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WO2025137236A1 - Compositions et procédés de modulation de la transduction de signal médiée par cdcp1 - Google Patents

Compositions et procédés de modulation de la transduction de signal médiée par cdcp1 Download PDF

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Publication number
WO2025137236A1
WO2025137236A1 PCT/US2024/060972 US2024060972W WO2025137236A1 WO 2025137236 A1 WO2025137236 A1 WO 2025137236A1 US 2024060972 W US2024060972 W US 2024060972W WO 2025137236 A1 WO2025137236 A1 WO 2025137236A1
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seq
heavy chain
sequence identity
cdcp1
light chain
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Dallas Benjamin Flies
Solomon Langermann
Shanmugan Paneer SELVAM
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NextCure Inc
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NextCure Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6849—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A61K47/68037—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a camptothecin [CPT] or derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2896—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against molecules with a "CD"-designation, not provided for elsewhere
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/33—Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value

Definitions

  • FIELD This relates generally to the field of immunomodulation, and more particularly to compositions and methods for modulating immune responses in a subject BACKGROUND [0003]
  • Immunotherapies have made significant advances in the treatment of diseases such as cancer (Iwai, Y., et al., Journal of Biomedical Science, 24:26 (2017). Early immunotherapies accelerated T-cell activity. Current immune-checkpoint inhibitors take the brakes off the anti-tumor immune responses.
  • PD-1 programmed cell death protein 1
  • monoclonal antibodies and other immune-checkpoint inhibitors have opened new avenues in cancer immunology. The failure of a large subset of cancer patients to respond to these new immunotherapies has led to intensified research to find new therapies.
  • compositions that increase CUB domain-containing protein 1 (CDCP1) mediated signal transduction thereby promoting a suppressive immunological response. Such compositions are useful for the treatment of inflammatory diseases and disorders and autoimmune diseases.
  • compositions that inhibit CDCP1 mediated signal transduction to thereby enhance or promote an activating immunological response. Such compositions are useful for the treatment of cancer and infectious diseases.
  • SUMMARY [0006] Compositions and methods of their use for modulating CDCP1 mediated signal transduction are provided.
  • One embodiment provides compositions and 1 064467-020PCT methods that induce, promote, or enhance CDCP1 mediated signal transduction.
  • immunomodulatory agents are provided that induce, promote, or enhance CDCP1 expression, ligand binding, crosslinking, signal transduction, or a combination thereof.
  • Another embodiment provides compositions and methods for inhibiting, reducing, or blocking CDCP1 mediated signal transduction.
  • immunomodulatory agents are provided that inhibit, reduce, or block CDCP1 expression, ligand binding, crosslinking, signal transduction, or a combination thereof.
  • Immunostimulatory agents also referred to as binding moieties
  • the disclosed immunomodulatory agents can be used to modulate an immune response in a subject in need thereof by inducing, promoting, or enhancing CDCP1 mediated signaling.
  • An immune response can be, for example, inducing, promoting, or enhancing Tregs activation or proliferation.
  • the disclosed immunomodulatory agents can be used to modulate an immune response in a subject in need thereof by inhibiting CDCP1 mediated signaling.
  • An immune response can be, for example, inhibiting, reducing, or blocking migration of immunosuppressive regulatory T cells (Tregs) and/or tumor-associated macrophages (TAMs) to the tumor microenvironment, depletion of tumor-resident Tregs, depletion of tumor-resident TAMs, depletion of tumor cells expressing CDCP1, or inhibiting, reducing, or blocking trafficking of Tregs, TAMs, or tumor cells.
  • the disclosed immunomodulatory agents can be used to modulate an immune response in a subject in need thereof by inhibiting CDCP1 mediated signaling to inhibit, reduce, or block tumor metastasis.
  • One embodiment provides an antibody or antigen binding fragment thereof that immunospecifically binds to CDCP1 (any one of SEQ ID NO:1-5) and induces, promotes, or enhances CDCP1 mediated signal transduction.
  • Another embodiment provides and anti-CDCP1 antibody or antigen binding fragment thereof that induces, promotes, or enhances the interaction between CDCP1 and its ligands.
  • Another embodiment provides an antibody or antigen binding fragment thereof that immunospecifically binds to CDCP1 (any one of SEQ ID NO:1-5) and 2 064467-020PCT inhibits, reduces, or blocks CDCP1 mediated signal transduction.
  • the agent is a CDCP1 fusion protein, for example a fusion protein that includes one or more extracellular domains of CDCP1 or functional variant thereof linked to an immunoglobulin domain.
  • An exemplary fusion protein includes the amino acid sequence having at least 80%, 90%, 95%, or 100% sequence identity to SEQ ID NO:1-5 or a fragment thereof.
  • the immunomodulatory agent is a CDCP1 protein (any one of SEQ ID NO:1-5) or a functional fragment or variant thereof.
  • the CDCP1 protein or functional fragment or variant thereof can have at least 80%, 90%, 95%, or 100% sequence identity to any one of SEQ ID NO:1-5.
  • the immunomodulatory agent is a soluble CDCP1 protein or a functional fragment or variant thereof.
  • the soluble CDCP1 protein can consist of one or more extracellular domains of CDCP1or a functional fragment or variant thereof.
  • One embodiment provides an immunomodulatory agent that specifically binds any one of SEQ ID NO:1-5 and modulates CDCP1 mediated signal transduction.
  • Another embodiment provides a fusion protein or an antigen binding fragment thereof comprising a CDCP1 protein having at least 99% sequence identity to SEQ ID NO: 1, 2, 3, 4, 5, or a functional variant thereof and linked to an immunoglobulin domain.
  • Other embodiments provide a fusion protein or an antigen binding fragment thereof having 80%, 85%, 90%, 95%, 99%, or 100% to any one of SEQ ID NO:6-17, wherein the fusion protein inhibits, reduces, or blocks CDCP1 mediated signal transduction.
  • Methods of promoting a suppressive immune response in a subject typically include administering to a subject in need thereof an effective amount of an immunomodulatory agent that induces, promotes, or enhances CDCP1 expression, ligand binding, crosslinking, signal transduction, or a combination thereof.
  • the subject can have, for example, inflammatory disease including, but not limited to autoimmune disease and transplant rejection disease.
  • Methods of increasing an immune response in a subject typically include administering to a subject in need thereof an effective amount of an 3 064467-020PCT immunomodulatory agent that inhibits, reduces, or blocks CDCP1 expression, ligand binding, crosslinking, signal transduction, or a combination thereof.
  • the subject can have, for example, a hyperproliferative disease, cancer or an infectious disease.
  • the subject, the cancer, or the disease is characterized by increased expression of CDCP1, increased expression of a CDCP1 ligand, or a combination thereof.
  • the cancer is any of a variety of cancers or abnormal proliferative growths as listed within this application.
  • the agent can be administered contemporaneously, in alternation, or in combination formulated as a unit dose, optionally with a one or more additional therapeutic agents including but not limited to a vaccine or a component thereof.
  • One embodiment provides an anti-CDCP1 antibody produced by a hybridoma.
  • Another embodiment provides an anti-CDCP1 antibody having at least one light chain or at least one heavy chain of the antibody produced by one or more of hybridomas. [0024] Another embodiment provides an antibody or antigen binding fragment thereof that immunospecifically binds to SEQ ID NO:1, 2, 3, 4, 5, or an ECD thereof.
  • the antibody or antigen binding fragment thereof comprises a variable light chain having at least 99% sequence identity to SEQ ID NO: 27, 31, 32, 42, 46, 47, 57, 61, 62, 72, 75, 76, 86, 90, 91, 100, 104, 105, 115, 119, 120, 130, 133, 134, 144, 148, 149, 159, 163, 164, 174, 178, 179, 284, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 399, 402, 403, 404, 405, 406, 407, 408, 409, 410, 411, 412, 413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, or 427; and a variable light chain having at least
  • Additional embodiments provide the antibody or antigen binding fragment thereof comprising complementarity-determining regions (CDRs) selected from the group of CDRs consisting of at least 99% sequence identity to SEQ ID NOs: 19-21, 28-30, 34-36, 43-45, 49-51, 58-60, 64-66, 73, 74, 78-80, 87-89, 93, 94, 102- 103, 107-109, 116-118, 122-124, 131, 132, 136-138, 145-147, 151-153, 160-162, 166-168, 175-177, 182-183, 190, 258, 259, 266, 285, 310-311, 355-357, 400-401, 428, 429-431, 433, or 434.
  • CDRs complementarity-determining regions
  • a humanized antibody or antigen binding fragment thereof comprising: a heavy chain variable domain of SEQ ID NO:180 and a light chain variable domain of SEQ ID NO:288; a heavy chain variable domain of SEQ ID NO:220 and a light chain variable domain of SEQ ID NO:291; a heavy chain variable domain of SEQ ID NO:180 and a light chain variable domain of SEQ ID NO: 288; a heavy chain variable domain of SEQ ID NO:220 and a light chain variable domain of SEQ ID NO:291); a heavy chain variable domain of SEQ ID NO:189 and a light chain variable domain of SEQ ID NO:288; a heavy chain variable domain of SEQ ID NO:196 and a light chain variable domain of SEQ ID NO:284; a heavy chain variable domain of SEQ ID NO:202 and a light chain variable domain of SEQ ID NO:288; a heavy chain variable domain of SEQ ID NO:208 and a light chain variable domain of SEQ ID NO:297
  • a humanized antibody or antigen binding fragment thereof comprising: a heavy chain variable domain of SEQ ID NO:309 and a light chain variable domain of SEQ ID NO:407; a heavy chain variable domain of 5 064467-020PCT SEQ ID NO:363 and a light chain variable domain of SEQ ID NO:416; a heavy chain variable domain of SEQ ID NO:369 and a light chain variable domain of SEQ ID NO:413; a heavy chain variable domain of SEQ ID NO:375 and a light chain variable domain of SEQ ID NO:413; a heavy chain variable domain of SEQ ID NO:317 and a light chain variable domain of SEQ ID NO:399; a heavy chain variable domain of SEQ ID NO::324 and a light chain variable domain of SEQ ID NO:404; a heavy chain variable domain of SEQ ID NO:330 and a light chain variable domain of SEQ ID NO:404; a heavy chain variable domain of SEQ ID NO:342 and a
  • the cytotoxic payload is selected from a group of therapeutics consisting of auristatins, maytansinoids, DNA alkylating agents, mitotic inhibitors, antitumor antibiotics, immunomodulating agents, gene therapy vectors, alkylating agents, antiangiogenic agents, antimetabolites, boron-containing agents, chemoprotective agents, hormone agents, glucocorticoids, photoactive therapeutic agents, oligonucleotides, radioactive isotopes, radiosensitizers, topoisomerase inhibitors, tyrosine kinase inhibitors, or combinations thereof.
  • compositions comprising an effective amount of the CDCP1 immunomodulatory agent provided herein to modulate CDCP1 expression, ligand binding, crosslinking, CDCP1 mediated signaling, or a combination thereof.
  • the composition further comprises one or more additional therapeutic agents selected from cytokines, chemotherapeutic agents, radionuclides, other immunotherapeutics, enzymes, antibiotics, antivirals, anti- parasitics, growth factors, growth inhibitors, hormones, hormone antagonists, antibodies and bioactive fragments thereof, antigen and vaccine formulations, peptide drugs, anti-inflammatories, ligands that bind to Toll-Like Receptors to activate the innate immune system, molecules that mobilize and optimize the adaptive immune system, other molecules that activate or up-regulate the action of cytotoxic T lymphocytes, natural killer cells and helper T-cells, other molecules that deactivate or down-regulate suppressor or regulatory T-cells, or combinations thereof.
  • the composition is administered with other immunomodulatory agents selected from PD-1 antagonists, CTLA4 antagonists, potentiating agents or other CDCP1 antagonists.
  • the subject or the disease or condition is characterized by increased expression of CDCP1 relative to express of CDCP1 in subjects without the disease or condition.
  • One embodiment provides a method for treating cancer or an infection in a subject in need thereof by administering to the subject an effective amount of a pharmaceutical composition including a CDCP1 monoclonal antibody, soluble 7 064467-020PCT CDCP1 polypeptide, CDCP1 fusion protein, or combinations thereof in an amount effective to inhibit, reduce, or block CDCP1 signal transduction in immune cells.
  • CDCP1 immunomodulatory agents can be used to treat inflammation and or autoimmune disorders, including but not limited CDCP1 fusion proteins.
  • anti-CDCP1 antibodies that bind to ligands of CDCP1 can be used to treat cancer.
  • One embodiment provides a method for assessing or predicting the efficacy of a treatment using an anti-CDCP1 binding moiety by assaying the cells of a subject in need of treatment to determine whether the cells express CDCP1, binding partners of CDCP1, or both.
  • a treatment is effective if it inhibits, reduces, or blocks CDCP1 expression, ligand binding, crosslinking, signal transduction, or a combination thereof.
  • Exemplary cells to be assayed include, but are not limited to, cancer cells obtained from the subjected.
  • Figure 1 shows anti-CDCP1 antibody binding to HCT116 cells.
  • Figure 2 shows cell internalization of the anti-CDCP1 antibodies.
  • Figures 3A-3H show that antibodies derived from the 1E12 and 5B4 hybridomas are internalized into HCT116 and 293T-CDCP1 cells.
  • Figures 4A-4C show cytotoxicity of the 5B4 antibody drug conjugated with exatecan.
  • Figures 5A-5B show Carterra kinetic profiling for binding studies for the variants binding to human and cynomolgus monkey CDCP1 (Carterra, SPR LSA Platform). 8 064467-020PCT
  • Figures 6A-6EE show binding studies for the variants binding to human and cynomolgus monkey CDCP1 using Octet kinetic analysis.
  • DETAILED DESCRIPTION [0047] The present invention may be understood more readily by reference to the following detailed description of preferred embodiments of the invention and the Examples included therein and to the Figures and their previous and following description. I. Definitions [0048] To facilitate an understanding of the principles and features of the various embodiments of the disclosure, various illustrative embodiments are explained herein.
  • Ranges may be expressed herein as from “about” or “approximately” or “substantially” one particular value and/or to “about” or “approximately” or “substantially” another particular value. When such a range is expressed, other exemplary embodiments include from the one particular value and/or to the other particular value.
  • immunomodulatory agent and “binding moiety” are used interchangeably.
  • CDP1 immunomodulatory agent refers to CUB domain-containing protein 1 (CDCP1) binding moieties including, but not limited to antibodies and antigen binding fragments thereof, and CDCP1 fusion proteins and binding fragments thereof.
  • a molecule is said to be able to “immunospecifically bind” a second molecule if such binding exhibits the specificity and affinity of an antibody to its cognate antigen.
  • Antibodies are said to be capable of immunospecifically binding to a target region or conformation (“epitope”) of an antigen if such binding involves the antigen recognition site of the immunoglobulin molecule.
  • An antibody that immunospecifically binds to a particular antigen may bind to other antigens with lower affinity if the other antigen has some sequence or conformational similarity that is recognized by the antigen recognition site as determined by, e.g., immunoassays, BIACORE® assays, or other assays known in the art, but would not bind to a totally unrelated antigen. In some embodiments, however, antibodies (and their antigen binding fragments) will not cross-react with other antigens. Antibodies may also bind to other molecules in a way that is not immunospecific, such as to FcR receptors, by virtue of binding domains in other regions/domains of the molecule that do not involve the antigen recognition site, such as the Fc region.
  • a molecule is said to “bind” a second molecule if such binding exhibits the specificity and affinity of a receptor to its cognate binding ligand.
  • a molecule can be capable of binding to more than one other molecule.
  • the term “antibody” is intended to denote an immunoglobulin molecule that possesses a “variable region” antigen recognition site.
  • the term “variable region” is intended to distinguish such domain of the immunoglobulin from domains that are broadly shared by antibodies (such as an antibody Fc domain).
  • the variable region includes a “hypervariable region” whose residues are responsible for antigen binding.
  • the hypervariable region includes amino acid residues from a “Complementarity Determining Region” or “CDR” (i.e., typically at approximately residues 24-34 (L1), 50-56 (L2) and 89-97 (L3) in the light chain variable domain and at approximately residues 27-35 (H1), 50-65 (H2) and 95- 102 (H3) in the heavy chain variable domain; Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD.
  • CDR Constantarity Determining Region
  • “hypervariable loop” i.e., residues 26-32 (L1), 50-52 (L2) and 91-96 (L3) in the light chain variable domain and 26-32 (H1), 53-55 (H2) and 96-101 (H3) in the heavy chain variable domain; Chothia and Lesk, 1987, J. Mol. Biol.196:901-917).
  • “Framework Region” or “FR” residues are those variable domain residues other than the hypervariable region residues as 10 064467-020PCT herein defined.
  • antibody includes monoclonal antibodies, multi-specific antibodies, human antibodies, humanized antibodies, synthetic antibodies, chimeric antibodies, camelized antibodies (See e.g., Muyldermans et al., 2001, Trends Biochem. Sci.26:230; Nuttall et al., 2000, Cur. Pharm. Biotech.1:253; Reichmann and Muyldermans, 1999, J. Immunol. Meth.231:25; International Publication Nos. WO 94/04678 and WO 94/25591; U.S.
  • antibodies include immunoglobulin molecules of any type (e.g., IgG, IgE, IgM, IgD, IgA and IgY), class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2) or subclass.
  • antigen binding fragment of an antibody refers to one or more portions of an antibody that contain the antibody’s Complementarity Determining Regions (“CDRs”) and optionally the framework residues that include the antibody’s “variable region” antigen recognition site and exhibit an ability to immunospecifically bind antigen.
  • CDRs Complementarity Determining Regions
  • Such fragments include Fab', F(ab') 2 , Fv, single chain (ScFv), and mutants thereof, naturally occurring variants, and fusion proteins including the antibody’s “variable region” antigen recognition site and a heterologous protein (e.g., a toxin, an antigen recognition site for a different antigen, an enzyme, a receptor or receptor ligand, etc.).
  • a heterologous protein e.g., a toxin, an antigen recognition site for a different antigen, an enzyme, a receptor or receptor ligand, etc.
  • fragment refers to a peptide or polypeptide including an amino acid sequence of at least 5 contiguous amino acid residues, at least 10 contiguous amino acid residues, at least 15 contiguous amino acid residues, at least 20 contiguous amino acid residues, at least 25 contiguous amino acid residues, at least 40 contiguous amino acid residues, at least 50 contiguous amino acid residues, at least 60 contiguous amino residues, at least 70 contiguous amino acid residues, at least 80 contiguous amino acid residues, at least 90 contiguous amino acid residues, at least 100 contiguous amino acid residues, at least 125 contiguous amino acid residues, at least 150 contiguous amino acid residues, at least 175 contiguous amino acid residues, at least 200 contiguous amino acid residues, or at least 250 contiguous amino acid residues.
  • modulate relates to a capacity to alter an effect, result, or activity (e.g., signal transduction).
  • modulation can be agonistic or antagonistic.
  • Antagonistic modulation can be partial (i.e., attenuating, but not abolishing) or it can completely abolish such activity (e.g., neutralizing).
  • Modulation can include internalization of a receptor following binding of an antibody or a reduction in expression of a receptor on the target cell.
  • Agonistic modulation can enhance or otherwise increase or enhance an activity (e.g., signal transduction).
  • such modulation can alter the nature of the interaction between a ligand and its cognate receptor so as to alter the nature of the elicited signal transduction.
  • the molecules can, by binding to the ligand or receptor, alter the ability of such molecules to bind to other ligands or receptors and thereby alter their overall activity.
  • such modulation will provide at least a 10% change in a measurable immune system activity, at least a 50% change in such activity, or at least a 2-fold, 5-fold, 10-fold, or at least a 100-fold change in such activity.
  • the term “substantially,” as used in the context of binding or exhibited effect is intended to denote that the observed effect is physiologically or therapeutically relevant.
  • a molecule is able to substantially block an activity of a ligand or receptor if the extent of blockage is physiologically or therapeutically relevant (for example if such extent is greater than 60% complete, greater than 70% complete, greater than 75% complete, greater than 80% complete, greater than 85% complete, greater than 90% complete, greater than 95% complete, or greater than 97% complete).
  • a molecule is said to have substantially the same immunospecificity and/or characteristic as another molecule, if such immunospecificities and characteristics are greater than 60% identical, greater than 70% identical, greater than 75% identical, greater than 80% identical, greater than 85% identical, greater than 90% identical, greater than 95% identical, or greater than 97% identical).
  • the “activating” or “stimulatory” signals encompass signals that result in enhancing an activity or enhancing signal transduction.
  • “suppressive” signals refer to signals that suppress immune activity.
  • derivative refers to an antibody or antigen-binding fragment thereof that immunospecifically binds to the same target of a parent or 12 064467-020PCT reference antibody but which differs in amino acid sequence from the parent or reference antibody or antigen binding fragment thereof by including one, two, three, four, five or more amino acid substitutions, additions, deletions or modifications relative to the parent or reference antibody or antigen binding fragment thereof.
  • such derivatives will have substantially the same immunospecificity and/or characteristics, or the same immunospecificity and characteristics as the parent or reference antibody or antigen binding fragment thereof.
  • the amino acid substitutions or additions of such derivatives can include naturally occurring (i.e., DNA-encoded) or non-naturally occurring amino acid residues.
  • derivatives encompasses, for example, chimeric or humanized variants, as well as variants having altered CH1, hinge, CH2, CH3 or CH4 regions, so as to form, for example antibodies, etc., having variant Fc regions that exhibit enhanced or impaired effector or binding characteristics.
  • a “chimeric antibody” is a molecule in which different portions of the antibody are derived from different immunoglobulin molecules such as antibodies having a variable region derived from a non-human antibody and a human immunoglobulin constant region.
  • the term “humanized antibody” refers to an immunoglobulin including a human framework region and one or more CDR’s from a non-human (usually a mouse or rat) immunoglobulin.
  • the non-human immunoglobulin providing the CDR's is called the “donor” and the human immunoglobulin providing the framework is called the “acceptor.”
  • Constant regions need not be present, but if they are, they should be substantially identical to human immunoglobulin constant regions, i.e., at least about 85-99%, or about 95% or more identical.
  • all parts of a humanized immunoglobulin, except possibly the CDR’s, are substantially identical to corresponding parts of natural human immunoglobulin sequences.
  • a humanized antibody is an antibody including a humanized light chain and a humanized heavy chain immunoglobulin.
  • a humanized antibody would not encompass a typical chimeric antibody, because, e.g., the entire variable region of a chimeric antibody is non-human.
  • endogenous concentration refers to the level at which a molecule is natively expressed (i.e., in the absence of expression vectors or recombinant promoters) by a cell (which cell can be a normal cell, a cancer cell or an infected cell). 13 064467-020PCT [0066]
  • the terms “treat,” “treating,” “treatment” and “therapeutic use” refer to the elimination, reduction or amelioration of one or more symptoms of a disease or disorder.
  • a “therapeutically effective amount” refers to that amount of a therapeutic agent sufficient to mediate a clinically relevant elimination, reduction or amelioration of such symptoms. An effect is clinically relevant if its magnitude is sufficient to impact the health or prognosis of a recipient subject.
  • a therapeutically effective amount may refer to the amount of therapeutic agent sufficient to delay or minimize the onset of disease, e.g., delay or minimize the spread of cancer.
  • a therapeutically effective amount may also refer to the amount of the therapeutic agent that provides a therapeutic benefit in the treatment or management of a disease.
  • prolactic agent refers to an agent that can be used in the prevention of a disorder or disease prior to the detection of any symptoms of such disorder or disease.
  • a “prophylactically effective” amount is the amount of prophylactic agent sufficient to mediate such protection.
  • a prophylactically effective amount may also refer to the amount of the prophylactic agent that provides a prophylactic benefit in the prevention of disease.
  • the term “cancer” refers to a neoplasm or tumor resulting from abnormal uncontrolled growth of cells.
  • the term “cancer” refers to a disease involving cells that have the potential to metastasize to distal sites and exhibit phenotypic traits that differ from those of non-cancer cells, for example, formation of colonies in a three-dimensional substrate such as soft agar or the formation of tubular networks or web-like matrices in a three-dimensional basement membrane or extracellular matrix preparation.
  • Non-cancer cells do not form colonies in soft agar and form distinct sphere-like structures in three-dimensional basement membrane or extracellular matrix preparations.
  • Exemplary cancers that can be treated by the antibody-drug conjugates of the invention include cancers of the gastrointestinal tract (colon carcinoma, rectal carcinoma, colorectal carcinoma, colorectal cancer, colorectal adenoma, hereditary nonpolyposis type 1, hereditary nonpolyposis type 2, hereditary nonpolyposis type 3, hereditary nonpolyposis type 6; colorectal cancer, hereditary nonpolyposis type 7, small and/or large bowel carcinoma, esophageal carcinoma, tylosis with esophageal cancer, stomach carcinoma, pancreatic carcinoma, pancreatic endocrine tumors), endometrial carcinoma, dermatofibrosarcoma protuberans, gallbladder carcinoma, 14 064467-020PCT biliary tract tumors, prostate cancer, prostate adenocarcino
  • the mixture is used to treat eye cancer, e.g., uveal melanoma.
  • an “immune cell” refers to any cell from the hemopoietic origin including, but not limited to, T cells, B cells, monocytes, dendritic cells, and macrophages.
  • inflammatory molecules refer to molecules that result in inflammatory responses including, but not limited to, cytokines and metalloproteases such as including, but not limited to, IL-1 ⁇ , TNF- ⁇ , TGF-beta, IFN- ⁇ , IL-18, IL-17, IL-6, IL-23, IL-22, IL-21, and MMPs.
  • valency refers to the number of binding sites available per molecule.
  • immunological humoral (antibody mediated) and/or a cellular (mediated by antigen-specific T cells or their secretion products) response directed against a peptide in a recipient patient.
  • a response can be an active response induced by administration of immunogen or a passive response induced by administration of antibody or primed T-cells.
  • a cellular immune response is elicited by the presentation of polypeptide epitopes in association with Class I or Class II MHC molecules to activate antigen-specific CD4 + T helper cells and/or CD8 + cytotoxic T cells.
  • the response may also involve activation of monocytes, macrophages, NK cells, basophils, dendritic cells, astrocytes, microglia cells, eosinophils, activation or recruitment of neutrophils or other components of innate immunity.
  • the presence of a cell-mediated immunological response can be determined by proliferation assays (CD4 + T cells) or CTL (cytotoxic T lymphocyte) assays.
  • the relative contributions of humoral and cellular responses to the protective or therapeutic effect of an immunogen can be distinguished by separately isolating antibodies and T-cells from an immunized syngeneic animal and measuring protective or therapeutic effect in a second subject.
  • An “immunogenic agent” or “immunogen” is capable of inducing an immunological response against itself on administration to a mammal, optionally in conjunction with an adjuvant. 16 064467-020PCT
  • the terms “individual,” “host,” “subject,” and “patient” are used interchangeably herein, and refer to a mammal, including, but not limited to, humans, rodents, such as mice and rats, and other laboratory animals.
  • polypeptide refers to a chain of amino acids of any length, regardless of modification (e.g., phosphorylation or glycosylation).
  • the term polypeptide includes proteins and fragments thereof.
  • the polypeptides can be “exogenous,” meaning that they are “heterologous,” i.e., foreign to the host cell being utilized, such as human polypeptide produced by a bacterial cell.
  • Polypeptides are disclosed herein as amino acid residue sequences. Those sequences are written left to right in the direction from the amino to the carboxy terminus.
  • amino acid residue sequences are denominated by either a three letter or a single letter code as indicated as follows: Alanine (Ala, A), Arginine (Arg, R), Asparagine (Asn, N), Aspartic Acid (Asp, D), Cysteine (Cys, C), Glutamine (Gln, Q), Glutamic Acid (Glu, E), Glycine (Gly, G), Histidine (His, H), Isoleucine (Ile, I), Leucine (Leu, L), Lysine (Lys, K), Methionine (Met, M), Phenylalanine (Phe, F), Proline (Pro, P), Serine (Ser, S), Threonine (Thr, T), Tryptophan (Trp, W), Tyrosine (Tyr, Y), and Valine (Val, V).
  • variant refers to a polypeptide or polynucleotide that differs from a reference polypeptide or polynucleotide, but retains essential properties.
  • a typical variant of a polypeptide differs in amino acid sequence from another, reference polypeptide. Generally, differences are limited so that the sequences of the reference polypeptide and the variant are closely similar overall and, in many regions, identical.
  • a variant and reference polypeptide may differ in amino acid sequence by one or more modifications (e.g., substitutions, additions, and/or deletions).
  • a substituted or inserted amino acid residue may or may not be one encoded by the genetic code.
  • a variant of a polypeptide may be naturally occurring such as an allelic variant, or it may be a variant that is not known to occur naturally.
  • Modifications and changes can be made in the structure of the polypeptides of the disclosure and still obtain a molecule having similar characteristics as the polypeptide (e.g., a conservative amino acid substitution). For example, certain amino acids can be substituted for other amino acids in a sequence without appreciable loss of activity. Because it is the interactive capacity and nature of a polypeptide that defines that polypeptide’s biological functional activity, certain 17 064467-020PCT amino acid sequence substitutions can be made in a polypeptide sequence and nevertheless obtain a polypeptide with like properties.
  • the hydropathic index of amino acids can be considered.
  • the importance of the hydropathic amino acid index in conferring interactive biologic function on a polypeptide is generally understood in the art. It is known that certain amino acids can be substituted for other amino acids having a similar hydropathic index or score and still result in a polypeptide with similar biological activity. Each amino acid has been assigned a hydropathic index on the basis of its hydrophobicity and charge characteristics.
  • Those indices are: isoleucine (+4.5); valine (+4.2); leucine (+3.8); phenylalanine (+2.8); cysteine/cystine (+2.5); methionine (+1.9); alanine (+1.8); glycine (-0.4); threonine (-0.7); serine (-0.8); tryptophan (-0.9); tyrosine (-1.3); proline (-1.6); histidine (-3.2); glutamate (-3.5); glutamine (-3.5); aspartate (-3.5); asparagine (-3.5); lysine (-3.9); and arginine (-4.5).
  • the relative hydropathic character of the amino acid determines the secondary structure of the resultant polypeptide, which in turn defines the interaction of the polypeptide with other molecules, such as enzymes, substrates, receptors, antibodies, antigens, and cofactors. It is known in the art that an amino acid can be substituted by another amino acid having a similar hydropathic index and still obtain a functionally equivalent polypeptide. In such changes, the substitution of amino acids whose hydropathic indices are within ⁇ 2 is preferred, those within ⁇ 1 are particularly preferred, and those within ⁇ 0.5 are even more particularly preferred.
  • Substitution of like amino acids can also be made on the basis of hydrophilicity, particularly where the biological functional equivalent polypeptide or peptide thereby created is intended for use in immunological embodiments.
  • the following hydrophilicity values have been assigned to amino acid residues: arginine (+3.0); lysine (+3.0); aspartate (+3.0 ⁇ 1); glutamate (+3.0 ⁇ 1); serine (+0.3); asparagine (+0.2); glutamine (+0.2); glycine (0); proline (-0.5 ⁇ 1); threonine (-0.4); alanine (-0.5); histidine (-0.5); cysteine (-1.0); methionine (-1.3); valine (-1.5); leucine (-1.8); isoleucine (-1.8); tyrosine (-2.3); phenylalanine (-2.5); tryptophan (-3.4).
  • amino acid can be substituted for another having a similar hydrophilicity value and still obtain a biologically equivalent, and in particular, an immunologically equivalent polypeptide.
  • substitution of amino acids whose hydrophilicity values are within ⁇ 2 is preferred, those within ⁇ 1 are particularly preferred, and those within ⁇ 0.5 are even more particularly preferred.
  • amino acid substitutions are generally based on the relative similarity of the amino acid side-chain substituents, for example, their hydrophobicity, hydrophilicity, charge, size, and the like.
  • substitutions that take various foregoing characteristics into consideration are well known to those of skill in the art and include (original residue: exemplary substitution): (Ala: Gly, Ser), (Arg: Lys), (Asn: Gln, His), (Asp: Glu, Cys, Ser), (Gln: Asn), (Glu: Asp), (Gly: Ala), (His: Asn, Gln), (Ile: Leu, Val), (Leu: Ile, Val), (Lys: Arg), (Met: Leu, Tyr), (Ser: Thr), (Thr: Ser), (Trp: Tyr), (Tyr: Trp, Phe), and (Val: Ile, Leu).
  • Embodiments of this disclosure thus contemplate functional or biological equivalents of a polypeptide as set forth above.
  • the polypeptides can include variants having about 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or more sequence identity to the polypeptide of interest.
  • the term “percent (%) sequence identity” is defined as the percentage of nucleotides or amino acids in a candidate sequence that are identical with the nucleotides or amino acids in a reference nucleic acid sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity.
  • Alignment for purposes of determining percent sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN, ALIGN-2 or Megalign (DNASTAR) software. Appropriate parameters for measuring alignment, including any algorithms needed to achieve maximal alignment over the full-length of the sequences being compared can be determined by known methods.
  • the % sequence identity of a given nucleotides or amino acids sequence C to, with, or against a given nucleic acid sequence D is calculated as follows: 100 times the fraction W/Z, where W is the number of nucleotides or amino acids scored as identical matches by the sequence alignment program in that program’s alignment of C and D, and where Z is the total number of nucleotides or amino acids in D. It will be appreciated that where the length of sequence C is not equal to the length of sequence D, the % sequence identity of C to D will not equal the % sequence identity of D to C.
  • compositions that specifically bind to CDCP1 and modulate signal transduction through CDCP1, for example to reduce, inhibit, or block CDCP1 mediated signal transduction in immune cells.
  • Representative immune cells include, but are not limited to, monocytes and T cells.
  • compositions that inhibit, reduce, or block the interaction with CDCP1 with one or more ligands of CDCP1, and thereby reduce, inhibit, or block CDCP1 mediated signal transduction in immune cells.
  • the binding moieties can bind directly to CDCP1 and inhibit, reduce or block the interaction of CDCP1 with one or more of its ligands.
  • the binding moieties specifically bind or to a complex of CDCP1 with one or more ligands.
  • CDCP1 Polypeptides are disclosed as well as binding moieties that specifically bind to CDCP1, for example bind immunospecifically to CDCP1, and inhibit, reduce or block CDCP1 mediated signal transduction in immune cells.
  • CDCP1 binding moiety binds to CDCP1 and inhibits, reduces or blocks the interaction or association of CDCP1 and one or more of ligands of CDCP1.
  • the polypeptides can include an amino acid sequence of full-length CDCP1, or a fragment or variant thereof, or a fusion protein thereof.
  • CDCP1 encodes a transmembrane protein which contains three extracellular CUB domains and acts as a substrate for Src family kinases.
  • CDCP1 is strongly expressed in tumors derived from lung, colon, ovary, or kidney. Although expression and phosphorylation of CDCP1 have been investigated in many tumor cell lines, the CDCP1 features responsible for transformation have not been fully evaluated. 20 064467-020PCT 1. Human CDCP1 [0090] Sequences for human CDCP1 are known in the art.
  • a consensus amino acid sequence for CDCP1 is MAGLNCGVSIALLGVLLLGAARLPRGAEAFEIALPRESNITVLIKLGTPTLLAK PCYIVISKRHITMLSIKSGERIVFTFSCQSPENHFVIEIQKNIDCMSGPCPFGEVQ LQPSTSLLPTLNRTFIWDVKAHKSIGLELQFSIPRLRQIGPGESCPDGVTHSISG RIDATVVRIGTFCSNGTVSRIKMQEGVKMALHLPWFHPRNVSGFSIANRSSIK RLCIIESVFEGEGSATLMSANYPEGFPEDELMTWQFVVPAHLRASVSFLNFNL SNCERKEERVEYYIPGSTTNPEVFKLEDKQPGNMAGNFNLSLQGCDQDAQSP GILRLQFQVLVQHPQNESNKIYVVDLSNERAMSLTIEPRPVKQSRKFVPGCFV CLESRTCSSNLTLTSGSKHKISFLCDDLTRLWMNVEKTISCTDHRYCQ
  • leading methionine is cleaved off in the mature polypeptide (i.e., a post-translationally modified polypeptide).
