Treatment of cancer with Anti-ILT3 antibodies

Abstract

The present invention relates to treatment of cancer using an anti-human ILT3 monoclonal antibody. The treatment may additionally comprise avelumab, nivolumab or cetuximab.

Description

TREATMENT OF CANCER WITH ANTLILT3 ANTIBODIESCROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority of U.S. Provisional Patent Application No. 63 / 616,635, filed December 31, 2023, the contents of which are all incorporated herein by reference in their entirety.REFERENCE TO AN ELECTRONIC SEQUENCE LISTING

[0002] The contents of the electronic sequence listing (BDB-P-020-PCT.xml; Size: 10,342 bytes; and Date of Creation: December 23, 2024) is herein incorporated by reference in its entirety.FIELD OF INVENTION

[0003] The present invention is in the field of immune checkpoint inhibition.BACKGROUND OF THE INVENTION

[0004] During cancer development, cancer cells can evade immune surveillance through various mechanisms. Understanding these mechanisms of escape is critical for developing novel cancer therapy. Cancer immunotherapy aims to re-activate the patients’ immune system for the elimination of cancer cells and is currently a highly active area in cancer research with unprecedented results in the clinic. Despite these advances, there is a constant need for new therapies that will allow for a more substantial increase in patients' survival and quality of life as a standalone treatment or in combination with other agents.

[0005] Leukocyte immunoglobulin-like receptor subfamily B member 4, (ILT3, CD85k, LILRB4) is expressed on various myeloid cells and specially on myeloid cells with immunosuppressive activity including tumor associated macrophages (TAM), myeloid derived suppressor cells (MDSCs) and tolerogenic dendritic cells (DCtol). ILT3 contains 2 extracellular immunoglobulin-like domains and 3 intracellular tyrosine-based inhibitory motifs (ITIMs). The expression of ILT3 in myeloid cells and in a soluble form was reported in various malignancies in association with tumor immune escape, metastasis and poorprognosis. ILT3 signaling on myeloid cells leads to reduced expression of co-stimulatory receptors and differentiation to an immunosuppressive phenotype. In addition to regulation of myeloid cell maturation and function, ILT3 signaling induces, through unknown ligands, T cell anergy, and differentiation to T regulatory and T suppressor phenotype.

[0006] For many years ILT3 ligands remained undefined, but recently there is accumulating evidence that ILT3 binds proteins in the tumor microenvironment (TME) and tumor extracellular matrix (ECM). Proteins such as Apolipoprotein E (APOE) and Fibronectin (FN1) are present in the TME and can bind ILT3. The binding of ILT3 to its ligands induces an immunosuppressive phenotype in myeloid cells, mediates the inhibition of T cells activity and creates an immunosuppressive TME which supports tumor growth and proliferation.

[0007] In concordance with this reported data, the inhibition of ILT3 using blocking antibodies is thought to increase tumor cell elimination. This may occur by inhibition of the immunosuppressive effect of tumor resident myeloid cells, thereby inducing proinflammatory phenotype of myeloid cells which support tumor infiltrated T cells’ (TILs’) activation and thereby remodeling the TME from an immunosuppressive to a proinflammatory TME. In total, ILT3 blocking increases the effector activity of various immune cells against the malignant cells. Anti-ILT3 antibodies have been disclosed in International Patent Application WO2006 / 138739, WO2018 / 089300, WO2019 / 099597, W02020 / 056077 andWO2023209716.

[0008] Some of the current cancer immunotherapies combat tumor progression by targeting proteins that aid in tumor immune evasion. However, such therapies are often inadequate due to primary tumor refractoriness and acquired tumor resistance. Thus, there remains a need for new and improved cancer immunotherapies.SUMMARY OF THE INVENTION

[0009] The present disclosure provides methods for cancer therapy using anti-human ILT3 antibody BND-35 or a related antibody.

[0010] According to a first aspect, there is provided a method of treating cancer in a human patient in need thereof, comprising administering to the patient a humanized monoclonal antihuman ILT3 IgG4antibody whose heavy chain CDR1-3 and light chain CDR1-3 comprise SEQ ID NOs: 1-6, respectively, in two or more treatment cycles, wherein each treatment cycle comprises a single dose of the anti-ILT3 antibody at 0.3-20 mg / kg per dose.

[0011] According to some embodiments, the dose is 0.3, 1, 3, 10, or 20 mg / kg.

[0012] According to some embodiments, each treatment cycle is at most four weeks.

[0013] According to some embodiments, each treatment cycle is about four weeks.

[0014] According to some embodiments, each treatment cycle is about two or three weeks.

[0015] According to some embodiments, the antibody comprises a heavy chain variable domain and a light chain variable domain comprising SEQ ID NOs: 7 and 8, respectively.

[0016] According to some embodiments, the antibody comprises a heavy chain comprising SEQ ID NO: 9, or SED ID NO: 9 without the C-terminal lysine; and a light chain comprising SEQ ID NO: 10.

[0017] According to some embodiments, the cancer is selected from the group consisting of breast cancer, biliary tract cancer, colorectal cancer, esophageal cancer, gastric cancer, gastroesophageal junction cancer, hepatobiliary cancer, head and neck cancer, lung cancer, renal cancer, skin cancer, ovarian cancer, pancreatic cancer, and soft tissue sarcoma.

[0018] According to some embodiments, the cancer is selected from breast cancer, cholangiocarcinoma, colorectal cancer, K-Ras wild-type colorectal cancer, N-Ras wild-type colorectal cancer, BRAF-mutant colorectal cancer, adenocarcinoma or squamous cell carcinoma of the esophagus, gastric or gastroesophageal junction adenocarcinoma, squamous cell carcinoma of the head and neck, non- small cell lung cancer, melanoma, ovarian cancer, pancreatic adenocarcinoma, renal cell carcinoma, and soft tissue sarcomas.

[0019] According to some embodiments, the antibody is administered at a first dose and a second dose, wherein a) the first dose is higher than the second dose, or b) the second dose is higher than the first dose.

[0020] According to some embodiments, the first dose is 20 mg / kg, and the second dose is 1 mg / kg; the first dose is 10 mg / kg, and the second dose is 1 mg / kg; the first dose is 3 mg / kg, and the second dose is 1 mg / kg; the first dose is 1 mg / kg, and the second dose is 0.3 mg / kg; or the first dose is 0.3 mg / kg, and the second dose is 0.1 mg / kg.

[0021] According to some embodiments, the antibody is administered to the patient by intravenous infusion.

[0022] According to some embodiments, the method further comprises administering a single dose of avelumab to the patient in each treatment cycle.

[0023] According to some embodiments, the avelumab is administered intravenously at 800 mg per dose.

[0024] According to some embodiments, the method further comprises administering a single dose of nivolumab to the patient in each treatment cycle.

[0025] According to some embodiments, the nivolumab is administered intravenously at 240 mg per dose.

[0026] According to some embodiments, each treatment cycle is about three weeks.

[0027] According to some embodiments, the method further comprises administering a single dose of cetuximab to the patient in each treatment cycle.

[0028] According to some embodiments, the cetuximab is administered intravenously at 500 mg / m2per dose.

[0029] According to some embodiments, the patient is premedicated with a histamine- 1 (Hi) receptor antagonist before each administration of cetuximab.

[0030] According to some embodiments, the Hi receptor antagonist is diphenhydramine, optionally administered at a dose of 50 mg.

[0031] According to some embodiments, each treatment cycle is about two weeks.

[0032] According to some embodiments, each treatment cycle is about four weeks.

[0033] According to some embodiments, the treatment is first line therapy.

[0034] According to some embodiments, the treatment is second line therapy.

[0035] According to some embodiments, the treatment is third line or later therapy.

[0036] According to another aspect, there is provided a method of treating breast cancer, biliary tract cancer, colorectal cancer, esophageal cancer, gastric cancer, gastroesophageal junction cancer, hepatobiliary cancer, head and neck cancer, lung cancer, renal cancer, skin cancer, ovarian cancer, pancreatic cancer, or soft tissue sarcoma in a human patient in need thereof, comprising administering to the patient by intravenous infusion a humanizedmonoclonal anti-human ILT3 antibody that comprises a heavy chain and a light chain having the amino acid sequences of SEQ ID NOs: 9 and 10, respectively, in two or more treatment cycles, wherein each treatment cycle comprises a single dose of the anti-ILT3 antibody at 0.1, 0.3, 1, 3, 10 or 20 mg / kg per dose, wherein each treatment cycle is about two to four weeks.

[0037] According to another aspect, there is provided a method of treating breast cancer, biliary tract cancer, esophageal cancer, gastric cancer, gastroesophageal junction cancer, hepatobiliary cancer, head and neck cancer, lung cancer, renal cancer, skin cancer, ovarian cancer, pancreatic cancer, or soft tissue sarcoma in a human patient in need thereof, comprising intravenously administering to the patient a) a humanized monoclonal anti-human ILT3 antibody that comprises a heavy chain and a light chain having the amino acid sequences of SEQ ID NOs: 9 and 10, respectively, and b) avelumab, in two or more treatment cycles, wherein each treatment cycle comprises a single dose of the anti-ILT3 antibody at 0.3, 1, 3, 10 or 20 mg / kg per dose, and a single 800 mg dose of avelumab, wherein each treatment cycle is about three weeks.

[0038] According to another aspect, there is provided a method of treating breast cancer, biliary tract cancer, esophageal cancer, gastric cancer, gastroesophageal junction cancer, hepatobiliary cancer, head and neck cancer, lung cancer, renal cancer, skin cancer, ovarian cancer, pancreatic cancer, or soft tissue sarcoma in a human patient in need thereof, comprising intravenously administering to the patient a) a humanized monoclonal anti-human ILT3 antibody that comprises a heavy chain and a light chain having the amino acid sequences of SEQ ID NOs: 9 and 10, respectively, and b) nivolumab, in two or more treatment cycles, wherein each treatment cycle comprises a single dose of the anti-ILT3 antibody at 0.3, 1, 3, 10 or 20 mg / kg per dose, and a single 240 mg dose of nivolumab, wherein each treatment cycle is about three weeks.

[0039] According to another aspect, there is provided a method of treating breast cancer, colorectal cancer, head and neck cancer, lung cancer, pancreatic cancer, renal cancer or soft tissue sarcoma in a human patient in need thereof, comprising intravenously administering to the patienta) a humanized monoclonal anti-human ILT3 antibody that comprises a heavy chain and a light chain having the amino acid sequences of SEQ ID NOs: 9 and 10, respectively, and b) cetuximab, in two or more treatment cycles, wherein each treatment cycle comprises a single dose of the anti-ILT3 antibody at 0.3, 1, 3, 10 or 20 mg / kg per dose, and a single 500 mg / m2dose of cetuximab, wherein each treatment cycle is about two to four weeks.

[0040] According to some embodiments, the patient is premedicated with diphenhydramine before each administration of cetuximab, optionally wherein the diphenhydramine is administered at a dose of 50 mg.

