EA045913B1 - TIM-3 ANTAGONISTS FOR TREATMENT AND DIAGNOSIS OF ONCOLOGICAL DISEASES - Google Patents

Description

Link to the list of sequences submitted electronically to EFS-WEB

The contents of the electronically submitted sequence listing in an ASCII text file (name: 3338.093PC01_SequenceListing_ST25.txt; size: 717,820 bytes and creation date: August 24, 2018) filed with the application are incorporated herein by reference in their entirety.

BACKGROUND OF THE INVENTION

T-cell immunoglobulin and mucin domain-containing protein 3 (TIM3), also known as hepatitis A virus cellular receptor 2 (HAVCR2), is a type I transmembrane protein that functions as a key regulator of immune responses. TIM3 was originally identified on activated IFN-Y-producing T cells (eg, CD4+ type 1 helper T cells and CD8+ cytotoxic T cells), and was shown to induce T cell death or exhaustion upon binding to one of its ligands (i.e., phosphatidylserine, galectin-9, HMGB1, CEACAM-1, and ILT4). More recent studies have shown that TIM3 expression is also important for regulating the activity of a variety of innate immune cells (eg, macrophages, monocytes, dendritic cells, mast cells, and natural killer cells); see Han G. et al., Front Immunol. 4:449 (2013). Like many inhibitory receptors (eg, PD-1 and CTLA-4), TIM3 expression is associated with many types of chronic diseases, including cancer (eg, melanoma, lung, liver, ovarian, etc.). High expression of TIM3 has been found on tumor-infiltrating lymphocytes (TILs) and some tumors from patients with advanced melanoma, non-small cell lung cancer, or follicular B-cell non-Hodgkin lymphoma. And the presence of TIM3+ T cells has been described as an effective indicator of lung cancer progression, with higher expression associated with poor prognosis; see Anderson A.C. Cancer Immunol Res. 2: 393-8 (2014). Studies have also shown a direct relationship between TIM3 and the inhibitory receptor PD-1. For example, many tumor-specific T cells express both PD-1 and TIM3, and these T cells have been shown to be more dysfunctional compared to T cells that express only PD-1 or TIM3; see Fourcade J. et al., J Exp Med. 207: 2175-2186 (2010).

The recent development of several immune checkpoint pathway inhibitors (eg, YERVOY and OPDIVO) has begun to provide new immunotherapeutic approaches for the treatment of many types of diseases, including cancer. Although such inhibitors have had promising results, a large proportion of patients are refractory to such treatment; see Sharma P. et al., Cell 168: 707–723 (2017). Accordingly, there remains a need to tailor treatment regimens to specific subpopulations and, potentially, to individual patients in order to increase effectiveness and minimize side effects.

The essence of the invention

Provided herein is an in vitro method for determining whether a patient having cancer will respond to treatment with a TIM-3 antagonist, comprising determining the patient's serum soluble TIM-3 titer and, if (i) the serum soluble TIM-3 titer is higher than in healthy control subjects, or (ii) the serum titer of soluble TIM-3 is at least 2100, 2200, 2300, 2400 or 2500 pg/ml (as determined, for example, in the method described in the examples), that subject , is likely to respond to treatment with a TIM-3 antagonist.

Provided herein is an in vitro method for determining whether a patient having cancer will respond to treatment with a TIM-3 antagonist, comprising determining the percentage of CD8+ TILs that are TIM-3 positive, and if the percentage is greater than 10% 20%, 30%, 40%, 50%, 60%, or 70%, this subject is likely to respond to treatment with a TIM-3 antagonist.

Provided herein is an in vitro method for determining whether a patient having cancer will respond to treatment with a TIM-3 antagonist, including determining the percentage of naïve, central memory (CM), effector memory (EM), and effector TILs that are TIM -3 positive, and if the percentage of EM TIL cells and/or effector TILs that are positive for TIM-3 is higher than the percentage of naïve TILs and/or CM TILs that are positive for TIM-3, then that subject, most likely to respond to treatment with a TIM-3 antagonist. Provided herein is an in vitro method for determining whether a patient having cancer will respond to treatment with a TIM-3 antagonist, including determining the percentage of dendritic cells, macrophages and natural killer (NK) cells that are TIM-3 positive TILs patient, and if the percentage is higher than their percentage in control subjects (eg, matched cancer patients who do not respond to treatment with a TIM-3 antagonist), then that subject is likely to respond to treatment with a TIM-3 antagonist. Provided herein is an in vitro method for determining whether a patient with cancer will respond to treatment with a combination of a PD-1/PD-L1 axis antagonist and a TIM-3 antagonist, comprising determining the frequency of positive PD-1 expression on tumor-infiltrating lymphocytes ( TIL) and the frequency of expression of TIM-3-positive TILs in a subject, where coexpression of PD-1 and TIM-3 on at least 5% of the subject's CD8+ TILs indicates that the subject is likely to respond to treatment with a PD axis antagonist combination -1/PD-L1 and TIM-3 antagonist.

Also provided herein is a TIM-3 antagonist for use in the treatment of a subject having cancer, wherein the treatment includes: (1) (a) determining the serum titer of soluble TIM-3 in

- 1 045913 subject and (b) administration of a TIM-3 antagonist to the subject if (i) the serum titer of soluble TIM-3 is higher than that of healthy control subjects or (ii) the serum titer of soluble TIM-3 is at least 2100 , 2200, 2300, 2400 or 2500 pg/ml (as determined, for example, by the method described in the examples); (2) (a) determining the percentage of CD8+ TILs that are TIM-3 positive in the subject, and (b) administering a TIM-3 antagonist to the subject if the percentage exceeds 10%, 20%, 30%, 40%, 50%, 60% or 70%; (3) (a) determining the percentage of naïve, central memory (CM), effector memory (EM), and effector TILs that are TIM-3 positive, and (b) administering a TIM-3 antagonist to the subject if the percentage is EM TIL and/or effector TILs that are TIM-3 positive are higher than the percentage of naïve TILs and/or CM TILs that are TIM-3 positive; or (4) (a) determining the percentage of dendritic cells, macrophages, and natural killer (NK) cells that are TIM-3 positive in the subject's TILs, and (b) administering a TIM-3 antagonist to the subject if the percentage is higher, than in control subjects (eg, matched cancer patients who do not respond to treatment with a TIM-3 antagonist).

The present disclosure further provides a combination therapy comprising a PD-1/PD-L1 axis antagonist and a TIM-3 antagonist for use in treating a subject having cancer, wherein the treatment comprises (i) determining the frequency of positive PD-1 expression on tumor infiltrating lymphocytes (TILs) and the frequency of expression of TIM-3-positive TILs in the subject, and (ii) administration of combination therapy if at least 5% of CD8+ TILs coexpress PD-1 and TIM-3.

In some embodiments, the TIM-3 antagonist for use in treating a subject having cancer (eg, monotherapy or combination therapy) is an anti-TIM3 antibody.

In some embodiments, an anti-TIM3 antibody comprises (i) a heavy chain variable region comprising CDR1, CDR2 and CDR3, and (ii) a heavy chain variable region comprising CDR1, CDR2 and CDR3, wherein:

(a) the CDR1 heavy chain contains an amino acid sequence selected from the group consisting of SEQ ID NO: 23-27;

(b) the CDR2 heavy chain contains an amino acid sequence selected from the group consisting of SEQ ID NO: 28-38;

(c) the CDR3 heavy chain contains an amino acid sequence selected from the group consisting of SEQ ID NO: 39-49;

(d) the CDR1 light chain contains an amino acid sequence selected from the group consisting of SEQ ID NOs: 50 and 51;

(e) the CDR2 light chain contains an amino acid sequence selected from the group consisting of SEQ ID NOs: 52 and 53; and (f) the CDR3 light chain comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 54-57.

In some embodiments, the TILs are CD4+ TILs.

In some embodiments, the TILs are CD8+ TILs.

In some embodiments, the PD-1/PD-L1 axis antagonist comprises an anti-PD-1 antibody or an anti-PD-L1 antibody.

In some embodiments, the anti-PD-1 antibody comprises nivolumab, pembrolizumab, MEDI0608, AMP-224, PDR001, BGB-A317, or any combination thereof.

In some embodiments, the anti-PD-L1 antibody comprises BMS-936559, MPDL3280A, MEDI4736, MSB0010718C, or any combination thereof.

In some embodiments, the cancer includes colon, kidney, or lung cancer.

Embodiments of the Invention

Embodiment 1. A method for determining whether a subject having cancer will respond to treatment with a TIM-3 antagonist, comprising determining a serum soluble TIM-3 titer in the subject and, if the serum soluble TIM-3 titer is higher than that of control subjects, this subject will most likely respond to treatment with a TIM-3 antagonist.

Embodiment 2. The method of Embodiment 1, wherein if a subject's serum soluble TIM-3 titer is at least 10% higher than that of control subjects, the subject is likely to respond to treatment with a TIM-antagonist. 3.

Embodiment 3. The method of Embodiment 1 or 2, wherein if the serum titer of soluble TIM-3 is at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90 % or 100% (two-fold) higher in a subject than in control subjects, that subject is more likely to respond to treatment with a TIM-3 antagonist.

Embodiment 4. The method of any one of Embodiments 1-3, wherein if the subject has a serum soluble TIM-3 titer of at least 2100, 2200, 2300, 2400, or 2500 pg/mL (as defined in, e.g., method described in the Examples), the subject is likely to respond to treatment with a TIM-3 antagonist.

- 2 045913

Embodiment 5. The method of any one of embodiments 1-4, wherein if the subject has a serum soluble TIM-3 titer of at least 3000 pg/ml (as determined, for example, in the method described in the examples), the the subject is likely to respond to treatment with a TIM-3 antagonist.

Embodiment 6. The method of any one of Embodiments 1-5, further comprising administering a therapeutically effective amount of a TIM-3 antagonist to a subject whose serum soluble TIM-3 titer is higher than that of control subjects.

Embodiment 7. A method of treating a subject having cancer, comprising administering to a subject having cancer and a serum soluble TIM-3 titer that is higher than that of control subjects, a therapeutically effective amount of a TIM-3 antagonist.

Embodiment 8. The method of Embodiment 7, wherein the subject has a serum soluble TIM-3 titer that is at least 10% higher in the subject than in the control subjects.

Embodiment 9. The method of Embodiment 7, wherein the subject has a serum soluble TIM-3 titer that is at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90 % or 100% (twofold) higher in this subject than the serum titer of soluble TIM-3 in control subjects.

Embodiment 10. The method of any one of embodiments 7-9, wherein the subject has a serum soluble TIM-3 titer of at least 2500 pg/ml (as determined, for example, in the method described in the examples).

Embodiment 11. The method of any one of embodiments 7-10, wherein the subject has a serum soluble TIM-3 titer of at least 3000 pg/ml (as determined, for example, in the method described in the examples).

Embodiment 12. The method of any one of embodiments 7-11, further comprising measuring a serum titer of soluble TIM-3 prior to administration.

Embodiment 13. A method of treating a subject having cancer with a TIM-3 antagonist, comprising determining a serum titer of soluble TIM-3 in the subject and, if the serum titer of soluble TIM-3 is higher than that of control subjects, administering to the subject a therapeutically effective amount of TIM-3 antagonist.

Embodiment 14. The method of Embodiment 13, wherein if a subject has a serum soluble TIM-3 titer that is at least 10% higher than control subjects, the subject is administered a therapeutically effective amount of a TIM-3 antagonist.

Embodiment 15. The method of Embodiment 13 or 14, wherein if the subject has a serum soluble TIM-3 titer that is at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% (two-fold) higher than subjects in the control group, the subject is administered a therapeutically effective amount of a TIM-3 antagonist.

Embodiment 16. The method of any one of embodiments 13-15, wherein if the subject has a serum soluble TIM-3 titer of at least 2100, 2200, 2300, 2400, or 2500 pg/ml (as defined in, e.g., method described in the Examples), the subject is administered a therapeutically effective amount of a TIM-3 antagonist.

Embodiment 17. The method of any one of embodiments 13-16, wherein if the subject has a serum soluble TIM-3 titer of at least 3000 pg/ml (as determined, for example, in the method described in the examples), this the subject is administered a therapeutically effective amount of a TIM-3 antagonist.

Embodiment 18. The method of any one of embodiments 1-17, wherein the soluble TIM-3 is differentially spliced soluble TIM-3 and/or exfoliated TIM3.

Embodiment 19. The method as in any one of embodiments 1-18, wherein the cancer is a solid tumor.

Embodiment 20. The method as in any one of embodiments 1-19, wherein the cancer is colon, kidney, or lung cancer.

Embodiment 21. The method of any one of embodiments 1-20, wherein the serum titer of soluble TIM-3 in control subjects is the arithmetic mean or mean titer of soluble TIM-3 of at least 10, 50, or 100 subjects.

Embodiment 22. The method of any one of embodiments 1-21, wherein the TIM-3 antagonist is a TIM-3 antibody.

Embodiment 23. The method of Embodiment 22, wherein the TIM-3 antibody comprises a heavy chain variable region comprising CDR1, CDR2 and CDR3 and a light chain variable region comprising CDR1, CDR2 and CDR3, wherein:

(a) the CDR1 heavy chain contains an amino acid sequence selected from the group consisting of SEQ ID NO: 23-27;

(b) the CDR2 heavy chain contains an amino acid sequence selected from the group with

- 3 045913 standing from SEQ ID NO: 28-38;

(c) the CDR3 heavy chain contains an amino acid sequence selected from the group consisting of SEQ ID NO: 39-49;

(d) the CDR1 light chain contains an amino acid sequence selected from the group consisting of SEQ ID NOs: 50 and 51;

(e) the CDR2 light chain contains an amino acid sequence selected from the group consisting of SEQ ID NOs: 52 and 53; and (f) the CDR3 light chain comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 54-57.

Embodiment 24. A method for determining whether a subject having cancer will respond to treatment with a combination of a PD-1/PD-L1 axis antagonist and a TIM-3 antagonist, comprising determining the frequency of positive expression of PD-1 on tumor infiltrating lymphocytes (TILs) and the frequency TIM-3 positive TILs of a subject, where coexpression of PD-1 and TIM-3 on at least 5% of the subject's CD8+ TILs indicates that the subject is likely to respond to treatment with a combination of a PD-1/PD- binding antagonist L1 and TIM3 antagonist.

Embodiment 25. The method of Embodiment 24, wherein coexpression of PD-1 and TIM-3 on at least 10%, 20%, 30%, or 40% of the subject's CD8+ TILs indicates that the subject is likely to , will respond to treatment with a combination of a PD-1/PD-L1 axis antagonist and a TIM3 antagonist.

Embodiment 26. The method of Embodiment 24 or 25, further comprising administering to a subject that has PD-1 and TIM-3 coexpression on at least 5% CD8+ TILs a combination of a PD-1/PD-L1 axis antagonist and an antagonist TIM3.

Embodiment 27. A method of treating a subject having cancer with a combination of a PD-1/PD-L1 axis antagonist and a TIM-3 antagonist, comprising administering to a subject having at least 5% coexpression of PD-1 and TIM-3 CD8+ TIL, a therapeutically effective amount of a combination of a PD-1/PD-L1 axis antagonist and a TIM-3 antagonist.

Embodiment 28. The method of Embodiment 27, wherein the subject has coexpression of PD-1 and TIM3 on at least 10%, 20%, 30%, 40% CD8+ TILs.

Embodiment 29. A method of treating a subject having cancer with a combination of a PD-1/PD-L1 axis antagonist and a TIM-3 antagonist, comprising determining the frequency of positive PD-1 expression on tumor infiltrating lymphocytes (TILs) and the frequency of TIM-3- positive TILs of the subject, and if PD-1 and TIM-3 are coexpressed on at least 5% of the subject's CD8+ TILs, then administering to that subject a combination of a PD-1/PD-L1 axis antagonist and a TIM-3 antagonist.

Embodiment 30. The method of Embodiment 29, wherein if PD-1 and TIM-3 are coexpressed on at least 10%, 20%, 30%, 40% of the subject's CD8+ TILs, the subject is administered a combination of a PD axis antagonist -1/PD-L1 and TIM-3 antagonist.

Embodiment 31. A method for determining whether a subject having cancer will respond to treatment with a TIM-3 antagonist, comprising determining the percentage of CD8+ TILs that are TIM-3 positive and if the percentage is greater than 10%, 20%, 30 %, 40%, 50%, 60%, or 70%, this subject is likely to respond to treatment with a TIM-3 antagonist.

Embodiment 32. A method of treating a subject having cancer with a TIM-3 antagonist, comprising administering to the subject whose CD8+ TIL percentage is greater than 10%, 20%, 30%, 40%, 50%, 60%, or 70%, a therapeutically effective amount of TIM-3 antagonist.

Embodiment 33. A method of treating a subject having cancer with a TIM-3 antagonist, comprising determining the percentage of CD8+ TILs that are TIM-3 positive and if the percentage is greater than 10%, 20%, 30%, 40%, 50% , 60% or 70%, administering to the subject a therapeutically effective amount of a TIM-3 antagonist.

Embodiment 34. A method for determining whether a subject having cancer will respond to treatment with a TIM-3 antagonist, comprising determining the percentage of naïve, SM, EM, and Teff TILs that are TIM-3 positive and if the percentage of effector TILs Memory T cells (EM) and/or effector T cells (Teff') positive for TIM-3 are higher than the percentage of TILs of naïve T cells and/or central memory T cells (CM T cells), which are positive for TIM-3, this subject is likely to respond to treatment with a TIM-3 antagonist.

Embodiment 35. The method of Embodiment 34, wherein the TILs are CD4+ TILs.

Embodiment 36. The method of Embodiment 34, wherein the TILs are CD8+ TILs.

Embodiment 37. The method of Embodiment 34, wherein frequencies are measured in CD4+ and CD8+ T cells, and if a higher percentage is observed in both CD4+ and CD8+ TIL cells, then that subject is more likely to respond to treatment with the antagonist TIM-3.

Embodiment 38. A method of treating a subject having cancer with a TIM-3 antagonist, comprising administering to the subject having a percentage of TIL effector memory T cells (EM) and/or effector T cells (Teff') positive for TIM-3, higher than percentage

- 4 045913

TILs of naive T cells and/or central memory T cells (CM T cells) that are positive for TIM-3, a therapeutically effective amount of a TIM-3 antagonist.

Embodiment 39. A method of treating a subject having cancer with a TIM-3 antagonist, comprising administering to the subject having a percentage of CD4+ TIL effector memory T cells (EM) and/or CD4+ effector T cells (Teff) positive for TIM-3 , higher than the percentage of CD4+ TIL naïve T cells and/or CD4+ central memory T cells (CM T cells) that are positive for TIM-3, a therapeutically effective amount of a TIM-3 antagonist.

Embodiment 40. A method of treating a subject having cancer with a TIM-3 antagonist, comprising administering to the subject having a percentage of CD8+ TIL effector memory T cells (EM) and/or CD8+ effector T cells (Teff) positive for TIM-3 , higher than the percentage of CD8+ TIL naïve T cells and/or CD8+ central memory T cells (CM T cells) that are positive for TIM-3, a therapeutically effective amount of a TIM-3 antagonist.

Embodiment 41. A method of treating a subject having cancer with a TIM-3 antagonist, comprising administering to the subject having (i) a percentage of CD4+ TIL effector memory T cells (EM) and/or CD4+ effector T cells (Teff') positive for TIM-3, higher than the percentage of CD4+ TIL naïve T cells and/or CD4+ central memory T cells (CM T cells) that are positive for TIM-3; and (ii) the percentage of CD8+ TIL effector memory (EM) T cells and/or CD8+ effector T cells (Teff”) positive for TIM-3 is higher than the percentage of CD8+ TIL naïve T cells and/or CD8+ central T cells -memory cells (SM T cells) that are positive for TIM-3, a therapeutically effective amount of a TIM-3 antagonist.

Embodiment 42. A method of treating a subject having cancer with a TIM-3 antagonist, comprising determining the percentage of naïve, SM, EM, and Teff TILs that are TIM-3 positive, and if the percentage of TIL effector memory (EM) cells and/or or effector T cells (Teff”) that are positive for TIM-3, higher than the percentage of TIL naïve T cells and/or central memory T cells (CM T cells) that are positive for TIM-3 administered to that subject a therapeutically effective amount of a TIM-3 antagonist.

Embodiment 43. The method of Embodiment 42, wherein the TILs are CD4+ TILs.

Embodiment 44. The method of Embodiment 42, wherein the TILs are CD8+ TILs.

Embodiment 45. The method of Embodiment 42, wherein frequencies are measured in CD4+ and CD8+ T cells, and if a higher percentage is observed in both CD4+ and CD8+ TIL cells, administering to the subject a therapeutically effective amount of a TIM-3 antagonist.

Embodiment 46. The method of any one of embodiments 34-45, wherein the difference in the level of TIM-3 positive cells is at least 50%.

Embodiment 47. The method of any one of embodiments 34-46, wherein the difference in the level of TIM-3 positive cells is at least 100%.

Embodiment 48. The method as in any one of Embodiments 34-47, wherein the naïve T cells are CCR7+CD45RO-, the Teff cells are CCR7-CD45RO-, the CM T cells are CCR7+CD45RO+, and EM T -cells are CCR7CD45RO+.

Embodiment 49. A method for determining whether a subject having cancer will respond to treatment with a TIM-3 antagonist, comprising determining the percentage of dendritic cells, macrophages, and natural killer (NK) cells that are TIM-3 positive in the subject's TILs, and , if the percentage is higher than that of control subjects, that subject is more likely to respond to treatment with a TIM-3 antagonist.

Embodiment 50. A method of treating a subject having cancer with a TIM-3 antagonist, comprising administering to the subject having a percentage of dendritic cells, macrophages, and natural killer (NK) cells that are TIM-3 positive in the subject's TILs, a therapeutically effective amount of a TIM antagonist. -3, where the percentage is higher than that of control group subjects.

Embodiment 51. A method of treating a subject having cancer with a TIM-3 antagonist, comprising determining in the subject the percentage of dendritic cells, macrophages, and natural killer (NK) cells that are TIM-3 positive in the subject's TILs, and if the percentage is higher than control subjects, administering to that subject a therapeutically effective amount of a TIM-3 antagonist.

Embodiment 52. The method of any one of embodiments 24-51, wherein the TIM-3 antagonist is a TIM-3 antibody.

- 5 045913

Embodiment 53. The method of Embodiment 52, wherein the TIM-3 antibody comprises a heavy chain variable region comprising CDR1, CDR2 and CDR3 and a light chain variable region comprising CDR1, CDR2 and CDR3, wherein:

(a) the CDR1 heavy chain contains an amino acid sequence selected from the group consisting of SEQ ID NO: 23-27;

(b) the CDR2 heavy chain contains an amino acid sequence selected from the group consisting of SEQ ID NO: 28-38;

(c) the CDR3 heavy chain contains an amino acid sequence selected from the group consisting of SEQ ID NO: 39-49;

(d) the CDR1 light chain contains an amino acid sequence selected from the group consisting of SEQ ID NOs: 50 and 51;

(e) the CDR2 light chain contains an amino acid sequence selected from the group consisting of SEQ ID NOs: 52 and 53; and (f) the CDR3 light chain comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 54-57.

Embodiment 54. The method of Embodiment 52, wherein VH contains an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-18, and VL contains an amino acid sequence selected from the group consisting of SEQ ID NOs: 19-22 .

Embodiment 55. The method as in any one of embodiments 24-30, wherein the PD-1/PD-L1 axis antagonist is an anti-PD-1 antibody, an anti-PD-L1 antibody, or any combination thereof.

Embodiment 56. The method of Embodiment 55, wherein the anti-PD-1 antibody comprises nivolumab, pembrolizumab, MEDI0608, AMP-224, PDR001, BGB-A317, or any combination thereof.

Embodiment 57. The method of Embodiment 55, wherein the anti-PD-L1 antibody comprises BMS-936559, MPDL3280A, MEDI4736, MSB0010718C, or any combination thereof.

Embodiment 58. A method for assessing the effectiveness of a TIM3 antagonist-containing treatment on a subject suffering from cancer, comprising determining a serum titer of soluble TIM-3 in the subject after administration of the treatment to the subject, and if the serum titer is comparable to the serum titer in a control subject, then treating , is likely to be an effective treatment in the subject.

Embodiment 59. The method of Embodiment 58, wherein the effective treatment reduces tumor size by at least about 10%, about 20%, about 30%, about 40%, or about 50% compared to size tumors before treatment.

Embodiment 60. The method of Embodiment 58 or 59, wherein successful treatment effectively increases the overall survival of the subject by at least about 6 months, at least 7 months, at least 8 months, at least , for 9 months, for at least 10 months, for at least 11 months, for at least 12 months, for at least 13 months, for at least 14 months, for at least 15 months, at least 16 months, at least 17 months, at least 18 months, at least 19 months, at least 20 months, at least 21 months , at least 22 months, at least 23 months, at least 24 months, at least 25 months, at least 26 months, at least 27 months, according to at least 28 months, at least 29 months, at least 30 months, at least 3 years, at least 3.5 years, at least 4 years, at least , for 4.5 years, for at least 5 years, or for at least 10 years.

Embodiment 61. The method of any one of embodiments 58 - 60, wherein successful treatment increases the overall survival of the subject by at least 1 month, at least 2 months, at least 3 months, at least , for 4 months, for at least 5 months, for at least 6 months, for at least 7 months, for at least 8 months, for at least 9 months, for at least 10 months, at least 11 months, at least 1 year, at least 15 months, at least 18 months, at least 2 years, at least 3 years for at least 4 years, or at least 5 years.

Embodiment 62. The method of any one of embodiments 58 to 61, wherein the TIM-3 antagonist is a TIM-3 antibody.

Embodiment 63. The method of Embodiment 62, wherein the TIM-3 antibody comprises a heavy chain variable region comprising CDR1, CDR2 and CDR3 and a light chain variable region comprising CDR1, CDR2 and CDR3, wherein:

(a) the CDR1 heavy chain contains an amino acid sequence selected from the group consisting of SEQ ID NO: 23-27;

(b) the CDR2 heavy chain contains an amino acid sequence selected from the group consisting of SEQ ID NO: 28-38;

- 6 045913 (c) the CDR3 heavy chain contains an amino acid sequence selected from the group consisting of SEQ ID NO: 39-49;

(d) the CDR1 light chain contains an amino acid sequence selected from the group consisting of SEQ ID NOs: 50 and 51;

(e) the CDR2 light chain contains an amino acid sequence selected from the group consisting of SEQ ID NOs: 52 and 53; and (f) the CDR3 light chain comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 54-57.

Embodiment 64. The method of Embodiment 23 or 53, wherein the TIM-3 antibody comprises:

(a1) a heavy chain variable region CDR1, CDR2 and CDR3 comprising SEQ ID NO: 23, 28, 39, respectively, and a light chain variable region CDR1, CDR2 and CDR3 comprising SEQ ID NO: 50, 52, 54, respectively;

(a2) the heavy chain variable region CDR1, CDR2 and CDR3 comprising SEQ ID NO: 23, 35, 39, respectively, and the light chain variable region CDR1, CDR2 and CDR3 comprising SEQ ID NO: 50, 52, 54, respectively;

(a3) the heavy chain variable region CDR1, CDR2 and CDR3 comprising SEQ ID NO: 23, 36, 39, respectively, and the light chain variable region CDR1, CDR2 and CDR3 comprising SEQ ID NO: 50, 52, 54, respectively;

(a4) the heavy chain variable region CDR1, CDR2 and CDR3 comprising SEQ ID NO: 23, 37, 39, respectively, and the light chain variable region CDR1, CDR2 and CDR3 comprising SEQ ID NO: 50, 52, 54, respectively;

(a5) the heavy chain variable region CDR1, CDR2 and CDR3 comprising SEQ ID NO: 23, 28, 46, respectively, and the light chain variable region CDR1, CDR2 and CDR3 comprising SEQ ID NO: 50, 52, 54, respectively;

(a6) the heavy chain variable region CDR1, CDR2 and CDR3 comprising SEQ ID NO: 23, 28, 47, respectively, and the light chain variable region CDR1, CDR2 and CDR3 comprising SEQ ID NO: 50, 52, 54, respectively;

(a7) the heavy chain variable region CDR1, CDR2 and CDR3 comprising SEQ ID NO: 23, 28, 48, respectively, and the light chain variable region CDR1, CDR2 and CDR3 comprising SEQ ID NO: 50, 52, 54, respectively;

(a8) the heavy chain variable region CDR1, CDR2 and CDR3 comprising SEQ ID NO: 23, 28, 49, respectively, and the light chain variable region CDR1, CDR2 and CDR3 comprising SEQ ID NO: 50, 52, 54, respectively;

(a9) the heavy chain variable region CDR1, CDR2 and CDR3 comprising SEQ ID NO: 23, 35, 46, respectively, and the light chain variable region CDR1, CDR2 and CDR3 comprising SEQ ID NO: 50, 52, 54, respectively;

(a1 0) heavy chain variable region CDR1, CDR2 and CDR3 comprising SEQ ID NO: 23, 35, 48, respectively, and light chain variable region CDR1, CDR2 and CDR3 comprising SEQ ID NO: 50, 52, 54, respectively ;

(b1) a heavy chain variable region CDR1, CDR2 and CDR3 comprising SEQ ID NO: 24, 29, 40, respectively, and a light chain variable region CDR1, CDR2 and CDR3 comprising SEQ ID NO: 50, 52, 55, respectively;

(b2) the heavy chain variable region CDR1, CDR2 and CDR3 comprising SEQ ID NO: 24, 38, 40, respectively, and the light chain variable region CDR1, CDR2 and CDR3 comprising SEQ ID NO: 50, 52, 55, respectively;

(c) a heavy chain variable region CDR1, CDR2 and CDR3 comprising SEQ ID NOs: 25, 30, 41, respectively, and a light chain variable region CDR1, CDR2 and CDR3 comprising SEQ ID NOs: 50, 52, 55, respectively;

(d) a heavy chain variable region CDR1, CDR2 and CDR3 comprising SEQ ID NOs: 26, 31, 42, respectively, and a light chain variable region CDR1, CDR2 and CDR3 comprising SEQ ID NOs: 50, 52, 54, respectively;

(e) a heavy chain variable region CDR1, CDR2 and CDR3 comprising SEQ ID NOs: 27, 32, 43, respectively, and a light chain variable region CDR1, CDR2 and CDR3 comprising SEQ ID NOs: 50, 52, 55, respectively;

(f) a heavy chain variable region CDR1, CDR2 and CDR3 comprising SEQ ID NOs: 27, 32, 43, respectively, and a light chain variable region CDR1, CDR2 and CDR3 comprising SEQ ID NOs: 50, 52, 57, respectively;

(g1) a heavy chain variable region CDR1, CDR2 and CDR3 comprising SEQ ID NO: 27, 32, 43, respectively, and a light chain variable region CDR1, CDR2 and CDR3 comprising SEQ ID NO: 51, 53, 56, respectively;

(g2) heavy chain variable region CDR1, CDR2 and CDR3 comprising SEQ ID NO: 27, 32,

- 7 045913

43, respectively, and the light chain variable region CDR1, CDR2 and CDR3 comprising SEQ ID NO: 50, 52, 57, respectively;

(g3) the heavy chain variable region CDR1, CDR2 and CDR3 comprising SEQ ID NO: 27, 32, 43, respectively, and the light chain variable region CDR1, CDR2 and CDR3 comprising SEQ ID NO: 50, 52, 55, respectively;

(h) a heavy chain variable region CDR1, CDR2 and CDR3 comprising SEQ ID NOs: 27, 33, 44, respectively, and a light chain variable region CDR1, CDR2 and CDR3 comprising SEQ ID NOs: 50, 52, 54, respectively; or (i) the heavy chain variable region CDR1, CDR2 and CDR3 comprising SEQ ID NO: 27, 34, 45, respectively, and the light chain variable region CDR1, CDR2 and CDR3 comprising SEQ ID NO: 50, 52, 55, respectively ;

where the antibody specifically binds to human TIM-3.

Embodiment 65. The method of Embodiment 23 or 53, wherein the TIM-3 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein VH and VL are selected from the group consisting of:

(a) VH and VL comprising SEQ ID NO: 1 and 19, respectively;

(b) VH and VL comprising SEQ ID NO: 2 and 20, respectively;

(c) VH and VL comprising SEQ ID NO: 3 and 20, respectively;

(d) VH and VL comprising SEQ ID NO: 4 and 19, respectively;

(e) VH and VL comprising SEQ ID NO: 5 and 20, respectively;

(f) VH and VL comprising SEQ ID NO: 5 and 21, respectively;

(g) VH and VL comprising SEQ ID NO: 5 and 22, respectively;

(h) VH and VL comprising SEQ ID NO: 6 and 19, respectively;

(i) VH and VL comprising SEQ ID NO: 7 and 20, respectively;

(j) VH and VL comprising SEQ ID NO: 17 and 22, respectively;

(k) VH and VL comprising SEQ ID NO: 16 and 20, respectively;

(l) VH and VL comprising SEQ ID NO: 8 and 19, respectively;

(m) VH and VL comprising SEQ ID NO: 9 and 19, respectively;

(n) VH and VL comprising SEQ ID NO: 10 and 19, respectively;

(o) VH and VL comprising SEQ ID NO: 11 and 19, respectively;

(p) VH and VL comprising SEQ ID NO: 12 and 19, respectively;

(q) VH and VL comprising SEQ ID NO: 13 and 19, respectively;

(r) VH and VL comprising SEQ ID NO: 14 and 19, respectively;

(s) VH and VL comprising SEQ ID NO: 15 and 19, respectively; and (t) VH and VL comprising SEQ ID NO: 18 and 19, respectively.

Embodiment 66. The method of Embodiment 23 or 53, wherein the TIM-3 antibody comprises:

(a1) the heavy and light chain sequences being SEQ ID NO: 136 (or 137) and 190, respectively;

(a2) the heavy and light chain sequences being SEQ ID NO: 68 (or 75) and 190, respectively;

(a3) the heavy and light chain sequences being SEQ ID NO: 82 (or 89) and 190, respectively;

(a4) the heavy and light chain sequences being SEQ ID NO: 138 (or 139) and 190, respectively;

(a5) the heavy and light chain sequences being SEQ ID NO: 96 (or 106) and 190, respectively;

(a6) the heavy and light chain sequences being SEQ ID NO: 116 (or 126) and 190, respectively;

(a7) the heavy and light chain sequences being SEQ ID NO: 140 (or 141) and 190, respectively;

(a8) the heavy and light chain sequences being SEQ ID NO: 97 (or 107) and 190, respectively;

(a9) the heavy and light chain sequences being SEQ ID NO: 117 (or 127) and 190, respectively;

(a10) heavy and light chain sequences representing SEQ ID NOs: 142 (or 143) and 190, respectively;

(a11) the heavy and light chain sequences being SEQ ID NO: 98 (or 108) and 190, respectively;

(a12) the heavy and light chain sequences being SEQ ID NO: 118 (or 128) and 190, respectively;

(a13) heavy and light chain sequences representing SEQ ID NO: 144 (or

- 8 045913

145) and 190, respectively;

(a14) the heavy and light chain sequences being SEQ ID NO: 99 (or 109) and 190, respectively;

(a15) the heavy and light chain sequences being SEQ ID NO: 119 (or 129) and 190, respectively;

(a16) the heavy and light chain sequences being SEQ ID NO: 146 (or 147) and 190, respectively;

(a17) the heavy and light chain sequences being SEQ ID NO: 100 (or 110) and 190, respectively;

(a18) the heavy and light chain sequences being SEQ ID NO: 120 (or 130) and 190, respectively;

(a19) heavy and light chain sequences representing SEQ ID NOs: 148 (or 149) and 190, respectively;

(a20) the heavy and light chain sequences being SEQ ID NO: 101 (or 111) and 190, respectively;

(a21) the heavy and light chain sequences being SEQ ID NO: 121 (or 131) and 190, respectively;

(a22) the heavy and light chain sequences being SEQ ID NO: 150 (or 151) and 190, respectively;

(a23) the heavy and light chain sequences being SEQ ID NO: 102 (or 112) and 190, respectively;

(a24) the heavy and light chain sequences being SEQ ID NO: 122 (or 132) and 190, respectively;

(a25) the heavy and light chain sequences being SEQ ID NO: 152 (or 153) and 190, respectively;

(a26) the heavy and light chain sequences being SEQ ID NO: 103 (or 113) and 190, respectively;

(a27) the heavy and light chain sequences being SEQ ID NO: 123 (or 133) and 190, respectively;

(a28) the heavy and light chain sequences being SEQ ID NO: 154 (or 155) and 190, respectively;

(a29) the heavy and light chain sequences being SEQ ID NO: 184 (or 185) and 190, respectively;

(a30) the heavy and light chain sequences being SEQ ID NO: 186 (or 187) and 190, respectively;

(a31) the heavy and light chain sequences being SEQ ID NO: 188 (or 189) and 190, respectively;

(b1) the heavy and light chain sequences being SEQ ID NO: 156 (or 157) and 191, respectively;

(b2) the heavy and light chain sequences being SEQ ID NO: 69 (or 76) and 191, respectively;

(b3) the heavy and light chain sequences being SEQ ID NO: 83 (or 90) and 191, respectively;

(b4) the heavy and light chain sequences being SEQ ID NOs: 158 (or 159) and 191, respectively;

(b5) the heavy and light chain sequences being SEQ ID NO: 104 (or 114) and 191, respectively;

(b6) the heavy and light chain sequences being SEQ ID NO: 124 (or 134) and 191, respectively;

(b7) the heavy and light chain sequences being SEQ ID NO: 160 (or 161) and 191, respectively;

(c1) the heavy and light chain sequences being SEQ ID NO: 162 (or 163) and 191, respectively;

(c2) the heavy and light chain sequences being SEQ ID NO: 70 (or 77) and 191, respectively;

(c3) the heavy and light chain sequences being SEQ ID NO: 84 (or 91) and 191, respectively;

(c4) the heavy and light chain sequences being SEQ ID NO: 164 (or 165) and 191, respectively;

(d1) the heavy and light chain sequences being SEQ ID NO: 166 (or 167) and 190, respectively;

(d2) the heavy and light chain sequences of SEQ ID NO: 71 (or 78) and

- 9 045913

190, respectively;

(d3) the heavy and light chain sequences being SEQ ID NO: 85 (or 92) and 190, respectively;

(d4) the heavy and light chain sequences being SEQ ID NO: 168 (or 169) and 190, respectively;

(e1. 1) the heavy and light chain sequences being SEQ ID NO: 170 (or 171) and 192, respectively;

(e1. 2) the heavy and light chain sequences being SEQ ID NO: 170 (or 171) and 193, respectively;

(e1. 3) the heavy and light chain sequences being SEQ ID NO: 170 (or 171) and 191, respectively;

(e2) the heavy and light chain sequences being SEQ ID NO: 72 (or 79) and 193, respectively;

(e3) the heavy and light chain sequences being SEQ ID NO: 86 (or 93) and 193, respectively;

(e4) the heavy and light chain sequences being SEQ ID NO: 172 (or 173) and 193, respectively;

(e5) the heavy and light chain sequences being SEQ ID NO: 105 (or 115) and 193, respectively;

(e6) the heavy and light chain sequences being SEQ ID NO: 125 (or 135) and 193, respectively;

(e7) the heavy and light chain sequences of SEQ ID NO: 174 (or 175) and 193, respectively;

(f1) the heavy and light chain sequences being SEQ ID NO: 176 (or 177) and 190, respectively;

(f2) the heavy and light chain sequences being SEQ ID NO: 73 (or 80) and 190, respectively;

(f3) the heavy and light chain sequences being SEQ ID NO: 87 (or 94) and 190, respectively;

(f4) the heavy and light chain sequences being SEQ ID NO: 178 (or 179) and 190, respectively;

(g1) the heavy and light chain sequences being SEQ ID NO: 180 (or 181) and 191, respectively;

(g2) the heavy and light chain sequences being SEQ ID NO: 74 (or 81) and 191, respectively;

(g3) the heavy and light chain sequences being SEQ ID NO: 88 (or 95) and 191, respectively; or (g4) the heavy and light chain sequences being SEQ ID NO: 182 (or 183) and 191, respectively;

where the antibody specifically binds to human TIM-3.

Embodiment 67. A method of treating a subject having cancer, comprising administering to a subject having cancer and having a serum titer of soluble TIM-3 that is higher than that of control subjects, a therapeutically effective amount of a TIM-3 antagonist, wherein the TIM-3 antagonist is is an antibody that contains a heavy chain and a light chain, wherein (i) the heavy chain includes CDR1, CDR2 and CDR3 of the heavy chain containing SEQ ID NO: 23, 35 and 46, respectively, and the light chain includes CDR1, CDR2 and CDR3 of the light chain containing SEQ ID NO: 50, 52 and 54, respectively; (ii) the heavy chain includes VH containing SEQ ID NO: 18, and the light chain includes VL containing SEQ ID NO: 19; or (iii) the heavy chain contains SEQ ID NO: 186 or 187 and the light chain contains SEQ ID NO: 190.

Embodiment 68. The method of Embodiment 67, wherein the subject has a serum soluble TIM-3 titer that is at least 10% higher in the subject than in control subjects.

Embodiment 69. The method of Embodiment 67, wherein the subject has a serum soluble TIM-3 titer that is at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90 % or 100% (twice) higher than that of control group subjects.

Embodiment 70. The method of any one of embodiments 67-69, wherein the subject has a serum soluble TIM-3 titer of at least 2100, 2200, 2300, 2400, or 2500 pg/ml (as determined, for example, in the method described in the examples).

Embodiment 71. The method of any one of embodiments 67 - 70, wherein the subject has a serum soluble TIM-3 titer of at least 3000 pg/ml (as determined, for example, in the method described in the examples).

Embodiment 72. The method according to any one of embodiments 67-71, additionally

- 10 045913 including measurement of serum titer of soluble TIM-3 before administration.

Embodiment 73. A method of treating a subject having cancer with a TIM-3 antagonist, comprising determining a serum titer of soluble TIM-3 in the subject, and if the serum titer of soluble TIM-3 is higher than that of control subjects, administering to the subject a therapeutically effective amount a TIM-3 antagonist, wherein the TIM-3 antagonist is an antibody that contains a heavy chain and a light chain, wherein: (i) the heavy chain includes heavy chain CDR1, CDR2 and CDR3 containing SEQ ID NOs: 23, 35 and 46, respectively, and the light chain includes CDR1, CDR2 and CDR3 of the light chain containing SEQ ID NO: 50, 52 and 54, respectively; (ii) the heavy chain includes VH containing SEQ ID NO: 18, and the light chain includes VL containing SEQ ID NO: 19; or (iii) the heavy chain contains SEQ ID NO: 186 or 187 and the light chain contains SEQ ID NO: 190.

Embodiment 74. The method of Embodiment 73, wherein if a subject has a serum soluble TIM-3 titer that is at least 10% higher than control subjects, the subject is administered a therapeutically effective amount of a TIM-3 antagonist.

Embodiment 75. The method of Embodiment 73 or 74, wherein if the subject has a serum soluble TIM-3 titer that is at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% (two-fold) higher than subjects in the control group, the subject is administered a therapeutically effective amount of a TIM-3 antagonist.

Embodiment 76. The method of any one of embodiments 73-75, wherein if the subject has a serum soluble TIM-3 titer of at least 2500 pg/ml (as determined, for example, in the method described in the examples), this the subject is administered a therapeutically effective amount of a TIM-3 antagonist.

Embodiment 77. The method of any one of embodiments 73-76, wherein if the subject has a serum soluble TIM-3 titer of at least 3000 pg/ml (as determined, for example, in the method described in the examples), this the subject is administered a therapeutically effective amount of a TIM-3 antagonist.

Embodiment 78. The method of any one of embodiments 67-77, wherein the soluble TIM-3 is differentially spliced soluble TIM-3 and/or desquamated TIM-3

Embodiment 79. The method as in any one of embodiments 67-78, wherein the cancer is a solid tumor.

Embodiment 80. The method as in any one of embodiments 67-79, wherein the cancer is colon, kidney, or lung cancer.

Embodiment 81. The method of any one of embodiments 67-80, wherein the serum soluble TIM-3 titer of control subjects is the arithmetic mean or mean soluble TIM-3 titer of at least 10, 50, or 100 subjects.

Embodiment 82. The method of any one of embodiments 67-81, wherein the TIM-3 antagonist is a TIM-3 antibody.

Embodiment 83. A method of treating a subject having cancer with a combination of a PD-1/PD-L1 axis antagonist and a TIM-3 antagonist, comprising administering to the subject having at least 5% coexpression of PD-1 and TIM-3 CD8+ TIL, a therapeutically effective amount of a combination of a PD-1/PD-L1 axis antagonist and a TIM-3 antagonist, wherein the TIM-3 antagonist is an antibody that contains a heavy chain and a light chain, wherein (i) the heavy chain includes CDR1, CDR2 and heavy chain CDR3 comprising SEQ ID NOs: 23, 35 and 46, respectively, and light chain comprising light chain CDR1, CDR2 and CDR3 comprising SEQ ID NOs: 50, 52 and 54, respectively; (ii) the heavy chain includes VH containing SEQ ID NO: 18, and the light chain includes VL containing SEQ ID NO: 19; or (iii) the heavy chain contains SEQ ID NO: 186 or 187 and the light chain contains SEQ ID NO: 190; and wherein the PD-1 antagonist is nivolumab.

Embodiment 84. The method of Embodiment 83, wherein the subject has coexpression of PD-1 and TIM-3 in at least 10%, 20%, 30%, 40% CD8+ TILs.

Embodiment 85. A method of treating a subject having cancer with a combination of a PD-1/PD-L1 axis antagonist and a TIM-3 antagonist, comprising determining the frequency of positive PD-1 expression on tumor infiltrating lymphocytes (TILs) and the frequency of TIM-3- positive TILs of the subject, and if PD-1 and TIM-3 are coexpressed on at least 5% of the subject's CD8+ TILs, then administering to that subject a combination of a PD-1/PD-L1 axis antagonist and a TIM-3 antagonist, in which the TIM antagonist -3 is an antibody that contains a heavy chain and a light chain, where: (i) the heavy chain includes CDR1, CDR2 and CDR3 of the heavy chain containing SEQ ID NO: 23, 35 and 46, respectively, and the light chain includes CDR1, CDR2 and light chain CDR3 containing SEQ ID NO: 50, 52 and 54, respectively; (ii) the heavy chain includes VH containing SEQ ID NO: 18, and the light chain includes VL containing SEQ ID NO: 19; or (iii) the heavy chain contains SEQ ID NO: 186 or 187 and the light chain contains SEQ ID NO: 190; and the PD-1 antagonist is nivolumab.

Embodiment 86. The method of Embodiment 85, wherein if PD-1 and TIM-3 are coexpressed on at least 10%, 20%, 30%, 40% of a subject's CD8+ TILs, the subject is given

- 11 045913 is a combination of a PD-1/PD-L1 axis antagonist and a TIM-3 antagonist.

Embodiment 87. A method of treating a subject having cancer with a TIM-3 antagonist, comprising administering to the subject whose percentage of CD8+ TILs is 10%, 20%, 30%, 40%, 50%, 60%, or 70% higher, therapeutically an effective amount of a TIM-3 antagonist, wherein the TIM-3 antagonist is an antibody that contains a heavy chain and a light chain, wherein (i) the heavy chain includes CDR1, CDR2 and CDR3 of the heavy chain containing SEQ ID NO: 23, 35 and 46 respectively, and the light chain includes light chain CDR1, CDR2 and CDR3 containing SEQ ID NO: 50, 52 and 54, respectively; (ii) the heavy chain includes VH containing SEQ ID NO: 18, and the light chain includes VL containing SEQ ID NO: 19; or (iii) the heavy chain contains SEQ ID NO: 186 or 187 and the light chain contains SEQ ID NO: 190.

Embodiment 88. A method of treating a subject having cancer with a TIM-3 antagonist, comprising determining the percentage of CD8+ TILs that are TIM-3 positive and if the percentage is greater than 10%, 20%, 30%, 40%, 50% , 60% or 70%, administering to the subject a therapeutically effective amount of a TIM-3 antagonist, wherein the TIM-3 antagonist is an antibody that contains a heavy chain and a light chain, wherein: (i) the heavy chain includes CDR1, CDR2 and CDR3 of the heavy chains containing SEQ ID NOs: 23, 35 and 46, respectively, and the light chain includes light chain CDR1, CDR2 and CDR3 containing SEQ ID NOs: 50, 52 and 54, respectively; (ii) the heavy chain includes VH containing SEQ ID NO: 18, and the light chain includes VL containing SEQ ID NO: 19; or (iii) the heavy chain contains SEQ ID NO: 186 or 187 and the light chain contains SEQ ID NO: 190.

Embodiment 89. A method of treating a subject having cancer with a TIM-3 antagonist, comprising administering to the subject having a percentage of dendritic cells, macrophages, and natural killer (NK) cells that are TIM-3 positive in the subject's TILs, a therapeutically effective amount of a TIM antagonist. -3, in which the percentage is higher than that of control group subjects, in which the TIM-3 antagonist is an antibody that contains a heavy chain and a light chain, where: (i) the heavy chain includes CDR1, CDR2 and CDR3 of the heavy chain containing SEQ ID NOs: 23, 35 and 46, respectively, and the light chain includes light chain CDR1, CDR2 and CDR3 containing SEQ ID NOs: 50, 52 and 54, respectively; (ii) the heavy chain includes VH containing SEQ ID NO: 18, and the light chain includes VL containing SEQ ID NO: 19; or (iii) the heavy chain contains SEQ ID NO: 186 or 187 and the light chain contains SEQ ID NO: 190.

