RU2819454C2 - Methods of immunotherapy of patients whose tumors are characterized by high load of passenger gene mutations - Google Patents

Abstract

FIELD: biotechnology.

SUBSTANCE: disclosed is use of an antibody which binds to PD1 and inhibits it, when producing a drug for treating a subject with cancer. Subject has a tumour with a total load of passenger gene mutations exceeding the background mutation load of the tumour. Selection of a patient with cancer for immunotherapy involves determining a total load of passenger tumour gene mutations in a patient with cancer, obtaining a background distribution for the mutation load of the tumour, normalizing the total load of passenger gene mutations relative to the baseline distribution and referring the patient with cancer to the category of responders for immunotherapy if the total load of passenger gene mutations exceeds the average value of the baseline distribution.

EFFECT: invention provides effective selection of patients-responders for cancer immunotherapy.

43 cl, 14 dwg, 4 tbl, 4 ex

Description

CROSS REFERENCE TO RELATED APPLICATION

This application claims benefit from U.S. Provisional Application No. 62/560955, filed September 20, 2017 and hereby incorporated by reference in its entirety.

TECHNICAL FIELD

The present invention generally relates to the field of immunotherapy. More specifically, the present invention relates to methods of administering immunotherapy to patients whose tumors have a high burden of passenger gene mutations.

BACKGROUND OF THE ART

Various publications are referenced throughout the description, including patents, patent applications, published patent applications, accession numbers, technical articles, and scientific articles. Each of these publications referred to is incorporated herein by reference in its entirety and for all purposes.

Recent studies have shown that patients whose tumors have a higher total tumor mutational burden (TMB) are more likely to benefit from immunotherapy due to increased presentation of neoantigens that can trigger an immune response. However, the overall mutational load includes driver gene mutations that may actually suppress immunogenicity and reduce sensitivity to treatment.

There is no developed method designed to identify passenger genes and mutations in them and assess immunogenicity. These and other disadvantages are solved in the present invention.

SHORT DESCRIPTION

It should be understood that both the following general description and the following detailed description are illustrative and explanatory only and are not limiting.

In a first aspect of the present invention, there is provided a method comprising obtaining genetic sequence data, wherein the genetic sequence data spans a plurality of genes and is obtained from a plurality of biological samples collected from subjects having multiple types of diseases, identifying a plurality of mutant genes for each of the plurality of biological samples, where each of the mutant genes contains a genetic sequence having at least one non-synonymous somatic mutation, determining the mutational load of the tumor for each biological sample based on the number of mutant genes in each biological sample for each type of disease, determining the average mutational load of the tumor for a set of mutant genes in multiple biological samples based on a certain number of mutant genes in each biological sample for each mutant gene and each type of disease, determining the proportion of biological samples containing the mutant gene for each mutant gene, determining the correlation coefficient between the average mutational load of the tumor and the proportion of biological samples containing a mutant gene. A higher correlation coefficient indicates that a particular gene is more likely to acquire somatic mutations in cancer types with a higher overall mutation rate (eg, passenger gene), whereas a lower correlation coefficient indicates that a particular gene is less likely to will acquire somatic mutations in cancer types characterized by a higher overall mutation frequency (eg, non-passenger gene).

In another aspect of the present invention, methods are provided for selecting a patient with cancer for immunotherapy. Typically, these methods involve determining the total passenger gene mutation load of a tumor in a patient with cancer, obtaining a background distribution for the tumor mutation load, normalizing the total passenger gene mutation burden relative to the background distribution, and classifying the patient with cancer as an immunotherapy responder if the total passenger gene mutation burden is gene mutations are at least approximately one and a half standard deviations above the mean of the background distribution.

Obtaining the background distribution may involve determining the mutation load for randomly selected genes in a plurality of tumor-derived samples, however, the number of randomly selected genes in each sample is preferably equal to the number of passenger genes used to calculate the total passenger gene mutation load. Normalizing the total load of passenger gene mutations relative to the background distribution may involve obtaining a z-score indicating the number of standard deviations from the mean of the background distribution.

The methods may further include determining whether the mutant tumor gene is classified as a passenger gene. Classifying a mutant tumor gene as a passenger gene may involve selecting a mutant tumor gene and matching the mutant gene to a structured data set covering passenger genes identified according to a passenger gene index. The passenger gene index may provide a correlation coefficient between the proportion of samples containing a mutated gene obtained from a cohort of cancer patients and the median number of mutated genes for each tumor type in the cohort of cancer patients.

The methods may further include administering a course of immunotherapy to a patient with cancer. A course of immunotherapy may involve administering a T-cell inhibitory receptor inhibitor to the patient. A course of immunotherapy may involve administering a T-cell activating receptor activator to the patient.

A course of immunotherapy may involve administering to the patient an antibody that binds to PD1. An antibody that binds to PD1 may contain at least a heavy chain variable region (HCVR) sequence of SEQ ID NO: 21 and a light chain variable region, or may contain at least a light chain variable region (LCVR) sequence of SEQ ID NO: 22 and heavy chain variable region. An antibody that binds to PD1 may comprise HCVR or SEQ ID NO: 21 and LCVR or SEQ ID NO: 22. This antibody that binds to PD1 may be administered in combination with an antibody that binds to LAG3.

A course of immunotherapy may involve administering to the patient an antibody that binds to PDL1. An antibody that binds to PDL1 may contain at least the HCVR sequence of SEQ ID NO: 122 and LCVR or may contain at least the LCVR sequence of SEQ ID NO: 123 and HCVR. An antibody that binds to PDL1 may comprise HCVR or SEQ ID NO: 122 and LCVR or SEQ ID NO: 123. This antibody that binds to PDL1 can be administered in combination with an antibody that binds to LAG3.

A course of immunotherapy may involve administering to the patient an antibody that binds to LAG3. An antibody that binds to LAG3 may contain at least the HCVR sequence of SEQ ID NO: 93 and LCVR or may contain at least the LCVR sequence of SEQ ID NO: 94 and HCVR. An antibody that binds to LAG3 may comprise HCVR or SEQ ID NO: 93 and LCVR or SEQ ID NO: 94. A given antibody that binds to LAG3 may be administered in combination with an antibody that binds PD1 or an antibody that binds to PDL1.

Additional advantages will be set forth in part in the description that follows or may be obtained through practice. The advantages will be realized and achieved by the features and combinations specifically set forth in the appended claims.

BRIEF DESCRIPTION OF GRAPHIC MATERIALS

The accompanying drawings, which are included in and constitute a part of this specification, illustrate embodiments and, together with the description, serve to explain the principles of the methods and systems.

Figure 1 is a flowchart illustrating an example of the method.

Figure 2 is a flowchart illustrating an example of the method.

Figure 3 is a flowchart illustrating another example of the method.

Figure 4 is a flowchart illustrating another example of the method.

Figure 5 provides a general overview of passenger gene characteristics.

Figure 6 shows scatterplots for the proportion of patients with a gene variant (y-axis) and the average total number of mutant genes (x-axis) for each cancer type.

Figure 7 shows the passenger gene index (PGI) richness for cancer driver genes and various other groups of genes.

Figure 8 shows the genes from the CGC with the highest (left) and lowest (right) PGI values and their corresponding cancer type with the highest percentage (>2%) of samples with mutations.

Figures 9A-C graphically represent a) measures of local immune cytolytic activity, b) TCR read counts, and c) clinical outcome in patient cohorts.

Figure 10 is a block diagram showing an exemplary operating environment for performing the disclosed methods.

Figure 11 shows the TMB in the cohort of patients in the phase 1 clinical trial.

Figure 12 shows the top 500 passenger genes with the highest passenger gene index (PGI).

DETAILED DESCRIPTION

Various terms related to aspects of the present invention are used throughout the specification and claims. Unless otherwise indicated, such terms are to be understood in their ordinary meaning in the art. Other specifically defined terms should be interpreted as defined herein.

As used in the specification and the accompanying claims, the singular form includes references to the plural unless the context clearly indicates otherwise.

Inhibition involves reducing, decreasing, blocking, preventing, slowing, inactivating, desensitizing, stopping and/or down-regulating the activity or expression of a molecule or signaling pathway of interest.

Embodiments of methods and systems are described below with reference to block diagrams and block diagrams illustrating methods, systems, devices, and computer program products. It will be understood that each block of the block diagram and flow chart illustrations and combinations of blocks in the block diagram and flow chart illustrations, respectively, can be implemented by computer program instructions. These computer program instructions may be loaded onto a general purpose computer, a special purpose computer, or other programmable data processing device that is a machine, whereby the instructions executed by the computer or other programmable data processing device implement the functions specified in the block or blocks of the block -scheme.

Such computer program instructions may also be stored in a computer readable storage device that can control a computer or other programmable data processing device to perform its functions properly, whereby the instructions stored in the computer readable storage device provide a finished product, including computer readable instructions intended to to implement a function specified in a block or blocks of a block diagram. Computer program instructions may also be loaded onto a computer or other programmable processing device to cause a number of process steps to be performed on the computer or other programmable device to produce a computer-implemented process, whereby the instructions executed on the computer or other programmable device enable the steps to implement the functions specified in the block or blocks of the block diagram.

Accordingly, the blocks of illustration in the form of block diagrams and block diagrams provide combinations of means for performing specified functions, combinations of steps for performing specified functions, and means represented by program commands for performing specified functions. It should also be understood that each block diagram and flowchart illustration and combination of block diagram and flowchart illustrations may be implemented by specialized hardware computer systems that perform the specified functions or steps or combinations. specialized hardware and computer programs.

The terms "subject" and "patient" are used interchangeably and include any animal. Preferred are mammals, including companion mammals (eg, cat, dog) and farm mammals (eg, pig, horse, cow), as well as rodents, including mice, rabbits and rats, guinea pigs and other rodents. Non-human primates are preferred, with humans being particularly preferred.

In accordance with the present invention, it has been discovered that in cancer, the total load of passenger gene mutations, as opposed to the total mutation load for all genes, serves as an accurate indicator of whether a patient with cancer is likely to respond to immunotherapy. Tumor mutational burden (TMB) can indicate the number of mutations within the coding region of the tumor genome. Mutant genes were assessed and classified according to their status as a passenger gene using the passenger gene index, which was used in large-scale cancer genome analysis. It was noted that the identified passenger genes were dominated by gene families known to have an excess of passenger mutations, including genes encoding large proteins, genes with low levels of expression, and genes with late DNA replication times. The total burden of passenger gene mutations positively correlates with tumor immunogenicity and favorable prognosis of clinical outcomes in patients. Accordingly, the present invention provides methods for classifying patients according to their passenger gene mutation load as part of a course of immunotherapy.

In cancer biology, driver mutations are thought to be at least to some extent involved in carcinogenesis or cell transformation. Passenger mutations are considered to be mutations that do not provide a growth advantage or do not contribute to the development of cancer. See Stratton MR et al . (2009) Nature. 458:719-24. Thus, passenger genes include those genes that contain passenger mutations. Non-limiting examples of mutations include substitutions, inversions, insertions and deletions of one or more nucleotides, codons, genes or chromosomes, as well as copy number changes.

In one aspect of the present invention, methods and systems for identifying or classifying passenger genes are provided. Among the identified passenger genes, families known to have an excessive number of passenger mutations predominate, such as particularly large proteins and genes with low expression levels or with late DNA replication times. In some embodiments, passenger genes may be identified or classified according to the Passenger Gene Index (PGI). Thus, for example, passenger genes can be identified or classified according to the PGI, which is the correlation coefficient between the proportion of samples obtained from a cohort of cancer patients that contain a mutated gene and the median number of mutated genes for each tumor type in the cohort of patients with cancer. cancer. Based on the identification of passenger genes, a structured data set covering passenger genes can be compiled.

Individual cancer patients can be screened to determine whether their tumors contain passenger genes and to determine the overall passenger gene mutation burden of their tumors. Based on a patient's passenger gene mutation burden, the patient can be classified according to its ability to respond positively to immunotherapy. Immunotherapy generally enhances the body's natural immune response to cancer and includes, but is not limited to, enhancing the T cell response to the tumor.

An example of an approach by which a patient with cancer can be assessed for response to immunotherapy is shown in FIG. 1 . In general terms, the methods involve determining the total passenger gene mutation burden of a tumor in a patient with cancer ( 110 ), obtaining a background distribution for the tumor mutational load ( 120 ), normalizing the total passenger gene mutation burden relative to the background distribution ( 130 ), and classifying the patient with cancer into a category responders to immunotherapy ( 140 ).

Also disclosed are methods of treating a patient with cancer using immunotherapy after the patient has been assessed for response to immunotherapy. For example, methods of treating a patient with cancer through immunotherapy are disclosed, comprising determining whether the patient with cancer is a responder to immunotherapy, comprising determining the patient's total tumor passenger gene mutation burden; obtaining a background distribution for tumor mutational load; normalizing the total load of passenger gene mutations relative to the background distribution and classifying the patient with cancer as having a responder genotype for immunotherapy if the total load of passenger gene mutations is at least about one and a half standard deviations above the mean value of the background distribution; and administering immunotherapy to a cancer patient classified as an immunotherapy responder.

Further disclosed are methods of treating a patient with a T-cell inhibitory receptor inhibitor, or a receptor on a tumor cell, or a treatment other than immunotherapy, where the patient suffers from cancer, the method comprising the following steps: determining whether the patient is a responder to immunotherapy by obtaining or obtaining a biological sample of a patient's tumor; performing or performing genotyping analysis on a biological sample to determine whether the patient has an immunotherapy responder genotype, performed by sequencing the biological sample to obtain sequence data; determining, based on sequence data, the total load of passenger gene mutations of a patient's tumor; obtaining, from sequence data, a background distribution for tumor mutational load; normalizing the total load of passenger gene mutations relative to the background distribution and classifying the patient as a responder to immunotherapy if the total load of passenger gene mutations is at least about one and a half standard deviations above the mean value of the background distribution; Moreover, if the patient has a genotype of a responder to immunotherapy, then a therapeutically effective amount of an inhibitor of the T-cell inhibitory receptor or a receptor on a tumor cell is administered, and if the patient does not have a genotype of a responder to immunotherapy, then an agent for treatment other than immunotherapy is administered . In some embodiments, the level of risk of an adverse clinical outcome for a patient with an immunotherapy responder genotype is lower following administration of a therapeutically effective amount of a T-cell inhibitory receptor or receptor inhibitor on a tumor cell compared to the risk that would be present when administering to the patient a treatment agent other than from immunotherapy. In some embodiments, T cell activation and/or immune cytolytic activity in a patient with an immunotherapy responder genotype is greater following administration of a therapeutically effective amount of a T cell inhibitory receptor or receptor inhibitor on a tumor cell than it would be when the patient is administered an agent to treatment other than immunotherapy.

Immunotherapeutic agents are disclosed for use in a method of treating a patient with cancer, the method comprising determining whether the patient with cancer is classified as a responder to immunotherapy, which is accomplished by determining the patient's total tumor passenger gene mutation load; obtaining a background distribution for tumor mutational load; normalization of the total load of passenger gene mutations relative to the background distribution; classifying a patient with cancer as having an immunotherapy responder genotype if the total load of passenger gene mutations is at least about one and a half standard deviations above the mean of the background distribution; and administering an immunotherapy agent to a cancer patient classified as an immunotherapy responder

In some preferred embodiments, determining the total passenger gene mutation burden of a tumor in a patient with cancer ( 110 ) may involve determining the total passenger gene mutation burden using any sequencing method that is used to define coding regions (“exome”) in the tumor genome. Whole genome sequencing methods can also be used.

Mutations in the exome can be determined using sequencing methods known in the art. For example, US 2013/0040863, incorporated herein by reference, describes methods for determining the nucleic acid sequence of a target nucleic acid molecule, including sequencing by synthesis, sequencing by ligation, or sequencing by hybridization, including for the purpose of identifying mutations, performing whole genome sequencing and exon sequencing. If necessary, various amplification methods can be used to obtain higher quantities, particularly small samples of nucleic acids, before sequencing.

Sequencing by synthesis (SBS) and sequencing by ligation can be performed using ePCR, which is used by 454 Lifesciences (Branford, CT) and Roche Diagnostics (Basel, Switzerland). Nucleic acids, such as genomic DNA or others of interest, can be fragmented, dispersed in water-in-oil emulsions, and diluted, thereby separating a single nucleic acid fragment from other fragments in the emulsion droplet. It is possible to use a bead, for example, carrying multiple copies of a primer, and perform an amplification whereby each drop of emulsion serves as a reaction "vessel" for amplifying one nucleic acid fragment into multiple copies. Other methods such as bridge PCR (Illumina, Inc.; San Diego, CA) or polony amplification (Agencourt/Applied Biosystems) can be used. US 2009/0088327; US 2010/0028885 and US 2009/0325172, each of which is incorporated herein by reference.

Manual or automated sequencing methods are well known in the art and include, but are not limited to, Sanger sequencing, pyrosequencing, hybridization sequencing, ligation sequencing, etc. Sequencing methods can be performed manually or using automated methods. In addition, the amplification methods set forth herein can be used to prepare nucleic acids for sequencing using commercially available methods such as automated Sanger sequencing (available from Applied Biosystems, Foster City, Calif.) or pyrosequencing (available from 454 Lifesciences , Branford, CT and Roche Diagnostics, Basel, Switzerland); for sequencing by synthesis methods commercially available from Illumina, Inc. (San Diego, CA) or Helicos (Cambridge, MA), or ligation sequencing methods being developed by Applied Biosystems based on their Agencourt platform (see also Ronaghi et al., Science 281:363 (1998); Dressman et al. , Proc. Natl. Sci. USA 100:8817-8822 (2003); .

A collection of nucleic acids in which a primer hybridizes with each nucleic acid in such a way that nucleic acid templates are formed and template-guided modification of the primer occurs. The modification can be detected to determine the sequence of the template. For example, primers can be modified by extension using a polymerase, and primer extension can be monitored under conditions that allow the identity and location of specific nucleotides to be determined. For example, one can monitor the extension and determine the sequence of nucleic acid templates using pyrosequencing, which is described in patent documents US 2005/0130173, US 2006/0134633, US patent No. 4971903; US Patent No. 6,258,568 and US Patent No. 6,210,891, each of which is incorporated herein by reference, and which is also commercially available. Elongation can also be monitored in accordance with the addition of polymerase-labeled nucleotide analogues using methods described, for example, in US patent No. 4863849; US patent No. 5302509; US patent No. 5763594; US Patent No. 5798210; US Patent No. 6001566; US Patent No. 6664079; U.S. patent document 2005/0037398 and US Patent No. 7057026, each of which is incorporated herein by reference. Polymerases useful in sequencing methods are generally enzymes with polymerase activity obtained from natural sources. It will be understood that polymerases can be modified to change their specificity for modified nucleotides, as described, for example, in patent document WO 01/23411; US Pat. No. 5,939,292 and WO 05/024010, each of which is incorporated herein by reference. In addition, polymerases do not necessarily need to be derived from biological systems. Polymerases that are useful in the present invention include any agent capable of catalyzing the extension of a nucleic acid-based primer directed by the template sequence to which the primer hybridizes. Typically, polymerases will be protein enzymes isolated from biological systems.