[0041] According to some embodiments, the humanized monoclonal anti -human ILT3 antibody is administered at a first dose and a second dose, optionally wherein the first dose is lower than the second dose.

[0042] According to another aspect, there is provided a method of treating cancer in a human patient in need thereof, comprising administering to the patient by intravenous infusion a humanized monoclonal anti-human ILT3 antibody that comprises a heavy chain and a light chain having the amino acid sequences of SEQ ID NOs: 9 and 10, respectively, in two or more treatment cycles, wherein each treatment cycle comprises a single dose of the anti-ILT3 antibody at 0.3, 1, 3, 10 or 20 mg / kg per dose, wherein the cancer is breast cancer, cholangiocarcinoma, colorectal cancer, adenocarcinoma or squamous cell carcinoma of the esophagus, gastric or gastroesophageal junction adenocarcinoma, squamous cell carcinoma of the head and neck, non-small cell lung cancer, melanoma, ovarian cancer, pancreatic adenocarcinoma, renal cell carcinoma, or soft tissue sarcomas, wherein each treatment cycle is about two to four weeks.

[0043] According to another aspect, there is provided a method of treating non-small cell lung cancer in a human patient in need thereof, comprising intravenously administering to the patient a) a humanized monoclonal anti-human ILT3 antibody that comprises a heavy chain and a light chain having the amino acid sequences of SEQ ID NOs: 9 and 10, respectively, and b) avelumab, in two or more treatment cycles, wherein each treatment cycle comprisesa single dose of the anti-ILT3 antibody at 1, 3, 10 or 20 mg / kg per dose, and a single 800 mg dose of avelumab, wherein each treatment cycle is about three weeks, and optionally wherein the treatment is second or third line therapy.

[0044] According to another aspect, there is provided a method of treating non-small cell lung cancer in a human patient in need thereof, comprising intravenously administering to the patient a) a humanized monoclonal anti-human ILT3 antibody that comprises a heavy chain and a light chain having the amino acid sequences of SEQ ID NOs: 9 and 10, respectively, and b) nivolumab, in two or more treatment cycles, wherein each treatment cycle comprises a single dose of the anti-ILT3 antibody at 1, 3, 10 or 20 mg / kg per dose, and a single 240 mg dose of nivolumab, wherein each treatment cycle is about three weeks, and optionally wherein the treatment is second or third line therapy.

[0045] According to another aspect, there is provided a method of treating gastric cancer or gastroesophageal junction adenocarcinoma in a human patient in need thereof, comprising intravenously administering to the patient a) a humanized monoclonal anti-human ILT3 antibody that comprises a heavy chain and a light chain having the amino acid sequences of SEQ ID NOs: 9 and 10, respectively, and b) avelumab, in two or more treatment cycles, wherein each treatment cycle comprises a single dose of the anti-ILT3 antibody at 1, 3, 10 or 20 mg / kg per dose, and a single 800 mg dose of avelumab, wherein each treatment cycle is about three weeks, and optionally wherein the treatment is third line or later therapy.

[0046] According to another aspect, there is provided a method of treating gastric cancer or gastroesophageal junction adenocarcinoma in a human patient in need thereof, comprising intravenously administering to the patient a) a humanized monoclonal anti-human ILT3 antibody that comprises a heavy chain and a light chain having the amino acid sequences of SEQ ID NOs: 9 and 10, respectively,b) nivolumab, in two or more treatment cycles, wherein each treatment cycle comprises a single dose of the anti-ILT3 antibody at 1, 3, 10 or 20 mg / kg per dose, and a single 240 mg dose of nivolumab, wherein each treatment cycle is about three weeks, and optionally wherein the treatment is third line or later therapy.

[0047] A method of treating colorectal cancer in a human patient in need thereof, comprising intravenously administering to the patient a) a humanized monoclonal anti-human ILT3 antibody that comprises a heavy chain and a light chain having the amino acid sequences of SEQ ID NOs: 9 and 10, respectively, and b) cetuximab, in two or more treatment cycles, wherein each treatment cycle comprises a single dose of the anti-ILT3 antibody at 1, 3, 10 or 20 mg / kg per dose, and a single 500 mg / m2dose of cetuximab, wherein each treatment cycle is about two to four weeks, and optionally wherein the treatment is third line or later therapy.

[0048] According to some embodiments, the patient is pretreated with diphenhydramine at a dose of 50 mg before each administration of cetuximab.

[0049] According to some embodiments, a) the cancer is unresectable; b) the cancer is metastatic; c) the patient is refractory to standard approved therapy; d) the patient is not a candidate for standard approved therapy; or e) any combination of a)-d).

[0050] According to another aspect, there is provided the use of a humanized monoclonal anti-human ILT3 IgG4 antibody for treating cancer in a patient by a method of the invention.

[0051] According to another aspect, there is provided a humanized monoclonal anti-human ILT3 IgG4antibody for use in treating cancer in a patient by a method of the invention.

[0052] Other features, objectives, and advantages of the invention are apparent in the detailed description that follows. It should be understood, however, that the detailed description, whileindicating embodiments and aspects of the invention, is given by way of illustration only, not limitation. Various changes and modification within the scope of the invention will become apparent to those skilled in the art from the detailed description.BRIEF DESCRIPTION OF THE DRAWINGS

[0053] Figure 1: Study Design Schematic. DL, dose level; CRC, colorectal cancer; GEJ, gastroesophageal junction adenocarcinoma; SCCHN, squamous cell carcinoma of the head and neck; TNBC, triple negative breast cancer; NSCLC, non-small cell lung cancer; RCC, renal cell carcinoma * In Sub-Part IB and 1C, the starting dose of BND-35 will be 3 mg / kg or one DL below the established BND-35 monotherapy MTD, if set at DL2 or DL3.DETAILED DESCRIPTION OF THE INVENTION

[0054] The present disclosure provides safe and efficacious cancer treatment with BND-35 or a related antibody (such as an antibody described herein, e.g., a humanized antibody having the same heavy and light chain CDRs or the same heavy and light chain variable domains as BND-35). BND-35 is a humanized monoclonal IgG4 antibody targeting human ILT3. See also PCT Patent Publications WO2023209716.I. Anti-ILT3 Antibodies

[0055] In some embodiments, a cancer therapy described herein uses an anti-ILT3 antibody that is BND-35 or a related antibody (e.g., an antibody described herein), or an antigenbinding portion of said anti-ILT3 antibody. The BND-35 heavy chain sequence (SEQ ID NO: 9) is shown below, with its variable domain sequence in boldface and italics (SEQ ID NO: 7) and its CDR1-3 (SEQ ID NOs: 1-3, respectively) underlined: OVOLVOSGAEVKKPGASVKVSCKASGYSFSGFYIDWVKQPPGKGLEWIGYIFPSSGETSYNQKFKGRVTMTVDKSTSTVYMELSSLRSEDTAVYYCARQAFYYFDYWGOGTTV 7VSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTF PAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCP APEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHN AKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQ PREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 9).

[0056] The BND-35 light chain sequence (SEQ ID NO: 10) is shown below, with its variable domain sequence in boldface and italics (SEQ ID NO: 8) and its CDR1-3 (SEQ ID NOs: 4- 6, respectively) underlined:DIVMTQSPDSLA VSLGERA TINCKSSOSLLSSSNOKNYLAWYOQKPGQAPRLLIYWA STRESGVPDRFAGSGSGTDFTLTISSLQAEDVAVYYCOOYYSYPLTFGOGTKLEIKR TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVT EQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 10).

[0057] In some embodiments, the anti-ILT3 antibody is of human IgG4 isotype subtype, optionally comprising mutations S225P and / or L232E (Eu numbering). In certain embodiments, (e.g., any of the embodiments described herein), the anti-ILT3 antibody is of isotype IgG4 and has mutations S225P and L232E (Eu numbering). In some embodiments, the S225P and L232E mutations are known as the S228P and L235E mutations. In some embodiments, S180 of SEQ ID NO: 10 is mutated to P. In some embodiments, L187 of SEQ ID NO: 10 is mutated to E. In some embodiments, SEQ ID NO: 10 comprises an A180P and a L187E mutation.

[0058] In certain embodiments, the anti-ILT3 antibody comprises the six CDR amino acid sequences of BND-35. The CDRs may be assigned, e.g., in accordance with IMGT definitions (Lefranc et al., Dev Comp Immunol. (2003) 27(l):55-77); or in accordance with the definitions of Kabat, Sequences of Proteins of Immunological Interest (National Institutes of Health, Bethesda, MD (1987 and 1991)); Chothia & Lesk, J Mol Biol. (1987) 196:901-17; Chothia et al., Nature (1989) 342:878-83; MacCallum et al., J Mol Biol. (1996) 262:732-45; or Honegger and Pluckthun, J Mol Biol. (2001) 309(3):657-70. In certain embodiments, the anti-ILT3 antibody comprises HCDR1-3 and LCDR1-3 amino acid sequences of SEQ ID NOs: 1-6, respectively.

[0059] In some embodiments, the anti-ILT3 antibody comprises the heavy and light chain variable domain amino acid sequences of BND-35. In certain embodiments, the anti-ILT3 antibody may comprise a heavy chain variable domain (VH) that is at least 90% (e.g., at least 95%, 98%, or 99%) identical in sequence to SEQ ID NO: 7, and a light chain variable domain (VL) that is at least 90% (e.g., at least 95%, 98%, or 99%) identical in sequence to SEQ ID NO: 8. Optionally, said antibody may comprise the six CDRs of BND-35 (e.g., SEQ ID NOs: 1-6). In certain embodiments, the anti-ILT3 antibody comprises a VH comprising SEQ ID NO: 7 and a VL comprising SEQ ID NO: 8.

[0060] In some embodiments, the anti-ILT3 antibody comprises the heavy and light chain amino acid sequences of BND-35. In certain embodiments, the anti-ILT3 antibody comprises a heavy chain (HC) that is at least 90% (e.g., at least 95%, 98%, or 99%) identical in sequence to SEQ ID NO: 9, and a light chain (LC) that is at least 90% (e.g., at least 95%, 98%, or 99%) identical in sequence to SEQ ID NO: 10. Optionally, said antibody may comprise the six CDRs (e.g., SEQ ID NOs: 1-6) or the VH and VL (e.g., SEQ ID NOs: 7 and 8, respectively) of BND-35. In certain embodiments, the anti-ILT3 antibody comprises an HC comprising SEQ ID NO: 9 (optionally without the C-terminal lysine) and an LC comprising SEQ ID NO: 10.

[0061] BND-35 can be provided, for example, in solid form (e.g., lyophilized form) that is reconstituted in a suitable pharmaceutical solution before administration to a patient, or in an aqueous pharmaceutical solution. In certain embodiments, the antibody is provided in a pharmaceutical composition that further comprises a pharmaceutically acceptable excipient.

