Combination therapy involving Anti-HLA-g antibodies and Anti- EGFR antibodies or Anti-PD-1 antibodies

Abstract

Disclosed are methods for treating a subject suffering from cancer by administering to the subject an anti human HLA-G antibody in combination with an anti EGFR or an anti PD- 1 therapy.

Description

COMBINATION THERAPY INVOLVING ANTLHLA-G ANTIBODIES AND ANTLEGFR ANTIBODIES AND ANTLPD-1 ANTIBODIES1. CROSS-REFERENCES AND RELATED APPLICATIONS

[0001] This application claims benefit of and priority to U.S. Provisional Application No. 63 / 650,730 filed May 22, 2024 and U.S. Provisional Application No. 63 / 751,079 filed January 29, 2025, the disclosure of each is incorporated herein by reference in its entirety.2. SEQUENCE LISTING

[0002] The instant application contains a Sequence Listing which has been submitted electronically in XML format compliant with WIPO Standard ST.26 and is hereby incorporated by reference in its entirety. Said XML copy, created on May 20, 2025, is named 144381- 0170_SL.xml and is 52,453 bytes in size.3. FIELD

[0003] Provided herein are combination therapies involving antibodies with binding specificity for HLA-G, antibodies with binding specificity for EGFR, and antibodies with binding specificity for PD-1.4. BACKGROUND

[0004] HLA-G histocompatibility antigen, class I, G, also known as human leukocyte antigen G (HLA-G), is a protein that in humans is encoded by the HLA-G gene. HLA-G belongs to the HLA nonclassical class I heavy chain paralogues. HLA-G is a heterodimer consisting of a heavy chain and a light chain (beta-2 microglobulin). There are membrane bound and soluble forms of HLA-G.

[0005] HLA-G is normally expressed at the maternal-fetal interface and other immune- privileged sites. HLA-G plays a role in immune tolerance in pregnancy, being expressed in the placenta by extravillous trophoblast cells, while the classical MHC class I genes (HLA-A and HLA-B) are not. As HLA-G was first identified in placenta samples, many studies have evaluated its role in pregnancy disorders, such as preeclampsia and recurrent pregnancy loss. See, Michita, Rafael Tomoyaet al., Human Immunology. 2016, 77 (10): 892-897, which is incorporated by reference herein in its entirety, including any drawings.

[0006] HLA-G has been shown to be immune-suppressive. By binding receptors expressed on various myeloid and lymphoid cells, HLA-G may directly inhibit the functions of NK cells, cytotoxic T-lymphocytes, B cells, neutrophils, monocytes, macrophages, and dendritic cells. HLA-G also inhibits T and NK cell proliferation and cytolytic activities.HLA-G suppresses phagocytosis and induces the generation or expansion of regulatory T cells.

[0007] HLA-G mediates immune function through at least three ITIM-containing inhibitory receptors, ILT2, ILT4, and KIR2DL4. On lymphoid and myeloid cells, for example, HLA-G mediates function through ILT2. On myeloid cells, HLA-G mediates function through ILT4. On decidual NK cells, HLA-G mediates immune function through KIR2DL4 and ILT2.

[0008] HLA-G is an immune checkpoint target. HLA-G can directly inhibit immune cell function through receptor binding and / or trogocytosis and impairment of chemotaxis. HLA- G can lend tumor cells a higher invasive and metastatic potential. HLA-G promotes evasion of tumor immune surveillance and enhances metastasis and the progression of malignancies. During tumor progression HLA-G has other effects, such as inhibition of immune cell cytolysis, induction of immune cell apoptosis, and / or the generation of regulatory cells through receptor binding and / or trogocytosis.

[0009] HLA-G expression is upregulated on a broad spectrum of tumors and is associated with poor prognosis and disease progression. Serum HLA-G levels are elevated in breast, lung, colorectal, gastric, esophageal, neuroblastoma, cervical, and hematological cancers. HLA-G has also been found to be correlated with clinical parameters in advanced disease, such as tumor metastasis, poor prognosis, immune escape, and tumor invasiveness.

[0010] The epidermal growth factor receptor (EGFR; ErbB-1; HER1 in humans) is a transmembrane protein that is a receptor for members of the epidermal growth factor family (EGF family) of extracellular protein ligands. The epidermal growth factor receptor is a member of the ErbB family of receptors, a subfamily of four closely related receptor tyrosine kinases: EGFR (ErbB-1), HER2 / neu (ErbB-2), Her 3 (ErbB-3), and Her 4 (ErbB-4). In many cancer types, mutations affecting EGFR expression or activity could result in more progressive cancer. Deficient signaling of the EGFR and other receptor tyrosine kinases in humans is associated with diseases such as Alzheimer's, while over-expression is associated with the development of a wide variety of tumors. Interruption of EGFR signaling, either by blocking EGFR binding sites on the extracellular domain of the receptor or by inhibiting intracellular tyrosine kinase activity, can prevent the growth of EGFR-expressing tumors and improve the patient's condition.

[0011] EGFR is a transmembrane protein that is activated by binding of its specific ligands, including epidermal growth factor and transforming growth factor a (TGFa). ErbB2 has no known direct activating ligand and may be in an activated state constitutively orbecome active upon heterodimerization with other family members such as EGFR. Upon activation by its growth factor ligands, EGFR undergoes a transition from an inactive monomeric form to an active homodimer.

[0012] EGFR dimerization stimulates its intrinsic intracellular protein-tyrosine kinase activity. As a result, autophosphorylation of several tyrosine (Y) residues in the C-terminal domain of EGFR occurs. These include Y992, Y1045, Y1068, Y1148, and Y1173.Autophosphorylation elicits downstream activation and signaling by several other proteins that associate with the phosphorylated tyrosines through their own phosphotyrosine-binding SH2 domains. These downstream signaling proteins initiate several signal transduction cascades, principally the MAPK, Akt, and JNK pathways, leading to DNA synthesis and cell proliferation. Such proteins modulate phenotypes such as cell migration, adhesion, and proliferation. The kinase domain of EGFR can also cross-phosphorylate tyrosine residues of other receptors it is aggregated with and can itself be activated in that manner.

[0013] Mutations that lead to EGFR overexpression (known as upregulation or amplification) have been associated with a number of cancers, including adenocarcinoma of the lung (40% of cases), anal cancers, glioblastoma (50%), and epithelial tumors of the head and neck (80-100%). These somatic mutations involving EGFR led to its constant activation, which produces uncontrolled cell division. In glioblastoma a specific mutation of EGFR, called EGFRvIII, is often observed. Mutations, amplifications, or misregulations of EGFR or family members are implicated in about 30% of all epithelial cancer.

[0014] Programmed death protein 1 (PD-1; CD279), encoded by the PDCD1 gene in humans, is a transmembrane protein consisting of 288 amino acids. PD-1 is an immune checkpoint receptor primarily expressed on activated T cells (particularly exhausted or chronically activated T cells), B cells, and NK cells. PD-1 interacts with two ligands: programmed death-ligand 1 (PD-L1) and programmed death-ligand 2 (PD-L2), which are members of the B7 family

[0015] PD-1 is an inhibitory receptor that is activated upon binding to its ligands, PD-L1 or PD-L2. PD-L1 is the primary ligand and is often expressed on the surface of tumor cells, tumor-associated macrophages, dendritic cells, and other cells within the tumor microenvironment. High PD-L1 expression is often correlated with poor prognosis in various cancers, including non-small cell lung cancer, melanoma, renal cell carcinoma, and head and neck cancers.

[0016] PD-1 plays a critical role in regulating immune responses. The PD-1 / PD-L1 interaction helps prevent T cell overactivation and maintains immune tolerance. It ishypothesized that cancer cells can exploit the PD-1 / PD-L1 axis to evade immune detection and destruction, contributing to unchecked tumor growth and metastasis.

[0017] Combination therapies involving antibodies with binding specificity for HLA-G and antibodies with binding specificity for EGFR are needed. Combination therapies involving antibodies with binding specificity for HLA-G and antibodies with binding specificity for PD-1 are also needed.5. SUMMARY

[0018] Provided herein are methods and pharmaceutical compositions for treatment of a subject suffering from cancer comprising an antibody which binds to HLA-G and an antibody which binds to EGFR. Provided herein are also methods and pharmaceutical compositions for treatment of a subject suffering from cancer comprising an antibody which binds to HLA- G and an antibody which binds to PD-1. In some embodiments, a method provided herein comprises administering to a subject: a) an antibody which binds to HLA-G; and b) optionally administering a subsequent dose of the antibody which binds to HLA-G. In some embodiments, the administration of the antibody which binds to HLA-G maintains serum drug concentrations above a target trough of about 50 pg / mL.

[0019] A first aspect provides a method for treatment of a subject suffering from cancer, comprising administering to the subject: a) an antibody which binds to HLA-G; b) optionally administering a subsequent dose of the antibody which binds to HLA-G; and c) an antibody which binds to an epidermal growth factor receptor (EGFR); wherein the administration of the antibody which binds to HLA-G maintains serum drug concentrations above a target trough of about 50 pg / mL.

[0020] A second aspect provides a method of treating colorectal cancer (CRC), the method comprising administering a therapeutically effective amount of an antibody which binds to HLA-G in combination with a therapeutically effective amount of an antibody which binds to an epidermal growth factor receptor (EGFR) to a human subject having or identified as having CRC. In some embodiments, the CRC tumor is characterized as having wild-type KRAS, wild-type RAS, wild-type BRAF, and / or as HER2-negative

[0021] A third aspect provides a method of treating head and neck squamous cell carcinoma (HNSCC), the method comprising administering a therapeutically effective amount of an antibody which binds to HLA-G in combination with a therapeutically effective amount of an antibody which binds to an epidermal growth factor receptor (EGFR) to ahuman subject having or identified as having HNSCC. In some embodiments, the HNSCC tumor is characterized as human papilloma virus (HPV) negative.

[0022] A fourth aspect provides a method of treating a head and neck squamous cell carcinoma (HNSCC) tumor that is characterized as human papilloma virus (HPV) negative, the method comprising administering a therapeutically effective amount of an antibody which binds to HLA-G in combination with a therapeutically effective amount of an antibody which binds to an epidermal growth factor receptor (EGFR), to a human subject having or identified as having HNSCC, the method comprising the steps of(a) determining whether the tumor tissue exhibits HPV markers, wherein a tumor exhibiting HPV markers is characterized as HPV-positive and a tumor not exhibiting HPV markers is characterized as HPV-negative;(b) if the tumor is characterized as HPV-positive, excluding the subject from treatment; and(c) if the tumor is characterized as HPV-negative, selecting the subject for treatment and administering to the subject having the HNSCC a therapeutically effective amount of an antibody which binds to HLA-G in combination with a therapeutically effective amount of an antibody which binds to an epidermal growth factor receptor (EGFR).

[0023] A fifth aspect provides a method for treating a subject suffering from cancer, comprising administering to the subject one or more cycles of dosing, wherein in a first cycle:(a) a first dose comprising an effective amount of an antibody which binds toHLA-G;(b) a first dose comprising an effective amount of an antibody which binds to epidermal growth factor receptor (EGFR)(i) at 400 mg / m2, or(ii) at 500 mg / m2; and / or(c) a first dose comprising leucovorin, fluorouracil (5-FU) and irinotecan (FOLFIRI), wherein the administration of the antibody which binds to HLA-G maintains serum drug concentrations at a target trough level of between about 10-100 pg / mL.

[0024] A sixth aspect provides a method for treatment of a subject suffering from cancer, comprising administering to the subject one or more cycles of dosing, wherein in a first cycle:(a) a first dose comprising an effective amount of an antibody which binds toHLA-G; and(b) a first dose comprising an effective amount of an antibody which binds to programmed cell death protein 1 (PD-1).

[0025] In some embodiments, the antibody which binds to HLA-G comprises or consists of a heavy chain variable region (VH) and a light chain variable region (VL), with VH and / or VL comprising:(i) a VHCDR1 having the sequence set forth in SEQ ID NO: 1 or SEQ ID NO:11,(ii) a VHCDR2 having the sequence set forth in SEQ ID NO: 21 or SEQ ID NO:31,(iii) a VHCDR3 having the sequence set forth in SEQ ID NO: 41,(iv) a VLCDR1 having the sequence set forth in SEQ ID NO: 51,(v) a VLCDR2 having the sequence set forth in SEQ ID NO: 61, and(vi) a VLCDR3 having the sequence set forth in SEQ ID NO: 71.

[0026] In some embodiments, the antibody which binds to an epidermal growth factor receptor (EGFR) comprises or consists of a heavy chain variable region (VH) and a light chain variable region (VL), VH and / or VL comprising:(i) a VHCDR1 having the sequence set forth in SEQ ID NO: 9 or SEQ ID NO:19,(ii) a VHCDR2 having the sequence set forth in SEQ ID NO: 29 or SEQ ID NO:39,(iii) a VHCDR3 having the sequence set forth in SEQ ID NO: SEQ ID NO: 49,(iv) a VLCDR1 having the sequence set forth in SEQ ID NO: SEQ ID NO: 59,(v) a VLCDR2 having the sequence set forth in SEQ ID NO: SEQ NO: 69, and(vi) a VLCDR3 having the sequence set forth in SEQ ID NO: 79.

[0027] In some embodiments,(i) the antibody which binds to HLA-G comprises or consists of a heavy chain variable region (VH) and a light chain variable region (VL), with the VH comprising, consisting of, or consisting essentially of a VH having the sequence set forth in SEQ ID NO: 81 and with the VL comprising, consisting of, or consisting essentially of a VL having the sequence set forth in SEQ ID NO: 91 or(ii) the antibody which binds to HLA-G comprises or consists of a heavy chain (HC) and a light chain (LC), the HC comprising, consisting of, or consisting essentially of a sequence set forth in SEQ ID NO: 101 or SEQ ID NO: 102 and of a LC comprising, consisting of, or consisting essentially of a sequence set forth in SEQ ID NO: 111 and(iii) the antibody which binds to an epidermal growth factor receptor (EGFR) comprises or consists of a heavy chain variable region (VH) and a light chain variable region (VL), the VH and / or VL comprising, consisting of, or consisting essentially of a VH having the sequence set forth in SEQ ID NO: 89 and of a VL comprising, consisting of, or consisting essentially of a VL having the sequence set forth in SEQ ID NO: 99 or(iv) the antibody which binds to EFGR comprises or consists of a heavy chain (HC) and a light chain (LC), the HC comprising, consisting of, or consisting essentially of a sequence set forth in SEQ ID NO: 109 and the LC comprising, consisting of, or consisting essentially of a sequence set forth in SEQ ID NO: 119.

[0028] Any cancer can be treated according to the methods set forth herein. In some embodiments, the cancer is Head and Neck Squamous Cell Carcinoma (HNSCC). In some embodiments, the cancer is colorectal cancer (CRC). In some embodiments, the cancer is triple negative breast cancer (TNBC). In some embodiments, the cancer is renal cell carcinoma (RCC). In some embodiments, the cancer is non-small cell lung cancer (NSCLC). In some embodiments, the cancer is acral melanoma (AM).

[0029] In some embodiments, the mCRC is characterized as having wild-type RAS, wildtype KRAS, wild-type BRAF, and / or as HER2-negative, when assessed by a qualified or validated assay in biopsy and / or ctDNA samples. In some embodiments, the subject’s human papillomavirus (HPV) status is characterized as HPV-negative or HPV-positive when assessed by a qualified or validated assay in biopsy and / or ctDNA samples. In some embodiments, a qualified or validated assay detecting the presence or absence of human papilloma virus (HPV) markers comprises, consists of, or consists essentially of Sanger Sequencing or Next Generation Sequencing.

[0030] In some embodiments, (i) the antibody which binds to HLA-G is administered prior to the antibody which binds the epidermal growth factor receptor (EGFR), (ii) the antibody which binds to HLA-G is administered after the antibody which binds the epidermal growth factor receptor (EGFR), or (iii) the antibody which binds to HLA-G is administered concurrently with the antibody which binds to epidermal growth factor receptor (EGFR).

[0031] In some embodiments, the subject is a human subject. In some embodiments, the subject derives a clinical benefit, the clinical benefit being overall survival (OS), progression- free survival (PFS), or objective response rate (ORR). In some embodiments, the treatment provides an ORR that is superior to that of a standard of care therapy(ies). In some embodiments, the treatment has an OS that is superior to that of a standard of care therapy(ies). In some embodiments, the subject has received at least one prior line oftherapy. In some embodiments, the at least one prior line of therapy is, independently, a treatment of advanced / metastatic disease. In some embodiments, the at least one prior line of therapy is a chemotherapy or immunotherapy. In some embodiments, the at least one prior line of therapy comprises, consists of, or consists essentially of one or more of 5- Fluoropyridine, oxaliplatin, irinotecan, cetuximab, Avastin®, Lonsurf®, or an anti-VEGF treatment.

[0032] In some embodiments, the antibody which binds HLA-G and the antibody which binds EGFR are administered in an amount sufficient to achieve 1, 2, 3, or 4 of the following in the subject:(i) target lesion regression;(ii) immune cell activation;(iii) increase in activity of myeloid cells, cytotoxic T lymphocytes, helper T cells, NK cells, T cells, B cells, neutrophils, monocytes, macrophages, and / or dendritic cells; and / or(iv) upregulation of one or more myeloid activation gene sets associated with antitumor activity in the tumor.

[0033] In some embodiments, the immune cell activation comprises, consists of, or consists essentially of:(i) increased frequency of ILT2+CD8+ T cells;(ii) increased percent of activated Ki67+NK cells; and / or(iii) increased frequency of Ki67+PD-1+HLA-DR+CD4 T cells.

[0034] In some embodiments, the cancer is a colorectal cancer. In some embodiments, the cancer is an advanced or metastatic colorectal cancer. In some embodiments, the cancer has received or progressed on at least 1, 2, 3, 4, or 5 prior treatments.

[0035] In some embodiments, the antibody which binds to PD-1 comprises, consists of, or consists essentially of consists of a heavy chain variable region (VH) and a light chain variable region (VL) the VH consisting of: (i) a VHCDR1 having the sequence set forth in SEQ ID NO: 3 or SEQ ID NO: 10; (ii) a VHCDR2 having the sequence set forth in SEQ ID NO: 23 or SEQ ID NO: 30; and (iii) a VHCDR3 having the sequence set forth in SEQ ID NO: 50; and the VL consisting of (iv) a VLCDR1 having the sequence set forth in SEQ ID NO: 60; (v) a VLCDR2 having the sequence set forth in SEQ ID NO: 70; and (vi) a VLCDR3 having the sequence set forth in SEQ ID NO: 80. In some embodiments, the antibody which binds to PD-1 comprises, consists of, or consists essentially of a heavy chain variable region (VH) and a light chain variable region (VL), with the VH comprising, consisting of, orconsisting essentially of a VH having the sequence set forth in SEQ ID NO: 90 and the VL comprising, consisting of, or consisting essentially of a VL having the sequence set forth in SEQ ID NO: 100. In some embodiments, the antibody which binds to PD-1 comprises or consists of a heavy chain (HC) and a light chain (LC), with the HC comprising, consisting of, or consisting essentially of a sequence set forth in SEQ ID NO: 110 and the LC comprising, consisting of, or consisting essentially of sequence set forth in SEQ ID NO: 120.

[0036] In some embodiments, the cancer is Head and Neck Squamous Cell Carcinoma (HNSCC). In some embodiments, the cancer is colorectal cancer (CRC). In some embodiments, the cancer is triple negative breast cancer (TNBC). In some embodiments, the cancer is renal cell carcinoma (RCC). In some embodiments, the cancer is non-small cell lung cancer (NSCLC). In some embodiments, the cancer is acral melanoma (AM). The cancer may be advanced or metastatic. In some embodiments, the cancer has received or progressed on at least 1, 2, 3, 4, or 5 prior treatments.6. BRIEF DESCRIPTION OF THE DRAWINGS

[0037] FIG. 1 demonstrates anti-tumor activity of TTX-080 administered in combination with cetuximab to subjects (N=13) with WT RAS, WT BRAF, and HER2 -negative mCRC. 9 / 13 (69%) of subject had at least 15% TL (target lesion) regression. Numbers on the bars indicate number of prior lines of therapy (LOT). One (1) subject not represented in FIG. 1 did not have target lesions per Central Review. PR = Partial Response; SD = Stable Disease; PD = Progressive Disease; NE = Non-Evaluable.

[0038] FIG. 2 demonstrates anti -turn or activity and disease control of TTX-080 administered in combination with cetuximab to subjects with WT RAS, WT BRAF, and HER2 -Negative mCRC. PFS rate at 36 Weeks was 47%. Median Progression Free Survival (PFS) was 24.4 (10.7, NA) weeks. PFS event rates were 75%. Follow up duration was 21 weeks (range 0-52). PD = Progressive Disease; PR = Partial Response; SD = Stable Disease.

[0039] FIG. 3 demonstrates anti-tumor activity of TTX-080 administered in combination with cetuximab to subjects with HPV-Negative mHNSCC. 6 / 7 (85%) of subjects had any level of Target Lesion (TL) regression. 5 / 7 (71%) had at least 20% TL regression and Disease Control Rate (DCR) of >90 days. Numbers on the bars indicate number of prior lines of therapy (LOT). CR = Complete Responder; PD = Progressive Disease; PR = Partial Response; SD = Stable Disease.

[0040] FIG. 4 demonstrates anti -tumor activity and disease control of TTX-080 administered in combination with cetuximab to subjects with HPV-Negative mHNSCC. PFS rate at 24 Weeks was 43%. Median Progression Free Survival (PFS) was 23.9 (9, NA) weeks. PFS event rates were 100%. Follow up duration was 24 weeks (range 9-48). CR = Complete Response; PD = Progressive Disease; PR = Partial Response; SD = Stable Disease; NE = Non-Evaluable.

[0041] FIG. 5A demonstrates increased activated NK cells detected in subjects administered TTX-080 as a monotherapy for advanced or metastatic colorectal cancer (mCRC).

[0042] FIG. 5B demonstrates increased activated ILT2+CD8+T cells detected in subjects administered TTX-080 as a monotherapy for advanced or metastatic colorectal cancer (mCRC).

[0043] FIG. 5C demonstrates increased activated NK cells detected in a subject who received TTX-080 as a monotherapy that achieved Partial Response (PR) by Central Read for advanced or metastatic colorectal cancer (mCRC).

[0044] FIG. 6 demonstrates evidence of NK Cell activation and increased antigenspecific T cells in the periphery from a subject having WT RAS, WT BRAF, and HER2- negative mCRC who received TTX-080 in combination with cetuximab. The subject had received 2 prior lines of treatment (LOT) including 5 Fluoropyridine, oxaliplatin, and Avastin®.

[0045] FIG. 7 demonstrates evidence of NK Cell activation and increased antigenspecific T cells in the periphery from a subject having WT RAS, WT BRAF, and HER2- negative mCRC who received TTX-080 in combination with cetuximab. The subject had received four (4) prior lines of treatment (LOT) including 5 Fluoropyridine, oxaliplatin, irinotecan, Avastin®, and Lonsurf®.

[0046] FIG. 8 shows model predicted TTX-080 serum concentrations after IV infusion of 0.6 mg / kg Q3W over 30 minutes to a 70-kg human.

[0047] FIG. 9 shows the serum drug (TTX-080) concentration after intravenous administration.

[0048] FIG. 10 shows the relationship between observed and model-predicted TTX-080 serum concentrations after IV administration.

[0049] FIG. 11 shows receptor occupancy (RO) after single-dose IV administration of TTX-080.

[0050] FIGs 12A and 12B show PK stimulation of TTX-080 at 15 mg / kg Q2W dosing in patients with advanced solid tumors. FIG. 12A shows stimulation excluding effects of ethnicity on clearance. FIG. 12B shows stimulation including effect of ethnicity on clearance. Abbreviations: Cp = serum concentration; PK = pharmacokinetics; Q2W = every 2 weeks. Lines represent values for individual patients (N = 188) based on post hoc parameters from the optimal model. The dashed line appears at the target trough concentration (50,000 ng / mL).

[0051] FIG. 13 shows TTX-080 combines with cetuximab to enhance macrophage phagocytosis. A549 lung cancer cells transduced to express HLA-G were labeled with Cell Trace Violet (CTV) and pre-incubated with cetuximab and / or TTX-080 Fab for 1 hour followed by co-culture with monocyte-derived macrophages. After 2 hours, cells were analyzed by flow cytometry to determine the percentage of CD1 lb+macrophages that phagocytosed target cells as evidenced by uptake of CTV signal. Data are shown as mean ± standard deviation (n = 2 replicates). Abbreviations: Ab=antibody.

[0052] FIG. 14 shows TTX-80 combines with pembrolizumab to enhance T cell functional activity. TTX-080 in combination with pembrolizumab enhanced ILT2+CD8+T cell degranulation (CD 107a) above either single agent alone. An isotype matched antibody was used as a negative control. The graphs show the mean ± standard deviation (n = 3 replicate wells) from 1 representative donor.7. DETAILED DESCRIPTION7.1. Definitions

[0053] Unless otherwise defined, all terms of art, notations and other scientific terminology used herein are intended to have the meanings commonly understood by those of skill in the art to which this invention pertains. In some cases, terms with commonly understood meanings are defined herein for clarity and / or for ready reference, and the inclusion of such definitions herein should not necessarily be construed to represent a difference over what is generally understood in the art. The techniques and procedures described or referenced herein are generally well understood and commonly employed using conventional methodologies by those skilled in the art, such as, for example, the widely utilized molecular cloning methodologies described in Sambrook et al., Molecular Cloning: A Laboratory Manual 2nd ed. (1989) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY. As appropriate, procedures involving the use of commercially available kits andreagents are generally carried out in accordance with manufacturer defined protocols and / or parameters unless otherwise noted.

[0054] As used herein, the singular forms “a,” “an,” and “the” include the plural referents unless the context clearly indicates otherwise.

[0055] The terms “HLA-G,” “human leukocyte antigen G,” and “HLA-G histocompatibility antigen, class I, G” are used interchangeably herein. Unless specified otherwise, the terms include any variants, isoforms, and species homologs of human HLA-G that are naturally expressed by cells, or that are expressed by cells transfected with an HLA-G gene.

[0056] The term “TTX-080” as used herein, refers to an anti HLA-G antibody consisting of a heavy chain variable region (VH) and a light chain variable region (VL) which consists of a VH consisting of: (i) a VHCDR1 having the sequence set forth in SEQ ID NO: 1 or SEQ ID NO: 11; (ii) a VHCDR2 having the sequence set forth in SEQ ID NO: 21 or SEQ ID NO: 31; and (iii) a VHCDR3 having the sequence set forth in SEQ ID NO: 41; and a VL comprising: (iv) a VLCDR1 having the sequence set forth in SEQ ID NO: 51; (v) a VLCDR2 having the sequence set forth in SEQ ID NO: 61; and (vi) a VLCDR3 having the sequence set forth in SEQ ID NO: 71. The VH consists of the sequence set forth in SEQ ID NO: 81, and the VL consists of the sequence set forth in SEQ ID NO: 91. The anti-HLA antibody comprises a heavy chain (HC) having a sequence set forth in SEQ ID NO: 101 or SEQ ID NO: 102, and a light chain (LC) having a sequence set forth in SEQ ID NO: 111. As set forth in the examples presented herein, TTX-080 shall mean an anti HLA-G antibody consisting of a heavy chain (HC) consisting of the sequence set forth in SEQ ID NO: 101 and a light chain (LC) having a sequence set forth in SEQ ID NO: 111. As used herein, the terms “TTX-080” and “an antibody which binds to HLA-G” and “an antibody which binds HLA-G” and “an anti HLA-G antibody” are used interchangeably.