  • the underlined amino acids 1 – 29 of SEQ ID NO:1 represent the signal peptide of CDCP1. In one embodiment, the signal peptide is cleaved off of the mature protein.
  • the unmarked amino acids 30 – 667 of SEQ ID NO:1 represent the extracellular domain of CDCP1.
  • the double underlined amino acid 668-836 of SEQ ID NO:1 represent the intracellular domain sequence 21 064467-020PCT
  • the CDCP1 binding moieties specifically bind, for example immunospecifically bind to the ECD (amino acids 30 – 667 of SEQ ID NO:1) of human CDCP1 having the following sequence: F EIALPRESNI TVLIKLGTPT 60 70 80 90 100 LLAKPCYIVI SKRHITMLSI KSGERIVFTF SCQSPENHFV IEIQKNIDCM 110 120 130 140 150 SGPCPFGEVQ LQPSTSLLPT LNRTFIWDVK AHKSIGLELQ FSIPRLRQIG 160 170 180 190 200 PGESCPDGVT HSISGRIDAT VVRIGTFCSN GTVSRIKMQE GVKMALHLPW 210 220 230 240 250 FHPRNVSGFS IANRSSIKRL CIIESVFEGE GSATLMSANY PEGFPEDE
  • One embodiment provides human CDCPI isoform 3 having the following sequence: MAGLNCGVSIALLGVLLLGAARLPRGAEAFEIALPRESNITVLIKLGTPTLLAK PCYIVISKRHITMLSIKSGERIVFTFSCQSPENHFVIEIQKNIDCMSGPCPFGEVQ 22 064467-020PCT LQPSTSLLPTLNRTFIWDVKAHKSIGLELQFSIPRLRQIGPGESCPDGVTHSISG RIDATVVRIGTFCSNGTVSRIKMQEGVKMALHLPWFHPRNVSGFSIANRSSIK RLCIIESVFEGEGSATLMSANYPEGFPEDELMTWQFVVPAHLRASVSFLNFNL SNCERKEERVEYYIPGSTTNPEVFKLEDKQPGNMAGNFNLSLQGCDQDAQSP GILRLQFQVLVQHPQNESSE (SEQ ID NO:3) Q9H5V8-3
  • the underlined sequence is the signal sequence.
  • Another embodiment provides an antibody or antigen binding fragment thereof that immunospecifically binds to SEQ ID NO:3 or and ECD thereof.
  • Murine CDCP1 [0098] The amino acid sequence for mouse CDCP1 is: 10 20 30 40 50 MAHSACGFSV ALLGALLLGT ARLLRGTEAS EIALPQRSGV TVSIKLGNPA 60 70 80 90 100 LPVKICYIVM SRQHITELII RPGERKSFTF SCSNPEKHFV LKIEKNIDCM 110 120 130 140 150 SGPCPFGEVH LQPSTSELPI LNRTFIWDVR AHKSIGLELQ FATPRLRQIG 160 170 180 190 200 PGESCADGVT HSISGHIDAT EVRIGTFCSN GTVSRIKMQE GVKMALHLPW 210 220 230 240 250 FHRRNVSGFS IANRSSIKRL CIIESVFEGE GSATLMSANY PGGFPEDELM 260
  • the human sequence for CD6 is 10 20 30 40 50 MWLFFGITGL LTAALSGHPS PAPPDQLNTS SAESELWEPG ERLPVRLTNG 60 70 80 90 100 SSSCSGTVEV RLEASWEPAC GALWDSRAAE AVCRALGCGG AEAASQLAPP 110 120 130 140 150 TPELPPPPAA GNTSVAANAT LAGAPALLCS GAEWRLCEVV EHACRSDGRR 160 170 180 190 200 ARVTCAENRA LRLVDGGGAC AGRVEMLEHG EWGSVCDDTW DLEDAHVVCR 210 220 230 240 250 QLGCGWAVQA LPGLHFTPGR GPIHRDQVNC SGAEAYLWDC PGLPGQHYCG 260 270 280 290 300 24 064467-020PCT HKEDAGAVCS EHQSWRLTGG ADRCEGQVEV HFRGVWNTVC DSEWYPSEAK 310 320 330 340 350 VLCQSLGCGT AVERPKGLPH
  • One embodiment provides an antibody or antigen binding fragment that immunospecifically binds SEQ ID NO: 5.
  • Amino acids 18-402 of SEQ ID NO:5 represent the ECD of human CD6.
  • One embodiment provides an antibody or antigen binding fragment thereof that immunospecifically binds to SEQ ID NO:5.
  • Another embodiment provides an antibody or antigen binding fragment thereof that immunospecifically binds to the ECD of mouse CD6 (amino acids 17-398 of UniProtKB - Q61003 (CD6_MOUSE) which is incorporated by reference in its entirety.
  • C. Immunomodulatory Agents or Binding Moieties [00105] Immunomodulatory agents or binding moieties including agonists and antagonists of CDCP1 are provided.
  • An agonist of CDCP1 typically induces, promotes, or enhances CDCP1 mediated signaling.
  • An antagonist of CDCP1 typically inhibits, reduces, or blocks CDCP1 mediated signaling.
  • the disclosed 25 064467-020PCT compositions and methods can be used to modulate CDCP1 and/or counter-receptor signaling on, for example, immune cells including but not limited to monocytes, Tregs, tumor-associated macrophages (TAMs), Myeloid Derived Suppressor Cells (MDSC), T cells, Th2 cells, myeloid cells including antigen-presenting cells (e.g., monocyte, macrophage, or dendritic cell), T cells, Natural Killer (NK) cells or a combination thereof.
  • immune cells including but not limited to monocytes, Tregs, tumor-associated macrophages (TAMs), Myeloid Derived Suppressor Cells (MDSC), T cells, Th2 cells, myeloid cells including antigen-presenting cells (e.g.
  • the compositions are specifically targeted to one or more cell types. In some embodiments, the disclosed compositions can be used on tumor cells.
  • the anti-CDCP1 agonists induce, promote, or enhance CDCP1 mediated signaling through a known ligand or unknown counter- receptor through CDCP1 interaction with said known or unknown counter-receptor.
  • the CDCP1 agonist binds to, induces, promotes or creates conformation change, or otherwise promotes CDCP1 mediated signal transduction.
  • the anti-CDCP1 antagonists inhibit, reduce, block, or otherwise disrupt signaling through a known or unknown counter-receptor through blockade of CDCP1 interaction with said known or unknown counter-receptor.
  • the CDCP1 antagonist binds to, inhibits, blocks, creates conformation change, or otherwise interferes with CDCP1 mediated signal transduction.
  • the immunomodulatory agent or binding moiety is an antibody. Suitable antibodies can be prepared by one of skill in the art. Nucleic acid and polypeptide sequences for CDCP1 are known in the art and exemplary sequences are provided above.
  • the sequences can be used, as discussed in more detail below, by one of skill in the art to prepare an antibody or antigen binding fragment thereof specific for CDCP1.
  • the antibody or antigen binding fragments therefore, can be an agonist or antagonist of CDCP1 mediated signaling.
  • the activity of an antibody or antigen binding fragment thereof that is specific for CDCP1 can be determined using functional assays that are known in the art, and include the assays discussed below. Typically, the assays include determining if the antibody or antigen binding fragment thereof increases (i.e., agonist) or decreases (i.e., antagonist) signaling through CDCP1.
  • the disclosed antibodies and antigen binding fragments thereof immunospecifically bind to human or mouse CDCP1.
  • the antibody binds to an extracellular domain of human or mouse CDCP1.
  • molecules are provided that can immunospecifically bind to CDCP1: (I) arrayed on the surface of a cell (especially a live cell); (II) arrayed on the surface of a cell (especially a live cell) at an endogenous concentration; (III) arrayed on the surface of a live cell, and modulates binding between CDCP1 and a ligand thereof; (IV) arrayed on the surface of a live cell, and reduces or inhibits immune response by CDCP1; (V) arrayed on the surface of a live cell, wherein the cell is a tumor cell; (VI) combinations of I-IV and V; (VII) combinations of I-III and V; and (VIII) arrayed on the surface of a live my
  • an antibody or antigen binding fragment thereof that specifically binds to CDCP1 purified proteins, polypeptides, fragments, fusions, or epitopes to CDCP1 or polypeptides expressed from nucleic acid sequences thereof, can be used.
  • the antibodies or antigen binding fragments thereof can be prepared using any suitable methods known in the art such as those discussed in more detail below.
  • a. Human and Humanized Antibodies [00113] In some embodiments, the antibodies are humanized antibodies. Many non-human antibodies (e.g., those derived from mice, rats, or rabbits) are naturally antigenic in humans, and thus can give rise to undesirable immune responses when administered to humans.
  • Transgenic animals e.g., mice
  • J(H) antibody heavy chain joining region
  • the antibodies are generated in other species and “humanized” for administration in humans.
  • Humanized forms of non-human (e.g., murine) antibodies are chimeric immunoglobulins, immunoglobulin chains or fragments thereof (such as Fv, Fab, Fab’, F(ab’) 2 , or other antigen-binding subsequences of antibodies) which contain minimal sequence derived from non- human immunoglobulin.
  • Humanized antibodies include human immunoglobulins (recipient antibody) in which residues from a complementarity determining region (CDR) of the recipient antibody are replaced by residues from a CDR of a non-human species (donor antibody) such as mouse, rat or rabbit having the desired specificity, affinity and capacity.
  • CDR complementarity determining region
  • Fv framework residues of the human immunoglobulin are replaced by corresponding non-human residues.
  • Humanized antibodies may also contain residues that are found neither in the recipient antibody nor in the imported CDR or framework sequences.
  • the humanized antibody will contain substantially all of at least one, and typically two, variable domains, in which all or substantially all, of the CDR regions correspond to those of a non-human immunoglobulin and all or substantially all of the FR regions are those of a human immunoglobulin consensus sequence.
  • the humanized antibody optimally also will contain at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin.
  • Fc immunoglobulin constant region
  • a humanized antibody has one or more amino acid residues introduced into it from a source that is non-human. These non-human amino acid residues are often referred to as “import” residues, which are typically taken from an “import” variable domain.
  • Antibody humanization techniques generally involve the use of recombinant DNA technology to manipulate the DNA sequence encoding one or more polypeptide chains of an antibody molecule. Humanization can be essentially performed by substituting rodent CDRs or CDR sequences for the corresponding sequences of a human antibody.
  • a humanized form of a nonhuman 28 064467-020PCT antibody is a chimeric antibody or fragment, wherein substantially less than an intact human variable domain has been substituted by the corresponding sequence from a non-human species.
  • humanized antibodies are typically human antibodies in which some CDR residues and possibly some FR residues are substituted by residues from analogous sites in rodent antibodies.
  • the choice of human variable domains, both light and heavy, to be used in making the humanized antibodies is very important in order to reduce antigenicity. According to the “best-fit” method, the sequence of the variable domain of a rodent antibody is screened against the entire library of known human variable domain sequences.
  • human sequence which is closest to that of the rodent is then accepted as the human framework (FR) for the humanized antibody.
  • Another method uses a particular framework derived from the consensus sequence of all human antibodies of a particular subgroup of light or heavy chains. The same framework may be used for several different humanized antibodies.
  • FR human framework
  • Another method uses a particular framework derived from the consensus sequence of all human antibodies of a particular subgroup of light or heavy chains. The same framework may be used for several different humanized antibodies.
  • FR human framework
  • the antibody can be bound to a substrate or labeled with a detectable moiety or both bound and labeled.
  • the detectable moieties contemplated with the present compositions include fluorescent, enzymatic and radioactive markers. 29 064467-020PCT b.
  • the antibodies are single-chain antibodies.
  • Methods for the production of single-chain antibodies are well known to those of skill in the art.
  • a single chain antibody is created by fusing together the variable domains of the heavy and light chains using a short peptide linker, thereby reconstituting an antigen binding site on a single molecule.
  • Single-chain antibody variable fragments (scFvs) in which the C-terminus of one variable domain is tethered to the N-terminus of the other variable domain via a 15 to 25 amino acid peptide or linker have been developed without significantly disrupting antigen binding or specificity of the binding.
  • the antibodies are monovalent antibodies.
  • In vitro methods are also suitable for preparing monovalent antibodies. Digestion of antibodies to produce fragments thereof, particularly, Fab fragments, can be accomplished using routine techniques known in the art. For instance, digestion can be performed using papain. Papain digestion of antibodies typically produces two identical antigen binding fragments, called Fab fragments, each with a single antigen binding site, and a residual Fc fragment.
  • the F(ab’)2 fragment is a bivalent fragment comprising two Fab’ fragments linked by a disulfide bridge at the hinge region.
  • Fab’-SH is the designation herein for Fab’ in which the cysteine residue(s) of the constant domains bear a free thiol group.
  • Antibody fragments originally were produced as pairs of Fab’ fragments which have hinge cysteines between them. Other chemical couplings of antibody fragments are also known. 30 064467-020PCT d.
  • Hybrid Antibodies [00123] In some embodiments, the antibodies are hybrid antibodies. In hybrid antibodies, one heavy and light chain pair is homologous to that found in an antibody raised against one epitope, while the other heavy and light chain pair is homologous to a pair found in an antibody raised against another epitope.
  • hybrids can be formed by fusion of hybridomas producing the respective component antibodies, or by recombinant techniques. Such hybrids may, of course, also be formed using chimeric chains.
  • Conjugates or Fusions of Antibody Fragments [00124]
  • the immunomodulatory agents are conjugates or fusions of antibody fragments.
  • the targeting function of the antibody can be used therapeutically by coupling the antibody or a fragment thereof with a therapeutic agent.
  • Such coupling of the antibody or fragment (e.g., at least a portion of an immunoglobulin constant region (Fc)) with the therapeutic agent can be achieved by making an immunoconjugate or by making a fusion protein, comprising the antibody or antibody fragment and the therapeutic agent.
  • Such coupling of the antibody or fragment with the therapeutic agent can be achieved by making an immunoconjugate or by making a fusion protein, or by linking the antibody or fragment to a nucleic acid such as an siRNA, comprising the antibody or antibody fragment and the therapeutic agent.
  • the antibody is modified to alter its half-life. In some embodiments, it is desirable to increase the half-life of the antibody so that it is present in the circulation or at the site of treatment for longer periods of time.
  • Antibodies can be engineered with Fc variants that extend half-life, e.g., using XtendTM antibody half-life prolongation technology (Xencor, Monrovia, CA). In other embodiments, the half-life of the anti-DNA antibody is decreased to reduce potential side effects.
  • the conjugates disclosed can be used for modifying a given biological response.
  • the drug moiety is not to be construed as limited to classical chemical therapeutic agents.
  • the drug moiety may be a protein or polypeptide possessing a desired biological activity.
  • Antibody-drug conjugates (ADC) of the invention are comprised of an anti- CDCP1 antibody, a cytotoxin and a linker.
  • Antibodies are comprised of light and heavy chains. Each chain is comprised of a variable domain and a constant domain.
  • the constant domain of the light chain can be kappa or lamba sequences as are well known in the art.
  • the heavy chain constant domain is comprised of a first constant domain, a hinge and an Fc domain.
  • Antibodies come in 5 classes, as determined by their sequences.
  • the classes are IgA, IgD, IgE, IgG and IgM.
  • the IgG antibodies comprise 4 subclasses, including IgG1, IgG2, IgG3 and IgG4.
  • the antibody-drug conjugates of the invention are typically of the IgG class and more typically either IgG1 or IgG4. If the IgG1 classes are utilized, the constant domain sequence can be wild type or contain specific mutations to reduce the binding to Fc gamma receptors.
  • Antibody-drug conjugates also encompass antibody fragments thereof, including antigen biding fragments, scFv, diabodies, single domain antibodies and nanobodies directed to CDCP1 and a linker that links a payload to the antibody.
  • the linker can be conjugated to the antibody by means well known in the art.
  • stochastic conjugation may be used to attach the linker to cysteine residues within the antibody.
  • Other means include site specific conjugation, where a specific sequence is added to either the heavy chain or light chain and will serve as linker location.
  • Examples include CAAX, as described in WO 2012/153193 and WO 2023/194800, wherein C is a cysteine residue, A is an aliphatic amino acid, and X is selected from glutamine, glutamate, serine, cysteine, methionine, alanine, and leucine.
  • An exemplary CAAX sequence is CVIM.
  • a preferred site-specific linker sequence is CVIM, which can be attached to the C-terminus of the light chain via a short spacer comprised of a series of 4, 5, 6, 7, 8, or more glycine residues.
  • a preferred spacer is a series of 7 glycine residues.
  • One embodiment provides an anti-CDCP1 antibody produced by a hybridoma selected from the group consisting of 1E12, 1H11, 3C7, 3D7, 3H8, 4B12, 4G11, 5B4, 5B8, 5B8, and 6A3.
  • Another embodiment provides an anti-CDCP1 antibody having at least one light chain or at least one heavy chain of the antibody produced by one or more of the hybridomas selected from the group consisting of 1E12, 1H11, 3C7, 3D7, 3H8, 4B12, 4G11, 5B4, 5B8, 5B8, and 6A3.
  • Another embodiment provides an anti-CDCP1 antibody having a variable light chain having at least 50, 60, 70, 80, 85, 90, 95, 96, 97, 98, 99, or 100% sequence identity to a variable light chain having an amino acid sequence according to SEQ ID NO: 27, 31, 32, 42, 46, 47, 57, 61, 62, 72, 75, 76, 86, 90, 91, 100, 104, 105, 115, 119, 120, 130, 133, 134, 144, 148, 149, 159, 163, 164, 174, 178, or 179.
  • Another embodiment provides an anti-CDCP1 antibody having a variable heavy chain having at least 50, 60, 70, 80, 85, 90, 95, 96, 97, 98, 99, or 100% sequence identity to a variable heavy chain having an amino acid sequence according to SEQ ID NO: 18, 22, 23, 24, 25, 26, 33, 37, 38, 39, 40, 41, 48, 49, 52, 53, 55, 56, 63, 67, 68, 69, 70, 71, 77, 81, 82, 83, 84, 85, 92, 95, 96, 97, 98, 99, 106, 110, 111, 112, 113, 114, 121, 125, 126, 127, 128, 129, 135, 139, 140, 141, 142, 143, 150, 154, 155, 156, 157, 158, 165, 169, 170, 171, 172, or 173.
  • Another embodiment provides an anti-CDCP1 antibody having a variable light chain having at least 50, 60, 70, 80, 85, 90, 95, 96, 97, 98, 99, or 100% sequence identity to a variable light chain having an amino acid sequence according to SEQ ID NO: 27, 31, 32, 42, 46, 47, 57, 61, 62, 72, 75, 76, 86, 90, 91, 100, 104, 105, 115, 119, 120, 130, 133, 134, 144, 148, 149, 159, 163, 164, 174, 178, or 179., and a variable heavy chain having at least 50, 60, 70, 80, 85, 90, 95, 96, 97, 98, 99, or 100% sequence identity to an amino acid sequence according to SEQ ID NO: 18, 22, 23, 24, 25, 26, 33, 37, 38, 39, 40, 41, 48, 49, 52, 53, 55, 56, 63, 67, 68, 69, 70, 71, 77
  • Another embodiment provides an anti-CDCP1 antibody having a complementarity-determining region (CDR) selected from the group of CDRs having an amino acid sequence selected from the group consisting of SEQ ID NOs: 19-21, 28-30, 34-36, 43-45, 49-51, 58-60, 64-66, 73, 74, 78-80, 87-89, 93, 94, 102-103, 107- 109, 116-118, 122-124, 131, 132, 136-138, 145-147, 151-153, 160-162, 166-168, and 175-177.
  • CDR complementarity-determining region
  • Another embodiment provides an anti-CDCP1 antibody having a plurality of CDRs selected from the group consisting of SEQ ID NOs: 19-21, 28-30, 34-36, 43-45, 49-51, 58-60, 64-66, 73, 74, 78-80, 87-89, 93, 94, 102-103, 107-109, 116-118, 122-124, 131, 132, 136-138, 145-147, 151-153, 160-162, 166-168, and 175- 177.
  • the plurality of CDRs can be from 2 -12.
  • a.1E12 Sequences i.1E12 Heavy Chain aa.1E12 Murine heavy chain variable region [00139]
  • One embodiment provides a 1E12 murine heavy chain variable region having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: EVQLQQSGAELVRPGASVKLSCTASGFNIKDGHMHWVMQRPEQGLEWIGW IDPENGDLEYASKFQGKATLTADTSSNTAYLQLSSLTSEDTAVYYCTTSRRG YFFDYWGQGTTLTVSS (SEQ ID NO: 18), with [00140] 1E12 CDRH1: DGHMH (SEQ ID NO: 19), [00141] 1E12 CDRH2: WIDPENGDLEYASKFQG (SEQ ID NO: 20), [00142] 1E12 CDRH3: SRRGYFFDY (SEQ ID NO: 21).
  • bb.1E12 Chimeric Heavy Chain, human wild type IgG1 constant domains [00143]
  • One embodiment provides a 1E12 chimeric heavy chain, human wild type IgG1 constant domain having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: EVQLQQSGAELVRPGASVKLSCTASGFNIKDGHMHWVMQRPEQGLEWIGWI DPENGDLEYASKFQGKATLTADTSSNTAYLQLSSLTSEDTAVYYCTTSRRGY FFDYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVT VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSN TKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV 34 064467-020PCT VVDVSHEDPEVK
  • the italicized sequence is the heavy chain constant domain (wild type).
  • cc.1E12 Chimeric Heavy Chain, human IgG1 constant domains DLE
  • One embodiment provides a 1E12 chimeric heavy chain, human IgG1 constant domain (DLE) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: EVQLQQSGAELVRPGASVKLSCTASGFNIKDGHMHWVMQRPEQGLEWIGW IDPENGDLEYASKFQGKATLTADTSSNTAYLQLSSLTSEDTAVYYCTTSRRG YFFDYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPV TVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPS NTKVDKKVEPKSCDKTHTCPPCPAPELLGGPDVFLFPPKPKDTLMISRTPE
  • the italicized sequence is the heavy chain constant domain with aspartic acid (D), leucine (L), and glutamic acid (E) mutations.
  • dd.1E12 Chimeric Heavy Chain, human IgG1 constant domains (FES) [00153]
  • One embodiment provides a 1E12 chimeric heavy chain, human IgG1 constant domain (FES) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: EVQLQQSGAELVRPGASVKLSCTASGFNIKDGHMHWVMQRPEQGLEWIGW IDPENGDLEYASKFQGKATLTADTSSNTAYLQLSSLTSEDTAVYYCTTSRRG 35 064467-020PCT YFFDYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPV TVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNV
  • the underlined and italicized sequence is the heavy chain constant domain with phenylalanine (F), glutamic acid (E), and serine (S) and mutations.
  • ee.1E12 Chimeric Heavy Chain, human IgG1 constant domains (AA) [00158]
  • One embodiment provides a 1E12 chimeric heavy chain, human IgG1 constant domain (AA) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: EVQLQQSGAELVRPGASVKLSCTASGFNIKDGHMHWVMQRPEQGLEWIGW IDPENGDLEYASKFQGKATLTADTSSNTAYLQLSSLTSEDTAVYYCTTSRRG YFFDYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPV TVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPS NTK
  • the dot underlined sequence is the heavy chain constant domain with alanine-alanine (AA) mutations.
  • G4P human IgG4 constant domain
  • One embodiment provides a 1E12 chimeric heavy chain, human IgG4 constant domain (G4P) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: EVQLQQSGAELVRPGASVKLSCTASGFNIKDGHMHWVMQRPEQGLEWIGW IDPENGDLEYASKFQGKATLTADTSSNTAYLQLSSLTSEDTAVYYCTTSRRG YFFDYWGQGTTLTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPV TVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVD
  • the dash underlined sequence is the IgG4 heavy chain constant domain.
  • ii.1E12 Light Chain aa.1E12 Murine light chain variable region One embodiment provides a 1E12 murine light chain variable region having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: DIQMTQTTPSLSASLGDRVTISCRASQDINNYLNWYQQKPDGTVKLLIYYTS RLHSGVPSRFSGSGSGTDYSLTISNLEQEDIAAYFCQQGNTLPWTFGGGTKL EIK (SEQ ID NO: 27) with [00169] CDRL1: RASQDINNYLN (SEQ ID NO: 28), [00170] CDRL2: YTSRLHS (SEQ ID NO: 29), [00171] CDRL3: QQGNTLPWT (SEQ ID NO: 30).
  • bb.1E12 Chimeric Light Chain, human kappa wild type constant domain [00172]
  • One embodiment provides a 1E12 human chimeric Light Chain, human kappa wild type constant domain having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: 37 064467-020PCT DIQMTQTTPSLSASLGDRVTISCRASQDINNYLNWYQQKPDGTVKLLIYYTS RLHSGVPSRFSGSGSGTDYSLTISNLEQEDIAAYFCQQGNTLPWTFGGGTKL EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSG NSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFN RGEC (SEQ ID NO: 31) with [00173] CDRL1: RASQDINNYLN (SEQ ID
  • the underlined sequence is the light chain constant domain (wild type, kappa).
  • cc. Chimeric Light Chain, human kappa wild type constant domain (CAAX) [00177]
  • One embodiment provides a 1E12 human chimeric Light Chain, human kappa wild type constant domain (CAAX) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: DIQMTQTTPSLSASLGDRVTISCRASQDINNYLNWYQQKPDGTVKLLIYYTS RLHSGVPSRFSGSGSGTDYSLTISNLEQEDIAAYFCQQGNTLPWTFGGGTKL EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSG NSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFN RGECGGGGGGGCVIM (SEQ ID
  • HC-1 variable region having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: EVQLVQSGAEVKKPGATVKISCKVSGFNIKDGYMHWVQQAPGKGLEWMGL VDPENGDTIYAEKFQGRVTITADTSTDTAYMELSSLRSEDTAVYYCATSRRG YFFDYWGQGTLVTVSS (SEQ ID NO:180) with [00182] CDR-H1 GFNIKDGY (SEQ ID NO:181), 38 064467-020PCT [00183] CDR-H2 VDPENGDT (SEQ ID NO:182), [00184] CDR-H3 ATSRRGYFFDY (SEQ ID NO:183).
  • bb.1E12 Humanized HC-1, human wild type IgG1 constant domains [00185]
  • One embodiment provides a 1E12 humanized HC-1, human wild type IgG1 constant domain having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: EVQLVQSGAEVKKPGATVKISCKVSGFNIKDGYMHWVQQAPGKGLEWMGL VDPENGDTIYAEKFQGRVTITADTSTDTAYMELSSLRSEDTAVYYCATSRRG YFFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPV TVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPS NTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC VVVDVSHEDPEVKFNWYVDGVEVHNAKTK
  • cc.1E12 Humanized HC-1, human IgG1 constant domains (DLE) [00186]
  • One embodiment provides a 1E12 humanized HC-1, human IgG1 constant domain (DLE) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: EVQLVQSGAEVKKPGATVKISCKVSGFNIKDGYMHWVQQAPGKGLEWMGL VDPENGDTIYAEKFQGRVTITADTSTDTAYMELSSLRSEDTAVYYCATSRRG YFFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPV TVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPS NTKVDKKVEPKSCDKTHTCPPCPAPELLGGPDVFLFPPKPKDTLMISRTPEVT CVVVDVSHEDPEVKFNWYVDGVEVH
  • One embodiment provides a 1E12 humanized HC-1, human IgG1 constant domain (FES) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: EVQLVQSGAEVKKPGATVKISCKVSGFNIKDGYMHWVQQAPGKGLEWMGL VDPENGDTIYAEKFQGRVTITADTSTDTAYMELSSLRSEDTAVYYCATSRRG YFFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPV TVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPS NTKVDKKVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTC VVVDVSHEDPEVKFN
  • One embodiment provides a 1E12 humanized HC-1, human IgG1 constant domain (AA) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: EVQLVQSGAEVKKPGATVKISCKVSGFNIKDGYMHWVQQAPGKGLEWMGL VDPENGDTIYAEKFQGRVTITADTSTDTAYMELSSLRSEDTAVYYCATSRRG YFFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPV TVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPS NTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVT CVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPRE
  • One embodiment provides a 1E12 humanized HC-1, human IgG4 constant domain (G4P) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: 40 064467-020PCT EVQLVQSGAEVKKPGATVKISCKVSGFNIKDGYMHWVQQAPGKGLEWMGL VDPENGDTIYAEKFQGRVTITADTSTDTAYMELSSLRSEDTAVYYCATSRRG YFFDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPV TVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPS NTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVV DVSQEDPEVQFN
  • HC-2 variable region having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: EVQLVQSGAEVKKPGATVKISCKVSGYTFTDGHMHWVQQAPGKGLEWMG WIDPENGDLEYASKFQGRVTITADTSTDTAYMELSSLRSEDTAVYYCATSRR GYFFDYWGQGTLVTVSS (SEQ ID NO:189) with [00191] CDR-H1 GYTFTDGH (SEQ ID NO:190), [00192] CDR-H2 IDPENGDL (SEQ ID NO:428), [00193] CDR-H3 ATSRRGYFFDY (SEQ ID NO:183).
  • bb.1E12 Humanized HC-2 human wild type IgG1 constant domains
  • One embodiment provides a 1E12 humanized HC-2, human wild type IgG1 constant domain having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: EVQLVQSGAEVKKPGATVKISCKVSGYTFTDGHMHWVQQAPGKGLEWMG WIDPENGDLEYASKFQGRVTITADTSTDTAYMELSSLRSEDTAVYYCATSRR GYFFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEP VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKP SNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVT CVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQY
  • One embodiment provides a 1E12 humanized HC-2, human IgG1 constant domain (DLE) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: EVQLVQSGAEVKKPGATVKISCKVSGYTFTDGHMHWVQQAPGKGLEWMG WIDPENGDLEYASKFQGRVTITADTSTDTAYMELSSLRSEDTAVYYCATSRR GYFFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEP VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKP SNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPDVFLFPPKPKDTLMISRTPEVT CVVVDVSHEDPEVKFNW
  • dd.1E12 Humanized HC-2, human IgG1 constant domains [00196]
  • One embodiment provides a 1E12 humanized HC-2, human IgG1 constant domain (FES) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: EVQLVQSGAEVKKPGATVKISCKVSGYTFTDGHMHWVQQAPGKGLEWMG WIDPENGDLEYASKFQGRVTITADTSTDTAYMELSSLRSEDTAVYYCATSRR GYFFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEP VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKP SNTKVDKKVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVT CVVVDVSHEDPEVKFNWYVDGVEVHNAKTK
  • One embodiment provides a 1E12 humanized HC-2, human IgG1 constant domain (AA) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: 42 064467-020PCT EVQLVQSGAEVKKPGATVKISCKVSGYTFTDGHMHWVQQAPGKGLEWMG WIDPENGDLEYASKFQGRVTITADTSTDTAYMELSSLRSEDTAVYYCATSRR GYFFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEP VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKP SNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEV TCVVVDVSHEDPEVKFNWY
  • One embodiment provides a 1E12 humanized HC-2, human IgG4 constant domain (G4P) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: EVQLVQSGAEVKKPGATVKISCKVSGYTFTDGHMHWVQQAPGKGLEWMG WIDPENGDLEYASKFQGRVTITADTSTDTAYMELSSLRSEDTAVYYCATSRR GYFFDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEP VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKP SNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVV VDVSQEDPEVQFNWYVDGVEVHNAK
  • HC-3) aa.1E12 Humanized Heavy Chain 3 (HC-3) aa.1E12 Humanized HC-3 Variable Domain
  • 1E12 humanized HC-3 variable region having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: EVQLVQSGAEVKKPGATVKISCKVSGFNIKDGHMHWVQQAPGKGLEWMGLI DPENGDLIYAEKFQGRVTITADTSTDTAYMELSSLRSEDTAVYYCTTSRRGYF FDYWGQGTLVTVSS (SEQ ID NO: 196) with [00200] CDR-H1 GFNIKDGH (SEQ ID NO:429), [00201] CDR-H2 IDPENGDL (SEQ ID NO:430), [00202] CDR-H3 TTSRRGYFFDY (SEQ ID NO:431).
  • bb.1E12 Humanized HC-3 human wild type IgG1 constant domains
  • One embodiment provides a 1E12 humanized HC-3, human wild type IgG1 constant domain having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: EVQLVQSGAEVKKPGATVKISCKVSGFNIKDGHMHWVQQAPGKGLEWMGLI DPENGDLIYAEKFQGRVTITADTSTDTAYMELSSLRSEDTAVYYCTTSRRGYF FDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTV SWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNT KVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV VVDVSHEDPEVKFNWYVDG
  • cc.1E12 Humanized HC-3, human IgG1 constant domains (DLE) [00204]
  • One embodiment provides a 1E12 humanized HC-3, human IgG1 constant domain (DLE) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: EVQLVQSGAEVKKPGATVKISCKVSGFNIKDGHMHWVQQAPGKGLEWMGLI DPENGDLIYAEKFQGRVTITADTSTDTAYMELSSLRSEDTAVYYCTTSRRGYF FDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTV SWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNT KVDKKVEPKSCDKTHTCPPCPAPELLGGPDVFLFPPKPKDTLMISRTPEVTCV VVDVSHEDPEVKFNWYVDGVEV
  • dd.1E12 Humanized HC-3, human IgG1 constant domains [00205]
  • One embodiment provides a 1E12 humanized HC-3, human IgG1 constant domain (FES) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: 44 064467-020PCT EVQLVQSGAEVKKPGATVKISCKVSGFNIKDGHMHWVQQAPGKGLEWMGLI DPENGDLIYAEKFQGRVTITADTSTDTAYMELSSLRSEDTAVYYCTTSRRGYF FDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTV SWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNT KVDKKVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCV VVDVSHEDPEVKFN
  • One embodiment provides a 1E12 humanized HC-3, human IgG1 constant domain (AA) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: EVQLVQSGAEVKKPGATVKISCKVSGFNIKDGHMHWVQQAPGKGLEWMGLI DPENGDLIYAEKFQGRVTITADTSTDTAYMELSSLRSEDTAVYYCTTSRRGYF FDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTV SWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNT KVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCV VVDVSHEDPEVKFNWYVDGVEVHNAKTKP
  • One embodiment provides a 1E12 humanized HC-3, human IgG4 constant domain (G4P) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: EVQLVQSGAEVKKPGATVKISCKVSGFNIKDGHMHWVQQAPGKGLEWMGLI DPENGDLIYAEKFQGRVTITADTSTDTAYMELSSLRSEDTAVYYCTTSRRGYF FDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTV SWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNT KVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVD VSQEDPEVQFNWYVDGVEVH
  • HC-4 Humanized Heavy Chain 4
  • HC-4 Variable Domain a 1E12 humanized HC-4 variable region having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: EVQLVQSGAEVKKPGATVKISCTASGFNIKDGHMHWVQQAPGKGLEWMGW IDPENGDLEYAEKFQGRVTITADTSTDTAYMELSSLRSEDTAVYYCTTSRRGY FFDYWGQGTLVTVSS (SEQ ID NO: 202) with [00209] CDR-H1 GFNIKDGH (SEQ ID NO:429), [00210] CDR-H2 IDPENGDL (SEQ ID NO:430), [00211] CDR-H3 TTSRRGYFFDY (SEQ ID NO:431).