Embodiment 90. A method of treating a subject having cancer with a TIM-3 antagonist, comprising determining in the subject the percentage of dendritic cells, macrophages, and natural killer (NK) cells that are TIM-3 positive in the subject's TILs, and if the percentage is higher, than in control subjects, administering to that subject a therapeutically effective amount of a TIM-3 antagonist, wherein the TIM-3 antagonist is an antibody that contains a heavy chain and a light chain, wherein: (i) the heavy chain includes CDR1, CDR2 and CDR3 of the heavy chain containing SEQ ID NOs: 23, 35 and 46, respectively, and the light chain includes light chain CDR1, CDR2 and CDR3 containing SEQ ID NOs: 50, 52 and 54, respectively; (ii) the heavy chain includes VH containing SEQ ID NO: 18, and the light chain includes VL containing SEQ ID NO: 19; or (iii) the heavy chain contains SEQ ID NO: 186 or 187 and the light chain contains SEQ ID NO: 190.

Brief description of drawings

In fig. 1A and 1B show the frequencies of TM3+ CD4+ T cells (Fig. 1A) and TIM3+ CD8+ T cells (Fig. 1B) in the peripheral blood of healthy individuals (Normal) and cancer patients (ie, colon, kidney, or lung). Frequencies are shown as percentages of total CD4+ T cells or CD8+ T cells. Each circle represents an individual patient, and the mean for each group is shown as a horizontal line.

In fig. 2A-2E show the frequencies of CD4+ T cells and CD8+ T cells that express TIM3 and/or PD-1 in tumor infiltrating lymphocytes (TILs) isolated from various cancer patients (ie, colon, kidney, or lung). The frequencies of TIM3+ CD4+ and TIM3+ CD8+ T cells are shown in Fig. 2A and 2B, respectively. In fig. 2A and 2B the frequencies of TIM3+ cells are shown as percentages of total CD4+ and CD8+ T cells in TILs, respectively. The frequencies of TIM3+ CD4+ and TIM3+ CD8+ T cells that also express PD-1 in TILs are shown in Fig. 2C and 2D, respectively. In fig. 2C and 2D frequencies of PD-1+ cells are shown as percentages of TIM3+ CD4+ and TIM3+ CD8+ T cells in TILs, respectively. In fig. Figure 2E shows a comparison of PD-1 expression on CD8+ T cells in TILs from all OM patients with low frequencies of TIM3+ CD8+ T cells (<8%) (left column) and high frequencies of TIM3+ CD8+ T cells (right column). PD-1 positive expression frequencies are presented as a percentage of TIM3+ CD8+ T cells. The P value shown was calculated using the Mann-Whitney test.

In fig. 3A-3C show the frequencies of various T cell subsets that express TIM3 in TILs from patients with various types of cancer: kidney, lung, colon, liver, ovarian, stomach, uterine, or gastrointestinal. In fig. 3A provides a gating strategy to identify different CD4+ and CD8+ T cell subpopulations: naïve (CCR7+ CD45RO-), central memory (CCR7+ CD45RO+), effector memory (CCR7-CD45RO+), and effector (CCR7-CD45RO-). On

- 12 045913 fig. 3B shows the frequencies of various subsets of CD4+ (upper panel) and CD8+ (lower panel) T cells that express TIM3 in TILs (n=27) from patients with various types of cancer. Frequencies shown are the percentage of TIM3+ cells in the CD4+ or CD8+ T cell subsets described above. In fig. 3C shows a comparison of the frequencies of TIM3+ cells in different CD4+ or CD8+ T cell subsets between TILs and matched blood.

In fig. 4A and 4B show the frequencies of CD8+ T cells that express TIM3 and/or PD-1 in TILs from patients with various types of cancer (ie, kidney, colon, uterine, or lung cancer). In fig. 4A shows the frequencies of CD8+ T cells that: (i) express only PD-1 (lighter shade of gray), (ii) express only TIM3 (darker shade of gray), and (ii) express both PD-1 and TIM3 (black). The x-axis represents individual cancer patients. In fig. 4B shows the flow cytometry-determined frequencies of CD8+ (left panel) and CD4+ (right panel) T cells that express: (i) PD-1 only (upper left quadrant in each panel), (ii) TIM3 only (lower right quadrant in each panel), and (ii) both PD-1 and TIM3 (upper right quadrant in each panel).

In fig. 5A and 5B show the frequencies of various myeloid cells (Fig. 5A) and NK cells (Fig. 5B) in TILs from patients with various cancer types that express TIM3. In fig. 5A frequencies of: (i) TIM3+ CD15+ granulocytes, (ii) TIM3+ plasmacytoid dendritic cells (pDCs), (iii) TIM3+ myeloid dendritic cells (mDCs) and (iv) TIM3+ monocytes/macrophages (CD14+ CD64+) in TILs from 10 cancer patients. In fig. Figure 5B shows the frequencies of TIM3+ CD16-CD56++ and CD16+ CD56+ CD3-NK cells in TILs from 10 cancer patients.

In fig. 6A and 6B show the level of soluble TIM3 protein in the serum of healthy subjects (normal) and cancer patients (colon, kidney and lung). In fig. Figure 6A shows data for each of the donors. In fig. Figure 6B shows the same data as in the diagram. TIM3 protein levels were measured by ELISA using sera from different patients (n=20). The **** symbol above the data points indicates a statistically significant difference (p<0.0001) between healthy patients and cancer patients. The ** symbol above the data points indicates a statistically significant difference (p<0.01) between healthy patients and cancer patients. P values were calculated using the Mann-Whitney test.

Detailed Description of the Invention

Definitions.

To make this description clearer, specific terms are first defined. Additional definitions are provided in the detailed description.

It should be noted that the term nucleotide sequence refers to one or more nucleotide sequences. As such, the terms one or more and at least one may be used interchangeably herein.

In addition, and/or when used herein should be understood as specifically disclosing each of the two identified features or components, with or without the other. Thus, the term and/or, when used in an expression such as A and/or B, is intended to include A and B, A or B, A (separately) and B (separately). Likewise, the term and/or when used in an expression such as A, B and/or C is intended to cover each of the following aspects: A, B and C; A, B or C; A or C; A or B; B or C; A and C; A and B; B and C; A (separately); B (separately) and C (separately).

It is understood that wherever aspects are described herein by the terms containing, similar aspects described by the terms consisting of and/or consisting essentially of are also provided.

Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure pertains. For example, Concise Dictionary of Biomedicine and Molecular Biology, Juo, Pei-Show, ^2nd ed., 2002, CRC Press; The Dictionary of Cell and Molecular Biology, ^3rd ed., 1999, Academic Press; and the Oxford Dictionary Of Biochemistry and Molecular Biology, Revised, 2000, Oxford University Press, provide one skilled in the art with a general vocabulary of many of the terms used in this disclosure.

Units, prefixes and symbols are designated in the form adopted according to the International System of Units SI (Systeme International de Unites (SI)). Numeric ranges include numbers that define the range. Amino acid sequences are written from left to right in aminocarboxyl orientation. Unless otherwise noted, nucleotide sequences are written from left to right in a 5'-3' orientation. The headings set forth herein are not intended to limit various aspects of the disclosure, which may be obtained by reference to the specification as a whole. Accordingly, the terms defined immediately below are more fully defined by reference to the specification in its entirety.

The term about is used here to mean about, roughly, about, or approximately. When the term about is used in conjunction with a numeric range, it modifies that range by extending the boundaries above and below the specified numeric values. Typically the term

- 13 045913 about can change the numerical value above and below the declared value with a deviation of, for example, 10 percent, up or down (above or below).

As used herein, the term T-cell immunoglobulin-mucin domain-containing protein 3, TIM3, or TIM-3 refers to a receptor that is a member of the T-cell immunoglobulin-mucin (TIM) domain protein family. The primary ligand for TIM3 includes phosphatidylserine (TIM3-L). TIM3 is also called hepatitis A virus cellular receptor 2 (HAVCR2) gene, T cell mucin immunoglobulin receptor 3, TIM-3, TIMD3, TIMD-3, kidney injury molecule-3, KIM-3 and CD366. The term TIM3 includes any variants or isoforms of TIM3 that are naturally expressed by cells. Accordingly, the antibodies described herein may cross-react with TIM3 of non-human species (eg, Cynomolgus TIM3). Alternatively, the antibodies may be specific for human TIM3 and not cross-reactive with other species. TIM3 or any of its variants and isoforms can either be isolated from cells or tissues that naturally express them or can be produced recombinantly using techniques well known in the art and/or described herein.

Two isoforms of human TIM3 have been identified. Isoform 1 (accession number NP_116171; SEQ ID NO: 194) consists of 301 amino acids and is a canonical sequence. Isoform 2 (accession number AAH20843; SEQ ID NO: 195) consists of 142 amino acids and is soluble. It lacks amino acid residues 143-301, which encode the transmembrane domain, cytoplasmic domain, and part of the extracellular domain of TIM3. Amino acid residues 132-142 also differ from the canonical sequence described above. Below are the amino acid sequences of the two known human isoforms of TIM3:

(A) human TIM3 isoform 1 (accession number NP_116171; SEQ ID NO: 194; encoded by the nucleotide sequence having accession number NM_032782.4; SEQ ID NO: 196):

MFSHLPFDCVLLLLLLLLTRSSEVEYRAEVGQNAYLPCFYTPAAPGNLVPVCWGKGACPVFECGNWLRTDERDVNYW TSRYWLNGDFRKGDVSLTIENVTLADSGIYCCRIQIPGIMNDEKFNLKLVIKPAKVTPAPTRQRDFTAAFPRMLTTRG HGPAETQTLGSLPDINLTQISTLANELRDSRLANDLRDSGATIRIGIYIGAGICAGL ALALIFGALIFKWYSHSKEKI QNLSLISLANLPPSGLANAVAEGIRSEENIYTIEENVYEVEEPNEYYCYVSSRQQPSQPLGCRFAMP (B) human TIM3 isoform 2 (accession number AAH20843; SEQ ID NO: 195; encoded by a nucleotide sequence having accession number BC020843.1; SEQ ID NO: 197):

MFSHLPFDCVLLLLLLLLTRSSEVEYRAEVGQNAYLPCFYTPAAPGNLVPVCWGKGACPVFECGNWLRTDERDVNYW

TSRYWLNGDFRKGDVSLTIENVTLADSGIYCCRIQIPGIMNDEKFNLKLVIKPGEWTFACHLYE

The signal sequence of isoforms 1 and 2 corresponds to amino acids 1-21 (underlined). Thus, mature isoforms 1 and 2 consist of amino acids 22 to 301 or 142, respectively. The extracellular domain of mature human TIM3 consists of amino acids 22-202 SEQ ID NO: 194 and has the amino acid sequence:

SEVEYRAEVGQNAYLPCFYTPAAPGNLVPVCWGKGACPVFECGNWLRTDERDVNYWTSRYWLNGDFRKGDVSLTIEN

VTLADSGIYCCRIQIPGIMNDEKFNLKLVIKPAKVTPAPTRQRDFTAAFPRMLTTRGHGPAETQTLGSLPDINLTQIS TLANELRDSRLANDLRDSGATIRIG (SEQ ID NO: 198).

The Cynomolgus TIM3 protein consists of the following amino acid sequence (including signal sequence):

MFSHLPFDCVLLLLLLLLTRSSEVEYIAEVGQNAYLPCSYTPAPPGNLVPVCWGKGACPVFDCSNWLRTENRDVNDR TSGRYWLKGDFHKGDVSLTIENVTLADSGVYCCRIQIPGIMNDEKHNLKLWIKPAKVTPAPTLQRDLTSAFPRMLTT GEHGPAETQTPGSLPDVNLTQIFTLTNELRDSGATIRTAIYIAAGISAGLAL ALIFGALIFKWYSHSKEKTQNLSLIS LANIPPSGLANAVAEGIRSEENIYTIEEDVYEVEEPNEYYCYVSSGQQPSQPLGCRFAMP(SEQ ID NO: 199).

The term TIM3 antagonist or anti-TIM3 antagonist refers to all antagonists that bind to human TIM3 protein or a ligand thereof or a nucleic acid encoding human TIM3 or a ligand thereof, respectively, suppress or inhibit the activity of human TIM3. Such an antagonist may be a peptide, nucleic acid or compound. More specifically, the antagonist may be an antisense oligonucleotide, siRNA, shRNA, microRNA, dsRNA, aptamer, PNA (peptide nucleic acid) targeting human TIM3 or a vector comprising it. In some embodiments, the antagonist may be an antibody or an antigen-binding fragment thereof that specifically binds to human TIM3 and suppresses or inhibits the activity of human TIM3. The term antibody or antibodies refers in some embodiments to a protein containing at least two heavy (H) chains and two light (L) chains interconnected by disulfide bonds. Each heavy chain consists of a heavy chain variable region (abbreviated here as VH) and a constant region

- 14 045913 heavy chain (abbreviated here as CH). In some antibodies, such as naturally occurring IgG antibodies, the heavy chain constant region consists of a hinge region and three domains, CH1, CH2 and CH3. In some antibodies, such as naturally occurring IgG antibodies, each light chain consists of a light chain variable region (abbreviated herein as VL) and a light chain constant region. The light chain constant region consists of a single domain (abbreviated here as CL). The VH and VL regions can be further subdivided into regions of hypervariability, called complementarity determining regions (CDRs), interspersed with regions that are more conserved, called framework regions (FR). Each VH and VL consists of three CDRs and four FRs, located from the amino terminus to the carboxy terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The heavy and light chain variable regions contain a binding domain that interacts with the antigen. Antibody constant regions can mediate the binding of immunoglobulins to host tissues or factors, including various cells of the immune system (eg, effector cells) and the first component (C1q) of the classical complement system. The heavy chain may or may not have a C-terminal lysine. Unless otherwise noted, amino acids in the variable regions are numbered using the Kabat numbering system and amino acids in the constant regions are numbered using the EU system. An IgG antibody, such as a human IgG1, IgG2, IgG3, and IgG4 antibody, as used herein, has in some embodiments the structure of a naturally occurring IgG antibody, that is, having the same number of heavy and light chains and disulfide bonds as a naturally occurring one. IgG antibody of the same subclass. For example, an anti-TIM3 IgG1, IgG2, IgG3 or IgG4 antibody consists of two heavy chains (HC) and two light chains (LC), in which the two heavy chains and the light chains are linked by the same number and arrangement of disulfide bridges that are found in natural antibodies IgG1, IgG2, IgG3 and IgG4, respectively (unless the antibody has been mutated to modify disulfide bridges).

The immunoglobulin can be from any of the commonly known isotypes, including, but not limited to, IgA, secretory IgA, IgG and IgM. The IgG isotype is subclassified into specific species: IgG1, IgG2, IgG3, and IgG4 in humans and IgG1, IgG2a, IgG2b, and IgG3 in mice. In certain embodiments, the anti-TIM3 antibodies described herein are of the IgG1 subtype. Immunoglobulins, such as IgG1, exist in several allotypes that differ from each other by no more than a few amino acids. Antibody includes, by way of example, both naturally occurring and non-naturally occurring antibodies; monoclonal and polyclonal antibodies; chimeric and humanized antibodies; human and non-human antibodies and fully synthetic antibodies.

The term antigen-binding portion of an antibody (also called antigen-binding fragment) as used herein refers to one or more antibody fragments that retain the ability to specifically bind an antigen (eg, human TIM3). It has been shown that the antigen-binding function of antibodies can be performed by fragments of full-length antibodies. Examples of binding fragments included in the definition of the term antigen-binding portion of an antibody, eg, a TIM3 antibody described herein, include: (i) a Fab fragment (papain cleavage fragment) or similar monovalent fragment consisting of VL, VH, CL and CH1 domains; (ii) an F(ab') ₂ fragment (pepsin cleavage fragment) or similar divalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; (iii) Fd fragment consisting of VH and CH1 domains; (iv) Fv fragment, consisting of the VL and VH domains of one arm of the antibody; (v) a dAb fragment (Ward et al., Nature 341:544-546 (1989)) consisting of a VH domain; (vi) an isolated complementarity determining region (CDR); and (vii) a combination of two or more isolated CDRs, which may optionally be connected by a synthetic linker. In addition, although the two domains of the Fv fragment, VL and VH, are encoded by different genes, they can be joined recombinantly using a synthetic linker that produces a single protein chain in which the VL and VH regions are paired to form monovalent molecules (known as single-chain Fv fragment (scFv)); see, for example, Bird et al., Science 242:423-426 (1988); and Huston et al., Proc. Natl. Acad. Sci. USA 85:5879-5883 (1988)). Such single chain antibodies are also included in the definition of the term antigen-binding portion of an antibody. These antibody fragments are prepared by conventional methods known to those skilled in the art, and these fragments are examined for their utility in the same manner as intact antibodies. Antigen-binding moieties can be obtained by recombinant DNA methods or by enzymatic or chemical digestion of intact immunoglobulins. The term monoclonal antibody, as used herein, refers to an antibody from a population of essentially homogeneous antibodies, that is, the individual antibodies contained in the population are substantially similar and bind the same epitope(s) (e.g., the antibodies exhibit specificity and single binding affinity), with the exception of possible variants that may arise during the production of a monoclonal antibody, such variants are usually present in small quantities. The definition of monoclonal indicates the nature of the antibody obtained from an essentially homogeneous population of antibodies, and

- 15 045913 it should not be construed as requiring the antibody to be produced by any particular method. The term human monoclonal antibody refers to an antibody from a population of essentially homogeneous antibodies that exhibits single binding specificity, and that has variable and optional constant regions derived from human germline immunoglobulin sequences. In some embodiments, the human monoclonal antibodies are produced by a hybridoma that includes a B cell derived from a transgenic non-human animal, such as a transgenic mouse, having a genome comprising a human heavy chain transgene and a light chain transgene fused to an immortalized cell.

The term recombinant human antibody, as used herein, includes all human antibodies that are produced, expressed, created or isolated by recombinant methods, such as (a) antibodies isolated from an animal (for example, a mouse) that is transgenic or transchromosomal for human immunoglobulin genes or a hybridoma derived therefrom, (b) antibodies isolated from a host cell transformed to express the antibody, for example, from a transfectome, (c) antibodies isolated from a recombinant human antibody combinatorial library, and (d) antibodies obtained , expressed, created or isolated by any other techniques that involve splicing human immunoglobulin gene sequences with other DNA sequences.

Such recombinant human antibodies contain variable and constant regions based on specific human germline immunoglobulin sequences that are encoded by germline genes but include subsequent rearrangements and mutations that occur, for example, during antibody maturation. As is known in the art (see, for example, Lonberg (2005) Nature Biotech. 23(9): 1117-1125), the variable region contains an antigen binding domain that is encoded by various genes that are rearranged to produce an antibody specific for a foreign antigen. In addition to rearrangement, the variable region can be further modified by multiple changes to a single amino acid (called somatic mutation or hypermutation) to increase the affinity of the antibody for a foreign antigen. The constant region will change with further reaction to the antigen (i.e., isotype switching). Consequently, rearranged and somatically mutated nucleic acid molecules that encode immunoglobulin light chain and heavy chain polypeptides in response to an antigen may not have sequence identity with the original nucleic acid molecules, but will instead be substantially identical or similar (i.e., have , at least 80% identity).

The term human antibody (HuMAb) refers to an antibody having variable regions in which both framework regions and CDR regions are derived from human germline immunoglobulin sequences. In addition, if the antibody contains a constant region, the constant region is also derived from human germline immunoglobulin sequences. The anti-T1M3 antibodies described herein may include amino acid residues not encoded by human germline immunoglobulin sequences (eg, mutations introduced by nonspecific or site-specific mutagenesis in vitro or somatic mutation in vivo). However, the term human antibody as used herein is not intended to include antibodies in which CDR sequences derived from the germ line of another mammalian species, such as a mouse, have been grafted onto human framework sequences. The terms human antibodies and fully human antibodies are used interchangeably.

The term humanized antibody refers to an antibody in which some, most or all of the amino acids outside the CDR domains of a non-human antibody are replaced with corresponding amino acids derived from human immunoglobulins. In some embodiments of a humanized form of an antibody, some, most, or all of the amino acids outside the CDR domains have been replaced with amino acids from human immunoglobulins, while some, most, or all of the amino acids in one or more CDR regions are unchanged. Minor additions, deletions, insertions, substitutions or modifications of amino acids are acceptable as long as they do not abolish the ability of the antibody to bind to a specific antigen. The humanized antibody retains antigen specificity similar to that of the parent antibody. The term chimeric antibody refers to an antibody in which the variable regions are derived from one species and the constant regions are derived from another species, such as an antibody in which the variable regions are derived from a mouse antibody and the constant regions are derived from a human antibody.

As used herein, the term isotype refers to a class of antibodies (eg, IgG1, IgG2, IgG3, IgG4, IgM, IgA1, IgA2, IgD, and IgE antibody) that are encoded by heavy chain constant region genes.

The term allotype refers to naturally occurring variants within a defined isotype group, where these variants differ by several amino acids (see, for example, Jefferis et al. (2009) mAbs 1:1). The anti-T1M3 antibodies described herein can be of any allotype. The antibodies used here, referred to as IgG1f, IgG1.1f or IgG1.3f isotype, are anti

- 16 045913 bodies IgG1, IgG1.1 without an effector and IgG1.3 without an effector, respectively, allotype f, i.e. having 214R, 356E and 358M in accordance with the EU index, as in Kabat, as shown, for example, in SEQ ID NO: 123.

The phrases antigen-recognizing antibody and antigen-specific antibody are used interchangeably herein with the term antibody that specifically binds an antigen.

The term isolated antibody, as used herein, is intended to mean an antibody that is substantially free of other proteins and cellular material.

The Fc receptor or FcR is a receptor that binds to the Fc region of an immunoglobulin. FcRs that bind to IgG antibody include the FcyR family of receptors, including allelic variants and alternatively spliced forms of these receptors. The FcyR family consists of three activating (FcyRI, FcyRIII and FcyRIV in mice; FcyRIA, FcyRIIA and FcyRIIIA in humans) and one inhibitory (FcyRIIB) receptor. Various properties of human FcyR are known in the art. Most innate effector cell types coexpress one or more activating FcyRs and an inhibitory FcyRIIB, while natural killer (NK) cells selectively express one activating Fc receptor (FcyRIII in mice and FcyRIIIA in humans) but not the inhibitory FcyRIIB in mice and humans . Human IgG1 binds to most human Fc receptors and is considered equivalent to mouse IgG2a in the types of activating Fc receptors it binds to.

The Fc region (fragment of the crystallizable region) or Fc domain or Fc domain refers to the C-terminal region of an antibody heavy chain that mediates binding of immunoglobulin to host tissues or factors, including binding to Fc receptors located on various cells of the immune system (eg, effector cells) or on the first component (C1q) of the classical complement system. Thus, the Fc region contains the antibody constant region excluding the first domain of the immunoglobulin constant region (eg, CH1 or CL). In the IgG, IgA and IgD antibody isotypes, the Fc region contains two identical protein fragments derived from the second (CH2) and third (CH3) constant domains of the two heavy chains of the antibody; The Fc regions of IgM and IgE contain three heavy chain constant domains (CH 2-4 domains) in each polypeptide chain. For IgG, the Fc region contains the immunoglobulin domains CH2 and CH3 and the hinge region between the domains CH1 and CH2. Although the definition of the boundaries of the immunoglobulin heavy chain Fc region may vary, as defined herein, the human IgG heavy chain Fc region is defined as extending from amino acid residue D221 for IgG1, V222 for IgG2, L221 for IgG3, and P224 for IgG4 to the carboxy terminus of the heavy chain , in which the numbering corresponds to the EU index, as in Kabat.

The CH2 domain of the human IgG Fc region is located from amino acid 237 to amino acid 340, and the CH3 domain is located on the C-terminal side of the CH2 domain in the Fc region, that is, it is from amino acid 341 to amino acid 447 or 446 (if the C-terminal lysine residue absent) or 445 (if the C-terminal glycine residue and lysine are absent) IgG. As used herein, an Fc region may be a native Fc sequence, including any allotype or Fc variant (eg, a non-naturally occurring Fc). Fc may also refer to this region alone or in the context of an Fc-containing protein polypeptide, such as an Fc region-containing binding protein, also referred to as an Fc fusion protein (eg, antibody or immunoadhesion).

A native sequence Fc region or native sequence Fc region includes an amino acid sequence that is identical to the amino acid sequence of the Fc region found in nature. Native sequence human Fc regions include native sequence human IgG1 Fc region; Fc region of human IgG2 with native sequence; Fc region of human IgG3 with native sequence; and the native sequence human IgG4 Fc region, as well as naturally occurring variants thereof. Native sequence Fc includes various allotypes of Fcs (see, for example, Jefferis et al. (2009) mAbs 1:1).

The term naturally occurring in relation to an object as used here refers to the fact that the object can be found in nature. For example, a polypeptide or polynucleotide sequence found in an organism (including viruses) that can be isolated from a source in nature and that has not been intentionally altered by humans in a laboratory occurs in nature. A polypeptide refers to a chain containing at least two consecutively linked amino acid residues with no upper limit on chain length. One or more amino acid residues in a protein may contain a modification, such as, but not limited to, glycosylation, phosphorylation, or disulfide bond formation. A protein may contain one or more polypeptides.

Conservative amino acid substitutions refer to replacements of an amino acid residue with an amino acid residue having a similar side chain. Families of amino acid residues having similar side chains have been identified in the field. These families include amino acids with

- 17 045913 basic side chains (e.g. lysine, arginine, histidine), acidic side chains (e.g. aspartic acid, glutamic acid), uncharged polar side chains (e.g. glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine, tryptophan), non-polar side chains (e.g. alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine), beta-branched side chains (e.g. threonine, valine, isoleucine) and aromatic side chains (e.g. tyrosine, phenylalanine, tryptophan , histidine). In some embodiments, a specific nonessential amino acid residue in the anti-TIM3 antibody is replaced with another amino acid residue from the same side chain family. Methods for identifying nucleotide and amino acid conservative substitutions that do not abolish antigen binding are well known in the art (see, for example, Brummell et al., Biochem. 32: 1180-1187 (1993); Kobayashi et al., Protein Eng. 12 (10):879-884 (1999); and Burks et al., Proc. Natl. Acad. Sci. USA 94:412-417 (1997)). For polypeptides, the term significant degree of homology indicates that the two polypeptides or their designated sequences, when optimally aligned and compared, are identical with corresponding amino acid insertions or deletions of at least 80% of the amino acids, at least 90-95 % or at least 98-99.5% of amino acids.

The percentage identity between two sequences is a function of the number of identical positions shared by the sequences (i.e. % homology = number of identical positions/total number of positions x 100), taking into account the number of gaps and the length of each gap that must be introduced for optimal alignment of the two sequences . Sequence comparison and determination of percent identity between two sequences can be performed using a mathematical algorithm, as described in the non-limiting examples below.

As used herein, the term vector is intended to refer to a nucleic acid molecule capable of transporting another nucleic acid to which it is associated. One type of vector is a plasmid, which refers to a circular double-stranded loop of DNA into which additional DNA segments can be ligated. Another type of vector is a viral vector, in which additional DNA segments can be ligated into the viral genome. Some vectors are capable of autonomous replication in the host cell into which they are introduced (eg, bacterial vectors having a bacterial origin of replication and mammalian episomal vectors). Other vectors (eg, non-episomal mammalian vectors) can be integrated into the host cell genome by insertion into the host cell and thereby replicate along with the host genome. Moreover, certain vectors can direct the expression of genes to which they are operatively linked. Such vectors are referred to in the context of the application as recombinant expression vectors (or simply expression vectors). In general, expression vectors for use in recombinant DNA methods are often in the form of plasmids. In the present description, plasmid and vector can be used interchangeably, since plasmid is the most commonly used form of vector. However, other forms of expression vectors are also included, such as viral vectors (eg, replication-defective retroviruses, adenoviruses, and adeno-associated viruses) that perform equivalent functions.

The term immune response is as understood in the art and generally refers to the biological response in a vertebrate to foreign or abnormal cells, such as cancer cells, that protects the body from these agents and the diseases caused by them. The immune response is mediated by the action of one or more cells of the immune system (eg, T lymphocyte, B lymphocyte, natural killer (NK) cell, macrophage, eosinophil, mast cell, dendritic cell, or neutrophil) and soluble macromolecules produced by any of these cells or liver (including antibodies, cytokines and complement), resulting in the selective targeting, binding, damage, destruction and/or removal from the body of vertebrate pathogens, cells or tissues infected with pathogens, cancer or other abnormal cells or, in cases of autoimmunity or pathological inflammation, normal human cells or tissues. The immune response includes, for example, activation or inhibition of a T cell, such as an effector T cell, Th cell, CD4+ cell, CD8+ T cell, or Treg cell, or activation or inhibition of any other cell of the immune system, such as an NK cell.

An immunomodulator or immunoregulator refers to an agent, for example an agent, that targets a component of a signaling pathway that may be involved in modulating, regulating or modifying the immune response. A modulating, regulating, or modifying immune response refers to any change in a cell of the immune system or in the activity of such a cell (eg, an effector T cell such as a Th1 cell). Such modulation involves stimulation or suppression of the immune system, which may be manifested by an increase or decrease in the number of different types of cells, an increase or decrease in the activity of these cells, or any other changes that may occur in the immune system. Both inhibitory and stimulatory immunomodulators have been identified, some of which may have improved function in the tumor microenvironment. In some embodiments, the immunomodulator targets a molecule on the surface of the T cell. An immunomodulatory target or an immunoregulatory target is a

- 18 045913 combat molecule, for example, a cell surface molecule, which is the target for binding, and whose activity is changed as a result of binding of the substance, agent, fragment, compound or molecule. Immunomodulatory targets include, for example, cell surface receptors (immunomodulatory receptors) and receptor ligands (immunomodulatory ligands).

Immunotherapy refers to the treatment of a subject suffering from, or at risk of contracting or recurrent disease, in a manner involving the induction, enhancement, suppression or other modification of the immune system or immune response. Immunostimulant therapy or immunostimulant therapy refers to therapy that results in enhancement (induction or enhancement) of the immune response in a subject, for example, to treat cancer.

The term T effector (Teff) cells refers to T cells (eg, CD4+ and CD8+ T cells) with cytolytic activity, as well as T helper (Th) cells, such as Th1 cells, whose cells secrete cytokines and activate and direct others. , immune cells, but do not include regulatory T cells (Treg cells). Certain anti-TIM3 antibodies described herein activate Teff cells, such as CD4+ and CD8+ Teff cells and Th1 cells.

The increased ability to stimulate the immune response or immune system may result from increased agonistic activity of T cell co-stimulatory receptors and/or increased antagonistic activity of inhibitory receptors. An increased ability to stimulate an immune response or immune system may be reflected in a fold increase in EC50 or maximum activity level in an assay that measures immune response, e.g., an assay that measures changes in cytokine or chemokine release, cytolytic activity (determined directly on target cells or indirectly through detection of CD 107a or granzymes) and proliferation. The ability to stimulate an immune response or immune system activity may be increased by at least 10%, 30%, 50%, 75%, 2-fold, 3-fold, 5-fold or more.

As used herein, the term associated refers to the association of two or more molecules. The bond may be covalent or non-covalent. The link may also be genetic (that is, recombinantly fused). Such linkages can be achieved using a wide range of techniques known in the art, such as chemical conjugation and recombinant protein production.

As used herein, the term administration refers to the physical administration of a composition containing a therapeutic agent to a subject using any of the various delivery methods and systems known to those skilled in the art. Various routes of administration of the anti-TIM3 antibodies described herein include intravenous, intraperitoneal, intramuscular, subcutaneous, spinal, or other parenteral routes of administration, such as by injection or infusion. The phrase parenteral administration as used herein means methods of administration other than enteral and local administration, typically by injection, and includes, without limitation, intravenous, intraperitoneal, intramuscular, intraarterial, intrathecal, intralymphatic, intralesional, intracapsular, intraorbital, intracardiac, intradermal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrasternal injection and infusion, as well as in vivo electroporation. Alternatively, the antibody described herein can be administered by a non-parenteral route, such as the topical, epidermal or mucosal route, for example, intranasally, orally, vaginally, rectally, sublingually or topically. Administration may also be performed, for example, once, multiple times and/or over one or more extended periods.

As used herein, the term T cell-mediated response refers to a response mediated by T cells, including effector T cells (eg, CD8+ cells) and T helper cells (eg, CD4+ cells). T cell mediated responses include, for example, cytotoxicity and T cell proliferation.

As used herein, the term cytotoxic T lymphocyte (CTL) response refers to the immune response induced by cytotoxic T cells. CTL responses are mediated primarily by CD8+ T cells.

As used herein, the terms inhibit or block (eg, related to inhibiting/blocking the binding of TIM3 ligand (TIM3-L) to TIM3 on cells) are used interchangeably and cover both partial and complete inhibition/blocking. In some embodiments, the anti-TIM3 antibody inhibits the binding of TIM3-L to TIM3 by at least 50%, such as about 60%, 70%, 80%, 90%, 95%, 99%, or 100%, as determined by , for example, as described below. In some embodiments, the anti-TIM3 antibody inhibits the binding of TIM3-L to TIM3 by no more than 50%, such as about 40%, 30%, 20%, 10%, 5%, or 1%, as determined by, for example, further described here.

As used herein, the expression inhibits tumor growth includes any measurable reduction in tumor growth, for example, inhibition of tumor growth by at least 10%, for example by at least 20%, by at least 30%, by at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least

- 19 045913

90%, at least 99% or 100%. The term cancer as used here refers to a broad group of diseases characterized by the uncontrolled growth of abnormal cells in the body. Unregulated cell division can lead to the formation of malignant tumors or cells that invade nearby tissues and can metastasize to distant parts of the body through the lymphatic system or bloodstream. Cancer or cancerous tissue may include a tumor.

As used herein, the term tumor refers to any mass of tissue resulting from excessive growth or proliferation of cells, either benign (noncancerous) or malignant (cancerous), including precancerous lesions. A tumor-infiltrating inflammatory cell is any type of cell that is normally involved in the inflammatory response in a subject and that infiltrates tumor tissue. Such cells include tumor-infiltrating lymphocytes (TILs), macrophages, monocytes, eosinophils, histiocytes, and dendritic cells. The terms TIL or tumor-infiltrating lymphocytes as used herein refer to tumor-infiltrating lymphocytes and other non-lymphocytic mononuclear immune cells.

A cancer patient responding to treatment with a TIM3 antagonist refers to a patient who is experiencing improvement in their cancer, as evidenced by the size of tumors (eg, smaller tumor size or no tumor after treatment), the rate of growth of tumors (eg, slowing or stopping growth after treatment), tumor cell number (eg, decreased number of tumor cells after treatment), immune system activity (eg, greater activity against foreign antigens and/or decreased T cell exhaustion), or any combination thereof.

The terms treat, treatment and therapy as used herein refer to any type of intervention or process performed or active agent administered to a subject for the purpose of reversing, alleviating, improving, inhibiting or slowing or preventing the progression, development, severity or recurrence of a symptom, complication, condition or biochemical features associated with disease or improved overall survival. The treatment may be in a subject who has the disease or in a subject who does not have the disease (eg, for prophylaxis). Programmed death-1 (PD-1) is an immunoinhibitory receptor belonging to the CD28 family. PD-1 is expressed predominantly on previously activated T cells in vivo and binds to two ligands, PD-L1 and PD-L2. As used herein, the term PD-1 includes human PD-1 (hPD-1), variants, isoforms and species homologs of hPD-1, as well as analogues sharing at least one epitope with hPD-1. The complete sequence of hPD-1 is available in GenBank under accession number U64863.

Programmed death ligand-1 (PD-L1) is one of two cell surface glycoprotein ligands for PD-1 (the other is PD-L2) that inhibit T cell activation and cytokine secretion when bound to PD-1. As used herein, the term PD-L1 includes human PD-L1 (hPD-L1), variants, isoforms and species homologs of hPD-L1, as well as analogues sharing at least one epitope with hPD-L1. The complete sequence of hPD-L1 is available in GenBank under accession number Q9NZQ7.

As used herein, the term PD-1/PD-L1 axis antagonist is an agent that inhibits the interaction between PD-1 and PD-L1. As used herein, a PD-1/PD-L1 axis binding antagonist includes a PD-1 binding antagonist and a PD-L1 binding antagonist.

The terms effector memory TILs and effector memory T cells refer to T lymphocytes, which in the present disclosure are characterized as CCR7-CD45RO+. The terms central memory TILs and central memory T cells refer to T lymphocytes, which in the present disclosure are characterized as CCR7+ CD45RO+. The terms naive TILs and naive T cells refer to T lymphocytes, which in the present disclosure are characterized as CCR7+ CD45RO-.

The terms effector TILs and effector T cells refer to T lymphocytes, which in the present disclosure are characterized as CCR7-CD45RO-. Hematologic malignancies include lymphoma, leukemia, myeloma or lymphoid malignancy, and cancer of the spleen and lymph nodes. Typical lymphomas include both B-cell lymphomas (B-cell hematologic cancers) and T-cell lymphomas. B-cell lymphomas include both Hodgkin lymphomas and most non-Hodgkin lymphomas. Non-limiting examples of B cell lymphomas include diffuse large B cell lymphoma, follicular lymphoma, mucosal lymphoid tissue lymphoma, small cell lymphocytic lymphoma (overlaps with chronic lymphoblastic leukemia), mantle cell lymphoma (MCL), Burkitt lymphoma, mediastinal large B cell lymphoma, macroglobulin emia Waldenström, nodal B-cell lymphoma from marginal zone cells, marginal zone lymphoma of the spleen, intravascular large B-cell lymphoma, primary effusion lymphoma, lymphogranulomatosis. Non-limiting examples of T-cell lymphomas include extranodal T-cell lymphoma, cutaneous T-cell lymphoma, anaplastic large cell lymphoma and angioimmunoblastic T-cell lymphoma. Hematologic malignancies also include leukemia, such as, but not limited to, secondary leukemia, chronic lymphocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, and acute lymphoblastic leukemia. Hematological malignancies

- 20 045913 natural neoplasms also include myelomas such as, but not limited to, multiple myeloma and smoldering multiple myeloma. Other hematologic and/or B-cell or T-cell cancers are included under the term hematologic malignancies.

The term effective dose or effective dosage regimen is defined as an amount sufficient to achieve or at least partially achieve the target effect. A therapeutically effective amount or therapeutically effective dosage regimen of a drug or therapeutic agent is any amount of a drug that, when administered alone or in combination with another therapeutic agent, promotes regression of the disease, as evidenced by a decrease in the severity of symptoms of the disease, an increase in the frequency and duration of asymptomatic periods of the disease or prevention of pathologies or disability due to illness. A therapeutically effective amount or dosage regimen of a drug includes a prophylactically effective amount or prophylactically effective dosage regimen, which is any amount of a drug that, when administered alone or in combination with another therapeutic agent to a subject at risk of developing a disease or suffering from a recurrence of a disease, arrests the development of or relapse of the disease. The ability of a therapeutic agent to promote disease regression or inhibit disease progression or relapse can be assessed using various techniques known to one of ordinary skill in the art, for example, in humans during clinical trials, in animal model systems predictive of efficacy in humans, or by assaying the activity of the agent. in in vitro assays.

By way of example, an anticancer agent is a drug that promotes regression of cancer in a subject. In some embodiments, a therapeutically effective amount of the drug promotes regression of the cancer until it is eradicated. Promoting cancer regression means that administration of an effective amount of a drug, alone or in combination with an antineoplastic agent, results in a decrease in tumor growth or size, tumor necrosis, a decrease in the severity of at least one symptom of the disease, an increase in the frequency and duration of asymptomatic periods of the disease, preventing impairment or disability due to disease or otherwise improving symptoms of a disease in a patient. In addition, the terms effective and treatment efficacy include both pharmacological effectiveness and physiological safety. Pharmacological efficacy refers to the ability of a drug to promote cancer regression in a patient. Physiological safety refers to the level of toxicity or other adverse physiological effects at the cellular, organ and/or organismal level (adverse effects) resulting from the administration of a drug.

For example, for the treatment of tumors, a therapeutically effective amount or dosage regimen of a drug inhibits cell growth or tumor growth by at least 20%, at least 40%, at least 60%, or at least 80% compared to untreated subjects. In some embodiments, a therapeutically effective amount or dosage regimen of a drug completely inhibits cell growth or tumor growth, that is, inhibits cell growth or tumor growth by 100%. The ability of a compound to inhibit tumor growth can be assessed using the assays described below. Alternatively, this property of the composition can be assessed by studying the ability of the compound to inhibit cell growth, such inhibition can be measured using in vitro assays known to one skilled in the art. In other embodiments described herein, tumor regression may be observed and continue for a period of at least 20 days, at least 40 days, or at least 60 days.

The term patient refers to a person (or human subject).

The term subject as used here refers to a human subject. The subject may be a subject having cancer.

The term weight-based dose or dosage regimen, as referred to herein, means that the dose that is administered to a patient is calculated based on the patient's weight. For example, when a 60 kg patient requires 3 mg/kg anti-TIM3 antibody, the appropriate amount of anti-TIM3 antibody (ie, 180 mg) to administer can be calculated and used.

The use of the term fixed dose in relation to the method of disclosure means that two or more different antibodies in one composition (for example, an anti-TIM3 antibody and a second antibody, for example, PD-1 or PD-L1 antibody) are present in the composition in certain (fixed) ratios together. In some embodiments, the fixed dose is based on the weight (eg, mg) of the antibodies. In some embodiments, the fixed dose is based on the concentration (eg, mg/ml) of the antibodies. In some embodiments, the ratio of the two antibodies (eg, anti-TIM3 and anti-PD1 or anti-PD-Lt) is at least 1:1, about 1:2, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, about 1:9, about 1:10, about 1:15, about 1:20, about 1:30, about 1:40, about 1:50, about 1:60, about 1:70, about 1:80, about 1:90, about 1:100, about

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1:120, about 1:140, about 1:160, about 1:180, about 1:200, about 200:1, about 180:1, about 160:1, about 140:1, about 120:1, about 100:1, about 90:1, about 80:1, about 70:1, about 60:1, about 50:1, about 40:1, about 30:1, about 20:1, about 15:1, about 10:1, about 9:1, about 8:1, about 7:1, about 6:1, about 5:1, about 4:1, about 3:1 or about 2:1 mg of the first antibody (eg, anti -T1M3 antibody) to mg of the second antibody. For example, a 2:1 ratio of anti-TIM3 antibody to PD-1 antibody, such as nivolumab, would mean that a vial or injection could contain about 480 mg of Yanti-TGMZ antibody and 240 mg of αntu-PD-1 antibody, or about 2 mg/day. ml anti-TIM3 antibody and 1 mg/ml anti-PD-1 antibody. Use of the term fixed dose in relation to the methods and doses described herein means a dose that is administered to a patient without taking into account the weight or body surface area (BSA) of the patient. Therefore, the fixed dose is not provided as a mg/kg dose, but as an absolute amount of the agent (eg, Yanti-TGMZ antibody). For example, a 60 kg person and a 100 kg person would receive the same dose of antibody (eg, 480 mg of anti-TIM3 antibody).

As used herein, the terms μg and μM are used interchangeably with μg and μM, respectively.

The various aspects described in this document are described in more detail in the following subsections.

Disclosure methods

The present disclosure is directed to methods for identifying a subject (e.g., a human cancer patient) suitable for treatment with an anti-TIM3 antagonist (e.g., an anti-TIM3 antibody) alone or in combination with another immune checkpoint inhibitor (e.g., an anti-PD-1 antibody) .

In some embodiments, the methods disclosed herein include measuring or determining the concentration of soluble TIM3 in the serum (TIM3 serum concentration) of a subject and comparing this concentration with the concentration of TIM3 in the serum of a control subject (eg, a healthy patient). If a subject's serum TIM3 concentration is higher than that of a control subject, then that subject is likely to respond to treatment with a Yanti-TGMZ antagonist. In some embodiments, a subject most likely to respond to treatment with an anti-TIM3 antagonist has a serum TIM3 concentration that is at least 10% higher than the concentration observed in a control subject. In other embodiments, the TIM3 serum concentration of the subject is greater than that of the control subject by at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% ( 2 times). In other embodiments, the TIM3 concentration in the subject's serum is at least 2500 pg/ml or at least 3000 pg/ml. In some embodiments, the methods disclosed herein include measuring or determining the percentage of tumor infiltrating lymphocytes (TILs) in a subject that are T1M3 positive. In other embodiments, if at least 10%, 20%, 30%, 40%, 50%, 60%, or 70% of the TILs in a subject are MMZ positive, the subject is likely to respond to treatment with TIM3 antagonist. In certain embodiments, the methods disclosed herein include measuring or determining the percentage of CD8+ tumor infiltrating lymphocytes (TILs) in a subject that are T1M3 positive. In some embodiments, if at least 10%, 20%, 30%, 40%, 50%, 60%, or 70% of a subject's CD8+ TILs are T1M3 positive, the subject is likely to respond to treatment with using a TIM3 antagonist. In certain embodiments, the methods disclosed herein include measuring or determining the percentage of CD4+ tumor infiltrating lymphocytes (TILs) in a subject that are T1M3 positive. In some embodiments, if at least 10%, 20%, 30%, 40%, 50%, 60%, or 70% of a subject's CD4+ TILs are T1MZ positive, that subject is likely to respond to treatment with using a TIM3 antagonist. In some embodiments, the methods disclosed herein include measuring or determining the percentage of CD4+ and CD8+ tumor infiltrating lymphocytes (TILs) in a subject that are T1M3 positive. In other embodiments, if at least 10%, 20%, 30%, 40%, 50%, 60%, or 70% of a subject's TlL CD4+ and/or CD8+ are T1M3 positive, that subject is likely will respond to treatment with a TIM3 antagonist. In some embodiments, the method includes measuring or determining the percentage of naive (CCR7+ CD45RO-), central memory (CM) (CCR7+ CD45RO+), effector memory (EM) (CCR7-CDRO+), and effector (Teff) (CCR7-CD45RO-) TILs, which are T1MZ-positive. If the percentage of T1MZ-positive EM and/or Teff TILs is higher than the percentage of T1MZ-positive naïve or CM TILs, then the subject is more likely to respond to treatment with a TIM3 antagonist. In some embodiments, the TILs are CD4+ TILs. In other embodiments, the TILs are CD8+ TILs.

In some embodiments, the methods disclosed herein enable the identification of a subject (eg, a human cancer patient) suitable for treatment with a combination of a TIM3 antagonist and a PD-1 antagonist. Such a subject may be identified by measuring or determining the percentage of tumor infiltrating lymphocytes (TILs) in the subject that are PD-1 positive and TIM3 positive, where at least 5% of the TILs are positive for both

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PD-1 and TIM3, a subject is likely to respond to treatment that includes both a TIM3 antagonist and a PD-1 antagonist. In some embodiments, the presence of coexpression of both PD-1 and TIM3 on at least 10%, 20%, 30%, or 40% of the TILs indicates that the subject is likely to respond to treatment including both a TIM antagonist 3 and a PD-1 antagonist. In some embodiments, the TILs are CD4+ TILs. In other embodiments, the TILs are CD8+ TILs. In some embodiments, if at least 5%, 10%, 20%, 30%, or 40% of both CD4+ and CD8+ TILs are positive for both PD-1 and TIM3, the subject is likely to respond to treatment , including both a TIM-3 antagonist and a PD-1 antagonist.

The present disclosure also provides methods of treating a subject (eg, a human cancer patient) suitable for treatment with a TIM3 antagonist (eg, an anti-TIM3 antibody), comprising administering to the subject a therapeutically effective amount of a TIM3 antagonist. A suitable subject for treatment with a TIM3 antagonist can be identified by any of the methods described above. The subject may be eligible for treatment with a TIM3 antagonist, alone or in combination with another immune checkpoint inhibitor (eg, ntti-PD-I antibody).

In some embodiments, the concentration of soluble TIM3 in the serum (serum TIM3 concentration) of a subject eligible for treatment with a TIM3 antagonist is higher than the concentration of soluble TIM3 observed in the serum of a control subject (eg, a healthy patient). In some embodiments, the subject's serum TIM3 concentration is at least 10% higher than that of the control subject. In other embodiments, the TIM3 concentration in the subject's serum is greater than that of the control subject by at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% (in 2 times). In some embodiments, the concentration of TIM3 in the subject's serum is at least 2500 pg/ml or at least 3000 pg/ml. In some embodiments, the subject's serum TIM3 concentration is measured or determined prior to administration, and if the subject's serum TIM3 concentration is higher than that of the control subject, a therapeutically effective amount of a TIM3 antagonist is administered to the subject.

In some embodiments, a subject suitable for treatment with a TIM3 antagonist has CD8+ TILs that are at least 10%, 20%, 30%, 40%, 50%, 60%, or 70% TIM3 positive. In some embodiments, the percentage of T1M3-positive CD8+ TILs is determined prior to administration, and if the percentage exceeds 10%, 20%, 30%, 40%, 50%, 60%, or 70% of total CD8+ TILs, then a therapeutically effective amount is administered to the subject TIM3 antagonist.

In some embodiments, a subject suitable for treatment with a TIM3 antagonist can be identified by measuring or determining the percentage of naïve, central memory (CM), effector memory (EM), and effector (Teff) TILs that are TIM3 positive. If the percentage of TIM3-positive EM and/or Teff TILs is higher than the percentage of TIM3-positive naïve or CM TILs, the subject is administered a therapeutically effective amount of a TIM3 antagonist. In some embodiments, the TILs are CD4+ TILs. In other embodiments, the TILs are CD8+ TILs. In some embodiments, the percentages of naive, central memory (CM), effector memory (EM), and effector (Teff) TIM3 positive TILs are determined prior to administration, and if the percentage of T1M3-positive EM and/or Teff TILs is higher than the percentage of naive and/or CM TIL, then the subject is administered a therapeutically effective amount of a TIM3 antagonist.