[0057] The terms “EGFR,” “epidermal growth factor receptor,” “ErbB-1,” and “HER1” are used interchangeably herein. Unless specified otherwise, the terms include any variants, isoforms, and species homologs of human EGFR that are naturally expressed by cells, or that are expressed by cells transfected with an EGFR gene.

[0058] An “anti -EGFR antibody” refers to an antibody that binds to EGFR. In some embodiments, the anti-EGFR antibody is cetuximab (also known as Erbitux®). As used herein, cetuximab consists of the anti-EGFR antibody comprises a VH consisting of: (i) a VHCDR1 having the sequence set forth in SEQ ID NO: 9 or SEQ ID NO: 19; (ii) a VHCDR2 having the sequence set forth in SEQ ID NO: 29 or SEQ ID NO: 39; and (iii) a VHCDR3having the sequence set forth in SEQ ID NO: SEQ ID NO: 49; and a VL comprising: (iv) a VLCDR1 having the sequence set forth in SEQ ID NO: 59; (v) a VLCDR2 having the sequence set forth in SEQ ID NO: 69; and (vi) a VLCDR3 having the sequence set forth in SEQ ID NO: 79. In some embodiments, cetuximab consists of a VH having the sequence set forth in SEQ ID NO: 89 and a VL having the sequence set forth in SEQ ID NO: 99. In some embodiments, cetuximab consists of a heavy chain (HC) having the sequence set forth in SEQ ID NO: 109 and a light chain (LC) having the sequence set forth in SEQ ID NO: 119. As set forth in the examples presented herein, cetuximab shall mean the anti-EGFR antibody consisting of a heavy chain (HC) consisting of the sequence set forth in SEQ ID NO: 109 and a light chain (LC) consisting of the sequence set forth in SEQ ID NO: 119. As used herein, the terms “an antibody which binds to EGFR” and “an anti EGFR antibody” are used interchangeably.

[0059] An “anti-PD-1 antibody” refers to an antibody that binds to PD-1. In some embodiments, the anti-PD-1 antibody is pembrolizumab (also known as Keytruda). As used herein, pembrolizumab consists of a heavy chain variable region (VH) and a light chain variable region (VL) the VH consisting of: (i) a VHCDR1 having the sequence set forth in SEQ ID NO: 3 or SEQ ID NO: 10; (ii) a VHCDR2 having the sequence set forth in SEQ ID NO: 23 or SEQ ID NO: 30; and (iii) a VHCDR3 having the sequence set forth in SEQ ID NO: 50; and the VL comprising (iv) a VLCDR1 having the sequence set forth in SEQ ID NO: 60; (v) a VLCDR2 having the sequence set forth in SEQ ID NO: 70; and (vi) a VLCDR3 having the sequence set forth in SEQ ID NO: 80. In some embodiments, pembrolizumab consists of a VH having the sequence set forth in SEQ ID NO: 90 and a VL having the sequence set forth in SEQ ID NO: 100. In some embodiments, pembrolizumab consists of a heavy chain (HC) having the sequence set forth in SEQ ID NO: 110 and a light chain (LC) having the sequence set forth in SEQ ID NO: 120. As set forth in the examples presented herein, pembrolizumab shall mean the anti-PD-1 antibody consisting of a heavy chain (HC) having the sequence set forth in SEQ ID NO: 110 and a light chain (LC) having a sequence set forth in SEQ ID NO: 120. As used herein, the terms “an antibody which binds to PD-1” and “an antibody which binds PD-1” and “an anti-PD-1 antibody” are used interchangeably.

[0060] The term “immunoglobulin” refers to a class of structurally related proteins generally comprising two pairs of polypeptide chains: one pair of light (L) chains and one pair of heavy (H) chains. In an “intact immunoglobulin,” all four of these chains are interconnected by disulfide bonds. The structure of immunoglobulins has been well characterized. See, e.g., Paul, Fundamental Immunology 7th ed., Ch. 5 (2013) LippincottWilliams & Wilkins, Philadelphia, PA. Briefly, each heavy chain typically comprises a heavy chain variable region (VH) and a heavy chain constant region (CH). The heavy chain constant region typically comprises three domains, CHI, CH2, and CH3. Each light chain typically comprises a light chain variable region (VL) and a light chain constant region. The light chain constant region typically comprises one domain, abbreviated CL.

[0061] The term “antibody” describes a type of immunoglobulin molecule and is used herein in its broadest sense. An antibody specifically includes intact antibodies (e.g., intact immunoglobulins) and antibody fragments. Antibodies comprise at least one antigen-binding domain. One example of an antigen-binding domain is an antigen binding domain formed by a VH-VL dimer.

[0062] The VH and VL regions may be further subdivided into regions of hypervariability (“hypervariable regions (HVRs);” also called “complementarity determining regions” (CDRs)) interspersed with regions that are more conserved. The more conserved regions are called framework regions (FRs). Each VH and VL generally comprises three CDRs and four FRs, arranged in the following order (from N-terminus to C-terminus): FR1 - CDR1 - FR2 - CDR2 - FR3 - CDR3 - FR4. The CDRs are involved in antigen binding and confer antigen specificity and binding affinity to the antibody. See Kabat et al., Sequences of Proteins of Immunological Interest 5th ed. (1991) Public Health Service, National Institutes of Health, Bethesda, MD, incorporated by reference in its entirety.

[0063] The light chain from any vertebrate species can be assigned to one of two types, called kappa and lambda, based on the sequence of the constant domain.

[0064] The heavy chain from any vertebrate species can be assigned to one of five different classes (or isotypes): IgA, IgD, IgE, IgG, and IgM. These classes are also designated a, 5, a, y, and p, respectively. The IgG and IgA classes are further divided into subclasses on the basis of differences in sequence and function. Humans express the following subclasses: IgGl, IgG2, IgG3, IgG4, IgAl, and IgA2.

[0065] The amino acid sequence boundaries of a CDR can be determined by one of skill in the art using any of a number of known numbering schemes, including those described by Kabat et al., supra (“Kabat” numbering scheme); Al-Lazikani et al., 1997, J. Mol. Biol.. 273:927-948 (“Chothia” numbering scheme); MacCallum et al., 1996, J. Mol. Biol. 262:732- 745 (“Contact” numbering scheme); Lefranc et al., Dev. Comp. Immunol., 2003, 27:55-77 (“IMGT” numbering scheme); and Honegge and Pluckthun, J. Mol. Biol., 2001, 309:657-70 (“AHo” numbering scheme), each of which is incorporated by reference in its entirety.

[0066] Table 1 provides the positions of CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR- H2, and CDR-H3 as identified by the Kabat and Chothia schemes. For CDR-H1, residue numbering is provided using both the Kabat and Chothia numbering schemes.

[0067] Unless otherwise specified, the numbering scheme used for identification of a particular CDR herein is the Kabat numbering scheme. Variant and equivalent antibodies with a Chothia numbering scheme are intended to be within the scope of the invention. Table 1 shows residues in CDRs according to Kabat and Chothia numbering schemes.* The C-terminus of CDR-H1, when numbered using the Kabat numbering convention, varies between H32 and H34, depending on the length of the CDR.

[0068] An “antibody fragment” comprises a portion of an intact antibody, such as the antigen binding or variable region of an intact antibody. Antibody fragments include, for example, Fv fragments, Fab fragments, F(ab’)2 fragments, Fab’ fragments, scFv (sFv) fragments, and scFv-Fc fragments. In some embodiments, an antibody that binds HLA-G and / or an antibody that binds EGFR includes antibody fragments of each of the specified antibodies.

[0069] “Fv” fragments comprise a non-covalently-linked dimer of one heavy chain variable domain and one light chain variable domain.

[0070] “Fab” fragments comprise, in addition to the heavy and light chain variable domains, the constant domain of the light chain and the first constant domain (Cm) of the heavy chain. Fab fragments may be generated, for example, by papain digestion of a full- length antibody.

[0071] “F(ab’)2” fragments contain two Fab’ fragments joined, near the hinge region, by disulfide bonds. F(ab’)2 fragments may be generated, for example, by pepsin digestion of anintact antibody. The F(ab’) fragments can be dissociated, for example, by treatment with B- mercaptoethanol.

[0072] “Single-chain Fv” or “sFv” or “scFv” antibody fragments comprise a VH domain and a VL domain in a single polypeptide chain. The VH and VL are generally linked by a peptide linker. See Pluckthun A. (1994). Antibodies from Escherichia coli. In Rosenberg M. & Moore G.P. (Eds.), The Pharmacology of Monoclonal Antibodies vol. 113 (pp. 269-315). Springer-Verlag, New York, incorporated by reference in its entirety. “scFv-Fc” fragments comprise an scFv attached to an Fc domain. For example, an Fc domain may be attached to the C-terminal of the scFv. The Fc domain may follow the VH or VL depending on the orientation of the variable domains in the scFv (i.e., VH-VL or VL-VH). Any suitable Fc domain known in the art or described herein may be used.

[0073] The term “monoclonal antibody” refers to an antibody from a population of substantially homogeneous antibodies. A population of substantially homogeneous antibodies comprises antibodies that are substantially similar and that bind the same epitope(s), except for variants that may normally arise during production of the monoclonal antibody. Such variants are generally present in only minor amounts. A monoclonal antibody is typically obtained by a process that includes the selection of a single antibody from a plurality of antibodies. For example, the selection process can be the selection of a unique clone from a plurality of clones, such as a pool of hybridoma clones, phage clones, yeast clones, bacterial clones, or other recombinant DNA clones. The selected antibody can be further altered, for example, to improve affinity for the target (“affinity maturation”), to humanize the antibody, to improve its production in cell culture, and / or to reduce its immunogenicity in a subject.

[0074] With regard to the binding of an antibody to a target molecule, the terms “binding” or “binds to” a particular antigen (e.g., a polypeptide target) or an epitope on a particular antigen mean binding that is measurably different from a non-selective interaction. Binding can be measured, for example, by determining binding of a molecule compared to binding of a control molecule. Binding can also be determined by competition with a control molecule that is similar to the target, such as an excess of non-labeled target. In that case, binding is indicated if the binding of the labeled target to a probe is competitively inhibited by the excess non-labeled target.

[0075] The term "pharmaceutically acceptable" describes substances, formulations, or components that meet the necessary criteria for safety, quality, and suitability for use in pharmaceutical products. These substances are deemed suitable for inclusion in drug productsintended for human consumption and have a minimal risk of causing harm or adverse effects, based on established standards and guidelines set by regulatory authorities. They are also free from impurities, contaminants, and substances that might compromise the quality and safety of the final pharmaceutical product. Pharmaceutically acceptable substances, including active pharmaceutical ingredients (APIs), excipients, solvents, and other components, must meet established quality standards, such as those outlined in pharmacopeias (e.g., United States Pharmacopeia, European Pharmacopoeia). Components that are pharmaceutically acceptable are compatible with each other and maintain stability over the intended shelf life of the pharmaceutical product. They do not interact in ways that would compromise the safety or efficacy of the product. Different routes of administration (oral, injectable, topical, etc.) may have specific requirements for substances to be considered pharmaceutically acceptable for that route. Substances must meet the relevant regulatory and quality standards for the intended route of administration.

[0076] Percent “identity” between a polypeptide sequence and a reference sequence is defined as the percentage of amino acid residues in the polypeptide sequence that are identical to the amino acid residues in the reference sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN, MEGALIGN (DNASTAR), CLUSTALW, or CLUSTAL OMEGA software. Those skilled in the art can determine appropriate parameters for aligning sequences, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared.

[0077] The term “amino acid” refers to the twenty common naturally occurring amino acids. Naturally occurring amino acids include alanine (Ala; A), arginine (Arg; R), asparagine (Asn; N), aspartic acid (Asp; D), cysteine (Cys; C); glutamic acid (Glu; E), glutamine (Gin; Q), Glycine (Gly; G); histidine (His; H), isoleucine (He; I), leucine (Leu; L), lysine (Lys; K), methionine (Met; M), phenylalanine (Phe; F), proline (Pro; P), serine (Ser; S), threonine (Thr; T), tryptophan (Trp; W), tyrosine (Tyr; Y), and valine (Vai; V).

[0078] A “cytokine” is a small protein or signaling molecule that plays a crucial role in cell communication and immune responses. They are produced by various cells, especially immune cells, and are involved in coordinating the body's defense mechanisms, inflammation, and cellular interactions. Cytokines act as messengers, transmitting signals between cells toregulate various physiological and immune processes. They regulate immune responses, inflammation, cell growth, differentiation, and tissue repair.

[0079] A pharmaceutically acceptable diluent is a substance used to dilute or reduce the concentration of an active pharmaceutical ingredient (API) or other components in a pharmaceutical formulation, making it suitable for administration to patients. Diluents are added to drug formulations for various reasons, including achieving the desired dosage strength, improving stability, aiding in drug delivery, and enhancing patient acceptance. Diluents should be compatible with the active ingredient and other excipients in the formulation. They should not adversely affect the stability, solubility, or bioavailability of the drug product. Diluents, like other excipients used in pharmaceutical formulations, must meet established regulatory standards for safety, quality, and purity. The choice of a pharmaceutically acceptable diluent can depend on the intended route of administration. Different routes (oral, injectable, topical, etc.) may have specific requirements for diluents. The choice of diluent may vary depending on the intended dosage form, such as tablets, capsules, solutions, suspensions, or injectable formulations. For oral formulations, diluents can impact the taste, texture, and ease of swallowing, which can influence patient compliance and acceptance.

[0080] A pharmaceutically acceptable carrier, also referred to as an excipient or vehicle, is a substance used in pharmaceutical formulations to provide a suitable medium or matrix for delivering active pharmaceutical ingredients (APIs) to patients. Carriers are inert substances that help achieve the desired physical characteristics, stability, and ease of administration of the final drug product. Carriers are used to formulate APIs into various dosage forms, such as tablets, capsules, creams, solutions, and injections. They provide a stable matrix for the API, aiding in its dispersion, dissolution, and overall effectiveness.

[0081] A pharmaceutically acceptable excipient is a substance added to a pharmaceutical formulation alongside the active pharmaceutical ingredient (API) to facilitate the preparation of the final dosage form, enhance stability, improve patient acceptance, or aid in the delivery of the medication. Excipients are inert substances that serve various functional roles in pharmaceutical products. Excipients are used for various purposes, such as binding, dilution, disintegration, dissolution, coloration, flavoring, preservation, and enhancing patient acceptability. They help achieve the desired physical and chemical properties of the final dosage form.

[0082] A “small molecule inhibitor” is a type of chemical compound that binds to a specific target molecule in cells and interferes with its activity, often by blocking or reducing its function.

[0083] As used herein, “Overall Survival” or “OS” shall refer to the time which begins at diagnosis (or at the start of treatment) and ends at death.

[0084] “Complete Response” or “CR” refers to the disappearance of all target lesions; any pathologic lymph nodes (whether target or nontarget lesions) must have reduction in short axis to less than 10mm.

[0085] “Duration of Response” and “DOR” shall refer to the time from first documentation of disease response (CR or PR) until first documentation of progression or death from any cause, whichever occurs first.

[0086] “Objective Response Rate” or “ORR” refers to the percentage of subjects with unconfirmed and confirmed CR or unconfirmed and confirmed PR.

[0087] “Partial Response” or “PR” refers to at least 30% decrease in the sum of diameters of target lesions; reference is the baseline diameters.

[0088] As used herein, “Progression Free Survival” or “PFS” refers to the time from the participant’s first dose of study treatment to the first date of either disease progression or death, whichever occurs first.

[0089] “Treating” or “treatment” of any disease or disorder refers, in certain embodiments, to ameliorating a disease or disorder that exists in a subject. In another embodiment, “treating” or “treatment” includes ameliorating at least one physical parameter, which may be indiscernible by the subject. In yet another embodiment, “treating” or “treatment” includes modulating the disease or disorder, either physically (e.g., stabilization of a discernible symptom) or physiologically (e.g., stabilization of a physical parameter) or both. In yet another embodiment, “treating” or “treatment” includes delaying or preventing the onset of the disease or disorder.

[0090] As used herein, the term “therapeutically effective amount” or “effective amount” refers to an amount of an antibody or composition that when administered to a subject is effective to treat a disease or disorder, such as cancer. In some embodiments, a therapeutically effective comprises or consists of exemplary doses of each antibody. In some embodiments, a therapeutically effective amount comprises or consists of determining an amount used to achieve a response according to a clinical endpoint. In some embodiments, the clinical endpoint comprises Objective Response Rate (ORR), Progression Free Survival (PFS), and / or Response Evaluation Criteria in Solid Tumors (“RECIST”). The term“effective amount” may refer to the individual dose of TTX-080 alone, or TTX-080 and each of the second therapeutic agent (e.g., cetuximab, pembrolizumab) combine to produce the desired effect for which they are administered.

[0091] As used herein, the term “subject” means a mammal. In some embodiments subjects include, but are not limited to, human, monkeys, dogs, cats, mice, rats, cows, horses, camels, avians, goats, and sheep. In some embodiments, the subject is a human. In some embodiments, the subject has cancer that can be treated with an antibody provided herein. In some embodiments, the subject is a human that is suspected to have cancer.

[0092] The term “Q2W” refers to administration of an effective amount of an antibody (such as, for example, TTX-080) alone or in a pharmaceutical composition to the subject every two weeks in a repeated pattern. Treatment will continue in a 14-day cycle until disease progression, death, report of adverse effects, or decision to discontinue treatment by the patient, physician, and / or investigator. The term “Q3W” refers to administration of an effective amount of the antibody alone or in a pharmaceutical composition to the subject every three weeks in a repeated pattern. Treatment will continue in a 21 -day cycle until disease progression, death, report of adverse effects, or decision to discontinue treatment by the patient, physician, and / or investigator. As used herein, the antibody may be administered in a first dose to the subject on the first day of the cycle (Cycle 1 Day 1). The subject may be administered with a subsequent dose in a subsequent cycle. The dosing may be evaluated to determine the maximum tolerated dose (MTD), optimal biological dose (OBD), and / or doselimiting toxicity (DLT). The doing may be administered via intravenous (IV) injection. An effective dose may be determined based on pharmacokinetics, safety, tolerability, and pharmacodynamics, monotherapy, and / or combination therapy with a second therapeutic agent. As an illustrating example, the subject may be administered a dose of 0.2-100 mg / kg IV Q2W or 0.2-100 mg / kg IV Q3W. Dosing may be administered in dose escalation depending on the clinical benefits and / or decision by the physician. In some embodiments, for example, without limitation, the subject is administered 0.2 mg / kg IV Q2W or Q3W in the first cycle, 0.6 mg / kg IV Q2W or Q3W in the second cycle, 2 mg / kg IV Q2W or Q3W in the third cycle, 6 mg / kg IV Q2W or Q3W in a fourth cycle, 10 mg / kg Q2W or Q3W in a fifth cycle, 15 mg / kg Q2W or Q3W in a sixth cycle, or 20 mg / kg Q2W or Q3W in a seventh cycle. Dosing may be administered in a pre-determined amount. For example, the subject may be administered 0.2 mg / kg IV Q2W or Q3W, 0.6 mg / kg IV Q2W or Q3W, 2 mg / kg IV Q2W or Q3W, 6 mg / kg IV Q2W or Q3W, 10 mg / kg IV Q2W or Q3W, 15 mg / kg IV Q2W or Q3W, or 20 mg / kg IV Q2W or Q3W in the first and each of the subsequent cycles. In the context ofadministration of the anti HLA-G antibody (TTX-080), the dosing is an effective amount to maintain serum drug concentration of TTX-080 at a targeted trough level between about 10 gg / mL to about 1200 gg / mL, such as about or above 50 gg / mL during the first cycle after administration of the first dose and / or each of the subsequent cycles.

[0093] The term “serum drug concentration” refers to the amount of a medication present in a subject’s blood serum at a specific time. Serum drug concentration typically vary between individuals due to factors such as age, weight, liver and kidney function, and prior treatment. As used herein, the serum drug concentration of the anti HLA-G antibody (TTX- 080) is maintained at target trough level between about 10 gg / mL to about 1200 gg / mL, such as about or above 50 gg / mL during the first cycle after administration of the first dose and / or each of the subsequent cycles.

[0094] The term “receptor occupancy” or “RO” refers to the percentage of receptors on a cell surface that are bound by a drug molecule of interest at a given time. The dosing and serum drug concentration of TTX-080 may achieve at least ECso, ECeo, EC70, ECso, or EC90 for receptor occupancy (RO).7.2. Methods of Treatment and Dosages

[0095] Provided herein are methods and / or compositions for treating a subject suffering from disease, such as cancer. The subject is (a) administered an antibody which binds to HLA-G in combination with an antibody which binds to epidermal growth factor (EGFR); (b) administered an antibody which binds to HLA-G in combination with an antibody which binds to EGFR, and FOLFIRI; or (c) administered an antibody which binds to HLA-G in combination with an antibody which binds to programmed death protein 1 (PD-1). Other compounds may also be administered. The combinations of antibodies and / or chemotherapy agents or small molecule drugs are administered at specified dosing regimens as described herein. Each of the combinations set forth herein may comprise or consist of a pharmaceutical composition.

[0096] The antibody which binds to HLA-G may be administered to a mammal, generally a human, in a pharmaceutically acceptable dosage form such as those known in the art and those discussed herein. For example, the antibody may be administered to a human intravenously as a bolus or by continuous infusion over a period of time, by intramuscular, intraperitoneal, intra-cerebrospinal, subcutaneous, infra-articular, intrasynovial, intrathecal, orintratumoral routes. The antibody may also be suitably administered by peritumoral, intralesional, or perilesional routes, to exert local as well as systemic therapeutic effects.

[0097] A first aspect thereof provides a method for treatment of a subject suffering from cancer, comprising administering to the subject: a) an antibody which binds to HLA-G; b) optionally administering a subsequent dose of the antibody which binds to HLA-G; and c) an antibody which binds to an epidermal growth factor receptor (EGFR), wherein the administration of the antibody which binds to HLA-G maintains serum drug concentrations above a target trough of about 50 pg / mL. In some embodiments, the HLA-G antibody is TTX-080.

[0098] In some embodiments, the administration of the antibody which binds to HLA-G maintains serum drug concentrations above a target trough of about 50 pg / mL during a first cycle. In some embodiments, the administration of the antibody which binds to HLA-G maintains serum drug concentrations above the target trough of about 50 pg / mL during the first cycle and subsequent cycles. In some embodiments, the antibody which binds to HLA- G is administered to the subject intravenously at 20 mg / kg over 30 minutes (± 5 minutes) at the start of each cycle.

[0099] In some embodiments, the antibody which binds to HLA-G and the antibody which binds to EGFR are administered at a 2-4 week interval. In some embodiments, the anti HLA-G antibody and the anti-EGFR antibody are administered every 3 weeks (Q3W). In some embodiments, the anti HLA-G antibody and the anti-EGFR antibody are administered every 2 weeks (Q2W). In some embodiments, the administration of the anti HLA-G antibody achieves at least ECeo, EC70, ECso, or EC90 for receptor occupancy (RO).

[0100] In some embodiments, the administration of the anti HLA-G antibody maintains a serum drug concentration at a target trough of between about 10 pg / mL- 100 pg / mL during a first and each of the subsequent cycles. In some embodiments, the administration maintains a serum drug concentration at a target trough of at least, about, or above 50 pg / mL, 60 pg / mL, 70 pg / mL, 80 pg / mL, 90 pg / mL, or 95 pg / mL during the first cycle and / or during each of the subsequent cycles. In some embodiments, the administration of the antibody which binds to HLA-G maintains serum drug concentrations above a target trough of about 50 pg / mL during a first cycle. In some embodiments, the administration of the antibody which binds to HLA- G maintains serum drug concentrations above a target trough of about 50 pg / mL during a first cycle and / or one or more subsequent cycles. In some embodiments, the administration of the antibody which binds to HLA-G maintains serum drug concentrations above a target trough of about 50 pg / mL.

[0101] In some embodiments, the antibody which binds to HLA-G is administered to the subject intravenously at 20 mg / kg over 30 minutes (± 5 minutes) at the start of each cycle. In some embodiments, the method comprises administering the anti HLA-G antibody at a 0.2 mg / kg -20 mg / kg to the subject in the first dose and / or each of the subsequent cycles. In some embodiments, the method comprises administering the anti HLA-G antibody at a 0.2 mg / kg, 0.6 mg / kg, 2 mg / kg, 6 mg / kg, 10 mg / kg, 12 mg / kg, 15 mg / kg, or 20 mg / kg to the subject in the first dose and / or each of the subsequent cycle. In some embodiments, the method comprises further administering an anti-EGFR antibody, which is administered at a) at a 400 mg / m2initial dose as an intravenous infusion (e.g., over 120 minutes), and at a subsequent dose of 250 mg / m2as an intravenous infusion (e.g., over 30 to 60 minutes) weekly; or b) at a 500 mg / m2intravenous infusion (e.g., over 120 minutes) every two weeks or three weeks. In some embodiments, the antibody which binds to an epidermal growth factor (EGFR) is an antibody-drug-conjugate (ADC).

[0102] In some embodiments, the method comprises administering in the first cycle: the anti HLA-G antibody at 0.2 mg / kg -20 mg / kg on Day 1 and the anti-EGFR antibody at 400 mg / m2on Day 1, and further administering in one or more subsequent cycles (Q3W): the anti HLA-G antibody at 0.2 mg / kg -20 mg / kg on Day 1, and the anti-EGFR antibody at between 100 mg / m2on -250 mg / m2on Day 1. In some embodiments, the method comprises administering in the first cycle: the anti HLA-G antibody at 20 mg / kg and the anti-EGFR antibody at 400 mg / m2on Day 1 and further administering in one or more subsequent cycles (Q3W) the anti HLA-G antibody at 20 mg / kg Q3W and the anti-EGFR antibody at 250 mg / m2Q3W. In some embodiments, the method comprises administering the anti HLA-G antibody and the anti-EGFR antibody at every 3 weeks (Q3W) via intravenous infusion.

[0103] In some embodiments, the method comprises administering in the first cycle and / or each of the subsequent cycles: the anti HLA-G antibody at 0.2 mg / kg -20 mg / kg Q3W on Day 1 and the anti-EGFR antibody at 100 mg / m2-500 mg / m2Q3W on Day 1. In some embodiments, the method comprises administering in the first cycle and / or each of the subsequent cycles: the anti HLA-G antibody at 20 mg / kg Q3W and the anti-EGFR antibody at 500 mg / m2Q3W.

[0104] In some embodiments, the cancer is a solid cancer. In some embodiments, the cancer is Head and Neck Squamous Cell Carcinoma (HNSCC). In some embodiments, the cancer is colorectal cancer (CRC). In some embodiments, the cancer is triple negative breast cancer (TNBC). In some embodiments, the cancer is renal cell carcinoma (RCC). In some embodiments, the cancer is non-small cell lung cancer (NSCLC). In some embodiments, thecancer is acral melanoma (AM). In some embodiments, the cancer has received or progressed on at least 1, 2, 3, 4, or 5 prior treatments.