  • bb.1E12 Humanized HC-4 human wild type IgG1 constant domains
  • One embodiment provides a 1E12 humanized HC-4, human wild type IgG1 constant domain having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: EVQLVQSGAEVKKPGATVKISCTASGFNIKDGHMHWVQQAPGKGLEWMGW IDPENGDLEYAEKFQGRVTITADTSTDTAYMELSSLRSEDTAVYYCTTSRRGY FFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVT VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSN TKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQ
  • cc.1E12 Humanized HC-4, human IgG1 constant domains (DLE) [00213]
  • One embodiment provides a 1E12 humanized HC-4, human IgG1 constant domain (DLE) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: 46 064467-020PCT EVQLVQSGAEVKKPGATVKISCTASGFNIKDGHMHWVQQAPGKGLEWMGW IDPENGDLEYAEKFQGRVTITADTSTDTAYMELSSLRSEDTAVYYCTTSRRGY FFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVT VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSN TKVDKKVEPKSCDKTHTCPPCPAPELLGGPDVFLFPPKPKDTLMISRTPEVTC VVVDVS
  • dd.1E12 Humanized HC-4, human IgG1 constant domains [00214]
  • One embodiment provides a 1E12 humanized HC-4, human IgG1 constant domain (FES) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: EVQLVQSGAEVKKPGATVKISCTASGFNIKDGHMHWVQQAPGKGLEWMGW IDPENGDLEYAEKFQGRVTITADTSTDTAYMELSSLRSEDTAVYYCTTSRRGY FFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVT VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSN TKVDKKVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCV VVDVSHEDPEVKFNWYVDGVEVHNAK
  • One embodiment provides a 1E12 humanized HC-4, human IgG1 constant domain (AA) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: EVQLVQSGAEVKKPGATVKISCTASGFNIKDGHMHWVQQAPGKGLEWMGW IDPENGDLEYAEKFQGRVTITADTSTDTAYMELSSLRSEDTAVYYCTTSRRGY FFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVT VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSN TKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTC VVVDVSHEDPEVKFNWYVDGVEVHNAK
  • One embodiment provides a 1E12 humanized HC-4, human IgG4 constant domain (G4P) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: EVQLVQSGAEVKKPGATVKISCTASGFNIKDGHMHWVQQAPGKGLEWMGW IDPENGDLEYAEKFQGRVTITADTSTDTAYMELSSLRSEDTAVYYCTTSRRGY FFDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVT VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSN TKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVD VSQEDPEVQFNWYVDGVEVH
  • v.1E12 Humanized Heavy Chain 5 (HC-5) aa.1E12 Humanized HC-5 Variable Domain
  • One embodiment provides a 1E12 humanized HC-5 variable region having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: EVQLVQSGAEVKKPGATVKISCKVSGFNIKDGHMHWVQQAPGKGLEWIGWI DPENGDLEYASKFQGRATLTADTSTDTAYMELSSLRSEDTAVYYCTTSRRGY FFDYWGQGTLVTVSS (SEQ ID NO: 208) with [00218] CDR-H1 GFNIKDGH (SEQ ID NO:429), [00219] CDR-H2 IDPENGDL (SEQ ID NO:430), [00220] CDR-H3 TTSRRGYFFDY (SEQ ID NO:431).
  • bb.1E12 Humanized HC-5, human wild type IgG1 constant domains [00221]
  • One embodiment provides a 1E12 humanized HC-5, human wild type IgG1 constant domain having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: 48 064467-020PCT EVQLVQSGAEVKKPGATVKISCKVSGFNIKDGHMHWVQQAPGKGLEWIGWI DPENGDLEYASKFQGRATLTADTSTDTAYMELSSLRSEDTAVYYCTTSRRGY FFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVT VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSN TKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV VVDVSHEDPEVK
  • cc.1E12 Humanized HC-5, human IgG1 constant domains (DLE) [00222]
  • One embodiment provides a 1E12 humanized HC-5, human IgG1 constant domain (DLE) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: EVQLVQSGAEVKKPGATVKISCKVSGFNIKDGHMHWVQQAPGKGLEWIGWI DPENGDLEYASKFQGRATLTADTSTDTAYMELSSLRSEDTAVYYCTTSRRGY FFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVT VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSN TKVDKKVEPKSCDKTHTCPPCPAPELLGGPDVFLFPPKPKDTLMISRTPEVTC VVVDVSHEDPEVKFNWYVDG
  • dd.1E12 Humanized HC-5, human IgG1 constant domains [00223]
  • One embodiment provides a 1E12 humanized HC-5, human IgG1 constant domain (FES) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: EVQLVQSGAEVKKPGATVKISCKVSGFNIKDGHMHWVQQAPGKGLEWIGWI DPENGDLEYASKFQGRATLTADTSTDTAYMELSSLRSEDTAVYYCTTSRRGY FFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVT VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSN TKVDKKVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCV VVDVSHEDPEVKFNWYVDGVEVH
  • ee.1E12 Humanized HC-5, human IgG1 constant domains [00224]
  • One embodiment provides a 1E12 humanized HC-5, human IgG1 constant domain (AA) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: EVQLVQSGAEVKKPGATVKISCKVSGFNIKDGHMHWVQQAPGKGLEWIGWI DPENGDLEYASKFQGRATLTADTSTDTAYMELSSLRSEDTAVYYCTTSRRGY FFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVT VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSN TKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTC VVVDVSHEDPEVKFNWYVDGVEVHNAK
  • One embodiment provides a 1E12 humanized HC-5, human IgG4 constant domain (G4P) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: EVQLVQSGAEVKKPGATVKISCKVSGFNIKDGHMHWVQQAPGKGLEWIGWI DPENGDLEYASKFQGRATLTADTSTDTAYMELSSLRSEDTAVYYCTTSRRGY FFDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVT VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSN TKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVD VSQEDPEVQFNWYVDGVEV
  • HC-6 variable region having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: EVQLVESGGGLVQPGGSLRLSCAVSGFNIKDGHMHWIRQAPGKGLEWVAWI DPENGDLEYASKFQGRITISRDDSKNTFYLQMNSLRAEDTAVYYCTTSRRGYF FDYWGQGTLVTVSS (SEQ ID NO:214) with [00227] CDR-H1 GFNIKDGH (SEQ ID NO:429), [00228] CDR-H2 IDPENGDL (SEQ ID NO:430), [00229] CDR-H3 TTSRRGYFFDY (SEQ ID NO:431).
  • bb.1E12 Humanized HC-6 human wild type IgG1 constant domains
  • One embodiment provides a 1E12 humanized HC-6, human wild type IgG1 constant domain having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: EVQLVESGGGLVQPGGSLRLSCAVSGFNIKDGHMHWIRQAPGKGLEWVAWI DPENGDLEYASKFQGRITISRDDSKNTFYLQMNSLRAEDTAVYYCTTSRRGYF FDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTV SWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNT KVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV VVDVSHEDPEVKFNWYVDGVEVHNAKTKPRE
  • cc.1E12 Humanized HC-6, human IgG1 constant domains (DLE) [00231]
  • One embodiment provides a 1E12 humanized HC-6, human IgG1 constant domain (DLE) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: EVQLVESGGGLVQPGGSLRLSCAVSGFNIKDGHMHWIRQAPGKGLEWVAWI DPENGDLEYASKFQGRITISRDDSKNTFYLQMNSLRAEDTAVYYCTTSRRGYF FDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTV SWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNT 51 064467-020PCT KVDKKVEPKSCDKTHTCPPCPAPELLGGPDVFLFPPKPKDTLMISRTPEVTCV VVDVS
  • dd.1E12 Humanized HC-6, human IgG1 constant domains [00232]
  • One embodiment provides a 1E12 humanized HC-6, human IgG1 constant domain (FES) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: EVQLVESGGGLVQPGGSLRLSCAVSGFNIKDGHMHWIRQAPGKGLEWVAWI DPENGDLEYASKFQGRITISRDDSKNTFYLQMNSLRAEDTAVYYCTTSRRGYF FDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTV SWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNT KVDKKVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCV VVDVSHEDPEVKFNWYVDGVEVHNA
  • ee.1E12 Humanized HC-6, human IgG1 constant domains [00233]
  • One embodiment provides a 1E12 humanized HC-6, human IgG1 constant domain (AA) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: EVQLVESGGGLVQPGGSLRLSCAVSGFNIKDGHMHWIRQAPGKGLEWVAWI DPENGDLEYASKFQGRITISRDDSKNTFYLQMNSLRAEDTAVYYCTTSRRGYF FDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTV SWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNT KVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCV VVDVSHEDPEVKFNWYVDGVEVHNAKTK
  • One embodiment provides a 1E12 humanized HC-6, human IgG4 constant domain (G4P) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: EVQLVESGGGLVQPGGSLRLSCAVSGFNIKDGHMHWIRQAPGKGLEWVAWI DPENGDLEYASKFQGRITISRDDSKNTFYLQMNSLRAEDTAVYYCTTSRRGYF FDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTV SWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNT KVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVD VSQED
  • HC-7 Humanized Heavy Chain 7
  • HC-7 Variable Domain One embodiment provides a 1E12 humanized HC-7 variable region having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: QVQLVQSGAEVKRPGASVKLSCTASGFNIKDGHMHWVRQAPGQGLEWIGWI DPENGDLEYAQKFQGRVTLTADTSSNTAYLQLSSLTSEDTAVYYCTTSRRGY FFDYWGQGTLVTVSS (SEQ ID NO:220) with [00236] CDR-H1 GFNIKDGH (SEQ ID NO:429), [00237] CDR-H2 IDPENGDL (SEQ ID NO:430), [00238] CDR-H3 TTSRRGYFFDY (SEQ ID NO:431).
  • bb.1E12 Humanized HC-7 human wild type IgG1 constant domains
  • One embodiment provides a 1E12 humanized HC-7, human wild type IgG1 constant domain having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: QVQLVQSGAEVKRPGASVKLSCTASGFNIKDGHMHWVRQAPGQGLEWIGWI DPENGDLEYAQKFQGRVTLTADTSSNTAYLQLSSLTSEDTAVYYCTTSRRGY FFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVT VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSN 53 064467-020PCT TKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV VVDVSHEDPEVK
  • cc.1E12 Humanized HC-7, human IgG1 constant domains (DLE) [00240]
  • One embodiment provides a 1E12 humanized HC-7, human IgG1 constant domain (DLE) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: QVQLVQSGAEVKRPGASVKLSCTASGFNIKDGHMHWVRQAPGQGLEWIGWI DPENGDLEYAQKFQGRVTLTADTSSNTAYLQLSSLTSEDTAVYYCTTSRRGY FFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVT VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSN TKVDKKVEPKSCDKTHTCPPCPAPELLGGPDVFLFPPKPKDTLMISRTPEVTC VVVDVSHEDPEVKFNW
  • dd.1E12 Humanized HC-7, human IgG1 constant domains [00241]
  • One embodiment provides a 1E12 humanized HC-7, human IgG1 constant domain (FES) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: QVQLVQSGAEVKRPGASVKLSCTASGFNIKDGHMHWVRQAPGQGLEWIGWI DPENGDLEYAQKFQGRVTLTADTSSNTAYLQLSSLTSEDTAVYYCTTSRRGY FFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVT VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSN TKVDKKVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCV VVDVSHEDPEVKFNWYVDG
  • One embodiment provides a 1E12 humanized HC-7, human IgG1 constant domain (AA) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: QVQLVQSGAEVKRPGASVKLSCTASGFNIKDGHMHWVRQAPGQGLEWIGWI DPENGDLEYAQKFQGRVTLTADTSSNTAYLQLSSLTSEDTAVYYCTTSRRGY FFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVT VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSN TKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTC VVVDVSHE
  • One embodiment provides a 1E12 humanized HC-7, human IgG4 constant domain (G4P) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: QVQLVQSGAEVKRPGASVKLSCTASGFNIKDGHMHWVRQAPGQGLEWIGWI DPENGDLEYAQKFQGRVTLTADTSSNTAYLQLSSLTSEDTAVYYCTTSRRGY FFDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVT VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSN TKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVD VSQEDPEVQFNWYV
  • HC-8 Humanized Heavy Chain 8
  • HC-8 Variable Domain One embodiment provides a 1E12 humanized HC-8 variable region having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: 55 064467-020PCT QVQLVQSGAEVKKPGASVKVSCKASGYTFTDGHMHWVRQAPGQGLEWIGW IDPENGDLEYASKFQGRVTLTRDTSSNTAYLELSSLTSEDTAVYYCTTSRRGY FFDYWGQGTLVTVSS (SEQ ID NO:226) with [00245] CDR-H1 GYTFTDGH (SEQ ID NO: 190), [00246] CDR-H2 IDPENGDL (SEQ ID NO:430), [00247] CDR-H3 TTSRRGYFFDY (SEQ ID NO:431).
  • bb.1E12 Humanized HC-8 human wild type IgG1 constant domains
  • One embodiment provides a 1E12 humanized HC-8, human wild type IgG1 constant domain having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: QVQLVQSGAEVKKPGASVKVSCKASGYTFTDGHMHWVRQAPGQGLEWIGW IDPENGDLEYASKFQGRVTLTRDTSSNTAYLELSSLTSEDTAVYYCTTSRRGY FFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVT VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSN TKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV VVDVSHEDPEVKFNWYVDGVEVHNAKTKPRE
  • cc.1E12 Humanized HC-8, human IgG1 constant domains [00249]
  • One embodiment provides a 1E12 humanized HC-8, human IgG1 constant domain (DLE) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: QVQLVQSGAEVKKPGASVKVSCKASGYTFTDGHMHWVRQAPGQGLEWIGW IDPENGDLEYASKFQGRVTLTRDTSSNTAYLELSSLTSEDTAVYYCTTSRRGY FFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVT VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSN TKVDKKVEPKSCDKTHTCPPCPAPELLGGPDVFLFPPKPKDTLMISRTPEVTC VVVDVSHEDPEVKFNWYVDGVEVH
  • One embodiment provides a 1E12 humanized HC-8, human IgG1 constant domain (FES) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: QVQLVQSGAEVKKPGASVKVSCKASGYTFTDGHMHWVRQAPGQGLEWIGW IDPENGDLEYASKFQGRVTLTRDTSSNTAYLELSSLTSEDTAVYYCTTSRRGY FFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVT VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSN TKVDKKVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCV VVDVSHEDPEVKFN
  • ee.1E12 Humanized HC-8, human IgG1 constant domains (AA) [00251]
  • One embodiment provides a 1E12 humanized HC-8, human IgG1 constant domain (AA) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: QVQLVQSGAEVKKPGASVKVSCKASGYTFTDGHMHWVRQAPGQGLEWIGW IDPENGDLEYASKFQGRVTLTRDTSSNTAYLELSSLTSEDTAVYYCTTSRRGY FFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVT VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSN TKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTC VVVDVSHEDPEVKFNWYVDGVEV
  • One embodiment provides a 1E12 humanized HC-8, human IgG4 constant domain (G4P) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: 57 064467-020PCT QVQLVQSGAEVKKPGASVKVSCKASGYTFTDGHMHWVRQAPGQGLEWIGW IDPENGDLEYASKFQGRVTLTRDTSSNTAYLELSSLTSEDTAVYYCTTSRRGY FFDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVT VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSN TKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVD VSQED
  • HC-9 variable region having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: QVQLVQSGAEVKKPGASVKVSCKASGFNIKDGHMHWVRQAPGQGLEWIGW IDPENGDLEYASKFQGRATLTADTSSNTAYLELSSLTSEDTAVYYCTTSRRGY FFDYWGQGTLVTVSS (SEQ ID NO:232) with [00254] CDR-H1 GFNIKDGH (SEQ ID NO:429), [00255] CDR-H2 IDPENGDL (SEQ ID NO:430), [00256] CDR-H3 TTSRRGYFFDY (SEQ ID NO:431).
  • bb.1E12 Humanized HC-9, human wild type IgG1 constant domains [00257]
  • One embodiment provides a 1E12 humanized HC-9, human wild type IgG1 constant domain having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: QVQLVQSGAEVKKPGASVKVSCKASGFNIKDGHMHWVRQAPGQGLEWIGW IDPENGDLEYASKFQGRATLTADTSSNTAYLELSSLTSEDTAVYYCTTSRRGY FFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVT VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSN TKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV VVDVSHEDPEVKFNWYVDGVEVHNAK
  • One embodiment provides a 1E12 humanized HC-9, human IgG1 constant domain (DLE) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: QVQLVQSGAEVKKPGASVKVSCKASGFNIKDGHMHWVRQAPGQGLEWIGW IDPENGDLEYASKFQGRATLTADTSSNTAYLELSSLTSEDTAVYYCTTSRRGY FFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVT VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSN TKVDKKVEPKSCDKTHTCPPCPAPELLGGPDVFLFPPKPKDTLMISRTPEVTC VVVDVSHEDP
  • dd.1E12 Humanized HC-9, human IgG1 constant domains [00259]
  • One embodiment provides a 1E12 humanized HC-9, human IgG1 constant domain (FES) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: QVQLVQSGAEVKKPGASVKVSCKASGFNIKDGHMHWVRQAPGQGLEWIGW IDPENGDLEYASKFQGRATLTADTSSNTAYLELSSLTSEDTAVYYCTTSRRGY FFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVT VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSN TKVDKKVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCV VVDVSHEDPEVKFNWYVDGVEVHNA
  • One embodiment provides a 1E12 humanized HC-9, human IgG1 constant domain (AA) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: 59 064467-020PCT QVQLVQSGAEVKKPGASVKVSCKASGFNIKDGHMHWVRQAPGQGLEWIGW IDPENGDLEYASKFQGRATLTADTSSNTAYLELSSLTSEDTAVYYCTTSRRGY FFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVT VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSN TKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTC VVVDVSHEDPEVKFN
  • One embodiment provides a 1E12 humanized HC-9, human IgG4 constant domain (G4P) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: QVQLVQSGAEVKKPGASVKVSCKASGFNIKDGHMHWVRQAPGQGLEWIGW IDPENGDLEYASKFQGRATLTADTSSNTAYLELSSLTSEDTAVYYCTTSRRGY FFDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVT VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSN TKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVD VSQEDPEVQFNWYVDGVEV
  • HC-10 variable region having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: QVQLVQSGAEVKKPGASVKVSCKASGFNIKDGYMHWVRQAPGQGLEWMG WIDPENGDTEYAQKFQGRVTLTRDTSINTAYLELSSLTSEDTAVYYCTTSRRG YFFDYWGQGTLVTVSS (SEQ ID NO:238) with [00263] CDR-H1 GFNIKDGH (SEQ ID NO:429), [00264] CDR-H2 IDPENGDT (SEQ ID NO: 239), [00265] CDR-H3 TTSRRGYFFDY (SEQ ID NO:431).
  • bb.1E12 Humanized HC-10 human wild type IgG1 constant domains
  • One embodiment provides a 1E12 humanized HC-10, human wild type IgG1 constant domain having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: QVQLVQSGAEVKKPGASVKVSCKASGFNIKDGYMHWVRQAPGQGLEWMG WIDPENGDTEYAQKFQGRVTLTRDTSINTAYLELSSLTSEDTAVYYCTTSRRG YFFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPV TVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPS NTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC VVVDVSHEDPEVKFNWY
  • cc.1E12 Humanized HC-10, human IgG1 constant domains (DLE) [00267]
  • One embodiment provides a 1E12 humanized HC-10, human IgG1 constant domain (DLE) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: QVQLVQSGAEVKKPGASVKVSCKASGFNIKDGYMHWVRQAPGQGLEWMG WIDPENGDTEYAQKFQGRVTLTRDTSINTAYLELSSLTSEDTAVYYCTTSRRG YFFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPV TVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPS NTKVDKKVEPKSCDKTHTCPPCPAPELLGGPDVFLFPPKPKDTLMISRTPEVT CVVVDVSHEDPEVKFNWYVDGVE
  • dd.1E12 Humanized HC-10, human IgG1 constant domains [00268]
  • One embodiment provides a 1E12 humanized HC-10, human IgG1 constant domain (FES) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: 61 064467-020PCT QVQLVQSGAEVKKPGASVKVSCKASGFNIKDGYMHWVRQAPGQGLEWMG WIDPENGDTEYAQKFQGRVTLTRDTSINTAYLELSSLTSEDTAVYYCTTSRRG YFFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPV TVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPS NTKVDKKVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTC VVVDVSHEDP
  • One embodiment provides a 1E12 humanized HC-10, human IgG1 constant domain (AA) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: QVQLVQSGAEVKKPGASVKVSCKASGFNIKDGYMHWVRQAPGQGLEWMG WIDPENGDTEYAQKFQGRVTLTRDTSINTAYLELSSLTSEDTAVYYCTTSRRG YFFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPV TVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPS NTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVT CVVVDVSHEDPEVKFNWYVDGVEVHNAKTKTK
  • One embodiment provides a 1E12 humanized HC-10, human IgG4 constant domain (G4P) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: QVQLVQSGAEVKKPGASVKVSCKASGFNIKDGYMHWVRQAPGQGLEWMG WIDPENGDTEYAQKFQGRVTLTRDTSINTAYLELSSLTSEDTAVYYCTTSRRG YFFDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPV TVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPS NTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVV DVSQEDPEVQFNWYVDGVEVHNA
  • One embodiment provides a 1E12 humanized HC-11 variable region having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: QVQLVQSGAEVKKPGASVKVSCKASGFNIKDGHMHWVRQAPGQGLEWMG WIDPENGDLEYAQKFQGRVTLTRDTSSNTAYLELSSLTSEDTAVYYCTTSRRG YFFDYWGQGTLVTVSS (SEQ ID NO:245) with [00272] CDR-H1 GFNIKDGH (SEQ ID NO:429), [00273] CDR-H2 IDPENGDL (SEQ ID NO:430), [00274] CDR-H3 TTSRRGYFFDY (SEQ ID NO:431).
  • One embodiment provides a 1E12 humanized HC-11, human IgG1 constant domain (FES) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: QVQLVQSGAEVKKPGASVKVSCKASGFNIKDGHMHWVRQAPGQGLEWMG WIDPENGDLEYAQKFQGRVTLTRDTSSNTAYLELSSLTSEDTAVYYCTTSRRG YFFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPV TVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPS NTKVDKKVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTC VVVDVSHEDPEVKFNWYVDGVEV
  • One embodiment provides a 1E12 humanized HC-11, human IgG1 constant domain (AA) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: QVQLVQSGAEVKKPGASVKVSCKASGFNIKDGHMHWVRQAPGQGLEWMG WIDPENGDLEYAQKFQGRVTLTRDTSSNTAYLELSSLTSEDTAVYYCTTSRRG YFFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPV TVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPS NTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVT CVVVDVSHEDPEVKFNWYVDGVEVHNAK
  • bb.1E12 Humanized HC-12, human wild type IgG1 constant domains [00284]
  • One embodiment provides a 1E12 humanized HC-12, human wild type IgG1 constant domain having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: 65 064467-020PCT QVQLVQSGAEVKKPGASVKVSCTASGFNIKDGHMHWVRQAPGQGLEWMG WIDPENGDLEYAQKFQGRVTLTRDTSSNTAYLELSSLTSEDTAVYYCTTSRRG YFFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPV TVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPS NTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC VVVDVSHEDPEV
  • One embodiment provides a 1E12 humanized HC-12, human IgG1 constant domain (FES) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: QVQLVQSGAEVKKPGASVKVSCTASGFNIKDGHMHWVRQAPGQGLEWMG WIDPENGDLEYAQKFQGRVTLTRDTSSNTAYLELSSLTSEDTAVYYCTTSRRG YFFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPV TVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPS NTKVDKKVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTC VVVDVSHEDPEVKFNWYVDGVEV
  • One embodiment provides a 1E12 humanized HC-12, human IgG1 constant domain (AA) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: QVQLVQSGAEVKKPGASVKVSCTASGFNIKDGHMHWVRQAPGQGLEWMG WIDPENGDLEYAQKFQGRVTLTRDTSSNTAYLELSSLTSEDTAVYYCTTSRRG YFFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPV TVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPS NTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVT CVVVDVSHEDPEVKFNWYVDGVEVHNAK
  • One embodiment provides a 1E12 humanized HC-13 variable region having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: EVQLLESGGGLVQPGGSLRLSCAASGFTFSDGHMHWVRQAPGKGLEWVSWI DPENGDLEYASKFQGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKSRRGY FFDYWGQGTLVTVSS (SEQ ID NO:257) with [00290] CDR-H1 GFTFSDGH (SEQ ID NO:258), [00291] CDR-H2 IDPENGDL (SEQ ID NO:430), [00292] CDR-H3 AKSRRGYFFDY (SEQ ID NO:259).
  • dd.1E12 Humanized HC-13, human IgG1 constant domains [00295]
  • One embodiment provides a 1E12 humanized HC-13, human IgG1 constant domain (FES) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: EVQLLESGGGLVQPGGSLRLSCAASGFTFSDGHMHWVRQAPGKGLEWVSWI DPENGDLEYASKFQGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKSRRGY FFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVT VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSN TKVDKKVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCV VVDVSHEDPEVKFNWYVDGVEVHNA
  • One embodiment provides a 1E12 humanized HC-13, human IgG4 constant domain (G4P) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: EVQLLESGGGLVQPGGSLRLSCAASGFTFSDGHMHWVRQAPGKGLEWVSWI DPENGDLEYASKFQGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKSRRGY FFDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVT VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSN TKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVD VSQED
  • One embodiment provides a 1E12 humanized HC-14 variable region having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: EVQLLESGGGLVQPGGSLRLSCAASGFNIKDGAMSWVRQAPGKGLEWVSAI DPENGDTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKSRRG YFFDYWGQGTLVTVSS (SEQ ID NO:265) with [00299] CDR-H1 GFNIKDGA (SEQ ID NO:266), [00300] CDR-H2 IDPENGDT (SEQ ID NO: 239), [00301] CDR-H3 AKSRRGYFFDY (SEQ ID NO:259).
  • bb.1E12 Humanized HC-14, human wild type IgG1 constant domains [00302]
  • One embodiment provides a 1E12 humanized HC-14, human wild type IgG1 constant domain having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: EVQLLESGGGLVQPGGSLRLSCAASGFNIKDGAMSWVRQAPGKGLEWVSAI DPENGDTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKSRRG YFFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPV TVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPS 70 064467-020PCT NTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC VVVDVSHEDPEVKFNW
  • cc.1E12 Humanized HC-14, human IgG1 constant domains (DLE) [00303]
  • One embodiment provides a 1E12 humanized HC-14, human IgG1 constant domain (DLE) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: EVQLLESGGGLVQPGGSLRLSCAASGFNIKDGAMSWVRQAPGKGLEWVSAI DPENGDTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKSRRG YFFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPV TVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPS NTKVDKKVEPKSCDKTHTCPPCPAPELLGGPDVFLFPPKPKDTLMISRTPEVT CVVVDVSHEDPEVKFNWYVDGVEVHNA
  • dd.1E12 Humanized HC-14, human IgG1 constant domains [00304]
  • One embodiment provides a 1E12 humanized HC-14, human IgG1 constant domain (FES) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: EVQLLESGGGLVQPGGSLRLSCAASGFNIKDGAMSWVRQAPGKGLEWVSAI DPENGDTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKSRRG YFFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPV TVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPS NTKVDKKVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTC VVVDVSHEDPEVKFNWYVDGVEVHNAKTK
  • One embodiment provides a 1E12 humanized HC-14, human IgG1 constant domain (AA) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: EVQLLESGGGLVQPGGSLRLSCAASGFNIKDGAMSWVRQAPGKGLEWVSAI DPENGDTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKSRRG YFFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPV TVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPS NTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVT CVVVDVSHEDPEVKFNWYV
  • One embodiment provides a 1E12 humanized HC-14, human IgG4 constant domain (G4P) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: EVQLLESGGGLVQPGGSLRLSCAASGFNIKDGAMSWVRQAPGKGLEWVSAI DPENGDTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKSRRG YFFDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPV TVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPS NTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVV DVSQEDPEVQFNWYVDGVEVHNAK
  • HC-15 Humanized Heavy Chain 15
  • HC-15 Humanized Heavy Chain 15
  • 1E12 humanized HC-15 variable region having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: 72 064467-020PCT EVQLLESGGGLVQPGGSLRLSCAASGFNIKDGHMSWVRQAPGKGLEWVSAI DPENGDLYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCTTSRRGY FFDYWGQGTLVTVSS (SEQ ID NO:272) with [00308] CDR-H1 GFNIKDGH (SEQ ID NO:429), [00309] CDR-H2 IDPENGDL (SEQ ID NO:430), [00310] CDR-H3 TTSRRGYFFDY (SEQ ID NO:431).
  • bb.1E12 Humanized HC-15 human wild type IgG1 constant domains
  • One embodiment provides a 1E12 humanized HC-15, human wild type IgG1 constant domain having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: EVQLLESGGGLVQPGGSLRLSCAASGFNIKDGHMSWVRQAPGKGLEWVSAI DPENGDLYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCTTSRRGY FFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVT VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSN TKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQ
  • cc.1E12 Humanized HC-15, human IgG1 constant domains (DLE) [00312]
  • One embodiment provides a 1E12 humanized HC-15, human IgG1 constant domain (DLE) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: EVQLLESGGGLVQPGGSLRLSCAASGFNIKDGHMSWVRQAPGKGLEWVSAI DPENGDLYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCTTSRRGY FFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVT VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSN TKVDKKVEPKSCDKTHTCPPCPAPELLGGPDVFLFPPKPKDTLMISRTPEVTC VVVDVSHEDPEVKFNWYVDGVE
  • One embodiment provides a 1E12 humanized HC-15, human IgG1 constant domain (FES) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: EVQLLESGGGLVQPGGSLRLSCAASGFNIKDGHMSWVRQAPGKGLEWVSAI DPENGDLYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCTTSRRGY FFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVT VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSN TKVDKKVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCV VVDVSHEDPEVK
  • ee.1E12 Humanized HC-15, human IgG1 constant domains (AA) [00314]
  • One embodiment provides a 1E12 humanized HC-15, human IgG1 constant domain (AA) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: EVQLLESGGGLVQPGGSLRLSCAASGFNIKDGHMSWVRQAPGKGLEWVSAI DPENGDLYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCTTSRRGY FFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVT VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSN TKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTC VVVDVSHEDPEVKFNWYVDGVEVH
  • One embodiment provides a 1E12 humanized HC-15, human IgG4 constant domain (G4P) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: 74 064467-020PCT EVQLLESGGGLVQPGGSLRLSCAASGFNIKDGHMSWVRQAPGKGLEWVSAI DPENGDLYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCTTSRRGY FFDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVT VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSN TKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVD VSQEDP
  • HC-16 Humanized Heavy Chain 16
  • HC-16 Humanized Heavy Chain 16
  • 1E12 humanized HC-16 variable region having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: EVQLLESGGGLVQPGGSLRLSCTASGFNIKDGHMHWVRQAPGKGLEWVSWI DPENGDLEYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCTTSRRGY FFDYWGQGTLVTVSS (SEQ ID NO:278) with [00317] CDR-H1 GFNIKDGH (SEQ ID NO:429), [00318] CDR-H2 IDPENGDL (SEQ ID NO:430), [00319] CDR-H3 TTSRRGYFFDY (SEQ ID NO:431).
  • bb.1E12 Humanized HC-16 human wild type IgG1 constant domains
  • One embodiment provides a 1E12 humanized HC-16, human wild type IgG1 constant domain having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: EVQLLESGGGLVQPGGSLRLSCTASGFNIKDGHMHWVRQAPGKGLEWVSWI DPENGDLEYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCTTSRRGY FFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVT VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSN TKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQ
  • One embodiment provides a 1E12 humanized HC-16, human IgG1 constant domain (DLE) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: EVQLLESGGGLVQPGGSLRLSCTASGFNIKDGHMHWVRQAPGKGLEWVSWI DPENGDLEYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCTTSRRGY FFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVT VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSN TKVDKKVEPKSCDKTHTCPPCPAPELLGGPDVFLFPPKPKDTLMISRTPEVTC VVVDVSHEDPEV
  • dd.1E12 Humanized HC-16, human IgG1 constant domains [00322]
  • One embodiment provides a 1E12 humanized HC-16, human IgG1 constant domain (FES) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: EVQLLESGGGLVQPGGSLRLSCTASGFNIKDGHMHWVRQAPGKGLEWVSWI DPENGDLEYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCTTSRRGY FFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVT VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSN TKVDKKVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCV VVDVSHEDPEVKFNWYVDGVEVHNA
  • ee.1E12 Humanized HC-16, human IgG1 constant domains (AA) [00323]
  • One embodiment provides a 1E12 humanized HC-16, human IgG1 constant domain (AA) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: 76 064467-020PCT EVQLLESGGGLVQPGGSLRLSCTASGFNIKDGHMHWVRQAPGKGLEWVSWI DPENGDLEYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCTTSRRGY FFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVT VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSN TKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTC VVVDVSHE
  • One embodiment provides a 1E12 humanized HC-16, human IgG4 constant domain (G4P) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: EVQLLESGGGLVQPGGSLRLSCTASGFNIKDGHMHWVRQAPGKGLEWVSWI DPENGDLEYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCTTSRRGY FFDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVT VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSN TKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVD VSQEDPEVQFNWYVDGVEV
  • LC-1 variable region having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: DIQMTQSPSSLSASVGDRVTITCRASQDINNYLAWYQQKPGKVPKLLIYYTST LQSGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCQQGNTLPWTFGQGTKVEI K (SEQ ID NO:284) with [00326] CDR-L1 QDINNY (SEQ ID NO:434), [00327] CDR-L2 YTS (SEQ ID NO:285), [00328] CDR-L3 QQGNTLPWT (SEQ ID NO: 30).
  • bb.1E12 humanized LC-1 human kappa wild type constant domain
  • One embodiment provides a 1E12 humanized LC-1, human kappa wild type constant domain having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: DIQMTQSPSSLSASVGDRVTITCRASQDINNYLAWYQQKPGKVPKLLIYYTST LQSGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCQQGNTLPWTFGQGTKVEI KRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGN SQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNR GEC (SEQ ID NO:286).
  • the underlined sequence is the light chain constant domain (wild type, kappa).
  • cc.1E12 Humanized LC-1, human kappa wild type constant domain (CAAX) [00331]
  • One embodiment provides a 1E12 humanized LC-1, human kappa wild type constant domain (CAAX) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: DIQMTQSPSSLSASVGDRVTITCRASQDINNYLAWYQQKPGKVPKLLIYYTST LQSGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCQQGNTLPWTFGQGTKVEI KRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGN SQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNR GECGGGGGGG
  • LC-2 variable region having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: DIQMTQSPSSLSASVGDRVTITCRASQDINNYLNWYQQKPGKVPKLLIYYTSR LHSGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCQQGNTLPWTFGQGTKVEI K (SEQ ID NO:288) with [00333] CDR-L1 QDINNY (SEQ ID NO:434), [00334] CDR-L2 YTS (SEQ ID NO:285), [00335] CDR-L3 QQGNTLPWT (SEQ ID NO: 30).
  • One embodiment provides a 1E12 humanized LC-2, human kappa wild type constant domain having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: DIQMTQSPSSLSASVGDRVTITCRASQDINNYLNWYQQKPGKVPKLLIYYTSR LHSGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCQQGNTLPWTFGQGTKVEI KRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGN SQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNR GEC (SEQ ID NO:289).
  • the underlined sequence is the light chain constant domain (wild type, kappa).
  • cc.1E12 Humanized LC-2, human kappa wild type constant domain (CAAX) [00338]
  • One embodiment provides a 1E12 humanized LC-2, human kappa wild type constant domain (CAAX) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: DIQMTQSPSSLSASVGDRVTITCRASQDINNYLNWYQQKPGKVPKLLIYYTSR LHSGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCQQGNTLPWTFGQGTKVEI KRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGN SQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNR GECGGGGGGG
  • xix.1E12 Humanized Light Chain 1 (LC-3) aa.1E12 Humanized LC-3 variable region
  • One embodiment provides a 1E12 humanized LC-3 variable region having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: DIQMTQSPSSLSASVGDRVTISCRASQDINNYLNWYQQKPGKAPKLLIYYTSR LHSGVPSRFSGSGSGTDFTLTISNLQPEDIATYFCQQGNTLPWTFGQGTKVEIK (SEQ ID NO:291) with [00340] CDR-L1 QDINNY (SEQ ID NO:434), [00341] CDR-L2 YTS (SEQ ID NO:285), [00342] CDR-L3 QQGNTLPWT (SEQ ID NO: 30).
