Methods of using Anti-HLA-g antibodies

Abstract

Disclosed are methods for treating a subject suffering from cancer by administering to the subject an anti human HLA-G antibody to maintain a serum drug concentration above a target trough of about 50 μg / mL during a first cycle and optionally at one or more subsequent cycles to maintain the serum drug concentration above target trough of about 50 μg / mL during subsequent cycles as well. The dosing regimen can be about 0.2-20 mg / kg Q3W. The dosing can also be at 2 to 4 week intervals. The cancer may be a solid cancer. The methods and dosing regimens can be used for monotherapy of anti human HLA-G antibody or combination therapy of anti human HLA-G antibody with an anti EGFR or an anti PD-1 therapy.

Description

METHODS OF USING ANTI-HLA-G ANTIBODIES1. CROSS-REFERENCES TO RELATED APPLICATIONS

[0001] This application claims benefit of and priority to U.S. Provisional Application No. 63 / 626,456. filed January 29. 2024. the disclosure of which is incorporated herein by reference in its entirety.2. SEQUENCE LISTING

[0002] The application contains a Sequence Listing which has been submitted electronically in .XML fonnat and is hereby incorporated by reference in its entirety. Said .XML copy, created on January 27, 2025, is named “1107368.00161. xml” and is 331,440 bytes in size. The sequence listing contained in this .XML file is part of the specification and is hereby incorporated by reference herein in its entirety.3. FIELD

[0003] Provided herein are methods of using antibodies with binding specificity for HLA-G and pharmaceutical compositions comprising the antibodies for therapeutic purposes.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 micro globulin). 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 may play 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 mediatesfunction 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 cancer (CRC), 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] HLA-G is an attractive target for diseases, including but not limited to cancers.5. SUMMARY

[0011] Provided herein are dosing regimens and methods for treating a subject in need thereof with an effective amount of an anti HLA-G antibody. The subject may have a health condition or disease such as a cancer, an autoimmune disease, or an infection.

[0012] In one aspect, a dosing regimen for treating a cancer in a subject is provided, comprising administering a pharmacal composition comprising an effective amount of an anti human HLA- G antibody to the subject in a first dose during a first cycle, wherein administration of the anti human HLA-G antibody maintains a serum drug concentration at a target trough level of between about 10 pg / mL-100 iig / L during the first cycle after administration of the first dose. In some embodiments, the dosing regimen further comprises administering the anti human HLA-G antibody in one or more subsequent doses in one or more subsequent cycles. In some embodiments, the administration maintains a serum drug concentration at a target trough of above 50 pg / mL during the first cycle and / or during each of the subsequent cycles. In some embodiments, the administration achieves at least ECeo, EC?o, ECso, or ECso for receptor occupancy (RO).

[0013] In some embodiments, the dosing regimen comprises administering the anti human HLA- G antibody at about 0.2-20 mg / kg to the subject in the first cycle and / or the subsequent cycles. In some embodiments, the dosing regimen comprises administering the anti human HLA-G antibody at 2 to 4 weeks intervals betw een the first cycle and each of the subsequent cy cles. In some embodiments, the dosing regimen comprises administering the anti human HLA-G antibody at 20 mg / kg Q3W in the first cycle and / or each of the subsequent cycles. In some embodiments, die dosing regimen comprisesadministering the anti human HLA-G antibody at 15 mg / kg Q2W in the first cycle and / or each of the subsequent cycles.

[0014] In some embodiments, the anti human HLA-G antibody comprises or consists of a heavy chain variable region (VH) and a light chain variable region (VL); the VH comprising: (i) a VHCDR1 having the sequence set forth in any one of SEQ ID NOS: 1-14 or SEQ ID NOS: 18-34; (ii) a VHCDR2 having the sequence set forth in any one of SEQ ID NOS: 38-50 or SEQ ID NOS: 54-71; and (iii) a VHCDR3 having the sequence set forth in any one of SEQ ID NOS: 76-101; and the VL comprising: (iv) a VLCDR1 having the sequence set forth in any one of SEQ ID NOS: 105-124; (v) a VLCDR2 having the sequence set forth in any one of SEQ ID NOS: 128-145: and (vi) a VLCDR3 having the sequence set forth in any one of SEQ ID NOS: 149-166. In some embodiments, the anti human HLA-G antibody consists of a VH consisting of: (i) a VHCDR1 having the sequence set forth in SEQ ID NO: 7 or SEQ ID NO: 25; (ii) a VHCDR2 having the sequence set forth in SEQ ID NO: 44 or SEQ ID NOS: 65; and (iii) a VHCDR3 having the sequence set forth in SEQ ID NO: 93 and a VL consisting of: (iv) a VLCDR1 having the sequence set forth in SEQ ID NO: 118: (v) a VLCDR2 having the sequence set forth in SEQ ID NO: 138; and (vi) a VLCDR3 having the sequence set forth in SEQ ID NO: 155.

[0015] In some embodiments, the VH comprises the sequence set forth in any one of SEQ ID NOS: 170-200 and the VL comprises the sequence set forth in any one of SEQ ID NOS: 204-228. In some embodiments, the VH sequence consists of the sequence set forth in SEQ ID NO: 192 and the VL sequence consists of the sequence is set forth in SEQ ID NO: 220.

[0016] In some embodiments, the anti-HLA antibody comprises a heavy chain (HC) having a sequence set forth in any one of SEQ ID NOS: 232-262 or SEQ ID NOS: 266-296 and a light chain (LC) having a sequence set forth in any one of SEQ ID NOS: 300-330. In some embodiments, the HC comprises a sequence set forth in SEQ ID NO: 254 and the LC comprises a sequence set forth in SEQ ID NO: 322 or the HC comprises a sequence set forth in SEQ ID NO: 288 and the VL comprises a sequence set forth in SEQ ID NO: 322. In some embodiments, the HC consists of a sequence set forth in SEQ ID NO: 254 and the LC consists of a sequence set forth in SEQ ID NO: 322 or the HC consists of a sequence set forth in SEQ ID NO: 288 and the VL consists of a sequence set forth in SEQ ID NO: 322.

[0017] In some embodiments, the dosing regimen further comprises administering an effective amount of one or more additional anti-cancer therapeutics selected from at least one of: (a) an anti- ILT2 antibody; (b) an anti-ILT3 antibody; (c) an anti-ILT4 antibody; (d) an anti-KIR2DL4 antibody; (e) an anti-HLA-E antibody; (I an anti-NKG2A antibody; (g) an anti-HLA-F antibody; (h) an anti- PD-L1 antibody; (i) an anti-PD-1 antibody; (j) an anti-CD38 antibody; (k) an anti-CD39 antibody; (1) an anti-CD73 antibody; (m) an anti -A2A receptor antibody; (n) an anti-A2B receptor antibody; (o) an anti-A2A / A2B dual receptor antibody and / or combination; (p) an anti-CD47 antibody; (q) an anti-CLTA-4 antibody; (r) an anti-LAG3 antibody; (s) an anti-TIM3 antibody ; (t) an anti-TIGIT antibody ; (u) an anti-VISTA antibody; (v) an anti-CD94 antibody; (w) an anti-EGFR antibody; (x) an anti- SIRPa antibody or SIPRaFc;(y) a bispecific antibody targeting a combination of any antibody from a) through x); (z) a small molecule inhibitor; (aa) a bi-specific T cell engager, CAR-T therapy, CAR-NK therapy. CAR-macrophage therapy, engineered cell therapy, and / or adoptive T cell therapy; (ab) an oncolytic virus; (ac) a chemotherapy; and / or (ad) an antibody-dependent cellular cytotoxicity (ADCC) therapy using one or more effector competent antibodies selected from a group consisting of an anti- CCR8, anti-TIGIT, anti-CD19, anti-CD20, anti-EGFR, anti-Her2, anti-SLAMMF7, anti-CD52, anti- BCMA. anti-GD2. and / or anti-CCR4.

[0018] In some embodiments, the dosing regimen further comprises administering the anti- EGFR antibody in an antibody -drug-conjugate (ADC).

[0019] In some embodiments, the anti-EGFR antibody is cetuximab. In some embodiments, the anti-EGFR antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL); the VH comprising: (i) a VHCDR1 having the sequence set forth in SEQ ID NO: 343 or SEQ ID NO: 344; (ii) a VHCDR2 having the sequence set forth in SEQ ID NO: 345 or SEQ ID NO: 346; and (iii) a VHCDR3 having the sequence set forth in SEQ ID NO: 347; and the VL comprising: (iv) a VLCDR1 having the sequence set forth in SEQ ID NO: 348; (v) a VLCDR2 having the sequence set forth in SEQ ID NO: 349; and (vi) a VLCDR3 having the sequence set forth in SEQ ID NO: 350. In some embodiments, the anti-EGFR antibody comprises a VH having a sequence set forth in SEQ ID NO: 351 and a VL having a sequence set forth in SEQ ID NO: 352. In some embodiments, the anti- EGFR antibody comprises a heavy chain (HC) having sequence set forth in SEQ ID NO: 353 and a light chain (LC) having a sequence set forth in SEQ ID NO: 354.

[0020] In some embodiments, the anti-PD-1 antibody is pembrolizumab. In some embodiments, the anti-PD-1 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL); the VH comprising: (i) a VHCDR1 having the sequence set forth in SEQ ID NO: 355; (ii) a VHCDR2 having the sequence set forth in SEQ ID NO: 356; and (iii) a VHCDR3 having the sequence set forth in SEQ ID NO: 357; and the VL comprising: (iv) a VLCDR1 having the sequence set forth in SEQ ID NO: 358; (v) a VLCDR2 having the sequence set forth in SEQ ID NO: 359; and (vi) a VLCDR3 having the sequence set forth in SEQ ID NO: 360. In some embodiments, the anti- PD-1 antibody comprises a VH having a sequence set forth in SEQ ID NO: 361 and a VL having a sequence set forth in SEQ ID NO: 362. In some embodiments, the anti-PD-1 antibody comprises a heavy chain (HC) having sequence set forth in SEQ ID NO: 363 and a light chain (LC) having a sequence set forth in SEQ ID NO: 364.

[0021] In some embodiments, the dosing regimen further comprising administering at least one of: (a) a chemotherapy; (b) a radiation therapy; (c) one or more additional therapeutics agents; and / or (d) one or more additional anti-cancer therapeutics. In some embodiments, the chemotherapycomprises administering one or more agents selected from the group consisting of 5 -fluorouracil (5- FU), folic acid or leucovorin, oxaliplatin, irinotecan, cyclophosphamide, cisplatin, carboplatin, methotrexate, gemcitabine, vincristine, vinblastine, paclitaxel, docetaxel, etoposide, doxorubicin, and bleomycin.

[0022] In some embodiments, the dosing regimen comprises administering one or more additional therapeutic agents comprise one or more immunostimulatory agents selected from at least one of an antagonist to an inhibitory receptor of an immune cell, an agonist of a co-stimulatory receptor of an immune cell, an ADCC competent antibody, a cytokine, an oncolytic virus, a chimeric antigen engineered T cell, and / or a bispecific or multi-specific T cell directed antibody.

[0023] In some embodiments, the dosing regimen comprises administering the pharmaceutical composition intravenously.6. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] FIG. 1A provides the binding profile of anti-human HLA-G antibody (TTX-080) to HLA-G-expressing 721.221 target cells. FIG. IB shows the activity of anti-human HLA-G antibody (TTX-080) to reverse HLA-G-mediated suppression of CD8 T cell effector function in a dosedependent manner in one representative donor, as illustrated by the percent of CD107a, IFN-a, and TNF- a. FIG. 1C shows the relationship of anti-human HLA-G antibody (TTX-080) binding to HLA- G+target cells and functional activity in a primary CD8 T cell assay. EC = effective concentration that achieves percentage of maximum effect. Immune activity (degranulation, cytokine secretion) of primary human T cells across multiple donors (mean and SD) and binding of TTX-080 to HLA-G+target cells are shown as EC values across a range of TTX-080 concentrations.

[0025] FIG. 2A and FIG. 2B provide the relationship between dose and serum concentration of anti-human HLA-G antibody (TTX-080) in solid human tumor xenograft mouse models, JEG-3 and HT-1376, respectively. FIG. 2C and FIG. 2D show the relationship between serum concentration and receptor occupancy in xenograft models, JEG-3 and HT-1376, respectively. FIG. 2E provides antihuman HLA-G antibody (TTX-080) serum concentrations across a range of RO values for both models in increments of 5 from EC5 to EC95.

[0026] FIG. 3 shows the relationship between receptor occupancy (converted to EC values) and the mean serum drug (TTX-080) concentration based on binding to HLA-G on HT-1376 tumor cells in a solid human tumor xenograft mouse model. EC = effective concentration that achieves percentage of maximum effect.

[0027] FIG. 4 shows the PK simulation of 20 mg / kg Q3W (i.e., Day 1 of each 21-day cycle) dosing in patients with advanced solid tumors.

[0028] FIG. 5 shows model predicted TTX-080 serum concentrations after IV infusion of 0.6 mg / kg Q3W over 30 minutes to a 70-kg human.

[0029] FIG. 6 shows the serum drug (TTX-080) concentration after intravenous administration.

[0030] FIG. 7 shows the relationship between observed and model-predicted TTX-080 serum concentrations after IV administration.

[0031] FIG. 8 shows receptor occupancy (RO) after single-dose IV administration of TTX-080.

[0032] FIGs 9A and 9B show PK stimulation of TTX-080 at 15 mg / kg Q2W dosing in patients with advanced solid tumors. FIG. 9A shows stimulation excluding effects of ethnicity on clearance. FIG. 9B 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)

[0033] FIG. 10A demonstrates increased activated NK cells detected in subjects administered TTX-080 as a monotherapy for advanced or metastatic colorectal cancer (mCRC).

[0034] FIG. 10B demonstrates increased activated ILT2+CD8+T cells detected in subjects administered TTX-080 as a monotherapy for advanced or metastatic colorectal cancer (mCRC).

[0035] FIG. IOC 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).7. DETAILED DESCRIPTION7.1. Definitions

[0036] 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 arc defined herein for clarity and / or for ready reference, and die 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 and reagents are generally carried out in accordance with manufacturer defined protocols and / or parameters unless otherwise noted.

[0037] As used herein, the singular form of a word includes the plural, unless the context clearly dictates otherwise. Thus, the references "a." "an" and "the" are generally inclusive of the plurals of the respective terms. For example, reference to "an ingredient" or "a method" includes a plurality of such "ingredients" or "methods."

[0038] The term “about" indicates and encompasses an indicated value and a range above and below that value. As used herein, "about," "approximately" and "substantially" are understood to refer to numbers in a range of numerals, for example the range of -10% to +10% of the referenced number, preferably -5% to +5% of the referenced number, more preferably -1% to +1% of the referenced number, most preferably -0.1% to +0.1% of the referenced number. In certain embodiments, the term “about” indicates the designated value ± 10%. ± 5%, or ± 1%. In certain embodiments, the term “about” indicates the designated value ± one standard deviation of that value.