Also provided herein are methods of treating a subject suitable for treatment with a combination of a TIM3 antagonist and a PD-1 antagonist, comprising administering to such subject a therapeutically effective amount of a combination of a PD-1 antagonist and a TIM3 antagonist. In one embodiment, a combination of a PD1 antagonist and a TIM3 antagonist is administered to a subject if at least 5% of the subject's CD8+ TILs are positive for both PD1 and TIM3 expression. In some embodiments, the percentage of CD8+ TILs that express both PD-1 and TIM3 in a subject is at least 10%, 20%, 30%, 40%, 50%, 60%, or 70%. In a specific embodiment, the percentage of CD8+ TILs in a subject that express both PD-1 and TIM3 is determined prior to administration of a combination of a PD-1 antagonist and a TIM3 antagonist.

In one embodiment, a combination of a TIM3 antagonist and a PD-1 antagonist is administered to a subject if at least 5% of the subject's CD4+ TILs are positive for both PD-1 and TIM3 expression. In some embodiments, the percentage of CD4+ TILs that express both PD-1 and TIM3 in a subject is at least 10%, 20%, 30%, 40%, 50%, 60%, or 70%. In some embodiments, the percentage of CD4+ TILs in a subject that express both PD-1 and TIM3 is determined prior to administration of a combination of a PD-1 antagonist and a TIM3 antagonist. In some embodiments, a combination of a TIM3 antagonist and a PD-1 antagonist is administered to a patient if at least 5% of the subject's CD8+ and CD4+ TILs are positive for both PD-1 and TIM3 expression. In some embodiments, the percentage of CD8+ and CD4+ TILs that express both PD-1 and TIM3 in a subject is at least 10%, 20%, 30%, 40%, 50%, 60%, or 70%. In some embodiments, the percentage of CD4+ and CD8+ TILs in a subject that express both PD-1 and TIM3 is determined prior to administration of the antagonist combination

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PD-1 and TIM3 antagonist.

In some embodiments, the TIM3 antagonist is co-administered with a therapeutically effective amount of a PD-1 antagonist (eg, an anti-PD-l antibody or an anti-PD-Ll antibody). In some embodiments, a PD-1 antagonist (eg, an anti-PD-1 antibody or an anti-PD-L1 antibody) is administered at a fixed dose of about 80 mg to about 1280 mg or a weight-based dose of about 1 mg/day. kg to about 12 mg/kg.

In some embodiments, a PD-1 antagonist (e.g., an anti-PD-1 antibody or an anti-PD-L1 antibody) used in combination with a TIM3 antagonist is administered at a fixed dose of about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg or about 1200 mg.

In some embodiments, the PD-1 antagonist (eg, anti-PD-1 antibody or anti-PD-L1 antibody) used in combination with a TIM3 antagonist is administered at a weight-based dose of about 1 mg/kg, about 2 mg/kg. kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about ll mg/kg or about 12 mg/kg.

In some embodiments, a PD-1 antagonist (e.g., anti-PD-1 antibody or anti-PD-L1 antibody) for combination therapy with a TIM3 antagonist (e.g., anti-TIM3 antibody) is administered at a dosing interval of about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks or about 6 weeks. In some embodiments, the dosing interval for a PD-1 antagonist (eg, anti-PD-l antibody or anti-PD-Ll antibody) is about 2 weeks. In some embodiments, the dosing interval of the PD-1 antagonist (eg, anti-PD-l antibody or anti-PD-Ll antibody) is about 3 weeks. In some embodiments, the dosing interval for a PD-1 antagonist (eg, anti-PD-l antibody or anti-PD-Ll antibody) is about 4 weeks.

In some embodiments, the PD-1 antagonist is administered at a weight-based dose of about 10 mg/kg approximately every 2 weeks. In some embodiments, the PD-1 antagonist is administered at a fixed dose of about 240 mg approximately every 2 weeks. In some embodiments, the PD-1 antagonist is administered at a fixed dose of about 480 mg approximately every 4 weeks. In some embodiments, the PD-1 antagonist is administered at a weight-based dose of about 2 mg/kg approximately every 3 weeks. In some embodiments, the PD-1 antagonist is administered at a fixed dose of about 1200 mg approximately every 3 weeks. In some embodiments, the PD-1 antagonist is administered at a fixed dose of about 200 mg approximately every 3 weeks.

The present disclosure further provides methods for assessing the effectiveness of a treatment comprising a TIM3 antagonist in a subject in need thereof (e.g., a human cancer patient), comprising determining or measuring a serum soluble TIM3 titer in the subject, wherein the serum soluble TIM3 titer in the subject indicates a response subject for treatment (for example, normalization of the disease, for example, restoration of immunological surveillance). In one embodiment, a normal serum titer of soluble TIM3 (eg, comparable to levels observed in a control subject, eg, a healthy patient) indicates that the treatment is effective in that subject. In some embodiments, a serum soluble TIM3 titer that is between that of the subject before treatment and a normal serum soluble TIM3 titer (e.g., comparable to levels observed in a control subject, e.g., a healthy patient) indicates that treatment of that subject is effective.

The present disclosure provides methods for assessing the effectiveness of a treatment comprising a TIM3 antagonist in a subject in need thereof (e.g., a human cancer patient), comprising determining or measuring a serum soluble TIM3 titer in the subject, wherein the serum soluble TIM3 titer in the subject is indicative of the subject's response to treatment . In some embodiments, a patient having cancer is administered a first dose of a TIM3 antagonist and the level of soluble TIM3 is measured in the subject's peripheral blood, wherein a decrease in the level of soluble TIM3 indicates that the subject is responding to the TIM3 antagonist and that additional doses may be administered to the subject. In some embodiments, 2 or more doses of a TIM3 antagonist are administered to a subject having cancer, and the level of soluble TIM3 is measured in the subject's peripheral blood, where a decrease in the level of soluble TIM3 indicates that the subject is responding to the TIM3 antagonist and that additional doses may be administered to the subject. In some embodiments, 1, 2, or more doses of a TIM3 antagonist are administered to a subject having cancer, and the level of soluble TIM3 is measured in the subject's peripheral blood at different times, at which time the dose of TIM3 administered to the subject is adjusted based on the level of decrease in soluble TIM3 in the subject's peripheral blood . For example, a higher dose may be administered if the level of soluble TIM3 does not decrease significantly after administration of a given dose of TIM3 antagonist. Thus, in general, blood soluble TIM3 levels can be used as a prognostic or stratification marker for subjects treated with a TIM3 antagonist. A decrease in soluble TIM3 levels that indicates that further treatment with a TIM3 antagonist is warranted may be a decrease of at least 5%, 10%, 20%, 25%,

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30%, 50%, 75%, 90% or 100% soluble TIM3. In some embodiments, the decrease in soluble TIM3 levels that indicates that further treatment with a TIM3 antagonist is warranted is a decrease of at least 5%, 10%, 20%, 25%, 30%, 50%, 75% , 90% or 100% soluble TIM3 isoform. In some embodiments, the decrease in soluble TIM3 levels that indicates that further treatment with a TIM3 antagonist is warranted is a decrease of at least 5%, 10%, 20%, 25%, 30%, 50%, 75% , 90% or 100% TIM3 shedding from the cell surface. In some embodiments, the decrease in soluble TIM3 that indicates that further treatment with a TIM3 antagonist is warranted is a decrease of at least 5%, 10%, 20%, 25%, 30%, 50%, 75%, 90% or 100% soluble isoform of TIM3 and/or TIM3 shed from the cell surface (in any ratio).

In some embodiments, the effective treatment cures the cancer (eg, reduces or maintains the size of the tumor) and/or reduces or alleviates symptoms associated with the cancer. In some embodiments, effective treatment reduces tumor size by at least 10%, about 20%, about 30%, about 40%, or about 50% compared to the tumor size before treatment.

In some embodiments, the effective treatment effectively increases the length of survival of the subject, for example, the overall survival of the subject. In some embodiments, the effective treatment improves the overall survival of the subject by at least 6 months by at least less less less less less less less less less less less less less less less less less less less less less less less less less less less less less less than less less less less less less less less less less less less less less less less less less less less less less less less less less less less than less less less less less less less less less less less less less less less less less less less less less less less less less less less less less less less than less less less less less less less less less less less less less less less less less less less less less less less less less less less less less than less less less less less less less less less less less less less less less less less less less less less less less less less less than less less less less less less less less less less less less less less less less less less less less than less than one for for months, for at least 8 months, for at least 9 months, for months, for months, for months, for months, for months, for months, at least at least at least at least at least at least at least , at least, at least, at least, at least, at least, for months, months, months, months, months, months, months, according to at least at least at least at least at least at least at least at least at least at least , at least, at least, at least, at least, on on on on on for months, for months, for months, for months, for months, for months, for months, for months, for at least 3 years, at least , for 3.5 years, for at least 4 years, for at least 4.5 years, for at least 5 years or for at least 10 years.

In some embodiments, effective treatment increases the duration of disease-free survival of the subject. In some embodiments, the effective treatment increases the duration of progression-free survival of a subject by at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least for 5 months, for at least 6 months, for at least 7 months, for at least 8 months, for at least 9 months, for at least 10 months, for at least 11 months, at least 1 year, at least 15 months, at least 18 months, at least 2 years, at least 3 years, at least 4 years or for at least 5 years.

In other embodiments, the frequencies of TIM3+ or TIM3+ NK myeloid cell subsets are determined, for example, in TILs. For example, TIM3+ cell frequencies may be determined in pDC, mDC, or CD14+ myeloid cells or in CD16-CD56+ or CD16+ CD56+ NK cells in a subject with cancer in which TIM3+ cell frequencies in one or more of these cell types predict response to a TIM antagonist -3.

Measuring TIM3 Expression and Frequency of TIM3 Positive Cells Among Cell Populations The present disclosure provides methods for identifying a subject (e.g., a human cancer patient) suitable for treatment with a TIM3 antagonist, alone or in combination with another immune checkpoint inhibitor (e.g., a PD-1 antagonist), involving measurement or determination of TIM3 expression. in a tissue sample obtained from the subject. Methods for measuring or determining TIM3 expression can be performed by any of the techniques described herein or known in the art. In some embodiments, the tissue sample obtained from the subject includes, but is not limited to, any clinically significant tissue sample, such as a tumor biopsy, a tissue biopsy sample, a fine needle aspiration sample, or a body fluid sample such as blood, plasma, serum, lymph, ascites fluid, cystic fluid or urine. In some embodiments, the tissue sample is taken from the metastasis. In some embodiments, tissue samples are collected from the subject at various points in time, for example, before treatment, during treatment, and/or after treatment. In some embodiments, tissue samples are taken from different locations in the subject, for example, from a sample of the primary tumor and a sample from a distant metastasis. In some embodiments, determination of TIM3 expression can be performed without obtaining a tissue sample from the subject. In some embodiments, identifying a suitable subject for treatment with a TIM3 antagonist includes (i) optionally providing a tissue sample obtained from a subject whose tissue sample contains tumor cells and/or tumor-infiltrating inflammatory cells (eg, TILs); and (ii) measuring or determining the percentage of cells in the tissue sample that express TIM3 based on levels expressed in a control subject (eg, a healthy patient).

In any of the methods described herein involving detecting or measuring TIM3 expression in a tissue sample, it should be understood that the step of obtaining a tissue sample from a patient is an optional step. That is, in certain embodiments, the method includes this step, while in other embodiments, this step is not included. It should also be understood that in certain embodiments, the step of measuring or determining TIM3 expression is performed using a transformative TIM3 expression assay (eg, flow cytometry). In other embodiments, no conversion step is involved and TIM3 expression is determined, for example, by reviewing a test report from a laboratory. In some embodiments, method steps within and including determining or measuring a TIM3 expression result provide an intermediate result that can be provided to a physician or other health care professional for use in selecting an appropriate candidate for treatment with a TIM3 antagonist, alone or in combination with another inhibitor. immune checkpoints (eg, TIM3 antagonist). In some embodiments, the step that provides the intermediate result is performed by a medical practitioner or a person acting under the direction of a medical practitioner. In other embodiments, these steps are performed by an independent laboratory or an independent person, such as a laboratory technician. In some embodiments, the proportion of cells expressing TIM3 is assessed by assaying for the presence of TIM3 RNA. In other embodiments, the presence of TIM3 RNA is determined by RT-PCR, in situ hybridization, or RNase protection. In some embodiments, the presence of TIM3 RNA is detected using an RT-PCR based assay. In other embodiments, the RT-PCR assay-based assessment includes measuring or determining the level of TIM3 RNA expression in a tissue sample relative to a predetermined level (eg, observed in a control subject).

In some embodiments, the proportion of cells expressing TIM3 is assessed by performing an assay for the presence of TIM3 protein. In other embodiments, the presence of a TIM3 polypeptide is detected using IHC (immunohistochemistry), enzyme-linked immunosorbent assay (ELISA), in vivo imaging, or flow cytometry. In some embodiments, TIM3 expression is analyzed by IHC. In other embodiments, cell surface expression of TIM3 is analyzed using, for example, IHC or in vivo imaging. In some embodiments, the proportion (or frequency) of cells that express TIM3 in a tissue sample is assessed using flow cytometry. In some embodiments, the tissue sample analyzed by flow cytometry contains tumor-infiltrating immune cells (eg, TILs). In some embodiments, the tissue sample analyzed by flow cytometry contains peripheral blood cells. In some embodiments, the flow cytometry is a multiplex assay. In some embodiments, the flow cytometry rate assessment includes detection of expression of markers including TIM3, CD4, CD8, CCR7, CD45RO, and any combination thereof. In some embodiments, the flow cytometry assessment includes assessing the proportion of CD4+ and CD8+ T cells in the tissue sample that express TIM3. In some embodiments, the flow cytometry assessment includes assessing the proportion of CD8+ and CD4+ T cells in the tissue sample that express TIM3; and are (i) CCR7+ CD45RO- (naïve T cells), (ii) CCR7- CD45RO- (Teff cells), (iii) CCR7+ CD45RO+ (SM cells), or (iv) CCR7-CD45RO+ (EM cells). In some embodiments, soluble TIM3 is measured in the peripheral blood of subjects. Any agent that binds to soluble TIM3 (eg, an agent that binds to the extracellular domain of human TIM3, such as further described in the examples) can be used to determine the level of soluble TIM3. In some embodiments, the level of both the soluble isoform of TIM3 and TIM3 isolated from TIM3-positive cells are measured. In some embodiments, the level of any of these forms of soluble TIM3 is measured. In some embodiments, the level of each soluble form of TIM3 is measured separately.

Measuring PD-1 Expression and Frequency of PDI-Positive Cells Among Cell Populations In some embodiments, identifying a subject (e.g., a human cancer patient) suitable for treatment comprising both a TIM3 antagonist and a PD-1 antagonist includes measuring or determining PD expression -1 in a tissue sample obtained from a subject. Methods for measuring or determining PD-1 expression can be carried out by any of the techniques described herein or known in the art.

In some embodiments, the tissue sample obtained from the subject includes, but is not limited to, any clinically significant tissue sample containing CD4+ and/or CD8+ T cells, such as a tumor biopsy, a tissue biopsy sample, a fine needle aspiration sample, or a body fluid sample, such as blood, plasma, serum, lymph, ascites fluid, cystic fluid or urine. In some embodiments, the tissue sample is taken from the metastasis. In some embodiments, tissue samples are collected from the subject at various points in time, for example, before treatment,

- 26 045913 during treatment and/or after treatment. In other embodiments, tissue samples are taken from different locations in the subject, for example, from a sample of the primary tumor and a sample from a distant metastasis.

In some embodiments, determination of PD-1 expression can be performed without obtaining a tissue sample from the subject. In some embodiments, identifying a suitable subject for treatment with a combination of a TIM3 antagonist and a PD-1 antagonist includes (i) optionally providing a tissue sample obtained from a subject whose tissue sample contains CD4+ and/or CD8+ tumor infiltrating lymphocytes (TILs); and (ii) measuring or determining the frequency of PD-1+ CD4+ and/or CD8+ TILs in the tissue sample, taking into account the frequencies observed in the tissue sample from a control subject (eg, a healthy patient). In some embodiments, the tissue sample obtained from the subject includes, but is not limited to, any clinically significant tissue sample, such as a tumor biopsy, a tissue biopsy sample, a fine needle aspiration sample, or a body fluid sample such as blood, plasma, serum, lymph, ascites fluid, cystic fluid or urine. In some embodiments, the tissue sample is taken from the metastasis. In some embodiments, tissue samples are collected from the subject at various points in time, for example, before treatment, during treatment, and/or after treatment. In some embodiments, tissue samples are taken from different locations in the subject, for example, from a sample of the primary tumor and a sample from a distant metastasis. In any of the methods described herein involving detecting or measuring PD-1 expression in a tissue sample, it should be understood that the step of obtaining a tissue sample from a patient is an optional step. That is, in certain embodiments, the method includes this step, while in other embodiments, this step is not included. It should also be understood that in certain embodiments, the step of measuring or determining PD-1 expression is performed using a transformative PD-1 expression assay (eg, flow cytometry). In other embodiments, no conversion step is involved and PD-1 expression is determined, for example, by reviewing a test report from a laboratory. In some embodiments, method steps within and including determining or measuring a PD-1 expression result provide an intermediate result that can be provided to a physician or other health care professional for use in selecting an appropriate candidate for treatment with a combination of a TIM3 antagonist and a PD antagonist -1. In some embodiments, the step that provides the intermediate result is performed by a medical practitioner or a person acting under the direction of a medical practitioner. In other embodiments, these steps are performed by an independent laboratory or an independent person, such as a laboratory technician. In some embodiments, the frequencies of PD-1+ CD4+ and/or PD-1+ CD8+ TILs are assessed by performing an assay to determine the presence of PD-1 RNA. In additional embodiments, the presence of PD-1 RNA is determined by RT-PCR, in situ hybridization, or RNase protection. In some embodiments, the presence of PD-1 RNA is detected using an RT-PCR based assay. In other embodiments, the RT-PCR assay-based assessment includes measuring or determining the frequencies of PD1+ CD4+ and/or PD-1+ CD8+ TILs in a tissue sample relative to a predetermined frequency level (eg, observed in a control subject).

In some embodiments, the frequencies of PD1+ CD4+ and/or PD-1+ CD8+ TILs are assessed by assaying for the presence of PD-1 protein. In additional embodiments, the presence of PD-1 protein is detected using IHC (immunohistochemistry), enzyme-linked immunosorbent assay (ELISA), in vivo imaging, or flow cytometry. In some embodiments, PD-1 expression is analyzed by IHC. In other embodiments, cell surface expression of PD-1 is analyzed using, for example, IHC or in vivo imaging.

In some embodiments, the proportion (or frequency) of CD4+ and/or CD8+ cells that express PD-1 in a tissue sample is assessed using flow cytometry. In some embodiments, the tissue sample analyzed by flow cytometry contains tumor-infiltrating immune cells (eg, TILs). In some embodiments, the tissue sample analyzed by flow cytometry contains peripheral blood cells. In some embodiments, the flow cytometry is a multiplex assay. In some embodiments, the flow cytometry rate assessment includes detection of expression of markers including PD-1, CD4, CD8, CCR7, CD45RO, and any combination thereof. In some embodiments, the flow cytometry assessment includes assessing the proportion of CD4+ and CD8+ T cells in the tissue sample that express PD-1. In some embodiments, the flow cytometry assessment includes assessing the proportion of CD8+ and CD4+ T cells in the tissue sample that express PD-1; and are (i) CCR7+ CD45RO- (naïve T cells), (ii) CCR7- CD45RO (Teff cells), (iii) CCR7+ CD45RO+ (SM cells) or (iv) CCR7-CD45RO+ (EM cells). Provided herein are methods for determining: (i) whether a subject having cancer is likely to respond to treatment with an immunotherapeutic agent, such as a TIM3 antagonist, or (ii) whether a subject having cancer responds to treatment with an immunotherapeutic agent, such as a TIM3 antagonist, that is administered subject.

- 27 045913

The methods include determining the frequency of T1M3-positive cells among defined cell populations. In some embodiments, the method includes determining the frequency of TIM3 positive cells in a given cell population in a subject having cancer, wherein a higher frequency of TIM3 positive cells in a given cell population in a subject having cancer compared to a control subject indicates that the subject is likely to respond to treatment with an immunotherapeutic agent such as a TIM3 antagonist. In some embodiments, the method includes determining the frequency of T1M3-positive cells in a given cell population in a subject with cancer who has received one or more administrations of an immunotherapeutic agent, such as a TIM3 antagonist, wherein the lower frequency of T1M3-positive cells in a given cell population in the subject with cancer cancer, after administration of an immunotherapeutic agent relative to that of a subject suffering from cancer, before administration of an immunotherapeutic agent, or before administration of a previous dose of an immunotherapeutic agent, indicates that the subject is likely to respond to treatment with an immunotherapeutic agent, such as a TIM3 antagonist. The above methods may include measuring (eg, by flow cytometry) the frequency of T1M3-positive cells in the following cell populations: tumor-infiltrating cells, such as tumor-infiltrating lymphocytes, and non-lymphoid tumor-infiltrating cells. In certain embodiments, the methods include measuring the frequency of T1M3-positive cells in: CD8+ TIL cells; CD4+ effector memory TIL cells (CD4+ EM cells; CD4+ CCR7CD45RO+ TIL cells); CD8+ effector memory TIL cells (CD8+ EM cells; CD8+CCR7CD45RO+ TIL cells); CD4+ effector TIL cells (CD4+ Teff cells; CD4+CCR7-CD45RO- T cells); CD8+ effector TIL cells (CD8+Teff cells; CD8+CCR7-CD45RO- T cells); tumor-infiltrating cells of myeloid origin, for example, pDC, mDC and CD14+ myeloid cells; tumor-infiltrating NK cells, for example, CD16-CD56++ NK cells and CD16+CD56+ NK cells. Some embodiments include measuring the frequency of TIM3 positive cells in more than one of these cell populations, such as 2, 3, 4, 5 or more, or all of these cell populations, where the higher frequency of TIM3 positive cells in one or more cell populations indicates that the subject is likely to respond to treatment with an immunotherapeutic agent, such as a TIM3 antagonist, or where there is a lower frequency of T1M3-positive cells in one or more cell populations in a subject who has received a dose of an immunotherapeutic agent, such as a TIM3 antagonist, relative to its frequency before receiving immunotherapeutic agent, indicates that the subject responds to treatment with the immunotherapeutic agent. Also provided herein are methods of treating a subject with an immunotherapeutic agent, such as a TIM3 antagonist, comprising administering to a subject having cancer a therapeutically effective amount of an immunotherapeutic agent, such as a TIM3 antagonist, wherein, prior to administration of the immunotherapy drug, the subject had a higher incidence of T1M3-positive cells in one or more given cell populations compared to a control subject, in which one or more given cell populations are selected from the group consisting of CD8+ TIL cells; CD4+ effector memory TIL cells (CD4+ EM cells; CD4+ CCR7-CD45RO+ TIL cells); CD8+ effector memory TIL cells (CD8+ EM cells; CD8+CCR7-CD45RO+ TIL cells); CD4+ effector TIL cells (CD4+ Teff cells; CD4+CCR7-CD45RO- T cells); CD8+ effector TIL cells (CD8+Teff cells; CD8+CCR7-CD45RO- T cells); tumor-infiltrating cells of myeloid origin, for example, pDC, mDC and CD14+ myeloid cells; tumor-infiltrating NK cells, for example, CD16-CD56++ NK cells and CD16+CD56+ NK cells.

Also provided herein are methods of treating a subject with an immunotherapeutic agent, such as a TIM3 antagonist, comprising administering to a subject having cancer a therapeutically effective amount of an immunotherapeutic agent, such as a TIM3 antagonist, wherein after administration of a first (or first several) dose(s) of the immunotherapeutic agent, such as a TIM3 antagonist, the subject had a lower frequency of T1M3-positive cells in one or more of these cell populations compared to that before administration of the first (or first several) dose(s) of an immunotherapeutic agent, such as a TIM3 antagonist, where one or more of these cell populations are selected from the group consisting of CD8+ TIL cells; CD4+ effector memory TIL cells (CD4+ EM cells; CD4+ CCR7-CD45RO+ TIL cells); CD8+ effector memory TIL cells (CD8+ EM cells; CD8+CCR7-CD45RO+ TIL cells); CD4+ effector TIL cells (CD4+ Teff cells; CD4+CCR7CD45RO- T cells); CD8+ effector TIL cells (CD8+Teff cells; CD8+CCR7-CD45RO- T cells); tumor-infiltrating cells of myeloid origin, for example, pDC, mDC and CD14+ myeloid cells; tumor-infiltrating NK cells, for example, CD16-CD56++ NK cells and CD16+CD56+ NK cells. Also provided herein are methods of treating a subject with an immunotherapeutic agent, such as a TIM3 antagonist, comprising first determining whether the subject is likely to respond to treatment with an immunotherapeutic agent, such as a TIM3 antagonist, for example, as described herein (e.g., preceding paragraphs) and if so, then a therapeutically effective amount of an immunotherapeutic agent, such as a TIM3 antagonist, is administered.

TIM3 antagonists.

In one aspect, the present invention discloses methods of using TIM3 antagonists for

- 28 045913 treatment of oncological diseases. TIM3 antagonists used herein include, but are not limited to, anti-TIM3 antibodies and antigen-binding portions thereof and soluble TIM3 polypeptides (eg, a TIM3-Fc fusion protein that is capable of binding to a TIM3 ligand). Other TIM3 antagonists include agents that bind to TIM3 ligands and inhibit their interaction with TIM3.

Anti-T1M3 antibodies.

Certain aspects of the present disclosure include administering to a subject in need thereof a therapeutically effective amount of an anti-TIM3 antibody or antigen-binding portion thereof. Anti-T1M3 antibodies (or VH/VL domains derived therefrom) suitable for use in the present invention can be prepared using methods well known in the art. Alternatively, anti-TIM3 antibodies may be used as are known in the art.

In some embodiments, anti-TIM3 antibodies or antigen-binding portions thereof exhibit one or more of the following functional properties:

(a) binding to soluble and/or membrane-bound human TIM3;

(b) binding to soluble and/or membrane-bound cynomolgus TIM3;

(c) induction or stimulation of an immune response;

(d) induction or stimulation of T cell activation, for example, Th1 cell activation (as evidenced, for example, by increased secretion and/or proliferation of cytokines);

(e) inducing or stimulating the proliferation of T cells (eg, CD4+, CD8+ T cells, Th1 cells or TILs), for example, in a co-culture assay;

(f) inducing or stimulating the production of IFN-γ by T cells, for example, Th1 cells or tumor infiltrating lymphocytes (TILs), such as TILs from human kidney, lung, pancreatic or breast cancers;

(g) blocking or inhibiting the binding of human TIM3 to PtdSer;

(h) lack of internalization or cell surface down-regulation of TIM3 upon binding to TIM3 on cells;

(i) binding to the extracellular domain of human TIM3 (i) CPVFECG (SEQ ID NO: 200); (ii) RIQIPGIMND (seq id NO: 202); (iii) CPVFECG and RIQIPGIMND (seq id NO: 200 and 202, respectively); or (iv) WTSRYWLNGDFR (SEQ ID NO: 201);

(j) competition or cross-blocking binding to a human TIM3 antibody related to TIM3 described herein (eg, 13A3, 3G4, 17C3, 17C8, 9F6 or any of TIM3.2-TIM3.18);

(k) binding to human TIM3, but not to human TIM3 having an amino acid substitution of one or more of the following amino acid residues: L48, C58, P59, V60, F61, E62, C63, G64, W78, S80, R81, W83, L84 , G86, D87, R89, D104, R111, Q113, G116, M118 and D120, as numbered in SEQ ID NO: 194; and (l) binding to human TIM3 ⁴⁹ VPVCWGKGACPVFE ⁶² (SEQ ID NO: 204) and ^U1 RIQIPGIMNDEKFNLKL ¹²⁷ (seq ID NO: 205) regions as determined by HDX-MS;

(m) the presence of heavy chain and/or light chain variable regions interacting with at least 5, 10, 15, 20 or all of the following amino acids of human TIM3: P50, V51, C52, P59, V60, F61, E62, C63 , G64, N65, V66, V67, L68, R69, D71, E72, D74, R111, Q113, G116, I117, M118, D120 and optionally T70 and/or I112, as determined by x-ray crystallography; and/or (n) competition with or cross-blocking with binding to human TIM3 13A3 or TIM3.18.IgG1.3.

In some embodiments, anti-TIM3 antibodies bind to human TIM3 with high affinity, e.g., with a KD of 10 ^-7 M or less, 10 ^-8 M or less, 10 ^-9 M or less, 10 ^-10 M or less, 10 ^-11 M or less, 10 ^-12 M or less, from 10 ^-12 M to 10 ^-7 M, from 10 ^-11 M to 10 ^-7 M, from 10 ^-10 M to 10 ^-7 M or from 10 ^-9 M to 10 ^-7 M. In some embodiments, the anti-TIM3 antibody binds to human soluble TIM3, for example, as determined by BIACORE™, with a KD of 10 ^-7 M or less, 10 ^-8 M or less, 10 ^-9 M (1 nM) or less, 10 ^-10 M or less, from 10 ^-12 M to 10 ^-7 M, from 10 ^-11 M to 10 ^-7 M, from 10 ^-10 M to 10 ^-7 M, from 10 ^-9 M to 10 ^-7 M or 10 ^-8 M to 10 ^-7 M. In some embodiments, the anti-TIM3 antibody binds to a bond (eg, a cell membrane bond) of human TIM3, such as on activated human CD4+ and CD8+ TIL, for example, as determined by flow cytometry and Scatchard plot, with a KD of 10 ^-7 M or less, 10 ^-8 M or less, 10 ^-9 M (1 pM) or less, 5x10 ^-10 M or less, 10 ^-10 M or less, from 10 ^-12 M to 10 ^-7 M, from 10 ^-11 M to 10 ^-8 M, from 10 ^-10 M to 10 ^-8 M, from 10 ^-9 M to 10 ^-8 M, from 10 ^-11 M to 10 ^-9 M or from 10 ^-10 M to 10 ^-9 M. In other embodiments, the anti-PM3 antibody binds to a binding (eg, cell membrane binding) of human TIM3, such as on activated human CD4+ and CD8+ TIL, for example, as determined by flow cytometry with an EC ₅₀ of 10 μg/ml or less, 5 μg/ml or less, 1 μg/ml or less, 0.9 μg/ml or less, 0.8 μg/ml or less, 0.7 µg/ml or less, 0.6 µg/ml or less, 0.5 µg/ml or less, 0.4 µg/ml or less, 0.3 µg/ml or

- 29 045913 less, 0.2 µg/ml or less, 0.1 µg/ml or less, 0.05 µg/ml or less or 0.01 µg/ml or less.

In some embodiments, anti-T1M3 antibodies suitable for the present disclosure bind to cynomolgus TIM3, e.g., a K _D of 10 ^-7 M or less, 10 ^-8 M or less, 10 ^-9 M or less, 10 ^-10 M or less, 10 ^-11 M or less, 10 ^-12 M or less, from 10 ^-12 M to 10 ^-7 M, from 10 ^-11 M to 10 ^-7 M, from 10 ^-10 M to 10 ^-7 M or from 10 ^-9 M to 10 ^-7 M. In some embodiments, the anti-TIM3 antibody binds to soluble cynomolgus TIM3, for example, as determined by BIACORE™, with a KD of 10 ^-7 M or less, 10 ^-8 M or less, 10 ^-9 M (1 nM) or less, 10 ^-10 M or less, 10 ^-12 M to 10 ^-7 M, 10 ^-11 M to 10 ^-7 M, 10 ^-10 M to 10 ^-7 M , from 10 ^-9 M to 10 ^-7 M or from 10 ^-8 M to 10 ^-7 M. In other embodiments, anti-TIM3 antibodies may bind to membrane-bound cynomolgus TIM3, for example, with an EC50 of 100 nM or less, 10 nM or less, 100 nM to 0.01 nM, 100 nM to 0.1 nM, 100 nM to 1 nM, or 10 nM to 1 nM, for example, as determined by flow cytometry. In some embodiments, the anti-TIM3 antibody binds to a junction (e.g., a cell membrane junction) of cynomolgus TIM3, such as on activated human CD4+ and CD8+ TILs, for example, as determined by flow cytometry and a Scatchard plot, with a K _D of 10 ^-7 M or less, 10 ^-8 M or less, 10 ^-9 M (1 nM) or less, 5x10 ^-10 M or less, 10 ^-10 M or less, from 10 ^-12 M to 10 ^-7 M, from 10 ^-11 M to 10 ^-8 M, from 10 ^-10 M to 10 ^-8 M, from 10 ^-9 M to 10 ^-8 M, from 10 ^-11 M to 10 ^-9 M or from 10 ^-10 M to 10 ^-9 M.

In some embodiments, dNTI-TGMZ antibodies stimulate or enhance the immune response, for example, by activating T cells, for example, in a tumor. For example, dNTI-TGMZ antibodies can activate or co-stimulate cells, as evidenced by, for example, increased secretion of cytokines (eg, IFN-γ) and/or increased proliferation, which may result from inhibition of TIM3-mediated T cell inhibitory activity. In some embodiments, T cell activation or TIM3 antibody costimulation occurs in the presence of CD3 stimulation. In some embodiments, the anti-PM3 antibody increases IFN-γ secretion by 50%, 100% (i.e., 2-fold), 3-fold, 4-fold, 5-fold or more, optionally up to a maximum of 10-fold, 30-fold , 100-fold, as measured, for example, on primary human T cells and/or T cells expressing human TIM3, such as tumor infiltrating lymphocytes (TILs).

In some studies, anti-PM3 antibodies inhibit the binding of phosphatidylserine to human TIM3 on cells, e.g., CHO cells or activated T cells expressing human TIM3, e.g., with an EC ₅₀ of 10 μg/ml or less, 1 μg/ml or less, from 0.01 µg/ml to 10 µg/ml, from 0.1 µg/ml to 10 µg/ml or from 0.1 µg/ml to 1 µg/ml.

In some embodiments, anti-TIM3 antibodies suitable for the present invention bind to an epitope, e.g., a conformational epitope, in the extracellular portion of human TIM3, e.g., in the Ig-like domain of the extracellular region, i.e., amino acids 22-202 of SEQ ID NO: 194. In some embodiments, the anti-TIM3 antibody binds to an epitope located at amino acids 22-120 of the extracellular domain of human TIM3 (SEQ ID NO: 194) or 1-99 of mature human TIM3 (SEQ ID NO: 198). In some embodiments, the anti-TIM3 antibody binds to an epitope within the region consisting of amino acids 58-64 of human TIM3 having SEQ ID NO: 194, which corresponds to amino acid residues 37-43 of mature human TIM3 (CPVFECG, SEQ ID NO: 200). In other embodiments, the anti-PM3 antibody binds to an epitope within the region consisting of amino acids 111-120 of human TIM3 having SEQ ID NO: 194, which corresponds to amino acid residues 90-99 of mature human TIM3 (RIQIPGIMND, SEQ ID NO: 202). In some embodiments, the αanti-TIM3 antibody binds to an epitope within the region consisting of the region consisting of amino acids 58-64 of human TIM3 having SEQ ID NO: 194 (CPVFECG, SEQ ID NO: 200) or to an epitope within the region consisting of amino acids 111-120 of human TIM3 having SEQ ID NO: 194 (RIQIPGIMND, SEQ ID NO: 202). In some embodiments, the anti-PM3 antibody binds to an epitope within the region consisting of amino acids 78-89 of human TIM3 having SEQ ID NO: 194, which corresponds to amino acid residues 57-83 of mature human TIM3 (WTSRYWLNGDFR, SEQ ID NO: 201). In some embodiments, the anti-TIM3 antibody binds substantially to the same epitope as 13A3, that is, an epitope (or region of human TIM3) containing one or more of amino acid residues C58, P59, F61, E62, C63, R111, and D120 SEQ ID NO: 194. In some embodiments, the anti-TIM3 antibody binds to an epitope (or region of human TIM3) containing one or more amino acid residues C58, P59, F61, E62, C63, D104, R111, Q113, and D120 SEQ ID NO: : 194.

In some embodiments, the anti-TIM3 antibody does not bind substantially, or only with significantly reduced binding affinity, to the human TIM3 protein, wherein one or more of amino acid residues C58, P59, F61, E62, C63, R111, and D120 SEQ ID NO: 194 is replaced by another amino acid, for example, in a non-conservative amino acid substitution. In other embodiments, the anti-TIM3 antibody does not bind significantly or only to a significant extent.

- 30 045913 but with reduced binding affinity to the human TIM3 protein, in which one or more amino acid residues C58, P59, F61, E62, C63, D104, R111, Q113 and D120 SEQ ID NO: 194 is replaced by another amino acid, for example, with a non-conservative amino acid replacement.

In some embodiments, the anti-TIM3 antibody binds substantially to the same epitope as 3G4, that is, an epitope (or region of human TIM3) containing one or more of amino acid residues C58, P59, V60, F61, E62, C63, G116, and M118 SEQ ID NO: 194. In some embodiments, the anti-TIM3 antibody binds to an epitope (or region of human TIM3) containing one or more of amino acid residues C58, P59, V60, F61, E62, C63, D104, G116, and M118 SEQ ID NO: 194. In some embodiments, the anti-TIM3 antibody does not bind significantly, or only with significantly reduced binding affinity, to the human TIM3 protein, in which one or more amino acid residues C58, P59, V60, F61, E62, C63, G116, and M118 SEQ ID NO: 194 is replaced by another amino acid, for example, in a non-conservative amino acid substitution. In some embodiments, the anti-TIM3 antibody does not bind substantially, or only with significantly reduced binding affinity, to the human TIM3 protein, wherein one or more of amino acid residues C58, P59, V60, F61, E62, C63, D104, G116, and M118 of SEQ ID NO: 194 is replaced by another amino acid, for example, in a non-conservative amino acid substitution.

In some embodiments, the anti-TZMS antibody binds substantially to the same epitope as 17C3, i.e. with an epitope (or region of human TIM3) containing one or more amino acid residues C58, P59, V60, F61, E62, C63, G64 and G116 SEQ ID NO: 194. In some embodiments, the anti-TIM3 antibody binds to the epitope (or region human TIM3) containing one or more amino acid residues C58, P59, V60, F61, E62, C63, G64, D104 and G116 SEQ ID NO: 194. In some embodiments, the anti-TIM3 antibody does not bind significantly or only significantly reduced binding affinity to the human TIM3 protein in which one or more amino acid residues C58, P59, V60, F61, E62, C63, G64 and G116 of SEQ ID NO: 194 is replaced by another amino acid, for example, in a non-conservative amino acid substitution. In some embodiments, the yanti-TGMZ antibody does not bind substantially, or only with significantly reduced binding affinity, to the human TIM3 protein, in which one or more amino acid residues C58, P59, V60, F61, E62, C63, G64, D104, and G116 of SEQ ID NO: 194 is replaced by another amino acid, for example, in a non-conservative amino acid substitution. In some embodiments, the anti-TIM3 antibody binds substantially to the same epitope as 8B9, i.e., an epitope (or region of human TIM3) containing one or more of amino acid residues L48, W78, S80, R81, W83, G86, D87 and R89 SEQ ID NO: 194. In some embodiments, the anti-TIM3 antibody binds to an epitope (or region of human TIM3) containing one or more of amino acid residues L48, W78, S80, R81, W83, L84, G86, D87, and R89 of SEQ ID NO: 194. In other embodiments, the yanti-TGMZ antibody binds to an epitope (or region of human TIM3) containing one or more of amino acid residues L48, W78, S80, R81, W83, G86, D87, R89, and D104 SEQ ID NO: 194. In some embodiments, the anti-TIM3 antibody does not bind substantially, or only with significantly reduced binding affinity, to the human TIM3 protein, wherein one or more of amino acid residues L48, W78, S80, R81, W83, G86, D87, and R89 of SEQ ID NO: 194 is replaced by another amino acid, for example, in a non-conservative amino acid substitution. In other embodiments, the anti-TIM3 antibody does not bind substantially, or only with significantly reduced binding affinity, to the human TIM3 protein, wherein one or more of amino acid residues L48, W78, S80, R81, W83, L84, G86, D87, and R89 of SEQ ID NO: 194 is replaced by another amino acid, for example, in a non-conservative amino acid substitution. In some embodiments, the ntti-TGMZ antibody does not bind significantly, or only with significantly reduced binding affinity, to the human TIM3 protein, in which one or more amino acid residues L48, W78, S80, R81, W83, G86, D87, R89, and D104 SEQ ID NO: 194 is replaced by another amino acid, for example, in a non-conservative amino acid substitution.

In other embodiments, anti-TIM3 antibodies suitable for use in the present disclosure compete for binding to human TIM3 with (or inhibit binding of) anti-TIM3 antibodies containing CDRs or variable regions described herein, for example, 13A3 antibody antibodies. 3G4, 17С3, 17С8, 9F6, 8В9, 8С4 and any of TIM3.2-TIM3. 18. In some embodiments, anti-TIM3 antibodies inhibit the binding of antibodies 13A3, 3G4, 17C3, 17C8, 9F6, 8B9, 8C4, or any of TIM3.2-TIM3. 18 with human TIM3 at least 50%, 60%, 70%, 80%, 90% or 100%. In some embodiments, 13A3, 3G4, 17C3, 17C8, 9F6, 8B9, 8C4, or any of TIM3. 2-TIM3. 18 inhibit the binding of anti-TIM3 antibodies to human TIM3 by at least 50%, 60%, 70%, 80%, 90% or 100%. In other embodiments, anti-TIM3 antibodies inhibit the binding of 13A3, 3G4, 17C3, 17C8, 9F6, 8B9, 8C4, or any of TIM3.2-TIM3.18 to human TIM3 by at least 50%, 60%, 70 %, 80%, 90% or 100%, and 13A3, 3G4, 17C3, 17C8, 9F6, 8B9, 8C4 or any of TIM3.2-TIM3.18 inhibit the binding of anti-TIM3 antibodies to human TIM3 by at least 50%, 60% 70%, 80%, 90% or 100% (for example,

- 31 045913 compete in both directions).

In some embodiments, the anti-T1M3 antibodies described herein have 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or all of the following features :

(1) binding to soluble human TIM3, for example, with a KD of 10 nM or less, for example, from 0.01 nM to 10 nM, for example, as measured by Biacore;

(2) binding to soluble cynomolgus TIM3, for example, with a KD of 100 nM or less, for example, from 0.01 nM to 100 nM, for example, according to Biacore;

(3) binding to membrane-bound human TIM3, eg, an EC ₅₀ of 1 μg/ml or less, eg, 0.01 μg/ml to 1 μg/ml, for example, as measured by flow cytometry;

(4) binding to membrane-bound human TIM3, for example, with a KD of 1 nM or less, for example, from 0.01 nM to 10 nM), for example, as measured by the Scatchard assay;

(5) binding to membrane-bound cynomolgus TIM3, for example, with an EC ₅₀ of 20 μg/ml or less, for example, from 0.01 μg/ml to 20 μg/ml, for example, as measured by flow cytometry;

(6) binding to membrane-bound cynomolgus TIM3, for example, with a K _D of 1 nM or less, for example, from 0.01 nM to 10 nM, for example, as measured by the Scatchard assay;

(7) inducing or enhancing T cell activation, e.g., by blocking or reducing the inhibitory effect of TIM3, as evidenced by (i) increased production of IFN-γ in TIM3-expressing T cells, e.g., III cells or TILs and/or (ii) ) increased proliferation of T cells expressing TIM-3, such as Th1 cells or TILs;

(8) stimulation of T cell proliferation in a mixed lymphocyte reaction (MLR) assay;

(9) inhibition of phosphatidylserine binding to TIM3;

(10) lack of internalization or downregulation of TIM3 at the cell surface upon binding to TIM3 on cells;

(11) binding to one of the following regions of the extracellular domain of human TIM3 (SEQ ID NO: 198): (a) CPVFECG (seq id NO: 200); (b) RIQIPGIMND (seq id NO: 202); (c) CPVFECG and RIQIPGIMND (seq id NO: 200 and 202, respectively) and (d) WTSRYWLNGDFR (SEQ ID NO: 201);

(12) decreased binding to human TIM3, where one or more amino acids L48, C58, P59, V60, F61, E62, C63, G64, W78, S80, R81, W83, L84, G86, D87, R89, D104 R111, Q113 , G116, M118 and D120 (as numbered in SEQ ID NO: 194) is replaced by a different amino acid compared to binding to wild-type human TIM3;

(13) competition in either one or both directions for binding to human TIM3 with an antibody containing the VH and VL domains of any of 13A3, 3G4, 17C3, 17C8, 9F6, 8B9, 8C4 or TIM3.7, TIM3.8, TIM3 .10, TIM3.11, TIM3.12, TIM3.13, TIM3.14, TIM3.15, TIM3.16, TIM3.18;

(14) binding to human TIM3 regions ⁴⁹ VPVCWGKGACPVFE ⁶² (seq id NO: 204) and ¹¹¹ RIQIPGIMNDEKFNLKL ¹²⁷ (SEQ ID NO: 205), as determined by HDX-MS (hydrogen-deuterium exchange mass spectrometry);

(15) having heavy chain and/or light chain variable regions interact with at least 5, 10, 15, 20 or all of the following amino acids of human TIM3: P50, V51, C52, P59, V60, F61, E62, C63, G64, N65, V66, V67, L68, R69, D71, E72, D74, R111, Q113, G116, I117, M118, D120, and optionally T70 and/or I112, as determined by X-ray crystallography (SEQ ID NO : 194); and/or (16) (a) having reduced binding to human TIM3, in which 1, 2, 3, 4, 5, 6, 7, 8 or 9 amino acids C58, P59, F61, E62, C63, R111, D120 and optionally, D104 and Q113 (SEQ ID NO: 194) are replaced with a different amino acid relative to binding to wild-type human TIM3; (b) binding to ⁴⁹ VPVCWGKGACPVFE ⁶² (SEQ ID NO:204), ¹¹¹ RIQIPGIMNDEKFNLKL ¹²⁷ (SEQ ID NO: 205) and ¹¹⁹ NDEKFNLKL ¹²⁷ (SEQ ID NO: 210), as determined by HDX-MS and/or (with ) compete or cross-block with binding to human TIM3 13A3 or TIM3.18.IgG1.3.

Accordingly, an antibody that exhibits one or more of these functional properties (e.g., biochemical, immunochemical, cellular, physiological or other biological activity, or the like), as determined in accordance with methodologies known in the art and described herein, should be understood as demonstrating a statistically significant difference in a particular activity compared to what is observed in the absence of the antibody, for example or when a control antibody of irrelevant specificity is present). In some embodiments, an anti-T1M3 antibody-induced increase in a measured parameter (e.g., T cell proliferation, cytokine production) in a given assay results in a statistically significant increase of at least 10% in the measured parameter, e.g., by at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 100% (i.e. 2 times), 3 times, 5 or 10 times, and in some In embodiments, the antibody described herein can increase the measurable

- 32 045913 parameter, for example, more than 92%, 94%, 95%, 97%, 98%, 99%, 100% (i.e. 2 times), 3 times, 5 times or 10 times, relative to the same analysis performed in the absence of the antibody. Conversely, santi-TGMZ antibody-induced decreases in a measured parameter (eg, tumor volume, TIM3-L binding to human TIM3) in this assay produce a statistically significant reduction of at least 10% in the measured parameter, e.g. 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%, and in some embodiments, an antibody described herein can reduce a measured parameter, for example, by more than 92%, 94 %, 95%, 97%, 98%, or 99%, relative to the same assay performed in the absence of the antibody. Standard assays for assessing the ability of antibodies to bind to TIM3 of various species are known in the art, including, for example, ELISA, Western blots and RIA. Binding kinetics, such as antibody binding affinity, can also be assessed using standard assays known in the art, such as the Biacore assay.

In some embodiments, αanti-TIM3 antibodies suitable for the present invention are not native antibodies or do not occur in nature. For example, in some embodiments, anti-TIM3 antibodies have post-translational modifications that are different from antibody modifications that occur naturally, such as having more, less, or a different type of post-translational modification.

In some embodiments, anti-TIM3 antibodies do not have agonistic activity, as determined, for example, by cross-linking anti-TIM3 antibodies in CHO-OKT3-CD32: T cell co-culture experiments, where such antibodies do not enhance activity without the participation of anti-TIM3 antibodies. -TIM3 itself. In some embodiments, yanti-TGMZ antibodies block the interaction of TIM3 with its ligand without stimulating agonist activity.

In some embodiments, anti-TGM3 antibodies enhance IL-12 production from monocytes or dendritic cells treated with LPS.

In some embodiments, anti-T1M3 antibodies restore tumor-infiltrating CD4+ and CD8+ T cells that coexpress PD-1 and TIM3 through combination treatment, thereby avoiding CD4+ and CD8+ T cell depletion.

Exemplary anti-T1M3 antibodies.

Specific anti-T1M3 antibodies suitable for the present invention are antibodies, for example, monoclonal, recombinant and/or human antibodies having the CDR and/or variable region sequences of antibodies 13A3, 3G4, 17C3, 17C8, 9F6, 8B9, 8C4 or any of TIM3.2-TIM3.18, as well as antibodies having at least 80% identity, for example at least 85%, at least 90%, at least 95% or at least 99 % of their variable region or CDR sequences. The amino acid sequences of VH 13A3, 8B9, 8C4, 17C3, 9F6, 3G4 and 17C8 are given in SEQ ID NO: 1-7, respectively.

The amino acid sequences of VH variants 13A3, 8B9 and 9F6 are given in SEQ ID NO: 8-18. The amino acid sequences of VL 13A3, 17C3 and 3G4 are shown in SEQ ID NO: 19. The amino acid sequences of VL 8B9, 8C4 and 17C8 are presented in SEQ ID NO: 20. The amino acid sequence of VL 9F6 or variants thereof are presented in SEQ ID NO: 20, 21 or 22 The amino acid sequences of VL variants 13A3 and 8B9 are shown in SEQ ID NO: 19 and SEQ ID NO: 20, respectively.

