown in the amino acid sequence according to SEQ ID NO: 184. In one embodiment, the anti-CD117 antibody or antigen-binding portion thereof comprises a heavy chain variable region as shown in the amino acid sequence of SEQ ID NO: 185 and a light chain variable region as shown in the amino acid sequence of SEQ ID NO: 186. In one embodiment, the anti-CD117 antibody or antigen-binding portion thereof comprises a heavy chain variable region as shown in the amino acid sequence of SEQ ID NO: 187 and a light chain variable region as shown in the amino acid sequence of SEQ ID NO: 188. In one embodiment, the anti-CD117 antibody or antigen-binding portion thereof comprises a heavy chain variable region as shown in the amino acid sequence of SEQ ID NO: 189 and a light chain variable region as shown in the amino acid sequence of SEQ ID NO: 190. In one embodiment, the anti-CD117 antibody or an antigen-binding portion thereof comprises a heavy chain variable region as shown in the amino acid sequence of SEQ ID NO: 191 and a light chain variable region as shown in the amino acid sequence of SEQ ID NO: 192. In one embodiment, the anti-CD117 antibody or antigen-binding portion thereof comprises a heavy chain variable region as shown in the amino acid sequence of SEQ ID NO: 193 and a light chain variable region as shown in the amino acid sequence of SEQ ID NO: 194. In one embodiment, the anti-CD117 antibody or antigen-binding portion thereof comprises a heavy chain variable region as shown in the amino acid sequence of SEQ ID NO: 195 and a light chain variable region as shown in the amino acid sequence of SEQ ID NO: 196. In one embodiment, the anti-CD117 antibody or antigen-binding portion thereof comprises a heavy chain variable region chain as shown in the amino acid sequence of SEQ ID NO: 197, and a light chain variable region as shown in the amino acid sequence of SEQ ID NO: 198. In one embodiment, the anti-CD117 antibody or antigen-binding portion thereof comprises a heavy chain variable region as shown in the amino acid sequence of SEQ ID NO: 199 and a light chain variable region as shown in the amino acid sequence of SEQ ID NO: 200. In one embodiment, the anti-CD117 antibody or antigen-binding portion thereof comprises a heavy chain variable region as shown in the amino acid sequence of SEQ ID NO: 201 and a light chain variable region as shown in the amino acid sequence of SEQ ID NO: 190. In one embodiment, the anti-CD117 antibody or antigen-binding portion thereof comprises a heavy chain variable region as shown in the amino acid sequence of SEQ ID NO: 202, and a light chain variable region as shown in the amino acid sequence of SEQ ID NO: 203. In one embodiment, the anti-CD117 antibody or antigen-binding portion thereof comprises a heavy chain variable region as shown in the amino acid sequence of SEQ ID NO: 204 and a light chain variable region as shown in the amino acid sequence of SEQ ID NO: 205. In one embodiment, the anti-CD117 antibody or antigen-binding portion thereof comprises a heavy chain variable region as shown in the amino acid sequence of SEQ ID NO: 206 and a light chain variable region as shown in the amino acid sequence of SEQ ID NO: 207. In one embodiment, the anti-CD117 antibody or antigen-binding portion thereof comprises a heavy chain variable region as shown in the amino acid sequence of SEQ ID NO: 208 and a light chain variable region chain as shown in the amino acid sequence of SEQ ID NO: 209. In one embodiment, the anti-CD117 antibody or antigen-binding portion thereof comprises a heavy chain variable region as shown in the amino acid sequence of SEQ ID NO: 210 and a light chain variable region as shown in the amino acid sequence of SEQ ID NO: 211. In one embodiment, the anti-CD117 antibody or antigen-binding portion thereof comprises a heavy chain variable region as shown in the amino acid sequence of SEQ ID NO: 212 and a light chain variable region as shown in the amino acid sequence of SEQ ID NO: 213. In one embodiment, the anti-CD117 antibody or antigen-binding portion thereof comprises a heavy chain variable region as shown in the amino acid sequence of SEQ ID NO: 214 and a light chain variable region as shown in the amino acid sequence of SEQ ID NO: 215. In one embodiment, the anti-CD117 antibody or antigen-binding portion thereof comprises a heavy chain variable region as shown in the amino acid sequence of SEQ ID NO: 216 and a light chain variable region as shown in the amino acid sequence of SEQ ID NO: 217. In one embodiment, the anti-CD117 antibody or antigen-binding portion thereof comprises a heavy chain variable region as shown in the amino acid sequence of SEQ ID NO: 218 and a light chain variable region as shown in the amino acid sequence of SEQ ID NO: 219. In one embodiment, the anti-CD117 antibody or antigen-binding portion thereof comprises a heavy chain variable region as shown in the amino acid sequence of SEQ ID NO: 220 and a light chain variable region as shown in the amino acid sequence of SEQ ID NO: 221. In one embodiment, the anti-CD117 antibody CD117 or an antigen-binding portion thereof comprises a heavy chain variable region as shown in the amino acid sequence of SEQ ID NO: 222 and a light chain variable region as shown in the amino acid sequence of SEQ ID NO: 223. In one embodiment, the anti-CD117 antibody or antigen-binding portion thereof comprises a heavy chain variable region as shown in the amino acid sequence of SEQ ID NO: 224 and a light chain variable region as shown in the amino acid sequence of SEQ ID NO: 225. In one embodiment, the anti-CD117 antibody or antigen-binding portion thereof comprises a heavy chain variable region as shown in the amino acid sequence of SEQ ID NO: 226 and a light chain variable region as shown in the amino acid sequence of SEQ ID NO: 227. In one embodiment, the anti-CD117 antibody or antigen-binding portion thereof comprises a heavy chain variable region as shown in the amino acid sequence of SEQ ID NO: 147, and a light chain variable region as shown in the amino acid sequence of SEQ ID NO: 228. In one embodiment, the anti-CD117 antibody or antigen-binding portion thereof comprises a heavy chain variable region as shown in the amino acid sequence of SEQ ID NO: 147 and a light chain variable region as shown in the amino acid sequence of SEQ ID NO: 229. In one embodiment, the anti-CD117 antibody or antigen-binding portion thereof comprises a heavy chain variable region as shown in the amino acid sequence of SEQ ID NO: 147 and a light chain variable region as shown in the amino acid sequence of SEQ ID NO: 230. In one embodiment, the anti-CD117 antibody or antigen-binding portion thereof comprises a heavy chain variable region as shown in the amino acid sequence of sequence according to SEQ ID NO: 147, and a light chain variable region as shown in the amino acid sequence according to SEQ ID NO: 231. In one embodiment, the anti-CD117 antibody or antigen-binding portion thereof comprises a heavy chain variable region as shown in the amino acid sequence according to SEQ ID NO: 147, and a light chain variable region as shown in the amino acid sequence according to SEQ ID NO: 232. In one embodiment, the anti-CD117 antibody or antigen-binding portion thereof comprises a heavy chain variable region as shown in the amino acid sequence according to SEQ ID NO: 147, and a light chain variable region as shown in the amino acid sequence according to SEQ ID NO: 233. In one embodiment, the anti-CD117 antibody or antigen-binding portion thereof comprises a heavy chain variable region as shown in the amino acid sequence of SEQ ID NO: 147 and a light chain variable region as shown in the amino acid sequence of SEQ ID NO: 234. In one embodiment, the anti-CD117 antibody or antigen-binding portion thereof comprises a heavy chain variable region as shown in the amino acid sequence of SEQ ID NO: 147 and a light chain variable region as shown in the amino acid sequence of SEQ ID NO: 235. In one embodiment, the anti-CD117 antibody or antigen-binding portion thereof comprises a heavy chain variable region as shown in the amino acid sequence of SEQ ID NO: 147 and a light chain variable region as shown in the amino acid sequence of SEQ ID NO: 236.

In one embodiment, an anti-CD117 antibody or antigen-binding portion thereof of an ADC described herein comprises a heavy chain variable region as shown in the amino acid sequence of SEQ ID NO: 147 and a light chain variable region as shown in the amino acid sequence of SEQ ID NO: 237. In one embodiment, an anti-CD117 antibody or antigen-binding portion thereof comprises a heavy chain variable region as shown in the amino acid sequence of SEQ ID NO: 243 and a light chain variable region as shown in the amino acid sequence of SEQ ID NO: 244. In one embodiment, an anti-CD117 antibody or antigen-binding portion thereof comprises a heavy chain variable region as shown in the amino acid sequence of SEQ ID NO: 251 and a light chain variable region as shown in the amino acid sequence of SEQ ID NO: 252. In one embodiment, an anti-CD117 antibody or antigen-binding portion thereof comprises a heavy chain variable region as shown in the amino acid sequence of SEQ ID NO: 253 and a light chain variable region as shown in the amino acid sequence of SEQ ID NO: 254. In one embodiment, the anti-CD117 antibody or antigen-binding portion thereof comprises a heavy chain variable region as shown in the amino acid sequence of SEQ ID NO: 243 and a light chain variable region as shown in the amino acid sequence of SEQ ID NO: 256. In one embodiment, the anti-CD117 antibody or antigen-binding portion thereof comprises a heavy chain variable region as shown in the amino acid sequence of SEQ ID NO: 258 and a light chain variable region as shown in the amino acid sequence of SEQ ID NO: 256. In one embodiment, the anti-CD117 antibody or antigen-binding portion thereof comprises a heavy chain variable region as shown in the amino acid sequence of SEQ ID NO: 260 and a light chain variable region as shown in the amino acid sequence of SEQ ID NO: 252. In one embodiment, the anti-CD117 antibody or antigen-binding portion thereof comprises a heavy chain variable region as shown in the amino acid sequence of SEQ ID NO: 258 and a light chain variable region as shown in the amino acid sequence of SEQ ID NO: 256. the antigen-binding portion comprises a heavy chain variable region as shown in the amino acid sequence of SEQ ID NO: 238 and a light chain variable region as shown in the amino acid sequence of SEQ ID NO: 239. In one embodiment, the anti-CD117 antibody or antigen-binding portion thereof comprises a heavy chain variable region as shown in the amino acid sequence of SEQ ID NO: 147 and a light chain variable region as shown in the amino acid sequence of SEQ ID NO: 239. In one embodiment, the anti-CD117 antibody or antigen-binding portion thereof comprises a heavy chain variable region as shown in the amino acid sequence of SEQ ID NO: 147 and a light chain variable region as shown in the amino acid sequence of SEQ ID NO: 240. In one embodiment, the anti-CD117 antibody or antigen-binding portion thereof comprises a heavy chain variable region, as shown in the amino acid sequence according to SEQ ID NO: 238, and a light chain variable region as shown in the amino acid sequence according to SEQ ID NO: 241. According to one embodiment, the anti-CD117 antibody or antigen-binding portion thereof comprises a heavy chain variable region as shown in the amino acid sequence according to SEQ ID NO: 238, and a light chain variable region as shown in the amino acid sequence according to SEQ ID NO: 242.

Some of the CD117 antibodies described herein are neutral antibodies, in that the antibodies do not significantly inhibit CD117 activity in a cell expressing CD117. Neutral antibodies can be identified, for example, using an in vitro stem cell factor (SCF)-dependent cell proliferation assay. In an SCF-dependent cell proliferation assay, a neutral anti-CD117 antibody will not kill CD34+ cells that depend on SCF to divide, since the neutral antibody will not block SCF binding to CD117, for example, to inhibit CD117 activity.

Neutral antibodies can be used for diagnostic purposes given their ability to specifically bind to human CD117, but they are also effective in killing CD117-expressing cells when conjugated to a cytotoxin such as those described herein. Typically, antibodies used in conjugates have agonist or antagonist activity unique to the antibody. However, this document describes a unique approach to conjugates, particularly in the context where the conjugate is used as a conditioning agent prior to stem cell transplantation. Although antagonist antibodies alone or in combination with a cytotoxin as a conjugate may be effective given the killing capacity of the antibody alone in addition to the cytotoxin, conditioning with a conjugate containing a neutral anti-CD117 antibody represents an alternative strategy in which the activity of the antibody is secondary to the action of the cytotoxin, but the internalization and affinity characteristics, such as off-rate, of the antibody are important for efficient delivery of the cytotoxin.

Examples of neutral anti-CD117 antibodies include Ab58, Ab61, Ab66, Ab67, Ab68, and Ab69. Comparison of the amino acid sequences of the CDRs of the neutral anti-CD117 antibodies reveals consensus sequences between the two groups of identified neutral antibodies. Ab58 and Ab61 have the same light chain CDRs and HC CDR3 with minor variations in HC CDR1 and HC CDR2. The consensus sequences for HC CDR1 and CDR2 are described in SEQ ID NOS: 133 and 134. Ab66, Ab67, Ab68, and Ab69 are also neutral antibodies. Although Ab66, Ab67, Ab68, and Ab69 have the same light chain CDRs and the same HC CDR3, these antibodies have variability within their HC CDR1 and HC CDR2 regions. The consensus sequences for these antibodies in the HC CDR1 and HC CDR2 regions are shown in SEQ ID NOs: 139 and 140, respectively.

Also provided herein are antagonist antibodies, including Ab54, Ab55, Ab56, and Ab57. Although Ab54, Ab55, Ab56, and Ab57 have the same light chain CDRs and the same HC CDR3, these antibodies have variability within their HC CDR1 and HC CDR2 regions. The consensus sequences for these antibodies in the HC CDR1 and HC CDR2 regions are provided in SEQ ID NOs: 127 and 128, respectively.

In one embodiment, the anti-CD117 antibody or antigen-binding fragment thereof comprises variable regions with an amino acid sequence that is at least 95%, 96%, 97%, or 99% identical to SEQ ID NO disclosed herein. Alternatively, the anti-CD117 antibody or antigen-binding fragment thereof comprises CDRs comprising SEQ ID NO disclosed herein with framework regions of the variable regions described herein with an amino acid sequence that is at least 95%, 96%, 97%, or 99% identical to SEQ ID NO disclosed herein.

The anti-CD117 antibodies described herein may be in the form of full-length antibodies, bispecific antibodies, dual variable domain antibodies, multichain or single-chain antibodies and/or binding fragments that specifically bind human CD117, including, but not limited to, Fab, Fab', (Fab')2, Fv), scFv (single chain Fv), surrobodies (including a surrogate light chain construct), single domain antibodies, camel antibodies, and the like. They may also be of or derived from any isotype, including, for example, IgA (e.g., IgA1 or IgA2), IgD, IgE, IgG (e.g., IgG1, IgG2, IgG3, or IgG4), or IgM. In some embodiments, the anti-CD117 antibody is an IgG (e.g., IgG1, IgG2, IgG3, or IgG4).

Antibodies for use in combination with the methods described herein include variants of the antibodies described above, such as antibody fragments that contain or lack an Fc domain, as well as humanized variants of the non-human antibodies described herein, and antibody-like protein scaffolds (e.g., Fn3 domains ¹⁰ ) comprising one or more, or all, of the CDRs or equivalent regions thereof of an antibody or antibody fragment described herein. Exemplary antigen-binding fragments of the above antibodies include a dual immunoglobulin variable domain, a single chain Fv molecule (scFv), a diabody, a triabody, a nanobody, an antibody-like protein scaffold, an Fv fragment, a Fab fragment, an F(ab') ₂ molecule, and a tandem d-scFv, among others.

According to one embodiment, antibodies to CD117 are provided that comprise one or more radioactively labeled amino acids. Radioactively labeled antibodies to CD117 can be used for both diagnostic and therapeutic purposes (another possible feature is conjugation with radioactively labeled molecules). Non-limiting examples of labels for polypeptides include, but are not limited to, ³ H, ¹⁴ C, ¹⁵ N, ³⁵ S, ⁹⁰ Y, ⁹⁹ Tc and ¹²⁵ I, ¹³¹ I and ¹⁸⁶ Re. Methods for producing radiolabeled amino acids and related peptide derivatives are known in the art (see, for example, Junghans et al., in Cancer Chemotherapy and Biotherapy 655-686 (2nd ed., Chafner and Longo, eds., Lippincott Raven (1996)) and U.S. Patent No. 4,681,581, U.S. Patent No. 4,735,210, U.S. Patent No. 5,101,827, U.S. Patent No. 5,102,990 (US RE35500), U.S. Patent No. 5,648,471, and U.S. Patent No. 5,697,902. For example, the radioisotope can be conjugated using the chloramine T method.

Antibodies to CD45

According to one embodiment, the present invention provides ADCs comprising antibodies and antigen-binding fragments thereof that specifically bind to a CD45 polypeptide, such as a human CD45 polypeptide, and uses thereof. According to an exemplary embodiment, an antibody or antigen-binding fragment thereof that specifically binds to a CD45 polypeptide comprises a heavy chain variable region and a light chain variable region.

CD45 is a hematopoietic cell-specific transmembrane protein tyrosine phosphatase essential for T- and B-cell antigen receptor-mediated signaling. CD45 comprises a large extracellular domain and a cytosolic phosphatase-containing domain. CD45 can act as either a positive or negative regulator depending on the nature of the stimulus and the cell type involved. Although there are a large number of possible permutations in the CD45 gene, only six isoforms have traditionally been identified in humans. The isoforms are RA, RO, RB, RAB, RBC, and RABC (Hermiston et al. 2003 “CD45: a critical regulator of signaling thresholds in immune cells.” Annu Rev Immunol. 2: 107–137). CD45RA is expressed on naive T cells, CD45RO is expressed on activated and memory T cells, some B cell subsets, activated monocytes/macrophages, and granulocytes. CD45RB is expressed on peripheral B cells, naive T cells, thymocytes, and weakly on macrophages and dendritic cells.

In certain embodiments, the anti-CD45 antibody is selected from apamistamab (also known as 90Y-BC8, Iomab-B, BC8; as described, e.g., in US20170326259, WO2017155937, and Orozco et al. Blood. 127.3 (2016): 352-359) or BC8-B10 (as described, e.g., in Li et al. PloS one 13.10 (2018): e0205135), each of which is incorporated by reference. Other anti-CD45 antibodies are described, e.g., in WO2003048327, WO2016016442, US20170226209, US20160152733, US9701756; US 20110076270 or US 7825222, each of which is incorporated by reference.

Antibodies to CD137

The present invention provides ADCs comprising antibodies and antigen-binding fragments thereof that specifically bind to a CD137 polypeptide, such as a human CD137 polypeptide, and uses thereof. According to an exemplary embodiment, an antibody or antigen-binding fragment thereof that specifically binds to a CD137 polypeptide comprises a heavy chain variable region and a light chain variable region.

T cells have been shown to express CD137 because this antigen is a member of the transmembrane receptor superfamily of TNF costimulatory molecules and is expressed on a variety of hematopoietic cells, promotes T cell activation, and regulates T cell proliferation and survival (see, e.g., Cannons et al., J. Immunol. 167: 1313-1324, 2001, the disclosure of which is incorporated herein by reference as it relates to CD137 expression by T cells). CD137 is alternatively referred to as tumor necrosis factor receptor superfamily 9 (TNFRSF9), 4-1BB, or is inducible by lymphocyte activation (ILA).

According to certain embodiments, the anti-CD137 antibody is selected from the following: ADG106 (as described, for example, in US20190055314, WO2019037711, WO2019036855); AGEN2373 (as described, for example, in WO2018191502, US20180344870); ATOR-1017 (as described, e.g., in WO2018091740, US20180118841) PE0166 (as described, e.g., in Song et al. AACR 2019, Abstract 2397/21), urelumab (also known as BMS-663513; as described, e.g., in WO2004010947, WO2005035584, US20090068192, US7659384, US8475790, US8137667, US20100183621, US8716452, US20120141494, US9382328, US20140193422, WO 2016029073, US 20160368998, WO 2017181034, US 20190062445, Chin et al. Nature communications. 9.1 (2018): 4679.; Segal et al. Clinical Cancer Research. 23.8 (2017): 1929-1936); and utomilumab (also known as PF-05082566, MOR-7480; as described, for example, in WO2012032433, US20120237498, US20140178368, WO2012145183, WO2015119923, WO2015179236, US20160152722, US20190031765, WO2017130076, Chin et al. Nature communications. 9.1 (2018): 4679.; Segal et al. Clinical Cancer Research. 24.8 (2018): 1816-1823; Fisher et al. Cancer Immunology, Immunotherapy. 61.10 (2012): 1721–1733), with each document incorporated by reference.

Other antibodies to CD137 have been described, for example, in WO2018134787, WO2019020774, WO2017077085, US20180327504, US20190099488, US2019006045, US20190015508, WO2019014328, US20190071510, WO2018127787, US20180258177, US10174122, WO2016110584, WO2018017761, WO2018098370, US20130149301, WO 2019027754, WO 2018156740, US 20160244528, WO 2016134358, US 10233251, US 20170226215, US 20160083474, WO 2017049452, US 20180282422, 2015188047, WO 2010132389, US 20120076722, US 20110177104, WO 2011031063, US 20080305113, US 20080008716, US 7829088, US 20090041763, WO 2006126835, Soderstromet al. Circulation J. 81.12 (2017): 1945–1952; Makkouk, et al. Annals of Oncology 28.2 (2016): 415–420; Martinez-Forero et al. J. of Immunology. 190.12 (2013): 6694–6706; Dubrote al. Cancer immunology, immunotherapy. 59.8 (2010): 1223–1233; each of which is incorporated by reference.

According to another embodiment, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region that comprises an amino acid sequence having at least 95% identity to an anti-CD137 antibody herein, such as at least 95%, 96%, 97%, 98%, 99%, or 100% identity to an anti-CD137 antibody herein. According to certain embodiments, the antibody comprises a modified heavy chain variable region (HC) comprising an HC variable domain of an anti-CD137 antibody herein or a variant thereof, wherein the variant (i) differs from the anti-CD137 antibody by 1, 2, 3, 4, or 5 amino acid substitutions, additions, or deletions; (ii) differs from the anti-CD137 antibody by no more than 5, 4, 3, 2, or 1 amino acid substitutions, additions, or deletions; (iii) differs from an anti-CD137 antibody by 1-5, 1-3, 1-2, 2-5, or 3-5 amino acid substitutions, additions, or deletions and/or (iv) comprises an amino acid sequence that is at least about 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to an anti-CD137 antibody, wherein in any of (i)-(iv), the amino acid substitution may be a conservative amino acid substitution or a non-conservative amino acid substitution; and wherein the modified heavy chain variable region may have enhanced biological activity compared to a heavy chain variable region of an anti-CD137 antibody while maintaining the CD137 binding specificity of the antibody.

In one embodiment, an anti-CD137 antibody that may be used in the methods and compositions (including ADCs) described herein is a murine anti-CD137 BBK2 antibody (Thermo Fisher; MS621PABX) or an anti-CD137 antibody comprising antigen-binding regions corresponding to the BBK2 antibody. The BBK2 antibody (which may also be referred to as a BBK-2 antibody or an anti-4-1BB antibody) is a murine monoclonal antibody (IgG1, kappa) that binds to the ectodomain of recombinant human 4-1BB protein (4-1BB is also known as CD137). In certain embodiments, the methods and compositions of the present disclosure include an anti-CD137 antibody comprising binding regions (e.g., CDRs) of the BBK2 antibody. According to another embodiment, the methods and compositions of the present disclosure comprise an antibody that competitively inhibits the binding of a BBK2 antibody to its epitope on CD137. According to certain embodiments, the CD137 antibody is a humanized BBK2 or a chimeric BBK2.

In one embodiment, the methods and compositions described herein comprise a chimeric anti-CD137 antibody (ch-BBK2) comprising the variable regions of a heavy and light chain of BBK2. In certain embodiments, the chimeric BBK2 antibody is an IgG1 antibody comprising human constant regions. The amino acid sequence of the heavy chain of ch-BBK2 is described in SEQ ID NO: 290, and the amino acid sequence of the light chain of ch-BBK2 is described in SEQ ID NO: 291. The CDRs (CDR1, CDR2, and CDR3) of each of the heavy and light chain sequences are described in bold below. The CDRs of BBK2 can be defined according to Kabat numbering. The CDRs, as defined according to Kabat numbering, are described below for each of the heavy and light chain sequences (highlighted in bold below). BBK2 variable regions are shown in italics.

Thus, in one embodiment, the amino acid sequences of the VH CDRs of the anti-CD137 BBK2 antibody (including ch-BBK2) are as follows: SYWIN (VH CDR1; SEQ ID NO: 292); NIYPSDSYTNYNQKFKD (VH CDR2; SEQ ID NO: 293) and NGVEGYPHYYAMEY (VH CDR3; SEQ ID NO: 294), and the amino acid sequences of the VL CDRs of the anti-CD137 BBK2 antibody (including ch-BBK2) are as follows: RASQDLSNHLY (VL CDR1; SEQ ID NO: 295); YTSRLHS (VL CDR2; SEQ ID NO: 296) and QQGYTLPYT (VL CDR3; SEQ ID NO: 297).

The variable region of the heavy chain of BBK2 is represented in SEQ ID NO: 298 as

. The light chain variable region of BBK2 is represented in SEQ ID NO: 299 as Anti-CD137 antibodies (including anti-CD137 ADCs) may comprise heavy and light chain variable region amino acid sequences as set forth in SEQ ID NOs: 298 and 299, respectively.

According to one embodiment, an anti-CD137 antibody, such as a chimeric antibody (ch-BBK2) or a humanized BBK2 antibody, comprises a heavy chain variable region comprising a CDR1 comprising the amino acid sequence of SEQ ID NO: 292, a CDR2 comprising the amino acid sequence of SEQ ID NO: 293, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 294; and comprises a light chain variable region comprising a CDR1 comprising the amino acid sequence of SEQ ID NO: 295, a CDR2 comprising the amino acid sequence of SEQ ID NO: 296, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 297.

According to one embodiment, an anti-CD137 antibody, such as a chimeric antibody (ch-BBK2) or a humanized BBK2 antibody, comprises a heavy chain variable region comprising a CDR1 comprising the amino acid sequence of SEQ ID NO: 292, a CDR2 comprising the amino acid sequence of SEQ ID NO: 293, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 294; and comprises a light chain variable region comprising a CDR1 comprising the amino acid sequence of SEQ ID NO: 295, a CDR2 comprising the amino acid sequence of SEQ ID NO: 296, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 297.

Thus, BBK2 antibodies, humanized BBK2 antibodies, or chimeric BBK2 antibodies can be used in CD137 ADCs and in the methods described herein. Each of these antibodies can be conjugated to any cytotoxin described below using methods known in the art and those described herein.

Antibodies to CD5

In certain embodiments, the compositions and methods described herein include an ADC comprising an antibody or fragment thereof that specifically binds to human CD5. Human CD5 is also referred to as LEU1 or T1. Human CD5 is a type I transmembrane glycoprotein found on the surface of thymocytes, T lymphocytes, and a subset of B lymphocytes. Two isoforms of human CD5 have been identified. Isoform 1 contains 438 amino acids and is described in Jones, et al. (1988) Nature 323 (6086), 346-349 et seq. (NCBI reference sequence: NP_001333385.1):

T cells have been shown to express CD5, which is a cell adhesion molecule involved in both the proliferative response of activated T cells and T helper function. It has also been shown to act as a receptor, delivering costimulatory signals to T cells by interacting with CD72, a cell surface protein unique to B cells. Antibodies or antigen-binding fragments thereof that bind CD5 can suppress T cell activation and T cell-mediated immune responses against hematopoietic stem cell transplants, for example by inhibiting the interaction between CD5 and CD72. Antibodies and antigen-binding fragments thereof that bind CD5 can also be used to directly kill CD5+ T cells, for example, by conjugating the antibody or antigen-binding fragment thereof to a cytotoxin (such as a cytotoxin described herein or known in the art) or by using an unconjugated antibody or antigen-binding fragment thereof capable of mobilizing complement proteins to the T cell.

Furthermore, subsets of activated B cells have been shown to express CD5, and this expression pattern is particularly prevalent among autoreactive B cells (Werner-Favre et al., European Journal of Immunology 19: 1209-1231 (1989), the disclosure of which is incorporated herein by reference in its entirety). CD5 has also been shown to be expressed by subsets of NK cells; specifically, patients with multiple myeloma have been shown to contain low-density CD5+ (CD5LOW+) NK cell populations, and this surface antigen is involved in NK cell activation (Ishiyama et al., Anticancer Research 14: 725-730 (1994), the disclosure of which is incorporated herein by reference in its entirety). Thus, antibodies or antigen-binding fragments thereof that specifically bind CD5 can be used to attenuate B cell and NK cell activation. Antibodies or antigen-binding fragments thereof that bind CD5 can also be used to kill CD5+ B cells and NK cells directly, such as by conjugating the antibody or antigen-binding fragment thereof to a cytotoxin (such as a cytotoxin described herein or known in the art) or by using an unconjugated antibody or antigen-binding fragment thereof capable of mobilizing complement proteins to a B cell or NK cell.

The present invention provides ADCs comprising antibodies and antigen-binding fragments thereof that specifically bind to a CD5 polypeptide, such as a human CD5 polypeptide, and uses thereof. According to an exemplary embodiment, an antibody or antigen-binding fragment thereof that specifically binds to a CD5 polypeptide comprises a heavy chain variable region and a light chain variable region.

According to one embodiment, the ADC comprises an antibody comprising a heavy chain variable region comprising one or more complementarity determining regions (CDRs). In one embodiment, the heavy chain variable region comprises a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 341. In one embodiment, the heavy chain variable region comprises a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 342. In one embodiment, the heavy chain variable region comprises a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 343. In one embodiment, the heavy chain variable region comprises one or more VH CDRs selected from the group consisting of SEQ ID NO: 341, SEQ ID NO: 342, and SEQ ID NO: 343. In one embodiment, the heavy chain variable region comprises two or more VH CDRs selected from the group consisting of SEQ ID NO: 341, SEQ ID NO: 342, and SEQ ID NO: 343. In one embodiment, the heavy chain variable region comprises a VH CDR1 comprising SEQ ID NO: 341, a VH CDR2 comprising SEQ ID NO: 342, and a VH CDR3 comprising SEQ ID NO: 343.

According to one embodiment, the ADC comprises an antibody comprising a light chain variable region comprising one or more complementarity determining regions (CDRs). In one embodiment, the light chain variable region comprises a VL CDR1 comprising the amino acid sequence of SEQ ID NO: 344. In one embodiment, the light chain variable region comprises a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 345. In one embodiment, the light chain variable region comprises a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 346. In one embodiment, the light chain variable region comprises one or more VL CDRs selected from the group consisting of SEQ ID NO: 344, SEQ ID NO: 345, and SEQ ID NO: 346. In one embodiment, the light chain variable region comprises two or more VL CDRs selected from the group consisting of SEQ ID NO: 344, SEQ ID NO: 345, and SEQ ID NO: 346. In one embodiment, the light chain variable region comprises a VL CDR1 comprising SEQ ID NO: 344, a VL CDR2 comprising SEQ ID NO: 345, and a VL CDR3 comprising SEQ ID NO: 346.

According to an exemplary embodiment, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region that comprises a VH CDR1 comprising SEQ ID NO: 341, a VH CDR2 comprising SEQ ID NO: 342, and a VH CDR3 comprising SEQ ID NO: 343, and a light chain variable region that comprises a VL CDR1 comprising SEQ ID NO: 344, a VL CDR2 comprising SEQ ID NO: 345, and a VL CDR3 comprising SEQ ID NO: 346.

In certain embodiments, one or more CDRs (i.e., one or more heavy chain CDRs characterized by SEQ ID NOs: 341-343 and/or one or more light chain CDRs characterized by SEQ ID NOs: 344-346) may comprise a conservative amino acid substitution (or 2, 3, 4, or 5 amino acid substitutions) while maintaining CD5 specificity of the antibody (i.e., a specificity similar to an antibody or antigen-binding fragment thereof that comprises a heavy chain CDR according to SEQ ID NOs: 341-343 and a light chain CDR according to SEQ ID NOs: 344-346).

In certain embodiments, the anti-CD5 antibody or antigen-binding fragment thereof is the murine 5D7 antibody or a humanized version thereof. The murine 5D7 antibody binds to human CD5 and is described in U.S. Patent Publication No. 20008/0245027, the contents of which, with respect to the antibody sequences disclosed therein, are incorporated herein by reference. SEQ ID NOS: 353-358, described in the summary sequence table, correspond to the CDRs of the murine anti-CD5 antibody, 5D7. The humanized version of the anti-CD5 antibody, 5D7, is described in SEQ ID NO: 359 (humanized heavy chain variable region) and SEQ ID NO: 360 (humanized light chain variable region). In one embodiment, the ADCs and uses thereof described herein comprise an antibody comprising the CDRs set forth in SEQ ID NOs: 353-358. In one embodiment, the ADCs and uses thereof described herein comprise an antibody comprising the heavy and light chain variable regions as set forth in SEQ ID NOs: 359 and 360, respectively.

In one embodiment, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region that comprises an amino acid sequence set forth in SEQ ID NO: 359. In another embodiment, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region that comprises an amino acid sequence having at least 95% identity to SEQ ID NO: 359, such as at least 95%, 96%, 97%, 98%, 99%, or 100% identity to SEQ ID NO: 359. In certain embodiments, the antibody comprises a modified heavy chain variable region (HC) comprising an HC variable domain comprising SEQ ID NO: 359, or a variant of SEQ ID NO: 359, wherein the variant (i) differs from SEQ ID NO: 359 by 1, 2, 3, 4, or 5 amino acid substitutions, additions, or deletions; (ii) differs from SEQ ID NO: 359 by no more than 5, 4, 3, 2, or 1 amino acid substitutions, additions, or deletions; (iii) differs from SEQ ID NO: 359 by 1-5, 1-3, 1-2, 2-5, or 3-5 amino acid substitutions, additions, or deletions and/or (iv) comprises an amino acid sequence that is at least about 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 359, wherein in any of (i)-(iv), the amino acid substitution may be a conservative amino acid substitution or a non-conservative amino acid substitution; and wherein the modified heavy chain variable region may have increased biological activity compared to the heavy chain variable region according to SEQ ID NO: 359, while maintaining the binding specificity of the CD5 antibody, i.e. is characterized by a binding specificity similar to the binding specificity of the antibody or antigen-binding fragment thereof, which contain SEQ ID NO: 359.

In one embodiment, the antibody or antigen-binding fragment thereof comprises a light chain variable region that comprises an amino acid sequence set forth in SEQ ID NO: 360. In another embodiment, the antibody or antigen-binding fragment thereof comprises a light chain variable region that comprises an amino acid sequence having at least 95% identity to SEQ ID NO: 360, such as at least 95%, 96%, 97%, 98%, 99%, or 100% identity to SEQ ID NO: 360. In certain embodiments, the antibody comprises a modified light chain variable region (LC) comprising an LC variable domain comprising SEQ ID NO: 360, or a variant of SEQ ID NO: 360, wherein the variant (i) differs from SEQ ID NO: 360 by 1, 2, 3, 4, or 5 amino acid substitutions, additions, or deletions; (ii) differs from SEQ ID NO: 360 by no more than 5, 4, 3, 2, or 1 amino acid substitutions, additions, or deletions; (iii) differs from SEQ ID NO: 360 by 1-5, 1-3, 1-2, 2-5, or 3-5 amino acid substitutions, additions, or deletions and/or (iv) comprises an amino acid sequence that is at least about 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 360, wherein in any of (i)-(iv), the amino acid substitution may be a conservative amino acid substitution or a non-conservative amino acid substitution; and wherein the modified light chain variable region may have increased biological activity compared to the light chain variable region according to SEQ ID NO: 360, while maintaining the binding specificity of the CD5 antibody, i.e. is characterized by a binding specificity similar to the binding specificity of the antibody or antigen-binding fragment thereof, which contain SEQ ID NO: 360.

In an exemplary embodiment, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region that comprises an amino acid sequence having at least 95% identity to SEQ ID NO: 359, such as at least 95%, 96%, 97%, 98%, 99%, or 100% identity to SEQ ID NO: 359, and a light chain variable region that comprises an amino acid sequence having at least 95% identity to SEQ ID NO: 360, such as at least 95%, 96%, 97%, 98%, 99%, or 100% identity to SEQ ID NO: 360. In one embodiment, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region that comprises SEQ ID NO: 359 and a light chain variable region that comprises SEQ ID NO: 360.

In another embodiment, the anti-CD5 antibody or antigen-binding fragment thereof may comprise a heavy chain variable region that comprises a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 353. In one embodiment, the heavy chain variable region comprises a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 354. In one embodiment, the heavy chain variable region comprises a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 355. In one embodiment, the heavy chain variable region comprises one or more VH CDRs selected from the group consisting of SEQ ID NO: 353, SEQ ID NO: 354, and SEQ ID NO: 355. In one embodiment, the heavy chain variable region comprises two or more VH CDRs selected from the group consisting of SEQ ID NO: 353, SEQ ID NO: 354, and SEQ ID NO: 355. According to one embodiment, the heavy chain variable region comprises a VH CDR1 comprising SEQ ID NO: 353, a VH CDR2 comprising SEQ ID NO: 354, and a VH CDR3 comprising SEQ ID NO: 355.

According to one embodiment, the light chain variable region comprises one or more complementarity determining regions (CDRs). In one embodiment, the light chain variable region comprises a VL CDR1 comprising the amino acid sequence of SEQ ID NO: 356. In one embodiment, the light chain variable region comprises a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 357. In one embodiment, the light chain variable region comprises a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 358. In one embodiment, the light chain variable region comprises one or more VL CDRs selected from the group consisting of SEQ ID NO: 356, SEQ ID NO: 357, and SEQ ID NO: 358. In one embodiment, the light chain variable region comprises two or more VL CDRs selected from the group consisting of SEQ ID NO: 356, SEQ ID NO: 357, and SEQ ID NO: 358. In one embodiment, the light chain variable region comprises a VL CDR1 comprising SEQ ID NO: 356, a VL CDR2 comprising SEQ ID NO: 357, and a VL CDR3 comprising SEQ ID NO: 358.

According to an exemplary embodiment, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region that comprises a VH CDR1 comprising SEQ ID NO: 353, a VH CDR2 comprising SEQ ID NO: 354, and a VH CDR3 comprising SEQ ID NO: 355, and a light chain variable region that comprises a VL CDR1 comprising SEQ ID NO: 356, a VL CDR2 comprising SEQ ID NO: 357, and a VL CDR3 comprising SEQ ID NO: 358.

In certain embodiments, one or more CDRs (i.e., one or more heavy chain CDRs characterized by SEQ ID NOs: 353-355 and/or one or more light chain CDRs characterized by SEQ ID NOs: 356-358) may comprise a conservative amino acid substitution (or 2, 3, 4, or 5 amino acid substitutions) while maintaining CD5 specificity of the antibody (i.e., a specificity similar to an antibody or antigen-binding fragment thereof that comprises a heavy chain CDR according to SEQ ID NOs: 353-355 and a light chain CDR according to SEQ ID NOs: 356-358).

Antibodies and antigen-binding fragments thereof capable of binding the CD5 antigen can be identified using methods known in the art and described herein, such as immunization, computer modeling methods, and in vitro selection methods such as the phage display and cell display platforms described below.

Anti-CD5 antibodies that can be used in combination with the compositions and methods described herein include antibodies that comprise one or both of the following variable regions or an amino acid sequence having at least 85% sequence identity thereto (e.g., an amino acid sequence having 85%, 90%, 95%, 97%, 98%, 99% or more sequence identity thereto):

V _L with amino acid sequence

V _H with amino acid sequence

Antibodies and antigen-binding fragments thereof comprising the above V _L and V _H sequences are described, for example, in U.S. Patent No. 5,869,619, the disclosure of which is incorporated herein by reference as it relates to CD5 antibodies and antigen-binding fragments thereof, such as the he1 antibody. In some embodiments, the anti-CD5 antibody or antigen-binding fragment thereof comprises the V _L and V _H chains of SEQ ID NO: 325 and SEQ ID NO: 326. In some embodiments, the anti-CD5 antibody or antigen-binding fragment thereof comprises the CDRs contained in the V _L and V _H chains of SEQ ID NO: 325 and SEQ ID NO: 326. In some embodiments, the anti-CD5 antibody or antigen-binding fragment thereof comprises the CDRs contained in the V _L and V _H chains of SEQ ID NO: 325 and SEQ ID NO: 326, and the remaining portions of the V _L and V _H sequences have at least 85% sequence identity (e.g., 85%, 90%, 95%, 97%, 98%, 99%, or more sequence identity) to the V _L and V _H sequences of SEQ ID NO: 325 and SEQ ID NO: 326.

