Cancer treatment methods

Abstract

The disclosure relates to methods for treating cancer with LILRB2 antibody products.

Description

CANCER TREATMENT METHODSCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of US provisional application No. 63 / 715,492 filed November 1, 2024 and US provisional application No. 63 / 807,369 filed May 16, 2025. These applications are incorporated herein by reference in their entirety.INCORPORATION BY REFERENCE OF THE SEQUENCE LISTING

[0002] This application contains, as a separate part of disclosure, a Sequence Listing in computer-readable form (Filename: 70815P2_Seqlisting. XML; 15,044 bytes dated October 30, 2025) which is incorporated by reference herein in its entirety.FIELD

[0003] The disclosure relates to treating cancer with LILRB2 antibody products.BACKGROUND

[0004] Cancer is characterized by the accumulation of growth-modifying genetic alterations, along with the ability to evade detection or elimination by the immune system. Cancer immunotherapy allows one to overcome this immune tolerance, leading to immune recognition and anti-tumor responses. However, tumors typically use multiple mechanisms to mediate immune evasion, such as reduction or loss of tumor antigenicity, immune evasion, or the presence of suppressive cellular or molecular factors in the tumor microenvironment (TME) that inhibit the killing of cancer cells by CD8+T cells.

[0005] The recent development of antibodies that target immune checkpoints has transformed the way malignant solid tumors are treated and has provided hope that even subjects with advanced disease may achieve a cure or long-term remission. Checkpoint inhibitor (CPI) antibodies targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1) have now established clear efficacy for first-line treatment of metastatic disease in numerous tumor types, including lung cancer (Reck eta / ., 2021, J Thorac Oncol, 16: 665-76), melanoma (Hodi et a!., 2018, Lancet Oncol, 19: 1480-92), head and neck cancer (Burtness, eta / ., 2019, Lancet, 394: 1915-28), and others (Vaddepally eta / ., 2022, Biomedicines, 10).

[0006] Despite this success, most subjects treated with these CPIs will either not respond or will ultimately progress or relapse (de Miguel and Calvo, 2020, Cancer Cell, 38: 326-33; Joshi etai., 2016, din Endocrinol (Oxf), 85: 331-9). Even in tumors considered sensitive to CPIs, or when combining anti-CTLA-4 and anti-PD-1 immunotherapies, approximately 50%of patients do not experience tumor shrinkage. In addition, the median treatment duration or progression-free survival (PFS) for all CPI treated patients remains relatively short, approximately 2 to 5 months (Kazandjian eta / ., 2016, Oncologist, 21: 634-42). Moreover, several of the most prevalent solid tumors, and the majority of hematological malignancies, have shown disappointing results with CPIs. In particular, hormone-receptor-positive breast cancer, some colorectal cancers, and prostate cancer are less responsive to this type of immune manipulation (Dirix etai., 2018, Breast Cancer Res Treat, 167: 671-86; Graff etai., 2016, Oncotarget, 7: 52810-17; Le, et al., 2015, N Eng I J Med, 372: 2509-20; Topalian et al., 2012, N Engl J Med, 366: 2443-54).

[0007] The failure of CPIs to treat certain tumors is in part due to immune evasion by the tumor. Several factors inhibit or limit the activity of antibodies targeted to checkpoints on T cells, including lack of inflammatory infiltrate (so-called "cold tumors") and factors in the tumor microenvironment (TME) that suppress T-cell activity despite release from checkpoint inhibition. Given the near-ubiquitous use of CPIs in modern oncology therapy, potentiation of their activity and broadening the scope of tumors in which they are active is a critical component of improving outcomes for patients with metastatic solid tumors.

[0008] Tumor-associated macrophages (TAMs) are important components of the TME and inhibit anti-tumor responses by several mechanisms (Mantovani, eta / ., 2011, Nat Rev Immunol, 11: 519-31; Cassetta and Pollard, 2018, Nat Rev Drug Discov, 17: 887-904;Garvin, eta / ., 2018, J Cancer Res Cl in Oncol, 144: 1253-63; Chen, eta / ., J Biomed Sci, 26: 78; Mantovani, etai., 2022, Nat Rev Drug Discov, 21: 799-820). They directly inhibit T-cell activation by engaging immune checkpoints, producing immunosuppressive cytokines e.g., interleukin (IL)-10 and transforming growth factor beta [TGF[3]), and promoting T-cell skewing toward a pro-cancer Th2 phenotype. High levels of tumor infiltration by TAMs generally predict an unfavorable prognosis in patients with solid tumors (Chen, etai., 2018, J din Invest, 128: 5647-62). Relieving the immunosuppression of TAMs in the TME to improve T-cell-mediated responses is a rational adjunct to CPI therapy.

[0009] Leukocyte immunoglobulin-like receptor B2 (LILRB2, also known as ILT4, LIR2, MIR-10, CD85d) is an ITIM containing immunosuppressive member of the leukocyte immunoglobulin-like receptor family that is expressed on cells of the myeloid lineage (monocytes, macrophages, dendritic cells, and granulocytes) but not on lymphocytes. In the TME, LILRB2 is found on myeloid-derived suppressor cells (MDSCs) and tumor-supporting tumor-associated macrophages (TAMs). LILRB2 appears to have a dual role in cancer biology, as an immune checkpoint on myeloid cells and as a tumor-supporting factor whenexpressed on tumor cells. Trans or cis interactions of LILRB2 with its ligands mediate immune suppression by myeloid cells and promote tumor immune evasion in the TME. Such ligands include human leukocyte antigen G (HLA-G), a nonclassical MHC class I molecule, as well as the classical HLA class I molecules HLA-A and HLA-B. In addition, ANGPTL2 and ANGPTL5 promote lung cancer development and survival via tumor-expressed LILRB2 by SHP1 signaling LILRB2 expression on myeloid cells in the TME or HLA-G expression by tumors correlates with poor survival in multiple cancers.

[0010] Recent data indicate that LILRB2 blockade in combination with a cytokine e.g., IL-4, IL-10) or an innate signal of differentiation / polarization promotes the development of anti-tumoral myeloid cells in vitro. In addition, combination of an anti-LILRB2 antibody with anti PD-1 treatment enhanced the tumor growth inhibition (TGI) in a humanized tumor model.

[0011] Antibodies that target and antagonize LILRB2 are currently being evaluated in clinical trials for the treatment of cancer, for example, MK-4830 (IgG4) (Agenus and Merck) and JTX-8064 (IgG4) (Jounce). Initial clinical data with the first in class anti-LILRB2 MK-4830 suggest that LILRB2 blockade abrogates a PD-1 resistance mechanism in patients with advanced solid tumors. MK-4830 dosed as monotherapy or in combination with pembrolizumab (anti-PD-1) was well tolerated and demonstrated dose-related evidence of target engagement and anti-tumor activity in patients that lacked predictive biomarkers associated with response to anti-PD-1 monotherapy. The overall response rate of MK-4830 / pembrolizumab combination treatment was 24%. The MK-4830 clinical trial data supports the development of anti-LILRB2 antibodies in combination with CPI therapy.

[0012] PCT Publication No. WO 2021 / 138079 Al discloses use of a combination of a PD-1 antagonist, an ILT4 (LILRB2) antagonist, and lenvatinib (a kinase inhibitor) for the treatment of cancers.

[0013] Cemiplimab (LIBTAYO®) is a PD-1 monoclonal antibody (mAb) approved in the United States (US), EU, and several countries worldwide for the treatment of patients with metastatic cutaneous squamous cell carcinoma (CSCC) or locally advanced CSCC who are not candidates for curative surgery or curative radiation. Additional indications for which cemiplimab is approved in at least 1 country include the treatment of patients with metastatic basal cell carcinoma (BCC) or locally advanced BCC, who were previously treated with a hedgehog pathway inhibitor (HHI) and adult patients with recurrent or metastatic cervical cancer with disease progression on or after platinum-basedchemotherapy. Cemiplimab is also approved for the first-line treatment of patients withmetastatic non-small cell lung cancer (NSCLC) or locally advanced NSCLC that is not a candidate for surgical resection or definitive chemoradiation, and whose tumors have no EGFR, ALK, or ROS1 aberrations. In this patient population, cemiplimab is approved as monotherapy in patients whose tumors have tumor proportion score (TPS) > 50% PD-L1 expression, and combined with chemotherapy in patients with any PD-L1 expression (LIBTAYO® 2023, LIBTAYO® (cemiplimab-rwlc) package insert. In. Tarrytown, NY:Regeneron Pharmaceuticals, Inc.; LIBTAYO® 2023, LIBTAYO® (cemiplimab) summary of product characteristics. In. Dublin, Ireland: Regeneron Pharmaceuticals, Inc.; Sezer, eta / ., 2021, Lancet, 397: 592-604).

[0014] Cemiplimab in combination with chemotherapy has been studied in the first-line treatment of patients with metastatic NSCLC or locally advanced and metastatic NSCLC, regardless of PD-L1 expression (with no EGFR, ALK, or ROS1 aberrations), and demonstrated OS benefit of the cemiplimab + chemotherapy when compared to chemotherapy plus placebo (Gogishvili, eta / ., 2022, Nat Med, 28: 2374-80).

[0015] There remains a need in the art for methods to treat cancer.SUMMARY

[0016] The disclosure provides methods of treating cancer using LILRB2 antibody products (also sometimes referred to herein as "anti-LILRB2 antibody products" herein).

[0017] The disclosure provides methods of providing cancer immunotherapy to a human subject in need thereof, the methods comprising administering to the subject a therapeutically effective amount of an LILRB2 antibody product, the antibody product comprising;(a) a CDR-H1 set forth in SEQ ID NO: 1, a CDR-H2 set forth in SEQ ID NO: 2, a CDR-H3 set forth in SEQ ID NO: 3 a CDR-L1 set forth in SEQ ID NO: 4, a CDR-L2 set forth in SEQ ID NO: 5, and a CDR-L3 set forth in SEQ ID NO: 6, as determined by the IMGT method; or(b) a CDR-H1 set forth in SEQ ID NO: 7, a CDR-H2 set forth in SEQ NO: 8, a CDR-H3 set forth in SEQ ID NO: 9, a CDR-L1 set forth in SEQ ID NO: 10, a CDR-L2 set forth in SEQ ID NO: 11, and a CDR-L3 set forth in SEQ ID NO: 12 as determined by the Kabat method.

[0018] The antibody product can comprise a heavy chain variable region having a sequence comprising SEQ ID NO: 13.

[0019] The antibody product can comprise a light chain variable region having a sequence comprising SEQ ID NO: 14.

[0020] The antibody product can comprise an IgGl heavy chain.

[0021] The antibody product can comprise a kappa light chain.

[0022] The antibody product can comprise a heavy chain having a sequence comprising SEQ ID NO: 15.

[0023] The antibody product can comprise a light chain having a sequence comprising SEQ ID NO: 16.

