TW202304979A - USES OF ANTI-TGFβ ANTIBODIES AND OTHER THERAPEUTIC AGENTS FOR THE TREATMENT OF PROLIFERATIVE DISEASES - Google Patents

Abstract

Therapies using TGF[beta] inhibitors, PD-1 inhibitors, and/or chemotherapeutic agents are disclosed. These drugs at certain doses (including flat dosing) and regimens can be used to treat or prevent proliferative diseases such as solid tumors, including pancreatic or colorectal cancers. Further combination and uses thereof are also disclosed.

Description

Use of anti-TGF beta antibodies and other therapeutic agents for the treatment of proliferative diseases

The present disclosure provides therapies and dosing regimens for the treatment of proliferative diseases using TGFβ inhibitors, PD-1 inhibitors and/or chemotherapeutic agents.

The transforming growth factor beta (TGFβ) protein family consists of three distinct isoforms (TGFβ1, TGFβ2 and TGFβ3) found in mammals. TGFβ proteins activate and regulate a variety of genetic responses that affect disease states, including cell proliferative, inflammatory, and cardiovascular disorders. The TGFβ family of multifunctional cytokines was originally named for its ability to transform normal fibroblasts into cells capable of anchorage-independent growth. TGFβ molecules are primarily produced by hematopoietic and neoplastic cells and can regulate (i.e. stimulate or inhibit) the growth and differentiation of cells from a variety of normal and neoplastic tissue sources (Sporn et al., Science, 233: 532 (1986)), And stimulate the formation and expansion of various stromal cells.

TGFβ is known to be involved in many proliferative and non-proliferative cellular processes, such as cell proliferation and differentiation, embryonic development, extracellular matrix formation, bone development, wound healing, hematopoiesis, and immune and inflammatory responses. See eg, Pircher et al., Biochem. Biophys. Res. Commun., 136: 30-37 (1986); Wakefield et al., Growth Factors, 1: 203- 218 (1989); Roberts and Sporn, in Handbook of Experimental Pharmacology eds. M. B. Sporn and A. B. Roberts (Springer, Heidelberg, 1990), pp. 419-472; Massague et al., Annual Rev. . Cell Biol. [Annual Review of Cell Biology], 6: 597-646 (1990); Singer and Clark, New Eng. J . Med. [New England Journal of Medicine], 341: 738-745 (1999). In addition, TGFβ is also used in the treatment and prevention of intestinal mucosal diseases (WO 2001/24813). TGFβ is also known to have strong immunosuppressive effects on various immune cell types, including cytotoxic T lymphocyte (CTL) suppression (Ranges et al., J .Exp. Med. [Journal of Experimental Medicine], 166: 991, 1987; Espevik et al., J. Immunol., 140: 2312, 1988), reduced B cell lymphopoiesis and kappa light chain expression (Lee et al., J. Exp. Med., 166 : 1290, 1987), negative regulation of hematopoiesis (Sing et al., Blood [blood], 72: 1504, 1988), downregulation of HLA-DR expression on tumor cells (Czarniecki et al., J. Immunol.[Journal of Immunology] , 140: 4217, 1988), and the inhibition of antigen-activated B lymphocyte proliferation in response to B cell growth factors (Petit-Koskas et al., Eur. J . Immunol.[European Journal of Immunology], 18: 111, 1988) . See also US Patent 7,527,791.

There is an unmet need for the use of TGFβ inhibitors, such as anti-TGFβ antibodies, to target various diseases and medical conditions. Furthermore, there exists a need for administering such TGFβ inhibitors in a manner to effectively treat various diseases and medical conditions, including proliferative diseases, while maintaining ease of administration.

Disclosed herein is a method of treating a proliferative disease in a subject in need thereof, the method comprising administering to the subject a TGFβ antibody and at least one additional therapeutic agent, wherein the TGFβ antibody is administered at about 1400 mg to about 2100 mg Doses are given every two, three, or four weeks. In some embodiments, the TGFβ antibody is administered at about 1400 mg every two weeks. In some embodiments, the TGFβ antibody is administered at about 2100 mg every two weeks. In some embodiments, the TGFβ antibody is administered at about 2100 mg every three weeks. In some embodiments, the TGFβ antibody is administered at about 45 mg/kg every three weeks. In some embodiments, the TGFβ antibody is administered at about 30 mg/kg every three weeks. In some embodiments, the TGFβ antibody is administered at about 20 mg/kg every three weeks.

The TGFβ antibody may comprise heavy chain CDR1, CDR2 and CDR3 of SEQ ID NO: 1, 2 and 3, respectively, and light chain CDR1, CDR2 and CDR3 of SEQ ID NO: 4, 5 and 6, respectively. The TGFβ antibody may comprise a heavy chain variable region and a light chain variable region shown in the amino acid sequences of SEQ ID NO: 7 and 8, respectively. The TGFβ antibody may comprise a heavy chain and a light chain shown in the amino acid sequences of SEQ ID NO: 9 and 10, respectively.

In some embodiments, the TGFβ antibody is a monoclonal antibody. In some embodiments, the TGFβ antibody is a fully human antibody.

In some embodiments, the TGFβ inhibitor is administered over a period of about 30 minutes.

In some embodiments, the additional therapeutic agent is one or more of the following: a PD-1 inhibitor, gemcitabine, nab-paclitaxel, folinic acid (leucovorin calcium or levoleucovorin), fluorouracil (5-FU), oxaliplatin (eloxatin), bevacizumab, or irinotecan .

For example, in some embodiments, the additional therapeutic agent includes a PD-1 inhibitor. The PD-1 inhibitor can be an anti-PD-1 antibody. In some embodiments, the anti-PD-1 antibody is PDR001 (spartalizumab), BGB-A317 (tislelizumab), or BGB-108. For example, the anti-PD-1 antibody is tislelizumab. Tislelizumab may have a heavy chain of SEQ ID NO: 321. Tislelizumab may have a light chain of SEQ ID NO: 322. In some embodiments, the anti-PD-1 antibody is administered at 100 mg weekly. In some embodiments, the anti-PD-1 antibody is tislelizumab and is administered at 300 mg every 28-day (ie, four-week) cycle (Q4W). In some embodiments, the anti-PD-1 antibody is tislelizumab and is administered at 200 mg every 21 day (ie, three week) cycle (Q3W).

In some embodiments, the additional therapeutic agent comprises gemcitabine. If gemcitabine is used, it can be administered at about 1000 mg/ ^m2 . In some embodiments, gemcitabine is administered on days 1, 8, and 15 of a 28-day cycle.

In some embodiments, the additional therapeutic agent comprises nab-paclitaxel. If nab-paclitaxel is used, it can be administered at about 125 mg/ ^m2 . In some embodiments, nab-paclitaxel is administered on days 1, 8, and 15 of a 28-day cycle.

In some embodiments, the additional therapeutic agent comprises gemcitabine and nab-paclitaxel. In some embodiments, the additional therapeutic agent includes a PD-inhibitor, gemcitabine, and nab-paclitaxel.

In some embodiments, the additional therapeutic agent comprises bevacizumab. If bevacizumab is used, it can be administered at about 5 mg/kg. In some embodiments, bevacizumab is administered on days 1 and 15 of a 28-day cycle.

In some embodiments, the additional therapeutic agent comprises 5-fluorouracil. If 5-fluorouracil is used, it can be administered at about 400 mg/ ^m2 . In some embodiments, 5-fluorouracil can be administered at about 2400 mg/ ^m2 . In some embodiments, the 5-fluorouracil is administered on days 1 and 15 of a 28-day cycle. In some embodiments, 5-fluorouracil is administered as an intravenous (IV) bolus. For example, 5-fluorouracil can be administered as an intravenous bolus injection of 400 mg/ ^m2 on days 1 and 15 of each 28-day cycle followed by a continuous intravenous infusion of 2400 mg/ ^m2 over 46 hours.

In some embodiments, the additional therapeutic agent comprises folinic acid. If folinic acid is used, it can be administered at about 400 mg/ ^m2 . In some embodiments, folinic acid is administered on days 1 and 15 of a 28-day cycle. In some cases, folinic acid can be replaced by levofolinic acid. If levofolinic acid is used, it can be administered at 200 mg/ ^m2 . In some embodiments, leucovorin is administered on days 1 and 15 of a 28-day cycle.

In some embodiments, the additional therapeutic agent comprises oxaliplatin. If oxaliplatin is used, it can be administered at about 85 mg/ ^m2 . In some embodiments, oxaliplatin is administered on days 1 and 15 of a 28-day cycle.

In some embodiments, the additional therapeutic agent comprises irinotecan. When irinotecan is used, it can be administered at about 180 mg/ ^m2 . In some embodiments, irinotecan is administered on days 1 and 15 of a 28-day cycle.

In some embodiments, the additional therapeutic agent includes bevacizumab, 5-fluorouracil, leucovorin, and oxaliplatin. In some embodiments, the additional therapeutic agent includes a PD-1 inhibitor, bevacizumab, 5-fluorouracil, leucovorin, and oxaliplatin. In some embodiments, the additional therapeutic agent includes bevacizumab, 5-fluorouracil, leucovorin, and irinotecan. In some embodiments, the additional therapeutic agent includes a PD-1 inhibitor, bevacizumab, 5-fluorouracil, leucovorin, and irinotecan.

In some embodiments, the TGFβ antibody and the one or more additional therapeutic agents are administered to the subject over 2 or more cycles. In some embodiments, the period may be 28 days long. In some cases, the period may be 21 days long.

The proliferative disease treatable with the TGFβ antibody and the one or more additional therapeutic agents can be pancreatic cancer or colorectal cancer.

Further disclosed herein is a method of treating pancreatic adenocarcinoma in a subject in need thereof, the method comprising administering to the subject 2100 mg of TGFβ antibody, 1000 mg/m ² of gemcitabine, and 125 mg/m ² of Nab-paclitaxel, wherein the TGFβ antibody is administered on Days 1 and 15 of a 28-day cycle, and gemcitabine and nab-paclitaxel are administered on Days 1, 8, and 15 of the cycle , and wherein the TGFβ antibody comprises heavy chain CDR1, CDR2 and CDR3 of SEQ ID NO: 1, 2 and 3, respectively, and light chain CDR1, CDR2 and CDR3 of SEQ ID NO: 4, 5 and 6, respectively.

In some embodiments, the method comprises administering a PD-1 inhibitor to the patient. The PD-1 inhibitor can be spartakizumab or tislelizumab. If spartakizumab is administered, it can be given at 400 mg every four (4) weeks. If tislelizumab is used, it can be administered at 100 mg/week of treatment. For example, tislelizumab could be given at 400 mg every four (4) weeks. In some embodiments, the TGFβ antibody, gemcitabine, and nab-paclitaxel (and optionally a PD-1 inhibitor) are administered to the subject over 2 or more cycles. In some embodiments, the TGFβ antibody, gemcitabine, and nab-paclitaxel (and optionally a PD-1 inhibitor) are administered intravenously to the subject.

Disclosed herein is a method of treating colorectal cancer in a subject in need thereof comprising administering to the subject 2100 mg of TGFβ antibody, 5 mg/kg of bevacizumab, 400 to 2400 mg/m ² of 5-fluorouracil, 400 mg/m ² of folinic acid, and 85 mg/m ² of oxaliplatin, wherein the TGFβ antibody, bevacizumab, 5-fluorouracil, leucovorin, and oxaliplatin in Administered on days 1 and 15 of a 28-day cycle, and wherein the TGFβ antibody comprises heavy chain CDR1, CDR2, and CDR3 of SEQ ID NO: 1, 2, and 3, respectively, and SEQ ID NO: 4, 5, respectively and 6 light chain CDR1, CDR2 and CDR3.

In some embodiments, the TGFβ antibody, bevacizumab, 5-fluorouracil, leucovorin, and oxaliplatin are administered to the subject over 2 or more cycles. In some embodiments, the TGFβ antibody, bevacizumab, 5-fluorouracil, leucovorin, and oxaliplatin are administered intravenously to the subject. In some embodiments, 5-fluorouracil is administered as an intravenous bolus of 400 mg/m2 followed by a continuous intravenous infusion of 2400 mg/m2 over 46 hours.

In some embodiments, the method of treating colorectal cancer in a subject in need thereof comprises administering to the subject 2100 mg of a TGFβ antibody, 5 mg/kg of bevacizumab, 400 to 2400 mg/m ² 5-fluorouracil, 400 mg/ ^m2 of folinic acid, and 180 mg/ ^m2 of irinotecan, where the TGFβ antibody, bevacizumab, 5-fluorouracil, leucovorin, and irinotecan were given in a 28-day cycle Administration on days 1 and 15 of , and wherein the TGFβ antibody comprises heavy chain CDR1, CDR2 and CDR3 of SEQ ID NO: 1, 2 and 3, respectively, and the heavy chain of SEQ ID NO: 4, 5 and 6, respectively Light chain CDR1, CDR2 and CDR3.

In some embodiments, the TGFβ antibody, bevacizumab, 5-fluorouracil, leucovorin, and irinotecan are administered to the subject over 2 or more cycles. In some embodiments, the TGFβ antibody, bevacizumab, 5-fluorouracil, leucovorin, and irinotecan are administered intravenously to the subject. In some embodiments, 5-fluorouracil is administered as an intravenous bolus of 400 mg/m2 followed by a continuous intravenous infusion of 2400 mg/m2 over 46 hours.

In some embodiments, the TGFβ inhibitor is administered concurrently with the one or more additional therapeutic agents. In some embodiments, the TGFβ inhibitor is administered prior to the one or more additional therapeutic agents. In some embodiments, the TGFβ inhibitor is administered after the one or more additional therapeutic agents.

In some embodiments, the TGFβ inhibitor and/or the one or more additional therapeutic agents are administered until remission.

In some embodiments, the additional therapeutic agent comprises cyclophosphamide or topotecan. When cyclophosphamide is used, it can be administered at 250 mg/ ^m2 . In some embodiments, the cyclophosphamide is administered for 5 days, eg, five consecutive days. In some embodiments, the additional therapeutic agent comprises topotecan administered at 0.75 mg/ ^m2 . When topotecan is used, its administration can be continued for 5 days, for example five consecutive days. In some embodiments, the proliferative disease is neuroblastoma.

In some embodiments, the additional therapeutic agent comprises gemcitabine. When gemcitabine is used, it can be administered at 675 mg/ ^m2 . In some embodiments, the gemcitabine is administered for 2 days, eg, on day 1 and day 8. In some embodiments, the proliferative disease is osteosarcoma.

In some embodiments, various combinations and dosages can be used in subjects considered to be pediatric patients (eg, under the age of 18).

Disclosed herein is a method of treating pancreatic adenocarcinoma or colorectal cancer in a subject in need thereof, the method comprising administering to the subject (a) 2100 mg of TGFβ antibody, (b) 500 mg/m ² Intravenous bolus followed by 46-hour continuous infusion of 5-fluorouracil at 2400 mg/ ^m2 , (c) leucovorin (folinic acid) administered intravenously at 400 mg/ ^m2 )) or levofolinic acid administered intravenously at 200 mg/ ^m2 , (d) irinotecan administered intravenously at 180 mg/ ^m2 , and (e) bevacizumab at 5 mg/kg, wherein the TGFβ antibody is administered on Day 1 (and optionally on Day 15) of a 28-day cycle, and wherein the 5-fluorouracil, leucovorin (or leucovorin), irinotecan, and bevacizumab are administered on Administered on days 1 and 15 of the 28-day cycle, and wherein the TGFβ antibody comprises heavy chain CDR1, CDR2, and CDR3 of SEQ ID NO: 1, 2, and 3, respectively, and SEQ ID NO: 4, Light chain CDR1, CDR2 and CDR3 of 5 and 6.

Disclosed herein is a method of treating pancreatic adenocarcinoma or colorectal cancer in a subject in need thereof, the method comprising administering to the subject (a) 2100 mg of TGFβ antibody, (b) 400 mg/m ² Intravenous bolus followed by 46-hour continuous infusion of 5-fluorouracil at 2400 mg/ ^m2 , (c) leucovorin (leucovorin) administered intravenously at 400 mg/ ^m2 or at 200 mg/m2 Leucovorin administered intravenously in ^m2 , (d) irinotecan administered intravenously at 180 mg/ ^m2 , and (e) bevacizumab at 5 mg/kg, wherein the TGFβ antibody was administered on day 28 Administered on Day 1 (and optionally on Day 15) of the cycle, and wherein the 5-fluorouracil, leucovorin (or leucovorin), irinotecan, and bevacizumab are administered on Day 1 of the 28-day cycle Administration on day 1 and day 15, and wherein the TGFβ antibody comprises heavy chain CDR1, CDR2 and CDR3 of SEQ ID NO: 1, 2 and 3, respectively, and light chain CDR1 of SEQ ID NO: 4, 5 and 6, respectively , CDR2 and CDR3.

Also disclosed herein is a method of treating pancreatic adenocarcinoma or colorectal cancer in a subject in need thereof, the method comprising administering to the subject (a) 2100 mg of TGFβ antibody, (b) 500 mg/m ² IV bolus followed by 46-hour continuous infusion of 5-fluorouracil at 2400 mg/ ^m2 , (c) leucovorin (leucovorin) administered IV at 400 mg/ ^m2 or 200 mg Leucovorin administered intravenously at 85 mg/m ² , (d) oxaliplatin administered intravenously at 85 mg/m ² , and (e) bevacizumab at 5 mg/kg, wherein the TGFβ antibody was administered at Administered on Day 1 (and optionally on Day 15) of a 28-day cycle, and wherein the 5-fluorouracil, leucovorin (or leucovorin), oxaliplatin, and bevacizumab were administered during the 28-day cycle Administration on days 1 and 15 of , and wherein the TGFβ antibody comprises heavy chain CDR1, CDR2 and CDR3 of SEQ ID NO: 1, 2 and 3, respectively.

Also disclosed herein is a method of treating pancreatic adenocarcinoma or colorectal cancer in a subject in need thereof, the method comprising administering to the subject (a) 2100 mg of TGFβ antibody, (b) 400 mg/m ² IV bolus followed by 46-hour continuous infusion of 5-fluorouracil at 2400 mg/ ^m2 , (c) leucovorin (leucovorin) administered IV at 400 mg/ ^m2 or 200 mg Leucovorin administered intravenously at 85 mg/m ² , (d) oxaliplatin administered intravenously at 85 mg/m ² , and (e) bevacizumab at 5 mg/kg, wherein the TGFβ antibody was administered at Administered on Day 1 (and optionally on Day 15) of a 28-day cycle, and wherein the 5-fluorouracil, leucovorin (or leucovorin), oxaliplatin, and bevacizumab were administered during the 28-day cycle Administration on days 1 and 15 of , and wherein the TGFβ antibody comprises heavy chain CDR1, CDR2 and CDR3 of SEQ ID NO: 1, 2 and 3, respectively.

The methods can further comprise administering to the patient a PD-1 inhibitor. In some embodiments, the PD-1 inhibitor is tislelizumab. Tislelizumab can have a heavy chain of SEQ ID NO: 321 and a light chain of SEQ ID NO: 322. In some embodiments, tislelizumab is administered intravenously at 300 mg on Day 1 of each 28-day cycle.

In some embodiments, the TGFβ antibody, 5-fluorouracil, leucovorin (or leucovorin), oxaliplatin, irinotecan, bevacizumab, or PD-1 inhibitors in 2 or more cycles Administered to the subject.

Also disclosed herein is a method of treating gastric cancer in a subject in need thereof, the method comprising administering to the subject (a) 2100 mg of TGFβ antibody, and (b) 200 mg of PD administered in a Q3W cycle -1 inhibitor, in combination with (c) oxaliplatin administered intravenously at 130 mg/ ^m on day 1, (d) orally ^twice daily at 1000 mg/m in a Q3W cycle (day 1- 14 days) of capecitabine (capecitabine), wherein the TGFβ antibody comprises heavy chain CDR1, CDR2 and CDR3 of SEQ ID NO: 1, 2 and 3, respectively, and SEQ ID NO: 4, 5 and 6 Light chain CDR1, CDR2 and CDR3. The PD-1 inhibitor can be tislelizumab. In some embodiments, the TGFβ antibody is administered at a dose of 1400 mg or 2100 mg in a Q2W cycle. In other embodiments, the PD-1 inhibitor is administered at a dose of 300 mg on a Q4W cycle.

Also disclosed herein is a method of treating gastric cancer in a subject in need thereof, the method comprising administering to the subject (a) 2100 mg of TGFβ antibody administered in a Q3W cycle, and (b) administered in a Q3W cycle 200 mg of PD-1 inhibitor, in combination with (c) oxaliplatin administered intravenously at 85 mg/ ^m2 (on day 1), (d) oxaliplatin administered intravenously at 400 mg/m2 Folinic acid or L-folinic acid administered intravenously at 200 mg/ ^m2 (on day 1), (e) 5-fluorouracil administered intravenously at 400 mg/ ^m2 (on day 1) and (f ) administered intravenously (on days 1-2) at 1200 mg/m ² daily in a Q2W cycle, wherein the TGFβ antibody comprises heavy chain CDR1, CDR2, and CDR3 of SEQ ID NO: 1, 2, and 3, respectively, and light chain CDR1, CDR2 and CDR3 of SEQ ID NO: 4, 5 and 6, respectively. The PD-1 inhibitor can be tislelizumab. In some embodiments, the TGFβ antibody is administered at a dose of 1400 mg or 2100 mg in a Q2W cycle. In other embodiments, the PD-1 inhibitor is administered at a dose of 300 mg on a Q4W cycle.

Other features, objects, and advantages of the invention will be apparent from the description and drawings, and from the scope of the claims.

incorporated by reference

All publications, patents, patent applications, and other documents cited in this application are hereby incorporated by reference in their entirety for all purposes to the same extent as if each individual publication, patent, patent application, or other document was cited in its entirety. Purposes are individually indicated to be incorporated by reference. In the event of an inconsistency between the teachings of one or more references incorporated herein and the present disclosure, the teachings of the present specification control. sequence listing

This application contains a Sequence Listing that has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. The ASCII copy created on December 17, 2021 is named PAT059084_SL.txt and is 350,107 bytes in size.

The immune system is responsible for the early detection and destruction of cancer cells. Cancer cells can escape immune surveillance through various mechanisms, such as decreased immune recognition, increased resistance to immune cell attack, or due to an immunosuppressive tumor microenvironment (Mittal et al., 2014). Some cancers produce TGFβ, a potent immunosuppressive interleukin, which antagonizes cytotoxic lymphocytes and promotes the recruitment of suppressive immune cells, thereby favoring tumor growth and progression (Wojtowicz-Praga-2003, Teicher, 2007, Yang et al. People, 2010).

TGFβ belongs to a large family of structurally related cytokines including: bone morphogenic proteins (BMPs), growth and differentiation factors, activins and inhibins. There are three isoforms of TGFβ ligands expressed in mammals, TGFβ1, 2 and 3. Under normal conditions, TGFβ maintains homeostasis and limits the growth of epithelial, endothelial, neural and hematopoietic cell lineages (by inducing anti-proliferative and apoptotic responses). Thus, alterations in TGFβ signaling pathways are believed to be associated with human disease, including cardiovascular disease, fibrosis, reproductive disorders, wound healing, and cancer (Wakefield and Hill, 2013).

NIS793 is a fully human IgG2, human/mouse cross-reactive, TGFβ neutralizing antibody. NIS793 acts at the ligand-receptor level. Compared to fresolimumab, a pan-TGFβ inhibitor in its lineage and all TGFβ isoforms, NIS793 more specifically antagonizes TGFβ1 and 2 and to a lesser extent TGFβ3.

To evade immune surveillance, cancer cells can additionally exploit immune checkpoint pathways that tightly regulate T cell activation, such as the PD-1/PD-L1 axis (Pardoll, 2012). Thus, antagonism of TGFβ alone or in combination with immune checkpoint blockade could stimulate more effective antitumor immunity. definition

Additional terms are defined below and throughout the application.

As used herein, the article "a and an" refers to one or more than one (eg, at least one) of the grammatical object of the article.

Unless the context clearly indicates otherwise, the term "or" is used herein to mean and be used interchangeably with the term "and/or".

"About" and "approximately" mean an acceptable degree of error for a measured quantity given the nature or precision of the measurement. Exemplary degrees of error are within 20%, typically within 10%, and more typically, within 5% of a given value or range of values. In some embodiments, when a numerical value refers to the term "about", the number is intended to also include the exact value of that number. For example, "about 10" includes, but is not limited to, a value of ten. It also includes 10±2, 10±1 or 10±0.5.

References to "in combination" or "in combination with" are not intended to imply that the therapies or therapeutic agents must be administered and/or formulated for delivery together, although such delivery methods are also described herein within the range. The therapeutic agents in the combination can be administered simultaneously with, before, or after one or more other additional therapies or therapeutic agents. The therapeutic agents or treatment regimens can be administered in any order. Typically, each agent will be administered at a dose and/or schedule established for that agent. It is also understood that the additional therapeutic agents used in the combination may be administered together in a single composition or separately in different compositions. Administration of the therapeutic agents can be in any order. The first agent and the additional agents (eg, second, third agents) can be administered by the same route of administration or by different routes of administration. In general, it is contemplated that the additional therapeutic agents used in combination will not be used at levels exceeding their use alone. In some embodiments, the levels used in combination will be lower than those used alone.

In some embodiments, the additional therapeutic agent is administered at or below a therapeutic dose. In certain embodiments, when the second therapeutic agent is administered in combination with the first therapeutic agent (e.g., an anti-TGFβ antibody molecule), the concentration of the second therapeutic agent required to achieve inhibition (e.g., growth inhibition) is greater than when administered alone Low for a second therapeutic agent (eg, anti-PD1 antibody molecule). In certain embodiments, when a first therapeutic agent is administered in combination with a second therapeutic agent, a lower concentration of the first therapeutic agent is required to achieve inhibition (eg, growth inhibition) than when the first therapeutic agent is administered alone. In certain embodiments, in combination therapy, the concentration of the second therapeutic agent required to achieve inhibition (e.g., growth inhibition) is lower, e.g., 10-20%, lower, than the therapeutic dose of the second therapeutic agent as monotherapy. 20-30%, 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 required to achieve inhibition (e.g., growth inhibition) is lower, e.g., 10-20%, lower, than the therapeutic dose of the first therapeutic agent as monotherapy. 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, or 80-90%.

The terms "inhibit", "inhibitor" or "antagonist" include the reduction of a certain parameter (eg activity) of a given molecule (eg immune checkpoint inhibitor or TGFβ inhibitor). For example, the term includes inhibiting at least 5%, 10%, 20%, 30%, 40% or more of an activity (eg, TGFβ, PD-1 or PD-L1 activity). Therefore, inhibition need not be 100%.

The term "activation", "activator" or "agonist" includes an increase in some parameter (eg activity) of a given molecule (eg 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 "anticancer 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 number of cancer cells, reduction in number of metastases, extension of life expectancy, reduction in cancer cell proliferation, cancer cell survival reduction in cancer rates, or improvement in various physiological symptoms associated with cancer. "Anticancer effect" can also be manifested by the ability of peptides, polynucleotides, cells and antibodies to prevent cancer from developing in the first place.

The term "anti-tumor effect" refers to a biological effect that can be manifested by various means, including but not limited to, for example, a decrease in tumor volume, a decrease in the number of tumor cells, a decrease in tumor cell proliferation, or a decrease in the survival rate of tumor cells.

The term "cancer" refers to diseases characterized by the rapid and uncontrolled growth of abnormal cells (eg, proliferative disorders). Cancer cells can be localized or spread to other parts of the body through the bloodstream and lymphatic system. Examples of various cancers are described herein and include, but are not limited to, solid tumors (e.g., lung cancer, breast cancer, prostate cancer, ovarian cancer, cervical cancer, skin cancer, pancreatic cancer, colorectal cancer, kidney cancer, liver cancer, and brain cancer) and hematological malignancies (e.g., lymphoma and leukemia, among others). The terms "tumor" and "cancer" are used interchangeably herein, eg, both terms encompass solid and liquid tumors, eg, 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 an immune system cell such as a helper cell (e.g., B cell, dendritic cell, etc.) Complex foreign antigens. T cells can recognize these complexes using their T cell receptor (TCR). APCs process antigens and present them to T cells.

The term "costimulatory molecule" refers to a cognate binding partner on a T cell that specifically binds to a costimulatory ligand, thereby mediating a T cell costimulatory response, such as but not limited to proliferation . Costimulatory molecules are cell surface molecules other than antigen receptors or their ligands that are required for an effective immune response. Costimulatory molecules include but are not limited to MHC class I molecules, TNF receptor proteins, immunoglobulin-like proteins, interleukin receptors, integrins, signaling lymphocyte activation 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, CD8α, CD8β, IL2Rβ, IL2R γ, IL7R α, 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 specifically binding to CD83.

As the term is used herein, an "immune effector cell" or "effector cell" refers to a cell that participates in an immune response (eg, promotes an immune effector response). Examples of immune effector cells include T cells, such as α/β T cells and γ/δ T cells, B cells, natural killer (NK) cells, natural killer T (NKT) cells, mast cells, and myeloid-derived phagocytes.

As the term is used herein, "immune effector" or "effector" "function" or "response" refers to, for example, the function or response of an immune effector cell that enhances or facilitates an immune attack of a target cell. For example, immune effector function or response refers to the properties of T or NK cells that promote killing of target cells or inhibit growth or proliferation. In the case of T cells, primary stimuli and co-stimulation are examples of immune effector functions or responses.

The term "effector function" refers to a specialized function of a cell. For example, the effector function of a T cell can be cytolytic activity or helper activity (including secretion of cytokines).

As used herein, the terms "treat, treatment and treating" refer to reducing or ameliorating the progression, severity and/or duration of, or ameliorating a disorder (e.g., a proliferative disorder) caused by the administration of one or more One or more symptoms (preferably, one or more identifiable symptoms) of the disorder. In particular embodiments, the terms "treat, treatment and treating" refer to the improvement of at least one measurable physical parameter of a proliferative disorder, such as tumor growth, but not necessarily a patient-discernible physical parameter. . In other embodiments, the terms "treat, treatment, and treating" refer to inhibiting proliferation, either physically, such as by stabilizing discernible symptoms, or physiologically, such as by stabilizing a physical parameter, or both. Progression of sexual disorders. In other embodiments, the terms "treat, treatment and treating" refer to reducing or stabilizing tumor size or cancer cell count.

Compositions, formulations and methods of the invention encompass compositions having a specified sequence, or a sequence that is substantially identical or similar to a specified sequence (e.g., at least 80%, 81%, 82%, 83%, 84%, 85% identical to a specified sequence) , 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical or more identical sequences) peptides and nucleic acids. In the context of amino acid sequences, the term "substantially identical" is used herein to refer to a first amino acid that contains i) an amino acid residue that is compared to an aligned amino acid residue in a second amino acid sequence identical, or ii) a sufficient or minimum number of amino acid residues that are conservative substitutions of aligned amino acid residues in the second amino acid sequence such that the first amino acid sequence and the second amino acid sequence The acid sequences may have a common domain and/or a common functional activity. For example, containing at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91% of a reference sequence (e.g., a sequence provided herein) %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identity of the amino acid sequence of the common domain.

In the context of nucleotide sequences, the term "substantially identical" is used herein to refer to a first nucleic acid sequence that contains a sufficient or minimal number of nucleotides that are identical to an aligned nucleotide in a second nucleic acid sequence. Nucleotides, so that the first nucleotide sequence and the second nucleotide sequence encode polypeptides with common functional activity, or encode common structural polypeptide domains or have common functional polypeptide activity. For example, at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91% with a reference sequence (e.g., a sequence provided herein) , 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical nucleotide sequences.

The term "functional variant" refers to a polypeptide having substantially the same amino acid sequence as a naturally occurring sequence, or a polypeptide encoded by substantially the same nucleotide sequence and capable of possessing one or more activities of the naturally occurring sequence .

Calculations of homology or sequence identity (the terms are used interchangeably herein) between sequences are performed as described below.

To determine the percent identity of two amino acid sequences or two nucleic acid sequences, the sequences are aligned for optimal comparison (e.g., between a first amino acid and a second amino acid or between a first nucleic acid sequence and Gaps are introduced in one or both of the second nucleic acid sequences for optimal alignment, and non-homologous sequences can be ignored for comparison purposes). In a preferred embodiment, the length of the reference sequences 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%. The amino acid residues or nucleotides at corresponding amino acid positions or nucleotide positions are then compared. 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, amino acid or nucleic acid "Identity" is equivalent to amino acid or nucleic acid "homology").

Taking into account the number of gaps and the length of each gap, the percent identity between two sequences is a function of the number of identical positions shared by the sequences that need to be introduced for optimal alignment of the two sequences right.

The comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm. In a preferred embodiment, the Needleman and Wunsch ((1970) J. Mol. Biol. [Journal of Molecular Biology] 48:444-453) algorithm (which has been incorporated into the GAP program in the GCG software package) is used Medium (available from www.gcg.com)), using a Blossum 62 matrix or a PAM250 matrix with gap weights of 16, 14, 12, 10, 8, 6, or 4 and 1, 2, 3, 4, 5, or 6 Length weights are used to determine the percent identity between two amino acid sequences. In yet another preferred embodiment, the NWSgapdna.CMP matrix and gap weights of 40, 50, 60, 70, or 80 and A length weight of 1, 2, 3, 4, 5, or 6 is used to determine the percent identity between two nucleotide sequences. A particularly preferred set of parameters (and parameters that should be used unless otherwise specified) is the Blossum 62 scoring matrix with a gap penalty of 12, a gap extension penalty of 4, and a frameshift gap penalty of 5.

The algorithm of E. Meyers and W. Miller ((1989) CABIOS [Computer Applications in Biological Sciences] 4:11-17) can be used (which has been incorporated into the ALIGN program (version 2.0)), using PAM120 weights A residue table, a gap length penalty of 12, and a gap penalty of 4 are used to determine the percent identity between two amino acid or nucleotide sequences.

The nucleic acid sequences and protein sequences described herein can be used as "query sequences" to perform searches against public databases, eg, to identify other family members or related sequences. Such searches can be performed using the NBLAST and XBLAST programs (version 2.0) of Altschul et al. (1990) J. Mol. Biol . 215:403-10. BLAST nucleotide searches can be performed with the NBLAST program (score = 100, wordlength = 12) to obtain nucleotide sequences homologous to nucleic acid molecules of the invention. BLAST protein searches can be performed with the XBLAST program (score = 50, wordlength = 3) to obtain amino acid sequences homologous to protein molecules of the invention. To obtain gapped alignments for comparison purposes, Gapped BLAST can be used as described in Altschul et al., (1997) Nucleic Acids Res. 25:3389-3402. When using BLAST and Gapped BLAST programs, 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 conditions of low stringency, medium stringency, high stringency, or very high stringency" describes conditions for hybridization and washing. Instructions for performing hybridization reactions can be found in Current Protocols in Molecular Biology , John Wiley & Sons, NY (1989), 6.3.1-6.3.6 . Aqueous and non-aqueous methods are described in this reference, and either can be used. The specific hybridization conditions involved in this article are as follows: 1) Low stringency hybridization conditions: Hybridization in 6X sodium chloride/sodium citrate (SSC) at approximately 45°C, followed by at least 50°C in 0.2X SSC, 0.1% SDS Wash twice under low stringency conditions (for low stringency conditions, the washing temperature can be increased to 55°C); 2) Medium stringency hybridization conditions: hybridize in 6X SSC at about 45°C, then in 0.2X SSC, 0.1% SDS Wash once or more times at medium 60°C; 3) high stringency hybridization conditions: hybridize at about 45°C in 6X SSC, then wash once or more times at 65°C in 0.2X SSC, 0.1% SDS; And preferably, 4) very high stringency hybridization conditions are 0.5M sodium phosphate, 7% SDS, 65°C, and then wash one or more times in 0.2X SSC, 1% SDS at 65°C. Very high stringency conditions (4) are the preferred conditions and conditions that should be used unless otherwise indicated.

It is understood that the molecules of the invention may have additional conservative or nonessential amino acid substitutions which do not substantially affect the function of the molecule.

The term "amino acid" is intended to include all molecules, whether natural or synthetic, which include both amine functional groups and acid functional groups and which can be included in polymers of naturally occurring amino acids. Exemplary amino acids include naturally occurring amino acids; their analogs, derivatives, and congeners; amino acid analogs with variant side chains; and all stereoisomers of any of the foregoing. As used herein, the term "amino acid" includes D-optical or L-optical isomers and peptidomimetics.

A "conservative amino acid substitution" is one 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 have been defined in the art. These families include amino acids with basic side chains (e.g., lysine, arginine, histidine), amino acids with acidic side chains (e.g., aspartic acid, glutamic acid), Amino acids with uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), with nonpolar Amino acids with side chains (eg , alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), amines with beta-branched side chains amino acids (eg, threonine, valine, isoleucine), and amino acids with aromatic side chains (eg, tyrosine, phenylalanine, tryptophan, histidine).

The terms "polypeptide", "peptide" and "protein" (if single-chain) are used interchangeably herein to refer to a polymer of amino acids of any length. The polymer can be linear or branched, it can contain modified amino acids, and it can be interrupted by non-amino acids. These terms also encompass amino acid polymers that have been modified; eg, disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation, such as conjugation with a labeling component. Polypeptides can be isolated from natural sources, can be produced by recombinant techniques from host eukaryotic or prokaryotic hosts, or can 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 nucleotides of any length in polymeric form, ie deoxyribonucleotides or ribonucleotides, or their analogs. A polynucleotide can be single-stranded or double-stranded, and if single-stranded, the polynucleotide can be coding or noncoding (antisense) stranded. A polynucleotide may include modified nucleotides, such as methylated nucleotides and nucleotide analogs. The sequence of nucleotides may be interrupted by non-nucleotide components. Polynucleotides may be further modified after polymerization, such as by conjugation with a labeling component. A nucleic acid may be a recombinant polynucleotide, or a polynucleotide of genomic, cDNA, semi-synthetic or synthetic origin which does not occur in nature or which is linked to another polynucleotide in a non-natural arrangement.

As used herein, the term "isolated" refers to material that has been removed from its original or natural environment, such as the natural environment in which 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 is isolated by human intervention from some or all of the coexisting materials in the natural system. Such polynucleotides can be part of a vector and/or such polynucleotides or polypeptides can be part of a composition and still be isolated in that such vector or composition is not part of its naturally occurring environment.

Various aspects of the invention are described in further detail below. Additional definitions are set forth throughout this application. TGFβ inhibitor

TGFβ belongs to a large family of structurally related cytokines including, for example, bone-morphogenic proteins (BMPs), growth and differentiation factors, activins and inhibins. In some embodiments, a TGFβ inhibitor described herein can bind to and/or inhibit one or more isoforms of TGFβ (eg, one, two, or all of TGFβ1, TGFβ2, or TGFβ3).

Inhibitors (eg, anti-TGFβ antibody molecules) are described throughout and can be used in the methods described throughout.

In some embodiments, the TGFβ inhibitor is NIS793, fusumumumab, PF-06952229, or AVID200.

In some embodiments, the TGFβ inhibitor comprises NIS973 or a compound disclosed in International Application Publication No. WO 2012/167143. NIS793 is also known as XOMA 089 or XPA.42.089. NIS793 is a fully human monoclonal antibody that specifically binds and neutralizes TGF-β 1 and 2 ligands.

The heavy chain CDR1, CDR2 and CDR3 of NIS793 respectively have the following amine sequences: GGTFSSYAIS (SEQ ID NO: 1); GIIPIFGTANYAQKFQG (SEQ ID NO: 2); and GLWEVRALPSVY (SEQ ID NO: 3).

The light chain CDR1, CDR2 and CDR3 of NIS793 respectively have the following amine sequences: GANDIGSKSVH (SEQ ID NO: 4); EDIIRPS (SEQ ID NO: 5); QVWDRDSDQYV (SEQ ID NO: 6).

The heavy chain variable region of NIS793 has the following amino acid sequence: QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARGLWEVRALPSVYWGQGTLVTVSS (SEQ ID NO: 7) (disclosed as SEQ ID NO: 6 in WO 2012/167143). The light chain variable region of NIS793 has the following amino acid sequence: SYELTQPPSVSVAPGQTARITCGANDIGSKSVHWYQQKAGQAPVLVVSEDIIRPSGIPERISGSNSGNTATLTISRVEAGDEADYYCQVWDRDSDQYVFGTGTKVTVLG (SEQ ID NO: 8) (disclosed as SEQ ID NO: 8 in WO 2012/167143).

NIS793的重鏈具有以下胺基酸序列：QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARGLWEVRALPSVYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVTSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGMEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK（SEQ ID NO: 9）。 NIS793的輕鏈具有以下胺基酸序列：SYELTQPPSVSVAPGQTARITCGANDIGSKSVHWYQQKAGQAPVLVVSEDIIRPSGIPERISGSNSGNTATLTISRVEAGDEADYYCQVWDRDSDQYVFGTGTKVTVLGQPKANPTVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADGSPVKAGVETTKPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS（SEQ ID NO: 10）。

NIS793 binds the human TGFβ isoform with high affinity. In general, NIS793 binds TGFβ1 and TGFβ2 with high affinity, and to a lesser extent TGFβ3. The KD _lines of NIS793 on human TGFβ were 14.6 pM (for TGFβ1), 67.3 pM (for TGFβ2), and 948 pM (for TGFβ3) in the Biacore assay. Given the high affinity binding to all three TGF[beta] isoforms, in certain embodiments NIS793 is expected to bind TGF[beta]1, 2 and 3 at the doses of NIS793 as described herein. NIS793 cross-reacts with rodent and macaque TGFβ and shows functional activity in vitro and in vivo, making rodents and macaques relevant species for toxicology studies.

In certain embodiments, a TGFβ inhibitor is used to treat cancer (eg, pancreatic cancer (such as PDAC) or gastrointestinal cancer (such as colorectal cancer)). In some embodiments, the TGFβ inhibitor is used in combination with a checkpoint inhibitor (eg, an inhibitor of PD1 described herein) for the treatment of cancer.

In some embodiments, the TGFβ inhibitor (eg, NIS793) is administered at a dose greater than 15 mg/kg. For example, the TGFβ inhibitor is administered at a dose of between 15.1 mg/kg and about 50 mg/kg. In some embodiments, the TGFβ inhibitor is administered at a dose of between about 16 mg/kg and about 50 mg/kg. In some embodiments, the TGFβ inhibitor is administered at a dose of between 16 mg/kg and about 50 mg/kg. In some embodiments, the TGFβ inhibitor is administered at a dose of between about 20 mg/kg and about 40 mg/kg. In some embodiments, the TGFβ inhibitor is administered at a dose of between about 25 mg/kg and about 35 mg/kg. In some embodiments, the TGFβ inhibitor is administered at a dose of about 20 mg/kg. In some embodiments, the TGFβ inhibitor is administered at a dose of about 30 mg/kg. In some embodiments, the TGFβ inhibitor is administered at a dose of about 45 mg/kg.

In some embodiments, the TGFβ inhibitor (eg, NIS793) is administered at a fixed dose. For example, in some embodiments, the TGFβ inhibitor is administered at a dose of between about 1000 mg to about 1600 mg. In some embodiments, the TGFβ inhibitor is administered at a dose of between about 1100 mg to about 1500 mg. In some embodiments, the TGFβ inhibitor is administered at a dose of between about 1200 to about 1400 mg. In some embodiments, the TGFβ inhibitor is administered at a dose of between about 1300 mg to about 1400 mg. In some embodiments, the TGFβ inhibitor is administered at a dose of between about 1300 mg to about 1500 mg. In some embodiments, the TGFβ inhibitor is administered at a dose of between about 1300 mg to about 1600 mg. In some embodiments, the TGFβ inhibitor is administered at a dose of between about 1200 mg to about 1500 mg. In some embodiments, the TGFβ inhibitor is administered at a dose of between about 1200 mg to about 1600 mg. In some embodiments, the TGFβ inhibitor is administered at a dose of between about 1400 mg to about 1500 mg. In some embodiments, the TGFβ inhibitor is administered at a dose of between about 1400 mg to about 1600 mg. In some embodiments, the TGFβ inhibitor is administered at a dose of between about 1100 mg to about 1600 mg. In some embodiments, the TGFβ inhibitor is administered at a dose of between 1100 mg to about 1400 mg. In some embodiments, the TGFβ inhibitor is administered at a dose of between about 1100 mg to about 1300 mg. In some embodiments, the TGFβ inhibitor is administered at a dose of between about 1100 mg to about 1200 mg. In some embodiments, the TGFβ inhibitor is administered at a dose between or about 1000 mg to about 1500 mg. In some embodiments, the TGFβ inhibitor is administered at a dose between or about 1000 mg to about 1400 mg. In some embodiments, the TGFβ inhibitor is administered at a dose between or about 1000 mg to about 1300 mg. In some embodiments, the TGFβ inhibitor is administered at a dose between or about 1000 mg to about 1200 mg. In some embodiments, the TGFβ inhibitor is administered at a dose between or about 1000 mg to about 1100 mg. In some embodiments, the TGFβ inhibitor is administered at a dose of about 1000 mg. In some embodiments, the TGFβ inhibitor is administered at a dose of about 1100 mg. In some embodiments, the TGFβ inhibitor is administered at a dose of about 1200 mg. In some embodiments, the TGFβ inhibitor is administered at a dose of about 1300 mg. In some embodiments, the TGFβ inhibitor is administered at a dose of about 1400 mg. In some embodiments, the TGFβ inhibitor is administered at a dose of about 1500 mg. In some embodiments, the TGFβ inhibitor is administered at a dose of about 1600 mg. In some embodiments, the TGFβ inhibitor is administered at a dose of between about 1200 mg to about 2100 mg.

In some embodiments, the TGFβ inhibitor is administered at a dose of between about 2000 mg to about 2500 mg. In some embodiments, the TGFβ inhibitor is administered at a dose of between about 2000 mg to about 2400 mg. In some embodiments, the TGFβ inhibitor is administered at a dose of between about 1900 mg to about 2300 mg. In some embodiments, the TGFβ inhibitor is administered at a dose of between about 1900 mg to about 2200 mg. In some embodiments, the TGFβ inhibitor is administered at a dose of between about 2000 mg to about 2100 mg. In some embodiments, the TGFβ inhibitor is administered at a dose of between about 2100 mg to about 2500 mg. In some embodiments, the TGFβ inhibitor is administered at a dose of between about 2100 to about 2400 mg. In some embodiments, the TGFβ inhibitor is administered at a dose of between about 2100 to about 2300 mg. In some embodiments, the TGFβ inhibitor is administered at a dose of between about 2100 to about 2200 mg. In some embodiments, the TGFβ inhibitor is administered at a dose of between about 2200 to about 2500 mg. In some embodiments, the TGFβ inhibitor is administered at a dose of between about 2200 to about 2400 mg. In some embodiments, the TGFβ inhibitor is administered at a dose of between about 2200 to about 2300 mg. In some embodiments, the TGFβ inhibitor is administered at a dose of between about 2300 mg to about 2500 mg. In some embodiments, the TGFβ inhibitor is administered at a dose of between about 2300 mg to about 2400 mg. In some embodiments, the TGFβ inhibitor is administered at a dose of between about 2400 mg to about 2500 mg. In some embodiments, the TGFβ inhibitor is administered at a dose of about 2000 mg. In some embodiments, the TGFβ inhibitor is administered at a dose of about 2100 mg. In some embodiments, the TGFβ inhibitor is administered at a dose of about 2200 mg. In some embodiments, the TGFβ inhibitor is administered at a dose of about 2300 mg. In some embodiments, the TGFβ inhibitor is administered at a dose of about 2400 mg. In some embodiments, the TGFβ inhibitor is administered at a dose of about 2500 mg.

In some embodiments, the TGFβ inhibitor is administered weekly, every two weeks, every three weeks, or every four weeks. In some embodiments, the TGFβ inhibitor is administered weekly. In some embodiments, the TGFβ inhibitor is administered every two weeks. In some embodiments, the TGFβ inhibitor is administered every three weeks. In some embodiments, the TGFβ inhibitor is administered every four to three weeks.

In some embodiments, the TGFβ inhibitor is administered intravenously.

In some embodiments, the TGFβ inhibitor is administered over a period of about 20 minutes to about 40 minutes. For example, the TGFβ inhibitor is administered over a period of about 30 minutes. In some embodiments, the TGFβ inhibitor is administered over a period of about one hour. In some embodiments, the TGFβ inhibitor is administered over a period of about two hours. In some embodiments, the TGFβ inhibitor is administered over a period of about three hours. In some embodiments, the TGFβ inhibitor is administered over a period of about four hours. In some embodiments, the TGFβ inhibitor is administered over a period of about five hours. In some embodiments, the TGFβ inhibitor is administered over a period of about six hours.

In some embodiments, the TGFβ inhibitor (eg, NIS793) is administered intravenously at a dose of between about 1300 mg to about 1500 mg (eg, about 1400 mg) once every two weeks. In some embodiments, the TGFβ inhibitor (eg, NIS793) is administered intravenously at a dose of between about 2000 mg to about 2200 mg (eg, about 2100 mg) once every two weeks. In some embodiments, the TGFβ inhibitor (eg, NIS793) is administered intravenously at a dose of between about 2000 mg to about 2200 mg (eg, about 2100 mg) once every three weeks.

In some embodiments, every two weeks at a dose of between about 1300 mg to about 1500 mg (eg, about 1400 mg) for a period of about 20 minutes to about 40 minutes (eg, about 30 minutes) Once, a TGFβ inhibitor (eg, NIS793) is administered intravenously. In some embodiments, every two weeks at a dose of between about 2000 mg to about 2200 mg (eg, about 2100 mg) for a period of about 20 minutes to about 40 minutes (eg, about 30 minutes) Once, a TGFβ inhibitor (eg, NIS793) is administered intravenously. In some embodiments, every three weeks at a dose of between about 2000 mg to about 2200 mg (eg, about 2100 mg) for a period of about 20 minutes to about 40 minutes (eg, about 30 minutes) Once, a TGFβ inhibitor (eg, NIS793) is administered intravenously.

In some embodiments, the TGFβ inhibitor (eg, NIS793 ). In some embodiments, the TGFβ inhibitor (eg, NIS793 ). In some embodiments, the TGFβ inhibitor (eg, NIS793 ).

In some embodiments, the methods described herein may further comprise one or more additional therapeutic agents, procedures or modalities. In some embodiments, a TGFβ inhibitor (eg, NIS793) is administered in combination with a PD1 inhibitor (eg, an anti-PD1 antibody molecule) and/or a PD-L inhibitor (PD-L1 and/or PD-L2). In one embodiment, the methods described herein comprise administering an inhibitor of the inhibitory (or immune checkpoint) molecules PD-1, PD-L1, PD-L2 and/or TGFβ. In one embodiment, the inhibitor is an antibody or antibody fragment that binds to PD-1, PD-L1, PD-L2 and/or TGFβ.

Alternatively, or in combination with the foregoing methods, the methods described herein may be administered or used with one or more of: an immunomodulatory agent (e.g., an activator of a co-stimulatory molecule or an inhibitor of an inhibitory molecule, such as an immune checkpoint molecules); vaccines, such as therapeutic cancer vaccines; or other forms of cellular immunotherapy.

In certain embodiments, the methods described herein are administered or used with modulators of co-stimulatory or inhibitory molecules (eg, co-inhibitory ligands or receptors). Other Exemplary TGFβ Inhibitors

In some embodiments, the TGFβ inhibitor comprises fusumumumab (CAS Registry Number: 948564-73-6). Fusumumumab is also known as GC1008. Fusumumumab is a human monoclonal antibody that binds and inhibits TGF-beta isoforms 1, 2, and 3.

夫蘇木單抗的重鏈具有以下胺基酸序列：QVQLVQSGAEVKKPGSSVKVSCKASGYTFSSNVISWVRQAPGQGLEWMGGVIPIVDIANYAQRFKGRVTITADESTSTTYMELSSLRSEDTAVYYCASTLGLVLDAMDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPSCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK（SEQ ID NO: 11）。

夫蘇木單抗的輕鏈具有以下胺基酸序列：ETVLTQSPGTLSLSPGERATLSCRASQSLGSSYLAWYQQKPGQAPRLLIYGASSRAPGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYADSPITFGQGTRLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC（SEQ ID NO: 12）。

Fusumumumab is disclosed, for example, in International Application Publication No. WO 2006/086469, and US Patent Nos. 8,383,780 and 8,591,901.

In some embodiments, the TGFβ inhibitor is PF-06952229. PF-06952229 is an inhibitor of TGFβR1, which prevents receptor signaling and TGF-βR1-mediated immunosuppression, thereby enhancing anti-tumor immune responses. PF-06952229 is disclosed, eg, in Yano et al . Immunology 2019; 157(3) 232-47.

In some embodiments, the TGFβ inhibitor is AVID200. AVID200 is a TGFβ receptor extracellular domain-IgG Fc fusion protein that selectively targets and neutralizes TGFβ isoforms 1 and 3. AVID200 is disclosed, for example, in O'Connor-McCourt, MD et al . Can. Res. [Cancer Research] 2018. 78(13). PD-1 inhibitor

PD-1 is a member of the CD28/CTLA-4 family that is expressed, for example, on activated CD4+ and CD8+ T cells, Tregs, and B cells. It negatively regulates effector T cell signaling and function. PD-1 is induced on tumor-infiltrating T cells and can lead to functional exhaustion or dysfunction (Keir et al. (2008) Annu. Rev. Immunol. 26:677-704; Pardoll et al. ( 2012) Nat Rev Cancer 12(4):252-64). PD-1 delivers co-inhibitory signals when bound to one of its two ligands, programmed death-ligand 1 (PD-L1) or programmed death-ligand 2 (PD-L2). PD-L1 is expressed on many cell types, including T cells, natural killer (NK) cells, macrophages, dendritic cells (DCs), B cells, epithelial cells, vascular endothelial cells, and on many types of tumors. High expression of PD-L1 on murine and human tumors is associated with poor clinical outcome in various cancers (Keir et al. (2008) Annu. Rev. Immunol. 26:677-704; Pardoll et al. (2012 ) Nat Rev Cancer 12(4):252-64). PD-L2 is expressed on dendritic cells, macrophages and some tumors. Blocking the PD-1 pathway has been validated preclinically and clinically for cancer immunotherapy. Both preclinical and clinical studies have demonstrated that anti-PD-1 blockade can restore the activity of effector T cells and generate a robust antitumor response. For example, blocking the PD-1 pathway can restore exhausted/dysfunctional effector T cell function (eg, proliferation, IFN-γ secretion, or cytolytic function) and/or suppress Treg cell function (Keir et al. (2008) Annu. Rev. . Immunol. 26:677-704; Pardoll et al. (2012) Nat Rev Cancer 12(4):252-64). Blockade of the PD-1 pathway can be achieved with antibodies, antigen-binding fragments thereof, immunoadhesins, fusion proteins, or oligopeptides of PD-1, PD-L1 and/or PD-L2.

As used herein, the term "planned death 1" or "PD-1" includes isotypes, mammals (e.g., human PD-1), species homologues of human PD-1, and species homologs of human PD-1 comprising at least one Epitope analogs. The amino acid sequence of PD-1 (eg, human PD-1) is known in the art, for example, Shinohara T et al. (1994) Genomics [Genomics] 23(3):704-6; Finger LR et al. Gene [Genes] (1997) 197(1-2):177-87.

In certain embodiments, a TGFβ inhibitor as described herein is administered in combination with a PD-1 inhibitor. In some embodiments, the PD-1 inhibitor is spartanizumab (PDR001, Novartis), nivolumab (Bristol-Myers Squibb), papi Bombumab (Merck & Co), Pidilizumab (CureTech), MEDI0680 (Medimmune), REGN2810 (Regeneron ( Regeneron), TSR-042 (Tesaro), PF-06801591 (Pfizer), BGB-A317 (also known as tislelizumab) (Beigene) , BGB-108 (Baekje), INCSHR1210 (Incyte), or AMP-224 (Amplimmun). 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 in the July 30, 2015 publication entitled "Antibody Molecules to PD-1 and Uses Thereof It is described in published US 2015/0210769. In one embodiment, the anti-PD-1 inhibitor is spartakizumab, also known as PDR001. In another embodiment, the anti-PD-1 inhibitor is tislelizumab, also known as BGB-A317.

In one embodiment, the anti-PD-1 antibody molecule comprises at least one, two, three, four, five or six complementarity determining regions (CDRs) from the heavy and light chain variable regions (or collectively All CDRs), the heavy and light chain variable regions comprising Table 1 (for example, the heavy and light chain variable region sequences from BAP049-plant-E or BAP049-plant-B disclosed in Table 1 ) are shown in Table 1 or the amino acid sequence encoded by the nucleotide sequence shown in Table 1 . In some embodiments, CDRs are defined according to Kabat (e.g., as listed in Table 1 ). In some embodiments, CDRs are defined according to Chothia (e.g., as listed in Table 1 ). In some embodiments, the CDRs are defined according to the combined CDRs of both Kabat and Josiah (e.g., as listed in Table 1 ). In one embodiment, the combination of Kabat and Josiah CDRs of VH CDR1 comprises the amino acid sequence GYTFTTYWMH (SEQ ID NO: 13). In one embodiment, with respect to the amino acid sequence shown in Table 1 , or the amino acid sequence encoded by the nucleotide sequence shown in Table 1 , one or more (or generally all) of the CDRs CDR) have one, two, three, four, five, six or more changes, such as amino acid substitutions (eg, conservative amino acid substitutions) or deletions.

In one embodiment, the anti-PD-1 antibody molecule comprises: VHCDR1 amino acid sequence comprising SEQ ID NO: 14, VHCDR2 amino acid sequence of SEQ ID NO: 15, and VHCDR3 amino acid sequence of SEQ ID NO: 16 The heavy chain variable region (VH) of the sequence; and the VLCDR1 amino acid sequence comprising SEQ ID NO: 23, the VLCDR2 amino acid sequence of SEQ ID NO: 24, and the VLCDR3 amino acid sequence of SEQ ID NO: 25 Light chain variable regions (VL), each disclosed in Table 1.

In one embodiment, the antibody molecule comprises: VHCDR1 encoded by the nucleotide sequence of SEQ ID NO: 37, VHCDR2 encoded by the nucleotide sequence of SEQ ID NO: 38, and the core of SEQ ID NO: 39 VH of the VHCDR3 encoded by the nucleotide sequence; and VLCDR1 encoded by the nucleotide sequence of SEQ ID NO: 42, VLCDR2 encoded by the nucleotide sequence of SEQ ID NO: 43, and the core of SEQ ID NO: 44 The VL of VLCDR3 encoded by the nucleotide sequence, each disclosed in Table 1 .

In one embodiment, the anti-PD-1 antibody molecule comprises: an amino acid sequence comprising SEQ ID NO: 19, or at least 85%, 86%, 87%, 88%, 89%, A VH of an amino acid sequence that is 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, or more identical. In one embodiment, the anti-PD-1 antibody molecule comprises: an amino acid sequence comprising SEQ ID NO: 33, or at least 85%, 86%, 87%, 88%, 89%, A VL of an amino acid sequence that is 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, or more identical. In one embodiment, the anti-PD-1 antibody molecule comprises: an amino acid sequence comprising SEQ ID NO: 29, or at least 85%, 86%, 87%, 88%, 89%, A VL of an amino acid sequence that is 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, or more identical. In one embodiment, the anti-PD-1 antibody molecule comprises: VH comprising the amino acid sequence of SEQ ID NO: 19 and VL comprising the amino acid sequence of SEQ ID NO: 33. In one embodiment, the anti-PD-1 antibody molecule comprises: VH comprising the amino acid sequence of SEQ ID NO: 19 and VL comprising the amino acid sequence of SEQ ID NO: 33.

In one embodiment, the antibody molecule comprises: the nucleotide sequence consisting of SEQ ID NO: 20, or having at least 85%, 86%, 87%, 88%, 89%, 90%, 91% with SEQ ID NO: 20 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, or higher identity of the nucleotide sequence encoded VH. In one embodiment, the antibody molecule comprises: the nucleotide sequence consisting of SEQ ID NO: 34 or 30, or having at least 85%, 86%, 87%, 88%, 89%, A VL encoded by a nucleotide sequence that is 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, or more identical. In one embodiment, the antibody molecule comprises: VH encoded by the nucleotide sequence of SEQ ID NO: 20 and VL encoded by the nucleotide sequence of SEQ ID NO: 34 or 30.

In one embodiment, the anti-PD-1 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 21, or at least 85%, 90%, 95%, or Amino acid sequences with 99% or greater identity. In one embodiment, the anti-PD-1 antibody molecule comprises: an amino acid sequence comprising SEQ ID NO: 35, or at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% or more identical amino acid sequences to the light chain. In one embodiment, the anti-PD-1 antibody molecule comprises: an amino acid sequence comprising SEQ ID NO: 31, or at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% or more identical amino acid sequences to the light chain. In one embodiment, the anti-PD-1 antibody molecule comprises: a heavy chain comprising the amino acid sequence of SEQ ID NO: 21 and a light chain comprising the amino acid sequence of SEQ ID NO: 35. In one embodiment, the anti-PD-1 antibody molecule comprises: a heavy chain comprising the amino acid sequence of SEQ ID NO: 21 and a light chain comprising the amino acid sequence of SEQ ID NO: 31.

In one embodiment, the antibody molecule comprises: the nucleotide sequence consisting of SEQ ID NO: 22, or having at least 85%, 86%, 87%, 88%, 89%, 90%, 91% with SEQ ID NO: 22 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, or higher identity of the heavy chain encoded by the nucleotide sequence. In one embodiment, the antibody molecule comprises: the nucleotide sequence consisting of SEQ ID NO: 36 or 32, or having at least 85%, 86%, 87%, 88%, 89%, A light chain encoded by a nucleotide sequence that is 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, or more identical. In one embodiment, the antibody molecule comprises: a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 22 and a light chain encoded by the nucleotide sequence of SEQ ID NO: 36 or 32.

In another embodiment, the anti-PD-1 antibody molecule (e.g., tislelizumab) comprises the following heavy chain and/or light chain, VH, VL, HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 : amino acid sequence heavy chain QVQLQESGPGLVKPSETLSLTCTVSGFSLTSYGVHWIRQPPGKGLEWIGVIYADGSTNYNPSLKSRVTISKDTSKNQVSLKLSSVTAADTAVYYCARAYGNYWYIDVWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPPVAGGPSVFLFPPKPKDTLMISRTPEVTCVVVAVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVVHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO: 321 light chain DIVMTQSPDSLAVSLGERATINCKSSESVSNDVAWYQQKPGQPPKLLINYAFHRFTGVPDRFSGSGYGTDFLTISSLQAEDVAVYYCHQAYSSPYTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQSGNSQESVTEQDSKDSTYSLSSTLLFKTHKADYEKHKVGLRAYACT SEQ ID NO: 322 variable heavy chain QVQLQESGPGLVKPSETLSLTCTVSGFSLTSYGVHWIRQPPGKGLEWIGVIYADGSTNYNPSLKSRVTISKDTSKNQVSLKLSSVTAADTAVYYCARAYGNYWYIDVWGQGTTVTVSS SEQ ID NO: 323 variable light chain DIVMTQSPDSLAVSLGERATINCKSSESVSNDVAWYQQKPGQPPKLLINYAFHRFTGVPDRFSGSGYGTDFTLTISSLQAEDVAVYYCHQAYSSPYTFGQGTKLEIK SEQ ID NO: 324 HCDR1 GFSLTSYGVH SEQ ID NO: 325 HCDR2 VIYADGSTNYNPSLKS SEQ ID NO: 326 HCDR3 ARAYGNYWYIDV SEQ ID NO: 327 LCDR1 KSSESVSNDVA SEQ ID NO: 328 LCDR2 YAFHRFT SEQ ID NO: 329 LCDR3 HQAYSSPYT SEQ ID NO: 330

In some embodiments, the PD-1 inhibitor is an anti-PD-1 antibody comprising SEQ ID NO: 321. In some embodiments, the PD-1 inhibitor is an anti-PD-1 antibody comprising SEQ ID NO: 322. In some embodiments, the PD-1 inhibitor is an anti-PD-1 antibody comprising SEQ ID NO: 321 and 322. In some embodiments, the PD-1 inhibitor comprises the HCDR and LCDR of tislelizumab as set forth in SEQ ID NOs: 325-330.

The antibody molecules described herein can be produced by vectors, host cells, and methods described in US 2015/0210769.

In some embodiments, the PD-1 inhibitor (eg, spartakizumab or tislelizumab) is administered in a plateau dose of between about 100 mg to about 600 mg. In some embodiments, the PD-1 inhibitor is administered at a dose of between about 100 mg to about 500 mg. In some embodiments, the PD-1 inhibitor is administered at a dose of between about 100 mg to about 400 mg. In some embodiments, the PD-1 inhibitor is administered at a dose of between about 100 mg to about 300 mg. In some embodiments, the PD-1 inhibitor is administered at a dose of between about 100 mg to about 200 mg. In some embodiments, the PD-1 inhibitor is administered at a dose of between about 200 mg to about 600 mg. In some embodiments, the PD-1 inhibitor is administered at a dose of between about 200 mg to about 500 mg. In some embodiments, the PD-1 inhibitor is administered at a dose of between about 200 mg to about 400 mg. In some embodiments, the PD-1 inhibitor is administered at a dose of between about 200 mg to about 300 mg. In some embodiments, the PD-1 inhibitor is administered at a dose of between about 300 mg to about 600 mg. In some embodiments, the PD-1 inhibitor is administered at a dose of between about 300 mg to about 500 mg. In some embodiments, the PD-1 inhibitor is administered at a dose of between about 300 mg to about 400 mg. In some embodiments, the PD-1 inhibitor is administered at a dose of between about 400 mg to about 600 mg. In some embodiments, the PD-1 inhibitor is administered at a dose of between about 400 mg to about 500 mg. In some embodiments, the PD-1 inhibitor is administered at a dose of between about 500 mg to about 600 mg. In some embodiments, the PD-1 inhibitor is administered at a dose of between about 600 mg to about 700 mg. In some embodiments, the PD-1 inhibitor is administered at a dose of between about 700 mg to about 800 mg. In some embodiments, the PD-1 inhibitor is administered at a dose of between about 800 mg to about 900 mg. In some embodiments, the PD-1 inhibitor is administered at a dose of between about 900 mg to about 1000 mg.

In some embodiments, the PD-1 inhibitor (eg, spartakizumab or tislelizumab) is administered in a flat dose of about 100 mg. In some embodiments, the PD-1 inhibitor is administered at a dose of about 200 mg. In some embodiments, the PD-1 inhibitor is administered at a dose of about 300 mg. In some embodiments, the PD-1 inhibitor is administered at a dose of about 400 mg. In some embodiments, the PD-1 inhibitor is administered at a dose of about 500 mg. In some embodiments, the PD-1 inhibitor is administered at a dose of about 600 mg. In some embodiments, the PD-1 inhibitor is administered at a dose of about 700 mg. In some embodiments, the PD-1 inhibitor is administered at a dose of about 800 mg. In some embodiments, the PD-1 inhibitor is administered at a dose of about 900 mg. In some embodiments, the PD-1 inhibitor is administered at a dose of about 1000 mg.

In some embodiments, the PD-1 inhibitor (eg, spartakizumab or tislelizumab) is administered every ten weeks. In some embodiments, the PD-1 inhibitor is administered every nine weeks. In some embodiments, the PD-1 inhibitor is administered every eight weeks. In some embodiments, the PD-1 inhibitor is administered every seven weeks. In some embodiments, the PD-1 inhibitor is administered every six weeks. In some embodiments, the PD-1 inhibitor is administered every five weeks. In some embodiments, the PD-1 inhibitor is administered every four weeks. In some embodiments, the PD-1 inhibitor is administered every three weeks. In some embodiments, the PD-1 inhibitor is administered every two weeks. In some embodiments, the PD-1 inhibitor is administered weekly.

In some embodiments, a PD-1 inhibitor (eg, spartakizumab or tislelizumab) is administered intravenously.

In some embodiments, the PD-1 inhibitor (eg, spartakizumab or tislelizumab) is administered over a period of about 20 minutes to 40 minutes (eg, about 30 minutes). In some embodiments, the PD-1 inhibitor is administered over a period of about 30 minutes. In some embodiments, the PD-1 inhibitor is administered over a period of about one hour. In some embodiments, the PD-1 inhibitor is administered over a period of about two hours. In some embodiments, the PD-1 inhibitor is administered over a period of about three hours. In some embodiments, the PD-1 inhibitor is administered over a period of about four hours. In some embodiments, the PD-1 inhibitor is administered over a period of about five hours. In some embodiments, the PD-1 inhibitor is administered over a period of about six hours.

In some embodiments, the PD-1 inhibitor (e.g., spartacuzumab) is administered intravenously at a dose of between about 300 mg to about 500 mg (e.g., about 400 mg) once every four weeks or tislelizumab). In some embodiments, the PD-1 inhibitor is administered intravenously at a dose of between about 200 mg to about 400 mg (eg, about 300 mg) once every three weeks. In some embodiments, spartakizumab or tislelizumab is administered at a dose of 400 mg once every four weeks. In some embodiments, spartakizumab or tislelizumab is administered at a dose of 300 mg once every four weeks. In some embodiments, spartakizumab or tislelizumab is administered at a dose of 300 mg every three weeks. In some embodiments, spartakizumab or tislelizumab is administered at a dose of 200 mg every three weeks.

In some embodiments, every two weeks at a dose of between about 300 mg to about 500 mg (eg, about 400 mg) for a period of about 20 minutes to about 40 minutes (eg, about 30 minutes) Once, a PD-1 inhibitor (eg, spartakizumab or tislelizumab) is administered intravenously. In some embodiments, every three weeks at a dose of between about 200 mg to about 400 mg (eg, about 300 mg) for a period of about 20 minutes to about 40 minutes (eg, about 30 minutes) Once, a PD-1 inhibitor was administered intravenously. In some embodiments, once every four weeks at a dose of between about 200 mg to about 400 mg (eg, about 300 mg) over a period of about 20 minutes to about 40 minutes (eg, about 30 minutes) , intravenous administration of PD-1 inhibitors. In some embodiments, every three weeks at a dose of between about 100 mg to about 300 mg (eg, about 200 mg) for a period of about 20 minutes to about 40 minutes (eg, about 30 minutes) Once, a PD-1 inhibitor was administered intravenously.

In some embodiments, the PD-1 inhibitor (eg, spartakizumab or tislelizumab) is administered weekly at a dose of about 100 mg. For example, a PD-1 inhibitor (eg, spartakizumab or tislelizumab) can be given at 1000 mg if the patient is given a 10-week dose. If given for 9 weeks, a PD-1 inhibitor (eg, spartakizumab or tislelizumab) can be given at 900 mg. If given for 8 weeks, a PD-1 inhibitor (eg, spartakizumab or tislelizumab) can be given at 800 mg. If given for 7 weeks, a PD-1 inhibitor (eg, spartakizumab or tislelizumab) can be given at 700 mg. If given for 6 weeks, a PD-1 inhibitor (eg, spartakizumab or tislelizumab) can be given at 600 mg. If given for 5 weeks, a PD-1 inhibitor (eg, spartakizumab or tislelizumab) can be given at 500 mg. If given in 4-week doses, a PD-1 inhibitor (eg, spartakizumab or tislelizumab) can be given at 400 mg. If given in 3-week doses, a PD-1 inhibitor (eg, spartakizumab or tislelizumab) can be given at 300 mg. If given in 2-week doses, a PD-1 inhibitor (eg, spartakizumab or tislelizumab) can be given at 200 mg. If a 1-week dose is given, a PD-1 inhibitor (eg, spartakizumab or tislelizumab) can be given at 100 mg.

For example, if an anti-PD-1 antibody such as tislelizumab is used, it can be given as an intravenous infusion at a dose of 200 mg every three weeks. Alternatively, tislelizumab can be administered as an intravenous infusion at a dose of 300 mg every four weeks. If an anti-PD-1 antibody (such as spartakizumab or tislelizumab) is used, it can be given as an IV infusion at a dose of 300 mg every three weeks. Alternatively, spartakizumab or tislelizumab can be administered as an intravenous infusion at a dose of 400 mg every four weeks.

In some embodiments, a PD-1 inhibitor (eg, spartakizumab or tislelizumab) is administered in combination with a TGFβ inhibitor (eg, NIS793). [ Table 1 ]. Amino acid and nucleotide sequences of exemplary anti-PD-1 antibody molecules BAP049- plant -B HC SEQ ID NO: 14 (Cabat) HCDR1 TYWMH SEQ ID NO: 15 (Cabat) HCDR2 NIYPGTGGSNFDEKFKN SEQ ID NO: 16 (Cabat) HCDR3 WTTGTGAY SEQ ID NO: 17 (Josiah) HCDR1 GYTFTTY SEQ ID NO: 18 (Josiah) HCDR2 YPGTGG SEQ ID NO: 16 (Josiah) HCDR3 WTTGTGAY SEQ ID NO: 19 VH EVQLVQSGAEVKKPGESLRISCKGSGYTFTTYWMHWVRQATGQGLEWMGNIYPGTGGSNFDEKFKNRVTITADKSTSTAYMELSSLRSEDTAVYYCTRWTTGTGAYWGQGTTVTVSS SEQ ID NO: 20 DNA VH GAGGTGCAGCTGGTGCAGTCAGGCGCCGAAGTGAAGAAGCCCGGCGAGTCACTGAGAATTAGCTGTAAAGGTTCAGGCTACACCTTCACTACCTACTGGATGCACTGGGTCCGCCAGGCTACCGGTCAAGGCCTCGAGTGGATGGGTAATATCTACCCCGGCACCGGCGGCTCTAACTTCGACGAGAAGTTTAAGAATAGAGTGACTATCACCGCCGATAAGTCTACTAGCACCGCCTATATGGAACTGTCTAGCCTGAGATCAGAGGACACCGCCGTCTACTACTGCACTAGGTGGACTACCGGCACAGGCGCCTACTGGGGTCAAGGCACTACCGTGACCGTGTCTAGC SEQ ID NO: 21 heavy chain EVQLVQSGAEVKKPGESLRISCKGSGYTFTTYWMHWVRQATGQGLEWMGNIYPGTGGSNFDEKFKNRVTITADKSTSTAYMELSSLRSEDTAVYYCTRWTTGTGAYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG SEQ ID NO: 22 DNA heavy chain GAGGTGCAGCTGGTGCAGTCAGGCGCCGAAGTGAAGAAGCCCGGCGAGTCACTGAGAATTAGCTGTAAAGGTTCAGGCTACACCTTCACTACCTACTGGATGCACTGGGTCCGCCAGGCTACCGGTCAAGGCCTCGAGTGGATGGGTAATATCTACCCCGGCACCGGCGGCTCTAACTTCGACGAGAAGTTTAAGAATAGAGTGACTATCACCGCCGATAAGTCTACTAGCACCGCCTATATGGAACTGTCTAGCCTGAGATCAGAGGACACCGCCGTCTACTACTGCACTAGGTGGACTACCGGCACAGGCGCCTACTGGGGTCAAGGCACTACCGTGACCGTGTCTAGCGCTAGCACTAAGGGCCCGTCCGTGTTCCCCCTGGCACCTTGTAGCCGGAGCACTAGCGAATCCACCGCTGCCCTCGGCTGCCTGGTCAAGGATTACTTCCCGGAGCCCGTGACCGTGTCCTGGAACAGCGGAGCCCTGACCTCCGGAGTGCACACCTTCCCCGCTGTGCTGCAGAGCTCCGGGCTGTACTCGCTGTCGTCGGTGGTCACGGTGCCTTCATCTAGCCTGGGTACCAAGACCTACACTTGCAACGTGGACCACAAGCCTTCCAACACTAAGGTGGACAAGCGCGTCGAATCGAAGTACGGCCCACCGTGCCCGCCTTGTCCCGCGCCGGAGTTCCTCGGCGGTCCCTCGGTCTTTCTGTTCCCACCGAAGCCCAAGGACACTTTGATGATTTCCCGCACCCCTGAAGTGACATGCGTGGTCGTGGACGTGTCACAGGAAGATCCGGAGGTGCAGTTCAATTGGTACGTGGATGGCGTCGAGGTGCACAACGCCAAAACCAAGCCGAGGGAGGAGCAGTTCAACTCCACTTACCGCGTCGTGTCCGTGCTGACGGTGCTGCATCAGGACTGGCTGAACGGGAAGGAGTACAAGTGCAAAGTGTCCAACAAGGGACTTCCTAGCTCAATCGAAAAGACCATCT CGAAAGCCAAGGGACAGCCCCGGGAACCCCAAGTGTATACCCTGCCACCGAGCCAGGAAGAAATGACTAAGAACCAAGTCTCATTGACTTGCCTTGTGAAGGGCTTCTACCCATCGGATATCGCCGTGGAATGGGAGTCCAACGGCCAGCCGGAAAACAACTACAAGACCACCCCTCCGGTGCTGGACTCAGACGGATCCTTCTTCCTCTACTCGCGGCTGACCGTGGATAAGAGCAGATGGCAGGAGGGAAATGTGTTCAGCTGTTCTGTGATGCATGAAGCCCTGCACAACCACTACACTCAGAAGTCCCTGTCCCTCTCCCTGGGA BAP049- plant -B LC SEQ ID NO: 23 (Cabat) LCDR1 KSSQSLLDSGNQKNFLT SEQ ID NO: 24 (Cabat) LCDR2 WASTRES SEQ ID NO: 25 (Cabat) LCDR3 QNDYSYPYT SEQ ID NO: 26 (Josiah) LCDR1 SQSLLDSGNQKNF SEQ ID NO: 27 (Josiah) LCDR2 WAS SEQ ID NO: 28 (Josiah) LCDR3 DYSYPY SEQ ID NO: 29 VL EIVLTQSPATLSSLSPGERATLSCKSSQSLLDSGNQKNFLTWYQQKPGKAPKLLIYWASTRESGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQNDYSYPYTFGQGTKVEIK SEQ ID NO: 30 DNA VL GAGATCGTCCTGACTCAGTCACCCGCTACCCTGAGCCTGAGCCCTGGCGAGCGGGCTACACTGAGCTGTAAATCTAGTCAGTCACTGCTGGATAGCGGTAATCAGAAGAACTTCCTGACCTGGTATCAGCAGAAGCCCGGTAAAGCCCCTAAGCTGCTGATCTACTGGGCCTCTACTAGAGAATCAGGCGTGCCCTCTAGGTTTAGCGGTAGCGGTAGTGGCACCGACTTCACCTTCACTATCTCTAGCCTGCAGCCCGAGGATATCGCTACCTACTACTGTCAGAACGACTATAGCTACCCCTACACCTTCGGTCAAGGCACTAAGGTCGAGATTAAG SEQ ID NO: 31 light chain EIVLTQSPATLSSLSPGERATLSCKSSQSLLDSGNQKNFLTWYQQKPGKAPKLLIYWASTRESGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQNDYSYPYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKFSTYSLSSTLTLKGLNSKADYECSK SEQ ID NO: 32 DNA light chain GAGATCGTCCTGACTCAGTCACCCGCTACCCTGAGCCTGAGCCCTGGCGAGCGGGCTACACTGAGCTGTAAATCTAGTCAGTCACTGCTGGATAGCGGTAATCAGAAGAACTTCCTGACCTGGTATCAGCAGAAGCCCGGTAAAGCCCCTAAGCTGCTGATCTACTGGGCCTCTACTAGAGAATCAGGCGTGCCCTCTAGGTTTAGCGGTAGCGGTAGTGGCACCGACTTCACCTTCACTATCTCTAGCCTGCAGCCCGAGGATATCGCTACCTACTACTGTCAGAACGACTATAGCTACCCCTACACCTTCGGTCAAGGCACTAAGGTCGAGATTAAGCGTACGGTGGCCGCTCCCAGCGTGTTCATCTTCCCCCCCAGCGACGAGCAGCTGAAGAGCGGCACCGCCAGCGTGGTGTGCCTGCTGAACAACTTCTACCCCCGGGAGGCCAAGGTGCAGTGGAAGGTGGACAACGCCCTGCAGAGCGGCAACAGCCAGGAGAGCGTCACCGAGCAGGACAGCAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCGACTACGAGAAGCATAAGGTGTACGCCTGCGAGGTGACCCACCAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAACAGGGGCGAGTGC BAP049- plant -E HC SEQ ID NO: 14 (Cabat) HCDR1 TYWMH SEQ ID NO: 15 (Cabat) HCDR2 NIYPGTGGSNFDEKFKN SEQ ID NO: 16 (Cabat) HCDR3 WTTGTGAY SEQ ID NO: 17 (Josiah) HCDR1 GYTFTTY SEQ ID NO: 18 (Josiah) HCDR2 YPGTGG SEQ ID NO: 16 (Josiah) HCDR3 WTTGTGAY SEQ ID NO: 19 VH EVQLVQSGAEVKKPGESLRISCKGSGYTFTTYWMHWVRQATGQGLEWMGNIYPGTGGSNFDEKFKNRVTITADKSTSTAYMELSSLRSEDTAVYYCTRWTTGTGAYWGQGTTVTVSS SEQ ID NO: 20 DNA VH GAGGTGCAGCTGGTGCAGTCAGGCGCCGAAGTGAAGAAGCCCGGCGAGTCACTGAGAATTAGCTGTAAAGGTTCAGGCTACACCTTCACTACCTACTGGATGCACTGGGTCCGCCAGGCTACCGGTCAAGGCCTCGAGTGGATGGGTAATATCTACCCCGGCACCGGCGGCTCTAACTTCGACGAGAAGTTTAAGAATAGAGTGACTATCACCGCCGATAAGTCTACTAGCACCGCCTATATGGAACTGTCTAGCCTGAGATCAGAGGACACCGCCGTCTACTACTGCACTAGGTGGACTACCGGCACAGGCGCCTACTGGGGTCAAGGCACTACCGTGACCGTGTCTAGC SEQ ID NO: 21 heavy chain EVQLVQSGAEVKKPGESLRISCKGSGYTFTTYWMHWVRQATGQGLEWMGNIYPGTGGSNFDEKFKNRVTITADKSTSTAYMELSSLRSEDTAVYYCTRWTTGTGAYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG SEQ ID NO: 22 DNA heavy chain GAGGTGCAGCTGGTGCAGTCAGGCGCCGAAGTGAAGAAGCCCGGCGAGTCACTGAGAATTAGCTGTAAAGGTTCAGGCTACACCTTCACTACCTACTGGATGCACTGGGTCCGCCAGGCTACCGGTCAAGGCCTCGAGTGGATGGGTAATATCTACCCCGGCACCGGCGGCTCTAACTTCGACGAGAAGTTTAAGAATAGAGTGACTATCACCGCCGATAAGTCTACTAGCACCGCCTATATGGAACTGTCTAGCCTGAGATCAGAGGACACCGCCGTCTACTACTGCACTAGGTGGACTACCGGCACAGGCGCCTACTGGGGTCAAGGCACTACCGTGACCGTGTCTAGCGCTAGCACTAAGGGCCCGTCCGTGTTCCCCCTGGCACCTTGTAGCCGGAGCACTAGCGAATCCACCGCTGCCCTCGGCTGCCTGGTCAAGGATTACTTCCCGGAGCCCGTGACCGTGTCCTGGAACAGCGGAGCCCTGACCTCCGGAGTGCACACCTTCCCCGCTGTGCTGCAGAGCTCCGGGCTGTACTCGCTGTCGTCGGTGGTCACGGTGCCTTCATCTAGCCTGGGTACCAAGACCTACACTTGCAACGTGGACCACAAGCCTTCCAACACTAAGGTGGACAAGCGCGTCGAATCGAAGTACGGCCCACCGTGCCCGCCTTGTCCCGCGCCGGAGTTCCTCGGCGGTCCCTCGGTCTTTCTGTTCCCACCGAAGCCCAAGGACACTTTGATGATTTCCCGCACCCCTGAAGTGACATGCGTGGTCGTGGACGTGTCACAGGAAGATCCGGAGGTGCAGTTCAATTGGTACGTGGATGGCGTCGAGGTGCACAACGCCAAAACCAAGCCGAGGGAGGAGCAGTTCAACTCCACTTACCGCGTCGTGTCCGTGCTGACGGTGCTGCATCAGGACTGGCTGAACGGGAAGGAGTACAAGTGCAAAGTGTCCAACAAGGGACTTCCTAGCTCAATCGAAAAGACCATCT CGAAAGCCAAGGGACAGCCCCGGGAACCCCAAGTGTATACCCTGCCACCGAGCCAGGAAGAAATGACTAAGAACCAAGTCTCATTGACTTGCCTTGTGAAGGGCTTCTACCCATCGGATATCGCCGTGGAATGGGAGTCCAACGGCCAGCCGGAAAACAACTACAAGACCACCCCTCCGGTGCTGGACTCAGACGGATCCTTCTTCCTCTACTCGCGGCTGACCGTGGATAAGAGCAGATGGCAGGAGGGAAATGTGTTCAGCTGTTCTGTGATGCATGAAGCCCTGCACAACCACTACACTCAGAAGTCCCTGTCCCTCTCCCTGGGA BAP049- plant -E LC SEQ ID NO: 23 (Cabat) LCDR1 KSSQSLLDSGNQKNFLT SEQ ID NO: 24 (Cabat) LCDR2 WASTRES SEQ ID NO: 25 (Cabat) LCDR3 QNDYSYPYT SEQ ID NO: 26 (Josiah) LCDR1 SQSLLDSGNQKNF SEQ ID NO: 27 (Josiah) LCDR2 WAS SEQ ID NO: 28 (Josiah) LCDR3 DYSYPY SEQ ID NO: 33 VL EIVLTQSPATLSSLSPGERATLSCKSSQSLLDSGNQKNFLTWYQQKPGQAPRLLIYWASTRESGVPSRFSGSGSGTDFTFTISSLEAEDAATYYCQNDYSYPYTFGQGTKVEIK SEQ ID NO: 34 DNA VL GAGATCGTCCTGACTCAGTCACCCGCTACCCTGAGCCTGAGCCCTGGCGAGCGGGCTACACTGAGCTGTAAATCTAGTCAGTCACTGCTGGATAGCGGTAATCAGAAGAACTTCCTGACCTGGTATCAGCAGAAGCCCGGTCAAGCCCCTAGACTGCTGATCTACTGGGCCTCTACTAGAGAATCAGGCGTGCCCTCTAGGTTTAGCGGTAGCGGTAGTGGCACCGACTTCACCTTCACTATCTCTAGCCTGGAAGCCGAGGACGCCGCTACCTACTACTGTCAGAACGACTATAGCTACCCCTACACCTTCGGTCAAGGCACTAAGGTCGAGATTAAG SEQ ID NO: 35 light chain EIVLTQSPATLSSLSPGERATLSCKSSQSLLDSGNQKNFLTWYQQKPGQAPRLLIYWASTRESGVPSRFSGSGSGTDFTFTISSLEAEDAATYYCQNDYSYPYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKFSTYSLSSTLTLKGLNSKADYECSK SEQ ID NO: 36 DNA light chain GAGATCGTCCTGACTCAGTCACCCGCTACCCTGAGCCTGAGCCCTGGCGAGCGGGCTACACTGAGCTGTAAATCTAGTCAGTCACTGCTGGATAGCGGTAATCAGAAGAACTTCCTGACCTGGTATCAGCAGAAGCCCGGTCAAGCCCCTAGACTGCTGATCTACTGGGCCTCTACTAGAGAATCAGGCGTGCCCTCTAGGTTTAGCGGTAGCGGTAGTGGCACCGACTTCACCTTCACTATCTCTAGCCTGGAAGCCGAGGACGCCGCTACCTACTACTGTCAGAACGACTATAGCTACCCCTACACCTTCGGTCAAGGCACTAAGGTCGAGATTAAGCGTACGGTGGCCGCTCCCAGCGTGTTCATCTTCCCCCCCAGCGACGAGCAGCTGAAGAGCGGCACCGCCAGCGTGGTGTGCCTGCTGAACAACTTCTACCCCCGGGAGGCCAAGGTGCAGTGGAAGGTGGACAACGCCCTGCAGAGCGGCAACAGCCAGGAGAGCGTCACCGAGCAGGACAGCAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCGACTACGAGAAGCATAAGGTGTACGCCTGCGAGGTGACCCACCAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAACAGGGGCGAGTGC BAP049- plant -B HC SEQ ID NO: 37 (Cabat) HCDR1 ACCTACTGGATGCAC SEQ ID NO: 38 (Cabat) HCDR2 AATATCTACCCCGGCACCGGCGGCTCTAACTTCGACGAGAAGTTTAAGAAT SEQ ID NO: 39 (Cabat) HCDR3 TGGACTACCGGCACAGGCGCCTAC SEQ ID NO: 40 (Josiah) HCDR1 GGCTACACCTTCACTACCTAC SEQ ID NO: 41 (Josiah) HCDR2 TACCCCGGCACCGGCGGC SEQ ID NO: 39 (Josiah) HCDR3 TGGACTACCGGCACAGGCGCCTAC BAP049- plant -B LC SEQ ID NO: 42 (Cabat) LCDR1 AAATCTAGTCAGTCACTGCTGGATAGCGGTAATCAGAAGAACTTCCTGACC SEQ ID NO: 43 (Cabat) LCDR2 TGGGCCTCTACTAGAGAATCA SEQ ID NO: 44 (Cabat) LCDR3 CAGAACGACTATAGCTACCCCTACACC SEQ ID NO: 45 (Josiah) LCDR1 AGTCAGTCACTGCTGGATAGCGGTAATCAGAAGAACTTC SEQ ID NO: 46 (Josiah) LCDR2 TGGGCCTCT SEQ ID NO: 47 (Josiah) LCDR3 GACTATAGCTACCCCTAC BAP049- plant -E HC SEQ ID NO: 37 (Cabat) HCDR1 ACCTACTGGATGCAC SEQ ID NO: 38 (Cabat) HCDR2 AATATCTACCCCGGCACCGGCGGCTCTAACTTCGACGAGAAGTTTAAGAAT SEQ ID NO: 39 (Cabat) HCDR3 TGGACTACCGGCACAGGCGCCTAC SEQ ID NO: 40 (Josiah) HCDR1 GGCTACACCTTCACTACCTAC SEQ ID NO: 41 (Josiah) HCDR2 TACCCCGGCACCGGCGGC SEQ ID NO: 39 (Josiah) HCDR3 TGGACTACCGGCACAGGCGCCTAC BAP049- plant -E LC SEQ ID NO: 42 (Cabat) LCDR1 AAATCTAGTCAGTCACTGCTGGATAGCGGTAATCAGAAGAACTTCCTGACC SEQ ID NO: 43 (Cabat) LCDR2 TGGGCCTCTACTAGAGAATCA SEQ ID NO: 44 (Cabat) LCDR3 CAGAACGACTATAGCTACCCCTACACC SEQ ID NO: 45 (Josiah) LCDR1 AGTCAGTCACTGCTGGATAGCGGTAATCAGAAGAACTTC SEQ ID NO: 46 (Josiah) LCDR2 TGGGCCTCT SEQ ID NO: 47 (Josiah) LCDR3 GACTATAGCTACCCCTAC

Tislelizumab is a humanized IgG monoclonal antibody against human planned cell death receptor 1 (PD-1), which has been approved by China's Food and Drug Administration (CFDA) for Different indications, including Hodgkin's lymphoma, urothelial carcinoma, hepatocellular carcinoma and squamous and non-squamous non-small cell lung cancer, and BLA for esophageal squamous cell carcinoma (ESCC) was accepted by FDA.