In some embodiments, the anti-CD5 antibody or antigen-binding fragment thereof comprises the following CDRs:

CDR-H1 with the amino acid sequence GYTFTNY (SEQ ID NO: 327);

CDR-H2 with the amino acid sequence NTHTGE (SEQ ID NO: 328);

CDR-H3 with the amino acid sequence RGYDWYFDV (SEQ ID NO: 329);

CDR-L1 with the amino acid sequence RASQDINSYLS (SEQ ID NO: 330);

CDR-L2 with the amino acid sequence RANRLVD (SEQ ID NO: 331); and

CDR-L3 with amino acid sequence QQYDESPWT (SEQ ID NO: 332);

Additional anti-CD5 antibodies that can be used in combination with the compositions and methods described herein include antibodies that comprise one or both of the following variable regions or an amino acid sequence having at least 85% sequence identity thereto (e.g., an amino acid sequence having 85%, 90%, 95%, 97%, 98%, 99% or more sequence identity thereto):

V _L with amino acid sequence

V _H with amino acid sequence

Antibodies and antigen-binding fragments thereof comprising the above V _L and V _H sequences are described, for example, in U.S. Patent No. 5,869,619, the disclosure of which is incorporated herein by reference as it relates to CD5 antibodies and antigen-binding fragments thereof, such as the he3 antibody. In some embodiments, the anti-CD5 antibody or antigen-binding fragment thereof comprises CDRs contained in the V _L and V _H chains of an antibody that comprises the V _L and V _H chains of SEQ ID NO: 327 and SEQ ID NO: 328. In some embodiments, the anti-CD5 antibody or antigen-binding fragment thereof comprises CDRs contained in the V _L and V _H chains of SEQ ID NO: 327 and SEQ ID NO: 328, and the remaining portions of the V _L and V _H sequences have at least 85% sequence identity (e.g., 85%, 90%, 95%, 97%, 98%, 99%, or more sequence identity) to the V _L and V _H sequences of SEQ ID NO: 327 and SEQ ID NO: 328.

In some embodiments, the anti-CD5 antibody or antigen-binding fragment thereof comprises the following CDRs:

CDR-H1 with the amino acid sequence GYTFTNY (SEQ ID NO: 335);

CDR-H2 with the amino acid sequence NTHYGE (SEQ ID NO: 336);

CDR-H3 with the amino acid sequence RRGYDWYFDV (SEQ ID NO: 337);

CDR-L1 with the amino acid sequence RASQDINSYLS (SEQ ID NO: 338);

CDR-L2 with the amino acid sequence RANRLES (SEQ ID NO: 339); and

CDR-L3 with the amino acid sequence QQYDESPWT (SEQ ID NO: 340).

Antibodies and antigen-binding fragments thereof comprising the above CDR sequences are described, for example, in U.S. Patent No. 5,869,619, the disclosure of which is incorporated herein by reference as it relates to CD5 antibodies and antigen-binding fragments thereof.

Other anti-CD5 antibodies that can be used in combination with the compositions and methods described herein include, for example, the anti-CD5 antibodies described in U.S. Patent Nos. 5,821,123; 5,766,886; 5,770,196; 7,153,932; 5,621,083; 6,649,742; 6,146,631; 5,756,699; 5,744,580; 6,376,217; 5,837,491 and 6,146,850, the disclosures of each of which are incorporated herein by reference as they relate to anti-CD5 antibodies and antigen-binding fragments thereof.

Other anti-CD5 antibodies that can be used in combination with the compositions and methods described herein include, for example, antibodies produced by the hybridoma cell line deposited as ATCC CRL 8000 (mouse anti-CD5 antibody OKT1). Such antibodies are described in U.S. Patent Nos. 4,515,894; 4,657,760; and 4,363,799, the disclosures of each of which are incorporated herein by reference as they relate to anti-CD5 antibodies and antigen-binding fragments thereof.

Anti-CD5 antibodies that can be used in combination with the compositions and methods described herein include those that comprise one, more, or all of the following CDRs:

CDR-H1 with the amino acid sequence GYSITSGYY (SEQ ID NO: 341);

CDR-H2 with the amino acid sequence ISYSGFT (SEQ ID NO: 342);

CDR-H3 with the amino acid sequence AGDRTGSWFAY (SEQ ID NO: 343);

CDR-L1 with the amino acid sequence QDISNY (SEQ ID NO: 344);

CDR-L2 with the amino acid sequence ATS (SEQ ID NO: 345); and

CDR-L3 with the amino acid sequence LQYASYPFT (SEQ ID NO: 346).

Antibodies and antigen-binding fragments thereof comprising the above CDR sequences are described, for example, in U.S. Patent No. 8,679,500, the disclosure of which is incorporated herein by reference as it relates to CD5 antibodies and antigen-binding fragments thereof.

Anti-CD5 antibodies that can be used in combination with the compositions and methods described herein include those that comprise one, more, or all of the following CDRs:

CDR-H1 with the amino acid sequence GYIFTNYG (SEQ ID NO: 347);

CDR-H2 with the amino acid sequence INTYNGEP (SEQ ID NO: 348);

CDR-H3 with the amino acid sequence ARGDYYGYEDY (SEQ ID NO: 349);

CDR-L1 with the amino acid sequence QGISNY (SEQ ID NO: 350);

CDR-L2 with the amino acid sequence YTS (SEQ ID NO: 351); and

CDR-L3 with amino acid sequence QQYSKLPWT (SEQ ID NO: 352).

Antibodies and antigen-binding fragments thereof containing the above CDR sequences are described, for example, in U.S. Patent No. 8,679,500.

Anti-CD5 antibodies that can be used in combination with the compositions and methods described herein include those that comprise one, more, or all of the following CDRs:

CDR-H1 with the amino acid sequence FSLSTSGMG (SEQ ID NO: 353);

CDR-H2 with the amino acid sequence WWDDD (SEQ ID NO: 354);

CDR-H3 with the amino acid sequence RRATGTGFDY (SEQ ID NO: 354

CDR-L1 with the amino acid sequence QDVGTA (SEQ ID NO: 356);

CDR-L2 with the amino acid sequence WTSTRHT (SEQ ID NO: 357); and

CDR-L3 with the amino acid sequence YNSYNT (SEQ ID NO: 358).

Antibodies and antigen-binding fragments thereof comprising the above CDR sequences are described, for example, in U.S. Patent Application Publication No. 2008/0254027, the disclosure of which is incorporated herein by reference as it relates to CD5 antibodies and antigen-binding fragments thereof.

Other anti-CD5 antibodies that can be used in combination with the compositions and methods described herein include, for example, anti-CD5 antibodies that are described in PCT Publication No. WO 1992/014491, such as anti-CD5 antibodies produced by a hybridoma cell line deposited with the Institut Pasteur under Ser. No. 1-1025 on January 10, 1991. The disclosure of PCT Publication No. WO 1992/014491 is incorporated herein by reference as it relates to anti-CD5 antibodies and antigen-binding fragments thereof.

Other anti-CD5 antibodies that can be used in combination with the compositions and methods described herein include, for example, anti-CD5 antibodies that are described in U.S. Patent Nos. 6,010,902 and 7,192,736, U.S. Patent Application Publication Nos. 2011/0250203 and 2017/0129128, and PCT Application Publication Nos. WO 2016/172606; WO 1994/023747; and WO 1996/041608; the disclosures of each of which are incorporated herein by reference as they relate to anti-CD5 antibodies and antigen-binding fragments thereof.

In some embodiments, anti-CD5 antibodies that may be used in combination with the compositions and methods described herein include those that comprise a combination of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 regions, as shown in the table below.

Antibodies and antigen-binding fragments thereof comprising the above CDR sequences from the above table are described, for example, in U.S. Patent Application Publication No. 2011/0250203, the disclosure of which is incorporated herein by reference as it relates to CD5 antibodies and antigen-binding fragments thereof.

Antibodies to CD2

The compositions and methods described herein include, in certain embodiments, an antibody or fragment thereof that specifically binds to human CD2. Human CD2 is also referred to as T-cell surface antigen T11/Leu-5, T11, CD2 (p50) antigen, and sheep red blood cell receptor (SRBC). CD2 is expressed on T cells. Two isoforms of human CD2 have been identified. Isoform 1 contains 351 amino acids as described in Seed, B. et al. (1987) 84: 3365-69 (see also Sewell et al. (1986) 83: 8718-22) and below (NCBI reference sequence: NP_001758.2):

The second CD2 isoform consists of 377 amino acids and is designated herein as the NCBI reference sequence: NP_001315538.1.

T cells and NK cells have been shown to express CD2, which is a cell adhesion molecule and a specific marker for such lymphocytes. For example, CD2 interacts with other adhesion molecules such as lymphocyte function-associated antigen-3 (LFA-3/CD58) to enhance T cell activation. Antibodies and antigen-binding fragments thereof capable of binding CD2 can suppress T cell activation and T cell-mediated immune responses against hematopoietic stem cell transplants, for example, by inhibiting the interaction between CD2 and LFA-3. Antibodies and antigen-binding fragments thereof that bind to this cell surface antigen can be identified using methods known in the art and described herein, including immunization, computational modeling methods, and in vitro selection methods such as the phage display and cell display platforms described below.

According to certain embodiments, the present invention provides an ADC comprising an antibody or antigen-binding fragment thereof that specifically binds to a CD2 polypeptide, such as a human CD2 polypeptide, and uses thereof.

According to one embodiment, the ADC comprises an anti-CD2 antibody comprising a heavy chain variable region that comprises one or more complementarity determining regions (CDRs). In one embodiment, the heavy chain variable region comprises a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 300. In one embodiment, the heavy chain variable region comprises a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 301. In one embodiment, the heavy chain variable region comprises a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 302. In one embodiment, the heavy chain variable region comprises one or more VH CDRs selected from the group consisting of SEQ ID NO: 300, SEQ ID NO: 301, and SEQ ID NO: 302. In one embodiment, the heavy chain variable region comprises two or more VH CDRs selected from the group consisting of SEQ ID NO: 300, SEQ ID NO: 301, and SEQ ID NO: 302. In one embodiment, the heavy chain variable region comprises a VH CDR1 comprising SEQ ID NO: 300, a VH CDR2 comprising SEQ ID NO: 301, and a VH CDR3 comprising SEQ ID NO: 302.

According to one embodiment, the ADC comprises an anti-CD2 antibody comprising a light chain variable region that comprises one or more complementarity determining regions (CDRs). In one embodiment, the light chain variable region comprises a VL CDR1 comprising the amino acid sequence of SEQ ID NO: 303. In one embodiment, the light chain variable region comprises a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 304. In one embodiment, the light chain variable region comprises a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 305. In one embodiment, the light chain variable region comprises one or more VL CDRs selected from the group consisting of SEQ ID NO: 303, SEQ ID NO: 304, and SEQ ID NO: 305. In one embodiment, the light chain variable region comprises two or more VL CDRs selected from the group consisting of SEQ ID NO: 303, SEQ ID NO: 304, and SEQ ID NO: 305. In one embodiment, the light chain variable region comprises a VL CDR1 comprising SEQ ID NO: 303, a VL CDR2 comprising SEQ ID NO: 304, and a VL CDR3 comprising SEQ ID NO: 305.

According to an exemplary embodiment, the anti-CD2 antibody or antigen-binding fragment thereof comprises a heavy chain variable region that comprises a VH CDR1 comprising SEQ ID NO: 300, a VH CDR2 comprising SEQ ID NO: 301, and a VH CDR3 comprising SEQ ID NO: 302, and a light chain variable region that comprises a VL CDR1 comprising SEQ ID NO: 303, a VL CDR2 comprising SEQ ID NO: 304, and a VL CDR3 comprising SEQ ID NO: 305.

In certain embodiments, one or more CDRs (i.e., one or more heavy chain CDRs characterized by SEQ ID NOs: 300-302 and/or one or more light chain CDRs characterized by SEQ ID NOs: 303-305) may comprise a conservative amino acid substitution (or 2, 3, 4, or 5 amino acid substitutions) while maintaining CD2 specificity of the antibody (i.e., a specificity similar to an antibody or antigen-binding fragment thereof that comprises a heavy chain CDR of SEQ ID NOs: 300-302 and a light chain CDR of SEQ ID NOs: 303-305).

In one embodiment, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region that comprises an amino acid sequence set forth in SEQ ID NO: 306. In another embodiment, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region that comprises an amino acid sequence having at least 95% identity to SEQ ID NO: 306, such as at least 95%, 96%, 97%, 98%, 99%, or 100% identity to SEQ ID NO: 306. In certain embodiments, the antibody comprises a modified heavy chain variable region (HC) comprising an HC variable domain comprising SEQ ID NO: 306, or a variant of SEQ ID NO: 306, wherein the variant (i) differs from SEQ ID NO: 306 by 1, 2, 3, 4, or 5 amino acid substitutions, additions, or deletions; (ii) differs from SEQ ID NO: 306 by no more than 5, 4, 3, 2, or 1 amino acid substitutions, additions, or deletions; (iii) differs from SEQ ID NO: 306 by 1-5, 1-3, 1-2, 2-5, or 3-5 amino acid substitutions, additions, or deletions and/or (iv) comprises an amino acid sequence that is at least about 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 306, wherein in any of (i)-(iv), the amino acid substitution may be a conservative amino acid substitution or a non-conservative amino acid substitution; and wherein the modified heavy chain variable region may have an increased biological activity compared to the heavy chain variable region according to SEQ ID NO: 306, while maintaining the binding specificity of the CD2 antibody, i.e. is characterized by a binding specificity similar to the binding specificity of the antibody or antigen-binding fragment thereof that comprises SEQ ID NO: 306. According to one embodiment, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region that differs from the amino acid sequence presented in SEQ ID NO: 306 by one, two, three or four amino acids. For example, an antibody or antigen-binding fragment thereof may comprise a heavy chain variable region that differs from the amino acid sequence set forth in SEQ ID NO: 306 at one, two, three, or four positions 12, 13, 28, and/or 48. In one embodiment, the heavy chain variable region differs from the amino acid sequence set forth in SEQ ID NO: 306 at positions 12, 13, 28, and 48. In one embodiment, the heavy chain variable region comprises one, two, three, or four of the following substitutions relative to the sequence set forth in SEQ ID NO: 306: K12Q; K13R; T28I; and M48V. In one embodiment, the heavy chain variable region comprises the substitutions K12Q; K13R; T28I; and M48V relative to SEQ ID NO: 306.

In one embodiment, the antibody or antigen-binding fragment thereof comprises a light chain variable region that comprises an amino acid sequence set forth in SEQ ID NO: 307. In another embodiment, the antibody or antigen-binding fragment thereof comprises a light chain variable region that comprises an amino acid sequence having at least 95% identity to SEQ ID NO: 307, such as at least 95%, 96%, 97%, 98%, 99%, or 100% identity to SEQ ID NO: 307. In certain embodiments, the antibody comprises a modified light chain variable region (LC) comprising an LC variable domain comprising SEQ ID NO: 307, or a variant of SEQ ID NO: 307, wherein the variant (i) differs from SEQ ID NO: 307 by 1, 2, 3, 4, or 5 amino acid substitutions, additions, or deletions; (ii) differs from SEQ ID NO: 307 by no more than 5, 4, 3, 2, or 1 amino acid substitutions, additions, or deletions; (iii) differs from SEQ ID NO: 307 by 1-5, 1-3, 1-2, 2-5, or 3-5 amino acid substitutions, additions, or deletions and/or (iv) comprises an amino acid sequence that is at least about 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 307, wherein in any of (i)-(iv), the amino acid substitution may be a conservative amino acid substitution or a non-conservative amino acid substitution; and wherein the modified light chain variable region may have increased biological activity compared to the light chain variable region according to SEQ ID NO: 307, while maintaining the binding specificity of the CD2 antibody, i.e. is characterized by a binding specificity similar to the binding specificity of the antibody or antigen-binding fragment thereof, which contain SEQ ID NO: 307.

In an exemplary embodiment, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region that comprises an amino acid sequence having at least 95% identity to SEQ ID NO: 306, such as at least about 95%, about 96%, about 97%, about 98%, about 99%, or 100% identity to SEQ ID NO: 306, and a light chain variable region that comprises an amino acid sequence having at least about 95% identity to SEQ ID NO: 307, such as at least about 95%, about 96%, about 97%, about 98%, about 99%, or 100% identity to SEQ ID NO: 307. In one embodiment, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region that comprises SEQ ID NO: 306 and a light chain variable region that comprises SEQ ID NO: 307. chain that comprises SEQ ID NO: 307. According to one embodiment, the antibody is an Ab1 antibody that comprises a heavy chain variable region comprising SEQ ID NO: 306 and a light chain variable region comprising SEQ ID NO: 307.

In one embodiment, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region that comprises an amino acid sequence set forth in SEQ ID NO: 308. In another embodiment, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region that comprises an amino acid sequence having at least 95% identity to SEQ ID NO: 308, such as at least about 95%, about 96%, about 97%, about 98%, about 99%, or 100% identity to SEQ ID NO: 308. In an exemplary embodiment, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region that comprises an amino acid sequence having at least 95% identity to SEQ ID NO: 308, such as at least about 95%, about 96%, about 97%, about 98%, about 99%, or 100% identity to SEQ ID NO: 308, and a light chain variable region that comprises an amino acid sequence having at least about 95% identity to SEQ ID NO: 309, such as at least about 95%, about 96%, about 97%, about 98%, about 99%, or 100% identity to SEQ ID NO: 309. In one embodiment, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region that comprises SEQ ID NO: 308 and a light chain variable region that comprises SEQ ID NO: 309. In one embodiment, the antibody is an Ab1a antibody that comprises a heavy chain variable region comprising SEQ ID NO: 308 and a light chain variable region comprising SEQ ID NO: 309.

According to one embodiment, the heavy chain variable region comprises one or more complementarity determining regions (CDRs). In one embodiment, the heavy chain variable region comprises a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 3131. In one embodiment, the heavy chain variable region comprises a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 314. In one embodiment, the heavy chain variable region comprises a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 315. In one embodiment, the heavy chain variable region comprises one or more VH CDRs selected from the group consisting of SEQ ID NO: 313, SEQ ID NO: 314, and SEQ ID NO: 315. In one embodiment, the heavy chain variable region comprises two or more VH CDRs selected from the group consisting of SEQ ID NO: 313, SEQ ID NO: 314, and SEQ ID NO: 315. In one embodiment the heavy chain variable region comprises a VH CDR1 comprising SEQ ID NO: 313, a VH CDR2 comprising SEQ ID NO: 314, and a VH CDR3 comprising SEQ ID NO: 315.

According to one embodiment, the heavy chain variable region comprises one or more complementarity determining regions (CDRs). In one embodiment, the heavy chain variable region comprises a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 313. In one embodiment, the heavy chain variable region comprises a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 314. In one embodiment, the heavy chain variable region comprises a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 316. In one embodiment, the heavy chain variable region comprises one or more VH CDRs selected from the group consisting of SEQ ID NO: 313, SEQ ID NO: 314, and SEQ ID NO: 316. In one embodiment, the heavy chain variable region comprises two or more VH CDRs selected from the group consisting of SEQ ID NO: 313, SEQ ID NO: 314, and SEQ ID NO: 316. In one embodiment, the heavy chain variable region comprises a VH CDR1 comprising SEQ ID NO: 313, a VH CDR2 comprising SEQ ID NO: 314, and a VH CDR3 comprising SEQ ID NO: 316.

According to one embodiment, the light chain variable region comprises one or more complementarity determining regions (CDRs). In one embodiment, the light chain variable region comprises a VL CDR1 comprising the amino acid sequence of SEQ ID NO: 317. In one embodiment, the light chain variable region comprises a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 318. In one embodiment, the light chain variable region comprises a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 319. In one embodiment, the light chain variable region comprises one or more VL CDRs selected from the group consisting of SEQ ID NO: 317, SEQ ID NO: 318, and SEQ ID NO: 319. In one embodiment, the light chain variable region comprises two or more VL CDRs selected from the group consisting of SEQ ID NO: 317, SEQ ID NO: 318, and SEQ ID NO: 319. In one embodiment, the light chain variable region comprises a VL CDR1 comprising SEQ ID NO: 317, a VL CDR2 comprising SEQ ID NO: 318, and a VL CDR3 comprising SEQ ID NO: 319.

According to an exemplary embodiment, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region that comprises a VH CDR1 comprising SEQ ID NO: 313, a VH CDR2 comprising SEQ ID NO: 314, and a VH CDR3 comprising SEQ ID NO: 315, and a light chain variable region that comprises a VL CDR1 comprising SEQ ID NO: 317, a VL CDR2 comprising SEQ ID NO: 318, and a VL CDR3 comprising SEQ ID NO: 319.

According to an exemplary embodiment, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region that comprises a VH CDR1 comprising SEQ ID NO: 313, a VH CDR2 comprising SEQ ID NO: 314, and a VH CDR3 comprising SEQ ID NO: 316, and a light chain variable region that comprises a VL CDR1 comprising SEQ ID NO: 317, a VL CDR2 comprising SEQ ID NO: 318, and a VL CDR3 comprising SEQ ID NO: 319.

In certain embodiments, one or more CDRs (i.e., one or more heavy chain CDRs characterized by SEQ ID NOs: 313-316 and/or one or more light chain CDRs characterized by SEQ ID NOs: 317-318) can comprise a conservative amino acid substitution (or 2, 3, 4, or 5 amino acid substitutions) while maintaining CD2 specificity of the antibody (i.e., a specificity similar to an antibody or antigen-binding fragment thereof that comprises a heavy chain CDR of SEQ ID NOs: 313-315 and a light chain CDR of SEQ ID NOs: 18-20; or that comprise a heavy chain CDR of SEQ ID NOs: 313, 314, 316 and a light chain CDR of SEQ ID NOs: 317-319).

In one embodiment, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region that comprises an amino acid sequence set forth in SEQ ID NO: 320. In another embodiment, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region that comprises an amino acid sequence having at least about 95% identity to SEQ ID NO: 320, such as at least about 95%, about 96%, about 97%, about 98%, about 99%, or 100% identity to SEQ ID NO: 320. In certain embodiments, the antibody comprises a modified heavy chain variable region (HC) comprising an HC variable domain comprising SEQ ID NO: 320, or a variant of SEQ ID NO: 320, wherein the variant (i) differs from SEQ ID NO: 320 by 1, 2, 3, 4, or 5 amino acid substitutions, additions, or deletions; (ii) differs from SEQ ID NO: 320 by no more than 5, 4, 3, 2, or 1 amino acid substitutions, additions, or deletions; (iii) differs from SEQ ID NO: 320 by 1-5, 1-3, 1-2, 2-5, or 3-5 amino acid substitutions, additions, or deletions and/or (iv) comprises an amino acid sequence that is at least about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 320, wherein in any of (i)-(iv), the amino acid substitution may be a conservative amino acid substitution or a non-conservative amino acid substitution; and wherein the modified heavy chain variable region may have increased biological activity compared to the heavy chain variable region according to SEQ ID NO: 320, while maintaining the binding specificity of the CD2 antibody, i.e. is characterized by a binding specificity similar to the binding specificity of the antibody or antigen-binding fragment thereof, which contain SEQ ID NO: 320.

In one embodiment, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region that comprises an amino acid sequence set forth in SEQ ID NO: 321. In another embodiment, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region that comprises an amino acid sequence having at least about 95% identity to SEQ ID NO: 321, such as at least about 95%, about 96%, about 97%, about 98%, about 99%, or 100% identity to SEQ ID NO: 321. In certain embodiments, the antibody comprises a modified heavy chain variable region (HC) comprising an HC variable domain comprising SEQ ID NO: 320, or a variant of SEQ ID NO: 321, wherein the variant (i) differs from SEQ ID NO: 321 by 1, 2, 3, 4, or 5 amino acid substitutions, additions, or deletions; (ii) differs from SEQ ID NO: 321 by no more than 5, 4, 3, 2, or 1 amino acid substitutions, additions, or deletions; (iii) differs from SEQ ID NO: 321 by 1-5, 1-3, 1-2, 2-5, or 3-5 amino acid substitutions, additions, or deletions and/or (iv) comprises an amino acid sequence that is at least about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 321, wherein in any of (i)-(iv), the amino acid substitution may be a conservative amino acid substitution or a non-conservative amino acid substitution; and wherein the modified heavy chain variable region may have increased biological activity compared to the heavy chain variable region according to SEQ ID NO: 321, while maintaining the binding specificity of the CD2 antibody, i.e. is characterized by a binding specificity similar to the binding specificity of the antibody or antigen-binding fragment thereof, which contain SEQ ID NO: 321.

In one embodiment, the antibody or antigen-binding fragment thereof comprises a light chain variable region that comprises an amino acid sequence set forth in SEQ ID NO: 322. In another embodiment, the antibody or antigen-binding fragment thereof comprises a light chain variable region that comprises an amino acid sequence having at least about 95% identity to SEQ ID NO: 322, such as at least about 95%, about 96%, about 97%, about 98%, about 99%, or 100% identity to SEQ ID NO: 322. In certain embodiments, the antibody comprises a modified light chain variable region (LC) comprising an LC variable domain comprising SEQ ID NO: 322, or a variant of SEQ ID NO: 322, wherein the variant (i) differs from SEQ ID NO: 322 by 1, 2, 3, 4, or 5 amino acid substitutions, additions, or deletions; (ii) differs from SEQ ID NO: 322 by no more than 5, 4, 3, 2, or 1 amino acid substitutions, additions, or deletions; (iii) differs from SEQ ID NO: 322 by 1-5, 1-3, 1-2, 2-5, or 3-5 amino acid substitutions, additions, or deletions and/or (iv) comprises an amino acid sequence that is at least about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 322, wherein in any of (i) to (iv), the amino acid substitution may be a conservative amino acid substitution or a non-conservative amino acid substitution; and wherein the modified light chain variable region may have increased biological activity compared to the light chain variable region according to SEQ ID NO: 322, while maintaining the binding specificity of the CD2 antibody, i.e. is characterized by a binding specificity similar to the binding specificity of the antibody or antigen-binding fragment thereof, which contain SEQ ID NO: 322.

In an exemplary embodiment, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region that comprises an amino acid sequence having at least 95% identity to SEQ ID NO: 320, such as at least about 95%, about 96%, about 97%, about 98%, or about 99% or 100% identity to SEQ ID NO: 320, and a light chain variable region that comprises an amino acid sequence having at least about 95% identity to SEQ ID NO: 322, such as at least about 95%, about 96%, about 97%, about 98%, or about 99% or 100% identity to SEQ ID NO: 322. In one embodiment, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region that comprises SEQ ID NO: 320 and a light chain variable region chain that contains SEQ ID NO: 322.

In an exemplary embodiment, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region that comprises an amino acid sequence having at least about 95% identity to SEQ ID NO: 321, such as at least about 95%, about 96%, about 97%, about 98%, or about 99%, of 100% identity to SEQ ID NO: 321, and a light chain variable region that comprises an amino acid sequence having at least about 95% identity to SEQ ID NO: 322, such as at least about 95%, about 96%, about 97%, about 98%, or about 99% or 100% identity to SEQ ID NO: 322. In one embodiment, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region that comprises SEQ ID NO: 321, and a light chain variable region comprising SEQ ID NO: 322.

Anti-CD2 antibodies that can be used in combination with the compositions and methods described herein include those that comprise one, more, or all of the following CDRs:

a. CDR-H1 with the amino acid sequence EYYMY (SEQ ID NO: 300);

b. CDR-H2 with the amino acid sequence RIDPEDGSIDYVEKFKK (SEQ ID NO: 301);

c. CDR-H3 with the amino acid sequence GKFNYRFAY (SEQ ID NO: 302);

d. CDR-L1 with the amino acid sequence RSSQSLLHSSGNTYLN (SEQ ID NO: 303);

e. CDR-L2 with the amino acid sequence LVSKLES (SEQ ID NO: 304); and

f. CDR-L3 with the amino acid sequence MQFTHYPYT (SEQ ID NO: 305).

Antibodies and antigen-binding fragments thereof comprising the above CDR sequences are described, for example, in U.S. Patent No. 6,849,258, the disclosure of which is incorporated herein by reference as it relates to anti-CD2 antibodies and antigen-binding fragments thereof.

Antibodies and fragments thereof disclosed in U.S. Patent Nos. 5,730,979; 5,817,311; 5,951,983; and 7,592,006; such as LO-CD2a, BTI-322, and antibodies produced by the hybridoma cell line deposited under ATCC Deposit No. HB 11423 (e.g., antibodies or antigen-binding fragments thereof comprising one or more, or all, of the CDR sequences of the LO-CD2a antibody isolated from the hybridoma cell line deposited under ATCC Deposit No. HB 11423) can be used in combination with the compositions and methods disclosed herein. Illustrative antibodies that may be used in combination with the compositions and methods described herein include humanized antibodies comprising one or more, or all, of the CDR sequences of an antibody isolated from a hybridoma cell line deposited under ATCC Deposit Number HB 11423, such as MEDI-507. MEDI-507 is a humanized anti-CD2 monoclonal antibody that comprises the CDR-H and CDR-L sequences of (a)-(f) above, and is described in Branco et al., Transplantation 68:1588-1596 (1999). MEDI-507 is further described in WO 99/03502 A1 and WO 1994/020619 A1; U.S. Patent Nos. US 7,592,006, US 6,849,258, US 5,951,983, US 5,817,311, and US 5,730,979; and U.S. Patent Publication Nos. US 2011/0280868, US 2004/0265315, and 2011/0091453, the disclosures of each of which are incorporated herein by reference as they relate to anti-CD2 antibodies and antigen-binding fragments thereof, such as the anti-CD2 antibody MEDI-507. In one embodiment, the anti-CD2 antibody is siplizumab or an antigen-binding fragment thereof.

Other anti-CD2 antibodies that can be used in combination with the compositions and methods described herein include, for example, the anti-CD2 antibodies that are described in U.S. Patent Nos. 6,541,611 and 7,250,167, the disclosures of each of which are incorporated herein by reference as they relate to anti-CD2 antibodies and antigen-binding fragments thereof, such as the anti-CD2 antibody LO-CD2b and antibodies produced by the hybridoma cell line deposited under ATCC Deposit Number PTA-802. Exemplary antibodies that can be used in combination with the compositions and methods described herein include humanized antibodies comprising one or more, or all, of the CDR sequences of an antibody isolated from the hybridoma cell line deposited under ATCC Deposit Number PTA-802.

Other anti-CD2 antibodies that can be used in combination with the compositions and methods described herein include, for example, the anti-CD2 antibodies that are described in U.S. Patent Nos. 5,795,572 and 5,807,734, the disclosures of each of which are incorporated herein by reference as they relate to anti-CD2 antibodies and antigen-binding fragments thereof, such as the anti-CD2 antibody produced by the hybridoma cell line deposited under ATCC Deposit No. HB 69277. For example, anti-CD2 antibodies and antigen-binding fragments thereof that can be used in combination with the compositions and methods described herein include those comprising a hinge region characterized by the amino acid sequence EPKSSDKTHTSPPSP (SEQ ID NO: 316), such as scFv fragments comprising a hinge region characterized by the amino acid sequence EPKSSDKTHTSPPSP (SEQ ID NO: 316). The inclusion of a hinge region with the amino acid sequence of SEQ ID NO: 316 may be advantageous because this hinge motif has been mutated relative to wild-type hinge region sequences to eliminate potentially reactive cysteine residues that may contribute to undesirable oxidative dimerization of a single-chain antibody fragment, such as an scFv fragment.

Other anti-CD2 antibodies that can be used in combination with the compositions and methods described herein include, for example, anti-CD2 antibodies that are described in U.S. Patent No. 6,764,688, such as the anti-CD2 antibody TS2/18 and antibodies produced by the hybridoma cell line deposited under ATCC Deposit No. HB-195. The disclosure of U.S. Patent No. 6,764,688 is incorporated herein by reference as it relates to anti-CD2 antibodies and antigen-binding fragments thereof.

Other anti-CD2 antibodies that can be used in combination with the compositions and methods described herein include, for example, anti-CD2 antibodies that are described in U.S. Patent Nos. 6,162,432, 6,558,662, 7,408,039, 7,332,157, 7,638,121, 7,939,062, and 7,115,259, U.S. Patent Application Publication Nos. 2006/0084107, 2014/0369974, 2002/0051784, and 2013/0183322, and PCT Publication No. WO 1992/016563, the disclosures of each of which are incorporated herein by reference as they relate to anti-CD2 antibodies and antigen-binding fragments thereof.

Antibodies to Her2

Antibodies specific to the Her2 antigen are known to those skilled in the art, such as trastuzumab.

Antibodies to PSMA

Antibodies specific to prostate specific membrane antigen (PSMA) contained in the ADC of the present invention have been disclosed in WO 2020/025564 A1, the disclosure of which is incorporated herein by reference in its entirety.

Fc mutations

The antibodies or binding fragments described herein may also include modifications and/or mutations that alter properties of the antibodies and/or fragments, such as properties that increase half-life, increase or decrease ADCC, etc., as known in the art.

According to one embodiment, the antibody or binding fragment thereof comprises a variant Fc region, wherein said variant Fc region comprises at least one amino acid modification relative to a wild-type Fc region such that said molecule has an altered affinity for FcgammaR. Certain amino acid positions in the Fc region are known from crystallographic studies to be in direct contact with FcγR. In particular, amino acids 234-239 (hinge region), amino acids 265-269 (B/C loop), amino acids 297-299 (C'/E loop), and amino acids 327-332 (F/G loop) (see Sondermann et al., 2000 Nature, 406: 267-273). Thus, the antibodies described herein (e.g., anti-CD117, CD45, CD137, CD2, CD5, CD262, or CD134 antibodies) can comprise variant Fc regions comprising a modification of at least one residue that makes direct contact with an FcγR based on structural and crystallographic analysis. In one embodiment, the Fc region of the antibody (or fragment thereof) comprises an amino acid substitution at amino acid 265 according to the EU index as in Kabat et al., Sequences of Proteins of Immunological Interest, 5th ed. Public Health Service, NH1, MD (1991), expressly incorporated herein by reference. "EU index according to Kabat" refers to the EU numbering of the human IgG1 antibody. "EU index" or "EU index according to Kabat" or "EU numbering scheme" refers to the EU numbering of an antibody (Edelman et al., 1969, Proc Natl Acad Sci USA 63:78-85, incorporated herein by reference in its entirety). In one embodiment, the Fc region comprises a D265A mutation. In one embodiment, the Fc region comprises a D265C mutation. In some embodiments, the Fc region of the antibody (or fragment thereof) comprises an amino acid substitution at amino acid 234 according to the EU index according to Kabat. In one embodiment, the Fc region comprises a L234A mutation. In some embodiments, the Fc region of the antibody (or fragment thereof) comprises an amino acid substitution at amino acid 235 according to the EU index according to Kabat. In one embodiment, the Fc region comprises a L235A mutation. In another embodiment, the Fc region comprises a L234A mutation and L235A. According to a further embodiment, the Fc region of the ADC antibody described herein comprises the mutation D265C, L234A and L235A.

In certain aspects, a variant IgG Fc domain comprises one or more amino acid substitutions that result in decreased or abolished binding affinity for Fc.gamma.R and/or C1q compared to a wild-type Fc domain lacking the one or more amino acid substitutions. Fc binding interactions are required for a variety of effector functions and downstream signaling events, including, but not limited to, antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). Accordingly, in certain aspects, an antibody comprising a modified Fc region (e.g., comprising the L234A, L235A, and D265C mutations) substantially reduces or abolishes effector functions.

The affinity for the Fc region can be determined using a variety of methods known in the art, such as, but not limited to, equilibrium methods (e.g., enzyme-linked immunosorbent assay (ELISA); KinExA, Rathanaswami et al. Analytical Biochemistry, Vol. 373:52-60, 2008; or radioimmunoassay (RIA)), or surface plasmon resonance assay or other kinetics-based assay mechanism (e.g., BIACORE™ assay or Octet™ assay (forteBIO)) and other methods such as indirect binding assays, competitive binding assays, fluorescence resonance energy transfer (FRET), gel electrophoresis and chromatography (e.g., gel filtration). These and other methods may employ a label on one or more components of interest and/or employ a variety of detection methods including, but not limited to, chromogenic, fluorescent, luminescent, or isotopic labels. A detailed discussion of binding affinities and kinetics can be found in Paul, W. E., ed., Fundamental Immunology, 4th ed., Lippincott-Raven, Philadelphia (1999), which focuses on antibody-immunogen interactions. One example of a competitive binding assay is a radioimmunoassay, which involves incubating a labeled antigen with an antibody of interest in the presence of increasing amounts of unlabeled antigen and detecting antibody bound to the labeled antigen. The affinity of the antibody of interest for a particular antigen and the dissociation rates of the binding can be determined from the data using Scatchard plot analysis. Competition with a second antibody can also be determined using a radioimmunoassay. In this case, the antigen is incubated with the antibody of interest conjugated to a labeled compound in the presence of increasing amounts of an unlabeled second antibody.

Antibodies can be further engineered to further modulate antibody half-life by introducing additional Fc mutations, such as those described, for example, in (Dall'Acqua et al. (2006) J Biol Chem 281: 23514-24), (Zalevsky et al. (2010) Nat Biotechnol 28: 157-9), (Hinton et al. (2004) J Biol Chem 279: 6213-6), (Hinton et al. (2006) J Immunol 176: 346-56), (Shields et al. (2001) J Biol Chem 276: 6591-604), (Petkova et al. (2006) Int Immunol 18: 1759-69), (Datta-Mannan et al. (2007) Drug Metab Dispos 35: 86–94), (Vaccaro et al. (2005) Nat Biotechnol 23: 1283–8), (Yeung et al. (2010) Cancer Res 70: 3269–77), and (Kim et al. (1999) Eur J Immunol 29: 2819–25), and include positions 250, 252, 253, 254, 256, 257, 307, 376, 380, 428, 434, and 435. Illustrative mutations that can be made individually or in combination are the T250Q, M252Y, 1253A, S254T, T256E, P2571, T307A, D376V, E380A, M428L, H433K, N434S, N434A, N434H, N434F, H435A and H435R

Thus, in one embodiment, the Fc region comprises a mutation that results in a decreased half-life. An antibody having a short half-life may be useful in some cases where the antibody is expected to act as a short-term therapeutic agent, such as in the conditioning step described herein, where the antibody is administered followed by HSCs. Ideally, the antibody should be substantially purified prior to delivery to HSCs, which also typically express an antigen targeted by the ADC described herein, such as CD117, but are not targeted by the ADC, unlike endogenous stem cells. In one embodiment, the Fc regions comprise a mutation at position 435 (EU index according to Kabat). In one embodiment, the mutation is the H435A mutation.

In one embodiment, an antibody described herein has a half-life of equal to or less than 24 hours, equal to or less than 22 hours, equal to or less than 20 hours, equal to or less than 18 hours, equal to or less than 16 hours, equal to or less than 14 hours, equal to or less than 13 hours, equal to or less than 12 hours, or equal to or less than 11 hours. In one embodiment, the half-life of the antibody is 11 hours - 24 hours; 12 hours - 22 hours; 10 hours - 20 hours; 8 hours - 18 hours; or 14 hours - 24 hours.