Thus, in some embodiments, anti-T[M3 antibodies comprise heavy and light chain variable regions, wherein the heavy chain variable region comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-18. In some embodiments, the light chain variable region comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 19-22.

In some embodiments, the anti-MMZ antibodies comprise:

(a) heavy and light chain variable region sequences comprising SEQ ID NOs: 1 and 19, respectively;

(b) heavy and light chain variable region sequences comprising SEQ ID NO: 2 and 20, respectively;

(c) heavy and light chain variable region sequences comprising SEQ ID NO: 3 and 20, respectively;

(d) heavy and light chain variable region sequences comprising SEQ ID NO: 4 and 19, respectively;

(e) heavy and light chain variable region sequences comprising SEQ ID NO: 5 and 20, respectively;

(f) heavy and light chain variable region sequences comprising SEQ ID NO: 5 and 21, respectively;

(g) heavy and light chain variable region sequences comprising SEQ ID NO: 5 and 22, respectively;

(h) heavy and light chain variable region sequences comprising SEQ ID NO: 6 and 19, respectively;

- 33 045913 (i) heavy and light chain variable region sequences comprising SEQ ID NOs: 7 and 20, respectively;

(j) heavy and light chain variable region sequences comprising SEQ ID NO: 17 and 22, respectively;

(k) heavy and light chain variable region sequences comprising SEQ ID NOs: 16 and 20, respectively;

(l) heavy and light chain variable region sequences comprising SEQ ID NO: 8 and 19, respectively;

(m) heavy and light chain variable region sequences comprising SEQ ID NO: 9 and 19, respectively;

(n) heavy and light chain variable region sequences comprising SEQ ID NO: 10 and 19, respectively;

(o) heavy and light chain variable region sequences comprising SEQ ID NO: 11 and 19, respectively;

(p) heavy and light chain variable region sequences comprising SEQ ID NO: 12 and 19, respectively;

(q) heavy and light chain variable region sequences comprising SEQ ID NOs: 13 and 19, respectively;

(r) heavy and light chain variable region sequences comprising SEQ ID NOs: 14 and 19, respectively;

(s) heavy and light chain variable region sequences comprising SEQ ID NOs: 15 and 19, respectively; or (t) the heavy and light chain variable region sequences comprising SEQ ID NOs: 18 and 19, respectively.

In some embodiments, anti-TIM3 antibodies comprise CDR1 heavy and light chain, CDR2 and CDR3 13A3, 8B9, 8C4, 17C3, 9F6, 3G4 and 17C8 or any of TIM3.2 - TIM3.18 or combinations thereof. The amino acid sequences of VH CDR1 13A3, 8B9, 8C4 and 17C3 are presented in SEQ ID NO: 23-26, respectively. The amino acid sequences of VH CDR1 9F6, 3G4 and 17C8 are presented in SEQ ID NO: 27.

The amino acid sequence of the VH CDR1 of the mutated 13A3 antibody (i.e., TIM3.10TIM3.18) is the same as that of the unmutated 13A3 antibody, i.e., SEQ ID NO: 23. The amino acid sequence of the VH CDR1 of the mutated 8B9 antibody (i.e., TIM3.8) is as follows the same as the unmutated 8B9 antibody, i.e., SEQ ID NO: 24. The amino acid sequence of the VH CDR1 of the mutated 9F6 antibody (i.e., TIM3.7) is the same as that of the unmutated 9F6 antibody, i.e., SEQ ID NO: 27. Amino acid sequences VH CDR2 13A3, 8B9, 8C4, 17C3, 9F6, 3G4 and 17C8 are presented in SEQ ID NO: 28-34, respectively. The VH CDR2 amino acid sequence of the 13A3 mutated antibodies TIM3.10, TIM3.17 and TIM3.18 is presented in SEQ ID NO: 35. The VH CDR2 amino acid sequence of the 13A3 mutated antibodies TIM3.11 and TIM3.12 is presented in SEQ ID NO: 36 and 37, respectively. The amino acid sequence of the VH CDR2 of the 13A3 mutated antibodies TIM3.13 and TIM3.16 is the same as that of the unmutated 13A3 antibody, i.e., SEQ ID NO: 28. The amino acid sequence of the VH CDR2 of the mutated antibody 8B9 (i.e., TIM3.8) is provided in SEQ ID NO: 38. The VH CDR2 amino acid sequence of the mutated 9F6 antibody (i.e., TIM3.7) is the same as that of the unmutated 9F6 antibody, i.e., SEQ ID NO: 32. The VH CDR3 amino acid sequences are 13A3, 8B9, 8C4, 17C3, 9F6, 3G4 and 17C8 are presented in SEQ ID NO: 39-45, respectively.

The VH CDR3 amino acid sequence of the 13A3 mutated antibodies (i.e., TIM3.10TIM3.12) is the same as that of the unmutated 13A3 antibody, i.e., SEQ ID NO: 39. The VH CDR3 amino acid sequence of the 13A3 mutated antibodies TIM3.13 and TIM3.18 is presented in SEQ ID NO: 46. The VH CDR3 amino acid sequence of the 13A3 mutated antibodies TIM3.15 and TIM3.17 is presented in SEQ ID NO: 48. The VH CDR3 amino acid sequences of the 13A3 mutated antibodies TIM3.14 and TIM3.16 are presented in SEQ ID NO: 47 and 49, respectively. The VH CDR3 amino acid sequence of the mutated 8B9 antibody (i.e., TIM3.8) is the same as that of the unmutated 8B9 antibody, i.e., SEQ ID NO: 40. The VH CDR3 amino acid sequence of the mutated 9F6 antibody (i.e., TIM3.7) is the same as that of the unmutated 8B9 antibody, i.e., SEQ ID NO: 40. as for the unmutated 9F6 antibody, i.e. SEQ ID NO: 43.

The amino acid sequences of VL CDR1 13A3, 8B9, 8C4, 17C3, 3G4 and 17C8 are presented in SEQ ID NO: 50. The amino acid sequences of VL CDR1 9F6 are presented in SEQ ID NO: 50 and 51. The amino acid sequences of VL CDR2 13A3, 8B9, 8C4, 17C3, 3G4 and 17C8 are presented in SEQ ID NO: 52. The amino acid sequences of VL CDR2 9F6 are presented in SEQ ID NOs: 52 and 53. The amino acid sequences of VL CDR3 13A3, 17C3 and 3G4 are presented in SEQ ID NO: 54. The amino acid sequences of VL CDR3 8B9, 8C4 and 17C8 are presented in SEQ ID NO: 55. The amino acid sequences of VL CDR3 9F6 are presented in SEQ ID NO: 55-57. Amino acid afterbirth

- 34 045913 VL CDR values of mutated antibodies 13A3, 8B9 and 9F6 are the same as those of the corresponding non-mutated antibodies. CDR regions are depicted using the Kabat system (Kabat, E. A., et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242). The Kabat system is the most common numbering system for a system called the EU index or EU numbering system, which is based on the sequential numbering of the first human IgG1 sequenced (the EU antibody; Edelman et al., 1969). Based on the Kabat numbering system described herein, antibody numbering can be converted to other systems known in the art, for example, the Chothia, IMGT, Martin (enhanced Chothia) or AHO numbering system.

In some embodiments, the anti-TIM3 antibodies or an antigen-binding portion thereof comprise:

(a) a heavy chain variable region CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 23-27;

(b) a heavy chain variable region CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 28-38;

(c) a heavy chain variable region CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 39-49;

(d) a CDR1 light chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 50 and 51;

(e) a light chain variable region CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 52 and 53; or (f) a CDR3 light chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 54-57;

where the antibody specifically binds to human TIM3.

In some embodiments, anti-TIM3 antibodies comprise heavy and light chain variable regions, wherein the heavy chain variable region CDR1, CDR2 and CDR3 comprises:

(a) SEQ ID NO: 23, 28 and 39;

(b) SEQ ID NO: 24, 29 and 40;

(c) SEQ ID NO: 25, 30 and 41;

(d) SEQ ID NO:26, 31 and 42;

(e) SEQ ID NO: 27, 32 and 43;

(f) SEQ ID NO: 27, 33 and 44;

(g) SEQ ID NO: 27, 34 and 45;

(h) SEQ ID NO: 23, 35 and 39;

(i) SEQ ID NO: 23, 36 and 39;

(j) SEQ ID NO: 23, 37 and 39;

(k) SEQ ID NO: 23, 28 and 46;

(l) SEQ ID NO: 23, 28 and 47;

(m) SEQ ID NO: 23, 28 and 48;

(n) SEQ ID NO: 23, 28 and 49;

(o) SEQ ID NO: 23, 35 and 46; or (p) SEQ ID NO: 23, 35 and 48;

where the antibody specifically binds to human TIM3.

In some embodiments, the human anti-TIM3 antibody comprises heavy and light chain variable regions, wherein the light chain variable region of CDR1, CDR2 and CDR3 comprises:

(a) SEQ ID NO: 50, 52 and 54;

(b) SEQ ID NO: 50, 52 and 55;

(c) SEQ ID NO: 51, 53 and 56; or (d) SEQ ID NO: 50, 52 and 57;

where the antibody specifically binds to human TIM3.

In some embodiments, the anti-TIM3 antibody comprises heavy and light chain variable regions, wherein:

(a1) the heavy chain variable region includes CDR1, CDR2 and CDR3 containing SEQ ID NOs: 23, 28, and 39, respectively, and the light chain variable region includes CDR1, CDR2 and CDR3 containing SEQ ID NOs: 50, 52, and 54, respectively;

(a2) the heavy chain variable region includes CDR1, CDR2 and CDR3 containing SEQ ID NOs: 23, 35, and 39, respectively, and the light chain variable region includes CDR1, CDR2 and CDR3 containing SEQ ID NOs: 50, 52, and 54, respectively;

(a3) the heavy chain variable region includes CDR1, CDR2 and CDR3 containing SEQ ID NOs: 23, 36, and 39, respectively, and the light chain variable region includes CDR1, CDR2 and CDR3 containing SEQ ID NOs: 50, 52, and 54, respectively;

(a4) the heavy chain variable region includes CDR1, CDR2 and CDR3 containing SEQ ID NO:

- 35 045913

23, 37, and 39, respectively, and the light chain variable region includes CDR1, CDR2 and CDR3 containing SEQ ID NO: 50, 52, and 54, respectively;

(a5) the heavy chain variable region includes CDR1, CDR2 and CDR3 containing SEQ ID NOs: 23, 28, and 46, respectively, and the light chain variable region includes CDR1, CDR2 and CDR3 containing SEQ ID NOs: 50, 52, and 54, respectively;

(a6) the heavy chain variable region includes CDR1, CDR2 and CDR3 containing SEQ ID NOs: 23, 28, and 47, respectively, and the light chain variable region includes CDR1, CDR2 and CDR3 containing SEQ ID NOs: 50, 52, and 54, respectively;

(a7) the heavy chain variable region includes CDR1, CDR2 and CDR3 containing SEQ ID NOs: 23, 28, and 48, respectively, and the light chain variable region includes CDR1, CDR2 and CDR3 containing SEQ ID NOs: 50, 52, and 54, respectively;

(a8) the heavy chain variable region includes CDR1, CDR2 and CDR3 containing SEQ ID NOs: 23, 28, and 49, respectively, and the light chain variable region includes CDR1, CDR2 and CDR3 containing SEQ ID NOs: 50, 52, and 54, respectively;

(a9) the heavy chain variable region includes CDR1, CDR2 and CDR3 containing SEQ ID NOs: 23, 35, and 46, respectively, and the light chain variable region includes CDR1, CDR2 and CDR3 containing SEQ ID NOs: 50, 52, and 54, respectively;

(a10) the heavy chain variable region includes CDR1, CDR2 and CDR3 containing SEQ ID NO: 23, 35, and 48, respectively, and the light chain variable region includes CDR1, CDR2 and CDR3 containing SEQ ID NO: 50, 52. and 54, respectively;

(b1) the heavy chain variable region includes CDR1, CDR2 and CDR3 containing SEQ ID NOs: 24, 29, and 40, respectively, and the light chain variable region includes CDR1, CDR2 and CDR3 containing SEQ ID NOs: 50, 52, and 55, respectively;

(b2) the heavy chain variable region includes CDR1, CDR2 and CDR3 containing SEQ ID NOs: 24, 38, and 40, respectively, and the light chain variable region includes CDR1, CDR2 and CDR3 containing SEQ ID NOs: 50, 52, and 55, respectively;

(c) the heavy chain variable region includes CDR1, CDR2 and CDR3 containing SEQ ID NOs: 25, 30, and 41, respectively, and the light chain variable region includes CDR1, CDR2 and CDR3 containing SEQ ID NOs: 50, 52, and 55, respectively;

(d) the heavy chain variable region includes CDR1, CDR2 and CDR3 containing SEQ ID NOs: 26, 31, and 42, respectively, and the light chain variable region includes CDR1, CDR2 and CDR3 containing SEQ ID NOs: 50, 52, and 54, respectively;

(e) the heavy chain variable region includes CDR1, CDR2 and CDR3 containing SEQ ID NOs: 27, 32, and 43, respectively, and the light chain variable region includes CDR1, CDR2 and CDR3 containing SEQ ID NOs: 50, 52, and 55, respectively;

(f) the heavy chain variable region includes CDR1, CDR2 and CDR3 containing SEQ ID NOs: 27, 32, and 43, respectively, and the light chain variable region includes CDR1, CDR2 and CDR3 containing SEQ ID NOs: 50, 52, and 57, respectively;

(g1) the heavy chain variable region includes CDR1, CDR2 and CDR3 containing SEQ ID NOs: 27, 32, and 43, respectively, and the light chain variable region includes CDR1, CDR2 and CDR3 containing SEQ ID NOs: 51, 53, and 56, respectively;

(g2) the heavy chain variable region includes CDR1, CDR2 and CDR3 containing SEQ ID NOs: 27, 32, and 43, respectively, and the light chain variable region includes CDR1, CDR2 and CDR3 containing SEQ ID NOs: 50, 52, and 57, respectively;

(g3) the heavy chain variable region includes CDR1, CDR2 and CDR3 containing SEQ ID NOs: 27, 32, and 43, respectively, and the light chain variable region includes CDR1, CDR2 and CDR3 containing SEQ ID NOs: 50, 52, and 55, respectively;

(h) the heavy chain variable region includes CDR1, CDR2 and CDR3 containing SEQ ID NOs: 27, 33, and 44, respectively, and the light chain variable region includes CDR1, CDR2 and CDR3 containing SEQ ID NOs: 50, 52, and 54 respectively; or (i) the heavy chain variable region includes CDR1, CDR2 and CDR3 containing SEQ ID NO: 27, 34, and 45, respectively, and the light chain variable region includes CDR1, CDR2 and CDR3 containing SEQ ID NO: 50, 52, and 55, respectively;

where the antibody specifically binds to human TIM3.

In some embodiments, anti-TIM3 antibodies useful for the present disclosure include CDR1 VH, CDR2 VH, CDR3 VL, CDR1 VL, CDR2 VL, and/or CDR3 VL, which are different from the corresponding CDR 13A3, 3G4, 17C3, 17C8, 9F6, 8B9, 8C4 or any of TIM3.2-TIM3.18 in 1, 2, 3, 4, 5, 1-2, 1-3, 1-4 or 1-5 amino acid changes (i.e. substitutions, additions or amino acid deletions). In some embodiments, an anti-TIM3 antibody useful in the present disclosure contains 1-5 amino acid changes in each of the 1, 2, 3, 4, 5, or 6 CDRs relative to the corresponding sequence in 13A3, 3G4, 17C3, 17C8, 9F6, 8B9 , 8С4 or any of TIM3.2 - TIM3.18. In some embodiments, the anti-TIM3 antibody contains a total of 1-5 amino acids

- 36 045913 lot changes in all CDRs relative to CDRs in 13A3, 3G4, 17С3, 17С8, 9F6, 8В9, 8С4 or any of TIM3.2-TIM3.18.

In some embodiments, the anti-TIM3 antibody comprises CDRs VH and VL consisting of CDR 13A3, wherein one or more amino acids in one or more CDRs are amino acids from one of the other anti-TIM3 antibodies described herein.

For example, in some embodiments, the anti-TIM3 antibody contains a CDR1 VH including one or more amino acid modifications relative to SRSYYWG (SEQ ID NO: 23), and may contain, for example, the following degenerate sequence: X ₁ X ₂ X ₃ X ₄ YX ₅ X ₆ (SEQ ID NO: 211), where X1 represents any amino acid, such as S or none; X ₂ represents any amino acid, for example R or none; X ₃ is any amino acid, for example S, R or D; X4 is any amino acid, for example Y or H; X5 is any amino acid, for example W or M; and X ₆ is any amino acid, for example G, N, S or H.

In some embodiments, the anti-TIM3 antibody contains a CDR2 VH including one or more amino acid modifications relative to SIYYSGFTYYNPSLKS (SEQ ID NO: 28), and may contain, for example, the following degenerate sequence: X ₁ IX ₂ X ₃ X ₄ GX ₅ X ₆ X ₇ X ₈ YX ₉ X ₁₀ X ₁₁ X ₁₂ X ₁₃ X ₁₄ (SEQ ID nO: 212), where X1 is any amino acid, for example, S, Y, I or F; X ₂ represents any amino acid, for example, Y, H, N or S; X ₃ is any amino acid, for example Y, P, G, T or S; X4 is any amino acid, for example S, T, R or G; X5 is any amino acid, for example F, S or D; X ₆ is any amino acid, for example S, T or I; X ₇ represents any amino acid, for example, I or none; X8 is any amino acid, for example Y, N or I; X ₉ is any amino acid, for example N, Q, S or A; X ₁₀ is any amino acid, for example P, S, Q or D; X11 is any amino acid, for example S or K; X ₁₂ is any amino acid, for example L, F or V; X ₁₃ is any amino acid, for example K or Q; and X ₁₄ is any amino acid, for example S or G.

In some embodiments, the anti-TIM3 antibody contains a CDR3 VH including one or more amino acid modifications relative to GGPYGDYAHWFDP (SEQ ID NO: 39), and may contain, for example, the following degenerate sequence: X1X2X3X4X5X6X7X8X9X10YGX11X12X13X14X15X16X17X18 (SEQ ID NO: 213), where X i represents is any amino acid, for example, D, E or absent; X ₂ represents any amino acid, for example, F, G or none; X3 is any amino acid, for example Y or none; X4 is any amino acid, for example G, S or none; X5 is any amino acid, for example G, T or S; X6 is any amino acid, for example G or S; X ₇ represents any amino acid, for example, N, W or none; X ₈ represents any amino acid, for example, Y, S, E or none; X9 is any amino acid, for example Y or none; X ₁₀ is any amino acid, for example P or Y; X11 is any amino acid, for example D or none; X ₁₂ is any amino acid, for example Y or none; X ₁₃ is any amino acid, for example A or none; X ₁₄ represents any amino acid, for example, H or none; X ₁₅ is any amino acid, for example, W or absent; X ₁₆ represents any amino acid, for example F or M; X ₁₇ is any amino acid, for example D or E; and X ₁₈ is any amino acid, for example P, I, V, Y or L.

The VH domain or one or more of its CDRs, anti-TIM3 antibodies suitable for the present invention can be linked to a constant domain to form a heavy chain, for example, a full-length heavy chain. Likewise, a VL domain or one or more of its CDRs described herein can be linked to a constant domain to form a light chain, eg, a full-length light chain. The full-length heavy chain (optionally without the C-terminal lysine residue (K) or the C-terminal glycine and lysine residues (GK)) and the full-length light chain combine to form the full-length antibody.

The VH domain of anti-TIM3 antibodies can be fused to a human IgG constant domain, such as IgG1, IgG2, IgG3, or IgG4, which are either naturally occurring or modified, for example, as further described herein. For example, the VH domain may comprise the amino acid sequence of any VH domain described herein fused to a human IgG, such as an IgG1, constant region, such as the following amino acid sequence of a wild-type human IgG1 constant domain:

- 37 045913

W LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDI AVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLS LSPGK (SEQ ID NO: 58) or the constant region in the allotype variant SEQ ID NO: 58 and has the following amino acids sequences:

ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSL

SSWTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKP KDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQD WLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGF YPSDI AVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLS

LSPGK (SEQ ID NO: 59; allotype-specific amino acid residues are in bold and underlined).

The VH domain of an anti-TIM3 antibody may comprise the amino acid sequence of any VH domain described herein fused to an effectorless constant region, for example, the following human IgG1 effectorless constant domain amino acid sequences:

ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSL

SSWTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAEGAPSVFLFPPKP KDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQD WLNGKEYKCKVSNKALPSSIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGF YPSDI AVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLS

LSPGK (SEQ ID NO: 60; IgG1.1f containing mutations L234A, L235E, G237A, A330S and P331S, which are underlined); or

ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSL

SSWTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAEGAPSVFLFPPKP KDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQD WLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGF YPSDI AVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLS

LSPGK (SEQ ID NO: 61; IgGL3f' containing mutations L234A, L235E and G237A, which are underlined).

For example, the IgG1 allotype variant contains K97R, D239E and/or L241M (underlined and in bold above) and numbered according to SEQ ID NO: 59-61. In the full-length heavy region, eg 8C4 (SEQ ID NO: 70) and according to EU numbering, these amino acid substitutions are numbered K214R, D356E and L358M. In some embodiments, the anti-T!M3 antibody constant region may contain one or more mutations or substitutions at amino acids L117, A118, G120, A213, and P214 (underlined above) as numbered in SEQ ID NOs: 59-61 or L234, A235 , G237, A330 and P331, according to EU numbering. In additional embodiments, the constant region of the anti-TIM3 antibody contains one or more mutations or substitutions at amino acids L117A, A118E, G120A, A213S, and P214S of SEQ ID NO: 58 or L234A, L235E, G237A, A330S, and P331S, as defined by EU numbering. The constant region of an anti-TIM3 antibody may also contain one or more mutations or substitutions L117A, A118E and G120A of SEQ ID NO:58 or L234A, L235E and G237A, according to EU numbering.

Alternatively, the VH domain of anti-TIM3 antibodies may contain the amino acid sequence

- 38 045913 the identity of any VH domain described herein fused to a human IgG4 constant region, for example the following human IgG4 amino acid sequence or variants thereof:

ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSL

SSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPSCPAPEFLGGPSVFLFPPKPKDT

LMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLN GKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALH NHYTQKSLSLSL

GK (SEQ ID NO: 63 containing S228P).

The VL domain of anti-TIM3 antibodies can be fused to the human kappa or lambda light chain constant domain. For example, the VL domain of an anti-TIM3 antibody may comprise the amino acid sequence of any VL domain described herein fused to the following human IgG1 kappa light chain amino acid sequence:

RTVAAPSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDST

YSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 64)

In some embodiments, the heavy chain constant region of anti-TIM3 antibodies includes a lysine or other amino acid at the C-terminus, for example, the latter amino acids are: LSPGK (SEQ ID NO: 65) in the heavy chain. In some embodiments, the heavy chain constant region does not contain one or more amino acids at the C-terminus, and has, for example, the C-terminal sequence LSPG (SEQ ID NO: 66) or LSP (SEQ ID NO: 67).

The amino acid sequences of the heavy and light chains of exemplary anti-TIM3 antibodies correspond to SEQ ID NO: 68-189 for heavy chains and SEQ ID NO: 190-193 for light chain.

In some embodiments, anti-TIM3 antibodies suitable for the present disclosure include:

(a1) the heavy and light chain sequences being SEQ ID NO: 136 (or 137) and 190, respectively;

(a2) the heavy and light chain sequences being SEQ ID NO: 68 (or 75) and 190, respectively;

(a3) the heavy and light chain sequences being SEQ ID NO: 82 (or 89)) and 190, respectively;

(a4) the heavy and light chain sequences being SEQ ID NO: 138 (or 139) and 190, respectively;

(a5) the heavy and light chain sequences being SEQ ID NO: 96 (or 106) and 190, respectively;

(a6) the heavy and light chain sequences being SEQ ID NO: 116 (or 126) and 190, respectively;

(a7) the heavy and light chain sequences being SEQ ID NO: 140 (or 141) and 190, respectively;

(a8) the heavy and light chain sequences being SEQ ID NO: 97 (or 107) and 190, respectively;

(a9) the heavy and light chain sequences being SEQ ID NO: 117 (or 127) and 190, respectively;

(a10) the heavy and light chain sequences being SEQ ID NOs: 142 (or 143) and 190, respectively;

(a11) the heavy and light chain sequences being SEQ ID NO: 98 (or 108) and 190, respectively;

(a12) the heavy and light chain sequences being SEQ ID NO: 118 (or 128) and 190, respectively;

(a13) the heavy and light chain sequences being SEQ ID NO: 144 (or 145) and 190, respectively;

(a14) the heavy and light chain sequences being SEQ ID NO: 99 (or 109) and 190, respectively;

(a15) the heavy and light chain sequences being SEQ ID NO: 119 (or 129) and 190, respectively;

(a16) the heavy and light chain sequences being SEQ ID NO: 146 (or 147) and 190, respectively;

- 39 045913 (a17) sequences 110) and 190, respectively;

(a18) sequences 130) and 190, respectively;

(a19) sequences 149) and 190, respectively;

(a20) sequences 111) and 190, respectively;

(a21) sequences 131) and 190, respectively;

(a22) sequences 151) and 190, respectively;

(a23) sequences 112) and 190, respectively;

(a24) sequences 132) and 190, respectively;

(a25) sequences 153) and 190, respectively;

(a26) sequences 113) and 190, respectively;

(a27) sequences 133) and 190, respectively;

(a28) sequences 155) and 190, respectively;

(a29) sequences 185) and 190, respectively;

(a30) sequences 187) and 190, respectively;

(a31) the heavy and light chain sequences of SEQ ID NOs: 100 (or the heavy and light chains of SEQ ID NOs: 120 (or the heavy and light chains of SEQ ID NOs: 148 (or the heavy and light chains of SEQ ID NOs: 148) , heavy and light chains, heavy and light chains, heavy and light chains, heavy and light chains, heavy and light chains, heavy and light chains, heavy and light chains, heavy and light chains, heavy and light chains, heavy and light chains , heavy and light chains,

SEQ ID NO: 101 (or

SEQ ID NO: 121 (or

SEQ ID NO: 150 (or

SEQ ID NO: 102 (or

SEQ ID NO: 122 (or

SEQ ID NO: 152 (or

SEQ ID NO: 103 (or

SEQ ID NO: 123 (or

SEQ ID NO: 154 (or

SEQ ID NO: 184 (or

SEQ ID NO: 186 (or

SEQ ID NO: 188 (or representing representing representing representing representing representing representing representing representing representing representing representing representing representing

189) and 190, respectively;

(b1) the heavy and light chain sequences being SEQ ID NO: 156 (or 157) and 191, respectively;

(b2) the heavy and light chain sequences being SEQ ID NO: 69 (or 76) and 191, respectively;

(b3) the heavy and light chain sequences being SEQ ID NO: 83 (or 90) and 191, respectively;

(b4) the heavy and light chain sequences being SEQ ID NOs: 158 (or 159) and 191, respectively;

(b5) the heavy and light chain sequences being SEQ ID NO: 104 (or 114) and 191, respectively;

(b6) the heavy and light chain sequences being SEQ ID NO: 124 (or 134) and 191, respectively;

(b7) the heavy and light chain sequences being SEQ ID NO: 160 (or 161) and 191, respectively;

(c1) the heavy and light chain sequences being SEQ ID NO: 162 (or 163) and 191, respectively;

(c2) the heavy and light chain sequences being SEQ ID NO: 70 (or 77) and 191, respectively;

(c3) the heavy and light chain sequences being SEQ ID NO: 84 (or 91) and 191, respectively;

(c4) the heavy and light chain sequences being SEQ ID NO: 164 (or 165) and 191, respectively;

(d1) the heavy and light chain sequences being SEQ ID NO: 166 (or 167) and 190, respectively;

(d2) the heavy and light chain sequences being SEQ ID NO: 71 (or 78) and 190, respectively;

(d3) the heavy and light chain sequences being SEQ ID NO: 85 (or 92) and 190, respectively;

(d4) the heavy and light chain sequences being SEQ ID NO: 168 (or 169) and 190, respectively;

(e1.1) the heavy and light chain sequences being SEQ ID NO: 170 (or 171) and 192, respectively;

- 40 045913 (e1.2) heavy and light chain sequences representing SEQ ID NO: 170 (or 171) and 193, respectively;

(e1.3) the heavy and light chain sequences being SEQ ID NO: 170 (or 171) and 191, respectively;

(e2) the heavy and light chain sequences being SEQ ID NO: 72 (or 79) and 193, respectively;

(e3) the heavy and light chain sequences of SEQ ID NO: 86 or 93) and 193, respectively;

(e4) the heavy and light chain sequences being SEQ ID NO: 172 (or 173) and 193, respectively;

(e5) the heavy and light chain sequences being SEQ ID NO: 105 (or 115) and 193, respectively;

(e6) the heavy and light chain sequences being SEQ ID NO: 125 (or 135) and 193, respectively;

(e7) the heavy and light chain sequences of SEQ ID NO: 174 (or 175) and 193, respectively;

(f1) the heavy and light chain sequences being SEQ ID NO: 176 (or 177) and 190, respectively;

(f2) the heavy and light chain sequences being SEQ ID NO: 73 (or 80) and 190, respectively;

(f3) the heavy and light chain sequences being SEQ ID NO: 87 (or 94) and 190, respectively;

(f4) the heavy and light chain sequences being SEQ ID NO: 178 (or 179) and 190, respectively;

(g1) the heavy and light chain sequences being SEQ ID NO: 180 (or 181) and 191, respectively;

(g2) the heavy and light chain sequences being SEQ ID NO: 74 (or 81) and 191, respectively;

(g3) the heavy and light chain sequences being SEQ ID NO: 88 (or 95) and 191, respectively; or (g4) the heavy and light chain sequences being SEQ ID NO: 182 (or 183) and 191, respectively;

where the antibody specifically binds to human TIM3.

Nucleic acid sequences encoding the heavy chain sequences of the TIM3 antibodies described herein (eg, in the previous section) are provided as SEQ ID NOs: 214-241, 247-291, 294-297. The nucleic acid sequences encoding the light chain sequences of the TIM3 antibodies described herein (e.g., in the previous section) are provided as SEQ ID NOs: 242-246 and 299.

In some embodiments, the anti-TIM3 antibody contains a combination of heavy and light chain sequences set forth herein, such as in the previous section, where the antibody contains two heavy chains and two light chains and may further contain at least one disulfide bond, linking two heavy chains together. Antibodies may also contain disulfide bonds linking each of the light chains to each of the heavy chains.

In other embodiments, the anti-TIM3 antibodies are human antibodies, humanized antibodies, or chimeric antibodies. In some embodiments, anti-TIM3 antibodies bind to a conformational epitope. In other embodiments, anti-TIM3 antibodies bind to amino acid residues in the following region of the extracellular domain of mature human TIM3 (SEQ ID NO: 198):

SEVEYRAEVGQNAYLPCFYTPAAPGNLVPVCWGKGACPVFECGNWLRTDERDVNYWTSRYWLNG

DFRKGDVSLTIENVTLADSGIYCCRIQIPGIMND (SEQ ID NO: 203), which corresponds to amino acid residues 1-99 of the extracellular domain of mature human TIM3 (SEQ ID NO: 198) or amino acids 22-120 of human TIM3 having SEQ ID NO: 194. In some embodiments, anti-TIM3 The antibodies described herein bind to amino acid residues in the following region of the human mature TIM3 extracellular domain (SEQ ID NO: 198): CPVFECG (SEQ ID NO: 200), which corresponds to amino acid residues 37-43 of the human mature TIM3 extracellular domain (SEQ ID NO: 198).

In some embodiments, anti-TIM3 antibodies bind to amino acid residues within the following region of the human mature TIM3 extracellular domain (SEQ ID NO: 198): WTSRYWLNGDFR (SEQ ID NO: 201), which corresponds to amino acid residues 57-83 of the human mature TIM3 extracellular domain (SEQ ID NO: 198).

- 41 045913

In some embodiments, anti-T1M3 antibodies bind to amino acid residues within the following region of the extracellular domain of mature human TIM3 (SEQ ID NO: 198): RIQIPGIMND (seq id no:

202), which corresponds to amino acid residues 90-99 of the extracellular domain of mature human TIM3 (SEQ ID NO: 198).

In some embodiments, anti-TIM3 antibodies have the same mode of binding to wild type and mutated human TIM3 as one or more of antibodies 13A3, 3G4, 17C3, 17C8, 9F6, 8B9, 8C4, and TIM3.2 to TIM3.18. In some embodiments, anti-TIM3 antibodies bind to amino acid residues within the following regions of the extracellular domain of mature human TIM3 (SEQ ID NO: 198):

CPVFECG (SEQ IDNO: 200), WTSRYWLNGDFRKGDVSLTIENVTLAD (SEQ Ш NO: 201), and/or RIQIPGIMND (SEQ Ш NO: 202).

In some embodiments, the anti-TIM3 antibody binds to (1) ⁴⁹ VPVCWGKGACPVFE ⁶² (SEQ IDNO: 204) and mRIQIPGIMNDEKFNLKL ¹²⁷ (SEQ IDNO: 205), or (2) ⁴⁰ YTPAAPGNLVPVCWGKGACPVFE ⁶² (SEQ IDNO: 206), ⁶⁶ WLRTDERDVNY ⁷⁷ (SEQ ID NO: 207), ⁷⁸ WTSRYWLNGDFRKGDVSL ⁹⁵ (SEQ ID NO: 208), ¹¹⁰ CRIQIPGIMNDEKFNLKL ¹²⁷ (SEQ ID NO: 209), and ¹¹⁹ NDEKFNLKL ¹²⁷ (SEQ ID NO: 210),

MS. In some embodiments, the anti-TIM3 antibody interacts with regions of amino acid residues 40-62 and 111-127 of hTIM3, but does not significantly interact with other regions, such as the region that is N-terminal to amino acid residue Y40, a region that is located between amino acid residues E62 and R111, and a region that is C-terminal to amino acid residue L127, as determined by HDX-MS. In some embodiments, the anti-TIM3 antibody has reduced binding to human TIM3, wherein one or more amino acids L48, C58, P59, V60, F61, E62, C63, G64, W78, S80, R81, W83, L84, G86, D87, R89, D104, R111, Q113, G116, M118 and D120 (as numbered in SEQ ID NO: 194) are replaced with a different amino acid relative to binding to wild-type human TIM3, and the antibody binds to (1) ⁴⁹ VPVCWGKGACPVFE ⁶² (SEQ ID NO: 204 ) and ---РЛQIPGIMNDEKFNLKL- ² ' ⁷ (SEQ ID NO: 205) or (2) ⁴⁰ YTPAAPGNLVPVCWGKGACPVFE ⁶² (SEQ IDNO: 206), ⁶⁶ VVLRTDERDVNY ⁷⁷ (SEQ ID NO: 207), ⁷⁸ WTSRYWLNGDFRKGDVSL ⁹⁵ (SEQ ID NO: 208), ¹¹⁰ CRIQIPGIMNDEKFNLKL ¹²⁷ (SEQ ID NO: 209), and ¹¹⁹ NDEKFNLKL ¹²⁷ (SEQ ID NO: 210), as determined by HDX-MS.

In some embodiments, the anti-TIM3 antibody has the same mode of binding to wild-type human TIM3 and mutated human TIM3 as TIM3.18.IgG1.3 or 13A3, that is, the antibody:

(i) binds to (1) ⁴⁹ VPVCWGKGACPVFE ⁶² (SEQ ID NO: 204), ⁿⁱ RIQIPGIMNDEKFNLKL ¹²⁷ (SEQ ID NO: 205) and ¹¹⁹ NDEKFNLKL ¹²⁷ (SEQ ID NO: 210), and, for example, does not significantly bind to (a ) peptides having sequences located at the N-terminus of amino acid residue 49; (b) peptides having sequences located between amino acid residues 62 and 111, for example, ⁷⁸ WTSRYWLNGDFRKGDVSL ⁹⁵ (SEQ id NO: 208)); and (c) peptides having sequences that are located at the C-terminus of amino acid residue 127, as determined by HDX-MS;

(ii) does not bind to human TIM3 or significantly reduces binding to human TIM3, having one or more of the following amino acid mutations, as determined, for example, using the yeast surface display method: C58, P59, F61, E62, C63, R111, D120 and optionally D104 and Q113 (numbered by SEQ ID NO: 194); and/or (ii i) has heavy chain and/or light chain variable regions interacting with at least 5, 10, 15, 20 or all of the following amino acids of human TIM3: P50, V51, C52, P59, V60, F61 , E62, C63, G64, N65, V66, V67, L68, R69, D71, E72, D74, R111, Q113, G116, I117, M118, D120 and optionally T70 and/or I112, as determined by X-ray crystallography (numbered by SEQ ID NO: 194).

In some embodiments, the anti-TIM3 antibody includes a heavy chain and a light chain,

- 42 045913 wherein the heavy chain is selected from the group consisting of SEQ ID NOs: 68-189 and the light chain is selected from the group consisting of SEQ ID NOs: 190-193.

As further discussed herein, the heavy chain constant region of the anti-TIM3 antibodies described herein can be of any isotype, such as IgG1, IgG2, IgG3 and IgG4, or combinations thereof and/or modifications thereof. The anti-T1M3 antibody may have effector function or may have reduced or non-effector function. In some embodiments, anti-TGM3 antibodies comprise a modified heavy chain constant region that provides improved properties to the antibody.

Additional TIM3 antagonists that may be used in the methods described herein include MBG-453, TSR-022, TRL-6061, BGBA425, LY-3321367, and any other TIM3 inhibitors, such as antibodies, peptides, small molecules, and bispecific molecules such as as bispecific antibodies (for example, anti-TIM3/anti-PD-1 bispecific molecules). TIM-3 antagonists are described, for example, in WO 2011/155607, WO 2011/159877, WO 2013/006490, CN 2010/4592388, WO 2015/109931, WO 2015/117002, WO 2016/068803, WO 2 016/068802, WO 2016/071448, WO 2016/111947, WO 2016/144803, WO 2016/161270, WO 2017/019897, US 2017/0029485, WO 2017/031242, WO 2017/055399, WO 201 7/055404, WO 2017/079112, WO 2017/079115, WO 2017/079116, PCT Appl. No. PCT/US2017/041946 and/or CN 2010/6632675.

PD-1 antagonists.

In one aspect, the present disclosure relates to methods of using a TIM3 antagonist in combination with a PD-1 antagonist. As used herein, PD-1 antagonists include, but are not limited to, PD-1 binding agents, PD-L1 binding agent and PD-L2 binding agents. PD-1 binding agents include antibodies that specifically bind to PD-1. PD-L1 and PD-L2 binding agents include antibodies that specifically bind to PD-L1 and/or PD-L2, as well as soluble PD-1 polypeptides that bind to PD-L1 and/or PD-L2.

Anti-PD-I antibodies.

Certain aspects of the present disclosure include administering to a subject in need thereof a therapeutically effective amount of an anti-PD-1 antibody or antigen-binding portion thereof. Human antibodies (HuMabs) that specifically bind to PD-1 with high affinity have been disclosed in US Patent No. 8,008,449. Other anti-PD-1 mAbs have been described, for example, in US Patent Nos. 6,808,710, 7,488,802, 8,168,757 and 8,354,509 and PCT publication WO 2012/145493. Each of the anti-PD-1 HuMAbs disclosed in US Pat. No. 8,008,449 has been demonstrated to exhibit one or more of the following characteristics: (a) binds to human PD-1 with a KD of 1 x 10 ^-7 M or less, as this was determined by surface plasmon resonance using the Biacore biosensor system; (b) does not substantially bind to human CD28, CTLA-4 or ICOS; (c) increases T cell proliferation in a Mixed Lymphocyte Reaction (MLR) assay; (d) increases interferon-gamma production in the MLR assay; (e) increases IL-2 secretion in the MLR assay; (f) binds to human PD-1 and cynomolgus PD-1; (g) inhibits the binding of PD-L1 and/or PD-L2 to PD-1; (h) stimulates antigen-specific memory responses; (i) stimulates antibody responses and (j) inhibits tumor cell growth in vivo. Anti-PD-1 Abs useful in the present invention include mAbs that specifically bind to human PD-1 and exhibit at least one, in some embodiments, at least five of the previous characteristics. In some embodiments, the anti-PD-1 antibody is nivolumab (OPDIVO®). In some embodiments, the anti-PD-1 antibody is pembrolizumab (KEYTRUDA®). In one embodiment, the anti-PD-1 antibody is nivolumab. Nivolumab (also known as OPDIVO®, formerly called 5C4, BMS-936558, MDX-1106 or ONO-4538) is a fully human IgG4 (S228P) antibody that acts as an inhibitor of the immune checkpoint receptor PD-1 that selectively prevents interaction with PD-1 ligands (PD-L1 and PD-L2), thereby blocking the down-regulation of antitumor T cell functions (US Patent No. 8,008,449; Wang et al., 2014 Cancer Immunol Res. 2(9):846-56). In another embodiment, the anti-PD-1 antibody is pembrolizumab. Pembrolizumab (also known as KEYTRUDA®, lambrolizumab and MK-3475) is a humanized monoclonal IgG4 antibody directed against the human cell surface receptor PD-1 (programmed death-1 or programmed cell death-1). Pembrolizumab is described, for example, in US patent Nos. 8,354,509 and 8,900,587; see also http://www.cancer.gov/dmgdictionary?cdrid=695789 (last accessed December 14, 2014). Pembrolizumab has been approved by the FDA for the treatment of relapsed or refractory melanoma.

In other embodiments, the anti-PD-1 antibody or fragment thereof cross-competes with MEDI0608. In yet other embodiments, the anti-PD-1 antibody or fragment thereof binds to the same epitope as MEDI0608. In some embodiments, the anti-PD-1 antibody has the same CDRs as MEDI0608. In other embodiments, the anti-PD-1 antibody is

- 43 045913

MEDI0608 (formerly known as AMP-514), which is a monoclonal antibody. MEDI0608 is described, for example, in US Pat. No. 8,609,089B2.

In some embodiments, the PD-1 antagonist is AMP-224, which is an F7 B7-DC fusion protein. AMP-224 is discussed in US Publication No. 2013/0017199 and worldwideweb.cancer.gov/publications/dictionaries/cancer-drug?cdrid=700595 (last accessed July 8, 2015). In some embodiments, the anti-PD-1 antibody is BGB-A317, which is a humanized monoclonal antibody. BGB-A317 is described in US Publication No. 2015/0079109.

Anti-PD-I antibodies used in the disclosed methods also include isolated Abs that specifically bind to human PD-1 and cross-compete for binding to human PD-1 with nivolumab (see, e.g., U.S. Patent Nos. 8,008,449 and 8,779,105; WO 2013/173223). The ability of an Ab to cross-compete for binding to an antigen indicates that the Abs bind to the same epitope region of the antigen and sterically interfere with the binding of other cross-competing Abs to that particular epitope region. Such cross-competitive Abs are expected to have functional properties very similar to those of nivolumab due to their binding to the same PD-1 epitope region. Cross-competing Abs can be readily identified based on their ability to cross-compete with nivolumab in standard PD-1 binding assays such as the Biacore assay, ELISA assays or flow cytometry (see, for example, WO 2013/173223).

In some embodiments, antibodies that cross-compete for binding to human PD-1 or bind to the same epitope region of human PD-1 as nivolumab are monoclonal antibodies. For the purpose of administration to human subjects, such cross-competitive antibodies are chimeric antibodies or humanized or human antibodies.

Such chimeric, humanized or human monoclonal antibodies can be prepared and isolated by methods well known in the art. Ahtu-PD-1-AB used in the methods of the described invention also include antigen-binding fragments of the above antibodies. It has been clearly demonstrated that the antigen-binding function of an antibody can be carried out by fragments of a full-length antibody. Examples of binding fragments encompassed by the term antigen-binding moiety of an antibody include (i) a Fab fragment, a monovalent fragment consisting of the VL, VH, CL and CH1 domains; (ii) F(ab') ₂ fragment, a bivalent fragment containing two Fab fragments linked by a disulfide bridge in the hinge region; (iii) Fd fragment consisting of VH and CH1 domains; and (iv) an Fv fragment consisting of the VL and VH domains of one arm of the antibody. Anti-PD-I antibodies suitable for use in the disclosed methods or compositions are antibodies that bind to PD-1 with high specificity and affinity, block the binding of PD-L1 and/or PD-L2, and inhibit the immunosuppressive effects of PD-1 signaling pathway. In any of the compositions or in any of the methods disclosed herein, the anti-PD-1 antibody includes an antigen binding moiety or fragment that binds to the PD-1 receptor and exhibits functional properties similar to those of whole antibodies in inhibiting ligand binding and in up-regulation of the immune system. In some embodiments, the anti-PD-1 antibody or antigen-binding portion thereof cross-competes with nivolumab for binding to human PD-1. In other embodiments, the anti-PD-1 antibody or antigen-binding portion thereof is a chimeric, humanized, or human monoclonal antibody or portion thereof. In some embodiments, the antibody is a humanized antibody. In other embodiments, the antibody is a human antibody. Antibodies of the IgG1, IgG2, IgG3 or IgG4 isotype can be used.

In some embodiments, the anti-RP-1 antibody or antigen-binding portion thereof comprises a heavy chain constant region that is an isotype of human IgG1 or IgG4. In some other embodiments, the IgG4 constant region sequence of an α anti-PD-1 α antibody heavy chain or an antigen binding portion thereof comprises the S228P mutation, which replaces a serine residue in the hinge region with a proline residue typically found at the corresponding position in IgG1 isotype antibodies. This mutation, which is present in nivolumab, prevents the exchange of the Fab arm with endogenous IgG4 antibodies, while maintaining low affinity for activation of Fc receptors associated with wild-type IgG4 antibodies (Wang et al., 2014 Cancer Immunol Res. 2( 9):846-56). In other embodiments, the antibody comprises a light chain constant region that is a human kappa or lambda chain constant region. In other embodiments, the anti-PD-1 antibody or antigen-binding portion thereof is a mAb or antigen-binding portion thereof. In some embodiments, any of the therapeutic methods described in the present invention, including the administration of an anti-PD-1 antibody, the anti-PD-1 antibody is nivolumab. In other embodiments, the anti-PD-1 antibody is pembrolizumab. In other embodiments, the anti-PD-1 antibody is selected from the human antibodies 17D8, 2D3, 4H1, 4A11, 7D3 and 5F4 described in US Pat. No. 8,008,449.

- 44 045913

In yet other embodiments, the anti-PD-1 antibody is MEDI0608 (formerly known as AMP-514), AMP-224, PDR001, or BGB-A317.

Anti-PD-LI antibodies.

In some embodiments, the anti-PD-1 antibody used in the methods may be replaced with another PD-1 or anti-PD-L1 antagonist. For example, since an anti-PD-L1 antibody prevents the interaction between PD-1 and PD-L1, thereby having similar effects on the PD-1 signaling pathway, an anti-PD-L1 antibody may replace the use of an anti-PD-1 antibody in methods described in the present invention. Thus, certain aspects of the present disclosure include administering to a subject in need thereof a therapeutically effective amount of an anti-PD-L1 antibody or antigen-binding portion thereof. In some embodiments, the anti-PD-LL· antibody used in the methods is BMS-936559 (formerly 12A4 or MDX-1105) (see, for example, US Pat. No. 7,943,743; WO 2013/173223). In other embodiments, the anti-PD-L1 antibody is MPDL3280A (also known as RG7446) (see, e.g., Herbst et al. (2013) J Clin Oncol 31 (suppl): 3000. Abstract; US Patent No. 8,217,149), MEDI4736 (also called durvalumab (IMFINZI®); Khleif (2013) in: Proceedings of the European Cancer Congress 2013; September 27–October 1, 2013; Amsterdam, the Netherlands). In some embodiments, antibodies that cross-compete for binding to human PD-L1 or bind to the same epitope region of human PD-L1 as the above PD-L1 antibodies are mAbs. In some embodiments, the anti-PD-L1 antibody or antigen-binding portion thereof competes for binding to BMS-936559, MPDL3280A, MEDI4736, or MSB0010718C to human PD-L1. For administration to human subjects, these cross-competitive antibodies may be chimeric antibodies or may be humanized or human antibodies. Such chimeric, humanized or human mAbs can be prepared and isolated by methods well known in the art; see US Patent No. 8,779,108 or US Patent Application 2014/0356353 filed May 6, 2014) or MSB0010718C (also called avelumab (BAVENCIO®)); see US patent application 2014/0341917). In some embodiments, the anti-PD-L1 antibody or antigen-binding portion thereof comprises a heavy chain constant region that is an isotype of human IgG1 or IgG4. In some embodiments, the anti-PD-Lt antibody is BMS-936559. In some embodiments, the anti-PD-Lt antibody is MPDL3280A (atezolizumab (TECENTRIQ®)). In some embodiments, the αanti-PD-L1 antibody is MEDI4736 (durvalumab (IMFINZI®)). In some embodiments, the anti-PD-L1 antibody is MSB0010718C (avelumab (BAVENCIO®)).

Pharmaceutical compositions.

Pharmaceutical compositions suitable for administration to patients are typically formulated for parenteral administration, for example, in a liquid carrier, or suitable for reconstitution in a liquid solution, or as a suspension for intravenous administration.