[0062] In some embodiments, a pharmaceutical composition comprising an anti-ILT3 antibody as recited herein (e.g., BND-35) is provided in an article of manufacture or kit such as one that comprises one or more containers containing the composition and a label associated with the container(s). The container may be a single use container (e.g., for intravenous delivery), such as a single use boule or vial, or a single use, pre-filled syringe or injector. In some embodiments, the container contains a single dose (e.g., a dose recited herein) of the anti-ILT3 antibody, wherein the container may be a vial or a pre-filled syringe or injector. In some embodiments, the article of manufacture or kit further comprises one or more containers comprising additional agents, e.g., those administered in addition to BND- 35 in the combination therapies described herein. For example, the one or more containers may comprise avelumab, nivolumab, cetuximab, or any combination thereof, e.g., in single or multiple doses described herein for those agents. In certain embodiments, an article of manufacture or kit of the present disclosure comprises 1) containers comprising BND-35; 2) containers comprising BND-35 and nivolumab; 3) containers comprising BND-35 and nivolumab; or 4) containers comprising BND-35 and cetuximab; optionally wherein the containers are for intravenous delivery.II. Patient Populations

[0063] The present disclosure relates to treatment of cancer in human patients in need thereof with BND-35 or a related anti-ILT3 antibody, such as an anti-ILT3 antibody described herein.The treatment may further comprise avelumab (e.g., in combination with chemotherapy such as carboplatin and / or pemetrexed), nivolumab (e.g., in combination with chemotherapy such as carboplatin and / or pemetrexed) or cetuximab.

[0064] In some embodiments, the patient is an adult (> 18 years of age).

[0065] In some embodiments, the patient has unresectable or metastatic disease and is refractory to or is not a candidate for standard approved therapy. In some embodiments, the patient has received and failed prior treatment with a PD-1 or PD-L1 immune checkpoint blockade therapy. In some embodiments, the patient has received and failed prior treatment with an anti-PD-1 or anti-PD-Ll blocking antibody. In some embodiments, the patient has received and failed prior treatment with pembrolizumab or another anti-PD-1 or anti-PD-Ll therapy. In some embodiments, the patient has received and failed prior treatment with avelumab or another anti-PD-1 or anti-PD-Ll therapy. In some embodiments, the patient has received and failed prior treatment with nivolumab or another anti-PD-1 or anti-PD-Ll therapy. In some embodiments, the patient has received and failed prior treatment with atezolizumab or another anti-PD-1 or anti-PD-Ll therapy. In some embodiments, the patient has received and failed prior treatment with durvalumab or another anti-PD-1 or anti-PD-Ll therapy. In some embodiments, the patient has received and failed prior treatment with any one of KN035, cosibelimab, socazolimab, AUNP12, CA-170 and BMS-986189 or another anti-PD-1 or anti-PD-Ll therapy. In some embodiments, the patient has received and failed prior treatment with fluoropyrimidine, oxaliplatin, or irinotecan, with bevacizumab and / or cetuximab. In some embodiments, the patient has received and failed prior treatment with fluoropyrimidine, oxaliplatin, irinotecan, bevacizumab and / or cetuximab. In some embodiments, the patient has received and failed prior treatment with cetuximab or another anti-EGFR therapy. In some embodiments, the patient has received and failed prior treatment with cetuximab or another EGFR inhibitor.

[0066] In some embodiments, the patient has Eastern Cooperative Oncology Group Performance Status (ECOG) of 0 or 1.

[0067] In some embodiments, the patient has been diagnosed with one or more conditions selected from the group consisting of: breast cancer (e.g., triple negative breast cancer), bile duct cancer (e.g., cholangiocarcinoma), esophageal cancer (e.g., adenocarcinoma or squamous cell carcinoma of the esophagus), colorectal cancer (e.g., K-Ras wild-type colorectal cancer, N-RAS wild-type colorectal cancer or BRAF-mutant colorectal cancer;optionally non-MSI-H disease or MSI-H disease), gastric cancer (e.g., gastric or gastroesophageal junction adenocarcinoma, optionally Siewert Types 2 and 3), pancreatic cancer (e.g., pancreatic adenocarcinoma), head and neck cancer (e.g., squamous cell carcinoma of the head and neck), lung cancer (e.g., non-small cell lung cancer, optionally stage IV non-squamous NSCLC as per American Joint Committee on Cancer [AJCC] 8th edition), renal cancer (e.g., renal cell carcinoma), soft tissue sarcoma, skin cancer (e.g., melanoma), and ovarian cancer.

[0068] In some embodiments, the patient does not have active, known, or suspected autoimmune disease (optionally except for one or more of type I diabetes mellitus, hypothyroidism only requiring hormone replacement, a skin disorder not requiring systemic treatment (such as vitiligo, psoriasis, or alopecia), or a condition not expected to recur in the absence of an external trigger).

[0069] In some embodiments, the patient demonstrates increased baseline levels of ILT3- positive immune cells (e.g., monocytes, macrophages, DCs, osteoclasts, and / or progenitor mast cells) prior to treatment. Levels of ILT3-positive immune cells may be increased from baseline by, e.g., by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, 300%, 400%, or 500%. Each possibility represents a separate embodiment of the invention.III. Treatment of Cancer

[0070] The present disclosure relates to treating cancer in a patient as described herein, with BND-35 or a related anti-ILT3 antibody (e.g., an anti-ILT3 antibody described herein). In some embodiments, the treatment further comprises avelumab, nivolumab or cetuximab.

[0071] The present therapies can be used as a first line therapy to treat treatment-naive patients, i.e., those who have not been treated with anti-cancer drugs (e.g., drugs against the specific cancer with which the patient presents). The present therapies can also be used to treat patients who have been treated with anti-cancer drugs (e.g., drugs against the specific cancer with which the patient presents), but these patients may have failed to respond to the previous treatment or may have since experienced worsening of the disease or renewed disease activity. In some embodiments, the present therapies are used as a second line therapy. In some embodiments, the present therapies are used as a third line or later therapy.

[0072] In some embodiments, the present therapies are used to treat a cancer that is unresectable. In some embodiments, the present therapies are used to treat a cancer that ismetastatic. In some embodiments, the patient is refractory to standard approved therapy. In some embodiments, the patient is not a candidate for standard approved therapy. Any combination of the above is also contemplated.

[0073] Administration of the anti-ILT3 antibody may be parenteral, e.g., intravenous. For example, the anti-ILT3 antibody may be administered through an intravenous infusion drip over about 15, 30, 45, 60, 75, or 90 minutes. In some embodiments, the antibody is intravenously administered at a dose of 0.05-50 mg / kg, such as at a dose of 0.1-20 mg / kg, e.g., about 0.1, 0.3, 0.5, 1, 1.5, 3, 5, 10, 15, or 20 mg / kg, per treatment cycle. In certain embodiments, the dose is 0.3, 1, 3, 10, or 20 mg / kg per treatment cycle. In particular embodiments, the dose is 0.1, 0.3, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 mg / kg per treatment cycle. In particular embodiments, the dose is 1, 3, 10, or 20 mg / kg per treatment cycle. In some embodiments, the antibody is intravenously administered at a dose of 3 mg / kg per treatment cycle. In some embodiments, each treatment cycle is about 3 days, 5 days, 1 week, 10 days, 2 weeks, 2 days, 3 weeks, 25 days, 4 weeks, 30 days, 1 month, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 2 months, 9 weeks, 10 weeks, 11 weeks, 12 weeks or 3 months. In some embodiments, each treatment cycle is about 1, 2, 3, 4, 5, 6, 7, or 8 weeks. In certain embodiments, each treatment cycle is about two weeks. In certain embodiments, each treatment cycle is about three weeks. In certain embodiments, each treatment cycle is about four weeks. In some embodiments, two to four weeks is two to three weeks. In some embodiments, two to four weeks is about two weeks. In some embodiments, two to four weeks is about three weeks. In some embodiments, two to four weeks is about four weeks. The therapy may comprise 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, or more treatment cycles (optionally consecutive). In particular embodiments, the therapy comprises two or more treatment cycles (optionally consecutive). Where treatment cycles are consecutive, there is no period of delay between cycles; for example, for consecutive two week treatment cycles, the day after day 14 of one treatment cycle would be day 1 of the next treatment cycle.

[0074] In certain embodiments, the antibody is administered through an intravenous infusion drip over about 30 minutes (e.g., at a dose of 0.3 mg / kg). In some embodiments, the antibody is administered through an intravenous infusion drip over about 60 minutes (e.g., at a dose of 0.3, 1, 3, 10, or 20 mg / kg).

[0075] In some embodiments, the anti-ILT3 antibody is intravenously administered at a dose of 1 mg / kg every two weeks.

[0076] In some embodiments, the anti-ILT3 antibody is intravenously administered at a dose of 3 mg / kg every two weeks.

[0077] In some embodiments, the anti-ILT3 antibody is intravenously administered at a dose of 10 mg / kg every two weeks.

[0078] In some embodiments, the anti-ILT3 antibody is intravenously administered at a dose of 20 mg / kg every two weeks.

[0079] In some embodiments, the anti-ILT3 antibody is intravenously administered at a dose of 1 mg / kg every three weeks.

[0080] In some embodiments, the anti-ILT3 antibody is intravenously administered at a dose of 3 mg / kg every three weeks.

[0081] In some embodiments, the anti-ILT3 antibody is intravenously administered at a dose of 10 mg / kg every three weeks.

[0082] In some embodiments, the anti-ILT3 antibody is intravenously administered at a dose of 20 mg / kg every three weeks.

[0083] In some embodiments, the anti-ILT3 antibody may be intravenously administered to the patient at two or more doses (e.g., doses recited above) in different treatment cycles. For example, the first administration of the antibody may be at a first dose and subsequent administration of the antibody may be at a second dose. In certain embodiments, the first dose is lower than the second dose. In certain embodiments, the first dose (“loading dose”) is higher than the second dose. For example, the first and second antibody doses may be: a) 20 mg / kg and 1 mg / kg; b) 10 mg / kg and 1 mg / kg; c) 3 mg / kg, and 1 mg / kg; or d) 1 mg / kg and 0.3 mg / kg.

[0084] In certain embodiments, the anti-ILT3 antibody is used to treat a cancer, e.g., a PD-1- related or PD-Ll-related cancer. A PD-l-related cancer may be, e.g., a cancer associated with the binding of PD-1 to PD-L1 and / or PD-L2 and may in some embodiments to be associated with elevated expression of PD-1 (e.g., as determined in a tumor sample from a patient). A PD-Ll-related cancer may be, e.g., a cancer associated with the binding of PD-L1 to PD-1 and may in some embodiments be associated with elevated expression of PD-L1 (e.g., asdetermined in a tumor sample from a patient). In some embodiments, the cancer is an EGFR expressing cancer. In some embodiments, the cancer is an EGFR overexpressing cancer. In particular embodiments, the cancer is selected from breast cancer (e.g., triple negative breast cancer), biliary tract cancer, cervical cancer, cholangiocarcinoma, colorectal cancer, esophageal cancer (e.g., adenocarcinoma or squamous cell carcinoma of the esophagus), gastric cancer, gastroesophageal junction adenocarcinoma, hepatobiliary cancer, hepatocellular carcinoma, head and neck cancer (e.g., squamous cell carcinoma of the head and neck), non-small cell lung cancer (e.g., non-squamous non-small cell lung cancer), renal cell carcinoma, skin squamous cell carcinoma, melanoma, ovarian cancer, pancreatic cancer, renal cell carcinoma, and soft tissue sarcoma.

