Cancer therapies targeting vista as monotherapy or in combination with Anti-pd1 antibody to treat cancer

Abstract

Provided herein are doses and dosing regimens for administration of an anti-VISTA antibody for treating cancer in human subjects. The anti-VISTA antibody may be administered as a monotherapy or in combination with an anti-PD-1 antibody.

Description

CANCER THERAPIES TARGETING VISTA CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Patent Application No.63 / 651,029, filed May 23, 2024, and U.S. Provisional Patent Application No. 63 / 617,092, filed January 3, 2024, U.S. Provisional Patent Application No. 63 / 593,556, filed October 27, 2023, and U.S. Provisional Patent Application No. 63 / 517,302, filed August 2, 2023, the contents of each of which are incorporated by reference herein in their entirety for all purposes. REFERENCE TO AN ELECTRONIC SEQUENCE LISTING

[0002] The contents of the electronic sequence listing (SEBI_026_001WO_SeqList_ST26.xml; Size: 8,175 bytes; and Date of Creation: July 26, 2024) are herein incorporated by reference in their entirety. TECHNICAL FIELD

[0003] The disclosure is related to medical uses of therapeutic antibodies. BACKGROUND

[0004] Immunotherapies, especially immune checkpoint inhibitors, are a cornerstone of cancer treatment. However, innate and / or acquired resistance to immunotherapies remains a major challenge. V domain Ig suppressor of T-cell activation (VISTA) is an immune checkpoint, which suppresses T-cell activation and is highly expressed on myeloid cells, including macrophages and neutrophils (Yuan et al., Trends in Immunology, 2021; 42(3):209-27). Clinical development of anti-VISTA antibodies has been challenging due to three major factors: 1) lack of clarity on the identity of the critical counter-receptor responsible for T-cell suppression; 2) high clearance via target-mediated drug disposition (TMDD) by VISTA+ neutrophils and monocytes at physiologic pH; and 3) cellular activation and cytokine release syndrome (CRS) at sub-therapeutic doses by engagement of VISTA in the blood. There is a need for cancer treatments using anti-VISTA antibodies that overcome these challenges and surmount immunotherapy resistance.SUMMARY

[0005] Provided herein is a method for ameliorating a symptom of a cancer in a subject in need thereof, the method comprising: administering to the subject an anti-V-domain immunoglobulin suppressor of T-cell activation (VISTA) antibody or an antigen-binding portion thereof, wherein the antibody or antigen-binding portion comprises a heavy chain variable (VH) region and a light chain variable (VL) region, wherein the VH region amino acid sequence comprises a heavy chain complementarity determining region 1 (HCDR1) comprising SEQ ID NO: 2, a heavy chain complementarity determining region 2 (HCDR2) comprising SEQ ID NO: 3 and a heavy chain complementarity determining region 3 (HCDR3) comprising SEQ ID NO: 4; and the VL region amino acid sequence comprises a light chain complementarity determining region 1 (LCDR1) comprising SEQ ID NO: 6, a light chain complementarity determining region 2 (LCDR2) comprising SEQ ID NO: 7 and a light chain complementarity determining region 3 (LCDR3) comprising SEQ ID NO: 8; wherein the antibody or antigen-binding portion is administered intravenously at a dose of about 0.3 mg / kg body weight, about 1.0 mg / kg body weight, about 3.0 mg / kg body weight, about 10 mg / kg body weight, or about 15 mg / kg body weight.

[0006] In some embodiments, the symptom of cancer is fatigue, pain, weight loss, or loss of appetite.

[0007] Provided herein is a method for reducing tumor burden in a subject in need thereof, the method comprising: administering to the subject an anti-VISTA antibody or an antigen-binding portion thereof, wherein the antibody or antigen-binding portion comprises a VH region and a VL region, wherein the VH region amino acid sequence comprises a HCDR1 comprising SEQ ID NO: 2, a HCDR2 comprising SEQ ID NO: 3 and a HCDR3 comprising SEQ ID NO: 4; and the VL region amino acid sequence comprises a LCDR1 comprising SEQ ID NO: 6, a LCDR2 comprising SEQ ID NO: 7 and a LCDR3 comprising SEQ ID NO: 8; wherein the antibody or antigen-binding portion is administered intravenously at a dose of about 0.3 mg / kg body weight, about 1.0 mg / kg body weight, about 3.0 mg / kg body weight, about 10 mg / kg body weight, or about 15 mg / kg body weight; and wherein the tumor burden is reduced compared to a baseline tumor burden measured before initial administration of the antibody or antigen- binding portion.

[0008] In some embodiments, the baseline tumor burden is measured not more than 4 weeks before initial administration of the antibody or antigen-binding portion.

[0009] Provided herein is a method for reducing size of a tumor in a subject in need thereof, the method comprising: administering to the subject an anti-VISTA antibody or an antigen- binding portion thereof, wherein the antibody or antigen-binding portion comprises a VH region and a VL region, wherein the VH region amino acid sequence comprises a HCDR1 comprising SEQ ID NO: 2, a HCDR2 comprising SEQ ID NO: 3 and a HCDR3 comprising SEQ ID NO: 4; and the VL region amino acid sequence comprises a LCDR1 comprising SEQ ID NO: 6, a LCDR2 comprising SEQ ID NO: 7 and a LCDR3 comprising SEQ ID NO: 8; wherein the antibody or antigen-binding portion is administered intravenously at a dose of about 0.3 mg / kg body weight, about 1.0 mg / kg body weight, about 3.0 mg / kg body weight, about 10 mg / kg body weight, or about 15 mg / kg body weight; and wherein the size of the tumor is reduced compared to the baseline size of the tumor measured before initial administration of the antibody or antigen-binding portion.

[0010] In some embodiments, the baseline size of the tumor is measured not more than 4 weeks before initial administration of the antibody or antigen-binding portion.

[0011] Provided herein is a method for treating cancer in a subject in need thereof, the method comprising: administering to the subject an anti-VISTA antibody or an antigen-binding portion thereof, wherein the antibody or antigen-binding portion comprises a VH region and a VL region, wherein the VH region amino acid sequence comprises a HCDR1 comprising SEQ ID NO: 2, a HCDR2 comprising SEQ ID NO: 3 and a HCDR3 comprising SEQ ID NO: 4; and the VL region amino acid sequence comprises a LCDR1 comprising SEQ ID NO: 6, a LCDR2 comprising SEQ ID NO: 7 and a LCDR3 comprising SEQ ID NO: 8; wherein the antibody or antigen-binding portion is administered intravenously at a dose of about 0.3 mg / kg body weight, about 1.0 mg / kg body weight, about 3.0 mg / kg body weight, about 10 mg / kg body weight, or about 15 mg / kg body weight.

[0012] Provided herein is a method for inducing an immune response against cancer cells in a subject in need thereof, the method comprising: administering to the subject an anti-VISTA antibody or an antigen-binding portion thereof, wherein the antibody or antigen-binding portion comprises a VH region and a VL region, wherein the VH region amino acid sequence comprises a HCDR1 comprising SEQ ID NO: 2, a HCDR2 comprising SEQ ID NO: 3 and a HCDR3 comprising SEQ ID NO: 4; and the VL region amino acid sequence comprises a LCDR1 comprising SEQ ID NO: 6, a LCDR2 comprising SEQ ID NO: 7 and a LCDR3 comprising SEQ ID NO: 8; wherein the antibody or antigen-binding portion is administered intravenously at a dose of about 0.3 mg / kg body weight, about 1.0 mg / kg body weight, about 3.0 mg / kg body weight, about 10 mg / kg body weight, or about 15 mg / kg body weight.

[0013] In some embodiments, the immune response is antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity or antibody-dependent cellular phagocytosis.

[0014] In some embodiments of the methods provided herein, the anti-VISTA antibody or antigen-binding portion comprises a VH region comprising the amino acid sequence of SEQ ID NO: 1, and a VL region comprising the amino acid sequence of SEQ ID NO: 5.

[0015] In some embodiments of the methods provided herein, the anti-VISTA antibody or antigen-binding portion comprises a human IgG1 constant region.

[0016] In some embodiments of the methods provided herein, the anti-VISTA antibody or antigen-binding portion comprises a VH region comprising the amino acid sequence of SEQ ID NO: 1, a VL region comprising the amino acid sequence of SEQ ID NO: 5, and a human IgG1 constant region.

[0017] In some embodiments of the methods provided herein, the anti-VISTA antibody or antigen-binding portion is formulated in 20 mM histidine, 50 mM sodium chloride, 180 mM sucrose, and 0.02% (w / v) polysorbate 80 at pH 6.0.

[0018] In some embodiments of the methods provided herein, the subject has a locally advanced, unresectable, or metastatic solid tumor. In some embodiments of the methods provided herein, the subject has head and neck cancer, breast cancer, colon cancer, pancreatic cancer, gastric cancer, esophageal cancer, gallbladder cancer, prostate cancer, uterine cancer, cervical cancer, endometrial cancer, ovarian cancer, kidney cancer, bladder cancer, thyroid cancer, lung cancer, melanoma, or sarcoma. In some embodiments, the kidney cancer is renal cell carcinoma (RCC). In some embodiments, the endometrial cancer is microsatellite stable (MSS) endometrial cancer. In some embodiments, the head and neck cancer is human papilloma (HPV)-positive head and neck cancer.

[0019] In some embodiments of the methods provided herein, the anti-VISTA antibody or antigen-binding portion is administered to the subject once every 3 weeks.

[0020] In some embodiments of the methods provided herein, the anti-VISTA antibody or antigen-binding portion is administered to the subject as a monotherapy. In some embodiments, the subject has MSS colorectal cancer (CRC), and the anti-VISTA antibody or antigen-binding portion is administered intravenously at a dose of about 15 mg / kg body weight as a monotherapy.

[0021] In some embodiments of the methods provided herein, the anti-VISTA antibody or antigen-binding portion is administered to the subject as a combination therapy. In some embodiments, the subject has MSS CRC, head and neck cancer, non-small cell lung cancer(NSCLC), or melanoma, and the anti-VISTA antibody or antigen-binding portion is administered as a combination therapy.

[0022] In some embodiments of the methods provided herein, the anti-VISTA antibody or antigen-binding portion is administered to the subject in combination with an anti-PD-1 antibody or antigen-binding portion thereof. In some embodiments, the anti-PD-1 antibody is cemiplimab. In some embodiments, the cemiplimab is administered to the subject intravenously at a dose of about 350 mg.

[0023] In some embodiments of the methods provided herein, the anti-VISTA antibody or antigen-binding portion is administered intravenously at a dose of about 15 mg / kg body weight, and the cemiplimab is administered to the subject intravenously at a dose of about 350 mg. In some embodiments of the methods provided herein, the anti-VISTA antibody or antigen- binding portion is administered intravenously at a dose of about 10 mg / kg body weight, and the cemiplimab is administered to the subject intravenously at a dose of about 350 mg. In some embodiments of the methods provided herein, the anti-VISTA antibody or antigen-binding portion is administered intravenously at a dose of about 3 mg / kg body weight, and the cemiplimab is administered to the subject intravenously at a dose of about 350 mg.

[0024] In some embodiments of the methods provided herein, the anti-VISTA antibody or antigen-binding portion and the cemiplimab are administered to the subject in the following order: (i) the anti-VISTA antibody or antigen-binding portion is administered on cycle 1, day 1; (ii) the cemiplimab is administered on cycle 1, day 2; and (iii) the anti-VISTA antibody or antigen-binding portion and the cemiplimab are administered on the same day of each cycle following cycle 1, and the anti-VISTA antibody or antigen-binding portion is administered before the cemiplimab.

[0025] In some embodiments of the methods provided herein, the subject had previously been treated with a cancer therapy other than an anti-VISTA antibody or antigen-binding portion.

[0026] Provided herein is a composition comprising an anti-VISTA antibody or an antigen- binding portion thereof, wherein the antibody or antigen-binding portion comprises a VH region and a VL region, wherein the VH region amino acid sequence comprises a HCDR1 comprising SEQ ID NO: 2, a HCDR2 comprising SEQ ID NO: 3 and a HCDR3 comprising SEQ ID NO: 4; and the VL region amino acid sequence comprises a LCDR1 comprising SEQ ID NO: 6, a LCDR2 comprising SEQ ID NO: 7 and a LCDR3 comprising SEQ ID NO: 8; about 20 mM histidine; about 50 mM sodium chloride; about 180 mM sucrose; and about 0.02% (w / v) polysorbate 80 at pH 6.0. In some embodiments of the pharmaceutical compositions provided herein, the VH region amino acid sequence comprises SEQ ID NO: 1,and the VL region amino acid sequence comprises SEQ ID NO: 5. In some embodiments of the pharmaceutical compositions provided herein, the anti-VISTA antibody or antigen-binding portion comprises a human IgG1 constant region. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] FIG. 1 is a schematic of a phase 1 / 2 study evaluating the anti-VISTA antibody SNS- 101 as a monotherapy and in combination with cemiplimab in patients with advanced solid tumors. “MTD” = maximum tolerated dose. “RP2D” = recommended Phase 2 dose. “SMC” = safety monitoring committee. “TBD” = to be decided. “CRC” = colorectal cancer. “NSCLC” = non-small cell lung cancer. “H&N” = head and neck cancer.

[0028] FIG. 2 is a schematic providing additional details on dose escalation and dose expansion in the phase 1 / 2 study evaluating the anti-VISTA antibody SNS-101 as a monotherapy and in combination with LIBTAYO®(cemiplimab) in patients with advanced solid tumors. “TBD” = to be decided. “Q3W” = every 3 weeks. “DLT” = dose-limiting toxicity. “CRC” = colorectal cancer. “NSCLC” = non-small cell lung cancer. “H&N” = head and neck cancer. “*” = LIBTAYO®(cemiplimab) 350 mg. “RP2D” = Recommended Phase 2 Dose. “MTD” = Maximum Tolerated Dose.

[0029] FIG. 3 is a graph depicting results of cytokine analysis in cohorts A1 to A5 (monotherapy) and B1 to B3 (combination therapy). In the x-axis labels, “C_D_” refers to the cycle number and the day number.