In general, such compositions typically contain a pharmaceutically acceptable carrier. As used herein, the term pharmaceutically acceptable means approved by a government regulatory agency or listed in the United States Pharmacopoeia or other generally accepted pharmacopoeia for use in animals, particularly humans. The term carrier refers to the diluent, adjuvant, excipient or carrier medium with which the compound is administered. Such pharmaceutical carriers may be sterile liquids such as water and oils, including petroleum oils, oils of animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, glycerin-polyethylene glycol ricinoleate and the like. As carriers, water or an aqueous solution, saline and aqueous solutions of dextrose and glycerol can be used, in particular for injection solutions, for example, containing a TIM3 antagonist and/or a PD-1 antagonist. Liquid compositions for parenteral administration can be formulated for administration by injection or continuous infusion. Routes of administration by injection or infusion include intravenous, intraperitoneal, intramuscular, intrathecal and subcutaneous. In some embodiments, the TIM3 antagonist and the PD-1 antagonist are administered intravenously, for example, in separate formulations, or together (in the same formulation or in separate formulations).

Patient populations.

Provided herein are clinical methods for treating cancer in human patients using immunotherapy described herein, for example, a TIM3 antagonist (eg, anti-TIM3 antibody), alone or in combination with another immune checkpoint inhibitor (eg, anti-PD- 1 antibody).

Examples of cancers that can be treated using the methods of the invention include liver cancer, hepatocellular carcinoma (HCC), bone cancer, pancreatic cancer, skin cancer, oral cancer, head or neck cancer, breast cancer, lung cancer, small cell lung cancer, NSCLC, cutaneous or intraocular malignant melanoma, kidney cancer, uterine cancer, ovarian cancer, colorectal cancer, colon cancer, rectal cancer, anal cancer,

- 45 045913 stomach cancer, testicular cancer, uterine cancer, fallopian tube carcinoma, endometrial carcinoma, cervical carcinoma, vaginal carcinoma, vulvar carcinoma, squamous cell carcinoma of the head and neck (SCCHN), non-Hodgkin's lymphoma, esophageal cancer, small intestine cancer, endocrine cancer systems, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, childhood solid tumors, lymphocytic lymphoma, bladder cancer, kidney or ureter cancer, renal pelvic carcinoma, central nervous system neoplasia ( CNS), primary CNS lymphoma, tumor angiogenesis, spinal tumor, brainstem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, environmental cancers including asbestos-related cancers, hematologic malignancies including e.g. multiple myeloma, B-cell lymphoma, Hodgkin's lymphoma/primary mediastinal B-cell lymphoma, non-Hodgkin's lymphomas, acute myeloid lymphoma, chronic myeloid leukemia, chronic lymphocytic leukemia, follicular lymphoma, diffuse large cell lymphoma, Burkitt's lymphoma, immunoblastic large cell lymphoma, B-lymphoblast precursor lymphomas, mantle cell lymphoma, acute lymphoblastic leukemia, mycosis fungoides, anaplastic large cell lymphoma, T-cell lymphoma, precursor T-lymphoblastic lymphoma, and any combination of these cancers. The present invention is also applicable to the treatment of metastatic cancers.

In some embodiments, patients suffer from cancer that is refractory to treatment with an immune checkpoint inhibitor. In some embodiments, the patient suffers from cancer that is not responsive to treatment with a PD-1 antagonist (eg, an anti-PD-1 antibody or an anti-PDL1 antibody). In some embodiments, the cancer is a solid tumor. In other embodiments, the cancer is colon, kidney, or lung cancer. Subjects may be examined or selected for one or more of the above-described clinical features before, during, or after treatment.

Types of immunotherapy.

In one aspect, immunotherapies provided herein include administration of a TIM3 antagonist (e.g., an anti-TIM3 antibody), alone or in combination with another immune checkpoint inhibitor (e.g., a PD-1 antagonist, e.g., an anti-PD-1 antibody ) for the treatment of subjects with cancer. In a specific embodiment, the TIM3 antagonist is an anti-TIM3 antibody described herein. In some embodiments, the PD-1 antagonist is the anti-PD-1 antibody nivolumab. In some embodiments, dosing regimens are adjusted to provide the optimal desired response (eg, effective response).

As used herein, additional or combined administration (co-administration) includes simultaneous administration of compounds in the same or different dosage forms or separate administration of compounds (eg, sequential administration). For example, a TIM3 antagonist and a PD-1 antagonist can be administered simultaneously in the same composition. Alternatively, the TIM3 antagonist and the PD-1 antagonist can be formulated to be administered separately and administered simultaneously or sequentially, for example, one antibody is administered about 30 minutes before the second antibody is administered.

For example, a TIM3 antagonist may be administered first, followed (eg immediately) by a PD-1 antagonist, or vice versa. In some embodiments, the PD-1 antagonist is administered before the TIM3 antagonist is administered. In some embodiments, the PD-1 antagonist is administered after administration of the TIM3 antagonist. In other embodiments, the TIM3 antagonist and the PD-1 antagonist are administered simultaneously. Such simultaneous or sequential administration preferably results in both antagonists being simultaneously present in the subjects receiving treatment.

The following examples are offered as illustrations and not as limitations. The contents of all references cited in this application are expressly incorporated herein by reference.

Examples

Example 1. Analysis of TIM3 expression levels on CD4 and CD8 T lymphocytes in cancer patients.

To begin evaluating the utility of using TIM3 expression to identify subjects (eg, human cancer patients) suitable for TIM3 antagonist treatment, fresh tumor tissue and matched peripheral blood samples were obtained from patients with lung, kidney, or colon cancer (ConversantBio, MT Group, Benaroya) and sent to the laboratory for analysis. Tumor tissue and blood samples were sent the night before at 4°C to HypoThermosol FRS (Biolife Solutions) and ACD Solution A (BD Biosciences), respectively. Samples were processed and analyzed within 24 h of collection.

Processing of tissues for immunophenotyping.

Tumor tissues were weighed and dissociated using a Miltenyi dissociation kit (Miltenyi, catalog number 130-095-929). Peripheral blood cells were treated with buffer

- 46 045913 for red blood cell (RBC) lysis (BioLegend, catalog number 420301). Cell suspensions (from tumor tissues or peripheral blood) were then washed twice in HBSS (no Ca, no Mg), stained with NIR Viability Dye (Molecular Probes by Life Technologies, catalog number L34976), blocked with human AB serum in phosphate Dulbecco's buffered saline (dPBS) and added to wells containing antibody cocktails (see Table 1 below) for incubation on ice in the dark for 45 min. Cells were then washed twice with dPBS/BSA/Na azide, fixed, and permeabilized using FoxP3 buffer kit (BioLegend, cat. no. 421403). Fluorescence controls with a combination of detectable labels minus one (FMO) were prepared for all antibodies and used to determine positive cell populations. Samples were acquired on a Fortessa flow cytometer (BD Biosciences), and data were analyzed using FlowJo software (TreeStar).

Antibody staining for flow cytometry analysis.

As shown in table. 1 (below), a 15-color panel was developed to test the expression of several markers; focused on TIM3 expression on CD8+ and CD4+ T cells.

Table 1

Antibodies used for immunofluorescence staining for T cell subsets

Marker Clone Fluorophore Provider Catalog no. Viability — Near IR ThermoFisher Scientific L10119 CD45 HI30 AF700 BD Biosciences 560566 CD3 SK7 BUV 395 BD Biosciences 564001 CD4 OKT4 BV 785 BioLegend 317442 FoxP3 206D AF647 BioLegend 320114 CD8a SKI BV605 BD Biosciences 564116 CD25 4E3 RE-e610 eBioscience 61-0257-42 PD-1 EH12.1 RegSR-Su5.5 Biolegend 329914 Tim-3 FAB2365G AlexaFluor488 R&D

As shown in table. 2 (below) and FIG. 1A and 1B, very few CD4+ and CD8+ T cells expressed TIM3 in whole blood of both healthy subjects and cancer patients. The frequency of TIM3+ CD4+ was slightly higher in TILs compared with whole blood, with no significant differences across tumor types (see Figures 2A and 2B). Compared to CD4+ T cells, a greater percentage of CD8+ T cells were TIM3+, with average frequencies ranging from 9.9 to 21% depending on tumor type. RCC and to a lesser extent CRC tended to show higher frequencies of TIM3+ CD8+ T cells than lung cancer patients; see table 3 (below) and fig. 2A and 2B.

table 2

Mean frequencies ± SD of TIM3+ CD4+ and TIM3+ CD8+ T cells in peripheral blood samples from healthy donors and patients with oncological disease (cancer)

Healthy (N=20) Lung cancer (N=15) RCC (N=19) CRC (N=16) % TIM3+ CD4+ T cells 1.1 ±0.4 1.3 ±0.6 1.4 ±0.8 1.2 ±0.6 % TIM3+ CD8+ T cells 1.3 ±0.4 1.9 ±1.3 1.8 ±1.2 23 ±14

Designations: N: sample number;

SD: standard deviation;

RCC: renal cell carcinoma;

CRC: colorectal carcinoma.

In addition to TIM3 expression, PD-1 expression was also assessed in TILs described above. As shown in table. 3 (below) and FIG. 2C and 2D, coexpression of PD-1 with TIM3+ cells varied significantly among patients, with patients having a higher frequency of TIM3+ CD8+ T cells (i.e., at least 8%, which was the average %TIM3+ CD8+ T cells in all three cancer types) showing higher coexpression with PD-1 compared with patients with lower frequencies of TIM3+ CD8+ T cells (see Fig. 2E, Mann-Whitney p < 0.0001).

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Table 3

Mean ± SD frequencies of TIM3+ and PD-1+ TIM3+ CD4+ and CD8+ T cells in TILs from cancer patients

Lung cancer RCC CRC (N=18) (N=23) (N=17)

% TIM3+ CD4+ T cells 6.7 ±4.5 6.2 ±6.6 7.4 ±7.1 % TIM3+ CD8+ T cells 9.9 ±11 21 ±23 15 ±15 % PD-1±(TIM3± CD4+ T cells) 58 ±11 47 ±20 53 ±25 % PD-1+ (TIM3+ CD8+ T cells) 58 ±17 63 ±32 72 ±16

Legend: SD: standard deviation;

TIL: tumor infiltrating lymphocytes;

RCC: renal cell carcinoma;

CRC: colorectal carcinoma;

N: sample number.

Example 2: Analysis of TIM3 expression in different T cell subsets.

To evaluate TIM3 expression on different T cell subsets, fresh tumor tissues and matched peripheral blood samples were obtained from patients with different types of cancer (MT Group, CINJ): renal cell carcinoma (n=16), colorectal (n=2) , liver (n=2), uterus (n=3), lung (n=1), ovary (n=1), stomach (n=1) and gastrointestinal tract (n=1). Samples were sent to the laboratory for analysis the previous evening at 4°C in HypoThermosol FRS (Biolife Solutions) and heparin (BD Biosciences), respectively. All samples were processed and stained within 24 h of collection.

Processing of tissues for immunophenotyping.

Tumor tissues were weighed and dissociated using a light cocktail of collagenase I, II, IV and DNase I, followed by Ficoll separation. Peripheral leukocytes were separated from erythrocytes using sedimentation buffer (Miltenyi Biotech). Cell suspensions (from tumor tissues or peripheral blood) were washed twice in phosphate buffered saline (PBS) without calcium and magnesium, and stained with near-infrared (NIR) Viability Dye (Molecular Probes by Life Technologies, catalog number L34976). Fc receptors were blocked with human gamma globulin (Jackson Immunoresearch) or mouse IgG serum (Sigma Aldrich) in FACS buffer (PBS containing 0.5% fetal bovine serum and 0.1% sodium azide), then the samples were stained with various antibody cocktails (see Table 1, 2, 3, 4) at 4°C in the dark for 45 minutes. Cells were then washed twice with FACS buffer and fixed with FACS lysis solution (BD Biosciences, cat. no. 349202). Fluorescence controls with a combination of detectable labels minus one (FMO) were prepared for a subset of antibodies and used to determine positive cell populations. Samples were acquired on a Fortessa flow cytometer (BD Biosciences), and data were analyzed using FlowJo software (TreeStar).

Antibody staining for flow cytometry analysis.

To assess the expression of TIM3 in various subpopulations of T cells, the above-treated cells were stained with a cocktail of antibodies presented in table. 4 (below). A typical example of a gating strategy is shown in FIG. 3A: CCR7+ CD45RO- (naive), CCR7+ CD45RO+ (central memory), CCR7-CD45RO+ (effector memory) and CCR7-CD45RO- (effector). The median frequency of these subpopulations in TILs is presented in Table. 5 (below).

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Table 4

Panel of antibodies for analysis of TIM3 expression in T cell subsets

Marker Clone Fluorophore Provider Catalog no. Vitality Near IR Invitrogen L34976 property — range CD45 HI30 BV480 BDBiosciences 566115 CD3 UCHT1 BUV496 BDBiosciences 564809 CD4 SK3 AF700 Biolegend 344622 CD8 RPA-T8 BUV395 BDBiosciences 563795 CD45RO HI 100 BV421 Biolegend 304224 CD 197 G043H7 BV711 Biolegend 353228 PD-1 MIH4 ARS BDBiosciences 558694 TIM3 7D3 BB515 BDBiosciences 565568

As shown in FIG. 3B, the frequency of TIM3+ cells varied depending on both the T cell subset and the individual patient, with a general trend toward a greater percentage of effector memory T cells and effector CD4+ and CD8+ cells expressing TIM3. The fact that a higher percentage of effector and effector memory T cells express TIM3 in some patients suggests the possibility of reactivation of the T cell response with TIM3 inhibition. In addition, data suggest that higher frequencies of TIM-3+ effector and/or TIM3+ effector memory T cells in TILs from a subject having cancer indicate that the subject will respond to TIM-3 antagonist cancer therapy. such as anti-TIM-3 antibody.

In whole blood, due to the very low frequency of TIM3+ T cells, there was no significant correlation between the frequency of TIM3+ T cells in TILs and in the corresponding whole blood (see Fig. 3C).

Table 5

Median frequencies of CD4 and CD8 T cell subsets

Median frequencies in TIL Naive Central memory Effector memory Effector %CD4+ 2.9 32 60 1.5 %CD8+ 2.1 5.2 68 19

As observed in example 1, a large proportion of TIM3+ CD8+ TILs were also PD-1 positive in the majority of samples analyzed (see Fig. 4A and 4B). Very few CD8+ TILs were TIM3+ PD-1−, and in approximately half of the samples, the majority of PD1+ CD8+ TILs were also positive for TIM3 expression. This result, along with that obtained in Example 1, supports the use of a combination of a PD-1 antagonist (eg, an anti-PD-1 antibody, such as nivolumab) with a TIM3 antagonist for the treatment of cancer, for example, in subjects who are TIM -3+ PD-1+.

Example 3. Analysis of TIM3 expression in various subpopulations of immune cells.

Because T cells are not the only immune cells expressing TIM3, both myeloid and NK cells isolated from TILs from a subset of the samples described in Example 2 were also assessed for TIM3 expression. The antibody cocktails used to identify these immune cell subsets were are presented in table. 6 and 7 (below).

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Table 6

Panel of antibodies for analysis of TIM3 expression in subsets of myeloid cells

Marker Clone Fluorophore Provider Catalog no. Vitality - Near IR Invitrogen L34976 property range CD3 SK7 BV605 BD biosciences 563219 CD19 HIB19 BV605 BD biosciences 562653 CD56 5.1N11 BV605 BD biosciences 562780 CD45 2D1 RegSR-Su5.5 Biolegend 340953 HLA-DR G46-6 BV510 BD biosciences 563083 CD14 M5E2 AF700 BD biosciences 557923 CD15 W6D3 BUV395 BD biosciences 740318 CDllc V-1u6 BV650 BD biosciences 563404 CD64 10.1 BV785 BD biosciences 740980 CD303 201A RE-Su7 Biolegend 354214 TIM3 7D3 BV421 BD biosciences 565562

Table 7

Panel of antibodies to analyze TIM3 expression in NK cells

Number by

Marker Clone Fluorophore Provider catalog Vitality - ARS-Su7 Invitrogen L34976 L34976 property CD45 2D1 RegSR-Su5.5 Biolegend 340953 CD 19 SJ25C1 BV605 BD biosciences 562653 CD27 L128 BV510 BD biosciences 563092 CD3 SK7 BV786 Biolegend 344842 CD16 3G8 AF700 BD biosciences 560713 CD56 NCAM16.2 BV650 BD biosciences 564057 CD57 NK-1 ARS BD biosciences 560845 TIM3 7D3 BV421 BD biosciences 565562

As shown in FIG. 5A, very few CD15+ granulocytes expressing TIM3. In contrast, the frequency of plasmacytoid dendritic cells (pDC), myeloid dendritic cells (mDC), and CD14+ CD64+ monocytes/macrophages expressing TIM3 varied among patients, with frequencies reaching 80% or more. The frequency of TIM3+ CD16− CD56+ and CD16+ CD56+ NK cell subsets also varied among patients, ranging from 15% to 95% (Figure 5B).

Example 4 Analysis of Soluble TIM3 Expression in Serum.

To compare the expression of soluble TIM3 in the serum of healthy subjects and cancer patients, frozen serum samples from 20 normal healthy volunteers, from 20 patients diagnosed with colon cancer, from 20 patients diagnosed with kidney cancer, and from 20 patients diagnosed with lung cancer were thawed on ice and tested at a 1:4 dilution of soluble TIM-3 with a commercially available ELISA kit (Quantikine ELISA, cat. no. DTIM30, R&D Systems).

As shown in FIG. 6A and 6B, the expression of soluble TIM3 (including the soluble isoform of both TIM3 and TIM3 isolated from the cell membrane) in patients diagnosed with cancer was significantly higher than that observed in healthy donors (colon and lung cancer vs. normal, p < 0.0001; kidney cancer versus normal, p<0.01, Mann-Whitney test). This result indicates that soluble TIM3 levels are increased in the serum of cancer patients compared with normal controls. Thus, soluble TIM-3 can be used as a stratification marker. Additional analysis will determine the correlation between soluble TIM3 expression and TIM3 expression levels in corresponding TIL subpopulations.

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Table 8

SEQ ID Antibody Description Sequences 1 13A3 VH QLQLQESGPGLVKPSETLSLTCTVSGGSISSRSYYWGWIRQPPGKGLEWIGSIYY SGFTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCATGGPYGDYAHWF DPWGQGTLVTVSS 2 8B9 VH QVQLQESGPGLVKPSETLSLTCTVSGGSISRHYWNWIRQPPGKGLEWIGYIHYSG STNYNSSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARDTGYYGMDIWGQG TTVTVSS 3 8C4 VH QVQLQESGPGLVKPSETLSLTCTVSGGSISRYYWSWIRQPPGKGLEWIGYIHYTG STNYNPSLKSRVT1SVDTSKNQFSLKLSSVTAADTAVYYCATDTGYYGMDVWGQG TTVTVSS 4 17C3 VH QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYYMHWVRQAPGQGLEWMGIINPRG DSIIYAQKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARDFYGSGNYYYGM DVWGQGTTVTVSS 5 9F6 VH QVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWVSFISGGGG STIYYADSVKGRFTISRDNAKNSLFLQMNSLRVEDTAVYYCARDGYSSGWYYYGM DVWGQGTAVTVSS 6 3G4 VH QVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWVSFISTSG SIIYYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAREGYSSSWSYYYG MDVWGQGTTVTVSS 7 17C8 VH QVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWVSFISSSG SIIYYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDGYSSGWEYYGM DVWGQGTTVTVSS 8 13A3 (N60Q) VH QLQLQESGPGLVKPSETLSLTCTVSGGSISSRSYYWGWIRQPPGKGLEWIGSIYY SGFTYYQPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCATGGPYGDYAHWF DPWGQGTLVTVSS 9 13A3 (N60S) VH QLQLQESGPGLVKPSETLSLTCTVSGGSISSRSYYWGWIRQPPGKGLEWIGSIYY SGFTYYSPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCATGGPYGDYAHWF DPWGQGTLVTVSS 10 13A3 (N60A) VH QLQLQESGPGLVKPSETLSLTCTVSGGSISSRSYYWGWIRQPPGKGLEWIGSIYY SGFTYYAPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCATGGPYGDYAHWF DPWGQGTLVTVSS eleven 13A3 (D101E) VH QLQLQESGPGLVKPSETLSLTCTVSGGSISSRSYYWGWIRQPPGKGLEWIGSIYY SGFTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCATGGPYGDYAHWF EPWGQGTLVTVSS 12 13A3 (P102V) VH QLQLQESGPGLVKPSETLSLTCTVSGGSISSRSYYWGWIRQPPGKGLEWIGSIYY SGFTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCATGGPYGDYAHWF DVWGQGTLVTVSS 13 13A3 (P102Y) VH QLQLQESGPGLVKPSETLSLTCTVSGGSISSRSYYWGWIRQPPGKGLEWIGSIYY SGFTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCATGGPYGDYAHWF DYWGQGTLVTVSS 14 13A3 (P102L) VH QLQLQESGPGLVKPSETLSLTCTVSGGSISSRSYYWGWIRQPPGKGLEWIGSIYY SGFTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCATGGPYGDYAHWF DLWGQGTLVTVSS

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15 13A3 (N60Q, P102Y) VH QLQLQESGPGLVKPSETLSLTCrVSGGSISSRSYYWGWIRQPPGKGLEWIGSIYY SGFTYYQPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCATGGPYGDYAHWF DYWGQGTLVTVSS 16 8B9 (S61P) VH QVQLQESGPGLVKPSETLSLTCYVSGGSISRHYWNWIRQPPGKGLEWIGYIHYSG STNYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARDTGYYGMDIWGQG TTVTVSS 17 9F6 (A108T) VH QVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWVSFISGGGG STIYYADSVKGRFTISRDNAKNSLFLQMNSLRVEDTAVYYCARDGYSSGWYYYGM DVWGQGTTVTVSS 18 13A3 (N60Q, D101E) VH QLQLQESGPGLVKPSETLSLTCYVSGGSISSRSYYWGWIRQPPGKGLEWIGSIYY SGFTYYQPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCATGGPYGDYAHWF EPWGQGTLVTVSS 19 13A3, 17C3, 3G4 VL E1VLTQSPGTLLSLPGERATLSCRASQSVSSSYLAWYQQ KPGQAPRLLIYGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGS SPITF GQGTRLEIK 20 8B9, 8C4, 17C8, 9F6 (VK3) VL E1VLTQSPGTLLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLL1YGASSR ATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSPLTFGGGTKVEIK 21 9F6 (VK1) VL A1QLTQSPSSLSSASVGDRVT1TCRASQG1SSALAWYQQKPGKAPKLL1YDASSLE SGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQFNSYPRTFGQGTKVEIK 22 9F6 (VK2) VL E1VLTQSPGTLLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLL1YGASSR ATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSLTFGGGTKVEIK 23 13 A3, including the following 13A3 variants: N60Q; N60S; N60A; D101E; P102V; P102Y; P102L; N60Q and P102Y; N60Q and D101E CDRl (VH) SRSYYWG 24 8В9, including 8B9 (S61P) option CDR1 (VH) RHYWN 25 8S4 CDRl (VH) RYYWS 26 17NW CDRl (VH) SYYMH 27 9F6, including 9F6 (A108T) option; 3G4; 17С8 CDRl (VH) DYYMS 28 13A3, including the following 13A3 variants: D101E, P102V, P102Y, and P102L CDR2 (VH) SIYYSGFTYYNPSLKS 29 8В9 CDR2 (VH) YIHYSGSTNYNSSLKS thirty 8S4 CDR2 (VH) YIHYTGSTNYNPSLKS 31 17NW CDR2 (VH) IINPRGDSIIYAQKFQG 32 9F6, including 9F6 (A108T) variant CDR2 (VH) FISGGGSTIYYADSVKG 33 3G4 CDR2 (VH) FISTSGSIIYYADSVKG 34 17С8 CDR2 (VH) FISSSGSIIYYADSVKG 35 13A3 (N60Q); 13A3 (N60Q, P102Y); 13A3 (N60Q, D101E) CDR2 (VH) SIYYSGFTYYQPSLKS 36 13A3 (N60S) CDR2 (VH) SIYYSGFTYYSPSLKS 37 13A3 (N60A) CDR2 (VH) SIYYSGFTYYAPSLKS 38 8В9 (S61P) CDR2 (VH) YIHYSGSTNYNPSLKS 39 13A3, including the following 13A3 variants: N60Q, N60S, N60A CDR3 (VH) GGPYGDYAHWFDP 40 8В9, including 8B9 (S61P) option CDR3 (VH) DTGYYGMDI

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41 8C4 CDR3 (VH) DTGYYGMDV 42 17C3 CDR3 (VH) DFYGSGNYYYGMDV 43 9F6, including 9F6 (A108T) variant CDR3 (VH) DGYSSGWYYYGMDV 44 3G4 CDR3 (VH) EGYSSSWSYYYGMDV 45 17С8 CDR3 (VH) DGYSSGWEYYGMDV 46 13A3 (D101E); 13A3 (N60Q, D101E) CDR3 (VH) GGPYGDYAHWFEP 47 13A3 (P102V) CDR3 (VH) GGPYGDYAHWFDV 48 13A3 (P102Y); 13A3 (N60Q, P102Y) CDR3 (VH) GGPYGDYAHWFDY 49 13A3 (P102L) CDR3 (VH) GGPYGDYAHWFDL 50 13A3, 8В9, 8С4, 17СЗ, 9F6 (VK2, VK3), 3G4, 17С8 CDR1 (VL) RASQSVSSSYLA 51 9F6 (VK1) CDR1 (VL) RASQGISSALA 52 13A3, 8В9, 8С4, 17СЗ, 9F6 (VK2, VK3), 3G4, 17С8 CDR2 (VL) GASS RAT 53 9F6 (VK1) CDR2 (VL) DASSLES 54 13A3, 17SZ, 3G4 CDR3 (VL) QQYGSSPIT 55 8В9, 8С4, 9F6 (VK3), 17С8 CDR3 (VL) QQYGSSPLT 56 9F6 (VK1) CDR3 (VL) QQFNSYPRT 57 9F6 (VK2) CDR3 (VL) QQYGSSLT 58 WT constant domain of human IgGl (same as IgGlza) ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA VLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCP PCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGV EVHNAKTKPREEQYNSTYRWSVLTVLHQD WLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYK TTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 59 human IgGl (allotypic variant) ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA VLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCP PCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGV EVHNAKTKPREEQYNSTYRWSVLTVLHQD WLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYK TTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 60 IgGl.1 constant domain (used in anti-T1MZ antibodies) ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA VLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCP PCPAPEAEGAPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGV EVHNAKTKPREEQYNSTYRWSVLTVLHQD WLNGKEYKCKVSNKALPSSIEKTIS KAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYK TTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 61 IgGl.3 constant domain (used in anti-T1MZ antibodies) ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA VLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCP PCPAPEAEGAPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGV EVHNAKTKPREEQYNSTYRWSVLTVLHQD WLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYK TTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 63 human IgG4 constant domain RTVAAPSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQES VTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 64 human kappa light chain IgGl LSPGK 65 LSPGK (C-terminal heavy chain) LSPG 66 LSPG (C-terminal heavy chain) LSP 67 LSP (C-terminal heavy chain) RTVAAPSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQES VTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 68 13A3 IgGl.If NS QLQLQESGPGLVKPSETLSLTCTVSGGSISSRSYYWGWIRQPPGKGLEWIGSIYY SGFTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCATGGPYGDYAHWF DPWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN

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SGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKR VEPKSCDKTHTCPPCPAPEAEGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVS NKALPSSIEKTISKAKGQPREPQ VYTLPPSREEMTKNQVSLTCLVKGFYPSDIAV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN HYTQKSLSLSPGK* 69 8B9 IgGl.lf NS QVQLQESGPGLVKPSETLSLTCTVSGGSISRHYWNWIRQPPGKGLEWIGYIHYSG STNYNSSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARDTGYYGMDIWGQG TTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTS GVHTFPAVLQSSGLYSLSSWTVPSSSLGTQ TYICNVNHKPSNTKVDKRVEPKSC DKTHTCPPCPAPEAEGAPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKF NWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPS SIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNG Q PENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKS LSLSPGK* 70 8C4 IgGl.lf NS QVQLQESGPGLVKPSETLSLTCTVSGGSISRYYWSWIRQPPGKGLEWIGYIHYTG STNYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCATDTGYYGMDVWGQG TTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTS GVHTFPAVLQSSGLYSLSSWTVPSSSLGTQTYIC NVNHKPSNTKVDKRVEPKSC DKTHTCPPCPAPEAEGAPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKF NWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPS SIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNG QPEN NYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKS LSLSPGK* 71 17C3 IgGl.lf NS QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYYMHWVRQAPGQGLEWMGIINPRG DSIIYAQKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARDFYGSGNYYYGM DVWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSWTVPSS SLGTQTYICNVNHKPSNTKVDKR VEPKSCDKTHTCPPCPAPEAEGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVS NKALPSSIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDI AV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN HYTQKSLSLSPGK* 72 9F6 IgGl.lf NS QVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWVSFISGGGG STIYYADSVKGRFTISRDNAKNSLFLQMNSLRVEDTAVYYCARDGYSSGWYYYGM DVWGQGTAVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLG EW ESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN HYTQKSLSLSPGK* 73 3G4 IgGl.lf NS QVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWVSFISTSG SIIYYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAREGYSSSWSYYYG MDVWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSW NSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTQ TYICNVNHKPSNTKVDK RVEPKSCDKTHTCPPCPAPEAEGAPSVFLFPPKPKDTLM1SRTPEVTCVWDVSH EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKV SNKALPSSIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIA VEWESNG QPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALH NHYTQKSLSLSPGK* 74 17C8 IgGl.lf NS QVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWVSFISSSG SIIYYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDGYSSGWEYYGM DVWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTQ TY1CNVNHKPSNTKVDKR VEPKSCDKTHTCPPCPAPEAEGAPSVFLFPPKPKDTLMISRTPEVTCVWDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVS NKALPSS1EKT1SKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD1AV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN HYTQKSLSLSPGK* 75 13A3 IgGl. If NS (without C-terminal K) QLQLQESGPGLVKPSETLSLTCTVSGGSISSRSYYWGWIRQPPGKGLEWIGSIYY SGFTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCATGGPYGDYAHWF DPWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSWTVP SSSLGTQTY1CNVNHKPSNTKVDKR VEPKSCDKTHTCPPCPAPEAEGAPSVFLFPPKPKDTLMISRTPEVTCVWDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVS NKALPSS1EKT1SKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGF YPSD1AV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN HYTQKSLSLSPG* 76 8B9 IgGl. If NS (without C-terminal K) QVQLQESGPGLVKPSETLSLTCTVSGGSISRHYWNWIRQPPGKGLEWIGYIHYSG STNYNSSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARDTGYYGMDIWGQG TTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTS GVHTFPAVLQSSGLYSLSSWTVPSSSLGTQ TY1CNVNHKPSNTKVDKRVEPKSC DKTHTCPPCPAPEAEGAPSVFLFPPKPKDTLM1SRTPEVTCVWDVSHEDPEVKF

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NWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPS SIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNG QPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKS LSLSPG* 77 8C4 IgGl. If NS (without C-terminal K) QVQLQESGPGLVKPSETLSLTCTVSGGSISRYYWSWIRQPPGKGLEWIGYIHYTG STNYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCATDTGYYGMDVWGQG TTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTS GVHTFPAVLQSSGLYSLSSWTVPSSSLGTQTYIC NVNHKPSNTKVDKRVEPKSC DKTHTCPPCPAPEAEGAPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKF NWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPS SIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNG QPEN NYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKS LSLSPG* 78 17C3 IgGl. If NS (without C-terminal K) QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYYMHWVRQAPGQGLEWMGIINPRG DSIIYAQKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARDFYGSGNYYYGM DVWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSWTVPSS SLGTQTYICNVNHKPSNTKVDKR VEPKSCDKTHTCPPCPAPEAEGAPSVFLFPPKPKDTLMISRTPEVTCVWDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVS NKALPSSIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN HYTQKSLSLSPG* 79 9F6 IgGl. If NS (without C-terminal K) QVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWVSFISGGGG STIYYADSVKGRFTISRDNAKNSLFLQMNSLRVEDTAVYYCARDGYSSGWYYYGM DVWGQGTAVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLG EW ESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN HYTQKSLSLSPG* 80 3G4 IgGl. If NS (without C-terminal K) QVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWVSFISTSG SIIYYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAREGYSSSWSYYYG MDVWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSW NSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTQ TYICNVNHKPSNTKVDK RVEPKSCDKTHTCPPCPAPEAEGAPSVFLFPPKPKDTLMISRTPEVTCVWDVSH EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKV SNKALPSSIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIA VEWESNGQ PENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALH NHYTQKSLSLSPG* 81 17C8 IgGl. If NS (without C-terminal K) QVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWVSFISSSG SIIYYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDGYSSGWEYYGM DVWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTQ TYICNVNHKPSNTKVDKR VEPKSCDKTHTCPPCPAPEAEGAPSVFLFPPKPKDTLMISRTPEVTCVWDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVS NKALPSSIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAV EWESNG QPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN HYTQKSLSLSPG* 82 13A3 IgGl.Sf NS QLQLQESGPGLVKPSETLSLTCTVSGGSISSRSYYWGWIRQPPGKGLEWIGSIYY SGFTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCATGGPYGDYAHWF DPWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSWTVP SSSLGTQTYICNVNHKPSNTKVDKR VEPKSCDKTHTCPPCPAPEAEGAPSVFLFPPKPKDTLMISRTPEVTCVWDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVS NKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDI AV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN HYTQKSLSLSPGK* 83 8B9 IgGl.Sf NS QVQLQESGPGLVKPSETLSLTCTVSGGSISRHYWNWIRQPPGKGLEWIGYIHYSG STNYNSSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARDTGYYGMDIWGQG TTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTS GVHTFPAVLQSSGLYSLSSWTVPSSSLGTQ TYICNVNHKPSNTKVDKRVEPKSC DKTHTCPPCPAPEAEGAPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKF NWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNG Q PENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKS LSLSPGK* 84 8C4 IgGl.Sf NS QVQLQESGPGLVKPSETLSLTCTVSGGSISRYYWSWIRQPPGKGLEWIGYIHYTG STNYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCATDTGYYGMDVWGQG TTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTS GVHTFPAVLQSSGLYSLSSWTVPSSSLGTQTYIC NVNHKPSNTKVDKRVEPKSC DKTHTCPPCPAPEAEGAPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKF NWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNG

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QPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKS LSLSPGK* 85 17C3 IgGl.Sf NS QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYYMHWVRQAPGQGLEWMGIINPRG DSIIYAQKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARDFYGSGNYYYGM DVWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSWTVPSS SLGTQTY1CNVNHKPSNTKVDKR VEPKSCDKTHTCPPCPAPEAEGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVS NKALPAP1EKT1SKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGF YPSD1AV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN HYTQKSLSLSPGK* 86 9F6 IgGl.Sf NS QVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWVSFISGGGG STIYYADSVKGRFTISRDNAKNSLFLQMNSLRVEDTAVYYCARDGYSSGWYYYGM DVWGQGTAVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLG TQTY1CNVNHKPSNTKVDKR VEPKSCDKTHTCPPCPAPEAEGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVS NKALPAP1EKT1SKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPS D1AV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN HYTQKSLSLSPGK* 87 3G4 IgGl.Sf NS QVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWVSFISTSG SIIYYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAREGYSSSWSYYYG MDVWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSW NSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTQ TYICNVNHKPSNTKVDK RVEPKSCDKTHTCPPCPAPEAEGAPSVFLFPPKPKDTLM1SRTPEVTCVWDVSH EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKV SNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIA VEWESNG QPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALH NHYTQKSLSLSPGK* 88 17C8 IgGl.Sf NS QVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWVSFISSSG SIIYYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDGYSSGWEYYGM DVWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTQ TY1CNVNHKPSNTKVDKR VEPKSCDKTHTCPPCPAPEAEGAPSVFLFPPKPKDTLMISRTPEVTCVWDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVS NKALPAP1EKT1SKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD1AV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN HYTQKSLSLSPGK* 89 13A3 IgG1.3f NS (without C-terminal K) QLQLQESGPGLVKPSETLSLTCTVSGGSISSRSYYWGWIRQPPGKGLEWIGSIYY SGFTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCATGGPYGDYAHWF DPWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSWTVP SSSLGTQTY1CNVNHKPSNTKVDKR VEPKSCDKTHTCPPCPAPEAEGAPSVFLFPPKPKDTLMISRTPEVTCVWDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVS NKALPAP1EKT1SKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGF YPSD1AV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN HYTQKSLSLSPG* 90 8B9 IgG1.3f NS (without C-terminal K) QVQLQESGPGLVKPSETLSLTCTVSGGSISRHYWNWIRQPPGKGLEWIGYIHYSG STNYNSSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARDTGYYGMDIWGQG TTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTS GVHTFPAVLQSSGLYSLSSWTVPSSSLGTQ TY1CNVNHKPSNTKVDKRVEPKSC DKTHTCPPCPAPEAEGAPSVFLFPPKPKDTLM1SRTPEVTCVWDVSHEDPEVKF NWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWES NG QPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKS LSLSPG* 91 8C4 IgG1.3f NS (without C-terminal K) QVQLQESGPGLVKPSETLSLTCTVSGGSISRYYWSWIRQPPGKGLEWIGYIHYTG STNYNPSLKSRVT1SVDTSKNQFSLKLSSVTAADTAVYYCATDTGYYGMDVWGQG TTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTS GVHTFPAVLQSSGLYSLSSWTVPSSSLGTQTY1 CNVNHKPSNTKVDKRVEPKSC DKTHTCPPCPAPEAEGAPSVFLFPPKPKDTLM1SRTPEVTCVWDVSHEDPEVKF NWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPA P1EKT1SKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD1AVEW ESNG QPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKS LSLSPG* 92 17C3 IgG1.3f NS (without C-terminal K) QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYYMHWVRQAPGQGLEWMGIINPRG DSIIYAQKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARDFYGSGNYYYGM DVWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSWTVPSS SLGTQTY1CNVNHKPSNTKVDKR VEPKSCDKTHTCPPCPAPEAEGAPSVFLFPPKPKDTLMISRTPEVTCVWDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVS NKALPAP1EKT1SKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFY PSD1AV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN HYTQKSLSLSPG*

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93 9F6 IgG1.3f NS (without C-terminal K) QVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWVSFISGGGG STIYYADSVKGRFTISRDNAKNSLFLQMNSLRVEDTAVYYCARDGYSSGWYYYGM DVWGQGTAVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLG TQTY1CNVNHKPSNTKVDKR VEPKSCDKTHTCPPCPAPEAEGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVS NKALPAP1EKT1SKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPS D1AV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN HYTQKSLSLSPG* 94 3G4 IgG1.3f NS (without C-terminal K) QVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWVSFISTSG SIIYYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAREGYSSSWSYYYG MDVWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSW NSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTQ TYICNVNHKPSNTKVDK RVEPKSCDKTHTCPPCPAPEAEGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSH EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKV SNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIA VEWESNG QPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALH NHYTQKSLSLSPG* 95 17C8 IgG1.3f NS (without C-terminal K) QVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWVSFISSSG SIIYYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDGYSSGWEYYGM DVWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTQ TY1CNVNHKPSNTKVDKR VEPKSCDKTHTCPPCPAPEAEGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVS NKALPAP1EKT1SKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD1 AV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN HYTQKSLSLSPG* 96 13A3 (N60Q) IgGl.lf NS QLQLQESGPGLVKPSETLSLTCTVSGGSISSRSYYWGWIRQPPGKGLEWIGSIYY SGFTYYQPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCATGGPYGDYAHWF DPWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSWT VPSSSLGTQTY1CNVNHKPSNTKVDKR VEPKSCDKTHTCPPCPAPEAEGAPSVFLFPPKPKDTLMISRTPEVTCVWDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVS NKALPSS1EKT1SKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVK GFYPSD1AV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN HYTQKSLSLSPGK* 97 13A3 (N60S) IgGl.lf NS QLQLQESGPGLVKPSETLSLTCTVSGGSISSRSYYWGWIRQPPGKGLEWIGSIYY SGFTYYSPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCATGGPYGDYAHWF DPWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSWTVP SSSLGTQTY1CNVNHKPSNTKVDKR VEPKSCDKTHTCPPCPAPEAEGAPSVFLFPPKPKDTLMISRTPEVTCVWDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVS NKALPSS1EKT1SKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGF YPSD1AV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN HYTQKSLSLSPGK* 98 13A3 (N60A) IgGl.lf NS QLQLQESGPGLVKPSETLSLTCTVSGGSISSRSYYWGWIRQPPGKGLEWIGSIYY SGFTYYAPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCATGGPYGDYAHWF DPWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSWTVP SSSLGTQTY1CNVNHKPSNTKVDKR VEPKSCDKTHTCPPCPAPEAEGAPSVFLFPPKPKDTLMISRTPEVTCVWDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVS NKALPSS1EKT1SKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGF YPSD1AV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN HYTQKSLSLSPGK* 99 13A3 (D101E) IgGl.lf NS QLQLQESGPGLVKPSETLSLTCTVSGGSISSRSYYWGWIRQPPGKGLEWIGSIYY SGFTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCATGGPYGDYAHWF EPWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSWTVP SSSLGTQTY1CNVNHKPSNTKVDKR VEPKSCDKTHTCPPCPAPEAEGAPSVFLFPPKPKDTLMISRTPEVTCVWDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVS NKALPSS1EKT1SKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGF YPSD1AV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN HYTQKSLSLSPGK* 100 13A3 (P102V) IgGl.lf NS QLQLQESGPGLVKPSETLSLTCTVSGGSISSRSYYWGWIRQPPGKGLEWIGSIYY SGFTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCATGGPYGDYAHWF DVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSWTVP SSSLGTQTYICNVNHKPSNTKVDKR VEPKSCDKTHTCPPCPAPEAEGAPSVFLFPPKPKDTLM1SRTPEVTCVWDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVS NKALPSSIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPS DIAV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN HYTQKSLSLSPGK* 101 13A3 (P102Y) IgGl.lf NS QLQLQESGPGLVKPSETLSLTCTVSGGSISSRSYYWGWIRQPPGKGLEWIGSIYY SGFTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCATGGPYGDYAHWF

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DYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKR VEPKSCDKTHTCPPCPAPEAEGAPSVFLFPPKPKDTLMISRTPEVTCVWDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYNSTY RWSVLTVLHQDWLNGKEYKCKVS NKALPSSIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN HYTQKSLSLSPGK* 102 13A3 (P102L) IgGl.lf NS QLQLQESGPGLVKPSETLSLTCTVSGGSISSRSYYWGWIRQPPGKGLEWIGSIYY SGFTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCATGGPYGDYAHWF DLWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSWTVP SSSLGTQTYICNVNHKPSNTKVDKR VEPKSCDKTHTCPPCPAPEAEGAPSVFLFPPKPKDTLMISRTPEVTCVWDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVS NKALPSSIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDI AV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN HYTQKSLSLSPGK* 103 13A3 (N60Q, P102Y) IgGl.lf NS QLQLQESGPGLVKPSETLSLTCTVSGGSISSRSYYWGWIRQPPGKGLEWIGSIYY SGFTYYQPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCATGGPYGDYAHWF DYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSWT VPSSSLGTQTYICNVNHKPSNTKVDKR VEPKSCDKTHTCPPCPAPEAEGAPSVFLFPPKPKDTLMISRTPEVTCVWDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVS NKALPSSIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPS DIAV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN HYTQKSLSLSPGK* 104 8B9 (S61P) IgGl.lf NS QVQLQESGPGLVKPSETLSLTCTVSGGSISRHYWNWIRQPPGKGLEWIGYIHYSG STNYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARDTGYYGMDIWGQG TTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTS GVHTFPAVLQSSGLYSLSSWTVPSSSLGTQ TYICNVNHKPSNTKVDKRVEPKSC DKTHTCPPCPAPEAEGAPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKF NWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPS SIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNG Q PENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKS LSLSPGK* 105 9F6 (A108T) IgGl.lf NS QVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWVSFISGGGG STIYYADSVKGRFTISRDNAKNSLFLQMNSLRVEDTAVYYCARDGYSSGWYYYGM DVWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLG EW ESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN HYTQKSLSLSPGK* 106 13A3 (N60Q) IgGl. If NS (without C-terminal K) QLQLQESGPGLVKPSETLSLTCTVSGGSISSRSYYWGWIRQPPGKGLEWIGSIYY SGFTYYQPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCATGGPYGDYAHWF DPWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSWT VPSSSLGTQTYICNVNHKPSNTKVDKR VEPKSCDKTHTCPPCPAPEAEGAPSVFLFPPKPKDTLMISRTPEVTCVWDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVS NKALPSSIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPS DIAV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN HYTQKSLSLSPG* 107 13A3 (N60S) IgGl. If NS (without C-terminal K) QLQLQESGPGLVKPSETLSLTCTVSGGSISSRSYYWGWIRQPPGKGLEWIGSIYY SGFTYYSPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCATGGPYGDYAHWF DPWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSWTVP SSSLGTQTYICNVNHKPSNTKVDKR VEPKSCDKTHTCPPCPAPEAEGAPSVFLFPPKPKDTLMISRTPEVTCVWDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVS NKALPSSIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDI AV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN HYTQKSLSLSPG* 108 13A3 (N60A) IgGl. If NS (without C-terminal K) QLQLQESGPGLVKPSETLSLTCTVSGGSISSRSYYWGWIRQPPGKGLEWIGSIYY SGFTYYAPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCATGGPYGDYAHWF DPWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSWTVP SSSLGTQTYICNVNHKPSNTKVDKR VEPKSCDKTHTCPPCPAPEAEGAPSVFLFPPKPKDTLMISRTPEVTCVWDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVS NKALPSSIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDI AV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN HYTQKSLSLSPG* 109 13A3 (D101E) IgGl. If NS (without C-terminal K) QLQLQESGPGLVKPSETLSLTCTVSGGSISSRSYYWGWIRQPPGKGLEWIGSIYY SGFTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCATGGPYGDYAHWF EPWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSWTVP SSSLGTQTYICNVNHKPSNTKVDKR

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VEPKSCDKTHTCPPCPAPEAEGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVS NKALPSSIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAV EWESNGQPENNYKTTPPVLDSDGS FFLYSKLTVDKSRWQQGNVFSCSVMHEALHN HYTQKSLSLSPG* 110 13A3 (P102V) IgGl. If NS (without C-terminal K) QLQLQESGPGLVKPSETLSLTCTVSGGSISSRSYYWGWIRQPPGKGLEWIGSIYY SGFTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCATGGPYGDYAHWF DVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSWTVP SSSLGTQTYICNVNHKPSNTKVDKR VEPKSCDKTHTCPPCPAPEAEGAPSVFLFPPKPKDTLMISRTPEVTCVWDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVS NKALPSSIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDI AV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN HYTQKSLSLSPG* 111 13A3 (P102Y) IgGl. If NS (without C-terminal K) QLQLQESGPGLVKPSETLSLTCTVSGGSISSRSYYWGWIRQPPGKGLEWIGSIYY SGFTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCATGGPYGDYAHWF DYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSWTVP SSSLGTQTYICNVNHKPSNTKVDKR VEPKSCDKTHTCPPCPAPEAEGAPSVFLFPPKPKDTLMISRTPEVTCVWDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVS NKALPSSIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDI AV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN HYTQKSLSLSPG* 112 13A3 (P102L) IgGl. If NS (without C-terminal K) QLQLQESGPGLVKPSETLSLTCTVSGGSISSRSYYWGWIRQPPGKGLEWIGSIYY SGFTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCATGGPYGDYAHWF DLWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSWTVP SSSLGTQTYICNVNHKPSNTKVDKR VEPKSCDKTHTCPPCPAPEAEGAPSVFLFPPKPKDTLMISRTPEVTCVWDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVS NKALPSSIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDI AV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN HYTQKSLSLSPG* 113 13A3 (N60Q, P102Y) IgGl. If NS (without C-terminal K) QLQLQESGPGLVKPSETLSLTCTVSGGSISSRSYYWGWIRQPPGKGLEWIGSIYY SGFTYYQPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCATGGPYGDYAHWF DYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSWT VPSSSLGTQTYICNVNHKPSNTKVDKR VEPKSCDKTHTCPPCPAPEAEGAPSVFLFPPKPKDTLMISRTPEVTCVWDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVS NKALPSSIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPS DIAV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN HYTQKSLSLSPG* 114 8B9 (S61P) IgGl. If NS (without C-terminal K) QVQLQESGPGLVKPSETLSLTCTVSGGSISRHYWNWIRQPPGKGLEWIGYIHYSG STNYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARDTGYYGMDIWGQG TTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTS GVHTFPAVLQSSGLYSLSSWTVPSSSLGTQ TYICNVNHKPSNTKVDKRVEPKSC DKTHTCPPCPAPEAEGAPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKF NWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPS SIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNG Q PENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKS LSLSPG* 115 9F6 (A108T) IgGl. If NS (without C-terminal K) QVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWVSFISGGGG STIYYADSVKGRFTISRDNAKNSLFLQMNSLRVEDTAVYYCARDGYSSGWYYYGM DVWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLG EW ESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN HYTQKSLSLSPG* 116 13A3 (N60Q) IgGl.Sf NS QLQLQESGPGLVKPSETLSLTCTVSGGSISSRSYYWGWIRQPPGKGLEWIGSIYY SGFTYYQPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCATGGPYGDYAHWF DPWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSWT VPSSSLGTQTYICNVNHKPSNTKVDKR VEPKSCDKTHTCPPCPAPEAEGAPSVFLFPPKPKDTLMISRTPEVTCVWDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVS NKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPS DIAV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN HYTQKSLSLSPGK* 117 13A3 (N60S) IgG1.3f NS QLQLQESGPGLVKPSETLSLTCTVSGGSISSRSYYWGWIRQPPGKGLEWIGSIYY SGFTYYSPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCATGGPYGDYAHWF DPWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSWTVP SSSLGTQTYICNVNHKPSNTKVDKR VEPKSCDKTHTCPPCPAPEAEGAPSVFLFPPKPKDTLMISRTPEVTCVWDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVS

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NKALPAP1EKT1SKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD1AV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN HYTQKSLSLSPGK* 118 13A3 (N60A) IgGl.Sf NS QLQLQESGPGLVKPSETLSLTCTVSGGSISSRSYYWGWIRQPPGKGLEWIGSIYY SGFTYYAPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCATGGPYGDYAHWF DPWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSWTVP SSSLGTQTY1CNVNHKPSNTKVDKR VEPKSCDKTHTCPPCPAPEAEGAPSVFLFPPKPKDTLM1SRTPEVTCVWDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVS NKALPAP1EKT1SKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVK GFYPSD1AV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN HYTQKSLSLSPGK* 119 13A3 (D101E) IgGl.Sf NS QLQLQESGPGLVKPSETLSLTCTVSGGSISSRSYYWGWIRQPPGKGLEWIGSIYY SGFTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCATGGPYGDYAHWF EPWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSWTVP SSSLGTQTY1CNVNHKPSNTKVDKR VEPKSCDKTHTCPPCPAPEAEGAPSVFLFPPKPKDTLM1SRTPEVTCVWDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVS NKALPAP1EKT1SKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVK GFYPSD1AV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN HYTQKSLSLSPGK* 120 13A3 (P102V) IgGl.Sf NS QLQLQESGPGLVKPSETLSLTCTVSGGSISSRSYYWGWIRQPPGKGLEWIGSIYY SGFTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCATGGPYGDYAHWF DVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSWTVP SSSLGTQTY1CNVNHKPSNTKVDKR VEPKSCDKTHTCPPCPAPEAEGAPSVFLFPPKPKDTLM1SRTPEVTCVWDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVS NKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFY PSDIAV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN HYTQKSLSLSPGK* 121 13A3 (P102Y) IgGl.Sf NS QLQLQESGPGLVKPSETLSLTCTVSGGSISSRSYYWGWIRQPPGKGLEWIGSIYY SGFTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCATGGPYGDYAHWF DYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSWTVP SSSLGTQTY1CNVNHKPSNTKVDKR VEPKSCDKTHTCPPCPAPEAEGAPSVFLFPPKPKDTLM1SRTPEVTCVWDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVS NKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFY PSDIAV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN HYTQKSLSLSPGK* 122 13A3 (P102L) IgGl.Sf NS QLQLQESGPGLVKPSETLSLTCTVSGGSISSRSYYWGWIRQPPGKGLEWIGSIYY SGFTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCATGGPYGDYAHWF DLWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSWTVP SSSLGTQTY1CNVNHKPSNTKVDKR VEPKSCDKTHTCPPCPAPEAEGAPSVFLFPPKPKDTLM1SRTPEVTCVWDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVS NKALPAP1EKT1SKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVK GFYPSD1AV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN HYTQKSLSLSPGK* 123 13A3 (N60Q, P102Y) IgGl.Sf NS QLQLQESGPGLVKPSETLSLTCTVSGGSISSRSYYWGWIRQPPGKGLEWIGSIYY SGFTYYQPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCATGGPYGDYAHWF DYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSWT VPSSSLGTQTY1CNVNHKPSNTKVDKR VEPKSCDKTHTCPPCPAPEAEGAPSVFLFPPKPKDTLM1SRTPEVTCVWDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVS NKALPAP1EKT1SKAKGQPREPQVYTLPPSREEMTKNQVSLTCLV KGFYPSD1AV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN HYTQKSLSLSPGK* 124 8B9 (S61P) IgGl.Sf NS QVQLQESGPGLVKPSETLSLTCTVSGGSISRHYWNWIRQPPGKGLEWIGYIHYSG STMYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARDTGYYGMDIWGQG TTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTS GVHTFPAVLQSSGLYSLSSWTVPSSSLGTQ TY1CNVNHKPSNTKVDKRVEPKSC DKTHTCPPCPAPEAEGAPSVFLFPPKPKDTLM1SRTPEVTCVWDVSHEDPEVKF NWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWES NG QPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKS LSLSPGK* 125 9F6 (A108T) IgGl.Sf NS QVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWVSFISGGGG STIYYADSVKGRFTISRDNAKNSLFLQMNSLRVEDTAVYYCARDGYSSGWYYYGM DVWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLG TQTY1CNVNHKPSNTKVDKR VEPKSCDKTHTCPPCPAPEAEGAPSVFLFPPKPKDTLM1SRTPEVTCVWDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVS NKALPAP1EKT1SKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPS D1AV

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EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN HYTQKSLSLSPGK* 126 13A3 (N60Q) IgG1.3f NS (without C-terminal K) QLQLQESGPGLVKPSETLSLTCTVSGGSISSRSYYWGWIRQPPGKGLEWIGSIYY SGFTYYQPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCATGGPYGDYAHWF DPWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSWT VPSSSLGTQTY1CNVNHKPSNTKVDKR VEPKSCDKTHTCPPCPAPEAEGAPSVFLFPPKPKDTLM1SRTPEVTCVWDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVS NKALPAP1EKT1SKAKGQPREPQVYTLPPSREEMTKNQVSLTCLV KGFYPSD1AV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN HYTQKSLSLSPG* 127 13A3 (N60S) IgG1.3f NS (without C-terminal K) QLQLQESGPGLVKPSETLSLTCTVSGGSISSRSYYWGWIRQPPGKGLEWIGSIYY SGFTYYSPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCATGGPYGDYAHWF DPWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSWTVP SSSLGTQTY1CNVNHKPSNTKVDKR VEPKSCDKTHTCPPCPAPEAEGAPSVFLFPPKPKDTLM1SRTPEVTCVWDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVS NKALPAP1EKT1SKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVK GFYPSD1AV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN HYTQKSLSLSPG* 128 13A3 (N60A) IgG1.3f NS (without C-terminal K) QLQLQESGPGLVKPSETLSLTCTVSGGSISSRSYYWGWIRQPPGKGLEWIGSIYY SGFTYYAPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCATGGPYGDYAHWF DPWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSWTVP SSSLGTQTY1CNVNHKPSNTKVDKR VEPKSCDKTHTCPPCPAPEAEGAPSVFLFPPKPKDTLM1SRTPEVTCVWDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVS NKALPAP1EKT1SKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVK GFYPSD1AV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN HYTQKSLSLSPG* 129 13A3 (D101E) IgG1.3f NS (without C-terminal K) QLQLQESGPGLVKPSETLSLTCTVSGGSISSRSYYWGWIRQPPGKGLEWIGSIYY SGFTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCATGGPYGDYAHWF EPWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSWTVP SSSLGTQTY1CNVNHKPSNTKVDKR VEPKSCDKTHTCPPCPAPEAEGAPSVFLFPPKPKDTLM1SRTPEVTCVWDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVS NKALPAP1EKT1SKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVK GFYPSD1AV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN HYTQKSLSLSPG* 130 13A3 (P102V) IgG1.3f NS (without C-terminal K) QLQLQESGPGLVKPSETLSLTCTVSGGSISSRSYYWGWIRQPPGKGLEWIGSIYY SGFTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCATGGPYGDYAHWF DVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSWTVP SSSLGTQTY1CNVNHKPSNTKVDKR VEPKSCDKTHTCPPCPAPEAEGAPSVFLFPPKPKDTLM1SRTPEVTCVWDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVS NKALPAP1EKT1SKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVK GFYPSD1AV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN HYTQKSLSLSPG* 131 13A3 (P102Y) IgG1.3f NS (without C-terminal K) QLQLQESGPGLVKPSETLSLTCTVSGGSISSRSYYWGWIRQPPGKGLEWIGSIYY SGFTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCATGGPYGDYAHWF DYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSWTVP SSSLGTQTY1CNVNHKPSNTKVDKR VEPKSCDKTHTCPPCPAPEAEGAPSVFLFPPKPKDTLM1SRTPEVTCVWDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVS NKALPAP1EKT1SKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVK GFYPSD1AV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN HYTQKSLSLSPG* 132 13A3 (P102L) IgG1.3f NS (without C-terminal K) QLQLQESGPGLVKPSETLSLTCTVSGGSISSRSYYWGWIRQPPGKGLEWIGSIYY SGFTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCATGGPYGDYAHWF DLWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSWTVP SSSLGTQTY1CNVNHKPSNTKVDKR VEPKSCDKTHTCPPCPAPEAEGAPSVFLFPPKPKDTLM1SRTPEVTCVWDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVS NKALPAP1EKT1SKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVK GFYPSD1AV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN HYTQKSLSLSPG* 133 13A3 (N60Q, P102Y) IgG1.3f NS (without C-terminal K) QLQLQESGPGLVKPSETLSLTCTVSGGSISSRSYYWGWIRQPPGKGLEWIGSIYY SGFTYYQPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCATGGPYGDYAHWF DYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSWT VPSSSLGTQTY1CNVNHKPSNTKVDKR VEPKSCDKTHTCPPCPAPEAEGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVS NKALPAP1EKT1SKAKGQPREPQVYTLPPSREEMTKNQVSLTCLV KGFYPSD1AV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN HYTQKSLSLSPG*

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134 8B9 (S61P) IgG1.3f NS (without C-terminal K) QVQLQESGPGLVKPSETLSLTCTVSGGSISRHYWNWIRQPPGKGLEWIGYIHYSG STNYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARDTGYYGMDIWGQG TTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTS GVHTFPAVLQSSGLYSLSSWTVPSSSLGTQ TY1CNVNHKPSNTKVDKRVEPKSC DKTHTCPPCPAPEAEGAPSVFLFPPKPKDTLM1SRTPEVTCVWDVSHEDPEVKF NWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWES NG QPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKS LSLSPG* 135 9F6 (A108T) IgG1.3f NS (without C-terminal K) QVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWVSFISGGGG STIYYADSVKGRFTISRDNAKNSLFLQMNSLRVEDTAVYYCARDGYSSGWYYYGM DVWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLG TQTYICNVNHKPSNTKVDKR VEPKSCDKTHTCPPCPAPEAEGAPSVFLFPPKPKDTLM1SRTPEVTCVWDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVS NKALPAP1EKT1SKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD 1AV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN HYTQKSLSLSPG* 136 13A3 h!gG4 NS QLQLQESGPGLVKPSETLSLTCTVSGGSISSRSYYWGWIRQPPGKGLEWIGSIYY SGFTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCATGGPYGDYAHWF DPWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSWTVP SSSLGTKTYTCNVDHKPSNTKVDKR VESKYGPPCPSCPAPEFLGGPSVFLFPPKPKDTLM1SRTPEVTCVWDVSQEDPE VQFNWYVDGVEVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKG LPSS1EKT1SKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVK GFYPSD1AVEWE SNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYT QKSLSLSLGK* 137 13A3 hlgG4 NS (without C-terminal K) QLQLQESGPGLVKPSETLSLTCTVSGGSISSRSYYWGWIRQPPGKGLEWIGSIYY SGFTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCATGGPYGDYAHWF DPWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSWTVP SSSLGTKTYTCNVDHKPSNTKVDKR VESKYGPPCPSCPAPEFLGGPSVFLFPPKPKDTLM1SRTPEVTCVWDVSQEDPE VQFNWYVDGVEVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKG LPSS1EKT1SKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVK GFYPSD1AVEWE SNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYT QKSLSLSLG* 138 TIMS .5 - 13A3 IgG4P NS QLQLQESGPGLVKPSETLSLTCTVSGGSISSRSYYWGWIRQPPGKGLEWIGSIYY SGFTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCATGGPYGDYAHWF DPWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSWTVP SSSLGTKTYTCNVDHKPSNTKVDKR VESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLM1SRTPEVTCVWDVSQEDPE VQFNWYVDGVEVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKG LPSS1EKT1SKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVK GFYPSD1AVEWE SNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYT QKSLSLSLGK* 139 TIM3.5 - 13A3 IgG4P NS (without C-terminal K) QLQLQESGPGLVKPSETLSLTCTVSGGSISSRSYYWGWIRQPPGKGLEWIGSIYY SGFTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCATGGPYGDYAHWF DPWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSWTVP SSSLGTKTYTCNVDHKPSNTKVDKR VESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLM1SRTPEVTCVWDVSQEDPE VQFNWYVDGVEVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKG LPSS1EKT1SKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVK GFYPSD1AVEWE SNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYT QKSLSLSLG* 140 TIM3.10 13A3 (N60Q) IgG4P NS QLQLQESGPGLVKPSETLSLTCTVSGGSISSRSYYWGWIRQPPGKGLEWIGSIYY SGFTYYQPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCATGGPYGDYAHWF DPWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSWT VPSSSLGTKTYTCNVDHKPSNTKVDKR VESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLM1SRTPEVTCVWDVSQEDPE VQFNWYVDGVEVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKG LPSS1EKT1SKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLV KGFYPSDLAVEWE SNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYT QKSLSLSLGK* 141 TIM3.10 13A3 (N60Q) IgG4P NS (without C-terminal K) QLQLQESGPGLVKPSETLSLTCTVSGGSISSRSYYWGWIRQPPGKGLEWIGSIYY SGFTYYQPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCATGGPYGDYAHWF DPWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSWT VPSSSLGTKTYTCNVDHKPSNTKVDKR VESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLM1SRTPEVTCVWDVSQEDPE VQFNWYVDGVEVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKG LPSS1EKT1SKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLV KGFYPSDLAVEWE SNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYT QKSLSLSLG* 142 TIM3.11 13A3 (N60S) IgG4P NS QLQLQESGPGLVKPSETLSLTCTVSGGSISSRSYYWGWIRQPPGKGLEWIGSIYY SGFTYYSPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCATGGPYGDYAHWF

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DPWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTKTYTCNVDHKPSNTKVDKR VESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLM1SRTPEVTCVWDVSQEDPE VQFNWYVDGVEVHNAKTKPREEQFNSTY RWSVLTVLHQDWLNGKEYKCKVSNKG LPSS1EKT1SKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDLAVEWE SNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYT QKSLSLSLGK* 143 TIM3.11 13A3 (N60S) IgG4P NS (without C-terminal K) QLQLQESGPGLVKPSETLSLTCTVSGGSISSRSYYWGWIRQPPGKGLEWIGSIYY SGFTYYSPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCATGGPYGDYAHWF DPWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSWTVP SSSLGTKTYTCNVDHKPSNTKVDKR VESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLM1SRTPEVTCVWDVSQEDPE VQFNWYVDGVEVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKG LPSS1EKT1SKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVK GFYPSDLAVEWE SNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYT QKSLSLSLG* 144 TIMS .12 13A3 (N60A) IgG4P NS QLQLQESGPGLVKPSETLSLTCTVSGGSISSRSYYWGWIRQPPGKGLEWIGSIYY SGFTYYAPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCATGGPYGDYAHWF DPWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSWTVP SSSLGTKTYTCNVDHKPSNTKVDKR VESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLM1SRTPEVTCVWDVSQEDPE VQFNWYVDGVEVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKG LPSS1EKT1SKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVK GFYPSDLAVEWE SNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYT QKSLSLSLGK* 145 TIMS .12 - ISAS (N60A) IgG4P NS (without C-terminal K) QLQLQESGPGLVKPSETLSLTCTVSGGSISSRSYYWGWIRQPPGKGLEWIGSIYY SGFTYYAPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCATGGPYGDYAHWF DPWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSWTVP SSSLGTKTYTCNVDHKPSNTKVDKR VESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLM1SRTPEVTCVWDVSQEDPE VQFNWYVDGVEVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKG LPSS1EKT1SKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVK GFYPSDLAVEWE SNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYT QKSLSLSLG* 146 TIMS.13 13A3 (D101E) IgG4P NS QLQLQESGPGLVKPSETLSLTCTVSGGSISSRSYYWGWIRQPPGKGLEWIGSIYY SGFTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCATGGPYGDYAHWF EPWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSWTVP SSSLGTKTYTCNVDHKPSNTKVDKR VESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLM1SRTPEVTCVWDVSQEDPE VQFNWYVDGVEVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKG LPSS1EKT1SKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVK GFYPSDLAVEWE SNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYT QKSLSLSLGK* 147 TIM3.13 13A3 (D101E) IgG4P NS (without C-terminal K) QLQLQESGPGLVKPSETLSLTCTVSGGSISSRSYYWGWIRQPPGKGLEWIGSIYY SGFTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCATGGPYGDYAHWF EPWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSWTVP SSSLGTKTYTCNVDHKPSNTKVDKR VESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLM1SRTPEVTCVWDVSQEDPE VQFNWYVDGVEVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKG LPSS1EKT1SKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVK GFYPSDLAVEWE SNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYT QKSLSLSLG* 148 TIM 3.14 13A3 (P102V) IgG4P NS QLQLQESGPGLVKPSETLSLTCTVSGGSISSRSYYWGWIRQPPGKGLEWIGSIYY SGFTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCATGGPYGDYAHWF DVWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSWTVP SSSLGTKTYTCNVDHKPSNTKVDKR VESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLM1SRTPEVTCVWDVSQEDPE VQFNWYVDGVEVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKG LPSS1EKT1SKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVK GFYPSDLAVEWE SNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYT QKSLSLSLGK* 149 TIM 3.14 13A3 (P102V) IgG4P NS (without C-terminal K) QLQLQESGPGLVKPSETLSLTCTVSGGSISSRSYYWGWIRQPPGKGLEWIGSIYY SGFTYYNPSLKSRVT1SVDTSKNQFSLKLSSVTAADTAVYYCATGGPYGDYAHWF DVWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSWTVP SSSLGTKTYTCNVDHKPSNTKVDKR VESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLM1SRTPEVTCVWDVSQEDPE VQFNWYVDGVEVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKG LPSS1EKT1SKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVK GFYPSDLAVEWE SNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYT QKSLSLSLG* 150 TIMS.15 13A3 (P102Y) IgG4P NS QLQLQESGPGLVKPSETLSLTCTVSGGSISSRSYYWGWIRQPPGKGLEWIGSIYY SGFTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCATGGPYGDYAHWF DYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSWTVP SSSLGTKTYTCNVDHKPSNTKVDKR

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VESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLM1SRTPEVTCVWDVSQEDPE VQFNWYVDGVEVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKG LPSS1EKT1SKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSD1AVEWE SNGQPENNYKTT PPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYT QKSLSLSLGK* 151 TIMS.15 13A3 (P102Y) IgG4P NS (without C-terminal K) QLQLQESGPGLVKPSETLSLTCTVSGGSISSRSYYWGWIRQPPGKGLEWIGSIYY SGFTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCATGGPYGDYAHWF DYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSWTVP SSSLGTKTYTCNVDHKPSNTKVDKR VESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLM1SRTPEVTCVWDVSQEDPE VQFNWYVDGVEVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKG LPSS1EKT1SKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVK GFYPSD1AVEWE SNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYT QKSLSLSLG* 152 TIM3.16 13A3 (P102L) IgG4P NS QLQLQESGPGLVKPSETLSLTCTVSGGSISSRSYYWGWIRQPPGKGLEWIGSIYY SGFTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCATGGPYGDYAHWF DLWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSWTVP SSSLGTKTYTCNVDHKPSNTKVDKR VESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLM1SRTPEVTCVWDVSQEDPE VQFNWYVDGVEVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKG LPSS1EKT1SKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVK GFYPSD1AVEWE SNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYT QKSLSLSLGK* 153 TIM3.16 13A3 (P102L) IgG4P NS (without C-terminal K) QLQLQESGPGLVKPSETLSLTCTVSGGSISSRSYYWGWIRQPPGKGLEWIGSIYY SGFTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCATGGPYGDYAHWF DLWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSWTVP SSSLGTKTYTCNVDHKPSNTKVDKR VESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLM1SRTPEVTCVWDVSQEDPE VQFNWYVDGVEVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKG LPSS1EKT1SKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVK GFYPSD1AVEWE SNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYT QKSLSLSLG* 154 TIMS.17 ISAS (N60Q, P102Y) IgG4P NS QLQLQESGPGLVKPSETLSLTCTVSGGSISSRSYYWGWIRQPPGKGLEWIGSIYY SGFTYYQPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCATGGPYGDYAHWF DYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSWT VPSSSLGTKTYTCNVDHKPSNTKVDKR VESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLM1SRTPEVTCVWDVSQEDPE VQFNWYVDGVEVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKG LPSS1EKT1SKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLV KGFYPSD1AVEWE SNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYT QKSLSLSLGK* 155 TIMS.17 ISAS (N60Q, P102Y) IgG4P NS (without C-terminal K) QLQLQESGPGLVKPSETLSLTCTVSGGSISSRSYYWGWIRQPPGKGLEWIGSIYY SGFTYYQPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCATGGPYGDYAHWF DYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSWT VPSSSLGTKTYTCNVDHKPSNTKVDKR VESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLM1SRTPEVTCVWDVSQEDPE VQFNWYVDGVEVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKG LPSS1EKT1SKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLV KGFYPSDLAVEWE SNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYT QKSLSLSLG* 156 8B9 IgGlza NS QVQLQESGPGLVKPSETLSLTCTVSGGSISRHYWNWIRQPPGKGLEWIGYIHYSG STNYNSSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARDTGYYGMDIWGQG TTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTS GVHTFPAVLQSSGLYSLSSWTVPSSSLGTQ TY1CNVNHKPSNTKVDKKVEPKSC DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLM1SRTPEVTCVWDVSHEDPEVKF NWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWES NG QPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKS LSLSPGK* 157 8B9 IgGlza NS (without C-terminal K) QVQLQESGPGLVKPSETLSLTCTVSGGSISRHYWNWIRQPPGKGLEWIGYIHYSG STNYNSSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARDTGYYGMDIWGQG TTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTS GVHTFPAVLQSSGLYSLSSWTVPSSSLGTQ TY1CNVNHKPSNTKVDKKVEPKSC DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLM1SRTPEVTCVWDVSHEDPEVKF NWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWES NG QPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKS LSLSPG* 158 8B9 IgG4P NS QVQLQESGPGLVKPSETLSLTCTVSGGSISRHYWNWIRQPPGKGLEWIGYIHYSG STNYNSSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARDTGYYGMDIWGQG TTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTS GVHTFPAVLQSSGLYSLSSWTVPSSSLGTK TYTCNVDHKPSNTKVDKRVESKYG PPCPPCPAPEFLGGPSVFLFPPKPKDTLM1SRTPEVTCVWDVSQEDPEVQFNWY VDGVEVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKGLPSSIE

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KTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPE NNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSL SLGK* 159 8B9 IgG4P NS (without C-terminal K) QVQLQESGPGLVKPSETLSLTCTVSGGSISRHYWNWIRQPPGKGLEWIGYIHYSG STNYNSSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARDTGYYGMDIWGQG TTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTS GVHTFPAVLQSSGLYSLSSWTVPSSSLGTK TYTCNVDHKPSNTKVDKRVESKYG PPCPPCPAPEFLGGPSVFLFPPKPKDTLM1SRTPEVTCVWDVSQEDPEVQFNWY VDGVEVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKGLPSSIE KTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWES NGQPE NNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSL SLG* 160 TIM3.8 - 8B9 (S61P) IgG4P NS QVQLQESGPGLVKPSETLSLTCTVSGGSISRHYWNWIRQPPGKGLEWIGYIHYSG STNYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARDTGYYGMDIWGQG TTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTS GVHTFPAVLQSSGLYSLSSVVTVPSSSLGT KTYTCNVDHKPSNTKVDKRVESKYG PPCPPCPAPEFLGGPSVFLFPPKPKDTLM1SRTPEVTCVWDVSQEDPEVQFNWY VDGVEVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKGLPSSIE KTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEW ESNGQPE NNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSL SLGK* 161 TIM3.8 - 8B9 (S61P) IgG4P NS (without C-terminal K) QVQLQESGPGLVKPSETLSLTCTVSGGSISRHYWNWIRQPPGKGLEWIGYIHYSG STNYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARDTGYYGMDIWGQG TTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTS GVHTFPAVLQSSGLYSLSSVVTVPSSSLGT KTYTCNVDHKPSNTKVDKRVESKYG PPCPPCPAPEFLGGPSVFLFPPKPKDTLM1SRTPEVTCVWDVSQEDPEVQFNWY VDGVEVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKGLPSSIE KTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEW ESNGQPE NNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSL SLG* 162 8C4 IgGlza NS QVQLQESGPGLVKPSETLSLTCTVSGGSISRYYWSWIRQPPGKGLEWIGYIHYTG STNYNPSLKSRVT1SVDTSKNQFSLKLSSVTAADTAVYYCATDTGYYGMDVWGQG TTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTS GVHTFPAVLQSSGLYSLSSWTVPSSSLGTQTY1 CNVNHKPSNTKVDKKVEPKSC DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLM1SRTPEVTCVWDVSHEDPEVKF NWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNG Q PENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKS LSLSPGK* 163 8C4 IgGlza NS (without C-terminal K) QVQLQESGPGLVKPSETLSLTCTVSGGSISRYYWSWIRQPPGKGLEWIGYIHYTG STNYNPSLKSRVT1SVDTSKNQFSLKLSSVTAADTAVYYCATDTGYYGMDVWGQG TTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTS GVHTFPAVLQSSGLYSLSSWTVPSSSLGTQTY1 CNVNHKPSNTKVDKKVEPKSC DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLM1SRTPEVTCVWDVSHEDPEVKF NWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNG Q PENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKS LSLSPG* 164 TIM3.6 - 8C4 IgG4P NS QVQLQESGPGLVKPSETLSLTCTVSGGSISRYYWSWIRQPPGKGLEWIGYIHYTG STNYNPSLKSRVT1SVDTSKNQFSLKLSSVTAADTAVYYCATDTGYYGMDVWGQG TTVTVSSTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPP KPKDTLM1SRTPEVTCVWDVSQEDPE VQFNWYVDGVEVHNAKTKPREEQFNSTY RWSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQ EEMTKNQVSLTCLVKGFYPSD1AVEWESNGQPENNYKTTPPVLDSDGSFFLYSRL TVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK* 165 TIM3.6 - 8C4 IgG4P NS (without C-terminal K) QVQLQESGPGLVKPSETLSLTCTVSGGSISRYYWSWIRQPPGKGLEWIGYIHYTG STNYNPSLKSRVT1SVDTSKNQFSLKLSSVTAADTAVYYCATDTGYYGMDVWGQG TTVTVSSTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPP KPKDTLM1SRTPEVTCVWDVSQEDPE VQFNWYVDGVEVHNAKTKPREEQFNSTY RWSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQ EEMTKNQVSLTCLVKGFYPSD1AVEWESNGQPENNYKTTPPVLDSDGSFFLYSRL TVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG* 166 17C3 IgGlza NS QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYYMHWVRQAPGQGLEWMGIINPRG DSIIYAQKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARDFYGSGNYYYGM DVWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSWTVPSS SLGTQTY1CNVNHKPSNTKVDKK VEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLM1SRTPEVTCVWDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVS NKALPAP1EKT1SKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGF YPSD1AV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN HYTQKSLSLSPGK* 167 17C3 IgGlza NS (without C-terminal K) QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYYMHWVRQAPGQGLEWMGIINPRG DSIIYAQKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARDFYGSGNYYYGM DVWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN

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SGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTQTY1CNVNHKPSNTKVDKK VEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVS NKALPAP1EKT1SKAKGQ PREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSD1AV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN HYTQKSLSLSPG* 168 TIM3.2 - 17C3 IgG4P NS QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYYMHWVRQAPGQGLEWMGIINPRG DSIIYAQKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARDFYGSGNYYYGM DVWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSWTVPSS SLGTKTYTCNVDHKPSNTKVDKR VESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLM1SRTPEVTCVWDVSQEDPE VQFNWYVDGVEVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKG LPSS1EKT1SKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGF YPSD1AVEWE SNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYT QKSLSLSLGK* 169 TIMS.2 - 17C3 IgG4P NS (without C-terminal K) QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYYMHWVRQAPGQGLEWMGIINPRG DSIIYAQKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARDFYGSGNYYYGM DVWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSWTVPSS SLGTKTYTCNVDHKPSNTKVDKR VESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLM1SRTPEVTCVWDVSQEDPE VQFNWYVDGVEVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKG LPSS1EKT1SKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGF YPSD1AVEWE SNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYT QKSLSLSLG* 170 9F6 IgGlza NS QVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWVSFISGGGG STIYYADSVKGRFTISRDNAKNSLFLQMNSLRVEDTAVYYCARDGYSSGWYYYGM DVWGQGTAVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLG TQTY1CNVNHKPSNTKVDKK VEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLM1SRTPEVTCVWDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVS NKALPAP1EKT1SKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPS D1AV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN HYTQKSLSLSPGK* 171 9F6 IgGlza NS (without C-terminal K) QVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWVSFISGGGG STIYYADSVKGRFTISRDNAKNSLFLQMNSLRVEDTAVYYCARDGYSSGWYYYGM DVWGQGTAVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLG TQTY1CNVNHKPSNTKVDKK VEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVS NKALPAP1EKT1SKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPS D1AV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN HYTQKSLSLSPG* 172 9F6 IgG4P NS QVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWVSFISGGGG STIYYADSVKGRFTISRDNAKNSLFLQMNSLRVEDTAVYYCARDGYSSGWYYYGM DVWGQGTAVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLG TKTYTCNVDHKPSNTKVDKR VESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLM1SRTPEVTCVWDVSQEDPE VQFNWYVDGVEVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKG LPSS1EKT1SKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPS D1AVEWE SNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYT QKSLSLSLGK* 173 9F6 IgG4P NS (without C-terminal K) QVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWVSFISGGGG STIYYADSVKGRFTISRDNAKNSLFLQMNSLRVEDTAVYYCARDGYSSGWYYYGM DVWGQGTAVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLG TKTYTCNVDHKPSNTKVDKR VESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLM1SRTPEVTCVWDVSQEDPE VQFNWYVDGVEVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKG LPSS1EKT1SKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPS D1AVEWE SNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYT QKSLSLSLG* 174 TIM3.7 - 9F6 (A108T) IgG4P NS QVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWVSFISGGGG STIYYADSVKGRFTISRDNAKNSLFLQMNSLRVEDTAVYYCARDGYSSGWYYYGM DVWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLG TKTYTCNVDHKPSNTKVDKR VESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLM1SRTPEVTCVWDVSQEDPE VQFNWYVDGVEVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKG LPSS1EKT1SKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPS DLAVEWE SNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYT QKSLSLSLGK* 175 TIM3.7 - 9F6 (A108T) IgG4P NS (without C-terminal K) QVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWVSFISGGGG STIYYADSVKGRFTISRDNAKNSLFLQMNSLRVEDTAVYYCARDGYSSGWYYYGM DVWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLG TKTYTCNVDHKPSNTKVDKR VESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLM1SRTPEVTCVWDVSQEDPE

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VQFNWYVDGVEVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKG LPSSIEKT1SKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDLAVEWE SNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYT QKSLSLSLG* 176 3G4 IgGlza NS QVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWVSFISTSG SIIYYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAREGYSSSWSYYYG MDVWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSW NSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTQ TY1CNVNHKPSNTKVDK KVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSH EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKV SNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIA VEWESNG QPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALH NHYTQKSLSLSPGK* 177 3G4 IgGlza NS (without C-terminal K) QVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWVSFISTSG SIIYYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAREGYSSSWSYYYG MDVWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSW NSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTQ TYICNVNHKPSNTKVDK KVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLM1SRTPEVTCVVVDVSH EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKV SNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIA VEWES NGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALH NHYTQKSLSLSPG* 178 TIM3.4 - 3G4 IgG4P NS QVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWVSFISTSG SIIYYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAREGYSSSWSYYYG MDVWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSW NSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTK TYTCNVDHKPSNTKVDK RVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLM1SRTPEVTCVWDVSQEDP EVQFNWYVDGVEVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNK GLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEW ES NGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHY TQKSLSLSLGK* 179 TIM3.4 - 3G4 IgG4P NS (without C-terminal K) QVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWVSFISTSG SIIYYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAREGYSSSWSYYYG MDVWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSW NSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTK TYTCNVDHKPSNTKVDK RVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLM1SRTPEVTCVWDVSQEDP EVQFNWYVDGVEVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNK GLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEW ES NGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHY TQKSLSLSLG* 180 17C8 IgG4 NS QVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWVSFISSSG SIIYYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDGYSSGWEYYGM DVWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTK TYTCNVDHKPSNTKVDKR VESKYGPPCPSCPAPEFLGGPSVFLFPPKPKDTLM1SRTPEVTCVWDVSQEDPE VQFNWYVDGVEVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKG LPSSIEKT1SKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSD1AVE WE SNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYT QKSLSLSLGK* 181 17C8 lgG4 NS (without Terminal K) QVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWVSFISSSG SIIYYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDGYSSGWEYYGM DVWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTK TYTCNVDHKPSNTKVDKR VESKYGPPCPSCPAPEFLGGPSVFLFPPKPKDTLM1SRTPEVTCVWDVSQEDPE VQFNWYVDGVEVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKG LPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWE SNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYT QKSLSLSLG* 182 TIM3.9 - 17C8 IgG4P NS QVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWVSFISSSG SIIYYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDGYSSGWEYYGM DVWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTK TYTCNVDHKPSNTKVDKR VESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLM1SRTPEVTCVWDVSQEDPE VQFNWYVDGVEVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKG LPSSIEKT1SKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSD1AVE WE SNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYT QKSLSLSLGK* 183 TIM3.9 - 17C8 IgG4P NS (without C-terminal K) QVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWVSFISSSG SIIYYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDGYSSGWEYYGM DVWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTK TYTCNVDHKPSNTKVDKR VESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLM1SRTPEVTCVWDVSQEDPE VQFNWYVDGVEVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKG LPSSIEKT1SKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSD1AVE WE

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SNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYT QKSLSLSLG* 184 13A3 (N60Q, D101E) IgGl.lf HC QLQLQESGPGLVKPSETLSLTCTVSGGSISSRSYYWGWIRQPPGKGLEWIGSIYY SGFTYYQPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCATGGPYGDYAHWF EPWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSWT VPSSSLGTQTY1CNVNHKPSNTKVDKR VEPKSCDKTHTCPPCPAPEAEGAPSVFLFPPKPKDTLM1SRTPEVTCVWDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVS NKALPSS1EKT1SKAKGQPREPQVYTLPPSREEMTKNQVSLTCLV KGFYPSD1AV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN HYTQKSLSLSPGK* 185 13A3 (N60Q, D101E) IgGl. If NS (without C-terminal K) QLQLQESGPGLVKPSETLSLTCTVSGGSISSRSYYWGWIRQPPGKGLEWIGSIYY SGFTYYQPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCATGGPYGDYAHWF EPWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSWT VPSSSLGTQTY1CNVNHKPSNTKVDKR VEPKSCDKTHTCPPCPAPEAEGAPSVFLFPPKPKDTLM1SRTPEVTCVVVDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVS NKALPSS1EKT1SKAKGQPREPQVYTLPPSREEMTKNQVSLTC LVKGFYPSD1AV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN HYTQKSLSLSPG* 186 13A3 (N60Q, D101E) IgG1.3f NS QLQLQESGPGLVKPSETLSLTCTVSGGSISSRSYYWGWIRQPPGKGLEWIGSIYY SGFTYYQPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCATGGPYGDYAHWF EPWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSWT VPSSSLGTQTY1CNVNHKPSNTKVDKR VEPKSCDKTHTCPPCPAPEAEGAPSVFLFPPKPKDTLM1SRTPEVTCVVVDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVS NKALPAP1EKT1SKAKGQPREPQVYTLPPSREEMTKNQVSLTC LVKGFYPSD1AV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN HYTQKSLSLSPGK* 187 13A3 (N60Q, D101E) IgG1.3f NS (without C-terminal K) QLQLQESGPGLVKPSETLSLTCTVSGGSISSRSYYWGWIRQPPGKGLEWIGSIYY SGFTYYQPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCATGGPYGDYAHWF EPWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSWT VPSSSLGTQTY1CNVNHKPSNTKVDKR VEPKSCDKTHTCPPCPAPEAEGAPSVFLFPPKPKDTLM1SRTPEVTCVVVDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVS NKALPAP1EKT1SKAKGQPREPQVYTLPPSREEMTKNQVSLTC LVKGFYPSD1AV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN HYTQKSLSLSPG* 188 TIM3.18 13A3 (N60Q, D101E) IgG4P NS QLQLQESGPGLVKPSETLSLTCTVSGGSISSRSYYWGWIRQPPGKGLEWIGSIYY SGFTYYQPSLKSRVT1SVDTSKNQFSLKLSSVTAADTAVYYCATGGPYGDYAHWF EPWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSWT VPSSSLGTKTYTCNVDHKPSNTKVDKR VESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLM1SRTPEVTCWVDVSQEDPE VQFNWYVDGVEVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKG LPSS1EKT1SKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLV KGFYPSDLAVEWE SNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYT QKSLSLSLGK* 189 TIM3.18 13A3 (N60Q, D101E) IgG4P NS (without C-terminal K) QLQLQESGPGLVKPSETLSLTCTVSGGSISSRSYYWGWIRQPPGKGLEWIGSIYY SGFTYYQPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCATGGPYGDYAHWF EPWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSWT VPSSSLGTKTYTCNVDHKPSNTKVDKR VESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLM1SRTPEVTCWVDVSQEDPE VQFNWYVDGVEVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKG LPSS1EKT1SKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLV KGFYPSDLAVEWE SNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYT QKSLSLSLG* 190 13A3, 17C3, 3G4 L.C. EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSR ATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSPITFGQGTRLEIKRT VAAPSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVT EQDSKDSTYSLSSTLTLSKADYEKHKVYACE VTHQGLSSPVTKSFNRGEC* 191 8B9, 8C4, 17C8, 9F6 (VK3) L.C. EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSR ATG1PDRFSGSGSGTDFTLT1SRLEPEDFAVYYCQQYGSSPLTFGGGTKVE1KRT VAAPSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVT EQDSKDSTYSLSSTLTLSKADYEKHKVY ACEVTHQGLSSPVTKSFNRGEC* 192 9F6 (VK1) L.C. AIQLTQSPSSLSASVGDRVTITCRASQGISSALAWYQQKPGKAPKLLIYDASSLE SGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQFNSYPRTFGQGTKVEIKRTV AAPSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTE QDSKDSTYSLSSTLTLSKADYEKHKV YACEVTHQGLSSPVTKSFNRGEC* 193 9F6 (VK2) L.C. EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSR ATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSLTFGGGTKVEIKRTV AAPSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTE QDSKDSTYSLSSTLTLSKADYEKHKVYACEV THQGLSSPVTKSFNRGEC* 194 TIM3 Isoform 1 (aa) MFSHLPFDCVLLLLLLLLTRSSEVEYRAEVGQNAYLPCFYTPAAPGNLVPVCWGK GACPVFECGNWLRTDERDVNYWTSRYWLNGDFRKGDVSLT1ENVTLADSG1YCC

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RIQIPGIMNDEKFNLKLVIKPAKVTPAPTRQRDFTAAFPRMLTTRGHGPAETQTL GSLPDINLTQISTLANELRDSRLANDLRDSGATIRIGIYIGAGICAGLALALIFG ALIFKWYSHSKEKIQNLSLISLANLPPSGLANAVAEGIRSEENIYTIEENVYEVE EPNEYYCYVSSRQQPSQPLGCRFAM 195 TIM3 Isoform 2 (aa) MFSHLPFDCVLLLLLLLLTRSSEVEYRAEVGQNAYLPCFYTPAAPGNLVPVCWGK GACPVFECGNWLRTDERDVNYWTSRYWLNGDFRKGDVSLT1ENVTLADSG1YCC RIQIPGIMNDEKFNLKLVIKPGEWTFACHLYE 196 TIM3 Isoform 1 (nt) AGAACACTTACAGGATGTGTGTAGTGTGGCATGACAGAGAACTTTGGTTTCCTTT AAT G T GAC T G T AGAC CTGGCAGTGTTACTATAAGAATCACTGGCAATCAGACACCCGGGTGTGCTGAGCT AGCACTCAGTGGGGG CGGCTACTGCTCATGTGATTGTGGAGTAGACAGTTGGAAGAAGTACCCAGTCCAT T T G GAGAG T T AAAAC TGTGCCTAACAGAG GTGTCCTCTGACTTTTCTTCTGCAAGCTCCATGTTTTCACA TCTTCCCTTTGACTG TGTCCTGCTGCTGCTGCTGCTACTACTTACAAGGTCCTCAGAAGTGGAATACAGA GCGGAGGTCGGTCAG AATGCCTATCTGCCCTGCTTCTACACCCCAGCCGCCCCAGGGAACCTCGTGCCCG TCTGCTGGGGCAAAG GAGCCTGTCCTGTGTTTGAATGTGGCAACGTGGTGCTCAGGACTGA TGAAAGGGA T G T GAAT T AT T G GAC ATCCAGATACTGGCTAAATGGGGATTTCCGCAAAGGAGATGTGTCCCTGACCATA GAGAAT G T GAC T STA GCAGACAGTGGGATCTACTGCTGCCGGATCCAAATCCCAGGCATAATGAATGATG AAAAT T TAAS S T GA AGTTGGTCATCAAACCAGCCAAGGTCACCCCTGCACCGACTCGGCAGAGAGACTT CACTGCAGCCTTTCC AAGGATGCTTACCACCAGGGGACATGGCCCAGCAGAGACACAGACACTGGGGAGC S T S S S T GAT AT AAAAT CTAACACAAATATCCACATTGGCCAATGAGTTACGGGACTCTAGATTGGCCAATG ACTTACGGGACTCTG GAGCAACCATCAGAATAGG CATCTACATCGGAGCAGGGATCTGTGCTGGGCTGGC TCTGGCTCTTATCTT CGGCGCTTTAATTTTCAAATGGTATTCTCATAGCAAAGAGAAGATACAGAATTTA AGCCTCATCTCTTTG GCCAACCTCCCTCCCTCAGGATTGGCAAATGCAGTAGCAGAGGGAATTCGCTCAG AAGAAAACAT S TATA CCATTGAAGAGAACGTATATGAAGTGGAGGAGCCCAATGAGTATTAT TGCTATGT CAGCAGCAGGCAGCA ACCCTCACAACCTTTGGGTTGTCGCTTTGCAATGCCATAGATCCAACCACCTTAT TTTTGAGCTTGGTGT TTTGTCTTTTTCAGAAACTATGAGCTGTGTCACCTGACTGGTTTTGGAGGTTCTG TCCACTGCTATGGAG S AGAG T T T T S S CAT T T T S AGAAGAT AAT GAC T S AC AT GG GAAT Т GAAC Т GG GAC С Т G С АС Т GAAC Т Т ААА CAGGCATGTCATTGCCTCTGTATTTAAGCCAACAGAGTTACCCAACCCAGAGACT GTTAATCATGGATGT TAGAGCTCAAACGGGCTTTTATATACACTAGGAATTCTTGACGTGGGGTCTCTGG AG СТССAGGAAATТС GGGCACATCATATGTCCATGAAACTTCAGATAAACTAGGGAAAACTGGGTGCTGA GGTGAAAGCATAACT TTTTTGGCACAGAAAGTCTAAAGGGGCCACTGATTTTCAAAGAGATCTGTGATCC _{CTTTTTGTTTTTTGT} TTTTGAGATGGAGTCTTGCTCTGTTGCCCAGGCTGGAGTGCAATGGCACAATCTC GGCTCACTGCAAGCT CCGCCTCCTGGGTTCAAGCGATTCTCCTGCCTCAGCCTCCTGAGTGGCTGGGATT ACAGGCATGCACCAC CATGCCCAGCTAATTTGTTGTATTTTTAGTAGAGACAGGGTTTCACCATGTTGGC CAGTGTGGTCTCAAA CTCCTGACCTCATGATTTGCCTGCCTCGGCCTCCCAAAGCACTGGGATTACAGGC G Т GAG С САС С АС АТ С С AG С С AG Т GAT С С T T AAAAGAT T AAGAGAT GAC T G GAC C AG GT C TAC C T T G AT C T TGAAGATTCCCTTGG AATGTTGAGATTTAGGCTTATTTGAGCACTGCCTGCCCAACTGTCAGTGCCAGTG CATAGCCCTTCTTTT GTCTCCCTTATGAAGACTGCCCTGCAGGGCTGAGATGTGGCAGGAGCTCCCAGGG AAAAAC GAAG T G CAT TTGATTGGTGTGTATT GGCCAAGTTTTGCTTGTTGTGTGCTTGAAAGAAAATATC TCTGACCAACTTCTG TATTCGTGGACCAAACTGAAGCTATATTTTTCACAGAAGAAGAAGCAGTGACGGG GAC ASAAAT T S T G T T GCCTGGTGGAAAGAAGGCAAAGGCCTTCAGCAATCTATATTACCAGCGCTGGATC S T T T GAC AGAGAG T G GTCCCTAAACTTAAATTTTCAAGACGGTATAGGCTTGATCTGTCTTGCTTATTGTT GCCCCCTGCGCCTAG

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S AC AAT T S T GAC AC AC AAT T G GAAC T TAS T AAAAAT TTTTTTTTACTGT TAAAAAA AAAAAAAAAAAA 197 T1M3 Isoform 2 (nt) ACTGCTCATGTGATTGTGGAGTAGACAGTTGGAAGAAGTACCCAGTCCATTTGGA GAGTTAAAACTGTGC CTAACAGAGGTGTCCTCTGACTTTTCTTCTGCAAGCTCCATGTTTTCACATCTTC CCTTTGACTGTGTCC TGCTGCTGCTGCTGCTACTACTTACAAGGTCCTCAGAAGTGGAATACAGAGCGGA GGTCGGTCAGAATGC CTATCTGCCCTGCTTCTACACCCCAGCCGCCCCAGGGAACCTCGTGCCCGTCTGC TGGGGCAAAGGAGCC TGTCCTGTGTTTGAATGTGGCAACGTGGTGCTCAGGACTGATGAAAGGGATGTGA AT TAT T G GAC AT S S A GATACTGGCTAAATGGGGATTTCCGCAAAGGGAGATGTGTCCCTGACCATAGAGAA T G T GAC T S TAG C AGA CAGTGGGATCTACTGCTGCCGGATCCAAATCCCAGGCATAATGAATGATGAAAAA TTTAACCTGAAGTTG GTCATCAAACCAGGTGAGTGGACATTTGCATGCCATCTTTATGAATAAGATTTAT S T G T G GAT S AT AT TA AAGGTACTGATTGTTCTCATCTCTGACTTCCCTAATTATAGCCCTGGAGGAGGGC CAC T AAGAC C T AAAG TTTAACAGGCCCCATTGGTGATGCTCAGTGATATTTAACACCTTCTCTCTGTTTT AAAACTCATGGGTGT GCCTGGGCGTGGTGGCTCGCGCCTCTGGTCCCAGCACTTTGGGAGGCTGAGGCCG GTGGATCATGAGGTC AGGAATTCGACAGCCTGGCCAACATGGTAAAACCTTGTCTCCACTAAAAATA CAAAAAAAT TAG C C AG GCATGGTTACGGGAGCCTGTAATTCTAGCTACTTGGGGGGCTGAAGCAGGAGAAT S A T T GAAC S T G GAA GTCGGAGGTTGCGGTAAGCCAAGATCTCGCCATTGTACTCCAGCCTGGCTGACAA GAGTGAAACTCTGTC SSAAAAAAAAAAAAAAAAAAAAAAAA 198 Extracellular domain of TIM3 SEVEYRAEVGQNAYLPCFYTPAAPGNLVPVCWGKGACPVFECGNWLRTDERDVN YWTSRYWLNGDFRKGDVSLTIENVTLADSGIYCCRIQIPGIMNDEKFNLKLVIKP AKVTPAPTRQRDFTAAFPRMLTTRGHGPAETQTLGSLPDINLTQISTLANELRDS RLAN D L RD S GAT I RI G 199 Cynomolgus monkey T1M3 protein MFSHLPFDCVLLLLLLLLTRSSEVEYIAEVGQNAYLPCSYTPAPPGNLVPVCWGK GACPVFDCSNWLRTENRDVNDRTSGRYWLKGDFHKGDVSLT1ENVTLADSGVYC CRIQIPGIMNDEKHNLKLWIKPAKVTPAPTLQRDLTSAFPRMLTTGEHGPAETQ TPGSLPDVNLTQIFTLTNELRDSGATIRTAIYIAAGISAGL ALALIFGALIFKWY SHSKEKTQNLSLISLANTPPSGLANAVAEGIRSEENIYTIEEDVYEVEEPNEYYC YVSSGQQPSQPLGCRFAMP 200 residues 37-43 of mature TIM3 ECD CPVFECG 201 residues 57-83 of mature TIM3 ECD WTSRYWLNGDFR 202 remnants 90-99 of mature TIM3 ECD R1Q1PG1MND 203 residues 1-99 of mature TIM3 ECD SEVEYRAEVGQNAYLPCFYTPAAPGNLVPVCWGKGACPVFECGNWLRTDERDVN YWTSRYWLNGDFRKGDVSLT1ENVTLADSG1YCCR1Q1PG1MND 204 remnants 49-62 of mature human T1MZ ECD VPVCWGKGAC PVFE 205 remains 111-127 mature human TIM3 ECD R1Q1PG1MNDEKFNLKL 206 remnants 40-62 of the mature human TIM3 ECD YTPAAPGNLVPVCWGKGACPVFE 207 residues 66-77 of mature human TIM3 ECD WLRTDERDVNY 208 residues 78-95 of mature human TIM3 ECD WTSRYWLNGDFRKGDVSL