In specific embodiments, tislelizumab can be administered in combination with a TGFβ antibody (eg, NIS793) and/or with any of the disclosed chemotherapeutic agents. The amino acid sequence of tislelizumab is disclosed above and includes SEQ ID NO: 321-330.

In some embodiments, tislelizumab is administered to the patient (in need thereof) at the doses disclosed throughout. For example, tislelizumab can be administered in a flat dose of about 200 mg to 400 mg. More specifically, in these embodiments, tislelizumab can be administered to the patient at a dose of 300 mg.

When tislelizumab is used, the frequency of dosing can be as described throughout. For example, a frequency of once every three weeks (Q3W) or once every four weeks (Q4W) may be used.

In a specific example, tislelizumab can be administered to the subject at a dose of 300 mg once every four weeks. In another embodiment, tislelizumab can be administered to the subject at a dose of 200 mg once every three weeks. 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 (plant 5C4) and other anti-PD-1 antibodies are disclosed in US 8,008,449 and WO 2006/121168. In one embodiment, the anti-PD-1 antibody molecule comprises one or more of the following: CDR sequences of nivolumab (or all CDR sequences in general), heavy chain or light chain variable region sequences, or heavy chain or Light chain sequences, eg, as disclosed 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 disclosed in Hamid, O. et al. (2013) New England Journal of Medicine 369 (2): 134-44, US 8,354,509, and WO 2009/114335 middle. In one embodiment, the anti-PD-1 antibody molecule comprises one or more of the following: CDR sequences of pembrolizumab (or all CDR sequences in general), heavy chain or light chain variable region sequences, or heavy chain or light chain Strand sequences, eg, as disclosed in Table 2.

In one embodiment, the anti-PD-1 antibody molecule is Pidelizumab (Yhao Technology Co., Ltd.), also known as CT-011. Pidelizumab and other anti-PD-1 antibodies are disclosed in Rosenblatt, J. et al., (2011) J Immunotherapy 34(5): 409-18; US 7,695,715; US 7,332,582; and US 8,686,119 . In one embodiment, the anti-PD-1 antibody molecule comprises one or more of the following: the CDR sequence (or all CDR sequences in general), the heavy chain or light chain variable region sequence, or the heavy chain Or the light chain sequence, for example, as disclosed in Table 2.

In one embodiment, the anti-PD-1 antibody molecule is MEDI0680 (Medimus Co., Ltd.), also known as AMP-514. MEDI0680 and other anti-PD-1 antibodies are disclosed in US 9,205,148 and WO 2012/145493. In one embodiment, the anti-PD-1 antibody molecule comprises one or more of the following: the CDR sequence of MEDI0680 (or all CDR sequences in general), the heavy chain or light chain variable region sequence, or the 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 of the following: the CDR sequence of REGN2810 (or all CDR sequences in general), the heavy chain or light chain variable region sequence, or the 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 of the following: PF-06801591 CDR sequence (or all CDR sequences in general), heavy chain or light chain variable region sequence, or 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 of the following: CDR sequences of BGB-A317 or BGB-108 (or all CDR sequences in general), heavy chain or light chain variable region sequences, or heavy or light chain sequences.

In one embodiment, the anti-PD-1 antibody molecule is INCSHR1210 (Incel), also known as INCSHR01210 or SHR-1210. In one embodiment, the anti-PD-1 antibody molecule comprises one or more of the following: the CDR sequence of INCSHR1210 (or all CDR sequences in general), the heavy chain or light chain variable region sequence, or the heavy chain or light chain sequence.

In one embodiment, the anti-PD-1 antibody molecule is TSR-042 (Tessaro), also known as ANB011. In one embodiment, the anti-PD-1 antibody molecule comprises one or more of the following: TSR-042 CDR sequence (or all CDR sequences in general), heavy chain or light chain variable region sequence, or heavy chain or light chain sequence.

Other known anti-PD-1 antibodies include those described, for example, in WO 2015/112800, WO 2016/092419, WO 2015/085847, WO 2014/179664, WO 2014/194302, WO 2014/209804, WO 2015 /200119, US 8,735,553, US 7,488,802, US 8,927,697, US 8,993,731, and US 9,102,727.

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

In one embodiment, the PD-1 inhibitor is a peptide that inhibits the PD-1 signaling pathway, eg, as described in US 8,907,053. In one embodiment, the PD-1 inhibitor is an immunoadhesin (e.g., one comprising the extracellular or PD-1 binding portion of PD-L1 or PD-L2 fused to a constant region, such as the Fc region of an immunoglobulin sequence). immunoadhesins). In one embodiment, the PD-1 inhibitor is AMP-224 (B7-DCIg (Amply), eg disclosed in WO 2010/027827 and WO 2011/066342). [ Table 2 ]. Amino acid sequences of other exemplary anti-PD-1 antibody molecules Nivolumab SEQ ID NO: 48 heavy chain QVQLVESGGGVVQPGRSLRLDCKASGITFSNSGMHWVRQAPGKGLEWVAVIWYDGSKRYYADSVKGRFTISRDNSKNTLFLQMNSLRAEDTAVYYCATNDDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO: 49 light chain EIVLTQSPATLSSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLNFGLRRADGYEKHKVYACEVKS pembrolizumab SEQ ID NO: 50 heavy chain QVQLVQSGVEVKKPGASVKVSCKASGYTFTNYYMYWVRQAPGQGLEWMGGINPSNGGTNFNEKFKNRVTLTTDSSTTTAYMELKSLQFDDTAVYYCARRDYRFDMGFDYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO: 51 light chain EIVLTQSPATLSSLSPGERATLSCRASKGVSTSGYSYLHWYQQKPGQAPRLLIYLASYLESGVPARFSGSGSGTDFTLTISSLEPEDFAVYYCQHSRDLPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLGSKADYEVECKGLSS Pidilizumab SEQ ID NO: 52 heavy chain QVQLVQSGSELKKPGASVKISCKASGYTFTNYGMNWVRQAPGQGLQWMGWINTDSGESTYAEEFKGRFVFSLDTSVNTAYLQITSLTAEDTGMYFCVRVGYDALDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 53 light chain EIVLTQSPSSLSASVGDRVTITCSARSSVSYMHWFQQKPGKAPKLWIYRTSNLASGVPSRFSGSGSGTSYCLTINSLQPEDFATYYCQQRSSFPLTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVPVTEQDSKDSTYSLSSTLTLFSKADYEVKQHKGLRS PD-L1 inhibitors

In certain embodiments, the methods described further comprise administering a PD-L1 inhibitor. In some embodiments, the PD-L1 inhibitor is FAZ053 (Novartis AG), Atezolizumab (Genentech/Roche), Avelumab (Merck Serono and Pfizer), Durvalumab (Medimus Limited/AstraZeneca), or BMS-936559 (Bristol- Myers Squibb Company). 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 in the April 21, 2016 publication entitled "Antibody Molecules to PD-L1 and Uses Thereof Disclosed in published US 2016/0108123.

In one embodiment, the anti-PD-L1 antibody molecule comprises at least one, two, three, four, five, or six complementarity determining regions (CDRs) (or a total of All CDRs above), the heavy and light chain variable regions comprising the heavy and light chain variable regions shown in Table 3 (for example, the heavy and light chain variable region sequences from BAP058-plant O, or BAP058-plant N disclosed in Table 3 ) or the amino acid sequence encoded by the nucleotide sequence shown in Table 3 . In some embodiments, CDRs are defined according to Kabat (e.g., as listed in Table 3 ). In some embodiments, the CDRs are defined according to Josiah (e.g., as listed in Table 3 ). In some embodiments, the CDRs are defined according to the combined CDRs of both Kabat and Josiah (e.g., as listed in Table 3 ). In one embodiment, the combination of Kabat and Josiah CDRs of VH CDR1 comprises the amino acid sequence GYTFTSYWMY (SEQ ID NO: 100). In one embodiment, with respect to the amino acid sequence shown in Table 3 , or the amino acid sequence encoded by the nucleotide sequence shown in Table 3 , one or more (or generally all) of the CDRs CDR) have one, two, three, four, five, six or more changes, such as amino acid substitutions (eg, conservative amino acid substitutions) or deletions.

In one embodiment, the anti-PD-L1 antibody molecule comprises: VHCDR1 amino acid sequence comprising SEQ ID NO: 54, VHCDR2 amino acid sequence of SEQ ID NO: 55, and VHCDR3 amino acid sequence of SEQ ID NO: 56 The heavy chain variable region (VH) of the sequence; and the VLCDR1 amino acid sequence comprising SEQ ID NO: 62, the VLCDR2 amino acid sequence of SEQ ID NO: 63, and the VLCDR3 amino acid sequence of SEQ ID NO: 64 Light chain variable regions (VL), each disclosed in Table 3.

In one embodiment, the anti-PD-L1 antibody molecule comprises: VHCDR1 encoded by the nucleotide sequence of SEQ ID NO: 81, VHCDR2 encoded by the nucleotide sequence of SEQ ID NO: 82, and VHCDR2 encoded by the nucleotide sequence of SEQ ID NO: VH of the VHCDR3 encoded by the nucleotide sequence of SEQ ID NO: 83; and VLCDR1 encoded by the nucleotide sequence of SEQ ID NO: 86, VLCDR2 encoded by the nucleotide sequence of SEQ ID NO: 87, and The VL of the VLCDR3 encoded by the nucleotide sequence of :88, each disclosed in Table 3 .

In one embodiment, the anti-PD-L1 antibody molecule comprises: an amino acid sequence comprising SEQ ID NO: 59, or at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, or higher Sexual amino acid sequence of VH. In one embodiment, the anti-PD-L1 antibody molecule comprises: an amino acid sequence comprising SEQ ID NO: 69, or at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, or higher Sexual amino acid sequence of VL. In one embodiment, the anti-PD-L1 antibody molecule comprises: an amino acid sequence comprising SEQ ID NO: 73, or at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, or higher Sexual amino acid sequence of VH. In one embodiment, the anti-PD-L1 antibody molecule comprises: an amino acid sequence comprising SEQ ID NO: 77, or at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, or higher Sexual amino acid sequence of VL. In one embodiment, the anti-PD-L1 antibody molecule comprises: VH comprising the amino acid sequence of SEQ ID NO: 59 and VL comprising the amino acid sequence of SEQ ID NO: 69. In one embodiment, the anti-PD-L1 antibody molecule comprises: VH comprising the amino acid sequence of SEQ ID NO: 73 and VL comprising the amino acid sequence of SEQ ID NO: 77.

In one embodiment, the antibody molecule comprises: the nucleotide sequence consisting of SEQ ID NO: 60, or having at least 80%, 81%, 82%, 83%, 84%, 85%, 86% with SEQ ID NO: 60 %, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, or higher identity nucleosides VH encoded by the acid sequence. In one embodiment, the antibody molecule comprises: the nucleotide sequence consisting of SEQ ID NO: 70, or having at least 80%, 81%, 82%, 83%, 84%, 85%, 86% with SEQ ID NO: 70 %, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, or higher identity nucleosides acid sequence encoded VL. In one embodiment, the antibody molecule comprises: the nucleotide sequence consisting of SEQ ID NO: 74, or having at least 80%, 81%, 82%, 83%, 84%, 85%, 86% with SEQ ID NO: 74 %, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, or higher identity nucleosides VH encoded by the acid sequence. In one embodiment, the antibody molecule comprises: the nucleotide sequence consisting of SEQ ID NO: 78, or having at least 80%, 81%, 82%, 83%, 84%, 85%, 86% with SEQ ID NO: 78 %, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, or higher identity nucleosides acid sequence encoded VL. In one embodiment, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 60 and a VL encoded by the nucleotide sequence of SEQ ID NO: 70. In one embodiment, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 72 and a VL encoded by the nucleotide sequence of SEQ ID NO: 78.

In one embodiment, the anti-PD-L1 antibody molecule comprises: an amino acid sequence comprising SEQ ID NO: 61, or at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, or higher Sexual amino acid sequence of the heavy chain. In one embodiment, the anti-PD-L1 antibody molecule comprises: an amino acid sequence comprising SEQ ID NO: 71, or at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, or higher Sexual amino acid sequence of the light chain. In one embodiment, the anti-PD-L1 antibody molecule comprises: an amino acid sequence comprising SEQ ID NO: 75, or at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, or higher Sexual amino acid sequence of the heavy chain. In one embodiment, the anti-PD-L1 antibody molecule comprises: an amino acid sequence comprising SEQ ID NO: 79, or at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, or higher Sexual amino acid sequence of the light chain. In one embodiment, the anti-PD-L1 antibody molecule comprises: a heavy chain comprising the amino acid sequence of SEQ ID NO: 61 and a light chain comprising the amino acid sequence of SEQ ID NO: 71. In one embodiment, the anti-PD-L1 antibody molecule comprises: a heavy chain comprising the amino acid sequence of SEQ ID NO: 75 and a light chain comprising the amino acid sequence of SEQ ID NO: 79.

In one embodiment, the antibody molecule comprises: the nucleotide sequence consisting of SEQ ID NO: 68, or having at least 80%, 81%, 82%, 83%, 84%, 85%, 86% with SEQ ID NO: 68 %, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, or higher identity nucleosides The heavy chain encoded by the acid sequence. In one embodiment, the antibody molecule comprises: the nucleotide sequence consisting of SEQ ID NO: 72, or having at least 80%, 81%, 82%, 83%, 84%, 85%, 86% with SEQ ID NO: 72 %, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, or higher identity nucleosides acid sequence encoded light chain. In one embodiment, the antibody molecule comprises: the nucleotide sequence consisting of SEQ ID NO: 76, or having at least 80%, 81%, 82%, 83%, 84%, 85%, 86% with SEQ ID NO: 76 %, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, or higher identity nucleosides acid sequence encoded heavy chain. In one embodiment, the antibody molecule comprises: the nucleotide sequence consisting of SEQ ID NO: 80, or having at least 80%, 81%, 82%, 83%, 84%, 85%, 86% with SEQ ID NO: 80 %, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, or higher identity nucleosides acid sequence encoded light chain. In one embodiment, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 68 and a light chain encoded by the nucleotide sequence of SEQ ID NO: 72. In one embodiment, the antibody molecule comprises: a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 76 and a light chain encoded by the nucleotide sequence of SEQ ID NO: 80.

The antibody molecules described herein can be produced by vectors, host cells, and methods described in US 2016/0108123. [ Table 3 ]. Amino acid and nucleotide sequences of exemplary anti-PD-L1 antibody molecules BAP058- Plant O HC SEQ ID NO: 54 (Cabat) HCDR1 SYWMY SEQ ID NO: 55 (Cabat) HCDR2 RIDPNSGSTKYNEKFKN SEQ ID NO: 56 (Cabat) HCDR3 DYRKGLYAMDY SEQ ID NO: 57 (Josiah) HCDR1 GYTFTSY SEQ ID NO: 58 (Josiah) HCDR2 DPNSGS SEQ ID NO: 56 (Josiah) HCDR3 DYRKGLYAMDY SEQ ID NO: 59 VH EVQLVQSGAEVKKPGATVKISCKVSGYTFTSYWMYWVRQARGQRLEWIGRIDPNSGSTKYNEKFKNRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDYRKGLYAMDYWGQGTTVTVSS SEQ ID NO: 60 DNA VH GAAGTGCAGCTGGTGCAGTCAGGCGCCGAAGTGAAGAAACCCGGCGCTACCGTGAAGATTAGCTGTAAAGTCTCAGGCTACACCTTCACTAGCTACTGGATGTACTGGGTCCGACAGGCTAGAGGGCAAAGACTGGAGTGGATCGGTAGAATCGACCCTAATAGCGGCTCTACTAAGTATAACGAGAAGTTTAAGAATAGGTTCACTATTAGTAGGGATAACTCTAAGAACACCCTGTACCTGCAGATGAATAGCCTGAGAGCCGAGGACACCGCCGTCTACTACTGCGCTAGAGACTATAGAAAGGGCCTGTACGCTATGGACTACTGGGGTCAAGGCACTACCGTGACCGTGTCTTCA SEQ ID NO: 61 heavy chain EVQLVQSGAEVKKPGATVKISCKVSGYTFTSYWMYWVRQARGQRLEWIGRIDPNSGSTKYNEKFKNRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDYRKGLYAMDYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG SEQ ID NO: 68 DNA heavy chain GAAGTGCAGCTGGTGCAGTCAGGCGCCGAAGTGAAGAAACCCGGCGCTACCGTGAAGATTAGCTGTAAAGTCTCAGGCTACACCTTCACTAGCTACTGGATGTACTGGGTCCGACAGGCTAGAGGGCAAAGACTGGAGTGGATCGGTAGAATCGACCCTAATAGCGGCTCTACTAAGTATAACGAGAAGTTTAAGAATAGGTTCACTATTAGTAGGGATAACTCTAAGAACACCCTGTACCTGCAGATGAATAGCCTGAGAGCCGAGGACACCGCCGTCTACTACTGCGCTAGAGACTATAGAAAGGGCCTGTACGCTATGGACTACTGGGGTCAAGGCACTACCGTGACCGTGTCTTCAGCTAGCACTAAGGGCCCGTCCGTGTTCCCCCTGGCACCTTGTAGCCGGAGCACTAGCGAATCCACCGCTGCCCTCGGCTGCCTGGTCAAGGATTACTTCCCGGAGCCCGTGACCGTGTCCTGGAACAGCGGAGCCCTGACCTCCGGAGTGCACACCTTCCCCGCTGTGCTGCAGAGCTCCGGGCTGTACTCGCTGTCGTCGGTGGTCACGGTGCCTTCATCTAGCCTGGGTACCAAGACCTACACTTGCAACGTGGACCACAAGCCTTCCAACACTAAGGTGGACAAGCGCGTCGAATCGAAGTACGGCCCACCGTGCCCGCCTTGTCCCGCGCCGGAGTTCCTCGGCGGTCCCTCGGTCTTTCTGTTCCCACCGAAGCCCAAGGACACTTTGATGATTTCCCGCACCCCTGAAGTGACATGCGTGGTCGTGGACGTGTCACAGGAAGATCCGGAGGTGCAGTTCAATTGGTACGTGGATGGCGTCGAGGTGCACAACGCCAAAACCAAGCCGAGGGAGGAGCAGTTCAACTCCACTTACCGCGTCGTGTCCGTGCTGACGGTGCTGCATCAGGACTGGCTGAACGGGAAGGAGTACAAGTGCAAAGTGTCCAACAAGGGACTTCCTAGCTCAATCGAAA AGACCATCTCGAAAGCCAAGGGACAGCCCCGGGAACCCCAAGTGTATACCCTGCCACCGAGCCAGGAAGAAATGACTAAGAACCAAGTCTCATTGACTTGCCTTGTGAAGGGCTTCTACCCATCGGATATCGCCGTGGAATGGGAGTCCAACGGCCAGCCGGAAAACAACTACAAGACCACCCCTCCGGTGCTGGACTCAGACGGATCCTTCTTCCTCTACTCGCGGCTGACCGTGGATAAGAGCAGATGGCAGGAGGGAAATGTGTTCAGCTGTTCTGTGATGCATGAAGCCCTGCACAACCACTACACTCAGAAGTCCCTGTCCCTCTCCCTGGGA BAP058- Plant O LC SEQ ID NO: 62 (Cabat) LCDR1 KASQDVGTAVA SEQ ID NO: 63 (Cabat) LCDR2 WASTRHT SEQ ID NO: 64 (Cabat) LCDR3 QQYNSYPLT SEQ ID NO: 65 (Josiah) LCDR1 SQDVGTA SEQ ID NO: 66 (Josiah) LCDR2 WAS SEQ ID NO: 67 (Josiah) LCDR3 YNSYPL SEQ ID NO: 69 VL AIQLTQSPSSLSASVGDRVTITCKASQDVGTAVAWYLQKPGQSPQLLIYWASTRHTGVPSRFSGSGSGTDFTFTISSLEAEDAATYYCQQYNSYPLTFGQGTKVEIK SEQ ID NO: 70 DNA VL GCTATTCAGCTGACTCAGTCACCTAGTAGCCTGAGCGCTAGTGTGGGCGATAGAGTGACTATCACCTGTAAAGCCTCTCAGGACGTGGGCACCGCCGTGGCCTGGTATCTGCAGAAGCCTGGTCAATCACCTCAGCTGCTGATCTACTGGGCCTCTACTAGACACACCGGCGTGCCCTCTAGGTTTAGCGGTAGCGGTAGTGGCACCGACTTCACCTTCACTATCTCTTCACTGGAAGCCGAGGACGCCGCTACCTACTACTGTCAGCAGTATAATAGCTACCCCCTGACCTTCGGTCAAGGCACTAAGGTCGAGATTAAG SEQ ID NO: 71 light chain AIQLTQSPSSLSASVGDRVTITCKASQDVGTAVAWYLQKPGQSPQLLIYWASTRHTGVPSRFSGSGSGTDFTFTISSLEAEDAATYYCQQYNSYPLTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEVKQHKGLS SEQ ID NO: 72 DNA light chain GCTATTCAGCTGACTCAGTCACCTAGTAGCCTGAGCGCTAGTGTGGGCGATAGAGTGACTATCACCTGTAAAGCCTCTCAGGACGTGGGCACCGCCGTGGCCTGGTATCTGCAGAAGCCTGGTCAATCACCTCAGCTGCTGATCTACTGGGCCTCTACTAGACACACCGGCGTGCCCTCTAGGTTTAGCGGTAGCGGTAGTGGCACCGACTTCACCTTCACTATCTCTTCACTGGAAGCCGAGGACGCCGCTACCTACTACTGTCAGCAGTATAATAGCTACCCCCTGACCTTCGGTCAAGGCACTAAGGTCGAGATTAAGCGTACGGTGGCCGCTCCCAGCGTGTTCATCTTCCCCCCCAGCGACGAGCAGCTGAAGAGCGGCACCGCCAGCGTGGTGTGCCTGCTGAACAACTTCTACCCCCGGGAGGCCAAGGTGCAGTGGAAGGTGGACAACGCCCTGCAGAGCGGCAACAGCCAGGAGAGCGTCACCGAGCAGGACAGCAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCGACTACGAGAAGCATAAGGTGTACGCCTGCGAGGTGACCCACCAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAACAGGGGCGAGTGC BAP058- Plant N HC SEQ ID NO: 54 (Cabat) HCDR1 SYWMY SEQ ID NO: 55 (Cabat) HCDR2 RIDPNSGSTKYNEKFKN SEQ ID NO: 56 (Cabat) HCDR3 DYRKGLYAMDY SEQ ID NO: 57 (Josiah) HCDR1 GYTFTSY SEQ ID NO: 58 (Josiah) HCDR2 DPNSGS SEQ ID NO: 56 (Josiah) HCDR3 DYRKGLYAMDY SEQ ID NO: 73 VH EVQLVQSGAEVKKPGATVKISCKVSGYTFTSYWMYWVRQATGQGLEWMGRIDPNSGSTKYNEKFKNRVTITADKSTSTAYMELSSLRSEDTAVYYCARDYRKGLYAMDYWGQGTTVTVSS SEQ ID NO: 74 DNA VH GAAGTGCAGCTGGTGCAGTCAGGCGCCGAAGTGAAGAAACCCGGCGCTACCGTGAAGATTAGCTGTAAAGTCTCAGGCTACACCTTCACTAGCTACTGGATGTACTGGGTCCGACAGGCTACCGGTCAAGGCCTGGAGTGGATGGGTAGAATCGACCCTAATAGCGGCTCTACTAAGTATAACGAGAAGTTTAAGAATAGAGTGACTATCACCGCCGATAAGTCTACTAGCACCGCCTATATGGAACTGTCTAGCCTGAGATCAGAGGACACCGCCGTCTACTACTGCGCTAGAGACTATAGAAAGGGCCTGTACGCTATGGACTACTGGGGTCAAGGCACTACCGTGACCGTGTCTTCA SEQ ID NO: 75 heavy chain EVQLVQSGAEVKKPGATVKISCKVSGYTFTSYWMYWVRQATGQGLEWMGRIDPNSGSTKYNEKFKNRVTITADKSTSTAYMELSSLRSEDTAVYYCARDYRKGLYAMDYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG SEQ ID NO: 76 DNA heavy chain GAAGTGCAGCTGGTGCAGTCAGGCGCCGAAGTGAAGAAACCCGGCGCTACCGTGAAGATTAGCTGTAAAGTCTCAGGCTACACCTTCACTAGCTACTGGATGTACTGGGTCCGACAGGCTACCGGTCAAGGCCTGGAGTGGATGGGTAGAATCGACCCTAATAGCGGCTCTACTAAGTATAACGAGAAGTTTAAGAATAGAGTGACTATCACCGCCGATAAGTCTACTAGCACCGCCTATATGGAACTGTCTAGCCTGAGATCAGAGGACACCGCCGTCTACTACTGCGCTAGAGACTATAGAAAGGGCCTGTACGCTATGGACTACTGGGGTCAAGGCACTACCGTGACCGTGTCTTCAGCTAGCACTAAGGGCCCGTCCGTGTTCCCCCTGGCACCTTGTAGCCGGAGCACTAGCGAATCCACCGCTGCCCTCGGCTGCCTGGTCAAGGATTACTTCCCGGAGCCCGTGACCGTGTCCTGGAACAGCGGAGCCCTGACCTCCGGAGTGCACACCTTCCCCGCTGTGCTGCAGAGCTCCGGGCTGTACTCGCTGTCGTCGGTGGTCACGGTGCCTTCATCTAGCCTGGGTACCAAGACCTACACTTGCAACGTGGACCACAAGCCTTCCAACACTAAGGTGGACAAGCGCGTCGAATCGAAGTACGGCCCACCGTGCCCGCCTTGTCCCGCGCCGGAGTTCCTCGGCGGTCCCTCGGTCTTTCTGTTCCCACCGAAGCCCAAGGACACTTTGATGATTTCCCGCACCCCTGAAGTGACATGCGTGGTCGTGGACGTGTCACAGGAAGATCCGGAGGTGCAGTTCAATTGGTACGTGGATGGCGTCGAGGTGCACAACGCCAAAACCAAGCCGAGGGAGGAGCAGTTCAACTCCACTTACCGCGTCGTGTCCGTGCTGACGGTGCTGCATCAGGACTGGCTGAACGGGAAGGAGTACAAGTGCAAAGTGTCCAACAAGGGACTTCCTAGCTCAATCGAAA AGACCATCTCGAAAGCCAAGGGACAGCCCCGGGAACCCCAAGTGTATACCCTGCCACCGAGCCAGGAAGAAATGACTAAGAACCAAGTCTCATTGACTTGCCTTGTGAAGGGCTTCTACCCATCGGATATCGCCGTGGAATGGGAGTCCAACGGCCAGCCGGAAAACAACTACAAGACCACCCCTCCGGTGCTGGACTCAGACGGATCCTTCTTCCTCTACTCGCGGCTGACCGTGGATAAGAGCAGATGGCAGGAGGGAAATGTGTTCAGCTGTTCTGTGATGCATGAAGCCCTGCACAACCACTACACTCAGAAGTCCCTGTCCCTCTCCCTGGGA BAP058- Plant N LC SEQ ID NO: 62 (Cabat) LCDR1 KASQDVGTAVA SEQ ID NO: 63 (Cabat) LCDR2 WASTRHT SEQ ID NO: 64 (Cabat) LCDR3 QQYNSYPLT SEQ ID NO: 65 (Josiah) LCDR1 SQDVGTA SEQ ID NO: 66 (Josiah) LCDR2 WAS SEQ ID NO: 67 (Josiah) LCDR3 YNSYPL SEQ ID NO: 77 VL DVVMTQSPLSLPVTLGQPASISCKASQDVGTAVAWYQQKPGQAPRLLIYWASTRHTGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQYNSYPLTFGQGTKVEIK SEQ ID NO: 78 DNA VL GACGTCGTGATGACTCAGTCACCCCTGAGCCTGCCCGTGACCCTGGGGCAGCCCGCCTCTATTAGCTGTAAAGCCTCTCAGGACGTGGGCACCGCCGTGGCCTGGTATCAGCAGAAGCCAGGGCAAGCCCCTAGACTGCTGATCTACTGGGCCTCTACTAGACACACCGGCGTGCCCTCTAGGTTTAGCGGTAGCGGTAGTGGCACCGAGTTCACCCTGACTATCTCTTCACTGCAGCCCGACGACTTCGCTACCTACTACTGTCAGCAGTATAATAGCTACCCCCTGACCTTCGGTCAAGGCACTAAGGTCGAGATTAAG SEQ ID NO: 79 light chain DVVMTQSPLSLPVTLGQPASISCKASQDVGTAVAWYQQKPGQAPRLLIYWASTRHTGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQYNSYPLTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEVKVKGLSS SEQ ID NO: 80 DNA light chain GACGTCGTGATGACTCAGTCACCCCTGAGCCTGCCCGTGACCCTGGGGCAGCCCGCCTCTATTAGCTGTAAAGCCTCTCAGGACGTGGGCACCGCCGTGGCCTGGTATCAGCAGAAGCCAGGGCAAGCCCCTAGACTGCTGATCTACTGGGCCTCTACTAGACACACCGGCGTGCCCTCTAGGTTTAGCGGTAGCGGTAGTGGCACCGAGTTCACCCTGACTATCTCTTCACTGCAGCCCGACGACTTCGCTACCTACTACTGTCAGCAGTATAATAGCTACCCCCTGACCTTCGGTCAAGGCACTAAGGTCGAGATTAAGCGTACGGTGGCCGCTCCCAGCGTGTTCATCTTCCCCCCCAGCGACGAGCAGCTGAAGAGCGGCACCGCCAGCGTGGTGTGCCTGCTGAACAACTTCTACCCCCGGGAGGCCAAGGTGCAGTGGAAGGTGGACAACGCCCTGCAGAGCGGCAACAGCCAGGAGAGCGTCACCGAGCAGGACAGCAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCGACTACGAGAAGCATAAGGTGTACGCCTGCGAGGTGACCCACCAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAACAGGGGCGAGTGC BAP058- Plant O HC SEQ ID NO: 81 (Cabat) HCDR1 AGCTACTGGATGTAC SEQ ID NO: 82 (Cabat) HCDR2 AGAATCGACCCTAATAGCGGCTCTACTAAGTATAACGAGAAGTTTAAGAAT SEQ ID NO: 83 (Cabat) HCDR3 GACTATAGAAAGGGCCTGTACGCTATGGACTAC SEQ ID NO: 84 (Josiah) HCDR1 GGCTACACCTTCACTAGCTAC SEQ ID NO: 85 (Josiah) HCDR2 GACCCTAATAGCGGCTCT SEQ ID NO: 83 (Josiah) HCDR3 GACTATAGAAAGGGCCTGTACGCTATGGACTAC BAP058- Plant O LC SEQ ID NO: 86 (Cabat) LCDR1 AAAGCCTCTCAGGACGTGGGCACCGCCGTGGCC SEQ ID NO: 87 (Cabat) LCDR2 TGGGCCTCTACTAGACACACC SEQ ID NO: 88 (Cabat) LCDR3 CAGCAGTATAATAGCTACCCCCTGACC SEQ ID NO: 89 (Josiah) LCDR1 TCTCAGGACGTGGGCACCGCC SEQ ID NO: 90 (Josiah) LCDR2 TGGGCCTCT SEQ ID NO: 91 (Josiah) LCDR3 TATAATAGCTACCCCCTG BAP058- Plant N HC SEQ ID NO: 81 (Cabat) HCDR1 AGCTACTGGATGTAC SEQ ID NO: 82 (Cabat) HCDR2 AGAATCGACCCTAATAGCGGCTCTACTAAGTATAACGAGAAGTTTAAGAAT SEQ ID NO: 83 (Cabat) HCDR3 GACTATAGAAAGGGCCTGTACGCTATGGACTAC SEQ ID NO: 84 (Josiah) HCDR1 GGCTACACCTTCACTAGCTAC SEQ ID NO: 85 (Josiah) HCDR2 GACCCTAATAGCGGCTCT SEQ ID NO: 83 (Josiah) HCDR3 GACTATAGAAAGGGCCTGTACGCTATGGACTAC BAP058- Plant N LC SEQ ID NO: 86 (Cabat) LCDR1 AAAGCCTCTCAGGACGTGGGCACCGCCGTGGCC SEQ ID NO: 87 (Cabat) LCDR2 TGGGCCTCTACTAGACACACC SEQ ID NO: 88 (Cabat) LCDR3 CAGCAGTATAATAGCTACCCCCTGACC SEQ ID NO: 89 (Josiah) LCDR1 TCTCAGGACGTGGGCACCGCC SEQ ID NO: 90 (Josiah) LCDR2 TGGGCCTCT SEQ ID NO: 91 (Josiah) 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 disclosed in US 8,217,149. In one embodiment, the anti-PD-L1 antibody molecule comprises one or more of the following: the CDR sequence of atezolizumab (or all CDR sequences in general), the heavy chain or light chain variable region sequence, or the heavy chain Or light chain sequences, e.g., as disclosed 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 disclosed in WO 2013/079174. In one embodiment, the anti-PD-L1 antibody molecule comprises one or more of the following: the CDR sequence of avelumab (or all CDR sequences in general), the heavy chain or light chain variable region sequence, or the heavy chain Or light chain sequences, e.g., as disclosed in Table 4 .

In one embodiment, the anti-PD-L1 antibody molecule is durvalumab (Medimus Limited/AstraZeneca), also known as MEDI4736. Durvalumab and other anti-PD-L1 antibodies are disclosed in US 8,779,108. In one embodiment, the anti-PD-L1 antibody molecule comprises one or more of the following: durvalumab CDR sequence (or all CDR sequences in general), heavy chain or light chain variable region sequence, or heavy chain Or light chain sequences, e.g., as disclosed 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 disclosed in US 7,943,743 and WO 2015/081158. In one embodiment, the anti-PD-L1 antibody molecule comprises one or more of the following: the CDR sequence of BMS-936559 (or all CDR sequences in general), the heavy chain or light chain variable region sequence, or the heavy chain or light chain Strand sequences, e.g., as disclosed in Table 4 .

Other known anti-PD-L1 antibodies include those described, for example, in WO 2015/181342, WO 2014/100079, WO 2016/000619, WO 2014/022758, WO 2014/055897, WO 2015/061668, WO 2013 US 8,168,179, US 8,552,154, US 8,460,927, and US 9,175,082.

In one embodiment, the anti-PD-L1 antibody competes with one of the anti-PD-L1 antibodies described herein for binding to the same epitope on PD-L1 and/or an antibody that binds to the same epitope on PD-L1. [ Table 4 ]. Amino acid sequences of other exemplary anti-PD-L1 antibody molecules Atezolizumab SEQ ID NO: 92 heavy chain EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 93 light chain DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYLYHPATFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLGSKADYEVECKQGLSS Avelumab SEQ ID NO: 94 heavy chain EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYIMMWVRQAPGKGLEWVSSIYPSGGITFYADTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARIKLGTVTTVDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 95 light chain QSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYDVSNRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYTSSSTRVFGTGTKVTVLGQPKANPTVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADGSPVKAGVETTKPSKQSNNKYAASSYLSLTPEQWKSHRSTY durvalumab SEQ ID NO: 96 heavy chain EVQLVESGGGLVQPGGSLRLSCAASGFTFSRYWMSWVRQAPGKGLEWVANIKQDGSEKYYVDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAREGGWFGELAFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 97 light chain EIVLTQSPGTLLSPGERATLSCRASQRVSSSYLAWYQQKPGQAPRLLIYDASSRATGIPDRFSGSGSGTDFLTISRLEPEDFAVYYCQQYGSLPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQSGNSQESVTEQDSKDSTYSLSSTLFSKADYEKHKVGLRAVYACT BMS-936559 SEQ ID NO: 98 VH QVQLVQSGAEVKKPGSSVKVSCKTSGDTFSTYAISWVRQAPGQGLEWMGGIIPIFGKAHYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYFCARKFHFVSGSPFGMDVWGQGTTVTVSS SEQ ID NO: 99 VL EIVLTQSPATLSSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPTFGQGTKVEIK Antibodies and antibody-like molecules

As used herein, the term "antibody molecule" refers to a protein, such as an immunoglobulin chain or fragment thereof, comprising at least one immunoglobulin variable domain sequence. The term "antibody molecule" includes, for example, monoclonal antibodies (including full-length antibodies having an immunoglobulin Fc region). In an embodiment, the antibody molecule comprises a full length antibody or a full length immunoglobulin chain. In an embodiment, the antibody molecule comprises a full-length antibody or an antigen-binding or functional fragment of a full-length immunoglobulin chain. In an 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 is aligned with a first epitope ( For example, a first target) has binding specificity and a second immunoglobulin variable domain sequence in the plurality has binding specificity for a second epitope (eg, a second target). In an embodiment, the multispecific antibody molecule is a bispecific antibody molecule.

In an embodiment, the antibody molecule is a monospecific antibody molecule and binds a single epitope (eg, a single target (eg TGFβ, like NIS793)). For example, a monospecific antibody molecule may have multiple immunoglobulin variable domain sequences, each immunoglobulin variable domain sequence binding the same epitope.

In an 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 is aligned with a first epitope ( For example, a first target) has binding specificity and a second immunoglobulin variable domain sequence in the plurality has binding specificity for a second epitope (eg, a second target). In an embodiment, the first and second epitopes are on the same antigen (eg, the same protein (or subunit of a multimeric protein)). In an embodiment, the first epitope and the second epitope overlap. In an embodiment, the first epitope and the second epitope do not overlap. In an embodiment, the first and second epitopes are on different antigens (eg different proteins (or different subunits of a multimeric protein)). In an embodiment, the multispecific antibody molecule comprises a third, fourth or fifth immunoglobulin variable domain. In an embodiment, the multispecific antibody molecule is a bispecific antibody molecule, a trispecific antibody molecule or a tetraspecific antibody molecule.

In an embodiment, the multispecific antibody molecule is a bispecific antibody molecule. Bispecific antibodies are specific for no more than two antigens. The bispecific antibody molecule is characterized by a first immunoglobulin variable domain sequence having binding specificity for a first epitope, and a second immunoglobulin variable structure having binding specificity for a second epitope domain sequence. In an embodiment, the first and second epitopes are on the same antigen (eg, the same protein (or subunit of a multimeric protein)). In an embodiment, the first epitope and the second epitope overlap. In an embodiment, the first epitope and the second epitope do not overlap. In an embodiment, the first and second epitopes are on different antigens (eg different proteins (or different subunits of a multimeric protein)). In an embodiment, the bispecific antibody molecule comprises a heavy chain variable domain sequence and a light chain variable domain sequence having binding specificity for a first epitope, and a heavy chain having binding specificity for a second epitope Variable domain sequences and light chain variable domain sequences. In an embodiment, a bispecific antibody molecule comprises a half antibody with binding specificity for a first epitope and a half antibody with binding specificity for a second epitope. In an embodiment, a bispecific antibody molecule comprises a half antibody, or fragment thereof, with binding specificity for a first epitope, and a half antibody, or fragment thereof, with binding specificity for a second epitope. In an embodiment, the bispecific antibody molecule comprises a scFv, or fragment thereof, with binding specificity for a first epitope, and a scFv, or fragment thereof, with binding specificity for a second epitope. In an embodiment, the first epitope is on TGFβ (1, 2 and/or 3) and the second epitope is on PD-1 (or PD-L1, or PD-L2).

Protocols for generating multispecific (e.g., bispecific or trispecific) or heterodimeric antibody molecules are known in the art; such protocols include, but are not limited to: "knob in a hole)" approach, such as described in US 5,731,168; electrostatically directed Fc pairing, as described, for example, in WO 09/089004, WO 06/106905 and WO 2010/129304; Source dimer formation, as described, for example, in WO 07/110205; Fab arm exchange, as described, for example, in WO 08/119353, WO 2011/131746 and WO 2013/060867; diabody conjugates, for example using Heterobifunctional reagents with amine-reactive groups and sulfhydryl-reactive groups to generate bispecific structures by antibody cross-linking, as described, for example, in US 4,433,059; Cycles of reduction and oxidation of sulfur bonds, bispecific antibody determinants produced by recombination of half-antibodies (heavy-light chain pairs or Fab) from different antibodies, as described, for example, in US 4,444,878; trifunctional antibodies, such as Three Fab' fragments cross-linked by sulfhydryl-reactive groups, as described, for example, in US 5,273,743; biosynthetic binding proteins, for example by a C-terminal tail, preferably by disulfide bonds or amine reactivity Chemical cross-linking cross-linked scFv pairs, as described for example in US 5,534,254; diabodies, for example Fab fragments with different binding specificities by means of a leucine zipper which has replaced the constant domain ( For example, c-fos and c-jun) dimerization, as described for example in US 5,582,996; bispecific and oligospecific monovalent and oligovalent receptors, such as VH- of two antibodies (two Fab fragments) CH1 regions, the VH-CH1 regions are linked by a polypeptide spacer between the CH1 region of one antibody and the VH region (typically with an associated light chain) of another antibody, as described, for example, in US 5,591,828 ; bispecific DNA - antibody conjugates, such as antibody or Fab fragments cross-linked by double-strand segments of DNA, as described, for example, in US 5,635,602; bispecific fusion proteins, such as containing two scFv (between them Expression constructs with a hydrophilic helical peptide linker (linker) and a complete constant region, as described, for example, in US 5,637,481; multivalent and multispecific binding proteins, such as those with an Ig heavy chain variable region binding region Polypeptide dimers of the first domain and the second domain of the Ig light chain variable region binding region, commonly referred to as diabodies (higher order structures have also been revealed, resulting in bispecific, trispecific, or tetraspecific molecule) as described, for example, in US 5,837,242; with linked VL and VH chains (which are further peptide spacer linked to the antibody hinge region and CH3 region) that can dimerize to form bispecific/multivalent molecules, as described, for example, in US 5,837,821; with short peptide linkers (eg, 5 or 10 amino acids) or in either orientation at all without linker-linked VH and VL domains that can form dimers to form bispecific diabodies; trimers and tetramers, as described for example in US 5,844,094; strings of VH domains (or VL domains in family members) linked by peptide bonds to C-terminal crosslinkable groups, which can Cross-linking groups are further associated with VL domains to form a series of FVs (or scFvs), as described, for example, in US 5,864,019; and single chain binding polypeptides having both VH and VL domains connected via peptide linkers Multivalent structures are assembled by non-covalent or chemical cross-linking to form eg homobivalent, heterobivalent, trivalent and tetravalent structures using scFv or diabody type formats as described eg in US 5,869,620. Additional exemplary multispecific and bispecific molecules and methods for their preparation are found, for example, in US 5,910,573, US 5,932,448, US 5,959,083, US 5,989,830, US 6,005,079, US 6,239,259, US 6,294,353, US 6,333,396, US 6,476,1958, US 6,476,1958, 6,670,453、US 6,743,896、US 6,809,185、US 6,833,441、US 7,129,330、US 7,183,076、US 7,521,056、US 7,527,787、US 7,534,866、US 7,612,181、US 2002/004587 A1、US 2002/076406 A1、US 2002/103345 A1、US 2003/ 207346 A1, US 2003/211078 A1, US 2004/219643 A1, US 2004/220388 A1, US 2004/242847 A1, US 2005/003403 A1, US 2005/004352 A1, US 2005/069552 A15/A0710 , US 2005/100543 A1, US 2005/136049 A1, US 2005/136051 A1, US 2005/163782 A1, US 2005/266425 A1, US 2006/083747 A1, US 2006/120960 A1, US 2006/21, 20449 2006/263367 A1, US 2007/004909 A1, US 2007/087381 A1, US 2007/128150 A1, US 2007/141049 A1, US 2007/154901 A1, US 2007/274985 A1, US 2008/050320 A1, 069820 A1, US 2008/152645 A1, US 2008/171855 A1, US 2008/241884 A1, US 2008/254512 A1, US 2008/260738 A1, US 2009/130106 A1, US 2009/158905 A1, US 2009/158905 A1, US 2007 , US 2009/162359 A1, US 2009/162360 A1, US 2009/17 5851 A1, US 2009/175867 A1, US 2009/232811 A1, US 2009/234105 A1, US 2009/263392 A1, US 2009/274649 A1, EP 346087 A2, WO 00/06605 A2, WO 02/072635 A2, WO 04/081051 A1, WO 06/020258 A2, WO 2007/044887 A2, WO 2007/095338 A2, WO 2007/137760 A2, WO 2008/119353 A1, WO 2009/021754 A2, WO 2009/068630/A1, WO 91 03493 A1, WO 93/23537 A1, WO 94/09131 A1, WO 94/12625 A2, WO 95/09917 A1, WO 96/37621 A2, WO 99/64460 A1.

"Fusion protein" and "fusion polypeptide" refer to a polypeptide having at least two moieties covalently linked together, wherein each moiety is a polypeptide having different properties. The property may be a biological property, such as in vitro or in vivo activity. The property can also be a simple chemical or physical property, such as binding to a target molecule, catalysis of a reaction, etc. The two moieties can be directly linked by a single peptide bond or by a peptide linker, but are in-frame with each other.

In embodiments, antibody molecules include diabodies, and single chain molecules, as well as antigen-binding fragments of antibodies (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 an embodiment, an antibody molecule comprises or consists of a heavy chain and a light chain (referred to herein as a half-antibody). In another example, the antibody molecule comprises two heavy (H) chain variable domain sequences and two light (L) chain variable domain sequences, thereby forming two antigen binding sites, the antibody molecule such as Fab, Fab', F(ab') ₂ , Fc, Fd, Fd', Fv, single chain antibody (e.g. scFv), single variable domain antibody, diabody (Dab) (bivalent and bispecific), and Chimeric (eg, humanized) antibodies, which can be produced by modifying whole antibodies or can be those synthesized de novo using recombinant DNA techniques. Such functional antibody fragments retain the ability to selectively bind to their respective antigens or receptors. Antibodies and antibody fragments may be from any class of antibodies, including but not limited to IgG, IgA, IgM, IgD, and IgE, and from any subclass (eg, IgGl, IgG2, IgG3, and IgG4). Preparations of antibody molecules can be monoclonal or polyclonal. Antibody molecules can also be human, humanized, CDR-grafted, or produced in vitro. The antibody can have, for example, an IgG1, IgG2, IgG3 or IgG4 heavy chain constant region. Antibodies can also have light chains such as kappa or lambda. The term "immunoglobulin" (Ig) is used interchangeably herein with the term "antibody".

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

The term "antibody" includes whole molecules and functional fragments thereof. The constant region of an antibody can be altered (e.g., mutated) to modify the properties of the antibody (e.g., to increase or decrease one or more of: Fc receptor binding, antibody glycosylation, number of cysteine residues, effector cell function or complement function).

Antibody molecules can also be single domain antibodies. A single domain antibody may comprise an antibody that is a portion of a complementarity determining region single domain polypeptide. Examples include, but are not limited to, heavy chain antibodies, antibodies naturally lacking light chains, single domain antibodies derived from conventional 4-chain antibodies, engineered antibodies, and single domain scaffolds other than those derived from antibodies. A single domain antibody can be any antibody described in the art, or any future single domain antibody. Single domain antibodies can be derived from any species including, but not limited to, mouse, human, camel, llama, fish, shark, goat, rabbit, and cow. According to another aspect of the invention, the single domain antibody is a naturally occurring single domain antibody, referred to as a heavy chain antibody lacking a light chain. Such single domain antibodies are disclosed, for example, in WO 94/04678. For reasons of clarity, such variable domains derived from heavy chain antibodies that naturally lack light chains are referred to herein as VHH or Nanobodies to distinguish them from the conventional VH of four-chain immunoglobulins. Such VHH molecules may be derived from antibodies produced in Camelidae species, such as camels, llamas, dromedaries, alpacas and guanacos. Species other than Camelidae can produce heavy chain antibodies that naturally lack light chains; such VHHs are within the scope of the invention.

The VH and VL regions can be subdivided into hypervariable regions called "complementarity determining regions" (CDRs), interspersed with more conserved regions called "framework regions" (FR or FW).

The framework regions and the extent of the CDRs have been precisely defined by a number of methods (see Kabat, EA et al. (1991) Sequences of Proteins of Immunological Interest [immunology interested protein sequence], 5th edition, US Department of Health and Human Services [US Department of Health and Human Services], NIH Publication No. 91-3242; Chothia, C. et al. (1987) J. Mol. Biol . [Journal of Molecular Biology] 196:901-917; and by Oxford Molecular AbM Antibody AbM definition used by Oxford Molecular's AbM antibody modeling software). See generally, eg, Protein Sequence and Structure Analysis of Antibody Variable Domains [Protein Sequence and Structure Analysis of Antibody Variable Domains] in: Antibody Engineering Lab Manual [Editors: Duebel, S. and Kontermann, R., in Springer-Verlag, Heidelberg).

As used herein, the terms "complementarity determining region" and "CDR" refer to amino acid sequences within the variable region of an antibody that confer antigen specificity and binding affinity. Typically, there are three CDRs (HCDR1, HCDR2, and HCDR3) in each heavy chain variable region and three CDRs (LCDR1, LCDR2, and LCDR3) in each light chain variable region.

The precise amino acid sequence boundaries for a given CDR can be determined using any of a number of well-known protocols, including those described in: Kabat et al. (1991), "Sequences of Proteins of Immunological Interest [Immunology Protein Sequences of Interest]", 5th edition, Public Health Service, National Institutes of Health, Bethesda, MD ("Kabat" numbering scheme ), Al-Lazikani et al., (1997) JMB 273, 927-948 (“Josia” numbering scheme). As used herein, CDRs defined according to the "Josia" numbering scheme are also sometimes 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); The CDR amino acid residues in the chain variable domain (VL) are numbered 24-34 (LCDR1), 50-56 (LCDR2) and 89-97 (LCDR3). According to Josiah, the CDR amino acids in VH are numbered 26-32 (HCDR1), 52-56 (HCDR2), and 95-102 (HCDR3); and the amino acid residues in VL are numbered 26-32 (LCDR1), 50-52 (LCDR2), and 91-96 (LCDR3). Defined by combining Kabat and Josiah's CDRs, which consist of amino acid residues 26-35 (HCDR1), 50-65 (HCDR2), and 95-102 (HCDR3) in human VH and amino acid residues in human VL Acid residues 24-34 (LCDR1), 50-56 (LCDR2) and 89-97 (LCDR3).

In general, unless otherwise indicated, an antibody molecule may comprise any combination of one or more Kabat CDRs and/or Josiah hypervariable loops. In one embodiment, the following definitions are used for the antibody molecule described in Table 1: HCDR1, according to the combined CDR definition of both Kabat and Josiah and HCCDR 2-3 and LCCDR 1-3, according to Kabat's CDR definition . By all definitions, each VH and VL typically includes three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.

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

The term "antigen combining site" refers to a portion of an antibody molecule comprising determinants that form the binding interface with a target (eg, TGFβ) or an epitope thereof. With respect to proteins (or protein mimetics), the antigen binding site typically includes one or more loops (with at least four amino acids or amino acid mimetics) that form the binding interface with the target polypeptide. Typically, the antigen binding site of an antibody molecule comprises at least one or two CDRs and/or hypervariable loops, or more typically 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 interfere with the binding of another antibody molecule (eg, an anti-TGFβ antibody molecule provided herein) to a target (eg, TGFβ1, 2 or 3). Interference with binding can be direct or indirect (eg, by allosteric modulation of the antibody molecule or target). The extent to which an antibody molecule is able to interfere with the binding of another antibody molecule to a target, and thus can be said to compete, can be determined using a competition binding assay (eg FACS assay, ELISA or BIACORE assay). In some embodiments, the competition binding assay is a quantitative competition assay. In some embodiments, in a competition binding assay (e.g., a competition assay described herein), when the binding of the first antibody molecule to the target is reduced by 10% or more, such as 20% or more, 30% or more , 40% or higher, 50% or higher, 55% or higher, 60% or higher, 65% or higher, 70% or higher, 75% or higher, 80% or higher, 85 % or higher, 90% or higher, 95% or higher, 98% or higher, 99% or higher, the first anti-TGFβ antibody molecule is said to compete with the second anti-TGFβ antibody molecule for binding to the target.

As used herein, the term "monoclonal antibody" or "monoclonal antibody composition" refers to a preparation of antibody molecules of single molecular composition. A monoclonal antibody composition exhibits a single binding specificity and affinity for a particular epitope. Monoclonal antibodies can be produced by hybridoma technology or methods that do not use hybridoma technology (such as recombinant methods).

An "effectively human" protein is one that does not elicit a neutralizing antibody response, such as a human anti-mouse antibody (HAMA) response. HAMAs may be problematic in many situations, for example, if the antibody molecule is administered repeatedly, such as in the case of treatment of chronic or recurrent disease. Due to increased clearance of antibodies in serum (see, e.g., Saleh et al., Cancer Immunol. Immunother. [Cancer Immunology, Immunotherapy], 32:180-190 (1990)), and also due to potential allergic reactions (see, e.g., LoBuglio et al., Hybridoma , 5:5117-5123 (1986)), HAMA responses can render repeated antibody administrations potentially ineffective.

The antibody molecules described throughout may be polyclonal or monoclonal antibodies. In other embodiments, antibodies can be produced recombinantly, such as by phage display or by combinatorial methods.

Phage display and combinatorial methods for generating antibodies are known in the art (as described in, e.g., Ladner et al., U.S. Pat. No. 5,223,409; Kang et al., International Publication No. WO 92/18619; Dower et al. People, 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 90/02 809; Fuchs et al., (1991) Bio/Technology 9:1370-1372; Hay et al., (1992) Hum Antibody Hybridomas [human antibody hybridomas] 3:81-85; Huse et al., (1989) Science [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[ Nature] 352:624-628; Gram et al., (1992) PNAS [Proceedings of the National Academy of Sciences] 89:3576-3580; Garrad et al. (1991) Bio/Technology 9:1373-1377; Hoogenboom et al. al, (1991) Nuc Acid Res 19:4133-4137; and Barbas et al (1991) PNAS [Proceedings of the National Academy of Sciences of the United States of America] 88:7978-7982).

In one embodiment, the antibody is a fully human antibody (e.g., an antibody made in a mouse that has been genetically engineered to produce antibodies from human immunoglobulin sequences), or a nonhuman antibody, such as a rodent (mouse or rat mouse), goat, primate (e.g. monkey), camel antibody. Preferably, the non-human antibody is a rodent (mouse or rat) antibody. Methods for producing rodent antibodies are known.

Human monoclonal antibodies can be produced using transgenic mice carrying human immunoglobulin genes rather than the mouse system. Splenocytes from such transgenic mice immunized with the antigen of interest were used to generate hybridomas secreting human mAbs with specific affinity for epitopes from human proteins (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).

An antibody can be an antibody molecule in which the variable regions or portions thereof (eg, CDRs) are produced in a non-human organism (eg, rat or mouse). Chimeric antibodies, CDR-grafted antibodies, and humanized antibodies belong to the present invention. Antibodies produced in non-human organisms (eg, rats or mice) and then modified, eg, in the variable framework or constant regions, to reduce antigenicity in humans are within the invention.

Chimeric antibodies can be produced by recombinant DNA techniques known in the art (see: Robinson et al., International Patent Publication PCT/US86/02269; Akira et al., European Patent Application 184,187; Taniguchi, M., European Patent Application 171,496; Morrison et al. , European Patent Application 173,494; Neuberger et al ., International Application WO 86/01533; Cabilly et al. , U.S. Patent Application No. 4,816,567; Cabilly et al. , European Patent Application 125,023; Better et al. (1988 Science 240:1041 -1043); Liu et al. (1987) PNAS 84:3439-3443; Liu et al. , 1987, J. Immunol. [Journal of Immunology] 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. [Journal of the National Cancer Institute] 80:1553-1559).

At least one or two, but usually all three (of heavy and/or light immunoglobulin chains) acceptor CDRs of a humanized or CDR-grafted antibody are replaced by donor 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. Only the number of CDRs required for the humanized antibody to bind to its target (eg, TGFβ) needs to be replaced. Preferably, the donor is a rodent antibody, such as a rat or mouse antibody, and the recipient will be a human framework or a human consensus framework. Typically, the immunoglobulin providing the CDRs is called the "donor" and the immunoglobulin providing the framework is called the "acceptor". In one embodiment, the donor immunoglobulin is non-human (eg, rodent). The acceptor framework is a naturally occurring (eg human) framework or consensus framework, or a sequence having about 85% or more identity thereto, preferably 90%, 95%, 99% or more identity.

As used herein, the term "consensus sequence" refers to a sequence formed by the most frequently occurring amino acids (or nucleotides) in a family of related sequences (see e.g. Winnaker, From Genes to Clones [From Genes to Clones] (Weinheim, Germany Publishing House (Verlagsgesellschaft, Weinheim, Germany) 1987). In a protein family, each position in the consensus sequence is occupied by the most frequently occurring amino acid at that position in the family. If two amino acids are equally frequent Either can be included in the consensus sequence."Consensus framework"refers to the framework regions in the consensus immunoglobulin sequence.

Antibodies can be humanized by methods known in the art (see, e.g., Morrison, SL, 1985, Science 229:1202-1207, Oi et al. , 1986, BioTechniques 4:214, and Queen et al. US 5,585,089, US 5,693,761 and US 5,693,762).

Humanized antibodies or CDR-grafted antibodies can be produced by CDR grafting or CDR substitution, wherein one, two or all CDRs of an immunoglobulin chain can be replaced. See, eg, U.S. Patent 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 5,225,539. Winter describes a CDR grafting method that can be used to prepare the humanized antibodies of the present invention (UK Patent Application GB 2188638A filed 26 March 1987; Winter US 5,225,539).

Humanized antibodies, in which specific amino acids have been substituted, deleted or added, are also within the scope of the invention. Criteria for selecting amino acids from donors are described in US 5,585,089, eg in columns 12-16 of US 5,585,089, eg in columns 12-16 of US 5,585,089. Additional techniques for humanizing antibodies are described in Padlan et al., EP 519596 Al, published December 23, 1992.

Antibody molecules can be single chain antibodies. Single-chain antibodies (scFv) can be engineered (see, e.g., Colcher, D. et al. (1999) Ann NY Acad Sci 880:263-80; and Reiter, Y. (1996) Clin Cancer Res [Clinical Cancer Research] 2:245-52). Single-chain antibodies can be dimerized or multimerized to generate multivalent antibodies specific for different epitopes of the same target protein.

In yet other embodiments, the antibody molecule has a heavy chain constant region, such as that of IgGl, IgG2, IgG3, IgG4, IgM, IgAl, IgA2, IgD, and IgE; specifically, such as IgGl, IgG2, IgG3, and (Human) heavy chain constant region of IgG4. In another embodiment, the antibody molecule has a light chain constant region, eg a (human) light chain constant region of kappa or lambda. The constant region can be altered (e.g., mutated) to modify the properties of the antibody (e.g., to increase or decrease one or more of: Fc receptor binding, antibody glycosylation, number of cysteine residues, effector cell function, and/or complement function). In one embodiment, the antibody has: 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 ability to bind an Fc receptor. For example, it is an isoform or subtype, fragment or other mutant that does not support binding to an Fc receptor, eg, it has a mutagenized or deleted Fc receptor binding region.

Methods for altering antibody constant regions are known in the art. Antibodies with altered function (e.g., altered affinity for effector ligands (such as FcR on cells) or the C1 component of complement) can be modified by replacing at least one amino acid in the constant portion of the antibody with a different residue. residues (see eg EP 388,151 Al, US Pat. No. 5,624,821 and US Pat. No. 5,648,260). Similar types of alterations can be described which, if applied to murine or other species immunoglobulins, would reduce or eliminate these functions.

An antibody molecule can be derivatized or linked to another functional molecule (eg, another peptide or protein). As used herein, a "derivatized" antibody molecule is one that has been modified. Derivatization methods include, but are not limited to, addition of fluorescent moieties, radioactive nucleotides, toxins, enzymes or affinity ligands such as biotin. Accordingly, the antibody molecules of the invention are intended to include derivatives and other modified forms of the antibodies described herein, including immunoadhesion molecules. For example, an antibody molecule can be functionally linked (by chemical coupling, genetic fusion, non-covalent association, or otherwise) to one or more other molecular entities, such as another antibody (e.g., a bispecific antibody or bispecific antibody). antibodies), detectable reagents, cytotoxic agents, agents and/or proteins or peptides that can mediate the association of an antibody or antibody portion with another molecule (eg streptavidin core region or polyhistidine tag).

One type of derivatized antibody molecule is produced by cross-linking two or more antibodies (of the same type or of different types, for example to create bispecific antibodies). Suitable crosslinkers include those that are heterobifunctional (having two distinctly different reactive species separated by a suitable spacer (e.g., mmaleimidobenzoyl-N-hydroxysuccinimidyl ester). functional groups) or those that are homobifunctional (for example, disuccinimidyl suberate). Such linkers are available from Pierce Chemical Company, Rockford, Ill.

Useful detectable agents that can be derivatized (or labeled) with the antibody molecules of the invention include fluorescent compounds, various enzymes, prosthetic groups, luminescent materials, bioluminescent materials, fluorescent emitting metal atoms such as europium (Eu), and others. Lanthanides and radioactive materials (described below). Exemplary fluorescent detectable agents include luciferin, fluorescein isothiocyanate, rhodamine, 5-dimethylamino-1-naphthalenesulfonyl chloride, phycoerythrin, and the like. Antibodies can also be derivatized with detectable enzymes, such as alkaline phosphatase, horseradish peroxidase, beta-galactosidase, acetylcholinesterase, glucose oxidase, and the like. When the antibody is derivatized with a detectable enzyme, detection can be performed by the addition of other reagents with which the enzyme produces a detectable reaction product. For example, the addition of hydrogen peroxide and diaminobenzidine resulted in a detectable colored reaction product in the presence of the detectable agent horseradish peroxidase. Antibody molecules can also be derivatized with prosthetic groups (eg, streptavidin/biotin and avidin/biotin). For example, antibodies can be derivatized with biotin and detected by indirect measurement of avidin or streptavidin binding. Examples of suitable fluorescent materials include umbelliferone, luciferin, fluorescein isothiocyanate, rhodamine, dichlorotriamine luciferin, dansyl chloride or phycoerythrin; examples of luminescent materials include luminol; and examples of bioluminescent materials include luciferase, luciferin, and aequorin.

Labeled antibody molecules can be used in a variety of contexts, e.g., in diagnostics and/or experiments, including (i) isolation of a predetermined antigen by standard techniques such as affinity chromatography or immunoprecipitation; (ii) detection of a predetermined antigen (e.g., after cell lysate fluid or cell supernatant) to assess protein abundance and expression patterns; (iii) to monitor protein levels in tissues as part of a clinical testing program, for example, to determine the efficacy of a given treatment regimen.

The antibody molecule can be conjugated to another molecular entity, typically a marker or a therapeutic agent (eg, cytotoxic or cytostatic agent) or moiety. Radioisotopes can be used in diagnostic or therapeutic applications.

The present invention provides radiolabeled antibody molecules and labeling methods thereof. In one embodiment, a method of labeling an antibody molecule is disclosed. The method involves contacting the antibody molecule with a chelating agent, thereby producing a conjugated antibody.

As noted above, antibody molecules can be conjugated to therapeutic agents. Therapeutically active radioisotopes have already been mentioned. Examples of other therapeutic agents include paclitaxel, cytochalasin B, gramicidin D, ethidium bromide, emetine, mitomycin, etoposide, tenoposide, vincristine, vinblastine, colchicine Alkaline, doxorubicin, daunorubicin, dihydroxyanthracindione, mitoxantrone, mithramycin, actinomycin D, 1-dehydrotestosterone, glucocorticoids, procaine, Tetracaine, lidocaine, propranolol, puromycin, maytansinoids such as maytansinoids (see, e.g., U.S. Pat. No. 5,208,020), CC-1065 (see, e.g., U.S. Pat. No. 5,475,092 , 5,585,499, 5,846, 545) and their analogs or congeners. Therapeutic agents include, but are not limited to, antimetabolites (e.g., methotrexate, 6-mercaptopurine, 6-thioguanine, cytarabine, 5-fluorouracil amine encarbamide), alkylating agents (e.g., nitrogen mustard , chlorambucil, CC-1065, melphalan, carmustine (BSNU) and lomustine (CCNU), cyclophosphamide, busulfan, dibromomannitol, streptozotocin, Mitomycin C and cis-dichlorodiaminoplatinum(II) (DDP) cisplatin), anthracyclines (such as daunorubicin (formerly known as daunorubicin) and doxorubicin), antibiotics (such as (formerly known as actinomycin), bleomycin, mithramycin, and antrimycin (AMC)), and antimitotic agents (eg, vincristine, vinblastine, paclitaxel, and maytansinoids).

In one aspect, the disclosure provides a method of providing a target binding molecule that specifically binds a target throughout the disclosure. For example, the target binding molecule is an antibody molecule. The method comprises: providing a target protein comprising at least a portion of a non-human protein that is homologous (at least 70%, 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% the same), but differ by at least an amino acid (e.g., at least one, two, three, four, five, six, seven, eight, or nine amino acids); obtain an antibody molecule that binds the antigen; and evaluate the binding agent at Efficacy in modulating target protein activity. The method can further comprise administering a binding agent (eg, an antibody molecule) or derivative (eg, a humanized antibody molecule) to the human subject.

The present disclosure provides isolated nucleic acid molecules (ie, polynucleotides) encoding any of the antibody molecules described throughout. Also disclosed are vectors comprising nucleic acid molecules and their host cells. Nucleic acid molecules include, but are not limited to, RNA, genomic DNA, and cDNA. combination

The methods of treatment described herein can include two or more other therapeutic agents, procedures or modes administered in combination.

In some embodiments, a TGFβ inhibitor (eg, NIS793) is administered in combination with a PD1 inhibitor (eg, an anti-PD1 antibody molecule). In some embodiments, the TGFβ inhibitor is administered on the same day as the PD1 inhibitor. In some embodiments, the TGFβ inhibitor is administered after initiation of administration of the PD1 inhibitor. In some embodiments, the TGFβ inhibitor is administered one hour after administration of the PD1 inhibitor is complete.

In some embodiments, the TGFβ inhibitor (eg, NIS793) is administered at a dose of between 1300 mg and 1500 mg (eg, about 1400 mg), eg, once every two weeks, and at a dose of between 300 mg to A dose of between 500 mg (eg, 400 mg) is administered, eg, every four weeks, with a PD1 inhibitor (eg, an anti-PD1 antibody molecule such as spartakizumab or tislelizumab).

In some embodiments, the TGFβ inhibitor (eg, NIS793) is administered at a dose of between 1300 mg and 1500 mg (eg, about 1400 mg), eg, once every two weeks, and at a dose of between 200 mg to A dose of between 400 mg (eg, 300 mg) is administered, eg, every four weeks, with a PD1 inhibitor (eg, an anti-PD1 antibody molecule such as spartakizumab or tislelizumab).

In some embodiments, the TGFβ inhibitor (eg, NIS793) is administered at a dose of between 1300 mg and 1500 mg (eg, about 1400 mg), eg, once every two weeks, and at a dose of between 200 mg to A dose of between 400 mg (eg, 300 mg) is administered, eg, every three weeks, with a PD1 inhibitor (eg, an anti-PD1 antibody molecule such as spartakizumab or tislelizumab).

In some embodiments, the TGFβ inhibitor (eg, NIS793) is administered at a dose of between 1300 mg and 1500 mg (eg, about 1400 mg), eg, once every two weeks, and at a dose of between 100 mg to A dose of between 300 mg (eg, 200 mg) is administered, eg, every three weeks, with a PD1 inhibitor (eg, an anti-PD1 antibody molecule such as spartakizumab or tislelizumab).

In some embodiments, the TGFβ inhibitor (eg, NIS793) is administered at a dose of between 1300 mg and 1500 mg (eg, about 1400 mg), eg, once every three weeks, and at a dose of between 100 mg to A dose of between 300 mg (eg, 200 mg) is administered, eg, every three weeks, with a PD1 inhibitor (eg, an anti-PD1 antibody molecule such as spartakizumab or tislelizumab).

In some embodiments, the TGFβ inhibitor (eg, NIS793) is administered at a dose of between 1300 mg and 1500 mg (eg, about 1400 mg), eg, once every three weeks, and at a dose of between 200 mg to A dose of between 400 mg (eg, 300 mg) is administered, eg, every four weeks, with a PD1 inhibitor (eg, an anti-PD1 antibody molecule such as spartakizumab or tislelizumab).

In some embodiments, the TGFβ inhibitor (eg, NIS793) is administered at a dose of between 2000 mg and 2200 mg (eg, about 2100 mg), eg, once every two weeks, and at a dose of between 300 mg to A dose of between 500 mg (eg, 400 mg) is administered, eg, every four weeks, with a PD1 inhibitor (eg, an anti-PD1 antibody molecule such as spartakizumab or tislelizumab).

In some embodiments, the TGFβ inhibitor (eg, NIS793) is administered at a dose between 2000 mg and 2200 mg (eg, about 2100 mg), eg, once every two weeks, and is administered at a dose of between 200 mg to A dose of between 400 mg (eg, 300 mg) is administered, eg, every four weeks, with a PD1 inhibitor (eg, an anti-PD1 antibody molecule such as spartakizumab or tislelizumab).

In some embodiments, the TGFβ inhibitor (eg, NIS793) is administered at a dose between 2000 mg and 2200 mg (eg, about 2100 mg), eg, once every two weeks, and is administered at a dose of between 200 mg to A dose of between 400 mg (eg, 300 mg) is administered, eg, every three weeks, with a PD1 inhibitor (eg, an anti-PD1 antibody molecule such as spartakizumab or tislelizumab).

In some embodiments, the TGFβ inhibitor (eg, NIS793) is administered at a dose of between 2000 mg and 2200 mg (eg, about 2100 mg), eg, once every two weeks, and at a dose of between 100 mg to A dose of between 300 mg (eg, 200 mg) is administered, eg, every three weeks, with a PD1 inhibitor (eg, an anti-PD1 antibody molecule such as spartakizumab or tislelizumab).

In some embodiments, the TGFβ inhibitor (eg, NIS793) is administered at a dose between 2000 mg and 2200 mg (eg, about 2100 mg), eg, once every three weeks, and at a dose of between 100 mg to A dose of between 300 mg (eg, 200 mg) is administered, eg, every three weeks, with a PD1 inhibitor (eg, an anti-PD1 antibody molecule such as spartakizumab or tislelizumab).

In some embodiments, the TGFβ inhibitor (eg, NIS793) is administered at a dose of between 2000 mg and 2200 mg (eg, about 2100 mg), eg, once every three weeks, and at a dose of between 300 mg to A dose of between 500 mg (eg, 400 mg) is administered, eg, every four weeks, with a PD1 inhibitor (eg, an anti-PD1 antibody molecule such as spartakizumab or tislelizumab).

In some embodiments, the TGFβ inhibitor (eg, NIS793) is administered at a dose of between 2000 mg and 2200 mg (eg, about 2100 mg), eg, once every three weeks, and is administered at a dose of between 200 mg to A dose of between 400 mg (eg, 300 mg) is administered, eg, every four weeks, with a PD1 inhibitor (eg, an anti-PD1 antibody molecule such as spartakizumab or tislelizumab).

In some embodiments, the TGFβ inhibitor (eg, NIS793) is administered at a dose of between 2000 mg and 2200 mg (eg, about 2100 mg), eg, once every three weeks, and is administered at a dose of between 200 mg to A dose of between 400 mg (eg, 300 mg) is administered, eg, every three weeks, with a PD1 inhibitor (eg, an anti-PD1 antibody molecule such as spartakizumab or tislelizumab).

In some embodiments, the TGFβ inhibitor (eg, at a dose of between 2000 mg and 2200 mg (eg, about 2100 mg), eg, once every four weeks (eg, on day 1 of a 28-day cycle) is administered , NIS793), and a PD1 inhibitor (eg, an anti-PD1 antibody molecule such as tislelizumab) is administered at a dose between 200 mg to 400 mg (eg, 300 mg), eg, once every four weeks .

In some embodiments, administered at a dose between 2000 mg and 2200 mg (eg, about 2100 mg), eg, twice every four weeks (eg, on days 1 and 15 of a 28-day cycle), A TGFβ inhibitor (eg, NIS793) and a PD1 inhibitor (eg, an anti-PD1 antibody molecule, such as tiramerone) administered at a dose between 200 mg and 400 mg (eg, 300 mg), eg, once every four weeks Lizizumab).

In certain embodiments, the methods described herein can be combined with other therapeutic agents (including antibody molecules, chemotherapeutics), other anticancer therapies (e.g., targeted anticancer therapies, gene therapy, viral therapy, RNA therapy, bone marrow transplantation, nanotherapy, or oncolytics), cytotoxic agents, immune-based therapy (e.g., cytokine or cell-based immunotherapy), surgery (e.g., lumpectomy or mastectomy), or radiation procedures , or one or more combinations of any of the foregoing. Additional therapy may be in the form of adjuvant or neoadjuvant therapy. In some embodiments, the additional therapy is an enzyme inhibitor (eg, a small molecule enzyme inhibitor) or a metastasis inhibitor. Exemplary cytotoxic agents that can be administered in combination include anti-microtubule agents, topoisomerase inhibitors, antimetabolites, mitotic inhibitors, alkylating agents, anthracyclines, vinca alkaloids, intercalating agents, able Agents that interfere with signaling pathways, agents that promote apoptosis, proteasome inhibitors, and radiation (eg, local or whole-body irradiation (eg, gamma irradiation)). In other embodiments, the additional therapy is surgery or radiation, or a combination thereof. In other embodiments, the additional therapy is a therapy targeting one or more of the PI3K/AKT/mTOR pathway, an HSP90 inhibitor, or a tubulin inhibitor.

Alternatively, or in combination with the foregoing, the methods described herein may be administered or used with one or more of: an immunomodulatory agent (e.g., an activator of a co-stimulatory molecule or an inhibitor of an inhibitory molecule, such as an immune checkpoint molecule ); vaccines, such as therapeutic cancer vaccines; or other forms of cellular immunotherapy.

In certain embodiments, the combinations described herein are administered or used with modulators of co-stimulatory or inhibitory molecules (eg, co-inhibitory ligands or receptors).

In one embodiment, the combinations described herein are administered or used in combination with inhibitors of the inhibitory (or immune checkpoint) molecules PD-1, PD-L1, PD-L2 and/or TGFβ. In one embodiment, the inhibitor is an antibody or antibody fragment that binds to PD-1, PD-L1, PD-L2 or TGFβ.

For combination therapy, in some embodiments, the TGFβ inhibitor is administered on the same day as the checkpoint inhibitor. In other embodiments, the TGFβ inhibitor is administered before administration of the checkpoint inhibitor is complete. In additional embodiments, the TGFβ inhibitor is administered after administration of the checkpoint inhibitor is complete. In some embodiments, the TGFβ inhibitor is administered concurrently with the checkpoint inhibitor. In some embodiments, the TGFβ inhibitor is administered until (partial or complete) remission. In some embodiments, a checkpoint inhibitor is administered until (partial or complete) remission.

Compounds of the disclosure can be administered in therapeutically effective amounts in combination therapy with one or more therapeutic agents (drug combinations) or modalities (eg, non-drug therapies). For example, synergistic effects may occur with other cancer agents. When the compounds of the present application are administered in combination with other therapies, the dosage of the co-administered compounds will of course vary depending on the type of co-drug employed, the particular drug employed, the condition being treated and the like.

The compounds may be administered sequentially (as a single formulation or separate formulations), separately or over a period of time concurrently with other drug therapies or treatment modalities. In general, combination therapy envisages the administration of two or more drugs during a single cycle or course of treatment. A therapeutic agent is, for example, a chemical compound, peptide, antibody, antibody fragment, or nucleic acid that has therapeutic activity or enhances therapeutic activity when administered to a patient in combination with a compound of the present disclosure.

In one aspect, TGFβ inhibitors (and/or PD1, PD-L1, or PD-L2 inhibitors) can be combined with other therapeutic agents (such as other anticancer agents, antiallergic agents, antinausea agents (or antiemetic agents) , analgesics, cytoprotectants, and combinations thereof).

In some embodiments, a TGFβ inhibitor is combined with one or more second agents (selected from PD-1 inhibitors, PD-L1 inhibitors, LAG-3 inhibitors, cytokines, A2A antagonists, GITR agonists , a TIM-3 inhibitor, a STING agonist, and a TLR7 agonist) in combination to treat a disease (eg, cancer).

In another embodiment, one or more chemotherapeutic agents are used in combination with a TGFβ inhibitor (and/or a PD1, PD-L1, or PD-L2 inhibitor) to treat a disease (e.g., cancer), wherein the chemotherapeutic Therapeutic agents include, but are not limited to, anastrozole (Arimidex®), bicalutamide (Casodex®), bleomycin sulfate (Blenoxane®), busulfan (Myleran®), busulfan injection (Busulfex®) , capecitabine (Xeloda®), N4-pentyloxycarbonyl-5-deoxy-5-fluorocytidine, carboplatin (Paraplatin®), carmustine (BiCNU®), chlorambucil ( Leukeran®), cisplatin (Platinol®), cladribine (Leustatin®), cyclophosphamide (Cytoxan® or Neosar®), cytarabine, cytosine arabinoside (Cytosar-U®), Glycoside liposome injection (DepoCyt®), dacarbazine (DTIC-Dome®), dactinomycin (actinomycin D, Cosmegan), daunorubicin hydrochloride (Cerubidine®), daunorubicin citrate liposome Injection (DaunoXome®), dexamethasone, docetaxel (Taxotere®), doxorubicin hydrochloride (Adriamycin®, Rubex®), etoposide (Vepesid®), fludarabine phosphate (Fludara®) , 5-fluorouracil (Adrucil®, Efudex®), flutamide (Eulexin®), tezacitibine (tezacitibine), gemcitabine (difluorodeoxycitidine), hydroxyurea (Hydrea®), idarabine Star (Idamycin®), Ifosfamide (IFEX®), Irinotecan (Camptosar®), L-Asparaginase (ELSPAR®), Leucovorin, Melphalan (Alkeran®), 6- Mercaptopurine (Purinethol®), methotrexate (Folex®), mitoxantrone (Novantrone®), gemtuzumab (mylotarg), paclitaxel (Taxol®), phoenix (Yttrium90/MX-DTPA), spray Implants of statin, polybenzprosan (polifeprosan) 20 with carmustine (Gliadel®), tamoxifen citrate (Nolvadex®), teniposide (Vumon®), 6-thioguanine , Thiotepa, Tirazamine (Tirazone®), Topotecan Hydrochloride for Injection (Hycamptin®), Vinblastine (Velban®), Vincristine (Oncovin®), Vinorelbine (Navelbine®), Epirou Bixing (Ellence®), Oxaliplatin (El oxatin®), exemestane (Aromasin®), letrozole (Femara®), and fulvestrant (Faslodex®). For example, a TGFβ inhibitor (eg, NIS793) can be combined with gemcitabine. In another example, a TGFβ inhibitor (eg, NIS793) can be combined with nab-paclitaxel. TGFβ inhibitors (eg, NIS793) can also be combined with both gemcitabine and nab-paclitaxel. In another example, a TGFβ inhibitor (eg, NIS793) can be combined with cyclophosphamide. TGFβ inhibitors (eg, NIS793) can also be combined with topotecan. In some instances, a TGFβ inhibitor (eg, NIS793) can be combined with both cyclophosphamide or topotecan. In some cases, a TGFβ inhibitor (eg, NIS793) can be combined with 5-fluorouracil, leucovorin (or leucovorin), irinotecan, bevacizumab, and optionally tislelizumab. In some cases, a TGFβ inhibitor (eg, NIS793) can be combined with 5-fluorouracil, leucovorin (or leucovorin), oxaliplatin, bevacizumab, and optionally tislelizumab. In some cases, TGFβ inhibitors (eg, NIS793) can be combined with oxaliplatin and capecitabine. In some instances, a TGFβ inhibitor (eg, NIS793) can be combined with oxaliplatin, folinic acid (or leucovorin), and 5-fluorouracil.

In other embodiments, a TGFβ inhibitor of the present disclosure (and/or a PD1, PD-L1, or PD-L2 inhibitor) is combined with one or more other anti-HER2 antibodies (e.g., trastuzumab as described above) anti-HER2, pertuzumab, margetuximab, or HT-19) or with other anti-HER2 conjugates (eg, ado-trastuzumab-emtansine ) (also known as Kadcyla®, or T-DM1)) in combination.

In other embodiments, TGFβ inhibitors of the present disclosure (and/or PD1, PD-L1, or PD-L2 inhibitors) are combined with one or more tyrosine kinase inhibitors (including but not limited to EGFR inhibitors, Her3 inhibitors, IGFR inhibitors, and Met inhibitors) for the treatment of diseases such as cancer.

For example, tyrosine kinase inhibitors include, but are not limited to, erlotinib (Tarceva®); linifanib (N-[4-(3-amino-1H-indazole-4 -yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea, also known as ABT 869, available from Genentech); sunitinib malate (Sutent®); Bosutinib (4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methylpiperone-1 -yl)propoxy]quinoline-3-carbonitrile, also known as SKI-606 and described in U.S. Pat. No. 6,780,996); dasatinib (Sprycel®); pazopanib (Votrient®) ; sorafenib (Nexavar®); vandetanib (ZD6474); and imatinib or imatinib mesylate (Gilvec® and Gleevec®).

Epidermal growth factor receptor (EGFR) inhibitors include, but are not limited to, erlotinib (Tarceva®), gefitinib (Iressa®); N-[4-[(3-chloro-4-fluoro Phenyl)amino]-7-[[(3''S'')-tetrahydro-3-furyl]oxy]-6-quinazolinyl]-4(dimethylamino)-2 -Butenamide, Tovok®); Vandetanib (Caprelsa®); Lapatinib (Tykerb®); (3R,4R)-4-Amino-1-((4-(( 3-methoxyphenyl)amino)pyrrolo[2,1-f][1,2,4]tri-(5-yl)methyl)piperidin-3-ol (BMS690514); carboxylate dihydrochloride Netinib (CI-1033); 6-[4-[(4-Ethyl-1-piperothyl)methyl]phenyl]-N-[(1R)-1-phenylethyl]-7H -Pyrrolo[2,3-d]pyrimidin-4-amine (AEE788, CAS 497839-62-0); Mubritinib (TAK165); Peritinib (EKB569); Afatinib ) (Gilotrif®); Neratinib (HKI-272); N-[4-[[1-[(3-fluorophenyl)methyl]-1H-indazol-5-yl]amine Base]-5-methylpyrrolo[2,1-f][1,2,4]tri-6-yl]-carbamic acid, (3S)-3-𠰌linyl methyl ester (BMS599626); N-(3,4-dichloro-2-fluorophenyl)-6-methoxy-7-[[(3aα,5β,6aα)-octahydro-2-methylcyclopenta[c]pyrrole-5 -yl]methoxy]-4-quinazolinamine (XL647, CAS 781613-23-8); and 4-[4-[[(1R)-1-phenylethyl]amino]-7H- Pyrrolo[2,3-d]pyrimidin-6-yl]-phenol (PKI166, CAS187724-61-4).

EGFR antibodies include, but are not limited to, cetuximab (Erbitux®); panitumumab (Vectibix®); matuzumab (EMD-72000); nimotuzumab (hR3); Zalutumumab; TheraCIM h-R3; MDX0447 (CAS 339151-96-1); and ch806 (mAb-806, CAS 946414-09-1).

Other HER2 inhibitors include, but are not limited to, Neratinib (HKI-272, (2E)-N-[4-[[3-chloro-4-[(pyridin-2-yl)methoxy]benzene yl]amino]-3-cyano-7-ethoxyquinolin-6-yl]-4-(dimethylamino)but-2-enamide and is described in PCT Publication No. WO 05 /028443); lapatinib or lapatinib ditosylate (Tykerb®); (3R,4R)-4-amino-1-((4-((3-methoxyphenyl)amine base)pyrrolo[2,1-f][1,2,4]tri-(5-yl)methyl)piperidin-3-ol (BMS690514); (2E)-N-[4-[(3 -Chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furyl]oxy]-6-quinazolinyl]-4-(dimethylamino) -2-Butenamide (BIBW-2992, CAS 850140-72-6); N-[4-[[1-[(3-fluorophenyl)methyl]-1H-indazol-5-yl] Amino]-5-methylpyrrolo[2,1-f][1,2,4]tris-6-yl]-carbamic acid, (3S)-3-metholinyl methyl ester (BMS 599626 , CAS 714971-09-2); canertinib dihydrochloride (PD183805 or CI-1033); and N-(3,4-dichloro-2-fluorophenyl)-6-methoxy-7-[ [(3aα,5β,6aα)-octahydro-2-methylcyclopenta[c]pyrrol-5-yl]methoxy]-4-quinazolinamine (XL647, CAS 781613-23-8).

HER3 inhibitors include, but are not limited to, LJM716, MM-121, AMG-888, RG7116, REGN-1400, AV-203, MP-RM-1, MM-111, and MEHD-7945A.

MET inhibitors include, but are not limited to, Cabozantinib (XL184, CAS 849217-68-1); Foretinib (GSK1363089, formerly known as XL880, CAS 849217-64-7); Tivantinib (ARQ197, CAS 1000873-98-2); 1-(2-hydroxy-2-methylpropyl) -N- (5-(7-methoxyquinolin-4-yloxy )pyridin-2-yl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro- 1H -pyrazole-4-carboxamide (AMG 458); (Xalkori®, PF-02341066); (3Z)-5-(2,3-dihydro-1H-indol-1-ylsulfonyl)-3-({3,5-dimethyl-4 -[(4-Methylpiperone-1-yl)carbonyl]-1H-pyrrol-2-yl}methylene)-1,3-dihydro-2H-indol-2-one (SU11271);( 3Z)-N-(3-chlorophenyl)-3-({3,5-dimethyl-4-[(4-methylpiper-1-yl)carbonyl]-1H-pyrrol-2-yl }methylene)-N-methyl-2-oxoindoline-5-sulfonamide (SU11274); (3Z)-N-(3-chlorophenyl)-3-{[3,5 -Dimethyl-4-(3-𠰌line-4-ylpropyl)-1H-pyrrol-2-yl]methylene}-N-methyl-2-oxoindoline-5-sulfonate Amide (SU11606); 6-[Difluoro[6-(1-methyl-1H-pyrazol-4-yl)-1,2,4-triazolo[4,3-b]butadiene-3- Base]methyl]-quinoline (JNJ38877605, CAS 943540-75-8); 2-[4-[1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo [4,5-b]pyrazole-6-yl]-1H-pyrazol-1-yl]ethanol (PF04217903, CAS 956905-27-4); N-((2R)-1,4-di㗁𠮿 -2-ylmethyl)-N-methyl-N'-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5] Cyclohepta[1,2-b]pyridin-7-yl]sulfonamide (MK2461, CAS 917879-39-1); 6-[[6-(1-methyl-1 H -pyrazole-4- base)-1,2,4-triazolo[4,3-b]diazolo[4,3- b ]diazo]-3-yl]thio]-quinoline (SGX523, CAS 1022150-57-7); and (3 Z )-5- [[(2,6-Dichlorophenyl)methyl]sulfonyl]-3-[[3,5-dimethyl-4-[[(2 R )-2-(1-pyrrolidinylmethyl Base)-1-pyrrolidinyl]carbonyl] -1H -pyrrol-2-yl]ylidene Methyl]-1,3-dihydro- 2H -indol-2-one (PHA665752, CAS 477575-56-7).

IGFR inhibitors include, but are not limited to, BMS-754807, XL-228, OSI-906, GSK0904529A, A-928605, AXL1717, KW-2450, MK0646, AMG479, IMCA12, MEDI-573, and BI836845. See eg, review by Yee, JNCI [Journal of the National Cancer Institute], 104;975 (2012).

In another embodiment, TGFβ inhibitors (and/or PD1, PD-L1, or PD-L2 inhibitors) are combined with one or more inhibitors of proliferation signaling pathways (including but not limited to MEK inhibitors, BRAF inhibitors, PI3K/Akt inhibitors, SHP2 inhibitors, and also mTOR inhibitors and CDK inhibitors) are used in combination to treat diseases such as cancer.