Alternatively, exon sequences can be determined using ligation sequencing as described, for example, in Shendure et al. Science 309:1728-1732 (2005); US Patent No. 5,599,675 and US Pat. No. 5,750,341, each of which is incorporated herein by reference. The sequences of nucleic acid templates can be determined using hybridization sequencing methods, such as those described in US Pat. No. 6,090,549; US Patent No. 6,401,267 and US Patent No. 6,620,584, each of which is incorporated herein by reference.

If necessary, exon sequence products are detected using a ligation assay such as an oligonucleotide ligation assay (OLA). OLA detection involves the template-dependent ligation of two smaller probes into one long probe using the target sequence in the amplicon as a template. In a specific embodiment, the single-stranded target sequence includes a first target domain and a second target domain that are adjacent and contiguous. The first OLA probe and the second OLA probe can be hybridized to complementary sequences of the respective target domains. The two OLA probes are then covalently linked to each other to form a modified probe. In certain embodiments in which probes hybridize directly adjacent to each other, a covalent bond may be formed by a ligase. One or both probes may include a labeled nucleoside, such as a peptide-linked tag. Accordingly, the presence of a ligated product can be determined by detecting a label. In particular embodiments, ligation probes may include priming sites designed to allow amplification of the product of the ligation probes using primers that hybridize to the priming sites, for example, during a PCR reaction.

Alternatively, ligation probes can be used in an extension-ligation assay where the hybridized probes are not contiguous and one or more nucleotides are added along with one or more means that allow the probes to be linked by the added nucleotides. In addition, a ligation assay or extension-ligation assay can be performed using a single gating probe instead of two separate ligation probes.

In some preferred embodiments, obtaining the background distribution ( 120 ) involves determining the mutational load for randomly selected genes in a plurality of tumor-derived samples, provided that the number of randomly selected genes in each sample equals the number of passenger genes used to calculate the total burden passenger gene mutations.

In some preferred embodiments, normalizing the total load of passenger gene mutations relative to the background distribution ( 130 ) involves obtaining a z-score indicating the number of standard deviations from the mean of the background distribution. In an alternative embodiment, p-values can be used. You can correlate z-scores with p-values. For example, a z-score of 1.65 equals a p-value of p<0.05, and a z-score of 2.3 equals a p-value of p<0.01.

Classification of a patient with cancer as a responder to immunotherapy can be done according to the ratio of the total load of passenger gene mutations and the average value of the background distribution. For example, a patient may be classified as an immunotherapy responder if the total load of passenger gene mutations is at least a certain standard deviation above the mean of the background distribution. The standard deviation may, for example, be at least about 1, at least about 1.5, at least about 2, at least about 2.5, at least about 3, or more than 3 standard deviations greater than the background mean. distributions.

In some embodiments, the cancer patient may suffer from squamous cell skin cancer (CSCC), bladder urothelial carcinoma (BLCA), invasive breast carcinoma (BRCA), cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), colon/rectal adenocarcinoma (CORE), glioblastoma multiforme (GBM), head and neck squamous cell carcinoma (HNSC), clear cell renal cell carcinoma (KIRC), renal papillary renal cell carcinoma (KIRP), acute myeloid leukemia (LAML), liver hepatocellular carcinoma (LIHC), low-grade brain gliomas (LGG), lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LUSC), ovarian serous cystadenocarcinoma (OV), pheochromocytoma and paraganglioma (PCPG), prostate adenocarcinoma (PRAD), cutaneous melanoma (SKCM), adenocarcinoma of the stomach.

In some embodiments, the methods further comprise classifying the mutant tumor gene as a passenger gene. Classifying a mutant tumor gene as a passenger gene may involve selecting a mutant tumor gene and matching the mutant gene to a structured data set covering passenger genes identified according to a passenger gene index. The passenger gene index may provide a correlation coefficient between the proportion of samples containing a mutated gene obtained from a cohort of cancer patients and the median number of mutated genes for each tumor type in the cohort of cancer patients.

If the cancer patient is classified as a responder to immunotherapy, the method may further include administering a course of immunotherapy to the cancer patient. In some embodiments, a course of immunotherapy involves administering to a patient a T-cell inhibitory receptor or receptor inhibitor on a tumor cell. In some embodiments, a T-cell inhibitory receptor or tumor cell receptor inhibitor may comprise an antibody or antigen-binding fragment thereof. In some embodiments, a course of immunotherapy involves administering to the patient a T-cell receptor activator, which stimulates T-cell activation and prolongs immune cytolytic activity.

In some embodiments, T-cell inhibitory receptors or receptors located on a tumor cell that can be targeted with inhibitors for immunotherapy include one or more of PD1, PDL1, CTLA4, LAG3, and TIM3. Thus, in some embodiments, a T-cell inhibitory receptor or tumor cell receptor inhibitor provides an antibody or antigen-binding fragment thereof that specifically binds to one or more of PD1, PDL1, CTLA4, LAG3, and TIM3. As part of a course of immunotherapy, an antibody or antigen-binding fragment thereof that specifically binds to one or more of PD1, PDL1, CTLA4, LAG3, and TIM3 may be administered to a patient with cancer, or any combination of two or more such antibodies or antigen-binding fragments thereof may be administered.

In some embodiments, a course of immunotherapy involves administering to a patient an antibody that binds to PD1. In some preferred embodiments, an antibody that binds to PD1 contains at least a heavy chain variable region (HCVR) sequence of SEQ ID NO:21 and a light chain variable region (LCVR) sequence of SEQ ID NO:22. In some embodiments, any of the antibodies or antigen binding fragments thereof that bind PD1 may be any of the antibodies or antigen binding fragments thereof described in US Patent Application No. 14/603776 (Publication No. US 2015-0203579), which is hereby included into this document by reference. For example, in some embodiments, an antibody or antigen binding fragment thereof that binds PD1 comprises an HCVR having an amino acid sequence selected from the sequences listed in Table 1 and an LCVR. In some embodiments, an antibody or antigen binding fragment thereof that binds PD1 comprises an LCVR characterized by an amino acid sequence selected from the sequences listed in Table 1 and an HCVR. In some embodiments, an antibody or antigen binding fragment thereof that binds PD1 comprises a pair of HCVR and LCVR, which is shown in Table 1. Other antibodies that bind PD1 (or antigen binding fragments thereof) may be used and include, but are not limited to, pembrolizumab, nivolumab, durvalumab, atezolizumab, pidilizumab, camrelizumab, PDR001, MED10680, JNJ-63723283 and MCLA-134.

Table 1. Amino acid sequence identifiers for anti-PD1 antibodies HCVR
SEQ ID NO: LCVR
SEQ ID NO: HCVR
SEQ ID NO: LCVR
SEQ ID NO: 1 2 28 26 3 4 29 26 5 6 thirty 26 7 8 31 26 9 10 32 26 eleven 12 33 26 13 14 34 26 15 16 35 26 17 18 36 26 19 20 37 26 21 22 38 24 23 24 39 24 25 26 40 24 27 26

In some embodiments, a course of immunotherapy involves administering to a patient an antibody that binds to the LAG3 protein (also known as CD223). In some embodiments, an antibody that binds to LAG3 contains at least the HCVR sequence of SEQ ID NO:93 and the LCVR sequence of SEQ ID NO:94. In some embodiments, the antibodies or antigen binding fragments thereof that bind LAG3 may be any of the antibodies or antigen binding fragments thereof described in US Patent Application No. 15/289032 (Publication No. US 2017-0101472), which is hereby incorporated herein. document by reference. For example, in some embodiments, an antibody or antigen binding fragment thereof that binds LAG3 comprises an HCVR having an amino acid sequence selected from the sequences listed in Table 2 and an LCVR. In some embodiments, an antibody or antigen binding fragment thereof that binds LAG3 comprises an LCVR characterized by an amino acid sequence selected from the sequences listed in Table 2 and an HCVR. In some embodiments, an antibody or antigen-binding fragment thereof that binds to LAG3 comprises a pair of HCVR and LCVR, which is shown in Table 2. Other antibodies that bind to LAG3 (or antigen-binding fragments thereof) may be used and include, but are not limited to, BMS- 986016 and GSK2381781.

Table 2. Amino acid sequence identifiers for anti-LAG3 antibodies HCVR
SEQ ID NO: LCVR
SEQ ID NO: HCVR
SEQ ID NO: LCVR
SEQ ID NO: 41 42 81 82 43 44 83 84 45 46 85 86 47 48 87 88 49 50 89 90 51 52 91 92 53 54 93 94 55 56 95 96 57 58 97 98 59 60 99 98 61 62 100 98 63 64 101 98 65 66 102 98 67 68 103 98 69 70 104 105 71 72 106 105 73 74 107 105 75 76 108 109 77 78 110 111 79 80

In some embodiments, a course of immunotherapy involves administering to a patient an antibody that binds to PDL1. In some preferred embodiments, an antibody that binds to PDL1 contains at least the HCVR sequence of SEQ ID NO:122 and the LCVR sequence of SEQ ID NO:123. In some embodiments, the antibodies or antigen binding fragments thereof that bind PDL1 may be any of the antibodies or antigen binding fragments thereof described in US Patent Application No. 14/603808 (Publication No. US 2015-0203580), which is hereby incorporated herein. document by reference. For example, in some embodiments, an antibody or antigen binding fragment thereof that binds PDL1 comprises an HCVR having an amino acid sequence selected from the sequences listed in Table 3 and an LCVR. In some embodiments, an antibody or antigen binding fragment thereof that binds PDL1 comprises an LCVR characterized by an amino acid sequence selected from the sequences listed in Table 3 and an HCVR. In some embodiments, an antibody or antigen binding fragment thereof that binds PDL1 comprises a pair of HCVR and LCVR, which is shown in Table 3. Other antibodies that bind PDL1 (or antigen binding fragments thereof) may be used and include, but are not limited to, one or more from avelumab, atezolizumab and durvalumab.

Table 3. Amino acid sequence identifiers for anti-PDL1 antibodies HCVR
SEQ ID NO: LCVR
SEQ ID NO: HCVR
SEQ ID NO: LCVR
SEQ ID NO: 112 113 137 138 114 115 139 140 116 117 141 142 118 119 143 144 120 121 145 146 122 123 147 146 124 125 148 146 126 127 149 146 128 129 150 146 130 131 151 146 132 133 152 146 134 133 153 146 135 136 154 146

In some embodiments, a course of immunotherapy involves administering to a patient an antibody that binds to CTLA4. In some embodiments, the antibodies or antigen binding fragments thereof that bind CTLA4 may be any of the antibodies or antigen binding fragments thereof described in US Provisional Application No. 62/537753, filed July 27, 2017, which is hereby incorporated herein document by reference. For example, in some embodiments, an antibody or antigen binding fragment thereof that binds CTLA4 comprises an HCVR having an amino acid sequence selected from the sequences listed in Table 4 and an LCVR. In some embodiments, an antibody or antigen binding fragment thereof that binds CTLA4 comprises an LCVR characterized by an amino acid sequence selected from the sequences listed in Table 4 and an HCVR. In some embodiments, an antibody or antigen binding fragment thereof that binds CTLA4 comprises a pair of HCVR and LCVR, which is shown in Table 4. Other antibodies that bind CTLA4 (or antigen binding fragments thereof) may be used and include, but are not limited to, one or more of ipilimumab and tremelimumab, as well as any of the antibodies or antigen-binding fragments thereof disclosed in US Pat. No. 6,984,720; 7605238 or 7034121, all of which are hereby incorporated herein by reference.

Table 4. Amino acid sequence identifiers for anti-CTLA4 antibodies HCVR LCVR HCVR LCVR 155 156 187 188 157 158 189 190 159 160 191 192 161 162 193 192 163 164 195 194 165 166 197 196 167 168 199 198 169 170 201 200 171 172 203 202 173 174 205 204 175 176 207 206 177 178 209 208 179 180 211 210 181 182 213 212 183 184 215 214 185 186 217 216

In some embodiments, a course of immunotherapy may involve administering to a patient a combination of one or more T-cell inhibitory receptor inhibitors. The combination may include a combination of antibodies, or a combination of antigen binding portions of such antibodies, or a combination of antibodies and antigen binding portions. Thus, for example, a course of immunotherapy may involve administering to a patient an antibody that binds PD1 in combination with a second course of immunotherapy, in particular an antibody that binds LAG3, or an antibody that binds PDL1, or an antibody that binds CTLA . A course of immunotherapy may involve administering to the patient an antibody that binds to PDL1 in combination with a second course of immunotherapy, in particular an antibody that binds to LAG3, or an antibody that binds to PD1, or an antibody that binds to CTLA. A course of immunotherapy may involve administering to the patient an antibody that binds to LAG3 in combination with a second course of immunotherapy, in particular an antibody that binds PD1, or an antibody that binds PDL1, or an antibody that binds CTLA. A course of immunotherapy may involve administering to the patient an antibody that binds CTLA4 in combination with a second course of immunotherapy, in particular an antibody that binds LAG3, or an antibody that binds PDL1, or an antibody that binds PD1. The antibody that binds to PD1 may include any antibody or antigen binding domain described or exemplified herein. The antibody that binds to PD1 may include any antibody or antigen binding domain described or exemplified herein. The antibody that binds to PDL1 may include any antibody or antigen binding domain described or exemplified herein. The antibody that binds to LAG3 may include any antibody or antigen binding domain described or exemplified herein. The antibody that binds to CTLA4 may include any antibody or antigen binding domain described or exemplified herein.

In some preferred embodiments, a course of immunotherapy involves administering to a patient a combination of an antibody or antigen-binding portion thereof that binds PD1 and an antibody or antigen-binding portion thereof that binds LAG3. In some preferred embodiments, an antibody that binds to PD1 comprises at least a heavy chain variable region (HCVR) sequence of SEQ ID NO:21 and a light chain variable region (LCVR) sequence of SEQ ID NO:22 and an antibody that binds with LAG3, contains at least the HCVR sequence of SEQ ID NO:93 and the LCVR sequence of SEQ ID NO:94.

In some preferred embodiments, a course of immunotherapy involves administering to a patient a combination of an antibody or antigen-binding portion thereof that binds PDL1 and an antibody or antigen-binding portion thereof that binds LAG3. In some preferred embodiments, an antibody that binds to PDL1 comprises at least a heavy chain variable region (HCVR) sequence of SEQ ID NO:122 and a light chain variable region (LCVR) sequence of SEQ ID NO:123 and an antibody that binds with LAG3, contains at least the HCVR sequence of SEQ ID NO:93 and the LCVR sequence of SEQ ID NO:94.

In some embodiments, the immunotherapeutic agent may be any of the known immunotherapeutic agents used to treat cancer. For example, the immunotherapy agent may be cemiplimab, nivolumab, pembrolizumab, atezolizumab, durvalumab, avelumab, ipilimumab, IFN-alpha, IL-2, or a combination thereof. In some embodiments, the immunotherapeutic agent may be an immune checkpoint inhibitor described herein or such agents as are well known in the art. For example, cemiplimab, nivolumab, pembrolizumab, atezolizumab, durvalumab, avelumab are known immune checkpoint inhibitors.

In some alternative embodiments, the course of immunotherapy comprises administering a T-cell activating receptor activator to the patient. In some preferred embodiments, the T cell activating receptor that can be targeted by immunotherapeutic activators includes one or more of CD28, CD40L, ICOS, and 4-1BB.

An example of an approach designed to determine the total burden of passenger gene mutations for a tumor in a patient with cancer is shown in FIG. 2 and fig. 3 . A genetic sample can be selected/obtained ( 202 ). The genetic sample may be a sample from a patient with cancer. The genetic sample may be obtained from a tumor of a patient with cancer. The genetic sample can be sequenced, resulting in genetic sequence data.

In some embodiments, sequence data may be obtained or collected using any method described herein. For example, sequence data can be obtained directly by performing the sequencing process on a sample. Alternatively or additionally, the sequence data may be obtained indirectly, for example from a third party, database and/or publication. In some embodiments, the sequence data is obtained using a computer system, such as from a data storage device or from a separate computer system.

In some embodiments, the sequence data may be an array of sequence data. The terms “mass sequencing” or “next generation sequencing” or “massively parallel sequencing” refer to any high-throughput sequencing technology in which DNA and/or RNA sequencing processes are carried out in parallel. For example, bulk sequencing methods are typically capable of producing more than one million polynucleic acid amplicons in a single assay. The terms “massive sequencing,” “massively parallel sequencing,” and “next generation sequencing” refer only to general methods, not necessarily generating more than 1 million marker sequences in a single run. Any mass sequencing method can be implemented in the disclosed methods and systems, such as sequencing using reversible terminator chemistry (eg, Illumina), pyrosequencing using emulsion droplets with polonium (eg, Roche), ion semiconductor sequencing (IonTorrent), single-molecule sequencing (e.g. Pacific Biosciences), massively parallel sequencing, etc.

In some embodiments, sequence data can be obtained through any sequencing method known in the art. For example, in some embodiments, sequencing data is generated using chain termination sequencing, ligation sequencing, synthesis sequencing, pyrosequencing, semiconductor ion sequencing, single-molecule real-time sequencing, tag sequencing, Dilute-`N`- sequencing Go and/or 454 sequencing.

In some embodiments, the sequence data is the result of a method in which a nucleic acid amplification method is performed to amplify at least a portion of one or more genomic loci or transcripts, followed by sequencing the resulting amplification product. Examples of nucleic acid amplification methods useful in implementing the methods disclosed herein include, but are not limited to, polymerase chain reaction (PCR), LATE-PCR, ligase chain reaction (LCR), strand displacement amplification (SDA), transcription-mediated amplification ( TMA), self-sustaining sequence replication (3SR), Qβ replicase amplification, nucleic acid sequence-based amplification (NASBA), repair chain reaction (RCR), boomerang DNA amplification (BDA) and/or rolling circle amplification (RCA) ).

In some embodiments, the method includes the step of performing a sequencing process on the sample. Any sample can be used as long as the sample contains DNA and/or RNA from the patient's tumor. The sample source may be, for example, solid tissue, such as obtained from a fresh, frozen and/or preserved organ, tissue sample, biopsy or aspirate; blood or any constituent components of blood, blood serum, whole blood; body fluids such as cerebrospinal fluid, amniotic fluid, peritoneal fluid or interstitial fluid.

Genetic sequence data can be analyzed ( 204 ) by a computational device to identify driver genes and to determine the number of mutations in the driver genes. If the number of mutations in driver genes is high ( 206 ), then this may be an indicator that the patient will respond to immunotherapy ( 210 ). If the number of mutations in driver genes is low ( 206 ), then this may be an indicator that the response to immunotherapy will be weak or absent ( 208 ). Mutations in driver genes may provide “key phenotypic hallmarks of cancer,” such as immune evasion.

In an alternative embodiment, genetic sequence data can be analyzed (212) by means of a computing device to identify passenger genes and to determine the number of mutations in passenger genes. If the number of mutations in passenger genes is high (216), then this may be an indicator (210) that the patient will respond to immunotherapy. If the number of mutations in passenger genes is low (216), then this may be an indicator (208) that the response to immunotherapy will be weak or absent. Although passenger genes do not have any causal relationship with tumorigenesis, mutations in passenger genes can be used to assess immunogenicity. In some embodiments, genetic sequence data can be analyzed (212) to identify passenger genes, determine the number of mutations in passenger genes, and determine the background distribution for tumor mutational load. The number of mutations in passenger genes can be analyzed relative to the background distribution to determine how many standard deviations (if at all) the number of mutations in passenger genes differs from the mean. If the number of standard deviations is high (e.g., at least 1, 1.5, 2, 2.5) (216), then the patient with cancer can be classified as a responder with the best response to immunotherapy (210). If the number of standard deviations is low (216), then the patient with cancer can be classified as a responder with a poor response to immunotherapy (208).

