RU2801208C2 - Anti-lag-3 dosing regimens and their use - Google Patents

Abstract

FIELD: biochemistry.

SUBSTANCE: invention relates to the use of an anti-LAG-3 antibody molecule in the treatment of cancer. Also the use of a pharmaceutical composition or a dosage form of a preparation containing an effective amount of an anti-LAG-3 antibody molecule, a method of treating cancer in a subject using the said antibody is disclosed.

EFFECT: invention makes it possible to effectively treat cancer using an anti-LAG-3 antibody molecule.

52 cl, 1 ex, 14 tbl

Description

Cross reference to related applications

This application claims priority of U.S. Provisional Application No. 62/534,798, filed July 20, 2017, and U.S. Provisional Application No. 62/643,992, filed March 16, 2018. The contents of the applications discussed above are hereby incorporated by reference in their entirety.

Sequence list

This application contains a sequence listing which is filed electronically in ASCII format and is hereby incorporated by reference in its entirety. The specified ASCII copy, created on July 17, 2018, is named C2160-7019WO_SL.txt and is 233,727 bytes in size.

State of the art

Lymphocyte activation gene-3 or LAG-3 (also known as CD223) is a member of the immunoglobulin supergene family and is expressed on activated T-lymphocytes (Huard et al . (1994) Immunogenetics 39:213), NK cells (Triebel et al . ( 1990) J. Exp. Med. 171:1393-1405), regulatory T lymphocytes (Huang et al. (2004) Immunity 21:503-513; Camisaschi et al . (2010) J Immunol. 184:6545-6551; Gagliani et al (2013) Nat Med 19:739-746) and on plasmacytoid dendritic cells (DC) (Workman et al . (2009) J Immunol 182:1885-1891). LAG-3 is a membrane protein encoded by a gene located on chromosome 12 and is structurally and genetically related to CD4.

Like CD4, LAG-3 can interact with MHC class II molecules on the cell surface (Baixeras et al . (1992) J. Exp. Med. 176:327-337; Huard et al . (1996) Eur. J. Immunol. 26 :1180-1186). Direct binding of LAG-3 to MHC class II has been suggested to play a role in the down-regulation of antigen-dependent stimulation of CD4 ⁺ T-lymphocytes (Huard et al . (1994) Eur. J. Immunol. 24:3216-3221), and blockade LAG-3 has also been shown to increase CD8 ⁺ lymphocyte activity in both tumor or endoantigen models (Gross et al . (2007) J Clin Invest. 117:3383-3392) and virus models (Blackburn et al . (2009) Nat Immunol 10:29-37). In addition, the intracytoplasmic region of LAG-3 can interact with LAP (LAG-3-associated protein), which is a signaling molecule involved in the down-regulation of the CD3/TCR activation pathway (Iouzalen et al . (2001) Eur. J. Immunol 31 :2885-2891). In addition, CD4 ⁺ CD25 ⁺ T regulatory lymphocytes (T _reg ) have been shown to express LAG-3 when activated, which contributes to suppressor activity of T _reg lymphocytes (Huang, C. et al . (2004) Immunity 21:503 -513). LAG-3 can also negatively regulate T-lymphocyte homeostasis via T _reg lymphocytes in both a T-lymphocyte dependent and independent manner (Workman, CJ and Vignali, DA (2005) J. Immunol. 174:688-695).

Therefore, there is a need for new therapeutic approaches that regulate LAG-3 functions and functions of LAG-3 expressing cells, including dosing regimens and formulations for anti-LAG-3 antibody molecules for the treatment of diseases such as cancer.

The essence of the invention

The present invention describes, at least in part, antibody molecules ( eg, humanized antibody molecules) that bind to lymphocyte activation gene-3 (LAG-3) with high affinity and specificity. Pharmaceutical compositions and dosage formulations containing anti-LAG-3 antibody molecules are also provided. The anti-LAG-3 antibody molecules described herein can be used (alone or in combination with other therapeutic agents, procedures, or interventions) to treat or prevent disorders such as malignant disorders (e.g., solid tumors and hematologic cancers). ), as well as infectious diseases (for example, chronic infectious disorders or sepsis). Thus, the present invention describes methods, including dosing regimens, for the treatment of various disorders using anti-LAG-3 antibody molecules. In certain embodiments, the anti-LAG-3 antibody molecule is administered or administered at a base or fixed dose.

Accordingly, in one aspect, the invention describes a method of treating (eg, slowing, reducing, alleviating, or preventing) a disorder, eg, a hyperproliferative condition or disorder (eg, cancer) in a subject.

In certain embodiments, the method comprises administering to a subject an anti-LAG-3 antibody molecule, such as the anti-LAG-3α antibody molecule described herein , at a dose of about 300 mg to about 500 mg, about 500 mg to about 700 mg. mg or from about 700 mg to about 900 mg once every three weeks or once every four weeks.

In certain embodiments, the anti-LAG-3 antibody molecule is administered at a dose of about 300 mg to about 500 mg once every three weeks or once every four weeks. In other embodiments, the anti-LAG-3 antibody molecule is administered at a dose of about 500 mg to about 700 mg once every three weeks or once every four weeks. In other embodiments, the anti-LAG-3 antibody molecule is administered at a dose of about 700 mg to about 900 mg once every three weeks or once every four weeks. In other embodiments, the anti-LAG-3 antibody molecule is administered at a dose of about 300 mg to about 500 mg, about 500 mg to about 700 mg, or about 700 mg to about 900 mg once every three weeks. In other embodiments, the anti-LAG-3 antibody molecule is administered at a dose of about 300 mg to about 500 mg, about 500 mg to about 700 mg, or about 700 mg to about 900 mg once every four weeks.

In some embodiments, the anti-LAG-3 antibody molecule is administered at a dose of about 300 mg to about 500 mg, such as about 350 mg to about 450 mg, about 300 mg to about 400 mg, or about 400 mg to about 500 mg, such as about 300 mg, about 350 mg, about 400 mg, about 450 mg, or about 500 mg once every three weeks. In certain embodiments, the anti-LAG-3 antibody molecule is administered at a dose of about 350 mg to about 450 mg, such as about 400 mg once every three weeks.

In some embodiments, the anti-LAG-3 antibody molecule is administered at a dose of about 500 mg to about 700 mg, such as about 550 mg to about 650 mg, about 500 mg to about 600 mg, or about 600 mg to about 700 mg, such as about 500 mg, about 533 mg, about 550 mg, about 600 mg, about 650 mg, or about 700 mg once every four weeks. In certain embodiments, the anti-LAG-3 antibody molecule is administered at a dose of about 500 mg to about 650 mg, such as about 533 mg or about 600 mg once every four weeks.

In some embodiments, the anti-LAG-3 antibody molecule is administered at a dose of about 700 mg to about 900 mg, such as about 750 mg to about 850 mg, about 700 mg to about 800 mg, or about 800 mg to about 900 mg, such as about 700 mg, about 750 mg, about 800 mg, about 850 mg, or about 900 mg once every four weeks. In certain embodiments, the anti-LAG-3 antibody molecule is administered at a dose of about 750 mg to about 850 mg, such as about 800 mg once every four weeks.

In some embodiments, the anti-LAG-3 antibody molecule is administered at a dose or dosing schedule that results in either one or both of the following:

(a) 50% or more (e.g., 60% or more, 70% or more, 80% or more, 85% or more, 90% or more, 95% or more, 99% or more) of soluble LAG-3 in the subject (eg, in blood) is associated with an anti-LAG-3 antibody molecule; or

(b) 50% or more (e.g., 60% or more, 70% or more, 80% or more, 85% or more, 90% or more, 95% or more, 99% or more) membrane-bound LAG- 3 in a subject (eg, cancer) are associated with an anti-LAG-3 antibody molecule.

In some embodiments, the binding of an anti-LAG-3 antibody molecule to soluble LAG-3 is determined in a blood sample (eg, a serum sample or a plasma sample). In some embodiments, binding of an anti-LAG-3 antibody molecule to membrane-bound LAG-3 is determined in a cancerous disease (eg, in a sample of cancerous tissue).

In some embodiments, binding of an anti-LAG-3 antibody molecule to soluble LAG-3, binding of an anti-LAG-3 antibody molecule to membrane-bound LAG-3, or both, is determined when the subject has a steady state trough. anti-LAG-3 antibody molecules. In some embodiments, the trough is the concentration of the anti-LAG-3 antibody molecule at about 24 weeks post-dose, or the lowest concentration that the anti-LAG-3 antibody reaches before the next dose. In some embodiments, the binding of an anti-LAG-3 antibody molecule to soluble LAG-3, the binding of an anti-LAG-3 antibody molecule to membrane-bound LAG-3, or both, is determined, e.g., measured in vitro ( eg by ELISA or cellular analysis) or in vivo (eg by image processing) or predicted by a PK/PD model, eg by the PK/PD model described herein.

In some embodiments, 60% or more of the soluble LAG-3 in a serum sample from a subject is bound to an anti-LAG-3 antibody molecule. In some embodiments, 80% or more of the soluble LAG-3 in a serum sample from a subject is bound to an anti-LAG-3 antibody molecule. In some embodiments, 90% or more of the soluble LAG-3 in a serum sample from a subject is bound to an anti-LAG-3 antibody molecule.

In some embodiments, 85% or more of the membrane-bound LAG-3 in a cancer or cancer tissue sample from a subject is bound to an anti-LAG-3 antibody molecule. In some embodiments, 90% or more of the membrane-bound LAG-3 in a cancer or cancer tissue sample from a subject is bound to an anti-LAG-3 antibody molecule. In some embodiments, 95% or more of the membrane-bound LAG-3 in a cancer or cancer tissue sample from a subject is bound to an anti-LAG-3 antibody molecule.

In some embodiments, 70% or more, 80% or more, or 90% or more of soluble LAG-3 in a serum sample from a subject is bound to an anti-LAG-3 antibody molecule, and 85% or more, 90% or more, or 95% or more of the membrane-bound LAG-3 in a cancer or in a cancer tissue sample from a subject is bound to an anti-LAG-3 antibody molecule.

In some embodiments, 70% or more of soluble LAG-3 in a serum sample from a subject is bound to an anti-LAG-3 antibody molecule, and 90% or more of membrane-bound LAG-3 in a cancer or cancer tissue sample from a subject, associated with an anti-LAG-3 antibody molecule. In some embodiments, 80% or more of the soluble LAG-3 in a serum sample from a subject is bound to an anti-LAG-3 antibody molecule, and 90% or more of the membrane-bound LAG-3 in a cancer or cancer tissue sample of the subject is bound to an anti-LAG-3 antibody molecule. In some embodiments, 90% or more of the soluble LAG-3 in a serum sample from a subject is associated with an anti-LAG-3 antibody molecule, and 90% or more of the membrane-bound LAG-3 in a cancer or cancer tissue sample of the subject is associated with an anti-LAG-3 antibody molecule.

In certain embodiments, the anti-LAG-3 antibody molecule is administered at a dose of about 300 mg to about 800 mg, such as about 300 mg to about 500 mg (e.g., about 400 mg) or about 600 mg to about 800 mg (e.g., , approximately 700 mg) once every three weeks. In some embodiments, the anti-LAG-3 antibody molecule is administered at a dose of about 300 mg to about 500 mg (eg, about 400 mg) once every three weeks.

In other embodiments, the anti-LAG-3 antibody molecule is administered at a dose of about 600 mg to about 1600 mg, such as about 600 mg to about 1000 mg (e.g., about 800 mg) or about 1200 mg to about 1600 mg (e.g., , approximately 1400 mg) once every four weeks. In some embodiments, the anti-LAG-3 antibody molecule is administered at a dose of about 600 mg to about 1000 mg (eg, about 800 mg) once every four weeks.

In some embodiments, the anti-LAG-3 antibody molecule is administered at a dose or dosing schedule that reduces one or both of the following:

(a) the level of free soluble LAG-3 in the subject (e.g., in blood), e.g., up to 50% or less (e.g., up to 40% or less, 30% or less, 20% or less, 15% or less, 10 % or less, 5% or less, or 1% or less) of the free soluble LAG-3 reference level; or

(b) the level of free membrane-bound LAG-3 in the subject (e.g. cancer), e.g. up to 50% or less (e.g. up to 40% or less, 30% or less, 20% or less, 15% or less , 10% or less, 5% or less, or 1% or less) of the reference level of membrane-bound LAG-3.

In some embodiments, the level of free soluble LAG-3 is determined in a blood sample (eg, a serum sample or a plasma sample). In some embodiments, the reference level of free soluble LAG-3 is the background level of free soluble LAG-3 in the subject, eg, prior to administration of the anti-LAG-3 antibody molecule, eg, according to a dosing regimen.

In some embodiments, the level of free membrane-bound LAG-3 is determined in a cancerous disease (eg, in a sample of cancerous tissue). In some embodiments, the reference level of free membrane-bound LAG-3 is the background level of free membrane-bound LAG-3 in the subject, e.g., prior to administration of an anti-LAG-3 antibody molecule, e.g., according to a dosing regimen.

In some embodiments, the level of free soluble LAG-3, the level of free membrane-bound LAG-3, or both, is determined when the subject has a stationary minimum level of anti-LAG-3 antibody molecules. In some embodiments, the trough is the concentration of the anti-LAG-3 antibody molecule at about 24 weeks post-dose, or the lowest concentration that the anti-LAG-3 antibody reaches before the next dose. In some embodiments, the level of free soluble LAG-3, the level of free membrane-bound LAG-3, or both is determined, e.g. measured in vitro (e.g. by ELISA or cell assay) or in vivo (e.g. , using image processing) or predicted from a PK/PD model, such as the PK/PD model described herein.

In some embodiments, the level of free soluble LAG-3 is reduced to 30% or less of a reference level of free soluble LAG-3 in a serum sample from a subject. In some embodiments, the level of free soluble LAG-3 is reduced to 20% or less of a reference level of free soluble LAG-3 in a serum sample from a subject. In some embodiments, the level of free soluble LAG-3 is reduced to 10% or less of a reference level of free soluble LAG-3 in a serum sample from a subject.

In some embodiments, the level of free membrane-bound LAG-3 is reduced to 15% or less of a reference level of free membrane-bound LAG-3 in a cancer or cancer tissue sample from a subject. In some embodiments, the level of free membrane-bound LAG-3 is reduced to 10% or less of a reference level of free membrane-bound LAG-3 in a cancer or cancer tissue sample from a subject. In some embodiments, the level of free soluble LAG-3 is reduced to 5% or less of a reference level of free membrane-bound LAG-3 in a cancer or cancer tissue sample from a subject.

In some embodiments, the level of free soluble LAG-3 is reduced to 30% or less, 20% or less, or 10% or less of the reference level of free soluble LAG-3 in a serum sample from the subject and the level of free membrane-bound LAG-3 is reduced up to 15% or less, 10% or less, or 5% or less of a reference level of free membrane-bound LAG-3 in a cancer or cancer tissue sample from a subject.

In some embodiments, the level of free soluble LAG-3 is reduced to 30% or less of the reference level of free soluble LAG-3 in a serum sample from the subject and the level of free membrane-bound LAG-3 is reduced to 10% or less of the reference level of free membrane -linked LAG-3 in a cancerous disease or in a sample of cancerous tissue from a subject. In some embodiments, the level of free soluble LAG-3 is reduced to 20% or less of the reference level of free soluble LAG-3 in a serum sample from the subject and the level of free membrane-bound LAG-3 is reduced to 10% or less of the reference level of free membrane -linked LAG-3 in a cancerous disease or in a sample of cancerous tissue from a subject. In some embodiments, the level of free soluble LAG-3 is reduced to 10% or less of the reference level of free soluble LAG-3 in a serum sample from the subject and the level of free membrane-bound LAG-3 is reduced to 10% or less of the reference level of free membrane -linked LAG-3 in a cancerous disease or in a sample of cancerous tissue from a subject.

In certain embodiments, the anti-LAG-3 antibody molecule is administered at a dose of about 300 mg to about 800 mg, e.g., about 300 mg to about 500 mg (e.g., about 400 mg) or about 600 mg to about 800 mg (eg, approximately 700 mg) once every three weeks. In some embodiments, the anti-LAG-3 antibody molecule is administered at a dose of about 300 mg to about 500 mg (eg, about 400 mg) once every three weeks.

In other embodiments, the anti-LAG-3 antibody molecule is administered at a dose of about 600 mg to about 1600 mg, such as about 600 mg to about 1000 mg (e.g., about 800 mg) or about 1200 mg to about 1600 mg (eg, approximately 1400 mg) once every four weeks. In some embodiments, the anti-LAG-3 antibody molecule is administered at a dose of about 600 mg to about 1000 mg (eg, about 800 mg) once every four weeks.

In some embodiments, the disorder is a cancer, such as the cancer described herein. In certain embodiments, the cancer is a solid tumor. In some embodiments, the cancer is a brain tumor, such as glioblastoma, gliosarcoma, or a recurrent brain tumor. In some embodiments, the cancer is pancreatic cancer, such as advanced pancreatic cancer. In some embodiments, the cancer is a skin cancer, such as melanoma (for example, melanoma stages II-IV, HLA-A2 positive melanoma, unresectable melanoma or metastatic melanoma) or Merkel cell carcinoma. In some embodiments, the cancer is a kidney cancer, such as renal cell carcinoma (RCC) (eg, metastatic renal cell carcinoma). In some embodiments, the cancer is breast cancer, such as metastatic breast carcinoma or breast carcinoma. Stage IV, for example, triple-negative breast cancer (TNBC). In some embodiments, the cancer is a virus-associated cancer. In some embodiments, the cancer is anal cancer (eg, anal squamous cell carcinoma). In some embodiments, the cancer is cervical cancer (eg, squamous cell carcinoma of the cervix). In some embodiments, the cancer is gastrointestinal cancer (eg, Epstein-Barr virus positive gastrointestinal cancer or gastrointestinal or gastroesophageal junction carcinoma). In some embodiments, the cancer is head and neck cancer (eg, HPV-positive and negative head and neck squam cell cancer (SCCHN)). In some embodiments, the cancer is nasopharyngeal cancer (NPC). In some embodiments, the cancer is a cancer of the penis (eg, squamous cell carcinoma of the penis). In some embodiments, the cancer is a vaginal or vulvar cancer (eg, squamous cell carcinoma of the vagina or vulva). In some embodiments, the cancer is colon and rectal cancer, e.g., recurrent colon and rectal cancer or metastatic colon and rectal cancer, e.g., microsatellite unstable colon and rectal cancer, microsatellite stable colon and rectal cancer, colon and rectal cancer surplus for mispair repair or colon and rectal cancer deficient for mispair repair. In some embodiments, the cancer is lung cancer, such as non-small cell lung cancer (NSCLC). In certain embodiments, the cancer is a hematologic cancer. In some embodiments, the cancer is leukemia. In some embodiments, the cancer is a lymphoma, such as Hodgkin's lymphoma (HL) or diffuse large B cell lymphoma (DLBCL) (eg, recurrent or refractory HL or DLBCL). In some embodiments, the cancer is a myeloma.

In other embodiments, the cancer is highly microsatellite unstable cancer. In some embodiments, the cancer is a metastatic cancer. In other embodiments, the cancer is a progressive cancer. In other embodiments, the cancer is recurrent or untreatable cancer. In other embodiments, the cancer is recurrent cancer.

In some embodiments, the anti-LAG-3 antibody molecule is administered by injection (e.g., intravenously or subcutaneously) at a dose (e.g., basal dose) of about 300 mg to about 500 mg (e.g., about 400 mg), from about 500 mg up to about 700 mg (eg, about 533 mg or about 600 mg) or from about 700 mg to about 900 mg (eg, about 800 mg). The dosing regimen (eg, baseline dosing regimen) may vary, for example, from once every three weeks to once every four weeks. In one embodiment, the anti-LAG-3 antibody molecule is administered intravenously at a dose of about 300 mg to 500 mg (eg, about 400 mg) once every three weeks. In one embodiment, the anti-LAG-3 antibody molecule is administered intravenously at a dose of about 500 mg to 700 mg (eg, about 533 mg or about 600 mg) once every four weeks. In one embodiment, the anti-LAG-3 antibody molecule is administered intravenously at a dose of about 700 mg to 900 mg (eg, about 800 mg) once every four weeks.

In one embodiment, an anti-LAG-3 antibody molecule is administered intravenously at a dose of about 400 mg once every three weeks for the treatment of a cancer described in the present invention. In one embodiment, an anti-LAG-3 antibody molecule is administered intravenously at a dose of about 533 mg or 600 mg once every four weeks for the treatment of a cancer described in the present invention. In one embodiment, an anti-LAG-3 antibody molecule is administered intravenously at a dose of about 800 mg once every four weeks for the treatment of a cancer described in the present invention.

In one embodiment, the method further comprises administering to the subject a PD-1 inhibitor (e.g., an anti-PD-1 antibody molecule described herein) or a PD-L1 inhibitor (e.g., an anti-PD-L1 antibody molecule described herein). document). In one embodiment, a PD-1 inhibitor (e.g., an anti-PD-1 antibody molecule described herein) is administered intravenously at a dose of about 200 mg to about 400 mg (e.g., about 300 mg) once every three weeks . In certain embodiments, an anti-LAG-3 antibody molecule (e.g., an anti-LAG-3 antibody molecule described herein) is administered to a subject along with an anti-PD-1 antibody molecule at a dose of about 200 mg to about 400 mg ( for example, approximately 300 mg) once every three weeks. In certain embodiments, an anti-LAG-3 antibody molecule (e.g., an anti-LAG-3 antibody molecule described herein) is administered at a dose of about 300 mg to about 500 mg (e.g., about 400 mg) once every three weeks, and a PD-1 inhibitor (eg, an anti-PD-1 antibody molecule described herein) is administered at a dose of about 200 mg to about 400 mg (eg, about 300 mg) once every three weeks. In other embodiments, an anti-LAG-3 antibody molecule (e.g., an anti-LAG-3 antibody molecule described herein) is administered to a subject along with an anti-PD-1 antibody molecule at a dose of about 300 mg to about 500 mg ( for example, approximately 400 mg) once every four weeks. In certain embodiments, an anti-LAG-3 antibody molecule (e.g., an anti-LAG-3 antibody molecule described herein) is administered at a dose of about 600 mg to about 1000 mg (e.g., about 800 mg) once every four weeks and a PD-1 inhibitor (eg, an anti-PD-1 antibody molecule described herein) is administered at a dose of about 300 mg to about 500 mg (eg, about 400 mg) once every four weeks. In one embodiment, the method includes administering to a subject an anti-LAG-3 antibody molecule (e.g., an anti-LAG-3 antibody molecule described herein) and a chemotherapeutic agent (e.g., a platinum agent (e.g., carboplatin, cisplatin, oxaliplatin, or tetraplatin) or a nucleotide analog or a precursor analog (eg capecitabine)). In one embodiment, a chemotherapeutic agent (e.g., a platinum agent, e.g., carboplatin) is administered intravenously at a dose to achieve an area under the curve (AUC) of about 4 to about 8, or about 5 to about 7 (e.g., AUC of about 6) once every three weeks. In certain embodiments, an anti-LAG-3 antibody molecule (e.g., an anti-LAG-3 antibody molecule described herein) is administered at a dose of about 300 mg to about 500 mg (e.g., about 400 mg) once every three weeks and the chemotherapeutic agent (eg, a platinum agent, eg, carboplatin) is administered at a dose to achieve an area under the curve (AUC) of about 4 to about 8 or about 5 to about 7 (eg, AUC of about 6) once every three weeks .

In one embodiment, the method comprises administering to a subject an anti-LAG-3 antibody molecule (e.g., an anti-LAG-3 antibody molecule described herein), a PD-1 inhibitor (e.g., an anti-PD-1 antibody molecule described herein) and a chemotherapeutic agent (eg, a platinum agent (eg, carboplatin, cisplatin, oxaliplatin, or tetraplatin) or a nucleotide analog or precursor analog (eg, capecitabine)). In certain embodiments, an anti-LAG-3 antibody molecule (e.g., an anti-LAG-3 antibody molecule described herein) is administered at a dose of about 300 mg to about 500 mg (e.g., about 400 mg) once every three weeks, a PD-1 inhibitor (e.g., an anti-PD-1 antibody molecule described herein) is administered at a dose of about 200 mg to about 400 mg (e.g., about 300 mg) once every three weeks, and a chemotherapeutic agent (e.g., , a platinum agent, eg, carboplatin) is administered at a dose to achieve an area under the curve (AUC) of about 4 to about 8, or about 5 to about 7 (eg, AUC of about 6) once every three weeks.

In certain embodiments, an anti-LAG-3 antibody molecule (e.g., an anti-LAG-3 antibody molecule described herein) or a combination containing an anti-LAG-3 antibody molecule (e.g., an anti-LAG-3 antibody molecule in combined with one or two components of a PD-1 inhibitor or a chemotherapeutic agent) is used to treat breast cancer, eg, triple negative breast cancer (TNBC), for example, according to the dosing regimen described herein.

In certain embodiments, the subject is not treated with PD-1 or PD-L1 therapy prior to receiving the anti-LAG-3 antibody molecule. In other embodiments, the subject is treated with PD-1 or PD-L1 therapy prior to receiving an anti-LAG-3 antibody molecule.

In certain embodiments, the subject is not being treated with a chemotherapeutic agent (eg, a platinum agent (eg, carboplatin, cisplatin, oxaliplatin, or tetraplatin) or a nucleotide analog or precursor analog (eg, capecitabine)) prior to receiving an anti-LAG-3 antibody molecule. In other embodiments, the subject is treated with a chemotherapeutic agent (e.g., a platinum agent (e.g., carboplatin, cisplatin, oxaliplatin, or tetraplatin) or a nucleotide analog or precursor analog (e.g., capecitabine)) prior to receiving an anti-LAG-3 antibody molecule.

In other embodiments, the subject has or is identified as having LAG-3 expression in tumor infiltrating lymphocytes (TILs).

In another aspect, the invention describes a method for reducing the activity (eg, growth, survival or viability, or all together) of hyperproliferative (eg, cancerous) cells. The method includes contacting a cell with an anti-LAG-3 antibody molecule, such as an anti-LAG-3 antibody molecule described herein. The method may be administered to a subject, e.g., as part of a therapeutic protocol, e.g., at a dose of about 300 mg to about 500 mg (e.g., about 400 mg), about 500 mg to about 700 mg (e.g., about 533 mg or about 600 mg) or from about 700 mg to about 900 mg (eg, about 800 mg) of an anti-LAG-3 antibody molecule once every three weeks or once every four weeks. In certain embodiments, the dose is from about 300 mg to about 500 mg (eg, about 400 mg) of an anti-LAG-3 antibody molecule once every three weeks. In other embodiments, the dosage is from about 500 mg to about 700 mg (eg, about 533 mg or about 600 mg) of an anti-LAG-3 antibody molecule once every four weeks. In other embodiments, the dose is from about 700 mg to about 900 mg (eg, about 800 mg) of an anti-LAG-3 antibody molecule once every four weeks.

The cancer cell may be, for example, a cell from the cancer tissue described herein, such as a solid tumor or a hematological cancer, for example, a brain tumor (e.g., glioblastoma, gliosarcoma, or recurrent brain tumor), pancreatic cancer (e.g., , advanced pancreatic cancer), skin cancer (eg, melanoma (eg, stage II-IV melanoma, HLA-A2 positive melanoma, unresectable melanoma, or metastatic melanoma) or Merkel cell carcinoma), kidney cancer (eg, renal cell carcinoma (RCC). ) (eg, metastatic renal cell carcinoma)), breast cancer (eg, metastatic breast carcinoma or stage IV breast carcinoma, such as triple-negative breast cancer (TNBC)), virus-associated cancer, anal cancer (eg. , anal squam cell carcinoma), cervical cancer (eg, squam cell carcinoma of the cervix), gastrointestinal cancer (eg, Epstein-Barr virus-positive gastrointestinal cancer or carcinoma of the gastrointestinal tract or gastroesophageal junction), head and neck cancer ( for example, HPV positive and negative squam cell carcinoma of the head and neck (SCCHN)), nasopharyngeal cancer (NPC), cancer of the penis (eg, squam cell carcinoma of the penis), vaginal or vulvar cancer (eg, squam cell carcinoma of the vagina or vulva), cancer colon and rectum (eg, recurrent colon and rectal cancer or metastatic colon and rectal cancer, eg, colon and rectal cancer with microsatellite instability, microsatellite stable colon and rectal cancer, colon and rectal cancer surplus for mispaired base repair or colorectal cancer deficient in mismatch repair), lung cancer (eg, non-small cell lung cancer (NSCLC)), leukemia, lymphoma (eg, Hodgkin's lymphoma (HL) or diffuse large B-cell lymphoma (DLBCL), eg, recurrent or refractory HL or DLBCL) or myeloma.

In certain embodiments, the cancer is a solid tumor. In some embodiments, the cancer is a brain tumor, such as glioblastoma, gliosarcoma, or a recurrent brain tumor. In some embodiments, the cancer is pancreatic cancer, such as advanced pancreatic cancer. In some embodiments, the cancer is a skin cancer, such as melanoma (eg, stage II-IV melanoma, HLA-A2 positive melanoma, unresectable melanoma, or metastatic melanoma) or Merkel cell carcinoma. In some embodiments, the cancer is a kidney cancer, such as renal cell carcinoma (RCC) (eg, metastatic renal cell carcinoma). In some embodiments, the cancer is breast cancer, such as metastatic breast carcinoma or stage IV breast carcinoma, such as triple negative breast cancer (TNBC). In some embodiments, the cancer is a virus-associated cancer. In some embodiments, the cancer is anal cancer (eg, anal squamous cell carcinoma). In some embodiments, the cancer is cervical cancer (eg, squamous cell carcinoma of the cervix). In some embodiments, the cancer is gastrointestinal cancer (eg, Epstein-Barr virus positive gastrointestinal cancer or gastrointestinal or gastroesophageal junction carcinoma). In some embodiments, the cancer is head and neck cancer (eg, HPV positive and squam cell cancer of the head and neck (SCCHN)). In some embodiments, the cancer is nasopharyngeal cancer (NPC). In some embodiments, the cancer is a cancer of the penis (eg, squamous cell carcinoma of the penis). In some embodiments, the cancer is a vaginal or vulvar cancer (eg, squamous cell carcinoma of the vagina or vulva). In some embodiments, the cancer is colon and rectal cancer, e.g., recurrent colon and rectal cancer or metastatic colon and rectal cancer, e.g., microsatellite unstable colon and rectal cancer, microsatellite stable colon and rectal cancer, colon and rectal cancer surplus for mispair repair or colon and rectal cancer deficient for mispair repair. In some embodiments, the cancer is lung cancer, such as non-small cell lung cancer (NSCLC). In certain embodiments, the cancer is a hematologic cancer. In some embodiments, the cancer is leukemia. In some embodiments, the cancer is a lymphoma, such as Hodgkin's lymphoma (HL) or diffuse large B cell lymphoma (DLBCL) (eg, recurrent or refractory HL or DLBCL). In some embodiments, the cancer is a myeloma.

In certain embodiments, the method further comprises contacting the cells with one or both of a PD-1 inhibitor (e.g., an anti-PD-1 antibody molecule described herein) or a chemotherapeutic agent (e.g., a platinum agent (e.g., carboplatin , cisplatin, oxaliplatin or tetraplatin) or a nucleotide analog or precursor analog (eg capecitabine)). The method may be administered to a subject, e.g., as part of a therapeutic protocol, e.g., at a dose of about 300 mg to about 500 mg (e.g., about 400 mg) of an anti-LAG-3 antibody molecule once every three weeks and at a dose of about 200 mg to about 400 mg (eg, about 300 mg) of a PD-1 inhibitor once every three weeks. The method can be carried out on a subject, e.g., as part of a therapeutic protocol, e.g., at a dose of about 600 mg to about 1000 mg (e.g., about 800 mg) of an anti-LAG-3 antibody molecule once every four weeks and at a dose of about 300 mg to about 500 mg (eg, about 400 mg) of a PD-1 inhibitor once every four weeks. The method can be carried out on a subject, e.g., as part of a therapeutic protocol, e.g., at a dose of about 300 mg to about 500 mg (e.g., about 400 mg) of an anti-LAG-3 antibody molecule once every three weeks and at a dose to achieve area under the curve (AUC) about 4 to about 8 or about 5 to about 7 (eg, AUC about 6) of the chemotherapeutic agent once every three weeks. The method can be carried out on a subject, e.g., as part of a therapeutic protocol, e.g., at a dose of about 300 mg to about 500 mg (e.g., about 400 mg) of an anti-LAG-3 antibody molecule once every three weeks, at a dose of about 200 mg to about 400 mg (e.g., about 300 mg) of a PD-1 inhibitor once every three weeks and at a dose of a chemotherapeutic agent to achieve an area under the curve (AUC) of about 4 to about 8 or about 5 to about 7 (e.g., AUC of about 6) one once every three weeks. In some embodiments, the cancer cell may be, for example, a breast cancer cell, such as a TNBC cell. In certain embodiments of the methods described herein, the method further comprises determining LAG-3 expression levels in tumor infiltrating lymphocytes (TIL) in a subject. In other embodiments, the level of LAG-3 expression is determined in a sample (eg, from a tumor biopsy) taken from the subject (eg, using immunohistochemistry). In certain embodiments, when there is a detectable level or elevated level of LAG-3 in the subject, an anti-LAG-3 antibody molecule is administered (e.g., an anti-LAG-3 antibody molecule sensitive to the detectable level or elevated level of LAG-3 in the subject is administered) . You can also use the stages of detection, for example, to monitor the effectiveness of a therapeutic agent described in this document. For example, the detection step can be used to monitor the performance of an anti-LAG-3 antibody molecule.

In another aspect, the invention describes a composition (eg, one or more compositions or dosage forms) that contains an anti-LAG-3 antibody molecule ( eg, an anti-LAG-3 antibody molecule as described herein). The present document also describes formulations, eg, dosage formulations and kits, eg, therapeutic kits, that contain an anti-LAG-3 antibody molecule ( eg, an anti-LAG-3 antibody molecule as described herein). In certain embodiments, the composition or formulation contains from about 300 mg to about 500 mg (e.g., about 400 mg), from about 500 mg to about 700 mg (e.g., about 533 mg or about 600 mg), or from about 700 mg to about up to 900 mg (eg, about 800 mg) of an anti-LAG-3 antibody molecule (eg, an anti-LAG-3 antibody molecule as described herein). In some embodiments, the composition or formulation is administered or applied once every three weeks or once every four weeks. In some embodiments, the composition or preparation contains about 400 mg of an anti-LAG-3 antibody molecule (eg, an anti-LAG-3 antibody molecule as described herein) and is administered or applied once every three weeks. In some embodiments, the composition or formulation contains about 533 mg or 600 mg of an anti-LAG-3 antibody molecule (eg, an anti-LAG-3 antibody molecule as described herein) and is administered or applied once every four weeks. In some embodiments, the composition or preparation contains about 800 mg of an anti-LAG-3 antibody molecule (eg, an anti-LAG-3 antibody molecule as described herein) and is administered or applied once every four weeks. In certain embodiments, the composition or preparation is used to treat a cancer, for example, a cancer described in the present invention.

Additional features or embodiments of the methods, dosage formulations, and kits described herein include one or more of the following elements.

Antibody molecules to LAG-3

In one embodiment, the anti-LAG-3 antibody molecule contains at least one, two, three, four, five, or six complementarity determining regions (CDRs) (or collectively all CDRs) from the heavy and light chain variable regions. containing the amino acid sequence shown in Table 5 (for example, from the heavy and light chain variable region sequence of BAP050-Clone I or BAP050-Clone J described in Table 5), or encoded by the sequence nucleotides shown in Table 5. In some embodiments, the CDRs are as defined by Kabat (e.g., as given in Table 5). In some embodiments, the CDRs match the definition of Chothia (eg, as shown in Table 5). In some embodiments, the CDRs correspond to the combined CDR definitions of both Kabat and Chothia (eg, as shown in Table 5). In one embodiment, the combination of CDR definitions according to Kabat and Chothia for VH CDR1 contains the amino acid sequence GFTLTNYGMN (SEQ ID NO: 766). In one embodiment, one or more CDRs (or collectively all CDRs) have one, two, three, four, five, six or more changes, such as amino acid substitutions (e.g., conservative amino acid substitutions) or deletions, compared to the sequence amino acids shown in Table 5 or the encoded sequence nucleotides shown in Table 5.

In one embodiment, the anti-LAG-3 antibody molecule comprises a heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO: 701, the VHCDR2 amino acid sequence of SEQ ID NO: 702, and the VHCDR3 amino acid sequence of SEQ ID NO: 703, and a light chain variable region (VL) containing the amino acid sequence of VLCDR1 SEQ ID NO: 710, the amino acid sequence of VLCDR2 SEQ ID NO: 711, and the amino acid sequence of VLCDR3 SEQ ID NO: 712, each of which is described in Table 5.

In one embodiment, the anti-LAG-3 antibody molecule comprises a VH containing VHCDR1 encoded by the nucleotide sequence of SEQ ID NO: 736 or 737, VHCDR2 encoded by the nucleotide sequence of SEQ ID NO: 738 or 739, and VHCDR3 encoded by the nucleotide sequence of SEQ ID NO: 740 or 741; and VL containing VLCDR1 encoded by the nucleotide sequence of SEQ ID NO: 746 or 747, VLCDR2 encoded by the nucleotide sequence of SEQ ID NO: 748 or 749, and VLCDR3 encoded by the nucleotide sequence of SEQ ID NO: 750 or 751, each of which is described in Table 5. In one embodiment, the anti-LAG-3 antibody molecule comprises a VH containing VHCDR1 encoded by the nucleotide sequence of SEQ ID NO: 758 or 737, VHCDR2 encoded by the nucleotide sequence of SEQ ID NO: 759 or 739, and VHCDR3 encoded by the sequence nucleotides of SEQ ID NO: 760 or 741; and VL containing VLCDR1 encoded by the nucleotide sequence of SEQ ID NO: 746 or 747, VLCDR2 encoded by the nucleotide sequence of SEQ ID NO: 748 or 749, and VLCDR3 encoded by the nucleotide sequence of SEQ ID NO: 750 or 751, each of which is described in Table 5.

In one embodiment, the anti-LAG-3 antibody molecule comprises a VH containing the amino acid sequence of SEQ ID NO: 706 or an amino acid sequence at least 85%, 90%, 95%, or 99% or greater identical to SEQ ID NO. : 706. In one embodiment, the anti-LAG-3 antibody molecule comprises a VL containing the amino acid sequence of SEQ ID NO: 718 or an amino acid sequence at least 85%, 90%, 95%, or 99% or greater identical to SEQ ID NO: 718. In one embodiment, the anti-LAG-3 antibody molecule comprises a VH containing the amino acid sequence of SEQ ID NO: 724 or the amino acid sequence of at least 85%, 90%, 95%, or 99% or higher identical to SEQ ID NO: 724. In one embodiment, the anti-LAG-3 antibody molecule contains a VL containing the amino acid sequence of SEQ ID NO: 730, or the amino acid sequence of at least 85%, 90%, 95 % or 99% or greater identical to SEQ ID NO: 730. In one embodiment, the anti-LAG-3 antibody molecule contains a VH containing the amino acid sequence of SEQ ID NO: 706 and a VL containing the amino acid sequence of SEQ ID NO: 718. In one embodiment, the anti-LAG-3 antibody molecule comprises a VH containing the amino acid sequence of SEQ ID NO: 724 and a VL containing the amino acid sequence of SEQ ID NO: 730,

In one embodiment, the antibody molecule contains a VH encoded by the nucleotide sequence of SEQ ID NO: 707 or 708, or by a nucleotide sequence at least 85%, 90%, 95%, or 99% or greater identical to SEQ ID NO: 707 or 708. In one embodiment, the antibody molecule comprises a VL encoded by the nucleotide sequence of SEQ ID NO: 719 or 720, or by a nucleotide sequence at least 85%, 90%, 95%, or 99% or greater identical to SEQ ID NO: 719 or 720. In one embodiment, the antibody molecule contains a VH encoded by the nucleotide sequence of SEQ ID NO: 725 or 726 or a nucleotide sequence of at least 85%, 90%, 95% or 99% or higher identical to SEQ ID NO: 725 or 726. In one embodiment, the antibody molecule contains a VL encoded by the nucleotide sequence of SEQ ID NO: 731 or 732 or the nucleotide sequence by at least 85%, 90%, 95% or 99% or higher identical to SEQ ID NO: 731 or 732. In one embodiment, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 707 or 708 and a VL encoded by the nucleotide sequence of SEQ ID NO: 719 or 720. In one of embodiments, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 725 or 726 and a VL encoded by the nucleotide sequence of SEQ ID NO: 731 or 732.

In one embodiment, the anti-LAG-3 antibody molecule comprises a heavy chain containing the amino acid sequence of SEQ ID NO: 709, or an amino acid sequence at least 85%, 90%, 95%, or 99% or greater identical to SEQ ID NO: 709. In one embodiment, the anti-LAG-3 antibody molecule comprises a light chain containing the amino acid sequence of SEQ ID NO: 721 or the amino acid sequence of at least 85%, 90%, 95%, or 99% or higher identical to SEQ ID NO: 721. In one embodiment, the anti-LAG-3 antibody molecule contains a heavy chain containing the amino acid sequence of SEQ ID NO: 727 or the amino acid sequence of at least 85%, 90%, 95 % or 99% or greater identical to SEQ ID NO: 727. In one embodiment, the anti-LAG-3 antibody molecule contains a light chain containing the amino acid sequence of SEQ ID NO: 733 or the amino acid sequence of at least 85%, 90%, 95%, or 99% or greater identical to SEQ ID NO: 733. In one embodiment, the anti-LAG-3 antibody molecule comprises a heavy chain containing the amino acid sequence of SEQ ID NO: 709 and a light chain containing the amino acid sequence SEQ ID NO: 721. In one embodiment, the anti-LAG-3 antibody molecule comprises a heavy chain containing the amino acid sequence of SEQ ID NO: 727 and a light chain containing the amino acid sequence of SEQ ID NO: 733.

In one embodiment, the antibody molecule contains a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 716 or 717 or a nucleotide sequence at least 85%, 90%, 95% or 99% or greater identical to SEQ ID NO: 716 or 717. In one embodiment, the antibody molecule comprises a light chain encoded by the nucleotide sequence of SEQ ID NO: 722 or 723 or a nucleotide sequence at least 85%, 90%, 95%, or 99% or greater identical to SEQ ID NO: 722 or 723. In one embodiment, the antibody molecule contains a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 728 or 729 or the nucleotide sequence of at least 85%, 90%, 95% or 99% or higher identical to SEQ ID NO: 728 or 729. In one embodiment, the antibody molecule contains a light chain encoded by the nucleotide sequence of SEQ ID NO: 734 or 735 or the nucleotide sequence by at least 85%, 90%, 95% or 99 % or greater identical to SEQ ID NO: 734 or 735. In one embodiment, the antibody molecule contains a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 716 or 717 and a light chain encoded by the nucleotide sequence of SEQ ID NO: 722 or 723. In one embodiment, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 728 or 729 and a light chain encoded by the nucleotide sequence of SEQ ID NO: 734 or 735.

Other exemplary LAG-3 inhibitors

In one embodiment, the anti-LAG-3 antibody molecule is BMS-986016 (Bristol-Myers Squibb) also known as BMS986016. BMS-986016 and other anti-LAG-3 antibodies are described in WO 2015/116539 and US Pat. No. 9,505,839, incorporated by reference in their entirety. In one embodiment, the anti-LAG-3 antibody molecule comprises one or more CDR sequences (or collectively, all CDR sequences), a heavy chain or light chain variable region sequence, or a BMS-986016 heavy chain or light chain sequence, e.g., as described in Table 6.

In one embodiment, the anti-LAG-3 antibody molecule is TSR-033 (Tesaro). In one embodiment, the anti-LAG-3 antibody molecule comprises one or more CDR sequences (or collectively, all CDR sequences), a heavy chain or light chain variable region sequence, or a TSR-033 heavy chain or light chain sequence.

In one embodiment, the anti-LAG-3 antibody molecule is IMP731 or GSK2831781 (GSK and Prima BioMed). IMP731 and other anti-LAG-3 antibodies are described in WO 2008/132601 and US Pat. No. 9,244,059, incorporated by reference in their entirety. In one embodiment, the anti-LAG-3 antibody molecule comprises one or more CDR sequences (or collectively, all CDR sequences), a heavy chain or light chain variable region sequence, or an IMP731 heavy chain or light chain sequence, e.g., as described in Table 6. In one embodiment, the anti-LAG-3 antibody molecule contains one or more CDR sequences (or collectively, all CDR sequences), a heavy chain or light chain variable region sequence, or a GSK2831781 heavy chain or light chain sequence.

In one embodiment, the anti-LAG-3 antibody molecule is IMP761 (Prima BioMed). In one embodiment, the anti-LAG-3 antibody molecule comprises one or more CDR sequences (or collectively, all CDR sequences), a heavy chain or light chain variable region sequence, or an IMP761 heavy chain or light chain sequence.

Other well-known anti-lag-3 antibodies include molecules described, for example, in WO 2008/132601, Wo 2010/019570, Wo 2014/140180, Wo 2015/16539, Wo 2015/200119, Wo 2016/028672, US Patent 9244059, US Pat. No. 9,505,839, incorporated by reference in its entirety.

In one embodiment, an anti-LAG-3 antibody is an antibody that competes for binding and/or binds to the same epitope on LAG-3 as one of the anti-LAG-3 antibodies described herein.

In one embodiment, the anti-LAG-3 inhibitor is a soluble LAG-3 protein, eg IMP321 (Prima BioMed), eg as described in WO 2009/044273, incorporated by reference in its entirety.

Preparations

The anti-LAG-3 antibody molecules described herein can be formulated into a formulation (eg, dosage form or dosage form) suitable for administration (eg, intravenous administration) to a subject as described herein. The formulation described herein may be a liquid formulation, a lyophilized formulation, or a diluted formulation.

In certain embodiments, the formulation is a liquid formulation. In some embodiments, the formulation (eg, liquid formulation) comprises an anti-LAG-3 antibody molecule (eg, an anti-LAG-3 antibody molecule described herein) and a buffering agent.

In some embodiments, the formulation (e.g., liquid formulation) comprises an anti-LAG-3 antibody molecule present at a concentration of 25 mg/mL to 250 mg/mL, such as 50 mg/mL to 200 mg/mL, 60 mg/mL to 180 mg/mL, 70 mg/mL to 150 mg/mL, 80 mg/mL to 120 mg/mL, 90 mg/mL to 110 mg/mL, 50 mg/mL to 150 mg /ml, 50 mg/ml to 100 mg/ml, 150 mg/ml to 200 mg/ml or 100 mg/ml to 200 mg/ml, e.g. at 50 mg/ml, 60 mg/ml, 70 mg/ml, 80 mg/ml, 90 mg/ml, 100 mg/ml, 110 mg/ml, 120 mg/ml, 130 mg/ml, 140 mg/ml or 150 mg/ml. In certain embodiments, an anti-LAG-3 antibody molecule present at a concentration of 80 mg/mL to 120 mg/mL, such as 100 mg/mL.

In some embodiments, the formulation (eg, liquid formulation) contains a buffering agent containing histidine (eg, a histidine buffer). In certain embodiments, the buffering agent (e.g., histidine buffer) is present at a concentration of 1 mM to 100 mM, e.g., 2 mM to 50 mM, 5 mM to 40 mM, 10 mM to 30 mM, 15 to 25 mM, 5 mM to 40 mM, 5 mM to 30 mM, 5 mM to 20 mM, 5 mM to 10 mM, 40 mM to 50 mM, 30 mM to 50 mM, 20 mM to 50 mM , 10 mM to 50 mM or 5 mM to 50 mM, e.g. at 2 mM, 5 mM, 10 mM, 15 mM, 20 mM, 25 mM, 30 mM, 35 mM, 40 mM, 45 mM or 50 mM . In some embodiments, the buffering agent (eg, histidine buffer) is present at a concentration of 15 mM to 25 mM, such as 20 mM. In other embodiments, the buffering agent (e.g., a histidine buffer) or formulation has a pH of 4 to 7, such as 5 to 6, such as 5, 5.5, or 6. In some embodiments, the buffering agent (e.g., a histidine buffer) or the preparation has a pH of 5 to 6, for example 5.5. In certain embodiments, the buffering agent contains a histidine buffer at a concentration of 15 mM to 25 mM (eg, at 20 mM) and has a pH of 5 to 6 (eg, 5.5). In certain embodiments, the buffering agent comprises histidine and histidine-HCl.

In some embodiments, the formulation (eg, liquid formulation) comprises an anti-LAG-3 antibody molecule present at a concentration of 80 to 120 mg/mL, eg, 100 mg/mL; and a buffering agent that contains a histidine buffer at a concentration of 15 mM to 25 mM (eg at 20 mM), at a pH of 5 to 6 (eg at 5.5).

In some embodiments, the formulation (eg, liquid formulation) further comprises a carbohydrate. In certain embodiments, the carbohydrate is sucrose. In some embodiments, the carbohydrate (e.g., sucrose) is present at a concentration of 50 mM to 500 mM, e.g., 100 mM to 400 mM, 150 mM to 300 mM, 180 mM to 250 mM, 200 mM to 240 mM 210 mM to 230 mM, 100 mM to 300 mM, 100 mM to 250 mM, 100 mM to 200 mM, 100 mM to 150 mM, 300 mM to 400 mM, 200 mM to 400 mM, or from 100 mM to 400 mM, for example at 100 mM, 150 mM, 180 mM, 200 mM, 220 mM, 250 mM, 300 mM, 350 mM or 400 mM. In some embodiments, the formulation contains a carbohydrate or sucrose present at a concentration of 200 mM to 250 mM, such as 220 mM.

In some embodiments, the formulation (eg, liquid formulation) comprises an anti-LAG-3 antibody molecule present at a concentration of 80 to 120 mg/mL, eg, 100 mg/mL; a buffering agent that contains a histidine buffer at a concentration of 15 mM to 25 mM (eg at 20 mM); and carbohydrate or sucrose present at a concentration of 200 mM to 250 mM, eg 220 mM, at a pH of 5 to 6 (eg 5.5).

In some embodiments, the formulation (eg, liquid formulation) further comprises a surfactant. In certain embodiments, the surfactant is polysorbate 20. In some embodiments, the surfactant or polysorbate 20) is present at a concentration of 0.005% to 0.1% (w/w), such as 0.01 % to 0.08%, from 0.02% to 0.06%, from 0.03% to 0.05%, from 0.01% to 0.06%, from 0.01% to 0.05% , 0.01% to 0.03%, 0.06% to 0.08%, 0.04% to 0.08% or 0.02% to 0.08% (w/w), e.g. at 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09% or 0, 1% (w/w). In some embodiments, the formulation contains a surfactant or polysorbate 20 present at a concentration of 0.03% to 0.05%, such as 0.04% (w/w).

In some embodiments, the formulation (eg, liquid formulation) comprises an anti-LAG-3 antibody molecule present at a concentration of 80 to 120 mg/mL, eg, 100 mg/mL; a buffering agent that contains a histidine buffer at a concentration of 15 mM to 25 mM (eg at 20 mM); carbohydrate or sucrose present at a concentration of 200 mM to 250 mM, for example at 220 mM; and a surfactant or polysorbate 20 present at a concentration of 0.03% to 0.05%, for example at 0.04% (w/w), at a pH of 5 to 6 (for example, at 5.5 ).

In some embodiments, the formulation (eg, liquid formulation) comprises an anti-LAG-3 antibody molecule present at a concentration of 100 mg/mL; a buffering agent that contains a histidine buffer (eg, histidine/histidine-HCl) at a concentration of 20 mM); carbohydrate or sucrose present at a concentration of 220 mM; and a surfactant or polysorbate 20 present at a concentration of 0.04% (w/w), at a pH of 5 to 6 (eg, 5.5).

The formulation described herein may be stored in a container. The container used for any of the formulations described herein may contain, for example, a vial, and optionally a stopper, a cap, or both. In certain embodiments, the vial is a failed glass vial, such as a 6R white glass vial. In other embodiments, the stopper is a rubber stopper, such as a gray rubber stopper. In other embodiments, the cap is a flip cap, such as an aluminum flip cap. In some embodiments, the container comprises a 6R white glass vial, a gray rubber stopper, and an aluminum flip cap. In some embodiments, the container (eg, vial) may be a disposable container. In certain embodiments, in a container (for example, vial) present, 25 mg/mL to 250 mg/mL, e.g. 50 mg/mL to 200 mg/mL, 60 mg/mL to 180 mg/mL, 70 mg/mL to 150 mg/mL , 80 mg/ml to 120 mg/ml, 90 mg/ml to 110 mg/ml, 50 mg/ml to 150 mg/ml, 50 mg/ml to 100 mg/ml, 150 mg/ml up to 200 mg/ml or 100 mg/ml to 200 mg/ml, e.g. 50 mg/ml, 60 mg/ml, 70 mg/ml, 80 mg/ml, 90 mg/ml, 100 mg/ml, 110 mg/ml, 120 mg/ml, 130 mg/ml, 140 mg/ml or 150 mg/ml anti-LAG-3 antibody molecules.

In another aspect, the invention describes therapeutic kits that contain anti-LAG-3 antibody molecules, compositions or preparations described herein, and instructions for use, for example, according to the dosing regimens described herein.

Therapeutic use

The anti-LAG-3 antibody molecules described herein can slow down, decrease or neutralize one or more LAG-3 activities, resulting in blockade or decrease in immune checkpoint expression. Thus, the anti-LAG-3 antibody molecules described herein can be used to treat or prevent a disorder (eg, cancer) when it is desired to enhance an immune response in a subject.

Accordingly, in another aspect, the method provides modulation of an immune response in a subject. The method includes administering to a subject an anti-LAG-3 antibody molecule described herein, according to the dosing regimen described herein, alone or in combination with one or more therapeutic agents, procedures, or treatments, such that the subject's immune response is modulated. . In one embodiment, the antibody molecules enhance, stimulate, or enhance an immune response in a subject. The subject may be a mammal, eg a primate, preferably a higher primate, eg a human (eg, a patient having the disorder described herein, or at risk for it). In one embodiment, the subject is in need of an enhanced immune response. In one embodiment, the subject has or is at risk for the disorder described herein, such as a cancer or infectious disorder as described herein. In certain embodiments, the subject is immunocompromised or at risk of developing it. For example, the subject is or should be undergoing chemotherapy treatment and/or radiation therapy. Alternatively, or in combination, the subject is immunocompromised, or at risk of developing it, as a result of infection.

In one aspect, a method is provided for treating (eg, one or more of reducing, slowing, or delaying the development of) a cancer or tumor in a subject. The method includes administering to a subject an anti-LAG-3 antibody molecule described herein according to the dosing regimen described herein, alone or in combination with one or more therapeutic agents, procedures, or treatments.

In certain embodiments, a cancer treatable with an anti-LAG-3 antibody molecule includes, but is not limited to, solid tumor, hematologic cancer (e.g., leukemia, lymphoma, myeloma, e.g., multiple myeloma), and metastatic disease. . In one embodiment, the cancer is a solid tumor. Examples of solid tumors include malignant neoplasms such as sarcomas and carcinomas such as adenocarcinomas of various organ systems such as those affecting the lungs, breast, ovaries, lymphatic organs, gastrointestinal tract (eg colon), rectum , genitals, and genitourinary tract (eg, kidney, urothelial cells, bladder cells, prostate), larynx, CNS (eg, brain, neural or glial cells), head and neck, skin (eg, melanoma), and pancreas and adenocarcinomas, which include malignancies such as colon cancer, rectal cancer, kidney cancer (eg, renal cell carcinoma (clear cell or non-clear cell renal cell carcinoma)), liver cancer, lung cancer (eg, non-small cell lung cancer (squamous or non-squamous non-small cell lung cancer), small intestine cancer, and esophageal cancer. The cancer may be early, intermediate, late stage or metastatic cancer.

In one embodiment, the cancer is selected from lung cancer (e.g., non-small cell lung cancer (NSCLC) (e.g., NSCLC with squamous and/or non-squamous histology or NSCLC adenocarcinoma) or small cell lung cancer (SCLC)), skin cancer (e.g., Merkel cell carcinoma or melanoma (for example, progressive melanoma)), ovarian cancer, mesothelioma, bladder cancer, soft tissue sarcoma (for example, hemangiopericytoma (HPC)), bone cancer (bone sarcoma), kidney cancer (for example, kidney cancer (for example , renal cell carcinoma)), liver cancer (eg, hepatocellular carcinoma), cholangiocarcinoma, sarcoma, myelodysplastic syndrome (MDS), prostate cancer, breast cancer (eg, breast cancer that does not express one, two, or all of the receptors from the estrogen receptor , progesterone receptor, or Her2/neu, such as triple-negative breast cancer), colorectal cancer, nasopharyngeal cancer, duodenal cancer, endometrial cancer, pancreatic cancer, head and neck cancer (eg, head and neck squamous cell carcinoma ( HNSCC)), anal cancer, gastroesophageal junction cancer, thyroid cancer (eg, anaplastic thyroid carcinoma), cervical cancer, neuroendocrine tumor (NET) (eg, atypical pulmonary carcinoid tumour), lymphoproliferative disease (eg, post-transplant lymphoproliferative disease), lymphoma (eg, T-cell lymphoma, B-cell lymphoma, or non-Hodgkin's lymphoma), myeloma (eg, multiple myeloma), or leukemia (eg, myeloid leukemia or lymphoid leukemia).

In certain embodiments, the cancer is a solid tumor. In some embodiments, the cancer is a brain tumor, such as glioblastoma, gliosarcoma, or a recurrent brain tumor. In some embodiments, the cancer is pancreatic cancer, such as advanced pancreatic cancer. In some embodiments, the cancer is a skin cancer, such as melanoma (eg, stage II-IV melanoma, HLA-A2 positive melanoma, unresectable melanoma, or metastatic melanoma) or Merkel cell carcinoma. In some embodiments, the cancer is a kidney cancer, such as renal cell carcinoma (RCC) (eg, metastatic renal cell carcinoma). In some embodiments, the cancer is breast cancer, such as metastatic breast carcinoma or stage IV breast carcinoma, such as triple negative breast cancer (TNBC). In some embodiments, the cancer is a virus-associated cancer. In some embodiments, the cancer is anal cancer (eg, anal squamous cell carcinoma). In some embodiments, the cancer is cervical cancer (eg, squamous cell carcinoma of the cervix). In some embodiments, the cancer is gastrointestinal cancer (eg, Epstein-Barr virus positive gastrointestinal cancer or gastrointestinal or gastroesophageal junction carcinoma). In some embodiments, the cancer is a head and neck cancer (eg, HPV positive and squam cell cancer of the head and neck (SCCHN)). In some embodiments, the cancer is nasopharyngeal cancer (NPC). In some embodiments, the cancer is a cancer of the penis (eg, squamous cell carcinoma of the penis). In some embodiments, the cancer is a vaginal or vulvar cancer (eg, squamous cell carcinoma of the vagina or vulva). In some embodiments, the cancer is colon and rectal cancer, e.g., recurrent colon and rectal cancer or metastatic colon and rectal cancer, e.g., microsatellite unstable colon and rectal cancer, microsatellite stable colon and rectal cancer, colon and rectal cancer surplus for mispair repair or colon and rectal cancer deficient for mispair repair. In some embodiments, the cancer is lung cancer, such as non-small cell lung cancer (NSCLC).

In certain embodiments, the cancer is a hematologic cancer. In some embodiments, the cancer is leukemia. In some embodiments, the cancer is a lymphoma, such as Hodgkin's lymphoma (HL) or diffuse large B cell lymphoma (DLBCL) (eg, recurrent or refractory HL or DLBCL). In some embodiments, the cancer is a myeloma.

In another embodiment, the cancer is selected from carcinoma (eg, advanced or metastatic carcinoma), melanoma, or lung carcinoma, eg, non-small cell lung carcinoma. In one embodiment, the cancer is lung cancer, such as non-small cell lung cancer or small cell lung cancer. In some embodiments, the non-small cell lung cancer is stage I (e.g., stages Ia or Ib), stage II (e.g., stage IIa or IIb), stage III (e.g., stage IIIa or IIIb), or stage IV non-small cell lung cancer. In one embodiment, the cancer is a melanoma, such as advanced melanoma. In one embodiment, the cancer is a progressive or unresectable melanoma that has not responded to other therapies. In other embodiments, the cancer is a BRAF-mutated melanoma (eg, BRAF V600 mutation). In another embodiment, the cancer is a hepatocarcinoma, eg, progressive hepatocarcinoma, with or without viral infection, eg, chronic viral hepatitis. In another embodiment, the cancer is prostate cancer, such as advanced prostate cancer. In yet another embodiment, the cancer is a myeloma, such as multiple myeloma. In yet another embodiment, the cancer is a kidney cancer, eg, renal cell carcinoma (RCC) (eg, metastatic RCC, non-clear cell renal cell carcinoma (nccRCC), or clear cell renal cell carcinoma (CCRCC)).

In one embodiment, the cancerous microenvironment has an increased level of LAG-3 expression. In one embodiment, the cancerous microenvironment has an increased level of PD-L1 expression. Alternatively, or in combination with this, the cancerous microenvironment may have increased expression of IFNγ and/or CD8.

In some embodiments, the subject has or is identified as having a tumor that has one or more of the factors of high level or expression of PD-L1 or as a tumor infiltrating lymphocyte (TIL)+ (e.g., as having an increased amount of TIL) or as so and so on. In certain embodiments, the subject has or is identified as having a tumor that has a high level or expression of PD-L1 and that is TIL+. In some embodiments, the methods described herein further comprise identifying a subject for the presence of a tumor that has one or more of the factors of high levels or expression of PD-L1, or is TIL+, or both. In certain embodiments, the methods described herein further comprise identifying a subject for the presence of a tumor that is high in or expressing PD-L1 and is TIL+. In some embodiments, tumors that are TIL+ are positive for CD8 and IFNγ. In some embodiments, the subject has or is identified as having a high percentage of cells that are positive for one, two or more of PD-L1, CD8, and/or IFNγ. In certain embodiments, the subject has or is identified as having a high percentage of cells that are positive for all PD-L1, CD8, and IFNγ proteins.

In some embodiments, the methods described herein further include identifying a subject for having a high percentage of cells that are positive for one, two or more of PD-L1, CD8, and/or IFNγ proteins. In certain embodiments, the methods described herein further include identifying a subject for the presence of a high percentage of cells that are positive for all of PD-L1, CD8, and IFNγ proteins. In some embodiments, the subject has or is identified as having one, two or more of PD-L1, CD8, and/or IFNγ, and one or more lung cancer diseases, e.g., squamous cell lung cancer or adenocarcinoma of the lung (e.g., NSCLC) ; head and neck cancer; squam cell cancer of the cervix; stomach cancer; esophageal cancer; thyroid cancer (eg, anaplastic thyroid carcinoma); skin cancer (eg Merkel cell carcinoma or melanoma), breast cancer (eg TNBC) and/or nasopharyngeal cancer (NPC). In certain embodiments, the methods described herein further describe identifying a subject with respect to the presence of one, two, or more of PD-L1, CD8, and/or IFNγ, and one or more lung cancer diseases, e.g., squamous cell lung cancer. or lung adenocarcinomas (eg, NSCLC); head and neck cancer; squam cell cancer of the cervix; stomach cancer; thyroid cancer (eg, anaplastic thyroid carcinoma); skin cancer (eg Merkel cell carcinoma or melanoma), neuroendocrine tumor, breast cancer (eg TNBC) and/or nasopharyngeal cancer.

The methods, compositions and formulations described herein are useful in the treatment of metastatic lesions associated with the cancers discussed above.

In another aspect, the invention provides a method of treating an infectious disease (e.g., the infectious disease described herein) in a subject, comprising administering to the subject an anti-LAG-3 antibody molecule described herein according to the dosage regimen described herein.

In addition, the present invention provides a method for enhancing an immune response to an antigen in a subject, comprising administering to the subject: (i) an antigen; and (ii) an anti-LAG-3 antibody molecule described herein according to the dosing regimen described herein such that the subject's immune response to the antigen is enhanced. The antigen may be, for example, a tumor antigen, a viral antigen, a bacterial antigen, or an antigen from a pathogen.

The anti-LAG-3 antibody molecule described herein may be administered to a subject systemically (e.g., orally, parenterally, subcutaneously, intravenously, rectally, intramuscularly, intraperitoneally, intranasally, transdermally, or by inhalation or intracavitary installation), topically, or by application. on mucous membranes, for example, in the nose, pharynx and bronchi. In certain embodiments, the anti-LAG-3 antibody molecule is administered intravenously at the base dose described herein.

Combination therapy

The anti-LAG-3 antibody molecules described herein may be used in combination with other therapeutic agents, procedures, or interventions.

In one embodiment, the methods described herein comprise administering to a subject a combination comprising an anti-LAG-3 antibody molecule described herein in combination with a therapeutic agent, procedure, or treatment, in an amount effective to treat or prevent disorders. In certain embodiments, the anti-LAG-3 antibody molecule is administered or administered according to the dosing regimen described herein. In other embodiments, the antibody molecule is administered or used as a composition or formulation as described herein.

The anti-LAG-3 antibody molecule and the therapeutic agent, procedure or treatment may be administered or administered simultaneously or sequentially in any order. Any combination and sequence of anti-LAG-3 antibody molecules and therapeutic agent, procedure, or treatment may be used (eg, as described herein). The antibody molecule and/or therapeutic agent, procedure or treatment may be administered or administered during periods of active disorder or during periods of remission or less active disease. The antibody molecule may be administered before, concurrently with, or after treatment with the therapeutic agent of a procedure or treatment.

In certain embodiments, an anti-LAG-3 antibody molecule described herein is administered in combination with one or more other antibody molecules, chemotherapy, another cancer therapy (e.g., targeted cancer therapy, gene therapy, viral therapy, RNA therapy , bone marrow transplant, nanotherapy, or oncolytic drugs), cytotoxic agents, immune-based therapy (eg, cytokine-based immune therapy or cellular immune therapy), surgical procedures (eg, lumpectomy or mastectomy), or radiation procedures, or a combination of any the procedures discussed above. Additional therapy may be in the form of supportive or neoadjuvant therapy. In some embodiments, the additional therapy is an enzymatic inhibitor (eg, a small molecule enzymatic inhibitor) or a metastatic inhibitor. Illustrative cytotoxic agents that can be administered in combination include anti-microtubule formation agents, topoisomerase inhibitors, antimetabolites, mitotic inhibitors, alkylating agents, anthracyclines, vinca alkaloids, intercalating agents, agents capable of interfering with signaling pathways, agents that promote apoptosis, proteasome inhibitors and radiation (eg local exposure or whole body exposure (eg gamma radiation)). In other embodiments, the additional therapy is surgery or radiation, or a combination thereof. In other embodiments, the adjunctive therapy is a therapy that targets one or more of the PI3K/AKT/mTOR pathway, an HSP90 inhibitor, or a tubulin inhibitor.

Alternatively, or in combination with the above combinations, an anti-LAG-3 antibody described herein may be administered or used in combination with one or more of: an immunomodulator (e.g., an activator of costimulatory an inhibitor molecule or an inhibitor molecule, eg an immune checkpoint molecule); vaccines, for example a therapeutic cancer vaccine; or other forms of cellular immunotherapy.

In certain embodiments, an anti-LAG-3 molecule described herein is administered or used in combination with a modulator of a co-stimulatory molecule or an inhibitory molecule, such as a co-inhibitory ligand or receptor.

In one embodiment, the anti-LAG-3 antibody molecule described herein is administered or used in combination with a modulator, such as an agonist, of a co-stimulatory molecule. In one embodiment, the agonist of the costimulatory molecule is selected from an agonist (e.g., an agonist antibody or antigen-binding fragment thereof, or a fusion protein in solution) ligand OX40, CD2, CD27, CDS, ICAM-1, LFA-1 (CD11a/CD18 ), ICOS (CD278), 4-1BB (CD137), GITR, CD30, CD40, BAFFR, HVEM, CD7, LIGHT, NKG2C, SLAMF7, NKp80, CD160, B7-H3, or an anti-CD83 ligand.

In another embodiment, an anti-LAG-3 antibody molecule described herein is administered or used in combination with a GITR agonist, such as an anti-GITR antibody molecule.

In one embodiment, an anti-LAG-3 antibody molecule described herein is administered or used in combination with an inhibitor of an inhibitory molecule (or immune checkpoint molecule) selected from PD-1, PD-L1, PD-L2, CTLA-4, TIM-3, LAG-3, CEACAM (eg, CEACAM-1, CEACAM-3, and/or CEACAM-5), VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4, and/or TGF beta. In one embodiment, the inhibitor is a soluble ligand (eg, CTLA-4-Ig) or an antibody or antibody fragment that binds to PD-1, LAG-3, PD-L1, PD-L2, or CTLA-4.

In another embodiment, an anti-LAG-3 antibody molecule described herein is administered or used in combination with a PD-1 inhibitor, such as an anti-PD-1 antibody molecule. In another embodiment, an anti-LAG-3 antibody molecule described herein is administered or used in combination with a TIM-3 inhibitor, such as an anti-TIM-3 antibody molecule. In another embodiment, an anti-LAG-3 antibody molecule described herein is administered or used in combination with a PD-L1 inhibitor, eg, an anti-PD-L1 antibody molecule.

In another embodiment, the anti-LAG-3 antibody molecule described herein is administered or used in combination with a chemotherapeutic agent. In certain embodiments, the chemotherapeutic agent contains a platinum agent (eg, carboplatin, cisplatin, oxaliplatin, or tetraplatin). In certain embodiments, the chemotherapeutic agent comprises cisplatin, permetrexed, or both. Cisplatin is also known as cisplatin, platinum, neoplatin, cismaplat, or cis-diammine dichloroplatin (II) (CDDP). Permetrexed is also known as (S)-2-(4-(2-(2-amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl)benzamido ) glutaric acid. In certain embodiments, the chemotherapeutic agent comprises a nucleotide analog or precursor analog (e.g., capecitabine, azacitidine, azathioprine, cytarabine, doxyfluridine, fluorouracil, gemcitabine, hydroxyurea, mercaptopurine, methotrexate, or thioguanine (phyoguanine)). In certain embodiments, the chemotherapeutic agent contains a hypomethylating agent (eg, decitabine). In one embodiment, the chemotherapeutic agent contains nab-paclitaxel.

Other exemplary chemotherapeutic agents that can be used in combination with an anti-LAG-3 antibody molecule include, but are not limited to, an alkylating agent (e.g., a bifunctional alkylator (e.g., cyclophosphamide, mechlorethamine, chlorambucil, or melphalan)), a monofunctional alkylator ( eg, dacarbazine (DTIC), nitrosourea or temozolomide (oral dacarbazine)), anthracycline (eg, daunorubicin, doxorubicin, epirubicin, idarubicin, mitoxantrone, or valrubicin), cytoskeletal disruptor or taxane (eg, paclitaxel, docetaxel, abraxane, or taxotere), epothilone , a histone deacetylase inhibitor ( eg, vorinostat or romidespin), a topoisomerase I inhibitor (eg, irinotecan or topotecan), a topoisomerase II inhibitor ( eg, etoposide, teniposide, or tafluposide), a kinase inhibitor (eg, bortezomib, erlotinib, gefitinib, imatinib, vemurafenib or vismodegib), a peptide antibiotic (such as bleomycin or actinomycin), a retinoid (such as tretitnoin, alitretinoin, or bexarotene), or a vinca alkaloid or derivative (such as vinblastine, vincristine, vindesine, or vinorelbine).

In another embodiment, an anti-LAG-3 antibody molecule described herein is administered or used in combination with a PD-1 inhibitor (e.g., an anti-PD-1 antibody molecule) and a TIM-3 inhibitor (e.g., an anti-PD-1 antibody molecule). -TIM-3). In another embodiment, an anti-LAG-3 antibody molecule described herein is administered or used in combination with a PD-1 inhibitor (e.g., an anti-PD-1 antibody molecule) and a PD-L1 inhibitor (e.g., an anti-PD-1 antibody molecule). -PD-L1). In another embodiment, an anti-LAG-3 antibody molecule described herein is administered or used in combination with a TIM-3 inhibitor (e.g., an anti-TIM-3 antibody molecule) and a PD-L1 inhibitor (e.g., an anti-TIM-3 antibody molecule). -PD-L1). In another embodiment, an anti-LAG-3 antibody molecule described herein is administered or used in combination with a PD-1 inhibitor (e.g., an anti-PD-1 antibody molecule) and a chemotherapeutic agent (e.g., a platinum agent (e.g., carboplatin, cisplatin, oxaliplatin or tetraplatin) or a nucleotide analog or precursor analog (e.g. capecitabine)). In another embodiment, an anti-LAG-3 antibody molecule described herein is administered or used in combination with a CEACAM inhibitor (e.g., a CEACAM-1, CEACAM-3, and/or CEACAM-5 inhibitor), e.g., an anti-LAG-3 antibody molecule. -CEACAM. In another embodiment, an anti-LAG-3 antibody molecule is administered or used in combination with a CEACAM-1 inhibitor, such as an anti-CEACAM-1 antibody molecule. In another embodiment, an anti-LAG-3 antibody molecule is administered or used in combination with a CEACAM-3 inhibitor, such as an anti-CEACAM-3 antibody molecule. In another embodiment, an anti-LAG-3 antibody molecule is administered or used in combination with a CEACAM-5 inhibitor, such as an anti-CEACAM-5 antibody molecule.

The combination of antibody molecules described in the present invention may be administered individually, eg as single antibody molecules, or linked, eg as a bispecific or trispecific antibody molecule. In one embodiment, a bispecific antibody is administered that comprises an anti-LAG-3 antibody molecule and an anti-PD-1, anti-CEACAM antibody molecule (e.g., anti-CEACAM-1, CEACAM-3 and/or anti-CEACAM- 5), anti-PD-L1 or anti-TIM-3. In certain embodiments, the antibody combination described herein is used to treat a cancer, eg, cancer as described herein (eg, solid tumor or hematologic malignancy).