In some aspects, the Fc region comprises two or more mutations that result in a decrease in half-life and significantly reduce or completely abolish the effector function of the antibody. In some embodiments, the Fc region comprises a mutation that results in a decrease in half-life and a mutation of at least one residue that can directly contact an FcγR (e.g., based on structural and crystallographic analysis). In one embodiment, the Fc region comprises an H435A mutation, an L234A mutation, and an L235A mutation. In one embodiment, the Fc region comprises an H435A mutation and a D265C mutation. In one embodiment, the Fc region comprises an H435A mutation, an L234A mutation, an L235A mutation, and a D265C mutation.

In some embodiments, the antibody or antigen-binding fragment thereof is conjugated to a cytotoxin (e.g., amatoxin) via a cysteine residue in the Fc domain of the antibody or antigen-binding fragment thereof. In some embodiments, the cysteine residue is introduced by mutation in the Fc domain of the antibody or antigen-binding fragment thereof. For example, the cysteine residue can be selected from the group consisting of Cys118, Cys239, and Cys265. In one embodiment, the Fc region of the anti-CD117 antibody (or fragment thereof) comprises an amino acid substitution at amino acid 265 according to the EU index according to Kabat. In one embodiment, the Fc region comprises the D265C mutation. In one embodiment, the Fc region comprises the D265C mutation and H435A. In one embodiment, the Fc region comprises the D265C mutation, L234A, and L235A. According to one embodiment, the Fc region comprises a mutation of D265C, L234A, L235A, and H435A.

According to some embodiments of these aspects, the cysteine residue occurs naturally in the Fc domain of the antibody or an antigen-binding fragment thereof. For example, the Fc domain can be an IgG Fc domain, such as a human IgG1 Fc domain, and the cysteine residue can be selected from the group consisting of Cys261, Csy321, Cys367, and Cys425.

For example, in one embodiment, the Fc region of antibody 67 is modified to include the D265C mutation (e.g., SEQ ID NO: 111). In another embodiment, the Fc region of antibody 67 is modified to include the D265C, L234A, and L235A mutations (e.g., SEQ ID NO: 112). In another embodiment, the Fc region of antibody 67 is modified to include the D265C and H435A mutations (e.g., SEQ ID NO: 113). In a further embodiment, the Fc region of antibody 67 is modified to include the D265C, L234A, L235A, and H435A mutations (e.g., SEQ ID NO: 114).

With respect to antibody 55, in one embodiment, the Fc region of antibody 55 is modified to include the D265C mutation (e.g., SEQ ID NO: 117). In another embodiment, the Fc region of antibody 55 is modified to include the D265C, L234A, and L235A mutations (e.g., SEQ ID NO: 118). In another embodiment, the Fc region of antibody 55 is modified to include the D265C and H435A mutations (e.g., SEQ ID NO: 119). In a further embodiment, the Fc region of antibody 55 is modified to include the D265C, L234A, L235A, and H435A mutations (e.g., SEQ ID NO: 120).

The Fc regions of any of antibody 54, antibody 55, antibody 56, antibody 57, antibody 58, antibody 61, antibody 66, antibody 67, antibody 68, or antibody 69 may be modified to include a D265C mutation (e.g., as in SEQ ID NO: 123); a D265C, L234A, and L235A mutation (e.g., as in SEQ ID NO: 124); a D265C and H435A mutation (e.g., as in SEQ ID NO: 125); or a D265C, L234A, L235A, and H435A mutation (e.g., as in SEQ ID NO: 126).

The variant Fc domains described herein are defined according to the amino acid modifications that comprise them. For all amino acid substitutions discussed herein with respect to the Fc region, the numbering always follows the EU index. Thus, for example, D265C is an Fc variant with an aspartic acid (D) at EU position 265 substituted with a cysteine (C) relative to the parent Fc domain. Similarly, for example, D265C/L234A/L235A defines an Fc variant with substitutions at EU positions 265 (D to C), 234 (L to A), and 235 (L to A) relative to the parent Fc domain. A variant may also be designated according to its final amino acid composition at the mutated EU amino acid positions. For example, the L234A/L235A mutant may be referred to as LALA. It should be noted that the order in which the substitutions are presented is arbitrary.

According to one embodiment, the antibody or antigen-binding fragment thereof comprises variable regions characterized by an amino acid sequence that is at least 95%, 96%, 97%, or 99% identical to SEQ ID No disclosed herein. Alternatively, the antibody or antigen-binding fragment thereof comprises CDRs comprising SEQ ID No disclosed herein with framework regions of the variable regions described herein, with an amino acid sequence that is at least 95%, 96%, 97%, or 99% identical to SEQ ID No disclosed herein.

According to one embodiment, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region and a heavy chain constant region with an amino acid sequence as disclosed herein. According to another embodiment, the antibody or antigen-binding fragment thereof comprises a light chain variable region and a light chain constant region with an amino acid sequence as disclosed herein. According to another embodiment, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region, a light chain variable region, a heavy chain constant region, and a light chain constant region with an amino acid sequence as disclosed herein.

Methods for identifying antibodies

The present document provides novel ADCs that can be used, for example, in methods for conditioning stem cell transplantation. Given the disclosure herein, other antibodies that can be used in the ADCs and methods of the present invention can be identified.

Methods for high-throughput screening of antibodies or libraries of antibody fragments for molecules capable of binding a cell surface antigen (e.g., CD117, CD45, CD2, CD5, CD134, CD252, CD137) can be used to identify and detect affinity-matured antibodies useful for treating cancers, autoimmune diseases, and conditioning a patient (e.g., a human patient) in need of hematopoietic stem cell therapy as described herein. Such methods include in vitro display methods known in the art such as, but not limited to, phage display, bacterial display, yeast display, mammalian cell display, ribosome display, mRNA display, and cDNA display. The use of phage display to isolate ligands that bind biologically relevant molecules has been reviewed in, for example, Felici et al., Biotechnol. Annual Rev. 1:149-183, 1995; Katz, Annual Rev. Biophys. Biomol. Struct. 26:27-45, 1997; and Hoogenboom et al., Immunotechnology 4:1-20, 1998, the disclosures of each of which are incorporated herein by reference as they relate to in vitro display methods. Randomized combinatorial peptide libraries have been generated to select polypeptides that bind cell surface antigens as described in Kay, Perspect. Drug Discovery Des. 2:251-268, 1995 and Kay et al., Mol. Divers. 1:139-140, 1996, the disclosures of each of which are incorporated herein by reference as they relate to the discovery of antigen-binding molecules. Proteins, such as multimeric proteins, have been successfully displayed by phages as functional molecules (see, e.g., EP 0349578; EP 4527839 and EP 0589877, and Chiswell and McCafferty, Trends Biotechnol. 10:80-84 1992, the disclosures of each of which are incorporated herein by reference as they relate to the use of in vitro display methods for the discovery of antigen-binding molecules). In addition, functional antibody fragments, such as Fab and scFv fragments, have been expressed in in vitro display formats (see, e.g., McCafferty et al., Nature 348:552-554, 1990; Barbas et al., Proc. Natl. Acad. Sci. USA 88:7978-7982, 1991; and Clackson et al., Nature 352:624-628, 1991, the disclosures of each of which are incorporated herein by reference as they relate to in vitro display platforms for the discovery of antigen-binding molecules). These methods can be used, among other things, to identify and enhance the affinity of antibodies that bind, for example, CD117, CD45, CD2, CD5, CD134, CD252, CD137 (e.g., GNNK+ CD117), which in turn can be used to deplete endogenous hematopoietic stem cells in a patient (e.g., a human patient) in need of hematopoietic stem cell transplantation therapy.

In addition to in vitro display methods, computational modeling methods can be used to design and identify antibodies and antibody fragments in silico that bind a cell surface antigen (e.g., CD117, CD45, CD2, CD5, CD134, CD252, CD137). For example, using computational modeling methods, one skilled in the art can screen libraries of antibodies and antibody fragments in silico for molecules capable of binding specific epitopes, such as extracellular epitopes of this antigen. Antibodies and antigen-binding fragments thereof identified by these computational methods can be used in combination with the therapeutic methods described herein, such as the methods for treating cancer and autoimmune disease described herein, and the patient conditioning procedures described herein.

Additional methods can be used to identify antibodies and antigen-binding fragments thereof that bind a cell surface antigen (e.g., CD117) on the surface of a cell (e.g., a cancer cell, an autoimmune cell, or a hematopoietic stem cell) and that are internalized by the cell, such as through receptor-mediated endocytosis. For example, the in vitro display methods described above can be adapted to screen for antibodies and antigen-binding fragments thereof that bind a cell surface antigen (e.g., CD117) on the surface of a cancer cell, an autoimmune cell, or a hematopoietic stem cell and that are subsequently internalized. Phage display is one such method that can be used in conjunction with this screening paradigm. To identify antibodies and fragments thereof that bind a cell surface antigen (e.g., CD117) and are subsequently internalized by cancer cells, autoimmune cells, or hematopoietic stem cells, one skilled in the art can adapt phage display techniques described, for example, in Williams et al., Leukemia 19:1432-1438, 2005, the disclosure of which is incorporated herein by reference in its entirety. For example, using mutagenesis techniques known in the art, recombinant phage libraries can be produced that encode antibodies, antibody fragments such as scFv fragments, Fab fragments, diabodies, triabodies, and Fn3 domains ¹⁰ , among others, or ligands that contain randomized amino acid cassettes (e.g., in one or more or all of the CDRs or equivalent regions thereof or an antibody or antibody fragment). The framework regions, hinge region, Fc domain, and other regions of antibodies or antibody fragments can be designed to be non-immunogenic in humans, such as by having human germline antibody sequences or sequences that exhibit only minor variations relative to human germline antibodies.

Using phage display techniques described herein or known in the art, phage libraries containing randomized antibodies or antibody fragments covalently linked to phage particles can be incubated with a target cell surface antigen (e.g., CD117), for example, by first incubating the phage library with blocking agents (such as, for example, milk protein, bovine serum albumin, and/or IgG to remove phage encoding antibodies or fragments thereof that exhibit non-specific protein binding and phage encoding antibodies or fragments thereof that bind Fc domains, and then incubating the phage library with a population of hematopoietic stem cells. The phage library can be incubated with target cells, such as cancer cells, autoimmune cells, or hematopoietic stem cells, for a time sufficient to allow the cell surface antigen-specific antibodies or antigen-binding fragments thereof to (e.g., CD117-specific antibodies or antigen-binding fragments thereof) to bind to a cell surface antigen (e.g., cell surface CD117) and then be internalized by cancer cells, autoimmune cells, or hematopoietic stem cells (e.g., 30 minutes to 6 hours at 4°C, e.g., 1 hour at 4°C). Phage containing antibodies or fragments thereof that do not exhibit sufficient affinity for one or more of these antigens to allow binding to and internalization by cancer cells, autoimmune cells, or hematopoietic stem cells can subsequently be removed by washing the cells, e.g., with cold (4°C) 0.1 M glycine buffer at pH 2.8. Phage bound to antibodies or fragments thereof that have been internalized by cancer cells, autoimmune cells or hematopoietic stem cells can be identified, for example, by lysing the cells and isolating the internalized phage from the cell culture medium. The phage can then be amplified in bacterial cells, for example, by incubating the bacterial cells with the isolated phage in 2xYT medium using methods known in the art. The phage isolated from this medium can then be characterized, for example, by determining the nucleic acid sequence of the gene(s) encoding the antibodies or fragments thereof inserted into the phage genome. The encoded antibodies or fragments thereof can subsequently be produced de novo by chemical synthesis (e.g., antibody fragments such as scFv fragments) or recombinant expression (e.g., full-length antibodies).

An exemplary method for in vitro development of antibodies to a cell surface antigen (e.g., an anti-CD117 antibody) for use with the compositions and methods described herein is phage display. Phage display libraries can be created by creating a designed series of mutations or variations in the coding sequence for the CDRs of an antibody or similar regions of an antibody-like framework (e.g., the BC, CD, and DE loops of the ¹⁰ Fn3 domains). The sequence encoding the template antibody into which these mutations are introduced can be, for example, a naive human germline sequence. These mutations can be made using standard mutagenesis techniques known in the art. Thus, each mutant sequence encodes an antibody corresponding to the template, except for one or more amino acid variations. Retroviral vectors and phage display vectors can be constructed using standard vector construction techniques known in the art. P3 phage display vectors, together with compatible protein expression vectors, can be used to generate phage display vectors to expand antibody diversity.

The mutated DNA provides sequence diversity, and each transformant phage displays one variant of the original template amino acid sequence encoded by the DNA, resulting in a phage population (library) displaying a huge number of different, but structurally related, amino acid sequences. Because of the well-defined structure of the antibody hypervariable regions, amino acid variations introduced into the phage display screen are expected to alter the binding properties of the binding peptide or domain without significantly altering its overall molecular structure.

In a typical screen, a phage library may be contacted and allowed to bind to one of the above antigens or their epitope. To facilitate the separation of binders and non-binders, it is convenient to immobilize the target on a solid support. Phage carrying a cell surface-binding moiety can complex with the target on the solid support, while non-binding phage remain in solution and can be washed away with excess buffer. Bound phage can then be released from the target by changing the buffer to an extreme pH (pH 2 or pH 10), changing the ionic strength of the buffer, adding denaturants, or other known methods.

The isolated phage can then be amplified by infecting bacterial cells, and the screening process can be repeated with a new pool that is now depleted of nonbinding antibodies and enriched for antibodies that bind the target antigen (e.g., CD117). Recovery of even a few binding phage is sufficient to amplify the phage for the next iteration of the screen. After several rounds of selection, the gene sequences encoding antibodies or their antigen-binding fragments obtained from selected phage clones in the binding pool are determined by conventional methods, thereby identifying the peptide sequence that confers binding affinity to the target. During the panning process, the sequence diversity of the population is reduced with each round of selection until the desired peptide-binding antibodies remain. Sequences may converge on a small number of related antibodies or their antigen-binding fragments. An increase in the number of phages recovered in each round of selection is an indication that library convergence has occurred on the screen.

Another method for identifying antibodies involves the use of humanized non-human antibodies that bind a target cell surface antigen (e.g., CD117), such as according to the following procedure. Consensus sequences of human antibody heavy and light chains are known in the art (see, e.g., the human germline sequence database "VBASE"; Kabat et al. Sequences of Proteins of Immunological Interest, 5th ed., U.S. Department of Health and Human Services, NIH Publication No. 91-3242, 1991; Tomlinson et al., J. Mol. Biol. 227:776-798, 1992; and Cox et al. Eur. J. Immunol. 24:827-836, 1994, the disclosures of which are each incorporated herein by reference as they relate to human antibody heavy chain and light chain consensus sequences. Using established procedures, one of skill in the art can identify the framework residues of the variable domain and CDRs of an antibody consensus sequence (e.g., by sequence alignment). One or several CDRs of the variable domains of the heavy chain and/or light chain of a human antibody consensus sequence with one or more corresponding CDRs of a non-human antibody that binds a cell surface antigen (e.g., CD117), as described herein, to produce a humanized antibody. This CDR exchange can be accomplished using gene editing techniques described herein or known in the art.

To produce humanized antibodies, a polynucleotide encoding the above consensus sequence can be recombinantly expressed in which one or more CDRs of the variable region have been replaced by one or more CDR sequences of the variable region of a non-human antibody that binds a target cell surface antigen (e.g., CD117). Since the affinity of an antibody for a hematopoietic stem cell antigen is determined primarily by the CDR sequences, the resulting humanized antibody is expected to exhibit an affinity for a hematopoietic stem cell antigen that is approximately the same as that of the non-human antibody from which the humanized antibody was derived. Methods for determining the affinity of an antibody for a target antigen include, for example, ELISA-based methods described herein and known in the art, as well as, among others, surface plasmon resonance, fluorescence anisotropy, and isothermal titration calorimetry.

The ability of an antibody or fragment thereof to be internalized can be assessed, for example, using radionuclide internalization assays known in the art. For example, antibodies or fragments thereof identified using the in vitro display methods described herein or known in the art can be functionalized by incorporating a radioactive isotope such as ¹⁸ F, ⁷⁵ Br, ⁷⁷ Br, ¹²² I, ¹²³ I, ¹²⁴ I, ¹²⁵ I, ¹²⁹ I, ¹³¹ I, ²¹¹ At, ⁶⁷ Ga, ¹¹¹ In, ⁹⁹ Tc, ¹⁶⁹ Yb, ¹⁸⁶ Re, ⁶⁴ Cu, ⁶⁷ Cu, ¹⁷⁷ Lu, ⁷⁷ As, ⁷² As, ⁸⁶ Y, ⁹⁰ Y, ⁸⁹ Zr, ²¹² Bi, ²¹³ Bi, or ²²⁵ Ac. For example, radioactive halogens such as ¹⁸ F, ⁷⁵ Br, ⁷⁷ Br, ¹²² I, ¹²³ I, ¹²⁴ I, ¹²⁵ I, ¹²⁹ I, ¹³¹ I, ²¹¹ At can be incorporated into antibodies or fragments thereof using beads such as polystyrene beads containing electrophilic halogen reagents (e.g., Iodination Beads, Thermo Fisher Scientific, Inc., Cambridge, MA). The radioactively labeled antibodies or fragments thereof can be incubated with cancer cells, autoimmune cells, or hematopoietic stem cells for a time sufficient to allow internalization (e.g., 30 minutes to 6 hours at 4°C, e.g., 1 hour at 4°C). The cells can then be washed to remove non-internalized antibodies or fragments thereof (e.g., using cold (4°C) 0.1 M glycine buffer at pH 2.8). Internalized antibodies or fragments thereof can be identified by detecting the emitted radiation (e.g., γ-radiation) of the recovered cancer cells, autoimmune cells, or hematopoietic stem cells compared to the emitted radiation (e.g., γ-radiation) of the recovered wash buffer.

Antibodies can be produced using recombinant methods and compositions, for example, as described in U.S. Patent No. 4,816,567. According to one embodiment, an isolated nucleic acid encoding an antibody as described herein is provided. Such a nucleic acid can encode an amino acid sequence comprising a VL and/or an amino acid sequence comprising a VH of an antibody (e.g., a light and/or heavy chain of an antibody). According to a further embodiment, one or more vectors (e.g., expression vectors) comprising such a nucleic acid are provided. According to a further embodiment, a host cell comprising such a nucleic acid is provided. In one such embodiment, the host cell comprises (e.g., has been transformed with): (1) a vector comprising a nucleic acid encoding an amino acid sequence comprising a VL antibody and an amino acid sequence comprising a VH antibody, or (2) a first vector comprising a nucleic acid encoding an amino acid sequence comprising a VL antibody and a second vector comprising a nucleic acid that encodes an amino acid sequence comprising a VH antibody. In one embodiment, the host cell is eukaryotic, such as a Chinese hamster ovary (CHO) cell or a lymphoid cell (e.g., a Y0, NS0, Sp20 cell). According to one embodiment, a method for producing an antibody to CLL-1 is provided, wherein the method comprises culturing a host cell comprising a nucleic acid encoding the antibody as described above under conditions suitable for expression of the antibody, and optionally isolating the antibody from the host cell (or a host cell culture medium).

For recombinant production of an antibody, nucleic acid encoding the antibody, for example as described above, is isolated and inserted into one or more vectors for subsequent cloning and/or expression in a host cell. Such nucleic acid can be readily isolated and sequenced using conventional procedures (e.g., using oligonucleotide probes that are capable of specifically binding to genes encoding the heavy and light chains of the antibody).

Suitable host cells for cloning or expressing vectors encoding antibodies include prokaryotic or eukaryotic cells as described herein. For example, antibodies can be produced in bacteria, particularly when glycosylation and Fc effector function are not required. For expression of antibody fragments and polypeptides in bacteria, see, for example, U.S. Patent Nos. 5,648,237, 5,789,199, and 5,840,523. (See also Charlton, Methods in Molecular Biology, Vol. 248 (BKC Lo, ed., Humana Press, Totowa, NJ, 2003), pp. 245-254, for a description of expression of antibody fragments in E. coli.) After expression, the antibody can be isolated from the bacterial cell paste in a soluble fraction and can be further purified.

Vertebrate cells can also be used as hosts. For example, mammalian cell lines adapted for growth in suspension can be used. Other examples of useful mammalian host cell lines are the SV40-transformed monkey kidney line CV1 (COS-7); the human mesonephros line (293 or 293 cells, as described, e.g., by Graham et al., J. Gen Virol. 36:59 (1977)); baby hamster kidney cells (BHK); mouse Sertoli cells (TM4 cells, as described, e.g., by Mather, Biol. Reprod. 23:243-251 (1980)); monkey kidney cells (CV1); African green monkey kidney cells (VERO-76); human cervical carcinoma cells (HELA); canine kidney cells (MDCK); Buffalo rat liver cells (BRL 3A); human lung cells (W138); human liver cells (Hep G2); mouse mammary tumor (MMT 060562); TRI cells, as described, e.g., in Mather et al., Annals N.Y. Acad. Sci. 383:44–68 (1982); MRC 5 cells; and FS4 cells. Other useful mammalian host cell lines include Chinese hamster ovary (CHO) cells, including DHFR-CHO cells (Urlaub et al., Proc. Natl. Acad. Sci. USA 77:4216 (1980)); and myeloma cell lines such as Y0, NS0, and Sp2/0. For a review of some mammalian host cell lines suitable for antibody production, see, e.g., Yazaki and Wu, Methods in Molecular Biology, Vol. 248 (B.K.C. Lo, ed., Humana Press, Totowa, N.J.), pp. 255-268 (2003).

Pharmaceutical compositions

According to one aspect of the present invention, the present invention relates to a pharmaceutical composition comprising said conjugate as described.

The said pharmaceutical composition may contain one or more pharmaceutically acceptable buffers, surfactants, diluents, carriers, excipients, fillers, binders, lubricants, glidants, disintegrants, adsorbents and/or preservatives.

In aqueous form, said pharmaceutical composition may be ready for administration, while in lyophilized form, said composition may be converted to liquid form before administration, for example, by adding water for injection, which may or may not contain a preservative, such as, for example, but not limited to, benzyl alcohol, antioxidants such as vitamin A, vitamin E, vitamin C, retinyl palmitate and selenium, amino acids cysteine and methionine, citric acid and sodium citrate, synthetic preservatives such as parabens methylparaben and propylparaben.

Said pharmaceutical composition may additionally contain one or more stabilizers, which may be, for example, an amino acid, a sugar polyol, a disaccharide and/or a polysaccharide. Said pharmaceutical composition may additionally contain one or more surfactants, one or more isotonizing agents, and/or one or more metal ion chelators, and/or one or more preservatives.

The pharmaceutical composition described herein may be suitable for at least intravenous, intramuscular or subcutaneous administration. Alternatively, said conjugate according to the present invention may be provided as a depot composition that provides a delayed release of the biologically active agent over a certain period of time.

According to another aspect of the present invention, there is provided a primary packaging, such as a pre-filled syringe or pen, a vial or an infusion bag, which contains the composition according to the previous aspect of the present invention.

The pre-filled syringe or pen may contain the composition either in lyophilized form (which must then be solubilized, for example with water for injection, before administration) or in aqueous form. Said syringe or pen is often a disposable product for single use only and may have a capacity of 0.1 to 20 ml. However, the syringe or pen may also be a reusable syringe or pen or a multi-dose syringe or pen.

Said vial may also contain the composition in lyophilized form or in aqueous form and may serve as a single-use or multiple-use device. As a multiple-use device, said vial may have a larger volume. Said infusion bag typically contains the composition in aqueous form and may have a volume of 20 to 5000 ml.

The ADCs described herein can be administered to a patient (e.g., a human patient suffering from an immune disease or cancer) in various dosage forms. For example, the ADCs described herein can be administered to a patient suffering from an immune disease or cancer in the form of an aqueous solution, such as an aqueous solution containing one or more pharmaceutically acceptable excipients. Suitable pharmaceutically acceptable excipients for use with the compositions and methods described herein include viscosity modifying agents. The aqueous solution can be sterilized using techniques known in the art.

Pharmaceutical formulations containing an ADC as described herein are prepared by mixing such ADC with one or more optional pharmaceutically acceptable carriers (Remington's Pharmaceutical Sciences, 16th edition, Osol, A. Ed. (1980)) in the form of lyophilized formulations or aqueous solutions. Pharmaceutically acceptable carriers are generally nontoxic to recipients at the dosages and concentrations employed and include, but are not limited to, the following: buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride; benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol and m-cresol); low molecular weight polypeptides (less than about 10 residues); proteins such as serum albumin, gelatin or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine or lysine; monosaccharides, disaccharides and other carbohydrates including glucose, mannose or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose, or sorbitol; salt-forming counterions such as sodium; metal complexes (e.g., Zn-protein complexes); and/or nonionic surfactants such as polyethylene glycol (PEG).

Methods of application

The ADCs described herein can be administered by a variety of routes, such as orally, transdermally, subcutaneously, intranasally, intravenously, intramuscularly, intraocularly, or parenterally. The most appropriate route of administration in any particular case will depend on the particular antibody or antigen-binding fragment being administered, the patient, the methods of formulation, the routes of administration (e.g., time of administration and route of administration), the patient's age, body weight, sex, severity of the disease, the patient's diet, and the rate of elimination from the patient's body.

An effective dose of the ADC, antibody, or antigen-binding fragment thereof described herein can range, for example, from about 0.001 to about 100 mg/kg body weight per single (e.g., bolus) administration, multiple administrations, or continuous administration, or to achieve an optimal serum concentration (e.g., a serum concentration of 0.0001-5000 μg/mL) of the antibody, antigen-binding fragment thereof. The dose can be administered one or more times (e.g., 2-10 times) per day, week, or month to a subject (e.g., a human) suffering from cancer, an autoimmune disease, or undergoing conditioning therapy in preparation for receiving a hematopoietic stem cell transplant. In the case of a conditioning procedure prior to hematopoietic stem cell transplantation, the ADC, antibody, or antigen-binding fragment thereof may be administered to the patient at a time that optimally promotes engraftment of exogenous hematopoietic stem cells, such as from 1 hour to 1 week (e.g., about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, about 24 hours, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, or about 7 days) or more before administration of the exogenous hematopoietic stem cell transplant. hematopoietic stem cells.

EXAMPLES

The following examples are presented to provide those of ordinary skill in the art with a description of how the compositions and methods described herein can be used, prepared, and evaluated, and are intended to serve solely as examples of the present invention and are not intended to limit the scope of what the present inventors believe to be their invention.

Example 1: Comparative study of amanitins

Three different amanitins were tested in parallel to determine their kinetics and tolerability as toxins. Figure 1 shows the structures of the three amanitin/linker conjugates. Figure 1A shows the amanitin/linker conjugate of formula (IV) (also called "Conjugate A" or "ADC A"), where amanitin contains a cleavable linker (BMP-Val-Ala-PAB) at AA1 (Asn). The amanitin of formula (IV) is based on amatoxin containing a thiotryptophan moiety. Figure 1B shows an amanitin/linker conjugate represented by formula (VI) (also referred to as "Conjugate B" or "ADC B"), wherein amanitin is conjugated to a non-cleavable linker at the 6' oxygen atom of the indole. The amanitin described in formula (VI) is based on an amatoxin containing a 6-hydroxytryptophan sulfoxide moiety. Figure 1C shows an amanitin/linker conjugate described herein by formula (IIa) (also referred to as "Conjugate C" or "ADC C"), including a non-cleavable linker at the 6' oxygen atom of the indole, wherein amanitin is based on an amatoxin containing a 6-hydroxythiotryptophan moiety.

Conjugates A, B, and C were tested in parallel for their potency on CD117-expressing cells with or without pre-incubation in human serum. ADCs A, B, and C were either pre-incubated in cell culture medium without human serum or in 50% human serum at 37°C for 48 hours. Titrated ADC was then added to Kasumi-1 cells and incubated for 3 days at 37°C and cell killing was determined using CellTiter-Glo. As shown in Figure 2, in the absence of serum incubation, cleavable conjugate A and non-cleavable conjugate C achieved similar potency by day 3, with non-cleavable conjugate B showing a decrease in maximal killing at higher concentrations. Each ADC conjugate demonstrated picomolar killing IC50s. When ADCs were pre-incubated for 48 hours in the presence of human serum, the potency of non-cleavable conjugate B was significantly reduced but maintained for cleavable conjugate A and non-cleavable conjugate C. Thus, cleavable and non-cleavable conjugates A and C were stable in serum, while non-cleavable conjugate B was inactivated in the presence of human serum as measured by in vitro cytotoxicity.

To determine differences in the kinetics of ADC-mediated cytotoxicity, Kasumi-1 cells were incubated with titrations of cleavable conjugate A or non-cleavable conjugate C for 3-7 days at 37°C, and cell viability was measured at days 3, 4, 5, 6, and 7 using CellTiter-Glo. As shown in Figure 3, significant differences in maximal cell killing were observed at high concentrations for cleavable and non-cleavable ADCs. When cells were incubated for 6 days at 37°C with ADC, both cleavable conjugate A and non-cleavable conjugate C were able to achieve nearly complete cell killing at high concentrations. Killing of more than 80% of Kasumi-1 cells in culture with 160 pM non-cleavable conjugate C could only be achieved after incubation of Kasumi-1 cells for 5 days or longer, while a similar threshold was reached for cleavable conjugate A after 3 days of incubation or longer.

Overall, enzyme-cleavable amanitin in Figure 1A (Conjugate A) and non-cleavable amanitin (Conjugate C in Figure 1C) showed long-term stability in serum, while amanitin/linker B showed instability and inactivation in serum. Non-cleavable conjugate C demonstrated enhanced cytotoxicity kinetics measured in an in vitro assay compared to the similar cleavable amanitin conjugate (Conjugate A).

Example 2: Anti-CD117 ADC demonstrates potent killing of AML cells and human CD34+ cells in vitro, selectively depletes human CD34+ cells in humanized mice, and demonstrates anti-AML activity in xenograft models

Anti-CD117 antibody (Ab85 with Fc modifications L234A, L235A, D265C, and H435A) was conjugated to conjugate C to form anti-CD117 ADC C. Anti-CD117 ADC C was tested both in vitro and in vivo for its ability to target and kill CD117-expressing cells and human HSCs.

Two in vitro assays were performed using anti-CD117 ADC C. The first tested the ability of the ADC to kill Kasumi-1 cells (an AML cell line) that express human CD117. As described in Fig. 4A, anti-CD117 ADC C (labeled “anti-CD117-AM” in Fig. 4A) was titrated and incubated with Kasumi-1 cells for 6 days at 37°C, and viability was assessed using CellTiter-Glo. The non-specific isotype-matched ADC C served as a control. The non-cleavable conjugate C demonstrated potent killing of Kasumi-1 cells with an IC50 of 6.4 pM. A similar cytotoxicity assay was performed in Figure 4B using pooled human bone marrow CD34+ cells. Human bone marrow CD34+ cells were incubated with non-cleavable conjugate C or the corresponding isotype control ADC for 6 days. Cell killing was determined by flow cytometry. Non-cleavable conjugate C demonstrated potent killing of primary human CD34+ CD90+ cells with an IC50 of 5.1 pM.

An in vivo assay was also performed to test the ability of anti-CD117 ADC C to selectively deplete human CD34+ cells. A single dose of 0.1, 0.3, or 1.0 mg/kg anti-CD117 ADC C was administered to humanized NSG mice. Controls included a 1 mg/kg dose of unconjugated antibody, which included a portion of the treatment with non-cleavable conjugate C and vehicle (PBS). At day 21, the number of human CD34+ cells was determined by flow cytometric analysis of bone marrow collected from the femurs of treated humanized NSG mice. As shown in Fig. 5, anti-CD117 ADC C was able to efficiently deplete human CD34+ cells, achieving greater than 95% depletion compared to PBS for both the 0.3 and 1 mg/kg doses. Unconjugated antibody did not show depletion compared to the vehicle control.

To evaluate the in vivo antitumor activity of ADCs, humanized NSG mice were implanted with Kasumi-1 cells and then treated with vehicle, 30 mg/kg cytarabine QDx5 (ARA-C), cleavable conjugate A (1 mg/kg 1×, 1 mg/kg QODx2), or 10 mg/kg isotype conjugated to cleavable amanitin (Fig. 1A). Additionally, Kasumi-1-implanted mice were treated with non-cleavable conjugate C (1 mg/kg 1×, 3 mg/kg 1×, 10 mg/kg 1×) or 10 mg/kg isotype conjugated to non-cleavable amanitin (Fig. 1C). Kaplan-Meier curves showing survival of animals treated as indicated are shown in Figure 6. Mice implanted with Kasumi-1 treated with cleavable conjugate A exhibit median survival greater than 50% at day 130 for the 1 mg/kg or 1 mg/kg QODx2 groups compared to animals treated with isotype, ARA-C, or vehicle. Mice treated with 3 mg/kg or 10 mg/kg non-cleavable conjugate C exhibit complete survival at day 130 compared to animals treated with isotype, ARA-C, 1 mg/kg non-cleavable conjugate C, or vehicle.

Thus, non-cleavable conjugate C exhibits potent cell killing in vitro of Kasumi-1 cells, an AML cell line, and primary human bone marrow CD34+ CD90+ cells. Conjugate C is able to deplete more than 95% of human CD34+ cells from the bone marrow of humanized NSG mice. Both cleavable and non-cleavable conjugates demonstrated potent antitumor activity in vivo.

Example 3: Efficacy and Tolerability of ADC C in Non-Human Primates (NHP)

To determine the efficacy of non-cleavable conjugate C in non-human primates, male cynomolgus macaques were treated with a single dose of non-cleavable conjugate C at doses of 0.5, 1.0, and 2.0 mg/kg. The 0.5 and 1.0 mg/kg doses contained Ab85 with the following Fc modifications: D265C H435A (EU numbering) conjugated to non-cleavable amanitin C (Fig. 1C). The 2.0 mg/kg dose contained Ab85 with the following Fc modifications: L234A L235A D265C H435A (EU numbering) conjugated to non-cleavable amanitin C (Fig. 1C). Bone marrow aspirates were collected from treated animals on day 7 and efficacy was assessed by quantification of CD34+ CD90+ CD45RA- populations by flow cytometry. Significant depletion was observed at the 0.5 and 1.0 mg/kg doses. Peripheral blood samples were collected throughout the 28-day study. Reticulocyte counts in animals treated with 0.5, 1.0, and 2.0 mg/kg were significantly reduced beginning on day 2, with reticulocyte recovery occurring in a dose-dependent manner. This is expected in the targeting pharmacology since reticulocytes are short-lived and progenitor populations in this hematopoietic lineage highly express CD117. Neutrophil depletion was observed beginning on day 18 for all treatment groups. This is also expected in the targeting pharmacology since neutrophils depend on hematopoietic stem cell differentiation for regeneration.

In addition to efficacy, the tolerability of ADCs containing either anti-CD117 ADC A or anti-CD117 ADC C was tested in NHPs. As shown in Figure 8, treatment of cynomolgus monkeys with 0.3 mg/kg of cleavable conjugate A conjugated to the CK6 antibody (Fc modifications D265C and H435A) resulted in modest, transient, and reversible increases in aspartate aminotransferase (AST) levels without increases above normal in alanine aminotransferase (ALT), lactate dehydrogenase (LDH), or total bilirubin (TBIL) over the course of the study. Treatment of animals with 0.6 mg/kg conjugate A resulted in larger increases in AST, ALT, LDH, and TBIL.

In cynomolgus monkeys treated with 0.5 and 1.0 mg/kg of non-cleavable conjugate C, Ab85 with the following Fc modifications: D265C H435A (EU numbering) conjugated to non-cleavable amanitin C (Fig. 1C), showed a moderate, transient and reversible increase in AST levels without increasing ALT, LDH and TBIL levels above normal throughout the study. Animals treated with 2.0 mg/kg of non-cleavable conjugate C, Ab85 with the following Fc modifications: L234A L235A D265C H435A (EU numbering) conjugated to non-cleavable amanitin C (Fig. 1C), showed greater increases in AST and ALT.

Pharmacokinetic characteristics were also studied for anti-CD117 ADC A compared to ADC C. As shown in Fig. 9, well-tolerated doses of ADC conjugate C provided burst saturation in NHP compared to ADC conjugate A. Pharmacokinetic data were also analyzed for ADC conjugate C with different Fc mutations. For both anti-CD117 ADC A and anti-CD117 ADC C, ex vivo cytotoxicity assays showed that both ADCs exhibited loss of efficacy at plasma concentrations below 100 ng/mL (data not shown).

Overall, ADC C against CD117 demonstrated efficacy at doses as low as 0.5 mg/kg and was tolerated at a single dose of 2.0 mg/kg in cynomolgus monkeys, while cleavable conjugate A was efficacious at doses as low as 0.3 mg/kg but not tolerated at a single dose of 0.6 mg/kg, supporting the conclusion that non-cleavable amanitin (Fig. 1C) is better tolerated.

Example 4: Destruction of primary human T cells using anti-CD2 ADC and anti-CD5 ADC

A study was conducted to determine whether the anti-CD2 and anti-CD5 D265C H435A antibodies used in ADC C (as described above and in Fig. 1) were as effective as conjugate A in killing primary T cells. Therefore, an in vitro cell killing assay was used. The study protocol is presented below:

Anti-CD2 ADCs A and C included the anti-CD2 antibody RPA with FC modifications D265C/H435A. Naked RPA was used as a control.

Anti-CD5 ADCs A and C included the anti-CD5 antibody 5D7 with Fc modifications D265C/H435A. Naked 5D7 was used as a control. As shown in Fig. 12, conjugate C demonstrated T cell depletion comparable to conjugate A. The efficacy results are also presented in the table below.

Figure 13 shows the results showing that CD2 is saturated by day 5, while some cells still express CD5.

The results above and in Figures 12 and 13 show that both anti-CD2 and anti-CD5 ADC C (D265C H435A) were as effective as conjugate A on primary human T cells in vitro.

Example 5: Efficacy of ADC C against CD45

In addition to CD2, CD5 and CD117, conjugate C was tested against conjugate A in the context of CD45 antibodies. A chimeric CD45 antibody, 3D6, was used in the experiments below (mouse 3D6 variable regions and human IgG1 framework with Fc modifications D265C and H435A).

An in vitro cell killing assay was performed to compare anti-CD45 ADC A and anti-CD45 ADC C. As shown in Fig. 14A, both ADC A and C were able to kill human bone marrow CD34+ cells as well as PBMC. A negative isotype control was also tested. As described in the table presented in Fig. 14A, both anti-CD45 ADC A and C were effective in killing CD34+ bone marrow and PBMC cells. This assay was repeated with anti-CD45 ADC A and B. As shown in Fig. 14B, anti-CD45 ADC A showed higher potency in killing CD34+ bone marrow cells compared to anti-CD45 ADC B. Both molecules were similarly effective in killing human and cynomolgus monkey PBMC.

A second in vitro cell killing assay was also performed using anti-CD45 ADCs A and C, examining the ability of each ADC to kill cells expressing either SKNO-1 or REH. The results are shown in Figure 13 (left panel represents the number of live SKNO-1 cells after exposure to anti-CD45 ADCs A or C; right panel represents the number of live REH cells after exposure to anti-CD45 ADCs A or C). The potency of each molecule in these assays is described in the table in Figure 13.

Anti-CD45 ADCs A and C were further tested for the ability of each ADC to deplete CD45+ cells in vivo. Both ADC A (cleavable) and ADC C (non-cleavable) were able to effectively deplete CD45+ cells in the humanized NSG mouse model. The results of the study are presented in Fig. 14. As shown in Fig. 16, both ADCs were able to deplete peripheral CD45+ cells as well as bone marrow (BM) CD34+ cells. The maximum total dose in mice for anti-CD45 ADC A was 3 mg/kg, whereas a much higher dose of ADC C was tolerated for anti-CD45 ADC C at greater than 51 mg/kg. Thus, efficacy was observed for both anti-CD45 ADCs, but ADC C was tolerated in mice at the higher doses.