[0039] Furthermore, all numerical ranges herein should be understood to include all integers, whole or fractions, within the range. Moreover, these numerical ranges should be construed as providing support for a claim directed to any number or subset of numbers in that range. For example, a disclosure of from 1 to 10 should be construed as supporting a range of from 1 to 8, from 3 to 7. from 1 to 9, from 3.6 to 4.6, from 3.5 to 9.9, and so forth.

[0040] The words "comprise," "comprises," and "comprising" are to be interpreted inclusively rather than exclusively. Likewise, the terms "include," "including" and "or" should all be construed to be inclusive, unless such a construction is clearly prohibited from the context. However, the embodiments provided by the present disclosure may lack any element that is not specifically disclosed herein. Thus, a disclosure of an embodiment defined using the term "comprising" is also a disclosure of embodiments "consisting essentially of’ and "consisting of' the disclosed components. The phrase "consisting essentially of’ limits the scope of the disclosed components to die specified materials or steps and those that do not materially affect the basic and novel characteristics of the disclosed invention. The phrase "consisting of’ excludes any element, step, or ingredient not specified.

[0041] As used herein, the term "example," particularly when followed by a listing of terms, is merely exemplary and illustrative, and should not be deemed to be exclusive or comprehensive. Any embodiment disclosed herein can be combined with any other embodiment disclosed herein unless explicitly indicated otherwise.

[0042] The term “combinations thereof includes every possible combination of elements to which the term refers.

[0043] The term "and / or" used in the context of "X and / or Y" should be interpreted as "X." or “Y,” or "X and Y."

[0044] As used herein, a “conjugate” refers to an “antibody-drug conjugate (ADC),” formed by chemically linking an antibody , a cytotoxic drug, and a linker molecule. This creates a single molecule that can selectively deliver the drug to target cells.

[0045] As used herein, “couple,” “coupled,” or “coupling” means two or more entities or elements are connected or joined together.

[0046] 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) Lippincott Williams & 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 (V ) and a light chain constant region. The light chain constant region typically comprises one domain, abbreviated CL.

[0047] 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 and antigen binding proteins. Antibodies comprise at least one antigenbinding domain. One example of an antigen-binding domain is an antigen binding domain formed by a VH -VL dimer. An “HLA-G antibody,” “anti-HLA-G antibody,” “HLA-G Ab,” “HLA-G-specific antibody,” or “anti-HLA-G Ab” is an antibody, as described herein, which binds specifically to the antigen HLA-G.

[0048] 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.

[0049] 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.

[0050] 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, s, 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.

[0051] 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); ALLazikani 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); andHonegge and Pliickthun, J. Mol. Biol., 2001, 309:657-70 (“AHo” numbering scheme), each of which is incorporated by reference in its entirety.

[0052] 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.

[0053] Unless otherwise specified, the numbering scheme used for identification of a particular CDR herein is the Kabat / Chothia numbering scheme. Where the residues encompassed by these tw o numbering schemes diverge, the numbering scheme is specified as either Kabat or Chothia.Table 1. 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.

[0054] The “EU numbering scheme” is generally used when referring to a residue in an antibody heavy chain constant region (e.g.. as reported in Kabat et al., supra). Unless stated otherwise, the EU numbering scheme is used to refer to residues in antibody heavy chain constant regions described herein.

[0055] 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')2fragments, Fab' fragments, scFv (sFv) fragments, and scFv-Fc fragments.

[0056] “Fv” fragments comprise a non-covalently-linked dimer of one heavy chain variable domain and one light chain variable domain.

[0057] “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 (CHI) of the heavy chain. Fab fragments may be generated, for example, by papain digestion of a full-length antibody.

[0058] “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 an intact antibody. The F(ab') fragments can be dissociated, for example, by treatment with B-mercaptoethanol.

[0059] “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 Pliickthun 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-tenninal of the scFv. The Fc domain may follow the VHor 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.

[0060] “Humanized” forms of non-human antibodies are chimeric antibodies that contain minimal sequence derived from the non-human antibody. A humanized antibody is generally a human immunoglobulin (recipient antibody) in which residues from one or more CDRs are replaced by residues from one or more CDRs of a non-human antibody (donor antibody). The donor antibody can be any suitable non-human antibody, such as a mouse, rat, rabbit, chicken, or non-human primate antibody having a desired specificity, affinity, or biological effect. In some instances, selected framework region residues of the recipient antibody are replaced by the corresponding framework region residues from the donor antibody. Humanized antibodies may also comprise residues that are not found in either the recipient antibody or the donor antibody. Such modifications may be made to further refine antibody function. For further details, see Jones et al.. Nature, 1986, 321:522-525; Riechmann et al., Nature, 1988, 332:323-329; and Presta, Curr. Op. Struct. Biol., 1992, 2:593-596, each of which is incorporated by reference in its entirety.

[0061] A “human antibody” is one which possesses an amino acid sequence corresponding to that of an antibody produced by a human or a human cell, or derived from a non-human source that utilizes a human antibody repertoire or human antibody -encoding sequences (e.g.. obtained from human sources or designed de novo). Human antibodies specifically exclude humanized antibodies.

[0062] 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: 7 or SEQ ID NO: 25; (ii) a VHCDR2 having the sequence set forth in SEQ ID NO: 44 or SEQ ID NO: 65; and (iii) a VHCDR3 having the sequence set forth in SEQ ID NO: 93; and a VL consisting of : (iv) a VLCDR1 having the sequence set forth in SEQ ID NO: 118; (v) a VLCDR2 having the sequence set forth in SEQ ID NO: 138; and (vi) a VLCDR3 having the sequence set forth in SEQ ID NO: 155. The VH consists of the sequence set forth in SEQ ID NO: 192 and the VL consists of the amino acid sequence set forth in SEQ ID NO: 220. The anti-HLA antibody comprises a heavy chain (HC) having a sequence set forth in SEQ ID NO: 254 and a light chain (LC) having a sequence set forth in SEQ ID NO: 322. As set forth in the examples presented herein, TTX-080 shall mean an anti HLA-G antibody consisting of aheavy chain (HC) consisting of the sequence set forth in SEQ ID NO: 254 and a light chain (LC) consisting of the sequence set forth in SEQ ID NO: 322.

[0063] An “anti-EGFR antibody” refers to an antibody that binds to EGFR. In some embodiments, the anti-EGFR antibody is cetuximab. 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: 343 or SEQ ID NO: 344; (ii) a VHCDR2 having the sequence set forth in SEQ ID NO: 345 or SEQ ID NO: 346; and (iii) a VHCDR3 having the sequence set forth in SEQ ID NO: 347; and a VL comprising: (iv) a VLCDR1 having the sequence set forth in SEQ ID NO: 348; (v) a VLCDR2 having the sequence set forth in SEQ ID NO: 349; and (vi) a VLCDR3 having the sequence set forth in SEQ ID NO: 350. In some embodiments, cetuximab consists of a VH sequence set forth in SEQ ID NO: 351 and a VL sequence set forth in SEQ ID NO: 352. In some embodiments, cetuximab consists of a heavy chain (HC) having sequence set forth in SEQ ID NO: 353 and a light chain (LC) having a sequence set forth in SEQ ID NO: 354. 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: 353 and a light chain (LC) consisting of the sequence set forth in SEQ ID NO: 354.

[0064] An “anti-PD-1 antibody” refers to an antibody that binds to PD-1. In some embodiments, the anti-PD-1 antibody is pembrolizumab. 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: 355; (ii) a VHCDR2 having the sequence set forth in SEQ ID NO: 356; and (iii) a VHCDR3 having the sequence set forth in SEQ ID NO: 357; and the VL consisting of (iv) a VLCDR1 having the sequence set forth in SEQ ID NO: 358; (v) a VLCDR2 having the sequence set forth in SEQ ID NO: 359; and (vi) a VLCDR3 having the sequence set forth in SEQ ID NO: 360. In some embodiments, pembrolizumab consists of a VH having a sequence having the amino acid sequence set forth in SEQ ID NO: 361 and a VL having a sequence set forth in SEQ ID NO: 362. In some embodiments, pembrolizumab consists of a heavy chain (HC) having the sequence set forth in SEQ ID NO: 363 and a light chain (LC) having the sequence set forth in SEQ ID NO: 364. As set forth in the examples presented herein, pembrolizumab shall mean the anti-PD-1 antibody consisting of a heavy chain (HC) consisting of the sequence set forth in SEQ ID NO: 363 and a light chain (LC) consisting of the sequence set forth in SEQ ID NO: 364.

[0065] “Affinity” refers to the strength of the sum total of non-covalent interactions between a single binding site of a molecule (e.g.. an antibody) and its binding partner (e.g.. an antigen). Unless indicated otherwise, as used herein, “binding affinity” refers to intrinsic binding affinity, which reflects a 1 : 1 interaction between members of a binding pair (e.g.. antibody and antigen). The affinity' of a molecule X for its partner Y can generally be represented by the dissociation constant (KD). Affinity’ can be measured by common methods known in the art, including those described herein.Affinity can be determined, for example, using surface plasmon resonance (SPR) technology, such as a Biacore® instrument, or using bio-layer interferometry technology', such as an Octet® instrument.

[0066] With regard to the binding of an antibody to a target molecule, the tenns “specific binding.” “specifically binds to," “specific for," “selectively binds.” and “selective for” a particular antigen (e.g., a polypeptide target) or an epitope on a particular antigen mean binding that is measurably different from a non-specific or non-selective interaction. Specific binding can be measured, for example, by determining binding of a molecule compared to binding of a control molecule. Specific 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, specific binding is indicated if the binding of the labeled target to a probe is competitively inhibited by the excess non-labeled target.

[0067] Percent “identity7” 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.

[0068] The term “amino acid” refers to the tw enty' 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 (lie; 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).

[0069] 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 to regulate various physiological and immune processes. They regulate immune responses, inflammation, cell growth, differentiation, and tissue repair.

[0070] 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 products intended 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 fromimpurities, 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 odrer 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 pharmacal 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.

[0071] 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. IDiluents 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.

[0072] 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.

[0073] 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 die desired physical and chemical properties of the final dosage form.

[0074] 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.

[0075] An “effector competent antibody.” also known as a functional antibody or effector-active antibody, is an antibody that is capable of engaging with the immune system's effector mechanisms to elicit specific immune responses against its target. Effector mechanisms are processes by which antibodies activate immune responses to eliminate target cells or pathogens. These mechanisms involve interactions with immune cells or proteins that enhance the immune response's effectiveness. Effector mechanisms include processes like antibody-dependent cellular cytotoxicity (ADCC), complement activation, and immune cell recruitment. In ADCC, antibodies bind to a target cell's surface antigens. Immune cells, particularly natural killer (NK) cells, recognize the bound antibodies and subsequently target and destroy the antibody -coated cells. In complement activation, antibodies activate the complement system, a cascade of proteins that leads to cell lysis, opsonization (enhancement of phagocytosis), and inflammation. In immune cell recruitment, antibodies facilitate the recruitment of immune cells, such as macrophages and neutrophils, to the site of infection or inflammation. Effector competent antibodies are employed in various therapeutic strategies, including antibody -based cancer therapies and treatments for infectious diseases. Monoclonal antibodies that can induce ADCC or complement activation have been developed to target cancer cells, enhancing the immune system's ability to eliminate tumors.

[0076] “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.

[0077] 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. 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.

[0078] As used herein, the term “subject” means a mammalian subject. Exemplary subjects include, but are not limited to humans, monkeys, dogs, cats, mice, rats, cows, horses, camels, avians, goats and sheep. In certain embodiments, the subject is a human. In some embodiments, the subject has cancer, an autoimmune disease or condition, and / or an infection that can be treated with anantibody provided herein. In some embodiments, the subject is a human that is suspected to have cancer, an autoimmune disease or condition, and / or an acute infection and chronic infection.

[0079] A “solid cancer,” also known as solid tumor, is a ty pe of cancer that form in the body's tissues and organs, resulting in the development of masses or lumps of abnormal cells. Solid cancers can occur in virtually any organ or tissue in the body. Common examples include but are not limited to breast cancer, lung cancer, colorectal cancer, prostate cancer, and ovarian cancer.

[0080] A “hematological cancer.” also known as hematologic cancer or blood cancer, refers to cancers that originate in the cells of the blood, bone marrow, or lymphatic system. Unlike solid cancers, hematological cancers primarily involve the production and function of blood cells and often affect the bone marrow's abi 1 ity to produce healthy blood cells. Hematological cancers are broadly categorized into three main types: leukemia, lymphoma, and myeloma. Leukemia is a cancer of the bone marroyv and blood, characterized by the rapid production of abnormal white blood cells. These abnormal cells crowd out healthy cells, leading to reduced production of red blood cells and platelets. Lymphoma is a cancer of the lymphatic system, which includes lymph nodes, lymphocytes (a type of yvhite blood cell), and lymphatic vessels. There are two main types: Hodgkin lymphoma and nonHodgkin lymphoma. Myeloma is a cancer that affects plasma cells, a type of white blood cell responsible for producing antibodies. In myeloma, abnormal plasma cells accumulate in the bone marrow and interfere with normal cell production.

[0081] An “immunostimulatoiy agent,” also known as an immune modulator or immunomodulatory agent, is a substance that influences the immune system's response, either by enhancing or suppressing its activity.

[0082] An “antagonist” is a type of molecule or substance that binds to a receptor or target in the body, blocking or inhibiting its activity. Antagonists work by preventing the natural or intended interactions between the receptor and its ligands, which are molecules that normally bind to the receptor to produce a response, leading to a reduction or inhibition of the receptor's signaling pathway.

[0083] An “agonist” is a type of molecule or substance that binds to a receptor or target in the body and activates its function. When an agonist binds to its specific receptor, it triggers a biological response or signal within the cell or tissue. This activation leads to downstream cellular responses, which can include changes in gene expression, enzyme activity, ion channel opening, or the release of signaling molecules. Agonists exhibit specificity for certain receptors, as their chemical structure allows them to interact with complementary binding sites on those receptors. Endogenous agonists are naturally produced molecules in the body that bind to receptors and regulate physiological functions. Synthetic agonists are artificially designed molecules that mimic the effects of endogenous agonists. Partial agonists bind to receptors but only activate them to a limited extent compared to full agonists.

[0084] Aii “oncolytic virus” is a type of virus that has been genetically modified or naturally evolved to selectively infect and destroy cancer cells while sparing normal healthy cells.

[0085] A chimeric antigen receptor (CAR) engineered T cell, often referred to as CAR T cell therapy, is an immunotherapy approach that involves genetically modifying a patient's own T cells to enhance their ability to recognize and attack cancer cells. A CAR is a synthetic receptor that combines an antigen-binding domain derived from an antibody with T cell signaling components.