  • One embodiment provides a 1E12 humanized LC-3, human kappa wild type constant domain having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: DIQMTQSPSSLSASVGDRVTISCRASQDINNYLNWYQQKPGKAPKLLIYYTSR LHSGVPSRFSGSGSGTDFTLTISNLQPEDIATYFCQQGNTLPWTFGQGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNS QESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRG EC (SEQ ID NO:292).
  • the underlined sequence is the light chain constant domain (wild type, kappa).
  • One embodiment provides a 1E12 humanized LC-3, human kappa wild type constant domain (CAAX) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: DIQMTQSPSSLSASVGDRVTISCRASQDINNYLNWYQQKPGKAPKLLIYYTSR LHSGVPSRFSGSGSGTDFTLTISNLQPEDIATYFCQQGNTLPWTFGQGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNS QESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRG ECGGGGGGGCVIM (SEQ ID NO: DIQMTQSP
  • LC-4 variable region having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: DIQMTQSPSSLSASVGDRVTITCRASQDINNYLNWYQQKPGKAPKLLIYYTSR LHSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQGNTLPWTFGQGTKVEIK (SEQ ID NO:294) with [00347] CDR-L1 QDINNY (SEQ ID NO:434), [00348] CDR-L2 YTS (SEQ ID NO:285), [00349] CDR-L3 QQGNTLPWT (SEQ ID NO: 30).
  • bb.1E12 humanized LC-4 human kappa wild type constant domain
  • One embodiment provides a 1E12 humanized LC-4, human kappa wild type constant domain having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: DIQMTQSPSSLSASVGDRVTITCRASQDINNYLNWYQQKPGKAPKLLIYYTSR LHSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQGNTLPWTFGQGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNS QESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRG EC (SEQ ID NO:295).
  • the underlined sequence is the light chain constant domain (wild type, kappa).
  • cc.1E12 Humanized LC-4, human kappa wild type constant domain (CAAX) [00352]
  • One embodiment provides a 1E12 humanized LC-4, human kappa wild type constant domain (CAAX) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: DIQMTQSPSSLSASVGDRVTITCRASQDINNYLNWYQQKPGKAPKLLIYYTSR LHSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQGNTLPWTFGQGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNS QESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRG ECGGGGGGGCVIM
  • LC-5 variable region having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: DIQMTQSPSSLSASVGDRVTITCRASQDINNYLNWYQQKPGKVPKLLIYYTSR LHSGVPSRFSGSGSGTDYTLTISSLQPEDVATYYCQQGNTLPWTFGQGTKVEI K (SEQ ID NO:297) with [00354] CDR-L1 QDINNY (SEQ ID NO: 434), [00355] CDR-L2 YTS (SEQ ID NO:285), [00356] CDR-L3 QQGNTLPWT (SEQ ID NO: 30).
  • One embodiment provides a 1E12 humanized LC-5, human kappa wild type constant domain having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: DIQMTQSPSSLSASVGDRVTITCRASQDINNYLNWYQQKPGKVPKLLIYYTSR LHSGVPSRFSGSGSGTDYTLTISSLQPEDVATYYCQQGNTLPWTFGQGTKVEI KRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGN SQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNR GEC (SEQ ID NO:298).
  • the underlined sequence is the light chain constant domain (wild type, kappa).
  • cc.1E12 Humanized LC-5, human kappa wild type constant domain (CAAX) [00359]
  • One embodiment provides a 1E12 humanized LC-5, human kappa wild type constant domain (CAAX) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: DIQMTQSPSSLSASVGDRVTITCRASQDINNYLNWYQQKPGKVPKLLIYYTSR LHSGVPSRFSGSGSGTDYTLTISSLQPEDVATYYCQQGNTLPWTFGQGTKVEI KRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGN SQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNR GECGGGGG
  • LC-6 variable region having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: DIQLTQSPSSLSASVGDRVTITCRASQDINNYLNWYQQKPGKAPKLLIYYTSR LHSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQGNTLPWTFGQGTKVEIK (SEQ ID NO:300) with [00361] CDR-L1 QDINNY (SEQ ID NO: 434), [00362] CDR-L2 YTS (SEQ ID NO:285), [00363] CDR-L3 QQGNTLPWT (SEQ ID NO: 30).
  • bb.1E12 humanized LC-6 human kappa wild type constant domain
  • One embodiment provides a 1E12 humanized LC-6, human kappa wild type constant domain having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: DIQLTQSPSSLSASVGDRVTITCRASQDINNYLNWYQQKPGKAPKLLIYYTSR LHSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQGNTLPWTFGQGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNS QESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRG EC (SEQ ID NO:301).
  • LC-7 Humanized Light Chain 7
  • LC-7 variable region having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: DIQMTQSPSSLSASVGDRVTITCRASQDINNYLNWYQQKPGKAPKLLIYYTSR LHSGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCQQGNTLPWTFGQGTKVEI K (SEQ ID NO:303) with [00368] CDR-L1 QDINNY (SEQ ID NO: 434), [00369] CDR-L2 YTS (SEQ ID NO:285), [00370] CDR-L3 QQGNTLPWT (SEQ ID NO: 30).
  • One embodiment provides a 1E12 humanized LC-7, human kappa wild type constant domain having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: DIQMTQSPSSLSASVGDRVTITCRASQDINNYLNWYQQKPGKAPKLLIYYTSR LHSGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCQQGNTLPWTFGQGTKVEI KRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGN SQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNR GEC (SEQ ID NO:304).
  • One embodiment provides a 1E12 humanized LC-8, human kappa wild type constant domain having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: DIQMTQSPSSLSASVGDRVTITCRASQDINNYLNWYQQKPGKAPKLLIYYTSS LQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQGNTLPWTFGQGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNS QESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRG EC (SEQ ID NO:307).
  • One embodiment provides a 1H11 murine heavy chain variable region having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: QVQLQQPGAELVKPGASVRLSCKASGYTFTNYWMHWLKQRPGRGLEWIGE IDPSDNSTYYSHEFSGKATLTVDKSSSTAYMQLSSLTSDDSAVYYCARSGGD GYYEGVDYWGQGTTLTVSS (SEQ ID NO: 33) with [00382] CDRH1: NYWMH (SEQ ID NO: 34), [00383] CDRH2: EIDPSDNSTYYSHEFSG (SEQ ID NO: 35), 85 064467-020PCT [00384] CDRH3: SGGDGYYEGVDY (SEQ ID NO: 36).
  • bb.1H11 Chimeric Heavy Chain human wild type IgG1 constant domains
  • One embodiment provides a 1H11 chimeric heavy chain, human wild type IgG1 constant domains having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: QVQLQQPGAELVKPGASVRLSCKASGYTFTNYWMHWLKQRPGRGLEWIGEI DPSDNSTYYSHEFSGKATLTVDKSSSTAYMQLSSLTSDDSAVYYCARSGGDG YYEGVDYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFP EPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNH KPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPE VTCVVVDVSHEDPEVKFNWYVDGVEVH
  • cc.1H11 Chimeric Heavy Chain, human IgG1 constant domains DLE
  • One embodiment provides a 1H11 chimeric heavy chain, human IgG1 constant domains (DLE) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: QVQLQQPGAELVKPGASVRLSCKASGYTFTNYWMHWLKQRPGRGLEWIGE IDPSDNSTYYSHEFSGKATLTVDKSSSTAYMQLSSLTSDDSAVYYCARSGGD GYYEGVDYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYF PEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVN HKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPDVFL
  • the italicized sequence is the heavy chain constant domain with aspartic acid (D), leucine (L), and glutamic acid (E) mutations.
  • dd.1H11 Chimeric Heavy Chain, human IgG1 constant domains (FES) [00395]
  • One embodiment provides a 1H11 chimeric heavy chain, human IgG1 constant domains (FES) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: QVQLQQPGAELVKPGASVRLSCKASGYTFTNYWMHWLKQRPGRGLEWIGE IDPSDNSTYYSHEFSGKATLTVDKSSSTAYMQLSSLTSDDSAVYYCARSGGD GYYEGVDYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYF PEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVN HKPS
  • the dot underlined sequence is the heavy chain constant domain with alanine-alanine (AA) mutations.
  • AA alanine-alanine
  • G4P human IgG1 constant domains
  • One embodiment provides a 1H11 chimeric heavy chain, human IgG1 constant domains (G4P) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: QVQLQQPGAELVKPGASVRLSCKASGYTFTNYWMHWLKQRPGRGLEWIGE IDPSDNSTYYSHEFSGKATLTVDKSSSTAYMQLSSLTSDDSAVYYCARSGGD GYYEGVDYWGQGTTLTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYF PEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVD HKPSNTKVDKRVESK
  • the dash underlined sequence is the IgG4 heavy chain constant domain.
  • 88 064467-020PCT ii.1H11 Light Chain aa.1H11 Murine light chain variable region One embodiment provides a 1H11 murine light chain variable region having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: DVVMTQTPLTLSVTIGQPASISCKSSQSLLYGNGETYLNWLLQRPGQSPKRLI YLVSKLDSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYYCLQSTHFPQTFGG GTKLEIK (SEQ ID NO: 42) with [00411] CDRL1: KSSQSLLYGNGETYLN (SEQ ID NO: 43), [00412] CDRL2: LVSKLDS (SEQ ID NO: 44), [00413] CDRL3: LQSTHFPQT (SEQ ID NO:
  • bb.1H11 Chimeric Light Chain, human kappa wild type constant domain [00414]
  • One embodiment provides a 1H11 chimeric heavy chain, human kappa wild type constant domains having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: DVVMTQTPLTLSVTIGQPASISCKSSQSLLYGNGETYLNWLLQRPGQSPKRLI YLVSKLDSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYYCLQSTHFPQTFGG GTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNA LQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVT KSFNRGEC (SEQ ID NO: 46) with [00415] CDRL1: KSSQSLLYGNGETYLN (SEQ ID NO: 43), [00
  • d.3C7 Sequences i.3C7 Heavy Chain aa.3C7 Murine heavy chain variable region [00423]
  • One embodiment provides a 3C7 murine heavy chain variable region having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: QVQLQQPGAELVKPGASVKLSCKASGYTFTNYWINWLKQRPGPGLKWIGSIS PETNITDYNEMFKTKATLTVDTSSNTAYMQLNSLTSDDSAVYYCAIFHSNSF AYWGQGTLVTVSA (SEQ ID NO: 48) with [00424] CDRH1: NYWIN (SEQ ID NO: 49), [00425] CDRH2: SISPETNITDYNEMFKT (SEQ ID NO: 50), [00426] CDRH3: FHSNSFAY (SEQ ID NO: 51).
  • cc.3C7 Chimeric Heavy Chain, human IgG1 constant domains DLE
  • One embodiment provides a 3C7 chimeric heavy chain, human IgG1 constant domains (DLE) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: QVQLQQPGAELVKPGASVKLSCKASGYTFTNYWINWLKQRPGPGLKWIGSIS PETNITDYNEMFKTKATLTVDTSSNTAYMQLNSLTSDDSAVYYCAIFHSNSF AYWGQGTLVTVSAASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTV SWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNT KVDKKVEPKSCDKTHTCPPCPAPELLGGPDVFLFPPKPKDTLMISRT
  • the italicized sequence is the heavy chain constant domain with aspartic acid (D), leucine (L), and glutamic acid (E) mutations dd.3C7 Chimeric Heavy Chain, human IgG1 constant domains (FES) [00437]
  • One embodiment provides a 3C7 chimeric heavy chain, human IgG1 constant domains (FES) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: 91 064467-020PCT QVQLQQPGAELVKPGASVKLSCKASGYTFTNYWINWLKQRPGPGLKWIGSIS PETNITDYNEMFKTKATLTVDTSSNTAYMQLNSLTSDDSAVYYCAIFHSNSF AYWGQGTLVTVSAASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTV SWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNH
  • the dot underlined sequence is the heavy chain constant domain with alanine-alanine (AA) mutations.
  • AA alanine-alanine
  • G4P human IgG1 constant domains
  • One embodiment provides a 3C7 chimeric heavy chain, human IgG4 constant domains (G4P) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: QVQLQQPGAELVKPGASVKLSCKASGYTFTNYWINWLKQRPGPGLKWIGSIS PETNITDYNEMFKTKATLTVDTSSNTAYMQLNSLTSDDSAVYYCAIFHSNSF AYWGQGTLVTVSAASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVS WNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTK VD
  • bb.3D7 Chimeric Heavy Chain human wild type IgG1 constant domains
  • One embodiment provides a 3D7 chimeric heavy chain, human wild type IgG1 constant domains having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: EVKVVESGGGLVQSGRSLRLSCATSGFIFSDFYMEWVRQAPGKGLEWVATSR NKDFDYETEYSASVKGRFIVSRDTSQSILYLQMNVLRVEDTAIYYCAREYRG AMDYWGQGISVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVT VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSN TKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQ
  • One embodiment provides a 3D7 chimeric heavy chain, human wild type IgG1 constant domains (DLE) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: EVKVVESGGGLVQSGRSLRLSCATSGFIFSDFYMEWVRQAPGKGLEWVATS RNKDFDYETEYSASVKGRFIVSRDTSQSILYLQMNVLRVEDTAIYYCAREYR GAMDYWGQGISVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEP VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKP SNTKVDKKVEPKSCDKTHTC
  • the italicized sequence is the heavy chain constant domain with aspartic acid (D), leucine (L), and glutamic acid (E) mutations dd.3D7 Chimeric Heavy Chain, human wild type IgG1 constant domains (FES) [00480]
  • One embodiment provides a 3D7 chimeric heavy chain, human wild type IgG1 constant domains (FES) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: EVKVVESGGGLVQSGRSLRLSCATSGFIFSDFYMEWVRQAPGKGLEWVATS RNKDFDYETEYSASVKGRFIVSRDTSQSILYLQMNVLRVEDTAIYYCAREYR GAMDYWGQGISVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEP VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKP SNTKV
  • the underlined and italicized sequence is the heavy chain constant domain with phenylalanine (F), glutamic acid (E), and serine (S) and mutations.
  • dd.3D7 Chimeric Heavy Chain, human wild type IgG1 constant domains (AA) [00485]
  • One embodiment provides a 3D7 chimeric heavy chain, human wild type IgG1 constant domains (AA) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: [00486] EVKVVESGGGLVQSGRSLRLSCATSGFIFSDFYMEWVRQAPGKG LEWVATSRNKDFDYETEYSASVKGRFIVSRDTSQSILYLQMNVLRVEDTAIY YCAREYRGAMDYWGQGISVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLV KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQ
  • the dot underlined sequence is the heavy chain constant domain with alanine-alanine (AA) mutations.
  • AA alanine-alanine
  • G4P human wild type IgG4 constant domains
  • One embodiment provides a 3D7 chimeric heavy chain, human wild type IgG4 constant domains (G4P) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: EVKVVESGGGLVQSGRSLRLSCATSGFIFSDFYMEWVRQAPGKGLEWVATS RNKDFDYETEYSASVKGRFIVSRDTSQSILYLQMNVLRVEDTAIYYCAREYR GAMDYWGQGISVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPV 97 064467-020PCT TVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHK
  • the dash underlined sequence is the IgG4 heavy chain constant domain.
  • ii.3D7 Light Chain aa.3D7 Murine light chain variable region One embodiment provides a 3D7 murine light chain variable region having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: DIQMTQTTPSLSASLGDRVTISCRASQDINNYLNWYQQKPAGTVKLLIFYTSK LHSGVPSRFSGSGSGTDYSLTINTLEPEDIATYYCQQYRDYPFTFGTGTNLEIK (SEQ ID NO: 72) with [00497] CDRL1: CDRL1: RASQDINNYLN (SEQ ID NO: 28), [00498] CDRL2: YTSKLHS (SEQ ID NO: 73), [00499] CDRL3: QQYRDYPFT (SEQ ID NO: 74).
  • bb.3D7 Chimeric Light Chain, human kappa wild type constant domain [00500]
  • One embodiment provides a 3D7 chimeric light chain, human kappa wild type constant domain having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: DIQMTQTTPSLSASLGDRVTISCRASQDINNYLNWYQQKPAGTVKLLIFYTSK LHSGVPSRFSGSGSGTDYSLTINTLEPEDIATYYCQQYRDYPFTFGTGTNLEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNS QESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRG EC (SEQ ID NO: 75) with [00501] CDRL1: CDRL1: RASQDINNYLN (SEQ ID NO: 28), 98 0644
  • the underlined sequence is the light chain constant domain (wild type, kappa).
  • cc.3D7 Chimeric Light Chain, human kappa wild type constant domain (CAAX) [00505]
  • One embodiment provides a 3D7 chimeric light chain, human kappa wild type constant domain (CAAX) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: DIQMTQTTPSLSASLGDRVTISCRASQDINNYLNWYQQKPAGTVKLLIFYTSK LHSGVPSRFSGSGSGTDYSLTINTLEPEDIATYYCQQYRDYPFTFGTGTNLEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNS QESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRG ECGGGGGGGCVIM (SEQ
  • the double underlined sequence is the light chain constant domain with CAAX Sequence.
  • f.3H8 Sequences i.3H8 Heavy Chain aa.3H8 Murine heavy chain variable region
  • One embodiment provides a 3H8 murine heavy chain variable region having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: DVQLQESGPGLVKPSQSLSLTCSVSGYSITSGYYWNWIRQFPGNELEWMGY MSYDGTNNYNPSLKNRISITRDTSKNQFFLNLNSVTTEDTATYYCARGPYYS NNPWFHFWGQGTLVTVSA (SEQ ID NO: 77) with [00511] CDRH1: SGYYWN (SEQ ID NO: 78), [00512] CDRH2: YMSYDGTNNYNPSLKN (SEQ ID NO: 79), [00513] CDRH3:
  • One embodiment provides a 3H8 chimeric heavy chain, human wild type IgG1 constant domains having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: DVQLQESGPGLVKPSQSLSLTCSVSGYSITSGYYWNWIRQFPGNELEWMGYM SYDGTNNYNPSLKNRISITRDTSKNQFFLNLNSVTTEDTATYYCARGPYYSNN PWFHFWGQGTLVTVSAASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEP VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKP SNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVT CVVVDVSHE
  • cc.3H8 Chimeric Heavy Chain, human IgG1 constant domains DLE
  • One embodiment provides a 3H8 chimeric heavy chain, human wild type IgG1 constant domains (DLE) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: DVQLQESGPGLVKPSQSLSLTCSVSGYSITSGYYWNWIRQFPGNELEWMGY MSYDGTNNYNPSLKNRISITRDTSKNQFFLNLNSVTTEDTATYYCARGPYYS NNPWFHFWGQGTLVTVSAASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFP EPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNH KPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPDV
  • the italicized sequence is the heavy chain constant domain with aspartic acid (D), leucine (L), and glutamic acid (E) mutations cc.3H8 Chimeric Heavy Chain, human wild type IgG1 constant domains (FES) [00524]
  • One embodiment provides a 3H8 chimeric heavy chain, human IgG1 constant domains (FES) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: DVQLQESGPGLVKPSQSLSLTCSVSGYSITSGYYWNWIRQFPGNELEWMGY MSYDGTNNYNPSLKNRISITRDTSKNQFFLNLNSVTTEDTATYYCARGPYYS NNPWFHFWGQGTLVTVSAASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFP EPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNH KPS
  • the underlined and italicized sequence is the heavy chain constant domain with phenylalanine (F), glutamic acid (E), and serine (S) and mutations.
  • dd.3H8 Chimeric Heavy Chain, human wild type IgG1 constant domains (AA) [00529]
  • One embodiment provides a 3H8 chimeric heavy chain, human IgG1 constant domains (AA) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: DVQLQESGPGLVKPSQSLSLTCSVSGYSITSGYYWNWIRQFPGNELEWMGY MSYDGTNNYNPSLKNRISITRDTSKNQFFLNLNSVTTEDTATYYCARGPYYS NNPWFHFWGQGTLVTVSAASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFP 101 064467-020PCT EPVTVSWNSGALTSGVHTFPAVLQSSGLYSL
  • the dot underlined sequence is the heavy chain constant domain with alanine-alanine (AA) mutations.
  • AA alanine-alanine
  • G4P human IgG4 constant domain
  • One embodiment provides a 3H8 chimeric heavy chain, human IgG4 constant domain (G4P) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: DVQLQESGPGLVKPSQSLSLTCSVSGYSITSGYYWNWIRQFPGNELEWMGY MSYDGTNNYNPSLKNRISITRDTSKNQFFLNLNSVTTEDTATYYCARGPYYS NNPWFHFWGQGTLVTVSAASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFP EPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDH KPSNTKVDKRVESKYGP
  • the dash underlined sequence is the IgG4 heavy chain constant domain.
  • 102 064467-020PCT ii.3H8 Light Chain aa.3H8 Murine light chain variable region
  • One embodiment provides a 3H8 murine light chain variable region having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: DIVMTQSQRFLSTSVGDRVSISCKASQNVGNVIAWYQQKPGQSPKVLIYLAS YRFSGVPDRFTGGGSGTVFTLTISNVQSEDLAAYFCQQYHSSPLTFGAGTKL ELK (SEQ ID NO: 86) with [00540] CDRL1: KASQNVGNVIA (SEQ ID NO: 87), [00541] CDRL2: LASYRFS (SEQ ID NO: 88), [00542] CDRL3: QQYHSSPLT (SEQ ID NO: 89).
  • bb.3H8 Chimeric Light Chain, human kappa wild type constant domain [00543]
  • One embodiment provides a 3H8 chimeric light chain, human kappa wild type constant domain having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: DIVMTQSQRFLSTSVGDRVSISCKASQNVGNVIAWYQQKPGQSPKVLIYLAS YRFSGVPDRFTGGGSGTVFTLTISNVQSEDLAAYFCQQYHSSPLTFGAGTKL ELKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQS GNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSF NRGEC (SEQ ID NO: 90) with [00544]
  • CDRL1 KASQNVGNVIA (SEQ ID NO: 87), [00545] CD
  • the underlined sequence is the light chain constant domain (wild type, kappa).
  • cc.3H8 Chimeric Light Chain, human kappa wild type constant domain (CAAX) [00548]
  • One embodiment provides a 3H8 chimeric light chain, human kappa wild type constant domain (CAAX) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: 103 064467-020PCT DIVMTQSQRFLSTSVGDRVSISCKASQNVGNVIAWYQQKPGQSPKVLIYLAS YRFSGVPDRFTGGGSGTVFTLTISNVQSEDLAAYFCQQYHSSPLTFGAGTKL ELKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQS GNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSF NR
  • the double underlined sequence is the light chain constant domain with CAAX Sequence.
  • g.4B12 Sequences i.4B12 Heavy Chain aa.4B12 Murine heavy chain variable region
  • One embodiment provides a 4B12 murine heavy chain variable region having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: DIQLQESGPGLVKPSQSLSLTCSVTGFSITSGYYWNWIRQFPGNKLEWMAYIS YDGRNNYNPSLKNRISITRDTSKNQFFLRLNSVTTEDTATYYCARAGIRRGG YYWGRGTTLTVSS (SEQ ID NO: 92) with [00554] CDRH1: SGYYWN (SEQ ID NO: 78), [00555] CDRH2: YISYDGRNNYNPSLKN (SEQ ID NO: 93), [00556] CDRH3: AGIRRGG
  • bb.4B12 Chimeric Heavy Chain human wild type IgG1 constant domains
  • One embodiment provides a 4B12 chimeric heavy chain, human wild type IgG1 constant domains having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: DIQLQESGPGLVKPSQSLSLTCSVTGFSITSGYYWNWIRQFPGNKLEWMAYIS YDGRNNYNPSLKNRISITRDTSKNQFFLRLNSVTTEDTATYYCARAGIRRGGY YWGRGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSW NSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKV DKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVV 104 064467-020PCT DVSHEDPEVKFNW
  • cc.4B12 Chimeric Heavy Chain, human IgG1 constant domains (DLE) [00561]
  • One embodiment provides a 4B12 chimeric heavy chain, human IgG1 constant domains (DLE) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: DIQLQESGPGLVKPSQSLSLTCSVTGFSITSGYYWNWIRQFPGNKLEWMAYIS YDGRNNYNPSLKNRISITRDTSKNQFFLRLNSVTTEDTATYYCARAGIRRGG YYWGRGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVS WNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTK VDKKVEPKSCDKTHTCPPCPAPELLGGPDVFLFPPKPKDTLMISRTPEVTCVV VDVSHEDPEVKFNWYVDG
  • One embodiment provides a 4B12 chimeric heavy chain, human IgG1 constant domains (AA) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: DIQLQESGPGLVKPSQSLSLTCSVTGFSITSGYYWNWIRQFPGNKLEWMAYIS YDGRNNYNPSLKNRISITRDTSKNQFFLRLNSVTTEDTATYYCARAGIRRGG YYWGRGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVS WNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTK VDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVV VDVSHEDPEVKFNWYVDGVEVHNAK
  • One embodiment provides a 4B12 chimeric heavy chain, human IgG4 constant domain (G4P) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: DIQLQESGPGLVKPSQSLSLTCSVTGFSITSGYYWNWIRQFPGNKLEWMAYIS YDGRNNYNPSLKNRISITRDTSKNQFFLRLNSVTTEDTATYYCARAGIRRGG YYWGRGTTLTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVS WNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTK VDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVS QEDP
  • ii.4B12 Light Chain aa.4B12 Murine light chain variable region [00577]
  • One embodiment provides a 4B12 murine light chain variable region having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: IVLTQSPVSLAVSLGQRATISCRASESVDNYGNSYVYWYQQKPGQPPKLLIYL SSYLESGVPARFSGSGSRTDFTLTIDPVETDDAATYYCQQNNEDPHSFGGGT KLEIK (SEQ ID NO: 100) with [00578] CDRL1: RASESVDNYGNSYVY (SEQ ID NO: 101), [00579] CDRL2: LSSYLES (SEQ ID NO: 102), [00580] CDRL3: QQNNEDPHS (SEQ ID NO: 103).
  • bb.4B12 Chimeric Light Chain human kappa wild type constant domain
  • One embodiment provides a 4B12 chimeric light chain, human kappa wild type constant domain having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: IVLTQSPVSLAVSLGQRATISCRASESVDNYGNSYVYWYQQKPGQPPKLLIYL SSYLESGVPARFSGSGSRTDFTLTIDPVETDDAATYYCQQNNEDPHSFGGGT KLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQ SGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKS FNRGEC (SEQ ID NO: 104) with [00582] CDRL1: RASESVDNYGNSYVY (SEQ ID NO: 104) with [00582] CDRL
  • the underlined sequence is the light chain constant domain (wild type, kappa).
  • cc.4B12 Chimeric Light Chain, human kappa wild type constant domain (CAAX) [00586]
  • One embodiment provides a 4B12 chimeric light chain, human kappa wild type constant domain (CAAX) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: IVLTQSPVSLAVSLGQRATISCRASESVDNYGNSYVYWYQQKPGQPPKLLIYL SSYLESGVPARFSGSGSRTDFTLTIDPVETDDAATYYCQQNNEDPHSFGGGT KLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQ SGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKS FNRGECGGGGGGGCVIM (
  • the double underlined sequence is the light chain constant domain with CAAX Sequence. 108 064467-020PCT h.4G11 Sequences i.4G11 Heavy Chain aa.4G11 Murine heavy chain variable region
  • One embodiment provides a 4G11 murine heavy chain variable region having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: EVQLQQSGAELVRPGASVKLSCTTSGFNIKDSLMHWVKQRPEQGLEWIGWI DPEDGEGKYVPKFQDKATITSDTSSNTVYLQLSSLTSEDSAIYYCVREWDGY SFDYWGQGTTLTVSS (SEQ ID NO: 106) with [00592] CDRH1: DSLMH (SEQ ID NO: 107), [00593] CDRH2: WIDPEDGEGKYVPKFQD (SEQ ID NO: 108),
  • bb.4G11 Chimeric Heavy Chain human wild type IgG1 constant domains
  • One embodiment provides a 4G11 chimeric heavy chain, human wild type IgG1 constant domains having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: EVQLQQSGAELVRPGASVKLSCTTSGFNIKDSLMHWVKQRPEQGLEWIGWID PEDGEGKYVPKFQDKATITSDTSSNTVYLQLSSLTSEDSAIYYCVREWDGYSF DYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVS WNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTK VDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVV VDVSHEDPEVKFNWYVDGVEVH
  • the italicized sequence is the heavy chain constant domain with aspartic acid (D), leucine (L), and glutamic acid (E) mutations dd.4G11 Chimeric Heavy Chain, human IgG1 constant domains (FES)
  • FES human IgG1 constant domains
  • One embodiment provides a 4G11 chimeric heavy chain, human IgG1 constant domains (FES) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: EVQLQQSGAELVRPGASVKLSCTTSGFNIKDSLMHWVKQRPEQGLEWIGWI DPEDGEGKYVPKFQDKATITSDTSSNTVYLQLSSLTSEDSAIYYCVREWDGY SFDYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVT VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTY
  • the underlined and italicized sequence is the heavy chain constant domain with phenylalanine (F), glutamic acid (E), and serine (S) and mutations.
  • ee.4G11 Chimeric Heavy Chain, human IgG1 constant domains (AA) [00610]
  • One embodiment provides a 4G11 chimeric heavy chain, human IgG1 constant domains (AA) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: EVQLQQSGAELVRPGASVKLSCTTSGFNIKDSLMHWVKQRPEQGLEWIGWI DPEDGEGKYVPKFQDKATITSDTSSNTVYLQLSSLTSEDSAIYYCVREWDGY SFDYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVT VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC
  • the dot underlined sequence is the heavy chain constant domain with alanine-alanine (AA) mutations.
  • AA alanine-alanine
  • G4P human IgG4 constant domain
  • One embodiment provides a 4G11 chimeric heavy chain, human IgG4 constant domain (G4P) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: EVQLQQSGAELVRPGASVKLSCTTSGFNIKDSLMHWVKQRPEQGLEWIGWI DPEDGEGKYVPKFQDKATITSDTSSNTVYLQLSSLTSEDSAIYYCVREWDGY SFDYWGQGTTLTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVT 111 064467-020PCT VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVD
  • the dash underlined sequence is the IgG4 heavy chain constant domain.
  • ii.4G11 Light Chain aa.4G11 Murine light chain variable region One embodiment provides a 4G11 murine light chain variable region having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: DVLMTQTPRSLPVSLGDQASISCRSSQSIVHSHGNTYLEWYLQKPGQSPKLLI YKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYYCFQGSHVPWTFGG GTKLEIK (SEQ ID NO: 115) with [00621] CDRL1: RSSQSIVHSHGNTYLE (SEQ ID NO: 116), [00622] CDRL2: KVSNRFS (SEQ ID NO: 117), [00623] CDRL3: FQGSHVPWT (SEQ ID NO: 118).
  • bb.4G11 Chimeric Light Chain, human kappa wild type constant domain One embodiment provides a 4G11 chimeric light chain, human kappa wild type constant domain having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: DVLMTQTPRSLPVSLGDQASISCRSSQSIVHSHGNTYLEWYLQKPGQSPKLLI YKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYYCFQGSHVPWTFGG GTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNA LQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVT KSFNRGEC (SEQ ID NO: 119) with 112 064467-020PCT [00625] CDRL1: RSSQSIVHSHGNTYLE (S
  • the underlined sequence is the light chain constant domain (wild type, kappa).
  • cc.4G11 Chimeric Light Chain, human kappa wild type constant domain (CAAX) [00629]
  • One embodiment provides a 4G11 chimeric light chain, human kappa wild type constant domain (CAAX) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: DVLMTQTPRSLPVSLGDQASISCRSSQSIVHSHGNTYLEWYLQKPGQSPKLLI YKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYYCFQGSHVPWTFGG GTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNA LQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVT KSFNRGECGGGGGGGCVIM
  • the double underlined sequence is the light chain constant domain with CAAX Sequence.
  • i.5B4 Sequences i.5B4 Heavy Chain aa.5B4 Murine heavy chain variable region
  • One embodiment provides a5B4 murine heavy chain variable region having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: QVQLQQSGPGLVRPGTSMKLSCKASGYTFTDYGITWVKQRPGQGLEWIGWI YPKDDSSTYNERFKGKATLTVDTSSSTAYMALHRLTSEDSAVYFCARGNWE TPFDYWGHGTTLTVSS (SEQ ID NO: 121) with [00635] CDRH1: DYGIT (SEQ ID NO: 122), [00636] CDRH2: WIYPKDDSSTYNERFKG (SEQ ID NO: 123), [00637] CDRH3: GNWETPFDY
  • bb.5B4 Chimeric Heavy Chain human wild type IgG1 constant domains
  • One embodiment provides a 5B4 chimeric heavy chain, human wild type IgG1 constant domains having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: QVQLQQSGPGLVRPGTSMKLSCKASGYTFTDYGITWVKQRPGQGLEWIGWI YPKDDSSTYNERFKGKATLTVDTSSSTAYMALHRLTSEDSAVYFCARGNWET PFDYWGHGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVT VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSN TKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV VVDVSHEDPEV
  • cc.5B4 Chimeric Heavy Chain, human IgG1 constant domains DLE
  • One embodiment provides a 5B4 chimeric heavy chain, human IgG1 constant domains (DLE) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: QVQLQQSGPGLVRPGTSMKLSCKASGYTFTDYGITWVKQRPGQGLEWIGWI YPKDDSSTYNERFKGKATLTVDTSSSTAYMALHRLTSEDSAVYFCARGNWE TPFDYWGHGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPV TVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPS NTKVDKKVEPKSCDKTHTCPPCPAPELLGGPDVFLFPPKPKPK
  • the italicized sequence is the heavy chain constant domain with aspartic acid (D), leucine (L), and glutamic acid (E) mutations dd.5B4 Chimeric Heavy Chain, human IgG1 constant domains (FES)
  • FES human IgG1 constant domains
  • One embodiment provides a 5B4 chimeric heavy chain, human IgG1 constant domains (FES) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: QVQLQQSGPGLVRPGTSMKLSCKASGYTFTDYGITWVKQRPGQGLEWIGWI YPKDDSSTYNERFKGKATLTVDTSSSTAYMALHRLTSEDSAVYFCARGNWE TPFDYWGHGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPV TVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHK
  • the underlined and italicized sequence is the heavy chain constant domain with phenylalanine (F), glutamic acid (E), and serine (S) and mutations.
  • ee.5B4 Chimeric Heavy Chain, human IgG1 constant domains (AA) [00653]
  • One embodiment provides a 5B4 chimeric heavy chain, human IgG1 constant domains (AA) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: QVQLQQSGPGLVRPGTSMKLSCKASGYTFTDYGITWVKQRPGQGLEWIGWI YPKDDSSTYNERFKGKATLTVDTSSSTAYMALHRLTSEDSAVYFCARGNWE TPFDYWGHGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPV 115 064467-020PCT TVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVT
  • the dot underlined sequence is the heavy chain constant domain with alanine-alanine (AA) mutations.
  • AA alanine-alanine
  • G4P human IgG4 constant domain
  • the chimeric heavy chain, human IgG4 constant domain (G4P) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: QVQLQQSGPGLVRPGTSMKLSCKASGYTFTDYGITWVKQRPGQGLEWIGWI YPKDDSSTYNERFKGKATLTVDTSSSTAYMALHRLTSEDSAVYFCARGNWE TPFDYWGHGTTLTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPV TVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPS NTKVDKRVESKYGPPCPPCPAPEFLGGPSVFL
  • the dash underlined sequence is the IgG4 heavy chain constant domain.