In some embodiments, passenger genes can be identified in large-scale analysis of the cancer genome according to a criterion referred to herein as the passenger gene index (PGI) ( 212 ). In some embodiments, PGI is based on the high correlation of genetic mutation rates (GMRs) in passenger genes with overall mutation rates in cancer, also called tumor mutational burden ( 214 ). Among the identified passenger genes, families known to have an excessive number of passenger mutations predominate, such as particularly large proteins and genes with low expression levels or with late DNA replication times. The accumulation of more passenger gene mutations will occur in cancer samples/types that have higher mutation rates, and the average number of mutant genes per sample in each cancer type can act as a surrogate for the likelihood of passenger mutations in that cancer type. . Thus, for each gene Xi _, PGI can be defined as a measure of the correlation between the percentage of samples with a mutation in gene _Xi and the average number of mutated genes per sample for each cancer type. A higher PGI indicates that a particular gene is more likely to acquire somatic mutations in cancer types that have a higher overall mutation rate. Genes with a low PGI value show a weak association between the two variables (as can, for example, be observed in the case of canonical cancer driver genes such as TP53, PIK3CA and KRAS). Among the genes characterized by the highest PGI, gene families known to have an excessive number of passenger mutations predominate, for example, particularly large proteins (>4000 amino acids), genes spanning large genomic loci (>1 Mb), genes with low expression levels, genes with late timing DNA replication, etc. The cumulative distribution function (CDF) for these gene families shows a sharp increasing trend at PGI>0.7, while genes in the Catalog of Somatic Mutations in Cancer (COSMIC) from the Cancer Gene Registry (CGC) characterized by a more uniform distribution. Two-sample Kolmogorov-Smirnov tests demonstrate a significant difference in the rank distribution of passenger gene families compared with that for genes from the CGC ( p =8.3×10 ^-19 for large proteins; p =2.9×10 ^-12 for genes spanning genomic locus >1 Mb; p =6.4×10 ^-35 for genes with low expression levels; p =2.7×10 ^-29 for genes with late replication). Similar results are obtained when samples are grouped by mutation rate (instead of cancer type) to calculate PGI.

The most significant passenger genes based on their highest PGI values may be tumor type neutral or tumor type specific. Thus, in some cases, the most significant passenger genes can be used in general, regardless of tumor type. Although these top passenger genes do not change regardless of tumor type, the top passenger genes may change over time due to the availability of additional samples. In some cases, the most significant passenger genes may vary among tumor types. In some cases, the most significant passenger genes may be identical among tumor types. In addition, if the most significant passenger genes are identical among tumor types, then the ranking within a given list of the most significant passenger genes may vary. For example, the top 50 passenger gene for breast cancer may be identical to the top 50 passenger gene for lung cancer, but the top-ranked passenger gene (meaning highest PGI) for breast cancer may be the fifth-ranked passenger gene for lung cancer . In some cases, the top 50 passenger genes for one tumor type may include 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, and up to and including 100 percent of the top 50 passenger genes for a second tumor type. Depending on the range of PGI values provided, a list of the most significant 25, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500 or even over 2000 passenger genes can be presented as a list of the most significant passenger genes genes. In some cases, the most significant passenger genes are consistent across patients. The same passenger gene list could be used for all patients, and each patient would have a different TMB.

In one embodiment, illustrated in FIG. 3 , a method ( 300 ) of obtaining genetic sequence data ( 310 ) is disclosed. Genetic sequence data can span multiple genes and can be obtained from multiple biological samples collected from subjects with multiple types of diseases. Many types of diseases can include types of cancer.

In some embodiments, the method ( 300 ) may include identifying a plurality of mutant genes for each plurality of biological samples ( 320 ), wherein each of the mutant genes comprises a genetic sequence characterized by the presence of at least one non-synonymous somatic mutation.

In some embodiments, the method ( 300 ) can determine the tumor mutational load for each biological sample based on the number of mutant genes in each biological sample ( 330 ). In a preferred embodiment, determining the tumor mutational load for each biological sample based on the number of mutant genes in each biological sample may involve adding the number of mutant genes in each patient sample.

Using the method ( 300 ), mutations in a gene (passenger or driver) can be identified, for example, by aligning mutant sequences with wild-type or reference sequences. Various alignment programs and algorithms are described in Smith and Waterman (1981) Adv. Appl. Math. 2:482; Needleman and Wunsch (1970) J. Mol. Biol. 48:443; Pearson and Lipman (1988) Proc. Natl. Acad. Sci. USA 85:2444; Higgins and Sharp (1988) Gene 73:237–244; Higgins and Sharp (1989) CABIOS 5:151-153; Corpet et al. (1988) Nucl. Acids Res. 16:10881-90; Huang et al. (1992) Computer Appl. in the Biosci. 8:155-65 and Pearson et al. (1994). Meth. Mol. Biol. 24:307-31, which are incorporated herein by reference. In Altschul et al. (1994) Nature Genet. 6:119-29 (incorporated herein by reference) provides a detailed discussion of methods for sequence alignment and homology calculations.

The NCBI Basic Local Alignment Search Tool (BLAST) (Altschul et al. 1990) is available from several sources, including the National Center for Biological Information (NCBI, Bethesda, MD) and the Internet, for use in conjunction with sequence analysis programs blastp, blastn, blastx, tblastn and tblastx. It can be accessed at </www.ncbi.nlmn.ih.gov/BLAST/>. A description of how to determine sequence identity using this program is available at </www.nebi.rlm.nih.gov/BLAST/blast-help.html>.

In some embodiments, for each disease type, the method ( 300 ) may include determining the average tumor mutational burden for a plurality of mutant genes in a plurality of biological samples based on the determined number of mutant genes in each biological sample ( 340 ). In a preferred embodiment, determining the average tumor mutational load for a plurality of mutant genes in a plurality of biological samples, based on the determined number of mutant genes in each biological sample, may involve adding the tumor mutational burden for each patient sample and dividing this sum by the number of patient samples for each type of disease.

In some embodiments, for each mutant gene and each disease type, the method ( 300 ) may include determining the proportion of biological samples containing the mutant gene ( 350 ).

In some embodiments, for each mutant gene, the method ( 300 ) may include determining a correlation coefficient between the average mutational load of the tumor and the proportion of biological samples containing the mutant gene ( 360 ).

In some embodiments, the method ( 300 ) may include determining whether a mutant gene is a passenger gene based on a correlation coefficient ( 370 ). A higher correlation coefficient indicates that a particular gene is more likely to acquire somatic mutations in cancer types with a higher overall mutation frequency (eg, a passenger gene), whereas a lower correlation coefficient indicates that a particular gene is less likely to will acquire somatic mutations in cancer types characterized by a higher overall mutation frequency (eg, non-passenger gene).

In an alternative embodiment, the method ( 300 ) may further comprise generating a list of mutant genes identified as passenger genes. In a certain aspect of a preferred embodiment, the list may represent an immunogenicity profile for a selected disease.

In some embodiments, illustrated in fig. 4, a method for selecting a patient for anticancer therapy is disclosed (400), involving the identification of multiple passenger genes present in a tumor sample from a patient with the disease (410).

In some embodiments, the method (400) may involve comparing multiple passenger genes with an immunogenicity profile for a disease (420). In a preferred embodiment, the immunogenicity profile can be obtained by performing the steps of obtaining genetic sequence data, where the genetic sequence data spans multiple genes and is obtained for multiple biological samples collected from subjects having multiple types of diseases, identifying multiple mutant genes for each of a plurality of biological samples, where each of the mutant genes contains a genetic sequence having at least one non-synonymous somatic mutation, determining the mutational load of the tumor for each biological sample based on the number of mutant genes in each biological sample for each type of disease, determining the average mutational load tumors for multiple mutant genes in multiple biological samples based on a certain number of mutant genes in each biological sample for each mutant gene and each disease type, determining the proportion of biological samples containing the mutant gene for each mutant gene, determining the correlation coefficient between the average mutational load of the tumor and the proportion of biological samples containing the mutant gene. In some embodiments, the mutant gene may be determined to be a passenger gene based on the correlation coefficient. A higher correlation coefficient indicates that a particular gene is more likely to acquire somatic mutations in cancer types with a higher overall mutation rate (eg, passenger gene), whereas a lower correlation coefficient indicates that a particular gene is less likely to will acquire somatic mutations in cancer types characterized by a higher overall mutation frequency (eg, non-passenger gene).

A list of mutant genes identified as passenger genes can be generated, the list representing the immunogenicity profile for the selected disease. In a preferred embodiment, determining the tumor mutational load for each biological sample based on the number of mutant genes in each biological sample may involve adding the number of mutant genes in each patient sample. In a preferred embodiment, determining the average tumor mutational load for a plurality of mutant genes in a plurality of biological samples, based on the determined number of mutant genes in each biological sample, may involve adding the tumor mutational burden for each patient sample and dividing this sum by the number of patient samples for each type of disease.

In some embodiments, PGI can be used to identify passenger genes for specific cancers, and then using the TMB score for passenger genes can identify patients who are responders to specific treatments, such as, but not limited to, anti-PD-1 antibody or to a combination of an anti-PD-1 antibody and another anti-cancer therapeutic agent. TMB for passenger genes can also be used to identify responders to other antibodies intended for the treatment of cancer, such as, but not limited to, anti-CD20 (chronic lymphocytic leukemia), anti-HER2 (breast cancer), anti-EGFR (colorectal and head cancers) and neck), anti-CD19 antibody (B-cell cancers) and anti-CD20 antibody (lymphoma), or a combination of an antibody intended for treatment and another anticancer therapeutic agent. In some embodiments, the other anticancer therapy may be a chemotherapy agent, an immunomodulatory agent (eg, a second antibody, a cytokine), radiation therapy, or surgery.

In some embodiments, comparing a plurality of passenger genes to an immunogenicity profile for a disease may involve determining the number of matches between the plurality of mutant genes and the list of mutant genes in the profile.

In some embodiments, if a plurality of passenger genes match the immunogenicity profile for a disease ( 430 ), then the method ( 400 ) can identify the patient as a candidate for immunotherapy.

In some embodiments, if a plurality of passenger genes does not match the immunogenicity profile for a disease ( 440 ), then the method ( 400 ) can identify the patient as not being a candidate for immunotherapy.

In an alternative embodiment, the method ( 400 ) may further include enrolling a patient in an immunotherapy program if the patient has been identified as a candidate for immunotherapy.

The disclosed immunotherapeutic agents can be used in combination with another antibody or antigen-binding fragments thereof, as well as with other anticancer therapeutic agents. Combination therapy agents can be administered simultaneously or sequentially. In some embodiments, two or more therapeutic agents may be formulated together with a pharmaceutically acceptable carrier to result in a pharmaceutical composition. In some embodiments, two or more therapeutic agents are separately formulated with a pharmaceutically acceptable carrier to result in two or more pharmaceutical compositions. By “pharmaceutically acceptable” is meant a material or carrier that may be selected to minimize any degradation of the active ingredient and to minimize any adverse side effects in the subject, as will be well known to one skilled in the art. Examples of carriers include dimyristoylphosphatidyl (DMPC), phosphate buffered saline, or multivesicular liposome. For example, PG:PC:cholesterol:peptide or PC:peptide can be used as carriers in the present invention. Other suitable pharmaceutically acceptable carriers and formulations thereof are described in Remington: The Science and Practice of Pharmacy ( ^19th ed.) ed. AR Gennaro, Mack Publishing Company, Easton, PA 1995. Typically, the appropriate amount of pharmaceutically acceptable salt is used in the formulation to make the formulation isotonic. Other examples of pharmaceutically acceptable carrier include, but are not limited to, saline solution, Ringer's solution, and dextrose solution. The pH of the solution may be from about 5 to about 8 or from about 7 to about 7.5. Additional carriers include sustained release formulations such as semi-permeable matrices of solid hydrophobic polymers containing the composition, the matrices being in the form of molded articles such as films, stents (which are implanted into vessels during angioplasty procedures), liposomes or microparticles. It will be apparent to those skilled in the art that certain carriers may be preferred depending, for example, on the route of administration and the concentration of the composition administered. These will most often be standard vehicles intended for administering drugs to humans, including solutions such as sterile water, saline and buffered solutions at physiological pH.

Pharmaceutical compositions may also include carriers, thickeners, diluents, buffers, preservatives, etc., provided that the intended activity of the immunotherapeutic agent of the present invention is not impaired. Pharmaceutical compositions may also include one or more active ingredients (in addition to the composition of the present invention), such as antimicrobial agents, anti-inflammatory agents, anesthetics, and the like. The pharmaceutical composition may be administered by a number of routes depending on whether topical or systemic treatment, and depending on the site to be treated.

Formulations for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions and emulsions. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Aqueous vehicles include water, alcohol/aqueous solutions, emulsions or suspensions, including physiological saline and buffered media. Carrier media for parenteral administration include sodium chloride solution, dextrose Ringer's solution, dextrose and sodium chloride, lactated Ringer's solution, or fixed oils. Intravenous carrier media include fluid and nutrient replenishment solutions, electrolyte replenishment solutions (such as Ringer's dextrose solutions), etc. Preservatives and other additives may also be present, such as, for example, antimicrobial agents, antioxidants, chelating agents and inert gases, etc.

Formulations for ophthalmic administration may include ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners, etc. may be necessary or desirable.

Compositions for oral administration include powders or granules, suspensions or solutions in water or non-aqueous media, capsules, sachets or tablets. Thickeners, flavoring agents, diluents, emulsifiers, dispersants or binders may be required. Some of the compositions can potentially be administered as a pharmaceutically acceptable acid or base addition salt formed by reaction with inorganic acids such as hydrochloric acid, hydrobromic acid, perchloric acid, nitric acid, thiocyanic acid, sulfuric acid and phosphoric acid, and with organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid, maleic acid and fumaric acid, or by reaction with an inorganic base such as sodium hydroxide, hydroxide ammonium, potassium hydroxide, and with organic bases such as mono-, di-, trialkyl- and arylamines and substituted ethanolamines.

Pharmaceutical compositions of the present invention suitable for injection use include sterile aqueous solutions or dispersions. In addition, the compositions may be in the form of sterile powders for extemporaneous preparation of sterile injectable solutions or dispersions. In general, the final injectable form must be sterile and have an appropriate level of fluidity to permit syringability. Pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, they should preferably be protected from the contaminating action of microorganisms such as bacteria and fungi. The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyol (eg, glycerin, propylene glycol and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.

For example, injection solutions can be prepared in which the carrier is a saline solution, a glucose solution, or a mixture of physiological saline and glucose solution. Injectable suspensions may also be prepared, in which case suitable liquid carriers, suspending agents, etc. may be used. Also included are solid form preparations which are intended to be converted immediately before use to liquid form preparations.

Formulations for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions and emulsions. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Aqueous vehicles include water, alcohol/aqueous solutions, emulsions or suspensions, including physiological saline and buffered media. Carrier media for parenteral administration include sodium chloride solution, dextrose Ringer's solution, dextrose and sodium chloride, lactated Ringer's solution, or fixed oils. Intravenous carrier media include fluid and nutrient replenishment solutions, electrolyte replenishment solutions (such as Ringer's dextrose solutions), etc. Preservatives and other additives may also be present, such as, for example, antimicrobial agents, antioxidants, chelating agents and inert gases, etc.

The pharmaceutical compositions of the present invention may be in a form suitable for topical administration, such as, for example, an aerosol, cream, ointment, lotion, powder, mouth rinses, throat rinses, and the like. Additionally, the compositions may be in a form suitable for use in transdermal devices. Such compositions can be prepared using the compound of the present invention or pharmaceutically acceptable salts thereof using conventional processing methods. By way of example, a cream or ointment is prepared by mixing a hydrophilic material and water together with a compound in an amount ranging from about 5 wt. % to approximately 10 wt. %, to obtain a cream or ointment characterized by the required consistency.

In compositions suitable for transdermal administration, the carrier optionally comprises a penetration enhancer and/or a suitable wetting agent, optionally combined with suitable additives of any nature in small proportions, wherein the additives do not have a significant deleterious effect on the skin. These additives may facilitate cutaneous administration and/or may be useful in preparing the required compositions. These compositions can be administered through a variety of means, for example, as a transdermal patch, as a spot application, or as an ointment.

The pharmaceutical compositions of the present invention may be in a form suitable for rectal administration, wherein the carrier is a solid. Preferably, the mixture is in the form of single dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. Suppositories can be suitably formed by first mixing the composition with softened or melted carrier(s), followed by cooling and molding.

In addition to the above-mentioned carrier ingredients, the pharmaceutical compositions described above may include, if necessary, one or more additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surfactants, thickeners, lubricants agents, preservatives (including antioxidants), etc. In addition, other auxiliary agents may be included in order to make the composition isotonic with respect to the blood of the intended recipient. Compositions containing the disclosed immunotherapeutic agent and/or pharmaceutically acceptable salts thereof may also be prepared in the form of a powder or liquid concentrate.

The exact dosage and frequency of administration will depend on the particular disclosed peptide, the product of the disclosed production method, a pharmaceutically acceptable salt, solvate or polymorph thereof, a hydrate thereof, a solvate thereof, a polymorph thereof or a stereochemically isomeric form thereof; the specific condition being treated and the severity of the condition being treated; from various factors that are specific to the history of the subject being dosed, such as age, weight, sex, degree of impairment and general physical condition of the particular subject, as well as from other drug that the individual may be taking; which is well known to those skilled in the art. In addition, it will be appreciated that said effective daily amount may be decreased or increased depending on the response of the subject being treated and/or depending on the judgment of the attending physician prescribing the compositions.

Depending on the mode of administration, the pharmaceutical composition will contain the active ingredient in an amount of from 0.05 to 99% by weight, preferably from 0.1 to 70% by weight, more preferably from 0.1 to 50% by weight and a pharmaceutically acceptable carrier in in an amount of from 1 to 99.95% by weight, preferably from 30 to 99.9% by weight, more preferably from 50 to 99.9% by weight, all percentage amounts being based on the total weight of the composition.

In an illustrative embodiment, some or all of the methods and systems may be implemented by one or more computers, such as the computer ( 1001 ) illustrated in FIG. 10 and described below. In some embodiments, the disclosed methods and systems may use one or more computers to perform one or more functions at one or more locations. In fig. 10 is a block diagram illustrating an exemplary operating environment for performing the disclosed methods. This illustrative operating environment is an example of an operating environment only and is not intended to imply any limitation as to the scope of application or functionality of the operating environment architecture. Nor should the operating environment be construed as in any way dependent on or requiring the presence of any of the components or combination thereof shown in the illustrative operating environment.

In some embodiments, the methods and systems of the present invention may operate with numerous other general purpose or special purpose computing system environments or configurations. Examples of well-known computing systems, environments and/or configurations that may be suitable for use with the systems and methods include, but are not limited to, personal computers, server computers, laptop computers, and multiprocessor systems. Additional examples include set-top boxes, programmable consumer electronics, networked computers, minicomputers, supercomputers, distributed computing environments that contain any of the foregoing systems or devices, and the like.