[0105] In some embodiments, the cancer is advanced or metastatic colorectal cancer (mCRC) and have received or progressed on 2 or 3 lines of system therapy. In some embodiments, the mCRC has microsatellite instability-low (MSI-L), microsatellite stability (MSS [negative for MSI-H / dMMR]), and / or KRAS wild-type (WT). In some embodiments, the mCRC has progressed on a prior anti-EGFR treatment. In some embodiments, the mCRC has not received a prior anti-EGFR treatment.

[0106] In some embodiments, the solid cancer is head and neck squamous cell carcinoma (HNSCC). In some embodiments, the HNSCC is advanced / metastatic HNSCC (mHNSCC). In some embodiments, the subject’s human papillomavirus (HPV) status is characterized as HPV-negative or HPV-positive when assessed by a qualified or validated assay, e.g., biopsy. In some embodiments, the qualified assay comprises, consists of, or consists essentially of immunohistochemistry (IHC) (e.g., pl6 IHC), Sanger Sequencing, and / or Next Generation Sequencing.

[0107] In some embodiments, the solid cancer is colorectal cancer (CRC) and / or metastatic CRC (mCRC). In some embodiments, the mCRC is characterized as having wildtype KRAS when assessed by a qualified or validated assay, e.g., biopsy and / or ctDNA samples. In some embodiments, the mCRC is characterized as having wild-type RAS, wildtype BRAF, and / or as HER2 -negative, when assessed by a qualified or validated assay, e.g., biopsy and / or ctDNA samples. In some embodiments, the mCRC the qualified or validated assay comprises, consists, or consists essentially of Sanger Sequencing or Next Generation Sequencing.

[0108] A second aspect provides a method of treating colorectal cancer (CRC), the method comprising administering a therapeutically effective amount of an antibody which binds to HLA-G in combination with a therapeutically effective amount of an antibody which binds to an epidermal growth factor receptor (EGFR), to a human subject having or identified as having CRC, wherein the CRC tumor is characterized as having wild-type KRAS, wildtype RAS, wild-type BRAF, and / or as HER2 -negative. In some embodiments, the antibody which binds to HLA-G is TTX-080. In some embodiments, the antibody which binds to EGFR is cetuximab.

[0109] In some embodiments, a qualified or validated assay detecting the presence or absence of wild-type KRAS, wild-type RAS, wild-type BRAF, and / or HER2, comprises, consists of, or consists essentially of Sanger Sequencing or Next Generation Sequencing.

[0110] In some embodiments, the administration of the antibody which binds to HLA-G maintains serum drug concentrations above a target trough of about 50 pg / mL during a first cycle. In some embodiments, the administration of the antibody which binds to HLA-G maintains serum drug concentrations above the target trough of about 50 pg / mL during the first cycle and subsequent cycles. In some embodiments, the antibody which binds to HLA-G is administered to the subject intravenously at 20 mg / kg over 30 minutes (± 5 minutes) at the start of each cycle. In some embodiments, each cycle comprises administering the antibody which binds to HLA-G at 2 to 4 week intervals, e.g., 2 weeks intervals (Q2W) or 3 week intervals (Q3W).

[0111] In some embodiments, the method further comprises administering an anti-EGFR antibody, which is administered at a) at a 400 mg / m2initial dose as an intravenous infusion (e.g., over 120 minutes), and at a subsequent dose of 250 mg / m2as an intravenous infusion (e.g., over 30 to 60 minutes) weekly; or b) at a 500 mg / m2intravenous infusion (e.g., over 120 minutes) every two weeks or three weeks.

[0112] In some embodiments, the antibody which binds to an epidermal growth factor (EGFR) is an antibody-drug-conjugate (ADC). In some embodiments, the subject has not previously received a treatment directed to epidermal growth factor (EGFR) (e.g., an anti- EGFR antibody treatment).

[0113] A third aspect provides a method of treating head and neck squamous cell carcinoma (HNSCC), the method comprising administering a therapeutically effective amount of an antibody which binds to HLA-G in combination with a therapeutically effective amount of an antibody which binds to an epidermal growth factor receptor (EGFR), to a human subject having or identified as having HNSCC, wherein the HNSCC tumor is characterized as human papilloma virus (HPV) negative. In some embodiments, the antibody which binds to HLA-G is TTX-080. In some embodiments, the antibody which binds to EGFR is cetuximab.

[0114] In some embodiments, human papilloma virus (HPV) is detected via a qualified or validated assay. In some embodiments, a qualified or validated assay detecting the presence or absence of human papilloma virus (HPV) comprises, consists of, or consists essentially of immunohistochemistry (IHC) (e.g., pl6 IHC), Sanger Sequencing, and / or Next Generation Sequencing.

[0115] In some embodiments, the administration of the antibody which binds to HLA-G maintains serum drug concentrations above a target trough of about 50 pg / mL during a first cycle. In some embodiments, the administration of the antibody which binds to HLA-Gmaintains serum drug concentrations above the target trough of about 50 pg / mL during the first cycle and subsequent cycles. In some embodiments, the antibody which binds to HLA-G is administered to the subject intravenously at 20 mg / kg over 30 minutes (± 5 minutes) at the start of each cycle. In some embodiments, each cycle comprises administering the antibody which binds to HLA-G at 2 to 4 week intervals, e.g., 2 weeks intervals (Q2W) or 3 week intervals (Q3W).

[0116] In some embodiments, the method further comprises administering an anti-EGFR antibody, which is administered at a) at a 400 mg / m2initial dose as an intravenous infusion (e.g., over 120 minutes), and at a subsequent dose of 250 mg / m2as an intravenous infusion (e.g., over 30 to 60 minutes) weekly; or b) at a 500 mg / m2intravenous infusion (e.g., over 120 minutes) every two weeks or three weeks. In some embodiments, the antibody which binds to an epidermal growth factor (EGFR) is an antibody-drug-conjugate (ADC).

[0117] A fourth aspect provides a method of treating a head and neck squamous cell carcinoma (HNSCC) tumor that is characterized as human papilloma virus (HPV) negative, the method comprising administering a therapeutically effective amount of an antibody which binds to HLA-G in combination with a therapeutically effective amount of an antibody which binds to an epidermal growth factor receptor (EGFR), to a human subject having or identified as having HNSCC, the method comprising the steps of: a) determining whether the tumor tissue exhibits HPV markers, wherein a tumor exhibiting HPV markers is characterized as HPV-positive and a tumor not exhibiting HPV markers is characterized as HPV-negative; and b) if the tumor is characterized as HPV-positive, excluding the subject from treatment; and if the tumor is characterized as HPV-negative, selecting the subject for treatment and administering to the subject having the HNSCC a therapeutically effective amount of an antibody which binds to HLA-G in combination with a therapeutically effective amount of an antibody which binds to an epidermal growth factor receptor (EGFR). In some embodiments, the antibody which binds to HLA-G is TTX-080. In some embodiments, the antibody which binds to EGFR is cetuximab.

[0118] In some embodiments, human papilloma virus (HPV) is detected via a qualified or validated assay. In some embodiments, a qualified or validated assay detecting the presence or absence of human papilloma virus (HPV) markers comprises, consists of, or consists essentially of Sanger Sequencing or Next Generation Sequencing.

[0119] In some embodiments, the administration of the antibody which binds to HLA-G maintains serum drug concentrations above a target trough of about 50 pg / mL during a first cycle. In some embodiments, the administration of the antibody which binds to HLA-Gmaintains serum drug concentrations above the target trough of about 50 pg / mL during the first cycle and subsequent cycles. In some embodiments, the antibody which binds to HLA- G is administered to the subject intravenously at 20 mg / kg over 30 minutes (± 5 minutes) at the start of each cycle. In some embodiments, each cycle comprises administering the antibody which binds to HLA-G at 2 to 4 week intervals, e.g., 2 weeks intervals (Q2W) or 3 week intervals (Q3W).

[0120] In some embodiments, the method comprises further administering an anti-EGFR antibody, which is administered at a) at a 400 mg / m2initial dose as an intravenous infusion (e.g., over 120 minutes), and at a subsequent dose of 250 mg / m2as an intravenous infusion (e.g., over 30 to 60 minutes) weekly; or b) at a 500 mg / m2intravenous infusion (e.g., over 120 minutes) every two weeks or three weeks. In some embodiments, the antibody which binds to an epidermal growth factor (EGFR) is an antibody-drug-conjugate (ADC).

[0121] In some embodiments of any of the above aspects, the antibody which binds to HLA-G is administered prior to the antibody which binds the epidermal growth factor receptor (EGFR). In some embodiments, the antibody which binds to HLA-G is administered after the antibody which binds to epidermal growth factor receptor (EGFR). In some embodiments, the antibody which binds to HLA-G is administered concurrently with the antibody which binds to epidermal growth factor receptor (EGFR). In some embodiments, the antibody which binds to HLA-G and the antibody which binds to epidermal growth factor receptor (EGFR) are administered about 30-minutes apart.

[0122] A fifth aspect provides a method of treating a subject suffering from cancer, comprising administering to the subject in a first cycle: a) a first dose comprising an effective amount of an anti HLA-G antibody; b) a first dose comprising an effective amount of an anti- epidermal growth factor receptor (EGFR) antibody (i) at 400 mg / m2, or (ii) at 500 mg / m2; and c) a first dose comprising FOLFIRI, wherein the administration of the anti HLA-G antibody maintains serum drug concentrations at a target trough level of between about 10- 100 pg / mL. In some embodiments, the administration of the anti HLA-G antibody maintains serum drug concentrations at a target trough level of above 50 pg / m in the first and / or the sequent cycles. In some embodiments, the method further comprises administering the antibody which binds to HLA-G, the antibody which binds to EGFR, and / or FOLFIRI in one or more subsequent cycles. In some embodiments, the antibody which binds to HLA-G is TTX-080. In some embodiments, the antibody which binds to EGFR is cetuximab. In some embodiments, FOLFIRI comprises folic acid or leucovorin, fluorouracil (5-FU), and irinotecan.

[0123] In some embodiments, the anti HLA-G antibody, the anti-EGFR antibody, and FOLFIRI are administered at a 2-4 week interval. In some embodiments, the anti HLA-G antibody, the anti-EGFR antibody, and FOLFIRI are administered every 2 weeks (Q2W). In some embodiments, the anti HLA-G antibody, the anti-EGFR antibody, and FOLFIRI are administered every 3 weeks (Q3W). In some embodiments, the anti HLA-G antibody, the anti-EGFR antibody, and FOLFIRI are administered by intravenous infusion (bolus or continuous). In some embodiments, the anti HLA-G antibody, the anti-EGFR antibody, and FOLFIRI are administered by IV Q2W or Q3W. In some embodiments, the administration of the anti HLA-G antibody achieves at least ECeo, EC 70, ECso. or EC90 for receptor occupancy (RO).

[0124] In some embodiments, the method further comprises administering the anti HLA- G antibody at 0.2-20 mg / kg to the subject in the first dose and / or each of the subsequent cycles. In some embodiments, the method further comprises administering the anti HLA-G antibody at 0.2 mg / kg, 0.6 mg / kg, 2 mg / kg, 6 mg / kg, 10 mg / kg, 12 mg / kg, 15 mg / kg, or 20 mg / kg to the subject in the first dose and / or each of the subsequent cycles. In some embodiments, the method further comprises administering leucovorin at between 100 mg / m2- 1000 mg / m2, or 200 mg / m2-400 mg / m2, 5-FU at between 200 mg / m2-400 mg / m2as IV bolus in Day 1 and between 1200 mg / m2-2400 mg / m2as continuous IV infusion in Day 2 or 3, and irinotecan at between 100 mg / m2-180 mg / m2IV. In some embodiments, the method further comprises administering leucovorin at about 100 mg / m2, about 200 mg / m2, about 300 mg / m2, about 400 mg / m2, or about 500 mg / m2, 5-FU at about 100 mg / m2, about 200 mg / m2, about 300 mg / m2, about 400 mg / m2, or about 500 mg / m2IV bolus, or about 1200 mg / m2, about 1600 mg / m2, about 2000 mg / m2, or about2 400 mg / m2continuous IV infusion over 46-48 h, and irinotecan at about 100 mg / m2, about 120 mg / m2, about 150 mg / m2, or about 180 mg / m2. In some embodiments, the method comprises administering an anti-EGFR antibody, which is administered at a) at a 400 mg / m2initial dose as an intravenous infusion (e.g., over 120 minutes), and at a subsequent dose of 250 mg / m2as an intravenous infusion (e.g., over 30 to 60 minutes) weekly; or b) at a 500 mg / m2intravenous infusion (e.g., over 120 minutes) every two weeks.

[0125] In some embodiments, the method comprises (a) administering in the first cycle (Q2W): the anti HLA-G antibody at 0.2 mg / kg -20 mg / kg, and further administering the anti- EGFR antibody at 400 mg / m2on Day 1, and further administering leucovorin at between 100 mg / m2-1000 mg / m2, or 200 mg / m2-400 mg / m2, 5-FU at between 200 mg / m2-400 mg / m2as IV bolus in Day 1 and between 1200 mg / m2-2400 mg / m2as continuous IV infusion in Day 2or 3, and irinotecan at between 100 mg / m2-180 mg / m2IV, and (b) further administering in one or more subsequent cycles (Q2W): the anti HLA-G antibody at 0.2 mg / kg -20 mg / kg on Day 1, leucovorin at between 100 mg / m2-1000 mg / m2, or 200 mg / m2-400 mg / m2, 5-FU at between 200 mg / m2-400 mg / m2as IV bolus and 400 mg / m2continuous IV infusion on Day 2 or Day 3, or between 1200 mg / m2-2400 mg / m2as continuous IV infusion, and irinotecan at between 100 mg / m2-180 mg / m2IV.

[0126] In some embodiments, the method further comprises (a) administering in the first cycle (Q2W): the anti HLA-G antibody at 15 mg / kg IV on Day 1, the anti-EGFR antibody at 400 mg / m2on Day 1, leucovorin at 400 mg / m2, 5-FU at 400 mg / m2as IV bolus in Day 1 and 2400 mg / m2continuous IV infusion on Day 2 or Day 3, and irinotecan at 180 mg / m2IV, and (b) further administering in one or more subsequent cycles (Q2W): the anti HLA-G antibody at 15 mg / kg IV on Day 1, and the anti-EGFR antibody at 250 mg / m2 IV, and further administering leucovorin at 400 mg / m2, 5-FU at 400 mg / m2as IV bolus and 2400 mg / m2as continuous IV infusion on Day 2 or Day 3, and irinotecan at 180 mg / m2on Day 1.

[0127] In some embodiments, the method further comprises (a) administering in the first cycle (Q2W), the anti HLA-G antibody at 15 mg / kg IV Q2W on Day 1, the anti-EGFR antibody at 500 mg / m2IV Q2W on Day 1, leucovorin at 400 mg / m2IV Q2W, 5-FU at 400 mg / m2IV bolus on Day 1 and 2400 mg / m2as continuous IV infusion on Day 2 or Day 3, and irinotecan at 180 mg / m2IV Q2W on Day 1, and (b) further administering in one or more subsequent cycles (Q2W), the anti HLA-G antibody at a 15 mg / kg IV Q2W on Day 1, the anti-EGFR antibody at 500 mg / m2IV Q2W on Day 1, leucovorin at 400 mg / m2IV Q2W, 5- FU at 400 mg / m2IV bolus on Day 1 and 2400 mg / m2as continuous IV infusion on Day 2 or Day 3, and irinotecan at 180 mg / m2IV Q2W on Day 1.

[0128] In some embodiments, the method further comprises administering the anti HLA- G antibody, the anti-EGFR antibody, and FOLFIRI in the first cycle and / or each of the subsequent cycles every two weeks. In some embodiments, the method comprises administering in the first cycle and / or each of the subsequent cycles, the anti HLA-G antibody at a 15 mg / kg IV Q2W on Day 1, the anti-EGFR antibody at 500 mg / m2IV Q2W on Day 1, leucovorin at 400 mg / m2IV Q2W, 5-FU at 400 mg / m2IV bolus on Day 1 and 2400 mg / m2as continuous IV infusion on Day 2 or Day 3, and irinotecan at 180 mg / m2IV Q2W on Day 1.

[0129] In some embodiments, the anti HLA-G antibody is TTX-080. In some embodiments, the anti-EGFR antibody is cetuximab. In some embodiments, FOLFIRI comprises 5 -fluorouracil (5-FU), folic acid or leucovorin, and irinotecan.

[0130] In some embodiments, the method further comprises administering leucovorin at 400 mg / m2, 5-FU at between 200 mg / m2-400 mg / m2IV bolus or between 1200 mg / m2-2400 mg / m2continuous IV infusion, and / or irinotecan at between 100 mg / m2-180 mg / m2. In some embodiments, the method further comprises administering in the first cycle, the antibody which binds to HLA-G at a 15 mg / kg on Day 1, the antibody which binds to EGFR at 400 mg / m2on Day 1, leucovorin at 400 mg / m2, 5-FU at 400 mg / m2IV bolus on Day 1 and 400 mg / m2continuous IV infusion on Day 2 or Day 3, and irinotecan at 400 mg / m2on Day 1. In some embodiments, the method further comprises administering in a subsequent cycle, the antibody which binds to HLA-G at a 15 mg / kg on Day 1, the antibody which binds to EGFR at between 100 mg / m2on -250 mg / m2on Day 1, leucovorin at 400 mg / m2, 5-FU at 400 mg / m2IV bolus on Day 1 and 2400 mg / m2continuous IV infusion on Day 2 or Day 3, and irinotecan at 180 mg / m2on Day 1. In some embodiments, the method further comprises administering in the first cycle and / or each of the subsequent cycles, the antibody which binds to HLA-G at a 15 mg / kg on Day 1, the antibody which binds to EGFR at 500 mg / m2on Day 1, leucovorin at 400 mg / m2, 5-FU at 400 mg / m2IV bolus on Day 1 and 2400 mg / m2continuous IV infusion on Day 2 or Day 3, and irinotecan at 400 mg / m2on Day 1.

[0131] In some embodiments, the cancer is Head and Neck Squamous Cell Carcinoma (HNSCC). In some embodiments, the cancer is colorectal cancer (CRC). In some embodiments, the cancer is triple negative breast cancer (TNBC). In some embodiments, the cancer is renal cell carcinoma (RCC). In some embodiments, the cancer is non-small cell lung cancer (NSCLC). In some embodiments, the cancer is acral melanoma (AM).

[0132] In some embodiments, the cancer has received or progressed on at least 1, 2, 3, 4, or 5 prior treatments. In some embodiments, the cancer has received or progressed on an oxaliplatin and 5-FU based chemotherapy. In some embodiments, the oxaliplatin and 5-FU based chemotherapy was administered with bevacizumab. In some embodiments, the oxaliplatin and 5-FU based chemotherapy was administered without bevacizumab.

[0133] In some embodiments, the cancer has not received a prior EGFR inhibitor therapy (e.g., an anti-EGFR antibody treatment). In some embodiments, the cancer has not received a prior irinotecan treatment. In some embodiments, the cancer has received and / or progressed on a prior irinotecan treatment. In some embodiments, the cancer has not received prior irinotecan treatments.

[0134] A sixth aspect provides a method for treating a subject suffering from cancer, comprising administering to the subject in a first cycle: a) a first dose comprising an effective amount of an anti HLA-G antibody; and b) a first dose comprising an effective amount of ananti-programmed cell death protein 1 (PD-1) antibody at 200 mg IV Q3W or 400 IV Q6W, wherein the administration of the anti HLA-G antibody maintains serum drug concentrations at a target trough level of between about 10-100 pg / mL. In some embodiments, the method further comprising administering the anti HLA-G antibody and the anti-PD-1 antibody in one or more subsequent cycles. In some embodiments, the administration of the anti HLA-G antibody maintains serum drug concentrations at a target trough level of above 50 pg / m in the first and / or the sequent cycles. In some embodiments, the antibody which binds to HLA-G is TTX-080. In some embodiments, the antibody which binds to PD-1 is pembrolizumab.

[0135] In some embodiments, the anti HLA-G antibody and the anti-PD-1 antibody are administered at a 2-4 week interval. In some embodiments the anti HLA-G antibody and the anti-PD-1 antibody are administered every two weeks (Q2W), every 3 weeks (Q3W), or every six weeks (Q6W). In some embodiments, the anti HLA-G antibody and the anti-PD-1 antibody are administered by intravenous infusion. In some embodiments, the administration of the anti HLA-G antibody achieves at least ECeo, EC70, EC so. or EC90 for receptor occupancy (RO).

[0136] In some embodiments, the method comprises administering the anti HLA-G antibody at 0.2-20 mg / kg to the subject in the first dose and / or each of the subsequent cycles. In some embodiments, the method comprises administering the anti HLA-G antibody at 0.2 mg / kg, 0.6 mg / kg, 2 mg / kg, 6 mg / kg, 10 mg / kg, 12 mg / kg, 15 mg / kg, or 20 mg / kg to the subject in the first dose and / or each of the subsequent cycles. In some embodiments, the method comprises further administering the anti PD-1 antibody at 100 mg-500 mg every three weeks (Q3W) or every six weeks (Q6W). In some embodiments, the method comprises further administering the anti PD-1 antibody at 100 mg, 200 mg, 300 mg, 400 mg, or 500 mg Q3Wor Q6W.

[0137] In some embodiments, the method comprises (a) administering the anti HLA-G antibody at 20 mg / kg Q3W and the anti PD-1 antibody at 200 mg Q3W and (b) further administering in one or more subsequent cycles (Q3W) the anti HLA-G antibody at 20 mg / kg Q3W and the anti PD-1 antibody at 400 mg Q6W.

[0138] In some embodiments, the method comprises administering the anti HLA-G antibody and the anti PD-1 antibody in a cycle and one or more subsequent cycles every three weeks. In some embodiments, the method comprises (a) administering in the first cycle the anti HLA-G antibody at 20 mg / kg Q3W and the anti PD-1 antibody at 200 mg Q3W and (b) further administering in one or more subsequent cycles (Q3W) the anti HLA-G antibody at20 mg / kg Q3W and the anti PD-1 antibody at 400 mg Q6W. In some embodiments, the anti HLA-G antibody is TTX-080. In some embodiments, the PD-1 antibody is pembrolizumab.

[0139] In some embodiments, the cancer is advanced or metastatic. In some embodiments, the cancer is Head and Neck Squamous Cell Carcinoma (HNSCC). In some embodiments, the cancer is colorectal cancer (CRC). In some embodiments, the cancer is triple negative breast cancer (TNBC). In some embodiments, the cancer is renal cell carcinoma (RCC). In some embodiments, the cancer is non-small cell lung cancer (NSCLC). In some embodiments, the cancer is acral melanoma (AM). In some embodiments, the cancer has received or progressed on at least 1, 2, 3, 4, or 5 prior treatments.

[0140] In some embodiments, the cancer has received or progressed on at least one line of checkpoint inhibitor therapy for the treatment of the advanced disease. In some embodiments, the checkpoint inhibitor at least one of a PD-1 inhibitor, a PD-L1 inhibitor, and / or a CTLA-4 inhibitor. In some embodiments, the cancer is human papilloma virus (HPV)-negative. In some embodiments, the subject has not experienced immune related or other adverse effects on a prior checkpoint inhibitor treatment that requires permanent discontinuation of the checkpoint inhibitor treatment.

[0141] In some embodiments of any of the above aspects, the antibody which binds toHLA-G is administered prior to the anti -PD-1 antibody. In some embodiments, the antibody which binds to HLA-G is administered after the anti-PD-1 antibody. In some embodiments, the antibody which binds to HLA-G is administered concurrently with the anti-PD-1 antibody. In some embodiments, the antibody which binds to HLA-G and the anti-PD-1 antibody are administered about 30-minutes apart.

[0142] In some embodiments, the subject is a human subject. In some embodiments, the subject derives a clinical benefit, the clinical benefit being overall survival (OS), progression- free survival (PFS), or objective response rate (ORR). In some embodiments, the treatment provides an ORR that is superior to that of a standard of care therapy (e.g., monotherapy of pembrolizumab, a derivative or an equivalent thereof, or in combination with one or more therapeutic agents).

[0143] In some embodiments, the antibody which binds HLA-G comprises TTX-080. In some embodiments, the antibody which binds to HLA-G comprises or consists of a heavy chain variable region (VH) and a light chain variable region (VL), with the VH comprising:(i) a VHCDR1 having the sequence set forth in SEQ ID NO: 1 or SEQ ID NO: 11,(ii) a VHCDR2 having the sequence set forth in SEQ ID NO: 21 or SEQ ID NO: 31, and(iii) a VHCDR3 having the sequence set forth in SEQ ID NO: 41, and the VL comprising:(iv) a VLCDR1 having the sequence set forth in SEQ ID NO: 51,(v) a VLCDR2 having the sequence set forth in SEQ ID NO: 61, and(vi) a VLCDR3 having the sequence set forth in SEQ ID NO: 71.In some embodiments, the antibody which binds to HLA-G comprises or consists of a heavy chain variable region (VH) and a light chain variable region (VL), with the VH comprising:(i) a VHCDR1 having the sequence set forth in SEQ ID NO: 1,(ii) a VHCDR2 having the sequence set forth in SEQ ID NO: 21, and(iii) a VHCDR3 having the sequence set forth in SEQ ID NO: 41, and the VL comprising:(iv) a VLCDR1 having the sequence set forth in SEQ ID NO: 51,(v) a VLCDR2 having the sequence set forth in SEQ ID NO: 61, and(vi) a VLCDR3 having the sequence set forth in SEQ ID NO: 71.In some embodiments, the antibody which binds to HLA-G comprises or consists of a heavy chain variable region (VH) and a light chain variable region (VL), with the VH comprising:(i) a VHCDR1 having the sequence set forth in SEQ ID NO: 11,(ii) a VHCDR2 having the sequence set forth in SEQ ID NO: 31, and(iii) a VHCDR3 having the sequence set forth in SEQ ID NO: 41, and the VL comprising:(iv) a VLCDR1 having the sequence set forth in SEQ ID NO: 51,(v) a VLCDR2 having the sequence set forth in SEQ ID NO: 61, and(vi) a VLCDR3 having the sequence set forth in SEQ ID NO: 71.

[0144] In some embodiments, the antibody which binds to HLA-G comprises or consists of a heavy chain variable region (VH) and a light chain variable region (VL), with the VH comprising, consisting of, or consisting essentially of a VH having the sequence set forth in SEQ ID NO: 81 and VL comprising, consisting of, or consisting essentially of a VL having the sequence set forth in SEQ ID NO: 91. In some embodiments, the antibody which binds to HLA-G comprises or consists of a heavy chain (HC) and a light chain (LC), the HC comprising, consisting of, or consisting essentially of a sequence set forth in SEQ ID NO: 101 or SEQ ID NO: 102 and of a LC comprising, consisting of, or consisting essentially of a sequence set forth in SEQ ID NO: 111.