[0086] 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 tw o 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 die maximum tolerated dose (MTD), optimal biological dose (OBD), and / or dose-limiting toxicity (DLT). The doing may be administered via intravenous (IV) infusion and / or 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 die 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 Q3 W, 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 of administration of the anti HLA-G antibody (TTX-080), the dosing is an effective amount to maintain serum drug concentration of TTX-080 at a target trough level between about 10 pg / mL to about 1200 pg / mL, such as about or above 50 pg / mL during the first cycle after administration of the first dose and / or during each of the subsequent cycles.

[0087] 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 individualsdue 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 pg / niL to about 1200 pg / mL, such as about or above 50 pg / mL during the first cycle after administration of the first dose and / or each of the subsequent cycles.

[0088] 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 EC5o, ECeo. EC?o, ECso, or EC90 for receptor occupancy (RO).7.2. Anti HLA-G Antibody

[0089] Provided herein are dosing regimens and methods for treating a subject suffering from diseases. The subject is administered an anti human HLA-G antibody. The anti human HLA-G antibody is provided and prepared as described in W02020069133A1, which is incorporated herein in its entirety by reference.

[0090] In the treatment dosing regimens or methods provided herein, the anti human HLA-G antibody comprises or consists of a heavy chain variable region (VH) and a light chain variable region (VL). In some embodiments, the VH may comprise: i) a VHCDR1 having the sequence having at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% similarity with any one set forth in SEQ ID NOS: 1-14 or SEQ ID NOS: 18-34; ii) a VHCDR2 having the sequence having at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% similarity with any one set forth in SEQ ID NOS: 38-50 or SEQ ID NOS: 54-71; and iii) a VHCDR3 having tire sequence having at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% similarity with any one set forth in SEQ ID NOS: 76-101. The VL may comprise: i) a VLCDR1 having the sequence having at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% similarity with any one set forth in SEQ ID NOS: 105-124; ii) a VLCDR2 having the sequence having at least 50%, 60%, 70%. 75%, 80%, 85%, 90%. 95%, or 99% similarity with any one set forth in SEQ ID NOS: 128-145; and iii) a VLCDR3 having the sequence having at least 50%, 60%, 70%, 75%, 80%. 85%, 90%, 95%, or 99% similarity with any one set forth in SEQ ID NOS: 149-166.

[0091] In the treatment dosing regimens or methods provided herein, the anti human HLA-G antibody consists of a heavy chain variable region (VH) and a light chain variable region (VL). In some embodiments, the VH comprises or consists of: i) a VHCDR1 having the sequence set forth in any one of SEQ ID NOS: 1-14 or SEQ ID NOS: 18-34; ii) a VHCDR2 having the sequence set forth in any one of SEQ ID NOS: 38-50 or SEQ ID NOS: 54-71; and iii) a VHCDR3 having the sequence set forth in any one of SEQ ID NOS: 76-101; and the VL comprises or consists of: i) a VLCDR1 having the sequence set forth in any one of SEQ ID NOS: 105-124; ii) a VLCDR2 having the sequence set forth in any one of SEQ ID NOS: 128-145; and iii) a VLCDR3 having the sequence set forth in any one of SEQ ID NOS: 149-166.

[0092] In some embodiments, the anti human HLA-G antibody comprises or consists of a VH comprising at least one of (i) a VHCDR1 having the sequence set forth in SEQ ID NO: 7 or SEQ ID NO: 25: (ii) a VHCDR2 having the sequence set forth in SEQ ID NO: 44 or SEQ ID NO: 65; and / or(iii) a VHCDR3 having the sequence set forth in SEQ ID NO: 93, and a VL comprising at least one of(iv) a VHCDL1 having the sequence set forth in SEQ ID NO: 118; (v) a VHCDL2 having the sequence set forth in SEQ ID NO: 138; and / or (vi) a VHCDL3 having the sequence set forth in SEQ ID NO: 155.

[0093] In some embodiments, the anti human HLA-G antibody comprises or consists of a VH comprising (i) a VHCDR1 having the sequence set forth in SEQ ID NO: 7 or SEQ ID NO: 25; (ii) a VHCDR2 having the sequence set forth in SEQ ID NO: 44 or SEQ ID NO: 65; and (iii) a VHCDR3 having the sequence set forth in SEQ ID NO: 93. and a VL comprising (iv) a VHCDL1 having the sequence set forth in SEQ ID NO: 1 18; (v) a VHCDL2 having the sequence set forth in SEQ ID NO: 138; and (vi) a VHCDL3 having the sequence set forth in SEQ ID NO: 155. In some embodiments, the VH comprises the sequence set forth in any one of SEQ ID NOS: 170-200 and the VL comprises the sequence set forth in any one of SEQ ID NOS: 204-228. In some embodiments, the VH comprises the sequence having at least 50%. 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% similarity with any one set forth in SEQ ID NOS: 170-200. and the VL comprises the sequence having at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% similarity with any one set forth in any one of SEQ ID NOS: 204-228. In some embodiments, a VH sequence that is at least 85% identical to the amino acid sequence set forth in SEQ ID NO: 192 and a VL sequence that is at least 85% identical to the amino acid sequence set forth in SEQ ID NO: 220. In some embodiments, a VH sequence that is at least 95% identical to the amino acid sequence set forth in SEQ ID NO: 192 and a VL sequence that is at least 95% identical to the amino acid sequence set forth in SEQ ID NO: 220. In some embodiments, the VH sequence is set forth in SEQ ID NO: 192 and the VL sequence is set forth in SEQ ID NO: 220.

[0094] In some embodiments, the anti human HLA-G antibody comprises a heavy chain (HC) having a sequence having at least 50%, 60%, 70%, 75%. 80%, 85%, 90%, 95%. or 99% similarity with any one of SEQ ID NOS: 232-262 or SEQ ID NOS: 266-296. and a light chain (LC) having a sequence having at least 50%, 60%, 70%. 75%, 80%, 85%, 90%. 95%. or 99% similarity with any one of SEQ ID NOS: 300-330. In some embodiments, the anti human HLA-G antibody comprises a HC having a sequence set forth in any one of SEQ ID NOS: 232-262. and a VL having a sequence set forth in any one of SEQ ID NOS: 300-330.

[0095] In some embodiments, the anti human HLA-G antibody comprises a heavy chain having a sequence at least 85%, 90%, or 95% identical to an amino acid sequence set forth in SEQ ID NO: 254 and a light chain having a sequence at least 85%, 90%. or 95% identical to an amino acid sequence set forth in SEQ ID NO: 322. In some embodiments, the anti human HLA-G antibody comprises a heavychain of SEQ ID NO: 254 and a light chain of SEQ ID NO: 322. In some embodiments, the anti human HLA-G antibody consists of a heavy chain of SEQ ID NO: 254 and a light chain of SEQ ID NO: 322.

[0096] In some embodiments, the anti human HLA-G antibody comprises a heavy chain having a sequence at least 85%, 90%, or 95% identical to an amino acid sequence set forth in SEQ ID NO: 288 and a light chain having a sequence at least 85%, 90%, or 95% identical to an amino acid sequence set forth in SEQ ID NO: 322. In some embodiments, the anti human HLA-G antibody comprises a heavy chain of SEQ ID NO: 288 and a light chain of SEQ ID NO: 322. In some embodiments, the anti human HLA-G antibody consists of a heavy chain of SEQ ID NO: 288 and a light chain of SEQ ID NO: 322.7.3. Dosages and Dosing Regimens

[0097] Provided herein are dosing regimens for administering the anti HLA-G antibody (TTX- 080) to a subject in need thereof. The subject may have a health condition or disease such as cancer, autoimmune disease, or infection. The dosing regimens may be used in a TTX-080 monotherapy, or in a combination therapy with a second therapeutic agent.

[0098] In one aspect, provided herein is a dosing regimen for treating a subject suffering from a cancer, comprising administering a pharmaceutical composition comprising an effective amount of an anti human HLA-G antibody to the subject in a first dose during a first cycle, wherein administration of the anti human HLA-G antibody maintains a serum drug concentration at a target trough level of between about 10 ug / mL- 100 pg / mL during the first cycle after administration of a first dose. In some embodiments, the dosing regimen further comprises administering the anti human HLA-G antibody in one or more subsequent doses in one or more subsequent cycles. In some embodiments, the administration achieves at least ECeo, EC70, ECso. or EC90 for receptor occupancy (RO). In some embodiments, the anti HLA-G antibody is TTX-080.

[0099] 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 maintains a serum drug concentration at a target trough of at least, about, or above 50 pg / mL during the first cycle and / or during each of the subsequent cycles. In some embodiments, the dosing regimen comprises administering the anti human HLA-G antibody at about 0.2-20 mg / kg to the subject in the first cycle and / or the subsequent cycles. In some embodiments, the dosing regimen comprises administering the anti human HLA-G antibody at 2 to 4 weeks intervals betw een the first cycle and each of the subsequent cycles.

[0100] In some embodiments, the dosing regimen comprises administering the anti human HLA- G antibody at 20 mg / kg Q3W in the first cycle and / or each of the subsequent cycles. In someembodiments, the dosing regimen comprises administering the anti human HLA-G antibody at 15 mg / kg Q2W in the first cycle and / or each of the subsequent cycles.

[0101] In some embodiments, the dosing regimen further comprises administering an effective amount of one or more additional anti-cancer therapeutics selected from at least one: (a) an anti-ILT2 antibody; (b) an anti-ILT3 antibody; (c) an anti-ILT4 antibody; (d) an anti-KIR2DL4 antibody; (e) an anti-HLA-E antibody; (1) an anti-NKG2A antibody; (g) an anti-HLA-F antibody; (h) an anti-PD-Ll antibody; (i) an anti-PD-1 antibody; (j) an anti-CD38 antibody; (k) an anti-CD39 antibody; (1) an anti- CD73 antibody; (m) an anti-A2A receptor antibody; (n) an anti-A2B receptor antibody; (o) an anti- A2A / A2B dual receptor antibody and / or combination; (p) an anti-CD47 antibody; (q) an anti-CLTA-4 antibody; (r) an anti-LAG3 antibody; (s) an anti-TIM3 antibody; (t) an anti-TIGIT antibody; (u) an anti- VISTA antibody; (v) an anti-CD94 antibody; (w) an anti-EGFR antibody; (x) an anti-SIRPa antibody or SIPRaFc;(y) a bispecific antibody targeting a combination of any antibody from a) through x); (z) a small molecule inhibitor; (aa) a bi-specific T cell engager, CAR-T therapy, CAR-NK therapy, CAR-macrophage therapy, engineered cell therapy, and / or adoptive T cell therapy; (ab) an oncolytic virus; (ac) a chemotherapy; and / or (ad) an antibody-dependent cellular cytotoxicity (ADCC) therapy using one or more effector competent antibodies selected from a group consisting of an anti- CCR8, anti-TIGIT. anti-CD19, anti-CD20, anti-EGFR. anti-Her2, anti-SLAMMF7, anti-CD52. anti- BCMA, anti-GD2, and / or anti-CCR4.

[0102] In some embodiments, the dosing regimen further comprises administering the anti- EGFR antibody in an antibody -drug-conjugate (ADC).

[0103] In some embodiments, the anti-EGFR antibody is cetuximab. In some embodiments, the anti-EGFR antibody comprises or consists of a heavy chain variable region (VH) and a light chain variable region (VL); the VH comprising or consisting of: (i) a VHCDR1 having the sequence set forth in SEQ ID NO: 343 or SEQ ID NO: 344; (ii) a VHCDR2 having the sequence set forth in SEQ ID NO: 345 or SEQ ID NO: 346; and (iii) a VHCDR3 having the sequence set forth in SEQ ID NO: 347; and the VL comprising or consisting of: (iv) a VLCDR1 having the sequence set forth in SEQ ID NO: 348; (v) a VLCDR2 having the sequence set forth in SEQ ID NO: 349; and (vi) a VLCDR3 having the sequence set forth in SEQ ID NO: 350. In some embodiments, the anti-EGFR antibody comprises or consists of a VH having a sequence set forth in SEQ ID NO: 351 and a VL having a sequence set forth in SEQ ID NO: 352. In some embodiments, the anti-EGFR antibody comprises or consists of a heavy chain (HC) having sequence set forth in SEQ ID NO: 353 and a light chain (LC) having a sequence set forth in SEQ ID NO: 354.

[0104] In some embodiments, the anti-PD-1 antibody is pembrolizumab. In some embodiments, the anti-PD-1 antibody comprises or consists of a heavy chain variable region (VH) and a light chain variable region (VL); the VH comprising or consisting of: (i) a VHCDR1 having the sequence set forth in SEQ ID NO: 355; (ii) a VHCDR2 having the sequence set forth in SEQ ID NO: 356; and (iii)a VHCDR3 having the sequence set forth in SEQ ID NO: 357; and the VL comprising or consisting of: (iv) a VLCDR1 having the sequence set forth in SEQ ID NO: 358; (v) a VLCDR2 having the sequence set forth in SEQ ID NO: 359; and (vi) a VLCDR3 having the sequence set forth in SEQ ID NO: 360. In some embodiments, the anti-PD-1 antibody comprises or consists of a VH having a sequence set forth in SEQ ID NO: 361 and a VL having a sequence set forth in SEQ ID NO: 362. hi some embodiments, the anti-PD-1 antibody comprises or consists of a heavy chain (HC) having sequence set forth in SEQ ID NO: 363 and a light chain (LC) having a sequence set forth in SEQ ID NO: 364.

[0105] In some embodiments, the dosing regimen further comprising administering at least one of: (a) a chemotherapy; (b) a radiation therapy; (c) one or more additional therapeutics agents; and / or (d) one or more additional anti-cancer therapeutics. In some embodiments, the chemotherapy comprises administering one or more agents selected from the group consisting of 5 -fluorouracil (5- FU). folic acid or leucovorin, oxaliplatin, irinotecan, cyclophosphamide, cisplatin, carboplatin, methotrexate, gemcitabine, vincristine, vinblastine, paclitaxel, docetaxel, etoposide, doxorubicin, and bleomycin. In some embodiments, wherein the chemotherapy comprises administering FOLFIRI (folic acid or leucovorin, fluorouracil, and irinotecan).

[0106] In some embodiments, the dosing regimen comprises administering an anti HLA-G antibody (TTX-080) in combination with an anti-EGFR antibody (e.g., cetuximab). In some embodiments, the dosing regimen comprises administering an anti HLA-G antibody (TTX-080) in combination with an anti-EGFR antibody (e.g., cetuximab) and FOLFIRI (folic acid or leucovorin, fluorouracil, and irinotecan).

[0107] In some embodiments, the dosing regimen comprises administering an anti HLA-G antibody (TTX-080) in combination with an anti-PD-1 antibody (e.g., pembrolizumab).

[0108] In some embodiments, the dosing regimen comprises administering one or more immunostimulatory agents selected from at least one of an antagonist to an inhibitory receptor of an immune cell, an agonist of a co-stimulatory receptor of an immune cell, an ADCC competent antibody, a cytokine, an oncolytic virus, a chimeric antigen engineered T cell, and / or a bispecific or multi-specific T cell directed antibody.