[0030] FIG.4A - FIG.4B are graphs depicting results of pharmacokinetic analysis in cohorts A1 to A5 (monotherapy; FIG.4A) and B1 to B3 (combination therapy; FIG.4B).

[0031] FIG. 5A - FIG. 5B are graphs depicting best overall change in size of tumor target lesions in subjects with at least one follow-up scan with monotherapy (FIG. 5A) and combination therapy (FIG. 5B). Dashed lines indicate progression (>=+20%) or partial response (-30%).

[0032] FIG. 6A - FIG. 6B are graphs depicting results of pharmacodynamic analysis T-cell phenotyping for monotherapy and combination cohorts. Results are shown for CD8+ T effector memory (TEM) cells and T effector memory CD45RA re-expressing (TEMRA) cells.

[0033] FIG. 7 is a graph depicting time of objective response in relationship to duration of treatment and time of treatment cessation in subjects with at least one follow-up scan. Subject numbers 01-001, 01-002, 01-004, 01-006, 01-008, 01-010, 03-004, 04-001, 04-002, 04-003, 04-004, 04-005, 04-007, 04-009, and 04-012 were treated with monotherapy. Subject numbers01-005, 01-009, 01-011, 01-012, 01-013, 01-014, 01-015, 01-016, 01-022, 03-003, 03-006, 03- 007, 04-006, 04-010, 04-013, 04-014, and 04-015 were treated with combination therapy.

[0034] FIG.8 depicts image of tumor assessments in patient number 01-005. DETAILED DESCRIPTION

[0035] VISTA is a B7-family member immune checkpoint that promotes T-cell and myeloid quiescence and is a potential target for cancer treatment in humans. As VISTA is highly expressed on myeloid cells, including those in the blood, antibodies binding VISTA at physiological pH 7.4 can result in rapid elimination from circulation through TMDD, making efficacious drug occupancy levels difficult to reach and potentially narrowing the therapeutic window. Further, the interaction of VISTA with its receptor P-selectin glycoprotein ligand-1 (PSGL-1) was demonstrated to be significantly enhanced by the acidic tumor microenvironment (TME) (Johnston et al. Nature, 2019; 574:565–570). Provided herein are therapeutic methods for treating cancer with an anti-VISTA antibody specific for the protonated, active form of VISTA, which is designed to disrupt the immunosuppressive VISTA:PSGL-1 interaction, avoid TMDD, and mitigate potential CRS. The anti-VISTA antibodies used in methods provided herein may be administered at higher doses than other anti-VISTA antibodies based on the safety and tolerability profile and favorable pharmacokinetic profile indicating linear elimination kinetics. The anti-VISTA antibodies used in methods provided herein have enhanced pharmacokinetic properties that enable less- frequent dosing.

[0036] VISTA is implicated in cancer resistance to inhibitors of programmed cell death protein-1 (PD-1) / programmed cell death-ligand 1 (PD-L1). Provided herein are combination therapies with anti-VISTA antibodies and anti-PD-1 antibodies to overcome innate and / or acquired resistance to anti-PD-1 blockade.

[0037] Provided herein is a method for treating or ameliorating cancer in a human subject in need thereof, the method comprising administering to the subject an anti-VISTA antibody or an antigen-binding portion thereof, wherein the antibody or antigen-binding portion comprises a heavy chain variable (VH) region and a light chain variable (VL) region, wherein the VH region amino acid sequence comprises a heavy chain complementarity determining region 1 (HCDR1) comprising SEQ ID NO: 2, a heavy chain complementarity determining region 2 (HCDR2) comprising SEQ ID NO: 3 and a heavy chain complementarity determining region 3 (HCDR3) comprising SEQ ID NO: 4; and the VL region amino acid sequence comprises alight chain complementarity determining region 1 (LCDR1) comprising SEQ ID NO: 6, a light chain complementarity determining region 2 (LCDR2) comprising SEQ ID NO: 7 and a light chain complementarity determining region 3 (LCDR3) comprising SEQ ID NO: 8. In some embodiments, the VH region amino acid sequence comprises SEQ ID NO: 1, and the VL region amino acid sequence comprises SEQ ID NO: 5. In some embodiments, the anti-VISTA antibody or antigen-binding portion comprises a human IgG1 constant region. Table 1. Amino acid sequences of exemplary anti-VISTA antibodyCDR sequences are underlined in variable region sequences.

[0038] In some embodiments, the antibody or antigen-binding portion is a Fab, a Fab', a F(ab')2, an Fv, an scFv, a maxibody, a minibody, a diabody, a triabody, a tetrabody, or a bis-scFv.

[0039] In some embodiments of the methods provided herein, the anti-VISTA antibody is an antibody referred to as “SNS-101”. SNS-101 comprises the CDR and variable region domains listed in Table 1. SNS-101 is a human monoclonal immunoglobulin G1 (IgG1) antibody that selectively targets the protonated, active form of VISTA.

[0040] In some embodiments, an anti-VISTA antibody or antigen-binding portion used in the methods provided herein is produced in Chinese hamster ovary (CHO) cells.

[0041] In some embodiments, the anti-VISTA antibody or antigen-binding portion is administered to a subject intravenously.

[0042] Provided herein is a pharmaceutical composition comprising an anti-VISTA antibody or an antigen-binding portion thereof, wherein the antibody or antigen-binding portion comprises a VH region and a VL region, wherein the VH region amino acid sequence comprises a HCDR1 comprising SEQ ID NO: 2, a HCDR2 comprising SEQ ID NO: 3 and a HCDR3 comprising SEQ ID NO: 4; and the VL region amino acid sequence comprises a LCDR1 comprising SEQ ID NO: 6, a LCDR2 comprising SEQ ID NO: 7 and a LCDR3 comprising SEQ ID NO: 8; about 20 mM histidine; about 50 mM sodium chloride; about 180 mM sucrose; and about 0.02% (w / v) polysorbate 80 at pH 6.0. In some embodiments, the pharmaceutical composition is diluted in sterile saline (0.9% NaCl) before administration to a subject. In some embodiments, the diluted intravenous dose preparation is aseptically prepared and administered intravenously over approximately 60 minutes.

[0043] In some embodiments, the anti-VISTA antibody or antigen-binding portion is administered intravenously at a dose of about 0.3 mg / kg body weight, about 1.0 mg / kg body weight, about 3.0 mg / kg body weight, about 10 mg / kg body weight, or about 15 mg / kg body weight.

[0044] Provided herein is a method for ameliorating a symptom of a cancer in a subject in need thereof, the method comprising: administering to the subject an anti-VISTA antibody or an antigen-binding portion thereof, wherein the antibody or antigen-binding portion comprises a VH region and a VL region, wherein the VH region amino acid sequence comprises a HCDR1 comprising SEQ ID NO: 2, a HCDR2 comprising SEQ ID NO: 3 and a HCDR3 comprising SEQ ID NO: 4; and the VL region amino acid sequence comprises a LCDR1 comprising SEQ ID NO: 6, a LCDR2 comprising SEQ ID NO: 7 and a LCDR3 comprising SEQ ID NO: 8; wherein the antibody or antigen-binding portion is administered intravenously at a dose of about 0.3 mg / kg body weight, about 1.0 mg / kg body weight, about 3.0 mg / kg body weight, about 10 mg / kg body weight, or about 15 mg / kg body weight.

[0045] In some embodiments, the symptom of cancer is fatigue, pain, weight loss, or loss of appetite.

[0046] Provided herein is a method for reducing tumor burden in a subject in need thereof, the method comprising: administering to the subject an anti-VISTA antibody or an antigen-binding portion thereof, wherein the antibody or antigen-binding portion comprises a VH region and a VL region, wherein the VH region amino acid sequence comprises a HCDR1 comprising SEQ ID NO: 2, a HCDR2 comprising SEQ ID NO: 3 and a HCDR3 comprising SEQ ID NO: 4; and the VL region amino acid sequence comprises a LCDR1 comprising SEQ ID NO: 6, a LCDR2 comprising SEQ ID NO: 7 and a LCDR3 comprising SEQ ID NO: 8; wherein the antibody orantigen-binding portion is administered intravenously at a dose of about 0.3 mg / kg body weight, about 1.0 mg / kg body weight, about 3.0 mg / kg body weight, about 10 mg / kg body weight, or about 15 mg / kg body weight; and wherein the tumor burden is reduced compared to a baseline tumor burden measured before initial administration of the antibody or antigen- binding portion.

[0047] In some embodiments, the baseline tumor burden is measured not more than 4 weeks before initial administration of the antibody or antigen-binding portion.

[0048] Provided herein is a method for reducing size of a tumor in a subject in need thereof, the method comprising: administering to the subject an anti-VISTA antibody or an antigen- binding portion thereof, wherein the antibody or antigen-binding portion comprises a VH region and a VL region, wherein the VH region amino acid sequence comprises a HCDR1 comprising SEQ ID NO: 2, a HCDR2 comprising SEQ ID NO: 3 and a HCDR3 comprising SEQ ID NO: 4; and the VL region amino acid sequence comprises a LCDR1 comprising SEQ ID NO: 6, a LCDR2 comprising SEQ ID NO: 7 and a LCDR3 comprising SEQ ID NO: 8; wherein the antibody or antigen-binding portion is administered intravenously at a dose of about 0.3 mg / kg body weight, about 1.0 mg / kg body weight, about 3.0 mg / kg body weight, about 10 mg / kg body weight, or about 15 mg / kg body weight; and wherein the size of the tumor is reduced compared to the baseline size of the tumor measured before initial administration of the antibody or antigen-binding portion.

[0049] In some embodiments, the baseline size of the tumor is measured not more than 4 weeks before initial administration of the antibody or antigen-binding portion.

[0050] Provided herein is a method for treating cancer in a subject in need thereof, the method comprising: administering to the subject an anti-VISTA antibody or an antigen-binding portion thereof, wherein the antibody or antigen-binding portion comprises a VH region and a VL region, wherein the VH region amino acid sequence comprises a HCDR1 comprising SEQ ID NO: 2, a HCDR2 comprising SEQ ID NO: 3 and a HCDR3 comprising SEQ ID NO: 4; and the VL region amino acid sequence comprises a LCDR1 comprising SEQ ID NO: 6, a LCDR2 comprising SEQ ID NO: 7 and a LCDR3 comprising SEQ ID NO: 8; wherein the antibody or antigen-binding portion is administered intravenously at a dose of about 0.3 mg / kg body weight, about 1.0 mg / kg body weight, about 3.0 mg / kg body weight, about 10 mg / kg body weight, or about 15 mg / kg body weight.

[0051] Provided herein is a method for inducing an immune response against cancer cells in a subject in need thereof, the method comprising: administering to the subject an anti-VISTA antibody or an antigen-binding portion thereof, wherein the antibody or antigen-bindingportion comprises a VH region and a VL region, wherein the VH region amino acid sequence comprises a HCDR1 comprising SEQ ID NO: 2, a HCDR2 comprising SEQ ID NO: 3 and a HCDR3 comprising SEQ ID NO: 4; and the VL region amino acid sequence comprises a LCDR1 comprising SEQ ID NO: 6, a LCDR2 comprising SEQ ID NO: 7 and a LCDR3 comprising SEQ ID NO: 8; wherein the antibody or antigen-binding portion is administered intravenously at a dose of about 0.3 mg / kg body weight, about 1.0 mg / kg body weight, about 3.0 mg / kg body weight, about 10 mg / kg body weight, or about 15 mg / kg body weight.

[0052] In some embodiments, the immune response against cancer cells is antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, or antibody-dependent cellular phagocytosis.

[0053] In some embodiments, anti-tumor activity induced by methods provided herein may be measured as objective response rate (ORR), duration of response (DoR), disease control rate (DCR) and progression free survival (PFS) by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (Eisenhauer et al., Eur J Cancer 2009; 45:228–47) and immune Response Evaluation Criteria in Solid Tumors (iRECIST) (Seymour et al., Lancet Oncol 2017; 18(3):E143-E152).

[0054] In some embodiments of the methods provided herein, the anti-VISTA antibody or antigen-binding portion comprises a VH region comprising the amino acid sequence of SEQ ID NO: 1, and a VL region comprising the amino acid sequence of SEQ ID NO: 5.

[0055] In some embodiments of the methods provided herein, the anti-VISTA antibody or antigen-binding portion comprises a human IgG1 constant region.

[0056] In some embodiments of the methods provided herein, the anti-VISTA antibody or antigen-binding portion comprises a VH region comprising the amino acid sequence of SEQ ID NO: 1, a VL region comprising the amino acid sequence of SEQ ID NO: 5, and a human IgG1 constant region.

[0057] In some embodiments of the methods provided herein, the anti-VISTA antibody or antigen-binding portion is formulated for intravenous administration. In some embodiments of the methods provided herein, the anti-VISTA antibody or antigen-binding portion is administered in a pharmaceutical composition comprising the antibody or antigen-binding portion, histidine, sodium chloride, sucrose, and polysorbate 80. In some embodiments of the methods provided herein, the anti-VISTA antibody or antigen-binding portion is formulated in 20 mM histidine, 50 mM sodium chloride, 180 mM sucrose, and 0.02% (w / v) polysorbate 80 at pH 6.0.

[0058] In some embodiments of the methods provided herein, the subject has a solid tumor.

[0059] In some embodiments of the methods provided herein, the subject has a locally advanced tumor. In some embodiments of the methods provided herein, the subject has an unresectable tumor. In some embodiments of the methods provided herein, the subject has a metastatic solid tumor. In some embodiments of the methods provided herein, the subject is refractory or intolerant to standard of care for advanced disease or not a candidate for standard of care therapy. In some embodiments of the methods provided herein, the subject has received and failed standard of care for advanced disease or not a candidate for standard of care therapy.