[0145] In some embodiments, the antibody which binds to HLA-G comprises or consists of a heavy chain (HC) and a light chain (LC), with the HC comprising, consisting of, or consisting essentially of a sequence set forth in SEQ ID NO: 101 and the LC comprising, consisting of, or consisting essentially of sequence set forth in SEQ ID NO: 111. In some embodiments, the antibody which binds to HLA-G comprises or consists of a heavy chain (HC) and a light chain (LC), with the HC comprising, consisting of, or consisting essentially of a sequence set forth in SEQ ID NO: 102 and the LC comprising, consisting of, or consisting essentially of sequence set forth in SEQ ID NO: 111.

[0146] In some embodiments, the VH sequence is at least 85% or at least 95% identical to the amino acid sequence set forth in SEQ ID NO: 81 and the VL sequence is at least 85% or at least 95% identical to the amino acid sequence set forth in SEQ ID NO: 91. In some embodiments, the HC comprises or consists of a sequence at least 85% or at least 95% identical to the amino acid sequence set forth in SEQ ID NO: 101 and the LC comprises or consists of a sequence least 85% or at least 95% identity to the amino acid sequence set forth in SEQ ID NO: 111. In some embodiments, the HC comprises or consists of a sequence at having least 85% or at least 95% identical to the amino acid sequence set forth in SEQ ID NO: 102 and the VL comprises or consists of a sequence having at least 85% or at least 95% identical to the amino acid sequence set forth in SEQ ID NO: 111.

[0147] In some embodiments, the anti-EGFR antibody is cetuximab. In some embodiments, the antibody which binds to an epidermal growth factor receptor (EGFR) comprises or consists of a heavy chain variable region (VH) and a light chain variable region (VL), with the VH comprising:(i) a VHCDR1 having the sequence set forth in SEQ ID NO: 9 or SEQ ID NO: 19,(ii) a VHCDR2 having the sequence set forth in SEQ ID NO: 29 or SEQ ID NO: 39,(iii) a VHCDR3 having the sequence set forth in SEQ ID NO: SEQ ID NO: 49, and the VL comprising(i) a VLCDR1 having the sequence set forth in SEQ ID NO: SEQ ID NO: 59,(ii) a VLCDR2 having the sequence set forth in SEQ ID NO: SEQ NO: 69, and(iii) a VLCDR3 having the sequence set forth in SEQ ID NO: 79.In some embodiments, the antibody which binds to an epidermal growth factor receptor(EGFR) comprises or consists of a heavy chain variable region (VH) and a light chain variable region (VL), with the VH comprising:(i) a VHCDR1 having the sequence set forth in SEQ ID NO: 9,(ii) a VHCDR2 having the sequence set forth in SEQ ID NO: 29,(iii) a VHCDR3 having the sequence set forth in SEQ ID NO: SEQ ID NO: 49, and the VL comprising(i) a VLCDR1 having the sequence set forth in SEQ ID NO: SEQ ID NO: 59,(ii) a VLCDR2 having the sequence set forth in SEQ ID NO: SEQ NO: 69, and(iii) a VLCDR3 having the sequence set forth in SEQ ID NO: 79.In some embodiments, the antibody which binds to an epidermal growth factor receptor (EGFR) comprises or consists of a heavy chain variable region (VH) and a light chain variable region (VL), with the VH comprising:(i) a VHCDR1 having the sequence set forth in SEQ ID NO: 19,(ii) a VHCDR2 having the sequence set forth in SEQ ID NO: 39,(iii) a VHCDR3 having the sequence set forth in SEQ ID NO: SEQ ID NO: 49, and the VL comprising(i) a VLCDR1 having the sequence set forth in SEQ ID NO: SEQ ID NO: 59,(ii) a VLCDR2 having the sequence set forth in SEQ ID NO: SEQ NO: 69, and(iii) a VLCDR3 having the sequence set forth in SEQ ID NO: 79.

[0148] In some embodiments, the antibody which binds to an epidermal growth factor receptor (EGFR) comprises or consists of a heavy chain variable region (VH) and a light chain variable region (VL), the VH comprising, consisting of, or consisting essentially of a VH having the sequence set forth in SEQ ID NO: 89 and of a VL comprising, consisting of, or consisting essentially of a VL having the sequence set forth in SEQ ID NO: 99. In some embodiments, the antibody which binds to EFGR comprises or consists of a heavy chain (HC) and a light chain (LC), the HC comprising, consisting of, or consisting essentially of a sequence set forth in SEQ ID NO: 109 and the LC comprising, consisting of, or consisting essentially of a sequence set forth in SEQ ID NO: 119.

[0149] In some embodiments, the anti-EGFR antibody comprises or consists of a heavy chain variable region (VH) that is least 85% or at least 95% identical to the amino acid sequence set forth in SEQ ID NO: 89 and a light chain variable region (VL) that is at least 85% or at least 95% identical to the amino acid sequence set forth in SEQ ID NO: 99. In some embodiments, the anti-EGFR antibody comprises or consists of a VH having a sequence set forth in SEQ ID NO: 89 and a VL having a sequence set forth in SEQ ID NO: 99. In some embodiments, the anti-EGFR antibody comprises or consists of a heavy chain (HC) that is at least 85% or at least 95% identical to the amino acid sequence set forth in SEQID NO: 109 and a light chain (LC) that is at least 85% or at least 95% identical to the amino acid sequence set forth in SEQ ID NO: 119.

[0150] In some embodiments, the antibody which binds to HLA-G comprises or consists of a heavy chain variable region (VH) and a light chain variable region (VL), with the VH comprising:(i) a VHCDR1 having the sequence set forth in SEQ ID NO: 1 or SEQ ID NO:11,(ii) a VHCDR2 having the sequence set forth in SEQ ID NO: 21 or SEQ ID NO:31, and(iii) a VHCDR3 having the sequence set forth in SEQ ID NO: 41, and the VL comprising:(iv) a VLCDR1 having the sequence set forth in SEQ ID NO: 51,(v) a VLCDR2 having the sequence set forth in SEQ ID NO: 61, and(vi) a VLCDR3 having the sequence set forth in SEQ ID NO: 71 and the antibody which binds to an epidermal growth factor receptor (EGFR) comprises or consists of a heavy chain variable region (VH) and a light chain variable region (VL), with the VH comprising:(i) a VHCDR1 having the sequence set forth in SEQ ID NO: 9 or SEQ ID NO:19,(ii) a VHCDR2 having the sequence set forth in SEQ ID NO: 29 or SEQ ID NO:39,(iii) a VHCDR3 having the sequence set forth in SEQ ID NO: SEQ ID NO: 49, and the VL comprising(i) a VLCDR1 having the sequence set forth in SEQ ID NO: SEQ ID NO: 59,(ii) a VLCDR2 having the sequence set forth in SEQ ID NO: SEQ NO: 69, and(iii) a VLCDR3 having the sequence set forth in SEQ ID NO: 79.In some embodiments, the antibody which binds to HLA-G comprises or consists of a heavy chain variable region (VH) and a light chain variable region (VL), with the VH comprising:(i) a VHCDR1 having the sequence set forth in SEQ ID NO: 1,(ii) a VHCDR2 having the sequence set forth in SEQ ID NO: 21, and(iii) a VHCDR3 having the sequence set forth in SEQ ID NO: 41, and the VL comprising:(iv) a VLCDR1 having the sequence set forth in SEQ ID NO: 51,(v) a VLCDR2 having the sequence set forth in SEQ ID NO: 61, and(vi) a VLCDR3 having the sequence set forth in SEQ ID NO: 71 and the antibody which binds to an epidermal growth factor receptor (EGFR) comprises or consists of a heavy chain variable region (VH) and a light chain variable region (VL), with the VH comprising:(i) a VHCDR1 having the sequence set forth in SEQ ID NO: 9,(ii) a VHCDR2 having the sequence set forth in SEQ ID NO: 29,(iii) a VHCDR3 having the sequence set forth in SEQ ID NO: SEQ ID NO: 49, and the VL comprising(i) a VLCDR1 having the sequence set forth in SEQ ID NO: SEQ ID NO: 59,(ii) a VLCDR2 having the sequence set forth in SEQ ID NO: SEQ NO: 69, and(iii) a VLCDR3 having the sequence set forth in SEQ ID NO: 79.In some embodiments, the antibody which binds to HLA-G comprises or consists of a heavy chain variable region (VH) and a light chain variable region (VL), with the VH comprising:(i) a VHCDR1 having the sequence set forth in SEQ ID NO: 11,(ii) a VHCDR2 having the sequence set forth in SEQ ID NO: 31, and(iii) a VHCDR3 having the sequence set forth in SEQ ID NO: 41, and the VL comprising:(iv) a VLCDR1 having the sequence set forth in SEQ ID NO: 51,(v) a VLCDR2 having the sequence set forth in SEQ ID NO: 61, and(vi) a VLCDR3 having the sequence set forth in SEQ ID NO: 71 and the antibody which binds to an epidermal growth factor receptor (EGFR) comprises or consists of a heavy chain variable region (VH) and a light chain variable region (VL), with the VH comprising:(i) a VHCDR1 having the sequence set forth in SEQ ID NO: 19,(ii) a VHCDR2 having the sequence set forth in SEQ ID NO: 39,(iii) a VHCDR3 having the sequence set forth in SEQ ID NO: SEQ ID NO: 49, and the VL comprising(i) a VLCDR1 having the sequence set forth in SEQ ID NO: SEQ ID NO: 59,(ii) a VLCDR2 having the sequence set forth in SEQ ID NO: SEQ NO: 69, and(iii) a VLCDR3 having the sequence set forth in SEQ ID NO: 79.

[0151] In some embodiments, the antibody which binds to HLA-G comprises or consists of a heavy chain variable region (VH) and a light chain variable region (VL), with the VH comprising, consisting of, or consisting essentially of a VH having the sequence set forth in SEQ ID NO: 81 and VL comprising, consisting of, or consisting essentially of a VL havingthe sequence set forth in SEQ ID NO: 91 and the antibody which binds to an epidermal growth factor receptor (EGFR) comprises or consists of a heavy chain variable region (VH) and a light chain variable region (VL), the VH comprising, consisting of, or consisting essentially of a VH having the sequence set forth in SEQ ID NO: 89 and of a VL comprising, consisting of, or consisting essentially of a VL having the sequence set forth in SEQ ID NO: 99. In some embodiments, the antibody which binds to HLA-G comprises or consists of a heavy chain (HC) and a light chain (LC), the HC comprising, consisting of, or consisting essentially of a sequence set forth in SEQ ID NO: 101 or SEQ ID NO: 102 and of a LC comprising, consisting of, or consisting essentially of a sequence set forth in SEQ ID NO: 111 and the antibody which binds to EFGR comprises or consists of a heavy chain (HC) and a light chain (LC), the HC comprising, consisting of, or consisting essentially of a sequence set forth in SEQ ID NO: 109 and the LC comprising, consisting of, or consisting essentially of a sequence set forth in SEQ ID NO: 119.

[0152] In some embodiments, the antibody which binds to HLA-G comprises or consists of a heavy chain (HC) and a light chain (LC), with the HC comprising, consisting of, or consisting essentially of a sequence set forth in SEQ ID NO: 101 and the LC comprising, consisting of, or consisting essentially of sequence set forth in SEQ ID NO: 111 and the antibody which binds to EFGR comprises or consists of a heavy chain (HC) and a light chain (LC), the HC comprising, consisting of, or consisting essentially of a sequence set forth in SEQ ID NO: 109 and the LC comprising, consisting of, or consisting essentially of a sequence set forth in SEQ ID NO: 119. In some embodiments, the antibody which binds to HLA-G comprises or consists of a heavy chain (HC) and a light chain (LC), with the HC comprising, consisting of, or consisting essentially of a sequence set forth in SEQ ID NO: 102 and the LC comprising, consisting of, or consisting essentially of sequence set forth in SEQ ID NO: 111 and the antibody which binds to EFGR comprises or consists of a heavy chain (HC) and a light chain (LC), the HC comprising, consisting of, or consisting essentially of a sequence set forth in SEQ ID NO: 109 and the LC comprising, consisting of, or consisting essentially of a sequence set forth in SEQ ID NO: 119.

[0153] In some embodiments, the anti-PD-1 antibody is pembrolizumab. In some embodiments, the antibody which binds to PD-1 comprises or consists of a heavy chain variable region (VH) and a light chain variable region (VL), with the VH comprising:(i) a VHCDR1 having the sequence set forth in any one of SEQ ID NO: 3 or SEQ ID NO: 10,(ii) a VHCDR2 having the sequence set forth in any one of SEQ ID NO: 23 or SEQ ID NO: 30, and(iii) a VHCDR3 having the sequence set forth in any one of SEQ ID NO: 50, and the VL comprising:(vi) a VLCDR1 having the sequence set forth in any one of SEQ ID NO: 60,(v) a VLCDR2 having the sequence set forth in any one of SEQ ID NO: 70, and(vi) a VLCDR3 having the sequence set forth in any one of SEQ ID NO: 80.In some embodiments, the antibody which binds to PD-1 comprises or consists of a heavy chain variable region (VH) and a light chain variable region (VL), with the VH comprising:(i) a VHCDR1 having the sequence set forth in any one of SEQ ID NO: 3,(ii) a VHCDR2 having the sequence set forth in any one of SEQ ID NO: 23, and(iii) a VHCDR3 having the sequence set forth in any one of SEQ ID NO: 50, and the VL comprising:(vi) a VLCDR1 having the sequence set forth in any one of SEQ ID NO: 60,(v) a VLCDR2 having the sequence set forth in any one of SEQ ID NO: 70, and(vi) a VLCDR3 having the sequence set forth in any one of SEQ ID NO: 80.In some embodiments, the antibody which binds to PD-1 comprises or consists of a heavy chain variable region (VH) and a light chain variable region (VL), with the VH comprising:(i) a VHCDR1 having the sequence set forth in any one of SEQ ID NO: 10,(ii) a VHCDR2 having the sequence set forth in any one of SEQ ID NO: 30, and(iii) a VHCDR3 having the sequence set forth in any one of SEQ ID NO: 50, and the VL comprising:(vi) a VLCDR1 having the sequence set forth in any one of SEQ ID NO: 60,(v) a VLCDR2 having the sequence set forth in any one of SEQ ID NO: 70, and(vi) a VLCDR3 having the sequence set forth in any one of SEQ ID NO: 80.

[0154] In some embodiments, the antibody which binds to PD-1 comprises or consists of a heavy chain variable region (VH) and a light chain variable region (VL), with the VH comprising, consisting of, or consisting essentially of a VH having the sequence set forth SEQ ID NO: 90 and the VL comprising, consisting of, or consisting essentially of a VL having the sequence set forth in SEQ ID NO: 100. In some embodiments, the antibody which binds to PD-1 comprises or consists of a heavy chain (HC) and a light chain (LC), with the HC comprising, consisting of, or consisting essentially of an HC having the sequence set forth in SEQ ID NO: 110 and an LC comprising, consisting of, or consisting essentially of an LC having the sequence set forth in SEQ ID NO: 120.

[0155] In some embodiments, the anti-PD-1 antibody comprises or consists of a heavy chain variable region (VH) which is at least 85% or at least 95% identical to the amino acid sequence set forth in SEQ ID NO: 90 and a light chain variable region (VL) which is at least 85% or at least 95% identical to the amino acid sequence set forth in SEQ ID NO: 100. In some embodiments, the anti-PD-1 antibody comprises or consists of a VH having a sequence set forth in SEQ ID NO: 90 and a VL having a sequence set forth in SEQ ID NO: 100. In some embodiments, the anti-PD-1 antibody comprises or consists of a heavy chain (HC) which is at least 85% or at least 95% identical to the amino acid sequence set forth in SEQ ID NO: 110 and a light chain (LC) which is at least 85% or at least 95% identical to the amino acid sequence set forth in SEQ ID NO: 120.

[0156] In some embodiments, the antibody which binds to HLA-G comprises or consists of a heavy chain variable region (VH) and a light chain variable region (VL), with the VH comprising:(i) a VHCDR1 having the sequence set forth in SEQ ID NO: 1 or SEQ ID NO: 11,(ii) a VHCDR2 having the sequence set forth in SEQ ID NO: 21 or SEQ ID NO: 31, and(iii) a VHCDR3 having the sequence set forth in SEQ ID NO: 41, and the VL comprising:(iv) a VLCDR1 having the sequence set forth in SEQ ID NO: 51,(v) a VLCDR2 having the sequence set forth in SEQ ID NO: 61, and(vi) a VLCDR3 having the sequence set forth in SEQ ID NO: 71 and the antibody which binds to PD-1 comprises or consists of a heavy chain variable region(VH) and a light chain variable region (VL), with the VH comprising:(i) a VHCDR1 having the sequence set forth in any one of SEQ ID NO: 3 or SEQ ID NO: 10,(ii) a VHCDR2 having the sequence set forth in any one of SEQ ID NO: 23 or SEQ ID NO: 30, and(iii) a VHCDR3 having the sequence set forth in any one of SEQ ID NO: 50, and the VL comprising:(vi) a VLCDR1 having the sequence set forth in any one of SEQ ID NO: 60,(v) a VLCDR2 having the sequence set forth in any one of SEQ ID NO: 70, and(vi) a VLCDR3 having the sequence set forth in any one of SEQ ID NO: 80.In some embodiments, the antibody which binds to HLA-G comprises or consists of a heavy chain variable region (VH) and a light chain variable region (VL), with the VH comprising:(i) a VHCDR1 having the sequence set forth in SEQ ID NO: 1,(ii) a VHCDR2 having the sequence set forth in SEQ ID NO: 21, and(iii) a VHCDR3 having the sequence set forth in SEQ ID NO: 41, and the VL comprising:(iv) a VLCDR1 having the sequence set forth in SEQ ID NO: 51,(v) a VLCDR2 having the sequence set forth in SEQ ID NO: 61, and(vi) a VLCDR3 having the sequence set forth in SEQ ID NO: 71 and the antibody which binds to PD-1 comprises or consists of a heavy chain variable region(VH) and a light chain variable region (VL), with the VH comprising:(i) a VHCDR1 having the sequence set forth in any one of SEQ ID NO: 3,(ii) a VHCDR2 having the sequence set forth in any one of SEQ ID NO: 23, and(iii) a VHCDR3 having the sequence set forth in any one of SEQ ID NO: 50, and the VL comprising:(vi) a VLCDR1 having the sequence set forth in any one of SEQ ID NO: 60,(v) a VLCDR2 having the sequence set forth in any one of SEQ ID NO: 70, and(vi) a VLCDR3 having the sequence set forth in any one of SEQ ID NO: 80.In some embodiments, the antibody which binds to HLA-G comprises or consists of a heavy chain variable region (VH) and a light chain variable region (VL), with the VH comprising:(i) a VHCDR1 having the sequence set forth in SEQ ID NO: 11,(ii) a VHCDR2 having the sequence set forth in SEQ ID NO: 31, and(iii) a VHCDR3 having the sequence set forth in SEQ ID NO: 41, and the VL comprising:(iv) a VLCDR1 having the sequence set forth in SEQ ID NO: 51,(v) a VLCDR2 having the sequence set forth in SEQ ID NO: 61, and(vi) a VLCDR3 having the sequence set forth in SEQ ID NO: 71 and the antibody which binds to PD-1 comprises or consists of a heavy chain variable region(VH) and a light chain variable region (VL), with the VH comprising:(i) a VHCDR1 having the sequence set forth in any one of SEQ ID NO: 10,(ii) a VHCDR2 having the sequence set forth in any one of SEQ ID NO: 30, and(iii) a VHCDR3 having the sequence set forth in any one of SEQ ID NO: 50, and the VL comprising:(vi) a VLCDR1 having the sequence set forth in any one of SEQ ID NO: 60,(v) a VLCDR2 having the sequence set forth in any one of SEQ ID NO: 70, and(vi) a VLCDR3 having the sequence set forth in any one of SEQ ID NO: 80.

[0157] In some embodiments, the antibody which binds to HLA-G comprises or consists of a heavy chain variable region (VH) and a light chain variable region (VL), with the VH comprising, consisting of, or consisting essentially of a VH having the sequence set forth in SEQ ID NO: 81 and VL comprising, consisting of, or consisting essentially of a VL having the sequence set forth in SEQ ID NO: 91 and the antibody which binds to PD-1 comprises or consists of a heavy chain variable region (VH) and a light chain variable region (VL), with the VH comprising, consisting of, or consisting essentially of a VH having the sequence set forth SEQ ID NO: 90 and the VL comprising, consisting of, or consisting essentially of a VL having the sequence set forth in SEQ ID NO: 100. In some embodiments, the antibody which binds to HLA-G comprises or consists of a heavy chain (HC) and a light chain (LC), the HC comprising, consisting of, or consisting essentially of a sequence set forth in SEQ ID NO: 101 or SEQ ID NO: 102 and of a LC comprising, consisting of, or consisting essentially of a sequence set forth in SEQ ID NO: 111 and the antibody which binds to PD-1 comprises or consists of a heavy chain (HC) and a light chain (LC), with the HC comprising, consisting of, or consisting essentially of an HC having the sequence set forth in SEQ ID NO: 110 and an LC comprising, consisting of, or consisting essentially of an LC having the sequence set forth in SEQ ID NO: 120.

[0158] In some embodiments, the antibody which binds to HLA-G comprises or consists of a heavy chain (HC) and a light chain (LC), with the HC comprising, consisting of, or consisting essentially of a sequence set forth in SEQ ID NO: 101 and the LC comprising, consisting of, or consisting essentially of sequence set forth in SEQ ID NO: 111 the antibody which binds to PD-1 comprises or consists of a heavy chain (HC) and a light chain (LC), with the HC comprising, consisting of, or consisting essentially of an HC having the sequence set forth in SEQ ID NO: 110 and an LC comprising, consisting of, or consisting essentially of an LC having the sequence set forth in SEQ ID NO: 120. In some embodiments, the antibody which binds to HLA-G comprises or consists of a heavy chain (HC) and a light chain (LC), with the HC comprising, consisting of, or consisting essentially of a sequence set forth in SEQ ID NO: 102 and the LC comprising, consisting of, or consisting essentially of sequence set forth in SEQ ID NO: 111 the antibody which binds to PD-1 comprises or consists of a heavy chain (HC) and a light chain (LC), with the HC comprising, consisting of, or consisting essentially of an HC having the sequence set forth in SEQ ID NO: 110 and an LCcomprising, consisting of, or consisting essentially of an LC having the sequence set forth in SEQ ID NO: 120.

[0159] Dosing is exemplified herein. The doctor will determine the dose which she considers most appropriate according to a preventive or curative treatment and according to the age, weight, condition, and other factors specific to the subject to be treated.

[0160] The amount of the antibody or composition comprising the antibody which will be effective in the prevention or treatment of a disorder or one or more symptoms thereof will vary with the nature and severity of the disease or condition and the route by which the antibody is administered. The frequency and dosage will also vary according to factors specific for each subject depending on the specific therapy (e.g., therapeutic or prophylactic agents) administered, the severity of the disorder, disease, or condition, the route of administration, as well as age, body, weight, response, and the past medical history of the subject. Effective doses may be extrapolated from dose-response curves derived from in vitro or animal model test systems.

[0161] Exemplary doses of a composition comprising an antibody which binds HLA-G include milligram or microgram amounts of the antibody per kilogram of subject or sample weight (e.g., about 10 micrograms per kilogram to about 50 milligrams per kilogram, about 100 micrograms per kilogram to about 25 milligrams per kilogram, or about 100 microgram per kilogram to about 10 milligrams per kilogram). Doses for the antibody which binds HLA-G can be administered in combination, as set forth herein, or as a monotherapy.

[0162] In some embodiments, the dosage of the antibody which binds HLA-G, based on weight of the antibody, administered to prevent, treat, manage, or ameliorate a disorder, or one or more symptoms thereof in a subject may be 0.1 mg / kg, 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 10 mg / kg, 15 mg / kg, 20mg / kg, 25 mg / kg, 30 mg / kg, 35 mg / kg 40 mg / kg, 45 mg / kg, 50 mg / kg or more of a subject’s body weight. In some embodiments, the dosage may be about 0.1 mg / kg, about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 10 mg / kg, about 15 mg / kg, about 20mg / kg, about 25 mg / kg, about 30 mg / kg, about 35 mg / kg about 40 mg / kg, about 45 mg / kg, about 50 mg / kg, about 55 mg / kg, about 60 mg / kg, about 65 mg / kg, about 70 mg / kg, about 75 mg / kg, about 80 mg / kg, about 85 mg / kg, about 90 mg / kg, about 95 mg / kg, about 100 mg / kg or more of a subject’s body weight.

[0163] In some embodiments, the dosage of the antibody which binds HLA-G or composition comprising the antibody which binds HLA-G administered to prevent, treat, manage, or ameliorate a disorder, or one or more symptoms thereof in a subject may be about0.1 mg to about 200 mg, about 0.1 mg to about 100 mg, about 0.1 mg to about 50 mg, about 0.1 mg to about 25 mg, about 0.1 mg to about 20 mg, about 0.1 mg to about 15 mg, about 0.1 mg to about 10 mg, about 0.1 mg to about 7.5 mg, about 0.1 mg to about 5 mg, about 0.1 to about 2.5 mg, about 0.25 mg to about 20 mg, about 0.25 to about 15 mg, about 0.25 to about 12 mg, about 0.25 to about 10 mg, about 0.25 mg to about 7.5 mg, about 0.25 mg to about 5 mg, about 0.25 mg to about 2.5 mg, about 0.5 mg to about 20 mg, about 0.5 to 15 mg, about 0.5 to 12 mg, about 0.5 to about 10 mg, about 0.5 mg to about 7.5 mg, about 0.5 mg to about 5 mg, about 0.5 mg to about 2.5 mg, about 1 mg to about 20 mg, about 1 mg to about 15 mg, about 1 mg to about 12 mg, about 1 mg to about 10 mg, about 1 mg to about 7.5 mg, about 1 mg to about 5 mg, or about 1 mg to about 2.5 mg. In some embodiments, the dosage of the antibody which binds HLA-G or composition comprising the antibody which binds HLA-G is 0.1 mg to 200 mg, 0.1 mg to 100 mg, 0.1 mg to 50 mg, 0.1 mg to 25 mg, 0.1 mg to 20 mg, 0.1 mg to 15 mg, 0.1 mg to 10 mg, 0.1 mg to 7.5 mg, 0.1 mg to 5 mg, 0.1 to 2.5 mg, 0.25 mg to 20 mg, 0.25 to 15 mg, 0.25 to 12 mg, 0.25 to 10 mg, 0.25 mg to 7.5 mg, 0.25 mg to 5 mg, 0.25 mg to 2.5 mg, 0.5 mg to 20 mg, 0.5 to 15 mg, 0.5 to 12 mg, 0.5 to 10 mg, 0.5 mg to 7.5 mg, 0.5 mg to 5 mg, 0.5 mg to 2.5 mg, 1 mg to 20 mg, 1 mg to 15 mg, 1 mg to 12 mg, 1 mg to 10 mg, 1 mg to 7.5 mg, 1 mg to 5 mg, or 1 mg to 2.5 mg.