For example, mitogen-activated protein kinase (MEK) inhibitors include, but are not limited to, XL-518 (also known as GDC-0973, CAS No. 1029872-29-4, available from ACC Corp.); 2- [(2-Chloro-4-iodophenyl)amino]-N-(cyclopropylmethoxy)-3,4-difluoro-benzamide (also known as CI-1040 or PD184352, and described In PCT Publication No. WO 2000035436); N-[(2R)-2,3-dihydroxypropoxy]-3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino ]-benzamide (also known as PD0325901 and described in PCT Publication No. WO 2002006213); 2,3-bis[amino[(2-aminophenyl)thio]methylene]-butanedi Nitrile (also known as U0126 and described in U.S. Patent No. 2,779,780); N-[3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-6-methoxy Phenyl]-1-[(2R)-2,3-dihydroxypropyl]-cyclopropanesulfonamide (also known as RDEA119 or BAY869766 and described in PCT Publication No. WO 2007014011); (3S,4R, 5Z,8S,9S,11E)-14-(ethylamino)-8,9,16-trihydroxy-3,4-dimethyl-3,4,9,19-tetrahydro-1H-2- benzoxacyclodecyne-1,7(8H)-dione] (also known as E6201 and described in PCT Publication No. WO 2003076424); 2'-amino-3'-methoxyflavone ( Also known as PD98059, available from Biaffin GmbH & Co., KG); (R)-3-(2,3-dihydroxypropyl)-6-fluoro-5-( 2-Fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (TAK-733, CAS 1035555-63-5 ); Pimasertib (AS-703026, CAS 1204531-26-9); and trametinib (GSK-1120212, CAS 1204531-25-80).

BRAF inhibitors include, but are not limited to, Vemurafenib (or Zelboraf®, PLX-4032, CAS 918504-65-1), GDC-0879, PLX-4720 (available from Symansis), Dabrafenib (or GSK2118436), LGX 818, CEP-32496, UI-152, RAF 265, Regorafenib (BAY 73-4506), CCT239065, or Sorafenib (or Soratosylate rafenib or Nexavar®).

Phosphoinositide 3-kinase (PI3K) inhibitors including, but not limited to, 4-[2-(1H-indazol-4-yl)-6-[[4-(methylsulfonyl)piperazol-1-yl ]methyl]thieno[3,2-d]pyrimidin-4-yl]𠰌line (also known as GDC0941, RG7321, GNE0941, Pictrelisib, or Pictilisib); and describing in PCT Publication Nos. WO 09/036082 and WO 09/055730); Tozasertib (VX680 or MK-0457, CAS 639089-54-6); (5Z)-5-[[4-(4 -pyridyl)-6-quinolinyl]methylene]-2,4-tetrahydrothiazolyldione (GSK1059615, CAS 958852-01-2); (1E,4S,4aR,5R,6aS,9aR)- 5-(Acetyloxy)-1-[(di-2-propenylamino)methylene]-4,4a,5,6,6a,8,9,9a-octahydro-11-hydroxy -4-(methoxymethyl)-4a,6a-dimethylcyclopenta[5,6]naphtho[1,2-c]pyran-2,7,10(1H)-trione (PX866 , CAS 502632-66-8); 8-phenyl-2-(𠰌olin-4-yl)-chromen-4-one (LY294002, CAS 154447-36-6); (S)-N1-( 4-Methyl-5-(2-(1,1,1-trifluoro-2-methylprop-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1,2-di Formamide (also known as BYL719 or Aperis); 2-(4-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl) -5,6-Dihydrobenzo[f]imidazo[1,2-d][1,4]oxazol-9-yl)-1H-pyrazol-1-yl)-2-methylpropane Amide (also known as GDC0032, RG7604, or Taselisib).

mTOR inhibitors include , but are not limited to, temsirolimus (Torisel®); [(1 R ,9 S ,12 S ,15 R ,16 E ,18 R ,19 R ,21 R ,23 S ,24 E ,26 E ,28 Z ,30 S ,32 S , 35 R )-1, 18-dihydroxy-19,30-dimethoxy-15,17,21,23, 29,35-hexamethyl-2,3,10,14,20-pentaoxo-11,36-di Oxa-4-azatricyclo[30.3.1.04,9]hexahexa-16,24,26,28-tetraen-12-yl]propyl]-2-methoxycyclohexyldimethylmethyne Phosphonates, also known as AP23573 and MK8669, and described in PCT Publication No. WO 03/064383); everolimus (Afinitor® or RAD001); rapamycin (AY22989, Sirolimus®); semamod (simapimod) (CAS 164301-51-3); (5-{2,4-bis[(3S)-3-methyl-4-yl]pyrido[2,3-d]pyrimidine-7- Base}-2-methoxyphenyl)methanol (AZD8055); 2-amino-8-[ trans -4-(2-hydroxyethoxy)cyclohexyl]-6-(6-methoxy- 3-pyridyl)-4-methyl-pyrido[2,3- d ]pyrimidin-7( 8H )-one (PF04691502, CAS 1013101-36-4); and N ² -[1,4-di Oxy-4-[[4-(4-Oxy-8-phenyl- 4H -1-benzopyran-2-yl)-4-yl]methoxy]butyl ]-L-sperniylglycyl-L-alpha-aspartyl L-serine-, inner salt (SF1126, CAS 936487-67-1).

CDK inhibitors include, but are not limited to, palbociclib (also known as PD-0332991, Ibrance®, 6-acetyl-8-cyclopentyl-5-methyl-2-{[5-(1-piperone )-2-pyridyl]amino}pyrido[2,3-d]pyrimidin-7(8 H )-one).

In yet another embodiment, a TGFβ inhibitor of the present disclosure (and/or a PD1, PD-L1, or PD-L2 inhibitor) is combined with one or more pro-apoptotics (including but not limited to IAP inhibitors, BCL2 inhibitors, MCL1 inhibitors, TRAIL agents, CHK inhibitors) are used in combination to treat diseases such as cancer.

For example, IAP inhibitors include, but are not limited to, LCL161, GDC-0917, AEG-35156, AT406, and TL32711. Other examples of IAP inhibitors include, but are not limited to, WO 04/005284, WO 04/007529, WO 05/097791, WO 05/069894, WO 05/069888, WO 05/094818, US 2006/0014700, US 2006/0025347, Those disclosed in WO 06/069063, WO 06/010118, WO 06/017295, and WO 08/134679.

BCL-2 inhibitors include but are not limited to 4-[4-[[2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohexen-1-yl]methyl]-1- Piperyl]-N-[[4-[[(1R)-3-(4-yl)-1-[(phenylthio)methyl]propyl]amino]-3-[(three Fluoromethyl)sulfonyl]phenyl]sulfonyl]benzamide (also known as ABT-263 and described in PCT Publication No. WO 09/155386); tetracarcinin A; antimycin; Gossypol ((-)BL-193); Obatoclax; Ethyl-2-amino-6-cyclopentyl-4-(1-cyano-2-ethoxy-2-oxo Ethyl)-4H chromone-3-carboxylate (HA14-1); Oblimersen (G3139, Genasense®); Bak BH3 peptide; (-)-Gossypol acetic acid (AT-101); 4-[4-[(4'-Chloro[1,1'-biphenyl]-2-yl)methyl]-1-piperyl]-N-[[4-[[(1R)-3 -(Dimethylamino)-1-[(phenylthio)methyl]propyl]amino]-3-nitrophenyl]sulfonyl]-benzamide (ABT-737, CAS 852808 -04-9); and Navitoclax (ABT-263, CAS 923564-51-6).

Pro-apoptotic receptor agonists (PARAs) include DR4 (TRAILR1) and DR5 (TRAILR2), including but not limited to Dulanermin (AMG-951, RhApo2L/TRAIL); Mapratumumab ( Mapatumumab (HRS-ETR1, CAS 658052-09-6); Lexatumumab (HGS-ETR2, CAS 845816-02-6); Apomab (Apomab®); Conatumumab ( AMG655, CAS 896731-82-1); and Tigatuzumab (CS1008, CAS 946415-34-5, available from Daiichi Sankyo).

Checkpoint kinase (CHK) inhibitors include, but are not limited to, 7-hydroxystaurosporine (UCN-01); 6-bromo-3-(1-methyl- 1H -pyrazol-4-yl)-5 -(3 R )-3-piperidinylpyrazolo[1,5- a ]pyrimidin-7-amine (SCH900776, CAS 891494-63-6); 5-(3-fluorophenyl)-3-urea N-[(S)-piperidin-3-yl]amide (AZD7762, CAS 860352-01-8); 4-[((3S)-1-azabicyclo[2.2 .2] Oct-3-yl)amino]-3-(1H-benzimidazol-2-yl)-6-chloroquinolin-2(1H)-one (CHIR 124, CAS 405168-58-3); 7-Aminodactinomycin (7-AAD), Isogranulatimide, debromohymenialdisine; N-[5-Bromo-4-methyl-2-[(2S)-2-𠰌linylmethoxy]-phenyl]- N'-(5-Methyl-2-pyroxyl)urea (LY2603618, CAS 911222-45-2); Sulforaphane (CAS 4478-93-7, 4-Methylsulfinylbutylisothio cyanate); 9,10,11,12-tetrahydro-9,12-epoxy-1 H -diindole[1,2,3- fg : 3',2',1'- kl ]pyrrole and TAT-S216A ( YGRKKRRQRRRLYRSPAMPENL ( SEQ ID NO: 318)), and CBP501 ((d-Bpa)sws(d-Phe-F5)(d-Cha)rrrqrr).

In additional embodiments, a TGFβ inhibitor of the present disclosure (and/or a PD1, PD-L1, or PD-L2 inhibitor) is combined with one or more immunomodulators (e.g., activators of co-stimulatory molecules or immune checkpoints). One or more of the inhibitors of point molecules) are used in combination to treat diseases (such as cancer).

In certain embodiments, the immunomodulatory agent is an activator of a costimulatory molecule. In one embodiment, the agonist of the co-stimulatory molecule is selected from the group consisting of OX40, CD2, CD27, CDS, ICAM-1, LFA-1 (CD11a/CD18), ICOS (CD278), 4-1BB (CD137), GITR, Agonists of CD30, CD40, BAFFR, HVEM, CD7, LIGHT, NKG2C, SLAMF7, NKp80, CD160, B7-H3, or CD83 ligands (eg, agonistic antibodies or antigen-binding fragments thereof, or soluble fusions). GITR agonist

In some embodiments, a GITR agonist is used in combination with a TGFβ inhibitor (and/or a PD1, PD-L1, or PD-L2 inhibitor) to treat a disease (eg, cancer). In some embodiments, the GITR agonist is GWN323 (Novartis AG), BMS-986156, MK-4166 or MK-1248 (Merck & Co.), 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 the 2016 publication entitled "Compositions and Methods of Use for Augmented Immune Response and Cancer Therapy" It is described in WO 2016/057846 published on April 14.

In one embodiment, the anti-GITR antibody molecule comprises at least one, two, three, four, five, or six complementarity determining regions (CDRs) from the heavy and light chain variable regions (or collectively All CDRs), the heavy and light chain variable regions comprise the amino acid sequences shown in Table 5 (for example, from the heavy and light chain variable region sequences of MAB7 disclosed in Table 5), or the amino acid sequences shown in Table 5 The amino acid sequence encoded by the nucleotide sequence shown in . In some embodiments, the CDRs are defined according to Kabat. In some embodiments, the CDRs are defined according to Josiah. In one embodiment, relative to the amino acid sequence, or the amino acid sequence encoded by the nucleotide sequence, one or more of the CDRs (or all CDRs in general) have one, two, three, four One, five, six or more changes, such as amino acid substitutions (eg, conservative amino acid substitutions) or deletions.

In one embodiment, the anti-GITR antibody molecule comprises: VHCDR1 amino acid sequence comprising SEQ ID NO: 109, VHCDR2 amino acid sequence of SEQ ID NO: 111, and VHCDR3 amino acid sequence of SEQ ID NO: 113 The heavy chain variable region (VH); and the VLCDR1 amino acid sequence containing SEQ ID NO: 114, the VLCDR2 amino acid sequence of SEQ ID NO: 116, and the light of the VLCDR3 amino acid sequence of SEQ ID NO: 118 Chain variable regions (VL), each disclosed in Table 5.

In one embodiment, the anti-GITR antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 101, or having at least 85%, 90%, 95%, or 99% or more of the amino acid sequence of SEQ ID NO: 101 Highly identical amino acid sequences. In one embodiment, the anti-GITR antibody molecule comprises a VL comprising the amino acid sequence of SEQ ID NO: 102, or having at least 85%, 90%, 95%, or 99% or more of the amino acid sequence of SEQ ID NO: 102 Highly identical amino acid sequences. In one embodiment, the anti-GITR antibody molecule comprises: VH comprising the amino acid sequence of SEQ ID NO: 101 and VL comprising the amino acid sequence of SEQ ID NO: 102.

In one embodiment, the antibody molecule comprises a VH consisting of the nucleotide sequence of SEQ ID NO: 105, or at least 85%, 90%, 95%, or 99% or higher identical to SEQ ID NO: 105 Sexual nucleotide sequence code. In one embodiment, the antibody molecule comprises a VL consisting of the nucleotide sequence of SEQ ID NO: 106, or at least 85%, 90%, 95%, or 99% or higher identical to SEQ ID NO: 106 Sexual nucleotide sequence code. In one embodiment, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 105 and a VL encoded by the nucleotide sequence of SEQ ID NO: 106.

In one embodiment, the anti-GITR antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 103, or at least 85%, 90%, 95%, or 99% identical to SEQ ID NO: 103 or higher identity amino acid sequences. In one embodiment, the anti-GITR antibody molecule comprises a light chain comprising the amino acid sequence of SEQ ID NO: 104, or at least 85%, 90%, 95%, or 99% identical to SEQ ID NO: 104 or higher identity amino acid sequences. In one embodiment, the anti-GITR antibody molecule comprises: a heavy chain comprising the amino acid sequence of SEQ ID NO: 103 and a light chain comprising the amino acid sequence of SEQ ID NO: 104.

In one embodiment, the antibody molecule comprises a heavy chain consisting of the nucleotide sequence of SEQ ID NO: 107, or having at least 85%, 90%, 95%, or 99% or more with SEQ ID NO: 107 Highly identical nucleotide sequence codes. In one embodiment, the antibody molecule comprises a light chain consisting of the nucleotide sequence of SEQ ID NO: 108, or having at least 85%, 90%, 95%, or 99% or more with SEQ ID NO: 108 Highly identical nucleotide sequence codes. In one embodiment, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 107 and a light chain encoded by the nucleotide sequence of SEQ ID NO: 108.

The antibody molecules described herein can be produced by vectors, host cells, and methods described in WO 2016/057846. [ Table 5 ] : Amino acid and nucleotide sequences of exemplary anti-GITR antibody molecules MAB7 SEQ ID NO: 101 VH EVQLVESGGGLVQSGGSLRLSCAASGFSLSSYGVDWVRQAPGKGLEWVGVIWGGGGTYYASSLMGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARHAYGHDGGFAMDYWGQGTLVTVSS SEQ ID NO: 102 VL EIVMTQSPATLSVSPGERATLSCRASESVSSNVAWYQQRPGQAPRLLIYGASNRATGIPARFSGSGSGTDFLTISRLEPEDFAVYYCGQSYSYPFTFGQGTKLEIK SEQ ID NO: 103 heavy chain EVQLVESGGGLVQSGGSLRLSCAASGFSLSSYGVDWVRQAPGKGLEWVGVIWGGGGTYYASSLMGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARHAYGHDGGFAMDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 104 light chain EIVMTQSPATLSVSPGERATLSCRASESVSSNVAWYQQRPGQAPRLLIYGASNRATGIPARFSGSGSGTDFLTISRLEPEDFAVYYCGQSYSYPFTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLLFSKADYEKHKGLNSSECG SEQ ID NO: 105 DNA VH GAGGTGCAGCTGGTGGAATCTGGCGGCGGACTGGTGCAGTCCGGCGGCTCTCTGAGACTGTCTTGCGCTGCCTCCGGCTTCTCCCTGTCCTCTTACGGCGTGGACTGGGTGCGACAGGCCCCTGGCAAGGGCCTGGAATGGGTGGGAGTGATCTGGGGCGGAGGCGGCACCTACTACGCCTCTTCCCTGATGGGCCGGTTCACCATCTCCCGGGACAACTCCAAGAACACCCTGTACCTGCAGATGAACTCCCTGCGGGCCGAGGACACCGCCGTGTACTACTGCGCCAGACACGCCTACGGCCACGACGGCGGCTTCGCCATGGATTATTGGGGCCAGGGCACCCTGGTGACAGTGTCCTCC SEQ ID NO: 106 DNA VL GAGATCGTGATGACCCAGTCCCCCGCCACCCTGTCTGTGTCTCCCGGCGAGAGAGCCACCCTGAGCTGCAGAGCCTCCGAGTCCGTGTCCTCCAACGTGGCCTGGTATCAGCAGAGACCTGGTCAGGCCCCTCGGCTGCTGATCTACGGCGCCTCTAACCGGGCCACCGGCATCCCTGCCAGATTCTCCGGCTCCGGCAGCGGCACCGACTTCACCCTGACCATCTCCCGGCTGGAACCCGAGGACTTCGCCGTGTACTACTGCGGCCAGTCCTACTCATACCCCTTCACCTTCGGCCAGGGCACCAAGCTGGAAATCAAG SEQ ID NO: 107 DNA heavy chain GAGGTGCAGCTGGTGGAATCTGGCGGCGGACTGGTGCAGTCCGGCGGCTCTCTGAGACTGTCTTGCGCTGCCTCCGGCTTCTCCCTGTCCTCTTACGGCGTGGACTGGGTGCGACAGGCCCCTGGCAAGGGCCTGGAATGGGTGGGAGTGATCTGGGGCGGAGGCGGCACCTACTACGCCTCTTCCCTGATGGGCCGGTTCACCATCTCCCGGGACAACTCCAAGAACACCCTGTACCTGCAGATGAACTCCCTGCGGGCCGAGGACACCGCCGTGTACTACTGCGCCAGACACGCCTACGGCCACGACGGCGGCTTCGCCATGGATTATTGGGGCCAGGGCACCCTGGTGACAGTGTCCTCCGCTAGCACCAAGGGCCCAAGTGTGTTTCCCCTGGCCCCCAGCAGCAAGTCTACTTCCGGCGGAACTGCTGCCCTGGGTTGCCTGGTGAAGGACTACTTCCCCGAGCCCGTGACAGTGTCCTGGAACTCTGGGGCTCTGACTTCCGGCGTGCACACCTTCCCCGCCGTGCTGCAGAGCAGCGGCCTGTACAGCCTGAGCAGCGTGGTGACAGTGCCCTCCAGCTCTCTGGGAACCCAGACCTATATCTGCAACGTGAACCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTGGAGCCCAAGAGCTGCGACAAGACCCACACCTGCCCCCCCTGCCCAGCTCCAGAACTGCTGGGAGGGCCTTCCGTGTTCCTGTTCCCCCCCAAGCCCAAGGACACCCTGATGATCAGCAGGACCCCCGAGGTGACCTGCGTGGTGGTGGACGTGTCCCACGAGGACCCAGAGGTGAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCACAACGCCAAGACCAAGCCCAGAGAGGAGCAGTACAACAGCACCTACAGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGACTGGCTGAACGGCAAAGAATACAAGTGCAAAGTCTCCAACAAGGCCCTGCCAG CCCCAATCGAAAAGACAATCAGCAAGGCCAAGGGCCAGCCACGGGAGCCCCAGGTGTACACCCTGCCCCCCAGCCGGGAGGAGATGACCAAGAACCAGGTGTCCCTGACCTGTCTGGTGAAGGGCTTCTACCCCAGCGATATCGCCGTGGAGTGGGAGAGCAACGGCCAGCCCGAGAACAACTACAAGACCACCCCCCCAGTGCTGGACAGCGACGGCAGCTTCTTCCTGTACAGCAAGCTGACCGTGGACAAGTCCAGGTGGCAGCAGGGCAACGTGTTCAGCTGCAGCGTGATGCACGAGGCCCTGCACAACCACTACACCCAGAAGTCCCTGAGCCTGAGCCCCGGCAAG SEQ ID NO: 108 DNA light chain GAGATCGTGATGACCCAGTCCCCCGCCACCCTGTCTGTGTCTCCCGGCGAGAGAGCCACCCTGAGCTGCAGAGCCTCCGAGTCCGTGTCCTCCAACGTGGCCTGGTATCAGCAGAGACCTGGTCAGGCCCCTCGGCTGCTGATCTACGGCGCCTCTAACCGGGCCACCGGCATCCCTGCCAGATTCTCCGGCTCCGGCAGCGGCACCGACTTCACCCTGACCATCTCCCGGCTGGAACCCGAGGACTTCGCCGTGTACTACTGCGGCCAGTCCTACTCATACCCCTTCACCTTCGGCCAGGGCACCAAGCTGGAAATCAAGCGTACGGTGGCCGCTCCCAGCGTGTTCATCTTCCCCCCCAGCGACGAGCAGCTGAAGAGCGGCACCGCCAGCGTGGTGTGCCTGCTGAACAACTTCTACCCCCGGGAGGCCAAGGTGCAGTGGAAGGTGGACAACGCCCTGCAGAGCGGCAACAGCCAGGAGAGCGTCACCGAGCAGGACAGCAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCGACTACGAGAAGCATAAGGTGTACGCCTGCGAGGTGACCCACCAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAACAGGGGCGAGTGC SEQ ID NO: 109 (Kabat) HCDR1 SYGVD SEQ ID NO: 110 (Josiah) HCDR1 GFSLSSY SEQ ID NO: 111 (Cabat) HCDR2 VIWGGGGTYYASSLMG SEQ ID NO: 112 (Josiah) HCDR2 WGGGG SEQ ID NO: 113 (Cabat) HCDR3 HAYGHDGGFAMDY SEQ ID NO: 113 (Josiah) HCDR3 HAYGHDGGFAMDY SEQ ID NO: 114 (Cabat) LCDR1 RASESVSSNVA SEQ ID NO: 115 (Josiah) LCDR1 SESVSSN SEQ ID NO: 116 (Cabat) LCDR2 GASNRAT SEQ ID NO: 117 (Josiah) LCDR2 GAS SEQ ID NO: 118 (Cabat) LCDR3 GQSYSYPFT SEQ ID NO: 119 (Josiah) 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 are disclosed, eg, in US 9,228,016 and WO 2016/196792. In one embodiment, the anti-GITR antibody molecule comprises one or more of the following: the CDR sequence of BMS-986156 (or all CDR sequences in general), the heavy chain or light chain variable region sequence, or the heavy chain or light chain sequence , for example, as disclosed in Table 6.

In one embodiment, the anti-GITR antibody molecule is MK-4166 or MK-1248 (Merck). MK-4166, MK-1248, and other anti-GITR antibodies are disclosed, for example, in US 8,709,424, WO 2011/028683, WO 2015/026684, and Mahne et al., Cancer Res. 2017;77(5):1108 -1118. In one embodiment, the anti-GITR antibody molecule comprises one or more of the following: the CDR sequences of MK-4166 or MK-1248 (or all of the CDR sequences in general), the heavy or light chain variable region sequences, or the heavy or light chain variable region sequences. chain or light chain sequence.

In one embodiment, the anti-GITR antibody molecule is TRX518 (Leap Therapeutics). TRX518 and other anti-GITR antibodies are disclosed in, eg, US 7,812,135, US 8,388,967, US 9,028,823, WO 2006/105021, and Ponte J et al., (2010) Clinical Immunology; 135:S96. In one embodiment, the anti-GITR antibody molecule comprises one or more of: the CDR sequence of TRX518 (or generally all CDR sequences), the heavy or light chain variable region sequence, or the heavy or light chain sequence.

In one embodiment, the anti-GITR antibody molecule is INCAGN1876 (Incel/Aeginas). INCAGN1876 and other anti-GITR antibodies are disclosed, eg, in US 2015/0368349 and WO 2015/184099. In one embodiment, the anti-GITR antibody molecule comprises one or more of: the CDR sequences of INCAGN1876 (or all of the CDR sequences in general), the heavy or light chain variable region sequences, or the heavy or light chain sequences.

In one embodiment, the anti-GITR antibody molecule is AMG 228 (Amgen). AMG 228 and other anti-GITR antibodies are disclosed, eg, in US 9,464,139 and WO 2015/031667. In one embodiment, the anti-GITR antibody molecule comprises one or more of the following: AMG 228 CDR sequences (or generally all CDR sequences), heavy chain or light chain variable region sequences, or heavy chain or light chain sequences .

In one embodiment, the anti-GITR antibody molecule is INBRX-110 (Inhibrx). INBRX-110 and other anti-GITR antibodies are disclosed, eg, in US 2017/0022284 and WO 2017/015623. In one embodiment, the GITR agonist comprises one or more of: the CDR sequences (or generally all CDR sequences) of INBRX-110, the heavy or light chain variable region sequences, or the heavy or light chain sequence.

In one embodiment, the GITR agonist (eg, fusion protein) is MEDI 1873 (Medimus Limited, UK), also known as MEDI1873. MEDI 1873 and other GITR agonists are disclosed in , e.g., US 2017/0073386, WO 2017/025610, and Ross et al., Cancer Res 2016;76(14 Suppl): Abstract nr 561. In one embodiment, the GITR agonist comprises the IgG Fc domain of MEDI 1873, the functional multimerization domain, and the receptor binding domain of glucocorticoid-induced TNF receptor ligand (GITRL) one or more of.

Additional known GITR agonists (eg, anti-GITR antibodies) include, eg, those described in WO 2016/054638.

In one embodiment, the anti-GITR antibody competes for binding to the same epitope on GITR and/or is an antibody that 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 (e.g., an immunoadhesin comprising the extracellular or binding portion of GITR) fused to a constant region (e.g., the Fc region of an immunoglobulin sequence). combine fragments). [ Table 6 ]: Amino acid sequences of other exemplary anti-GITR antibody molecules BMS-986156 SEQ ID NO: 120 VH QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVIWYEGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGGSMVRGDYYYGMDVWGQGTTVTVSS SEQ ID NO: 121 VL AIQLTQSPSSLSASVGDRVTITCRASQGISSALAWYQQKPGKAPKLLIYDASSLESGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQFNSYPYTFGQGTKLEIK

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, CTLA4, TIM3, LAG3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4 and/or TGFRβ. In one embodiment, an inhibitor of an immune checkpoint molecule inhibits PD-1, PD-L1, LAG-3, TIM-3 or CTLA4, or any combination thereof.

Inhibition by inhibitory molecules can be at the DNA, RNA or protein level. In some embodiments, inhibitory nucleic acids (eg, dsRNA, siRNA, or shRNA) can be used to inhibit the expression of inhibitory molecules. In other embodiments, the inhibitor of the inhibitory signal is a polypeptide, e.g., a soluble ligand (e.g., PD-1-Ig or CTLA-4 Ig) or an antibody or antigen-binding fragment thereof that binds the inhibitory molecule; e.g., Antibodies or fragments thereof (herein also called "antibody molecules").

In one embodiment, the antibody molecule is a whole antibody or a fragment thereof (eg, Fab, F(ab')2, Fv, or single chain Fv fragment (scFv)). In yet other embodiments, the antibody molecule has a heavy chain constant region (Fc) selected from, for example, the heavy chain constant regions of IgGl, IgG2, IgG3, IgG4, IgM, IgAl, IgA2, IgD, and IgE in particular, a heavy chain constant region selected from eg IgG1, IgG2, IgG3, and IgG4, more particularly, a heavy chain constant region of IgG1 or IgG4 (eg, human IgG1 or IgG4). In one embodiment, the heavy chain constant region is human IgGl or human IgG4. In one embodiment, the constant region is altered (e.g., mutated) to modify the properties of the antibody molecule (e.g., to increase or decrease Fc receptor binding, antibody glycosylation, number of cysteine residues, effector cell function, or one or more of the complement functions).

In certain embodiments, the 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 PD-1 or PD-L1, and a second binding specificity, such as for TGFβ, TIM-3, LAG-3, or PD- Second binding specificity for L2. In one embodiment, the bispecific antibody molecule binds to PD-1 or PD-L1 and TIM-3. In another embodiment, the bispecific antibody molecule binds to PD-1 or PD-L1 and TGFβ. In another embodiment, the bispecific antibody molecule binds to PD-1 and TGFβ. Any combination of the aforementioned molecules can be combined in a multispecific antibody molecule (e.g., comprising a first binding specificity for PD-1 or PD-1, and two binding specificities for TGFβ, TIM-3, LAG-3, or PD-L2). Trispecific antibodies with one or more second and third binding specificities).

In certain embodiments, the immunomodulator is an inhibitor of PD-1 (eg, human PD-1). In another embodiment, the immunomodulator is an inhibitor of PD-L1 (eg, human PD-L1). In one embodiment, the inhibitor of PD-1 or PD-L1 is an antibody molecule to PD-1 or PD-L1. PD-1 or PD-L1 inhibitors can be administered alone, or in combination with other immunomodulators, such as inhibitors of TGFβ, LAG-3, TIM-3, or CTLA4. In an exemplary embodiment, an inhibitor of PD-1 or PD-L1 (e.g., an anti-TGFβ, or an anti-PD-1 or PD-L1 antibody molecule) is combined with a LAG-3 inhibitor (e.g., an anti-LAG-3 antibody Molecule) combined administration. In another embodiment, an inhibitor of TGFβ, PD-1, or PD-L1 (e.g., an anti-TGFβ, or an anti-PD-1 or PD-L1 antibody molecule) is combined with a TIM-3 inhibitor (e.g., an anti-TIM- 3 antibody molecules) combined administration. In yet other embodiments, an inhibitor of TGFβ, PD-1, or PD-L1 (e.g., an anti-TGFβ or anti-PD-L1 antibody molecule) is combined with a LAG-3 inhibitor (e.g., an anti-LAG-3 antibody molecule) and TIM-3 inhibitors (eg, anti-TIM-3 antibody molecules) are administered in combination.

Other combinations of immunomodulators and PD-1 inhibitors (e.g., one or more of PD-L2, CTLA4, TIM3, LAG3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4, and/or TGFR) are also included in this expose inside. Any antibody molecule known in the art or disclosed herein can be used in the above combinations of checkpoint molecule inhibitors. CTLA-4 inhibitors

In some embodiments, a TGFβ inhibitor of the present disclosure (and/or a PD1, PD-L1, or PD-L2 inhibitor) is used in combination with a CTLA-4 inhibitor to treat a disease (eg, cancer). In some embodiments, the PD-1 inhibitor is selected from Ipilimumab (MDX-010, MDX-101, or Yervoy, Bristol-Myers Squibb), tremelimumab (replaced Ticilimumab (Pfizer/AstraZeneca), AGEN1181 (Aeginas), Zalifrelimab (AGEN1884, Aeginas), IBI310 (Innovent Biologics)), LAG-3 inhibitor

In some embodiments, a TGFβ inhibitor of the present disclosure (and/or a PD1, PD-L1, or PD-L2 inhibitor) is used in combination with a LAG-3 inhibitor to treat a disease (eg, cancer). In some embodiments, the LAG-3 inhibitor is selected from LAG525 (Novartis), BMS-986016 (Bristol-Myers Squibb), or TSR-033 (Tesaro). Exemplary LAG-3 Inhibitors

In one embodiment, the LAG-3 inhibitor is an anti-LAG-3 antibody molecule. In one embodiment, the LAG-3 inhibitor is an anti-LAG-3 antibody molecule, as described in the September 17, 2015, "Antibody Molecules to LAG-3 and Uses Thereof" Disclosed in published US 2015/0259420.

In one embodiment, the anti-LAG-3 antibody molecule comprises at least one, two, three, four, five or six complementarity determining regions (CDRs) (or a total of All CDRs above), the heavy and light chain variable regions comprising the heavy and light chain variable regions shown in Table 7 (for example, the heavy and light chain variable region sequences from BAP050-plant I or BAP050-plant J disclosed in Table 7) Amino acid sequence, or encoded by the nucleotide sequence shown in Table 7. In some embodiments, the CDRs are defined according to Kabat (eg, as listed in Table 7). In some embodiments, the CDRs are defined according to Josiah (eg, as listed in Table 7). In some embodiments, the CDRs are defined according to the combined CDRs of both Kabat and Josiah (eg, as listed in Table 7). In one embodiment, the combination of Kabat and Josiah CDRs of VH CDR1 comprises the amino acid sequence GFTLTNYGMN (SEQ ID NO: 122). In one embodiment, relative to the amino acid sequence shown in Table 7, or encoded by the nucleotide sequence shown in Table 7, one or more of the CDRs (or generally all CDRs) have a , two, three, four, five, six or more changes, such as amino acid substitutions (eg, conservative amino acid substitutions) or deletions.

In one embodiment, the anti-LAG-3 antibody molecule comprises: VHCDR1 amino acid sequence comprising SEQ ID NO: 123, VHCDR2 amino acid sequence of SEQ ID NO: 124, and VHCDR3 amino acid sequence of SEQ ID NO: 125 The heavy chain variable region (VH) of the sequence; and the VLCDR1 amino acid sequence comprising SEQ ID NO: 132, the VLCDR2 amino acid sequence of SEQ ID NO: 133, and the VLCDR3 amino acid sequence of SEQ ID NO: 134 Light chain variable regions (VL), each disclosed in Table 7.

In one embodiment, the anti-LAG-3 antibody molecule comprises: VHCDR1 encoded by the nucleotide sequence of SEQ ID NO: 158 or 159, VHCDR2 encoded by the nucleotide sequence of SEQ ID NO: 160 or 161, and VH of VHCDR3 encoded by the nucleotide sequence of SEQ ID NO: 162 or 163; The VLCDR2 encoded by the sequence, and the VL of VLCDR3 encoded by the nucleotide sequence of SEQ ID NO: 172 or 173 are each disclosed in Table 7. In one embodiment, the anti-LAG-3 antibody molecule comprises: VHCDR1 encoded by the nucleotide sequence of SEQ ID NO: 180 or 159, VHCDR2 encoded by the nucleotide sequence of SEQ ID NO: 181 or 161, and VH of VHCDR3 encoded by the nucleotide sequence of SEQ ID NO: 182 or 163; The VLCDR2 encoded by the sequence, and the VL of VLCDR3 encoded by the nucleotide sequence of SEQ ID NO: 172 or 173 are each disclosed in Table 7.

In one embodiment, the anti-LAG-3 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 128, or at least 85%, 90%, 95%, or 99% identical to SEQ ID NO: 128 or higher identity amino acid sequences. In one embodiment, the anti-LAG-3 antibody molecule comprises a VL comprising the amino acid sequence of SEQ ID NO: 140, or at least 85%, 90%, 95%, or 99% identical to SEQ ID NO: 140 or higher identity amino acid sequences. In one embodiment, the anti-LAG-3 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 146, or at least 85%, 90%, 95%, or 99% identical to SEQ ID NO: 146 or higher identity amino acid sequences. In one embodiment, the anti-LAG-3 antibody molecule comprises a VL comprising the amino acid sequence of SEQ ID NO: 152, or at least 85%, 90%, 95%, or 99% identical to SEQ ID NO: 152 or higher identity amino acid sequences. In one embodiment, the anti-LAG-3 antibody molecule comprises: VH comprising the amino acid sequence of SEQ ID NO: 128 and VL comprising the amino acid sequence of SEQ ID NO: 140. In one embodiment, the anti-LAG-3 antibody molecule comprises: VH comprising the amino acid sequence of SEQ ID NO: 146 and VL comprising the amino acid sequence of SEQ ID NO: 152.

In one embodiment, the antibody molecule comprises a VH consisting of, or having at least 85%, 90%, 95%, or 99% of the nucleotide sequence of SEQ ID NO: 129 or 130 or higher identity nucleotide sequence codes. In one embodiment, the antibody molecule comprises a VL consisting of, or having at least 85%, 90%, 95%, or 99% of the nucleotide sequence of SEQ ID NO: 141 or 142 or higher identity nucleotide sequences. In one embodiment, the antibody molecule comprises a VH consisting of, or having at least 85%, 90%, 95%, or 99% of the nucleotide sequence of SEQ ID NO: 147 or 148 or higher identity nucleotide sequence codes. In one embodiment, the antibody molecule comprises a VL consisting of, or having at least 85%, 90%, 95%, or 99% of the nucleotide sequence of SEQ ID NO: 153 or 154 or higher identity nucleotide sequences. In one embodiment, the antibody molecule comprises: VH encoded by the nucleotide sequence of SEQ ID NO: 129 or 130 and VL encoded by the nucleotide sequence of SEQ ID NO: 141 or 142. In one embodiment, the antibody molecule comprises: VH encoded by the nucleotide sequence of SEQ ID NO: 147 or 148 and VL encoded by the nucleotide sequence of SEQ ID NO: 153 or 154.

In one embodiment, the anti-LAG-3 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 131, or at least 85%, 90%, 95%, or Amino acid sequences with 99% or greater identity. In one embodiment, the anti-LAG-3 antibody molecule comprises a light chain comprising the amino acid sequence of SEQ ID NO: 143, or at least 85%, 90%, 95%, or Amino acid sequences with 99% or greater identity. In one embodiment, the anti-LAG-3 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 149, or at least 85%, 90%, 95%, or Amino acid sequences with 99% or greater identity. In one embodiment, the anti-LAG-3 antibody molecule comprises a light chain comprising the amino acid sequence of SEQ ID NO: 155, or at least 85%, 90%, 95%, or Amino acid sequences with 99% or greater identity. In one embodiment, the anti-LAG-3 antibody molecule comprises: a heavy chain comprising the amino acid sequence of SEQ ID NO: 131 and a light chain comprising the amino acid sequence of SEQ ID NO: 143. In one embodiment, the anti-LAG-3 antibody molecule comprises: a heavy chain comprising the amino acid sequence of SEQ ID NO: 149 and a light chain comprising the amino acid sequence of SEQ ID NO: 155.

In one embodiment, the antibody molecule comprises a heavy chain consisting of the nucleotide sequence of SEQ ID NO: 138 or 139, or having at least 85%, 90%, 95%, or 99% or more identical nucleotide sequence codes. In one embodiment, the antibody molecule comprises a light chain consisting of the nucleotide sequence of SEQ ID NO: 144 or 145, or having at least 85%, 90%, 95%, or Nucleotide sequences with 99% or greater identity. In one embodiment, the antibody molecule comprises a heavy chain consisting of the nucleotide sequence of SEQ ID NO: 150 or 151, or having at least 85%, 90%, 95%, or 99% or more identical nucleotide sequence codes. In one embodiment, the antibody molecule comprises a light chain consisting of the nucleotide sequence of SEQ ID NO: 156 or 157, or having at least 85%, 90%, 95%, or Nucleotide sequences with 99% or greater identity. In one embodiment, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 138 or 139 and a light chain encoded by the nucleotide sequence of SEQ ID NO: 144 or 145. In one embodiment, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 150 or 151 and a light chain encoded by the nucleotide sequence of SEQ ID NO: 156 or 157.

The antibody molecules described herein can be produced by vectors, host cells, and methods described in US 2015/0259420. Table 7. Amino acid and nucleotide sequences of exemplary anti-LAG-3 antibody molecules BAP050- Plant I HC SEQ ID NO: 123 (Cabat) HCDR1 NYGMN SEQ ID NO: 124 (Kabat) HCDR2 WINTDTGEPTYADDFKG SEQ ID NO: 125 (Kabat) HCDR3 NPPYYYGTNNAEAMDY SEQ ID NO: 126 (Josiah) HCDR1 GFTLTNY SEQ ID NO: 127 (Josiah) HCDR2 NTDTGE SEQ ID NO: 125 (Josiah) HCDR3 NPPYYYGTNNAEAMDY SEQ ID NO: 128 VH QVQLVQSGAEVKKPGASVKVSCKASGFTLTNYGMNWVRQARGQRLEWIGWINTDTGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARNPPYYYGTNNAEAMDYWGQGTTVTVSS SEQ ID NO: 129 DNA VH CAAGTGCAGCTGGTGCAGTCGGGAGCCGAAGTGAAGAAGCCTGGAGCCTCGGTGAAGGTGTCGTGCAAGGCATCCGGATTCACCCTCACCAATTACGGGATGAACTGGGTCAGACAGGCCCGGGGTCAACGGCTGGAGTGGATCGGATGGATTAACACCGACACCGGGGAGCCTACCTACGCGGACGATTTCAAGGGACGGTTCGTGTTCTCCCTCGACACCTCCGTGTCCACCGCCTACCTCCAAATCTCCTCACTGAAAGCGGAGGACACCGCCGTGTACTATTGCGCGAGGAACCCGCCCTACTACTACGGAACCAACAACGCCGAAGCCATGGACTACTGGGGCCAGGGCACCACTGTGACTGTGTCCAGC SEQ ID NO: 130 DNA VH CAGGTGCAGCTGGTGCAGTCTGGCGCCGAAGTGAAGAAACCTGGCGCCTCCGTGAAGGTGTCCTGCAAGGCCTCTGGCTTCACCCTGACCAACTACGGCATGAACTGGGTGCGACAGGCCAGGGGCCAGCGGCTGGAATGGATCGGCTGGATCAACACCGACACCGGCGAGCCTACCTACGCCGACGACTTCAAGGGCAGATTCGTGTTCTCCCTGGACACCTCCGTGTCCACCGCCTACCTGCAGATCTCCAGCCTGAAGGCCGAGGATACCGCCGTGTACTACTGCGCCCGGAACCCCCCTTACTACTACGGCACCAACAACGCCGAGGCCATGGACTATTGGGGCCAGGGCACCACCGTGACCGTGTCCTCT SEQ ID NO: 131 heavy chain QVQLVQSGAEVKKPGASVKVSCKASGFTLTNYGMNWVRQARGQRLEWIGWINTDTGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARNPPYYYGTNNAEAMDYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG SEQ ID NO: 138 DNA heavy chain CAAGTGCAGCTGGTGCAGTCGGGAGCCGAAGTGAAGAAGCCTGGAGCCTCGGTGAAGGTGTCGTGCAAGGCATCCGGATTCACCCTCACCAATTACGGGATGAACTGGGTCAGACAGGCCCGGGGTCAACGGCTGGAGTGGATCGGATGGATTAACACCGACACCGGGGAGCCTACCTACGCGGACGATTTCAAGGGACGGTTCGTGTTCTCCCTCGACACCTCCGTGTCCACCGCCTACCTCCAAATCTCCTCACTGAAAGCGGAGGACACCGCCGTGTACTATTGCGCGAGGAACCCGCCCTACTACTACGGAACCAACAACGCCGAAGCCATGGACTACTGGGGCCAGGGCACCACTGTGACTGTGTCCAGCGCGTCCACTAAGGGCCCGTCCGTGTTCCCCCTGGCACCTTGTAGCCGGAGCACTAGCGAATCCACCGCTGCCCTCGGCTGCCTGGTCAAGGATTACTTCCCGGAGCCCGTGACCGTGTCCTGGAACAGCGGAGCCCTGACCTCCGGAGTGCACACCTTCCCCGCTGTGCTGCAGAGCTCCGGGCTGTACTCGCTGTCGTCGGTGGTCACGGTGCCTTCATCTAGCCTGGGTACCAAGACCTACACTTGCAACGTGGACCACAAGCCTTCCAACACTAAGGTGGACAAGCGCGTCGAATCGAAGTACGGCCCACCGTGCCCGCCTTGTCCCGCGCCGGAGTTCCTCGGCGGTCCCTCGGTCTTTCTGTTCCCACCGAAGCCCAAGGACACTTTGATGATTTCCCGCACCCCTGAAGTGACATGCGTGGTCGTGGACGTGTCACAGGAAGATCCGGAGGTGCAGTTCAATTGGTACGTGGATGGCGTCGAGGTGCACAACGCCAAAACCAAGCCGAGGGAGGAGCAGTTCAACTCCACTTACCGCGTCGTGTCCGTGCTGACGGTGCTGCATCAGGACTGGCTGAACGGGAAGGAGTACAAGTGCAAAGTGTCCAACAAGGGACTTC CTAGCTCAATCGAAAAGACCATCTCGAAAGCCAAGGGACAGCCCCGGGAACCCCAAGTGTATACCCTGCCACCGAGCCAGGAAGAAATGACTAAGAACCAAGTCTCATTGACTTGCCTTGTGAAGGGCTTCTACCCATCGGATATCGCCGTGGAATGGGAGTCCAACGGCCAGCCGGAAAACAACTACAAGACCACCCCTCCGGTGCTGGACTCAGACGGATCCTTCTTCCTCTACTCGCGGCTGACCGTGGATAAGAGCAGATGGCAGGAGGGAAATGTGTTCAGCTGTTCTGTGATGCATGAAGCCCTGCACAACCACTACACTCAGAAGTCCCTGTCCCTCTCCCTGGGA SEQ ID NO: 139 DNA heavy chain CAGGTGCAGCTGGTGCAGTCTGGCGCCGAAGTGAAGAAACCTGGCGCCTCCGTGAAGGTGTCCTGCAAGGCCTCTGGCTTCACCCTGACCAACTACGGCATGAACTGGGTGCGACAGGCCAGGGGCCAGCGGCTGGAATGGATCGGCTGGATCAACACCGACACCGGCGAGCCTACCTACGCCGACGACTTCAAGGGCAGATTCGTGTTCTCCCTGGACACCTCCGTGTCCACCGCCTACCTGCAGATCTCCAGCCTGAAGGCCGAGGATACCGCCGTGTACTACTGCGCCCGGAACCCCCCTTACTACTACGGCACCAACAACGCCGAGGCCATGGACTATTGGGGCCAGGGCACCACCGTGACCGTGTCCTCTGCTTCTACCAAGGGGCCCAGCGTGTTCCCCCTGGCCCCCTGCTCCAGAAGCACCAGCGAGAGCACAGCCGCCCTGGGCTGCCTGGTGAAGGACTACTTCCCCGAGCCCGTGACCGTGTCCTGGAACAGCGGAGCCCTGACCAGCGGCGTGCACACCTTCCCCGCCGTGCTGCAGAGCAGCGGCCTGTACAGCCTGAGCAGCGTGGTGACCGTGCCCAGCAGCAGCCTGGGCACCAAGACCTACACCTGTAACGTGGACCACAAGCCCAGCAACACCAAGGTGGACAAGAGGGTGGAGAGCAAGTACGGCCCACCCTGCCCCCCCTGCCCAGCCCCCGAGTTCCTGGGCGGACCCAGCGTGTTCCTGTTCCCCCCCAAGCCCAAGGACACCCTGATGATCAGCAGAACCCCCGAGGTGACCTGTGTGGTGGTGGACGTGTCCCAGGAGGACCCCGAGGTCCAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCACAACGCCAAGACCAAGCCCAGAGAGGAGCAGTTTAACAGCACCTACCGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGACTGGCTGAACGGCAAAGAGTACAAGTGTAAGGTCTCCAACAAGGGCCTGC CAAGCAGCATCGAAAAGACCATCAGCAAGGCCAAGGGCCAGCCTAGAGAGCCCCAGGTCTACACCCTGCCACCCAGCCAAGAGGAGATGACCAAGAACCAGGTGTCCCTGACCTGTCTGGTGAAGGGCTTCTACCCAAGCGACATCGCCGTGGAGTGGGAGAGCAACGGCCAGCCCGAGAACAACTACAAGACCACCCCCCCAGTGCTGGACAGCGACGGCAGCTTCTTCCTGTACAGCAGGCTGACCGTGGACAAGTCCAGATGGCAGGAGGGCAACGTCTTTAGCTGCTCCGTGATGCACGAGGCCCTGCACAACCACTACACCCAGAAGAGCCTGAGCCTGTCCCTGGGC BAP050- Plant I LC SEQ ID NO: 132 (Cabat) LCDR1 SSSQDISNYLN SEQ ID NO: 133 (Kabat) LCDR2 YTSTLHL SEQ ID NO: 134 (Cabat) LCDR3 QQYYNLPWT SEQ ID NO: 135 (Josiah) LCDR1 SQDISNY SEQ ID NO: 136 (Josiah) LCDR2 YTS SEQ ID NO: 137 (Josiah) LCDR3 YYNLPW SEQ ID NO: 140 VL DIQMTQSPSSLSASVGDRVTITCSSSQDISNYLNWYLQKPGQSPQLLIYYTSTLHLGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQYYNLPWTFGQGTKVEIK SEQ ID NO: 141 DNA VL GATATTCAGATGACTCAGTCACCTAGTAGCCTGAGCGCTAGTGTGGGCGATAGAGTGACTATCACCTGTAGCTCTAGTCAGGATATCTCTAACTACCTGAACTGGTATCTGCAGAAGCCCGGTCAATCACCTCAGCTGCTGATCTACTACACTAGCACCCTGCACCTGGGCGTGCCCTCTAGGTTTAGCGGTAGCGGTAGTGGCACCGAGTTCACCCTGACTATCTCTAGCCTGCAGCCCGACGACTTCGCTACCTACTACTGTCAGCAGTACTATAACCTGCCCTGGACCTTCGGTCAAGGCACTAAGGTCGAGATTAAG SEQ ID NO: 142 DNA VL GACATCCAGATGACCCAGTCCCCCTCCAGCCTGTCTGCTTCCGTGGGCGACAGAGTGACCATCACCTGTTCCTCCAGCCAGGACATCTCCAACTACCTGAACTGGTATCTGCAGAAGCCCGGCCAGTCCCCTCAGCTGCTGATCTACTACACCTCCACCCTGCACCTGGGCGTGCCCTCCAGATTTTCCGGCTCTGGCTCTGGCACCGAGTTTACCCTGACCATCAGCTCCCTGCAGCCCGACGACTTCGCCACCTACTACTGCCAGCAGTACTACAACCTGCCCTGGACCTTCGGCCAGGGCACCAAGGTGGAAATCAAG SEQ ID NO: 143 light chain DIQMTQSPSSLSASVGDRVTITCSSSQDISNYLNWYLQKPGQSPQLLIYYTSTLHLGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQYYNLPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLSKADYEVECKQGLSS SEQ ID NO: 144 DNA light chain GATATTCAGATGACTCAGTCACCTAGTAGCCTGAGCGCTAGTGTGGGCGATAGAGTGACTATCACCTGTAGCTCTAGTCAGGATATCTCTAACTACCTGAACTGGTATCTGCAGAAGCCCGGTCAATCACCTCAGCTGCTGATCTACTACACTAGCACCCTGCACCTGGGCGTGCCCTCTAGGTTTAGCGGTAGCGGTAGTGGCACCGAGTTCACCCTGACTATCTCTAGCCTGCAGCCCGACGACTTCGCTACCTACTACTGTCAGCAGTACTATAACCTGCCCTGGACCTTCGGTCAAGGCACTAAGGTCGAGATTAAGCGTACGGTGGCCGCTCCCAGCGTGTTCATCTTCCCCCCCAGCGACGAGCAGCTGAAGAGCGGCACCGCCAGCGTGGTGTGCCTGCTGAACAACTTCTACCCCCGGGAGGCCAAGGTGCAGTGGAAGGTGGACAACGCCCTGCAGAGCGGCAACAGCCAGGAGAGCGTCACCGAGCAGGACAGCAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCGACTACGAGAAGCATAAGGTGTACGCCTGCGAGGTGACCCACCAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAACAGGGGCGAGTGC SEQ ID NO: 145 DNA light chain GACATCCAGATGACCCAGTCCCCCTCCAGCCTGTCTGCTTCCGTGGGCGACAGAGTGACCATCACCTGTTCCTCCAGCCAGGACATCTCCAACTACCTGAACTGGTATCTGCAGAAGCCCGGCCAGTCCCCTCAGCTGCTGATCTACTACACCTCCACCCTGCACCTGGGCGTGCCCTCCAGATTTTCCGGCTCTGGCTCTGGCACCGAGTTTACCCTGACCATCAGCTCCCTGCAGCCCGACGACTTCGCCACCTACTACTGCCAGCAGTACTACAACCTGCCCTGGACCTTCGGCCAGGGCACCAAGGTGGAAATCAAGCGTACGGTGGCCGCTCCCAGCGTGTTCATCTTCCCCCCAAGCGACGAGCAGCTGAAGAGCGGCACCGCCAGCGTGGTGTGTCTGCTGAACAACTTCTACCCCAGGGAGGCCAAGGTGCAGTGGAAGGTGGACAACGCCCTGCAGAGCGGCAACAGCCAGGAGAGCGTCACCGAGCAGGACAGCAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCGACTACGAGAAGCACAAGGTGTACGCCTGTGAGGTGACCCACCAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAACAGGGGCGAGTGC BAP050- Plant J HC SEQ ID NO: 123 (Cabat) HCDR1 NYGMN SEQ ID NO: 124 (Kabat) HCDR2 WINTDTGEPTYADDFKG SEQ ID NO: 125 (Kabat) HCDR3 NPPYYYGTNNAEAMDY SEQ ID NO: 126 (Josiah) HCDR1 GFTLTNY SEQ ID NO: 127 (Josiah) HCDR2 NTDTGE SEQ ID NO: 125 (Josiah) HCDR3 NPPYYYGTNNAEAMDY SEQ ID NO: 146 VH QVQLVQSGAEVKKPGASVKVSCKASGFTLTNYGMNWVRQAPGQGLEWMGWINTDTGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARNPPYYYGTNNAEAMDYWGQGTTVTVSS SEQ ID NO: 147 DNA VH CAGGTGCAGCTGGTGCAGTCAGGCGCCGAAGTGAAGAAACCCGGCGCTAGTGTGAAAGTCAGCTGTAAAGCTAGTGGCTTCACCCTGACTAACTACGGGATGAACTGGGTCCGCCAGGCCCCAGGTCAAGGCCTCGAGTGGATGGGCTGGATTAACACCGACACCGGCGAGCCTACCTACGCCGACGACTTTAAGGGCAGATTCGTGTTTAGCCTGGACACTAGTGTGTCTACCGCCTACCTGCAGATCTCTAGCCTGAAGGCCGAGGACACCGCCGTCTACTACTGCGCTAGAAACCCCCCCTACTACTACGGCACTAACAACGCCGAGGCTATGGACTACTGGGGTCAAGGCACTACCGTGACCGTGTCTAGC SEQ ID NO: 148 DNA VH CAGGTGCAGCTGGTGCAGTCTGGCGCCGAAGTGAAGAAACCTGGCGCCTCCGTGAAGGTGTCCTGCAAGGCCTCTGGCTTCACCCTGACCAACTACGGCATGAACTGGGTGCGACAGGCCCCTGGACAGGGCCTGGAATGGATGGGCTGGATCAACACCGACACCGGCGAGCCTACCTACGCCGACGACTTCAAGGGCAGATTCGTGTTCTCCCTGGACACCTCCGTGTCCACCGCCTACCTGCAGATCTCCAGCCTGAAGGCCGAGGATACCGCCGTGTACTACTGCGCCCGGAACCCCCCTTACTACTACGGCACCAACAACGCCGAGGCCATGGACTATTGGGGCCAGGGCACCACCGTGACCGTGTCCTCT SEQ ID NO: 149 heavy chain QVQLVQSGAEVKKPGASVKVSCKASGFTLTNYGMNWVRQAPGQGLEWMGWINTDTGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARNPPYYYGTNNAEAMDYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG SEQ ID NO: 150 DNA heavy chain CAGGTGCAGCTGGTGCAGTCAGGCGCCGAAGTGAAGAAACCCGGCGCTAGTGTGAAAGTCAGCTGTAAAGCTAGTGGCTTCACCCTGACTAACTACGGGATGAACTGGGTCCGCCAGGCCCCAGGTCAAGGCCTCGAGTGGATGGGCTGGATTAACACCGACACCGGCGAGCCTACCTACGCCGACGACTTTAAGGGCAGATTCGTGTTTAGCCTGGACACTAGTGTGTCTACCGCCTACCTGCAGATCTCTAGCCTGAAGGCCGAGGACACCGCCGTCTACTACTGCGCTAGAAACCCCCCCTACTACTACGGCACTAACAACGCCGAGGCTATGGACTACTGGGGTCAAGGCACTACCGTGACCGTGTCTAGCGCTAGCACTAAGGGCCCGTCCGTGTTCCCCCTGGCACCTTGTAGCCGGAGCACTAGCGAATCCACCGCTGCCCTCGGCTGCCTGGTCAAGGATTACTTCCCGGAGCCCGTGACCGTGTCCTGGAACAGCGGAGCCCTGACCTCCGGAGTGCACACCTTCCCCGCTGTGCTGCAGAGCTCCGGGCTGTACTCGCTGTCGTCGGTGGTCACGGTGCCTTCATCTAGCCTGGGTACCAAGACCTACACTTGCAACGTGGACCACAAGCCTTCCAACACTAAGGTGGACAAGCGCGTCGAATCGAAGTACGGCCCACCGTGCCCGCCTTGTCCCGCGCCGGAGTTCCTCGGCGGTCCCTCGGTCTTTCTGTTCCCACCGAAGCCCAAGGACACTTTGATGATTTCCCGCACCCCTGAAGTGACATGCGTGGTCGTGGACGTGTCACAGGAAGATCCGGAGGTGCAGTTCAATTGGTACGTGGATGGCGTCGAGGTGCACAACGCCAAAACCAAGCCGAGGGAGGAGCAGTTCAACTCCACTTACCGCGTCGTGTCCGTGCTGACGGTGCTGCATCAGGACTGGCTGAACGGGAAGGAGTACAAGTGCAAAGTGTCCAACAAGGGACTTC CTAGCTCAATCGAAAAGACCATCTCGAAAGCCAAGGGACAGCCCCGGGAACCCCAAGTGTATACCCTGCCACCGAGCCAGGAAGAAATGACTAAGAACCAAGTCTCATTGACTTGCCTTGTGAAGGGCTTCTACCCATCGGATATCGCCGTGGAATGGGAGTCCAACGGCCAGCCGGAAAACAACTACAAGACCACCCCTCCGGTGCTGGACTCAGACGGATCCTTCTTCCTCTACTCGCGGCTGACCGTGGATAAGAGCAGATGGCAGGAGGGAAATGTGTTCAGCTGTTCTGTGATGCATGAAGCCCTGCACAACCACTACACTCAGAAGTCCCTGTCCCTCTCCCTGGGA SEQ ID NO: 151 DNA heavy chain CAGGTGCAGCTGGTGCAGTCTGGCGCCGAAGTGAAGAAACCTGGCGCCTCCGTGAAGGTGTCCTGCAAGGCCTCTGGCTTCACCCTGACCAACTACGGCATGAACTGGGTGCGACAGGCCCCTGGACAGGGCCTGGAATGGATGGGCTGGATCAACACCGACACCGGCGAGCCTACCTACGCCGACGACTTCAAGGGCAGATTCGTGTTCTCCCTGGACACCTCCGTGTCCACCGCCTACCTGCAGATCTCCAGCCTGAAGGCCGAGGATACCGCCGTGTACTACTGCGCCCGGAACCCCCCTTACTACTACGGCACCAACAACGCCGAGGCCATGGACTATTGGGGCCAGGGCACCACCGTGACCGTGTCCTCTGCTTCTACCAAGGGGCCCAGCGTGTTCCCCCTGGCCCCCTGCTCCAGAAGCACCAGCGAGAGCACAGCCGCCCTGGGCTGCCTGGTGAAGGACTACTTCCCCGAGCCCGTGACCGTGTCCTGGAACAGCGGAGCCCTGACCAGCGGCGTGCACACCTTCCCCGCCGTGCTGCAGAGCAGCGGCCTGTACAGCCTGAGCAGCGTGGTGACCGTGCCCAGCAGCAGCCTGGGCACCAAGACCTACACCTGTAACGTGGACCACAAGCCCAGCAACACCAAGGTGGACAAGAGGGTGGAGAGCAAGTACGGCCCACCCTGCCCCCCCTGCCCAGCCCCCGAGTTCCTGGGCGGACCCAGCGTGTTCCTGTTCCCCCCCAAGCCCAAGGACACCCTGATGATCAGCAGAACCCCCGAGGTGACCTGTGTGGTGGTGGACGTGTCCCAGGAGGACCCCGAGGTCCAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCACAACGCCAAGACCAAGCCCAGAGAGGAGCAGTTTAACAGCACCTACCGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGACTGGCTGAACGGCAAAGAGTACAAGTGTAAGGTCTCCAACAAGGGCCTGC CAAGCAGCATCGAAAAGACCATCAGCAAGGCCAAGGGCCAGCCTAGAGAGCCCCAGGTCTACACCCTGCCACCCAGCCAAGAGGAGATGACCAAGAACCAGGTGTCCCTGACCTGTCTGGTGAAGGGCTTCTACCCAAGCGACATCGCCGTGGAGTGGGAGAGCAACGGCCAGCCCGAGAACAACTACAAGACCACCCCCCCAGTGCTGGACAGCGACGGCAGCTTCTTCCTGTACAGCAGGCTGACCGTGGACAAGTCCAGATGGCAGGAGGGCAACGTCTTTAGCTGCTCCGTGATGCACGAGGCCCTGCACAACCACTACACCCAGAAGAGCCTGAGCCTGTCCCTGGGC BAP050- Plant J LC SEQ ID NO: 132 (Cabat) LCDR1 SSSQDISNYLN SEQ ID NO: 133 (Kabat) LCDR2 YTSTLHL SEQ ID NO: 134 (Cabat) LCDR3 QQYYNLPWT SEQ ID NO: 135 (Josiah) LCDR1 SQDISNY SEQ ID NO: 136 (Josiah) LCDR2 YTS SEQ ID NO: 137 (Josiah) LCDR3 YYNLPW SEQ ID NO: 152 VL DIQMTQSPSSLSASVGDRVTITCSSSQDISNYLNWYQQKPGKAPKLLIYYTSTLHLGIPPRFSGSGYGTDFLTINNIESEDAAYYFCQQYYNLPWTFGQGTKVEIK SEQ ID NO: 153 DNA VL GATATTCAGATGACTCAGTCACCTAGTAGCCTGAGCGCTAGTGTGGGCGATAGAGTGACTATCACCTGTAGCTCTAGTCAGGATATCTCTAACTACCTGAACTGGTATCAGCAGAAGCCCGGTAAAGCCCCTAAGCTGCTGATCTACTACACTAGCACCCTGCACCTGGGAATCCCCCCTAGGTTTAGCGGTAGCGGCTACGGCACCGACTTCACCCTGACTATTAACAATATCGAGTCAGAGGACGCCGCCTACTACTTCTGTCAGCAGTACTATAACCTGCCCTGGACCTTCGGTCAAGGCACTAAGGTCGAGATTAAG SEQ ID NO: 154 DNA VL GACATCCAGATGACCCAGTCCCCCTCCAGCCTGTCTGCTTCCGTGGGCGACAGAGTGACCATCACCTGTTCCTCCAGCCAGGACATCTCCAACTACCTGAACTGGTATCAGCAGAAGCCCGGCAAGGCCCCCAAGCTGCTGATCTACTACACCTCCACCCTGCACCTGGGCATCCCCCCTAGATTCTCCGGCTCTGGCTACGGCACCGACTTCACCCTGACCATCAACAACATCGAGTCCGAGGACGCCGCCTACTACTTCTGCCAGCAGTACTACAACCTGCCCTGGACCTTCGGCCAGGGCACCAAGGTGGAAATCAAG SEQ ID NO: 155 light chain DIQMTQSPSSLSASVGDRVTITCSSSSQDISNYLNWYQQKPGKAPKLLIYYTSTLHLGIPPRFSGSGYGTDFLTLTINNIESEDAAYYFCQQYYNLPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSGTLTLSKADYACEKQGLRFSS SEQ ID NO: 156 DNA light chain GATATTCAGATGACTCAGTCACCTAGTAGCCTGAGCGCTAGTGTGGGCGATAGAGTGACTATCACCTGTAGCTCTAGTCAGGATATCTCTAACTACCTGAACTGGTATCAGCAGAAGCCCGGTAAAGCCCCTAAGCTGCTGATCTACTACACTAGCACCCTGCACCTGGGAATCCCCCCTAGGTTTAGCGGTAGCGGCTACGGCACCGACTTCACCCTGACTATTAACAATATCGAGTCAGAGGACGCCGCCTACTACTTCTGTCAGCAGTACTATAACCTGCCCTGGACCTTCGGTCAAGGCACTAAGGTCGAGATTAAGCGTACGGTGGCCGCTCCCAGCGTGTTCATCTTCCCCCCCAGCGACGAGCAGCTGAAGAGCGGCACCGCCAGCGTGGTGTGCCTGCTGAACAACTTCTACCCCCGGGAGGCCAAGGTGCAGTGGAAGGTGGACAACGCCCTGCAGAGCGGCAACAGCCAGGAGAGCGTCACCGAGCAGGACAGCAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCGACTACGAGAAGCATAAGGTGTACGCCTGCGAGGTGACCCACCAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAACAGGGGCGAGTGC SEQ ID NO: 157 DNA light chain GACATCCAGATGACCCAGTCCCCCTCCAGCCTGTCTGCTTCCGTGGGCGACAGAGTGACCATCACCTGTTCCTCCAGCCAGGACATCTCCAACTACCTGAACTGGTATCAGCAGAAGCCCGGCAAGGCCCCCAAGCTGCTGATCTACTACACCTCCACCCTGCACCTGGGCATCCCCCCTAGATTCTCCGGCTCTGGCTACGGCACCGACTTCACCCTGACCATCAACAACATCGAGTCCGAGGACGCCGCCTACTACTTCTGCCAGCAGTACTACAACCTGCCCTGGACCTTCGGCCAGGGCACCAAGGTGGAAATCAAGCGTACGGTGGCCGCTCCCAGCGTGTTCATCTTCCCCCCAAGCGACGAGCAGCTGAAGAGCGGCACCGCCAGCGTGGTGTGTCTGCTGAACAACTTCTACCCCAGGGAGGCCAAGGTGCAGTGGAAGGTGGACAACGCCCTGCAGAGCGGCAACAGCCAGGAGAGCGTCACCGAGCAGGACAGCAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCGACTACGAGAAGCACAAGGTGTACGCCTGTGAGGTGACCCACCAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAACAGGGGCGAGTGC BAP050- Plant I HC SEQ ID NO: 158 (Cabat) HCDR1 AATTACGGGATGAAC SEQ ID NO: 159 (Kabat) HCDR1 AACTACGGCATGAAC SEQ ID NO: 160 (Cabat) HCDR2 TGGATTAACACCGACACCGGGGAGCCTACCTACGCGGACGATTTCAAGGGA SEQ ID NO: 161 (Cabat) HCDR2 TGGATCAACACCGACACCGGCGAGCCTACCTACGCCGACGACTTCAAGGGC SEQ ID NO: 162 (Cabat) HCDR3 AACCCGCCCTACTACTACGGAACCAACAACGCCGAAGCCATGGACTAC SEQ ID NO: 163 (Kabat) HCDR3 AACCCCCCCTTACTACTACGGCACCAACAACGCCGAGGCCATGGACTAT SEQ ID NO: 164 (Josiah) HCDR1 GGATTCACCCTCACCAATTAC SEQ ID NO: 165 (Josiah) HCDR1 GGCTTCACCCTGACCAACTAC SEQ ID NO: 166 (Josiah) HCDR2 AACACCGACACCGGGGAG SEQ ID NO: 167 (Josiah) HCDR2 AACACCGACACCGGCGAG SEQ ID NO: 162 (Josiah) HCDR3 AACCCGCCCTACTACTACGGAACCAACAACGCCGAAGCCATGGACTAC SEQ ID NO: 163 (Josiah) HCDR3 AACCCCCCCTTACTACTACGGCACCAACAACGCCGAGGCCATGGACTAT BAP050- Plant I LC SEQ ID NO: 168 (Cabat) LCDR1 AGCTCTAGTCAGGATATCTCTAACTACCTGAAC SEQ ID NO: 169 (Cabat) LCDR1 TCCTCCAGCCAGGACATCTCCAACTACCTGAAC SEQ ID NO: 170 (Cabat) LCDR2 TACACTAGCACCCTGCACCTG SEQ ID NO: 171 (Kabat) LCDR2 TACACCTCCACCCTGCACCTG SEQ ID NO: 172 (Kabat) LCDR3 CAGCAGTACTATAACCTGCCCTGGACC SEQ ID NO: 173 (Cabat) LCDR3 CAGCAGTACTACAACCTGCCCTGGACC SEQ ID NO: 174 (Josiah) LCDR1 AGTCAGGATATCTCTAACTAC SEQ ID NO: 175 (Josiah) LCDR1 AGCCAGGACATCTCCAACTAC SEQ ID NO: 176 (Josiah) LCDR2 TACACTAGC SEQ ID NO: 177 (Josiah) LCDR2 TACACCTCC SEQ ID NO: 178 (Josiah) LCDR3 TACTATAACCTGCCCTGG SEQ ID NO: 179 (Josiah) LCDR3 TACTACAACCTGCCCTGG BAP050- Plant J HC SEQ ID NO: 180 (Cabat) HCDR1 AACTACGGGATGAAC SEQ ID NO: 159 (Kabat) HCDR1 AACTACGGCATGAAC SEQ ID NO: 181 (Cabat) HCDR2 TGGATTAACACCGACACCGGCGAGCCTACCTACGCCGACGACTTTAAGGGC SEQ ID NO: 161 (Cabat) HCDR2 TGGATCAACACCGACACCGGCGAGCCTACCTACGCCGACGACTTCAAGGGC SEQ ID NO: 182 (Cabat) HCDR3 AACCCCCCCTACTACTACGGCACTAACAACGCCGAGGCTATGGACTAC SEQ ID NO: 163 (Kabat) HCDR3 AACCCCCCCTTACTACTACGGCACCAACAACGCCGAGGCCATGGACTAT SEQ ID NO: 183 (Josiah) HCDR1 GGCTTCACCCTGACTAACTAC SEQ ID NO: 165 (Josiah) HCDR1 GGCTTCACCCTGACCAACTAC SEQ ID NO: 166 (Josiah) HCDR2 AACACCGACACCGGGGAG SEQ ID NO: 167 (Josiah) HCDR2 AACACCGACACCGGCGAG SEQ ID NO: 182 (Josiah) HCDR3 AACCCCCCCTACTACTACGGCACTAACAACGCCGAGGCTATGGACTAC SEQ ID NO: 163 (Josiah) HCDR3 AACCCCCCCTTACTACTACGGCACCAACAACGCCGAGGCCATGGACTAT BAP050- Plant J LC SEQ ID NO: 168 (Cabat) LCDR1 AGCTCTAGTCAGGATATCTCTAACTACCTGAAC SEQ ID NO: 169 (Cabat) LCDR1 TCCTCCAGCCAGGACATCTCCAACTACCTGAAC SEQ ID NO: 170 (Cabat) LCDR2 TACACTAGCACCCTGCACCTG SEQ ID NO: 171 (Kabat) LCDR2 TACACCTCCACCCTGCACCTG SEQ ID NO: 172 (Kabat) LCDR3 CAGCAGTACTATAACCTGCCCTGGACC SEQ ID NO: 173 (Cabat) LCDR3 CAGCAGTACTACAACCTGCCCTGGACC SEQ ID NO: 174 (Josiah) LCDR1 AGTCAGGATATCTCTAACTAC SEQ ID NO: 175 (Josiah) LCDR1 AGCCAGGACATCTCCAACTAC SEQ ID NO: 176 (Josiah) LCDR2 TACACTAGC SEQ ID NO: 177 (Josiah) LCDR2 TACACCTCC SEQ ID NO: 178 (Josiah) LCDR3 TACTATAACCTGCCCTGG SEQ ID NO: 179 (Josiah) LCDR3 TACTACAACCTGCCCTGG Other Exemplary LAG-3 Inhibitors

In one embodiment, the LAG-3 inhibitor is an anti-LAG-3 antibody molecule. In one embodiment, the LAG-3 inhibitor is BMS-986016 (Bristol-Myers Squibb), also known as BMS986016. BMS-986016 and other anti-LAG-3 antibodies are disclosed in WO 2015/116539 and US 9,505,839. In one embodiment, the anti-LAG-3 antibody molecule comprises one or more of the following: the CDR sequence of BMS-986016 (or all CDR sequences in general), the heavy chain or light chain variable region sequence, or the heavy chain or Light chain sequences, for example, are disclosed in Table 8.

In one embodiment, the anti-LAG-3 antibody molecule is TSR-033 (Tessaro). In one embodiment, the anti-LAG-3 antibody molecule comprises one or more of the following: TSR-033 CDR sequence (or all CDR sequences in general), heavy chain or light chain variable region sequence, or 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 disclosed in WO 2008/132601 and US 9,244,059. In one embodiment, the anti-LAG-3 antibody molecule comprises one or more of the following: the CDR sequence of IMP731 (or all CDR sequences in general), the heavy chain or light chain variable region sequence, or the heavy chain or light chain Sequences, for example, are disclosed in Table 8. In one embodiment, the anti-LAG-3 antibody molecule comprises one or more of the following: CDR sequences (or generally all CDR sequences) of GSK2831781, heavy chain or light chain variable region sequences, or heavy chain or light chain sequence.

In one embodiment, the anti-LAG-3 antibody molecule is IMP761 (Prima Biopharma). In one embodiment, the anti-LAG-3 antibody molecule comprises one or more of the following: the CDR sequence of IMP761 (or all CDR sequences in general), the heavy chain or light chain variable region sequence, or the heavy chain or light chain sequence.

Other known anti-LAG-3 antibodies include, for example, those described in WO 2008/132601, WO 2010/019570, WO 2014/140180, WO 2015/116539, WO 2015/200119, WO 2016/028672, US 9,244,059, US 9,505,839 .

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

In one embodiment, the anti-LAG-3 inhibitor is a soluble LAG-3 protein, eg, IMP321 (Prima Biopharma), eg, as disclosed in WO 2009/044273. [ Table 8 ] . Amino acid sequences of other exemplary anti-LAG-3 antibody molecules BMS-986016 SEQ ID NO: 184 heavy chain QVQLQQWGAGLLKPSETLSLTCAVYGGSFSDYYWNWIRQPPGKGLEWIGEINHRGSTNSNPSLKSRVTLSLDTSKNQFSLKLRSVTAADTAVYYCAFGYSDYEYNWFDPWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO: 185 light chain EIVLTQSPATLSSLSPGERATLSCRASQSISSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFLTISSLEPEDFAVYYCQQRSNWPLTFGQGTNLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLNFGLRRADGYEKHKVYACEVKS IMP731 SEQ ID NO: 186 heavy chain QVQLKESGPGLVAPSQSLSITCTVSGFSLTAYGVNWVRQPPGKGLEWLGMIWDDGSTDYNSALKSRLSISKDNSKSQVFLKMNSLQTDDTARYYCAREGDVAFDYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 187 light chain DIVMTQSPSSLAVSVGQKVTMSCKSSQSLLNGSNQKNYLAWYQQKPGQSPKLLVYFASTRDSGVPDRFIGSGSGTDFLTLTISSVQAEDLADYFCLQHFGTPPTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKFSTYSLSSTLTLKGLNSKADYECSK TIM-3 inhibitor

In certain embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of TIM-3. In some embodiments, a TGFβ inhibitor of the present disclosure (and/or a PD1, PD-L1, or PD-L2 inhibitor) is used in combination with a TIM-3 inhibitor to treat a disease (eg, cancer). In some embodiments, the TIM-3 inhibitor is MGB453 (Novartis), LY3321367 (Eli Lilly), Sym023 (Symphogen), BGB-A425 (Baekje), INCAGN-2390 (Aeginas/Inset), MBS-986258 (BMS/Five Prime), RO-7121661 (Roche), LY-3415244 (Eli Lilly), or TSR-022 ( Tessaro Corporation). 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 the August 6, 2015 publication entitled "Antibody Molecules to TIM-3 and Uses Thereof [TIM-3's antibody molecule and its use]" Disclosed in published US 2015/0218274.

In one embodiment, the anti-TIM-3 antibody molecule comprises at least one, two, three, four, five or six complementarity determining regions (CDRs) (or a total of All CDRs above), the heavy and light chain variable regions comprising the amine groups shown in Table 9 (for example, the heavy and light chain variable region sequences from ABTIM3-hum11 or ABTIM3-hum03 disclosed in Table 9) acid sequence, or encoded by the nucleotide sequence shown in Table 9. In some embodiments, the CDRs are defined according to Kabat (eg, as listed in Table 9). In some embodiments, the CDRs are defined according to Josiah (eg, as listed in Table 9). In one embodiment, relative to the amino acid sequence shown in Table 9, or encoded by the nucleotide sequence shown in Table 9, one or more of the CDRs (or generally all CDRs) have a , two, three, four, five, six or more changes, such as amino acid substitutions (eg, conservative amino acid substitutions) or deletions.

In one embodiment, the anti-TIM-3 antibody molecule comprises: the VHCDR1 amino acid sequence comprising SEQ ID NO: 189, the VHCDR2 amino acid sequence of SEQ ID NO: 190, and the VHCDR3 amino acid sequence of SEQ ID NO: 191 The heavy chain variable region (VH) of the sequence; and the VLCDR1 amino acid sequence comprising SEQ ID NO: 198, the VLCDR2 amino acid sequence of SEQ ID NO: 199, and the VLCDR3 amino acid sequence of SEQ ID NO: 200 Light chain variable regions (VL), each disclosed in Table 9. In one embodiment, the anti-TIM-3 antibody molecule comprises: VHCDR1 amino acid sequence comprising SEQ ID NO: 189, VHCDR2 amino acid sequence of SEQ ID NO: 208, and VHCDR3 amino acid sequence of SEQ ID NO: 191 The heavy chain variable region (VH) of the sequence; and the VLCDR1 amino acid sequence comprising SEQ ID NO: 198, the VLCDR2 amino acid sequence of SEQ ID NO: 199, and the VLCDR3 amino acid sequence of SEQ ID NO: 200 Light chain variable regions (VL), each disclosed in Table 9.

In one embodiment, the anti-TIM-3 antibody molecule comprises a VH that comprises the amino acid sequence of SEQ ID NO: 194, or at least 85%, 90%, 95%, or 99% identical to SEQ ID NO: 194 or higher identity amino acid sequences. In one embodiment, the anti-TIM-3 antibody molecule comprises a VL comprising the amino acid sequence of SEQ ID NO: 204, or at least 85%, 90%, 95%, or 99% identical to SEQ ID NO: 204 or higher identity amino acid sequences. In one embodiment, the anti-TIM-3 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 210, or having at least 85%, 90%, 95%, or 99% of the amino acid sequence of SEQ ID NO: 210 or higher identity amino acid sequences. In one embodiment, the anti-TIM-3 antibody molecule comprises a VL comprising the amino acid sequence of SEQ ID NO: 214, or at least 85%, 90%, 95%, or 99% identical to SEQ ID NO: 214 or higher identity amino acid sequences. In one embodiment, the anti-TIM-3 antibody molecule comprises: VH comprising the amino acid sequence of SEQ ID NO: 194 and VL comprising the amino acid sequence of SEQ ID NO: 204. In one embodiment, the anti-TIM-3 antibody molecule comprises: VH comprising the amino acid sequence of SEQ ID NO: 210 and VL comprising the amino acid sequence of SEQ ID NO: 214.

In one embodiment, the antibody molecule comprises a VH consisting of the nucleotide sequence of SEQ ID NO: 195, or at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 195 Sexual nucleotide sequence code. In one embodiment, the antibody molecule comprises a VL consisting of the nucleotide sequence of SEQ ID NO: 205, or at least 85%, 90%, 95%, or 99% or higher identical to SEQ ID NO: 205 Sexual nucleotide sequence code. In one embodiment, the antibody molecule comprises a VH consisting of the nucleotide sequence of SEQ ID NO: 211, or at least 85%, 90%, 95%, or 99% or more identical to SEQ ID NO: 211 Sexual nucleotide sequence code. In one embodiment, the antibody molecule comprises a VL consisting of the nucleotide sequence of SEQ ID NO: 215, or at least 85%, 90%, 95%, or 99% or higher identical to SEQ ID NO: 215 Sexual nucleotide sequence code. In one embodiment, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 195 and a VL encoded by the nucleotide sequence of SEQ ID NO: 205. In one embodiment, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 211 and a VL encoded by the nucleotide sequence of SEQ ID NO: 215.

In one embodiment, the anti-TIM-3 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 196, or at least 85%, 90%, 95%, or Amino acid sequences with 99% or greater identity. In one embodiment, an anti-TIM-3 antibody molecule comprises a light chain comprising the amino acid sequence of SEQ ID NO: 206, or at least 85%, 90%, 95%, or Amino acid sequences with 99% or greater identity. In one embodiment, the anti-TIM-3 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 212, or at least 85%, 90%, 95%, or Amino acid sequences with 99% or greater identity. In one embodiment, the anti-TIM-3 antibody molecule comprises a light chain comprising the amino acid sequence of SEQ ID NO: 216, or at least 85%, 90%, 95%, or Amino acid sequences with 99% or greater identity. In one embodiment, the anti-TIM-3 antibody molecule comprises: a heavy chain comprising the amino acid sequence of SEQ ID NO: 196 and a light chain comprising the amino acid sequence of SEQ ID NO: 206. In one embodiment, the anti-TIM-3 antibody molecule comprises: a heavy chain comprising the amino acid sequence of SEQ ID NO: 212 and a light chain comprising the amino acid sequence of SEQ ID NO: 216.

In one embodiment, the antibody molecule comprises a heavy chain consisting of the nucleotide sequence of SEQ ID NO: 197, or having at least 85%, 90%, 95%, or 99% or more with SEQ ID NO: 197 Highly identical nucleotide sequence codes. In one embodiment, the antibody molecule comprises a light chain consisting of the nucleotide sequence of SEQ ID NO: 207, or having at least 85%, 90%, 95%, or 99% or more with SEQ ID NO: 207 Highly identical nucleotide sequence codes. In one embodiment, the antibody molecule comprises a heavy chain consisting of the nucleotide sequence of SEQ ID NO: 213, or having at least 85%, 90%, 95%, or 99% or more with SEQ ID NO: 213 Highly identical nucleotide sequence codes. In one embodiment, the antibody molecule comprises a light chain consisting of the nucleotide sequence of SEQ ID NO: 217, or having at least 85%, 90%, 95%, or 99% or more with SEQ ID NO: 217 Highly identical nucleotide sequence codes. In one embodiment, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 197 and a light chain encoded by the nucleotide sequence of SEQ ID NO: 207. In one embodiment, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 213 and a light chain encoded by the nucleotide sequence of SEQ ID NO: 217.