In some embodiments, the calculations provided by the disclosed methods and systems can be performed using software components. The disclosed systems and methods may be described in the general context of computer-executable instructions, such as blocks of programs executed by one or more computers or other devices. Typically, program units include program code, routines, programs, objects, components, structured data sets, etc., that perform specific tasks or provide implementations of specific types of abstract data. The disclosed methods can also be practiced using networked and distributed computing environments in which tasks are performed by remote processing devices that are connected through a communications network. In a distributed computing environment, program blocks can be located both in a local and in a remote computer storage environment, including a storage device.

In addition, one skilled in the art will appreciate that the systems and methods disclosed herein may be implemented by a general purpose computing device such as computer 1001 . The components of the computer 1001 may include, but are not limited to, one or more processors 1003 , system memory 1012 , and a system bus 1013 that connects various system components, including the one or more processors 1003 to system memory 1012 . The system can use parallel computing processing.

The system bus 1013 is one or more of several possible types of bus structures, including a memory bus or memory controller, a peripheral bus, an accelerated graphics port, or a local bus using any of a variety of bus architectures. Bus 1013 and all buses referred to herein may also be implemented over a wired or wireless network connection, each of the subsystems, including one or more processors 1003 , mass storage device 1004 , operating system 1005 , software 1006 for PGI, PGI data 1007 , network adapter 1008 , system memory 1012 , I/O interface 1010 , graphics adapter 1009 , display device 1011 , and user-machine interface 1002 , may reside within one or more remote computing devices 1014a , b, c , located in physically separate locations, connected via buses of this type, resulting in a fully distributed system.

Computer 1001 typically contains a number of different computer readable media. Exemplary storage media can be any available media that is accessed by the computer 1001 and includes, for example, but is not limited to, both volatile and non-volatile media, removable and non-removable media. System memory 1012 includes computer-readable media in the form of volatile storage, such as random access memory (RAM), and/or non-volatile storage, such as read-only memory (ROM). System memory 1012 typically contains data, such as data about PGI 1007 , and/or program blocks, such as operating system 1005 and software for PGI 1006 , that are directly accessible to one or more processors 1003 and/or or are currently being processed with their help. The PGI data 1007 may include coverage data and/or expected coverage data.

In some embodiments, computer 1001 may also include other removable/non-removable volatile/non-volatile computer storage media. As an example, in FIG. 10 illustrates a mass storage device 1004 that can provide non-volatile storage of program code, machine-readable instructions, structured data sets, program blocks, and other data for the computer 1001 . For example, without limitation, the mass storage device 1004 may be a hard disk drive, a removable magnetic disk, a removable optical disk, magnetic tape cartridges or other magnetic storage devices, flash memory cards, CD-ROMs, digital versatile discs (DVDs), or other optical memory, random access memory (RAM), read-only memory (ROM), electrically erasable programmable read-only memory (EEPROM), etc.

Optionally, any number of program blocks may be stored on mass storage device 1004 , including, by way of example, operating system 1005 and PGI software 1006 . Both operating system 1005 and PGI software 1006 (or some combination thereof) may contain program elements and PGI software 1006 . PGI data 1007 may also be stored on mass storage device 1004 . PGI data 1007 may be stored in any one or more databases known in the art. Examples of such databases include DB2®, Microsoft® Access, Microsoft® SQL Server, Oracle®, mySQL, PostgreSQL, etc. Databases can be centralized or distributed across multiple systems.

In an alternative embodiment, a user may enter commands and information into the computer 1001 using an input device (not shown). Examples of such input devices include, but are not limited to, a keyboard, a pointing device (such as a mouse), a microphone, a joystick, a scanner, tactile input devices such as gloves and other body coverings, and the like. These and other input devices data may be coupled to one or more processors 1003 via a user-machine interface 1002 , which are coupled to the system bus 1013 , but may be coupled via other interface and bus structures, such as a parallel port, a game port, an IEEE 1394 port (also known as a Firewire port), serial port, or universal serial bus (USB).

In an alternative embodiment, display device 1011 may also be coupled to system bus 1013 via an interface such as graphics adapter 1009 . It is contemplated that the computer 1001 may have more than one graphics adapter 1009 , and the computer 1001 may have more than one display device 1011 . For example, the display device may be a monitor, LCD (liquid crystal display), or projector. In addition to the display device 1011 , other output peripherals may include components such as speakers (not shown) and a printer (not shown) that may be coupled to the computer 1001 via an input/output interface 1010 . Any step and/or result of the methods may be output in any form to an output device. Such output may be presented in any form of visual representation, including, but not limited to, text, graphics, animation, audio, tactile forms, etc. The display 1011 and the computer 1001 may be part of the same device or separate devices.

The computer 1001 may operate in a network environment using logical connections with one or more remote computing devices 1014 a, b, c . By way of example, the remote computing device may be a personal computer, laptop, smartphone, server, router, network computer, peer-to-peer device or other shared network node, etc. Logical connections between computer 1001 and remote computing device 1014 a, b, c may be established via a network 1015 such as a local area network (LAN) and/or a wide area network (WAN). Such network connections may be made through the network adapter 1008 . The network adapter 1008 may be implemented in both wired and wireless environments. Such network environments are traditional and common in residential, office, enterprise-scale computer networks, intranets, and the Internet.

For purposes of illustration, application programs and other executable program components, such as the operating system 1005 , are illustrated herein as discrete units, although it will be understood that such programs and components reside at different times in different memory components of the computing device 1001 and their execution is implemented by one or more computer processors 1003 . In one aspect, at least a portion of the PGI software 1006 and/or PGI data 1007 may be stored on and/or executed on one or more of the computing device 1001, remote computing devices 1014 a, b, c, and/or combinations thereof. Thus, use of PGI software 1006 and/or PGI data 1007 may be implemented within a cloud computing environment where PGI software 1006 and/or PGI data 1007 may be accessed over a network 1015 (e.g., the Internet ). Moreover, in one aspect, PGI data 1007 can be synchronized between one or more of the computing device 1001, remote computing devices 1014 a, b, c, and/or combinations thereof.

The PGI software implementation 1006 may be stored on computer-readable media or transmitted over some type of computer-readable media. Any of the disclosed methods may be performed by computer-readable instructions implemented on computer-readable media. Machine-readable media can be any accessible media that can be accessed by a computer. By way of example and without limitation, computer-readable media may include “computer storage media” and “communication media”. “Computer storage media” includes volatile and non-volatile removable and non-removable media implemented in any method or technology for storing information, such as machine-readable instructions, structured data sets, program blocks or other data. Exemplary computer storage media includes, but is not limited to, RAM, ROM, EEPROM, flash memory or other storage technology, CD-ROM, digital versatile disk (DVD) or other optical storage device, magnetic tape cassettes, magnetic tape, magnetic storage device disks or other magnetic storage devices or any other medium that can be used to store the required information and which can be accessed using a computer.

The methods and systems may use artificial intelligence techniques such as machine learning and iterative learning. Examples of such techniques include, but are not limited to, expert systems, analogical reasoning, Bayesian networks, behavioral artificial intelligence, neural networks, fuzzy logic systems, evolutionary modeling (e.g., genetic algorithms), swarm intelligence (e.g., ant colony algorithms), and hybrid intelligent systems (for example, expert inference rules obtained through a neural network, or production rules obtained as a result of statistical learning).

Unless expressly stated otherwise, in no case is it intended that any method set forth herein should be construed as requiring its steps to be performed in a particular order. Accordingly, unless the claims actually indicate the order of the steps, or the claims or description specifically indicate that the steps are to be limited to a particular order, the order is in no way intended to be inferred from the context. This is true for any possible implicit basis for interpretation, including the logic of the order of stages or the sequence of technological operations; common meaning derived from grammatical construction or punctuation; the number or type of embodiments described in the specification.

The following examples are presented to describe the present invention in more detail. They are intended to illustrate the invention and not to limit it.

Example 1

Passenger Gene Index

The passenger gene index (PGI) method included all TCGA samples grouped by cancer type, with the median number of mutant genes determined for each group. Mutations were limited to somatic non-silent mutations only by comparing solid tumors with similar samples of normal blood or solid tissue, with the exception of acute myeloid leukemia, in which tumor blood cells were compared with normal solid tissue. Mutation profiles were compiled in the form of a binary matrix in such a way that if any locus corresponding to a gene carries a mutation in a given patient, then the bit is set. PGI was calculated for each gene X _i as a Pearson correlation metric between the proportion of samples with a mutation in gene X _i and the median number of mutated genes for each cancer type. Before calculating the correlation scores, an extremely small amount of uniformly distributed noise was added to the proportion of samples with a mutation to avoid problems caused by all zero input values.

Example 2

Z-score for tumor burden of driver and passenger gene mutations

The method for determining the z-score for TMB driver/passenger genes is as follows. To calculate the z-score for TMB, the background distribution for TMB was first determined using 1000 randomly selected gene sets of equal size. The numbers of mutant driver/passenger genes were then compared to the background distribution to calculate a z-score indicating how many standard deviations a given number differs from the background mean. Driver genes were downloaded from the COSMIC cancer gene registry on January 22, 2015, and passenger genes were defined as the n most significant genes ranked by PGI derived from TCGA data.

Example 3

Tumor burden of passenger gene mutations and response to immunotherapy

To calculate the passenger gene index (PGI), a list of somatic non-silent mutations was compiled for 6685 samples from 20 tumor types according to the TCGA. Somatic mutations were determined by comparing the tumor genome with a germline genome, for example, obtained from a normal blood sample from the same patient. The median number of altered genes per sample ranged from 9 in acute myeloid leukemia to 289 in cutaneous melanoma, representing a more than 32-fold difference between the cancer types with the lowest and highest mutation rates ( Figure 5 ). This is consistent with previous observations that skin and lung cancer samples had the highest mutation rates due to exposure to environmental mutagens. In fig. Figure 5 shows the number of non-silent somatic mutations per sample in 6685 cancer exomes according to TCGA.

The 20 cancer types included in this study were bladder urothelial carcinoma (BLCA), invasive breast carcinoma (BRCA), cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), colon/rectal adenocarcinoma (CORE), glioblastoma multiforme (GBM), head and neck squamous cell carcinoma (HNSC), clear cell renal cell carcinoma (KIRC), renal papillary renal cell carcinoma (KIRP), acute myeloid leukemia (LAML), liver hepatocellular carcinoma (LIHC), low-grade brain glioma (LGG), lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LUSC), serous ovarian cystadenocarcinoma (OV), pheochromocytoma and paraganglioma (PCPG), prostate adenocarcinoma (PRAD), cutaneous melanoma (SKCM), gastric adenocarcinoma (STAD), thyroid carcinoma (THCA) and endometrioid carcinoma of the uterus (UCEC).

It has been hypothesized that the accumulation of more passenger gene mutations will occur in cancer types with higher overall mutation rates, and that the average number of altered genes per sample in each cancer type may act as a surrogate for the likelihood of occurrence. passenger mutations in this type of cancer. For each gene _Xi, the PGI was determined as a measure of the correlation between the percentage of samples with a gene _Xi variant and the average number of altered genes per sample for each cancer type. A higher PGI score indicated that a particular gene was more likely to acquire somatic mutations in cancer types characterized by a higher overall mutation frequency. Passenger genes show a strong linear relationship between the two variables, although weak associations were observed for canonical cancer genes such as TP53, PIK3CA, and KRAS ( Figure 6 ). In fig. Figure 6 illustrates scatterplots for the proportion of patients with a gene variant (y-axis) and the average total number of mutant genes (x-axis) for each cancer type. The top row shows a high linear relationship for the most significant passenger genes (MUC16, r=0.979; ADAM2, r=0.972; COL5A2, r=0.968), and the bottom row shows a weak association of the 2 variables for canonical cancer genes (TP53, r=0.301; PIK3CA, r=0.120; KRAS, r=0.222).

Genes with the highest PGI values are dominated by gene families known to have an excess of passenger mutations, such as particularly large proteins (>4000 amino acids), genes spanning large genomic loci (>1 Mb), genes with low levels of expression, and genes with late DNA replication time. The cumulative distribution function (CDF) for these gene families shows a sharp upward trend at PG>I0.7, while driver genes in the Catalog of Somatic Mutations in Cancer (COSMIC) from the Cancer Gene Registry (CGC) show a more even distribution ( Fig. .7 ). In fig. Figure 7 illustrates PGI richness for cancer driver genes and various other groups of genes. The dotted lines (above) show the proportion of genes at different PGI values, and the vertical lines (below) indicate the rank of individual genes. The two-sample Kolmogorov-Smirnov test was used to examine differences in gene distribution for each group compared with the cancer gene distribution. Two-sample Kolmogorov-Smirnov tests demonstrated a significant difference in the rank distribution of passenger gene families compared with that of genes from the CGC ( p =8.3×10 ^-19 for large proteins; p =2.9×10 ^-12 for genes spanning genomic locus >1 Mb; p =6.4×10 ^-35 for genes with low expression levels; p =2.7×10 ^-29 for genes with late replication). Similar results were observed after grouping samples by mutation rate (instead of cancer type) to calculate PGI. Although some genes from the CGC also have high PGI values, they have not been validated for inclusion in the most significant altered genes for cancer types according to TCGA. For example, KDR (kinase domain-containing receptor) has the highest mutation rate in melanoma (14% in SKCM), but the causal relationship for KDR is known only in relation to the development of non-small cell lung carcinoma and angiosarcoma. Similarly, no validated cases were identified in the cancer type with the highest gene alteration scores for the top 30 genes from the CGC. Conversely, 16 of the 30 driver genes from the CGCs with the lowest PGI value are validated for their corresponding gene-altered cancer type ( Figure 8 ). In fig. Figure 8 shows that genes from CGCs with low PGI are more likely to be validated for the cancer type with altered genes. In fig. Figure 8 shows the CGC genes with the highest (left) and lowest (right) PGI values and their corresponding cancer type with the highest percentage (>2%) of samples with mutations. Abbreviations marked with an asterisk represent the cancer type validated by the CGC for the gene. None of the cancer types with genes from the CGC with the highest PGI were validated, while 16/30 cancer types with genes from the CGC with the lowest PGI were validated.

PGI was used as a criterion to select passenger genes, and tumor mutational burden (TMB) of selected passenger genes was used to stratify the patient cohort that was more likely to respond to immunotherapy. To demonstrate this approach, measures of local immune cytolytic activity and T cell receptor (TCR) read counts were used as a surrogate for immunogenicity, testing whether there was any difference in immunogenicity between patients with high and low TMB in TCGA data. For each patient, TMB was calculated using 3 different approaches, namely (i) traditional total TMB, (ii) TMB by driver genes, and (iii) TMB by passenger genes. To quantify cytolytic activity, we used a simple RNA-based criterion that is based on the gene expression levels of two key cytolytic effectors, granzyme A (GZMA) and perforin (PRF1). It was found that cytolytic activity rates were significantly different (p<0.05 according to the Mann-Whitney U test) in patients with high and low TMB passenger genes in 7 different types of cancer (colon adenocarcinoma, p<4.6 × 10 ^{- 11} ; invasive breast carcinoma, p<5.0×10 ^-4 ; lung adenocarcinoma, p<7.7×10 ^-4 ; endometrioid carcinoma of the uterine cervix, p<9.9×10 ^-4 ; p<2.2×10 ^-3 ; squamous cell carcinoma of the lung, p<5.7×10 ^-3 ; prostate adenocarcinoma, p<2.1×10 ^-2 ), and the differences are more significant compared with those which are obtained using the common TMB and TMB driver genes in the corresponding cancer types ( Fig. 9A ).

TCRs are responsible for recognizing peptide-MHC complexes, and their diversity is directly related to the number of foreign or mutant proteins, such as cancer cell neoantigens. Analysis of the β TCR repertoire was performed using TCGA RNA-seq data, and the β number of TCR reads was compared between patients with high and low TMB passenger genes. In fig. Figure 9B shows that the detected number of reads for TCR β was significantly different between patients with high and low TMB in 8 different types of cancer (endometrioid carcinoma of the uterus, p < 3.2 x 10 ^-6 ; adenocarcinoma of the colon, p < 4.5 x 10 ^-6 ; squamous cell carcinoma of the cervix, p<2.4×10 ^-3 ; invasive breast carcinoma, p<7.3×10 ^-3 ; skin melanoma, p<9.2×10 ^-3 ; p<1.5×10 ^-2 ; serous ovarian cystadenocarcinoma, p<2.7×10 ^-2 ; prostate adenocarcinoma, p<3.8×10 ^-2 ). Consistent with the observations regarding cytolytic activity, differences in TCR β are more significant between groups formed by TMB passenger genes compared to those formed by total TMB and TMB driver genes.

Finally, testing was performed to determine whether there was any survival benefit associated with TMB based on the TCGA data. In cervical and lung squamous cell carcinoma (CESC and LUSC), total TMB, although not statistically significant, showed a trend towards a positive correlation with better survival outcome, whereas TMB driver genes were associated with poor prognosis ( Figure 9C ). In fig. Figure 9C shows clinical outcome for patient cohorts grouped by mutational load by (i) all genes, (ii) driver genes, and (iii) passenger genes in cutaneous melanoma (SKCM), cervical squamous cell carcinoma (CESC), and endocervical adenocarcinoma, and Lung squamous cell carcinoma (LUSC) demonstrates significant differences in survival only in cohorts of patients grouped by TMB by passenger genes, but not by overall TMB/TMB by driver genes. SKCM demonstrates a significant difference in patient survival between the high and low total TMB/TMB passenger gene groups.

Only when using TMB passenger genes, the difference in survival outcome between the high and low TMB patient groups was statistically significant for both CESC and LUSC. In cutaneous melanoma (SKCM), stratification of patients using both TMB passenger genes and total TMB shows a similar significant separation in survival curves, indicating that driver gene mutations that have a strong effect on immunogenicity suppression in melanoma are present at very low rates. quantity or missing. 110 patients were randomized into two equally sized groups based on mutational load using an independent dataset of CTLA-4 blockade in metastatic melanoma. Stratification using TMB for 200 passenger genes increased the clinical benefit rate for the selected patient population from baseline 24.55% to 36.36% (Fisher's exact test, p=0.0035). Stratification of patients using overall TMB provided the same increase in clinical benefit, further supporting observations regarding cytolytic activity, TCR detection, and survival benefit in melanoma using TCGA data.

In fig. Figure 11 presents TMB scores for a cohort of patients in a phase 1 clinical trial of PD1 inhibition. Closed circles, closed squares, and closed triangles indicate patients with partial response (PR), stable disease (SD), and progressive disease (PD), respectively. Open figures represent data for individual patients, and filled figures represent the mean within each of the PR/SD/PD groups. Total TMB scores are given as the total number of mutant genes (left y-axis), and TMB scores for driver/passenger genes are given as z-score (right y-axis). Comparisons of both PR with PD and PR with PD+SD demonstrate statistically significant differences in the TMB score for passenger genes, regardless of the number of most significant passenger genes used (50/100/1000). For the PR group, no significant difference in total TMB or TMB for driver genes was obtained.