In another embodiment, an anti-LAG-3 antibody molecule is administered or used in combination with an anti-PD-1 antibody molecule, e.g., for the treatment of brain cancer (e.g., glioblastoma), melanoma, kidney cancer (e.g., renal cell carcinoma), viral cancer (eg, anal cancer, cervical cancer, gastrointestinal cancer, head and neck cancer, nasopharyngeal (NPC) cancer, penis or vaginal or vulvar cancer), colon and rectal cancer, or lung cancer (eg, non-small cell cancer lung (NSCLC)). In certain embodiments, an anti-LAG-3 antibody molecule is administered or used in combination with an anti-PD-1 antibody molecule, for example, to treat breast cancer, such as triple negative breast cancer (TNBC).

In another embodiment, an anti-LAG-3 antibody molecule is administered or used in combination with a chemotherapeutic agent (e.g., gemcitabine, paclitaxel, e.g., for the treatment of pancreatic cancer or breast cancer.

In another embodiment, an anti-LAG-3 antibody molecule is administered or used in combination with a chemotherapeutic agent (e.g., a platinum agent (e.g., carboplatin, cisplatin, oxaliplatin, or tetraplatin) or a nucleotide analog or precursor analog (e.g., capecitabine)), e.g. , for the treatment of breast cancer, such as TNBC. In certain embodiments, an anti-LAG-3 antibody molecule is administered or used in combination with an anti-PD-1 antibody molecule and a chemotherapeutic agent (e.g., a platinum agent (e.g., carboplatin, cisplatin, oxaliplatin, or tetraplatin) or a nucleotide analog or precursor analog (eg capecitabine)), eg for the treatment of breast cancer, eg TNBC. In other embodiments, an anti-LAG-3 antibody molecule is administered or used in combination with a cytokine. The cytokine can be administered as a fusion molecule with an anti-LAG-3 antibody molecule or as separate compositions. In other embodiments, the anti-LAG-3 antibody molecule is administered or used in combination with one, two, three or more cytokines, eg, as a fusion molecule or as separate compositions. In one embodiment, the cytokine is an interleukin (IL) selected from one, two, three or more of IL-1, IL-2, IL-12, IL-15, or IL-21. In one embodiment, the bispecific antibody molecule has a first binding specificity for a first target (e.g., LAG-3), a second binding specificity for a second target (e.g., PD-1, TIM-3, or PD-L1), and optionally binds to an interleukin domain (for example, IL-12), for example, with full-length IL-12 or its part. In certain embodiments, the combination of an anti-LAG-3 antibody molecule and a cytokine described herein is used to treat a cancer, eg a cancer as described herein (eg a solid tumor).

In other embodiments, an anti-LAG-3 antibody molecule is administered or used in combination with an antibody specific for HLA C, for example, an antibody specific for killer cell immunoglobulin-like receptors (also referred to herein as an “anti-KIR antibody”) . In certain embodiments, the combination of an anti-LAG-3 antibody molecule and an anti-KIR antibody is used to treat cancer, eg, cancer as described herein (eg, solid tumor, eg, progressive solid tumor).

In other embodiments, the anti-LAG-3 antibody molecule is administered or used in combination with cellular immunotherapy (eg, PROVENGE® (eg, Sipuleucel-T)) and optionally in combination with cyclophosphamide. In certain embodiments, the combination of an anti-LAG-3 antibody molecule, PROVENGE®, and/or cyclophosphamide is used to treat a cancer, eg, cancer as described herein (eg, prostate cancer, eg, advanced prostate cancer).

In other embodiments, an anti-LAG-3 antibody molecule is administered or used in combination with a vaccine, eg, a cancer vaccine (eg, a dendritic renal cell carcinoma (DC-RCC) vaccine). In one embodiment, the vaccine has a peptide backbone, a DNA backbone, an RNA backbone, or an antigenic backbone, or a combination thereof. In some embodiments, the vaccine contains one or more peptides, nucleic acids (eg, DNA or RNA), antigens, or a combination thereof. In certain embodiments, the combination of an anti-TIM-3 antibody molecule and a DC-RCC vaccine is used to treat a cancer, e.g., cancer as described herein (e.g., renal cell carcinoma, e.g., metastatic renal cell carcinoma (RCC) or clear cell renal cell carcinoma). carcinomas (CCRCC)).

In other embodiments, an anti-LAG-3 antibody molecule is administered or used in combination with an excipient.

In other embodiments, an anti-LAG-3 antibody molecule is administered or used in combination with chemotherapy and/or immunotherapy. For example, an anti-LAG-3 antibody molecule can be used to treat myeloma alone or in combination with one or more of: chemotherapy or other anti-cancer agents (e.g., thalidomide analogs, e.g., lenalidomide), anti-PD-1 antibody molecules , tumor antigen-sensitized dendritic cells, fusion products (eg, electrofusion) of tumor cells and dendritic cells, or vaccination with an immunoglobulin idiotype produced by plasma malignant cells. In other embodiments, an anti-LAG-3 antibody molecule is administered or used in combination with an anti-PD-1 antibody molecule to treat myeloma, eg, multiple myeloma.

In other embodiments, an anti-LAG-3 antibody molecule is administered or used in combination with chemotherapy to treat lung cancer, eg, non-small cell lung cancer. In other embodiments, the anti-LAG-3 antibody molecule is administered or administered in standard, eg, NSCLC, lung chemotherapy, eg, platinum doublet therapy for the treatment of lung cancer. In other embodiments, an anti-LAG-3 antibody molecule is administered or used in combination with an indolamine-pyrrole 2,3-dioxygenase (IDO) inhibitor (e.g., (4E)-4-[(3-chloro-4-fluoroanilino)- nitrosomethylidene]-1,2,5-oxadiazol-3-amine (also known as INCB24360), indoxymod (1-methyl-D-tryptophan), α-cyclohexyl-5H-imidazo[5,1-a]isoindole-5- ethanol (also known as NLG919) and the like) in a subject with advanced or metastatic cancer (eg, a patient with metastatic and recurrent NSCL cancer).

In other embodiments, an anti-LAG-3 antibody molecule is administered or used in combination with one or more of: an immune strategy (eg, interleukin-2 or interferon-α), a target agent (eg, a VEGF inhibitor such as a monoclonal antibody on VEGF); a VEGF tyrosine kinase inhibitor such as sunitinib, sorafenib, axitinib and pazopanib; an RNAi inhibitor; or an inhibitor of the late mediator of VEGF signaling, eg, the mammalian target inhibitor of rapamycin (mTOR), eg, everolimus and temsirolimus. Any of these combinations can be used to treat kidney cancer, eg, renal cell carcinoma (RCC) (eg, clear cell renal cell carcinoma (CCRCC) or non-clear cell renal cell carcinoma (nccRCC) or metastatic RCC) or liver cancer (eg, hepatocellular carcinoma).

In other embodiments, an anti-LAG-3 antibody molecule is administered or used in combination with a MEK inhibitor (eg, a MEK inhibitor as described herein). In some embodiments, the combination of an anti-LAG-3 antibody molecule and a MEK inhibitor is used to treat a cancer (eg, the cancer described herein). In some embodiments, the cancer treatable with this combination is selected from melanoma, colorectal cancer, non-small cell lung cancer, ovarian cancer, breast cancer, prostate cancer, pancreatic cancer, hematologic malignancy, or renal cell carcinoma. In certain embodiments, the cancer comprises a BRAF mutation (eg, a BRAF V600E mutation), wild-type BRAF, wild-type KRAS, or an activating KRAS mutation. The cancer may be early, intermediate or late stage.

In other embodiments, an anti-LAG-3 antibody molecule is administered or administered in combination with one, two, or all of the chemotherapeutic agents (e.g., a platinum agent (e.g., carboplatin, oxaliplatin, cisplatin, or tetraplatin) or a nucleotide analog or precursor analog (e.g., capecitabine)), leucovorin, or 5-FU (e.g. in co-treatment with FOLFOX). Alternatively, or in combination, this combination further comprises a VEGF inhibitor (eg, a VEGF inhibitor as described herein). In some embodiments, the combination of an anti-LAG-3 antibody molecule, a FOLFOX co-treatment, and a VEGF inhibitor is used to treat a cancer (eg, the cancer described herein). In some embodiments, the cancer treatable with this combination is selected from melanoma, colorectal cancer, non-small cell lung cancer, ovarian cancer, breast cancer, prostate cancer, pancreatic cancer, hematologic malignancy, or renal cell carcinoma. The cancer may be early, intermediate or late stage.

In other embodiments, an anti-LAG-3 antibody molecule is administered or used in conjunction with a tyrosine kinase inhibitor (eg, axitinib) to treat renal cell carcinoma and other solid tumors.

In other embodiments, an anti-LAG-3 antibody molecule is administered or administered in conjunction with an agent that targets the 4-1BB receptor (e.g., an antibody that stimulates signaling through the 4-1BB (CD-137), e.g., PF-2566 ). In other embodiments, an anti-TIM-3 antibody molecule is administered or used in combination with a tyrosine kinase inhibitor (eg, axitinib) and an agent that targets the 4-1BB receptor.

An anti-LAG-3 antibody molecule can bind to a substance, such as a cytotoxic agent or residue (eg, a therapeutic drug; a radiation-emitting compound; molecules of plant, fungal, or bacterial origin; or a biological protein (eg, a protein toxin ) or to a particle (eg, a recombinant virus particle, eg, via the protein coat of the virus.) For example, an antibody can bind to a radioactive isotope, such as an α-, β-, or γ-source, or a β- and γ-source.

Immunomodulators

The anti-LAG-3 antibody molecules described herein can be used in combination with one or more immunomodulators.

In certain embodiments, the immunomodulator is an inhibitor of an immune checkpoint molecule. In one embodiment, the immunomodulator is an inhibitor of PD-1, PD-L1, PD-L2, CTLA-4, TIM-3, CEACAM (e.g. CEACAM-1, -3 and/or -5), VISTA, BTLA , TIGIT, LAIR1, CD160, 2B4 and/or TGF beta. In one embodiment, the immune checkpoint molecule inhibitor inhibits PD-1, PD-L1, TIM-3, CEACAM (eg, CEACAM-1, -3 and/or -5), CTLA-4, or any combination thereof.

Inhibition of an inhibitory molecule can be at the DNA, RNA or protein level. In embodiments, an inhibitory nucleic acid (eg, dsRNA, siRNA, or shRNA) can be used to slow the expression of an inhibitory molecule. In other embodiments, the inhibitor of the inhibitory signal is a polypeptide, such as a soluble ligand (eg, PD-1-Ig or CTLA-4 Ig) or an antibody molecule that binds to the inhibitory molecule; for example, it is an antibody molecule that binds to PD-1, PD-L1, PD-L2, CEACAM (e.g. CEACAM-1, -3 and/or -5), CTLA-4, TIM-3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4 and/or TGF beta, or a combination thereof.

In certain embodiments, the anti-LAG-3 antibody molecule is in the form of a bispecific or multispecific antibody molecule. In one embodiment, the bispecific antibody molecule has a first binding specificity for LAG-3 and a second binding specificity, e.g., a second binding specificity for PD-1, PD-L1, CEACAM (e.g., CEACAM-1, -3 and/or - 5), TIM-3 or PD-L2. In one embodiment, the bispecific antibody molecule binds (i) to PD-1 or PD-L1 (ii) and to LAG-3. In another embodiment, the bispecific antibody molecule binds to LAG-3 and TIM-3. In another embodiment, the bispecific antibody molecule binds to LAG-3 and CEACAM (eg, CEACAM-1, -3 and/or -5). In another embodiment, the bispecific antibody molecule binds to LAG-3 and CEACAM-1. In yet another embodiment, the bispecific antibody molecule binds to LAG-3 and CEACAM-3. In yet another embodiment, the bispecific antibody molecule binds to LAG-3 and CEACAM-5.

In other embodiments, an anti-LAG-3 antibody molecule is used in combination with a bispecific or multispecific antibody molecule. In another embodiment, the bispecific antibody molecule binds to PD-1 or PD-L1. In yet another embodiment, the bispecific antibody molecule binds to PD-1 and PD-L2. In another embodiment, the bispecific antibody molecule binds to CEACAM (eg, CEACAM-1, -3 and/or -5) and TIM-3.

Any combination of the above molecules can be converted into a multispecific antibody molecule, e.g. a trispecific antibody that has a first binding specificity for LAG-3 and a second and third binding specificity for two or more of: PD-1, PD-L1, CEACAM ( for example with CEACAM-1, -3 and/or -5), TIM-3 or PD-L2.

In certain embodiments, the immunomodulator is a PD-1 inhibitor, such as human PD-1. In another embodiment, the immunomodulator is a PD-L1 inhibitor, eg, human PD-L1. In one embodiment, the PD-1 or PD-L1 inhibitor is an anti-PD-1 or PD-L1 antibody molecule (eg, an anti-PD-1 or anti-PD-L1 antibody molecule as described herein).

The combination of a PD-1 or PD-L1 inhibitor with an anti-LAG-3 antibody molecule may further comprise one or more additional immunomodulators, for example in combination with a TIM-3 inhibitor, CEACAM (e.g., CEACAM-1, -3 and/or - 5) or CTLA-4. In one embodiment, a PD-1 or PD-L1 inhibitor (e.g., an anti-PD-1 or anti-PD-L1 antibody molecule) is administered in combination with an anti-LAG-3 antibody molecule and a TIM-3 inhibitor (e.g., anti-TIM-3 antibody molecule). In another embodiment, a PD-1 or PD-L1 inhibitor (e.g., an anti-PD-1 or anti-PD-L1 antibody molecule) is administered in combination with an anti-LAG-3 antibody molecule and a CEACAM inhibitor (e.g., a CEACAM- 1, -3 and/or -5), for example, an anti-CEACAM antibody molecule. In another embodiment, a PD-1 or PD-L1 inhibitor (e.g., an anti-PD-1 or anti-PD-L1 antibody molecule) is administered in combination with an anti-LAG-3 antibody molecule and a CEACAM-1 inhibitor (e.g., a anti-CEACAM-1 antibodies). In another embodiment, a PD-1 or PD-L1 inhibitor (e.g., an anti-PD-1 or anti-PD-L1 antibody molecule) is administered in combination with an anti-LAG-3 antibody molecule and a CEACAM-5 inhibitor (e.g., a anti-CEACAM-5 antibodies). In yet another embodiment, a PD-1 or PD-L1 inhibitor (e.g., an anti-PD-1 or anti-PD-L1 antibody molecule) is administered in combination with an anti-LAG-3 antibody molecule and a TIM-3 inhibitor (e.g., , an anti-TIM-3 antibody molecule). Other combinations of immunomodulators with an anti-LAG-3 antibody molecule and a PD-1 inhibitor including, for example, one or more of PD-L2, CTLA-4, LAG-3, CEACAM (e.g., CEACAM-1, -3 and/or - 5), VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4 and/or TGF beta) are also covered by the present invention. Any of the antibody molecules known in the art or described in the present invention can be used in the above combinations of checkpoint inhibitor molecules.

In other embodiments, the immunomodulator is an inhibitor of CEACAM (eg CEACAM-1, -3 and/or -5), eg human CEACAM (eg CEACAM-1, -3 and/or -5). In one embodiment, the immunomodulator is a CEACAM-1 inhibitor, such as human CEACAM-1. In another embodiment, the immunomodulator is a CEACAM-3 inhibitor, eg human CEACAM-3. In another embodiment, the immunomodulator is a CEACAM-5 inhibitor, such as human CEACAM-5. In one embodiment, the CEACAM inhibitor (eg CEACAM-1, -3 and/or -5) is an anti-CEACAM antibody molecule (eg CEACAM-1, -3 and/or -5). The combination of a CEACAM (e.g. CEACAM-1, -3 and/or -5) inhibitor and an anti-LAG-3 antibody molecule may further comprise one or more additional immunomodulators, e.g. in combination with a TIM-3 inhibitor, PD-1, PD -L1 or CTLA-4.

In other embodiments, the immunomodulator is an inhibitor of TIM-3, such as human TIM-3. In one embodiment, the TIM-3 inhibitor is an anti-TIM-3 antibody molecule. The combination of a TIM-3 inhibitor and an anti-LAG-3 antibody molecule may further comprise one or more additional immunomodulators, e.g. in combination with a CEACAM inhibitor (e.g., CEACAM-1, -3 and/or -5), PD-1, PD -L1 or CTLA-4.

In certain embodiments, the immunomodulator used in the combinations described herein (eg, in combination with a therapeutic agent selected from an antigen-presenting combination) is an activator or agonist of a co-stimulatory molecule. In one embodiment, the co-stimulatory molecule agonist is selected from an agonist (e.g., agonist antibody or antigen-binding fragment or soluble fusion thereof) OX40, CD2, CD27, CD28, CDS, ICAM-1, LFA-1 (CD11a/CD18), ICOS (CD278), 4-1BB (CD137), GITR, CD30, CD40, BAFFR, HVEM, CD7, LIGHT, NKG2C, SLAMF7, NKp80, CD160, B7-H3, or an anti-CD83 ligand.

In other embodiments, the immunomodulator is a GITR agonist. In one embodiment, the GITR agonist is an anti-GITR antibody molecule. The anti-GITR antibody molecule and the anti-LAG-3 antibody molecule may be in the form of separate antibody formulations or a bispecific antibody molecule. The combination of a GITR agonist with an anti-LAG-3 antibody molecule may further comprise one or more additional immunomodulators, e.g. -5) or TIM-3. In some embodiments, the anti-GITR antibody molecule is a bispecific antibody that binds to GITR and PD-1, PD-L1, CTLA-4, CEACAM (e.g., CEACAM-1, -3 and/or -5) or TIM -3. In other embodiments, the GITR agonist may be administered in combination with one or more additional costimulatory molecule activators, e.g. ), 4-1BB (CD137), CD30, CD40, BAFFR, HVEM, CD7, LUNK, NKG2C, SLAMF7, NKp80, CD160, B7-H3, or with an anti-CD83 ligand.

In other embodiments, the immunomodulator is an OX40 agonist. In one embodiment, the OX40 agonist is an anti-OX40 antibody molecule. The OX40 antibody molecule and the anti-LAG-3 antibody molecule may be in the form of separate antibody formulations or a bispecific antibody molecule. The combination of an OX40 agonist with an anti-LAG-3 antibody molecule may further comprise one or more additional immunomodulators, e.g. -5) or TIM-3. In some embodiments, the anti-OX40 antibody molecule is a bispecific antibody that binds to OX40 and PD-1, PD-L1, CTLA-4, CEACAM (e.g., CEACAM-1, -3 and/or -5) or TIM -3. In other embodiments, the OX40 agonist may be administered in combination with another co-stimulatory molecule, e.g., a GITR agonist, CD2, CD27, CD28, CDS, ICAM-1, LFA-1 (CD11a/CD18), ICOS (CD278), 4- 1BB (CD137), CD30, CD40, BAFFR, HVEM, CD7, LUNK, NKG2C, SLAMF7, NKp80, CD160, B7-H3, or with an anti-CD83 ligand.

Note that only illustrative inhibitor combinations of inhibitors or agonists of costimulatory checkpoint molecules are provided herein. Additional combinations of these agents are covered by the present invention.

Biomarkers

In certain embodiments, any of the methods described herein further comprise evaluating or monitoring the effectiveness of a therapy (e.g., monotherapy or combination therapy) described herein for a subject (e.g., a subject having a cancer, e.g., cancer, described in this document). The method includes obtaining a value for assessing the effectiveness of therapy, where the specified value of the assessment is an indicator of the effectiveness of therapy.

In embodiments, the measure of therapy effectiveness includes a measure of one, two, three, four, five, six, seven, eight, nine, or more (e.g., all) of the following:

(i) tumor infiltrating lymphocyte phenotype parameter (TIL);

(ii) a myeloid cell population parameter;

(iii) a surface expression marker parameter;

(iv) an immunological response biomarker parameter;

(v) systemic cytokine modulation parameter;

(vi) circulating free DNA parameter (cfDNA);

(vii) systemic immunomodulation parameter;

(viii) microbiome parameter;

(ix) an activation marker parameter for circulating immune cells, or

(x) parameter of circulating cytokines.

In some embodiments, the TIL phenotype parameter includes the level or activity of one, two, three, four, or more (e.g., all) hematoxylin and eosin (H&E) staining components for TIL, CD8, FOXP3, CD4, or CD3 counts, in a subject, e.g. , in a sample from a subject (eg, in a tumor tissue sample).

In some embodiments, the myeloid cell population parameter includes the level or activity of one or both of CD68 or CD163 components in a subject, eg, in a sample from the subject (eg, in a tumor tissue sample).

In some embodiments, the surface expression marker parameter includes the level or activity of one, two, three, or more (e.g., all) of the TIM-3, PD-1, PD-L1, or LAG-3 components in a subject, e.g., in a sample from the subject (eg, in a tumor tissue sample). In certain embodiments, the level of TIM-3, PD-1, PD-L1, or LAG-3 is determined by immunohistochemistry (IHC). In certain embodiments, the TIM-3 level is determined.

In some embodiments, the immunological response biomarker parameter includes the level or sequence of one or more nucleic acid-based markers in a subject, eg, in a sample from the subject (eg, in a tumor tissue sample).

In some embodiments, the systemic cytokine modulation parameter includes the level or activity of one, two, three, four, five, six, seven, eight, or more (e.g., all) of IL-18, IFN-γ, ITAC (CXCL11), IL-6, IL-10, IL-4, IL-17, IL-15, or TGF-beta, in a subject, eg, in a sample from the subject (eg, in a blood sample, eg, in a plasma sample).

In some embodiments, the cfDNA parameter includes the sequence or level of one or more components of circulating tumor DNA (cfDNA) molecules in a subject, e.g., in a sample from the subject (e.g., in a blood sample, e.g., in a plasma sample).

In some embodiments, the systemic immunomodulation parameter includes a phenotypic characterization of an activated immune cell, e.g., a CD3 expressing cell, a CD8 expressing cell, or both, in a subject, e.g., in a sample from the subject (e.g., in a blood sample, for example, in the PBMC sample).

In some embodiments, the microbiome parameter includes the sequence or level of expression of one or more genes in the microbiome of a subject, eg, in a sample from the subject (eg, in a stool sample).

In some embodiments, the circulating immune cell activation marker parameter includes the level or activity of one, two, three, four, five, or more (e.g., all) of circulating CD8+, HLA-DR+Ki67+, T-lymphocytes, IFN-γ, IL-18 or CXCL11 (IFN-γ-induced CCK)-expressing cells in a sample (eg a blood sample, eg a plasma sample).

In some embodiments, the circulating cytokine parameter includes the level or activity of IL-6 in a subject, eg, in a sample from the subject (eg, in a blood sample, eg, in a plasma sample).

In some embodiments of any of the methods described herein, the therapy comprises a combination of an anti-TIM-3 antibody molecule described herein and a second inhibitor of an immune checkpoint molecule, e.g., a PD-1 inhibitor (e.g., an anti-TIM-3 antibody molecule). PD-1) or a PD-L1 inhibitor (eg, an anti-PD-L1 antibody molecule).

In some embodiments of any of the methods described herein, a measure of one or more parameters (i)-(x) is obtained from a sample taken from a subject. In some embodiments, the sample is selected from a tumor sample, a blood sample (eg, a plasma sample or a PBMC sample), or a stool sample.

In some embodiments of any of the methods described herein, the subject is assessed before, during, or after receiving therapy.

In some embodiments of any of the methods described herein, a measure of one or more of the parameters from (i)-(x) evaluates a profile for one or more of the parameters from gene expression, flow cytometry, or protein expression.

In some embodiments of any of the methods described herein, the presence of an increased level or activity of one, two, three, four, five, or more (e.g., all) of the components of circulating CD8+, HLA-DR+Ki67+, T-lymphocytes, IFN -γ, IL-18 or CXCL11 (IFN-γ-induced CCK)-expressing cells and/or the presence of a reduced level or activity of IL-6 in a subject or sample is a positive indicator of the effectiveness of therapy.

Alternatively, or in combination with the methods described herein, in response to a given value, one, two, three, four or more (e.g., all) of:

(i) administering therapy to a subject;

(ii) administering modified doses of therapy;

(iii) changing the regimen or timing of therapy;

(iv) administering to the subject an additional agent (e.g., a therapeutic agent as described herein) in combination with therapy, or

(v) administering an alternative therapy to the subject.

Additional Embodiments

In certain embodiments, any of the methods described herein further comprises identifying in a subject or in a sample (e.g., in a sample from a subject containing cancer cells and/or immune cells such as TIL) the presence of LAG-3, obtaining while the evaluation values for LAG-3. The method may further include comparing the score value for LAG-3 with a reference value, such as a control value. If the LAG-3 score is greater than a reference value, such as a reference value, the subject is administered a therapeutically effective amount of an anti-LAG-3 antibody molecule described herein, and optionally in combination with a second therapeutic agent, procedure, or treatment, described herein to thereby treat cancer.

In other embodiments, any of the methods described herein further comprise identifying in the subject or in a sample (e.g., in a sample from the subject containing cancer cells and/or immune cells such as TIL) the presence of PD-L1, thereby obtaining the most magnitude scores for PD-L1. The method may further include comparing the evaluation value for PD-L1 with a reference value, such as a reference value. If the score for PD-L1 is greater than a reference value, such as a reference value, the subject is administered a therapeutically effective amount of an anti-LAG-3 antibody molecule described herein, and optionally in combination with a second therapeutic agent, procedure, or treatment, described herein to thereby treat cancer.

In other embodiments, any of the methods described herein further comprises identifying in the subject or in a sample (e.g., in a sample from the subject containing cancer cells and optionally immune cells such as TIL) the presence of one, two, or all components from PD-L1, CD8 or IFN-γ, thereby obtaining a score value for one, two or all of the components from PD-L1, CD8 and IFN-γ. The method may further include comparing the score values for PD-L1, CD8, and/or IFN-γ with a reference value, eg, a control value. If the score values for PD-L1, CD8, and/or IFN-γ are greater than the reference value, e.g., control values, the subject is administered a therapeutically effective amount of the anti-LAG-3 antibody molecule described herein, and optionally in combination with a second therapeutic agent, procedure or treatment described herein for the treatment of cancer.

The subject may have a cancer described herein, such as a solid tumor or a hematologic cancer, e.g., a brain tumor (e.g., glioblastoma, gliosarcoma, or recurrent brain tumor), pancreatic cancer (e.g., advanced pancreatic cancer), skin cancer (eg, melanoma (eg, stage II-IV melanoma, HLA-A2 positive melanoma, unresectable melanoma, or metastatic melanoma) or Merkel cell carcinoma), kidney cancer (eg, renal cell carcinoma (RCC) (eg, metastatic renal cell carcinoma )), breast cancer (eg, metastatic breast carcinoma or stage IV breast carcinoma, eg, triple-negative breast cancer (TNBC)), virus-associated cancer, anal cancer (eg, anal squam cell carcinoma) , cervical cancer (eg, squam cell carcinoma of the cervix), gastrointestinal cancer (eg, Epstein-Barr virus-positive gastrointestinal cancer or carcinoma of the gastrointestinal tract or gastroesophageal junction), head and neck cancer (eg, HPV positive and negative cancer squam cell carcinoma of the head and neck (SCCHN)), nasopharyngeal cancer (NPC), penile cancer (eg, squam cell carcinoma of the penis), vaginal or vulvar cancer (eg, squam cell carcinoma of the vagina or vulva), colon and rectal cancer (eg, recurrent colorectal cancer or metastatic colorectal cancer, eg, colorectal cancer with microsatellite instability, microsatellite stable colorectal cancer, colorectal cancer surplus for mispaired base repair, or colorectal cancer deficient regarding mismatch repair), lung cancer (eg, non-small cell lung cancer (NSCLC)), leukemia, lymphoma (eg, Hodgkin's lymphoma (HL) or diffuse large B-cell lymphoma (DLBCL), eg, relapsed or refractory HL or DLBCL ), myeloma, or metastatic lesions from cancer.

All publications, patent applications, patents and other references discussed in this document are incorporated by reference in their entirety.

Other features, objects and advantages of the present invention will become apparent from the description and from the claims.

Detailed description of the invention

LAG-3 (CD223) is an immune checkpoint inhibitor that binds MHC II, LSECtin and Galectin-3. LAG-3 is expressed on the surface of immune cells, including CD4+ and CD8+ effector T lymphocytes, regulatory T lymphocytes (Treg), natural killer (NK) cells, and plasmacytoid dendritic cells. Engagement with LAG-3 has been shown to negatively regulate T-lymphocyte signaling with an increase in Treg suppressive function, which is expected to then decrease the activity of T-lymphocytes against tumor cells. Blockade of LAG-3 has been shown to activate T lymphocytes, increasing the proliferation and secretion of cytokines (IFN-γ) of T lymphocytes.

Accordingly, the present invention describes, at least in part, antibody molecules ( eg, humanized antibody molecules) that bind LAG-3 with high affinity and specificity. Pharmaceutical compositions and dosage formulations containing anti-LAG-3 antibody molecules are also provided. The anti-LAG-3 antibody molecules described herein can be used (alone or in combination with other therapeutic agents, procedures, or interventions) to treat or prevent disorders such as cancer disorders (e.g., solid tumors and hematologic cancers). ), as well as infectious diseases (for example, chronic infectious disorders or sepsis). For example, the anti-LAG-3 antibody molecules described herein may be used in combination with other therapeutic agents (e.g., one or both of a PD-1 inhibitor component (e.g., the anti-PD-1 antibody molecule described herein). document) or a chemotherapeutic agent (e.g., a platinum agent (e.g., with carboplatin, cisplatin, oxaliplatin, or tetraplatin) or with a nucleotide analog or precursor analog (e.g., capecitabine))), e.g., for the treatment or prevention of cancer (e.g., the cancer described herein), for example, breast cancer, for example, triple negative breast cancer (TNBC). Thus, the present invention describes methods, including dosing regimens, for treating various disorders using an anti-LAG-3 antibody molecule. In certain embodiments, the anti-LAG-3 antibody molecule is administered or administered at a base or fixed dose.

Definitions

Other terms are defined below and throughout the application.

As used herein, the singular definition refers to one or more (eg, at least one) grammatical entity.

The term “or” is used herein to refer to and is used interchangeably with the term “and/or” unless the context clearly dictates otherwise.

“About” and “approximately”, as a rule, should mean an acceptable degree of error for the quantity being measured, given the nature or measurement accuracy. Exemplary error rates are within 20 percent (%), typically within 10%, and more commonly within 5% of a given value or range of values.

By "combination" or "in combination with" it is not intended that the therapy or therapeutic agents be administered simultaneously and/or prepared for delivery together, although these delivery methods are within the scope described herein. Therapeutic agents in combination may be administered simultaneously with, before or after one or more other adjunctive therapies or therapeutic agents. The therapeutic agents or therapeutic protocol may be administered in any order. Typically, each agent will be administered at a dose and/or timing schedule determined for that agent. In addition, it will be apparent that the additional therapeutic agent used in this combination may be administered together in a single composition or administered separately in different compositions. Generally, additional therapeutic agents used in combination are expected to be used at levels that do not exceed those at which they are used alone. In some embodiments, levels used in combination will be lower than levels used alone.

In embodiments, the additional therapeutic agent is administered at or below the therapeutic dose. In certain embodiments, the concentration of the second therapeutic agent that is required to achieve inhibition, e.g., growth inhibition, is lower when the second therapeutic agent is administered in combination with the first therapeutic agent, e.g., an anti-LAG-3 antibody molecule, than when the second therapeutic agent is agent is administered individually. In certain embodiments, the concentration of the first therapeutic agent that is required to achieve inhibition, such as growth inhibition, is lower when the first therapeutic agent is administered in combination with the second therapeutic agent than when the first therapeutic agent is administered alone. In certain embodiments, in combination therapy, the concentration of the second therapeutic agent that is required to achieve inhibition, e.g., growth inhibition, is lower than the therapeutic dose of the second therapeutic agent as monotherapy, e.g., 10-20% lower, 20-30% lower. , 30-40%, 40-50%, 50-60%, 60-70%, 70-80% or 80-90%. In certain embodiments, in combination therapy, the concentration of the first therapeutic agent that is required to achieve inhibition, e.g., growth inhibition, is lower than the therapeutic dose of the first therapeutic agent alone, e.g., 10-20% lower, 20-30% lower. , 30-40%, 40-50%, 50-60%, 60-70%, 70-80% or 80-90%.

The term "inhibition", "inhibitor" or "antagonist" includes the reduction of a certain parameter, such as activity, of a given molecule, such as an immune checkpoint inhibitor. For example, this term includes inhibition of activity, for example, activity of PD-1 or PD-L1, at least 5%, 10%, 20%, 30%, 40% or more. Thus, inhibition should not be 100%.

The term "activation", "activator" or "agonist" includes an increase in a certain parameter, for example, the activity of a given molecule, for example, a co-stimulatory molecule. For example, the term includes an increase in activity, eg co-stimulatory activity, of at least 5%, 10%, 25%, 50%, 75% or more.

The term “anti-cancer effect” refers to a biological effect that can be manifested by various means, including, but not limited to, for example, reduction in tumor volume, reduction in the number of cancer cells, reduction in the number of metastases, increase in life expectancy, reduction in cancer cell proliferation, reduction the survival of cancer cells or the alleviation of various physiological symptoms associated with a malignant condition. "Anti-cancer effect" can also be manifested by the ability of peptides, polynucleotides, cells and antibodies to prevent the occurrence of cancer for the first time.

The term “antitumor effect” refers to a biological effect that can be exerted by various means, including, but not limited to, for example, shrinking tumor volume, reducing tumor cell numbers, reducing tumor cell proliferation, or reducing tumor cell survival.

The term "cancer" refers to a disease characterized by the rapid and uncontrolled growth of aberrant cells. Cancer cells can spread locally or through the bloodstream and lymphatic system to other parts of the body. Examples of the various cancers described herein include, but are not limited to, solid tumors such as lung cancer, breast cancer, prostate cancer, ovarian cancer, cervical cancer, skin cancer, pancreatic cancer, colon cancer, and rectum, kidney cancer, liver cancer and brain cancer, and hematological malignancies such as lymphoma and leukemia, and the like. The terms "tumor" and "cancer" are used interchangeably herein, for example, both terms cover solid and liquid, for example, diffuse or circulating tumors. As used herein, the term "cancer" or "tumor" includes premalignant as well as malignant cancers and tumors.

The term "antigen presenting cell" or "APC" refers to a cell of the immune system, such as an A cell (e.g., B cell, dendritic cell, and the like), that presents a foreign antigen complexed with major histocompatibility complexes (MHC ) on their surface. T lymphocytes can recognize these complexes using their T lymphocyte receptors (TCRs). APC processes antigens and presents them to T-lymphocytes.

The term "costimulatory molecule" refers to a cognate binding partner on a T lymphocyte that specifically binds to a costimulatory ligand, thereby mediating a costimulatory response of the T lymphocyte, such as, but not limited to, proliferation. Costimulatory molecules are molecules on the surface of cells, other than antigen receptors or their ligands, that are essential for an effective immune response. Costimulatory molecules include, but are not limited to, MHC class I molecules, TNF receptor proteins, immunoglobulin-like proteins, cytokine receptors, integrins, lymphocyte activation signaling molecules (SLAM proteins), activating NK cell receptors, BTLA, Toll ligand receptor, OX40, CD2 , CD7, CD27, CD28, CD30, CD40, CDS, ICAM-1, LFA-1 (CD11a/CD18), 4-1BB (CD137), B7-H3, CDS, ICAM-1, ICOS (CD278), GITR, BAFFR, LIGHT, HVEM (LIGHTR), KIRDS2, SLAMF7, NKp80 (KLRF1), NKp44, NKp30, NKp46, CD19, CD4, CD8alpha, CD8beta, IL2R beta, IL2R gamma, IL7R alpha, ITGA4, VLA1, CD49a, ITGA4, IA4 , CD49D, ITGA6, VLA-6, CD49f, ITGAD, CD11d, ITGAE, CD103, ITGAL, CD11a, LFA-1, ITGAM, CD11b, ITGAX, CD11c, ITGB1, CD29, ITGB2, CD18, LFA-1, ITGB7, NKG2D , NKG2C, TNFR2, TRANCE/RANKL, DNAM1 (CD226), SLAMF4 (CD244, 2B4), CD84, CD96 (Tactile), CEACAM1, CRTAM, Ly9 (CD229), CD160 (BY55), PSGL1, CD100 (SEMA4D), CD69 , SLAMF6 (NTB-A, Ly108), SLAM (SLAMF1, CD150, IPO-3), BLAME (SLAMF8), SELPLG (CD162), LTBR, LAT, GADS, SLP-76, PAG/Cbp, CD19a and a ligand that binds specifically to CD83.

“Immune effector cell” or “effector cell”, as such a term is used herein, refers to a cell that is involved in an immune response, for example, in accelerating an immune effector response. Examples of immune effector cells include T lymphocytes, such as alpha/beta T lymphocytes and gamma/delta T lymphocytes, B cells, natural killer (NK), natural killer T (NKT) lymphocytes, mast cells, and phagocytes of myeloid origin.

“Immune effector” or “effector”, “function” or “response”, as the term is used herein, refers to a function or response, for example, of an immune effector cell that enhances or accelerates the target cell's immune response. For example, an immune effector function or response refers to a property of a T-lymphocyte or NK cell that contributes to killing or inhibiting the growth or proliferation of a target cell. In the case of the T-lymphocyte, primary stimulation and co-stimulation are examples of an immune effector function or response.

The term "effector function" refers to a specific function of the cell. The effector function of the T-lymphocyte may, for example, be a cytolytic activity or a helper activity, including the secretion of cytokines.

As used herein, the terms "treat", "treating", and "treating" refer to reducing or alleviating the development, severity and/or duration of a disorder, such as a proliferative disorder, or alleviating one or more symptoms (preferably one or more recognizable symptoms) of a disorder resulting from the administration of one or more therapies. In specific embodiments, the terms “treat”, “treatment”, and “treating” refer to alleviation of at least one measurable physical parameter of a proliferative disorder, such as tumor growth, not necessarily discernible by the patient. In other embodiments, the terms “treat”, “treating”, and “treating” refer to slowing the progression of a proliferative disorder, either physically, such as by stabilizing a discernible symptom, or physiologically, such as by stabilizing a physical parameter, or both. . In other embodiments, the terms “treat”, “treatment”, and “treatment” refer to the reduction or stabilization of tumor size or cancer cell counts.

The compositions, preparations and methods of the present invention encompass polypeptides and nucleic acids having said sequences or sequences substantially identical or similar to them, for example sequences at least 85%, 90%, 95% or greater identical to said sequence. In the context of an amino acid sequence, the term “substantially identical” is used herein to refer to a first amino acid that contains a sufficient or minimum number of amino acid residues that i) are identical or ii) are conservative substitutions of aligned amino acid residues in a second amino acid sequence, so that the first and second amino acid sequences may share a common structural domain and/or a common functional activity. For example, these are amino acid sequences that contain a common structural domain having at least about 85%, 90%. 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with a reference sequence, such as the sequence provided herein.

In the context of a nucleotide sequence, the term "substantially identical" is used herein to refer to a first nucleic acid sequence that contains a sufficient or minimum number of nucleotides that are identical to aligned nucleotides in a second nucleic acid sequence such that the first and second nucleotide sequences encode a polypeptide, having a common functional activity or encode a common structural domain or a common functional activity of the polypeptide. For example, these nucleotide sequences have at least about 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with a reference sequence, for example, with the sequence proposed in this document.

The term “functional variant” refers to polypeptides that have an amino acid sequence substantially identical to a naturally occurring sequence, or are encoded by a substantially identical nucleotide sequence, and may have one or more of the activities of a naturally occurring sequence.

The calculation of homology or sequence identity between sequences (these terms are used interchangeably herein) is performed as follows.

To determine the percent identity of two amino acid sequences or two nucleic acid sequences, the sequences are aligned for purposes of optimal comparison (e.g., breaks may be introduced in one or both of the first and second amino acid or nucleic acid sequences for optimal alignment, and non-homologous sequences may be ignored for comparison purposes) . In a preferred embodiment, the length of the reference sequence aligned for comparison purposes is at least 30%, preferably at least 40%, more preferably at least 50%, 60% and even more preferably at least 70%, 80%, 90%, 100% of the length of the reference sequence. Amino acid residues or nucleotides are then compared at the corresponding amino acid positions or nucleotide positions. When a position in the first sequence is occupied by the same amino acid residue or nucleotide as the corresponding position in the second sequence, then the molecules are identical at that position (as used herein, “identity” of an amino acid or nucleic acid is equivalent to “homology” of an amino acid or nucleic acid ).

The percent identity between two sequences is a function of the number of identical positions common to the sequences, given the number of breaks and the length of each break that must be entered to optimally align the two sequences.

Comparing sequences and determining percent identity between two sequences can be done using a mathematical algorithm. In a preferred embodiment, the percent identity between two amino acid sequences is determined using the algorithm of Needleman and Wunsch ((1970) J. Mol. Biol. 48:444-453), which is included in the GAP program of the GCG software package (available at www.gcg .com), using either a Blossum 62 die or a PAM250 die, and a break weight of 16, 14, 12, 10, 8, 6, or 4, and a length weight of 1, 2, 3, 4, 5, or 6. B in another preferred embodiment, the percent identity between two nucleotide sequences is determined using the GAP program of the GCG software package (available at www.gcg.com), using the NWSgapdna matrix. CMP and a gap weight of 40, 50, 60, 70, or 80 and a length weight of 1, 2, 3, 4, 5, or 6. A particularly preferred set of parameters (to be used unless otherwise noted) is the Blossum 62 score matrix and a gap penalty of 12, a gap extension penalty of 4, and a gap frameshift penalty of 5.

The percent identity between two amino acid or nucleotide sequences can be determined using the algorithm of E. Meyers and W. Miller ((1989) CABIOS , 4:11-17), which is included in the ALIGN program (version 2.0), using the PAM120 Residue Weight Table , a gap extension penalty of 12, and a gap penalty of 4.

The nucleic acid and protein sequences described herein can be used as a “query sequence” to search public databases, for example, to identify other family members or related sequences. Such a search can be performed using the programs NBLAST and XBLAST (version 2.0) of Altschul, et al. (1990) J. Mol. Biol. 215:403-10. BLAST nucleotide searches can be performed using the NBLAST program: score=100, wordlength=12 to obtain nucleotide sequences homologous to the nucleic acid molecules (SEQ ID NO: 1) of the present invention. BLAST protein searches can be performed using the XBLAST program: score=50, wordlength=3 to obtain amino acid sequences homologous to the protein molecules of the present invention. To obtain discontinuous alignments for comparison purposes, Gapped BLAST can be used as described in Altschul et al. , (1997) Nucleic Acids Res. 25:3389-3402, when the BLAST and Gapped BLAST programs are used, the default parameters of the respective programs (eg, XBLAST and NBLAST) can be used. See www.ncbi.nlm.nih.gov.

As used herein, the term "hybridizes under low stringency, medium stringency, high stringency, or very high stringency" describes hybridization and washing conditions. Instructions for performing a hybridization reaction can be found in Current Protocols in Molecular Biology , John Wiley & Sons, NY (1989), 6.3.1-6.3.6, which is incorporated by reference. This reference describes aqueous and non-aqueous methods, and both can be used. Specific hybridization conditions referred to herein are as follows: 1) low stringency hybridization conditions in 6X sodium chloride/sodium citrate (SSC) at about 45°C, followed by two washes in 0.2X SSC, 0.1% SDS, at least at a temperature of 50°C (the temperature of the washings can be increased to 55°C for low stringency conditions); 2) medium stringency hybridization conditions in 6X SSC at about 45°C, followed by one or more washes in 0.2X SSC, 0.1% SDS at 60°C; 3) high stringency hybridization conditions in 6X SSC at about 45°C, followed by one or more washes in 0.2X SSC, 0.1% SDS at 65°C; and preferably 4) very stringent hybridization conditions are 0.5M sodium phosphate, 7% SDS at 65°C followed by one or more washes in 0.2X SSC, 1% SDS at 65°C. Very stringent conditions (4) are the preferred conditions and should be used unless otherwise noted.

It is understood that the molecules of the present invention may have additional conservative or non-essential amino acid substitutions that do not significantly affect their function.

The term "amino acid" is intended to encompass all molecules, both natural and synthetic, that contain both an amino and an acid functionality and can be incorporated into a polymer from naturally occurring amino acids. Exemplary amino acids include naturally occurring amino acids; their analogues, derivatives and congeners; amino acid analogs having side chain variants; and all stereoisomers of any of the above entities. As used herein, the term "amino acid" includes both D- and L-optical isomers and peptidomimetics.

"Conservative amino acid substitution" is a substitution in which an amino acid residue is replaced with an amino acid residue having a similar side chain. Families of amino acid residues having similar side chains are defined in the art. These families include amino acids with basic side chains (eg, lysine, arginine, histidine), acidic side chains (eg, aspartic acid, glutamic acid), uncharged polar side chains (eg, glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), with nonpolar side chains (e.g. alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), beta-branched side chains (e.g. threonine, valine, isoleucine) and aromatic side chains (e.g. tyrosine, phenylalanine, tryptophan, histidine).

The terms "polypeptide", "peptide" and "protein" (if the chain is single) are used interchangeably herein to refer to polymers of amino acids of any length. The polymer may be linear or branched, it may contain modified amino acids, and it may be interrupted by groups other than amino acids. The terms also cover the amino acid polymer that is being modified; for example, via disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation such as conjugation to a label component. The polypeptide may be isolated from natural sources, may be obtained by recombinant techniques from a eukaryotic or prokaryotic host, or may be the product of synthetic procedures.

The terms "nucleic acid", "nucleic acid sequence", "nucleotide sequence" or "polynucleotide sequence" and "polynucleotide" are used interchangeably. They refer to the polymeric form of nucleotides, or deoxyribonucleotides, or ribonucleotides, or their analogs of any length. The polynucleotide may be either single stranded or double stranded, and if single stranded, may be a coding strand or a non-coding strand (antisense strand). The polynucleotide may contain modified nucleotides such as methylated nucleotides and nucleotide analogs. The sequence of nucleotides may be interrupted by groups other than nucleotides. The polynucleotide may be further modified after polymerization, for example by conjugation to a label component. The nucleic acid may be a recombinant polynucleotide or a polynucleotide of genomic origin, derived from cDNA, polysynthetic or synthetic origin, a polynucleotide that either does not occur in nature or binds to another polynucleotide in an arrangement not found in nature.

The term "isolated" as used herein refers to material that has been removed from its original or natural environment (eg, from the natural environment if it occurs naturally). For example, a naturally occurring polynucleotide or polypeptide present in a living animal is not isolated, but the same polynucleotide or polypeptide separated by human intervention from some or all of the coexisting materials in the natural system is isolated. Such polynucleotides may be part of a vector and/or such polynucleotides or polypeptides may be part of compositions and still be isolated such that such vector or composition is not part of its natural environment.

Various aspects of the present invention are described in more detail below. Additional definitions are given throughout the description.

Dosing regimens

The anti-LAG-3 antibody molecules described herein may be administered according to the dosage regimen described herein to treat (e.g., delay, reduce, alleviate, or prevent) a disorder, e.g., a hyperproliferative condition or disorder (e.g., cancer). ) in the subject. In certain embodiments, the anti-LAG-3 antibody molecule is administered to the subject at a dose of about 200 mg to about 2000 mg, such as every two, three or four weeks.

In some aspects, the invention describes a method of treating cancer in a subject, the method comprising administering to the subject an anti-LAG-3 antibody molecule (e.g., an anti-LAG-3 antibody molecule described herein) at the dose or dosage schedule described herein. .

In some embodiments, the anti-LAG-3 antibody molecule is administered at a dose or dosing schedule that results in binding, eg, saturates soluble LAG-3 in the subject. In some embodiments, the anti-LAG-3 antibody molecule is administered at a dose or dosing schedule that results in at least 50%, 60%, 70%, 80%, 85%, 90%, 95% , 98% or 99% binding, e.g., saturation of soluble LAG-3 in the subject, e.g., within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12, 24, 36 or 48 weeks of introduction.

In some embodiments, the anti-LAG-3 antibody molecule is administered at a dose or dosing schedule that results in at least 50%, 60%, 70%, 80%, 90%, 95%, 98% or 99% binding, e.g., LAG-3 occupancy in a subject's tumor, e.g., within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 24, 36, or 48 weeks introductions.

In other embodiments, the anti-LAG-3 antibody molecule is administered at a dose or dosing schedule that results in at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 98% or 99% binding, eg, saturation, of soluble LAG-3 in a subject; and which results in at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 98%, or 99% binding, e.g., LAG-3 occupancy in a subject's tumor. In embodiments, saturation and/or fullness occurs, for example, within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 24, 36, or 48 weeks of administration.

In some embodiments, the anti-LAG-3 antibody molecule is administered at a dose or dosing schedule that results in one or both of the following:

(a) 40% or more (for example, 50% or more, 60% or more, 70% or more, 80% or more, 85% or more, 90% or more, 95% or more, 99% or more) soluble LAG-3 in a subject (eg, blood) binds to an anti-LAG-3 antibody molecule; or

(b) 50% or more (e.g., 60% or more, 70% or more, 80% or more, 85% or more, 90% or more, 95% or more, 99% or more) membrane-bound LAG- 3 in a subject (eg, cancerous tissue) binds to an anti-LAG-3 antibody molecule.

In some embodiments, binding of an anti-LAG-3 antibody molecule to soluble LAG-3 is detected in a blood sample (eg, serum sample or plasma sample). In some embodiments, binding of an anti-LAG-3 antibody molecule to membrane-bound LAG-3 is determined in a cancerous disease (eg, in a sample of cancerous tissue).

In some embodiments, binding of an anti-LAG-3 antibody molecule to soluble LAG-3, binding of an anti-LAG-3 antibody molecule to membrane-bound LAG-3, or both, is determined when the subject has a steady state trough. anti-LAG-3 antibody molecules. In some embodiments, the trough is the concentration of the anti-LAG-3 antibody molecule about 24 weeks after administration, or the lowest concentration that the anti-LAG-3 antibody molecule reaches before the next dose. In some embodiments, the binding of an anti-LAG-3 antibody molecule to soluble LAG-3, the binding of an anti-LAG-3 antibody molecule to membrane-bound LAG-3, or both, is determined, e.g., measured in vitro ( eg by ELISA or cellular analysis) or in vivo (eg by image processing) or predicted by a PK/PD model, eg by the PK/PD model described herein.

In some embodiments, 50% or more of the soluble LAG-3 in a serum sample from a subject is associated with an anti-LAG-3 antibody molecule. In some embodiments, 60% or more of the soluble LAG-3 in a serum sample from a subject is associated with an anti-LAG-3 antibody molecule. In some embodiments, 70% or more of the soluble LAG-3 in a serum sample from a subject is associated with an anti-LAG-3 antibody molecule. In some embodiments, 80% or more of the soluble LAG-3 in a serum sample from a subject is associated with an anti-LAG-3 antibody molecule. In some embodiments, 90% or more of the soluble LAG-3 in a serum sample from a subject is associated with an anti-LAG-3 antibody molecule.

In some embodiments, 85% or more of the membrane-bound LAG-3 in a cancer or cancer tissue sample of a subject is associated with an anti-LAG-3 antibody molecule. In some embodiments, 90% or more of the membrane-bound LAG-3 in a cancer or cancer tissue sample of a subject is associated with an anti-LAG-3 antibody molecule. In some embodiments, 95% or more of the membrane-bound LAG-3 in a cancer or cancer tissue sample of a subject is associated with an anti-LAG-3 antibody molecule.

In some embodiments, 50% or more, 60% or more, 70% or more, 80% or more, or 90% or more of soluble LAG-3 in a serum sample from a subject is associated with an anti-LAG-3 antibody molecule, and 85% or more, 90% or more, or 95% or more of the membrane-bound LAG-3 in a cancer or cancer tissue sample of a subject is associated with an anti-LAG-3 antibody molecule.

In some embodiments, 50% or more of soluble LAG-3 in a serum sample from a subject is associated with an anti-LAG-3 antibody molecule and 90% or more of membrane-bound LAG-3 in a cancer or in a cancer tissue sample of a subject is associated with the molecule anti-LAG-3 antibodies. In some embodiments, 60% or more of soluble LAG-3 in a serum sample from a subject is associated with an anti-LAG-3 antibody molecule, and 90% or more of membrane-bound LAG-3 in a cancer or cancer tissue sample of a subject is associated with an anti-LAG-3 antibody molecule. In some embodiments, 70% or more of the soluble LAG-3 in a serum sample from a subject is associated with an anti-LAG-3 antibody molecule, and 90% or more of membrane-bound LAG-3 in a cancer or cancer tissue sample of the subject is associated with an anti-LAG-3 antibody molecule. In some embodiments, 80% or more of the soluble LAG-3 in a serum sample from a subject is associated with an anti-LAG-3 antibody molecule, and 90% or more of the membrane-bound LAG-3 in a cancer or cancer tissue sample of the subject is associated with an anti-LAG-3 antibody molecule. In some embodiments, 90% or more of the soluble LAG-3 in a serum sample from a subject is associated with an anti-LAG-3 antibody molecule, and 90% or more of the membrane-bound LAG-3 in a cancer or cancer tissue sample of the subject is associated with an anti-LAG-3 antibody molecule.

In some embodiments, the anti-LAG-3 antibody molecule is administered at a dose or dosing schedule that reduces one or both of the following:

(a) the level of free soluble LAG-3 in the subject, e.g., up to 40% or less (e.g., up to 50% or less, 40% or less, 30% or less, 20% or less, 15% or less, 10% or less, 5% or less, or 1% or less) of the free soluble LAG-3 reference level; or

(b) the level of free membrane-bound LAG-3 in the subject, e.g., up to 50% or less (e.g., up to 40% or less, 30% or less, 20% or less, 15% or less, 10% or less, 5% or less or 1% or less) of the reference level of membrane-bound LAG-3.

In some embodiments, the level of free soluble LAG-3 is determined in a blood sample (eg, a serum sample or a plasma sample). In some embodiments, the reference level of free soluble LAG-3 is the background level of free soluble LAG-3 in the subject, eg, prior to administration of the anti-LAG-3 antibody molecule, eg, according to a dosing regimen.

In some embodiments, the level of free membrane-bound LAG-3 is determined in the cancer tissue (eg, in a sample of cancer tissue). In some embodiments, the reference level of free membrane-bound LAG-3 is the background level of free membrane-bound LAG-3 in the subject, e.g., prior to administration of an anti-LAG-3 antibody molecule, e.g., according to a dosing regimen.

In some embodiments, the level of free soluble LAG-3, the level of free membrane-bound LAG-3, or both, is determined when the subject has a stationary trough of an anti-LAG-3 antibody molecule. In some embodiments, the trough is the concentration of the anti-LAG-3 antibody molecule about 24 weeks after administration, or the lowest concentration that the anti-LAG-3 antibody molecule reaches before the next dose. In some embodiments, the level of free soluble LAG-3, the level of free membrane-bound LAG-3, or both is determined, e.g., measured in vitro (e.g., by ELISA or cell assay) or in vivo (e.g., using image processing) or predicted from a PK/PD model, such as the PK/PD model described herein.

In some embodiments, the level of free soluble LAG-3 is reduced to 50% or less of a reference level of free soluble LAG-3 in a serum sample from a subject. In some embodiments, the level of free soluble LAG-3 is reduced to 40% or less of a reference level of free soluble LAG-3 in a serum sample from a subject. In some embodiments, the level of free soluble LAG-3 is reduced to 30% or less of a reference level of free soluble LAG-3 in a serum sample from a subject. In some embodiments, the level of free soluble LAG-3 is reduced to 20% or less of a reference level of free soluble LAG-3 in a serum sample from a subject. In some embodiments, the level of free soluble LAG-3 is reduced to 10% or less of a reference level of free soluble LAG-3 in a serum sample from a subject.

In some embodiments, the level of free membrane-bound LAG-3 is reduced to 15% or less of a reference level of free membrane-bound LAG-3 in the cancer or in a cancer tissue sample of the subject. In some embodiments, the level of free membrane-bound LAG-3 is reduced to 10% or less of a reference level of free membrane-bound LAG-3 in the cancer or in a sample of cancerous tissue from a subject. In some embodiments, the level of free soluble LAG-3 is reduced to 5% or less of a reference level of free membrane-bound LAG-3 in a cancerous disease or in a sample of cancerous tissue from a subject.

In some embodiments, the level of free soluble LAG-3 is reduced to 50% or less, 40% or less, 30% or less, 20% or less, or 10% or less of a reference level of free soluble LAG-3 in a serum sample from the subject and the level of free membrane-bound LAG-3 is reduced to 15% or less, 10% or less, or 5% or less of a reference level of free membrane-bound LAG-3 in the cancer or cancer tissue sample of the subject.

In some embodiments, the level of free soluble LAG-3 is reduced to 50% or less of the reference level of free soluble LAG-3 in a serum sample from the subject and the level of free membrane-bound LAG-3 is reduced to 10% or less of the reference level of free membrane -linked LAG-3 in cancer or in a cancerous tissue sample from a subject. In some embodiments, the level of free soluble LAG-3 is reduced to 40% or less of the reference level of free soluble LAG-3 in a serum sample from the subject and the level of free membrane-bound LAG-3 is reduced to 10% or less of the reference level of free membrane -linked LAG-3 in cancer or in a cancerous tissue sample from a subject. In some embodiments, the level of free soluble LAG-3 is reduced to 30% or less of the reference level of free soluble LAG-3 in a serum sample from the subject and the level of free membrane-bound LAG-3 is reduced to 10% or less of the reference level of free membrane -linked LAG-3 in cancer or in a cancerous tissue sample from a subject. In some embodiments, the level of free soluble LAG-3 is reduced to 20% or less of the reference level of free soluble LAG-3 in a serum sample from the subject and the level of free membrane-bound LAG-3 is reduced to 10% or less of the reference level of free membrane -linked LAG-3 in cancer or in a cancerous tissue sample from a subject. In some embodiments, the level of free soluble LAG-3 is reduced to 10% or less of the reference level of free soluble LAG-3 in a serum sample from the subject and the level of free membrane-bound LAG-3 is reduced to 10% or less of the reference level of free membrane -linked LAG-3 in cancer or in a cancerous tissue sample from a subject.

In certain embodiments, the dose or dosing schedule results in a trough (eg, steady state trough) of the anti-LAG-3 antibody molecule that is greater than C _crit (eg, as described in Example 1). In some embodiments _, Ccrit is the concentration below which a non-linear PK is observed. In some embodiments, C _crit is about 60 nM.

In some embodiments, the anti-LAG-3 antibody molecule is administered at the dosage regimen described herein.

In some embodiments, the anti-LAG-3 antibody molecule is administered at a dose of about 200 mg to about 1600 mg, about 300 mg to about 1500 mg, about 400 mg to about 1400 mg, about 500 mg to about 1300 mg, about 600 mg to about 1200 mg, about 700 mg to about 1100 mg, about 800 mg to about 1000 mg, about 200 mg to about 1400 mg, about 200 mg to about 1200 mg, about 200 mg to about 1000 mg, about 200 mg to about up to 800 mg, about 200 mg up to about 600 mg, about 200 mg up to about 400 mg, about 1400 mg up to about 1600 mg, about 1200 mg up to about 1600 mg, about 1000 mg up to about 1600 mg, about 800 mg up to about 1600 mg, from about 600 mg to about 1600 mg, from about 400 mg to about 1600 mg, from about 200 mg to about 600 mg, from about 300 mg to about 700 mg, from about 400 mg to about 800 mg, from about 500 mg to about 900 mg, from about 600 mg to about 1000 mg, from about 700 mg to about 1100 mg, from about 800 mg to about 1200 mg, from about 900 mg to about 1300 mg, from about 1000 mg to about 1400 mg, about 1100 mg to about 1500 mg, or from about 1200 mg to about 1600 mg, for example, once every two weeks, once every three weeks, or once every four weeks.

In some embodiments, the anti-LAG-3 antibody molecule is administered at a dose of about 200 mg to about 600 mg, about 250 mg to about 550 mg, about 300 mg to about 500 mg, about 350 mg to about 450 mg , from about 200 mg to about 400 mg, from about 400 mg to about 600 mg, for example, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, for example, once every three weeks or once every four weeks. In certain embodiments, the anti-LAG-3 antibody molecule is administered at a dose of about 300 mg to about 500 mg, e.g., about 300 mg, about 320 mg, about 340 mg, about 360 mg, about 380 mg, about 400 mg, about 420 mg, about 440 mg, about 460 mg, about 480 mg, or about 500 mg once every three weeks. In certain embodiments, the anti-LAG-3 antibody molecule is administered at a dose of about 350 mg to about 450 mg, such as about 400 mg once every three weeks.

In some embodiments, the anti-LAG-3 antibody molecule is administered at a dose of about 600 mg to about 1000 mg, about 650 mg to about 950 mg, about 700 mg to about 900 mg, about 750 mg to about 950 mg, about 600 mg to about 800 mg, about 800 mg to about 1000 mg, e.g., about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, for example, once every three weeks or once every four weeks. In certain embodiments, the anti-LAG-3 antibody molecule is administered at a dose of about 900 mg to about 1100 mg, e.g., about 900 mg, about 920 mg, about 940 mg, about 960 mg, about 980 mg, about 900 mg, about 920 mg, about 940 mg, about 960 mg, about 980 mg, or about 1000 mg once every four weeks. In certain embodiments, the anti-LAG-3 antibody molecule is administered at a dose of about 950 mg to about 1050 mg, such as about 1000 mg once every four weeks.

In some embodiments, the anti-LAG-3 antibody molecule is administered at a dose of about 500 mg to about 900 mg, about 550 mg to about 850 mg, about 600 mg to about 800 mg, about 650 mg to about 750 mg e.g. about 500mg, about 550mg, about 600mg, about 650mg, about 700mg, about 750mg, about 800mg, about 850mg, about 900mg, e.g. once every three weeks or once every four weeks. In certain embodiments, the anti-LAG-3 antibody molecule is administered at a dose of about 600 mg to about 800 mg, e.g., about 600 mg, about 620 mg, about 640 mg, about 660 mg, about 680 mg, about 700 mg, about 720 mg, about 740 mg, about 760 mg, about 780 mg, or about 800 mg once every three weeks. In certain embodiments, the anti-LAG-3 antibody molecule is administered at a dose of about 650 mg to about 750 mg, such as about 700 mg once every three weeks.

In some embodiments, the anti-LAG-3 antibody molecule is administered at a dose of about 1200 mg to about 1600 mg, about 1250 mg to about 1550 mg, about 1300 mg to about 1500 mg, about 1350 mg to about 1450 mg e.g. about 1200 mg, about 1250 mg, about 1300 mg, about 1350 mg, about 1400 mg, about 1450 mg, about 1500 mg, about 1550 mg, about 1600 mg, for example, once every three weeks or once every four weeks. In certain embodiments, the anti-LAG-3 antibody molecule is administered at a dose of about 1300 mg to about 1500 mg, e.g., about 1300 mg, about 1320 mg, about 1340 mg, about 1360 mg, about 1380 mg, about 1400 mg, about 1420 mg, about 1440 mg, about 1460 mg, about 1480 mg, or about 1500 mg once every four weeks. In certain embodiments, the anti-LAG-3 antibody molecule is administered at a dose of about 1350 mg to about 1450 mg, such as about 1400 mg once every four weeks.

In some embodiments, the anti-LAG-3 antibody molecule is administered at a dose of about 400 mg to about 700 mg, about 450 mg to about 650 mg, about 500 mg to about 600 mg, about 450 mg to about 550 mg, from about 500 mg to about 600 mg, from about 550 mg to about 650 mg, from about 600 mg to about 700 mg, from about 500 mg to about 550 mg, from about 550 mg to about 600 mg, from about 600 mg up to 650 mg, for example, about 400 mg, about 450 mg, about 500 mg, about 533 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, for example, every four weeks. In certain embodiments, the anti-LAG-3 antibody molecule is administered at a dose of about 450 mg to about 650 mg, such as about 450 mg, about 500 mg, about 533 mg, about 550 mg, about 600 mg, or about 650 mg alone. once every four weeks. In certain embodiments, the anti-LAG-3 antibody molecule is administered at a dose of about 500 mg to about 650 mg, such as about 533 mg or about 600 mg once every four weeks.

In some embodiments, the anti-LAG-3 antibody molecule is administered at a dose of about 2000 mg or less, about 1900 mg or less, about 1800 mg or less, about 1700 mg or less, about 1600 mg or less, about 1500 mg, or less, about 1400 mg or less, about 1300 mg or less, about 1200 mg or less, about 1100 mg or less, about 1000 mg or less, about 900 mg or less, about 800 mg or less, about 700 mg or less, about 600 mg or less, about 533 mg or less, about 500 mg or less, about 400 mg or less, about 300 mg or less, about 250 mg or less, or about 200 mg or less once every other week, once every three weeks or once every four weeks.

In some embodiments, the disorder is a cancer, such as the cancer described herein. In certain embodiments, the cancer is a solid tumor. In some embodiments, the cancer is a brain tumor, such as glioblastoma, gliosarcoma, or a recurrent brain tumor. In some embodiments, the cancer is pancreatic cancer, such as advanced pancreatic cancer. In some embodiments, the cancer is a skin cancer, such as melanoma (eg, stage II-IV melanoma, HLA-A2 positive melanoma, unresectable melanoma, or metastatic melanoma) or Merkel cell carcinoma. In some embodiments, the cancer is a kidney cancer, such as renal cell carcinoma (RCC) (eg, metastatic renal cell carcinoma). In some embodiments, the cancer is breast cancer, such as metastatic breast carcinoma or stage IV breast carcinoma, such as triple negative breast cancer (TNBC). In some embodiments, the cancer is a virus-associated cancer. In some embodiments, the cancer is anal cancer (eg, anal squamous cell carcinoma). In some embodiments, the cancer is cervical cancer (eg, squamous cell carcinoma of the cervix). In some embodiments, the cancer is gastrointestinal cancer (eg, Epstein-Barr virus positive gastrointestinal cancer or gastrointestinal or gastroesophageal junction carcinoma). In some embodiments, the cancer is a head and neck cancer (eg, HPV-positive and -negative head and neck squam cell cancer (SCCHN)). In some embodiments, the cancer is nasopharyngeal cancer (NPC). In some embodiments, the cancer is a cancer of the penis (eg, squamous cell carcinoma of the penis). In some embodiments, the cancer is a vaginal or vulvar cancer (eg, squamous cell carcinoma of the vagina or vulva). In some embodiments, the cancer is colon and rectal cancer, e.g., recurrent colon and rectal cancer or metastatic colon and rectal cancer, e.g., microsatellite unstable colon and rectal cancer, microsatellite stable colon and rectal cancer, colon and rectal cancer surplus for mispair repair or colon and rectal cancer deficient for mispair repair. In some embodiments, the cancer is lung cancer, such as non-small cell lung cancer (NSCLC). In certain embodiments, the cancer is a hematologic cancer. In some embodiments, the cancer is leukemia. In some embodiments, the cancer is a lymphoma, such as Hodgkin's lymphoma (HL) or diffuse large B cell lymphoma (DLBCL) (eg, recurrent or refractory HL or DLBCL). In some embodiments, the cancer is a myeloma.

In other embodiments, the cancer is highly microsatellite unstable cancer. In some embodiments, the cancer is a metastatic cancer. In other embodiments, the cancer is a progressive cancer. In other embodiments, the cancer is recurrent or untreatable cancer. In other embodiments, the cancer is an unresectable cancer.

In one embodiment, the cancer is Merkel cell carcinoma. In other embodiments, the cancer is melanoma. In other embodiments, the cancer is breast cancer, such as triple negative breast cancer (TNBC) or HER2 negative breast cancer. In other embodiments, the cancer is a renal cell carcinoma (eg, clear cell renal cell carcinoma (CCRCC) or non-clear cell renal cell carcinoma (nccRCC)). In other embodiments, the cancer is thyroid cancer, such as anaplastic thyroid carcinoma (ATC). In other embodiments, the cancer is a neuroendocrine tumor (NET), such as an atypical pulmonary carcinoid tumor or NET in the pancreas, gastrointestinal (GI) tract, or lungs. In certain embodiments, the cancer is non-small cell lung cancer (NSCLC) (eg, squam cell NSCLC or non-squamous NSCLC). In certain embodiments, the cancer is fallopian tube cancer. In certain embodiments, the cancer is highly microsatellite unstable colon cancer (CRC with high MSI) or microsatellite stable colon cancer (MSS CRC).

In some embodiments, an anti-LAG-3 antibody molecule is administered in combination with an anti-PD-1 antibody molecule (eg, an anti-PD-1 antibody molecule described herein). Without wishing to be bound by theory, it is believed that in some embodiments, anti-LAG-3 therapy is expected to have additional effects in combination with anti-PD-1 therapy, as observed in mice (Woo et al. Cancer Research 72: 917 -927 (2012)). The anti-PD-1 antibody molecule can be administered with or without a chemotherapeutic agent (eg, with a platinum agent (eg, carboplatin, cisplatin, oxaliplatin, or tetraplatin) or with a nucleotide analog or precursor analog (eg, capecitabine)). Without wishing to be bound by theory, it is believed that in some embodiments, the addition of a chemotherapeutic agent will further enhance the efficacy of anti-LAG-3 immunotherapy, alone or in combination with anti-PD-1 immunotherapy, by making the tumor more immune-reactive and/or by altering the environment. tumor microenvironment to achieve an optimal antitumor immune response.

In certain embodiments, the anti-PD-1 antibody molecule is administered at a dose of about 300 mg to about 500 mg (e.g., about 400 mg) once every four weeks, or from about 200 mg to about 400 mg (e.g., about 300 mg ) once every three weeks. In some embodiments, the anti-PD-1 antibody molecule is administered at a dose of about 300 mg to about 500 mg (eg, about 400 mg) once every four weeks. In some embodiments, the anti-PD-1 antibody molecule is administered at a dose of about 200 mg to about 400 mg (eg, about 300 mg) once every three weeks.

In certain embodiments, the anti-LAG-3 antibody molecule is administered at a dose of about 300 mg to about 500 mg (e.g., about 400 mg) once every three weeks and the anti-PD-1 antibody molecule is administered at a dose of about 200 mg of about up to 400 mg (eg, about 300 mg) once every three weeks. In certain embodiments, the anti-LAG-3 antibody molecule is administered at a dose of about 300 mg to about 500 mg (e.g., about 400 mg) once every three weeks and the anti-PD-1 antibody molecule is administered at a dose of about 300 mg to about up to 500 mg (eg, about 400 mg) once every four weeks. In certain embodiments, the anti-LAG-3 antibody molecule is administered at a dose of about 700 mg to about 900 mg (e.g., about 800 mg) once every four weeks and the anti-PD-1 antibody molecule is administered at a dose of about 200 mg of about up to 400 mg (eg, about 300 mg) once every three weeks. In certain embodiments, the anti-LAG-3 antibody molecule is administered at a dose of about 700 mg to about 900 mg (e.g., about 800 mg) once every four weeks and the anti-PD-1 antibody molecule is administered at a dose of about 300 mg of about up to 500 mg (eg, about 400 mg) once every four weeks. In certain embodiments, the anti-LAG-3 antibody molecule is administered at a dose of about 500 mg to 650 mg (e.g., about 533 mg or about 600 mg) once every four weeks and the anti-PD-1 antibody molecule is administered at a dose of about 200 mg to about 400 mg (eg, about 300 mg) once every three weeks. In certain embodiments, the anti-LAG-3 antibody molecule is administered at a dose of about 500 mg to 650 mg (e.g., about 533 mg or about 600 mg) once every four weeks and the anti-PD-1 antibody molecule is administered at a dose of about 300 mg to about 500 mg (eg, about 400 mg) once every four weeks.

In some embodiments, the anti-TIM-3 antibody molecule is administered in combination with a chemotherapeutic agent (eg, a platinum agent (eg, carboplatin, cisplatin, oxaliplatin, or tetraplatin) or a nucleotide analog or precursor analog (eg, capecitabine)). In some embodiments, the chemotherapeutic agent is a platinum agent. In certain embodiments, the platinum agent is carboplatin. In certain embodiments, the platinum agent is cisplatin. In certain embodiments, the platinum agent is oxaliplatin. In certain embodiments, the platinum agent is tetraplatin.

In some embodiments, the chemotherapeutic agent is a nucleotide analog or a precursor analog. In certain embodiments, the nucleotide analog or precursor analog is capecitabine.

In certain embodiments, the anti-LAG-3 antibody molecule is administered at a dose of about 300 mg to 500 mg (e.g., about 400 mg) once every three weeks and the chemotherapeutic agent (e.g., a platinum agent, e.g., carboplatin) is administered at a dose of to achieve an area under the curve (AUC) of about 4 to about 8 or about 5 to about 7 (eg, AUC of about 6) once every three weeks.

In certain embodiments, the anti-LAG-3 antibody molecule is administered at a dose of about 300 mg to about 500 mg (e.g., about 400 mg) once every three weeks, the anti-PD-1 antibody molecule is administered at a dose of about 200 mg of about up to 400 mg (eg, about 300 mg) once every three weeks, and the chemotherapeutic agent (eg, a platinum agent, eg, carboplatin) is administered at a dose to achieve an area under the curve (AUC) of about 4 to about 8, or about 5 up to about 7 (eg, AUC from about 6) once every three weeks.

In certain embodiments, the anti-LAG-3 antibody molecule is LAG525 and the anti-PD-1 antibody molecule is PDR001 (spartalizumab).

In some embodiments, the anti-LAG-3 antibody molecule is LAG525 and the chemotherapeutic agent is a platinum agent. In certain embodiments, the anti-LAG-3 antibody molecule is LAG525 and the platinum agent is carboplatin. In certain embodiments, the anti-LAG-3 antibody molecule is LAG525 and the platinum agent is cisplatin. In certain embodiments, the anti-LAG-3 antibody molecule is LAG525 and the platinum agent is oxaliplatin. In certain embodiments, the anti-LAG-3 antibody molecule is LAG525 and the platinum agent is tetraplatin.

In some embodiments, the anti-LAG-3 antibody molecule is LAG525, the chemotherapeutic agent is a platinum agent, and the anti-PD-1 antibody molecule is PDR001 (spartalizumab). In certain embodiments, the anti-LAG-3 antibody molecule is LAG525, the platinum agent is carboplatin, and the anti-PD-1 antibody molecule is PDR001 (spartalizumab). In certain embodiments, the anti-LAG-3 antibody molecule is LAG525, the platinum agent is cisplatin, and the anti-PD-1 antibody molecule is PDR001 (spartalizumab). In certain embodiments, the anti-LAG-3 antibody molecule is LAG525, the platinum agent is oxaliplatin, and the anti-PD-1 antibody molecule is PDR001 (spartalizumab). In certain embodiments, the anti-LAG-3 antibody molecule is LAG525, the platinum agent is tetraplatin, and the anti-PD-1 antibody molecule is PDR001 (spartalizumab).