[0024] The disclosure provides methods of providing cancer immunotherapy to a human subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of an antibody product that recognizes human LILRB2, in which the antibody product consists essentially of a bivalent, monospecific, IgG antibody comprising a heavy chain variable region comprising SEQ ID NO: 13 and a light chain variable region comprising SEQ ID NO: 14.

[0025] The disclosure provides methods of providing cancer immunotherapy to a human subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of an antibody product that recognizes human LILRB2, in which the antibody product consists essentially of a bivalent, monospecific, humanized IgGl antibody comprising a heavy chain having a sequence comprising SEQ ID NO: 15 and a light chain having a sequence comprising SEQ ID NO: 16.

[0026] The antibody product can be bound by an Fc receptor expressed on an immunosuppressive macrophage or other myeloid cell of the subject.

[0027] The antibody product can be bound by CD16 (FcyRIIIa), CD32 (FcyRII), or CD64 (FcyRI) expressed on an immunosuppressive macrophage or other myeloid cell of the subject.

[0028] The antibody product can bind to LILRB2 expressed on a myeloid cell and is bound by CD16 (FcyRIIIa), CD32 (FcyRII), or CD64 (FcyRI) expressed on the same myeloid cell of the subject.

[0029] The antibody product can bind to LILRB2 on a first cell of the subject and is bound by CD16 (FcyRIIIa), CD32 (FcyRII), or CD64 (FcyRI) expressed on a second cell of the subject.

[0030] The cancer can comprise a solid tumor.

[0031] The cancer can be a sarcoma or carcinoma.

[0032] The cancer can be glioblastoma multiforme, head and neck cancer, kidney renal clear cell cancer, acute myeloid leukemia, pancreatic adenocarcinoma, cutaneous melanoma, stomach adenocarcinoma, testicular germ cell cancer, gastric cancer, Merkel cell carcinoma, dendritic sarcoma, non-small cell lung cancer, papillary thyroid cancer, cutaneous squamous cell carcinoma, liposarcoma, leiomyosarcoma, endometrial cancer, urothelial cancer, pleomorphic sarcoma, or ovarian cancer.

[0033] The cells in the tumor can express or overexpress LILRB2.

[0034] The methods provided herein can further comprise administering to the subject an effective amount of a PD-1 antagonist.

[0035] The PD-1 antagonist can be an anti-PD-1 antibody product.

[0036] The PD-1 antibody product can be nivolumab, pembrolizumab, cemiplimab, dostarlimab, pimivalimab, spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalimab, MEDI0680, balstilimab, retifanlimab, or zimberelimab, or a PD-1 binding domain of any of them.

[0037] The PD-1 antagonist can be cemiplimab or a PD-1 binding domain thereof.

[0038] The disclosure provides methods of providing cancer immunotherapy to a human subject in need thereof, the methods comprising administering to the subject a combination comprising:(a) a dose of an LILRB2 antibody product comprising;(i) a CDR-H1 set forth in SEQ ID NO: 1, a CDR-H2 set forth in SEQ ID NO: 2, a CDR-H3 set forth in SEQ ID NO: 3 a CDR-L1 set forth in SEQ ID NO: 4, a CDR-L2 set forth in SEQ ID NO: 5, and a CDR-L3 set forth in SEQ ID NO: 6, as determined by the IMGT method: or(ii) a CDR-H1 set forth in SEQ ID NO: 7, a CDR-H2 set forth in SEQ NO: 8, a CDR-H3 set forth in SEQ ID NO: 9, a CDR-L1 set forth in SEQ ID NO: 10, a CDR- L2 set forth in SEQ ID NO: 11, and a CDR-L3 set forth in SEQ ID NO: 12 as determined by the Kabat method; and(b) a dose of a PD-1 antagonist;wherein the dose of the LILRB2 antibody product and the dose of the PD-1 antagonist are selected to provide a therapeutic effect in the subject.

[0039] The dose of the LILRB2 antibody product can be sufficient to obtain more than 90% occupancy of LILRB2 in the subject for at least 21 days.

[0040] The dose of the LILRB2 antibody product can be sufficient to obtain blood concentration in the subject of at least the EC90for at least 21 days.

[0041] The dose of the LILRB2 antibody product can be between about 100 mg and about 1,600 mg.

[0042] The dose of the LILRB2 antibody product can be between about 200 mg and about 1,600 mg.

[0043] The dose of the LILRB2 antibody product can be about 200 mg, about 400 mg, about 800 mg, or about 1,600 mg.

[0044] The dose of the PD-1 antibody product can about 800 mg.

[0045] The dose of the PD-1 antibody product can be about 350 mg / kg.

[0046] The disclosure provides methods of providing cancer immunotherapy to a human subject in need thereof, the method comprising administering to the subject a combination comprising:(a) a dose of about 100 mg to about 1,600 mg of a bivalent, monospecific, humanized IgGl LILRB2 antibody, in which the antibody comprises a heavy chain having a sequence comprising SEQ ID NO: 15 and a light chain having a sequence comprising SEQ ID NO: 16; and(b) a dose of about 350 mg of cemiplimab.

[0047] The LILRB2 antibody can be administered by IV infusion over about 30 to about 60 minutes.

[0048] The cemiplimab can be administered by IV infusion over about 60 minutes.

[0049] The LILRB2 antibody and the cemiplimab can be administered q3w in 21-day cycles.

[0050] The disclosure provides methods of providing cancer immunotherapy to a human subject in need thereof, in which cells of the cancer express or overexpress LILRB2, the methods comprising administering to the subject a therapeutically effective amount of an LILRB2 antibody product that recognizes human LILRB2, in which the antibody product consists essentially of a bivalent, monospecific, humanized IgGl antibody comprising aheavy chain having a sequence comprising SEQ ID NO: 15 and a light chain having a sequence comprising SEQ ID NO: 16.

[0051] The administering of the antibody product can comprise administering an amount the antibody product effective to mediate killing of cells of the cancer through antibodydependent cellular toxicity.

[0052] The administering of the antibody product can comprise administering an amount of the antibody product effective to relieve LILRB2-mediated suppression of T cells in the subject.

[0053] The methods can further comprise administering to the subject a PD-1 antagonist in an amount sufficient to relieve PD-1 / PD-L1 axis-mediated immunosuppression of T cells in the subject.

[0054] The antibody product can increase an immune response, slow or prevent tumor growth, inhibit tumor-mediated immune suppression, eliminate or shrink a tumor, slow or prevent tumor spread or metastasis, deplete or block an activity of tumor-associated macrophages, decrease tumor-associated macrophage-mediated immune suppression, reduce or reverse T cell suppression, or a combination thereof.

[0055] The disclosure provides an aqueous pharmaceutical composition adapted for intravenous administration of an LILRB2 antibody product to a recipient subject, in which the antibody product comprises a bivalent, monospecific, humanized IgGl antibody comprising a heavy chain having a sequence comprising SEQ ID NO: 15 and a light chain having a sequence comprising SEQ ID NO: 16, the composition comprising about 20 mg / mL to about 70 mg / mL of the antibody product in a pharmaceutically acceptable buffer, and having a pH of about 5.0 to about 5.4.

[0056] The composition can comprise about 50 mg / mL of the antibody product, about 10 mM sodium acetate, about 9% (w / v) sucrose, and about 0.015% (w / w) polysorbate 80, and having a pH of about 5.2.

[0057] The disclosure provides methods of treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of the pharmaceutical composition provided herein.

[0058] The methods can comprise administering to the subject an amount of the composition sufficient to deliver a dose of about 100 mg to about 1,600 mg of the antibody product.

[0059] The disclosure provides a pharmaceutical product comprising a glass vial containing about 2 mL to about 25 mL of the composition of any of claims 39-40 and a closure means affixed to the vial, enabling stable maintenance of the composition at -20 °C protected from light for at least 18 months.

[0060] The disclosure provides kits comprising a solution in a vial containing an LILRB2 antibody product formulated in sodium acetate, sucrose and polysorbate 80.

[0061] The solution can consist of 10 mM sodium acetate, 9% (w / v) sucrose, 0.015% (w / w) polysorbate 80, pH 5.2.

[0062] The vial can contain a nominal fill volume of about 4 mL comprising the antibody product formulated at 50 mg / mL in 10 mM sodium acetate, 9% (w / v) sucrose, 0.015% (w / w) polysorbate 80, pH 5.2.

[0063] The antibody product in the kits can comprise:(a) a CDR-H1 set forth in SEQ ID NO: 1, a CDR-H2 set forth in SEQ ID NO: 2, a CDR-H3 set forth in SEQ ID NO: 3 a CDR-L1 set forth in SEQ ID NO: 4, a CDR-L2 set forth in SEQ ID NO: 5, and a CDR-L3 set forth in SEQ ID NO: 6, as determined by the IMGT method; or(b) a CDR-H1 set forth in SEQ ID NO: 7, a CDR-H2 set forth in SEQ NO: 8, a CDR-H3 set forth in SEQ ID NO: 9, a CDR-L1 set forth in SEQ ID NO: 10, a CDR-L2 set forth in SEQ ID NO: 11, and a CDR-L3 set forth in SEQ ID NO: 12 as determined by the Kabat method.

[0064] The antibody product can comprise a heavy chain variable region having a sequence comprising SEQ ID NO: 13.

[0065] The antibody product can comprise a light chain variable region having a sequence comprising SEQ ID NO: 14.

[0066] The antibody product can comprise an IgGl heavy chain.

[0067] The antibody product can comprise a kappa light chain.

[0068] The antibody product can comprise a heavy chain having a sequence comprising SEQ ID NO: 15.

[0069] The antibody product can comprise a light chain having a sequence comprising SEQ ID NO: 16.

[0070] The following Drawings and Detailed Description (including the Examples) illustrate various non-limiting aspects of the subject matter contemplated herein.BRIEF DESCRIPTION OF THE DRAWINGS

[0071] Aspects of the disclosure are illustrated by the following figures.

[0072] Fig. 1 shows PK parameters estimated for OR502 in cynomolgus monkey.

[0073] Fig. 2 shows soluble OR502 induces minimal or no cytokine release in human whole blood. Heparinized whole blood samples from 8-18 healthy donors were treated with OR502 (green circle), hlgGl isotype control (white circle), or anti-CD52 IgGl (alemtuzumab) reference antibody (blue diamonds) at the indicated concentrations (1, 5, 50 or 150 pg / mL). LPS (1 pg / mL) was included as a positive control for cytokine release. Plasma was collected 24 hr after treatment of whole blood. IFN-γ, IL-1β, IL-2, IL-6 and TNF-α levels were quantified using V-Plex Meso Scale Discovery kits. Cytokine concentrations were analyzed with MSD Discovery Workbench and GraphPad Prism. Each symbol represents the median cytokine secretion per donor. Avalues were calculated by Friedman nonparametric test using Dunn's multiple comparisons for OR502, IgGl isotype control and anti-CD52 treatment groups (* p<0.05, ** p <0.01, *** p <0.001, **** p <0.0001; ns = not significant).