Example 4

Tumor burden of passenger gene mutations and clinical response to immunotherapy

Somatic mutation data from a phase 1 study of a human monoclonal antibody to PD-1 (programmed cell death protein 1) as a monotherapy and in combination with other anticancer therapeutics were used to evaluate the clinical response of various cancers to an immunotherapy agent. Overall, clinical response data were obtained from 74 patients with advanced cancer (n=8 partial response, PR; n=29 stable disease, SD; n=37 progressive disease, PD). Total TMB is defined as the total number of mutated genes, with driver/passenger gene TMB scores represented by z-scores to normalize to the total TMB score in patients. Z-scores were calculated by comparing the number of mutant driver/passenger genes to the background distribution using randomly selected genes of equal size. Higher z-scores indicate higher mutation burden in selected driver/passenger gene groups regardless of background total TMB score. The total TMB and the z-score for TMB by driver genes do not differentiate between PR and other patient groups, whereas the z-scores for TMB by passenger genes in patients with PR are significantly higher than those in patients in the PD or PD groups +SD. The results are consistent with the TMB values calculated using the top 50, 100, 500 (Fig. 12), and top 1000 passenger genes.

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LIST OF SEQUENCES

<110> Ridgeneron

<120> Methods of immunotherapy for patients whose tumors

characterized by a high passenger load

gene mutations

<130> 37595.0015P1

<150> 62/560.955

<151> 2017-09-20

<160> 217

<170> PatentIn version 3.5

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Thr Leu Ser Leu Thr Cys Thr Val Ser Asp Asp Ser Ile Ser Ser Thr

20 25 30

Thr Tyr Tyr Trp Ala Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu

35 40 45

Trp Ile Gly Ser Met Ser Tyr Asn Gly Asn Asn Tyr Tyr Asn Pro Ser

50 55 60

Leu Lys Ser Arg Val Ala Ile Ser Ala Gly Thr Ser Gln Lys Gln Phe

65 70 75 80

Ser Leu Lys Leu Thr Ser Val Thr Ala Ala Asp Thr Ala Val Tyr His

85 90 95

Cys Ala Arg His Leu Gly Tyr Asn Gly Asn Trp Tyr Pro Phe Asp Phe

100 105 110

Trp Gly Gln Gly Ile Leu Val Thr Val Ser Ser

115 120

<210> 16

<211> 108

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 16

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser

20 25 30

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

35 40 45

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

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro

85 90 95

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

100 105

<210> 17

<211> 122

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 17

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

1 5 10 15

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

20 25 30

Ala Met His Trp Val Arg Gln Thr Pro Gly Lys Ala Leu Glu Trp Val

35 40 45

Ser Gly Ile Asn Trp Ser Gly Asn Asn Ile Gly Tyr Ala Asp Ser Val

50 55 60

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

65 70 75 80

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

85 90 95

Thr Lys Asp Ile Ser Ile Thr Gly Thr Leu Asp Ala Phe Asp Val Trp

100 105 110

Gly Gln Gly Thr Met Val Thr Val Ser Ser

115 120

<210> 18

<211> 107

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 18

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

1 5 10 15

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

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105

<210> 19

<211> 116

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 19

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

1 5 10 15

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

20 25 30

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

35 40 45

Ala Ile Ile Trp Ser Asp Gly Asp Ser Glu Tyr Asn Leu Asp Ser Val

50 55 60

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

65 70 75 80

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

85 90 95

Ala Arg Asp Arg Asp Leu Glu Asp Ile Trp Gly Gln Gly Thr Met Val

100 105 110

Thr Val Ser Ser

115

<210> 20

<211> 107

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 20

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

1 5 10 15

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

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105

<210> 21

<211> 117

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 21

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

1 5 10 15

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

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

Val Lys Trp Gly Asn Ile Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu

100 105 110

Val Thr Val Ser Ser

115

<210> 22

<211> 107

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 22

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

1 5 10 15

Asp Ser Ile Thr Ile Thr Cys Arg Ala Ser Leu Ser Ile Asn Thr Phe

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

Thr Phe Gly Pro Gly Thr Val Val Asp Phe Arg

100 105

<210> 23

<211> 121

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 23

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

1 5 10 15

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

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

Ala Arg Asp Trp Gln Tyr Leu Ile Glu Arg Tyr Phe Asp Tyr Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 24

<211> 108

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 24

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser

20 25 30

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

35 40 45

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

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro

85 90 95

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

100 105

<210> 25

<211> 121

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 25

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

1 5 10 15

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

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

Leu Gln Met Asn Ser Leu Gly Ala Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

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

100 105 110

Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 26

<211> 108

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 26

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

1 5 10 15

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

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

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

100 105

<210> 27

<211> 121

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 27

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

1 5 10 15

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

20 25 30

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

35 40 45

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

50 55 60

Lys Gly Arg Phe Ile Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu His

65 70 75 80

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

85 90 95

Ala Arg Asp Trp Gln Tyr Leu Ile Asp Arg Tyr Phe Asp Phe Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 28

<211> 121

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 28

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

1 5 10 15

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

20 25 30

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

35 40 45

Ser Gly Ile Gly Trp Ser Ser Gly Ser Ile Gly Tyr Ala Asp Ser Val

50 55 60

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

65 70 75 80

Leu Gln Met Asp Ser Leu Arg Pro Glu Asp Ser Ala Leu Tyr Tyr Cys

85 90 95

Ala Lys Ala Tyr Thr Phe Met Ile Thr Leu Tyr Phe Asp Tyr Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 29

<211> 121

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 29

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

1 5 10 15

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

20 25 30

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

35 40 45

Ser Gly Ser Gly Trp Asn Arg Gly Ser Leu Gly Tyr Ala Asp Ser Val

50 55 60

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

65 70 75 80

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

85 90 95

Ala Lys Gly Phe Val Val Val Ser Ala Ala Tyr Phe Asp Tyr Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 30

<211> 121

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 30

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

1 5 10 15

Ser Val Lys Val Ser Cys Lys Val Ser Gly Val Thr Phe Arg Asn Phe

20 25 30

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

35 40 45

Gly Gly Ile Ile Pro Phe Phe Ser Ala Ala Asn Tyr Ala Gln Ser Phe

50 55 60

Gln Gly Arg Val Thr Ile Thr Pro Asp Glu Ser Thr Ser Thr Ala Phe

65 70 75 80

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

85 90 95

Ala Arg Glu Gly Glu Arg Gly His Thr Tyr Gly Phe Asp Tyr Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 31

<211> 121

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 31

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ser Gly Arg

1 5 10 15

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

20 25 30

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

35 40 45

Ser Gly Ile Asn Trp Asn Arg Gly Arg Thr Gly Tyr Ala Asp Ser Val

50 55 60

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

65 70 75 80

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

85 90 95

Ala Lys Ala Glu Gln Trp Leu Asp Glu Gly Tyr Phe Asp Tyr Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 32

<211> 121

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 32

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Arg Gly Gly

1 5 10 15

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

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

Ala Lys Asp Gln Gly Gly Ser Tyr Pro Tyr Tyr Phe His Tyr Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 33

<211> 121

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 33

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

1 5 10 15

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

20 25 30

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

35 40 45

Ser Gly Ile Gly Trp Ser Asn Val Lys Ile Gly Tyr Ala Asp Ser Val

50 55 60

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

65 70 75 80

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

85 90 95

Val Lys Ala Tyr Thr Ser Met Leu Thr Leu Tyr Phe Asp Tyr Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 34

<211> 118

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 34

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

1 5 10 15

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

20 25 30

Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Ile Ile Asn Pro Ser Asp Gly Ser Thr Ser Asn Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr

65 70 75 80

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

85 90 95

Ala Arg Arg Val Ala Gly Asp Ile Phe Asp Ile Trp Gly Gln Gly Thr

100 105 110

Met Val Thr Val Ser Ser

115

<210> 35

<211> 119

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 35

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

1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Tyr

20 25 30

His Trp Asn Trp Ile Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Ile

35 40 45

Gly Tyr Ile Tyr Tyr Ile Gly Ser Thr Asp Tyr Asn Pro Ser Leu Glu

50 55 60

Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu

65 70 75 80

Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala

85 90 95

Arg Val Pro Val Gly Ala Thr Gly Ala Ser Asp Val Trp Gly Gln Gly

100 105 110

Thr Met Val Thr Val Ser Ser

115

<210> 36

<211> 121

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 36

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

1 5 10 15

Ser Leu Arg Leu Ser Cys Val Val Ser Gly Phe Thr Phe Glu Asp Tyr

20 25 30

Gly Leu Ser Trp Val Arg Gln Ile Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

Thr Arg Asp Arg Gln Trp Leu Met Gln Trp Tyr Phe Asp Tyr Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 37

<211> 119

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 37

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

1 5 10 15

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

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

Ala Lys Ser Ala His Trp Asn Phe Phe Phe Asp Tyr Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ser

115

<210> 38

<211> 121

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 38

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

1 5 10 15

Ser Leu Arg Leu Ser Cys Val Ala Ser Gly Phe Ala Leu His Asp Tyr

20 25 30

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

35 40 45

Ser Ser Ile Ser Trp Asn Ser Gly Val Ile Gly Tyr Ala Asp Ser Leu

50 55 60

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

65 70 75 80

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

85 90 95

Ala Lys Gly Ser Gly Ser Tyr Tyr Val Ser Trp Phe Asp Pro Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 39

<211> 123

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 39

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

1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Asp Ser Ile Ser Ser Thr

20 25 30

Ala Tyr His Trp Asp Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu

35 40 45

Trp Ile Gly Thr Ile Thr Tyr Asn Gly Asn Thr Tyr Phe Asn Pro Ser

50 55 60

Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe

65 70 75 80

Ser Leu Lys Leu Leu Ser Met Thr Ala Ala Glu Thr Ala Val Phe Tyr

85 90 95

Cys Ala Arg His Leu Gly Tyr Asn Ser Asp Phe Phe Pro Phe Asp Phe

100 105 110

Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 40

<211> 119

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 40

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

1 5 10 15

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

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

Val Lys Val Arg Asn Tyr Asp Gly Ser Phe Asp Ile Trp Gly Gln Gly

100 105 110

Thr Met Val Thr Val Ser Ser

115

<210> 41

<211> 124

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 41

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

1 5 10 15

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

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

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

100 105 110

Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser

115 120

<210> 42

<211> 107

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 42

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

1 5 10 15

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

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105

<210> 43

<211> 128

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 43

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

1 5 10 15

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

20 25 30

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

35 40 45

Ala Leu Ile Trp Tyr Asp Gly Thr Asn Lys Lys Tyr Gly Asp Ser Val

50 55 60

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

65 70 75 80

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

85 90 95

Ala Arg Asp Cys Gly His Ser Gly Asn Asp Arg Gly Thr Tyr Tyr Tyr

100 105 110

Tyr Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser

115 120 125

<210> 44

<211> 108

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 44

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

1 5 10 15

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

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

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

100 105

<210> 45

<211> 119

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 45

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

1 5 10 15

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

20 25 30

Tyr Trp Asn Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Gly Glu Ile Ser His Arg Gly Thr Thr Asn Tyr Asn Pro Ser Leu Lys

50 55 60

Ser Arg Val Thr Ile Ser Leu Asp Thr Ser Lys Asn Gln Phe Ser Leu

65 70 75 80

Lys Leu Thr Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ser

85 90 95

Arg Asp Glu Glu Leu Glu Phe Arg Phe Phe Asp Tyr Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ser

115

<210> 46

<211> 107

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 46

Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Val

35 40 45

Tyr Gly Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly

50 55 60

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

65 70 75 80

Glu Asp Phe Ala Phe Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Leu

85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105

<210> 47

<211> 119

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 47

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

1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Asp Ser Ile Ile Ser Asn

20 25 30

Ser Tyr Tyr Trp Gly Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu

35 40 45

Trp Ile Gly Asn Phe Phe Tyr Thr Gly Ala Thr Tyr Tyr Asn Pro Ser

50 55 60

Leu Lys Ser Arg Val Thr Ile Ser Ala Asp Thr Ser Lys Asn Gln Phe

65 70 75 80

Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Leu Tyr Tyr

85 90 95

Cys Ala Ser Tyr Asn Arg Asn Tyr Arg Phe Asp Pro Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ser

115

<210> 48

<211> 108

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 48

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

1 5 10 15

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

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

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

100 105

<210> 49

<211> 127

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 49

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

1 5 10 15

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

20 25 30

Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile

35 40 45

Gly Glu Ile Asn His Ser Gly Asn Ala Asp Tyr Asn Pro Ser Leu Lys

50 55 60

Ser Arg Val Ser Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu

65 70 75 80

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

85 90 95

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

100 105 110

Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser

115 120 125

<210> 50

<211> 108

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 50

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Leu Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ile Ser Ser

20 25 30

Phe Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

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

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Arg Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Asn Ser Pro

85 90 95

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

100 105

<210> 51

<211> 129

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 51

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

1 5 10 15

Thr Leu Thr Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ser Asn Ala

20 25 30

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

35 40 45

Trp Leu Ala His Ile Phe Ser Asn Asp Glu Lys Ser Tyr Ser Thr Ser

50 55 60

Leu Arg Thr Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys Ser Gln Val

65 70 75 80

Val Leu Thr Val Thr Asn Leu Asp Pro Val Asp Thr Ala Thr Tyr Phe

85 90 95

Cys Ala Arg Ile Pro Glu Phe Thr Ser Ser Ser Trp Ala Leu Tyr Tyr

100 105 110

Phe Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser

115 120 125

Ser

<210> 52

<211> 108

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 52

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Ser Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Ile Thr Ser Thr

20 25 30

Tyr Phe Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Ile Tyr Ala Thr Ser Ser Arg Ala Thr Gly Val Pro Asp Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

65 70 75 80

Pro Asp Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Arg Ser Pro

85 90 95

Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Val Lys

100 105

<210> 53

<211> 121

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 53

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

1 5 10 15

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

20 25 30

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

35 40 45

Gly Trp Ile Ser Ala Tyr Asn Asp Asn Thr Asn Tyr Ala Gln Lys Leu

50 55 60

Gln Gly Arg Val Thr Met Thr Ala Asp Thr Ser Thr Asn Thr Ala Tyr

65 70 75 80

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

85 90 95

Val Arg Trp Asn Trp Gly Ser Val Tyr Trp Tyr Phe Asp Leu Trp Gly

100 105 110

Arg Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 54

<211> 108

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 54

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ile Ile Ser Ser Ser

20 25 30

Tyr Phe Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

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

50 55 60

Gly Ser Val Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Met Tyr Phe Cys Gln Gln Tyr Gly Asn Ser Pro

85 90 95

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

100 105

<210> 55

<211> 117

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 55

Gln Ile Thr Leu Lys Glu Ser Gly Pro Thr Leu Val Lys Pro Thr Gln

1 5 10 15

Thr Leu Thr Leu Thr Cys Thr Phe Ser Gly Phe Ser Leu Asn Thr His

20 25 30

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

35 40 45

Trp Leu Ala Leu Ile Tyr Gly Asn Asp Val Lys Asn Tyr Ser Pro Ser

50 55 60

Leu Glu Thr Arg Leu Thr Ile Ala Lys Asp Thr Ser Lys Asn Gln Val

65 70 75 80

Val Leu Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Phe

85 90 95

Cys Ser Tyr Ile Thr Gly Glu Gly Met Tyr Trp Gly Gln Gly Thr Leu

100 105 110

Val Thr Val Ser Ser

115

<210> 56

<211> 111

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 56

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

1 5 10 15

Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Asn Leu Met Tyr Ser

20 25 30

Asp Gly Asn Thr Tyr Leu Asn Trp Phe His Gln Arg Pro Gly Gln Ser

35 40 45

Pro Arg Arg Leu Ile Tyr Lys Val Ser Asn Arg Asp Ser Gly Val Pro

50 55 60

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

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Gly

85 90 95

Thr His Trp Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 57

<211> 119

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 57

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

1 5 10 15

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

20 25 30

Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile

35 40 45

Gly Glu Ile Asn His Arg Gly Asn Thr Asn Tyr Asn Pro Ser Leu Lys

50 55 60

Ser Arg Val Thr Ile Ser Leu Asp Thr Ser Lys Lys Gln Phe Ser Leu

65 70 75 80

Asn Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Met Tyr Tyr Cys Thr

85 90 95

Arg Asp Glu Glu Gln Glu Leu Arg Phe Leu Asp Tyr Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ser

115

<210> 58

<211> 107

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 58

Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Asp Ile Ser Thr Tyr

20 25 30

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

35 40 45

Tyr Gly Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly

50 55 60

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

65 70 75 80

Glu Asp Phe Ala Phe Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Leu

85 90 95

Thr Phe Gly Gly Gly Thr Glu Val Glu Ile Lys

100 105

<210> 59

<211> 122

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 59

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

1 5 10 15

Thr Leu Ser Leu Thr Cys Val Val His Gly Gly Ser Phe Ser Gly Tyr

20 25 30

Tyr Trp Asn Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile

35 40 45

Gly Glu Ile Asn His Arg Gly Asn Thr Asn Tyr Asn Pro Ser Leu Lys

50 55 60

Ser Arg Val Thr Val Ser Glu Asp Thr Ser Lys Asn Gln Phe Ser Leu

65 70 75 80

Lys Leu Ser Ser Leu Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Val

85 90 95

Arg Gly Glu Asp Tyr Asp Phe Trp Ser Asp Tyr Tyr Asn Asp Tyr Trp

100 105 110

Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 60

<211> 107

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 60

Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Thr Ile Ser Ser Tyr

20 25 30

Leu Ala Trp His Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile

35 40 45

Tyr Asp Ala Ser Lys Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly

50 55 60

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

65 70 75 80

Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Leu

85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105

<210> 61

<211> 124

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 61

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

1 5 10 15

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

20 25 30

Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile

35 40 45

Gly Glu Ile Asn His Arg Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys

50 55 60

Ser Arg Ala Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu

65 70 75 80

Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ser

85 90 95

Arg Gly Glu Asp Tyr Tyr Asp Ser Ser Gly Tyr Ser Tyr Tyr Phe Asp

100 105 110

Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 62

<211> 107

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 62

Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr

20 25 30

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

35 40 45

Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly

50 55 60

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

65 70 75 80

Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Leu

85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105

<210> 63

<211> 122

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 63

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

1 5 10 15

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

20 25 30

Tyr Trp Asn Trp Ile Arg Gln Ser Pro Gly Thr Gly Leu Glu Trp Ile

35 40 45

Gly Glu Ile Asn His Arg Gly Asn Ile Asn Phe Asn Pro Ser Leu Lys

50 55 60

Ser Arg Val Thr Ile Ser Glu Asp Thr Ser Lys Asn Gln Phe Ser Leu

65 70 75 80

Arg Leu Asn Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala

85 90 95

Arg Gly Glu Asp Tyr Asp Ile Trp Ser Gly Tyr Tyr Arg Glu Tyr Trp

100 105 110

Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 64

<211> 107

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 64

Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr

20 25 30

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

35 40 45

Tyr Asp Ala Ser Lys Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly

50 55 60

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

65 70 75 80

Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Leu

85 90 95

Ala Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105

<210> 65

<211> 119

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 65

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

1 5 10 15

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

20 25 30

Tyr Trp Asn Trp Ile Arg Gln Pro Pro Glu Lys Gly Leu Glu Trp Ile

35 40 45

Gly Glu Ile Asn His Arg Gly Asn Thr Asn Tyr Asn Pro Ser Leu Lys

50 55 60

Ser Arg Val Thr Ile Ser Val Asp Met Ser Lys Asn Gln Phe Ser Leu

65 70 75 80

Gln Leu Asn Ser Val Thr Val Ala Asp Thr Ala Leu Tyr Tyr Cys Ala

85 90 95

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

100 105 110

Thr Thr Val Thr Val Ser Ser

115

<210> 66

<211> 107

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 66

Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Asp Ile Ser Thr Tyr

20 25 30

Leu Ala Trp His Gln Gln Lys Pro Gly Gln Pro Pro Arg Leu Leu Ile

35 40 45

Tyr Gly Ser Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly

50 55 60

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

65 70 75 80

Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Leu

85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105

<210> 67

<211> 124

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 67

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

1 5 10 15

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

20 25 30

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

35 40 45

Ser Val Ile Ser Gly Gly Gly Gly Arg Thr Tyr Tyr Thr Asp Ser Val

50 55 60

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

65 70 75 80

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

85 90 95

Ala Lys Glu Arg Val Thr Gly Ile Asp His Tyr Tyr Tyr Gly Val Asp

100 105 110

Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser

115 120

<210> 68

<211> 107

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 68

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

1 5 10 15

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

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105

<210> 69

<211> 130

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 69

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

1 5 10 15

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

20 25 30

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

35 40 45

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

50 55 60

Lys Gly Arg Val Thr Ile Ser Arg Asp Asn Ala Lys Asn Leu Leu Tyr

65 70 75 80

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

85 90 95

Ala Arg Asp Gly Gly His Tyr Asp Ile Leu Thr Gly Ser Met Ser Tyr

100 105 110

Tyr Tyr Tyr Ala Leu Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val

115 120 125

Ser Ser

130

<210> 70

<211> 108

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 70

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

1 5 10 15

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

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

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

100 105

<210> 71

<211> 121

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 71

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

1 5 10 15

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

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

Ala Leu Asp Ile Met Ala Thr Val Gly Gly Leu Phe Asn Asn Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 72