Anti-CD45 ADCs A and C were also tested for their ability to deplete peripheral lymphocytes, bone marrow (BM) HSCs, and lymphocytes in humanized NSG mice. Anti-CD45 ADCs A and C were each delivered to mice at a dose of 1 mg/kg. The results of these studies are described in Fig. 15 and show that anti-CD45 ADCs A and C exhibited comparable depletion of peripheral lymphocytes, HSCs, and BM lymphocytes at day 7 post-injection at a dose of 1 mg/kg. Anti-CD45 ADC A exhibited a modest, transient, reversible elevation of liver enzymes at a dose of 1 mg/kg, while virtually no elevation of liver enzymes was observed with anti-CD45 ADC C at the same dose of 1 mg/kg.

Example 6: Characterization of ADCs A and C against CD137

Anti-CD137 ADC A and ADC C were tested for their ability to kill T cells as well as stability in serum. In this example, the anti-CD137 antibody BBK2 was used. An in vitro T cell killing assay was performed, where the results shown in Figure 16 demonstrated that both anti-CD137 ADC A and C were able to kill activated T cells compared to isotype control ADC A and C. Additionally, the cell line stability in serum was tested for both anti-CD137 ADC A and anti-CD137 ADC C over 48 hours as described in Figure 17.

Example 7: Synthesis of S-deoxy-5'-hydroxyamaninamide

The ADCs of formula (Ha) described herein were prepared from the corresponding linker-amatoxin conjugates by standard methods known to those skilled in the art. The penultimate amatoxin-linker conjugate for the ADC of formula (IIa) (compound 14; Scheme 3) can be prepared from amatoxin derivative 11 according to the general procedure for O-alkylation of the related amatoxin (α-amanitin) described in U.S. Patent Application Publication No. 2018/0043033, the disclosure of which is incorporated herein by reference in its entirety. Amatoxin derivative 11 can be prepared according to the procedures disclosed in International Patent Application Publication No. WO 2019/030173, the disclosure of which is incorporated herein by reference in its entirety. Compound 7 (Scheme 1) can be prepared according to the methods described in International Patent Application Publication No. WO 2014/009025, the disclosure of which is incorporated herein in its entirety.

Example 8: Amanitin derivatives

Various amanitin derivatives were used for conjugation with target-specific antibodies (Fig. 18, Fig. 19). They were prepared according to the methods disclosed in WO 2018/115466 and WO 2019/197654, the disclosures of which are incorporated herein in their entirety.

Example 9: Conjugation method

Antibodies directed to Her2 or prostate-specific membrane antigen (PSMA) were conjugated to amatoxin-linker conjugates using the so-called Thiornab technology. In this approach, conjugation occurs by conjugating the maleimide moiety of the toxin-linker construct to the free SH group of an engineered cysteine residue in the antibody, as shown in the following reaction scheme:

The principles of this conjugation method are disclosed in Junutula et al. (2008), the contents of which are incorporated herein by reference,

The antibodies directed to Her2 (trastuzumab) or prostate-specific membrane antigen (PSMA) used in the present experiments contain a D265C substitution in both Fc domains to provide a cysteine residue that contains such a free SH group. The corresponding technology is disclosed in WO 2016142049 A1, assigned to the present applicant, the contents of which are incorporated herein by reference, and provides a homogeneous product with a fixed drug-to-antibody ratio ("DAR") of 2 and site-specific conjugation.

Example 10: Cytotoxicity Assay with Anti-Her2 ADC In Vitro

The cytotoxic activity of amatoxin conjugates against Her2 was assessed in vitro using target-positive tumor cell lines and a chemiluminescent BrdU incorporation assay (Roche Diagnostics). Cell viability was determined after 96 h of incubation with different concentrations of conjugates at 37°C and 5% _CO2 by measuring fixed and permeabilized cells with an anti-BrdU-HRP antibody in a BMG Labtech Optima microplate reader. The _EC50 value of the dose response curve was calculated using Graphpad Prism 4.0 software.

The cytotoxic activity of trastuzumab carrying the D265C mutation (T-D265C) conjugated to compound 30.2867 (formula (A)) and compound 30.0880 (formula (B)), respectively, via its D265C moiety, was tested in SKBR-3, NCI-N87, BT474, and JIMT-1 cell lines (Fig. 20). T-D265C-30.2867 was slightly superior to T-D265C-30.0880 in all cell lines tested.

Example 11: Stability of anti-Her2 ADC in human, mouse and cynomolgus monkey plasma

The ADC conjugates T-D265C-30.2867 and T-D265C-30.0880, respectively, directed against the Her2 antigen were incubated with human, mouse, and cynomolgus monkey plasma and phosphate-buffered saline (PBS, control), respectively, for 0, 4, and 10 days. The samples were subjected to sodium dodecyl sulfate (SDS)-polyacrylamide gel electrophoresis (SDS-PAGE), and the antibody heavy chain molecules were detected with amanitin-specific polyclonal antiserum by Western blotting (Fig. 21).

ADC conjugate T-D265C-30.2867 showed higher stability in plasma compared to all tested species compared to ADC conjugate T-D265C-30.0880. T-D265C-30.2867 showed lower stability in MP than in HP and CP, respectively.

To further evaluate the stability, the in vitro cytotoxic activity of ADC T-D265C-30.2867 after incubation for 0, 4 and 10 days, respectively, in human plasma, mouse plasma, cynomolgus monkey plasma and PBS (phosphate buffered saline, control), respectively, was analyzed in SKBR-3 cells (Fig. 22), NCI-N87 cells (Fig. 23) and JIMT-1 cells (Fig. 24).

After 4 days of incubation in human plasma, mouse plasma and cynomolgus monkey plasma, respectively, the cytotoxic potential of T-D265C-30.2867 on SKBR-3 cells decreased only slightly. After 10 days of incubation in human plasma and cynomolgus monkey plasma, the cytotoxic potential decreased 20-fold, but in mouse plasma a 33-fold decrease was observed. Incubation in PBS at 37°C had almost no effect on the cytotoxic potential of T-D265C-30.2867 on SKBR-3 cells (Fig. 22, Table 7).

After 4 days of incubation in human plasma, mouse plasma and cynomolgus monkey plasma, respectively, the cytotoxic potential of T-D265C-30.2867 on NCI-N87 cells was only slightly reduced. After 10 days of incubation in human plasma and cynomolgus monkey plasma, the cytotoxic potential was reduced by 15-fold, but approximately 50% residual cell viability was observed after 10 days of incubation in cynomolgus monkey plasma. After 10 days of incubation in mouse plasma, a 67-fold reduction was observed. Incubation in PBS at 37°C had little effect on the cytotoxic potential of T-D265C-30.2867 on NCI-N87 cells (Fig. 23).

After 4 days of incubation in human and cynomolgus monkey plasma, the cytotoxic potential of T-D265C-30.2867 on JIMT-1 cells decreased only slightly. After 4 days of incubation in mouse plasma, T-D265C-30.2867 showed no cytotoxic potential on JIMT-1 cells at all. After 10 days of incubation in human plasma, mouse plasma, and cynomolgus monkey plasma, no cytotoxic potential on JIMT-1 cells was observed. Incubation in PBS at 37°C had almost no effect on the cytotoxic potential of T-D265C-30.2867 on JIMT-1 cells (Fig. 24).

Example 12: Efficacy of anti-Her2 ADC in a mouse xenograft tumor model in vivo

In the JIMT-1 xenograft mouse model, female NMRI athymic mice were inoculated with 5× ¹⁰⁶ JIMT-1 breast cancer cells per mouse subcutaneously in the right flank. At an average tumor volume of ~120 ^mm3 , animals were divided into three groups on day 0. On the same day, animals received a single intravenous dose of amanitin-based antibody-drug conjugates (ADC). Tumor volume and body weight were determined twice weekly.

As shown in Fig. 25, the in vivo efficacy of T-D265C-30.2867 was better than that of T-D265C-30.0880. At 113 days after treatment, 0/10 animals receiving a dose of 2 mg/kg and 4/10 animals receiving a dose of 6 mg/kg T-D265C-30.2867 were alive; in the latter group, 1/4 animals were tumor-free. In contrast, at 113 days after treatment, 0/10 animals receiving a dose of 2 mg/kg and 0/10 animals receiving a dose of 6 mg/kg T-D265C-30.0880 were alive. After 113 days of treatment, 4/10 animals that received a dose of 1 mg/kg T-P265C-30.1699 were alive, and 1/4 of the animals were tumor-free.

With the corresponding NCI-N87 xenograft mouse tumor model, as shown in Fig. 26, again the cytotoxic efficacy of T-D265C-30.2867 in vivo was superior to that of T-D265C-30.0880. At 141 days post-treatment, 0/10 animals receiving the 2 mg/kg dose and 3/10 animals receiving the 6 mg/kg dose of T-D265C-30.2867 were alive; however, in the latter group, 0/3 animals were tumor-free. In contrast, at 141 days post-treatment, 0/10 animals receiving the 2 mg/kg dose and 0/10 animals receiving the 6 mg/kg dose of T-D265C-30.0880 were alive. At 141 days post-treatment, 0/10 animals that received a dose of 1 mg/kg T-D265C-30.1699 were also alive.

Example 13: In vitro cytotoxicity assay with anti-PSMA ADC

The in vitro cytotoxic activity of the anti-PSMA antibody carrying the D265C mutation (h3/F11-D265C-Var16) conjugated to compound 30.2867 (formula (A)) and compound 30.0880 (formula (B)) respectively via its D265C residue was tested on LNCap-, 22RV1- (both PSMA-positive) and PC3 (PSMA-negative) cell lines (Fig. 27). Compound h3/F11-D265C-Var16-30.2867 slightly outperformed h3/F11-D265C-Var16-30.0880 on one of the two cell lines tested. No cytotoxic potential was observed on the PSMA-negative PC3 cell line.

Example 14: Stability of anti-PSMA ADC in human, mouse and cynomolgus monkey plasma

The ADC conjugates h3/F11-D265C-Var16-30.2867 and h3/F11-D265C-Var16-30.0880, respectively, directed against the PSMA antigen were incubated in human, mouse, and cynomolgus monkey plasma and phosphate-buffered saline (PBS, control) for 0, 4, and 10 days, respectively. The samples were subjected to sodium dodecyl sulfate (SDS-polyacrylamide (SDS-PAGE) gel electrophoresis, and the antibody heavy chain molecules were detected with amanitin-specific polyclonal antiserum by Western blotting.

h3/F11-D265C-Var16-30.2867 showed higher plasma stability in all plasma types tested compared to h3/F11-D265C-Var16-30.0880. h3/F11-D265C-Var16-30.2867 showed lower stability in mouse plasma than in human plasma and cynomolgus monkey plasma, respectively.

Example 15: Efficacy of ADC against PSMA in a mouse xenograft tumor model in vivo

In the LNCap xenograft tumor model in mice, male SCID CB17 mice were inoculated with 2.5 × 10 ⁶ LNCap prostate carcinoma cells per mouse subcutaneously in the right flank. At an average tumor volume of ~150 mm ³ , animals were randomized to groups on day 0. On the same day, animals received a single intravenous dose of amanitin-based anti-PSMA antibody-drug conjugates (ADC). Tumor volume and body weight were determined twice weekly.

As shown in Fig. 28, the in vivo efficacy of h3/F11-D265C-Var16-30.2867 was better than that of h3/F11-D265C-Var16-30.0880.

Example 16: Tolerability study in monkeys

A tolerability study was conducted in monkeys with a non-binding anti-digoxigenin ADC (DIG-D265C-30.2867) using escalating doses from 1 mg/kg to 20 mg/kg. The results of LDH, AST, ALT parameters showed good tolerability (Fig. 29). The pharmacokinetic data for ADC and amatoxin in serum are shown in Fig. 30 and Fig. 31, respectively. Both animals died 15 and 19 days, respectively, after the last dose (20 mg/kg). The maximum tolerated dose (MTD) was 15 mg/kg < MTD < 20 mg/kg.

Example 17: In vitro cytotoxicity assay using structurally diverse amanitin derivatives

The in vitro cytotoxic activity of the ADCs listed in Table 8, which contain an anti-Her2 antibody carrying the D265C mutation (T-D265C, anti-Her2-D265C) conjugated to structurally distinct amanitin derivatives via its D265C residue, was tested in LMT-1 cells, NCI-N87 cells, and SKBR-3 cells.

The cytotoxic efficiencies of the respective ADCs against JIMT-1 cells (Fig. 32), NCI-N87 cells (Fig. 33), and SKBR-3 cells (Fig. 34), respectively, are shown in Table 9.

The in vitro cytotoxic activity of the ADCs listed in Table 10, which contain an anti-PSMA antibody carrying the D265C mutation (h3/F11-D265C-Var16, anti-PSMA-D265C) conjugated to structurally distinct amanitin derivatives via its D265C residue, was tested in LNCap- and 22RV1 cell lines (both PSMA-positive).

The cytotoxic efficiencies of the respective ADCs on LNCap (Fig. 35) and 22RV1 (Fig. 36) cells, respectively, are shown in Table 11.

Example 18: Efficacy of anti-PSMA ADCs containing structurally diverse amanitin derivatives in a mouse xenograft tumor model in vivo

In the LNCap xenograft tumor model in mice, male SCID CB17 mice were inoculated with 2.5 × ¹⁰⁶ LNCap prostate carcinoma cells per mouse subcutaneously in the right flank. At an average tumor volume of ~150 mm3 ^{, animals} were randomized to groups on day 0. On the same day, animals received a single intravenous dose of one of the structurally diverse amanitin-based anti-PSMA antibody-drug conjugates (ADCs) listed in Table 6. Tumor volume and body weight were determined twice weekly.

The results for ADCs containing amanitin derivatives with different structures are shown in Figures 37-42 and Table 12. ADCs containing non-cleavable linkers conjugated to the 6'-hydroxy group of tryptophan (amino acid 4) of amatoxin, in particular h3/F11-D265C-Var16-30.2867 with a thioether bridge between Trp and Cys, were shown to have high cytotoxic potency in vivo compared to ADCs containing cleavable linkers conjugated to either amino acid 4 or amino acid 1 of amatoxin.

Example 19: Efficacy of ADCs containing antibodies with the LALA and/or D265C mutation

The efficacy of ADCs containing antibodies containing both the L234A and L235A mutations and the D265C mutation was tested in a cell line-derived tumor xenograft (CDX) mouse model. Anti-Her2 ADCs containing the L234A/L235A/D265C triple mutations and the amatoxin-linker construct HDP30.2060 and HDP30.2867, respectively (T-LALA-D265C-30.2060 and T-LALA-D265C-30.2867, respectively) were tested in Her2-positive NCI-N87 cells. The results are shown in Fig. 43. Anti-PSMA ADCs containing the L234A/L235A/D265C triple mutations and the amatoxin-linker construct HDP30.2060 and HDP30.2867, respectively (h3/F11-LALA-D265C-Var16-30.2060 and h3/F11-LALA-D265C-Var16-30.2867, respectively) were tested in PSMA-positive LNCap cells. The results are shown in Fig. 44. In both studies, ADCs carrying the triple mutation were shown to be effective in reducing tumor volumes in the respective mouse CDX models.

Compared to ADCs without the L234A/L235A/D265C mutations, the same range of production yields was obtained using ADCs containing antibodies characterized by the L234A/L235A mutations and the D265C mutation. Furthermore, the mutations did not affect the conjugation yields obtained with the corresponding antibodies compared to antibodies without the mutations.

Example 20: In vitro cytotoxicity assay on target cells versus non-target cells

As shown in Fig. 45, the in vitro cytotoxic potential of Her2-specific ADCs containing the antibody carrying the L234A/L235A mutations and/or the D265C mutation, compared to ADCs without the mutation and to control ADCs containing the same antibody carrying other mutations (A118C, D265A), assessed in a 96-hour BrdU assay on Her2-positive SKBR-3 cells, was comparable; complete cytotoxicity was observed for all mutants and control ADCs.

In contrast, when the in vitro cytotoxic potential of Her2-specific ADCs containing an antibody bearing the L234A/L235A mutations and/or the D265C mutation was assessed in a 96-hour CTG assay (Fig. 46) and a 120-hour CTG assay (Fig. 47) in the Her2-negative macrophage cell line THP-1 compared to the corresponding ADC without mutations in the same antibody backbone, non-specific toxicity was observed with the ADC without the mutation in the antibody (T-30.1699, Fig. 46A,C; Fig. 47C) at ADC concentrations higher than 10 ^-10 -10 ^-9 M. Using an ADC containing an antibody bearing the L234A/L235A mutations (“LALA”) (T-LALA-30.1699) or the D265C mutation (T-D265C) or all three mutations (T-LALA-D265C-30.1699), no such non-specific toxicity to non-target THP-1 cells was observed in the 96-hour CTG assay (Fig. 46A, B), even at 10- to 100-fold higher ADC concentrations. Using an ADC containing the antibody carrying the D265A mutation (T-D265A-30.1699), no non-specific toxicity to non-target THP-1 cells was observed. In the 120-hour CTG assay, these data were essentially confirmed; the non-specific toxicity of the ADC without the antibody mutation was significantly higher than that of the ADC containing the antibody carrying a single or triple mutation (Fig. 47C). The combination of LALA and D265C (or D265A) mutations appeared to have an additive or even synergistic effect in terms of reducing non-specific toxicity to non-target cells (Fig. 47C, D). Non-specific cytotoxicity to THP-1 cells was shown to be mediated by the Fcγ receptor, suggesting that those ATACs that do not exhibit cytotoxicity to THP-1 cells (LALA, D265C, and D265A variants) have reduced interaction with the Fcγ receptor and, in turn, reduced FcγR-mediated uptake.

Thus, the L234A/L235A and D265A/C mutations abolish the non-specific toxicity of ADC to THP-1 cells under the conditions tested.

Example 21: Effect of LALA and/or D265C mutations in ADC on FcgR binding

The interaction of ADC with FcgR was tested using biolayer interferometry (BLI). The results of these binding studies are shown in Table 13.

As shown in Table 13, the introduction of the LALA, D265A, or D265C mutations into the antibody included in the ADC significantly reduces the affinity for FcgRI and also reduces binding to FcgRIIa and FcgRIIIa. The combination with the D265 mutation (D265C, D265A) further dramatically reduces binding to FcgRI.

Example 22: Effect of LALA and/or D265C mutations in ADC on in vivo tolerability

The tolerability of ADCs containing Her2- or PSMA-specific antibodies carrying mutations, respectively, was assessed in mice. The results are shown in Table 14. All antibodies used were characterized by the same scaffold and did not show cross-reactivity in mice.

As shown in Table 14, with ADCs containing the amatoxin/linker compound HDP 30.2060 and antibodies carrying the LALA and D265C mutations, the maximum tolerated dose was significantly higher than for ADCs containing the indicated amatoxin/linker compound and antibodies carrying only the D265C mutation. With ADCs containing the amatoxin/linker compound HDP 30.2867 and antibodies carrying the LALA and D265C mutations, tolerability was even higher.

The tolerability of ADCs containing antibodies carrying the relevant mutations was also assessed in non-human primates. All antibodies used shared the same scaffold and were not bound in non-human primates. Anti-PSMA ADCs h3/F11-LALA-D265C-Var16-30.2060 (carrying both LALA and D265C mutations), h3/F11-D265C-Var16-30.2060 (carrying only the D265C mutation) and anti-digoxigenin ADCs DIG-D265C-30.2060 and DIG-D265C-30.2867 (carrying only the D265C mutation) were evaluated for dose escalation tolerability in cynomolgus monkeys.

Groups of 2 female animals were injected with h3/F11-LALA-D265C-Var16-30.2060 on days 1 (1 mg/kg), 23 (3 mg/kg), 44 (5 mg/kg), 65 (6 mg/kg), 86 (7.5 mg/kg), 128 (10 mg/kg), h3/F11-D265C-Var16-30.2060 on days 1 (1 mg/kg), 23 (3 mg/kg), and 44 (5 mg/kg), DIG-D265C-30.2060 on days 1 (1 mg/kg), 22 (3 mg/kg), 43 (5 mg/kg), 64 (7.5 mg/kg), or DIG-D265C-30.2867 on days 1 (1 mg/kg), 22 (3 mg/kg), 43 (5 mg/kg), 64 (7.5 mg/kg), 106 (10 mg/kg), 148 (15 mg/kg), and 196 (20 mg/kg). The animals were monitored over time for blood biochemistry and hematology parameters, body weight, food intake, clinical signs, and mortality. In addition, blood samples were collected for pharmacokinetic studies. At the end of the experiments, tissue samples were used for histopathological studies.

Doses up to 7.5 mg/kg h3/F11-LALA-D265C-Var16-30.2060 (with LALA and D265C mutations), 3 mg/kg h3/F11-D265C-Var16-30.2060 (with D265C mutation only), 5 mg/kg DIG-D265C-30.2060, and 15 mg/kg DIG-D265C-30.2867 (with D265C mutation only) were well tolerated with no evidence of renal injury in serum parameters and no change in body weight or food intake. Doses of 10 mg/kg h3/F11-LALA-D265C-Var16-30.2060, 5 mg/kg h3/F11-D265C-Var16-30.2060, 7.5 mg/kg DIG-D265C-30.2060 and 20 mg/kg DIG-D265C-30.2867 resulted in death of the animals. The results are presented in Table 15.

Data in non-human primates confirmed that for ADCs containing antibodies carrying both the LALA and D265C mutations, the maximum tolerated dose was significantly higher than for ADCs containing antibodies carrying only the D265C mutation. Tolerability was particularly high with ADCs containing the amatoxin/linker HDP 30.2867 compound and antibodies carrying both the LALA and D265C mutations.

Other implementation options

All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each independent publication or patent application was specifically and individually indicated to be incorporated by reference.

Although the present invention has been described in connection with specific embodiments thereof, it is to be understood that it is susceptible to further modifications, and it is intended that the present application cover any variations, applications or adaptations of the present invention, following generally the principles of the present invention and including such departures from the present invention as are within the known or usual practice in the art to which the present invention pertains and can be applied to the essential features set forth herein above and fall within the scope of the claims.

Other embodiments are within the scope of the claims.

--->

SEQUENCE LIST

<110> Heidelberg Pharma Research GmbH

<120> AMATOXIN ANTIBODY DRUG CONJUGATES

AND THEIR APPLICATIONS

<130> HD 40727

<160> 564

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Ser Tyr Trp Ile Gly

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Ile Ile Tyr Pro Gly Asp Ser Asp Thr Arg Tyr Ser Pro Ser Phe Gln

1 5 10 15

Gly

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His Gly Arg Gly Tyr Asn Gly Tyr Glu Gly Ala Phe Asp Ile

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Arg Ala Ser Gln Gly Ile Ser Ser Ala Leu Ala

1 5 10

<210> 5

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<223> /note="Description of the artificial sequence:

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Asp Ala Ser Ser Leu Glu Ser

1 5

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<211> 10

<212> PRT

<213> Artificial sequence

<220>

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<223> /note="Description of the artificial sequence:

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Cys Gln Gln Phe Asn Ser Tyr Pro Leu Thr

1 5 10

<210> 7

<211> 120

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

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<400> 7

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr

20 25 30

Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Val Ile Ser Glu Asn Gly Ser Asp Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Asp Arg Gly Gly Ala Val Ser Tyr Phe Asp Val Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 8

<211> 109

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

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<400> 8

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Ser Ser Tyr

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Ala Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Leu Pro Tyr

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr

100 105

<210> 9

<211> 121

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

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<400> 9

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Ala

20 25 30

Asp Met Asp Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Gly Arg Thr Arg Asn Lys Ala Gly Ser Tyr Thr Thr Glu Tyr Ala Ala

50 55 60

Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Ser

65 70 75 80

Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr

85 90 95

Tyr Cys Ala Arg Glu Pro Lys Tyr Trp Ile Asp Phe Asp Leu Trp Gly

100 105 110

Arg Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 10

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

Synthetic

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<400> 10

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr

20 25 30

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ile Ala Pro Tyr

85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105

<210> 11

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

Synthetic

peptide"

<400> 11

Phe Thr Phe Ser Asp Ala Asp Met Asp

1 5

<210> 12

<211> 19

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

Synthetic

peptide"

<400> 12

Arg Thr Arg Asn Lys Ala Gly Ser Tyr Thr Thr Glu Tyr Ala Ala Ser

1 5 10 15

Val Lys Gly

<210> 13

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 13

Ala Arg Glu Pro Lys Tyr Trp Ile Asp Phe Asp Leu

1 5 10

<210> 14

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 14

Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn

1 5 10

<210> 15

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

Synthetic

peptide"

<400> 15

Ala Ala Ser Ser Leu Gln Ser

1 5

<210> 16

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 16

Gln Gln Ser Tyr Ile Ala Pro Tyr Thr

1 5

<210> 17

<211> 363

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polynucleotide"

<400> 17

gaggtgcagc tggtggagtc tgggggaggc ttggtccagc ctggagggtc cctgagactc

60

tcctgtgcag cctctggatt caccttcagt gacgccgaca tggactgggt ccgccaggct

120

ccagggaagg ggctggagtg ggttggccgt actagaaaca aagcaggaag ttacaccaca

180

gaatacgccg cgtctgtgaa aggcagattc accatctcaa gagatgattc aaagaactca

240

ctgtatctgc aaatgaacag cctgaaaacc gaggacacgg cggtgtacta ctgcgccaga

300

gagcctaaat actggatcga cttcgaccta tgggggagag gtaccttggt caccgtctcc

360

tca

363

<210> 18

<211> 321

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polynucleotide"

<400> 18

gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc

60

atcacttgcc gggcaagtca gagcattagc agctatttaa attggtatca gcagaaacca

120

gggaaagccc ctaagctcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca

180

aggttcagtg gcagtggatc tgggacagat ttcactctca ccatcagcag tctgcaacct

240

gaagattttg caacttacta ctgtcagcaa agctacatcg ccccttacac ttttggcgga

300

gggaccaagg ttgagatcaa a

321

<210> 19

<211> 119

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 19

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Arg Ile Tyr

20 25 30

Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Gly Ile Ile Pro Asp Phe Gly Val Ala Asn Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gly Gly Leu Asp Thr Asp Glu Phe Asp Leu Trp Gly Arg Gly

100 105 110

Thr Leu Val Thr Val Ser Ser

115

<210> 20

<211> 106

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 20

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Asn Ser Tyr

20 25 30

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Val Ser Asp Ile Thr

85 90 95

Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105

<210> 21

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 21

Gly Thr Phe Arg Ile Tyr Ala Ile Ser

1 5

<210> 22

<211> 17

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 22

Gly Ile Ile Pro Asp Phe Gly Val Ala Asn Tyr Ala Gln Lys Phe Gln

1 5 10 15

Gly

<210> 23

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 23

Ala Arg Gly Gly Leu Asp Thr Asp Glu Phe Asp Leu

1 5 10

<210> 24

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 24

Arg Ala Ser Gln Ser Ile Asn Ser Tyr Leu Asn

1 5 10

<210> 25

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 25

Ala Ala Ser Ser Leu Gln Ser

1 5

<210> 26

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 26

Gln Gln Gly Val Ser Asp Ile Thr

1 5

<210> 27

<211> 357

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polynucleotide"

<400> 27

caggtgcagc tggtgcagtc tggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc

60

tcctgcaagg cttctggagg caccttccga atctatgcta tcagctgggt gcgacaggcc

120

cctggacaag ggcttgagtg gatgggaggg atcatccctg acttcggtgt agcaaactac

180

gcacagaagt tccagggcag agtcacgatt accgcggacg aatccacgag cacagcctac

240

atggagctga gcagcctgag atctgaggac acggcggtgt actactgcgc cagaggtgga

300

ttggacacag acgagttcga cctatggggg agaggtacct tggtcaccgt ctcctca

357

<210> 28

<211> 318

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polynucleotide"

<400> 28

gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc

60

atcacttgcc gggcaagtca gagcattaac agctatttaa attggtatca gcagaaacca

120

gggaaagccc ctaagctcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca

180

aggttcagtg gcagtggatc tgggacagat ttcactctca ccatcagcag tctgcaacct

240

gaagattttg caacttacta ctgtcagcaa ggagtcagtg acatcacttt tggcggaggg

300

accaaggttg agatcaaa

318

<210> 29

<211> 119

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 29

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr

20 25 30

Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gly Gly Leu Asp Thr Asp Glu Phe Asp Leu Trp Gly Arg Gly

100 105 110

Thr Leu Val Thr Val Ser Ser

115

<210> 30

<211> 106

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 30

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Asn Ser Tyr

20 25 30

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Val Ser Asp Ile Thr

85 90 95

Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105

<210> 31

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 31

Gly Thr Phe Ser Ser Tyr Ala Ile Ser

1 5

<210> 32

<211> 17

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 32

Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe Gln

1 5 10 15

Gly

<210> 33

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 33

Ala Arg Gly Gly Leu Asp Thr Asp Glu Phe Asp Leu

1 5 10

<210> 34

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 34

Arg Ala Ser Gln Ser Ile Asn Ser Tyr Leu Asn

1 5 10

<210> 35

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 35

Ala Ala Ser Ser Leu Gln Ser

1 5

<210> 36

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 36

Gln Gln Gly Val Ser Asp Ile Thr

1 5

<210> 37

<211> 357

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polynucleotide"

<400> 37

caggtgcagc tggtgcagtc tggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc

60

tcctgcaagg cttctggagg caccttcagc agctatgcta tcagctgggt gcgacaggcc

120

cctggacaag ggcttgagtg gatgggaggg atcatcccta tctttggtac agcaaactac

180

gcacagaagt tccagggcag agtcacgatt accgcggacg aatccacgag cacagcctac

240

atggagctga gcagcctgag atctgaggac acggcggtgt actactgcgc cagaggtgga

300

ttggacacag acgagttcga cctatggggg agaggtacct tggtcaccgt ctcctca

357

<210> 38

<211> 318

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polynucleotide"

<400> 38

gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc

60

atcacttgcc gggcaagtca gagcattaac agctatttaa attggtatca gcagaaacca

120

gggaaagccc ctaagctcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca

180

aggttcagtg gcagtggatc tgggacagat ttcactctca ccatcagcag tctgcaacct

240

gaagattttg caacttacta ctgtcagcaa ggagtcagtg acatcacttt tggcggaggg

300

accaaggttg agatcaaa

318

<210> 39

<211> 119

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 39

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Leu Tyr

20 25 30

Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Gly Ile Ile Pro Ala Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gly Gly Leu Asp Thr Asp Glu Phe Asp Leu Trp Gly Arg Gly

100 105 110

Thr Leu Val Thr Val Ser Ser

115

<210> 40

<211> 106

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 40

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Asn Ser Tyr

20 25 30

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Val Ser Asp Ile Thr

85 90 95

Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105

<210> 41

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 41

Gly Thr Phe Ser Leu Tyr Ala Ile Ser

1 5

<210> 42

<211> 17

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 42

Gly Ile Ile Pro Ala Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe Gln

1 5 10 15

Gly

<210> 43

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 43

Ala Arg Gly Gly Leu Asp Thr Asp Glu Phe Asp Leu

1 5 10

<210> 44

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 44

Arg Ala Ser Gln Ser Ile Asn Ser Tyr Leu Asn

1 5 10

<210> 45

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 45

Ala Ala Ser Ser Leu Gln Ser

1 5

<210> 46

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 46

Gln Gln Gly Val Ser Asp Ile Thr

1 5

<210> 47

<211> 357

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polynucleotide"

<400> 47

caggtgcagc tggtgcagtc tggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc

60

tcctgcaagg cttctggagg caccttcagc ctctatgcta tctcctgggt gcgacaggcc

120

cctggacaag ggcttgagtg gatgggaggg atcatccctg ccttcggtac cgcaaactac

180

gcacagaagt tccagggcag agtcacgatt accgcggacg aatccacgag cacagcctac

240

atggagctga gcagcctgag atctgaggac acggcggtgt actactgcgc cagaggtgga

300

ttggacacag acgagttcga cctatggggg agaggtacct tggtcaccgt ctcctca

357

<210> 48

<211> 318

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polynucleotide"

<400> 48

gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc

60

atcacttgcc gggcaagtca gagcattaac agctatttaa attggtatca gcagaaacca

120

gggaaagccc ctaagctcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca

180

aggttcagtg gcagtggatc tgggacagat ttcactctca ccatcagcag tctgcaacct

240

gaagattttg caacttacta ctgtcagcaa ggagtcagtg acatcacttt tggcggaggg

300

accaaggttg agatcaaa

318

<210> 49

<211> 119

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 49

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Leu Tyr

20 25 30

Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Gly Ile Ile Pro His Phe Gly Leu Ala Asn Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gly Gly Leu Asp Thr Asp Glu Phe Asp Leu Trp Gly Arg Gly

100 105 110

Thr Leu Val Thr Val Ser Ser

115

<210> 50

<211> 106

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 50

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Asn Ser Tyr

20 25 30

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Val Ser Asp Ile Thr

85 90 95

Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105

<210> 51

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 51

Gly Thr Phe Ser Leu Tyr Ala Ile Ser

1 5

<210> 52

<211> 17

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 52

Gly Ile Ile Pro His Phe Gly Leu Ala Asn Tyr Ala Gln Lys Phe Gln

1 5 10 15

Gly

<210> 53

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 53

Ala Arg Gly Gly Leu Asp Thr Asp Glu Phe Asp Leu

1 5 10

<210> 54

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 54

Arg Ala Ser Gln Ser Ile Asn Ser Tyr Leu Asn

1 5 10

<210> 55

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 55

Ala Ala Ser Ser Leu Gln Ser

1 5

<210> 56

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 56

Gln Gln Gly Val Ser Asp Ile Thr

1 5

<210> 57

<211> 357

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polynucleotide"

<400> 57

caggtgcagc tggtgcagtc tggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc

60

tcctgcaagg cttctggagg caccttctcc ctctatgcta tcagctgggt gcgacaggcc

120

cctggacaag ggcttgagtg gatgggaggg atcatccctc acttcggtct cgcaaactac

180

gcacagaagt tccagggcag agtcacgatt accgcggacg aatccacgag cacagcctac

240

atggagctga gcagcctgag atctgaggac acggcggtgt actactgcgc cagaggtgga

300

ttggacacag acgagttcga cctatggggg agaggtacct tggtcaccgt ctcctca

357

<210> 58

<211> 318

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polynucleotide"

<400> 58

gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc

60

atcacttgcc gggcaagtca gagcattaac agctatttaa attggtatca gcagaaacca

120

gggaaagccc ctaagctcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca

180

aggttcagtg gcagtggatc tgggacagat ttcactctca ccatcagcag tctgcaacct

240

gaagattttg caacttacta ctgtcagcaa ggagtcagtg acatcacttt tggcggaggg

300

accaaggttg agatcaaa

318

<210> 59

<211> 123

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 59

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr

20 25 30

Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Lys Gly Pro Pro Thr Tyr His Thr Asn Tyr Tyr Tyr Met Asp Val

100 105 110

Trp Gly Lys Gly Thr Thr Val Thr Val Ser Ser

115 120

<210> 60

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 60

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Trp

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Thr Asn Ser Phe Pro Tyr

85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105

<210> 61

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 61

Phe Thr Phe Ser Asn Tyr Ala Met Ser

1 5

<210> 62

<211> 17

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 62

Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys

1 5 10 15

Gly

<210> 63

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 63

Ala Lys Gly Pro Pro Thr Tyr His Thr Asn Tyr Tyr Tyr Met Asp Val

1 5 10 15

<210> 64

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 64

Arg Ala Ser Gln Gly Ile Ser Ser Trp Leu Ala

1 5 10

<210> 65

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 65

Ala Ala Ser Ser Leu Gln Ser

1 5

<210> 66

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 66

Gln Gln Thr Asn Ser Phe Pro Tyr Thr

1 5

<210> 67

<211> 369

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polynucleotide"

<400> 67

gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc

60

tcctgtgcag cctctggatt cacctttagc aattatgcca tgagctgggt ccgccaggct

120

ccagggaagg ggctggagtg ggtctcagct attagtggta gtggtggtag cacatactac

180

gcagactccg tgaagggccg gttcaccatc tccagagaca attccaagaa cacgctgtat

240

ctgcaaatga acagcctgag agccgaggac acggcggtgt actactgcgc caagggccct

300

cctacatacc acacaaacta ctactacatg gacgtatggg gcaagggtac aactgtcacc

360

gtctcctca

369

<210> 68

<211> 321

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polynucleotide"

<400> 68

gacatccaga tgacccagtc tccatcttcc gtgtctgcat ctgtaggaga cagagtcacc

60

atcacttgtc gggcgagtca gggtattagc agctggttag cctggtatca gcagaaacca

120

gggaaagccc ctaagctcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca

180

aggttcagcg gcagtggatc tgggacagat ttcactctca ccatcagcag cctgcagcct

240

gaagattttg caacttatta ctgtcagcaa acaaatagtt tcccttacac ttttggcgga

300

gggaccaagg ttgagatcaa a

321

<210> 69

<211> 123

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 69

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Val Met Ile Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Asp Ser Val Thr Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Lys Gly Pro Pro Thr Tyr His Thr Asn Tyr Tyr Tyr Met Asp Val

100 105 110

Trp Gly Lys Gly Thr Thr Val Thr Val Ser Ser

115 120

<210> 70

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 70

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Trp

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Thr Asn Ser Phe Pro Tyr

85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105

<210> 71

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 71

Phe Thr Phe Ser Ser Tyr Val Met Ile

1 5

<210> 72

<211> 17

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 72

Ser Ile Ser Gly Asp Ser Val Thr Thr Tyr Tyr Ala Asp Ser Val Lys

1 5 10 15

Gly

<210> 73

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 73

Ala Lys Gly Pro Pro Thr Tyr His Thr Asn Tyr Tyr Tyr Met Asp Val

1 5 10 15

<210> 74

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 74

Arg Ala Ser Gln Gly Ile Ser Ser Trp Leu Ala

1 5 10

<210> 75

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 75

Ala Ala Ser Ser Leu Gln Ser

1 5

<210> 76

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 76

Gln Gln Thr Asn Ser Phe Pro Tyr Thr

1 5

<210> 77

<211> 369

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polynucleotide"

<400> 77

gaggtgcagc tgttggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc

60

tcctgtgcag cctctggatt cacctttagc agctatgtca tgatctgggt ccgccaggct

120

ccagggaagg ggctggagtg ggtctcaagc attagtggtg acagcgtaac aacatactac

180

gcagactccg tgaagggccg gttcaccatc tccagagaca attccaagaa cacgctgtat

240

ctgcaaatga acagcctgag agccgaggac acggcggtgt actactgcgc caagggccct

300

cctacatacc acacaaacta ctactacatg gacgtatggg gcaagggtac aactgtcacc

360

gtctcctca

369

<210> 78

<211> 321

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

Synthetic

polynucleotide"

<400> 78

gacatccaga tgacccagtc tccatcttcc gtgtctgcat ctgtaggaga cagagtcacc

60

atcacttgtc gggcgagtca gggtattagc agctggttag cctggtatca gcagaaacca

120

gggaaagccc ctaagctcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca

180

aggttcagcg gcagtggatc tgggacagat ttcactctca ccatcagcag cctgcagcct

240

gaagattttg caacttatta ctgtcagcaa acaaatagtt tcccttacac ttttggcgga

300

gggaccaagg ttgagatcaa a

321

<210> 79

<211> 121

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 79

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp His

20 25 30

Tyr Met Asp Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Gly Arg Thr Arg Asn Lys Ala Ser Ser Tyr Thr Thr Glu Tyr Ala Ala