In some embodiments, the anti-LAG-3 antibody molecule is LAG525 and the chemotherapeutic agent is a nucleotide analog or a precursor analog. In certain embodiments, the anti-LAG-3 antibody molecule is LAG525 and the nucleotide analog or precursor analog is capecitabine.

In some embodiments, the anti-LAG-3 antibody molecule is LAG525, the chemotherapeutic agent is a nucleotide analog or precursor analog, and the anti-PD-1 antibody molecule is PDR001 (spartalizumab). In certain embodiments, the anti-LAG-3 antibody molecule is LAG525, the nucleotide analog or precursor analog is capecitabine, and the anti-PD-1 antibody molecule is PDR001 (spartalizumab).

Any of the dosages described in the present invention may be repeated once, twice, three times, four times, five times, six times, seven times, eight times, nine times, ten times or more.

antibody molecules

The present invention describes methods, compositions and preparations that contain an antibody molecule that binds to LAG-3 of a mammal, such as a human. For example, an antibody molecule binds specifically to an epitope, eg, a linear or conformational epitope (eg, an epitope as described herein) of LAG-3.

As used herein, the term "antibody molecule" refers to a protein, for example, an immunoglobulin chain or fragment thereof, containing at least one immunoglobulin variable domain sequence. The term "antibody molecule" includes, for example, a monoclonal antibody (including a full-length antibody that contains the Fc region of an immunoglobulin). In one embodiment, the antibody molecule comprises a full length antibody or a full length immunoglobulin chain. In one embodiment, the antibody molecule comprises an antigen-binding or functional fragment of a full length antibody or a full length immunoglobulin chain. In one embodiment, the antibody molecule is a multispecific antibody molecule, for example, it contains a plurality of immunoglobulin variable domain sequences, wherein the first immunoglobulin variable domain sequence of the plurality has a binding specificity for the first epitope and the second immunoglobulin variable domain sequence of the plurality has a specificity binding to the second epitope. In one embodiment, the multispecific antibody molecule is a bispecific antibody molecule.

In one embodiment, the antibody molecule is a monospecific antibody molecule and binds to a single epitope. For example, a monospecific antibody molecule may have multiple immunoglobulin variable domain sequences, each of which binds to the same epitope.

In one embodiment, the antibody molecule is a multispecific antibody molecule, e.g., it comprises a plurality of immunoglobulin variable domain sequences, wherein a first immunoglobulin variable domain sequence of the plurality has a binding specificity for a first epitope and a second immunoglobulin variable domain sequence of the plurality has specificity of binding to the second epitope. In one embodiment, the first and second epitopes are on the same antigen, eg, on the same protein (or subunit of a multimeric protein). In one embodiment, the first and second epitopes overlap. In one embodiment, the first and second epitopes do not overlap. In one embodiment, the first and second epitopes are on different antigens, eg on different proteins (or on different subunits of a multimeric protein). In one embodiment, the multispecific antibody molecule contains a third, fourth, or fifth immunoglobulin variable domain. In one embodiment, the multispecific antibody molecule is a bispecific antibody molecule, a trispecific antibody molecule, or a tetraspecific antibody molecule.

In one embodiment, the multispecific antibody molecule is a bispecific antibody molecule. A bispecific antibody has specificity for no more than two antigens. The bispecific antibody molecule is characterized by a first immunoglobulin variable domain sequence that has a binding specificity for a first epitope and a second immunoglobulin variable domain sequence that has a binding specificity for a second epitope. In one embodiment, the first and second epitopes are on the same antigen, eg, on the same protein (or subunit of a multimeric protein). In one embodiment, the first and second epitopes overlap. In one embodiment, the first and second epitopes do not overlap. In one embodiment, the first and second epitopes are on different antigens, eg on different proteins (or on different subunits of a multimeric protein). In one embodiment, the bispecific antibody molecule comprises a heavy chain variable domain sequence and a light chain variable domain sequence that have a binding specificity for a first epitope, and a heavy chain variable domain sequence and a light chain variable domain sequence that have a binding specificity for a second epitope. . In one embodiment, the bispecific antibody molecule comprises half an antibody having a binding specificity for a first epitope and half an antibody having a binding specificity for a second epitope. In one embodiment, the bispecific antibody molecule comprises half of the antibody or fragment thereof having a binding specificity for a first epitope and half of an antibody or fragment thereof having a binding specificity for a second epitope. In one embodiment, the bispecific antibody molecule comprises an scFv or fragment thereof that has a binding specificity for a first epitope and an scFv or fragment thereof that has a binding specificity for a second epitope. In one embodiment, the first epitope is located on LAG-3 and the second epitope is located on PD-1, TIM-3, CEACAM (eg, CEACAM-1 and/or CEACAM-5), PD-L1, or PD-L2.

Protocols for generating multispecific (eg, bispecific or trispecific) or heterodimeric antibody molecules are known in the art; including, for example, but not limited to, the ridge-to-bottom approach described, for example, in US Pat. No. 5,731,168; electrostatically controlled Fc-pairing, as described, for example, in WO 09/089004, WO 06/106905 and WO 2010/129304; formation of heterodimers of genetically engineered domains with strand exchange (SEED), as described, for example, in WO 07/110205; exchanging Fab fragments as described, for example, in WO 08/119353, WO 2011/131746 and WO 2013/060867; a dual antibody conjugate, eg, by crosslinking antibodies to generate a bispecific structure, using a heterobifunctional reagent containing an amine reactive group and a sulfhydryl reactive group, as described, eg, in US Pat. No. 4,433,059; bispecific antibody determinants generated by recombination of antibody halves (heavy-light chain or Fab pairs) from different antibodies through a cycle of reduction and oxidation of disulfide bonds between the two heavy chains, as described, for example, in US Pat. No. 4,444,878; trifunctional antibodies, eg three Fab' fragments, cross-linked with sulfhydryl-reactive groups as described, for example, in US Pat. No. 5,273,743; biosynthetic binding proteins, eg a pair of scFvs, cross-linked with C-terminal tails, preferably by disulfide or amine reactive chemical crosslinking, as described, for example, in US Pat. No. 5,534,254; bifunctional antibodies, eg, Fab fragments with different binding specificities dimerized with leucine zippers (eg, c-fos and c-jun) in which the constant domain has been replaced, as described, for example, in US Pat. No. 5,582,996; bispecific and oligospecific mono- and oligovalent receptors, e.g., the VH-CH1 regions of two antibodies (two Fab fragments) linked via a polypeptide spacer between the CH1 region of one antibody and the VH region of the other antibody, typically with associated light chains as described, for example , in US Pat. No. 5,591,828; bispecific DNA-antibody conjugates, eg, cross-linking of antibodies or Fab fragments through a double-stranded piece of DNA, as described, for example, in US Pat. No. 5,635,602; bispecific fusion proteins, eg, an expression construct containing two scFvs with a hydrophilic helical peptide linker between them and a complete constant region, as described, for example, in US Pat. No. 5,637,481; multivalent and multispecific binding proteins, for example, a dimer of polypeptides containing a first domain with an Ig heavy chain variable region binding region and a second domain with an Ig light chain variable region binding region, commonly referred to as diabodies (higher-order structures are also described, creating bispecific, trispecific or tetraspecific molecules as described, for example, in US Pat. described, for example, in US Pat. as described, for example, in US patent No. 5844094; a strand of VH domains (or VL domains in family members) connected by peptide bonds with cross-linked groups at the C-terminus, further associated with VL domains to form a series of FVs (or scFvs), as described, for example, in US patent No. 5864019 ; and both VH and VL domain binding single chain polypeptides linked via a peptide linker that are combined into multivalent structures via non-covalent or chemical cross-linking to form, for example, homobivalent, heterobivalent, trivalent and tetravalent structures using both the scFV type format , and a diabody type format as described, for example, in US Pat. No. 5,869,620. US6333396 US6476198 US6511663 US6670453 US6743896 US6809185 US6833441 US7129330 US7183076 US7521056 US7527787 US7534866 US7612181 US2002/004587 A1, US2002/076406A1, US2002/103345A1, US2003/207346A1, US2003/211078A1, US2004/219643A1, US2004 /220388A1, US2004/242847A1, US2005/003403A1, US2005/004352A1, US2005/069552A1, US2005/079170A1, US2005/100543A1, US2005/136049A1, US2005/1 36051A1, US2005/163782A1, US2005/266425A1, US2006/083747A1, US2006/120960A1 , US2006/204493A1, US2006/263367A1, US2007/004909A1, US2007/087381A1, US2007/128150A1, US2007/141049A1, US2007/154901A1 US2008/050370A1, US2008/069820A1, US2008/152645A1, US2008/171855A1, US2008 /241884A1, US2008/254512A1, US2008/260738A1, US2009/130106A1, US2009/148905A1, US2009/155275A1, US2009/162359A1, US2009/162360A1, US2009/1 75851A1, US2009/175867A1, US2009/232811A1, US2009/234105A1, US2009/263392A1 , US2009/274649A1, in European patent EP346087A2, in patent applications WO00/06605A2, WO02/072635A2, WO04/081051A1, WO06/020258A2, WO2007/044887A2, WO2007/0953 38A2, WO2007/137760A2, WO2008/119353A1, WO2009/021754A2, WO2009/068630A1, WO91/03493A1, WO93/23537A1, WO94/09131A1, WO94/12625A2, WO95/09917A1, WO96/37621A2, WO99/64460A1. The contents of the applications mentioned above are incorporated herein by reference in their entirety.

In other embodiments, an anti-LAG-3 antibody molecule (e.g., a monospecific, bispecific, or multispecific antibody molecule) is covalently linked, such as fused, to another partner, such as a protein, such as one, two, or more cytokines, such as a fusion molecule, such as a fusion protein. In other embodiments, the fusion molecule contains one or more proteins, such as one, two or more cytokines. In one embodiment, the cytokine is an interleukin (IL) selected from one, two, three or more of IL-1, IL-2, IL-12, IL-15, or IL-21. In one embodiment, the bispecific antibody molecule has a first binding specificity for a first target (e.g., LAG-3), a second binding specificity for a second target (e.g., PD-1 or TIM-3), and optionally associated with an interleukin domain ( eg, IL-12), eg, with full-length IL-12 or part of it.

"Fusion protein" and "fusion polypeptide" refers to a polypeptide having at least two parts covalently linked together, where each part is a polypeptide having different properties. The properties may be a biological property such as in vitro or in vivo activity. The property may also be a simple chemical or physical property such as binding to a target molecule, catalyzing a reaction, and the like. The two parts can be linked directly with a single peptide bond or with a peptide linker, but are in reading frame with each other.

In one embodiment, the antibody molecule includes a diabody, and a single chain molecule, as well as an antigen-binding antibody fragment (eg, Fab, F(ab') ₂ and Fv). For example, an antibody molecule may comprise a heavy (H) chain variable domain sequence (abbreviated herein as VH) and a light (L) chain variable domain sequence (abbreviated herein as VL). In one embodiment, the antibody molecule contains, or consists of, a heavy chain and a light chain (referred to herein as half of the antibody. In another example, the antibody molecule contains two heavy (H) chain variable domain sequences and two light chain variable domain sequences (L) chains, thereby forming two antigen binding sites such as Fab, Fab', F(ab') ₂ , Fc, Fd, Fd', Fv, single chain antibodies (eg scFv), single variable domain antibodies, diabodies (Dab) (bivalent and bispecific) and chimeric (e.g. humanized) antibodies, which can be obtained by modifying whole antibodies or antibodies synthesized de novo using recombinant DNA technologies These functional antibody fragments retain the ability to selectively bind their respective antigen or receptor Antibodies and antibody fragments can be from any class of antibody, including but not limited to IgG, IgA, IgM, IgD, and IgE, and from any subclass (e.g., IgG1, IgG2, IgG3, and IgG4) of antibodies. The preparation of antibody molecules can be monoclonal or polyclonal. The antibody molecule may also be a human, germanized, CDR-grafted or in vitro generated antibody. The antibody may have a heavy chain constant region selected from, for example, IgG1, IgG2, IgG3, or IgG4. The antibody may also have a light chain selected from, for example, a kappa or lambda chain. In this document, the term "immunoglobulin" (Ig) is used interchangeably with the term "antibody".

Examples of antigen-binding fragments of an antibody molecule include: (i) a Fab fragment, a monovalent fragment consisting of the VL, VH, CL, and CH1 domains; (ii) an F(ab')2 fragment, a bivalent fragment containing two Fab fragments linked by a disulfide bridge in the hinge region; (iii) an Fd fragment consisting of VH and CH1 domains; (iv) an Fv fragment consisting of the VL and VH domains of a single antibody fragment, (v) a diabody fragment (dAb) which consists of a VH domain; (vi) a camelid variable domain or a camel variable domain; (vii) single chain Fv (scFv), see eg Bird et al. (1988) Science 242:423-426; and Huston et al. (1988) Proc. Natl. Acad. sci. USA 85:5879-5883); (viii) single domain antibody. These antibody fragments are prepared using conventional techniques known to those skilled in the art, and the fragments are screened for utility in the same manner as intact antibodies.

The term "antibody" includes intact molecules as well as their functional fragments. Antibody constant regions can be altered, such as mutated, to modify the properties of the antibody (eg, to increase or decrease one or more of: Fc receptor binding, antibody glycosylation, cysteine residue count, effector cell function, or complement function).

The antibody molecules may also be single domain antibodies. Single domain antibodies may include antibodies in which complementarity determining regions are part of a single domain polypeptide. Examples include, but are not limited to, heavy chain antibodies, antibodies lacking naturally light chains, single domain antibodies derived from conventional 4-chain antibodies, engineered antibodies, and non-antibody derived single domain scaffolds. Single domain antibodies can be any single domain antibodies known in the art or any future single domain antibodies. Single domain antibodies can be obtained from any species, including, but not limited to, mice, humans, camels, llamas, fish, sharks, goats, rabbits, and cattle. According to another aspect of the present invention, the single domain antibody is a naturally occurring single domain antibody known as a heavy chain antibody lacking light chains. Such single domain antibodies are described, for example, in WO 94/04678. For clarity, this variable domain derived from a heavy chain antibody naturally lacking a light chain is referred to herein as a VHH or nanobody to distinguish it from conventional VH four chain immunoglobulins. Such a VHH molecule can be obtained from antibodies grown in Camelidae species such as camel, llama, dromedary, alpaca and guanaco. Species other than the Camelidae can produce heavy chain antibodies that naturally lack a light chain; such VHHs are within the scope of the present invention.

The VH and VL regions can be subdivided into regions of hypervariability called "complementarity determining regions" (CDRs), between which are regions that are more conserved, called "reading frame regions (FR or FW).

Frame and CDR extents are accurately determined using a number of methods (see Kabat , EA, et al . (1991) Sequences of Proteins of Immunological, Interest, Fifth Edition, US Department of Health and Human Services, NIH Publication No. 91- 3242; Chothia, C. et al . (1987) J. Mol. Biol . 196:901-917; and the AbM definition used by Oxford Molecular's AbM antibody modeling software. See , in general, e.g., Protein Sequence and Structure Analysis of Antibody Variable Domains, in: Antibody Engineering Lab Manual (Ed.: Duebel, S. and Kontermann, R., Springer-Verlag, Heidelberg).

The terms “complementarity determining region” and “CDR,” as used herein, refer to the sequence of amino acids in the variable regions of an antibody that confer antigen specificity and binding affinity. In general, there are three CDRs in each of the heavy chain variable regions (HCDR1, HCDR2, and HCDR3) and three CDRs in each of the light chain variable regions (LCDR1, LCDR2, and LCDR3).

The exact amino acid sequence boundaries of a given CDR can be determined using any of a number of well known schemes, including those described by Kabat et al. (1991), “Sequences of Proteins of Immunological Interest,” 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (“Kabat” numbering scheme), Al-Lazikani et al. , (1997) JMB 273,927-948 (numbering scheme “Chothia”). As used herein, CDRs defined according to the “Chothia” numbering scheme are sometimes also referred to as “hypervariable loops”.

For example, according to Kabat, the CDR amino acid residues in the heavy chain variable domain (VH) are numbered 31-35 (HCDR1), 50-65 (HCDR2), and 95-102 (HCDR3); and the CDR amino acid residues in the light chain variable domain (VL) are numbered 24-34 (LCDR1), 50-56 (LCDR2) and 89-97 (LCDR3). According to Chothia, the CDR amino acids in VH are numbered 26-32 (HCDR1), 52-56 (HCDR2), and 95-102 (HCDR3); and amino acid residues in VL are numbered 26-32 (LCDR1), 50-52 (LCDR2) and 91-96 (LCDR3). When combining the CDR definitions of both Kabat and Chothia, the CDR consists of amino acid residues 26-35 (HCDR1), 50-65 (HCDR2), and 95-102 (HCDR3) in the human VH and amino acid residues 24-34 (LCDR1) , 50-56 (LCDR2) and 89-97 (LCDR3) in human VL.

Generally, unless otherwise indicated, anti-LAG-3 antibody molecules may contain any combination of one or more Kabat CDRs and/or Chothia hypervariable loops. In one embodiment, the following definitions are used for anti-LAG-3 antibody molecules: for HCDR1 according to the combined CDR definitions of both Kabat and Chothia, and for HCCDR 2-3 and LCCDR 1-3 according to the Kabat CDR definition. By all definitions, each VH and VL typically contains three CDRs and four FRs, ranging from amino to carboxy in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.

As used herein, an “immunoglobulin variable domain sequence” refers to an amino acid sequence that can form the structure of an immunoglobulin variable domain. For example, the sequence may contain all or part of the amino acid sequence of a naturally occurring variable domain. For example, the sequence may or may not contain one, two or more N- or C-terminal amino acids, or may contain other changes that are compatible with the formation of protein structure.

The term "antigen binding site" refers to that portion of an antibody molecule that contains determinants that form an interface that binds to a LAG-3 polypeptide or epitope thereof. For proteins (or protein mimetics), the antigen binding site typically contains one or more loops (of at least four amino acids or amino acid mimetics) that form an interface that binds to the LAG-3 polypeptide. Typically, the antigen-binding site of an antibody molecule contains at least one or two CDRs and/or hypervariable loops, or more commonly at least three, four, five or six CDRs and/or hypervariable loops.

The terms "compete" or "cross-compete" are used interchangeably herein to refer to the ability of an antibody molecule to influence the binding of an anti-LAG-3 antibody molecule, e.g., the anti-LAG-3 antibody molecule provided herein, to a target, e.g., LAG-3 people. The effect on binding may be direct or indirect (eg, through allosteric modulation of the antibody or target molecule). The degree to which an antibody molecule can interfere with the binding of another antibody molecule to a target, and therefore whether competition can be considered, can be determined using the assay. competitive binding, for example, a FACS assay, an ELISA assay, or a BIACORE assay. In some embodiments, the competitive binding assay is a quantitative competitive assay. In some embodiments, the first anti-LAG-3 antibody molecule is said to compete for target binding with the second anti-LAG-3 antibody molecule when the first antibody molecule's binding to the target is reduced by 10% or more, e.g., 20% or more, 30% or more, 40% or more, 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more , 80% or more, 85% or more, 90% or more, 95% or more, 98% or more, 99% or more in a competitive binding assay (e.g., in the competitive assay described herein). document).

The terms “monoclonal antibody” or “monoclonal antibody composition”, as used herein, refers to the preparation of antibody molecules of a monomolecular composition. The composition of the monoclonal antibody shows a single specificity and binding affinity for a particular epitope. The monoclonal antibody can be produced by hybridoma technology or by methods that do not use hybridoma technology (eg, recombinant methods).

An "effectively human" protein is a protein that does not elicit a neutralizing antibody response, such as an anti-mouse human antibody (HAMA) response. HAMA can be a problem in a number of circumstances, for example if the antibody molecule is administered multiple times, such as in the treatment of a chronic or recurrent disease state. A HAMA reaction can render repeated administration of the antibody potentially ineffective due to increased serum clearance of the antibody (see e.g. Saleh et al. , Cancer Immunol. Immunother. 32:180-190 (1990)), as well as potential allergic reactions. (see , for example, LoBuglio et al., Hybridoma , 5:5117-5123 (1986)).

The antibody molecule may be a polyclonal or monoclonal antibody. In other embodiments, the antibody may be produced recombinantly, for example, produced using phage display or combinatorial methods.

Phage display and combinatorial methods for generating antibodies are known in the art (as described, for example, in Ladner et al. US Pat. No. 5,223,409; Kang et al. International Publication No. WO 92/18619; Dower et al. International Publication No. WO 91/17271 Winter et al, International Publication No. WO 92/20791, Markland et al, International Publication No. WO 92/15679, Breitling et al, International Publication No. WO 93/01288, McCafferty et al, International Publication No. WO 92/01047; Garrard et al International Publication No WO 92/09690 Ladner et al International Publication No WO 90/02809 Fuchs et al (1991) Bio/Technology 9:1370-1372 Hay et al (1992) Hum Antibody Hybridomas 3:81-85 Huse et al (1989) Science 246:1275-1281 Griffths et al (1993) EMBO J 12:725-734 Hawkins et al (1992) J Mol Biol 226:889-896 ; Clackson et al. (1991) Nature 352:624-628; Gram et al. (1992) PNAS 89:3576-3580; Garrad et al. (1991) Bio/Technology 9:1373-1377; Hoogenboom et al. ( 1991) Nuc Acid Res 19:4133-4137; and Barbas et al. (1991) PNAS 88:7978-7982, the contents of which are all incorporated herein by reference).

In one embodiment, the antibody is a fully human antibody (e.g., an antibody derived from a mouse that is genetically engineered to produce an antibody from a human immunoglobulin sequence), or a non-human antibody, such as a rodent (mouse or rat), goat , primate (for example, monkeys), camel. Preferably, the non-human antibody is a rodent (mouse or rat antibody). Methods for producing rodent antibodies are known in the art.

Human monoclonal antibodies can be generated using transgenic mice carrying human immunoglobulin genes instead of the mouse system. Splenocytes from these transgenic mice, immunized with an antigen of interest, are used to produce hybridomas that secrete human mAbs with specific affinities for human protein epitopes (see , for example, Wood et al. International application WO 91/00906, Kucherlapati et al. PCT Publication WO 91/10741 Lonberg et al International Application WO 92/03918 Kay et al International Application 92/03917 Lonberg, N. et al 1994 Nature 368:856-859 Green, LL et al 1994 Nature Genet 7:13-21 Morrison, SL et al 1994 Proc Natl Acad Sci USA 81:6851-6855 Bruggeman et al 1993 Year Immunol 7:33-40 Tuaillon et al 1993 PNAS 90:3720-3724; Bruggeman et al. 1991 Eur J Immunol 21:1323-1326).

The antibody may be an antibody in which the variable region or part thereof, such as the CDR, is generated in a non-human body, such as in a rat or a mouse. Chimeric, CDR-grafted and humanized antibodies are covered by the present invention. Antibodies generated in a non-human body, such as a rat or mouse, and then modified, such as in a variable reading frame or in a constant region, to reduce human antigenicity are within the scope of the present invention.

Chimeric antibodies can be made using recombinant DNA technologies known in the art ( see Robinson et al. , International Patent Publication PCT/US86/02269; Akira, et al., EP application 184,187; Taniguchi, M., EP application). Patent 171,496; Morrison et al., EP Application 173,494; Neuberger et al ., WO 86/01533; Cabilly et al ., US Patent No. 4,816,567; Cabilly et al. , EP Application 125,023; (1988 Science 240:1041-1043); Liu et al. (1987) PNAS 84:3439-3443; Liu et al ., 1987, J. Immunol. 139:3521-3526; Sun et al. (1987) PNAS 84 :214-218; Nishimura et al ., 1987, Canc. Res. 47:999-1005; Wood et al. (1985) Nature 314:446-449; and Shaw et al ., 1988, J. Natl Cancer Inst. 80:1553-1559).

A humanized or CDR-grafted antibody will have at least one or two, but typically all three, of the recipient's CDRs (from immunoglobulin heavy and/or light chains) replaced by the donor's CDRs. The antibody may be replaced with at least a portion of the non-human CDRs, or only some of the CDRs may be replaced with non-human CDRs. It is only necessary to change the amount of CDR required to bind the humanized antibody to PD-1. Preferably, the donor will be a rodent antibody, such as a rat or mouse antibody, and the recipient will be a human reading frame or a human consensus reading frame. Typically, an immunoglobulin providing a CDR is referred to as a "donor" and an immunoglobulin providing a reading frame is referred to as an "acceptor". In one embodiment, the donor immunoglobulin is not from a human (eg, from a rodent). An acceptor reading frame is a naturally occurring (for example, human) reading frame or consensus reading frame, or sequence about 85% or greater, preferably 90%, 95%, 99% or greater identical to it.

As used herein, the term "consensus sequence" refers to a sequence formed from the most frequently occurring amino acids (or nucleotides) in a family of related sequences (see , for example, Winnaker, From Genes to Clones (Verlagsgesellschaft, Weinheim, Germany 1987). in a family of proteins, each position in the consensus sequence is occupied by the amino acid that occurs most frequently in that position of the family.If two amino acids occur with equal frequency, either one can be included in the consensus sequence. .

The antibody can be humanized using methods known in the art (see , for example, Morrison, SL, 1985, Science 229:1202-1207, by Oi et al., 1986, BioTechniques 4:214, and by Queen et al. US Pat. No. 5,585,089 , US Pat. No. 5,693,761 and US Pat. No. 5,693,762, the contents of which are all hereby incorporated by reference).

Humanized or CDR-grafted antibodies can be obtained by CDR grafting or CDR substitution, where one, two or all of the immunoglobulin chain CDRs can be replaced. See , for example, US Pat. No. 5,225,539; Jones et al. 1986 Nature 321:552-525; Verhoeyan et al. 1988 Science 239:1534; Beidler et al. 1988 J. Immunol. 141:4053-4060; Winter, US Pat. No. 5,225,539, the contents of all of them are hereby expressly incorporated by reference. Winter describes a CDR grafting method that can be used to prepare the humanized antibodies of the present invention (UK GB 2188638A, filed Mar. 26, 1987; Winter, US 5225539), the contents of which are expressly incorporated by reference.

Also within the scope of the present invention are humanized antibodies in which specific amino acids are substituted, eliminated or added. The criteria for selecting amino acids from a donor are described in US Pat. Other antibody humanization technologies are described in Padlan et al. EP 519596 A1 published December 23, 1992.

The antibody molecule may be a single chain antibody. The single chain antibody (scFV) may be engineered (see , for example, Colcher, D. et al. (1999) Ann NY Acad Sci 880:263-80; and Reiter, Y. (1996) Clin Cancer Res 2:245- 52). A single chain antibody can dimerize or multimerize to generate multivalent antibodies having specificities for different epitopes of the same target protein.

In yet another embodiment, the antibody molecule has a heavy chain constant region selected, for example, from heavy chain constant regions of IgG1, IgG2, IgG3, IgG4, IgM, IgA1, IgA2, IgD, and IgE; in particular selected, for example, from the heavy chain constant regions of IgG1, IgG2, IgG3 and IgG4 (eg human). In another embodiment, the antibody molecule has a light chain constant region selected from , for example, kappa or lambda (eg, human) light chain constant regions. The constant region can be changed, eg, mutated, to modify the properties of the antibody (eg, to increase or decrease one or more of Fc receptor binding, antibody glycosylation, cysteine residue count, effector cell function, and/or complement function). In one embodiment, the antibody has: an effector function and can fix complement. In other embodiments, the antibody does not recruit effector cells or fix complement. In another embodiment, the antibody has reduced or no Fc receptor binding capacity. For example, it is an isotype or subtype, fragment, or other mutant that does not support binding to an Fc receptor, for example, it has a mutated or deleted Fc receptor binding region.

Methods for changing the constant region of an antibody are known in the art. Antibodies with altered function, such as altered affinity for an effector ligand such as an FcR on a cell or the C1 component of complement, can be generated by substituting at least one amino acid residue in the constant portion of an antibody with another residue (see e.g. EP 388151 A1, US Pat. No. 5,624,821 and US Pat. No. 5,648,260, the contents of all of which are hereby incorporated by reference). A similar type of change can be described which, if applied to an immunoglobulin of a mouse or other species, would reduce or eliminate these functions.

An antibody molecule may be derivatized or associated with another functional molecule (eg, another peptide or protein). As used herein, a "derivatized" antibody molecule is one that is modified. Derivatization methods include, but are not limited to, the addition of a fluorescent moiety, a radionucleotide, a toxin, an enzyme, or an affinity ligand such as biotin. Accordingly, the antibody molecules of the present invention are intended to include derivatized and otherwise modified forms of the antibodies described herein, including immunoadhesion molecules. For example, an antibody molecule may be operably linked (by chemical bonding, genetic fusion, non-covalent association, or otherwise) to one or more other molecular entities, such as another antibody (e.g., a bispecific antibody or diabody), a detectable agent, a cytotoxic agent, a pharmaceutical agent. and/or a protein or peptide that can mediate association of the antibody or antibody portion with another molecule (such as a streptavidin core region or a polyhistidine tag).

One type of derivatized antibody molecule is obtained by cross-linking two or more antibodies (of the same type or different types, for example, to create bispecific antibodies). Suitable crosslinkers include crosslinkers that are heterobifunctional, having two different reactive groups separated by an appropriate spacer (eg, m-maleimidobenzoyl-N-hydroxysuccinimide ester) or homobifunctional (eg, disuccinimidyl suberate). Such linkers are available from Pierce Chemical Company, Rockford, Ill.

Useful detectable agents with which to derivatize (or label) an antibody molecule of the present invention include fluorescent compounds, various enzymes, prosthetic groups, luminescent materials, bioluminescent materials, fluorescent metal atoms such as europium (Eu) and other lanthanides, and radioactive materials (described below). Exemplary fluorescent detectable agents include fluorescein, fluorescein isothiocyanate, rhodamine, 5-dimethylamine - 1-naphthalenesulfonyl chloride, phycoerythrin, and the like. The antibody can also be derivatized with detectable enzymes such as alkaline phosphatase, horseradish peroxidase, β-galactosidase, acetylcholinesterase, glucose oxidase, and the like. When an antibody is derivatized with a detectable enzyme, it is detected by adding additional reagents that the enzyme uses to produce a detectable reaction product. For example, when the detectable agent horseradish peroxidase is present, the addition of hydrogen peroxide and diaminobenzidine results in a colored reaction product that is detectable. An antibody molecule can also be derivatized with a prosthetic group (eg streptavidin/biotin and avidin/biotin). For example, an antibody can be derivatized with biotin, and detected by indirect measurement of avidin or streptavidin binding. Examples of suitable fluorescent materials include umbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, dansyl chloride or phycoerythrin; an example of a luminescent material includes luminal; and examples of bioluminescent materials include luciferase, luciferin, and aequorin.

The labeled antibody molecule can be used, for example, diagnostically and/or experimentally in a number of contexts, including (i) isolation of a given antigen using standard techniques such as affinity chromatography or immunoprecipitation; (ii) detecting a given antigen (eg, in a cell lysate or cell supernatant) to assess the content and pattern of protein expression; (iii) monitoring tissue protein levels as part of a clinical trial procedure, for example, to determine the effectiveness of a given treatment regimen.

Antibody molecules can be conjugated to another molecular entity, typically a label, or to a therapeutic (eg, cytotoxic or static) agent or moiety. Radioactive isotopes can be used in diagnostic or therapeutic applications.

The present invention provides radiolabeled antibody molecules and methods for labeling them. In one embodiment, a method for labeling an antibody molecule is described. The method includes bringing into contact the antibody molecule with a chelating agent, thereby obtaining a conjugated antibody.

As discussed above, an antibody molecule may be conjugated to a therapeutic agent. Therapeuti- cally active radioisotopes have already been considered. Examples of other therapeutic agents include taxa, cytochalazin B, gramicyide D, eTIDIROMID, emin, mitomycin, ethoside, tenosoposide, vincristine, vinblastin, colchicin, doxorubicin, dowenorubicin, digidroxiantracyndium, mitoxanthon, mitramitsin, and assetomicin d, 1-degi d, 1- Drotestosterone, glucocorticoids, prokain, tetracaine, lidocaine, propranolol, puromycin, maytansinoids, e.g. maytansinol (see e.g. US Pat. No. 5208020), CC-1065 ( see e.g. US Pat. Nos. 5475092, 5585499, 5846545) and their analogs or homologues Therapeutic agents include, but are not limited to, antimetabolites (eg, methotrexate, 6-mercaptopurine, 6-thioguanine, cytarabine, 5-fluorouracil decarbazine), alkylating agents (eg, mechlorethamine, thiotepa chlorambucil, CC-1065, melphalan, carmustine (BSNU ) and lomustine (CCNU), cyclophosphamide, busulfan, dibromomannitol, streptozotocin, mitomycin C, and cis-dichlorodiamine platinum(II) (DDP) cisplatin), anthracyclines (eg, daunorubicin (formerly daunomycin) and doxorubicin), antibiotics (eg, dactinomycin ( formerly actinomycin), bleomycin, mithramycin and anthramycin (AMC)) and anti-mitotic agents (eg vincristine, vinblastine, taxol and maytansinoids).

In one aspect, the invention provides a method for obtaining a target binding molecule that specifically binds to the target described in the present invention, for example, LAG-3. For example, the target binding molecule is an antibody molecule. The method includes: obtaining a target protein that contains at least a portion of a non-human protein, the portion is homologous (identical at least 70, 75, 80, 85, 87, 90, 92, 94, 95, 96 , 97, 98%) of the corresponding portion of the target human protein, but differs by at least one amino acid (eg, at least one, two, three, four, five, six, seven, eight, or nine amino acids); obtaining an antibody molecule that specifically binds to the antigen; and assessing the effectiveness of the binding agent on the modulation activity of the target protein. The method may further include administering a binding agent (eg, an antibody molecule) or derivative (eg, a humanized antibody molecule) to a human subject.

The present invention provides an isolated nucleic acid molecule encoding the above antibody molecule, its vectors and host cells. A nucleic acid molecule includes, but is not limited to, RNA, genomic DNA, and cDNA.

Exemplary anti-LAG-3 antibody molecules

In one embodiment, the LAG-3 inhibitor is an anti-LAG-3 antibody molecule as described in US Pat. incorporated by reference in its entirety.

In one embodiment, the anti-LAG-3 antibody molecule contains at least one, two, three, four, five, or six complementarity determining regions (CDRs) (or collectively all CDRs) from the severe and mild variable region chains containing the amino acid sequence shown in Table 5 (for example, the heavy and light chain variable region sequences from BAP050-Clone I or BAP050-Clone J described in Table 5), or they are encoded by the nucleotide sequence shown in Table 5. In some embodiments, the CDRs are as defined by Kabat (eg, as shown in Table 5). In some embodiments, the CDRs match the definition of Chothia (eg, as shown in Table 5). In some embodiments, the CDRs correspond to the combined CDR definitions of both Kabat and Chothia (eg, as shown in Table 5). In one embodiment, the combination of Kabat and Chothia CDR of VH CDR1 contains the amino acid sequence GFTLTNYGMN (SEQ ID NO: 766). In one embodiment, one or more CDRs (or collectively all CDRs) have one, two, three, four, five, six or more changes, such as amino acid substitutions (e.g., conservative amino acid substitutions) or deletions, compared to the sequence amino acids shown in Table 5, or they are encoded by the nucleotide sequence shown in Table 5.

In one embodiment, the anti-LAG-3 antibody molecule comprises a heavy chain variable region (VH) comprising the amino acid sequence of VHCDR1 of SEQ ID NO: 701, the amino acid sequence of VHCDR2 of SEQ ID NO: 702, and the amino acid sequence of VHCDR3 of SEQ ID NO: 702, and the amino acid sequence of VHCDR3 of SEQ ID NO: 703; and a light chain variable region (VL) containing the amino acid sequence of VLCDR1 SEQ ID NO: 710, the amino acid sequence of VLCDR2 SEQ ID NO: 711, and the amino acid sequence of VLCDR3 SEQ ID NO: 712, each of which is described in Table 5.

In one embodiment, the anti-LAG-3 antibody molecule comprises a VH comprising VHCDR1 encoded by the nucleotide sequence of SEQ ID NO: 736 or 737, VHCDR2 encoded by the nucleotide sequence of SEQ ID NO: 738 or 739, and VHCDR3 encoded by the nucleotide sequence of SEQ ID NO: 740 or 741; and VL containing VLCDR1 encoded by the nucleotide sequence of SEQ ID NO: 746 or 747, VLCDR2 encoded by the nucleotide sequence of SEQ ID NO: 748 or 749, and VLCDR3 encoded by the nucleotide sequence of SEQ ID NO: 750 or 751, each of which is described in Table 5. In one embodiment, the anti-LAG-3 antibody molecule comprises a VH containing VHCDR1 encoded by the nucleotide sequence of SEQ ID NO: 758 or 737, VHCDR2 encoded by the nucleotide sequence of SEQ ID NO: 759 or 739, and VHCDR3 encoded by the sequence nucleotides of SEQ ID NO: 760 or 741; and VL containing VLCDR1 encoded by the nucleotide sequence of SEQ ID NO: 746 or 747, VLCDR2 encoded by the nucleotide sequence of SEQ ID NO: 748 or 749, and VLCDR3 encoded by the nucleotide sequence of SEQ ID NO: 750 or 751, each is described in Table 5.

In one embodiment, the anti-LAG-3 antibody molecule comprises a VH containing the amino acid sequence of SEQ ID NO: 706 or an amino acid sequence at least 85%, 90%, 95%, or 99% or greater identical to SEQ ID NO. : 706. In one embodiment, the anti-LAG-3 antibody molecule comprises a VL containing the amino acid sequence of SEQ ID NO: 718 or an amino acid sequence at least 85%, 90%, 95%, or 99% or greater identical to SEQ ID NO: 718. In one embodiment, the anti-LAG-3 antibody molecule comprises a VH containing the amino acid sequence of SEQ ID NO: 724 or the amino acid sequence of at least 85%, 90%, 95%, or 99% or higher identical to SEQ ID NO: 724. In one embodiment, the anti-LAG-3 antibody molecule contains a VL containing the amino acid sequence of SEQ ID NO: 730 or the amino acid sequence of at least 85%, 90%, 95% or 99% or greater identical to SEQ ID NO: 730. In one embodiment, the anti-LAG-3 antibody molecule comprises a VH containing the amino acid sequence of SEQ ID NO: 706 and a VL containing the amino acid sequence of SEQ ID NO: 718. In one of the embodiments, the anti-LAG-3 antibody molecule comprises a VH containing the amino acid sequence of SEQ ID NO: 724 and a VL containing the amino acid sequence of SEQ ID NO: 730.

In one embodiment, the antibody molecule contains a VH encoded by a nucleotide sequence of SEQ ID NO: 707 or 708, or a nucleotide sequence at least 85%, 90%, 95%, or 99% or greater identical to SEQ ID NO: 707 or 708. In one embodiment, the antibody molecule comprises a VL encoded by the nucleotide sequence of SEQ ID NO: 719 or 720, or by a nucleotide sequence at least 85%, 90%, 95%, or 99% or greater identical to SEQ ID NO: 719 or 720. In one embodiment, the antibody molecule contains a VH encoded by the nucleotide sequence of SEQ ID NO: 725 or 726, or the nucleotide sequence, at least 85%, 90%, 95%, or 99% or higher identical to SEQ ID NO: 725 or 726. In one embodiment, the antibody molecule contains a VL encoded by the nucleotide sequence of SEQ ID NO: 731 or 732, or the nucleotide sequence, at least 85%, 90%, 95%, or 99 % or greater identical to SEQ ID NO: 731 or 732. In one embodiment, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 707 or 708 and a VL encoded by the nucleotide sequence of SEQ ID NO: 719 or 720. In one of the embodiments, the antibody molecule comprises VH encoded by the nucleotide sequence of SEQ ID NO: 725 or 726 and VL encoded by the nucleotide sequence of SEQ ID NO: 731 or 732.

In one embodiment, the anti-LAG-3 antibody molecule comprises a heavy chain containing the amino acid sequence of SEQ ID NO: 709 or an amino acid sequence at least 85%, 90%, 95%, or 99% or greater identical to SEQ ID NO: 709. In one embodiment, the anti-LAG-3 antibody molecule comprises a light chain containing the amino acid sequence of SEQ ID NO: 721 or an amino acid sequence of at least 85%, 90%, 95%, or 99%, or above identical to SEQ ID NO: 721. In one embodiment, the anti-LAG-3 antibody molecule contains a heavy chain containing the amino acid sequence of SEQ ID NO: 727 or the amino acid sequence of at least 85%, 90%, 95% or 99% or greater identical to SEQ ID NO: 727. In one embodiment, the anti-LAG-3 antibody molecule comprises a light chain containing the amino acid sequence of SEQ ID NO: 733 or the amino acid sequence of at least 85%, 90 %, 95% or 99% or greater identical to SEQ ID NO: 733. In one embodiment, the anti-LAG-3 antibody molecule comprises a heavy chain containing the amino acid sequence of SEQ ID NO: 709 and a light chain containing the amino acid sequence of SEQ ID NO: 721. In one embodiment, the anti-LAG-3 antibody molecule comprises a heavy chain containing the amino acid sequence of SEQ ID NO: 727 and a light chain containing the amino acid sequence of SEQ ID NO: 733.

In one embodiment, the antibody molecule contains a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 716 or 717 or a nucleotide sequence at least 85%, 90%, 95% or 99% or greater identical to SEQ ID NO: 716 or 717. In one embodiment, the antibody molecule comprises a light chain encoded by the nucleotide sequence of SEQ ID NO: 722 or 723, or a nucleotide sequence at least 85%, 90%, 95%, or 99% or greater identical to SEQ ID NO: 722 or 723. In one embodiment, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 728 or 729 or the nucleotide sequence by at least 85%, 90%, 95%, or 99%, or above identical to SEQ ID NO: 728 or 729. In one embodiment, the antibody molecule contains a light chain encoded by the nucleotide sequence of SEQ ID NO: 734 or 735 or the nucleotide sequence of at least 85%, 90%, 95% or 99% or greater identical to SEQ ID NO: 734 or 735. In one embodiment, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 716 or 717 and a light chain encoded by the nucleotide sequence of SEQ ID NO: 722 or 723 In one embodiment, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 728 or 729 and a light chain encoded by the nucleotide sequence of SEQ ID NO: 734 or 735.

The antibody molecules described herein can be generated using the vectors, host cells, and methods described in US Pat. No. 2015/0259420, incorporated by reference in its entirety.

Table 5 . Amino acid and nucleotide sequences of exemplary anti-LAG-3 antibody molecules

BAP050-Clone I HC SEQ ID NO: 701 (Kabat) HCDR1 NYGMN SEQ ID NO: 702 (Kabat) HCDR2 WINTDTGEPTYADDFKG SEQ ID NO: 703 (Kabat) HDDR3 NPPYYYGTNNAEAMDY SEQ ID NO: 704 (Chothia) HCDR1 GFTLTNY SEQ ID NO: 705 (Chothia) HCDR2 NTDTGE SEQ ID NO: 703 (Chothia) HDDR3 NPPYYYGTNNAEAMDY SEQ ID NO:706 vh QVQLVQSGAEVKKPGASVKVSCKASGFTLTNYGMNWVRQARGQRLEWIGWINTDTGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARNPPYYYGTNNAEAMDYWGQGTTVTVSS SEQ ID NO: 707 DNA VH Caagtgcagctggtgcagtcgggagccgaagtgaagaagcctggagcctcggtgaaggtgtcgtgcaaggcatccggattcaccctcaccaattacgggatgaactgggtcagacaggccggggtcaacggctggagtggatcggatggattaacaccgacaccggggagcctacctacgcggacgatttcaagggacggttcgtgttct ccctcgacacctccgtgtccaccgcctacctccaaatctcctcactgaaagcggaggacaccgccgtgtactattgcgcgaggaacccgccctactactacggaaccaacaacgccgaagccatggactactggggccagggcaccactgtgactgtgtccagc SEQ ID NO: 708 DNA VH CAGGTGCAGCTGGTGCAGTCTGGCGCCGAAGTGAAGAAACCTGGCGCCTCCGTGAAGGTGTCCTGCAAGGCCTCTGGCTTCACCCTGACCAACTACGCATGAACTGGGTGCGACAGGCCAGGGGCCAGCGGCTGGAATGGATCGGCTGGATCAACACCGACACCGGCGAGCCTACCTACGCCGACGACTTCAAGGGCAGATTCGTGTTCTCCCTGGACA CCTCCGTGTCCACCGCCTACCTGCAGATCTCCAGCCTGAAGGCCGAGGATACCGCCGTGTACTACTGCCCGGAACCCCCCCTTACTACTACGGCACCAACAACGCCGAGGCCATGGACTATTGGGGCCAGGGCACCACCGTGACCGTGTCCTCT SEQ ID NO: 709 heavy chain QVQLVQSGAEVKKPGASVKVSCKASGFTLTNYGMNWVRQARGQRLEWIGWINTDTGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARNPPYYYGTNNAEAMDYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSS SLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWES NGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG SEQ ID NO: 716 heavy chain DNA caagtgcagctggtgcagtcgggagccgaagtgaagaagcctggagcctcggtgaaggtgtcgtgtgcaaggcatccggattcaccctcaccaattacgggatgaactgggtcagacaggcccggggtcaacggctggagtggatcggatggattaacaccgacaccggggagcctacctacgcggacgatttcaagggacggttcgtgtt ctccctcgacacctccgtgtccaccgcctacctccaaatctcctcactgaaagcggaggacaccgccgtgtactattgcgcgaggaacccgccctactactacggaaccaacaacgccgaagccatggactactggggccagggcaccactgtgactgtgtccagcgcgtccactaagggcccgtccgtgttccccctggcaccttgtag ccggagcactagcgaatccaccgctgccctcggctgcctggtcaaggattacttcccggagcccgtgaccgtgtcctggaacagcggagccctgacctccggagtgcacaccttccccgctgtgctgcagagctccgggctgtactcgctgtcgtcggtggtcacggtgccttcatctagcctgggtaccaagacctacacttg caacgtggaccacaagccttccaacactaaggtggacaagcgcgtcgaatcgaagtacggcccaccgtgcccgccttgtcccgcgccggagttcctcggcggtccctcggtctttctgttcccaccgaagcccaaggacactttgatgatttcccgcacccctgaagtgacatgcgtggtcgtggacgtgtcacagga agatccgggaggtgcagttcaattggtacgtggatggcgtcgaggtgcacaacgccaaaaccaagccgagggaggagcagttcaactccacttaccgcgtcgtgtccgtgctgacggtgctgcatcaggactggctgaacgggaaggagtacaagtgcaaagtgtccaacaagggacttcctagctcaatcgaaaagaccatctcgaa agccaagggacagccccgggaaccccaagtgtataccctgccaccgagccaggaagaaatgactaagaaccaagtctcattgacttgccttgtgaagggcttctacccatcggatatcgccgtggaatgggagtccaacggccagccggaaaaacaactacaagaccacccctccggtgctggactcagacggatccttcttcctctactcgcggctgaccg tggataagagcagatggcaggagggaaatgtgttcagctgttctgtgatgcatgaagccctgcacaaccactacactcagaagtccctgtccctctccctggga SEQ ID NO: 717 heavy chain DNA CAGGTGCAGCTGGTGCAGTCTGGCGCCGAAGTGAAGAAACCTGGCGCCTCCGTGAAGGTGTCCTGCAAGGCCTCTGGCTTCACCCTGACCAACTACGCATGAACTGGGTGCGACAGGCCAGGGGCCAGCGGCTGGAATGGATCGGCTGGATCAACACCGACACCGGCGAGCCTACCTACGCCGACGACTTCAAGGGCAGATTCGTGTTCTCCCTGGACA CCTCCGTGTCCACCGCCTACCTGCAGATCTCCAGCCCTGAAGGCCGAGGATACCGCCGTGTACTACTGCCCGGAACCCCCCCTTACTACTACGGCACCAACAACGCCGAGGCCATGGACTATTGGGGCCAGGGCACCACCGTGACCGTGTCCTCTGCTTCTACCAAGGGGCCCAGCGTGTTCCCCCTGGCCCCCTGCTCCAGAAGCACCAGCGAGAGCACAGCCGCCCTGGGCTG CCTGGTGAAGGACTACTTCCCCGAGCCCGTGACCGTGTCCTGGAACAGCGGAGCCCTGACCAGCGGCGTGCACACCTTCCCCGCCGTGCTGCAGAGCAGCGGCCTGTACAGCCTGAGCAGCGTGGTGACCGTGCCCAGCAGCAAGCCTGGGCACCAAGACCTACACCTGTAACGTGGACCACAAGCCCAGCAACACCAAGGTGGACAAGAGGGTGGAGAGCAAGTACGGCCC ACCCTGCCCCCCCTGCCCAGCCCCCGAGTTCCTGGGCGGACCCAGCGTGTTCCTGTTCCCCCCCAAGCCCAAGGACACCCTGATGATCAGCAGAACCCCCGAGGTGACCTGTGTGTGGTGGTGGACGTGTCCCAGGAGGACCCCGAGGTCCAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCACAACGCCAAGACCAAGCCCAGAGAGGAGCAGTTTAACAGCACCTACC GGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGACTGGCTGAACGGCAAAGAGTACAAGTGTAAGGTCTCCAACAAGGGCCTGCCAAGCAGCATCGAAAAGACCATCAGCAAGGCCAAGGGCCAGCCTAGAGAGCCCCAGGTCTACACCCTGCCACCCAGCCAAGAGGATGACCAAGAACCAGGTGTCCCTGACCTGTCTGGTGAAGGGCTTCTACCCAAGCGACAT CGCCGTGGAGTGGGAGAGCAACGGCCAGCCCGAGAACAACTACAAGACCACCCCCCCAGTGCTGGACAGCGACGGCAGCTTCTTCCTGTACAGCAGGCTGACCGTGGACAAGTCCAGATGGCAGGAGGGCAACGTCTTTAGCTGCTCCGTGATGCACGAGGCCCTGCACAACCACTACACCCAGAAGAGCCTGAGCCTGTCCCTGGGC BAP050-Clone I LC SEQ ID NO: 710 (Kabat) LCDR1 SSSQDISNYLN SEQ ID NO: 711 (Kabat) LCDR2 YTSTLHL SEQ ID NO: 712 (Kabat) LCDR3 QQYYNLPWT SEQ ID NO: 713 (Chothia) LCDR1 SQDISNY SEQ ID NO: 714 (Chothia) LCDR2 YTS SEQ ID NO: 715 (Chothia) LCDR3 YYNLPW SEQ ID NO: 718 VL DIQMTQSPSSLSASVGDRVTITCSSSQDISNYLNWYLQKPGQSPQLLIYYTSTLHLGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQYYNLPWTFGQGTKVEIK SEQ ID NO: 719 DNA VL Gatattcagatgactcagtcacctagtagcctgagcgctagtgtgggcgatagagtgactatcacctgtagctctagtcaggatatctctaactacctgaactggtatctgcagaagcccggtcaatcacctcagctgctgatctactacacactagcaccctgcacctgggcgtgccctctaggtttagcggtagcggtagtggcaccgagttcaccct gactatctctagcctgcagcccgacgacttcgctacctactactactgtcagcagtactataacctgccctggaccttcggtcaaggcactaaggtcgagattaag SEQ ID NO: 720 DNA VL GACATCCAGATGACCCAGTCCCCCTCAGCCTGTCTGCTTCCGTGGGCGACAAGTGTGACCATCACCTGTTCCTCAGCCAGGACATCTCCAACTACCTGAACTGGTATCTGCAGAAGCCCGGCCAGTCCCTCAGCTGCTGATCTACTACACCTCCACCCTGCACCTGGGCGTGCCCTCCAGATTTTCCGGCTCTGGCTCTGGCACCGAGTTTACCCTGACCATCAGCTCCCTGCA GCCCGACGACTTCGCCACCTACTACTGCCAGCAGTACTACAACCTGCCCTGGACCTTCGGCCAGGGCACCAAGGTGGAAATCAAG SEQ ID NO: 721 light chain DIQMTQSPSSLSASVGDRVTITCSSSQDISNYLNWYLQKPGQSPQLLIYYTSTLHLGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQYYNLPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADY EKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 722 light chain DNA Gatattcagatgactcagtcacctagtagcctgagcgctagtgtgggcgatagagtgactatcacctgtagctctagtcaggatatctctaactacctgaactggtatctgcagaagcccggtcaatcacctcagctgctgatctactacacactagcaccctgcacctgggcgtgccctctaggtttagcggtagcggtagtggcaccgagttcaccct gactatctctagcctgcagcccgacgacttcgctacctactactactgtcagcagtactataacctgccctggaccttcggtcaaggcactaaggtcgagattaagcgtacggtggccgctcccagcgtgttcatcttcccccccagcgacgagcagctgaagagcggcaccgccagcgtggtgtgcctgctgaacaacttctac ccccgggaggccaaggtgcagtggaaggtggacaacgccctgcagagcggcaacagccaggagagcgtcaccgagcaggacagcaaggactccacctacagcctgagcagcaccctgaccctgagcaaggccgactacgagaagcataaggtgtacgcctgcgaggtgacccaccagggcctgtccagccccgtgaccaagagcttcaaca ggggcgagtgc SEQ ID NO: 723 light chain DNA GACATCCAGATGACCCAGTCCCCCTCAGCCTGTCTGCTTCCGTGGGCGACAAGTGTGACCATCACCTGTTCCTCAGCCAGGACATCTCCAACTACCTGAACTGGTATCTGCAGAAGCCCGGCCAGTCCCTCAGCTGCTGATCTACTACACCTCCACCCTGCACCTGGGCGTGCCCTCCAGATTTTCCGGCTCTGGCTCTGGCACCGAGTTTACCCTGACCATCAGCTCCCTGCA GCCCGACGACTTCGCCACCTACTACTGCCAGCAGTACTACAACCTGCCCTGGACCTTCGGCCAGGGCACCAAGGTGGAAATCAAGCGTACGGTGGCCGCTCCCAGCGTGTTCATCTTCCCCCCAAGCGACGAGCAGCTGAAGCGGCACCGCCAGCGTGGTGTGTCTGCTGAACAACTTCTACCCCAGGGAGGCCAAGGTGCAGTGGAAGGTGGACAACGCCCCTGCAGCGG CAACAGCCAGGAGAGCGTCACCGAGCAGGACAGCAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCGACTACGAGAAGCACAAGGTGTACGCCTGTGAGGTGACCCACCAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAACAGGGGCGAGTGC BAP050-Clone J HC SEQ ID NO: 701 (Kabat) HCDR1 NYGMN SEQ ID NO: 702 (Kabat) HCDR2 WINTDTGEPTYADDFKG SEQ ID NO: 703 (Kabat) HDDR3 NPPYYYGTNNAEAMDY SEQ ID NO: 704 (Chothia) HCDR1 GFTLTNY SEQ ID NO: 705 (Chothia) HCDR2 NTDTGE SEQ ID NO: 703 (Chothia) HDDR3 NPPYYYGTNNAEAMDY SEQ ID NO: 724 vh QVQLVQSGAEVKKPGASVKVSCKASGFTLTNYGMNWVRQAPGQGLEWMGWINTDTGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARNPPYYYGTNNAEAMDYWGQGTTVTVSS SEQ ID NO: 725 DNA VH Caggtgcagctggtgcagtcaggcgccgaagtgaagaaacccggcgctagtgtgaaagtcagctgtaaagctagtggcttcaccctgactaactacgggatgaactgggtccgccaggccccaggtcaaggcctcgagtggatgggctggattaacaccgacaccggcgagcctacctacgccgacgactttaagggcagattcgt gtttagcctggacactagtgtgtctaccgcctacctgcagatctctagcctgaaggccgaggacaccgccgtctactactgcgctagaaaccccccctactactacggcactaacaacgccgaggctatggactactggggtcaaggcactaccgtgaccgtgtctagc SEQ ID NO: 726 DNA VH CAGGTGCAGCTGGTGCAGTCTGGCGCCGAAGTGAAGAAACCTGGCGCCTCCGTGAAGGTGTCCTGCAAGGCCTCTGGCTTCACCCTGACCAACTACGGCATGAACTGGGTGCGACAGGCCCCTGGACAGGGCCTGGAATGGATGGGCTGGATCAACACCGACACCGGCGAGCCTACCTACGCCGACGACTTCAAGGGCAGATTCGTGTTCTCCCTGGACA CCTCCGTGTCCACCGCCTACCTGCAGATCTCCAGCCTGAAGGCCGAGGATACCGCCGTGTACTACTGCCCGGAACCCCCCCTTACTACTACGGCACCAACAACGCCGAGGCCATGGACTATTGGGGCCAGGGCACCACCGTGACCGTGTCCTCT SEQ ID NO: 727 heavy chain QVQLVQSGAEVKKPGASVKVSCKASGFTLTNYGMNWVRQAPGQGLEWMGWINTDTGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARNPPYYYGTNNAEAMDYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSS SLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWES NGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG SEQ ID NO: 728 heavy chain DNA caggtgcagctggtgcagtcaggcgccgaagtgaagaaacccggcgctagtgtgaaagtcagctgtaaagctagtggcttcaccctgactaactacgggatgaactgggtccgccaggccccaggtcaaggcctcgagtggatgggctggattaacccgacaccggcgagcctacctacgccgacgactttaagggcagattcg tgtttagcctggacactagtgtgtctaccgcctacctgcagatctctagcctgaaggccgaggacaccgccgtctactactgcgctagaaaccccccctactactacggcactaacaacgccgaggctatggactactggggtcaaggcactaccgtgaccgtgtctagcgctagcactaagggcccgtccgtgttccccctggcacctt gtagccggagcactagcgaatccaccgctgccctcggctgcctggtcaaggattacttcccggagcccgtgaccgtgtcctggaacagcggagccctgacctccggagtgcacaccttccccgctgtgctgcagagctccgggctgtactcgctgtcgtcggtggtcacggtgccttcatctagcctgggtaccaagacctacact tgcaacgtggaccacaagccttccaacactaaggtggacaagcgcgtcgaatcgaagtacggcccaccgtgcccgccttgtcccgcgccggagttcctcggcggtccctcggtctttctgttcccaccgaagcccaaggacactttgatgatttcccgcacccctgaagtgacatgcgtggtcgtggacgtgtcaca ggaagatccggaggtgcagttcaattggtacgtggatggcgtcgaggtgcacaacgccaaaaccaagccgagggaggagcagttcaactccacttaccgcgtcgtgtccgtgctgacggtgctgcatcaggactggctgaacgggaaggagtacaagtgcaaagtgtccaacaagggacttcctagctcaatcgaaaagaccatctc gaaagccaagggacagccccgggaaccccaagtgtataccctgccaccgagccaggaagaaatgactaagaaccaagtctcattgacttgccttgtgaagggcttctacccatcggatatcgccgtggaatgggagtccaacggccagccggaaaacaactacaagaccacccctccggtgctggactcagacggatccttcttcctctactcggctga ccgtggataagagcagatggcaggagggaaatgtgttcagctgttctgtgatgcatgaagccctgcacaaccactacactcagaagtccctgtccctctccctggga SEQ ID NO: 729 heavy chain DNA CAGGTGCAGCTGGTGCAGTCTGGCGCCGAAGTGAAGAAACCTGGCGCCTCCGTGAAGGTGTCCTGCAAGGCCTCTGGCTTCACCCTGACCAACTACGGCATGAACTGGGTGCGACAGGCCCCTGGACAGGGCCTGGAATGGATGGGCTGGATCAACACCGACACCGGCGAGCCTACCTACGCCGACGACTTCAAGGGCAGATTCGTGTTCTCCCTGGACA CCTCCGTGTCCACCGCCTACCTGCAGATCTCCAGCCCTGAAGGCCGAGGATACCGCCGTGTACTACTGCCCGGAACCCCCCCTTACTACTACGGCACCAACAACGCCGAGGCCATGGACTATTGGGGCCAGGGCACCACCGTGACCGTGTCCTCTGCTTCTACCAAGGGGCCCAGCGTGTTCCCCCTGGCCCCCTGCTCCAGAAGCACCAGCGAGAGCACAGCCGCCCTGGGCTG CCTGGTGAAGGACTACTTCCCCGAGCCCGTGACCGTGTCCTGGAACAGCGGAGCCCTGACCAGCGGCGTGCACACCTTCCCCGCCGTGCTGCAGAGCAGCGGCCTGTACAGCCTGAGCAGCGTGGTGACCGTGCCCAGCAGCAAGCCTGGGCACCAAGACCTACACCTGTAACGTGGACCACAAGCCCAGCAACACCAAGGTGGACAAGAGGGTGGAGAGCAAGTACGGCCC ACCCTGCCCCCCCTGCCCAGCCCCCGAGTTCCTGGGCGGACCCAGCGTGTTCCTGTTCCCCCCCAAGCCCAAGGACACCCTGATGATCAGCAGAACCCCCGAGGTGACCTGTGTGTGGTGGTGGACGTGTCCCAGGAGGACCCCGAGGTCCAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCACAACGCCAAGACCAAGCCCAGAGAGGAGCAGTTTAACAGCACCTACC GGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGACTGGCTGAACGGCAAAGAGTACAAGTGTAAGGTCTCCAACAAGGGCCTGCCAAGCAGCATCGAAAAGACCATCAGCAAGGCCAAGGGCCAGCCTAGAGAGCCCCAGGTCTACACCCTGCCACCCAGCCAAGAGGATGACCAAGAACCAGGTGTCCCTGACCTGTCTGGTGAAGGGCTTCTACCCAAGCGACAT CGCCGTGGAGTGGGAGAGCAACGGCCAGCCCGAGAACAACTACAAGACCACCCCCCCAGTGCTGGACAGCGACGGCAGCTTCTTCCTGTACAGCAGGCTGACCGTGGACAAGTCCAGATGGCAGGAGGGCAACGTCTTTAGCTGCTCCGTGATGCACGAGGCCCTGCACAACCACTACACCCAGAAGAGCCTGAGCCTGTCCCTGGGC BAP050-Clone J LC SEQ ID NO: 710 (Kabat) LCDR1 SSSQDISNYLN SEQ ID NO: 711 (Kabat) LCDR2 YTSTLHL SEQ ID NO: 712 (Kabat) LCDR3 QQYYNLPWT SEQ ID NO: 713 (Chothia) LCDR1 SQDISNY SEQ ID NO: 714 (Chothia) LCDR2 YTS SEQ ID NO: 715 (Chothia) LCDR3 YYNLPW SEQ ID NO: 730 VL DIQMTQSPSSLSASVGDRVTITCSSSQDISNYLNWYQQKPGKAPKLLIYYTSTLHLGIPPRFSGSGYGTDFTLTINNIESEDAAYYFCQQYYNLPWTFGQGTKVEIK SEQ ID NO: 731 DNA VL Gatattcagatgactcagtcacctagtagcctgagcgctagtgtgggcgatagagtgactatcacctgtagctctagtcaggatatctctaactacctgaactggtatcagcagaagcccggtaaagcccctaagctgctgatctactacactagcaccctgcacctgggaatcccccctaggtttagcggtagcggctacggcaccgacttcaccctgactattaac aatatcgagtcagaggacgccgcctactacttctgtcagcagtactataacctgccctggaccttcggtcaaggcactaaggtcgagattaag SEQ ID NO: 732 DNA VL GACATCCAGATGACCCAGTCCCCCTCAGCCTGTCTGCTTCCGTGGGCGACAAGAGTGACCATCACCTGTTCCTCAGCCAGGACATCTCCAACTACCTGAACTGGTATCAGCAGAAGCCCGGCAAGGCCCCCAAGCTGCTGATCTACTACACCTCCACCCTGCACCTGGGCATCCCCCCTAGATTCTCCGGCTCTGGCTACGGCACCGACTTCACCCTGACCATCAACAACATCGAGTC CGAGGACGCCGCCTACTACTTCTGCCAGCAGTACTACAACCTGCCCTGGACCTTCGGCCAGGGCACCAAGGTGGAAATCAAG SEQ ID NO: 733 light chain DIQMTQSPSSLSASVGDRVTITCSSSQDISNYLNWYQQKPGKAPKLLIYYTSTLHLGIPPRFSGSGYGTDFTLTINNIESEDAAYYFCQQYYNLPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK HKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 734 light chain DNA Gatattcagatgactcagtcacctagtagcctgagcgctagtgtgggcgatagagtgactatcacctgtagctctagtcaggatatctctaactacctgaactggtatcagcagaagcccggtaaagcccctaagctgctgatctactacactagcaccctgcacctgggaatcccccctaggtttagcggtagcggctacggcaccgacttcaccctgactattaac aatatcgagtcagaggacgccgcctactacttctgtcagcagtactataacctgccctggaccttcggtcaaggcactaaggtcgagattaagcgtacggtggccgctcccagcgtgttcatcttcccccccagcgacgagcagctgaagagcggcaccgccagcgtggtgtgcctgctgaacaacttctacccccgggagg ccaaggtgcagtggaaggtggacaacgccctgcagagcggcaacagccaggagagcgtcaccgagcaggacagcaaggactccacctacagcctgagcagcaccctgaccctgagcaaggccgactacgagaagcataaggtgtacgcctgcgaggtgacccaccagggcctgtccagccccgtgaccaagagcttcaacaggggcgag tgc SEQ ID NO: 735 light chain DNA GACATCCAGATGACCCAGTCCCCCTCAGCCTGTCTGCTTCCGTGGGCGACAAGAGTGACCATCACCTGTTCCTCAGCCAGGACATCTCCAACTACCTGAACTGGTATCAGCAGAAGCCCGGCAAGGCCCCCAAGCTGCTGATCTACTACACCTCCACCCTGCACCTGGGCATCCCCCCTAGATTCTCCGGCTCTGGCTACGGCACCGACTTCACCCTGACCATCAACAACATCGAGTC CGAGGACGCCGCCTACTTCTGCCAGCAGTACTACAACCTGCCCTGGACCTTCGGCCAGGGCACCAAGGTGGAAATCAAGCGTACGGTGGCCGCTCCCAGCGTGTTCATCTTCCCCCCAAGCGACGAGCAGCTGAAGCGGCACCGCCAGCGTGTGTGTGTCTGCTGAACAACTTCTACCCCAGGGAGGCCAAGGTGCAGTGGAAGGTGGACAACCCCTGCAGAGCGGCA ACAGCCAGGAGAGCGTCACCGAGCAGGACAGCAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCGACTACGAGAAGCACAAGGTGTACGCCTGTGAGGTGACCCACCAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAACAGGGGCGAGTGC BAP050-Clone I HC SEQ ID NO: 736 (Kabat) HCDR1 aattacgggatgaac SEQ ID NO: 737 (Kabat) HCDR1 AACTACGGCATGAAC SEQ ID NO: 738 (Kabat) HCDR2 tggattaacaccgacaccggggagcctacctacgcggacgatttcaaggga SEQ ID NO: 739 (Kabat) HCDR2 TGGATCAACACCGACACCGGCGAGCCTACCTACGCCGACGACTTCAAGGGC SEQ ID NO: 740 (Kabat) HDDR3 aacccgccctactactacggaaccaacaacgccgaagccatggactac SEQ ID NO: 741 (Kabat) HDDR3 AACCCCCCTTACTACTACGGCACCAACAACGCCGAGGCCATGGACTAT SEQ ID NO: 742 (Chothia) HCDR1 ggattcaccctcaccaattac SEQ ID NO: 743 (Chothia) HCDR1 GGCTTCACCCTGACCAACTAC SEQ ID NO: 744 (Chothia) HCDR2 aacaccgacaccggggag SEQ ID NO: 745 (Chothia) HCDR2 AACACCGACACCGGCGAG SEQ ID NO: 740 (Chothia) HDDR3 aacccgccctactactacggaaccaacaacgccgaagccatggactac SEQ ID NO: 741 (Chothia) HDDR3 AACCCCCCTTACTACTACGGCACCAACAACGCCGAGGCCATGGACTAT BAP050-Clone I LC SEQ ID NO: 746 (Kabat) LCDR1 agctctagtcaggatatctctaactacctgaac SEQ ID NO: 747 (Kabat) LCDR1 TCCTCCAGCCAGGACATCTCCAACTACCTGAAC SEQ ID NO: 748 (Kabat) LCDR2 tacactagcaccctgcacctg SEQ ID NO: 749 (Kabat) LCDR2 TACACCTCCACCCTGCACCTG SEQ ID NO: 750 (Kabat) LCDR3 cagcagtactataacctgccctggacc SEQ ID NO: 751 (Kabat) LCDR3 CAGCAGTACTACAACCTGCCCTGGACC SEQ ID NO: 752 (Chothia) LCDR1 agtcaggatatctctaactac SEQ ID NO: 753 (Chothia) LCDR1 AGCCAGGACATCTCCAACTAC SEQ ID NO: 754 (Chothia) LCDR2 tacactagc SEQ ID NO: 755 (Chothia) LCDR2 TACACCTCC SEQ ID NO: 756 (Chothia) LCDR3 tactataacctgccctgg SEQ ID NO: 757 (Chothia) LCDR3 TACTACAACCTGCCCTGG BAP050-Clone J HC SEQ ID NO: 758 (Kabat) HCDR1 aactacgggatgaac SEQ ID NO: 737 (Kabat) HCDR1 AACTACGGCATGAAC SEQ ID NO: 759 (Kabat) HCDR2 tggattaacaccgacaccggcgagcctacctacgccgacgactttaagggc SEQ ID NO: 739 (Kabat) HCDR2 TGGATCAACACCGACACCGGCGAGCCTACCTACGCCGACGACTTCAAGGGC SEQ ID NO: 760 (Kabat) HDDR3 aaccccccctactactacggcactaacaacgccgaggctatggactac SEQ ID NO: 741 (Kabat) HDDR3 AACCCCCCTTACTACTACGGCACCAACAACGCCGAGGCCATGGACTAT SEQ ID NO: 761 (Chothia) HCDR1 ggcttcaccctgactaactac SEQ ID NO: 743 (Chothia) HCDR1 GGCTTCACCCTGACCAACTAC SEQ ID NO: 744 (Chothia) HCDR2 aacaccgacaccggggag SEQ ID NO: 745 (Chothia) HCDR2 AACACCGACACCGGCGAG SEQ ID NO: 760 (Chothia) HDDR3 aaccccccctactactacggcactaacaacgccgaggctatggactac SEQ ID NO: 741 (Chothia) HDDR3 AACCCCCCTTACTACTACGGCACCAACAACGCCGAGGCCATGGACTAT BAP050-Clone J LC SEQ ID NO: 746 (Kabat) LCDR1 agctctagtcaggatatctctaactacctgaac SEQ ID NO: 747 (Kabat) LCDR1 TCCTCCAGCCAGGACATCTCCAACTACCTGAAC SEQ ID NO: 748 (Kabat) LCDR2 TACACTAGCACCCTGCACCTG SEQ ID NO: 749 (Kabat) LCDR2 TACACCTCCACCCTGCACCTG SEQ ID NO: 750 (Kabat) LCDR3 cagcagtactataacctgccctggacc SEQ ID NO: 751 (Kabat) LCDR3 CAGCAGTACTACAACCTGCCCTGGACC SEQ ID NO: 752 (Chothia) LCDR1 agtcaggatatctctaactac SEQ ID NO: 753 (Chothia) LCDR1 AGCCAGGACATCTCCAACTAC SEQ ID NO: 754 (Chothia) LCDR2 TACACTAGC SEQ ID NO: 755 (Chothia) LCDR2 TACACCTCC SEQ ID NO: 756 (Chothia) LCDR3 tactataacctgccctgg SEQ ID NO: 757 (Chothia) LCDR3 TACTACAACCTGCCCTGG

In one embodiment, the anti-LAG-3 antibody molecule contains at least one or two heavy chain variable domains (optionally containing a constant region), at least one or two light chain variable domains (optionally containing a constant region) or both, containing the amino acid sequence of any of BAP050-hum01, BAP050-hum02, BAP050-hum03, BAP050-hum04, BAP050-hum05, BAP050-hum06, BAP050-hum07, BAP050-hum08, BAP050-hum09, BAP050 -hum10, BAP050-hum11, BAP050-hum12, BAP050-hum13, BAP050-hum14, BAP050-hum15, BAP050-hum16, BAP050-hum17, BAP050-hum18, BAP050-hum19, BAP050-hum20, huBAP050(Ser) (e.g., BAP050-hum01-Ser BAP050-hum02-Ser BAP050-hum03-Ser BAP050-hum04-Ser BAP050-hum05-Ser BAP050-hum06-Ser BAP050-hum07-Ser BAP050-hum08-Ser BAP050- hum09-Ser BAP050-hum10-Ser BAP050-hum11-Ser BAP050-hum12-Ser BAP050-hum13-Ser BAP050-hum14-Ser BAP050-hum15-Ser BAP050-hum18-Ser BAP050-hum19- Ser or BAP050-hum20-Ser), BAP050-Clone-F, BAP050-Clone-G, BAP050-Clone-H, BAP050-Clone-I or BAP050-Clone-J; or as described in Table 1 of US patent 2015/0259420, or it is encoded by the nucleotide sequence in Table 1; or a sequence substantially identical (eg, at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or greater identical) to any of the above sequences.

In yet another embodiment, an anti-LAG-3 antibody molecule comprises at least one, two, or three complementarity determining regions (CDRs) from a heavy chain variable region and/or a light chain variable region of an antibody described herein, for example, an antibody selected from any of BAP050-hum01, BAP050-hum02, BAP050-hum03, BAP050-hum04, BAP050-hum05, BAP050-hum06, BAP050-hum07, BAP050-hum08, BAP050-hum09, BAP050-hum10, BAP050- hum11, BAP050-hum12, BAP050-hum13, BAP050-hum14, BAP050-hum15, BAP050-hum16, BAP050-hum17, BAP050-hum18, BAP050-hum19, BAP050-hum20, huBAP050(Ser) (e.g. BAP050-hum01-Ser) BAP050-hum02-Ser BAP050-hum03-Ser BAP050-hum04-Ser BAP050-hum05-Ser BAP050-hum06-Ser BAP050-hum07-Ser BAP050-hum08-Ser BAP050-hum09-Ser BAP050 -hum10-Ser, BAP050-hum11-Ser, BAP050-hum12-Ser, BAP050-hum13-Ser, BAP050-hum14-Ser, BAP050-hum15-Ser, BAP050-hum18-Ser, BAP050-hum19-Ser or BAP050-hum20 -Ser), BAP050-Clone-F, BAP050-Clone-G, BAP050-Clone-H, BAP050-Clone-I or BAP050-Clone-J; or as described in Table 1 of US patent 2015/0259420, or it is encoded by the nucleotide sequence in Table 1; or a sequence substantially identical (eg, at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or greater identical) to any of the above sequences.