[0164] In some embodiments, a subject with cancer and / or advanced refractory / resistant solid tumors receives an anti HLA-G antibody described herein (TTX-080) at between about 0.2 to about 100 mg / kg IV Q2W or Q3W. In some embodiments, a subject with cancer and / or advanced refractory / resistant solid tumors receives an anti HLA-G antibody described herein (TTX-080) at between about 0.6 to about 90 mg / kg IV Q2W or Q3W, between about 2 to about 80 mg / kg IV Q2W or Q3W, between about 6 to about 95 mg / kg IV Q2W or Q3W, between about 10 to about 70 mg / kg IV Q2W or Q3W, between about 15 to about 60 mg / kg IV Q2W or Q3W, between about 15 to about 40 mg / kg IV Q2W or Q3W, or between about 10 to about 30 mg / kg IV Q2W or Q3W. In some embodiments, the anti HLA-G antibody is in combination, as set forth herein, or as a monotherapy.

[0165] In some embodiments, a subject with cancer and / or advanced refractory / resistant solid tumors receives an anti HLA-G antibody described herein (TTX-080) at about 0.2 mg / kg IV Q2W or Q3W, about 0.6 mg / kg IV Q2W or Q3W, about 2 mg / kg IV Q2W or Q3W, about 6 mg / kg IV Q2W or Q3W, about 10 mg / kg IV Q2W or Q3W, about 15 mg / kg IV Q2W or Q3W, about 20 mg / kg IV Q2W or Q3W, about 25 mg / kg IV Q2W or Q3W, about 30 mg / kg IV Q2W or Q3W, about 35 mg / kg IV Q2W or Q3W, about 40 mg / kg IVQ2W or Q3W, about 45 mg / kg IV Q2W or Q3W, about 50 mg / kg IV Q2W or Q3W, about 55 mg / kg IV Q2W or Q3W, about 60 mg / kg IV Q2W or Q3W, about 65 mg / kg IV Q2W or Q3W, about 70 mg / kg IV Q2W or Q3W, about 75 mg / kg IV Q2W or Q3W, about 80 mg / kg IV Q2W or Q3W, about 85 mg / kg IV Q2W or Q3W, about 90 mg / kg IV Q2W or Q3W, about 95 mg / kg IV Q2W or Q3W, or about 100 mg / kg IV Q2W or Q3W in combination as set forth herein. In some embodiments, the anti HLA-G antibody is in combination, as set forth herein, or as a monotherapy.

[0166] In some embodiments, a subject with cancer and / or advanced refractory / resistant solid tumors receives an anti HLA-G antibody described herein (TTX-080) at 0.2 mg / kg IV Q2W or Q3W. In some embodiments, a subject with cancer and / or advanced refractory / resistant solid tumors receives an anti HLA-G antibody described herein (TTX- 080) at 0.6 mg / kg IV Q2W or Q3W. In some embodiments, a subject with cancer and / or advanced refractory / resistant solid tumors receives an anti HLA-G antibody described herein (TTX-080) at 2 mg / kg IV Q2W or Q3W. In some embodiments, a subject with cancer and / or advanced refractory / resistant solid tumors receives an anti HLA-G antibody described herein (TTX-080) at 6 mg / kg IV Q2W or Q3W. In some embodiments, a subject with cancer and / or advanced refractory / resistant solid tumors receives an anti HLA-G antibody described herein (TTX-080) at 10 mg / kg IV Q2W or Q3W. In some embodiments, a subject with cancer and / or advanced refractory / resistant solid tumors receives an anti HLA-G antibody described herein (TTX-080) at 15 mg / kg IV Q2W or Q3W. In some embodiments, a subject with cancer and / or advanced refractory / resistant solid tumors receives an anti HLA-G antibody described herein (TTX-080) at 20 mg / kg IV Q2W or Q3W.

[0167] In some embodiments, a subject with cancer and / or advanced refractory / resistant solid tumors receives an anti HLA-G antibody described herein (TTX-080) at 25 mg / kg IV Q2W or Q3W. In some embodiments, a subject with cancer and / or advanced refractory / resistant solid tumors receives an anti HLA-G antibody described herein (TTX- 080) at 30 mg / kg IV Q2W or Q3W. In some embodiments, a subject with cancer and / or advanced refractory / resistant solid tumors receives an anti HLA-G antibody described herein (TTX-080) at 35 mg / kg IV Q2W or Q3W. In some embodiments, a subject with cancer and / or advanced refractory / resistant solid tumors receives an anti HLA-G antibody described herein (TTX-080) at 40 mg / kg IV Q2W or Q3W. In some embodiments, a subject with cancer and / or advanced refractory / resistant solid tumors receives an anti HLA-G antibody described herein (TTX-080) at 45 mg / kg IV Q2W or Q3W. In some embodiments, a subject with cancer and / or advanced refractory / resistant solid tumors receives an anti HLA-Gantibody described herein (TTX-080) at 50 mg / kg IV Q2W or Q3W. In some embodiments, a subject with cancer and / or advanced refractory / resistant solid tumors receives an anti HLA- G antibody described herein (TTX-080) at 55 mg / kg IV Q2W or Q3W. In some embodiments, a subject with cancer and / or advanced refractory / resistant solid tumors receives an anti HLA-G antibody described herein (TTX-080) at 60 mg / kg IV Q2W or Q3W.

[0168] In some embodiments, a subject with cancer and / or advanced refractory / resistant solid tumors receives an anti HLA-G antibody described herein (TTX-080) at 65 mg / kg IV Q2W or Q3W. In some embodiments, a subject with cancer and / or advanced refractory / resistant solid tumors receives an anti HLA-G antibody described herein (TTX- 080) at 70 mg / kg IV Q2W or Q3W. In some embodiments, a subject with cancer and / or advanced refractory / resistant solid tumors receives an anti HLA-G antibody described herein (TTX-080) at 75 mg / kg IV Q2W or Q3W. In some embodiments, a subject with cancer and / or advanced refractory / resistant solid tumors receives an anti HLA-G antibody described herein (TTX-080) at 80 mg / kg IV Q2W or Q3W. In some embodiments, a subject with cancer and / or advanced refractory / resistant solid tumors receives an anti HLA-G antibody described herein (TTX-080) at 85 mg / kg IV Q2W or Q3W. In some embodiments, a subject with cancer and / or advanced refractory / resistant solid tumors receives an anti HLA-G antibody described herein (TTX-080) at 90 mg / kg IV Q2W or Q3W. In some embodiments, a subject with cancer and / or advanced refractory / resistant solid tumors receives an anti HLA- G antibody described herein (TTX-080) at 95 mg / kg IV Q2W or Q3W. In some embodiments, a subject with cancer and / or advanced refractory / resistant solid tumors receives an anti HLA-G antibody described herein (TTX-080) at 100 mg / kg IV Q2W or Q3W.

[0169] Doses can also be administered according to a suitable schedule, for example, once, two times, three times, or four times weekly. It may be necessary to use dosages of the antibody which binds HLA-G outside the ranges disclosed herein in some cases, as will be apparent to those of ordinary skill in the art. Furthermore, it is noted that the clinician or treating physician will know how and when to interrupt, adjust, or terminate therapy in conjunction with subject response.

[0170] Different therapeutically effective amounts may be applicable for different diseases and conditions. Similarly, amounts sufficient to prevent, manage, treat, or ameliorate such disorders, but insufficient to cause, or sufficient to reduce, adverse effects associated with the antibodies provided herein are also encompassed by the herein described dosage amounts and dose frequency schedules. Further, when a subject is administeredmultiple dosages of an antibody which binds HLA-G or composition provided herein, not all of the dosages need be the same. For example, the dosage administered to the subject may be increased to improve the prophylactic or therapeutic effect of the composition or it may be decreased to reduce one or more side effects that a particular subject is experiencing.

[0171] In some embodiments, treatment or prevention can be initiated with one or more loading doses of the antibody which binds HLA-G or composition provided herein followed by one or more maintenance doses.

[0172] In some embodiments, a dose of the antibody which binds HLA-G or composition provided herein can be administered to achieve a steady-state concentration of the antibody in blood or serum of the subject. The steady-state concentration can be determined by measurement according to techniques available to those of skill or can be based on the physical characteristics of the subject such as height, weight and age.

[0173] In some embodiments, the administration of the anti human HLA-G antibody maintains a serum drug concentration at or above a target trough of 50 pg / mL or about 50 pg / mL during a first cycle and / or each of the subsequent cycle. In some embodiments, the administration of the antibody which binds HLA-G maintains a serum drug concentration from 50 pg / mL to 1200 pg / mL or from about 50 pg / mL to about 1200 pg / mL during the first cycle. In some embodiments, the administration of the anti human HLA-G antibody maintains a serum drug concentration from 50 pg / mL to 1200 pg / mL or from about 50 pg / mL to about 1200 pg / mL during the first cycle and the one or more subsequent cycles. In some embodiments, the administration of the antibody which binds HLA-G maintains a serum drug concentration at or above a target trough of 50 pg / mL or about 50 pg / mL during a first cycle.

[0174] In some embodiments, the serum drug concentration target trough during the first cycle and / or each of the subsequent cycles is maintained at from 50 pg / mL to 100 pg / mL, from 50 pg / mL to 200 pg / mL, from 50 pg / mL to 300 pg / mL, from 50 pg / mL to 400 pg / mL, from 50 pg / mL to 500 pg / mL, from 50 pg / mL to 600 pg / mL, from 50 pg / mL to 700 pg / mL, from 50 pg / mL to 800 pg / mL, from 50 pg / mL to 900 pg / mL, from 50 pg / mL to 1000 pg / mL, from 50 pg / mL to 1100, from 50 pg / mL to 1200 pg / mL, pg / mL, from 100 pg / mL to 200 pg / mL, from 100 pg / mL to 300 pg / mL, from 100 pg / mL to 400 pg / mL, from 100 pg / mL to 500 pg / mL, from 100 pg / mL to 600 pg / mL, from 100 pg / mL to 700 pg / mL, from 100 pg / mL to 800 pg / mL, from 100 pg / mL to 900, from 100 pg / mL to 1000, from 100 pg / mL to 1100, from 100 pg / mL to 1200, from 200 pg / mL to 300 pg / mL, from 200 pg / mL to 400 pg / mL, from 200 pg / mL to 500 pg / mL, from 200 pg / mL to 600 pg / mL, from 200 pg / mL to 700qg / mL, from 200 qg / mL to 800 qg / mL, from 200 qg / mL to 900 qg / mL, from 200 qg / mL to 1000 qg / mL, from 200 qg / mL to 1100 qg / mL, from 200 qg / mL to 1200 qg / mL, from 300 qg / mL to 400 qg / mL, from 300 qg / mL to 500 qg / mL, from 300 qg / mL to 600 qg / mL, from 300 qg / mL to 700 qg / mL, from 300 qg / mL to 800 qg / mL, from 300 qg / mL to 900 qg / mL, from 300 qg / mL to 1000 qg / mL, from 300 qg / mL to 1100 qg / mL, from 300 qg / mL to 1200 qg / mL, from 400 qg / mL to 500 qg / mL, from 400 qg / mL to 600 qg / mL, from 400 qg / mL to 700 qg / mL, from 400 qg / mL to 800 qg / mL, from 400 qg / mL to 900 qg / mL, from 400 qg / mL to 1000 qg / mL, from 400 qg / mL to 1100 qg / mL, from 400 qg / mL to 1200 qg / mL, from 500 qg / mL to 600 qg / mL, from 500 qg / mL to 700 qg / mL, from 500 qg / mL to 800 qg / mL, from 500 qg / mL to 900 qg / mL, from 500 qg / mL to 1000 qg / mL, from 500 qg / mL to 1100 qg / mL, from 500 qg / mL to 1200 qg / mL, from 600 qg / mL to 700 qg / mL, from 600 qg / mL to 800 qg / mL, from 600 qg / mL to 900 qg / mL, from 600 qg / mL to 1000 qg / mL, from 600 qg / mL to 1100 qg / mL, from 600 qg / mL to 1200 qg / mL, from 700 qg / mL to 800 qg / mL, from 700 qg / mL to 900 qg / mL, from 700 qg / mL to 1000 qg / mL, from 700 qg / mL to 1100 qg / mL, from 700 qg / mL to 1200 qg / mL, from 800 qg / mL to 900 qg / mL, from 800 qg / mL to 1000 qg / mL, from 800 qg / mL to 1100 qg / mL, from 800 qg / mL to 1200 qg / mL, from 900 qg / mL to 1000 qg / mL, from 900 qg / mL to 1100 qg / mL, from 900 qg / mL to 1200 qg / mL, from 1000 qg / mL to 1100 qg / mL, from 1000 qg / mL to 1200 qg / mL, from 1100 qg / mL to 1200 qg / mL, or any other subrange of from 50 qg / mL to 1200 qg / mL. Any range may include or exclude the starting and ending concentrations in the range.

[0175] In some embodiments, the serum drug concentration target trough during the first cycle and / or each of the subsequent cycles is maintained at from about 50 qg / mL to about 100 qg / mL, from about 50 qg / mL to about 200 qg / mL, from about 50 qg / mL to about 300 qg / mL, from about 50 qg / mL to about 400 qg / mL, from about 50 qg / mL to about 500 qg / mL, from about 50 qg / mL to about 600 qg / mL, from about 50 qg / mL to about 700 qg / mL, from about 50 qg / mL to about 800 qg / mL, from about 50 qg / mL to about 900 qg / mL, from about 50 qg / mL to about 1000 qg / mL, from about 50 qg / mL to about 1100, from about 50 qg / mL to about 1200 qg / mL, from about 100 qg / mL to about 200 qg / mL, from about 100 qg / mL to about 300 qg / mL, from about 100 qg / mL to about 400 qg / mL, from about 100 qg / mL to about 500 qg / mL, from about 100 qg / mL to about 600 qg / mL, from about 100 qg / mL to about 700 qg / mL, from about 100 qg / mL to about 800 qg / mL, from about 100 qg / mL to about 900, from about 100 qg / mL to about 1000, from about 100 qg / mL to about 1100, from about 100 qg / mL to about 1200, from about 200 qg / mL to about 300 qg / mL, from about 200 qg / mL to about 400 qg / mL, from about 200 qg / mL to about 500 qg / mL, from about 200qg / mL to about 600 qg / mL, from about 200 qg / mL to about 700 qg / mL, from about 200 qg / mL to about 800 qg / mL, from about 200 qg / mL to about 900 qg / mL, from about 200 qg / mL to about 1000 qg / mL, from about 200 qg / mL to about 1100 qg / mL, from about 200 qg / mL to about 1200 qg / mL, from about 300 qg / mL to about 400 qg / mL, from about 300 qg / mL to about 500 qg / mL, from about 300 qg / mL to about 600 qg / mL, from about 300 qg / mL to about 700 qg / mL, from about 300 qg / mL to about 800 qg / mL, from about 300 qg / mL to about 900 qg / mL, from about 300 qg / mL to about 1000 qg / mL, from about 300 qg / mL to about 1100 qg / mL, from about 300 qg / mL to about 1200 qg / mL, from 400 about qg / mL to about 500 qg / mL, from about 400 qg / mL to about 600 qg / mL, from about 400 qg / mL to about 700 qg / mL, from about 400 qg / mL to about 800 qg / mL, from about 400 qg / mL to about 900 qg / mL, from about 400 qg / mL to about 1000 qg / mL, from about 400 qg / mL to about 1100 qg / mL, from about 400 qg / mL to about 1200 qg / mL, from about 500 qg / mL to about 600 qg / mL, from about 500 qg / mL to about 700 qg / mL, from 500 qg / mL to 800 qg / mL, from about 500 qg / mL to about 900 qg / mL, from about 500 qg / mL to about 1000 qg / mL, from about 500 qg / mL to about 1100 qg / mL, from about 500 qg / mL to about 1200 qg / mL, from about 600 qg / mL to about 700 qg / mL, from about 600 qg / mL to about 800 qg / mL, from about 600 qg / mL to about 900 qg / mL, from about 600 qg / mL to about 1000 qg / mL, from about 600 qg / mL to about 1100 qg / mL, from about 600 qg / mL to about 1200 qg / mL, from about 700 qg / mL to about 800 qg / mL, from about 700 qg / mL to about 900 qg / mL, from about 700 qg / mL to about 1000 qg / mL, from about 700 qg / mL to about 1100 qg / mL, from about 700 qg / mL to about 1200 qg / mL, from about 800 qg / mL to about 900 qg / mL, from about 800 qg / mL to about 1000 qg / mL, from about 800 qg / mL to about 1100 qg / mL, from about 800 qg / mL to about 1200 qg / mL, from about 900 qg / mL to about 1000 qg / mL, from about 900 qg / mL to about 1100 qg / mL, from about 900 qg / mL to about 1200 qg / mL, from about 1000 qg / mL to about 1100 qg / mL, from about 1000 qg / mL to about 1200 qg / mL, from about 1100 qg / mL to about 1200 qg / mL, or any other subrange of from 50 qg / mL to 1200 qg / mL. Any range may include or exclude the starting and ending concentrations in the range.

[0176] In some embodiments, the serum drug concentration target trough during the first cycle and / or each of the subsequent cycles is maintained at 50 qg / mL, 55 qg / mL, 60 qg / mL, 65 qg / mL, 70 qg / mL, 75 qg / mL, 80 qg / mL, 85 qg / mL, 90 qg / mL, 95 qg / mL, 100 qg / mL, 150 qg / mL, 200 qg / mL, 250 qg / mL, 300 qg / mL, 350 qg / mL, 400 qg / mL, 450 qg / mL, 500 qg / mL, 550 qg / mL, 600 qg / mL, 650 qg / mL, 700 qg / mL, 750 qg / mL, 800 qg / mL, or any other number above 50 qg / mL; or about 50 qg / mL, about 55 qg / mL, about 60 qg / mL, about65 qg / mL, about 70 qg / mL, about 75 qg / mL, about 80 qg / mL, about 85 qg / mL, about 90 qg / mL, about 95 qg / mL, about 100 qg / mL, about 150 qg / mL, about 200 qg / mL, about 250 qg / mL, about 300 qg / mL, about 350 qg / mL, about 400 qg / mL, about 450 qg / mL, about 500 qg / mL, about 550 qg / mL, about 600 qg / mL, about 650 qg / mL, about 700 qg / mL, about 750 qg / mL, about 800 qg / mL, about 850 qg / mL, about 900 qg / mL, about 9500 qg / mL, about1000 qg / mL, about 1050 qg / mL, about 1100 qg / mL, about 1150 qg / mL, about 1200 qg / mL or about any number above 50 qg / mL.

[0177] In some embodiments, the administration of 20mg / kg maintains the serum drug concentrations at or above the target trough of 50 qg / mL or about 50 qg / mL during the first cycle and the one or more subsequent cycles. In some embodiments, the administration of 20mg / kg maintains the serum drug concentrations at or above the target trough of 50 qg / mL or about 50 qg / mL during the first cycle and the one or more subsequent cycles at a dosing interval between 2-4 weeks, every 2 weeks, every 3 weeks, or every 4 weeks. In some embodiments, the administration maintains the serum drug concentrations at or above the target trough of 50 qg / mL or about 50 qg / mL during the first cycle, second cycle, third cycle, fourth cycle, fifth cycle, sixth cycle, seventh cycle, eighth cycle, ninth cycle, or tenth cycle.

[0178] The administration may maintain the serum drug concentrations at or above the target trough of 50 qg / mL or about 50 qg / mL during the first cycle and the one or more subsequent cycles for about 50%, 60% 70%, 80%, 90%, 95%, or more of patients.

[0179] In some embodiments, administration may be repeated, and the administrations may be separated by at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, 6 months, or any other suitable intervals.

[0180] In some embodiments, the antibody which binds EGFR comprises cetuximab, also known as Erbitux®. Cetuximab is a recombinant, human / mouse chimeric monoclonal antibody that binds specifically to the extracellular domain of the human epidermal growth factor receptor (EGFR). Cetuximab is composed of the Fv regions of a murine anti-EGFR antibody with human IgGl heavy and kappa light chain constant regions and has an approximate molecular weight of 152 kDa. Cetuximab is produced in mammalian (murine myeloma) cell culture.

[0181] Cetuximab has been approved to treat patients with cancers, such as head and neck cancers, which have returned in the same location or spread to other parts of the body and for head and neck cancers that have progressed following platinum-based chemotherapy. Cetuximab can also be used on metastatic colorectal cancers (mCRC) that expresses EGFR.

[0182] Erbitux® is a sterile, clear, colorless liquid of pH 7.0 to 7.4, supplied at a concentration of 2 mg / mL in 100 mg (50 mL) or 200 mg (100 mL), single-use vials. Erbitux® is usually administered through intravenous (IV) injection and the IV dosage can be determined by a qualified medical professional according to factors such as the nature and severity of the disease or condition, the specific therapy (e.g., therapeutic or prophylactic agents) administered, as well as age, body, weight, response, and the past medical history of the subject.

[0183] In some embodiments, the dosage of the antibody which binds EGFR or composition comprising the antibody which binds EGFR administered to prevent, treat, manage, or ameliorate a disorder, or one or more symptoms thereof in a subject may be about 0.1 mg / kg to 100 mg / kg. The amount administered will depend on variables such as the type and extent of disease or indication to be treated, the overall health of the patient, the in vivo potency of the antibody, the pharmaceutical formulation, and the route of administration.

[0184] In some embodiments, the antibody which binds EGFR (e.g., cetuximab) is administered at a dosage amount of from about 50 mg / m2to about 700 mg / m2. In some embodiments, antibody which binds EGFR is administered at a dosage amount of from about 100 mg / m2to about 600 mg / m2. In some embodiments, the antibody which binds EGFR is administered at a dosage amount of from 200 mg / m2to about 500 mg / m2. In some embodiments, the antibody which binds EGFR is administered at a dosage amount of about 50 mg / m2, about 60 mg / m2, about 70 mg / m2, about 80 mg / m2, about 90 mg / m2, about 100 mg / m2, about 125 mg / m2, about 150 mg / m2, about 175 mg / m2, about 200 mg / m2, about 250 mg / m2, about 300 mg / m2, about 350 mg / m2, about 400 mg / m2, about 450 mg / m2, about 500 mg / m2, about 550 mg / m2, about 600 mg / m2, about or about 700 mg / m2. In some embodiments, the antibody which binds EGFR is administered at a dosage amount of 50 mg / m2, 60 mg / m2, 70 mg / m2, 80 mg / m2, 90 mg / m2, 100 mg / m2, 125 mg / m2, 150 mg / m2, 175 mg / m2, 200 mg / m2, 250 mg / m2, 300 mg / m2, 350 mg / m2, 400 mg / m2, 450 mg / m2, 500 mg / m2, 550 mg / m2, 600 mg / m2, or about 700 mg / m2.

[0185] In some embodiments, administration of the antibody which binds EGFR (e.g., cetuximab) may be repeated, and the administrations may be separated by at least 1 day, 2 days, 3 days, 5 days, 7 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, 6 months, every week, every other week, or any other suitable intervals.

[0186] In some embodiments, the antibody which binds EGFR is administered at a 400 mg / m2initial dose as a 120-minute intravenous infusion followed by 250 mg / m2weekly infused over 60 minutes. In some embodiments, the cetuximab is administered at a 500 mg / m2intravenous infusion (e.g., over 120 minutes) every two weeks.

[0187] In some embodiments, the antibody which binds to HLA-G is administered prior to the antibody which binds the epidermal growth factor receptor (EGFR). In some embodiments, the antibody which binds to HLA-G is administered after the antibody which binds to epidermal growth factor receptor (EGFR). In some embodiments, the antibody which binds to HLA-G is administered concurrently with the antibody which binds to epidermal growth factor receptor (EGFR). In some embodiments, the antibody which binds to HLA-G and the antibody which binds to epidermal growth factor receptor (EGFR) are administered about 30-minutes apart. In some embodiments, the antibody which binds to HLA-G and the antibody which binds to epidermal growth factor receptor (EGFR) are administered between about 10 and about 90 minutes apart. In some embodiments, the antibody which binds to HLA-G and the antibody which binds to epidermal growth factor receptor (EGFR) are administered about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 85, or about 90-minutes apart.

[0188] In some embodiments, the antibody which binds HLA-G and the antibody which binds EGFR are administered in an amount sufficient to achieve 1, 2, 3, or 4 of the following in the subject: a) target lesion regression; b) immune cell activation; c) increase in activity of myeloid cells, cytotoxic T lymphocytes, helper T cells, NK cells, T cells, B cells, neutrophils, monocytes, macrophages, and / or dendritic cells; and / or d) upregulation of myeloid activation gene sets (e.g., gene sets known to be associated with anti-tumor activity) in the tumor.

[0189] In some embodiments, the immune cell activation comprises, consists, or consists essentially of: a) increased frequency of ILT2+CD8+ T cells; c) increased percent of activated Ki67+NK cells; and / or d) increased frequency of Ki67+PD-1+HLA-DR+CD4 T cells.

[0190] In some embodiments, the immune cell activation is detected using flow cytometry of a sample, e.g., a sample from the subject (e.g., a sample comprising the subject’s peripheral blood mononuclear cells). In some embodiments, the upregulation of myeloid activation gene sets in the tumor is measured by RNAseq.

[0191] In some embodiments, the antibody which binds PD-1 is pembrolizumab, also known as Keytruda. Pembrolizumab (Keytruda®) is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligand, PD-L1 and / or PD-L2. Pembrolizumab is approved to treat a wide range of cancers, such as melanoma, non-small cell lung cancer, gastroesophageal junction cancer, head and neck squamous cell carcinoma, Hodgkin lymphoma, stomach cancer, cervical cancer, and triple negative breast cancer.

[0192] Pembrolizumab comes in a sterile, clear, colorless solution of pH 5.2 to 5.8, supplied at a concentration of 25 mg / mL in single-use vials. It is usually administered through intravenous (IV) injection and the IV dosage can be determined by a qualified medical professional according to factors such as the nature and severity of the disease or condition, the specific therapy (e.g., therapeutic or prophylactic agents) administered, as well as age, body weight, response, and the past medical history of the subject.

[0193] In some embodiments, the dosage of an antibody which binds to PD-1, (an anti PD-1 antibody such as pembrolizumab) or a composition comprising the anti PD-1 antibody is between about 10 mg to 1000 mg, 100 mg to 800 mg, 150 mg to 600 mg, 200 mg to 500 mg, or 300 mg to 400 mg via intravenous infusion every three weeks (Q3W) or every six weeks (Q6W) or every two weeks (Q2W). In some embodiments, the dosage of the anti PD- 1 antibody or a composition comprising the anti PD-1 antibody is about 10 mg, about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, or about 1000 mg via intravenous infusion every three weeks (Q3W) or every six weeks (Q6W) or every two weeks (Q2W). In some embodiments, the dosage of the anti PD-1 antibody or a composition comprising the anti PD-1 antibody is about 200 mg every 3 weeks (Q3W). In some embodiments, the dosage of the anti PD-1 antibody or a composition comprising the anti PD-1 antibody is about 400 mg every 6 weeks (Q6W). In some embodiments, the dosage of the anti PD-1 antibody or a composition comprising the anti PD-1 antibody is 200 mg IV over 30 minutes Q3W.