50 55 60

Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Ser

65 70 75 80

Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr

85 90 95

Tyr Cys Ala Arg Glu Pro Lys Tyr Trp Ile Asp Phe Asp Leu Trp Gly

100 105 110

Arg Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 80

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 80

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr

20 25 30

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ile Ala Pro Tyr

85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105

<210> 81

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 81

Phe Thr Phe Ser Asp His Tyr Met Asp

1 5

<210> 82

<211> 19

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 82

Arg Thr Arg Asn Lys Ala Ser Ser Tyr Thr Thr Glu Tyr Ala Ala Ser

1 5 10 15

Val Lys Gly

<210> 83

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 83

Ala Arg Glu Pro Lys Tyr Trp Ile Asp Phe Asp Leu

1 5 10

<210> 84

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 84

Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn

1 5 10

<210> 85

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 85

Ala Ala Ser Ser Leu Gln Ser

1 5

<210> 86

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 86

Gln Gln Ser Tyr Ile Ala Pro Tyr Thr

1 5

<210> 87

<211> 363

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polynucleotide"

<400> 87

gaggtgcagc tggtggagtc tgggggaggc ttggtccagc ctggagggtc cctgagactc

60

tcctgtgcag cctctggatt caccttcagt gaccactaca tggactgggt ccgccaggct

120

ccagggaagg ggctggagtg ggttggccgt actagaaaca aagctagtag ttacaccaca

180

gaatacgccg cgtctgtgaa aggcagattc accatctcaa gagatgattc aaagaactca

240

ctgtatctgc aaatgaacag cctgaaaacc gaggacacgg cggtgtacta ctgcgccaga

300

gagcctaaat actggatcga cttcgaccta tgggggagag gtaccttggt caccgtctcc

360

tca

363

<210> 88

<211> 321

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

Synthetic

polynucleotide"

<400> 88

gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc

60

atcacttgcc gggcaagtca gagcattagc agctatttaa attggtatca gcagaaacca

120

gggaaagccc ctaagctcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca

180

aggttcagtg gcagtggatc tgggacagat ttcactctca ccatcagcag tctgcaacct

240

gaagattttg caacttacta ctgtcagcaa agctacatcg ccccttacac ttttggcgga

300

gggaccaagg ttgagatcaa a

321

<210> 89

<211> 121

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 89

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg

1 5 10 15

Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Ser Asp His

20 25 30

Asp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Gly Arg Thr Arg Asn Ala Ala Gly Ser Tyr Thr Thr Glu Tyr Ala Ala

50 55 60

Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Ser

65 70 75 80

Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr

85 90 95

Tyr Cys Ala Arg Glu Pro Lys Tyr Trp Ile Asp Phe Asp Leu Trp Gly

100 105 110

Arg Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 90

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 90

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr

20 25 30

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ile Ala Pro Tyr

85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105

<210> 91

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 91

Phe Thr Phe Ser Asp His Asp Met Asn

1 5

<210> 92

<211> 19

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 92

Arg Thr Arg Asn Ala Ala Gly Ser Tyr Thr Thr Glu Tyr Ala Ala Ser

1 5 10 15

Val Lys Gly

<210> 93

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 93

Ala Arg Glu Pro Lys Tyr Trp Ile Asp Phe Asp Leu

1 5 10

<210> 94

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 94

Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn

1 5 10

<210> 95

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 95

Ala Ala Ser Ser Leu Gln Ser

1 5

<210> 96

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 96

Gln Gln Ser Tyr Ile Ala Pro Tyr Thr

1 5

<210> 97

<211> 363

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polynucleotide"

<400> 97

gaggtgcagc tggtggagtc tgggggaggc ttggtacagc cagggcggtc cctgagactc

60

tcctgtacag cttctggatt caccttcagt gaccacgaca tgaactgggt ccgccaggct

120

ccagggaagg ggctggagtg ggttggccgt actagaaacg ccgctggaag ttacaccaca

180

gaatacgccg cgtctgtgaa aggcagattc accatctcaa gagatgattc aaagaactca

240

ctgtatctgc aaatgaacag cctgaaaacc gaggacacgg cggtgtacta ctgcgccaga

300

gagcctaaat actggatcga cttcgaccta tgggggagag gtaccttggt caccgtctcc

360

tca

363

<210> 98

<211> 321

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polynucleotide"

<400> 98

gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc

60

atcacttgcc gggcaagtca gagcattagc agctatttaa attggtatca gcagaaacca

120

gggaaagccc ctaagctcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca

180

aggttcagtg gcagtggatc tgggacagat ttcactctca ccatcagcag tctgcaacct

240

gaagattttg caacttacta ctgtcagcaa agctacatcg ccccttacac ttttggcgga

300

gggaccaagg ttgagatcaa a

321

<210> 99

<211> 121

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 99

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Val Asp His

20 25 30

Asp Met Asp Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Gly Arg Thr Arg Asn Lys Leu Gly Ser Tyr Thr Thr Glu Tyr Ala Ala

50 55 60

Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Ser

65 70 75 80

Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr

85 90 95

Tyr Cys Ala Arg Glu Pro Lys Tyr Trp Ile Asp Phe Asp Leu Trp Gly

100 105 110

Arg Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 100

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 100

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr

20 25 30

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ile Ala Pro Tyr

85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105

<210> 101

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 101

Phe Thr Phe Val Asp His Asp Met Asp

1 5

<210> 102

<211> 19

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 102

Arg Thr Arg Asn Lys Leu Gly Ser Tyr Thr Thr Glu Tyr Ala Ala Ser

1 5 10 15

Val Lys Gly

<210> 103

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 103

Ala Arg Glu Pro Lys Tyr Trp Ile Asp Phe Asp Leu

1 5 10

<210> 104

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 104

Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn

1 5 10

<210> 105

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 105

Ala Ala Ser Ser Leu Gln Ser

1 5

<210> 106

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 106

Gln Gln Ser Tyr Ile Ala Pro Tyr Thr

1 5

<210> 107

<211> 363

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polynucleotide"

<400> 107

gaggtgcagc tggtggagtc tgggggaggc ttggtccagc ctggagggtc cctgagactc

60

tcctgtgcag cctctggatt caccttcgta gaccacgaca tggactgggt ccgccaggct

120

ccagggaagg ggctggagtg ggttggccgt actagaaaca aactaggaag ttacaccaca

180

gaatacgccg cgtctgtgaa aggcagattc accatctcaa gagatgattc aaagaactca

240

ctgtatctgc aaatgaacag cctgaaaacc gaggacacgg cggtgtacta ctgcgccaga

300

gagcctaaat actggatcga cttcgaccta tgggggagag gtaccttggt caccgtctcc

360

tca

363

<210> 108

<211> 321

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polynucleotide"

<400> 108

gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc

60

atcacttgcc gggcaagtca gagcattagc agctatttaa attggtatca gcagaaacca

120

gggaaagccc ctaagctcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca

180

aggttcagtg gcagtggatc tgggacagat ttcactctca ccatcagcag tctgcaacct

240

gaagattttg caacttacta ctgtcagcaa agctacatcg ccccttacac ttttggcgga

300

gggaccaagg ttgagatcaa a

321

<210> 109

<211> 214

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 109

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr

20 25 30

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ile Ala Pro Tyr

85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala

100 105 110

Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly

115 120 125

Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala

130 135 140

Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln

145 150 155 160

Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser

165 170 175

Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr

180 185 190

Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser

195 200 205

Phe Asn Arg Gly Glu Cys

210

<210> 110

<211> 451

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 110

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Ala

20 25 30

Asp Met Asp Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Gly Arg Thr Arg Asn Lys Ala Gly Ser Tyr Thr Thr Glu Tyr Ala Ala

50 55 60

Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Ser

65 70 75 80

Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr

85 90 95

Tyr Cys Ala Arg Glu Pro Lys Tyr Trp Ile Asp Phe Asp Leu Trp Gly

100 105 110

Arg Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser

115 120 125

Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala

130 135 140

Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val

145 150 155 160

Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala

165 170 175

Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val

180 185 190

Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His

195 200 205

Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys

210 215 220

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly

225 230 235 240

Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

245 250 255

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

260 265 270

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

275 280 285

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

290 295 300

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

305 310 315 320

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

325 330 335

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

340 345 350

Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser

355 360 365

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

370 375 380

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

385 390 395 400

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

405 410 415

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

420 425 430

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

435 440 445

Pro Gly Lys

450

<210> 111

<211> 451

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 111

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Ala

20 25 30

Asp Met Asp Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Gly Arg Thr Arg Asn Lys Ala Gly Ser Tyr Thr Thr Glu Tyr Ala Ala

50 55 60

Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Ser

65 70 75 80

Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr

85 90 95

Tyr Cys Ala Arg Glu Pro Lys Tyr Trp Ile Asp Phe Asp Leu Trp Gly

100 105 110

Arg Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser

115 120 125

Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala

130 135 140

Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val

145 150 155 160

Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala

165 170 175

Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val

180 185 190

Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His

195 200 205

Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys

210 215 220

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly

225 230 235 240

Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

245 250 255

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Cys Val Ser His

260 265 270

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

275 280 285

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

290 295 300

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

305 310 315 320

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

325 330 335

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

340 345 350

Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser

355 360 365

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

370 375 380

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

385 390 395 400

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

405 410 415

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

420 425 430

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

435 440 445

Pro Gly Lys

450

<210> 112

<211> 451

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 112

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Ala

20 25 30

Asp Met Asp Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Gly Arg Thr Arg Asn Lys Ala Gly Ser Tyr Thr Thr Glu Tyr Ala Ala

50 55 60

Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Ser

65 70 75 80

Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr

85 90 95

Tyr Cys Ala Arg Glu Pro Lys Tyr Trp Ile Asp Phe Asp Leu Trp Gly

100 105 110

Arg Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser

115 120 125

Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala

130 135 140

Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val

145 150 155 160

Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala

165 170 175

Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val

180 185 190

Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His

195 200 205

Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys

210 215 220

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly

225 230 235 240

Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

245 250 255

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Cys Val Ser His

260 265 270

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

275 280 285

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

290 295 300

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

305 310 315 320

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

325 330 335

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

340 345 350

Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser

355 360 365

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

370 375 380

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

385 390 395 400

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

405 410 415

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

420 425 430

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

435 440 445

Pro Gly Lys

450

<210> 113

<211> 451

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 113

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Ala

20 25 30

Asp Met Asp Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Gly Arg Thr Arg Asn Lys Ala Gly Ser Tyr Thr Thr Glu Tyr Ala Ala

50 55 60

Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Ser

65 70 75 80

Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr

85 90 95

Tyr Cys Ala Arg Glu Pro Lys Tyr Trp Ile Asp Phe Asp Leu Trp Gly

100 105 110

Arg Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser

115 120 125

Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala

130 135 140

Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val

145 150 155 160

Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala

165 170 175

Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val

180 185 190

Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His

195 200 205

Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys

210 215 220

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly

225 230 235 240

Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

245 250 255

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Cys Val Ser His

260 265 270

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

275 280 285

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

290 295 300

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

305 310 315 320

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

325 330 335

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

340 345 350

Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser

355 360 365

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

370 375 380

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

385 390 395 400

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

405 410 415

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

420 425 430

His Glu Ala Leu His Asn Ala Tyr Thr Gln Lys Ser Leu Ser Leu Ser

435 440 445

Pro Gly Lys

450

<210> 114

<211> 451

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 114

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Ala

20 25 30

Asp Met Asp Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Gly Arg Thr Arg Asn Lys Ala Gly Ser Tyr Thr Thr Glu Tyr Ala Ala

50 55 60

Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Ser

65 70 75 80

Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr

85 90 95

Tyr Cys Ala Arg Glu Pro Lys Tyr Trp Ile Asp Phe Asp Leu Trp Gly

100 105 110

Arg Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser

115 120 125

Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala

130 135 140

Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val

145 150 155 160

Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala

165 170 175

Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val

180 185 190

Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His

195 200 205

Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys

210 215 220

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly

225 230 235 240

Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

245 250 255

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Cys Val Ser His

260 265 270

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

275 280 285

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

290 295 300

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

305 310 315 320

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

325 330 335

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

340 345 350

Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser

355 360 365

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

370 375 380

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

385 390 395 400

Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val

405 410 415

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

420 425 430

His Glu Ala Leu His Asn Ala Tyr Thr Gln Lys Ser Leu Ser Leu Ser

435 440 445

Pro Gly Lys

450

<210> 115

<211> 213

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 115

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Asn Ser Tyr

20 25 30

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Val Ser Asp Ile Thr

85 90 95

Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro

100 105 110

Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr

115 120 125

Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys

130 135 140

Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu

145 150 155 160

Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser

165 170 175

Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala

180 185 190

Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe

195 200 205

AsnArgGlyGluCys

210

<210> 116

<211> 449

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 116

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Arg Ile Tyr

20 25 30

Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Gly Ile Ile Pro Asp Phe Gly Val Ala Asn Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gly Gly Leu Asp Thr Asp Glu Phe Asp Leu Trp Gly Arg Gly

100 105 110

Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe

115 120 125

Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu

130 135 140

Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp

145 150 155 160

Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu

165 170 175

Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser

180 185 190

Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro

195 200 205

Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys

210 215 220

Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro

225 230 235 240

Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser

245 250 255

Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp

260 265 270

Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn

275 280 285

Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val

290 295 300

Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu

305 310 315 320

Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys

325 330 335

Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr

340 345 350

Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr

355 360 365

Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu

370 375 380

Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu

385 390 395 400

Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys

405 410 415

Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu

420 425 430

Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly

435 440 445

Lys

<210> 117

<211> 449

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 117

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Arg Ile Tyr

20 25 30

Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Gly Ile Ile Pro Asp Phe Gly Val Ala Asn Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gly Gly Leu Asp Thr Asp Glu Phe Asp Leu Trp Gly Arg Gly

100 105 110

Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe

115 120 125

Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu

130 135 140

Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp

145 150 155 160

Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu

165 170 175

Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser

180 185 190

Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro

195 200 205

Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys

210 215 220

Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro

225 230 235 240

Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser

245 250 255

Arg Thr Pro Glu Val Thr Cys Val Val Cys Val Ser His Glu Asp

260 265 270

Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn

275 280 285

Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val

290 295 300

Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu

305 310 315 320

Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys

325 330 335

Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr

340 345 350

Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr

355 360 365

Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu

370 375 380

Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu

385 390 395 400

Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys

405 410 415

Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu

420 425 430

Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly

435 440 445

Lys

<210> 118

<211> 449

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 118

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Arg Ile Tyr

20 25 30

Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Gly Ile Ile Pro Asp Phe Gly Val Ala Asn Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gly Gly Leu Asp Thr Asp Glu Phe Asp Leu Trp Gly Arg Gly

100 105 110

Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe

115 120 125

Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu

130 135 140

Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp

145 150 155 160

Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu

165 170 175

Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser

180 185 190

Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro

195 200 205

Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys

210 215 220

Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro

225 230 235 240

Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser

245 250 255

Arg Thr Pro Glu Val Thr Cys Val Val Cys Val Ser His Glu Asp

260 265 270

Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn

275 280 285

Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val

290 295 300

Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu

305 310 315 320

Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys

325 330 335

Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr

340 345 350

Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr

355 360 365

Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu

370 375 380

Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu

385 390 395 400

Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys

405 410 415

Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu

420 425 430

Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly

435 440 445

Lys

<210> 119

<211> 449

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 119

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Arg Ile Tyr

20 25 30

Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Gly Ile Ile Pro Asp Phe Gly Val Ala Asn Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gly Gly Leu Asp Thr Asp Glu Phe Asp Leu Trp Gly Arg Gly

100 105 110

Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe

115 120 125

Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu

130 135 140

Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp

145 150 155 160

Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu

165 170 175

Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser

180 185 190

Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro

195 200 205

Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys

210 215 220

Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro

225 230 235 240

Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser

245 250 255

Arg Thr Pro Glu Val Thr Cys Val Val Cys Val Ser His Glu Asp

260 265 270

Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn

275 280 285

Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val

290 295 300

Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu

305 310 315 320

Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys

325 330 335

Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr

340 345 350

Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr

355 360 365

Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu

370 375 380

Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu

385 390 395 400

Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys

405 410 415

Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu

420 425 430

Ala Leu His Asn Ala Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly

435 440 445

Lys

<210> 120

<211> 449

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 120

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Arg Ile Tyr

20 25 30

Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Gly Ile Ile Pro Asp Phe Gly Val Ala Asn Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gly Gly Leu Asp Thr Asp Glu Phe Asp Leu Trp Gly Arg Gly

100 105 110

Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe

115 120 125

Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu

130 135 140

Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp

145 150 155 160

Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu

165 170 175

Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser

180 185 190

Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro

195 200 205

Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys

210 215 220

Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro

225 230 235 240

Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser

245 250 255

Arg Thr Pro Glu Val Thr Cys Val Val Cys Val Ser His Glu Asp

260 265 270

Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn

275 280 285

Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val

290 295 300

Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu

305 310 315 320

Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys

325 330 335

Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr

340 345 350

Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr

355 360 365

Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu

370 375 380

Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu

385 390 395 400

Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys

405 410 415

Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu

420 425 430

Ala Leu His Asn Ala Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly

435 440 445

Lys

<210> 121

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 121

Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu

1 5 10 15

Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe

20 25 30

Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln

35 40 45

Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser

50 55 60

Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu

65 70 75 80

Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser

85 90 95

Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys

100 105

<210> 122

<211> 330

<212> PRT

<213> Homo sapiens

<400> 122

Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys

1 5 10 15

Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr

20 25 30

Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser

35 40 45

Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser

50 55 60

Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr

65 70 75 80

Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys

85 90 95

Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys

100 105 110

Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro

115 120 125

Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys

130 135 140

Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp

145 150 155 160

Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu

165 170 175

Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu

180 185 190

His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn

195 200 205

Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly

210 215 220

Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu

225 230 235 240

Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr

245 250 255

Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn

260 265 270

Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe

275 280 285

Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn

290 295 300

Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr

305 310 315 320

Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

325 330

<210> 123

<211> 330

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 123

Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys

1 5 10 15

Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr

20 25 30

Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser

35 40 45

Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser

50 55 60

Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr

65 70 75 80

Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys

85 90 95

Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys

100 105 110

Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro

115 120 125

Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys

130 135 140

Val Val Val Cys Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp

145 150 155 160

Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu

165 170 175

Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu

180 185 190

His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn

195 200 205

Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly

210 215 220

Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu

225 230 235 240

Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr

245 250 255

Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn

260 265 270

Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe

275 280 285

Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn

290 295 300

Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr

305 310 315 320

Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

325 330

<210> 124

<211> 330

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 124

Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys

1 5 10 15

Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr

20 25 30

Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser

35 40 45

Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser

50 55 60

Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr

65 70 75 80

Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys

85 90 95

Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys

100 105 110

Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro

115 120 125

Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys

130 135 140

Val Val Val Cys Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp

145 150 155 160

Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu

165 170 175

Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu

180 185 190

His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn

195 200 205

Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly

210 215 220

Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu

225 230 235 240

Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr

245 250 255

Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn

260 265 270

Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe

275 280 285

Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn

290 295 300

Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr

305 310 315 320

Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

325 330

<210> 125

<211> 330

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 125

Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys

1 5 10 15

Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr

20 25 30

Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser

35 40 45

Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser

50 55 60

Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr

65 70 75 80

Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys

85 90 95

Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys

100 105 110

Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro

115 120 125

Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys

130 135 140

Val Val Val Cys Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp

145 150 155 160

Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu

165 170 175

Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu

180 185 190

His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn

195 200 205

Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly

210 215 220

Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu

225 230 235 240

Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr

245 250 255

Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn

260 265 270

Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe

275 280 285

Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn

290 295 300

Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn Ala Tyr Thr

305 310 315 320

Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

325 330

<210> 126

<211> 330

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 126

Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys

1 5 10 15

Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr

20 25 30

Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser

35 40 45

Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser

50 55 60

Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr

65 70 75 80

Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys

85 90 95

Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys

100 105 110

Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro

115 120 125

Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys

130 135 140

Val Val Val Cys Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp

145 150 155 160

Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu

165 170 175

Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu

180 185 190

His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn

195 200 205

Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly

210 215 220

Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu

225 230 235 240

Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr

245 250 255

Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn

260 265 270

Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe

275 280 285

Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn

290 295 300

Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn Ala Tyr Thr

305 310 315 320

Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

325 330

<210> 127

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<220>

<221> OPTION

<222> (4)..(4)

<223> /replace="Arg"

<220>

<221> OPTION

<222> (5)..(5)

<223> /replace="Ile" or "Leu"

<220>

<221> SITE

<222> (1)..(9)

<223> /note="Variant residues given in sequence,

have no preference over residues in annotations

for alternative provisions"

<400> 127

Gly Thr Phe Ser Ser Tyr Ala Ile Ser

1 5

<210> 128

<211> 17

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<220>

<221> OPTION

<222> (5)..(5)

<223> /replace="Asp" or "Ala" or "His"

<220>

<221> OPTION

<222> (8)..(8)

<223> /replace="Val" or "Leu"

<220>

<221> SITE

<222> (1)..(17)

<223> /note="Variant residues given in sequence,

have no preference over residues in annotations

for alternative provisions"

<400> 128

Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe Gln

1 5 10 15

Gly

<210> 129

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 129

Ala Arg Gly Gly Leu Asp Thr Asp Glu Phe Asp Leu

1 5 10

<210> 130

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 130

Arg Ala Ser Gln Ser Ile Asn Ser Tyr Leu Asn

1 5 10

<210> 131

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 131

Ala Ala Ser Ser Leu Gln Ser

1 5

<210> 132

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 132

Gln Gln Gly Val Ser Asp Ile Thr

1 5

<210> 133

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<220>

<221> OPTION

<222> (5)..(5)

<223> /replace="Ser"

<220>

<221> OPTION

<222> (7)..(7)

<223> /replace="Val"

<220>

<221> OPTION

<222> (9)..(9)

<223> /replace="Ile"

<220>

<221> SITE

<222> (1)..(9)

<223> /note="Variant residues given in sequence,

have no preference over residues in annotations

for alternative provisions"

<400> 133

Phe Thr Phe Ser Asn Tyr Ala Met Ser

1 5

<210> 134

<211> 17

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<220>

<221> OPTION

<222> (1)..(1)

<223> /replace="Ser"

<220>

<221> OPTION

<222> (5)..(5)

<223> /replace="Asp"

<220>

<221> OPTION

<222> (6)..(6)

<223> /replace="Ser"

<220>

<221> OPTION

<222> (7)..(7)

<223> /replace="Val"

<220>

<221> OPTION

<222> (8)..(8)

<223> /replace="Thr"

<220>

<221> SITE

<222> (1)..(17)

<223> /note="Variant residues given in sequence,

have no preference over residues in annotations

for alternative provisions"

<400> 134

Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys

1 5 10 15

Gly

<210> 135

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 135

Ala Lys Gly Pro Pro Thr Tyr His Thr Asn Tyr Tyr Tyr Met Asp Val

1 5 10 15

<210> 136

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 136

Arg Ala Ser Gln Gly Ile Ser Ser Trp Leu Ala

1 5 10

<210> 137

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 137

Ala Ala Ser Ser Leu Gln Ser

1 5

<210> 138

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 138

Gln Gln Thr Asn Ser Phe Pro Tyr Thr

1 5

<210> 139

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<220>

<221> OPTION

<222> (4)..(4)

<223> /replace="Val"

<220>

<221> OPTION

<222> (6)..(6)

<223> /replace="Ala"

<220>

<221> OPTION

<222> (7)..(7)

<223> /replace="Asp"

<220>

<221> OPTION

<222> (9)..(9)

<223> /replace="Asn"

<220>

<221> SITE

<222> (1)..(9)

<223> /note="Variant residues given in sequence,

have no preference over residues in annotations

for alternative provisions"

<400> 139

Phe Thr Phe Ser Asp His Tyr Met Asp

1 5

<210> 140

<211> 19

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<220>

<221> OPTION

<222> (5)..(5)

<223> /replace="Ala"

<220>

<221> OPTION

<222> (6)..(6)

<223> /replace="Leu"

<220>

<221> OPTION

<222> (7)..(7)

<223> /replace="Gly"

<220>

<221> SITE

<222> (1)..(19)

<223> /note="Variant residues given in sequence,

have no preference over residues in annotations

for alternative provisions"

<400> 140

Arg Thr Arg Asn Lys Ala Ser Ser Tyr Thr Thr Glu Tyr Ala Ala Ser

1 5 10 15

Val Lys Gly

<210> 141

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 141

Ala Arg Glu Pro Lys Tyr Trp Ile Asp Phe Asp Leu

1 5 10

<210> 142

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 142

Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn

1 5 10

<210> 143

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 143

Ala Ala Ser Ser Leu Gln Ser

1 5

<210> 144

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 144

Gln Gln Ser Tyr Ile Ala Pro Tyr Thr

1 5

<210> 145

<211> 976

<212> PRT

<213> Homo sapiens

<400> 145

Met Arg Gly Ala Arg Gly Ala Trp Asp Phe Leu Cys Val Leu Leu Leu

1 5 10 15

Leu Leu Arg Val Gln Thr Gly Ser Ser Gln Pro Ser Val Ser Pro Gly

20 25 30

Glu Pro Ser Pro Pro Ser Ile His Pro Gly Lys Ser Asp Leu Ile Val

35 40 45

Arg Val Gly Asp Glu Ile Arg Leu Leu Cys Thr Asp Pro Gly Phe Val

50 55 60

Lys Trp Thr Phe Glu Ile Leu Asp Glu Thr Asn Glu Asn Lys Gln Asn

65 70 75 80

Glu Trp Ile Thr Glu Lys Ala Glu Ala Thr Asn Thr Gly Lys Tyr Thr

85 90 95

Cys Thr Asn Lys His Gly Leu Ser Asn Ser Ile Tyr Val Phe Val Arg

100 105 110

Asp Pro Ala Lys Leu Phe Leu Val Asp Arg Ser Leu Tyr Gly Lys Glu

115 120 125

Asp Asn Asp Thr Leu Val Arg Cys Pro Leu Thr Asp Pro Glu Val Thr

130 135 140

Asn Tyr Ser Leu Lys Gly Cys Gln Gly Lys Pro Leu Pro Lys Asp Leu

145 150 155 160

Arg Phe Ile Pro Asp Pro Lys Ala Gly Ile Met Ile Lys Ser Val Lys

165 170 175

Arg Ala Tyr His Arg Leu Cys Leu His Cys Ser Val Asp Gln Glu Gly

180 185 190

Lys Ser Val Leu Ser Glu Lys Phe Ile Leu Lys Val Arg Pro Ala Phe

195 200 205

Lys Ala Val Pro Val Val Ser Val Ser Lys Ala Ser Tyr Leu Leu Arg

210 215 220

Glu Gly Glu Glu Phe Thr Val Thr Cys Thr Ile Lys Asp Val Ser Ser

225 230 235 240

Ser Val Tyr Ser Thr Trp Lys Arg Glu Asn Ser Gln Thr Lys Leu Gln

245 250 255

Glu Lys Tyr Asn Ser Trp His His Gly Asp Phe Asn Tyr Glu Arg Gln

260 265 270

Ala Thr Leu Thr Ile Ser Ser Ala Arg Val Asn Asp Ser Gly Val Phe

275 280 285

Met Cys Tyr Ala Asn Asn Thr Phe Gly Ser Ala Asn Val Thr Thr Thr

290 295 300

Leu Glu Val Val Asp Lys Gly Phe Ile Asn Ile Phe Pro Met Ile Asn

305 310 315 320

Thr Thr Val Phe Val Asn Asp Gly Glu Asn Val Asp Leu Ile Val Glu

325 330 335

Tyr Glu Ala Phe Pro Lys Pro Glu His Gln Gln Trp Ile Tyr Met Asn

340 345 350

Arg Thr Phe Thr Asp Lys Trp Glu Asp Tyr Pro Lys Ser Glu Asn Glu

355 360 365

Ser Asn Ile Arg Tyr Val Ser Glu Leu His Leu Thr Arg Leu Lys Gly

370 375 380

Thr Glu Gly Gly Thr Tyr Thr Phe Leu Val Ser Asn Ser Asp Val Asn

385 390 395 400

Ala Ala Ile Ala Phe Asn Val Tyr Val Asn Thr Lys Pro Glu Ile Leu

405 410 415

Thr Tyr Asp Arg Leu Val Asn Gly Met Leu Gln Cys Val Ala Ala Gly

420 425 430

Phe Pro Glu Pro Thr Ile Asp Trp Tyr Phe Cys Pro Gly Thr Glu Gln

435 440 445

Arg Cys Ser Ala Ser Val Leu Pro Val Asp Val Gln Thr Leu Asn Ser

450 455 460

Ser Gly Pro Pro Phe Gly Lys Leu Val Val Gln Ser Ser Ile Asp Ser

465 470 475 480

Ser Ala Phe Lys His Asn Gly Thr Val Glu Cys Lys Ala Tyr Asn Asp

485 490 495

Val Gly Lys Thr Ser Ala Tyr Phe Asn Phe Ala Phe Lys Gly Asn Asn

500 505 510

Lys Glu Gln Ile His Pro His Thr Leu Phe Thr Pro Leu Leu Ile Gly

515 520 525

Phe Val Ile Val Ala Gly Met Met Cys Ile Ile Val Met Ile Leu Thr

530 535 540

Tyr Lys Tyr Leu Gln Lys Pro Met Tyr Glu Val Gln Trp Lys Val Val

545 550 555 560

Glu Glu Ile Asn Gly Asn Asn Tyr Val Tyr Ile Asp Pro Thr Gln Leu

565 570 575

Pro Tyr Asp His Lys Trp Glu Phe Pro Arg Asn Arg Leu Ser Phe Gly

580 585 590

Lys Thr Leu Gly Ala Gly Ala Phe Gly Lys Val Val Glu Ala Thr Ala

595 600 605

Tyr Gly Leu Ile Lys Ser Asp Ala Ala Met Thr Val Ala Val Lys Met

610 615 620

Leu Lys Pro Ser Ala His Leu Thr Glu Arg Glu Ala Leu Met Ser Glu

625 630 635 640

Leu Lys Val Leu Ser Tyr Leu Gly Asn His Met Asn Ile Val Asn Leu

645 650 655

Leu Gly Ala Cys Thr Ile Gly Gly Pro Thr Leu Val Ile Thr Glu Tyr

660 665 670

Cys Cys Tyr Gly Asp Leu Leu Asn Phe Leu Arg Arg Lys Arg Asp Ser

675 680 685

Phe Ile Cys Ser Lys Gln Glu Asp His Ala Glu Ala Ala Leu Tyr Lys

690 695 700

Asn Leu Leu His Ser Lys Glu Ser Ser Cys Ser Asp Ser Thr Asn Glu

705 710 715 720

Tyr Met Asp Met Lys Pro Gly Val Ser Tyr Val Val Pro Thr Lys Ala

725 730 735

Asp Lys Arg Arg Ser Val Arg Ile Gly Ser Tyr Ile Glu Arg Asp Val

740 745 750

Thr Pro Ala Ile Met Glu Asp Asp Glu Leu Ala Leu Asp Leu Glu Asp

755 760 765

Leu Leu Ser Phe Ser Tyr Gln Val Ala Lys Gly Met Ala Phe Leu Ala

770 775 780

Ser Lys Asn Cys Ile His Arg Asp Leu Ala Ala Arg Asn Ile Leu Leu

785 790 795 800

Thr His Gly Arg Ile Thr Lys Ile Cys Asp Phe Gly Leu Ala Arg Asp

805 810 815

Ile Lys Asn Asp Ser Asn Tyr Val Val Lys Gly Asn Ala Arg Leu Pro

820 825 830

Val Lys Trp Met Ala Pro Glu Ser Ile Phe Asn Cys Val Tyr Thr Phe

835 840 845

Glu Ser Asp Val Trp Ser Tyr Gly Ile Phe Leu Trp Glu Leu Phe Ser

850 855 860

Leu Gly Ser Ser Pro Tyr Pro Gly Met Pro Val Asp Ser Lys Phe Tyr

865 870 875 880

Lys Met Ile Lys Glu Gly Phe Arg Met Leu Ser Pro Glu His Ala Pro

885 890 895

Ala Glu Met Tyr Asp Ile Met Lys Thr Cys Trp Asp Ala Asp Pro Leu

900 905 910

Lys Arg Pro Thr Phe Lys Gln Ile Val Gln Leu Ile Glu Lys Gln Ile

915 920 925

Ser Glu Ser Thr Asn His Ile Tyr Ser Asn Leu Ala Asn Cys Ser Pro

930 935 940

Asn Arg Gln Lys Pro Val Val Asp His Ser Val Arg Ile Asn Ser Val

945 950 955 960

Gly Ser Thr Ala Ser Ser Ser Gln Pro Leu Leu Val His Asp Asp Val

965 970 975

<210> 146

<211> 972

<212> PRT

<213> Homo sapiens

<400> 146

Met Arg Gly Ala Arg Gly Ala Trp Asp Phe Leu Cys Val Leu Leu Leu

1 5 10 15

Leu Leu Arg Val Gln Thr Gly Ser Ser Gln Pro Ser Val Ser Pro Gly

20 25 30

Glu Pro Ser Pro Pro Ser Ile His Pro Gly Lys Ser Asp Leu Ile Val

35 40 45

Arg Val Gly Asp Glu Ile Arg Leu Leu Cys Thr Asp Pro Gly Phe Val

50 55 60

Lys Trp Thr Phe Glu Ile Leu Asp Glu Thr Asn Glu Asn Lys Gln Asn

65 70 75 80

Glu Trp Ile Thr Glu Lys Ala Glu Ala Thr Asn Thr Gly Lys Tyr Thr

85 90 95

Cys Thr Asn Lys His Gly Leu Ser Asn Ser Ile Tyr Val Phe Val Arg

100 105 110

Asp Pro Ala Lys Leu Phe Leu Val Asp Arg Ser Leu Tyr Gly Lys Glu

115 120 125

Asp Asn Asp Thr Leu Val Arg Cys Pro Leu Thr Asp Pro Glu Val Thr

130 135 140

Asn Tyr Ser Leu Lys Gly Cys Gln Gly Lys Pro Leu Pro Lys Asp Leu

145 150 155 160

Arg Phe Ile Pro Asp Pro Lys Ala Gly Ile Met Ile Lys Ser Val Lys

165 170 175

Arg Ala Tyr His Arg Leu Cys Leu His Cys Ser Val Asp Gln Glu Gly

180 185 190

Lys Ser Val Leu Ser Glu Lys Phe Ile Leu Lys Val Arg Pro Ala Phe

195 200 205

Lys Ala Val Pro Val Val Ser Val Ser Lys Ala Ser Tyr Leu Leu Arg

210 215 220

Glu Gly Glu Glu Phe Thr Val Thr Cys Thr Ile Lys Asp Val Ser Ser

225 230 235 240

Ser Val Tyr Ser Thr Trp Lys Arg Glu Asn Ser Gln Thr Lys Leu Gln

245 250 255

Glu Lys Tyr Asn Ser Trp His His Gly Asp Phe Asn Tyr Glu Arg Gln

260 265 270

Ala Thr Leu Thr Ile Ser Ser Ala Arg Val Asn Asp Ser Gly Val Phe

275 280 285

Met Cys Tyr Ala Asn Asn Thr Phe Gly Ser Ala Asn Val Thr Thr Thr

290 295 300

Leu Glu Val Val Asp Lys Gly Phe Ile Asn Ile Phe Pro Met Ile Asn

305 310 315 320

Thr Thr Val Phe Val Asn Asp Gly Glu Asn Val Asp Leu Ile Val Glu

325 330 335

Tyr Glu Ala Phe Pro Lys Pro Glu His Gln Gln Trp Ile Tyr Met Asn

340 345 350

Arg Thr Phe Thr Asp Lys Trp Glu Asp Tyr Pro Lys Ser Glu Asn Glu

355 360 365

Ser Asn Ile Arg Tyr Val Ser Glu Leu His Leu Thr Arg Leu Lys Gly

370 375 380

Thr Glu Gly Gly Thr Tyr Thr Phe Leu Val Ser Asn Ser Asp Val Asn

385 390 395 400

Ala Ala Ile Ala Phe Asn Val Tyr Val Asn Thr Lys Pro Glu Ile Leu

405 410 415

Thr Tyr Asp Arg Leu Val Asn Gly Met Leu Gln Cys Val Ala Ala Gly

420 425 430

Phe Pro Glu Pro Thr Ile Asp Trp Tyr Phe Cys Pro Gly Thr Glu Gln

435 440 445

Arg Cys Ser Ala Ser Val Leu Pro Val Asp Val Gln Thr Leu Asn Ser

450 455 460

Ser Gly Pro Pro Phe Gly Lys Leu Val Val Gln Ser Ser Ile Asp Ser

465 470 475 480

Ser Ala Phe Lys His Asn Gly Thr Val Glu Cys Lys Ala Tyr Asn Asp

485 490 495

Val Gly Lys Thr Ser Ala Tyr Phe Asn Phe Ala Phe Lys Glu Gln Ile

500 505 510

His Pro His Thr Leu Phe Thr Pro Leu Leu Ile Gly Phe Val Ile Val

515 520 525

Ala Gly Met Met Cys Ile Ile Val Met Ile Leu Thr Tyr Lys Tyr Leu

530 535 540

Gln Lys Pro Met Tyr Glu Val Gln Trp Lys Val Val Glu Glu Ile Asn

545 550 555 560

Gly Asn Asn Tyr Val Tyr Ile Asp Pro Thr Gln Leu Pro Tyr Asp His

565 570 575

Lys Trp Glu Phe Pro Arg Asn Arg Leu Ser Phe Gly Lys Thr Leu Gly

580 585 590

Ala Gly Ala Phe Gly Lys Val Val Glu Ala Thr Ala Tyr Gly Leu Ile

595 600 605

Lys Ser Asp Ala Ala Met Thr Val Ala Val Lys Met Leu Lys Pro Ser

610 615 620

Ala His Leu Thr Glu Arg Glu Ala Leu Met Ser Glu Leu Lys Val Leu

625 630 635 640

Ser Tyr Leu Gly Asn His Met Asn Ile Val Asn Leu Leu Gly Ala Cys

645 650 655

Thr Ile Gly Gly Pro Thr Leu Val Ile Thr Glu Tyr Cys Cys Tyr Gly

660 665 670

Asp Leu Leu Asn Phe Leu Arg Arg Lys Arg Asp Ser Phe Ile Cys Ser

675 680 685

Lys Gln Glu Asp His Ala Glu Ala Ala Leu Tyr Lys Asn Leu Leu His

690 695 700

Ser Lys Glu Ser Ser Cys Ser Asp Ser Thr Asn Glu Tyr Met Asp Met

705 710 715 720

Lys Pro Gly Val Ser Tyr Val Val Pro Thr Lys Ala Asp Lys Arg Arg

725 730 735

Ser Val Arg Ile Gly Ser Tyr Ile Glu Arg Asp Val Thr Pro Ala Ile

740 745 750

Met Glu Asp Asp Glu Leu Ala Leu Asp Leu Glu Asp Leu Leu Ser Phe

755 760 765

Ser Tyr Gln Val Ala Lys Gly Met Ala Phe Leu Ala Ser Lys Asn Cys

770 775 780

Ile His Arg Asp Leu Ala Ala Arg Asn Ile Leu Leu Thr His Gly Arg

785 790 795 800

Ile Thr Lys Ile Cys Asp Phe Gly Leu Ala Arg Asp Ile Lys Asn Asp

805 810 815

Ser Asn Tyr Val Val Lys Gly Asn Ala Arg Leu Pro Val Lys Trp Met

820 825 830

Ala Pro Glu Ser Ile Phe Asn Cys Val Tyr Thr Phe Glu Ser Asp Val

835 840 845

Trp Ser Tyr Gly Ile Phe Leu Trp Glu Leu Phe Ser Leu Gly Ser Ser

850 855 860

Pro Tyr Pro Gly Met Pro Val Asp Ser Lys Phe Tyr Lys Met Ile Lys

865 870 875 880

Glu Gly Phe Arg Met Leu Ser Pro Glu His Ala Pro Ala Glu Met Tyr

885 890 895

Asp Ile Met Lys Thr Cys Trp Asp Ala Asp Pro Leu Lys Arg Pro Thr

900 905 910

Phe Lys Gln Ile Val Gln Leu Ile Glu Lys Gln Ile Ser Glu Ser Thr

915 920 925

Asn His Ile Tyr Ser Asn Leu Ala Asn Cys Ser Pro Asn Arg Gln Lys

930 935 940

Pro Val Val Asp His Ser Val Arg Ile Asn Ser Val Gly Ser Thr Ala

945 950 955 960

Ser Ser Ser Gln Pro Leu Leu Val His Asp Asp Val

965 970

<210> 147

<211> 123

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 147

Gln Val Gln Leu Val Gln Ser Gly Ala Ala Val Lys Lys Pro Gly Glu

1 5 10 15

Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Arg Phe Thr Thr Tyr

20 25 30

Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met

35 40 45

Gly Ile Ile Tyr Pro Gly Asp Ser Asp Thr Arg Tyr Ser Pro Ser Phe

50 55 60

Gln Gly Gln Val Thr Ile Ser Ala Gly Lys Ser Ile Ser Thr Ala Tyr

65 70 75 80

Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys

85 90 95

Ala Arg His Gly Arg Gly Tyr Asn Gly Tyr Glu Gly Ala Phe Asp Ile

100 105 110

Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser

115 120

<210> 148

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 148

Ala Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Val Ser Ser Ala

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Asp Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Asn Ser Tyr Pro Leu