In another embodiment, the anti-LAG-3 antibody molecule contains at least one, two or three CDRs (or collectively all CDRs) from the heavy chain variable region containing the amino acid sequence as shown in Table 1 of US Patent 2015/ 0259420, or it is encoded by the nucleotide sequence shown in Table 1. In one embodiment, one or more CDRs (or collectively all CDRs) have one, two, three, four, five, six or more changes, such as substitutions or deletions amino acids, compared to the amino acid sequence shown in Table 1, or it is encoded by the nucleotide sequence shown in Table 1.

In yet another embodiment, the anti-LAG-3 antibody molecule contains at least one, two or three CDRs (or collectively all CDRs) from the light chain variable region containing the amino acid sequence shown in Table 1 of US Patent 2015/ 0259420, or it is encoded by the nucleotide sequence shown in Table 1. In one embodiment, one or more CDRs (or collectively all CDRs) have one, two, three, four, five, six or more changes, such as substitutions or deletions amino acids compared to the amino acid sequence shown in Table 1, or it is encoded by the nucleotide sequence shown in Table 1. In certain embodiments, the anti-PD-L1 antibody molecule contains substitutions in the light chain CDR, for example, one or more substitutions in CDR1, CDR2 and/or CDR3 of the light chain.

In another embodiment, the anti-LAG-3 antibody molecule contains at least one, two, three, four, five, or six CDRs (or collectively all CDRs) of the heavy and light chain variable regions containing the amino acid sequence shown in Table 1, or it is encoded by the nucleotide sequence shown in Table 1 of US patent 2015/0259420. In one embodiment, one or more CDRs (or collectively all CDRs) have one, two, three, four, five, six or more changes, such as amino acid substitutions or deletions, compared to the amino acid sequence shown in Table 1, or it is encoded by the nucleotide sequence shown in Table 1.

Other exemplary anti-LAG-3 antibody molecules

In one embodiment, the anti-LAG-3 antibody molecule is BMS-986016 (Bristol-Myers Squibb), also known as BMS986016. BMS-986016, and other anti-LAG-3 antibodies are described in WO 2015/116539 and US Pat. No. 9,505,839, incorporated by reference in their entirety. In one embodiment, the anti-LAG-3 antibody molecule comprises one or more CDR sequences (or collectively, all CDR sequences), a heavy chain or light chain variable region sequence, or a BMS-986016 heavy chain or light chain sequence, e.g., as described in Table 6.

In one embodiment, the anti-LAG-3 antibody molecule is TSR-033 (Tesaro). In one embodiment, the anti-LAG-3 antibody molecule comprises one or more CDR sequences (or collectively, all CDR sequences), a heavy chain or light chain variable region sequence, or a TSR-033 heavy chain or light chain sequence.

In one embodiment, the anti-LAG-3 antibody molecule is IMP731 or GSK2831781 (GSK and Prima BioMed). IMP731 and other anti-LAG-3 antibodies are described in WO 2008/132601 and US Pat. No. 9,244,059, incorporated by reference in their entirety. In one embodiment, the anti-LAG-3 antibody molecule comprises one or more CDR sequences (or collectively, all CDR sequences), a heavy chain or light chain variable region sequence, or an IMP731 heavy chain or light chain sequence, e.g., as described in Table 6. In one embodiment, the anti-LAG-3 antibody molecule contains one or more CDR sequences (or collectively, all CDR sequences), heavy chain or light chain variable region sequences, or heavy chain or light chain sequences from GSK2831781.

In one embodiment, the anti-LAG-3 antibody molecule is IMP761 (Prima BioMed). In one embodiment, the anti-LAG-3 antibody molecule comprises one or more CDR sequences (or collectively, all CDR sequences), heavy chain or light chain variable region sequences, or IMP761 heavy chain or light chain sequences.

Other well-known anti-lag-3 antibodies include antibodies described, for example, in WO 2008/132601, Wo 2010/019570, Wo 2014/140180, Wo 2015/16539, Wo 2015/200119, Wo 2016/028672, in the US Patent 9244059 , US Pat. No. 9,505,839, incorporated by reference in its entirety.

In one embodiment, an anti-LAG-3 antibody is an antibody that competes for binding and/or binds to the same epitope on LAG-3 as one of the anti-LAG-3 antibodies described herein.

In one embodiment, the anti-LAG-3 inhibitor is a soluble LAG-3 protein, eg IMP321 (Prima BioMed), eg as described in WO 2009/044273, incorporated by reference in its entirety.

Table 6 . Amino acid sequences of other exemplary anti-LAG-3 antibody molecules

BMS-986016 SEQ ID NO: 762 heavy chain QVQLQQWGAGLLKPSETLSLTCAVYGGSFSDYYWNWIRQPPGKGLEWIGEINHRGSTNSNPSLKSRVTLSLDTSKNQFSLKLRSVTAADTAVYYCAFGYSDYEYNWFDPWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSS SLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWES NGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO: 763 light chain EIVLTQSPATLSLSPGERATLSCRASQSISSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPLTFGQGTNLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEV THQGLSSPVTKSFNRGEC IMP731 SEQ ID NO: 764 heavy chain QVQLKESGPGLVAPSQSLSITCTVSGFSLTAYGVNWVRQPPGKGLEWLGMIWDDGSTDYNSALKSRLSISKDNSKSQVFLKMNSLQTDDTARYYCAREGDVAFDYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC NVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNY KTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 765 light chain DIVMTQSPSSLAVSVGQKVTMSCKSSQSLLNGSNQKNYLAWYQQKPGQSPKLLVYFASTRDSGVPDRFIGSGSGTDFTLTISSVQAEDLADYFCLQHFGTPPTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADY EKHKVYACEVTHQGLSSPVTKSFNRGEC

PD-1 inhibitors

In certain embodiments, the anti-LAG-3 antibody molecule described herein is administered in combination with a PD-1 inhibitor. In some embodiments, the PD-1 inhibitor is selected from PDR001 or Spartalizumab (Novartis), Nivolumab (Bristol-Myers Squibb), Pembrolizumab (Merck & Co), Pidilizumab (CureTech), MEDI0680 (Medimmune), REGN2810 (Regeneron), TSR- 042 (Tesaro), PF-06801591 (Pfizer), BGB-A317 (Beigene), BGB-108 (Beigene), INCSHR1210 (Incyte), or AMP-224 (Amplimmune).

Exemplary PD-1 Inhibitors

In one embodiment, the PD-1 inhibitor is an anti-PD-1 antibody molecule. In one embodiment, the PD-1 inhibitor is an anti-PD-1 antibody molecule as described in US Pat. as reference in its entirety.

In one embodiment, the anti-PD-1 antibody molecule contains at least one, two, three, four, five, or six complementarity determining regions (CDRs) (or collectively all CDRs) from the severe and mild variable regions. chains containing the amino acid sequence shown in Table 1 (for example, from the BAP049-Clone-E or BAP049-Clone-B heavy and light chain variable region sequences described in Table 1), or it is encoded by the nucleotide sequence shown in Table 1. In some embodiments, the CDRs are as defined by Kabat (eg, as shown in Table 1). In some embodiments, the CDRs match the definition of Chothia (eg, as shown in Table 1). In some embodiments, the CDRs correspond to the combined CDR definitions of both Kabat and Chothia (eg, as shown in Table 1). In one embodiment, the combination of CDR definitions according to Kabat and Chothia VH CDR1 contains the amino acid sequence GYTFTTYWMH (SEQ ID NO: 541). In one embodiment, one or more CDRs (or collectively all CDRs) have one, two, three, four, five, six or more changes, such as amino acid substitutions (e.g., conservative amino acid substitutions) or deletions, compared to the sequence amino acids shown in Table 1, or it is encoded by the nucleotide sequence shown in Table 1.

In one embodiment, the anti-PD-1 antibody molecule comprises a heavy chain variable region (VH) comprising the VHCDR1 amino acid sequence of SEQ ID NO: 501, the VHCDR2 amino acid sequence of SEQ ID NO: 502, and the VHCDR3 amino acid sequence of SEQ ID NO: 503; and a light chain variable region (VL) containing the amino acid sequence of VLCDR1 SEQ ID NO: 510, the amino acid sequence of VLCDR2 SEQ ID NO: 511, and the amino acid sequence of VLCDR3 SEQ ID NO: 512, each of which is described in Table 1.

In one embodiment, the antibody molecule comprises a VH comprising VHCDR1 encoded by the nucleotide sequence of SEQ ID NO: 524, VHCDR2 encoded by the nucleotide sequence of SEQ ID NO: 525, and VHCDR3 encoded by the nucleotide sequence of SEQ ID NO: 526; and VL containing VLCDR1 encoded by the nucleotide sequence of SEQ ID NO: 529, VLCDR2 encoded by the nucleotide sequence of SEQ ID NO: 530 and VLCDR3 encoded by the nucleotide sequence of SEQ ID NO: 531, each of which is described in Table 1.

In one embodiment, the anti-PD-1 antibody molecule comprises a VH containing the amino acid sequence of SEQ ID NO: 506, or an amino acid sequence at least 85%, 90%, 95%, or 99% or greater identical to SEQ ID NO: 506. In one embodiment, the anti-PD-1 antibody molecule comprises a VL containing the amino acid sequence of SEQ ID NO: 520, or an amino acid sequence of at least 85%, 90%, 95%, or 99%, or above identical to SEQ ID NO: 520. In one embodiment, the anti-PD-1 antibody molecule comprises a VL containing the amino acid sequence of SEQ ID NO: 516 or the amino acid sequence of at least 85%, 90%, 95% or 99% or greater identical to SEQ ID NO: 516. In one embodiment, the anti-PD-1 antibody molecule comprises a VH containing the amino acid sequence of SEQ ID NO: 506 and a VL containing the amino acid sequence of SEQ ID NO: 520. In one of embodiments, the anti-PD-1 antibody molecule comprises a VH containing the amino acid sequence of SEQ ID NO: 506 and a VL containing the amino acid sequence of SEQ ID NO: 516.

In one embodiment, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 507, or by a nucleotide sequence at least 85%, 90%, 95%, or 99% or greater identical to SEQ ID NO: 507. B in one embodiment, the antibody molecule contains a VL encoded by a nucleotide sequence of SEQ ID NO: 521 or 517 or a nucleotide sequence at least 85%, 90%, 95%, or 99% or greater identical to SEQ ID NO: 521 or 517 In one embodiment, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 507 and a VL encoded by the nucleotide sequence of SEQ ID NO: 521 or 517.

In one embodiment, the anti-PD-1 antibody molecule comprises a heavy chain containing the amino acid sequence of SEQ ID NO: 508 or an amino acid sequence at least 85%, 90%, 95%, or 99% or greater identical to SEQ ID NO: 508. In one embodiment, the anti-PD-1 antibody molecule comprises a light chain containing the amino acid sequence of SEQ ID NO: 522 or an amino acid sequence of at least 85%, 90%, 95%, or 99%, or above identical to SEQ ID NO: 522. In one embodiment, the anti-PD-1 antibody molecule contains a light chain containing the amino acid sequence of SEQ ID NO: 518 or the amino acid sequence of at least 85%, 90%, 95% or 99% or greater identical to SEQ ID NO: 518. In one embodiment, the anti-PD-1 antibody molecule comprises a heavy chain containing the amino acid sequence of SEQ ID NO: 508 and a light chain containing the amino acid sequence of SEQ ID NO: 522 In one embodiment, the anti-PD-1 antibody molecule comprises a heavy chain containing the amino acid sequence of SEQ ID NO: 508 and a light chain containing the amino acid sequence of SEQ ID NO: 518.

In one embodiment, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 509 or a nucleotide sequence at least 85%, 90%, 95%, or 99% or greater identical to SEQ ID NO: 509. B in one embodiment, the antibody molecule contains a light chain encoded by a nucleotide sequence of SEQ ID NO: 523 or 519 or a nucleotide sequence at least 85%, 90%, 95% or 99% or greater identical to SEQ ID NO: 523 or 519. In one embodiment, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 509 and a light chain encoded by the nucleotide sequence of SEQ ID NO: 523 or 519.

The antibody molecules described herein can be generated using the vectors, host cells, and methods described in US Pat. No. 2015/0210769, incorporated by reference in its entirety.

Table 1 . Amino acid and nucleotide sequences of exemplary anti-PD-1 antibody molecules

BAP049-Clone-B HC SEQ ID NO: 501 (Kabat) HCDR1 TYWMH SEQ ID NO: 502 (Kabat) HCDR2 NIYPGTGGSNFDEKFKN SEQ ID NO: 503 (Kabat) HDDR3 WTTGTGAY SEQ ID NO: 504 (Chothia) HCDR1 GYTFTTY SEQ ID NO: 505 (Chothia) HCDR2 YPGTGG SEQ ID NO: 503 (Chothia) HDDR3 WTTGTGAY SEQ ID NO: 506 vh EVQLVQSGAEVKKPGESLRISCKGSGYTFTTYWMHWVRQATGQGLEWMGNIYPGTGGSNFDEKFKNRVTITADKSTSTAYMELSSLRSEDTAVYYCTRWTTGTGAYWGQGTTVTVSS SEQ ID NO: 507 DNA VH Gaggtgcagctggtgcagtcaggcgccgaagtgaagaagcccggcgagtcactgagaattagctgtaaaaggttcaggctacaccttcactacctactggatgcactgggtccgccaggctaccggtcaaggcctcgagtggatgggtaatatctaccccggcaccggcggctctaacttcgacgagaagtttaagaatagagtgactatcacc gccgataagtctactactcaccgcctatatggaactgtctagcctgagatcagaggacaccgccgtctactactgcactaggtggactaccggcacaggcgcctactggggtcaaggcactaccgtgaccgtgtctagc SEQ ID NO: 508 heavy chain EVQLVQSGAEVKKPGESLRISCKGSGYTFTTYWMHWVRQATGQGLEWMGNIYPGTGGSNFDEKFKNRVTITADKSTSTAYMELSSLRSEDTAVYYCTRWTTGTGAYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCN VDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYK TTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG SEQ ID NO: 509 heavy chain DNA gaggtgcagctggtgcagtcaggcgccgaagtgaagaagcccggcgagtcactgagaattagctgtaaaggttcaggctacaccttcactacctactggatgcactgggtccgccaggctaccggtcaaggcctcgagtggatgggtaatatctaccccggcaccggcggctctaacttcgacgagaagtttaagaatagagtgactatca ccgccgataagtctactagcaccgcctatatggaactgtctagcctgagatcagaggacaccgccgtctactactgcactaggtggactaccggcacaggcgcctactggggtcaaggcactaccgtgaccgtgtctagcgctagcactaagggcccgtccgtgttccccctggcaccttgtagccggagcactagcgaatccaccgctgcc ctcggctgcctggtcaaggattacttcccggagcccgtgaccgtgtcctggaacagcggagccctgacctccggagtgcacaccttccccgctgtgctgcagagctccgggctgtactcgctgtcgtcggtggtcacggtgccttcatctagcctgggtaccaagacctacacttgcaacgtggaccacaagccttccaacacta aggtggacaagcgcgtcgaatcgaagtacggcccaccgtgcccgccttgtcccgcgccggagttcctcggcggtccctcggtctttctgttcccaccgaagcccaaggacactttgatgatttcccgcacccctgaagtgacatgcgtggtcgtggacgtgtcacaggaagatccggaggtgcagttcaattgg tacgtggatggcgtcgaggtgcacaacgccaaaaccaagccgagggaggagcagttcaactccacttaccgcgtcgtgtccgtgctgacggtgctgcatcaggactggctgaacgggaaggagtacaagtgcaaagtgtccaacaagggacttcctagctcaatcgaaaagaccatctcgaaagccaagggacagccccgggaaccccaagt gtataccctgccaccgagccaggaagaaatgactaagaaccaagtctcattgacttgccttgtgaagggcttctacccatcggatatcgccgtggaatgggagtccaacggccagccggaaaaacaactacaagaccacccctccggtgctggactcagacggatccttcttcctctactcgcggctgaccgtggataagagcagatggcaggagggaa atgtgttcagctgttctgtgatgcatgaagccctgcacaaccactacactcagaagtccctgtccctctccctggga BAP049-Clone-B LC SEQ ID NO: 510 (Kabat) LCDR1 KSSQSLLDSGNQKNFLT SEQ ID NO: 511 (Kabat) LCDR2 WASTRES SEQ ID NO: 512 (Kabat) LCDR3 QNDYSYPYT SEQ ID NO: 513 (Chothia) LCDR1 SQSLLDSGNQKNF SEQ ID NO: 514 (Chothia) LCDR2 WAS SEQ ID NO: 515 (Chothia) LCDR3 DYSYPY SEQ ID NO: 516 VL EIVLTQSPATLSLSPGERATLSCKSSQSLLDSGNQKNFLTWYQQKPGKAPKLLIYWASTRESGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQNDYSYPYTFGQGTKVEIK SEQ ID NO: 517 DNA VL Gagatcgtcctgactcagtcacccgctaccctgagcctgagccctggcgagcgggctacactgagctgtaaatctagtcagtcactgctggatagcggtaatcagaagaacttcctgacctggtatcagcagaagcccggtaaagcccctaagctgctgatctactgggcctctactagagaatcaggcgtgccctctaggtttagcgg tagcggtagtggcaccgacttcaccttcactatctctagcctgcagcccgaggatatcgctacctactactactgtcagaacgactatagctacccctacaccttcggtcaaggcactaaggtcgagattaag SEQ ID NO: 518 light chain EIVLTQSPATLSLSPGERATLSCKSSQSLLDSGNQKNFLTWYQQKPGKAPKLLIYWASTRESGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQNDYSYPYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK HKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 519 light chain DNA Gagatcgtcctgactcagtcacccgctaccctgagcctgagccctggcgagcgggctacactgagctgtaaatctagtcagtcactgctggatagcggtaatcagaagaacttcctgacctggtatcagcagaagcccggtaaagcccctaagctgctgatctactgggcctctactagagaatcaggcgtgccctctaggtttagcgg tagcggtagtggcaccgacttcaccttcactatctctagcctgcagcccgaggatatcgctacctactactgtcagaacgactatagctacccctacaccttcggtcaaggcactaaggtcgagattaagcgtacggtggccgctcccagcgtgttcatcttccccccagcgacgagcagctgaagagcggcaccgccagcgtggtgt gcctgctgaacaacttctacccccgggaggccaaggtgcagtggaaggtggacaacgccctgcagagcggcaacagccaggagagcgtcaccgagcaggacagcaaggactccacctacagcctgagcagcaccctgaccctgagcaaggccgactacgagaagcataaggtgtacgcctgcgaggtgacccaccagggcctgtccagcc ccgtgaccaagagcttcaacaggggcgagtgc BAP049-Clone-E HC SEQ ID NO: 501 (Kabat) HCDR1 TYWMH SEQ ID NO: 502 (Kabat) HCDR2 NIYPGTGGSNFDEKFKN SEQ ID NO: 503 (Kabat) HDDR3 WTTGTGAY SEQ ID NO: 504 (Chothia) HCDR1 GYTFTTY SEQ ID NO: 505 (Chothia) HCDR2 YPGTGG SEQ ID NO: 503 (Chothia) HDDR3 WTTGTGAY SEQ ID NO: 506 vh EVQLVQSGAEVKKPGESLRISCKGSGYTFTTYWMHWVRQATGQGLEWMGNIYPGTGGSNFDEKFKNRVTITADKSTSTAYMELSSLRSEDTAVYYCTRWTTGTGAYWGQGTTVTVSS SEQ ID NO: 507 DNA VH Gaggtgcagctggtgcagtcaggcgccgaagtgaagaagcccggcgagtcactgagaattagctgtaaaaggttcaggctacaccttcactacctactggatgcactgggtccgccaggctaccggtcaaggcctcgagtggatgggtaatatctaccccggcaccggcggctctaacttcgacgagaagtttaagaatagagtgactatcacc gccgataagtctactactcaccgcctatatggaactgtctagcctgagatcagaggacaccgccgtctactactgcactaggtggactaccggcacaggcgcctactggggtcaaggcactaccgtgaccgtgtctagc SEQ ID NO: 508 heavy chain EVQLVQSGAEVKKPGESLRISCKGSGYTFTTYWMHWVRQATGQGLEWMGNIYPGTGGSNFDEKFKNRVTITADKSTSTAYMELSSLRSEDTAVYYCTRWTTGTGAYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCN VDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYK TTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG SEQ ID NO: 509 heavy chain DNA gaggtgcagctggtgcagtcaggcgccgaagtgaagaagcccggcgagtcactgagaattagctgtaaaggttcaggctacaccttcactacctactggatgcactgggtccgccaggctaccggtcaaggcctcgagtggatgggtaatatctaccccggcaccggcggctctaacttcgacgagaagtttaagaatagagtgactatca ccgccgataagtctactagcaccgcctatatggaactgtctagcctgagatcagaggacaccgccgtctactactgcactaggtggactaccggcacaggcgcctactggggtcaaggcactaccgtgaccgtgtctagcgctagcactaagggcccgtccgtgttccccctggcaccttgtagccggagcactagcgaatccaccgctgcc ctcggctgcctggtcaaggattacttcccggagcccgtgaccgtgtcctggaacagcggagccctgacctccggagtgcacaccttccccgctgtgctgcagagctccgggctgtactcgctgtcgtcggtggtcacggtgccttcatctagcctgggtaccaagacctacacttgcaacgtggaccacaagccttccaacacta aggtggacaagcgcgtcgaatcgaagtacggcccaccgtgcccgccttgtcccgcgccggagttcctcggcggtccctcggtctttctgttcccaccgaagcccaaggacactttgatgatttcccgcacccctgaagtgacatgcgtggtcgtggacgtgtcacaggaagatccggaggtgcagttcaattgg tacgtggatggcgtcgaggtgcacaacgccaaaaccaagccgagggaggagcagttcaactccacttaccgcgtcgtgtccgtgctgacggtgctgcatcaggactggctgaacgggaaggagtacaagtgcaaagtgtccaacaagggacttcctagctcaatcgaaaagaccatctcgaaagccaagggacagccccgggaaccccaagt gtataccctgccaccgagccaggaagaaatgactaagaaccaagtctcattgacttgccttgtgaagggcttctacccatcggatatcgccgtggaatgggagtccaacggccagccggaaaaacaactacaagaccacccctccggtgctggactcagacggatccttcttcctctactcgcggctgaccgtggataagagcagatggcaggagggaa atgtgttcagctgttctgtgatgcatgaagccctgcacaaccactacactcagaagtccctgtccctctccctggga BAP049-Clone-E LC SEQ ID NO: 510 (Kabat) LCDR1 KSSQSLLDSGNQKNFLT SEQ ID NO: 511 (Kabat) LCDR2 WASTRES SEQ ID NO: 512 (Kabat) LCDR3 QNDYSYPYT SEQ ID NO: 513 (Chothia) LCDR1 SQSLLDSGNQKNF SEQ ID NO: 514 (Chothia) LCDR2 WAS SEQ ID NO: 515 (Chothia) LCDR3 DYSYPY SEQ ID NO: 520 VL EIVLTQSPATLSLSPGERATLSCKSSQSLLDSGNQKNFLTWYQQKPGQAPRLLIYWASTRESGVPSRFSGSGSGTDFTFTISSLEAEDAATYYCQNDYSYPYTFGQGTKVEIK SEQ ID NO: 521 DNA VL Gagatcgtcctgactcagtcacccgctaccctgagcctgagccctggcgagcgggctacactgagctgtaaatctagtcagtcactgctggatagcggtaatcagaagaacttcctgacctggtatcagcagaagcccggtcaagcccctagactgctgatctactgggcctctactagagaatcaggcgtgccctctaggtttagcggtag cggtagtggcaccgacttcaccttcactatctctagcctggaagccgaggacgccgctacctactactgtcagaacgactatagctacccctacaccttcggtcaaggcactaaggtcgagattaag SEQ ID NO: 522 light chain EIVLTQSPATLSLSPGERATLSCKSSQSLLDSGNQKNFLTWYQQKPGQAPRLLIYWASTRESGVPSRFSGSGSGTDFTFTISSLEAEDAATYYCQNDYSYPYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHK VYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 523 light chain DNA Gagatcgtcctgactcagtcacccgctaccctgagcctgagccctggcgagcgggctacactgagctgtaaatctagtcagtcactgctggatagcggtaatcagaagaacttcctgacctggtatcagcagaagcccggtcaagcccctagactgctgatctactgggcctctactagagaatcaggcgtgccctctaggtttagcggtag cggtagtggcaccgacttcaccttcactatctctagcctggaagccgaggacgccgctacctactactgtcagaacgactatagctacccctacaccttcggtcaaggcactaaggtcgagattaagcgtacggtggccgctcccagcgtgttcatcttcccccccagcgacgagcagctgaagagcggcaccgccagcgtggtgtgcc tgctgaacaacttctacccccgggaggccaaggtgcagtggaaggtggacaacgccctgcagagcggcaacagccaggagagcgtcaccgagcaggacagcaaggactccacctacagcctgagcagcaccctgaccctgagcaaggccgactacgagaagcataaggtgtacgcctgcgaggtgacccaccagggcctgtccagccccg tgaccaagagcttcaacaggggcgagtgc BAP049-Clone-B HC SEQ ID NO: 524 (Kabat) HCDR1 ACCTACTGGATGAC SEQ ID NO: 525 (Kabat) HCDR2 AATATCTACCCCGGCACCGGCGGCTCTAACTTCGACGAGAAGTTTAAGAAT SEQ ID NO: 526 (Kabat) HDDR3 TGGACTACCGGCACAGGCGCCTAC SEQ ID NO: 527 (Chothia) HCDR1 GGCTACACCTTCACTACCTAC SEQ ID NO: 528 (Chothia) HCDR2 TACCCCGGCACCGGCGGC SEQ ID NO: 526 (Chothia) HDDR3 TGGACTACCGGCACAGGCGCCTAC BAP049-Clone-B LC SEQ ID NO: 529 (Kabat) LCDR1 AAATCTAGTCAGTCACTGCTGGATAGCGGTAATCAGAAGAACTTCCTGACC SEQ ID NO: 530 (Kabat) LCDR2 TGGGCCTCTACTAGAGAATCA SEQ ID NO: 531 (Kabat) LCDR3 CAGAACGACTATAGCTACCCCTACACC SEQ ID NO: 532 (Chothia) LCDR1 AGTCAGTCACTGCTGGATAGCGGTAATCAGAAGAACTTC SEQ ID NO: 533 (Chothia) LCDR2 TGGGCCTCT SEQ ID NO: 534 (Chothia) LCDR3 GACTATAGCTACCCCTAC BAP049-Clone-E HC SEQ ID NO: 524 (Kabat) HCDR1 ACCTACTGGATGAC SEQ ID NO: 525 (Kabat) HCDR2 AATATCTACCCCGGCACCGGCGGCTCTAACTTCGACGAGAAGTTTAAGAAT SEQ ID NO: 526 (Kabat) HDDR3 TGGACTACCGGCACAGGCGCCTAC SEQ ID NO: 527 (Chothia) HCDR1 GGCTACACCTTCACTACCTAC SEQ ID NO: 528 (Chothia) HCDR2 TACCCCGGCACCGGCGGC SEQ ID NO: 526 (Chothia) HDDR3 TGGACTACCGGCACAGGCGCCTAC BAP049-Clone-E LC SEQ ID NO: 529 (Kabat) LCDR1 AAATCTAGTCAGTCACTGCTGGATAGCGGTAATCAGAAGAACTTCCTGACC SEQ ID NO: 530 (Kabat) LCDR2 TGGGCCTCTACTAGAGAATCA SEQ ID NO: 531 (Kabat) LCDR3 CAGAACGACTATAGCTACCCCTACACC SEQ ID NO: 532 (Chothia) LCDR1 AGTCAGTCACTGCTGGATAGCGGTAATCAGAAGAACTTC SEQ ID NO: 533 (Chothia) LCDR2 TGGGCCTCT SEQ ID NO: 534 (Chothia) LCDR3 GACTATAGCTACCCCTAC

Other exemplary PD-1 inhibitors

In one embodiment, the anti-PD-1 antibody molecule is Nivolumab (Bristol-Myers Squibb), also known as MDX-1106, MDX-1106-04, ONO-4538, BMS-936558, or OPDIVO®. Nivolumab (Clone 5C4) and other anti-PD-1 antibodies are described in US Pat. No. 8,008,449 and WO 2006/121168, incorporated by reference in their entirety. In one embodiment, the anti-PD-1 antibody molecule comprises one or more CDR sequences (or collectively, all CDR sequences), a heavy chain or light chain variable region sequence, or a nivolumab heavy chain or light chain sequence, e.g., as described in Table 2.

In one embodiment, the anti-PD-1 antibody molecule is Pembrolizumab (Merck & Co), also known as Lambrolizumab, MK-3475, MK03475, SCH-900475, or KEYTRUDA®. Pembrolizumab and other anti-PD-1 antibodies are described in Hamid, O. et al . (2013) New England Journal of Medicine 369 (2): 134-44, in US Pat. No. 8,354,509 and WO 2009/114335, incorporated by reference in their entirety. In one embodiment, the anti-PD-1 antibody molecule comprises one or more CDR sequences (or collectively, all CDR sequences), a heavy chain or light chain variable region sequence, or a pembrolizumab heavy chain or light chain sequence, e.g., as described in Table 2.

In one embodiment, the anti-PD-1 antibody molecule is Pidilizumab (CureTech), also known as CT-011. Pidilizumab, and other anti-PD-1 antibodies are described in Rosenblatt, J. et al. (2011) J Immunotherapy 34(5): 409-18, in US Pat. No. 7,695,715, US Pat. No. 7,332,582, and US Pat. No. 8,686,119 incorporated by reference in their entirety. In one embodiment, the anti-PD-1 antibody molecule comprises one or more CDR sequences (or collectively, all CDR sequences), a heavy chain or light chain variable region sequence, or a Pidilizumab heavy chain or light chain sequence, e.g., as described in Table 2.

In one embodiment, the anti-PD-1 antibody molecule is MEDI0680 (Medimmune), also known as AMP-514. MEDI0680, and other anti-PD-1 antibodies are described in US Pat. No. 9,205,148 and WO 2012/145493, incorporated by reference in their entirety. In one embodiment, the anti-PD-1 antibody molecule comprises one or more CDR sequences (or collectively, all CDR sequences), a heavy chain or light chain variable region sequence, or a MEDI0680 heavy chain or light chain sequence.

In one embodiment, the anti-PD-1 antibody molecule is REGN2810 (Regeneron). In one embodiment, the anti-PD-1 antibody molecule comprises one or more CDR sequences (or collectively, all CDR sequences), a heavy chain or light chain variable region sequence, or a REGN2810 heavy chain or light chain sequence.

In one embodiment, the anti-PD-1 antibody molecule is PF-06801591 (Pfizer). In one embodiment, the anti-PD-1 antibody molecule comprises one or more CDR sequences (or collectively, all CDR sequences), a heavy chain or light chain variable region sequence, or a PF-06801591 heavy chain or light chain sequence.

In one embodiment, the anti-PD-1 antibody molecule is BGB-A317 or BGB-108 (Beigene). In one embodiment, the anti-PD-1 antibody molecule comprises one or more CDR sequences (or collectively, all CDR sequences), a heavy chain or light chain variable region sequence, or a heavy chain or light chain sequence of BGB-A317 or BGB- 108.

In one embodiment, the anti-PD-1 antibody molecule is INCSHR1210 (Incyte), also known as INCSHR01210 or SHR-1210. In one embodiment, the anti-PD-1 antibody molecule comprises one or more CDR sequences (or collectively, all CDR sequences), a heavy chain or light chain variable region sequence, or an INCSHR1210 heavy chain or light chain sequence.

In one embodiment, the anti-PD-1 antibody molecule is TSR-042 (Tesaro), also known as ANB011. In one embodiment, the anti-PD-1 antibody molecule comprises one or more CDR sequences (or collectively, all CDR sequences), a heavy chain or light chain variable region sequence, or a TSR-042 heavy chain or light chain sequence.

Other known anti-PD-1 antibodies include those described in, for example, WO 2015/112800, WO 2016/092419, WO 2015/085847, WO 2014/179664, WO 2014/194302, WO 2014/209804, WO 2015/20011 9 , in US Pat. No. 8,735,553, US Pat. No. 7,488,802, US Pat.

In one embodiment, an anti-PD-1 antibody is an antibody that competes for binding and/or binds to the same epitope on PD-1 as one of the anti-PD-1 antibodies described herein.

In one embodiment, the PD-1 inhibitor is a peptide that slows down the PD-1 signaling pathway, for example, as described in US Pat. No. 8,907,053, incorporated by reference in its entirety. In one embodiment, the PD-1 inhibitor is an immunoadhesin (e.g., an immunoadhesin comprising an extracellular or PD-1 binding portion from PD-L1 or PD-L2 fused to a constant region (e.g., the Fc region of an immunoglobulin sequence). In one embodiment, the PD-1 inhibitor is AMP-224 (B7-DCIg (Amplimmune), for example, as described in WO 2010/027827 and WO 2011/066342, incorporated by reference in its entirety).

Table 2 . Amino acid sequences of other exemplary anti-PD-1 antibody molecules

Nivolumab SEQ ID NO: 535 heavy chain QVQLVESGGGVVQPGRSLRLDCKASGITFSNSGMHWVRQAPGKGLEWVAVIWYDGSKRYYADSVKGRFTISRDNSKNTLFLQMNSLRAEDTAVYYCATNDDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCN VDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYK TTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO: 536 light chain EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEV THQGLSSPVTKSFNRGEC pembrolizumab SEQ ID NO: 537 heavy chain QVQLVQSGVEVKKPGASVKVSCKASGYTFTNYYMYWVRQAPGQGLEWMGGINPSNGGTNFNEKFKNRVTLTTDSSTTTAYMELKSLQFDDTAVYYCARRDYRFDMGFDYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLG TKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQ PENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO: 538 light chain EIVLTQSPATLSLSPGERATLSCRASKGVSTSGYSYLHWYQQKPGQAPRLLIYLASYLESGVPARFSGSGSGTDFTLTISSLEPEDFAVYYCQHSRDDLPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKV YACEVTHQGLSSPVTKSFNRGEC Pidilizumab SEQ ID NO: 539 heavy chain QVQLVQSGSELKKPGASVKISCKASGYTFTNYGMNWVRQAPGQGLQWMGWINTDSGESTYAEEFKGRFVFSLDTSVNTAYLQITSLTAEDTGMYFCVRVGYDALDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTY ICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNY KTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 540 light chain EIVLTQSPSSLSASVGDRVTITCSARSSVSYMHWFQQKPGKAPKLWIYRTSNLASGVPSRFSGSGSGTSYCLTINSLQPEDFATYYCQQRSSFPLTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKV YACEVTHQGLSSPVTKSFNRGEC

PD-L1 inhibitors

In certain embodiments, the anti-LAG-3 antibody molecule described herein is administered in combination with a PD-L1 inhibitor. In some embodiments, the PD-L1 inhibitor is selected from FAZ053 (Novartis), Atezolizumab (Genentech/Roche), Avelumab (Merck Serono and Pfizer), Durvalumab (MedImmune/AstraZeneca), or BMS-936559 (Bristol-Myers Squibb).

Exemplary PD-L1 Inhibitors

In one embodiment, the PD-L1 inhibitor is an anti-PD-L1 antibody molecule. In one embodiment, the PD-L1 inhibitor is an anti-PD-L1 antibody molecule as described in US Pat. as reference in its entirety.

In one embodiment, the anti-PD-L1 antibody molecule contains at least one, two, three, four, five, or six complementarity determining regions (CDRs) (or collectively all CDRs) from the severe and mild variable region. chain containing the amino acid sequence shown in Table 3 (e.g., from the BAP058-Clone O or BAP058-Clone N heavy and light chain variable region sequence described in Table 3) or encoded by the nucleotide sequence shown in Table 3. In some embodiments, implementation, the CDRs are as defined by Kabat (eg, as shown in Table 3). In some embodiments, the CDRs match the definition of Chothia (eg, as shown in Table 3). In some embodiments, the CDRs correspond to the combined CDR definitions of both Kabat and Chothia (eg, as shown in Table 3). In one embodiment, the combination of CDR definitions according to Kabat and Chothia VH CDR1 contains the amino acid sequence GYTFTSYWMY (SEQ ID NO: 647). In one embodiment, one or more CDRs (or collectively all CDRs) have one, two, three, four, five, six or more changes, such as amino acid substitutions (e.g., conservative amino acid substitutions) or deletions, compared to the sequence amino acids shown in Table 3, or they are encoded by the nucleotide sequence shown in Table 3.

In one embodiment, the anti-PD-L1 antibody molecule comprises a heavy chain variable region (VH) comprising the amino acid sequence VHCDR1 SEQ ID NO: 601, the amino acid sequence VHCDR2 SEQ ID NO: 602, and the amino acid sequence VHCDR3 SEQ ID NO: 603 ; and a light chain variable region (VL) comprising the amino acid sequence of VLCDR1 SEQ ID NO: 609, the amino acid sequence of VLCDR2 SEQ ID NO: 610, and the amino acid sequence of VLCDR3 SEQ ID NO: 611, each of which is described in Table 3.

In one embodiment, the anti-PD-L1 antibody molecule comprises a VH comprising VHCDR1 encoded by the nucleotide sequence of SEQ ID NO: 628, VHCDR2 encoded by the nucleotide sequence of SEQ ID NO: 629, and VHCDR3 encoded by the nucleotide sequence of SEQ ID NO: 630 ; and VL containing VLCDR1 encoded by the nucleotide sequence of SEQ ID NO: 633, VLCDR2 encoded by the nucleotide sequence of SEQ ID NO: 634, and VLCDR3 encoded by the nucleotide sequence of SEQ ID NO: 635, each of which is described in Table 3.

In one embodiment, the anti-PD-L1 antibody molecule comprises a VH containing the amino acid sequence of SEQ ID NO: 606 or an amino acid sequence at least 85%, 90%, 95%, or 99% or greater identical to SEQ ID NO. : 606. In one embodiment, the anti-PD-L1 antibody molecule comprises a VL containing the amino acid sequence of SEQ ID NO: 616 or an amino acid sequence at least 85%, 90%, 95%, or 99% or greater identical to SEQ ID NO: 616. In one embodiment, the anti-PD-L1 antibody molecule contains a VH containing the amino acid sequence of SEQ ID NO: 620 or the amino acid sequence of at least 85%, 90%, 95%, or 99% or higher identical to SEQ ID NO: 620, In one embodiment, the anti-PD-L1 antibody molecule contains a VL containing the amino acid sequence of SEQ ID NO: 624 or the amino acid sequence of at least 85%, 90%, 95% or 99% or greater identical to SEQ ID NO: 624. In one embodiment, the anti-PD-L1 antibody molecule comprises a VH containing the amino acid sequence of SEQ ID NO: 606 and a VL containing the amino acid sequence of SEQ ID NO: 616. In one of the embodiments, the anti-PD-L1 antibody molecule comprises a VH containing the amino acid sequence of SEQ ID NO: 620 and a VL containing the amino acid sequence of SEQ ID NO: 624.

In one embodiment, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 607, or a nucleotide sequence at least 85%, 90%, 95%, or 99% or greater identical to SEQ ID NO: 607. B in one embodiment, the antibody molecule comprises a VL encoded by the nucleotide sequence of SEQ ID NO: 617, or a nucleotide sequence at least 85%, 90%, 95%, or 99% or greater identical to SEQ ID NO: 617. In one of the embodiments, the antibody molecule contains a VH encoded by the nucleotide sequence of SEQ ID NO: 621, or a nucleotide sequence at least 85%, 90%, 95% or 99% or higher identical to SEQ ID NO: 621. In one of embodiments, the antibody molecule contains a VL encoded by the nucleotide sequence of SEQ ID NO: 625, or a nucleotide sequence at least 85%, 90%, 95%, or 99% or higher identical to SEQ ID NO: 625. In one embodiment, embodiment, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 607 and a VL encoded by the nucleotide sequence of SEQ ID NO: 617. In one embodiment, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 621 and a VL encoded by the nucleotide sequence of SEQ ID NO: 625.

In one embodiment, the anti-PD-L1 antibody molecule comprises a heavy chain containing the amino acid sequence of SEQ ID NO: 608 or an amino acid sequence that is at least 85%, 90%, 95%, or 99% or greater identical to SEQ ID NO: 608. In one embodiment, the anti-PD-L1 antibody molecule comprises a light chain containing the amino acid sequence of SEQ ID NO: 618 or an amino acid sequence of at least 85%, 90%, 95%, or 99%, or above identical to SEQ ID NO: 618. In one embodiment, the anti-PD-L1 antibody molecule contains a heavy chain containing the amino acid sequence of SEQ ID NO: 622 or the amino acid sequence of at least 85%, 90%, 95% or 99% or greater identical to SEQ ID NO: 622. In one embodiment, the anti-PD-L1 antibody molecule comprises a light chain containing the amino acid sequence of SEQ ID NO: 626 or the amino acid sequence of at least 85%, 90 %, 95% or 99% or greater identical to SEQ ID NO: 626. In one embodiment, the anti-PD-L1 antibody molecule comprises a heavy chain containing the amino acid sequence of SEQ ID NO: 608 and a light chain containing the amino acid sequence of SEQ ID NO: 618. In one embodiment, the anti-PD-L1 antibody molecule comprises a heavy chain containing the amino acid sequence of SEQ ID NO: 622 and a light chain containing the amino acid sequence of SEQ ID NO: 626.

In one embodiment, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 615 or a nucleotide sequence at least 85%, 90%, 95%, or 99% or greater identical to SEQ ID NO: 615. B in one embodiment, the antibody molecule comprises a light chain encoded by a nucleotide sequence of SEQ ID NO: 619 or a nucleotide sequence at least 85%, 90%, 95%, or 99% or greater identical to SEQ ID NO: 619. In one of the embodiments, the antibody molecule contains a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 623 or a nucleotide sequence at least 85%, 90%, 95% or 99% or higher identical to SEQ ID NO: 623. In one of embodiments, the antibody molecule contains a light chain encoded by the nucleotide sequence of SEQ ID NO: 627 or a nucleotide sequence that is at least 85%, 90%, 95%, or 99% or greater identical to SEQ ID NO: 627. In one embodiment, embodiment, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 615 and a light chain encoded by the nucleotide sequence of SEQ ID NO: 619. In one embodiment, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 623 , and a light chain encoded by the nucleotide sequence of SEQ ID NO: 627.

The antibody molecules described herein can be generated using the vectors, host cells, and methods described in US Pat. No. 2016/0108123, incorporated by reference in its entirety.

Table 3 . Amino acid and nucleotide sequences of exemplary anti-PD-L1 antibody molecules

BAP058-Clone O HC SEQ ID NO: 601 (Kabat) HCDR1 SYWMY SEQ ID NO: 602 (Kabat) HCDR2 RIDPNSGSTKYNEKFKN SEQ ID NO: 603 (Kabat) HDDR3 DYRKGLYAMDY SEQ ID NO: 604 (Chothia) HCDR1 GYTFTSY SEQ ID NO: 605 (Chothia) HCDR2 DPNSGS SEQ ID NO: 603 (Chothia) HDDR3 DYRKGLYAMDY SEQ ID NO: 606 vh EVQLVQSGAEVKKPGATVKISCKVSGYTFTSYWMYWVRQARGQRLEWIGRIDPNSGSTKYNEKFKNRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDYRKGLYAMDYWGQGTTVTVSS SEQ ID NO: 607 DNA VH GAAGTGCAGCTGGTGCAGTCAGGCGCCGAAGTGAAGAAACCCGGCGCTACCGTGAAGATTAGCTGTAAAGTCTCAGGCTACACCTTCACTAGCTACTGGATGTACTGGGTCCGACAGGCTAGAGGGCAAAGACTGGAGTGGATCGGTAGAATCGACCCTAATAGCGGCTCTACTAAGTATAACGAGAAGTTTAAGAATAGGTTCACTATTAGTAGGGATAACT CTAAGAACACCCTGTACCCTGCAGATGAATAGCCTGAGAGCCGAGGACACCGCCGTCTACTACTGCCGCTAGAGACTATAGAAAGGGCCTGTACGCTATGGACTACTGGGGTCAAGGCACTACCGTGACCGTGTCTTCA SEQ ID NO: 608 heavy chain EVQLVQSGAEVKKPGATVKISCKVSGYTFTSYWMYWVRQARGQRLEWIGRIDPNSGSTKYNEKFKNRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDYRKGLYAMDYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTK TYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP ENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG SEQ ID NO: 615 heavy chain DNA GAAGTGCAGCTGGTGCAGTCAGGCGCCGAAGTGAAGAAACCCGGCGCTACCGTGAAGATTAGCTGTAAAGTCTCAGGCTACACCTTCACTAGCTACTGGATGTACTGGGTCCGACAGGCTAGAGGGCAAAGACTGGAGTGGATCGGTAGAATCGACCCTAATAGCGGCTCTACTAAGTATAACGAGAAGTTTAAGAATAGGTTCACTATTAGTAGGGATAACT CTAAGAACACCCTGTACCCTGCAGATGAATAGCCTGAGAGCCGAGGACACCGCCGTCTACTACTGCGCTAGAGACTATAGAAAGGGCCTGTACGCTATGGACTACTGGGGTCAAGGCACTACCGTGACCGTGTCTTCAGCTAGCACTAAGGGCCCGTCCGTGTTCCCCCTGGCACCTTGTAGCCGGAGCACTAGCGAATCCACCGCTGCCCTCGGCTGCCTGGTCAAGGATTTCCC GGAGCCCGTGACCGTGTCCTGGAACAGCGGAGCCCTGACCTCCGGAGTGCACACCTTCCCCGCTGTGCTGCAGAGCTCCGGGCTGTACTCGCTGTCGTCGGTGGTCACGGTGCCTTCATCTAGCCTGGGTACCAAGACCTACACTTGCAACGTGGACCACAAGCCTTCCAACACTAAGGTGGACAAGCGCGTCGAATCGAAGTACGGCCCACCGTGCCCGCCTTGTC CCGCGCCGGAGTTCCTCGGCGGTCCCTCGGTCTTTCTGTTCCCACCGAAGCCCAAGGACACTTTGATGATTTCCCGCACCCCTGAAGTGACATGCGTGGTCGTGGACGTGTCACAGGAAGATCCGGAGTGTCAGTTCAATTGGTACGTGGATGGCGTCGAGTGCACAACGCCAAAACCAAGCCGAGGGAGGAGCAGTTCAACTCCACTTACCGCGTCGTGTCCG TGCTGACGGTGCTGCATCAGGACTGGCTGAACGGGAAGGAGTACAAGTGCAAAGTGTCCAACAAGGGACTTCCTAGCTCAATCGAAAAGACCATCTCGAAAGCCAAGGGACAGCCCCGGGAACCCCAAGTGTATACCCTGCCACCGAGCCAGGAAGAAATGACTAAGAACCAAGTCTCATTGACTTGCCTTGTGAAGGCTTCTACCCATCGGATATCGCCGTGGAATGG GAGTCCAACGGCCAGCCGGAAAACAACTACAAGACCACCCCTCCGGTGCTGGACTCAGACGGATCCTTCTTCCTACTCGCGGCTGACCGTGGATAAGAGCAGATGGCAGGAGGGAAATGTGTTCAGCTGTTCTGTGATGCATGAAGCCCTGCACAACCACTACACTCAGAAGTCCCTGTCCCTCTCCCTGGGA BAP058-Clone O LC SEQ ID NO: 609 (Kabat) LCDR1 KASQDVGTAVA SEQ ID NO: 610 (Kabat) LCDR2 WASTRHT SEQ ID NO: 611(Kabat) LCDR3 QQYNSYPLT SEQ ID NO: 612 (Chothia) LCDR1 SQDVGTA SEQ ID NO: 613 (Chothia) LCDR2 WAS SEQ ID NO: 614 (Chothia) LCDR3 YNSYPL SEQ ID NO: 616 VL AIQLTQSPSSLSASVGDRVTITCKASQDVGTAVAWYLQKPGQSPQLLIYWASTRHTGVPSRFSGSGSGTDFTFTISSLEAEDAATYYCQQYNSYPLTFGQGTKVEIK SEQ ID NO: 617 DNA VL GCTATTCAGCTGACTCAGTCACCTAGTAGCCTGAGCCGCTAGTGTGTGGGCGATAGAGTGACTATCACCTGTAAAGCCTCTCAGGACGTGGGCACCGCCGTGGCCTGGTATCTGCAGAAGCCTGGTCAATCACCTCAGCTGCTGATCTACTGGGCCTCTACTAGACACACCGGCGTGCCCTCTAGGTTTAGCGGTAGCGGTAGTGGCACCGACTTCACCTTCACTATCTCT TCACTGGAAGCCGAGGACGCCGCTACCTACTACTGTCAGCAGTATAATAGCTACCCCCTGACCTTCGGTCAAGGCACTAAGGTCGAGATTAAG SEQ ID NO: 618 light chain AIQLTQSPSSLSASVGDRVTITCKASQDVGTAVAWYLQKPGQSPQLLIYWASTRHTGVPSRFSGSGSGTDFTFTISSLEAEDAATYYCQQYNSYPLTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKV YACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 619 light chain DNA GCTATTCAGCTGACTCAGTCACCTAGTAGCCTGAGCCGCTAGTGTGTGGGCGATAGAGTGACTATCACCTGTAAAGCCTCTCAGGACGTGGGCACCGCCGTGGCCTGGTATCTGCAGAAGCCTGGTCAATCACCTCAGCTGCTGATCTACTGGGCCTCTACTAGACACACCGGCGTGCCCTCTAGGTTTAGCGGTAGCGGTAGTGGCACCGACTTCACCTTCACTATCTCT TCACTGGAAGCCGAGGACGCCCGCTACCTACTACTGTCAGCAGTATAATAGCTACCCCCTGACCTTCGGTCAAGGCACTAAGGTCGAGATTAAGCGTACGGTGGCCGCTCCCAGCGTGTTCATCTTCCCCCCCAGCGACGAGCAGCTGAAGAGCGGCACCGCCAGCGTGTGTGTGCCTGCTGAACAACTTCTACCCCCGGGAGGCCAAGGTGCAGTGGAAGGTGGACAACGCCCT GCAGAGCGGCAACAGCCAGGAGAGCGTCACCGAGCAGGACAGCAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCGACTACGAGAAGCATAAGGTGTACGCCTGCGAGGTGACCCACCAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAACAGGGGCGAGTGC BAP058-Clone N HC SEQ ID NO: 601 (Kabat) HCDR1 SYWMY SEQ ID NO: 602 (Kabat) HCDR2 RIDPNSGSTKYNEKFKN SEQ ID NO: 603 (Kabat) HDDR3 DYRKGLYAMDY SEQ ID NO: 604 (Chothia) HCDR1 GYTFTSY SEQ ID NO: 605 (Chothia) HCDR2 DPNSGS SEQ ID NO: 603 (Chothia) HDDR3 DYRKGLYAMDY SEQ ID NO: 620 vh EVQLVQSGAEVKKPGATVKISCKVSGYTFTSYWMYWVRQATGQGLEWMGRIDPNSGSTKYNEKFKNRVTITADKSTSTAYMELSSLRSEDTAVYYCARDYRKGLYAMDYWGQGTTVTVSS SEQ ID NO: 621 DNA VH GAAGTGCAGCTGGTGCAGTCAGGCGCCGAAGTGAAGAAACCCGGCGCTACCGTGAAGATTAGCTGTAAAGTCTCAGGCTACACCTTCACTAGCTACTGGATGTACTGGGTCCGACAGGCTACCGGTCAAGGCCTGGAGTGGATGGGTAGAATCGACCCTAATAGCGGCTCTACTAAGTATAACGAGAAGTTTAAGAATAGAGTGACTATCACCGCCGATAAGTCT ACTAGCACCGCCTATATGGAACTGTCTAGCCTGAGATCAGAGGACACCGCCGTCTACTACTGCGCTAGAGACTATAGAAAGGGCCTGTACGCTATGGACTACTGGGTCAAGGCACTACCGTGACCGTGTCTTCA SEQ ID NO: 622 heavy chain EVQLVQSGAEVKKPGATVKISCKVSGYTFTSYWMYWVRQATGQGLEWMGRIDPNSGSTKYNEKFKNRVTITADKSTSTAYMELSSLRSEDTAVYYCARDYRKGLYAMDYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTY TCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPEN NYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG SEQ ID NO: 623 heavy chain DNA GAAGTGCAGCTGGTGCAGTCAGGCGCCGAAGTGAAGAAACCCGGCGCTACCGTGAAGATTAGCTGTAAAGTCTCAGGCTACACCTTCACTAGCTACTGGATGTACTGGGTCCGACAGGCTACCGGTCAAGGCCTGGAGTGGATGGGTAGAATCGACCCTAATAGCGGCTCTACTAAGTATAACGAGAAGTTTAAGAATAGAGTGACTATCACCGCCGATAAGTCT ACTAGCACCGCCTATATGGAACTGTCTAGCCTGAGATCAGAGGACACCGCCGTCTACTACTGCGCTAGAGACTATAGAAAGGGCCTGTACGCTATGGACTACTGGGGTCAAGGCACTACCGTGACCGTGTCTTCAGCTAGCACTAAGGGCCCGTCCGTGTTCCCCCTGGCACCTTGTAGCCGGAGCACTAGCGAATCCACCGCTGCCCTCGGCTGCCTGGTCAAGGATTACTTCCCGGA GCCCGTGACCGTGTCCTGGAACAGCGGAGCCCTGACCTCCGGAGTGCACACCTTCCCCGCTGTGTGCTGCAGCTCCGGGCTGTACTCGCTGTCGTCGGTGGTCACGGTGCCTTCATCTAGCCTGGGTACCAAAGACCTACACTTGCAACGTGGACCACAAGCCTTCCAACACTAAGGTGGACAAGCGCGTCGAATCGAAGTACGGCCCACCGTGCCCGCCTTGTCCCGC GCCGGAGTTCCTCGGCGGTCCCTCGGTCTTTCTGTTCCCACCGAAGCCCAAGGACACTTTGATGATTTCCCGCACCCCTGAAGTGACATGCGTGGTCGTGGACGTGTCACAGGAAGATCCGGAGGTGCAGTTCAATTGGTACGTGGATGGCGTCGAGTGCACAACGCCAAAACCAAGCCGAGGGAGGAGCAGTTCAACTCCACTTACCGCGTCGTGTCCGTGCT GACGGTGCTGCATCAGGACTGGCTGAACGGGAAGGAGTACAAGTGCAAAGTGTCCAACAAGGGACTTCCTAGCTCAATCGAAAAGACCATCTCGAAAGCCAAGGGACAGCCCCGGGAACCCCAAGTGTATACCCTGCCACCGAGCCAGGAAGAAATGACTAAGAACCAAGTCTCATTGACTTGCCTTGTGAAGGCTTCTACCCATCGGATATCGCCGTGGAATGGGAG TCAACGGCCAGCCGGAAAACAACTACAAGACCACCCCTCCGGTGCTGGACTCAGACGGATCCTTCTTCCTCTACTCGCGGCTGACCGTGGATAAGAGCAGATGGCAGGAGGGAAATGTGTTCAGCTGTTCTGTGATGCATGAAGCCCTGCACAACCACTACACTCAGAAGTCCCTGTCCCTCTCCCTGGGA BAP058-Clone N LC SEQ ID NO: 609 (Kabat) LCDR1 KASQDVGTAVA SEQ ID NO: 610 (Kabat) LCDR2 WASTRHT SEQ ID NO: 611(Kabat) LCDR3 QQYNSYPLT SEQ ID NO: 612 (Chothia) LCDR1 SQDVGTA SEQ ID NO: 613 (Chothia) LCDR2 WAS SEQ ID NO: 614 (Chothia) LCDR3 YNSYPL SEQ ID NO: 624 VL DVVMTQSPLSLPVTLGQPASISCKASQDVGTAVAWYQQKPGQAPRLLIYWASTRHTGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQYNSYPLTFGQGTKVEIK SEQ ID NO: 625 DNA VL GACGTCGTGATGACTCAGTCACCCCTGAGCCTGCCCGTGACCCTGGGGCAGCCCGCCTCTATTAGCTGTAAAGCCTCTCAGGACGTGGGCACCGCCGTGGCCTGGTATCAGCAGAAGCCAGGGCAAGCCCCTAGACTGCTGATCTACTGGGCCTCTACTAGACACACCGGCGTGCCCTCTAGGTTTAGCGGTAGCGGTAGTGGCACCGAGTTCACCCTGACTAT CTCTTCACTGCAGCCCGACGACTTCGCTACCTACTACTGTCAGCAGTATAATAGCTACCCCCTGACCTTCGGTCAAGGCACTAAGGTCGAGATTAAG SEQ ID NO: 626 light chain DVVMTQSPLSLPVTLGQPASISCKASQDVGTAVAWYQQKPGQAPRLLIYWASTRHTGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQYNSYPLTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKH KVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 627 light chain DNA GACGTCGTGATGACTCAGTCACCCCTGAGCCTGCCCGTGACCCTGGGGCAGCCCGCCTCTATTAGCTGTAAAGCCTCTCAGGACGTGGGCACCGCCGTGGCCTGGTATCAGCAGAAGCCAGGGCAAGCCCCTAGACTGCTGATCTACTGGGCCTCTACTAGACACACCGGTGCCCTCTAGGTTTAGCGGTAGCGGTAGTGGCACCGAGTTCACCCTGACT CTCTTCACTGCAGCCCGACGACTTCGCTACCTACTACTGTCAGCAGTATAATAGCTACCCCCTGACCTTCGGTCAAGGCACTAAGGTCGAGATTAAGCGTACGGTGGCCGCTCCCAGCGTGTTCATCTTCCCCCCCAGCGACGAGCAGCTGAAGCGGCACCGCCAGCGTGTGTGTGCCTGCTGAACAACTTCTACCCCCGGGAGGCCAAGGTGCAGTGGAAGGTGGACAACGCC CTGCAGAGCGGCAACAGCCAGGAGAGCGTCACCGAGCAGGACAGCAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCGACTACGAGAAGCATAAGGTGTACGCCTGCGAGGTGACCCACCAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAACAGGGGCGAGTGC BAP058-Clone O HC SEQ ID NO: 628 (Kabat) HCDR1 AGCTACTGGATGTAC SEQ ID NO: 629 (Kabat) HCDR2 AGAATCGACCCTAATAGCGGCCTCTACTAAGTATAACGAGAAGTTTAAGAAT SEQ ID NO: 630 (Kabat) HDDR3 GACTATAGAAAGGGCCTGTACGCTATGGACTAC SEQ ID NO: 631 (Chothia) HCDR1 GGCTACACCTTCACTAGCTAC SEQ ID NO: 632 (Chothia) HCDR2 GACCCTAATAGCGGCTCT SEQ ID NO: 630 (Chothia) HDDR3 GACTATAGAAAGGGCCTGTACGCTATGGACTAC BAP058-Clone O LC SEQ ID NO: 633 (Kabat) LCDR1 AAAGCCTCTCAGGACGTGGGCACCGCCGTGGCC SEQ ID NO: 634 (Kabat) LCDR2 TGGGCCTCTACTAGACACACC SEQ ID NO: 635 (Kabat) LCDR3 CAGCAGTATAATAGCTACCCCCTGACC SEQ ID NO: 636 (Chothia) LCDR1 TCTCAGGACGTGGGCACCGCC SEQ ID NO: 637 (Chothia) LCDR2 TGGGCCTCT SEQ ID NO: 638 (Chothia) LCDR3 TATAATAGCTACCCCCTG BAP058-Clone N HC SEQ ID NO: 628 (Kabat) HCDR1 AGCTACTGGATGTAC SEQ ID NO: 629 (Kabat) HCDR2 AGAATCGACCCTAATAGCGGCCTCTACTAAGTATAACGAGAAGTTTAAGAAT SEQ ID NO: 630 (Kabat) HDDR3 GACTATAGAAAGGGCCTGTACGCTATGGACTAC SEQ ID NO: 631 (Chothia) HCDR1 GGCTACACCTTCACTAGCTAC SEQ ID NO: 632 (Chothia) HCDR2 GACCCTAATAGCGGCTCT SEQ ID NO: 630 (Chothia) HDDR3 GACTATAGAAAGGGCCTGTACGCTATGGACTAC BAP058-Clone N LC SEQ ID NO: 633 (Kabat) LCDR1 AAAGCCTCTCAGGACGTGGGCACCGCCGTGGCC SEQ ID NO: 634 (Kabat) LCDR2 TGGGCCTCTACTAGACACACC SEQ ID NO: 635 (Kabat) LCDR3 CAGCAGTATAATAGCTACCCCCTGACC SEQ ID NO: 636 (Chothia) LCDR1 TCTCAGGACGTGGGCACCGCC SEQ ID NO: 637 (Chothia) LCDR2 TGGGCCTCT SEQ ID NO: 638 (Chothia) LCDR3 TATAATAGCTACCCCCTG

Other exemplary PD-L1 inhibitors

In one embodiment, the anti-PD-L1 antibody molecule is Atezolizumab (Genentech/Roche) also known as MPDL3280A, RG7446, RO5541267, YW243.55.S70, or TECENTRIQ™. Atezolizumab and other anti-PD-L1 antibodies are described in US Pat. No. 8,217,149, incorporated by reference in its entirety. In one embodiment, the anti-PD-L1 antibody molecule comprises one or more CDR sequences (or collectively, all CDR sequences), a heavy chain or light chain variable region sequence, or an atezolizumab heavy chain or light chain sequence, e.g., as described in Table 4.

In one embodiment, the anti-PD-L1 antibody molecule is Avelumab (Merck Serono and Pfizer) also known as MSB0010718C. Avelumab and other anti-PD-L1 antibodies are described in WO 2013/079174, incorporated by reference in its entirety. In one embodiment, the anti-PD-L1 antibody molecule comprises one or more CDR sequences (or collectively, all CDR sequences), an avelumab heavy chain or light chain variable region sequence, or an avelumab heavy chain or light chain sequence, for example, as described in Table 4.

In one embodiment, the anti-PD-L1 antibody molecule is Durvalumab (MedImmune/AstraZeneca), also known as MEDI4736. Durvalumab and other anti-PD-L1 antibodies are described in US Pat. No. 8,779,108, incorporated by reference in its entirety. In one embodiment, the anti-PD-L1 antibody molecule comprises one or more CDR sequences (or collectively, all CDR sequences), a heavy chain or light chain variable region sequence, or a Durvalumab heavy chain or light chain sequence, e.g., as described in Table 4.

In one embodiment, the anti-PD-L1 antibody molecule is BMS-936559 (Bristol-Myers Squibb) also known as MDX-1105 or 12A4. BMS-936559 and other anti-PD-L1 antibodies are described in US Pat. No. 7,943,743 and WO 2015/081158, incorporated by reference in their entirety. In one embodiment, the anti-PD-L1 antibody molecule comprises one or more CDR sequences (or collectively, all CDR sequences), a heavy chain or light chain variable region sequence, or a BMS-936559 heavy chain or light chain sequence, e.g., as described in Table 4.

Other known anti-PD-L1 antibodies include those described in, for example, WO 2015/181342, WO 2014/100079, WO 2016/000619, WO 2014/022758, WO 2014/055897, WO 2015/061668, WO 2013/0791 74 , Wo 2012/145493, Wo 2015/112805, Wo 2015/109124, Wo 2015/195163, in the US Patent 8168179, US Patent 8552154, US Patent 8460927 and US Patent 9175082, included as references in its entirety.

In one embodiment, an anti-PD-L1 antibody is an antibody that competes for binding and/or binds to the same epitope on PD-L1 as one of the anti-PD-L1 antibodies described herein.

Table 4 . Amino acid sequences of other exemplary anti-PD-L1 antibody molecules

Atezolizumab SEQ ID NO: 639 heavy chain EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQ TYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP ENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 640 light chain DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYLYHPATFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHK VYACEVTHQGLSSPVTKSFNRGEC Avelumab SEQ ID NO: 641 heavy chain EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYIMMWVRQAPGKGLEWVSSIYPSGGITFYADTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARIKLGTVTTVDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQ TYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQP ENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 642 light chain QSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYDVSNRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYTSSSTRVFGTGTKVTVLGQPKANPTVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADGSPVKAGVETTKPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVT HEGSTVEKTVAPTECS SEQ ID NO: 643 heavy chain EVQLVESGGGLVQPGGSLRLSCAASGFTFSRYWMSWVRQAPGKGLEWVANIKQDGSEKYYVDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAREGGWFGELAFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSL GTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNG QPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 644 light chain EIVLTQSPGTLSLSPGERATLSCRASQRVSSSYLAWYQQKPGQAPRLLIYDASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSLPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVY ACEVTHQGLSSPVTKSFNRGEC BMS-936559 SEQ ID NO: 645 vh QVQLVQSGAEVKKPGSSVKVSCKTSGDTFSTYAISWVRQAPGQGLEWMGGIIPIFGKAHYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYFCARKFHFVSGSPFGMDVWGQGTTVTVSS SEQ ID NO: 646 VL EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPTFGQGTKVEIK

TIM-3 inhibitors

In certain embodiments, the anti-LAG-3 antibody molecule described herein is administered in combination with a TIM-3 inhibitor. In some embodiments, the TIM-3 inhibitor is MGB453 (Novartis) or TSR-022 (Tesaro).

Exemplary TIM-3 Inhibitors

In one embodiment, the TIM-3 inhibitor is an anti-TIM-3 antibody molecule. In one embodiment, the TIM-3 inhibitor is an anti-TIM-3 antibody molecule as described in US Pat. links in their entirety.

In one embodiment, the anti-TIM-3 antibody molecule contains at least one, two, three, four, five, or six complementarity determining regions (CDRs) (or collectively all CDRs) from the heavy and light chain variable regions. , containing the amino acid sequence as shown in Table 7 (for example, from the heavy and light chain variable region sequence of ABTIM3-hum11 or ABTIM3-hum03 described in Table 7), or it is encoded by the nucleotide sequence shown in Table 7. In some embodiments, implementation , CDRs are as defined by Kabat (eg, as shown in Table 7). In some embodiments, the CDRs match the definition of Chothia (eg, as shown in Table 7). In one embodiment, one or more CDRs (or collectively all CDRs) have one, two, three, four, five, six or more changes, such as amino acid substitutions (e.g., conservative amino acid substitutions) or deletions, compared to the sequence amino acids shown in Table 7, or they are encoded by the nucleotide sequence shown in Table 7.

In one embodiment, the anti-TIM-3 antibody molecule comprises a heavy chain variable region (VH) comprising the amino acid sequence VHCDR1 SEQ ID NO: 801, the amino acid sequence VHCDR2 SEQ ID NO: 802, and the amino acid sequence VHCDR3 SEQ ID NO: 803 and a light chain variable region (VL) comprising the amino acid sequence of VLCDR1 SEQ ID NO: 810, the amino acid sequence of VLCDR2 SEQ ID NO: 811, and the amino acid sequence of VLCDR3 SEQ ID NO: 812, each of which is described in Table 7. In one embodiment, , the anti-TIM-3 antibody molecule contains a heavy chain variable region (VH) containing the amino acid sequence of VHCDR1 SEQ ID NO: 801, the amino acid sequence of VHCDR2 SEQ ID NO: 820, and the amino acid sequence of VHCDR3 SEQ ID NO: 803; and a light chain variable region (VL) containing the amino acid sequence of VLCDR1 SEQ ID NO: 810, the amino acid sequence of VLCDR2 SEQ ID NO: 811, and the amino acid sequence of VLCDR3 SEQ ID NO: 812, each of which is described in Table 7.

In one embodiment, the anti-TIM-3 antibody molecule comprises a VH containing the amino acid sequence of SEQ ID NO: 806 or an amino acid sequence at least 85%, 90%, 95%, or 99% or greater identical to SEQ ID NO. : 806. In one embodiment, the anti-TIM-3 antibody molecule comprises a VL containing the amino acid sequence of SEQ ID NO: 816 or an amino acid sequence at least 85%, 90%, 95% or 99% or greater identical to SEQ ID NO: 816. In one embodiment, the anti-TIM-3 antibody molecule comprises a VH containing the amino acid sequence of SEQ ID NO: 822 or the amino acid sequence of at least 85%, 90%, 95%, or 99% or higher identical to SEQ ID NO: 822. In one embodiment, the anti-TIM-3 antibody molecule contains a VL containing the amino acid sequence of SEQ ID NO: 826 or the amino acid sequence of at least 85%, 90%, 95% or 99% or greater identical to SEQ ID NO: 826. In one embodiment, the anti-TIM-3 antibody molecule comprises a VH containing the amino acid sequence of SEQ ID NO: 806 and a VL containing the amino acid sequence of SEQ ID NO: 816. In one of the embodiments, the anti-TIM-3 antibody molecule comprises a VH containing the amino acid sequence of SEQ ID NO: 822 and a VL containing the amino acid sequence of SEQ ID NO: 826.

In one embodiment, the antibody molecule comprises a VH encoded by a nucleotide sequence of SEQ ID NO: 807 or a nucleotide sequence at least 85%, 90%, 95%, or 99% or greater identical to SEQ ID NO: 807. In one in embodiments, the antibody molecule contains a VL encoded by the nucleotide sequence of SEQ ID NO: 817 or a nucleotide sequence at least 85%, 90%, 95%, or 99% or greater identical to SEQ ID NO: 817. In one embodiment, embodiment, the antibody molecule contains a VH encoded by the nucleotide sequence of SEQ ID NO: 823 or a nucleotide sequence at least 85%, 90%, 95%, or 99% or greater identical to SEQ ID NO: 823. In one embodiment, the antibody molecule contains a VL encoded by the nucleotide sequence of SEQ ID NO: 827 or a nucleotide sequence at least 85%, 90%, 95% or 99% or higher identical to SEQ ID NO: 827. In one embodiment, the antibody molecule contains a VH encoded by the nucleotide sequence of SEQ ID NO: 807 and a VL encoded by the nucleotide sequence of SEQ ID NO: 817. In one embodiment, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 823 and a VL encoded by the nucleotide sequence of SEQ ID NO: 823 SEQ ID NO: 827.

In one embodiment, the anti-TIM-3 antibody molecule comprises a heavy chain containing the amino acid sequence of SEQ ID NO: 808 or an amino acid sequence at least 85%, 90%, 95%, or 99% or greater identical to SEQ ID NO: 808. In one embodiment, the anti-TIM-3 antibody molecule comprises a light chain containing the amino acid sequence of SEQ ID NO: 818 or an amino acid sequence of at least 85%, 90%, 95%, or 99%, or above identical to SEQ ID NO: 818. In one embodiment, the anti-TIM-3 antibody molecule contains a heavy chain containing the amino acid sequence of SEQ ID NO: 824 or the amino acid sequence of at least 85%, 90%, 95% or 99% or greater identical to SEQ ID NO: 824. In one embodiment, the anti-TIM-3 antibody molecule comprises a light chain containing the amino acid sequence of SEQ ID NO: 828 or the amino acid sequence of at least 85%, 90 %, 95% or 99% or greater identical to SEQ ID NO: 828. In one embodiment, the anti-TIM-3 antibody molecule comprises a heavy chain containing the amino acid sequence of SEQ ID NO: 808 and a light chain containing the amino acid sequence of SEQ ID NO: 818. In one embodiment, the anti-TIM-3 antibody molecule comprises a heavy chain containing the amino acid sequence of SEQ ID NO: 824 and a light chain containing the amino acid sequence of SEQ ID NO: 828.

In one embodiment, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 809 or a nucleotide sequence at least 85%, 90%, 95%, or 99% or greater identical to SEQ ID NO: 809. B in one embodiment, the antibody molecule comprises a light chain encoded by a nucleotide sequence of SEQ ID NO: 819 or a nucleotide sequence at least 85%, 90%, 95%, or 99% or greater identical to SEQ ID NO: 819. In one in embodiments, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 825 or a nucleotide sequence at least 85%, 90%, 95%, or 99% or greater identical to SEQ ID NO: 825. In one of embodiments, the antibody molecule contains a light chain encoded by the nucleotide sequence of SEQ ID NO: 829 or a nucleotide sequence at least 85%, 90%, 95%, or 99% or higher identical to SEQ ID NO: 829. In one embodiment, embodiment, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 809 and a light chain encoded by the nucleotide sequence of SEQ ID NO: 819. In one embodiment, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 825 , and a light chain encoded by the nucleotide sequence of SEQ ID NO: 829.

The antibody molecules described herein can be generated using the vectors, host cells, and methods described in US Pat. No. 2015/0218274, incorporated by reference in its entirety.