[0074] Fig. 3A-B shows OR502 serum concentrations. 3A shows OR502 serum concentrations in human subjects during Cycle 1 of OR502 monotherapy dosing. 3B shows OR502 serum concentrations in human subjects during Cycle 1 of OR502 monotherapy dosing or OR502 in combination with cemiplimab

[0075] Fig. 4A-C shows peripheral receptor occupancy on myeloid cells in monotherapy.4A Classical monocytes. 4B Intermediate monocytes. 4C Neutrophils.

[0076] Fig. 5A-C shows peripheral receptor occupancy on myeloid cells in combination therapy. 5A Classical monocytes. 5B Intermediate monocytes. 5C Neutrophils.

[0077] Fig. 6A-B shows change in tumor size over the duration of OR502 treatment in all evaluable subjects in the monotherapy cohort. Fig. 6C shows change in tumor size over the duration of OR502 treatment in all evaluable subjects in the combination cohort.

[0078] Fig. 7 shows the best response in the monotherapy cohort.DETAILED DESCRIPTION

[0079] Unless otherwise defined herein, scientific and technical terms used herein have the meanings that are commonly understood by those of ordinary skill in the art to which the claimed subject matter belongs.Antibodv products

[0080] The disclosure provides antibody products that specifically bind to human LILRB2.

[0081] "PD-1 antagonist" means any chemical compound or biological molecule that blocks binding of PD-1 expressed on an immune cell (T cell, B cell or NKT cell) to PD-L1 expressed on a cancer cell, and preferably also blocks binding of the immune-cell expressed PD-1 to PD-L2 expressed on a cancer cell. Alternative names or synonyms are given for PD-1 and its ligands. For PD-1: PDCD1, PD1, CD279 and SLEB2; for PD-L1: PDCD1L1, PDL1, B7H1, B7-4, CD274 and B7-H; and for PD-L2: PDCD1L2, PDL2, B7-DC, Btdc, and CD273. In any of the treatment methods, medicaments and disclosed uses in which a human individual is being treated, the PD-1 antagonist blocks binding of human PD-L1 to human PD-1, and preferably blocks binding of both human PD-L1 and PD-L2 to human PD-1. Human PD-1 amino acid sequences can be found in NCBI Locus No.: NP 005009. Human PD-L1 and PD-L2 amino acid sequences can be found in NCBI Locus No.: NP 054862 and NP 079515, respectively.

[0082] "LILRB2 antagonist" means any chemical compound or biological molecule that blocks binding of LILRB2 to HLA-G, HLA-A, HLA-B, HLA-F, or an angiopoietin-like protein (ANGPTL, such as ANGPTL2, or ANGPTL5,). Alternative names or synonyms for LILRB2 and its ligands include but are not limited to: ILT4, ILT-4, MIR10, MIR-10, LIR2, LIR-2, CD85D for ILT4; MHC-G or major histocompatibility complex, class I, G for HLA-G; major histocompatibility complex, class I, A for HLA-A; AS, B-4901, major histocompatibility complex, class I, B for HLA-B; CDA12, HLA-CDA12, or major histocompatibility complex, class I, F for HLA-F; angiopoietin-3, ANG3, ANGPT3, ARP1, UNQ162, angiopoietin like 2 for ANGPTL2; ARP4, HF ARP, PGAR, UNQ171, angiopoietin like 54 for ANGPTL5; and CDT6,. In any of the treatment methods, medicaments and disclosed uses in which a human individual is being treated, the LILRB2 antagonist blocks binding of human LILRB2 to human HLA-G, HLA-A, HLA-B, HLA-C, HLA-F, ANGPTL2, or ANGPTL5. Human LILRB2 precursor amino acid sequence can be found in NCBI Locus No.: AAB88119.1. Human HLA-G, HLA-A, HLA-B, HLA-C and HLA-F precursor amino acid sequences can be found in NCBI Locus No.: P17693.1, P04439.2, P01889.3, P10321-1, and P30511.3, respectively. Human ANGPTL2, and ANGPTL5 precursor amino acid sequences can be found in NCBI Locus No. Q9UKU9-1 and Q86XS5, respectively. OR502 is an LILRB2 antagonist used herein.

[0083] The protein sequence of human LILRB2 (NM_005874.5) is set out in SEQ ID NO: 47. This gene is a member of the leukocyte immunoglobulin-like receptor (LIR) family, which is found in a gene cluster at chromosomal region 19ql3.4. The encoded protein belongs tothe subfamily B class of LIR receptors which contain two or four extracellular immunoglobulin domains, a transmembrane domain, and two to four cytoplasmic immunoreceptor tyrosine-based inhibitory motifs (ITIMs). The receptor is expressed on immune cells where it binds to MHC class I molecules on antigen-presenting cells and transduces a negative signal that inhibits stimulation of an immune response. It is thought to control inflammatory responses and cytotoxicity to help focus the immune response and limit autoreactivity. Multiple transcript variants encoding different isoforms have been found for this gene. The nucleotide sequence of a human cDNA encoding LILRB2 (NM_005874.5) is set out in SEQ ID NO: 53.

[0084] The terms "polypeptide" and "protein" are used interchangeably herein in the conventional way to refer to a molecule formed of amino acids. The polypeptides are not limited to a specific length. Peptides are included within polypeptides, unless specifically indicated otherwise. The terms neither specify nor exclude post-expression modifications of the polypeptide, for example, glycosylation, acetylation, phosphorylation, and the like, as well as other modifications known in the art, both naturally occurring and non-naturally occurring. Polypeptides of interest in the context of the antibodies of this disclosure include, but are not limited to, polypeptide fragments comprising CDRs which are capable of binding LILRB2 protein expressed by myeloid cells or cancer cells.

[0085] The term "polypeptide fragment" refers to a polypeptide that has an aminoterminal deletion, a carboxyl -terminal deletion, and / or an internal deletion as compared with the full-length native protein. Such fragments can also contain modified amino acids as compared with the native protein. Fragments are about 5 to 500 amino acids long. For example, fragments can be at least 5, 6, 8, 10, 14, 20, 50, 70, 100, 110, 150, 200, 250, 300, 350, 400, or 450 amino acids long. Polypeptide fragments include immunologically functional fragments of antibodies, including binding domains. In the case of LILRB2 antibody, useful fragments include, but are not limited to, a CDR region, a variable domain of a heavy or light chain, a portion of an antibody chain or just its variable region including two CDRs, and the like.

[0086] The term "isolated protein" referred to herein means that a subject protein (1) is free of at least some other proteins with which it would normally be found, (2) is essentially free of other proteins from the same source, (3) is expressed by a cell from a different species, (4) has been separated from at least about 50 percent of polynucleotides, lipids, carbohydrates, or other materials with which it is associated in nature, (5) is operably associated (by covalent or noncovalent interaction) with a polypeptide with which it is notassociated in nature, or (6) does not occur in nature. Genomic DNA, cDNA, mRNA, or other RNA, of synthetic origin, or any combination thereof can encode such an isolated protein. Preferably, the isolated protein is substantially free from proteins or polypeptides or other contaminants that are found in its natural environment that would interfere with its therapeutic, diagnostic, prophylactic, research or other use.

[0087] A "variant" of a polypeptide e.g., an antibody) comprises an amino acid sequence in which one or more amino acid residues are inserted into, deleted from and / or substituted into the amino acid sequence relative to another polypeptide sequence. Variants include fusion proteins.

[0088] A "derivative" of a polypeptide is a polypeptide e.g., an antibody) that has been chemically modified in some manner distinct from insertion, deletion, or substitution variants, e.g., via conjugation to another chemical moiety.

[0089] The term "antibody" generally includes an immunoglobulin protein that comprises one or more polypeptide chains and that is immunologically functional, including specifically binding to an antigen. In humans, antibodies typically comprise four linked polypeptide chains, a "tetramer" including two identical "heavy" chains and two identical smaller "light" chains. The two heavy chains are each linked to one light chain and are also linked to one another in parallel. The linkages impart a roughly Y-shaped structure to the antibody, such that the linked portions of the heavy chains form the leg of the "Y", and each light chain (with the portion of the heavy chain to which it is linked) forms an arm of the "Y". Each arm of the antibody contains an antigen binding site, so the typical antibody can bind two of antigens. In humans there exist five basic types or classes of antibodies, differentiated by the structure of the heavy regions and by their functional purpose: IgG, IgA, IgE, IgD, IgM. Intact antibodies in some classes in humans can differ from the typical tetrameric "Y" structural unit, such as circulating IgM antibodies that contain five such units linked at their bases in a roughly circular array. More detail on antibody structure and function is provided elsewhere herein.

[0090] In a typical antibody, each pair or couplet in the tetrameric unit includes one full-length "light" chain (about 25 kDa) and one full-length "heavy" chain (about 50-70 kDa). Each individual immunoglobulin chain is composed of several "immunoglobulin domains," each consisting of roughly 90 to 110 amino acids and expressing a characteristic folding pattern. These domains are the basic units of which antibody polypeptide chains are composed. The amino-terminal portion of each chain typically includes a variable domain that is responsible for antigen recognition. The carboxy-terminal portion is more conservedevolutionarily than the amino-terminal end of the chain and is referred to as the "constant region" or "C region."

[0091] The term "heavy chain" includes a full-length immunoglobulin heavy chain and fragments thereof having sufficient variable domain sequence to confer binding specificity, either alone or together with a light chain variable domain. Heavy chains are typically classified as mu (p), delta (6), gamma (y), alpha (a), or epsilon (E) chains, and these define the antibody's isotype as IgM, IgD, IgG, IgA, and IgE, respectively. IgG has several subtypes, including, but not limited to, IgGl, IgG2, IgG3, and IgG4. IgM subtypes include IgM, and IgM2. IgA subtypes include IgAl and IgA2. In humans, the IgA and IgD isotypes contain four heavy chains and four light chains; the IgG and IgE isotypes contain two heavy chains and two light chains; and the IgM isotype contains five heavy chains and five light chains. The heavy chain C region typically comprises one or more domains that can be responsible for effector function. The number of heavy chain constant region domains will depend on the isotype. Full-length IgG heavy chains, for example, each contain three C region domains known as CHI, CH2 and CH3, with the CH3 being closest to the carboxy terminus. The antibody products that are provided can have any of these isotypes and subtypes. For example, an LILRB2 antibody product can be an intact antibody of the IgGl or IgG4 subtype.

[0092] The term "light chain" includes a full-length immunoglobulin light chain and fragments thereof having sufficient variable domain sequence to confer binding specificity, either alone or together with a heavy chain variable domain. Human light chains generally are classified as kappa (K) or lambda (A) light chains. A full-length light chain includes an amino-terminal variable domain (VL) and a carboxy terminal constant domain (CL).