<211> 108

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 72

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser

20 25 30

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

35 40 45

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

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro

85 90 95

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

100 105

<210> 73

<211> 120

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 73

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

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Arg His

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

Ala Arg Ala Pro Tyr Thr Arg Gln Gly Tyr Phe Asp Leu Trp Gly Arg

100 105 110

Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 74

<211> 113

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 74

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

1 5 10 15

Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Leu Tyr Ser

20 25 30

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

35 40 45

Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val

50 55 60

Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr

65 70 75 80

Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln

85 90 95

Asp Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile

100 105 110

Lys

<210> 75

<211> 118

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 75

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

1 5 10 15

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

20 25 30

Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Asp Trp Met

35 40 45

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

50 55 60

Leu Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Thr Thr Val Tyr

65 70 75 80

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

85 90 95

Ala Arg Glu Asn Trp Asn Ser Tyr Phe Asp Asn Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Ser Ser

115

<210> 76

<211> 113

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 76

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

1 5 10 15

Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Leu Tyr Ser

20 25 30

Ser Asn Asn Lys Asn Phe Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln

35 40 45

Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val

50 55 60

Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr

65 70 75 80

Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Leu Tyr Tyr Cys Gln Gln

85 90 95

Tyr Tyr Gly Ala Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile

100 105 110

Lys

<210> 77

<211> 119

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 77

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

1 5 10 15

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

20 25 30

Thr Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

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

100 105 110

Thr Leu Val Thr Val Ser Ser

115

<210> 78

<211> 113

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 78

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

1 5 10 15

Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Leu Tyr Thr

20 25 30

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

35 40 45

Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val

50 55 60

Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr

65 70 75 80

Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln

85 90 95

Tyr Tyr Asn Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile

100 105 110

Lys

<210> 79

<211> 120

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 79

Gln Ile Thr Leu Lys Glu Ser Gly Pro Thr Leu Val Lys Pro Thr Gln

1 5 10 15

Thr Leu Thr Leu Thr Cys Thr Phe Ser Gly Phe Ser Leu Ser Thr Asn

20 25 30

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

35 40 45

Trp Leu Gly Ile Ile Tyr Trp Asn Asp Asp Lys Arg Tyr Ser Pro Ser

50 55 60

Leu Arg Ser Arg Leu Thr Ile Thr Lys Asp Thr Ser Lys Asn Gln Val

65 70 75 80

Val Leu Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr

85 90 95

Cys Ala His Arg Gly Leu Phe Gly Gly Trp Phe Asp Pro Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 80

<211> 107

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 80

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

1 5 10 15

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

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105

<210> 81

<211> 122

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 81

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

1 5 10 15

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

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

Ser Lys Val Ala Ala Ala Asn Asn Tyr Tyr Tyr Ala Leu Asp Val Trp

100 105 110

Gly Gln Gly Thr Thr Val Thr Val Ser Ser

115 120

<210> 82

<211> 112

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 82

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

1 5 10 15

Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu His Ser

20 25 30

Asn Gly Tyr Lys Tyr Leu Asp Trp Tyr Leu Gln Lys Pro Gly Gln Ser

35 40 45

Pro Gln Leu Leu Ile Tyr Leu Val Ser Asn Arg Ala Ser Gly Val Pro

50 55 60

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

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ala

85 90 95

Leu Gln Thr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 83

<211> 127

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 83

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

1 5 10 15

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

20 25 30

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

35 40 45

Ala Val Ile Trp Asn Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val

50 55 60

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

65 70 75 80

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

85 90 95

Ala Arg Asp Gly Glu Val Glu Tyr Ser Ser Ser Asn Tyr Asn Tyr Tyr

100 105 110

Gly Leu Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser

115 120 125

<210> 84

<211> 107

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 84

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

1 5 10 15

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

20 25 30

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

35 40 45

Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

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

65 70 75 80

Glu Asp Ile Val Thr Tyr Tyr Cys Gln Gln Tyr Asp Asp Leu Pro Ile

85 90 95

Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys

100 105

<210> 85

<211> 125

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 85

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

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Phe His Asn Phe

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

Ala Lys Asp Arg Gly Tyr Asp Tyr Ser Gly Ser Tyr Tyr Asn Trp Phe

100 105 110

Asp Pro Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120 125

<210> 86

<211> 109

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 86

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

1 5 10 15

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

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

Leu Phe Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys

100 105

<210> 87

<211> 128

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 87

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

1 5 10 15

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

20 25 30

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

35 40 45

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

50 55 60

Lys Gly Arg Phe Thr Met Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr

65 70 75 80

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

85 90 95

Ala Arg Asp Gly Asn Ile Trp Ser Gly Tyr Tyr Ala Ala Tyr Tyr Phe

100 105 110

Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser

115 120 125

<210> 88

<211> 112

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 88

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

1 5 10 15

Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser

20 25 30

Asp Gly Lys Thr Tyr Leu Ser Trp Leu Gln Gln Arg Pro Gly Gln Pro

35 40 45

Pro Arg Leu Leu Ile Tyr Lys Ile Ser Asn Arg Phe Ser Gly Val Pro

50 55 60

Asp Arg Ile Ser Gly Ser Gly Ala Gly Thr Asp Phe Thr Leu Lys Ile

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ala

85 90 95

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

100 105 110

<210> 89

<211> 122

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 89

Gln Val Gln Leu Gln Gln Trp Gly Ala Gly Leu Leu Asn Pro Ser Glu

1 5 10 15

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

20 25 30

Tyr Trp Asn Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile

35 40 45

Gly Glu Ile Asn His Arg Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys

50 55 60

Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu

65 70 75 80

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

85 90 95

Arg Gly Glu Asp Tyr Asp Ile Trp Asn Gly Tyr Tyr Gln Glu Lys Trp

100 105 110

Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 90

<211> 107

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 90

Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Ile Ser Thr Tyr

20 25 30

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

35 40 45

Tyr Asp Ala Ser Lys Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly

50 55 60

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

65 70 75 80

Glu Asp Phe Val Val Tyr Tyr Cys His Gln Arg Ser Asn Trp Pro Leu

85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105

<210> 91

<211> 117

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 91

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

1 5 10 15

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

20 25 30

Tyr Trp Ser Trp Leu Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile

35 40 45

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

50 55 60

Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Lys Gln Phe Ser Leu

65 70 75 80

Lys Leu Thr Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala

85 90 95

Arg Thr Ile Ser Thr Trp Trp Phe Ala Pro Trp Gly Gln Gly Thr Leu

100 105 110

Val Thr Val Ser Ser

115

<210> 92

<211> 106

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 92

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

1 5 10 15

Gly Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Asn Asn

20 25 30

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

35 40 45

Tyr Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Gly Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser

65 70 75 80

Glu Asp Phe Ala Val Tyr Ser Cys Gln Gln Tyr Asn Asn Trp Leu Thr

85 90 95

Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105

<210> 93

<211> 123

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 93

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

1 5 10 15

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

20 25 30

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

35 40 45

Ala Ile Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val

50 55 60

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

65 70 75 80

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

85 90 95

Ala Ser Val Ala Thr Ser Gly Asp Phe Asp Tyr Tyr Gly Met Asp Val

100 105 110

Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser

115 120

<210> 94

<211> 107

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 94

Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Thr Thr Leu Ser Cys Arg Ala Ser Gln Arg Ile Ser Thr Tyr

20 25 30

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

35 40 45

Tyr Asp Ala Ser Lys Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Gly Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro

65 70 75 80

Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Leu

85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105

<210> 95

<211> 119

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 95

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

1 5 10 15

Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Asn Tyr

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys

85 90 95

Ala Arg Arg Asp Thr Ile Phe Pro Ser Tyr Pro Leu Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ser

115

<210> 96

<211> 112

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 96

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

1 5 10 15

Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu Asn Ser

20 25 30

Asn Gly Tyr Asn Phe Leu Asp Trp Tyr Leu Gln Lys Pro Gly Gln Ser

35 40 45

Pro Gln Leu Leu Ile Tyr Leu Val Ser Asn Arg Ala Ser Gly Val Pro

50 55 60

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

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Ile Gly Val Tyr Tyr Cys Met Gln Ala

85 90 95

Leu Gln Thr Pro Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys

100 105 110

<210> 97

<211> 120

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 97

Gln Ile Thr Leu Lys Glu Ser Gly Pro Thr Leu Val Lys Pro Thr Gln

1 5 10 15

Thr Leu Thr Leu Thr Cys Thr Phe Ser Gly Phe Ser Leu Ser Thr Asn

20 25 30

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

35 40 45

Trp Leu Thr Leu Ile Tyr Trp Asn Glu Asn Lys His Tyr Ser Pro Ser

50 55 60

Leu Lys Asn Arg Ile Thr Ile Thr Lys Asp Thr Ser Lys Asn Gln Val

65 70 75 80

Val Leu Thr Met Thr Asn Leu Asp Pro Val Asp Thr Ala Thr Tyr Tyr

85 90 95

Cys Val His Arg Gly Trp Leu Gly Ala Ile Phe Ala Tyr Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 98

<211> 108

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 98

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

1 5 10 15

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

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

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

100 105

<210> 99

<211> 126

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 99

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

1 5 10 15

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

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

Ala Lys Gly Thr Gly Gln Gln Val Asp Leu Tyr Asn Tyr Tyr Tyr Ala

100 105 110

Leu Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser

115 120 125

<210> 100

<211> 129

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 100

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

1 5 10 15

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

20 25 30

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

35 40 45

Ala Val Ile Trp Tyr Asp Gly Ser Asn Lys His Tyr Ala Asp Ser Val

50 55 60

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

65 70 75 80

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

85 90 95

Ala Arg Asp Lys Gly Ile Ser Gly Ile Lys Gly Gly Ser Tyr Tyr Tyr

100 105 110

Tyr Tyr Ala Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser

115 120 125

Ser

<210> 101

<211> 120

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 101

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

1 5 10 15

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

20 25 30

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

35 40 45

Gly Arg Ile Lys Asn Lys Ile Asp Gly Gly Thr Thr Asp Tyr Ala Ala

50 55 60

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

65 70 75 80

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

85 90 95

Tyr Cys Ser Thr Val Asp Tyr Asn Trp Tyr Phe Asp Phe Trp Gly Arg

100 105 110

Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 102

<211> 129

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 102

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

1 5 10 15

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

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

Ala Arg Asp Arg Gly Val Ala Thr Phe Thr Arg Gly Asn Tyr Tyr Tyr

100 105 110

Asn Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser

115 120 125

Ser

<210> 103

<211> 129

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 103

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

1 5 10 15

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

20 25 30

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

35 40 45

Ala Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val

50 55 60

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

65 70 75 80

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

85 90 95

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

100 105 110

Tyr Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser

115 120 125

Ser

<210> 104

<211> 118

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 104

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

1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ile Thr Asn

20 25 30

Ser Tyr Tyr Trp Gly Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu

35 40 45

Trp Ile Gly Ser Ile Tyr Tyr Ser Gly Arg Thr Tyr Tyr Asn Pro Ser

50 55 60

Leu Glu Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe

65 70 75 80

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

85 90 95

Cys Ala Arg Glu Gly Asp Pro Ser Leu Asp Pro Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Ser Ser

115

<210> 105

<211> 108

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 105

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser

20 25 30

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

35 40 45

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

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro

85 90 95

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

100 105

<210> 106

<211> 121

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 106

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

1 5 10 15

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

20 25 30

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

35 40 45

Ser His Ile Ser Gly Ser Gly Gly Asn Ser Tyr Ser Ala Asp Ser Val

50 55 60

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

65 70 75 80

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

85 90 95

Ser Leu Asp Ile Met Ala Thr Val Gly Gly Leu Phe Ala Tyr Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 107

<211> 131

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 107

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

1 5 10 15

Ser Leu Arg Leu Ser Cys Val Ala Ser Gly Phe Ile Phe Ser Phe Tyr

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

Gly Arg Asp Gln Gly Ile Ser Tyr Tyr Asp Ile Leu Thr Gly Asn Tyr

100 105 110

Asn Tyr Tyr Tyr Gly Val Asp Val Trp Gly Gln Gly Thr Thr Val Thr

115 120 125

Val Ser Ser

130

<210> 108

<211> 119

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 108

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

1 5 10 15

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

20 25 30

Tyr Trp Asn Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Gly Glu Ile Ser His Arg Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys

50 55 60

Ser Arg Val Thr Ile Ser Leu Asp Thr Ser Lys Asn Gln Phe Ser Leu

65 70 75 80

Lys Leu Thr Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ser

85 90 95

Arg Asp Glu Glu Leu Glu Phe Arg Phe Phe Asp Tyr Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ser

115

<210> 109

<211> 107

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 109

Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Val

35 40 45

Tyr Gly Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly

50 55 60

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

65 70 75 80

Glu Asp Phe Ala Phe Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Leu

85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105

<210> 110

<211> 124

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 110

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

1 5 10 15

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

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

Thr Lys Glu Ser Thr Thr Gly Thr Tyr Ser Tyr Phe Tyr Gly Met Asp

100 105 110

Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser

115 120

<210> 111

<211> 107

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 111

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

1 5 10 15

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

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105

<210> 112

<211> 121

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 112

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

1 5 10 15

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

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

Ala Asn Thr Tyr Tyr Asp Phe Trp Ser Gly His Phe Asp Tyr Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 113

<211> 107

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 113

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

1 5 10 15

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

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr His Ser Tyr Ser Tyr

85 90 95

Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 114

<211> 121

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 114

Gln Glu His Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg

1 5 10 15

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

20 25 30

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

35 40 45

Ala Ala Leu Trp Ser Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val

50 55 60

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

65 70 75 80

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

85 90 95

Ala Arg Gly Arg Gly Ala Pro Gly Ile Pro Ile Phe Gly Tyr Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 115

<211> 107

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 115

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

1 5 10 15

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

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Ala Ile Lys

100 105

<210> 116

<211> 130

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 116

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

1 5 10 15

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

20 25 30

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

35 40 45

Gly Arg Ile Lys Arg Lys Thr Asp Gly Gly Thr Thr Asp Tyr Ala Ala

50 55 60

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

65 70 75 80

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

85 90 95

Tyr Cys Thr Thr Asp Asp Ile Val Val Val Pro Ala Val Met Arg Glu

100 105 110

Tyr Tyr Phe Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val

115 120 125

Ser Ser

130

<210> 117

<211> 107

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 117

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

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Thr Ser Gln Gly Ile Arg Asn Asp

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 118

<211> 121

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 118

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

1 5 10 15

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

20 25 30

Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Trp Ile Asn Pro Asn Ser Gly Thr Lys Lys Tyr Ala His Lys Phe

50 55 60

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

65 70 75 80

Met Ile Leu Ser Ser Leu Ile Ser Asp Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Asp Glu Asp Trp Asn Phe Gly Ser Trp Phe Asp Ser Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 119

<211> 112

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 119

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

1 5 10 15

Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Thr Leu Val His Gly

20 25 30

Asp Gly Asn Thr Tyr Leu Ser Trp Ile Gln Gln Arg Pro Gly Gln Pro

35 40 45

Pro Arg Leu Leu Ile Tyr Lys Val Ser Asn Gln Phe Ser Gly Val Pro

50 55 60

Asp Arg Phe Ser Gly Ser Gly Ala Gly Thr Asp Phe Thr Leu Lys Ile

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Val Gly Leu Tyr Phe Cys Met Gln Ala

85 90 95

Thr His Phe Pro Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys

100 105 110

<210> 120

<211> 121

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 120

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

1 5 10 15

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

20 25 30

Tyr Ile His Trp Val Arg Gln Ala Pro Gly His Gly Leu Glu Trp Met

35 40 45

Gly Trp Leu Asn Pro Asn Thr Gly Thr Thr Lys Tyr Ile Gln Asn Phe

50 55 60

Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ser Ser Thr Ala Tyr

65 70 75 80

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

85 90 95

Ala Arg Asp Glu Asp Trp Asn Tyr Gly Ser Trp Phe Asp Thr Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 121

<211> 112

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 121

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

1 5 10 15

Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Pro Ser Leu Val His Ser

20 25 30

Asp Gly Asn Thr Tyr Leu Ser Trp Leu Gln Gln Arg Pro Gly Gln Pro

35 40 45

Pro Arg Leu Leu Ile Tyr Lys Ile Ser Asn Arg Phe Ser Gly Val Pro

50 55 60

Asp Arg Phe Ser Gly Ser Gly Ala Gly Thr Asp Phe Thr Leu Lys Ile

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ala

85 90 95

Thr His Phe Pro Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Arg

100 105 110

<210> 122

<211> 120

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 122

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

1 5 10 15

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

20 25 30

Gly Met Thr Trp Val Arg Gln Ala Pro Gly Arg Gly Leu Glu Trp Val

35 40 45

Ser Gly Ile His Trp His Gly Lys Arg Thr Gly Tyr Ala Asp Ser Val

50 55 60

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

65 70 75 80

Leu Gln Met Asn Ser Leu Lys Gly Glu Asp Thr Ala Leu Tyr His Cys

85 90 95

Val Arg Gly Gly Met Ser Thr Gly Asp Trp Phe Asp Pro Trp Gly Gln

100 105 110

Gly Thr Leu Val Ile Val Ser Ser

115 120

<210> 123

<211> 108

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 123

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

1 5 10 15

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

20 25 30

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

35 40 45

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

50 55 60

Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Asn Leu Gln Pro

65 70 75 80

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

85 90 95

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

100 105

<210> 124

<211> 120

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 124

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

1 5 10 15

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

20 25 30

Gly Met Thr Trp Val Arg Gln Val Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Gly Ile His Trp Ser Gly Arg Ser Thr Gly Tyr Ala Asp Ser Val

50 55 60

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

65 70 75 80

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

85 90 95

Ala Arg Gly Gly Met Ser Thr Gly Asp Trp Phe Asp Pro Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 125