The antibody molecules described herein can be produced by vectors, host cells, and methods described in US 2015/0218274. [ Table 9 ]. Amino acid and nucleotide sequences of exemplary anti-TIM-3 antibody molecules ABTIM3-hum11 SEQ ID NO: 189 (Cabat) HCDR1 SYNMH SEQ ID NO: 190 (Cabat) HCDR2 DIYPGNGDTSYNQKFKG SEQ ID NO: 191 (Cabat) HCDR3 VGGAFPMDY SEQ ID NO: 192 (Josiah) HCDR1 GYTFTSY SEQ ID NO: 193 (Josiah) HCDR2 YPGNGD SEQ ID NO: 191 (Josiah) HCDR3 VGGAFPMDY SEQ ID NO: 194 VH QVQLVQSGAEVKKPGSSVKVSCKASGYTFTSYNMHWVRQAPGQGLEWMGDIYPGNGDTSYNQKFKGRVTITADKSTSTVYMELSSLRSEDTAVYYCARVGGAFPMDYWGQGTTVTVSS SEQ ID NO: 195 DNA VH CAGGTGCAGCTGGTGCAGTCAGGCGCCGAAGTGAAGAAACCCGGCTCTAGCGTGAAAGTTTCTTGTAAAGCTAGTGGCTACACCTTCACTAGCTATAATATGCACTGGGTTCGCCAGGCCCCAGGGCAAGGCCTCGAGTGGATGGGCGATATCTACCCCGGGAACGGCGACACTAGTTATAATCAGAAGTTTAAGGGTAGAGTCACTATCACCGCCGATAAGTCTACTAGCACCGTCTATATGGAACTGAGTTCCCTGAGGTCTGAGGACACCGCCGTCTACTACTGCGCTAGAGTGGGCGGAGCCTTCCCTATGGACTACTGGGGTCAAGGCACTACCGTGACCGTGTCTAGC SEQ ID NO: 196 heavy chain QVQLVQSGAEVKKPGSSVKVSCKASGYTFTSYNMHWVRQAPGQGLEWMGDIYPGNGDTSYNQKFKGRVTITADKSTSTVYMELSSLRSEDTAVYYCARVGGAFPMDYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG SEQ ID NO: 197 DNA heavy chain CAGGTGCAGCTGGTGCAGTCAGGCGCCGAAGTGAAGAAACCCGGCTCTAGCGTGAAAGTTTCTTGTAAAGCTAGTGGCTACACCTTCACTAGCTATAATATGCACTGGGTTCGCCAGGCCCCAGGGCAAGGCCTCGAGTGGATGGGCGATATCTACCCCGGGAACGGCGACACTAGTTATAATCAGAAGTTTAAGGGTAGAGTCACTATCACCGCCGATAAGTCTACTAGCACCGTCTATATGGAACTGAGTTCCCTGAGGTCTGAGGACACCGCCGTCTACTACTGCGCTAGAGTGGGCGGAGCCTTCCCTATGGACTACTGGGGTCAAGGCACTACCGTGACCGTGTCTAGCGCTAGCACTAAGGGCCCGTCCGTGTTCCCCCTGGCACCTTGTAGCCGGAGCACTAGCGAATCCACCGCTGCCCTCGGCTGCCTGGTCAAGGATTACTTCCCGGAGCCCGTGACCGTGTCCTGGAACAGCGGAGCCCTGACCTCCGGAGTGCACACCTTCCCCGCTGTGCTGCAGAGCTCCGGGCTGTACTCGCTGTCGTCGGTGGTCACGGTGCCTTCATCTAGCCTGGGTACCAAGACCTACACTTGCAACGTGGACCACAAGCCTTCCAACACTAAGGTGGACAAGCGCGTCGAATCGAAGTACGGCCCACCGTGCCCGCCTTGTCCCGCGCCGGAGTTCCTCGGCGGTCCCTCGGTCTTTCTGTTCCCACCGAAGCCCAAGGACACTTTGATGATTTCCCGCACCCCTGAAGTGACATGCGTGGTCGTGGACGTGTCACAGGAAGATCCGGAGGTGCAGTTCAATTGGTACGTGGATGGCGTCGAGGTGCACAACGCCAAAACCAAGCCGAGGGAGGAGCAGTTCAACTCCACTTACCGCGTCGTGTCCGTGCTGACGGTGCTGCATCAGGACTGGCTGAACGGGAAGGAGTACAAGTGCAAAGTGTCCAACAAGGGACTTCCTAGCTCAATCGAAAAGACCA TCTCGAAAGCCAAGGGACAGCCCCGGGAACCCCAAGTGTATACCCTGCCACCGAGCCAGGAAGAAATGACTAAGAACCAAGTCTCATTGACTTGCCTTGTGAAGGGCTTCTACCCATCGGATATCGCCGTGGAATGGGAGTCCAACGGCCAGCCGGAAAACAACTACAAGACCACCCCTCCGGTGCTGGACTCAGACGGATCCTTCTTCCTCTACTCGCGGCTGACCGTGGATAAGAGCAGATGGCAGGAGGGAAATGTGTTCAGCTGTTCTGTGATGCATGAAGCCCTGCACAACCACTACACTCAGAAGTCCCTGTCCCTCTCCCTGGGA SEQ ID NO: 198 (Cabat) LCDR1 RASESVEYYGTSLMQ SEQ ID NO: 199 (Cabat) LCDR2 AAS NVES SEQ ID NO: 200 (Cabat) LCDR3 QQSRKDPST SEQ ID NO: 201 (Josiah) LCDR1 SESVEYYGTSL SEQ ID NO: 202 (Josiah) LCDR2 AAS SEQ ID NO: 203 (Josiah) LCDR3 SRKDPS SEQ ID NO: 204 VL AIQLTQSPSSLSASVGDRVTITCRASESVEYYGTSLMQWYQQKPGKAPKLLIYAASNVESGVPSRFSGSGSGTDFTLTISSLQPEDFATYFCQQSRKDPSTFGGGTKVEIK SEQ ID NO: 205 DNA VL GCTATTCAGCTGACTCAGTCACCTAGTAGCCTGAGCGCTAGTGTGGGCGATAGAGTGACTATCACCTGTAGAGCTAGTGAATCAGTCGAGTACTACGGCACTAGCCTGATGCAGTGGTATCAGCAGAAGCCCGGGAAAGCCCCTAAGCTGCTGATCTACGCCGCCTCTAACGTGGAATCAGGCGTGCCCTCTAGGTTTAGCGGTAGCGGTAGTGGCACCGACTTCACCCTGACTATCTCTAGCCTGCAGCCCGAGGACTTCGCTACCTACTTCTGTCAGCAGTCTAGGAAGGACCCTAGCACCTTCGGCGGAGGCACTAAGGTCGAGATTAAG SEQ ID NO: 206 light chain AIQLTQSPSSLSASVGDRVTITCRASESVEYYGTSLMQWYQQKPGKAPKLLIYAASNVESGVPSRFSGSGSGTDFTLTISSLQPEDFATYFCQQSRKDPSTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLGSKADYEVECKQGLS SEQ ID NO: 207 DNA light chain GCTATTCAGCTGACTCAGTCACCTAGTAGCCTGAGCGCTAGTGTGGGCGATAGAGTGACTATCACCTGTAGAGCTAGTGAATCAGTCGAGTACTACGGCACTAGCCTGATGCAGTGGTATCAGCAGAAGCCCGGGAAAGCCCCTAAGCTGCTGATCTACGCCGCCTCTAACGTGGAATCAGGCGTGCCCTCTAGGTTTAGCGGTAGCGGTAGTGGCACCGACTTCACCCTGACTATCTCTAGCCTGCAGCCCGAGGACTTCGCTACCTACTTCTGTCAGCAGTCTAGGAAGGACCCTAGCACCTTCGGCGGAGGCACTAAGGTCGAGATTAAGCGTACGGTGGCCGCTCCCAGCGTGTTCATCTTCCCCCCCAGCGACGAGCAGCTGAAGAGCGGCACCGCCAGCGTGGTGTGCCTGCTGAACAACTTCTACCCCCGGGAGGCCAAGGTGCAGTGGAAGGTGGACAACGCCCTGCAGAGCGGCAACAGCCAGGAGAGCGTCACCGAGCAGGACAGCAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCGACTACGAGAAGCATAAGGTGTACGCCTGCGAGGTGACCCACCAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAACAGGGGCGAGTGC ABTIM3-hum03 SEQ ID NO: 189 (Cabat) HCDR1 SYNMH SEQ ID NO: 208 (Cabat) HCDR2 DIYPGQGDTSYNQKFKG SEQ ID NO: 191 (Cabat) HCDR3 VGGAFPMDY SEQ ID NO: 192 (Josiah) HCDR1 GYTFTSY SEQ ID NO: 209 (Josiah) HCDR2 YPGQGD SEQ ID NO: 191 (Josiah) HCDR3 VGGAFPMDY SEQ ID NO: 210 VH QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYNMHWVRQAPGQGLEWIGDIYPGQGDTSYNQKFKGRATMTADKSTSTVYMELSSLRSEDTAVYYCARVGGAFPMDYWGQGTLVTVSS SEQ ID NO: 211 DNA VH CAGGTGCAGCTGGTGCAGTCAGGCGCCGAAGTGAAGAAACCCGGCGCTAGTGTGAAAGTTAGCTGTAAAGCTAGTGGCTATACTTTCACTTCTTATAATATGCACTGGGTCCGCCAGGCCCCAGGTCAAGGCCTCGAGTGGATCGGCGATATCTACCCCGGTCAAGGCGACACTTCCTATAATCAGAAGTTTAAGGGTAGAGCTACTATGACCGCCGATAAGTCTACTTCTACCGTCTATATGGAACTGAGTTCCCTGAGGTCTGAGGACACCGCCGTCTACTACTGCGCTAGAGTGGGCGGAGCCTTCCCAATGGACTACTGGGGTCAAGGCACCCTGGTCACCGTGTCTAGC SEQ ID NO: 212 heavy chain QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYNMHWVRQAPGQGLEWIGDIYPGQGDTSYNQKFKGRATMTADKSTSTVYMELSSLRSEDTAVYYCARVGGAFPMDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG SEQ ID NO: 213 DNA heavy chain CAGGTGCAGCTGGTGCAGTCAGGCGCCGAAGTGAAGAAACCCGGCGCTAGTGTGAAAGTTAGCTGTAAAGCTAGTGGCTATACTTTCACTTCTTATAATATGCACTGGGTCCGCCAGGCCCCAGGTCAAGGCCTCGAGTGGATCGGCGATATCTACCCCGGTCAAGGCGACACTTCCTATAATCAGAAGTTTAAGGGTAGAGCTACTATGACCGCCGATAAGTCTACTTCTACCGTCTATATGGAACTGAGTTCCCTGAGGTCTGAGGACACCGCCGTCTACTACTGCGCTAGAGTGGGCGGAGCCTTCCCAATGGACTACTGGGGTCAAGGCACCCTGGTCACCGTGTCTAGCGCTAGCACTAAGGGCCCGTCCGTGTTCCCCCTGGCACCTTGTAGCCGGAGCACTAGCGAATCCACCGCTGCCCTCGGCTGCCTGGTCAAGGATTACTTCCCGGAGCCCGTGACCGTGTCCTGGAACAGCGGAGCCCTGACCTCCGGAGTGCACACCTTCCCCGCTGTGCTGCAGAGCTCCGGGCTGTACTCGCTGTCGTCGGTGGTCACGGTGCCTTCATCTAGCCTGGGTACCAAGACCTACACTTGCAACGTGGACCACAAGCCTTCCAACACTAAGGTGGACAAGCGCGTCGAATCGAAGTACGGCCCACCGTGCCCGCCTTGTCCCGCGCCGGAGTTCCTCGGCGGTCCCTCGGTCTTTCTGTTCCCACCGAAGCCCAAGGACACTTTGATGATTTCCCGCACCCCTGAAGTGACATGCGTGGTCGTGGACGTGTCACAGGAAGATCCGGAGGTGCAGTTCAATTGGTACGTGGATGGCGTCGAGGTGCACAACGCCAAAACCAAGCCGAGGGAGGAGCAGTTCAACTCCACTTACCGCGTCGTGTCCGTGCTGACGGTGCTGCATCAGGACTGGCTGAACGGGAAGGAGTACAAGTGCAAAGTGTCCAACAAGGGACTTCCTAGCTCAATCGAAAAGACCA TCTCGAAAGCCAAGGGACAGCCCCGGGAACCCCAAGTGTATACCCTGCCACCGAGCCAGGAAGAAATGACTAAGAACCAAGTCTCATTGACTTGCCTTGTGAAGGGCTTCTACCCATCGGATATCGCCGTGGAATGGGAGTCCAACGGCCAGCCGGAAAACAACTACAAGACCACCCCTCCGGTGCTGGACTCAGACGGATCCTTCTTCCTCTACTCGCGGCTGACCGTGGATAAGAGCAGATGGCAGGAGGGAAATGTGTTCAGCTGTTCTGTGATGCATGAAGCCCTGCACAACCACTACACTCAGAAGTCCCTGTCCCTCTCCCTGGGA SEQ ID NO: 198 (Cabat) LCDR1 RASESVEYYGTSLMQ SEQ ID NO: 199 (Cabat) LCDR2 AAS NVES SEQ ID NO: 200 (Cabat) LCDR3 QQSRKDPST SEQ ID NO: 201 (Josiah) LCDR1 SESVEYYGTSL SEQ ID NO: 202 (Josiah) LCDR2 AAS SEQ ID NO: 203 (Josiah) LCDR3 SRKDPS SEQ ID NO: 214 VL DIVLTQSPDSLAVSLGERATINCRASESVEYYGTSLMQWYQQKPGQPPKLLIYAASNVESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQSRKDPSTFGGGTKVEIK SEQ ID NO: 215 DNA VL GATATCGTCCTGACTCAGTCACCCGATAGCCTGGCCGTCAGCCTGGGCGAGCGGGCTACTATTAACTGTAGAGCTAGTGAATCAGTCGAGTACTACGGCACTAGCCTGATGCAGTGGTATCAGCAGAAGCCCGGTCAACCCCCTAAGCTGCTGATCTACGCCGCCTCTAACGTGGAATCAGGCGTGCCCGATAGGTTTAGCGGTAGCGGTAGTGGCACCGACTTCACCCTGACTATTAGTAGCCTGCAGGCCGAGGACGTGGCCGTCTACTACTGTCAGCAGTCTAGGAAGGACCCTAGCACCTTCGGCGGAGGCACTAAGGTCGAGATTAAG SEQ ID NO: 216 light chain DIVLTQSPDSLAVSLGERATINCRASESVEYYGTSLMQWYQQKPGQPPKLLIYAASNVESGVPDRFSGSGSGTDFLTISSLQAEDVAVYYCQQSRKDPSTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEVKQHKSS SEQ ID NO: 217 DNA light chain GATATCGTCCTGACTCAGTCACCCGATAGCCTGGCCGTCAGCCTGGGCGAGCGGGCTACTATTAACTGTAGAGCTAGTGAATCAGTCGAGTACTACGGCACTAGCCTGATGCAGTGGTATCAGCAGAAGCCCGGTCAACCCCCTAAGCTGCTGATCTACGCCGCCTCTAACGTGGAATCAGGCGTGCCCGATAGGTTTAGCGGTAGCGGTAGTGGCACCGACTTCACCCTGACTATTAGTAGCCTGCAGGCCGAGGACGTGGCCGTCTACTACTGTCAGCAGTCTAGGAAGGACCCTAGCACCTTCGGCGGAGGCACTAAGGTCGAGATTAAGCGTACGGTGGCCGCTCCCAGCGTGTTCATCTTCCCCCCCAGCGACGAGCAGCTGAAGAGCGGCACCGCCAGCGTGGTGTGCCTGCTGAACAACTTCTACCCCCGGGAGGCCAAGGTGCAGTGGAAGGTGGACAACGCCCTGCAGAGCGGCAACAGCCAGGAGAGCGTCACCGAGCAGGACAGCAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCGACTACGAGAAGCATAAGGTGTACGCCTGCGAGGTGACCCACCAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAACAGGGGCGAGTGC Other Exemplary TIM-3 Inhibitors

In one embodiment, the anti-TIM-3 antibody molecule is TSR-022 (AnaptysBio/Tessaro). In one embodiment, the anti-TIM-3 antibody molecule comprises one or more of the following: CDR sequences of TSR-022 (or all CDR sequences in general), heavy chain or light chain variable region sequences, or heavy chain or light chain sequence. In one embodiment, the anti-TIM-3 antibody molecule comprises one or more of the following: APE5137 or APE5121 CDR sequences (or generally all CDR sequences), heavy chain or light chain variable region sequences, or heavy chain or Light chain sequences, eg, as disclosed in Table 10. APE5137, APE5121, and other anti-TIM-3 antibodies are disclosed in WO 2016/161270.

In one embodiment, the anti-TIM-3 antibody molecule is antibody plant F38-2E2. In one embodiment, the anti-TIM-3 antibody molecule comprises one or more of the following: F38-2E2 CDR sequence (or all CDR sequences in general), heavy chain or light chain variable region sequence, or heavy chain or light chain sequence.

In one embodiment, the anti-TIM-3 antibody molecule is LY3321367 (Eli Lilly). In one embodiment, the anti-TIM-3 antibody molecule comprises one or more of the following: the CDR sequence of LY3321367 (or all CDR sequences in general), the heavy chain variable region sequence and/or the light chain variable region sequence, Or heavy chain sequence and/or light chain sequence.

In one embodiment, the anti-TIM-3 antibody molecule is Sym023 (Symphogen). In one embodiment, the anti-TIM-3 antibody molecule comprises one or more of the following: the CDR sequence of Sym023 (or all CDR sequences in general), the heavy chain variable region sequence and/or the light chain variable region sequence, Or heavy chain sequence and/or light chain sequence.

In one embodiment, the anti-TIM-3 antibody molecule is BGB-A425 (Beigene). In one embodiment, the anti-TIM-3 antibody molecule comprises one or more of the following: the CDR sequence of BGB-A425 (or all CDR sequences in general), the heavy chain variable region sequence and/or the light chain variable region sequence, or heavy chain sequence and/or light chain sequence.

In one embodiment, the anti-TIM-3 antibody molecule is INCAGN-2390 (Agenus/Incyte). In one embodiment, the anti-TIM-3 antibody molecule comprises one or more of the following: the CDR sequence of INCAGN-2390 (or all CDR sequences in general), the heavy chain variable region sequence and/or the light chain variable region sequence , or a heavy chain sequence and/or a light chain sequence.

In one embodiment, the anti-TIM-3 antibody molecule is BMS-986258 (BMS/Five Columns). In one embodiment, the anti-TIM-3 antibody molecule comprises one or more of the following: the CDR sequence of BMS-986258 (or all CDR sequences in general), the heavy chain variable region sequence and/or the light chain variable region sequence , or a heavy chain sequence and/or a light chain sequence.

In one embodiment, the anti-TIM-3 antibody or inhibitor molecule is RO-7121661 (Roche). In one embodiment, the anti-TIM-3 antibody molecule comprises one or more of the following: the CDR sequence (or generally all CDR sequences) of the TIM-3 binding arm of RO-7121661, the heavy chain variable region sequence and/or A light chain variable region sequence, or a heavy chain sequence and/or a light chain sequence.

In one embodiment, the anti-TIM-3 antibody or inhibitor molecule is LY-3415244 (Eli Lilly). In one embodiment, the anti-TIM-3 antibody molecule comprises one or more of the following: the CDR sequence (or generally all CDR sequences) of the TIM-3 binding arm of LY-3415244, the heavy chain variable region sequence and/or A light chain variable region sequence, or a heavy chain sequence and/or a light chain sequence.

Other known anti-TIM-3 antibodies include, for example , those described in WO 2016/111947, WO 2016/071448, WO 2016/144803, US 8,552,156, US 8,841,418, and US 9,163,087.

In one embodiment, the anti-TIM-3 antibody competes for binding to and/or binds to the same epitope on TIM-3 as one of the anti-TIM-3 antibodies described herein Antibody. [ Table 10 ] . Amino acid sequences of other exemplary anti-TIM-3 antibody molecules APE5137 SEQ ID NO: 218 VH EVQLLESGGGLVQPGGSLRLSCAAASGFTFSSYDMSWVRQAPGKGLDWVSTISGGGTYTYYQDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASMDYWGQGTTVTVSSA SEQ ID NO: 219 VL DIQMTQSPSSLSASVGDRVTITCRASQSIRRYLNWYHQKPGKAPKLLIYGASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFAVYYCQQSHSAPLTFGGGTKVEIKR APE5121 SEQ ID NO: 220 VH EVQVLESGGGLVQPGGSLRLYCVASGFTFSGSYAMSWVRQAPGKGLEWVSAISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKKYYVGPADYWGQGTLVTVSSG SEQ ID NO: 221 VL DIVMTQSPDSLAVSLGERATINCKSSQSVLYSSNNKNYLAWYQHKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYSSPLTFGGGTKIEVK Cytokines

In yet another embodiment, the TGFβ inhibitor (and/or PD1, PD-L1, or PD-L2 inhibitor) of the present disclosure is combined with one or more cytokines (including but not limited to interferon, IL-2 , IL-15, IL-7, or IL21) in combination. In certain embodiments, a TGFβ inhibitor (and/or a PD1, PD-L1, or PD-L2 inhibitor) 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 AG), ATL-803 (Altor) or CYP0150 (Cytune) . Exemplary IL-15/IL-15Ra complexes

In one embodiment, the cytokine is IL-15 complexed with a soluble form of IL-15 receptor alpha (IL-15Ra). The IL-15/IL-15Ra complex may comprise a soluble form of IL-15 bound covalently or non-covalently to IL-15Ra. In a specific embodiment, human IL-15 is non-covalently associated with a soluble form of IL-15Ra. In a particular embodiment, the human IL-15 of the formulation comprises the amino acid sequence of SEQ ID NO: 222 in Table 11 or has at least 85%, 90%, 95%, or 99% of SEQ ID NO: 222, or higher identity amino acid sequence, and the soluble form of human IL-15Ra comprises the amino acid sequence of SEQ ID NO: 223 in Table 11 or has at least 85%, 90%, An amino acid sequence of 95%, or 99%, or higher identity, as described in WO 2014/066527. The molecules described herein can be produced by vectors, host cells, and methods described in WO 2007084342. [ Table 11 ] . Amino acid and nucleotide sequences of exemplary IL-15/IL-15Ra complexes NIZ985 SEQ ID NO: 222 hIL-15 NWVNVISDLKKIEDLIQSMHIDATLYTESDVHPSCKVTAMKCFLLELQVISLESGDASIHDTVENLIILANNSLSSNGNVTESGCKECEELEEKNIKEFLQSFVHIVQMFINTS SEQ ID NO: 223 human soluble IL-15Ra ITCPPPMSVEHADIWVKSYSLYSRERYICNSGFKRKAGTSSLECVLNKATNVAHWTTPSLKCIRDPALVHQRPAPPSTVTTAGVTPQPESLSPSGKEPAASSPSSNNTAATTAAIVPGSQLMPSKSPSTGTTEISSHESSHGTPSQTTAKNWELTASASHQPPGVYPQG Other exemplary IL-15/IL-15Ra complexes

In one embodiment, the IL-15/IL-15Ra complex is ALT-803, IL-15/IL-15Ra Fc fusion protein (IL-15N72D:IL-15RaSu/Fc soluble complex). ALT-803 is described in WO 2008/143794. In one embodiment, the IL-15/IL-15Ra Fc fusion protein comprises the sequence disclosed in Table 12.

In one embodiment, the IL-15/IL-15Ra complex comprises IL-15 (CYP0150, Cyton Pharmaceuticals) fused to the sushi domain of IL-15Ra. The sushi domain of IL-15Ra refers to the domain that starts at the first cysteine residue after the message peptide of IL-15Ra and ends at the fourth cysteine residue after the message peptide. Complexes of IL-15 fused to the sushi domain of IL-15Ra are described in WO 2007/04606 and WO 2012/175222. In one embodiment, the IL-15/IL-15Ra sushi domain fusion comprises the sequence as disclosed in Table 12. [ Table 12 ] . Amino acid sequences of other exemplary IL-15/IL-15Ra complexes ALT-803 SEQ ID NO: 224 IL-15N72D NWVNVISDLKKIEDLIQSMHIDATLYTESDVHPSCKVTAMKCFLLELQVISLESGDASIHDTVENLIILANDSLSSNGNVTESGCKECEELEEKNIKEFLQSFVHIVQMFINTS SEQ ID NO: 225 IL-15RaSu/Fc ITCPPPMSVEHADIWVKSYSLYSRERYICNSGFKRKAGTSSLTECVLNKATNVAHWTTPSLKCIREPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK IL-15/IL-15Ra sushi domain fusion ( CYP0150 ) SEQ ID NO: 226 hIL-15 NWVNVISDLKKIEDLIQSMHIDATLYTESDVHPSCKVTAMKCFLLELQVISLESGDASIHDTVENLIILANNSLSSNGNVTESGCKECEELEXKNIKEFLQSFVHIVQMFINTS where X is E or K SEQ ID NO: 227 Human IL-15Ra sushi and hinge domain ITCPPPMSVEHADIWVKSYSLYSRERYICNSGFKRKAGTSSLETCVLNKATNVAHWTTPSLKCIRDPALVHQRPAPP

In yet another embodiment, a TGFβ inhibitor of the present disclosure (and/or a PD1, PD-L1, or PD-L2 inhibitor) is combined with one or more toll-like receptors (TLRs, such as TLR7, TLR8, TLR9) combination of agonists to treat diseases such as cancer. In some embodiments, the compounds of the present disclosure can be used in combination with a TLR7 agonist or a TLR7 agonist conjugate.

In some embodiments, the TLR7 agonist comprises a compound disclosed in International Application Publication No. WO2011/049677. In some embodiments, the TLR7 agonist comprises 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)- 2-methylphenethyl)benzo[f][1,7]nalidin-8-yl)propanoic acid. In some embodiments, the TLR7 agonist comprises a compound having the formula:

In another embodiment, a TGFβ inhibitor of the present disclosure (and/or a PD1, PD-L1, or PD-L2 inhibitor) is used in combination with one or more angiogenesis inhibitors to treat cancer, such as: bevacizumab Monoclonal antibody (Avastin®), axitinib (Inlyta®); Brivanib alaninate (BMS-582664, ( S )-(( R )-1-(4-(4 -Fluoro-2-methyl- 1H -indol-5-yloxy)-5-methylpyrrolo[2,1- f ][1,2,4]tril-6-yloxy) propan-2-yl)2-aminopropionic acid); sorafenib (Nexavar®); pazopanib (Votrient®); sunitinib malate (Sutent®); (AZD2171, CAS 288383-20-1); Vargatef (BIBF1120, CAS 928326-83-4); Foretinib (GSK1363089); Telatinib (BAY57-9352 , CAS 332012-40-5); Apatinib (YN968D1, CAS 811803-05-1); Imatinib (Gleevec®); Ponatinib (AP24534, CAS 943319 -70-8); Tivozanib (AV951, CAS 475108-18-0); Regorafenib (BAY73-4506, CAS 755037-03-7); Vatalanib di-salt Vatalanib dihydrochloride (PTK787, CAS 212141-51-0); Brivanib (BMS-540215, CAS 649735-46-6); vandetanib (Caprelsa® or AZD6474); Motesanib diphosphate (AMG706, CAS 857876-30-3, N-(2,3-dihydro-3,3-dimethyl-1H-indol-6-yl)-2-[ (4-pyridylmethyl)amino]-3-pyridinecarboxamide, described in PCT Publication No. WO 02/066470); Dovitinib dilactic acid (TKI258, CAS 852433-84 -2); Linfanib (ABT869, CAS 796967-16-3); Cabozantinib (XL184, CA S 849217-68-1); Lestaurtinib (CAS 111358-88-4); N-[5-[[[5-(1,1-dimethylethyl)-2-oxazole base]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide (BMS38703, CAS 345627-80-7); (3R,4R)-4-amino-1-((4- ((3-methoxyphenyl)amino)pyrrolo[2,1-f][1,2,4]tris-5-yl)methyl)piperidin-3-ol (BMS690514); N -(3,4-Dichloro-2-fluorophenyl)-6-methoxy-7-[[(3aα,5β,6aα)-octahydro-2-methylcyclopenta[ c ]pyrrole-5- base]methoxy]-4-quinazolinamine (XL647, CAS 781613-23-8); 4-methyl-3-[[1-methyl-6-(3-pyridyl)-1 H - Pyrazolo[3,4- d ]pyrimidin-4-yl]amino] -N- [3-(trifluoromethyl)phenyl]-benzamide (BHG712, CAS 940310-85-0); Or Apocyb (Eylea®).

When bevacizumab is used in combination with other therapeutic agents such as TGFβ inhibitors and/or PD-1 inhibitors, it can be administered intravenously to patients. For example, bevacizumab can be administered intravenously to a patient at a dose of 5 mg/kg. Bevacizumab may also be administered weekly, every two weeks, every three weeks, or every four weeks for a given period of time. For example, bevacizumab is administered at a dose of 5 mg/kg on days 1 and 15 of each cycle (eg, a 21-day or 28-day cycle).

In another embodiment, the TGFβ inhibitors (and/or PD1, PD-L1, or PD-L2 inhibitors) of the present disclosure are used in combination with one or more heat shock protein inhibitors to treat cancer, for example: tanspirin Tanespimycin (17-allylamino-17-desmethoxygeldanamycin, also known as KOS-953 and 17-AAG, available from SIGMA and described in U.S. Patent No. 4,261,989); Retaspimycin (IPI504), Ganetespib (STA-9090); [6-chloro-9-(4-methoxy-3,5-dimethyl Pyridin-2-ylmethyl)-9H-purin-2-yl]amine (BIIB021 or -CNF2024, CAS 848695-25-0); trans-4-[[2-(aminocarbonyl)-5-[ 4,5,6,7-tetrahydro-6,6-dimethyl-4-oxo-3-(trifluoromethyl)-1 H -indazol-1-yl]phenyl]amino] Cyclohexylglycinate (SNX5422 or PF04929113, CAS 908115-27-5); 5-[2,4-Dihydroxy-5-(1-methylethyl)phenyl] -N -ethyl-4- [4-(4-𠰌linylmethyl)phenyl]-3-isoxazolamide (AUY922, CAS 747412-49-3); or 17-dimethylaminoethylamino-17- Demethoxygeldanamycin (17-DMAG).

In yet another embodiment, a TGFβ inhibitor of the present disclosure (and/or a PD1, PD-L1, or PD-L2 inhibitor) is used in combination with one or more HDAC inhibitors or other epigenetic modifiers. Exemplary HDAC inhibitors include, but are not limited to, Voninostat (Zolinza®); Romidepsin (Istodax®); Treichostatin A (TSA); Oxamflatin; Vorinostat (Zolinza®, suberoylaniline hydroxamic acid); Pyroxamide (syberoyl-3-aminopyridinamide hydroxamic acid); Trapoxin A (RF-1023A); Trapoxin B (RF- 10238); cyclo[(α S ,2 S )-α-amino-η-oxo-2-oxiranyl-octyl- O -methyl-D-tyryl-L-isoleucyl -L-prolinyl](Cyl-1); cyclo[(α S ,2 S )-α-amino-η-oxo-2-oxiranyloctyl- O -methyl-D-phenol Amido-L-isoleucyl-( 2S )-2-piperidinylcarbonyl](Cyl-2); Cyclo[L-Alanyl-D-Alanyl-(2S)-n L-α-aminooxirane octyl-D-prolinyl] (HC-toxin); cyclo[(α S ,2 S )-α-amino-η-oxo-2-oxirane Alkyloctyl-D-phenylpropanyl-L-leucyl-(2 S )-2-piperidinecarbonyl] (WF-3161); Chlamydocin ((S)-cyclo(2- Methacrylamide-L-phenylalanyl-D-prolinyl-η-oxo-L-α-aminooxiranyl octyl); histone deacetylase inhibitor (Apicidin) (cyclo (8-oxo-L-2-aminodecyl-1-methoxy-L-tryptaminoyl-L-isoleucyl-D-2-piperidinecarbonyl); lomidyl Star (Istodax®, FR-901228); 4-Phenylbutyrate; Spiruchostatin A; Mylproin (valproic acid); Entinostat (MS-275, N-(2-aminophenyl) -4-[N-(pyridin-3-yl-methoxycarbonyl)-amino-methyl]-benzamide); Depudecin (4,5:8,9-bisanhydride-1,2,6 ,7,11-pentadeoxy-D- threo - D- ido -undec-1,6-dienol); 4-(acetylamino)-N-(2-aminophenyl) -Benzamide (also known as CI-994); N1-(2-aminophenyl)-N8-phenyl-suberamide (also known as BML-210); 4-(dimethylamine base)-N-(7-(hydroxylamino)-7-oxoheptyl)benzamide (also known as M344); (E)-3-(4-(((2-(1H- Indol-3-yl)ethyl)(2-hydroxyethyl)amino)-methyl)phenyl)-N-hydroxyacryloyl panobinostat (Farydak®); monostat (Mocetinostat) and belistat (also known as PXD101, Beleodaq®, or ( 2E ) -N -hydroxy-3-[3-(phenyl sulfamoyl)phenyl]prop-2-enamide) or chidamide (also known as CS055 or HBI-8000, (E)-N-(2-amino-5-fluorobenzene yl)-4-((3-(pyridin-3-yl)acrylamido)methyl)benzamide). Other epigenetic modifiers include but are not limited to inhibitors of EZH2 (enhancer of zeste homolog 2), EED (embryo ectoderm development) or LSD1 (lysine-specific histone demethylase 1A or KDM1A) .

In yet another embodiment, the TGFβ inhibitor (and/or PD1, PD-L1, or PD-L2 inhibitor) disclosed herein is combined with indoleamine-pyrrole 2,3-dioxygenase (IDO) ( For example, Indoximod (also known as NLG-8189), α-cyclohexyl-5H-imidazo[5,1-a]isoindole-5-ethanol (also known as NLG919), or (4E )-4-[(3-Chloro-4-fluoroanilino)-nitrosomethylene]-1,2,5-oxadiazol-3-amine (also known as INCB024360)) combination of drugs to treat cancer. chimeric antigen receptor

The present disclosure provides TGFβ inhibitors (and/or PD1, PD-L1, or PD-L2 inhibitors) for use in combination with adoptive immunotherapy methods and agents, such as chimeric antigen receptor (CAR) immune effector cells (such as T cells), or chimeric TCR-transduced immune effector cells (e.g., T cells). This section describes commonly used TGFβ inhibitors (and/or PD1, PD-L1, or PD-L2 inhibitors) Combinatorial CAR technology, and CAR reagents (eg, cells and compositions) and methods are described.

In general, aspects of the present disclosure pertain to or include an isolated nucleic acid molecule encoding a chimeric antigen receptor (CAR), wherein the CAR comprises an antigen-binding domain (e.g., an antibody or an antibody) that binds a tumor antigen as described herein. fragment, TCR or TCR fragment), transmembrane domains (e.g., transmembrane domains described herein), and intracellular signaling domains (e.g., intracellular signaling domains described herein) (e.g., including costimulatory domains (eg, costimulatory domains described herein) and/or primary signaling domains (eg, primary signaling domains described herein). In other aspects, the present disclosure includes: Host cells for nucleic acids and isolated proteins encoded by such nucleic acid molecules. The CAR nucleic acid constructs, encoded proteins, vectors contained, host cells, pharmaceutical compositions, and methods of administration and treatment related to the present disclosure are listed in the International Patent It is disclosed in detail in the application publication number WO 2015142675.

In one aspect, the disclosure pertains to an isolated nucleic acid molecule encoding a chimeric antigen receptor (CAR), wherein the CAR comprises an antigen binding domain that binds a tumor-supporting antigen (e.g., a tumor-supporting antigen as described herein) (e.g., an antibody or antibody fragment, TCR or TCR fragment), a transmembrane domain (e.g., a transmembrane domain described herein), and an intracellular signaling domain (e.g., an intracellular signaling domain described herein) (e.g., an intracellular signaling domain and/or a primary signaling domain (e.g., a secondary signaling domain described herein) comprising a co-stimulatory domain (e.g., a co-stimulatory domain described herein). In some embodiments Among them, the tumor-supporting antigen is an antigen present on stromal cells or myeloid-derived suppressor cells (MDSC).In other aspects, the disclosure is characterized by polypeptides encoded by such nucleic acids and polypeptides containing such nucleic acids and/or polypeptides host cell.

Alternatively, aspects of the present disclosure pertain to isolated nucleic acids encoding chimeric T cell receptors (TCRs) comprising TCR alpha and/or TCR beta variable domains, specific for a cancer antigen described herein. See, eg, Dembic et al., Nature, 320, 232-238 (1986), Schumacher, Nat. Rev. Immunol . , 2, 512-519 (2002), Kershaw et al., Nat . Rev. Immunol. [Nature Review of Immunology] , 5, 928-940 (2005), Xue et al., Clin. Exp. Immunol. [Clinical and Experimental Immunology] , 139, 167-172 (2005), Rossig et al. People, Mol. Ther. [Molecular Therapy] , 10, 5-18 (2004), and Murphy et al., Immunity [Immunology] , 22, 403-414 (2005); (Morgan et al . J. Immunol. [Immunology Journal of Science] , 171, 3287-3295 (2003), Hughes et al., Hum.Gene Ther. [Human Gene Therapy] , 16, 1-16 (2005), Zhao et al., J. Immunol. [Journal of Immunology] , 174, 4415-4423 (2005), Roszkowski et al., Cancer Res. [Cancer Research] , 65, 1570-1576 (2005), and Engels et al., Hum. Gene Ther. [Human Gene Therapy] , 16, 799 -810 (2005); US2009/03046557. Such chimeric TCRs can recognize, for example, cancer antigens such as MART-1, gp-100, p53, and NY-ESO-1, MAGE A3/A6, MAGEA3, SSX2, HPV- 16 E6 or HPV-16 E7. In other aspects, the disclosure features polypeptides encoded by such nucleic acids and host cells containing such nucleic acids and/or polypeptides.

The sequences of non-limiting examples of different components that can be part of a CAR are listed in Table 11a, where "aa" represents an amino acid and "na" represents a nucleic acid encoding the corresponding peptide.

surface 11a. CAR The sequence of different components of ( aa- amino acid sequence, na- nucleic acid sequence). SEQ ID NO: illustrate sequence SEQ ID NO: 285 EF-1 promoter (na) CGTGAGGCTCCGGTGCCCGTCAGTGGGCAGAGCGCACATCGCCCACAGTCCCCGAGAAGTTGGGGGGAGGGGTCGGCAATTGAACCGGTGCCTAGAGAAGGTGGCGCGGGGTAAACTGGGAAAGTGATGTCGTGTACTGGCTCCGCCTTTTTCCCGAGGGTGGGGGAGAACCGTATATAAGTGCAGTAGTCGCCGTGAACGTTCTTTTTCGCAACGGGTTTGCCGCCAGAACACAGGTAAGTGCCGTGTGTGGTTCCCGCGGGCCTGGCCTCTTTACGGGTTATGGCCCTTGCGTGCCTTGAATTACTTCCACCTGGCTGCAGTACGTGATTCTTGATCCCGAGCTTCGGGTTGGAAGTGGGTGGGAGAGTTCGAGGCCTTGCGCTTAAGGAGCCCCTTCGCCTCGTGCTTGAGTTGAGGCCTGGCCTGGGCGCTGGGGCCGCCGCGTGCGAATCTGGTGGCACCTTCGCGCCTGTCTCGCTGCTTTCGATAAGTCTCTAGCCATTTAAAATTTTTGATGACCTGCTGCGACGCTTTTTTTCTGGCAAGATAGTCTTGTAAATGCGGGCCAAGATCTGCACACTGGTATTTCGGTTTTTGGGGCCGCGGGCGGCGACGGGGCCCGTGCGTCCCAGCGCACATGTTCGGCGAGGCGGGGCCTGCGAGCGCGGCCACCGAGAATCGGACGGGGGTAGTCTCAAGCTGGCCGGCCTGCTCTGGTGCCTGGCCTCGCGCCGCCGTGTATCGCCCCGCCCTGGGCGGCAAGGCTGGCCCGGTCGGCACCAGTTGCGTGAGCGGAAAGATGGCCGCTTCCCGGCCCTGCTGCAGGGAGCTCAAAATGGAGGACGCGGCGCTCGGGAGAGCGGGCGGGTGAGTCACCCACACAAAGGAAAAGGGCCTTTCCGTCCTCAGCCGTCGCTTCATGTGACTCCACGGAGTACCGGGCGCCGTCCAGGCACCTCGATTAGTTCTCGAGCTTTTGGAGTACGTCGTCTTTAGG TTGGGGGGAGGGGTTTTATGCGATGGAGTTTCCCCCACTGAGTGGGTGGAGACTGAAGTTAGGCCAGCTTGGCACTTGATGTAATTCTCCTTGGAATTTGCCCTTTTTGAGTTTGGATCTTGGTTCATTCTCAAGCCTCAGACAGTGGTTCAAAGTTTTTTTCTTCCATTTCAGGTGTCGTGA SEQ ID NO: 283 Leading sequence (aa) MALPVTALLLPLALLLLHAARP SEQ ID NO: 299 leading sequence (na) ATGGCCCTGCCTGTGACAGCCCTGCTGCTGCCTCTGGCTCTGCTGCTGCATGCCGCTAGACCC the SEQ ID NO: 300 leading sequence (na) ATGGCCCTCCCTGTCACCGCCCTGCTGCTTCCGCTGGCTCTTCTGCTCCACGCCGCTCGGCCC SEQ ID NO: 265 CD8 hinge (aa) TTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACD SEQ ID NO: 269 CD8 hinge (na) ACCACGACGCCAGCGCCGCGACCACCAACACCGGCGCCCACCATCGCGTCGCAGCCCCTGTCCCTGCGCCCAGAGGCGTGCCGGCCAGCGGCGGGGGGCGCAGTGCACACGAGGGGGCTGGACTTCGCCTGTGAT SEQ ID NO: 268 IgG4 hinge (aa) ESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGKM SEQ ID NO: 270 IgG4 hinge (na) GAGAGCAAGTACGGCCCTCCCTGCCCCCCTTGCCCTGCCCCCGAGTTCCTGGGCGGACCCAGCGTGTTCCTGTTCCCCCCCAAGCCCAAGGACACCCTGATGATCAGCCGGACCCCCGAGGTGACCTGTGTGGTGGTGGACGTGTCCCAGGAGGACCCCGAGGTCCAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCACAACGCCAAGACCAAGCCCCGGGAGGAGCAGTTCAATAGCACCTACCGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGACTGGCTGAACGGCAAGGAATACAAGTGTAAGGTGTCCAACAAGGGCCTGCCCAGCAGCATCGAGAAAACCATCAGCAAGGCCAAGGGCCAGCCTCGGGAGCCCCAGGTGTACACCCTGCCCCCTAGCCAAGAGGAGATGACCAAGAACCAGGTGTCCCTGACCTGCCTGGTGAAGGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAACGGCCAGCCCGAGAACAACTACAAGACCACCCCCCCTGTGCTGGACAGCGACGGCAGCTTCTTCCTGTACAGCCGGCTGACCGTGGACAAGAGCCGGTGGCAGGAGGGCAACGTCTTTAGCTGCTCCGTGATGCACGAGGCCCTGCACAACCACTACACCCAGAAGAGCCTGAGCCTGTCCCTGGGCAAGATG SEQ ID NO: 271 IgD hinge (aa) RWPESPKAQASSVPTAQPQAEGSLAKATTAPATTRNTGRGGEEKKKEKEKEEQEERETKTPECPSHTQPLGVYLLTPAVQDLWLRDKATFTCFVVGSDLKDAHLTWEVAGKVPTGGVEEGLLERHSNGSQSQHSRLTLPRSLWNAGTSVTCTLNHPSLPPQRLMALREPAAQAPVKLSLNLLASSDPPEAASWLLCEVSGFSPPNILLMWLEDQREVNTSGFAPARPPPQPGSTTFWAWSVLRVPAPPSPQPATYTCVVSHEDSRTLLNASRSLEVSYVTDH SEQ ID NO: 272 IgD hinge (na) AGGTGGCCCGAAAGTCCCAAGGCCCAGGCATCTAGTGTTCCTACTGCACAGCCCCAGGCAGAAGGCAGCCTAGCCAAAGCTACTACTGCACCTGCCACTACGCGCAATACTGGCCGTGGCGGGGAGGAGAAGAAAAAGGAGAAAGAGAAAGAAGAACAGGAAGAGAGGGAGACCAAGACCCCTGAATGTCCATCCCATACCCAGCCGCTGGGCGTCTATCTCTTGACTCCCGCAGTACAGGACTTGTGGCTTAGAGATAAGGCCACCTTTACATGTTTCGTCGTGGGCTCTGACCTGAAGGATGCCCATTTGACTTGGGAGGTTGCCGGAAAGGTACCCACAGGGGGGGTTGAGGAAGGGTTGCTGGAGCGCCATTCCAATGGCTCTCAGAGCCAGCACTCAAGACTCACCCTTCCGAGATCCCTGTGGAACGCCGGGACCTCTGTCACATGTACTCTAAATCATCCTAGCCTGCCCCCACAGCGTCTGATGGCCCTTAGAGAGCCAGCCGCCCAGGCACCAGTTAAGCTTAGCCTGAATCTGCTCGCCAGTAGTGATCCCCCAGAGGCCGCCAGCTGGCTCTTATGCGAAGTGTCCGGCTTTAGCCCGCCCAACATCTTGCTCATGTGGCTGGAGGACCAGCGAGAAGTGAACACCAGCGGCTTCGCTCCAGCCCGGCCCCCACCCCAGCCGGGTTCTACCACATTCTGGGCCTGGAGTGTCTTAAGGGTCCCAGCACCACCTAGCCCCCAGCCAGCCACATACACCTGTGTTGTGTCCCATGAAGATAGCAGGACCCTGCTAAATGCTTCTAGGAGTCTGGAGGTTTCCTACGTGACTGACCATT SEQ ID NO: 273 GS hinge/linker (aa) GGGGSGGGGS SEQ ID NO: 274 GS hinge/linker (na) GGTGGCGGAGGTTCTGGAGGTGGAGGTTCC SEQ ID NO: 266 CD8 transmembrane (aa) IYIWAPLAGTCGVLLLSLVITLYC SEQ ID NO: 267 CD8 transmembrane (na) ATCTACATCTGGGCGCCCTTGGCCGGGACTTGTGGGGTCCTTCTCCTGTCACTGGTTATCACCCTTACTGC SEQ ID NO: 301 CD8 transmembrane (na) ATCTACATTTGGGCCCCTCTGGCTGGTACTTGCGGGGTCCTGCTGCTTTCACTCGTGATCACTCTTTACTGT SEQ ID NO: 279 4-1BB intracellular domain (aa) KRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCEL the SEQ ID NO: 281 4-1BB intracellular domain (na) AAACGGGGCAGAAAGAAACTCCTGTATATATTCAAACAACCATTTATGAGACCAGTACAAACTACTCAAGAGGAAGATGGCTGTAGCTGCCGATTTCCAGAAGAAGAAGAAGGAGGATGTGAACTG SEQ ID NO: 302 4-1BB intracellular domain (na) AAGCGCGGTCGGAAGAAGCTGCTGTACATCTTTTAAGCAACCCTTCATGAGGCCTGTGCAGACTACTCAAGAGGAGGACGGCTGTTCATGCCGGTTCCCAGAGGAGGAGGAAGGCGGCTGCGAACTG SEQ ID NO: 280 CD27 (aa) QRRKYRSNKGESPVEPAEPCRYSCPREEEGSTIPIQEDYRKPEPACSP SEQ ID NO: 282 CD27 (na) CAACGAAGGAAATATAGATCAAACAAAGGAGAAAGTCCTGTGGAGCCTGCAGAGCCTTGTCGTTACAGCTGCCCCAGGGAGGAGGAGGGCAGCACCATCCCCATCCAGGAGGATTACCGAAAACCGGAGCCTGCCTGCTCCCCC SEQ ID NO: 275 CD3-ζ (aa) RVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR SEQ ID NO: 277 CD3-ζ (na) AGAGTGAAGTTCAGCAGGAGCGCAGACGCCCCCGCGTACAAGCAGGGCCAGAACCAGCTCTATAACGAGCTCAATCTAGGACGAAGAGAGGAGTACGATGTTTTGGACAAGAGACGTGGCCGGGACCCTGAGATGGGGGGAAAGCCGAGAAGGAAGAACCCTCAGGAAGGCCTGTACAATGAACTGCAGAAAGATAAGATGGCGGAGGCCTACAGTGAGATTGGGATGAAAGGCGAGCGCCGGAGGGGCAAGGGGCACGATGGCCTTTACCAGGGTCTCAGTACAGCCACCAAGGACACCTACGACGCCCTTCACATGCAGGCCCTGCCCCCTCGC SEQ ID NO: 303 CD3-ζ (na) CGCGTGAAATTCAGCCGCAGCGCAGATGCTCCAGCCTACAAGCAGGGGCAGAACCAGCTCTACAACGAACTCAATCTTGGTCGGAGAGAGGAGTACGACGTGCTGGACAAGCGGAGAGGACGGGACCCAGAAATGGGCGGGAAGCCGCGCAGAAAGAATCCCCAAGAGGGCCTGTACAACGAGCTCCAAAAGGATAAGATGGCAGAAGCCTATAGCGAGATTGGTATGAAAGGGGAACGCAGAAGAGGCAAAGGCCACGACGGACTGTACCAGGGACTCAGCACCGCCACCAAGGACACCTATGACGCTCTTCACATGCAGGCCCTGCCGCCTCGG SEQ ID NO: 276 CD3-ζ (aa) RVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR SEQ ID NO: 278 CD3-ζ (na) AGAGTGAAGTTCAGCAGGAGCGCAGACGCCCCCGCGTACCAGCAGGGCCAGAACCAGCTCTATAACGAGCTCAATCTAGGACGAAGAGAGGAGTACGATGTTTTGGACAAGAGACGTGGCCGGGACCCTGAGATGGGGGGAAAGCCGAGAAGGAAGAACCCTCAGGAAGGCCTGTACAATGAACTGCAGAAAGATAAGATGGCGGAGGCCTACAGTGAGATTGGGATGAAAGGCGAGCGCCGGAGGGGCAAGGGGCACGATGGCCTTTACCAGGGTCTCAGTACAGCCACCAAGGACACCTACGACGCCCTTCACATGCAGGCCCTGCCCCCTCGC SEQ ID NO: 304 Linker (aa) GGGGS SEQ ID NO: 305 PD-1 extracellular domain (aa) PGWFLDSPDRPWNPPTFSPALLVVTEGDNATFTCSFSNTSESFVLNWYRMSPSNQTDKLAAFPEDRSQPGQDCRFRVTQLPNGRDFHMSVVRARRNDSGTYLCGAISLAPKAQIKESLRAELRVTERRAEVPTAHPSPSPRPAGQFQTLV SEQ ID NO: 306 PD-1 extracellular domain (na) CCCGGATGGTTTCTGGACTCTCCGGATCGCCCGTGGAATCCCCCAACCTTCTCACCGGCACTCTTGGTTGTGACTGAGGGCGATAATGCGACCTTCACGTGCTCGTTCTCCAACACCTCCGAATCATTCGTGCTGAACTGGTACCGCATGAGCCCGTCAAACCAGACCGACAAGCTCGCCGCGTTTCCGGAAGATCGGTCGCAACCGGGACAGGATTGTCGGTTCCGCGTGACTCAACTGCCGAATGGCAGAGACTTCCACATGAGCGTGGTCCGCGCTAGGCGAAACGACTCCGGGACCTACCTGTGCGGAGCCATCTCGCTGGCGCCTAAGGCCCAAATCAAAGAGAGCTTGAGGGCCGAACTGAGAGTGACCGAGCGCAGAGCTGAGGTGCCAACTGCACATCCATCCCCATCGCCTCGGCCTGCGGGGCAGTTTCAGACCCTGGTC SEQ ID NO: 307 PD-1 CAR with signal (aa) MALPVTALLLPLALLLHAARPPGWFLDSPDRPWNPPTFSPALLVVTEGDNATFTCSFSNTSESFVLNWYRMSPSNQTDKLAAFPEDRSQPGQDCRFRVTQLPNGRDFHMSVVRARRNDSGTYLCGAISLAPKAQIKESLRAELRVTERRAEVPTAHPSPSPRPAGQFQTLVTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR SEQ ID NO: 308 PD-1 CAR (na) ATGGCCCTCCCTGTCACTGCCCTGCTTCTCCCCCTCGCACTCCTGCTCCACGCCGCTAGACCACCCGGATGGTTTCTGGACTCTCCGGATCGCCCGTGGAATCCCCCAACCTTCTCACCGGCACTCTTGGTTGTGACTGAGGGCGATAATGCGACCTTCACGTGCTCGTTCTCCAACACCTCCGAATCATTCGTGCTGAACTGGTACCGCATGAGCCCGTCAAACCAGACCGACAAGCTCGCCGCGTTTCCGGAAGATCGGTCGCAACCGGGACAGGATTGTCGGTTCCGCGTGACTCAACTGCCGAATGGCAGAGACTTCCACATGAGCGTGGTCCGCGCTAGGCGAAACGACTCCGGGACCTACCTGTGCGGAGCCATCTCGCTGGCGCCTAAGGCCCAAATCAAAGAGAGCTTGAGGGCCGAACTGAGAGTGACCGAGCGCAGAGCTGAGGTGCCAACTGCACATCCATCCCCATCGCCTCGGCCTGCGGGGCAGTTTCAGACCCTGGTCACGACCACTCCGGCGCCGCGCCCACCGACTCCGGCCCCAACTATCGCGAGCCAGCCCCTGTCGCTGAGGCCGGAAGCATGCCGCCCTGCCGCCGGAGGTGCTGTGCATACCCGGGGATTGGACTTCGCATGCGACATCTACATTTGGGCTCCTCTCGCCGGAACTTGTGGCGTGCTCCTTCTGTCCCTGGTCATCACCCTGTACTGCAAGCGGGGTCGGAAAAAGCTTCTGTACATTTTCAAGCAGCCCTTCATGAGGCCCGTGCAAACCACCCAGGAGGAGGACGGTTGCTCCTGCCGGTTCCCCGAAGAGGAAGAAGGAGGTTGCGAGCTGCGCGTGAAGTTCTCCCGGAGCGCCGACGCCCCCGCCTATAAGCAGGGCCAGAACCAGCTGTACAACGAACTGAACCTGGGACGGCGGGAAGAGTACGATGTGCTGGACAAGCGGCGCGGCCGGGACCCCGAAATGGGCGGGAAGCCTAGAAGAA AGAACCCTCAGGAAGGCCTGTATAACGAGCTGCAGAAGGACAAGATGGCCGAGGCCTACTCCGAAATTGGGATGAAGGGAGAGCGGCGGAGGGGAAAGGGGCACGACGGCCTGTACCAAGGACTGTCCACCGCCACCAAGGACACATACGATGCCCTGCACATGCAGGCCCTTCCCCCTCGC SEQ ID NO: 232 Linker (aa) (Gly-Gly-Gly-Ser)n, where n = 1-10 the SEQ ID NO: 230 Linker (aa) (Gly4 Ser)4 SEQ ID NO: 231 Linker (aa) (Gly4 Ser)3 SEQ ID NO: 309 Linker (aa) (Gly3Ser) SEQ ID NO: 310 Poly A (na) [a] _50-5000 SEQ ID NO: 311 PD1 CAR (aa) PGWFLDSPDRPWNPPTFSPALLVVTEGDNATFTCSFSNTSESFVLNWYRMSPSNQTDKLAAFPEDRSQPGQDCRFRVTQLPNGRDFHMSVVRARRNDSGTYLCGAISLAPKAQIKESLRAELRVTERRAEVPTAHPSPSPRPAGQFQTLV TTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR SEQ ID NO: 312 ICOS intracellular domain (aa) TKKKYSSSVHDPGEYMFMRAVNTAKKSRLTDVTL SEQ ID NO: 313 ICOS intracellular domain (na) ACAAAAAAGAAGTATCATCCAGTGTGCACGACCCTAACGGTGAATACATGTTCATGAGAGCAGTGAACACAGCCAAAAAATCCAGACTCACAGATGTGACCCTA SEQ ID NO: 314 ICOS™ domain (aa) TTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDFWLPIGCAAFVVVCILGCILICWL SEQ ID NO: 315 ICOS™ domain (na) ACCACGACGCCAGCGCCGCGACCACCAACACCGGCGCCCACCATCGCGTCGCAGCCCCTGTCCCTGCGCCCAGAGGCGTGCCGGCCAGCGGCGGGGGGCGCAGTGCACACGAGGGGCTGGACTTCGCCTGTGATTTCTGGTTACCCATAGGATGTGCAGCCTTTGTTGTAGTCTGCATTTTGGGATGCATACTTATTTGTTGGCTT SEQ ID NO: 316 CD28 intracellular domain (aa) RSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRS SEQ ID NO: 317 CD28 intracellular domain (na) AGGAGTAAGAGGAGCAGGCTCCTGCACAGTGACTACATGAACATGACTCCCCGCCGCCCCGGGCCCACCCGCAAGCATTACCAGCCCTATGCCCCACCACGCGACTTCGCAGCCTATCGCTCC target

The present disclosure provides cells, such as immune effector cells (e.g., T cells, NK cells) comprising or at any time comprising gRNA molecules or CRISPR systems as described herein, which immune effector cells are further engineered to contain the immune effector The cell is directed to one or more CARs of an undesired cell (eg, a cancer cell). This is achieved by an antigen-binding domain on the CAR that is specific for a cancer-associated antigen. There are two classes of cancer-associated antigens (tumor antigens) that can be targeted by the CARs of the present disclosure: (1) cancer-associated antigens expressed on the surface of cancer cells; and (2) cancer-associated antigens that are themselves intracellular, however, this Fragments of an antigen (peptide) are presented on the surface of cancer cells by MHC (major histocompatibility complex).

In some embodiments, the tumor antigen is selected from one or more of the following: CD19; CD123; CD22; CD30; CD171; CS-1 (also known as CD2 subgroup 1, CRACC, SLAMF7, CD319, and 19A24); C-type lectin-like molecule-1 (CLL-1 or CLECL1); CD33; epidermal growth factor receptor variant III (EGFRvIII); ganglioside G2 (GD2); ganglioside GD3 (aNeu5Ac(2-8 )aNeu5Ac(2-3)bDGalp(1-4)bDGlcp(1-1)Cer); TNF receptor family member B cell maturation (BCMA); Tn antigen ((Tn Ag) or (GalNAcα-Ser/Thr)) ; Prostate-specific membrane antigen (PSMA); Receptor tyrosine kinase-like orphan receptor 1 (ROR1); Fms-like tyrosine kinase 3 (FLT3); Tumor-associated glycoprotein 72 (TAG72); CD38; CD44v6; Cancer Embryonic antigen (CEA); Epithelial cell adhesion molecule (EPCAM); B7H3 (CD276); KIT (CD117); Interleukin-13 receptor subunit α-2 (IL-13Ra2 or CD213A2); Mesothelin; Prostate Stem Cell Antigen (PSCA); Protease Serine 21 (Testin or PRSS21); Vascular Endothelial Growth Factor Receptor 2 (VEGFR2); Lewis (Y) Antigen; CD24; Platelets Derived growth factor receptor beta (PDGFR-beta); stage-specific embryonic antigen-4 (SSEA-4); CD20; folate receptor alpha; receptor tyrosine protein kinase ERBB2 (Her2/neu); mucin 1 , cell surface associated (MUC1); epidermal growth factor receptor (EGFR); neural cell adhesion molecule (NCAM); prostatic enzyme; prostatic acid phosphatase (PAP); mutated elongation factor 2 (ELF2M); ephrin B2 ; Fibroblast Activation Protein α (FAP); Insulin-like Growth Factor 1 Receptor (IGF-I Receptor), Carbonic Anhydrase IX (CAIX); Proteasome (Prosome, Macropain) Subunit, β Type, 9 (LMP2 ); glycoprotein 100 (gp100); oncogene fusion protein (bcr-abl) consisting of breakpoint cluster region (BCR) and Abelson murine leukemia virus oncogene homolog 1 (Abl); tyrosinase; liver Ligandin type A receptor 2 (EphA2); fucosyl GM1; sialic acid Lewis adhesion molecule (sLe); ganglioside GM3 (aNeu5Ac(2-3)bDGalp(1-4)bDGlcp(1-1) Cer); Transglutaminase 5 (TGS5); High Molecular Weight-Melanoma-Associated Antigen (HMWMAA); o - Acetyl-GD2 ganglioside (OAcGD2); folate receptor beta; tumor endothelial marker 1 (TEM1/CD248); tumor endothelial marker 7-related (TEM7R); claudin 6 (CLDN6); Hormone receptor (TSHR); G protein-coupled receptor class C group 5, member D (GPRC5D); Chromosome X open reading frame 61 (CXORF61); CD97; CD179a; Anaplastic lymphoma kinase (ALK); Polysialic acid ; placenta-specific 1 (PLAC1); hexasaccharide moiety of globoH glycosylceramide (GloboH); mammary gland differentiation antigen (NY-BR-1); urolytic protein 2 (UPK2); hepatitis A virus cell receptor 1 (HAVCR1); adrenergic receptor beta 3 (ADRB3); pan-nexin 3 (PANX3); G protein-coupled receptor 20 (GPR20); lymphocyte antigen 6 complex, locus K 9 (LY6K); olfactory receptor TCR gamma alternative reading frame protein (TARP); Wilms tumor protein (WT1); Cancer/testis antigen 1 (NY-ESO-1); Cancer/testis antigen 2 (LAGE-1a); Melanoma-associated antigen 1 (MAGE-A1); ETS translocation variant gene 6, located on chromosome 12p (ETV6-AML); sperm protein 17 (SPA17); X antigen family, member 1A (XAGE1); angiopoietin binding Cell Surface Receptor 2 (Tie 2); Melanoma Cancer Testis Antigen-1 (MAD-CT-1); Melanoma Cancer Testis Antigen-2 (MAD-CT-2); Fos-Associated Antigen 1; Tumor Protein p53 (p53); p53 mutant; prostate-specific protein (prostein); surviving protein (surviving); telomerase; prostate cancer tumor antigen-1 (PCTA-1 or galectin 8), T cell 1 recognized Melanoma antigen (MelanA or MART1); rat sarcoma (Ras) mutant; human telomerase reverse transcriptase (hTERT); sarcoma translocation breakpoint; melanoma inhibitor of apoptosis (ML-IAP); ERG (transmembrane protease, serine 2 (TMPRSS2) ETS fusion gene); N-acetylglucosaminyltransferase V (NA17); paired box protein Pax-3 (PAX3); androgen receptor; cyclins B1; v-myc avian myeloma virus oncogene neuroblastoma-derived homolog (MYCN); Ras homolog family member C (RhoC); tyrosinase-related protein 2 (TRP-2); cytochrome P450 1B1 (CYP1B1); CCCTC-binding factor (zinc finger protein)-like (BORIS or Brother of the Regulator of Imprinted Sites), squamous cell recognized by T cells Stem cell carcinoma antigen (SART3); paired box protein Pax-5 (PAX5); preacrosomal protein sp32 (OY-TES1); lymphocyte-specific protein tyrosine kinase (LCK); kinase ankyrin 4 (AKAP -4); Synovial sarcoma, X breakpoint 2 (SSX2); Receptor for advanced glycation end products (RAGE-1); Renal ubiquitin 1 (RU1); Renal ubiquitin 2 (RU2); ; human papillomavirus E6 (HPV E6); human papillomavirus E7 (HPV E7); intestinal carboxylesterase; mutated heat shock protein 70-2 (mut hsp70-2); CD79a; CD79b; CD72; Leukocyte-associated immunoglobulin-like receptor 1 (LAIR1); Fc fragment of IgA receptor (FCAR or CD89); Leukocyte immunoglobulin-like receptor subfamily A member 2 (LILRA2); CD300 molecule-like family member f (CD300LF ); C-type lectin domain family 12 member A (CLEC12A); bone marrow stromal cell antigen 2 (BST2); EGF-like module-containing mucin-like hormone receptor-like 2 (EMR2); lymphocyte antigen 75 (LY75) Glypican-3 (GPC3); Fc receptor-like 5 (FCRL5); and Immunoglobulin lambda-like polypeptide 1 (IGLL1).

A CAR described herein may comprise an antigen binding domain (eg, an antibody or antibody fragment, TCR or TCR fragment) that binds a tumor-supporting antigen (eg, a tumor-supporting antigen as described herein). In some embodiments, the tumor-supporting antigen is an antigen present on a stromal cell or a myeloid-derived suppressor cell (MDSC). Stromal cells can secrete growth factors to promote cell division in the microenvironment. MDSC cells can inhibit T cell proliferation and activation. Without wishing to be bound by theory, in some embodiments, cells expressing the CAR destroy tumor-supporting cells, thereby indirectly inhibiting tumor growth or survival.

In an embodiment, the stromal cell antigen is selected from one or more of the following: bone marrow stromal cell antigen 2 (BST2), fibroblast activation protein (FAP) and tenascin. In an embodiment, the FAP-specific antibody is sirozumab, competes for binding with sirozumab, or has the same CDR as sirozumab. In an embodiment, the MDSC antigen is selected from one or more of: CD33, CD11b, C14, CD15, and CD66b. Therefore, in some embodiments, the tumor-supporting antigen is selected from one or more of the following: bone marrow stromal cell antigen 2 (BST2), fibroblast activation protein (FAP) or tenascin, CD33, CD11b, C14, CD15, and CD66b. Antigen-binding domain structure

In some embodiments, the antigen binding domain of the encoded CAR molecule comprises an antibody, antibody fragment, scFv, Fv, Fab, (Fab')2, single domain antibody (SDAB), VH or VL domain, camelid VHH Domain or bifunctional (eg, bispecific) hybrid antibodies (eg, Lanzavecchia et al., Eur. J. Immunol. 17, 105 (1987)).

In some cases, scFv can be prepared according to methods known in the art (see, e.g., Bird et al., (1988) Science 242:423-426 and Huston et al., (1988) Proc. Natl. Acad. Sci. USA [Proceedings of the National Academy of Sciences of the United States of America] 85:5879-5883). ScFv molecules can be generated by linking the VH and VL regions together using a flexible polypeptide linker. The scFv molecule comprises a linker (eg, a Ser-Gly linker) of optimized length and/or amino acid composition. Linker length can greatly affect how the variable regions of scFvs fold and interact. Indeed, intrachain folding can be prevented if short polypeptide linkers (eg, between 5-10 amino acids) are employed. Interchain folding is also required to bring the two variable domains together to form a functional epitope binding site. For examples of linker orientation and size, see, e.g., Hollinger et al. 1993 Proc Natl Acad. Sci. U.S.A. 90:6444-6448, U.S. Patent Application Publication Nos. 2007/0014794, and PCT Publication Nos. WO 2006/020258 and WO 2007/024715.

A scFv may comprise between its VL and VH regions a protein having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 , 20, 25, 30, 35, 40, 45, 50, or more amino acid residue linkers. A linker sequence can comprise any naturally occurring amino acid. In some embodiments, the linker sequence comprises the amino acids glycine and serine. In another embodiment, the linker sequence comprises a glycine and serine repeat sequence set, such as (Gly ₄ Ser)n, wherein n is a positive integer equal to or greater than 1 (SEQ ID NO: 232). In one embodiment, the linker may be (Gly ₄ Ser) ₄ (SEQ ID NO: 230) or (Gly ₄ Ser) ₃ (SEQ ID NO: 231). Variations in linker length can preserve or enhance activity, resulting in superior efficacy in activity studies.

In another aspect, the antigen binding domain is a T cell receptor ("TCR") or a fragment thereof, such as a single chain TCR (scTCR). Methods for preparing such TCRs are known in the art. See, for example, Willemsen RA et al., Gene Therapy 7: 1369-1377 (2000); Zhang T et al., Cancer Gene Ther 11: 487-496 (2004); Aggen et al., Gene Ther .[Gene Therapy] 19(4): 365-74 (2012). For example, scTCRs can be engineered to contain Vα and Vβ genes from T cell plants linked by linkers such as flexible peptides. This pathway is very useful for cancer-associated targets that are themselves intracellular, however, fragments of such antigens (peptides) are presented by the MHC on the surface of cancer cells.

In certain embodiments, the encoded antigen binding domain has a binding affinity KD of 10 ⁻⁴ M to 10 ⁻⁸ M.

In one embodiment, the encoded CAR molecule comprises an antigen-binding domain whose binding affinity KD for the target antigen is 10 ^-4 M to 10 ^-8 M, such as 10 ^-5 M to 10 ^-7 M, such as 10 ^-6 M or 10 ^-7 M. In one embodiment, the binding affinity of the antigen binding domain is at least 5-fold, 10-fold, 20-fold, 30-fold, 50-fold, 100-fold, or 1,000-fold lower than the binding affinity of a reference antibody (eg, an antibody described herein). In one embodiment, the encoded antigen binding domain has a binding affinity that is at least 5-fold lower than the binding affinity of a reference antibody (eg, the antibody from which the antigen binding domain is derived). In one aspect, such antibody fragments are functional in that they provide a biological response that may include, but is not limited to, activation of an immune response, inhibition of signaling originating from its target antigen, inhibition of kinase activity, etc. , as understood by the skilled artisan.

In one aspect, the antigen binding domain of the CAR is a scFv antibody fragment that is humanized compared to the murine sequence of the scFv from which it is derived.

In one aspect, the antigen binding domain (eg, scFv) of the CAR of the present disclosure is encoded by a nucleic acid molecule whose sequence has been codon-optimized for expression in mammalian cells. In one aspect, the entire CAR construct of the present disclosure is encoded by a nucleic acid molecule whose entire sequence has been codon optimized for expression in mammalian cells. Codon optimization refers to the discovery that the frequency of synonymous codons (ie, codons encoding the same amino acid) in coding DNA is skewed across species. This codon degeneracy allows the same polypeptide to be encoded by various nucleotide sequences. A variety of codon optimization methods are known in the art and include, for example, those disclosed in at least US Pat. Nos. 5,786,464 and 6,114,148. Antigen-binding domain (and targeting antigen)

In one embodiment, the antigen-binding domain against CD19 is described in, for example, the antigen-binding portion (eg, CDR) of a CAR, antibody, or antigen-binding fragment thereof: PCT Publication WO 2012/079000; PCT Publication WO 2014/153270 ; Kochenderfer, J.N., et al., J. Immunother. [Journal of Immunotherapy] 32 (7), 689-702 (2009); Kochenderfer, J.N., et al., Blood [blood], 116 (20), 4099-4102 (2010 ); PCT Publication WO 2014/031687; Bejcek, Cancer Research, 55, 2346-2351, 1995; or US Pat. No. 7,446,190.

In one embodiment, the antigen-binding domain directed against mesothelin is an antigen-binding portion (eg, CDR) of an antibody, antigen-binding fragment, or CAR as described, eg, in PCT Publication WO 2015/090230. In one embodiment, the antigen binding domain for mesothelin is described in, e.g., PCT publications WO 1997/025068, WO 1999/028471, WO 2005/014652, WO 2006/099141, WO 2009/045957, WO 2009/068204 , WO 2013/142034, WO 2013/040557, or the antibody, antigen-binding fragment, or antigen-binding portion (eg, CDR) of CAR of WO 2013/063419. In one embodiment, the antigen binding domain against mesothelin is the antigen binding portion (eg CDR) of the antibody, antigen binding fragment or CAR described in WO/2015/090230.

In one embodiment, the antigen-binding domain against CD123 is an antigen-binding portion (eg, CDR) of an antibody, antigen-binding fragment, or CAR as described, eg, in PCT Publication WO 2014/130635. In one embodiment, the antigen binding domain against CD123 is described in, for example, PCT publications WO 2014/138805, WO 2014/138819, WO 2013/173820, WO 2014/144622, WO 2001/66139, WO 2010/126066, WO 2014/144622, or the antibody, antigen-binding fragment, or antigen-binding portion (eg, CDR) of CAR of US2009/0252742. In one embodiment, the antigen binding domain against CD123 is the antigen binding portion (eg CDR) of the antibody, antigen binding fragment or CAR described in WO/2016/028896.

In one embodiment, the antigen binding domain against EGFRvIII is an antigen binding portion (eg CDR) of an antibody, antigen binding fragment or CAR as described eg in WO/2014/130657.

In one embodiment, the antigen binding domain against CD22 is the antigen binding portion (eg, CDR) of an antibody as described, eg, in: Haso et al., Blood [blood], 121(7): 1165-1174 (2013) ; Wayne et al., Clin Cancer Res [Clinical Cancer Research] 16(6): 1894-1903 (2010); Kato et al., Leuk Res [Leukemia Research] 37(1):83-88 (2013); Creative BioMart [ Creative Biomart] (creativebiomart.net): MOM-18047-S(P).

In one embodiment, the antigen-binding domain against CS-1 is the CDR antigen-binding portion (eg, CDR) of elotuzumab (BMS), see, eg, Tai et al., 2008, Blood [blood] 112( 4):1329-37; Tai et al., 2007, Blood. [Blood] 110(5):1656-63.

In one embodiment, the antigen-binding domain against CLL-1 is an antigen-binding portion (such as a CDR) of an antibody that can be obtained from R&D, ebiosciences, or Abcam, and the antibody are eg PE-CLL1-hu Cat. No. 353604 (BioLegend); and PE-CLL1 (CLEC12A) Cat. No. 562566 (BD). In one embodiment, the antigen binding domain against CLL-1 is the antigen binding portion (eg CDR) of the antibody, antigen binding fragment or CAR described in WO/2016/014535.

In one embodiment, the antigen binding domains against CD33 are antigen binding portions (eg, CDRs) of an antibody as described, eg, in: Bross et al., Clin Cancer Res 7(6):1490-1496 (2001) (gemtuzumab ozogamicin, hP67.6); Caron et al., Cancer Res [Cancer Research] 52(24):6761-6767 (1992) (lintuzumab, HuM195); Lapusan et al, Invest New Drugs 30(3):1121-1131 (2012) (AVE9633); Aigner et al, Leukemia 27(5): 1107-1115 (2013) (AMG330, CD33 BiTE); Dutour et al, Adv hematol [Advances in Hematology] 2012:683065 (2012); and Pizzitola et al, Leukemia [Leukemia] doi: 10.1038/Lue.2014.62 (2014). In one embodiment, the antigen binding domain against CD33 is the antigen binding portion (eg CDR) of the antibody, antigen binding fragment or CAR described in WO/2016/014576.

In one embodiment, the antigen binding domain for GD2 is the antigen binding portion (e.g., CDR) of an antibody as described, e.g., in: Mujoo et al., Cancer Res 47(4):1098-1104 (1987 ); Cheung et al., Cancer Res [Cancer Research] 45(6):2642-2649 (1985); Cheung et al., J Clin Oncol [Journal of Clinical Oncology] 5(9):1430-1440 (1987); Cheung et al, J Clin Oncol 16(9):3053-3060 (1998); Handgretinger et al, Cancer Immunol Immunother 35(3):199-204 (1992) . In some embodiments, the antigen binding domain against GD2 is an antigen binding portion of an antibody selected from the group consisting of: mAb 14.18, 14G2a, ch14.18, hu14.18, 3F8, hu3F8, 3G6, 8B6, 60C3, 10B8, ME36 .1, and 8H9, see eg WO 2012033885, WO 2013040371, WO 2013192294, WO 2013061273, WO 2013123061, WO 2013074916, and WO 201385552. In some embodiments, the antigen-binding domain directed against GD2 is the antigen-binding portion of an antibody described in US Publication No.: 20100150910 or PCT Publication No.: WO 2011160119.

In one embodiment, the antigen binding domains against BCMA are the antigen binding portions (eg CDRs) of antibodies described eg in WO 2012163805, WO200112812, and WO 2003062401. In one embodiment, the antigen binding domain against BCMA is the antigen binding portion (eg CDR) of the antibody, antigen binding fragment or CAR described in WO/2016/014565.

In one embodiment, the antigen-binding domains directed against the Tn antigen are antigen-binding portions (eg, CDRs) of antibodies as described, for example, in US 8,440,798; Brooks et al., PNAS [Proceedings of the National Academy of Sciences of the United States of America] 107(22) :10056-10061 (2010); and Stone et al., OncoImmunology [Tumor Immunology] 1(6):863-873 (2012).

In one embodiment, the antigen binding domain for PSMA is described in, for example, the antigen binding portion (eg, CDR) of an antibody in: Parker et al., Protein Expr Purif 89(2):136- 145 (2013), US 20110268656 (J591 ScFv); Frigerio et al., European J Cancer 49(9):2223-2232 (2013) (scFvD2B); WO 2006125481 (mAbs 3/A12, 3/E7 and 3/F11) and single-chain antibody fragments (scFv A5 and D7).

In one embodiment, the antigen binding domain for ROR1 is described in, for example, the antigen binding portion (eg, CDR) of an antibody in: Hudecek et al., Clin Cancer Res 19(12):3153-3164 (2013); WO 2011159847; and US 20130101607.

In one embodiment, the antigen binding domain against FLT3 is described in antibodies such as WO 2011076922, US 5777084, EP 0754230, US 20090297529 and several commercial catalog antibodies (R&D, Electronic Biosciences, Abcam ) antigen-binding portion (eg, CDR).

In one embodiment, the antigen-binding domain directed against TAG72 is the antigen-binding portion (eg, CDR) of an antibody as described, eg, in Hombach et al., Gastroenterology 113(4):1163-1170 (1997) antibody; and Abcam ab691.

In one embodiment, the antigen-binding domain directed against FAP is the antigen-binding portion (eg, CDR) of an antibody described, eg, in Ostermann et al., Clinical Cancer Research 14:4584-4592 (2008) (FAP5 ), the antibody in U.S. Patent Publication No. 2009/0304718; cilozumab (see, e.g., Hofheinz et al., Oncology Research and Treatment [Oncology Research and Treatment] 26(1), 2003); and Tran et al. , J Exp Med 210(6):1125-1135 (2013).

In one embodiment, the antigen-binding domain to CD38 is the antigen-binding portion (eg, CDR) of the following antibody: daratumumab (see, eg, Groen et al., Blood 116(21): 1261-1262 (2010); MOR202 (see eg, US 8,263,746); or the antibody described in US 8,362,211.

In one embodiment, the antigen-binding domains directed against CD44v6 are the antigen-binding portions (eg, CDRs) of antibodies described, eg, in Casucci et al., Blood 122(20):3461-3472 (2013).

In one embodiment, the antigen-binding domain directed against CEA is the antigen-binding portion (eg, CDR) of an antibody as described, eg, in Chmielewski et al., Gastoenterology 143(4):1095-1107 (2012).

In one embodiment, the antigen binding domain against EPCAM is an antigen binding portion (eg CDR) of an antibody selected from: MT110, EpCAM-CD3 bispecific Ab (see eg clinicaltrials.gov/ct2/show/NCT00635596) ; edrolizumab; 3622W94; ING-1; and adelimumab (MT201).

In one embodiment, the antigen binding domain directed against PRSS21 is the antigen binding portion (eg, CDR) of an antibody described in US Pat. No. 8,080,650.

In one embodiment, the antigen-binding domain against B7H3 is the antigen-binding portion (eg, CDR) of antibody MGA271 (Macrogenics).

In one embodiment, the antigen binding domains against KIT are the antibodies described eg in US 7915391 , US 20120288506 and the antigen binding portions (eg CDRs) of several commercial catalog antibodies.

In one embodiment, the antigen binding domain against IL-13Ra2 is described eg in WO 2008/146911, the antibody in WO 2004087758, several commercial catalog antibodies and the antigen binding portion (eg CDR) of the antibody in WO 2004087758.

In one embodiment, the antigen binding domain against CD30 is the antigen binding portion (eg CDR) of an antibody as described eg in US 7090843 B1 and EP 0805871 .

In one embodiment, the antigen binding domains against GD3 are antigen binding portions (eg, CDRs) of antibodies described, eg, in US 7253263; US 8,207,308; US 20120276046; EP 1013761; WO 2005035577;

In one embodiment, the antigen-binding domain against CD171 is the antigen-binding portion (e.g., CDR) of an antibody as described, e.g., in Hong et al., J Immunother 37(2):93-104 (2014) .

In one embodiment, the antigen binding domain directed against IL-11Ra is the antigen binding portion of an antibody available from Abcam (Cat. No. ab55262) or Novus Biologicals (Cat. No. EPR5446) (e.g. CDRs). In another embodiment, the antigen binding domain directed against IL-11Ra is a peptide, see eg Huang et al., Cancer Res 72(1):271-281 (2012).

In one embodiment, the antigen binding domain against PSCA is the antigen binding portion (eg, CDR) of an antibody as described, eg, in: Morgenroth et al., Prostate [Prostate] 67(10):1121-1131 (2007)( scFv 7F5); Nejatollahi et al, J of Oncology 2013 (2013), Article ID 839831 (scFv C5-II); and US Patent Publication No. 20090311181.

In one embodiment, the antigen-binding domain against VEGFR2 is described, for example, in the antigen-binding portion of an antibody (e.g., CDR ).

In one embodiment, the antigen-binding domain to LewisY is described, for example, in the antigen-binding portion (e.g., CDR) of an antibody in Kelly et al., Cancer Biother Radiopharm 23(4): 411-423 (2008) (hu3S193 Ab (scFvs)); Dolezal et al., Protein Engineering 16(1):47-56 (2003) (NC10 scFv).

In one embodiment, the antigen-binding domain against CD24 is the antigen-binding portion (eg, CDR) of an antibody as described, eg, in Maliar et al., Gastroenterology 143(5):1375-1384 (2012).

In one embodiment, the antigen-binding domain against PDGFR-β is the antigen-binding portion (eg, CDR) of antibody Abcam ab32570.

In one embodiment, the antigen-binding domain against SSEA-4 is antibody MC813 (Cell Signaling), or the antigen-binding portion (eg, CDR) of other commercially available antibodies.

In one embodiment, the antigen-binding domain against CD20 is an antigen-binding portion (eg, CDR) of the antibody rituximab, ofatumumab, ocrelizumab, veltuzumab, or GA101.

In one embodiment, the antigen binding domain against folate receptor alpha is antibody IMGN853 or an antigen binding portion (eg CDR) of an antibody described in: US 20120009181; US 4851332; LK26: US5952484.

In one embodiment, the antigen-binding domain against ERBB2 (Her2/neu) is the antigen-binding portion (eg, CDR) of the antibody trastuzumab, or pertuzumab.

In one embodiment, the antigen-binding domain against MUCl is the antigen-binding portion (eg, CDR) of antibody SAR566658.

In one embodiment, the antigen-binding domain against EGFR is an antigen-binding portion of the antibody cetuximab, panitumumab, zatumumab, nimotuzumab, or matuzumab (e.g. CDR).

In one embodiment, the antigen-binding domain directed against NCAM is the antigen-binding portion (eg, CDR) of the antibody: antibody plant 2-2B: MAB5324 (EMD Millipore).

In one embodiment, the antigen-binding domain directed against ephrin B2 is the antigen-binding portion (e.g., CDR) of an antibody as described, e.g., in Abengozar et al., Blood 119(19):4565-4576 (2012) .

In one embodiment, the antigen binding domain for the IGF-I receptor is the antigen binding portion (eg, CDR) of an antibody as described, eg, in US 8344112 B2; EP 2322550 A1; WO 2006/138315, or PCT/ US2006/022995.

In one embodiment, the antigen-binding domain directed against CAIX is the antigen-binding portion (eg, CDR) of antibody plant 303123 (R&D Systems).

In one embodiment, the antigen binding domain against LMP2 is the antigen binding portion (eg CDR) of an antibody as described eg in US 7,410,640, or US 20050129701.

In one embodiment, the antigen binding domain against gp100 is antibody HMB45, NKIβB, or an antigen binding portion (eg, CDR) of an antibody described in WO 2013165940 or US 20130295007.

In one embodiment, the antigen binding domain for tyrosinase is an antigen binding portion (eg, CDR) of an antibody as described, eg, in US 5843674; or US 19950504048.

In one embodiment, the antigen binding domain against EphA2 is the antigen binding portion (eg, CDR) of an antibody as described, eg, in Yu et al., Mol Ther [Molecular Therapy] 22(1):102-111 (2014).

In one embodiment, the antigen binding domain against GD3 is an antigen binding portion (eg, CDR) of an antibody as described, eg, in US 7253263; US 8,207,308; US 20120276046; EP 1013761 A3; 20120276046; WO 2005035577; 6437098.

In one embodiment, the antigen binding domain against fucosyl GM1 is the antigen binding portion (eg CDR) of an antibody as described eg in US 20100297138; or WO 2007/067992.

In one embodiment, the antigen binding domain against sLe is the antigen binding portion (eg, CDR) of antibody G193 (for lewis Y), see Scott AM et al, Cancer Res 60: 3254-61 (2000) , also as described in Neeson et al., J Immunol 2013 May 190 (Conference Abstract Supplement) 177.10.

In one embodiment, the antigen binding domain against GM3 is the antigen binding portion (eg CDR) of antibody CA 2523449 (mAb 14F7).

In one embodiment, the antigen binding domain to HMWMAA is the antigen binding portion (eg, CDR) of an antibody as described, eg, in Kmiecik et al., Oncoimmunology 3(1): e27185 (2014) ( PMID: 24575382) (mAb9.2.27); US 6528481; WO 2010033866; or US 20140004124.

In one embodiment, the antigen binding domain against o-acetyl-GD2 is the antigen binding portion (eg, CDR) of antibody 8B6.

In one embodiment, the antigen binding domain against TEM1/CD248 is the antigen binding portion (eg, CDR) of an antibody as described, eg, in: Marty et al., Cancer Lett 235(2):298-308 (2006); Zhao et al., J Immunol Methods 363(2):221-232 (2011).

In one embodiment, the antigen binding domain against CLDN6 is the antigen binding portion (eg CDR) of antibody IMAB027 (Ganymed Pharmaceuticals), see eg clinicaltrial.gov/show/NCT02054351.

In one embodiment, the antigen binding domain for TSHR is the antigen binding portion (eg, CDR) of an antibody as described, eg, in US 8,603,466; US 8,501,415; or US 8,309,693.

In one embodiment, the antigen-binding domain against GPRC5D is the antigen-binding portion (eg, CDR) of the following antibody: antibody FAB6300A (R&D Systems); or LS-A4180 (Lifespan Biosciences).

In one embodiment, the antigen binding domain to CD97 is the antigen binding portion (eg, CDR) of an antibody as described, eg, in US 6,846,911; de Groot et al., J Immunol 183(6): 4127-4134 (2009); or the antibody from R&D: MAB3734.

In one embodiment, the antigen-binding domain directed against ALK is the antigen-binding portion of an antibody described, e.g., in Mino-Kenudson et al., Clin Cancer Res 16(5):1561-1571 (2010) ( such as CDRs).

In one embodiment, the antigen-binding domain directed against polysialic acid is the antigen-binding portion of an antibody described, e.g., in Nagae et al., J Biol Chem 288(47):33784-33796 (2013) ( such as CDRs).

In one embodiment, the antigen binding domain directed against PLAC1 is the antigen binding portion (eg, CDR) of an antibody as described in: eg Ghods et al., Biotechnol Appl Biochem [Biochemistry Biotechnology Applications] 2013 doi: 10.1002/bab .1177.

In one embodiment, the antigen-binding domain to GloboH is the antigen-binding portion of the antibody VK9; or as described, for example, in Kudryashov V et al., Glycoconj J. 15(3):243- 9 (1998), Antibodies in Lou et al., Proc Natl Acad Sci USA [Proceedings of the National Academy of Sciences] 111(7):2482-2487 (2014); MBr1: Bremer E-G et al. J Biol Chem [J Biol Chem] 259:14773–14777 (1984).

In one embodiment, the antigen binding domain against NY-BR-1 is described, e.g., in Jager et al., Appl Immunohistochem Mol Morphol 15(1):77-83 (2007) The antigen-binding portion (eg, CDR) of an antibody.

In one embodiment, the antigen binding domain directed against WT-1 is the antigen binding portion (e.g., CDR) of an antibody described in, e.g., Dao et al., Sci Transl Med 5(176):176ra33 (2013); or WO 2012/135854.

In one embodiment, the antigen binding domain directed against MAGE-A1 is that of an antibody described, e.g., in Willemsen et al., J Immunol 174(12):7853-7858 (2005) (TCR-like scFv). Antigen binding portion (eg CDR).

In one embodiment, the antigen-binding domain against sperm protein 17 is described, for example, in the antigen-binding portion (eg, CDR) of an antibody in: Song et al., Target Oncol [Target Oncol] Aug. 14, 2013( PMID: 23943313); Song et al., Med Oncol [Medical Oncology] 29(4):2923-2931 (2012).

In one embodiment, the antigen binding domain against Tie 2 is the antigen binding portion (eg, CDR) of antibody AB33 (Cell Signaling Technology).

In one embodiment, the antigen binding domain against MAD-CT-2 is the antigen binding portion (eg CDR) of an antibody described eg in PMID: 2450952, US 7635753.

In one embodiment, the antigen-binding domain against Fos-related antigen 1 is the antigen-binding portion (eg, CDR) of antibody 12F9 (Rofus Biologics).

In one embodiment, the antigen binding domain against MelanA/MART1 is the antigen binding portion (eg, CDR) of an antibody described in: EP 2514766 A2; or US 7,749,719.

In one embodiment, the antigen-binding domain directed against the sarcoma translocation breakpoint is that of an antibody described, for example, in Luo et al., EMBO Mol. Med. [EMBO Molecular Medicine] 4(6):453-461 (2012). Antigen binding portion (eg CDR).

In one embodiment, the antigen-binding domain directed against TRP-2 is the antigen-binding portion of an antibody described, e.g., in Wang et al., J Exp Med. [Journal of Experimental Medicine] 184(6):2207-16 (1996) (e.g. CDRs).

In one embodiment, the antigen binding domain directed against CYP1B1 is the antigen binding portion (eg, CDR) of an antibody as described, eg, in Maecker et al., Blood 102(9): 3287-3294 (2003).

In one embodiment, the antigen-binding domain against RAGE-1 is the antigen-binding portion (eg, CDR) of antibody MAB5328 (EMD Millipore). In one embodiment, the antigen-binding domain against human telomerase reverse transcriptase is the antigen-binding portion (eg, CDR) of the following antibody: Antibody catalog number: LS-B95-100 (Laishibang Biotechnology Co., Ltd.)

In one embodiment, the antigen-binding domain against intestinal carboxylesterase is the antigen-binding portion (eg, CDR) of the following antibody: antibody 4F12: catalog number: LS-B6190-50 (Lai Shi Bang Biotechnology Co., Ltd.)).

In one embodiment, the antigen-binding domain for mut hsp70-2 is the antigen-binding portion (for example, CDR) of the following antibody: antibody (Laishibang Biotechnology Company: single strain: catalog number: LS-C133261-100 (Laishibang Biotechnology Company: Shibang Biotechnology Company)).

In one embodiment, the antigen binding domain directed against CD79a is the antigen binding portion (e.g., CDR) of the following antibody: antibody anti-CD79a antibody [HM47/A9] (ab3121) available from Abcam; Antibody CD79A Antibody No. 3351 available from Antibody Technologies Inc.; or Antibody HPA017748 - Anti-CD79A antibody produced in rabbit and available from Sigma Aldrich.

In one embodiment, the antigen-binding domain directed against CD79b is the antigen-binding portion (eg, CDR) of the antibody polatuzumab vedotin (anti-CD79b) (described in Dornan et al., 「Therapeutic potential of an anti-CD79b antibody-drug conjugate, anti-CD79b-vc-MMAE, for the treatment of non-Hodgkin lymphoma The therapeutic potential of King's lymphoma] "Blood. [Blood] 2009 September 24; 114(13):2721-9. doi: 10.1182/blood-2009-02-205500.Epub July 24, 2009 ), or bispecific antibody anti-CD79b/CD3 (described in "4507 Pre-Clinical Characterization of T Cell-Dependent Bispecific Antibody Anti-CD79b/CD3 As a Potential Therapy for B Cell Malignancies [4507 T Cell-Dependent Bispecific Antibody Preclinical Characterization of Anti-CD79b/CD3 as a Potential Therapy for B Cell Malignancies]" Abstracts of 56 ^th ASH Annual Meeting and Exposition [56th ASH Annual Meeting and Exposition Abstracts], San Francisco, CA December 6, 2014 to the middle of the 9th).

In one embodiment, the antigen-binding domain directed against CD72 is the antigen-binding portion (eg, CDR) of the antibody J3-109 (described in Myers and Uckun, "An anti-CD72 immunotoxin against therapy-refractory B-lineage acute lymphoblastic leukemia [Anti-CD72 immunotoxin anti-therapy refractory B-lineage acute lymphoblastic leukemia]” Leuk Lymphoma. [Leukemia Lymphoma] 1995 Jun; 18(1-2):119-22) or anti-CD72 (10D6 .8.1, mIgG1) (described in Polson et al., "Antibody-Drug Conjugates for the Treatment of Non-Hodgkin's Lymphoma: Target and Linker-Drug Selection [Antibody-Drug Conjugates for the Treatment of Non-Hodgkin's Lymphoma : Targets and Linkers - Drug Selection]” Cancer Res 2009 Mar 15 69;2358.

In one embodiment, the antigen-binding domain against LAIR1 is the antigen-binding portion (eg, CDR) of the following antibody: antibody ANT-301 LAIR1 antibody available from ProSpec; or anti-human CD305 (LAIR1) antibody.

In one embodiment, the antigen-binding domain against FCAR is the antigen-binding portion (eg, CDR) of the antibody CD89/FCAR antibody (catalogue number 10414-H08H) available from Sino Biological Company.

In one embodiment, the antigen-binding domain against LILRA2 is the antibody LILRA2 monoclonal antibody (M17) (plant 3C7) available from Abnova, or the small Antigen-binding portion (e.g., CDRs) of a mouse anti-LILRA2 antibody (monoclonal (2D7)).

In one embodiment, the antigen-binding domain against CD300LF is an antibody mouse anti-CMRF35-like molecule 1 antibody (monoclonal [UP-D2]) available from Baijin Biotechnology; or available from R&D Systems Antigen-binding portion (e.g., CDRs) of the rat anti-CMRF35-like molecule 1 antibody (monoclonal [234903]).

In one embodiment, the antigen-binding domain against CLEC12A is the antigen-binding portion (eg, CDR) of an antibody bispecific T cell engager (BiTE) scFv-antibody and ADC (described in Noordhuis et al., "Targeting of CLEC12A In Acute Myeloid Leukemia by Antibody-Drug-Conjugates and Bispecific CLL-1xCD3 BiTE Antibody [Targeting CLEC12A in Acute Myeloid Leukemia by Antibody-Drug-Conjugates and Bispecific CLL-1xCD3 BiTE Antibody]” 53 ^rd ASH Annual Meeting and Exposition [53rd ASH Annual Meeting and Exposition], December 10-13, 2011), and MCLA-117 (Merus).

In one embodiment, the antigen-binding domain directed against BST2 (also known as CD317) is the antibody mouse anti-CD317 antibody (monoclonal [3H4]) available from Antibodies-Online or available from R&D Systems, Inc. The antigen-binding portion (e.g. CDR) of the mouse anti-CD317 antibody (monoclonal [696739]) was obtained.

In one embodiment, the antigen-binding domain of EMR2 (also known as CD312) is an antibody mouse anti-CD312 antibody (monoclonal [LS-B8033]) available from Lai Shi Bang Biotechnology Co., Ltd. or available from R&D System The antigen-binding portion (e.g., CDR) of a mouse anti-CD312 antibody (monoclonal [494025]) obtained by the company.

In one embodiment, the antigen binding domain against LY75 is the antibody mouse anti-lymphocyte antigen 75 antibody (monoclonal [HD30]) available from EMD Millipore or available from Life Technologies Antigen-binding portion (e.g., CDRs) of mouse anti-lymphocyte antigen 75 antibody (monoclonal [A15797]).

In one embodiment, the antigen-binding domain against GPC3 is the antigen-binding portion (eg, CDR) of the antibody hGC33 (described in Nakano K, Ishiguro T, Konishi H et al. Generation of a humanized anti-glypican 3 antibody by CDR grafting and stability optimization. [Produce humanized anti-glypican 3 antibody by CDR grafting and stability optimization] Anticancer Drugs. [Anticancer Drugs] 2010 November; 21(10):907 -916), or MDX-1414, HN3, or YP7 (all three antibodies are described in Feng et al., "Glypican-3 antibodies: a new therapeutic target for liver cancer. [Glypican-3 antibodies: liver cancer New therapeutic targets]” FEBS Lett. [Federation of European Biochemical Societies Letters] 2014 Jan 21; 588(2):377-82).

In one embodiment, the antigen-binding domain directed against FCRL5 is the antigen-binding portion (e.g., CDR) of an anti-FcRL5 antibody as described in: Elkins et al., "FcRL5 as a target of antibody-drug conjugates for the treatment of multiple myeloma [FcRL5 as a target for antibody-drug conjugates in multiple myeloma]" Mol Cancer Ther. 2012 Oct;11(10):2222-32. In one embodiment, the antigen-binding domains directed against FCRL5 are the antigen-binding portions (e.g., CDRs) of anti-FcRL5 antibodies described in, e.g., WO 2001/038490, WO/2005/117986, WO 2006/039238, WO 2006/076691, WO 2010/114940, WO 2010/120561, or WO 2014/210064.

In one embodiment, the antigen-binding domain for IGLL1 is the antigen-binding portion (eg, CDR) of the following antibody: the antibody mouse anti-immunoglobulin lambda-like polypeptide 1 (monoclonal [ AT1G4]), a mouse anti-immunoglobulin lambda-like polypeptide 1 antibody (monoclonal [HSL11]) available from Baijin Biotechnology.

In one embodiment, the antigen binding domain comprises one, two, three (eg all three) heavy chain CDRs (HC CDR1, HC CDR2 and HC CDR3) from the antibodies listed above, and/or from One, two, three (eg all three) of the light chain CDRs (LC CDR1 , LC CDR2 and LC CDR3) of the antibodies listed above. In one embodiment, the antigen binding domain comprises the heavy chain variable region and/or the variable light chain region of the antibodies listed above.