Table 7 . Amino acid and nucleotide sequences of exemplary anti-TIM-3 antibody molecules

ABTIM3-hum11 SEQ ID NO: 801 (Kabat) HCDR1 SYNMH SEQ ID NO: 802 (Kabat) HCDR2 DIYPGNGDTSYNQKFKG SEQ ID NO: 803 (Kabat) HDDR3 VGGAFPMDY SEQ ID NO: 804 (Chothia) HCDR1 GYTFTSY SEQ ID NO: 805 (Chothia) HCDR2 YPGNGD SEQ ID NO: 803 (Chothia) HDDR3 VGGAFPMDY SEQ ID NO: 806 vh QVQLVQSGAEVKKPGSSVKVSCKASGYTFTSYNMHWVRQAPGQGLEWMGDIYPGNGDTSYNQKFKGRVTITADKSTSTVYMELSSLRSEDTAVYYCARVGGAFPMDYWGQGTTVTVSS SEQ ID NO: 807 DNA VH CAGGTGCAGCTGGTGCAGTCAGGCGCCGAAGTGAAGAAACCCGGCCTAGCGTGAAAGTTTCTTGTAAAGCTAGTGGCTACACCTTCACTAGCTATAATATGCACTGGGTTCGCCAGGCCCCAGGGCAAGGCCTCGAGTGGATGGGCGATATCTACCCCGGGAACGGCGACACTAGTTATAATCAGAAGTTTAAGGGTAGAGTCACTATCACCGCCGATAAGTCTACT AGCACCGTCTATATGGAACTGAGTTCCCTGAGGTCTGAGGACACCGCCGTCTACTACTGCGCTAGAGTGGGCGGAGCCTTCCCTATGGACTACTGGGGTCAAGGCACTACCGTGACCGTGTCTAGC SEQ ID NO: 808 heavy chain QVQLVQSGAEVKKPGSSVKVSCKASGYTFTSYNMHWVRQAPGQGLEWMGDIYPGNGDTSYNQKFKGRVTITADKSTSTVYMELSSLRSEDTAVYYCARVGGAFPMDYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTK TYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP ENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG SEQ ID NO: 809 heavy chain DNA CAGGTGCAGCTGGTGCAGTCAGGCGCCGAAGTGAAGAAACCCGGCCTAGCGTGAAAGTTTCTTGTAAAGCTAGTGGCTACACCTTCACTAGCTATAATATGCACTGGGTTCGCCAGGCCCCAGGGCAAGGCCTCGAGTGGATGGGCGATATCTACCCCGGGAACGGCGACACTAGTTATAATCAGAAGTTTAAGGGTAGAGTCACTATCACCGCCGATAAGTCTACT AGCACGTCTATATGGAACTGAGTTCCCTGAGGTCTGAGGACACCGCCGTCTACTACTGCGCTAGAGTGGGCGGAGCCTTCCCTATGGACTACTGGGGTCAAGGCACTACCGTGACCGTGTCTAGCGCTAGCACTAAGGGCCCGTCCGTGTTCCCCCTGGCACCTTGTAGCCGGAGCACTAGCGAATCCACCGCTGCCCTCGGCTGCCTGGTCAAGGATTACTTCCCGGAGCCC GTGACCGTGTCCTGGAACAGCGGAGCCCTGACCTCCGGAGTGCACACCTTCCCCGCTGTGCTGCAGAGCTCCGGGCTGTACTCGCTGTCGTCGGTGGTCACGGTGCCTTCATCTAGCCTGGGTACCAAAGACCTACACTTGCAACGTGGACCACAAGCCTTCCAACACTAAGGTGGACAAGCGCGTCGAATCGAAGTACGGCCCACCGTGCCCGCCTTGTCCCGCGCCG GAGTTCCTCGGCGGTCCCTCGGTCTTTCTGTTCCCACCGAAGCCCAAGGACACTTTGATGATTTCCCGCACCCCTGAAGTGACATGCGTGGTCGTGGACGTGTCACAGGAAGATCCGGAGTGCAGTTCAATTGGTACGTGGATGGCGTCGAGGTGCACAACGCCAAAACCAAGCCGAGGAGGAGCAGTTCAACTCCACTTACCGCGTCGTGTCCGTGCTGACG GTGCTGCATCAGGACTGGCTGAACGGGAAGGAGTACAAGTGCAAAGTGTCCAACAAGGGACTTCCTAGCTCAATCGAAAAGACCATCTCGAAAGCCAAGGGACAGCCCCGGGAACCCCAAGTGTATACCCTGCCACCGAGCCAGGAAGAAATGACTAAGAACCAAGTCTCATTGACTTGCCTTGTGAAGGCTTCTACCCATCGGATATCGCCGTGGAATGGGAGTCCA ACGGCCAGCCGGAAAACAACTACAAGACCACCCCTCCGGTGCTGGACTCAGACGGATCCTTCTTCCTCTACTCGCGGCTGACCGTGGATAAGAGCAGATGGCAGGAGGAAATGTGTTCAGCTGTTCTGTGATGCATGAAGCCCTGCACAACCACTACACTCAGAAGTCCCTGTCCCTCTCCCTGGGA SEQ ID NO: 810 (Kabat) LCDR1 RASESVEYYGTSLMQ SEQ ID NO: 811 (Kabat) LCDR2 AASNVES SEQ ID NO: 812 (Kabat) LCDR3 QQSRKDPST SEQ ID NO: 813 (Chothia) LCDR1 SESVEYYGTSL SEQ ID NO: 814 (Chothia) LCDR2 AAS SEQ ID NO: 815 (Chothia) LCDR3 SRKDPS SEQ ID NO: 816 VL AIQLTQSPSSLSASVGDRVTITCRASESVEYYGTSLMQWYQQKPGKAPKLLIYAASNVESGVPSRFSGSGSGTDFTLTISSLQPEDFATYFCQQSRKDPSFGGGTKVEIK SEQ ID NO: 817 DNA VL GCTATTCAGCTGACTCAGTCACCTAGTAGCCTGAGCGCTAGTGTGTGGGCGATAGAGTGACTATCACCTGTAGAGCTAGTGAATCAGTCGAGTACTACGGCACTAGCCTGATGCAGTGGTATCAGCAGAAGCCCGGGAAAGCCCCTAAGCTGCTGATCTACGCCGCCTCTAACGTGGAATCAGGCGTGCCCTCTAGGTTTAGCGGTAGCGGTAGTGGCACCGACTTCACCC TGACTATCTCTAGCCTGCAGCCCGAGGACTTCGCTACCTACTTCTGTCAGCAGTCTAGGAAGGACCCTAGCACCTTCGGCGGAGGCACTAAGGTCGAGATTAAG SEQ ID NO: 818 light chain AIQLTQSPSSLSASVGDRVTITCRASESVEYYGTSLMQWYQQKPGKAPKLLIYAASNVESGVPSRFSGSGSGTDFTLTISSLQPEDFATYFCQQSRKDPSTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKH KVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 819 light chain DNA GCTATTCAGCTGACTCAGTCACCTAGTAGCCTGAGCGCTAGTGTGTGGGCGATAGAGTGACTATCACCTGTAGAGCTAGTGAATCAGTCGAGTACTACGGCACTAGCCTGATGCAGTGGTATCAGCAGAAGCCCGGGAAAGCCCCTAAGCTGCTGATCTACGCCGCCTCTAACGTGGAATCAGGCGTGCCCTCTAGGTTTAGCGGTAGCGGTAGTGGCACCGACTTCACCC TGACTATCTCTAGCCTGCAGCCCGAGGACTTCGCTACCTACTTCTGTCAGCAGTCTAGGAAGGACCCTAGCACCTTCGGCGGAGGCACTAAGGTCGAGATTAAGCGTACGGTGGCCGCTCCCAGCGTGTTCATCTTCCCCCCCAGCGACGAGCAGCTGAAGAGCGGCACCGCCAGCGTGGTGTGCCTGCTGAACAACTTCTACCCCCGGGAGGCCAAGGTGCAGTGGAAGGTG GACAAACGCCCTGCAGCGGCAACAGCCAGGAGAGCGTCACCGAGCAGGACAGCAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCGACTACGAGAAGCATAAGGTGTACGCCTGCGAGGTGACCCACCAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAACAGGGGCGAGTGC ABTIM3-hum03 SEQ ID NO: 801 (Kabat) HCDR1 SYNMH SEQ ID NO: 820 (Kabat) HCDR2 DIYPGQGDTSYNQKFKG SEQ ID NO: 803 (Kabat) HDDR3 VGGAFPMDY SEQ ID NO: 804 (Chothia) HCDR1 GYTFTSY SEQ ID NO: 821 (Chothia) HCDR2 YPGQGD SEQ ID NO: 803 (Chothia) HDDR3 VGGAFPMDY SEQ ID NO: 822 vh QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYNMHWVRQAPGQGLEWIGDIYPGQGDTSYNQKFKGRATMTADKSTSTVYMELSSLRSEDTAVYYCARVGGAFPMDYWGQGTLVTVSS SEQ ID NO: 823 DNA VH CAGGTGCAGCTGGTGCAGTCAGGCGCCGAAGTGAAGAAACCCGGCCTAGTGTGAAAGTTAGCTGTAAAGCTAGTGGCTATACTTTCACTTCTTATAATATGCACTGGGTCCGCCAGGCCCCAGGTCAAGGCCTCGAGTGGATCGGCGATATCTACCCCGGTCAAGGCGACACTTCCTATAATCAGAAGTTTAAGGGTAGAGCTACTATGACCGCCGATAAGTCTACT TCTACCGTCTATATGGAACTGAGTTCCCTGAGGTCTGAGGACACCGCCGTCTACTACTGCGCTAGAGTGGGCGGAGCCTTCCCAATGGACTACTGGGGTCAAGGCACCCTGGTCACCGTGTCTAGC SEQ ID NO: 824 heavy chain QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYNMHWVRQAPGQGLEWIGDIYPGQGDTSYNQKFKGRATMTADKSTSTVYMELSSLRSEDTAVYYCARVGGAFPMDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLG TKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQ PENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG SEQ ID NO: 825 heavy chain DNA CAGGTGCAGCTGGTGCAGTCAGGCGCCGAAGTGAAGAAACCCGGCCTAGTGTGAAAGTTAGCTGTAAAGCTAGTGGCTATACTTTCACTTCTTATAATATGCACTGGGTCCGCCAGGCCCCAGGTCAAGGCCTCGAGTGGATCGGCGATATCTACCCCGGTCAAGGCGACACTTCCTATAATCAGAAGTTTAAGGGTAGAGCTACTATGACCGCCGATAAGTCTACT TCTACCGTCTATATGGAACTGAGTTCCCTGAGGTCTGAGGACACCGCCGTCTACTACTACTGCGCTAGAGTGGGCGGAGCCTTCCCAATGGACTACTGGGGTCAAGGCACCCTGGTCACCGTGTCTAGCGCTAGCACTAAGGGCCCGTCCGTGTTCCCCCTGGCACCTTGTAGCCGGAGCACTAGCGAATCCACCGCTGCCCTCGGCTGCCTGGTCAAGGATTACTTCCCGGAGC CCGTGACCGTGTCCTGGAACAGCGGAGCCCTGACCTCCGGAGTGCACACCTTCCCCGCTGTGCTGCAGCTCCGGGCTGTACTCGCTGTCGTCGGTGGTCACGGTGCCTTCATCTAGCCTGGGTACCAAAGACCTACACTTGCAACGTGGACCACAAGCCTTCCAACACTAAGGTGGACAAGCGCGTCGAATCGAAGTACGGCCCACCGTGCCCGCCTTGTCCCGCGC CGGAGTTCCTCGGCGGTCCCTCGGTCTTTCTGTTCCCACCGAAGCCCAAGGACACTTTGATGATTTCCCGCACCCCTGAAGTGACATGCGTGGTCGTGGACGTGTCACAGGAAGATCCGGAGTGTCAGTTCAATTGGTACGTGGATGGCGTCGAGGTGCACAACGCCAAAACCAAGCCGAGGGAGGAGCAGTTCAACTCCACTTACCGCGTCGTGTCCGTGCTGA CGGTGCTGCATCAGGACTGGCTGAACGGGAAGGAGTACAAGTGCAAAGTGTCCAACAAGGGACTTCCTAGCTCAATCGAAAAGACCATCTCGAAAGCCAAGGGACAGCCCCGGGAACCCCAAGTGTATACCCTGCCACCGAGCCAGGAAGAAATGACTAAGAACCAAGTCTCATTGACTTGCCTTGTGAAGGCTTCTACCCATCGGATATCGCCGTGGAATGGGAGTC CAACGGCCAGCCGGAAAACAACTACAAGACCACCCCTCCGGTGCTGGACTCAGACGGATCCTTCTTCCTCTACTCGCGGCTGACCGTGGATAAGAGCAGATGGCAGGAGGAAATGTGTTCAGCTGTTCTGTGATGCATGAAGCCCTGCACAACCACTACACTCAGAAGTCCCTGTCCCTCTCCCTGGGA SEQ ID NO: 810 (Kabat) LCDR1 RASESVEYYGTSLMQ SEQ ID NO: 811 (Kabat) LCDR2 AASNVES SEQ ID NO: 812 (Kabat) LCDR3 QQSRKDPST SEQ ID NO: 813 (Chothia) LCDR1 SESVEYYGTSL SEQ ID NO: 814 (Chothia) LCDR2 AAS SEQ ID NO: 815 (Chothia) LCDR3 SRKDPS SEQ ID NO: 826 VL DIVLTQSPDSLAVSLGERATINCRASESVEYYGTSLMQWYQQKPGQPPKLLIYAASNVESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQSRKDPSTFGGGTKVEIK SEQ ID NO: 827 DNA VL GATATCGTCCTGACTCAGTCACCCGATAGCCTGGCCGTCAGCCTGGGCGAGCGGGCTACTATTAACTGTAGAGCTAGTGAATCAGTCGAGTACTACGGCACTAGCCTGATGCAGTGGTATCAGCAGAAGCCCGGTCAACCCCCTAAGCTGCTGATCTACGCCGCCTCTAACGTGGAATCAGGCGTGCCCGATAGGTTTAGCGGTAGCGGTAGTGGCACCGACTTCAC CCTGACTATTAGTAGCCTGCAGGCCGAGGACGTGGCCGTCTACTACTGTCAGCAGTCTAGGAAGGACCCTAGCACCTTCGGCGGAGGCACTAAGGTCGAGATTAAG SEQ ID NO: 828 light chain DIVLTQSPDSLAVSLGERATINCRASESVEYYGTSLMQWYQQKPGQPPKLLIYAASNVESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQSRKDPSFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADY EKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 829 light chain DNA GATATCGTCCTGACTCAGTCACCCGATAGCCTGGCCGTCAGCCTGGGCGAGCGGGCTACTATTAACTGTAGAGCTAGTGAATCAGTCGAGTACTACGGCACTAGCCTGATGCAGTGGTATCAGCAGAAGCCCGGTCAACCCCCTAAGCTGCTGATCTACGCCGCCTCTAACGTGGAATCAGGCGTGCCCGATAGGTTTAGCGGTAGCGGTAGTGGCACCGACTTCAC CCTGACTATTAGTAGCCTGCAGGCCGAGGACGTGGCCGTCTACTGTCAGCAGTCTAGGAAGGACCCTAGCACCTTCGGCGGAGGCACTAAGGTCGAGATTAAGCGTACGGTGGCCGCTCCCAGCGTGTTCATCTTCCCCCCCAGCGACGAGCAGCTGAAGAGCGGCACCGCCAGCGTGTGTGTGCCTGCTGAACAACTTCTACCCCCGGGAGGCCAAGGTGCAGTGGAAGG TGGACAACGCCCTGCAGAGCGGCAACAGCCAGGAGAGCGTCACCGAGCAGGACAGCAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCGACTACGAGAAGCATAAGGTGTACGCCTGCGAGGTGACCCACCAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAACAGGGGCGAGTGC

Other exemplary TIM-3 inhibitors

In one embodiment, the anti-TIM-3 antibody molecule is TSR-022 (AnaptysBio/Tesaro). In one embodiment, the anti-TIM-3 antibody molecule comprises one or more CDR sequences (or collectively, all CDR sequences), a heavy chain or light chain variable region sequence, or a TSR-022 heavy chain or light chain sequence. In one embodiment, the anti-TIM-3 antibody molecule contains one or more CDR sequences (or collectively, all CDR sequences), a heavy chain or light chain variable region sequence, or an APE5137 or APE5121 heavy chain or light chain sequence, e.g., as described in Table 8. APE5137, APE5121 and other anti-TIM-3 antibodies are described in WO 2016/161270, incorporated by reference in its entirety.

In one embodiment, the anti-TIM-3 antibody molecule is an F38-2E2 antibody clone. In one embodiment, the anti-TIM-3 antibody molecule comprises one or more CDR sequences (or collectively, all CDR sequences), a heavy chain or light chain variable region sequence, or an F38-2E2 heavy chain or light chain sequence.

Other known anti-TIM-3 antibodies include those described, for example, in WO 2016/111947, WO 2016/071448, WO 2016/144803, US Pat. No. 8,552,156, US Pat. in all its fullness.

In one embodiment, the anti-TIM-3 antibody is an antibody that competes for binding and/or binds to the same epitope on TIM-3 as one of the anti-TIM-3 antibodies described herein.

Table 8 . Amino acid sequences of other exemplary anti-TIM-3 antibody molecules

APE5137 SEQ ID NO: 830 vh EVQLLESGGGLVQPGGSLRLSCAAASGFTFSSYDMSWVRQAPGKGLDWVSTISGGGTYYQDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASMDYWGQGTTVTVSSA SEQ ID NO: 831 VL DIQMTQSPSSLSASVGDRVTITCRASQSIRRYLNWYHQKPGKAPKLLIYGASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFAVYYCQQSHSAPLTFGGGTKVEIKR APE5121 SEQ ID NO: 832 vh EVQVLESGGGLVQPGGSLRLYCVASGFTFSGSYAMSWVRQAPGKGLEWVSAISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKKYYVGPADYWGQGTLVTVSSG SEQ ID NO: 833 VL DIVMTQSPDSLAVSLGERATINCKSSQSVLYSSNNKNYLAWYQHKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYSSPLTFGGGTKIEVK

GITR agonists

In certain embodiments, the anti-LAG-3 antibody molecule described herein is administered in combination with a GITR agonist. In some embodiments, the GITR agonist is GWN323 (NVS), BMS-986156, MK-4166 or MK-1248 (Merck), TRX518 (Leap Therapeutics), INCAGN1876 (Incyte/Agenus), AMG 228 (Amgen), or INBRX- 110 (Inhibrx).

Exemplary GITR agonists

In one embodiment, the GITR agonist is an anti-GITR antibody molecule. In one embodiment, the GITR agonist is an anti-GITR antibody molecule as described in WO 2016/057846, published April 14, 2016, entitled “Compositions and Methods of Use for Augmented Immune Reaction and Cancer Therapy”, incorporated by reference in its entirety.

In one embodiment, the anti-GITR antibody molecule contains at least one, two, three, four, five, or six complementarity determining regions (CDRs) (or collectively all CDRs) from the heavy and light chain variable regions, containing the amino acid sequence shown in Table 9 (e.g., from the MAB7 heavy and light chain variable region sequence described in Table 9), or encoded by the nucleotide sequence shown in Table 9. In some embodiments, the CDRs are as defined by Kabat (e.g., as shown in Table 9). In some embodiments, the CDRs match the definition of Chothia (eg, as shown in Table 9). In one embodiment, one or more CDRs (or collectively all CDRs) have one, two, three, four, five, six or more changes, such as amino acid substitutions (e.g., conservative amino acid substitutions) or deletions, compared to the sequence amino acids shown in Table 9, or they are encoded by the nucleotide sequence shown in Table 9.

In one embodiment, the anti-GITR antibody molecule comprises a heavy chain variable region (VH) comprising the amino acid sequence of VHCDR1 of SEQ ID NO: 909, the amino acid sequence of VHCDR2 of SEQ ID NO: 911, and the amino acid sequence of VHCDR3 of SEQ ID NO: 913; and a light chain variable region (VL) containing the amino acid sequence of VLCDR1 SEQ ID NO: 914, the amino acid sequence of VLCDR2 SEQ ID NO: 916, and the amino acid sequence of VLCDR3 SEQ ID NO: 918, each of which is described in Table 9.

In one embodiment, the anti-GITR antibody molecule comprises a VH containing the amino acid sequence of SEQ ID NO: 901 or an amino acid sequence at least 85%, 90%, 95%, or 99% or greater identical to SEQ ID NO: 901 In one embodiment, the anti-GITR antibody molecule comprises a VL comprising the amino acid sequence of SEQ ID NO: 902 or an amino acid sequence at least 85%, 90%, 95%, or 99% or greater identical to SEQ ID NO: 902. In one embodiment, the anti-GITR antibody molecule comprises a VH containing the amino acid sequence of SEQ ID NO: 901 and a VL containing the amino acid sequence of SEQ ID NO: 902.

In one embodiment, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 905, or a nucleotide sequence at least 85%, 90%, 95%, or 99% or greater identical to SEQ ID NO: 905. B in one embodiment, the antibody molecule comprises a VL encoded by the nucleotide sequence of SEQ ID NO: 906, or a nucleotide sequence at least 85%, 90%, 95%, or 99% or greater identical to SEQ ID NO: 906. In one of the embodiments, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 905 and a VL encoded by the nucleotide sequence of SEQ ID NO: 906.

In one embodiment, the anti-GITR antibody molecule comprises a heavy chain containing the amino acid sequence of SEQ ID NO: 903 or an amino acid sequence at least 85%, 90%, 95%, or 99% or greater identical to SEQ ID NO: 903. In one embodiment, the anti-GITR antibody molecule comprises a light chain containing the amino acid sequence of SEQ ID NO: 904 or an amino acid sequence at least 85%, 90%, 95%, or 99% or greater identical to SEQ ID NO: 904. In one embodiment, the anti-GITR antibody molecule comprises a heavy chain containing the amino acid sequence of SEQ ID NO: 903 and a light chain containing the amino acid sequence of SEQ ID NO: 904.

In one embodiment, the antibody molecule contains a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 907, or a nucleotide sequence at least 85%, 90%, 95%, or 99% or greater identical to SEQ ID NO: 907. In one embodiment, the antibody molecule comprises a light chain encoded by a nucleotide sequence of SEQ ID NO: 908 or a nucleotide sequence at least 85%, 90%, 95%, or 99% or greater identical to SEQ ID NO: 908. B In one embodiment, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 907 and a light chain encoded by the nucleotide sequence of SEQ ID NO: 908.

The antibody molecules described herein can be generated using the vectors, host cells, and methods described in WO 2016/057846, incorporated by reference in its entirety.

Table 9 : Amino acid and nucleotide sequences of exemplary anti-GITR antibody molecules

MAB7 SEQ ID NO: 901 vh EVQLVESGGGLVQSGGSLRLSCAASGFSLSSYGVDWVRQAPGKGLEWVGVIWGGGGTYYASSLMGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARHAYGHDGGFAMDYWGQGTLVTVSS SEQ ID NO: 902 VL EIVMTQSPATLSVSPGERATLSCRASESVSSNVAWYQQRPGQAPRLLIYGASNRATGIPARFSGSGSGTDFTLTISRLEPEDFAVYYCGQSYSYPFTFGQGTKLEIK SEQ ID NO: 903 heavy chain EVQLVESGGGLVQSGGSLRLSCAASGFSLSSYGVDWVRQAPGKGLEWVGVIWGGGGTYYASSLMGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARHAYGHDGGFAMDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSL GTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNG QPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 904 light chain EIVMTQSPATLSVSPGERATLSCRASESVSSNVAWYQQRPGQAPRLLIYGASNRATGIPARFSGSGSGTDFTLTISRLEPEDFAVYYCGQSYSYPFTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQ GLSSPVTKSFNRGEC SEQ ID NO: 905 DNA VH GAGGTGCAGCTGGTGGAATCTGGCGGCGGACTGGTGCAGTCCGGGCTCTCTGAGACTGTCTTGCGCTGCCTCCGGCTTCTCCCTGTCCTCTTACGGCGTGGACTGGGTGCGACAGGCCCCTGGCAAGGGCCTGGAATGGGTGGGAGTGATCTGGGGCGGAGGCGGCACCTACTACGCCTCTTCCCTGATGGGCCGGTTCACCATCTCCCG GGACAACTCCAAGAACACCCTGTACCTGCAGATGAACTCCCTGCGGGCCGAGGACACCGCCGTGTACTACTGCGCCAGACACGCCTACGGCCACGACGGCGGCTTCGCCATGGATTATTGGGGCCAGGGCACCCTGGTGACAGTGTCCTCC SEQ ID NO: 906 DNA VL GAGATCGTGATGACCCAGTCCCCCGCCACCCTGTCTGTGTCTCCCGGCGAGAGCCACCCTGAGCTGCAGAGCCTCCGAGTCCGTGTCCTCCAACGTGGCCTGGTATCAGCAGAGACCTGGTCAGGCCCCTCGGCTGCTGATCTACGGCGCCCTCTAACCGGGCCACCGGCATCCCTGCCAGATTCTCCGGCTCCGGCAGCGGCACCGACTTCACCCTGACCATCTCCCGGCTG GAACCCCGAGGACTTCGCCGTGTACTACTGCGGCCAGTCCTACTCATACCCCTTCACCTTCGGCCAGGGCACCAAGCTGGAAATCAAG EQ ID NO: 907 heavy chain DNA
CAAGCTGACCGTGGACAAGTCCAGGTGGCAGCAGGGCAACGTGTTCAGCTGCAGCGTGATGCACGAGGCCCTGCAAACCACTACACCCCAGAAGTCCCTGAGCCTGAGCCCCGGCAAG SEQ ID NO: 908 light chain DNA GAGATCGTGATGACCCAGTCCCCCGCCACCCTGTCTGTGTCTCCCGGCGAGAGCCACCCTGAGCTGCAGAGCCTCCGAGTCCGTGTCCTCCAACGTGGCCTGGTATCAGCAGAGACCTGGTCAGGCCCCTCGGCTGCTGATCTACGGCGCCCTCTAACCGGGCCACCGGCATCCCTGCCAGATTCTCCGGCTCCGGCAGCGGCACCGACTTCACCCTGACCATCTCCCGGCTG GAACCCGAGGACTTCGCCGTGTACTGCGGCAGTCCTACTCATACCCCTTCACCTTCGGCCAGGGCACCAAGCTGGAAATCAAGCGTACGGTGGCCGCTCCCAGCGTGTTCATCTTCCCCCAGCGACGAGCAGCTGAAGCGGCACCGCCAGCGTGTGTGTGCCTGCTGAACAACTTCTACCCCCGGGAGGCCAAGGTGCAGTGGAAGGTGGACAACGCCCCTGCAGAG CGGCAACAGCCAGGAGAGCGTCACCGAGCAGGACAGCAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCGACTACGAGAAGCATAAGGTGTACGCCTGCGAGGTGACCCACCAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAACAGGGGCGAGTGC SEQ ID NO: 909 (KABAT) HCDR1 SYGVD SEQ ID NO: 910 (CHOTHIA) HCDR1 GFSLSSY SEQ ID NO: 911 (KABAT) HCDR2 VIWGGGGTYYASSLMG SEQ ID NO: 912 (CHOTHIA) HCDR2 WGGGG SEQ ID NO: 913 (KABAT) HDDR3 HAYGHDGGFAMDY SEQ ID NO: 913 (CHOTHIA) HDDR3 HAYGHDGGFAMDY SEQ ID NO: 914 (KABAT) LCDR1 RASESVSSNVA SEQ ID NO: 915 (CHOTHIA) LCDR1 SESVSSN SEQ ID NO: 916 (KABAT) LCDR2 GASNRAT SEQ ID NO: 917 (CHOTHIA) LCDR2 GAS SEQ ID NO: 918 (KABAT) LCDR3 GQSYSYPFT SEQ ID NO: 919 (CHOTHIA) LCDR3 SYSYPF

Other exemplary GITR agonists

In one embodiment, the anti-GITR antibody molecule is BMS-986156 (Bristol-Myers Squibb), also known as BMS 986156 or BMS986156. BMS-986156, and other anti-GITR antibodies described in, for example, US Pat. No. 9,228,016 and WO 2016/196792, incorporated by reference in their entirety. In one embodiment, the anti-GITR antibody molecule comprises one or more CDR sequences (or collectively, all CDR sequences), a heavy chain or light chain variable region sequence, or a BMS-986156 heavy chain or light chain sequence, e.g., as described in Table 10.

In one embodiment, the anti-GITR antibody molecule is MK-4166 or MK-1248 (Merck). MK-4166, MK-1248 and other anti-GITR antibodies have been described, for example, in US patent 8709424, WO 2011/028683, WO 2015/026684 and Mahneet al. Cancer Res. 2017; 77(5):1108-1118, incorporated by reference in their entirety. In one embodiment, the anti-GITR antibody molecule comprises one or more CDR sequences (or collectively, all CDR sequences), a heavy chain or light chain variable region sequence, or an MK-4166 or MK-1248 heavy chain or light chain sequence.

In one embodiment, the anti-GITR antibody molecule is TRX518 (Leap Therapeutics). TRX518 and other anti-GITR antibodies are described, for example, in US Pat. No. 7,812,135, US Pat. No. 8,388,967, US Pat. (2010) Clinical Immunology ; 135:S96, incorporated by reference in their entirety. In one embodiment, the anti-GITR antibody molecule comprises one or more CDR sequences (or collectively, all CDR sequences), a heavy chain or light chain variable region sequence, or a TRX518 heavy chain or light chain sequence.

In one embodiment, the anti-GITR antibody molecule is INCAGN1876 (Incyte/Agenus). INCAGN1876 and other anti-GITR antibodies are described, for example, in US 2015/0368349 and WO 2015/184099, incorporated by reference in their entirety. In one embodiment, the anti-GITR antibody molecule comprises one or more CDR sequences (or collectively, all CDR sequences), a heavy chain or light chain variable region sequence, or an INCAGN1876 heavy chain or light chain sequence.

In one embodiment, the anti-GITR antibody molecule is AMG 228 (Amgen). AMG 228 and other anti-GITR antibodies are described in, for example, US Pat. No. 9,464,139 and WO 2015/031667, incorporated by reference in their entirety. In one embodiment, the anti-GITR antibody molecule comprises one or more CDR sequences (or collectively, all CDR sequences), a heavy chain or light chain variable region sequence, or an AMG 228 heavy chain or light chain sequence.

In one embodiment, the anti-GITR antibody molecule is INBRX-110 (Inhibrx). INBRX-110 and other anti-GITR antibodies, such as those described in US 2017/0022284 and WO 2017/015623, are incorporated by reference in their entirety. In one embodiment, the GITR agonist comprises one or more CDR sequences (or collectively, all CDR sequences), a heavy chain or light chain variable region sequence, or an INBRX-110 heavy chain or light chain sequence.

In one embodiment, the GITR agonist ( e.g. fusion protein ) is MEDI 1873 (MedImmune), also known as MEDI1873. MEDI 1873 and other GITR agonists are described, for example, in US 2017/0073386, WO 2017/025610 and Ross et al. Cancer Res 2016; 76(14 Suppl): Abstract nr 561, incorporated by reference in its entirety. In one embodiment, the GITR agonist comprises one or more IgG Fc domains, a functional multimerization domain, and a glucocorticoid-induced TNF receptor ligand ligand (GITRL) MEDI 1873 receptor binding domain.

Other known GITR agonists (eg, anti-GITR antibodies) include those described, for example, in WO 2016/054638, incorporated by reference in its entirety.

In one embodiment, an anti-GITR antibody is one that competes for binding and/or binds to the same epitope on GITR as one of the anti-GITR antibodies described herein.

In one embodiment, the GITR agonist is a peptide that activates the GITR signaling pathway. In one embodiment, the GITR agonist is an immunoadhesin binding fragment (eg, an immunoadhesin binding fragment containing an extracellular or GITR binding portion of GITRL) fused to a constant region (eg, an Fc region of an immunoglobulin sequence).

Table 10 : Amino acid sequence of other exemplary anti-GITR antibody molecules

BMS-986156 SEQ ID NO: 920 vh QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVIWYEGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGGSMVRGDYYYGMDVWGQGTTVTVSS SEQ ID NO: 921 VL AIQLTQSPSSLSASVGDRVTITCRASQGISSALAWYQQKPGKAPKLLIYDASSLESGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQFNSYPYTFGQGTKLEIK

IL15/IL-15Ra complexes

In certain embodiments, the anti-LAG-3 antibody molecule described herein is administered in combination with an IL-15/IL-15Ra complex. In some embodiments, the IL-15/IL-15Ra complex is selected from NIZ985 (Novartis), ATL-803 (Altor), or CYP0150 (Cytune).

Exemplary IL-15/IL-15Ra complexes

In one embodiment, the IL-15/IL-15Ra complex comprises human IL-15 complexed with a soluble form of human IL-15Ra. The complex may contain IL-15 covalently or non-covalently linked to a soluble form of IL-15Ra. In a specific embodiment, human IL-15 is non-covalently linked to a soluble form of IL-15Ra. In a specific embodiment, the human IL-15 composition contains the amino acid sequence of SEQ ID NO: 1001 in Table 11 and the soluble form of human IL-15Ra contains the amino acid sequence of SEQ ID NO: 1002 in Table 11 as described in WO 2014/066527 included in as reference in its entirety. The molecules described herein can be generated using the vectors, host cells, and methods described in WO 2007/084342, incorporated by reference in its entirety.

Table 11 . Amino acid and nucleotide sequences of exemplary IL-15/IL-15Ra complexes

NIZ985 SEQ ID NO: 1001 human IL-15 NWVNVISDLKKIEDLIQSMHIDATLYTESDVHPSCKVTAMKCFLLELQVISLESGDASIHDTVENLIILANNSLSSNGNVTESGCKECEELEEKNIKEFLQSFVHIVQMFINTS SEQ ID NO: 1002 Soluble human IL-15Ra ITCPPPMSVEHADIWVKSYSLYSRERYICNSGFKRKAGTSSLTECVLNKATNVAHWTTPSLKCIRDPALVHQRPAPPSTVTTAGVTPQPESLSPSGKEPAASSPSSNNTAATTAAIVPGSQLMPSKSPSTGTTEISSHESSHGTPSQTTAKNWELTASASHQPPGVYPQG

Other exemplary IL-15/IL-15Ra complexes

In one embodiment, the IL-15/IL-15Ra complex is ALT-803, an IL-15/IL-15Ra Fc fusion protein (soluble IL-15N72D:IL-15RaSu/Fc complex). ALT-803 is described in WO 2008/143794, incorporated by reference in its entirety. In one embodiment, the IL-15/IL-15Ra Fc fusion protein contains the sequences as described in Table 12.

In one embodiment, the IL-15/IL-15Ra complex contains IL-15 fused to the land domain of IL-15Ra (CYP0150, Cytune). The sushi domain of IL-15Ra refers to the domain starting at the first cysteine residue after the IL-15Ra signal peptide and ending at the fourth cysteine residue after said signal peptide. The complex of IL-15 fused to the land domain of IL-15Ra is described in WO 2007/04606 and WO 2012/175222, incorporated by reference in its entirety. In one embodiment, the IL-15/IL-15Ra land fusion protein contains sequences as described in Table 12.

Table 12 . Amino acid sequences of other exemplary IL-15/IL-15Ra complexes

ALT-803 (Altor) SEQ ID NO: 1003 IL-15N72D NWVNVISDLKKIEDLIQSMHIDATLYTESDVHPSCKVTAMKCFLLELQVISLESGDASIHDTVENLIILANDSLSSNGNVTESGCKECEELEEKNIKEFLQSFVHIVQMFINTS SEQ ID NO: 1004 IL-15RaSu/Fc ITCPPPMSVEHADIWVKSYSLYSRERYICNSGFKRKAGTSSLTECVLNKATNVAHWTTPSLKCIREPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQ VYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK Fusion of the IL-15 sushi domain of IL-15Ra (Cytune) SEQ ID NO:1005 IL-15 Human NWVNVISDLKKIEDLIQSMHIDATLYTESDVHPSCKVTAMKCFLLELQVISLESGDASIHDTVENLIILANNSLSSNGNVTESGCKECEELEXKNIKEFLQSFVHIVQMFINTS
Where X is E or K SEQ ID NO:1006 land domain and human IL-15Ra hinge domain ITCPPPMSVEHADIWVKSYSLYSRERYICNSGFKRKAGTSSLTECVLNKATNVAHWTTPSLKCIRDPALVHQRPAPP

Pharmaceutical compositions, formulations and kits

In another aspect, the present invention provides compositions, eg, pharmaceutically acceptable compositions, which comprise the anti-LAG-3 antibody molecule described herein, formulated with a pharmaceutically acceptable carrier. As used herein, a "pharmaceutically acceptable carrier" includes any and all diluents, dispersion media, isotonic and retarding agents, and the like, which are physiologically compatible. The carrier may be suitable for intravenous, intramuscular, subcutaneous, parenteral, rectal, spinal, or epidermal administration (e.g., by injection or infusion).

The compositions described herein may be in a variety of forms. They include, for example, liquid, semi-solid and solid dosage forms such as liquid solutions (eg solutions for injections and infusions), dispersions or suspensions, liposomes and suppositories. The preferred form depends on the intended mode of administration and therapeutic application. Typical preferred compositions are in the form of injection or infusion solutions. The preferred mode of administration is parenteral (eg, intravenous, subcutaneous, intraperitoneal, intramuscular). In a preferred embodiment, the antibody is administered by intravenous infusion or injection. In another preferred embodiment, the antibody is administered by intramuscular or subcutaneous injection.

The phrases “parenteral administration” and “parenteral administration”, as used herein, mean modes of administration other than enteral and topical administration, usually by injection, and include, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital , intracardial, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrasternal injection and infusion.

In general, therapeutic compositions must be sterile and stable under the conditions of preparation and storage. The composition may be formulated as a solution, microemulsion, dispersion, liposome, or other ordered structure appropriate for a high concentration of the antibody. Sterile injectable solutions can be prepared by administering the active compound (e.g., an antibody or antibody portion) in the required amount in an appropriate solvent with one or a combination of the ingredients listed above, as required, followed by filtered sterilization. Typically, dispersions are prepared by incorporating the active compound into a sterile drug medium which contains the basic dispersion medium and the necessary other ingredients from those listed above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze drying, which yield a powder of the active ingredient plus any additional desired ingredient from a pre-sterile filtered solution thereof. Appropriate fluidity of the solution can be maintained, for example, by using a coating such as lecithin, by maintaining the required particle size in the case of a dispersion and when using surfactants. Prolonged absorption of injectable compositions can be obtained by introducing into the composition an agent that delays absorption, for example, monostearate salts and gelatin.

An anti-LAG-3 antibody molecule or composition described herein may be formulated into a formulation (eg, dosage form or dosage form) suitable for administration (eg, intravenous administration) to a subject as described herein. The formulation described herein may be a liquid formulation, a lyophilized formulation, or a diluted formulation.

In certain embodiments, the formulation is a liquid formulation. In some embodiments, the formulation (eg, liquid formulation) comprises an anti-LAG-3 antibody molecule (eg, an anti-LAG-3 antibody molecule described herein) and a buffering agent.

In some embodiments, the formulation (e.g., liquid formulation) contains an anti-LAG-3 antibody molecule present at a concentration of 25 mg/mL to 250 mg/mL, such as 50 mg/mL to 200 mg/mL, 60 mg/mL to 180 mg/mL, 70 mg/mL to 150 mg/mL, 80 mg/mL to 120 mg/mL, 90 mg/mL to 110 mg/mL, 50 mg/mL to 150 mg /ml, 50 mg/ml to 100 mg/ml, 150 mg/ml to 200 mg/ml or 100 mg/ml to 200 mg/ml, e.g. at 50 mg/ml, 60 mg/ml, 70 mg/ml, 80 mg/ml, 90 mg/ml, 100 mg/ml, 110 mg/ml, 120 mg/ml, 130 mg/ml, 140 mg/ml or 150 mg/ml. In certain embodiments, the anti-LAG-3 antibody molecule is present at a concentration of 80 mg/mL to 120 mg/mL, such as at 100 mg/mL.

In some embodiments, the formulation (eg, liquid formulation) contains a buffering agent containing histidine (eg, a histidine buffer). In certain embodiments, the buffering agent (e.g., histidine buffer) is present at a concentration of 1 mM to 100 mM, e.g., 2 mM to 50 mM, 5 mM to 40 mM, 10 mM to 30 mM, 15 to 25 mM, 5 mM to 40 mM, 5 mM to 30 mM, 5 mM to 20 mM, 5 mM to 10 mM, 40 mM to 50 mM, 30 mM to 50 mM, 20 mM to 50 mM , 10 mM to 50 mM or 5 mM to 50 mM, e.g. at 2 mM, 5 mM, 10 mM, 15 mM, 20 mM, 25 mM, 30 mM, 35 mM, 40 mM, 45 mM or 50 mM . In some embodiments, the buffering agent (eg, histidine buffer) is present at a concentration of 15 mM to 25 mM, such as 20 mM. In other embodiments, the buffering agent (e.g., histidine buffer) has a pH of 4 to 7, e.g., 5 to 6, e.g., 5, 5.5, or 6. In some embodiments, the buffering agent (e.g., histidine buffer ) has a pH of 5 to 6, for example 5.5. In certain embodiments, the buffering agent contains a histidine buffer at a concentration of 15 mM to 25 mM (eg, at 20 mM) and has a pH of 5 to 6 (eg, at 5.5). In certain embodiments, the buffering agent comprises histidine and histidine-HCl.

In some embodiments, the formulation (eg, liquid formulation) comprises an anti-LAG-3 antibody molecule present at a concentration of 80 to 120 mg/mL, eg, 100 mg/mL; and a buffering agent that contains a histidine buffer at a concentration of 15 mM to 25 mM (eg, at 20 mM) and has a pH of 5 to 6 (eg, 5.5).

In some embodiments, the formulation (eg, liquid formulation) further comprises a carbohydrate. In certain embodiments, the carbohydrate is sucrose. In some embodiments, a carbohydrate (e.g., sucrose) present at a concentration of 50 mM to 500 mM, e.g., 100 mM to 400 mM, 150 mM to 300 mM, 180 mM to 250 mM, 200 mM to 240 mm, from 210 mm to 230 mm, from 100 mm to 300 mm, from 100 mm to 250 mm, from 100 mm to 200 mm, from 100 mm to 150 mm, from 300 mm to 400 mm, from 200 mm to 400 mm or from 100 mM to 400 mM, for example at 100 mM, 150 mM, 180 mM, 200 mM, 220 mM, 250 mM, 300 mM, 350 mM or 400 mM. In some embodiments, the formulation contains a carbohydrate or sucrose present at a concentration of 200 mM to 250 mM, such as 220 mM.

In some embodiments, the formulation (eg, liquid formulation) comprises an anti-LAG-3 antibody molecule present at a concentration of 80 to 120 mg/mL, eg, 100 mg/mL; a buffering agent which contains a histidine buffer at a concentration of 15 mM to 25 mM (eg at 20 mM) and has a pH of 5 to 6 (eg 5.5); and the carbohydrate or sucrose is present at a concentration of 200 mM to 250 mM, for example at 220 mM.

In some embodiments, the formulation (eg, liquid formulation) further comprises a surfactant. In certain embodiments, the surfactant is polysorbate 20, In some embodiments, the surfactant or polysorbate 20) is present at a concentration of 0.005% to 0.1% (w/w), such as 0.01 % to 0.08%, from 0.02% to 0.06%, from 0.03% to 0.05%, from 0.01% to 0.06%, from 0.01% to 0.05% , 0.01% to 0.03%, 0.06% to 0.08%, 0.04% to 0.08% or 0.02% to 0.08% (w/w), e.g. at 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09% or 0, 1% (w/w). In some embodiments, the formulation contains a surfactant or polysorbate 20 present at a concentration of 0.03% to 0.05%, such as 0.04% (w/w).

In some embodiments, the formulation (eg, liquid formulation) comprises an anti-LAG-3 antibody molecule present at a concentration of 80 to 120 mg/mL, eg, 100 mg/mL; a buffering agent which contains a histidine buffer at a concentration of 15 mM to 25 mM (eg at 20 mM) and has a pH of 5 to 6 (eg 5.5); a carbohydrate or sucrose present at a concentration of 200 mM to 250 mM, for example at 220 mM; and a surfactant or polysorbate 20 present at a concentration of 0.03% to 0.05%, such as 0.04% (w/w).

In some embodiments, the formulation (eg, liquid formulation) comprises an anti-LAG-3 antibody molecule present at a concentration of 100 mg/mL; a buffering agent which contains a histidine buffer (eg histidine/histidine-HCl) at a concentration of 20 mM) and has a pH of 5.5; carbohydrate or sucrose present at a concentration of 220 mM; and a surfactant or polysorbate 20 present at a concentration of 0.04% (w/w).

In some embodiments, a liquid formulation is prepared by diluting a formulation containing an anti-LAG-3 antibody molecule described herein. For example, the drug preparation may be diluted with a solution containing one or more excipients (eg, concentrated excipients). In some embodiments, the solution contains one, two, or all of histidine, sucrose, or polysorbate 20. In certain embodiments, the solution contains the same excipient(s) as the drug formulation. Exemplary excipients include, but are not limited to, an amino acid (eg, histidine), a carbohydrate (eg, sucrose), or a surfactant (eg, polysorbate 20). In certain embodiments, the liquid preparation is an undiluted lyophilized preparation. In other embodiments, the liquid preparation is a diluted lyophilized preparation. In some embodiments, the drug is stored as a liquid. In other embodiments, the formulation is formulated as a liquid and then dried, such as by lyophilization or spray drying, prior to storage.

In certain embodiments, 0.5 ml to 10 ml (e.g., 0.5 ml to 8 ml, 1 ml to 6 ml, or 2 ml to 5 ml, e.g., 1 ml, 1.2 ml, 1.5 ml, 2 ml, 3 ml, 4 ml, 4.5 ml or 5 ml) liquid preparation is filled into each container (eg vial). In other embodiments, the liquid preparation is filled into a container (e.g., vial) such that the volume to be extracted is at least 1 ml (e.g., at least 1.2 ml, at least 1.5 ml, at least at least 2 ml, at least 3 ml, at least 4 ml, or at least 5 ml) of liquid preparation can be withdrawn from each container (eg vial). In certain embodiments, the liquid formulation is withdrawn from the container (eg, vial) without dilution at the site of the clinical study. In certain embodiments, the liquid formulation is diluted from the drug formulation and removed from the container (eg, vial) at the site of the clinical study. In certain embodiments, the drug (eg, liquid formulation) is administered by injection into an infusion bag, eg, within 1 hour (eg, within 45 minutes, 30 minutes, or 15 minutes) prior to infusion into the patient.

The formulation described herein may be stored in a container. The container used for any of the formulations described herein may include, for example, a vial and optionally a stopper, cap, or both. In certain embodiments, the vial is a glass vial, such as a 6R white glass vial. In other embodiments, the stopper is a rubber stopper, such as a gray rubber stopper. In other embodiments, the cap is a flip cap, such as an aluminum flip cap. In some embodiments, the container comprises a 6R white glass vial, a gray rubber stopper, and an aluminum flip cap. In some embodiments, the container (eg, vial) is a disposable container. In certain embodiments, 25 mg/mL to 250 mg/mL is present in the container (e.g., vial), e.g., 50 mg/mL to 200 mg/mL, 60 mg/mL to 180 mg/mL, 70 mg /ml to 150 mg/ml, from 80 mg/ml to 120 mg/ml, from 90 mg/ml to 110 mg/ml, from 50 mg/ml to 150 mg/ml, from 50 mg/ml to 100 mg/ ml, 150 mg/ml to 200 mg/ml or 100 mg/ml to 200 mg/ml, e.g. 50 mg/ml, 60 mg/ml, 70 mg/ml, 80 mg/ml, 90 mg/ml , 100 mg/ml, 110 mg/ml, 120 mg/ml, 130 mg/ml, 140 mg/ml, or 150 mg/ml anti-LAG-3 antibody molecules.

In some embodiments, the drug is a lyophilized drug. In certain embodiments, the lyophilized preparation is lyophilized or dried from a liquid preparation containing the anti-LAG-3 antibody molecule described herein. For example, 1 to 5 ml, eg 1 to 2 ml, of a liquid formulation may be filled into a container (eg, vial) and lyophilized.

In some embodiments, the drug is a diluted drug. In certain embodiments, the diluted preparation is diluted from a lyophilized preparation containing the anti-LAG-3 antibody molecule described herein. For example, a diluted preparation may be prepared by dissolving the lyophilized preparation in a diluent such that the protein is dispersed in the diluted preparation. In some embodiments, the lyophilized preparation is diluted with 1 ml 5 ml, eg 1 ml 2 ml, eg 1.2 ml, water or injection buffer. In certain embodiments, the lyophilized preparation is diluted with 1 ml to 2 ml water for injection, for example, at the site of a clinical trial.

In some embodiments, the diluted preparation contains an anti-LAG-3 antibody molecule (eg, an anti-LAG-3 antibody molecule described herein) and a buffering agent.

In some embodiments, the diluted formulation contains an anti-LAG-3 antibody molecule present at a concentration of 25 mg/mL to 250 mg/mL, e.g., 50 mg/mL to 200 mg/mL, 60 mg/mL to 180 mg/ml, 70 mg/ml to 150 mg/ml, 80 mg/ml to 120 mg/ml, 90 mg/ml to 110 mg/ml, 50 mg/ml to 150 mg/ml, 50 mg/ml to 100 mg/ml, 150 mg/ml to 200 mg/ml, or 100 mg/ml to 200 mg/ml, e.g. 50 mg/ml, 60 mg/ml, 70 mg/ml, 80 mg /ml, 90 mg/ml, 100 mg/ml, 110 mg/ml, 120 mg/ml, 130 mg/ml, 140 mg/ml or 150 mg/ml. In certain embodiments, the anti-LAG-3 antibody molecule is present at a concentration of 80 mg/mL to 120 mg/mL, such as at 100 mg/mL.

In some embodiments, the diluted preparation contains a buffering agent containing histidine (eg, a histidine buffer). In certain embodiments, the buffering agent (e.g., histidine buffer) is present at a concentration of 1 mM to 100 mM, e.g., 2 mM to 50 mM, 5 mM to 40 mM, 10 mM to 30 mM, 15 to 25 mM, 5 mM to 40 mM, 5 mM to 30 mM, 5 mM to 20 mM, 5 mM to 10 mM, 40 mM to 50 mM, 30 mM to 50 mM, 20 mM to 50 mM , 10 mM to 50 mM or 5 mM to 50 mM, e.g. at 2 mM, 5 mM, 10 mM, 15 mM, 20 mM, 25 mM, 30 mM, 35 mM, 40 mM, 45 mM or 50 mM . In some embodiments, the buffering agent (eg, histidine buffer) is present at a concentration of 15 mM to 25 mM, such as 20 mM. In other embodiments, the buffering agent (e.g., a histidine buffer) has a pH of 4 to 7, such as 5 to 6, such as 5, 5.5, or 6. In some embodiments, the buffering agent (e.g., a histidine buffer) has a pH of 5 to 6, for example 5.5. In certain embodiments, the buffering agent contains a histidine buffer at a concentration of 15 mM to 25 mM (eg, at 20 mM) and has a pH of 5 to 6 (eg, 5.5). In certain embodiments, the buffering agent comprises histidine and histidine-HCl.

In some embodiments, the diluted formulation contains an anti-LAG-3 antibody molecule present at a concentration of 80 to 120 mg/mL, such as 100 mg/mL; and a buffering agent that contains a histidine buffer at a concentration of 15 mM to 25 mM (eg, at 20 mM) and has a pH of 5 to 6 (eg, 5.5).

In some embodiments, the diluted formulation further comprises a carbohydrate. In certain embodiments, the carbohydrate is sucrose. In some embodiments, the carbohydrate (e.g., sucrose) is present at a concentration of 50 mM to 500 mM, e.g., 100 mM to 400 mM, 150 mM to 300 mM, 180 mM to 250 mM, 200 mM to 240 mM 210 mM to 230 mM, 100 mM to 300 mM, 100 mM to 250 mM, 100 mM to 200 mM, 100 mM to 150 mM, 300 mM to 400 mM, 200 mM to 400 mM, or from 100 mM to 400 mM, for example at 100 mM, 150 mM, 180 mM, 200 mM, 220 mM, 250 mM, 300 mM, 350 mM or 400 mM. In some embodiments, the formulation contains a carbohydrate or sucrose present at a concentration of 200 mM to 250 mM, such as 220 mM.

In some embodiments, the diluted formulation contains an anti-LAG-3 antibody molecule present at a concentration of 80 to 120 mg/mL, such as 100 mg/mL; a buffering agent that contains a histidine buffer at a concentration of 15 mM to 25 mM (eg at 20 mM) and has a pH of 5 to 6 (eg 5.5); and carbohydrate or sucrose present at a concentration of 200 mM to 250 mM, for example at 220 mM.

In some embodiments, the diluted formulation further comprises a surfactant. In certain embodiments, the surfactant is polysorbate 20. In some embodiments, the surfactant or polysorbate 20 is present at a concentration of 0.005% to 0.1% (w/w), such as 0.01% up to 0.08%, from 0.02% to 0.06%, from 0.03% to 0.05%, from 0.01% to 0.06%, from 0.01% to 0.05%, 0.01% to 0.03%, 0.06% to 0.08%, 0.04% to 0.08%, or 0.02% to 0.08% (w/w), e.g. , at 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09% or 0.1 % (w/w). In some embodiments, the formulation contains a surfactant or polysorbate 20 present at a concentration of 0.03% to 0.05%, such as 0.04% (w/w).

In some embodiments, the diluted formulation contains an anti-LAG-3 antibody molecule present at a concentration of 80 to 120 mg/mL, such as 100 mg/mL; a buffering agent that contains a histidine buffer at a concentration of 15 mM to 25 mM (eg at 20 mM) and has a pH of 5 to 6 (eg 5.5); a carbohydrate or sucrose present at a concentration of 200 mM to 250 mM, for example at 220 mM; and a surfactant or polysorbate 20 present at a concentration of 0.03% to 0.05%, such as 0.04% (w/w).

In some embodiments, the diluted preparation contains an anti-LAG-3 antibody molecule present at a concentration of 100 mg/ml; a buffering agent that contains a histidine buffer (eg, histidine/histidine-HCl) at a concentration of 20 mM and has a pH of 5.5; carbohydrate or sucrose present at a concentration of 220 mM; and a surfactant or polysorbate 20 present at a concentration of 0.04% (w/w).

In some embodiments, the drug is diluted such that the recoverable volume is at least 1 ml (e.g., at least 1.2 ml, 1.5 ml, 2 ml, 2.5 ml, or 3 ml) of the diluted preparation can be removed from a container (eg vial) containing a diluted drug. In certain embodiments, the drug is diluted and/or removed from the container (eg, vial) at the site of the clinical study. In certain embodiments, the drug (eg, the diluted formulation) is administered into an infusion bag, eg, within 1 hour (eg, within 45 minutes, 30 minutes, or 15 minutes) prior to infusion to the patient.

Other exemplary buffering agents that can be used in the formulation described herein include, but are not limited to, arginine buffer, citrate buffer, or phosphate buffer. Other exemplary carbohydrates that can be used in the formulation described herein include, but are not limited to, trehalose, mannitol, sorbitol, or a combination thereof. The formulation described herein may also contain a tonicity regulator, eg sodium chloride, and/or a stabilizing agent, eg an amino acid (eg, glycine, arginine, methionine, or a combination thereof).

Antibody molecules can be administered using a variety of methods known in the art, although for many therapeutic applications, the preferred route/mode of administration is intravenous injection or infusion. For example, antibody molecules can be administered by intravenous infusion at a rate greater than 20 mg/min, such as 20-40 mg/min, and typically at a rate equal to or greater than 40 mg/min to achieve a dose of about 35 up to 440 mg/m², typically about 70 to 310 mg/m², and more often, from about 110 to 130 mg / m². In embodiments, antibody molecules can be administered via intravenous infusion at a rate of less than 10 mg/min; preferably equal to or less than 5 mg/min to achieve a dose of about 1 to 100 mg/m², preferably from about 5 to 50 mg/m², about 7 to 25 mg/m², and more preferably about 10 mg/m². As will be apparent to those skilled in the art, the route and/or mode of administration will vary depending on the desired results. In certain embodiments, the active compound may be formulated with a carrier that will protect the compound from rapid release, such as a controlled release formulation, including implants, transdermal patches, and microencapsulated delivery systems. Biodegradable, biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid can be used. Many methods for preparing such formulations are patented or generally known to those skilled in the art.Look, For example,Sustained and Controlled Release Drug Delivery Systems, J. R. Robinson, ed., Marcel Dekker, Inc., New York, 1978.

In certain embodiments, the antibody molecule may be administered orally, for example, via an inert diluent or an assimilative edible carrier. The compound (and other ingredients, if desired) may also be enclosed in a hard or soft shell gelatin capsule, compressed into tablets, or administered directly to the subject's diet. For oral therapeutic administration, the compounds may be provided with excipients and used in the form of ingestible tablets, buccal tablets, dragees, capsules, elixirs, suspensions, syrups, wafers, and the like. For administration of a compound of the present invention by administration other than parenteral administration, it may be necessary to coat the compound or co-administer the compound with some material to prevent its deactivation. Therapeutic compositions may also be administered using medical devices known in the art.

Dosing regimens are adjusted to provide the optimum desired response (eg, therapeutic response). For example, a single bolus may be administered, multiple divided doses may be administered over time, or the dose may be proportionally decreased or increased as dictated by the needs of the therapeutic situation. It is particularly advantageous to formulate parenteral compositions in unit dosage form for ease of administration and dosage uniformity. Dosage unit form, as used herein, refers to physically discrete units suitable for use as unitary dosages for subjects to be treated; each unit contains a predetermined amount of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification of unit dosage forms of the present invention is dictated by and directly dependent on (a) the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the field of compounding such an active compound for the treatment of sensitivity in individuals.

An exemplary, non-limiting range for a therapeutically or prophylactically effective amount of an antibody molecule is 50 mg to 1500 mg, typically 80 mg to 1200 mg. In certain embodiments, the anti-LAG-3 antibody molecule is administered by injection (e.g., subcutaneously or intravenously) at a dose (e.g., base dose) of about 60 mg to about 100 mg (e.g., about 80 mg), from about 200 mg up to about 300 mg (eg, about 240 mg) or from about 1000 mg to about 1500 mg (eg, about 1200 mg). The dosing regimen (eg, baseline dosing regimen) may vary, for example, from once a week to once every 2, 3, 4, 5 or 6 weeks. In one embodiment, the anti-LAG-3 antibody molecule is administered at a dose of about 60 mg to about 100 mg (eg, about 80 mg) once every two weeks or once every four weeks. In one embodiment, the anti-LAG-3 antibody molecule is administered at a dose of about 200 mg to about 300 mg (eg, about 240 mg) once every two weeks or once every four weeks. In one embodiment, the anti-LAG-3 antibody molecule is administered at a dose of about 1000 mg to about 1500 mg (eg, about 1200 mg) once every two weeks or once every four weeks. In one embodiment, the anti-LAG-3 antibody molecule is administered at a dose of about 80 mg once every four weeks. In one embodiment, the anti-LAG-3 antibody molecule is administered at a dose of about 240 mg once every four weeks. In one embodiment, the anti-LAG-3 antibody molecule is administered at a dose of about 1200 mg once every four weeks. While not wishing to be bound by theory, in some embodiments, a baseline or fixed dosage may be beneficial to patients, for example, to save on drug delivery and to reduce pharmaceutical errors.

The antibody molecule can be administered by intravenous infusion at a rate greater than 20 mg/min, such as 20-40 mg/min, and typically at a rate equal to or greater than 40 mg/min to achieve a dose of about 35 to 440 mg/m², typically about 70 to 310 mg/m², and more often, from about 110 to 130 mg / m². In embodiments, at an infusion rate of about 110 to 130 mg/m²achieved level of about 3 mg/kg. In other embodiments, the antibody molecule may be administered by intravenous infusion at a rate of less than 10 mg/min, such as equal to or less than 5 mg/min to achieve a dose of about 1 to 100 mg/m², for example, from about 5 to 50 mg/m², about 7 to 25 mg/m² or, about 10 mg/m². In some embodiments, the antibody is infused over a period of about 30 minutes. It should be noted that dosage amounts may vary with the type and severity of the condition to be alleviated. In addition, it should be understood that for any particular subject, particular dosage regimens must be adjusted over time according to the needs of the individual and the professional judgment of the person administering the compositions or overseeing the administration of the compositions, and that the dosage ranges given herein are illustrative only and not are intended to limit the scope or implementation of the claimed composition.

Pharmaceutical compositions of the present invention may contain a "therapeutically effective amount" or "prophylactically effective amount" of an antibody or antibody portion of the present invention. "Therapeutically effective amount" refers to the amount effective at the required doses and for the necessary periods of time to achieve the desired therapeutic result. The therapeutically effective amount of the modified antibody or antibody fragment may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the antibody or antibody portion to elicit the desired response in the individual. A therapeutically effective amount is also one in which any toxic or deleterious effects of the modified antibody or antibody fragment are outweighed by the therapeutically beneficial effects. A "therapeutically effective dosage" preferably retards a measurable parameter, e.g., tumor growth rate, by at least about 20%, more preferably at least about 40%, even more preferably at least about 60%, and even more preferably, at least about 80% compared to untreated subjects. The ability of a compound to slow down a measurable parameter, such as cancer, can be assessed in an animal model system predictive of efficacy in human tumors. Alternatively, this property of the composition can be assessed by testing the ability of the compound to inhibit, such inhibition is assessed in vitro using assays known to those skilled in the art.

"Prophylactically effective amount" refers to the amount effective at the required dosages and for the necessary periods of time to achieve the desired prophylactic result. Generally, since a prophylactic dose is used in subjects prior to or at an early stage of disease, the prophylactically effective amount will be less than the therapeutically effective amount.

Also within the scope of the present invention is a kit containing an anti-LAG-3 antibody molecule, composition or formulation as described herein. The kit may contain one or more other elements, including: instructions for use (eg, according to the dosing regimen described herein); other reagents, for example, a label, a therapeutic agent, or an agent useful in chelating or otherwise linking an antibody to a label or therapeutic agent, or a radioprotective composition; devices or other materials for preparing antibodies for administration; pharmaceutically acceptable carriers and devices or other materials for administration to a subject.

Application of Anti-LAG-3 Antibody Molecules

The anti-LAG-3 antibody molecules described herein can be used to modify the immune response in a subject. In some embodiments, the immune response is enhanced, stimulated, or up-regulated. In certain embodiments, the immune response is inhibited, reduced, or down-regulated. For example, these antibody molecules can be administered to cells in culture, such as in vitro or ex vivo , or in a subject, such as in vivo , to treat, prevent, and/or diagnose various disorders such as cancers, immune disorders, and infectious diseases. .

As used herein, the term “subject” is intended to include non-human humans and animals. In some embodiments, the subject is a human subject, eg, a human patient, having a disorder or condition characterized by abnormal LAG-3 functioning. Typically, the subject has at least some LAG-3 protein, including a LAG-3 epitope, that binds to the antibody molecule, eg, a sufficiently high level of protein and epitope to support binding of the antibody and LAG-3. The term “non-human animal” includes mammals and non-mammals such as non-human primates. In some embodiments, the subject is a human. In some embodiments, the subject is a human patient in need of an enhanced immune response. The methods and compositions described herein are useful in the treatment of human patients having a disorder that can be treated by modulating (eg, enhancing or slowing down) the immune response. In certain embodiments, the patient has or is at risk for a disorder described herein, such as breast cancer, such as triple negative breast cancer (TNBC). In certain embodiments, the TNBC patient is more immunogenic than other breast cancer subtypes, has higher PD-L1 expression, and/or has increased tumor infiltrating lymphocyte (TIL) infiltration (Loi et al. (2014) Ann Oncol; 25: 1544-50; Mittendorf et al. (2014) Cancer Immunol Res; 2:361-70). In one embodiment, the patient does not demonstrate liver metastasis.

Combination immunotherapy approaches suggest that synergistic blockade of co-inhibitory receptors exhibits superior antitumor activity than a single agent (Wolchok et al. (2013) New Engl J Med; 369: 122-33). LAG-3 is a co-inhibitory receptor that can interact with PD-1 to inhibit immune responses (Anderson et al. (2016) Immunity; 44: 989-1004). Combined inhibition of the PD-1 and LAG-3 checkpoints synergistically enhances antitumor responses compared to inhibition of either checkpoint on its own (Woo et al. (2012) Cancer Res; 72: 917-27).

Also, there is increasing evidence that cytotoxic agents affect the host tumor environment, making it more favorable for the immune response, and as a result, the combination of immunotherapy with cytotoxic agents may have a synergistic effect to increase therapeutic efficacy (Zitvogel et al. (Zitvogel et al. ( 2013) Immunity; 39: 74-88). Importantly, chemotherapy can induce immunogenic cell death, which facilitates efficient antigen presentation and has been shown to trigger potent T-lymphocyte responses in preclinical models (Kroemer et al. (2013) Immunol; 31:51-72; Pfirschke et al. (2016) Immunity 44:343-54 Lu et al (2017) Biomedical Res 28:828-34). Without wishing to be bound by theory, it is contemplated that in some embodiments, chemotherapy (eg, a platinum agent) will create an early microenvironment during T-lymphocyte activation (eg, increased antigen concentration and/or antigen availability) that will favor the onset of LAG-3+CD8+ T-lymphocytes that require only LAG3 inhibition to differentiate into tumor antigen-specific effector cells. Although the main mechanism of action of platinum agents is thought to be the induction of apoptosis of cancer cells in response to their covalent binding to DNA, recent studies show that cellular molecules other than DNA can potentially act as targets and that part of the antitumor effects of platinum drugs is mediated through immune system modulation (Hato et al. (2014) Clin Cancer Res; 20: 2831-7). These immunogenic effects include modulation of STAT signaling (Lesterhuis et al. (2011) J Clin Invest; 121:3100-08); induction of an immunogenic type of cancer cell death by exposure to calreticulin and release of ATP and high mobility group protein box-1 (HMGB-1) (Kroemer et al. (2013) Immunol; 31:51-72; Tesniere et al. (2010) Oncogenel ; 29: 482-91); and enhancing the effector immune response through modulation of programmed death receptor 1 ligand and expression of the mannose-6-phosphate receptor (Liu et al . (2010) Br J Cancer; 102:115-23). Without wishing to be bound by theory, it is contemplated that in some embodiments, combining platinum with immune checkpoint blockade will enhance immunotherapy, whereby platinum may provide immunogenic cell death, sensitization of tumor cells to CTL lysis, and down-regulation of PD-L.

In some embodiments, the subject is not treated with a therapeutic agent, procedure, or treatment prior to receiving an anti-LAG-3 antibody molecule. In other embodiments, the subject is treated with a therapeutic agent, procedure, or treatment prior to receiving an anti-LAG-3 antibody molecule.

In certain embodiments, the subject is not treated with anti-LAG-3 therapy prior to receiving the anti-LAG-3 antibody molecule. In other embodiments, the subject is treated with anti-LAG-3 therapy prior to receiving an anti-LAG-3 antibody molecule.

In certain embodiments, the subject is not treated with PD-1/PD-L1 therapy prior to receiving the anti-LAG-3 antibody molecule. In other embodiments, the subject is treated with PD-1/PD-L1 therapy prior to receiving an anti-LAG-3 antibody molecule.

In certain embodiments, the subject is not treated with a chemotherapeutic agent (e.g., a platinum agent (e.g., carboplatin, cisplatin, oxaliplatin, or tetraplatin) or a nucleotide analog or precursor analog (e.g., capecitabine)) prior to receiving an anti-LAG-3 antibody molecule. In other embodiments, the subject is treated with a chemotherapeutic agent (e.g., a platinum agent (e.g., carboplatin, cisplatin, oxaliplatin, or tetraplatin) or a nucleotide analog or precursor analog (e.g., capecitabine)) prior to receiving an anti-LAG-3 antibody molecule.

In certain embodiments, the subject is identified as having LAG-3 expression in tumor-infiltrating lymphocytes. In other embodiments, the subject has no detectable level of LAG-3 expression in tumor-infiltrating lymphocytes.

Ways to treat cancer

In one aspect, the present invention relates to the treatment of a subject in vivo using an anti-LAG-3 antibody molecule (e.g., an anti-LAG-3 antibody molecule described herein), or a composition or formulation comprising an anti-LAG antibody molecule. -3 (for example, the composition or preparation described herein), so that the growth of malignant tumors is slowed down or reduced.

In certain embodiments, the anti-LAG-3 antibody molecule is administered in an amount effective to treat the cancer or its metastatic lesion. In some embodiments, the anti-LAG-3 antibody molecule is administered at a dose of about 100 mg to about 2000 mg once every two weeks, once every three weeks, or once every four weeks. For example, an anti-LAG-3 antibody molecule may be administered at a dose of about 200 mg to about 1000 mg, about 300 mg to about 900 mg, about 200 mg to about 600 mg, about 300 mg to about 500 mg, about 600 to about 1000 mg, about 700 mg to about 900 mg, or about 400 mg to about 800 mg once every three weeks or once every four weeks. In one embodiment, the anti-LAG-3 antibody molecule is administered at a dose of about 300 mg to 500 mg (eg, about 400 mg) once every three weeks. In one embodiment, the anti-LAG-3 antibody molecule is administered at a dose of about 700 mg to about 900 mg (eg, about 800 mg) once every four weeks. In one embodiment, the anti-LAG-3 antibody molecule is administered at a dose of about 500 mg to about 700 mg (eg, about 533 mg or about 600 mg) once every four weeks.

An anti-LAG-3 antibody, or a composition or preparation containing an anti-LAG-3 antibody molecule, can be used alone to slow the growth of malignant tumors. Alternatively, an anti-LAG-3 antibody or a composition or preparation comprising an anti-LAG-3 antibody molecule can be used in combination with one or more of: standard medical treatment (eg, for cancer or infectious disorders), another antibody, or an antigen-binding fragment thereof, an immunomodulator (eg, an activator of a costimulatory molecule or an inhibitor of an inhibitory molecule); vaccines, for example a therapeutic cancer vaccine; or other forms of cellular immunotherapy as described herein.

Accordingly, in one embodiment, the invention provides a method of slowing the growth of tumor cells in a subject, comprising administering to the subject a therapeutically effective amount of an anti-LAG-3 antibody molecule described herein, for example, according to the dosage regimen described herein. In one embodiment, the anti-LAG-3 antibody molecule is administered in the form of a composition or preparation as described herein.

In one embodiment, the method is useful for treating cancer in vivo . To achieve antigen-specific immune enhancement, an anti-LAG-3 antibody molecule can be administered together with the antigen of interest. When the anti-LAG-3 antibody is administered in combination with one or more agents, the combination may be administered in any order or simultaneously.

In another aspect, a method is provided for treating a subject, eg, reducing or alleviating a hyperproliferative condition or disorder (eg, cancer), eg, solid tumor, hematologic cancer, soft tissue tumor, or metastatic lesion, in a subject. The method includes administering to a subject an anti-LAG-3 antibody molecule, or a composition or preparation comprising an anti-LAG-3 antibody molecule, as described herein, according to a dosing regimen described herein.

As used herein, the term "cancer" is intended to include all types of malignant growth or oncogenic processes, metastatic tissues or malignantly transformed cells, tissues or organs, regardless of histopathological type or stage of invasiveness. Examples of malignant disorders include, but are not limited to, solid tumors, hematologic cancers, soft tissue tumors, and metastatic lesions. Examples of solid tumors include malignancies such as sarcomas and carcinomas (including adenocarcinomas and squamous cell carcinomas), various organ systems such as neoplasms affecting the liver, lungs, breast, lymphatic system, gastrointestinal tract (eg colon) , urogenital tract (eg, kidney, urothelial, bladder cells), prostate, CNS (eg, brain, neural or glial cells), skin, pancreas, and larynx. Adenocarcinomas include malignancies such as most colon cancers, rectal cancer, renal cell carcinoma, liver cancer, non-small cell lung carcinoma, small intestine cancer, and esophageal cancer. Squamous cell carcinomas include malignancies in, for example, the lungs, esophagus, skin, head and neck, mouth, anus, and cervix. In one embodiment, the cancer is a melanoma, such as an advanced stage of melanoma. Metastatic lesions of the above cancers can also be treated or prevented using the methods and compositions of the present invention.

Exemplary cancers whose growth can be retarded using antibody molecules, compositions or formulations as described herein generally include immunotherapy responsive cancers. Non-limiting examples of typical cancers for treatment include melanoma (eg, metastatic malignant melanoma), kidney cancer (eg, clear cell carcinoma), prostate cancer (eg, hormone-resistant adenocarcinoma of the prostate), breast cancer, colon cancer, and lung cancer (eg, non-small cell lung cancer). In addition, refractory or recurrent cancers can be treated using the antibody molecules described herein.

Examples of other cancers that can be treated include, but are not limited to, basal cell carcinoma, bile duct cancer; bladder cancer; bone cancer; brain cancer and CNS; primary CNS lymphoma; neoplasms of the central nervous system (CNS); mammary cancer; cervical cancer; choriocarcinoma; cancer of the colon and rectum; connective tissue cancer; cancer of the digestive system; endometrial cancer; esophageal carcinoma; eye cancer; head and neck cancer; gastrointestinal cancer; intraepithelial neoplasm; kidney cancer; throat cancer; leukemia (including acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic or acute leukemia); liver cancer; lung cancer (eg, small cell and non-small cell); lymphoma, including Hodgkin's and non-Hodgkin's lymphoma; lymphocytic lymphoma; melanoma, for example, cutaneous or intraocular malignant melanoma; myeloma; neuroblastoma; cancer of the oral cavity (eg, lips, tongue, mouth, and larynx); ovarian cancer; pancreas cancer; prostate cancer; retinoblastoma; rhabdomyosarcoma; rectal cancer; cancer of the respiratory system; sarcoma; skin cancer; stomach cancer; testicular cancer; thyroid cancer; uterine cancer; urinary system cancer, hepatocarcinoma, anal cancer, fallopian tube carcinoma, vaginal carcinoma, vulvar carcinoma, small intestine cancer, endocrine system cancer, parathyroid cancer, adrenal gland cancer, soft tissue sarcoma, urethral cancer, penile cancer, solid tumors in children, spinal axis tumor, brainstem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid cancer, squam cell cancer, T-lymphoma, environmental cancers, including asbestos-induced diseases, and other carcinomas and sarcomas, and combinations of these cancer diseases.