[0194] In some embodiments, any of the methods described herein further comprises administering one or more of the following: a) administering chemotherapy; b) administering radiation therapy; and / or c) administering one or more additional therapeutic agents.In some embodiments, one or more additional chemotherapeutic agents comprise FOLFIRI. In some embodiments, the antibody which binds to EGFR is administered in combination with a small molecule inhibitor of EGFR. In some embodiments, the small molecule inhibitor is one or more of Gefitinib, Erlotinob, Afatinib, Aacomitinib, Osimertinib, or Neratinob.7.3. Cancers

[0195] For cancers, the antibodies and methods provided herein are generally administered to a human or other organism or animal in a pharmaceutically acceptable dosage form. Any suitable cancer may be treated with the methods provided herein. In some embodiments, the cancer is a solid cancer. In some embodiments, the solid cancer is an advanced refractory / resistant solid cancer.

[0196] In some embodiments, the cancer is Head and Neck Squamous Cell Carcinoma (HNSCC). In some embodiments, the cancer is colorectal cancer (CRC). In some embodiments, the cancer is triple negative breast cancer (TNBC). In some embodiments, the cancer is renal cell carcinoma (RCC). In some embodiments, the cancer is non-small cell lung cancer (NSCLC). In some embodiments, the cancer is acral melanoma (AM). In some embodiments, the caner is advanced or metastatic. In some embodiments, the cancer has received or progressed on one or more prior therapeutic treatments.

[0197] In some embodiments, the solid cancer is colorectal cancer (CRC). In some embodiments, the colorectal cancer (CRC) is an advanced refractory / resistant colorectal cancer (CRC). In some embodiments, the colorectal cancer (CRC) is metastatic CRC (mCRC). In some embodiments, the mCRC is characterized as having wild-type RAS, wildtype BRAF, wild-type KRAS, and / or as HER2-negative, when assessed by a qualified or validated assay, e.g., biopsy and / or ctDNA samples. In some embodiments, the mCRC is characterized as having mutant KRAS when assessed by a qualified or validated assay, e.g., biopsy and / or ctDNA samples. In some embodiments, the mCRC is characterized as having mutant RAS, mutant BRAF, and / or as HER2 -positive, when assessed by a qualified or validated assay, e.g., biopsy and / or ctDNA samples. In some embodiments, mCRC is microsatellite stable. In some embodiments, the qualified or validated assay comprises, consists of, or consists essentially of Sanger Sequencing or Next Generation Sequencing.

[0198] In some embodiments, the cancer has received or progressed on at least 1, 2, 3, 4, or 5 prior treatments. In some embodiments, the cancer has received or progressed on an oxaliplatin and 5-FU based chemotherapy. In some embodiments, the oxaliplatin and 5-FU based chemotherapy is administered with bevacizumab. In some embodiments, theoxaliplatin and 5-FU based chemotherapy is administered without bevacizumab. In some embodiments, the mCRC has progressed on a prior anti-EGFR treatment. In some embodiments, the mCRC has not received a prior anti-EGFR treatment. In some embodiments, the cancer has not received a prior irinotecan treatment. In some embodiments, the cancer has received and / or progressed on a prior irinotecan treatment.

[0199] In some embodiments, the solid cancer is head and neck squamous cell carcinoma (HNSCC). In some embodiments, the head and neck squamous cell carcinoma (HNSCC) is advanced / metastatic HNSCC (mHNSCC). In some embodiments, the head and neck squamous cell carcinoma (HNSCC) is an advanced refractory / resistant head and neck squamous cell carcinoma (HNSCC). In some embodiments, the subject’s human papillomavirus (HPV) status is characterized as HPV-negative or HPV-positive when assessed by a qualified or validated assay, e.g., biopsy. In some embodiments, the qualified assay comprises, consists of, or consists essentially of immunohistochemistry (IHC) (e.g., pl6 IHC), Sanger Sequencing, and / or Next Generation Sequencing.

[0200] In some embodiments, the cancer has received or progressed on at least 1, 2, 3, 4, or 5 prior treatments. In some embodiments, the cancer has received or progressed on at least one line of checkpoint inhibitor therapy for the treatment of the advanced disease. In some embodiments, the checkpoint inhibitor at least one of a PD-1 inhibitor, a PD-L1 inhibitor, and / or a CTLA-4 inhibitor.

[0201] In some embodiments, the cancer is non-small cell lung cancer (NSCLC). In some embodiments, the cancer is human papilloma virus (HPV)-negative. In some embodiments, the cancer has received or progressed on at least 1, 2, 3, 4, or 5 prior treatments. In some embodiments, the cancer has received or progressed on at least one line of checkpoint inhibitor therapy for the treatment of the advanced disease. In some embodiments, the checkpoint inhibitor at least one of a PD-1 inhibitor, a PD-L1 inhibitor, and / or a CTLA-4 inhibitor.

[0202] In some embodiments, the cancer is triple negative breast cancer (TNBC). In some embodiments, the cancer has received or progressed on at least 1, 2, 3, 4, or 5 prior treatments. In some embodiments, the cancer has received or progressed on at least one line of checkpoint inhibitor therapy for the treatment of the advanced disease. In some embodiments, the subject has not experienced immune related or other adverse effects on a prior checkpoint inhibitor treatment that requires permanent discontinuation of the checkpoint inhibitor treatment. In some embodiments, the checkpoint inhibitor at least one of a PD-1 inhibitor, a PD-L1 inhibitor, and / or a CTLA-4 inhibitor.

[0203] In some embodiments, the cancer is acral melanoma (AC). In some embodiments, the cancer has received or progressed on at least 1, 2, 3, 4, or 5 prior treatments. In some embodiments, the cancer has received or progressed on radiation therapy, immunotherapy, targeted therapy based on a genomic alteration in the tumor, or chemotherapy.

[0204] In some embodiments, the cancer is renal cell carcinoma (RCC). In some embodiments, the cancer has received or progressed on at least 1, 2, 3, 4, or 5 prior treatments. In some embodiments, the cancer has received or progressed on radiation therapy, immunotherapy, targeted therapy, stem cell therapy, or chemotherapy.

[0205] Any suitable cancer may be treated with the antibodies provided herein. Illustrative suitable cancers include, for example, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), adrenocortical carcinoma, anal cancer, appendix cancer, astrocytoma, basal cell carcinoma, brain tumor, bile duct cancer, bladder cancer, bone cancer, breast cancer, bronchial tumor, Burkitt Lymphoma, carcinoma of unknown primary origin, cardiac tumor, cervical cancer, chordoma, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myeloproliferative neoplasm, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, ductal carcinoma, embryonal tumor, endometrial cancer, ependymoma, esophageal cancer, esthesioneuroblastoma, fibrous histiocytoma, Ewing sarcoma, eye cancer, germ cell tumor, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor, gestational trophoblastic disease, glioma, hairy cell leukemia, hepatocellular cancer, histiocytosis, Hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumor, Kaposi sarcoma, kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, leukemia, lip and oral cavity cancer, liver cancer, lobular carcinoma in situ, lymphoma, macroglobulinemia, malignant fibrous histiocytoma, melanoma, Merkel cell carcinoma, mesothelioma, metastatic squamous neck cancer with occult primary, midline tract carcinoma involving NUT gene, mouth cancer, multiple endocrine neoplasia syndrome, multiple myeloma, mycosis fungoides, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasm, nasal cavity and par nasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytomas, pituitary tumor, pleuropulmonary blastoma, primary central nervous system lymphoma, prostate cancer, rectal cancer, renal pelvis and ureter cancer, retinoblastoma, rhabdoid tumor, salivary gland cancer, Sezary syndrome, skin cancer, small intestine cancer, soft tissue sarcoma, spinal cord tumor, stomach cancer, T-cell lymphoma,teratoid tumor, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, urethral cancer, uterine cancer, vaginal cancer, vulvar cancer, and Wilms tumor.

[0206] In some embodiments, the methods and compositions achieve 1, 2, 3, or 4 of the following in the subject: a) target lesion regression; b) immune cell activation; c) increase in activity of myeloid cells, cytotoxic T lymphocytes, helper T cells, NK cells, T cells, B cells, neutrophils, monocytes, macrophages, and / or dendritic cells; and / or d) upregulation of myeloid activation gene sets (e.g., gene sets known to be associated with anti -turn or activity) in the tumor. In some embodiments, the immune cell activation comprises, consists, or consists essentially of increased frequency of ILT2+CD8+ T cells; increased percent of activated Ki67+NK cells; and / or increased frequency of Ki67+PD-1+HLA-DR+CD4 T cells. In some embodiments, the immune cell activation is detected using flow cytometry of a sample, e.g., a sample from the subject (e.g., a sample comprising the subject’s peripheral blood mononuclear cells). In some embodiments, the upregulation of myeloid activation gene sets in the tumor is measured by RNAseq.

[0207] In some embodiments, the cancer has received or progressed on at least 1, 2, 3, 4, or 5 prior treatments. In some embodiments, the at least 1, 2, 3, 4, or 5 prior treatments is, independently, a treatment of advanced / metastatic disease. In some embodiments, the at least one prior line of therapy is a chemotherapy or immunotherapy. In some embodiments, the at least one prior line of therapy comprises, consists of, or consists essentially of one or more of 5 Fluoropyridine, oxaliplatin, irinotecan, cetuximab, Avastin®, Lonsurf®, and / or an anti- VEGF treatment. In some embodiments, the at least one prior line of therapy comprises 5 Fluoropyridine. In some embodiments, the at least one prior line of therapy comprises oxaliplatin. In some embodiments, the at least one prior line of therapy comprises irinotecan. In some embodiments, the at least one prior line of therapy comprises cetuximab. In some embodiments, the at least one prior line of therapy comprises Avastin®. In some embodiments, the at least one prior line of therapy comprises Lonsurf®. In some embodiments, the at least one prior line of therapy comprises an anti-VEGF treatment. In some embodiments, the at least one prior line of therapy comprises an anti-EGFR inhibitor. In some embodiments, the at least one prior line of therapy comprises oxaliplatin and 5-FU based chemotherapy in the first line or adjuvant setting. In some embodiments, the at least one prior line therapy comprise FOLFOX (folic acid, oxaliplatin, and fluorouracil). In some embodiments, the at least one prior line of therapy comprises an anti-PD-1 inhibitor orcheckpoint inhibitor. In some embodiments, the at least one prior line of therapy comprises bevacizumab.

[0208] In some embodiments, the solid tumor has received or progressed on at least 2 prior treatments. In some embodiments, the solid tumor has received or progressed on at least 3 prior treatments. In some embodiments, the subject has received at least one of a prior anti-EGFR therapy, anit-PD-1 therapy, anti-PD-Ll therapy, anti-CTLA4 therapy, and / or an oxaliplatin and 5-FU based chemotherapy. In some embodiments, the subject has not received a prior anti-EGFR therapy. In some embodiments, the subject has not received a prior checkpoint inhibitor therapy such as an anit-PD-1 therapy, anti-PD-Ll therapy, anti- CTLA4 therapy, or small molecule inhibitors.

[0209] In some embodiments, the cancer has progressed on a prior treatment of cetuximab. In some embodiments, the cancer has no prior treatment of cetuximab. In some embodiments, the cancer has progressed on or received prior oxaliplatin and 5-FU based chemotherapy in the first line or adjuvant. In some embodiments, the cancer has progressed on or received bevacizumab. In some embodiments, the cancer has no prior treatment of bevacizumab.7.4. Antibody Combinations

[0210] The antibody combinations provided herein combine an antibody that binds HLA- G and (a) antibodies that bind EGFR. In some embodiments, the antibody which binds HLA- G is provided and prepared as described in W02020069133A1, which is incorporated herein in its entirety by reference. In some embodiments, the antibody with binding specificity for EGFR is provided and prepared as described in US6217866B1 and / or W02003007988A1, which are each independently incorporated herein in their entirety by reference. Non-limiting examples of EGFR inhibitors for cancer treatment include cetuximab, panitumumab, erlotinib, gefitinib, afatinib, and osimertinib.

[0211] Also provided herein are antibody combinations that combine an antibody that binds HLA-G and antibodies with binding specificity for PD-1. In some embodiments, the antibody with binding specificity for PD-1 is provided and prepared as described in US8354509B2 and / or WO2008156712A1, which are each independently incorporated herein in their entirety by reference. In some embodiments, the subject is administered an antibody which binds to HLA-G in combination with a small molecule or a checkpoint inhibitor, including but not limited to, PD-1, programmed death protein ligand 1 (PD-L1), and / or cytotoxic T-lymphocyte antigen 4 (CTLA-4). Non-limiting examples of checkpointinhibitors for cancer treatment include pembrolizumab, nivolumab, atezolizumab, avelumab, durvalumab, and ipilimumab.7.4.1. CDR-H1+CDR-H2+CDR-H3 Regions of the Antibodies

[0212] In some embodiments, the antibody that binds to HLA-G comprises a VH sequence comprising a CDR-H1 sequence comprising, consisting of, or consisting essentially of a VHCDR1 having the sequence set forth in SEQ ID NO: 1 or SEQ ID NO: 11, a CDR-H2 sequence comprising, consisting of, or consisting essentially of a VHCDR2 having the sequence set forth in SEQ ID NO: 21 or SEQ ID NO: 31, and a CDR-H3 sequence comprising, consisting of, or consisting essentially of a VHCDR3 having the sequence set forth in SEQ ID NO: 41. In some embodiments, the HLA-G CDR-H1 sequence, CDR-H2 sequence, and the CDR-H3 sequence are all from a single illustrative VH sequence provided in this disclosure. For example, in some embodiments, the CDR-H1, CDR-H2, and CDR-H3 of HLA-G are all from a single illustrative VH sequence having SEQ ID NO: 81.

[0213] In some embodiments, the antibody that binds to EGFR comprises a VH sequence comprising a CDR-H1 sequence comprising, consisting of, or consisting essentially of a VHCDR1 having the sequence set forth in SEQ ID NO: 9 or SEQ ID NO: 19, a CDR-H2 sequence comprising, consisting of, or consisting essentially of a VHCDR2 having the sequence set forth in SEQ ID NO: 29 or SEQ ID NO: 39, and a CDR-H3 sequence comprising, consisting of, or consisting essentially of a VHCDR3 having the sequence set forth in SEQ ID NO: 49. In some embodiments, the EGFR CDR-H1 sequence, CDR-H2 sequence, and the CDR-H3 sequence are all from a single illustrative VH sequence provided in this disclosure. For example, in some embodiments, the CDR-H1, CDR-H2, and CDR-H3 of the EGFR are all from a single illustrative VH sequence having SEQ ID NO: 89.

[0214] In some embodiments, the antibody that binds to HLA-G comprises a VHCDR1 having the sequence set forth in SEQ ID NO: 1 or SEQ ID NO: 11, a VHCDR2 having the sequence set forth in SEQ ID NO: 21 or SEQ ID NO: 31, and a VHCDR3 having the sequence set forth in SEQ ID NO: 41 and the antibody that binds to EGFR comprises a VHCDR1 having the sequence set forth SEQ ID NO: 9 or SEQ ID NO: 19, a VHCDR2 having the sequence set forth in SEQ ID NO: 29 or SEQ ID NO: 39, and a VHCDR3 having the sequence set forth in comprising SEQ ID NO: 49.

[0215] In some embodiments, the CDR-H1, CDR-H2, and CDR-H3 of HLA-G are all from a single illustrative VH sequence having SEQ ID NO: 81 and the CDR-H1, CDR-H2, and CDR-H3 of EGFR are all from a single illustrative VH sequence having SEQ ID NO: 89.

[0216] In some embodiments, the antibody that binds PD-1 comprises a VH comprising a CDR-H1 sequence comprising, consisting of, or consisting essentially of a VHCDR1 having the sequence set forth in SEQ ID NO: 3 or SEQ ID NO: 10, a CDR-H2 sequence comprising, consisting of, or consisting essentially of a VHCDR2 having the sequence set forth in SEQ ID NO: 23 or SEQ ID NO: 30, and a CDR-H3 sequence comprising, consisting of, or consisting essentially of a VHCDR3 having the sequence set forth in SEQ ID NO: 50. In some embodiments, the PD-1 CDR-H1 sequence, CDR-H2 sequence, and the CDR-H3 sequence are all from a single illustrative VH sequence provided in this disclosure. For example, in some embodiments, the CDR-H1, CDR-H2, and CDR-H3 of the PD-1 are all from a single illustrative VH sequence having SEQ ID NO: 90.

[0217] In some embodiments, the antibody that binds to HLA-G comprises a VHCDR1 having the sequence set forth in SEQ ID NO: 1 or SEQ ID NO: 11, a VHCDR2 having the sequence set forth in SEQ ID NO: 21 or SEQ ID NO: 31, and a VHCDR3 having the sequence set forth in SEQ ID NO: 41 and the antibody binds to PD-1 comprises a VHCRD1 having the sequence set forth in SEQ ID NO: 3 or SEQ ID NO: 10, a VHCDR2 having the sequence set forth in SEQ ID NO: 23 or SEQ ID NO: 30, and a VHCDR3 having the sequence set forth in SEQ ID NO: 50.

[0218] In some embodiments, the CDR-H1, CDR-H2, and CDR-H3 of HLA-G are all from a single illustrative VH sequence having SEQ ID NO: 81 and the CDR-H1, CDR-H2, and CDR-H3 of PD-1 are all from a single illustrative VH sequence having SEQ ID NO: 90.7.4.2. VH Sequences

[0219] In some embodiments, the antibody that binds HLA-G comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 81. In some embodiments, the antibody that binds EGFR comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 89. In some embodiments, the antibody that binds PD-1 comprises a VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 90. Any of these three may be combined in single or multiple quantities as contemplated by the invention.7.4.3. CDR-L1 + CDR-L2 + CDR-L3 Regions of the Antibody

[0220] In some embodiments, the antibody that binds to HLA-G comprises a VL sequence comprising a CDR-L1 sequence comprising, consisting of, or consisting essentially of a VLCDR1 having the sequence set forth in SEQ ID NO: 51, a CDR-L2 sequence comprising, consisting of, or consisting essentially of a VLCDR2 having the sequence set forth in SEQ ID NO: 61, and a CDR-L3 sequence comprising, consisting of, or consisting ofa VLCDR3 having the sequence set forth in SEQ ID NO: 71. In some embodiments, the HLA-G CDR-L1 sequence, CDR-L2 sequence, and CDR-L3 sequence are all from a single illustrative VL sequence provided in this disclosure. For example, in some embodiments, the HLA-G CDR-L1, CDR-L2, and CDR-L3 are all from a single illustrative VL sequence having SEQ ID NO: 91.

[0221] In some embodiments, the antibody which binds to EGFR comprises a VL sequence comprising a CDR-L1 sequence comprising, consisting of, or consisting essentially of a VLCDR1 having the sequence set forth in SEQ ID NO: 59, a CDR-L2 sequence comprising, consisting of, or consisting essentially of a VLCDR2 having the sequence set forth in SEQ ID NO: 69, and a CDR-L3 sequence comprising, consisting of, or consisting essentially of a VLCDR3 having the sequence set forth in SEQ ID NO: 79. In some embodiments, the EGFR CDR-L1 sequence, CDR-L2 sequence, and CDR-L3 sequence are all from a single illustrative VL sequence provided in this disclosure. For example, in some embodiments, the EGFR CDR-L1, CDR-L2, and CDR-L3 are all from a single illustrative VL sequence having SEQ ID NO: 99.

[0222] In some embodiments, the antibody that binds to HLA-G comprises a VLCDR1 having the sequence set forth in SEQ ID NO: 51, a VLCDR2 having the sequence set forth in SEQ ID NO: 61, and a VLCDR3 having the sequence set forth in SEQ ID NO: 71 and the antibody that binds to EGFR comprises a VLCDR1 having the sequence set forth SEQ ID NO: 59, a VLCDR2 having the sequence set forth in SEQ ID NO: 69, and a VLCDR3 having the sequence set forth in comprising SEQ ID NO: 79.

[0223] In some embodiments, the antibody which binds to PD-1 comprises a VL sequence comprising a CDR-L1 sequence comprising, consisting of, or consisting essentially of a VLCDR1 having the sequence set forth in SEQ ID NO: 60, a CDR-L2 sequence comprising, consisting of, or consisting essentially of a VLCDR2 having the sequence set forth in SEQ ID NO: 70, and a CDR-L3 sequence comprising, consisting of, or consisting essentially of a VLCDR3 having the sequence set forth in SEQ ID NO: 80. In some embodiments, the CDR-L1 sequence, CDR-L2 sequence, and CDR-L3 sequence are all from a single illustrative VL sequence provided in this disclosure. For example, in some embodiments, the PD-1 CDR-L1, CDR-L2, and CDR-L3 are all from a single illustrative VL sequence having SEQ ID NO: 100.

[0224] In some embodiments, the antibody that binds to HLA-G comprises a VLCDR1 having the sequence set forth in SEQ ID NO: 51, a VLCDR2 having the sequence set forth in SEQ ID NO: 61, and a VLCDR3 having the sequence set forth in SEQ ID NO: 71 and theantibody that binds to PD-1 comprises a VLCDR1 having the sequence set forth SEQ ID NO: 60, a VLCDR2 having the sequence set forth in SEQ ID NO: 70, and a VLCDR3 having the sequence set forth in comprising SEQ ID NO: 80.7.4.4. VL Sequences

[0225] In some embodiments, the antibody that binds to HLA-G comprises a VL sequence comprising, consisting of, or consisting essentially of sequence SEQ ID NO: 91. In some embodiments, the antibody that binds to EGFR comprises a VL sequence comprising, consisting of, or consisting essentially of sequence SEQ ID NO: 99. In some embodiments, the antibody that binds to PD-1 comprises a VL sequence comprising, consisting of, or consisting essentially of sequence SEQ ID NO: 100. Any of these three may be combined in single or multiple quantities as contemplated by the invention.7.4.5. VH - VL Pairs

[0226] In some embodiments, the antibody which binds HLA-G comprises a VH sequence and a VL sequence, the VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 81 and the VL sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 91. In some embodiments, the antibody which binds EGFR comprises a VH sequence and a VL sequence, the VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 89 and the VL sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 99. In some embodiments, the antibody which binds PD-1 comprises a VH sequence and a VL sequence, the VH sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 90 and the VL sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 100. VH and VL may be combined in any suitable pair.7.4.6. CDR-H1 + CDR-H2 + CDR-H3 + CDR-L1 + CDR-L2 + CDR-L3

[0227] In some embodiments, the antibody which binds to HLA-G comprises or consists of a heavy chain variable region (VH) and a light chain variable region (VL), with VH and / or VL comprising: a) a VHCDR1 having the sequence set forth in SEQ ID NO: 1 or SEQ ID NO:11, b) a VHCDR2 having the sequence set forth in SEQ ID NO: 21 or SEQ ID NO: 31, c) a VHCDR3 having the sequence set forth in SEQ ID NO: 41, d) a VLCDR1 having the sequence set forth in SEQ ID NO: 51, e) a VLCDR2 having the sequence set forth in SEQ ID NO: 61, andf) a VLCDR3 having the sequence set forth in SEQ ID NO: 71.

[0228] In some embodiments, the antibody which binds to EGFR comprises or consists of a heavy chain variable region (VH) and a light chain variable region (VL), with VH and / or VL comprising: a) a VHCDR1 having the sequence set forth in SEQ ID NO: 9 or SEQ ID NO:19, b) a VHCDR2 having the sequence set forth in SEQ ID NO: 29 or SEQ ID NO:39, c) a VHCDR3 having the sequence set forth in SEQ ID NO: 49, d) a VLCDR1 having the sequence set forth in SEQ ID NO: 59, e) a VLCDR2 having the sequence set forth in SEQ ID NO: 69, and f) a VLCDR3 having the sequence set forth in SEQ ID NO: 79.

[0229] In some embodiments, the antibody which binds to PD-1 comprises or consists of a heavy chain variable region (VH) and a light chain variable region (VL), with the VH comprising: a) a VHCDR1 having the sequence set forth in any one of SEQ ID NO: 3 or SEQ ID NO: 10, b) a VHCDR2 having the sequence set forth in any one of SEQ ID NO: SEQ ID NO: 23 or 30, and c) a VHCDR3 having the sequence set forth in any one of SEQ ID NO: 50, and the VL comprising: d) a VLCDR1 having the sequence set forth in any one of SEQ ID NO: 60, e) a VLCDR2 having the sequence set forth in any one of SEQ ID NO: 70, and f) a VLCDR3 having the sequence set forth in any one of SEQ ID NO: 80.

[0230] Any of CDRs set forth above may be in single or multiple quantities as contemplated by the invention.7.4.7. HC+LC

[0231] In some embodiments, the antibody that binds HLA-G, EGFR, or PD-1 comprises or consists of one or more heavy chains consisting of an HC sequence and one or more light chains consisting of an LC sequence. In some embodiments, the antibody that binds HLA-G, EGFR, or PD-1 comprises or consists of two identical heavy chains comprising, consistingof, or consisting essentially of an HC sequence and two identical light chains comprising, consisting of, or consisting essentially of an LC sequence.

[0232] In some embodiments, the HC sequence of the antibody that binds HLA-G is an HC sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 101 or SEQ ID NO: 102 and the LC sequence of the antibody that binds HLA-G is an LC sequence comprising, consisting of, or consisting essentially of any one of SEQ ID NO: 111. In some embodiments, the HC sequence of the antibody that binds EGFR is an HC sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 109 and the LC sequence of the antibody that binds EGFR is an LC sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 119. In some embodiments, the HC sequence of the antibody that binds PD-1 is an HC sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 110 and the LC sequence of the antibody that binds PD-1 is an LC sequence comprising, consisting of, or consisting essentially of SEQ ID NO: 120.

[0233] In some embodiments, the HC sequence of the antibody that binds HLA-G is an HC sequence comprising or consisting of SEQ ID NO: 101 or 102 and the LC sequence is an LC sequence comprising or consisting of SEQ ID NO: 111 and the HC sequence of the antibody that binds EGFR is an HC sequence comprising or consisting of SEQ ID NO: 109 and the LC sequence is an LC sequence comprising or consisting of SEQ ID NO: 119. In some embodiments, the HC sequence of the antibody that binds HLA-G is an HC sequence comprising or consisting of SEQ ID NO: 101 and the LC sequence is an LC sequence comprising or consisting of SEQ ID NO: 111 and the HC sequence of the antibody that binds EGFR is an HC sequence comprising or consisting of SEQ ID NO: 109 and the LC sequence is an LC sequence comprising or consisting of SEQ ID NO: 119. In some embodiments, the HC sequence of the antibody that binds HLA-G is an HC sequence comprising or consisting of SEQ ID NO: 102 and the LC sequence is an LC sequence comprising or consisting of SEQ ID NO: 111 and the HC sequence of the antibody that binds EGFR is an HC sequence comprising or consisting of SEQ ID NO: 109 and the LC sequence is an LC sequence comprising or consisting of SEQ ID NO: 119.