In another aspect, the antigen binding domain comprises a humanized antibody or antibody fragment. In some aspects, non-human antibodies are humanized, wherein specific sequences or regions of the antibody are modified to increase similarity to antibodies or fragments thereof naturally occurring in humans. In one aspect, the antigen binding domain is humanized.

In an embodiment, the antigen binding domain of a CAR (eg, a CAR expressed by a cell of the disclosure) binds CD19. CD19 is found on B cells throughout lineage differentiation from the pre/progenitor B cell stage through the terminally differentiated plasma cell stage. In an embodiment, the antigen binding domain is a murine scFv domain that binds human CD19, eg, the antigen binding domain of CTL019 (eg, SEQ ID NO: 252). In an embodiment, the antigen binding domain is derived from a humanized antibody or antibody fragment (eg scFv domain) of murine CTL019 scFv. In an embodiment, the antigen binding domain is a human antibody or antibody fragment that binds to human CD19. Exemplary scFv domains (and their sequences, eg, CDR, VL and VH sequences) that bind CD19 are provided in Table 12a. The scFv domain sequences provided in Table 12a include a light chain variable region (VL) and a heavy chain variable region (VH). VL and VH are attached by a linker comprising the sequence GGGGSGGGGSGGGGS (SEQ ID NO: 231 ), for example, in the following orientation: VL-linker-VH. [ Table 12a ] . Antigen-binding domains that bind to CD19 antigen name amino acid sequence SEQ ID NO: CD19 muCTL019 DIQMTQTTSSLSASLGDRVTISCRASQDISKYLNWYQQKPDGTVKLLIYHTSRLHSGVPSRFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPYTFGGGTKLEITGGGGSGGGGSGGGGSEVKLQESGPGLVAPSQSLSVTCTVSGVSLPDYGVSWIRQPPRKGLEWLGVIWGSETTYYNSALKSRLTIIKDNSKSQVFLKMNSLQTDDTAIYYCAKHYYYGGSYAMDYWGQGTSVTVSS 233 CD19 huscFv1 EIVMTQSPATLSLSPGERATLSCRASQDISKYLNWYQQKPGQAPRLLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYFCQQGNTLPYTFGQGTKLEIKGGGGSGGGGSGGGGSQVQLQESGPGLVKPSETLSLTCTVSGVSLPDYGVSWIRQPPGKGLEWIGVIWGSETTYYSSSLKSRVTISKDNSKNQVSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSS 234 CD19 huscFv2 EIVMTQSPATLSLSPGERATLSCRASQDISKYLNWYQQKPGQAPRLLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYFCQQGNTLPYTFGQGTKLEIKGGGGSGGGGSGGGGSQVQLQESGPGLVKPSETLSLTCTVSGVSLPDYGVSWIRQPPGKGLEWIGVIWGSETTYYQSSLKSRVTISKDNSKNQVSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSS 235 CD19 huscFv3 QVQLQESGPGLVKPSETLSLTCTVSGVSLPDYGVSWIRQPPGKGLEWIGVIWGSETTYYSSSLKSRVTISKDNSKNQVSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSEIVMTQSPATLSLSPGERATLSCRASQDISKYLNWYQQKPGQAPRLLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYFCQQGNTLPYTFGQGTKLEIK 236 CD19 huscFv4 QVQLQESGPGLVKPSETLSLTCTVSGVSLPDYGVSWIRQPPGKGLEWIGVIWGSETTYYQSSLKSRVTISKDNSKNQVSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSEIVMTQSPATLSLSPGERATLSCRASQDISKYLNWYQQKPGQAPRLLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYFCQQGNTLPYTFGQGTKLEIK 237 CD19 huscFv5 EIVMTQSPATLSLSPGERATLSCRASQDISKYLNWYQQKPGQAPRLLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYFCQQGNTLPYTFGQGTKLEIKGGGGSGGGGSGGGGSGGGGSQVQLQESGPGLVKPSETLSLTCTVSGVSLPDYGVSWIRQPPGKGLEWIGVIWGSETTYYSSSLKSRVTISKDNSKNQVSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSS 238 CD19 huscFv6 EIVMTQSPATLSLSPGERATLSCRASQDISKYLNWYQQKPGQAPRLLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYFCQQGNTLPYTFGQGTKLEIKGGGGSGGGGSGGGGSGGGGSQVQLQESGPGLVKPSETLSLTCTVSGVSLPDYGVSWIRQPPGKGLEWIGVIWGSETTYYQSSLKSRVTISKDNSKNQVSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSS 239 CD19 huscFv7 QVQLQESGPGLVKPSETLSLTCTVSGVSLPDYGVSWIRQPPGKGLEWIGVIWGSETTYYSSSLKSRVTISKDNSKNQVSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSEIVMTQSPATLSLSPGERATLSCRASQDISKYLNWYQQKPGQAPRLLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYFCQQGNTLPYTFGQGTKLEIK 240 CD19 huscFv8 QVQLQESGPGLVKPSETLSLTCTVSGVSLPDYGVSWIRQPPGKGLEWIGVIWGSETTYYQSSLKSRVTISKDNSKNQVSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSEIVMTQSPATLSLSPGERATLSCRASQDISKYLNWYQQKPGQAPRLLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYFCQQGNTLPYTFGQGTKLEIK 241 CD19 huscFv9 EIVMTQSPATLSLSPGERATLSCRASQDISKYLNWYQQKPGQAPRLLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYFCQQGNTLPYTFGQGTKLEIKGGGGSGGGGSGGGGSGGGGSQVQLQESGPGLVKPSETLSLTCTVSGVSLPDYGVSWIRQPPGKGLEWIGVIWGSETTYYNSSLKSRVTISKDNSKNQVSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSS 242 CD19 Hu scFv10 QVQLQESGPGLVKPSETLSLTCTVSGVSLPDYGVSWIRQPPGKGLEWIGVIWGSETTYYNSSLKSRVTISKDNSKNQVSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSEIVMTQSPATLSLSPGERATLSCRASQDISKYLNWYQQKPGQAPRLLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYFCQQGNTLPYTFGQGTKLEIK 243 CD19 Hu scFv11 EIVMTQSPATLSLSPGERATLSCRASQDISKYLNWYQQKPGQAPRLLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYFCQQGNTLPYTFGQGTKLEIKGGGGSGGGGSGGGGSQVQLQESGPGLVKPSETLSLTCTVSGVSLPDYGVSWIRQPPGKGLEWIGVIWGSETTYYNSSLKSRVTISKDNSKNQVSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSS 244 CD19 Hu scFv12 QVQLQESGPGLVKPSETLSLTCTVSGVSLPDYGVSWIRQPPGKGLEWIGVIWGSETTYYNSSLKSRVTISKDNSKNQVSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSEIVMTQSPATLSLSPGERATLSCRASQDISKYLNWYQQKPGQAPRLLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYFCQQGNTLPYTFGQGTKLEIK 245

The sequences of the CDR sequences of the scFv domains of the CD19 antigen binding domains provided in Table 12a are shown in Table 12b (for the heavy chain variable domain) and Table 12c (for the light chain variable domain). "ID" represents the corresponding SEQ ID NO for each CDR. [ Table 12b ] . Heavy chain variable domain CDRs illustrate FW HCDR1 ID HCDR2 ID HCDR3 ID Rat_CART19 GVSLPDYGVS 319 VIWGSETTYYNSALKS 320 HYYYGGSYAMDY 246 Humanized_CART19a VH4 GVSLPDYGVS 319 VIWGSETTYY S S S LKS 296 HYYYGGSYAMDY 246 Humanized_CART19b VH4 GVSLPDYGVS 319 VIWGSETTYY Q S S LKS 295 HYYYGGSYAMDY 246 Humanized_CART19c VH4 GVSLPDYGVS 319 VIWGSETTYYNS S LKS 284 HYYYGGSYAMDY 246 [ Table 12c ] . Light chain variable domain CDRs illustrate FW LCDR1 ID LCDR2 ID LCDR3 ID Rat_CART19 RASQDISKYLN 251 HTSRLHS 250 QQGNTLPYT 247 Humanized_CART19a VK3 RASQDISKYLN 251 HTSRLHS 250 QQGNTLPYT 247 Humanized_CART19b VK3 RASQDISKYLN 251 HTSRLHS 250 QQGNTLPYT 247 Humanized_CART19c VK3 RASQDISKYLN 251 HTSRLHS 250 QQGNTLPYT 247

In an embodiment, the antigen binding domain comprises an anti-CD19 antibody or fragment thereof (eg scFv). For example, the antigen binding domain comprises a variable heavy chain and a variable light chain listed in Table 12d. The linker sequence connecting the variable heavy and variable light chains may be any of the linker sequences described herein, or alternatively may be GSTSGSGKPGSGEGSTKG (SEQ ID NO: 248). The light and heavy chain variable regions of the scFv can be, for example, in any of the following orientations: light chain variable region-linker-heavy chain variable region or heavy chain variable region-linker-light chain variable region. [ Table 12d ] . Additional anti-CD19 antibody binding domains Ab name VH sequence VL sequence SJ25-C1 QVQLLESGAELVRPGSSVKISCKASGYAFSSYWMNWVKQRPGQGLEWIGQIYPGDGDTNYNGKFKGQATLTADKSSSTAYMQLSGLTSEDSAVYSCARKTISSVVDFYFDYWGQGTTVT (SEQ ID NO: 249) ELVLTQSPKFMSTSVGDRVSVTCKASQNVGTNVAWYQQKPGQSPKPLIYSATYRNSGVPDRFTGSGSGTDFLTITNVQSKDLADYFYFCQYNRYPYTSGGGTKLEIKRRS (SEQ ID NO: 229) ScFv sequence SJ25-C1 scFv QVQLLESGAELVRPGSSVKISCKASGYAFSSYWMNWVKQRPGQGLEWIGQIYPGDGDTNYNGKFKGQATLTADKSSSTAYMQLSGLTSEDSAVYSCARKTISSVVDFYFDYWGQGTTVTGSTSGSGKPGSGEGSTKGELVLTQSPKFMSTSVGDRVSVTCKASQNVGTNVAWYQQKPGQSPKPLIYSATYRNSGVPDRFTGSGSGTDFTLTITNVQSKDLADYFYFCQYNRYPYTSGGGTKLEIKRRS (SEQ ID NO: 228)

In one embodiment, the CD19 binding domain comprises one or more (eg, all three) of the light chain complementarity determining region 1 (LC CDR1 ) of a CD19 binding domain described herein (eg, as provided in Table 12a or 15). ), light chain complementarity determining region 2 (LC CDR2) and light chain complementarity determining region 3 (LC CDR3), and/or one or more of the CD19 binding domains described herein (such as provided in Table 12a or 16) one (eg all three) of heavy chain complementarity determining region 1 (HC CDR1), heavy chain complementarity determining region 2 (HC CDR2) and heavy chain complementarity determining region 3 (HC CDR3). In one embodiment, the CD19 binding domain comprises one, two or all of LC CDR1, LC CDR2 and LC CDR3 having any amino acid sequence as provided in Table 12c; and having any amino acid sequence as provided in Table 12b One, two or all of HC CDR1, HC CDR2 and HC CDR3 of the amino acid sequence.

Any known CD19 CAR in the art, such as the CD19 antigen-binding domain of any known CD19 CAR, can be used to construct a CAR according to the present disclosure. For example, LG-740; CD19 CARs are described in: US Pat. No. 8,399,645; US Pat. No. 7,446,190; Xu et al., Leuk Lymphoma. [Leukemia Lymphoma] 2013 54(2):255-260 (2012); Cruz et al., Blood [blood] 122(17):2965-2973 (2013); Brentjens et al., Blood [blood] 118(18):4817-4828 (2011); Kochenderfer et al., Blood [blood] 116( 20):4099-102 (2010); Kochenderfer et al., Blood 122 (25):4129-39 (2013); and 16th Annu Meet Am Soc Gen Cell Ther (ASGCT) [American Society for Gene and Cell Therapy ( ASGCT) 16th Annual Conference] (May 15-18, Salt Lake City) 2013, Abstract 10. In one embodiment, the antigen-binding domain against CD19 is described in, for example, the antigen-binding portion (eg, CDR) of a CAR, antibody, or antigen-binding fragment thereof: PCT Publication WO 2012/079000; PCT Publication WO 2014/153270 ; Kochenderfer, J.N., et al., J. Immunother. [Journal of Immunotherapy] 32 (7), 689-702 (2009); Kochenderfer, J.N., et al., Blood [blood], 116 (20), 4099-4102 (2010 ); PCT Publication WO 2014/031687; Bejcek, Cancer Research, 55, 2346-2351, 1995; or US Pat. No. 7,446,190.

In an embodiment, the antigen binding domain of a CAR (eg, a CAR expressed by a cell of the disclosure) binds BCMA. BCMA was found to be preferentially expressed in mature B lymphocytes. In an embodiment, the antigen binding domain is a murine scFv domain that binds to human BCMA. In an embodiment, the antigen binding domain is a humanized antibody or antibody fragment (eg scFv domain) that binds human BCMA. In an embodiment, the antigen binding domain is a human antibody or antibody fragment that binds to human BCMA. In an embodiment, an exemplary BCMA CAR construct was generated using the VH and VL sequences from PCT Publication WO 2012/0163805. In embodiments, additional exemplary BCMA CAR constructs were generated using the VH and VL sequences from PCT Publication WO 2016/014565. In an embodiment, additional exemplary BCMA CAR constructs were generated using the VH and VL sequences from PCT Publication WO 2014/122144. In embodiments, additional exemplary BCMA CAR constructs were generated using CAR molecules, and/or VH and VL sequences from PCT Publication WO 2016/014789. In embodiments, additional exemplary BCMA CAR constructs were generated using CAR molecules, and/or VH and VL sequences from PCT Publication WO 2014/089335. In embodiments, additional exemplary BCMA CAR constructs were generated using CAR molecules, and/or VH and VL sequences from PCT Publication WO 2014/140248.

Any BCMA CAR known in the art, such as the BMCA antigen binding domain of any known BCMA CAR, can be used in accordance with the present disclosure. For example, those described herein. Exemplary CAR molecules

In one aspect, a CAR (eg, a CAR expressed by a cell of the disclosure) comprises a CAR molecule comprising an antigen binding domain that binds a B cell antigen (eg, such as CD19 or BCMA as described herein).

In one embodiment, the CAR comprises a CAR molecule comprising a CD19 antigen binding domain (e.g., a murine, human or humanized antibody or antibody fragment that specifically binds CD19), a transmembrane domain, and intracellular signaling Domains (eg, intracellular signaling domains comprising co-stimulatory domains and/or primary signaling domains).

Exemplary CAR molecules described herein are provided in Table 12e. The CAR molecule in Table 12e comprises a CD19 antigen binding domain, such as the amino acid sequence of any of the CD19 antigen binding domains provided in Table 12a. [ Table 12e ] . Exemplary CD19 CAR molecules antigen name amino acid sequence SEQ ID NO: CD19 CTL019 MALPVTALLLPLALLLHAARPDIQMTQTTSSLSASLGDRVTISCRASQDISKYLNWYQQKPDGTVKLLIYHTSRLHSGVPSRFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPYTFGGGTKLEITGGGGSGGGGSGGGGSEVKLQESGPGLVAPSQSLSVTCTVSGVSLPDYGVSWIRQPPRKGLEWLGVIWGSETTYYNSALKSRLTIIKDNSKSQVFLKMNSLQTDDTAIYYCAKHYYYGGSYAMDYWGQGTSVTVSSTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 252 CD19 CAR 1 MALPVTALLLPLALLLHAARPEIVMTQSPATLSLSPGERATLSCRASQDISKYLNWYQQKPGQAPRLLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYFCQQGNTLPYTFGQGTKLEIKGGGGSGGGGSGGGGSQVQLQESGPGLVKPSETLSLTCTVSGVSLPDYGVSWIRQPPGKGLEWIGVIWGSETTYYSSSLKSRVTISKDNSKNQVSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSSTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 253 CD19 CAR 2 MALPVTALLLPLALLLHAARPEIVMTQSPATLSLSPGERATLSCRASQDISKYLNWYQQKPGQAPRLLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYFCQQGNTLPYTFGQGTKLEIKGGGGSGGGGSGGGGSQVQLQESGPGLVKPSETLSLTCTVSGVSLPDYGVSWIRQPPGKGLEWIGVIWGSETTYYQSSLKSRVTISKDNSKNQVSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSSTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 254 CD19 CAR 3 MALPVTALLLPLALLLHAARPQVQLQESGPGLVKPSETLSLTCTVSGVSLPDYGVSWIRQPPGKGLEWIGVIWGSETTYYSSSLKSRVTISKDNSKNQVSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSEIVMTQSPATLSLSPGERATLSCRASQDISKYLNWYQQKPGQAPRLLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYFCQQGNTLPYTFGQGTKLEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 255 CD19 CAR 4 MALPVTALLLPLALLLHAARPQVQLQESGPGLVKPSETLSLTCTVSGVSLPDYGVSWIRQPPGKGLEWIGVIWGSETTYYQSSLKSRVTISKDNSKNQVSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSEIVMTQSPATLSLSPGERATLSCRASQDISKYLNWYQQKPGQAPRLLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYFCQQGNTLPYTFGQGTKLEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 256 CD19 CAR 5 MALPVTALLLPLALLLHAARPEIVMTQSPATLSLSPGERATLSCRASQDISKYLNWYQQKPGQAPRLLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYFCQQGNTLPYTFGQGTKLEIKGGGGSGGGGSGGGGSGGGGSQVQLQESGPGLVKPSETLSLTCTVSGVSLPDYGVSWIRQPPGKGLEWIGVIWGSETTYYSSSLKSRVTISKDNSKNQVSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSSTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 257 CD19 CAR 6 MALPVTALLLPLALLLHAARPEIVMTQSPATLSLSPGERATLSCRASQDISKYLNWYQQKPGQAPRLLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYFCQQGNTLPYTFGQGTKLEIKGGGGSGGGGSGGGGSGGGGSQVQLQESGPGLVKPSETLSLTCTVSGVSLPDYGVSWIRQPPGKGLEWIGVIWGSETTYYQSSLKSRVTISKDNSKNQVSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSSTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 258 CD19 CAR 7 MALPVTALLLPLALLLHAARPQVQLQESGPGLVKPSETLSLTCTVSGVSLPDYGVSWIRQPPGKGLEWIGVIWGSETTYYSSSLKSRVTISKDNSKNQVSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSEIVMTQSPATLSLSPGERATLSCRASQDISKYLNWYQQKPGQAPRLLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYFCQQGNTLPYTFGQGTKLEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 259 CD19 CAR 8 MALPVTALLLPLALLLHAARPQVQLQESGPGLVKPSETLSLTCTVSGVSLPDYGVSWIRQPPGKGLEWIGVIWGSETTYYQSSLKSRVTISKDNSKNQVSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSEIVMTQSPATLSLSPGERATLSCRASQDISKYLNWYQQKPGQAPRLLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYFCQQGNTLPYTFGQGTKLEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 260 CD19 CAR 9 MALPVTALLLPLALLLHAARPEIVMTQSPATLSLSPGERATLSCRASQDISKYLNWYQQKPGQAPRLLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYFCQQGNTLPYTFGQGTKLEIKGGGGSGGGGSGGGGSGGGGSQVQLQESGPGLVKPSETLSLTCTVSGVSLPDYGVSWIRQPPGKGLEWIGVIWGSETTYYNSSLKSRVTISKDNSKNQVSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSSTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 261 CD19 CAR 10 MALPVTALLLPLALLLHAARPEIVMTQSPATLSLSPGERATLSCRASQDISKYLNWYQQKPGQAPRLLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYFCQQGNTLPYTFGQGTKLEIKGGGGSGGGGSGGGGSGGGGSQVQLQESGPGLVKPSETLSLTCTVSGVSLPDYGVSWIRQPPGKGLEWIGVIWGSETTYYNSSLKSRVTISKDNSKNQVSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSSTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 262 CD19 CAR 11 MALPVTALLLPLALLLHAARPQVQLQESGPGLVKPSETLSLTCTVSGVSLPDYGVSWIRQPPGKGLEWIGVIWGSETTYYNSSLKSRVTISKDNSKNQVSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSEIVMTQSPATLSLSPGERATLSCRASQDISKYLNWYQQKPGQAPRLLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYFCQQGNTLPYTFGQGTKLEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 263 CD19 CAR 12 MALPVTALLLPLALLLHAARPEIVMTQSPATLSLSPGERATLSCRASQDISKYLNWYQQKPGQAPRLLIYHTSRLHSGIPARFSGSGSGTDYTLTISSLQPEDFAVYFCQQGNTLPYTFGQGTKLEIKGGGGSGGGGSGGGGSQVQLQESGPGLVKPSETLSLTCTVSGVSLPDYGVSWIRQPPGKGLEWIGVIWGSETTYYNSSLKSRVTISKDNSKNQVSLKLSSVTAADTAVYYCAKHYYYGGSYAMDYWGQGTLVTVSSTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 264

In one aspect, a CAR (e.g., a CAR expressed by a cell of the present disclosure) comprises a CAR molecule comprising an antigen-binding domain that binds BCMA, e.g., comprising a BCMA antigen-binding domain (e.g., specifically binds BCMA (e.g., human BCMA) ), a transmembrane domain, and an intracellular signaling domain (eg, an intracellular signaling domain comprising a co-stimulatory domain and/or a primary signaling domain).

Exemplary CAR molecules for the CARs described herein are provided in Table 1 of WO 2016/014565. transmembrane domain

Regarding the transmembrane domain, in various embodiments, the CAR can be designed to comprise a transmembrane domain attached to the extracellular domain of the CAR. The transmembrane domain may include one or more additional amino acids adjacent to the transmembrane region, such as one or more amino acids associated with the extracellular region of a protein of transmembrane origin (e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 to 15 amino acids) and/or one or more additional amine groups associated with intracellular regions of transmembrane-derived proteins Acids (eg, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 up to 15 amino acids of the intracellular region). In one aspect, the transmembrane domain is a domain that is related to one of the other domains of the CAR, for example, in one embodiment, the transmembrane domain can be derived from a signaling domain, costimulatory domain, or hinge domain. of the same protein. In another aspect, the transmembrane domain is not derived from the same protein from which any other domain of the CAR is derived. In some cases, transmembrane domains can be selected or modified by amino acid substitutions to avoid binding of such domains to transmembrane domains of the same or different surface membrane proteins, for example to minimize interaction with receptor complexes. interactions with other members. In one aspect, the transmembrane domain is capable of homodimerization with another CAR on the cell surface of the CAR-expressing cell. In various aspects, the amino acid sequence of the transmembrane domain can be modified or substituted in order to minimize interaction with the binding domain of a natural binding partner present in the same CAR-expressing cell.

Transmembrane domains can be derived from natural sources or from recombinant sources. Where native in origin, this domain may be derived from any membrane-bound or transmembrane protein. In one aspect, the transmembrane domain is capable of signaling to one or more intracellular domains whenever the CAR binds a target. Transmembrane domains specifically used in the present disclosure may include at least, for example, the alpha, beta or zeta chain of a T cell receptor, CD28, CD27, CD3 epsilon, CD45, CD4, CD5, CD8, CD9, CD16, CD22, CD33, One or more transmembrane regions of CD37, CD64, CD80, CD86, CD134, CD137, CD154. In some embodiments, the transmembrane domain can include at least, for example, KIRDS2, OX40, CD2, CD27, LFA-1 (CD11a, CD18), ICOS (CD278), 4-1BB (CD137), GITR, CD40, BAFFR, HVEM (LIGHTR), SLAMF7, NKp80 (KLRF1), NKp44, NKp30, NKp46, CD160, CD19, IL2Rβ, IL2Rγ, IL7Rα, ITGA1, 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, TNFR2, DNAM1 (CD226), SLAMF4 (CD244, 2B4), CD84, CD96 (Tactile), CEACAM1, CRTAM, Ly9 (CD229), CD160 (BY55), PSGL1, CD100 (SEMA4D), SLAMF6 (NTB-A, Ly108), SLAM (SLAMF1, CD150, IPO-3), BLAME ( One or more transmembrane regions of SLAMF8), SELPLG (CD162), LTBR, PAG/Cbp, NKG2D, NKG2C.

In some cases, the transmembrane domain can be attached to the extracellular region of the CAR (eg, the antigen-binding domain of the CAR) by a hinge (eg, from a human protein). For example, in one embodiment, the hinge may be a human Ig (immunoglobulin) hinge (eg, IgG4 hinge, IgD hinge), a GS linker (eg, the GS linker described herein), a KIR2DS2 hinge, or a CD8a hinge. In one embodiment, the hinge or spacer comprises (eg consists of) the amino acid sequence of SEQ ID NO: 265. In one aspect, the transmembrane domain comprises (eg, consists of) the transmembrane domain of SEQ ID NO: 266.

In certain embodiments, the encoded transmembrane domain comprises a CD8 transmembrane having at least one, two or three modifications, but no more than 20, 10 or 5 modifications, of the amino acid sequence of SEQ ID NO: 266 The amino acid sequence of the domain, or a sequence having at least 95% identity to the amino acid sequence of SEQ ID NO: 266. In one embodiment, the encoded transmembrane domain comprises the sequence of SEQ ID NO: 266.

In other embodiments, the CAR-encoding nucleic acid molecule comprises a nucleotide sequence of the transmembrane domain of CD8, for example comprising a sequence of SEQ ID NO: 267 or SEQ ID NO: 304, or a sequence having at least 95% identity thereof.

In certain embodiments, the encoded antigen binding domain is linked to the transmembrane domain by a hinge region. In one embodiment, the encoded hinge region comprises the amino acid sequence of CD8 hinge, such as SEQ ID NO: 265; or the amino acid sequence of IgG4 hinge, such as SEQ ID NO: 268, or with SEQ ID NO: 265 or SEQ ID NO: 268 is a sequence having at least 95% identity. In other embodiments, the nucleic acid sequence encoding the hinge region comprises the sequence of SEQ ID NO: 269 or SEQ ID NO: 270 corresponding to the CD8 hinge or IgG4 hinge, respectively, or has at least 95% identity with SEQ ID NO: 269 or 270 sexual sequence.

In one aspect, the hinge or spacer comprises an IgG4 hinge.例如，在一個實施方式中，該鉸鏈或間隔區包含胺基酸序列ESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGKM（SEQ ID NO: 268）的鉸鏈。在一些實施方式中，該鉸鏈或間隔區包含由GAGAGCAAGTACGGCCCTCCCTGCCCCCCTTGCCCTGCCCCCGAGTTCCTGGGCGGACCCAGCGTGTTCCTGTTCCCCCCCAAGCCCAAGGACACCCTGATGATCAGCCGGACCCCCGAGGTGACCTGTGTGGTGGTGGACGTGTCCCAGGAGGACCCCGAGGTCCAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCACAACGCCAAGACCAAGCCCCGGGAGGAGCAGTTCAATAGCACCTACCGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGACTGGCTGAACGGCAAGGAATACAAGTGTAAGGTGTCCAACAAGGGCCTGCCCAGCAGCATCGAGAAAACCATCAGCAAGGCCAAGGGCCAGCCTCGGGAGCCCCAGGTGTACACCCTGCCCCCTAGCCAAGAGGAGATGACCAAGAACCAGGTGTCCCTGACCTGCCTGGTGAAGGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAACGGCCAGCCCGAGAACAACTACAAGACCACCCCCCCTGTGCTGGACAGCGACGGCAGCTTCTTCCTGTACAGCCGGCTGACCGTGGACAAGAGCCGGTGGCAGGAGGGCAACGTCTTTAGCTGCTCCGTGATGCACGAGGCCCTGCACAACCACTACACCCAGAAGAGCCTGAGCCTGTCCCTGGGCAAGATG（SEQ ID NO: 270）的核苷酸序列編碼的鉸鏈。

In one aspect, the hinge or spacer comprises an IgD hinge.例如，在一個實施方式中，該鉸鏈或間隔區包含RWPESPKAQASSVPTAQPQAEGSLAKATTAPATTRNTGRGGEEKKKEKEKEEQEERETKTPECPSHTQPLGVYLLTPAVQDLWLRDKATFTCFVVGSDLKDAHLTWEVAGKVPTGGVEEGLLERHSNGSQSQHSRLTLPRSLWNAGTSVTCTLNHPSLPPQRLMALREPAAQAPVKLSLNLLASSDPPEAASWLLCEVSGFSPPNILLMWLEDQREVNTSGFAPARPPPQPGSTTFWAWSVLRVPAPPSPQPATYTCVVSHEDSRTLLNASRSLEVSYVTDH的胺基酸序列（SEQ ID NO: 271）的鉸鏈。在一些實施方式中，該鉸鏈或間隔區包含由AGGTGGCCCGAAAGTCCCAAGGCCCAGGCATCTAGTGTTCCTACTGCACAGCCCCAGGCAGAAGGCAGCCTAGCCAAAGCTACTACTGCACCTGCCACTACGCGCAATACTGGCCGTGGCGGGGAGGAGAAGAAAAAGGAGAAAGAGAAAGAAGAACAGGAAGAGAGGGAGACCAAGACCCCTGAATGTCCATCCCATACCCAGCCGCTGGGCGTCTATCTCTTGACTCCCGCAGTACAGGACTTGTGGCTTAGAGATAAGGCCACCTTTACATGTTTCGTCGTGGGCTCTGACCTGAAGGATGCCCATTTGACTTGGGAGGTTGCCGGAAAGGTACCCACAGGGGGGGTTGAGGAAGGGTTGCTGGAGCGCCATTCCAATGGCTCTCAGAGCCAGCACTCAAGACTCACCCTTCCGAGATCCCTGTGGAACGCCGGGACCTCTGTCACATGTACTCTAAATCATCCTAGCCTGCCCCCACAGCGTCTGATGGCCCTTAGAGAGCCAGCCGCCCAGGCACCAGTTAAGCTTAGCCTGAATCTGCTCGCCAGTAGTGATCCCCCAGAGGCCGCCAGCTGGCTCTTATGCGAAGTGTCCGGCTTTAGCCCGCCCAACATCTTGCTCATGTGGCTGGAGGACCAGCGAGAAGTGAACACCAGCGGCTTCGCTCCAGCCCGGCCCCCACCCCAGCCGGGTTCTACCACATTCTGGGCCTGGAGTGTCTTAAGGGTCCCAGCACCACCTAGCCCCCAGCCAGCCACATACACCTGTGTTGTGTCCCATGAAGATAGCAGGACCCTGCTAAATGCTTCTAGGAGTCTGGAGGTTTCCTACGTGACTGACCATT（SEQ ID NO: 272）的核苷酸序列編碼的鉸鏈。

In one aspect, the transmembrane domain may be recombinant, in which case it will primarily comprise hydrophobic residues, such as leucine and valine. In one aspect, a triplet of phenylalanine, tryptophan, and valine can be found at each end of the recombinant transmembrane domain.

Optionally, short oligopeptide or polypeptide linkers, between 2 and 10 amino acids in length, can form linkages between the transmembrane domain and the cytoplasmic region of the CAR. The glycine-serine doublet provides a particularly suitable linker. For example, in one aspect, the linker comprises the amino acid sequence of GGGGSGGGGS (SEQ ID NO: 273). In some embodiments, the linker is encoded by the nucleotide sequence of GGTGGCGGAGGTTCTGGAGGTGGAGGTTCC (SEQ ID NO: 274).

In one aspect, the hinge or spacer comprises a KIR2DS2 hinge. signaling domain

In embodiments of the disclosure having intracellular signaling domains, such domains may contain, for example, one or more of a primary signaling domain and/or a co-stimulatory signaling domain. In some embodiments, the intracellular signaling domain comprises a sequence encoding a primary signaling domain. In some embodiments, the intracellular signaling domain comprises a co-stimulatory signaling domain. In some embodiments, the intracellular signaling domain comprises a primary signaling domain and a co-stimulatory signaling domain.

The intracellular signaling sequences within the cytoplasmic portion of the CAR of the present disclosure can be linked to each other in random or specified order. Optionally, short oligopeptide or polypeptide linkers, e.g., between 2 and 10 amino acids in length (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids) Linkages between intracellular signaling sequences can be formed. In one embodiment, a glycine-serine doublet can be used as a suitable linker. In one embodiment, single amino acids (eg, alanine, glycine) can be used as suitable linkers.

In one aspect, the intracellular signaling domain is designed to comprise two or more (eg, 2, 3, 4, 5, or more) co-stimulatory signaling domains. In embodiments, two or more (eg, 2, 3, 4, 5, or more) costimulatory signaling domains are separated by a linker molecule (eg, a linker molecule described herein). In one embodiment, the intracellular signaling domain comprises two co-stimulatory signaling domains. In some embodiments, the linker molecule is a glycine residue. In some embodiments, the linker is an alanine residue. primary signaling domain

The primary signaling domain regulates the primary activation of the TCR complex either in a stimulatory or inhibitory manner. Primary intracellular signaling domains that act in a stimulatory manner may contain signaling motifs known as immunoreceptor tyrosine-based activation motifs or ITAMs.

Examples of ITAMs containing primary intracellular signaling domains of particular use in this disclosure include those of the following: CD3 ζ, common FcR gamma (FCER1G), Fc gamma RIIa, FcR beta (Fc epsilon R1b), CD3 gamma, CD3 delta , CD3 epsilon, CD79a, CD79b, DAP10, and DAP12. In one embodiment, the CAR of the present disclosure comprises an intracellular signaling domain, such as the primary signaling domain of CD3-ζ.

In one embodiment, the encoded primary signaling domain comprises a functional signaling domain of CD3 zeta. The encoded CD3 ζ primary signaling domain may comprise at least one, two or three modified amines having the amino acid sequence of SEQ ID NO: 275 or SEQ ID NO: 276, but no more than 20, 10 or 5 modified amines An amino acid sequence, or a sequence having at least 95% identity to the amino acid sequence of SEQ ID NO: 275 or SEQ ID NO: 276. In some embodiments, the encoded primary signaling domain comprises the sequence of SEQ ID NO: 275 or SEQ ID NO: 276. In other embodiments, the nucleic acid sequence encoding the primary signaling domain comprises the sequence of SEQ ID NO: 277, SEQ ID NO: 303, or SEQ ID NO: 278, or a sequence that is at least 95% identical. co-stimulatory signaling domain

In some embodiments, the encoded intracellular signaling domain comprises a co-stimulatory signaling domain. For example, an intracellular signaling domain can comprise a primary signaling domain and a co-stimulatory signaling domain. In some embodiments, the encoded co-stimulatory signaling domain comprises a functional signaling domain of a protein selected from one or more of: CD27, CD28, 4-1BB (CD137), OX40, CD30, CD40, PD -1, ICOS, lymphocyte function-associated antigen-1 (LFA-1), CD2, CD7, LIGHT, NKG2C, B7-H3, ligands specifically binding to CD83, CDS, ICAM-1, GITR, BAFFR , HVEM (LIGHTR), SLAMF7, NKp80 (KLRF1), CD160, CD19, CD4, CD8α, CD8β, IL2R β, IL2R γ, IL7R α, 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, 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, NKp44, NKp30, NKp46, or NKG2D.

In certain embodiments, the encoded co-stimulatory signaling domain comprises at least one, two or three modifications, but no more than 20, 10, of the amino acid sequence of SEQ ID NO: 279 or SEQ ID NO: 280 Or 5 modified amino acid sequences, or a sequence having at least 95% identity with the amino acid sequence of SEQ ID NO: 279 or SEQ ID NO: 280. In one embodiment, the encoded co-stimulatory signaling domain comprises the sequence of SEQ ID NO: 279 or SEQ ID NO: 280. In other embodiments, the nucleic acid sequence encoding the co-stimulatory signaling domain comprises the sequence of SEQ ID NO: 281, SEQ ID NO: 305, or SEQ ID NO: 282, or a sequence at least 95% identical thereto.

In other embodiments, the encoded intracellular domain comprises the sequence of SEQ ID NO: 279 or SEQ ID NO: 280, and the sequence of SEQ ID NO: 275 or SEQ ID NO: 276, comprising an intracellular signaling domain The sequences of are represented in the same frame and appear as a single polypeptide chain.

In certain embodiments, the nucleic acid sequence encoding the intracellular signaling domain comprises the sequence of SEQ ID NO: 281, SEQ ID NO: 305, or SEQ ID NO: 282, and sequences at least 95% identical thereto, And the sequence of SEQ ID NO: 277, SEQ ID NO: 306, or SEQ ID NO: 278 or a sequence having at least 95% identity thereto.

In some embodiments, the nucleic acid molecule further encodes a leader sequence. In one embodiment, the leader sequence comprises the sequence of SEQ ID NO: 283.

In one aspect, the intracellular signaling domain is designed to comprise the signaling domain of CD3-zeta and the signaling domain of CD28. In one aspect, the intracellular signaling domain is designed to comprise the signaling domain of CD3-ζ and the signaling domain of 4-1BB. In one aspect, the signaling domain of 4-1BB is the signaling domain of SEQ ID NO: 279. In one aspect, the signaling domain of CD3-ζ is the signaling domain of SEQ ID NO: 275.

In one aspect, the intracellular signaling domain is designed to comprise the signaling domain of CD3-zeta and the signaling domain of CD27. In one aspect, the signaling domain of CD27 comprises the amino acid sequence of QRRKYRSNKGESPVEPAEPCRYSCPREEEGSTIPIQEDYRKPEPACSP (SEQ ID NO: 280). In one aspect, the signaling domain of CD27 is encoded by the nucleic acid sequence of CAACGAAGGAAATATAGATCAAACAAAGGAGAAAGTCCTGTGGAGCCTGCAGAGCCTTGTCGTTACAGCTGCCCCAGGGAGGAGGAGGGCAGCACCATCCCCATCCAGGAGGATTACCGAAAACCGGAGCCTGCCTGCTCCCCC (SEQ ID NO: 282). carrier

In another aspect, the present disclosure pertains to vectors comprising a nucleic acid sequence encoding a CAR described herein. In one embodiment, the vector is selected from DNA vectors, RNA vectors, plastids, lentiviral vectors, adenoviral vectors or retroviral vectors. In one embodiment, the vector is a lentiviral vector. These vectors, or portions thereof, can be used, inter alia, to generate template nucleic acids as described herein for use with the CRISPR systems described herein. Alternatively, the vectors can be used to deliver nucleic acids directly to cells, such as immune effector cells, such as T cells, such as allogeneic T cells (independent of the CRISPR system).

The present disclosure also provides vectors into which the DNA of the present disclosure is inserted. Delivery systems derived from retroviruses such as lentiviruses are suitable tools for long-term gene transfer, as they allow long-term stable integration of the transgene and its propagation in daughter cells. Lentiviral vectors have the added advantage of vectors derived from oncoretroviruses, such as murine leukemia virus, in that they can transduce non-proliferative cells, such as hepatocytes. They also have the added advantage of low immunogenicity. The retroviral vector may also be, for example, a gamma retroviral vector. A gammaretroviral vector may include, for example, a promoter, a packaging signal (ψ), a primer binding site (PBS), one or more (e.g., two) long terminal repeats (LTRs), and a transgene of interest (e.g., gene encoding CAR). Gamma retroviral vectors may lack viral structural genes (such as gag, pol, and env). Exemplary gamma retroviral vectors include murine leukemia virus (MLV), spleen focus forming virus (SFFV), and myeloproliferative sarcoma virus (MPSV), and vectors derived therefrom. Other gammaretroviral vectors are described, for example, in Tobias Maetzig et al., "Gammaretroviral Vectors: Biology, Technology and Application [gammaretroviral vectors: Biology/Technology and Application]" Viruses. [Virus] June 2011; 3( 6): 677-713.

In another embodiment, the carrier system comprising the nucleic acid encoding the desired CAR of the present disclosure is an adenovirus carrier (A5/35). In another embodiment, expression of a CAR-encoding nucleic acid can be accomplished using transposons such as the Sleeping Beauty system, crisper, CAS9, and zinc finger nucleases. See June et al. 2009 Nature Reviews Immunology 9.10: 704-716.

Nucleic acids can be cloned into many types of vectors. For example, nucleic acids can be cloned into vectors including, but not limited to, plastids, phagemids, phage derivatives, animal viruses, and cosmids. Vehicles of particular interest include expression vehicles, replication vehicles, probe generation vehicles and sequencing vehicles.

Disclosed herein are methods for generating in vitro transcribed RNA CARs. The disclosure also includes CAR-encoding RNA constructs that can be directly transfected into cells. Methods for generating mRNA for use in transfection may include in vitro transcription (IVT) of the template with specially designed primers, followed by the addition of polyA to generate mRNAs containing 3' and 5' untranslated sequences ("UTR"), 5 A construct of 'cap and/or internal ribosome entry site (IRES), nucleic acid to be expressed, and polyA tail, typically 50-2000 bases in length (SEQ ID NO: 310). The RNA thus produced can efficiently transfect different types of cells. In one aspect, the template includes the sequence of the CAR. Non-viral delivery methods

In some aspects, a nucleic acid encoding a CAR described herein can be delivered to a cell or tissue or subject using non-viral methods.

In some embodiments, non-viral methods include the use of transposons (also known as transposable elements). In some embodiments, a transposon line can insert itself into a piece of DNA at a location in the genome, for example, a piece of DNA capable of replicating itself and inserting a copy of it into the genome, or a line can be spliced out of a longer nucleic acid and inserted into A piece of DNA at another location in the genome. For example, a transposon comprises a DNA sequence consisting of inverted repeats for transposition flanking a gene.

In some embodiments, by using gene insertion (using SBTS) and gene editing (using nucleases (e.g., zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), CRISPR/Cas systems, or engineered meganuclease reengineered homing endonuclease)) to generate cells expressing the CARs described herein, such as T cells or NK cells.

In some embodiments, by subjecting the cells to (a) comprising (e.g., as described herein) one or more gRNA molecules and (e.g., as described herein) one or more Cas molecules (e.g., , a Cas9 molecule), and (b) a nucleic acid (eg, a template nucleic acid molecule as described herein) comprising a sequence encoding a CAR (eg, as described herein) is contacted to produce a cell of the present disclosure, such as a T cell or NK cells, such as allogeneic T cells (e.g., described herein) (e.g., expressing a CAR described herein). Without being bound by theory, the composition of (a) above will induce a break at or near the genomic DNA targeted by the targeting domain(s) of the gRNA molecule(s), and the nucleic acid of (b) will incorporate a break at or near the break. into (eg, partially or fully) the genome such that upon integration, the encoded CAR molecule is expressed. In embodiments, the expression of the CAR will be controlled by a promoter or other regulatory element endogenous to the genome (eg, a promoter controlling the expression of a gene from the nucleic acid inserted in (b)). In other embodiments, the nucleic acid of (b) further comprises (e.g., as described herein) a promoter and/or other regulatory elements (e.g., the EF1-α promoter) operably linked to the CAR-encoding sequence ), so that the expression of the CAR is under the control of the promoter and/or other regulatory elements upon integration. Additional features of the present disclosure are described elsewhere in this application, e.g. In the section on gene insertion and homologous recombination. In an embodiment, the above-mentioned composition of a) is a composition comprising RNP (containing one or more gRNA molecules). In embodiments, RNPs comprising gRNAs targeting unique target sequences are introduced into the cell simultaneously, eg, as a mixture of RNPs comprising one or more gRNAs. In embodiments, RNPs comprising gRNAs targeting unique target sequences are introduced sequentially into cells.

In some embodiments, the use of non-viral delivery methods allows the reprogramming of cells, such as T cells or NK cells, and infusion of these cells directly into a subject. Advantages of non-viral vehicles include, but are not limited to, the ease and relatively low cost of producing sufficient quantities to satisfy a patient population, stability during storage, and lack of immunogenicity. Promoter

In one embodiment, the carrier further comprises a promoter. In some embodiments, the promoter is selected from the group consisting of EF-1 promoter, CMV IE gene promoter, EF-1α promoter, ubiquitin C promoter, or phosphoglycerate kinase (PGK) promoter. In one embodiment, the promoter is the EF-1 promoter. In one embodiment, the EF-1 promoter comprises the sequence of SEQ ID NO: 285. Host Cells for CAR Expression

As noted above, in some aspects, the present disclosure pertains to a cell, such as an immune effector cell (eg, a population of cells, such as a population of immune effector cells), comprising a nucleic acid molecule, CAR polypeptide molecule, or vehicle as described herein.

In certain aspects of the present disclosure, immune effector cells, such as T cells, can be obtained from blood units collected from a subject using any number of techniques known to those skilled in the art, such as Ficoll™ isolation. In a preferred aspect, cells from the circulating blood of the individual are obtained by apheresis. Apheresis products typically contain lymphocytes, including T cells, monocytes, granulocytes, B cells, other nucleated white blood cells, red blood cells, and platelets. In one aspect, cells collected by apheresis can be washed to remove the plasma fraction and optionally placed in an appropriate buffer or culture medium for subsequent processing steps. In one embodiment of the present invention, the cells are washed with phosphate buffered saline (PBS). In alternative embodiments, the wash solution lacks calcium and may lack magnesium, or may lack many, if not all, divalent cations.

An initial activation step in the absence of calcium can result in an amplified activation. As will be readily understood by those skilled in the art, the washing step can be accomplished by methods known to those skilled in the art, such as by using a semi-automatic "flow-through" centrifuge (e.g., Cobe 2991 Cell Processor, Baxter CytoMate, or Haemonetics Cell Saver 5). After washing, the cells can be resuspended in various biocompatible buffers, such as, for example, Ca-free, Mg-free PBS, Bomalis A, or other saline solutions with or without buffers. Alternatively, an apheresis sample can be stripped of unwanted components and the cells resuspended directly in culture medium.

It should be appreciated that the methods of the present application can utilize media conditions comprising 5% or less (e.g., 2%) human AB serum, and use known media conditions and compositions, such as those described in: Smith et al. , "Ex vivo expansion of human T cells for adoptive immunotherapy using the novel Xeno-free CTS Immune Cell Serum Replacement [using the novel Xeno-free CTS immune cell serum substitute for adoptive immunotherapy of human T cells ex vivo expansion]" Clinical & Translational Immunology (2015) 4, e31; doi: 10.1038/cti.2014.31.

In one aspect, T cells are isolated from peripheral blood lymphocytes by lysing erythrocytes and depleting monocytes, eg, by PERCOLL ^™ gradient centrifugation or by countercurrent centrifugation.

The methods described herein may include, for example, using, for example, negative selection techniques such as those described herein to select a particular subpopulation of immune effector cells (e.g., T cells), which subpopulation is a T regulatory cell depleted population, CD25+ depleted reduced cells. Preferably, the T regulatory-depleted cell population contains less than 30%, 25%, 20%, 15%, 10%, 5%, 4%, 3%, 2%, 1% CD25+ cells.

In one embodiment, T regulatory cells (eg, CD25+ T cells) are depleted from the population using an anti-CD25 antibody or fragment thereof, or the CD25 binding ligand IL-2. In one embodiment, an anti-CD25 antibody or fragment thereof, or a CD25-binding ligand is conjugated to or otherwise coated on a substrate (eg, beads). In one embodiment, an anti-CD25 antibody or fragment thereof is conjugated to a substrate as described herein.

In one embodiment, T regulatory cells (eg, CD25+ T cells) are removed from the population using a CD25 depleting agent from Miltenyi ^™ . In one embodiment, the ratio of cells to CD25 depleting agent is 1e7 cells to 20 uL, or 1e7 cells to 15 uL, or 1e7 cells to 10 uL, or 1e7 cells to 5 uL, or 1e7 cells to 2.5 uL, or 1e7 cells to 1.25 uL. In one embodiment, for example for T regulatory cell (eg CD25+) depletion greater than 500 million cells/ml is used. In additional aspects, a cell concentration of 600, 700, 800, or 900 million cells/ml is used.

In one embodiment, the population of immune effector cells to be depleted comprises about 6 x ¹⁰⁹ CD25+ T cells. In other aspects, the population of immune effector cells to be depleted comprises about 1 x ¹⁰⁹ to 1 x ¹⁰¹⁰ CD25+ T cells, and any integer value therebetween. In one embodiment, the resulting population of T regulatory-depleted cells has 2 x ¹⁰⁹ T regulatory cells (eg, CD25+ cells) or fewer (eg, 1 x ¹⁰⁹ , 5 x ¹⁰⁸ , 1 x 10 ⁸ , 5 x 10 ⁷ , 1 x 10 ⁷ or fewer CD25+ cells).

In one embodiment, T regulatory cells (eg, CD25+ cells) are removed from this population using the CliniMAC system with a depleting tube set (eg, like tube 162-01). In one embodiment, the CliniMAC system is run on a depletion setting (eg like DEPLETION 2.1).

Without wishing to be bound by a particular theory, reducing negative regulator levels of immune cells in a subject prior to apheresis or during manufacture of a CAR-expressing cell product (e.g., reducing unwanted immune cells such as T _REG cells )) can reduce the subject's risk of relapse. For example, methods to deplete T _REG cells are known in the art. Methods of reducing T _REG cells include, but are not limited to, cyclophosphamide, anti-GITR antibodies (anti-GITR antibodies described herein), CD25 depletion, and combinations thereof.

In some embodiments, the method of manufacture comprises reducing (eg, depleting) the number of T _REG cells prior to making the CAR-expressing cells. For example, the method of manufacture includes contacting a sample (e.g., an apheresis sample) with an anti-GITR antibody and/or an anti-CD25 antibody (or a fragment thereof, or a CD25-binding ligand), e.g., in the manufacture of CAR-expressing cells (e.g., T cells, NK cells) products before depleting T _REG cells.

In an embodiment, the subject is pre-treated with one or more T _REG cell-reducing therapies prior to harvesting the cells for CAR-expressing cell product production, thereby reducing the subject's risk of relapse to CAR-expressing cell therapy. In embodiments, methods of reducing T _REG cells include, but are not limited to, administering to a subject one or more of cyclophosphamide, anti-GITR antibody, CD25 depletion, or a combination thereof. Administration of one or more of cyclophosphamide, anti-GITR antibody, CD25 depletion, or a combination thereof can occur before, during, or after infusion of the CAR-expressing cell product.

In an embodiment, the subject is pre-treated with cyclophosphamide prior to harvesting the cells for production of the CAR-expressing cell product, thereby reducing the subject's risk of relapse to the CAR-expressing cell therapy. In an embodiment, the subject is pre-treated with an anti-GITR antibody prior to harvesting the cells for production of the CAR-expressing cell product, thereby reducing the subject's risk of relapse to the CAR-expressing cell therapy.

In one embodiment, the cell population to be removed is neither regulatory T cells, nor tumor cells, nor cells that otherwise negatively affect the expansion and/or function of CART cells (e.g. expressing CD14, CD11b, CD33 , CD15, or other markers expressed by potentially immunosuppressive cells). In one embodiment, it is contemplated that such cells are removed in parallel with regulatory T cells and/or tumor cells, or after depletion, or in another order.

The methods described herein may comprise more than one selection step, eg more than one depletion step. Enrichment of a T cell population by negative selection can be accomplished, for example, with a combination of antibodies directed against surface markers specific to the negatively selected cells. One method is cell sorting and/or selection by negative magnetic immunoadsorption or flow cytometry using detection of cell surface markers present on negatively selected cells. A mixture of monoclonal antibodies. For example, to enrich for CD4+ cells by negative selection, the monoclonal antibody cocktail can include antibodies against CD14, CD20, CD11b, CD16, HLA-DR, and CD8.

The methods described herein may further comprise removing cells from a population expressing a tumor antigen (e.g., a tumor antigen that does not comprise CD25, such as CD19, CD30, CD38, CD123, CD20, CD14, or CD11b), thereby providing T regulatory depleted ( For example CD25+ depleted) and tumor antigen depleted cell populations that are suitable for expressing a CAR such as a CAR described herein. In one embodiment, cells expressing tumor antigens are depleted simultaneously with T regulatory, eg, CD25+ cells. For example, an anti-CD25 antibody or fragment thereof, and an anti-tumor antigen antibody or fragment thereof can be attached to the same substrate (e.g., beads) that can be used to remove cells, or anti-CD25 antibody or fragment thereof, or anti-tumor antigen antibody or fragment thereof. ), can be attached to separate beads (a mixture of which can be used to remove cells). In other embodiments, the depletion of T regulatory cells (eg, CD25+ cells) and the depletion of cells expressing tumor antigens are sequential and can occur, eg, in any order.

Also provided are methods comprising removing cells (e.g., one or more of PD1+ cells, LAG3+ cells, and TIM3+ cells) from a population expressing a checkpoint inhibitor, such as a checkpoint inhibitor described herein, thereby providing T Populations of regulatory depleted (eg CD25+ depleted) cells and checkpoint inhibitor depleted cells (eg PD1+, LAG3+ and/or TIM3+ depleted cells). Exemplary checkpoint inhibitors include B7-H1, B7-1, CD160, P1H, 2B4, PD1, TIM3, CEACAM (eg CEACAM-1, CEACAM-3 and/or CEACAM-5), LAG3, TIGIT, CTLA-4 , BTLA and LAIR1. In one embodiment, cells expressing a checkpoint inhibitor are depleted simultaneously with T regulatory, eg, CD25+ cells. For example, an anti-CD25 antibody or fragment thereof, and an anti-checkpoint inhibitor antibody or fragment thereof can be attached to the same bead that can be used to remove cells, or an anti-CD25 antibody or fragment thereof, and an anti-checkpoint inhibitor antibody or fragment thereof , can be attached to separate beads (a mixture of which can be used to remove cells). In other embodiments, the depletion of T regulatory cells (eg, CD25+ cells) and the depletion of cells expressing a checkpoint inhibitor are sequential and can occur, eg, in any order.

The methods described herein may include a positive selection step. For example, T cells can be isolated by incubating with anti-CD3/anti-CD28 (eg 3 x 28) conjugated beads (eg DYNABEADS® M-450 CD3/CD28 T) for a period of time sufficient to positively select the desired T cells. In one embodiment, the period of time is about 30 minutes. In other embodiments, the period of time ranges from 30 minutes to 36 hours or longer and all integer values therebetween. In other embodiments, the period of time is at least 1, 2, 3, 4, 5, or 6 hours. In yet another embodiment, the period of time is 10 to 24 hours, such as 24 hours. In any situation where fewer T cells are present, such as isolating tumor-infiltrating lymphocytes (TILs) from tumor tissue or from immunocompromised individuals, longer incubation times can be used to isolate T cells compared to other cell types. In addition, using longer incubation times can increase the efficiency of CD8+ T cell capture. Thus, by simply shortening or prolonging the time that T cells are allowed to bind to CD3/CD28 beads and/or by increasing or decreasing the ratio of beads to T cells (as further described herein), it is possible to either start the culture or at the beginning of the culture. Other time points during the process preferentially select for or target T cell subsets. Additionally, by increasing or decreasing the ratio of anti-CD3 and/or anti-CD28 antibodies on beads or other surfaces, T cell subsets can be preferentially selected or targeted at the initiation of culture or at other desired time points.

In one embodiment, a T cell population can be selected that expresses one or more of: IFN-γ, TNFα, IL-17A, IL-2, IL-3, IL-4, GM-CSF, IL-10, IL-13, granzyme B, and perforin, or other appropriate molecules (eg, other cytokines). The method for screening cell expression can be obtained through, for example, PCT Publication No. WO 2013/126712.

To isolate desired cell populations by positive or negative selection, the concentration of cells and surfaces (eg particles such as beads) can be varied. In some aspects, it may be desirable to significantly reduce the volume in which beads and cells are mixed together (eg, increase the concentration of cells) to ensure maximum cell and bead contact. For example, in one aspect, a concentration of 10 billion cells/ml, 9 billion/ml, 8 billion/ml, 7 billion/ml, 6 billion/ml, or 5 billion/ml is used. In one aspect, a concentration of 1 billion cells/ml is used. In yet another aspect, a cell concentration of 75, 80, 85, 90, 95, or 100 million cells/ml is used. In additional aspects, concentrations of 125 or 150 million cells/ml can be used.

Use of high concentrations can result in increased cell yield, cell activation, and cell expansion. Furthermore, the use of high cell concentrations allows more efficient capture of cells that may weakly express the target antigen of interest (such as CD28-negative T cells), or cells from samples where many tumor cells are present (such as leukemic blood, tumor tissue, etc.). Such cell populations may have therapeutic value and are desirable. For example, using high concentrations of cells allows for more efficient selection of CD8+ T cells that typically have a weaker CD28 expression.

In a related aspect, it may be desirable to use lower cell concentrations. Particle-cell interactions are minimized by significantly diluting the mixture of T cells and surfaces such as particles (eg, beads). This selects for cells expressing large quantities of the desired antigen to be bound to the particle. For example, CD4+ T cells exhibit higher levels of CD28 and are more efficiently captured than CD8+ T cells at dilute concentrations. In one aspect, the concentration of cells used is 5 x ¹⁰⁶ /ml. In other aspects, the concentration used can be from about 1 x ¹⁰⁵ /ml to 1 x ¹⁰⁶ /ml, and any integer value therebetween.

In other aspects, the cells can be incubated on a rotator at different speeds at 2°C-10°C or at room temperature for different lengths of time.

T cells used for stimulation can also be frozen after washing steps. Without wishing to be bound by theory, the freezing and subsequent thawing steps provide a more uniform product by removing granulocytes and to some extent monocytes in the cell population. Following a washing step to remove plasma and platelets, cells can be suspended in freezing solution. While many freezing solutions and parameters are known in the art and will be useful in this situation, one method involves the use of PBS containing 20% DMSO and 8% human serum albumin, or 10% dextran 40 and 5% glucose, 20% human serum albumin and 7.5% DMSO, or containing 31.25% Bomalis-A, 31.25% glucose 5%, 0.45% NaCl, 10% dextran 40 and 5% glucose, 20 % human serum albumin and 7.5% DMSO, or other suitable cell freezing medium containing e.g. In the gas phase of the nitrogen storage tank. Other methods of controlled freezing can be used as well as immediate uncontrolled freezing at -20°C or in liquid nitrogen.

In certain aspects, cryopreserved cells are thawed and washed as described herein, and allowed to stand at room temperature for one hour prior to activation using the methods of the present disclosure.

It is also contemplated in the context of the present disclosure that blood samples or apheresis products are collected from a subject for a period of time before expansion of cells as described herein may be required. Thus, a source of cells to be expanded can be harvested at any necessary time point, and the desired cells, such as T cells, can be isolated and frozen for subsequent use in immune effector cell therapy for patients who would benefit from immune effector cell therapy Any number of diseases or conditions, such as those described herein. In one aspect, a blood sample or apheresis is taken from a substantially healthy subject. In certain aspects, a blood sample or apheresis is taken from a substantially healthy subject who is at risk of developing a disease, but has not yet developed a disease, and the cells of interest are isolated and frozen for later use. In some aspects, T cells can be expanded, frozen, and used later. In certain aspects, samples are collected from patients shortly after diagnosis of a particular disease as described herein but before any treatment. In a further aspect, cells are isolated from a blood sample or apheresis from a subject prior to any number of relevant treatment modalities, including but not limited to treatment with agents such as natalizumab monoclonal antibody (natalizumab, efalizumab, antiviral agents), chemotherapy, radiation, immunosuppressive agents (such as cyclosporine, azathioprine, methotrexate, mycophenolate mofetil, and FK506), antibodies or Other immune depleting agents (eg, CAMPATH, anti-CD3 antibodies, cyclophosphamide, fludarabine, cyclosporine, FK506, rapamycin, mycophenolic acid, steroids, FR901228), and irradiation.

In additional aspects of the present disclosure, the T cells are obtained directly from the patient after weaning the subject off of treatment with functional T cells. In this regard, it has been observed that following certain cancer treatments (particularly those with drugs that disrupt the immune system), shortly after treatment during which the patient would normally recover from treatment, the quality of the T cells obtained is due to their ex vivo The ability to amplify may be optimal or improved. Likewise, following ex vivo manipulation using the methods described herein, the cells may be in an optimal state for enhanced engraftment and in vivo expansion. Thus, collection of blood cells, including T cells, dendritic cells, or other cells of the hematopoietic lineage during this recovery phase is contemplated in the context of the present disclosure. Additionally, in certain aspects, mobilization (e.g., with GM-CSF) and adjustment protocols can be used to create a pathology in a subject wherein repopulation, recycling, regeneration, and/or expansion of specific cell types This is advantageous, especially within a defined time window after treatment. Illustrative cell types include T cells, B cells, dendritic cells, and other cells of the immune system.

In one embodiment, immune effector cells expressing a CAR molecule (eg, a CAR molecule described herein) are obtained from a subject who has received a low immunoenhancing dose of an mTOR inhibitor. In an embodiment, the population of immune effector cells (e.g., T cells) engineered to express a CAR is harvested after sufficient time (or following a sufficient dose of a low immunoenhancing dose of an mTOR inhibitor) such that in the subject or the level of PD1-negative immune effector cells (e.g., T cells), or the ratio of PD1-negative immune effector cells (e.g., T cells)/PD1-positive immune effector cells (e.g., T cells) harvested from the subject has increased at least transiently up.

In other embodiments, populations of immune effector cells (e.g., T cells) that have been, or will be, engineered to express a CAR can be treated ex vivo by exposure to an amount of an mTOR inhibitor that increases PD1-negative The number of immune effector cells (eg, T cells), or increasing the ratio of PD1-negative immune effector cells (eg, T cells)/PD1-positive immune effector cells (eg, T cells).

In one embodiment, the population of T cells is diacylglycerol kinase (DGK) deficient. DGK-deficient cells include cells that do not express DGK RNA, or protein, or have reduced, or inhibited, DGK activity. DGK-deficient cells can be generated by genetic methods, such as administration of RNA interference agents (eg siRNA, shRNA, miRNA) to reduce or prevent DGK expression. Alternatively, DGK-deficient cells can be generated by treatment with a DGK inhibitor as described herein.

In one embodiment, the T cell population is Ikaros deficient. Ikaros-deficient cells include cells that do not express Ikaros RNA, or protein, or have reduced or suppressed Ikaros activity, and Ikaros-deficient cells can be generated by genetic methods, such as administering RNA interfering agents (such as siRNA, shRNA, miRNA) to Reduce or prevent Ikaros manifestations. Alternatively, Ikaros-deficient cells can be generated by treatment with an Ikaros inhibitor (eg, lenalidomide).

In an embodiment, the population of T cells is DGK deficient and Ikaros deficient, eg, does not express DGK and Ikaros, or has reduced or suppressed DGK and Ikaros activities. Such DGK and Ikaros deficient cells can be generated by any of the methods described herein.

In an embodiment, NK cells are obtained from a subject. In another embodiment, the NK cell line is an NK cell line, such as NK-92 cell line (Conkwest Company).

In some aspects, the cells of the disclosure (e.g., the immune effector cells of the disclosure, e.g., the CAR-expressing cells of the disclosure) are induced pluripotent stem cells (“iPSCs”) or embryonic stem cells (ESCs), or are derived from iPSCs. and/or T cells generated from (eg, differentiated from) ESCs. For example, iPSCs can be generated from peripheral blood T lymphocytes (eg, peripheral blood T lymphocytes isolated from healthy volunteers) by methods known in the art. Likewise, such cells can be differentiated into T cells by methods known in the art. See eg, Themeli M. et al., Nat. Biotechnol . [Nature Biotechnology], 31, pp. 928-933 (2013); doi: 10.1038/nbt.2678; WO 2014/165707.

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WO 2016/103155 US 9580437 EP 3237418 A51   

US 9,512,084 WO/2015/079417 A52   

WO 2010/002655 US 8,519,129 A53   

WO 2010/002655 US 8,519,129 A54   

WO 2010/002655 雌激素受體拮抗劑 In another embodiment, a TGFβ inhibitor of the present disclosure (and/or a PD1, PD-L1, or PD-L2 inhibitor) is combined with the patents and patent applications listed in Table 13 or cited in Table 13. One or more of the above therapeutic agents are used in combination to treat cancer. Each publication (including all structures therein) is listed in Table 13. Table 13 . Second dose number generic trade name Compound structure Patent / Patent Application Publication A1 Sotrastaurin

EP 1682103 US 2007/142401 WO 2005/039549 A2 Nilotinib HCl Monohydrate TASIGNA®

HCl • H ₂ O WO 2004/005281 US 7,169,791 A3

WO 2011/023773 A4

WO 2012/149413 A6

WO 2010/029082 A7

WO 2015/107493 A8 WO 2015/107495 A9

WO 2011/076786 A10 Deerasirox EXJADE®

WO 1997/049395 A11 Letrozole FEMARA®

US 4,978,672 A12

WO 2013/124826 US 2013/0225574 A13

WO 2013/111105 A14

WO2007/121484 A15 Imatinib Mesylate GLEEVEC®

mesylate WO 1999/003854 A16 capmatinib

Dihydrochloride EP 2099447 US 7,767,675 US 8,420,645 A17 Ruxolitinib Phosphate JAKAFI®

H ₃ PO ₄ WO 2007/070514; EP 2474545 US 7,598,257; WO 2014/018632 A18 panobinostat

WO 2014/072493 WO 2002/022577 EP 1870399 A20

WO 2008/016893 EP 2051990 US 8,552,003 A21

WO2015/022662 A22 Ceritinib ZYKADIA™

WO 2008/073687 US 8,039,479 A23 Ribociclib KISQALI®

US 8,415,355 US 8,685,980 A24

WO 2010/007120 A26

WO 2011/101409 A27 Human monoclonal antibody to HER3 WO 2012/022814 EP 2606070 US 8,735,551 A28 Antibody Drug Conjugates (ADCs) WO 2014/160160 A29 Monoclonal antibody or Fab to M-CSF WO 2004/045532 A30 Midostaurin

WO 2003/037347 EP 1441737 US 2012/252785 A31 Everolimus AFINITOR®

WO 1994/009010 WO 2014/085318 A32

WO 2007/030377 US 7,482,367 A34

WO 2006/122806 A35

WO 2008/073687 US 8,372,858 A36 Penspodar AMDRAY™

EP 296122 A37 Vatalanib succinate

succinate WO 98/35958 A38

WO 2014/141104 A39 Asciminib

WO 2013/171639 WO 2013/171640 WO 2013/171641 WO2013/171642 A42

or its choline salt WO 2010/015613 WO 2013030803 US 7,989,497, A43 WO 2017/025918 WO 2011/121418 US 8,796,284 A44

WO 2010/101849 A45

WO 2014/130310 A46 Trametinib

WO 2005/121142 US 7,378,423 A47 Darafini

WO 2009/137391 US 7,994,185 A49 Octreotide

US 4,395,403 EP 0 029 579 A50

WO 2016/103155 US 9580437 EP 3237418 A51

US 9,512,084 WO/2015/079417 A52

WO 2010/002655 US 8,519,129 A53

WO 2010/002655 US 8,519,129 A54

WO 2010/002655 estrogen receptor antagonist

In some embodiments, an estrogen receptor (ER) antagonist is used in combination with a TGFβ inhibitor (and/or a PD1, PD-L1, or PD-L2 inhibitor) to treat a disease (eg, cancer). In some embodiments, the estrogen receptor antagonist is a selective estrogen receptor degrader (SERD). SERD is an estrogen receptor antagonist that binds to the receptor and causes, for example, degradation or downregulation of the receptor (Boer K. et al., (2017) Therapeutic Advances in Medical Oncology [Oncology Medicine Treatment Progress] 9(7): 465- 479). ER is a hormone-activated transcription factor important for, for example, the growth, development and physiology of the human reproductive system. ER is activated by, for example, the hormone estrogen (17β-estradiol). ER manifestations and signaling are involved in cancer (eg, breast cancer), such as ER positive (ER+) breast cancer. In some embodiments, the SERD is selected from LSZ102, fulvestrant, brilanestrant, or elacestrant. Exemplary Estrogen Receptor Antagonists

In some embodiments, the SERD comprises a compound disclosed in International Application Publication No. WO 2014/130310. In some embodiments, the SERD comprises LSZ102. LSZ102 has the chemical name: (E)-3-(4-((2-(2-(1,1-difluoroethyl)-4-fluorophenyl)-6-hydroxybenzo[b]thiophene-3 -yl)oxy)phenyl)acrylic acid. Other Exemplary Estrogen Receptor Antagonists

In some embodiments, the SERD comprises fulvestrant (CAS Registry Number: 129453-61-8) or a compound disclosed in International Application Publication No. WO 2001/051056. Fulvestrant is also known as ICI 182780, ZM 182780, FASLODEX®, or (7α,17β)-7-{9-[(4,4,5,5,5-pentafluoropentyl)sulfinyl] Nonyl}estra-1,3,5(10)-triene-3,17-diol. Fulvestrex is a high affinity estrogen receptor antagonist with IC50 of 0.29 nM.

In some embodiments, the SERD comprises Erastran (CAS Registry Number: 722533-56-4) or a compound disclosed in US Pat. No. 7,612,114. Erastran is also known as RAD1901, ER-306323, or (6R)-6-{2-[ethyl({4-[2-(ethylamino)ethyl]phenyl}methyl)amino] -4-methoxyphenyl}-5,6,7,8-tetralin-2-ol. Erastrol is an orally bioavailable, non-steroidal binding selective estrogen receptor modulator (SERM) and SERD. Erastran is also disclosed, for example, in Garner F et al., (2015) Anticancer Drugs [Anticancer Drugs] 26(9):948-56.

In some embodiments, the SERD is a compound disclosed in Bristrant (CAS Registry No.: 1365888-06-7) or International Application Publication No. WO 2015/136017. Brisatrant is also known as GDC-0810, ARN810, RG-6046, RO-7056118, or (2E)-3-{4-[(1E)-2-(2-chloro-4-fluorophenyl)-1 -(1H-Indazol-5-yl)but-1-en-1-yl]phenyl}prop-2-enoic acid. Brixtene is a next-generation orally bioavailable selective SERD with an IC50 of 0.7 nM. The Bliss group is also disclosed, for example, in Lai A. et al. (2015) Journal of Medicinal Chemistry [医药化学杂志] 58(12): 4888-4904.

In some embodiments, the SERD is selected from RU 58668, GW7604, AZD9496, bazedoxifene, pipendoxifene, arzoxifene, OP-1074, or acobifene, e.g., as described in McDonell et al. ( 2015) Disclosed in Journal of Medicinal Chemistry [Journal of Medicinal Chemistry] 58(12) 4883-4887. Other exemplary estrogen receptor antagonists are disclosed, for example, in WO 2011/156518, WO 2011/159769, WO 2012/037410, WO 2012/037411, and US 2012/0071535. CDK4/6 inhibitors

In some embodiments, an inhibitor of cyclin-dependent kinase 4 or 6 (CDK4/6) is used in combination with a TGFβ inhibitor (and/or a PD1, PD-L1, or PD-L2 inhibitor) to treat a disease (such as cancer). In some embodiments, the CDK4/6 inhibitor is selected from ribociclib, abemaciclib (Eli Lilly), or palbociclib. Exemplary CDK4/6 Inhibitors

In some embodiments, the CDK4/6 inhibitor comprises ribociclib (CAS registry number: 1211441-98-3) or a compound disclosed in US Pat. Nos. 8,415,355 and 8,685,980.

In some embodiments, the CDK4/6 inhibitor comprises a compound disclosed in International Application Publication No. WO 2010/020675, and US Patent Nos. 8,415,355 and 8,685,980.

In some embodiments, the CDK4/6 inhibitor comprises ribociclib (CAS Registry Number: 1211441-98-3). Ribociclib is also known as LEE011, KISQALI®, or 7-cyclopentyl-N,N-dimethyl-2-((5-(piperone-1-yl)pyridin-2-yl)amino) -7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide. Other Exemplary CDK4/6 Inhibitors

In some embodiments, the CDK4/6 inhibitor comprises Abeciclib (CAS Registry Number: 1231929-97-7). Abecicil is also known as LY835219 or N-[5-[(4-ethyl-1-piperyl)methyl]-2-pyridyl]-5-fluoro-4-[4-fluoro-2-methyl Base-1-(1-methylethyl)-1H-benzimidazol-6-yl]-2-pyrimidinamine. Abecicil is a CDK inhibitor selective for CDK4 and CDK6 and disclosed eg in Torres-Guzman R et al. (2017) Oncotarget 10.18632/oncotarget.17778.

In some embodiments, the CDK4/6 inhibitor comprises palbociclib (CAS Registry Number: 571190-30-2). Palbociclib is also known as PD-0332991, IBRANCE® or 6-acetyl-8-cyclopentyl-5-methyl-2-{[5-(1-piperyl)-2-pyridyl]amine Base}pyrido[2,3-d]pyrimidin-7(8H)-one. Palbociclib inhibits CDK4 (with an IC50 of 11 nM) and CDK6 (with an IC50 of 16 nM) and is disclosed eg in Finn et al. (2009) Breast Cancer Research 11(5): R77. CXCR2 inhibitors

In some embodiments, an inhibitor of chemokine (CXC motif) receptor 2 (CXCR2) is used in combination with a TGFβ inhibitor (and/or a PD1, PD-L1, or PD-L2 inhibitor) to treat Disease (such as cancer). In some embodiments, the CXCR2 inhibitor is selected from 6-chloro-3-((3,4-dioxo-2-(pentan-3-ylamino)cyclobut-1-en-1-yl )amino)-2-hydroxy-N-methoxy-N-methylbenzenesulfonamide, danirixin, reparixin, or navarixin. Exemplary CXCR2 Inhibitors

。 其他示例性 CXCR2 抑制劑 In some embodiments, the CXCR2 inhibitor comprises US Patent Nos. 7989497, 8288588, 8329754, 8722925, 9115087, US Application Publication Nos. US 2010/0152205, US 2011/0251205 and US 2011/0251206, and International Application Publication Compounds disclosed in WO 2008/061740, WO 2008/061741, WO 2008/062026, WO 2009/106539, WO 2010/063802, WO 2012/062713, WO 2013/168108, WO 2010/015613 and WO 2013/030803 . In some embodiments, the CXCR2 inhibitor comprises 6-chloro-3-((3,4-dioxo-2-(pentan-3-ylamino)cyclobut-1-en-1-yl )amino)-2-hydroxy-N-methoxy-N-methylbenzenesulfonamide or a choline salt thereof. In some embodiments, the CXCR2 inhibitor comprises 6-chloro-3-((3,4-dioxo-2-(pentan-3-ylamino)cyclobut-1-en-1-yl )amino)-2-hydroxy-N-methoxy-N-methylbenzenesulfonamide choline salt. In some embodiments, the CXCR2 inhibitor is 2-hydroxy-N,N,N-trimethylethyl-1-ammonium 3-chloro-6-({3,4-dioxo-2-[( Pentane-3-yl)amino]cyclobut-1-en-1-yl}amino)-2-(N-methoxy-N-methylsulfamoyl)phenol ester (i.e., 6- Chloro-3-((3,4-dioxo-2-(pentane-3-ylamino)cyclobut-1-en-1-yl)amino)-2-hydroxy-N-methoxy yl-N-methylbenzenesulfonamide choline salt) and has the following chemical structure:

. Other Exemplary CXCR2 Inhibitors

In some embodiments, the CXCR2 inhibitor comprises Danilicin (CAS Registry Number: 954126-98-8). Danilicin is also known as GSK1325756 or 1-(4-chloro-2-hydroxy-3-piperidin-3-ylsulfonylphenyl)-3-(3-fluoro-2-methylphenyl)urea. Danilicin is disclosed in, for example, Miller et al. Eur J Drug Metab Pharmacokinet [European Journal of Drug Metabolism and Pharmacokinetics] (2014) 39:173-181; and Miller et al. BMC Pharmacology and Toxicology [BMC Pharmacology and Toxicology] (2015), 16:18.

In some embodiments, the CXCR2 inhibitor comprises rapalicin (CAS Registry Number: 266359-83-5). Ripalicin is also known as repertaxin or (2R)-2-[4-(2-methylpropyl)phenyl]-N-methylsulfonylpropionamide. Noncompetitive allosteric inhibitors of CXCR1/2 in Ripari-Galaxy. Ripalicin is disclosed, eg, in Zarbock et al. Br J Pharmacol. [British Journal of Pharmacology] 2008; 155(3):357-64.

In some embodiments, the CXCR2 inhibitor comprises navaricin. Navaricin is also known as MK-7123, SCH 527123, PS291822, or 2-hydroxy-N,N-dimethyl-3-[[2-[[(1R)-1-(5-methylfuran- 2-yl)propyl]amino]-3,4-dioxocyclobuten-1-yl]amino]benzamide. Navaricin is disclosed in, for example, Ning et al. Mol Cancer Ther. [Molecular Cancer Therapeutics] 2012; 11(6):1353-64. CSF-1/1R binding agent

In some embodiments, a CSF-1/1R binding agent is used in combination with a TGFβ inhibitor (and/or a PD1, PD-L1, or PD-L2 inhibitor) to treat a disease (eg, cancer). In some embodiments, the CSF-1/1R binding agent is selected from an inhibitor of macrophage colony stimulating factor (M-CSF), e.g., a monoclonal antibody or Fab to M-CSF (e.g., MCS110), CSF-1R Tyrosine kinase inhibitors (e.g., 4-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)oxy)-N-methyl pyridinamide or BLZ945), receptor tyrosine kinase inhibitors (RTKs) (eg, pexidartinib), or antibodies targeting CSF-1R (eg, emactuzumab or FPA008). In some embodiments, the CSF-1/1R inhibitor is BLZ945. In some embodiments, the CSF-1/1R binding agent is MCS110. In other embodiments, the CSF-1/1R binding agent is perdatinib. Exemplary CSF-1 binding agents

In some embodiments, the CSF-1/1R binding agent comprises an inhibitor of macrophage colony stimulating factor (M-CSF). M-CSF is also sometimes called CSF-1. In certain embodiments, the CSF-1/1R binding agent is an antibody to CSF-1 (eg, MCS110). In other embodiments, the CSF-1/1R binding agent is an inhibitor of CSF-1R (eg, BLZ945).

In some embodiments, the CSF-1/1R binding agent comprises a monoclonal antibody or Fab to M-CSF (eg, MCS110/H-RX1 ) or a CSF-1 binding agent disclosed in International Application Publication No. WO 2004/ 045532 and WO 2005/068503 (including H-RX1 or 5H4, eg, antibody molecules or Fab fragments directed against M-CSF) and US 9079956. [ Table 13a ]. Amino acid and nucleotide sequences of an exemplary anti-M-CSF antibody molecule (MCS110) (H-RX1) HC QVQLQESGPGLVKPSQTLSLTCTVSDYSITSDYAWNWIRQFPGKGLEWMGYISYSGSTSYNPSLKSRITISRDTSKNQFSLQLNSVTAADTAVYYCASFDYAHAMDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK（SEQ ID NO: 286） (H-RX1) LC DIVLTQSPAFLSVTPGEKVTFTCQASQSIGTSIHWYQQKTDQAPKLLIKYASESISGIPSRFSGSGSGTDFTLTISSVEAEDAADYYCQQINSWPTTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC（SEQ ID NO: 287） Heavy chain CDR1 (Kabat) SDYAWN (SEQ ID NO: 288) Heavy chain CDR2 (Kabat) YISYSGSTSYNPSLKS (SEQ ID NO: 289) Heavy chain CDR3 (Kabat) FDYAHAMDY (SEQ ID NO: 290) Light chain CDR1 (Kabat) QASQSIGTSIH (SEQ ID NO: 291) Light chain CDR2 (Kabat) YASESIS (SEQ ID NO: 292) Light chain CDR3 (Kabat) QQINSWPTT (SEQ ID NO: 293)

In another embodiment, the CSF-1/1R binding agent comprises a CSF-1R tyrosine kinase inhibitor, 4-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo [d] Thiazol-6-yl)oxy)-N-methylpyridinamide (BLZ945), or compounds disclosed in International Application Publication No. WO 2007/121484 and US Patent Nos. 7,553,854, 8,173,689 and 8,710,048. Other Exemplary CSF-1/1R Binding Agents

In some embodiments, the CSF-1/1R binding agent comprises perdatinib (CAS Registry No. 1029044-16-3). Perdatinib is also known as PLX3397 or 5-((5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl)-N-((6-(trifluoromethyl) Pyridin-3-yl)methyl)pyridin-2-amine. Pedatinib is a small molecule receptor tyrosine kinase (RTK) inhibitor of KIT, CSF1R, and FLT3. FLT3, CSF1R, and FLT3 are overexpressed or mutated in many cancer cell types and play major roles in tumor cell proliferation and metastasis. PLX3397 can bind to and inhibit the phosphorylation of stem cell factor receptor (KIT), colony-stimulating factor-1 receptor (CSF1R), and FMS-like tyrosine kinase 3 (FLT3), which may lead to inhibition of tumor cell proliferation and downregulation of osteolysis Macrophages, osteoclasts, and mast cells in metastatic disease.

In some embodiments, the CSF-1/1R binding agent is emactuzumab. Emetuzumab is also known as RG7155 or RO5509554. Emituzumab is a humanized IgG1 mAb targeting CSF1R. In some embodiments, the CSF-1/1R binding agent is FPA008. FPA008 is a humanized mAb that inhibits CSF1R. A2aR antagonist

In some embodiments, an adenosine A2a receptor (A2aR) antagonist (e.g., an inhibitor of the A2aR pathway, such as an adenosine inhibitor, such as an inhibitor of A2aR or CD-73) is combined with a TGFβ inhibitor (and/or PD1, PD-L1, or PD-L2 inhibitors) to treat diseases (such as cancer). In some embodiments, the A2aR antagonist is selected from PBF509/NIR178 (Palobiofarma/Novartis), CPI444/V81444 (Corvus/Genentech), AZD4635/HTL -1071 (AstraZeneca/Heptares), Vipadenant (Redox/Juno), GBV-2034 (Globavir), AB928 (Arabia Arcus Biosciences), Theophylline, Itraphylline (Kyowa Hakko Kogyo), Tozadinan/SYN-115 (Acorda), KW -6356 (Kyowa Hakko Kogyo Co., Ltd.), ST-4206 (Leadiant Biosciences), and Predinan/SCH 420814 (Merck/Schering). Exemplary A2aR Antagonists

In some embodiments, the A2aR antagonist comprises PBF509 (NIR178) or a compound disclosed in US Patent No. 8,796,284 or International Application Publication No. WO 2017/025918. PBF509 (NIR178) is also known as NIR178. Other Exemplary A2aR Antagonists

In certain embodiments, the A2aR antagonist comprises CPI444/V81444. CPI-444 and other A2aR antagonists are disclosed in International Application Publication No. WO 2009/156737. In certain embodiments, the A2aR antagonist is (S)-7-(5-methylfuran-2-yl)-3-((6-(((tetrahydrofuran-3-yl)oxy)methyl) pyridin-2-yl)methyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine. In certain embodiments, the A2aR antagonist is (R)-7-(5-methylfuran-2-yl)-3-((6-(((tetrahydrofuran-3-yl)oxy)methyl) pyridin-2-yl)methyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine, or a racemate thereof. In certain embodiments, the A2aR antagonist is 7-(5-methylfuran-2-yl)-3-((6-(((tetrahydrofuran-3-yl)oxy)methyl)pyridine-2- base)methyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine.

In certain embodiments, the A2aR antagonist is AZD4635/HTL-1071. A2aR antagonists are disclosed in International Application Publication No. WO 2011/095625. In certain embodiments, the A2aR antagonist is 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-trispurin-3 -amine.

In certain embodiments, the A2aR antagonist is ST-4206 (Ridian Biosciences). In certain embodiments, the A2aR antagonist is an A2aR antagonist described in US Patent No. 9,133,197.

In certain embodiments, the A2aR antagonist is an A2aR antagonist described in US Patent Nos. 8,114,845 and 9,029,393, US Application Publication Nos. 2017/0015758 and 2016/0129108.

In some embodiments, the A2aR antagonist is istradefylline (CAS registry number: 155270-99-8). Itradefylline is also known as KW-6002 or 8-[(E)-2-(3,4-dimethoxyphenyl)vinyl]-1,3-diethyl-7-methyl-3 ,7-Dihydro-1H-purine-2,6-dione. For example, istradefylline is disclosed in LeWitt et al., (2008) Annals of Neurology 63(3): 295-302).

In some embodiments, the A2aR antagonist is Tozzadinan (Biotie). Tozzadinan is also known as SYN115 or 4-Hydroxy-N-(4-methoxy-7-𠰌lin-4-yl-1,3-benzothiazol-2-yl)-4-methylpiperidine -1-Formamide. Tozardinan blocks the action of endogenous adenosine on A2a receptors, leading to enhanced action of dopamine on D2 receptors, and inhibits the action of glutamate on mGluR5 receptors. In some embodiments, the A2aR antagonist is Predinam (CAS Registry Number: 377727-87-2). Predinan is also known as SCH 420814 or 2-(2-furyl)-7-[2-[4-[4-(2-methoxyethoxy)phenyl]-1-piperyl] Ethyl]7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine. Predinam was developed as a drug that acts as a potent and selective antagonist of adenosine A2A receptors.

In some embodiments, the A2aR antagonist is vipadinam. Vipadinam is also known as BIIB014, V2006, or 3-[(4-amino-3-methylphenyl)methyl]-7-(furan-2-yl)triazolo[4,5-d ] pyrimidin-5-amine. Other exemplary A2aR antagonists include, eg, ATL-444, MSX-3, SCH-58261, SCH-412,348, SCH-442,416, VER-6623, VER-6947, VER-7835, CGS-15943, and ZM-241,385.

In some embodiments, the A2aR antagonist is an A2aR pathway antagonist (eg, a CD-73 inhibitor, eg, an anti-CD73 antibody) is MEDI9447. MEDI9447 is a monoclonal antibody specific to CD73. Targeting the extracellular production of adenosine by CD73 reduces the immunosuppressive effect of adenosine. MEDI9447 is reported to have a range of activities, eg, inhibition of CD73 ectonucleotidase activity, relief of AMP-mediated lymphocyte suppression, and inhibition of syngeneic tumor growth. MEDI9447 can drive changes in both myeloid and lymphoid-infiltrating leukocyte populations in the tumor microenvironment. These changes include, for example, an increase in CD8 effector cells and activated macrophages, and a decrease in the proportion of myeloid-derived suppressor cells (MDSCs) and regulatory T lymphocytes. IDO inhibitor

In some embodiments, an inhibitor of indoleamine 2,3-dioxygenase (IDO) and/or tryptophan 2,3-dioxygenase (TDO) is combined with a TGFβ inhibitor (and/or PD1 , PD-L1, or PD-L2 inhibitors) to treat diseases (such as cancer). In some embodiments, the IDO inhibitor is selected from (4E)-4-[(3-chloro-4-fluoroanilino)-nitrosomethylene]-1,2,5-oxadiazole-3- Amine (also known as epacadostat or INCB24360), indotimod (), (1-methyl-D-tryptophan), alpha-cyclohexyl-5H-imidazo[5,1- a] Isoindole-5-ethanol (also known as NLG919), Indomod, and BMS-986205 (formerly known as F001287). Exemplary IDO inhibitors

In some embodiments, the IDO/TDO inhibitor is Indotimod (New Link Genetics). Indotimod, the D-isomer of 1-methyl-tryptophan, is an orally administered small molecule inhibitor of the indoleamine 2,3-dioxygenase (IDO) pathway that disrupts Mechanisms by which tumors evade immune-mediated destruction.

In some embodiments, the IDO/TDO inhibitor is NLG919 (Neuline Genetics). NLG919 is a potent IDO (indoleamine-(2,3)-dioxygenase) pathway inhibitor with Ki/EC50 of 7 nM/75 nM in cell-free assays.

In some embodiments, the IDO/TDO inhibitor is Edorestat (CAS Registry Number: 1204669-58-8). Edostat is also known as INCB24360 or INCB024360 (Inset Corporation). Edorestat is a potent and selective indoleamine 2,3-dioxygenase (IDO1) inhibitor with an IC50 of 10 nM against other related enzymes such as IDO2 or tryptophan 2,3-dioxygenase Oxygenase (TDO)) is highly selective.

In some embodiments, the IDO/TDO inhibitor is F001287 (Flexus/BMS). F001287 is a small molecule inhibitor of indoleamine 2,3-dioxygenase 1 (IDO1). STING agonist

In some embodiments, a STING agonist is used in combination with a TGFβ inhibitor (and/or a PD1, PD-L1, or PD-L2 inhibitor) to treat a disease (eg, cancer). In some embodiments, the STING agonist is a cyclic dinucleotide, such as a cyclic dinucleotide comprising a purine or pyrimidine nucleobase (e.g., adenosine, guanine, uracil, thymine, or cytosine nucleobase). Nucleotides. In some embodiments, the nucleobases of the cyclic dinucleotides comprise the same nucleobase or different nucleobases.

In some embodiments, the STING agonist comprises an adenosine or guanosine nucleobase. In some embodiments, the STING agonist comprises an adenosine nucleobase and a guanosine nucleobase. In some embodiments, the STING agonist comprises two adenosine nucleobases or two guanosine nucleobases.

In some embodiments, the STING agonist comprises a modified cyclic dinucleotide, eg, comprising a modified nucleobase, a modified ribose sugar, or a modified phosphate linkage. In some embodiments, the modified cyclic dinucleotide comprises a modified phosphate linkage, such as a phosphorothioate linkage.

In some embodiments, the STING agonist comprises a cyclic dinucleotide (e.g., a modified cyclic dinucleotide) having a 2',5' or 3',5' phosphate linkage. In some embodiments, the STING agonist comprises a cyclic dinucleotide (eg, a modified cyclic dinucleotide) having Rp or Sp stereochemistry around the phosphate bond.

In some embodiments, the STING agonist is MK-1454 (Merck & Co.). MK-1454 is a cyclic dinucleotide stimulator of the STING pathway-activating interferon gene (STING) agonist. Exemplary STING agonists are disclosed, eg, in PCT Publication No. WO 2017/027645. Galectin inhibitors

In some embodiments, a galectin (e.g., galectin-1 or galectin-3) inhibitor is combined with a TGFβ inhibitor (and/or a PD1, PD-L1, or PD-L2 inhibitor ) in combination to treat diseases such as cancer. In some embodiments, the combination comprises a galectin-1 inhibitor and a galectin-3 inhibitor. In some embodiments, the combination comprises a bispecific inhibitor (eg, a bispecific antibody molecule) that targets both galectin-1 and galectin-3. In some embodiments, the galectin inhibitor is selected from the group consisting of anti-galectin antibody molecules, GR-MD-02 (Galectin Therapeutics), Galectin-3C (Mandel Mandal Med), Anginex, or OTX-008 (OncoEthix, Merck). The galectins are a family of proteins that bind sugars to beta-galactosidases.