[0060] In some embodiments of the methods provided herein, the subject has head and neck cancer, breast cancer, colon cancer, pancreatic cancer, gastric cancer, esophageal cancer, gallbladder cancer, prostate cancer, uterine cancer, cervical cancer, endometrial cancer, ovarian cancer, kidney cancer, bladder cancer, thyroid cancer, lung cancer, melanoma, or sarcoma. In some embodiments of the methods provided herein, the kidney cancer is renal cell carcinoma (RCC). In some embodiments of the methods provided herein, the subject has small cell lung cancer (SCLC). In some embodiments of the methods provided herein, the subject has non- small cell lung cancer (NSCLC). In some embodiments of the methods provided herein, the head and neck cancer is human papilloma virus (HPV)-positive head and neck cancer. In some embodiments of the methods provided herein, the HPV-positive head and neck cancer is pembrolizumab-resistant. In some embodiments of the methods provided herein, the subject has endometrial cancer. In some embodiments of the methods provided herein, the subject has duodenal cancer. In some embodiments of the methods provided herein, the subject has a granulosa cell tumor.

[0061] In some embodiments of the methods provided herein, the subject has Ewing sarcoma. In some embodiments of the methods provided herein, the subject has a soft tissue sarcoma (e.g., a PEComa). In some embodiments of the methods provided herein, the subject has a squamous cell carcinoma. In some embodiments of the methods provided herein, the subject has a solitary fibrous tumor (e.g., hemangiopericytoma). In some embodiments of the methods provided herein, the subject has an adenocystic carcinoma. In some embodiments of the methods provided herein, the subject has a leiomyosarcoma.

[0062] In some embodiments of the methods provided herein, the subject has microsatellite stable (MSS) colorectal cancer (CRC). In some embodiments of the methods provided herein, the subject has MSS endometrial cancer. Microsatellite stability status in CRC and endometrial cancer may be important for clinical outcome and treatment efficacy. The term “microsatellite” or “microsatellite DNA” refers to segments of short repetitive DNA sequences. In some embodiments, microsatellite DNA serves as a biomarker for DNA stability. The term“microsatellite stable” refers to DNA that is considered stable because the number of microsatellite repeats is the same in healthy (non-tumor) cells and / or tumor cells in a subject. In some embodiments, a tumor cell is microsatellite stable when the tumor cell contains the same number of microsatellite repeats as a healthy (non-tumor) cell in a subject. The term “microsatellite instable” or “microsatellite instability” refers to microsatellite DNA that changes in length (i.e., shows instability) when DNA mismatch repair processes are not working properly. In some embodiments, a tumor cell is considered microsatellite instable when the microsatellite DNA is longer than the microsatellite DNA of a healthy (non-tumor) cell in a subject. In some embodiments, a tumor cell is considered microsatellite instable when the microsatellite DNA is shorter than the microsatellite DNA of a healthy (non-tumor) cell in a subject.

[0063] In some embodiments, a subject has a tumor characterized as a “hot” tumor. In some embodiments, a subject has a tumor characterized as a “cold” tumor. In some embodiments, “hot” tumors may contain more than a defined threshold of inflammatory cells. In some embodiments, “cold” tumors may show an absence of immune cells, or only peripheral invasion of immune cells. Potential characterization of tumors is described in, for example, Zemek et al., Front. Immunol. (2020) 11:223; Galon et al., Nat Rev Drug Discov. (2019) 18:197–218; Hedge et al., Clin Cancer Res. (2016) 22:1865. In some embodiments, a “cold” tumor is CRC. In some embodiments, a “hot” tumor is NSCLC, head and neck cancer, or melanoma. In some embodiments, a subject with a “hot” tumor been previously treated with a PD-1 or a PD-L1 checkpoint inhibitor.

[0064] In some embodiments, a subject has the following characteristics: 18 years of age or older; histologically or cytologically documented locally advanced, unresectable or metastatic solid tumor; refractory or intolerant to standard of care for advanced disease or not a candidate for standard of care therapy (i.e., patient refusal, medical contraindication, etc.); measurable disease, as defined by RECIST version 1.1; Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1; and a life expectancy of ^ 3 months.

[0065] In some embodiments, a subject had previously been treated with a cancer therapy other than an anti-VISTA antibody or antigen-binding portion. In some embodiments, a subject had previously been treated with carboplatin and / or fluorouracil (5FU). In some embodiments, a subject had previously been treated with a PD-1 inhibitor. In some embodiments, a subject’s cancer is resistant to a PD-1 inhibitor. In some embodiments, a subject had previously been treated with an anti-PD-1 antibody or antigen-binding portion. In some embodiments, a subject had previously been treated with nivolumab or pembrolizumab. In some embodiments, asubject had previously been treated with pembrolizumab, carboplatin and 5FU. In some embodiments, a subject had previously been treated with a PD-L1 inhibitor. In some embodiments, a subject’s cancer is resistant to a PD-L1 inhibitor. In some embodiments, a subject had previously been treated with an anti-PD-L1 antibody or antigen-binding portion.

[0066] In some embodiments of the methods provided herein, the anti-VISTA antibody or antigen-binding portion is administered to the subject once every 3 weeks. In some embodiments, the anti-VISTA antibody or antigen-binding portion is administered to the subject once every 3 weeks ± 1 day, 3 weeks ± 2 days, or 3 weeks ± 3 days.

[0067] In some embodiments of the methods provided herein, the anti-VISTA antibody or antigen-binding portion is administered to the subject as a monotherapy.

[0068] In some embodiments of the methods provided herein, the subject has MSS CRC, and the anti-VISTA antibody or antigen-binding portion is administered to the subject as a monotherapy. In some embodiments of the methods provided herein, the subject has MSS CRC, and the anti-VISTA antibody or antigen-binding portion is administered to the subject as a monotherapy intravenously at a dose of about 15 mg / kg body weight.

[0069] In some embodiments of the methods provided herein, the anti-VISTA antibody or antigen-binding portion is administered to the subject as a combination therapy. In some embodiments, the anti-VISTA antibody or antigen-binding portion is administered to the subject as a combination therapy with a PD-1 inhibitor.

[0070] In some embodiments of the methods provided herein, the anti-VISTA antibody or antigen-binding portion is administered to the subject in combination with an anti-PD-1 antibody or antigen-binding portion thereof. In some embodiments, the anti-PD-1 antibody is cemiplimab (also known as LIBTAYO®). In some embodiments, the cemiplimab is administered to the subject intravenously at a dose of about 350 mg. In some embodiments, the cemiplimab is administered to the subject intravenously at a dose of about 350 mg over 30 minutes.

[0071] In some embodiments of the methods provided herein, the subject has MSS CRC, head and neck cancer, NSCLC, or melanoma, and the anti-VISTA antibody or antigen-binding portion is administered to the subject as a combination therapy (e.g., with an anti-PD-1 antibody or antigen-binding portion thereof). In some embodiments of the methods provided herein, the subject has MSS CRC, head and neck cancer, NSCLC, or melanoma, and the anti- VISTA antibody or antigen-binding portion is administered to the subject as a combination therapy with cemiplimab. In some embodiments of the methods provided herein, the subject has MSS CRC, head and neck cancer, NSCLC, or melanoma, and the anti-VISTA antibody orantigen-binding portion is administered to the subject intravenously at a dose of about 15 mg / kg body weight, and the cemiplimab is administered to the subject intravenously at a dose of about 350 mg. In some embodiments of the methods provided herein, the subject has head and neck cancer, NSCLC, or melanoma, and the anti-VISTA antibody or antigen-binding portion is administered to the subject intravenously at a dose of about 3 mg / kg body weight, and the cemiplimab is administered to the subject intravenously at a dose of about 350 mg. In some embodiments of the methods provided herein, the subject has MSS CRC, head and neck cancer, NSCLC, or melanoma and had been previously treated with a PD-1 checkpoint inhibitor or a PD-L1 checkpoint inhibitor, and the anti-VISTA antibody or antigen-binding portion is administered to the subject as a combination therapy (e.g., with an anti-PD-1 antibody or antigen-binding portion thereof).

[0072] In some embodiments of the methods provided herein, the anti-VISTA antibody or antigen-binding portion and the cemiplimab are administered to the subject in the following order: (i) the anti-VISTA antibody or antigen-binding portion is administered on cycle 1, day 1; (ii) the cemiplimab is administered on cycle 1, day 2; and (iii) the anti-VISTA antibody or antigen-binding portion and the cemiplimab are administered on the same day of each cycle following cycle 1, and the anti-VISTA antibody or antigen-binding portion is administered before the cemiplimab.

[0073] In some embodiments of the methods provided herein, the anti-VISTA antibody or antigen-binding portion and the cemiplimab are administered to the subject once every 3 weeks. In some embodiments, the anti-VISTA antibody or antigen-binding portion and the cemiplimab are administered to the subject once every 3 weeks ± 1 day, 3 weeks ± 2 days, or 3 weeks ± 3 days.

[0074] In some embodiments of the methods provided herein, the anti-VISTA antibody or antigen-binding portion is administered to the subject intravenously at a dose of about 0.3 mg / kg body weight, about 1.0 mg / kg body weight, about 3.0 mg / kg body weight, about 10 mg / kg body weight, or about 15 mg / kg body weight; and the cemiplimab is administered to the subject intravenously at a dose of about 350 mg.

[0075] In some embodiments of the methods provided herein, the anti-VISTA antibody or antigen-binding portion is administered to the subject intravenously at a dose of about 0.3 mg / kg body weight; and the cemiplimab is administered to the subject intravenously at a dose of about 350 mg. In some embodiments of the methods provided herein, the anti-VISTA antibody or antigen-binding portion is administered to the subject intravenously at a dose of about 1.0 mg / kg body weight; and the cemiplimab is administered to the subject intravenouslyat a dose of about 350 mg. In some embodiments of the methods provided herein, the anti- VISTA antibody or antigen-binding portion is administered to the subject intravenously at a dose of about 3.0 mg / kg body weight; and the cemiplimab is administered to the subject intravenously at a dose of about 350 mg. In some embodiments of the methods provided herein, the anti-VISTA antibody or antigen-binding portion is administered to the subject intravenously at a dose of about 10 mg / kg body weight; and the cemiplimab is administered to the subject intravenously at a dose of about 350 mg. In some embodiments of the methods provided herein, the anti-VISTA antibody or antigen-binding portion is administered to the subject intravenously at a dose of about 15 mg / kg body weight; and the cemiplimab is administered to the subject intravenously at a dose of about 350 mg.

[0076] Unless otherwise noted, the terms used herein have definitions as ordinarily used in the art. Some terms are defined below, and additional definitions can be found within the rest of the detailed description.

[0077] The term “a” or “an” refers to one or more of that entity, i.e., can refer to plural referents. As such, the terms “a,” “an,” “one or more,” and “at least one” are used interchangeably herein. In addition, reference to “an element” by the indefinite article “a” or “an” does not exclude the possibility that more than one of the elements is present, unless the context clearly requires that there is one and only one of the elements.

[0078] Throughout this application, the term “about” is used to indicate that a value includes the inherent variation of error for the device, or the method being employed to determine the value, or the variation that exists among the samples being measured. Unless otherwise stated or otherwise evident from the context, the term “about” means within 10% above or below the reported numerical value (except where such number would exceed 100% of a possible value or go below 0%). When used in conjunction with a range or series of values, the term “about” applies to the endpoints of the range or each of the values enumerated in the series, unless otherwise indicated. As used in this application, the terms “about” and “approximately” are used as equivalents.

[0079] As used herein, the terms “treat,” “treating” or “treatment of” (and grammatical variations thereof) mean that the severity of the subject's condition is reduced, at least partially improved, or stabilized and / or that some alleviation, mitigation, decrease or stabilization in at least one clinical symptom is achieved and / or there is a delay in the progression of the disease or disorder.

[0080] In the present description, any concentration range, percentage range, ratio range, or integer range is to be understood to include the value of any integer within the recited rangeand, when appropriate, fractions thereof (such as one tenth and one hundredth of an integer), unless otherwise indicated. The use of the alternative (e.g., “or”) should be understood to mean either one, both, or any combination thereof of the alternatives. As used herein, the terms “include” and “comprise” are used synonymously.

[0081] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. All documents, or portions of documents, cited herein, including but not limited to patents, patent applications, articles, books, and treatises, are hereby expressly incorporated by reference in their entirety for any purpose. In the event that one or more of the incorporated documents or portions of documents define a term that contradicts that term’s definition in the application, the definition that appears in this application controls. However, mention of any reference, article, publication, patent, patent publication, and patent application cited herein is not, and should not be taken as an acknowledgment, or any form of suggestion, that they constitute valid prior art or form part of the common general knowledge in any country in the world.

[0082] The disclosure will be further clarified by the following examples, which are intended to be purely exemplary of the disclosure and in no way limiting. EXAMPLES EXAMPLE 1: PHASE 1 / 2 STUDY EVALUATING SNS-101 AS MONOTHERAPY AND IN COMBINATION WITH CEMIPLIMAB IN PATIENTS WITH ADVANCED SOLID TUMORS 1. INTRODUCTION 1.1 Study rationale

[0083] SNS-101 is a monoclonal antibody, selectively targeting the active / protonated form of VISTA found at low pH in the tumor microenvironment (TME). SNS-101 binds to VISTA at pH 6.0 with high affinity and blocks the interaction between the T-cell checkpoint, P-selectin glycoprotein ligand-1 (PSGL-1) and VISTA. Based on preclinical data, SNS-101, either as monotherapy or in combination therapy with a programmed cell death protein-1 (PD-1) blocker, cemiplimab, is expected to exhibit an acceptable tolerability profile and demonstrate anti-tumor activity in adult patients with advanced solid tumors.2. OBJECTIVES AND ENDPOINTS Table 2. Phase 1 Dose Escalation and Dose Expansion: Part A Monotherapy and Part B CombinationTable 3. Phase 2 Cohort Expansion3. STUDY DESIGN

[0084] This is a first-in-human, Phase 1 / 2 open-label, multi-center, dose escalation and expansion study to evaluate the safety, tolerability, PK, pharmacodynamics, and efficacy of SNS-101, an anti-VISTA IgG1 monoclonal antibody as monotherapy or in combination with cemiplimab in patients with advanced solid tumors. 3.1 Overall Design

[0085] A schematic of the study is provided in FIG. 1 and additional dose escalation details are provided in FIG.2. Table 4 provides the Schedule of Assessments (SoA) for the study.