[0093] In the light and heavy chains, the variable and constant regions are naturally joined by a "J" region of about twelve or more amino acids, with the heavy chain further including a "D" region of about ten more amino acids. See, e.g., Fundamental Immunology, 2nd ed., Ch. 7 (Paul, ed.) 1989, New York: Raven Press.

[0094] Variable domains of immunoglobulin chains generally exhibit the same overall structure, comprising relatively conserved framework regions (FR) joined by three hypervariable regions, more often called "complementarity determining regions" or CDRs. The CDRs from the two chains of each heavy chain / light chain pair mentioned above typically are aligned by the framework regions to form a structure that binds specifically with a particular epitope on the target protein e.g., LILRB2). From N-terminal to C-terminal, naturally occurring light and heavy chain variable regions both typically conform with thefollowing order of these elements: FR1, CDR1, FR2, CDR2, FR3, CDR3 and FR4. Numbering systems have been devised for assigning numbers to amino acids that occupy positions in each of these domains.

[0095] The current art utilizes various numbering schemes with different definitions of CDR lengths and positions. For example, the Kabat numbering scheme is based on sequence alignment and uses "variability parameter" of a given amino acid position (the number of different amino acids at a given position divided by the frequency of the most occurring amino acid at that position) to predict CDRs [Kabat et al. in Sequences of Proteins of Immunological Interest, 5th Ed., US Dept, of Health and Human Services, PHS, NIH, NIH Publication no. 91-3242 (1991)]. The Chothia numbering scheme, on the other hand, is a structure-based numbering scheme where antibody crystal structures are aligned to define the loop structures as CDRs [Chothia and Lesk, J Moi Biol 1987 196:901-17; Chothia eta / ., Nature. 1989342:878-83]. The Martin numbering scheme focuses on the structure alignment of different framework regions of unconventional lengths [Martin, "Protein Sequence and Structure Analysis of Antibody Variable Domains." In: Kontermann and Dubel, eds. Antibody Engineering. Springer; Berlin, Germany: 2014. pp. 33-51]. The ImMunoGeneTics (IMGT) numbering scheme is a standardized numbering system based on alignments of sequences from a complete reference gene database including the whole immunoglobulin superfamily [Lefranc eta / ., Dev Comp Immunol. 2003 27(1): 55-77;(www.imgt.org / IMGTScientificChart / Nomenclature / IMGT-FRCDRdefinition.html)]. The Honneger numbering scheme (AHo) is based on structural alignments of the 3D structure of the variable regions and uses structurally conserved Co positions to deduce framework and CDR lengths [Honegger eta / ., J Mol Biol. 2001 309(3): 657-70]. One of ordinary skill in the art understands that the definition of a CDR will vary based on the method used.

[0096] Some of the antibody products that are provided have the structure typically associated with naturally occurring antibodies. Thus, the term "antibody product" includes an intact antibody of any class or subclass, or a fragment thereof, that can compete with the intact antibody for specific binding to the target antigen, and includes chimeric, humanized, fully human, and bispecific antibodies, as well as other forms. As noted, an intact antibody generally will comprise at least two full-length heavy chains and two full-length light chains, but in some instances can include fewer chains such as antibodies naturally occurring in camelids, which can comprise only heavy chains, and V NAR domains from sharks. Antibody products can be derived solely from a single source, or can be "chimeric," that is, different portions of the antibody can be derived from two different antibodies. For example, thecomplementarity determining regions that impart the binding specificity of an antibody, can be derived from a rat or murine source, while the framework region of the variable regions is derived from a different species source, such as a human. In other chimeric forms, the light and heavy variable domains (optionally with a constant domain) can be derived from one species and one or more constant domains from another species. See, e.g., US Patent No. 11352444. The antibody products provided can be produced in hybridomas, by recombinant DNA techniques, or by enzymatic or chemical cleavage of intact antibodies. Unless otherwise indicated, the term "antibody product" includes, in addition to antibodies comprising two full-length heavy chains and two full-length light chains (such as IgG antibodies), antibodies of other isotypes, derivatives, variants, and fragments thereof. The antibody products provided include, but are not limited to, monoclonal antibodies, human antibodies, chimeric antibodies, and humanized antibodies. Immunologically functional antibody fragments provided include, but are not limited to, scFv, Fab, Fab', F(ab')2, and domain antibody products.

[0097] An "immunologically functional fragment" (or simply "fragment") of an immunoglobulin, as used herein, refers to a portion of an antibody, comprising a light chain or a heavy chain (or both) and is capable of binding specifically to an antigen, but the light chain or heavy chain (or both) lacks at least some of the amino acids present in a full-length chain. Such fragments are biologically active in that they bind specifically to the target antigen and can compete with intact antibodies for specific binding to a given epitope. Such a fragment will retain at least one CDR present in the full-length light or heavy chain and can comprise a single heavy chain and / or light chain or portion thereof. These biologically active fragments can be produced by recombinant DNA techniques or can be produced by enzymatic or chemical cleavage of intact antibodies. Immunologically functional immunoglobulin fragments include, but are not limited to, Fab, Fab', F(ab')2, Fv, domain antibodies and single-chain antibodies, and can be derived from any mammalian source, including but not limited to human, mouse, rat, camelid or rabbit. It is contemplated further that a functional portion of the inventive antibodies, for example, one or more CDRs, could be covalently bound to a second protein or to a small molecule to create a therapeutic agent directed to a particular target in the body, possessing bifunctional therapeutic properties, or having a prolonged serum half-life.

[0098] A "Fab fragment" comprises one light chain (VL+CL) and a portion of a heavy chain that includes the variable domain and the CHI domain (VH+CH1). The heavy chain of a Fab molecule cannot form a disulfide bond with another heavy chain molecule.

[0099] An "Fc" region contains two heavy chain fragments each comprising the CH2 and CH3 domains of an antibody and in some cases the lower hinge region. The two heavy chain fragments are held together by two or more disulfide bonds (typically in the hinge region) and by hydrophobic interactions of the CH3 domains.

[0100] A "Fab' fragment" contains one light chain and a portion of one heavy chain that contains the VH domain and the CHI domain and also the region between the CHI and CH2 domains, such that an interchain disulfide bond can be formed between the two heavy chains of two Fab' fragments to form a F(ab')z molecule.

[0101] A "F(ab')z fragment" contains two light chains and two heavy chains each containing a portion of the constant region between the CHI and CH2 domains, such that an interchain disulfide bond is formed between the two heavy chains. A F(ab')z fragment thus is composed of two Fab' fragments that are held together by a disulfide bond between the two heavy chains.

[0102] The "Fv region" comprises the variable domains from both the heavy and light chains, but lacks the constant domains.

[0103] "Single-chain antibodies" are Fv molecules in which the heavy and light chain variable domains have been connected by a flexible linker to form a single polypeptide chain, which forms an antigen-binding region. Single chain antibodies are discussed in detail, for example, in PCT Publication No. WO 88 / 01649 and U. S. Patent Nos. 4,946,778 and 5,260,203.

[0104] A "domain antibody" is an immunologically functional immunoglobulin fragment containing only the variable domain of a heavy chain or the variable domain of a light chain. In some instances, two or more VH domains are covalently joined with a peptide linker to create a bivalent domain antibody. The two VH domains of a bivalent domain antibody can target the same or different antigens.

[0105] A "bivalent antibody" comprises two antigen binding sites. In some instances, the two binding sites have the same antigen specificities. However, bivalent antibodies can be bi specific (see below).

[0106] A "multispecific antibody" is one that targets more than one antigen or epitope.

[0107] A "bispecific," "dual-specific" or "bifunctional" antibody is a hybrid antibody having two different antigen binding sites. Bispecific antibodies are a species of multispecific antibody and can be produced by a variety of methods including, but not limited to, fusionof hybridomas or linking of Fab' fragments. See, e.g., Songsivilai and Lachmann, Ch'n Exp Immunol. 1990 79:315-21; Kostelny eta / ., J Immunol. 1992 148:1547-53. The two binding sites of a bispecific antibody will bind to two different epitopes, which can reside on the same or different protein targets. A "trispecific" antibody has three different antigen binding sites.

[0108] The term "neutralizing antibody" refers to an antibody that binds to a ligand, prevents binding of the ligand to its binding partner and interrupts the biological response that otherwise would result from the ligand binding to its binding partner. In assessing the binding and specificity of an antibody or immunologically functional fragment thereof, an antibody or fragment will substantially inhibit binding of a ligand to its binding partner when an excess of antibody reduces the quantity of binding partner bound to the ligand by at least about 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 95%, 97%, 99% or more (as measured in an in vitro competitive binding assay). In the case of antibody products that bind to LILRB2, a neutralizing antibody product will diminish the ability of LILRB2 to bind to one or more of its ligands thereby inhibiting LILRB2 activity (e.g., as shown in the Examples herein).

[0109] The term "competition" when used in the context of antibody products that compete for the same epitope means competition between antibodies is determined by an assay in which the antibody product under test prevents or inhibits specific binding of a reference antibody product to a common antigen e.g., LILRB2 or a fragment thereof). Numerous types of competitive binding assays can be used, for example: solid phase direct or indirect radioimmunoassay (RIA), solid phase direct or indirect enzyme immunoassay (EIA), sandwich competition assay [e.g., Stahli eta / ., Methods Enzymol 1983 9:242-53]; solid phase direct biotin-avidin EIA [e.g., Kirkland eta / ., J Immunol. 1986 137:3614-9]; solid phase direct labeled assay, solid phase direct labeled sandwich assay [e.g., Harlow and Lane, Antibodies, A Laboratory Manual, Cold Spring Harbor Press (1988)]; solid phase direct label RIA using 1-125 label [e.g., Morel eta / ., Moiec Immunol 1988 25:7-15]; solid phase direct biotin-avidin EIA [e.g., Cheung eta / ., Virology. 1990 176:546-52]; and direct labeled RIA [Moldenhauer eta / ., Scand J Immunol. 1990 32:77-82]. Typically, such an assay involves the use of purified antigen bound to a solid surface or cells bearing either of these, an unlabeled test antibody and a labeled reference antibody. Competitive inhibition is measured by determining the amount of label bound to the solid surface or cells in the presence of the test antibody. Usually, the test antibody is present in excess. Antibodies identified by competition assay (competing antibodies) include antibodies binding to thesame epitope as the reference antibody and antibodies binding to an epitope sufficiently proximal to the epitope bound by the reference antibody for steric hindrance to occur.Usually, when a competing antibody is present in excess, it will inhibit specific binding of a reference antibody to a common antigen by at least 40%, 45%, 50%, 55%, 60%, 65%, 70% or 75%. In some instance, binding is inhibited by at least 80%, 85%, 90%, 95%, or 97% or more by a selective binding agent, such as an antibody, and additionally capable of being used in an animal to produce antibodies capable of binding to that antigen. An antigen can possess one or more epitopes that are capable of interacting with different antibodies.