85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105

<210> 149

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 149

Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Thr Asp

20 25 30

Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Asp Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Asn Ser Tyr Pro Leu

85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105

<210> 150

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 150

Ala Ile Arg Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Thr Pro Lys Leu Leu Ile

35 40 45

Tyr Asp Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Asn Ser Tyr Pro Leu

85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105

<210> 151

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 151

Ala Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp

20 25 30

Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Asp Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Asn Ser Tyr Pro Leu

85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Asp Ile Lys

100 105

<210> 152

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 152

Asn Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ala Ile Ser Asp Tyr

20 25 30

Leu Ala Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Leu Asn Ser Tyr Pro Leu

85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105

<210> 153

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 153

Ala Ile Arg Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Ile Ile Ala Cys Arg Ala Ser Gln Gly Ile Gly Gly Ala

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Asn Ala Pro Lys Val Leu Val

35 40 45

Tyr Asp Ala Ser Thr Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Gly Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Asn Ser Tyr Pro Leu

85 90 95

Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 154

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

Synthetic

polypeptide"

<400> 154

Asp Ile Ala Met Thr Gln Ser Pro Pro Ser Leu Ser Ala Phe Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ile Ser Ser

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Asp Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Arg Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Asn Ser Tyr Pro Leu

85 90 95

Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 155

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 155

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Ala

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Ala Gly Lys Ala Pro Lys Val Leu Ile

35 40 45

Ser Asp Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Asn Gly Tyr Pro Leu

85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Asp Ile Lys

100 105

<210> 156

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 156

Ala Ile Arg Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Gly Ile Arg Asn Asp

20 25 30

Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Phe Asn Ser Tyr Pro Leu

85 90 95

Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 157

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 157

Asn Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Thr Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Gly Thr Ser

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Pro Pro Lys Leu Leu Ile

35 40 45

Tyr Asp Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Leu Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Asn Ser Tyr Pro Ile

85 90 95

Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys

100 105

<210> 158

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 158

Ala Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Gly Asp Tyr

20 25 30

Leu Thr Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile

35 40 45

Tyr Gly Ala Ser Ser Leu Gln Ser Gly Val Pro Pro Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Val Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Leu Asn Ser Tyr Pro Leu

85 90 95

Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 159

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 159

Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Val Arg Ser Thr

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Asp Ala Ser Ile Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Asn Gly Tyr Pro Leu

85 90 95

Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys

100 105

<210> 160

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 160

Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp

20 25 30

Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Asp Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Asn Ser Tyr Pro Leu

85 90 95

Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 161

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 161

Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Phe

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Asp Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Ala Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Leu Asn Gly Tyr Pro Leu

85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105

<210> 162

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 162

Ala Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Gly Ser Ala

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Ile Gly Pro Lys Leu Leu Ile

35 40 45

Tyr Asp Ala Ser Thr Leu Glu Ser Gly Val Pro Ala Arg Phe Ser Gly

50 55 60

Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Thr Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Asn Gly Tyr Pro Leu

85 90 95

Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 163

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 163

Ala Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Thr Ser Ala

20 25 30

Leu Ala Trp Tyr Gln Glu Lys Pro Gly Lys Ala Pro Asn Leu Leu Ile

35 40 45

Tyr Asp Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Tyr Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Leu Asn Ser Tyr Pro Leu

85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Asp Ile Lys

100 105

<210> 164

<211> 121

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 164

Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Arg Lys Pro Gly Glu

1 5 10 15

Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr

20 25 30

Ala Met Tyr Trp Val Lys Gln Ala Pro Gly Lys Gly Leu Lys Trp Met

35 40 45

Gly Trp Ile Asn Thr Tyr Thr Gly Lys Pro Thr Tyr Ala Asp Asp Phe

50 55 60

Lys Gly Arg Phe Val Phe Ser Leu Glu Ala Ser Ala Asn Thr Ala Asn

65 70 75 80

Leu Gln Ile Ser Asn Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys

85 90 95

Ala Arg Ala Arg Gly Leu Val Asp Asp Tyr Val Met Asp Ala Trp Gly

100 105 110

Gln Gly Thr Ser Val Thr Val Ser Ser

115 120

<210> 165

<211> 108

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 165

Ser Tyr Glu Leu Ile Gln Pro Pro Ser Ala Ser Val Thr Leu Gly Asn

1 5 10 15

Thr Val Ser Leu Thr Cys Val Gly Asp Glu Leu Ser Lys Arg Tyr Ala

20 25 30

Gln Trp Tyr Gln Gln Lys Pro Asp Lys Thr Ile Val Ser Val Ile Tyr

35 40 45

Lys Asp Ser Glu Arg Pro Ser Gly Ile Ser Asp Arg Phe Ser Gly Ser

50 55 60

Ser Ser Gly Thr Thr Ala Thr Leu Thr Ile His Gly Thr Leu Ala Glu

65 70 75 80

Asp Glu Ala Asp Tyr Tyr Cys Leu Ser Thr Tyr Ser Asp Asp Asn Leu

85 90 95

Pro Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu

100 105

<210> 166

<211> 117

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 166

Glu Val Gln Leu Gln Gln Tyr Gly Ala Glu Leu Gly Lys Pro Gly Thr

1 5 10 15

Ser Val Arg Leu Ser Cys Lys Val Ser Gly Tyr Asn Ile Arg Asn Thr

20 25 30

Tyr Ile His Trp Val Asn Gln Arg Pro Gly Glu Gly Leu Glu Trp Ile

35 40 45

Gly Arg Ile Asp Pro Thr Asn Gly Asn Thr Ile Ser Ala Glu Lys Phe

50 55 60

Lys Thr Lys Ala Thr Leu Thr Ala Asp Thr Ser Ser His Thr Ala Tyr

65 70 75 80

Leu Gln Phe Ser Gln Leu Lys Ser Asp Asp Thr Ala Ile Tyr Phe Cys

85 90 95

Ala Leu Asn Tyr Glu Gly Tyr Ala Asp Tyr Trp Gly Gln Gly Val Met

100 105 110

Val Thr Gly Ser Ser

115

<210> 167

<211> 106

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

Synthetic

polypeptide"

<400> 167

Asp Ile Gln Met Thr Gln Ser Pro Ser Phe Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Asn Cys Lys Ala Ser Gln Asn Ile Asn Lys Tyr

20 25 30

Leu Asn Trp Tyr Gln Gln Lys Val Gly Glu Ala Pro Lys Arg Leu Ile

35 40 45

Phe Lys Thr Asn Ser Leu Gln Thr Gly Ile Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Thr

65 70 75 80

Glu Asp Val Ala Thr Tyr Phe Cys Phe Gln Tyr Asn Ile Gly Tyr Thr

85 90 95

Phe Gly Ala Gly Thr Lys Val Glu Leu Lys

100 105

<210> 168

<211> 124

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 168

Glu Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln

1 5 10 15

Ser Leu Ser Leu Thr Cys Ser Val Thr Gly Tyr Ser Ile Ser Ser Asn

20 25 30

Tyr Arg Trp Asn Trp Ile Arg Lys Phe Pro Gly Asn Lys Val Glu Trp

35 40 45

Met Gly Tyr Ile Asn Ser Ala Gly Ser Thr Asn Tyr Asn Pro Ser Leu

50 55 60

Lys Ser Arg Ile Ser Met Thr Arg Asp Thr Ser Lys Asn Gln Phe Phe

65 70 75 80

Leu Gln Val Asn Ser Val Thr Thr Glu Asp Thr Ala Thr Tyr Tyr Cys

85 90 95

Ala Arg Ser Leu Arg Gly Tyr Ile Thr Asp Tyr Ser Gly Phe Phe Asp

100 105 110

Tyr Trp Gly Gln Gly Val Met Val Thr Val Ser Ser

115 120

<210> 169

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 169

Asp Ile Arg Met Thr Gln Ser Pro Ala Ser Leu Ser Ala Ser Leu Gly

1 5 10 15

Glu Thr Val Asn Ile Glu Cys Leu Ala Ser Glu Asp Ile Phe Ser Asp

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ser Pro Gln Leu Leu Ile

35 40 45

Tyr Asn Ala Asn Ser Leu Gln Asn Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Arg Tyr Ser Leu Lys Ile Asn Ser Leu Gln Ser

65 70 75 80

Glu Asp Val Ala Thr Tyr Phe Cys Gln Gln Tyr Lys Asn Tyr Pro Leu

85 90 95

Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 170

<211> 117

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 170

Glu Val Gln Leu Gln Gln Tyr Gly Ala Glu Leu Gly Lys Pro Gly Thr

1 5 10 15

Ser Val Arg Leu Ser Cys Lys Leu Ser Gly Tyr Lys Ile Arg Asn Thr

20 25 30

Tyr Ile His Trp Val Asn Gln Arg Pro Gly Lys Gly Leu Glu Trp Ile

35 40 45

Gly Arg Ile Asp Pro Ala Asn Gly Asn Thr Ile Tyr Ala Glu Lys Phe

50 55 60

Lys Ser Lys Val Thr Leu Thr Ala Asp Thr Ser Ser Asn Thr Ala Tyr

65 70 75 80

Met Gln Leu Ser Gln Leu Lys Ser Asp Asp Thr Ala Leu Tyr Phe Cys

85 90 95

Ala Met Asn Tyr Glu Gly Tyr Glu Asp Tyr Trp Gly Gln Gly Val Met

100 105 110

Val Thr Val Ser Ser

115

<210> 171

<211> 106

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 171

Asp Ile Gln Met Thr Gln Ser Pro Ser Phe Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Ser Val Thr Ile Asn Cys Lys Ala Ser Gln Asn Ile Asn Lys Tyr

20 25 30

Leu Asn Trp Tyr Gln Gln Lys Leu Gly Glu Ala Pro Lys Arg Leu Ile

35 40 45

His Lys Thr Asp Ser Leu Gln Thr Gly Ile Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Val Ala Thr Tyr Phe Cys Phe Gln Tyr Lys Ser Gly Phe Met

85 90 95

Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys

100 105

<210> 172

<211> 120

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 172

Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu

1 5 10 15

Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr

20 25 30

Ala Val Tyr Trp Val Ile Gln Ala Pro Gly Lys Gly Leu Lys Trp Met

35 40 45

Gly Trp Ile Asn Thr Tyr Thr Gly Lys Pro Thr Tyr Ala Asp Asp Phe

50 55 60

Lys Gly Arg Phe Val Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Asn

65 70 75 80

Leu Gln Ile Ser Asn Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys

85 90 95

Ala Arg Gly Ala Gly Met Thr Lys Asp Tyr Val Met Asp Ala Trp Gly

100 105 110

Arg Gly Val Leu Val Thr Val Ser

115 120

<210> 173

<211> 108

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 173

Ser Tyr Glu Leu Ile Gln Pro Pro Ser Ala Ser Val Thr Leu Gly Asn

1 5 10 15

Thr Val Ser Leu Thr Cys Val Gly Asp Glu Leu Ser Lys Arg Tyr Ala

20 25 30

Gln Trp Tyr Gln Gln Lys Pro Asp Lys Thr Ile Val Ser Val Ile Tyr

35 40 45

Lys Asp Ser Glu Arg Pro Ser Asp Ile Ser Asp Arg Phe Ser Gly Ser

50 55 60

Ser Ser Gly Thr Thr Ala Thr Leu Thr Ile His Gly Thr Leu Ala Glu

65 70 75 80

Asp Glu Ala Asp Tyr Tyr Cys Leu Ser Thr Tyr Ser Asp Asp Asn Leu

85 90 95

Pro Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu

100 105

<210> 174

<211> 116

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 174

Gln Val Gln Leu Lys Glu Ser Gly Pro Gly Leu Val Gln Pro Ser Gln

1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Ser Tyr

20 25 30

Leu Val His Trp Val Arg Gln Pro Pro Gly Lys Thr Leu Glu Trp Val

35 40 45

Gly Leu Met Trp Asn Asp Gly Asp Thr Ser Tyr Asn Ser Ala Leu Lys

50 55 60

Ser Arg Leu Ser Ile Ser Arg Asp Thr Ser Lys Ser Gln Val Phe Leu

65 70 75 80

Lys Met His Ser Leu Gln Ala Glu Asp Thr Ala Thr Tyr Tyr Cys Ala

85 90 95

Arg Glu Ser Asn Leu Gly Phe Thr Tyr Trp Gly His Gly Thr Leu Val

100 105 110

Thr Val Ser Ser

115

<210> 175

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 175

Asp Ile Gln Met Thr Gln Ser Pro Ala Ser Leu Ser Ala Ser Leu Glu

1 5 10 15

Glu Ile Val Thr Ile Thr Cys Lys Ala Ser Gln Gly Ile Asp Asp Asp

20 25 30

Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ser Pro Gln Leu Leu Ile

35 40 45

Tyr Asp Val Thr Arg Leu Ala Asp Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Arg Ser Gly Thr Gln Tyr Ser Leu Lys Ile Ser Arg Pro Gln Val

65 70 75 80

Ala Asp Ser Gly Ile Tyr Tyr Cys Leu Gln Ser Tyr Ser Thr Pro Tyr

85 90 95

Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys

100 105

<210> 176

<211> 117

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 176

Glu Val Gln Leu Gln Gln Tyr Gly Ala Glu Leu Gly Lys Pro Gly Thr

1 5 10 15

Ser Val Arg Leu Ser Cys Lys Val Ser Gly Tyr Asn Ile Arg Asn Thr

20 25 30

Tyr Ile His Trp Val His Gln Arg Pro Gly Glu Gly Leu Glu Trp Ile

35 40 45

Gly Arg Ile Asp Pro Thr Asn Gly Asn Thr Ile Ser Ala Glu Lys Phe

50 55 60

Lys Ser Lys Ala Thr Leu Thr Ala Asp Thr Ser Ser Asn Thr Ala Tyr

65 70 75 80

Met Gln Phe Ser Gln Leu Lys Ser Asp Asp Thr Ala Ile Tyr Phe Cys

85 90 95

Ala Met Asn Tyr Glu Gly Tyr Ala Asp Tyr Trp Gly Gln Gly Val Met

100 105 110

Val Thr Val Ser Ser

115

<210> 177

<211> 106

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 177

Asp Ile Gln Met Thr Gln Ser Pro Ser Phe Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Leu Thr Ile Asn Cys Lys Ala Ser Gln Asn Ile Asn Lys Tyr

20 25 30

Leu Asn Trp Tyr Gln Gln Lys Leu Gly Glu Ala Pro Lys Arg Leu Ile

35 40 45

Phe Lys Thr Asn Ser Leu Gln Thr Gly Ile Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Val Ala Thr Tyr Phe Cys Phe Gln Tyr Asn Ile Gly Phe Thr

85 90 95

Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys

100 105

<210> 178

<211> 124

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 178

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ser Gly Arg

1 5 10 15

Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Val Ser Asp Tyr

20 25 30

Tyr Met Ala Trp Val Arg Gln Ala Pro Thr Lys Gly Leu Glu Trp Val

35 40 45

Ala Thr Ile Asn Tyr Asp Gly Ser Thr Thr Tyr His Arg Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Ser Thr Leu Tyr

65 70 75 80

Leu Gln Met Asp Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys

85 90 95

Ala Arg His Gly Asp Tyr Gly Tyr His Tyr Gly Ala Tyr Tyr Phe Asp

100 105 110

Tyr Trp Gly Gln Gly Val Met Val Thr Val Ser Ser

115 120

<210> 179

<211> 109

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 179

Asp Ile Val Leu Thr Gln Ser Pro Ala Leu Ala Val Ser Leu Gly Gln

1 5 10 15

Arg Ala Thr Ile Ser Cys Arg Ala Ser Gln Thr Val Ser Leu Ser Gly

20 25 30

Tyr Asn Leu Ile His Trp Tyr Gln Gln Arg Thr Gly Gln Gln Pro Lys

35 40 45

Leu Leu Ile Tyr Arg Ala Ser Asn Leu Ala Pro Gly Ile Pro Ala Arg

50 55 60

Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Pro

65 70 75 80

Val Gln Ser Asp Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Ser Arg Glu

85 90 95

Ser Trp Thr Phe Gly Gly Gly Thr Asn Leu Glu Met Lys

100 105

<210> 180

<211> 116

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 180

Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu

1 5 10 15

Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr

20 25 30

Ala Ile His Trp Val Lys Gln Ala Pro Gly Gln Gly Leu Arg Trp Met

35 40 45

Ala Trp Ile Asn Thr Glu Thr Gly Lys Pro Thr Tyr Ala Asp Asp Phe

50 55 60

Lys Gly Arg Phe Val Phe Ser Leu Glu Ala Ser Ala Ser Thr Ala His

65 70 75 80

Leu Gln Ile Ser Asn Leu Lys Asn Glu Asp Thr Ala Thr Phe Phe Cys

85 90 95

Ala Gly Gly Ser His Trp Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser

115

<210> 181

<211> 108

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 181

Ser Tyr Glu Leu Ile Gln Pro Pro Ser Ala Ser Val Thr Leu Glu Asn

1 5 10 15

Thr Val Ser Ile Thr Cys Ser Gly Asp Glu Leu Ser Asn Lys Tyr Ala

20 25 30

His Trp Tyr Gln Gln Lys Pro Asp Lys Thr Ile Leu Glu Val Ile Tyr

35 40 45

Asn Asp Ser Glu Arg Pro Ser Gly Ile Ser Asp Arg Phe Ser Gly Ser

50 55 60

Ser Ser Gly Thr Thr Ala Ile Leu Thr Ile Arg Asp Ala Gln Ala Glu

65 70 75 80

Asp Glu Ala Asp Tyr Tyr Cys Leu Ser Thr Phe Ser Asp Asp Asp Leu

85 90 95

Pro Ile Phe Gly Gly Gly Thr Lys Leu Thr Val Leu

100 105

<210> 182

<211> 108

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 182

Ser Tyr Glu Leu Ile Gln Pro Pro Ser Thr Ser Val Thr Leu Gly Asn

1 5 10 15

Thr Val Ser Leu Thr Cys Val Gly Asn Glu Leu Pro Lys Arg Tyr Ala

20 25 30

Tyr Trp Phe Gln Gln Lys Pro Asp Gln Ser Ile Val Arg Leu Ile Tyr

35 40 45

Asp Asp Asp Arg Arg Pro Ser Gly Ile Ser Asp Arg Phe Ser Gly Ser

50 55 60

Ser Ser Gly Thr Thr Ala Thr Leu Thr Ile Arg Asp Ala Gln Ala Glu

65 70 75 80

Asp Glu Ala Tyr Tyr Tyr Cys His Ser Thr Tyr Thr Asp Asp Lys Val

85 90 95

Pro Ile Phe Gly Gly Gly Thr Lys Leu Thr Val Leu

100 105

<210> 183

<211> 123

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 183

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg

1 5 10 15

Ser Met Lys Leu Ser Cys Lys Ala Ser Gly Phe Thr Phe Ser Asn Tyr

20 25 30

Asp Met Ala Trp Val Arg Gln Ala Pro Thr Arg Gly Leu Glu Trp Val

35 40 45

Ala Ser Ile Ser Tyr Asp Gly Ile Thr Ala Tyr Tyr Arg Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Glu Asn Ala Lys Ser Thr Leu Tyr

65 70 75 80

Leu Gln Leu Val Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys

85 90 95

Thr Thr Glu Gly Gly Tyr Val Tyr Ser Gly Pro His Tyr Phe Asp Tyr

100 105 110

Trp Gly Gln Gly Val Met Val Thr Val Ser Ser

115 120

<210> 184

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 184

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Met Ser Val Ser Leu Gly

1 5 10 15

Asp Thr Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Gly Ile Phe

20 25 30

Val Asn Trp Phe Gln Gln Lys Pro Gly Arg Ser Pro Arg Arg Met Ile

35 40 45

Tyr Arg Ala Thr Asn Leu Ala Asp Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Arg Ser Gly Ser Asp Tyr Ser Leu Thr Ile Ser Ser Leu Glu Ser

65 70 75 80

Glu Asp Val Ala Asp Tyr His Cys Leu Gln Tyr Asp Glu Phe Pro Arg

85 90 95

Thr Phe Gly Gly Gly Thr Lys Leu Glu Leu Lys

100 105

<210> 185

<211> 117

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 185

Glu Val Gln Leu Gln Gln Tyr Gly Ala Glu Leu Gly Lys Pro Gly Thr

1 5 10 15

Ser Val Arg Leu Ser Cys Lys Val Ser Gly Tyr Lys Ile Arg Asn Thr

20 25 30

Tyr Ile His Trp Val Asn Gln Arg Pro Gly Lys Gly Leu Glu Trp Ile

35 40 45

Gly Arg Ile Asp Pro Ala Asn Gly Asn Thr Ile Tyr Ala Glu Lys Phe

50 55 60

Lys Ser Lys Val Thr Leu Thr Ala Asp Thr Ser Ser Asn Thr Ala Tyr

65 70 75 80

Met Gln Leu Ser Gln Leu Lys Ser Asp Asp Thr Ala Leu Tyr Phe Cys

85 90 95

Ala Met Asn Tyr Glu Gly Tyr Glu Asp Tyr Trp Gly Gln Gly Val Met

100 105 110

Val Thr Val Ser Ser

115

<210> 186

<211> 106

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 186

Asp Ile Gln Met Thr Gln Ser Pro Ser Phe Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Ser Val Thr Ile Asn Cys Lys Ala Ser Gln Asn Ile Asn Lys Tyr

20 25 30

Leu Asn Trp Tyr Gln Gln Lys Leu Gly Glu Ala Pro Lys Arg Leu Ile

35 40 45

His Lys Thr Asn Ser Leu Gln Pro Gly Phe Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Val Ala Ala Tyr Phe Cys Phe Gln Tyr Asn Ser Gly Phe Thr

85 90 95

Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys

100 105

<210> 187

<211> 125

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 187

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr

20 25 30

Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Trp Met Asn Pro His Ser Gly Asp Thr Gly Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg His Gly Arg Gly Tyr Asn Gly Tyr Glu Gly Ala Phe Asp Ile

100 105 110

Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser

115 120 125

<210> 188

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 188

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Gly Asn Glu

20 25 30

Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Ala Ala Ser Asn Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp Asn Leu Pro Leu

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 189

<211> 125

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 189

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr

20 25 30

Tyr Leu His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Trp Ile Asn Pro Asn Ser Gly Asp Thr Asn Tyr Ala Gln Asn Phe

50 55 60

Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg His Gly Arg Gly Tyr Asn Gly Tyr Glu Gly Ala Phe Asp Ile

100 105 110

Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser

115 120 125

<210> 190

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

Synthetic

polypeptide"

<400> 190

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp

20 25 30

Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Asp Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Leu Asn Gly Tyr Pro Leu

85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105

<210> 191

<211> 125

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 191

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr

20 25 30

Tyr Leu His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Trp Ile Asn Pro Asn Ser Gly Gly Thr Asn Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg His Gly Arg Gly Tyr Glu Gly Tyr Glu Gly Ala Phe Asp Ile

100 105 110

Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser

115 120 125

<210> 192

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 192

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp

20 25 30

Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Asp Ala Ser Glu Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Leu Asn Gly Tyr Pro Ile

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 193

<211> 125

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 193

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr

20 25 30

Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Trp Leu Asn Pro Ser Gly Gly Gly Thr Ser Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg His Gly Arg Gly Tyr Asp Gly Tyr Glu Gly Ala Phe Asp Ile

100 105 110

Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser

115 120 125

<210> 194

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 194

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp

20 25 30

Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Leu Asn Gly Tyr Pro Leu

85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105

<210> 195

<211> 125

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 195

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Ser Thr Tyr

20 25 30

Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Ile Ile Asn Pro Ser Gly Gly Ser Thr Ser Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr

65 70 75 80

Met Lys Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg His Gly Arg Gly Tyr Glu Gly Tyr Glu Gly Ala Phe Asp Ile

100 105 110

Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser

115 120 125

<210> 196

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 196

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asp Asp

20 25 30

Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Asn Gly Phe Pro Leu

85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105

<210> 197

<211> 125

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 197

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr

20 25 30

Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Ile Ile Asn Pro Ser Gly Gly Asn Thr Asn Tyr Ala Gln Asn Phe

50 55 60

Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg His Gly Arg Gly Tyr Asn Ala Tyr Glu Gly Ala Phe Asp Ile

100 105 110

Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser

115 120 125

<210> 198

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 198

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp

20 25 30

Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Val Asn Gly Tyr Pro Leu

85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105

<210> 199

<211> 125

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 199

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr

20 25 30

Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Val Ile Asn Pro Thr Val Gly Gly Ala Asn Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg His Gly Arg Gly Tyr Asn Glu Tyr Glu Gly Ala Phe Asp Ile

100 105 110

Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser

115 120 125

<210> 200

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 200

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Asp Ile Ser Asp Tyr

20 25 30

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Ser Phe Pro Leu

85 90 95

Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 201

<211> 125

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 201

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Leu Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Ser Ser Tyr

20 25 30

Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Val Ile Asn Pro Asn Gly Ala Gly Thr Asn Phe Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg His Gly Arg Gly Tyr Glu Gly Tyr Glu Gly Ala Phe Asp Ile

100 105 110

Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser

115 120 125

<210> 202

<211> 125

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 202

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Thr Tyr

20 25 30

Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Trp Ile Asn Pro Thr Gly Gly Gly Thr Asn Tyr Ala Gln Asn Phe

50 55 60

Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg His Gly Arg Gly Tyr Glu Gly Tyr Glu Gly Ala Phe Asp Ile

100 105 110

Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser

115 120 125

<210> 203

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 203

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp

20 25 30

Val Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Leu Ser Gly Tyr Pro Ile

85 90 95

Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 204

<211> 125

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 204

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr

20 25 30

Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Met Ile Asn Pro Ser Gly Gly Ser Thr Asn Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg His Gly Arg Gly Tyr Asn Asp Tyr Glu Gly Ala Phe Asp Ile

100 105 110

Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser

115 120 125

<210> 205

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 205

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Asp Trp

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Glu Ala Ser Asn Leu Glu Gly Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Asn Ser Phe Pro Tyr

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 206

<211> 125

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 206

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ile Phe Ser Ala Tyr

20 25 30

Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Ile Ile Asn Pro Ser Gly Gly Ser Thr Arg Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg His Gly Arg Gly Tyr Gly Gly Tyr Glu Gly Ala Phe Asp Ile

100 105 110

Trp Asp Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser

115 120 125

<210> 207

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 207

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Gly Asp Tyr

20 25 30

Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Leu Asn Gly Tyr Pro Ile

85 90 95

Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys

100 105

<210> 208

<211> 125

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 208

Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu

1 5 10 15

Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Arg Phe Thr Ser Tyr

20 25 30

Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met

35 40 45

Gly Ile Ile Tyr Pro Asp Asp Ser Asp Thr Arg Tyr Ser Pro Ser Phe

50 55 60

Gln Gly Gln Val Thr Ile Ser Val Asp Lys Ser Asn Ser Thr Ala Tyr

65 70 75 80

Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys

85 90 95

Ala Arg His Gly Arg Gly Tyr Asn Gly Tyr Glu Gly Ala Phe Asp Ile

100 105 110

Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser

115 120 125

<210> 209

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 209

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Tyr

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Tyr Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Ala Ser Phe Pro Ile

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 210

<211> 125

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 210

Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu

1 5 10 15

Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Ser Ser Phe Pro Asn Ser

20 25 30

Trp Ile Ala Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met

35 40 45

Gly Ile Ile Tyr Pro Ser Asp Ser Asp Thr Arg Tyr Ser Pro Ser Phe

50 55 60

Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr

65 70 75 80

Leu Gln Trp Ser Ser Leu Glu Ala Ser Asp Thr Ala Met Tyr Tyr Cys

85 90 95

Ala Arg His Gly Arg Gly Tyr Asn Gly Tyr Glu Gly Ala Phe Asp Ile

100 105 110

Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser

115 120 125

<210> 211

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 211

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Tyr

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Asp Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Leu Asn Ser Tyr Pro Leu

85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105

<210> 212

<211> 125

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 212

Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu

1 5 10 15

Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Asp Ser Tyr

20 25 30

Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met

35 40 45

Gly Ile Met Tyr Pro Gly Asp Ser Asp Thr Arg Tyr Ser Pro Ser Phe

50 55 60

Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr

65 70 75 80

Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys

85 90 95

Ala Arg His Gly Arg Gly Tyr Asn Ala Tyr Glu Gly Ala Phe Asp Ile

100 105 110

Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser

115 120 125

<210> 213

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 213

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Asn Asn Trp

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Asp Ala Phe Ile Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Leu Asn Ser Tyr Pro Leu

85 90 95

Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys

100 105

<210> 214

<211> 124

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 214

Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu

1 5 10 15

Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Asn Trp

20 25 30

Ile Ala Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met Gly

35 40 45

Ile Ile Tyr Pro Gly Asp Ser Glu Thr Arg Tyr Ser Pro Ser Phe Gln

50 55 60

Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr Leu

65 70 75 80

Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys Ala

85 90 95

Arg His Gly Arg Gly Tyr Tyr Gly Tyr Glu Gly Ala Phe Asp Ile Trp

100 105 110

Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser

115 120

<210> 215

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 215

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Asp Asn

20 25 30

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Ile Ser Phe Pro Leu

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 216

<211> 125

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

Synthetic

polypeptide"

<400> 216

Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu

1 5 10 15

Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Asn Phe Thr Ser Tyr

20 25 30

Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met

35 40 45

Gly Val Ile Tyr Pro Asp Asp Ser Glu Thr Arg Tyr Ser Pro Ser Phe

50 55 60

Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr

65 70 75 80

Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys

85 90 95

Ala Arg His Gly Arg Gly Tyr Asn Gly Tyr Glu Gly Ala Phe Asp Ile

100 105 110

Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser

115 120 125

<210> 217

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 217

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Arg Asp Ile Arg Asp Asp

20 25 30

Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Asn Ser Phe Pro Leu

85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105

<210> 218

<211> 124

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 218

Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu

1 5 10 15

Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Thr Phe Asn Thr Tyr

20 25 30

Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met Gly

35 40 45

Ile Ile Tyr Pro Gly Asp Ser Gly Thr Arg Tyr Ser Pro Ser Phe Gln

50 55 60

Gly Gln Val Thr Ile Ser Ala Asp Lys Ala Ile Ser Thr Ala Tyr Leu

65 70 75 80

Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys Ala

85 90 95

Arg His Ser Arg Gly Tyr Asn Gly Tyr Glu Gly Ala Phe Asp Ile Trp

100 105 110

Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser

115 120

<210> 219

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 219

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Asn Tyr

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Asn Ser Phe Pro Val

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 220

<211> 125

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 220

Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu

1 5 10 15

Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Asn Phe Thr Thr Tyr

20 25 30

Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met

35 40 45

Gly Ile Ile His Pro Ala Asp Ser Asp Thr Arg Tyr Asn Pro Ser Phe

50 55 60

Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr

65 70 75 80

Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys

85 90 95

Ala Arg His Gly Arg Gly Tyr Asn Gly Tyr Glu Gly Ala Phe Asp Ile

100 105 110

Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser

115 120 125

<210> 221

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 221

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Val Ser Gln Gly Ile Ser Ser Tyr

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Asn Ser Phe Pro Leu

85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105

<210> 222

<211> 125

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 222

Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu

1 5 10 15

Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Arg Phe Ser Asn Tyr

20 25 30

Trp Ile Ala Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met

35 40 45

Gly Ile Ile Tyr Pro Asp Asn Ser Asp Thr Arg Tyr Ser Pro Ser Phe

50 55 60

Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr

65 70 75 80

Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys

85 90 95

Ala Arg His Gly Arg Gly Tyr Asp Gly Tyr Glu Gly Ala Phe Asp Ile

100 105 110

Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser

115 120 125

<210> 223

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 223

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Ser Asp

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Gly Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Asn Ser Phe Pro Leu

85 90 95

Ser Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 224

<211> 124

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 224

Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu

1 5 10 15

Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Arg Phe Ala Ser Tyr

20 25 30

Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met

35 40 45

Gly Ile Thr Tyr Pro Gly Asp Ser Glu Thr Arg Tyr Asn Pro Ser Gln

50 55 60

Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr Leu

65 70 75 80

Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys Ala

85 90 95

Arg His Gly Arg Gly Tyr Gly Gly Tyr Glu Gly Ala Phe Asp Ile Trp

100 105 110

Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser

115 120

<210> 225

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 225

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp

20 25 30

Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Asn Ser Phe Pro Leu

85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105

<210> 226

<211> 125

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 226

Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu

1 5 10 15

Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Ser Tyr

20 25 30

Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met

35 40 45

Gly Ile Ile Tyr Pro Gly Asp Ser Asp Thr Arg Tyr Ser Pro Ser Phe

50 55 60

Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr

65 70 75 80

Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys

85 90 95

Ala Arg His Gly Arg Gly Tyr Asn Gly Tyr Glu Gly Ala Phe Asp Ile

100 105 110

Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser

115 120 125

<210> 227

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 227

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Asn Trp

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Thr Asn Ser Phe Pro Leu

85 90 95

Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys

100 105

<210> 228

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 228

Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Val Ile Ser Ala

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Asp Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Asn Ser Tyr Pro Leu

85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105

<210> 229

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 229

Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Ser Ala

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Asp Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Asn Ser Tyr Pro Leu

85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105

<210> 230

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 230

Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Val Gly Ser Ala

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Asp Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Asn Ser Tyr Pro Leu

85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105

<210> 231

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 231

Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Val Ile Ser Ala

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Asp Ala Ser Ile Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Asn Ser Tyr Pro Leu

85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105

<210> 232

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 232

Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Ser Ala

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Asp Ala Ser Ile Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Asn Ser Tyr Pro Leu

85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105

<210> 233

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 233

Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Val Gly Ser Ala

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Asp Ala Ser Ile Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Asn Ser Tyr Pro Leu

85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105

<210> 234

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

Synthetic

polypeptide"

<400> 234

Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Ala

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Asp Ala Ser Ile Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Asn Ser Tyr Pro Leu

85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105

<210> 235

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 235

Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Val Ile Ser Ala

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Asp Ala Ser Thr Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Asn Ser Tyr Pro Leu

85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105

<210> 236

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 236

Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Ser Ala

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Asp Ala Ser Thr Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Asn Ser Tyr Pro Leu

85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105

<210> 237

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 237

Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Val Gly Ser Ala

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Asp Ala Ser Thr Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Asn Ser Tyr Pro Leu

85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105

<210> 238

<211> 123

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 238

Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu

1 5 10 15

Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Arg Phe Thr Thr Ser

20 25 30

Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met

35 40 45

Gly Ile Ile Tyr Pro Gly Asp Ser Asp Thr Arg Tyr Ser Pro Ser Phe

50 55 60

Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr

65 70 75 80

Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys

85 90 95

Ala Arg His Gly Leu Gly Tyr Asn Gly Tyr Glu Gly Ala Phe Asp Ile

100 105 110

Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 239

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 239

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Gly Ser Ala

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Asp Ala Ser Thr Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Asn Gly Tyr Pro Leu

85 90 95

Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys

100 105

<210> 240

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 240

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Arg Gly Ile Ser Asp Tyr

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Asn Ser Phe Pro Ile

85 90 95

Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys

100 105

<210> 241

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 241

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Gly Ser Ala

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Asp Ala Ser Thr Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Leu Asn Gly Tyr Pro Leu

85 90 95

Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys

100 105

<210> 242

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 242

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Gly Ser Ala

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Leu Asn Gly Tyr Pro Leu

85 90 95

Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys

100 105

<210> 243

<211> 123

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

Synthetic

polypeptide"

<400> 243

Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu

1 5 10 15

Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Asn Tyr

20 25 30

Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met

35 40 45

Ala Ile Ile Asn Pro Arg Asp Ser Asp Thr Arg Tyr Arg Pro Ser Phe

50 55 60

Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr

65 70 75 80

Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys

85 90 95

Ala Arg His Gly Arg Gly Tyr Glu Gly Tyr Glu Gly Ala Phe Asp Ile

100 105 110

Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 244

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 244

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ser Ser Gln Gly Ile Arg Ser Asp

20 25 30

Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Asn Gly Phe Pro Leu

85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105

<210> 245

<211> 5

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 245

Asn Tyr Trp Ile Gly

1 5

<210> 246

<211> 17

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 246

Ile Ile Asn Pro Arg Asp Ser Asp Thr Arg Tyr Arg Pro Ser Phe Gln

1 5 10 15

Gly

<210> 247

<211> 14

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 247

His Gly Arg Gly Tyr Glu Gly Tyr Glu Gly Ala Phe Asp Ile

1 5 10

<210> 248

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 248

Arg Ser Ser Gln Gly Ile Arg Ser Asp Leu Gly

1 5 10

<210> 249

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 249

Asp Ala Ser Asn Leu Glu Thr

1 5

<210> 250

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 250

Gln Gln Ala Asn Gly Phe Pro Leu Thr

1 5

<210> 251

<211> 123

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 251

Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu

1 5 10 15

Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Asn Tyr

20 25 30

Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met

35 40 45

Gly Ile Ile Tyr Pro Gly Asp Ser Asp Ile Arg Tyr Ser Pro Ser Leu

50 55 60

Gln Gly Gln Val Thr Ile Ser Val Asp Thr Ser Thr Ser Thr Ala Tyr

65 70 75 80

Leu Gln Trp Asn Ser Leu Lys Pro Ser Asp Thr Ala Met Tyr Tyr Cys

85 90 95

Ala Arg His Gly Arg Gly Tyr Asn Gly Tyr Glu Gly Ala Phe Asp Ile

100 105 110

Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 252

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 252

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Gly Asp Ser

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Leu Asn Gly Tyr Pro Ile

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 253

<211> 17

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 253

Ile Ile Tyr Pro Gly Asp Ser Asp Ile Arg Tyr Ser Pro Ser Leu Gln

1 5 10 15

Gly

<210> 254

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 254

Arg Ala Ser Gln Gly Ile Gly Asp Ser Leu Ala

1 5 10

<210> 255

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 255

Gln Gln Leu Asn Gly Tyr Pro Ile Thr

1 5

<210> 256

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 256

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp

20 25 30

Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Asp Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Leu Asn Gly Tyr Pro Ile

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 257

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 257

Arg Ala Ser Gln Gly Ile Arg Asn Asp Leu Gly

1 5 10

<210> 258

<211> 123

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 258

Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu

1 5 10 15

Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Asn Tyr

20 25 30

Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met

35 40 45

Gly Ile Ile Tyr Pro Gly Asp Ser Leu Thr Arg Tyr Ser Pro Ser Phe

50 55 60

Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr

65 70 75 80

Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys

85 90 95

Ala Arg His Gly Arg Gly Tyr Asn Gly Tyr Glu Gly Ala Phe Asp Ile

100 105 110

Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 259

<211> 17

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 259

Ile Ile Tyr Pro Gly Asp Ser Leu Thr Arg Tyr Ser Pro Ser Phe Gln

1 5 10 15

Gly

<210> 260

<211> 123

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 260

Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu

1 5 10 15

Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Asn Tyr

20 25 30

Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met

35 40 45

Gly Ile Ile Tyr Pro Gly Asp Ser Asp Thr Arg Tyr Ser Pro Ser Phe

50 55 60

Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr

65 70 75 80

Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys

85 90 95

Ala Arg His Gly Arg Gly Tyr Asn Gly Tyr Glu Gly Ala Phe Asp Ile

100 105 110

Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 261

<211> 123

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 261

Gln Val Gln Leu Val Gln Ser Gly Ala Ala Val Lys Lys Pro Gly Glu

1 5 10 15

Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Arg Phe Thr Ser Tyr

20 25 30

Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met

35 40 45

Gly Ile Ile Tyr Pro Gly Asp Ser Asp Thr Arg Tyr Ser Pro Ser Phe

50 55 60

Gln Gly Gln Val Thr Ile Ser Ala Gly Lys Ser Ile Ser Thr Ala Tyr

65 70 75 80

Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys

85 90 95

Ala Arg His Gly Arg Gly Tyr Asn Gly Tyr Glu Gly Ala Phe Asp Ile

100 105 110

Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser

115 120

<210> 262

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 262

Ala Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Ala

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Asp Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Asn Ser Tyr Pro Leu