[0085] Anti-ILT3 Antibody Monotherapy

[0086] In some embodiments, an anti-ILT3 antibody described herein is administered alone (monotherapy). In certain embodiments, the anti-ILT3 antibody monotherapy is used to treat a cancer selected from breast cancer, biliary tract cancer, esophageal cancer, gastric cancer, gastroesophageal junction cancer, head and neck cancer, non-small cell lung cancer, melanoma, ovarian cancer, pancreatic cancer, renal cell cancer, and soft tissue sarcoma. In certain embodiments, the anti-ILT3 antibody monotherapy is used to treat a cancer selected from breast cancer, biliary tract cancer, colorectal cancer, esophageal cancer, gastric cancer, gastroesophageal junction cancer, head and neck cancer, non-small cell lung cancer, melanoma, ovarian cancer, pancreatic cancer, renal cell cancer, and soft tissue sarcoma. In certain embodiments, the anti-ILT3 antibody monotherapy is used to treat a cancer selected from breast cancer, cholangiocarcinoma, colorectal cancer, adenocarcinoma or squamous cell carcinoma of the esophagus, gastric or gastroesophageal junction adenocarcinoma, squamous cell carcinoma of the head and neck, non-small cell lung cancer, melanoma, ovarian cancer, pancreatic adenocarcinoma, renal cell carcinoma, and soft tissue sarcomas. In some embodiments, the treatment may comprise BND-35 at a dose of 0.3, 1, 3, 10, or 20 mg / kg per treatment cycle. In some embodiments, the treatment may comprise BND-35 at a dose of 1, 3, 10, or 20 mg / kg per treatment cycle. In certain embodiments, each treatment cycle is about two to four weeks.

[0087] Anti-ILT3 Antibody and Avelumab

[0088] In some embodiments, the anti-ILT3 antibody described herein (e.g., BND-35) is administered in combination with an anti-PD-1 or anti-PD-Ll agent, e.g., an anti-PD-Llantibody such as avelumab. In certain embodiments, the avelumab is administered intravenously to the patient (such as through intravenous infusion drip over, for example, about 30 minutes), for example at a dose of 100, 150, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700, 710, 720, 730, 740, 750, 760, 770, 780, 790, 800, 810, 820, 830, 840, 850, 860, 870, 880, 890, 900, 910, 920, 930, 940, 950, 960, 970, 980, 990 or 1000 mg per treatment cycle. In particular embodiments, the avelumab is administered intravenously to the patient at a dose of 800 mg per treatment cycle.

[0089] In some embodiments, the combination therapy comprising an anti-ILT3 antibody described herein (e.g., BND-35) and an anti-PD-1 or anti-PD-Ll agent (e.g., avelumab) is used to treat a cancer selected from breast cancer, biliary tract cancer, esophageal cancer, gastric cancer, gastroesophageal cancer, head and neck cancer, lung cancer, melanoma, ovarian cancer, pancreatic cancer, renal cancer, and soft tissue sarcoma. In some embodiments, the combination therapy comprising an anti-ILT3 antibody described herein (e.g., BND-35) and an anti-PD-1 or anti-PD-Ll agent (e.g., avelumab) is used to treat a cancer selected from breast cancer, cholangiocarcinoma, adenocarcinoma or squamous cell carcinoma of the esophagus, gastric or gastroesophageal junction adenocarcinoma, squamous cell carcinoma of the head and neck, non- small cell lung cancer, melanoma, ovarian cancer, pancreatic adenocarcinoma, renal cell carcinoma, and soft tissue sarcomas. For example, the combination therapy may comprise BND-35 at a dose of 1, 3, 10, or 20 mg / kg per treatment cycle and avelumab at a dose of 800 mg per treatment cycle. In certain embodiments, each treatment cycle is about two to four weeks. In certain embodiments, each treatment cycle is about three weeks.

[0090] In some embodiments, the combination therapy comprising an anti-ILT3 antibody described herein (e.g., BND-35) and an anti-PD-1 or anti-PD-Ll agent (e.g., avelumab) is used to treat lung cancer, e.g., non-small cell lung cancer. For example, the combination therapy may comprise BND-35 at a dose of 1, 3, 10, or 20 mg / kg per treatment cycle and avelumab at a dose of 800 mg per treatment cycle. In certain embodiments, each treatment cycle is about two weeks. In certain embodiments, each treatment cycle is about three weeks. In certain embodiments, the combination therapy is second or third line therapy.

[0091] In some embodiments, the combination therapy comprising an anti-ILT3 antibody described herein (e.g., BND-35) and an anti-PD-1 or anti-PD-Ll agent (e.g., avelumab) isused to treat gastric cancer or gastroesophageal junction adenocarcinoma. For example, the combination therapy may comprise BND-35 at a dose of 1, 3, 10, or 20 mg / kg per treatment cycle and avelumab at a dose of 800 mg per treatment cycle. In certain embodiments, each treatment cycle is about three weeks. In certain embodiments, each treatment cycle is about two to four weeks. In certain embodiments, the combination therapy is third line or later therapy.

[0092] In some embodiments, the combination therapy comprising an anti-ILT3 antibody described herein (e.g., BND-35) and an anti-PD-1 or anti-PD-Ll agent (e.g., avelumab) is used to treat breast cancer or triple negative breast cancer. For example, the combination therapy may comprise BND-35 at a dose of 1, 3, 10, or 20 mg / kg per treatment cycle and avelumab at a dose of 800 mg per treatment cycle. In certain embodiments, each treatment cycle is about three weeks. In certain embodiments, each treatment cycle is about two to four weeks. In certain embodiments, the combination therapy is third line or later therapy.

[0093] Anti-ILT3 Antibody and Nivolumab / pembrolizumab

[0094] In some embodiments, the anti-ILT3 antibody described herein (e.g., BND-35) is administered in combination with an anti-PD-1 or anti-PD-Ll agent, e.g., an anti-PD-1 antibody such as nivolumab. In certain embodiments, the nivolumab is administered intravenously to the patient (such as through intravenous infusion drip over, for example, about 30 minutes), for example at a dose of 100, 150, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490 or 500 mg per treatment cycle. In particular embodiments, the nivolumab is administered intravenously to the patient at a dose of 240 mg per treatment cycle.

[0095] In some embodiments, the combination therapy comprising an anti-ILT3 antibody described herein (e.g., BND-35) and an anti-PD-1 or anti-PD-Ll agent (e.g., nivolumab) is used to treat a cancer selected from breast cancer, biliary tract cancer, esophageal cancer, gastric cancer, gastroesophageal cancer, head and neck cancer, lung cancer, melanoma, ovarian cancer, pancreatic cancer, renal cancer, and soft tissue sarcoma. In some embodiments, the combination therapy comprising an anti-ILT3 antibody described herein (e.g., BND-35) and an anti-PD-1 or anti-PD-Ll agent (e.g., nivolumab) is used to treat a cancer selected from breast cancer, cholangiocarcinoma, adenocarcinoma or squamous cell carcinoma of the esophagus, gastric or gastroesophageal junction adenocarcinoma, squamous cell carcinoma of the head and neck, non- small cell lung cancer, melanoma, ovarian cancer,pancreatic adenocarcinoma, renal cell carcinoma, and soft tissue sarcomas. For example, the combination therapy may comprise BND-35 at a dose of 1, 3, 10, or 20 mg / kg per treatment cycle and nivolumab at a dose of 240 mg per treatment cycle. In certain embodiments, each treatment cycle is about two to four weeks. In certain embodiments, each treatment cycle is about three weeks.

[0096] In some embodiments, the combination therapy comprising an anti-ILT3 antibody described herein (e.g., BND-35) and an anti-PD-1 or anti-PD-Ll agent (e.g., nivolumab) is used to treat lung cancer, e.g., non-small cell lung cancer. For example, the combination therapy may comprise BND-35 at a dose of 1, 3, 10, or 20 mg / kg per treatment cycle and pembrolizumab at a dose of 200 mg per treatment cycle. In certain embodiments, each treatment cycle is about two to four weeks. In certain embodiments, each treatment cycle is about three weeks. In certain embodiments, the combination therapy is second or third line therapy.

[0097] In some embodiments, the combination therapy comprising an anti-ILT3 antibody described herein (e.g., BND-35) and an anti-PD-1 or anti-PD-Ll agent (e.g., nivolumab) is used to treat gastric cancer or gastroesophageal junction adenocarcinoma. For example, the combination therapy may comprise BND-35 at a dose of 1, 3, 10, or 20 mg / kg per treatment cycle and pembrolizumab at a dose of 200 mg per treatment cycle. In certain embodiments, each treatment cycle is about three weeks. In certain embodiments, each treatment cycle is about two to four weeks. In certain embodiments, the combination therapy is third line or later therapy.

[0098] In some embodiments, the combination therapy comprising an anti-ILT3 antibody described herein (e.g., BND-35) and an anti-PD-1 or anti-PD-Ll agent (e.g., nivolumab) is used to treat breast cancer or triple negative breast cancer. For example, the combination therapy may comprise BND-35 at a dose of 1, 3, 10, or 20 mg / kg per treatment cycle and pembrolizumab at a dose of 800 mg per treatment cycle. In certain embodiments, each treatment cycle is about three weeks. In certain embodiments, each treatment cycle is about two to four weeks. In certain embodiments, the combination therapy is third line or later therapy.

[0099] Anti-ILT3 Antibody and Cetuximab

[0100] In some embodiments, the anti-ILT3 antibody described herein (e.g., BND-35) is administered in combination with an anti-EGFR agent, e.g., an anti-EGFR antibody such ascetuximab. In certain embodiments, the cetuximab is administered intravenously (such as through intravenous infusion drip, for example, over about 120 minutes) to the patient, e.g., at a dose of 400, 450, 500, 550, or 600 mg / m2 per treatment cycle. In particular embodiments, the cetuximab is administered intravenously to the patient at a dose of 500 mg / m2 per treatment cycle. Optionally, one or more administrations of cetuximab (e.g., all administrations) may be preceded by premedication with a histamine- 1 (Hl) receptor antagonist (and additionally or alternatively with acetaminophen / paracetamol and / or corticosteroids). Administration of the Hl receptor antagonist may be intravenous (such as through intravenous infusion drip, for example over about 30-60 minutes). In certain embodiments, the Hl receptor antagonist is diphenhydramine. The diphenhydramine may be administered at a dose of, e.g., 30, 40, or 50 mg per treatment cycle, and in particular embodiments is administered at a dose of 50 mg per treatment cycle.

[0101] In some embodiments, the combination therapy comprising an anti-ILT3 antibody described herein (e.g., BND-35) and an anti-EGFR agent (e.g., cetuximab) is administered in treatment cycles of about one, two, or three, weeks. In certain embodiments, each treatment cycle is about two to four weeks.