  • Murine light chain variable region [00663]
  • One embodiment provides a 5B4 murine light chain variable region having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: DVLLTQTPLSLPVSLGDQASISCKSSQSIVHSNGNTYLEWYLQKPGQSPRFLI YEVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYYCFQGSHVPWTFGG GTKLEIK (SEQ ID NO: 130) with [00664] CDRL1: KSSQSIVHSNGNTYLE (SEQ ID NO: 131), [00665] CDRL2: EVSNRFS (SEQ ID NO: 132), [00666] CDRL3: FQGSHVPWT (SEQ
  • bb.5B8 Chimeric Heavy Chain human wild type IgG1 constant domains
  • One embodiment provides a 5B8 chimeric heavy chain, human wild type IgG1 constant domains having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: QAYLQQSGTELVSPGASVKMSCKASGYTFSNYNLHWVRQTPRQGLEWIGSIY PGNGDASFNQNFKGKATLTVDISSSTAYLQFSSLTSEDSAVYFCARSGDYDYF DYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVS WNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTK VDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVV 118 064467-020PCT VDVSHEDPEVKFNW
  • cc.5B8 Chimeric Heavy Chain, human IgG1 constant domains DLE
  • One embodiment provides a 5B8 chimeric heavy chain, human IgG1 constant domains (DLE) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: QAYLQQSGTELVSPGASVKMSCKASGYTFSNYNLHWVRQTPRQGLEWIGSI YPGNGDASFNQNFKGKATLTVDISSSTAYLQFSSLTSEDSAVYFCARSGDYD YFDYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVT VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSN TKVDKKVEPKSCDKTHTCPPCPAPELLGGPDVFLFP
  • the italicized sequence is the heavy chain constant domain with aspartic acid (D), leucine (L), and glutamic acid (E) mutations 119 064467-020PCT dd.5B8 Chimeric Heavy Chain, human IgG1 constant domains (FES) [00691]
  • One embodiment provides a 5B8 chimeric heavy chain, human IgG1 constant domains (FES) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: QAYLQQSGTELVSPGASVKMSCKASGYTFSNYNLHWVRQTPRQGLEWIGSI YPGNGDASFNQNFKGKATLTVDISSSTAYLQFSSLTSEDSAVYFCARSGDYD YFDYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVT VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT
  • the underlined and italicized sequence is the heavy chain constant domain with phenylalanine (F), glutamic acid (E), and serine (S) and mutations.
  • ee.5B8 Chimeric Heavy Chain, human IgG1 constant domains (AA) [00696]
  • One embodiment provides a 5B8 chimeric heavy chain, human IgG1 constant domains (AA) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: QAYLQQSGTELVSPGASVKMSCKASGYTFSNYNLHWVRQTPRQGLEWIGSI YPGNGDASFNQNFKGKATLTVDISSSTAYLQFSSLTSEDSAVYFCARSGDYD YFDYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVT VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNH
  • the dot underlined sequence is the heavy chain constant domain with alanine-alanine (AA) mutations.
  • AA alanine-alanine
  • G4P human IgG4 constant domain
  • One embodiment provides a 5B8 chimeric heavy chain, human IgG4 constant domain (G4P) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: QAYLQQSGTELVSPGASVKMSCKASGYTFSNYNLHWVRQTPRQGLEWIGSI YPGNGDASFNQNFKGKATLTVDISSSTAYLQFSSLTSEDSAVYFCARSGDYD YFDYWGQGTTLTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVT VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSN TKVDKRVESKYGPPC
  • the dash underlined sequence is the IgG4 heavy chain constant domain.
  • ii.5B8 Light Chain aa.5B8 Murine light chain variable region One embodiment provides a 5B8 murine light chain variable region having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: DIQMTQTTSSLSASLGDRVTISCRASQGINNYLNWYQQKPDGTVKLLIYYTS KLHSGVPSRFSGSGSTTDYSLTISNLEQEDIATYFCQQIDTFPPTFGGGTKLEI K (SEQ ID NO: 144) with 121 064467-020PCT [00707] CDRL1: RASQGINNYLN (SEQ ID NO: 145), [00708] CDRL2: YTSKLHS (SEQ ID NO: 146), [00709] CDRL3: QQIDTFPPT (SEQ ID NO: 147).
  • bb.5B8 Chimeric Light Chain, human kappa wild type constant domain [00710]
  • One embodiment provides a 5B8 chimeric light chain, human kappa wild type constant domain having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: DIQMTQTTSSLSASLGDRVTISCRASQGINNYLNWYQQKPDGTVKLLIYYTS KLHSGVPSRFSGSGSTTDYSLTISNLEQEDIATYFCQQIDTFPPTFGGGTKLEI KRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGN SQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNR GEC (SEQ ID NO: 148) with [00711] CDRL1: RASQGINNYLN (SEQ ID NO: 145), [00712] CDRL
  • the underlined sequence is the light chain constant domain (wild type, kappa).
  • cc.5B8 Chimeric Light Chain, human kappa wild type constant domain (CAAX) [00715]
  • One embodiment provides a 5B8 chimeric light chain, human kappa wild type constant domain (CAAX) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: DIQMTQTTSSLSASLGDRVTISCRASQGINNYLNWYQQKPDGTVKLLIYYTS KLHSGVPSRFSGSGSTTDYSLTISNLEQEDIATYFCQQIDTFPPTFGGGTKLEI KRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGN SQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNR GECGGGGGGGCVIM (SEQ
  • the double underlined sequence is the light chain constant domain with CAAX Sequence.
  • k.5H4 Sequences i.5H4 Heavy Chain aa.5H4 Murine heavy chain variable region
  • One embodiment provides a 5H4 murine heavy chain variable region having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: QVTLKESGPGILQPSQTLSLTCSFSGFSLSTFGVGVGWFRQSSGKGLEWLAHI WWDDEKYSNPALKTRLSISKDTSKNQVFLKIANVDTADTATHYCARIDSTV VAYAYWGQGTTLTVSS (SEQ ID NO: 150) with [00721] CDRH1: TFGVGVG (SEQ ID NO: 151), [00722] CDRH2: HIWWDDEKYSNPALKT (SEQ ID NO: 152), [00723] CDRH3: I
  • bb.5H4 Chimeric Heavy Chain human wild type IgG1 constant domains
  • One embodiment provides a 5H4 chimeric heavy chain, human wild type IgG1 constant domains having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: QVTLKESGPGILQPSQTLSLTCSFSGFSLSTFGVGVGWFRQSSGKGLEWLAHI WWDDEKYSNPALKTRLSISKDTSKNQVFLKIANVDTADTATHYCARIDSTVV AYAYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVT VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSN TKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQ
  • cc.5H4 Chimeric Heavy Chain, human IgG1 constant domains (DLE) [00729]
  • One embodiment provides a 5H4 chimeric heavy chain, human IgG1 constant domains (DLE) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: QVTLKESGPGILQPSQTLSLTCSFSGFSLSTFGVGVGWFRQSSGKGLEWLAHI WWDDEKYSNPALKTRLSISKDTSKNQVFLKIANVDTADTATHYCARIDSTV VAYAYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEP VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKP SNTKVDKKVEPKSCDKTHTCPPCPAPELLG
  • the italicized sequence is the heavy chain constant domain with aspartic acid (D), leucine (L), and glutamic acid (E) mutations dd.5H4 Chimeric Heavy Chain, human IgG1 constant domains (FES)
  • FES human IgG1 constant domains
  • One embodiment provides a 5H4 chimeric heavy chain, human IgG1 constant domains (FES) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: QVTLKESGPGILQPSQTLSLTCSFSGFSLSTFGVGVGWFRQSSGKGLEWLAHI WWDDEKYSNPALKTRLSISKDTSKNQVFLKIANVDTADTATHYCARIDSTV VAYAYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEP VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKP SNTKV
  • the underlined and italicized sequence is the heavy chain constant domain with phenylalanine (F), glutamic acid (E), and serine (S) and mutations.
  • ee.5H4 Chimeric Heavy Chain, human IgG1 constant domains (AA) [00739]
  • One embodiment provides a 5H4 chimeric heavy chain, human IgG1 constant domains (AA) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: QVTLKESGPGILQPSQTLSLTCSFSGFSLSTFGVGVGWFRQSSGKGLEWLAHI WWDDEKYSNPALKTRLSISKDTSKNQVFLKIANVDTADTATHYCARIDSTV VAYAYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEP VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKP SNTKV
  • the dot underlined sequence is the heavy chain constant domain with alanine-alanine (AA) mutations.
  • AA alanine-alanine
  • G4P human IgG4 constant domain
  • One embodiment provides a 5H4 chimeric heavy chain, human IgG4 constant domain (G4P) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: 125 064467-020PCT QVTLKESGPGILQPSQTLSLTCSFSGFSLSTFGVGVGWFRQSSGKGLEWLAHI WWDDEKYSNPALKTRLSISKDTSKNQVFLKIANVDTADTATHYCARIDSTV VAYAYWGQGTTLTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPV TVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPS NTKVDKRVE
  • the dash underlined sequence is the IgG4 heavy chain constant domain.
  • ii.5H4 Light Chain aa.5H4 Murine light chain variable region [00749]
  • One embodiment provides a5H4 murine light chain variable region having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: DVLMTQTPLSLPVSLGDQASISCRSSQTILHSDGNTYLEWYLQKPGQSPKLLI YKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYYCFQGSHVPYTFGG GTKLE (SEQ ID NO: 159) with [00750]
  • CDRL1 RSSQTILHSDGNTYLE (SEQ ID NO: 160), [00751]
  • CDRL2 KVSNRFS (SEQ ID NO: 161), [00752]
  • CDRL3 FQGSHVPYT (SEQ ID NO: 162).
  • bb.5H4 Chimeric Light Chain, human kappa wild type constant domain [00753]
  • One embodiment provides a5H4 chimeric light chain, human kappa wild type constant domain having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: DVLMTQTPLSLPVSLGDQASISCRSSQTILHSDGNTYLEWYLQKPGQSPKLLI YKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYYCFQGSHVPYTFGG GTKLERTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNAL 126 064467-020PCT QSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVT KSFNRGEC (SEQ ID NO: 163) with [00754] CDRL1: RSSQTILHSDGNTYLE (S
  • the underlined sequence is the light chain constant domain (wild type, kappa).
  • cc.5H4 Chimeric Light Chain, human kappa wild type constant domain (CAAX) [00758]
  • One embodiment provides a 5H4 chimeric light chain, human kappa wild type constant domain (CAAX) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: DVLMTQTPLSLPVSLGDQASISCRSSQTILHSDGNTYLEWYLQKPGQSPKLLI YKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYYCFQGSHVPYTFGG GTKLERTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNAL QSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVT KSFNRGECGGGGGGGCVIM (S
  • the double underlined sequence is the light chain constant domain with CAAX Sequence.
  • l.5H4 Humanized Sequences i.5H4 Humanized Heavy Chain 1 (HC-1) aa.5H4 Humanized HC-1 variable region
  • One embodiment provides a 5H4 humanized HC-1 variable region having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: QVTLKESGPTLVKPTQTLTLTCTFSGFSLSTFGVGVGWIRQPPGKALEWLALI WWDDEKRYGPSLKSRLTITKDTSKNQVVLTMTNMDPVDTATYYCAHIDSTV VAYAYWGQGTMVTVSS (SEQ ID NO:309) with [00764] CDR-H1 GFSLSTFGVG (SEQ ID NO:432), 127 064467-020PCT [00765] CDR-H2 IWWDDEK (SEQ ID NO:310), [00
  • bb.5H4 Humanized HC-1, human wild type IgG1 constant domains [00767]
  • One embodiment provides a 5H4 humanized HC-1, human wild type IgG1 constant domain having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: QVTLKESGPTLVKPTQTLTLTCTFSGFSLSTFGVGVGWIRQPPGKALEWLALI WWDDEKRYGPSLKSRLTITKDTSKNQVVLTMTNMDPVDTATYYCAHIDSTV VAYAYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEP VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKP SNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVT CVVVDVSHEDPEVKFNWYVDGVEVHNAKTK
  • One embodiment provides a 5H4 humanized HC-1, human IgG1 constant domain (FES) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: QVTLKESGPTLVKPTQTLTLTCTFSGFSLSTFGVGVGWIRQPPGKALEWLALI WWDDEKRYGPSLKSRLTITKDTSKNQVVLTMTNMDPVDTATYYCAHIDSTV VAYAYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEP VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKP SNTKVDKKVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVT CVVVDVSHEDPEVK
  • One embodiment provides a 5H4 humanized HC-1, human IgG1 constant domain (AA) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: QVTLKESGPTLVKPTQTLTLTCTFSGFSLSTFGVGVGWIRQPPGKALEWLALI WWDDEKRYGPSLKSRLTITKDTSKNQVVLTMTNMDPVDTATYYCAHIDSTV VAYAYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEP VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKP SNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEV TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKP
  • One embodiment provides a 5H4 humanized HC-1, human IgG4 constant domain (G4P) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: 129 064467-020PCT QVTLKESGPTLVKPTQTLTLTCTFSGFSLSTFGVGVGWIRQPPGKALEWLALI WWDDEKRYGPSLKSRLTITKDTSKNQVVLTMTNMDPVDTATYYCAHIDSTV VAYAYWGQGTMVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEP VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKP SNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVV VDVSQEDPEV
  • HC-2 variable region having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: QVTLKESGPTLVKPTQTLTLTCTFSGFSLSTFGVGVGWIRQPPGKALEWLALI WWDDEKRYGPSLKSRLTITKDTSKNQVVLTMTNMDPVDTATYYCARIDSTV VAYAYWGQGTMVTVSS (SEQ ID NO:317) with [00773] CDR-H1 GFSLSTFGVG (SEQ ID NO:432), [00774] CDR-H2 IWWDDEK (SEQ ID NO:310), [00775] CDR-H3 ARIDSTVVAYAY (SEQ ID NO: 433).
  • bb.5H4 Humanized HC-2 human wild type IgG1 constant domains
  • One embodiment provides a 5H4 humanized HC-2, human wild type IgG1 constant domain having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: QVTLKESGPTLVKPTQTLTLTCTFSGFSLSTFGVGVGWIRQPPGKALEWLALI WWDDEKRYGPSLKSRLTITKDTSKNQVVLTMTNMDPVDTATYYCARIDSTV VAYAYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEP VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKP SNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVT CVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQ
  • One embodiment provides a 5H4 humanized HC-2, human IgG1 constant domain (DLE) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: QVTLKESGPTLVKPTQTLTLTCTFSGFSLSTFGVGVGWIRQPPGKALEWLALI WWDDEKRYGPSLKSRLTITKDTSKNQVVLTMTNMDPVDTATYYCARIDSTV VAYAYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEP VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKP SNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPDVFLFPPKPKDTLMISRTPEVT CVVVDVSHEDPEVKFNW
  • One embodiment provides a 5H4 humanized HC-2, human IgG1 constant domain (FES) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: QVTLKESGPTLVKPTQTLTLTCTFSGFSLSTFGVGVGWIRQPPGKALEWLALI WWDDEKRYGPSLKSRLTITKDTSKNQVVLTMTNMDPVDTATYYCARIDSTV VAYAYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEP VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKP SNTKVDKKVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVT CVVVDVSHEDPEVKFNWYVDGVEVHNAK
  • One embodiment provides a 5H4 humanized HC-2, human IgG1 constant domain (AA) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: 131 064467-020PCT QVTLKESGPTLVKPTQTLTLTCTFSGFSLSTFGVGVGWIRQPPGKALEWLALI WWDDEKRYGPSLKSRLTITKDTSKNQVVLTMTNMDPVDTATYYCARIDSTV VAYAYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEP VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKP SNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEV TCVVVDVSHEDPEVKFN
  • One embodiment provides a 5H4 humanized HC-2, human IgG4 constant domain (G4P) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: QVTLKESGPTLVKPTQTLTLTCTFSGFSLSTFGVGVGWIRQPPGKALEWLALI WWDDEKRYGPSLKSRLTITKDTSKNQVVLTMTNMDPVDTATYYCARIDSTV VAYAYWGQGTMVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEP VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKP SNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVV VDVSQEDPEVQFNWYVDGVEVHNA
  • HC-3) aa.5H4 Humanized Heavy Chain 3 (HC-3)
  • HC-3 variable region a 5H4 humanized HC-3 variable region having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: QVTLKESGPTLVKPTQTLTLTCSFSGFSLSTFGVGVGWIRQPPGKALEWLAHI WWDDEKYYGPSLKSRLTITKDTSKNQVVLTMTNMDPVDTATYYCARIDSTV VAYAYWGQGTMVTVSS (SEQ ID NO:324) with [00782] CDR-H1 GFSLSTFGVG (SEQ ID NO:432), [00783] CDR-H2 IWWDDEK (SEQ ID NO:310), [00784] CDR-H3 ARIDSTVVAYAY (SEQ ID NO: 433).
  • bb.5H4 Humanized HC-3 human wild type IgG1 constant domains
  • One embodiment provides a 5H4 humanized HC-3, human wild type IgG1 constant domain having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: QVTLKESGPTLVKPTQTLTLTCSFSGFSLSTFGVGVGWIRQPPGKALEWLAHI WWDDEKYYGPSLKSRLTITKDTSKNQVVLTMTNMDPVDTATYYCARIDSTV VAYAYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEP VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKP SNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVT CVVVDVSHEDPEVKFNW
  • cc.5H4 humanized HC-3, human IgG1 constant domains (DLE) [00786]
  • One embodiment provides a 5H4 humanized HC-3, human IgG1 constant domain (DLE) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: QVTLKESGPTLVKPTQTLTLTCSFSGFSLSTFGVGVGWIRQPPGKALEWLAHI WWDDEKYYGPSLKSRLTITKDTSKNQVVLTMTNMDPVDTATYYCARIDSTV VAYAYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEP VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKP SNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPDVFLFPPKPKDTLMISRTPEVT CVVVDVSHEDPEVKFNWYVDG
  • One embodiment provides a 5H4 humanized HC-3, human IgG1 constant domain (FES) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: 133 064467-020PCT QVTLKESGPTLVKPTQTLTLTCSFSGFSLSTFGVGVGWIRQPPGKALEWLAHI WWDDEKYYGPSLKSRLTITKDTSKNQVVLTMTNMDPVDTATYYCARIDSTV VAYAYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEP VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKP SNTKVDKKVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVT CVVVDVSHEDP
  • One embodiment provides a 5H4 humanized HC-3, human IgG1 constant domain (AA) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: QVTLKESGPTLVKPTQTLTLTCSFSGFSLSTFGVGVGWIRQPPGKALEWLAHI WWDDEKYYGPSLKSRLTITKDTSKNQVVLTMTNMDPVDTATYYCARIDSTV VAYAYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEP VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKP SNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEV TCVVVDVSHEDPEVKFNWYVDGVEVHNA
  • One embodiment provides a 5H4 humanized HC-3, human IgG4 constant domain (G4P) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: QVTLKESGPTLVKPTQTLTLTCSFSGFSLSTFGVGVGWIRQPPGKALEWLAHI WWDDEKYYGPSLKSRLTITKDTSKNQVVLTMTNMDPVDTATYYCARIDSTV VAYAYWGQGTMVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEP VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKP SNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVV VDVSQEDPEVQFNWYVDGVEV
  • HC-4 variable region having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: QVTLKESGPTLVKPTQTLTLTCTFSGFSLSTFGVGVGWIRQPPGKALEWLAHI WWDDEKYSNPALKTRLTITKDTSKNQVVLTMTNMDPVDTATYYCAHIDSTV VAYAYWGQGTMVTVSS (SEQ ID NO:330) with [00791] CDR-H1 GFSLSTFGVG (SEQ ID NO:432), [00792] CDR-H2 IWWDDEK (SEQ ID NO:310), [00793] CDR-H3 AHIDSTVVAYAY (SEQ ID NO:311).
  • bb.5H4 Humanized HC-4 human wild type IgG1 constant domains
  • One embodiment provides a 5H4 humanized HC-4, human wild type IgG1 constant domain having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: QVTLKESGPTLVKPTQTLTLTCTFSGFSLSTFGVGVGWIRQPPGKALEWLAHI WWDDEKYSNPALKTRLTITKDTSKNQVVLTMTNMDPVDTATYYCAHIDSTV VAYAYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEP VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKP SNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVT CVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPRE
  • cc.5H4 humanized HC-4, human IgG1 constant domains (DLE) [00795]
  • One embodiment provides a 5H4 humanized HC-4, human IgG1 constant domain (DLE) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: 135 064467-020PCT QVTLKESGPTLVKPTQTLTLTCTFSGFSLSTFGVGVGWIRQPPGKALEWLAHI WWDDEKYSNPALKTRLTITKDTSKNQVVLTMTNMDPVDTATYYCAHIDSTV VAYAYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEP VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKP SNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPDVFLFPPKPKDTLMISRTPEVT CVVVDVS
  • dd.5H4 humanized HC-4, human IgG1 constant domains [00796]
  • One embodiment provides a 5H4 humanized HC-4, human IgG1 constant domain (FES) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: QVTLKESGPTLVKPTQTLTLTCTFSGFSLSTFGVGVGWIRQPPGKALEWLAHI WWDDEKYSNPALKTRLTITKDTSKNQVVLTMTNMDPVDTATYYCAHIDSTV VAYAYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEP VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKP SNTKVDKKVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVT CVVVDVSHEDPEVKFNWYVDGVEVHNA
  • One embodiment provides a 5H4 humanized HC-4, human IgG1 constant domain (AA) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: QVTLKESGPTLVKPTQTLTLTCTFSGFSLSTFGVGVGWIRQPPGKALEWLAHI WWDDEKYSNPALKTRLTITKDTSKNQVVLTMTNMDPVDTATYYCAHIDSTV VAYAYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEP VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKP SNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEV TCVVVDVSHEDPEVKFNWYVDGVEVHNAK
  • One embodiment provides a 5H4 humanized HC-4, human IgG4 constant domain (G4P) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: QVTLKESGPTLVKPTQTLTLTCTFSGFSLSTFGVGVGWIRQPPGKALEWLAHI WWDDEKYSNPALKTRLTITKDTSKNQVVLTMTNMDPVDTATYYCAHIDSTV VAYAYWGQGTMVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEP VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKP SNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVV VDVSQEDPEVQFNWYVDGVEVH
  • HC-6 variable region having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: QVTLRESGPALVKPTQTLTLTCTFSGFSLSTFGVGVGWIRQPPGKALEWLAHI WWDDEKYSNPALKTRLTISKDTSKNQVVLTMTNMDPVDTATYYCARIDSTV VAYAYWGQGSLVTVSS (SEQ ID NO:336) with [00800] CDR-H1 GFSLSTFGVG (SEQ ID NO:432), [00801] CDR-H2 IWWDDEK (SEQ ID NO:310), [00802] CDR-H3 ARIDSTVVAYAY (SEQ ID NO: 433).
  • bb.5H4 Humanized HC-6, human wild type IgG1 constant domains [00803]
  • One embodiment provides a 5H4 humanized HC-6, human wild type IgG1 constant domain having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: 137 064467-020PCT QVTLRESGPALVKPTQTLTLTCTFSGFSLSTFGVGVGWIRQPPGKALEWLAHI WWDDEKYSNPALKTRLTISKDTSKNQVVLTMTNMDPVDTATYYCARIDSTV VAYAYWGQGSLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEP VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKP SNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVT CVVVDVSHEDPEVK
  • cc.5H4 humanized HC-6, human IgG1 constant domains (DLE) [00804]
  • One embodiment provides a 5H4 humanized HC-6, human IgG1 constant domain (DLE) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: QVTLRESGPALVKPTQTLTLTCTFSGFSLSTFGVGVGWIRQPPGKALEWLAHI WWDDEKYSNPALKTRLTISKDTSKNQVVLTMTNMDPVDTATYYCARIDSTV VAYAYWGQGSLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEP VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKP SNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPDVFLFPPKPKDTLMISRTPEVT CVVVDVSHEDPEVKFNWYVDGVE
  • One embodiment provides a 5H4 humanized HC-6, human IgG1 constant domain (AA) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: QVTLRESGPALVKPTQTLTLTCTFSGFSLSTFGVGVGWIRQPPGKALEWLAHI WWDDEKYSNPALKTRLTISKDTSKNQVVLTMTNMDPVDTATYYCARIDSTV VAYAYWGQGSLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEP VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKP SNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEV TCVVVDVSHEDPEVKFNWYVDGVEVHNAK
  • One embodiment provides a 5H4 humanized HC-6, human IgG4 constant domain (G4P) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: QVTLRESGPALVKPTQTLTLTCTFSGFSLSTFGVGVGWIRQPPGKALEWLAHI WWDDEKYSNPALKTRLTISKDTSKNQVVLTMTNMDPVDTATYYCARIDSTV VAYAYWGQGSLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPV TVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPS NTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVV DVSQEDPEVQFNWYVDGVEVHNA
  • HC-7 variable region having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: QVTLRESGPALVKPTQTLTLTCTVSGFSLSTFGVGVGWIRQPPGKALEWLAHI WWDDEKYSNPALKTRLTISKDTSKNQVVLTMTNMDPVDTATYYCARIDSTV VAYAYWGQGSLVTVSS (SEQ ID NO:342) with [00809] CDR-H1 GFSLSTFGVG (SEQ ID NO:432), [00810] CDR-H2 IWWDDEK (SEQ ID NO:310), [00811] CDR-H3 ARIDSTVVAYAY (SEQ ID NO: 433).
  • One embodiment provides a 5H4 humanized HC-7, human IgG1 constant domain (AA) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: QVTLRESGPALVKPTQTLTLTCTVSGFSLSTFGVGVGWIRQPPGKALEWLAHI WWDDEKYSNPALKTRLTISKDTSKNQVVLTMTNMDPVDTATYYCARIDSTV VAYAYWGQGSLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEP VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKP SNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEV TCVVVDVSHEDPEVKFNWYVDGVEVHNAK
  • One embodiment provides a 5H4 humanized HC-7, human IgG4 constant domain (G4P) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: QVTLRESGPALVKPTQTLTLTCTVSGFSLSTFGVGVGWIRQPPGKALEWLAHI WWDDEKYSNPALKTRLTISKDTSKNQVVLTMTNMDPVDTATYYCARIDSTV VAYAYWGQGSLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPV TVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPS NTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVV DVSQEDPEV
  • HC-8 variable region having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: QVTLKESGPTLVKPTQTLTLTCSFSGFSLSTFGVGVGWIRQPPGKALEWLAHI WWDDEKYSNPALKTRLTISKDTSKNQVVLTMTNVDPVDTATYYCARIDSTV VAYAYWGQGTLVTVSS (SEQ ID NO:348) with [00818] CDR-H1 GFSLSTFGVG (SEQ ID NO:432), [00819] CDR-H2 IWWDDEK (SEQ ID NO:310), [00820] CDR-H3 ARIDSTVVAYAY (SEQ ID NO: 433).
  • bb.5H4 Humanized HC-8 human wild type IgG1 constant domains
  • One embodiment provides a 5H4 humanized HC-8, human wild type IgG1 constant domain having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: QVTLKESGPTLVKPTQTLTLTCSFSGFSLSTFGVGVGWIRQPPGKALEWLAHI WWDDEKYSNPALKTRLTISKDTSKNQVVLTMTNVDPVDTATYYCARIDSTV VAYAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEP VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKP 142 064467-020PCT SNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVT CVVVDVSHEDPEVKFNWY
  • cc.5H4 humanized HC-8, human IgG1 constant domains (DLE) [00822]
  • One embodiment provides a 5H4 humanized HC-8, human IgG1 constant domain (DLE) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: QVTLKESGPTLVKPTQTLTLTCSFSGFSLSTFGVGVGWIRQPPGKALEWLAHI WWDDEKYSNPALKTRLTISKDTSKNQVVLTMTNVDPVDTATYYCARIDSTV VAYAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEP VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKP SNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPDVFLFPPKPKDTLMISRTPEVT CVVVDVSHEDPEVKFNWYVDGVE
  • dd.5H4 humanized HC-8, human IgG1 constant domains [00823]
  • One embodiment provides a 5H4 humanized HC-8, human IgG1 constant domain (FES) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: QVTLKESGPTLVKPTQTLTLTCSFSGFSLSTFGVGVGWIRQPPGKALEWLAHI WWDDEKYSNPALKTRLTISKDTSKNQVVLTMTNVDPVDTATYYCARIDSTV VAYAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEP VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKP SNTKVDKKVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVT CVVVDVSHEDPEVKFNWYVDGVEVHNA
  • One embodiment provides a 5H4 humanized HC-8, human IgG1 constant domain (AA) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: QVTLKESGPTLVKPTQTLTLTCSFSGFSLSTFGVGVGWIRQPPGKALEWLAHI WWDDEKYSNPALKTRLTISKDTSKNQVVLTMTNVDPVDTATYYCARIDSTV VAYAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEP VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKP SNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEV TCVVVDVSHEDPEVK
  • One embodiment provides a 5H4 humanized HC-8, human IgG4 constant domain (G4P) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: QVTLKESGPTLVKPTQTLTLTCSFSGFSLSTFGVGVGWIRQPPGKALEWLAHI WWDDEKYSNPALKTRLTISKDTSKNQVVLTMTNVDPVDTATYYCARIDSTV VAYAYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPV TVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPS NTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVV DVSQEDPEVQFNWYVDGVEVHNA
  • HC-9 variable region having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: 144 064467-020PCT EVQLLESGGGLVQPGGSLRLSCAASGFSLSTFGVSWVRQAPGKGLEWVSAIW WDDETYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKIDSTVV AYAYWGQGTLVTVSS (SEQ ID NO:354) with [00827] CDR-H1 GFSLSTFG (SEQ ID NO:355), [00828] CDR-H2 IWWDDET (SEQ ID NO:356), [00829] CDR-H3 AKIDSTVVAYAY (SEQ ID NO:357), bb.5H4 Humanized Heavy Chain 9 (SEQ ID NO:357), bb.5H4 Humanized Heavy Chain 9 (SEQ ID NO:357), bb.5H4 Humanized Heavy Chain
  • cc.5H4 humanized HC-9, human IgG1 constant domains (DLE) [00831]
  • One embodiment provides a 5H4 humanized HC-9, human IgG1 constant domain (DLE) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: EVQLLESGGGLVQPGGSLRLSCAASGFSLSTFGVSWVRQAPGKGLEWVSAIW WDDETYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKIDSTVV AYAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPV TVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPS NTKVDKKVEPKSCDKTHTCPPCPAPELLGGPDVFLFPPKPKDTLMISRTPEVT CVVVDVSHEDPEVKFNWYVDGVEV
  • One embodiment provides a 5H4 humanized HC-9, human IgG1 constant domain (FES) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: EVQLLESGGGLVQPGGSLRLSCAASGFSLSTFGVSWVRQAPGKGLEWVSAIW WDDETYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKIDSTVV AYAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPV TVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPS NTKVDKKVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTC VVVDVSHEDPEV
  • One embodiment provides a 5H4 humanized HC-9, human IgG1 constant domain (AA) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: EVQLLESGGGLVQPGGSLRLSCAASGFSLSTFGVSWVRQAPGKGLEWVSAIW WDDETYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKIDSTVV AYAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPV TVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPS NTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVT CVVVDVSHEDPEVKFNWYVDGVEVHNAKTKP
  • One embodiment provides a 5H4 humanized HC-9, human IgG4 constant domain (G4P) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: 146 064467-020PCT EVQLLESGGGLVQPGGSLRLSCAASGFSLSTFGVSWVRQAPGKGLEWVSAIW WDDETYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKIDSTVV AYAYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVT VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSN TKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVD VSQED
  • HC-10 variable region having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: QVTLKESGPTLVKPTQTLTLTCSFSGFSLSTFGVGVGWIRQSPGKALEWLALI WWDDEKYYNPSLKTRLSISKDTSKNQVFLTMTNVDPADTATYYCARIDSTV VAYAYWGQGTLVTVSS (SEQ ID NO:363) with [00836] CDR-H1 GFSLSTFGVG (SEQ ID NO:432), [00837] CDR-H2 IWWDDEK (SEQ ID NO:310), [00838] CDR-H3 ARIDSTVVAYAY (SEQ ID NO: 433).
  • One embodiment provides a 5H4 humanized HC-10, human IgG1 constant domain (DLE) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: QVTLKESGPTLVKPTQTLTLTCSFSGFSLSTFGVGVGWIRQSPGKALEWLALI WWDDEKYYNPSLKTRLSISKDTSKNQVFLTMTNVDPADTATYYCARIDSTV VAYAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEP VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKP SNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPDVFLFPPKPKDTLMISRTPEVT CVVVDVSHEDPEVKFNW
  • One embodiment provides a 5H4 humanized HC-10, human IgG1 constant domain (AA) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: 148 064467-020PCT QVTLKESGPTLVKPTQTLTLTCSFSGFSLSTFGVGVGWIRQSPGKALEWLALI WWDDEKYYNPSLKTRLSISKDTSKNQVFLTMTNVDPADTATYYCARIDSTV VAYAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEP VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKP SNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEV TCVVVDVSHEDPEVKFNW
  • One embodiment provides a 5H4 humanized HC-10, human IgG4 constant domain (G4P) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: QVTLKESGPTLVKPTQTLTLTCSFSGFSLSTFGVGVGWIRQSPGKALEWLALI WWDDEKYYNPSLKTRLSISKDTSKNQVFLTMTNVDPADTATYYCARIDSTV VAYAYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPV TVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPS NTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVV DVSQEDPEVQFNWYVDGVEVHNAKTK
  • HC-12 variable region having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: QVTLKESGPTLVKPTQTLTLTCSFSGFSLSTFGVGVGWIRQSPGKALEWLAHI WWDDEKYYNPSLKTRLSISKDTSKNQVFLTMTNVDPADTATYYCARIDSTV VAYAYWGQGTLVTVSS (SEQ ID NO:369) with [00845] CDR-H1 GFSLSTFGVG (SEQ ID NO:432), [00846] CDR-H2 IWWDDEK (SEQ ID NO:310), 149 064467-020PCT [00847] CDR-H3 ARIDSTVVAYAY (SEQ ID NO: 433).
  • bb.5H4 Humanized HC-12, human wild type IgG1 constant domains [00848]
  • One embodiment provides a 5H4 humanized HC-12, human wild type IgG1 constant domain having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: QVTLKESGPTLVKPTQTLTLTCSFSGFSLSTFGVGVGWIRQSPGKALEWLAHI WWDDEKYYNPSLKTRLSISKDTSKNQVFLTMTNVDPADTATYYCARIDSTV VAYAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEP VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKP SNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVT CVVVDVSHEDPEVKFNWYVDGVEVHNAKTK
  • cc.5H4 humanized HC-12, human IgG1 constant domains (DLE) [00849]
  • One embodiment provides a 5H4 humanized HC-12, human IgG1 constant domain (DLE) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: QVTLKESGPTLVKPTQTLTLTCSFSGFSLSTFGVGVGWIRQSPGKALEWLAHI WWDDEKYYNPSLKTRLSISKDTSKNQVFLTMTNVDPADTATYYCARIDSTV VAYAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEP VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKP SNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPDVFLFPPKPKDTLMISRTPEVT CVVVDVSHEDPEVKFNWYVDGVEV
  • One embodiment provides a 5H4 humanized HC-12, human IgG1 constant domain (FES) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: 150 064467-020PCT QVTLKESGPTLVKPTQTLTLTCSFSGFSLSTFGVGVGWIRQSPGKALEWLAHI WWDDEKYYNPSLKTRLSISKDTSKNQVFLTMTNVDPADTATYYCARIDSTV VAYAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEP VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKP SNTKVDKKVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVT CVVVDVSHEDPEVKFNW
  • bb.5H4 Humanized HC-13, human wild type IgG1 constant domains [00857]
  • One embodiment provides a 5H4 humanized HC-13, human wild type IgG1 constant domain having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: QVTLKESGPTLVKPTQTLTLTCSFSGFSLSTFGVGVGWIRQSPGKALEWLAHI WWDDEKYSNPALKTRLSISKDTSKNQVFLTMTNVDPADTATYYCARIDSTV VAYAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEP VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKP SNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVT CVVVDVSHEDPEVKFNWYVDGVEVHNAKTKP
  • cc.5H4 humanized HC-13, human IgG1 constant domains (DLE) [00858]
  • One embodiment provides a 5H4 humanized HC-13, human IgG1 constant domain (DLE) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: 152 064467-020PCT QVTLKESGPTLVKPTQTLTLTCSFSGFSLSTFGVGVGWIRQSPGKALEWLAHI WWDDEKYSNPALKTRLSISKDTSKNQVFLTMTNVDPADTATYYCARIDSTV VAYAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEP VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKP SNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPDVFLFPPKPKDTLMISRTPEVT CVVVDVSHEDP
  • One embodiment provides a 5H4 humanized HC-13, human IgG1 constant domain (FES) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: QVTLKESGPTLVKPTQTLTLTCSFSGFSLSTFGVGVGWIRQSPGKALEWLAHI WWDDEKYSNPALKTRLSISKDTSKNQVFLTMTNVDPADTATYYCARIDSTV VAYAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEP VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKP SNTKVDKKVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVT CVVVDVSHEDPEVKFNWYVDGVEVHNAKTKTK
  • bb.5H4 Humanized LC-2, human kappa wild type constant domain [00900]
  • One embodiment provides a 5H4 humanized LC-2, human kappa wild type constant domain having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: DIVMTQTPLSLSVTPGQPASISCRSSQTILHSDGNTYLEWYLQKPGQSPQLLIY KVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHVPYTFGQGT KLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQ SGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKS FNRGEC (SEQ ID NO:405).