85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105

<210> 263

<211> 5

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 263

Thr Tyr Trp Ile Gly

1 5

<210> 264

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 264

Arg Ala Ser Gln Gly Val Ile Ser Ala Leu Ala

1 5 10

<210> 265

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 265

Asp Ala Ser Ile Leu Glu Ser

1 5

<210> 266

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 266

Gln Gln Phe Asn Ser Tyr Pro Leu Thr

1 5

<210> 267

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 267

Arg Ala Ser Gln Gly Val Gly Ser Ala Leu Ala

1 5 10

<210> 268

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 268

Asp Ala Ser Thr Leu Glu Ser

1 5

<210> 269

<211> 330

<212> PRT

<213> Homo sapiens

<400> 269

Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys

1 5 10 15

Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr

20 25 30

Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser

35 40 45

Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser

50 55 60

Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr

65 70 75 80

Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys

85 90 95

Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys

100 105 110

Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro

115 120 125

Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys

130 135 140

Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp

145 150 155 160

Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu

165 170 175

Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu

180 185 190

His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn

195 200 205

Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly

210 215 220

Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu

225 230 235 240

Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr

245 250 255

Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn

260 265 270

Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe

275 280 285

Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn

290 295 300

Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr

305 310 315 320

Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

325 330

<210> 270

<211> 330

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 270

Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys

1 5 10 15

Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr

20 25 30

Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser

35 40 45

Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser

50 55 60

Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr

65 70 75 80

Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys

85 90 95

Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys

100 105 110

Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro

115 120 125

Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys

130 135 140

Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp

145 150 155 160

Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu

165 170 175

Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu

180 185 190

His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn

195 200 205

Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly

210 215 220

Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu

225 230 235 240

Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr

245 250 255

Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn

260 265 270

Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe

275 280 285

Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn

290 295 300

Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr

305 310 315 320

Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

325 330

<210> 271

<211> 330

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

Synthetic

polypeptide"

<400> 271

Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys

1 5 10 15

Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr

20 25 30

Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser

35 40 45

Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser

50 55 60

Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr

65 70 75 80

Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys

85 90 95

Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys

100 105 110

Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro

115 120 125

Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys

130 135 140

Val Val Val Cys Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp

145 150 155 160

Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu

165 170 175

Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu

180 185 190

His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn

195 200 205

Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly

210 215 220

Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu

225 230 235 240

Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr

245 250 255

Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn

260 265 270

Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe

275 280 285

Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn

290 295 300

Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr

305 310 315 320

Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

325 330

<210> 272

<211> 330

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 272

Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys

1 5 10 15

Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr

20 25 30

Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser

35 40 45

Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser

50 55 60

Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr

65 70 75 80

Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys

85 90 95

Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys

100 105 110

Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro

115 120 125

Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys

130 135 140

Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp

145 150 155 160

Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu

165 170 175

Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu

180 185 190

His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn

195 200 205

Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly

210 215 220

Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu

225 230 235 240

Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr

245 250 255

Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn

260 265 270

Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe

275 280 285

Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn

290 295 300

Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn Ala Tyr Thr

305 310 315 320

Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

325 330

<210> 273

<211> 330

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 273

Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys

1 5 10 15

Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr

20 25 30

Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser

35 40 45

Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser

50 55 60

Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr

65 70 75 80

Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys

85 90 95

Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys

100 105 110

Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro

115 120 125

Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys

130 135 140

Val Val Val Cys Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp

145 150 155 160

Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu

165 170 175

Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu

180 185 190

His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn

195 200 205

Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly

210 215 220

Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu

225 230 235 240

Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr

245 250 255

Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn

260 265 270

Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe

275 280 285

Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn

290 295 300

Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr

305 310 315 320

Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

325 330

<210> 274

<211> 330

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 274

Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys

1 5 10 15

Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr

20 25 30

Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser

35 40 45

Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser

50 55 60

Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr

65 70 75 80

Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys

85 90 95

Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys

100 105 110

Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro

115 120 125

Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys

130 135 140

Val Val Val Cys Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp

145 150 155 160

Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu

165 170 175

Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu

180 185 190

His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn

195 200 205

Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly

210 215 220

Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu

225 230 235 240

Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr

245 250 255

Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn

260 265 270

Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe

275 280 285

Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn

290 295 300

Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn Ala Tyr Thr

305 310 315 320

Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

325 330

<210> 275

<211> 453

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 275

Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu

1 5 10 15

Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Asn Tyr

20 25 30

Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met

35 40 45

Ala Ile Ile Asn Pro Arg Asp Ser Asp Thr Arg Tyr Arg Pro Ser Phe

50 55 60

Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr

65 70 75 80

Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys

85 90 95

Ala Arg His Gly Arg Gly Tyr Glu Gly Tyr Glu Gly Ala Phe Asp Ile

100 105 110

Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly

115 120 125

Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly

130 135 140

Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val

145 150 155 160

Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe

165 170 175

Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val

180 185 190

Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val

195 200 205

Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys

210 215 220

Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu

225 230 235 240

Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr

245 250 255

Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val

260 265 270

Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val

275 280 285

Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser

290 295 300

Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu

305 310 315 320

Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala

325 330 335

Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro

340 345 350

Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln

355 360 365

Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala

370 375 380

Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr

385 390 395 400

Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu

405 410 415

Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser

420 425 430

Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser

435 440 445

Leu Ser Pro Gly Lys

450

<210> 276

<211> 453

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 276

Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu

1 5 10 15

Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Asn Tyr

20 25 30

Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met

35 40 45

Ala Ile Ile Asn Pro Arg Asp Ser Asp Thr Arg Tyr Arg Pro Ser Phe

50 55 60

Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr

65 70 75 80

Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys

85 90 95

Ala Arg His Gly Arg Gly Tyr Glu Gly Tyr Glu Gly Ala Phe Asp Ile

100 105 110

Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly

115 120 125

Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly

130 135 140

Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val

145 150 155 160

Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe

165 170 175

Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val

180 185 190

Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val

195 200 205

Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys

210 215 220

Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala

225 230 235 240

Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr

245 250 255

Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val

260 265 270

Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val

275 280 285

Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser

290 295 300

Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu

305 310 315 320

Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala

325 330 335

Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro

340 345 350

Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln

355 360 365

Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala

370 375 380

Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr

385 390 395 400

Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu

405 410 415

Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser

420 425 430

Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser

435 440 445

Leu Ser Pro Gly Lys

450

<210> 277

<211> 453

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 277

Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu

1 5 10 15

Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Asn Tyr

20 25 30

Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met

35 40 45

Ala Ile Ile Asn Pro Arg Asp Ser Asp Thr Arg Tyr Arg Pro Ser Phe

50 55 60

Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr

65 70 75 80

Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys

85 90 95

Ala Arg His Gly Arg Gly Tyr Glu Gly Tyr Glu Gly Ala Phe Asp Ile

100 105 110

Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly

115 120 125

Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly

130 135 140

Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val

145 150 155 160

Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe

165 170 175

Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val

180 185 190

Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val

195 200 205

Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys

210 215 220

Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala

225 230 235 240

Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr

245 250 255

Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Cys Val

260 265 270

Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val

275 280 285

Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser

290 295 300

Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu

305 310 315 320

Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala

325 330 335

Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro

340 345 350

Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln

355 360 365

Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala

370 375 380

Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr

385 390 395 400

Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu

405 410 415

Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser

420 425 430

Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser

435 440 445

Leu Ser Pro Gly Lys

450

<210> 278

<211> 453

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 278

Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu

1 5 10 15

Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Asn Tyr

20 25 30

Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met

35 40 45

Ala Ile Ile Asn Pro Arg Asp Ser Asp Thr Arg Tyr Arg Pro Ser Phe

50 55 60

Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr

65 70 75 80

Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys

85 90 95

Ala Arg His Gly Arg Gly Tyr Glu Gly Tyr Glu Gly Ala Phe Asp Ile

100 105 110

Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly

115 120 125

Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly

130 135 140

Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val

145 150 155 160

Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe

165 170 175

Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val

180 185 190

Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val

195 200 205

Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys

210 215 220

Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala

225 230 235 240

Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr

245 250 255

Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Cys Val

260 265 270

Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val

275 280 285

Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser

290 295 300

Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu

305 310 315 320

Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala

325 330 335

Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro

340 345 350

Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln

355 360 365

Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala

370 375 380

Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr

385 390 395 400

Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu

405 410 415

Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser

420 425 430

Val Met His Glu Ala Leu His Asn Ala Tyr Thr Gln Lys Ser Leu Ser

435 440 445

Leu Ser Pro Gly Lys

450

<210> 279

<211> 453

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 279

Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu

1 5 10 15

Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Arg Phe Thr Thr Ser

20 25 30

Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met

35 40 45

Gly Ile Ile Tyr Pro Gly Asp Ser Asp Thr Arg Tyr Ser Pro Ser Phe

50 55 60

Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr

65 70 75 80

Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys

85 90 95

Ala Arg His Gly Leu Gly Tyr Asn Gly Tyr Glu Gly Ala Phe Asp Ile

100 105 110

Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly

115 120 125

Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly

130 135 140

Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val

145 150 155 160

Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe

165 170 175

Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val

180 185 190

Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val

195 200 205

Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys

210 215 220

Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu

225 230 235 240

Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr

245 250 255

Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val

260 265 270

Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val

275 280 285

Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser

290 295 300

Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu

305 310 315 320

Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala

325 330 335

Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro

340 345 350

Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln

355 360 365

Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala

370 375 380

Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr

385 390 395 400

Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu

405 410 415

Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser

420 425 430

Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser

435 440 445

Leu Ser Pro Gly Lys

450

<210> 280

<211> 453

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 280

Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu

1 5 10 15

Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Arg Phe Thr Thr Ser

20 25 30

Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met

35 40 45

Gly Ile Ile Tyr Pro Gly Asp Ser Asp Thr Arg Tyr Ser Pro Ser Phe

50 55 60

Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr

65 70 75 80

Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys

85 90 95

Ala Arg His Gly Leu Gly Tyr Asn Gly Tyr Glu Gly Ala Phe Asp Ile

100 105 110

Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly

115 120 125

Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly

130 135 140

Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val

145 150 155 160

Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe

165 170 175

Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val

180 185 190

Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val

195 200 205

Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys

210 215 220

Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala

225 230 235 240

Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr

245 250 255

Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val

260 265 270

Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val

275 280 285

Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser

290 295 300

Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu

305 310 315 320

Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala

325 330 335

Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro

340 345 350

Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln

355 360 365

Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala

370 375 380

Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr

385 390 395 400

Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu

405 410 415

Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser

420 425 430

Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser

435 440 445

Leu Ser Pro Gly Lys

450

<210> 281

<211> 453

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 281

Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu

1 5 10 15

Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Arg Phe Thr Thr Ser

20 25 30

Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met

35 40 45

Gly Ile Ile Tyr Pro Gly Asp Ser Asp Thr Arg Tyr Ser Pro Ser Phe

50 55 60

Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr

65 70 75 80

Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys

85 90 95

Ala Arg His Gly Leu Gly Tyr Asn Gly Tyr Glu Gly Ala Phe Asp Ile

100 105 110

Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly

115 120 125

Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly

130 135 140

Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val

145 150 155 160

Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe

165 170 175

Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val

180 185 190

Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val

195 200 205

Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys

210 215 220

Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala

225 230 235 240

Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr

245 250 255

Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Cys Val

260 265 270

Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val

275 280 285

Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser

290 295 300

Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu

305 310 315 320

Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala

325 330 335

Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro

340 345 350

Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln

355 360 365

Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala

370 375 380

Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr

385 390 395 400

Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu

405 410 415

Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser

420 425 430

Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser

435 440 445

Leu Ser Pro Gly Lys

450

<210> 282

<211> 453

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 282

Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu

1 5 10 15

Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Arg Phe Thr Thr Ser

20 25 30

Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met

35 40 45

Gly Ile Ile Tyr Pro Gly Asp Ser Asp Thr Arg Tyr Ser Pro Ser Phe

50 55 60

Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr

65 70 75 80

Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys

85 90 95

Ala Arg His Gly Leu Gly Tyr Asn Gly Tyr Glu Gly Ala Phe Asp Ile

100 105 110

Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly

115 120 125

Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly

130 135 140

Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val

145 150 155 160

Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe

165 170 175

Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val

180 185 190

Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val

195 200 205

Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys

210 215 220

Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala

225 230 235 240

Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr

245 250 255

Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Cys Val

260 265 270

Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val

275 280 285

Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser

290 295 300

Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu

305 310 315 320

Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala

325 330 335

Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro

340 345 350

Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln

355 360 365

Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala

370 375 380

Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr

385 390 395 400

Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu

405 410 415

Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser

420 425 430

Val Met His Glu Ala Leu His Asn Ala Tyr Thr Gln Lys Ser Leu Ser

435 440 445

Leu Ser Pro Gly Lys

450

<210> 283

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 283

Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu

1 5 10 15

Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe

20 25 30

Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln

35 40 45

Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser

50 55 60

Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu

65 70 75 80

Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser

85 90 95

Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys

100 105

<210> 284

<211> 214

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 284

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ser Ser Gln Gly Ile Arg Ser Asp

20 25 30

Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Asn Gly Phe Pro Leu

85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala

100 105 110

Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly

115 120 125

Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala

130 135 140

Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln

145 150 155 160

Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser

165 170 175

Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr

180 185 190

Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser

195 200 205

Phe Asn Arg Gly Glu Cys

210

<210> 285

<211> 214

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 285

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Gly Ser Ala

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Leu Asn Gly Tyr Pro Leu

85 90 95

Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys Arg Thr Val Ala Ala

100 105 110

Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly

115 120 125

Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala

130 135 140

Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln

145 150 155 160

Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser

165 170 175

Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr

180 185 190

Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser

195 200 205

Phe Asn Arg Gly Glu Cys

210

<210> 286

<211> 5

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 286

Thr Ser Trp Ile Gly

1 5

<210> 287

<211> 14

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 287

His Gly Leu Gly Tyr Asn Gly Tyr Glu Gly Ala Phe Asp Ile

1 5 10

<210> 288

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 288

Arg Ala Ser Gln Gly Ile Gly Ser Ala Leu Ala

1 5 10

<210> 289

<211> 10

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 289

Cys Gln Gln Leu Asn Gly Tyr Pro Leu Thr

1 5 10

<210> 290

<211> 453

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 290

Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Arg Pro Gly Ala

1 5 10 15

Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr

20 25 30

Trp Ile Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile

35 40 45

Gly Asn Ile Tyr Pro Ser Asp Ser Tyr Thr Asn Tyr Asn Gln Lys Phe

50 55 60

Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Asn Thr Val Tyr

65 70 75 80

Met Gln Leu Asn Ser Pro Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys

85 90 95

Thr Arg Asn Gly Val Glu Gly Tyr Pro His Tyr Tyr Ala Met Glu Tyr

100 105 110

Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Ala Ser Thr Lys Gly

115 120 125

Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly

130 135 140

Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val

145 150 155 160

Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe

165 170 175

Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val

180 185 190

Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val

195 200 205

Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys

210 215 220

Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu

225 230 235 240

Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr

245 250 255

Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val

260 265 270

Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val

275 280 285

Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser

290 295 300

Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu

305 310 315 320

Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala

325 330 335

Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro

340 345 350

Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln

355 360 365

Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala

370 375 380

Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr

385 390 395 400

Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu

405 410 415

Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser

420 425 430

Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser

435 440 445

Leu Ser Pro Gly Lys

450

<210> 291

<211> 214

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 291

Asp Ile Gln Met Thr Gln Thr Thr Ser Ala Leu Ser Ala Ser Leu Gly

1 5 10 15

Asp Arg Val Thr Ile Gly Cys Arg Ala Ser Gln Asp Leu Ser Asn His

20 25 30

Leu Tyr Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile

35 40 45

Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Arg Asn Leu Glu Gln

65 70 75 80

Glu Asp Val Ala Thr Tyr Phe Cys Gln Gln Gly Tyr Thr Leu Pro Tyr

85 90 95

Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala

100 105 110

Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly

115 120 125

Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala

130 135 140

Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln

145 150 155 160

Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser

165 170 175

Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr

180 185 190

Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser

195 200 205

Phe Asn Arg Gly Glu Cys

210

<210> 292

<211> 5

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 292

Ser Tyr Trp Ile Asn

1 5

<210> 293

<211> 17

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 293

Asn Ile Tyr Pro Ser Asp Ser Tyr Thr Asn Tyr Asn Gln Lys Phe Lys

1 5 10 15

Asp

<210> 294

<211> 14

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 294

Asn Gly Val Glu Gly Tyr Pro His Tyr Tyr Ala Met Glu Tyr

1 5 10

<210> 295

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 295

Arg Ala Ser Gln Asp Leu Ser Asn His Leu Tyr

1 5 10

<210> 296

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 296

Tyr Thr Ser Arg Leu His Ser

1 5

<210> 297

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 297

Gln Gln Gly Tyr Thr Leu Pro Tyr Thr

1 5

<210> 298

<211> 123

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 298

Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Arg Pro Gly Ala

1 5 10 15

Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr

20 25 30

Trp Ile Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile

35 40 45

Gly Asn Ile Tyr Pro Ser Asp Ser Tyr Thr Asn Tyr Asn Gln Lys Phe

50 55 60

Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Asn Thr Val Tyr

65 70 75 80

Met Gln Leu Asn Ser Pro Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys

85 90 95

Thr Arg Asn Gly Val Glu Gly Tyr Pro His Tyr Tyr Ala Met Glu Tyr

100 105 110

Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser

115 120

<210> 299

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 299

Asp Ile Gln Met Thr Gln Thr Thr Ser Ala Leu Ser Ala Ser Leu Gly

1 5 10 15

Asp Arg Val Thr Ile Gly Cys Arg Ala Ser Gln Asp Leu Ser Asn His

20 25 30

Leu Tyr Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile

35 40 45

Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Arg Asn Leu Glu Gln

65 70 75 80

Glu Asp Val Ala Thr Tyr Phe Cys Gln Gln Gly Tyr Thr Leu Pro Tyr

85 90 95

Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 300

<211> 5

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 300

Glu Tyr Tyr Met Tyr

1 5

<210> 301

<211> 17

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 301

Arg Ile Asp Pro Glu Asp Gly Ser Ile Asp Tyr Val Glu Lys Phe Lys

1 5 10 15

Lys

<210> 302

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 302

Gly Lys Phe Asn Tyr Arg Phe Ala Tyr

1 5

<210> 303

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 303

Arg Ser Ser Gln Ser Leu Leu His Ser Ser Gly Asn Thr Tyr Leu Asn

1 5 10 15

<210> 304

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 304

Leu Val Ser Lys Leu Glu Ser

1 5

<210> 305

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 305

Met Gln Phe Thr His Tyr Pro Tyr Thr

1 5

<210> 306

<211> 118

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 306

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Glu Tyr

20 25 30

Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Leu Met

35 40 45

Gly Arg Ile Asp Pro Glu Asp Gly Ser Ile Asp Tyr Val Glu Lys Phe

50 55 60

Lys Lys Lys Val Thr Leu Thr Ala Asp Thr Ser Ser Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Thr Ser Asp Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gly Lys Phe Asn Tyr Arg Phe Ala Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Ser Ser

115

<210> 307

<211> 112

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 307

Asp Val Val Met Thr Gln Ser Pro Pro Ser Leu Leu Val Thr Leu Gly

1 5 10 15

Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu His Ser

20 25 30

Ser Gly Asn Thr Tyr Leu Asn Trp Leu Leu Gln Arg Pro Gly Gln Ser

35 40 45

Pro Gln Pro Leu Ile Tyr Leu Val Ser Lys Leu Glu Ser Gly Val Pro

50 55 60

Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile

65 70 75 80

Ser Gly Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Phe

85 90 95

Thr His Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 308

<211> 118

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 308

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Gln Arg Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ile Phe Thr Glu Tyr

20 25 30

Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Leu Val

35 40 45

Gly Arg Ile Asp Pro Glu Asp Gly Ser Ile Asp Tyr Val Glu Lys Phe

50 55 60

Lys Lys Lys Val Thr Leu Thr Ala Asp Thr Ser Ser Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Thr Ser Asp Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gly Lys Phe Asn Tyr Arg Phe Ala Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Ser Ser

115

<210> 309

<211> 112

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 309

Asp Val Val Met Thr Gln Ser Pro Pro Ser Leu Leu Val Thr Leu Gly

1 5 10 15

Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu His Ser

20 25 30

Ser Gly Asn Thr Tyr Leu Asn Trp Leu Leu Gln Arg Pro Gly Gln Ser

35 40 45

Pro Gln Pro Leu Ile Tyr Leu Val Ser Lys Leu Glu Ser Gly Val Pro

50 55 60

Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile

65 70 75 80

Ser Gly Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Phe

85 90 95

Thr His Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 310

<211> 120

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 310

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr

20 25 30

Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Val Ile Ser Glu Asn Gly Ser Asp Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Asp Arg Gly Gly Ala Val Ser Tyr Phe Asp Val Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 311

<211> 109

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 311

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Ser Ser Tyr

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Ala Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Leu Pro Tyr

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr

100 105

<210> 312

<211> 351

<212> PRT

<213> Homo sapiens

<400> 312

Met Ser Phe Pro Cys Lys Phe Val Ala Ser Phe Leu Leu Ile Phe Asn

1 5 10 15

Val Ser Ser Lys Gly Ala Val Ser Lys Glu Ile Thr Asn Ala Leu Glu

20 25 30

Thr Trp Gly Ala Leu Gly Gln Asp Ile Asn Leu Asp Ile Pro Ser Phe

35 40 45

Gln Met Ser Asp Asp Ile Asp Asp Ile Lys Trp Glu Lys Thr Ser Asp

50 55 60

Lys Lys Lys Ile Ala Gln Phe Arg Lys Glu Lys Glu Thr Phe Lys Glu

65 70 75 80

Lys Asp Thr Tyr Lys Leu Phe Lys Asn Gly Thr Leu Lys Ile Lys His

85 90 95

Leu Lys Thr Asp Asp Gln Asp Ile Tyr Lys Val Ser Ile Tyr Asp Thr

100 105 110

Lys Gly Lys Asn Val Leu Glu Lys Ile Phe Asp Leu Lys Ile Gln Glu

115 120 125

Arg Val Ser Lys Pro Lys Ile Ser Trp Thr Cys Ile Asn Thr Thr Leu

130 135 140

Thr Cys Glu Val Met Asn Gly Thr Asp Pro Glu Leu Asn Leu Tyr Gln

145 150 155 160

Asp Gly Lys His Leu Lys Leu Ser Gln Arg Val Ile Thr His Lys Trp

165 170 175

Thr Thr Ser Leu Ser Ala Lys Phe Lys Cys Thr Ala Gly Asn Lys Val

180 185 190

Ser Lys Glu Ser Ser Val Glu Pro Val Ser Cys Pro Glu Lys Gly Leu

195 200 205

Asp Ile Tyr Leu Ile Ile Gly Ile Cys Gly Gly Gly Ser Leu Leu Met

210 215 220

Val Phe Val Ala Leu Leu Val Phe Tyr Ile Thr Lys Arg Lys Lys Gln

225 230 235 240

Arg Ser Arg Arg Asn Asp Glu Glu Leu Glu Thr Arg Ala His Arg Val

245 250 255

Ala Thr Glu Glu Arg Gly Arg Lys Pro His Gln Ile Pro Ala Ser Thr

260 265 270

Pro Gln Asn Pro Ala Thr Ser Gln His Pro Pro Pro Pro Pro Gly His

275 280 285

Arg Ser Gln Ala Pro Ser His Arg Pro Pro Pro Pro Gly His Arg Val

290 295 300

Gln His Gln Pro Gln Lys Arg Pro Pro Ala Pro Ser Gly Thr Gln Val

305 310 315 320

His Gln Gln Lys Gly Pro Pro Leu Pro Arg Pro Arg Val Gln Pro Lys

325 330 335

Pro Pro His Gly Ala Ala Glu Asn Ser Leu Ser Pro Ser Ser Asn

340 345 350

<210> 313

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 313

Gly Phe Thr Phe Ser Ser Tyr

1 5

<210> 314

<211> 5

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 314

Ser Gly Gly Gly Phe

1 5

<210> 315

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 315

Ser Ser Tyr Gly Glu Ile Met Asp Tyr

1 5

<210> 316

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 316

Ser Ser Tyr Gly Glu Leu Met Asp Tyr

1 5

<210> 317

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 317

Arg Ala Ser Gln Arg Ile Gly Thr Ser Ile His

1 5 10

<210> 318

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 318

Tyr Ala Ser Glu Ser Ile Ser

1 5

<210> 319

<211> 10

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 319

Gln Gln Ser His Gly Trp Pro Phe Thr Phe

1 5 10

<210> 320

<211> 117

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 320

Glu Val Lys Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly

1 5 10 15

Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Asp Met Ser Trp Val Arg Gln Thr Pro Glu Lys Arg Leu Glu Trp Val

35 40 45

Ala Ser Ile Ser Gly Gly Gly Phe Leu Tyr Tyr Leu Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Arg Asn Ile Leu Tyr Leu

65 70 75 80

His Met Thr Ser Leu Arg Ser Glu Asp Thr Ala Met Tyr Tyr Cys Ala

85 90 95

Arg Ser Ser Tyr Gly Glu Ile Met Asp Tyr Trp Gly Gln Gly Thr Ser

100 105 110

Val Thr Val Ser Ser

115

<210> 321

<211> 117

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 321

Glu Val Lys Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly

1 5 10 15

Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Asp Met Ser Trp Val Arg Gln Thr Pro Glu Lys Arg Leu Glu Trp Val

35 40 45

Ala Ser Ile Ser Gly Gly Gly Phe Leu Tyr Tyr Leu Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Arg Asn Ile Leu Tyr Leu

65 70 75 80

His Met Thr Ser Leu Arg Ser Glu Asp Thr Ala Met Tyr Tyr Cys Ala

85 90 95

Arg Ser Ser Tyr Gly Glu Leu Met Asp Tyr Trp Gly Gln Gly Thr Ser

100 105 110

Val Thr Val Ser Ser

115

<210> 322

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 322

Asp Ile Leu Leu Thr Gln Ser Pro Ala Ile Leu Ser Val Ser Pro Gly

1 5 10 15

Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gln Arg Ile Gly Thr Ser

20 25 30

Ile His Trp Tyr Gln Gln Arg Thr Thr Gly Ser Pro Arg Leu Leu Ile

35 40 45

Lys Tyr Ala Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Ser

65 70 75 80

Glu Asp Val Ala Asp Tyr Tyr Cys Gln Gln Ser His Gly Trp Pro Phe

85 90 95

Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Glu

100 105

<210> 323

<211> 324

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 323

Ala Lys Thr Thr Pro Pro Ser Val Tyr Pro Leu Ala Pro Gly Ser Ala

1 5 10 15

Ala Gln Thr Asn Ser Met Val Thr Leu Gly Cys Leu Val Lys Gly Tyr

20 25 30

Phe Pro Glu Pro Val Thr Val Thr Trp Asn Ser Gly Ser Leu Ser Ser

35 40 45

Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Asp Leu Tyr Thr Leu

50 55 60

Ser Ser Ser Val Thr Val Pro Ser Ser Thr Trp Pro Ser Glu Thr Val

65 70 75 80

Thr Cys Asn Val Ala His Pro Ala Ser Ser Thr Lys Val Asp Lys Lys

85 90 95

Ile Val Pro Arg Asp Cys Gly Cys Lys Pro Cys Ile Cys Thr Val Pro

100 105 110

Glu Val Ser Ser Val Phe Ile Phe Pro Pro Lys Pro Lys Asp Val Leu

115 120 125

Thr Ile Thr Leu Thr Pro Lys Val Thr Cys Val Val Val Asp Ile Ser

130 135 140

Lys Asp Asp Pro Glu Val Gln Phe Ser Trp Phe Val Asp Asp Val Glu

145 150 155 160

Val His Thr Ala Gln Thr Gln Pro Arg Glu Glu Gln Phe Asn Ser Thr

165 170 175

Phe Arg Ser Val Ser Glu Leu Pro Ile Met His Gln Asp Trp Leu Asn

180 185 190

Gly Lys Glu Phe Lys Cys Arg Val Asn Ser Ala Ala Phe Pro Ala Pro

195 200 205

Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Arg Pro Lys Ala Pro Gln

210 215 220

Val Tyr Thr Ile Pro Pro Pro Lys Glu Gln Met Ala Lys Asp Lys Val

225 230 235 240

Ser Leu Thr Cys Met Ile Thr Asp Phe Phe Pro Glu Asp Ile Thr Val

245 250 255

Glu Trp Gln Trp Asn Gly Gln Pro Ala Glu Asn Tyr Lys Asn Thr Gln

260 265 270

Pro Ile Met Asp Thr Asp Gly Ser Tyr Phe Val Tyr Ser Lys Leu Asn

275 280 285

Val Gln Lys Ser Asn Trp Glu Ala Gly Asn Thr Phe Thr Cys Ser Val

290 295 300

Leu His Glu Gly Leu His Asn His His Thr Glu Lys Ser Leu Ser His

305 310 315 320

Ser Pro Gly Lys

<210> 324

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 324

Arg Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu

1 5 10 15

Gln Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe

20 25 30

Tyr Pro Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg

35 40 45

Gln Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser

50 55 60

Thr Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu

65 70 75 80

Arg His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser

85 90 95

Pro Ile Val Lys Ser Phe Asn Arg Asn Glu Cys

100 105

<210> 325

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 325

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Met Ser Ala Ser Leu Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Asn Ser Tyr

20 25 30

Leu Ser Trp Phe Gln Gln Lys Pro Gly Lys Ser Pro Lys Thr Leu Ile

35 40 45

Tyr Arg Ala Asn Arg Leu Val Asp Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Tyr

65 70 75 80

Glu Asp Phe Gly Ile Tyr Tyr Cys Gln Gln Tyr Asp Glu Ser Pro Trp

85 90 95

Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 326

<211> 118

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 326

Gln Ile Gln Leu Val Gln Ser Gly Pro Gly Leu Lys Lys Pro Gly Gly

1 5 10 15

Ser Val Arg Ile Ser Cys Ala Ala Ser Gly Tyr Thr Phe Thr Asn Tyr

20 25 30

Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys Gly Leu Arg Trp Met

35 40 45

Gly Trp Ile Asn Thr His Thr Gly Glu Pro Thr Tyr Ala Asp Asp Phe

50 55 60

Lys Gly Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr

65 70 75 80

Leu Gln Ile Asn Ser Leu Arg Ala Glu Asp Thr Ala Thr Tyr Phe Cys

85 90 95

Thr Arg Arg Gly Tyr Asp Trp Tyr Phe Asp Val Trp Gly Gln Gly Thr

100 105 110

Thr Val Thr Val Ser Ser

115

<210> 327

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 327

Gly Tyr Thr Phe Thr Asn Tyr

1 5

<210> 328

<211> 6

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 328

Asn Thr His Thr Gly Glu

1 5

<210> 329

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 329

Arg Gly Tyr Asp Trp Tyr Phe Asp Val

1 5

<210> 330

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 330

Arg Ala Ser Gln Asp Ile Asn Ser Tyr Leu Ser

1 5 10

<210> 331

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 331

Arg Ala Asn Arg Leu Val Asp

1 5

<210> 332

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 332

Gln Gln Tyr Asp Glu Ser Pro Trp Thr

1 5

<210> 333

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 333

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Asn Ser Tyr

20 25 30

Leu Ser Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Thr Leu Ile

35 40 45

Tyr Arg Ala Asn Arg Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Tyr

65 70 75 80

Glu Asp Phe Gly Ile Tyr Tyr Cys Gln Gln Tyr Asp Glu Ser Pro Trp

85 90 95

Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 334

<211> 119

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 334

Glu Ile Gln Leu Val Gln Ser Gly Gly Gly Leu Val Lys Pro Gly Gly

1 5 10 15

Ser Val Arg Ile Ser Cys Ala Ala Ser Gly Tyr Thr Phe Thr Asn Tyr

20 25 30

Gly Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Met

35 40 45

Gly Trp Ile Asn Thr His Tyr Gly Glu Pro Thr Tyr Ala Asp Ser Phe

50 55 60

Lys Gly Thr Arg Thr Phe Ser Leu Asp Asp Ser Lys Asn Thr Ala Tyr

65 70 75 80

Leu Gln Ile Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Phe Cys

85 90 95

Thr Arg Arg Gly Tyr Asp Trp Tyr Phe Asp Val Trp Gly Gln Gly Gly

100 105 110

Thr Thr Val Thr Val Ser Ser

115

<210> 335

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 335

Gly Tyr Thr Phe Thr Asn Tyr

1 5

<210> 336

<211> 6

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 336

Asn Thr His Tyr Gly Glu

1 5

<210> 337

<211> 10

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 337

Arg Arg Gly Tyr Asp Trp Tyr Phe Asp Val

1 5 10

<210> 338

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 338

Arg Ala Ser Gln Asp Ile Asn Ser Tyr Leu Ser

1 5 10

<210> 339

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 339

Arg Ala Asn Arg Leu Glu Ser

1 5

<210> 340

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 340

Gln Gln Tyr Asp Glu Ser Pro Trp Thr

1 5

<210> 341

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 341

Gly Tyr Ser Ile Thr Ser Gly Tyr Tyr

1 5

<210> 342

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 342

Ile Ser Tyr Ser Gly Phe Thr

1 5

<210> 343

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 343

Ala Gly Asp Arg Thr Gly Ser Trp Phe Ala Tyr

1 5 10

<210> 344

<211> 6

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 344

Gln Asp Ile Ser Asn Tyr

1 5

<210> 345

<211> 3

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 345

Ala Thr Ser

1

<210> 346

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 346

Leu Gln Tyr Ala Ser Tyr Pro Phe Thr

1 5

<210> 347

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 347

Gly Tyr Ile Phe Thr Asn Tyr Gly

1 5

<210> 348

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 348

Ile Asn Thr Tyr Asn Gly Glu Pro

1 5

<210> 349

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 349

Ala Arg Gly Asp Tyr Tyr Gly Tyr Glu Asp Tyr

1 5 10

<210> 350

<211> 6

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 350

Gln Gly Ile Ser Asn Tyr

1 5

<210> 351

<211> 3

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 351

Tyr Thr Ser

1

<210> 352

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 352

Gln Gln Tyr Ser Lys Leu Pro Trp Thr

1 5

<210> 353

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 353

Phe Ser Leu Ser Thr Ser Gly Met Gly

1 5

<210> 354

<211> 5

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 354

Trp Trp Asp Asp Asp

1 5

<210> 355

<211> 10

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 355

Arg Arg Ala Thr Gly Thr Gly Phe Asp Tyr

1 5 10

<210> 356

<211> 6

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 356

Gln Asp Val Gly Thr Ala

1 5

<210> 357

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 357

Trp Thr Ser Thr Arg His Thr

1 5

<210> 358

<211> 6

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 358

Tyr Asn Ser Tyr Asn Thr

1 5

<210> 359

<211> 120

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 359

Gln Val Thr Leu Lys Glu Ser Gly Pro Val Leu Val Lys Pro Thr Glu

1 5 10 15

Thr Leu Thr Leu Thr Cys Thr Phe Ser Gly Phe Ser Leu Ser Thr Ser

20 25 30

Gly Met Gly Val Gly Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu

35 40 45

Trp Val Ala His Ile Trp Trp Asp Asp Asp Val Tyr Tyr Asn Pro Ser

50 55 60

Leu Lys Ser Arg Leu Thr Ile Thr Lys Asp Ala Ser Lys Asp Gln Val

65 70 75 80

Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr

85 90 95

Cys Val Arg Arg Arg Ala Thr Gly Thr Gly Phe Asp Tyr Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 360

<211> 106

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 360

Asn Ile Val Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Asp Val Gly Thr Ala

20 25 30

Val Ala Trp Tyr Gln Gln Lys Pro Asp Gln Ser Pro Lys Leu Leu Ile

35 40 45

Tyr Trp Thr Ser Thr Arg His Thr Gly Val Pro Asp Arg Phe Thr Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Ile Ala Thr Tyr Phe Cys His Gln Tyr Asn Ser Tyr Asn Thr

85 90 95

Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 361

<211> 120

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 361

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr

20 25 30

Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Val Ile Ser Glu Asn Gly Ser Asp Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Asp Arg Gly Gly Ala Val Ser Tyr Phe Asp Val Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 362

<211> 109

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 362

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Ser Ser Tyr

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Ala Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Leu Pro Tyr