[0102] In some embodiments, the combination therapy comprising an anti-ILT3 antibody described herein (e.g., BND-35) and an anti-EGFR agent (e.g., cetuximab) is used to treat a cancer selected from breast cancer, colorectal cancer, head and neck cancer, non-small cell lung cancer, pancreatic cancer, renal cancer and soft tissue sarcoma. In some embodiments, the hepatobiliary cancer is hepatocellular carcinoma, gallbladder cancer, or cholangiocarcinoma. In some embodiments, the combination therapy comprising an anti- ILT3 antibody described herein (e.g., BND-35) and an anti-EGFR agent (e.g., cetuximab) is used to treat a cancer selected from breast cancer, K-Ras wild-type colorectal cancer, N-Ras wild-type colorectal cancer, BRAF-mutant colorectal cancer, squamous cell carcinoma of the head and neck, non-small cell lung cancer, pancreatic adenocarcinoma, renal cell carcinoma, and soft tissue sarcomas.

[0103] In some embodiments, the combination therapy comprising an anti-ILT3 antibody described herein (e.g., BND-35) and an anti-EGFR agent (e.g., cetuximab) is used to treat colorectal cancer. For example, the combination therapy may comprise BND-35 at a dose of 1, 3, 10, or 20 mg / kg per treatment cycle and cetuximab at a dose of 500 mg / m2 per treatment cycle. In certain embodiments, each treatment cycle is about two to four weeks. In certain embodiments, the combination therapy is third line or later therapy. Optionally, eachadministration of cetuximab may be preceded by premedication with diphenhydramine, e.g., at a dose of 50 mg per treatment cycle. In some embodiments, the colorectal cancer is selected from K-Ras wild-type colorectal cancer, N-Ras wild-type colorectal cancer, and BRAF- mutant colorectal cancer.

[0104] In some embodiments, the combination therapy comprising an anti-ILT3 antibody described herein (e.g., BND-35) and an anti-EGFR agent (e.g., cetuximab) is used to treat breast cancer or triple negative breast cancer. For example, the combination therapy may comprise BND-35 at a dose of 1, 3, 10, or 20 mg / kg per treatment cycle and cetuximab at a dose of 500 mg per treatment cycle. In certain embodiments, each treatment cycle is about three weeks. In certain embodiments, each treatment cycle is about two to four weeks. In certain embodiments, the combination therapy is third line or later therapy.

[0105] As used herein, the term “treatment cycle” refers to a period during which agents that comprise a therapeutic regimen are administered on proscribed days; the treatment cycle may be repeated on a regular schedule. For example, in a two-week treatment cycle of BND-35 monotherapy, BND-35 may be administered on day 1 of each cycle (e.g., every two weeks). For combination therapies described herein, the recited doses of the agents may be administered on the same day of the treatment cycle, on different days of the treatment cycle, or any combination thereof for more than two agents. For example, BND-35 may be administered on the same or different days of the treatment cycle from avelumab, nivolumab or cetuximab. In some embodiments, the agents are provided with every administration of BND-35. In some embodiments, the agents are provided with at most every administration of BND-35. In some embodiments, not every dose of BND-35 is coupled to a dose of the agents. That is avelumab, nivolumab or cetuximab may be administered with each BND-35 administration, but some administrations of BND-35 may be alone (e.g., avelumab, nivolumab or cetuximab every other cycle) or BND-35 and the agents may be administered alternately. In certain embodiments, the recited doses of the agents are all administered on the same day of the treatment cycle. In some embodiments, avelumab, nivolumab or cetuximab will be administered first, followed by BND-35. In certain embodiments, BND-35 administration starts at least about 30 minutes after completion of avelumab administration. In certain embodiments, BND-35 administration starts at least about 30 minutes after completion of nivolumab administration. In certain embodiments, BND-35 administration starts at least about 60 minutes after completion of cetuximab administration.

[0106] In certain embodiments, doses recited herein for any or all agents in the described therapies are single doses per treatment cycle.

[0107] In some embodiments (e.g., in the event of a noted or expected infusion reaction), intravenous infusion(s) in a treatment recited herein may be preceded by a prophylactic premedication. In certain embodiments, the premedication may be diphenhydramine (e.g., at a dose of about 50 mg) and / or acetaminophen / paracetamol (e.g., at a dose of about 325-1000 mg). In some embodiments, the premedication is administered at least about 15, 30, or 45 (e.g., at least about 30) minutes before subsequent treatment infusions. In some embodiments, infusion reactions may also be treated or prevented using corticosteroids (e.g., up to about 25 mg of hydrocortisone sodium succinate or equivalent).

[0108] The present therapies are contemplated to be efficacious in cancer patients. The therapies may, e.g., result in inhibition of tumor growth, tumor regression, slowing or reversal of metastasis, prolonged survival, prolonged progression-free survival, prevention of cancer recurrence or residual disease, alleviation of cancer symptoms, or any combination thereof. In some embodiments, the therapies increase immune activity in the patient. The increased immune activity may be demonstrated, e.g., by increased levels of CD62L on the surface of classical monocytes. CD62L, also known as L-selectin, is a cell adhesion molecule that plays a role in regulating the recruitment of monocytes to tissues from the blood during inflammation. Additionally, or alternatively, the increased immune activity may be demonstrated by increased levels of immune activation markers such as CD69 (e.g., on ILT3- expressing natural killer T cells) and CD107a (e.g., on ILT3-expressing CD8 T cells and natural killer cells).

[0109] In some embodiments, the present therapies increase expression of CD62L on classical monocytes in patients. In some embodiments, the present therapies increase the levels of cytokines such as CCL4, CXCL11, CCL23, granzyme B, TNFa, IFNy, GM-CSF, or any combination thereof, in patients. In some embodiments, the present therapies downregulate CCL7 in patients.

[0110] Any combination of the above effects is also contemplated.

[0111] Unless otherwise defined herein, scientific and technical terms used in connection with the present disclosure shall have the meanings that are commonly understood by those of ordinary skill in the art. Exemplary methods and materials are described below, although methods and materials similar or equivalent to those described herein can also be used in thepractice or testing of the present disclosure. In case of conflict, the present specification, including definitions, will control. Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular. Throughout this specification and embodiments, the words “have” and “comprise,” or variations such as “has,” “having,” “comprises,” or “comprising,” will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers. All publications and other references mentioned herein are incorporated by reference in their entirety. Although a number of documents are cited herein, this citation does not constitute an admission that any of these documents forms part of the common general knowledge in the art. As used herein, the term “approximately” or “about” as applied to one or more values of interest refers to a value that is similar to a stated reference value. In certain embodiments, the term refers to a range of values that fall within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in either direction (greater than or less than) of the stated reference value unless otherwise stated or otherwise evident from the context.

[0112] According to the present disclosure, back-references in the dependent claims are meant as short-hand writing for a direct and unambiguous disclosure of each and every combination of claims that is indicated by the back-reference. Any treatment method disclosed herein may be used to treat any individual as defined herein. Further, headers herein are created for ease of organization and are not intended to limit the scope of the claimed invention in any manner.

[0113] In order that this invention may be better understood, the following examples are set forth. These examples are for purposes of illustration only and are not to be construed as limiting the scope of the invention in any manner.EXAMPLESExample 1: Study of BND-35 Administered Alone and in Combination with Other Therapeutics in Participants with Advanced Solid Tumors

[0114] This Example outlines the protocol for an open-label, multicenter, Phase 1, first-in- human study of the safety, tolerability, and anti-tumor activity of intravenous BND-35, a humanized monoclonal IgG4 antibody targeting ILT3. The study evaluates BND-35, as a single agent and when combined with avelumab, nivolumab or with cetuximab, for treatment of cancer patients with advanced solid tumors where no other standard of care treatment option is available. Given the known mechanism of action of ILT3 and its potential role incancer, the study focuses on tumor types relevant to ILT3 blockade. Tumor types included in BND-35-cetuximab combination cohorts are tumors known to over-express the EGFR protein.Study Design

[0115] The proposed study is comprised of two parts - a dose escalation phase (Part 1) and a dose optimization phase (Part 2). Part 1 is comprised of three sub-parts: BND-35 administered as a monotherapy (Sub-Part 1A), BND-35 administered in combination with avelumab (Sub-Part IB), BND-35 administered in combination with cetuximab (Sub-Part 1C) and BND-35 administered in combination with nivolumab (Sub-Part ID). Part 2 is composed of two sub-parts: a dose optimization part where up to two doses of BND-35 per indication are administered in combination with avelumab (Sub-Part 2A), cetuximab (SubPart 2B) or nivolumab (Sub-Part 2C). The study design schematic is presented in Figure 1 and further detailed below.

[0116] The objectives for the dose escalation phase (Part 1) are to assess the safety and tolerability, and to determine the MTD (or MAAD, if no MTD is reached) and the recommended dose(s) of BND-35 when administered alone and in combination with avelumab, with nivolumab or with cetuximab. Dose escalation in all three sub-parts will follow a standard “3 + 3” design enrolling at least 3 participants per dose level cohort. The dose escalation phase of the study will enroll cancer patients with advanced disease who are refractory to or are not candidates for standard approved therapy.

[0117] Part 2, which includes at least four cohorts, is designed to assess preliminary antitumor activity and optimal dose of BND-35 in combination in cancer patients with select advanced solid tumors and a likelihood of sensitivity to immunotherapies as observed with other checkpoint inhibitors. It will enroll participants with unresectable or metastatic disease. The proposed study aims to establish proof-of-concept for BND-35 as a monotherapy or in combination with: 1) the anti-PDLl monoclonal antibody avelumab; 2) the anti-EGFR monoclonal antibody cetuximab; or 3) the anti-PDl monoclonal antibody nivolumab. Part 2 is divided into three sub-parts: in Sub-Part 2A / 2B / 2C (Dose Optimization), the preliminary anti-tumor activity and optimal dose of BND-35 is assessed in combination with the aforementioned anti-tumor agents.Objectives

[0118] The primary objectives of the dose escalation phase of this study (Part 1) are to assess the safety and tolerability of BND-35, the MTD or MAAD, and the recommendeddoses of BND-35 for optimization when administered alone or in combination with avelumab, nivolumab or with cetuximab.

[0119] The secondary objectives of the dose escalation phase of this study are:• To assess preliminary anti-tumor activity of BND-35 as a monotherapy and in combination with avelumab, nivolumab or with cetuximab;• To characterize the pharmacokinetics (PK) of BND-35 as a monotherapy and in combination with avelumab, nivolumab or with cetuximab; and• To characterize the immunogenicity of BND-35 as a monotherapy and in combination with avelumab, nivolumab or with cetuximab.

[0120] The exploratory objectives of the dose escalation phase of this study are:• To explore potential associations between BND-35 anti-tumor activity and select biomarker measures in the tumor and peripheral blood; and• To explore the associations between BND-35 serum PK, safety, efficacy, and clinical biomarkers.