[0086] This study is being conducted in three parts: • Part A: Phase 1 Monotherapy Dose Escalation and Dose Expansion (SNS-101 alone)• Part B: Phase 1 Combination Dose Escalation and Dose Expansion (SNS-101 in combination with cemiplimab) • Part C: Phase 2 Cohort Expansion (SNS-101 alone or in combination with cemiplimab)

[0087] For all parts of the study, after consenting to participate, patients will complete screening assessments during a Screening Period of up to 28 days. Once enrolled, patients will be monitored for safety by TEAE assessments, physical examinations, vital signs, laboratory tests, and electrocardiograms (ECGs). PK and biomarker samples will also be collected. Disease assessments by computed tomography (CT) or magnetic resonance imaging (MRI) will be conducted during Screening and every 6 weeks (±5 days) from Cycle 1 Day 1.

[0088] To further understand the mechanism of action of SNS-101, a newly obtained biopsy or archival biopsy will be requested prior to Cycle 1 Day 1 in patients starting at the 1.0 mg / kg dose level. In lieu of a fresh biopsy, archival tissue will be accepted (ideally if it was sampled prior to intervening treatment). If the patient is unable to undergo a fresh biopsy and no sample is available prior to treatment, any archival tissue may be acceptable with the Sponsor’s approval. An on-treatment biopsy will be obtained at Cycle 2 Day 1 (+ 1 week), as long as safe and medically feasible. 3.1.1 Part A, Monotherapy Dose Escalation / Dose Expansion and Part B, Combination Dose Escalation / Dose Expansion

[0089] Initially, patients will enroll in the monotherapy dose escalation cohorts. Once a dose level is cleared for the Dose-Limiting Toxicity (DLT) observation period by the Safety Monitoring Committee (SMC), the next monotherapy dose escalation cohort may be initiated in a sequential manner.

[0090] The SMC will also review emerging safety data, PK profile, pharmacodynamic activity and preliminary clinical activity upon completion of each dose level in order to decide whether to initiate Part B (combination therapy) for dose escalation at the highest cleared dose level of SNS-101.

[0091] For monotherapy and combination therapy assessment, dose escalation / de-escalation will proceed following the Bayesian Optimal Interval (BOIN) design until the MTD / RP2D is determined (Liu et al., Journal of the Royal Statistical Society. Series C: Applied Statistics. 2015 Apr 1;64(3):507-523; Yuan et al., Trends in Immunology. 2021;42(3):209-27). The resulting MTD / RP2D for the combination arm may differ from, but not exceed, that of the monotherapy arm.

[0092] All patients will receive SNS-101 as an intravenous (IV) infusion once every 3 weeks, either alone or in combination with cemiplimab IV. For the combination treatment, SNS-101and cemiplimab will be administered on the same day, with the exception of Cycle 1 when SNS-101 will be administered on Day 1 and cemiplimab will be administered as an IV infusion on Day 2.

[0093] Once the dose escalation portion is complete, enrollment will expand to targeted tumor types:

[0094] Approximately 10 patients with colorectal cancer (CRC) will be enrolled in the Monotherapy Dose Expansion. Additional tumor types and doses may be considered upon consultation with the Sponsor.

[0095] Approximately 50 patients with CRC, head and neck cancer (H&N), melanoma, and non-small cell lung cancer (NSCLC) will be enrolled in the Combination Dose Expansion. A minimum of 8 and a maximum of 10 CRC patients will be enrolled in the Combination Dose Expansion. Additional tumor types and doses may be considered upon consultation with the Sponsor.

[0096] Intra-patient dose escalations are allowed, after consultation with the Medical Monitor, provided that the dose level has been deemed safe and tolerable by the SMC. This can occur only if patients have received at least three cycles of their assigned starting dose, have had their first tumor assessment, have had no Grade 2 or higher toxicity regardless of causality, and shown no evidence of intolerance requiring dose interruption or reduction for toxicity. Monotherapy patients may receive combination therapy following the criteria as above if the combination dose level has been deemed safe and tolerable by the SMC. 3.1.2 Part C, Cohort Expansion

[0097] The Phase 2 portion will be initiated once the MTD / RP2D has been established. Multiple expansion cohorts may be evaluated for evidence of preliminary treatment effectiveness, using a single-arm, Simon two-stage minimax design incorporating an interim futility analysis.

[0098] Tumor types for these cohorts will be determined based on data from the dose escalation phase of the study and emerging results from preclinical studies or other scientific data. A protocol amendment will be implemented prior to the initiation of the Phase 2 portion of the study. 3.2 Justification for SNS-101 Dose

[0099] The proposed first-in-human starting dose for SNS-101 is 0.3 mg / kg administered IV, and the maximum dose planned for evaluation is 15 mg / kg. The conservative starting dose of 0.3 mg / kg was chosen based on results in immune reactivity studies and from PK and pharmacodynamic modeling and provides a large safety margin based on the SNS-101exposure at the minimum anticipated biologic effect level (MABEL) observed in the Good Laboratory Practice toxicology study. 4. STUDY POPULATION

[0100] Patients must meet all eligibility criteria to be considered for enrollment into the study. Protocol waivers for eligibility will not be permitted. 4.1 Inclusion Criteria

[0101] Patients who meet all of the following criteria may be eligible to participate in the study: 1. Provide signed IRB / Independent Ethics Committee (IEC) approved informed consent in accordance with institutional guidelines. 2. Is 18 years of age or older at the time of signing the informed consent form (ICF). 3. Histologically or cytologically documented locally advanced, unresectable or metastatic solid tumor. 4. Having received and failed or was intolerant to standard of care for advanced disease or not candidates for standard of care therapy (i.e., patient refusal, medical contraindication, etc.) with the following tumor types for patients in Phase 1 dose expansion cohorts: a. Microsatellite Stable (MSS) CRC (both monotherapy and combination cohorts); no more than 3 lines of prior systemic therapy for metastatic disease. b. H&N cancer (combination cohort only); no more than 2 lines of prior systemic therapy for metastatic disease. c. Melanoma (combination cohort only); no more than 3 lines of prior systemic therapy for metastatic disease, including at least 1 prior treatment with a BRAF inhibitor for patients with a BRAF mutation. d. NSCLC (combination cohort only); no more than 2 lines of prior systemic therapy including at least 1 prior treatment with a targeted therapy for patients with a mutation such as EGFR, ALK, KRAS or RET. e. Patients with H&N cancer, melanoma, and NSCLC (or additional tumor types that typically respond to PD1 / PD-L1 monotherapy) must have received a prior PD1 / PD-L1 where best response was stable disease and progression occurred during treatment or within 3 months of last dose of PD1 / PD-L1. Additional tumor types and doses may be considered upon consultation with the Sponsor. 5. Measurable disease, as defined by RECIST version 1.1 (Investigator assessment). 6. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.7. Have a life expectancy of ^ 3 months. 8. Be willing to provide pre-treatment (archival or fresh) and on-treatment tumor biopsy samples assuming they are deemed by the Investigator to be safe and accessible. 9. Adequate organ function per Table 6. 10. Fertility criteria: • Women of childbearing potential (WOCBP) and fertile males with WOCBP partners must use highly effective contraception (failure rate <1%) during the study and for 180 days after the study. • Patients must agree not to donate eggs (ova, oocytes) or sperm during the study and for 180 days after the study. 4.2 Exclusion Criteria

[0102] Patients who meet any of the following criteria will not be eligible to participate in the study:

[0103] Cancer-Specific Exclusion Criteria: 1. Use of anti-PD-1 / PD-L1 targeting monoclonal antibody therapy, monoclonal antibody therapy, chemotherapy, biologic, investigational, or radiotherapy within 2 weeks of Cycle 1 Day 1. 2. Clinically significant unresolved toxicities from prior anticancer therapy (presence of CTAE ^ Grade 2 toxicity excluding Grade 2 neuropathy or alopecia). 3. Grade 3 or higher immune related AE on prior PD-1 / PD-L1 blockade or prior agents targeting stimulatory or co-inhibitory T cell receptor. Note: Patients with ^ Grade 3 endocrinopathies on prior PD-1 / PDL-1 blockade that are adequately controlled with hormone supplementation may be included in the study. 4. Known other previous / current malignancy requiring treatment within ^ 2 years except for limited disease treated with curative intent, such as carcinoma in situ, squamous or basal cell skin carcinoma, or superficial bladder carcinoma. 5. Known asymptomatic or symptomatic brain metastasis or leptomeningeal disease.

[0104] General Medical Exclusion Criteria: 6. History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins. 7. Known hypersensitivity allergy or contraindication to biopharmaceuticals produced in Chinese hamster ovary cells or any component of the PD-1 / PD-L1 inhibitor formulation; andfor patients receiving combination, known hypersensitivity to cemiplimab or any of its excipients or contraindicated to cemiplimab per approved local labeling. 8. Active or inactive autoimmune disease or syndrome (e.g., rheumatoid arthritis, moderate or severe psoriasis, multiple sclerosis, inflammatory bowel disease) that has required systemic treatment in the past 2 years or who are receiving systemic therapy for autoimmune or inflammatory disease (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Note: Vitiligo, resolved childhood asthma / atopy, hypothyroidism, stable on hormone replacement, controlled asthma, Type 1 diabetes, Graves’ disease or Hashimoto’s disease or with Medical Monitor approval, will be eligible if all other eligibility criteria are met. 9. Medical illness requiring systemic glucocorticoid use of > 10 mg / day prednisone equivalent (inhaled, topical, and intranasal steroids are allowed) within 14 days of Cycle 1 Day 1. 10. History of transient ischemic attack, cerebrovascular accident, or seizures with the last 12 months. 11. Personal or familial history of hemophagocytic lymphohistiocytosis or macrophage activation syndrome. 12. QTc > 480 msec (average of triplicate measurements at Screening) according to Fredericia’s QT correction formula 13. Clinically significant cardiovascular disease such as uncontrolled congestive heart failure (NYHA Class 2-4), unstable angina, myocardial infarction, coronary / peripheral artery bypass graft surgery in the prior 6 months. Pulmonary embolism is exclusionary if the patient is not on a stable dose of anti-coagulant. 14. History of non-infectious pneumonitis or interstitial pulmonary disease that required steroids or ongoing pneumonitis or interstitial pulmonary disease. 15. Has uncontrolled infection with human immunodeficiency virus (HIV), hepatitis B (HBV), or hepatitis C (HCV) infection; or has a diagnosis of immunodeficiency. Notes: • Patients with known HIV infection who have controlled infection (undetectable viral load (HIV RNA PCR) and CD4 count above 350 either spontaneously or on a stable antiviral regimen) are permitted. For patients with controlled HIV infection, monitoring will be performed per local standards. • Patients with hepatitis B (HBsAg+) who have controlled infection (serum hepatitis B virus DNA PCR that is below the limit of detection and receiving anti-viral therapy for hepatitis B) are permitted. Patients with controlled infections must undergo periodic monitoring of HBVDNA. Patients must remain on anti-viral therapy for at least 6 months beyond the last dose of investigational study drug. • Patients who are hepatitis C virus antibody positive (HCV Ab+) who have controlled infection (undetectable HCV RNA by PCR either spontaneously or in response to a successful prior course of anti-HCV therapy) may be enrolled into the study. 16. Ongoing active infection requiring systemic antibiotics or viral infection. 17. Uncontrolled intercurrent condition, therapy or laboratory abnormality that could confound the results of the trial or limit the patient’s study compliance. 18. Prior allogeneic stem cell or solid organ transplant. 19. Received a live, attenuated vaccine within 28 days prior to Cycle 1 Day 1, or anticipation that such a live attenuated vaccine will be required during the trial. 20. Known previous or ongoing, active psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial. 21. Major surgery within 4 weeks prior to Cycle 1 Day 1. 22. Women who are pregnant or breastfeeding. 5. STUDY TREATMENT AND STUDY DRUG MANAGEMENT 5.1 Description of Study Drug

[0105] SNS-101 Drug Product for Injection (25 mg / mL, 10 mL fill) is a monoclonal antibody formulated in a buffer system at pH 6.0. The physical appearance is colorless to slightly yellow solution that is clear to slightly opalescent that is essentially free from visible particulates.

[0106] SNS-101 Drug Product for Injection (abbreviated SNS-101) will be diluted in 0.9% sterile saline prior to administration using an IV-bag delivery system containing a 0.2 or 0.22^m in-line filter. The diluted drug will be administered as a single IV infusion over approximately 60 minutes.

[0107] For combination treatment, cemiplimab will be supplied as a liquid in sterile, single- use vials at a concentration of 50 mg / mL. It is a clear to slightly opalescent, colorless to pale yellow solution that may contain trace amounts of translucent to white particles in a single- dose vial. Cemiplimab will be administered at a dose of 350 mg, as an intravenous infusion over 30 minutes every 3 weeks. 5.2 Packaging and Labeling

[0108] SNS-101 and cemiplimab will be packaged and labeled according to current Good Manufacturing Practice (cGMP) guidelines and applicable laws and / or regulations.5.3 Storage Conditions

[0109] SNS-101 and cemiplimab will be refrigerated at the site at 2 to 8 °C and should not be frozen. Refrigerator temperature will be logged daily. 5.4 Treatments Administered

[0110] SNS-101 and cemiplimab will be administered once every 3 weeks at the proposed dose levels noted in Table 7.

[0111] For patients the combination group, SNS-101 will be administered on Cycle 1 Day 1 and cemiplimab will be administered on Cycle 1 Day 2. In subsequent cycles, SNS-101 and cemiplimab will be administered on the same day. SNS-101 will be administered first followed by cemiplimab. When the SNS-101 administration is completed, cemiplimab may commence. 5.4.1. Guidelines for Dose Modifications and Treatment Discontinuation

[0112] Dose reductions

[0113] SNS-101: allowed to the next lowest dose where the DLT period has been cleared by the SMC. Medical Monitor should be contacted prior to implementing the dose modification.