In some embodiments, the disorder is a cancer, such as the cancer described herein. In certain embodiments, the cancer is a solid tumor. In some embodiments, the cancer is a brain tumor, such as glioblastoma, gliosarcoma, or a recurrent brain tumor. In some embodiments, the cancer is pancreatic cancer, such as advanced pancreatic cancer. In some embodiments, the cancer is a skin cancer, such as melanoma (eg, stage II-IV melanoma, HLA-A2 positive melanoma, unresectable melanoma, or metastatic melanoma) or Merkel cell carcinoma. In some embodiments, the cancer is a kidney cancer, such as renal cell carcinoma (RCC) (eg, metastatic renal cell carcinoma) or previously untreated metastatic kidney cancer. In some embodiments, the cancer is breast cancer, such as metastatic breast carcinoma or stage IV breast carcinoma, such as triple negative breast cancer (TNBC). In some embodiments, the cancer is a virus-associated cancer. In some embodiments, the cancer is anal cancer (eg, anal squamous cell carcinoma). In some embodiments, the cancer is cervical cancer (eg, squamous cell carcinoma of the cervix). In some embodiments, the cancer is gastrointestinal cancer (eg, Epstein-Barr virus positive gastrointestinal cancer or gastrointestinal or gastroesophageal junction carcinoma). In some embodiments, the cancer is a head and neck cancer (eg, HPV-positive and -negative head and neck squam cell cancer (SCCHN)). In some embodiments, the cancer is nasopharyngeal cancer (NPC). In some embodiments, the cancer is a cancer of the penis (eg, squamous cell carcinoma of the penis). In some embodiments, the cancer is a vaginal or vulvar cancer (eg, squamous cell carcinoma of the vagina or vulva). In some embodiments, the cancer is colon and rectal cancer, e.g., recurrent colon and rectal cancer or metastatic colon and rectal cancer, e.g., microsatellite unstable colon and rectal cancer, microsatellite stable colon and rectal cancer, colon and rectal cancer surplus for mispair repair or colon and rectal cancer deficient for mispair repair. In some embodiments, the cancer is lung cancer, such as non-small cell lung cancer (NSCLC). In certain embodiments, the cancer is a hematologic cancer. In some embodiments, the cancer is leukemia. In some embodiments, the cancer is a lymphoma, such as Hodgkin's lymphoma (HL) or diffuse large B cell lymphoma (DLBCL) (eg, recurrent or refractory HL or DLBCL). In some embodiments, the cancer is a myeloma. In some embodiments, the cancer is highly microsatellite unstable cancer. In some embodiments, the cancer is a metastatic cancer. In other embodiments, the cancer is a progressive cancer. In other embodiments, the cancer is recurrent or untreatable cancer.

In one embodiment, the cancer is Merkel cell carcinoma. In other embodiments, the cancer is melanoma. In other embodiments, the cancer is breast cancer, such as triple negative breast cancer (TNBC) or HER2 negative breast cancer. In other embodiments, the cancer is a renal cell carcinoma (eg, clear cell renal cell carcinoma (CCRCC) or non-clear cell renal cell carcinoma (nccRCC)). In other embodiments, the cancer is thyroid cancer, such as anaplastic thyroid carcinoma (ATC). In other embodiments, the cancer is a neuroendocrine tumor (NET), such as an atypical pulmonary carcinoid tumor or NET in the pancreas, gastrointestinal (GI) tract, or lungs. In certain embodiments, the cancer is non-small cell lung cancer (NSCLC) (eg, squamous NSCLC or non-squamous NSCLC). In certain embodiments, the cancer is fallopian tube cancer. In certain embodiments, the cancer is highly microsatellite unstable colon and rectal cancer (CRC with high MSI) or microsatellite stable colon and rectal cancer (CRC MSS).

In other embodiments, the cancer is a hematologic malignancy or cancer, including but not limited to leukemia or lymphoma. For example, an anti-LAG-3 antibody molecule can be used to treat cancers and malignancies, including, but not limited to, for example, acute leukemia, eg, B-cell acute lymphoid leukemia (“BALL”), acute T lymphoid leukemia -lymphocytes (“TALL”), acute lymphoid leukemia (ALL); chronic leukemia, eg chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL); additional hematologic cancer or hematologic condition, e.g. B-cell prolymphocytic leukemia, blast plasmacytoid dendritic cell neoplasm, Burkitt's lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, hairy cell leukemia, small cell or non-small cell follicular lymphoma, malignant lymphoproliferative conditions, MALT lymphoma, mantle cell lymphoma, marginal zone lymphoma, multiple myeloma, myelodysplasia and myelodysplastic syndrome, non-Hodgkin's lymphoma, plasmablastic lymphoma, plasmacytoid dendritic cell neoplasm, Waldenström's disease, and "preleukemia", which are a diverse set of hematological conditions linked by inefficient production (or dysplasia) of myeloid blood cells, and the like.

As used herein, the term “subject” is intended to include humans and non-human animals. In some embodiments, the subject is a human subject, such as a human patient, having a disorder or condition characterized by abnormal LAG-3 functioning. Typically, the subject has at least some LAG-3 protein containing a LAG-3 epitope that is associated with the antibody molecule, such as a sufficiently high level of protein and epitope to support binding of the antibody to LAG-3. The term "non-human animals" includes mammals and non-mammals such as non-human primates. In some embodiments, the subject is a human. In some embodiments, the subject is a human patient in need of an enhanced immune response. The methods and compositions described herein are useful in the treatment of human patients having a disorder that can be treated by modulating (eg, enhancing or slowing down) the immune response.

In some embodiments, an anti-LAG-3 antibody molecule, or a composition or preparation comprising an anti-LAG-3 antibody molecule, is administered as a single agent. In other embodiments, an anti-LAG-3 antibody molecule, or a composition or preparation comprising an anti-LAG-3 antibody molecule, is administered in combination with a second therapeutic agent or treatment, such as a PD-1 inhibitor, a PD-L1 inhibitor, or chemotherapeutic agent. In some embodiments, the PD-1 inhibitor is an anti-PD-1 antibody molecule, such as an anti-PD-1 antibody described herein. In some embodiments, the PD-L1 inhibitor is an anti-PD-L1 antibody molecule, such as an anti-PD-L1 antibody molecule described herein. In some embodiments, the chemotherapeutic agent is a platinum agent. In certain embodiments, the platinum agent is carboplatin. In certain embodiments, the platinum agent is cisplatin. In certain embodiments, the platinum agent is oxaliplatin. In certain embodiments, the platinum agent is tetraplatin.

In some embodiments, the chemotherapeutic agent is a nucleotide analog or a precursor analog. In certain embodiments, the nucleotide analog or precursor analog is capecitabine.

In certain embodiments, the cancer is a solid tumor. In some embodiments, an anti-LAG-3 antibody molecule, or a composition or preparation comprising an anti-LAG-3 antibody molecule, is administered as a single agent for treating a solid tumor. In other embodiments, an anti-LAG-3 antibody molecule, or a composition or preparation comprising an anti-LAG-3 antibody molecule, is administered in combination with a second therapeutic agent or treatment, such as a PD-1 inhibitor or a PD-L1 inhibitor, to solid tumor treatment. In some embodiments, the PD-1 inhibitor is an anti-PD-1 antibody molecule, e.g. anti-PD-1 antibodies, described in this document. In certain embodiments, the anti-PD-1 antibody molecule is PDR001 (spartalizumab). In certain embodiments, the anti-PD-1 antibody molecule is REGN2810. In other embodiments, the anti-PD-1 antibody molecule is nivolumab. In some embodiments, the PD-L1 inhibitor is an anti-PD-L1 antibody molecule, such as an anti-PD-L1 antibody molecule described herein.

In certain embodiments, the cancer is breast cancer, such as triple negative breast cancer (TNBC). In some embodiments, an anti-LAG-3 antibody molecule, or a composition or preparation comprising an anti-LAG-3 antibody molecule, is administered as a single agent for the treatment of breast cancer (eg, TNBC). In other embodiments, an anti-LAG-3 antibody molecule, or a composition or preparation comprising an anti-LAG-3 antibody molecule, is administered in combination with a second therapeutic agent, e.g., a PD-1 inhibitor, for the treatment of breast cancer (e.g., TNBC). In some embodiments, the PD-1 inhibitor is an anti-PD-1 antibody molecule, such as an anti-PD-1 antibody, as described herein. In certain embodiments, the anti-PD-1 antibody molecule is PDR001 (spartalizumab). In certain embodiments, the anti-PD-1 antibody molecule is REGN2810. In other embodiments, the anti-PD-1 antibody molecule is nivolumab. In certain embodiments, the anti-LAG-3 antibody molecule is administered at a dose of about 300 mg to about 500 mg (e.g., about 400 mg) once every three weeks and the PD-1 inhibitor is administered at a dose of about 200 mg to about 400 mg. mg (eg, about 300 mg) once every three weeks for the treatment of breast cancer (eg, TNBC). In certain embodiments, an anti-LAG-3 antibody molecule (e.g., an anti-LAG-3 antibody molecule described herein) is administered at a dose of about 600 mg to about 1000 mg (e.g., about 800 mg) once every four weeks, and a PD-1 inhibitor (eg, an anti-PD-1 antibody molecule described herein) is administered at a dose of about 300 mg to about 500 mg (eg, about 400 mg) once every four weeks for the treatment of breast cancer. glands (for example, TNBC).

In certain embodiments, the cancer is breast cancer, such as triple negative breast cancer (TNBC). In some embodiments, an anti-LAG-3 antibody molecule, or a composition or preparation comprising an anti-LAG-3 antibody molecule, is administered in combination with a second therapeutic agent, e.g., a chemotherapeutic agent, for the treatment of breast cancer (e.g., TNBC ). In some embodiments, the chemotherapeutic agent is a platinum agent. In certain embodiments, the platinum agent is carboplatin. In certain embodiments, the platinum agent is cisplatin. In certain embodiments, the platinum agent is oxaliplatin. In certain embodiments, the platinum agent is tetraplatin. In some embodiments, the chemotherapeutic agent is a nucleotide analog or a precursor analog. In certain embodiments, the nucleotide analog or precursor analog is capecitabine. In certain embodiments, the anti-LAG-3 antibody molecule is administered at a dose of about 300 mg to about 500 mg (e.g., about 400 mg) once every three weeks, and the chemotherapeutic agent is administered at a dose to achieve area under the curve (AUC) about 4 to about 8 or about 5 to about 7 (eg, AUC about 6) once every three weeks for the treatment of breast cancer (eg, TNBC).

In certain embodiments, the cancer is breast cancer, such as triple negative breast cancer (TNBC). In some embodiments, an anti-LAG-3 antibody molecule, or a composition or formulation comprising an anti-LAG-3 antibody molecule, is administered in combination with a PD-1 inhibitor and a breast cancer chemotherapeutic agent (eg, TNBC). In some embodiments, the PD-1 inhibitor is an anti-PD-1 antibody molecule, such as an anti-PD-1 antibody, as described herein. In certain embodiments, the anti-PD-1 antibody molecule is PDR001 (spartalizumab). In certain embodiments, the anti-PD-1 antibody molecule is REGN2810. In other embodiments, the anti-PD-1 antibody molecule is nivolumab. In some embodiments, the chemotherapeutic agent is a platinum agent. In certain embodiments, the platinum agent is carboplatin. In certain embodiments, the platinum agent is cisplatin. In certain embodiments, the platinum agent is oxaliplatin. In certain embodiments, the platinum agent is tetraplatin. In some embodiments, the chemotherapeutic agent is a nucleotide analog or a precursor analog. In certain embodiments, the nucleotide analog or precursor analog is capecitabine. In certain embodiments, the anti-LAG-3 antibody molecule is administered at a dose of about 300 mg to about 500 mg (e.g., about 400 mg) once every three weeks, the PD-1 inhibitor is administered at a dose of about 200 mg to about 400 mg (eg, about 300 mg) once every three weeks, and the chemotherapeutic agent is administered at a dose to achieve an AUC of about 4 to about 8 or about 5 to about 7 (eg, AUC of about 6) once every three weeks for treatment breast cancer (eg TNBC).

In certain embodiments, the cancer is a brain tumor. In some embodiments, the brain tumor is a glioblastoma (eg, recurrent glioblastoma). In some embodiments, an anti-LAG-3 antibody molecule, or a composition or preparation comprising an anti-LAG-3 antibody molecule, is administered as a single agent for treating a brain tumor. In other embodiments, an anti-LAG-3 antibody molecule, or a composition or preparation comprising an anti-LAG-3 antibody molecule, is administered in combination with a second therapeutic agent or treatment, such as a PD-1 inhibitor or a PD-L1 inhibitor, to brain tumor treatment. In some embodiments, the PD-1 inhibitor is an anti-PD-1 antibody molecule, such as an anti-PD-1 antibody, as described herein. In certain embodiments, the anti-PD-1 antibody molecule is PDR001 (spartalizumab). In other embodiments, the anti-PD-1 antibody molecule is nivolumab. In some embodiments, the PD-L1 inhibitor is an anti-PD-L1 antibody molecule, such as an anti-PD-L1 antibody molecule described herein.

In certain embodiments, the cancer is pancreatic cancer. In some embodiments, the pancreatic cancer is advanced pancreatic cancer. In some embodiments, an anti-LAG-3 antibody molecule, or a composition or preparation comprising an anti-LAG-3 antibody molecule, is administered as a single agent for the treatment of pancreatic cancer. In other embodiments, an anti-LAG-3 antibody molecule, or a composition or formulation comprising an anti-LAG-3 antibody molecule, is administered in combination with a second therapeutic agent or treatment for the treatment of pancreatic cancer. In some embodiments, the second therapeutic agent or treatment comprises a chemotherapeutic agent (eg, gemcitabine).

In certain embodiments, the cancer is melanoma. In some embodiments, the melanoma is HLA-A2 positive, stage II, III, or IV melanoma, unresectable melanoma, or metastatic melanoma. In some embodiments, an anti-LAG-3 antibody molecule, or a composition or preparation comprising an anti-LAG-3 antibody molecule, is administered as a single agent for the treatment of melanoma. In other embodiments, an anti-LAG-3 antibody molecule, or a composition or preparation comprising an anti-LAG-3 antibody molecule, is administered in combination with a second therapeutic agent or treatment for melanoma. In some embodiments, the second therapeutic agent or method is an HLA-A2 peptide. In certain embodiments, an anti-LAG-3 antibody molecule, or a composition or formulation comprising an anti-LAG-3 antibody molecule, and optionally an HLA-A2 peptide, is administered to a patient without melanoma disease. In some embodiments, the second therapeutic agent or method comprises a PD-1 inhibitor or a PD-L1 inhibitor. In some embodiments, the PD-1 inhibitor is an anti-PD-1 antibody molecule, such as an anti-PD-1 antibody, as described herein. In certain embodiments, the anti-PD-1 antibody molecule is PDR001. In some embodiments, the PD-L1 inhibitor is an anti-PD-L1 antibody molecule, such as an anti-PD-L1 antibody molecule described herein.

In certain embodiments, the cancer is kidney cancer. In some embodiments, the kidney cancer is renal cell carcinoma (RCC), such as metastatic renal cell carcinoma. In some embodiments, an anti-LAG-3 antibody molecule, or a composition or preparation comprising an anti-LAG-3 antibody molecule, is administered as a single agent for the treatment of kidney cancer. In other embodiments, an anti-LAG-3 antibody molecule, or a composition or preparation comprising an anti-LAG-3 antibody molecule, is administered in combination with a second therapeutic agent or treatment, such as a PD-1 inhibitor or a PD-L1 inhibitor, to kidney cancer treatment. In some embodiments, the PD-1 inhibitor is an anti-PD-1 antibody molecule, such as an anti-PD-1 antibody, as described herein. In certain embodiments, the anti-PD-1 antibody molecule is PDR001. In some embodiments, the PD-L1 inhibitor is an anti-PD-L1 antibody molecule, such as an anti-PD-L1 antibody molecule described herein.

In certain embodiments, the cancer is breast cancer. In some embodiments, the breast cancer is a metastatic breast carcinoma. In some embodiments, the breast cancer is triple negative breast cancer (TNBC). In some embodiments, an anti-LAG-3 antibody molecule, or a composition or preparation comprising an anti-LAG-3 antibody molecule, is administered as a single agent for the treatment of breast cancer. In other embodiments, an anti-LAG-3 antibody molecule, or a composition or preparation comprising an anti-LAG-3 antibody molecule, is administered in combination with a second therapeutic agent or treatment for the treatment of breast cancer. In certain embodiments, the second therapeutic agent or method is a chemotherapeutic agent (eg, paclitaxel). In certain embodiments, the anti-LAG-3 antibody molecule is administered at a dose of about 700 mg to about 900 mg once every four weeks for the treatment of breast cancer (eg, TNBC).

In certain embodiments, the cancer is a viral tumor. In some embodiments, the viral tumor is selected from anal cancer (e.g. anal squamous cell carcinoma), cervical cancer (e.g. cervical squamous cell carcinoma), gastrointestinal cancer (e.g. intestinal tract or gastroesophageal junction), head and neck cancer (eg, HPV-positive and negative head and neck squam cell carcinoma (SCCHN)), nasopharyngeal cancer (NPC), penile cancer (eg, squamous cell carcinoma of the penis), vaginal or vulvar cancer (eg, squamous cell carcinoma of the vagina or vulva). In some embodiments, an anti-LAG-3 antibody molecule, or a composition or preparation comprising an anti-LAG-3 antibody molecule, is administered as a single agent for treating a viral tumor. In other embodiments, an anti-LAG-3 antibody molecule, or a composition or preparation comprising an anti-LAG-3 antibody molecule, is administered in combination with a second therapeutic agent or treatment, such as a PD-1 inhibitor or a PD-L1 inhibitor, to treatment for the treatment of a viral tumor. In some embodiments, the PD-1 inhibitor is an anti-PD-1 antibody molecule, such as an anti-PD-1 antibody, as described herein. In certain embodiments, the anti-PD-1 antibody molecule is PDR001. In other embodiments, the anti-PD-1 antibody molecule is nivolumab. In some embodiments, the PD-L1 inhibitor is an anti-PD-L1 antibody molecule, such as an anti-PD-L1 antibody molecule described herein.

In certain embodiments, the cancer is selected from anal cancer (e.g., anal squamous cell carcinoma), cervical cancer (e.g., cervical squamous cell carcinoma), gastrointestinal cancer (e.g., Epstein-Barr virus-positive gastrointestinal cancer, or gastrointestinal carcinoma). tract or gastroesophageal junction), head and neck cancer (eg, HPV positive and negative head and neck squam cell carcinoma (SCCHN)), nasopharyngeal cancer (NPC), penile cancer (eg, squamous cell carcinoma of the penis), or vaginal or vulvar cancer (eg , squamous cell carcinoma of the vagina or vulva). In some embodiments, an anti-LAG-3 antibody molecule, or a composition or formulation comprising an anti-LAG-3 antibody molecule, is administered as a single agent for treating cancer. In other embodiments, an anti-LAG-3 antibody molecule, or a composition or preparation comprising an anti-LAG-3 antibody molecule, is administered in combination with a second therapeutic agent or treatment, such as a PD-1 inhibitor or a PD-L1 inhibitor, to cancer treatment. In some embodiments, the PD-1 inhibitor is an anti-PD-1 antibody molecule, such as an anti-PD-1 antibody, as described herein. In certain embodiments, the anti-PD-1 antibody molecule is PDR001. In other embodiments, the anti-PD-1 antibody molecule is nivolumab. In some embodiments, the PD-L1 inhibitor is an anti-PD-L1 antibody molecule, such as an anti-PD-L1 antibody molecule described herein.

In certain embodiments, the cancer is colon and rectal cancer. In some embodiments, the colon and rectal cancer is recurrent colon and rectal cancer, metastatic colon and rectal cancer, colon and rectal cancer with microsatellite instability, microsatellite stable colon and rectal cancer, colon and rectal cancer relatively mismatch repair, or colorectal cancer deficient in mismatch repair. In some embodiments, an anti-LAG-3 antibody molecule, or a composition or preparation comprising an anti-LAG-3 antibody molecule, is administered as a single agent for the treatment of colorectal cancer. In other embodiments, an anti-LAG-3 antibody molecule, or a composition or preparation comprising an anti-LAG-3 antibody molecule, is administered in combination with a second therapeutic agent or treatment, such as a PD-1 inhibitor or a PD-L1 inhibitor, to treatment of colon and rectal cancer. In some embodiments, the PD-1 inhibitor is an anti-PD-1 antibody molecule, such as an anti-PD-1 antibody, as described herein. In certain embodiments, the anti-PD-1 antibody molecule is PDR001. In other embodiments, the anti-PD-1 antibody molecule is nivolumab. In some embodiments, the PD-L1 inhibitor is an anti-PD-L1 antibody molecule, such as an anti-PD-L1 antibody molecule described herein.

In certain embodiments, the cancer is lung cancer. In some embodiments, the lung cancer is non-small cell lung cancer (NSCLC). In some embodiments, an anti-LAG-3 antibody molecule, or a composition or preparation comprising an anti-LAG-3 antibody molecule, is administered as a single agent for the treatment of lung cancer. In other embodiments, an anti-LAG-3 antibody molecule, or a composition or preparation comprising an anti-LAG-3 antibody molecule, is administered in combination with a second therapeutic agent or treatment, such as a PD-1 inhibitor or a PD-L1 inhibitor, to lung cancer treatment. In some embodiments, the PD-1 inhibitor is an anti-PD-1 antibody molecule, such as an anti-PD-1 antibody, as described herein. In certain embodiments, the anti-PD-1 antibody molecule is PDR001. In other embodiments, the anti-PD-1 antibody molecule is nivolumab. In some embodiments, the PD-L1 inhibitor is an anti-PD-L1 antibody molecule, such as an anti-PD-L1 antibody molecule described herein.

In certain embodiments, the cancer is a hematologic cancer. In some embodiments, the hematologic cancer is a lymphoma, such as Hodgkin's lymphoma (HL) or diffuse large B cell lymphoma (DCBCL) (eg, recurrent or refractory HL or DCBCL). In some embodiments, an anti-LAG-3 antibody molecule, or a composition or formulation comprising an anti-LAG-3 antibody molecule, is administered as a single agent for the treatment of a hematologic cancer. In other embodiments, an anti-LAG-3 antibody molecule, or a composition or formulation comprising an anti-LAG-3 antibody molecule, is administered in combination with a second therapeutic agent or treatment for the treatment of a hematologic cancer.

The methods and compositions described herein are useful in the treatment of metastatic lesions associated with the cancers discussed above.

In some embodiments, the method further comprises determining if the tumor tissue sample is positive for one or more of the PD-L1, CD8, and IFN-γ markers, and if the tumor tissue sample is positive for one or more, e.g., two or all three markers, then the patient is administered therapeutically effective amounts of anti-LAG-3 antibody molecules, optionally in combination with one or more other immunomodulatory or anticancer agents, as described herein.

In some embodiments, an anti-LAG-3 antibody molecule is used to treat cancer that expresses LAG-3. Cancers expressing LAG-3 include, for example, colorectal cancer (Xiao and Freeman Cancer Discov. 2015; 5(1):16-8), breast cancer (Bottai et al. Breast Cancer Res. 2016; 18 (1): 121), prostate cancer (Sfanos et al. Clin Cancer Res. 2008; 14(11):3254-61), lung cancer (He et al. J Thorac Oncol. 2017; 12(5): 814- 823) and liver cancer (Pedroza-Gonzalez et al. Oncoimmunology. 2015; 4(6):e1008355). A cancer expressing LAG-3 may be a metastatic cancer.

In other embodiments, the anti-LAG-3 antibody molecule is used to treat cancer that is highly microsatellite unstable (MSI-H) or mismatch repair (dMMR) deficient. Identification of MSI-H or dMMR tumor status for patients can be determined, for example, using polymerase chain reaction (PCR) assays for MSI-H status or immunohistochemical (IHC) assays for dMMR. Methods for identifying the MSI-H or dMMR status of a tumor are described, for example, in Ryan et al. Crit Rev Oncol Hematol. 2017; 116:38-57; Dietmeier and Hofstadter. Lab Invest 2001 , 81:1453-1456; Kawakami et al. Curr Treat Options Oncol. 2015; 16(7): 30).

Combination therapy described herein may include a composition of the present invention co-formulated and/or co-administered with one or more additional therapeutic agents, e.g. one or more anti-cancer agents, cytotoxic or cytostatic agents, hormonal treatments, vaccines and/ or other immunotherapy. In other embodiments, the antibody molecules are administered in combination with other therapeutic modalities, including surgery, radiation, cryosurgery, and/or thermotherapy. Such combination therapy can advantageously utilize lower dosages of administered therapeutic agents, thus avoiding potential toxicities or complications associated with various monotherapies.

The methods, compositions and combinations described herein (for example, anti-LAG-3 antibodies and methods of using them) can be used in combination with other agents or therapeutic interventions, for example, with a second therapeutic agent selected from one or more agents, listed in Table 6 of WO 2017/019897, the contents of which are incorporated by reference in their entirety. In one embodiment, the methods described herein comprise administering to a subject an anti-LAG-3 antibody molecule as described in WO2017/019894 (optionally in combination with one or more inhibitors of PD-1, PD-L1, TIM-3 , CEACAM (e.g., CEACAM-1 and/or CEACAM-5) or CTLA-4)), in addition, they include the introduction of a second therapeutic agent selected from one or more of the agents listed in Table 6 of WO 2017/019897, in the amount of effective for treating or preventing a disorder, such as a disorder as described herein, such as cancer. When administered in combination, the anti-LAG-3 antibody molecule, the additional agent (e.g., second or third agent), or all together, may be administered in an amount or at a dose that is higher, lower, or the same as the amount or dosage of each agent. used individually, for example, as monotherapy. In certain embodiments, the administered amount or dosage of the anti-LAG-3 antibody molecule, additional agent (e.g., second or third agent), or all together, is lower (e.g., at least 20%, at least 30 %, at least 40% or at least 50%) than the amount or dosage of each agent used individually, for example, as monotherapy. In other embodiments, the amount or dosage of the anti-LAG-3 antibody molecule, additional agent (e.g., second or third agent), or both, that results in the desired effect (e.g., cancer treatment) is lower (e.g., at least , 20%, at least 30%, at least 40%, or at least 50% lower).

In other embodiments, the additional therapeutic agent is selected from one or more of the agents listed in Table 6 of WO 2017/019894. In some embodiments, the additional therapeutic agent is selected from one or more of: 1) a protein kinase C (PKC) inhibitor; 2) heat shock protein 90 inhibitor (HSP90); 3) a phosphoinositide 3-kinase inhibitor (PI3K) and/or a rapamycin target (mTOR); 4) a cytochrome P450 inhibitor (eg, a CYP17 inhibitor or a 17alpha-hydroxylase/C17-20 lyase inhibitor); 5) an agent that forms complex compounds with iron; 6) an aromatase inhibitor; 7) a p53 inhibitor, eg an inhibitor of the p53/Mdm2 interaction; 8) an apoptosis inducing agent; 9) an angiogenesis inhibitor; 10) an aldosterone synthase inhibitor; 11) protein receptor inhibitor Smoothened (SMO); 12) a prolactin receptor (PRLR) inhibitor; 13) Wnt signaling inhibitor; 14) a CDK4/6 inhibitor; 15) fibroblast growth factor receptor 2 (FGFR2)/fibroblast growth factor receptor 4 (FGFR4) inhibitor; 16) a macrophage colony stimulating factor (M-CSF) inhibitor; 17) an inhibitor of one or more processes from c-KIT, Flt3 (eg, FLK2/STK1) or PKC histamine release; 18); an inhibitor of one or more of VEGFR-2 (eg, FLK-1/KDR), PDGFRbeta, c-KIT, or Raf kinases C; 19) a somatostatin agonist and/or a growth hormone releasing inhibitor; 20) an anaplastic lymphomakinase (ALK) inhibitor; 21) an insulin-like growth factor 1 receptor (IGF-1R) inhibitor; 22) P-glycoprotein 1 inhibitor; 23) an endothelial vascular growth factor receptor (VEGFR) inhibitor; 24) BCR-ABL kinase inhibitor; 25) an FGFR inhibitor; 26) CYP11B2 inhibitor; 27) an HDM2 inhibitor, eg an HDM2-p53 interaction inhibitor; 28) a tyrosine kinase inhibitor; 29) c-MET inhibitor; 30) a JAK inhibitor; 31) DAC inhibitor; 32) 11β-hydroxylase inhibitor; 33) an IAP inhibitor; 34) a PIM kinase inhibitor; 35) porcupine inhibitor; 36) a BRAF inhibitor, eg BRAF V600E or wild-type BRAF; 37) HER3 inhibitor; 38) MEK inhibitor; or 39) a lipid kinase inhibitor, for example as described in Table 6 of WO 2017/019894.

Additional combination therapy embodiments comprising the anti-LAG-3 antibody molecule described herein are described in WO 2017/019894, which is incorporated by reference in its entirety.

Ways to treat infectious diseases

The present invention describes methods of treating infectious diseases using an anti-LAG-3 antibody molecule (e.g., an anti-LAG-3 antibody molecule described herein), or a composition or preparation containing an anti-LAG-3 antibody molecule (e.g., composition or preparation described herein). In certain embodiments, the antibody molecule, composition, or drug is administered to the subject according to the dosing regimen described herein.

In certain embodiments, the anti-LAG-3 antibody molecule is administered in an amount effective to treat an infectious disease or symptoms thereof. In some embodiments, the anti-LAG-3 antibody molecule is administered at a dose of about 100 mg to about 2000 mg once every two weeks, once every three weeks, or once every four weeks. For example, an anti-LAG-3 antibody molecule may be administered at a dose of about 200 mg to about 1000 mg, about 300 mg to about 900 mg, about 200 mg to about 600 mg, about 300 mg to about 500 mg, about 600 to about 1000 mg, about 700 mg to about 900 mg, or about 400 mg to about 800 mg once every three weeks or once every four weeks. In one embodiment, the anti-LAG-3 antibody molecule is administered at a dose of about 300 mg to 500 mg (eg, about 400 mg) once every three weeks. In one embodiment, the anti-LAG-3 antibody molecule is administered at a dose of about 700 mg to about 900 mg (eg, about 800 mg) once every four weeks. In one embodiment, the anti-LAG-3 antibody molecule is administered at a dose of about 500 mg to about 700 mg (eg, about 533 mg or about 600 mg) once every four weeks.

Certain methods described herein are used to treat subjects who are exposed to specific toxins or pathogens. Without wishing to be bound by theory, it is believed that in some embodiments, anti-LAG-3 antibodies can stimulate NK cell-mediated killing of target cells and can enhance IFN-gamma secretion and proliferation of CD4+ T lymphocytes. Accordingly, in certain embodiments, the anti-LAG-3 antibody molecules, compositions and formulations described herein are useful in stimulating an immune response to an infectious agent. Accordingly, another aspect of the present invention provides a method of treating an infectious disease in a subject, comprising administering to the subject an anti-LAG-3 antibody molecule, or a composition or preparation comprising an anti-LAG-3 antibody molecule, for example, according to the dosing regimen described herein, so that the subject is cured of an infectious disease. In the treatment of an infection (eg, acute and/or chronic), the administration of anti-LAG-3 antibody molecules can be combined with conventional therapies, in addition to or instead of stimulating the host's natural immune defenses against infection. The host's natural immune defense against infection includes, but is not limited to, inflammation, fever, antibody-mediated host defense, T-lymphocyte-mediated host defense, including lymphokine secretion, and cytotoxic T-lymphocytes (especially during viral infection), complement-mediated lysis and opsonization (facilitated phagocytosis) and phagocytosis. The ability of anti-LAG-3 antibody molecules to reactivate dysfunctional T lymphocytes would be useful in the treatment of chronic infections, especially those in which cell-mediated immunity is essential for complete recovery.

Similar to their use in tumors as discussed in the previous section, the anti-LAG-3 antibody molecules, compositions and preparations described herein can be used alone or in combination with a second therapeutic agent or treatment, or as an adjuvant, in combined with a vaccine to stimulate an immune response to a pathogen or toxin. Examples of pathogens for which a therapeutic approach may be particularly useful include pathogens for which there is currently no effective vaccine or pathogens for which conventional vaccines are not fully effective. These include, but are not limited to HIV, hepatitis (A, B and C), influenza, herpes, giardia, malaria, leishmania, Staphylococcus aureus, Pseudomonas aeruginosa . Therapy with anti-LAG-3 antibody molecules is also useful against established infections by agents such as HIV that present altered antigens during infections.

Accordingly, in some embodiments, an anti-LAG-3 antibody molecule, composition or preparation described herein is used to treat a subject who has an infection or is at risk of infection. Infection refers, for example, to a disease or condition attributed to the presence in the host of a foreign organism or agent that multiplies in the host. Infections typically involve crossing a normal mucosal or other tissue barrier by an infecting organism or agent. A subject that has an infection is one that has objectively measurable infectious organisms or agents present in the subject's body. A subject at risk of infection is one that is predisposed to developing an infection. Such a subject may include, for example, a subject known or expected to have been or will be exposed to an infecting organism or agent. A subject at risk of infection may also include a subject with a condition associated with an impaired ability to mount an immune response to an infecting organism or agent, e.g., a subject with a hereditary or acquired immunodeficiency, a subject undergoing radiation therapy or chemotherapy, a subject with a burn injury, a subject with a traumatic injury, a subject undergoing surgery or other invasive medical or dental procedure.

Infections are broadly classified as bacterial, viral, fungal or parasitic in relation to the category of the infecting organism or agent involved. Other less common types of infection include, for example, infections including rickettsia, mycoplasma, and prurigo, bovine spongiform encephalopathy (BSE), and prion diseases (eg, kuru and Creutzfeldt-Jakob disease). Examples of bacteria, viruses, fungi and parasites that cause infection are well known in the art. The infection may be acute, subacute, chronic or latent, and it may be local or systemic. In addition, the infection may be primarily intracellular or extracellular, during at least one phase of the life cycle of the infecting organism or agent in the host.

Viruses

In certain embodiments, an anti-LAG-3 antibody molecule, composition or formulation described herein is used to treat a viral infection or disease associated with a virus.

Examples of viruses found to cause infections in humans include, but are not limited to: Retroviridae (for example, human immunodeficiency viruses such as HIV-1 (also referred to as HTLV-III), HIV-2, LAV, or HTLV- III/LAV or HIV-III, and other isolates such as HIV-LP; Picornaviridae (eg, polioviruses, hepatitis A virus; enteroviruses, human coxsackieviruses, rhinoviruses, ECHO viruses); Calciviridae (eg, strains that cause gastroenteritis ); Togaviridae (e.g. equine encephalitis viruses, rubella viruses; Flaviviridae (e.g. dengue fever viruses, encephalitis viruses, yellow fever viruses); Coronaviridae (e.g. coronaviruses); Rhabdoviridae (e.g. vesicular stomatitis viruses, rabies viruses); Filoviridae ( e.g. Ebola viruses); Paramyxoviridae (e.g. parainfluenza viruses, mumps virus, measles viruses, respiratory syncytial virus); Orthomyxoviridae (e.g. influenza viruses); Bungaviridae (e.g. Hantaan viruses, Bunga viruses, phleboviruses and nairoviruses); Arena viridae (hemorrhagic fever viruses); Reoviridae (eg reoviruses, orbiviruses and rotaviruses); Birnaviridae; Hepadnaviridae (hepatitis B virus); Parvoviridae (parvoviruses); Papovaviridae (papilloma viruses, polyoma viruses); Adenoviridae (most adenoviruses); Herpesviridae (herpes simplex virus (HSV) 1 and 2, varicella zoster virus, cytomegalovirus (CMV), herpes virus; Poxyiridae (poxviruses, vaccinia viruses, poxviruses); and Iridoviridae (e.g. African swine fever virus); and unclassified viruses (e.g. causative agents of spongiform encephalopathies, hepatitis delta agent (considered to be a defective satellite of hepatitis B virus), non-A, non-B hepatitis agents (class 1=enterally transmitted; class 2=parenterally transmitted (eg, hepatitis C); Norwalk and related viruses and astroviruses).Some examples of pathogenic viruses that cause infections treatable using the methods of the present invention include HIV, hepatitis (A, B or C), herpes virus (for example, VZV, HSV-1, HAV-6, HSV- II, and CMV, Epstein-Barr virus), adenovirus, influenza virus, flaviviruses, ECHO virus, rhinovirus, coxsackievirus, coronavirus, respiratory syncytial virus, mumps virus, rotavirus, measles virus, rubella virus, parvovirus, bovine virus smallpox virus, HTLV virus, dengue virus, human papillomavirus, molluscum virus, poliovirus, rabies virus, JC virus, and arbovirus encephalitis.

For infections resulting from exposure to viruses, anti-LAG-3 antibody molecules can be combined by application before, after, or simultaneously with standard therapy for the treatment of viral infections. Such standard therapy varies depending on the type of virus, although administration of human serum containing antibodies (eg, IgA, IgG) specific to the virus may be effective in most cases.

Some examples of pathogenic viruses that cause infections that can be treated using these methods include HIV, hepatitis (A, B, or C), herpes viruses (for example, VZV, HSV-1, HAV-6, HSV-II, and CMV, Epstein-Barr virus), adenovirus, influenza virus, flaviviruses, echovirus, rhinovirus, coxsackievirus, coronavirus, respiratory syncytial virus, mumps virus, rotavirus, measles virus, rubella virus, parvovirus, vaccinia virus, HTLV virus, dengue virus , papillomavirus, molluscum virus, poliovirus, rabies virus, JC virus, encephalitis arbovirus, and ebolavirus (for example, BDBV, EBOV, RESTV, SUDV, and TAFV).

In one embodiment, the infection is an influenza infection. Influenza infection can result in fever, cough, muscle pain, headache, and malaise, which often occur with seasonal epidemics. Influenza is also associated with a number of postinfectious disorders such as encephalitis, myopericarditis, Goodpasture's syndrome, and Reye's syndrome. Influenza infection also suppresses normal pulmonary antibacterial defenses, such that patients recovering from influenza are at increased risk of developing bacterial pneumonia. Influenza virus surface proteins show marked antigenic variation resulting from mutation and recombination. Thus, cytolytic T-lymphocytes represent the host's main drug medium for virus elimination after infection. Influenza is classified into three main types: A, B, and C. Type A influenza is unique in that it infects both humans and many other animals (such as pigs, horses, birds, and seals), and is the main cause of pandemic flu. Also, when a cell is infected with two different strains of type A influenza, the segmented RNA genomes of the two original types of virus mix during replication, creating a hybrid replicant resulting in new epidermal strains. Type B influenza does not replicate in animals and thus has less genetic variation, while type C influenza has only one serotype.

Most conventional therapies are palliatives for symptoms resulting from infection, while the host's immune response actually eliminates the disease entirely. However, certain strains (such as type A influenza) can cause more serious illness and death. Type A influenza can be treated both clinically and prophylactically by administering the cyclic amine inhibitors amantadine and rimantadine, which slow the replication of the virus. However, the clinical benefit of these drugs is limited due to the relatively high rate of adverse reactions, their narrow antiviral spectrum (influenza A only), and the propensity of the virus to establish resistance. Administration of serum IgG antibodies to the major influenza surface proteins, hemagglutinin and neuraminidase, can prevent pulmonary infection, while mucosal IgA is required to prevent infection of the upper respiratory tract and trachea. The most effective modern treatment for influenza is vaccination with the introduction of a virus inactivated with formalin or β-propiolactone.

In another embodiment, the infection is a hepatitis infection, such as a hepatitis B or C infection.

Hepatitis B virus (HB-V) is the most infectious bloodborne pathogen known. It is a major cause of acute and chronic hepatitis and hepatic carcinoma, as well as lifelong chronic infection. After infection, the virus replicates in hepatocytes, which then also shed the HBsAg surface antigen. Detection of excessive serum HBsAg levels is used as a standard diagnostic tool for hepatitis B infection. An acute infection may resolve or it may develop into a chronic persistent infection. Current treatments for chronic HBV include α-interferon, which increases human leukocyte class I antigen (HLA) expression on the surface of hepatocytes, thereby facilitating their recognition by cytotoxic T-lymphocytes. In addition, the nucleoside analogues ganciclovir, famciclovir, and lamivudine also show some efficacy in the treatment of HBV infection in clinical studies. Additional treatments for HBV include pegylated interferon-alpha, adenfovir, entecavir, and telbuvidin. Although passive immunity can be conferred by parenteral administration of serum anti-HBsAg antibodies, vaccination with inactivated or recombinant HBsAg also confers resistance to infection. Anti-LAG-3 antibody molecules can be combined with conventional treatments for hepatitis B infection to provide a therapeutic benefit.

Hepatitis C virus (HC-V) infection can lead to chronic hepatitis, resulting in cirrhosis. Although symptoms are similar to infections resulting from hepatitis B infection, in stark contrast to HB-V, infected hosts may be asymptomatic for 10 to 20 years. The anti-LAG-3 antibody molecule may be administered as monotherapy or in combination with standard treatment for hepatitis C infection. For example, the anti-LAG-3 antibody molecule may be administered along with one or more of Sovaldi (sofosbuvir), Olysio (simeprevir), plus ribavirin or pegylated interferon. Although regimens that include Incivek (telaprevir) or Victrelis (boceprevir) plus ribavirin and pegylated interferon are also approved, they are associated with increased side effects and longer treatment and, for this reason, are not considered preferred regimens.

Conventional treatment for HC-V infection involves administering a combination of α-interferon and ribavirin. A promising potential therapy for HC-V infection is the protease inhibitor telaprevir (VX-960). Complementary therapies include: anti-PD-1 antibody (MDX-1106, Medarex), bavituximab (an antibody that binds the anionic phospholipid phosphatidylserine in a B2-glycoprotein I dependent manner, Peregrine Pharmaceuticals), anti-HPV antibody(s) coated with viral E2 protein (eg ATL 6865-Ab68+Ab65, XTL Pharmaceuticals) and Civacir® (human anti-HCV polyclonal immunoglobulin). The anti-LAG-3 antibodies of the present invention may be combined with one or more of these treatments for hepatitis C infection for therapeutic benefit. Protease, polymerase and NS5A inhibitors that can be used in combination with anti-LAG-3 antibody molecules to specifically treat hepatitis C infection include those described in US Pat. No. 2013/0045202, incorporated herein by reference.

In another embodiment, the infection is a measles virus. After an incubation period of 9-11 days, hosts infected with the measles virus develop fever, cough, runny nose, and conjunctivitis. Within 1-2 days, an erythematous maculopapular rash develops that rapidly spreads throughout the body. Because the infection also suppresses cellular immunity, the host is at higher risk of developing bacterial superinfections, including otitis media, pneumonia, and postinfectious encephalomyelitis. Acute infection is associated with significant morbidity and mortality, especially in malnourished patients.

Measles treatment involves passive administration of mixed human IgG, which can prevent infection in non-immunized subjects even if taken a week after exposure. However, pre-immunization with live attenuated virus is the most effective treatment and prevents disease in more than 95% of those immunized. Since there is one serotype of this virus, one immunization or infection usually results in protection for life after infection.

In a small proportion of infected hosts, measles can develop into SSPE, which is a chronic progressive neurological disorder resulting from persistent infection of the central nervous system. SSPE is caused by clonal variants of the measles virus with defects that affect virion assembly and budding. For these patients, it would be desirable to reactivate T-lymphocytes with anti-LAG-3 antibody molecules in such a way as to facilitate removal of the virus.

In another embodiment, the infection is HIV. HIV targets CD4 ⁺ cells, including T-lymphocytes, macrophage monocytes, follicular dendritic cells, and Langerhans cells, and CD4 ⁺ helper/inducer cells are depleted. As a result, the host acquires an acute defect in cell-mediated immunity. HIV infection results in AIDS in at least 50% of individuals and is transmitted through sexual contact, administration of infected blood or blood products, artificial insemination with infected semen, exposure to blood-containing needles or syringes, and transmission from an infected mother to her child during childbirth.

An HIV-infected host may be asymptomatic or may develop an acute illness that resembles mononucleosis: fever, headache, sore throat, malaise, and rash. Symptoms may progress to progressive immune dysfunction, including persistent fever, night sweats, weight loss, unexplained diarrhea, eczema, psoriasis, seborrheic eczema, herpes zoster, thrush, and oral hairy leukoplakia. Opportunistic parasite host infections are common in patients whose infections develop into AIDS.

HIV treatment includes antiviral therapy, including nucleoside analogs, zidovudine (AST) either alone or in combination with didanosine or zalcitabine, dideoxyinosine, dideoxycytidine, lamidvudine, stavudine; reverse transcriptase inhibitors such as delavirdine, nevirapine, loviride; and proteinase inhibitors such as saquinavir, ritonavir, indinavir and nelfinavir. Anti-LAG-3 antibody molecules can be combined with conventional treatment for HIV infection to provide a therapeutic benefit.

In another embodiment, the infection is a cytomegalovirus (CMV). CMV infection is often associated with persistent, latent, and recurrent infection. CMV infects and remains latent in monocytes and progenitor cells of granulocyte-monocytes. The clinical symptoms of CMV include mononucleosis-like symptoms (ie, fever, swollen tonsils, malaise) and a tendency to develop an allergic skin rash to antibiotics. The virus is spread through direct contact. The virus exists in urine, saliva, semen and, to a lesser extent, other bodily fluids. Transmission can also occur from an infected mother to her fetus or newborn and through blood transfusion and organ transplantation. CMV infection results in a general weakening of cellular immunity, characterized by attenuated blastogenic responses to non-specific mitogens and specific CMV antigens, a decrease in cytotoxic capacity, and an increase in the number of CD8 lymphocytes among CD4 ⁺ lymphocytes.

Treatment for CMV infection includes the antiviral drugs ganciclovir, foscarnet, and cidovir, but these drugs are usually prescribed only to immunocompromised patients. Anti-LAG-3 antibody molecules can be combined with conventional treatment for cytomegalovirus infections for therapeutic benefit.

In another embodiment, the infection is an Epstein-Barr virus (EBV). EBV can establish persistent and latent infections and primarily affects B cells. Infection with EBV results in the clinical condition of infectious mononucleosis, which includes fever, sore throat, often with exudate, generalized lymphadenopathy, and splenomegaly. Hepatitis is also present, which can develop into jaundice.

Although typical treatment for EBV infection is palliative for symptoms, EBV has been associated with the development of certain cancers such as Burkitt's lymphoma and nasopharyngeal cancer. Thus, elimination of the viral infection before these complications would be of great benefit. Anti-LAG-3 antibody molecules can be combined with conventional Epstein-Barr virus treatment for therapeutic benefit.

In another embodiment, the infection is a herpes simplex virus (HSV). HSV is transmitted through direct contact with an infected host. Direct infection may be asymptomatic but usually results in blisters containing infectious particles. The disease manifests itself as cycles of active disease periods in which lesions appear and disappear as the virus latently infects the ganglion for a subsequent outbreak. The lesions may be on the face, genitals, eyes and/or hands. In some cases, the infection can also cause encephalitis.

Treatment of herpes infection is directed primarily at resolution of symptomatic outbreaks and includes systemic antiviral drugs such as: acyclovir (eg, Zovirax®), valacyclovir, famciclovir, penciclovir, and topical drugs such as docosanol (Abreva®), tromantadine, and zilactin . Removal of latent herpes infections would be of great clinical benefit. Anti-LAG-3 antibody molecules can be combined with conventional treatment for herpes virus infection for therapeutic benefit.

In another embodiment, the infection is human T-lymphotropic virus (HTLV-1, HTLV-2). HTLV is transmitted through sexual contact, breastfeeding, or exposure to contaminated blood. The virus activates a subset of _TH cells called Th1 cells, resulting in their overproliferation and overproduction of Th1-associated cytokines (eg, IFN-γ and TNF-α). This, in turn, results in suppression of Th2 lymphocytes and a decrease in the production of Th2 cytokines (eg, IL-4, IL-5, IL-10, and IL-13), causing a decrease in the ability of the infected host to mount an adequate immune response to invasive organisms that require a Th2-dependent response to eliminate (eg, parasitic infections, production of mucosal and humoral antibodies).

HTLV infections lead to opportunistic infections resulting in bronchiectasis, dermatitis, and superinfections with Staphylococcus spp. and Strongyloides spp., resulting in death from polymicrobial sepsis. HTLV infection can also lead directly to adult T-lymphocyte leukemia/lymphoma and to the upper motor neuron progressive demyelination disease known as HAM/TSP. Elimination of latent HTLV infections would be of great clinical benefit. Anti-LAG-3 antibody molecules can be combined with conventional treatment for HTLV infection for therapeutic benefit.

In another embodiment, the infection is human papillomavirus (HPV). HPV primarily affects keratinocytes and exists in two forms: cutaneous and genital. Transmission is thought to occur through direct contact and/or sexual activity. Both skin and genital HPV infection can result in papillomas and latent infections, and sometimes recurrent infections, which are controlled by the host's immune system, which controls symptoms and blocks the appearance of papillomas, but leaves the host able to transmit infections to others.

HPV infection can also lead to certain cancers such as cervical, anal, vulvar, penile, and oropharyngeal cancers. There is no known cure for HPV infection, but the current treatment is the topical application of imiquimod, which stimulates the immune system to affect the affected area. Elimination of latent HPV infections would be of great clinical benefit. Anti-LAG-3 antibodies of the present invention can be combined with conventional treatment for HPV infection for therapeutic benefit.

In another embodiment, the infection is an Ebola virus (EBOV). EBOV is one of five known Ebolaviruses . EBOV causes an acute and often fatal hemorrhagic fever in humans and mammals, known as Ebola virus disease (EVD). Transmission occurs through contact with the blood, secretions, organs, or other bodily fluids of infected patients. Currently, there is no proven treatment or vaccine.

bacteria

In certain embodiments, an anti-LAG-3 antibody molecule, composition or formulation described herein is used to treat a bacterial infection or disease associated with a bacterium.

Bacteria include both gram-negative and gram-positive bacteria. Examples of gram-positive bacteria include, but are not limited to, Pasteurella spp., Staphylococci spp., and cervical Streptococcus. Examples of gram-negative bacteria include, but are not limited to, Escherichia coli, cervical Pseudomonas, and cervical Salmonella. Specific examples of infectious bacteria include, but are not limited to: Helicobacter pyloris, Borrelia burgdorferi, Legionella pneumophilia, Mycobacteria spp. (e.g., M. tuberculosis, M. avium, M. intracellulare, M. kansasii, M. gordonae), Staphylococcus aureus, Neisseria gonorrhoeae, Neisseria meningitidis, Listeria monocytogenes, Streptococcus pyogenes (Group A Streptococcus), Streptococcus agalactiae (Group B Streptococcus ), Streptococcus (viridans group), Streptococcus faecalis, Streptococcus bovis, Streptococcus (anaerobic spp.), Streptococcus pneumoniae, pathogenic Campylobacter spp., Enterococcus spp., Haemophilus influenzae, Bacillus anthracis, Corynebacterium diphtheriae, Corynebacterium spp., Erysipelothri x rhusiopathiae, Clostridium perfringens, Clostridium tetani, Enterobacter aerogenes, Klebsiella pneumoniae, Pasturella multocida, Bacteroides spp., Fusobacterium nucleatum, Streptobacillus moniliformis, Treponema pallidum, Treponema pertenue, Leptospira, Mycobacterium leprae, Rickettsia and Actinomyces israelii. Some examples of pathogenic bacteria that cause infections treatable by the methods described herein include Chlamydia, Rickettsiosis bacteria, Mycobacteria, Staphylococci, Streptococci, Pneumococci, Meningococci and Gonococci, Klebsiella, Proteus, Serratia, Pseudomonas aeruginosa, Legionella, Diphtheria, Salmonella, Bacillus , cholera, tetanus, botulism, anthrax, plague, leptospirosis, and Lyme disease bacteria.

Some examples of pathogenic bacteria causing infections, cured by the present invention, include syphilis, Chlamydia , Rickettsial Bacteria , Mycobacteria , Staphylococci , Streptococci , Pneumonococci , Meningocci and Con OCOCCI , Klebsiella , Proteus , Serratia , Pseudomonas , Legionella, Diphtheria, Salmonella, bacilli , cholera, tetanus , botulism , anthrax , plague, leptospirosis and Lymes disease . Anti-LAG-3 antibody molecules can be used in combination with existing treatments for the above infections. For example, treatments for syphilis include penicillin (eg, penicillin G), tetracycline, doxycycline, ceftriaxone, and azithromycin.

Lyme disease, caused by Borrelia burgdorferi, is transmitted to humans by tick bites. The disease first presents as a localized rash, then flu-like symptoms follow, including malaise, fever, headache, neck stiffness, and joint pain. Later manifestations may include migratory and multi-articular arthritis, neurological and cardiac lesions with cranial nerve palsy and radiculopathy, myocarditis, and arrhythmia. Some cases of Lyme disease become persistent, resulting in irreversible lesions like tertiary syphilis. Modern therapy for Lyme disease mainly involves the administration of antibiotics. Antibiotic-resistant strains can be treated with hydroxychloroquine or methotrexate. Patients not responding to antibiotics, patients with neuropathic pain may be treated with gabapentin. Minocycline may be useful in advanced/chronic Lyme disease with neurological or other inflammatory manifestations.

Other forms of borreliosis, such as those resulting from infection with B. recurentis, B. hermsii, B. turicatae, B. parikeri., B. hispanica, B. duttonii and B. persica , and leptospirosis (for example, L. interrogans ), usually resolve spontaneously unless blood titers reach concentrations that cause intrahepatic obstruction.

fungi and parasites

In certain embodiments, an anti-LAG-3 antibody molecule, composition or formulation described herein is used to treat a fungal or parasitic infection or disease associated with a fungus or parasite.

Examples of fungi include: Aspergillus spp., Blastomyces dermatitidis, Candida albicans, other Candida spp., Coccidioides immitis, Cryptococcus neoformans, Histoplasma capsulatum, Chlamydia trachomatis, Nocardia spp., Pneumocystis carinii . Some examples of pathogenic fungi that cause infections that can be treated using the methods of the present invention. include Candida ( albicans, krusei, glabrata, tropicalis , and the like), Cryptococcus neoformans, Aspergillus ( fumigatus, niger , and the like), Genus Mucorales ( mucor, absidia, rhizophus ), Sporothrix schenkii, Blastomyces dermatitidis, Paracoccidioides brasiliensis, Coccidioides immitis and Histoplasma capsulatum .

Parasites include, but are not limited to, blood contact and/or tissue parasites such as Babesia microti, Babesia divergens, Entamoeba histolytica, Giardia lamblia, Leishmania tropica, Leishmania spp., Leishmania braziliensis, Leishmania donovani, Plasmodium falciparum, Plasmodium malariae, Plasmodium ovale , Plasmodium vivax, and Toxoplasma gondii, Trypanosoma gambiense and Trypanosoma rhodesiense (African sleeping sickness), Trypanosoma cruzi (Chagas disease) and Toxoplasma gondii , flatworms, roundworms. Some examples of pathogenic parasites that cause infections that can be treated using the methods described herein include Entamoeba histolytica, Balantidium coli, Naegleriafowleri, Acanthamoeba sp., Giardia lambia, Cryptosporidium sp., Pneumocystis carinii, Plasmodium vivax, Babesia microti, Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani, Toxoplasma gondii and Nippostrongylus brasiliensis .

Some examples of pathogenic fungi that cause infections that can be treated using the methods of the present invention includecandida(albicans, krusei, glabrata, tropicalis,And the like), Cryptococcus neoformans, Aspergillus(fumigatus, niger,etc), Genus Mucorales(mucor, absidia, rhizophus), Sporothrix schenkii, Blastomyces dermatitidis, Paracoccidioides brasiliensis, Coccidioides immitisAndHistoplasma capsulatum.

Some examples of pathogenic parasites that cause infections that can be treated using the methods described in the present invention include Entamoeba histolytica, Balantidium coli, Naegleriafowleri, Acanthamoeba sp., Giardia lambia, Cryptosporidium sp., Pneumocystis carinii, Plasmodium vivax, Babesia microti, Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani, Toxoplasma gondii and Nippostrongylus brasiliensis .

Nucleic acids

The anti-LAG-3 antibody molecules described herein may be encoded by the nucleic acids described herein. Nucleic acids can be used to produce the anti-LAG-3 antibody molecules described herein.

In certain embodiments, the nucleic acid comprises nucleotide sequences that encode the heavy and light chain variable regions and CDRs of anti-LAG-3 antibody molecules, as described herein. For example, the present invention describes first and second nucleic acids encoding the heavy and light chain variable regions, respectively, of an anti-LAG-3 antibody molecule selected from one or more of the antibody molecules described in the present invention, e.g., the antibody of U.S. Patent Table 1 2015/0259420. The nucleic acid may comprise a nucleotide sequence encoding any of the amino acid sequences in the Tables herein, or a sequence substantially identical thereto (e.g., a sequence that is at least about 85%, 90%, 95%, 99%, or more identical to or differing by no more than 3, 6, 15, 30, or 45 nucleotides from the sequences shown in Table 1. For example, this document describes the first and second nucleic acids encoding the variable regions of the heavy and light chains, respectively, of an antibody molecule anti-LAG-3 selected from one or more molecules, for example, any of BAP050-hum01, BAP050-hum02, BAP050-hum03, BAP050-hum04, BAP050-hum05, BAP050-hum06, BAP050-hum07, BAP050-hum08, BAP050 -hum09 BAP050-hum10 BAP050-hum11 BAP050-hum12 BAP050-hum13 BAP050-hum14 BAP050-hum15 BAP050-hum16 BAP050-hum17 BAP050-hum18 BAP050-hum19 BAP050-hum20 (ser ) (ex. Ser, BAP050-hum09-Ser, BAP050-hum10-Ser, BAP050-hum11-Ser, BAP050-hum12-Ser, BAP050-hum13-Ser, BAP050-hum14-Ser, BAP050-hum19-Ser or BAP050-hum20-Ser), BAP050-Clone-F, BAP050-Clone-G, BAP050-Clone-H, BAP050-Clone-I or BAP050-Clone-J as shown in Table 1, or sequence essentially identical to it.

In certain embodiments, the nucleic acid may comprise a nucleotide sequence encoding at least one, two, or three CDRs from a heavy chain variable region having an amino acid sequence as shown in Table 1, or a sequence substantially homologous thereto (e.g., , a sequence that is at least about 85%, 90%, 95%, 99% or more identical to it and/or having one or more substitutions, eg conservative substitutions). In some embodiments, the nucleic acid may comprise a nucleotide sequence encoding at least one, two, or three CDRs from the light chain variable region, having an amino acid sequence as shown in Table 1, or a sequence substantially homologous thereto (e.g., , a sequence that is at least about 85%, 90%, 95%, 99% or more identical to it and/or having one or more substitutions, eg conservative substitutions). In some embodiments, the nucleic acid may comprise a nucleotide sequence encoding at least one, two, three, four, five, or six CDRs from the heavy and light chain variable regions having an amino acid sequence as shown in Table 1, or a sequence substantially homologous to it (eg, sequence at least about 85%, 90%, 95%, 99% or more identical to it and/or having one or more substitutions, for example, conservative substitutions).

In certain embodiments, the nucleic acid may comprise a nucleotide sequence encoding at least one, two, or three CDRs from a heavy chain variable region having a nucleotide sequence as shown in Table 1, a sequence substantially homologous to it (e.g., a sequence at least about 85%, 90%, 95%, 99% or more identical to it and/or capable of hybridizing under the stringency conditions described herein). In some embodiments, the nucleic acid may comprise a nucleotide sequence encoding at least one, two, or three CDRs from a light chain variable region having a nucleotide sequence as shown in Table 1, or a sequence substantially homologous thereto (e.g., , a sequence at least about 85%, 90%, 95%, 99% or more identical to it, and/or capable of hybridizing under the stringency conditions described herein). In certain embodiments, the nucleic acid may comprise a nucleotide sequence encoding at least one, two, three, four, five, or six CDRs from the heavy and light chain variable regions having the nucleotide sequence as shown in Table 1, or the sequence substantially homologous to it (eg, a sequence at least about 85%, 90%, 95%, 99% or more identical to it and/or capable of hybridizing under the stringency conditions described herein). Nucleic acids described in the present invention include deoxyribonucleotides or ribonucleotides, or their analogues. The polynucleotide can be either single stranded or double stranded and, if single stranded, it can be a coding strand or a non-coding (antisense) strand. The polynucleotide may contain modified nucleotides such as methylated nucleotides and nucleotide analogs. The sequence of nucleotides may be interrupted by non-nucleotide components. The polynucleotide may be further modified after polymerization, for example by conjugation with a labeling moiety. The nucleic acid may be a recombinant polynucleotide or a genomic cDNA polynucleotide of semi-synthetic or synthetic origin that is either not naturally occurring or linked to another polynucleotide in an artificial arrangement.

In certain embodiments, the nucleotide sequence that encodes an anti-LAG-3 antibody molecule is codon-optimized.

In some embodiments, nucleic acids are described comprising nucleotide sequences that encode heavy and light chain variable regions and CDRs of anti-LAG-3 antibody molecules as described herein. For example, the present invention describes first and second nucleic acids encoding the heavy and light chain variable regions, respectively, of an anti-LAG-3 antibody molecule according to Table 1, or a sequence substantially identical thereto. For example, the nucleic acid may comprise a nucleotide sequence encoding an anti-LAG-3 antibody molecule according to Table 1, or a sequence substantially identical to that nucleotide sequence (e.g., a sequence that is at least about 85%, 90%, 95%, 99% or more identical to it or differing by no more than 3, 6, 15, 30 or 45 nucleotides from the above nucleotide sequence.

In certain embodiments, the nucleic acid may comprise a nucleotide sequence encoding at least one, two, or three CDRs or hypervariable loops from a heavy chain variable region, having an amino acid sequence as shown in Table 1, or a sequence substantially homologous to her (for example, the sequence is at least about 85%, 90%, 95%, 99% or more identical to it and / or having one, two, three or more substitutions, insertions or deletions, for example, conservative substitutions).

In certain embodiments, the nucleic acid may comprise a nucleotide sequence encoding at least one, two, or three CDRs or hypervariable loops from a light chain variable region having an amino acid sequence as shown in Table 1, or a sequence substantially homologous to her (for example, the sequence is at least about 85%, 90%, 95%, 99% or more identical to it and / or having one, two, three or more substitutions, insertions or deletions, for example, conservative substitutions).

In some embodiments, the nucleic acid may comprise a nucleotide sequence encoding at least one, two, three, four, five, or six CDRs or hypervariable loops from the heavy and light chain variable regions having the amino acid sequence as shown in Table 1 , or a sequence substantially homologous to it (e.g., a sequence at least about 85%, 90%, 95%, 99% or more identical to it, and / or having one, two, three or more substitutions, inserts or deletions, such as conservative substitutions).

In some embodiments, the nucleic acid is isolated or recombinant.

The nucleic acids described herein may be present in a single vector or in separate vectors present in the same host cell or in separate host cells, as described herein in more detail.

Vectors and host cells

The anti-LAG-3 antibody molecules described herein can be produced using host cells and vectors containing the nucleic acids described herein. The nucleic acids may be present in a single vector or in separate vectors present in the same host cell or in separate host cells.

In one embodiment, the vectors contain nucleotides encoding the antibody molecule described herein. In one embodiment, the vectors contain the nucleotide sequences described herein. Vectors include, but are not limited to, a virus, plasmid, cosmid, lambda phage, or yeast artificial chromosome (YAC).

Numerous vector systems can be used. For example, one class of vectors uses DNA elements that are derived from animal viruses such as bovine papilloma virus, polyoma virus, adenovirus, vaccinia virus, baculovirus, retrovirus (Rous sarcoma virus, MMTV or MOMLV), or SV40 virus. . Another class of vectors uses RNA elements derived from RNA viruses such as Semliki forest virus, eastern equine encephalitis, and flaviviruses.

In addition, cells that stably integrate DNA into their chromosomes can be selected by introducing one or more markers that allow selection of transfected host cells. The marker may provide, for example, prototropy relative to an auxotrophic host, resistance to a biocide (eg, antibiotics), or resistance to heavy metals such as copper, or the like. The selectable marker gene can either bind directly to the DNA sequences to be expressed or be introduced into the same cell via co-transformation. Additional elements may also be required for optimal mRNA synthesis. These elements may include splicing signals as well as transcriptional promoters, enhancers and stop codons.

Once prepared for expression, an expression vector or DNA sequence containing the constructs, the expression vectors can be transfected or introduced into an appropriate host cell. Various technologies can be used to achieve this, such as, for example, protoplast fusion, calcium phosphate precipitation, electroporation, retroviral transduction, viral transfection, genetic gun, lipid-based transfection, or other conventional technologies. In the case of protoplast fusion, the cells are grown in the medium and tested for the corresponding activity. Methods and conditions for culturing the resulting transfected cells and recovering the antibody molecules produced are known to those skilled in the art and may vary or be optimized depending on the particular expression vector and mammalian host cell used, based on the present disclosure.

In certain embodiments, the host cell contains a nucleic acid encoding an anti-LAG-3 antibody molecule as described herein. In other embodiments, the host cell is genetically engineered to contain a nucleic acid encoding an anti-LAG-3 antibody molecule.

In one embodiment, the host cell is genetically engineered using an expression cassette. The phrase "expression cassette" refers to nucleotide sequences that can effect gene expression in hosts compatible with such sequences. Such cassettes may contain a promoter, an open reading frame with or without introns, and a stop codon. Can also use additional factors necessary or useful in the implementation of the expression, such as, for example, an inducible promoter. In certain embodiments, the host cell contains the vector described herein.

The cell may be, but is not limited to, a eukaryotic cell, a bacterial cell, an insect cell, or a human cell. Suitable eukaryotic cells include, but are not limited to, Vero cells, HeLa cells, COS cells, CHO cells, HEK293 cells, BHK cells, and MDCKII cells. Suitable insect cells include, but are not limited to, Sf9 cells.

In some embodiments, the host cell is a eukaryotic cell, such as a mammalian cell, an insect cell, a yeast cell, or a prokaryotic cell, such as E. coli . For example, a mammalian cell may be a cultured cell or cell line. Exemplary mammalian cells include lymphocytic cell lines (eg, NSO), Chinese hamster ovary (CHO) cells, COS cells, oocyte cells, and cells from a transgenic animal, eg, mammary epithelial cell.

EXAMPLES

The examples below are provided to assist in understanding the invention, but are not intended to limit its scope in any way and should not be construed as such.

Example 1: Population pharmacokinetics and pharmacodynamics of exemplary anti-LAG-3 antibody and soluble LAG-3

Essence

The objectives of the present study are to predict the relationship between serum anti-LAG-3 antibody concentration and LAG-3 occupancy in serum (soluble LAG-3) and tumor (membrane-bound LAG-3); to evaluate the relationship between dose of anti-LAG-3 antibody and pharmacokinetics (PK) and determine whether PK variation is dose dependent; to estimate the expected spread of stationary minimum levels of anti-LAG-3 depending on the fixed dosing and dosing by body weight of the recipient; and to assess whether the co-administration of the anti-PD-1 antibody affects the exposure of the anti-LAG-3 antibody.

The following methods are used in this study. A two-chamber linear population PK model is used to describe the concentration of anti-LAG-3 antibody. The standard binding model for describing target-mediated drug consumption is used to describe data for soluble LAG-3; use the quasi-equilibrium approximation. Analysis of independent variables is used to evaluate the effect of mass on excretion and both central and peripheral volume. Graphical analysis is used to evaluate the effect of co-administration of anti-PD-1 antibody on the clearance of anti-LAG-3 antibody. A model simulation is performed to identify the relationship between anti-LAG-3 antibody dose and free LAG-3, both for soluble LAG-3 in serum and membrane-bound LAG-3 in the tumor.

From this study, the following results are obtained. The relationship between dose and free LAG-3 in serum and tumor is characterized. The PK of an anti-LAG-3 antibody appears non-linear at doses below 80 mg every 2-4 weeks and linear at doses above 240 mg every 3-4 weeks. The fixed dosing regimen and the dosing regimen by body weight of the recipient are predicted to give a comparable spread in the minimum concentrations at steady state. No obvious effect of co-administration with anti-PD-1 antibody on anti-LAG-3 PK antibody was observed.

The relationship between anti-LAG-3 antibody dose and receptor occupancy, for both serum soluble LAG-3 and intratumoral occupancy of the membrane-bound LAG-3 receptor, at doses of 240 mg and above, is well characterized by the model. At lower doses (eg, 80 mg every 2-4 weeks), non-linearity in the PK of the anti-LAG-3 antibody is observed in some patients. Above 240 mg every 3-4 weeks, the PK of the anti-LAG-3 antibody appears linear. The non-linearity is thought to be related to target-mediated drug uptake, as has been observed for many other monoclonal antibodies. Fixed dosing and dosing by body weight of the recipient, as predicted, give a comparable dispersion of stationary minimum levels of anti-LAG-3 antibody. Co-administration of an anti-PD-1 antibody does not show any apparent effect on the PK of an anti-LAG-3 antibody.

The observations illustrated in this Example can be used to guide dose selection for the anti-LAG-3 antibody molecules described herein.

Data

The present study utilizes data from a dose escalation study in patients with advanced solid tumors where exemplary anti-LAG-3 antibody, LAG525, is given both as monotherapy and in combination with exemplary anti-PD-1 antibody, PDR001. Anti-LAG-3 antibody concentration and soluble LAG-3 concentration are measured at different time points (pre-infusion, hour 1, day 1, 7, 10, 14).

Anti-LAG-3 antibody is quantified by liquid chromatography/mass spectroscopy (LC/MS) with a lower limit of quantitation of 250 ng/mL (1.7 nM). Total soluble LAG-3 is quantified by immunoassay immunosorbent assay (ELISA) in human serum at a lower limit of quantitation of 0.146 ng/mL (1 pM).

One data set is generated and validated at the most critical level. All measurements of anti-LAG-3 antibody and soluble LAG-3 are included in this assay. No data is excluded or classified as outliers.

Methods

This study is carried out using a non-linear mixed effects modeling approach, where the model has two components: a structural model that takes into account systematic trends in the data, and a random effects model that takes into account both the scatter between subjects and the residual scatter around these trends. The explanatory variable model describes how explanatory variables are introduced. The PopPKPD model is fitted simultaneously to both PK and soluble LAG-3 data. The model is then modeled with additional assumptions to obtain predictions regarding the inhibition of membrane-bound LAG-3 in the tumor.

The analysis is carried out using the Monolix software system, version 2016R1 using the MODESIM high performance computing environment. The R technical computing package is used to explore data to aid in model building and to present final results.

Although multiple models are explored in the first analysis of these data, only one structural model is used because this model is found to be adequate for the purposes of the study.

structural model. WITHThe PKPD structural model for anti-LAG-3 concentration, soluble LAG-3, and complex is a standard binding model used to describe target-mediated drug uptake (TMDD) with a quasi-equilibrium approximation (Mager & Krzyzanski.Pharmaceutical Research 22, 1589-1596 (2005)), so that the differential equations describe the drug as a whole, the target as a whole, and the peripheral concentration of the drug, and the algebraic expressions below are used to calculate the concentrations of the free drug, the free target, and their complex.

The Michaelis-Menten version of this model is also used for fitting. In preliminary analysis, this model does not improve the fit and therefore it is no longer explored.

Random effects model. The PK model is parameterized with the following four parameters: excretion, central volume, peripheral volume, and intercameral clearance, and the PD model (for soluble LAG-3) adds the following four parameters: initial sLAG-3, stationary sLAG-3 for a high dose of anti- LAG-3, clearance rate of the antibody-sLAG-3 complex, and dissociation constant. Log-normally distributed random effects add to all eight parameters.

Model of independent variables. Analysis of independent variables is used to evaluate the effect of mass on excretion and central volume. A graphical analysis is used to evaluate the effect of anti-PD-1 antibody on the PK of anti-LAG-3 antibody by comparing the concentration of anti-LAG-3 antibody in patients who are taking identical dosing regimens of anti-LAG-3 antibody and either taking or not take an anti-PD-1 antibody. Formal analysis of independent variables is not performed because patients at the lowest dose of anti-LAG-3 antibody (0.3 mg/kg q2w) have the lowest elimination rate and also always take anti-PD-1 antibody. The lower clearance at the lowest dose is thought to be related to target-mediated drug uptake, but this effect has been observed to interfere with the formal assessment of anti-PD-1 antibody as an independent variable in clearance.

Comparison of a fixed dosing regimen and a dosing regimen scaled by body weight. Anti-LAG-3 antibody troughs at week 24 (approximately 6 months) are modeled for 1000 patients using a 10 mg/kg or 700 mg every 2, 3 or 4 week model. Preliminary model fittings have shown that the final half-life of anti-LAG-3 antibody is approximately 2 weeks, so all patients are expected to be at steady state by week 24; also, week 24 is the minimum for all dosing regimens studied (q2w, q3w, q4w). The median value and 95% predictive interval are displayed on the graph. A typical patient is considered to weigh 80 kg, so an equivalent fixed dose regimen can be calculated (eg, 1 mg/kg corresponds to 80 mg). However, the median weight in the population in this study is close to 70 kg. For this reason, for specific simulations, 10mg/kg is compared to 700mg.

Prediction of LAG-3 inhibition in serum and tumor. Modeling with the PKPD model above is used to estimate LAG-3 occupancy at 6-month lows when PK is at steady state. Two different estimates of LAG-3 occupancy are proposed: (1) the ratio of serum free soluble LAG-3 versus background soluble LAG-3, which is calculated directly from the PKPD model; and (2) occupancy of membrane-bound LAG-3 in the tumor (RO).

The prediction of inhibition of intratumoral LAG-3 is thought to be more relevant to guide dose selection, as this is the site at which tumor-infiltrating lymphocytes interact with the tumor.

The use of this approach to predict target occupancy in a tumor involves a number of assumptions: (1) the estimated serum dissociation constant of anti-LAG-3 antibody and sLAG-3 is the same as that for anti-LAG-3 antibody and membrane-bound LAG-3 in a tumor (2) ABC _ISF =30% in human tumors based on mouse data (Deng et al. MAbs, vol. 8, 593-603 (2016)); (3) the tumor can be considered like homogeneous tissues; (4) membrane-bound LAG-3 does not accumulate in the tumor in the presence of the drug; (5) anti-LAG-3 antibody is in high excess relative to the concentration of membrane-bound LAG-3 in the tumor; and (6) binding between LAG-3 and its endogenous binding partners (eg, MHCII) is not modeled and is not thought to significantly affect downregulation prediction.

In addition to these assumptions, it is necessary to choose the desired level of inhibition for the desired proportion of the patient population. Typically, 60-90% inhibition is required for antagonists, and thus an occupancy of 90-95% is the target for this assay (Grimwood & Hartig. Pharmacology & Therapeutics 122, 281-301 (2009); Tiwari et al. AAPS Journal 1 -10 (2016) Agoram British Journal of Clinical Pharmacology 67, 153-160 (2009)).

For this simulation experiment, the following doses were tested in the q2w, q3w, and q4w regimens for 1000 patients: 10, 20, 30, 50, 70, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000 mg. The 5th, 25th, 50th, 75th, 95th percentiles are then calculated for PK and for the occupancy of soluble LAG-3 in serum and membrane-bound LAG-3 in the tumor.

results

A total of 196 patients are included in this analysis with median follow-up times of 30 and 29.5 days for anti-LAG-3 antibody and soluble LAG-3 assessments, respectively. A summary of the number of patients per dosing regimen sorted by total monthly dose (mean total dose over four weeks) is shown in Table 13 .