[0110] The term "epitope" includes any determinant capable of specifically binding to an antibody or to a T-cell receptor. An epitope is a region of an antigen that is bound by an antibody that specifically targets that antigen, and when the antigen is a protein, includes specific amino acids that directly contact the antibody. Most often, epitopes reside on proteins, but in some instances can reside on other kinds of molecules, such as nucleic acids. Epitope determinants can include chemically active surface groupings of molecules such as amino acids, sugar side chains, phosphoryl or sulfonyl groups, and can have specific three-dimensional structural characteristics, and / or specific charge characteristics. Generally, antibodies specific for a particular target antigen will preferentially recognize an epitope on the target antigen in a complex mixture of proteins and / or macromolecules.

[0111] An antibody product "specifically binds" its target antigen when the dissociation constant (Kd) is less than 100 nM. The antibody specifically binds antigen with "high affinity" when the Kd is less than 10 nM and with "very high affinity" when the Kd is less than 0.5 nM. The antibody product can have a Kd in the range from about 0.5 nM to about 500 nM. The antibody product can have a Kd in the range from about 100 to about 500 nM. One of skill in the art will recognize that specifically binding does not mean exclusive binding, rather it allows for some degree of non-specific binding as is typical in biological reactions between groups with affinity to one another.

[0112] As used herein, the term "affinity" refers to the equilibrium constant for the reversible binding of two agents and can be expressed as the equilibrium dissociation constant, KD, a calculated ratio of the dissociation constant and the association constant (Koff / Kon), between the antibody and its antigen. Affinity can also be expressed as the association constant, KA, which is the reciprocal of KD. The antibody products disclosed herein exhibit binding affinity as measured by KDfor human LILRB2 and for human LILRB1 in the range of 10'4M or less, or ranging down to 10'16M or lower, e.g., about 10'4, 10'5, 10’6, IO’7, 10’8, 10’9, 10’10, 10’11, IO’12, IO’13, 10’14, IO’15, 10’16M or less). Antibodiesdescribed herein can specifically bind to a human LILRB2 polypeptide or to a human LILRB1 polypeptide with a KDof less than or equal to 10’4M, less than or equal to about 10’5M, less than or equal to about 10’6M, less than or equal to 10’7M, or less than or equal to 10’8M. Methods for determining the affinity of two molecules are well known in the art and include, for example, equilibrium dialysis, surface plasmon resonance (SPR), bio-layer interferometry (BLI), and the like.

[0113] As used herein, an antibody product is said to be "immunospecific" or "specific" for, or to "specifically bind" when that an antibody product forms a complex with an antigen that is relatively stable under physiologic conditions. The terms "preferentially binds" or "specifically binds" mean that the antibodies or fragments thereof bind to an epitope with greater affinity than it binds unrelated amino acid sequences, and, if cross-reactive to other polypeptides containing the epitope, are not toxic at the levels at which they are formulated for administration to human use. Such affinity can be at least 1-fold greater, at least 2-fold greater, at least 3-fold greater, at least 4-fold greater, at least 5-fold greater, at least 6-fold greater, at least 7-fold greater, at least 8-fold greater, at least 9-fold greater, 10-fold greater, at least 20-fold greater, at least 30-fold greater, at least 40-fold greater, at least 50-fold greater, at least 60-fold greater, at least 70-fold greater, at least 80-fold greater, at least 90-fold greater, at least 100-fold greater, or at least 1000-fold greater than the affinity of the antibody product for unrelated amino acid sequences. The terms are also applicable where for example, an antibody product is specific for a particular epitope that is carried by more than one antigen, in which case the antibody or antigen-binding fragment thereof carrying the antigen-binding domain will be able to specifically bind to the epitope found in the different antigens.

[0114] The term "identity" refers to a relationship between the sequences of two or more polypeptide molecules or two or more nucleic acid molecules, as determined by aligning and comparing the sequences. "Percent identity" means the percent of identical residues between the amino acids or nucleotides in the compared molecules and is calculated based on the size of the smallest of the molecules being compared. For these calculations, gaps in alignments (if any) must be addressed by a particular mathematical model or computer program (Ze., an "algorithm"). Methods that can be used to calculate the identity of the aligned nucleic acids or polypeptides include those described in Computational Molecular Biology, (Lesk, Ed.), 1988, New York: Oxford University Press; Biocomputing Informatics and Genome Projects, (Smith, ed.), 1993, New York: Academic Press; Computer Analysis of Sequence Data, Parti, (Griffin and Griffin, eds.), 1994, New Jersey: Humana Press;Sequence Analysis in Molecular Biology, (von Heinje), 1987, New York: Academic Press; Sequence Analysis Primer, (Gribskov and Devereux, eds.), 1991, New York: M. Stockton Press; and Carillo etai., SIAM J Applied Math. 198848(5): 1073-82.

[0115] In calculating percent identity, the sequences being compared are aligned in a way that gives the largest match between the sequences. An exemplary computer program used to determine percent identity is the GCG program package, which includes GAP (Devereux et ai., Nuci Acid Res. 1984 12:387-95; Genetics Computer Group, University of Wisconsin, Madison, Wise.). The computer algorithm GAP is used to align the two polypeptides or polynucleotides for which the percent sequence identity is to be determined. The sequences are aligned for optimal matching of their respective amino acid or nucleotide (the "matched span", as determined by the algorithm). A gap opening penalty (which is calculated as 3.times. (3X) the average diagonal, in which the "average diagonal" is the average of the diagonal of the comparison matrix being used; the "diagonal" is the score or number assigned to each perfect amino acid match by the particular comparison matrix) and a gap extension penalty (which is usually 1 / 10 times the gap opening penalty), as well as a comparison matrix such as PAM 250 or BLOSUM 62 are used in conjunction with the algorithm. A standard comparison matrix \e.g., Dayhoff etai., Atlas of Protein Sequence and Structure, 5:345-352 (1978) for the PAM 250 comparison matrix; Henikoff etai., Proc Nati Acad Sci USA. 1992 89:10915-9 for the BLOSUM 62 comparison matrix] can also be used by the algorithm.

[0116] Recommended parameters for determining percent identity for polypeptides or nucleotide sequences using the GAP program are the following: Algorithm: Needleman et ai., J Moi Biol 197048:443-53; Comparison matrix: BLOSUM 62 from Henikoff etai., 1992, supra; Gap Penalty: 12 (but with no penalty for end gaps); Gap Length Penalty: 4;Threshold of Similarity: 0.

[0117] Certain alignment schemes for aligning two amino acid sequences can result in matching of only a short region of the two sequences, and this small aligned region can have very high sequence identity even though there is no significant relationship between the two full-length sequences. Accordingly, the selected alignment method (GAP program) can be adjusted if so desired to result in an alignment that spans at least 50 contiguous amino acids of the target polypeptide.

[0118] Other exemplary programs that compare and align pairs of sequences include, but are not limited to, ALIGN (Myers and Miller, Comput Appi Biosci. 19884(1): 11-7); FASTA (Pearson and Lipman, Proc Nati Acad Sci USA. 1988 85(8):2444-8; Pearson, MethodsEnzymoL 1990 183:63-98); and gapped BLAST (Altschul eta!., Nucleic Acids Res 1997 25(17): 3389-402), BLASTP, BLASTN, or GCG (Devereux etai., Nucleic Acids Res. 1984 12(1 Pt 1): 387-95).

[0119] "Amino acid" includes its normal meaning in the art. The twenty naturally-occurring amino acids and their abbreviations follow conventional usage. See Immunoiogy-A Synthesis, 2nd ed. (Golub and Gren, Eds.), Sinauer Associates: Sunderland, Mass. (1991). Stereoisomers e.g., D-amino acids) of the twenty conventional amino acids, unnatural amino acids such as a-, a-di substituted amino acids, N-alkyl amino acids, and other unconventional amino acids can be suitable components. Examples of unconventional amino acids include: 4-hydroxyproline, gamma-carboxyglutamate, £-N, N, N-trimethyllysine, s-N-acetyllysine, O-phosphoserine, N-acetylserine, N-formylmethionine, 3-methylhistidine, 5-hydroxylysine, o-N-methylarginine, and other similar amino acids and imino acids e.g., 4-hydroxyproline). In the polypeptide notation used herein, the left-hand direction is the amino terminal direction, and the right-hand direction is the carboxyl -terminal direction, in accordance with standard usage and convention.

[0120] Table 1 below sets out heavy and light chain variable domains for an LILRB2-specific humanized antibody designated OR502, as well as corresponding full-length heavy (hlgGl) and light (kappa) chains provided herein. IMGT and Kabat CDRs are presented in Table 2. CDRs of the two variable domains are indicated: IMGT in double underline; Kabat in bold.Table 1 - Variable Regions and Full Length Heavy and Light ChainsTable 2 - Complementarity Determining Regions

[0121] The skilled artisan recognizes that antibody products, such as full-length intact antibodies and LILRB2-binding antibody fragments, can be prepared based on the heavy chain and light chain variable domains given in Table 1, or on the CDRs given in Table 2.

[0122] Antibody products can comprise a light chain variable domain comprising a sequence of amino acids that differs from the sequence of a light chain variable domain described herein at only 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues, in which each such sequence difference is independently either a deletion, insertion or substitution of one amino acid. The light chain variable region in some antibodies comprises a sequence of amino acids that has at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to an amino acid sequence of a light chain variable region in Table 1.

[0123] Antibody products can comprise a heavy chain variable domain comprising a sequence of amino acids that differs from the sequence of a heavy chain variable domain provided herein at only 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 amino acid residues, in which each such sequence difference is independently either a deletion, insertion or substitution of one amino acid. The heavy chain variable region in some antibodies comprises a sequence of amino acids that has at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of the heavy chain variable region in Table 1. Still other antibody products include variant forms of a variant light chain and a variant heavy chain as just described.

[0124] The antibody products that are provided can include one, two, three, four, five, or all six CDRs. Some antibody products include both the light chain CDR3 and the heavy chain CDR3. Certain antibody products have variant forms of the CDRs, with one or more (Ze., 2, 3, 4, 5 or 6) of the CDRs each having at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%sequence identity to a CDR sequence. For example, the antibody product can include both a light chain CDR3 and a heavy chain CDR3 that each have at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% sequence identity to the light chain CDR3 sequence and the heavy chain CDR3, respectively. The CDR sequences of the antibody products that are provided can also differ from the CDR sequences in Table 2 such that the amino acid sequence for any given CDR differs from the sequence listed in Table 2 by no more than one, two, three, four or five amino acid residues. Differences from the listed sequences are conservative substitutions.