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209 residues 110-127 of mature human T1MZ ECD CR1Q1PG1MNDEKFNLKL 210 remains 119-127 mature human Т1МЗ ECD NDEKFNLKL 211 13A3 VH CDR1 degenerate Х1Х2ХЗХ4YX5X6 (numbers represent subtypes) 212 13A3 VH CDR2 degenerate X11X2X3X4GX5X6X7X8YX9X10X11X12X13X14 (numbers represent subtypes) 213 13A3 VH CDR3 degenerate X1X2X3X4X5X6X7X8X9X10YGX11X12X13X14X15X16X17X18 (numbers represent subtypes) 214 13A3 IgGl.lf NS CAGCTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGT CCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGCAGTAGAAGTTACTACTGGGG CTGGATCCGCCAGCCCCCAGGGAAGGGGCTGGAGTGGATTGGGAGTATCTATTAT AGTGGGTTCACCTACTACAACCCGTCCCTCAAGAGTCGAGTCACCATATCCGTTG ACACGTCCAAGAACCAGTT CTCCCTGAAGCTGAGCTCTGTGACCGCCGCAGACAC GGCTGTGTATTATTGTGCGACAGGGGGGCCCTACGGTGACTACGCCCACTGGTTC GACCCCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCTAGCACCAAGGGCC CATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGC CCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACTGTC GTGGAAC TCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAG GACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCA GACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGA GTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTG AAGCCGAAGGGGCCC CGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCT CATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAA GACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCA AGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCT CACCGTCCTGCACCAGGACTGGCTGAATGGCAAG GAGTACAAGTGCAAGGTCTCC AACAAAGCCCTCCCAAGCAGCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGC CCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAA CCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTG GAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGC TGGACT CCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAG GTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAAC CACTACACGCAGAAGAGCCTCTCCCTGTCCCCGGGTAAATGA 215 8B9 IgGl.lf NS CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGT CCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGTCGTCACTACTGGAACTGGAT CCGGCAGCCCCCAGGGAAGGGACTGGAGTGGATTGGGTATATCCATTACAGTGGA AGCACCAACTACAATTCCTCCCTCAAGAGTCGAGTCACCATATCAGTAGACACGT CCAAGAACCAGTTCTCCCTGA AGCTGAGCTCTGTGACCGCTGCGGACACGGCCGT GTATTACTGTGCGAGAGATACTGGGTACTACGGTATGGACATCTGGGGCCAAGGG ACCACGGTCACCGTCTCCTCAGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGG CACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAA GGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCT GACCAGC GGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCA GCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGT GAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGT GACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAAGCCGAAGGGGCCCCGT CAGTCTTCCTCTTC CCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCC TGAGGTCCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTC AACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGG AGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGA CTGGCTGAATGGCAAGGAGTACAAGTGCA T CTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGT CTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGC CTCTCCCTGTCCCCGGGTAAATGA 216 8C4 IgGl.lf NS CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGT CCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGTCGTTACTACTGGAGCTGGAT CCGGCAGCCCCCAGGGAAGGGACTGGAGTGGATTGGGTATATCCATTACACTGGG AGCACCAACTACAACCCCTCCCTCAAGAGTCGAGTCACCATATCAGTAGACACGT CCAAGAACCAGTTCTCCCTGA AGCTGAGCTCTGTGACCGCAGCGGACACGGCCGT GTATTACTGTGCGACAGATACGGGCTACTACGGTATGGACGTCTGGGGCCAAGGG ACCACGGTCACCGTCTCCTCAGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGG CACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAA GGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGA CCAGC GGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCA GCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGT

- 71 045913

GAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGT GACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAAGCCGAAGGGGCCCCGT CAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCC TGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTC AACTGGTACGTGGACGGC GTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGG AGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGA CTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAAGC AGCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGT ACACCCTGCCCCCATCCCGGGAGGAATGACCAAGAACCA GGTCAGCCTGACCTG CCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGG CAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCT TCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGT CTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGC CTCTCCCTGTC CCCGGGTAAAATGA 217 17C3 IgGl.lf NS CAGGTGCAGTTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGA AGGTCTCCTGCAAGGCATCTGGATACACTTTCACCAGCTACTATATGCACTGGGT GCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGAATAATCAACCCTAGGGGT GATAGCATAATCTACGCACAGAAGTTCCAGGGCAGAGTCACCATGACCAGGGACA CGTCCACGAGCACAGTC TACATGGAGCTGAGCAGCCTGAGATCTGAGGACACGGC CGTGTATTACTGTGCGAGAGATTTCTATGGTTCGGGAAACTACTACTACGGTATG GACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCAGCTAGCACCAAGGGCC CATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGC CCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACTG TCGTGGAAC TCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAG GACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCA GACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGA GTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTG AAGCCGAAGGGGC CCCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCT CATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAA GACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCA AGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCT CACCGTCCTGCACCAGGACTGGCTGAATGGCA AGGAGTACAAGTGCAAGGTCTCC AACAAAGCCCTCCCAAGCAGCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGC CCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAA CCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTG GAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGC TGC ACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAG GTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAAC CACTACACGCAGAAGAGCCTCTCCCTGTCCCCGGGTAAATGA 218 9F6 IgGl.lf NS CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCAAGCCTGGAGGGTCCCTGA GACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTGACTACTACATGAGCTGGAT CCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTTTCATTCATTAGTGGTGGTGGT AGTACCATATACTACGCAGACTCTGTGAAGGGCCGATTCACCATCTCCAGGGACA ACGCCAAGAACTCGCTGTT TCTGCAAATGAACAGCCTGAGAGTCGAGGACACGGC TGTGTATTACTGTGCGAGAGATGGCTATAGCAGTGGCTGGTACTACTACGGTATG GACGTCTGGGGCCAAGGGACCGCGGTCACCGTCTCCTCAGCTAGCACCAAGGGCC CATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGC CCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGG TGTCGTGGAAC TCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAG GACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCA GACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGA GTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTG AAGCCGAAG GCCCCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCT CATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAA GACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCA AGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCT CACCGTCCTGCACCAGGACTGGCTGAAT T GGACTCCGACGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAG GTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAAC CACTACACGCAGAAGAGCCTCTCCCTGTCCCCGGGTAAATGA 219 3G4 IgGl.lf NS CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCAAGCCTGGAGGGTCCCTGA GACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTGACTACTACATGAGCTGGAT CCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTTTCATTCATTAGTACTAGTGGT AGTATCATATACTACGCAGACTCTGTGAAGGGCCGATTCACCATCTCCAGGGACA ACGCCAAGAACTCACTGTATC TGCAAATGAACAGCCTGAGAGCCGAGGACACGGC TGTGTATTACTGTGCGAGAGAAGGGTATAGCAGCAGCTGGTCCTACTACTACGGT ATGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCAGCTAGCACCAAGG GCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGC GGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGAC GGTGTCGTGG AACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCT CAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCAC

- 72 045913

CCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAG AGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCAC CTGAAGCCGAAGGGGCCCCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACAC CCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCAC GAAGACCCTGAGGTCAAGTTCA ACTGGTACGTGGACGGCGTGGAGGTGCATAATG CCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGT CCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTC TCCAACAAAGCCCTCCCAAGCAGCATCGAGAAAACCATCTCCAAAGCCAAAGGGC AGCCCCAAAGCCAAAGGGC AGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGAT GACCAA GAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCC GTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCG TGCTGGACTCCGACGGCTCCTTCTTCCTTAGCAAGCTCACCGTGGACAAGAG CAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCAC AACCACTACGCAGAAGAGCC TCTCCCTGTCCCCGGGTAAATGA 220 17C8 IgGl.If NS CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCAAGCCTGGAGGGTCCCTGA GACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTGACTACTACATGAGCTGGAT CCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTTTCATTCATTAGTAGTAGTGGT AGTATCATATACTACGCAGACTCTGTGAAGGGCCGATTCACCATCTCCAGGGACA ACGCCAAGAACTCACTGTA TCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGC TGTGTATTACTGTGCGAGAGATGGGTATAGCAGTGGCTGGGAGTACTACGGTATG GACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCAGCTAGCACCAAGGGCC CATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGC CCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGG TGTCGTGGAAC TCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAG GACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCA GACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGA GTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTG AAGCCGAAG GCCCCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCT CATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAA GACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCA AGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCT CACCGTCCTGCACCAGGACTGGCTGAAT T GGACTCCGACGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAG GTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAAC CACTACACGCAGAAGAGCCTCTCCCTGTCCCCGGGTAAATGA 221 13A3 IgGl. If NS (without C-terminal K) CAGCTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGT CCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGCAGTAGAAGTTACTACTGGGG CTGGATCCGCCAGCCCCCAGGGAAGGGGCTGGAGTGGATTGGGAGTATCTATTAT AGTGGGTTCACCTACTACAACCCGTCCCTCAAGAGTCGAGTCACCATATCCGTTG ACACGTCCAAGAACCAGTT CTCCCTGAAGCTGAGCTCTGTGACCGCCGCAGACAC GGCTGTGTATTATTGTGCGACAGGGGGGCCCTACGGTGACTACGCCCACTGGTTC GACCCCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCTAGCACCAAGGGCC CATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGC CCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACTGTC GTGGAAC TCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAG GACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCA GACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGA GTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTG AAGCCGAAGGGGCCC CGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCT CATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAA GACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCA AGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCT CACCGTCCTGCACCAGGACTGGCTGAATGGCAAG GAGTACAAGTGCAAGGTCTCC AACAAAGCCCTCCCAAGCAGCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGC CCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAA CCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTG GAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGC TGGACT CCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAG GTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAAC CACTACACGCAGAAGAGCCTCTCCCTGTCCCCGGGTTGA 222 8B9 IgGl. If NS (without C-terminal K) CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGT CCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGTCGTCACTACTGGAACTGGAT CCGGCAGCCCCCAGGGAAGGGACTGGAGTGGATTGGGTATATCCATTACAGTGGA AGCACCAACTACAATTCCTCCCTCAAGAGTCGAGTCACCATATCAGTAGACACGT CCAAGAACCAGTTCTCCCTGA AGCTGAGCTCTGTGACCGCTGCGGACACGGCCGT GTATTACTGTGCGAGAGATACTGGGTACTACGGTATGGACATCTGGGGCCAAGGG ACCACGGTCACCGTCTCCTCAGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGG CACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAA GGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCT GACCAGC GGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCA GCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGT

- 73 045913

GAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGT GACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAAGCCGAAGGGGCCCCGT CAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCC TGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTC AACTGGTACGTGGACGGC GTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGG AGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGA CTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAAGC AGCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGT ACACCCTGCCCCCATCCCGGGAGGAATGACCAAGAACCA GGTCAGCCTGACCTG CCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGG CAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCT TCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGT CTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGC CTCTCCCTGTC CCCGGGTTGA 223 8C4 IgGl. If NS (without C-terminal K) CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGT CCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGTCGTTACTACTGGAGCTGGAT CCGGCAGCCCCCAGGGAAGGGACTGGAGTGGATTGGGTATATCCATTACACTGGG AGCACCAACTACAACCCCTCCCTCAAGAGTCGAGTCACCATATCAGTAGACACGT CCAAGAACCAGTTCTCCCTGA AGCTGAGCTCTGTGACCGCAGCGGACACGGCCGT GTATTACTGTGCGACAGATACGGGCTACTACGGTATGGACGTCTGGGGCCAAGGG ACCACGGTCACCGTCTCCTCAGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGG CACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAA GGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGA CCAGC GGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCA GCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGT GAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGT GACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAAGCCGAAGGGGCCCCGT CAGTCTTCCCTTCCC CCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCC TGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTC AACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGG AGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGA CTGGCTGAATGGCAAGGAGTACAAGTGCAAG GTCTCCAACAAAGCCCTCCCAAGC AGCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGT ACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTG CCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGG CAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCT TCT TCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGT CTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGC CTCTCCCTGTCCCCGGGTTGA 224 17C3 IgGl. If NS (without C-terminal K) CAGGTGCAGTTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGA AGGTCTCCTGCAAGGCATCTGGATACACTTTCACCAGCTACTATATGCACTGGGT GCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGAATAATCAACCCTAGGGGT GATAGCATAATCTACGCACAGAAGTTCCAGGGCAGAGTCACCATGACCAGGGACA CGTCCACGAGCACAGTC TACATGGAGCTGAGCAGCCTGAGATCTGAGGACACGGC CGTGTATTACTGTGCGAGAGATTTCTATGGTTCGGGAAACTACTACTACGGTATG GACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCAGCTAGCACCAAGGGCC CATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGC CCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACTG TCGTGGAAC TCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAG GACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCA GACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGA GTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTG AAGCCGAAGGGGC CCCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCT CATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAA GACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCA AGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCT CACCGTCCTGCACCAGGACTGGCTGAATGGCA AGGAGTACAAGTGCAAGGTCTCC AACAAAGCCCTCCCAAGCAGCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGC CCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAA CCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTG GAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGC TGC ACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAG GTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAAC CACTACACGCAGAAGAGCCTCTCCCTGTCCCCGGGTTGA 225 9F6 IgGl. If NS (without C-terminal K) CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCAAGCCTGGAGGGTCCCTGA GACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTGACTACTACATGAGCTGGAT CCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTTTCATTCATTAGTGGTGGTGGT AGTACCATATACTACGCAGACTCTGTGAAGGGCCGATTCACCATCTCCAGGGACA ACGCCAAGAACTCGCTGTT TCTGCAAATGAACAGCCTGAGAGTCGAGGACACGGC TGTGTATTACTGTGCGAGAGATGGCTATAGCAGTGGCTGGTACTACTACGGTATG GACGTCTGGGGCCAAGGGACCGCGGTCACCGTCTCCTCAGCTAGCACCAAGGGCC CATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGC CCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGG TGTCGTGGAAC TCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAG GACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCA

- 74 045913

GACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGA GTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCG AAGCCGAAGGGGCCCCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCT CATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAA GACCCTGAGGTCAAGTT CAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCA AGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCT CACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCC AACAAAGCCCTCCCAAGCAGCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGC CCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGA GATGACCAAGAA CCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTG GAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGC TGGACTCCGACGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAG GTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAAC CACTACACGCAGA AGAGCCTCTCCCTGTCCCCGGGTTGA 226 3G4 IgGl. If NS (without C-terminal K) CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCAAGCCTGGAGGGTCCCTGA GACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTGACTACTACATGAGCTGGAT CCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTTTCATTCATTAGTACTAGTGGT AGTATCATATACTACGCAGACTCTGTGAAGGGCCGATTCACCATCTCCAGGGACA ACGCCAAGAACTCACTGTATC TGCAAATGAACAGCCTGAGAGCCGAGGACACGGC TGTGTATTACTGTGCGAGAGAAGGGTATAGCAGCAGCTGGTCCTACTACTACGGT ATGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCAGCTAGCACCAAGG GCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGC GGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGAC GGTGTCGTGG AACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCT CAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCAC CCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAG AGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCAC CTGAAGCCGAAGGG CCCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACAC CCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCAC GAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATG CCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGT CCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAG TACAAGTGCAAGGTC TCCAACAAAGCCCTCCCAAGCAGCATCGAGAAAACCATCTCCAAAGCCAAAGGGC AGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGGAGGAGATGACCAA GAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCC GTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCG TGCTGGACTCCGA CGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAG CAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCAC AACCACTACACGCAGAAGAGCCTCTCCCTGTCCCCGGGTTGA 227 17C8 IgGl. If NS (without C-terminal K) CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCAAGCCTGGAGGGTCCCTGA GACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTGACTACTACATGAGCTGGAT CCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTTTCATTCATTAGTAGTAGTGGT AGTATCATATACTACGCAGACTCTGTGAAGGGCCGATTCACCATCTCCAGGGACA ACGCCAAGAACTCACTGTA TCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGC TGTGTATTACTGTGCGAGAGATGGGTATAGCAGTGGCTGGGAGTACTACGGTATG GACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCAGCTAGCACCAAGGGCC CATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGC CCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGG TGTCGTGGAAC TCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAG GACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCA GACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGA GTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTG AAGCCGAAG GCCCCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCT CATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAA GACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCA AGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCT CACCGTCCTGCACCAGGACTGGCTGAAT T GGACTCCGACGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAG GTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAAC CACTACACGCAGAAGAGCCTCTCCCTGTCCCCGGGTTGA 228 13A3 IgGl.Sf NS CAGCTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGT CCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGCAGTAGAAGTTACTACTGGGG CTGGATCCGCCAGCCCCCAGGGAAGGGGCTGGAGTGGATTGGGAGTATCTATTAT AGTGGGTTCACCTACTACAACCCGTCCCTCAAGAGTCGAGTCACCATATCCGTTG ACACGTCCAAGAACCAGTT CTCCCTGAAGCTGAGCTCTGTGACCGCCGCAGACAC GGCTGTGTATTATTGTGCGACAGGGGGGCCCTACGGTGACTACGCCCACTGGTTC GACCCCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCTAGCACCAAGGGCC CATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGC CCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACTGTC GTGGAAC TCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAG GACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCA

- 75 045913

GACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGA GTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCG AAGCCGAAGGGGCCCCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCT CATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAA GACCCTGAGGTCAAGTT CAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCA AGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCT CACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCC AAC AAAG C C C T C C C AG C C C C C AT C GAGAAAAC C AT C T C C AAAG C CAAAG GG C AG C CCCGAGA ACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAA CCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTG GAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGC TGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAG GTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTG ATGCATGAGGCTCTGCACAAC CACTACACGCAGAAGAGCCTCTCCCTGTCCCCGGGTAAATGA 229 8B9 IgGl.Sf NS AGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGTC CCTCACCTGCACTGTCTCTGGTGGCTCCATCAGTCGTCACTACTGGAACTGGATC CGGCAGCCCCCAGGGAAGGGACTGGAGTGGATTGGGTATATCCATTACAGTGGAA GCACCAACTACAATTCCTCCCTCAAGAGTCGAGTCACCATATCAGTAGACACGTC CAAGAACCAGTTCTCCCTGA AGCTGAGCTCTGTGACCGCTGCGGACACGGCCGTG TATTACTGTGCGAGAGATACTGGGTACTACGGTATGGACATCTGGGGCCAAGGGA CCACGGTCACCGTCTCCTCAGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGC ACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAG GACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCT GACCAGCG GCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAG CGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTG AATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTG ACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAAGCCGAAGGGGCCCCGTC AGTCTTCCCTCTTCCCCCCA AAACCCAAGGACACCCTCATGATCTCCCGGACCCCT GAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCA ACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGA GCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGAC TGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTC CAACAAAGCCCTCCCAGCCC CCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTA CACCCTGCCCCCATCCCGGGGAGGATGACCAAGAACCAGGTCAGCCTGACCTGC CTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGC AGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTT CTTCCT CTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTC TTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCC TCTCCCTGTCCCCGGGTAAATGA 230 8C4 IgGl.Sf NS CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGT CCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGTCGTTACTACTGGAGCTGGAT CCGGCAGCCCCCAGGGAAGGGACTGGAGTGGATTGGGTATATCCATTACACTGGG AGCACCAACTACAACCCCTCCCTCAAGAGTCGAGTCACCATATCAGTAGACACGT CCAAGAACCAGTTCTCCCTGA AGCTGAGCTCTGTGACCGCAGCGGACACGGCCGT GTATTACTGTGCGACAGATACGGGCTACTACGGTATGGACGTCTGGGGCCAAGGG ACCACGGTCACCGTCTCCTCAGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGG CACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAA GGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGA CCAGC GGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCA GCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGT GAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGT GACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAAGCCGAAGGGGCCCCGT CAGTCTTCCCTTCCC CCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCC TGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTC AACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGG AGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGA CTGGCTGAATGGCAAGGAGTACAAGTGCAAG GTCTCCAACAAAGCCCTCCCAGCC CCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGT ACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTG CCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGG CAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCT TCTTC CTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGT CTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGC CTCTCCCTGTCCCCGGGTAAATGA 231 17C3 IgGl.Sf NS CAGGTGCAGTTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGA AGGTCTCCTGCAAGGCATCTGGATACACTTTCACCAGCTACTATATGCACTGGGT GCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGAATAATCAACCCTAGGGGT GATAGCATAATCTACGCACAGAAGTTCCAGGGCAGAGTCACCATGACCAGGGACA CGTCCACGAGCACAGTC TACATGGAGCTGAGCAGCCTGAGATCTGAGGACACGGC CGTGTATTACTGTGCGAGAGATTTCTATGGTTCGGGAAACTACTACTACGGTATG GACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCAGCTAGCACCAAGGGCC CATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGC CCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACTG TCGTGGAAC TCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAG GACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCA

- 76 045913

GACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGA GTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCG AAGCCGAAGGGGCCCCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCT CATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAA GACCCTGAGGTCAAGTT CAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCA AGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCT CACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCC AAC AAAG C C C T C C C AG C C C C C AT C GAGAAAAC C AT C T C C AAAG C CAAAG GG C AG C CCCGAGA ACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAA CCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTG GAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGC TGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAG GTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTG ATGCATGAGGCTCTGCACAAC CACTACACGCAGAAGAGCCTCTCCCTGTCCCCGGGTAAATGA 232 9F6 IgGl.Sf NS CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCAAGCCTGGAGGGTCCCTGA GACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTGACTACTACATGAGCTGGAT CCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTTTCATTCATTAGTGGTGGTGGT AGTACCATATACTACGCAGACTCTGTGAAGGGCCGATTCACCATCTCCAGGGACA ACGCCAAGAACTCGCTGTT TCTGCAAATGAACAGCCTGAGAGTCGAGGACACGGC TGTGTATTACTGTGCGAGAGATGGCTATAGCAGTGGCTGGTACTACTACGGTATG GACGTCTGGGGCCAAGGGACCGCGGTCACCGTCTCCTCAGCTAGCACCAAGGGCC CATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGC CCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGG TGTCGTGGAAC TCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAG GACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCA GACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGA GTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTG AAGCCGAAG GCCCCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCT CATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAA GACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCA AGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCT CACCGTCCTGCACCAGGACTGGCTGAAT T GGACTCCGACGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAG GTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAAC CACTACACGCAGAAGAGCCTCTCCCTGTCCCCGGGTAAATGA 233 3G4 IgGl.Sf NS CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCAAGCCTGGAGGGTCCCTGA GACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTGACTACTACATGAGCTGGAT CCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTTTCATTCATTAGTACTAGTGGT AGTATCATATACTACGCAGACTCTGTGAAGGGCCGATTCACCATCTCCAGGGACA ACGCCAAGAACTCACTGTATC TGCAAATGAACAGCCTGAGAGCCGAGGACACGGC TGTGTATTACTGTGCGAGAGAAGGGTATAGCAGCAGCTGGTCCTACTACTACGGT ATGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCAGCTAGCACCAAGG GCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGC GGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGAC GGTGTCGTGG AACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCT CAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCAC CCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAG AGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCAC CTGAAGCCGAAGGG CCCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACAC CCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCAC GAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATG CCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGT CCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAG TACAAGTGCAAGGTC TCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGC AGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGGAGGAGATGACCAA GAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCC GTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCG TGCTGGACTCCGA CGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAG CAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCAC AACCACTACACGCAGAAGAGCCTCTCCCTGTCCCCGGGTAAATGA 234 1708 IgGl.Sf NS CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCAAGCCTGGAGGGTCCCTGA GACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTGACTACTACATGAGCTGGAT CCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTTTCATTCATTAGTAGTAGTGGT AGTATCATATACTACGCAGACTCTGTGAAGGGCCGATTCACCATCTCCAGGGACA ACGCCAAGAACTCACTGTA TCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGC TGTGTATTACTGTGCGAGAGATGGGTATAGCAGTGGCTGGGAGTACTACGGTATG GACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCAGCTAGCACCAAGGGCC CATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGC CCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGG TGTCGTGGAAC TCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAG GACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCA

- 77 045913

GACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGA GTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCG AAGCCGAAGGGGCCCCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCT CATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAA GACCCTGAGGTCAAGTT CAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCA AGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCT CACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCC AAC AAAG C C S T S C C AG C C C C C AT C GAGAAAAC C AT C T C C AAAG C CAAAG GG C AG C CCC GAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAA CCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTG GAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGC TGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAG GTGGCAGCAGGGGAACGTCTTCTCATGCTC CGTGATGCATGAGGCTCTGCACAAC CACTACACGCAGAAGAGCCTCTCCCTGTCCCCGGGTAAATGA 235 13A3 IgG1.3f NS (without C-terminal K) CAGCTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGT CCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGCAGTAGAAGTTACTACTGGGG CTGGATCCGCCAGCCCCCAGGGAAGGGGCTGGAGTGGATTGGGAGTATCTATTAT AGTGGGTTCACCTACTACAACCCGTCCCTCAAGAGTCGAGTCACCATATCCGTTG ACACGTCCAAGAACCAGTT CTCCCTGAAGCTGAGCTCTGTGACCGCCGCAGACAC GGCTGTGTATTATTGTGCGACAGGGGGGCCCTACGGTGACTACGCCCACTGGTTC GACCCCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCTAGCACCAAGGGCC CATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGC CCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACTGTC GTGGAAC TCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAG GACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCA GACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGA GTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTG AAGCCGAAGGGGCCC CGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCT CATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAA GACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCA AGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCT CACCGTCCTGCACCAGGACTGGCTGAATGGCAAG GAGTACAAGTGCAAGGTCTCC AACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGC CCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAA CCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTG GAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGC TGGACT CCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAG GTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAAC CACTACACGCAGAAGAGCCTCTCCCTGTCCCCGGGTTGA 236 8B9 IgG1.3f NS (without C-terminal K) AGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGTC CCTCACCTGCACTGTCTCTGGTGGCTCCATCAGTCGTCACTACTGGAACTGGATC CGGCAGCCCCCAGGGAAGGGACTGGAGTGGATTGGGTATATCCATTACAGTGGAA GCACCAACTACAATTCCTCCCTCAAGAGTCGAGTCACCATATCAGTAGACACGTC CAAGAACCAGTTCTCCCTGA AGCTGAGCTCTGTGACCGCTGCGGACACGGCCGTG TATTACTGTGCGAGAGATACTGGGTACTACGGTATGGACATCTGGGGCCAAGGGA CCACGGTCACCGTCTCCTCAGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGC ACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAG GACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCT GACCAGCG GCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAG CGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTG AATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTG ACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAAGCCGAAGGGGCCCCGTC AGTCTTCCCTCTTCCCCCCA AAACCCAAGGACACCCTCATGATCTCCCGGACCCCT GAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCA ACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGA GCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGAC TGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTC CAACAAAGCCCTCCCAGCCC CCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTA CACCCTGCCCCCATCCCGGGGAGGATGACCAAGAACCAGGTCAGCCTGACCTGC CTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGC AGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTT CTTCCT CTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTC TTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCC TCTCCCTGTCCCCGGGTTGA 237 8C4 IgG1.3f NS (without C-terminal K) CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGT CCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGTCGTTACTACTGGAGCTGGAT CCGGCAGCCCCCAGGGAAGGGACTGGAGTGGATTGGGTATATCCATTACACTGGG AGCACCAACTACAACCCCTCCCTCAAGAGTCGAGTCACCATATCAGTAGACACGT CCAAGAACCAGTTCTCCCTGA AGCTGAGCTCTGTGACCGCAGCGGACACGGCCGT GTATTACTGTGCGACAGATACGGGCTACTACGGTATGGACGTCTGGGGCCAAGGG ACCACGGTCACCGTCTCCTCAGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGG CACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAA GGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGA CCAGC GGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCA GCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGT

- 78 045913

GAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGT GACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAAGCCGAAGGGGCCCCGT CAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCC TGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTC AACTGGTACGTGGACGGC GTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGG AGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGA CTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCC CCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGT ACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGG TCAGCCTGACCTG CCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGG CAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCT TCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGT CTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGC CTCTCCCTGTCCC CGGGTTGA 238 17C3 IgG1.3f NS (without C-terminal K) CAGGTGCAGTTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGA AGGTCTCCTGCAAGGCATCTGGATACACTTTCACCAGCTACTATATGCACTGGGT GCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGAATAATCAACCCTAGGGGT GATAGCATAATCTACGCACAGAAGTTCCAGGGCAGAGTCACCATGACCAGGGACA CGTCCACGAGCACAGTC TACATGGAGCTGAGCAGCCTGAGATCTGAGGACACGGC CGTGTATTACTGTGCGAGAGATTTCTATGGTTCGGGAAACTACTACTACGGTATG GACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCAGCTAGCACCAAGGGCC CATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGC CCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACTG TCGTGGAAC TCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAG GACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCA GACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGA GTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTG AAGCCGAAGGGGC CCCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCT CATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAA GACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCA AGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCT CACCGTCCTGCACCAGGACTGGCTGAATGGCA AGGAGTACAAGTGCAAGGTCTCC AACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGC CCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAA CCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTG GAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGC TGC ACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAG GTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAAC CACTACACGCAGAAGAGCCTCTCCCTGTCCCCGGGTTGA 239 9F6 IgG1.3f NS (without C-terminal K) CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCAAGCCTGGAGGGTCCCTGA GACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTGACTACTACATGAGCTGGAT CCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTTTCATTCATTAGTGGTGGTGGT AGTACCATATACTACGCAGACTCTGTGAAGGGCCGATTCACCATCTCCAGGGACA ACGCCAAGAACTCGCTGTT TCTGCAAATGAACAGCCTGAGAGTCGAGGACACGGC TGTGTATTACTGTGCGAGAGATGGCTATAGCAGTGGCTGGTACTACTACGGTATG GACGTCTGGGGCCAAGGGACCGCGGTCACCGTCTCCTCAGCTAGCACCAAGGGCC CATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGC CCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGG TGTCGTGGAAC TCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAG GACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCA GACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGA GTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTG AAGCCGAAG GCCCCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCT CATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAA GACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCA AGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCT CACCGTCCTGCACCAGGACTGGCTGAAT T GGACTCCGACGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAG GTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAAC CACTACACGCAGAAGAGCCTCTCCCTGTCCCCGGGTTGA 240 3G4 IgG1.3f NS (without C-terminal K) CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCAAGCCTGGAGGGTCCCTGA GACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTGACTACTACATGAGCTGGAT CCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTTTCATTCATTAGTACTAGTGGT AGTATCATATACTACGCAGACTCTGTGAAGGGCCGATTCACCATCTCCAGGGACA ACGCCAAGAACTCACTGTATC TGCAAATGAACAGCCTGAGAGCCGAGGACACGGC TGTGTATTACTGTGCGAGAGAAGGGTATAGCAGCAGCTGGTCCTACTACTACGGT ATGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCAGCTAGCACCAAGG GCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGC GGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGAC GGTGTCGTGG AACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCT CAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCAC

- 79 045913

CCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAG AGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCAC CTGAAGCCGAAGGGGCCCCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACAC CCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCAC GAAGACCCTGAGGTCAAGTTCA ACTGGTACGTGGACGGCGTGGAGGTGCATAATG CCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGT CCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTC TCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGC AGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGAT GACCAA GAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCC GTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCG TGCTGGACTCCGACGGCTCCTTCTTCCTTAGCAAGCTCACCGTGGACAAGAG CAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCAC AACCACTACGCAGAAGAGCC TCTCCCTGTCCCCGGGTTGA 241 17C8 IgG1.3f NS (without C-terminal K) CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCAAGCCTGGAGGGTCCCTGA GACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTGACTACTACATGAGCTGGAT CCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTTTCATTCATTAGTAGTAGTGGT AGTATCATATACTACGCAGACTCTGTGAAGGGCCGATTCACCATCTCCAGGGACA ACGCCAAGAACTCACTGTA TCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGC TGTGTATTACTGTGCGAGAGATGGGTATAGCAGTGGCTGGGAGTACTACGGTATG GACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCAGCTAGCACCAAGGGCC CATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGC CCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGG TGTCGTGGAAC TCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAG GACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCA GACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGA GTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTG AAGCCGAAG GCCCCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCT CATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAA GACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCA AGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCT CACCGTCCTGCACCAGGACTGGCTGAAT T GGACTCCGACGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAG GTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAAC CACTACACGCAGAAGAGCCTCTCCCTGTCCCCGGGTTGA 242 13A3, 17C3, 3G4 L.C. GAAATTGTGTTGACGCAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGGGAAAGAG CCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCAGCTACTTAGCCTGGTA CCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGGTGCATCCAGCAGG GCCACTGGCATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTC TCACCATCAGCAGACTGGAGCCTGAAGA TTTTGCAGTGTATTACTGTCAGCAGTA TGGTAGCTCACCGATCACCTTCGGCCAAGGGACACGACTGGAGATTAAACGTACG GTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTG GAACTGCCTCTGTTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGT ACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCA CA GAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCA AAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCT GAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG 243 8B9, 8C4, 17C8 L.C. GAAATTGTGTTGACGCAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGGGAAAGAG CCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCAGCTACTTAGCCTGGTA CCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGGTGCATCCAGCAGG GCCACTGGCATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTC TCACCATCAGCAGACTGGAGCCTGAAGA TTTTGCAGTGTATTACTGTCAGCAGTA TGGTAGCTCACCTCTCACTTTCGGCGGAGGGACCAAGGTGGAGATCAAACGTACG GTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTG GAACTGCCTCTGTTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGT ACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCA CA GAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCA AAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCT GAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG 244 9F6 (VK3) L.C. GAAATTGTGTTGACGCAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGGGAAAGAG CCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCAGCTACTTAGCCTGGTA CCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGGTGCATCCAGCAGG GCCACTGGCATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTC TCACCATCAGCAGACTGGAGCCTGAAGA TTTTGCAGTGTATTACTGTCAGCAGTA TGGTAGCTCACCGCTCACTTTCGGCGGAGGGACCAAGGTGGAGATCAAACGTACG GTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTG GAACTGCCTCTGTTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGT ACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCA CA GAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCA AAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCT GAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG

- 80 045913

245 9F6 (VK1) L.C. GCCATCCAGTTGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAG TCACCATCACTTGCCGGGCAAGTCAGGGCATTAGCAGTGCTTTAGCCTGGTATCA GCAGAAACCAGGGAAAGCTCCTAAGCTCCTGATCTATGATGCCTCCAGTTTGGAA AGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCA CCATCAGCAGCCTGCAGC CTGAAGATTTTGCAACTTATTACTGTCAACAGTTTAA TAGTTACCCTCGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAACGTACGGTG GCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAA CTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACA GTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAG AGTGTCACAGAG CAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAG CAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAG CTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG 246 9F6 (VK2) L.C. GAAATTGTGTTGACGCAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGGGAAAGAG CCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCAGCTACTTAGCCTGGTA CCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGGTGCATCCAGCAGG GCCACTGGCATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTC TCACCATCAGCAGACTGGAGCCTGAAGA TTTTGCAGTGTATTACTGTCAGCAGTA TGGTAGCTCACTCACTTTCGGCGGAGGGACCAAGGTGGAGATCAAACGTACGGTG GCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAA CTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACA GTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAG CAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAG CAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAG CTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG 247 13A3 (N60Q) IgGl.lf HC CAGCTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGT CCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGCAGTAGAAGTTACTACTGGGG CTGGATCCGCCAGCCCCCAGGGAAGGGGCTGGAGTGGATTGGGAGTATCTATTAT AGTGGGTTCACCTACTACCAACCGTCCCTCAAGAGTCGAGTCACCATATCCGTTG ACACGTCCAAGAACCAGTT CTCCCTGAAGCTGAGCTCTGTGACCGCCGCAGACAC GGCTGTGTATTATTGTGCGACAGGGGGGCCCTACGGTGACTACGCCCACTGGTTC GACCCCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCTAGCACCAAGGGCC CATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGC CCTGGGCTGCCTGGTCAAGGACIACTTCCCCGAACCGGTGACTG TCGTGGAAC TCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAG GACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCA GACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGA GTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTG AAGCCGAAGGGGC CCCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCT CATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAA GACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCA AGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCT CACCGTCCTGCACCAGGACTGGCTGAATGGCA AGGAGTACAAGTGCAAGGTCTCC AACAAAGCCCTCCCAAGCAGCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGC CCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAA CCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTG GAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGC TGC ACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAG GTGGCAGCAGGGGAACGTCTTCrCATGCTCCGTGATGCATGAGGCTCTGCACAAC CACTACACGCAGAAGAGCCTCTCCCTGTCCCCGGGTAAATGA 248 13A3 (N60S) IgGl.lf HC CAGCTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGT CCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGCAGTAGAAGTTACTACTGGGG CTGGATCCGCCAGCCCCCAGGGAAGGGGCTGGAGTGGATTGGGAGTATCTATTAT agtgggttcacctactactcaccgtccctcaagagtcgagtcaccatatccgttg ACACGTCCA AGAACCAGTTCTCCCTGAAGCTGAGCTCTGTGACCGCCGCAGACAC GGCTGTGTATTATTGTGCGACAGGGGGGCCCTACGGTGACTACGCCCACTGGTTC GACCCCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCTAGCACCAAGGGCC CATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGC CCTGGGCTGCCTGGTCAAGGACIACTTCCCCGAACC AAG CCGAAGGGGCCCCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCT CATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAA GACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCA AGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCT CACCGTCCTGCACCAGGACT CTGAATGGCAAGGAGTACAAGTGCAAGGTCTCC AACAAAGCCCTCCCAAGCAGCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGC CCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAA CCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTG GAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCC CGTGC TGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAG GTGGCAGCAGGGGAACGTCTTCrCATGCTCCGTGATGCATGAGGCTCTGCACAAC CACTACACGCAGAAGAGCCTCTCCCTGTCCCCGGGTAAATGA

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249 13A3 (N60A) IgGl.If HC CAGCTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGT CCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGCAGTAGAAGTTACTACTGGGG CTGGATCCGCCAGCCCCCAGGGAAGGGGCTGGAGTGGATTGGGAGTATCTATTAT AGTGGGTTCACCTACTACGCACCGTCCCTCAAGAGTCGAGTCACCATATCCGTTG ACACGTCCAAGAACCAGTT CTCCCTGAAGCTGAGCTCTGTGACCGCCGCAGACAC GGCTGTGTATTATTGTGCGACAGGGGGGCCCTACGGTGACTACGCCCACTGGTTC GACCCCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCTAGCACCAAGGGCC CATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGC CCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACTGTC GTGGAAC TCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAG GACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCA GACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGA GTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTG AAGCCGAAGGGGCCC CGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCT CATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAA GACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCA AGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCT CACCGTCCTGCACCAGGACTGGCTGAATGGCAAG GAGTACAAGTGCAAGGTCTCC AACAAAGCCCTCCCAAGCAGCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGC CCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAA CCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTG GAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGC TGGACT CCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAG GTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAAC CACTACACGCAGAAGAGCCTCTCCCTGTCCCCGGGTAAATGA 250 13A3 (D101E) IgGl.If HC CAGCTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGT CCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGCAGTAGAAGTTACTACTGGGG CTGGATCCGCCAGCCCCCAGGGAAGGGGCTGGAGTGGATTGGGAGTATCTATTAT AGTGGGTTCACCTACTACAACCCGTCCCTCAAGAGTCGAGTCACCATATCCGTTG ACACGTCCAAGAACCAGTT CTCCCTGAAGCTGAGCTCTGTGACCGCCGCAGACAC GGCTGTGTATTATTGTGCGACAGGGGGGCCCTACGGTGACTACGCCCACTGGTTC GAACCCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCTAGCACCAAGGGCC CATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGC CCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACTGTC GTGGAAC TCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAG GACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCA GACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGA GTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTG AAGCCGAAGGGGCCC CGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCT CATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAA GACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCA AGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCT CACCGTCCTGCACCAGGACTGGCTGAATGGCAAG GAGTACAAGTGCAAGGTCTCC AACAAAGCCCTCCCAAGCAGCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGC CCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAA CCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTG GAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGC TGGACT CCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAG GTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAAC CACTACACGCAGAAGAGCCTCTCCCTGTCCCCGGGTAAATGA 251 13A3 (P102V) IgGl.If HC CAGCTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGT CCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGCAGTAGAAGTTACTACTGGGG CTGGATCCGCCAGCCCCCAGGGAAGGGGCTGGAGTGGATTGGGAGTATCTATTAT AGTGGGTTCACCTACTACAACCCGTCCCTCAAGAGTCGAGTCACCATATCCGTTG ACACGTCCAAGAACCAGTT CTCCCTGAAGCTGAGCTCTGTGACCGCCGCAGACAC GGCTGTGTATTATTGTGCGACAGGGGGGCCCTACGGTGACTACGCCCACTGGTTC GACGTATGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCTAGCACCAAGGGCC CATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGC CCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACTG TCGTGGAAC TCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAG GACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCA GACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGA GTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTG AAGCCGAAGGGGC CCCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCT CATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAA GACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCA AGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCT CACCGTCCTGCACCAGGACTGGCTGAATGGCA AGGAGTACAAGTGCAAGGTCTCC AACAAAGCCCTCCCAAGCAGCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGC CCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAA CCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTG GAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGC TGC ACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAG GTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAAC CACTACACGCAGAAGAGCCTCTCCCTGTCCCCGGGTAAATGA

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252 13A3 (P102Y) IgGl.lf NS CAGCTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGT CCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGCAGTAGAAGTTACTACTGGGG CTGGATCCGCCAGCCCCCAGGGAAGGGGCTGGAGTGGATTGGGAGTATCTATTAT AGTGGGTTCACCTACTACAACCCGTCCCTCAAGAGTCGAGTCACCATATCCGTTG ACACGTCCAAGAACCAGTT CTCCCTGAAGCTGAGCTCTGTGACCGCCGCAGACAC GGCTGTGTATTATTGTGCGACAGGGGGGCCCTACGGTGACTACGCCCACTGGTTC GACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCTAGCACCAAGGGCC CATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGC CCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCG TGGAAC TCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAG GACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCA GACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGA GTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTG AAGCCGAAGGGGCCCCG TCAGTCTTTCCTTCCCCCCAAAACCCAAGGACACCCT CATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAA GACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCA AGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCT CACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGA GTACAAGTGCAAGGTCTCC AACAAAGCCCTCCCAAGCAGCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGC CCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAA CCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTG GAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGC TGGACTCC GACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAG GTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAAC CACTACACGCAGAAGAGCCTCTCCCTGTCCCCGGGTAAATGA 253 13A3 (P102L) IgGl.lf NS CAGCTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGT CCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGCAGTAGAAGTTACTACTGGGG CTGGATCCGCCAGCCCCCAGGGAAGGGGCTGGAGTGGATTGGGAGTATCTATTAT AGTGGGTTCACCTACTACAACCCGTCCCTCAAGAGTCGAGTCACCATATCCGTTG ACACGTCCAAGAACCAGTT CTCCCTGAAGCTGAGCTCTGTGACCGCCGCAGACAC GGCTGTGTATTATTGTGCGACAGGGGGGCCCTACGGTGACTACGCCCACTGGTTC GACCTATGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCTAGCACCAAGGGCC CATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGC CCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACTGTC GTGGAAC TCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAG GACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCA GACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGA GTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTG AAGCCGAAGGGGCCC CGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCT CATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAA GACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCA AGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCT CACCGTCCTGCACCAGGACTGGCTGAATGGCAAG GAGTACAAGTGCAAGGTCTCC AACAAAGCCCTCCCAAGCAGCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGC CCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAA CCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTG GAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGC TGGACT CCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAG GTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAAC CACTACACGCAGAAGAGCCTCTCCCTGTCCCCGGGTAAATGA 254 13A3 (N60Q, P102Y) IgGl.lf NS CAGCTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGT CCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGCAGTAGAAGTTACTACTGGGG CTGGATCCGCCAGCCCCCAGGGAAGGGGCTGGAGTGGATTGGGAGTATCTATTAT AGTGGGTTCACCTACTACCAACCGTCCCTCAAGAGTCGAGTCACCATATCCGTTG ACACGTCCAAGAACCAGTT CTCCCTGAAGCTGAGCTCTGTGACCGCCGCAGACAC GGCTGTGTATTATTGTGCGACAGGGGGGCCCTACGGTGACTACGCCCACTGGTTC GACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCTAGCACCAAGGGCC CATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGC CCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCG TGGAAC TCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAG GACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCA GACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGA GTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTG AAGCCGAAGGGGCCCCG TCAGTCTTTCCTTCCCCCCAAAACCCAAGGACACCCT CATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAA GACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCA AGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCT CACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGA GTACAAGTGCAAGGTCTCC AACAAAGCCCTCCCAAGCAGCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGC CCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAA CCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTG GAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGC TGGACTCC GACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAG GTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAAC CACTACACGCAGAAGAGCCTCTCCCTGTCCCCGGGTAAATGA

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255 8B9 (S61P) IgGl.If NS CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGT CCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGTCGTCACTACTGGAACTGGAT CCGGCAGCCCCCAGGGAAGGGACTGGAGTGGATTGGGTATATCCATTACAGTGGA AGCACCAACTACAATCCCTCCCTCAAGAGTCGAGTCACCATATCAGTAGACACGT CCAAGAACCAGTTCTCCCTGA AGCTGAGCTCTGTGACCGCTGCGGACACGGCCGT GTATTACTGTGCGAGAGATACTGGGTACTACGGTATGGACATCTGGGGCCAAGGG ACCACGGTCACCGTCTCCTCAGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGG CACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAA GGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCT GACCAGC GGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCA GCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGT GAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGT GACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAAGCCGAAGGGGCCCCGT CAGTCTTCCTCTTC CCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCC TGAGGTCCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTC AACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGG AGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGA CTGGCTGAATGGCAAGGAGTACAAGTGCA T CTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGT CTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGC CTCTCCCTGTCCCCGGGTAAATGA 256 9F6 (A108T) IgGl.If HC CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCAAGCCTGGAGGGTCCCTGA GACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTGACTACTACATGAGCTGGAT CCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTTTCATTCATTAGTGGTGGTGGT AGTACCATATACTACGCAGACTCTGTGAAGGGCCGATTCACCATCTCCAGGGACA ACGCCAAGAACTCGCTGTT TCTGCAAATGAACAGCCTGAGAGTCGAGGACACGGC TGTGTATTACTGTGCGAGAGATGGCTATAGCAGTGGCTGGTACTACTACGGTATG GACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCAGCTAGCACCAAGGGCC CATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGC CCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGG TGTCGTGGAAC TCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAG GACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCA GACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGA GTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTG AAGCCGAAG GCCCCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCT CATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAA GACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCA AGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCT CACCGTCCTGCACCAGGACTGGCTGAAT T GGACTCCGACGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAG GTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAAC CACTACACGCAGAAGAGCCTCTCCCTGTCCCCGGGTAAATGA 257 13A3 (N60Q) IgGl. If NS (without C-terminal K) CAGCTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGT CCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGCAGTAGAAGTTACTACTGGGG CTGGATCCGCCAGCCCCCAGGGAAGGGGCTGGAGTGGATTGGGAGTATCTATTAT AGTGGGTTCACCTACTACCAACCGTCCCTCAAGAGTCGAGTCACCATATCCGTTG ACACGTCCAAGAACCAGTT CTCCCTGAAGCTGAGCTCTGTGACCGCCGCAGACAC GGCTGTGTATTATTGTGCGACAGGGGGGCCCTACGGTGACTACGCCCACTGGTTC GACCCCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCTAGCACCAAGGGCC CATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGC CCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACTGTC GTGGAAC TCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAG GACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCA GACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGA GTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTG AAGCCGAAGGGGCCC CGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCT CATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAA GACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCA AGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCT CACCGTCCTGCACCAGGACTGGCTGAATGGCAAG GAGTACAAGTGCAAGGTCTCC AACAAAGCCCTCCCAAGCAGCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGC CCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAA CCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTG GAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGC TGGACT CCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAG GTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAAC CACTACACGCAGAAGAGCCTCTCCCTGTCCCCGGGTTGA

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258 13A3 (N60S) IgGl. If NS (without C-terminal K) CAGCTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGT CCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGCAGTAGAAGTTACTACTGGGG CTGGATCCGCCAGCCCCCAGGGAAGGGGCTGGAGTGGATTGGGAGTATCTATTAT AGTGGGTTCACCACTACTCACCGTCCCTCAAGAGTCGAGTCACCATATCCGTTG ACACGTCCAAGAACCAGTT CTCCCTGAAGCTGAGCTCTGTGACCGCCGCAGACAC GGCTGTGTATTATTGTGCGACAGGGGGGCCCTACGGTGACTACGCCCACTGGTTC GACCCCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCTAGCACCAAGGGCC CATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGC CCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACTGTC GTGGAAC TCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAG GACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCA GACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGA GTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTG AAGCCGAAGGGGCCC CGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCT CATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAA GACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCA AGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCT CACCGTCCTGCACCAGGACTGGCTGAATGGCAAG GAGTACAAGTGCAAGGTCTCC AACAAAGCCCTCCCAAGCAGCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGC CCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAA CCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTG GAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGC TGGACT CCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAG GTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAAC CACTACACGCAGAAGAGCCTCTCCCTGTCCCCGGGTTGA 259 13A3 (N60A) IgGl. If NS (without C-terminal K) CAGCTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGT CCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGCAGTAGAAGTTACTACTGGGG CTGGATCCGCCAGCCCCCAGGGAAGGGGCTGGAGTGGATTGGGAGTATCTATTAT AGTGGGTTCACCTACTACGCACCGTCCCTCAAGAGTCGAGTCACCATATCCGTTG ACACGTCCAAGAACCAGTT CTCCCTGAAGCTGAGCTCTGTGACCGCCGCAGACAC GGCTGTGTATTATTGTGCGACAGGGGGGCCCTACGGTGACTACGCCCACTGGTTC GACCCCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCTAGCACCAAGGGCC CATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGC CCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACTGTC GTGGAAC TCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAG GACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCA GACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGA GTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTG AAGCCGAAGGGGCCC CGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCT CATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAA GACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCA AGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCT CACCGTCCTGCACCAGGACTGGCTGAATGGCAAG GAGTACAAGTGCAAGGTCTCC AACAAAGCCCTCCCAAGCAGCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGC CCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAA CCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTG GAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGC TGGACT CCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAG GTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAAC CACTACACGCAGAAGAGCCTCTCCCTGTCCCCGGGTTGA 260 13A3 (D101E) IgGl. If NS (without C-terminal K) CAGCTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGT CCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGCAGTAGAAGTTACTACTGGGG CTGGATCCGCCAGCCCCCAGGGAAGGGGCTGGAGTGGATTGGGAGTATCTATTAT AGTGGGTTCACCTACTACAACCCGTCCCTCAAGAGTCGAGTCACCATATCCGTTG ACACGTCCAAGAACCAGTT CTCCCTGAAGCTGAGCTCTGTGACCGCCGCAGACAC GGCTGTGTATTATTGTGCGACAGGGGGGCCCTACGGTGACTACGCCCACTGGTTC GAACCCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCTAGCACCAAGGGCC CATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGC CCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACTGTC GTGGAAC TCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAG GACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCA GACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGA GTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTG AAGCCGAAGGGGCCC CGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCT CATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAA GACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCA AGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCT CACCGTCCTGCACCAGGACTGGCTGAATGGCAAG GAGTACAAGTGCAAGGTCTCC AACAAAGCCCTCCCAAGCAGCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGC CCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAA CCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTG GAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGC TGGACT CCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAG GTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAAC CACTACACGCAGAAGAGCCTCTCCCTGTCCCCGGGTTGA