[0234] In some embodiments, the HC sequence of the antibody that binds HLA-G is an HC sequence comprising or consisting of SEQ ID NO: 101 or 102 and the LC sequence is an LC sequence comprising or consisting of SEQ ID NO: 111 and the HC sequence of the antibody that binds PD-1 is an HC sequence comprising or consisting of SEQ ID NO: 110 and the LC sequence is an LC sequence comprising or consisting of SEQ ID NO: 120. In some embodiments, the HC sequence of the antibody that binds HLA-G is an HC sequencecomprising or consisting of SEQ ID NO: 101 and the LC sequence is an LC sequence comprising or consisting of SEQ ID NO: 111 and the HC sequence of the antibody that binds PD-1 is an HC sequence comprising or consisting of SEQ ID NO: 110 and the LC sequence is an LC sequence comprising or consisting of SEQ ID NO: 120. In some embodiments, the HC sequence of the antibody that binds HLA-G is an HC sequence comprising or consisting of SEQ ID NO: 102 and the LC sequence is an LC sequence comprising or consisting of SEQ ID NO: 111 and the HC sequence of the antibody that binds PD-1 is an HC sequence comprising or consisting of SEQ ID NO: 110 and the LC sequence is an LC sequence comprising or consisting of SEQ ID NO: 120.7.4.8. Preparation of Antibodies

[0235] HLA-G, EGFR, or PD-1 antigens may used for production of antibodies. They may be intact proteins or fragments of the antigens. They may be in the form of an isolated protein or expressed by a cell. Other forms of antigens useful for generating antibodies will be apparent to those skilled in the art. In some embodiments, the antibody which binds HLA- G may be prepared as described in W02020069133A1. In some embodiments, the antibody with binding specificity for EGFR may be prepared as described in US6217866B1 and / or W02003007988A1. In some embodiments, the antibody with binding specificity for PD-1 is may be prepared as described in US8354509B2 and / or WO2008156712A1.

[0236] DNA encoding the antibodies may be readily isolated and sequenced using conventional procedures (e.g., by using oligonucleotide probes that are capable of binding specifically to genes encoding the heavy and light chains of the monoclonal antibodies). Thus, the hybridoma cells can serve as a useful source of DNA encoding antibodies with the desired properties. Once isolated, the DNA may be placed into expression vectors, which are then transfected into host cells such as bacteria (e.g., E. coif), yeast (e.g., Saccharomyces or Pichia sp.), COS cells, Chinese hamster ovary (CHO) cells, or myeloma cells that do not otherwise produce antibody, to produce the monoclonal antibodies. Other ways may be useful for generating antibodies will be apparent to those skilled in the art.7.5. Pharmaceutical Compositions

[0237] Some embodiments comprise a pharmaceutical composition of any of the embodiments set forth herein such as, for example, an antibody which binds to HLA-G and an antibody which binds to EGFR and / or an antibody which binds to HLA-G and an antibody which binds to PD-1. Any antibody, agent, and / or drug used in the methods of treatmentprovided herein can be provided in any appropriate pharmaceutical composition and be administered by any suitable route of administration. Suitable routes of administration include, but are not limited to, the inhalation, intra-arterial, intradermal, intramuscular, intraperitoneal, intravenous, nasal, parenteral, pulmonary, and subcutaneous routes.

[0238] The pharmaceutical composition may comprise one or more pharmaceutical excipients. Any suitable pharmaceutical excipient may be used, and one of ordinary skill in the art is capable of selecting suitable pharmaceutical excipients. Accordingly, the pharmaceutical excipients provided below are intended to be illustrative, and not limiting. Additional pharmaceutical excipients include, for example, those described in the Handbook of Pharmaceutical Excipients, Rowe et al. (Eds.) 6th Ed. (2009), incorporated by reference in its entirety.

[0239] The pharmaceutical composition may comprise an anti-foaming agent. Any suitable anti-foaming agent may be used. For example, the anti-foaming agent may be selected from the group consisting of an alcohol, an ether, an oil, a wax, a silicone, a surfactant, and combinations thereof. In some embodiments, the anti-foaming agent is selected from a mineral oil, a vegetable oil, ethylene bis stearamide, a paraffin wax, an ester wax, a fatty alcohol wax, a long chain fatty alcohol, a fatty acid soap, a fatty acid ester, a silicon glycol, a fluorosilicone, a polyethylene glycol-polypropylene glycol copolymer, polydimethylsiloxane-silicon dioxide, ether, octyl alcohol, capryl alcohol, sorbitan trioleate, ethyl alcohol, 2-ethyl-hexanol, dimethicone, oleyl alcohol, simethicone, and combinations thereof.

[0240] The pharmaceutical composition may comprise a cosolvent. Illustrative examples of cosolvents include ethanol, poly(ethylene) glycol, butylene glycol, dimethylacetamide, glycerin, and propylene glycol.

[0241] The pharmaceutical composition may comprise a buffer. Illustrative examples of buffers include acetate, borate, carbonate, lactate, malate, phosphate, citrate, hydroxide, diethanolamine, monoethanolamine, glycine, methionine, guar gum, and monosodium glutamate.

[0242] The pharmaceutical composition may comprise a carrier or filler. Illustrative examples of carriers or fillers include lactose, maltodextrin, mannitol, sorbitol, chitosan, stearic acid, xanthan gum, and guar gum.

[0243] The pharmaceutical composition may comprise a surfactant. Illustrative examples of surfactants include t / -alpha tocopherol, benzalkonium chloride, benzethonium chloride, cetrimide, cetylpyridinium chloride, docusate sodium, glyceryl behenate, glycerylmonooleate, lauric acid, macrogol 15 hydroxystearate, myristyl alcohol, phospholipids, polyoxyethylene alkyl ethers, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearates, polyoxylglycerides, sodium lauryl sulfate, sorbitan esters, and vitamin E polyethylene(glycol) succinate.

[0244] The pharmaceutical composition may comprise an anti-caking agent. Illustrative examples of anti-caking agents include calcium phosphate (tribasic), hydroxymethyl cellulose, hydroxypropyl cellulose, and magnesium oxide.

[0245] Other excipients that may be used with the pharmaceutical compositions include, for example, albumin, antioxidants, antibacterial agents, antifungal agents, bioabsorbable polymers, chelating agents, controlled release agents, diluents, dispersing agents, dissolution enhancers, emulsifying agents, gelling agents, ointment bases, penetration enhancers, preservatives, solubilizing agents, solvents, stabilizing agents, and sugars. Specific examples of each of these agents are described, for example, in the Handbook of Pharmaceutical Excipients, Rowe et al. (Eds.) 6th Ed. (2009), The Pharmaceutical Press, incorporated by reference in its entirety.

[0246] The pharmaceutical composition may comprise a solvent. For example, the solvent may be saline solution, such as a sterile isotonic saline solution or dextrose solution. As another example, the solvent may be water for injection.

[0247] The pharmaceutical composition may be in a particulate form, such as a microparticle or a nanoparticle. Microparticles and nanoparticles may be formed from any suitable material, such as a polymer or a lipid. For example, the microparticles or nanoparticles may be micelles, liposomes, or polymersomes.

[0248] The pharmaceutical composition may be a single unit dosage form comprising a prophylactically or therapeutically effective amount of the antibody.

[0249] The pharmaceutical composition may be an anhydrous pharmaceutical composition and / or a dosage form comprising an antibody used herein, since water can facilitate the degradation of an antibody.

[0250] The anhydrous pharmaceutical compositions and dosage forms may be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions. Pharmaceutical compositions and dosage forms that comprise lactose and at least one active ingredient that comprises a primary or secondary amine can be anhydrous if substantial contact with moisture and / or humidity during manufacturing, packaging, and / or storage is expected.

[0251] An anhydrous pharmaceutical composition should be prepared and stored such that its anhydrous nature is maintained. Accordingly, anhydrous compositions can be packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e.g., vials), blister packs, and strip packs.7.5.1. Parenteral Dosage Forms

[0252] The antibodies, agents, and / or drugs used in the methods of treatment provided herein can be in parenteral dosage forms. Parenteral dosage forms can be administered to subjects by various routes including, but not limited to, subcutaneous, intravenous (including bolus injection), intramuscular, and intra-arterial. Because their administration typically bypasses subjects’ natural defenses against contaminants, parenteral dosage forms are typically, sterile or capable of being sterilized prior to administration to a subject. Examples of parenteral dosage forms include, but are not limited to, solutions ready for injection, dry products ready to be dissolved or suspended in a pharmaceutically acceptable vehicle for injection, suspensions ready for injection, and emulsions.

[0253] Suitable vehicles that can be used to provide parenteral dosage forms are well known to those skilled in the art. Examples include, but are not limited to: Water for Injection USP; aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer’s Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer’s Injection; water miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

[0254] Excipients that increase the solubility of one or more of the antibodies used herein can also be incorporated into the parenteral dosage forms.7.6. Response

[0255] In some embodiments a response in the subject is measured. Any method can be used to assess response. Some embodiments provide for assessing response using RECIST criteria (See, recist.eortc.org / recist-l-l-2 / and New response evaluation criteria in solid tumors: Revised RECIST guideline (version 1.1), European Journal of Cancer 45 (2009) 228- 247, incorporated by reference in their entirety herein).

[0256] Different methods may be used to measure a tumor. Some internal cancer tumors will show up on an x-ray or CT scan and can be measured with a ruler. Blood tests, includingthose that measure organ function can be performed. A tumor marker test can be done for certain cancers.

[0257] In some embodiments, the response rate is measured according to complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD). Under the RECIST criteria, CR is the disappearance of all target lesions; any pathologic lymph nodes (whether target or nontarget lesions) must have reduction in short axis to less than 10mm. Under the RECIST criteria, PR is an at least 30% decrease in the sum of diameters of target lesions compared to the reference of the baseline diameters. Under the RECIST criteria, stable disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum lesion diameter since the treatment started. Lastly, under the RECIST criteria, PD is the at least 20% increase in the sum of the lesion diameter of target lesions or the appearance of one or more new lesions. In some embodiments, the subject has a response that is SD. In some embodiments, the subject has a response that is PR. In some embodiments, the subject has a response that is CR.

[0258] In some embodiments, the response rate is measured according to the objective response rate (ORR), progression free survival (PFS), and / or overall survival (OS). In some embodiments, the subject derives a clinical benefit, such as OS, PFS, or ORR.

[0259] In some embodiments, the response rate is measured according to the ORR. The ORR refers to the percentage of subjects with unconfirmed and confirmed CR or unconfirmed and confirmed PR.

[0260] In some embodiments, the subject derives a clinical benefit, the clinical benefit being overall survival (OS), progression-free survival (PFS), or objective response rate (ORR). In some embodiments, the treatment provides an ORR that is superior to that of a standard of care therapy(ies). In some embodiments, treatment has an OS that is superior to that of a standard of care therapy(ies). Standard of care therapies may include therapies currently used to treat mCRC, mCRC tumors, mHNSCC, or mHNSCC tumors, such as cetuximab monotherapy. Standard or care therapies may also include therapies for triple negative breast cancer (TNBC), renal cell carcinoma (RCC), non-small cell lung cancer (NSCLC), and / or (AM). In some embodiments, the treatment disclosed herein provides a response rate that is 20% or greater, such as 30% or greater, 40% or greater, or 50% or greater, than standard of care therap(ies).

[0261] Other measures of an increased response rate of cancer treatment include intervals of overall survival (that is time to death from any cause, measured from diagnosis orfrom initiation of the treatment being evaluated)) and cancer-free survival (that is, the length of time after a complete response cancer remains undetectable).8. EXAMPLES8.1. Example 1: Combination of the antibody that binds HLA-G (TTX-080) and Cetuximab in Patients with Metastatic Colorectal Cancer (mCRC) Drives Anti-Tumor Activity in Subjects with WT RAS, WT BRAE, and HER2-Negative mCRC

[0262] HLA-G antibodies are prepared as described in W02020069133A1, which is incorporated herein in its entirety by reference. EGFR antibodies are prepared as described in US6217866B1 and / or W02003007988A1, each of which are each independently incorporated herein in their entirety by reference. PD-1 antibodies are prepared as described in US8354509B2 and / or WO2008156712A1, each of which are each independently incorporated herein in their entirety by reference. To evaluate the safety and preliminary efficacy of TTX-080 in combination with cetuximab, subjects with advanced refractory / resistant solid tumors were enrolled in a Phase lb clinical study (NCT04485013).

[0263] Subjects with metastatic colorectal cancer (mCRC) have high unmet clinical needs. Cetuximab is the current standard of care and is approved as a monotherapy for treatment in mCRC. Previously reported studies showed that, when used as monotherapy in WT RAS mCRC, cetuximab achieved 10%- 19% objective response rate (ORR) (best response). (Shapiro et al., CCR 2017; Loree et al., CCR 2021). Moreover, cetuximab monotherapy previously showed 3.5-5.2 months Progression Free Survival (PFS) estimates in similar WT RAS populations. (Shapiro et al., CCR 2017; Loree et al., CCR 2021).

[0264] Subjects for the Phase lb clinical study were evaluated for inclusion in the study based on certain criteria, including age, type of patient and disease characteristics, and informed consent.

[0265] 25 subjects with metastatic colorectal cancer (mCRC) were enrolled in a study to determine the potential clinical benefit of TTX-080 in combination with cetuximab. Subjects identified for inclusion in the study were determined to have wild-type (WT) KRAS, Anti- EGFR naive mCRC. 16 out of 25 subjects were identified as having WT RAS, WT BRAF, and HER2 -negative tumors. Mutational status was determined using tumoral DNA (e.g., DNA was isolated form subject tumor biopsies and was sequenced using TruSight Oncology 500 (Illumina, Inc)), or ctDNA (e.g., cell free DNA Streck tubes were used to collect samples from subjects, which were subsequently analyzed using the Guardant Health Infinity Assay). 22 out of 25 WT KRAS subjects and 14 out of 16 WT RAS, WT BRAF, and HER2-negativesubjects were tumor response evaluable (e.g., had at least one post treatment scan). The median age of subjects in the WT KRAS group was 63 (21, 80), with 48% female and 52% male (Table 2).

[0266] For monotherapy, subjects were administered TTX-080 at 20 mg / kg IV over 30 minutes (±5 minutes) Q3W as monotherapy. For combination therapy, cetuximab was administered at 400 mg / m2IV over 120 minutes on Day 1 loading dose, with subsequent weekly doses of 250 mg / m2IV over 30 to 60 minutes in combination with administration of TTX-080 at 20 mg / kg IV over 30 minutes (±5 minutes) Q3W. On days when cetuximab and TTX-080 were both administered, TTX-080 was administered first, followed by a 30-minutewait period, and subsequent administration of cetuximab. After administration of the therap(ies), subjects were monitored for a 15-minute period to observe the subject for any events.

[0267] TTX-080 in combination with cetuximab demonstrated anti-tumor activity in subjects with WT RAS, BRAF, HER2-negative mCRC (See FIG. 2). Subjects in this subgroup had received a median of 2 prior lines of treatment (Range 1-5). All subjects had received 5-fuoropyrimidine. Seventy-eight percent (78%) of patients had received prior bevacizumab and more than 75% had received oxaliplatin and or irinotecan. In 14 tumor response evaluable patients with WT RAS, BRAF, HER2 -negative mCRC, TTX-080 plus cetuximab achieved an overall best response (ORR) in 4 patients (29%), a partial response (PR) in 4 patients (29%) and stable disease (SD) in 6 patients (43%). Nine (9) of 13 (69%) patients had at least 15% target lesion regression (FIG. 1) and 10 of 14 patients had disease control rate (DCR) of greater than 90 days (71%) (Table 3). Median progression-free survival (PFS) was 24.4 (10.7, NA) weeks, with a 36-week PFS rate of 47%, and follow-up duration was 21 weeks (range 0-52) (FIG. 2). Table 3 shows response Rates of TTX-080 in combination with Cetuximab in Anti-EGFR naive mCRC Subjects by Central Review.(*Best Response is PR or CR reported by Central Reading Center from start of treatment until discontinuation. All 5 responders received prior 5FU. 80% received prior oxaliplatin and bevacizumab. Response evaluable were patients who had a post baseline assessment. ORR determined by central review.)

[0268] The most common Grade 3 adverse events (AEs) in patients with mCRC were increases in AST (n=3) and ALT (n=3), fatigue (n=l), dermatitis acneiform (n=l) and myalgias (n=l) (Table 4). Treatment Related Adverse Events (TRAEs) are any AE related to TTX-080 with or without being related to cetuximab. No subject had investigator reported TTX-080 related Serious Adverse Events (SAEs). Grade 3 AST / ALT elevation considered to be immune-related in subject with PR, resolved with steroids. Grade 5 acute respiratory failure possibly relates to TTX-080 or cetuximab. Study Safety Review Team (SRT) adjudicated it to be unlikely related TTX-080 or cetuximab. Table 4 shows treatment-Related Adverse Events (TRAEs) of TTX-080 in combination with Cetuximab in Subjects with Anti- EGFR-naive mCRC8.2. Example 2: Combination of the antibody that binds HLA-G (TTX-080) and Cetuximab in Patients with Metastatic Head and Neck Squamous Cell Carcinoma (mHNSCC) Drives Anti-Tumor Activity in Subjects with HPV-negative mHNSCC

[0269] To evaluate the safety and preliminary efficacy of TTX-080 in combination with cetuximab, subjects with advanced refractory / resistant solid tumors were enrolled in a Phase lb clinical study (NCT04485013).

[0270] Subjects with locally advanced / metastatic HNSCC have high unmet clinical need. Cetuximab as a monotherapy is approved for treatment of mHNSCC. In previously reported studies, cetuximab as a monotherapy in mHNSCC achieved 13% ORR (best response) in all comers (Vermoken et al., JCO 2007) and 25% ORR in HPV-negative subjects (Adkins et al., Oral Biology 2021).

[0271] Subjects for the Phase lb clinical study were evaluated for inclusion in the study based on certain criteria, including age, type of patient and disease characteristics, and informed consent.

[0272] 23 subjects with advanced / metastatic mHNSCC were enrolled in a study to determine the potential clinical benefit of TTX-080 in combination with cetuximab. 18 out of the 23 subjects had determined human papilloma virus (HPV) statuses. 7 out of 18 subjects were HPV-negative and 11 out of 18 were HPV-positive. HPV status was determined by patient tumor biopsies. For example, HPV status may be determined from RNA isolated from patient tumor biopsies and analyzed by the NanoSTring PanCancer IO 260 Panel or ctDNA (e.g., cell free DNA Streck tubes were used to collect samples from subjects, which were subsequently analyzed using the Guardant Health Infinity Assay). The median age of the subjects was 54 (45, 83), with 17% female and 83% male (Table 5).*Cetuximab administered in the non-metastatic setting.

[0273] For monotherapy, subjects were administered TTX-080 at 20 mg / kg IV over 30 minutes (±5 minutes) Q3W as monotherapy. For combination therapy, cetuximab was administered at 400 mg / m2IV over 120 minutes on Day 1 loading dose, with subsequent weekly doses of 250 mg / m2IV over 30 to 60 minutes in combination with administration of TTX-080 at 20 mg / kg IV over 30 minutes (±5 minutes) Q3W. On days when cetuximab and TTX-080 were both administered, TTX-080 was administered first, followed by a 30-minute wait period, and subsequent administration of cetuximab. After administration of the therap(ies), subjects were monitored for a 15-minute period to observe the subject for any events.

[0274] TTX-080 in combination with cetuximab generated anti-tumor activity in patients with human papillomavirus (HPV)-negative mHNSCC. Patients in this subgroup had received a median of 1 prior line of treatment (Range 1, 2). All patients had received a prior immunotherapy treatment. In 7 tumor response evaluable patients, TTX-080 plus cetuximab achieved an overall best response (ORR) in 4 patients (57%), 1 CR (14%), 3 PRs (43%) and 1 SD (14%) (Table 6). Five (5) patients (71%) had at least 20% target lesion regression and DCR of greater than 90 days (71%) (FIG. 3; Table 6). Median PFS was 23.9 (9, NA) weeks, with a 24-week PFS rate of 43% (FIG. 4). Table 6. shows response Rates of TTX-080 in combination with cetuximab in HPV-Negative mHNSCC by Central Review.*Best Response is PR or CR reported by Central Reading Center from start of treatment until discontinuation. ORR determined by central review.

[0275] The most common Grade 2 AEs were anemia (n=2), fatigue (n=l) and an increase in AST (n=l). One (1) patient experienced Grade 4 anemia. No serious adverse event (SAE) related to TTX-080 was reported in mHNSCC subjects receiving TTX-080 in combination with cetuximab (Table 7).

[0276] These data demonstrate that TTX-080 in combination with cetuximab showed higher response rates in HPV-negative mHNSCC (57%) subject compared to historically published cetuximab monotherapy data (Vermoken et al., JCO 2007; Adkins et al., Oral Biology 2021). Moreover, the median PFS was approximately 6-months with TTX- 080 in combination with cetuximab.8.3. Example 3: Additional Clinical and Translational Data

[0277] Beyond the data from the Phase lb clinical study (NCT04485013) as evaluated in Examples 1 and 2, the data of the study show additional benefits of TTX-080 as a monotherapy or in combination with cetuximab.

[0278] TTX-080 monotherapy induces statistically significant on-mechanism immune cell activation in the periphery and in the tumor. Peripheral changes in subjects detected by flow cytometry from subject PBMCs include increased % of activated Ki67+NK cells (innate - MO A), increased frequency of IL2+CD8+T cells (antigen experienced TEMRA population), and increased frequency of activated Ki67+PD-1+HLA-DR+CD4 T cells (biological activity). The cell populations were analyzed via CellEngine® and statistical analysis using R. Statistical significance was determined using Tukey-Kramer HSD test. Moreover, tumoral changes detected by RNAseq and GSEA analysis include TTX-080 monotherapy upregulation of myeloid activation gene sets known to be associated with antitumor activity.

[0279] Data from TTX-080 monotherapy and TTX-080 in combination with cetuximab in Anti-EGFR pretreated subjects supports potential contribution of TTX-080 to the clinical activity of combination. For example, out of 25 subjects enrolled in TTX-080 monotherapy, 30% had CBR >90 days with two subjects staying on treatment fafteror 9 (FIG. 5A and FIG. 5B) and 15 months prior to progression. Moreover, one subject who received TTX-080 only in the TTX-080 cetuximab combo arm achieved PR by Central Read (FIG. 5C). Out of 23 subjects who were not expected to receive benefit from cetuximab (e.g., received anti-EGFR as last line with PD prior to enrollment or who had tumors with mutations in RAS, BRAF, or HER-2 positivity), 3 subjects (1 CR and 2 PR) reported responses (ORR 13%).

[0280] A 63 -year-old Caucasian female having WT RAS, WT BRAF, and HER2- negative mCRC was enrolled in the Phase lb clinical study and received TTX-080 in combination with cetuximab (as described in Example 1, above). The subject had received 2 prior lines of treatment (LOT) including 5 Fluoropyridine, oxaliplatin, and Avastin®. The subject achieved PR by Central Read with 33% reduction in target lesion and the target lesion in the liver completely disappeared. The subject was on treatment for 11 months prior to PD. Evidence of NK Cell activation and increased antigen-specific T cells in the periphery from the subject are presented in FIG. 6.

[0281] A 53-year-old Caucasian male having WT RAS, WT BRAF, and HER2-negative mCRC was enrolled in the Phase lb clinical study and received TTX-080 in combination with cetuximab (as described in Example 1, above). The subject had received four (4) prior-n -lines of treatment (LOT) including 5 Fluoropyridine, oxaliplatin, irinotecan, Avastin®, and Lonsurf®. The subject achieved PR by Central Read with 100% reduction in target lesion. The subject was on treatment for 12 months prior to PD. Evidence of NK Cell activation and increased antigen-specific T cells in the periphery from the subject are presented in FIG. 7.8.4. Example 4: Clinical trial investigations of TTX-080 HLA-G antagonist in subjects with advanced cancers

[0282] The Phase la was an open label, multicenter, dose escalation clinical trial to determine the safety, tolerability, MTD or OBD and the RP2D of TTX-080 when administered as a single agent. The Phase lb is a dose expansion of TTX-080 monotherapy and in combination with either pembrolizumab or cetuximab in adult subjects with advanced refractory / resistant solid malignancies, including head and neck squamous cell carcinoma (HNSCC), non-small cell lung cancer (NSCLC), colorectal cancer (CRC), triple negative breast cancer (TNBC), renal cell carcinoma (RCC), and acral melanoma (AM). Additionally, the study will seek to evaluate the pharmacokinetics and immunogenicity of TTX-080, and preliminary efficacy of TTX-080 as a monotherapy and in combination with pembrolizumab or cetuximab.

[0283] In Phase la, patients with advanced solid tumors (e.g., HNSCC, mCRC) received single agent TTX-080 at escalating doses in a 3+3 design from 0.2-20 mg / kg IV Q3W. Patients with advanced refractory / resistant solid tumors received TTX-080 at 0.2 mg / kg, 0.6 mg / kg, 2 mg / kg, 6 mg / kg, 10 mg / kg, and 20 mg / kg IV (dose-escalation phase) Q3W. Accelerated titration design was used for the first cohort (Cohort 1, 0.2 mg / kg Q3W) and standard 3+3 design was used for subsequent cohorts (Cohort 2, 0.6 mg / kg Q3W; Cohort 3, 2 mg / kg Q3W; Cohort 4, 6 mg / kg Q3W; Cohort 5, 10 mg / kg Q3W; Cohort 6, 20 mg / kg Q3W). Biopsies and blood samples were collected for biomarker analyses.8.5. Example 5: Phase la / lb analyses of anti-human HLA-G antibody (TTX- 080), a first in class HLA-G antagonist

[0284] This example summarizes additional interim results from the Phase la / lb clinical trial study described in Examples 1-4 herein. The study analyzes anti-human HLA-G antibody (TTX-080), a first in class HLA-G antagonist as (a) monotherapy in patients (pts) with advanced / metastatic colorectal cancer (mCRC); (b) in combination with cetuximab inpatients with advanced / metastatic head and neck squamous cell (mHNSCC), or advanced / metastatic colorectal cancer (mCRC); and (c) in combination with pembrolizumab in patients with advanced / metastatic head and neck squamous cell (mHNSCC), advanced / metastatic non-small cell lung cancer (mNSCLC), or advanced / metastatic triple negative breast cancer (mTNBC).

[0285] As of the data lock point of 22 October 2024, 81 patients have received TTX-080 as monotherapy, 43 patients have received TTX-080 in combination with pembrolizumab, and 78 patients received TTX-080 in combination with cetuximab.

[0286] Serial blood samples for the measurement of serum concentrations of TTX-080 were collected at baseline and after dosing at each cycle. FIG. 8 shows model predicted TTX-080 serum concentrations after IV infusion of 0.6 mg / kg Q3W over 30 minutes to a 70-kg human. As of May 16, 2021, 30 patients across 6 dose escalation cohorts have received TTX-080 as a single agent by IV infusion Q3W at doses from 0.2 mg / kg to 20 mg / kg; 26 patients (Cohorts 1 to 6) had available PK data. Serum concentration data (mean, SD) over time for each cohort are shown in FIG. 9. For each dose, serum concentration data was plotted against nominal time for subjects, who had at minimum data 21 days post-TTX-080 treatment. The mean and standard deviation at each nominal timepoint was plotted for each dose group, except when it could not be calculated (n< 2); in those instances, individual serum concentration data was plotted.

[0287] Individual subject PK analysis (Phoenix 64 WinNonlin Version 8, Certara Corporation, St. Louis, MO, USA) performed on 24 out of 26 patients (2 patients excluded based on limited data) from Cohorts 1-6 identified an open, 2-compartment IV infusion model that was consistent with the observed data for all subjects. FIG. 10 shows predicted vs. observed TTX-080 serum concentrations lie along a line of identity. In the 0.2, 0.6, 2.0, 6.0 and 10.0 mg / kg Q3W dose groups, receptor occupancy data demonstrated that doses greater than or equal to 0.2 mg / kg achieved and maintained maximal levels of peripheral blood receptor occupancy through 21 days post-Cycle 1 and post-Cycle 2 on HLA-G+T cells (FIG. 10), suggesting saturation of peripheral HLA-G at all dose levels.