[0121] The primary objectives of the dose optimization phase of this study (Part 2) are to assess the preliminary antitumor activity of BND-35 (alone or in combination with avelumab, nivolumab, or cetuximab), and to define the optimal dose of BND-35 in combination with avelumab, nivolumab, or cetuximab.

[0122] The secondary objectives of the dose expansion / optimization phase of this study are:• To assess additional parameters of anti-tumor activity of BND-35;• To further assess the safety and tolerability of BND-35;• To further characterize the PK of BND-35 and avelumab, nivolumab or cetuximab (in combination only for dose optimization / expansion); and• To further characterize the immunogenicity of BND-35.

[0123] The exploratory objectives of the dose expansion / optimization phase of this study are:• To explore the potential associations between BND-35 anti-tumor activity and select biomarker measures in the tumor and peripheral blood;• To explore the associations between BND-35 serum PK, safety, efficacy, and clinical biomarkers; and optionally• To explore the effect of BND-35 on patient-reported outcomes (PROs).EndpointsDose Escalation (Part 1)

[0124] The primary endpoints for the dose escalation phase of this study (Sub-Parts 1A / 1B / 1C) are to assess:1. Incidence of Serious Adverse Events (SAEs), incidence and severity of treatment- emergent AEs (TEAEs) coded to preferred term and system organ class using the Medical Dictionary for Regulatory Activities (MedDRA) and graded according to the CTCAE v5.0, and laboratory abnormalities classified by severity using CTCAE v5.0; and2. Incidence of TEAEs meeting protocol defined DLT criteria and the proportion of patients who discontinue the study due to TEAEs.

[0125] The secondary endpoints for the dose escalation phase are to assess:1. Objective Response Rate (ORR), defined as the proportion of participants with a best overall response of Complete Response (CR) or Partial Response (PR) per RECIST vl.l;2. PK parameters of BND-35 (Cmax, Ctrough or Ctau, Tmax, T1 / 2, AUC); and3. Incidence of anti-drug antibodies (ADA), including neutralizing ADA (nADA), to BND-35.

[0126] The exploratory endpoints for the dose escalation phase are to assess:1. Correlation / measure of BND-35 anti-tumor activity by pretreatment level of biomarkers of interest; correlation / measure of association of anti-tumor activity and change from baseline in biomarkers of interest; and2. Correlation / measure of the association between BND-35 serum PK, select outcomes, and biomarkers of interest.Dose Qptimization / Expansion (Part 2)

[0127] The primary endpoint for the dose optimization / expansion phase is to assess ORR per RECIST vl.l (other datapoints may be utilized to supplement assessment of optimal BND-35 dose).

[0128] The secondary endpoints for the dose optimization / expansion phase are to assess:1. progression-free survival (PFS) defined as the time from the date of first dose of study drug to the date of first documented disease progression or death due to any cause, whichever occurs first, to estimate median PFS using Kaplan-Meier (K-M) methodology; PFS rate at 3, 6, 9, 12 months, and up to 24 months per RECIST vl.l; Disease Control Rate (DCR, rate of CR, PR or Stable Disease (SD)); Duration of Response (DoR) defined as theduration between first documentation of CR or PR to first documentation of disease progression or death from any cause, whichever occurs first;2. Incidence of SAEs and TEAEs, as described above;3. PK parameters of BND-35 (C max? C trough or Ctau? Tmax, TI / 2, AUC); and4. Incidence of ADA, including nADA, to BND-35.

[0129] The exploratory endpoints for the dose optimization / expansion phase are to assess:1. Correlation / measure of BND-35 anti-tumor activity by pretreatment level of biomarkers of interest; correlation / measure of association of anti-tumor activity and change from baseline in biomarkers of interest; and2. Correlation / measure of the association between BND-35 serum PK, select outcomes, and biomarkers of interest.Study Population

[0130] Study participants are selected based on the following inclusion and exclusion criteria:Inclusion Criteria1) Type of Participant and Target Disease Characteristics a) Patients with unresectable or metastatic disease who are refractory to or are not candidates for standard approved therapy* b) Participants must have histologic confirmation of malignancy. c) Participants must have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) vl.l. d) All single agent dose escalation (Sub-Part 1A) participants treated at dose levels equal and greater than 1 mg / kg (>1 mg / kg) and all combination dose escalation (Sub-Parts 1B / 1C) and dose optimization / expansion phase (Part 2) participants must have at least one lesion accessible for biopsy. e) Eastern Cooperative Oncology Group Performance Status (ECOG) of 0 or 1. f) Estimated life expectancy of more than 3 months. g) Sub-Part 1A (BND-35 Monotherapy Dose Escalation) Tumor Types:(1) Breast cancer, cholangiocarcinoma, colorectal cancer, adenocarcinoma or squamous cell carcinoma of the esophagus, gastric or gastroesophageal junction adenocarcinoma, squamous cell carcinoma of the head and neck, non-small celllung cancer, melanoma, ovarian cancer, pancreatic adenocarcinoma, renal cell carcinoma, or soft tissue sarcomas. h) Sub-Part IB (BND-35 in Combination with Avelumab Dose Escalation) Tumor Types:(1) Triple negative breast cancer (PD-L1 combined positive score (CPS) of 10 or higher), gastric or gastroesophageal junction adenocarcinoma (PD-L1 CPS score of 1 or higher), non- small cell lung cancer, renal cell carcinoma, or urothelial carcinoma.(2) Patients with prior exposure to immune checkpoint inhibitors (including avelumab) are allowed to enroll. i) Sub-Part 1C (BND-35 in Combination with Cetuximab Dose Escalation) Tumor Types:(1) Breast cancer, Ras wild-type colorectal cancer (right and leftsided tumors), squamous cell carcinoma of the head and neck, non-small cell lung cancer or soft tissue sarcomas.(2) Participants with prior exposure to EGFR inhibitors (including cetuximab) are allowed to enroll. j) Sub-Part ID (BND-35 in Combination with Nivolumab Dose Escalation) Tumor Types:(1) Breast cancer, cholangiocarcinoma, colorectal cancer, adenocarcinoma or squamous cell carcinoma of the esophagus, gastric or gastroesophageal junction adenocarcinoma, squamous cell carcinoma of the head and neck, non-small cell lung cancer, melanoma, ovarian cancer, pancreatic adenocarcinoma, renal cell carcinoma, or soft tissue sarcomas. k) Part 2A (BND-35 in Combination with Avalumab Dose Optimization) Tumor Types:(1) Upon SRC decision l) Part 2B (BND-35 in Combination with Cetuximab Dose Optimization) Tumor Types:(1) Upon SRC decision m) Part 2C (BND-35 in Combination with Nivolumab Dose Optimization) Tumor Types:(1) Upon SRC decision2) Physical and Laboratory Findings a) Participants must have adequate organ function as defined by the following: i) Lymphocyte count > 500 / mm3ii) Neutrophil count > 1, 500 / mm3iii) Platelet count > 100, 000 / mm3iv) Hemoglobin concentration > 9.0g / dL v) AST and ALT < 3.0 x ULN or < 5.0 x ULN in patients with hepatocellular carcinoma or if liver metastases are present vi) Total bilirubin < 1.5 x ULN (except participants with Gilbert Syndrome who must have a total bilirubin level of < 3.0 x ULN) vii) Creatinine clearance (observed or estimated using the Cockcroft- Gault equation) > 45 mL / min3) All single-agent dose escalation (Sub-Part 1A) patients treated at BND-35 dose levels equal and greater than 1 mg / kg (>1 mg / kg) and all combination dose escalation (Sub-Part 1B / 1C) and dose optimization phase (Part 2) patients have provided an evaluable tumor tissue sample during the screening period. The tumor tissue sample may be fresh or archival if obtained within 3 months prior to enrollment.4) Age and Reproductive Status a) Males and Females, at least 18 years old. b) Women of childbearing potential (WOCBP) must have a negative serum within 72 hours prior to the start of study treatment. c) Women must not be breastfeeding. d) Women of childbearing potential (WOCBP) must agree to follow instructions for method(s) of contraception for the duration of treatment with study treatment and 10 months duration after last dose of study drug. e) WOCBP who are continuously not heterosexually active are exempt from contraceptive requirements, but still must undergo pregnancy testing as described in this section. f) Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with study treatment and 7 months duration after the last dose of study drug. In addition, male participants must be willing to refrain from sperm donation during this time.Exclusion Criteria

[0131] Exclusionary criteria for participants include the following:1) Medical Conditions a) Active, known or suspected autoimmune disease within the last 5 years. Participants with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll. b) Condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of start of study treatment. Inhaled or topical steroids, and adrenal replacement steroid doses < 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease. c) History or clinical evidence of CNS primary tumors or metastases including leptomeningeal metastases unless they have been previously treated, are asymptomatic, and have had no requirement for steroids or enzymeinducing anticonvulsants in the last 14 days before screening. d) Known history of positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS). e) Acute or chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. f) Prior second non-hematological malignancy active within the previous 3 years except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast. g) Prior hematological malignancy active within the previous 5 years. h) Participants after solid organ or allogeneic hematopoietic stem cell transplant. i) History of life-threatening toxicity related to prior immune therapy (e.g., anti-CTLA-4 or anti-PD-l / PD-Ll treatment or any other antibody or drug specifically targeting co- stimulation of immune cells or immune checkpoint pathways) except those that are unlikely to re-occur with standard countermeasures (e.g., hormone replacement after adrenal crisis). j) History of Grade 3 or 4 infusion reaction, Grade 3 or 4 neurologicaltoxicity, Grade 2, 3 or 4 myocarditis, Grade 4 nephritis, AST or ALT increases to more than 8 times ULN or total bilirubin increases to more than 3 times ULN, or Grade 4 colitis related to prior avelumab / nivolumab or other anti- PD(L)-1 antibodies (for Sub-Part IB and ID). k) History of life-threatening toxicity, Grade 3 or 4 infusion reaction, or three or more occurrences of Grade 3 or 4 dermatologic toxicity related to prior cetuximab or other anti-EGFR antibodies (for Sub-Part 1C and 2B). l) History of clinically significant hypomagnesemia, hypocalcemia, or hypokalemia related to prior cetuximab or other anti-EGFR antibodies (for SubPart 1C and 2B). m) History of Grade 2 or higher pneumonitis or interstitial lung disease. n) Unstable or deteriorating cardiovascular disease within the previous 6 months prior to screening including but not limited to the following:Unstable angina or myocardial infarction; i) Transient ischemic attack (TIA) / cerebrovascular accident (CVA); ii) Congestive heart failure (New York Heart Association [NYHA] Class III or IV); iii) Uncontrolled clinically significant arrhythmias or arrhythmias requiring medication for rate control. iv) Uncontrolled or poorly controlled hypertension (>180 mmHg systolic or > 130 mmHg diastolic). o) Any major surgery within 4 weeks of study drug administration.Participants must have recovered from the effects of major surgery at least 14 days before the first dose of the study drug. p) Any condition (including medical, emotional, psychiatric, or logistical) that, in the opinion of the Investigator, would preclude the participant from adhering to the protocol or would increase the risk associated with study participation or study drug administration or interfere with the interpretation of study results.2) Prior / Concomitant Therapy a) Immunosuppressive agents or immunosuppressive doses of systemic corticosteroids (except as permitted in the study protocol). b) Cytotoxic anti-cancer agents, unless at least 4 weeks have elapsed from last dose of prior anti-cancer therapy and initiation of study therapy. c) Non-cytotoxic anti-cancer agents, unless at least 4 weeks or 5 half-lives (whichever is shorter) have elapsed from the last dose of prior anti-cancer therapy and the initiation of study therapy. d) Use of other investigational drugs (drugs not marketed for any indication) within 28 days before first study drug administration. e) Prior immune therapy treatments (for example, but not limited to: anti- CTLA4, anti-PD-Ll, anti-PD-L2, anti-PD-1, IL-2), unless at least 4 weeks or 5 half-lives (whichever is shorter) have elapsed from the last dose of immune therapy and initiation of study therapy. f) Prior treatment with ILT3 -targeting agents. g) Inability to comply with restrictions and prohibited treatments. h) Treatment with botanical preparations (e.g. herbal supplements or traditional Chinese medicines) intended for general health support or to treat the disease under study within 2 weeks prior to study drug administration. i) Administration of a live attenuated vaccine within 28 days prior to the first dose of study therapy.3) Allergies and Adverse Drug Reaction a) History of allergy or hypersensitivity to study drug components. b) History of any clinically significant drug allergy (such as anaphylaxis, hepatotoxicity, or hypersensitivity reactions) to other monoclonal antibodies or biological therapy. c) History of allergic reactions attributed to compounds of chemical or biologic composition similar to those of cetuximab, or if the participant had red meat allergy / tick bite history (Sub -Part 1C and 2B).Study Interventions AdministeredDose Escalation Phase (Part 1)