- 85 045913

261 13A3 (P102V) IgGl. If NS (without C-terminal K) CAGCTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGT CCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGCAGTAGAAGTTACTACTGGGG CTGGATCCGCCAGCCCCCAGGGAAGGGGCTGGAGTGGATTGGGAGTATCTATTAT AGTGGGTTCACCTACTACAACCCGTCCCTCAAGAGTCGAGTCACCATATCCGTTG ACACGTCCAAGAACCAGTT CTCCCTGAAGCTGAGCTCTGTGACCGCCGCAGACAC GGCTGTGTATTATTGTGCGACAGGGGGGCCCTACGGTGACTACGCCCACTGGTTC GACGTATGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCTAGCACCAAGGGCC CATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGC CCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACTG TCGTGGAAC TCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAG GACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCA GACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGA GTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTG AAGCCGAAGGGGC CCCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCT CATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAA GACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCA AGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCT CACCGTCCTGCACCAGGACTGGCTGAATGGCA AGGAGTACAAGTGCAAGGTCTCC AACAAAGCCCTCCCAAGCAGCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGC CCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAA CCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTG GAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGC TGC ACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAG GTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAAC CACTACACGCAGAAGAGCCTCTCCCTGTCCCCGGGTTGA 2 62 13A3 (P102Y) IgGl. If NS (without C-terminal K) CAGCTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGT CCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGCAGTAGAAGTTACTACTGGGG CTGGATCCGCCAGCCCCCAGGGAAGGGGCTGGAGTGGATTGGGAGTATCTATTAT AGTGGGTTCACCTACTACAACCCGTCCCTCAAGAGTCGAGTCACCATATCCGTTG ACACGTCCAAGAACCAGTT CTCCCTGAAGCTGAGCTCTGTGACCGCCGCAGACAC GGCTGTGTATTATTGTGCGACAGGGGGGCCCTACGGTGACTACGCCCACTGGTTC GACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCTAGCACCAAGGGCC CATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGC CCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCG TGGAAC TCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAG GACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCA GACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGA GTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTG AAGCCGAAGGGGCCCCG TCAGTCTTTCCTTCCCCCCAAAACCCAAGGACACCCT CATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAA GACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCA AGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCT CACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGA GTACAAGTGCAAGGTCTCC AACAAAGCCCTCCCAAGCAGCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGC CCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAA CCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTG GAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGC TGGACTCC GACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAG GTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAAC CACTACACGCAGAAGAGCCTCTCCCTGTCCCCGGGTTGA 263 13A3 (P102L) IgGl. If NS (without C-terminal K) CAGCTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGT CCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGCAGTAGAAGTTACTACTGGGG CTGGATCCGCCAGCCCCCAGGGAAGGGGCTGGAGTGGATTGGGAGTATCTATTAT AGTGGGTTCACCTACTACAACCCGTCCCTCAAGAGTCGAGTCACCATATCCGTTG ACACGTCCAAGAACCAGTT CTCCCTGAAGCTGAGCTCTGTGACCGCCGCAGACAC GGCTGTGTATTATTGTGCGACAGGGGGGCCCTACGGTGACTACGCCCACTGGTTC GACCTATGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCTAGCACCAAGGGCC CATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGC CCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACTGTC GTGGAAC TCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAG GACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCA GACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGA GTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTG AAGCCGAAGGGGCCC CGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCT CATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAA GACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCA AGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCT CACCGTCCTGCACCAGGACTGGCTGAATGGCAAG GAGTACAAGTGCAAGGTCTCC AACAAAGCCCTCCCAAGCAGCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGC CCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAA CCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTG GAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGC TGGACT CCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAG GTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAAC CACTACACGCAGAAGAGCCTCTCCCTGTCCCCGGGTTGA

- 86 045913

264 13A3 (N60Q, P102Y) IgGl. If NS (without C-terminal K) CAGCTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGT CCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGCAGTAGAAGTTACTACTGGGG CTGGATCCGCCAGCCCCCAGGGAAGGGGCTGGAGTGGATTGGGAGTATCTATTAT AGTGGGTTCACCTACTACCAACCGTCCCTCAAGAGTCGAGTCACCATATCCGTTG ACACGTCCAAGAACCAGTT CTCCCTGAAGCTGAGCTCTGTGACCGCCGCAGACAC GGCTGTGTATTATTGTGCGACAGGGGGGCCCTACGGTGACTACGCCCACTGGTTC GACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCTAGCACCAAGGGCC CATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGC CCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCG TGGAAC TCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAG GACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCA GACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGA GTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTG AAGCCGAAGGGGCCCCG TCAGTCTTTCCTTCCCCCCAAAACCCAAGGACACCCT CATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAA GACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCA AGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCT CACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGA GTACAAGTGCAAGGTCTCC AACAAAGCCCTCCCAAGCAGCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGC CCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAA CCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTG GAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGC TGGACTCC GACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAG GTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAAC CACTACACGCAGAAGAGCCTCTCCCTGTCCCCGGGTTGA 265 8B9 (S61P) IgGl. If NS (without C-terminal K) CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGT CCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGTCGTCACTACTGGAACTGGAT CCGGCAGCCCCCAGGGAAGGGACTGGAGTGGATTGGGTATATCCATTACAGTGGA AGCACCAACTACAATCCCTCCCTCAAGAGTCGAGTCACCATATCAGTAGACACGT CCAAGAACCAGTTCTCCCTGA AGCTGAGCTCTGTGACCGCTGCGGACACGGCCGT GTATTACTGTGCGAGAGATACTGGGTACTACGGTATGGACATCTGGGGCCAAGGG ACCACGGTCACCGTCTCCTCAGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGG CACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAA GGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCT GACCAGC GGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCA GCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGT GAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGT GACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAAGCCGAAGGGGCCCCGT CAGTCTTCCTCTTC CCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCC TGAGGTCCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTC AACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGG AGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGA CTGGCTGAATGGCAAGGAGTACAAGTGCA T CTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGT CTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGC CTCTCCCTGTCCCCGGGTTGA 266 9F6 (A108T) IgGl. If NS (without C-terminal K) CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCAAGCCTGGAGGGTCCCTGA GACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTGACTACTACATGAGCTGGAT CCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTTTCATTCATTAGTGGTGGTGGT AGTACCATATACTACGCAGACTCTGTGAAGGGCCGATTCACCATCTCCAGGGACA ACGCCAAGAACTCGCTGTT TCTGCAAATGAACAGCCTGAGAGTCGAGGACACGGC TGTGTATTACTGTGCGAGAGATGGCTATAGCAGTGGCTGGTACTACTACGGTATG GACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCAGCTAGCACCAAGGGCC CATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGC CCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGG TGTCGTGGAAC TCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAG GACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCA GACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGA GTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTG AAGCCGAAG GCCCCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCT CATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAA GACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCA AGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCT CACCGTCCTGCACCAGGACTGGCTGAAT T GGACTCCGACGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAG GTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAAC CACTACACGCAGAAGAGCCTCTCCCTGTCCCCGGGTTGA

- 87 045913

267 13A3 (N60Q) IgGl.Sf NS CAGCTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGT CCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGCAGTAGAAGTTACTACTGGGG CTGGATCCGCCAGCCCCCAGGGAAGGGGCTGGAGTGGATTGGGAGTATCTATTAT AGTGGGTTCACCTACTACCAACCGTCCCTCAAGAGTCGAGTCACCATATCCGTTG ACACGTCCAAGAACCAGTT CTCCCTGAAGCTGAGCTCTGTGACCGCCGCAGACAC GGCTGTGTATTATTGTGCGACAGGGGGGCCCTACGGTGACTACGCCCACTGGTTC GACCCCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCTAGCACCAAGGGCC CATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGC CCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACTGTC GTGGAAC TCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAG GACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCA GACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGA GTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTG AAGCCGAAGGGGCCC CGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCT CATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAA GACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCA AGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCT CACCGTCCTGCACCAGGACTGGCTGAATGGCAAG GAGTACAAGTGCAAGGTCTCC AACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGC CCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAA CCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTG GAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGC TGGACT CCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAG GTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAAC CACTACACGCAGAAGAGCCTCTCCCTGTCCCCGGGTAAATGA 268 13A3 (N60S) IgGl.Sf NS CAGCTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGT CCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGCAGTAGAAGTTACTACTGGGG CTGGATCCGCCAGCCCCCAGGGAAGGGGCTGGAGTGGATTGGGAGTATCTATTAT AGTGGGTTCACCACTACTCACCGTCCCTCAAGAGTCGAGTCACCATATCCGTTG ACACGTCCAAGAACCAGTT CTCCCTGAAGCTGAGCTCTGTGACCGCCGCAGACAC GGCTGTGTATTATTGTGCGACAGGGGGGCCCTACGGTGACTACGCCCACTGGTTC GACCCCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCTAGCACCAAGGGCC CATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGC CCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACTGTC GTGGAAC TCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAG GACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCA GACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGA GTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTG AAGCCGAAGGGGCCC CGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCT CATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAA GACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCA AGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCT CACCGTCCTGCACCAGGACTGGCTGAATGGCAAG GAGTACAAGTGCAAGGTCTCC AACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGC CCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAA CCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTG GAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGC TGGACT CCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAG GTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAAC CACTACACGCAGAAGAGCCTCTCCCTGTCCCCGGGTAAATGA 269 13A3 (N60A) IgGl.Sf NS CAGCTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGT CCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGCAGTAGAAGTTACTACTGGGG CTGGATCCGCCAGCCCCCAGGGAAGGGGCTGGAGTGGATTGGGAGTATCTATTAT AGTGGGTTCACCTACTACGCACCGTCCCTCAAGAGTCGAGTCACCATATCCGTTG ACACGTCCAAGAACCAGTT CTCCCTGAAGCTGAGCTCTGTGACCGCCGCAGACAC GGCTGTGTATTATTGTGCGACAGGGGGGCCCTACGGTGACTACGCCCACTGGTTC GACCCCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCTAGCACCAAGGGCC CATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGC CCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACTGTC GTGGAAC TCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAG GACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCA GACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGA GTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTG AAGCCGAAGGGGCCC CGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCT CATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAA GACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCA AGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCT CACCGTCCTGCACCAGGACTGGCTGAATGGCAAG GAGTACAAGTGCAAGGTCTCC AACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGC CCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAA CCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTG GAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGC TGGACT CCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAG GTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAAC CACTACACGCAGAAGAGCCTCTCCCTGTCCCCGGGTAAATGA

- 88 045913

270 13A3 (D101E) IgG1.3f NS CAGCTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGT CCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGCAGTAGAAGTTACTACTGGGG CTGGATCCGCCAGCCCCCAGGGAAGGGGCTGGAGTGGATTGGGAGTATCTATTAT AGTGGGTTCACCTACTACAACCCGTCCCTCAAGAGTCGAGTCACCATATCCGTTG ACACGTCCAAGAACCAGTT CTCCCTGAAGCTGAGCTCTGTGACCGCCGCAGACAC GGCTGTGTATTATTGTGCGACAGGGGGGCCCTACGGTGACTACGCCCACTGGTTC GAACCCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCTAGCACCAAGGGCC CATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGC CCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACTGTC GTGGAAC TCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAG GACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCA GACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGA GTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTG AAGCCGAAGGGGCCC CGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCT CATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAA GACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCA AGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCT CACCGTCCTGCACCAGGACTGGCTGAATGGCAAG GAGTACAAGTGCAAGGTCTCC AACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGC CCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAA CCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTG GAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGC TGGACT CCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAG GTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAAC CACTACACGCAGAAGAGCCTCTCCCTGTCCCCGGGTAAATGA 271 13A3 (P102V) IgGl.Sf NS CAGCTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGT CCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGCAGTAGAAGTTACTACTGGGG CTGGATCCGCCAGCCCCCAGGGAAGGGGCTGGAGTGGATTGGGAGTATCTATTAT AGTGGGTTCACCTACTACAACCCGTCCCTCAAGAGTCGAGTCACCATATCCGTTG ACACGTCCAAGAACCAGTT CTCCCTGAAGCTGAGCTCTGTGACCGCCGCAGACAC GGCTGTGTATTATTGTGCGACAGGGGGGCCCTACGGTGACTACGCCCACTGGTTC GACGTATGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCTAGCACCAAGGGCC CATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGC CCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACTG TCGTGGAAC TCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAG GACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCA GACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGA GTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTG AAGCCGAAGGGGC CCCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCT CATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAA GACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCA AGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCT CACCGTCCTGCACCAGGACTGGCTGAATGGCA AGGAGTACAAGTGCAAGGTCTCC AACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGC CCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAA CCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTG GAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGC TGC ACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAG GTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAAC CACTACACGCAGAAGAGCCTCTCCCTGTCCCCGGGTAAATGA 272 13A3 (P102Y) IgGl.Sf NS CAGCTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGT CCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGCAGTAGAAGTTACTACTGGGG CTGGATCCGCCAGCCCCCAGGGAAGGGGCTGGAGTGGATTGGGAGTATCTATTAT AGTGGGTTCACCTACTACAACCCGTCCCTCAAGAGTCGAGTCACCATATCCGTTG ACACGTCCAAGAACCAGTT CTCCCTGAAGCTGAGCTCTGTGACCGCCGCAGACAC GGCTGTGTATTATTGTGCGACAGGGGGGCCCTACGGTGACTACGCCCACTGGTTC GACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCTAGCACCAAGGGCC CATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGC CCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCG TGGAAC TCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAG GACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCA GACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGA GTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTG AAGCCGAAGGGGCCCCG TCAGTCTTTCCTTCCCCCCAAAACCCAAGGACACCCT CATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAA GACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCA AGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCT CACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGA GTACAAGTGCAAGGTCTCC AACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGC CCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAA CCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTG GAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGC TGGACTCC GACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAG GTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAAC CACTACACGCAGAAGAGCCTCTCCCTGTCCCCGGGTAAATGA

- 89 045913

273 13A3 (P102L) IgGl.Sf NS CAGCTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGT CCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGCAGTAGAAGTTACTACTGGGG CTGGATCCGCCAGCCCCCAGGGAAGGGGCTGGAGTGGATTGGGAGTATCTATTAT AGTGGGTTCACCTACTACAACCCGTCCCTCAAGAGTCGAGTCACCATATCCGTTG ACACGTCCAAGAACCAGTT CTCCCTGAAGCTGAGCTCTGTGACCGCCGCAGACAC GGCTGTGTATTATTGTGCGACAGGGGGGCCCTACGGTGACTACGCCCACTGGTTC GACCTATGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCTAGCACCAAGGGCC CATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGC CCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACTGTC GTGGAAC TCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAG GACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCA GACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGA GTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTG AAGCCGAAGGGGCCC CGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCT CATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAA GACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCA AGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCT CACCGTCCTGCACCAGGACTGGCTGAATGGCAAG GAGTACAAGTGCAAGGTCTCC AACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGC CCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAA CCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTG GAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGC TGGACT CCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAG GTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAAC CACTACACGCAGAAGAGCCTCTCCCTGTCCCCGGGTAAATGA 274 13A3 (N60Q, P102Y) IgG1.3f NS CAGCTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGT CCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGCAGTAGAAGTTACTACTGGGG CTGGATCCGCCAGCCCCCAGGGAAGGGGCTGGAGTGGATTGGGAGTATCTATTAT AGTGGGTTCACCTACTACCAACCGTCCCTCAAGAGTCGAGTCACCATATCCGTTG ACACGTCCAAGAACCAGTT CTCCCTGAAGCTGAGCTCTGTGACCGCCGCAGACAC GGCTGTGTATTATTGTGCGACAGGGGGGCCCTACGGTGACTACGCCCACTGGTTC GACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCTAGCACCAAGGGCC CATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGC CCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCG TGGAAC TCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAG GACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCA GACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGA GTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTG AAGCCGAAGGGGCCCCG TCAGTCTTTCCTTCCCCCCAAAACCCAAGGACACCCT CATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAA GACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCA AGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCT CACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGA GTACAAGTGCAAGGTCTCC AAC AAAG C C C T C C C AG C C C C C AT C GAGAAAAC C AT C T C C AAAG C CAAAG GG C AG C CCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAA CCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTG GAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGC TGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAG GTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAAC CACTACACGCAGAAGAGCCTCTC CCTGTCCCCGGGTAAATGA 275 8B9 (S61P) IgGl.Sf NS CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGT CCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGTCGTCACTACTGGAACTGGAT CCGGCAGCCCCCAGGGAAGGGACTGGAGTGGATTGGGTATATCCATTACAGTGGA AGCACCAACTACAATCCCTCCCTCAAGAGTCGAGTCACCATATCAGTAGACACGT CCAAGAACCAGTTCTCCCTGA AGCTGAGCTCTGTGACCGCTGCGGACACGGCCGT GTATTACTGTGCGAGAGATACTGGGTACTACGGTATGGACATCTGGGGCCAAGGG ACCACGGTCACCGTCTCCTCAGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGG CACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAA GGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCT GACCAGC GGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCA GCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGT GAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGT GACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAAGCCGAAGGGGCCCCGT CAGTCTTCCTCTTC CCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCC TGAGGTCCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTC AACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGG AGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGA CTGGCTGAATGGCAAGGAGTACAAGTGCA AGGTCTCCAACAAAGCCCTCCCAGCC CCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGT ACACCCTGCCCCCATCCCGGGAGGAATGACCAAGAACCAGGTCAGCCTGACCTG CCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGG CAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCT TCT TCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGT CTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGC CTCTCCCTGTCCCCGGGTAAATGA

- 90 045913

276 9F6 (A108T) IgGl.Sf NS CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCAAGCCTGGAGGGTCCCTGA GACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTGACTACTACATGAGCTGGAT CCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTTTCATTCATTAGTGGTGGTGGT AGTACCATATACTACGCAGACTCTGTGAAGGGCCGATTCACCATCTCCAGGGACA ACGCCAAGAACTCGCTGTT TCTGCAAATGAACAGCCTGAGAGTCGAGGACACGGC TGTGTATTACTGTGCGAGAGATGGCTATAGCAGTGGCTGGTACTACTACGGTATG GACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCAGCTAGCACCAAGGGCC CATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGC CCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGG TGTCGTGGAAC TCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAG GACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCA GACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGA GTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTG AAGCCGAAG GCCCCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCT CATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAA GACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCA AGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCT CACCGTCCTGCACCAGGACTGGCTGAAT T GGACTCCGACGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAG GTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAAC CACTACACGCAGAAGAGCCTCTCCCTGTCCCCGGGTAAATGA 277 13A3 (N60Q) IgG1.3f NS (without C-terminal K) CAGCTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGT CCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGCAGTAGAAGTTACTACTGGGG CTGGATCCGCCAGCCCCCAGGGAAGGGGCTGGAGTGGATTGGGAGTATCTATTAT AGTGGGTTCACCTACTACCAACCGTCCCTCAAGAGTCGAGTCACCATATCCGTTG ACACGTCCAAGAACCAGTT CTCCCTGAAGCTGAGCTCTGTGACCGCCGCAGACAC GGCTGTGTATTATTGTGCGACAGGGGGGCCCTACGGTGACTACGCCCACTGGTTC GACCCCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCTAGCACCAAGGGCC CATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGC CCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACTGTC GTGGAAC TCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAG GACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCA GACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGA GTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTG AAGCCGAAGGGGCCC CGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCT CATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAA GACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCA AGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCT CACCGTCCTGCACCAGGACTGGCTGAATGGCAAG GAGTACAAGTGCAAGGTCTCC AACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGC CCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAA CCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTG GAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGC TGGACT CCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAG GTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAAC CACTACACGCAGAAGAGCCTCTCCCTGTCCCCGGGTTGA 278 13A3 (N60S) IgG1.3f NS (without C-terminal K) CAGCTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGT CCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGCAGTAGAAGTTACTACTGGGG CTGGATCCGCCAGCCCCCAGGGAAGGGGCTGGAGTGGATTGGGAGTATCTATTAT AGTGGGTTCACCACTACTCACCGTCCCTCAAGAGTCGAGTCACCATATCCGTTG ACACGTCCAAGAACCAGTT CTCCCTGAAGCTGAGCTCTGTGACCGCCGCAGACAC GGCTGTGTATTATTGTGCGACAGGGGGGCCCTACGGTGACTACGCCCACTGGTTC GACCCCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCTAGCACCAAGGGCC CATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGC CCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACTGTC GTGGAAC TCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAG GACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCA GACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGA GTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTG AAGCCGAAGGGGCCC CGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCT CATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAA GACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCA AGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCT CACCGTCCTGCACCAGGACTGGCTGAATGGCAAG GAGTACAAGTGCAAGGTCTCC AACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGC CCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAA CCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTG GAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGC TGGACT CCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAG GTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAAC CACTACACGCAGAAGAGCCTCTCCCTGTCCCCGGGTTGA

- 91 045913

279 13A3 (N60A) IgG1.3f NS (without C-terminal K) CAGCTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGT CCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGCAGTAGAAGTTACTACTGGGG CTGGATCCGCCAGCCCCCAGGGAAGGGGCTGGAGTGGATTGGGAGTATCTATTAT AGTGGGTTCACCTACTACGCACCGTCCCTCAAGAGTCGAGTCACCATATCCGTTG ACACGTCCAAGAACCAGTT CTCCCTGAAGCTGAGCTCTGTGACCGCCGCAGACAC GGCTGTGTATTATTGTGCGACAGGGGGGCCCTACGGTGACTACGCCCACTGGTTC GACCCCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCTAGCACCAAGGGCC CATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGC CCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACTGTC GTGGAAC TCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAG GACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCA GACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGA GTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTG AAGCCGAAGGGGCCC CGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCT CATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAA GACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCA AGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCT CACCGTCCTGCACCAGGACTGGCTGAATGGCAAG GAGTACAAGTGCAAGGTCTCC AACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGC CCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAA CCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTG GAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGC TGGACT CCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAG GTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAAC CACTACACGCAGAAGAGCCTCTCCCTGTCCCCGGGTTGA 280 13A3 (D101E) IgG1.3f NS (without C-terminal K) CAGCTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGT CCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGCAGTAGAAGTTACTACTGGGG CTGGATCCGCCAGCCCCCAGGGAAGGGGCTGGAGTGGATTGGGAGTATCTATTAT AGTGGGTTCACCTACTACAACCCGTCCCTCAAGAGTCGAGTCACCATATCCGTTG ACACGTCCAAGAACCAGTT CTCCCTGAAGCTGAGCTCTGTGACCGCCGCAGACAC GGCTGTGTATTATTGTGCGACAGGGGGGCCCTACGGTGACTACGCCCACTGGTTC GAACCCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCTAGCACCAAGGGCC CATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGC CCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACTGTC GTGGAAC TCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAG GACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCA GACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGA GTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTG AAGCCGAAGGGGCCC CGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCT CATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAA GACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCA AGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCT CACCGTCCTGCACCAGGACTGGCTGAATGGCAAG GAGTACAAGTGCAAGGTCTCC AACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGC CCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAA CCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTG GAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGC TGGACT CCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAG GTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAAC CACTACACGCAGAAGAGCCTCTCCCTGTCCCCGGGTTGA 281 13A3 (P102V) IgG1.3f NS (without C-terminal K) CAGCTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGT CCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGCAGTAGAAGTTACTACTGGGG CTGGATCCGCCAGCCCCCAGGGAAGGGGCTGGAGTGGATTGGGAGTATCTATTAT AGTGGGTTCACCTACTACAACCCGTCCCTCAAGAGTCGAGTCACCATATCCGTTG ACACGTCCAAGAACCAGTT CTCCCTGAAGCTGAGCTCTGTGACCGCCGCAGACAC GGCTGTGTATTATTGTGCGACAGGGGGGCCCTACGGTGACTACGCCCACTGGTTC GACGTATGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCTAGCACCAAGGGCC CATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGC CCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACTG TCGTGGAAC TCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAG GACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCA GACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGA GTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTG AAGCCGAAGGGGC CCCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCT CATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAA GACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCA AGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCT CACCGTCCTGCACCAGGACTGGCTGAATGGCA AGGAGTACAAGTGCAAGGTCTCC AACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGC CCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAA CCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTG GAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGC TGC ACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAG GTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAAC CACTACACGCAGAAGAGCCTCTCCCTGTCCCCGGGTTGA

- 92 045913

282 13A3 (P102Y) IgG1.3f NS (without C-terminal K) CAGCTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGT CCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGCAGTAGAAGTTACTACTGGGG CTGGATCCGCCAGCCCCCAGGGAAGGGGCTGGAGTGGATTGGGAGTATCTATTAT AGTGGGTTCACCTACTACAACCCGTCCCTCAAGAGTCGAGTCACCATATCCGTTG ACACGTCCAAGAACCAGTT CTCCCTGAAGCTGAGCTCTGTGACCGCCGCAGACAC GGCTGTGTATTATTGTGCGACAGGGGGGCCCTACGGTGACTACGCCCACTGGTTC GACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCTAGCACCAAGGGCC CATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGC CCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCG TGGAAC TCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAG GACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCA GACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGA GTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTG AAGCCGAAGGGGCCCCG TCAGTCTTTCCTTCCCCCCAAAACCCAAGGACACCCT CATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAA GACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCA AGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCT CACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGA GTACAAGTGCAAGGTCTCC AACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGC CCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAA CCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTG GAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGC TGGACTCC GACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAG GTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAAC CACTACACGCAGAAGAGCCTCTCCCTGTCCCCGGGTTGA 283 13A3 (P102L) IgG1.3f NS (without C-terminal K) CAGCTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGT CCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGCAGTAGAAGTTACTACTGGGG CTGGATCCGCCAGCCCCCAGGGAAGGGGCTGGAGTGGATTGGGAGTATCTATTAT AGTGGGTTCACCTACTACAACCCGTCCCTCAAGAGTCGAGTCACCATATCCGTTG ACACGTCCAAGAACCAGTT CTCCCTGAAGCTGAGCTCTGTGACCGCCGCAGACAC GGCTGTGTATTATTGTGCGACAGGGGGGCCCTACGGTGACTACGCCCACTGGTTC GACCTATGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCTAGCACCAAGGGCC CATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGC CCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACTGTC GTGGAAC TCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAG GACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCA GACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGA GTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTG AAGCCGAAGGGGCCC CGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCT CATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAA GACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCA AGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCT CACCGTCCTGCACCAGGACTGGCTGAATGGCAAG GAGTACAAGTGCAAGGTCTCC AACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGC CCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAA CCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTG GAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGC TGGACT CCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAG GTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAAC CACTACACGCAGAAGAGCCTCTCCCTGTCCCCGGGTTGA 284 13A3 (N60Q, P102Y) IgG1.3f NS (without C-terminal K) CAGCTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGT CCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGCAGTAGAAGTTACTACTGGGG CTGGATCCGCCAGCCCCCAGGGAAGGGGCTGGAGTGGATTGGGAGTATCTATTAT AGTGGGTTCACCTACTACCAACCGTCCCTCAAGAGTCGAGTCACCATATCCGTTG ACACGTCCAAGAACCAGTT CTCCCTGAAGCTGAGCTCTGTGACCGCCGCAGACAC GGCTGTGTATTATTGTGCGACAGGGGGGCCCTACGGTGACTACGCCCACTGGTTC GACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCTAGCACCAAGGGCC CATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGC CCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCG TGGAAC TCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAG GACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCA GACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGA GTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTG AAGCCGAAGGGGCCCCG TCAGTCTTTCCTTCCCCCCAAAACCCAAGGACACCCT CATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAA GACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCA AGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCT CACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGA GTACAAGTGCAAGGTCTCC AAC AAAG S S S T S S S AG C S S S S AT C GAGAAAAC C AT S T S S AAAG C CAAAG GG C AG C CCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAA CCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTG GAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGC TGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAG GTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAAC CACTACACGCAGAAGAGCCTCTC CCTGTCCCCGGGTTGA

- 93 045913

285 8B9 (S61P) IgG1.3f NS (without C-terminal K) CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGT CCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGTCGTCACTACTGGAACTGGAT CCGGCAGCCCCCAGGGAAGGGACTGGAGTGGATTGGGTATATCCATTACAGTGGA AGCACCAACTACAATCCCTCCCTCAAGAGTCGAGTCACCATATCAGTAGACACGT CCAAGAACCAGTTCTCCCTGA AGCTGAGCTCTGTGACCGCTGCGGACACGGCCGT GTATTACTGTGCGAGAGATACTGGGTACTACGGTATGGACATCTGGGGCCAAGGG ACCACGGTCACCGTCTCCTCAGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGG CACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAA GGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCT GACCAGC GGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCA GCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGT GAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGT GACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAAGCCGAAGGGGCCCCGT CAGTCTTCCTCTTC CCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCC TGAGGTCCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTC AACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGG AGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGA CTGGCTGAATGGCAAGGAGTACAAGTGCA AGGTCTCCAACAAAGCCCTCCCAGCC CCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGT ACACCCTGCCCCCATCCCGGGAGGAATGACCAAGAACCAGGTCAGCCTGACCTG CCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGG CAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCT TCT TCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGT CTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGC CTCTCCCTGTCCCCGGGTTGA 286 9F6 (A108T) IgG1.3f NS (without C-terminal K) CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCAAGCCTGGAGGGTCCCTGA GACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTGACTACTACATGAGCTGGAT CCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTTTCATTCATTAGTGGTGGTGGT AGTACCATATACTACGCAGACTCTGTGAAGGGCCGATTCACCATCTCCAGGGACA ACGCCAAGAACTCGCTGTT TCTGCAAATGAACAGCCTGAGAGTCGAGGACACGGC TGTGTATTACTGTGCGAGAGATGGCTATAGCAGTGGCTGGTACTACTACGGTATG GACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCAGCTAGCACCAAGGGCC CATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGC CCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGG TGTCGTGGAAC TCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAG GACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCA GACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGA GTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTG AAGCCGAAG GCCCCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCT CATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAA GACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCA AGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCT CACCGTCCTGCACCAGGACTGGCTGAAT T GGACTCCGACGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAG GTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAAC CACTACACGCAGAAGAGCCTCTCCCTGTCCCCGGGTTGA 287 13A3 (N60Q, D101E) IgGl.lf NS CAGCTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGT CCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGCAGTAGAAGTTACTACTGGGG CTGGATCCGCCAGCCCCCAGGGAAGGGGCTGGAGTGGATTGGGAGTATCTATTAT AGTGGGTTCACCTACTACCAACCGTCCCTCAAGAGTCGAGTCACCATATCCGTTG ACACGTCCAAGAACCAGTT CTCCCTGAAGCTGAGCTCTGTGACCGCCGCAGACAC GGCTGTGTATTATTGTGCGACAGGGGGGCCCTACGGTGACTACGCCCACTGGTTC GAACCCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCTAGCACCAAGGGCC CATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGC CCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACTGTC GTGGAAC TCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAG GACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCA GACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGA GTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTG AAGCCGAAGGGGCCC CGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCT CATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAA GACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCA AGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCT CACCGTCCTGCACCAGGACTGGCTGAATGGCAAG GAGTACAAGTGCAAGGTCTCC AACAAAGCCCTCCCAAGCAGCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGC CCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAA CCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTG GAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGC TGGACT CCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAG GTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAAC CACTACACGCAGAAGAGCCTCTCCCTGTCCCCGGGTAAATGA

- 94 045913

288 13A3 (N60Q, D101E) IgGl. If NS (without C-terminal K) CAGCTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGT CCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGCAGTAGAAGTTACTACTGGGG CTGGATCCGCCAGCCCCCAGGGAAGGGGCTGGAGTGGATTGGGAGTATCTATTAT AGTGGGTTCACCTACTACCAACCGTCCCTCAAGAGTCGAGTCACCATATCCGTTG ACACGTCCAAGAACCAGTT CTCCCTGAAGCTGAGCTCTGTGACCGCCGCAGACAC GGCTGTGTATTATTGTGCGACAGGGGGGCCCTACGGTGACTACGCCCACTGGTTC GAACCCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCTAGCACCAAGGGCC CATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGC CCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACTGTC GTGGAAC TCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAG GACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCA GACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGA GTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTG AAGCCGAAGGGGCCC CGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCT CATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAA GACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCA AGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCT CACCGTCCTGCACCAGGACTGGCTGAATGGCAAG GAGTACAAGTGCAAGGTCTCC AACAAAGCCCTCCCAAGCAGCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGC CCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAA CCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTG GAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGC TGGACT CCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAG GTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAAC CACTACACGCAGAAGAGCCTCTCCCTGTCCCCGGGTTGA 289 13A3 (N60Q, D101E) IgG1.3f NS CAGCTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGT CCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGCAGTAGAAGTTACTACTGGGG CTGGATCCGCCAGCCCCCAGGGAAGGGGCTGGAGTGGATTGGGAGTATCTATTAT AGTGGGTTCACCTACTACCAACCGTCCCTCAAGAGTCGAGTCACCATATCCGTTG ACACGTCCAAGAACCAGTT CTCCCTGAAGCTGAGCTCTGTGACCGCCGCAGACAC GGCTGTGTATTATTGTGCGACAGGGGGGCCCTACGGTGACTACGCCCACTGGTTC GAACCCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCTAGCACCAAGGGCC CATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGC CCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACTGTC GTGGAAC TCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAG GACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCA GACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGA GTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTG AAGCCGAAGGGGCCC CGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCT CATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAA GACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCA AGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCT CACCGTCCTGCACCAGGACTGGCTGAATGGCAAG GAGTACAAGTGCAAGGTCTCC AAC AAAG S S S T S S S AG C S S S S AT C GAGAAAAC C AT S T S S AAAG C CAAAG GG C AG C CCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAA CCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTG GAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGC TGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAG GTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAAC CACTACACGCAGAAGAGCCTCTC CCTGTCCCCGGGTAAATGA 290 13A3 (N60Q, D101E) IgG1.3f NS (without C-terminal K) CAGCTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGT CCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGCAGTAGAAGTTACTACTGGGG CTGGATCCGCCAGCCCCCAGGGAAGGGGCTGGAGTGGATTGGGAGTATCTATTAT AGTGGGTTCACCTACTACCAACCGTCCCTCAAGAGTCGAGTCACCATATCCGTTG ACACGTCCAAGAACCAGTT CTCCCTGAAGCTGAGCTCTGTGACCGCCGCAGACAC GGCTGTGTATTATTGTGCGACAGGGGGGCCCTACGGTGACTACGCCCACTGGTTC GAACCCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCTAGCACCAAGGGCC CATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGC CCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACTGTC GTGGAAC TCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAG GACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCA GACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGA GTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTG AAGCCGAAGGGGCCC CGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCT CATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAA GACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCA AGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCT CACCGTCCTGCACCAGGACTGGCTGAATGGCAAG GAGTACAAGTGCAAGGTCTCC AAC AAAG S S S T S S S AG C S S S S AT C GAGAAAAC CAT S T S S AAAG C CAAAG GG C AG C CCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAA CCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTG GAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGC TGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAG GTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAAC CACTACACGCAGAAGAGCCTCTCCCTGTCCCCGGGTTGA

- 95 045913

291 13A3 (N60Q, D101E) (TIM3.18) IgG1.3f (T168C) (without C-terminal K) CAGCTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGT CCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGCAGTAGAAGTTACTACTGGGG CTGGATTCGCCAGCCCCCAGGGAAGGGGCTGGAGTGGATTGGGAGTATCTATTAT AGTGGGTTCACCTACTACCAACCGTCCCTCAAGAGTCGAGTCACCATATCCGTTG ACACGTCCAAGAACCAGTT CTCCCTGAAGCTGAGCTCTGTGACCGCCGCAGACAC GGCTGTGTATTATTGTGCGACAGGGGGGCCCTACGGTGACTACGCCCACTGGTTC GAACCCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCTAGCACCAAGGGCC CATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGC CCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACTGTC GTGGAAC TCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAG GACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCA GACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGA GTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTG AAGCCGAAGGGGCCC CGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCT CATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAA GACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCA AGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCT CACCGTCCTGCACCAGGACTGGCTGAATGGCAAG GAGTACAAGTGCAAGGTCTCC AAC AAAG S S S T S S S AG C S S S S AT C GAGAAAAC S AT S T S S AAAG S CAAAG GG S AG S CCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAA CCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTG GAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGC TGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAG GTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAAC CACTACACGCAGAAGAGCCTCTC CCTGTCCCCGGGTTGA 292 13A3 (N60Q, D101E) (TIM3.18) IgG1.3f NS with signaling protein (underlined) MRAWIFFLLCLAGRALAQLQLQESGPGLVKPSETLSLTCTVSGGSISSRSYYWGW IRQPPGKGLEWIGSIYYSGFTYYQPSLKSRVTISVDTSKNQFSLKLSSVTAADTA VYYCATGGPYGDYAHWFEPWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAAL GCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTQT Y1CNVNHKPSNTKVDKRVEPKSCD KTHTCPPCPAPEAEGAPSVFLFPPKPKDTLM 1SRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLT VLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQ VSLTCLVKGFYPSD1AVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV DKSRW QQGNVESCSVMHEALHNHYTQKSLSLSPGK* 293 13A3 (N60Q, D101E) (TIM3.18) IgG1.3f NS (without C-terminal K) with signaling protein (underlined) MRAWIFFLLCLAGRALAQLQLQESGPGLVKPSETLSLTCTVSGGSISSRSYYWGW IRQPPGKGLEWIGSIYYSGFTYYQPSLKSRVTISVDTSKNQFSLKLSSVTAADTA VYYCATGGPYGDYAHWFEPWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAAL GCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTQT Y1CNVNHKPSNTKVDKRVEPKSCD KTHTCPPCPAPEAEGAPSVFLFPPKPKDTLM 1SRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLT VLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQ VSLTCLVKGFYPSD1AVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV DKSRW QQGNVFSCSVMHEALHNHYTQKSLSLSPG* 294 13A3 (N60Q, D101E) (TIM3.18) IgG1.3f NS with signaling protein (underlined) ATGAGGGCTTGGATCTTCTTTCTGCTCTGCCTGGCCGGGAGAGCGCTCGCCACAGC TGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGTCCCT CACCTGCACTGTCTCTGGTGGCTCCATCAGCAGTAGAAGTTACTACTGGGGCTGG ATCCGCCAGCCCCCAGGGAAGGGGCTGGAGTGGATTGGGAGTATCTATTATAGTG GGTTCACCTACTACCAACCGTCCCTCAAGAGTCGAGTCACCATATCCGTTGACAC GTCCAAGAACCAGTTCTCC CTGAAGCTGAGCTCTGTGACCGCCGCAGACACGGCT GTGTATTATTGTGCGACAGGGGGGCCCTACGGTGACTACGCCCACTGGTTCGAAC CCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCTAGCACCAAGGGCCCATC GGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTG GGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACTGTC GTGGAACTCAG GCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACT CTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACC TACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTG AGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAAGC CGAAGGGGCCC CGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATG ATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACC CTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGAC AAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACC GTCCTGCACCAGGACTGGCTGAATGGCAAG GAGTACAAGTGCAAGGTCTCCAACA AAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCG AGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAG GTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGT GGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTG GA CTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGG CAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACT ACACGCAGAAGAGCCTCTCCCTGTCCCCGGGTAAATGA 295 13A3 (N60Q, D101E) (TIM3.18) IgG1.3f NS (without C-terminal K) with signaling protein (underlined) ATGAGGGCTTGGATCTTCTTTCTGCTCTGCCTGGCCGGGAGAGCGCTCGCCACAGC TGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGTCCCT CACCTGCACTGTCTCTGGTGGCTCCATCAGCAGTAGAAGTTACTACTGGGGCTGG ATCCGCCAGCCCCCAGGGAAGGGGCTGGAGTGGATTGGGAGTATCTATTATAGTG GGTTCACCTACTACCAACCGTCCCTCAAGAGTCGAGTCACCATATCCGTTGACAC GTCCAAGAACCAGTTCTCC CTGAAGCTGAGCTCTGTGACCGCCGCAGACACGGCT

- 96 045913

GTGTATTATTGTGCGACAGGGGGGCCCTACGGTGACTACGCCCACTGGTTCGAAC CCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCTAGCACCAAGGGCCCATC GGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTG GGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAG GCGCCCTGACCAGCGGCGTG CACACCTTCCCGGCTGTCCTACAGTCCTCAGGACT CTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACC TACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTG AGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAAGC CGAAGGGGCCCCGTCAGTCTTCCTCTTCCCCAAAACCCAAGGA CACCCTCATG ATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACC CTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGAC AAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACC GTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACA AAGCC CTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCG AGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAG GTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGT GGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGA CTCCGACGGCTCCTTCTTCCTCTATAGCAAGC TCACCGTGGACAAGAGCAGGTGG CAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACT ACACGCAGAAGAGCCTCTCCCTGTCCCCGGGTTGA 296 13A3 (N60Q, D101E) (TIM3.18) IgG1.3f HC (T168C) with signal sequence (underlined) ATGAGGGCTTGGATCTTCTTTCTGCTCTGCCTGGCCGGGAGAGCGCTCGCACAGC TGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGTCCCT CACCTGCACTGTCTCTGGTGGCTCCATCAGCAGTAGAAGTTACTACTGGGGCTGG ATTCGCCAGCCCCCAGGGAAGGGGCTGGAGTGGATTGGGAGTATCTATTATAGTG GGTTCACCACTACCAACCGTC CCTCAAGAGTCGAGTCACCATATCCGTTGACAC GTCCAAGAACCAGTTCTCCCTGAAGCTGAGCTCTGTGACCGCCGCAGACACGGCT GTGTATTATTGTGCGACAGGGGGGCCCTACGGTGACTACGCCCACTGGTTCGAAC CCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCTAGCACCAAGGGCCCATC GGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCA CAGCGGCCCTG GGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAG GCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACT CTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACC TACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTG AGCCCAAATC TTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAAGC CGAAGGGGCCCCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATG ATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACC CTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGAC AAAGCCGCGGGAGGAGCAGTACAACAGCACG TACCGTGTGGTCAGCGTCCTCACC GTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACA AAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCG AGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAG GTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAG T GGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGA CTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGG CAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACT ACACGCAGAAGAGCCTCTCCCTGTCCCCGGGTAAATGA 297 13A3 (N60Q, D101E) (TIM3.18) IgG1.3f NS (T168C) (without Terminal K) with signal sequence (underlined) ATGAGGGCTTGGATCTTCTTTCTGCTCTGCCTGGCCGGGAGAGCGCTCGCACAGC TGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGTCCCT CACCTGCACTGTCTCTGGTGGCTCCATCAGCAGTAGAAGTTACTACTGGGGCTGG ATTCGCCAGCCCCCAGGGAAGGGGCTGGAGTGGATTGGGAGTATCTATTATAGTG GGTTCACCACTACCAACCGTC CCTCAAGAGTCGAGTCACCATATCCGTTGACAC GTCCAAGAACCAGTTCTCCCTGAAGCTGAGCTCTGTGACCGCCGCAGACACGGCT GTGTATTATTGTGCGACAGGGGGGCCCTACGGTGACTACGCCCACTGGTTCGAAC CCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCTAGCACCAAGGGCCCATC GGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCA CAGCGGCCCTG GGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAG GCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACT CTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACC TACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTG AGCCCAAATC TTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAAGC CGAAGGGGCCCCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATG ATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACC CTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGAC AAAGCCGCGGGAGGAGCAGTACAACAGCACG TACCGTGTGGTCAGCGTCCTCACC GTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACA AAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCG AGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAG GTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAG T GGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGA CTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGG CAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACT ACACGCAGAAGAGCCTCTCCCTGTCCCCGGGTTGA 298 13A3 (N60Q, D101E) (TIM3.18) LC with signal in series MRAW1FFLLCLAGRALAE1VLTQSPGTLLSLSPGERATLSCRASQSVSSSYLAWYQ QKPGQAPRLLIYGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYG SSPITFGQGTRLEIKRTVAAPSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQ

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Claims (12)

stu (underlined) WKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLS SPVTKSFNRGEC* 299 13A3 (N60Q, D101E) (TIM3.18) LC with signal sequence (underlined) ATGAGGGCTTGGATCTTCTTTCTGCTCTGCCTGGCCGGGCGCGCCTTGGCCGAAA TTGTGTTGACGCAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCAC CCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCAGCTACTTAGCCTGGTACCAG CAGAAACCTGGCCAGCTCCCAGGCTCCTCATCTATGGTGCATCCAGCAGGGCCA CTGGCATCCCAGACAGGTTCAGTGGC AGTGGGTCTGGGACAGACTTCACTCTCAC CATCAGCAGACTGGAGCCTGAAGATTTTGCAGTGTATTACTGTCAGCAGTATGGT AGCTCACCGATCACCTTCGGCCAAGGGACACGACTGGAGATTAAACGTACGGTGG CTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAAC TGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCAGAGAGGCCAAA GTACAG TGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGC AGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGC AGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGC TCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG This PCT application claims priority to U.S. Provisional Patent Application No. 62/551,137, filed August 28, 2017, the contents of which are incorporated herein by reference in their entirety. CLAIM 1. An in vitro method for determining whether a subject having cancer will respond to treatment with an anti-TIM3 antibody, comprising determining the percentage of naïve TILs, central memory (CM) TILs, effector memory (EM) TILs, and effector TILs that are TIM- 3 positive, and if the percentage of EM TILs and/or effector TILs that are TIM-3 positive is higher than the percentage of naïve TILs and/or CM TILs that are TIM-3 positive, that subject will respond to anti-TIM3 treatment antibody; wherein cancer includes colon, kidney or lung cancer. 2. The in vitro method of claim 1, wherein the anti-TIM3 antibody comprises: (i) a heavy chain variable region comprising CDR1, CDR2 and CDR3, and (ii) a light chain variable region comprising CDR1, CDR2 and CDR3, wherein: (a) the CDR1 heavy chain contains an amino acid sequence selected from the group consisting of SEQ ID NO: 23-27; (b) the CDR2 heavy chain contains an amino acid sequence selected from the group consisting of SEQ ID NO: 28-38; (c) the CDR3 heavy chain contains an amino acid sequence selected from the group consisting of SEQ ID NO: 39-49; (d) the CDR1 light chain contains an amino acid sequence selected from the group consisting of SEQ ID NOs: 50 and 51; (e) the CDR2 light chain contains an amino acid sequence selected from the group consisting of SEQ ID NOs: 52 and 53; and (f) the CDR3 light chain comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 54-57. 3. The in vitro method according to claim 1, wherein the TILs are CD4+ TILs. 4. The in vitro method according to claim 1, wherein the TILs are CD8+ TILs. 5. The in vitro method according to any one of claims 1 to 4, wherein the difference in the level of TIM-3 positive cells is at least 50%. 6. The in vitro method according to any one of claims 1 to 4, wherein the difference in the level of TIM-3 positive cells is at least 100%. 7. The in vitro method according to any one of claims 1 to 4, wherein naïve TILs are CCR7+CD45RO-, effector TILs are CCR7-CD45RO-, CM TILs are CCR7+CD45RO+ and EM TILs are CCR7-CD45RO+. 8. In vitro method according to any one of claims 1 to 7, wherein the treatment further comprises administering a PD-1 antagonist. 9. The in vitro method of claim 8, wherein the PD-1 comprises an anti-PD-1 antibody or an anti-PD-L1 antibody. 10. The in vitro method of claim 9, wherein the anti-PD-1 antibody comprises nivolumab, pembrolizumab, MEDI0608, AMP-224, PDR001, BGB-A317, or any combination thereof. 11. The in vitro method of claim 9 or 10, wherein the PD-1 antagonist is administered at a fixed dose of about 240 mg approximately every 2 weeks. 12. The in vitro method of claim 9, wherein the anti-PD-L1 antibody includes BMS-936559, MPDL3280A, MEDI4736, MSB0010718C, or any combination thereof. -