[0114] Cemiplimab: not permitted.

[0115] General treatment-hold guidelines

[0116] General treatment-hold guidelines for management treatment-related TEAEs is provided in Table 8. In the event that treatment needs to be interrupted or discontinued due to a toxicity, both SNS-101 and cemiplimab will be interrupted / discontinued. 5.5 Prior and Concomitant Therapy

[0117] All treatments including any prescription or over-the-counter medications taken by the patients 30 days prior to Cycle 1 Day 1 and at any time during the study are regarded as concomitant treatments and will be recorded. At subsequent visits, changes to current medications or medications used since the last documentation of medications will be recorded. Concomitant medications will be collected until 30 days after the last dose of study medication or until the start of a new anti-cancer treatment, whichever comes first. 5.5.1 Allowed Treatments

[0118] The following concomitant treatments are permitted during this study: • Supportive treatment as medically indicated (e.g., acetaminophen, ibuprofen, diphenhydramine, H2 blockers, etc.). • Prophylactic antiemetic premedication including corticosteroids (low dose ^10 mg / day prednisone equivalent) and 5-hydroxytryptamine 3 antagonists. • Supportive treatment with cannabis, if medically indicated.• Patients receiving substrates of cytochrome P450 (CYP) enzymes with narrow therapeutic index should be monitored closely and have doses adjusted as necessary. 5.5.2 Prohibited Treatments

[0119] Medications such as those listed below are not permitted in the course of the trial: • Concurrent treatment with other investigational drugs. • Concurrent treatment with any other anticancer therapy including radiotherapy. í Exceptions include bisphosphonates and RANKL antagonists, and palliative radiotherapy. • Chronic systemic corticosteroid therapy or any other form of immunosuppressive therapy. Intranasal and inhaled corticosteroids, or systemic corticosteroids at physiological doses (^ 10 mg / day of prednisone, or an equivalent corticosteroid) are permitted. • Traditional herbal medicines should not be administered because the ingredients of many herbal medicines are not fully studied, and their use may result in unanticipated drug-drug interactions that may cause or confound assessment of toxicity. However, if the Investigator feels herbal medication is warranted the Sponsor should be consulted. • Initiation or increased dose of granulocyte colony-stimulating factors (e.g., granulocyte colony-stimulating factor, granulocyte / macrophage colony-stimulating factor, and / or pegfilgrastim) is strongly discouraged. • Patients are not allowed to receive immunostimulatory agents, including but not limited to interferon (IFN)-Į, IFN-Ȗ, or interleukin (IL)-2, during the entire trial. These agents, in combination with study treatment, could potentially increase the risk for autoimmune conditions. 5.5.3 Rescue Medications

[0120] Immune-mediated events should be recognized early and treated promptly to avoid potential major complications. In the event of CRS, patients may receive supportive care such as IV fluids, corticosteroids, tocilizumab, antibiotics, vasopressor support at the Investigator’s discretion. CRS and ICANS assessment and management should be performed per the most current CARTOX criteria: www[.]mdanderson[.]org / documents / for- physicians / algorithms / clinicalmanagement / clin-management-cytokine-release-web- algorithm.pdf (brackets can be removed from URL to reach website). Patients should receive appropriate medical intervention necessary to treat medical conditions as they arise. 5.5.4 Premedication

[0121] If a patient experiences CRS of any grade severity and is able to continue on study treatment for the next cycle, premedication must be used with subsequent infusions for a periodof at least two cycles. Premedication should be administered 30 minutes prior to the SNS-101 infusion and should, at a minimum, include: • Acetaminophen 650 mg orally • Diphenhydramine 12.5-25 mg IV or 25-50 mg orally Additional premedications can be used depending on institutional guidelines such as ibuprofen, corticosteroids, and / or tocilizumab. Supportive care using antiemetics such as ondansetron is permitted. 5.6 Patient Enrollment

[0122] Once a patient is determined to be eligible for the study and eligibility has been confirmed by the Sponsor or designee, the patient will be assigned to an open cohort in Part A (monotherapy) or Part B (combination therapy). Instructions for obtaining cohort assignment will be provided in reference materials provided for the study. All patients who sign the ICF will be assigned a patient study number which will be retained for the duration of the study. 5.7 Blinding

[0123] This is an open-label study, there will be no randomization or blinding. 6. STUDY ASSESSMENTS AND PROCEDURES

[0124] Table 4 provides an outline of the procedures required at each visit along with their associated windows. 6.1 Informed Consent

[0125] All patients must sign and date the most current approved ICF before any study specific procedures are performed. Procedures conducted as per standard of care or routine clinical management that are obtained before signing of the ICF may be utilized for screening / baseline purposes. 6.2 Demographics

[0126] Demographics will include gender, year of birth, race, and ethnicity. 6.3 Medical, Surgical and Cancer History

[0127] A complete medical and surgical history will be obtained during screening. Medical history will include details regarding the patient’s overall medical and surgical history as well as detailed information regarding the patient’s previous treatment, including systemic treatments, radiation and surgeries, pathology, risk stratification, etc. since their original diagnosis. PD-L1 status will be collected if previously obtained.6.4 Safety Assessments 6.4.1 Physical Examinations, Including Height and Weight

[0128] A complete physical examination will include, at a minimum, head, eyes, ears, nose, throat and cardiovascular, dermatological, musculoskeletal, respiratory, gastrointestinal and neurological systems. Additionally, any signs and symptoms, other than those associated with a definitive diagnosis, should be collected at baseline and during the study. During the study, a targeted, symptom-directed exam, as clinically indicated will be performed within 72 hours of Day 1 of each cycle. Height (screening only) and weight will also be collected. 6.4.2 Eastern Cooperative Oncology Performance Status

[0129] The health, activity, and well-being of the patient will be measured by the ECOG performance status and will be assessed on a scale of 0 to 5 with 0 being fully active and 5 being dead. ECOG performance status will be collected at Screening and within 3 days of Day 1 of each cycle. 6.4.3 Vital Signs

[0130] Vital signs will include temperature, blood pressure, pulse rate and respiratory rate. See Tables 9 and 10. 6.4.4 Electrocardiograms

[0131] Triplicate 12-lead electrocardiograms (ECGs), separated by 3-5 minutes, will be obtained at screening, at Cycle 1 pre-dose and 3-hours post end of infusion (±15 minutes), Cycle 2 pre-dose, and when clinically indicated. Patients should be resting in a supine position for at least 10 minutes prior to ECG collection. 6.4.5 Clinical Safety Laboratory Assessments

[0132] Local laboratory testing will be used for the safety laboratory assessments provided in Table 11. See the SoA for timing and frequency 6.5 Research Assessments

[0133] The Schedule of Assessments provides a collection timeline for each sample. 6.5.1 Pharmacokinetics

[0134] Serum samples will be obtained for PK assessments (see Table 5). 6.5.2 ADA

[0135] Serum samples will be analyzed for antibodies against SNS-101 (see Table 5). 6.5.3 Immuno-genomic Profiling

[0136] Whole blood, plasma and tissue samples will be collected for comprehensive tumor immunogenomic profiling that may include analysis of ctDNA, microsatellite instability (MSI), tumor mutational burden (TMB) and mutation analysis, and immune phenotyping.6.5.4 Research / Immunology Samples

[0137] In order to evaluate the effect of SNS-101 on the tumor microenvironment, on immune cell phenotypes and to explore potential biomarkers, serum, plasma and whole blood / peripheral blood mononuclear cells will be collected. Analyses may include, but are not limited to cytokine / chemokine analysis, immune protein expression analysis (flow cytometry), DNA / RNA sequencing, single cell RNA sequencing, etc. 6.5.5. Tumor Biopsy

[0138] A pre-treatment fresh or archived tissue sample is required at study entry. Ideally, the pretreatment tissue sample will have been obtained after any other intervening therapy. If the patient is unable to undergo a fresh biopsy and no sample is available prior to treatment, any archival tissue may be acceptable with the Sponsor’s approval. At Cycle 2 Day 1 (+1 week), all patients will undergo a mandatory tumor biopsy sample collection, if safe and medically feasible. Tumor tissue should be of good quality based on total and viable tumor content. If a tumor biopsy is to be obtained from an intended target lesion during eligibility assessment, the biopsy should be performed prior to obtaining the baseline scan. Otherwise, a new baseline scan should be obtained. Archival and fresh tumor tissue samples should be representative tumor specimens in formalin-fixed paraffin embedded (FFPE) blocks (preferred) or at least 15 unstained slides, with an associated pathology report, should be submitted for intra-tumoral immunology assessments. 6.5.5.1. Tissue Assays

[0139] Available tumor tissue collected from pre- and post-treatment may be evaluated by immunohistochemistry or other analytic modalities, which may include single-cell RNA sequencing, “bulk” DNA / RNA sequencing and / or Nanostring™-based transcriptional analysis. 6.5.6 Human Leukocyte Antigen

[0140] Human leukocyte antigen (HLA) will be collected at the local lab to explore whether there is a correlation between HLA status and the frequency of certain immune related adverse events. 6.6 Efficacy Assessments 6.6.1 Tumor Assessments

[0141] Tumor imaging should be performed by CT or MRI, if CT is contraindicated. The same imaging technique should be used for a patient throughout the trial. CT scans must include chest, abdomen and pelvis. A chest, abdomen and pelvis scan should be performed at baseline. Post baseline assessments should remain consistent for the remainder of the study. CT / MRI of the brain is required if there is suspicion of brain metastasis.

[0142] Initial (screening) tumor assessments must be performed within 28 days prior Cycle 1 Day 1. The Investigator / site radiologist must review pre-trial images to confirm the patient has measurable disease per RECIST v1.1. Tumor assessments performed as standard of care prior to obtaining informed consent and within 28 days of the first dose of study treatment may be used rather than repeating tests.

[0143] On-study imaging assessments will be performed every 6 weeks (±5 days) from the Cycle 1 Day 1 visit, independent of treatment delays. The Sponsor may request digitized scans to confirm response.

[0144] RECIST v1.1 will be used by the site for treatment decisions until the first radiologic evidence of progressive disease (PD). Following the first radiologic evidence of PD by RECIST v1.1, treatment decisions may be made by using iRECIST to accommodate tumor response patterns seen with checkpoint inhibitor therapy including pembrolizumab treatment (e.g., tumor flare). This was described by Nishino, J Immunother Cancer. 2016 Jun 21;4:30 and is used in immunotherapy clinical trials. Patients will be allowed to continue treatment during confirmation of disease progression as long as the patient meets the following criteria: • Is clinically stable per the Investigator’s discretion. • Does not have signs and symptoms indicating clinically significant progression of disease. • Has stable performance status. • Does not have symptomatic rapid disease progression requiring urgent medical intervention (e.g., symptomatic pleural effusion, spinal cord compression). • Signs a separate “continued participation” informed consent that will include the following “continuing treatment beyond progression will not prevent / delay an imminent intervention to prevent serious complications of disease progression and is not standard of care”.

[0145] Additional treatment response evaluation by RECIST v1.1 and iRECIST may be performed at the Sponsor’s discretion. If progression is confirmed, study treatment should be discontinued.

[0146] Patients who discontinue from treatment for reasons other than disease progression (e.g., toxicity) will continue scheduled tumor assessments until disease progression, start of new anti-cancer therapy, withdrawal of consent, or death. Investigators may perform additional scans or more frequent assessments if clinically indicated. 7. STATISTICAL CONSIDERATIONS 7.1 Sample Size Determination 7.1.1 Part A & B, Phase 1 Dose Escalation and Dose Expansion

[0147] In the Phase 1 Dose Escalation portion of the study, up to 49 patients in total will be enrolled across up to 8 dose cohorts on monotherapy and combination therapy escalation combined, with each cohort planned to enroll up to 6 patients. The total number of patients enrolled in Phase 1 Dose Escalation will be driven by the safety review conducted by the SMC. An additional 60 patients in total will be enrolled among 4 targeted tumor types in dose expansion. Approximately 10 patients will be enrolled in monotherapy dose expansion cohort. Approximately 50 patients will be enrolled in the combination dose expansion cohort. 7.1.2 Part C, Phase 2 Cohort Expansion

[0148] The Phase 2 portion of the study for both monotherapy and combination therapy, is intended to evaluate preliminary evidence of an efficacy signal in specific disease indication cohorts. For each respective disease cohort in the Phase 2 expansion part, a Simon’s 2-stage minmax design will be used to allow early stopping if the response rate at the pre-defined interim futility assessment is not sufficiently promising to warrant further development. The protocol will be amended to update the statistical section for Part C once the indication cohorts are confirmed. 7.2 Populations for Analyses

[0149] The following analysis populations will be used for this study: • The Safety Population will include all patients who receive at least 1 dose of SNS-101. • The Efficacy Evaluable Population will include all patients who receive at least 1 dose of SNS-101 and have at least 1 follow-up tumor response assessment. • The PK population will include all patients who receive at least 1 dose of SNS-101 and have at least 1 evaluable PK sample. 7.3 Statistical Analyses

[0150] The Statistical Analysis Plan will be developed and finalized before database lock and will describe the patient populations to be included in the analyses, and procedures for accounting for missing, unused, and spurious data. This section is a summary of the planned statistical analyses of the primary and secondary endpoints. 7.3.1 General Methods

[0151] Descriptive statistics (number evaluated [n], mean, median, standard deviation, minimum, and maximum) will be presented for continuous variables. The number and percentage of patients in each category will be presented for categorical variables. As appropriate, 95% confidence intervals will be included. Summaries will be presented by cohort and overall patients combined in Phase 1. All data collected will be presented in by-patient data listings. Patient disposition and demographic characteristics including age, gender and racewill be summarized by phase and cohort. All analyses will be carried out using SAS statistical software v9.4. Statistical analyses will be carried out separately for the dose escalation stages of the study (Part A monotherapy and Part B combination therapy). All secondary analyses will be descriptive only with no hypothesis testing. 7.3.2 Part A, Phase 1 Monotherapy Dose Escalation

[0152] SNS-101 is administered as an IV infusion. Five dose cohorts will be evaluated as follows: • Cohort 1: SNS-1010.3 mg / kg • Cohort 2: SNS-1011.0 mg / kg • Cohort 3: SNS-1013.0 mg / kg • Cohort 4: SNS-10110.0 mg / kg • Cohort 5: SNS-10115.0 mg / kg

[0153] The dose escalation process will begin with a sentinel dose, 0.3 mg / kg, which will be assigned a cohort size of 1 patient only. If no DLT is observed in the single patient at 0.3 mg / kg, patients will be assigned to subsequent dose levels in cohorts of size 3. In accordance with the applied dose escalation algorithm, enrollment will proceed sequentially across increasing dose cohorts as approved by the SMC. A possible intermediate dose of 5 mg / kg may be introduced at Sponsor’s discretion during the dose escalation stage.