[0132] BND-35 Monotherapy Dose Escalation (Sub-Part 1A): BND-35 will be administered to participants in escalating doses. Each participant will be administered BND- 35 in two-week intervals at one of the following planned dose levels: 0.3 mg / kg, 1 mg / kg, 3 mg / kg, 10 mg / kg, or 20 mg / kg.

[0133] BND-35 Combination with Avelumab Dose Escalation (Sub-Part IB): BND-35 will be administered in escalating doses in combination with avelumab. The starting dose of BND-35 in Sub-Part IB will be 1 mg / kg or one dose level below the established BND-35 monotherapy MTD, the lower of the two. The dose of BND-35 will be escalated up to BND-35 monotherapy MTD (or MAAD, if no MTD is reached) following the same escalation scheme of Sub-Part 1A. All participants will receive avelumab at a dose of 800 mg. Treatment will be administered in two-week intervals.

[0134] All patients administered with avelumab will be premedicated with an antihistamine and with acetaminophen prior to the first 4 avelumab infusions. Premedication should be administered for subsequent avelumab doses based upon clinical judgement and presence / severity of prior infusion reactions.

[0135] BND-35 Combination with Cetuximab Dose Escalation (Sub-Part 1C): BND-35 will be administered in escalating doses in combination with cetuximab. The starting dose of BND-35 in Sub-Part 1C will be Img / kg or one dose level below the established BND-35 monotherapy MTD, the lower of the two. The dose of BND-35 will be escalated up to BND- 35 monotherapy MTD (or MAAD, if no MTD is reached) following the same escalation scheme of Sub-Part 1A. All participants will receive cetuximab at a dose of 500 mg / m2.Treatment will be administered in two-week intervals. Premedication with a histamine- 1 (Hl) receptor antagonist will be given prior to each cetuximab dosing.

[0136] BND-35 Combination with Nivolumab Dose Escalation (Sub-Part ID): BND-35 will be administered in escalating doses in combination with nivolumab. The starting dose of BND-35 in Sub-Part IB will be 1 mg / kg or one dose level below the established BND-35 monotherapy MTD, the lower of the two. The dose of BND-35 will be escalated up to BND- 35 monotherapy MTD (or MAAD, if no MTD is reached) following the same escalation scheme of Sub-Part 1A. All participants will receive nivolumab at a dose of 240 mg.Treatment will be administered in two-week intervals.Dose Expansion / Qptimization Phase (Part 2)

[0137] BND-35 Combination Dose Optimization (Sub-Part 2A): BND-35 will be administered in combination with the anti-PDLl monoclonal antibody avelumab at a dose of 800 mg. The dose level of BND-35 in Sub-Part 2A will be determined based on data from each sub-part of the dose escalation phase.

[0138] BND-35 Combination Dose Expansion (Sub-Part 2B): BND-35 will be administered in combination with the anti-EGFR monoclonal antibody cetuximab at a dose of 500 mg / m2. The dose level of BND-35 in Sub-Part 2B will be determined based on data from the dose escalation phase.

[0139] BND-35 Combination Dose Optimization (Sub-Part 2C): BND-35 will be administered in combination with the anti-PDl monoclonal antibody nivolumab at a dose of240 mg. The dose level of BND-35 in Sub-Part 2A will be determined based on data from each sub-part of the dose escalation phase.

[0140] Study treatments and modes of administration are summarized in Table 1 below:Table 1. Study Treatments*Intermediate doses may be includedBND-35 Treatment

[0141] The actual BND-35 dose to be administered to each patient will be determined by the patient’s weight in kilograms, which will be determined on the day of each BND-35 dosing. If the patient’s weight is within 10% of the Cycle 1 Day 1 weight, study drug doses do not need to be recalculated depending on institutional guidelines / preference.

[0142] BND-35 is to be administered as an IV infusion, with a 0.2-micron pore size, low- protein binding in-line filter at the protocol- specified doses. BND-35 will be infused over 60 (± 10) minutes at all dosage levels. For all study patients, infusions will require a 60-minute observation period following the completion of the infusion of the first two doses and a 30- minute observation period following the completion of all subsequent doses. Vital signs aremeasured during infusions. BND-35 is not to be administered as an IV push or bolus injection.

[0143] BND-35 infusions must be promptly followed by a flush of diluent to clear the line. Care must be taken to assure sterility of the prepared solution as the product does not contain any antimicrobial preservative or bacteriostatic agent.

[0144] Patients may be dosed within a ±2-day window, except Cycle 1 in the Dose Escalation phase during which any changes in timing of visits require Sponsor approval. In combination cohorts, both study drugs should be administered on the same day. In combination cohorts drug administration visits, avelumab, nivolumab or cetuximab will be infused first, followed by BND-35. The BND-35 infusion will start at least 30 minutes after completion of the avelumab infusion, at least 30 minutes after completion of the nivolumab infusion and at least 60 minutes after the cetuximab infusion.

[0145] Premedication is not recommended for BND-35. Patients should be carefully monitored for infusion reactions during BND-35 administration. If an acute infusion reaction is noted, patients should be managed as is standard for such reactions.

[0146] Doses of BND-35 may be interrupted, delayed, or discontinued depending on how well the patient tolerates the treatment. Dosing visits are not skipped, only delayed. In the case that an infusion cannot be administered at a scheduled visit, it should be administered as soon as possible.Avelumab Treatment

[0147] Avelumab will be administered according to its recommended dosage and administration as described in its Prescribing Information.

[0148] All patients should receive avelumab at a dose of 800 mg every two weeks. Avelumab should be infused intravenously over 30 (± 5) minutes through an intravenous line containing a sterile, non-pyrogenic, low-protein binding 0.2 micron to 1.2 micron in-line or add-on filter. Other drugs should not be co-administered through the same infusion line. Avelumab must not be administered as an intravenous push or bolus injection. In combination cohort drug administration visits, avelumab will be infused first, followed by BND-35. Vital signs will be measured during infusions.

[0149] Premedication with a histamine-1 (Hi) receptor antagonist and with acetaminophen will be given prior to the first 4 avelumab infusions. Premedication should be administered for subsequent avelumab doses based upon clinical judgement and presence / severity of prior infusion reactions.

[0150] No escalations or reductions of avelumab dose are allowed. Patients may be dosed within a ±2-day window, except Cycle 1 in the Dose Escalation phase during which any changes in timing of visits require Sponsor approval. Doses of avelumab may be interrupted, delayed, or discontinued depending on how well the patient tolerates the treatment. Dosing visits are not skipped, only delayed. In the case that an infusion cannot be administered at a scheduled visit, it should be administered as soon as possible.

[0151] Care must be taken to assure sterility of the prepared solution as avelumab does not contain any preservative.Nivolumab Treatment

[0152] Nivolumab will be administered according to its recommended dosage and administration as described in its Prescribing Information.

[0153] All patients should receive nivolumab at a dose of 240 mg every two weeks.Nivolumab should be infused intravenously over 30 (± 5) minutes through an intravenous line containing a sterile, non-pyrogenic, low-protein binding 0.2 micron to 1.2 micron in-line or add-on filter. Other drugs should not be co-administered through the same infusion line. Nivolumab must not be administered as an intravenous push or bolus injection. In combination cohort drug administration visits, nivolumab will be infused first, followed by BND-35. Vital signs will be measured during infusions.

[0154] Premedications are not recommended for the first dose of nivolumab. Patients should be carefully monitored for infusion reactions during nivolumab administration. If an acute infusion reaction is noted, patients should be managed as is standard for such reactions.

[0155] No escalations or reductions of nivolumab dose are allowed. Patients may be dosed within a ±2-day window, except Cycle 1 in the Dose Escalation phase during which any changes in timing of visits require Sponsor approval. Doses of nivolumab may be interrupted, delayed, or discontinued depending on how well the patient tolerates the treatment. Dosing visits are not skipped, only delayed. In the case that an infusion cannot be administered at a scheduled visit, it should be administered as soon as possible.

[0156] Care must be taken to assure sterility of the prepared solution as nivolumab does not contain any preservative.Cetuximab Treatment

[0157] Cetuximab will be administered according to its recommended dosage and administration as described in its Prescribing Information.

[0158] All patients should receive cetuximab at a dose of 500 mg / m2 every two weeks. Cetuximab should be infused intravenously over 120 (-5, +30) minutes through a low protein binding 0.22-micrometer in-line filter. Cetuximab must not be administered as an intravenous push or bolus injection and the infusion rate should not exceed 10 mg / min. A separate infusion line must be used for the infusion, and the line must be flushed with sterile sodium chloride 0.9% solution for injection at the end of infusion. In combination cohort drug administration visits, cetuximab will be infused first, followed by BND-35. Vital signs are measured during infusions.

[0159] All patients administered cetuximab will be premedicated with a histamine- 1 (Hl) receptor antagonist intravenously (e.g., diphenhydramine 50 mg) 30-60 minutes prior to each cetuximab dosing. Use of other premedication protocols is allowed after discussion with the Medical Monitor. Patients should be carefully monitored for infusion reactions during cetuximab administration.

[0160] Cetuximab dosage may be modified for adverse reactions management. Patients may be dosed within a +2-day window (except Cycle 1 in the Dose Escalation phase during which any changes in timing of visits require Sponsor approval). Doses of cetuximab may be interrupted, delayed, or discontinued depending on how well the patient tolerates the treatment. Dosing visits are not skipped, only delayed. In the case that an infusion cannot be administered at a scheduled visit, it should be administered as soon as possible. See Section 9.2 for details on cetuximab dose delays due to toxicity.