Table 13 . Summary of dosing regimens and number of patients

Average total dose of anti-LAG-3 over 4 weeks (mg) Category Anti-LAG-3 mode Anti-PD-1 mode Number of patients Number of patients with PK Number of patients with sLAG-3 2400 high 15 mg/kg q2w No 6 6 6 1600 high 10 mg/kg q2w No 6 6 6 1000 high 1000 mg q4w 400 mg q4w 6 6 1 800 high 10 mg/kg q4w No eleven eleven eleven 800 high 600 mg q3w 300 mg q3w 12 7 6 800 high 800 mg q4w 400 mg q4w 12 7 6 800 high 400 mg q2w No 23 16 16 800 high 5 mg/kg q2w No 6 6 6 600 average 300 mg q2w 400 mg q4w 6 5 5 533 average 400 mg q3w 300 mg q3w 6 5 4 480 average 240 mg q2w 400 mg q4w 6 4 3 480 average 240 mg q2w No 23 15 15 480 average 240 mg q2w 240 mg q2w 6 6 6 480 average 3 mg/kg q2w No 12 eleven eleven 400 average 5 mg/kg q4w No 6 6 6 400 average 400 mg q4w 400 mg q4w 6 3 3 400 average 400 mg q4w No 5 5 5 320 average 240 mg q3w 300 mg q3w 20 12 9 240 average 3 mg/kg q4w No 5 5 5 160 low 1 mg/kg q2w 1 mg/kg q2w 6 6 6 160 low 80 mg q2w 80 mg q2w 6 6 6 160 low 80 mg q2w 240 mg q2w 5 5 5 160 low 80 mg q2w 400 mg q4w eleven eleven 8 160 low 1 mg/kg q2w No 13 13 13 80 low 80 mg q4w 240 mg q4w 7 7 7 48 very low 0.3 mg/kg q2w 1 mg/kg q2w 6 6 6

Anti-LAG-3 antibody and soluble LAG-3 data are obtained. Anti-LAG-3 antibody concentration data for the first 4 weeks are normalized to the first dose in mg. The dose of anti-LAG-3 antibody is stratified into four groups (very low, low, moderate and high) in relation to the estimated total monthly dosage (over 28 days, in mg). For doses scaled by body weight, the total dose in mg is calculated for an 80 kg patient. There is a greater decrease in anti-LAG-3 antibody concentration for some patients for very low and low dose data than for medium and high dose data, showing PK non-linearity at lower doses. Stratification groups are chosen to illustrate this non-linearity.

Receive normalized concentrations of anti-LAG-3 antibody two weeks (all regimens) after the first dose. At lower doses (80 mg and below), there is a decrease in normalized drug concentration in some patients, indicating PK non-linearity. Model-based data analysis can also help to better characterize this non-linearity using all available data.

PKPD Model Fits

The PK parameters used are typical for a monoclonal antibody. When modeling parameters, the end half life and its 5-95% predictive interval are estimated to be 17.0 (7.0, 59.9) days. The estimated dissociation constant of 1.5 nM (Kd) is higher than that measured in the Biacore assay (0.1 nM) but comparable to that measured in the in vitro cellular assay (1.9-2.3 nM). Visual predictive control of anti-LAG-3 antibody concentration normalized to total monthly dose shows a good description of PK data, except for the low and very low dose groups where PK non-linearity is observed. The largest dose of anti-LAG-3 antibody in each panel is simulated. Modeling well describes the curves for sLAG-3, for all doses above 3 mg/kg (or 240 mg) q4w. For these low dose data, PK is overestimated and thus sLAG-3 is also overestimated.

Assuming faster removal at lower doses, the Michaelis-Menten PK model with non-linear removal has been explored previously. However, the fit did not improve significantly. In addition, the additional error is generally estimated to be approximately 20 nM, which is much larger than the minimum concentrations observed at 0.3 mg/kg q2w or 80 mg q4w, even for models with non-linear removal. Thus, only a linear model is used in this Example, provided that the model overestimates trough concentrations at lower doses (eg, 80 mg q2w).

To establish a threshold at which PK non-linearity becomes relevant, population prediction for anti-LAG-3 antibody is examined compared to measurements. Note that below the critical concentration C _crit =60 nM, the prediction for the population predicts the measurement in excess; it is below C _crit when a non-linear PK begins to be observed. Using experience modeling, the proportion of patients expected to be above C _crit at the minimum is estimated in Table 14.

Comparison of predictions for fixed dosing versus mass dosing

Modeling for trough anti-LAG-3 antibody at 6 months for 700 mg and 10 mg/kg dosing is done for both fixed dosing and dosing scaled by body weight. Because the exponent relating weight to elimination is close to 0.5, the predicted scatter in anti-LAG-3 antibody trough levels is comparable for patients on fixed or weight-based dosing, as has been observed for other drugs as well (Bai et al. al Clinical pharmacokinetics 51, 119-135 (2012); Wang et al., The Journal of Clinical Pharmacology 49, 1012-1024 (2009)). Since the PK pattern of the anti-LAG-3 antibody is linear above 240 mg, similar results should be observed for any dose above 240 mg.

Prediction occupancy LAG-3

The simulated concentration of free LAG-3 is compared to background using the PKPD model. Recall that this model does not capture the PK non-linearity observed at lower doses, and thus, at doses below 240 mg, there is likely to be lower LAG-3 inhibition than predicted. Reducing free soluble LAG-3 to 10% requires doses that are more than 10 times higher than to reduce intratumoral membrane-bound LAG-3 to 10%. This is because soluble LAG-3 accumulates approximately 75-fold in serum, while membrane-bound LAG-3 is not expected to accumulate.

The simulation results above are shown in Table 14 , which shows the dose required for 75%, 90%, and 95% of patients to meet the following three criteria at steady state:

1. LAG525 minimum above C _crit

2. Tumor membrane-bound receptor free of LAG-3 below 10% of background

3. Receptor free of soluble LAG-3 in serum below 10% of background

Table 14 . The predicted dose (mg) required for 75%, 90%, and 95% of patients in the hospital to meet the PK or PD criteria specified for the q2w, q3w, and q4w regimens.

Dose for 75% of patients to meet criteria: Criteria q2w q3w q4w LAG525 minimum above Ccrit 100 210 350 Free mLAG-3 in tumor < 10% of background
Serum free sLAG-3 < 10% of background 100
> 2000 200
> 2000 400
> 2000 Dose for 90% of patients to meet the criteria: Criteria q2w q3w q4w LAG525 minimum above Ccrit 170 410 740 Free mLAG-3 in tumor < 10% of background
Serum free sLAG-3 < 10% of background 200
> 2000 400
> 2000 800
> 2000 Doses for 95% of patients to meet the criteria: Criteria q2w q3w q4w LAG525 minimum above Ccrit 270 670 1190 Free mLAG-3 in tumor < 10% of background
Serum free sLAG-3 < 10% of background 400
> 2000 700
> 2000 1400
> 2000

Note that the _doses required for linear PK (minimum anti-LAG-3 antibody > Ccrit ) and the dose required to reduce tumor free mLAG-3 to <10% of background are similar. This result is consistent with the hypothesis that target-mediated drug uptake by tumor-infiltrating lymphocytes is the driving force behind rapid clearance at low doses.

For antagonists, it is typical to target receptor occupancy of 90-95% (or 5-10% of free targets compared to background) over the entire dosing interval, but this rule of thumb does not work for LAG-3 or for inhibitors at the immune checkpoint in general. If it is desired to achieve such receptor occupancy in the majority of patients, it would be important to give a sufficiently large dose so that rapid clearance is not observed at lower concentrations. Visual predictive control of anti-LAG-3 antibody concentration normalized to total monthly dose suggests that doses above 240 mg q4w may be sufficient to eliminate this non-linearity. Table 14 predicts that 400 mg q3w or 800 mg q4w would result in 90% receptor occupancy (10% free LAG-3 versus background) in 90% of patients.

Thus, this study demonstrates that the relationship between dose of exemplary anti-LAG-3 antibody, LAG525, and receptor occupancy, for both serum soluble LAG-3 and intratumoral membrane-bound LAG-3 at doses of 240 mg and above, is well characterized. using the model. At lower doses (eg, 80 mg every 2-4 weeks), non-linearity in the PK of the anti-LAG-3 antibody is observed in some patients. Above 240 mg every 3-4 weeks, the PK of the anti-LAG-3 antibody appears linear. The non-linearity is thought to be related to target-mediated drug uptake, as has been observed for many other monoclonal antibodies. Fixing dosing and dosing by body weight are predicted to give a comparable spread in steady state trough levels of anti-LAG-3 antibody. Co-administration of the anti-PD-1 antibody, PDR001 shows no apparent effect on the PK of the anti-LAG-3 antibody.

Inclusion as links

All publications, patents, and access numbers discussed herein are hereby incorporated by reference in their entirety, as if each individual publication or patent were specifically and individually identified as being incorporated by reference.

Equivalents

While specific embodiments of the subject invention are discussed, the above description is illustrative and not restrictive. Many variations of the present invention will become apparent to those skilled in the art upon review of the present description and the following claims. The full scope of the present invention is to be determined by reference to the claims, together with the full scope of their equivalents, and to the description, together with such variations.

--->

SEQUENCE LIST

<110> NOVARTIS AG

<120> ANTI-LAG-3 DOSING REGIMENS AND THEIR USE

<130> C2160-7019WO

<140>

<141>

<150> 62/534.798

<151> 2017-07-20

<150> 62/643.992

<151> 2018-03-16

<160> 1006

<170>PatentIn version 3.5

<210> 1

<400> 1

000

<210> 2

<400> 2

000

<210> 3

<400> 3

000

<210> 4

<400> 4

000

<210> 5

<400> 5

000

<210> 6

<400> 6

000

<210> 7

<400> 7

000

<210> 8

<400> 8

000

<210> 9

<400> 9

000

<210> 10

<400> 10

000

<210> 11

<400> 11

000

<210> 12

<400> 12

000

<210> 13

<400> 13

000

<210> 14

<400> 14

000

<210> 15

<400> 15

000

<210> 16

<400> 16

000

<210> 17

<400> 17

000

<210> 18

<400> 18

000

<210> 19

<400> 19

000

<210> 20

<400> 20

000

<210> 21

<400> 21

000

<210> 22

<400> 22

000

<210> 23

<400> 23

000

<210> 24

<400> 24

000

<210> 25

<400> 25

000

<210> 26

<400> 26

000

<210> 27

<400> 27

000

<210> 28

<400> 28

000

<210> 29

<400> 29

000

<210> 30

<400> 30

000

<210> 31

<400> 31

000

<210> 32

<400> 32

000

<210> 33

<400> 33

000

<210> 34

<400> 34

000

<210> 35

<400> 35

000

<210> 36

<400> 36

000

<210> 37

<400> 37

000

<210> 38

<400> 38

000

<210> 39

<400> 39

000

<210> 40

<400> 40

000

<210> 41

<400> 41

000

<210> 42

<400> 42

000

<210> 43

<400> 43

000

<210> 44

<400> 44

000

<210> 45

<400> 45

000

<210> 46

<400> 46

000

<210> 47

<400> 47

000

<210> 48

<400> 48

000

<210> 49

<400> 49

000

<210> 50

<400> 50

000

<210> 51

<400> 51

000

<210> 52

<400> 52

000

<210> 53

<400> 53

000

<210> 54

<400> 54

000

<210> 55

<400> 55

000

<210> 56

<400> 56

000

<210> 57

<400> 57

000

<210> 58

<400> 58

000

<210> 59

<400> 59

000

<210> 60

<400> 60

000

<210> 61

<400> 61

000

<210> 62

<400> 62

000

<210> 63

<400> 63

000

<210> 64

<400> 64

000

<210> 65

<400> 65

000

<210> 66

<400> 66

000

<210> 67

<400> 67

000

<210> 68

<400> 68

000

<210> 69

<400> 69

000

<210> 70

<400> 70

000

<210> 71

<400> 71

000

<210> 72

<400> 72

000

<210> 73

<400> 73

000

<210> 74

<400> 74

000

<210> 75

<400> 75

000

<210> 76

<400> 76

000

<210> 77

<400> 77

000

<210> 78

<400> 78

000

<210> 79

<400> 79

000

<210> 80

<400> 80

000

<210> 81

<400> 81

000

<210> 82

<400> 82

000

<210> 83

<400> 83

000

<210> 84

<400> 84

000

<210> 85

<400> 85

000

<210> 86

<400> 86

000

<210> 87

<400> 87

000

<210> 88

<400> 88

000

<210> 89

<400> 89

000

<210> 90

<400> 90

000

<210> 91

<400> 91

000

<210> 92

<400> 92

000

<210> 93

<400> 93

000

<210> 94

<400> 94

000

<210> 95

<400> 95

000

<210> 96

<400> 96

000

<210> 97

<400> 97

000

<210> 98

<400> 98

000

<210> 99

<400> 99

000

<210> 100

<400> 100

000

<210> 101

<400> 101

000

<210> 102

<400> 102

000

<210> 103

<400> 103

000

<210> 104

<400> 104

000

<210> 105

<400> 105

000

<210> 106

<400> 106

000

<210> 107

<400> 107

000

<210> 108

<400> 108

000

<210> 109

<400> 109

000

<210> 110

<400> 110

000

<210> 111

<400> 111

000

<210> 112

<400> 112

000

<210> 113

<400> 113

000

<210> 114

<400> 114

000

<210> 115

<400> 115

000

<210> 116

<400> 116

000

<210> 117

<400> 117

000

<210> 118

<400> 118

000

<210> 119

<400> 119

000

<210> 120

<400> 120

000

<210> 121

<400> 121

000

<210> 122

<400> 122

000

<210> 123

<400> 123

000

<210> 124

<400> 124

000

<210> 125

<400> 125

000

<210> 126

<400> 126

000

<210> 127

<400> 127

000

<210> 128

<400> 128

000

<210> 129

<400> 129

000

<210> 130

<400> 130

000

<210> 131

<400> 131

000

<210> 132

<400> 132

000

<210> 133

<400> 133

000

<210> 134

<400> 134

000

<210> 135

<400> 135

000

<210> 136

<400> 136

000

<210> 137

<400> 137

000

<210> 138

<400> 138

000

<210> 139

<400> 139

000

<210> 140

<400> 140

000

<210> 141

<400> 141

000

<210> 142

<400> 142

000

<210> 143

<400> 143

000

<210> 144

<400> 144

000

<210> 145

<400> 145

000

<210> 146

<400> 146

000

<210> 147

<400> 147

000

<210> 148

<400> 148

000

<210> 149

<400> 149

000

<210> 150

<400> 150

000

<210> 151

<400> 151

000

<210> 152

<400> 152

000

<210> 153

<400> 153

000

<210> 154

<400> 154

000

<210> 155

<400> 155

000

<210> 156

<400> 156

000

<210> 157

<400> 157

000

<210> 158

<400> 158

000

<210> 159

<400> 159

000

<210> 160

<400> 160

000

<210> 161

<400> 161

000

<210> 162

<400> 162

000

<210> 163

<400> 163

000

<210> 164

<400> 164

000

<210> 165

<400> 165

000

<210> 166

<400> 166

000

<210> 167

<400> 167

000

<210> 168

<400> 168

000

<210> 169

<400> 169

000

<210> 170

<400> 170

000

<210> 171

<400> 171

000

<210> 172

<400> 172

000

<210> 173

<400> 173

000

<210> 174

<400> 174

000

<210> 175

<400> 175

000

<210> 176

<400> 176

000

<210> 177

<400> 177

000

<210> 178

<400> 178

000

<210> 179

<400> 179

000

<210> 180

<400> 180

000

<210> 181

<400> 181

000

<210> 182

<400> 182

000

<210> 183

<400> 183

000

<210> 184

<400> 184

000

<210> 185

<400> 185

000

<210> 186

<400> 186

000

<210> 187

<400> 187

000

<210> 188

<400> 188

000

<210> 189

<400> 189

000

<210> 190

<400> 190

000

<210> 191

<400> 191

000

<210> 192

<400> 192

000

<210> 193

<400> 193

000

<210> 194

<400> 194

000

<210> 195

<400> 195

000

<210> 196

<400> 196

000

<210> 197

<400> 197

000

<210> 198

<400> 198

000

<210> 199

<400> 199

000

<210> 200

<400> 200

000

<210> 201

<400> 201

000

<210> 202

<400> 202

000

<210> 203

<400> 203

000

<210> 204

<400> 204

000

<210> 205

<400> 205

000

<210> 206

<400> 206

000

<210> 207

<400> 207

000

<210> 208

<400> 208

000

<210> 209

<400> 209

000

<210> 210

<400> 210

000

<210> 211

<400> 211

000

<210> 212

<400> 212

000

<210> 213

<400> 213

000

<210> 214

<400> 214

000

<210> 215

<400> 215

000

<210> 216

<400> 216

000

<210> 217

<400> 217

000

<210> 218

<400> 218

000

<210> 219

<400> 219

000

<210> 220

<400> 220

000

<210> 221

<400> 221

000

<210> 222

<400> 222

000

<210> 223

<400> 223

000

<210> 224

<400> 224

000

<210> 225

<400> 225

000

<210> 226

<400> 226

000

<210> 227

<400> 227

000

<210> 228

<400> 228

000

<210> 229

<400> 229

000

<210> 230

<400> 230

000

<210> 231

<400> 231

000

<210> 232

<400> 232

000

<210> 233

<400> 233

000

<210> 234

<400> 234

000

<210> 235

<400> 235

000

<210> 236

<400> 236

000

<210> 237

<400> 237

000

<210> 238

<400> 238

000

<210> 239

<400> 239

000

<210> 240

<400> 240

000

<210> 241

<400> 241

000

<210> 242

<400> 242

000

<210> 243

<400> 243

000

<210> 244

<400> 244

000

<210> 245

<400> 245

000

<210> 246

<400> 246

000

<210> 247

<400> 247

000

<210> 248

<400> 248

000

<210> 249

<400> 249

000

<210> 250

<400> 250

000

<210> 251

<400> 251

000

<210> 252

<400> 252

000

<210> 253

<400> 253

000

<210> 254

<400> 254

000

<210> 255

<400> 255

000

<210> 256

<400> 256

000

<210> 257

<400> 257

000

<210> 258

<400> 258

000

<210> 259

<400> 259

000

<210> 260

<400> 260

000

<210> 261

<400> 261

000

<210> 262

<400> 262

000

<210> 263

<400> 263

000

<210> 264

<400> 264

000

<210> 265

<400> 265

000

<210> 266

<400> 266

000

<210> 267

<400> 267

000

<210> 268

<400> 268

000

<210> 269

<400> 269

000

<210> 270

<400> 270

000

<210> 271

<400> 271

000

<210> 272

<400> 272

000

<210> 273

<400> 273

000

<210> 274

<400> 274

000

<210> 275

<400> 275

000

<210> 276

<400> 276

000

<210> 277

<400> 277

000

<210> 278

<400> 278

000

<210> 279

<400> 279

000

<210> 280

<400> 280

000

<210> 281

<400> 281

000

<210> 282

<400> 282

000

<210> 283

<400> 283

000

<210> 284

<400> 284

000

<210> 285

<400> 285

000

<210> 286

<400> 286

000

<210> 287

<400> 287

000

<210> 288

<400> 288

000

<210> 289

<400> 289

000

<210> 290

<400> 290

000

<210> 291

<400> 291

000

<210> 292

<400> 292

000

<210> 293

<400> 293

000

<210> 294

<400> 294

000

<210> 295

<400> 295

000

<210> 296

<400> 296

000

<210> 297

<400> 297

000

<210> 298

<400> 298

000

<210> 299

<400> 299

000

<210> 300

<400> 300

000

<210> 301

<400> 301

000

<210> 302

<400> 302

000

<210> 303

<400> 303

000

<210> 304

<400> 304

000

<210> 305

<400> 305

000

<210> 306

<400> 306

000

<210> 307

<400> 307

000

<210> 308

<400> 308

000

<210> 309

<400> 309

000

<210> 310

<400> 310

000

<210> 311

<400> 311

000

<210> 312

<400> 312

000

<210> 313

<400> 313

000

<210> 314

<400> 314

000

<210> 315

<400> 315

000

<210> 316

<400> 316

000

<210> 317

<400> 317

000

<210> 318

<400> 318

000

<210> 319

<400> 319

000

<210> 320

<400> 320

000

<210> 321

<400> 321

000

<210> 322

<400> 322

000

<210> 323

<400> 323

000

<210> 324

<400> 324

000

<210> 325

<400> 325

000

<210> 326

<400> 326

000

<210> 327

<400> 327

000

<210> 328

<400> 328

000

<210> 329

<400> 329

000

<210> 330

<400> 330

000

<210> 331

<400> 331

000

<210> 332

<400> 332

000

<210> 333

<400> 333

000

<210> 334

<400> 334

000

<210> 335

<400> 335

000

<210> 336

<400> 336

000

<210> 337

<400> 337

000

<210> 338

<400> 338

000

<210> 339

<400> 339

000

<210> 340

<400> 340

000

<210> 341

<400> 341

000

<210> 342

<400> 342

000

<210> 343

<400> 343

000

<210> 344

<400> 344

000

<210> 345

<400> 345

000

<210> 346

<400> 346

000

<210> 347

<400> 347

000

<210> 348

<400> 348

000

<210> 349

<400> 349

000

<210> 350

<400> 350

000

<210> 351

<400> 351

000

<210> 352

<400> 352

000

<210> 353

<400> 353

000

<210> 354

<400> 354

000

<210> 355

<400> 355

000

<210> 356

<400> 356

000

<210> 357

<400> 357

000

<210> 358

<400> 358

000

<210> 359

<400> 359

000

<210> 360

<400> 360

000

<210> 361

<400> 361

000

<210> 362

<400> 362

000

<210> 363

<400> 363

000

<210> 364

<400> 364

000

<210> 365

<400> 365

000

<210> 366

<400> 366

000

<210> 367

<400> 367

000

<210> 368

<400> 368

000

<210> 369

<400> 369

000

<210> 370

<400> 370

000

<210> 371

<400> 371

000

<210> 372

<400> 372

000

<210> 373

<400> 373

000

<210> 374

<400> 374

000

<210> 375

<400> 375

000

<210> 376

<400> 376

000

<210> 377

<400> 377

000

<210> 378

<400> 378

000

<210> 379

<400> 379

000

<210> 380

<400> 380

000

<210> 381

<400> 381

000

<210> 382

<400> 382

000

<210> 383

<400> 383

000

<210> 384

<400> 384

000

<210> 385

<400> 385

000

<210> 386

<400> 386

000

<210> 387

<400> 387

000

<210> 388

<400> 388

000

<210> 389

<400> 389

000

<210> 390

<400> 390

000

<210> 391

<400> 391

000

<210> 392

<400> 392

000

<210> 393

<400> 393

000

<210> 394

<400> 394

000

<210> 395

<400> 395

000

<210> 396

<400> 396

000

<210> 397

<400> 397

000

<210> 398

<400> 398

000

<210> 399

<400> 399

000

<210> 400

<400> 400

000

<210> 401

<400> 401

000

<210> 402

<400> 402

000

<210> 403

<400> 403

000

<210> 404

<400> 404

000

<210> 405

<400> 405

000

<210> 406

<400> 406

000

<210> 407

<400> 407

000

<210> 408

<400> 408

000

<210> 409

<400> 409

000

<210> 410

<400> 410

000

<210> 411

<400> 411

000

<210> 412

<400> 412

000

<210> 413

<400> 413

000

<210> 414

<400> 414

000

<210> 415

<400> 415

000

<210> 416

<400> 416

000

<210> 417

<400> 417

000

<210> 418

<400> 418

000

<210> 419

<400> 419

000

<210> 420

<400> 420

000

<210> 421

<400> 421

000

<210> 422

<400> 422

000

<210> 423

<400> 423

000

<210> 424

<400> 424

000

<210> 425

<400> 425

000

<210> 426

<400> 426

000

<210> 427

<400> 427

000

<210> 428

<400> 428

000

<210> 429

<400> 429

000

<210> 430

<400> 430

000

<210> 431

<400> 431

000

<210> 432

<400> 432

000

<210> 433

<400> 433

000

<210> 434

<400> 434

000

<210> 435

<400> 435

000

<210> 436

<400> 436

000

<210> 437

<400> 437

000

<210> 438

<400> 438

000

<210> 439

<400> 439

000

<210> 440

<400> 440

000

<210> 441

<400> 441

000

<210> 442

<400> 442

000

<210> 443

<400> 443

000

<210> 444

<400> 444

000

<210> 445

<400> 445

000

<210> 446

<400> 446

000

<210> 447

<400> 447

000

<210> 448

<400> 448

000

<210> 449

<400> 449

000

<210> 450

<400> 450

000

<210> 451

<400> 451

000

<210> 452

<400> 452

000

<210> 453

<400> 453

000

<210> 454

<400> 454

000

<210> 455

<400> 455

000

<210> 456

<400> 456

000

<210> 457

<400> 457

000

<210> 458

<400> 458

000

<210> 459

<400> 459

000

<210> 460

<400> 460

000

<210> 461

<400> 461

000

<210> 462

<400> 462

000

<210> 463

<400> 463

000

<210> 464

<400> 464

000

<210> 465

<400> 465

000

<210> 466

<400> 466

000

<210> 467

<400> 467

000

<210> 468

<400> 468

000

<210> 469

<400> 469

000

<210> 470

<400> 470

000

<210> 471

<400> 471

000

<210> 472

<400> 472

000

<210> 473

<400> 473

000

<210> 474

<400> 474

000

<210> 475

<400> 475

000

<210> 476

<400> 476

000

<210> 477

<400> 477

000

<210> 478

<400> 478

000

<210> 479

<400> 479

000

<210> 480

<400> 480

000

<210> 481

<400> 481

000

<210> 482

<400> 482

000

<210> 483

<400> 483

000

<210> 484

<400> 484

000

<210> 485

<400> 485

000

<210> 486

<400> 486

000

<210> 487

<400> 487

000

<210> 488

<400> 488

000

<210> 489

<400> 489

000

<210> 490

<400> 490

000

<210> 491

<400> 491

000

<210> 492

<400> 492

000

<210> 493

<400> 493

000

<210> 494

<400> 494

000

<210> 495

<400> 495

000

<210> 496

<400> 496

000

<210> 497

<400> 497

000

<210> 498

<400> 498

000

<210> 499

<400> 499

000

<210> 500

<400> 500

000

<210> 501

<211> 5

<212> Protein

<213> Artificial sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 501

Thr Tyr Trp Met His

15

<210> 502

<211> 17

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 502

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

1 5 10 15

Asn

<210> 503

<211> 8

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 503

Trp Thr Thr Gly Thr Gly Ala Tyr

15

<210> 504

<211> 7

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 504

Gly Tyr Thr Phe Thr Thr Tyr

15

<210> 505

<211> 6

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 505

Tyr Pro Gly Thr Gly Gly

15

<210> 506

<211> 117

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 506

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

1 5 10 15

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

20 25 30

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

35 40 45

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

50 55 60

Lys Asn Arg Val Thr Ile Thr Ala Asp Lys 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

Thr Arg Trp Thr Thr Gly Thr Gly Ala Tyr Trp Gly Gln Gly Thr Thr

100 105 110

Val Thr Val Ser Ser

115

<210> 507

<211> 351

<212> DNA

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 507

gaggtgcagc tggtgcagtc aggcgccgaa gtgaagaagc ccggcgagtc actgagaatt

60

agctgtaaag gttcaggcta caccttcact acctactgga tgcactgggt ccgccaggct

120

accggtcaag gcctcgagtg gatgggtaat atctaccccg gcaccggcgg ctctaacttc

180

gacgagaagt ttaagaatag agtgactatc accgccgata agtctactag caccgcctat

240

atggaactgt ctagcctgag atcagaggac accgccgtct actactgcac taggtggact

300

accggcacag gcgcctactg gggtcaaggc actaccgtga ccgtgtctag c

351

<210> 508

<211> 443

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 508

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

1 5 10 15

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

20 25 30

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

35 40 45

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

50 55 60

Lys Asn Arg Val Thr Ile Thr Ala Asp Lys 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

Thr Arg Trp Thr Thr Gly Thr Gly Ala Tyr Trp Gly Gln Gly Thr Thr

100 105 110

Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu

115 120 125

Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys

130 135 140

Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser

145 150 155 160

Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser

165 170 175

Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser

180 185 190

Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn

195 200 205

Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro

210 215 220

Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe

225 230 235 240

Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val

245 250 255

Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe

260 265 270

Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro

275 280 285

Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr

290 295 300

Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val

305 310 315 320

Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala

325 330 335

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

340 345 350

Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly

355 360 365

Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro

370 375 380

Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser

385 390 395 400

Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu

405 410 415

Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His

420 425 430

Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly

435 440

<210> 509

<211> 1329

<212> DNA

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 509

gaggtgcagc tggtgcagtc aggcgccgaa gtgaagaagc ccggcgagtc actgagaatt 60

agctgtaaag gttcaggcta caccttcact acctactgga tgcactgggt ccgccaggct 120

accggtcaag gcctcgagtg gatgggtaat atctaccccg gcaccggcgg ctctaacttc 180

240 gacgagaagt ttaagaatag agtgactatc accgccgata

atggaactgt ctagcctgag atcagaggac accgccgtct actactgcac taggtggact 300

accggcacag gcgcctactg gggtcaaggc actaccgtga ccgtgtctag cgctagcact 360

aagggcccgt ccgtgttccc cctggcacct tgtagccgga gcactagcga atccaccgct 420

gccctcggct gcctggtcaa ggattacttc ccggagcccg tgaccgtgtc ctggaacagc 480

ggagccctga cctccggagt gcacaccttc cccgctgtgc tgcagagctc cgggctgtac 540

tcgctgtcgt cggtggtcac ggtgccttca tctagcctgg gtaccaagac ctacacttgc 600

aacgtggacc acaagccttc caacactaag gtggacaagc gcgtcgaatc gaagtacggc 660

ccaccgtgcc cgccttgtcc cgcgccggag ttcctcggcg gtccctcggt ctttctgttc 720

ccaccgaagc ccaaggacac tttgatgatt tcccgcaccc ctgaagtgac atgcgtggtc 780

gtggacgtgt cacaggaaga tccggaggtg cagttcaatt ggtacgtgga tggcgtcgag

gtgcacaacg ccaaaaccaa gccgagggag gagcagttca actccactta ccgcgtcgtg 900

tccgtgctga cggtgctgca tcaggactgg ctgaacggga aggagtacaa gtgcaaagtg 960

tccaacaagg gacttcctag ctcaatcgaa aagaccatct cgaaagccaa gggacagccc

1020

cgggaacccc aagtgtatac cctgccaccg agcggaag aaatgactaa gaaccaagtc

1080

tcattgactt gccttgtgaa gggcttctac ccatcggata tcgccgtgga atgggagtcc

1140

aacggccagc cggaaaacaa ctacaagacc acccctccgg tgctggactc agacggatcc

1200

ttcttcctct actcgcggct gaccgtggat aagagcagat ggcaggaggg aaatgtgttc

1260

agctgttctg tgatgcatga agccctgcac aaccactaca ctcagaagtc cctgtccctc

1320

tccctggga

1329

<210> 510

<211> 17

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 510

Lys Ser Ser Gln Ser Leu Leu Asp Ser Gly Asn Gln Lys Asn Phe Leu

1 5 10 15

Thr

<210> 511

<211> 7

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 511

Trp Ala Ser Thr Arg Glu Ser

15

<210> 512

<211> 9

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 512

Gln Asn Asp Tyr Ser Tyr Pro Tyr Thr

15

<210> 513

<211> 13

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 513

Ser Gln Ser Leu Leu Asp Ser Gly Asn Gln Lys Asn Phe

1 5 10

<210> 514

<211> 3

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 514

Trp Ala Ser

1

<210> 515

<211> 6

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 515

Asp Tyr Ser Tyr Pro Tyr

15

<210> 516

<211> 113

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 516

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 Lys Ser Ser Gln Ser Leu Leu Asp Ser

20 25 30

Gly Asn Gln Lys Asn Phe Leu Thr Trp Tyr Gln Gln Lys Pro Gly Lys

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

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

100 105 110

Lys

<210> 517

<211> 339

<212> DNA

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 517

gagatcgtcc tgactcagtc acccgctacc ctgagcctga gccctggcga gcgggctaca 60

ctgagctgta aatctagtca gtcactgctg gatagcggta atcagaagaa cttcctgacc 120

tggtatcagc agaagcccgg taaagcccct aagctgctga tctactgggc ctctactaga 180

gaatcaggcg tgccctctag gtttagcggt agcggtagtg gcaccgactt caccttcact 240

atctctagcc tgcagcccga ggatatcgct acctactact gtcagaacga ctatagctac 300

ccctacacct tcggtcaagg cactaaggtc gagattaag 339

<210> 518

<211> 220

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 518

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 Lys Ser Ser Gln Ser Leu Leu Asp Ser

20 25 30

Gly Asn Gln Lys Asn Phe Leu Thr Trp Tyr Gln Gln Lys Pro Gly Lys

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

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

100 105 110

Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp

115 120 125

Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn

130 135 140

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

145 150 155 160

Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp

165 170 175

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

180 185 190

Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser

195 200 205

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

210 215 220

<210> 519

<211> 660

<212> DNA

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 519

gagatcgtcc tgactcagtc acccgctacc ctgagcctga gccctggcga gcgggctaca 60

ctgagctgta aatctagtca gtcactgctg gatagcggta atcagaagaa cttcctgacc 120

tggtatcagc agaagcccgg taaagcccct aagctgctga tctactgggc ctctactaga 180

gaatcaggcg tgccctctag gtttagcggt agcggtagtg gcaccgactt caccttcact 240

atctctagcc tgcagcccga ggatatcgct acctactact gtcagaacga ctatagctac 300

ccctacacct tcggtcaagg cactaaggtc gagattaagc gtacggtggc cgctcccagc 360

gtgttcatct tcccccccag cgacgagcag ctgaagagcg gcaccgccag cgtggtgtgc 420

ctgctgaaca acttctaccc ccgggaggcc aaggtgcagt ggaaggtgga caacgccctg 480

cagagcggca acagccagga gagcgtcacc gagcaggaca gcaaggactc cacctacagc 540

ctgagcagca ccctgaccct gagcaaggcc gactacgaga agcataaggt gtacgcctgc 600

gaggtgaccc accagggcct gtccagcccc gtgaccaaga gcttcaacag gggcgagtgc 660

<210> 520

<211> 113

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 520

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 Lys Ser Ser Gln Ser Leu Leu Asp Ser

20 25 30

Gly Asn Gln Lys Asn Phe Leu Thr Trp Tyr Gln Gln Lys Pro Gly Gln

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

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

100 105 110

Lys

<210> 521

<211> 339

<212> DNA

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 521

gagatcgtcc tgactcagtc acccgctacc ctgagcctga gccctggcga gcgggctaca 60

ctgagctgta aatctagtca gtcactgctg gatagcggta atcagaagaa cttcctgacc 120

tggtatcagc agaagcccgg tcaagcccct agactgctga tctactgggc ctctactaga 180

gaatcaggcg tgccctctag gtttagcggt agcggtagtg gcaccgactt caccttcact 240

atctctagcc tggaagccga ggacgccgct acctactact gtcagaacga ctatagctac 300

ccctacacct tcggtcaagg cactaaggtc gagattaag 339

<210> 522

<211> 220

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 522

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 Lys Ser Ser Gln Ser Leu Leu Asp Ser

20 25 30

Gly Asn Gln Lys Asn Phe Leu Thr Trp Tyr Gln Gln Lys Pro Gly Gln

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

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

100 105 110

Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp

115 120 125

Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn

130 135 140

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

145 150 155 160

Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp

165 170 175

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

180 185 190

Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser

195 200 205

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

210 215 220

<210> 523

<211> 660

<212> DNA

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 523

gagatcgtcc tgactcagtc acccgctacc ctgagcctga gccctggcga gcgggctaca 60

ctgagctgta aatctagtca gtcactgctg gatagcggta atcagaagaa cttcctgacc 120

tggtatcagc agaagcccgg tcaagcccct agactgctga tctactgggc ctctactaga 180

gaatcaggcg tgccctctag gtttagcggt agcggtagtg gcaccgactt caccttcact 240

atctctagcc tggaagccga ggacgccgct acctactact gtcagaacga ctatagctac 300

ccctacacct tcggtcaagg cactaaggtc gagattaagc gtacggtggc cgctcccagc 360

gtgttcatct tcccccccag cgacgagcag ctgaagagcg gcaccgccag cgtggtgtgc 420

ctgctgaaca acttctaccc ccgggaggcc aaggtgcagt ggaaggtgga caacgccctg 480

cagagcggca acagccagga gagcgtcacc gagcaggaca gcaaggactc cacctacagc 540

ctgagcagca ccctgaccct gagcaaggcc gactacgaga agcataaggt gtacgcctgc 600

gaggtgaccc accagggcct gtccagcccc gtgaccaaga gcttcaacag gggcgagtgc 660

<210> 524

<211> 15

<212> DNA

<213> Faux Sequence

<220>

<221> source

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

Synthetic oligonucleotide"

<400> 524

acctactgga tgcac 15

<210> 525

<211> 51

<212> DNA

<213> Faux Sequence

<220>

<221> source

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

Synthetic oligonucleotide"

<400> 525

aatatctacc ccggcaccgg cggctctaac ttcgacgaga agtttaagaa t 51

<210> 526

<211> 24

<212> DNA

<213> Faux Sequence

<220>

<221> source

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

Synthetic oligonucleotide"

<400> 526

tggactaccg gcacaggcgc ctac 24

<210> 527

<211> 21

<212> DNA

<213> Faux Sequence

<220>

<221> source

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

Synthetic oligonucleotide"

<400> 527

ggctacacct tcactaccta c 21

<210> 528

<211> 18

<212> DNA

<213> Faux Sequence

<220>

<221> source

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

Synthetic oligonucleotide"

<400> 528

taccccggca ccggcggc 18

<210> 529

<211> 51

<212> DNA

<213> Faux Sequence

<220>

<221> source

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

Synthetic oligonucleotide"

<400> 529

aaatctagtc agtcactgct ggatagcggt aatcagaaga acttcctgac c 51

<210> 530

<211> 21

<212> DNA

<213> Faux Sequence

<220>

<221> source

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

Synthetic oligonucleotide"

<400> 530

tgggcctcta ctagagaatc a 21

<210> 531

<211> 27

<212> DNA

<213> Faux Sequence

<220>

<221> source

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

Synthetic oligonucleotide"

<400> 531

cagaacgact atagctaccc ctacacc 27

<210> 532

<211> 39

<212> DNA

<213> Faux Sequence

<220>

<221> source

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

Synthetic oligonucleotide"

<400> 532

agtcagtcac tgctggatag cggtaatcag aagaacttc 39

<210> 533

<211> 9

<212> DNA

<213> Faux Sequence

<220>

<221> source

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

Synthetic oligonucleotide"

<400> 533

tgggcctct

9

<210> 534

<211> 18

<212> DNA

<213> Faux Sequence

<220>

<221> source

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

Synthetic oligonucleotide"

<400> 534

gactatagct acccctac 18

<210> 535

<211> 440

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 535

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

1 5 10 15

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

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 Lys Arg 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 Thr Asn Asp Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser

100 105 110

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

115 120 125

Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp

130 135 140

Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr

145 150 155 160

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

165 170 175

Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys

180 185 190

Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp

195 200 205

Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala

210 215 220

Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro

225 230 235 240

Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val

245 250 255

Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val

260 265 270

Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln

275 280 285

Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln

290 295 300

Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly

305 310 315 320

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

325 330 335

Arg Glu Pro Gln Val Tyr Thr Leu Pro Ser Gln Glu Glu Met Thr

340 345 350

Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser

355 360 365

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

370 375 380

Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr

385 390 395 400

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

405 410 415

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

420 425 430

Ser Leu Ser Leu Ser Leu Gly Lys

435 440

<210> 536

<211> 214

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 536

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 Ser Ser Asn Trp Pro Arg

85 90 95

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

100 105 110

Pro Ser Val Phe Ile Phe Pro Ser Asp Glu Gln Leu Lys Ser Gly

115 120 125

Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala

130 135 140

Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln

145 150 155 160

Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser

165 170 175

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

180 185 190

Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser

195 200 205

Phe Asn Arg Gly Glu Cys

210

<210> 537

<211> 447

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 537

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

35 40 45

Gly Gly Ile Asn Pro Ser Asn Gly Gly Thr Asn Phe Asn Glu Lys Phe

50 55 60

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

65 70 75 80

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

85 90 95

Ala Arg Arg Asp Tyr Arg Phe Asp Met Gly Phe Asp Tyr Trp Gly Gln

100 105 110

Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val

115 120 125

Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala

130 135 140

Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser

145 150 155 160

Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val

165 170 175

Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro

180 185 190

Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys

195 200 205

Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro

210 215 220

Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val

225 230 235 240

Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr

245 250 255

Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu

260 265 270

Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys

275 280 285

Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser

290 295 300

Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys

305 310 315 320

Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile

325 330 335

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

340 345 350

Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu

355 360 365

Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn

370 375 380

Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser

385 390 395 400

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

405 410 415

Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu

420 425 430

His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys

435 440 445

<210> 538

<211> 218

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 538

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 Lys Gly Val Ser Thr Ser

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

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

100 105 110

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

115 120 125

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

130 135 140

Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser

145 150 155 160

Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr

165 170 175

Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys

180 185 190

His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro

195 200 205

Val Thr Lys Ser Phe Asn Arg Gly Glu Cys

210 215

<210> 539

<211> 447

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 539

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

1 5 10 15

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

20 25 30

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

35 40 45

Gly Trp Ile Asn Thr Asp Ser Gly Glu Ser Thr Tyr Ala Glu Glu Phe

50 55 60

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

65 70 75 80

Leu Gln Ile Thr Ser Leu Thr Ala Glu Asp Thr Gly Met Tyr Phe Cys

85 90 95

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

100 105 110

Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu

115 120 125

Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys

130 135 140

Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser

145 150 155 160

Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser

165 170 175

Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser

180 185 190

Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn

195 200 205

Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His

210 215 220

Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val

225 230 235 240

Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr

245 250 255

Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu

260 265 270

Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys

275 280 285

Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser

290 295 300

Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys

305 310 315 320

Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile

325 330 335

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

340 345 350

Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu

355 360 365

Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn

370 375 380

Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser

385 390 395 400

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

405 410 415

Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu

420 425 430

His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

435 440 445

<210> 540

<211> 213

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 540

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

1 5 10 15

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

20 25 30

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

35 40 45

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

50 55 60

Gly Ser Gly Thr Ser Tyr Cys Leu Thr Ile Asn Ser Leu Gln Pro Glu

65 70 75 80

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

85 90 95

Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala Pro

100 105 110

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

115 120 125

Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys

130 135 140

Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu

145 150 155 160

Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser

165 170 175

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

180 185 190

Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe

195 200 205

Asn Arg Gly Glu Cys

210

<210> 541

<211> 10

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 541

Gly Tyr Thr Phe Thr Thr Tyr Trp Met His

1 5 10

<210> 542

<400> 542

000

<210> 543

<400> 543

000

<210> 544

<400> 544

000

<210> 545

<400> 545

000

<210> 546

<400> 546

000

<210> 547

<400> 547

000

<210> 548

<400> 548

000

<210> 549

<400> 549

000

<210> 550

<400> 550

000

<210> 551

<400> 551

000

<210> 552

<400> 552

000

<210> 553

<400> 553

000

<210> 554

<400> 554

000

<210> 555

<400> 555

000

<210> 556

<400> 556

000

<210> 557

<400> 557

000

<210> 558

<400> 558

000

<210> 559

<400> 559

000

<210> 560

<400> 560

000

<210> 561

<400> 561

000

<210> 562

<400> 562

000

<210> 563

<400> 563

000

<210> 564

<400> 564

000

<210> 565

<400> 565

000

<210> 566

<400> 566

000

<210> 567

<400> 567

000

<210> 568

<400> 568

000

<210> 569

<400> 569

000

<210> 570

<400> 570

000

<210> 571

<400> 571

000

<210> 572

<400> 572

000

<210> 573

<400> 573

000

<210> 574

<400> 574

000

<210> 575

<400> 575

000

<210> 576

<400> 576

000

<210> 577

<400> 577

000

<210> 578

<400> 578

000

<210> 579

<400> 579

000

<210> 580

<400> 580

000

<210> 581

<400> 581

000

<210> 582

<400> 582

000

<210> 583

<400> 583

000

<210> 584

<400> 584

000

<210> 585

<400> 585

000

<210> 586

<400> 586

000

<210> 587

<400> 587

000

<210> 588

<400> 588

000

<210> 589

<400> 589

000

<210> 590

<400> 590

000

<210> 591

<400> 591

000

<210> 592

<400> 592

000

<210> 593

<400> 593

000

<210> 594

<400> 594

000

<210> 595

<400> 595

000

<210> 596

<400> 596

000

<210> 597

<400> 597

000

<210> 598

<400> 598

000

<210> 599

<400> 599

000

<210> 600

<400> 600

000

<210> 601

<211> 5

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 601

Ser Tyr Trp Met Tyr

15

<210> 602

<211> 17

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 602

Arg Ile Asp Pro Asn Ser Gly Ser Thr Lys Tyr Asn Glu Lys Phe Lys

1 5 10 15

Asn

<210> 603

<211> 11

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 603

Asp Tyr Arg Lys Gly Leu Tyr Ala Met Asp Tyr

1 5 10

<210> 604

<211> 7

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 604

Gly Tyr Thr Phe Thr Ser Tyr

15

<210> 605

<211> 6

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 605

Asp Pro Asn Ser Gly Ser

15

<210> 606

<211> 120

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 606

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

1 5 10 15

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

20 25 30

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

35 40 45

Gly Arg Ile Asp Pro Asn Ser Gly Ser Thr Lys Tyr Asn Glu Lys Phe

50 55 60

Lys Asn 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 Asp Tyr Arg Lys Gly Leu Tyr Ala Met Asp Tyr Trp Gly Gln

100 105 110

Gly Thr Thr Val Thr Val Ser Ser

115 120

<210> 607

<211> 360

<212> DNA

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 607

gaagtgcagc tggtgcagtc aggcgccgaa gtgaagaaac ccggcgctac cgtgaagatt 60

agctgtaaag tctcaggcta caccttcact agctactgga tgtactggggt ccgacaggct 120

aggggcaaa gactggagtg gatcggtaga atcgacccta atagcggctc tactaagtat 180

aacgagaagt ttaagaatag gttcactatt agtagggata actctaagaa caccctgtac 240

ctgcagatga atagcctgag agccgaggac accgccgtct actactgcgc tagagactat 300

agaaagggcc tgtacgctat ggactactgg ggtcaaggca ctaccgtgac cgtgtcttca 360

<210> 608

<211> 446

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 608

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

1 5 10 15

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

20 25 30

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

35 40 45

Gly Arg Ile Asp Pro Asn Ser Gly Ser Thr Lys Tyr Asn Glu Lys Phe

50 55 60

Lys Asn 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 Asp Tyr Arg Lys Gly Leu Tyr Ala Met Asp Tyr Trp Gly Gln

100 105 110

Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val

115 120 125

Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala

130 135 140

Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser

145 150 155 160

Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val

165 170 175

Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro

180 185 190

Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys

195 200 205

Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro

210 215 220

Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val

225 230 235 240

Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr

245 250 255

Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu

260 265 270

Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys

275 280 285

Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser

290 295 300

Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys

305 310 315 320

Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile

325 330 335

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

340 345 350

Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu

355 360 365

Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn

370 375 380

Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser

385 390 395 400

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

405 410 415

Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu

420 425 430

His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly

435 440 445

<210> 609

<211> 11

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 609

Lys Ala Ser Gln Asp Val Gly Thr Ala Val Ala

1 5 10

<210> 610

<211> 7

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 610

Trp Ala Ser Thr Arg His Thr

15

<210> 611

<211> 9

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 611

Gln Gln Tyr Asn Ser Tyr Pro Leu Thr

15

<210> 612

<211> 7

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 612

Ser Gln Asp Val Gly Thr Ala

15

<210> 613

<211> 3

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 613

Trp Ala Ser

1

<210> 614

<211> 6

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 614

Tyr Asn Ser Tyr Pro Leu

15

<210> 615

<211> 1338

<212> DNA

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 615

gaagtgcagc tggtgcagtc aggcgccgaa gtgaagaaac ccggcgctac cgtgaagatt 60

agctgtaaag tctcaggcta caccttcact agctactgga tgtactggggt ccgacaggct 120

aggggcaaa gactggagtg gatcggtaga atcgacccta atagcggctc tactaagtat 180

aacgagaagt ttaagaatag gttcactatt agtagggata actctaagaa caccctgtac 240

ctgcagatga atagcctgag agccgaggac accgccgtct actactgcgc tagagactat 300

agaaagggcc tgtacgctat ggactactgg ggtcaaggca ctaccgtgac cgtgtcttca 360

gctagcacta agggcccgtc cgtgttcccc ctggcacctt gtagccggag cactagcgaa 420

tccaccgctg ccctcggctg cctggtcaag gattacttcc cggagcccgt gaccgtgtcc 480

tggaacagcg gagccctgac ctccggagtg cacaccttcc ccgctgtgct gcagagctcc 540

gggctgtact cgctgtcgtc ggtggtcacg gtgccttcat ctagcctggg taccaagacc 600

tacacttgca acgtggacca caagccttcc aacactaagg tggacaagcg cgtcgaatcg 660

aagtacggcc caccgtgccc gccttgtccc gcgccggagt tcctcggcgg tccctcggtc 720

tttctgttcc caccgaagcc caaggacact ttgatgattt cccgcacccc tgaagtgaca 780

tgcgtggtcg tggacgtgtc acaggaagat ccggaggtgc agttcaattg gtacgtggat 840

ggcgtcgagg tgcacaacgc caaaaccaag ccgagggagg agcagttcaa ctccacttac 900

cgcgtcgtgt ccgtgctgac ggtgctgcat caggactggc tgaacgggaa ggagtacaag 960

tgcaaagtgt ccaacaaggg acttcctagc tcaatcgaaa agaccatctc gaaagccaag

1020

ggacagcccc gggaacccca agtgtatacc ctgccaccga gccaggaaga aatgactaag

1080

aaccaagtct cattgacttg ccttgtgaag ggcttctacc catcggatat cgccgtggaa

1140

tgggagtcca acggccagcc ggaaaacaac tacaagacca cccctccggt gctggactca

1200

gacggatcct tcttcctcta ctcgcggctg accgtggata agagcagatg gcaggaggga

1260

aatgtgttca gctgttctgt gatgcatgaa gccctgcaca accactacac tcagaagtcc

1320

ctgtccctct ccctggga 1338

<210> 616

<211> 107

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 616

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

1 5 10 15

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

20 25 30

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

35 40 45

Tyr Trp Ala Ser Thr Arg His 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 Glu Ala

65 70 75 80

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

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 617

<211> 321

<212> DNA

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 617

gctattcagc tgactcagtc acctagtagc ctgagcgcta gtgtgggcga tagagtgact 60

atcacctgta aagcctctca ggacgtgggc accgccgtgg cctggtatct gcagaagcct 120

ggtcaatcac ctcagctgct gatctactgg gcctctacta gacacaccgg cgtgccctct 180

aggtttagcg gtagcggtag tggcaccgac ttcaccttca ctatctcttc actggaagcc 240

gaggacgccg ctacctacta ctgtcagcag tataatagct accccctgac cttcggtcaa 300

ggcactaagg tcgagattaa g 321

<210> 618

<211> 214

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 618

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

1 5 10 15

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

20 25 30

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

35 40 45

Tyr Trp Ala Ser Thr Arg His 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 Glu Ala

65 70 75 80

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

85 90 95

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

100 105 110

Pro Ser Val Phe Ile Phe Pro Ser Asp Glu Gln Leu Lys Ser Gly

115 120 125

Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala

130 135 140

Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln

145 150 155 160

Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser

165 170 175

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

180 185 190

Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser

195 200 205

Phe Asn Arg Gly Glu Cys

210

<210> 619

<211> 642

<212> DNA

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 619

gctattcagc tgactcagtc acctagtagc ctgagcgcta gtgtgggcga tagagtgact 60

atcacctgta aagcctctca ggacgtgggc accgccgtgg cctggtatct gcagaagcct 120

ggtcaatcac ctcagctgct gatctactgg gcctctacta gacacaccgg cgtgccctct 180

aggtttagcg gtagcggtag tggcaccgac ttcaccttca ctatctcttc actggaagcc 240

gaggacgccg ctacctacta ctgtcagcag tataatagct accccctgac cttcggtcaa 300

ggcactaagg tcgagattaa gcgtacggtg gccgctccca gcgtgttcat cttccccccc 360

agcgacgagc agctgaagag cggcaccgcc agcgtggtgt gcctgctgaa caacttctac 420

ccccgggagg ccaaggtgca gtggaaggtg gacaacgccc tgcagagcgg caacagccag 480

gagagcgtca ccgagcagga cagcaaggac tccacctaca gcctgagcag caccctgacc 540

ctgagcaagg ccgactacga gaagcataag gtgtacgcct gcgaggtgac ccaccagggc 600

ctgtccagcc ccgtgaccaa gagcttcaac aggggcgagt gc 642

<210> 620

<211> 120

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 620

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

1 5 10 15

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

20 25 30

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

35 40 45

Gly Arg Ile Asp Pro Asn Ser Gly Ser Thr Lys Tyr Asn Glu Lys Phe

50 55 60

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

65 70 75 80

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

85 90 95

Ala Arg Asp Tyr Arg Lys Gly Leu Tyr Ala Met Asp Tyr Trp Gly Gln

100 105 110

Gly Thr Thr Val Thr Val Ser Ser

115 120

<210> 621

<211> 360

<212> DNA

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 621

gaagtgcagc tggtgcagtc aggcgccgaa gtgaagaaac ccggcgctac cgtgaagatt 60

agctgtaaag tctcaggcta caccttcact agctactgga tgtactggggt ccgacaggct 120

accggtcaag gcctggagtg gatgggtaga atcgacccta atagcggctc tactaagtat 180

aacgagaagt ttaagaatag agtgactatc accgccgata agtctactag caccgcctat 240

atggaactgt ctagcctgag atcagaggac accgccgtct actactgcgc tagagactat 300

agaaagggcc tgtacgctat ggactactgg ggtcaaggca ctaccgtgac cgtgtcttca 360

<210> 622

<211> 446

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 622

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

1 5 10 15

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

20 25 30

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

35 40 45

Gly Arg Ile Asp Pro Asn Ser Gly Ser Thr Lys Tyr Asn Glu Lys Phe

50 55 60

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

65 70 75 80

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

85 90 95

Ala Arg Asp Tyr Arg Lys Gly Leu Tyr Ala Met Asp Tyr Trp Gly Gln

100 105 110

Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val

115 120 125

Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala

130 135 140

Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser

145 150 155 160

Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val

165 170 175

Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro

180 185 190

Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys

195 200 205

Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro

210 215 220

Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val

225 230 235 240

Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr

245 250 255

Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu

260 265 270

Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys

275 280 285

Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser

290 295 300

Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys

305 310 315 320

Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile

325 330 335

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

340 345 350

Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu

355 360 365

Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn

370 375 380

Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser

385 390 395 400

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

405 410 415

Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu

420 425 430

His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly

435 440 445

<210> 623

<211> 1338

<212> DNA

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 623

gaagtgcagc tggtgcagtc aggcgccgaa gtgaagaaac ccggcgctac cgtgaagatt 60

agctgtaaag tctcaggcta caccttcact agctactgga tgtactggggt ccgacaggct 120

accggtcaag gcctggagtg gatgggtaga atcgacccta atagcggctc tactaagtat 180

aacgagaagt ttaagaatag agtgactatc accgccgata agtctactag caccgcctat 240

atggaactgt ctagcctgag atcagaggac accgccgtct actactgcgc tagagactat 300

agaaagggcc tgtacgctat ggactactgg ggtcaaggca ctaccgtgac cgtgtcttca 360

gctagcacta agggcccgtc cgtgttcccc ctggcacctt gtagccggag cactagcgaa 420

tccaccgctg ccctcggctg cctggtcaag gattacttcc cggagcccgt gaccgtgtcc 480

tggaacagcg gagccctgac ctccggagtg cacaccttcc ccgctgtgct gcagagctcc 540

gggctgtact cgctgtcgtc ggtggtcacg gtgccttcat ctagcctggg taccaagacc 600

tacacttgca acgtggacca caagccttcc aacactaagg tggacaagcg cgtcgaatcg 660

aagtacggcc caccgtgccc gccttgtccc gcgccggagt tcctcggcgg tccctcggtc 720

tttctgttcc caccgaagcc caaggacact ttgatgattt cccgcacccc tgaagtgaca 780

tgcgtggtcg tggacgtgtc acaggaagat ccggaggtgc agttcaattg gtacgtggat 840

ggcgtcgagg tgcacaacgc caaaaccaag ccgagggagg agcagttcaa ctccacttac 900

cgcgtcgtgt ccgtgctgac ggtgctgcat caggactggc tgaacgggaa ggagtacaag 960

tgcaaagtgt ccaacaaggg acttcctagc tcaatcgaaa agaccatctc gaaagccaag

1020

ggacagcccc gggaacccca agtgtatacc ctgccaccga gccaggaaga aatgactaag

1080

aaccaagtct cattgacttg ccttgtgaag ggcttctacc catcggatat cgccgtggaa

1140

tgggagtcca acggccagcc ggaaaacaac tacaagacca cccctccggt gctggactca

1200

gacggatcct tcttcctcta ctcgcggctg accgtggata agagcagatg gcaggaggga

1260

aatgtgttca gctgttctgt gatgcatgaa gccctgcaca accactacac tcagaagtcc

1320

ctgtccctct ccctggga 1338

<210> 624

<211> 107

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 624

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

1 5 10 15

Gln Pro Ala Ser Ile Ser Cys Lys Ala Ser Gln Asp Val Gly Thr Ala

20 25 30

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

35 40 45

Tyr Trp Ala Ser Thr Arg His Thr 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 Ser Tyr Pro Leu

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 625

<211> 321

<212> DNA

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 625

gacgtcgtga tgactcagtc acccctgagc ctgcccgtga ccctggggca gcccgcctct 60

attagctgta aagcctctca ggacgtgggc accgccgtgg cctggtatca gcagaagcca 120

gggcaagccc ctagactgct gatctactgg gcctctacta gacacaccgg cgtgccctct 180

aggtttagcg gtagcggtag tggcaccgag ttcaccctga ctatctcttc actgcagccc 240

gacgacttcg ctacctacta ctgtcagcag tataatagct accccctgac cttcggtcaa 300

ggcactaagg tcgagattaa g 321

<210> 626

<211> 214

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 626

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

1 5 10 15

Gln Pro Ala Ser Ile Ser Cys Lys Ala Ser Gln Asp Val Gly Thr Ala

20 25 30

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

35 40 45

Tyr Trp Ala Ser Thr Arg His Thr 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 Ser Tyr Pro Leu

85 90 95

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

100 105 110

Pro Ser Val Phe Ile Phe Pro Ser Asp Glu Gln Leu Lys Ser Gly

115 120 125

Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala

130 135 140

Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln

145 150 155 160

Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser

165 170 175

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

180 185 190

Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser

195 200 205

Phe Asn Arg Gly Glu Cys

210

<210> 627

<211> 642

<212> DNA

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 627

gacgtcgtga tgactcagtc acccctgagc ctgcccgtga ccctggggca gcccgcctct 60

attagctgta aagcctctca ggacgtgggc accgccgtgg cctggtatca gcagaagcca 120

gggcaagccc ctagactgct gatctactgg gcctctacta gacacaccgg cgtgccctct 180

aggtttagcg gtagcggtag tggcaccgag ttcaccctga ctatctcttc actgcagccc 240

gacgacttcg ctacctacta ctgtcagcag tataatagct accccctgac cttcggtcaa 300

ggcactaagg tcgagattaa gcgtacggtg gccgctccca gcgtgttcat cttccccccc 360

agcgacgagc agctgaagag cggcaccgcc agcgtggtgt gcctgctgaa caacttctac 420

ccccgggagg ccaaggtgca gtggaaggtg gacaacgccc tgcagagcgg caacagccag 480

gagagcgtca ccgagcagga cagcaaggac tccacctaca gcctgagcag caccctgacc 540

ctgagcaagg ccgactacga gaagcataag gtgtacgcct gcgaggtgac ccaccagggc 600

ctgtccagcc ccgtgaccaa gagcttcaac aggggcgagt gc 642

<210> 628

<211> 15

<212> DNA

<213> Faux Sequence

<220>

<221> source

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

Synthetic oligonucleotide"

<400> 628

agctactgga tgtac 15

<210> 629

<211> 51

<212> DNA

<213> Faux Sequence

<220>

<221> source

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

Synthetic oligonucleotide"

<400> 629

agaatcgacc ctaatagcgg ctctactaag tataacgaga agtttaagaa t 51

<210> 630

<211> 33

<212> DNA

<213> Faux Sequence

<220>

<221> source

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

Synthetic oligonucleotide"

<400> 630

gactatagaa agggcctgta cgctatggac tac 33

<210> 631

<211> 21

<212> DNA

<213> Faux Sequence

<220>

<221> source

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

Synthetic oligonucleotide"

<400> 631

ggctacacct tcactagcta c 21

<210> 632

<211> 18

<212> DNA

<213> Faux Sequence

<220>

<221> source

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

Synthetic oligonucleotide"

<400> 632

gaccctaata gcggctct 18

<210> 633

<211> 33

<212> DNA

<213> Faux Sequence

<220>

<221> source

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

Synthetic oligonucleotide"

<400> 633

aaagcctctc aggacgtggg caccgccgtg gcc 33

<210> 634

<211> 21

<212> DNA

<213> Faux Sequence

<220>

<221> source

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

Synthetic oligonucleotide"

<400> 634

tgggcctcta ctagacacac c 21

<210> 635

<211> 27

<212> DNA

<213> Faux Sequence

<220>

<221> source

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

Synthetic oligonucleotide"

<400> 635

cagcagtata atagctaccc cctgacc 27

<210> 636

<211> 21

<212> DNA

<213> Faux Sequence

<220>

<221> source

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

Synthetic oligonucleotide"

<400> 636

tctcaggacg tgggcaccgc c 21

<210> 637

<211> 9

<212> DNA

<213> Faux Sequence

<220>

<221> source

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

Synthetic oligonucleotide"

<400> 637

tgggcctct

9

<210> 638

<211> 18

<212> DNA

<213> Faux Sequence

<220>

<221> source

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

Synthetic oligonucleotide"

<400> 638

tataatatagct accccctg 18

<210> 639

<211> 448

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 639

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

1 5 10 15

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

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

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

100 105 110

Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro

115 120 125

Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly

130 135 140

Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn

145 150 155 160

Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln

165 170 175

Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser

180 185 190

Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser

195 200 205

Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr

210 215 220

His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser

225 230 235 240

Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg

245 250 255

Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro

260 265 270

Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala

275 280 285

Lys Thr Lys Pro Arg Glu Glu Gln Tyr Ala Ser Thr Tyr Arg Val Val

290 295 300

Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr

305 310 315 320

Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr

325 330 335

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

340 345 350

Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys

355 360 365

Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser

370 375 380

Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp

385 390 395 400

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

405 410 415

Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala

420 425 430

Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

435 440 445

<210> 640

<211> 214

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 640

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

1 5 10 15

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

20 25 30

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

35 40 45

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

50 55 60

Ser 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 Leu Tyr His Pro Ala

85 90 95

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

100 105 110

Pro Ser Val Phe Ile Phe Pro Ser Asp Glu Gln Leu Lys Ser Gly

115 120 125

Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala

130 135 140

Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln

145 150 155 160

Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser

165 170 175

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

180 185 190

Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser

195 200 205

Phe Asn Arg Gly Glu Cys

210

<210> 641

<211> 450

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 641

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

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

35 40 45

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

100 105 110

Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val

115 120 125

Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala

130 135 140

Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser

145 150 155 160

Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val

165 170 175

Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro

180 185 190

Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys

195 200 205

Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp

210 215 220

Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly

225 230 235 240

Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile

245 250 255

Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu

260 265 270

Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His

275 280 285

Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg

290 295 300

Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys

305 310 315 320

Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu

325 330 335

Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr

340 345 350

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

355 360 365

Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp

370 375 380

Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val

385 390 395 400

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

405 410 415

Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His

420 425 430

Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

435 440 445

Gly Lys

450

<210> 642

<211> 216

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 642

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

1 5 10 15

Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr

20 25 30

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

35 40 45

Met Ile Tyr Asp Val Ser Asn Arg Pro Ser Gly Val Ser Asn Arg Phe

50 55 60

Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu

65 70 75 80

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

85 90 95

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

100 105 110

Pro Lys Ala Asn Pro Thr Val Thr Leu Phe Pro Pro Ser Ser Glu Glu

115 120 125

Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr

130 135 140

Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Gly Ser Pro Val Lys

145 150 155 160

Ala Gly Val Glu Thr Thr Lys Pro Ser Lys Gln Ser Asn Asn Lys Tyr

165 170 175

Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His

180 185 190

Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys

195 200 205

Thr Val Ala Pro Thr Glu Cys Ser

210 215

<210> 643

<211> 451

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 643

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 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 Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

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

100 105 110

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

115 120 125

Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala

130 135 140

Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val

145 150 155 160

Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala

165 170 175

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

180 185 190

Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His

195 200 205

Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys

210 215 220

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly

225 230 235 240

Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

245 250 255

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

260 265 270

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

275 280 285

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

290 295 300

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

305 310 315 320

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser Ile

325 330 335

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

340 345 350

Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser

355 360 365

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

370 375 380

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

385 390 395 400

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

405 410 415

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

420 425 430

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

435 440 445

Pro Gly Lys

450

<210> 644

<211> 215

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 644

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 Arg 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 Asp 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 Leu Pro

85 90 95

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

100 105 110

Ala Pro Ser Val Phe Ile Phe Pro Ser Asp Glu Gln Leu Lys Ser

115 120 125

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

130 135 140

Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser

145 150 155 160

Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu

165 170 175

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

180 185 190

Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys

195 200 205

Ser Phe Asn Arg Gly Glu Cys

210 215

<210> 645

<211> 123

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 645

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 Thr Ser Gly Asp Thr Phe Ser Thr Tyr

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

Ala Arg Lys Phe His Phe Val Ser Gly Ser Pro Phe Gly Met Asp Val

100 105 110

Trp Gly Glyn Gly Thr Thr Val Thr Val Ser Ser

115 120

<210> 646

<211> 106

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 646

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 Thr

85 90 95

Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 647

<211> 10

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 647

Gly Tyr Thr Phe Thr Ser Tyr Trp Met Tyr

1 5 10

<210> 648

<400> 648

000

<210> 649

<400> 649

000

<210> 650

<400> 650

000

<210> 651

<400> 651

000

<210> 652

<400> 652

000

<210> 653

<400> 653

000

<210> 654

<400> 654

000

<210> 655

<400> 655

000

<210> 656

<400> 656

000

<210> 657

<400> 657

000

<210> 658

<400> 658

000

<210> 659

<400> 659

000

<210> 660

<400> 660

000

<210> 661

<400> 661

000

<210> 662

<400> 662

000

<210> 663

<400> 663

000

<210> 664

<400> 664

000

<210> 665

<400> 665

000

<210> 666

<400> 666

000

<210> 667

<400> 667

000

<210> 668

<400> 668

000

<210> 669

<400> 669

000

<210> 670

<400> 670

000

<210> 671

<400> 671

000

<210> 672

<400> 672

000

<210> 673

<400> 673

000

<210> 674

<400> 674

000

<210> 675

<400> 675

000

<210> 676

<400> 676

000

<210> 677

<400> 677

000

<210> 678

<400> 678

000

<210> 679

<400> 679

000

<210> 680

<400> 680

000

<210> 681

<400> 681

000

<210> 682

<400> 682

000

<210> 683

<400> 683

000

<210> 684

<400> 684

000

<210> 685

<400> 685

000

<210> 686

<400> 686

000

<210> 687

<400> 687

000

<210> 688

<400> 688

000

<210> 689

<400> 689

000

<210> 690

<400> 690

000

<210> 691

<400> 691

000

<210> 692

<400> 692

000

<210> 693

<400> 693

000

<210> 694

<400> 694

000

<210> 695

<400> 695

000

<210> 696

<400> 696

000

<210> 697

<400> 697

000

<210> 698

<400> 698

000

<210> 699

<400> 699

000

<210> 700

<400> 700

000

<210> 701

<211> 5

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 701

Asn Tyr Gly Met Asn

15

<210> 702

<211> 17

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 702

Trp Ile Asn Thr Asp Thr Gly Glu Pro Thr Tyr Ala Asp Asp Phe Lys

1 5 10 15

gly

<210> 703

<211> 16

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 703

Asn Pro Pro Tyr Tyr Tyr Gly Thr Asn Asn Ala Glu Ala Met Asp Tyr

1 5 10 15

<210> 704

<211> 7

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 704

Gly Phe Thr Leu Thr Asn Tyr

15

<210> 705

<211> 6

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 705

Asn Thr Asp Thr Gly Glu

15

<210> 706

<211> 125

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 706

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 Phe Thr Leu Thr Asn Tyr

20 25 30

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

35 40 45

Gly Trp Ile Asn Thr Asp Thr Gly Glu Pro Thr Tyr Ala Asp Asp Phe

50 55 60

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

65 70 75 80

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

85 90 95

Ala Arg Asn Pro Pro Tyr Tyr Tyr Gly Thr Asn Asn Ala Glu Ala Met

100 105 110

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

115 120 125

<210> 707

<211> 375

<212> DNA

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 707

caagtgcagc tggtgcagtc gggagccgaa gtgaagaagc ctggagcctc ggtgaaggtg 60

tcgtgcaagg catccggatt caccctcacc aattacggga tgaactgggt cagacaggcc 120

cggggtcaac ggctggagtg gatcggatgg attaacaccg acaccgggga gcctacctac 180

gcggacgatt tcaagggacg gttcgtgttc tccctcgaca cctccgtgtc caccgcctac 240

ctccaaatct cctcactgaa agcggaggac accgccgtgt actattgcgc gaggaacccg 300

ccctactact acggaaccaa caacgccgaa gccatggact actggggcca gggcaccact 360

gtgactgtgt ccagc 375

<210> 708

<211> 375

<212> DNA

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 708

caggtgcagc tggtgcagtc tggcgccgaa gtgaagaaac ctggcgcctc cgtgaaggtg 60

tcctgcaagg cctctggctt caccctgacc aactacggca tgaactgggt gcgacaggcc 120

aggggccagc ggctggaatg gatcggctgg atcaacaccg acaccggcga gcctacctac 180

gccgacgact tcaagggcag attcgtgttc tccctggaca cctccgtgtc caccgcctac 240

ctgcagatct ccagcctgaa ggccgaggat accgccgtgt actactgcgc ccggaaccccc 300

ccttactact acggcaccaa caacgccgag gccatggact attggggcca gggcaccacc 360

gtgaccgtgt cctct 375

<210> 709

<211> 451

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 709

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 Phe Thr Leu Thr Asn Tyr

20 25 30

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

35 40 45

Gly Trp Ile Asn Thr Asp Thr Gly Glu Pro Thr Tyr Ala Asp Asp Phe

50 55 60

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

65 70 75 80

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

85 90 95

Ala Arg Asn Pro Pro Tyr Tyr Tyr Gly Thr Asn Asn Ala Glu Ala Met

100 105 110

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

115 120 125

Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser

130 135 140

Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu

145 150 155 160

Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His

165 170 175

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

180 185 190

Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys

195 200 205

Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu

210 215 220

Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu

225 230 235 240

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

245 250 255

Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser

260 265 270

Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu

275 280 285

Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr

290 295 300

Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn

305 310 315 320

Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser

325 330 335

Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln

340 345 350

Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val

355 360 365

Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val

370 375 380

Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro

385 390 395 400

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

405 410 415

Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val

420 425 430

Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu

435 440 445

Ser Leu Gly

450

<210> 710

<211> 11

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 710

Ser Ser Ser Gln Asp Ile Ser Asn Tyr Leu Asn

1 5 10

<210> 711

<211> 7

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 711

Tyr Thr Ser Thr Leu His Leu

15

<210> 712

<211> 9

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 712

Gln Gln Tyr Tyr Asn Leu Pro Trp Thr

15

<210> 713

<211> 7

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 713

Ser Gln Asp Ile Ser Asn Tyr

15

<210> 714

<211> 3

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 714

Tyr Thr Ser

1

<210> 715

<211> 6

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 715

Tyr Tyr Asn Leu Pro Trp

15

<210> 716

<211> 1353

<212> DNA

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 716

caagtgcagc tggtgcagtc gggagccgaa gtgaagaagc ctggagcctc ggtgaaggtg 60

tcgtgcaagg catccggatt caccctcacc aattacggga tgaactgggt cagacaggcc 120

cggggtcaac ggctggagtg gatcggatgg attaacaccg acaccgggga gcctacctac 180

gcggacgatt tcaagggacg gttcgtgttc tccctcgaca cctccgtgtc caccgcctac 240

ctccaaatct cctcactgaa agcggaggac accgccgtgt actattgcgc gaggaacccg 300

ccctactact acggaaccaa caacgccgaa gccatggact actggggcca gggcaccact 360

gtgactgtgt ccagcgcgtc cactaagggc ccgtccgtgt tccccctggc accttgtagc 420

cggagcacta gcgaatccac cgctgccctc ggctgcctgg tcaaggatta cttcccggag 480

cccgtgaccg tgtcctggaa cagcggagcc ctgacctccg gagtgcacac cttccccgct 540

gtgctgcaga gctccgggct gtactcgctg tcgtcggtgg tcacggtgcc ttcatctagc 600

ctgggtacca agacctacac ttgcaacgtg gaccacaagc cttccaacac taaggtggac 660

aagcgcgtcg aatcgaagta cggcccaccg tgcccgcctt gtcccgcgcc ggagttcctc 720

ggcggtccct cggtctttct gttcccaccg aagcccaagg acactttgat gatttcccgc 780

acccctgaag tgacatgcgt ggtcgtggac gtgtcacagg aagatccgga ggtgcagttc 840

aattggtacg tggatggcgt cgaggtgcac aacgccaaaa ccaagccgag ggaggagcag 900

ttcaactcca cttaccgcgt cgtgtccgtg ctgacggtgc tgcatcagga ctggctgaac 960

gggaaggagt acaagtgcaa agtgtccaac aagggacttc ctagctcaat cgaaaagacc

1020

atctcgaaag ccaagggaca gccccgggaa ccccaagtgt ataccctgcc accgagccag

1080

gaagaaatga ctaagaacca agtctcattg acttgccttg tgaagggctt ctacccatcg

1140

gatatcgccg tggaatggga gtccaacggc cagccggaaa acaactacaa gaccacccct

1200

ccggtgctgg actcagacgg atccttcttc ctctactcgc ggctgaccgt ggataagagc

1260

agatggcagg agggaaatgt gttcagctgt tctgtgatgc atgaagccct gcacaaccac

1320

tacactcaga agtccctgtc cctctccctg gga 1353

<210> 717

<211> 1353

<212> DNA

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 717

caggtgcagc tggtgcagtc tggcgccgaa gtgaagaaac ctggcgcctc cgtgaaggtg 60

tcctgcaagg cctctggctt caccctgacc aactacggca tgaactgggt gcgacaggcc 120

aggggccagc ggctggaatg gatcggctgg atcaacaccg acaccggcga gcctacctac 180

gccgacgact tcaagggcag attcgtgttc tccctggaca cctccgtgtc caccgcctac 240

ctgcagatct ccagcctgaa ggccgaggat accgccgtgt actactgcgc ccggaaccccc 300

ccttactact acggcaccaa caacgccgag gccatggact attggggcca gggcaccacc 360

gtgaccgtgt cctctgcttc taccaagggg cccagcgtgt tccccctggc cccctgctcc 420

agaagcacca gcgagagcac agccgccctg ggctgcctgg tgaaggacta cttccccgag 480

cccgtgaccg tgtcctggaa cagcggagcc ctgaccagcg gcgtgcacac cttccccgcc 540

gtgctgcaga gcagcggcct gtacagcctg agcagcgtgg tgaccgtgcc cagcagcagc 600

ctgggcacca agacctacac ctgtaacgtg

aagagggtgg agagcaagta cggcccaccc tgccccccct gcccagcccc cgagttcctg 720

ggcggaccca gcgtgttcct gttccccccc aagcccaagg acaccctgat gatcagcaga 780

acccccgagg tgacctgtgt ggtggtggac gtgtcccagg aggaccccga ggtccagttc 840

aactggtacg tggacggcgt ggaggtgcac aacgccaaga ccaagcccag agaggagcag 900

tttaacagca cctaccgggt ggtgtccgtg ctgaccgtgc tgcaccagga ctggctgaac 960

ggcaaagagt acaagtgtaa ggtctccaac aagggcctgc caagcagcat cgaaaagacc

1020

atcagcaagg ccaagggcca gcctagagag ccccaggtct acaccctgcc acccagccaa

1080

gaggagatga ccaagaacca ggtgtccctg acctgtctgg tgaagggctt ctacccaagc

1140

gacatcgccg tggagtggga gagcaacggc cagcccgaga acaactacaa gaccaccccc

1200

ccagtgctgg acagcgacgg cagcttcttc ctgtacagca ggctgaccgt ggacaagtcc

1260

agatggcagg agggcaacgt ctttagctgc tccgtgatgc acgaggccct gcacaaccac

1320

tacacccaga agagcctgag cctgtccctg ggc 1353

<210> 718

<211> 107

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 718

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 Ser Ser Ser Gln Asp Ile Ser Asn Tyr