[0154] All patients in each dose escalation cohort will be followed over the DLT period. If at the end of dose escalation under the BOIN approach the RP2D is not reached, additional cohorts may be considered, based on the emerging data. However, this may require recalibration of the DLT probability boundaries, hence a possible protocol amendment, to obtain good operation characteristics that achieve the desirable probability of correctly estimating and selecting the MTD.

[0155] Individual patients may continue receiving their assigned SNS-101 treatment until disease progression, unacceptable toxicity, or other reason for treatment discontinuation until the end of study.

[0156] In Part A of the study, the dose-escalation strategy for SNS-101 is guided by the BOIN design with the targeted DLT rate of ^^^^=0.30 and the optimal equivalence probability interval (0.236, 0.358). Table 12 presents a tabulation of the cumulative number of DLTs to guide the escalation / de-escalation decision process under the BOIN design algorithm for the stipulated number of patients (up to 24) treated at a given dose. The top row of the table represents the possible cumulative number of patients enrolled at any given dose at any stage of dose escalation. The values in the body of the table represent the cumulative number ofDLTs observed at that dose relative to the total enrolled. Dose-escalation decisions will be guided by this table.

[0157] For example, using Table 12, the following decisions can be made after a cumulative 9 patients have received a given dose: • If 2 or fewer DLTs are observed, escalate the next cohort to the next higher dose; • If 4 or more DLTs are observed, de-escalate the next cohort to the previous lower dose; • If 5 or more DLTs are observed, de-escalate to the previous lower dose and mark the current and all higher doses as unacceptably toxic so that they will not be used again in the remainder of the trial. In this situation, the previous dose becomes the RP2D.

[0158] Note: If 2 out of 2 patients have DLTs at the lowest dose level, the Sponsor can choose to terminate the study or to enroll 1 more patient, based on recommendations from the SMC.

[0159] In addition to the above rules for dose escalation governed by BOIN, the following additional rules will be adhered to during the DLT period for a given dose cohort: • One Grade ^ 2 CRS event: Limit the maximum dose increment to 100%. • Two or more Grade ^ 2 CRS events: Limit the maximum dose increment to 50%. • One DLT: Limit the maximum dose increment to 50%

[0160] The combination dose escalation stage (Part B) will be initiated based on emerging data from the monotherapy dose escalation and SMC recommendation. The dose escalation strategy for the Part B combination dose escalation will also follow the BOIN design as described for Part A.

[0161] For the Monotherapy Dose Expansion of 10 patients, the response estimate and both 90% and 80% exact confidence intervals will be calculated to provide an estimate of efficacy in this more defined population. Similarly, for the Combination Dose Expansion, 90% and 80% exact confidence intervals will be calculated, as will the subset of CRC patients in this group.

[0162] Table 13 provides guidance on the response rate at both 90% and 80% confidence intervals using the exact method. Table 13 also provides guidance on any subset of 10 patients such as the first 10 patients enrolled to combination dose expansion.

[0163] Table 14 provides guidance on the response rate at both 90% and 80% confidence intervals using the exact method for the Combination expansion cohort (N=30). Consideration for curtailing further enrollment may be given, if after the first 10 patients are evaluable, there are few responses. 7.3.3 Part C, Phase 2 Cohort Expansion

[0164] Once the monotherapy and combination therapy RP2D(s) are determined in Part A / B, the Phase 2 expansion cohort stage can be initiated. The statistical analyses for the Phase 2expansion will use Simon’s 2-stage design. In addition to testing the primary hypothesis on the ORR, all other analyses for the secondary objectives will be descriptive only with no hypothesis testing. 7.3.4 Safety Analyses

[0165] Safety evaluations will be based on the incidence, severity, attribution, and type of AEs, and changes in the patient’s vital signs and clinical laboratory results, summarized using the Safety Analysis Set. Summarization of toxicity data will focus on the incidence of TEAEs, defined as any AE that occurs on or after the date of the first dose of study medication through 90 days after the last dose of study medication (or until the start of a new anti-cancer treatment), any event that is considered study drug-related regardless of the start date of the event, or any event that is present at Baseline but worsens in intensity. The incidence of SAEs, AEs, study drug related AEs, and AEs leading to discontinuation or death will be presented in tabular form by system organ class and preferred term. AEs will be assessed for severity according to the NCI CTCAE, version 5.0. A presentation of DLTs among patients in the dose escalation portion will be presented. Other safety evaluations including vital signs and laboratory results will be summarized descriptive over time, to include changes from baseline. 7.3.5 Interim Analyses

[0166] No interim analysis is planned. However, as required for each disease expansion cohort under the Simon’s 2-stage design, a futility assessment will be carried out at the end of Stage 1 of the 2-stage design, which will be implemented for each of disease cohorts in Phase 2. This is not a formal interim analysis.hchacea eeslis hc,a01sfef S,. , . ya.at eetu r ef 71 0 1,D1,Dd3D1±X 2tDr)aylP( BnoX 1 D X X X X X X X 1 - ot8X X X X X X X X X X X X X 2 - 4Tnnoi t,yF,3Poitahg Ego T,TBs dnniieloF PCtul a Pmw d ta ,,O necsxlneac ax / th ettHRch mSo dig yN W(rel gier giecneH T:I:tsedayh ru otac eh idws G:s ts n te n ps,si isg g n CEbyrsietoitycm oiars arli gahc ryh nimdot nigdGias daltysisyldiaou olu naflreo inctim deecpll ulpmulOlat elt-efme ani rygaTn )TA g ylInIrc e nD MacucFniycSniCE iV21aShCrUhToCPa L eHrPnoslisalt ie atdeg dni gnmiitirtorfo5 fe 5leblabTae TeeSeSX X X;RoahX XerH= nu;s t TsSamTmil hgene ICopimuoX X X X Xrpm dta Ew =e rho eorR;sPcBs teylTk C lc adXbf e=o eO Pwyc noBdn WtE6 ;e neM ;yX Xe=rnmo uqdelitTeOve mes udni E; = robhu ehX X X X Xtsap Wlu g sncspo6rQnit OebXobG;e al .yltsmyor g miutmnoum holio ni ts11X Xsns tlcbdielDonias oi i nmorcy 1C sstrOor y C.1eseapevhtht n BXslsllaldit oer=ita t ar pH 2traPataaeviX X X X Xd tp=SoTT yaredoP;Dofme ca ; grm=Cnnsnno in oyaorTr itfrofTetsaede dnertr2X XerPe PPa; a i ctEm n=a S a=ts 2e.ne xReb blvGeeOlClll)i2 oyisug C ac S; iwwafneil s Eis tn do Dniir ; yfhno eve bmhv a irentosasoer ys ip g ti itada arp= e meilpnlorcid col wtci=goE sr piTLisetfto i on ne tdebnitmin ou ymnewe E ied P; ev mi m A: ra oid eDufaenisyka nmocge sgmI / psosesmt vta er na sc ttnora a Crsu:yhaur- lt etaadmr don hicr seb sa erl r r TStE ioiAmo ttacdeeoz ir n donado 03a-ih tu aP nmes p o oI ySc wmmmC du / e i lAmIeRas uTuTERtSE niA ovveei=laesCerrb= Bt 1m enihbGmr Eralcm yot ciACEonAS 1PCca 2W**A L Xsuo on mh olX oimtIWbcelloA D X X X C A eussiT X X X X X X X X X X X X dKnPadotost tld os sBe se5 p5 o1p5 o5p5nhnecam li so + s ± s1± es+ s1± esd ( rI) uo ( rI) uo (I ) od ( rI) u(I ) odrP T er ninini enio neaPOhEm3OhEm6OE mrPOhEm3OiEmrPeseyRg ay. Day y y yDaDa a a5yaniD D Dn 1 1 1 2 2 2elDee ele e e e eclcl l l lb rcyc c c cS&y y1 C8C5y1&y y5a C C1 C8C1TyaD 2elcX X XyCnodemrofrX X Xepebdluohsscsie#tispXeniokiobc raommra utht 1Pne0= m1Kt -SPaerN ,n t- Sroisn ofX XuOf ;InOIgfnionEe ehd enr yclt nfooX X X X X XEs=tffI a1y oOysadtE pDessao,soib 6e b5 p5eid ro lc er+(sI )r 1u±(eso obmyaC B selOnioh I )Onide itnutdtrpEm3 EmrPa hn agsemyra1 Prasay yur fDaDaDd-ry ooaf sbaw3 3 3+4itoele e e 1 nlaD 4emll lclycl l T a vielita fclleC&ycyc y1 C8C5y a1C DO= hEAcr cyIOo cDACL -A* #&E ** T^Table 6. Organ function criteriaTable 7. Study Treatment CohortsThe Phase 2 dose will be determined based on the data from the Phase 1 dose escalation and dose expansion portion of the study.Table 8. General Guidelines for Management of Treatment-Related TEAEsTable 9. Vital Signs for Monotherapy CohortsTable 10. Vital Signs for Combination CohortsTable 11. Laboratory Analytes35 91 yes8o1 4 7 9ohce74 7nansgo 1 9ciD ,seaDt63 6 Ca1 8MSN de5It3 6 8Oa 1meorrfBeT 43 6ss1 8 noih tt neriet 3ta 1 3 5 7adnd Pen fo 21 2 5 7 )8m 5 mUrgenbo123. ceim1 4 60rku ,aN 0 624 6 3n2oMe-v1 .0desnito a (i l9 2 4 5laabs u,ivr rc mu 8etoseC1 3 5ninDyntoipsoi7 1 3 5 liet bala ht,a6 1 3 4 bosc rTs pLE-5 1 2 4TDe LDDev / lan 4 0 2 3 ahoimi. stt t nal 3 0 2 3poyti eitac e cix aps2 0 1* hto 2E 2dte ngfs ani oto 1 0 1A t N03 iu. moDro ≤ ≥ ≥0i =l-2e,l .fteTcLT T^^soeveneinDLDLD^d^ =le taaf pdinofo fo ,euoi#t f #f# tT so efar Ldtrocie iieT D: semG.Ateata2l lta L now1l1acaescnsiDit ollolE emise aivehrnb-elEmaDuesrtta eoT sbAb ft AI*roTable 13Table 14EXAMPLE 2: RESULTS FROM PHASE 1 / 2 STUDY EVALUATING SNS-101 AS MONOTHERAPY AND IN COMBINATION WITH CEMIPLIMAB IN PATIENTS WITH ADVANCED SOLID TUMORS

[0167] Initial results were generated from a first in human, Phase 1 / 2 open label, multicenter, dose escalation / expansion study of SNS-101 + / - cemiplimab (cemi) in patients with advanced solid tumors with primary (unfavorable candidates for immunotherapy) or acquired PD-1 therapy resistance (progressed on prior anti-PD-1 therapy), and who have received and failed or were intolerant to standard of care for advanced disease or not candidates for standard of care therapy, with an ECOG 0 or 1. Enrolled patientsrepresented a broad range of tumor types to determine safety and tolerability as quickly as possible. SNS-101 + / - cemi was given as an IV infusion once every 3 weeks. Patients were not routinely prophylaxed for CRS.

[0168] Primary endpoints: Evaluate safety and tolerability of SNS-101 + / - cemi and establish MTD / RP2D. Secondary endpoints: Determine PK profile, assess immunogenicity and evaluate preliminary anti-tumor activity.

[0169] Dose escalation enrollment was completed with 16 patients in the monotherapy arm and 18 patients in the combination arm. Patients cleared all planned dosing cohorts of SNS-101 + / - cemi with no dose limiting toxicities (DLT) observed (see FIG. 2).

[0170] Enrolled patients in the monotherapy arm were: 75% males with median age of 61.5 (min 35, max 79), 88% white, 6% Asian, 6% not reported, and 63% with ECOG 1. Enrolled patients in the combination arm were: 61% males with median age of 62 (min 33, max 81), 77% white, 11% African American, 6% Asian, 6% not reported, and 78% with ECOG 1. Details are provided in Table 15. Table 15. Treatment history and cancer type of enrolled patients*Sarcoma: Leiomyosarcoma, Ewing Sarcoma, PEComa, hemangiopericytoma (mono) and leiomyosarcoma and desmoplastic small round cell (combo) **Other Tumor Types: Small cell lung carcinoma, gallbladder, adenocystic carcinoma maxillary sinus, and mediastinal carcinoma (mono) and ovarian, duodenal, granulosa cell tumor (germ cell)

[0171] Primary endpoints for safety and tolerability were achieved. SNS-101 monotherapy and in combination with cemi was well-tolerated with no dose-limiting toxicities observed (Table 16). Most common adverse events were: fatigue (n=5), cough (n=4), and rash maculo-papular, pleural effusion and pyrexia (n=3, each).

[0172] Monotherapy: 13 / 16 patients (81%) experienced at least one TEAE, majority of AEs being Grade 1 or 2. One patient experienced Grade 1 CRS at 15 mg / kg SNS-101.