  • LC-3) aa.5H4 Humanized Light Chain 3 (LC-3) aa.5H4 Humanized LC-3 variable region
  • One embodiment provides a 5H4 humanized LC-3 variable region having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: 163 064467-020PCT DIVMTQTPLSLSVTPGQPASISCRSSQTILHSDGNTYLEWYLQKPGQSPQLLIY KVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHVPYTFGQGT KLEIK (SEQ ID NO:407) with [00904] CDR-L1 QTILHSDGNTY (SEQ ID NO:400), [00905] CDR-L2 KVS (SEQ ID NO:401), [00906] CDR-L3 FQGSHVPYT (SEQ ID NO: 162).
  • bb.5H4 Humanized LC-3, human kappa wild type constant domain [00907]
  • One embodiment provides a 5H4 humanized LC-3, human kappa wild type constant domain having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: DIVMTQTPLSLSVTPGQPASISCRSSQTILHSDGNTYLEWYLQKPGQSPQLLIY KVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHVPYTFGQGT KLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQ SGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKS FNRGEC (SEQ ID NO:408).
  • the underlined sequence is the light chain constant domain (wild type, kappa).
  • cc.5H4 Humanized LC-3, human kappa wild type constant domain (CAAX) [00909]
  • One embodiment provides a 5H4 humanized LC-3, human kappa wild type constant domain (CAAX) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: DIVMTQTPLSLSVTPGQPASISCRSSQTILHSDGNTYLEWYLQKPGQSPQLLIY KVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHVPYTFGQGT KLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQ SGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKS FNRGECGGGGGGGCV
  • LC-5 variable region having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: 164 064467-020PCT DVVMTQTPLSLSVTPGQPASISCRSSQTILHSDGNTYLEWYLQKPGQSPQLLIY KVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHVPYTFGQGT KLEIK (SEQ ID NO:410) with [00911] CDR-L1 QTILHSDGNTY (SEQ ID NO:400), [00912] CDR-L2 KVS (SEQ ID NO:401), [00913] CDR-L3 FQGSHVPYT (SEQ ID NO: 162).
  • bb.5H4 Humanized LC-5, human kappa wild type constant domain [00914]
  • One embodiment provides a 5H4 humanized LC-5, human kappa wild type constant domain having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: DVVMTQTPLSLSVTPGQPASISCRSSQTILHSDGNTYLEWYLQKPGQSPQLLIY KVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHVPYTFGQGT KLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQ SGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKS FNRGEC (SEQ ID NO:411).
  • the underlined sequence is the light chain constant domain (wild type, kappa).
  • cc.5H4 Humanized LC-5, human kappa wild type constant domain (CAAX) [00916]
  • One embodiment provides a 5H4 humanized LC-5, human kappa wild type constant domain (CAAX) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: DVVMTQTPLSLSVTPGQPASISCRSSQTILHSDGNTYLEWYLQKPGQSPQLLIY KVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHVPYTFGQGT KLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQ SGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKS FNRGECGGGGGGG
  • LC-6 variable region having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: 165 064467-020PCT DVVMTQTPLSLPVTLGQPASISCRSSQTILHSDGNTYLEWYLQKPGQSPQLLIY KVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHVPYTFGQGT KLEIK (SEQ ID NO:413) with [00918] CDR-L1 QTILHSDGNTY (SEQ ID NO:400), [00919] CDR-L2 KVS (SEQ ID NO:401), [00920] CDR-L3 FQGSHVPYT (SEQ ID NO: 162).
  • bb.5H4 Humanized LC-6, human kappa wild type constant domain [00921]
  • One embodiment provides a 5H4 humanized LC-6, human kappa wild type constant domain having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: DVVMTQTPLSLPVTLGQPASISCRSSQTILHSDGNTYLEWYLQKPGQSPQLLIY KVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHVPYTFGQGT KLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQ SGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKS FNRGEC (SEQ ID NO:414).
  • the underlined sequence is the light chain constant domain (wild type, kappa).
  • cc.5H4 Humanized LC-6, human kappa wild type constant domain (CAAX) [00923]
  • One embodiment provides a 5H4 humanized LC-6, human kappa wild type constant domain (CAAX) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: DVVMTQTPLSLPVTLGQPASISCRSSQTILHSDGNTYLEWYLQKPGQSPQLLIY KVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHVPYTFGQGT KLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQ SGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKS FNRGECGGGGGGG
  • LC-9 variable region having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: 168 064467-020PCT DIVMTQSPDSLSVSLGERATINCRSSQTILHSDGNTYLEWYQQKPGQPPKLLIY KVSNRFSGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCFQGSHVPYTFGGGT KVEIK (SEQ ID NO:422) with [00939] CDR-L1 QTILHSDGNTY (SEQ ID NO:400), [00940] CDR-L2 KVS (SEQ ID NO:401), [00941] CDR-L3 FQGSHVPYT (SEQ ID NO: 162).
  • the underlined sequence is the light chain constant domain (wild type, kappa).
  • cc.5H4 Humanized LC-9, human kappa wild type constant domain (CAAX) [00944]
  • One embodiment provides a 5H4 humanized LC-9, human kappa wild type constant domain (CAAX) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: DIVMTQSPDSLSVSLGERATINCRSSQTILHSDGNTYLEWYQQKPGQPPKLLIY KVSNRFSGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCFQGSHVPYTFGGGT KVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNAL QSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVT KSFNRGECGGGGGGGCVIM (S
  • bb.6A3 Chimeric Heavy Chain, human wild type IgG1 constant domains [00956]
  • One embodiment provides a 6A3 chimeric heavy chain, human wild type IgG1 constant domains having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: QAYLQQSGAELVRPGASVKMSCKASGYTFISYNMHWVKQTPRQGLEWIGTI YPVNGDTSYNQNFKGKATLTVDKSSRTAYMQLSSLTSEDSAVYFCAREETN WVGFDFWGQGTSLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEP VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKP SNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVT CVVVDVSHEDPEVKFNWY
  • the italicized sequence is the heavy chain constant domain with aspartic acid (D), leucine (L), and glutamic acid (E) mutations dd.6A3 Chimeric Heavy Chain, human IgG1 constant domains (FES)
  • FES human IgG1 constant domains
  • One embodiment provides a 6A3 chimeric heavy chain, human IgG1 constant domains (FES) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: QAYLQQSGAELVRPGASVKMSCKASGYTFISYNMHWVKQTPRQGLEWIGTI YPVNGDTSYNQNFKGKATLTVDKSSRTAYMQLSSLTSEDSAVYFCAREETN WVGFDFWGQGTSLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPE PVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTY
  • the underlined and italicized sequence is the heavy chain constant domain with phenylalanine (F), glutamic acid (E), and serine (S) and mutations.
  • One embodiment provides a 6A3 chimeric heavy chain, human IgG1 constant domains (AA) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: QAYLQQSGAELVRPGASVKMSCKASGYTFISYNMHWVKQTPRQGLEWIGTI YPVNGDTSYNQNFKGKATLTVDKSSRTAYMQLSSLTSEDSAVYFCAREETN WVGFDFWGQGTSLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPE PVTVSWNSGALTSGVHTFPAVLQSSGLY
  • the dot underlined sequence is the heavy chain constant domain with alanine-alanine (AA) mutations.
  • AA alanine-alanine
  • G4P human IgG4 constant domain
  • One embodiment provides a 6A3 chimeric heavy chain, human IgG4 constant domain (G4P) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: QAYLQQSGAELVRPGASVKMSCKASGYTFISYNMHWVKQTPRQGLEWIGTI YPVNGDTSYNQNFKGKATLTVDKSSRTAYMQLSSLTSEDSAVYFCAREETN WVGFDFWGQGTSLTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEP VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKP SNTKVDKRVE
  • the dash underlined sequence is the IgG4 heavy chain constant domain.
  • ii.6A3 Light Chain aa.6A3 Murine light chain variable region [00981]
  • One embodiment provides a 6A3 murine light chain variable region having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: DIVMTQAAFSNSVTLGTSASISCRSSKSLKYTDGITYLYWYLQRPGQSPQLLI YRMSNLASGVPDRFSGSGSGTDFTLRISRVEAEDVGVYYCAQMLEFPYTFGS GTKLEIK (SEQ ID NO: 174) with [00982] CDRL1: RSSKSLKYTDGITYLY (SEQ ID NO: 175), [00983] CDRL2: RMSNLAS (SEQ ID NO: 176), [00984] CDRL3: AQMLEFPYT (SEQ ID NO: 177).
  • bb.6A3 Chimeric Light Chain, human kappa wild type constant domain [00985]
  • One embodiment provides a 6A3 chimeric light chain, human kappa wild type constant domain having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: DIVMTQAAFSNSVTLGTSASISCRSSKSLKYTDGITYLYWYLQRPGQSPQLLI YRMSNLASGVPDRFSGSGSGTDFTLRISRVEAEDVGVYYCAQMLEFPYTFGS GTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNA LQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVT KSFNRGEC (SEQ ID NO: 178) with [00986]
  • CDRL1 RSSKSLKYTDGITYLY (SEQ ID NO: 175)
  • CDRL2
  • the underlined sequence is the light chain constant domain (wild type, kappa). 174 064467-020PCT cc.6A3 Chimeric Light Chain, human kappa wild type constant domain (CAAX) [00990]
  • One embodiment provides a 6A3 chimeric light chain, human kappa wild type constant domain (CAAX) having at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or 100% sequence identity with the following amino acid sequence: DIVMTQAAFSNSVTLGTSASISCRSSKSLKYTDGITYLYWYLQRPGQSPQLLI YRMSNLASGVPDRFSGSGSGTDFTLRISRVEAEDVGVYYCAQMLEFPYTFGS GTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNA LQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVT KSFNRGECG
  • An ADCs of the invention comprises an antibody to CDCP1 and at least one drug(s), whereby the antibody and the at least one drug are conjugated by a linker.
  • the term “linker,” as used herein, refers to a chemical moiety that may be bifunctional or multifunctional, and is used to attach an antibody to a drug moiety.
  • a linker may include one conjugating component or may include multiple components.
  • the linker may include a spacer, which is a moiety that extends the drug linkage to avoid, for example, shielding the active site of the antibody or improving the solubility of the ADC.
  • linkers include a stretcher unit and an amino acid unit.
  • the linker described herein may be cleavable, non-cleavable and hydrophilic or hydrophobic.
  • the cleavable linker is cleavable under intracellular or extracellular conditions, by which an active agent is released from an antibody construct-active agent conjugate in the intracellular environment.
  • the cleavable linker can be cleaved by a cleaving agent present in an intracellular environment (e.g., lysosomes, endosomes, or caveolea).
  • the peptidyl linker cleavable by an intracellular protease may be, for example, a Val-Cit linker, a Phe-Lys linker (e.g., see U.S. Patent No.6,214,345, which describes the synthesis of doxorubicin using a Val-Cit linker), or a Val-Ala linker.
  • the Val-Cit linker or the Val-Ala linker may contain a pentafluorophenyl group and may contain a succinimide group or a maleimide group.
  • Val-Cit linker or the Val-Ala linker may contain a pentafluorophenyl group, may contain a 4-aminobenzoic acid (PABA) group and a maleimide group, and may contain a PABA group and a succinimide group.
  • Another linker may be acetyl cholinesterase/butryl cholinesterase (AChE/BChE).
  • a further linker may be an ⁇ -secretase cleavable linker.
  • a cleavable linker may be easily hydrolyzed in a pH-sensitive manner, i.e., at certain pH values. Generally, the pH-sensitive linker may be hydrolyzed under acidic conditions.
  • acid-labile linkers that can be hydrolyzed in lysosomes (e.g., hydrazone, semicarbazone, thiosemicarbazone, cis- aconic amides, orthoesters, acetals, and ketals) may be used (e.g., see: U.S. Patent NOs.5,122,368, 5,824,805, and 5,622,929; and Dubowchik and Walker, 1999, Pharm. Therapeutics 83:67-123; and Neville et al., 1989, Biol. Chem.264:14653- 14661).
  • linkers are relatively stable under neutral pH conditions, such as in blood, but are unstable at pH 5.5, which is the approximate pH of lysosomes, or less than pH 5.0.
  • hydrolysable linkers include thioether linkers (e.g., thioethers attached to a therapeutic agent via an acylhydrazone bond) (e.g., see U.S. Patent No.5,622,929).
  • thioether linkers e.g., thioethers attached to a therapeutic agent via an acylhydrazone bond
  • the linker is cleavable under reducing conditions (e.g., a disulfide linker).
  • various disulfide linkers including N-succinimidyl-5- 176 064467-020PCT acetylthioacetate (SATA), N-succinimidyl-3-(2-pyridyldithio)propionate (SPDP), N- succinimidyl-3-(2-pyridyldithio)butyrate (SPDB), and N-succinimidyl-oxycarbonyl- alpha-methyl-alpha-(2-pyridyl-thio)toluene)- (SMPT), and those that can be formed using SPDB and SMPT (e.g., see: Thorpe et al., 1987, Cancer Res.47:5924-5931; and U.S.
  • SPDB N-succinimidyl-5- 176 064467-020PCT acetylthioacetate
  • SPDP N-succinimidyl-3-(2-pyridyldithio)
  • the linker may be a malonate linker (Johnson et al., 1995, Anticancer Res.15:1387-93), a maleimidobenzoyl linker (Lau et al., 1995, Bioorg- Med-Chem.3(10):1299-1304), a 3'-N-amide analogue (Lau et al., 1995, Bioorg-Med- Chem.3(10):1305-12), a ⁇ -glucuronide linker (Jeffery et al., 2006, Bioconjug Chem.
  • the non-cleavable linker may be a maleimidocaproyl linker.
  • the maleimidocaproyl linker may include N-maleimidomethylcyclohexane-1-carboxylate.
  • the maleimidocaproyl linker may contain a succinimide group.
  • the maleimidocaproyl linker may contain a pentafluorophenyl group.
  • the linker may be a combination of a maleimide group and one or more polyethylene glycol molecules.
  • the linker may be a combination of a maleimidocaproyl group and one or more polyethylene glycol molecules.
  • the linker may be a maleimide-PEG4 linker.
  • the linker may be a combination of a maleimidocaproyl linker containing a succinimide group and one or more polyethylene glycol molecules.
  • the linker may be a combination of a pentafluorophenyl group and a maleimidocaproyl linker containing one or more polyethylene glycol molecules.
  • the linker may contain a maleimide linked to a polyethylene glycol molecule, wherein the polyethylene glycol allows for more linker flexibility or allows longer linkers to be used.
  • the linker may be a (maleimidocaproyl)-(valine-citrulline)-(para-aminobenzyloxycarbonyl) linker. [001004] In certain embodiments, the linker may be a cleavable linker.
  • the linker may be a protease cleavable linker, an acid-cleavable linker, a disulfide linker, a self-immolative linker or a self-stabilizing linker, a malonate linker, a maleimidobenzoyl linker, a 3'-N-amide analogue, a ⁇ - glucuronide linker, or a ⁇ -galactoside linker.
  • the protease cleavable linker may include a thiol-reactive spacer or a dipeptide, and more specifically, the protease cleavable linker may include a thiol-reactive maleimidocaproyl spacer, a valine-citrulline dipeptide, or a p-amino-benzyloxycarbonyl spacer. 177 064467-020PCT [001007] In certain embodiments, the acid-cleavable linker may be a hydrazine linker or a quaternary ammonium linker.
  • Exemplary antibody drug conjugates are disclosed in US 10,583,197, US 9,993,568, US 9,951,072, US 9,919,057, US 9,669,107, US 11,413,353, US 11,173,214, US 11,167,040, US 10,980,890, US 10,583,197, US 10,383,949, US 10,273,235, US 10,183,997, and US 10,118,965, the contents of each of which is fully incorporated by reference herein.
  • a linker covalently attaches an antibody to a drug moiety.
  • An ADC is prepared using a linker having reactive functionality for binding to the antibody and the drug.
  • a cysteine thiol, or an amine, e.g., N-terminus or amino acid side chain such as lysine, of the antibody may form a bond with a functional group of the linker.
  • a linker has a functionality that is capable of reacting with a free cysteine present on an antibody to form a covalent bond.
  • Nonlimiting exemplary such reactive functionalities include maleimide, haloacetamides, ⁇ - haloacetyl, activated esters such as succinimide esters, 4-nitrophenyl esters, pentafluorophenyl esters, tetrafluorophenyl esters, anhydrides, acid chlorides, sulfonyl chlorides, isocyanates, and isothiocyanates.
  • a linker has a functionality that is capable of reacting with an electrophilic group present on an antibody.
  • Exemplary electrophilic groups include, but are not limited to, aldehyde and ketone carbonyl groups.
  • a heteroatom of the reactive functionality of the linker can react with an electrophilic group on an antibody and form a covalent bond to an antibody unit.
  • Nonlimiting exemplary such reactive functionalities include, but are not limited to, hydrazide, oxime, amino, hydrazine, thiosemicarbazone, hydrazine carboxylate, and arylhydrazide.
  • Suitable linkers include, for example, cleavable and non-cleavable linkers.
  • a linker may be a “cleavable linker,” facilitating release of a drug.
  • Nonlimiting exemplary cleavable linkers include acid-labile linkers (e.g., comprising hydrazone), protease-sensitive (e.g., peptidase-sensitive) linkers, photolabile linkers, or disulfide-containing linkers (Chari et al., Cancer Research 52:127-131 (1992); U.S. Pat. No.5,208,020).
  • a cleavable linker is typically susceptible to cleavage under intracellular conditions.
  • Suitable cleavable linkers include, for example, a peptide linker cleavable by an intracellular protease, such as lysosomal protease or an endosomal protease.
  • the linker can be a dipeptide linker, such as a valine-citrulline (val-cit) or a phenylalanine-lysine (phe-lys) linker.
  • Linkers are preferably stable extracellularly in a sufficient manner to be therapeutically effective. Before transport or delivery into a cell, the ADC is preferably stable and remains intact, i.e. the antibody remains conjugated to the drug moiety. Linkers that are stable outside the target cell may be cleaved at some efficacious rate once inside the cell.
  • an effective linker will: (i) maintain the specific binding properties of the antibody; (ii) allow delivery, e.g., intracellular delivery, of the drug moiety; and (iii) maintain the therapeutic effect, e.g., cytotoxic effect, of a drug moiety.
  • the linker is cleavable under intracellular conditions, such that cleavage of the linker sufficiently releases the drug from the antibody in the intracellular environment to be therapeutically effective.
  • the cleavable linker is pH-sensitive, i.e., sensitive to hydrolysis at certain pH values. Typically, the pH-sensitive linker is hydrolyzable under acidic conditions.
  • an acid-labile linker that is hydrolyzable in the lysosome e.g., a hydrazone, semicarbazone, thiosemicarbazone, cis-aconitic amide, orthoester, acetal, ketal, or the like
  • a hydrazone, semicarbazone, thiosemicarbazone, cis-aconitic amide, orthoester, acetal, ketal, or the like can be used.
  • a hydrazone, semicarbazone, thiosemicarbazone, cis-aconitic amide, orthoester, acetal, ketal, or the like can be used.
  • the hydrolyzable linker is a thioether linker (such as, e.g., a thioether attached to the therapeutic agent via an acylhydrazone bond (see, e.g., U.S. Pat. No.5,622,929).
  • the linker is cleavable under reducing conditions (e.g., a disulfide linker).
  • disulfide linkers are known in the art, including, 179 064467-020PCT for example, those that can be formed using SATA (N-succinimidyl-5- acetylthioacetate), SPDP (N-succinimidyl-3-(2-pyridyldithio)propionate), SPDB (N- succinimidyl-3-(2-pyridyldithio)butyrate) and SMPT (N-succinimidyloxycarbonyl- alpha-methyl-alpha-(2-pyridyl-dithio)toluene), SPDB and SMPT.
  • SATA N-succinimidyl-5- acetylthioacetate
  • SPDP N-succinimidyl-3-(2-pyridyldithio)propionate
  • SPDB N- succinimidyl-3-(2-pyridyldithio)butyrate
  • the linker is cleavable by a cleaving agent, e.g., an enzyme, which is present in the intracellular environment (e.g., within a lysosome or endosome or caveolca).
  • a cleaving agent e.g., an enzyme
  • the linker can be, e.g., a peptidyl linker that is cleaved by an intracellular peptidase or protease enzyme, including, but not limited to, a lysosomal or endosomal protease.
  • the peptidyl linker is at least two amino acids long or at least three amino acids long.
  • Cleaving agents can include cathepsins B and D and plasmin, all of which are known to hydrolyze dipeptide drug derivatives resulting in the release of active drug inside target cells (see. e.g., Dubowchik and Walker, 1999, Pharm. Therapeutics 83:67-123).
  • peptidyl linkers that are cleavable by enzymes that are present in CDCP1-expressing cells. Examples of such linkers are described, e.g., in U.S. Pat. No.6,214,345, incorporated herein by reference in its entirety and for all purposes.
  • the peptidyl linker cleavable by an intracellular protease is a Val-Cit linker or a Phe-Lys linker (see, e.g., U.S. Pat. No.6,214,345, which describes the synthesis of doxorubicin with the val-cit linker).
  • the linker is a malonate linker (Johnson et al., 1995, Anticancer Res.15:1387-93), a maleimidobenzoyl linker (Lau et al., 1995, Bioorg-Med-Chem.3(10):1299-1304), or a 3′-N-amide analog (Lau et al., 1995, Bioorg-Med-Chem.3(10): 1305-12).
  • the ADC does not internalize into cell, yet linkers described in previous examples can be used to release locally payload to increase synaptic and neural functions or decrease inflammation.
  • the linker unit is not cleavable, and the drug is released, for example, by antibody degradation. See U.S. Publication No. 20050238649 incorporated by reference herein in its entirety.
  • An ADC comprising a 180 064467-020PCT non-cleavable linker may be designed such that the ADC remains substantially outside the cell and interacts with certain receptors on a target cell surface such that the binding of the ADC initiates (or prevents) a particular cellular signaling pathway.
  • the linker is substantially hydrophilic linker (e.g., PEG4Mal and sulfo-SPDB).
  • a hydrophilic linker may be used to reduce the extent to which the drug may be pumped out of resistant cells through MDR (multiple drug resistance) or functionally similar transporters.
  • the linker upon cleavage, the linker functions to directly or indirectly inhibit cell growth and/or cell proliferation.
  • the linker upon cleavage, can function as an intercalating agent, thereby inhibiting macromolecular biosynthesis (e.g. DNA replication, RNA transcription, and/or protein synthesis).
  • the linker is designed to facilitate bystander killing (the killing of neighboring cells) through diffusion of the linker-drug and/or the drug alone to neighboring cells. In other embodiments, the linker promotes cellular internalization.
  • the presence of a sterically hindered disulfide can increase the stability of a particular disulfide bond, enhancing the potency of the ADC.
  • the linker includes a sterically hindered disulfide linkage.
  • a sterically hindered disulfide refers to a disulfide bond present within a particular molecular environment, wherein the environment is characterized by a particular spatial arrangement or orientation of atoms, typically within the same molecule or compound, which prevents or at least partially inhibits the reduction of the disulfide bond.
  • the presence of bulky (or sterically hindering) chemical moieties and/or bulky amino acid side chains proximal to the disulfide bond prevents or at least partially inhibits the disulfide bond from potential interactions that would result in the reduction of the disulfide bond.
  • the aforementioned linker types are not mutually exclusive.
  • the linker used in the ADCs described herein is a non- cleavable linker that promotes cellular internalization.
  • the ADC has the following formula (formula I): Ab-(L-D) n (I) [001027] or a pharmaceutically acceptable salt or solvate thereof; wherein Ab is the antibody, e.g., anti-CDCP1, and (L-D) is a Linker-Drug moiety.
  • the Linker-Drug 181 064467-020PCT moiety is made of L- which is a Linker, and -D, which is a drug moiety having, for example, cytostatic, cytotoxic, or otherwise therapeutic activity against a target cell, e.g., CDCP1; and n is an integer from 1 to 20. [001028] In some embodiments, n ranges from 1 to 8, 1 to 7, 1 to 6, 1 to 5, 1 to 4, 1 to 3, 1 to 2, or is 1. [001029] In some embodiments, the -D moieties are the same. In yet another embodiment, the -D moieties are different.
  • a linker component comprises an “amino acid unit.”
  • the amino acid unit allows for cleavage of the linker by a protease, thereby facilitating release of the drug from the immunoconjugate upon exposure to intracellular proteases, such as lysosomal enzymes (Doronina et al. (2003) Nat. Biotechnol.21:778-784).
  • Exemplary amino acid units include, but are not limited to, dipeptides, tripeptides, tetrapeptides, and pentapeptides.
  • Exemplary dipeptides include, but are not limited to, valine-citrulline (vc or val-cit), alanine-phenylalanine (af or ala-phe); phenylalanine-lysine (fk or phe- lys); phenylalanine-homolysine (phe-homolys); and N-methyl-valine-citrulline (Me- val-cit).
  • Exemplary tripeptides include, but are not limited to, glycine-valine-citrulline (gly-val-cit) and glycine-glycine-glycine (gly-gly-gly).
  • amino acid unit may comprise amino acid residues that occur naturally and/or minor amino acids and/or non-naturally occurring amino acid analogs, such as citrulline
  • Amino acid units can be designed and optimized for enzymatic cleavage by a particular enzyme, for example, a tumor-associated protease, cathepsin B, C and D, or a plasmin protease.
  • the amino acid unit is valine-citrulline (vc or val-cit).
  • the amino acid unit is phenylalanine-lysine (i.e., fk).
  • the amino acid unit is N-methylvaline-citrulline.
  • the amino acid unit is 5-aminovaleric acid, homo phenylalanine lysine, tetraisoquinolinecarboxylate lysine, cyclohexylalanine lysine, isonepecotic acid lysine, beta-alanine lysine, glycine serine valine glutamine and isonepecotic acid.
  • Another approach for the generation of ADCs involves the use of heterobifunctional cross-linkers which link the anti-CDCP1 antibody to the drug moiety.
  • cross-linkers examples include N-succinimidyl 4-(5- nitro-2-pyridyldithio)-pentanoate or the highly water-soluble analog N- sulfosuccinimidyl 4-(5-nitro-2-pyridyldithio)-pentanoate.
  • SPDB N-s
  • the antibodies may be modified with the cross-linkers N-succinimidyl 4- (5-nitro-2-pyridyldithio)-pentanoate, N-sulfosuccinimidyl 4-(5-nitro-2-pyridyldithio)- pentanoate, SPDB, SNPB, SSNPB, SMNP, SCPB, or SSCPB can then react with a small excess of a particular drug that contains a thiol moiety to give excellent yields of an ADC (see also U.S. Pat. No.6,913,748, incorporated by reference herein).
  • charged linkers are used to conjugate anti-CDCP1 antibodies, to drugs to form ADCs.
  • Charged linkers include linkers that become charged after cell processing.
  • the presence of a charged group(s) in the linker of a particular ADC or on the drug after cellular processing provides several advantages, such as (i) greater water solubility of the ADC, (ii) ability to operate at a higher concentration in aqueous solutions, (iii) ability to link a greater number of drug molecules per antibody, potentially resulting in higher potency, (iv) potential for the charged conjugate species to be retained inside the target cell, resulting in higher potency, and (v) improved sensitivity of multidrug resistant cells, which would be unable to export the charged drug species from the cell.
  • the charged or pro-charged cross-linkers are those containing sulfonate, phosphate, carboxyl or quaternary amine substituents that significantly increase the solubility of the ADCs, especially for ADCs with 2 to 20 conjugated drugs.
  • Conjugates prepared from linkers containing a pro-charged moiety would produce one or more charged moieties after the conjugate is metabolized in a cell.
  • linkers that can be used with the compositions and methods include valine-citrulline; maleimidocaproyl; amino benzoic acids; p- aminobenzylcarbamoyl (PAB); lysosomal enzyme-cleavable linkers; maleimidocaproyl-polyethylene glycol (MC(PEG)6-OH); N-methyl-valine citrulline; N-succinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC); N- Succinimidyl 4-(2-pyridyldithio)butanoate (SPDB); and N-Succinimidyl 4-(2- pyridylthio)pentanoate (SPP) (See also US 2011/0076232).
  • SMCC N-maleimidomethyl)cyclohexane-1-carboxylate
  • SPDB N- Succinimidyl 4-(2-pyridyldithio
  • Another linker for use 183 064467-020PCT includes an avidin-biotin linkage to provide an avidin-biotin-containing ADC (See also U.S. Pat. No.4,676,980, PCT publication Nos. WO1992/022332A2, WO1994/016729A1, WO1995/015770A 1, WO1997/031655A2, WO1998/035704A1, WO1999/019500A1, WO2001/09785A2, WO2001/090198A1, WO2003/093793A2, WO2004/050016A2, WO2005/081898A2, WO2006/083562A2, WO2006/089668A1, WO2007/150020A1, WO2008/135237A1, WO2010/111198A1, WO2011/057216A1, WO2011/058321A1, WO2012/027494A1, and EP77671B1), wherein some such linkers are resistant to biot
  • Additional linkers that may be used include a cohesin/dockerin pair to provide a cohesion-dockerin- containing ADC (See PCT publication Nos. WO2008/097866A2, WO2008/097870A2, WO2008/103947A2, and WO2008/103953A2).
  • Additional linkers may contain non-peptide polymers (examples include, but are not limited to, polyethylene glycol, polypropylene glycol, polyoxyethylated polyols, polyvinyl alcohol, polysaccharides, dextran, polyvinyl ethyl ether, PLA (poly(lactic acid)), PLGA (poly(lactic acid-glycolic acid)), and combinations thereof, wherein a preferred polymer is polyethylene glycol) (See also PCT publication No. WO2011/000370). Additional linkers are also described in WO 2004-010957, U.S. Publication No.20060074008, U.S. Publication No.20050238649, and U.S.
  • the conjugation of the drug to the antibody via a linker can be accomplished by any technique known in the art.
  • a number of different reactions are available for covalent attachment of drugs and linkers to antibodies. This may be accomplished by reaction of the amino acid residues of the antibody, including the amine groups of lysine, the free carboxylic acid groups of glutamic and aspartic acid, the sulfhydryl groups of cysteine and the various moieties of the aromatic amino acids.
  • One of the most commonly used non-specific methods of covalent attachment is the carbodiimide reaction to link a carboxy (or amino) group of a compound to amino (or carboxy) groups of the antibody.
  • bifunctional agents such as dialdehydes or imidoesters have been used to link the amino group of a compound to amino groups of an antibody.
  • the Schiff base reaction also involves the periodate oxidation of a drug that contains glycol or hydroxy groups, thus forming an aldehyde which is then reacted with the binding agent. Attachment occurs via formation of a Schiff base with amino 184 064467-020PCT groups of the antibody.
  • Isothiocyanates can also be used as coupling agents for covalently attaching drugs to antibodies. Other techniques are known to the skilled artisan and within the scope of the disclosure.
  • an intermediate which is the precursor of the linker, is reacted with the drug under appropriate conditions.
  • reactive groups are used on the drug or the intermediate.
  • the product of the reaction between the drug and the intermediate, or the derivatized drug, is subsequently reacted with the anti-CDCP1 antibodies under appropriate conditions.
  • the antibody drug conjugate has a structure represented by Formula Ia or pharmaceutically acceptable salt thereof: Formula I wherein Ab is an anti-CDCP1 antibody; each instance of W is -C(O)-, -C(O)NR'-, -C(O)O-, -SO 2 NR'-, -P(O)R''NR'-, -SONR'-, -PO2NR’-, or -NR’C(O)-; each instance of R' and R'' is independently hydrogen, C1-8 alkyl, C3-8 cycloalkyl, C1-8 alkoxy, C 1-8 alkylthio, mono- or di-C 1-8 alkylamino, heteroaryl or aryl; each instance of Z is independently C 1-8 alkyl, halogen, cyano, or
  • W is -C(O)NR'-, further wherein the C is directly bonded to the phenyl ring of Formula Ia, and NR' is bonded to Y.
  • Y comprises a peptide and the peptide comprises at least one hydrophilic amino acid, preferably an amino acid having a side chain having a moiety that bears a charge at neutral pH in aqueous solution (e.g., an amine, guanidine, or carboxyl moiety), most preferably each amino acid of the peptide is independently selected from alanine, aspartate, asparagine, glutamate, glutamine, glycine, lysine, ornithine, proline, serine, and threonine.
  • Y is covalently bonded to the antibody by a thioether bond, and the thioether bond comprises a sulfur atom of a cysteine of the antibody.
  • Y comprises an oxime and: the oxygen atom of the oxime is on the side of Y that is linked to W and the carbon atom of the oxime is on the side of Y that is linked to Ab; or the carbon atom of the oxime is on the side of Y that is linked to W and the oxygen atom of the oxime is on the side of Y that is linked to Ab.
  • Y comprises a connection unit represented by Formula III or Formula IV: -(CH2)r(V(CH2)p)q- Formula III, 186 064467-020PCT -(CH2CH2X)w- Formula IV;
  • V is a single bond, -O-, -S-, -NR 1 -, -C(O)NR 2 -, -NR 3 C(O)-, -NR 4 SO2-, or -SO2NR 5 -, preferably -O-;
  • X is -O-, C 1-8 alkylene, or -NR 1 -, preferably -O-;
  • R 1 to R 5 are each independently hydrogen, C 1-6 alkyl, C 1-6 alkyl C 6-20 aryl, or C 1-6 alkyl C3-20 heteroaryl;
  • r is an integer from 1 to 10, preferably 2;
  • p is an integer from 0 to 12, preferably 2;
  • q is an integer from 1 to 20, preferably 2, 5, or 11
  • Y comprises -(CH 2 CH 2 O)w-, -O(CH 2 CH 2 O) w -, or -(CH2CH2O)wCH2-, wherein w is an integer from 1 to 20, preferably 2 to 10.
  • Y comprises a moiety represented by Formula V, VI, VII, VIII or IX: Formula V, Formula VI, Formula VII, Formula VIII 187 064467-020PCT
  • Formula IX L 1 is a single bond or C 1-30 alkylene; and R 11 is hydrogen or C 1-10 alkyl.
  • Y is linear.