The galectin family of proteins comprises at least galectin-1, galectin-2, galectin-3, galectin-4, galectin-7, and galectin- 8. Galectins are also called S-type lectins, and are soluble proteins that have, for example, intracellular and extracellular functions.

Galectin-1 and galectin-3 are highly expressed in different tumor types. Galectin-1 and galectin-3 can promote angiogenesis and/or reprogram myeloid cells to a pro-neoplastic phenotype, such as enhancing immunosuppression of myeloid cells. Soluble galectin-3 can also bind and/or inactivate infiltrating T cells. Exemplary Galectin Inhibitors

In some embodiments, the galectin inhibitor is an antibody molecule. In an embodiment, the antibody molecule is a monospecific antibody molecule and binds a single epitope. For example, a monospecific antibody molecule having multiple immunoglobulin variable domain sequences, each of which binds the same epitope. In an embodiment, the galectin inhibitor is an anti-galectin (eg, anti-galectin-1 or anti-galectin-3) antibody molecule. In some embodiments, the galectin inhibitor is an anti-galectin-1 antibody molecule. In some embodiments, the galectin inhibitor is an anti-galectin-3 antibody molecule.

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

In an embodiment, the galectin inhibitor is a multispecific antibody molecule. In an embodiment, the multispecific antibody molecule is a bispecific antibody molecule. Bispecific antibodies are specific for no more than two antigens. The bispecific antibody molecule is characterized by a first immunoglobulin variable domain sequence having binding specificity for a first epitope, and a second immunoglobulin variable structure having binding specificity for a second epitope domain sequence. In an embodiment, the first and second epitopes are on the same antigen (eg, the same protein (or subunit of a multimeric protein)). In an embodiment, the first epitope and the second epitope overlap. In an embodiment, the first epitope and the second epitope do not overlap. In an embodiment, the first and second epitopes are on different antigens (eg different proteins (or different subunits of a multimeric protein)). In an embodiment, the bispecific antibody molecule comprises a heavy chain variable domain sequence and a light chain variable domain sequence having binding specificity for a first epitope and a heavy chain variable domain sequence having binding specificity for a second epitope. Variable domain sequences and light chain variable domain sequences. In an embodiment, a bispecific antibody molecule comprises a half antibody with binding specificity for a first epitope and a half antibody with binding specificity for a second epitope. In an embodiment, a bispecific antibody molecule comprises a half antibody, or fragment thereof, with binding specificity for a first epitope, and a half antibody, or fragment thereof, with binding specificity for a second epitope. In an embodiment, the bispecific antibody molecule comprises a scFv, or fragment thereof, with binding specificity for a first epitope, and a scFv, or fragment thereof, with binding specificity for a second epitope. In an embodiment, the galectin inhibitor is a bispecific antibody molecule. In an embodiment, the first epitope is on Galectin-1 and the second epitope is on Galectin-3.

Protocols for generating bispecific or heterodimeric antibody molecules are known in the art; such protocols include, but are not limited to: the "knob in a hole" approach, e.g. in US 5731168 described; electrostatically directed Fc pairing as described eg in WO 09/089004, WO 06/106905 and WO 2010/129304; stock exchange engineered domain (SEED) heterodimer formation as eg described in WO 07 /110205; Fab arm exchange, as described for example in WO 08/119353, WO 2011/131746 and WO 2013/060867; diabody conjugates, for example using amine reactive groups and sulfhydryl reactive groups Grouped heterobifunctional reagents are cross-linked by antibodies to generate bispecific structures, as described, for example, in US 4433059; by cycles of reduction and oxidation of the disulfide bonds between the two heavy chains, by Bispecific antibody determinants produced by recombining half-antibodies (heavy-light chain pairs or Fab) from different antibodies, as described, for example, in US 4444878; trifunctional antibodies, such as trifunctional antibodies cross-linked by thiol-reactive groups a Fab' fragment, as described, for example, in US 5,273,743; biosynthetic binding proteins, such as scFv pairs cross-linked by C-terminal tails, preferably by disulfide bonds or amine-reactive chemical cross-linking, such as For example, as described in US 5534254; diabodies, such as Fab fragments with different binding specificities, which are separated by leucine zippers (for example, c-fos and c-jun) that have replaced the constant domains. Polymerization, as described for example in US 5582996; bispecific and oligospecific monovalent and oligovalent receptors, e.g. VH-CH1 regions of two antibodies (two Fab fragments), which VH-CH1 regions are mediated by A polypeptide spacer link between the CH1 region of one antibody and the VH region (typically with an associated light chain) of another antibody, as described for example in US 5591828; bispecific DNA - antibody conjugates, For example antibody or Fab fragments are cross-linked by double strands of DNA, as described for example in US 5635602; bispecific fusion proteins, for example containing two scFv with a hydrophilic helical peptide linker between them and a complete Expression constructs for constant regions, as described, for example, in US 5637481; multivalent and multispecific binding proteins, for example with the first domain of an Ig heavy chain variable region binding region and an Ig light chain variable region binding region Polypeptide dimers of the second domain, commonly referred to as diabodies (higher order structures are also revealed, resulting in bispecific, trispecific or tetraspecific molecules), as described for example in US 5837242; with linkage Miniature antibody constructs of VL and VH chains (which are further linked to the antibody hinge and CH3 regions with peptide spacers) that can dimerize to form bispecific/multispecific Valence molecules, as described, for example, in US5837821; VH and VL domains linked with short peptide linkers (eg, 5 or 10 amino acids) or with no linkers at all in either orientation, the VH and VL Domains can form dimers to form bispecific diabodies; trimers and tetramers, as described for example in US 5844094; strings of VH domains (or VL domains in family members), which Linked by peptide bonds to C-terminal crosslinkable groups which are further associated with the VL domains to form a series of FVs (or scFvs), as described, for example, in US 5864019; and Single-chain binding polypeptides with both VH and VL domains connected via peptide linkers are assembled into multivalent structures by non-covalent or chemical cross-linking to form e.g. Bivalent, trivalent and tetravalent structures, as described, for example, in US 5,869,620. Additional exemplary multispecific and bispecific molecules and methods for their preparation are found, for example, in US 5910573, US 5932448, US 5959083, US 5989830, US 6005079, US 6239259, US 6294353, US 6333396, US 6476198, US 6511663, US 6670453 、US 6743896、US 6809185、US 6833441、US 7129330、US 7183076、US 7521056、US 7527787、US 7534866、US 7612181、US 2002/004587 A1、US 2002/076406 A1、US 2002/103345 A1、US 2003/207346 A1, US 2003/211078 A1, US 2004/219643 A1, US 2004/220388 A1, US 2004/242847 A1, US 2005/003403 A1, US 2005/004352 A1, US 2005/069552 A1, US 2000/A1, 2000/07917 US 2005/100543 A1, US 2005/136049 A1, US 2005/136051 A1, US 2005/163782 A1, US 2005/266425 A1, US 2006/083747 A1, US 2006/120960 A1, US 2006/104493 A1 /263367 A1, US 2007/004909 A1, US 2007/087381 A1, US 2007/128150 A1, US 2007/141049 A1, US 2007/154901 A1, US 2007/274985 A1, US 2008/050370 A120/0680 A1, US 2008/152645 A1, US 2008/171855 A1, US 2008/241884 A1, US 2008/254512 A1, US 2008/260738 A1, US 2009/130106 A1, US 2009/148905 A1, US 2009/A15527 US 2009/162359 A1, US 2009/162360 A1, US 2009/175851 A1, US 2009/175867 A1, US 2009/232811 A1, US 2009/234105 A1, US 2009/263392 A1, US 2009/274649 A1, EP 346087 A2, WO 00/06605 A2, WO 02/072635 A2, WO 04/081051 A1, WO06/020258 A2, WO 2007/ 044887 A2, WO 2007/095338 A2, WO 2007/137760 A2, WO 2008/119353 A1, WO 2009/021754 A2, WO 2009/068630 A1, WO 91/03493 A1, WO 93/23537 A1, WO 94/09131 A , WO 94/12625 A2, WO 95/09917 A1, WO 96/37621 A2, WO 99/64460 A1.

In other embodiments, the anti-galectin (eg, anti-galectin-1 or anti-galectin-3) antibody molecule (eg, monospecific, bispecific, or multispecific antibody molecule) Covalently linked (eg fused) to another partner (protein, eg as a fusion molecule, such as a fusion protein). In one embodiment, the bispecific antibody molecule has a first binding specificity for a first target (eg, for galectin-1) and a second binding specificity for a second target (eg, for galectin-3). binding specificity.

The present invention provides isolated nucleic acid molecules encoding the above antibody molecules, their vehicles and host cells. Nucleic acid molecules include, but are not limited to, RNA, genomic DNA, and cDNA.

In some embodiments, a galectin inhibitor is a peptide, such as a protein, that can bind to and inhibit the function of a galectin (eg, galectin-1 or galectin-3). In some embodiments, a galectin inhibitor is a peptide that can bind to and inhibit the function of galectin-3. In some embodiments, the galectin inhibitor is the peptide galectin-3C. In some embodiments, the galectin inhibitor is galectin-3 disclosed in US Patent 6,770,622.

Galectin-3C is an N-terminally truncated protein of galectin-3 and functions, for example, as a competitive inhibitor of galectin-3. Galectin-3C prevents glycoconjugation of endogenous galectin-3 with e.g. cancer cells (e.g. laminin on the surface) and other β-galactosidases on the extracellular matrix (ECM) combination of things. Galectin-3C and other exemplary galectin inhibitory peptides are disclosed in US Patent 6,770,622.

In some embodiments, the galectin-3C comprises the amino acid sequence of SEQ ID NO: 294 or amino acids substantially identical (eg, 90%, 95%, or 99% identical) thereto. GAPAGPLIVPYNLPLPGGVVPRMLITILGTVKPNANRIALDFQRGNDVAFHFNPRFNENNRRVIVCNTKLDNNWGREERQSVFPFESGKPFKIQVLVEPDHFKVAVNDAHLLQYNHRVKKLNEISKLGISGDIDITSASYTMI (SEQ ID NO: 294).

In some embodiments, a galectin inhibitor is a peptide that binds to and inhibits the function of galectin-1. In some embodiments, the galectin inhibitor is the peptide Anginex: Anginex is an anti-angiogenic peptide that binds galectin-1 (Salomonsson E, et al., (2011) Journal of Biological Chemistry, pp. 286(16):13801-13804. Binding of Anginex to galectin-1 may interfere with, for example, the pro-angiogenic effects of galectin-1.

In some embodiments, a galectin (eg, galectin-1 or galectin-3) inhibitor is a non-peptide topomimetic molecule. In some embodiments, the non-peptide topomimetic galectin inhibitor is OTX-008 (OncoEthix). In some embodiments, the non-peptidic topological mimic is the non-peptidic topological mimic disclosed in US Pat. No. 8,207,228. OTX-008 (also known as PTX-008 or Calixarene 0118) is a selective allosteric inhibitor of galectin-1. OTX-008 has a chemical name: N-[2-(dimethylamino)ethyl]-2-{[26,27,28-tris({[2-(dimethylamino)ethyl]amine Methylformyl}methoxy)pentacyclo[19.3.1.1,7.1,.15,]eight octacos-1(25),3(28),4,6,9(27),1012,15,17 ,19(26),21,23-Dodecen-25-yl]oxy}acetamide.

In some embodiments, the galectin (eg, galectin-1 or galectin-3) inhibitor is a carbohydrate-based compound. In some embodiments, the galectin inhibitor is GR-MD-02 (Galectin Therapeutics).

In some embodiments, GR-MD-02 is a galectin-3 inhibitor. GR-MD-02 is a galactose-forked polysaccharide, also known as eg galactose arabino-rhamnogalacturonate. GR-MD-02 and other galactose-forked polysaccharide polymers such as, for example, galactose arabino-rhamnogalacturonate are disclosed in US Patent No. 8,236,780 and US Publication 2014/0086932. MEK inhibitors

In some embodiments, a MEK inhibitor is used in combination with a TGFβ inhibitor (and/or a PD1, PD-L1, or PD-L2 inhibitor) to treat a disease (eg, cancer). In some embodiments, the MEK inhibitor is selected from trametinib, selumetinib, AS703026, BIX 02189, BIX 02188, CI-1040, PD0325901, PD98059, U0126, XL-518, G-38963, or G02443714. In some embodiments, the MEK inhibitor is trametinib. Exemplary MEK Inhibitors

In some embodiments, the MEK inhibitor is trametinib. Trametinib is also known as JTP-74057, TMT212, N-(3-{3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl -2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl}phenyl)acetamide, or Mekinist ( CAS No. 871700-17-3). Other Exemplary MEK Inhibitors

In some embodiments, the MEK inhibitor comprises selumetinib, which has the chemical name: (5-[(4-bromo-2-chlorophenyl)amino]-4-fluoro-N-(2-hydroxy Ethoxy)-1-methyl-1H-benzimidazole e-6-carboxamide. Selumetinib is also known as AZD6244 or ARRY 142886, eg as described in PCT Publication No. WO 2003077914.

In some embodiments, the MEK inhibitor comprises AS703026, BIX 02189 or BIX 02188.

In some embodiments, the MEK inhibitor comprises 2-[(2-chloro-4-iodophenyl)amino]-N-(cyclopropylmethoxy)-3,4-difluoro-benzoyl Amine (also known as CI-1040 or PD184352), eg, as described in PCT Publication No. WO 2000035436).

In some embodiments, the MEK inhibitor comprises N-[(2R)-2,3-dihydroxypropoxy]-3,4-difluoro-2-[(2-fluoro-4-iodophenyl) Amino]-benzamide (also known as PD0325901), eg, as described in PCT Publication No. WO 2002006213).

In some embodiments, the MEK inhibitor comprises 2'-amino-3'-methoxyflavone (also known as PD98059), which is available from Biaffin GmbH & Co., KG, Germany get.

In some embodiments, the MEK inhibitor comprises 2,3-bis[amino[(2-aminophenyl)thio]methylene]-succinonitrile (also known as U0126), e.g., as described in the U.S. Patent No. 2,779,780).

In some embodiments, the MEK inhibitor comprises XL-518 (also known as GDC-0973), which has CAS number 1029872-29-4 and is available from ACC Corp.

In some embodiments, the MEK inhibitor comprises G-38963.

In some embodiments, the MEK inhibitor comprises G02443714 (also known as AS703206).

Further examples of MEK inhibitors are disclosed in WO 2013/019906, WO 03/077914, WO 2005/121142, WO 2007/04415, WO 2008/024725 and WO 2009/085983. Additional examples of MEK inhibitors include, but are not limited to, 2,3-bis[amino[(2-aminophenyl)thio]methylene]-succinonitrile (also known as U0126 and described in U.S. Pat. No. 2,779,780); (3S,4R,5Z,8S,9S,11E)-14-(ethylamino)-8,9,16-trihydroxy-3,4-dimethyl-3,4,9 , 19-tetrahydro-1H-2-benzoxacyclotetradecyne-1,7(8H)-dione] (also known as E6201, described in PCT Publication No. WO 2003076424); Vemurafenib (PLX-4032, CAS 918504-65-1); (R)-3-(2,3-dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)- 8-Methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (TAK-733, CAS 1035555-63-5); Pimasertib (AS-703026 , CAS 1204531-26-9); 2-(2-fluoro-4-iodophenylamino)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo- 1,6-Dihydropyridine-3-carboxamide (AZD 8330); and 3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-N-(2-hydroxy Ethoxy)-5-[(3-oxo-[1,2]㗁𠯤alkan-2-yl)methyl]benzamide (CH 4987655 or Ro 4987655). c-MET inhibitor

In some embodiments, a c-MET inhibitor is used in combination with a TGFβ inhibitor (and/or a PD1, PD-L1, or PD-L2 inhibitor) to treat a disease (eg, cancer). c-MET (a receptor tyrosine kinase overexpressed or mutated in many tumor cell types) plays a key role in tumor cell proliferation, survival, invasion, metastasis and tumor angiogenesis. Inhibition of c-MET can induce cell death in tumor cells that overexpress c-MET protein or express constitutively activated c-MET protein.

In some embodiments, the c-MET inhibitor is selected from capmatinib (INC280), JNJ-3887605, AMG 337, LY2801653, MSC2156119J, crizotinib, tilvantinib, or govatinib (golvatinib). Exemplary c-MET inhibitors

In some embodiments, the c-MET inhibitor comprises capmatinib (INC280) or a compound described in US Pat. Nos. 7,767,675 and US 8,461,330. Other Exemplary c-MET Inhibitors

In some embodiments, the c-MET inhibitor comprises JNJ-38877605. JNJ-38877605 is an orally available small molecule inhibitor of c-Met. JNJ-38877605 selectively binds to c-MET, thereby inhibiting c-MET phosphorylation and disrupting c-Met signaling pathway.

In some embodiments, the c-Met inhibitor is AMG 208. AMG 208 is a selective small molecule inhibitor of c-MET. AMG 208 inhibits both ligand-dependent and ligand-independent activation of c-MET and inhibits its tyrosine kinase activity, which may lead to cell growth inhibition in tumors overexpressing c-Met.

In some embodiments, the c-Met inhibitor comprises AMG 337. AMG 337 is an orally bioavailable inhibitor of c-Met. AMG 337 selectively binds to c-MET, thereby disrupting the c-MET signaling pathway.

In some embodiments, the c-Met inhibitor comprises LY2801653. LY2801653 is an orally available small molecule inhibitor of c-Met. LY2801653 selectively binds to c-MET, thereby inhibiting c-MET phosphorylation and disrupting c-Met signaling pathway.

In some embodiments, the c-Met inhibitor comprises MSC2156119J. MSC2156119J is an orally bioavailable c-Met inhibitor. MSC2156119J selectively binds to c-MET, inhibits c-MET phosphorylation and disrupts c-Met-mediated signaling pathways.

In some embodiments, the c-MET inhibitor is capmatinib. Capmatinib is also known as INCB028060. Capmatinib is an orally bioavailable c-MET inhibitor. Capmatinib selectively binds to c-Met, thereby inhibiting c-Met phosphorylation and disrupting c-Met signaling pathways.

In some embodiments, the c-MET inhibitor comprises crizotinib. Crizotinib is also known as PF-02341066. Crizotinib is an orally available aminopyridine-based inhibitor of the receptor tyrosine kinase anaplastic lymphoma kinase (ALK) and c-Met/hepatocyte growth factor receptor (HGFR). Crizotinib binds to and inhibits ALK kinase and ALK fusion proteins in an ATP-competitive manner. In addition, crizotinib inhibits c-Met kinase and disrupts the c-Met signaling pathway. In conclusion, the agent inhibits tumor cell growth.

In some embodiments, the c-MET inhibitor comprises govatinib. Govatinib is an orally bioavailable dual kinase inhibitor of c-MET and VEGFR-2, which has potential antitumor activity. Govatinib binds to and inhibits the activity of c-MET and VEGFR-2, which may inhibit tumor cell growth and the survival of tumor cells overexpressing these receptor tyrosine kinases.

In some embodiments, the c-MET inhibitor is tivantinib. Tivantinib is also known as ARQ 197. Tivanatinib is an orally bioavailable small molecule inhibitor of c-MET. Tivanatinib binds the c-MET protein and disrupts the c-Met signaling pathway, which induces cell death in tumor cells that overexpress c-MET protein or express constitutively activated c-Met protein. IL-1β inhibitor

The interleukin-1 (IL-1) family of cytokines is a group of secreted pleiotropic cytokines that play an important role in inflammation and immune responses. Increases in IL-1 have been observed in a variety of clinical settings including cancer (Apte et al. (2006) Cancer Metastasis Rev. pp. 387-408; Dinarello (2010) Eur.J. Immunol. Journal of Science] pp. 599-606). The IL-1 family includes inter alia IL-1 beta (IL-1b) and IL-1 alpha (IL-1a). IL-1b is elevated in lung, breast, and colorectal cancers (Voronov et al. (2014) Front Physiol. p. 114) and is associated with poor prognosis (Apte et al. (2000) Adv. Exp. Med. Biol. [Advances in Experimental Medicine and Biology] pp. 277-88). Without wishing to be bound by theory, it is believed that, in some embodiments, secreted IL-1b derived from the tumor microenvironment and by malignant cells promotes tumor cell proliferation, increases invasiveness, and suppresses anti-tumor immune responses (in part by recruiting inhibitory Neutrophils) (Apte et al. (2006) Cancer Metastasis Rev. pp. 387-408; Miller et al. (2007) J. Immunol. pp. 6933-42). Experimental data indicate that inhibition of IL-1b leads to a reduction in tumor burden and metastasis (Voronov et al. (2003) Proc. Natl. Acad. Sci. USA pp. 2645-50).

In some embodiments, interleukin-1β (IL-1β) is used in combination with a TGFβ inhibitor (and/or a PD1, PD-L1, or PD-L2 inhibitor) to treat a disease (eg, cancer). In some embodiments, the IL-1β inhibitor is selected from canakinumab, gevokizumab, anakinra, or Rilonacept. In some embodiments, the IL-1β inhibitor is canakinumab. Exemplary IL-1β Inhibitors

In some embodiments, the IL-1β inhibitor is canakinumab. Canakinumab is also known as ACZ885 or ILARIS®. Canakinumab is a human monoclonal IgG1/κ antibody that neutralizes the biological activity of human IL-1β.

Canakinumab is disclosed in eg WO 2002/16436, US 7,446,175, and EP 1313769.卡那單抗的重鏈可變區具有以下胺基酸序列：MEFGLSWVFLVALLRGVQCQVQLVESGGGVVQPGRSLRLSCAASGFTFSVYGMNWVRQAPGKGLEWVAIIWYDGDNQYYADSVKGRFTISRDNSKNTLYLQMNGLRAEDTAVYYCARDLRTGPFDYWGQGTLVTVSS（SEQ ID NO: 297）（在US 7,446,175中揭露為SEQ ID NO: 1）。 The light chain variable region of canakinumab has the following amino acid sequence: MLPSQLIGFLLLWVPASRGEIVLTQSPDFQSVTPKEKVTITCRASQSIGSSLHWYQQKPDQSPKLLIKYASQSFSGVPSRFSGSGSGTDFLTINSLEAEDAAAYYCHQSSSLPFTFGPGTKVDIK (SEQ ID NO: 298) (disclosed in US 7,446,175) as ID NO: SE

Canakinumab has been used, for example, in the treatment of periodic cryopyrin-associated syndrome (CAPS) in adults and children, in the treatment of systemic juvenile idiopathic arthritis (SJIA), in adults with acute gouty Symptomatic treatment of arthritis flares, and for other IL-1β-driven inflammatory diseases. Without wishing to be bound by theory, it is believed that in some embodiments, an IL-1β inhibitor (e.g., canakinumab) can increase an anti-tumor immune response, for example by blocking one or more functions of IL-1b, including For example the effect of recruiting immune-suppressive neutrophils on the tumor microenvironment, stimulating tumor angiogenesis and/or promoting metastasis (Dinarello (2010) Eur.J. Immunol. pp. 599-606).

In some embodiments, the combinations described herein include an IL-1β inhibitor, canakinumab, or a compound disclosed in WO 2002/16436, and an inhibitor of an immune checkpoint molecule (e.g., an inhibitor of PD-1 (eg, anti-PD-1 antibody molecule)). IL-1 is a secreted pleiotropic cytokine that plays an important role in inflammation and immune response. Increases in IL-1 have been observed in a variety of clinical settings including cancer (Apte et al. (2006) Cancer Metastasis Rev. pp. 387-408; Dinarello (2010) Eur.J. Immunol. Journal of Science] pp. 599-606). IL-1b is elevated in lung, breast, and colorectal cancers (Voronov et al. (2014) Front Physiol. p. 114) and is associated with poor prognosis (Apte et al. (2000) Adv. Exp. Med. Biol. [Advances in Experimental Medicine and Biology] pp. 277-88). Without wishing to be bound by theory, it is believed that, in some embodiments, secreted IL-1b derived from the tumor microenvironment and by malignant cells promotes tumor cell proliferation, increases invasiveness, and suppresses anti-tumor immune responses (in part by recruiting inhibitory Neutrophils) (Apte et al. (2006) Cancer Metastasis Rev. pp. 387-408; Miller et al. (2007) J. Immunol. pp. 6933-42). Experimental data indicate that inhibition of IL-1b leads to a reduction in tumor burden and metastasis (Voronov et al. (2003) Proc. Natl. Acad. Sci. USA [Proceedings of the National Academy of Sciences of the United States of America] pp. 2645-50). Canakinumab binds IL-1b and inhibits IL-1-mediated signaling. Thus, in certain embodiments, an IL-1β inhibitor (e.g., canakinumab) enhances or is used to enhance the immune-mediated anti-tumor effect of a PD-1 inhibitor (e.g., an anti-PD-1 antibody molecule) .

In some embodiments, the IL-1β inhibitor, canakinumab or a compound disclosed in WO 2002/16436, and an inhibitor of an immune checkpoint molecule (eg, an inhibitor of PD-1 (eg, anti-PD -1 antibody molecules)) are each administered in doses and/or schedules, combined to achieve the desired anti-tumor activity. MDM2 inhibitor

In some embodiments, mouse double minute 2 homolog (MDM2) is used in combination with a TGFβ inhibitor (and/or a PD1, PD-L1, or PD-L2 inhibitor) to treat a disease (eg, cancer) . The human homologue of MDM2 is also known as HDM2. In some embodiments, the MDM2 inhibitors described herein are also referred to as HDM2 inhibitors. In some embodiments, the MDM2 inhibitor is selected from HDM201 or CGM097.

In an embodiment, the MDM2 inhibitor comprises (S)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-2-(4-(methyl(((1r,4S )-4-(4-methyl-3-oxopiper-1-yl)cyclohexyl)methyl)amino)phenyl)-1,2-dihydroisoquinoline-3(4H)- Ketone (also known as CGM097) or a compound disclosed in PCT Publication No. WO 2011/076786 for the treatment of disorders such as those described herein). In one embodiment, a therapeutic agent disclosed herein is used in combination with CGM097.

In an embodiment, the MDM2 inhibitor comprises an inhibitor of p53 and/or p53/Mdm2 interaction. In an embodiment, the MDM2 inhibitor comprises (S)-5-(5-chloro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-6-(4-chloro Phenyl)-2-(2,4-dimethoxypyrimidin-5-yl)-1-isopropyl-5,6-dihydropyrrolo[3,4-d]imidazole-4(1H)- Ketone (also known as HDM201) or a compound disclosed in PCT Publication No. WO 2013/111105 for the treatment of disorders such as those described herein. In one embodiment, a therapeutic agent disclosed herein is used in combination with HDM201. In some embodiments, HDM201 is administered orally.

In one embodiment, the combinations disclosed herein are useful for the treatment of cancer in vivo. For example, the combination can be used to inhibit the growth of cancerous tumors. The combination can also be used in combination with one or more of: standard of care treatment (e.g., for cancer or infectious disorders), vaccines (e.g., therapeutic cancer vaccines), cell therapy, radiation therapy, Surgery or any other therapeutic agent or modality to treat the disorders herein. For example, to achieve an antigen-specific boost of immunity, the combination can be administered with the antigen of interest. Pharmaceutical compositions, formulations and kits

In another aspect, the disclosure provides compositions, such as pharmaceutically acceptable compositions, comprising the combinations described herein formulated together with a pharmaceutically acceptable carrier. As used herein, "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, isotonic and absorption delaying agents, and the like that are physiologically compatible. The carrier can be suitable for intravenous, intramuscular, subcutaneous, parenteral, rectal, spinal or epidermal administration (eg, by injection or infusion).

The compositions described herein can take a variety of forms. These include, for example, liquid, semi-solid and solid dosage forms, such as liquid solutions (eg, injectable and infusible solutions), dispersions or suspensions, liposomes and suppositories. The preferred form depends on the intended mode of administration and therapeutic use. Such inhibitors, including antibody inhibitors, may be in the form of injectable or infusible solutions. The mode of administration is parenteral (eg, intravenous, subcutaneous, intraperitoneal, intramuscular). In embodiments, the antibody is administered by intravenous infusion or injection. In another embodiment, the antibody is administered by intramuscular or subcutaneous injection.

As used herein, the phrases "parenteral administration" and "parenteral administration" mean modes of administration other than enteral and topical administration, usually by injection, and include, but are not limited to, intravenous, Intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcutaneous, intraarticular, subcapsular, subarachnoid, intraspinal, epidural, and sternal Injections and infusions.

Therapeutic compositions typically should be sterile and stable under the conditions of manufacture and storage. The composition can be formulated as a solution, microemulsion, dispersion, liposome, or other ordered structure suitable to high antibody concentration. Sterile injectable solutions can be prepared by incorporating the active compound (e.g., antibody or antibody portion) in the required amount in an appropriate solvent, as required, with one or a combination of ingredients enumerated above, Then filter sterilize. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated 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 other desired ingredient from a previously sterile-filtered solution thereof. For example, the proper fluidity of the solution can be maintained by the use of coatings such as lecithin, by the maintenance of the desired particle size in the case of dispersions and by the use of surfactants. Prolonged absorption of the injectable compositions can be brought about by including in the composition agents which delay absorption (for example, monostearate salts and gelatin).

The combinations or compositions described herein can be formulated into formulations (eg, dosage formulations or dosage forms) suitable for administration (eg, intravenous administration) to a subject described herein. The formulations described herein can be liquid formulations, lyophilized formulations, or reconstituted formulations.

In certain embodiments, the formulation is a liquid formulation. In some embodiments, the formulation (eg, liquid formulation) comprises a TGFβ inhibitor (eg, an anti-TGFβ antibody molecule as described herein) and a buffer. In some embodiments, the formulation (eg, a liquid formulation) comprises a PD-1 inhibitor (eg, an anti-PD-1 antibody molecule described herein) and a buffer. In some embodiments, the formulation (eg, a liquid formulation) comprises a PD-L1 inhibitor (eg, an anti-PD-L1 antibody molecule described herein) and a buffer. In some embodiments, the formulation (eg, liquid formulation) comprises a PD-L2 inhibitor (eg, anti-PD-L2 antibody) and a buffer.

In some embodiments, the formulation (eg, liquid formulation) comprises an anti-TGFβ or anti-PD1 (or anti-PD-L1/L2) antibody molecule as disclosed herein at about 25 mg/mL to about 250 mg/mL concentration exists. In some embodiments, the formulation comprises an anti-TGFβ or anti-PD1 (or anti-PD-L1/L2) antibody molecule at a concentration of about 50 mg/mL to about 200 mg/mL. In some embodiments, the formulation comprises an anti-TGFβ or anti-PD1 (or anti-PD-L1/L2) antibody molecule at a concentration of about 60 mg/mL to about 180 mg/mL. In some embodiments, the formulation comprises an anti-TGFβ or anti-PD1 (or anti-PD-L1/L2) antibody molecule at a concentration of about 70 mg/mL to about 150 mg/mL. In some embodiments, the formulation comprises an anti-TGFβ or anti-PD1 (or anti-PD-L1/L2) antibody molecule at a concentration of about 80 mg/mL to about 120 mg/mL. In some embodiments, the formulation comprises an anti-TGFβ or anti-PD1 (or anti-PD-L1/L2) antibody molecule at a concentration of about 90 mg/mL to about 110 mg/mL. In some embodiments, the formulation comprises an anti-TGFβ or anti-PD1 (or anti-PD-L1/L2) antibody molecule at a concentration of about 50 mg/mL to about 150 mg/mL. In some embodiments, the formulation comprises an anti-TGFβ or anti-PD1 (or anti-PD-L1/L2) antibody molecule at a concentration of about 50 mg/mL to about 100 mg/mL. In some embodiments, the formulation comprises an anti-TGFβ or anti-PD1 (or anti-PD-L1/L2) antibody molecule at a concentration of about 150 mg/mL to about 200 mg/mL. In some embodiments, the formulation comprises an anti-TGFβ or anti-PD1 (or anti-PD-L1/L2) antibody molecule at a concentration of about 100 mg/mL to about 200 mg/mL. In some embodiments, the formulation comprises an anti-TGFβ or anti-PD1 (or anti-PD-L1/L2) antibody molecule at a concentration of about 50 mg/mL. In some embodiments, the formulation comprises an anti-TGFβ or anti-PD1 (or anti-PD-L1/L2) antibody molecule at a concentration of about 60 mg/mL. In some embodiments, the formulation comprises an anti-TGFβ or anti-PD1 (or anti-PD-L1/L2) antibody molecule at a concentration of about 70 mg/mL. In some embodiments, the formulation comprises an anti-TGFβ or anti-PD1 (or anti-PD-L1/L2) antibody molecule at a concentration of about 80 mg/mL. In some embodiments, the formulation comprises an anti-TGFβ or anti-PD1 (or anti-PD-L1/L2) antibody molecule at a concentration of about 90 mg/mL. In some embodiments, the formulation comprises an anti-TGFβ or anti-PD1 (or anti-PD-L1/L2) antibody molecule at a concentration of about 100 mg/mL. In some embodiments, the formulation comprises an anti-TGFβ or anti-PD1 (or anti-PD-L1/L2) antibody molecule at a concentration of about 110 mg/mL. In some embodiments, the formulation comprises an anti-TGFβ or anti-PD1 (or anti-PD-L1/L2) antibody molecule at a concentration of about 120 mg/mL. In some embodiments, the formulation comprises an anti-TGFβ or anti-PD1 (or anti-PD-L1/L2) antibody molecule at a concentration of about 130 mg/mL. In some embodiments, the formulation comprises an anti-TGFβ or anti-PD1 (or anti-PD-L1/L2) antibody molecule at a concentration of about 140 mg/mL. In some embodiments, the formulation comprises an anti-TGFβ or anti-PD1 (or anti-PD-L1/L2) antibody molecule at a concentration of about 150 mg/mL. In some embodiments, the formulation comprises an anti-TGFβ or anti-PD1 (or anti-PD-L1/L2) antibody molecule at a concentration of about 80 mg/mL to about 120 mg/mL (e.g., about 100 mg /mL).

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

In some embodiments, the formulation (eg, a liquid formulation) comprises: an antibody molecule as disclosed herein, present at a concentration of 80 to 120 mg/mL (eg, 100 mg/mL); and histamine A buffering agent of an acid buffer having a concentration of 15 mM to 25 mM (eg, 20 mM) and a pH of 5 to 6 (eg, 5.5).

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

In some embodiments, the formulation (eg, liquid formulation) comprises: an antibody molecule as disclosed herein, present at a concentration of 80 mg/mL to 120 mg/mL (eg, 100 mg/mL); comprising A buffer of histidine buffer having a concentration of 15 mM to 25 mM (for example, 20 mM) and a pH of 5 to 6 (for example, 5.5); and a buffer of 200 mM to 250 mM (for example, 220 mM) concentration of carbohydrates or sucrose present.

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 about 0.005% to about 0.1% (w/w), such as about 0.01% to about 0.08%, about 0.02% to about 0.06%, about 0.03% to about 0.05%, about 0.01% to about 0.06%, about 0.01% to about 0.05%, about 0.01% to about 0.03%, about 0.06% to about 0.08%, about 0.04% to about 0.08%, or about 0.02 % to about 0.08% (w/w), such as about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, or about 0.1 %(w/w). In some embodiments, the formulation comprises a surfactant or polysorbate 20 present at a concentration of about 0.03% to about 0.05% (eg, about 0.04%) (w/w) .

In some embodiments, the formulation (eg, liquid formulation) comprises: an antibody molecule as disclosed herein, present at a concentration of about 80 to 120 mg/mL (eg, 100 mg/mL); a buffer , which contains a histidine buffer at a concentration of 15 mM to 25 mM (eg, 20 mM) and a pH of 5 to 6 (eg, 5.5); at a concentration of 200 mM to 250 mM (eg, 220 mM) carbohydrate or sucrose present; and surfactant or polysorbate 20 present at a concentration of 0.03% to 0.05% (eg 0.04%) (w/w).

In some embodiments, the formulation (eg, liquid formulation) comprises: an antibody molecule as disclosed herein, present at a concentration of 100 mg/mL; a buffer comprising a concentration of 20 mM and a pH Histidine buffer (e.g., histidine/histidine-HCL) at 5.5; carbohydrate or sucrose present at a concentration of 220 mM; and surfactant or polysorbate 20 at 0.04% (w /w) concentration exists.

In some embodiments, a liquid formulation is prepared by diluting a formulation comprising an antibody molecule described herein. For example, a drug substance formulation can be diluted with a solution comprising one or more excipients (eg, concentrated excipients). In some embodiments, the solution comprises one, two, or all of histidine, sucrose, or polysorbate 20. In certain embodiments, the solution contains the same one or more excipients as the drug substance formulation. Exemplary excipients include, but are not limited to, amino acids (eg, histidine), carbohydrates (eg, sucrose), or surfactants (eg, polysorbate 20). In certain embodiments, the liquid formulation is not a reconstituted lyophilized formulation. In other embodiments, the liquid formulation is a reconstituted lyophilized formulation. In some embodiments, the formulation is stored as a liquid. In other embodiments, the formulation is prepared as a liquid and then dried (eg, by lyophilization or spray drying) prior to storage.

In certain embodiments, each container (eg, vial) is filled with about 0.5 mL to about 10 mL (eg, about 0.5 mL to about 8 mL, about 1 mL to about 6 mL, or about 2 mL to about 5 mL) mL, eg about 1 mL, about 1.2 mL, about 1.5 mL, about 2 mL, about 3 mL, about 4 mL, about 4.5 mL, about 5 mL, about 5.5 mL, about 6 mL, about 6.5 mL, about 7 mL , about 7.5 mL, about 8 mL, about 8.5 mL, about 9 mL, about 9.5 mL, or about 10 mL) of liquid formulations. In other embodiments, the liquid formulation is filled into containers (eg, vials) such that the extractable volume of the liquid formulation per container (eg, vial) is at least 1 mL (eg, at least 1.2 mL, at least 1.5 mL, at least 2 mL, at least 3 mL, at least 4 mL, or at least 5 mL). In certain embodiments, liquid formulations are extracted from containers (eg, vials) and not diluted at the clinical site. In certain embodiments, the liquid formulation is diluted from the drug substance formulation and extracted from the container (eg, vial) at the clinical site. In certain embodiments, the formulation (eg, a liquid formulation) is injected into the infusion bag within 1 hour (eg, within 45 minutes, 30 minutes, or 15 minutes) of the start of infusion into the patient.

The formulations described herein can be stored in containers. Containers for any of the formulations described herein can include, for example, vials with optional stoppers, caps, or both. In certain embodiments, the vial is a glass vial, eg, a 6R white glass vial. In other embodiments, the stopper is a rubber stopper, eg, a gray rubber stopper. In other embodiments, the cover is a flip top, for example, an aluminum flip top. 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 single-use container. In certain embodiments, about 250 mg to about 1500 mg of an antibody molecule as described herein is present in the container. In some embodiments, the container contains about 300 mg to about 1250 mg of antibody. In some embodiments, the container contains about 350 mg to about 1200 mg of antibody. In some embodiments, the container contains about 400 mg to about 1100 mg of antibody. In some embodiments, the container contains about 450 mg to about 1000 mg of antibody. In some embodiments, the container contains about 500 mg to about 900 mg of antibody. In some embodiments, the container contains about 600 mg to about 800 mg of antibody. In some embodiments, the container contains about 300 mg of antibody. In some embodiments, the container contains about 400 mg of antibody. In some embodiments, the container contains about 500 mg of antibody. In some embodiments, the container contains about 600 mg of antibody. In some embodiments, the container contains about 700 mg of antibody. In some embodiments, the container contains about 800 mg of antibody. In some embodiments, the container contains about 900 mg of antibody. In some embodiments, the container contains about 1000 mg of antibody.

In some embodiments, the formulation is a lyophilized formulation. In certain embodiments, a lyophilized formulation is lyophilized or dried from a liquid formulation comprising an antibody molecule described herein. Each container (eg, vial) can be filled with, eg, about 1 mL to about 10 mL, eg, about 6 mL to about 8 mL, of the liquid formulation and lyophilized.

In some embodiments, the formulation is a reconstituted formulation. In certain embodiments, a reconstituted formulation is reconstituted from a lyophilized formulation comprising an antibody molecule described herein. For example, a reconstituted formulation is prepared by dissolving a lyophilized formulation in a diluent such that the protein is dispersed in the reconstituted formulation. In some embodiments, the lyophilized formulation is reconstituted with about 1 mL to about 15 mL, eg, about 5 mL to about 9 mL or about 7 mL of water for injection or buffer. In certain embodiments, eg, in a clinical setting, the lyophilized formulation is reconstituted with about 6 mL to about 8 mL of water for injection.

In some embodiments, the reconstituted formulation comprises an antibody molecule (eg, an anti-TGFβ or anti-PD-1 (or anti-PD-L1/2) antibody molecule as disclosed herein) and a buffer.

In some embodiments, the reconstituted formulation comprises an anti-TGFβ or anti-PD1 (or anti-PD-L1/2) antibody molecule at a concentration of about 25 mg/mL to about 250 mg/mL. In some embodiments, the reconstituted formulation comprises an anti-TGFβ or anti-PD1 (or anti-PD-L1/2) antibody molecule at a concentration of about 50 mg/mL to about 200 mg/mL. In some embodiments, the reconstituted formulation comprises an anti-TGFβ or anti-PD1 (or anti-PD-L1/2) antibody molecule at a concentration of about 60 mg/mL to about 180 mg/mL. In some embodiments, the reconstituted formulation comprises an anti-TGFβ or anti-PD1 (or anti-PD-L1/2) antibody molecule at a concentration of about 70 mg/mL to about 150 mg/mL. In some embodiments, the reconstituted formulation comprises an anti-TGFβ or anti-PD1 (or anti-PD-L1/2) antibody molecule at a concentration of about 80 mg/mL to about 120 mg/mL. In some embodiments, the reconstituted formulation comprises an anti-TGFβ or anti-PD1 (or anti-PD-L1/2) antibody molecule at a concentration of about 90 mg/mL to about 110 mg/mL. In some embodiments, the reconstituted formulation comprises an anti-TGFβ or anti-PD1 (or anti-PD-L1/2) antibody molecule at a concentration of about 50 mg/mL to about 150 mg/mL. In some embodiments, the reconstituted formulation comprises an anti-TGFβ or anti-PD1 (or anti-PD-L1/2) antibody molecule at a concentration of about 50 mg/mL to about 100 mg/mL. In some embodiments, the reconstituted formulation comprises an anti-TGFβ or anti-PD1 (or anti-PD-L1/2) antibody molecule at a concentration of about 150 mg/mL to about 200 mg/mL. In some embodiments, the reconstituted formulation comprises an anti-TGFβ or anti-PD1 (or anti-PD-L1/2) antibody molecule at a concentration of about 100 mg/mL to about 200 mg/mL. In some embodiments, the reconstituted formulation comprises an anti-TGFβ or anti-PD1 (or anti-PD-L1/2) antibody molecule at a concentration of about 50 mg/mL. In some embodiments, the reconstituted formulation comprises an anti-TGFβ or anti-PD1 (or anti-PD-L1/2) antibody molecule at a concentration of about 60 mg/mL. In some embodiments, the reconstituted formulation comprises an anti-TGFβ or anti-PD1 (or anti-PD-L1/2) antibody molecule at a concentration of about 70 mg/mL. In some embodiments, the reconstituted formulation comprises an anti-TGFβ or anti-PD1 (or anti-PD-L1/2) antibody molecule at a concentration of about 80 mg/mL. In some embodiments, the reconstituted formulation comprises an anti-TGFβ or anti-PD1 (or anti-PD-L1/2) antibody molecule at a concentration of about 90 mg/mL. In some embodiments, the reconstituted formulation comprises an anti-TGFβ or anti-PD1 (or anti-PD-L1/2) antibody molecule at a concentration of about 100 mg/mL. In some embodiments, the reconstituted formulation comprises an anti-TGFβ or anti-PD1 (or anti-PD-L1/2) antibody molecule at a concentration of about 110 mg/mL. In some embodiments, the reconstituted formulation comprises an anti-TGFβ or anti-PD1 (or anti-PD-L1/2) antibody molecule at a concentration of about 120 mg/mL. In some embodiments, the reconstituted formulation comprises an anti-TGFβ or anti-PD1 (or anti-PD-L1/2) antibody molecule at a concentration of about 130 mg/mL. In some embodiments, the reconstituted formulation comprises an anti-TGFβ or anti-PD1 (or anti-PD-L1/2) antibody molecule at a concentration of about 140 mg/mL. In some embodiments, the reconstituted formulation comprises an anti-TGFβ or anti-PD1 (or anti-PD-L1/2) antibody molecule at a concentration of about 150 mg/mL. In some embodiments, the reconstituted formulation comprises an anti-TGFβ or anti-PD1 (or anti-PD-L1/2) antibody molecule at a concentration of about 80 mg/mL to about 120 mg/mL (e.g., about 100 mg/mL).

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

In some embodiments, the reconstituted formulation comprises: an antibody molecule as disclosed herein, present at a concentration of about 80 to about 120 mg/mL (eg, 100 mg/mL); and a buffer, the buffer The reagent comprises a histidine buffer at a concentration of about 15 mM to about 25 mM (eg, 20 mM) and a pH of 5 to 6 (eg, 5.5).

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

In some embodiments, the reconstituted formulation comprises: an antibody molecule disclosed herein at a concentration of about 80 to about 120 mg/mL (eg, 100 mg/mL); a buffer comprising Histidine buffer at a concentration of about 15 mM to about 25 mM (eg, 20 mM) and a pH of about 5 to about 6 (eg, 5.5); and at a concentration of about 200 mM to about 250 mM (eg, 220 mM) The concentration of carbohydrates or sucrose present.

In some embodiments, the reconstituted 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 about 0.005% to about 0.1% (w/w), such as about 0.01% to about 0.08%, about 0.02% to about 0.06%, about 0.03% to about 0.05%, about 0.01% to about 0.06%, about 0.01% to about 0.05%, about 0.01% to about 0.03%, about 0.06% to about 0.08%, about 0.04% to about 0.08%, or about 0.02 % to about 0.08% (w/w), such as about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, or about 0.1 %(w/w). In some embodiments, the formulation comprises a surfactant or polysorbate 20 present at a concentration of about 0.03% to about 0.05% (eg, about 0.04%) (w/w) .

In some embodiments, the reconstituted formulation comprises: an antibody molecule as disclosed herein, present at a concentration of about 80 to about 120 mg/mL (eg, 100 mg/mL); a buffer, the buffer A histidine buffer comprising a concentration of about 15 mM to about 25 mM (eg, 20 mM) and a pH of about 5 to about 6 (eg, 5.5); at about 200 mM to about 250 mM (eg, 220 mM) carbohydrate or sucrose present at a concentration of ; and surfactant or polysorbate 20 present at a concentration of about 0.03% to about 0.05% (eg 0.04%) (w/w).

In some embodiments, the reconstituted formulation comprises: an antibody molecule as disclosed herein, present at a concentration of 100 mg/mL; a buffer comprising histamine at a concentration of 20 mM at a pH of 5.5 Acid buffer (e.g., histidine/histidine-HCL); carbohydrate or sucrose at a concentration of 220 mM; and surfactant or polysorbate 20 at a concentration of 0.04% (w/w) exist.

In some embodiments, the formulation is reconstituted such that the extractable volume of the reconstituted formulation that can be drawn from a container (e.g., a vial) containing the reconstituted formulation is at least 1 mL (e.g., at least 1.2 mL, 1.5 mL, 2 mL, 2.5 mL, 3 mL, 3.5 mL, 4 mL, 4.5 mL, 5 mL, 5.5 mL, 6 mL, 6.5 mL, 7 mL, 7.5 mL, 8 mL, 8.5 mL, 9 mL, 9.5 mL or 10 mL). In certain embodiments, the formulation is reconstituted and/or extracted from a container (eg, vial) at the clinical site. In certain embodiments, the formulation (e.g., a reconstituted formulation) is injected into the infusion bag within 1 hour (e.g., within 45 minutes, 30 minutes, or 15 minutes) of the start of the infusion into the patient .

In some embodiments, the reconstituted formulation has a fill volume of about 1 mL to about 5 mL. In certain embodiments, the reconstituted formulation has a fill volume of about 2 mL to about 4 mL. In some embodiments, the reconstituted formulation has a fill volume of about 3 mL. In some embodiments, the reconstituted formulation has a fill volume of about 3.2 mL. In some embodiments, the reconstituted formulation has a fill volume of about 3.4 mL. In some embodiments, the reconstituted formulation has a fill volume of about 3.6 mL. In some embodiments, the reconstituted formulation has a fill volume of about 3.8 mL.

Other exemplary buffers that can be used in the formulations described herein include, but are not limited to, arginine buffer, citrate buffer, or phosphate buffer. Other exemplary carbohydrates that can be used in the formulations described herein include, but are not limited to, trehalose, mannitol, sorbitol, or combinations thereof. The formulations described herein may also contain tonicity agents (e.g., sodium chloride) and/or stabilizers (e.g., amino acids (e.g., glycine, arginine, methionine, or combinations thereof) ).

Antibody molecules can be administered by a variety of methods known in the art, but for many therapeutic applications the preferred route/mode of administration is intravenous injection or infusion. For example, the antibody molecule can be administered by intravenous infusion at a rate in excess of 20 mg/min, such as 20-40 mg/min, and typically greater than or equal to 40 mg/min, to achieve about 35 to 440 mg/m ² , typically at a dosage of about 70 mg/m ² to about 310 mg/m ² and more typically about 110 mg/m ² to about 130 mg/m ² . In embodiments, the antibody molecule can be administered by intravenous infusion at a rate of less than 10 mg/min; preferably less than or equal to 5 mg/min, to achieve about ¹ mg/m to about 100 mg/m ² , preferably about 5 mg/m ² to about 50 mg/m ² , about 7 mg/m ² to about 25 mg/m ² and more preferably about 10 mg/m ² . As will be understood by those skilled in the art, the route and/or mode of administration will vary depending on the desired result. In certain embodiments, the active compounds are prepared with carriers that will protect the compound against rapid release, such as a controlled release formulation, including implants, transdermal patches, and microencapsulated delivery systems. Biodegradable, biocompatible polymers may be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Many methods for the preparation of such formulations are patented or generally known to those skilled in the art. See, eg, Sustained and Controlled Release Drug Delivery Systems , edited by JR Robinson, Marcel Dekker, Inc., New York, 1978.

In certain embodiments, antibody molecules can be administered orally, eg, with an inert diluent or an assimilable edible carrier. The compound (and other ingredients, if desired) may also be enclosed in hard or soft shell gelatin capsules, compressed into tablets, or incorporated directly into the subject's diet. For oral therapeutic administration, the compounds can be mixed with excipients and used in the form of ingestible tablets, buccal tablets, lozenges, capsules, elixirs, suspensions, syrups, wafers, and the like. To administer a compound of the invention by means other than parenteral administration, it may be necessary to coat or co-administer the compound with a material to prevent its inactivation. Therapeutic compositions can also be administered using medical devices known in the art.

Dosage regimens are adjusted to provide the optimum desired response (eg, a therapeutic response). For example, a single bolus injection can be administered, several divided doses can be administered over time or the dose can be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is especially advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subjects to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the invention are 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 importance of formulating such active compound for the treatment of a subject. Inherent limitations in the field of sensitivity.

The antibody molecule can be administered by intravenous infusion at a rate in excess of 20 mg/min, such as 20-40 mg/min, and typically greater than or equal to 40 mg/min, to achieve about 35 mg/ ^m to about 440 mg /m ² , typically about 70 mg/m ² to about 310 mg/m ² , and more typically about 110 mg/m ² to about 130 mg/m ² . In an embodiment, the infusion rate is from about 110 mg/m ² to about 130 mg/m ² to a 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 less than or equal to 5 mg/min, to achieve about 1 mg/m ² to about 100 mg/m ² , For example a dose of about 5 mg/m ² to about 50 mg/m ² , about 7 mg/m ² to about 25 mg/m ² , or about 10 mg/m ² . In some embodiments, the antibody is infused over a period of about 30 minutes. It is to be noted that dosage values may vary with the type and severity of the condition to be alleviated. It is further understood that for any particular subject, the particular dosage regimen should be adjusted over time according to the individual needs and the professional judgment of the person using or supervising the administration of the composition, and that the dosage ranges set forth herein are exemplary only and are not intended to intended to limit the scope or practice of a claimed composition.

The pharmaceutical composition of the present invention may include a "therapeutically effective amount" or "prophylactically effective amount" of the antibody or antibody part of the present invention. A "therapeutically effective amount" means an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result. A therapeutically effective amount of a modified antibody or antibody fragment can vary depending on factors such as disease state, age, sex, and body weight of the individual, as well as the ability of the antibody or antibody portion to elicit a desired response in the individual. A therapeutically effective amount is also one in which any toxic or detrimental effects of the modified antibody or antibody fragment are outweighed by the therapeutically beneficial effects. A "therapeutically effective dose" preferably inhibits a measurable parameter, such as inhibition of tumor growth rate by at least about 20%, more preferably at least about 40%, and even more preferably, relative to untreated subjects. At least about 60%, and still more preferably at least about 80%. The ability of compounds to inhibit a measurable parameter, such as cancer, can be assessed in animal model systems predictive of human tumor efficacy. Alternatively, this property of the composition can be assessed by examining the ability of the compound to inhibit, in vitro, by assays known to those skilled in the art.

A "prophylactically effective amount" refers to an amount effective, in dosages and for the period of time required, to achieve the desired prophylactic result. Typically, such a prophylactically effective amount will be less than a therapeutically effective amount because the prophylactic dose is administered in the subject prior to or early in the disease.

Kits comprising the combinations, compositions or formulations described herein are also within the scope of the present disclosure. The kit may include one or more other elements, including: instructions for use (e.g., according to the dosage regimen described herein); other reagents, such as labels, therapeutic agents, or antibodies for chelating or otherwise conjugating; Reagents with markers or therapeutic agents or radioprotective compositions; devices or other materials for preparing antibodies for administration; pharmaceutically acceptable carriers; and devices or other materials for administration to a subject . chemotherapeutic agent

Compounds disclosed throughout (eg, TGFβ inhibitors (eg, NIS793) or PD-1 inhibitors (eg, tislelizumab)) can be used in combination with chemotherapeutic agents. Therapeutic agents may include, but are not limited to, anastrozole (Arimidex®), bicalutamide (Casodex®), bleomycin sulfate (Blenoxane®), busulfan (Myleran®), busulfan injection (Busulfex® ), capecitabine (Xeloda®), N4-pentyloxycarbonyl-5-deoxy-5-fluorocytidine, carboplatin (Paraplatin®), carmustine (BiCNU®), chlorambucil ( Leukeran®), cisplatin (Platinol®), cladribine (Leustatin®), cyclophosphamide (Cytoxan® or Neosar®), cytarabine, cytosine arabinoside (Cytosar-U®), Glycoside liposome injection (DepoCyt®), dacarbazine (DTIC-Dome®), dactinomycin (actinomycin D, Cosmegan), daunorubicin hydrochloride (Cerubidine®), daunorubicin citrate liposome Injection (DaunoXome®), dexamethasone, docetaxel (Taxotere®), doxorubicin hydrochloride (Adriamycin®, Rubex®), etoposide (Vepesid®), fludarabine phosphate (Fludara®) , 5-fluorouracil (Adrucil®, Efudex®), flutamide (Eulexin®), tezacitibine, gemcitabine (difluorodeoxycytidine), hydroxyurea (Hydrea®), idarubicin (Idamycin®), ifosf Amamide (IFEX®), Irinotecan (Camptosar®), L-Asparaginase (ELSPAR®), Leucovorin, Melphalan (Alkeran®), 6-Mercaptopurine (Purinethol®), Amine Pterin (Folex®), mitoxantrone (Novantrone®), Mylotar, paclitaxel (Taxol®) or nab-paclitaxel, phoenix (Yttrium90/MX-DTPA), pentostatin, carlimus polifeprosan 20 (Gliadel®), tamoxifen citrate (Nolvadex®), teniposide (Vumon®), 6-thioguanine, thiotepa, tirapazamine (Tirazone ®), topotecan hydrochloride for injection (Hycamptin®), vinblastine (Velban®), vincristine (Oncovin®), vinorelbine (Navelbine®), epirubicin (Ellence®), Saliplatin (Eloxatin®), Exemestane (Aromasin®), Letrozole (Femara®), and Fulvestrant (Faslodex®).

In some embodiments, gemcitabine can be used in combination with any of the therapeutic molecules disclosed throughout. For example, a TGFβ inhibitor (eg, NIS793) in combination with gemcitabine can be used to treat patients. PD-1 inhibitors (eg, PDR001, BGB-A317, or BGB-108) can be used in combination with gemcitabine or gemcitabine and a TGFβ inhibitor.

In some embodiments, nab-paclitaxel can be used in combination with any of the therapeutic molecules disclosed throughout. For example, a TGFβ inhibitor (eg, NIS793) in combination with nab-paclitaxel can be used to treat patients. A PD-1 inhibitor (eg, PDR001, BGB-A317, or BGB-108) can be used in combination with nab-paclitaxel or nab-paclitaxel and a TGFβ inhibitor (eg, NIS793). In some combinations, TGFβ inhibitors (eg, NIS793) can be used in combination with gemcitabine and nab-paclitaxel. In some combinations, a TGFβ inhibitor (eg, NIS793) can be used in combination with a PD-1 inhibitor (eg, PDR001, BGB-A317, or BGB-108), gemcitabine, and nab-paclitaxel.

When gemcitabine is used in combination with other therapeutic agents, it can be administered intravenously to the patient. For example, gemcitabine can be administered intravenously to a patient at a dose of 1000 mg/ ^m2 . Gemcitabine may also be administered weekly, every two weeks, every three weeks, or every four weeks for a given period of time. For example, gemcitabine is administered at a dose of 1000 mg/ ^m2 on days 1, 8, and 15 of each cycle (eg, a 21-day or 28-day cycle). In some instances, gemcitabine can be administered intravenously to a patient at a dose of 675 mg/ ^m2 . For example, gemcitabine is administered at a dose of 675 mg/ ^m2 on days 1 and 8 of each cycle (eg, a 21-day or 28-day cycle).

When nab-paclitaxel is used in combination with other therapeutic agents, it can be administered intravenously to the patient. For example, nab-paclitaxel can be administered intravenously to a patient at a dose of 125 mg/ ^m2 . Nab-paclitaxel can also be administered weekly, every two weeks, every three weeks, or every four weeks for a given period of time. For example, nab-paclitaxel is administered at a dose of 125 mg/ ^m2 on days 1, 8, and 15 of each cycle (eg, a 21-day or 28-day cycle).

In some embodiments, 5-fluorouracil can be used in combination with any of the therapeutic molecules disclosed throughout. For example, a TGFβ inhibitor (eg, NIS793) in combination with 5-fluorouracil can be used to treat a patient.

When 5-fluorouracil is used in combination with other therapeutic agents, it can be administered intravenously to the patient. For example, 5-fluorouracil can be administered intravenously (eg, administered using an intravenous bolus) to a patient at a dose of 400 mg/m ² to 2400 mg/m ² . The 5-fluorouracil may also be administered weekly, every two weeks, every three weeks, or every four weeks for a given period of time. For example, 5-fluorouracil is administered as an IV bolus of 400 mg/ ^m2 on days 1 and 15 of each cycle (eg, 21-day or 28-day cycle) followed by 2400 mg/ ^m2 on a 46-hour basis. Administered by continuous intravenous infusion.

In some embodiments, folinic acid can be used in combination with any of the therapeutic molecules disclosed throughout. For example, a TGFβ inhibitor (eg, NIS793) in combination with folinic acid can be used to treat a patient.

When folinic acid is used in combination with other therapeutic agents, it can be administered intravenously to the patient. For example, folinic acid can be administered intravenously to a patient at a dose of 400 mg/ ^m2 . Folinic acid may also be administered once a week, once every two weeks, once every three weeks, or once every four weeks for a given period of time. For example, folinic acid is administered at a dose of 400 mg/ ^m2 on days 1 and 15 of each cycle (eg, a 21-day or 28-day cycle).

In some embodiments, folinic acid can be used as a substitute for folinic acid. In those cases, leucovorin can be administered at 200 mg/ ^mg2 . Further, leucovorin may be administered on days 1 and 15 of a 28-day cycle.

In some embodiments, oxaliplatin can be used in combination with any of the therapeutic molecules disclosed throughout. For example, a TGFβ inhibitor (eg, NIS793) in combination with oxaliplatin can be used to treat a patient.

When oxaliplatin is used in combination with other therapeutic agents, it can be administered intravenously to the patient. For example, oxaliplatin can be administered intravenously to a patient at a dose of 85 mg/ ^m2 . Oxaliplatin can also be administered weekly, every two weeks, every three weeks, or every four weeks for a given period of time. For example, oxaliplatin is administered at a dose of 85 mg/ ^m2 on days 1 and 15 of each cycle (eg, a 21-day or 28-day cycle).

In some embodiments, irinotecan may be used in combination with any of the therapeutic molecules disclosed throughout. For example, a TGFβ inhibitor (eg, NIS793) in combination with irinotecan can be used to treat a patient.

When irinotecan is used in combination with other therapeutic agents, it can be administered intravenously to the patient. For example, irinotecan can be administered intravenously to a patient at a dose of 180 mg/ ^m2 . Irinotecan may also be administered weekly, every two weeks, every three weeks, or every four weeks for a given period of time. For example, irinotecan is administered at a dose of 180 mg/ ^m2 on days 1 and 15 of each cycle (eg, a 21-day or 28-day cycle).

In some embodiments, a TGFβ inhibitor (eg, NIS793) can be combined with gemcitabine and nab-paclitaxel. In some embodiments, a TGFβ inhibitor (eg, NIS793) can be combined with a PD-1 inhibitor (eg, PDR001, BGB-A317, or BGB-108), gemcitabine, and nab-paclitaxel. In some embodiments, a TGFβ inhibitor (eg, NIS793) can be combined with bevacizumab, 5-fluorouracil, leucovorin, and oxaliplatin. In some embodiments, a TGFβ inhibitor (eg, NIS793) can be combined with a PD-1 inhibitor (eg, PDR001, BGB-A317, or BGB-108), bevacizumab, 5-fluorouracil, leucovorin, and oxage Platinum combination. In some embodiments, a TGFβ inhibitor (eg, NIS793) can be combined with bevacizumab, 5-fluorouracil, leucovorin, and irinotecan. In some embodiments, a TGFβ inhibitor (eg, NIS793) can be combined with a PD-1 inhibitor (eg, PDR001, BGB-A317, or BGB-108), bevacizumab, 5-fluorouracil, leucovorin, and iritinib Health combination.

In some embodiments, cyclophosphamide can be used in combination with any of the therapeutic molecules disclosed throughout, such as a TGFβ inhibitor (eg, NIS793), to treat a patient. When cyclophosphamide is used in combination with other therapeutic agents (eg, TGFβ inhibitors (eg, NIS793)), it can be administered to the patient intravenously or as an oral drug. For example, cyclophosphamide can be administered intravenously to a patient at a dose of 250 mg/ ^m2 . Cyclophosphamide can also be administered daily for an amount of time. For example, cyclophosphamide can be administered over 5 days, eg, five consecutive days. For example, cyclophosphamide is administered at a dose of 250 mg/ ^m2 for five consecutive days.

In some embodiments, topotecan can be used in combination with any of the therapeutic molecules disclosed throughout, such as a TGFβ inhibitor (eg, NIS793), to treat a patient. When topotecan is used in combination with other therapeutic agents (eg, TGFβ inhibitors (eg, NIS793)), it can be administered intravenously to the patient. For example, topotecan can be administered intravenously to a patient at a dose of 0.75 mg/ ^m2 . Topotecan may also be administered over the course of a certain amount of time, eg, 30 minutes. Topotecan can also be administered over 5 days, eg, five consecutive days. For example, topotecan is administered at a dose of 0.75 mg/ ^m2 for five consecutive days. Further exemplary combinations and dosage regimens

The compounds and/or therapeutic agents disclosed throughout can be used in any combination. Furthermore, each therapeutic agent can be used in a manner that is not unduly toxic but effective for its intended purpose. The following combinations and/or dosage regimens are for illustrative purposes only and do not exhaustively encompass all contemplated combinations and/or dosage regimens. Those skilled in the art can further envisage different combinations and/or dosage regimens disclosed throughout the specification.

In combination, NIS793 is administered to patients with gemcitabine and nab-paclitaxel. The three-component combination is administered intravenously to the patient. In this three-component combination, NIS793 is administered to patients at a dose of 2100 mg on Days 1 and 15 of each cycle (eg, 21-day or 28-day cycle). Gemcitabine is administered to patients at a dose of 1000 mg/m2 on Days 1, 8, and ¹⁵ of each cycle (eg, 21-day or 28-day cycle) in this three-component combination. Nab-paclitaxel is administered to patients at a dose of 125 mg/m2 on Days 1, 8, and ¹⁵ of each cycle (e.g., 21-day or 28-day cycle) in this three-component combination . In this combination, pancreatic cancer is treated, eg, metastatic pancreatic adenocarcinoma.

In combination, NIS793 is administered to patients with bevacizumab, 5-fluorouracil, leucovorin, and oxaliplatin. The five-component combination is administered intravenously (in some cases, intravenous bolus or continuous intravenous infusion) to the patient. In this five-component combination, NIS793 is administered to patients at a dose of 2100 mg on Days 1 and 15 of each cycle (eg, 21-day or 28-day cycle). Bevacizumab is administered to patients at a dose of 5 mg/kg on Days 1 and 15 of each cycle (eg, 21-day or 28-day cycle) in this five-component combination. For example, in this five-component combination 5-fluorouracil is given as an intravenous bolus injection of 400 mg/ ^m2 followed by 2400 mg / ^m2 is administered to the patient as a continuous intravenous infusion over 46 hours. Leucovorin is administered to patients at a dose of 400 mg/ ^m2 on Days 1 and 15 of each cycle (eg, 21-day or 28-day cycle) in this five-component combination. Oxaliplatin in this five-component combination is administered to patients at a dose of 85 mg/ ^m2 on Days 1 and 15 of each cycle (eg, 21-day or 28-day cycle). In this combination, colorectal cancer is treated, eg, metastatic colorectal cancer.

In combination, NIS793 is administered to patients with bevacizumab, 5-fluorouracil, leucovorin, and irinotecan. The five-component combination is administered intravenously (in some cases, intravenous bolus or continuous intravenous infusion) to the patient. In this five-component combination, NIS793 is administered to patients at a dose of 2100 mg on Days 1 and 15 of each cycle (eg, 21-day or 28-day cycle). Bevacizumab is administered to patients at a dose of 5 mg/kg on Days 1 and 15 of each cycle (eg, 21-day or 28-day cycle) in this five-component combination. For example, in this five-component combination 5-fluorouracil is given as an intravenous bolus injection of 400 mg/ ^m2 followed by 2400 mg / ^m2 is administered to the patient as a continuous intravenous infusion over 46 hours. Leucovorin is administered to patients at a dose of 400 mg/ ^m2 on Days 1 and 15 of each cycle (eg, 21-day or 28-day cycle) in this five-component combination. Irinotecan is administered to patients at a dose of 180 mg/ ^m2 on Days 1 and 15 of each cycle (eg, 21-day or 28-day cycle) in this five-component combination. In this combination, colorectal cancer is treated, eg, metastatic colorectal cancer.

In combination, NIS793 is administered to patients with oxaliplatin and capecitabine. The three-component combination is administered intravenously (in some cases, intravenous bolus or continuous intravenous infusion) to the patient. NIS793 was administered to patients at a dose of 2100 mg every three weeks (Q3W) in this three-component combination. Oxaliplatin in this three-component combination was administered intravenously to patients at a dose of 130 mg/ ^m2 on day 1 of the Q3W cycle. Capecitabine was orally administered to patients in this three-component combination at a dose of 1000 mg/m ² twice daily (days 1-14) in a Q3W cycle. Tislelizumab was administered to patients as needed at a dose of 200 mg every three weeks (Q3W). In this combination, gastric cancer is treated.

In combination, NIS793 is administered to patients with oxaliplatin, folinic acid (or leucovorin), and 5-fluorouracil. The combination is administered to the patient intravenously (in some cases, as an intravenous bolus or continuous intravenous infusion). NIS793 was administered to patients at a dose of 2100 mg every three weeks (Q3W) in this four-component combination. Oxaliplatin was administered to patients at a dose of 85 mg/ ^m2 on Day 1 of the Q2W cycle. Folinic acid was administered at a dose of 400 mg/ ^m2 (or levofolinic acid at a dose of 200 mg/ ^m2 ) on day 1 of the Q2W cycle. 5-Fluorouracil was administered intravenously at 400 mg/ ^m2 on Day 1 of the Q2W cycle followed by 1200 mg/ ^m2 on Days 1-2. Tislelizumab was administered at a dose of 300 mg every four weeks (Q4W) as needed. In this combination, gastric cancer is treated.

In combination, NIS793 is administered to patients with oxaliplatin and capecitabine. The combination is administered to the patient intravenously (in some cases, as an intravenous bolus or continuous intravenous infusion). NIS793 was administered to patients at a dose of 2100 mg every two weeks (Q2W) in this three-component combination. Oxaliplatin in this three-component combination was administered intravenously at a dose of 130 mg/ ^m2 on day 1 of the Q3W cycle. In this three-component combination capecitabine was administered orally at a dose of 1000 mg/m ² twice daily (days 1-14) in a Q3W cycle. Tislelizumab was administered at a dose of 200 mg every three weeks (Q3W). In this combination, gastric cancer is treated.

In combination, NIS793 is administered to patients with oxaliplatin, folinic acid (or leucovorin), and 5-fluorouracil. The combination is administered to the patient intravenously (in some cases, as an intravenous bolus or continuous intravenous infusion). NIS793 was administered to patients at a dose of 2100 mg every two weeks (Q2W) in this four-component combination. Oxaliplatin was administered to patients at a dose of 85 mg/ ^m2 on Day 1 of the Q2W cycle. Folinic acid was administered at a dose of 400 mg/ ^m2 (or levofolinic acid at a dose of 200 mg/ ^m2 ) on day 1 of the Q2W cycle. 5-Fluorouracil was administered intravenously at 400 mg/ ^m2 on Day 1 of the Q2W cycle followed by 1200 mg/ ^m2 on Days 1-2. Tislelizumab was administered at a dose of 300 mg every four weeks (Q4W) as needed. In this combination, gastric cancer is treated.

In combination, NIS793 is administered to patients with cyclophosphamide or topotecan. The three-component combination is administered intravenously to the patient. NIS793 was administered to patients in this three-component combination based on the patient's body weight: (a) at a dose of 45 mg/kg for patients weighing less than 20 kg; (b) for patients weighing between 20-40 kg and (c) for patients weighing more than 40 kg, administered at a dose of 20 mg/kg. Cyclophosphamide was administered intravenously to patients at a dose of 250 mg/ ^m2 for 5 consecutive days (on days 1-5) in this three-component combination. Topotecan was administered intravenously to patients in this three-component combination at a dose of 0.75 mg/ ^m2 for 5 consecutive days (on days 1-5). In some instances, the three-component combination is useful in the treatment of neuroblastoma. In some instances, the patient population is a pediatric patient population (eg, under the age of 18).

In combination, NIS793 is administered to patients with gemcitabine. The combination is administered intravenously to the patient. In this combination, NIS793 was administered to patients based on their body weight: (a) at a dose of 45 mg/kg for patients weighing less than 20 kg; (b) for patients weighing between 20-40 kg , administered at a dose of 30 mg/kg; and (c) for patients weighing greater than 40 kg, administered at a dose of 20 mg/kg. Gemcitabine in this combination is administered intravenously to patients once a week (eg, on Days 1 and 8) at a dose of 675 mg/m ² . In some instances, the combination is useful in the treatment of osteosarcoma. In some instances, the patient population is a pediatric patient population (eg, under the age of 18). Diagnosing Subjects and Treating Subjects

As used herein, the term "subject" is intended to include humans and non-human animals. In some embodiments, the subject is a human subject. The term "non-human animal" includes mammals and non-mammals, such as non-human primates. In some embodiments, the subject is human. In some embodiments, the subject is a human patient in need of an enhanced immune response. The combinations described herein are suitable for use in the treatment of human patients with disorders treatable by modulating (eg, enhancing or suppressing) the immune response. In certain embodiments, the patient has, or is at risk of, a disorder described herein, eg, a cancer described herein.

In some cases, subjects treated using the methods disclosed herein are known to have a disease or condition which, in some cases, would benefit from the methods described herein. For example, in some cases, a subject has been detected and/or diagnosed with a disease. The detection and/or diagnosis can be from a physician or other qualified medical personnel. In some cases, detection and/or diagnosis may be self-guided based on one or more symptoms (such as raised lumps, lumps, etc.). Accordingly, in some embodiments, a subject may be in need of the methods described herein for treatment of his or her disease or condition. The term "in need of" means that the subject (or a person treating the subject) is aware of the presence of a condition or disease (eg, a proliferative disease such as cancer).

In certain embodiments, the subject has been identified as having TGFβ(1, 2, or 3) expression in one or more of his tumors (or tumor microenvironment). In certain embodiments, the subject has been identified as having PD-1 expression in one or more of his tumors (or tumor microenvironment). In certain embodiments, the subject has been identified as having PD-L1 expression in one or more of his tumors (or tumor microenvironment). In certain embodiments, the subject has been identified as having PD-L2 expression in one or more of his tumors (or tumor microenvironment). In some embodiments, the subject has been identified as having both TGFβ(1, 2, or 3) and PD-1 expression in one or more of his tumors (or tumor microenvironment). In some embodiments, the subject has been identified as having both TGFβ(1, 2, or 3) and PD-L1 expression in one or more of his tumors (or tumor microenvironment). In some embodiments, the subject has been identified as having both TGFβ(1, 2, or 3) and PD-L2 expression in one or more of his tumors (or tumor microenvironment). Once such biomarkers are found, treatment can be carried out using the methods described.

In some embodiments, the subject weighs between about 5 kg and about 500 kg. In some embodiments, the subject is between about 10 kg and about 400 kg. In some embodiments, the subject is between about 15 kg and about 300 kg. In some embodiments, the subject is between about 20 kg and about 200 kg. In some embodiments, the subject is between about 25 kg and about 150 kg. In some embodiments, the subject is between about 40 kg and about 125 kg. In some embodiments, the subject is between about 50 kg and about 100 kg. In some embodiments, the subject is between about 65 kg and about 85 kg. In some embodiments, the subject is about 40 kg. In some embodiments, the subject is about 45 kg. In some embodiments, the subject is about 50 kg. In some embodiments, the subject is about 55 kg. In some embodiments, the subject is about 60 kg. In some embodiments, the subject is about 65 kg. In some embodiments, the subject is about 70 kg. In some embodiments, the subject is about 75 kg. In some embodiments, the subject is about 80 kg. In some embodiments, the subject is about 85 kg. In some embodiments, the subject is about 90 kg. In some embodiments, the subject is about 95 kg. In some embodiments, the subject is about 100 kg. In some embodiments, the subject is about 110 kg. In some embodiments, the subject is about 120 kg. In some embodiments, the subject is about 130 kg. In some embodiments, the subject is about 140 kg. In some embodiments, the subject is about 150 kg. cancer

In some embodiments, the methods are used to treat cancer, such as myelofibrosis (e.g., primary myelofibrosis (PMF), post-essential thrombocythemia myelofibrosis (PET-MF), polycythemia vera postmorbid myelofibrosis (PPV-MF)), leukemia (e.g., acute myeloid leukemia (AML), such as relapsed or refractory AML or de novo AML; or chronic lymphocytic leukemia (CLL)), lymphoma ( eg, T-cell lymphoma, B-cell lymphoma, non-Hodgkin's lymphoma, or small lymphocytic lymphoma (SLL)), myeloma (eg, multiple myeloma), lung cancer (eg, non-small cell Lung cancer (NSCLC) (eg, NSCLC with squamous and/or nonsquamous histology, or NSCLC adenocarcinoma), or small cell lung cancer (SCLC), skin cancer (eg, Merkel cell carcinoma) or melanoma (eg, advanced melanoma)), ovarian cancer, mesothelioma, bladder cancer, soft tissue sarcomas (eg, hemangiopericytoma (HPC)), bone cancer (osteosarcoma), kidney cancer (eg, kidney cancer ( renal cancer) (e.g., renal cell carcinoma)), liver cancer (e.g., hepatocellular carcinoma), cholangiocarcinoma, sarcoma, myelodysplastic syndrome (MDS) (e.g., low-risk MDS), prostate cancer, breast cancer (e.g., non-expressing One, both, or all of estrogen receptor, progesterone receptor, or Her2/neu breast cancer (eg, triple-negative breast cancer), colorectal cancer, nasopharyngeal cancer, duodenal cancer, endometrial cancer, pancreatic cancer Carcinoma (eg, pancreatic ductal adenocarcinoma (PDAC)), head and neck cancer (eg, head and neck squamous cell carcinoma (HNSCC)), anal cancer, gastroesophageal cancer, thyroid cancer (eg, anaplastic thyroid carcinoma), cervical cancer , or neuroendocrine neoplasms (NETs) (eg, atypical lung carcinoid).

In certain embodiments, the patient is not eligible for standard treatment regimens with established benefit in patients with one or more of the cancers described herein. In some embodiments, the subject is ineligible for chemotherapy. In some embodiments, the chemotherapy is intensive induction chemotherapy. For example, the methods described herein can be used to treat adult patients with one or more cancers as described. In certain embodiments, the inhibitor (TGFβ and/or PD1) is administered in an amount effective to treat cancer or a symptom thereof.

The compositions, formulations, or methods described herein can be used to inhibit the growth of cancerous tumors. Alternatively, the compositions, formulations, or methods described herein may be used in combination with one or more of standard of care treatments for cancer, another antibody or antigen-binding fragment thereof, an immunomodulator (e.g., co- activators of stimulatory molecules or inhibitors of inhibitory molecules); vaccines, such as therapeutic cancer vaccines; or other forms of cellular immunotherapy as described herein. In one embodiment, the method is applicable to the treatment of cancer in vivo.

In another aspect, provided is a method of treating, eg, alleviating or ameliorating, a hyperproliferative condition or disorder (eg, cancer), eg, a solid tumor, a hematological cancer, a soft tissue tumor, or a metastatic lesion in a subject. The method includes performing a method described herein, or a composition or formulation described herein, according to a dosage regimen described herein.

As used herein, the term "cancer" is meant to include all types of cancerous growths or oncogenic processes, metastatic tissues or malignantly transformed cells, tissues or organs, regardless of histopathological type or stage of invasion. Examples of cancerous disorders include, but are not limited to, hematological cancers, solid tumors, soft tissue tumors, and metastatic lesions.

Examples of solid tumors include, but are not limited to, malignancies (e.g., sarcomas) and carcinomas (including adenocarcinomas and squamous cell carcinomas) of various organ systems, such as those affecting the liver, lung, breast, lymph, gastrointestinal (e.g., colon), Those of the anus, genitals, and genitourinary tract (eg, kidney, urothelium, bladder), prostate, CNS (eg, brain, nerve, or glial cells), head and neck, skin, pancreas, and pharynx. Adenocarcinomas include malignancies such as most cancers of the colon, rectum, kidney (e.g., renal cell carcinoma (e.g., clear cell or non-clear cell renal cell carcinoma)), liver, lung cancer (e.g., non-small cell lung cancer (e.g., squamous or non-squamous non-small cell lung cancer), small bowel cancer, and esophageal cancer. Squamous cell carcinomas include, for example, malignancies in the lung, esophagus, skin, head and neck region, oral cavity, anus, and cervix. In one embodiment, the cancer is melanoma, such as advanced melanoma. Cancer can be early, intermediate, late or can be metastatic cancer. The combinations described herein can also be used to treat or prevent metastatic lesions of the above cancers.

In certain embodiments, the cancer is a solid tumor. In some embodiments, the cancer is ovarian cancer. In other embodiments, the cancer is lung cancer, such as small cell lung cancer (SCLC) or non-small cell lung cancer (NSCLC). In other embodiments, the cancer is mesothelioma. In other embodiments, the cancer is skin cancer, such as Merkel cell carcinoma or melanoma. In other embodiments, the cancer is kidney cancer, such as renal cell carcinoma (RCC). In other embodiments, the cancer is bladder cancer. In other embodiments, the cancer is a soft tissue sarcoma, such as hemangiopericytoma (HPC). In other embodiments, the cancer is bone cancer, such as osteosarcoma. In other embodiments, the cancer is colorectal cancer. In other embodiments, the cancer is pancreatic cancer (eg, PDAC). In other embodiments, the cancer is nasopharyngeal carcinoma. In other embodiments, the cancer is breast cancer. In other embodiments, the cancer is duodenal cancer. In other embodiments, the cancer is endometrial cancer. In other embodiments, the cancer is adenocarcinoma, such as unknown adenocarcinoma. In other embodiments, the cancer is liver cancer, such as hepatocellular carcinoma. In other embodiments, the cancer is cholangiocarcinoma. In other embodiments, the cancer is sarcoma. In certain embodiments, the cancer is myelodysplastic syndrome (MDS) (eg, high risk MDS or low risk MDS). In some embodiments, the cancer is neuroblastoma. In certain embodiments, the cancer is osteosarcoma.

In another embodiment, the cancer is carcinoma (eg, advanced or metastatic cancer), melanoma, or lung cancer (eg, non-small cell lung cancer). 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., stage Ia or Ib), stage II (e.g., stage IIa or stage IIb), stage III (e.g., stage IIIa or IIIb), or stage IV non-small cell lung cancer Small Cell Lung Cancer. In one embodiment, the cancer is melanoma, such as advanced melanoma. In one embodiment, the cancer is advanced or unresectable melanoma unresponsive to other therapies. In other embodiments, the cancer is melanoma with a BRAF mutation (eg, a BRAF V600 mutation). In another embodiment, the cancer is liver cancer (eg, advanced liver cancer) 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 myeloma, such as multiple myeloma. In yet another embodiment, the cancer is renal cancer, such as renal cell carcinoma (RCC) (eg, metastatic RCC, non-clear cell renal cell carcinoma (nccRCC), or clear cell renal cell carcinoma (CCRCC)).

In some embodiments, the cancer is an MSI high cancer. In some embodiments, the cancer is metastatic cancer. In other embodiments, the cancer is advanced cancer. In other embodiments, the cancer is relapsed or refractory cancer.

Exemplary cancers whose growth can be inhibited using the methods, compositions, or formulations disclosed herein include cancers that typically respond to immunotherapy. Additionally, refractory or recurrent malignancies can be treated using the combinations described herein.

Examples of other cancers that may be treated include, but are not limited to, basal cell carcinoma, biliary tract cancer; bladder cancer; bone cancer; brain and CNS cancers; primary CNS lymphoma; central nervous system (CNS) tumors; breast cancer; cervical cancer ; choriocarcinoma; colorectal cancer; connective tissue cancer; digestive system cancer; endometrial cancer; esophageal cancer; eye cancer; head and neck cancer; gastric cancer; leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic or acute leukemia); liver cancer; lung cancer (e.g., small cell and non-small cell); lymphoma (including Hodgkin and non-Hodgkin King's lymphoma); lymphocytic lymphoma; melanoma, e.g., malignant melanoma of the skin or eye; myeloma; neuroblastoma; cancer of the oral cavity (e.g., lip, tongue, mouth, and pharynx); Ovarian cancer; pancreatic cancer; prostate cancer; retinoblastoma; rhabdomyosarcoma; rectal cancer; respiratory system cancer; sarcoma; skin cancer; stomach cancer; testicular cancer; thyroid cancer; uterine cancer; urinary system cancer, liver cancer, anal region cancer , fallopian tube cancer, vaginal cancer, vulvar cancer, small intestine cancer, endocrine system cancer, parathyroid cancer, adrenal gland cancer, soft tissue sarcoma, urethral cancer, penile cancer, childhood solid tumor, spinal cord axis tumor, brainstem glioma, pituitary adenoma , Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, T-cell lymphoma, environmentally induced cancers (including those induced by asbestos), and other carcinomas and sarcomas, and combinations of these cancers.

The methods and therapeutic agents described herein may include co-formulation and/or Co-administered composition. In other embodiments, the antibody molecule is administered in combination with other therapeutic treatment modalities, including surgery, radiation, cryosurgery, and/or hyperthermia. Such combination therapy may advantageously utilize lower doses of the therapeutic agents administered, thereby avoiding possible toxicity or complications associated with various monotherapies.

When administered in combination, a TGFβ inhibitor, a PD-1 inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor, one or more additional agents, or all may be used alone (e.g., as a monotherapy) A higher, lower or same amount or dose of each agent in ) is administered. In certain embodiments, TGFβ inhibitors, PD-1 inhibitors, PD-L1 inhibitors, or PD-L2 inhibitors, one or more additional agents, or all are administered in amounts or dose ratios used alone (e.g. , as monotherapy) the amount or dose of each agent is low (eg, at least 20%, at least 30%, at least 40%, or at least 50%). In other embodiments, a TGFβ inhibitor, a PD-1 inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor, one or more additional agents, or The overall amount or dosage is lower (eg, at least 20%, at least 30%, at least 40%, or at least 50% lower).

In other embodiments, the additional therapeutic agent is from the agents listed in Table 6 of WO 2017/019897. In some embodiments, the additional therapeutic agent is one or more of: 1) a protein kinase C (PKC) inhibitor; 2) a heat shock protein 90 (HSP90) inhibitor; 3) a phosphoinositide 3-kinase ( PI3K) and/or inhibitors of target of rapamycin (mTOR); 4) inhibitors of cytochrome P450 (eg, CYP17 inhibitors or 17α-hydroxylase/C17-20 lyase inhibitors); 5) Iron chelators; 6) aromatase inhibitors; 7) p53 inhibitors, eg, inhibitors of p53/Mdm2 interaction; 8) apoptosis inducers; 9) angiogenesis inhibitors; 10) aldosterone synthase inhibitors ; 11) smooth (SMO) receptor inhibitors; 12) prolactin receptor (PRLR) inhibitors; 13) Wnt signaling inhibitors; 14) CDK4/6 inhibitors; 15) fibroblast growth factor receptor 2 ( FGFR2)/Fibroblast Growth Factor Receptor 4 (FGFR4) Inhibitors; 16) Inhibitors of Macrophage Colony Stimulating Factor (M-CSF); 17) c-KIT, Histamine Release, Flt3 (e.g. FLK2/STK1 ) or PKC; 18) inhibitors of one or more of VEGFR-2 (e.g., FLK-1/KDR), PDGFRβ, c-KIT, or Raf kinase C; 19) somatostatin-stimulating agonists and/or growth hormone release inhibitors; 20) anaplastic lymphoma kinase (ALK) inhibitors; 21) insulin-like growth factor 1 receptor (IGF-1R) inhibitors; 22) P-glycoprotein 1 inhibitors ;23) Inhibitors of vascular endothelial growth factor receptor (VEGFR); 24) BCR-ABL kinase inhibitors; 25) FGFR inhibitors; 26) Inhibitors of CYP11B2; 27) HDM2 inhibitors, such as HDM2-p53 interacting 28) Inhibitors of tyrosine kinases; 29) Inhibitors of c-MET; 30) Inhibitors of JAK; 31) Inhibitors of DAC; 32) Inhibitors of 11β-hydroxylase; 33) IAP 34) Inhibitors of PIM Kinase; 35) Inhibitors of Bocupine; 36) Inhibitors of BRAF (such as BRAF V600E or wild-type BRAF); 37) Inhibitors of HER3; 38) Inhibition of MEK or 39) an inhibitor of a lipid kinase (eg, as described in Table 6 of WO 2017/019897). Pediatric patients

In some cases, the patient population can be an adult population or a pediatric population. For pediatric patients, NIS793 is indicated for the treatment of children with recurrent or refractory solid tumors. Single agent and/or combination therapy can be used to treat pediatric patients with recurrent or refractory solid tumors.

In some embodiments, NIS793 (or other TGFβ inhibitors), cyclophosphamide, and topotecan may be used to treat patients, such as pediatric patients, with neuroblastoma (eg, relapsed or refractory neuroblastoma) .

In some embodiments, NIS793 (or other TGFβ inhibitors) and gemcitabine can be used to treat patients, eg, pediatric patients, with osteosarcoma (eg, recurrent measurable osteosarcoma).

In some embodiments, the patient population is greater than 12 months and less than 21 years of age. For example, in treating neuroblastoma, the patient population can be older than 12 months and younger than 21 years. In some embodiments, the patient population can be greater than or equal to 12 months of age and the patient population encompasses adult patients younger than 39 years of age (between > 12 months and < 39 years of age).

Patients treated with each of the therapies (and combinations) described throughout must have had histological verification of malignancy at initial diagnosis or at recurrence. Patients with recurrent or refractory solid tumors can be treated with the various therapies (and combinations) described throughout. In some embodiments, patients with relapsed or refractory neuroblastoma can be treated with the various therapies (and combinations) described throughout. In some embodiments, patients with relapsed or refractory osteosarcoma can be treated with the various therapies (and combinations) described throughout.

In some embodiments, those patients weighing less than 20 kg may be administered a TGFβ inhibitor (eg, NIS793) at a dose of 45 mg/kg. In some embodiments, those patients weighing between 20 kg and 40 kg may be administered a TGFβ inhibitor (eg, NIS793) at a dose of 30 mg/kg. In some embodiments, those patients weighing greater than 40 kg may be administered a TGFβ inhibitor (eg, NIS793) at a dose of 20 mg/kg. Dosing for each group can be every 3 weeks, which can be considered a single cycle. In some instances, treatment of a patient can continue for as many as 35 cycles.

For some patients (eg, those with neuroblastoma and therefore "in need"), cyclophosphamide and/or topotecan may be administered in combination with a TGFβ inhibitor (eg, NIS793). For some patients (eg, those with osteosarcoma and therefore "in need"), gemcitabine can be administered in combination with a TGFβ inhibitor (eg, NIS793).