[0173] Combination therapy: 14 / 18 patients (78%) experienced at least TEAE, with the majority of AEs Grade 1 or 2. One patient experienced Grade 1 CRS at 15 mg / kg SNS- 101 plus cemi. Four patients experienced immune-mediated events: • Grade 3 diabetic ketoacidosis at 3 mg / kg SNS-101 plus cemi • Grade 2 rash maculo-papular at 3 mg / kg SNS-101 plus cemi • Two patients with elevated liver enzymes both at 10 mg / kg SNS-101 + cemi (one with Grade 3 ALT / Grade 1 AST and one with Grade 3 ALT / AST)

[0174] No significant changes to key cytokine levels across all cohorts were observed (FIG. 3). Data were consistent with lack of observed CRS to date at all dose levels and with SNS-101 ex vivo whole blood analysis (Thisted et al. “SNS-101, a conditionally active anti-VISTA antibody, potentiates anti-tumor effects of PD1 blockade and displays favorable pharmacokinetic and cytokine release characteristics.” Keystone Symposia on Next Generation Antibody Therapeutics, Banff, Alberta, Canada, February 19-22, 2023).Table 16. Summary of adverse events*One patient experienced an SAE, Grade 5 bronchial obstruction, that resulted in death; related to disease progression, not to SNS-101 # One patient discontinued due to immune-mediated AEs of Grade 3 AST and ALT

[0175] Regarding secondary endpoints, pharmacologically favorable PK properties were observed. SNS-101 exhibited linear elimination profile of a monoclonal antibody consistent with lack of TMDD irrespective of combination with cemi (see FIG. 4A and FIG. 4B). Dose-proportional increases in exposure were observed. Results supported Q3W dosing.

[0176] Data for best overall change in size of tumor target lesions in subjects with at least one follow-up scan are shown in FIG. 5A (monotherapy) and FIG. 5B (combination therapy).

[0177] In monotherapy-treated patients: 7 patients achieved stable disease as best overall response. 2 patients have prolonged stable disease, currently on treatment out to 42+ weeks and 24+ weeks. One pembrolizumab-resistant HPV+ H&N patient at 15 mg / kg SNS-101 had tumor regression of 17%; discontinued at Week 12 due to progression of disease (PD).

[0178] In combination therapy-treated patients: 1 MSS endometrial patient at 3 mg / kg + cemi had confirmed PR (59% decrease); ongoing 30+ weeks. 1 MSS colon patient at 3 mg / kg + cemi had tumor regression of 27%; discontinued at Week 18 due to PD. 1 RCCpt at 10 mg / kg + cemi had tumor regression of 18%; discontinued due to immune-mediated toxicity.

[0179] Regarding exploratory endpoints, dose-dependent changes in specific T-cell populations indicated potential SNS-101-related pharmacological effect. Phenotypic shift of circulating (antigen experienced) effector T-cells toward increased peripheral homing and effector function (TEMRA) was observed (see FIG. 6A and FIG. 6B). CD8+ TEM cells were CD3+ / CD8+ / CCR7- / CD45RA-. CD8+ TEMRA cells were CD3+ / CD8+ / CCR7- / CD45RA+.

[0180] Time of objective response in relationship to duration of treatment and time of treatment cessation in subjects with at least one follow-up scan is shown in FIG.7.

[0181] Additional data for patient 01-005 were as follows: immuno-oncology (I / O)-naïve MSS Endometrial Cancer with PR. Patient was treated with 3.0 mg / kg SNS-101 + cemi. Patient is a 68-year-old female with endometrial carcinoma, diagnosed Dec 2020, ECOG 0. Patient was ER / PR positive, HER negative; PD-1 / PD-L1: not tested.

[0182] Prior Treatment / Surgery: Total laparoscopic hysterectomy with bilateral salpingo- oophorectomy, and additional sentinel lymph node dissection, Dec 2020. Paclitaxel / Carboplatin (adjuvant setting), Feb 2021 to Aug 2021. Anastrozole (metastatic setting), Aug 2023 to Sep 2023.

[0183] Adverse Events: Grade 3 diabetic ketoacidosis 4 days after Cycle 3 infusions, related to SNS-101 and cemi, AESI (immune-mediated) and SAE (hospitalization). Patient recovered and maintained on insulin and continued study therapy.

[0184] Tumor assessments are shown in FIG.8.

[0185] Additional data for patient 04-010 were as follows: I / O-naïve MSS Colon Cancer. Patient was treated with 3.0 mg / kg SNS-101 + cemi. Patient is a 62-year-old male with colon cancer; diagnosed Jan 2017, ECOG 1. PD-1 / PD-L1: Negative.

[0186] Prior Treatment / Surgery: Received 7 prior lines of therapy in the metastatic setting with the last 3 therapies investigational.

[0187] Adverse Events: Grade 2 dry skin, related to SNS-101, not related to cemi; Grade 2 rash maculo-papular, related to SNS-101 and cemi, AESI (immune-mediated), resolved after treatment with prednisone; Grade 2 pruritis, related to SNS-101 and cemi.

[0188] Tumor Assessments: 6-Week Scans: Stable Disease (19% decrease); 12-Week Scans: Stable Disease (27% decrease); 18-Week Scans: Progressive Disease (23% increase from nadir).

[0189] SNS-101 is a pH dependent VISTA targeting mAb that has demonstrated the following in a predominantly “cold” solid tumor patient population: • An absence of severe CRS at pharmacologically relevant dose levels. • An absence of TMDD and a half-life compatible with Q3W dosing. • Dose-dependent shift in circulating (antigen experienced) effector T-cells toward increased peripheral homing and effector function (TEMRA). • Both the monotherapy and SNS-101 + cemiplimab combination were well tolerated in a population of advanced, refractory solid tumors.

[0190] Preliminary signs of encouraging clinical activity in combination with cemiplimab in patients with microsatellite stable disease (CRC and endometrial) were observed.

[0191] SNS-101 has been well tolerated and effectively dosed ^ 10-fold higher than first- generation VISTA targeting antibodies.

[0192] Dose expansion cohorts are underway in both monotherapy and combination therapy. In the monotherapy dose expansion arm, up to 10 patients with MSS CRC at a dose level of 15 mg / kg are planned to be enrolled. In the combination dose expansion arm, up to 50 patients with MSS CRC, head and neck cancer (H&N), non-small cell lung cancer (NSCLC), and melanoma are planned to be enrolled at dose levels of 15 mg / kg SNS-101 + cemi or 3 mg / kg SNS-101 + cemi.

[0193] The solid tumor types were selected to focus the cancer indications on a basket of more commonly occurring histologies, including both “hot” (NSCLC, H&N, Melanoma) and “cold” (CRC) tumors where SNS-101 is believed to have potential to provide clinical benefit based on VISTA biology and supporting preclinical data. All patients with “hot” tumors enrolling into the expansion arm are expected to have been previously treated with a PD1 / L1 checkpoint inhibitor. NUMBERED EMBODIMENTS

[0194] Notwithstanding the appended claims, the disclosure sets forth the following numbered embodiments:

[0195] Embodiment 1. A method for ameliorating a symptom of a cancer in a subject in need thereof, the method comprising: administering to the subject an anti-V- domain immunoglobulin suppressor of T-cell activation (VISTA) antibody or an antigen- binding portion thereof, wherein the antibody or antigen-binding portion comprises a heavy chain variable (VH) region and a light chain variable (VL) region, wherein the VH region amino acid sequence comprises a heavy chain complementarity determining region 1 (HCDR1) comprising SEQ ID NO: 2, a heavy chain complementarity determining region 2 (HCDR2) comprising SEQ ID NO: 3 and a heavy chain complementarity determining region 3 (HCDR3) comprising SEQ ID NO: 4; and the VL region amino acid sequence comprises a light chain complementarity determining region 1 (LCDR1) comprising SEQ ID NO: 6, a light chain complementarity determining region 2 (LCDR2) comprising SEQ ID NO: 7 and a light chain complementarity determining region 3 (LCDR3) comprising SEQ ID NO: 8; wherein the antibody or antigen-binding portion is administered intravenously at a dose of about 0.3 mg / kg body weight, about 1.0 mg / kg body weight, about 3.0 mg / kg body weight, about 10 mg / kg body weight, or about 15 mg / kg body weight.

[0196] Embodiment 2. The method of embodiment 1, wherein the symptom of cancer is fatigue, pain, weight loss, or loss of appetite.

[0197] Embodiment 3. A method for reducing tumor burden in a subject in need thereof, the method comprising: administering to the subject an anti-VISTA antibody or an antigen-binding portion thereof, wherein the antibody or antigen-binding portion comprises a VH region and a VL region, wherein the VH region amino acid sequence comprises a HCDR1 comprising SEQ ID NO: 2, a HCDR2 comprising SEQ ID NO: 3 and a HCDR3 comprising SEQ ID NO: 4; and the VL region amino acid sequence comprises a LCDR1 comprising SEQ ID NO: 6, a LCDR2 comprising SEQ ID NO: 7 and a LCDR3 comprising SEQ ID NO: 8; wherein the antibody or antigen-binding portion is administered intravenously at a dose of about 0.3 mg / kg body weight, about 1.0 mg / kg body weight, about 3.0 mg / kg body weight, about 10 mg / kg body weight, or about 15 mg / kg body weight; and wherein the tumor burden is reduced compared to a baseline tumor burden measured before initial administration of the antibody or antigen-binding portion.

[0198] Embodiment 4. The method of embodiment 3, wherein the baseline tumor burden is measured not more than 4 weeks before initial administration of the antibody or antigen-binding portion.

[0199] Embodiment 5. A method for reducing size of a tumor in a subject in need thereof, the method comprising: administering to the subject an anti-VISTA antibody or an antigen-binding portion thereof, wherein the antibody or antigen-binding portion comprises a VH region and a VL region, wherein the VH region amino acid sequence comprises a HCDR1 comprising SEQ ID NO: 2, a HCDR2 comprising SEQ ID NO: 3 and a HCDR3 comprising SEQ ID NO: 4; and the VL region amino acid sequence comprises a LCDR1 comprising SEQ ID NO: 6, a LCDR2 comprising SEQ ID NO: 7 and a LCDR3 comprising SEQ ID NO: 8; wherein the antibody or antigen-binding portion is administered intravenously at a dose of about 0.3 mg / kg body weight, about 1.0 mg / kg body weight, about 3.0 mg / kg body weight, about 10 mg / kg body weight, or about 15 mg / kg body weight; and wherein the size of the tumor is reduced compared to the baseline size of the tumor measured before initial administration of the antibody or antigen-binding portion.

[0200] Embodiment 6. The method of embodiment 5, wherein the baseline size of the tumor is measured not more than 4 weeks before initial administration of the antibody or antigen-binding portion.

[0201] Embodiment 7. A method for treating cancer in a subject in need thereof, the method comprising: administering to the subject an anti-VISTA antibody or an antigen- binding portion thereof, wherein the antibody or antigen-binding portion comprises a VH region and a VL region, wherein the VH region amino acid sequence comprises a HCDR1 comprising SEQ ID NO: 2, a HCDR2 comprising SEQ ID NO: 3 and a HCDR3 comprising SEQ ID NO: 4; and the VL region amino acid sequence comprises a LCDR1 comprising SEQ ID NO: 6, a LCDR2 comprising SEQ ID NO: 7 and a LCDR3 comprising SEQ ID NO: 8; wherein the antibody or antigen-binding portion is administered intravenously at a dose of about 0.3 mg / kg body weight, about 1.0 mg / kg body weight, about 3.0 mg / kg body weight, about 10 mg / kg body weight, or about 15 mg / kg body weight.

[0202] Embodiment 8. A method for inducing an immune response against cancer cells in a subject in need thereof, the method comprising: administering to the subject ananti-VISTA antibody or an antigen-binding portion thereof, wherein the antibody or antigen-binding portion comprises a VH region and a VL region, wherein the VH region amino acid sequence comprises a HCDR1 comprising SEQ ID NO: 2, a HCDR2 comprising SEQ ID NO: 3 and a HCDR3 comprising SEQ ID NO: 4; and the VL region amino acid sequence comprises a LCDR1 comprising SEQ ID NO: 6, a LCDR2 comprising SEQ ID NO: 7 and a LCDR3 comprising SEQ ID NO: 8; wherein the antibody or antigen- binding portion is administered intravenously at a dose of about 0.3 mg / kg body weight, about 1.0 mg / kg body weight, about 3.0 mg / kg body weight, about 10 mg / kg body weight, or about 15 mg / kg body weight.

[0203] Embodiment 9. The method of embodiment 8, wherein the immune response is antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity or antibody-dependent cellular phagocytosis.

[0204] Embodiment 10. The method of any one of embodiments 1-9, wherein the VH region amino acid sequence comprises SEQ ID NO: 1, and the VL region amino acid sequence comprises SEQ ID NO: 5.

[0205] Embodiment 11. The method of any one of embodiments 1-10, wherein the anti-VISTA antibody or antigen-binding portion comprises a human IgG1 constant region.

[0206] Embodiment 12. The method of any one of embodiments 1-11, wherein the anti-VISTA antibody or antigen-binding portion is formulated in 20 mM histidine, 50 mM sodium chloride, 180 mM sucrose, and 0.02% (w / v) polysorbate 80 at pH 6.0.

[0207] Embodiment 13. The method of any one of embodiments 1-12, wherein the subject has a locally advanced, unresectable, or metastatic solid tumor.

[0208] Embodiment 14. The method of any one of embodiments 1-13, wherein the subject has head and neck cancer, breast cancer, colon cancer, pancreatic cancer, gastric cancer, esophageal cancer, gallbladder cancer, prostate cancer, uterine cancer, cervical cancer, endometrial cancer, ovarian cancer, kidney cancer, bladder cancer, thyroid cancer, lung cancer, melanoma, or sarcoma.

[0209] Embodiment 15. The method of embodiment 14, wherein the kidney cancer is renal cell carcinoma (RCC).

[0210] Embodiment 16. The method of embodiment 14, wherein the endometrial cancer is microsatellite stable (MSS) endometrial cancer.

[0211] Embodiment 17. The method of embodiment 14, wherein the head and neck cancer is human papilloma (HPV)-positive head and neck cancer.

[0212] Embodiment 18. The method of any one of embodiments 1-17, wherein the anti-VISTA antibody or antigen-binding portion is administered to the subject once every 3 weeks.