[0109] In some embodiments, the dosing regimen comprises administering an inhibitory receptor selected from at least one of ILT2, ILT3, ILT4, KIR2DL4, CTLA-4, PD-1, CD39, CD73. PD-L1 , PD- L2, LAG-3, Tim3, TIGIT, B7-H3, B7-H4. neuritin, BTLA. CECAM-1, CECAM-5, VISTA, LAIR1 , CD 160. 2B4,TGF-B NKG2A, CD47. SIPRa, and / or a killer-cell immunoglobulin-like receptor (KIR).

[0110] In some embodiments, the dosing regimen comprises administering a co-stimulatory receptor selected from at least one of 0X40, CD2, CD27, ICAM-1, LFA-1, ICOS (CD278), 4- IBB (CD137), GITR, CD28, CD30, CD40, BAFFR, HVEM, CD7, LIGHT, NKG2C, SLAMF7, NKp30, NKp46, NKp80, CD 160, and / or a CD83 ligand.

[0111] In some embodiments, the dosing regimen comprises administering an ADCC competent antibody comprises at least one antibody selected from an anti- CD19, anti-CD20. anti-EGFR, anti- Her2, anti-SLAMF7, anti-CD52, anti-BCMA. anti-GD2. anti-CD38, anti-CCR8, anti-TIGIT, and / or or anti-CCR4 antibody.

[0112] In some embodiments, the dosing regimen comprises administering cytokine selected from at least one of IL-1, IL-2, IL-4, IL-5. IL-7, IL-10. IL-11, IL-12, IL-13. IL-15. IL-18. IL-21, and / or IL-27.

[0113] In some embodiments, the dosing regimen comprises administering an oncolytic virus selected from the group consisting of a herpes simplex virus, a vesicular stomatitis virus, an adenovirus, a Newcastle disease virus, a vaccinia virus, and a maraba virus.

[0114] In some embodiments, the dosing regimen comprises administering a chimeric antigen engineered T cell. In some embodiments, the dosing regimen comprises administering a bispecific or multi-specific T cell directed antibody.

[0115] In human therapeutics, the doctor or physician will determine the dosology 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.

[0116] 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 doseresponse curves derived from in vitro or animal model test systems.

[0117] Exemplaty doses of a composition 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).

[0118] In some embodiments, the dosage of the antibody, 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, or more of a subject’s body weight, 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, about20mg / kg, or more of a subject’s body weight; or 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, or 15 mg / kg or more of a subject’s body weight.

[0119] In some embodiments, the dosage of the antibody or composition comprising the antibody administered to prevent, treat, manage, or ameliorate a disorder, or one or more symptoms thereof in a subject may be about 0.1 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 or composition comprising the antibody 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.

[0120] In some embodiments, a subject with advanced solid tumors receives single agent anti HLA-G antibody (TTX-080) at escalating doses in a 3+3 design from 0.2-20 mg / kg IV Q3W. In some embodiments, a subject with advanced refractory / resistant solid tumors receives TTX-080 at about 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 may be used for the first cohort (Cohort 1, 0.2 mg / kg Q3W) and standard 3+3 design may be 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). In some embodiments, the cancer is colorectal cancer (CRC).

[0121] In some embodiments, a subject with advanced refractory / resistant solid tumors receives anti HLA-G antibody (TTX-080) at between about 0.2 to about 100 mg / kg IV Q2W or Q3W. In some embodiments, a subject with advanced refractory / resistant solid tumors receives anti HLA-G antibody (TTX-080) at betw een 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.

[0122] In some embodiments, a subject with advanced refractory / resistant solid tumors receives anti HLA-G antibody (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 IV Q2W 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 Q3 W, or about 100 mg / kg IV Q2W or Q3W.

[0123] In some embodiments, a subject with advanced refractory / resistant solid tumors receives anti HLA-G antibody (TTX-080) at 0.2 mg / kg IV Q2W or Q3W. In some embodiments, a subject with advanced refractory / resistant solid tumors receives anti HLA-G antibody (TTX-080) at 0.6 mg / kg IV Q2W or Q3W. In some embodiments, a subject with advanced refractory / resistant solid tumors receives anti HLA-G antibody (TTX-080) at 2 mg / kg IV Q2W or Q3W. In some embodiments, a subject with advanced refractory / resistant solid tumors receives anti HLA-G antibody (TTX-080) at 6 mg / kg IV Q2W or Q3W. In some embodiments, a subject with advanced refractory' / resistant solid tumors receives anti HLA-G antibody (TTX-080) at 10 mg / kg IV Q2W or Q3W. In some embodiments, a subject with advanced refractory / resistant solid tumors receives anti HLA-G antibody (TTX-080) at 15 mg / kg IV Q2W or Q3W. In some embodiments, a subject with advanced refractory / resistant solid tumors receives anti HLA-G antibody (TTX-080) at 20 mg / kg IV Q2W or Q3W.

[0124] In some embodiments, a subject with advanced solid tumors receives anti HLA-G antibody (TTX-080) in combination with cetuximab, an anti-EGFR antibody or inhibitor, or a derivative or equivalent thereof at about 0.2 mg / kg, 0.6 mg / kg. 2 mg / kg, 6 mg / kg. 10 mg / kg. 15 mg / kg, or 20 mg / kg IV. 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 has progressed on a prior treatment of cetuximab. In some embodiments, the cancer has no prior treatment of cetuximab.

[0125] In some embodiments, a subject with advanced refractory / resistant solid tumors receives anti HLA-G antibody (TTX-080) in combination with cetuximab, an anti-EGFR antibody or inhibitor, or a derivative or equivalent thereof at betw een 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 1 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.

[0126] In some embodiments, a subject with advanced refractory / resistant solid tumors receives anti HLA-G antibody (TTX-080) in combination with cetuximab, an anti-EGFR antibody or inhibitor, or a derivative or equivalent thereof 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 IV Q2W 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 Q3 W, 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.

[0127] In some embodiments, a subject with advanced solid tumors receives anti HLA-G antibody (TTX-080) in combination with cetuximab, an anti-EGFR antibody or inhibitor, or a derivative or equivalent thereof at 0.2 mg / kg Q2W or Q3W. In some embodiments, a subject with advanced solid tumors receives anti HLA-G antibody (TTX-080) in combination with cetuximab, an anti-EGFR antibody or inhibitor, or a derivative or equivalent thereof at 0.6 mg / kg Q2W or Q3W.

[0128] In some embodiments, a subject with advanced solid tumors receives anti HLA-G antibody (TTX-080) in combination with cetuximab, an anti-EGFR antibody or inhibitor, or a derivative or equivalent thereof at 2 mg / kg Q2W or Q3W. In some embodiments, a subject with advanced solid tumors receives anti HLA-G antibody (TTX-080) in combination with cetuximab, an anti-EGFR antibody or inhibitor, or a derivative or equivalent thereof at 6 mg / kg Q2W or Q3W. In some embodiments, a subject with advanced solid tumors receives anti HLA-G antibody (TTX-080) in combination with cetuximab, an anti-EGFR antibody or inhibitor, or a derivative or equivalent thereof at 10 mg / kg Q2W or Q3W. In some embodiments, a subject with advanced solid tumors receives anti HLA-G antibody (TTX-080) in combination with cetuximab, an anti-EGFR antibody or inhibitor, or a derivative or equivalent thereof at 15 mg / kg Q2W or Q3W. In some embodiments, a subject with advanced solid tumors receives anti HLA-G antibody (TTX-080) in combination with cetuximab, an anti-EGFR antibody or inhibitor, or a derivative or equivalent thereof at 20 mg / kg Q2W or Q3W.

[0129] In some embodiments, a subject with advanced solid tumors receives anti HLA-G antibody (TTX-080) in combination with pembrolizumab, an anti-PD-1 antibody or inhibitor, a checkpoint inhibitor, or a derivative or equivalent thereof at about 0.2 mg / kg, 0.6 mg / kg. 2 mg / kg, 6 mg / kg, 10 mg / kg, 15 mg / kg, or 20 mg / kg IV. In some embodiments, the cancer is Head and Neck Squamous Cell Carcinoma (HNSCC). In some embodiments, the cancer is non-small cell lung cancer (NSCLC). In some embodiments, the cancer has progressed on one or more prior checkpoint inhibitortreatment (e g., anti-PD-1, anti-PD-Ll, anti-CTLA-4). In some embodiments, the cancer has no prior treatment of one or more checkpoint inhibitor (e.g., anti-PD-1, anti-PD-Ll, anti-CTLA-4).

[0130] In some embodiments, a subject with advanced refractory / resistant solid tumors receives anti HLA-G antibody (TTX-080) in combination with pembrolizumab, an anti-PD-1 antibody or inhibitor, a checkpoint inhibitor, or a derivative or equivalent thereof 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.

[0131] In some embodiments, a subject with advanced refractory / resistant solid tumors receives anti HLA-G antibody (TTX-080) in combination with pembrolizumab, an anti-PD-1 antibody or inhibitor, a checkpoint inhibitor, or a derivative or equivalent thereof 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 IV Q2W or Q3W, about 45 mg / kg IV Q2W or Q3W, about 0 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.

[0132] In some embodiments, a subject with advanced solid tumors receives anti HLA-G antibody (TTX-080) in combination with pembrolizumab, an anti-PD-1 antibody or inhibitor, a checkpoint inhibitor, or a derivative or equivalent thereof at 0.2 mg / kg Q2W or Q3W. In some embodiments, a subject with advanced solid tumors receives anti HLA-G antibody (TTX-080) in combination with pembrolizumab, an anti-PD-1 antibody or inhibitor, a checkpoint inhibitor, or a derivative or equivalent thereof at 0.6 mg / kg Q2W or Q3W. In some embodiments, a subject with advanced solid tumors receives anti HLA-G antibody (TTX-080) in combination with pembrolizumab. an anti-PD-1 antibody or inhibitor, a checkpoint inhibitor, or a derivative or equivalent thereof at 2 mg / kg Q2W or Q3W. In some embodiments, a subject with advanced solid tumors receives anti HLA-G antibody (TTX-080) in combination with pembrolizumab, an anti-PD-1 antibody or inhibitor, a checkpoint inhibitor, or a derivative or equivalent thereof at 6 mg / kg Q2W or Q3W. In some embodiments, a subject with advanced solid tumors receives anti HLA-G antibody (TTX-080) in combination with pembrolizumab. an anti-PD-1 antibody or inhibitor, a checkpoint inhibitor, or a derivative or equivalent thereof at 10 mg / kg Q2W or Q3W. In some embodiments, a subject with advanced solid tumors receives anti HLA-G antibody (TTX-080) in combination with pembrolizumab, an anti-PD-1 antibody or inhibitor, a checkpoint inhibitor, or a derivative orequivalent thereof at 15 mg / kg Q2W or Q3W. In some embodiments, a subject with advanced solid tumors receives anti HLA-G antibody (TTX-080) in combination with pembrolizumab, an anti-PD-1 antibody or inhibitor, a checkpoint inhibitor, or a derivative or equivalent thereof at 20 mg / kg Q2W or Q3W.

[0133] In some embodiments, a subject with advanced solid tumors receives anti HLA-G antibody (TTX-080) in combination with cetuximab and FOLFIRI (folic acid or leucovorin fluorouracil, and irinotecan) at about 0.2 mg / kg. 0.6 mg / kg, 2 mg / kg, 6 mg / kg, 10 mg / kg, 15 mg / kg, or 20 mg / kg IV. In some embodiments, the cancer is colorectal cancer (CRC). In some embodiments, the cancer is metastatic RAS. BRAF and HER2 wild type colorectal cancer (CRC) and 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. In some embodiments, the cancer has no prior treatment of cetuximab.

[0134] In some embodiments, a subject with advanced refractory / resistant solid tumors receives anti HLA-G antibody (TTX-080) in combination with cetuximab, an anti-EGFR antibody or inhibitor, or a derivative or equivalent thereof, and FOLFIRI 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 betw een about 10 to about 30 mg / kg IV Q2W or Q3W.

[0135] In some embodiments, a subject with advanced rcfractory / rcsistant solid tumors receives anti HLA-G antibody (TTX-080) in combination with cetuximab, an anti-EGFR antibody or inhibitor, or a derivative or equivalent thereof, and FOLFIRI 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 IV Q2W 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.

[0136] In some embodiments, a subject with advanced solid tumors receives anti HLA-G antibody (TTX-080) in combination with cetuximab, an anti-EGFR antibody or inhibitor, or a derivative or equivalent thereof and FOLFIRI at 0.2 mg / kg Q2W or Q3W. In some embodiments, a subject with advanced solid tumors receives anti HLA-G antibody (TTX-080) in combination with cetuximab, an anti-EGFR antibody or inhibitor, or a derivative or equivalent thereof and FOLFIRI at0.6 mg / kg Q2W or Q3W. In some embodiments, a subject with advanced solid tumors receives anti HLA-G antibody (TTX-080) in combination with cetuximab, an anti-EGFR antibody or inhibitor, or a derivative or equivalent thereof and FOLFIRI at 2 mg / kg Q2W or Q3W. In some embodiments, a subject with advanced solid tumors receives anti HLA-G antibody (TTX-080) in combination with cetuximab, an anti-EGFR antibody or inhibitor, or a derivative or equivalent thereof and FOLFIRI at 6 mg / kg Q2W or Q3W. In some embodiments, a subject with advanced solid tumors receives anti HLA-G antibody (TTX-080) in combination with cetuximab, an anti-EGFR antibody or inhibitor, or a derivative or equivalent thereof and FOLFIRI at 10 mg / kg Q2W or Q3W. In some embodiments, a subject with advanced solid tumors receives anti HLA-G antibody (TTX-080) in combination with cetuximab, an anti-EGFR antibody or inhibitor, or a derivative or equivalent thereof and FOLFIRI at 15 mg / kg Q2W or Q3W. In some embodiments, a subject with advanced solid tumors receives anti HLA-G antibody (TTX-080) in combination with cetuximab and FOLFIRI at 20 mg / kg Q2W or Q3W.

[0137] In some embodiments, a subject with advanced solid tumors receives anti HLA-G antibody (TTX-080) at a dosage between about 0.2 to about 100 mg / kg IV Q2W or Q3W as a monotherapy. In some embodiments, the solid tumor is acral melanoma (AM), or advanced or metastatic acral melanoma (AM) and the subject has received or progressed on a prior treatment (e.g., at least 1, 2, 3, 4. or 5 prior treatments). In some embodiments, the solid tumor is triple negative breast cancer (TNBC, estrogen and progesterone receptor negative and HER2 negative) or metastatic TNBC and the subject has received or progressed on a prior treatment (e.g., at least 1, 2, 3, 4, or 5 prior treatments). In some embodiments, the TNBC or metastatic TNBC tumor has received or progressed on a prior checkpoint inhibitor therapy. In some embodiments, the solid tumor is renal cell carcinoma and the subject has received or progressed on a prior treatment (e.g., at least 1, 2, 3, 4, or 5 prior treatments). In some embodiments, the solid tumor is colorectal cancer (CRC) or metastatic CRC and die subject has received or progressed on a prior treatment (e.g., at least 1, 2, 3, 4, or 5 prior treatments). In some embodiments, the solid tumor is head and neck squamous cell cancer and the subject has received or progressed on a prior treatment (e.g., at least 1, 2, 3, 4, or 5 prior treatments). 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.