  • the term “linear”, when used in the context of variable Y, refers to a unit that couples the antibody to a single therapeutically active agent (e.g., a drug or diagnostic agent) via an unbranched covalent moiety (e.g., a via C1-50 alkylene).
  • a single therapeutically active agent e.g., a drug or diagnostic agent
  • an unbranched covalent moiety e.g., a via C1-50 alkylene.
  • the term “linear”, when used in the context of variable Y does not preclude substitution (e.g., alkyl, aryl, or heteroaryls) on Y, provided that said substituents are not therapeutically active agents or coupled to further active agents.
  • Y is branched.
  • the term “branched”, when used in the context of variable Y, refers to a unit that couples the antibody to multiple therapeutically active agents (e.g., drugs and/or diagnostic agents) via a covalent moiety.
  • Y may comprise an alkylene that splits at a branching point into multiple alkylene chains, each of which covalently links the antibody to one or more therapeutically active agents (e.g., drugs).
  • Y comprises: [001050] i) a branching unit covalently coupled to Ab by a primary linker; [001051] ii) a first branch, which couples a first therapeutically active substance, via a first cleavage group, to the branching unit; and [001052] iiia) a second branch, which couples a second therapeutically active substance, via a second cleavage group, to the branching unit; or [001053] iiib) a second branch which couples an alkyl or heteroalkyl (e.g., a polyethylene glycol monomer or a polyethylene glycol oligomer) to the branching unit.
  • an alkyl or heteroalkyl e.g., a polyethylene glycol monomer or a polyethylene glycol oligomer
  • At least one branching unit has a structure represented wherein G 1 , G 2 , G 3 is each independently a bond, R 30 is hydrogen or C 1-30 alkyl; R 40 is hydrogen or L 5 -COOR 50 ; R 50 is hydrogen or C1-30 alkyl; and L 2 , L 3 , L 4 , and L 5 are each independently a bond or alkylene.
  • the branching unit is a nitrogen atom.
  • the branching unit is an amide and the primary linker comprises the carbonyl of the amide.
  • the branching unit is an amide and the secondary linker comprises the carbonyl of the amide. In certain preferred embodiments, the branching unit is lysine.
  • the antibody comprises an amino acid motif recognizable by an isoprenoid transferase at the C-terminus of the antibody, and the thioether bond comprises a sulfur atom of a cysteine of the amino acid motif.
  • the isoprenoid transferase is farnesyl protein transferase (FTase) or geranylgeranyl transferase (GGTase).
  • the amino acid motif has a CY1Y1X sequence, further wherein: C is cysteine; each Y1 independently is an aliphatic amino acid; 189 064467-020PCT X is selected from glutamine, glutamate, serine, cysteine, methionine, alanine, and leucine; and the thioether bond comprises a sulfur atom of a cysteine of the amino acid motif.
  • each Y1 is independently selected from alanine, isoleucine, leucine, methionine, and valine.
  • the amino acid motif comprises a CVIM or CVLL.
  • the conjugate comprises at least one of 1 to 20 amino acids between the antibody and the amino acid motif, and at least one of the amino acids is glycine.
  • the amino acid motif has the sequence GGGGGGGCVIM.
  • glucuronide-based linker connects drug units to an antibody in which its glucuronide unit comprises a glycosidase recognition site that is cleavable by an enzyme having ⁇ -glucuronidase activity thereby releasing free drug. Glucuronide-based linkers improve the solubility of ADCs and exhibit sufficient serum stability to provide targeted delivery of a conjugated drug to a targeted cell. 5.
  • Anti-CDCP1 antibodies may be conjugated to at least one payload.
  • the payloads of the invention can be, for example, auristatins, maytansinoids, DNA alkylating agents, mitotic inhibitors, antitumor antibiotics, immunomodulatory agents, alkylating agents, antiangiogenic agents, antimetabolites, boron-containing agents, photoactive therapeutic agents, radionuclide agents, topoisomerase inhibitors and tyrosine kinase inhibitors.
  • auristatins may be conjugated to at least one auristatin.
  • Auristatins represent a group of dolastatin analogs that have generally been shown to possess anticancer activity by interfering with microtubule dynamics and GTP hydrolysis, thereby inhibiting cellular division.
  • Auristatin E U.S. Pat. No.5,635,483 is a synthetic analogue of the marine natural product dolastatin 10, a compound that inhibits tubulin polymerization by binding to the same site on tubulin as the anticancer drug vincristine (G. R. Pettit, Prog. Chem. Org. Nat. Prod, 70: 1-79 (1997)).
  • Dolastatin 10, auristatin PE, and auristatin E are linear peptides having four amino acids, three of which are unique to the dolastatin class of compounds.
  • Exemplary embodiments of the auristatin subclass of mitotic inhibitors include, but are not limited to, monomethyl auristatin D (MMAD or auristatin D derivative), monomethyl auristatin E (MMAE or auristatin E derivative), monomethyl auristatin F (MMAF or auristatin F derivative), auristatin F phenylenediamine (AFP), auristatin EB (AEB), auristatin EFP (AEFP), and 5-benzoylvaleric acid-AE ester (AEVB).
  • MMAD or auristatin D derivative monomethyl auristatin E (MMAE or auristatin E derivative
  • MMAF or auristatin F derivative monomethyl auristatin F phenylenediamine (AFP), a
  • anti-CDCP1 antibodies are conjugated to at least one MMAE (mono-methyl auristatin E).
  • MMAE Monomethyl auristatin E
  • mAb monoclonal antibody
  • the linker linking MMAE to the anti-CDCP1 antibody is stable in extracellular fluid (i.e., the medium or environment that is external to cells), but is cleaved by cathepsin once the ADC has bound to the specific cancer cell antigen and entered the cancer cell, thus releasing the toxic MMAE and activating the potent anti-mitotic mechanism.
  • the antibody is coupled to a single drug and, therefore, has a DAR of 1.
  • the ADC will have a DAR of 2 to 8, or, alternatively, 2 to 4.
  • Maytansinoids are potent antitumor agents that were originally isolated from members of the higher plant families Celastraceae, Rhamnaceae and Euphorbiaceae, as well as some species of mosses (Kupchan et al, J. Am. Chem. Soc.94:1354-1356 [1972]; Wani et al, J. Chem. Soc. Chem.
  • Maytansinoids have been shown to inhibit tumor cell growth in vitro using cell culture models, and in vivo using laboratory animal systems. Moreover, the cytotoxicity of maytansinoids is 1.000-fold greater than conventional chemotherapeutic agents, such as, for example, methotrexate, daunorubicin, and vincristine (see. e.g., U.S. Pat. No.5,208,020).
  • Maytansinoids to include maytansine, maytansinol, C-3 esters of maytansinol, and other maytansinol analogues and derivatives see, e.g., U.S. Pat.
  • C- 3 esters of maytansinol can be naturally occurring or synthetically derived. Moreover, both naturally occurring and synthetic C-3 maytansinol esters can be classified as a C- 3 ester with simple carboxylic acids, or a C-3 ester with derivatives of N-methyl-L- alanine, the latter being more cytotoxic than the former. Synthetic maytansinoid analogues are described in, for example, Kupchan et al., J. Med. Chem., 21, 31-37 (1978).
  • Suitable maytansinoids for use in antibody-drug conjugates can be isolated from natural sources, synthetically produced, or semi-synthetically produced. Moreover, the maytansinoid can be modified in any suitable manner, so long as sufficient cytotoxicity is preserved in the ultimate conjugate molecule. In this regard, maytansinoids lack suitable functional groups to which antibodies can be linked. A linking moiety desirably is utilized to link the maytansinoid to the antibody to form the conjugate.
  • DM4 4-methyl-4-mercapto-1- oxopentyl)-maytansine
  • maytansinoids include, but are not limited, to DM1 (N 2′ -deacetyl-N 2′ -(3-mercapto-1-oxopropyl)-maytansine; also referred to as mertansine, drug maytansinoid 1; ImmunoGen, Inc.; see also Chari et al.
  • DNA alkylating agent includes a family of DNA alkylating agents including indolino-benzodiazepines (IGNs).
  • IGNs represent a chemical class of cytotoxic molecules with high in vitro potency (IC.sub.50 values in the low pmol/L range) toward cancer cells.
  • IGN DNA alkylating agents that can be used as a cytotoxic payload in an ADC are described in Miller et al. (2016) Molecular Cancer Therapeutics, 15(8)).
  • the IGN compounds described in Miller et al. bind to the minor groove of DNA followed by covalent reaction of guanine residues with the two imine functionalities in the molecule resulting in cross- linking of DNA.
  • the structure of an exemplary IGN is provided below. d.
  • drugs that may be used in ADCs i.e., drugs that may be conjugated to the anti-CDCP1 antibodies
  • examples of drugs that may be used in ADCs include mitotic inhibitors, antitumor antibiotics, immunomodulating agents, gene therapy vectors, alkylating agents, antiangiogenic agents, antimetabolites, boron-containing agents, chemoprotective agents, hormone agents, glucocorticoids, photoactive therapeutic agents, oligonucleotides, radioactive isotopes, radiosensitizers, topoisomerase inhibitors, tyrosine kinase inhibitors, and combinations thereof.
  • mitotic inhibitors i.e., antitumor antibiotics, immunomodulating agents, gene therapy vectors, alkylating agents, antiangiogenic agents, antimetabolites, boron-containing agents, chemoprotective agents, hormone agents, glucocorticoids, photoactive therapeutic agents, oligonucleotides, radioactive isotopes, radiosen
  • anti-CDCP1 antibodies may be conjugated to one or more mitotic inhibitor(s) to form an ADC for the treatment of cancer.
  • mitotic inhibitor refers to a cytotoxic and/or therapeutic agent that blocks mitosis or cell division, a biological process particularly important to cancer cells.
  • a mitotic inhibitor disrupts microtubules such that cell division is prevented, often by affecting microtubule polymerization or microtubule depolymerization.
  • an anti-CDCP1 antibody is conjugated to one or more mitotic 193 064467-020PCT inhibitor(s) that disrupts microtubule formation by inhibiting tubulin polymerization.
  • the mitotic inhibitor used in the ADCs is IXEMPRA® (ixabepilone).
  • mitotic inhibitors that may be used in the anti-CDCP1 ADCs include dolastatins, e.g., dolastatin 10 and dolastatin 15, and plant alkaloids, e.g., a taxane and vinca alkaloid, e.g., indesine sulfate, vincristine, vinblastine and vinorelbine. Included in the genus of mitotic inhibitors are auristatins and maytansinoids, described above. [001076] Anti-CDCP1 antibodies described herein may be conjugated to at least one taxane.
  • Taxane compounds have also previously been described in U.S. Pat.
  • Taxanes include, but are not limited to, docetaxel (TAXOTERE®; Sanofi Aventis), paclitaxel (ABRAXANE® or TAXOLTM; Abraxis Oncology), and nanoparticle paclitaxel (ABI- 007/ABRAXANE®; Abraxis Bioscience).
  • Antitumor Antibiotics may be conjugated to one or more antitumor antibiotic(s) for the treatment of cancer.
  • antitumor antibiotic means an antineoplastic drug that blocks cell growth by interfering with DNA and is made from a microorganism.
  • antitumor antibiotics either break up DNA strands or slow down or stop DNA synthesis.
  • antitumor antibiotics that may be included in the anti-CDCP1 ADCs include, but are not limited to, 194 064467-020PCT actinomycines (e.g., pyrrolo[2,1-c][1,4]benzodiazepines), anthracyclines, calicheamicins, and duocarmycins.
  • additional antitumor antibiotics that may be used in the anti-CDCP1 ADCs include bleomycin (BLENOXANETM, Bristol-Myers Squibb), mitomycin, and plicamycin (also known as mithramycin). g.
  • cancer vaccine refers to a composition (e.g., a tumor antigen and a cytokine) that elicits a tumor-specific immune response. The response is elicited from the subject's own immune system by administering the cancer vaccine, or, in the case of the instant disclosure, administering an ADC comprising an anti-CDCP1 antibody and a cancer vaccine.
  • the immune response results in the eradication of tumor cells in the body (e.g., primary or metastatic tumor cells).
  • the use of cancer vaccines generally involves the administration of a particular antigen or group of antigens that are, for example, present on the surface a particular cancer cell, or present on the surface of a particular infectious agent shown to facilitate cancer formation.
  • the use of cancer vaccines is for prophylactic purposes, while in other embodiments, the use is for therapeutic purposes.
  • Non-limiting examples of cancer vaccines that may be used in the anti-CDCP1 ADCs include, recombinant bivalent human papillomavirus (HPV) vaccine types 16 and 18 vaccine (CERVARIX®, GlaxoSmithKline), recombinant quadrivalent human papillomavirus (HPV) types 6, 11, 16, and 18 195 064467-020PCT vaccine (GARDASIL®, Merck & Company), and sipuleucel-T (PROVENGE®, Dendreon).
  • the anti-CDCP1 antibody is conjugated to at least one cancer vaccine that is either an immunostimulator or is an immunosuppressant.
  • the anti-CDCP1 antibodies may be conjugated to at least one cytokine.
  • cytokine generally refers to proteins released by one cell population which act on another cell as intercellular mediators. Cytokines directly stimulate immune effector cells and stromal cells at the tumor site and enhance tumor cell recognition by cytotoxic effector cells (Lee and Margolin (2011) Cancers 3:3856). Numerous animal tumor model studies have demonstrated that cytokines have broad anti-tumor activity and this has been translated into a number of cytokine-based approaches for cancer therapy (Lee and Margoli, supra).
  • cytokines include, but are not limited to, parathyroid hormone; thyroxine; insulin; proinsulin; relaxin; prorelaxin; glycoprotein hormones such as follicle stimulating hormone (FSH), thyroid stimulating hormone (TSH), and luteinizing hormone (LH); hepatic growth factor; fibroblast growth factor; prolactin; placental lactogen; tumor necrosis factor; mullerian-inhibiting substance; mouse gonadotropin-associated peptide; inhibin; activin; vascular endothelial growth factor: integrin; thrombopoietin (TPO); nerve growth factors such as NGF; platelet-growth factor; transforming growth factors (TGFs); insulin-
  • TGFs transforming growth factors
  • the term cytokine includes proteins from natural sources or from recombinant cell culture and biologically active equivalents of the native sequence cytokines.
  • the disclosure provides an ADC comprising an anti-CDCP1 antibody described herein and a cytokine.
  • the anti-CDCP1 antibodies may be conjugated to at least one colony stimulating factor (CSF).
  • CSFs colony stimulating factors
  • CSFs are growth factors that assist the bone marrow in making red blood cells. Because some cancer treatments 196 064467-020PCT (e.g., chemotherapy) can affect white blood cells (which help fight infection), colony- stimulating factors may be introduced to help support white blood cell levels and strengthen the immune system.
  • Colony-stimulating factors may also be used following a bone marrow transplant to help the new marrow start producing white blood cells.
  • Representative examples of CSFs that may be used in the anti-CDCP1 ADCs include, but are not limited to erythropoietin (Epoetin), filgrastim (NEUPOGEN® (also known as granulocyte colony-stimulating factor (G-CSF); Amgen, Inc.), sargramostim (LEUKINE® (granulocyte-macrophage colony- stimulating factor and GM-CSF); Genzyme Corporation), promegapoietin, and Oprelvekin (recombinant IL-11; Pfizer, Inc.).
  • an ADC may comprise an anti-CDCP1 antibody described herein and a CSF.
  • the anti-CDCP1 antibodies may be conjugated to one or more alkylating agent(s).
  • Alkylating agents are a class of antineoplastic compounds that attaches an alkyl group to DNA. Examples of alkylating agents that may be used in the ADCs include, but are not limited to, alkyl sulfonates, ethylenimimes, methylamine derivatives, epoxides, nitrogen mustards, nitrosoureas, triazines and hydrazines. i.
  • the anti-CDCP1 antibodies described herein are conjugated to at least one antiangiogenic agent.
  • Antiangiogenic agents inhibit the growth of new blood vessels. Antiangiogenic agents exert their effects in a variety of ways. In some embodiments, these agents interfere with the ability of a growth factor to reach its target.
  • vascular endothelial growth factor VEGF
  • VEGF vascular endothelial growth factor
  • certain antiangiogenic agents which prevent the interaction of VEGF with its cognate receptor, prevent VEGF from initiating angiogenesis. In other embodiments, these agents interfere with intracellular signaling cascades.
  • a cascade of other chemical signals is initiated to promote the growth of blood vessels.
  • certain enzymes for example, some tyrosine kinases, which are known to facilitate intracellular signaling cascades that contribute to, for example, cell proliferation, are targets for cancer treatment.
  • these agents interfere with intercellular signaling cascades.
  • these agents disable specific targets that activate and promote cell growth or by directly interfering with 197 064467-020PCT the growth of blood vessel cells.
  • Angiogenesis inhibitory properties have been discovered in more than 300 substances with numerous direct and indirect inhibitory effects.
  • antiangiogenic agents include, but are not limited to, angiostatin, ABX EGF, C1-1033, PKI-166, EGF vaccine, EKB-569, GW2016, ICR-62, EMD 55900.
  • Erlotinib (TARCEVA®), angiostatin, arrestin, endostatin, BAY 12-9566 and w/fluorouracil or doxorubicin, canstatin, carboxyamidotriozole and with paclitaxel, EMD121974, S-24, vitaxin, dimethylxanthenone acetic acid, IM862, Interleukin-12, Interleukin-2, NM-3, HuMV833, PTK787, RhuMab, angiozyme (ribozyme), IMC-1C11, Neovastat, marimstat, prinomastat, BMS-275291, COL-3, MM1270, SU101, SU6668, SU11248, SU5416, with paclitaxel, with gemcitabine and cisplatin, and with irinotecan and cisplatin and with radiation, tecogalan, temozolomide and PEG interferon ⁇ 2b, tetrathiomoly
  • tyrosine kinase inhibitors e.g., erlotinib (TARCEVA®, Genentech, Inc.), imatinib (GLEEVEC®, Novartis Pharmaceutical Corporation), gefitinib (IRESSA®, AstraZeneca Pharmaceuticals), dasatinib (SPRYCEL®, Brystol- Myers Squibb), sunitinib (SUTENT®, Pfizer, Inc.), nilotinib (TASIGNA®, Novartis Pharmaceutical Corporation), lapatinib (TYKERB®, GlaxoSmithKline Pharmaceuticals), sorafenib (NEXAVAR®, Bayer and Onyx), phosphoinositide 3- kinases (PI3K).
  • erlotinib TARCEVA®, Genentech, Inc.
  • imatinib GLEEVEC®, Novartis Pharmaceutical Corporation
  • gefitinib IRESSA®, AstraZeneca Pharmaceuticals
  • the anti-CDCP1 antibodies may be conjugated to at least one antimetabolite.
  • Antimetabolites are types of chemotherapy treatments that are very similar to normal substances within the cell. When the cells incorporate an antimetabolite into the cellular metabolism, the result is negative for the cell, e.g., the cell is unable to divide. Antimetabolites are classified according to the substances with which they interfere.
  • antimetabolies examples include, but are not limited to, a folic acid antagonist (e.g., methotrexate), a pyrimidine antagonist (e.g., 5-Fluorouracil, Foxuridine, Cytarabine, Capecitabine, and Gemcitabine), a purine antagonist (e.g., 6-Mercaptopurine and 6-Thioguanine) and an 198 064467-020PCT adenosine deaminase inhibitor (e.g., Cladribine, Fludarabine, Nelarabine and Pentostatin), as described in more detail below. k.
  • a folic acid antagonist e.g., methotrexate
  • a pyrimidine antagonist e.g., 5-Fluorouracil, Foxuridine, Cytarabine, Capecitabine, and Gemcitabine
  • a purine antagonist e.g., 6-Mercaptopurine and 6-Thioguanine
  • the anti-CDCP1 antibody may be conjugated to at least one boron containing agent.
  • Boron-containing agents comprise a class of cancer therapeutic compounds which interfere with cell proliferation.
  • Representative examples of boron containing agents include, but are not limited, to borophycin and bortezomib (VELCADE®, Millenium Pharmaceuticals).
  • boron containing agents include, but are not limited, to borophycin and bortezomib (VELCADE®, Millenium Pharmaceuticals).
  • VELCADE® borophycin and bortezomib
  • the anti-CDCP1 antibodies may be conjugated to at least one chemoprotective agent. Chemoprotective drugs are a class of compounds, which help protect the body against specific toxic effects of chemotherapy.
  • Chemoprotective agents may be administered with various chemotherapies in order to protect healthy cells from the toxic effects of chemotherapy drugs, while simultaneously allowing the cancer cells to be treated with the administered chemotherapeutic.
  • Representative chemoprotective agents include, but are not limited to amifostine (ETHYOL®, Medimmune, Inc.), which is used to reduce renal toxicity associated with cumulative doses of cisplatin, dexrazoxane (TOTECT®, Apricus Pharma; ZINECARD®), for the treatment of extravasation caused by the administration of anthracycline (TOTECT®), and for the treatment of cardiac-related complications caused by the administration of the antitumor antibiotic doxorubicin (ZINECARD®), and mesna (MESNEX®, Bristol-Myers Squibb), which is used to prevent hemorrhagic cystitis during chemotherapy treatment with ifocfamide.
  • amifostine ETHYOL®, Medimmune, Inc.
  • TOTECT® Apric
  • the anti-CDCP1 antibodies may be conjugated to at least one photoactive therapeutic agent.
  • Photoactive therapeutic agents include compounds that can be deployed to kill treated cells upon exposure to electromagnetic radiation of a particular wavelength. Therapeutically relevant compounds absorb electromagnetic radiation at wavelengths which penetrate tissue.
  • the compound is administered in a non-toxic form that is capable of producing a photochemical effect that is toxic to cells or tissue upon sufficient activation. In other preferred embodiments, these compounds are retained by cancerous tissue and are readily cleared from normal tissues. Non-limiting examples include various chromagens and dyes. 199 064467-020PCT n.
  • Radionuclide Agents (Radioactive Isotopes) [001090]
  • the anti-CDCP1 antibodies may be conjugated to at least one radionuclide agent.
  • Radionuclide agents comprise agents that are characterized by an unstable nucleus that is capable of undergoing radioactive decay. The basis for successful radionuclide treatment depends on sufficient concentration and prolonged retention of the radionuclide by the cancer cell. Other factors to consider include the radionuclide half-life, the energy of the emitted particles, and the maximum range that the emitted particle can travel.
  • the therapeutic agent is a radionuclide selected from the group consisting of 111 In, 177 Lu, 212 Bi, 213 Bi, 211 At, 62 Cu, 64 Cu, 67 Cu, 90 Y, 125 I, 131 I, 32 P, 33 P, 47 Sc, 111 Ag, 67 Ga, 142 Pr, 153 Sm, 161 Th, 166 Dy, 166 Ho, 186 Re, 188 Re, 189 Re, 212 Pb, 223 Ra, 225 Ac, 59 Fe, 75 Se, 77 As, 89 Sr, 99 Mo, 105 Rh, 109 Pd, 143 Pr, 149 Pm, 169 Er, 194 Ir, 198 Au, 199 Au, and 211 Pb.
  • a radionuclide selected from the group consisting of 111 In, 177 Lu, 212 Bi, 213 Bi, 211 At, 62 Cu, 64 Cu, 67 Cu, 90 Y, 125 I, 131 I, 32 P, 33 P, 47 Sc, 111
  • radionuclides that substantially decay with Auger-emitting particles.
  • Decay energies of useful beta-particle-emitting nuclides are preferably Dy-152.
  • Decay energies of useful alpha-particle-emitting radionuclides are preferably 2,000-10,000 keV, more preferably 3,000-8.000 keV, and most preferably 4,000-7,000 keV.
  • Additional potential radioisotopes of use include 11 C, 13 N, 15 0, 75 Br, 198 Au, 224 Ac, 126 I, 133 I, 77 Br, 113m In, 95 Ru, 97 Ru, 103 Ru, 105 Ru, 107 Hg, 203 Hg, 121m Te, 122 Te, 125m Te, 165 Tm, 167 Tm, 168 Tm, 197 Pt, 109 Pd, 105 Rh, 142 Pr, 143 Pr, 161 Tb, 166 Ho, 199 Au, 57 Co, 58 Co, 51 Cr, 59 Fe, 75 Se, 201 Tl, 225 Ac, 76 Br, 169 Yb, and the like.
  • the anti-CDCP1 antibodies may be conjugated to at least one radiosensitizer.
  • the term “radiosensitizer,” as used herein, is defined as a molecule, preferably a low molecular weight molecule, administered to animals in therapeutically effective amounts to increase the sensitivity of the cells to be radiosensitized to electromagnetic radiation and/or to promote the treatment of diseases that are treatable with electromagnetic radiation.
  • Radiosensitizers are agents that make cancer cells more sensitive to radiation therapy, while typically having much less of an effect on normal cells. Thus, the radiosensitizer can be used in combination with a radiolabeled antibody or ADC.
  • Radiosensitizer can result in enhanced efficacy when compared to treatment with the radiolabeled antibody or antibody fragment alone.
  • Radiosensitizers are described in D. M. 200 064467-020PCT Goldberg (ed.), Cancer Therapy with Radiolabeled Antibodies, CRC Press (1995). Examples of radiosensitizers include gemcitabine, 5-fluorouracil, taxane, and cisplatin. [001092] Radiosensitizers may be activated by electromagnetic radiation of X- rays.
  • X-ray activated radiosensitizers include, but are not limited to, the following: metronidazole, misonidazole, desmethylmisonidazole, pimonidazole, etanidazole, nimorazole, mitomycin C.
  • radiosensitizers may be activated using photodynamic therapy (PDT).
  • photodynamic radiosensitizers include, but are not limited to, hematoporphyrin derivatives, Photofrin®, benzoporphyrin derivatives, NPe6, tin etioporphyrin (SnET2), pheoborbide a, bacteriochlorophyll a, naphthalocyanines, phthalocyanines, zinc phthalocyanine, and therapeutically effective analogs and derivatives of the same.
  • SnET2 tin etioporphyrin
  • pheoborbide a bacteriochlorophyll a
  • naphthalocyanines phthalocyanines
  • zinc phthalocyanine zinc phthalocyanine
  • therapeutically effective analogs and derivatives of the same p. Topoisomerase Inhibitors
  • Topoisomerase inhibitors are chemotherapy agents designed to interfere with the action of topoisomerase enzymes (topoisomerase I and II), which are enzymes that control the changes in DNA structure by catalyzing then breaking and rejoining of the phosphodiester backbone of DNA strands during the normal cell cycle.
  • DNA topoisomerase I inhibitors include, but are not limited to, camptothecins and its derivatives irinotecan (CPT-11, CAMPTOSAR®, Pfizer, Inc.), deruxtecan (DXd; DX-8951 derivative), exatecan and topotecan (HYCAMTIN®, GlaxoSmithKline Pharmaceuticals).
  • DNA topoisomerase II inhibitors include, but are not limited to, amsacrine, daunorubicin, doxotrubicin, epipodophyllotoxins, ellipticines, epirubicin, etoposide, razoxane, and teniposide.
  • the anti-CDCP1 antibodies may be conjugated to at least one tyrosine kinase inhibitor.
  • Tyrosine kinases are enzymes within the cell that function to attach phosphate groups to the amino acid tyrosine. By blocking the ability of protein tyrosine kinases to function, tumor growth may be inhibited.
  • tyrosine 201 064467-020PCT kinases examples include, but are not limited to, Axitinib, Bosutinib, Cediranib, Cabozantinib, Dasatinib. Erlotinib, Gefitinib, Imatinib. Lapatinib, Lenvatinib, Lestaurtinib, Nilotinib. Savolitinib, Semaxanib, Sorafenib, Sunitinib, Tivozanib and Vandetanib. r.
  • agents that may be used in the ADCs include, but are not limited to, abrin (e.g. abrin A chain), alpha toxin. Aleurites fordii proteins, amatoxin, crotin, curcin, dianthin proteins, diptheria toxin (e.g. diphtheria A chain and nonbinding active fragments of diphtheria toxin), deoxyribonuclease (Dnase), gelonin, mitogellin, modeccin A chain.
  • abrin e.g. abrin A chain
  • Aleurites fordii proteins e.g. amatoxin, crotin, curcin, dianthin proteins
  • diptheria toxin e.g. diphtheria A chain and nonbinding active fragments of diphtheria toxin
  • Dnase deoxyribonuclease
  • gelonin mitogellin
  • modeccin A chain e.g.
  • Pseudomonas endotoxin Pseudomonas exotoxin (e.g. exotoxin A chain (from Pseudomonas aeruginosa)), restrictocin, ricin A chain, ribonuclease (Rnase), Sapaonaria officinalis inhibitor, saporin, alpha-sarcin.
  • Pseudomonas endotoxin Pseudomonas exotoxin (e.g. exotoxin A chain (from Pseudomonas aeruginosa)), restrictocin, ricin A chain, ribonuclease (Rnase), Sapaonaria officinalis inhibitor, saporin, alpha-sarcin.
  • Staphylcoccal enterotoxin-A tetanus toxin, cisplatin, carboplatin, and oxaliplatin
  • proteasome inhibitors e.g. PS-341 [bortezomib or VELCADE®]
  • HDAC inhibitors vorinostat (ZOLINZA®, Merck & Company. Inc.)
  • belinostat entinostat
  • mocetinostat e.g., and panobinostat
  • COX-2 inhibitors substituted ureas
  • heat shock protein inhibitors e.g. Geldanamycin and its numerous analogs
  • adrenocortical suppressants e.g. Geldanamycin and its numerous analogs
  • the agent is pyrrolobenzodiazepine (PBD).
  • the agent is a PARP inhibitor, e.g., olaparib, rucaparib, niraparib, or iniparib.
  • the PARP inhibitor is olaparib.
  • the PARP inhibitor is rucaparib.
  • the PARP inhibitor is niraparib. In one embodiment, the PARP inhibitor is iniparib. In one embodiment, the agent is saporin toxin.
  • the aforementioned groups of drug moieties that may be used in the anti-CDCP1 ADCs are not exclusive, in that certain examples of drugs may be found in more than one category, e.g., ansamitocins are both mitotic inhibitors and antitumor antibiotics. 202 064467-020PCT [001098] All stereoisomers of the above drug moieties are contemplated for use herein, i.e. any combination of R and S configurations at the chiral carbons of D.
  • anti-CDCP1 antibodies or ADCs are used with any of the foregoing agents in a combination therapy to treat cancer, where the agent is administered prior to, at the same time as, or following administration of the anti- CDCP1 antibody or ADC to the subject.
  • Vectors and Host Cells [0001] Vectors encoding the proteins, polypeptides, fragments, variants and fusions thereof are also provided. Nucleic acids, such as those described above, can be inserted into vectors for expression in cells.
  • expression control sequences include promoters, enhancers, and transcription terminating regions.
  • a promoter is an expression control sequence composed of a region of a DNA molecule, typically within 100 nucleotides upstream of the point at which transcription starts (generally near the initiation site for RNA polymerase II). To bring a coding sequence under the control of a promoter, it is necessary to position the translation initiation site of the translational reading frame of the polypeptide between one and about fifty nucleotides downstream of the promoter.
  • Enhancers provide expression specificity in terms of time, location, and level. Unlike promoters, enhancers can function when located at various distances from the transcription site. An enhancer also can be located downstream from the transcription initiation site.
  • a coding sequence is “operably linked” and “under the control” of expression control sequences in a cell when RNA 203 064467-020PCT polymerase is able to transcribe the coding sequence into mRNA, which then can be translated into the protein encoded by the coding sequence.
  • Suitable expression vectors include, without limitation, plasmids and viral vectors derived from, for example, bacteriophage, baculoviruses, tobacco mosaic virus, herpes viruses, cytomegalo virus, retroviruses, vaccinia viruses, adenoviruses, and adeno-associated viruses.
  • An expression vector can include a tag sequence.
  • Tag sequences are typically expressed as a fusion with the encoded polypeptide. Such tags can be inserted anywhere within the polypeptide including at either the carboxyl or amino terminus.
  • Nucleic acids can be transfected into mammalian cells by techniques including, for example, calcium phosphate co-precipitation, DEAE-dextran-mediated transfection, lipofection, electroporation, or microinjection.
  • Host cells e.g., a prokaryotic cell or a eukaryotic cell such as a CHO cell
  • the vectors described can be used to express the proteins, polypeptides, fragments, variants and fusions thereof in cells.
  • An exemplary vector includes, but is not limited to, an adenoviral vector.
  • engineered bacteria may be used as vectors.
  • Nucleic acids may also be delivered by other carriers, including liposomes, polymeric micro- and nanoparticles and polycations such as asialoglycoprotein/polylysine. 205 064467-020PCT
  • physical means well-known in the art can be used for direct transfer of DNA, including administration of plasmid DNA and particle-bombardment mediated gene transfer.
  • Small Molecules [0011]
  • the immunomodulatory agent can be a small molecule. Small molecules agonists and antagonists B7-H4 are known in the art or can be identified using routine screening methods.
  • screening assays can include random screening of large libraries of test compounds. Alternatively, the assays may be used to focus on particular classes of compounds suspected of modulating the level of B7-H4. Assays can include determinations of B7-H4 signaling activity, or inhibitory response mediated by B7-H4. Other assays can include determinations of nucleic acid transcription or translation, mRNA levels, mRNA stability, mRNA degradation, transcription rates, and translation rates. [001100] 8. Proteins and Polypeptides a. Protein and Polypeptide Compositions [001101] The immunomodulatory or binding agent can be a CDCP1 protein, polypeptide, or fusion protein.
  • the immunomodulatory agent or binding moiety can be an isolated or recombinant protein or polypeptide, or functional fragment, variant, or fusion protein thereof of CDCP1.
  • the CDCP1 protein or polypeptide, or functional fragment, variant, or fusion protein thereof can be an agonist or an antagonist.
  • an antagonist of CDCP1 is a CDCP1 polypeptide or a fragment or fusion protein thereof that binds to a ligand of CDCP1.
  • the polypeptide can be a soluble fragment, for example the extracellular domain of CDCP1, or a functional fragment thereof, or a fusion protein thereof.
  • a soluble ligand of CDCP1 may serve as an antagonist, decreasing CDCP1 mediated signal transduction.
  • the activity of a protein or polypeptide of CDCP1, or any fragment, variant or fusion protein thereof can be determined using functional assays that are known in the art, and include the assays discussed below.
  • the assays include determining if the protein, polypeptide or fragment, variant or fusion protein thereof increases (i.e., agonist) or decreases (i.e., antagonist) signaling through the 206 064467-020PCT CDCP1 receptor.
  • the assay includes determining if the protein, polypeptide or fragment, variant, or fusion protein thereof increases (i.e., agonist) or decreases (i.e., antagonist) the immune response associated with CDCP1.
  • the assays include determining if the protein, polypeptide or fragment, variant, or fusion protein thereof increases (i.e., agonist) or decreases (i.e., antagonist) signaling through CDCP1.
  • the assay includes determining if the protein, polypeptide or fragment, variant, or fusion protein thereof decreases (i.e., agonist) or increases (i.e., antagonist) an immune response regulated by CDCP1.
  • the assay includes determining if the protein, polypeptide or fragment, variant, or fusion protein thereof increases (i.e., antagonist) the apoptosis and differentiation of acute myeloid leukemia cells and acute lymphoblastic leukemia cells resulting in reduced self-renewal capacity of AML and ALL stem cells.
  • Nucleic acid and polypeptide sequences for CDCP1 are known in the art and exemplary protein and peptide sequences are provided above. The sequences can be used, as discussed in more detail below, by one of skill in the art to prepare any protein or polypeptide of CDCP1, or any fragment, variant, or fusion protein thereof.
  • the proteins, polypeptides, fragments, variants, and fusions thereof of CDCP1 are expressed from nucleic acids that include sequences that encode a signal sequence.
  • the signal sequence is generally cleaved from the immature polypeptide to produce the mature polypeptide lacking the signal sequence.