[0125] When an antibody product is said to bind an epitope of LILRB2, what is meant is that the antibody product specifically binds to a region of LILRB2 specified by certain residues e.g., one or more specified segments of LILRB2 protein). In binding to an LILRB2 epitope, an antibody does not necessarily contact every residue within the LILRB2 peptide comprising the specified residues. Nor does every single amino acid substitution or deletionwithin the LILRB2 peptide necessarily significantly affect binding affinity. Exact epitope specificity of an antibody can be determined in various ways. One approach, for example, involves testing a collection of overlapping peptides of about fifteen amino acids spanning the sequence of LILRB2 and differing in increments of a small number of amino acids e.g., three amino acids). The peptides are immobilized within the wells of a microtiter dish.Immobilization can be achieved by biotinylating one terminus of the peptides. Optionally, different samples of the same peptide can be biotinylated at the N and C terminus and immobilized in separate wells for purposes of comparison. This is useful for identifying endspecific antibodies. Optionally, additional peptides can be included terminating at a particular amino acid of interest. This approach is useful for identifying end-specific antibodies to internal fragments of LILRB2. An antibody product is screened for specific binding to each of the various peptides. The epitope is defined as occurring within a segment of amino acids that is common to all peptides to which the antibody shows specific binding.

[0126] Antibody products that compete with one of the exemplified antibodies for specific binding to LILRB2 are also provided. Such antibody products can also bind to the same epitope as one of the exemplified antibodies. Antibody products that compete with or bind to the same epitope as the exemplified antibody or fragment are expected to show similar functional properties. The exemplified antibody products include those with the heavy and light chains, variable domains and CDRs provided in Table 1 or 2. Competing antibody products can include those that bind to the epitope described in the section on antibodies and epitopes above.

[0127] The antibody products provided include monoclonal antibodies that bind to LILRB2. Monoclonal antibodies can be produced using any technique known in the art, e.g., by immortalizing spleen cells harvested from the transgenic animal after completion of the immunization schedule. The spleen cells can be immortalized using any technique known in the art, e.g., by fusing them with myeloma cells to produce hybridomas. Myeloma cells for use in hybridoma-producing fusion procedures preferably are non-antibody-producing, have high fusion efficiency, and enzyme deficiencies that render them incapable of growing in certain selective media which support the growth of only the desired fused cells (hybridomas). Examples of suitable cell lines for use in mouse fusions include Sp-20, P3-X63 / Ag8, P3-X63-Ag8.653, NSl / l. Ag 4 1, Sp210-Agl4, FO, NSO / U, MPC-11, MPC11-X45-GTG 1.7. and S194 / 5XXO Bui; examples of cell lines used in rat fusions include R210. RCY3, Y3-Ag 1.2.3, IR983F, and 4B210. Other cell lines useful for cell fusions are U-266, GM1500-GRG2, LICR-LON-HMy2, and UC729-6.

[0128] In some instances, a hybridoma cell line is produced by immunizing an animal e.g., a transgenic animal having human immunoglobulin sequences) with a LILRB2 immunogen; harvesting spleen cells from the immunized animal; fusing the harvested spleen cells to a myeloma cell line, thereby generating hybridoma cells; establishing hybridoma cell lines from the hybridoma cells, and identifying a hybridoma cell line that produces an antibody that binds a LILRB2 polypeptide. Such hybridoma cell lines, and LILRB2 monoclonal antibodies produced by them, are provided herein.

[0129] Monoclonal antibodies secreted by a hybridoma cell line can be purified using any useful technique known in the antibody arts. Hybridomas or monoclonal antibodies can be further screened to identify monoclonal antibodies with particular properties.

[0130] Chimeric and humanized antibodies based upon the foregoing sequences are also provided. Monoclonal antibodies for use as therapeutic agents can be modified in various ways prior to use. One example is a "chimeric" antibody, which is an antibody composed of protein segments from different antibodies that are covalently joined to produce functional immunoglobulin light or heavy chains or immunologically functional portions thereof.Generally, a portion of the heavy chain and / or light chain is identical with or homologous to a corresponding sequence in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is / are identical with or homologous to a corresponding sequence in antibodies derived from another species or belonging to another antibody class or subclass. For methods relating to chimeric antibodies, see, for example, U. S. Patent No. 4,816,567; and Morrison eta / ., Proc Natl Acad Sci USA. 1985 81:6851-5. CDR grafting is described, for example, in U. S. Patent Nos. 6,180,370, 5,693,762, 5,693,761, 5,585,089, and 5,530,101.

[0131] Generally, the goal of making a chimeric antibody is to create a chimera in which the number of amino acids from the intended patient species is maximized. One example is the "CDR-grafted" antibody, in which the antibody comprises one or more complementarity determining regions (CDRs) from a particular species or belonging to a particular antibody class or subclass, while the remainder of the antibody chain(s) is / are identical with or homologous to a corresponding sequence in antibodies derived from another species or belonging to another antibody class or subclass. For use in humans, the V region or selected CDRs from a rodent antibody often are grafted into a human antibody, replacing the naturally occurring V regions or CDRs of the human antibody.

[0132] "Humanized" antibody products are provided. Generally, a humanized antibody is produced from a monoclonal antibody raised initially in a non-human animal. Certain aminoacid residues in this monoclonal antibody, typically from non-antigen recognizing portions of the antibody, are modified to be homologous to corresponding residues in a human antibody of corresponding isotype. Humanization can be performed, for example, using various methods by substituting at least a portion of a rodent variable region with the corresponding regions of a human antibody [e.g., U. S. Patent Nos. 5,585,089, and 5,693,762; Jones eta!., Nature. 1986321:522-5; Riechmann eta / ., Nature. 1988 332:323-7; Verhoeyen eta / ., Science. 1988 239:1534-6]. Constant regions from species other than human can be used along with the human variable region(s) to produce hybrid antibodies.

[0133] Fully human antibodies are also provided. Methods are known for making fully human antibodies specific for a given antigen without exposing human beings to the antigen ("fully human antibodies"). One means for implementing the production of fully human antibodies is the "humanization" of the mouse humoral immune system. Introduction of human immunoglobulin (Ig) loci into mice in which the endogenous Ig genes have been inactivated is one means of producing fully human monoclonal antibodies (MAbs) in mouse, an animal that can be immunized with any desirable antigen. Using fully human antibodies can minimize the immunogenic and allergic responses that can sometimes be caused by administering mouse or mouse-derivatized monoclonal antibodies to humans as therapeutic agents.

[0134] Fully human antibodies can be produced by immunizing transgenic animals (usually mice) that are capable of producing a repertoire of human antibodies in the absence of endogenous immunoglobulin production. Antigens for this purpose typically have six or more contiguous amino acids, and optionally are conjugated to a carrier, such as a hapten. See, for example, Jakobovits eta / ., Proc Natl Acad Sci USA. 1993 90:2551-5; Jakobovits et at., Nature. 1993 362:255-8; and Bruggemann etai., Year Immunol. 1993 7:33-40. In one example of such a method, transgenic animals are produced by incapacitating the endogenous mouse immunoglobulin loci encoding the mouse heavy and light immunoglobulin chains therein, and inserting into the mouse genome large fragments of human genome DNA containing loci that encode human heavy and light chain proteins. Partially modified animals, which have less than the full complement of human immunoglobulin loci, are then cross-bred to obtain an animal having all of the desired immune system modifications. When administered an immunogen, these transgenic animals produce antibodies that are immunospecific for the immunogen but have human rather than murine amino acid sequences, including the variable regions. For further details of such methods, see, for example, WO96 / 33735 and W094 / 02602. Additional methods relating totransgenic mice for making human antibodies are described in U. S. Patent Nos. 5,545,807; 6,713,610; 6,673,986; 6,162,963; 5,545,807; 6,300,129; 6,255,458; 5,877,397; 5,874,299 and 5,545,806; in PCT Publication Nos. WO 91 / 10741, WO 90 / 04036, and in EPO Publication No. EP 546073B1. The transgenic mice, referred to herein as "HuMab" mice, contain a human immunoglobulin gene minilocus that encodes unrearranged human heavy (g and gamma) and kappa light chain immunoglobulin sequences, together with targeted mutations that inactivate the endogenous gamma and kappa chain loci (Lonberg eta!., Nature. 1994 368:856-9). Accordingly, the aforementioned mice exhibit reduced expression of mouse IgM or kappa and in response to immunization the introduced human heavy and light chain transgenes undergo class switching and somatic mutation to generate high affinity human IgG kappa monoclonal antibodies. An exemplary mouse with the entire human immunoglobulin locus in its germline is the XenoMouse (Abgenix). Another is the Velocilmmune mouse (Regeneron Pharmaceuticals). Others are the RenMab mouse and the RenLite mouse (Biocytogen), and, more recently the AlivaMab Mouse (Ablexis).

[0135] Using hybridoma technology, antigen-specific human monoclonal antibodies with the desired specificity can be produced and selected from the transgenic mice such as those described above. Such antibodies can be cloned and expressed using a suitable vector and host cell, or the antibodies can be harvested from cultured hybridoma cells.

[0136] Fully human antibodies can also be derived from phage-display libraries (as disclosed in Hoogenboom and Winter, J Mol Biol. 1992 227(2): 381-8; and Marks eta / ., J Mol Bio! 1991 222:581-97. Phage display techniques mimic immune selection through the display of antibody repertoires on the surface of filamentous bacteriophage, and subsequent selection of phage by their binding to an antigen of choice. One such technique is described in PCT Publication No. WO 99 / 10494, which describes the isolation of high affinity and functional agonistic antibodies for c-MpI and MuSK receptors using such an approach.

[0137] Single chain antibodies are provided. Single chain antibodies are formed by linking heavy and light chain variable domain (Fv region) fragments (such as those shown in Table 10 or in Table 12) via an amino acid bridge (short peptide linker), resulting in a single polypeptide chain. Such single-chain Fv regions (scFvs) can be prepared by fusing DNA encoding a peptide linker between DNAs encoding the two variable domain polypeptides (VL and VH). The resulting polypeptides can fold back on themselves to form antigen-binding monomers, or they can form multimers e.g., dimers, trimers, or tetramers), depending on the length of a flexible linker between the two variable domains. Techniques developed for the production of single chain antibodies include those described in U. S. Pat. No. 4,946,778;Bird eta!., Science. 1988242:423-6; Huston eta!., Proc Nat! Acad Sci USA. 1988 85:5879-83; Ward eta!., Nature. 1989 334:544-6; and de Graaf eta!., Methods Mo! Biol 2002 178:379-87. A "diabody" is a dimer of scFV.

[0138] Antibodies provided herein that are of one subclass can be changed to antibodies from a different subclass using subclass switching methods. For example, the variable domains depicted in Table 1 can be attached to constant domains of any desired Ig subtype. Such techniques allow the preparation of new antibodies that possess the antigen-binding properties of a given antibody (the parent antibody), but also exhibit biological properties associated with an antibody isotype or subclass different from that of the parent antibody. Recombinant DNA techniques can be employed. Cloned DNA encoding particular antibody polypeptides can be employed in such procedures, e.g., DNA encoding the constant domain of an antibody of the desired isotype. See, e.g., Lantto etai., Methods Moi Biol 2002 178:303-16. Accordingly, the antibodies that are provided include a desired isotype (for example, IgA, IgGl, IgG2, IgG3, IgG4, IgE, and IgD).