[0138] In some embodiments, a subject with advanced solid tumors receives anti HLA-G antibody (TTX-080) at a dosage between about 0.2 to about 100 mg / kg IV Q2W or Q3W in combination with one or more additional therapeutic agents. In some embodiments, the solid tumor is head and neck squamous cell cancer and the subject has received or progressed on a prior treatment (e.g., at least 1. 2, 3, 4, or 5 prior treatments). In some embodiment, the subject is administered TTX- 080 with an anti-EGFR antibody or inhibitor (e.g., cetuximab). In some embodiment, the subject is administered TTX-080 with an anti-PD-1 antibody or inhibitor (e.g., pembrolizumab). In some embodiments, the solid tumor has received or progressed on at least 2 or at least 3 prior treatments.

[0139] In some embodiments, the solid tumor is colorectal cancer (CRC) or metastatic CRC and the subject has received or progressed on a prior treatment (e.g., at least 1, 2, 3, 4, or 5 prior treatments). In some embodiments, the solid tumor is metastatic CRC and is microsatellite instability low or microsatellite stable, and has wild type KRAS. In some embodiments, the subject has received at least one prior anti-EGFR therapy. In some embodiments, the subject has not received a prior anti- EGFR therapy. In some embodiments, the subject is administered TTX-080 with an anti-EGFR antibody or inhibitor (e.g., cetuximab). In some embodiments, the subject is administered TTX-080 with an anti-EGFR antibody or inhibitor (e.g.. cetuximab) and FOLFIRI (folic acid or leucovorin fluorouracil, and irinotecan).

[0140] In some embodiments, the solid tumor is metastatic CRC with wild type RAS, wild type BRAF, HER2 -negative, and is microsatellite stable. In some embodiments, the subject has not received a prior anti-EGFR treatment, a 5-FU and oxaliplatin-based chemotherapy with or without bevacizumab in the front-line setting, and / or FOLFOX in the adjuvant setting.

[0141] In some embodiments, the solid tumor is a non-small cell lung cancer and the subject has received or progressed on a prior treatment (e.g., at least 1, 2, 3, 4, or 5 prior treatments). In some embodiments, the subject has received at least one prior anti-PD-1 or checkpoint inhibitor therapy. In some embodiments, the subject has not received a prior anti-PD-1 therapy. In some embodiments, the subject is administered TTX-080 with an anti-PD-1 antibody or inhibitor (e.g., pembrolizumab).

[0142] 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 administered multiple dosages of a 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.

[0143] In some embodiments, treatment or prevention can be initiated with one or more loading doses of the antibody or composition provided herein followed by one or more maintenance doses. In some embodiments, a dose of the antibody 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.

[0144] In some embodiments, after the first cycle, the anti human HLA-G antibody is administered at one or more subsequent doses during one or more corresponding subsequent cycles.

[0145] 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 firstcycle and / or each of the subsequent cycle. In some embodiments, the administration of the anti human HLA-G antibody maintains a serum drug concentration from 50 gg / mL to 800 gg / niL or from about 50 gg / mL to about 800 gg / mL during the first cycle and the one or more subsequent cycles. In some embodiments, the administration of the anti human HLA-G antibody maintains a serum drug concentration from 50 gg / mL to 800 ng / niL or from about 50 iig / mL to about 800 gg / mL during the first cycle and / or each of the subsequent cycle.

[0146] In some embodiments, the serum drug concentration target trough during the first cycle and / or each of the subsequent cycle is maintained at from 50 qg / mL to 100 gg / mL, from 50 g / L to 200 gg / mL, from 50 gg / mL to 300 gg / mL. from 50 gg / mL to 400 gg / mL. from 50 gg / mL to 500 gg / mL. from 50 gg / mL to 600 iig / mL. from 50 gg / mL to 700 gg / mL. from 50 gg / mL to 800 gg / mL, from 100 gg / mL to 200 gg / mL, from 100 gg / mL to 300 gg / mL, from 100 gg / mL to 400 gg / mL, from 100 gg / mL to 500 gg / mL, from 100 gg / mL to 600 gg / mL, from 100 gg / mL to 700 gg / mL, from 100 gg / mL to 800 gg / mL. from 200 gg / mL to 300 gg / mL, from 200 gg / mL to 400 gg / mL, from 200 gg / mL to 500 gg / mL, from 200 gg / mL to 600 gg / mL, from 200 gg / mL to 700 gg / mL, from 200 gg / mL to 800 gg / mL, from 300 gg / mL to 400 gg / mL, from 300 gg / mL to 500 gg / mL, from 300 gg / mL to 600 gg / mL, from 300 gg / mL to 700 gg / mL, from 300 gg / mL to 800 gg / mL, from 400 gg / mL to 500 gg / mL, from 400 gg / mL to 600 gg / mL, from 400 gg / mL to 700 gg / mL, from 400 gg / mL to 800 gg / mL, from 500 gg / mL to 600 gg / mL, from 500 gg / mL to 700 gg / mL, from 500 gg / mL to 800 gg / mL, from 600 gg / mL to 700 gg / mL, from 600 gg / mL to 800 gg / mL, from 700 gg / mL to 800 gg / mL, or any other subrange of from 50 gg / mL to 800 gg / mL. Any range may include or exclude the starting and ending concentrations in the range.

[0147] In some embodiments, the serum drug concentration target trough during die first cycle and / or each of the subsequent cycle is maintained at from about 50 gg / mL to about 100 gg / mL, from about 50 gg / mL to about 200 gg / mL, from about 50 gg / mL to about 300 gg / mL, from about 50 gg / mL to about 400 gg / mL, from about 50 gg / mL to about 500 gg / mL, from about 50 gg / mL to about 600 gg / mL, from about 50 gg / mL to about 700 gg / mL, from about 50 gg / mL to about 800 gg / mL, from about 100 gg / mL to about 200 gg / mL. from about 100 gg / mL to about 300 gg / mL. from about 100 gg / mL to about 400 gg / mL, from about 100 gg / mL to about 500 gg / mL, from about 100 gg / mL to about 600 gg / mL. from about 100 gg / mL to about 700 gg / mL. from about 100 gg / mL to about 800 gg / mL, from about 200 gg / mL to about 300 gg / mL, from about 200 gg / mL to about 400 gg / mL. from about 200 gg / mL to about 500 gg / mL, from about 200 gg / mL to about 600 gg / mL, from about 200 gg / mL to about 700 gg / mL, from about 200 gg / mL to about 800 gg / mL, from about 300 gg / mL to about 400 gg / mL, from about 300 gg / mL to about 500 gg / mL, from about 300 gg / mL to about 600 gg / mL, from about 300 gg / mL to about 700 gg / mL, from about 300 gg / mL to about 800 gg / mL, from about 400 gg / mL to about 500 gg / mL. from about 400 gg / mL to about 600 gg / mL, from about 400 gg / mL to about 700 gg / mL. from about 400 gg / mL to about 800 gg / mL, from about 500 gg / mL to about 600 gg / mL, from about 500 gg / mL to about 700 gg / mL, from about 500 gg / mL to about 800qg / mL, from about 600 qg / mL to about 700 qg / mL, from about 600 qg / mL to about 800 qg / mL, from about 700 qg / mL to about 800 qg / mL, or any other subrange of from about 50 qg / mL to about 800 qg / mL. Any range may include or exclude the starting and ending concentrations in the range.

[0148] In some embodiments, the serum drug concentration target trough during the first cycle and / or each of the subsequent cycle is maintained at 50 qg / mL 55 qg / mL. 60 qg / L. 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 / L. or any other number above 50 qg / mL; or about 50 qg / mL, about 55 qg / mL. about 60 qg / mL. about 65 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. or about any number above 50 qg / mL.

[0149] 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 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 scrum 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.

[0150] 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.

[0151] 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.

[0152] In some embodiments, the dosing regimen comprises administering the anti-HLA-G antibody as described herein between about 0.2-200 mg / kg to the subject at a 2-4 weeks interval. The dosing regimen maintains a serum drug concentration about the target trough between 10 qg / mL to 1000 qg / mL. In some embodiments, the dosing regimen comprises administering about 20 mg / kg Q3W to the subject. In some embodiments, the administration maintains the drug serum concentration at about or above 50 qg / mL. In some embodiments, the dosing regimen comprises dosing at 2 to 4 week intervals. In some embodiments, the dosing regimen comprises between about 0.2-20 mg / kg at a 2 week, 3 week, or 4 week interval.7.3.1. Subject and Administration

[0153] The anti human HLA-G antibody 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, or intratumoral routes. The antibody may also be suitably administered by peritumoral, intralesional, or perilesional routes, to exert local as well as systemic therapeutic effects. The intraperitoneal route may be particularly useful, for example, in the treatment of ovarian tumors.

[0154] In some embodiments, the subject is a human subject.

[0155] The dose can be administered according to a suitable schedule, for example, once, two times, three times, or for times weekly. It may be necessary to use dosages of the antibody 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.

[0156] In some embodiments, the method or dosing regimen described herein comprises administering the pharmaceutical composition comprising anti-HLA-G antibody via intravenous injection, subcutaneous injection, intramuscular injection, topical, inhalation, rectal administration, vaginal administration, transdermal administration, sublingual, and / or buccal. In some embodiments, the method or dosing regimen described herein comprises administering the pharmaceutical composition comprising anti-HLA-G antibody via intravenous injection.7.4. Method for Treatment of Diseases

[0157] In the treatment methods provided herein, the anti human HLA-G antibody may be administered to the subject for the treatment of any disease or condition involving HLA-G. such as cancer, autoimmune disease, and infection.

[0158] In some embodiments, the cancer is a solid cancer. In some embodiments, an advanced refractory / resistant solid malignancy. In some embodiments, the cancer is metastatic.

[0159] Any suitable cancer may be treated with the anti human HLA-G antibody. Illustrative suitable cancers include, for example, a 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), acral melanoma (AM), bladder cancer, choriocarcinoma, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), adrenocortical carcinoma, anal cancer, appendix cancer, astrocytoma, basal cell carcinoma, brain tumor, bile duct 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, craniopharyngioma, cutaneous T-cell lymphoma,ductal carcinoma, embry onal tumor, endometrial cancer, ependymoma, esophageal cancer, estliesioneuroblastoma, 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, lung cancer, 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, 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 cell cancer, renal pelvis and ureter cancer, retinoblastoma, rhabdoid tumor, salivary gland cancer, Sezary syndrome, skin cancer, small cell lung 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. In some embodiments, the cancer is selected from breast, lung, gastric, esophageal, neuroblastoma, cervical, and hematological cancers.

[0160] In some embodiments, the cancer is selected from at least one of a 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), acral melanoma (AM), bladder cancer, and / or choriocarcinoma.

[0161] In some embodiments, the cancer is head and neck squamous cell carcinoma (HNSCC). In some embodiments, the cancer has progressed on one or more prior checkpoint inhibitor treatment (e.g., anti-PD-1, anti-PD-Ll, anti-CTLA-4). In some embodiments, the cancer has no prior treatment of one or more checkpoint inhibitor (e.g., anti-PD-1. anti-PD-Ll. anti-CTLA-4).

[0162] In some embodiments, the cancer is colorectal cancer (CRC) or metastatic CRC (mCRC).

[0163] In some embodiments, the cancer has progressed on or received one or more lines of prior cancer therapy. In some embodiments, the cancer has received prior treatment of at least one of an anti-EGFR antibody, an anti-PD-1 antibody, a 5-FU and oxaliplatin-based chemotherapy with or without bevacizumab, and / or FOLFOX. In some embodiments, the cancer has not received prior treatment of an anti-EGFR antibody.

[0164] In some embodiments, the disease is an autoimmune disease. Any suitable autoimmune disease may be treated with the anti human HLA-G antibody. Illustrative suitable autoimmune diseases, or diseases with an autoimmune component, include, for example, acute disseminated encephalomyelitis (ADEM), acute necrotizing hemorrhagic leukoencephalitis, Addison's disease, agammaglobulinemia, alopecia areata, amyloidosis, ankylosing spondylitis. anti-GBM / anti-TBM nephritis, antiphospholipid syndrome (APS), autoimmune angioedema, autoimmune aplastic anemia, autoimmune dysautonomia, autoimmune hepatitis, autoimmune hyperlipidemia, autoimmune immunodeficiency, autoimmune inner ear disease (AIED). autoimmune myocarditis, autoimmune oophoritis, autoimmune pancreatitis, autoimmune retinopathy, autoimmune thrombocytopenic purpura (ATP), autoimmune thyroid disease, autoimmune urticarial, axonal & neuronal neuropathies, Balo disease, Behcet’s disease, bullous pemphigoid, cardiomyopathy, Castleman disease, Celiac disease, Chagas disease, chronic fatigue syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic recurrent multifocal osteomyelitis (CRMO), Churg-Strauss syndrome, cicatricial pemphigoid / benign mucosal pemphigoid, Crohn’s disease. Cogans syndrome, cold agglutinin disease, colitis, congenital heart block, coxsackie myocarditis, CREST disease, essential mixed cryoglobulinemia, demyelinating neuropathies, dermatitis herpetiformis, dermatomyositis, Devic’s disease (neuromyelitis optica), discoid lupus, Dressier’s syndrome, endometriosis, eosinophilic esophagitis, eosinophilic fasciitis, erythema nodosum, experimental allergic encephalomyelitis, Evans syndrome, fibromyalgia, fibrosing alveolitis, giant cell arteritis (temporal arteritis), giant cell myocarditis, glomerulonephritis, Goodpasture's syndrome, granulomatosis with polyangiitis (GPA) (formerly called Wegener's Granulomatosis), Graves' disease, Guillain-Barre syndrome, Hashimoto’s encephalitis, Hashimoto’s thyroiditis, hemolytic anemia, Henoch-Schonlein purpura, herpes gestationis, hypogammaglobulinemia, idiopathic thrombocytopenic purpura (ITP), IgA nephropathy, IgG4-related sclerosing disease, immunoregulatory lipoproteins, inclusion body myositis, inflammatory bowel disease, interstitial cystitis juvenile arthritis uvenile diabetes (Type 1 diabetes), juvenile myositis. Kawasaki syndrome, Lambert-Eaton syndrome, leukocytoclastic vasculitis, lichen planus, lichen sclerosus, ligneous conjunctivitis, linear IgA disease (LAD), lupus (SLE), Lyme disease (chronic), Meniere’s disease, microscopic polyangiitis, mixed connective tissue disease (MCTD), Mooren’s ulcer, Mucha- Habermann disease, multiple sclerosis, myasthenia gravis, myositis, narcolepsy, neuromyelitis optica (Devic’s), neutropenia, ocular cicatricial pemphigoid, optic neuritis, palindromic rheumatism, PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcus), paraneoplastic cerebellar degeneration, paroxysmal nocturnal hemoglobinuria (PNH). Parry Romberg syndrome, Parsonnage-Turner syndrome, pars planitis (peripheral uveitis), pemphigus, peripheral neuropathy, perivenous encephalomyelitis, pernicious anemia, POEMS syndrome, polyarteritis nodosa, type I. II. & III autoimmune polyglandular syndromes, polymyalgia rheumatic, polymyositis, postmyocardial infarction syndrome, postpericardiotomy syndrome, progesterone dermatitis, primary’biliary cirrhosis, rim ary sclerosing cholangitis, psoriasis, psoriatic arthritis, idiopathic pulmonary fibrosis, pyoderma gangrenosum, pure red cell aplasia, Raynauds phenomenon, reactive arthritis, reflex sympathetic dystrophy, Reiter’s syndrome, relapsing polychondritis, restless legs syndrome, retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, sarcoidosis, Schmidt syndrome, scleritis, scleroderma, Sjogren's syndrome, sperm & testicular autoimmunity, stiff person syndrome, subacute bacterial endocarditis (SBE), Susac’s syndrome, sympathetic ophthalmia, Takayasu’s arteritis, temporal arteritis / giant cell arteritis, thrombotic disease, thrombocytopenic purpura (TTP), Tolosa-Hunt syndrome, transverse myelitis, type 1 diabetes, ulcerative colitis, undifferentiated connective tissue disease (UCTD), uveitis, vasculitis, vesiculobullous dermatosis, vitiligo, and Wegener’s granulomatosis (now termed Granulomatosis with Polyangiitis (GPA).101651 In some embodiments, the disease is an infection. Any suitable infection may be treated with the anti human HLA-G antibody. Illustrative suitable infections include, for example, hepatitis A virus, hepatitis B virus, hepatitis C virus (HCV), human immunodeficiency virus (HIV), and other viral infections.