20 25 30

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

35 40 45

Tyr Tyr Thr Ser Thr Leu His Leu 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 Tyr Asn Leu Pro Trp

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 719

<211> 321

<212> DNA

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 719

gatattcaga tgactcagtc acctagtagc ctgagcgcta gtgtgggcga tagagtgact 60

atcacctgta gctctagtca ggatatctct aactacctga actggtatct gcagaagccc 120

ggtcaatcac ctcagctgct gatctactac actagcaccc tgcacctggg cgtgccctct 180

aggtttagcg gtagcggtag tggcaccgag ttcaccctga ctatctctag cctgcagccc 240

gacgacttcg ctacctacta ctgtcagcag tactataacc tgccctggac cttcggtcaa 300

ggcactaagg tcgagattaa g 321

<210> 720

<211> 321

<212> DNA

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 720

gacatccaga tgacccagtc cccctccagc ctgtctgctt ccgtgggcga cagagtgacc 60

atcacctgtt cctccagcca ggacatctcc aactacctga actggtatct gcagaagccc 120

ggccagtccc ctcagctgct gatctactac acctccaccc tgcacctggg cgtgccctcc 180

agattttccg gctctggctc tggcaccgag tttaccctga ccatcagctc cctgcagccc 240

gacgacttcg ccacctacta ctgccagcag tactacaacc tgccctggac cttcggccag 300

ggcaccaagg tggaaatcaa g 321

<210> 721

<211> 214

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 721

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 Ser Ser Ser Gln Asp Ile Ser Asn Tyr

20 25 30

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

35 40 45

Tyr Tyr Thr Ser Thr Leu His Leu 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 Tyr Asn Leu Pro Trp

85 90 95

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

100 105 110

Pro Ser Val Phe Ile Phe Pro Ser Asp Glu Gln Leu Lys Ser Gly

115 120 125

Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala

130 135 140

Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln

145 150 155 160

Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser

165 170 175

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

180 185 190

Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser

195 200 205

Phe Asn Arg Gly Glu Cys

210

<210> 722

<211> 642

<212> DNA

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 722

gatattcaga tgactcagtc acctagtagc ctgagcgcta gtgtgggcga tagagtgact 60

atcacctgta gctctagtca ggatatctct aactacctga actggtatct gcagaagccc 120

ggtcaatcac ctcagctgct gatctactac actagcaccc tgcacctggg cgtgccctct 180

aggtttagcg gtagcggtag tggcaccgag ttcaccctga ctatctctag cctgcagccc 240

gacgacttcg ctacctacta ctgtcagcag tactataacc tgccctggac cttcggtcaa 300

ggcactaagg tcgagattaa gcgtacggtg gccgctccca gcgtgttcat cttccccccc 360

agcgacgagc agctgaagag cggcaccgcc agcgtggtgt gcctgctgaa caacttctac 420

ccccgggagg ccaaggtgca gtggaaggtg gacaacgccc tgcagagcgg caacagccag 480

gagagcgtca ccgagcagga cagcaaggac tccacctaca gcctgagcag caccctgacc 540

ctgagcaagg ccgactacga gaagcataag gtgtacgcct gcgaggtgac ccaccagggc 600

ctgtccagcc ccgtgaccaa gagcttcaac aggggcgagt gc 642

<210> 723

<211> 642

<212> DNA

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 723

gacatccaga tgacccagtc cccctccagc ctgtctgctt ccgtgggcga cagagtgacc 60

atcacctgtt cctccagcca ggacatctcc aactacctga actggtatct gcagaagccc 120

ggccagtccc ctcagctgct gatctactac acctccaccc tgcacctggg cgtgccctcc 180

agattttccg gctctggctc tggcaccgag tttaccctga ccatcagctc cctgcagccc 240

gacgacttcg ccacctacta ctgccagcag tactacaacc tgccctggac cttcggccag 300

ggcaccaagg tggaaatcaa gcgtacggtg gccgctccca gcgtgttcat cttcccccca 360

agcgacgagc agctgaagag cggcaccgcc agcgtggtgt gtctgctgaa caacttctac 420

cccagggagg ccaaggtgca gtggaaggtg gacaacgccc tgcagagcgg caacagccag 480

gagagcgtca ccgagcagga cagcaaggac tccacctaca gcctgagcag caccctgacc 540

ctgagcaagg ccgactacga gaagcacaag gtgtacgcct gtgaggtgac ccaccagggc 600

ctgtccagcc ccgtgaccaa gagcttcaac aggggcgagt gc 642

<210> 724

<211> 125

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 724

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 Phe Thr Leu Thr Asn Tyr

20 25 30

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

35 40 45

Gly Trp Ile Asn Thr Asp Thr Gly Glu Pro Thr Tyr Ala Asp Asp Phe

50 55 60

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

65 70 75 80

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

85 90 95

Ala Arg Asn Pro Pro Tyr Tyr Tyr Gly Thr Asn Asn Ala Glu Ala Met

100 105 110

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

115 120 125

<210> 725

<211> 375

<212> DNA

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 725

caggtgcagc tggtgcagtc aggcgccgaa gtgaagaaac ccggcgctag tgtgaaagtc 60

agctgtaaag ctagtggctt caccctgact aactacggga tgaactgggt ccgccaggcc 120

ccaggtcaag gcctcgagtg gatgggctgg attaacaccg acaccggcga gcctacctac 180

gccgacgact ttaagggcag attcgtgttt agcctggaca ctagtgtgtc taccgcctac 240

ctgcagatct ctagcctgaa ggccgaggac accgccgtct actactgcgc tagaaacccc 300

ccctactact acggcactaa caacgccgag gctatggact actggggtca aggcactacc 360

gtgaccgtgt ctagc 375

<210> 726

<211> 375

<212> DNA

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 726

caggtgcagc tggtgcagtc tggcgccgaa gtgaagaaac ctggcgcctc cgtgaaggtg 60

tcctgcaagg cctctggctt caccctgacc aactacggca tgaactgggt gcgacaggcc 120

cctggacagg gcctggaatg gatgggctgg atcaacaccg acaccggcga gcctacctac 180

gccgacgact tcaagggcag attcgtgttc tccctggaca cctccgtgtc caccgcctac 240

ctgcagatct ccagcctgaa ggccgaggat accgccgtgt actactgcgc ccggaaccccc 300

ccttactact acggcaccaa caacgccgag gccatggact attggggcca gggcaccacc 360

gtgaccgtgt cctct 375

<210> 727

<211> 451

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 727

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 Phe Thr Leu Thr Asn Tyr

20 25 30

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

35 40 45

Gly Trp Ile Asn Thr Asp Thr Gly Glu Pro Thr Tyr Ala Asp Asp Phe

50 55 60

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

65 70 75 80

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

85 90 95

Ala Arg Asn Pro Pro Tyr Tyr Tyr Gly Thr Asn Asn Ala Glu Ala Met

100 105 110

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

115 120 125

Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser

130 135 140

Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu

145 150 155 160

Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His

165 170 175

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

180 185 190

Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys

195 200 205

Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu

210 215 220

Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu

225 230 235 240

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

245 250 255

Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser

260 265 270

Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu

275 280 285

Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr

290 295 300

Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn

305 310 315 320

Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser

325 330 335

Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln

340 345 350

Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val

355 360 365

Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val

370 375 380

Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro

385 390 395 400

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

405 410 415

Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val

420 425 430

Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu

435 440 445

Ser Leu Gly

450

<210> 728

<211> 1353

<212> DNA

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 728

caggtgcagc tggtgcagtc aggcgccgaa gtgaagaaac ccggcgctag tgtgaaagtc 60

agctgtaaag ctagtggctt caccctgact aactacggga tgaactgggt ccgccaggcc 120

ccaggtcaag gcctcgagtg gatgggctgg attaacaccg acaccggcga gcctacctac 180

gccgacgact ttaagggcag attcgtgttt agcctggaca ctagtgtgtc taccgcctac 240

ctgcagatct ctagcctgaa ggccgaggac accgccgtct actactgcgc tagaaacccc 300

ccctactact acggcactaa caacgccgag gctatggact actggggtca aggcactacc 360

gtgaccgtgt ctagcgctag cactaagggc ccgtccgtgt tccccctggc accttgtagc 420

cggagcacta gcgaatccac cgctgccctc ggctgcctgg tcaaggatta cttcccggag 480

cccgtgaccg tgtcctggaa cagcggagcc ctgacctccg gagtgcacac cttccccgct 540

gtgctgcaga gctccgggct gtactcgctg tcgtcggtgg tcacggtgcc ttcatctagc 600

ctgggtacca agacctacac ttgcaacgtg gaccacaagc cttccaacac taaggtggac 660

aagcgcgtcg aatcgaagta cggcccaccg tgcccgcctt gtcccgcgcc ggagttcctc 720

ggcggtccct cggtctttct gttcccaccg aagcccaagg acactttgat gatttcccgc 780

acccctgaag tgacatgcgt ggtcgtggac gtgtcacagg aagatccgga ggtgcagttc 840

aattggtacg tggatggcgt cgaggtgcac aacgccaaaa ccaagccgag ggaggagcag 900

ttcaactcca cttaccgcgt cgtgtccgtg ctgacggtgc tgcatcagga ctggctgaac 960

gggaaggagt acaagtgcaa agtgtccaac aagggacttc ctagctcaat cgaaaagacc

1020

atctcgaaag ccaagggaca gccccgggaa ccccaagtgt ataccctgcc accgagccag

1080

gaagaaatga ctaagaacca agtctcattg acttgccttg tgaagggctt ctacccatcg

1140

gatatcgccg tggaatggga gtccaacggc cagccggaaa acaactacaa gaccacccct

1200

ccggtgctgg actcagacgg atccttcttc ctctactcgc ggctgaccgt ggataagagc

1260

agatggcagg agggaaatgt gttcagctgt tctgtgatgc atgaagccct gcacaaccac

1320

tacactcaga agtccctgtc cctctccctg gga 1353

<210> 729

<211> 1353

<212> DNA

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 729

caggtgcagc tggtgcagtc tggcgccgaa gtgaagaaac ctggcgcctc cgtgaaggtg 60

tcctgcaagg cctctggctt caccctgacc aactacggca tgaactgggt gcgacaggcc 120

cctggacagg gcctggaatg gatgggctgg atcaacaccg acaccggcga gcctacctac 180

gccgacgact tcaagggcag attcgtgttc tccctggaca cctccgtgtc caccgcctac 240

ctgcagatct ccagcctgaa ggccgaggat accgccgtgt actactgcgc ccggaaccccc 300

ccttactact acggcaccaa caacgccgag gccatggact attggggcca gggcaccacc 360

gtgaccgtgt cctctgcttc taccaagggg cccagcgtgt tccccctggc cccctgctcc 420

agaagcacca gcgagagcac agccgccctg ggctgcctgg tgaaggacta cttccccgag 480

cccgtgaccg tgtcctggaa cagcggagcc ctgaccagcg gcgtgcacac cttccccgcc 540

gtgctgcaga gcagcggcct gtacagcctg agcagcgtgg tgaccgtgcc cagcagcagc 600

ctgggcacca agacctacac ctgtaacgtg

aagagggtgg agagcaagta cggcccaccc tgccccccct gcccagcccc cgagttcctg 720

ggcggaccca gcgtgttcct gttccccccc aagcccaagg acaccctgat gatcagcaga 780

acccccgagg tgacctgtgt ggtggtggac gtgtcccagg aggaccccga ggtccagttc 840

aactggtacg tggacggcgt ggaggtgcac aacgccaaga ccaagcccag agaggagcag 900

tttaacagca cctaccgggt ggtgtccgtg ctgaccgtgc tgcaccagga ctggctgaac 960

ggcaaagagt acaagtgtaa ggtctccaac aagggcctgc caagcagcat cgaaaagacc

1020

atcagcaagg ccaagggcca gcctagagag ccccaggtct acaccctgcc acccagccaa

1080

gaggagatga ccaagaacca ggtgtccctg acctgtctgg tgaagggctt ctacccaagc

1140

gacatcgccg tggagtggga gagcaacggc cagcccgaga acaactacaa gaccaccccc

1200

ccagtgctgg acagcgacgg cagcttcttc ctgtacagca ggctgaccgt ggacaagtcc

1260

agatggcagg agggcaacgt ctttagctgc tccgtgatgc acgaggccct gcacaaccac

1320

tacacccaga agagcctgag cctgtccctg ggc 1353

<210> 730

<211> 107

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 730

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 Ser Ser 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 Tyr Thr Ser Thr Leu His Leu Gly Ile Pro Arg Phe Ser Gly

50 55 60

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

65 70 75 80

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

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 731

<211> 321

<212> DNA

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 731

gatattcaga tgactcagtc acctagtagc ctgagcgcta gtgtgggcga tagagtgact 60

atcacctgta gctctagtca ggatatctct aactacctga actggtatca gcagaagccc 120

ggtaaagccc ctaagctgct gatctactac actagcaccc tgcacctggg aatcccccct 180

aggtttagcg gtagcggcta cggcaccgac ttcaccctga ctattaacaa tatcgagtca 240

gaggacgccg cctactactt ctgtcagcag tactataacc tgccctggac cttcggtcaa 300

ggcactaagg tcgagattaa g 321

<210> 732

<211> 321

<212> DNA

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 732

gacatccaga tgacccagtc cccctccagc ctgtctgctt ccgtgggcga cagagtgacc 60

atcacctgtt cctccagcca ggacatctcc aactacctga actggtatca gcagaagccc 120

ggcaaggccc ccaagctgct gatctactac acctccaccc tgcacctgggg catcccccct 180

agattctccg gctctggcta cggcaccgac ttcaccctga ccatcaacaa catcgagtcc 240

gaggacgccg cctactactt ctgccagcag tactacaacc tgccctggac cttcggccag 300

ggcaccaagg tggaaatcaa g 321

<210> 733

<211> 214

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 733

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 Ser Ser 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 Tyr Thr Ser Thr Leu His Leu Gly Ile Pro Arg Phe Ser Gly

50 55 60

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

65 70 75 80

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

85 90 95

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

100 105 110

Pro Ser Val Phe Ile Phe Pro Ser Asp Glu Gln Leu Lys Ser Gly

115 120 125

Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala

130 135 140

Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln

145 150 155 160

Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser

165 170 175

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

180 185 190

Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser

195 200 205

Phe Asn Arg Gly Glu Cys

210

<210> 734

<211> 642

<212> DNA

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 734

gatattcaga tgactcagtc acctagtagc ctgagcgcta gtgtgggcga tagagtgact 60

atcacctgta gctctagtca ggatatctct aactacctga actggtatca gcagaagccc 120

ggtaaagccc ctaagctgct gatctactac actagcaccc tgcacctggg aatcccccct 180

aggtttagcg gtagcggcta cggcaccgac ttcaccctga ctattaacaa tatcgagtca 240

gaggacgccg cctactactt ctgtcagcag tactataacc tgccctggac cttcggtcaa 300

ggcactaagg tcgagattaa gcgtacggtg gccgctccca gcgtgttcat cttccccccc 360

agcgacgagc agctgaagag cggcaccgcc agcgtggtgt gcctgctgaa caacttctac 420

ccccgggagg ccaaggtgca gtggaaggtg gacaacgccc tgcagagcgg caacagccag 480

gagagcgtca ccgagcagga cagcaaggac tccacctaca gcctgagcag caccctgacc 540

ctgagcaagg ccgactacga gaagcataag gtgtacgcct gcgaggtgac ccaccagggc 600

ctgtccagcc ccgtgaccaa gagcttcaac aggggcgagt gc 642

<210> 735

<211> 642

<212> DNA

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 735

gacatccaga tgacccagtc cccctccagc ctgtctgctt ccgtgggcga cagagtgacc 60

atcacctgtt cctccagcca ggacatctcc aactacctga actggtatca gcagaagccc 120

ggcaaggccc ccaagctgct gatctactac acctccaccc tgcacctgggg catcccccct 180

agattctccg gctctggcta cggcaccgac ttcaccctga ccatcaacaa catcgagtcc 240

gaggacgccg cctactactt ctgccagcag tactacaacc tgccctggac cttcggccag 300

ggcaccaagg tggaaatcaa gcgtacggtg gccgctccca gcgtgttcat cttcccccca 360

agcgacgagc agctgaagag cggcaccgcc agcgtggtgt gtctgctgaa caacttctac 420

cccagggagg ccaaggtgca gtggaaggtg gacaacgccc tgcagagcgg caacagccag 480

gagagcgtca ccgagcagga cagcaaggac tccacctaca gcctgagcag caccctgacc 540

ctgagcaagg ccgactacga gaagcacaag gtgtacgcct gtgaggtgac ccaccagggc 600

ctgtccagcc ccgtgaccaa gagcttcaac aggggcgagt gc 642

<210> 736

<211> 15

<212> DNA

<213> Faux Sequence

<220>

<221> source

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

Synthetic oligonucleotide"

<400> 736

aattacggga tgaac 15

<210> 737

<211> 15

<212> DNA

<213> Faux Sequence

<220>

<221> source

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

Synthetic oligonucleotide"

<400> 737

aactacggca tgaac 15

<210> 738

<211> 51

<212> DNA

<213> Faux Sequence

<220>

<221> source

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

Synthetic oligonucleotide"

<400> 738

tggattaaca ccgacaccgg ggagcctacc tacgcggacg atttcaaggg a 51

<210> 739

<211> 51

<212> DNA

<213> Faux Sequence

<220>

<221> source

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

Synthetic oligonucleotide"

<400> 739

tggatcaaca ccgacaccgg cgagcctacc tacgccgacg acttcaaggg c 51

<210> 740

<211> 48

<212> DNA

<213> Faux Sequence

<220>

<221> source

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

Synthetic oligonucleotide"

<400> 740

aacccgccct actactacgg aaccaacaac gccgaagcca tggactac 48

<210> 741

<211> 48

<212> DNA

<213> Faux Sequence

<220>

<221> source

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

Synthetic oligonucleotide"

<400> 741

aacccccctt actactacgg caccaacaac gccgaggcca tggactat 48

<210> 742

<211> 21

<212> DNA

<213> Faux Sequence

<220>

<221> source

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

Synthetic oligonucleotide"

<400> 742

ggattcaccc tcaccaatta c 21

<210> 743

<211> 21

<212> DNA

<213> Faux Sequence

<220>

<221> source

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

Synthetic oligonucleotide"

<400> 743

ggcttcaccc tgaccaacta c 21

<210> 744

<211> 18

<212> DNA

<213> Faux Sequence

<220>

<221> source

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

Synthetic oligonucleotide"

<400> 744

aacaccgaca ccggggag 18

<210> 745

<211> 18

<212> DNA

<213> Faux Sequence

<220>

<221> source

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

Synthetic oligonucleotide"

<400> 745

aacaccgaca ccggcgag 18

<210> 746

<211> 33

<212> DNA

<213> Faux Sequence

<220>

<221> source

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

Synthetic oligonucleotide"

<400> 746

agctctagtc aggatatctc taactacctg aac 33

<210> 747

<211> 33

<212> DNA

<213> Faux Sequence

<220>

<221> source

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

Synthetic oligonucleotide"

<400> 747

tcctccagcc aggacatctc caactacctg aac 33

<210> 748

<211> 21

<212> DNA

<213> Faux Sequence

<220>

<221> source

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

Synthetic oligonucleotide"

<400> 748

tacactagca ccctgcacct g 21

<210> 749

<211> 21

<212> DNA

<213> Faux Sequence

<220>

<221> source

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

Synthetic oligonucleotide"

<400> 749

tacacctcca ccctgcacct g 21

<210> 750

<211> 27

<212> DNA

<213> Faux Sequence

<220>

<221> source

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

Synthetic oligonucleotide"

<400> 750

cagcagtact ataacctgcc ctggacc 27

<210> 751

<211> 27

<212> DNA

<213> Faux Sequence

<220>

<221> source

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

Synthetic oligonucleotide"

<400> 751

cagcagtact acaacctgcc ctggacc 27

<210> 752

<211> 21

<212> DNA

<213> Faux Sequence

<220>

<221> source

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

Synthetic oligonucleotide"

<400> 752

agtcaggata tctctaacta c 21

<210> 753

<211> 21

<212> DNA

<213> Faux Sequence

<220>

<221> source

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

Synthetic oligonucleotide"

<400> 753

agccaggaca tctccaacta c 21

<210> 754

<211> 9

<212> DNA

<213> Faux Sequence

<220>

<221> source

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

Synthetic oligonucleotide"

<400> 754

tacactagc

9

<210> 755

<211> 9

<212> DNA

<213> Faux Sequence

<220>

<221> source

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

Synthetic oligonucleotide"

<400> 755

tacacctcc

9

<210> 756

<211> 18

<212> DNA

<213> Faux Sequence

<220>

<221> source

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

Synthetic oligonucleotide"

<400> 756

tactataacc tgccctgg 18

<210> 757

<211> 18

<212> DNA

<213> Faux Sequence

<220>

<221> source

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

Synthetic oligonucleotide"

<400> 757

tactacaacc tgccctgg 18

<210> 758

<211> 15

<212> DNA

<213> Faux Sequence

<220>

<221> source

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

Synthetic oligonucleotide"

<400> 758

aactacggga tgaac 15

<210> 759

<211> 51

<212> DNA

<213> Faux Sequence

<220>

<221> source

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

Synthetic oligonucleotide"

<400> 759

tggattaaca ccgacaccgg cgagcctacc tacgccgacg actttaaggg c 51

<210> 760

<211> 48

<212> DNA

<213> Faux Sequence

<220>

<221> source

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

Synthetic oligonucleotide"

<400> 760

aaccccccct actactacgg cactaacaac gccgaggcta tggactac 48

<210> 761

<211> 21

<212> DNA

<213> Faux Sequence

<220>

<221> source

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

Synthetic oligonucleotide"

<400> 761

ggcttcaccc tgactaacta c 21

<210> 762

<211> 447

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 762

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 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 Ser Asn Pro Ser Leu Lys

50 55 60

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

65 70 75 80

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

85 90 95

Phe Gly Tyr Ser Asp Tyr Glu Tyr Asn Trp Phe Asp Pro Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val

115 120 125

Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala

130 135 140

Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser

145 150 155 160

Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val

165 170 175

Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro

180 185 190

Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys

195 200 205

Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro

210 215 220

Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val

225 230 235 240

Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr

245 250 255

Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu

260 265 270

Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys

275 280 285

Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser

290 295 300

Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys

305 310 315 320

Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile

325 330 335

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

340 345 350

Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu

355 360 365

Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn

370 375 380

Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser

385 390 395 400

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

405 410 415

Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu

420 425 430

His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys

435 440 445

<210> 763

<211> 214

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 763

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 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 Gln Gly Thr Asn Leu Glu Ile Lys Arg Thr Val Ala Ala

100 105 110

Pro Ser Val Phe Ile Phe Pro Ser Asp Glu Gln Leu Lys Ser Gly

115 120 125

Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala

130 135 140

Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln

145 150 155 160

Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser

165 170 175

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

180 185 190

Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser

195 200 205

Phe Asn Arg Gly Glu Cys

210

<210> 764

<211> 446

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 764

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

1 5 10 15

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

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

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

100 105 110

Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala

115 120 125

Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu

130 135 140

Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly

145 150 155 160

Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser

165 170 175

Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu

180 185 190

Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr

195 200 205

Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr

210 215 220

Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe

225 230 235 240

Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro

245 250 255

Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val

260 265 270

Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr

275 280 285

Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val

290 295 300

Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

305 310 315 320

Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser

325 330 335

Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro

340 345 350

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

355 360 365

Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly

370 375 380

Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp

385 390 395 400

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

405 410 415

Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His

420 425 430

Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

435 440 445

<210> 765

<211> 220

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 765

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

1 5 10 15

Gln Lys Val Thr Met Ser Cys Lys Ser Ser Gln Ser Leu Leu Asn Gly

20 25 30

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

35 40 45

Ser Pro Lys Leu Leu Val Tyr Phe Ala Ser Thr Arg Asp Ser Gly Val

50 55 60

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

65 70 75 80

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

85 90 95

His Phe Gly Thr Pro Pro Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile

100 105 110

Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp

115 120 125

Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn

130 135 140

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

145 150 155 160

Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp

165 170 175

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

180 185 190

Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser

195 200 205

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

210 215 220

<210> 766

<211> 10

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 766

Gly Phe Thr Leu Thr Asn Tyr Gly Met Asn

1 5 10

<210> 767

<400> 767

000

<210> 768

<400> 768

000

<210> 769

<400> 769

000

<210> 770

<400> 770

000

<210> 771

<400> 771

000

<210> 772

<400> 772

000

<210> 773

<400> 773

000

<210> 774

<400> 774

000

<210> 775

<400> 775

000

<210> 776

<400> 776

000

<210> 777

<400> 777

000

<210> 778

<400> 778

000

<210> 779

<400> 779

000

<210> 780

<400> 780

000

<210> 781

<400> 781

000

<210> 782

<400> 782

000

<210> 783

<400> 783

000

<210> 784

<400> 784

000

<210> 785

<400> 785

000

<210> 786

<400> 786

000

<210> 787

<400> 787

000

<210> 788

<400> 788

000

<210> 789

<400> 789

000

<210> 790

<400> 790

000

<210> 791

<400> 791

000

<210> 792

<400> 792

000

<210> 793

<400> 793

000

<210> 794

<400> 794

000

<210> 795

<400> 795

000

<210> 796

<400> 796

000

<210> 797

<400> 797

000

<210> 798

<400> 798

000

<210> 799

<400> 799

000

<210> 800

<400> 800

000

<210> 801

<211> 5

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 801

Ser Tyr Asn Met His

15

<210> 802

<211> 17

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 802

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

1 5 10 15

gly

<210> 803

<211> 9

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 803

Val Gly Gly Ala Phe Pro Met Asp Tyr

15

<210> 804

<211> 7

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 804

Gly Tyr Thr Phe Thr Ser Tyr

15

<210> 805

<211> 6

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 805

Tyr Pro Gly Asn Gly Asp

15

<210> 806

<211> 118

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 806

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 Tyr Thr Phe Thr Ser Tyr

20 25 30

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

35 40 45

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

50 55 60

Lys Gly Arg Val Thr Ile Thr Ala Asp Lys 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 Val Gly Gly Ala Phe Pro Met Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Thr Val Thr Val Ser Ser

115

<210> 807

<211> 354

<212> DNA

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 807

caggtgcagc tggtgcagtc aggcgccgaa gtgaagaaac ccggctctag cgtgaaagtt

60

tcttgtaaag ctagtggcta caccttcact agctataata tgcactgggt tcgccaggcc

120

ccagggcaag gcctcgagtg gatgggcgat atctaccccg ggaacggcga cactagttat

180

aatcagaagt ttaagggtag agtcactatc accgccgata agtctactag caccgtctat

240

atggaactga gttccctgag gtctgaggac accgccgtct actactgcgc tagagtgggc

300

ggagccttcc ctatggacta ctggggtcaa ggcactaccg tgaccgtgtc tagc

354

<210> 808

<211> 444

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 808

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 Tyr Thr Phe Thr Ser Tyr

20 25 30

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

35 40 45

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

50 55 60

Lys Gly Arg Val Thr Ile Thr Ala Asp Lys 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 Val Gly Gly Ala Phe Pro Met Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro

115 120 125

Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly

130 135 140

Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn

145 150 155 160

Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln

165 170 175

Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser

180 185 190

Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser

195 200 205

Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys

210 215 220

Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu

225 230 235 240

Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu

245 250 255

Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln

260 265 270

Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys

275 280 285

Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu

290 295 300

Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys

305 310 315 320

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

325 330 335

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

340 345 350

Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys

355 360 365

Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln

370 375 380

Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly

385 390 395 400

Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln

405 410 415

Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn

420 425 430

His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly

435 440

<210> 809

<211> 1332

<212> DNA

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 809

caggtgcagc tggtgcagtc aggcgccgaa gtgaagaaac ccggctctag cgtgaaagtt 60

tcttgtaaag ctagtggcta caccttcact agctataata tgcactgggt tcgccaggcc 120

ccagggcaag gcctcgagtg gatgggcgat atctaccccg ggaacggcga cactagttat 180

aatcagaagt ttaagggtag agtcactatc accgccgata agtctactag caccgtctat 240

atggaactga gttccctgag gtctgaggac accgccgtct actactgcgc tagagtgggc 300

ggagccttcc ctatggacta ctggggtcaa ggcactaccg tgaccgtgtc tagcgctagc 360

actaagggcc cgtccgtgtt ccccctggca ccttgtagcc ggagcactag cgaatccacc 420

gctgccctcg gctgcctggt caaggattac ttcccggagc ccgtgaccgt gtcctggaac 480

agcggagccc tgacctccgg agtgcacacc ttccccgctg tgctgcagag ctccgggctg 540

tactcgctgt cgtcggtggt cacggtgcct tcatctagcc tgggtaccaa gacctacact 600

tgcaacgtgg accacaagcc ttccaacact aaggtggaca agcgcgtcga atcgaagtac 660

ggcccaccgt gcccgccttg tcccgcgccg gagttcctcg gcggtccctc ggtctttctg 720

ttcccaccga agcccaagga cactttgatg atttcccgca cccctgaagt gacatgcgtg 780

gtcgtggacg tgtcacagga agatccggag gtgcagttca attggtacgt ggatggcgtc 840

gaggtgcaca acgccaaaac caagccgagg gaggagcagt tcaactccac ttaccgcgtc 900

gtgtccgtgc tgacggtgct gcatcaggac tggctgaacg ggaaggagta caagtgcaaa 960

gtgtccaaca agggacttcc tagctcaatc gaaaagacca tctcgaaagc caagggacag

1020

ccccgggaac cccaagtgta taccctgcca ccgagccagg aagaaatgac taagaaccaa

1080

gtctcattga cttgccttgt gaagggcttc tacccatcgg atatcgccgt ggaatggggag

1140

tccaacggcc agccggaaaa caactacaag accacccctc cggtgctgga ctcagacgga

1200

tccttcttcc tctactcgcg gctgaccgtg gataagagca gatggcagga gggaaatgtg

1260

ttcagctgtt ctgtgatgca tgaagccctg cacaaccact acactcagaa gtccctgtcc

1320

ctctccctgg ga 1332

<210> 810

<211> 15

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 810

Arg Ala Ser Glu Ser Val Glu Tyr Tyr Gly Thr Ser Leu Met Gln

1 5 10 15

<210> 811

<211> 7

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 811

Ala Ala Ser Asn Val Glu Ser

15

<210> 812

<211> 9

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 812

Gln Gln Ser Arg Lys Asp Pro Ser Thr

15

<210> 813

<211> 11

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 813

Ser Glu Ser Val Glu Tyr Tyr Gly Thr Ser Leu

1 5 10

<210> 814

<211> 3

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 814

Ala Ala Ser

1

<210> 815

<211> 6

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 815

Ser Arg Lys Asp Pro Ser

15

<210> 816

<211> 111

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 816

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

1 5 10 15

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

20 25 30

Gly Thr Ser Leu Met Gln Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro

35 40 45

Lys Leu Leu Ile Tyr Ala Ala Ser Asn Val Glu Ser Gly Val Pro Ser

50 55 60

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

65 70 75 80

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

85 90 95

Lys Asp Pro Ser Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105 110

<210> 817

<211> 333

<212> DNA

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 817

gctattcagc tgactcagtc acctagtagc ctgagcgcta gtgtgggcga tagagtgact 60

atcacctgta gagctagtga atcagtcgag tactacggca ctagcctgat gcagtggtat 120

cagcagaagc ccgggaaagc ccctaagctg ctgatctacg ccgcctctaa cgtggaatca 180

ggcgtgccct taggtttag cggtagcggt agtggcaccg acttcaccct gactatctct 240

agcctgcagc ccgaggactt cgctacctac ttctgtcagc agtctaggaa ggaccctagc 300

accttcggcg gaggcactaa ggtcgagatt aag 333

<210> 818

<211> 218

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 818

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

1 5 10 15

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

20 25 30

Gly Thr Ser Leu Met Gln Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro

35 40 45

Lys Leu Leu Ile Tyr Ala Ala Ser Asn Val Glu Ser Gly Val Pro Ser

50 55 60

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

65 70 75 80

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

85 90 95

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

100 105 110

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

115 120 125

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

130 135 140

Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser

145 150 155 160

Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr

165 170 175

Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys

180 185 190

His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro

195 200 205

Val Thr Lys Ser Phe Asn Arg Gly Glu Cys

210 215

<210> 819

<211> 654

<212> DNA

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 819

gctattcagc tgactcagtc acctagtagc ctgagcgcta gtgtgggcga tagagtgact 60

atcacctgta gagctagtga atcagtcgag tactacggca ctagcctgat gcagtggtat 120

cagcagaagc ccgggaaagc ccctaagctg ctgatctacg ccgcctctaa cgtggaatca 180

ggcgtgccct taggtttag cggtagcggt agtggcaccg acttcaccct gactatctct 240

agcctgcagc ccgaggactt cgctacctac ttctgtcagc agtctaggaa ggaccctagc 300

accttcggcg gaggcactaa ggtcgagatt aagcgtacgg tggccgctcc cagcgtgttc 360

atcttccccc ccagcgacga gcagctgaag agcggcaccg ccagcgtggt gtgcctgctg 420

aacaacttct acccccggga ggccaaggtg cagtggaagg tggacaacgc cctgcagagc 480

ggcaacagcc aggagagcgt caccgagcag gacagcaagg actccaccta cagcctgagc 540

agcaccctga ccctgagcaa ggccgactac gagaagcata aggtgtacgc ctgcgaggtg 600

acccaccagg gcctgtccag ccccgtgacc aagagcttca acaggggcga gtgc 654

<210> 820

<211> 17

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 820

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

1 5 10 15

gly

<210> 821

<211> 6

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 821

Tyr Pro Gly Glyn Gly Asp

15

<210> 822

<211> 118

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 822

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

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

35 40 45

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

50 55 60

Lys Gly Arg Ala Thr Met Thr Ala Asp Lys 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 Val Gly Gly Ala Phe Pro Met Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Ser Ser

115

<210> 823

<211> 354

<212> DNA

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 823

caggtgcagc tggtgcagtc aggcgccgaa gtgaagaaac ccggcgctag tgtgaaagtt 60

agctgtaaag ctagtggcta tactttcact tcttataata tgcactgggt ccgccaggcc 120

ccaggtcaag gcctcgagtg gatcggcgat atctaccccg gtcaaggcga cacttcctat 180

aatcagaagt ttaagggtag agctactatg accgccgata agtctacttc taccgtctat 240

atggaactga gttccctgag gtctgaggac accgccgtct actactgcgc tagagtgggc 300

ggagccttcc caatggacta ctggggtcaa ggcaccctgg tcaccgtgtc tagc 354

<210> 824

<211> 444

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 824

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

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

35 40 45

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

50 55 60

Lys Gly Arg Ala Thr Met Thr Ala Asp Lys 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 Val Gly Gly Ala Phe Pro Met Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro

115 120 125

Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly

130 135 140

Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn

145 150 155 160

Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln

165 170 175

Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser

180 185 190

Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser

195 200 205

Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys

210 215 220

Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu

225 230 235 240

Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu

245 250 255

Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln

260 265 270

Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys

275 280 285

Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu

290 295 300

Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys

305 310 315 320

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

325 330 335

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

340 345 350

Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys

355 360 365

Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln

370 375 380

Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly

385 390 395 400

Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln

405 410 415

Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn

420 425 430

His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly

435 440

<210> 825

<211> 1332

<212> DNA

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 825

caggtgcagc tggtgcagtc aggcgccgaa gtgaagaaac ccggcgctag tgtgaaagtt 60

agctgtaaag ctagtggcta tactttcact tcttataata tgcactgggt ccgccaggcc 120

ccaggtcaag gcctcgagtg gatcggcgat atctaccccg gtcaaggcga cacttcctat 180

aatcagaagt ttaagggtag agctactatg accgccgata agtctacttc taccgtctat 240

atggaactga gttccctgag gtctgaggac accgccgtct actactgcgc tagagtgggc 300

ggagccttcc caatggacta ctggggtcaa ggcaccctgg tcaccgtgtc tagcgctagc 360

actaagggcc cgtccgtgtt ccccctggca ccttgtagcc ggagcactag cgaatccacc 420

gctgccctcg gctgcctggt caaggattac ttcccggagc ccgtgaccgt gtcctggaac 480

agcggagccc tgacctccgg agtgcacacc ttccccgctg tgctgcagag ctccgggctg 540

tactcgctgt cgtcggtggt cacggtgcct tcatctagcc tgggtaccaa gacctacact 600

tgcaacgtgg accacaagcc ttccaacact aaggtggaca agcgcgtcga atcgaagtac 660

ggcccaccgt gcccgccttg tcccgcgccg gagttcctcg gcggtccctc ggtctttctg 720

ttcccaccga agcccaagga cactttgatg atttcccgca cccctgaagt gacatgcgtg 780

gtcgtggacg tgtcacagga agatccggag gtgcagttca attggtacgt ggatggcgtc 840

gaggtgcaca acgccaaaac caagccgagg gaggagcagt tcaactccac ttaccgcgtc 900

gtgtccgtgc tgacggtgct gcatcaggac tggctgaacg ggaaggagta caagtgcaaa 960

gtgtccaaca agggacttcc tagctcaatc gaaaagacca tctcgaaagc caagggacag

1020

ccccgggaac cccaagtgta taccctgcca ccgagccagg aagaaatgac taagaaccaa

1080

gtctcattga cttgccttgt gaagggcttc tacccatcgg atatcgccgt ggaatggggag

1140

tccaacggcc agccggaaaa caactacaag accacccctc cggtgctgga ctcagacgga

1200

tccttcttcc tctactcgcg gctgaccgtg gataagagca gatggcagga gggaaatgtg

1260

ttcagctgtt ctgtgatgca tgaagccctg cacaaccact acactcagaa gtccctgtcc

1320

ctctccctgg ga 1332

<210> 826

<211> 111

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 826

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

1 5 10 15

Glu Arg Ala Thr Ile Asn Cys Arg Ala Ser Glu Ser Val Glu Tyr Tyr

20 25 30

Gly Thr Ser Leu Met Gln Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

Lys Asp Pro Ser Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105 110

<210> 827

<211> 333

<212> DNA

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 827

gatatcgtcc tgactcagtc acccgatagc ctggccgtca gcctgggcga gcgggctact 60

attaactgta gagctagtga atcagtcgag tactacggca ctagcctgat gcagtggtat 120

cagcagaagc ccggtcaacc ccctaagctg ctgatctacg ccgcctctaa cgtggaatca 180

ggcgtgcccg ataggtttag cggtagcggt agtggcaccg acttcaccct gactattagt 240

agcctgcagg ccgaggacgt ggccgtctac tactgtcagc agtctaggaa ggaccctagc 300

accttcggcg gaggcactaa ggtcgagatt aag 333

<210> 828

<211> 218

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 828

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

1 5 10 15

Glu Arg Ala Thr Ile Asn Cys Arg Ala Ser Glu Ser Val Glu Tyr Tyr

20 25 30

Gly Thr Ser Leu Met Gln Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

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

100 105 110

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

115 120 125

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

130 135 140

Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser

145 150 155 160

Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr

165 170 175

Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys

180 185 190

His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro

195 200 205

Val Thr Lys Ser Phe Asn Arg Gly Glu Cys

210 215

<210> 829

<211> 654

<212> DNA

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 829

gatatcgtcc tgactcagtc acccgatagc ctggccgtca gcctgggcga gcgggctact 60

attaactgta gagctagtga atcagtcgag tactacggca ctagcctgat gcagtggtat 120

cagcagaagc ccggtcaacc ccctaagctg ctgatctacg ccgcctctaa cgtggaatca 180

ggcgtgcccg ataggtttag cggtagcggt agtggcaccg acttcaccct gactattagt 240

agcctgcagg ccgaggacgt ggccgtctac tactgtcagc agtctaggaa ggaccctagc 300

accttcggcg gaggcactaa ggtcgagatt aagcgtacgg tggccgctcc cagcgtgttc 360

atcttccccc ccagcgacga gcagctgaag agcggcaccg ccagcgtggt gtgcctgctg 420

aacaacttct acccccggga ggccaaggtg cagtggaagg tggacaacgc cctgcagagc 480

ggcaacagcc aggagagcgt caccgagcag gacagcaagg actccaccta cagcctgagc 540

agcaccctga ccctgagcaa ggccgactac gagaagcata aggtgtacgc ctgcgaggtg 600

acccaccagg gcctgtccag ccccgtgacc aagagcttca acaggggcga gtgc 654

<210> 830

<211> 114

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 830

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 Ala Ser Gly Phe Thr Phe Ser Ser

20 25 30

Tyr Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Asp Trp

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

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

100 105 110

Ser Ala

<210> 831

<211> 108

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 831

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 Arg Arg Tyr

20 25 30

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

35 40 45

Tyr Gly 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 Phe Ala Val Tyr Tyr Cys Gln Gln Ser His Ser Ala Pro Leu

85 90 95

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

100 105

<210> 832

<211> 120

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 832

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

1 5 10 15

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

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

Cys Ala Lys Lys Tyr Tyr Val Gly Pro Ala Asp Tyr Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ser Gly

115 120

<210> 833

<211> 113

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 833

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 His 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 Ser Ser Pro Leu Thr Phe Gly Gly Gly Thr Lys Ile Glu Val

100 105 110

Lys

<210> 834

<400> 834

000

<210> 835

<400> 835

000

<210> 836

<400> 836

000

<210> 837

<400> 837

000

<210> 838

<400> 838

000

<210> 839

<400> 839

000

<210> 840

<400> 840

000

<210> 841

<400> 841

000

<210> 842

<400> 842

000

<210> 843

<400> 843

000

<210> 844

<400> 844

000

<210> 845

<400> 845

000

<210> 846

<400> 846

000

<210> 847

<400> 847

000

<210> 848

<400> 848

000

<210> 849

<400> 849

000

<210> 850

<400> 850

000

<210> 851

<400> 851

000

<210> 852

<400> 852

000

<210> 853

<400> 853

000

<210> 854

<400> 854

000

<210> 855

<400> 855

000

<210> 856

<400> 856

000

<210> 857

<400> 857

000

<210> 858

<400> 858

000

<210> 859

<400> 859

000

<210> 860

<400> 860

000

<210> 861

<400> 861

000

<210> 862

<400> 862

000

<210> 863

<400> 863

000

<210> 864

<400> 864

000

<210> 865

<400> 865

000

<210> 866

<400> 866

000

<210> 867

<400> 867

000

<210> 868

<400> 868

000

<210> 869

<400> 869

000

<210> 870

<400> 870

000

<210> 871

<400> 871

000

<210> 872

<400> 872

000

<210> 873

<400> 873

000

<210> 874

<400> 874

000

<210> 875

<400> 875

000

<210> 876

<400> 876

000

<210> 877

<400> 877

000

<210> 878

<400> 878

000

<210> 879

<400> 879

000

<210> 880

<400> 880

000

<210> 881

<400> 881

000

<210> 882

<400> 882

000

<210> 883

<400> 883

000

<210> 884

<400> 884

000

<210> 885

<400> 885

000

<210> 886

<400> 886

000

<210> 887

<400> 887

000

<210> 888

<400> 888

000

<210> 889

<400> 889

000

<210> 890

<400> 890

000

<210> 891

<400> 891

000

<210> 892

<400> 892

000

<210> 893

<400> 893

000

<210> 894

<400> 894

000

<210> 895

<400> 895

000

<210> 896

<400> 896

000

<210> 897

<400> 897

000

<210> 898

<400> 898

000

<210> 899

<400> 899

000

<210> 900

<400> 900

000

<210> 901

<211> 121

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 901

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 Ser Leu Ser Ser Tyr

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

Arg His Ala Tyr Gly His Asp Gly Gly Phe Ala Met Asp Tyr Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 902

<211> 107

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 902

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

1 5 10 15

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

20 25 30

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

65 70 75 80

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

85 90 95

Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 903

<211> 451

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 903

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 Ser Leu Ser Ser Tyr

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

Arg His Ala Tyr Gly His Asp Gly Gly Phe Ala Met Asp Tyr Trp Gly

100 105 110

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

115 120 125

Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala

130 135 140

Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val

145 150 155 160

Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala

165 170 175

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

180 185 190

Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His

195 200 205

Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys

210 215 220

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly

225 230 235 240

Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

245 250 255

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His

260 265 270

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

275 280 285

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr

290 295 300

Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly

305 310 315 320

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

325 330 335

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val

340 345 350

Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser

355 360 365

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu

370 375 380

Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro

385 390 395 400

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

405 410 415

Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met

420 425 430

His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser

435 440 445

Pro Gly Lys

450

<210> 904

<211> 214

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 904

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

1 5 10 15

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

20 25 30

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

65 70 75 80

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

85 90 95

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

100 105 110

Pro Ser Val Phe Ile Phe Pro Ser Asp Glu Gln Leu Lys Ser Gly

115 120 125

Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala

130 135 140

Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln

145 150 155 160

Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser

165 170 175

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

180 185 190

Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser

195 200 205

Phe Asn Arg Gly Glu Cys

210

<210> 905

<211> 363

<212> DNA

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 905

60

tcttgcgctg cctccggctt ctccctgtcc tcttacggcg tggactgggt gcgacaggcc 120

cctggcaagg gcctggaatg ggtgggagtg atctggggcg gaggcggcac ctactacgcc 180

tcttccctga tgggccggtt caccatctcc cgggacaact ccaagaacac cctgtacctg 240

cagatgaact ccctgcgggc cgaggacacc gccgtgtact actgcgccag acacgcctac 300

ggccacgacg gcggcttcgc catggattat tggggccagg gcaccctggt gacagtgtcc 360

tcc

363

<210> 906

<211> 321

<212> DNA

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 906

gagatcgtga tgacccagtc ccccgccacc ctgtctgtgt ctcccggcga gagagccacc 60

ctgagctgca gagcctccga gtccgtgtcc tccaacgtgg cctggtatca gcagagacct 120

ggtcaggccc ctcggctgct gatctacggc gcctctaacc gggccaccgg catccctgcc 180

agattctccg gctccggcag cggcaccgac ttcaccctga ccatctcccg gctggaaccc 240

gaggacttcg ccgtgtacta ctgcggccag tcctactcat accccttcac cttcggccag 300

ggcaccaagc tggaaatcaa g 321

<210> 907

<211> 1353

<212> DNA

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 907

60

tcttgcgctg cctccggctt ctccctgtcc tcttacggcg tggactgggt gcgacaggcc 120

cctggcaagg gcctggaatg ggtgggagtg atctggggcg gaggcggcac ctactacgcc 180

tcttccctga tgggccggtt caccatctcc cgggacaact ccaagaacac cctgtacctg 240

cagatgaact ccctgcgggc cgaggacacc gccgtgtact actgcgccag acacgcctac 300

ggccacgacg gcggcttcgc catggattat tggggccagg gcaccctggt gacagtgtcc 360

tccgctagca ccaagggccc aagtgtgttt cccctggccc ccagcagcaa gtctacttcc 420

ggcggaactg ctgccctgggg ttgcctggtg aaggactact tccccgagcc cgtgacagtg 480

tcctggaact ctggggctct gacttccggc gtgcacacct tccccgccgt gctgcagagc 540

agcggcctgt acagcctgag cagcgtggtg acagtgccct ccagctctct gggaacccag 600

acctatatct gcaacgtgaa ccacaagccc agcaacacca aggtggacaa gagagtggag 660

cccaagagct gcgacaagac ccacacctgc cccccctgcc cagctccaga actgctggga 720

gggccttccg tgttcctgtt cccccccaag cccaaggaca ccctgatgat cagcaggacc 780

cccgaggtga cctgcgtggt ggtggacgtg tcccacgagg acccagaggt gaagttcaac 840

tggtacgtgg acggcgtgga ggtgcacaac gccaagacca agcccagaga ggagcagtac 900

aacagcacct acagggtggt gtccgtgctg accgtgctgc accaggactg gctgaacggc 960

aaagaataca agtgcaaagt ctccaacaag gccctgccag ccccaatcga aaagacaatc

1020

agcaaggcca agggccagcc acgggagccc caggtgtaca ccctgccccc cagccggggag

1080

gagatgacca agaaccaggt gtccctgacc tgtctggtga agggcttcta ccccagcgat

1140

atcgccgtgg agtgggagag caacggccag cccgagaaca actacaagac caccccccca

1200

gtgctggaca gcgacggcag cttcttcctg tacagcaagc tgaccgtgga caagtccagg

1260

tggcagcagg gcaacgtgtt cagctgcagc gtgatgcacg aggccctgca caaccactac

1320

acccagaagt ccctgagcct gagccccggc aag 1353

<210> 908

<211> 642

<212> DNA

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 908

gagatcgtga tgacccagtc ccccgccacc ctgtctgtgt ctcccggcga gagagccacc 60

ctgagctgca gagcctccga gtccgtgtcc tccaacgtgg cctggtatca gcagagacct 120

ggtcaggccc ctcggctgct gatctacggc gcctctaacc gggccaccgg catccctgcc 180

agattctccg gctccggcag cggcaccgac ttcaccctga ccatctcccg gctggaaccc 240

gaggacttcg ccgtgtacta ctgcggccag tcctactcat accccttcac cttcggccag 300

ggcaccaagc tggaaatcaa gcgtacggtg gccgctccca gcgtgttcat cttccccccc 360

agcgacgagc agctgaagag cggcaccgcc agcgtggtgt gcctgctgaa caacttctac 420

ccccgggagg ccaaggtgca gtggaaggtg gacaacgccc tgcagagcgg caacagccag 480

gagagcgtca ccgagcagga cagcaaggac tccacctaca gcctgagcag caccctgacc 540

ctgagcaagg ccgactacga gaagcataag gtgtacgcct gcgaggtgac ccaccagggc 600

ctgtccagcc ccgtgaccaa gagcttcaac aggggcgagt gc 642

<210> 909

<211> 5

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 909

Ser Tyr Gly Val Asp

15

<210> 910

<211> 7

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 910

Gly Phe Ser Leu Ser Ser Tyr

15

<210> 911

<211> 16

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 911

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

1 5 10 15

<210> 912

<211> 5

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 912

Trp Gly Gly Gly Gly

15

<210> 913

<211> 13

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 913

His Ala Tyr Gly His Asp Gly Gly Phe Ala Met Asp Tyr

1 5 10

<210> 914

<211> 11

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 914

Arg Ala Ser Glu Ser Val Ser Ser Asn Val Ala

1 5 10

<210> 915

<211> 7

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 915

Ser Glu Ser Val Ser Ser Asn

15

<210> 916

<211> 7

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 916

Gly Ala Ser Asn Arg Ala Thr

15

<210> 917

<211> 3

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 917

Gly Ala Ser

1

<210> 918

<211> 9

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 918

Gly Gln Ser Tyr Ser Tyr Pro Phe Thr

15

<210> 919

<211> 6

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 919

Ser Tyr Ser Tyr Pro Phe

15

<210> 920

<211> 124

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 920

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

100 105 110

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

115 120

<210> 921

<211> 107

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 921

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

1 5 10 15

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

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 922

<400> 922

000

<210> 923

<400> 923

000

<210> 924

<400> 924

000

<210> 925

<400> 925

000

<210> 926

<400> 926

000

<210> 927

<400> 927

000

<210> 928

<400> 928

000

<210> 929

<400> 929

000

<210> 930

<400> 930

000

<210> 931

<400> 931

000

<210> 932

<400> 932

000

<210> 933

<400> 933

000

<210> 934

<400> 934

000

<210> 935

<400> 935

000

<210> 936

<400> 936

000

<210> 937

<400> 937

000

<210> 938

<400> 938

000

<210> 939

<400> 939

000

<210> 940

<400> 940

000

<210> 941

<400> 941

000

<210> 942

<400> 942

000

<210> 943

<400> 943

000

<210> 944

<400> 944

000

<210> 945

<400> 945

000

<210> 946

<400> 946

000

<210> 947

<400> 947

000

<210> 948

<400> 948

000

<210> 949

<400> 949

000

<210> 950

<400> 950

000

<210> 951

<400> 951

000

<210> 952

<400> 952

000

<210> 953

<400> 953

000

<210> 954

<400> 954

000

<210> 955

<400> 955

000

<210> 956

<400> 956

000

<210> 957

<400> 957

000

<210> 958

<400> 958

000

<210> 959

<400> 959

000

<210> 960

<400> 960

000

<210> 961

<400> 961

000

<210> 962

<400> 962

000

<210> 963

<400> 963

000

<210> 964

<400> 964

000

<210> 965

<400> 965

000

<210> 966

<400> 966

000

<210> 967

<400> 967

000

<210> 968

<400> 968

000

<210> 969

<400> 969

000

<210> 970

<400> 970

000

<210> 971

<400> 971

000

<210> 972

<400> 972

000

<210> 973

<400> 973

000

<210> 974

<400> 974

000

<210> 975

<400> 975

000

<210> 976

<400> 976

000

<210> 977

<400> 977

000

<210> 978

<400> 978

000

<210> 979

<400> 979

000

<210> 980

<400> 980

000

<210> 981

<400> 981

000

<210> 982

<400> 982

000

<210> 983

<400> 983

000

<210> 984

<400> 984

000

<210> 985

<400> 985

000

<210> 986

<400> 986

000

<210> 987

<400> 987

000

<210> 988

<400> 988

000

<210> 989

<400> 989

000

<210> 990

<400> 990

000

<210> 991

<400> 991

000

<210> 992

<400> 992

000

<210> 993

<400> 993

000

<210> 994

<400> 994

000

<210> 995

<400> 995

000

<210> 996

<400> 996

000

<210> 997

<400> 997

000

<210> 998

<400> 998

000

<210> 999

<400> 999

000

<210> 1000

<400> 1000

000

<210> 1001

<211> 114

<212> Protein

<213> Homo sapiens

<400> 1001

Asn Trp Val Asn Val Ile Ser Asp Leu Lys Lys Ile Glu Asp Leu Ile

1 5 10 15

Gln Ser Met His Ile Asp Ala Thr Leu Tyr Thr Glu Ser Asp Val His

20 25 30

Pro Ser Cys Lys Val Thr Ala Met Lys Cys Phe Leu Leu Glu Leu Gln

35 40 45

Val Ile Ser Leu Glu Ser Gly Asp Ala Ser Ile His Asp Thr Val Glu

50 55 60

Asn Leu Ile Ile Leu Ala Asn Ser Leu Ser Ser Asn Gly Asn Val

65 70 75 80

Thr Glu Ser Gly Cys Lys Glu Cys Glu Glu Leu Glu Glu Lys Asn Ile

85 90 95

Lys Glu Phe Leu Gln Ser Phe Val His Ile Val Gln Met Phe Ile Asn

100 105 110

Thr Ser

<210> 1002

<211> 170

<212> Protein

<213> Homo sapiens

<400> 1002

Ile Thr Cys Pro Pro Pro Met Ser Val Glu His Ala Asp Ile Trp Val

1 5 10 15

Lys Ser Tyr Ser Leu Tyr Ser Arg Glu Arg Tyr Ile Cys Asn Ser Gly

20 25 30

Phe Lys Arg Lys Ala Gly Thr Ser Ser Leu Thr Glu Cys Val Leu Asn

35 40 45

Lys Ala Thr Asn Val Ala His Trp Thr Thr Pro Ser Leu Lys Cys Ile

50 55 60

Arg Asp Pro Ala Leu Val His Gln Arg Pro Ala Pro Pro Ser Thr Val

65 70 75 80

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

85 90 95

Lys Glu Pro Ala Ala Ser Ser Pro Ser Ser Asn Asn Thr Ala Ala Thr

100 105 110

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

115 120 125

Ser Thr Gly Thr Thr Glu Ile Ser Ser His Glu Ser Ser His Gly Thr

130 135 140

Pro Ser Gln Thr Thr Ala Lys Asn Trp Glu Leu Thr Ala Ser Ala Ser

145 150 155 160

His Gln Pro Pro Gly Val Tyr Pro Gln Gly

165 170

<210> 1003

<211> 114

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 1003

Asn Trp Val Asn Val Ile Ser Asp Leu Lys Lys Ile Glu Asp Leu Ile

1 5 10 15

Gln Ser Met His Ile Asp Ala Thr Leu Tyr Thr Glu Ser Asp Val His

20 25 30

Pro Ser Cys Lys Val Thr Ala Met Lys Cys Phe Leu Leu Glu Leu Gln

35 40 45

Val Ile Ser Leu Glu Ser Gly Asp Ala Ser Ile His Asp Thr Val Glu

50 55 60

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

65 70 75 80

Thr Glu Ser Gly Cys Lys Glu Cys Glu Glu Leu Glu Glu Lys Asn Ile

85 90 95

Lys Glu Phe Leu Gln Ser Phe Val His Ile Val Gln Met Phe Ile Asn

100 105 110

Thr Ser

<210> 1004

<211> 297

<212> Protein

<213> Faux Sequence

<220>

<221> source

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

Synthetic polypeptide"

<400> 1004

Ile Thr Cys Pro Pro Pro Met Ser Val Glu His Ala Asp Ile Trp Val

1 5 10 15

Lys Ser Tyr Ser Leu Tyr Ser Arg Glu Arg Tyr Ile Cys Asn Ser Gly

20 25 30

Phe Lys Arg Lys Ala Gly Thr Ser Ser Leu Thr Glu Cys Val Leu Asn

35 40 45

Lys Ala Thr Asn Val Ala His Trp Thr Thr Pro Ser Leu Lys Cys Ile

50 55 60

Arg Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro

65 70 75 80

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

85 90 95

Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val

100 105 110

Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr

115 120 125

Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu

130 135 140

Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His

145 150 155 160

Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys

165 170 175

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

180 185 190

Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Ser Arg Asp Glu Leu

195 200 205

Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro

210 215 220

Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn

225 230 235 240

Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu

245 250 255

Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val

260 265 270

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

275 280 285

Lys Ser Leu Ser Leu Ser Pro Gly Lys

290 295

<210> 1005

<211> 114

<212> Protein

<213> Homo sapiens

<220>

<221> MOD_RES

<222> (93)..(93)

<223> Glu or Lys

<400> 1005

Asn Trp Val Asn Val Ile Ser Asp Leu Lys Lys Ile Glu Asp Leu Ile

1 5 10 15

Gln Ser Met His Ile Asp Ala Thr Leu Tyr Thr Glu Ser Asp Val His

20 25 30

Pro Ser Cys Lys Val Thr Ala Met Lys Cys Phe Leu Leu Glu Leu Gln

35 40 45

Val Ile Ser Leu Glu Ser Gly Asp Ala Ser Ile His Asp Thr Val Glu

50 55 60

Asn Leu Ile Ile Leu Ala Asn Ser Leu Ser Ser Asn Gly Asn Val

65 70 75 80

Thr Glu Ser Gly Cys Lys Glu Cys Glu Glu Leu Glu Xaa Lys Asn Ile

85 90 95

Lys Glu Phe Leu Gln Ser Phe Val His Ile Val Gln Met Phe Ile Asn

100 105 110

Thr Ser

<210> 1006

<211> 77

<212> Protein

<213> Homo sapiens

<400> 1006

Ile Thr Cys Pro Pro Pro Met Ser Val Glu His Ala Asp Ile Trp Val

1 5 10 15

Lys Ser Tyr Ser Leu Tyr Ser Arg Glu Arg Tyr Ile Cys Asn Ser Gly

20 25 30

Phe Lys Arg Lys Ala Gly Thr Ser Ser Leu Thr Glu Cys Val Leu Asn

35 40 45

Lys Ala Thr Asn Val Ala His Trp Thr Thr Pro Ser Leu Lys Cys Ile

50 55 60

Arg Asp Pro Ala Leu Val His Gln Arg Pro Ala Pro Pro

65 70 75

<---

Claims (59)

1. Use of an anti-LAG-3 antibody molecule at a dose of 300 to 700 mg or 900 to 1300 mg once every two weeks, once every three weeks, or once every four weeks, in the treatment of cancer in a subject, where the anti-LAG-3 antibody molecule contains a heavy chain variable region (VH) containing the amino acid sequence of VHCDR1 SEQ ID NO: 701, the amino acid sequence of VHCDR2 SEQ ID NO: 702 and the amino acid sequence of VHCDR3 SEQ ID NO: 703; and a light chain variable region (VL) comprising the amino acid sequence of VLCDR1 SEQ ID NO: 710, the amino acid sequence of VLCDR2 SEQ ID NO: 711, and the amino acid sequence of VLCDR3 SEQ ID NO: 712. 2. A method of treating cancer in a subject, comprising administering to the subject an anti-LAG-3 antibody molecule at a dose of 300 to 700 mg or 900 to 1300 mg once every two weeks, once every three weeks, or once every four weeks, where the anti-LAG-3 antibody molecule contains a heavy chain variable region (VH) containing the amino acid sequence of VHCDR1 SEQ ID NO: 701, the amino acid sequence of VHCDR2 SEQ ID NO: 702 and the amino acid sequence of VHCDR3 SEQ ID NO: 703; and a light chain variable region (VL) comprising the amino acid sequence of VLCDR1 SEQ ID NO: 710, the amino acid sequence of VLCDR2 SEQ ID NO: 711, and the amino acid sequence of VLCDR3 SEQ ID NO: 712. 3. Use according to claim 1 or method according to claim 2, wherein the anti-LAG-3 antibody molecule is used at a dose of 300 to 700 mg once every two weeks. 4. The use or method of claim 3, wherein the anti-LAG-3 antibody molecule is administered at a dose of 300 to 700 mg once every three weeks. 5. Use according to claim 1 or method according to claim 2, wherein the anti-LAG-3 antibody molecule is used at a dose of 300 to 700 mg or 900 to 1300 mg once every four weeks. 6. The use or method of claim 5 wherein the anti-LAG-3 antibody molecule is administered at a dose of 300, 400, 600, or 1000 mg once every two weeks, once every three weeks, or once every four weeks. 7. The use according to any one of claims 1 or 3-6 or the method according to any one of claims 2-6, wherein the antibody molecule comprises a VH containing the amino acid sequence of SEQ ID NO: 706 and a VL containing the amino acid sequence of SEQ ID NO: 718 . 8. The use according to any one of claims 1 or 3-7 or the method according to any one of claims 2-7, wherein the antibody molecule comprises a heavy chain containing the amino acid sequence of SEQ ID NO: 709 and a light chain containing the amino acid sequence of SEQ ID NO : 721. 9. The use according to any one of claims 1 or 3-6, or the method according to any one of claims 2-6, wherein the antibody molecule comprises a VH containing the amino acid sequence of SEQ ID NO: 724 and a VL containing the amino acid sequence of SEQ ID NO: 730 . 10. The use according to any one of claims 1, 3-6 or 9 or the method according to any one of claims 2-6 or 9, wherein the antibody molecule comprises a heavy chain containing the amino acid sequence of SEQ ID NO: 727 and a light chain containing the sequence amino acids SEQ ID NO: 733. 11. The use according to any one of claims 1 or 3-10, or the method according to any one of claims 2-10, wherein the cancer is a solid tumor or a hematological cancer. 12. The use according to any one of claims 1 or 3-11 or the method according to any one of claims 2-11, wherein the cancer is brain cancer, pancreatic cancer, skin cancer, kidney cancer, breast cancer, virus-associated cancer disease, anal cancer, cervical cancer, gastrointestinal cancer, head and neck cancer, nasopharyngeal (NPC) cancer, penile cancer, vaginal or vulvar cancer, colon and rectal cancer, lung cancer, leukemia, lymphoma, myeloma, or metastatic disease in cancer disease. 13. The use or method of claim 12, wherein the cancer is brain cancer, which is glioblastoma or gliosarcoma. 14. The use or method of claim 12 wherein the cancer is skin cancer which is melanoma or Merkel cell carcinoma. 15. The use or method of claim 12, wherein the cancer is kidney cancer, which is renal cell carcinoma (RCC). 16. The use or method of claim 12, wherein the cancer is breast cancer, which is breast carcinoma or triple negative breast cancer (TNBC). 17. Use according to or method according to claim 12, wherein the cancer is a viral cancer, which is anal cancer, cervical cancer, gastrointestinal cancer, head and neck cancer, nasopharyngeal (NPC) cancer, penile cancer, or vaginal or vulvar cancer. 18. The use or method of claim 12, wherein the cancer is colon and rectal cancer, which is colon and rectal cancer with microsatellite instability, microsatellite stable colon and rectal cancer, colon and rectal cancer surplus for mismatch repair, or Colon and rectal cancer is deficient in terms of mispaired base repair. 19. The use or method of claim 12, wherein the cancer is lung cancer, which is non-small cell lung cancer (NSCLC). 20. The use or method of claim 12 wherein the cancer is a lymphoma that is Hodgkin's lymphoma (HL) or diffuse large B cell lymphoma (DLBCL). 21. The use of any one of claims 1 or 3-20, or the method of any one of claims 2-20, wherein the cancer is advanced cancer, metastatic cancer, recurrent cancer, recurrent cancer, or unresectable cancer. 22. Use according to any one of claims 1, 3-21, or method according to any one of claims 2-21, wherein the anti-LAG-3 antibody molecule is used in combination with a second therapeutic agent or treatment. 23. Use according to any one of claims 1, 3-22, or method according to any one of claims 2-22, wherein the anti-LAG-3 antibody molecule is used in combination with a PD-1 inhibitor. 24. The use or method of claim 23 wherein the PD-1 inhibitor is PDR001, nivolumab, pembrolizumab, MEDI0680, REGN2810, PF-06801591, BGB-A317, INCHR1210, TSR-042, or AMP-224. 25. The use or method of claim 23 or 24 wherein the PD-1 inhibitor is used at a dose of 300 mg once every three weeks or 400 mg once every four weeks. 26. The use of any one of claims 1, 3-25, or the method of any one of claims 2-25, wherein the anti-LAG-3 antibody molecule is used in combination with a PD-L1 inhibitor. 27. The use or method of claim 26 wherein the PD-L1 inhibitor is FAZ053, atezolizumab, avelumab, durvalumab, or BMS-936559. 28. Use according to any one of claims 1, 3-27, or method according to any one of claims 2-27, wherein the anti-LAG-3 antibody molecule is used in combination with a chemotherapeutic agent. 29. The use or method of claim 28 wherein the chemotherapeutic agent is a platinum agent and a nucleotide analog or precursor analog. 30. The use or method of claim 29 wherein the platinum agent is carboplatin, cisplatin, oxaliplatin, or tetraplatin. 31. The use or method of claim 29 wherein the nucleotide analog or precursor analog comprises capecitabine. 32. The use according to any one of claims 1, 3-31, or the method according to any one of claims 2-31, wherein the anti-LAG-3 antibody molecule is used to treat NSCLC cancer, melanoma, kidney cancer, glioblastoma, virus associated cancer or cancer of the colon and rectum. 33. The use or method of claim 32 wherein the anti-LAG-3 antibody molecule is used in combination with an anti-PD-1 antibody molecule. 34. The use of any one of claims 1, 3-31, or the method of any one of claims 2-31, wherein the anti-LAG-3 antibody molecule is used to treat pancreatic cancer or breast cancer. 35. The use or method of claim 34, wherein the cancer is breast cancer, which is TNBC. 36. The use or method of claim 34 or 35, wherein the anti-LAG-3 antibody molecule is used in combination with an anti-PD-1 antibody molecule. 37. The use or method of any one of claims 34-36, wherein the anti-LAG-3 antibody molecule is used in combination with a chemotherapeutic agent. 38. The use or method of claim 37 wherein the chemotherapeutic agent is selected from a platinum agent or a nucleotide analog or precursor analog. 39. The use or method of claim 38 wherein the platinum agent is carboplatin, cisplatin, oxaliplatin, or tetraplatin. 40. The use or method of claim 38 wherein the nucleotide analog or precursor analog comprises capecitabine. 41. Use according to any one of claims 1 or 3-40, or method according to any one of claims 2-40, wherein the subject has or is identified as having LAG-3 expression in tumor infiltrating lymphocytes (TIL). 42. The use of any one of claims 1 or 3-41, or the method of any one of claims 2-41, wherein the subject has or is identified as having a cancer that expresses PD-L1. 43. The use of a pharmaceutical composition containing an effective amount of an anti-LAG-3 antibody molecule at a dose of 300 to 700 mg or 900 to 1300 mg once every two weeks, once every three weeks or once every four weeks, in the treatment cancer in the subject where the anti-LAG-3 antibody molecule contains a heavy chain variable region (VH) containing the amino acid sequence of VHCDR1 SEQ ID NO: 701, the amino acid sequence of VHCDR2 SEQ ID NO: 702 and the amino acid sequence of VHCDR3 SEQ ID NO: 703; and a light chain variable region (VL) comprising the amino acid sequence of VLCDR1 SEQ ID NO: 710, the amino acid sequence of VLCDR2 SEQ ID NO: 711, and the amino acid sequence of VLCDR3 SEQ ID NO: 712. 44. Use of a dosage form containing an effective amount of an anti-LAG-3 antibody molecule at a dose of 300 to 700 mg once every three weeks or 900 to 1300 mg once every four weeks in the treatment of cancer in a subject, where the anti-LAG-3 antibody molecule contains a heavy chain variable region (VH) containing the amino acid sequence of VHCDR1 SEQ ID NO: 701, the amino acid sequence of VHCDR2 SEQ ID NO: 702 and the amino acid sequence of VHCDR3 SEQ ID NO: 703; and a light chain variable region (VL) comprising the amino acid sequence of VLCDR1 SEQ ID NO: 710, the amino acid sequence of VLCDR2 SEQ ID NO: 711, and the amino acid sequence of VLCDR3 SEQ ID NO: 712. 45. Use according to claim 43 or 44, where the dose is: a) 300 to 700 mg once every two weeks; (b) 300 to 700 mg once every three weeks; (c) 300 to 700 mg or 900 to 1300 mg once every four weeks. 46. Use according to claim 43 or 44, where the dose is 300, 400, 600 or 1000 mg once every two weeks, once every three weeks or once every four weeks. 47. Application according to any one of paragraphs. 43-46, where the antibody molecule contains a VH containing the amino acid sequence of SEQ ID NO: 706 and a VL containing the amino acid sequence of SEQ ID NO: 718. 48. Application according to any one of paragraphs. 43-46, where the antibody molecule contains a heavy chain containing the amino acid sequence of SEQ ID NO: 709 and a light chain containing the amino acid sequence of SEQ ID NO: 721. 49. Use according to any one of claims 43-46, wherein the antibody molecule comprises a VH containing the amino acid sequence of SEQ ID NO: 724 and a VL containing the amino acid sequence of SEQ ID NO: 730. 50. Application according to any one of paragraphs. 43-46 or 49, where the antibody molecule contains a heavy chain containing the amino acid sequence of SEQ ID NO: 727 and a light chain containing the amino acid sequence of SEQ ID NO: 733. 51. Application according to any one of paragraphs. 43-50, where the cancer is a solid tumor or a hematological cancer. 52. Application according to any one of paragraphs. 43-51, where the cancer is brain cancer, pancreatic cancer, skin cancer, kidney cancer, breast cancer, viral cancer, anal cancer, cervical cancer, gastrointestinal cancer, head and neck cancer, nasopharyngeal cancer (NPC ), penile cancer, vaginal or vulvar cancer, colon and rectal cancer, lung cancer, leukemia, lymphoma, myeloma, or metastatic cancer.