<211> 108

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 125

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

1 5 10 15

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

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

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

100 105

<210> 126

<211> 115

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 126

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

1 5 10 15

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

20 25 30

Tyr Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

Arg Gly Ile Arg Gly Leu Asp Val Trp Gly Gln Gly Thr Thr Val Thr

100 105 110

Val Ser Ser

115

<210> 127

<211> 108

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 127

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

1 5 10 15

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

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

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

100 105

<210> 128

<211> 115

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 128

Glu Glu Arg Leu Val Glu Ser Gly Gly Asp Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ile Thr Val Gly Thr Asn

20 25 30

Tyr Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

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

50 55 60

Gly Arg Phe Ile Met Ser Arg Gln Thr Ser Lys Asn Thr Leu Tyr Leu

65 70 75 80

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

85 90 95

Arg Gly Ile Arg Gly Leu Asp Val Trp Gly Gln Gly Thr Met Val Thr

100 105 110

Val Ser Ser

115

<210> 129

<211> 108

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 129

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

1 5 10 15

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

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

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

100 105

<210> 130

<211> 118

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 130

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

1 5 10 15

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

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

Met Glu Leu Ser Ser Leu Lys Ser Gly Asp Thr Ala Val Tyr Phe Cys

85 90 95

Ala Arg Asn Trp Gly Leu Gly Ser Phe Tyr Ile Trp Gly Gln Gly Thr

100 105 110

Met Val Thr Val Ser Ser

115

<210> 131

<211> 108

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 131

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Phe Asn Phe Asn

20 25 30

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

35 40 45

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

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asn Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Gly Val Phe Tyr Cys Gln Gln Tyr Glu Ser Ala Pro

85 90 95

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

100 105

<210> 132

<211> 115

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 132

Glu Val Gln Leu Val Glu Ser Gly Gly Asp Leu Val His Pro Gly Arg

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Pro Phe Asp Glu Tyr

20 25 30

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

35 40 45

Ser Gly Ile Ser Trp Ser Asn Asn Asn Ile Gly Tyr Ala Asp Ser Val

50 55 60

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

65 70 75 80

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

85 90 95

Ala Lys Ser Gly Ile Phe Asp Ser Trp Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser

115

<210> 133

<211> 105

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 133

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

1 5 10 15

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

20 25 30

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

35 40 45

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

50 55 60

Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Arg Pro Glu Asp Phe

65 70 75 80

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

85 90 95

Gly Gln Gly Thr Arg Leu Glu Ile Lys

100 105

<210> 134

<211> 118

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 134

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

1 5 10 15

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

20 25 30

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

35 40 45

Thr Leu Ile Ser Tyr Glu Gly Arg Asn Lys Tyr Tyr Ala Asp Ser Val

50 55 60

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

65 70 75 80

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

85 90 95

Ala Lys Asp Arg Thr Leu Tyr Gly Met Asp Val Trp Gly Gln Gly Thr

100 105 110

Thr Val Thr Val Ser Ser

115

<210> 135

<211> 121

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 135

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

1 5 10 15

Thr Leu Thr Leu Thr Cys Thr Phe Ser Gly Phe Ser Leu Ser Thr Asn

20 25 30

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

35 40 45

Trp Leu Ala Arg Ile Asp Trp Asp Gly Val Lys Tyr Tyr Asn Thr Ser

50 55 60

Leu Lys Thr Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Val

65 70 75 80

Val Leu Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Phe Tyr

85 90 95

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

100 105 110

Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 136

<211> 108

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 136

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

1 5 10 15

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

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

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

100 105

<210> 137

<211> 115

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 137

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

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Glu Phe Thr Val Gly Thr Asn

20 25 30

His Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

Arg Gly Leu Gly Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr

100 105 110

Val Ser Ser

115

<210> 138

<211> 107

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 138

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

1 5 10 15

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

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

Glu Asp Val Ala Thr Tyr Tyr Cys Gln Lys Tyr Asn Ser Ala Pro Arg

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 139

<211> 120

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 139

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Arg Gly Glu

1 5 10 15

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

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

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

100 105 110

Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 140

<211> 107

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 140

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

1 5 10 15

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

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105

<210> 141

<211> 130

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 141

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

1 5 10 15

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

20 25 30

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

35 40 45

Ala Asn Ile Lys Gln Asp Gly Ser Glu Lys Tyr Tyr Val Asp Ser Val

50 55 60

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

65 70 75 80

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

85 90 95

Ala Arg Asp Asp Ile Val Val Val Pro Ala Pro Met Gly Tyr Tyr Tyr

100 105 110

Tyr Tyr Phe Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val

115 120 125

Ser Ser

130

<210> 142

<211> 107

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 142

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

1 5 10 15

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

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 143

<211> 123

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 143

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

1 5 10 15

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

20 25 30

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

35 40 45

Ser Gly Ile Ser Trp Thr Gly Gly Asn Met Asp Tyr Ala Asn Ser Val

50 55 60

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

65 70 75 80

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

85 90 95

Val Lys Asp Ile Arg Gly Ile Val Ala Thr Gly Gly Ala Phe Asp Ile

100 105 110

Trp Gly Arg Gly Thr Met Val Thr Val Ser Ser

115 120

<210> 144

<211> 107

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 144

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

1 5 10 15

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

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys

100 105

<210> 145

<211> 115

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 145

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

1 5 10 15

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

20 25 30

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

35 40 45

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

50 55 60

Gly Arg Phe Thr Ile Ser Arg Gln Thr Ser Gln Asn Thr Leu Tyr Leu

65 70 75 80

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

85 90 95

Arg Gly Ile Arg Gly Phe Asp Ile Trp Gly Gln Gly Thr Met Val Thr

100 105 110

Val Ser Ser

115

<210> 146

<211> 108

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 146

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

1 5 10 15

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

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

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

100 105

<210> 147

<211> 115

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 147

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

1 5 10 15

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

20 25 30

Tyr Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

Arg Gly Ile Arg Gly Phe Asp Ile Trp Gly Gln Gly Thr Met Val Thr

100 105 110

Val Ser Ser

115

<210> 148

<211> 124

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 148

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

1 5 10 15

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

20 25 30

Ala Met His Trp Val Arg Gln Thr Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

Val Lys Asp Ile Arg Gly Asn Trp Asn Tyr Gly Gly Asn Trp Phe Asp

100 105 110

Pro Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 149

<211> 115

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 149

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

1 5 10 15

Ser Leu Arg Leu Ser Cys Glu Ala Ser Gly Phe Thr Val Gly Val Asn

20 25 30

His Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

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

50 55 60

Gly Arg Leu Thr Ile Phe Arg Gln Thr Ser Gln Asn Thr Val Tyr Leu

65 70 75 80

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

85 90 95

Arg Gly Ile Gly Gly Leu Asp Ile Trp Gly Arg Gly Thr Met Val Thr

100 105 110

Val Ser Ser

115

<210> 150

<211> 123

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 150

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

1 5 10 15

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

20 25 30

Ala Leu His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

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

50 55 60

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

65 70 75 80

Leu Gln Met Ser Ser Leu Arg Thr Glu Asp Thr Ala Ile Tyr Tyr Cys

85 90 95

Thr Arg Asp Ile Arg Gly Asn Trp Lys Tyr Gly Gly Trp Phe Asp Pro

100 105 110

Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 151

<211> 120

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 151

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

1 5 10 15

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

20 25 30

Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Asp Trp Met

35 40 45

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

50 55 60

Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Asn Thr Phe Tyr

65 70 75 80

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

85 90 95

Ala Arg Glu Gly Ser Thr His His Asn Ser Phe Asp Pro Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 152

<211> 114

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 152

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

1 5 10 15

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

20 25 30

Phe Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

Arg Gly Gly Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val

100 105 110

Ser Ser

<210> 153

<211> 118

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 153

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

1 5 10 15

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

20 25 30

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

35 40 45

Gly Glu Ile Ile Pro Ile Leu Gly Ala Ala Asn Tyr Ala Gln Asn Phe

50 55 60

Gln Gly Arg Val Thr Phe Thr Thr Asp Glu Ser Thr Asn Thr Ala Tyr

65 70 75 80

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

85 90 95

Ala Arg Asp Arg Thr Ser Gly Gly Phe Asp Pro Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Ser Ser

115

<210> 154

<211> 119

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 154

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

1 5 10 15

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

20 25 30

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

35 40 45

Gly Trp Ile Ser Pro Tyr Asn Gly Tyr Thr Asp Tyr Ala Gln Lys Leu

50 55 60

Gln Gly Arg Val Thr Leu Thr Thr Asp Thr Ser Thr Thr Thr Ala Tyr

65 70 75 80

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

85 90 95

Ser Arg Gly Arg Gly Pro Tyr Trp Ser Phe Asp Leu Trp Gly Arg Gly

100 105 110

Thr Leu Val Thr Val Ser Ser

115

<210> 155

<211> 117

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 155

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

1 5 10 15

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

20 25 30

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

35 40 45

Gly Trp Ile Ser Val Tyr Asn Gly Asn Ile Asn Tyr Ala Gln Lys Phe

50 55 60

Lys Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr

65 70 75 80

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

85 90 95

Ala Arg Val Thr Gln Phe Gly Met Asp Val Trp Gly Gln Gly Thr Thr

100 105 110

Val Thr Val Ser Ser

115

<210> 156

<211> 107

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 156

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

1 5 10 15

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

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys

100 105

<210> 157

<211> 128

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 157

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

1 5 10 15

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

20 25 30

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

35 40 45

Gly Arg Ile Arg Gly Lys Ala Asn Ser Phe Ala Thr Ala Tyr Ser Ala

50 55 60

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

65 70 75 80

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

85 90 95

Phe Cys Thr Arg Glu Asp Gln Gln Leu Val Arg Pro Tyr Tyr Tyr His

100 105 110

Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser

115 120 125

<210> 158

<211> 107

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 158

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

1 5 10 15

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

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105

<210> 159

<211> 123

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 159

Gln Ile Thr Leu Lys Glu Ser Gly Pro Thr Leu Val Lys Pro Thr Gln

1 5 10 15

Thr Leu Thr Leu Thr Cys Thr Phe Ser Gly Phe Ser Leu Ser Thr Ser

20 25 30

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

35 40 45

Trp Leu Ala Leu Ile Tyr Trp Asn Asp His Glu Arg Tyr Ser Pro Ser

50 55 60

Leu Lys Ser Arg Leu Thr Ile Thr Lys Asp Thr Ser Lys Asn Leu Val

65 70 75 80

Val Leu Ala Met Ala Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Phe

85 90 95

Cys Ala His Arg Asn Ile Glu Tyr Arg Arg Ser Tyr Phe Phe Asp Tyr

100 105 110

Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 160

<211> 107

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 160

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

1 5 10 15

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

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys

100 105

<210> 161

<211> 118

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 161

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

1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Asn Ser Tyr

20 25 30

Tyr Trp Thr Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile

35 40 45

Gly Tyr Val Tyr Tyr Ser Gly Ser Thr Thr Tyr Asn Pro Ser Leu Lys

50 55 60

Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Phe Leu

65 70 75 80

Asn Leu Asn Ser Val Thr Ala Ala Glu Thr Ala Val Tyr Tyr Cys Ala

85 90 95

Arg Gly Thr Leu Gly Tyr Tyr Gly Met Asp Val Trp Gly Gln Gly Thr

100 105 110

Thr Val Thr Val Ser Ser

115

<210> 162

<211> 108

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 162

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Phe Ser Asn Asn

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Arg Ser Pro

85 90 95

Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105

<210> 163

<211> 118

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 163

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

1 5 10 15

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

20 25 30

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

35 40 45

Ala Val Thr Trp Tyr Asp Gly Ser Asn Lys His Tyr Ala Asp Ser Val

50 55 60

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

65 70 75 80

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

85 90 95

Val Arg Gly Gly His Leu Gly Ala Phe Asp Ile Trp Gly Gln Gly Thr

100 105 110

Met Val Thr Val Ser Ser

115

<210> 164

<211> 107

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 164

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr

20 25 30

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

35 40 45

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

50 55 60

Gly Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro

65 70 75 80

Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro Phe

85 90 95

Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys

100 105

<210> 165

<211> 121

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 165

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

1 5 10 15

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

20 25 30

Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Trp Ile Asn Pro Asn Asn Gly Val Ser Asn Tyr Ala Gln Lys Phe

50 55 60

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

65 70 75 80

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

85 90 95

Ala Arg Glu Arg Ala Ser Trp Asp Tyr Asn Gly Val Asp Val Trp Gly

100 105 110

Gln Gly Thr Thr Val Thr Val Ser Ser

115 120

<210> 166

<211> 112

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 166

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

1 5 10 15

Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu His Ser

20 25 30

Asn Gly Tyr Ser Tyr Leu Asp Trp Tyr Leu Gln Lys Pro Gly Gln Ser

35 40 45

Pro Gln Leu Leu Ile Tyr Leu Gly Ser Asn Arg Ala Ser Gly Val Pro

50 55 60

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

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Gly

85 90 95

Leu Gln Pro Pro Asn Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 167

<211> 118

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 167

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

1 5 10 15

Thr Leu Ser Leu Thr Cys Ile Val Ser Gly Gly Ser Thr Ser Ser Asn

20 25 30

Thr Tyr Tyr Trp Gly Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu

35 40 45

Trp Ile Gly Thr Ile His Tyr Ser Gly Asn Pro Tyr Tyr Asp Pro Ser

50 55 60

Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn His Phe

65 70 75 80

Ser Leu Lys Leu Asn Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr

85 90 95

Cys Thr Arg Gln Tyr Ile Asn Phe Phe Asp Phe Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Ser Ser

115

<210> 168

<211> 107

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 168

Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Val Thr Leu Ser Cys Arg Ala Ser Gln Ser Ile Ser Arg Tyr

20 25 30

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

35 40 45

Tyr Asp Ala Ser Asn Arg Ala Thr Asp Ile Pro Ala Arg Phe Ser Gly

50 55 60

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

65 70 75 80

Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Ile

85 90 95

Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys

100 105

<210> 169

<211> 121

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 169

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

1 5 10 15

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

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

Ala Lys Asp Leu Gly Gly Asp Asp Tyr Tyr Gly Met Asp Val Trp Gly

100 105 110

Gln Gly Thr Thr Val Thr Val Ser Ser

115 120

<210> 170

<211> 108

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 170

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Arg Thr

20 25 30

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

35 40 45

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

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro

85 90 95

Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 171

<211> 122

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 171

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

1 5 10 15

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

20 25 30

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

35 40 45

Ser Tyr Ile Ser Ser Ser Gly Gly Asn Ile Phe Tyr Ala Asp Ser Val

50 55 60

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

65 70 75 80

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

85 90 95

Ala Arg Gly Leu Glu Pro Tyr His Tyr Tyr Tyr Gly Met Asp Val Trp

100 105 110

Gly Gln Gly Thr Thr Val Thr Val Ser Ser

115 120

<210> 172

<211> 107

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 172

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

1 5 10 15

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

20 25 30

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

35 40 45

Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

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

65 70 75 80

Glu Asp Ile Ala Thr Tyr Phe Cys Gln His Tyr Asp Asn Leu Pro Phe

85 90 95

Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys

100 105

<210> 173

<211> 123

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 173

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

1 5 10 15

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

20 25 30

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

35 40 45

Ser Ala Ile Ser Gly Arg Gly Gly Asn Ser Tyr Tyr Ala Asp Ser Val

50 55 60

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

65 70 75 80

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

85 90 95

Ala Lys Ala Glu Arg Gly Tyr Ser Tyr Gly Phe Asn Trp Phe Asp Pro

100 105 110

Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 174

<211> 107

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 174

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

1 5 10 15

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

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105

<210> 175

<211> 120

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 175

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

1 5 10 15

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

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

Ala Arg Gly Gly Gly Arg Leu Ser Tyr Tyr His Asp Tyr Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 176

<211> 107

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 176

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

1 5 10 15

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

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys

100 105

<210> 177

<211> 119

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 177

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

1 5 10 15

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

20 25 30

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

35 40 45

Gly Trp Ile Thr Ala Tyr Asn Gly Asn Ser Asn Tyr Ala Gln Lys Leu

50 55 60

Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Gly Thr Ala Tyr

65 70 75 80

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

85 90 95

Ala Arg Arg Gly Asp Tyr Leu Gly Val Phe Pro Tyr Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ser

115

<210> 178

<211> 107

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 178

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

1 5 10 15

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

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105

<210> 179

<211> 116

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 179

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

1 5 10 15

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

20 25 30

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

35 40 45

Ser Ser Ile Arg Thr Ser Gly Thr Thr Lys Tyr Tyr Ala Asp Ser Met

50 55 60

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

65 70 75 80

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

85 90 95

Ala Gly Gly Gly Thr Phe Leu His Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser

115

<210> 180

<211> 108

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 180

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

1 5 10 15

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

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Lys Ser Phe Pro Met

85 90 95

Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 181

<211> 122

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 181

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

1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Thr Ser Gly

20 25 30

Gly Tyr Tyr Trp Ser Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu

35 40 45

Trp Ile Gly Tyr Ile Phe Tyr Ser Gly Ile Thr Asn Tyr Asn Pro Ser

50 55 60

Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe

65 70 75 80

Ser Leu Lys Leu Thr Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr

85 90 95

Cys Ala Thr Tyr Asn Ser Leu Arg Leu Tyr Tyr Gly Met Asp Val Trp

100 105 110

Gly Gln Gly Thr Thr Val Thr Val Ser Ser

115 120

<210> 182

<211> 112

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 182

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

1 5 10 15

Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val Tyr Gly

20 25 30

Asp Gly Asn Thr Tyr Leu Asn Trp Phe Gln Gln Arg Pro Gly Gln Ser

35 40 45

Pro Arg Arg Leu Ile Tyr Lys Val Ser Asn Arg Asp Ser Gly Val Pro

50 55 60

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

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ser

85 90 95

Thr His Trp Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105 110

<210> 183

<211> 120

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 183

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

1 5 10 15

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

20 25 30

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

35 40 45

Gly Arg Ser Arg Asp Lys Ala Asn Ser Phe Thr Thr Glu Tyr Val Ala

50 55 60

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

65 70 75 80

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

85 90 95

Tyr Cys Ala Arg Thr Asn Tyr Asp Phe Ser Leu Asp Val Trp Gly Gln

100 105 110

Gly Thr Thr Val Thr Val Ser Ser

115 120

<210> 184

<211> 107

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 184

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

1 5 10 15

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

20 25 30

Leu Ala Trp Phe Gln Gln Lys Pro Gly Asn Ala Pro Lys Ser Leu Ile

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys

100 105

<210> 185

<211> 118

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 185

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

1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Tyr

20 25 30

His Trp Ser Trp Ile Arg Gln Pro Leu Gly Lys Gly Leu Glu Trp Ile

35 40 45

Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys

50 55 60

Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu

65 70 75 80

Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala

85 90 95

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

100 105 110

Leu Val Thr Val Ser Ser

115

<210> 186

<211> 107

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 186

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

1 5 10 15

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

20 25 30

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

35 40 45

Ser Lys Ala Ser Thr Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

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

65 70 75 80

Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ile Tyr Ser Trp

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 187

<211> 120

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 187

Gln Ile Thr Leu Lys Glu Ser Gly Pro Thr Leu Val Lys Pro Thr Gln

1 5 10 15

Thr Leu Thr Leu Thr Cys Thr Phe Ser Gly Phe Ser Leu Ser Thr Ser

20 25 30

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

35 40 45

Trp Leu Ala Leu Ile Tyr Trp Asn Asp Asp Lys Arg Phe Ser Pro Ser

50 55 60

Leu Lys Ser Arg Leu Thr Ile Thr Lys Asp Thr Ser Lys Asn Gln Val

65 70 75 80

Val Leu Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr

85 90 95

Cys Ala His Arg Arg Leu Gly Leu Tyr Tyr Phe Asp Tyr Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 188