[0139] Antibody products provided can include one or more of the CDRs of any of the heavy chain variable domains exemplified herein, where such CDRs are determined according to IMGT, Kabat or other method: (i) a CDR-H1 with at least 80% sequence identity to the CDR-H1 of SEQ ID NO: 1 or 7; (ii) a CDR-H2 with at least 80% sequence identity to the CDR-H2 of SEQ ID NO: SEQ ID NO: 2 or 8; and (iii) a CDR-H3 with at least 80% sequence identity to the CDR-H3 of SEQ ID NO: SEQ ID NO: 3 or 9. Antibody products provided can include one or more of the CDRs of any of the light chain variable domains exemplified herein, where such CDRs are determined according to IMGT, Kabat or other method: (i) a CDR-L1 with at least 80% sequence identity to the CDR-L1 of SEQ ID NO: 4 or 10; (ii) a CDR-L2 with at least 80% sequence identity to the CDR-L2 of SEQ ID NO: 5 or 11; and (iii) a CDR-L3 with at least 80% sequence identity to the CDR-L3 of SEQ ID NO: 6 or 12. In some embodiments, the CDRs will have at least 85%, at least 90%, at least 95%, or least 99% identity to the determined CDR sequences. Antibody products can include one, two, three, four, five or all six of the foregoing CDRs, as long as they specifically bind hLILRB2.

[0140] Antibody products provided can include one or more of the following exemplary heavy chain IMGT CDRs: (i) a CDR-H1 with at least 80% sequence identity to SEQ ID NO: 1; (ii) a CDR-H2 with at least 80% sequence identity to SEQ ID NO: 2; and (iii) a CDR-H3 with at least 80% sequence identity to SEQ ID NO: 3. Antibody products provided can include one or more of the following light chain CDRs: (i) a CDR-L1 with at least 80% sequence identity to SEQ ID NO: 4; (ii) a CDR-L2 with at least 80% sequence identity to SEQ ID NO:5; and (Hi) a CDR-L3 with at least 80% sequence identity to SEQ ID NO: 6. In some embodiments, the CDRs will have at least 85%, at least 90%, at least 95%, or least 99% identity to the specified CDR sequences. Antibody products can include one, two, three, four, five or all six of the foregoing CDRs, as long as they specifically bind hLILRB2.

[0141] Antibody products provided can include one or more of the following exemplary heavy chain Kabat CDRs: (i) a CDR-H1 with at least 80% sequence identity to SEQ ID NO: 7; (ii) a CDR-H2 with at least 80% sequence identity to SEQ ID NO: 8; and (iii) a CDR-H3 with at least 80% sequence identity to SEQ ID NO: 9. Antibody products provided can include one or more of the following light chain CDRs: (i) a CDR-L1 with at least 80% sequence identity to SEQ ID NO: 10; (ii) a CDR-L2 with at least 80% sequence identity to SEQ ID NO: 11; and (iii) a CDR-L3 with at least 80% sequence identity to SEQ ID NO: 12. In some embodiments, the CDRs will have at least 85%, at least 90%, at least 95%, or least 99% identity to the specified CDR sequences. Antibody products can include one, two, three, four, five or all six of the foregoing CDRs, as long as they specifically bind hLILRB2.

[0142] Antibody products provided can include (a) a heavy chain variable region having 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, 99% or greater sequence identity with SEQ ID NO: 13; (b) a light chain variable region having at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, 99% or greater sequence identity with SEQ ID NOs: 14; or (c) a heavy chain variable region of (a) and a light chain variable region of (b).

[0143] Other antibody products provided compete with an antibody such as those described above for specific binding to a LILRB2 polypeptide. For example, antibody products are provided that compete with an antibody that consists of two identical heavy chains and two identical light chains, in which the heavy chains comprise SEQ ID NO: 15, and the light chains comprise SEQ ID NO: 16.

[0144] LILRB2 antibody product are provided that have a half-life of at least one day in vitro or in vivo e.g., when administered to a human subject). The antibody product can have a half-life of at least three days. The antibody product can have a half-life of four days or longer. The antibody product can have a half-life of eight days or longer.Variants

[0145] Variant forms of LILRB2 antibody products disclosed herein e.g., variant forms of antibody products having sequences listed in Tables 1 and 2) are provided. For example, antibody products can have one or more conservative amino acid substitutions in one or more of the heavy or light chain variable regions, or CDRs, listed in Tables 10 and 12.

[0146] Naturally occurring amino acids can be divided into classes based on common side chain properties: 1) hydrophobic: norleucine, Met, Ala, Vai, Leu, He; 2) neutral hydrophilic: Cys, Ser, Thr, Asn, Gin; 3) acidic: Asp, Glu; 4) basic: His, Lys, Arg; 5) residues that influence chain orientation: Gly, Pro; and 6) aromatic: Trp, Tyr, Phe. Conservative amino acid substitutions can involve exchange of a member of one of these classes with another member of the same class. Conservative amino acid substitutions can encompass non-naturally occurring amino acid residues, which are typically incorporated by chemical peptide synthesis rather than by synthesis in biological systems. These include peptidomimetics and other reversed or inverted forms of amino acid moieties.

[0147] Non-conservative substitutions can involve the exchange of a member of one of the above classes for a member from another class. Such substituted residues can be introduced into regions of the antibody product that are homologous with human antibodies, or into the non-homologous regions of the molecule.

[0148] In making such changes, the hydropathic index of amino acids can be considered. The hydropathic profile of a protein is calculated by assigning each amino acid a numerical value ("hydropathy index") and then repetitively averaging these values along the peptide chain. Each amino acid has been assigned a hydropathic index on the basis of its hydrophobicity and charge characteristics. They are: isoleucine (+4.5); valine (+4.2); leucine (+3.8); phenylalanine (+2.8); cysteine / cystine (+2.5); methionine (+1.9); alanine (+1.8); glycine (-0.4); threonine (-0.7); serine (-0.8); tryptophan (-0.9); tyrosine (-1.3); proline (-1.6); histidine (-3.2); glutamate (-3.5); glutamine (-3.5); aspartate (-3.5); asparagine (-3.5); lysine (-3.9); and arginine (-4.5).

[0149] The importance of the hydropathic profile in conferring interactive biological function on a protein is understood in the art \e.g., Kyte and Doolittle, J Mol Biol. 1982 157:105-31]. It is known that certain amino acids can be substituted for other amino acids having a similar hydropathic index or score and still retain a similar biological activity. In making changes based upon the hydropathic index, the substitution of amino acids whose hydropathic indices are within ±0.2 can be made. The substitution of amino acids whose hydropathic indices are within ±0.1 can also be made. The substitution of amino acids whose hydropathic indices are within ±0.5 can also be made.

[0150] It is also understood in the art that the substitution of like residues in amino acid sequences can be made effectively on the basis of relative hydrophilicity or hydrophobicity of the residues, particularly where the biologically functional protein or peptide thereby created is intended for use in immunological molecules, as in the present case. The greatestlocal average hydropathic character of a protein, as governed by the hydrophilicity of its adjacent amino acids, can correlate with its immunogenicity and antigen-binding or immunogenicity, that is, with a biological property of the protein.

[0151] Various methods are known for estimating the hydrophilicity or hydrophobicity of amino acid residues in proteins. A comparative survey of such methods is given at Biswas eta!., J Chromatogr A. 1000(l-2):637-55. Hopp and Woods Mol Immunol. 1983 20(4):483-9) assigned the hydrophilicity values amino acid residues: arginine (+3.0); lysine (+3.0); aspartate (+3.0 ±0.1); glutamate (+3.0 ±0.1); serine (+0.3); asparagine (+0.2); glutamine (+0.2); glycine (0); threonine (-0.4); proline (-0.5 ±0.1); alanine (-0.5); histidine (-0.5); cysteine (-1.0); methionine (-1.3); valine (-1.5); leucine (-1.8); isoleucine (-1.8); tyrosine (-2.3); phenylalanine (-2.5) and tryptophan (-3.4). In this ranking system, more hydrophilic residues are assigned positive values, and less hydrophilic residues negative. In making changes based upon similar hydrophilicity values, the substitution of amino acids whose hydrophilicity values are within ±0.2 is included, otherwise those which are within ±0.1 are included or those within ±0.5 are included. In some instances, one can also identify epitopes from primary amino acid sequences on the basis of hydrophilicity. These regions are also referred to as "epitopic core regions."

[0152] A skilled artisan will be able to determine suitable variants of polypeptides as set forth herein using well-known techniques. One skilled in the art can identify suitable areas of the molecule that can be changed without destroying activity by targeting regions not believed to be important for activity. The skilled artisan also will be able to identify residues and portions of the molecules that are conserved among similar polypeptides. Even areas that can be important for biological activity or for structure can be subject to conservative amino acid substitutions without destroying the biological activity or without adversely affecting the polypeptide structure.

[0153] Additionally, one skilled in the art can review structure-function studies identifying residues in similar polypeptides that are important for activity or structure. In view of such a comparison, one can predict the importance of amino acid residues in a protein that correspond to amino acid residues important for activity or structure in similar proteins. One skilled in the art can opt for chemically similar amino acid substitutions for such predicted important amino acid residues.

[0154] One skilled in the art can also analyze the three-dimensional structure and amino acid sequence in relation to that structure in similar polypeptides. In view of such information, one skilled in the art can predict the alignment of amino acid residues of anantibody with respect to its three-dimensional structure. One skilled in the art can choose not to make radical changes to amino acid residues predicted to be on the surface of the protein, since such residues can be involved in important interactions with other molecules. Moreover, one skilled in the art can generate test variants containing a single amino acid substitution at each desired amino acid residue. These variants can then be screened using assays for LILRB2 activity (see Examples below), thus yielding information regarding which amino acids can be changed and which must not be changed. In other words, based on information gathered from such routine experiments, one skilled in the art can readily determine the amino acid positions where further substitutions should be avoided either alone or in combination with other mutations.

[0155] Substantial modifications in the functional and / or biochemical characteristics of the antibody products described herein can be achieved by creating substitutions in the amino acid sequence of the heavy and light chains that differ significantly in their effect on maintaining (a) the structure of the molecular backbone in the area of the substitution, for example, as a sheet or helical conformation, (b) the charge or hydrophobicity of the molecule at the target site, or (c) the bulkiness of the side chain. A "conservative amino acid substitution" can involve a substitution of a native amino acid residue with a normative residue that has little or no effect on the polarity or charge of the amino acid residue at that position. Furthermore, any native residue in the polypeptide can also be substituted with alanine, as has been previously described for alanine scanning mutagenesis.