  • the signal sequence can be replaced by the signal sequence of another polypeptide using standard molecule biology techniques to affect the expression levels, secretion, solubility, or other property of the polypeptide CDCP1 proteins with and without a signal sequence are disclosed. It is understood that in some cases, the mature protein as it is known or described in the art, i.e., the protein sequence without the signal sequence, is a putative mature protein.
  • a signal sequence can be removed by a cellular peptidase to yield a mature protein.
  • the sequence of the mature protein can be determined or confirmed using methods that are known in the art.
  • Fragments [001105] As used herein, a fragment of CDCP1 refers to any subset of the polypeptide that is at least one amino acid shorter than full length protein. Useful fragments include those that retain the ability to bind to their natural ligand or ligands.
  • a polypeptide that is a fragment of any full-length CDCP1 typically has at least 20 percent, 30 percent, 40 percent, 50 percent, 60 percent, 70 percent, 80 percent, 90 207 064467-020PCT percent, 95 percent, 98 percent, 99 percent, 100 percent, or even more than 100 percent of the ability to bind its natural ligand respectively as compared to the full- length protein.
  • Fragments of CDCP1 include cell free fragments. Cell free polypeptides can be fragments of full-length, transmembrane, polypeptides that may be shed, secreted or otherwise extracted from the producing cells.
  • Cell free fragments of polypeptides can include some or all of the extracellular domain of the polypeptide, and lack some or all of the intracellular and/or transmembrane domains of the full- length protein.
  • polypeptide fragments include the entire extracellular domain of the full-length protein.
  • the cell free fragments of the polypeptides include fragments of the extracellular domain that retain biological activity of full-length protein.
  • the extracellular domain can include 1, 2, 3, 4, or 5 contiguous amino acids from the transmembrane domain, and/or 1, 2, 3, 4, or 5 contiguous amino acids from the signal sequence.
  • the extracellular domain can have 1, 2, 3, 4, 5 or more amino acids removed from the C- terminus, N-terminus, or both.
  • the extracellular domain is the only functional domain of the fragment (e.g., the ligand binding domain).
  • Variants of CDCP1, and fragments thereof are also provided.
  • the variant is at least 50, 60, 70, 80, 85, 90, 95, 96, 97, 98, or 99 percent identical to any one of SEQ ID NO:1 or 3.
  • Useful variants include those that increase biological activity, as indicated by any of the assays described herein, or that increase half-life or stability of the protein.
  • the protein and polypeptides of CDCP1, and fragments, variants, and fusion proteins thereof can be engineered to increase biological activity.
  • a CDCP1 polypeptide, protein, or fragment, variant or fusion thereof has been modified with at least one amino acid substitution, deletion, or insertion that increases a function thereof.
  • variant polypeptides can be engineered to have an increased half- life relative to wildtype. These variants typically are modified to resist enzymatic degradation. Exemplary modifications include modified amino acid residues and modified peptide bonds that resist enzymatic degradation. Various modifications to achieve this are known in the art. The variants can be modified to adjust for effects of affinity for the receptor on the half-life of proteins, polypeptides, fragments, or fusions thereof at serum and endosomal pH. 208 064467-020PCT iii.
  • Fusion polypeptides have a first fusion partner including all or a part of a human or mouse CDCP1 polypeptide fused to a second polypeptide directly or via a linker peptide sequence that is fused to the second polypeptide.
  • the ECD of human or mouse CDCP1 or a fragment thereof is fused to a second polypeptide.
  • the fusion proteins optionally contain a domain that functions to dimerize or multimerize two or more fusion proteins.
  • the peptide/polypeptide linker domain can either be a separate domain, or alternatively can be contained within one of the other domains (first polypeptide or second polypeptide) of the fusion protein.
  • the domain that functions to dimerize or multimerize the fusion proteins can either be a separate domain, or alternatively can be contained within one of the other domains (first polypeptide, second polypeptide or peptide/polypeptide linker domain) of the fusion protein.
  • the dimerization/multimerization domain and the peptide/polypeptide linker domain are the same.
  • Fusion proteins disclosed herein are of formula I: N-R 1 -R 2 -R 3 -C wherein “N” represents the N-terminus of the fusion protein, “C” represents the C- terminus of the fusion protein.
  • R1 is a polypeptide or protein of CDCP1 or fragment or variant thereof
  • R 2 is an optional peptide/polypeptide linker domain
  • R 3 is a second polypeptide.
  • R 3 may be a polypeptide or protein of CDCP1, or fragment or variant thereof and R1 may be a second polypeptide.
  • the CDCP1 polypeptide is the extracellular domain, for example ECL-2, or a fragment thereof such as the Ig-like C2-domain, or the region framed by the cysteines that form a disulfide bond as discussed above.
  • Dimerization or multimerization can occur between or among two or more fusion proteins through dimerization or multimerization domains.
  • dimerization or multimerization of fusion proteins can occur by chemical crosslinking.
  • the dimers or multimers that are formed can be homodimeric/homomultimeric or heterodimeric/heteromultimeric.
  • the fusion protein includes the extracellular domain of CDCP1, or a fragment or variant thereof, fused to an Ig Fc region.
  • Recombinant Ig fusion proteins can be prepared by fusing the coding region of the extracellular domain of an extracellular domain or a fragment or variant thereof to the 209 064467-020PCT Fc region of human IgG1, IgG2, IgG3 or IgG4 or mouse IgG2a, or other suitable Ig domain, as described previously (Chapoval, et al., Methods Mol. Med., 45:247-255 (2000)).
  • One embodiment provides a fusion protein having 85%, 90%, 95%, or 100% sequence identity to CDCP1 Fc (IgG1 Fc; wild type) with the following sequence: MAGLNCGVSIALLGVLLLGAARLPRGAEAFEIALPRESNITVLIKLGTPTLLAK PCYIVISKRHITMLSIKSGERIVFTFSCQSPENHFVIEIQKNIDCMSGPCPFGEVQ LQPSTSLLPTLNRTFIWDVKAHKSIGLELQFSIPRLRQIGPGESCPDGVTHSISG RIDATVVRIGTFCSNGTVSRIKMQEGVKMALHLPWFHPRNVSGFSIANRSSIK RLCIIESVFEGEGSATLMSANYPEGFPEDELMTWQFVVPAHLRASVSFLNFNL SNCERKEERVEYYIPGSTTNPEVFKLEDKQPGNMAGNFNLSLQGCDQDAQSP GILRLQFQVLVQHPQNESNKIYVVDLSNERAMSLTIEPRPVKQ
  • the underlined sequence is the signal sequence.
  • the unmarked sequence is the extracellular sequence.
  • the bolded sequence is a linker.
  • the double underlined sequence is Fc Domain (IgG1 wild type).
  • One embodiment provides a fusion protein having 85%, 90%, 95%, or 100% sequence identity to CDCP1 Fc (IgG1 Fc; wild type) with the following sequence: FEIALPRESNITVLIKLGTPTLLAKPCYIVISKRHITMLSIKSGERIVFTFSCQSPE NHFVIEIQKNIDCMSGPCPFGEVQLQPSTSLLPTLNRTFIWDVKAHKSIGLELQ FSIPRLRQIGPGESCPDGVTHSISGRIDATVVRIGTFCSNGTVSRIKMQEGVKM ALHLPWFHPRNVSGFSIANRSSIKRLCIIESVFEGEGSATLMSANYPEGFPEDEL 210 064467-020PCT MTWQFVVPAHLRASVSFLNFNLSNCERKEERVEYY
  • CDCP1 Fc IgG1 Fc; FES
  • the underlined sequence is the signal sequence.
  • the unmarked sequence is the extracellular sequence.
  • the bolded sequence is a linker.
  • the double underlined sequence is Fc Domain (IgG1 FES).
  • Another embodiment provides a fusion protein having 85%, 90%, 95%, or 100% sequence identity to CDCP1 Fc (IgG1 Fc; FES) having the following sequence: [001120] FEIALPRESNITVLIKLGTPTLLAKPCYIVISKRHITMLSIKSGERIVF TFSCQSPENHFVIEIQKNIDCMSGPCPFGEVQLQPSTSLLPTLNRTFIWDVKAH KSIGLELQFSIPRLRQIGPGESCPDGVTHSISGRIDATVVRIGTFCSNGTVSRIKM QEGVKMALHLPWFHPRNVSGFSIANRSSIKRLCIIESVFEGEGSATLMSANYPE GFPEDELMTWQFVVPAHLRASVSFLNFNLSNCERKEERVEYYIPGSTTNPEVF K
  • CDCP1 Fc IgG4 Fc; G4P
  • the underlined sequence is the signal sequence.
  • the unmarked sequence is the extracellular sequence.
  • the bolded sequence is a linker.
  • the double underlined sequence is Fc Domain (IgG1 wild type).
  • One embodiment provides a fusion protein having 85%, 90%, 95%, or 100% sequence identity to CDCP1 isoform 3 Fc (IgG1 Fc; wild type) with the following sequence: FEIALPRESNITVLIKLGTPTLLAKPCYIVISKRHITMLSIKSGERIVFTFSCQSPE NHFVIEIQKNIDCMSGPCPFGEVQLQPSTSLLPTLNRTFIWDVKAHKSIGLELQ FSIPRLRQIGPGESCPDGVTHSISGRIDATVVRIGTFCSNGTVSRIKMQEGVKM ALHLPWFHPRNVSGFSIANRSSIKRLCIIESVFEGEGSATLMSANYPEGFPEDEL MTWQFVVPAHLRASVSFLNFNLSNCERKEERVEYYIPGSTTNPEVF
  • the disclosed immunomodulatory agents As further studies are conducted, information will emerge regarding appropriate dosage levels for treatment of various conditions in various patients, and the ordinary skilled worker, considering the therapeutic context, age, and general health of the recipient, will be able to ascertain proper dosing.
  • the selected dosage depends upon the desired therapeutic effect, on the route of administration, and on the duration of the treatment desired.
  • dosage levels of 0.001 to 20 mg/kg of body weight daily are administered to mammals. Generally, for intravenous injection or infusion, dosage may be lower.
  • the antibody-drug conjugates is administered locally, for example by injection directly into a site to be treated.
  • Liposomal or proteinoid encapsulation may be used to formulate the compositions.
  • Liposomal encapsulation may be used and the liposomes may be derivatized with various polymers (e.g., U.S. Patent No.5,013,556). See also Marshall, K. In: Modern Pharmaceutics Edited by G. S. Banker and C. T. Rhodes Chapter 10, 1979.
  • the formulation will include the peptide (or chemically modified forms thereof) and inert ingredients which protect peptide in the stomach environment, and release of the biologically active material in the intestine.
  • the agents can be chemically modified so that oral delivery of the derivative is efficacious.
  • liquid dosage forms for oral administration including pharmaceutically acceptable emulsions, solutions, suspensions, and syrups, which may contain other components including inert diluents; adjuvants such as wetting agents, emulsifying and suspending agents; and sweetening, flavoring, and perfuming agents.
  • Controlled release oral formulations may be desirable.
  • the agent can be incorporated into an inert matrix which permits release by either diffusion or leaching mechanisms, e.g., gums. Slowly degenerating matrices may also be incorporated into the formulation.
  • Topical administration does not work well for most peptide formulations, although it can be effective especially if applied to the lungs, nasal, oral (sublingual, buccal), vaginal, or rectal mucosa.
  • Compositions can be delivered to the lungs while inhaling and traverse across the lung epithelial lining to the blood stream when delivered either as an aerosol or spray dried particles having an aerodynamic diameter of less than about 5 microns.
  • a wide range of mechanical devices designed for pulmonary delivery of therapeutic products can be used, including but not limited to nebulizers, metered dose inhalers, and powder inhalers, all of which are familiar to those skilled in the art.
  • Some specific examples of commercially available devices are the Ultravent nebulizer (Mallinckrodt Inc., St. Louis, Mo.); the Acorn II nebulizer (Marquest Medical Products, Englewood, Colo.); the Ventolin metered dose inhaler (Glaxo Inc., Research Triangle Park, N.C.); and the Spinhaler powder inhaler (Fisons Corp., Bedford, Mass.). Nektar, Alkermes and Mannkind all have inhalable insulin powder preparations approved or in clinical trials where the technology could be applied to the formulations described herein.
  • Formulations for administration to the mucosa will typically be spray dried drug particles, which may be incorporated into a tablet, gel, capsule, suspension or emulsion. Standard pharmaceutical excipients are available from any formulator.
  • Transdermal formulations may also be prepared. These will typically be ointments, lotions, sprays, or patches, all of which can be prepared using standard technology. Transdermal formulations may require the inclusion of penetration enhancers. 4. Controlled Delivery Polymeric Matrices [001155] The antibody-drug conjugates disclosed herein can also be administered in controlled release formulations.
  • Controlled release polymeric devices can be made for long term release systemically following implantation of a polymeric device (rod, cylinder, film, disk) or injection (microparticles).
  • the matrix can be in the form of microparticles such as microspheres, where the agent is dispersed within a solid polymeric matrix or microcapsules, where the core is of a different material than the polymeric shell, and the peptide is dispersed or suspended in the core, which may be liquid or solid in nature.
  • microparticles, microspheres, and microcapsules are used interchangeably.
  • the polymer may be in the form of a hydrogel (typically in absorbing up to about 90% by weight of water), and can optionally be crosslinked with multivalent ions or polymers.
  • the matrices can be formed by solvent evaporation, spray drying, solvent extraction and other methods known to those skilled in the art.
  • Bioerodible microspheres can be prepared using any of the methods developed for making microspheres for drug delivery, for example, as described by Mathiowitz and Langer, 221 064467-020PCT J.
  • the devices can be formulated for local release to treat the area of implantation or injection – which will typically deliver a dosage that is much less than the dosage for treatment of an entire body – or systemic delivery. These can be implanted or injected subcutaneously, into the muscle, fat, or swallowed. III. Methods of Administration [001159]
  • the compositions provided herein are to be understood as exemplary compositions related to the present disclosure. Such are not intended to be limiting of the scope of the present disclosure.
  • compositions described herein can be administered to a subject in need thereof, either alone or in combination with a pharmaceutically acceptable excipient and/or carrier, in an amount sufficient to induce an appropriate anti-tumor response.
  • Administration can include injection, infusion, other methods disclosed herein, and other methods known in the art.
  • Administration includes but is not limited to intravenous, intramuscular, subcutaneous, and the like.
  • the response can comprise, without limitation, specific immune response, non-specific immune response, both specific and non- specific response, innate response, primary immune response, adaptive immunity, secondary immune response, memory immune response, immune cell activation, immune cell proliferation, immune cell differentiation, and cytokine expression.
  • the invention provides a method of treating cancer in a mammal by administering to the mammal an effective amount of an antibody-drug conjugate of the invention.
  • Effective amounts of the antibody-drug conjugate can be determined by one of skill in the art with consideration of individual differences in age, weight, tumor size, extent of infection or metastasis, and condition of the patient (i.e. subject). It can generally be stated that the antibody-drug conjugate can be administered simultaneously or separately from other agents subject to the same or different dosing and timing regimens, as described herein.
  • the antibody- drug conjugates may also be administered multiple times at these dosages.
  • the antibody-drug conjugates can be administered by using infusion techniques that are commonly known in immunotherapy (Rosenberg, et al., New Eng.
  • the optimal dosage and treatment regime for a particular patient can 222 064467-020PCT readily be determined by one skilled in the art of medicine by monitoring the patient for signs of disease and adjusting the treatment accordingly.
  • An effective amount for a particular patient may vary depending on factors such as the condition being treated, the overall health of the patient, the route and dose of administration and the severity of side effects. Guidance for methods of treatment and diagnosis is available (Maynard, et al., Interpharm Press, 1996; Dent, Urch Publ., 2001).
  • An effective amount of the antibody-drug conjugates described herein may be given in one dose, but is not restricted to one dose.
  • the administrations can also be spaced by time intervals of one day, two days, three days, four days, five days, six days, seven days, eight days, nine days, ten days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, and combinations thereof.
  • the disclosure is not limited to dosing intervals that are spaced equally in time, but encompass doses at non-equal intervals, such as a priming schedule consisting of administration at 1 day, 4 days, 7 days, and 25 days, just to provide a non-limiting example.
  • the antibody-drug conjugates of the present invention can be administered in a dose, or dosages, where each dose comprises about 0.1mg, 0.5mg, 1mg, 2, mg, 3 mg, 4, mg, 5mg, 10mg, 15mg, 20mg, 30mg, 40mg, 50mg, 60mg, 70mg, 80mg, 90mg, 100mg, 200mg, 250mg, 300mg, 350mg, 400mg, 500mg, 600mg, and the like.
  • the antibody-drug conjugates of the present invention can be administered in a dose, or dosages, where each dose is dependent on subject body weight.
  • a dose, or dosages can be administered at about 0.1mg/kg, abount 0.5 mg/kg, about 1 mg/kg, at about 2mg/kg, about 2.5mg/kg, about 3mg/kg, about 3.4mg/kg, about 4mg/kg, anout 4.5mg/kg, about 5mg/kg, about 5.5mg/kg, about 6mg/kg, about 6.5mg/kg, 223 064467-020PCT about 7mg/kg, about 7.5mg/kg, about 8mg/kg, about 8.5mg/kg, about 9mg/kg, anout 9.5mg/kg, about 10mg/kg, about 10.5mg/kg, about 11mg/kg, about 11.5mg/kg, about 12mg/kg, and the like.
  • a dosing schedule of, for example, once/week, twice/week, three times/week, four times/week, five times/week, six times/week, seven times/week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, and the like, is available for the antibody-drug conjugates disclosed herein.
  • the dosing schedules encompass dosing for a total period of time of, for example, one week, two weeks, three weeks, four weeks, five weeks, six weeks, two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, and twelve months.
  • a dosing schedule of 400mg once every six weeks may have a similar benefit-risk profile in a subject undergoing a dosing schedule of 200mg once every 3 weeks.
  • cycles of the above dosing schedules can be repeated about, e.g., every seven days; every 14 days; every 21 days; every 28 days; every 35 days; 42 days; every 49 days; every 56 days; every 63 days; every 70 days; and the like.
  • An interval of non-dosing can occur between a cycle, where the interval can be about, e.g., seven days; 14 days; 21 days; 28 days; 35 days; 42 days; 49 days; 56 days; 63 days; 70 days; and the like.
  • Dosing schedules of the present disclosure can be related to cycles.
  • a dosing schedule for an antibody-drug conjugate disclosed herein may be designed such that doses are given on certain days of a cycle.
  • doses may be administered on days 1, 15, and 29 of a repeating 42-day cycle.
  • cycle may repeat until a subject exhibits adverse side effects to doses.
  • a cycle can additionally repeat until a subject is sufficiently cured of a disease.
  • An effective amount of a therapeutic agent is one that will decrease or ameliorate the symptoms normally by at least 10%, more normally by at least 20%, most normally by at least 30%, typically by at least 40%, more typically by at least 50%, most typically by at least 60%, often by at least 70%, more often by at least 80%, and most often by at least 90%, conventionally by at least 95%, more conventionally by at least 99%, and most conventionally by at least 99.9%.
  • Administration of doses, or dosages, of antibody-drug conjugates disclosed herein can be subject to change. The dosing and timing regimens may be changed according to factors known in the art. As non-limiting examples, administration of dosages of the antibody-drug conjugates may be delayed allowing for resolution of any observed toxicities.
  • administration of antibody-drug conjugates disclosed herein should not occur after certain times have elapsed.
  • administration of the CDCP1 antibody-drug conjugate should generally not be delayed greater than 28-days between sequential doses, though this is subject to change. If a dose of the antibody-drug conjugates disclosed herein is missed, a subject in need thereof may remain on the original treatment schedule with the antibody-drug conjugates disclosed herein being administered at the time of next planned dose.
  • Formulations of therapeutic agents may be prepared for storage by mixing with physiologically acceptable carriers, excipients, or stabilizers in the form of, e.g., lyophilized powders, slurries, aqueous solutions or suspensions.
  • physiologically acceptable carriers e.g., lyophilized powders, slurries, aqueous solutions or suspensions.
  • an antibody is a mammalian antibody.
  • Phage techniques can be used to isolate an initial antibody or to generate variants with altered specificity or avidity characteristics. Such techniques are routine and well known in the art.
  • the antibody is produced by recombinant means known in the art.
  • the disclosed antibodies can be modified by recombinant means to increase greater efficacy of the antibody in mediating the desired function.
  • antibodies can be modified by substitutions using recombinant means.
  • the substitutions will be conservative substitutions.
  • at least one amino acid in the constant region of the antibody can be replaced with a different residue. See, e.g., U.S. Pat. No.5,624,821, U.S. Pat. No.6,194,551, Application No. WO 9958572; and Angal, et al., Mol. Immunol.30:105-08 (1993).
  • the modification in amino acids includes deletions, additions, and substitutions of amino acids.
  • the antibodies are labeled by joining, either covalently or non-covalently, a substance which provides for a detectable signal.
  • labels and conjugation 226 064467-020PCT techniques are known and are reported extensively in both the scientific and patent literature. These antibodies can be screened for binding to proteins, polypeptides, or fusion proteins of CDCP1. See, e.g., Antibody Engineering: A Practical Approach (Oxford University Press, 1996).
  • suitable antibodies with the desired biologic activities can be identified using in vitro assays including but not limited to: proliferation, migration, adhesion, soft agar growth, angiogenesis, cell-cell communication, apoptosis, transport, signal transduction, and in vivo assays such as the inhibition of tumor growth.
  • the antibodies provided herein can also be useful in diagnostic applications. As capture or non-neutralizing antibodies, they can be screened for the ability to bind to the specific antigen without inhibiting the receptor-binding or biological activity of the antigen. As neutralizing antibodies, the antibodies can be useful in competitive binding assays.
  • Antibodies that can be used in the disclosed compositions and methods include whole immunoglobulin (i.e., an intact antibody) of any class, fragments thereof, and synthetic proteins containing at least the antigen binding variable domain of an antibody.
  • the variable domains differ in sequence among antibodies and are used in the binding and specificity of each particular antibody for its particular antigen. However, the variability is not usually evenly distributed through the variable domains of antibodies. It is typically concentrated in three segments called complementarity determining regions (CDRs) or hypervariable regions both in the light chain and the heavy chain variable domains. The more highly conserved portions of the variable domains are called the framework (FR).
  • CDRs complementarity determining regions
  • FR framework
  • the antibody-drug conjugates and the additional therapeutic agent can be administered as part of a therapeutic regimen. For example, if a first therapeutic agent can be administered to a subject every fourth day, the second therapeutic agent can be administered on the first, second, third, or fourth day, or combinations thereof. The first therapeutic agent or second therapeutic agent may be repeatedly administered throughout the entire treatment regimen.
  • tamoxifen (Z)-2-[4- (1,2-diphenylbut-1-enyl)phenoxy]-NN-dimethyl-ethanamine, NOLVADEX®, ISTUBAL®, VALODEX®), doxorubicin (ADRIAMYCIN®), Akti-1/2, HPPD, rapamycin, and lapatinib (TYKERB®, Glaxo SmithKline).
  • Humanized monoclonal antibodies with therapeutic potential as chemotherapeutic agents in combination with the P13K inhibitors of the invention include: alemtuzumab, apolizumab, aselizumab, atlizumab, bapineuzumab, bevacizumab, bivatuzumab mertansine, cantuzumab mertansine, cedelizumab, certolizumab pegol, cidfusituzumab, cidtuzumab, daclizumab, eculizumab, efalizumab, epratuzumab, erlizumab, felvizumab, fontolizumab, gemtuzumab ozogamicin, inotuzumab ozogamicin, ipilimumab, labetuzumab, lintuzumab, matuzumab, mepolizumab, motavizumab, motovizum
  • alkyl refers to a saturated linear or branched-chain monovalent hydrocarbon radical of one to twelve carbon atoms, wherein the alkyl radical may be optionally substituted independently with one or more substituents described below.
  • alkyl groups include, but are not limited to, methyl (Me, -CH3 ), ethyl (Et, CH2) [001198]
  • the additional therapeutic agents are selected based on the condition, disorder or disease to be treated.
  • the immunomodulatory agent can be co-administered with one or more additional agents that function to enhance or promote an immune response or reduce or inhibit an immune response.
  • Antimicrobials [001199]
  • a CDCP1 immunomodulatory agent can be used in a preventive or prophylactic role in the treatment and prevention of disease as discussed above, and also in the context of severe trauma injuries like major burn, open bone fracture, accidental amputation or other wounds. Therefore, the CDCP1 immunomodulatory agents can be administered to the subject in combination with an antimicrobial such as an antibiotic, an antifungal, an antiviral, an antiparasitics, or essential oil.
  • the subject is administered the CDCP1 immunomodulatory agent and/or the antimicrobial at time of admission to the hospital to prevent further bacterial, fungal or viral complications.
  • the antibiotic can target pathogens and the CDCP1 immunomodulatory agent can stimulate the immune system to provide an enhanced response to treat or prevent further infection or disease.
  • Chemotherapeutic Agents [001201] The CDCP1 immunomodulatory agents can be combined with one or more chemotherapeutic agents and pro-apoptotic agents.
  • chemotherapeutic agents include, but are not limited to amsacrine, bleomycin, busulfan, capecitabine, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, 238 064467-020PCT clofarabine, crisantaspase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, docetaxel, doxorubicin, epirubicin, etoposide, fludarabine, fluorouracil, gemcitabine, hydroxycarbamide, idarubicin, ifosfamide, irinotecan, leucovorin, liposomal doxorubicin, liposomal daunorubicin, lomustine, melphalan, mercaptopurine, mesna, methotrexate, mitomycin, mitoxantrone, ox
  • a specific example of an anti-PD-1 antibody is an antibody described in Kosak, US 20070166281 (pub.19 July 2007) at par.42), a human anti-PD-1 antibody, which in some embodiments is administered at a dose of 3 mg/kg.
  • exemplary PD-1 receptor antagonists include, but are not limited to B7-DC polypeptides, including homologs and variants of these, as well as active fragments of any of the foregoing, and fusion proteins that incorporate any of these.
  • the fusion protein includes the soluble portion of B7-DC coupled to the Fc portion of an antibody, such as human IgG, and does not incorporate all or part of the transmembrane portion of human B7-DC.
  • the PD-1 antagonist can also be a fragment of a mammalian B7-H1, for example from mouse or primate, such as a human, wherein the fragment binds to and blocks PD-1 but does not result in inhibitory signal transduction through PD-1.
  • the fragments can also be part of a fusion protein, for example an Ig fusion protein.
  • Other useful polypeptides PD-1 antagonists include those that bind to the ligands of the PD-1 receptor. These include the PD-1 receptor protein, or soluble fragments thereof, which can bind to the PD-1 ligands, such as B7-H1 or B7-DC, and prevent binding to the endogenous PD-1 receptor, thereby preventing inhibitory signal transduction.
  • B7-H1 has also been shown to bind the protein B7.1 (Butte et al., Immunity, Vol.27, pp.111-122, (2007)). Such fragments also include the soluble ECD portion of the PD-1 protein that includes mutations, such as the A99L mutation, that increases binding to the natural ligands (Molnar et al., PNAS, 105:10483-10488 (2008)). B7-1 or soluble fragments thereof, which can bind to the B7-H1 ligand and prevent binding to the endogenous PD-1 receptor, thereby preventing inhibitory signal transduction, are also useful.
  • PD-1 and B7-H1 anti-sense nucleic acids can also be PD-1 antagonists.
  • Such anti-sense molecules prevent expression of PD-1 on T cells as well as production of T cell ligands, such as B7-H1, PD-L1 and/or PD-L2.
  • T cell ligands such as B7-H1, PD-L1 and/or PD-L2.
  • siRNA for example, of about 21 nucleotides in length, which is specific for the gene encoding PD-1, or encoding a PD-1 ligand, and which oligonucleotides can be readily purchased commercially
  • carriers such as polyethyleneimine (see Cubillos-Ruiz et al., J. Clin.
  • an anti-CTLA4 antibody contemplated for use in the methods of the invention includes an antibody as described in PCT/US2006/043690 (Fischkoff et al., WO/2007/056539).
  • Dosages for anti-PD-1, anti-B7-H1, and anti-CTLA4 antibody are known in the art and can be in the range of, for example, 0.1 to 100 mg/kg, or with shorter ranges of 1 to 50 mg/kg, or 10 to 20 mg/kg.
  • An appropriate dose for a human subject can be between 5 and 15 mg/kg, with 10 mg/kg of antibody (for example, human anti-PD-1 antibody) being a specific embodiment.
  • an anti-CTLA4 antibody useful in the methods of the invention are Ipilimumab, a human anti-CTLA4 antibody, administered at a dose of, for example, about 10 mg/kg, and Tremelimumab a human anti-CTLA4 antibody, administered at a dose of, for example, about 15 mg/kg.
  • the antagonist is a small molecule. A series of small organic compounds have been shown to bind to the B7-1 ligand to prevent binding to CTLA4 (see Erbe et al., J. Biol.
  • additional therapeutic agents include a potentiating agent.
  • the potentiating agent acts to increase efficacy of the immune response up-regulator, possibly by more than one mechanism, although the precise mechanism of action is not essential to the broad practice of the present invention.
  • the potentiating agent is cyclophosphamide.
  • Cyclophosphamide (CTX, Cytoxan ® , or Neosar ® ) is an oxazahosphorine drug and analogs include ifosfamide (IFO, Ifex), perfosfamide, trophosphamide (trofosfamide; Ixoten), and pharmaceutically acceptable salts, solvates, prodrugs and metabolites thereof (US patent application 20070202077 which is incorporated in its entirety).
  • Ifosfamide (MITOXANA ® ) is a structural analog of cyclophosphamide and its mechanism of action is considered to be identical or substantially similar to that of 242 064467-020PCT cyclophosphamide.
  • Perfosfamide (4-hydroperoxycyclophosphamide) and trophosphamide are also alkylating agents, which are structurally related to cyclophosphamide. For example, perfosfamide alkylates DNA, thereby inhibiting DNA replication and RNA and protein synthesis.
  • New oxazaphosphorines derivatives have been designed and evaluated with an attempt to improve the selectivity and response with reduced host toxicity (Liang J, Huang M, Duan W, Yu XQ, Zhou S. Design of new oxazaphosphorine anticancer drugs. Curr Pharm Des.2007;13(9):963- 78. Review).
  • Mafosfamide is an oxazaphosphorine analog that is a chemically stable 4-thioethane sulfonic acid salt of 4-hydroxy-CPA.
  • Glufosfamide is IFO derivative in which the isophosphoramide mustard, the alkylating metabolite of IFO, is glycosidically linked to a beta-D-glucose molecule. Additional cyclophosphamide analogs are described in US patent 5,190,929 entitled “Cyclophosphamide analogs useful as anti-tumor agents” which is incorporated herein by reference in its entirety. [001223] While CTX itself is nontoxic, some of its metabolites are cytotoxic alkylating agents that induce DNA crosslinking and, at higher doses, strand breaks. Many cells are resistant to CTX because they express high levels of the detoxifying enzyme aldehyde dehydrogenase (ALDH).
  • ALDH aldehyde dehydrogenase
  • CTX targets proliferating lymphocytes, as lymphocytes (but not hematopoietic stem cells) express only low levels of ALDH, and cycling cells are most sensitive to DNA alkylation agents.
  • Low doses of CTX ⁇ 200 mg/kg can have immune stimulatory effects, including stimulation of anti-tumor immune responses in humans and mouse models of cancer (Brode & Cooke Crit Rev. Immunol.28:109-126 (2008)). These low doses are sub-therapeutic and do not have a direct anti-tumor activity. In contrast, high doses of CTX inhibit the anti-tumor response.
  • CTX has also been shown to induce type I IFN expression and promote homeostatic proliferation of lymphocytes.
  • Treg depletion is most often cited as the mechanism by which CTX potentiates the anti-tumor immune response. This conclusion is based in part by the results of adoptive transfer experiments.
  • CTX treatment at Day 9 gives a 75% cure rate. Transfer of purified Treg at Day 12 almost completely inhibited the CTX response (van der Most et al. Cancer Immunol. Immunother. 58:1219-1228 (2009).
  • a similar result was observed in the HHD2 tumor model: adoptive transfer of CD4+CD25+ Treg after CTX pretreatment eliminated therapeutic response to vaccine (Taieb, J. J. Immunol.176:2722-2729 (2006)).
  • CTX is a safe, well-tolerated, and effective agent for promoting anti-tumor immune responses
  • the optimal dose for CTX to potentiate an anti-tumor immune response is one that lowers overall T cell counts by lowering Treg levels below the normal range but is subtherapeutic (see Machiels et al. Cancer Res.61:3689-3697 (2001)).
  • a dose of 300 mg/m 2 has usually been used.
  • 300 mg/m 2 is 8 mg/kg, or 624 mg of total protein.
  • efficacy has been seen at doses ranging from 15 – 150 mg/kg, which relates to 0.45 – 4.5 mg of total protein in a 30g mouse (Machiels et al. Cancer Res.61:3689-3697 (2001), Hengst et al Cancer Res.41:2163-2167 (1981), Hengst Cancer Res.40:2135-2141 (1980)).
  • mg/m 2 doses may be used but unit doses administered over a finite time interval may also be used.
  • unit doses may be administered on a daily basis for a finite time period, such as up to 3 days, or up to 5 days, or up to 7 days, or up to 10 days, or up to 15 days or up to 20 days or up to 25 days, are all specifically contemplated by the invention.
  • the same regimen may be applied for the other potentiating agents recited herein.
  • the potentiating agent is an agent that reduces activity and/or number of regulatory T lymphocytes (T-regs), such as Sunitinib 244 064467-020PCT (SUTENT ® ), anti-TGF ⁇ or Imatinib (GLEEVAC ® ).
  • T-regs regulatory T lymphocytes
  • the recited treatment regimen may also include administering an adjuvant.
  • Useful potentiating agents also include mitosis inhibitors, such as paclitaxol, aromatase inhibitors (e.g. Letrozole) and angiogenesis inhibitors (VEGF inhibitors e.g.
  • the therapeutic agent can be a small molecule that inhibits or reduces differentiation, proliferation, activity, and/or cytokine production and/or secretion by Th1, Th17, Th22, and/or other cells that secrete, or cause other cells to secrete, inflammatory molecules, including, but not limited to, IL-1 ⁇ , TNF- ⁇ , TGF-beta, IFN- ⁇ , IL-18 IL-17, IL-6, IL-23, IL-22, IL-21, and MMPs.
  • inflammatory molecules including, but not limited to, IL-1 ⁇ , TNF- ⁇ , TGF-beta, IFN- ⁇ , IL-18 IL-17, IL-6, IL-23, IL-22, IL-21, and MMPs.
  • Table 12 shows is a summary of Carterra and Octet data for the variants binding to human and cynomolgus monkey CDCP1.

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Abstract

L'invention concerne des agents immunomodulateurs et destructeurs ciblés de CDCP1 (administration de charge utile de toxine) qui modulent l'expression de CDCP1, la liaison de ligand, la réticulation, la signalisation médiée par CDCP1, et/ou la survie de cellules exprimant CDCP1 ou une combinaison de ces fonctions. Les agents immunomodulateurs de CDCP1 comprennent un polypeptide ou des protéines de fusion de CDCP1 soluble, des anticorps anti-CDCP1 et des conjugués anticorps-médicament. De tels agents peuvent être utilisés pour moduler une réponse immunitaire, affecter la survie de cellules malignes exprimant CDCP1 ou les deux chez un sujet en ayant besoin.
PCT/US2024/060972 2023-12-21 2024-12-19 Compositions et procédés de modulation de la transduction de signal médiée par cdcp1 Pending WO2025137236A1 (fr)

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US20190225703A1 (en) * 2015-10-12 2019-07-25 Innate Pharma Cd73 blocking agents
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US20190225703A1 (en) * 2015-10-12 2019-07-25 Innate Pharma Cd73 blocking agents
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