<211> 107

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 188

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

1 5 10 15

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

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Val His Ile Tyr Pro Phe

85 90 95

Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys

100 105

<210> 189

<211> 122

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 189

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

1 5 10 15

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

20 25 30

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

35 40 45

Gly Trp Ile Ser Ala Tyr Asn Gly Asn Thr Asn Tyr Ala Gln Lys Leu

50 55 60

Gln Gly Arg Leu Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr

65 70 75 80

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

85 90 95

Ser Arg Asp Gly Pro Phe Lys Ile Ser Phe Phe Gly Met Asp Val Trp

100 105 110

Gly Gln Gly Thr Thr Val Thr Val Ser Ser

115 120

<210> 190

<211> 108

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 190

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

1 5 10 15

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

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

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

100 105

<210> 191

<211> 118

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 191

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

1 5 10 15

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

20 25 30

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

35 40 45

Ala Val Ile Trp Tyr Asp Gly Arg Asn Lys His Tyr Val Asp Ser Val

50 55 60

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

65 70 75 80

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

85 90 95

Val Arg Gly Gly Gln Leu Gly Ala Phe Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Ser Ser

115

<210> 192

<211> 108

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 192

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser

20 25 30

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

35 40 45

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

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro

85 90 95

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

100 105

<210> 193

<211> 118

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 193

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

1 5 10 15

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

20 25 30

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

35 40 45

Ala Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val

50 55 60

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

65 70 75 80

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

85 90 95

Ala Arg Gly Gly Pro Trp Gly Ala Phe Asp Ile Trp Gly Gln Gly Thr

100 105 110

Met Val Thr Val Ser Ser

115

<210> 194

<211> 108

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 194

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

1 5 10 15

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

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Glu

100 105

<210> 195

<211> 122

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 195

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

1 5 10 15

Thr Leu Ser Leu Thr Cys Ser Val Ser Gly Gly Ser Ile Ser Asn Gly

20 25 30

Gly Tyr Tyr Trp Ser Trp Ile Arg Gln His Pro Gly Gln Gly Leu Glu

35 40 45

Trp Ile Gly Tyr Ile Tyr Tyr Ile Gly Asn Thr Tyr Tyr Asn Pro Ser

50 55 60

Leu Glu Ser Arg Val Thr Met Ser Ile Asp Thr Ser Lys Asn Gln Phe

65 70 75 80

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

85 90 95

Cys Ala Arg Gln Glu Phe Val Pro Gly Ala Glu Tyr Phe Leu His Trp

100 105 110

Gly Gln Gly Ile Leu Val Thr Val Ser Ser

115 120

<210> 196

<211> 107

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 196

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

1 5 10 15

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

20 25 30

Leu Gly Trp His Gln Gln Lys Ser Gly Lys Ala Pro Lys Ser Leu Ile

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 197

<211> 122

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 197

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

1 5 10 15

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

20 25 30

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

35 40 45

Ser Gly Ile Ser Trp Asn Ser Asn Ser Leu Gly Tyr Ala Asp Ser Val

50 55 60

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

65 70 75 80

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

85 90 95

Val Lys Asp Val Thr Arg Leu Glu Leu Arg Gly Phe Leu Asp Tyr Trp

100 105 110

Gly Gln Gly Thr Gln Val Thr Val Ser Ser

115 120

<210> 198

<211> 108

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 198

Glu Ile Val Leu Thr Gln Ser Pro Asp Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser

20 25 30

Phe Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

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

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Arg Ser Pro

85 90 95

Trp Thr Phe Gly Gln Gly Thr Lys Val Ala Ile Lys

100 105

<210> 199

<211> 118

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 199

Asp Arg Gln Met Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg

1 5 10 15

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

20 25 30

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

35 40 45

Ala Val Ile Trp Tyr Asp Gly Arg Asn Lys Asn Tyr Ala Asp Ser Val

50 55 60

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

65 70 75 80

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

85 90 95

Gly Arg Val His Gln Phe Gly Ala Phe Asp Ile Trp Gly Gln Gly Thr

100 105 110

Met Val Thr Val Ser Ser

115

<210> 200

<211> 108

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 200

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

1 5 10 15

Asp Arg Ile Thr Ile Thr Cys Arg Gly Ser Gln Asn Ile Gly Ser Phe

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

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

100 105

<210> 201

<211> 121

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 201

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

1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Asn Asn Gly

20 25 30

Gly His Tyr Trp Thr Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu

35 40 45

Trp Ile Gly Tyr Ile Tyr Tyr Ile Gly Thr Thr Tyr Tyr Asn Pro Ser

50 55 60

Leu Glu Ser Arg Leu Ser Leu Ser Val Asp Thr Ser Lys Asn Gln Phe

65 70 75 80

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

85 90 95

Cys Ala Arg Ser Ser Leu Ser Val Ser Glu Ala Phe Asp Val Trp Gly

100 105 110

Gln Gly Thr Met Val Thr Val Ser Ser

115 120

<210> 202

<211> 108

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 202

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

1 5 10 15

Asp Arg Phe Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Gly Ser Phe

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

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

100 105

<210> 203

<211> 121

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 203

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

1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Asn Gly

20 25 30

Gly Tyr Tyr Trp Thr Trp Ile Arg Gln Asn Pro Gly Lys Gly Leu Glu

35 40 45

Trp Ile Gly Tyr Ile Tyr Tyr Ile Gly Thr Thr Tyr Tyr Asn Pro Ser

50 55 60

Leu Glu Ser Arg Leu Ser Leu Ser Val Asp Thr Ser Lys Asn Gln Phe

65 70 75 80

Ser Leu Lys Leu Thr Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr

85 90 95

Cys Ala Arg Ser Ser Leu Ala Val Ser Glu Ala Phe Asp Ile Trp Gly

100 105 110

Gln Gly Thr Met Val Thr Val Ser Ser

115 120

<210> 204

<211> 108

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 204

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

1 5 10 15

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

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Tyr Thr Thr Pro Pro

85 90 95

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

100 105

<210> 205

<211> 121

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 205

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

1 5 10 15

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

20 25 30

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

35 40 45

Gly Trp Ile Asn Pro His Ser Gly Gly Thr Lys Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Leu Thr Arg Asp Thr Ser Ile Asn Thr Ala Tyr

65 70 75 80

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

85 90 95

Ala Arg Ile Gly Gly Gly Gly Tyr Ser Ser Tyr Phe Asp Tyr Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 206

<211> 107

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 206

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

1 5 10 15

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

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

Thr Phe Gly Ser Gly Thr Lys Val Asp Ile Lys

100 105

<210> 207

<211> 121

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 207

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

1 5 10 15

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

20 25 30

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

35 40 45

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

50 55 60

Lys Gly Arg Phe Ala Ile Ser Arg Asp Asn Ser Lys Asn Met Leu Tyr

65 70 75 80

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

85 90 95

Ala Lys Glu Pro Ser His Trp Asn Gly Glu Ala Phe Asp Ile Trp Gly

100 105 110

Gln Gly Thr Met Val Thr Val Ser Ser

115 120

<210> 208

<211> 108

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 208

Glu Ile Val Leu Thr Gln Ser Pro Asp Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Thr Val Ser Asn Ser

20 25 30

His Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

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

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Ser Leu Thr Ile Ile Arg Leu Glu

65 70 75 80

Pro Asp Asp Phe Ala Val Tyr Phe Cys Gln Gln His Glu Ser Ser Pro

85 90 95

Pro Thr Phe Gly Gln Gly Ala Lys Leu Glu Ile Lys

100 105

<210> 209

<211> 122

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 209

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

1 5 10 15

Thr Leu Ser Phe Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Asn

20 25 30

Tyr Tyr Tyr Trp Gly Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu

35 40 45

Trp Ile Gly Ser Ile Tyr His Thr Gly Asn Ala Tyr Asp Asn Pro Ser

50 55 60

Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe

65 70 75 80

Ser Leu Asn Leu Asn Ser Val Thr Ala Ala Asp Thr Ala Ile Tyr Tyr

85 90 95

Cys Ala Arg His His Ser Ser Ser Ser Trp Trp Tyr Phe Asp Val Trp

100 105 110

Gly Arg Gly Thr Leu Val Ile Val Ser Ser

115 120

<210> 210

<211> 108

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 210

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Trp Ile Ser Ser Ser

20 25 30

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

35 40 45

Ile Tyr Gly Ala Phe Ser Arg Ala Pro Gly Ile Pro Gly Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro

85 90 95

Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Asn

100 105

<210> 211

<211> 121

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 211

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

1 5 10 15

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

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

Ala Lys Asp Lys Gly Gly Asp Asp Tyr Tyr Gly Met Asp Val Trp Gly

100 105 110

Gln Gly Thr Thr Val Thr Val Ser Ser

115 120

<210> 212

<211> 108

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 212

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

1 5 10 15

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

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Asn

100 105

<210> 213

<211> 122

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 213

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

1 5 10 15

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

20 25 30

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

35 40 45

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

50 55 60

Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Thr Thr Val Tyr

65 70 75 80

Met Asp Val Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Phe Cys

85 90 95

Ala Arg Asp Gly Pro Ile Thr Ile Ser Tyr Phe Gly Met Asp Val Trp

100 105 110

Gly Gln Gly Thr Thr Val Thr Val Ser Ser

115 120

<210> 214

<211> 108

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 214

Glu Ile Val Leu Thr Gln Ser Pro Asp Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ala Gly Ser

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Thr Ser Pro

85 90 95

Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Thr

100 105

<210> 215

<211> 118

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 215

Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Val Asn Arg Tyr

20 25 30

Gly Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Val Thr Trp Tyr Asp Gly Arg Asn Lys Tyr Phe Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Ser Phe Ser Arg Asp Ser Ser Thr Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gly Gly Leu Phe Gly Tyr Phe Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Ser Ser

115

<210> 216

<211> 107

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 216

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile

35 40 45

Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Ile Leu Thr Ile Asn Arg Leu Glu Pro

65 70 75 80

Glu Asp Phe Ala Val Tyr Tyr Cys Gln His Tyr Gly Asn Ser Pro Trp

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 217

<211> 118

<212> Protein

<213> Artificial sequence

<220>

<223> synthetic construction; antigen binding domain

<400> 217

Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Gly Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Val Ile Trp Tyr Gly Gly Asn Asn Lys Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr His Cys

85 90 95

Ala Arg Ser Gly Asn Phe Gly Ala Phe Asp Ile Trp Gly Gln Gly Thr

100 105 110

Met Val Thr Val Ser Ser

115

<---

Claims (46)

1. The use of an antibody that binds to and inhibits PD1 in the manufacture of a medicament for the treatment of a subject with cancer, wherein the subject has been determined to have a tumor with a total load of passenger gene mutations that exceeds the background mutation load of the tumor. 2. Application according to claim 1, where the load of passenger gene mutations is determined to be greater than the background mutation load, by means of: determining the total load of tumor passenger gene mutations; creating a background mutational load of the tumor; And normalization of the total load of passenger gene mutations in relation to the background mutation load. 3. The use of claim 2, wherein the background mutation load is determined based on randomly selected tumor genes, and wherein the number of randomly selected genes is equal to the number of passenger genes used to determine the total passenger gene mutation load. 4. Application according to any one of paragraphs. 2, 3, characterized in that the normalization of the total load of passenger gene mutations in relation to the background mutation load includes obtaining a z-score indicating the number of standard deviations from the average value of the background mutation load. 5. Application according to any one of paragraphs. 2-4, further including classifying the mutant gene in the tumor as a passenger gene. 6. The use of claim 5, wherein classifying a mutant gene in a tumor as a passenger gene includes selecting a mutant gene from the tumor and matching the mutant gene to a data structure containing passenger genes determined according to the passenger gene index. 7. The use of claim 6, wherein the passenger gene index provides a correlation coefficient between the proportion of samples containing the mutant gene obtained from a cohort of cancer patients and the median number of mutant genes for each tumor type in the cohort of cancer patients. 8. Application according to any one of paragraphs. 1-7, wherein the antibody that binds to and inhibits PD1 includes a heavy chain variable region (HCVR) sequence comprising the amino acid sequence of SEQ ID NO: 21. 9. The use of claim 2, further comprising obtaining genetic sequence data, wherein the genetic sequence data comprises a plurality of genes and is obtained from a tumor of a patient. 10. Use according to claim 2, wherein the passenger gene mutation load is greater than the background mutation load, when the normalized passenger gene mutation load is at least about 1, at least about 1.5, at least about 2, at least about 2.5, at least about 3, or more than 3 standard deviations above the average background mutation load. 11. The use of claim 1, wherein the passenger gene mutation burden is determined based on one or more passenger genes with a genetic mutation rate that is highly correlated with the overall tumor mutation rate. 12. Use according to claim 1, wherein the cancer is squamous cell carcinoma of the skin (CSCC), urothelial carcinoma of the bladder (BLCA), invasive carcinoma of the breast (BRCA), squamous cell carcinoma of the cervix and endocervical adenocarcinoma (CESC), adenocarcinoma of the colon/ rectal cell carcinoma (CORE), glioblastoma multiforme (GBM), head and neck squamous cell carcinoma (HNSC), clear cell renal cell carcinoma (KIRC), renal papillary renal cell carcinoma (KIRP), acute myeloid leukemia (LAML), liver hepatocellular carcinoma (LIHC) ), low-grade glioma (LGG), lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LUSC), ovarian serous cystadenocarcinoma (OV), pheochromocytoma and paraganglioma (PCPG), prostate adenocarcinoma (PRAD), cutaneous melanoma (SKCM ) endometrioid carcinoma of the uterine body or adenocarcinoma of the stomach. 13. Use according to claim 1, wherein the cancer includes lung cancer. 14. Use according to claim 13, wherein the lung cancer includes non-small cell lung carcinoma. 15. Use according to claim 1, wherein the cancer includes skin cancer. 16. Use according to claim 15, wherein the skin cancer includes skin squamous cell carcinoma (CSCC). 17. Use according to claim 1, wherein the cancer includes cervical cancer. 18. Use according to claim 8, wherein the cancer is cutaneous squamous cell carcinoma of the skin (CSCC), urothelial carcinoma of the bladder (BLCA), invasive carcinoma of the breast (BRCA), squamous cell carcinoma of the cervix and endocervical adenocarcinoma (CESC), adenocarcinoma of the colon /rectal (CORE), glioblastoma multiforme (GBM), head and neck squamous cell carcinoma (HNSC), clear cell renal carcinoma (KIRC), renal papillary renal cell carcinoma (KIRP), acute myeloid leukemia (LAML), hepatocellular carcinoma of the liver ( LIHC), low-grade brain glioma (LGG), lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LUSC), ovarian serous cystadenocarcinoma (OV), pheochromocytoma and paraganglioma (PCPG), prostate adenocarcinoma (PRAD), cutaneous melanoma ( SKCM), endometrioid carcinoma of the uterine body or adenocarcinoma of the stomach. 19. Use according to claim 8, wherein the cancer includes lung cancer. 20. Use according to claim 19, wherein the lung cancer includes non-small cell lung carcinoma. 21. Use according to claim 8, wherein the cancer includes skin cancer. 22. Use according to claim 21, wherein the skin cancer includes skin squamous cell carcinoma (CSCC). 23. Use according to claim 8, wherein the cancer includes cervical cancer. 24. The use of claim 8, wherein the antibody that binds to and inhibits PD1 further comprises a light chain variable region (LCVR) sequence comprising the amino acid sequence of SEQ ID NO: 22. 25. Use according to claim 24, wherein the cancer is squamous cell carcinoma of the skin (CSCC), urothelial carcinoma of the bladder (BLCA), invasive carcinoma of the breast (BRCA), squamous cell carcinoma of the cervix and endocervical adenocarcinoma (CESC), adenocarcinoma of the colon/ rectal cell carcinoma (CORE), glioblastoma multiforme (GBM), head and neck squamous cell carcinoma (HNSC), clear cell renal cell carcinoma (KIRC), renal papillary renal cell carcinoma (KIRP), acute myeloid leukemia (LAML), liver hepatocellular carcinoma (LIHC) ), low-grade glioma (LGG), lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LUSC), ovarian serous cystadenocarcinoma (OV), pheochromocytoma and paraganglioma (PCPG), prostate adenocarcinoma (PRAD), cutaneous melanoma (SKCM ) endometrioid carcinoma of the uterine body or adenocarcinoma of the stomach. 26. Use according to claim 24, wherein the cancer includes lung cancer. 27. Use according to claim 26, wherein the lung cancer includes non-small cell lung carcinoma. 28. Use according to claim 24, wherein the cancer includes skin cancer. 29. Use according to claim 28, wherein the skin cancer includes skin squamous cell carcinoma (CSCC). 30. Use according to claim 24, wherein the cancer includes cervical cancer. 31. The use of claim 24, wherein the antibody that binds to and inhibits PD1 includes cemiplimab. 32. Use according to claim 31, wherein the cancer is squamous cell carcinoma of the skin (CSCC), urothelial carcinoma of the bladder (BLCA), invasive carcinoma of the breast (BRCA), squamous cell carcinoma of the cervix and endocervical adenocarcinoma (CESC), adenocarcinoma of the colon/ rectal cell carcinoma (CORE), glioblastoma multiforme (GBM), head and neck squamous cell carcinoma (HNSC), clear cell renal cell carcinoma (KIRC), renal papillary renal cell carcinoma (KIRP), acute myeloid leukemia (LAML), liver hepatocellular carcinoma (LIHC) ), low-grade glioma (LGG), lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LUSC), ovarian serous cystadenocarcinoma (OV), pheochromocytoma and paraganglioma (PCPG), prostate adenocarcinoma (PRAD), cutaneous melanoma (SKCM ) endometrioid carcinoma of the uterine body or adenocarcinoma of the stomach. 33. Use according to claim 31, wherein the cancer includes lung cancer. 34. Use according to claim 33, wherein the lung cancer includes non-small cell lung carcinoma. 35. Use according to claim 31, wherein the cancer includes skin cancer. 36. Use according to claim 35, wherein the skin cancer includes skin squamous cell carcinoma (CSCC). 37. Use according to claim 31, wherein the cancer includes cervical cancer. 38. Use of an antibody according to any one of paragraphs. 1-37, where the use also includes an antibody that binds to and inhibits LAG3. 39. The use of claim 38, wherein the antibody that binds to and inhibits LAG3 comprises a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 93. 40. Use according to claim 38 or 39, wherein the antibody that binds to and inhibits LAG3 also contains a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 94. 41. Use of an antibody according to any one of paragraphs. 1-37, where the use also includes an antibody that binds to and inhibits PDL1. 42. The use of claim 41, wherein the antibody that binds to and inhibits PDL1 comprises at least the sequence HCVR SEQ ID NO: 122 and the sequence LCVR SEQ ID NO: 123. 43. Use of an antibody according to any one of paragraphs. 1-37, where the use also includes an antibody that binds to and inhibits CTLA4.