In some embodiments, a TGFβ inhibitor (eg, NIS793) can be used in combination with an additional therapeutic agent. In some instances, the additional therapeutic agent includes cyclophosphamide or topotecan. When cyclophosphamide is used, it can be administered at 250 mg/ ^m2 . In some embodiments, the cyclophosphamide is administered for 5 days, eg, five consecutive days. In some embodiments, the additional therapeutic agent comprises topotecan administered at 0.75 mg/ ^m2 . When topotecan is used, its administration can be continued for 5 days, for example five consecutive days. In some embodiments, the proliferative disease is neuroblastoma.

In some embodiments, the additional therapeutic agent comprises gemcitabine. When gemcitabine is used, it can be administered at 675 mg/ ^m2 . In some embodiments, the gemcitabine is administered for 2 days, eg, on day 1 and day 8. In some embodiments, the proliferative disease is osteosarcoma.

In some cases, each cycle is 21 days long. The treatment of the patient can last about 2 years. EXAMPLES Example 1 : Pharmaceutical Products

A TGF beta inhibitor called NIS793 is made into a powder that can be used as an infusion solution. The powder is supplied in glass vials with rubber stoppers that are sealed with flip caps. Each vial contains 100 mg of NIS793 lyophilizate. Drug products are produced using standard aseptic processing. In addition to NIS793, this medicinal product contains the following pharmaceutical excipients: L-histidine/L-histidine hydrochloride monohydrate, polysorbate 20, and sucrose. The vial has a 20% overfill to allow the entire dose to be withdrawn.

This drug product is designed to be reconstituted with 1 mL of Sterile Water for Injection prior to administration to obtain a 100 mg/mL solution of NIS793.

NIS793 concentrate for infusion solution is supplied in glass vials with rubber stoppers, which are sealed with flip caps. Each vial contains 700 mg NIS793 in 7 mL solution. The drug product solution contains the same quantitative and qualitative excipients as NIS793 powder (for infusion solution after reconstitution in sterile water). Similarly, a 7% overfill was provided to allow the entire dose to be withdrawn. Example 2 : People Study

The drug product containing NIS793 as described in Example 1 was used in clinical trials. Table 5 below provides an overview of ongoing human trials. [ Table 5 ] Ongoing human studies Research Population (number of subjects enrolled) Number of subjects exposed to NIS793 research title NIS793 dose/ frequency/ formulation patient research CNIS793X2101 Advanced solid tumors (120) 120 Phase I/Ib, open-label, multicenter dose-escalation study of NIS793 in combination with PDR001 in adult patients with advanced malignancies 0.3-30 mg/kg Q3W 20-30 mg/kg Q2W 2100 mg Q3W as a single agent or in combination with PDR001 concentrate for infusion solution (liquid in vial; 25 mg NIS793 in 0.25 mL). After the initial treatment of the 2 cohorts, the drug product has been replaced by powder for infusion solution. Powder for infusion solution (lyophilized in vial; 100 mg NIS793)

One human study has been initiated and is ongoing: first-in-human study, CNIS793X2101, "Phase I/Ib, open-label, multicenter dose-escalation study of NIS793 in combination with PDR001 in adult patients with advanced malignancies". A total of 120 patients were treated with NIS793 as a single agent or in combination with PDR001 (Table 5). Pharmacokinetics, metabolism and pharmacodynamics in humans

Characterized the PK data of NIS793 from the CNIS793X2101 study (75 patients, cut-off date 4 May 2020). In step-up cohorts, NIS793 was targeted as single agent (NIS793: 0.3-1 mg/kg Q3W) and in combination with PDR001 (NIS793/PDR001: 0.3 mg/kg/100 mg Q3W, 0.3-30 mg/kg/300 mg Q3W and 20-30 mg/kg Q2W/400 mg Q4W) derived PK parameter estimates are presented in Table 6 (Cycle 1) and Table 7 (Cycle 3). Additionally, a summary of the PK parameter estimates derived for the combination of NIS793 and PDR001 (NIS793/PDR001: 2100 mg/300 mg Q3W) in the extended cohorts of MSS-CRC and NSCLC is presented in Table 8 . The mean concentration-time profiles for each dose cohort of NIS793 are plotted in Figure 1 (Cycle 1) and Figure 2 (Cycle 3).

Following administration of NIS793 by intravenous infusion over 30 minutes, an approximate dose proportional increase in NIS793 exposure (ie, Cycle 1 Cmax and AUClast) from 0.3 mg/kg to 30 mg/kg was observed. Moderate accumulation (approximately up to 2.0-fold) of NIS793 was observed based on the ratio of AUClast and Cmax at cycle 3 compared to cycle 1. PK variability was low to moderate (eg, Cmax 12.1% to 73.3%), as indicated by inter-subject variability (CV%).

PDR001 was administered in combination with NIS793 (100 or 300 mg Q3W and 400 mg Q4W) at three doses and two dosing schedules. The PK of PDR001 in combination with NIS793 was similar to the single agent data from PDR001 clinical trial studies. [ Table 6 ] Summary of PK parameters of NIS793 by Cycle 1 treatment in single agent and combination studies (step-up) cycle 1 treat statistics AUClast (h*ng/mL) Clast (ng/mL ) Cmax (ng/mL ) NIS793 0.3 mg/kg Q3W Liquid (N=3) N 3 3 3 Mean (SD) 1140000 (439000) 1060 (358) 7180 (923) Average CV% 38.7 33.7 12.9 NIS793 1 mg/kg Q3W liquid (N=4) N 4 4 4 Mean (SD) 4170000 (478000) 4320 (814) 24900 (3580) Average CV% 11.5 18.9 14.4 NIS793 1 mg/kg Q3W lyophilizate (N=4) N 4 4 4 Mean (SD) 4770000 (1460000) 4780 (1640) 27600.0 (10400) Average CV% 30.6 34.4 37.8 NIS793 0.3 mg/kg Q3W + PDR 100 mg Q3W (N=4) N 5 5 5 Mean (SD) 1360000 (339000) 1400 (498) 6440 (1560) Average CV% 24.9 39.7 24.2 NIS793 0.3 mg/kg Q3W + PDR 300 mg Q3W (N=5) N 5 5 5 Mean (SD) 1700000 (539000) 1530 (722) 11200 (6530) Average CV% 31.6 47.0 58.3 NIS793 1 mg/kg Q3W + PDR 300 mg Q3W (N=5) N 5 5 5 Mean (SD) 5850000 (1510000) 8790 (8440) 30800 (6040) Average CV% 25.7 96.1 19.6 NIS793 3 mg/kg Q3W + PDR 300 mg Q3W (N=5) N 5 5 5 Mean (SD) 11400000 (2330000) 14300 (4830) 58400 (7750) Average CV% 20.4 33.8 13.3 NIS793 10 mg/kg Q3W + PDR 300 mg Q3W (N=5) N 5 5 5 Mean (SD) 3750000 (10200000) 44800 (9630) 181000 (41500) Average CV% 27.2 21.5 22.9 NIS793 30 mg/kg Q3W + PDR 300 mg Q3W (N=7) N 6 6 6 Mean (SD) 90900000 (25200000) 133000 (336900) 519000 (100000) Average CV% 27.1 27.7 19.3 NIS793 20 mg/kg Q2W + PDR 400 N 6 6 6 mg Q4W (N = 11) Mean (SD) 54500000 (15600000) 107000 (29400) 333000 (85600) Average CV% 28.7 27.5 25.7 NIS793 30 mg/kg Q2W + PDR 400 N 4 4 4 mg Q4W (N = 11) Mean (SD) 69100000 (18100000) 154000 (37700) 439000 (96900) Average CV% 26.2 24.5 23.4 N: number of patients with preliminary PK; n: number of patients with available PK parameter values; "-": not applicable; CV%: coefficient of variation (%) = sd/mean*100. [ Table 7 ] Summary of PK parameters of NIS793 by Cycle 3 treatment in single agent and combination studies (ascending) cycle 3 treat statistics AUClast (h*ng/mL) Clast ( ng/mL ) Cmax ( ng/mL ) NIS793 0.3 mg/kg Q3W liquid (N=3) N 2 2 2 Mean (SD) 1820000 (467000) 1900 (735) 8750 (2340) Average CV% 25.7 38.7 26.8 NIS793 1 mg/kg Q3W liquid (N=4) N 3 3 3 Mean (SD) 2910000 (877000) 4290 (2480) 9830 (3500) Average CV% 30.2 57.8 35.6 NIS793 1 mg/kg Q3W lyophilizate (N=4) N 3 3 3 Mean (SD) 4090000 (2200000) 6350 (2860) 13800 (4970) Average CV% 54.0 45.1 36.1 NIS793 0.3 mg/kg Q3W + PDR 100 mg Q3W (N=4) N 2 2 2 Mean (SD) 2530000 (441000) 2960 (750) 8990 (2990) Average CV% 17.4 25.3 33.3 NIS793 0.3 mg/kg Q3W + PDR 300 mg Q3W (N=5) N 4 4 4 Mean (SD) 2960000 (753000) 3330 (1540) 11600 (3530) Average CV% 25.4 46.2 30.3 NIS793 1 mg/kg Q3W + PDR 300 mg Q3W (N=5) N 3 3 3 Mean (SD) 5630000 (1500000) 9710 (2780) 31300 (5070) Average CV% 26.6 28.6 16.2 NIS793 3 mg/kg Q3W + PDR 300 mg Q3W (N=5) N 3 3 3 Mean (SD) 13900000 (5910000) 16100 (8810) 55200 (11300) Average CV% 42.5 54.8 20.5 NIS793 10 mg/kg Q3W + PDR 300 mg Q3W (N=5) N 4 4 4 Mean (SD) 69200000 (9110000) 95900 (36800) 220000 (48600) Average CV% 13.2 38.4 22.1 NIS793 30 mg/kg Q3W + PDR 300 N 2 3 3 mg Q3W (N=7) Mean (SD) 242000000 (24000000) 228000 (80800) 713000 (522000) Average CV% 9.93 35.5 73.3 NIS793 20 mg/kg Q2W + PDR 400 N 3 3 3 mg Q4W (N=6) Mean (SD) 149000000 (138000000) 154000 (45200) 524000 (155000) Average CV% 92.7 29.3 29.6 NIS793 30 mg/kg Q2W + PDR 400 N 0 0 0 mg Q4W (N=11) Mean (SD) - - - Average CV% - - -

N: number of patients with preliminary PK; n: number of patients with available PK parameter values; "-": not applicable; CV%: coefficient of variation (%) = sd/mean*100. [ Table 8 ] Summary of PK parameters of NIS793 2100 mg Q3W at Cycles 1 and 3 in the Combination Study (Extended) cycle 1 treat statistics AUClast (h*ng/mL) Clast ( ng/mL ) Cmax ( ng/mL ) NIS793 2100 mg Q3W + PDR 300 mg Q3W, MSS-CRC (N = 40) N twenty one twenty one twenty one Mean (SD) 94700000 (51500000) 206000 (150000) 547000 (121000) Average CV% 54.4 72.7 22.2 NIS793 2100 mg Q3W + PDR 300 mg Q3W, NSCLC (N=20) N 2 2 2 Mean (SD) 140000000 (59900000) 180000 (50200) 743000 (79200) Average CV% 42.9 28.0 10.7 cycle 3 treat statistics AUClast (h*ng/mL) Clast ( ng/mL ) Cmax ( ng/mL ) NIS793 2100 mg Q3W + PDR 300 mg Q3W, MSS-CRC (N=40) N 3 3 3 Mean (SD) 95500000 (88500000) 341000 (313000) 590000 (319000) Average CV% 92.6 91.7 54.0 N: number of patients with preliminary PK; n: number of patients with available PK parameter values; "-": not applicable; CV%: coefficient of variation (%) = sd/mean*100.

A population PK analysis was performed using concentration data from the dose-escalation phase of study CNIS793X2101 to characterize the pharmacokinetic profile of NIS793, including the effect of body weight as a covariate on clearance and volume of distribution. The analysis showed that the pharmacokinetics of NIS793 are well described using a two-compartment model with first-order elimination from the central compartment. This is consistent with the observation that NIS793 PK is dose-proportional and time-dependent based on non-compartmental assays.

該表中的肌酸酐閾值源自利用CDC公開的兒童長度和身高數據估算GFR的Schwartz公式（Schwartz等人. J. Peds [兒科學雜誌], 106:522, 1985）。 足夠的肝功能，定義為： ●         膽紅素（軛合的膽紅素 + 非軛合的膽紅素的總和）≤ 1.5 x 年齡的正常上限（ULN）。 ●         ALT（SGPT）≤ 135 U/L。出於本研究的目的，ALT的ULN為45 U/L。 ●         血清白蛋白 ≥ 2 g/dL。 足夠的心功能，定義為： ●         縮短分數 ＞ 27%，且左心室射血分數 ＞ 50%。 ●         入組前6個月內無臨床上顯著的心律不整、中風或心肌梗死 ●         QTc ≤ 480 ms ●         高血壓必須藉由穩定劑量的藥物得到良好的控制，持續至少2週 知情同意書：所有患者和/或其父母或合法授權的代表必須簽署書面知情同意書。在適當的時候，將根據機構的指導方針獲得同意。 排除標準：妊娠或哺乳： 由於尚無有關人類胎兒或致畸毒性的可用資訊，因此不會將孕婦或哺乳期婦女納入本研究。月經初潮後的女孩必須進行妊娠測試。對於具有生殖潛力的男性或女性，除非他們同意在該研究期間使用兩種有效的節育方法，包括醫學上接受的屏障或避孕方法（例如，男用或女用避孕套），否則不得參與。禁欲係可接受的節育方法。 伴隨用藥 皮質類固醇：在入組前至少7天未使用穩定或減少劑量的皮質類固醇的接受皮質類固醇的患者不符合資格。如果用於修改與先前療法有關的 免疫不良事件，則自最後一劑皮質類固醇以來必須已經過去了 ≥ 14天。 研究性的：當前正在接受另一種研究藥物的患者不符合資格。 抗癌劑：當前正在接受其他抗癌劑的患者不符合資格 [接受羥基脲的白血病患者除外，這可能會持續到方案療法開始前24小時]。 移植後抗GVHD劑：正在接受環孢素、他克莫司或其他藥劑以預防骨髓移植後移植物抗宿主病的患者不符合參加該試驗的資格。 感染：感染不受控制的患者不符合資格。 先前接受過實體器官移植的患者不符合資格。 研究者認為可能無法遵守該研究的安全監測要求的患者不符合資格。 帶有嚴重不癒合性傷口的患者（CTCAE ≥ 3 級傷口併發症、裂開或傷口感染） 在研究治療開始後3個月內發生中風或短暫性缺血性發作或其他缺血性事件或血栓栓塞事件的患者 提出的研究設計： 研究階段：這係一項單一藥劑NIS793在反復性/難治性實性瘤中，以及連同組合療法的NIS793的擴展群組在復發性/難治性神經母細胞瘤或骨肉瘤中的研究。 該研究的階段I係使用滾動6設計的單一藥劑劑量發現階段。將對多達6名患者進行PK擴展，以獲得至少6名年齡 ＜ 12歲的患者和6名年齡 ≥ 12歲的患者的PK。階段I的主要終點係治療的第一治療週期期間劑量限制性毒性（DLT）的發生率。一個治療週期定義為21天（3個日曆週）。 將使用劑量限制性毒性的標準PEP-CTN定義來定義MTD或RP2D。簡而言之，DLT將被定義為疑似與NIS793療法有關的AE或異常實驗室值（即，評估為與疾病進展、間發性疾病或伴隨用藥無關），包括那些導致不能滿足重新治療的標準，或不能在新週期預定開始日期的7天內開始新週期的療法的AE和異常實驗室值。儘管DLT可以在NIS793治療的任何週期期間發生，但出於劑量遞增和確定RP2D的目的，只有在前3週期間發生的DLT才會被考慮用於有關劑量降級的決定。 劑量發現階段的第一群組將以每3週45 mg/kg（BW ＜ 20 kg）、30 mg/kg（BW 20-40 kg）和20 mg/kg（BW ＞ 40 kg）的起始劑量進行治療。該劑量係藉由對針對接受推薦劑量的成人的暴露進行藥物動力學建模確定的。如果NIS793的該起始劑量水平超過MTD（在劑量確認和PK群組中 ＞ 2/6的患者或 ＞ 33%的患者具有DLT），將對劑量水平-1（30%劑量減少）進行評估。如果劑量水平1未超過MTD，會將其宣佈為R2PD，並且不會進行進一步的劑量遞增。如果劑量水平-1超過MTD，該研究將暫停以評估藥物動力學並審查所有毒性，以確定是否應藉由方案修正來採用替代性的給藥或時間表。 患者將繼續治療直至出現不可接受的毒性、確認的疾病進展死亡或因任何其他原因（即失訪、受試者/父母/監護人決定或撤回同意）終止該研究治療，繼續治療持續最多35個週期（約2年）。 然後在擴展群組中將推薦劑量的NIS793與環磷醯胺和拓撲替康組合用於神經母細胞瘤患者或與吉西他濱組合用於骨肉瘤患者。擴展階段將由兩個群組組成：反復性難治性骨肉瘤和反復性/難治性神經母細胞瘤。將使用BOIN設計在每個群組中分別監測耐受性。 神經母細胞瘤患者將使用來自階段1部分的RP2D的NIS793與環磷醯胺和拓撲替康組合進行治療。主要終點將是使用RECIST v1.1在可測量疾病患者中確定的客觀反應或使用MIBG Curie評分在MIBG可評估疾病患者中確定的客觀反應。客觀反應將是完全或部分反應。將使用西蒙（Simon）2階段設計（10+10）。 骨肉瘤患者將接受NIS793與吉西他濱的組合。我們將使用9+15的西蒙最優兩階段設計。將針對單側替代方案，對真實EFS率為0.12的零假設進行檢驗。在第一階段，將累計9名患者。如果如11.4節中所定義的在9名可評估患者中有1名或更少的患者在24週（8個週期）後無事件，則將停止該研究並得出結論，該藥劑不會引起臨床上顯著的反應。如果至少2名患者在24週後無事件，則將另外的15名患者累計，獲得總共24名反應可評估的患者。直到至少2名反應可評估的患者持續24週無事件，第2階段才會開始。步驟1的入組將暫停，直到所有患者都達到24週無事件評估或直到至少2名患者達到他們的24週無事件評估。每名患者的無事件狀態將由患者開始療法後24週的狀態定義。 患者將繼續組合治療直至出現不可接受的毒性、確認的疾病進展死亡或因任何其他原因（即失訪、受試者/父母/監護人決定或撤回同意）終止該研究治療，繼續組合治療持續最多35個週期（約2年）。    研究方案

估計的樣本量（含對估計的解釋）：該研究的單一藥劑劑量確定部分將對最少4名患者和最多18名患者（6名劑量水平1、6名劑量水平-1、6名PK擴展）進行，以確定NIS793的RP2D和藥物動力學。將內置單一劑量降級。可能會入組另外10-20名神經母細胞瘤患者，以確定NIS793與環磷醯胺和拓撲替康組合的活性。最少9名和最多24名骨肉瘤患者可能接受NIS793與吉西他濱的組合。（最多62名患者） 治療計畫：在階段I劑量發現期間，NIS793劑量將以劑量水平1開始，並將在需要時降級。 ●         每3週NIS793 45 mg/kg（BW ＜ 20 kg）、30 mg/kg（BW 20-40 kg）和20 mg/kg（BW ＞ 40 kg）（可探索另外的/中間的劑量水平或更低頻率的投與） 一旦確定了NIS793的RP2D，將激活擴展群組。 神經母細胞瘤群組中的患者將接受： ●         RP2D的NIS793 ●         環磷醯胺：250 mg/m ²/靜脈內劑量 x 5天，第1-5天 ●         拓撲替康：0.75 mg/m ²/靜脈內劑量 x 5天，第1-5天 骨肉瘤患者將接受： ●         RP2D的NIS793 ●         吉西他濱：675 mg/m2/劑量，第1天和第8天 一個單治療週期將定義為21天。 將每2個週期 x 5，然後每4個週期進行疾病評估。最大週期數為35（大約2年）。 相關性研究和 PK/PD 研究所要求的生物標誌物測定 * （包括基因組學） 生物標誌物名稱 測定 該所提出研究的測定目的 所測試的組織/ 體液和測定的時間 強制性的還是視需要的？ CLIA?** （是/ 否） TGFβ特徵 RNA定序 基因表現特徵-對反應的預測 腫瘤樣本 根據HCP判斷 否 ctDNA NGS小組 探索持久的反應並鑒定復發的風險理解ctDNA在該部分中的臨床效用 血液 視需要的 否 骨髓 NGS和RNA定序小組 鑒定與骨髓轉移風險相關的新生物標誌物 骨髓 根據HCP判斷 否 腫瘤樣本 NGS和RNA定序小組 預測的分子突變和分子預後得分和抗性的潛在分子驅動因素 腫瘤樣本 根據HCP判斷 否 PK（NIS793）、PD（總TGFβ-1）和ADA（抗NIS793）。 ELISA 進行PK和免疫原性評估，並與基於成人數據和暴露-反應/安全性和免疫原性/暴露/安全性分析的預測進行比較（探索性） 血液 強制性的 NA * PK/PD：藥物動力學/藥效學 ** 如果測定結果將在任何時候（無論在進行研究或停止研究時）報告給患者/患者家屬或患者的醫師，則測定必須在經CLIA批准的實驗室進行。 等同物 Although a covariate of clearance in the body weight (BW) pedigree PK model, the power model had an estimated index of 0.55 (CV% = 40%), predicted exposure and stability between weight-based and fixed-dose regimens. The trough concentrations in the phenotype were comparable across different BW categories. This analysis supports the use of fixed or flat dosing on a mg basis regardless of patient weight, as weight-based dosing does not reduce inter-individual variability. Model-based simulations indicated that a dose of 2100 mg would match the exposure observed at 30 mg/kg. In addition, a dose of 1400 mg would match the exposure observed at 20 mg/kg. Example 3 : Pediatric Study Design Objectives Main objectives: 1) To estimate the phase 2 recommended dose (RP2D) of NIS793 as a single agent in children with recurrent or refractory solid tumors. 2) To define and describe the toxicity of NIS793 alone and in combination with chemotherapy. 3) To characterize the pharmacokinetics of NIS793 alone and in combination with chemotherapy in children with recurrent or refractory solid tumors. Secondary objectives: 4) To define the preliminary antitumor activity of NIS793 alone in patients with relapsed refractory solid tumors. 5) Obtain initial Phase 2 efficacy data on the antitumor activity of NIS793 in combination with cyclophosphamide and topotecan in pediatric patients with relapsed or refractory neuroblastoma. 6) To estimate the proportion of patients with recurrent measurable osteosarcoma treated with NIS793 in combination with gemcitabine at 24 weeks who were event-free (%EF) Exploratory objectives: 7) To explore the immunogenicity of NIS793 in this population . 8) Explore biomarkers of NIS793 activity, including ctDNA, in tumor samples by RNA sequencing (RNAseq) for TGFβ characterization Brief Eligibility Criteria Required: Inclusion Criteria: Age: • Phase I Cohort: Patients must be > 12 months and ≤ 21 years old at study entry. ● Neuroblastoma Expansion Cohort: Patients must be >12 months and ≤21 years old at study entry. Osteosarcoma expansion cohort : Patients must be ≥ 12 months and ≤ 39 years old at study entry. Diagnosis: Patients must have had histological confirmation of malignancy at initial diagnosis or at recurrence. ● Phase I Part: Patients with recurrent or refractory solid tumors are eligible, patients with primary CNS tumors are excluded. Neuroblastoma Extension: Patients with relapsed or refractory neuroblastoma Osteosarcoma Extension: Patients with relapsed or refractory osteosarcoma Disease Status: Phase 1 Part: Patients must have measurable disease or evaluable disease. ● Neuroblastoma: Patients must have measurable disease or MIBG-evaluable disease at enrollment. • Osteosarcoma cohort: Patients must have measurable disease at enrollment. ● Patients with known untreated brain parenchymal central nervous system metastatic disease are not eligible. Performance level: Karnofsky ≥ 50% for patients aged > 16 years; and Lansky ≥ 50 for patients aged ≤ 16 years. [ Note: For the purposes of evaluating performance scores, patients who are unable to walk due to paralysis but are in a wheelchair will be considered able to walk]. Prior Therapy: • Patients must have fully recovered from the acute toxic effects of all prior anticancer therapy and meet a minimum duration from prior anticancer therapy prior to enrollment. • Patients must have no previous exposure to specific anti-TGFβ therapy. ● Patients with neuroblastoma who were enrolled in the expansion cohort may have previously received cyclophosphamide and topotecan. ● Patients with osteosarcoma may have previously received gemcitabine. Organ function requirements: Adequate bone marrow function, defined as: For patients with solid tumors without known bone marrow involvement: Peripheral absolute neutrophil count (ANC) ≥ 1000/mm3 Platelet count ≥ 100,000/mm3 (independent of Transfusion, defined as not receiving platelet transfusion for at least 7 days prior to enrollment) Patients with known bone marrow metastatic disease will be eligible to participate in the study provided they meet blood counts (transfusions are acceptable provided they are known not to be difficult to perform red blood cell or platelet transfusion). Hematologic toxicity in these patients will not be evaluable. At least 2 of 3 patients in each cohort must be evaluable for hematologic toxicity during the dose-escalation portion of the study. If dose-limiting hematologic toxicity is observed during dose escalation, all subsequent patients enrolled in the dose-escalation portion must be evaluable for hematologic toxicity. Adequate renal function, defined as: Creatinine clearance or radioisotope GFR ≥ 70 ml/min/1.73 ^m2 or serum creatinine based on age/gender as follows:

The creatinine thresholds in this table are derived from Schwartz's formula for estimating GFR using CDC published children's length and height data (Schwartz et al. J. Peds, 106:522, 1985). Adequate liver function, defined as: Bilirubin (sum of conjugated + unconjugated bilirubin) ≤ 1.5 x upper limit of normal (ULN) for age. ● ALT (SGPT) ≤ 135 U/L. For the purposes of this study, the ULN for ALT was 45 U/L. ● Serum albumin ≥ 2 g/dL. Adequate cardiac function, defined as: Fractional shortening > 27% and left ventricular ejection fraction > 50%. ● No clinically significant arrhythmia, stroke or myocardial infarction within 6 months before enrollment ● QTc ≤ 480 ms ● Hypertension must be well controlled by stable doses of drugs for at least 2 weeks Informed consent: all patients And/or their parents or legally authorized representatives must sign a written informed consent. When appropriate, consent will be obtained in accordance with institutional guidelines. Exclusion Criteria: Pregnancy or Lactation: Pregnant or lactating women will not be included in this study as no information is available on human fetal or teratogenic toxicity. Girls after menarche must have a pregnancy test. Males or females of reproductive potential shall not participate unless they agree to use two effective methods of birth control, including medically accepted barrier or contraceptive methods (eg, male or female condoms), during the study period. Abstinence is an acceptable method of birth control. Concomitant corticosteroids: Patients receiving corticosteroids who were not on a stable or reduced dose of corticosteroids for at least 7 days prior to enrollment were not eligible. If used to modify an immunologic adverse event related to prior therapy, ≥ 14 days must have elapsed since the last dose of corticosteroid. Investigational: Patients who are currently receiving another study drug are not eligible. Anticancer Agents: Patients currently receiving other anticancer agents are not eligible [except for leukaemic patients receiving hydroxyurea, which may continue up to 24 hours before the start of protocol therapy]. Post-transplant anti-GVHD agents: Patients who were receiving cyclosporine, tacrolimus, or other agents to prevent graft-versus-host disease after bone marrow transplantation were not eligible for the trial. Infection: Patients with uncontrolled infection are not eligible. Patients who have previously received a solid organ transplant are not eligible. Patients who in the investigator's opinion may not be able to comply with the safety monitoring requirements of the study were not eligible. Patients with severe non-healing wounds (CTCAE ≥ Grade 3 wound complications, dehiscence, or wound infection) who had a stroke or transient ischemic attack or other ischemic event or thrombosis within 3 months of the start of study treatment Patients with embolic events Proposed Study Design: Study Phase: This is a single agent NIS793 in relapsed/refractory solid tumors, and an expansion cohort of NIS793 in combination with combination therapy in relapsed/refractory neuroblastoma or osteosarcoma Research. Phase I of the study was a single-agent dose-finding phase using a rolling 6 design. PK extension will be performed on up to 6 patients to obtain PK for at least 6 patients aged <12 years and 6 patients aged ≥12 years. The primary endpoint of Phase I was the incidence of dose-limiting toxicities (DLTs) during the first cycle of treatment. A treatment cycle was defined as 21 days (3 calendar weeks). The standard PEP-CTN definition of dose-limiting toxicity will be used to define MTD or RP2D. Briefly, DLTs will be defined as AEs or abnormal laboratory values suspected to be related to NIS793 therapy (i.e., assessed not to be related to disease progression, episodic disease, or concomitant medications), including those resulting in failure to meet criteria for retreatment , or AEs and abnormal laboratory values of therapy that could not start a new cycle within 7 days of the scheduled start date of the new cycle. Although DLTs could occur during any cycle of NIS793 treatment, for the purposes of dose escalation and determination of RP2D, only DLTs occurring during the first 3 weeks were considered for decisions regarding dose downscaling. The first cohort in the dose-finding phase will start at 45 mg/kg (BW < 20 kg), 30 mg/kg (BW 20-40 kg) and 20 mg/kg (BW > 40 kg) every 3 weeks for treatment. The dose was determined by pharmacokinetic modeling of the exposure for adults receiving the recommended dose. If this starting dose level of NIS793 exceeds the MTD (>2/6 patients or >33% of patients had a DLT in the dose confirmation and PK cohorts), a dose level -1 (30% dose reduction) will be evaluated. If dose level 1 does not exceed the MTD, it will be declared R2PD and no further dose escalation will be performed. If dose level-1 exceeds the MTD, the study will be suspended to assess pharmacokinetics and review any toxicities to determine if alternative dosing or schedules should be employed through protocol modification. Patients will continue treatment until death due to unacceptable toxicity, confirmed disease progression, or discontinuation of study treatment for any other reason (i.e., loss to follow-up, subject/parent/guardian decision, or withdrawal of consent) for a maximum of 35 cycles (about 2 years). The recommended dose of NIS793 was then combined with cyclophosphamide and topotecan in patients with neuroblastoma or with gemcitabine in patients with osteosarcoma in an expansion cohort. The expansion phase will consist of two cohorts: relapsed refractory osteosarcoma and relapsed/refractory neuroblastoma. Tolerability will be monitored separately in each cohort using a BOIN design. Patients with neuroblastoma will be treated with RP2D's NIS793 from the Phase 1 portion in combination with cyclophosphamide and topotecan. The primary endpoint will be objective response as determined in patients with measurable disease using RECIST v1.1 or in patients with MIBG evaluable disease using the MIBG Curie score. Objective responses will be complete or partial responses. A Simon 2-stage design (10+10) will be used. Patients with osteosarcoma will receive NIS793 in combination with gemcitabine. We will use a Simon optimal two-stage design of 9+15. The null hypothesis of a true EFS rate of 0.12 will be tested against a one-sided alternative. In the first phase, 9 patients will be accrued. If 1 or fewer of 9 evaluable patients are event-free after 24 weeks (8 cycles) as defined in Section 11.4, the study will be stopped and it will be concluded that the agent does not cause Clinically significant response. If at least 2 patients were event-free after 24 weeks, an additional 15 patients were aggregated for a total of 24 response-evaluable patients. Phase 2 will not start until at least 2 responder-evaluable patients remain event-free for 24 weeks. Enrollment in Step 1 will be suspended until all patients have reached their 24-week event-free assessment or until at least 2 patients have achieved their 24-week event-free assessment. Each patient's event-free status will be defined by the patient's status at 24 weeks after starting therapy. Patients will continue combination therapy until death due to unacceptable toxicity, confirmed disease progression, or discontinuation of the study treatment for any other reason (i.e., loss to follow-up, subject/parent/guardian decision, or withdrawal of consent) for a maximum of 35 cycle (about 2 years). research proposal

Estimated sample size (with explanation for estimates): The single-agent dose-determining portion of the study will be administered to a minimum of 4 patients and a maximum of 18 patients (6 dose level 1, 6 dose level -1, 6 PK expansion) performed to determine the RP2D and pharmacokinetics of NIS793. Downgrade the built-in single dose. An additional 10-20 neuroblastoma patients may be enrolled to determine the activity of NIS793 in combination with cyclophosphamide and topotecan. A minimum of 9 and a maximum of 24 osteosarcoma patients may receive NIS793 in combination with gemcitabine. (up to 62 patients) Treatment plan: During Phase I dose finding, NIS793 doses will be initiated at dose level 1 and will be escalated as needed. NIS793 45 mg/kg (BW < 20 kg), 30 mg/kg (BW 20-40 kg ) and 20 mg/kg (BW > 40 kg) every 3 weeks (additional/intermediate dose levels or more may be explored Low frequency administration) Once the RP2D of NIS793 is determined, the expansion cohort will be activated. Patients in the neuroblastoma cohort will receive: NIS793 for RP2D Cyclophosphamide : 250 mg/ ^m2 /iv dose x 5 days, Days 1-5 Topotecan : 0.75 mg/ ^m2 /iv dose x 5 days, Days 1-5 Osteosarcoma patients will receive: • NIS793 for RP2D • Gemcitabine: 675 mg/m2/dose, Days 1 and 8 A single treatment cycle will be defined as 21 days. Disease assessment will be done every 2 cycles x 5 and then every 4 cycles. The maximum number of cycles is 35 (approximately 2 years). Correlation studies and biomarker assays required for PK/PD studies * ( including genomics) Biomarker name determination The assay purpose of the proposed study Tissues/fluids tested and timing of measurements Mandatory or optional? CLIA?** (yes/ no) TGFβ signature RNA sequencing Gene Expression Signatures - Prediction of Response tumor sample Judging by HCP no ctDNA NGS team Exploring Durable Responses and Identifying Risk of Relapse Understanding the Clinical Utility of ctDNA in the Part blood as needed no marrow NGS and RNA Sequencing Group Identification of new biomarkers associated with risk of bone marrow metastasis marrow Judging by HCP no tumor sample NGS and RNA Sequencing Group Predicted molecular mutations and molecular prognostic scores and potential molecular drivers of resistance tumor sample Judging by HCP no PK (NIS793), PD (total TGFβ-1) and ADA (anti-NIS793). ELISA Perform PK and immunogenicity assessments and compare to predictions based on adult data and exposure-response/safety and immunogenicity/exposure/safety analyzes (exploratory) blood compulsory NA *PK/PD: Pharmacokinetics/Pharmacodynamics** If assay results are to be reported to the patient/patient's family or the patient's physician at any time (whether on study conduct or when the study is discontinued), the assay must be in a CLIA-approved laboratory. equivalent

While specific embodiments of the present invention have been discussed, the foregoing description is intended to be illustrative rather than restrictive. Many modifications of the invention will become apparent to those skilled in the art after reviewing the specification and the following claims. The full scope of the invention should be determined by reference to the claimed claims and their full scope of equivalents and the specification together with such changes.

none

[ FIG. 1 ] shows the average concentration-time profile of each dose cohort of NIS793 in cycle 1.

[ FIG. 2 ] shows the average concentration-time profile of each dose cohort of NIS793 in cycle 3.

[ FIG. 3 ] Dosage and administration of different combinations of NIS793, spartakizumab or tislelizumab, gemcitabine, and/or nab-paclitaxel are shown. Patients were given NIS793 (2100 mg) every 2 weeks, spartacuzumab or tislelizumab (400 mg) every 4 weeks, and gemcitabine on days 1, 8, and 15 (1000 mg/m ² ) and nab-paclitaxel (125 mg/m ² ) on days 1, 8, and 15 (Figure 2). A cycle is 28 days.