[0166] In one aspect, provided herein is a method for treating a subject suffering from a cancer, comprising: (a) administering to the subject a dosing regimen comprising administration of a pharmaceutical composition comprising an effective amount of an anti human HLA-G antibody comprising or consisting of a heavy chain variable region (VH) and a light chain variable region (VL); the VH comprising: (i) a VHCDR1 having the sequence set forth in any one of SEQ ID NOS: 1-14 or SEQ ID NOS: 18-34; (ii) a VHCDR2 having the sequence set forth in any one of SEQ ID NOS: 38-50 or SEQ ID NOS: 54-71; and (iii) a VHCDR3 having the sequence set forth in any one of SEQ ID NOS: 76-101; and the VL comprising: (iv) a VLCDR1 having the sequence set forth in any one of SEQ ID NOS: 105-124; (ii) a VLCDR2 having the sequence set forth in any one of SEQ ID NOS: 128-145; and (iii) a VLCDR3 having the sequence set forth in any one of SEQ ID NOS: 149- 166, wherein administration of the anti human HLA-G antibody maintains a serum drug concentration at a target trough level of between about 10 pg / m-l 00 pg / mL during a first cycle after administration of a first dose; and optionally administering one or more subsequent doses of the anti human HLA-G antibody in one or more subsequent cycles. In some embodiments, the administration maintains the serum drug concentration at a target trough level of above 50 pg / mL during the first cycle and / or during the subsequent cycles.

[0167] In one aspect, provided herein is a method for treating a subject suffering from cancer, which comprises administering an anti human HLA-G antibody consisting of a heavy chain variable region (VH) and a light chain variable region (VL). The VH may comprise: (i) a VHCDR1 having the sequence set forth in SEQ ID NOS: 1-14 or SEQ ID NOS: 18-34; (ii) a VHCDR2 having the sequence set forth in SEQ ID NOS: 38-50 or SEQ ID NOS: 54-71; and (iii) a VHCDR3 having the sequence set forth in SEQ ID NOS: 76-101. The VL may comprise: (vi) a VLCDR1 having the sequence set forthin SEQ ID NOS: 105-124; (v) a VLCDR2 having the sequence set forth in SEQ IDNOS: 128-145; and (vi) a VLCDR3 having the sequence set forth in SEQ ID NOS: 149-166. Administration maintains serum drug concentrations above a target trough of about 50 pg / mL during a first cycle. Optionally, the anti human HLA-G antibody is administered at a subsequent dose. In some embodiments, the administration maintains serum drug concentrations above the target trough level of about 50 pg / mL during the first cycle and subsequent cycles. In some embodiments, the administration achieves at least ECeo, EC70, ECso. or EC90 for receptor occupancy (RO).

[0168] In some embodiments, the dosing regimens for use in the methods is as described in Section 7.3 herein. The methods and dosing regimens maintains serum drug concentrations of TTX- 080 at a target trough level sufficient to achieve at least ECeo for receptor occupancy, partial response, complete response, inhibitor or delay progression, increased or improved overall response rate (ORR), increased or improved duration of response (DoR). increased or improved progression-free survival (PFS). and / or increased or improved overall survival (OS) characterized by RECIST 1.1.

[0019] In some embodiments, the dosing regimen comprises about 20 mg / kg every three weeks (Q3W). In some embodiments, the dosing regimen comprises dosing at 2 to 4 week intervals.

[0170] In some embodiments, the cancer is a solid cancer. In some embodiments, the cancer is an advanced refractor / resistant solid malignancies. In some embodiments, the solid cancer is Head and Neck squamous cell carcinoma, non-small cell lung cancer (NSCLC) colorectal cancer (CRC), triple negative breast cancer (TNBC), renal cell carcinoma (RCC), acral melanoma (AM), bladder cancer, and / or choriocarcinoma.

[0171] In some embodiments, the VH of the anti-HLA G antibody comprises the sequence set forth in any one of SEQ ID NOS: 170-200, and the VL comprises the sequence set forth in any one of SEQ ID NOS: 204-228. In some embodiments, the anti-HLA G antibody comprises a heavy chain (HC) having any of SEQ ID NOS: 232-262 or SEQ ID NOS: 266-296, and a light chain having (LC) having any one of SEQ ID NOS: 300-330.

[0172] In some embodiments, the subject is further administered an effective amount of an additional anti-cancer therapeutics. In some embodiments, the subject is further administered an effective amount of: a) an anti-ILT2 antibody; b) an anti-ILT3 antibody; c) an anti-ILT4 antibody; d) an anti-KIR2DL4 antibody; e) an anti-HLA-E antibody; 1) an anti-NKG2A antibody; g) an anti-HLA- F antibody; h) an anti-PD-Ll antibody; i) an anti-PD-1 antibody; j) an anti-CD38 antibody; k) an anti- CD39 antibody; 1) an anti-CD73 antibody; m) an anti-A2A receptor antibody; n) an anti-A2B receptor antibody; o) an anti-A2A / A2B dual receptor antibody and / or combination; p) an anti-CD47 antibody; q) an anti-CLTA-4 antibody; r) an anti-LAG3 antibody; s) an anti-TIM3 antibody; t) an anti-TIGIT antibody; u) an anti- VISTA antibody; v) an anti-CD94 antibody; w) an anti-EGFR antibody; x) an anti-SIRPa antibody SIPRaFc; y) a bispecific antibody targeting a combination of any antibody from a) through x); z) a small molecule inhibitor; aa) a bi-specific T cell engager, CAR-T therapy, CAR-NK therapy, CAR-macrophage therapy, engineered cell therapy, and / or adoptive T cell therapy; ab) an oncolytic virus; ac) chemotherapy; and / or ad) an ADCC capable therapy using effector competent antibodies such as anti-CCR8, anti-TIGIT, anti-CD19, anti-CD20, anti-EGFR, anti-Her2, anti- SLAMMF7. anti-CD52, anti-BCMA, anti-GD2, and / or anti-CCR4.

[0173] In some embodiments, the anti-EGFR antibody comprises cetuximab. In some embodiments, the subject is further administered an effective amount of an antibody-drug-conjugate (ADC). In some embodiments, the ADC comprises an anti-EGFR antibody. In some embodiments, the ADC comprises a bifunctional EGFR antibody- TGF[3 immune modulating payload conjugate.

[0174] In some embodiments, the anti-PD-1 antibody is pembrolizumab.

[0175] In some embodiments, the method further comprises: (a) administering chemotherapy, (b) administering radiation therapy, (c) administering one or more additional therapeutics agents, and / or (d) administering one or more additional anti-cancer therapeutics. In some embodiments, the one or more additional therapeutic agents comprise one or more immuno sti ulatory agents. In some embodiments, the one or more immunostimulatory agents comprise at least one of an antagonist to an inhibitory’ receptor of an immune cell, an agonist of a co-stimulatory receptor of an immune cell, a costimulatory receptor, an ADCC competent antibody, a cytokine, an oncolytic virus, a chimeric antigen engineered T cell, and / or a bispecific or multi-specific T cell directed antibody.

[0176] In some embodiments, the subject is further administered an effective amount of an antibody -drug -conjugate (ADC). In some embodiments, the ADC comprises an anti-EGFR antibody. In some embodiments, the ADC comprises a bifunctional EGFR antibody coupled to a TGF|3 immune modulating payload. In some embodiments, the ADC comprises a bispecific antibody targeting EGFR and Leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5). In some embodiments, the EGFR and LGR5 bispecific antibody is as described in Argiles et al. 2021 (merus.nl / wp-content / uploads / 2021 / 01 / MCLA-158_ASCO_GI_final.pdf), which is herein incorporated by reference in its entirety. For example, BCA101 is a first-in-class bifunctional EGFR antibody coupled to a TGF[3 immune modulating payload. BCA101 is well tolerated and has clinical activity as monotherapy and in combination with pembrolizumab in advanced solid tumor.

[0177] In some embodiments, the one or more immunostimulatory agents comprise a chimeric antigen engineered T cell. A chimeric antigen (receptor) (CAR) engineered T cell, often referred to as CAR T cell therapy, is an immunotherapy approach that involves genetically modifying a patient's own T cells to enhance their ability7to recognize and attack cancer cells. A CAR is a synthetic receptor drat combines an antigen-binding domain derived from an antibody with T cell signaling components.

[0178] In some embodiments, the one or more immunostimulatory agents comprise a bi- or multi-specific T cell directed antibody. Bi- or multi-specific T cell-directed antibodies are antibodies that simultaneously engage T cells and cancer cells, bringing T cells in close proximity’ to cancercells, facilitating the immune system's ability to recognize and destroy cancer cells with high specificity . By bringing T cells into direct contact with cancer cells, these antibodies help activate T cells and trigger their cytotoxic response against the cancer cells. Bi-specific antibodies can be designed as T cell engagers (TCEs) or bispecific T cell engagers (BiTEs). BiTEs are a type of bispecific antibody that binds to both a tumor-specific antigen and a T cell receptor.

[0179] In some embodiments, the inhibitory receptor is at least one of ILT2, ILT3, ILT4, KIR2DL4, CTLA-4. PD-1, CD39, CD73, PD-L1, PD-L2, LAG-3, Tim3, TIGIT. B7-H3. B7-H4, neuritin, BTLA. CECAM-1 , CECAM-5, VISTA, LAIR1 , CD 160, 2B4,TGF-B NKG2A, CD47. SIPRa, and / or a Killer-cell immunoglobulin-like receptor (KIR).

[0180] In some embodiments, the co-stimulatory receptor is at least one of 0X40, CD2, CD27. ICAM-1. LFA-1, ICOS (CD278), 4-1BB (CD 137). GITR, CD28, CD30. CD40, BAFFR, HVEM. CD7, LIGHT, NKG2C. SLAMF7, NKp30, NKp46, NKp80, CD 160, and / or a CD83 ligand.

[0181] In some embodiments, the one or more immunostimulatory agents comprise or consist of an ADCC competent antibody comprising or consisting of an anti- CD 19, anti-CD20, anti-EGFR, anti-Her2, anti-SLAMF7, anti-CD52, anti-BCMA. anti-GD2. anti-CD38, anti-CCR8, anti-TIGIT, and / or or anti-CCR4 antibody.

[0182] In some embodiments, the cytokine is at least one of IL-1, IL-2, IL-4, IL-5, IL-7, IL-10, IL-11, IL-12, IL-13, IL-15, IL-18. IL-21, and / or IL-27.

[0183] In some embodiments, the oncolytic virus is a Herpes simplex virus, a Vesicular stomatitis virus, an adenovirus, a Newcastle disease virus, a vaccinia virus, or a maraba virus.

[0184] In some embodiments, the dosing regimen for use in the method comprises administering the anti human HLA-G antibody at about 0.2-20 mg / kg to the subject. In some embodiments, the method comprises administering the anti human HLA-G antibody at 0.2 mg / kg, 0.6 mg / kg, 2 mg / kg, 6 mg / kg. 10 mg / kg, 15 mg / kg, or 20 mg / kg in the first cycle. In some embodiments, the method further comprises administering the anti human HLA-G antibody at 0.2 mg / kg, 0.6 mg / kg. 2 mg / kg, 6 mg / kg. 1 mg / kg, 15 mg / kg, or 20 mg / kg in the subsequent cycles.

[0185] In some embodiments, the dosing regimen for use in the method comprises administering the anti human HLA-G antibody at 0.2 mg / kg Q3W, 0.6 mg / kg Q3W, 2 mg / kg Q3W, 6 mg / kg Q3W, 10 mg / kg Q3W, 15 mg / kg Q3W, or 20 mg / kg Q3W in the first cycle and each of the subsequent cycles. In some embodiments, the dosing regimen for use in the method comprises administering tire anti human HLA-G antibody at 20 mg / kg Q3W in the first cycle. In some embodiments, the dosing regimen for use in the method comprises administering the anti human HLA-G antibody at 20 mg / kg Q3W to the subject in the first cycle and each of subsequent cycles.

[0186] In some embodiments, the dosing regimen for use in the method comprises administering the anti human HLA-G antibody at 0.2 mg / kg Q2W. 0.6 mg / kg Q2W, 2 mg / kg Q2W, 6 mg / kg Q2W. 10 mg / kg Q2W, 15 mg / kg Q2W, or 20 mg / kg Q2W in the first cycle and each of the subsequentcycles. In some embodiments, the dosing regimen for use in the method comprises administering tire anti human HLA-G antibody at 15 mg / kg Q2W in the first cycle. In some embodiments, the dosing regimen for use in the method comprises administering the anti human HLA-G antibody at 15 mg / kg Q2W to the subject in the first cycle and each of subsequent cycles.

[0187] In some embodiments, the HC of the anti HLA-G antibody for use in the method comprises a sequence set forth in SEQ ID NO: 254 and the LC comprises a sequence set forth in SEQ ID NO: 322, or the HC comprises a sequence set forth in SEQ ID NO: 288 and the VL comprises a sequence set forth in SEQ ID NO: 322.