[0213] Embodiment 19. The method of any one of embodiments 1-18, wherein the anti-VISTA antibody or antigen-binding portion is administered to the subject as a monotherapy.

[0214] Embodiment 20. The method of embodiment 19, wherein the subject has MSS colorectal cancer (CRC), and wherein the anti-VISTA antibody or antigen-binding portion is administered intravenously at a dose of about 15 mg / kg body weight.

[0215] Embodiment 21. The method of any one of embodiments 1-18, wherein the anti-VISTA antibody or antigen-binding portion is administered to the subject as a combination therapy.

[0216] Embodiment 22. The method of embodiment 21, wherein the subject has MSS CRC, head and neck cancer, non-small cell lung cancer (NSCLC), or melanoma.

[0217] Embodiment 23. The method of embodiment 21, wherein the anti-VISTA antibody or antigen-binding portion is administered to the subject in combination with an anti-PD-1 antibody or antigen-binding portion thereof.

[0218] Embodiment 24. The method of embodiment 23, wherein the anti-PD-1 antibody is cemiplimab.

[0219] Embodiment 25. The method of embodiment 24, wherein the cemiplimab is administered to the subject intravenously at a dose of about 350 mg.

[0220] Embodiment 26. The method of embodiment 24, wherein the anti-VISTA antibody or antigen-binding portion is administered intravenously at a dose of about 15 mg / kg body weight, and the cemiplimab is administered to the subject intravenously at a dose of about 350 mg.

[0221] Embodiment 27. The method of embodiment 24, wherein the anti-VISTA antibody or antigen-binding portion is administered intravenously at a dose of about 10 mg / kg body weight, and the cemiplimab is administered to the subject intravenously at a dose of about 350 mg.

[0222] Embodiment 28. The method of embodiment 24, wherein the anti-VISTA antibody or antigen-binding portion is administered intravenously at a dose of about 3 mg / kg body weight, and the cemiplimab is administered to the subject intravenously at a dose of about 350 mg.

[0223] Embodiment 29. The method of any one of embodiments 24-28, wherein the anti-VISTA antibody or antigen-binding portion and the cemiplimab are administered to the subject in the following order: (i) the anti-VISTA antibody or antigen-binding portion is administered on cycle 1, day 1; (ii) the cemiplimab is administered on cycle 1, day 2; and (iii) the anti-VISTA antibody or antigen-binding portion and the cemiplimab are administered on the same day of each cycle following cycle 1, and the anti-VISTA antibody or antigen-binding portion is administered before the cemiplimab.

[0224] Embodiment 30. The method of any one of embodiments 1-29, wherein the subject had previously been treated with a cancer therapy other than an anti-VISTA antibody or antigen-binding portion.

[0225] Embodiment 31. A pharmaceutical composition comprising an anti-VISTA antibody or an antigen-binding portion thereof, wherein the antibody or antigen-binding portion comprises a VH region and a VL region, wherein the VH region amino acid sequence comprises a HCDR1 comprising SEQ ID NO: 2, a HCDR2 comprising SEQ ID NO: 3 and a HCDR3 comprising SEQ ID NO: 4; and the VL region amino acid sequence comprises a LCDR1 comprising SEQ ID NO: 6, a LCDR2 comprising SEQ ID NO: 7 and a LCDR3 comprising SEQ ID NO: 8; about 20 mM histidine; about 50 mM sodium chloride; about 180 mM sucrose; and about 0.02% (w / v) polysorbate 80 at pH 6.0.

[0226] Embodiment 32. The pharmaceutical composition of embodiment 31, wherein the VH region amino acid sequence comprises SEQ ID NO: 1, and the VL region amino acid sequence comprises SEQ ID NO: 5.

[0227] Embodiment 33. The pharmaceutical composition of embodiment 31 or 32, wherein the anti-VISTA antibody or antigen-binding portion comprises a human IgG1 constant region.

Claims

CLAIMS 1. A method for ameliorating a symptom of a cancer in a subject in need thereof, the method comprising: administering to the subject an anti-V-domain immunoglobulin suppressor of T- cell activation (VISTA) antibody or an antigen-binding portion thereof, wherein the antibody or antigen-binding portion comprises a heavy chain variable (VH) region and a light chain variable (VL) region, wherein the VH region amino acid sequence comprises a heavy chain complementarity determining region 1 (HCDR1) comprising SEQ ID NO: 2, a heavy chain complementarity determining region 2 (HCDR2) comprising SEQ ID NO: 3 and a heavy chain complementarity determining region 3 (HCDR3) comprising SEQ ID NO: 4; and the VL region amino acid sequence comprises a light chain complementarity determining region 1 (LCDR1) comprising SEQ ID NO: 6, a light chain complementarity determining region 2 (LCDR2) comprising SEQ ID NO: 7 and a light chain complementarity determining region 3 (LCDR3) comprising SEQ ID NO: 8; wherein the antibody or antigen-binding portion is administered intravenously at a dose of about 0.3 mg / kg body weight, about 1.0 mg / kg body weight, about 3.0 mg / kg body weight, about 10 mg / kg body weight, or about 15 mg / kg body weight.

2. The method of claim 1, wherein the symptom of cancer is fatigue, pain, weight loss, or loss of appetite.

3. A method for reducing tumor burden in a subject in need thereof, the method comprising: administering to the subject an anti-VISTA antibody or an antigen-binding portion thereof, wherein the antibody or antigen-binding portion comprises a VH region and a VL region, wherein the VH region amino acid sequence comprises a HCDR1 comprising SEQ ID NO: 2, a HCDR2 comprising SEQ ID NO: 3 and a HCDR3 comprising SEQ ID NO: 4; and the VL region amino acid sequence comprises a LCDR1 comprising SEQ ID NO: 6, a LCDR2 comprising SEQ ID NO: 7 and a LCDR3 comprising SEQ ID NO: 8;wherein the antibody or antigen-binding portion is administered intravenously at a dose of about 0.3 mg / kg body weight, about 1.0 mg / kg body weight, about 3.0 mg / kg body weight, about 10 mg / kg body weight, or about 15 mg / kg body weight; and wherein the tumor burden is reduced compared to a baseline tumor burden measured before initial administration of the antibody or antigen-binding portion.

4. The method of claim 3, wherein the baseline tumor burden is measured not more than 4 weeks before initial administration of the antibody or antigen-binding portion.

5. A method for reducing size of a tumor in a subject in need thereof, the method comprising: administering to the subject an anti-VISTA antibody or an antigen-binding portion thereof, wherein the antibody or antigen-binding portion comprises a VH region and a VL region, wherein the VH region amino acid sequence comprises a HCDR1 comprising SEQ ID NO: 2, a HCDR2 comprising SEQ ID NO: 3 and a HCDR3 comprising SEQ ID NO: 4; and the VL region amino acid sequence comprises a LCDR1 comprising SEQ ID NO: 6, a LCDR2 comprising SEQ ID NO: 7 and a LCDR3 comprising SEQ ID NO: 8; wherein the antibody or antigen-binding portion is administered intravenously at a dose of about 0.3 mg / kg body weight, about 1.0 mg / kg body weight, about 3.0 mg / kg body weight, about 10 mg / kg body weight, or about 15 mg / kg body weight; and wherein the size of the tumor is reduced compared to the baseline size of the tumor measured before initial administration of the antibody or antigen-binding portion.

6. The method of claim 5, wherein the baseline size of the tumor is measured not more than 4 weeks before initial administration of the antibody or antigen-binding portion.

7. A method for treating cancer in a subject in need thereof, the method comprising: administering to the subject an anti-VISTA antibody or an antigen-binding portion thereof, wherein the antibody or antigen-binding portion comprises a VH region and a VL region, wherein the VH region amino acid sequence comprises a HCDR1 comprising SEQ ID NO: 2, a HCDR2 comprising SEQ ID NO: 3 and a HCDR3 comprising SEQ ID NO: 4;and the VL region amino acid sequence comprises a LCDR1 comprising SEQ ID NO: 6, a LCDR2 comprising SEQ ID NO: 7 and a LCDR3 comprising SEQ ID NO: 8; wherein the antibody or antigen-binding portion is administered intravenously at a dose of about 0.3 mg / kg body weight, about 1.0 mg / kg body weight, about 3.0 mg / kg body weight, about 10 mg / kg body weight, or about 15 mg / kg body weight.

8. A method for inducing an immune response against cancer cells in a subject in need thereof, the method comprising: administering to the subject an anti-VISTA antibody or an antigen-binding portion thereof, wherein the antibody or antigen-binding portion comprises a VH region and a VL region, wherein the VH region amino acid sequence comprises a HCDR1 comprising SEQ ID NO: 2, a HCDR2 comprising SEQ ID NO: 3 and a HCDR3 comprising SEQ ID NO: 4; and the VL region amino acid sequence comprises a LCDR1 comprising SEQ ID NO: 6, a LCDR2 comprising SEQ ID NO: 7 and a LCDR3 comprising SEQ ID NO: 8; wherein the antibody or antigen-binding portion is administered intravenously at a dose of about 0.3 mg / kg body weight, about 1.0 mg / kg body weight, about 3.0 mg / kg body weight, about 10 mg / kg body weight, or about 15 mg / kg body weight.

9. The method of claim 8, wherein the immune response is antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity or antibody-dependent cellular phagocytosis.

10. The method of any one of claims 1-9, wherein the VH region amino acid sequence comprises SEQ ID NO: 1, and the VL region amino acid sequence comprises SEQ ID NO:

5.

11. The method of any one of claims 1-10, wherein the anti-VISTA antibody or antigen-binding portion comprises a human IgG1 constant region.

12. The method of any one of claims 1-11, wherein the anti-VISTA antibody or antigen-binding portion is formulated in 20 mM histidine, 50 mM sodium chloride, 180 mM sucrose, and 0.02% (w / v) polysorbate 80 at pH 6.

0.

13. The method of any one of claims 1-12, wherein the subject has a locally advanced, unresectable, or metastatic solid tumor.

14. The method of any one of claims 1-13, wherein the subject has head and neck cancer, breast cancer, colon cancer, pancreatic cancer, gastric cancer, esophageal cancer, gallbladder cancer, prostate cancer, uterine cancer, cervical cancer, endometrial cancer, ovarian cancer, kidney cancer, bladder cancer, thyroid cancer, lung cancer, melanoma, or sarcoma.

15. The method of claim 14, wherein the kidney cancer is renal cell carcinoma (RCC).

16. The method of claim 14, wherein the endometrial cancer is microsatellite stable (MSS) endometrial cancer.

17. The method of claim 14, wherein the head and neck cancer is human papilloma (HPV)-positive head and neck cancer.

18. The method of any one of claims 1-17, wherein the anti-VISTA antibody or antigen-binding portion is administered to the subject once every 3 weeks.

19. The method of any one of claims 1-18, wherein the anti-VISTA antibody or antigen-binding portion is administered to the subject as a monotherapy.

20. The method of claim 19, wherein the subject has MSS colorectal cancer (CRC), and wherein the anti-VISTA antibody or antigen-binding portion is administered intravenously at a dose of about 15 mg / kg body weight.

21. The method of any one of claims 1-18, wherein the anti-VISTA antibody or antigen-binding portion is administered to the subject as a combination therapy.

22. The method of claim 21, wherein the subject has MSS CRC, head and neck cancer, non-small cell lung cancer (NSCLC), or melanoma.

23. The method of claim 21, wherein the anti-VISTA antibody or antigen-binding portion is administered to the subject in combination with an anti-PD-1 antibody or antigen-binding portion thereof.

24. The method of claim 23, wherein the anti-PD-1 antibody is cemiplimab.

25. The method of claim 24, wherein the cemiplimab is administered to the subject intravenously at a dose of about 350 mg.

26. The method of claim 24, wherein the anti-VISTA antibody or antigen-binding portion is administered intravenously at a dose of about 15 mg / kg body weight, and the cemiplimab is administered to the subject intravenously at a dose of about 350 mg.

27. The method of claim 24, wherein the anti-VISTA antibody or antigen-binding portion is administered intravenously at a dose of about 10 mg / kg body weight, and the cemiplimab is administered to the subject intravenously at a dose of about 350 mg.

28. The method of claim 24, wherein the anti-VISTA antibody or antigen-binding portion is administered intravenously at a dose of about 3 mg / kg body weight, and the cemiplimab is administered to the subject intravenously at a dose of about 350 mg.

29. The method of any one of claims 24-28, wherein the anti-VISTA antibody or antigen-binding portion and the cemiplimab are administered to the subject in the following order:(i) the anti-VISTA antibody or antigen-binding portion is administered on cycle 1, day 1; (ii) the cemiplimab is administered on cycle 1, day 2; and (iii) the anti-VISTA antibody or antigen-binding portion and the cemiplimab are administered on the same day of each cycle following cycle 1, and the anti-VISTA antibody or antigen-binding portion is administered before the cemiplimab.

30. The method of any one of claims 1-29, wherein the subject had previously been treated with a cancer therapy other than an anti-VISTA antibody or antigen-binding portion.

31. A pharmaceutical composition comprising an anti-VISTA antibody or an antigen- binding portion thereof, wherein the antibody or antigen-binding portion comprises a VH region and a VL region, wherein the VH region amino acid sequence comprises a HCDR1 comprising SEQ ID NO: 2, a HCDR2 comprising SEQ ID NO: 3 and a HCDR3 comprising SEQ ID NO: 4; and the VL region amino acid sequence comprises a LCDR1 comprising SEQ ID NO: 6, a LCDR2 comprising SEQ ID NO: 7 and a LCDR3 comprising SEQ ID NO: 8; about 20 mM histidine; about 50 mM sodium chloride; about 180 mM sucrose; and about 0.02% (w / v) polysorbate 80 at pH 6.

0.

32. The pharmaceutical composition of claim 31, wherein the VH region amino acid sequence comprises SEQ ID NO: 1, and the VL region amino acid sequence comprises SEQ ID NO:

5.

33. The pharmaceutical composition of claim 31 or 32, wherein the anti-VISTA antibody or antigen-binding portion comprises a human IgG1 constant region.

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