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr

100 105

<210> 363

<211> 438

<212> PRT

<213> Homo sapiens

<400> 363

Met Val Cys Ser Gln Ser Trp Gly Arg Ser Ser Lys Gln Trp Glu Asp

1 5 10 15

Pro Ser Gln Ala Ser Lys Val Cys Gln Arg Leu Asn Cys Gly Val Pro

20 25 30

Leu Ser Leu Gly Pro Phe Leu Val Thr Tyr Thr Pro Gln Ser Ser Ile

35 40 45

Ile Cys Tyr Gly Gln Leu Gly Ser Phe Ser Asn Cys Ser His Ser Arg

50 55 60

Asn Asp Met Cys His Ser Leu Gly Leu Thr Cys Leu Glu Pro Gln Lys

65 70 75 80

Thr Thr Pro Pro Thr Thr Arg Pro Pro Pro Thr Thr Thr Pro Glu Pro

85 90 95

Thr Ala Pro Pro Arg Leu Gln Leu Val Ala Gln Ser Gly Gly Gln His

100 105 110

Cys Ala Gly Val Val Glu Phe Tyr Ser Gly Ser Leu Gly Gly Thr Ile

115 120 125

Ser Tyr Glu Ala Gln Asp Lys Thr Gln Asp Leu Glu Asn Phe Leu Cys

130 135 140

Asn Asn Leu Gln Cys Gly Ser Phe Leu Lys His Leu Pro Glu Thr Glu

145 150 155 160

Ala Gly Arg Ala Gln Asp Pro Gly Glu Pro Arg Glu His Gln Pro Leu

165 170 175

Pro Ile Gln Trp Lys Ile Gln Asn Ser Ser Cys Thr Ser Leu Glu His

180 185 190

Cys Phe Arg Lys Ile Lys Pro Gln Lys Ser Gly Arg Val Leu Ala Leu

195 200 205

Leu Cys Ser Gly Phe Gln Pro Lys Val Gln Ser Arg Leu Val Gly Gly

210 215 220

Ser Ser Ile Cys Glu Gly Thr Val Glu Val Arg Gln Gly Ala Gln Trp

225 230 235 240

Ala Ala Leu Cys Asp Ser Ser Ser Ala Arg Ser Ser Leu Arg Trp Glu

245 250 255

Glu Val Cys Arg Glu Gln Gln Cys Gly Ser Val Asn Ser Tyr Arg Val

260 265 270

Leu Asp Ala Gly Asp Pro Thr Ser Arg Gly Leu Phe Cys Pro His Gln

275 280 285

Lys Leu Ser Gln Cys His Glu Leu Trp Glu Arg Asn Ser Tyr Cys Lys

290 295 300

Lys Val Phe Val Thr Cys Gln Asp Pro Asn Pro Ala Gly Leu Ala Ala

305 310 315 320

Gly Thr Val Ala Ser Ile Ile Leu Ala Leu Val Leu Leu Val Val Leu

325 330 335

Leu Val Val Cys Gly Pro Leu Ala Tyr Lys Lys Leu Val Lys Lys Phe

340 345 350

Arg Gln Lys Lys Gln Arg Gln Trp Ile Gly Pro Thr Gly Met Asn Gln

355 360 365

Asn Met Ser Phe His Arg Asn His Thr Ala Thr Val Arg Ser His Ala

370 375 380

Glu Asn Pro Thr Ala Ser His Val Asp Asn Glu Tyr Ser Gln Pro Pro

385 390 395 400

Arg Asn Ser His Leu Ser Ala Tyr Pro Ala Leu Glu Gly Ala Leu His

405 410 415

Arg Ser Ser Met Gln Pro Asp Asn Ser Ser Asp Ser Asp Tyr Asp Leu

420 425 430

His Gly Ala Gln Arg Leu

435

<210> 364

<211> 450

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 364

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr

20 25 30

Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val

115 120 125

Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala

130 135 140

Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser

145 150 155 160

Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val

165 170 175

Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro

180 185 190

Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys

195 200 205

Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp

210 215 220

Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly

225 230 235 240

Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile

245 250 255

Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu

260 265 270

Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His

275 280 285

Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg

290 295 300

Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys

305 310 315 320

Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu

325 330 335

Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr

340 345 350

Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu

355 360 365

Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp

370 375 380

Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val

385 390 395 400

Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp

405 410 415

Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His

420 425 430

Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

435 440 445

Gly Lys

450

<210> 365

<211> 450

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 365

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr

20 25 30

Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val

115 120 125

Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala

130 135 140

Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser

145 150 155 160

Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val

165 170 175

Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro

180 185 190

Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys

195 200 205

Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp

210 215 220

Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly

225 230 235 240

Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile

245 250 255

Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Cys Val Ser His Glu

260 265 270

Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His

275 280 285

Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg

290 295 300

Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys

305 310 315 320

Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu

325 330 335

Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr

340 345 350

Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu

355 360 365

Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp

370 375 380

Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val

385 390 395 400

Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp

405 410 415

Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His

420 425 430

Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

435 440 445

Gly Lys

450

<210> 366

<211> 450

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 366

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr

20 25 30

Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val

115 120 125

Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala

130 135 140

Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser

145 150 155 160

Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val

165 170 175

Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro

180 185 190

Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys

195 200 205

Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp

210 215 220

Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly

225 230 235 240

Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile

245 250 255

Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu

260 265 270

Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His

275 280 285

Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg

290 295 300

Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys

305 310 315 320

Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu

325 330 335

Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr

340 345 350

Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu

355 360 365

Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp

370 375 380

Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val

385 390 395 400

Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp

405 410 415

Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His

420 425 430

Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

435 440 445

Gly Lys

450

<210> 367

<211> 450

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 367

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr

20 25 30

Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val

115 120 125

Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala

130 135 140

Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser

145 150 155 160

Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val

165 170 175

Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro

180 185 190

Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys

195 200 205

Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp

210 215 220

Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly

225 230 235 240

Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile

245 250 255

Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Cys Val Ser His Glu

260 265 270

Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His

275 280 285

Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg

290 295 300

Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys

305 310 315 320

Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu

325 330 335

Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr

340 345 350

Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu

355 360 365

Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp

370 375 380

Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val

385 390 395 400

Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp

405 410 415

Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His

420 425 430

Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

435 440 445

Gly Lys

450

<210> 368

<211> 120

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 368

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr

20 25 30

Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 369

<211> 214

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 369

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Asn Thr Ala

20 25 30

Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro Pro

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala

100 105 110

Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly

115 120 125

Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala

130 135 140

Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln

145 150 155 160

Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser

165 170 175

Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr

180 185 190

Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser

195 200 205

Phe Asn Arg Gly Glu Cys

210

<210> 370

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 370

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Asn Thr Ala

20 25 30

Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro Pro

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 371

<211> 450

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 371

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Tyr Phe

20 25 30

Asp Ile Asn Trp Leu Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Gly Ile Ser Pro Gly Asp Ser Asn Val Asn Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Leu Thr Ile Asp Thr Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Asp Gly Asn Phe Pro Tyr Tyr Ala Met Asp Ser Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val

115 120 125

Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala

130 135 140

Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser

145 150 155 160

Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val

165 170 175

Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro

180 185 190

Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys

195 200 205

Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp

210 215 220

Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly

225 230 235 240

Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile

245 250 255

Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu

260 265 270

Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His

275 280 285

Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg

290 295 300

Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys

305 310 315 320

Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu

325 330 335

Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr

340 345 350

Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu

355 360 365

Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp

370 375 380

Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val

385 390 395 400

Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp

405 410 415

Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His

420 425 430

Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

435 440 445

Gly Lys

450

<210> 372

<211> 450

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

Synthetic

polypeptide"

<400> 372

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Tyr Phe

20 25 30

Asp Ile Asn Trp Leu Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Gly Ile Ser Pro Gly Asp Ser Asn Val Asn Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Leu Thr Ile Asp Thr Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Asp Gly Asn Phe Pro Tyr Tyr Ala Met Asp Ser Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val

115 120 125

Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala

130 135 140

Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser

145 150 155 160

Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val

165 170 175

Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro

180 185 190

Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys

195 200 205

Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp

210 215 220

Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly

225 230 235 240

Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile

245 250 255

Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Cys Val Ser His Glu

260 265 270

Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His

275 280 285

Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg

290 295 300

Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys

305 310 315 320

Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu

325 330 335

Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr

340 345 350

Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu

355 360 365

Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp

370 375 380

Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val

385 390 395 400

Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp

405 410 415

Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His

420 425 430

Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

435 440 445

Gly Lys

450

<210> 373

<211> 450

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 373

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Tyr Phe

20 25 30

Asp Ile Asn Trp Leu Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Gly Ile Ser Pro Gly Asp Ser Asn Val Asn Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Leu Thr Ile Asp Thr Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Asp Gly Asn Phe Pro Tyr Tyr Ala Met Asp Ser Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val

115 120 125

Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala

130 135 140

Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser

145 150 155 160

Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val

165 170 175

Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro

180 185 190

Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys

195 200 205

Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp

210 215 220

Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly

225 230 235 240

Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile

245 250 255

Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu

260 265 270

Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His

275 280 285

Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg

290 295 300

Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys

305 310 315 320

Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu

325 330 335

Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr

340 345 350

Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu

355 360 365

Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp

370 375 380

Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val

385 390 395 400

Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp

405 410 415

Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His

420 425 430

Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

435 440 445

Gly Lys

450

<210> 374

<211> 450

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 374

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Tyr Phe

20 25 30

Asp Ile Asn Trp Leu Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Gly Ile Ser Pro Gly Asp Ser Asn Val Asn Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Leu Thr Ile Asp Thr Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Asp Gly Asn Phe Pro Tyr Tyr Ala Met Asp Ser Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val

115 120 125

Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala

130 135 140

Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser

145 150 155 160

Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val

165 170 175

Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro

180 185 190

Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys

195 200 205

Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp

210 215 220

Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly

225 230 235 240

Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile

245 250 255

Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Cys Val Ser His Glu

260 265 270

Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His

275 280 285

Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg

290 295 300

Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys

305 310 315 320

Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu

325 330 335

Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr

340 345 350

Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu

355 360 365

Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp

370 375 380

Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val

385 390 395 400

Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp

405 410 415

Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His

420 425 430

Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

435 440 445

Gly Lys

450

<210> 375

<211> 120

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 375

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Tyr Phe

20 25 30

Asp Ile Asn Trp Leu Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Gly Ile Ser Pro Gly Asp Ser Asn Val Asn Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Leu Thr Ile Asp Thr Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Asp Gly Asn Phe Pro Tyr Tyr Ala Met Asp Ser Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 376

<211> 218

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 376

Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly

1 5 10 15

Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser

20 25 30

Ser Gly Gln Thr Tyr Leu His Trp Tyr Gln Gln Lys Pro Gly Gln Ser

35 40 45

Pro Gln Leu Leu Ile Tyr Thr Val Ser Asn Arg Ala Ser Gly Val Pro

50 55 60

Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Val Gly Thr Tyr Tyr Cys Ser Gln Ser

85 90 95

Thr His Val Pro Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg

100 105 110

Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln

115 120 125

Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr

130 135 140

Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser

145 150 155 160

Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr

165 170 175

Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys

180 185 190

His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro

195 200 205

Val Thr Lys Ser Phe Asn Arg Gly Glu Cys

210 215

<210> 377

<211> 111

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 377

Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly

1 5 10 15

Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser

20 25 30

Ser Gly Gln Thr Tyr Leu His Trp Tyr Gln Gln Lys Pro Gly Gln Ser

35 40 45

Pro Gln Leu Leu Ile Tyr Thr Val Ser Asn Arg Ala Ser Gly Val Pro

50 55 60

Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Val Gly Thr Tyr Tyr Cys Ser Gln Ser

85 90 95

Thr His Val Pro Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105 110

<210> 378

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 378

Gly Tyr Thr Phe Thr Tyr Phe

1 5

<210> 379

<211> 17

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 379

Gly Ile Ser Pro Gly Asp Ser Asn Val Asn Tyr Ala Gln Lys Phe Gln

1 5 10 15

Gly

17

<210> 380

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 380

Asp Gly Asn Phe Pro Tyr Tyr Ala Met Asp Ser

1 5 10

<210> 381

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 381

Arg Ser Ser Gln Ser Leu Val His Ser Ser Gly Gln Thr Tyr Leu His

1 5 10 15

<210> 382

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 382

Thr Val Ser Asn Arg Ala Ser

1 5

<210> 383

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 383

Ser Gln Ser Thr His Val Pro Thr

1 5

<210> 384

<211> 450

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 384

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr

20 25 30

Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val

115 120 125

Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala

130 135 140

Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser

145 150 155 160

Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val

165 170 175

Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro

180 185 190

Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys

195 200 205

Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp

210 215 220

Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly

225 230 235 240

Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile

245 250 255

Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu

260 265 270

Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His

275 280 285

Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg

290 295 300

Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys

305 310 315 320

Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu

325 330 335

Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr

340 345 350

Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu

355 360 365

Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp

370 375 380

Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val

385 390 395 400

Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp

405 410 415

Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His

420 425 430

Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

435 440 445

Gly Lys

450

<210> 385

<211> 450

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 385

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr

20 25 30

Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val

115 120 125

Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala

130 135 140

Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser

145 150 155 160

Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val

165 170 175

Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro

180 185 190

Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys

195 200 205

Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp

210 215 220

Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly

225 230 235 240

Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile

245 250 255

Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Cys Val Ser His Glu

260 265 270

Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His

275 280 285

Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg

290 295 300

Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys

305 310 315 320

Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu

325 330 335

Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr

340 345 350

Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu

355 360 365

Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp

370 375 380

Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val

385 390 395 400

Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp

405 410 415

Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His

420 425 430

Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

435 440 445

Gly Lys

450

<210> 386

<211> 450

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 386

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr

20 25 30

Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val

115 120 125

Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala

130 135 140

Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser

145 150 155 160

Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val

165 170 175

Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro

180 185 190

Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys

195 200 205

Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp

210 215 220

Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly

225 230 235 240

Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile

245 250 255

Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu

260 265 270

Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His

275 280 285

Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg

290 295 300

Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys

305 310 315 320

Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu

325 330 335

Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr

340 345 350

Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu

355 360 365

Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp

370 375 380

Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val

385 390 395 400

Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp

405 410 415

Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His

420 425 430

Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

435 440 445

Gly Lys

450

<210> 387

<211> 450

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 387

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr

20 25 30

Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val

115 120 125

Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala

130 135 140

Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser

145 150 155 160

Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val

165 170 175

Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro

180 185 190

Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys

195 200 205

Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp

210 215 220

Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly

225 230 235 240

Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile

245 250 255

Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Cys Val Ser His Glu

260 265 270

Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His

275 280 285

Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg

290 295 300

Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys

305 310 315 320

Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu

325 330 335

Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr

340 345 350

Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu

355 360 365

Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp

370 375 380

Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val

385 390 395 400

Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp

405 410 415

Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His

420 425 430

Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

435 440 445

Gly Lys

450

<210> 388

<211> 120

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 388

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr

20 25 30

Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 389

<211> 214

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 389

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Asn Thr Ala

20 25 30

Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro Pro

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala

100 105 110

Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly

115 120 125

Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala

130 135 140

Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln

145 150 155 160

Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser

165 170 175

Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr

180 185 190

Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser

195 200 205

Phe Asn Arg Gly Glu Cys

210

<210> 390

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 390

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Asn Thr Ala

20 25 30

Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro Pro

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 391

<211> 450

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 391

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Tyr Phe

20 25 30

Asp Ile Asn Trp Leu Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Gly Ile Ser Pro Gly Asp Ser Asn Val Asn Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Leu Thr Ile Asp Thr Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Asp Gly Asn Phe Pro Tyr Tyr Ala Met Asp Ser Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val

115 120 125

Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala

130 135 140

Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser

145 150 155 160

Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val

165 170 175

Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro

180 185 190

Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys

195 200 205

Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp

210 215 220

Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly

225 230 235 240

Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile

245 250 255

Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu

260 265 270

Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His

275 280 285

Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg

290 295 300

Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys

305 310 315 320

Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu

325 330 335

Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr

340 345 350

Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu

355 360 365

Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp

370 375 380

Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val

385 390 395 400

Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp

405 410 415

Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His

420 425 430

Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

435 440 445

Gly Lys

450

<210> 392

<211> 450

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 392

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Tyr Phe

20 25 30

Asp Ile Asn Trp Leu Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Gly Ile Ser Pro Gly Asp Ser Asn Val Asn Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Leu Thr Ile Asp Thr Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Asp Gly Asn Phe Pro Tyr Tyr Ala Met Asp Ser Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val

115 120 125

Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala

130 135 140

Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser

145 150 155 160

Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val

165 170 175

Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro

180 185 190

Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys

195 200 205

Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp

210 215 220

Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly

225 230 235 240

Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile

245 250 255

Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Cys Val Ser His Glu

260 265 270

Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His

275 280 285

Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg

290 295 300

Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys

305 310 315 320

Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu

325 330 335

Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr

340 345 350

Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu

355 360 365

Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp

370 375 380

Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val

385 390 395 400

Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp

405 410 415

Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His

420 425 430

Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

435 440 445

Gly Lys

450

<210> 393

<211> 450

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 393

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Tyr Phe

20 25 30

Asp Ile Asn Trp Leu Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Gly Ile Ser Pro Gly Asp Ser Asn Val Asn Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Leu Thr Ile Asp Thr Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Asp Gly Asn Phe Pro Tyr Tyr Ala Met Asp Ser Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val

115 120 125

Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala

130 135 140

Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser

145 150 155 160

Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val

165 170 175

Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro

180 185 190

Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys

195 200 205

Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp

210 215 220

Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly

225 230 235 240

Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile

245 250 255

Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu

260 265 270

Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His

275 280 285

Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg

290 295 300

Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys

305 310 315 320

Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu

325 330 335

Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr

340 345 350

Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu

355 360 365

Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp

370 375 380

Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val

385 390 395 400

Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp

405 410 415

Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His

420 425 430

Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

435 440 445

Gly Lys

450

<210> 394

<211> 450

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 394

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Tyr Phe

20 25 30

Asp Ile Asn Trp Leu Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Gly Ile Ser Pro Gly Asp Ser Asn Val Asn Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Leu Thr Ile Asp Thr Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Asp Gly Asn Phe Pro Tyr Tyr Ala Met Asp Ser Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val

115 120 125

Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala

130 135 140

Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser

145 150 155 160

Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val

165 170 175

Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro

180 185 190

Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys

195 200 205

Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp

210 215 220

Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly

225 230 235 240

Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile

245 250 255

Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Cys Val Ser His Glu

260 265 270

Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His

275 280 285

Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg

290 295 300

Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys

305 310 315 320

Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu

325 330 335

Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr

340 345 350

Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu

355 360 365

Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp

370 375 380

Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val

385 390 395 400

Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp

405 410 415

Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His

420 425 430

Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

435 440 445

Gly Lys

450

<210> 395

<211> 120

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

Synthetic

polypeptide"

<400> 395

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Tyr Phe

20 25 30

Asp Ile Asn Trp Leu Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Gly Ile Ser Pro Gly Asp Ser Asn Val Asn Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Leu Thr Ile Asp Thr Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Asp Gly Asn Phe Pro Tyr Tyr Ala Met Asp Ser Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 396

<211> 218

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 396

Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly

1 5 10 15

Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser

20 25 30

Ser Gly Gln Thr Tyr Leu His Trp Tyr Gln Gln Lys Pro Gly Gln Ser

35 40 45

Pro Gln Leu Leu Ile Tyr Thr Val Ser Asn Arg Ala Ser Gly Val Pro

50 55 60

Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Val Gly Thr Tyr Tyr Cys Ser Gln Ser

85 90 95

Thr His Val Pro Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg

100 105 110

Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln

115 120 125

Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr

130 135 140

Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser

145 150 155 160

Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr

165 170 175

Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys

180 185 190

His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro

195 200 205

Val Thr Lys Ser Phe Asn Arg Gly Glu Cys

210 215

<210> 397

<211> 111

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

polypeptide"

<400> 397

Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly

1 5 10 15

Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser

20 25 30

Ser Gly Gln Thr Tyr Leu His Trp Tyr Gln Gln Lys Pro Gly Gln Ser

35 40 45

Pro Gln Leu Leu Ile Tyr Thr Val Ser Asn Arg Ala Ser Gly Val Pro

50 55 60

Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Val Gly Thr Tyr Tyr Cys Ser Gln Ser

85 90 95

Thr His Val Pro Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105 110

<210> 398

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

Synthetic

peptide"

<400> 398

Gly Tyr Thr Phe Thr Tyr Phe

1 5

<210> 399

<211> 17

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 399

Gly Ile Ser Pro Gly Asp Ser Asn Val Asn Tyr Ala Gln Lys Phe Gln

1 5 10 15

Gly

<210> 400

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 400

Asp Gly Asn Phe Pro Tyr Tyr Ala Met Asp Ser

1 5 10

<210> 401

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 401

Arg Ser Ser Gln Ser Leu Val His Ser Ser Gly Gln Thr Tyr Leu His

1 5 10 15

<210> 402

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 402

Thr Val Ser Asn Arg Ala Ser

1 5

<210> 403

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 403

Ser Gln Ser Thr His Val Pro Thr

1 5

<210> 404

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 404

Glu Pro Lys Ser Ser Asp Lys Thr His Thr Ser Pro Pro Ser Pro

1 5 10 15

<210> 405

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<220>

<221> OPTION

<222> (7)..(7)

<223> /replace="Asp"

<220>

<221> SITE

<222> (1)..(8)

<223> /note="Variant residues given in sequence,

have no preference over residues in annotations

for alternative provisions"

<400> 405

Ile Trp Gly Ile Gly Cys Asn Pro

1 5

<210> 406

<211> 10

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 406

Ser Gly Tyr Ser Phe Thr Gly Tyr Thr Met

1 5 10

<210> 407

<211> 10

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 407

Ser Gly Tyr Ser Phe Thr Asp Tyr Thr Met

1 5 10

<210> 408

<211> 10

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 408

Ser Gly Phe Thr Phe Ser Asn Tyr Ala Met

1 5 10

<210> 409

<211> 10

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 409

Ser Gly Phe Thr Phe Ser Ser Tyr Ala Met

1 5 10

<210> 410

<211> 10

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 410

Ser Gly Tyr Ser Phe Thr Ala Tyr Asn Ile

1 5 10

<210> 411

<211> 10

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 411

Ser Gly Tyr Ser Phe Thr Ala Tyr Ser Met

1 5 10

<210> 412

<211> 10

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 412

Ser Gly Tyr Thr Phe Thr Asn Phe Ala Ile

1 5 10

<210> 413

<211> 10

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 413

Ser Gly Phe Asn Ile Lys Asp Thr Tyr Met

1 5 10

<210> 414

<211> 10

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 414

Ser Gly Tyr Ser Phe Thr Ser Tyr Trp Met

1 5 10

<210> 415

<211> 10

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 415

Ser Gly Phe Ser Leu Thr Asn Tyr Asp Val

1 5 10

<210> 416

<211> 10

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 416

Ser Gly Phe Thr Phe Ser Asn Tyr Gly Met

1 5 10

<210> 417

<211> 10

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 417

Ser Gly Tyr Ile Phe Ala Asn Tyr Gly Met

1 5 10

<210> 418

<211> 10

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 418

Ser Gly Tyr Asn Phe Thr Asn Tyr Gly Met

1 5 10

<210> 419

<211> 10

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 419

Ser Gly Tyr Thr Phe Thr Asn Tyr Gly Met

1 5 10

<210> 420

<211> 10

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

Synthetic

peptide"

<400> 420

Ser Gly Tyr Thr Phe Thr Asp Tyr Tyr Ile

1 5 10

<210> 421

<211> 10

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 421

Ser Gly Asn Thr Phe Thr Asn Phe Tyr Leu

1 5 10

<210> 422

<211> 10

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 422

Ser Glu Phe Thr Phe Ser Asn Tyr Ala Met

1 5 10

<210> 423

<211> 10

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 423

Ser Gly Tyr Thr Phe Thr Ser Tyr Arg Met

1 5 10

<210> 424

<211> 10

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 424

Ser Gly Tyr Met Phe Thr Asn His Gly Met

1 5 10

<210> 425

<211> 10

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 425

Ser Gly Tyr Met Phe Thr Asn Tyr Gly Met

1 5 10

<210> 426

<211> 10

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 426

Ser Gly Tyr Ile Phe Thr Asn Tyr Gly Met

1 5 10

<210> 427

<211> 10

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 427

Ser Gly Phe Asn Ile Lys Asp Tyr Tyr Ile

1 5 10

<210> 428

<211> 10

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 428

Ser Gly Tyr Thr Phe Ile Asn Tyr Gly Met

1 5 10

<210> 429

<211> 10

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 429

Ser Gly Tyr Thr Phe Thr Asp Tyr Phe Ile

1 5 10

<210> 430

<211> 10

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 430

Ser Gly Tyr Ile Phe Thr Gly Tyr Asn Ile

1 5 10

<210> 431

<211> 10

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 431

Leu Ile Asn Pro Tyr Asn Gly Gly Thr Thr

1 5 10

<210> 432

<211> 10

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 432

Leu Ile Asn Pro Tyr Asn Gly Gly Thr Met

1 5 10

<210> 433

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 433

Ser Ile Ser Ser Gly Gly Asn Thr Phe

1 5

<210> 434

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 434

Ser Ile Ser Ser Gly Gly Ser Thr Tyr

1 5

<210> 435

<211> 10

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 435

Ser Ile Asp Pro Tyr Tyr Gly Asp Thr Lys

1 5 10

<210> 436

<211> 10

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 436

Leu Ile Ser Ser Asn Ser Gly Asp Val Ser

1 5 10

<210> 437

<211> 10

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 437

Leu Ile Ser Thr Ser Ser Gly Asp Val Ser

1 5 10

<210> 438

<211> 10

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 438

Arg Ile Asp Pro Ala Asn Gly Asn Thr Lys

1 5 10

<210> 439

<211> 10

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 439

Met Ile His Pro Ser Asp Ser Glu Thr Arg

1 5 10

<210> 440

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 440

Val Ile Trp Ser Gly Gly Asn Thr Asp

1 5

<210> 441

<211> 10

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 441

Ala Ile Asn Ser Asn Gly Asp Ile Thr Tyr

1 5 10

<210> 442

<211> 10

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 442

Leu Ile Asn Pro Tyr Asn Gly Gly Thr Arg

1 5 10

<210> 443

<211> 10

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 443

Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr

1 5 10

<210> 444

<211> 10

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 444

Trp Ile Tyr Pro Gly Gly Gly Asn Thr Arg

1 5 10

<210> 445

<211> 10

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 445

Cys Ile Tyr Pro Gly Asn Val Lys Thr Lys

1 5 10

<210> 446

<211> 10

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 446

Thr Ile Ser Ser Gly Gly Ser Tyr Thr Tyr

1 5 10

<210> 447

<211> 10

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 447

Arg Ile Asp Pro Tyr Asp Ser Gly Thr His

1 5 10

<210> 448

<211> 10

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 448

Trp Ile Asp Pro Glu Asn Gly Arg Thr Glu

1 5 10

<210> 449

<211> 10

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 449

Glu Ile Tyr Pro Gly Ser Ser Asn Thr Tyr

1 5 10

<210> 450

<211> 10

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 450

Ala Val Tyr Pro Gly Asn Gly Asp Thr Ser

1 5 10

<210> 451

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 451

Cys Ala Arg Asp Tyr Tyr Gly Ser Ser Pro Asp Phe Asp Tyr Trp

1 5 10 15

<210> 452

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 452

Cys Ala Arg Asp Asn Tyr Gly Ser Ser Pro Asp Phe Asp Tyr Trp

1 5 10 15

<210> 453

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 453

Cys Ala Arg Asp Asn Tyr Gly Ser Ser Pro Tyr Phe Asp Tyr Trp

1 5 10 15

<210> 454

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 454

Cys Val Arg Tyr Tyr Tyr Gly Val Thr Tyr Trp Tyr Phe Asp Val Trp

1 5 10 15

<210> 455

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 455

Cys Val Arg Tyr Tyr Tyr Gly Ile Arg Tyr Trp Tyr Phe Asp Val Trp

1 5 10 15

<210> 456

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 456

Cys Ala Arg Arg Met Ile Thr Met Gly Asp Trp Tyr Phe Asp Val Trp

1 5 10 15

<210> 457

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 457

Cys Ala Arg Arg Met Ile Thr Thr Gly Asp Trp Tyr Phe Asp Val Trp

1 5 10 15

<210> 458

<211> 14

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 458

Cys Ala Arg His Tyr Gly Ala His Asn Tyr Phe Asp Tyr Trp

1 5 10

<210> 459

<211> 14

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 459

Cys Ala Arg His Tyr Gly Ala Asn Asn Tyr Phe Asp Tyr Trp

1 5 10

<210> 460

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 460

Cys Ala Arg Glu Glu Asn Tyr Tyr Gly Thr Tyr Tyr Phe Asp Tyr Trp

1 5 10 15

<210> 461

<211> 14

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 461

Cys Ala Arg Trp Gly Asp His Asp Asp Ala Met Asp Phe Trp

1 5 10

<210> 462

<211> 17

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 462

Cys Ala Arg Asn His Gly Asp Gly Tyr Phe Asn Trp Tyr Phe Asp Val

1 5 10 15

Trp

<210> 463

<211> 17

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 463

Cys Ala Arg Asn His Gly Asp Gly Tyr Tyr Asn Trp Tyr Phe Asp Val

1 5 10 15

Trp

<210> 464

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 464

Cys Ala Arg Gly Thr Ala Trp Phe Thr Tyr Trp

1 5 10

<210> 465

<211> 14

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 465

Cys Ala Arg Asp Gly Asp Asp Gly Trp Asp Ile Asp Val Trp

1 5 10

<210> 466

<211> 13

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 466

Cys Ala Arg Arg Gly Thr Tyr Trp His Phe Asp Val Trp

1 5 10

<210> 467

<211> 13

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 467

Cys Ala Arg Arg Gly Ser Tyr Trp His Phe Asp Val Trp

1 5 10

<210> 468

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 468

Cys Ala Arg Arg Ser Thr Leu Val Phe Asp Tyr Trp

1 5 10

<210> 469

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 469

Cys Ala Arg Asn Gly Tyr Trp Tyr Phe Asp Val Trp

1 5 10

<210> 470

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 470

Cys Ala Lys Glu Gly Asp Tyr Asp Gly Thr Ala Tyr Phe Asp Tyr Trp

1 5 10 15

<210> 471

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 471

Cys Ala Arg Arg Arg Asp Gly Asn Phe Asp Tyr Trp

1 5 10

<210> 472

<211> 10

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 472

Cys Val Arg His Gly Tyr Phe Asp Val Trp

1 5 10

<210> 473

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 473

Cys Ala Phe Tyr Asp Gly Ala Tyr Trp

1 5

<210> 474

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 474

Cys Ala Ser Tyr Asp Pro Asp Tyr Trp

1 5

<210> 475

<211> 14

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 475

Cys Ala Arg Asp Thr Thr Ala Thr Tyr Tyr Phe Asp Tyr Trp

1 5 10

<210> 476

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 476

Cys Ala Arg Arg Val Ala Thr Tyr Phe Asp Val Trp

1 5 10

<210> 477

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 477

Cys Thr Arg Arg Ser His Ile Thr Leu Asp Tyr Trp

1 5 10

<210> 478

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 478

Cys Ala Arg Arg Arg Thr Thr Ala Phe Asp Tyr Trp

1 5 10

<210> 479

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 479

Cys Asn Asn Gly Asn Tyr Val Arg His Tyr Tyr Phe Asp Tyr Trp

1 5 10 15

<210> 480

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 480

Cys Thr Arg Arg Arg Glu Ile Thr Phe Asp Tyr Trp

1 5 10

<210> 481

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 481

Cys Ala Arg Ser Gly Ile Ser Pro Phe Thr Tyr Trp

1 5 10

<210> 482

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 482

Cys Ala Lys Tyr Asp Arg Phe Phe Ala Ser Trp

1 5 10

<210> 483

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 483

Ser Gln Gly Ile Ser Asn His Leu

1 5

<210> 484

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 484

Ser Gln Gly Ile Arg Asn Tyr Leu

1 5

<210> 485

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 485

Ser Gln Gly Ile Asn Asn Tyr Leu

1 5

<210> 486

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 486

Ser Gln Ser Val Asp His Asp Gly Asp Ser Tyr Met

1 5 10

<210> 487

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 487

Ser Gln Ser Val Asp Tyr Asp Gly Asp Ser Tyr Met

1 5 10

<210> 488

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 488

Ser Gln Asp Ile Ser Asn Tyr Leu

1 5

<210> 489

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 489

Ser Gln Asp Ile Ser Thr Tyr Leu

1 5

<210> 490

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 490

Thr Ser Ser Ile Ser Ser Ser Tyr Leu

1 5

<210> 491

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 491

Asn Ser Ser Val Ser Ser Ser Tyr Leu

1 5

<210> 492

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 492

Ser Glu Asn Ile Tyr Tyr Asn Leu

1 5

<210> 493

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 493

Ser Glu Asn Ile Tyr Gly Tyr Phe

1 5

<210> 494

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 494

Ser Gln Asp Ile Asn Asn Tyr Ile

1 5

<210> 495

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 495

Ser Gln Asp Ile Asn Lys Tyr Ile

1 5

<210> 496

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 496

Ser Glu Asn Ile Tyr Ser Tyr Leu

1 5

<210> 497

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 497

Ser Gln Asp Val Arg Thr Asp Val

1 5

<210> 498

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 498

Ser Gln Asp Val Ile Thr Ala Val

1 5

<210> 499

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 499

Ser Gln Ser Ile Gly Thr Ser Ile

1 5

<210> 500

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 500

Ser Ser Gln Ser Leu Leu Asn Gln Lys Asn Tyr Leu

1 5 10

<210> 501

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 501

Ser Ser Ser Val Ser Ser Ser Tyr Leu

1 5

<210> 502

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 502

Ser Gln Thr Ile Gly Thr Ser Ile

1 5

<210> 503

<211> 14

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 503

Ser Gln Ser Leu Leu Tyr Ser Ser Asp Gln Lys Asn Tyr Leu

1 5 10

<210> 504

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 504

Asn Ser Ser Val Ser Tyr Met

1 5

<210> 505

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 505

Ser Ser Ser Leu Ser Tyr Met

1 5

<210> 506

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 506

Ser Gln Arg Ile Gly Thr Ser Met

1 5

<210> 507

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 507

Ser Gln Asn Ile Gly Thr Ser Ile

1 5

<210> 508

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 508

Ile Ser Ser Val Ser Tyr Met

1 5

<210> 509

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 509

Ser Gln Thr Ile Ala Thr Ser Ile

1 5

<210> 510

<211> 13

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 510

Ser Gln Ser Leu Val His Ser Asn Gly Asn Thr Tyr Leu

1 5 10

<210> 511

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 511

Asn Glu Ser Val Glu Tyr Ser Gly Thr Ser Leu Met

1 5 10

<210> 512

<211> 5

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 512

Tyr Phe Thr Ser Ser

1 5

<210> 513

<211> 5

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 513

Tyr Tyr Thr Ser Ser

1 5

<210> 514

<211> 5

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 514

Tyr Ala Ala Ser Asn

1 5

<210> 515

<211> 5

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 515

Tyr Tyr Thr Ser Arg

1 5

<210> 516

<211> 5

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 516

Phe Tyr Thr Ser Arg

1 5

<210> 517

<211> 5

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 517

Tyr Gly Thr Ser Asn

1 5

<210> 518

<211> 5

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 518

Tyr Asn Ala Asn Ser

1 5

<210> 519

<211> 5

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 519

Tyr Asn Ala Lys Thr

1 5

<210> 520

<211> 5

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 520

His Tyr Thr Ser Thr

1 5

<210> 521

<211> 5

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 521

Tyr His Thr Ser Thr

1 5

<210> 522

<211> 5

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

Synthetic

peptide"

<400> 522

Tyr Ser Ala Ser Phe

1 5

<210> 523

<211> 5

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 523

Tyr Ser Ala Ser Tyr

1 5

<210> 524

<211> 5

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial sequence:

Synthetic

peptide"

<400> 524

Lys Ser Ala Ser Glu

1 5

<210> 525

<211> 5

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 525

Tyr Trp Ala Ser Thr

1 5

<210> 526

<211> 5

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 526

Tyr Ser Thr Ser Asn

1 5

<210> 527

<211> 5

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 527

Lys Asn Ala Ser Glu

1 5

<210> 528

<211> 5

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 528

Tyr Asp Thr Ser Lys

1 5

<210> 529

<211> 5

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 529

Tyr Asp Thr Ser Asn

1 5

<210> 530

<211> 5

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 530

Lys Asp Ala Ser Glu

1 5

<210> 531

<211> 5

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 531

Tyr Ala Thr Ser Asn

1 5

<210> 532

<211> 5

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 532

Tyr Lys Val Ser Asn

1 5

<210> 533

<211> 5

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 533

Ser Ala Ala Ser Asn

1 5

<210> 534

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 534

Cys Gln Gln Tyr Ser Asn Leu Pro Tyr Thr Phe

1 5 10

<210> 535

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 535

Cys Gln Gln Tyr Ser Lys Ile Pro Tyr Thr Cys

1 5 10

<210> 536

<211> 10

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 536

Cys Gln Gln Asn Tyr Glu Asp Pro Thr Phe

1 5 10

<210> 537

<211> 10

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 537

Cys Gln Gln Ser Asn Glu Asp Pro Thr Phe

1 5 10

<210> 538

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 538

Cys Gln Gln Gly Asp Ala Leu Pro Trp Thr Phe

1 5 10

<210> 539

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 539

Cys Gln Gln Gly Asn Ser Leu Pro Phe Thr Phe

1 5 10

<210> 540

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 540

Cys Gln Gln Trp Ser Ser Arg Pro Pro Thr Phe

1 5 10

<210> 541

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 541

Cys Gln Gln Tyr Ser Gly Tyr Pro Leu Thr Phe

1 5 10

<210> 542

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 542

Cys Gln Gln Tyr Ser Asp Tyr Pro Leu Thr Phe

1 5 10

<210> 543

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 543

Cys Gln Gln Arg Ser Tyr Phe Pro Phe Thr Phe

1 5 10

<210> 544

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 544

Cys Lys Gln Val Tyr Asp Val Pro Phe Thr Phe

1 5 10

<210> 545

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 545

Cys Gln His His Tyr Gly Thr Pro Phe Thr Phe

1 5 10

<210> 546

<211> 10

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 546

Cys Leu Gln Tyr Asp Asn Leu Trp Thr Phe

1 5 10

<210> 547

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 547

Cys Gln His His Tyr Gly Tyr Pro Tyr Thr Phe

1 5 10

<210> 548

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 548

Cys Gln Gln Tyr Ser Asn Leu Pro Leu Thr Phe

1 5 10

<210> 549

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 549

Cys Gln Gln His Tyr Thr Ser Pro Trp Thr Phe

1 5 10

<210> 550

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 550

Cys Gln Gln His Tyr Ser Thr Pro Trp Thr Phe

1 5 10

<210> 551

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 551

Cys Gln Gln Ser Asn Arg Trp Pro Leu Thr Phe

1 5 10

<210> 552

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 552

Cys Gln Asn Asp Tyr Asp Tyr Pro Tyr Thr Phe

1 5 10

<210> 553

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 553

Cys His Gln Tyr His Arg Ser Pro Leu Thr Phe

1 5 10

<210> 554

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 554

Cys Gln Gln Thr Phe Asp Val Pro Trp Thr Phe

1 5 10

<210> 555

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 555

Cys Gln Gln Ser Asn Ser Trp Pro Leu Thr Tyr

1 5 10

<210> 556

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 556

Cys Gln Gln Tyr Tyr Asn Tyr Pro Leu Thr Phe

1 5 10

<210> 557

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 557

Cys Gln Gln Trp Ser Ser Asn Pro Phe Thr Phe

1 5 10

<210> 558

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 558

Cys Lys Gln Ala Tyr Asp Val Pro Trp Thr Phe

1 5 10

<210> 559

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 559

Cys Gln Gln Trp Ser Ser Phe Pro Pro Thr Phe

1 5 10

<210> 560

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 560

Cys Gln Gln Ser Asn Ser Trp Pro Leu Thr Phe

1 5 10

<210> 561

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 561

Cys Gln Gln Ser Asp Ser Trp Pro Leu Thr Phe

1 5 10

<210> 562

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 562

Cys Gln Gln Trp Ser Ser Asn Pro Arg Thr Phe

1 5 10

<210> 563

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 563

Cys Trp Gln Asn Thr His Phe Pro Gln Thr Phe

1 5 10

<210> 564

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic

peptide"

<400> 564

Cys Gln Gln Ser Arg Gln Val Pro Leu Thr Phe

1 5 10

<---

Claims (29)

1. Amatoxin, which has the structure of the formula (An) Formula (An), where n is 2, 3, 4, 5, 6, 7, 8 or 9, with high plasma stability and in vivo tolerability. 2. Amatoxin according to claim 1, which is a structure of formula (A) Formula (A) (HDP 30.2867). 3. An amatoxin according to claim 1 or 2 for use in the preparation of an antibody drug conjugate (ADC). 4. An antibody drug conjugate (ADC) with high plasma stability and in vivo tolerability, comprising an antibody conjugated to an amatoxin via a linker, wherein the ADC has a structure of formula (Ia) (Ia), where Q is S; L represents -(CH ₂ ) _n -, where n is an integer from 1 to 6; Z represents a maleimide group; and Ab is an antibody that specifically binds to Her2 or PSMA. 5. The ADC of claim 4, wherein L is -( _CH2 ) _n- , where n is 6. 6. ADC according to claim 4, which is a structure of formula ( IIa ) ( IIa ). 7. An ADC according to any one of claims 4 to 6, wherein the antibody comprises an Fc region comprising at least one mutation selected from the group consisting of D265C, D265A, A118C, L234A or L235A (according to the EU index). 8. The ADC of any one of claims 4-7, wherein said antibody specifically binds to PSMA and comprises CDRH1 according to SEQ ID NO: 378, CDRH2 according to SEQ ID NO: 379, CDRH3 according to SEQ ID NO: 380, CDRL1 according to SEQ ID NO: 381, CDRL2 according to SEQ ID NO: 382 and CDRL3 according to SEQ ID NO: 383. 9. The ADC of claim 8, wherein said antibody comprises a heavy chain variable region according to SEQ ID NO: 375 and a light chain variable region according to SEQ ID NO: 377. 10. The ADC of claim 9, wherein said antibody comprises a heavy chain according to SEQ ID NO: 371, SEQ ID NO: 372, SEQ ID NO: 373 or SEQ ID NO: 374 and a light chain according to SEQ ID NO: 376 or an antigen-binding fragment thereof. 11. An antibody drug conjugate (ADC), wherein said antibody drug conjugate comprises an antibody that specifically binds to human PSMA and comprises a heavy chain with an amino acid sequence according to SEQ ID NO: 374 and a light chain with an amino acid sequence according to SEQ ID NO: 376 and which is conjugated to a compound HDP30.2867. 12. The antibody drug conjugate (ADC) of claim 11, wherein the drug to antibody ratio (DAR) is 1, 2, 3, or 4. 13. The ADC of claim 12, wherein the DAR is 2. 14. Use of an ADC according to any one of claims 4-13 for the treatment of cancer. 15. The use according to claim 14, wherein the cancer is selected from the group consisting of breast cancer, pancreatic cancer, cholangiocarcinoma, colorectal cancer, lung cancer, ovarian cancer, prostate cancer, gastric cancer, kidney cancer, malignant melanoma, hemoblastosis, leukemia and malignant lymphoma. 16. The use according to claim 15, wherein the cancer is prostate cancer.