[0188] In some embodiments, the chemotherapy comprises administering one or more agents selected from the group consisting of 5 -fluorouracil (5-FU). folic acid or leucovorin, oxaliplatin, irinotecan, cyclophosphamide, cisplatin, carboplatin. methotrexate, gemcitabine, vincristine, vinblastine, paclitaxel, docetaxel, etoposide, doxorubicin, and bleomycin. In some embodiments, the chemotherapy comprises administering FOLFIRI (folic acid or leucovorin, oxaliplatin, fluorouracil (5-FU), and irinotecan).

[0189] In some embodiments, the anti-EGFR antibody comprises cetuximab, such as Erbitux®. Cetuximab is a recombinant, human / mouse chimeric monoclonal antibody that binds specifically to die 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.

[0190] 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 that expresses EGFR.

[0191] 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.

[0192] In some embodiments, the anti-PD-1 antibody is pembrolizumab. Pembrolizumab is a humanized antibody used in cancer immunotherapy that treats cancers, such as melanoma, lung cancer, head and neck cancer, Hodgkin lymphoma, stomach cancer, cervical cancer, and certain types of breast cancer. It can be administered by slow intravenous injection. It stimulates the subject body's immune system to fight cancer cells. Specifically, pembrolizumab targets and blocks PD-1 protein on die surface of T cells.7.5. Pharmaceutical Composition

[0193] In one aspect, disclosed herein are pharmaceutical compositions comprising a pharmaceutically effective amount of an anti human HLA-G antibody comprising or consisting of a heavy chain variable region (VH) and a light chain variable region (VL); the VH comprising: (i) a VHCDR1 having the sequence set forth in any one of SEQ ID NOS: 1-14 or SEQ ID NOS: 18-34; (ii) a VHCDR2 having the sequence set forth in any one of SEQ ID NOS: 38-50 or SEQ ID NOS: 54-71; and (iii) a VHCDR3 having the sequence set forth in any one of SEQ ID NOS: 76-101; and the VL comprising: (iv) a VLCDR1 having the sequence set forth in any one of SEQ ID NOS: 105-124; (v) a VLCDR2 having the sequence set forth in any one of SEQ ID NOS: 128-145; and; and (vi) a VLCDR3 having the sequence set forth in any one of SEQ ID NOS: 149-166, and a pharmaceutically acceptable excipient.

[0194] In some embodiments, the pharmacal composition comprises one or more effective doses of the anti HLA-G antibody. In some embodiments, the pharmaceutical composition comprises a dosage of the anti HLA-G antibody at between about 0.2 mg / kg to about 20 mg / kg.

[0195] In some embodiments, the pharmaceutical composition further comprises one or more effective doses of one or more therapeutic agents. In some embodiments, the pharmaceutical composition further comprises one or more doses of a chemotherapy agent, a radiation therapy agent, an anti-cancer therapeutic agent. In some embodiments, the pharmaceutical composition further comprises one or more doses of an anti-EGFR antibody or an anti drug conjugate comprising the anti- EGFR antibody. In some embodiments, the anti-EGFR antibody is cetuximab.

[0196] In some embodiments, the pharmaceutical composition further comprises one or more doses of an anti PD-1 antibody or a PD-1 blocker. In some embodiments, the anti PD-1 antibody is pembrolizumab.

[0197] Any antibody, agent, and / or drug used in the methods of treatment provided 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, intraarterial, intradermal, intramuscular, intraperitoneal, intravenous, nasal, parenteral, pulmonary, and subcutaneous routes.

[0198] 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 pharmacal 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.

[0199] The pharmaceutical composition may comprise an anti-foaming agent. Any suitable antifoaming agent may be used. For example, the anti-foaming agent may be selected from the groupconsisting of an alcohol, an ether, an oil, a wax, a silicone, a surfactant, and combinations thereof. In some aspects, 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.

[0200] The pharmaceutical composition may comprise a cosolvent. Illustrative examples of cosolvents include ethanol, poly(ethylene) glycol, but lene glycol, dimethylacetamide, glycerin, and propylene glycol.

[0201] 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.

[0202] 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.

[0203] The pharmaceutical composition may comprise a surfactant. Illustrative examples of surfactants include d-alpha tocopherol, benzalkonium chloride, benzethonium chloride, cetrimide, cetylpyridinium chloride, docusate sodium, glyceryl behenate, glyceryl monooleate, lauric acid, macrogol 15 hydroxy stearate, 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.

[0204] 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.

[0205] 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.

[0206] 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.

[0207] 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.

[0208] The pharmaceutical composition may be a single unit dosage form comprising a prophylactically or therapeutically effective amount of the antibody.

[0209] 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.

[0210] 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.

[0211] 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.7.6. Parenteral Dosage Forms

[0212] 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.

[0213] 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 nonaqueous vehicles such as. but not limited to, com oil. cottonseed oil, peanut oil, sesame oil. ethyl oleate, isopropyl myristate, and benzyl benzoate.

[0214] Excipients that increase the solubility of one or more of the antibodies used herein can also be incorporated into the parenteral dosage forms.7.7. Kits

[0215] In one aspect, provided herein are a kit comprising a pharmaceutical composition comprising the anti HLA-G antibody as described herein, and instructions for administering the pharmaceutical composition according to any of the methods or dosing regimens described herein.8. EXAMPLES8.1. Example 1: Relationship of anti-human HLA-G antibody (TTX-080) Binding to HLA-G+Target Cells and Functional Activity in a Primary T Cell Assay

[0216] Antibodies are prepared as described in W02020069133A1, which is incorporated herein in its entirety by reference. To determine the binding relationship of anti-human HLA-G antibody (TTX-080) to HLA-G expressed on target cells used in functional assays, 721.221 cells engineered to express HLA-G were plated in 96-well plates and incubated with a titration of anti-human HLA-G antibody (TTX-080) for 1 hr at 4°C. Following anti-human HLA-G antibody (TTX-080) incubation, cells were spun down, washed 3 times, and then incubated with APC-conjugated goat anti-human IgG secondary antibody (Jackson ImmunoResearch) and Fixable viability Dye eFluor780 (Invitrogen) for 30 minutes at 4°C. Cells were then washed, resuspended in wash buffer and analyzed on the BD Fortessa flow cytometer.

[0217] Sample data was exported as FCS files and analyzed using FlowJo software vlO. The geometric mean fluorescence intensity (GMFI) was calculated for APC and exported in Excel format. Following GMFI calculation, a 4-parametric nonlinear regression curve fit (log(agonist) vs response) was used to calculate the EC50 value after having transformed the antibody concentration to loglO values. This analysis was performed using Prism 7.02 (GraphPad).

[0218] FIG. 1A shows anti-human HLA-G antibody (TTX-080) bound to HLA-G+721.221 cells in a dose-dependent manner with an EC50 of 1.316 nM. A table of EC values at increments of 5 from EC5 to EC95 is provided.

[0219] To evaluate the ability of anti-human HLA-G antibody (TTX-080) to block HLA-G- mediated suppression of CD8+T-cell function, human CD8+T cells were stimulated overnight with ImmunoCult Human CD3 / CD28 T Cell activator (StemCell Technologies) and co-cultured with HLA-G+721.221 target cells pre-treated with anti-human HLA-G antibody (TTX-080); CD8 T-cell degranulation and intracellular cytokines were measured. Briefly, CD8+T cells were isolated from human PBMC using an Easy Sep Human CD81T Cell Isolation Kit (StemCell Technologies) and incubated with ImmunoCult for 1 hour. Following the incubation, T cells were mixed with 721.221 cells pretreated with a titration of anti-human HLA-G antibody (TTX-080) and co-cultured overnight at 37°C. In the morning. Monensin Solution (ThermoFisher) and eFluor 450-CD107a (ThermoFisher)were added; the final amount of each reagent was 0.5 pg / mL antibody and 2 pM Monensin. The assay was incubated for 4 hours.

[0220] After the incubation, cells were washed and stained with Fixable viability Dye eFluor780 and antibodies against cell surface markers - Alexa Fluor 700-CD8 (Biolegend) and PE-CD85j / ILT2 (Biolegend). Intracellular staining was then performed by incubating with fixation / penneabilization reagent followed by an incubation with Brilliant Violet 711 -IFN-y (Biolegend) and APC-TNF-a (Biolegend) for 20 minutes at 4°C. Cells were washed and acquired on a BD Fortessa flow cytometer using the high throughput sampler.

[0221] Exported sample FCS files were analyzed using FlowJo software. CD8+T cell populations were defined based on CD8+ILT2+or CD8+ILT2_. The CD107a, IFN-y or TNF-a populations were gated on each CD8+T cell population and determined using fluorescence minus one cells and unstimulated cells. The percent CD 107a, IFN-y or TNF-a was exported as a table in Microsoft Excel format. Microsoft Excel or GraphPad Prism 8 was used to calculate averages. The standard deviations for each group were calculated in Microsoft Excel.

[0222] FIG. IB shows anti-human HLA-G antibody (TTX-080) reverses HLA-G-mediated suppression of ILT2 CD8 T cell effector function in a dose-dependent manner (one representative donor).

[0223] An integrated analysis of in vitro binding (FIG. 1A) and functional activity (FIG. IB) data was performed to determine the concentrations of anti-human HLA-G antibody (TTX-080) required to achieve effect levels as a percent of the maximum effect (calculated as EC values). EC values for anti-human HLA-G antibody (TTX-080) binding to HLA-G+target cells and functional activity (across multiple donors and T cell functional readouts that include CD 107a, TNF-a, IFN-a) were compared to identify the level of binding required to achieve maximal functional activity.

[0224] EC values were obtained using the following formula:where F is a fraction of the full response and ECso, and Hill Slope (H) were provided as output parameters from nonlinear regression analysis in GraphPad Prism.

[0225] FIG. 1C provides the EC values for anti-human HLA-G antibody (TTX-080) binding to HLA-G+target cells and functional activity (across multiple donors and T cell functional readouts CD107a, IFN-y, and TNF-a). The concentrations of anti-human HLA-G antibody (TTX-080) required for maximal functional activity (EC95) were lower than required for maximal binding. Extrapolation of the functional data at EC95 (mean and standard deviation [SD]) and associated anti-human HLA-G antibody (TTX-080) concentrations (highlighted in gray) shows that a range of target cell binding (EC60 to EC90) elicited maximal functional activity of immune cells.

[0226] Based on this relationship, anti-human HLA-G antibody (TTX-080) binding to HLA-G+cells at EC90 was determined to provide a suitable estimate for predicting binding requirements necessary to achieve maximal functional activity.8.2. Example 2: PK / PD Modeling of Human Tumor Xenograft Mouse Models

[0227] In mice implanted with HLA-G+human tumor cell lines JEG-3 (human choriocarcinoma) and HT-1376 (human bladder carcinoma), the PD relationship between intra-tumoral RO and mean serum concentration was evaluated.

[0228] For JEG-3 tumor xenografts, female Nude (Nu / Nu) mice were implanted subcutaneously with IxlO6JEG-3 cells. Eleven days after tumor implantation, tumor volume was measured, and the mice with JEG-3 tumors were randomized into 8 groups of 3 mice each based on similar tumor volume. Twelve days after tumor implantation, the mice were treated with a single IV dose of antihuman HLA-G antibody (TTX-080) antibody ranging from 0.55 pg to 400 pg.

[0229] For HT-1376 tumor xenografts, female NCG mice were implanted subcutaneously with 5xl06HT-1376 cells. Twenty-five days after tumor implantation, tumor volume was measured, and the mice were randomized into 9 groups of 3 mice each based on similar tumor volume. Twenty-eight days after tumor implantation, the mice were treated with a single IV dose of anti-human HLA-G antibody (TTX-080) ranging from 0.55 pg to 1200 pg.

[0230] Two hours after IV injection, blood was collected from the tail. One day after IV injection, mice were euthanized by CO2 inhalation w ith blood collected by cardiac puncture, and the tumors were collected. Blood collected at the 2-hour and 24-hour time points was analyzed for serum anti-human HLA-G antibody (TTX-080) concentrations using an anti-human / non-human primate IgG MSD kit (Meso Scale Discovery).

[0231] Disaggregated tumor samples w ere stained to identify viable tumor cells and assess receptor occupancy by flow cytometry. The amount of occupied receptor was measured using a secondary antibody to detect bound anti-human HLA-G antibody (TTX-080) to quantify die mean fluorescence intensity of each sample. Data was exported as FCS files and then analyzed using FlowJo. For each tumor sample, the percent RO was calculated relative to a fully saturated sample by dividing the MFI of the unsaturated sample by the MFI of the saturated sample and then multiplying by 100.

[0232] To examine the relationship between dose and serum concentration of anti-human HLA- G antibody (TTX-080). the mean concentrations (N = 3) were plotted vs. dose (FIG. 2A and FIG. 2B for JEG-3 and HT-1376, respectively). A power model, i.e.Cone = a X Dosebwhere a and b are constants, which allows direct assessment of linearity, w as fit to the data using linear regression of natural log-transformed data. The relationship between the mean ROs (N = 3) and the mean serum concentrations appeared to be consistent with a sigmoid Emax modelwhere E = RO, C = Concentration, Emax is the maximum response, EC}0is the concentration at half-maximal response, and is the slope factor. The pharmacodynamic (PD) model was fit to the data using Phoenix™ 64 WinNonlin® Version 8. The creation of in-text graphs was done using SigmaPlot Version 12.0.

[0233] In JEG-3 and HT-1376 tumors, anti-human HLA-G antibody (TTX-080) target coverage increased in a dose-dependent manner (FIG. 2C and FIG. 2D, respectively). The highest receptor occupancy (69.9%) was observed at the highest dose (400 pg) for JEG-3 tumors. In HT-1376 tumors, receptor occupancy (> 90%) plateaued at doses of 400 and 1200 pg.

[0234] In vivo RO determination was then analyzed to determine the serum levels of anti-human HLA-G antibody (TTX-080) required to drive TTX-080 target engagement in HLA-G+solid tumors. Between the two models, the RO data for HT-1376 demonstrated that higher serum levels of antihuman HLA-G antibody (TTX-080) were required for tumor target engagement and was therefore selected for further evaluation. FIG. 2E provides anti-human HLA-G antibody (TTX-080) serum concentrations across a range of EC values for both models in increments of 5 from EC5 to EC95.8.3. Example 3: Relationship between Receptor Occupancy and the Mean Serum anti-human HLA-G antibody Concentration in HT-1376 Tumor-Bearing Mice

[0235] Based on the in vitro and in vivo data provided in the previous examples (e.g., Example 2, FIG.l and FIG. 2), the minimum anti-human HLA-G antibody (TTX-080) scrum concentration that is predicted to achieve maximal drug activity in patients with solid tumors was identified.