none

         
           <![CDATA[ <110> Swiss company Novartis (NOVARTIS AG)]]>
           <![CDATA[ <120> Use of anti-TGFb antibody and other therapeutic agents for the treatment of proliferative diseases]]>
           <![CDATA[ <130> PAT059084]]>
           <![CDATA[ <160> 330 ]]>
           <![CDATA[ <170> PatentIn Version 3.5]]>
           <![CDATA[ <210> 1]]>
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          Gly Gly Thr Phe Ser Ser Tyr Ala Ile Ser
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           <![CDATA[ <210> 2]]>
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          Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe Gln
          1 5 10 15
          Gly
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          Gly Leu Trp Glu Val Arg Ala Leu Pro Ser Val Tyr
          1 5 10
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          Gly Ala Asn Asp Ile Gly Ser Lys Ser Val His
          1 5 10
           <![CDATA[ <210> 5]]>
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          Glu Asp Ile Ile Arg Pro Ser
          1 5
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          Gln Val Trp Asp Arg Asp Ser Asp Gln Tyr Val
          1 5 10
           <![CDATA[ <210> 7]]>
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          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr
                      20 25 30
          Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
                  35 40 45
          Gly Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe
              50 55 60
          Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Gly Leu Trp Glu Val Arg Ala Leu Pro Ser Val Tyr Trp Gly
                      100 105 110
          Gln Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 8]]>
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          Ser Tyr Glu Leu Thr Gln Pro Pro Ser Val Ser Val Ala Pro Gly Gln
          1 5 10 15
          Thr Ala Arg Ile Thr Cys Gly Ala Asn Asp Ile Gly Ser Lys Ser Val
                      20 25 30
          His Trp Tyr Gln Gln Lys Ala Gly Gln Ala Pro Val Leu Val Val Ser
                  35 40 45
          Glu Asp Ile Ile Arg Pro Ser Gly Ile Pro Glu Arg Ile Ser Gly Ser
              50 55 60
          Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Arg Val Glu Ala Gly
          65 70 75 80
          Asp Glu Ala Asp Tyr Tyr Cys Gln Val Trp Asp Arg Asp Ser Asp Gln
                          85 90 95
          Tyr Val Phe Gly Thr Gly Thr Lys Val Thr Val Leu Gly
                      100 105
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          Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
          1 5 10 15
          Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr
                      20 25 30
          Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
                  35 40 45
          Gly Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe
              50 55 60
          Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr
          65 70 75 80
          Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Arg Gly Leu Trp Glu Val Arg Ala Leu Pro Ser Val 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 Cys Ser Arg Ser Thr Ser Glu Ser 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
          Thr Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His
                  195 200 205
          Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys
              210 215 220
          Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala 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 Gln Phe Asn Trp Tyr Val Asp Gly Met Glu Val His Asn Ala Lys
                  275 280 285
          Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser
              290 295 300
          Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
          305 310 315 320
          Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile
                          325 330 335
          Ser Lys Thr 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 Met 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
           <![CDATA[ <210> 10]]>
           <![CDATA[ <211> 214]]>
           <![CDATA[ <212> PRT]]>
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          Ser Tyr Glu Leu Thr Gln Pro Pro Ser Val Ser Val Ala Pro Gly Gln
          1 5 10 15
          Thr Ala Arg Ile Thr Cys Gly Ala Asn Asp Ile Gly Ser Lys Ser Val
                      20 25 30
          His Trp Tyr Gln Gln Lys Ala Gly Gln Ala Pro Val Leu Val Val Ser
                  35 40 45
          Glu Asp Ile Ile Arg Pro Ser Gly Ile Pro Glu Arg Ile Ser Gly Ser
              50 55 60
          Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Arg Val Glu Ala Gly
          65 70 75 80
          Asp Glu Ala Asp Tyr Tyr Cys Gln Val Trp Asp Arg Asp Ser Asp Gln
                          85 90 95
          Tyr Val Phe Gly Thr Gly Thr Lys Val Thr Val Leu Gly Gln Pro Lys
                      100 105 110
          Ala Asn Pro Thr Val Thr Leu Phe Pro Pro Ser Ser Glu Glu Leu Gln
                  115 120 125
          Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr Pro Gly
              130 135 140
          Ala Val Thr Val Ala Trp Lys Ala Asp Gly Ser Pro Val Lys Ala Gly
          145 150 155 160
          Val Glu Thr Thr Lys Pro Ser Lys Gln Ser Asn Asn Lys Tyr Ala Ala
                          165 170 175
          Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His Arg Ser
                      180 185 190
          Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys Thr Val
                  195 200 205
          Ala Pro Thr Glu Cys Ser
              210
           <![CDATA[ <210> 11]]>
           <![CDATA[ <211> 447]]>
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          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 Ser Ser Asn
                      20 25 30
          Val Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
                  35 40 45
          Gly Gly Val Ile Pro Ile Val Asp Ile Ala Asn Tyr Ala Gln Arg Phe
              50 55 60
          Lys Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Thr 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 Ser Thr Leu Gly Leu Val Leu Asp Ala Met Asp Tyr Trp Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
                  115 120 125
          Phe Pro Leu Ala Pro 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 Ser 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
           <![CDATA[ <210> 12]]>
           <![CDATA[ <211> 215]]>
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           <![CDATA[ <400> 12]]>
          Glu Thr Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
          1 5 10 15
          Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Leu Gly Ser Ser
                      20 25 30
          Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
                  35 40 45
          Ile Tyr Gly Ala Ser Ser Arg Ala Pro 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 Ala Asp Ser Pro
                          85 90 95
          Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys Arg Thr Val Ala
                      100 105 110
          Ala Pro Ser Val Phe Ile Phe Pro 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
           <![CDATA[ <210> 13]]>
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          Gly Tyr Thr Phe Thr Thr Tyr Trp Met His
          1 5 10
           <![CDATA[ <210> 14]]>
           <![CDATA[ <211> 5]]>
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          Thr Tyr Trp Met His
          1 5
           <![CDATA[ <210> 15]]>
           <![CDATA[ <211> 17]]>
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           <![CDATA[ <400> 15]]>
          Asn Ile Tyr Pro Gly Thr Gly Gly Ser Asn Phe Asp Glu Lys Phe Lys
          1 5 10 15
          Asn
           <![CDATA[ <210> 16]]>
           <![CDATA[ <211> 8]]>
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          Trp Thr Thr Gly Thr Gly Ala Tyr
          1 5
           <![CDATA[ <210> 17]]>
           <![CDATA[ <211> 7]]>
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          Gly Tyr Thr Phe Thr Thr Tyr
          1 5
           <![CDATA[ <210> 18]]>
           <![CDATA[ <211> 6]]>
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          Tyr Pro Gly Thr Gly Gly
          1 5
           <![CDATA[ <210> 19]]>
           <![CDATA[ <211> 117]]>
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           <![CDATA[ <400> 19]]>
          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
           <![CDATA[ <210> 20]]>
           <![CDATA[ <211> 351]]>
           <![CDATA[ <212>DNA]]>
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          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
           <![CDATA[ <210> 21]]>
           <![CDATA[ <211> 443]]>
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           <![CDATA[ <400> 21]]>
          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
           <![CDATA[ <210> 22]]>
           <![CDATA[ <211> 1329]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
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          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 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 840
          gtgcacaacg ccaaaaccaa gccgaggggag gagcagttca actccactta ccgcgtcgtg 900
          tccgtgctga cggtgctgca tcaggactgg ctgaacggga aggagtacaa gtgcaaagtg 960
          tccaacaagg gacttcctag ctcaatcgaa aagaccatct cgaaagccaa gggacagccc 1020
          cgggaacccc aagtgtatac cctgccaccg agccaggaag aaatgactaa gaaccaagtc 1080
          tcattgactt gccttgtgaa gggcttctac ccatcggata tcgccgtgga atgggagtcc 1140
          aacggccagc cggaaaacaa ctacaagacc accccctccgg tgctggactc agacggatcc 1200
          ttcttcctct actcgcggct gaccgtggat aagagcagat ggcaggaggg aaatgtgttc 1260
          agctgttctg tgatgcatga agccctgcac aacccactaca ctcagaagtc cctgtccctc 1320
          tccctggga 1329
           <![CDATA[ <210> 23]]>
           <![CDATA[ <211> 17]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 23]]>
          Lys Ser Ser Gln Ser Leu Leu Asp Ser Gly Asn Gln Lys Asn Phe Leu
          1 5 10 15
          Thr
           <![CDATA[ <210> 24]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 24]]>
          Trp Ala Ser Thr Arg Glu Ser
          1 5
           <![CDATA[ <210> 25]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 25]]>
          Gln Asn Asp Tyr Ser Tyr Pro Tyr Thr
          1 5
           <![CDATA[ <210> 26]]>
           <![CDATA[ <211> 13]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 26]]>
          Ser Gln Ser Leu Leu Asp Ser Gly Asn Gln Lys Asn Phe
          1 5 10
           <![CDATA[ <210> 27]]>
           <![CDATA[ <211> 3]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 27]]>
          Trp Ala Ser
          1           
           <![CDATA[ <210> 28]]>
           <![CDATA[ <211> 6]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 28]]>
          Asp Tyr Ser Tyr Pro Tyr
          1 5
           <![CDATA[ <210> 29]]>
           <![CDATA[ <211> 113]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 29]]>
          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
           <![CDATA[ <210> 30]]>
           <![CDATA[ <211> 339]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 30]]>
          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
           <![CDATA[ <210> 31]]>
           <![CDATA[ <211> 220]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 31]]>
          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
           <![CDATA[ <210> 32]]>
           <![CDATA[ <211> 660]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 32]]>
          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 tccccccccag 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
           <![CDATA[ <210> 33]]>
           <![CDATA[ <211> 113]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 33]]>
          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
           <![CDATA[ <210> 34]]>
           <![CDATA[ <211> 339]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 34]]>
          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
           <![CDATA[ <210> 35]]>
           <![CDATA[ <211> 220]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 35]]>
          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
           <![CDATA[ <210> 36]]>
           <![CDATA[ <211> 660]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 36]]>
          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 tccccccccag 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
           <![CDATA[ <210> 37]]>
           <![CDATA[ <211> 15]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 37]]>
          acctactgga tgcac 15
           <![CDATA[ <210> 38]]>
           <![CDATA[ <211> 51]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 38]]>
          aatatctacc ccggcaccgg cggctctaac ttcgacgaga agtttaagaa t 51
           <![CDATA[ <210> 39]]>
           <![CDATA[ <211> 24]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 39]]>
          tggactaccg gcacaggcgc ctac 24
           <![CDATA[ <210> 40]]>
           <![CDATA[ <211> 21]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 40]]>
          ggctacacct tcactaccta c 21
           <![CDATA[ <210> 41]]>
           <![CDATA[ <211> 18]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 41]]>
          taccccggca ccggcggc 18
           <![CDATA[ <210> 42]]>
           <![CDATA[ <211> 51]]>
           <![CDATA[ <212>]]> DNA
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Biology]]>
           <![CDATA[ <400> 42]]>
          aaatctagtc agtcactgct ggatagcggt aatcagaaga acttcctgac c 51
           <![CDATA[ <210> 43]]>
           <![CDATA[ <211> 21]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 43]]>
          tgggcctcta ctagagaatc a 21
           <![CDATA[ <210> 44]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 44]]>
          cagaacgact atagctaccc ctacacc 27
           <![CDATA[ <210> 45]]>
           <![CDATA[ <211> 39]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 45]]>
          agtcagtcac tgctggatag cggtaatcag aagaacttc 39
           <![CDATA[ <210> 46]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 46]]>
          tgggccctct 9
           <![CDATA[ <210> 47]]>
           <![CDATA[ <211> 18]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 47]]>
          gactatagct accccctac 18
           <![CDATA[ <210> 48]]>
           <![CDATA[ <211> 440]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 48]]>
          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 Gly Leu Tyr
                          165 170 175
          Ser Leu Ser 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 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
           <![CDATA[ <210> 49]]>
           <![CDATA[ <211> 214]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 49]]>
          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 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
           <![CDATA[ <210> 50]]>
           <![CDATA[ <211> 447]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 50]]>
          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 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
           <![CDATA[ <210> 51]]>
           <![CDATA[ <211> 218]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 51]]>
          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 Pro Ser Asp Glu Gln
                  115 120 125
          Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn 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
           <![CDATA[ <210> 52]]>
           <![CDATA[ <211> 447]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 52]]>
          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
           <![CDATA[ <210> 53]]>
           <![CDATA[ <211> 213]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 53]]>
          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
           <![CDATA[ <210> 54]]>
           <![CDATA[ <211> 5]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 54]]>
          Ser Tyr Trp Met Tyr
          1 5
           <![CDATA[ <210> 55]]>
           <![CDATA[ <211> 17]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 55]]>
          Arg Ile Asp Pro Asn Ser Gly Ser Thr Lys Tyr Asn Glu Lys Phe Lys
          1 5 10 15
          Asn
           <![CDATA[ <210> 56]]>
           <![CDATA[ <211> 11]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <22]]>0>]]&gt;
           <br/> &lt;![CDATA[ &lt;223&gt;biological]]&gt;
           <br/>
           <br/> &lt;![CDATA[ &lt;400&gt;56]]&gt;
           <br/>
           <br/> <![CDATA[Asp Tyr Arg Lys Gly Leu Tyr Ala Met Asp Tyr
          1 5 10
           <![CDATA[ <210> 57]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 57]]>
          Gly Tyr Thr Phe Thr Ser Tyr
          1 5
           <![CDATA[ <210> 58]]>
           <![CDATA[ <211> 6]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 58]]>
          Asp Pro Asn Ser Gly Ser
          1 5
           <![CDATA[ <210> 59]]>
           <![CDATA[ <211> 120]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 59]]>
          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
           <![CDATA[ <210> 60]]>
           <![CDATA[ <211> 360]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 60]]>
          gaagtgcagc tggtgcagtc aggcgccgaa gtgaagaaac ccggcgctac cgtgaagatt 60
          agctgtaaag tctcaggcta caccttcact agctactgga tgtactgggt ccgacaggct 120
          agagggcaaa 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
           <![CDATA[ <210> 61]]>
           <![CDATA[ <211> 446]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 61]]>
          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
           <![CDATA[ <210> 62]]>
           <![CDATA[ <211> 11]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 62]]>
          Lys Ala Ser Gln Asp Val Gly Thr Ala Val Ala
          1 5 10
           <![CDATA[ <210> 63]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 63]]>
          Trp Ala Ser Thr Arg His Thr
          1 5
           <![CDATA[ <210> 64]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 64]]>
          Gln Gln Tyr Asn Ser Tyr Pro Leu Thr
          1 5
           <![CDATA[ <210> 65]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 65]]>
          Ser Gln Asp Val Gly Thr Ala
          1 5
           <![CDATA[ <210> 66]]>
           <![CDATA[ <211> 3]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 66]]>
          Trp Ala Ser
          1           
           <![CDATA[ <210> 67]]>
           <![CDATA[ <211> 6]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 67]]>
          Tyr Asn Ser Tyr Pro Leu
          1 5
           <![CDATA[ <210> 68]]>
           <![CDATA[ <211> 1338]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 68]]>
          gaagtgcagc tggtgcagtc aggcgccgaa gtgaagaaac ccggcgctac cgtgaagatt 60
          agctgtaaag tctcaggcta caccttcact agctactgga tgtactgggt ccgacaggct 120
          agagggcaaa 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
           <![CDATA[ <210> 69]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 69]]>
          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
           <![CDATA[ <210> 70]]>
           <![CDATA[ <211> 321]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 70]]>
          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
           <![CDATA[ <210> 71]]>
           <![CDATA[ <211> 214]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 71]]>
          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 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
           <![CDATA[ <210> 72]]>
           <![CDATA[ <211> 642]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 72]]>
          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
           <![CDATA[ <210> 73]]>
           <![CDATA[ <211> 120]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 73]]>
          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
           <![CDATA[ <210> 74]]>
           <![CDATA[ <211> 360]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 74]]>
          gaagtgcagc tggtgcagtc aggcgccgaa gtgaagaaac ccggcgctac cgtgaagatt 60
          agctgtaaag tctcaggcta caccttcact agctactgga tgtactgggt 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
           <![CDATA[ <210> 75]]>
           <![CDATA[ <211> 446]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 75]]>
          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
           <![CDATA[ <210> 76]]>
           <![CDATA[ <211> 1338]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 76]]>
          gaagtgcagc tggtgcagtc aggcgccgaa gtgaagaaac ccggcgctac cgtgaagatt 60
          agctgtaaag tctcaggcta caccttcact agctactgga tgtactgggt 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
           <![CDATA[ <210> 77]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 77]]>
          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
           <![CDATA[ <210> 78]]>
           <![CDATA[ <211> 321]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 78]]>
          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
           <![CDATA[ <210> 79]]>
           <![CDATA[ <211> 214]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 79]]>
          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 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
           <![CDATA[ <210> 80]]>
           <![CDATA[ <211> 642]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 80]]>
          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
           <![CDATA[ <210> 81]]>
           <![CDATA[ <211> 15]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 81]]>
          agctactgga tgtac 15
           <![CDATA[ <210> 82]]>
           <![CDATA[ <211> 51]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 82]]>
          agaatcgacc ctaatagcgg ctctactaag tataacgaga agtttaagaa t 51
           <![CDATA[ <210> 83]]>
           <![CDATA[ <211> 33]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 83]]>
          gactatagaa agggcctgta cgctatggac tac 33
           <![CDATA[ <210> 84]]>
           <![CDATA[ <211> 21]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 84]]>
          ggctacacct tcactagcta c 21
           <![CDATA[ <210> 85]]>
           <![CDATA[ <211> 18]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 85]]>
          gaccctaata gcggctct 18
           <![CDATA[ <210> 86]]>
           <![CDATA[ <211> 33]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 86]]>
          aaagcctctc aggacgtggg caccgccgtg gcc 33
           <![CDATA[ <210> 87]]>
           <![CDATA[ <211> 21]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 87]]>
          tgggcctcta ctagacacac c 21
           <![CDATA[ <210> 88]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 88]]>
          cagcagtata atagctaccc cctgacc 27
           <![CDATA[ <210> 89]]>
           <![CDATA[ <211> 21]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 89]]>
          tctcaggacg tgggcaccgc c 21
           <![CDATA[ <210> 90]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 90]]>
          tgggccctct 9
           <![CDATA[ <210> 91]]>
           <![CDATA[ <211> 18]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 91]]>
          tataatagct accccctg 18
           <![CDATA[ <210> 92]]>
           <![CDATA[ <211> 448]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 92]]>
          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 Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
                          165 170 175
          Ser Ser Gly Leu Tyr Ser Leu Ser 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
           <![CDATA[ <210> 93]]>
           <![CDATA[ <211> 214]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 93]]>
          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 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
           <![CDATA[ <210> 94]]>
           <![CDATA[ <211> 450]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 94]]>
          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
           <![CDATA[ <210> 95]]>
           <![CDATA[ <211> 216]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 95]]>
          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
           <![CDATA[ <210> 96]]>
           <![CDATA[ <211> 451]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial]]> sequence
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 96]]>
          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
           <![CDATA[ <210> 97]]>
           <![CDATA[ <211> 215]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 97]]>
          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 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
           <![CDATA[ <210> 98]]>
           <![CDATA[ <211> 123]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 98]]>
          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 Gln Gly Thr Thr Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 99]]>
           <![CDATA[ <211> 106]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> ]]> biological
           <![CDATA[ <400> 99]]>
          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
           <![CDATA[ <210> 100]]>
           <![CDATA[ <211> 10]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 100]]>
          Gly Tyr Thr Phe Thr Ser Tyr Trp Met Tyr
          1 5 10
           <![CDATA[ <210]]>> 101]]>
           <br/> &lt;![CDATA[ &lt;211&gt;121]]&gt;
           <br/> &lt;![CDATA[ &lt;212&gt;PRT]]&gt;
           <br/> &lt;![CDATA[ &lt;213&gt; Artificial Sequence]]&gt;
           <br/>
           <br/> &lt;![CDATA[ &lt;220&gt;]]&gt;
           <br/> &lt;![CDATA[ &lt;223&gt;biological]]&gt;
           <br/>
           <br/> &lt;![CDATA[ &lt;400&gt;101]]&gt;
           <br/>
           <br/> <![CDATA[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 Ser Tyr
                      20 25 30
          Gly Val Asp Trp Val Arg Gln Ala Pro Gly Lys Gly Leu 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
           <![CDATA[ <210> 102]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 102]]>
          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
           <![CDATA[ <210> 103]]>
           <![CDATA[ <211> 451]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 103]]>
          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 Ser Tyr
                      20 25 30
          Gly Val Asp Trp Val Arg Gln Ala Pro Gly Lys Gly Leu 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
           <![CDATA[ <210> 104]]>
           <![CDATA[ <211> 214]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 104]]>
          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 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
           <![CDATA[ <210> 105]]>
           <![CDATA[ <211> 363]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 105]]>
          gaggtgcagc tggtggaatc tggcggcgga ctggtgcagt ccggcggctc tctgagactg 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
           <![CDATA[ <210> 106]]>
           <![CDATA[ <211> 321]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 106]]>
          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 acccccttcac cttcggccag 300
          ggcaccaagc tggaaatcaa g 321
           <![CDATA[ <210> 107]]>
           <![CDATA[ <211> 1353]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 107]]>
          gaggtgcagc tggtggaatc tggcggcgga ctggtgcagt ccggcggctc tctgagactg 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 ctgccctggg ttgcctggtg aaggactact tccccgagcc cgtgacagtg 480
          tcctggaact ctggggctct gacttccggc gtgcacacct tccccgccgt gctgcagagc 540
          agcggcctgt acagcctgag cagcgtggtg acagtgccct ccagctctct gggaacccag 600
          acctatatct gcaacgtgaa ccacaagccc agcaaccacca aggtggaca gagagtggag 660
          cccaagagct gcgacaagac ccacacctgc cccccctgcc cagctccaga actgctggga 720
          gggccttccg tgttcctgtt cccccccaag cccaaggaca ccctgatgat cagcaggacc 780
          cccgaggtga cctgcgtggt ggtggacgtg tcccacgagg accccagaggt gaagttcaac 840
          tggtacgtgg acggcgtgga ggtgcacaac gccaagacca agcccagaga ggagcagtac 900
          aacagcacct acagggtggt gtccgtgctg accacgtgctgc 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 agtggggagag caacggccag cccgagaaca actacaagac caccccccca 1200
          gtgctggaca gcgacggcag cttcttcctg tacagcaagc tgaccgtgga caagtccagg 1260
          tggcagcagg gcaacgtgtt cagctgcagc gtgatgcacg aggccctgca caaccactac 1320
          accccagaagt ccctgagcct gagccccggc aag 1353
           <![CDATA[ <210> 108]]>
           <![CDATA[ <211> 642]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 108]]>
          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 acccccttcac 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
           <![CDATA[ <210> 109]]>
           <![CDATA[ <211> 5]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 109]]>
          Ser Tyr Gly Val Asp
          1 5
           <![CDATA[ <210> 110]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 110]]>
          Gly Phe Ser Leu Ser Ser Tyr
          1 5
           <![CDATA[ <210> 111]]>
           <![CDATA[ <211> 16]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 111]]>
          Val Ile Trp Gly Gly Gly Gly Thr Tyr Tyr Ala Ser Ser Leu Met Gly
          1 5 10 15
           <![CDATA[ <210> 112]]>
           <![CDATA[ <211> 5]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 112]]>
          Trp Gly Gly Gly Gly
          1 5
           <![CDATA[ <210> 113]]>
           <![CDATA[ <211> 13]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 113]]>
          His Ala Tyr Gly His Asp Gly Gly Phe Ala Met Asp Tyr
          1 5 10
           <![CDATA[ <210> 114]]>
           <![CDATA[ <211> 11]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 114]]>
          Arg Ala Ser Glu Ser Val Ser Ser Asn Val Ala
          1 5 10
           <![CDATA[ <210> 115]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 115]]>
          Ser Glu Ser Val Ser Ser Asn
          1 5
           <![CDATA[ <210> 116]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 116]]>
          Gly Ala Ser Asn Arg Ala Thr
          1 5
           <![CDATA[ <210> 117]]>
           <![CDATA[ <211> 3]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 117]]>
          Gly Ala Ser
          1           
           <![CDATA[ <210> 118]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 118]]>
          Gly Gln Ser Tyr Ser Tyr Pro Phe Thr
          1 5
           <![CDATA[ <210> 119]]>
           <![CDATA[ <211> 6]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 119]]>
          Ser Tyr Ser Tyr Pro Phe
          1 5
           <![CDATA[ <210> 120]]>
           <![CDATA[ <211> 124]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 120]]>
          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
           <![CDATA[ <210> 121]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 121]]>
          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 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
           <![CDATA[ <210> 122]]>
           <![CDATA[ <211> 10]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 122]]>
          Gly Phe Thr Leu Thr Asn Tyr Gly Met Asn
          1 5 10
           <![CDATA[ <210> 123]]>
           <![CDATA[ <211> 5]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 123]]>
          Asn Tyr Gly Met Asn
          1 5
           <![CDATA[ <210> 124]]>
           <![CDATA[ <211> 17]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 124]]>
          Trp Ile Asn Thr Asp Thr Gly Glu Pro Thr Tyr Ala Asp Asp Phe Lys
          1 5 10 15
          Gly
           <![CDATA[ <210> 125]]>
           <![CDATA[ <211> 16]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 125]]>
          Asn Pro Pro Tyr Tyr Tyr Gly Thr Asn Asn Asn Ala Glu Ala Met Asp Tyr
          1 5 10 15
           <![CDATA[ <210> 126]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 126]]>
          Gly Phe Thr Leu Thr Asn Tyr
          1 5
           <![CDATA[ <210> 127]]>
           <![CDATA[ <211> 6]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 127]]>
          Asn Thr Asp Thr Gly Glu
          1 5
           <![CDATA[ <210> 128]]>
           <![CDATA[ <211> 125]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 128]]>
          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
           <![CDATA[ <210> 129]]>
           <![CDATA[ <211> 375]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 129]]>
          caagtgcagc tggtgcagtc gggagccgaa gtgaagaagc ctggagcctc ggtgaaggtg 60
          tcgtgcaagg catccggatt caccctcacc aattacggga tgaactgggt cagacaggcc 120
          cggggtcaac ggctggagtg gatcggatgg attaacaccg acaccggggga 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
           <![CDATA[ <210> 130]]>
           <![CDATA[ <211> 375]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 130]]>
          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
          gtgaccgtgtcctct 375
           <![CDATA[ <210> 131]]>
           <![CDATA[ <211> 451]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 131]]>
          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
           <![CDATA[ <210> 132]]>
           <![CDATA[ <211> 11]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> ]]> biological
           <![CDATA[ <400> 132]]>
          Ser Ser Ser Gln Asp Ile Ser Asn Tyr Leu Asn
          1 5 10
           <![CDATA[ <210> 133]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 133]]>
          Tyr Thr Ser Thr Leu His Leu
          1 5
           <![CDATA[ <210> 134]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 134]]>
          Gln Gln Tyr Tyr Asn Leu Pro Trp Thr
          1 5
           <![CDATA[ <210> 135]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 135]]>
          Ser Gln Asp Ile Ser Asn Tyr
          1 5
           <![CDATA[ <210> 136]]>
           <![CDATA[ <211> 3]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 136]]>
          Tyr Thr Ser
          1           
           <![CDATA[ <210> 137]]>
           <![CDATA[ <211> 6]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 137]]>
          Tyr Tyr Asn Leu Pro Trp
          1 5
           <![CDATA[ <210> 138]]>
           <![CDATA[ <211> 1353]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 138]]>
          caagtgcagc tggtgcagtc gggagccgaa gtgaagaagc ctggagcctc ggtgaaggtg 60
          tcgtgcaagg catccggatt caccctcacc aattacggga tgaactgggt cagacaggcc 120
          cggggtcaac ggctggagtg gatcggatgg attaacaccg acaccggggga 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 gaggttcctc 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
           <![CDATA[ <210> 139]]>
           <![CDATA[ <211> 1353]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 139]]>
          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 cccagcgtgttccccctggc 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 gaccacaagc ccagcaacac caaggtggac 660
          aagagggtgg agagcaagta cggccaccc tgccccccct gcccagcccc cgagttcctg 720
          ggcggaccca gcgtgttcct gttccccccc aagcccaagg acaccctgat gatcagcaga 780
          accccccgagg tgacctgtgt ggtggtggac gtgtcccagg aggacccccga 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 gaccacccccc 1200
          ccagtgctgg acagcgacgg cagcttcttc ctgtacagca ggctgaccgt ggacaagtcc 1260
          agatggcagg agggcaacgt ctttagctgc tccgtgatgc acgaggccct gcacaaccac 1320
          tacacccaga agagcctgag cctgtccctg ggc 1353
           <![CDATA[ <210> 140]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 140]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys 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
           <![CDATA[ <210> 141]]>
           <![CDATA[ <211> 321]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 141]]>
          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
           <![CDATA[ <210> 142]]>
           <![CDATA[ <211> 321]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 142]]>
          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
           <![CDATA[ <210> 143]]>
           <![CDATA[ <211> 214]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 143]]>
          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 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
           <![CDATA[ <210> 144]]>
           <![CDATA[ <211> 642]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 144]]>
          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
           <![CDATA[ <210> 145]]>
           <![CDATA[ <211> 642]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 145]]>
          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
           <![CDATA[ <210> 146]]>
           <![CDATA[ <211> 125]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 146]]>
          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
           <![CDATA[ <210> 147]]>
           <![CDATA[ <211> 375]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 147]]>
          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 tagaaaccccc 300
          ccctactact acggcactaa caacgccgag gctatggact actggggtca aggcactacc 360
          gtgaccgtgt ctagc 375
           <![CDATA[ <210> 148]]>
           <![CDATA[ <211> 375]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 148]]>
          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
          gtgaccgtgtcctct 375
           <![CDATA[ <210> 149]]>
           <![CDATA[ <211> 451]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 149]]>
          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
           <![CDATA[ <210> 150]]>
           <![CDATA[ <211> 1353]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 150]]>
          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 tagaaaccccc 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 gaggttcctc 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
           <![CDATA[ <210> 151]]>
           <![CDATA[ <211> 1353]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 151]]>
          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 cccagcgtgttccccctggc 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 gaccacaagc ccagcaacac caaggtggac 660
          aagagggtgg agagcaagta cggccaccc tgccccccct gcccagcccc cgagttcctg 720
          ggcggaccca gcgtgttcct gttccccccc aagcccaagg acaccctgat gatcagcaga 780
          accccccgagg tgacctgtgt ggtggtggac gtgtcccagg aggacccccga 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 gaccacccccc 1200
          ccagtgctgg acagcgacgg cagcttcttc ctgtacagca ggctgaccgt ggacaagtcc 1260
          agatggcagg agggcaacgt ctttagctgc tccgtgatgc acgaggccct gcacaaccac 1320
          tacacccaga agagcctgag cctgtccctg ggc 1353
           <![CDATA[ <210> 152]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 152]]>
          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 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
           <![CDATA[ <210> 153]]>
           <![CDATA[ <211> 321]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 153]]>
          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
           <![CDATA[ <210> 154]]>
           <![CDATA[ <211> 321]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 154]]>
          gacatccaga tgacccagtc cccctccagc ctgtctgctt ccgtgggcga cagagtgacc 60
          atcacctgtt cctccagcca ggacatctcc aactacctga actggtatca gcagaagccc 120
          ggcaaggccc ccaagctgct gatctactac acctccaccc tgcacctggg catcccccct 180
          agattctccg gctctggcta cggcaccgac ttcaccctga ccatcaacaa catcgagtcc 240
          gaggacgccg cctactactt ctgccagcag tactacaacc tgccctggac cttcggccag 300
          ggcaccaagg tggaaatcaa g 321
           <![CDATA[ <210> 155]]>
           <![CDATA[ <211> 214]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 155]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys 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 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 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
           <![CDATA[ <210> 156]]>
           <![CDATA[ <211> 642]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 156]]>
          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
           <![CDATA[ <210> 157]]>
           <![CDATA[ <211> 642]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 157]]>
          gacatccaga tgacccagtc cccctccagc ctgtctgctt ccgtgggcga cagagtgacc 60
          atcacctgtt cctccagcca ggacatctcc aactacctga actggtatca gcagaagccc 120
          ggcaaggccc ccaagctgct gatctactac acctccaccc tgcacctggg 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
           <![CDATA[ <210> 158]]>
           <![CDATA[ <211> 15]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 158]]>
          aattacggga tgaac 15
           <![CDATA[ <210> 159]]>
           <![CDATA[ <211> 15]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 159]]>
          aactacggca tgaac 15
           <![CDATA[ <210> 160]]>
           <![CDATA[ <211> 51]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 160]]>
          tggattaaca ccgacaccgg ggagcctacc tacgcggacg atttcaaggg a 51
           <![CDATA[ <210> 161]]>
           <![CDATA[ <211> 51]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 161]]>
          tggatcaaca ccgacaccgg cgagcctacc tacgccgacg acttcaaggg c 51
           <![CDATA[ <210> 162]]>
           <![CDATA[ <211> 48]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 162]]>
          aacccgccct actactacgg aaccaacaac gccgaagcca tggactac 48
           <![CDATA[ <210> 163]]>
           <![CDATA[ <211> 48]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 163]]>
          aacccccctt actactacgg caccaacaac gccgaggcca tggactat 48
           <![CDATA[ <210> 164]]>
           <![CDATA[ <211> 21]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 164]]>
          ggattcaccc tcaccaatta c 21
           <![CDATA[ <210> 165]]>
           <![CDATA[ <211> 21]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 165]]>
          ggcttcaccc tgaccaacta c 21
           <![CDATA[ <210> 166]]>
           <![CDATA[ <211> 18]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 166]]>
          aacaccgaca ccggggag 18
           <![CDATA[ <210> 167]]>
           <![CDATA[ <211> 18]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 167]]>
          aacaccgaca ccggcgag 18
           <![CDATA[ <210> 168]]>
           <![CDATA[ <211> 33]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 168]]>
          agctctagtc aggatatctc taactacctg aac 33
           <![CDATA[ <210> 169]]>
           <![CDATA[ <211> 33]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 169]]>
          tcctccagcc aggacatctc caactacctg aac 33
           <![CDATA[ <210> 170]]>
           <![CDATA[ <211> 21]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 170]]>
          tacactagca ccctgcacct g 21
           <![CDATA[ <210> 171]]>
           <![CDATA[ <211> 21]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 171]]>
          tacacctcca ccctgcacct g 21
           <![CDATA[ <210> 172]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 172]]>
          cagcagtact ataacctgcc ctggacc 27
           <![CDATA[ <210> 173]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 173]]>
          cagcagtact acaacctgcc ctggacc 27
           <![CDATA[ <210> 174]]>
           <![CDATA[ <211> 21]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 174]]>
          agtcaggata tctctaacta c 21
           <![CDATA[ <210> 175]]>
           <![CDATA[ <211> 21]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 175]]>
          agccaggaca tctccaacta c 21
           <![CDATA[ <210> 176]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 176]]>
          tacactagc 9
           <![CDATA[ <210> 177]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 177]]>
          tacacctcc 9
           <![CDATA[ <210> 178]]>
           <![CDATA[ <211> 18]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 178]]>
          tactataacc tgccctgg 18
           <![CDATA[ <210> 179]]>
           <![CDATA[ <211> 18]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 179]]>
          tactacaacc tgccctgg 18
           <![CDATA[ <210> 180]]>
           <![CDATA[ <211> 15]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 180]]>
          aactacggga tgaac 15
           <![CDATA[ <210> 181]]>
           <![CDATA[ <211> 51]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 181]]>
          tggattaaca ccgacaccgg cgagcctacc tacgccgacg actttaaggg c 51
           <![CDATA[ <210> 182]]>
           <![CDATA[ <211> 48]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 182]]>
          aaccccccct actactacgg cactaacaac gccgaggcta tggactac 48
           <![CDATA[ <210> 183]]>
           <![CDATA[ <211> 21]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 183]]>
          ggcttcaccc tgactaacta c 21
           <![CDATA[ <210> 184]]>
           <![CDATA[ <211> 447]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 184]]>
          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
           <![CDATA[ <210> 185]]>
           <![CDATA[ <211> 214]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 185]]>
          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 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 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
           <![CDATA[ <210> 186]]>
           <![CDATA[ <211> 446]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 186]]>
          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 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
           <![CDATA[ <210> 187]]>
           <![CDATA[ <211> 220]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 187]]>
          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
           <![CDATA[ <210> 188]]>
           <![CDATA[ <211> 10]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 188]]>
          Gly Phe Thr Leu Thr Asn Tyr Gly Met Asn
          1 5 10
           <![CDATA[ <210> 189]]>
           <![CDATA[ <211> 5]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 189]]>
          Ser Tyr Asn Met His
          1 5
           <![CDATA[ <210> 190]]>
           <![CDATA[ <211> 17]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 190]]>
          Asp Ile Tyr Pro Gly Asn Gly Asp Thr Ser Tyr Asn Gln Lys Phe Lys
          1 5 10 15
          Gly
           <![CDATA[ <210> 191]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 191]]>
          Val Gly Gly Ala Phe Pro Met Asp Tyr
          1 5
           <![CDATA[ <210> 192]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 192]]>
          Gly Tyr Thr Phe Thr Ser Tyr
          1 5
           <![CDATA[ <210> 193]]>
           <![CDATA[ <211> 6]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 193]]>
          Tyr Pro Gly Asn Gly Asp
          1 5
           <![CDATA[ <210> 194]]>
           <![CDATA[ <211> 118]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 194]]>
          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
           <![CDATA[ <210> 195]]>
           <![CDATA[ <211> 354]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 195]]>
          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
           <![CDATA[ <210> 196]]>
           <![CDATA[ <211> 444]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 196]]>
          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 Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
                          165 170 175
          Ser Ser Gly Leu Tyr Ser Leu Ser 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
           <![CDATA[ <210> 197]]>
           <![CDATA[ <211> 1332]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 197]]>
          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
           <![CDATA[ <210> 198]]>
           <![CDATA[ <211> 15]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 198]]>
          Arg Ala Ser Glu Ser Val Glu Tyr Tyr Gly Thr Ser Leu Met Gln
          1 5 10 15
           <![CDATA[ <210> 199]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 199]]>
          Ala Ala Ser Asn Val Glu Ser
          1 5
           <![CDATA[ <210> 200]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 200]]>
          Gln Gln Ser Arg Lys Asp Pro Ser Thr
          1 5
           <![CDATA[ <210> 201]]>
           <![CDATA[ <211> 11]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 201]]>
          Ser Glu Ser Val Glu Tyr Tyr Gly Thr Ser Leu
          1 5 10
           <![CDATA[ <210> 202]]>
           <![CDATA[ <211> 3]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 202]]>
          Ala Ala Ser
          1           
           <![CDATA[ <210> 203]]>
           <![CDATA[ <211> 6]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 203]]>
          Ser Arg Lys Asp Pro Ser
          1 5
           <![CDATA[ <210> 204]]>
           <![CDATA[ <211> 111]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 204]]>
          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
           <![CDATA[ <210> 205]]>
           <![CDATA[ <211> 333]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 205]]>
          gctattcagc tgactcagtc acctagtagc ctgagcgcta gtgtgggcga tagagtgact 60
          atcacctgta gagctagtga atcagtcgag tactacggca ctagcctgat gcagtggtat 120
          cagcagaagc ccgggaaagc ccctaagctg ctgatctacg ccgcctctaa cgtggaatca 180
          ggcgtgccct ctaggtttag cggtagcggt agtggcaccg acttcaccct gactatctct 240
          agcctgcagc ccgaggactt cgctacctac ttctgtcagc agtctaggaa ggaccctagc 300
          accttcggcg gaggcactaa ggtcgagatt aag 333
           <![CDATA[ <210> 206]]>
           <![CDATA[ <211> 218]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 206]]>
          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 Pro Ser Asp Glu Gln
                  115 120 125
          Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn 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
           <![CDATA[ <210> 207]]>
           <![CDATA[ <211> 654]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 207]]>
          gctattcagc tgactcagtc acctagtagc ctgagcgcta gtgtgggcga tagagtgact 60
          atcacctgta gagctagtga atcagtcgag tactacggca ctagcctgat gcagtggtat 120
          cagcagaagc ccgggaaagc ccctaagctg ctgatctacg ccgcctctaa cgtggaatca 180
          ggcgtgccct ctaggtttag 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 accccccggga ggccaaggtg cagtggaagg tggacaacgc cctgcagagc 480
          ggcaacagcc aggagagcgt caccgagcag gacagcaagg actccaccta cagcctgagc 540
          agcaccctga ccctgagcaa ggccgactac gagaagcata aggtgtacgc ctgcgaggtg 600
          accccaccagg gcctgtccag ccccgtgacc aagagcttca acaggggcga gtgc 654
           <![CDATA[ <210> 208]]>
           <![CDATA[ <211> 17]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 208]]>
          Asp Ile Tyr Pro Gly Gln Gly Asp Thr Ser Tyr Asn Gln Lys Phe Lys
          1 5 10 15
          Gly
           <![CDATA[ <210> 209]]>
           <![CDATA[ <211> 6]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 209]]>
          Tyr Pro Gly Gln Gly Asp
          1 5
           <![CDATA[ <210> 210]]>
           <![CDATA[ <211> 118]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 210]]>
          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
           <![CDATA[ <210> 211]]>
           <![CDATA[ <211> 354]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 211]]>
          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
           <![CDATA[ <210> 212]]>
           <![CDATA[ <211> 444]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 212]]>
          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 Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
                          165 170 175
          Ser Ser Gly Leu Tyr Ser Leu Ser 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
           <![CDATA[ <210> 213]]>
           <![CDATA[ <211> 1332]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 213]]>
          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
           <![CDATA[ <210> 214]]>
           <![CDATA[ <211> 111]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 214]]>
          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
           <![CDATA[ <210> 215]]>
           <![CDATA[ <211> 333]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 215]]>
          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 ggacccctagc 300
          accttcggcg gaggcactaa ggtcgagatt aag 333
           <![CDATA[ <210> 216]]>
           <![CDATA[ <211> 218]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 216]]>
          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 Pro Ser Asp Glu Gln
                  115 120 125
          Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn 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
           <![CDATA[ <210> 217]]>
           <![CDATA[ <211> 654]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 217]]>
          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 ggacccctagc 300
          accttcggcg gaggcactaa ggtcgagatt aagcgtacgg tggccgctcc cagcgtgttc 360
          atcttccccc ccagcgacga gcagctgaag agcggcaccg ccagcgtggt gtgcctgctg 420
          aacaacttct accccccggga ggccaaggtg cagtggaagg tggacaacgc cctgcagagc 480
          ggcaacagcc aggagagcgt caccgagcag gacagcaagg actccaccta cagcctgagc 540
          agcaccctga ccctgagcaa ggccgactac gagaagcata aggtgtacgc ctgcgaggtg 600
          accccaccagg gcctgtccag ccccgtgacc aagagcttca acaggggcga gtgc 654
           <![CDATA[ <210> 218]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 218]]>
          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
           <![CDATA[ <210> 219]]>
           <![CDATA[ <211> 108]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 219]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
          1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln 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
           <![CDATA[ <210> 220]]>
           <![CDATA[ <211> 120]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 220]]>
          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
           <![CDATA[ <210> 221]]>
           <![CDATA[ <211> 113]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 221]]>
          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
           <![CDATA[ <210> 222]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 222]]>
          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 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
           <![CDATA[ <210> 223]]>
           <![CDATA[ <211> 170]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 223]]>
          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 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
           <![CDATA[ <210> 224]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 224]]>
          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
           <![CDATA[ <210> 225]]>
           <![CDATA[ <211> 297]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 225]]>
          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 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
           <![CDATA[ <210> 226]]>
           <![CDATA[ <211> 114]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 226]]>
          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 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
           <![CDATA[ <210> 227]]>
           <![CDATA[ <211> 77]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 227]]>
          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
           <![CDATA[ <210> 228]]>
           <![CDATA[ <211> 248]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 228]]>
          Gln Val Gln Leu Leu Glu Ser Gly Ala Glu Leu Val Arg Pro Gly Ser
          1 5 10 15
          Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Ser Tyr
                      20 25 30
          Trp Met Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
                  35 40 45
          Gly Gln Ile Tyr Pro Gly Asp Gly Asp Thr Asn Tyr Asn Gly Lys Phe
              50 55 60
          Lys Gly Gln Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr
          65 70 75 80
          Met Gln Leu Ser Gly Leu Thr Ser Glu Asp Ser Ala Val Tyr Ser Cys
                          85 90 95
          Ala Arg Lys Thr Ile Ser Ser Val Val Asp Phe Tyr Phe Asp Tyr Trp
                      100 105 110
          Gly Gln Gly Thr Thr Val Thr Gly Ser Thr Ser Gly Ser Gly Lys Pro
                  115 120 125
          Gly Ser Gly Glu Gly Ser Thr Lys Gly Glu Leu Val Leu Thr Gln Ser
              130 135 140
          Pro Lys Phe Met Ser Thr Ser Val Gly Asp Arg Val Ser Val Thr Cys
          145 150 155 160
          Lys Ala Ser Gln Asn Val Gly Thr Asn Val Ala Trp Tyr Gln Gln Lys
                          165 170 175
          Pro Gly Gln Ser Pro Lys Pro Leu Ile Tyr Ser Ala Thr Tyr Arg Asn
                      180 185 190
          Ser Gly Val Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe
                  195 200 205
          Thr Leu Thr Ile Thr Asn Val Gln Ser Lys Asp Leu Ala Asp Tyr Phe
              210 215 220
          Tyr Phe Cys Gln Tyr Asn Arg Tyr Pro Tyr Thr Ser Ser Gly Gly Gly Thr
          225 230 235 240
          Lys Leu Glu Ile Lys Arg Arg Ser
                          245
           <![CDATA[ <210> 229]]>
           <![CDATA[ <211> 111]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 229]]>
          Glu Leu Val Leu Thr Gln Ser Pro Lys Phe Met Ser Thr Ser Val Gly
          1 5 10 15
          Asp Arg Val Ser Val Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Asn
                      20 25 30
          Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Pro Leu Ile
                  35 40 45
          Tyr Ser Ala Thr Tyr Arg Asn Ser Gly Val Pro Asp Arg Phe Thr Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Thr Asn Val Gln Ser
          65 70 75 80
          Lys Asp Leu Ala Asp Tyr Phe Tyr Phe Cys Gln Tyr Asn Arg Tyr Pro
                          85 90 95
          Tyr Thr Ser Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Arg Ser
                      100 105 110
           <![CDATA[ <210> 230]]>
           <![CDATA[ <211> 20]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 230]]>
          Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
          1 5 10 15
          Gly Gly Gly Ser
                      20
           <![CDATA[ <210> 231]]>
           <![CDATA[ <211> 15]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 231]]>
          Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
          1 5 10 15
           <![CDATA[ <210> 232]]>
           <![CDATA[ <211> 4]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 232]]>
          Gly Gly Gly Ser
          1               
           <![CDATA[ <210> 233]]>
           <![CDATA[ <211> 242]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 233]]>
          Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Ser Leu Ser Ala Ser Leu Gly
          1 5 10 15
          Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Ser Lys Tyr
                      20 25 30
          Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile
                  35 40 45
          Tyr His Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln
          65 70 75 80
          Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Tyr
                          85 90 95
          Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Thr Gly Gly Gly Gly Ser
                      100 105 110
          Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Lys Leu Gln Glu
                  115 120 125
          Ser Gly Pro Gly Leu Val Ala Pro Ser Gln Ser Leu Ser Val Thr Cys
              130 135 140
          Thr Val Ser Gly Val Ser Leu Pro Asp Tyr Gly Val Ser Trp Ile Arg
          145 150 155 160
          Gln Pro Pro Arg Lys Gly Leu Glu Trp Leu Gly Val Ile Trp Gly Ser
                          165 170 175
          Glu Thr Thr Tyr Tyr Asn Ser Ala Leu Lys Ser Arg Leu Thr Ile Ile
                      180 185 190
          Lys Asp Asn Ser Lys Ser Gln Val Phe Leu Lys Met Asn Ser Leu Gln
                  195 200 205
          Thr Asp Asp Thr Ala Ile Tyr Tyr Cys Ala Lys His Tyr Tyr Tyr Gly
              210 215 220
          Gly Ser Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val
          225 230 235 240
          Ser Ser
           <![CDATA[ <210> 234]]>
           <![CDATA[ <211> 242]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 234]]>
          Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
          1 5 10 15
          Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Asp Ile Ser Lys Tyr
                      20 25 30
          Leu Asn Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
                  35 40 45
          Tyr His Thr Ser Arg Leu His Ser Gly Ile Pro Ala Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Val Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Tyr
                          85 90 95
          Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Gly Ser
                      100 105 110
          Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Gln Glu
                  115 120 125
          Ser Gly Pro Gly Leu Val Lys Pro Ser Glu Thr Leu Ser Leu Thr Cys
              130 135 140
          Thr Val Ser Gly Val Ser Leu Pro Asp Tyr Gly Val Ser Trp Ile Arg
          145 150 155 160
          Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile Gly Val Ile Trp Gly Ser
                          165 170 175
          Glu Thr Thr Tyr Tyr Ser Ser Ser Leu Lys Ser Arg Val Thr Ile Ser
                      180 185 190
          Lys Asp Asn Ser Lys Asn Gln Val Ser Leu Lys Leu Ser Ser Val Thr
                  195 200 205
          Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Lys His Tyr Tyr Tyr Gly
              210 215 220
          Gly Ser Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val
          225 230 235 240
          Ser Ser
           <![CDATA[ <210> 235]]>
           <![CDATA[ <211> 242]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 235]]>
          Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
          1 5 10 15
          Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Asp Ile Ser Lys Tyr
                      20 25 30
          Leu Asn Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
                  35 40 45
          Tyr His Thr Ser Arg Leu His Ser Gly Ile Pro Ala Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Val Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Tyr
                          85 90 95
          Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Gly Ser
                      100 105 110
          Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Gln Glu
                  115 120 125
          Ser Gly Pro Gly Leu Val Lys Pro Ser Glu Thr Leu Ser Leu Thr Cys
              130 135 140
          Thr Val Ser Gly Val Ser Leu Pro Asp Tyr Gly Val Ser Trp Ile Arg
          145 150 155 160
          Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile Gly Val Ile Trp Gly Ser
                          165 170 175
          Glu Thr Thr Tyr Tyr Gln Ser Ser Leu Lys Ser Arg Val Thr Ile Ser
                      180 185 190
          Lys Asp Asn Ser Lys Asn Gln Val Ser Leu Lys Leu Ser Ser Val Thr
                  195 200 205
          Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Lys His Tyr Tyr Tyr Gly
              210 215 220
          Gly Ser Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val
          225 230 235 240
          Ser Ser
           <![CDATA[ <210> 236]]>
           <![CDATA[ <211> 242]]>
           <![CDATA[ <212]]>> PRT]]&gt;
           <br/> &lt;![CDATA[ &lt;213&gt; Artificial Sequence]]&gt;
           <br/>
           <br/> &lt;![CDATA[ &lt;220&gt;]]&gt;
           <br/> &lt;![CDATA[ &lt;223&gt;biological]]&gt;
           <br/>
           <br/> &lt;![CDATA[ &lt;400&gt;236]]&gt;
           <br/>
           <br/> <![CDATA[Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
          1 5 10 15
          Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Val Ser Leu Pro Asp Tyr
                      20 25 30
          Gly Val Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
                  35 40 45
          Gly Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr Ser Ser Ser Ser Leu Lys
              50 55 60
          Ser Arg Val Thr Ile Ser Lys Asp Asn Ser Lys Asn Gln Val Ser Leu
          65 70 75 80
          Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
                          85 90 95
          Lys His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr Trp Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Val Ser Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
                  115 120 125
          Gly Ser Gly Gly Gly Gly Ser Glu Ile Val Met Thr Gln Ser Pro Ala
              130 135 140
          Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala
          145 150 155 160
          Ser Gln Asp Ile Ser Lys Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly
                          165 170 175
          Gln Ala Pro Arg Leu Leu Ile Tyr His Thr Ser Arg Leu His Ser Gly
                      180 185 190
          Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr Leu
                  195 200 205
          Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Val Tyr Phe Cys Gln
              210 215 220
          Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu
          225 230 235 240
          Ile Lys
           <![CDATA[ <210> 237]]>
           <![CDATA[ <211> 242]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 237]]>
          Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
          1 5 10 15
          Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Val Ser Leu Pro Asp Tyr
                      20 25 30
          Gly Val Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
                  35 40 45
          Gly Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr Gln Ser Ser Leu Lys
              50 55 60
          Ser Arg Val Thr Ile Ser Lys Asp Asn Ser Lys Asn Gln Val Ser Leu
          65 70 75 80
          Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
                          85 90 95
          Lys His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr Trp Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Val Ser Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
                  115 120 125
          Gly Ser Gly Gly Gly Gly Ser Glu Ile Val Met Thr Gln Ser Pro Ala
              130 135 140
          Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala
          145 150 155 160
          Ser Gln Asp Ile Ser Lys Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly
                          165 170 175
          Gln Ala Pro Arg Leu Leu Ile Tyr His Thr Ser Arg Leu His Ser Gly
                      180 185 190
          Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr Leu
                  195 200 205
          Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Val Tyr Phe Cys Gln
              210 215 220
          Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu
          225 230 235 240
          Ile Lys
           <![CDATA[ <210> 238]]>
           <![CDATA[ <211> 247]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 238]]>
          Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
          1 5 10 15
          Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Asp Ile Ser Lys Tyr
                      20 25 30
          Leu Asn Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
                  35 40 45
          Tyr His Thr Ser Arg Leu His Ser Gly Ile Pro Ala Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Val Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Tyr
                          85 90 95
          Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Gly Ser
                      100 105 110
          Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln
                  115 120 125
          Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu Thr
              130 135 140
          Leu Ser Leu Thr Cys Thr Val Ser Gly Val Ser Leu Pro Asp Tyr Gly
          145 150 155 160
          Val Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile Gly
                          165 170 175
          Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr Ser Ser Ser Leu Lys Ser
                      180 185 190
          Arg Val Thr Ile Ser Lys Asp Asn Ser Lys Asn Gln Val Ser Leu Lys
                  195 200 205
          Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Lys
              210 215 220
          His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr Trp Gly Gln Gly
          225 230 235 240
          Thr Leu Val Thr Val Ser Ser
                          245
           <![CDATA[ <210> 239]]>
           <![CDATA[ <211> 247]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400]]>> 239]]>
           <br/>
           <br/> <![CDATA[Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
          1 5 10 15
          Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Asp Ile Ser Lys Tyr
                      20 25 30
          Leu Asn Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
                  35 40 45
          Tyr His Thr Ser Arg Leu His Ser Gly Ile Pro Ala Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Val Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Tyr
                          85 90 95
          Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Gly Ser
                      100 105 110
          Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln
                  115 120 125
          Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu Thr
              130 135 140
          Leu Ser Leu Thr Cys Thr Val Ser Gly Val Ser Leu Pro Asp Tyr Gly
          145 150 155 160
          Val Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile Gly
                          165 170 175
          Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr Gln Ser Ser Leu Lys Ser
                      180 185 190
          Arg Val Thr Ile Ser Lys Asp Asn Ser Lys Asn Gln Val Ser Leu Lys
                  195 200 205
          Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Lys
              210 215 220
          His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr Trp Gly Gln Gly
          225 230 235 240
          Thr Leu Val Thr Val Ser Ser
                          245
           <![CDATA[ <210> 240]]>
           <![CDATA[ <211> 247]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 240]]>
          Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
          1 5 10 15
          Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Val Ser Leu Pro Asp Tyr
                      20 25 30
          Gly Val Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
                  35 40 45
          Gly Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr Ser Ser Ser Ser Leu Lys
              50 55 60
          Ser Arg Val Thr Ile Ser Lys Asp Asn Ser Lys Asn Gln Val Ser Leu
          65 70 75 80
          Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
                          85 90 95
          Lys His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr Trp Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Val Ser Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
                  115 120 125
          Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ile Val Met
              130 135 140
          Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr
          145 150 155 160
          Leu Ser Cys Arg Ala Ser Gln Asp Ile Ser Lys Tyr Leu Asn Trp Tyr
                          165 170 175
          Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr His Thr Ser
                      180 185 190
          Arg Leu His Ser Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly
                  195 200 205
          Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala
              210 215 220
          Val Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gln
          225 230 235 240
          Gly Thr Lys Leu Glu Ile Lys
                          245
           <![CDATA[ <210> 241]]>
           <![CDATA[ <211> 247]]>
           <![CDATA[ <212> ]]>PRT
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 241]]>
          Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
          1 5 10 15
          Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Val Ser Leu Pro Asp Tyr
                      20 25 30
          Gly Val Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
                  35 40 45
          Gly Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr Gln Ser Ser Leu Lys
              50 55 60
          Ser Arg Val Thr Ile Ser Lys Asp Asn Ser Lys Asn Gln Val Ser Leu
          65 70 75 80
          Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
                          85 90 95
          Lys His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr Trp Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Val Ser Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
                  115 120 125
          Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ile Val Met
              130 135 140
          Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr
          145 150 155 160
          Leu Ser Cys Arg Ala Ser Gln Asp Ile Ser Lys Tyr Leu Asn Trp Tyr
                          165 170 175
          Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr His Thr Ser
                      180 185 190
          Arg Leu His Ser Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly
                  195 200 205
          Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala
              210 215 220
          Val Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gln
          225 230 235 240
          Gly Thr Lys Leu Glu Ile Lys
                          245
           <![CDATA[ <210> 242]]>
           <![CDATA[ <211> 247]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 242]]>
          Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
          1 5 10 15
          Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Asp Ile Ser Lys Tyr
                      20 25 30
          Leu Asn Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
                  35 40 45
          Tyr His Thr Ser Arg Leu His Ser Gly Ile Pro Ala Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Val Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Tyr
                          85 90 95
          Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Gly Ser
                      100 105 110
          Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln
                  115 120 125
          Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu Thr
              130 135 140
          Leu Ser Leu Thr Cys Thr Val Ser Gly Val Ser Leu Pro Asp Tyr Gly
          145 150 155 160
          Val Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile Gly
                          165 170 175
          Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr Asn Ser Ser Leu Lys Ser
                      180 185 190
          Arg Val Thr Ile Ser Lys Asp Asn Ser Lys Asn Gln Val Ser Leu Lys
                  195 200 205
          Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Lys
              210 215 220
          His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr Trp Gly Gln Gly
          225 230 235 240
          Thr Leu Val Thr Val Ser Ser
                          245
           <![CDATA[ <210> 243]]>
           <![CDATA[ <211> 247]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 243]]>
          Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
          1 5 10 15
          Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Val Ser Leu Pro Asp Tyr
                      20 25 30
          Gly Val Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
                  35 40 45
          Gly Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr Asn Ser Ser Leu Lys
              50 55 60
          Ser Arg Val Thr Ile Ser Lys Asp Asn Ser Lys Asn Gln Val Ser Leu
          65 70 75 80
          Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
                          85 90 95
          Lys His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr Trp Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Val Ser Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
                  115 120 125
          Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ile Val Met
              130 135 140
          Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr
          145 150 155 160
          Leu Ser Cys Arg Ala Ser Gln Asp Ile Ser Lys Tyr Leu Asn Trp Tyr
                          165 170 175
          Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr His Thr Ser
                      180 185 190
          Arg Leu His Ser Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly
                  195 200 205
          Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala
              210 215 220
          Val Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gln
          225 230 235 240
          Gly Thr Lys Leu Glu Ile Lys
                          245
           <![CDATA[ <210> 244]]>
           <![CDATA[ <211> 242]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 244]]>
          Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
          1 5 10 15
          Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Asp Ile Ser Lys Tyr
                      20 25 30
          Leu Asn Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
                  35 40 45
          Tyr His Thr Ser Arg Leu His Ser Gly Ile Pro Ala Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Val Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Tyr
                          85 90 95
          Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Gly Ser
                      100 105 110
          Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Gln Glu
                  115 120 125
          Ser Gly Pro Gly Leu Val Lys Pro Ser Glu Thr Leu Ser Leu Thr Cys
              130 135 140
          Thr Val Ser Gly Val Ser Leu Pro Asp Tyr Gly Val Ser Trp Ile Arg
          145 150 155 160
          Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile Gly Val Ile Trp Gly Ser
                          165 170 175
          Glu Thr Thr Tyr Tyr Asn Ser Ser Leu Lys Ser Arg Val Thr Ile Ser
                      180 185 190
          Lys Asp Asn Ser Lys Asn Gln Val Ser Leu Lys Leu Ser Ser Val Thr
                  195 200 205
          Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Lys His Tyr Tyr Tyr Gly
              210 215 220
          Gly Ser Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val
          225 230 235 240
          Ser Ser
           <![CDATA[ <210> 245]]>
           <![CDATA[ <211> 242]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 245]]>
          Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
          1 5 10 15
          Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Val Ser Leu Pro Asp Tyr
                      20 25 30
          Gly Val Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
                  35 40 45
          Gly Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr Asn Ser Ser Leu Lys
              50 55 60
          Ser Arg Val Thr Ile Ser Lys Asp Asn Ser Lys Asn Gln Val Ser Leu
          65 70 75 80
          Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
                          85 90 95
          Lys His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr Trp Gly Gln
                      100 105 110
          Gly Thr Leu Val Thr Val Ser Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
                  115 120 125
          Gly Ser Gly Gly Gly Gly Ser Glu Ile Val Met Thr Gln Ser Pro Ala
              130 135 140
          Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala
          145 150 155 160
          Ser Gln Asp Ile Ser Lys Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly
                          165 170 175
          Gln Ala Pro Arg Leu Leu Ile Tyr His Thr Ser Arg Leu His Ser Gly
                      180 185 190
          Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr Leu
                  195 200 205
          Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Val Tyr Phe Cys Gln
              210 215 220
          Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu
          225 230 235 240
          Ile Lys
           <![CDATA[ <210> 246]]>
           <![CDATA[ <211>]]> 12
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 246]]>
          His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr
          1 5 10
           <![CDATA[ <210> 247]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 247]]>
          Gln Gln Gly Asn Thr Leu Pro Tyr Thr
          1 5
           <![CDATA[ <210> 248]]>
           <![CDATA[ <211> 18]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 248]]>
          Gly Ser Thr Ser Gly Ser Gly Lys Pro Gly Ser Gly Glu Gly Ser Thr
          1 5 10 15
          Lys Gly
           <![CDATA[ <210> 249]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 249]]>
          Gln Val Gln Leu Leu Glu Ser Gly Ala Glu Leu Val Arg Pro Gly Ser
          1 5 10 15
          Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Ser Tyr
                      20 25 30
          Trp Met Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
                  35 40 45
          Gly Gln Ile Tyr Pro Gly Asp Gly Asp Thr Asn Tyr Asn Gly Lys Phe
              50 55 60
          Lys Gly Gln Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr
          65 70 75 80
          Met Gln Leu Ser Gly Leu Thr Ser Glu Asp Ser Ala Val Tyr Ser Cys
                          85 90 95
          Ala Arg Lys Thr Ile Ser Ser Val Val Asp Phe Tyr Phe Asp Tyr Trp
                      100 105 110
          Gly Gln Gly Thr Thr Val Thr
                  115
           <![CDATA[ <210> 250]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 250]]>
          His Thr Ser Arg Leu His Ser
          1 5
           <![CDATA[ <210> 251]]>
           <![CDATA[ <211> 11]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 251]]>
          Arg Ala Ser Gln Asp Ile Ser Lys Tyr Leu Asn
          1 5 10
           <![CDATA[ <210> 252]]>
           <![CDATA[ <211> 486]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 252]]>
          Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
          1 5 10 15
          His Ala Ala Arg Pro Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Ser Leu
                      20 25 30
          Ser Ala Ser Leu Gly Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln
                  35 40 45
          Asp Ile Ser Lys Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr
              50 55 60
          Val Lys Leu Leu Ile Tyr His Thr Ser Arg Leu His Ser Gly Val Pro
          65 70 75 80
          Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile
                          85 90 95
          Ser Asn Leu Glu Gln Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly
                      100 105 110
          Asn Thr Leu Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Thr
                  115 120 125
          Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu
              130 135 140
          Val Lys Leu Gln Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln Ser
          145 150 155 160
          Leu Ser Val Thr Cys Thr Val Ser Gly Val Ser Leu Pro Asp Tyr Gly
                          165 170 175
          Val Ser Trp Ile Arg Gln Pro Pro Arg Lys Gly Leu Glu Trp Leu Gly
                      180 185 190
          Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr Asn Ser Ala Leu Lys Ser
                  195 200 205
          Arg Leu Thr Ile Ile Lys Asp Asn Ser Lys Ser Gln Val Phe Leu Lys
              210 215 220
          Met Asn Ser Leu Gln Thr Asp Asp Thr Ala Ile Tyr Tyr Cys Ala Lys
          225 230 235 240
          His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr Trp Gly Gln Gly
                          245 250 255
          Thr Ser Val Thr Val Ser Ser Thr Thr Thr Pro Ala Pro Arg Pro Pro
                      260 265 270
          Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu
                  275 280 285
          Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp
              290 295 300
          Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly
          305 310 315 320
          Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg
                          325 330 335
          Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln
                      340 345 350
          Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu
                  355 360 365
          Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala
              370 375 380
          Pro Ala Tyr Lys Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu
          385 390 395 400
          Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp
                          405 410 415
          Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu
                      420 425 430
          Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile
                  435 440 445
          Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr
              450 455 460
          Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met
          465 470 475 480
          Gln Ala Leu Pro Pro Arg
                          485
           <![CDATA[ <210> 253]]>
           <![CDATA[ <211> 486]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 253]]>
          Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
          1 5 10 15
          His Ala Ala Arg Pro Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu
                      20 25 30
          Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln
                  35 40 45
          Asp Ile Ser Lys Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Gln Ala
              50 55 60
          Pro Arg Leu Leu Ile Tyr His Thr Ser Arg Leu His Ser Gly Ile Pro
          65 70 75 80
          Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile
                          85 90 95
          Ser Ser Leu Gln Pro Glu Asp Phe Ala Val Tyr Phe Cys Gln Gln Gly
                      100 105 110
          Asn Thr Leu Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
                  115 120 125
          Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln
              130 135 140
          Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu Thr
          145 150 155 160
          Leu Ser Leu Thr Cys Thr Val Ser Gly Val Ser Leu Pro Asp Tyr Gly
                          165 170 175
          Val Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile Gly
                      180 185 190
          Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr Ser Ser Ser Leu Lys Ser
                  195 200 205
          Arg Val Thr Ile Ser Lys Asp Asn Ser Lys Asn Gln Val Ser Leu Lys
              210 215 220
          Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Lys
          225 230 235 240
          His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr Trp Gly Gln Gly
                          245 250 255
          Thr Leu Val Thr Val Ser Ser Thr Thr Thr Pro Ala Pro Arg Pro Pro
                      260 265 270
          Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu
                  275 280 285
          Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp
              290 295 300
          Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly
          305 310 315 320
          Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg
                          325 330 335
          Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln
                      340 345 350
          Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu
                  355 360 365
          Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala
              370 375 380
          Pro Ala Tyr Lys Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu
          385 390 395 400
          Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp
                          405 410 415
          Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu
                      420 425 430
          Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile
                  435 440 445
          Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr
              450 455 460
          Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met
          465 470 475 480
          Gln Ala Leu Pro Pro Arg
                          485
           <![CDATA[ <210> 254]]>
           <![CDATA[ <211> 486]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 254]]>
          Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
          1 5 10 15
          His Ala Ala Arg Pro Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu
                      20 25 30
          Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln
                  35 40 45
          Asp Ile Ser Lys Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Gln Ala
              50 55 60
          Pro Arg Leu Leu Ile Tyr His Thr Ser Arg Leu His Ser Gly Ile Pro
          65 70 75 80
          Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile
                          85 90 95
          Ser Ser Leu Gln Pro Glu Asp Phe Ala Val Tyr Phe Cys Gln Gln Gly
                      100 105 110
          Asn Thr Leu Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
                  115 120 125
          Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln
              130 135 140
          Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu Thr
          145 150 155 160
          Leu Ser Leu Thr Cys Thr Val Ser Gly Val Ser Leu Pro Asp Tyr Gly
                          165 170 175
          Val Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile Gly
                      180 185 190
          Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr Gln Ser Ser Leu Lys Ser
                  195 200 205
          Arg Val Thr Ile Ser Lys Asp Asn Ser Lys Asn Gln Val Ser Leu Lys
              210 215 220
          Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Lys
          225 230 235 240
          His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr Trp Gly Gln Gly
                          245 250 255
          Thr Leu Val Thr Val Ser Ser Thr Thr Thr Pro Ala Pro Arg Pro Pro
                      260 265 270
          Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu
                  275 280 285
          Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp
              290 295 300
          Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly
          305 310 315 320
          Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg
                          325 330 335
          Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln
                      340 345 350
          Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu
                  355 360 365
          Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala
              370 375 380
          Pro Ala Tyr Lys Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu
          385 390 395 400
          Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp
                          405 410 415
          Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu
                      420 425 430
          Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile
                  435 440 445
          Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr
              450 455 460
          Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met
          465 470 475 480
          Gln Ala Leu Pro Pro Arg
                          485
           <![CDATA[ <21]]>0> 255]]&gt;
           <br/> &lt;![CDATA[ &lt;211&gt;486]]&gt;
           <br/> &lt;![CDATA[ &lt;212&gt;PRT]]&gt;
           <br/> &lt;![CDATA[ &lt;213&gt; Artificial Sequence]]&gt;
           <br/>
           <br/> &lt;![CDATA[ &lt;220&gt;]]&gt;
           <br/> &lt;![CDATA[ &lt;223&gt;biological]]&gt;
           <br/>
           <br/> &lt;![CDATA[ &lt;400&gt;255]]&gt;
           <br/>
           <br/> <![CDATA[Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
          1 5 10 15
          His Ala Ala Arg Pro Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu
                      20 25 30
          Val Lys Pro Ser Glu Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Val
                  35 40 45
          Ser Leu Pro Asp Tyr Gly Val Ser Trp Ile Arg Gln Pro Pro Gly Lys
              50 55 60
          Gly Leu Glu Trp Ile Gly Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr
          65 70 75 80
          Ser Ser Ser Leu Lys Ser Arg Val Thr Ile Ser Lys Asp Asn Ser Lys
                          85 90 95
          Asn Gln Val Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala
                      100 105 110
          Val Tyr Tyr Cys Ala Lys His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met
                  115 120 125
          Asp Tyr Trp Gly Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ser Gly Gly Gly
              130 135 140
          Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ile Val Met
          145 150 155 160
          Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr
                          165 170 175
          Leu Ser Cys Arg Ala Ser Gln Asp Ile Ser Lys Tyr Leu Asn Trp Tyr
                      180 185 190
          Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr His Thr Ser
                  195 200 205
          Arg Leu His Ser Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly
              210 215 220
          Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala
          225 230 235 240
          Val Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gln
                          245 250 255
          Gly Thr Lys Leu Glu Ile Lys Thr Thr Thr Pro Ala Pro Arg Pro Pro
                      260 265 270
          Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu
                  275 280 285
          Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp
              290 295 300
          Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly
          305 310 315 320
          Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg
                          325 330 335
          Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln
                      340 345 350
          Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu
                  355 360 365
          Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala
              370 375 380
          Pro Ala Tyr Lys Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu
          385 390 395 400
          Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp
                          405 410 415
          Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu
                      420 425 430
          Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile
                  435 440 445
          Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr
              450 455 460
          Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met
          465 470 475 480
          Gln Ala Leu Pro Pro Arg
                          485
           <![CDATA[ <210> 256]]>
           <![CDATA[ <211> 486]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 256]]>
          Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
          1 5 10 15
          His Ala Ala Arg Pro Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu
                      20 25 30
          Val Lys Pro Ser Glu Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Val
                  35 40 45
          Ser Leu Pro Asp Tyr Gly Val Ser Trp Ile Arg Gln Pro Pro Gly Lys
              50 55 60
          Gly Leu Glu Trp Ile Gly Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr
          65 70 75 80
          Gln Ser Ser Leu Lys Ser Arg Val Thr Ile Ser Lys Asp Asn Ser Lys
                          85 90 95
          Asn Gln Val Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala
                      100 105 110
          Val Tyr Tyr Cys Ala Lys His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met
                  115 120 125
          Asp Tyr Trp Gly Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ser Gly Gly Gly
              130 135 140
          Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ile Val Met
          145 150 155 160
          Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr
                          165 170 175
          Leu Ser Cys Arg Ala Ser Gln Asp Ile Ser Lys Tyr Leu Asn Trp Tyr
                      180 185 190
          Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr His Thr Ser
                  195 200 205
          Arg Leu His Ser Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly
              210 215 220
          Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala
          225 230 235 240
          Val Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gln
                          245 250 255
          Gly Thr Lys Leu Glu Ile Lys Thr Thr Thr Pro Ala Pro Arg Pro Pro
                      260 265 270
          Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu
                  275 280 285
          Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp
              290 295 300
          Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly
          305 310 315 320
          Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg
                          325 330 335
          Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln
                      340 345 350
          Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu
                  355 360 365
          Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala
              370 375 380
          Pro Ala Tyr Lys Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu
          385 390 395 400
          Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp
                          405 410 415
          Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu
                      420 425 430
          Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile
                  435 440 445
          Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr
              450 455 460
          Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met
          465 470 475 480
          Gln Ala Leu Pro Pro Arg
                          485
           <![CDATA[ <210> 257]]>
           <![CDATA[ <211> 491]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 257]]>
          Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
          1 5 10 15
          His Ala Ala Arg Pro Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu
                      20 25 30
          Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln
                  35 40 45
          Asp Ile Ser Lys Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Gln Ala
              50 55 60
          Pro Arg Leu Leu Ile Tyr His Thr Ser Arg Leu His Ser Gly Ile Pro
          65 70 75 80
          Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile
                          85 90 95
          Ser Ser Leu Gln Pro Glu Asp Phe Ala Val Tyr Phe Cys Gln Gln Gly
                      100 105 110
          Asn Thr Leu Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
                  115 120 125
          Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
              130 135 140
          Gly Gly Gly Ser Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val
          145 150 155 160
          Lys Pro Ser Glu Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Val Ser
                          165 170 175
          Leu Pro Asp Tyr Gly Val Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly
                      180 185 190
          Leu Glu Trp Ile Gly Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr Ser
                  195 200 205
          Ser Ser Leu Lys Ser Arg Val Thr Ile Ser Lys Asp Asn Ser Lys Asn
              210 215 220
          Gln Val Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val
          225 230 235 240
          Tyr Tyr Cys Ala Lys His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met Asp
                          245 250 255
          Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Thr Thr Thr Pro
                      260 265 270
          Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu
                  275 280 285
          Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His
              290 295 300
          Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu
          305 310 315 320
          Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr
                          325 330 335
          Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe
                      340 345 350
          Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg
                  355 360 365
          Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser
              370 375 380
          Arg Ser Ala Asp Ala Pro Ala Tyr Lys Gln Gly Gln Asn Gln Leu Tyr
          385 390 395 400
          Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys
                          405 410 415
          Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn
                      420 425 430
          Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu
                  435 440 445
          Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly
              450 455 460
          His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr
          465 470 475 480
          Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
                          485 490
           <![CDATA[ <210> 258]]>
           <![CDATA[ <211> 491]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 258]]>
          Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
          1 5 10 15
          His Ala Ala Arg Pro Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu
                      20 25 30
          Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln
                  35 40 45
          Asp Ile Ser Lys Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Gln Ala
              50 55 60
          Pro Arg Leu Leu Ile Tyr His Thr Ser Arg Leu His Ser Gly Ile Pro
          65 70 75 80
          Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile
                          85 90 95
          Ser Ser Leu Gln Pro Glu Asp Phe Ala Val Tyr Phe Cys Gln Gln Gly
                      100 105 110
          Asn Thr Leu Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
                  115 120 125
          Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
              130 135 140
          Gly Gly Gly Ser Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val
          145 150 155 160
          Lys Pro Ser Glu Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Val Ser
                          165 170 175
          Leu Pro Asp Tyr Gly Val Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly
                      180 185 190
          Leu Glu Trp Ile Gly Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr Gln
                  195 200 205
          Ser Ser Leu Lys Ser Arg Val Thr Ile Ser Lys Asp Asn Ser Lys Asn
              210 215 220
          Gln Val Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val
          225 230 235 240
          Tyr Tyr Cys Ala Lys His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met Asp
                          245 250 255
          Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Thr Thr Thr Pro
                      260 265 270
          Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu
                  275 280 285
          Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His
              290 295 300
          Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu
          305 310 315 320
          Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr
                          325 330 335
          Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe
                      340 345 350
          Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg
                  355 360 365
          Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser
              370 375 380
          Arg Ser Ala Asp Ala Pro Ala Tyr Lys Gln Gly Gln Asn Gln Leu Tyr
          385 390 395 400
          Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys
                          405 410 415
          Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn
                      420 425 430
          Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu
                  435 440 445
          Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly
              450 455 460
          His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr
          465 470 475 480
          Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
                          485 490
           <![CDATA[ <210> 259]]>
           <![CDATA[ <211> 491]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 259]]>
          Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
          1 5 10 15
          His Ala Ala Arg Pro Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu
                      20 25 30
          Val Lys Pro Ser Glu Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Val
                  35 40 45
          Ser Leu Pro Asp Tyr Gly Val Ser Trp Ile Arg Gln Pro Pro Gly Lys
              50 55 60
          Gly Leu Glu Trp Ile Gly Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr
          65 70 75 80
          Ser Ser Ser Leu Lys Ser Arg Val Thr Ile Ser Lys Asp Asn Ser Lys
                          85 90 95
          Asn Gln Val Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala
                      100 105 110
          Val Tyr Tyr Cys Ala Lys His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met
                  115 120 125
          Asp Tyr Trp Gly Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ser Gly Gly Gly
              130 135 140
          Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
          145 150 155 160
          Ser Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro
                          165 170 175
          Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Asp Ile Ser Lys
                      180 185 190
          Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
                  195 200 205
          Ile Tyr His Thr Ser Arg Leu His Ser Gly Ile Pro Ala Arg Phe Ser
              210 215 220
          Gly Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln
          225 230 235 240
          Pro Glu Asp Phe Ala Val Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro
                          245 250 255
          Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Thr Thr Thr Pro
                      260 265 270
          Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu
                  275 280 285
          Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His
              290 295 300
          Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu
          305 310 315 320
          Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr
                          325 330 335
          Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe
                      340 345 350
          Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg
                  355 360 365
          Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser
              370 375 380
          Arg Ser Ala Asp Ala Pro Ala Tyr Lys Gln Gly Gln Asn Gln Leu Tyr
          385 390 395 400
          Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys
                          405 410 415
          Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn
                      420 425 430
          Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu
                  435 440 445
          Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly
              450 455 460
          His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr
          465 470 475 480
          Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
                          485 490
           <![CDATA[ <210> 260]]>
           <![CDATA[ <211> 491]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 260]]>
          Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
          1 5 10 15
          His Ala Ala Arg Pro Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu
                      20 25 30
          Val Lys Pro Ser Glu Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Val
                  35 40 45
          Ser Leu Pro Asp Tyr Gly Val Ser Trp Ile Arg Gln Pro Pro Gly Lys
              50 55 60
          Gly Leu Glu Trp Ile Gly Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr
          65 70 75 80
          Gln Ser Ser Leu Lys Ser Arg Val Thr Ile Ser Lys Asp Asn Ser Lys
                          85 90 95
          Asn Gln Val Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala
                      100 105 110
          Val Tyr Tyr Cys Ala Lys His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met
                  115 120 125
          Asp Tyr Trp Gly Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ser Gly Gly Gly
              130 135 140
          Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
          145 150 155 160
          Ser Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro
                          165 170 175
          Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Asp Ile Ser Lys
                      180 185 190
          Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
                  195 200 205
          Ile Tyr His Thr Ser Arg Leu His Ser Gly Ile Pro Ala Arg Phe Ser
              210 215 220
          Gly Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln
          225 230 235 240
          Pro Glu Asp Phe Ala Val Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro
                          245 250 255
          Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Thr Thr Thr Pro
                      260 265 270
          Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu
                  275 280 285
          Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His
              290 295 300
          Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu
          305 310 315 320
          Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr
                          325 330 335
          Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe
                      340 345 350
          Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg
                  355 360 365
          Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser
              370 375 380
          Arg Ser Ala Asp Ala Pro Ala Tyr Lys Gln Gly Gln Asn Gln Leu Tyr
          385 390 395 400
          Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys
                          405 410 415
          Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn
                      420 425 430
          Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu
                  435 440 445
          Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly
              450 455 460
          His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr
          465 470 475 480
          Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
                          485 490
           <![CDATA[ <210> 261]]>
           <![CDATA[ <211> 491]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 261]]>
          Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
          1 5 10 15
          His Ala Ala Arg Pro Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu
                      20 25 30
          Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln
                  35 40 45
          Asp Ile Ser Lys Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Gln Ala
              50 55 60
          Pro Arg Leu Leu Ile Tyr His Thr Ser Arg Leu His Ser Gly Ile Pro
          65 70 75 80
          Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile
                          85 90 95
          Ser Ser Leu Gln Pro Glu Asp Phe Ala Val Tyr Phe Cys Gln Gln Gly
                      100 105 110
          Asn Thr Leu Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
                  115 120 125
          Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
              130 135 140
          Gly Gly Gly Ser Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val
          145 150 155 160
          Lys Pro Ser Glu Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Val Ser
                          165 170 175
          Leu Pro Asp Tyr Gly Val Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly
                      180 185 190
          Leu Glu Trp Ile Gly Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr Asn
                  195 200 205
          Ser Ser Leu Lys Ser Arg Val Thr Ile Ser Lys Asp Asn Ser Lys Asn
              210 215 220
          Gln Val Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val
          225 230 235 240
          Tyr Tyr Cys Ala Lys His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met Asp
                          245 250 255
          Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Thr Thr Thr Pro
                      260 265 270
          Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu
                  275 280 285
          Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His
              290 295 300
          Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu
          305 310 315 320
          Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr
                          325 330 335
          Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe
                      340 345 350
          Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg
                  355 360 365
          Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser
              370 375 380
          Arg Ser Ala Asp Ala Pro Ala Tyr Lys Gln Gly Gln Asn Gln Leu Tyr
          385 390 395 400
          Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys
                          405 410 415
          Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn
                      420 425 430
          Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu
                  435 440 445
          Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly
              450 455 460
          His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr
          465 470 475 480
          Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
                          485 490
           <![CDATA[ <210> 262]]>
           <![CDATA[ <211> 491]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 262]]>
          Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
          1 5 10 15
          His Ala Ala Arg Pro Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu
                      20 25 30
          Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln
                  35 40 45
          Asp Ile Ser Lys Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Gln Ala
              50 55 60
          Pro Arg Leu Leu Ile Tyr His Thr Ser Arg Leu His Ser Gly Ile Pro
          65 70 75 80
          Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile
                          85 90 95
          Ser Ser Leu Gln Pro Glu Asp Phe Ala Val Tyr Phe Cys Gln Gln Gly
                      100 105 110
          Asn Thr Leu Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
                  115 120 125
          Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
              130 135 140
          Gly Gly Gly Ser Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val
          145 150 155 160
          Lys Pro Ser Glu Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Val Ser
                          165 170 175
          Leu Pro Asp Tyr Gly Val Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly
                      180 185 190
          Leu Glu Trp Ile Gly Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr Asn
                  195 200 205
          Ser Ser Leu Lys Ser Arg Val Thr Ile Ser Lys Asp Asn Ser Lys Asn
              210 215 220
          Gln Val Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val
          225 230 235 240
          Tyr Tyr Cys Ala Lys His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met Asp
                          245 250 255
          Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Thr Thr Thr Pro
                      260 265 270
          Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu
                  275 280 285
          Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His
              290 295 300
          Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu
          305 310 315 320
          Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr
                          325 330 335
          Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe
                      340 345 350
          Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg
                  355 360 365
          Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser
              370 375 380
          Arg Ser Ala Asp Ala Pro Ala Tyr Lys Gln Gly Gln Asn Gln Leu Tyr
          385 390 395 400
          Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys
                          405 410 415
          Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn
                      420 425 430
          Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu
                  435 440 445
          Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly
              450 455 460
          His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr
          465 470 475 480
          Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
                          485 490
           <![CDATA[ <210> 263]]>
           <![CDATA[ <211> 491]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 263]]>
          Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
          1 5 10 15
          His Ala Ala Arg Pro Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu
                      20 25 30
          Val Lys Pro Ser Glu Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Val
                  35 40 45
          Ser Leu Pro Asp Tyr Gly Val Ser Trp Ile Arg Gln Pro Pro Gly Lys
              50 55 60
          Gly Leu Glu Trp Ile Gly Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr
          65 70 75 80
          Asn Ser Ser Leu Lys Ser Arg Val Thr Ile Ser Lys Asp Asn Ser Lys
                          85 90 95
          Asn Gln Val Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala
                      100 105 110
          Val Tyr Tyr Cys Ala Lys His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met
                  115 120 125
          Asp Tyr Trp Gly Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ser Gly Gly Gly
              130 135 140
          Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
          145 150 155 160
          Ser Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro
                          165 170 175
          Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Asp Ile Ser Lys
                      180 185 190
          Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
                  195 200 205
          Ile Tyr His Thr Ser Arg Leu His Ser Gly Ile Pro Ala Arg Phe Ser
              210 215 220
          Gly Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln
          225 230 235 240
          Pro Glu Asp Phe Ala Val Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro
                          245 250 255
          Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Thr Thr Thr Pro
                      260 265 270
          Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu
                  275 280 285
          Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His
              290 295 300
          Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu
          305 310 315 320
          Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr
                          325 330 335
          Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe
                      340 345 350
          Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg
                  355 360 365
          Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser
              370 375 380
          Arg Ser Ala Asp Ala Pro Ala Tyr Lys Gln Gly Gln Asn Gln Leu Tyr
          385 390 395 400
          Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys
                          405 410 415
          Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn
                      420 425 430
          Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu
                  435 440 445
          Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly
              450 455 460
          His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr
          465 470 475 480
          Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
                          485 490
           <![CDATA[ <210> 264]]>
           <![CDATA[ <211> 486]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 264]]>
          Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
          1 5 10 15
          His Ala Ala Arg Pro Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu
                      20 25 30
          Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln
                  35 40 45
          Asp Ile Ser Lys Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Gln Ala
              50 55 60
          Pro Arg Leu Leu Ile Tyr His Thr Ser Arg Leu His Ser Gly Ile Pro
          65 70 75 80
          Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile
                          85 90 95
          Ser Ser Leu Gln Pro Glu Asp Phe Ala Val Tyr Phe Cys Gln Gln Gly
                      100 105 110
          Asn Thr Leu Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
                  115 120 125
          Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln
              130 135 140
          Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu Thr
          145 150 155 160
          Leu Ser Leu Thr Cys Thr Val Ser Gly Val Ser Leu Pro Asp Tyr Gly
                          165 170 175
          Val Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile Gly
                      180 185 190
          Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr Asn Ser Ser Leu Lys Ser
                  195 200 205
          Arg Val Thr Ile Ser Lys Asp Asn Ser Lys Asn Gln Val Ser Leu Lys
              210 215 220
          Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Lys
          225 230 235 240
          His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr Trp Gly Gln Gly
                          245 250 255
          Thr Leu Val Thr Val Ser Ser Thr Thr Thr Pro Ala Pro Arg Pro Pro
                      260 265 270
          Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu
                  275 280 285
          Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp
              290 295 300
          Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly
          305 310 315 320
          Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg
                          325 330 335
          Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln
                      340 345 350
          Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu
                  355 360 365
          Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala
              370 375 380
          Pro Ala Tyr Lys Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu
          385 390 395 400
          Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp
                          405 410 415
          Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu
                      420 425 430
          Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile
                  435 440 445
          Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr
              450 455 460
          Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met
          465 470 475 480
          Gln Ala Leu Pro Pro Arg
                          485
           <![CDATA[ <210> 265]]>
           <![CDATA[ <211> 45]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 265]]>
          Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala
          1 5 10 15
          Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly
                      20 25 30
          Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp
                  35 40 45
           <![CDATA[ <210> 266]]>
           <![CDATA[ <211> 24]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 266]]>
          Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu
          1 5 10 15
          Ser Leu Val Ile Thr Leu Tyr Cys
                      20
           <![CDATA[ <210> 267]]>
           <![CDATA[ <211> 72]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 267]]>
          atctacatct gggcgccctt ggccggggact tgtggggtcc ttctcctgtc actggttatc 60
          accctttact gc 72
           <![CDATA[ <210> 268]]>
           <![CDATA[ <211> 230]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 268]]>
          Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe
          1 5 10 15
          Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
                      20 25 30
          Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
                  35 40 45
          Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val
              50 55 60
          Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser
          65 70 75 80
          Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
                          85 90 95
          Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser
                      100 105 110
          Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
                  115 120 125
          Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln
              130 135 140
          Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
          145 150 155 160
          Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
                          165 170 175
          Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu
                      180 185 190
          Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser
                  195 200 205
          Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
              210 215 220
          Leu Ser Leu Gly Lys Met
          225 230
           <![CDATA[ <210> 269]]>
           <![CDATA[ <211> 135]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 269]]>
          accacgacgc cagcgccgcg accaccaaca ccggcgccca ccatcgcgtc gcagcccctg 60
          tccctgcgcc cagaggcgtg ccggccagcg gcggggggcg cagtgcacac gagggggctg 120
          gacttcgcct gtgat 135
           <![CDATA[ <210> 270]]>
           <![CDATA[ <211> 690]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 270]]>
          gagagcaagt acggccctcc ctgcccccct tgccctgccc ccgagttcct gggcggaccc 60
          agcgtgttcc tgttcccccc caagcccaag gacaccctga tgatcagccg gacccccgag 120
          gtgacctgtg tggtggtgga cgtgtcccag gaggacccccg aggtccagtt caactggtac 180
          gtggacggcg tggaggtgca caacgccaag accaagcccc gggaggagca gttcaatagc 240
          acctaccggg tggtgtccgt gctgaccgtg ctgcaccagg actggctgaa cggcaaggaa 300
          tacaagtgta aggtgtccaa caagggcctg cccagcagca tcgagaaaac catcagcaag 360
          gccaagggcc agcctcggga gccccaggtg tacaccctgc cccctagcca agaggagatg 420
          accaagaacc aggtgtccct gacctgcctg gtgaagggct tctaccccag cgacatcgcc 480
          gtggagtggg agagcaacgg ccagcccgag aacaactaca agaccacccc ccctgtgctg 540
          gacagcgacg gcagcttctt cctgtacagc cggctgaccg tggacaagag ccggtggcag 600
          gagggcaacg tctttagctg ctccgtgatg cacgaggccc tgcacaacca ctacacccag 660
          aagagcctga gcctgtccct gggcaagatg 690
           <![CDATA[ <210> 271]]>
           <![CDATA[ <211> 282]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 271]]>
          Arg Trp Pro Glu Ser Pro Lys Ala Gln Ala Ser Ser Val Pro Thr Ala
          1 5 10 15
          Gln Pro Gln Ala Glu Gly Ser Leu Ala Lys Ala Thr Thr Ala Pro Ala
                      20 25 30
          Thr Thr Arg Asn Thr Gly Arg Gly Gly Glu Glu Lys Lys Lys Glu Lys
                  35 40 45
          Glu Lys Glu Glu Gln Glu Glu Arg Glu Thr Lys Thr Pro Glu Cys Pro
              50 55 60
          Ser His Thr Gln Pro Leu Gly Val Tyr Leu Leu Thr Pro Ala Val Gln
          65 70 75 80
          Asp Leu Trp Leu Arg Asp Lys Ala Thr Phe Thr Cys Phe Val Val Gly
                          85 90 95
          Ser Asp Leu Lys Asp Ala His Leu Thr Trp Glu Val Ala Gly Lys Val
                      100 105 110
          Pro Thr Gly Gly Val Glu Glu Gly Leu Leu Glu Arg His Ser Asn Gly
                  115 120 125
          Ser Gln Ser Gln His Ser Arg Leu Thr Leu Pro Arg Ser Leu Trp Asn
              130 135 140
          Ala Gly Thr Ser Val Thr Cys Thr Leu Asn His Pro Ser Leu Pro Pro
          145 150 155 160
          Gln Arg Leu Met Ala Leu Arg Glu Pro Ala Ala Gln Ala Pro Val Lys
                          165 170 175
          Leu Ser Leu Asn Leu Leu Ala Ser Ser Asp Pro Pro Glu Ala Ala Ser
                      180 185 190
          Trp Leu Leu Cys Glu Val Ser Gly Phe Ser Pro Pro Asn Ile Leu Leu
                  195 200 205
          Met Trp Leu Glu Asp Gln Arg Glu Val Asn Thr Ser Gly Phe Ala Pro
              210 215 220
          Ala Arg Pro Pro Pro Gln Pro Gly Ser Thr Thr Phe Trp Ala Trp Ser
          225 230 235 240
          Val Leu Arg Val Pro Ala Pro Pro Ser Pro Gln Pro Ala Thr Tyr Thr
                          245 250 255
          Cys Val Val Ser His Glu Asp Ser Arg Thr Leu Leu Asn Ala Ser Arg
                      260 265 270
          Ser Leu Glu Val Ser Tyr Val Thr Asp His
                  275 280
           <![CDATA[ <210> 272]]>
           <![CDATA[ <211> 847]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 272]]>
          aggtggcccg aaagtcccaa ggcccaggca tctagtgttc ctactgcaca gccccaggca 60
          gaaggcagcc tagccaaagc tactactgca cctgccacta cgcgcaatac tggccgtggc 120
          ggggaggaga agaaaaagga gaaagagaaa gaagaacagg aagagaggga gaccaagacc 180
          cctgaatgtc catcccatac ccagccgctg ggcgtctatc tcttgactcc cgcagtacag 240
          gacttgtggc ttagagataa ggccaccttt acatgtttcg tcgtgggctc tgacctgaag 300
          gatgcccatt tgacttggga ggttgccgga aaggtaccca caggggggggt tgaggaaggg 360
          ttgctggagc gccattccaa tggctctcag agccagcact caagactcac ccttccgaga 420
          tccctgtgga acgccggggac ctctgtcaca tgtactctaa atcatcctag cctgccccca 480
          cagcgtctga tggcccttag agagccagcc gcccaggcac cagttaagct tagcctgaat 540
          ctgctcgcca gtagtgatcc cccagaggcc gccagctggc tcttatgcga agtgtccggc 600
          tttagcccgc ccaacatctt gctcatgtgg ctggaggacc agcgagaagt gaacaccagc 660
          ggcttcgctc cagcccggcc cccaccccag ccgggttcta ccacattctg ggcctggagt 720
          gtcttaaggg tcccagcacc acctagcccc cagccagcca catacacctg tgttgtgtcc 780
          catgaagata gcaggacccct gctaaatgct tctaggagtc tggaggtttc ctacgtgact 840
          gaccatt 847
           <![CDATA[ <210> 273]]>
           <![CDATA[ <211> 10]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 273]]>
          Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
          1 5 10
           <![CDATA[ <210> 274]]>
           <![CDATA[ <211> 30]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 274]]>
          ggtggcggag gttctggagg tggaggttcc 30
           <![CDATA[ <210> 275]]>
           <![CDATA[ <211> 112]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Biology]]>
           <![CDATA[ <400> 275]]>
          Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Lys Gln Gly
          1 5 10 15
          Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr
                      20 25 30
          Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys
                  35 40 45
          Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys
              50 55 60
          Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg
          65 70 75 80
          Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala
                          85 90 95
          Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
                      100 105 110
           <![CDATA[ <210> 276]]>
           <![CDATA[ <211> 112]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 276]]>
          Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly
          1 5 10 15
          Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr
                      20 25 30
          Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys
                  35 40 45
          Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys
              50 55 60
          Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg
          65 70 75 80
          Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala
                          85 90 95
          Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
                      100 105 110
           <![CDATA[ <210> 277]]>
           <![CDATA[ <211> 336]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 277]]>
          agagtgaagt tcagcaggag cgcagacgcc cccgcgtaca agcagggcca gaaccagctc 60
          tataacgagc tcaatctagg acgaagagag gagtacgatg ttttggacaa gagacgtggc 120
          cgggaccctg agatgggggg aaagccgaga aggaagaacc ctcaggaagg cctgtacaat 180
          gaactgcaga aagataagat ggcggaggcc tacagtgaga ttgggatgaa aggcgagcgc 240
          cggaggggca aggggcacga tggcctttac cagggtctca gtacagccac caaggacacc 300
          tacgacgccc ttcacatgca ggccctgccc cctcgc 336
           <![CDATA[ <210> 278]]>
           <![CDATA[ <211> 336]]>
           <![CDATA[ <212> ]]>DNA
           <![CDATA[ <213> ]]> Artificial sequence
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 278]]>
          agagtgaagt tcagcaggag cgcagacgcc cccgcgtacc agcagggcca gaaccagctc 60
          tataacgagc tcaatctagg acgaagagag gagtacgatg ttttggacaa gagacgtggc 120
          cgggaccctg agatgggggg aaagccgaga aggaagaacc ctcaggaagg cctgtacaat 180
          gaactgcaga aagataagat ggcggaggcc tacagtgaga ttgggatgaa aggcgagcgc 240
          cggaggggca aggggcacga tggcctttac cagggtctca gtacagccac caaggacacc 300
          tacgacgccc ttcacatgca ggccctgccc cctcgc 336
           <![CDATA[ <210> 279]]>
           <![CDATA[ <211> 42]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 279]]>
          Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met
          1 5 10 15
          Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe
                      20 25 30
          Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu
                  35 40
           <![CDATA[ <210> 280]]>
           <![CDATA[ <211> 48]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 280]]>
          Gln Arg Arg Lys Tyr Arg Ser Asn Lys Gly Glu Ser Pro Val Glu Pro
          1 5 10 15
          Ala Glu Pro Cys Arg Tyr Ser Cys Pro Arg Glu Glu Glu Gly Ser Thr
                      20 25 30
          Ile Pro Ile Gln Glu Asp Tyr Arg Lys Pro Glu Pro Ala Cys Ser Pro
                  35 40 45
           <![CDATA[ <210> 281]]>
           <![CDATA[ <211> 126]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 281]]>
          aaacggggca gaaagaaact cctgtatata ttcaaacaac catttatgag accagtacaa 60
          actactcaag aggaagatgg ctgtagctgc cgatttccag aagaagaaga aggaggatgt 120
          gaactg 126
           <![CDATA[ <210> 282]]>
           <![CDATA[ <211> 144]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 282]]>
          caacgaagga aatatagatc aaacaaagga gaaagtcctg tggagcctgc agagccttgt 60
          cgttacagct gccccaggga ggaggagggc agcaccatcc ccatccagga ggattaccga 120
          aaaccggagc ctgcctgctc cccc 144
           <![CDATA[ <210> 283]]>
           <![CDATA[ <211> 21]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 283]]>
          Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
          1 5 10 15
          His Ala Ala Arg Pro
                      20
           <![CDATA[ <210> 284]]>
           <![CDATA[ <211> 16]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 284]]>
          Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr Asn Ser Ser Leu Lys Ser
          1 5 10 15
           <![CDATA[ <210> 285]]>
           <![CDATA[ <211> 1184]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 285]]>
          cgtgaggctc cggtgcccgt cagtgggcag agcgcacatc gcccacagtc cccgagaagt 60
          tgggggggagg ggtcggcaat tgaaccggtg cctagagaag gtggcgcggg gtaaactggg 120
          aaagtgatgt cgtgtactgg ctccgccttt ttcccgaggg tgggggagaa ccgtatataa 180
          gtgcagtagt cgccgtgaac gttctttttc gcaacgggtt tgccgccaga acacaggtaa 240
          gtgccgtgtg tggttcccgc gggcctggcc tctttacggg ttatggccct tgcgtgcctt 300
          gaattacttc cacctggctg cagtacgtga ttcttgatcc cgagcttcgg gttggaagtg 360
          ggtgggagag ttcgaggcct tgcgcttaag gagccccttc gcctcgtgct tgagttgagg 420
          cctggcctgg gcgctggggc cgccgcgtgc gaatctggtg gcaccttcgc gcctgtctcg 480
          ctgctttcga taagtctcta gccattaaa atttttgatg acctgctgcg acgctttttt 540
          tctggcaaga tagtcttgta aatgcgggcc aagatctgca cactggtatt tcggtttttg 600
          gggccgcggg cggcgacggg gcccgtgcgt cccagcgcac atgttcggcg aggcggggcc 660
          tgcgagcgcg gccaccgaga atcggacggg ggtagtctca agctggccgg cctgctctgg 720
          tgcctggcct cgcgccgccg tgtatcgccc cgccctgggc ggcaaggctg gcccggtcgg 780
          caccagttgc gtgagcggaa agatggccgc ttcccggccc tgctgcaggg agctcaaaat 840
          ggaggacgcg gcgctcggga gagcgggcgg gtgagtcacc cacacaaagg aaaagggcct 900
          ttccgtcctc agccgtcgct tcatgtgact ccacggagta ccgggcgccg tccaggcacc 960
          tcgattagtt ctcgagcttt tggagtacgt cgtctttagg ttggggggag gggttttatg 1020
          cgatggagtt tccccaacact gagtgggtgg agactgaagt taggccagct tggcacttga 1080
          tgtaattctc cttggaattt gccctttttg agtttggatc ttggttcatt ctcaagcctc 1140
          agacagtggt tcaaagtttt tttcttccat ttcaggtgtc gtga 1184
           <![CDATA[ <210> 286]]>
           <![CDATA[ <211> 448]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 286]]>
          Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
          1 5 10 15
          Thr Leu Ser Leu Thr Cys Thr Val Ser Asp Tyr Ser Ile Thr Ser Asp
                      20 25 30
          Tyr Ala Trp Asn Trp Ile Arg Gln Phe Pro Gly Lys Gly Leu Glu Trp
                  35 40 45
          Met Gly Tyr Ile Ser Tyr Ser Gly Ser Thr Ser Tyr Asn Pro Ser Leu
              50 55 60
          Lys Ser Arg Ile Thr Ile Ser Arg Asp Thr Ser Lys Asn Gln Phe Ser
          65 70 75 80
          Leu Gln Leu Asn Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Ser Phe Asp Tyr Ala His Ala 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 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 Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
                          165 170 175
          Ser Ser Gly Leu Tyr Ser Leu Ser 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 Arg 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 Asn 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
           <![CDATA[ <210> 287]]>
           <![CDATA[ <211> 214]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 287]]>
          Asp Ile Val Leu Thr Gln Ser Pro Ala Phe Leu Ser Val Thr Pro Gly
          1 5 10 15
          Glu Lys Val Thr Phe Thr Cys Gln Ala Ser Gln Ser Ile Gly Thr Ser
                      20 25 30
          Ile His Trp Tyr Gln Gln Lys Thr Asp Gln Ala Pro Lys Leu Leu Ile
                  35 40 45
          Lys Tyr Ala Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Val Glu Ala
          65 70 75 80
          Glu Asp Ala Ala Asp Tyr Tyr Cys Gln Gln Ile Asn Ser Trp Pro Thr
                          85 90 95
          Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala
                      100 105 110
          Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
                  115 120 125
          Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
              130 135 140
          Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
          145 150 155 160
          Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
                          165 170 175
          Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
                      180 185 190
          Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
                  195 200 205
          Phe Asn Arg Gly Glu Cys
              210
           <![CDATA[ <210> 288]]>
           <![CDATA[ <211> 6]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 288]]>
          Ser Asp Tyr Ala Trp Asn
          1 5
           <![CDATA[ <210> 289]]>
           <![CDATA[ <211> 16]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 289]]>
          Tyr Ile Ser Tyr Ser Gly Ser Thr Ser Tyr Asn Pro Ser Leu Lys Ser
          1 5 10 15
           <![CDATA[ <210> 290]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 290]]>
          Phe Asp Tyr Ala His Ala Met Asp Tyr
          1 5
           <![CDATA[ <210> 291]]>
           <![CDATA[ <211> 11]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 291]]>
          Gln Ala Ser Gln Ser Ile Gly Thr Ser Ile His
          1 5 10
           <![CDATA[ <210> 292]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 292]]>
          Tyr Ala Ser Glu Ser Ile Ser
          1 5
           <![CDATA[ <210> 293]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 293]]>
          Gln Gln Ile Asn Ser Trp Pro Thr Thr
          1 5
           <![CDATA[ <210> 294]]>
           <![CDATA[ <211> 143]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 294]]>
          Gly Ala Pro Ala Gly Pro Leu Ile Val Pro Tyr Asn Leu Pro Leu Pro
          1 5 10 15
          Gly Gly Val Val Pro Arg Met Leu Ile Thr Ile Leu Gly Thr Val Lys
                      20 25 30
          Pro Asn Ala Asn Arg Ile Ala Leu Asp Phe Gln Arg Gly Asn Asp Val
                  35 40 45
          Ala Phe His Phe Asn Pro Arg Phe Asn Glu Asn Asn Asn Arg Arg Val Ile
              50 55 60
          Val Cys Asn Thr Lys Leu Asp Asn Asn Trp Gly Arg Glu Glu Arg Gln
          65 70 75 80
          Ser Val Phe Pro Phe Glu Ser Gly Lys Pro Phe Lys Ile Gln Val Leu
                          85 90 95
          Val Glu Pro Asp His Phe Lys Val Ala Val Asn Asp Ala His Leu Leu
                      100 105 110
          Gln Tyr Asn His Arg Val Lys Lys Leu Asn Glu Ile Ser Lys Leu Gly
                  115 120 125
          Ile Ser Gly Asp Ile Asp Ile Thr Ser Ala Ser Tyr Thr Met Ile
              130 135 140
           <![CDATA[ <210> 295]]>
           <![CDATA[ <211> 16]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 295]]>
          Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr Gln Ser Ser Leu Lys Ser
          1 5 10 15
           <![CDATA[ <210> 296]]>
           <![CDATA[ <211> 16]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 296]]>
          Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr Ser Ser Ser Leu Lys Ser
          1 5 10 15
           <![CDATA[ <210> 297]]>
           <![CDATA[ <211> 137]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 297]]>
          Met Glu Phe Gly Leu Ser Trp Val Phe Leu Val Ala Leu Leu Arg Gly
          1 5 10 15
          Val Gln Cys Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln
                      20 25 30
          Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
                  35 40 45
          Ser Val Tyr Gly Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
              50 55 60
          Glu Trp Val Ala Ile Ile Trp Tyr Asp Gly Asp Asn Gln Tyr Tyr Ala
          65 70 75 80
          Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn
                          85 90 95
          Thr Leu Tyr Leu Gln Met Asn Gly Leu Arg Ala Glu Asp Thr Ala Val
                      100 105 110
          Tyr Tyr Cys Ala Arg Asp Leu Arg Thr Gly Pro Phe Asp Tyr Trp Gly
                  115 120 125
          Gln Gly Thr Leu Val Thr Val Ser Ser
              130 135
           <![CDATA[ <210> 298]]>
           <![CDATA[ <211> 126]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Human process]]> column
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 298]]>
          Met Leu Pro Ser Gln Leu Ile Gly Phe Leu Leu Leu Trp Val Pro Ala
          1 5 10 15
          Ser Arg Gly Glu Ile Val Leu Thr Gln Ser Pro Asp Phe Gln Ser Val
                      20 25 30
          Thr Pro Lys Glu Lys Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile
                  35 40 45
          Gly Ser Ser Leu His Trp Tyr Gln Gln Lys Pro Asp Gln Ser Pro Lys
              50 55 60
          Leu Leu Ile Lys Tyr Ala Ser Gln Ser Phe Ser Gly Val Pro Ser Arg
          65 70 75 80
          Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asn Ser
                          85 90 95
          Leu Glu Ala Glu Asp Ala Ala Ala Tyr Tyr Cys His Gln Ser Ser Ser
                      100 105 110
          Leu Pro Phe Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys
                  115 120 125
           <![CDATA[ <210> 299]]>
           <![CDATA[ <211> 63]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 299]]>
          atggccctgc ctgtgacagc cctgctgctg cctctggctc tgctgctgca tgccgctaga 60
          ccc 63
           <![CDATA[ <210> 300]]>
           <![CDATA[ <211> 63]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 300]]>
          atggccctcc ctgtcaccgc cctgctgctt ccgctggctc ttctgctcca cgccgctcgg 60
          ccc 63
           <![CDATA[ <210> 301]]>
           <![CDATA[ <211> 72]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 301]]>
          atctacattt gggcccctct ggctggtact tgcggggtcc tgctgctttc actcgtgatc 60
          actcttact gt 72
           <![CDATA[ <210> 302]]>
           <![CDATA[ <211> 126]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 302]]>
          aagcgcggtc ggaagaagct gctgtacatc tttaagcaac ccttcatgag gcctgtgcag 60
          actactcaag aggaggacgg ctgttcatgc cggttcccag aggagggagga aggcggctgc 120
          gaactg 126
           <![CDATA[ <210> 303]]>
           <![CDATA[ <211> 336]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 303]]>
          cgcgtgaaat tcagccgcag cgcagatgct ccagcctaca agcaggggca gaaccagctc 60
          tacaacgaac tcaatcttgg tcggagagag gagtacgacg tgctggacaa gcggagagga 120
          cgggacccag aaatgggcgg gaagccgcgc agaaagaatc cccaagaggg cctgtacaac 180
          gagctccaaa aggtaagat ggcagaagcc tatagcgaga ttggtatgaa agggggaacgc 240
          agaagaggca aaggccacga cggactgtac cagggactca gcaccgccac caaggacacc 300
          tatgacgctc ttcacatgca ggccctgccg cctcgg 336
           <![CDATA[ <210> 304]]>
           <![CDATA[ <211> 5]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 304]]>
          Gly Gly Gly Gly Ser
          1 5
           <![CDATA[ <210> 305]]>
           <![CDATA[ <211> 150]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 305]]>
          Pro Gly Trp Phe Leu Asp Ser Pro Asp Arg Pro Trp Asn Pro Pro Thr
          1 5 10 15
          Phe Ser Pro Ala Leu Leu Val Val Thr Glu Gly Asp Asn Ala Thr Phe
                      20 25 30
          Thr Cys Ser Phe Ser Asn Thr Ser Glu Ser Phe Val Leu Asn Trp Tyr
                  35 40 45
          Arg Met Ser Pro Ser Asn Gln Thr Asp Lys Leu Ala Ala Phe Pro Glu
              50 55 60
          Asp Arg Ser Gln Pro Gly Gln Asp Cys Arg Phe Arg Val Thr Gln Leu
          65 70 75 80
          Pro Asn Gly Arg Asp Phe His Met Ser Val Val Arg Ala Arg Arg Asn
                          85 90 95
          Asp Ser Gly Thr Tyr Leu Cys Gly Ala Ile Ser Leu Ala Pro Lys Ala
                      100 105 110
          Gln Ile Lys Glu Ser Leu Arg Ala Glu Leu Arg Val Thr Glu Arg Arg
                  115 120 125
          Ala Glu Val Pro Thr Ala His Pro Ser Pro Ser Pro Arg Pro Ala Gly
              130 135 140
          Gln Phe Gln Thr Leu Val
          145 150
           <![CDATA[ <210> 306]]>
           <![CDATA[ <211> 450]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 306]]>
          cccggatggt ttctggactc tccggatcgc ccgtggaatc ccccaacctt ctcaccggca 60
          ctcttggttg tgactgaggg cgataatgcg accttcacgt gctcgttctc caacacctcc 120
          gaatcattcg tgctgaactg gtaccgcatg agcccgtcaa accagaccga caagctcgcc 180
          gcgtttccgg aagatcggtc gcaaccggga caggattgtc ggttccgcgt gactcaactg 240
          ccgaatggca gagacttcca catgagcgtg gtccgcgcta ggcgaaacga ctccgggacc 300
          tacctgtgcg gagccatctc gctggcgcct aaggcccaaa tcaaagagag cttgagggcc 360
          gaactgagag tgaccgagcg cagagctgag gtgccaactg cacatccatc cccatcgcct 420
          cggcctgcgg ggcagtttca gaccctggtc 450
           <![CDATA[ <210> 307]]>
           <![CDATA[ <211> 394]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 307]]>
          Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
          1 5 10 15
          His Ala Ala Arg Pro Pro Gly Trp Phe Leu Asp Ser Pro Asp Arg Pro
                      20 25 30
          Trp Asn Pro Pro Thr Phe Ser Pro Ala Leu Leu Val Val Thr Glu Gly
                  35 40 45
          Asp Asn Ala Thr Phe Thr Cys Ser Phe Ser Asn Thr Ser Glu Ser Phe
              50 55 60
          Val Leu Asn Trp Tyr Arg Met Ser Pro Ser Asn Gln Thr Asp Lys Leu
          65 70 75 80
          Ala Ala Phe Pro Glu Asp Arg Ser Gln Pro Gly Gln Asp Cys Arg Phe
                          85 90 95
          Arg Val Thr Gln Leu Pro Asn Gly Arg Asp Phe His Met Ser Val Val
                      100 105 110
          Arg Ala Arg Arg Asn Asp Ser Gly Thr Tyr Leu Cys Gly Ala Ile Ser
                  115 120 125
          Leu Ala Pro Lys Ala Gln Ile Lys Glu Ser Leu Arg Ala Glu Leu Arg
              130 135 140
          Val Thr Glu Arg Arg Ala Glu Val Pro Thr Ala His Pro Ser Pro Ser
          145 150 155 160
          Pro Arg Pro Ala Gly Gln Phe Gln Thr Leu Val Thr Thr Thr Pro Ala
                          165 170 175
          Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser
                      180 185 190
          Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr
                  195 200 205
          Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala
              210 215 220
          Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys
          225 230 235 240
          Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met
                          245 250 255
          Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe
                      260 265 270
          Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg
                  275 280 285
          Ser Ala Asp Ala Pro Ala Tyr Lys Gln Gly Gln Asn Gln Leu Tyr Asn
              290 295 300
          Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg
          305 310 315 320
          Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro
                          325 330 335
          Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala
                      340 345 350
          Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Arg Gly Lys Gly His
                  355 360 365
          Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp
              370 375 380
          Ala Leu His Met Gln Ala Leu Pro Pro Arg
          385 390
           <![CDATA[ <210> 308]]>
           <![CDATA[ <211> 1182]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 308]]>
          atggccctcc ctgtcactgc cctgcttctc cccctcgcac tcctgctcca cgccgctaga 60
          ccaccccggat ggtttctgga ctctccggat cgcccgtgga atcccccaac cttctcaccg 120
          gcactcttgg ttgtgactga gggcgataat gcgaccttca cgtgctcgtt ctccaacacc 180
          tccgaatcat tcgtgctgaa ctggtaccgc atgagcccgt caaaccagac cgacaagctc 240
          gccgcgtttc cggaagatcg gtcgcaaccg ggacaggatt gtcggttccg cgtgactcaa 300
          ctgccgaatg gcagagactt ccacatgagc gtggtccgcg ctaggcgaaa cgactccggg 360
          acctacctgt gcggagccat ctcgctggcg cctaaggccc aaatcaaaga gagcttgagg 420
          gccgaactga gagtgaccga gcgcagagct gaggtgccaa ctgcacatcc atccccatcg 480
          cctcggcctg cggggcagtt tcagaccctg gtcacgacca ctccggcgcc gcgcccaccg 540
          actccggccc caactatcgc gagccagccc ctgtcgctga ggccggaagc atgccgccct 600
          gccgccggag gtgctgtgca tacccgggga ttggacttcg catgcgacat ctacatttgg 660
          gctcctctcg ccggaacttg tggcgtgctc cttctgtccc tggtcatcac cctgtactgc 720
          aagcggggtc ggaaaaagct tctgtacatt ttcaagcagc ccttcatgag gcccgtgcaa 780
          accacccagg aggaggacgg ttgctcctgc cggttccccg aagaggaaga aggaggttgc 840
          gagctgcgcg tgaagttctc ccggagcgcc gacgcccccg cctataagca gggccagaac 900
          cagctgtaca acgaactgaa cctgggacgg cgggaagagt acgatgtgct ggacaagcgg 960
          cgcggccggg accccgaaat gggcgggaag cctagaagaa agaaccctca ggaaggcctg 1020
          tataacgagc tgcagaagga caagatggcc gaggcctact ccgaaattgg gatgaaggga 1080
          gagcggcgga ggggaaaggg gcacgacggc ctgtaccaag gactgtccac cgccaccaag 1140
          gacacatacg atgccctgca catgcaggcc cttccccctc gc 1182
           <![CDATA[ <210> 309]]>
           <![CDATA[ <211> 4]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 309]]>
          Gly Gly Gly Ser
          1               
           <![CDATA[ <210> 310]]>
           <![CDATA[ <211> 50]]>
           <![CDATA[ <212> RNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 310]]>
          aaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaa 50
           <![CDATA[ <210> 311]]>
           <![CDATA[ <211> 373]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 311]]>
          Pro Gly Trp Phe Leu Asp Ser Pro Asp Arg Pro Trp Asn Pro Pro Thr
          1 5 10 15
          Phe Ser Pro Ala Leu Leu Val Val Thr Glu Gly Asp Asn Ala Thr Phe
                      20 25 30
          Thr Cys Ser Phe Ser Asn Thr Ser Glu Ser Phe Val Leu Asn Trp Tyr
                  35 40 45
          Arg Met Ser Pro Ser Asn Gln Thr Asp Lys Leu Ala Ala Phe Pro Glu
              50 55 60
          Asp Arg Ser Gln Pro Gly Gln Asp Cys Arg Phe Arg Val Thr Gln Leu
          65 70 75 80
          Pro Asn Gly Arg Asp Phe His Met Ser Val Val Arg Ala Arg Arg Asn
                          85 90 95
          Asp Ser Gly Thr Tyr Leu Cys Gly Ala Ile Ser Leu Ala Pro Lys Ala
                      100 105 110
          Gln Ile Lys Glu Ser Leu Arg Ala Glu Leu Arg Val Thr Glu Arg Arg
                  115 120 125
          Ala Glu Val Pro Thr Ala His Pro Ser Pro Ser Pro Arg Pro Ala Gly
              130 135 140
          Gln Phe Gln Thr Leu Val Thr Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr
          145 150 155 160
          Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala
                          165 170 175
          Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe
                      180 185 190
          Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val
                  195 200 205
          Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys
              210 215 220
          Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr
          225 230 235 240
          Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Glu
                          245 250 255
          Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro
                      260 265 270
          Ala Tyr Lys Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly
                  275 280 285
          Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro
              290 295 300
          Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr
          305 310 315 320
          Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly
                          325 330 335
          Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln
                      340 345 350
          Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln
                  355 360 365
          Ala Leu Pro Pro Arg
              370
           <![CDATA[ <210> 312]]>
           <![CDATA[ <211> 35]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 312]]>
          Thr Lys Lys Lys Tyr Ser Ser Ser Val His Asp Pro Asn Gly Glu Tyr
          1 5 10 15
          Met Phe Met Arg Ala Val Asn Thr Ala Lys Lys Ser Arg Leu Thr Asp
                      20 25 30
          Val Thr Leu
                  35
           <![CDATA[ <210> 313]]>
           <![CDATA[ <211> 105]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 313]]>
          acaaaaaaga agtattcatc cagtgtgcac gaccctaacg gtgaatacat gttcatgaga 60
          gcagtgaaca cagccaaaaa atccagactc acagatgtga cccta 105
           <![CDATA[ <210> 314]]>
           <![CDATA[ <211> 69]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 314]]>
          Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala
          1 5 10 15
          Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly
                      20 25 30
          Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Phe Trp Leu
                  35 40 45
          Pro Ile Gly Cys Ala Ala Phe Val Val Val Cys Ile Leu Gly Cys Ile
              50 55 60
          Leu Ile Cys Trp Leu
          65
           <![CDATA[ <210> 315]]>
           <![CDATA[ <211> 207]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 31]]>5
          accacgacgc cagcgccgcg accaccaaca ccggcgccca ccatcgcgtc gcagcccctg 60
          tccctgcgcc cagaggcgtg ccggccagcg gcggggggcg cagtgcacac gagggggctg 120
          gacttcgcct gtgatttctg gttacccata ggatgtgcag cctttgttgt agtctgcatt 180
          ttgggatgca tacttatttg ttggctt 207
           <![CDATA[ <210> 316]]>
           <![CDATA[ <211> 41]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 316]]>
          Arg Ser Lys Arg Ser Arg Leu Leu His Ser Asp Tyr Met Asn Met Thr
          1 5 10 15
          Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala Pro
                      20 25 30
          Pro Arg Asp Phe Ala Ala Tyr Arg Ser
                  35 40
           <![CDATA[ <210> 317]]>
           <![CDATA[ <211> 123]]>
           <![CDATA[ <212>DNA]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 317]]>
          aggagtaaga ggagcaggct cctgcacagt gactacatga acatgactcc ccgccgcccc 60
          gggcccaccc gcaagcatta ccagccctat gccccaccac gcgacttcgc agcctatcgc 120
          tcc 123
           <![CDATA[ <210> 318]]>
           <![CDATA[ <211> 22]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 318]]>
          Tyr Gly Arg Lys Lys Arg Arg Gln Arg Arg Arg Leu Tyr Arg Ser Pro
          1 5 10 15
          Ala Met Pro Glu Asn Leu
                      20
           <![CDATA[ <210> 319]]>
           <![CDATA[ <211> 10]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 319]]>
          Gly Val Ser Leu Pro Asp Tyr Gly Val Ser
          1 5 10
           <![CDATA[ <210> 320]]>
           <![CDATA[ <211> 16]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> biological]]>
           <![CDATA[ <400> 320]]>
          Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr Asn Ser Ala Leu Lys Ser
          1 5 10 15
           <![CDATA[ <210> 321]]>
           <![CDATA[ <211> 445]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> heavy chain]]>
           <![CDATA[ <400> 321]]>
          Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
          1 5 10 15
          Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Ser Tyr
                      20 25 30
          Gly Val His Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
                  35 40 45
          Gly Val Ile Tyr Ala Asp Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
              50 55 60
          Ser Arg Val Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Val Ser Leu
          65 70 75 80
          Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
                          85 90 95
          Arg Ala Tyr Gly Asn Tyr Trp Tyr Ile Asp Val 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 Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
                          165 170 175
          Ser Ser Gly Leu Tyr Ser Leu Ser 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 Pro Val Ala 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 Ala 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 Val 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 Lys 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 Lys
                  435 440 445
           <![CDATA[ <210> 322]]>
           <![CDATA[ <211> 214]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> light chain]]>
           <![CDATA[ <400> 322]]>
          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 Glu Ser Val Ser Asn Asp
                      20 25 30
          Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile
                  35 40 45
          Asn Tyr Ala Phe His Arg Phe Thr Gly Val Pro Asp Arg Phe Ser Gly
              50 55 60
          Ser Gly Tyr Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala
          65 70 75 80
          Glu Asp Val Ala Val Tyr Tyr Cys His Gln Ala Tyr Ser Ser Pro Tyr
                          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 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
           <![CDATA[ <210> 323]]>
           <![CDATA[ <211> 118]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> VHC]]>
           <![CDATA[ <400> 323]]>
          Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
          1 5 10 15
          Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Ser Tyr
                      20 25 30
          Gly Val His Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
                  35 40 45
          Gly Val Ile Tyr Ala Asp Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
              50 55 60
          Ser Arg Val Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Val Ser Leu
          65 70 75 80
          Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
                          85 90 95
          Arg Ala Tyr Gly Asn Tyr Trp Tyr Ile Asp Val Trp Gly Gln Gly Thr
                      100 105 110
          Thr Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 324]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> Tislelizumab LHC]]>
           <![CDATA[ <400> 324]]>
          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 Glu Ser Val Ser Asn Asp
                      20 25 30
          Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile
                  35 40 45
          Asn Tyr Ala Phe His Arg Phe Thr Gly Val Pro Asp Arg Phe Ser Gly
              50 55 60
          Ser Gly Tyr Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala
          65 70 75 80
          Glu Asp Val Ala Val Tyr Tyr Cys His Gln Ala Tyr Ser Ser Pro Tyr
                          85 90 95
          Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
                      100 105
           <![CDATA[ <210> 325]]>
           <![CDATA[ <211> 10]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223>HCDR1]]>
           <![CDATA[ <400> 325]]>
          Gly Phe Ser Leu Thr Ser Tyr Gly Val His
          1 5 10
           <![CDATA[ <210> 326]]>
           <![CDATA[ <211> 16]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223>HCDR2]]>
           <![CDATA[ <400> 326]]>
          Val Ile Tyr Ala Asp Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys Ser
          1 5 10 15
           <![CDATA[ <210> 327]]>
           <![CDATA[ <211> 12]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223>HCDR3]]>
           <![CDATA[ <400> 327]]>
          Ala Arg Ala Tyr Gly Asn Tyr Trp Tyr Ile Asp Val
          1 5 10
           <![CDATA[ <210> 328]]>
           <![CDATA[ <211> 11]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223>LCDR1]]>
           <![CDATA[ <400> 328]]>
          Lys Ser Ser Glu Ser Val Ser Asn Asp Val Ala
          1 5 10
           <![CDATA[ <210> 329]]>
           <![CDATA[ <211> 7]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> LCDR2]]>
           <![CDATA[ <400> 329]]>
          Tyr Ala Phe His Arg Phe Thr
          1 5
           <![CDATA[ <210> 330]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial Sequence]]>
           <![CDATA[ <220>]]>
           <![CDATA[ <223> LCDR3]]>
           <![CDATA[ <400> 330]]>
          His Gln Ala Tyr Ser Ser Pro Tyr Thr
          1 5
          
      

Claims (101)

A method of treating a proliferative disease in a subject in need thereof, the method comprising administering to the subject a TGF beta antibody and at least one additional therapeutic agent, wherein the TGF beta antibody is dosed at about 1400 mg to about 2100 mg or about 20 mg/kg to about 45 mg/kg every two or three weeks. The method of claim 1, wherein the TGFβ antibody is administered at about 1400 mg every two weeks. The method according to claim 1, wherein the TGFβ antibody is administered once every two weeks at about 30 mg/kg. The method according to claim 1, wherein the TGFβ antibody is administered at about 2100 mg every two weeks, three weeks or four weeks. The method according to claim 1, wherein the TGFβ antibody is administered at about 20 mg/kg every three weeks. The method according to claim 1, wherein the TGFβ antibody is administered at about 45 mg/kg every three weeks. The method according to any one of claims 1 to 6, wherein the TGFβ antibody comprises heavy chain CDR1, CDR2 and CDR3 of SEQ ID NO: 1, 2 and 3, respectively, and SEQ ID NO: 4, 5 and 6 light chain CDR1, CDR2 and CDR3. The method according to any one of claims 1 to 7, wherein the TGFβ antibody comprises a heavy chain variable region and a light chain variable region shown in the amino acid sequences of SEQ ID NO: 7 and 8, respectively. The method according to any one of claims 1 to 8, wherein the TGFβ antibody comprises a heavy chain and a light chain respectively shown in the amino acid sequences of SEQ ID NO: 9 and 10. The method according to any one of claims 1 to 9, wherein the TGFβ antibody is a monoclonal antibody. The method according to any one of claims 1 to 10, wherein the TGFβ antibody is a fully human antibody. The method of any one of claims 1 to 11, wherein the TGFβ inhibitor is administered over a period of about 30 minutes. The method according to any one of claims 1 to 12, wherein the additional therapeutic agent is one or more of the following: PD-1 inhibitors, gemcitabine, nab-paclitaxel, leucovorin calcium folate), leucovorin, fluorouracil (5-FU), oxaliplatin (eloxatin), bevacizumab, irinotecan, cyclophosphamide, capecitabine, or topotecan. The method of any one of claims 1-13, wherein the additional therapeutic agent comprises a PD-1 inhibitor. The method according to claim 14, wherein the PD-1 inhibitor is an anti-PD-1 antibody. The method according to claim 15, wherein the anti-PD-1 antibody is PDR001 (spartalizumab), BGB-A317 (tislelizumab), or BGB-108. The method according to claim 16, wherein the anti-PD-1 antibody is tislelizumab. The method according to any one of claims 15-17, wherein the anti-PD-1 antibody is administered at 300 mg per 28-day cycle or 200 mg per 21-day cycle. The method of any one of claims 1-18, wherein the additional therapeutic agent comprises gemcitabine. The method according to claim 19, wherein the gemcitabine is administered at about 1000 mg/m ² . The method of claim 20, wherein gemcitabine is administered on days 1, 8 and 15 of a 28-day cycle. The method as claimed in item 19, wherein gemcitabine is administered at 675 mg/m ² . The method of any one of claims 19-22, wherein gemcitabine is administered on days 1 and 8 of a 21-day cycle. The method of any one of claims 1-23, wherein the additional therapeutic agent comprises nab-paclitaxel. The method of claim 24, wherein nab-paclitaxel is administered at about 125 mg/m ² . The method of claim 24 or 25, wherein nab-paclitaxel is administered on days 1, 8 and 15 of a 28-day cycle. The method of any one of claims 1-26, wherein the additional therapeutic agent comprises gemcitabine and nab-paclitaxel. The method of any one of claims 1-27, wherein the additional therapeutic agent comprises a PD-1 inhibitor, gemcitabine, and nab-paclitaxel. The method of any one of claims 1-28, wherein the additional therapeutic agent comprises bevacizumab. The method of claim 29, wherein the bevacizumab is administered at about 5 mg/kg. The method of claim 29 or 30, wherein the bevacizumab is administered on days 1 and 15 of a 28-day cycle. The method of any one of claims 1-31, wherein the additional therapeutic agent comprises 5-fluorouracil. The method of claim 32, wherein 5-fluorouracil is administered at about 400 mg/m ² . The method of claim 32, wherein 5-fluorouracil is administered at about 2400 mg/m ² . The method of any one of claims 32-34, wherein 5-fluorouracil is administered on days 1 and 15 of a 28-day cycle. The method of any one of claims 32-35, wherein the 5-fluorouracil is administered as an intravenous bolus. The method according to any one of claims 32-36, wherein 5-fluorouracil is injected intravenously at 400 mg/m ² followed by 2400 mg/m ² on days 1 and 15 of each 28-day cycle It is administered as a continuous intravenous infusion over 46 hours. The method of any one of claims 1-37, wherein the additional therapeutic agent comprises folinic acid or levofolinic acid. The method according to claim 38, wherein folinic acid or levofolinic acid is administered at about 400 mg/m ² or 200 mg/m ² , respectively. The method of claim 38 or 39, wherein folinic acid or levofolinic acid is administered on day 1 and day 15 of a 28-day cycle. The method of any one of claims 1-40, wherein the additional therapeutic agent comprises oxaliplatin. The method of claim 41, wherein oxaliplatin is administered at about 85 mg/m ² . The method of claim 41 or 42, wherein oxaliplatin is administered on days 1 and 15 of a 28-day cycle. The method of any one of claims 1-43, wherein the additional therapeutic agent comprises irinotecan. The method of claim 44, wherein irinotecan is administered at about 180 mg/m ² . The method of claim 44 or 45, wherein irinotecan is administered on days 1 and 15 of a 28-day cycle. The method of any one of claims 1-46, wherein the additional therapeutic agent comprises bevacizumab, 5-fluorouracil, folinic acid (or leucovorin), and oxaliplatin. The method of any one of claims 1-47, wherein the additional therapeutic agent includes a PD-1 inhibitor, bevacizumab, 5-fluorouracil, folinic acid (or leucovorin), and oxali platinum. The method of any one of claims 1-46, wherein the additional therapeutic agent comprises bevacizumab, 5-fluorouracil, leucovorin, and irinotecan. The method of any one of claims 1-46 and 49, wherein the additional therapeutic agent comprises a PD-1 inhibitor, bevacizumab, 5-fluorouracil, leucovorin, and irinotecan. The method of any one of claims 1-50, wherein the TGFβ antibody and the one or more additional therapeutic agents are administered to the subject over 2 or more cycles. The method of any one of claims 1-51, wherein the proliferative disease is pancreatic cancer or colorectal cancer. The method of any one of claims 1 to 52, wherein the additional therapeutic agent comprises cyclophosphamide and topotecan. The method as claimed in item 53, wherein cyclophosphamide is administered at 250 mg/m ² . The method of claim 53 or 54, wherein cyclophosphamide is administered for five (5) days. The method of claim 55, wherein the five (5) days are consecutive days. The method of any one of claims 53-56, wherein topotecan is administered at 0.75 mg/m ² . The method of any one of claims 53-57, wherein topotecan is administered for five (5) days. The method of claim 58, wherein the five (5) days are consecutive days. The method of any one of claims 1-59, wherein the proliferative disease is neuroblastoma or osteosarcoma. The method of any one of claims 1-60, wherein the subject is a pediatric patient. A method of treating pancreatic adenocarcinoma in a subject in need thereof, the method comprising administering to the subject 2100 mg of TGFβ antibody, 1000 mg/ ^m of gemcitabine, and 125 mg/ ^m of albumin-bound Paclitaxel, wherein the TGFβ antibody is administered on days 1 and 15 of a 28-day cycle, and gemcitabine and nab-paclitaxel are administered on days 1, 8, and 15 of the cycle, and wherein the The TGFβ antibody comprises heavy chain CDR1, CDR2 and CDR3 of SEQ ID NO: 1, 2 and 3, respectively, and light chain CDR1, CDR2 and CDR3 of SEQ ID NO: 4, 5 and 6, respectively. The method of claim 62, further comprising administering a PD-1 inhibitor to the patient. The method according to claim 63, wherein the PD-1 inhibitor is spartalizumab or tislelizumab. The method of claim 64, wherein the PD-1 inhibitor is spartakizumab and is administered at 400 mg every four (4) weeks. The method of claim 64, wherein the PD-inhibitor is tislelizumab and is administered at 100 mg weekly. The method of claim 66, wherein tislelizumab is administered at 400 mg every four (4) weeks. The method of any one of claims 62-67, wherein the TGFβ antibody, gemcitabine, and nab-paclitaxel (and optionally a PD-1 inhibitor) are administered to the subject. The method of any one of claims 62-68, wherein the TGFβ antibody, gemcitabine and nab-paclitaxel (and optionally a PD-1 inhibitor) are administered to the subject intravenously. A method of treating colorectal cancer in a subject in need thereof, the method comprising administering to the subject 2100 mg of TGFβ antibody, 5 mg/kg of bevacizumab, 400 to 2400 mg/m of ⁵ - Fluorouracil, folinic acid at 400 mg/ ^m2 , and oxaliplatin at 85 mg/ ^m2 , where the TGFβ antibody, bevacizumab, 5-fluorouracil, leucovorin, and oxaliplatin are given in 28-day cycles Administration on days 1 and 15 of , and wherein the TGFβ antibody comprises heavy chain CDR1, CDR2 and CDR3 of SEQ ID NO: 1, 2 and 3, respectively, and the heavy chain of SEQ ID NO: 4, 5 and 6, respectively Light chain CDR1, CDR2 and CDR3. The method of claim 70, wherein the TGFβ antibody, bevacizumab, 5-fluorouracil, leucovorin, and oxaliplatin are administered to the subject in 2 or more cycles. The method of claim 70 or 71, wherein the TGFβ antibody, bevacizumab, 5-fluorouracil, leucovorin, and oxaliplatin are administered to the subject intravenously. The method according to any one of claims 70-72, wherein 5-fluorouracil is administered as an intravenous bolus injection of 400 mg/m2 followed by a continuous intravenous infusion of 2400 mg/m2 for 46 hours. A method of treating colorectal cancer in a subject in need thereof, the method comprising administering to the subject 2100 mg of TGFβ antibody, 5 mg/kg of bevacizumab, 400 to 2400 mg/m of ⁵ - Fluorouracil, folinic acid at 400 mg/ ^m2 , and irinotecan at 180 mg/ ^m2 , where the TGFβ antibody, bevacizumab, 5-fluorouracil, leucovorin, and irinotecan are administered on day 2 of a 28-day cycle Administered on day 1 and day 15, and wherein the TGFβ antibody comprises heavy chain CDR1, CDR2, and CDR3 of SEQ ID NO: 1, 2, and 3, respectively, and light chain of SEQ ID NO: 4, 5, and 6, respectively CDR1, CDR2 and CDR3. The method of claim 74, wherein the TGFβ antibody, bevacizumab, 5-fluorouracil, leucovorin, and irinotecan are administered to the subject in 2 or more cycles. The method of claim 74 or 75, wherein the TGFβ antibody, bevacizumab, 5-fluorouracil, leucovorin, and irinotecan are administered to the subject intravenously. The method of any one of claims 74-76, wherein 5-fluorouracil is administered as an intravenous bolus injection of 400 mg/ ^m2 followed by a continuous intravenous infusion of 2400 mg/m2 for 46 hours. A method of treating neuroblastoma in a subject in need thereof, the method comprising administering to the subject 20, 30, or 45 mg/kg of an antibody to TGFβ, 250 mg/ ^m of cyclophosphamide, and 0.75 mg/ ^m of topotecan, wherein the TGFβ antibody is administered every 3 weeks and cyclophosphamide and topotecan are administered on days 1 to 5 of a 21-day cycle, and wherein the TGFβ antibody comprises heavy chain CDR1, CDR2 and CDR3 of SEQ ID NO: 1, 2 and 3, respectively, and light chain CDR1, CDR2 and CDR3 of SEQ ID NO: 4, 5 and 6, respectively. A method of treating osteosarcoma in a subject in need thereof, the method comprising administering to the subject 20, 30, or 45 mg/kg of TGFβ antibody and 675 mg/ ^m of gemcitabine, wherein the TGFβ antibody per 3-week administration and gemcitabine is administered on days 1 and 8 of a 21-day cycle, and wherein the TGFβ antibody comprises heavy chain CDR1, CDR2, and CDR3 of SEQ ID NO: 1, 2, and 3, respectively, and Light chain CDR1, CDR2 and CDR3 of SEQ ID NO: 4, 5 and 6. The method of claim 78 or 79, wherein the subject has a body weight of 20 kg or less and receives administration of the TGFβ antibody at 45 mg/kg. The method of claim 78 or 79, wherein the subject has a body weight of 20 kg and 40 kg and therebetween and receives an administration of the TGFβ antibody at 30 mg/kg. The method according to claim 78 or 79, wherein the subject has a body weight of 40 kg or more and receives 20 mg/kg of the TGFβ antibody. The method of claim 78 or 79, wherein the subject is under eighteen (18) years old. The method of any one of claims 1 to 83, wherein the TGFβ inhibitor is administered concurrently with the one or more additional therapeutic agents. The method of any one of claims 1 to 83, wherein the TGFβ inhibitor is administered before the one or more additional therapeutic agents. The method of any one of claims 1 to 83, wherein the TGFβ inhibitor is administered after the one or more additional therapeutic agents. The method of any one of claims 1 to 83, wherein the TGFβ inhibitor and/or the one or more additional therapeutic agents are administered until remission. A method of treating pancreatic adenocarcinoma or colorectal cancer in a subject in need thereof, the method comprising administering to the subject: (a) 2100 mg of TGFβ antibody, (b) ^{intravenously} at 500 mg/m Bolus followed by continuous infusion of 5-fluorouracil at 2400 mg/ ^m2 over 46 hours, (c) leucovorin (leucovorin) administered intravenously at 400 mg/ ^m2 or intravenously at 200 mg/ ^m2 Leucovorin administered internally, (d) irinotecan administered intravenously at 180 mg/m ² , and (e) bevacizumab at 5 mg/kg, wherein the TGFβ antibody was administered on day 1 of a 28-day cycle (and optionally on Day 15), and wherein the 5-fluorouracil, folinic acid (or leucovorin), irinotecan, and bevacizumab are administered on Days 1 and 15 of the 28-day cycle Administration, and wherein the TGFβ antibody comprises heavy chain CDR1, CDR2 and CDR3 of SEQ ID NO: 1, 2 and 3, respectively, and light chain CDR1, CDR2 and CDR3 of SEQ ID NO: 4, 5 and 6, respectively. A method of treating pancreatic adenocarcinoma or colorectal cancer in a subject in need thereof, the method comprising administering to the subject: (a) 2100 mg of TGFβ antibody, (b) ^{intravenously} at 500 mg/m Bolus followed by continuous infusion of 5-fluorouracil at 2400 mg/ ^m2 over 46 hours, (c) leucovorin (leucovorin) administered intravenously at 400 mg/ ^m2 or intravenously at 200 mg/ ^m2 Leucovorin administered internally, (d) oxaliplatin administered intravenously at 85 mg/m ² , and (e) bevacizumab at 5 mg/kg, wherein the TGFβ antibody was administered on day 1 of a 28-day cycle day (and optionally on day 15), and wherein the 5-fluorouracil, leucovorin (or leucovorin), oxaliplatin, and bevacizumab are administered on days 1 and 1 of the 28-day cycle 15 days of administration, and wherein the TGFβ antibody comprises heavy chain CDR1, CDR2 and CDR3 of SEQ ID NO: 1, 2 and 3, respectively. The method of claim 88 or 89, further comprising administering a PD-1 inhibitor to the patient. The method of claim 90, wherein the PD-1 inhibitor is tislelizumab having a heavy chain of SEQ ID NO: 321 and a light chain of SEQ ID NO: 322. The method of claim 91, wherein tislelizumab is administered intravenously at 300 mg on day 1 of each 28-day cycle. The method according to any one of claims 88-92, wherein the TGFβ antibody, 5-fluorouracil, folinic acid (or leucovorin), oxaliplatin, irinotecan, bevacizumab or PD-1 The inhibitor is administered to the subject over 2 or more cycles. A method of treating gastric cancer in a subject in need thereof, the method comprising administering to the subject: (a) 2100 mg of TGFβ antibody, (b) oxaliplatin administered ^{intravenously} at 130 mg/m , and (c) capecitabine orally twice daily at 1000 mg/m ² , wherein the TGFβ antibody is administered once every three weeks, and wherein oxaliplatin is administered on Day 1 of a Q3W cycle, And capecitabine is administered on days 1-14 of the cycle, and wherein the TGFβ antibody comprises heavy chain CDR1, CDR2, and CDR3 of SEQ ID NO: 1, 2, and 3, respectively, and SEQ ID NO: Light chain CDR1, CDR2 and CDR3 of 4, 5 and 6. A method of treating gastric cancer in a subject in need thereof, the method comprising administering to the subject: (a) 2100 mg of TGFβ antibody, (b) oxaliplatin administered ^{intravenously} at 130 mg/m , and (c) capecitabine orally twice daily at 1000 mg/m ² , wherein the TGFβ antibody is administered once every two weeks, and wherein oxaliplatin is administered on Day 1 of a Q3W cycle , and capecitabine is administered on days 1-14 of the cycle, and wherein the TGFβ antibody comprises heavy chain CDR1, CDR2, and CDR3 of SEQ ID NO: 1, 2, and 3, respectively, and SEQ ID NO: : Light chain CDR1, CDR2 and CDR3 of 4, 5 and 6. A method of treating gastric cancer in a subject in need thereof, the method comprising administering to the subject: (a) 2100 mg of TGFβ antibody, (b) oxaliplatin administered ^{intravenously} at 85 mg/m , (c) folinic acid (folinic acid) administered intravenously at 400 mg/ ^m2 or levofolinic acid administered intravenously at 200 mg/ ^m2 , and (d) folinic acid administered intravenously at 400 mg/ ^m2 Bolus followed by 5-fluorouracil administered intravenously at 1200 mg/ ^m2 daily, wherein the TGFβ antibody is administered every three weeks, and wherein the oxaliplatin, leucovorin (or leucovorin), 5-fluorouracil Administered on day 1 of a Q2W cycle, and the 1200 mg is administered intravenously on days 1-2 of the cycle, and wherein the TGFβ antibody comprises heavy chain CDR1, CDR2 and CDR3, and light chain CDR1, CDR2 and CDR3 of SEQ ID NO: 4, 5 and 6, respectively. A method of treating gastric cancer in a subject in need thereof, the method comprising administering to the subject: (a) 2100 mg of TGFβ antibody, (b) oxaliplatin administered ^{intravenously} at 85 mg/m , (c) folinic acid (folinic acid) administered intravenously at 400 mg/ ^m2 or levofolinic acid administered intravenously at 200 mg/ ^m2 , and (d) folinic acid administered intravenously at 400 mg/ ^m2 Bolus followed by 5-fluorouracil administered intravenously at 1200 mg/ ^m2 daily, wherein the TGFβ antibody is administered biweekly, and wherein the oxaliplatin, leucovorin (or leucovorin), 5-fluorouracil Administered on day 1 of a Q2W cycle, and the 1200 mg is administered intravenously on days 1-2 of the cycle, and wherein the TGFβ antibody comprises heavy chain CDR1, CDR2 and CDR3, and light chain CDR1, CDR2 and CDR3 of SEQ ID NO: 4, 5 and 6, respectively. The method of claim 94 or 97, further comprising administering a PD-1 inhibitor to the patient. The method of claim 98, wherein the PD-1 inhibitor is tislelizumab having a heavy chain of SEQ ID NO: 321 and a light chain of SEQ ID NO: 322. The method of claim 99, wherein tislelizumab is administered intravenously at 300 mg on day 1 of each 28-day cycle. The method according to claim 99, wherein tislelizumab is administered intravenously at 200 mg every three weeks.

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