[0288] Peripheral blood receptor occupancy was evaluated during Cycle 1 and Cycle 2 on CD4+and CD8+T cells by flow cytometry using fluorescent-labeled TTX-080 to detect free HLA-G. C2D1 and C3D1 samples were taken 21 days post-Cycle 1 and 21 days post-Cycle 2, respectively. Based on available RO data as of May 14, 2021, only 1 patient each from Cohort 4 and 5 are represented in the graph. Data for all patients in Cohorts 1-3 are plotted;for Cohorts 2 and 3, the mean ± standard error of the mean are shown. FIG. 11 shows receptor occupancy (RO) after single-dose IV administration of TTX-080.

[0289] FIGs 12A and 12B show PK stimulation of TTX-080 at 15 mg / kg Q2W dosing in patients with advanced solid tumors. FIG. 12A shows stimulation excluding effects of ethnicity on clearance. FIG. 12B shows stimulation including effect of ethnicity on clearance. Abbreviations: Cp = serum concentration; PK = pharmacokinetics; Q2W = every 2 weeks. Lines represent values for individual patients (N = 188) based on post hoc parameters from the optimal model. The dashed line appears at the target trough concentration (50,000 ng / mL).

[0290] The model-predicted PK parameters were summarized by cohort / dose in Table 8. Taking into account the small number of subjects in Groups 1 through 4 compared to Cohorts 5 and 6, there was good concordance among the 6 cohorts and doses with respect to the geometric mean values for the primary PK parameters. The geometric mean ty2p ranged from 263 to 465 hours (11.0 to 19.3 days). At the higher doses, 6 mg / kg, 10 mg / kg, and 20 mg / kg, the geometric mean t’ / 2p was 285 hr (11.9 days), 263 hr (11.0 days), and 268 hr (11.2 days), respectively.Table 8. TTX-080 Dose Escalation CohortsAbbreviations: CLD2, intercompartmental clearance; CL, clearance from the central compartment; VI, volume of the central compartment; V2, volume of the peripheral compartment; Vss, volume of distribution, stead-state; tl / 2P, elimination half-life.aGeometric mean and % CV are shown for all PK parameters. The CV was not calculated if N = 1.bN = 6 patients ongoing out of target enrollment of 20.

[0291] Additionally, a nonlinear mixed-effects modeling approach (NONMEM version 7.5.0, ICON Development Solutions, Hanover, MD, USA) was implemented to develop a population PK model from 26 patients to identify potential covariates that correlate with drug clearance and to inform dosing decisions. This approach identified that a base two- compartment model with first-order elimination provided a good fit to the observed data. Further analysis suggested that clearance increased with weight or lean body mass. Accordingly, incorporation of systemic parameters scaled by weight raised to an estimated power was adopted as the optimal model. Analysis of other covariates showed there was no evidence that age, sex, organ impairment, or dose level influenced the pharmacokinetic parameters of TTX-080.

[0292] TTX-080 demonstrated an acceptable safety profile as monotherapy with decreased appetite, arthralgia, and fatigue as the most common TTX-080-related adverse effects (AEs) across all dose cohorts from the Phase la dose escalation part. In the TTX-080 combination arms with either cetuximab or pembrolizumab, the safety profile was consistent with published safety profile of cetuximab and pembrolizumab with no new safety signals identified in either of these combination arms.8.6. Example 6: Phase lb analyses of anti-human HLA-G antibody (TTX-080) in combination with cetuximab in patients with head and neck squamous cell cancer (HNSCC)

[0293] This example illustrates dosing regimens for TTX-080 combination therapy with cetuximab for treating patients with advanced / metastatic head and neck squamous cell cancer(HNSCC) and have received 1 or 2 lines of prior treatments for the advanced / metastatic disease.

[0294] Cetuximab was given (a) at 400 mg / m2IV bolus over 120 minutes on Day 1 loading dose with subsequent weekly doses of 250 mg / m2continuous IV infusion over 30-60 minutes in combination with TTX-080 20 mg / kg IV Q3W (i.e., Day 1 of each 21-day cycle), or (b) at 500 mg / m2IV over 30 minutes (±5 minutes).

[0295] In patients with HNSCC, overall response rate (ORR) was 13%, with 1 patient achieving a complete response (CR) and 2 patients with partial response (PR). The CBR was 45%. Specifically, in 7 patients with HPV negative HNSCC, the best overall response (BOR) was 57% (1 CR, 3 PR).8.7. Example 7: Phase lb analyses of anti-human HLA-G antibody (TTX-080) in combination with cetuximab in patients with metastatic colorectal cancer (mCRC) with MSI-L / MSS and wild type KRAS

[0296] This example illustrates dosing regimens for TTX-080 combination therapy with cetuximab for treating patients with metastatic colorectal cancer (mCRC) with MSI-L / MSS and wild type KRAS, and have received 1, 2, 3, 4, or 5 lines of prior treatments. Patients may have received a prior anti-EGFR therapy or have not received a prior anti-EGFR therapy for the treatment of the advanced / metastatic disease.

[0297] Cetuximab was given (a) at 400 mg / m2IV bolus over 120 minutes on Day 1 loading dose with subsequent weekly doses of 250 mg / m2continuous IV infusion over 30-60 minutes in combination with TTX-080 20 mg / kg IV Q3W (i.e., Day 1 of each 21-day cycle), or (b) at 500 mg / m2IV over 30 minutes (±5 minutes).

[0298] In the WT KRAS patients (n=22) and in the WT RAS / BRAF / HER2-negative group (n=14), the best overall response (BOR) was 23% (5 PR) and 29% (4 PR) respectively. Stable disease was observed in 45% and 43% of patients, respectively, while progressive disease occurred in 27% of WT KRAS and 21% of WT RAS / BRAF / HER2-negative patients. These findings demonstrated that cetuximab and TTX-080 combinations could have potential synergistic effect and provide significant clinical benefits, particularly for KRAS wild-type CRC patients.8.8. Example 8: Phase lb analyses of anti-human HLA-G antibody (TTX-080) in combination with pembrolizumab in patients with head and neck squamous cell carcinoma (HNSCC), non-small cell lung cancer (NSCLC), and renal cell carcinoma (RCC), or triple negative breast cancer (TNBC)

[0299] This example illustrates dosing regimens for TTX-080 combination therapy with pembrolizumab for treating patients with head and neck squamous cell carcinoma (HNSCC), non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), and / or triple negative breast cancer (TNBC).

[0300] Patients with advanced or metastatic head and neck squamous cell carcinoma, non-small cell lung cancer, renal cell carcinoma, or triple negative breast cancer have received or progressed on 1, 2, or 3 prior lines of systemic therapy, including at least one checkpoint inhibitor therapy administered for the treatment of the advanced / metastatic disease.

[0301] TTX-080 at 20 mg / kg IV was administered over 30 minutes (± 5 minutes) Q3W(i.e., Day 1 of each 21-day cycle) with pembrolizumab at 200 mg IV over 30 minutes Q3W.

[0302] TTX-080 in combination with pembrolizumab is predicted to be effective in treating head and neck squamous cell carcinoma, non-small cell lung cancer, renal cell carcinoma, and / or triple negative breast cancer as compared to pembrolizumab monotherapy and / or in combination with a second therapeutic agent.8.9. Example 9: Phase lb analyses of anti-human HLA-G antibody (TTX-080) in combination with cetuximab and FOLFIRI in patients with metastatic colorectal cancer (mCRC)

[0303] This example illustrates dosing regimens for (a) TTX-080 combination therapy with cetuximab and FOLFIRI or (b) cetuximab in combination with FOLFIRI (folic acid or leucovorin, fluorouracil, irinotecan) for treating patients with metastatic colorectal cancer (mCRC).

[0304] The tumors are MSS (negative for MSLH / dMMR), WT for RAS (N-RAS and K-RAS) WT for BRAF, and HER2 -negative. Patients have previously received 5-FU and oxaliplatin containing chemotherapy (with or without bevacizumab) in the adjuvant or frontline metastatic setting. Patients may have received prior FOLFOX, and / or prior irinotecan in the first-line metastatic setting with an oxaliplatin and 5-FU containing regimen (for example FOLFOXIRI or FOLFIRINOX). Patients have not received prior anti-EGFR therapy such as cetuximab or panitumumab.

[0305] TTX-080 at 20 mg / kg IV is administered over 30 minutes (± 5 minutes) Q2W(i.e., Day 1 of each 14-day cycle) with (i) leucovorin (LV) at 400 mg / m2IV Q2W on Day 1, (ii) fluorouracil (5-FU) at 400 mg / m2IV bolus Q2W on Day 1 followed immediately by 2400 mg / m2continuous IV infusion Q2W over the next 46-48 hours , and (iii) irinotecan at 180 mg / m2IV Q2W on Day 1.

[0306] TTX-080 in combination with cetuximab and FOLFIRI is predicted to be effective in treating metastatic colorectal cancer that has progressed on a prior therapy as compared to cetuximab in combination with FOLFIRI.8.10. Example 10: TTX-080 combines with cetuximab to enhance macrophage phagocytosis

[0307] This example demonstrates potential clinical benefit of TTX-080 in combination with cetuximab.

[0308] To determine the potential clinical benefit of TTX-080 in combination with cetuximab, TTX-080 was evaluated in a macrophage assay where cetuximab was used to induce phagocytosis of EGFR+A549 lung cancer cells. In this assay, A549 cells engineered to express HLA-G were pretreated with cetuximab and / or TTX-080 Fab prior to a 2-hour coculture with monocyte-derived macrophages. Next, cells were analyzed by flow cytometry to determine the percentage of CD1 lb+macrophages that were positive for target cell phagocytosis. As shown in FIG. 13, the combination of TTX-080 Fab with cetuximab significantly increased target cell phagocytosis compared to cetuximab alone.8.11. Example 11: TTX-080 combines with pembrolizumab to enhance T cell functional activity

[0309] This example demonstrates potential clinical benefit of TTX-080 in combination with pembrolizumab.

[0310] Human tumor cells engineered to express both HLA-G and PD-L1 were cocultured with primary human CD8+T cells. As shown in FIG. 14, combining TTX-080 with pembrolizumab enhanced the effector function of ILT2+CD8+T cells, as reflected by increased CD 107a level, more than either single agent alone.Table S: Sequences

[0311] Table S provides sequences referred to herein.9. EQUIVALENTS AND INCORPORATION BY REFERNCE

[0312] The disclosure set forth above may encompass multiple distinct inventions with independent utility. Although each of these inventions has been disclosed in its preferred form(s), the specific embodiments thereof as disclosed and illustrated herein are not to be considered in a limiting sense, because numerous variations are possible. It should be understood that various changes in form and details may be made therein by those skilled in the relevant art without departing from the spirit and scope of the present invention. The subject matter of the inventions includes all novel and nonobvious combinations and subcombinations of the various elements, features, functions, and / or properties disclosed herein. The following claims particularly point out certain combinations and subcombinations regarded as novel and nonobvious. Inventions embodied in other combinations and subcombinations of features, functions, elements, and / or properties may be claimed in this application, in applications claiming priority from this application, or in related applications. Such claims, whether directed to a different invention or to the same invention, and whether broader, narrower, equal, or different in scope in comparison to the original claims, also are regarded as included within the subject matter of the inventions of the present disclosure.

[0313] All references, issued patents, and patent applications cited within the text of this specification are incorporated herein by reference in their entirety for all purposes.

Claims

WHAT IS CLAIMED IS:

1. A method for treatment of a subject suffering from cancer, comprising administering to the subject one or more cycles of administration, each comprising:(a) an antibody which binds to HLA-G; and(b) an antibody which binds to an epidermal growth factor receptor (EGFR); wherein the administration of the antibody which binds to HLA-G maintains serum drug concentrations above a target trough of about 50 pg / mL.

2. A method of treating colorectal cancer (CRC), the method comprising administering a therapeutically effective amount of an antibody which binds to HLA-G in combination with a therapeutically effective amount of an antibody which binds to an epidermal growth factor receptor (EGFR), to a human subject having or identified as having CRC, wherein the CRC tumor is characterized as having wild-type KRAS, wild-type RAS, wild-type BRAF, and / or as HER2-negative.

3. A method of treating head and neck squamous cell carcinoma (HNSCC), the method comprising administering a therapeutically effective amount of an antibody which binds to HLA-G in combination with a therapeutically effective amount of an antibody which binds to an epidermal growth factor receptor (EGFR), to a human subject having or identified as having HNSCC, wherein the HNSCC tumor is characterized as human papilloma virus (HPV) negative.

4. A method of treating a head and neck squamous cell carcinoma (HNSCC) tumor that is characterized as human papilloma virus (HPV) negative, the method comprising administering a therapeutically effective amount of an antibody which binds to HLA-G in combination with a therapeutically effective amount of an antibody which binds to an epidermal growth factor receptor (EGFR), to a human subject having or identified as having HNSCC, the method comprising the steps of:(a) determining whether the tumor tissue exhibits HPV markers, wherein a tumor exhibiting HPV markers is characterized as HPV-positive and a tumor not exhibiting HPV markers is characterized as HPV-negative;(b) if the tumor is characterized as HPV-positive, excluding the subject from treatment; and(c) if the tumor is characterized as HPV-negative, selecting the subject for treatment and administering to the subject having the HNSCC a therapeutically effective amount of an antibody which binds to HLA-G in combination with atherapeutically effective amount of an antibody which binds to an epidermal growth factor receptor (EGFR).

5. A method for treatment of a subject suffering from cancer, comprising administering to the subject one or more cycles of dosing, wherein in a first cycle:(a) a first dose comprising an effective amount of an antibody which binds to HLA-G;(b) a first dose comprising an effective amount of an antibody which binds to epidermal growth factor receptor (EGFR)(i) at 400 mg / m2, or(ii) at 500 mg / m2; and(c) a first dose comprising leucovorin, fluorouracil (5-FU) and irinotecan (FOLFIRI), wherein the administration of the antibody which binds to HLA-G maintains serum drug concentrations at a target trough level of between about 10-100 pg / mL.

6. A method for treatment of a subject suffering from cancer, comprising administering to the subject one or more cycles of dosing, wherein in a first cycle:(a) a first dose comprising an effective amount of an antibody which binds to HLA-G; and(b) a first dose comprising an effective amount of an antibody which binds to programmed cell death protein 1 (PD-1) at 200 mg IV Q3W or 400 mg IV Q6W, wherein the administration of the antibody which binds to HLA-G maintains serum drug concentrations at a target trough level of between about 10-100 pg / mL.

7. The method of any one of claims 1-6, wherein the administration of the antibody which binds to HLA-G maintains serum drug concentrations above the target trough of about 50 pg / mL during the first cycle and / or one or more subsequent cycles.

8. The method of any one of claims 1-7, wherein the antibody which binds to HLA-G is administered to the subject intravenously at 0.2-20 mg / kg over 30 minutes (± 5 minutes) at the start of each cycle, optionally wherein a cycle comprises dosing the antibody which binds to HLA-G at 2 to 4 week intervals.

9. The method of any one of claims 1-8, wherein the antibody which binds to HLA-G comprises or consists of a heavy chain variable region (VH) and a light chain variable region (VL), the VH and / or VL comprising:(i) a VHCDR1 having the sequence set forth in any one of SEQ ID NO: 1 or SEQ ID NO: 11,(ii) a VHCDR2 having the sequence set forth in any one of SEQ ID NO: 21 or SEQ ID NO: 31,(iii) a VHCDR3 having the sequence set forth in any one of SEQ ID NO: 41,(iv) a VLCDR1 having the sequence set forth in any one of SEQ ID NO: 51,(v) a VLCDR2 having the sequence set forth in any one of SEQ ID NO: 61, and(vi) a VLCDR3 having the sequence set forth in any one of SEQ ID NO: 71.

10. The method of any one of claims 1-9, wherein the antibody which binds to an epidermal growth factor receptor (EGFR) comprises or consists of a heavy chain variable region (VH) and a light chain variable region (VL), the VH and / or VL comprising:(i) a VHCDR1 having the sequence set forth in SEQ ID NO: 9 or SEQ ID NO:19,(ii) a VHCDR2 having the sequence set forth in SEQ ID NO: 29 or SEQ ID NO:39,(iii) a VHCDR3 having the sequence set forth in SEQ ID NO: SEQ ID NO: 49,(iv) a VLCDR1 having the sequence set forth in SEQ ID NO: SEQ ID NO: 59,(v) a VLCDR2 having the sequence set forth in SEQ ID NO: SEQ NO: 69, and(vi) a VLCDR3 having the sequence set forth in SEQ ID NO: 79.

11. The method of any one of claims 1-10, wherein(i) the antibody which binds to HLA-G comprises or consists of a heavy chain variable region (VH) and a light chain variable region (VL), with the VH comprising, consisting of, or consisting essentially of VH comprising, consisting of, or consisting essentially of a VH having the sequence set forth in SEQ ID NO: 81 and with the VL comprising, consisting of, or consisting essentially of a VL having the sequence set forth in SEQ ID NO: 91 or(ii) the antibody which binds to HLA-G comprises or consists of a heavy chain (HC) and a light chain (LC), the HC comprising, consisting of, or consisting essentially of a sequence set forth in SEQ ID NO: 101 or SEQ ID NO: 102 and of a LC comprising, consisting of, or consisting essentially of a sequence set forth in SEQ ID NO: 111 and(iii) the antibody which binds to an epidermal growth factor receptor (EGFR) comprises or consists of a heavy chain variable region (VH) and a light chain variable region (VL), the VH and / or VL comprising, consisting of, or consisting essentially of a VH having the sequence set forth in SEQ ID NO: 89 and of a VL comprising, consisting of, or consisting essentially of a VL having the sequence set forth in SEQ ID NO: 99 or(iv) the antibody which binds to EFGR comprises or consists of a heavy chain (HC) and a light chain (LC), the HC comprising, consisting of, or consisting essentially of a sequence set forth in SEQ ID NO: 109 and of a LC comprising, consisting of, or consisting essentially of a sequence set forth in SEQ ID NO: 119.

12. The method of any one of claims 1-11, wherein the antibody which binds to an epidermal growth factor receptor (EGFR) is administered:(i) at a 400 mg / m2initial dose as an intravenous infusion, and is administered at a subsequent dose of 250 mg / m2intravenously infused weekly; or(ii) at a 500 mg / m2intravenous infusion every two weeks.

13. The method of any one of claims 1-12, wherein the subject has not previously received a treatment directed to epidermal growth factor (EGFR), and / or optionally, the EGFR treatment is an anti-EGFR antibody treatment, or wherein the antibody which binds to an epidermal growth factor (EGFR) is an antibody-drug-conjugate (ADC).

14. The method of any one of claims 1-13, wherein the cancer is colorectal cancer (CRC) or head and neck squamous cell carcinoma (HNSCC), optionally, the cancer is advanced or metastatic colorectal cancer (mCRC) or advanced or metastatic head and neck squamous cell carcinoma (mHNSCC).

15. The method of any one of claims 1-14,(i) wherein the mCRC is characterized as having wild-type RAS, wild-type BRAF, and / or as HER2-negative, when assessed by a qualified or validated assay in biopsy and / or ctDNA samples or(ii) wherein the subject’s human papillomavirus (HPV) status is characterized as HPV-negative or HPV-positive when assessed by a qualified or validated assay in biopsy and / or ctDNA samples; and / or wherein a qualified or validated assay detecting the presence or absence of human papilloma virus (HPV) markers comprises, consists of, or consists essentially of Sanger Sequencing or Next Generation Sequencing.

16. The method of any one of claims 1-15,(i) wherein the antibody which binds to HLA-G is administered prior to the antibody which binds the epidermal growth factor receptor (EGFR),(ii) wherein the antibody which binds to HLA-G is administered after the antibody which binds the epidermal growth factor receptor (EGFR), or(iii) wherein the antibody which binds to HLA-G is administered concurrently with the antibody which binds to epidermal growth factor receptor (EGFR).

17. The method of any one of claims 1-16,(i) wherein the subject is human;(ii) wherein the subject derives a clinical benefit, the clinical benefit being overall survival (OS), progression-free survival (PFS), or objective response rate (ORR);(iii) wherein the treatment provides an ORR that is superior to that of a standard of care therapy(ies);(iv) wherein treatment has an OS that is superior to that of a standard of care therapy(ies);(v) wherein the subject has received at least one prior line of systemic therapy;(vi) wherein the at least one prior line of therapy is, independently, a treatment of advanced / metastatic disease;(vii) wherein the at least one prior line of therapy is a chemotherapy or immunotherapy; and / or(viii) wherein the at least one prior line of therapy comprises, consists, or consists essentially of one or more of 5 Fluoropyridine, oxaliplatin, irinotecan, cetuximab, Avastin®, Lonsurf®, and / or an anti-VEGF treatment.

18. The method of any one of claims 1-17, wherein the antibody which binds HLA-G and the antibody which binds EGFR are administered in an amount sufficient to achieve 1, 2, 3, or 4 of the following in the subject:(i) target lesion regression;(ii) immune cell activation;(iii) increase in activity of myeloid cells, cytotoxic T lymphocytes, helper T cells, NK cells, T cells, B cells, neutrophils, monocytes, macrophages, and / or dendritic cells; and / or(iv) upregulation of one or more myeloid activation gene sets associated with antitumor activity in the tumor.

19. The method of claim 18, wherein the immune cell activation comprises, consists of, or consists essentially of(i) increased frequency of ILT2+CD8+ T cells;(ii) increased percent of activated Ki67+NK cells; and / or(iii) increased frequency of Ki67+PD-1+HLA-DR+CD4 T cells.

20. The method of any one of claims 5 and 7-19,(i) further comprising administering leucovorin at 400 mg / m2, 5-FU at between 200 mg / m2-400 mg / m2IV bolus or between 1200 mg / m2-2400 mg / m2continuous IV infusion, and / or irinotecan at between 100 mg / m2-180 mg / m2;(ii) further comprising administering in the first cycle, the antibody which binds to HLA-G at a 15 mg / kg on Day 1, the antibody which binds to EGFR at 400 mg / m2on Day 1, leucovorin at 400 mg / m2, 5-FU at 400 mg / m2IV bolus on Day 1 and 400 mg / m2continuous IV infusion on Day 2 or Day 3, and irinotecan at 400 mg / m2on Day 1;(iii) further comprising administering in a subsequent cycle, the antibody which binds to HLA-G at a 15 mg / kg on Day 1, the antibody which binds to EGFR at between 100 mg / m2on -250 mg / m2on Day 1, leucovorin at 400 mg / m2, 5-FU at 400 mg / m2IV bolus on Day 1 and 2400 mg / m2continuous IV infusion on Day 2 or Day 3, and irinotecan at 180 mg / m2on Day 1; and / or(iv) comprising administering in the first cycle and / or each of the subsequent cycles, the antibody which binds to HLA-G at a 15 mg / kg on Day 1, the antibody which binds to EGFR at 500 mg / m2on Day 1, leucovorin at 400 mg / m2, 5-FU at 400 mg / m2IV bolus on Day 1 and 2400 mg / m2continuous IV infusion on Day 2 or Day 3, and irinotecan at 400 mg / m2on Day 1.

21. The method of any one of claims 5 and 7-20, wherein the antibody which binds to HLA-G, the antibody which binds to EGFR, and FOLFIRI are administered at a 2-4 weeks interval, optionally, wherein the antibody which binds to HLA-G, the antibody which binds to EGFR, and FOLFIRI are administered every 2 weeks (Q2W).

22. The method of any one of claims 5 and 7-21,(i) wherein the cancer is a colorectal cancer;(ii) wherein the cancer is an advanced or metastatic colorectal cancer;(iii) the cancer has received or progressed on at least 1, 2, 3, 4, or 5 prior treatments; wherein the cancer has received or progressed on an oxaliplatin and 5-FU based chemotherapy;(iv) wherein the oxaliplatin and 5-FU based chemotherapy is administered with or without bevacizumab;(v) wherein the cancer has not received a prior EGFR inhibitor therapy;(vi) wherein the cancer has received a prior irinotecan treatment or wherein the cancer has not received a prior irinotecan treatment; and / or(vii) wherein the cancer is wild-type RAS, wild-type BRAF, and / or HER2- negative.

23. The method of any one of claims 6-19, further comprising administering the antibody which binds to HLA-G at 20 mg / kg Q3W and the antibody which binds to PD-1 at 200 mg Q3W, or administering the antibody which binds to HLA-G at 20 mg / kg Q3W and the antibody which binds to PD-1 at 400 mg Q6W.

24. The method of any one of claims 6-19 and 23,(i) wherein the antibody which binds to PD-1 comprises or consists of a heavy chain variable region (VH) and a light chain variable region (VL), with the VH comprising, consisting of, or consisting essentially of a VH having the sequence set forth in SEQ ID NO: 90 and the VL comprising, consisting of, or consisting essentially of a VL having the sequence set forth in SEQ ID NO: 100; and / or(ii) wherein the antibody which binds to PD-1 comprises or consists of a heavy chain (HC) and a light chain (LC), with the HC comprising, consisting of, or consisting essentially of a sequence set forth in SEQ ID NO: 110 and the LC comprising, consisting of, or consisting essentially of sequence set forth in SEQ ID NO: 120.

25. The method of any one of claims 6-19 and 23-24,(i) wherein the cancer is advanced or metastatic;(ii) wherein the cancer has received or progressed on at least 1, 2, 3, 4, or 5 prior treatments;(iii) wherein the cancer is selected from a head and neck squamous cell carcinoma (HNSCC), non-small cell lung cancer (NSCLC), or triple negative breast cancer (TNBC);(iv) wherein the cancer is wherein the cancer is a head and neck squamous cell carcinoma (HNSCC) and is human papilloma virus (HPV)-negative;(v) wherein the cancer is a non-small cell lung cancer (NSCLC) and has received and / or progressed on at least one prior checkpoint inhibitor treatment, and optionally wherein the prior checkpoint inhibitor treatment is selected from a PD-1 inhibitor, a PD-L1 inhibitor, and a CTLA-4 inhibitor; and / or(vi) wherein the cancer is a triple negative breast cancer (TNBC) and has received and / or progressed on at least one prior checkpoint inhibitor treatment, and optionally the subject has not experienced immune related or other adverse effects on a prior checkpoint inhibitor treatment that requires permanent discontinuation of the checkpoint inhibitor treatment, wherein the prior checkpoint inhibitor is selected froma PD-1 inhibitor, a programmed death protein ligand 1 (PD-L1) inhibitor, and a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor.

26. The method of any one of claims 6-19 and 23-25, further comprising administering the antibody which binds to HLA-G, the antibody which binds to EGFR, and FOLFIRI intravenously.

27. The method of any one of claims 1-26, wherein the administration of the antibody which binds to HLA-G achieves at least ECeo, EC70, ECso, or EC90 for receptor occupancy (RO).

28. The method of any one of claims 1-27, wherein the EGFR inhibitor therapy is cetuximab or panitumumab, and / or optionally, wherein the EGFR inhibitor therapy is cetuximab.

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