[0236] In FIG. 3, the relationship between RO on HT-1376 tumor cells (calculated as EC values) and anti-human HLA-G antibody (TTX-080) serum concentration shows that 19.0 to 52.1 pg / mL of TTX-080 was needed to achieve RO levels from 60 to 90% (highlighted in gray), respectively. Based on in vitro data, those levels of RO are predicted to provide complete reversal of HLA-G-mediated suppression of tumor-infiltrating immune cells. Taken together, the data support defining the optimal biological dose (OBD) as one that achieves anti-human HLA-G antibody (TTX-080) exposure above a 50 pg / mL serum trough concentration (the approximate EC90 for RO) throughout the dosing interval to provide maximal drug activity in patients with solid malignancies.8.4. Example 4: Determination of Optimal Biological Dose

[0237] To inform dosing decisions, simulations using the population PK model (established with Phase la data) were performed to determine the OBD of anti-human HLA-G antibody (TTX-080).The OBD is defined as a dose that maintains serum concentrations of TTX-080 at or above a 50 pg / uL trough level. Under each dosing regimen scenario, simulations (FIG. 4) were conducted using the post hoc (individual) parameters from the population model. In this case, the number of simulated subjects is the same as the number of subjects included in the model. Based on the simulations, it ispredicted that dosing 20 mg / kg Q3W will provide drug exposure that maintains serum drug concentrations above the 50 pg / mL target trough (shown as a dashed line in FIG. 4) in most patients during the first cycle and greater than 95% of patients in cycles thereafter. The thick line in FIG. 4 represents the running median. Trough concentrations > 50 pg / mL were achieved in 16 out of 26 patients after the first dose and all but one patient at second and later doses. For 9 of 10 patients whose trough concentration after the first dose was < 50 pg / mL, the duration of TTX-080 serum concentrations < 50 pg / mL never exceeded two days.8.5. Example 5: Determining Receptor Occupancy (RO) of HLA-G following administration of TTX-080

[0238] To determine peripheral receptor occupancy of HLA-G following IV administration of TTX- 080, cryopreserved peripheral blood mononuclear cells (PBMC) were stained with fluorescent-labeled TTX-080 to detect free HLA-G on CD4+and CD8+T cells. The percent of occupied receptor w as calculated relative to baseline using a saturated control and after background subtraction.

[0239] As ser forth in Example 7, below, for 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. 7). suggesting saturation of peripheral HLA-G at all dose levels.8.6. Example 6: Clinical trial investigations of TTX-080 HLA-G antagonist in subjects with advanced cancers

[0240] The Phase la was an open label, multiccntcr, dose escalation clinical trial to determine die 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.

[0241] 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. 10mg / kg Q3W; Cohort 6, 20 mg / kg Q3W). Biopsies and blood samples were collected for biomarker analyses.8.7. Example 7: Phase la / lb analyses of anti-human HLA-G antibody (TTX-080), a first in class HLA-G antagonist

[0242] This example summarizes interim results from the Phase la / lb clinical trial study described in Example 6 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 in patients 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).

[0243] 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.

[0244] Serial blood samples for the measurement of serum concentrations of TTX-080 were collected at baseline and after dosing at each cycle. FIG. 5 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 pharmacokinetics (PK) data. Serum concentration data (mean, SD) over time for each cohort are shown in FIG. 6. For each dose, serum concentration data was plotted against nominal time for subjects, who had at minim um 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.

[0245] 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. 7 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. 7), suggesting saturation of peripheral HLA-G at all dose levels. 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 dataas 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. 8 shows receptor occupancy (RO) after single-dose IV administration of TTX-080.

[0246] FIGs 9A and 9B show PK stimulation of TTX-080 at 15 mg / kg Q2W dosing in patients with advanced solid tumors. FIG. 9A shows stimulation excluding effects of ethnicity on clearance. FIG. 9B 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).

[0247] The model-predicted PK parameters were summarized by cohort / dose in Table 2. 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 tUf) 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'Af) was 285 hr (11.9 days), 263 hr (11.0 days), and 268 hr (11.2 days), respectively.Abbreviations: 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 / 20, 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

[0248] 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 covariatcs that correlate with drug clearance and to inform dosing decisions. This approach identified that a base tw o-co partment model with first-orderelimination 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

[0249] 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 percentage of activated K167 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 anti-tumor activity.

[0250] Data from TTX-080 monotherapy and TTX-080 in combination with cetuximab in anti- EGFR pretreated subjects with advanced / metastatic colorectal cancer (mCRC) 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 Evo subjects staying on treatment for 9 (FIG. 10A and FIG. 10B) 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. 10C). 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%).

[0251] 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.Table S: Sequences

[0252] Table S provides sequences referred to herein.9. EQUIVALENTS AND INCORPORATION BY REFERENCE

[0253] The disclosure set forth above may encompass multiple distinct inventions with independent utility. Although each of these inventions has been disclosed in its preferred fonn(s), thespecific 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.

[0254] 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

CLAIMSWHAT IS CLAIMED IS:

1. A dosing regimen for treating a subject suffering from a cancer, comprising administering a pharmaceutical composition comprising an effective amount of an anti human HLA-G antibody to the subject in a first dose during a first cycle, wherein administration of the anti human HLA-G antibody maintains a serum drug concentration at a target trough level of between about 10 pg / mL-100 pg / mL during the first cycle after administration of the first dose.

2. The dosing regimen of claim 1, further comprising administering the anti human HLA-G antibody in one or more subsequent doses in one or more subsequent cycles.

3. The dosing regimen of claim 1 or 2, wherein the administration maintains a semm drug concentration at a target trough of above 50 pg / mL during the first cycle and / or during each of the subsequent cycles.

4. The dosing regimen of any one of claims 1-3, comprising administering the anti human HLA-G antibody at about 0.2-20 mg / kg to the subject in the first cycle and / or the subsequent cycles.

5. The dosing regimen of any one of claims 1-4, comprising administering the anti human HLA-G antibody at 2 to 4 weeks intervals between the first cycle and each of the subsequent cycles.

6. The dosing regimen of claim 5, wherein the dosing regimen comprises administering die anti human HLA-G antibody at 20 mg / kg Q3W in die first cycle and / or each of the subsequent cycles.

7. The dosing regimen of claim 5, wherein the dosing regimen comprises administering the anti human HLA-G antibody at 15 mg / kg Q2W in the first cycle and / or each of die subsequent cycles.

8. The dosing regimen of any one of claims 1-7, wherein the administration achieves at least ECeo, EC?o, ECso, or EC90 for receptor occupancy (RO).

9. The dosing regimen of any one of claims 1-8, wherein the anti human HLA-G antibody comprises or consists of a heavy chain variable region (VH) and a light chain variable region (VL); the VH comprising:(i) a VH-compIcmcntarv determining region (CDR) 1 having the sequence set forth in any one of SEQ ID NOS: 1-14 or SEQ ID NOS: 18-34;(ii) a VHCDR2 having the sequence set forth in any one of SEQ ID NOS: 38-50 or SEQ ID NOS: 54-71; and(iii) a VHCDR3 having the sequence set forth in any one of SEQ ID NOS: 76- 101; and the VL comprising:(iv) a VLCDR1 having the sequence set forth in any one of SEQ ID NOS: 105- 124;(v) a VLCDR2 having the sequence set forth in any one of SEQ ID NOS: 128- 145; and(vi) a VLCDR3 having the sequence set forth in any one of SEQ ID NOS: 149- 166.

10. The dosing regimen of any one of claims 1-9, wherein the VH comprises the sequence set forth in any one of SEQ ID NOS: 170-200. and the VL comprises the sequence set forth in any one of SEQ ID NOS: 204-228.

11. The dosing regimen of claim 10, wherein the VH sequence is at least 85% identical to the amino acid sequence set forth in SEQ ID NO: 192, and the VL sequence is at least 85% identical to the amino acid sequence set forth in SEQ ID NO: 220.

12. The dosing regimen of any one of claims 1-11, wherein the anti HLA-G antibody comprises a heavy chain (HC) having a sequence set forth in any one of SEQ ID NOS: 232-262 or SEQ ID NOS: 266-296, and a light chain (LC) having a sequence set forth in any one of SEQ ID NOS: 300-330.

13. The dosing regimen of claim 12, wherein the HC comprises a sequence set forth in SEQ ID NO: 254 and the LC comprises a sequence set forth in SEQ ID NO: 322, or the HC comprises a sequence set forth in SEQ ID NO: 288 and the VL comprises a sequence set forth in SEQ ID NO: 322.

14. The dosing regimen of any one of claims 1-13. further comprising administering an effective amount of one or more additional anti -cancer therapeutics selected from at least one:(a) an anti-ILT2 antibody;(b) an anti-ILT3 antibody;(c) an anti-ILT4 antibody;(d) an anti-KIR2DL4 antibody ;(e) an anti-HLA-E antibody;(1) an anti-NKG2A antibody;(g) an anti-HLA-F antibody;(h) an anti-PD-Ll antibody;(i) an anti-PD-1 antibody;(j) an anti-CD38 antibody;(k) an anti-CD39 antibody;(l) an anti-CD73 antibody;(m) an anti-A2A receptor antibody;(n) an anti-A2B receptor antibody;(o) an anti-A2A / A2B dual receptor antibody and / or combination;(p) an anti-CD47 antibody;(q) an anti-CLTA-4 antibody;(r) an anti-LAG3 antibody;(s) an anti-TIM3 antibody;(t) an anti-TIGIT antibody;(u) an anti- VI ST A antibody;(v) an anti-CD94 antibody;(w) an anti-EGFR antibody;(x) an anti-SIRPa antibody or SIPRaFc;(y) a bispecific antibody targeting a combination of any antibody from a) through x);(z) a small molecule inhibitor;(aa) a bi-specific T cell engager, CAR-T therapy, CAR-NK therapy, CAR-macrophage therapy, engineered cell therapy, and / or adoptive T cell therapy;(ab) an oncolytic virus;(ac) a chemotherapy; and / or(ad) an antibody -dependent cellular cytotoxicity (ADCC) therapy using one or more effector competent antibodies selected from a group consisting of an anti-CCR8. anti-TIGIT, anti-CD19, anti-CD20, anti-EGFR, anti-Her2, anti-SLAMMF7. anti-CD52, anti-BCMA, anti- GD2, and / or anti-CCR4.

15. The dosing regimen of any one of claims 1-14. further comprising administering the anti-EGFR antibody in an antibody -drug-conjugate (ADC).

16. The dosing regimen of any one of claims 1-15, wherein the anti-EGFR antibody is cetuximab.

17. The dosing regimen of claim 16, wherein the anti-EGFR antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL); the VH comprising:(i) a VHCDR1 having the sequence set forth in SEQ ID NO: 343 or SEQ ID NO: 344;(ii) a VHCDR2 having the sequence set forth in SEQ ID NO: 345 or SEQ ID NO: 346; and(iii) a VHCDR3 having the sequence set forth in SEQ ID NO: 347; and the VL comprising:(iv) a VLCDR1 having the sequence set forth in SEQ ID NO: 348;(v) a VLCDR2 having the sequence set forth in SEQ ID NO: 349; and(vi) a VLCDR3 having the sequence set forth in SEQ ID NO: 350.

18. The dosing regimen of claim 16 or 17, wherein the anti-EGFR antibody comprises a VH having a sequence set forth in SEQ ID NO: 351 and a VL having a sequence set forth in SEQ ID NO: 352.

19. The dosing regimen of any one of claims 16-18, wherein the anti-EGFR antibody comprises a heavy chain (HC) having sequence set forth in SEQ ID NO: 353 and a light chain (LC) having a sequence set forth in SEQ ID NO: 354.

20. The dosing regimen of any one of claims 1-19, wherein the anti-PD-1 antibody is pembrolizumab.

21. The dosing regimen of claim 20, wherein the anti-PD-1 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL); the VH comprising:(i) a VHCDR1 having the sequence set forth in SEQ ID NO: 355;(ii) a VHCDR2 having the sequence set forth in SEQ ID NO: 356; and(iii) a VHCDR3 having the sequence set forth in SEQ ID NO: 357; and the VL comprising:(iv) a VLCDR1 having the sequence set forth in SEQ ID NO: 358:(v) a VLCDR2 having the sequence set forth in SEQ ID NO: 359; and(vi) a VLCDR3 having the sequence set forth in SEQ ID NO: 360.

22. The dosing regimen of claim 20 or 21. wherein the anti-PD-1 antibody comprises a VH having a sequence set forth in SEQ ID NO: 361 and a VL having a sequence set forth in SEQ ID NO: 362.

23. The dosing regimen of any one of claims 20-22, wherein the anti-PD-1 antibody comprises a heavy chain (HC) having sequence set forth in SEQ ID NO: 363 and a light chain (LC) having a sequence set forth in SEQ ID NO: 364.

24. The dosing regimen of any one of claims 20-23, further comprising administering at least one of:(a) a chemotherapy;(b) a radiation therapy;(c) one or more additional therapeutics agents; and / or(d) one or more additional anti-cancer therapeutics.

25. The dosing regimen of claim 24, wherein the chemotherapy comprises administering one or more agents selected from the group consisting of 5-fluorouracil (5-FU), folic acid or leucovorin, oxaliplatin, irinotecan, cyclophosphamide, cisplatin, carboplatin, methotrexate, gemcitabine, vincristine, vinblastine, paclitaxel, docetaxel, etoposide, doxorubicin, and bleomycin.

26. The dosing regimen of claim 24, wherein the one or more additional therapeutic agents comprise one or more immuno stimulatory agents selected from at least one of an antagonist to an inhibitory receptor of an immune cell, an agonist of a co-stimulatory receptor of an immune cell,an ADCC competent antibody, a cytokine, an oncolytic vims, a chimeric antigen engineered T cell, and / or a bispecific or multi-specific T cell directed antibody.

27. The dosing regimen of any one of claims 1-26, comprising administering the pharmaceutical composition intravenously.

28. A method for treating a subject suffering from a cancer, comprising administering to the subject the dosing regimen of any one of claims 1-27.

29. The dosing regimen of any one of claims 1-27 or the method of claim 28, wherein the cancer is an advanced refractory / resistant solid malignancy.

30. The dosing regimen of any one of claims 1-27 or the method of claim 28, wherein the cancer is selected from at least one of a 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). acral melanoma (AM), bladder cancer, and / or choriocarcinoma.

31. The dosing regimen of any one of claims 1-27 or the method of claim 28, wherein the cancer has progressed on or received one or more lines of prior cancer therapy selected from at least one of an anti-EGFR antibody, an anti-PD-1 antibody, a 5-FU and oxaliplatin-based chemotherapy with or without bevacizumab. and / or FOLFOX.

32. The dosing regimen of any one of claims 1-27 or the method of claim 28, wherein the cancer has not received prior treatment of an anti-EGFR antibody.

33. A pharmaceutical composition comprising an effective amount of an anti HLA-G antibody for use in tire dosing regimen of any one of claims 1-27 or the method of claim 28, and a pharmaceutically acceptable excipient.

34. A kit, comprising(a) the pharmaceutical composition of claim 33; and(b) instructions for administering the pharmaceutical composition according to the dosing regimen of any one of claims 1-27 or the method of claim 28.