[0161] Care must be taken to assure sterility of the prepared solution as cetuximab does not contain any antimicrobial preservative or bacteriostatic agent.

[0162] Patients administered cetuximab should be instructed to limit sun exposure during treatment and for 2 months after the last dose of cetuximab. Prophylactic use of oral tetracyclines, topical corticosteroids and moisturizers should be considered for prevention of dermatological toxicity.

[0163] Patients presenting with signs and symptoms suggestive of keratitis such as acute or worsening eye inflammation, lacrimation, light sensitivity, blurred vision, eye pain and / or red eye should be referred promptly to an ophthalmologist.

Claims

CLAIMS1. A method of treating cancer in a human patient in need thereof, comprising administering to the patient a humanized monoclonal anti-human ILT3 IgG4 antibody whose heavy chain CDR1-3 and light chain CDR1-3 comprise SEQ ID NOs: 1-6, respectively, in two or more treatment cycles, wherein each treatment cycle comprises a single dose of the anti-ILT3 antibody at 0.3-20 mg / kg per dose.

2. The method of claim 1, wherein the dose is 0.3, 1, 3, 10, or 20 mg / kg.

3. The method of claim 1 or 2, wherein each treatment cycle is at most every 4 weeks.

4. The method of any one of claims 1-3, wherein the antibody comprises a heavy chain variable domain and a light chain variable domain comprising SEQ ID NOs: 7 and 8, respectively.

5. The method of claim 4, wherein the antibody comprises a heavy chain comprising SEQ ID NO: 9, or SED ID NO: 9 without the C-terminal lysine; and a light chain comprising SEQ ID NO: 10.

6. The method of any one of claims 1-5, wherein the cancer is selected from the group consisting of breast cancer, biliary tract cancer, colorectal cancer, esophageal cancer, gastric cancer, gastroesophageal junction cancer, hepatobiliary cancer, head and neck cancer, lung cancer, renal cancer, skin cancer, ovarian cancer, pancreatic cancer, and soft tissue sarcoma.

7. The method of claim 6, wherein the cancer is selected from breast cancer, cholangiocarcinoma, colorectal cancer, K-Ras wild-type colorectal cancer, N-Ras wild-type colorectal cancer, BRAF-mutant colorectal cancer, adenocarcinoma or squamous cell carcinoma of the esophagus, gastric or gastroesophageal junction adenocarcinoma, squamous cell carcinoma of the head and neck, non-small cell lung cancer, melanoma, ovarian cancer, pancreatic adenocarcinoma, renal cell carcinoma, and soft tissue sarcomas.

8. The method of any one of claims 1-7, wherein the antibody is administered at a firstdose and a second dose, wherein a) the first dose is higher than the second dose, or b) the second dose is higher than the first dose.

9. The method of claim 8, wherein: the first dose is 20 mg / kg, and the second dose is 1 mg / kg; the first dose is 10 mg / kg, and the second dose is 1 mg / kg; the first dose is 3 mg / kg, and the second dose is 1 mg / kg; the first dose is 1 mg / kg, and the second dose is 0.3 mg / kg; or the first dose is 0.3 mg / kg, and the second dose is 0.1 mg / kg.

10. The method of any one of claims 1-9, wherein the antibody is administered to the patient by intravenous infusion.

11. The method of any one of claims 1-10, further comprising administering a single dose of avelumab to the patient in each treatment cycle.

12. The method of claim 11, wherein the avelumab is administered intravenously at 800 mg per dose.

13. The method of any one of claims 1-10, further comprising administering a single dose of cetuximab to the patient in each treatment cycle.

14. The method of claim 13, wherein the cetuximab is administered intravenously at 500 mg / m2per dose.

15. The method of any one of claims 11 to 14, wherein the patient is premedicated with a histamine- 1 (Hi) receptor antagonist before each administration of cetuximab.

16. The method of claim 15, wherein the Hi receptor antagonist is diphenhydramine, optionally administered at a dose of 50 mg.

17. The method of any one of claims 11-16, wherein each treatment cycle is about two orthree weeks.

18. The method of any one of claims 1-17, wherein said treatment is first line therapy.

19. The method of any one of claims 1-17, wherein said treatment is second line therapy.

20. The method of any one of claims 1-17, wherein said treatment is third line or later therapy.

21. A method of treating breast cancer, biliary tract cancer, colorectal cancer, esophageal cancer, gastric cancer, gastroesophageal junction cancer, hepatobiliary cancer, head and neck cancer, lung cancer, renal cancer, skin cancer, ovarian cancer, pancreatic cancer, or soft tissue sarcoma in a human patient in need thereof, comprising administering to the patient by intravenous infusion a humanized monoclonal anti-human ILT3 antibody that comprises a heavy chain and a light chain having the amino acid sequences of SEQ ID NOs: 9 and 10, respectively, in two or more treatment cycles, wherein each treatment cycle comprises a single dose of the anti-ILT3 antibody at 0.1, 0.3, 1, 3, 10 or 20 mg / kg per dose, wherein each treatment cycle is about two to four weeks.

22. A method of treating breast cancer, biliary tract cancer, esophageal cancer, gastric cancer, gastroesophageal junction cancer, hepatobiliary cancer, head and neck cancer, lung cancer, renal cancer, skin cancer, ovarian cancer, pancreatic cancer, or soft tissue sarcoma in a human patient in need thereof, comprising intravenously administering to the patient a) a humanized monoclonal anti-human ILT3 antibody that comprises a heavy chain and a light chain having the amino acid sequences of SEQ ID NOs: 9 and 10, respectively, and b) avelumab, in two or more treatment cycles, wherein each treatment cycle comprises a single dose of the anti-ILT3 antibody at 0.3, 1, 3, 10 or 20 mg / kg per dose, and a single 800 mg dose of avelumab, wherein each treatment cycle is about three weeks.

23. The method of claim 22, wherein the patient is premedicated with diphenhydramine before each administration of avelumab, optionally wherein the diphenhydramine is administered at a dose of 50 mg.

24. A method of treating breast cancer, colorectal cancer, head and neck cancer, lung cancer, pancreatic cancer, renal cancer or soft tissue sarcoma in a human patient in need thereof, comprising intravenously administering to the patient a) a humanized monoclonal anti-human ILT3 antibody that comprises a heavy chain and a light chain having the amino acid sequences of SEQ ID NOs: 9 and 10, respectively, and b) cetuximab, in two or more treatment cycles, wherein each treatment cycle comprises a single dose of the anti-ILT3 antibody at 0.3, 1, 3, 10 or 20 mg / kg per dose, and a single 500 mg / m2dose of cetuximab, wherein each treatment cycle is about two to four weeks.

25. The method of claim 24, wherein the patient is premedicated with diphenhydramine before each administration of cetuximab, optionally wherein the diphenhydramine is administered at a dose of 50 mg.

26. The method of any one of claims 21-25, wherein the humanized monoclonal antihuman ILT3 antibody is administered at a first dose and a second dose, optionally wherein the first dose is lower than the second dose.

27. A method of treating cancer in a human patient in need thereof, comprising administering to the patient by intravenous infusion a humanized monoclonal anti-human ILT3 antibody that comprises a heavy chain and a light chain having the amino acid sequences of SEQ ID NOs: 9 and 10, respectively, in two or more treatment cycles, wherein each treatment cycle comprises a single dose of the anti-ILT3 antibody at 0.3, 1, 3, 10 or 20 mg / kg per dose, wherein the cancer is breast cancer, cholangiocarcinoma, colorectal cancer, adenocarcinoma or squamous cell carcinoma of the esophagus, gastric or gastroesophageal junction adenocarcinoma, squamous cell carcinoma of the head and neck, non-small cell lung cancer, melanoma, ovarian cancer, pancreatic adenocarcinoma, renal cell carcinoma, or soft tissue sarcomas, wherein each treatment cycle is about two to four weeks.

28. A method of treating non-small cell lung cancer in a human patient in need thereof, comprising intravenously administering to the patienta) a humanized monoclonal anti-human ILT3 antibody that comprises a heavy chain and a light chain having the amino acid sequences of SEQ ID NOs: 9 and 10, respectively, and b) avelumab, in two or more treatment cycles, wherein each treatment cycle comprises a single dose of the anti-ILT3 antibody at 1, 3, 10 or 20 mg / kg per dose, and a single 800 mg dose of avelumab, wherein each treatment cycle is about three weeks, and optionally wherein the treatment is second or third line therapy.

29. A method of treating gastric cancer or gastroesophageal junction adenocarcinoma in a human patient in need thereof, comprising intravenously administering to the patient a) a humanized monoclonal anti-human ILT3 antibody that comprises a heavy chain and a light chain having the amino acid sequences of SEQ ID NOs: 9 and 10, respectively, and b) avelumab, in two or more treatment cycles, wherein each treatment cycle comprises a single dose of the anti-ILT3 antibody at 1, 3, 10 or 20 mg / kg per dose, and a single 800 mg dose of avelumab, wherein each treatment cycle is about three weeks, and optionally wherein the treatment is third line or later therapy.

30. A method of treating triple negative breast cancer in a human patient in need thereof, comprising intravenously administering to the patient a) a humanized monoclonal anti-human ILT3 antibody that comprises a heavy chain and a light chain having the amino acid sequences of SEQ ID NOs: 9 and 10, respectively, and b) avelumab, in two or more treatment cycles, wherein each treatment cycle comprises a single dose of the anti-ILT3 antibody at 1, 3, 10 or 20 mg / kg per dose, and a single 800 mg dose of avelumab, wherein each treatment cycle is about three weeks, and optionally wherein the treatment is second or third line therapy.

31. A method of treating colorectal cancer in a human patient in need thereof, comprising intravenously administering to the patient a) a humanized monoclonal anti-human ILT3 antibody that comprises a heavy chain and a light chain having the amino acid sequences of SEQ ID NOs: 9 and 10, respectively, and b) cetuximab, in two or more treatment cycles, wherein each treatment cycle comprises a single dose of the anti-ILT3 antibody at 1, 3, 10 or 20 mg / kg per dose, and a single 500 mg / m2dose of cetuximab, wherein each treatment cycle is about two to four weeks, and optionally wherein the treatment is third line or later therapy.

32. The method of claim 31, wherein the patient is pretreated with diphenhydramine at a dose of 50 mg before each administration of cetuximab.

33. The method of any one of claims 1-32, wherein a) the cancer is unresectable; b) the cancer is metastatic; c) the patient is refractory to standard approved therapy; d) the patient is not a candidate for standard approved therapy; or e) any combination of a)-d).

34. Use of a humanized monoclonal anti-human ILT3 IgG4 antibody for treating cancer in a patient by a method of any one of claims 1-33.

35. A humanized monoclonal anti-human ILT3 IgG4 antibody for use in treating cancer in a patient by a method of any one of claims 1-33.

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