[0156] Amino acid substitutions (whether conservative or non-conservative) of the subject antibodies can be implemented by those skilled in the art by applying routine techniques. Amino acid substitutions include, but are not limited to, substitutions that: (1) reduce susceptibility to proteolysis, (2) reduce susceptibility to oxidation, (3) alter binding affinity for forming protein complexes, (4) alter ligand or antigen binding affinities, and / or (4) confer or modify other physicochemical or functional properties on such polypeptides. For example, single or multiple amino acid substitutions e.g., conservative amino acid substitutions) can be made in the naturally-occurring sequence. Substitutions can be made in that portion of the antibody that lies outside the domain(s) forming intermolecular contacts). Conservative amino acid substitutions can be used that do not substantially change the structural characteristics of the parent sequence e.g., one or more replacement amino acids that do not disrupt the secondary structure that characterizes the parent or native antibody). Examples of art-recognized polypeptide secondary and tertiary structures are described in Proteins, Structures and Molecular Principles (Creighton, ed.), 1984, NewYork: W. H. Freeman and Company; Introduction to Protein Structure (Branden and Tooze, eds.), 1991, New York: Garland Publishing; and Thornton etai., Nature. 1991 354(6349): 105-6, which are each incorporated herein by reference.

[0157] Glycosylation variants of the antibody products are provided in which the number and / or type of glycosylation site(s) has been altered compared to the amino acid sequences of the parent polypeptide. Antibody product variants can comprise a greater or a lesser number of N-linked glycosylation sites than the native antibody. An N-linked glycosylation site is characterized by the sequence: Asn-X-Ser or Asn-X-Thr, in which the amino acid residue designated as X can be any amino acid residue except proline. The substitution of amino acid residues to create this sequence provides a potential new site for the addition of an N-linked carbohydrate chain. Alternatively, substitutions that eliminate or alter this sequence will prevent addition of an N-linked carbohydrate chain present in the native polypeptide. For example, the glycosylation can be reduced by the deletion of an Asn or by substituting the Asn with a different amino acid. For example, one or more new N-linked sites are created. Antibodies typically have a N-linked glycosylation site in the Fc region.

[0158] Additional antibody product variants include cysteine variants in which one or more cysteine residues in the parent or native amino acid sequence are deleted from or substituted with another amino acid (e.g., serine). Cysteine variants are useful, inter alia when antibodies must be refolded into a biologically active conformation. Cysteine variants can have fewer cysteine residues than the native antibody, and typically have an even number to minimize interactions resulting from unpaired cysteines.Effector Functions

[0159] Antibody structure affects the role that the antibody plays in the immune system and the effects that the antibody can induce or influence. See, e.g., Vidarsson etai., Front Immunol. 2014 5(Art. 5): 1-17. Examples of antibody effector functions include: Clq binding and complement dependent cytotoxicity; Fc receptor binding; antibody-dependent cell-mediated cytotoxicity (ADCC); phagocytosis; down-regulation of cell surface receptors e.g., B cell receptor); and B cell activation. Typically, the Fc-mediated functions involve binding of the Fc portion of an antibody by specialized receptor molecules, "Fc receptors" or "FcR," expressed by the cell whose function is to be affected.

[0160] IgG is considered the most versatile immunoglobulin because it carries out all of the functions of immunoglobulin molecules in some embodiments. IgG is the major Ig in serum, and the only class of Ig that crosses the placenta. IgG also fixes complement,although the IgG4 subclass does not. Macrophages, monocytes, polymorphonuclear leukocytes (PMNs), and some lymphocytes have receptors for the Fc region of IgG. Not all subclasses bind equally well: IgG2 and IgG4 do not bind to Fc receptors. A consequence of binding to the Fc receptors on PMNs, monocytes, and macrophages is that the cell now internalizes the antigen better in some cases. IgG is an opsonin that enhances phagocytosis. Binding of IgG to Fc receptors on other types of cells results in the activation of other functions.

[0161] The FcR can be a native sequence human FcR. Moreover, a preferred FcR is one that binds an IgG antibody (a gamma ("y") receptor) and includes receptors of the FcyRI (CD64), FcyRII (CD32), and FcyRIII (CD16) subclasses, including allelic variants and alternatively spliced forms of these receptors FcyRII receptors include FcyRIIA (an "activating receptor") and FcyRIIB (an "inhibiting receptor"), which have similar amino acid sequences that differ primarily in the cytoplasmic domains thereof. Activating receptor FcyRIIA contains an immunoreceptor tyrosine- based activation motif (ITAM) in its cytoplasmic domain. Inhibiting receptor FcyRIIB contains an immunoreceptor tyrosine- based inhibition motif (ITIM) in its cytoplasmic domain.

[0162] "Antibody-dependent cell-mediated cytotoxicity" or "ADCC" refers to a form of cytotoxicity in which secreted Ig bound to Fc receptors (FcRs) present on certain cytotoxic cells e.g., Natural Killer (NK) cells, neutrophils, and macrophages) enable these cytotoxic effector cells to bind specifically to an antigen-bearing target cell and subsequently kill the target cell with cytotoxins. The antibodies "arm" the cytotoxic cells and are required for such killing. The primary cells for mediating ADCC, NK cells, express FcyRIII only, whereas monocytes express FcyRI, FcyRII, and FcyRIII. To assess ADCC activity of a molecule of interest, an in vitro i DCC assay is performed in some embodiments. Useful effector cells for such assays include peripheral blood mononuclear cells (PBMC) and Natural Killer (NK) cells.

[0163] Alternatively, or additionally, in some embodiments, ADCC activity of the molecule of interest is assessed in vivo, e.g., in an animal model.

[0164] In some embodiments, the antibodies of the disclosure bind to a surface membrane protein of and are internalized by M2-like macrophages. This internalization process is believed to be involved in the observed alteration of the functional immunosuppressive characteristics of these cells, i.e., the differentiation of the cells from M2 status to subtly activated state, without killing them or inhibiting their proliferation. In some embodiments, upon internalization, the antibodies decrease the expression of immunosuppressive soluble factors while increasing expression of soluble factors thatstimulate or promote the activity or proliferation of T cells, including CD4+ helper T cells and cytotoxic lymphocytes.

[0165] For certain therapeutic applications, the internalization process is employed for purposes of killing or decreasing the activity or proliferation of a target cell that expresses a LILRB2 protein. The number of antibody molecules internalized will be sufficient or adequate to kill a cell or inhibit its growth. Depending on the potency of an antibody or antibody conjugate, in some instances, the uptake of a single antibody molecule into the cell is sufficient to kill the target cell to which the antibody binds. For example, certain toxins are highly potent in killing such that internalization of one molecule of the toxin conjugated to the antibody is sufficient to kill the targeted cell.

[0166] In some embodiments, the LILRB2 antibody or antigen-binding fragment provided herein is conjugated or linked to a therapeutic moiety, an imaging or detectable moiety, or an affinity tag. Methods for conjugating or linking polypeptides are well known in the art. Associations (binding) between compounds and labels include any means known in the art including, but not limited to, covalent and non-covalent interactions, chemical conjugation, as well as recombinant techniques. An antibody or antigen-binding fragment thereof is conjugated to, or recombinantly engineered with, an affinity tag {e.g., a purification tag), in some embodiments. Affinity tags such as, for example, poly-histidine {e.g., His6) tags are conventional in the art.

[0167] In some embodiments, the LILRB2 antibody or antigen-binding fragment further comprises a detectable moiety. Detections accomplished, for example, in vitro, in vivoov ex vivo. In vitro assays for the detection and / or determination (quantification, qualification, etc.) of, e.g., hLILRB2 protein expressed by macrophages using the antibodies or antigenbinding fragments thereof include but are not limited to, for example, ELISAs, RIAs, and western blots. In some embodiments, in vitro detection, diagnosis, or monitoring of the antigen of the antibodies occurs by obtaining a sample {e.g., a blood sample) from a subject and testing the sample in, for example, a standard ELISA assay.Derivatives

[0168] Derivatives of the LILRB2 antibody products described herein are also provided. The derivatized antibody product can comprise any molecule or substance that imparts a desired property to the antibody product, such as increased half-life in a particular use. The derivatized antibody product can comprise, for example, a detectable (or labeling) moiety {e.g., a radioactive, colorimetric, antigenic or enzymatic molecule, a detectable bead (suchas a magnetic or electrodense (e.g., gold) bead), or a molecule that binds to another molecule (e.g., biotin or streptavidin)), a therapeutic or diagnostic moiety (e.g., a radioactive, cytotoxic, or pharmaceutically active moiety), or a molecule that increases the suitability of the antibody for a particular use (e.g., administration to a subject, such as a human subject, or other in vivoov in vitro uses). Examples of molecules that can be used to derivatize an antibody product include albumin (eg., human serum albumin) and polyethylene glycol (PEG). Albumin-linked and PEGylated derivatives of antibody products can be prepared using techniques well known in the art. The antibody can be conjugated or otherwise linked to transthyretin (TTR) or a TTR variant. The TTR or TTR variant can be chemically modified with, for example, a chemical selected from the group consisting of dextran, poly(n-vinyl pyrrolidone), polyethylene glycols, polypropylene glycol homopolymers, polypropylene oxide / ethylene oxide co-polymers, polyoxyethylated polyols and polyvinyl alcohols.

[0169] Other derivatives include covalent or aggregative conjugates of LILRB2 antibody products, with other proteins or polypeptides, such as by expression of recombinant fusion proteins comprising heterologous polypeptides fused to the N-terminus or C-terminus of an LILRB2 antibody product. For example, the conjugated peptide can be a heterologous signal (or leader) polypeptide, e.g., the yeast alpha-factor leader, or a peptide such as an epitope tag. LILRB2 antibody product-containing fusion proteins can comprise peptides added to facilitate purification or identification of the LILRB2 antibody product e.g., poly-His). An LILRB2 antibody product also can be linked to the FLAG peptide as described in Hopp etai., Bio / Technoiogy 19886:1204-10, and U. S. Pat. No. 5,011,912. The FLAG peptide is highly antigenic and provides an epitope reversibly bound by a specific monoclonal antibody (mAb), enabling rapid assay and facile purification of expressed recombinant protein.Reagents useful for preparing fusion proteins in which the FLAG peptide is fused to a given polypeptide are commercially available (Sigma, St. Louis, Mo.).

[0170] Oligomers that contain one or more LILRB2 antibody products can be employed as LILRB2 antagonists. Oligomers can be in the form of covalently-linked or non-covalently-linked dimers, trimers, or higher. Oligomers comprising two or more LILRB2 antibody products are contemplated for use, with one example being a homodimer. Other oligomers include heterodimers, homotrimers, heterotrimers, homotetramers, heterotetramers, etc.

[0171] Oligomers can comprise multiple LILRB2 antibody products joined via covalent or non-covalent interactions between peptide moieties fused to the LILRB2 antibody polypeptides. Such peptides can be peptide linkers (spacers), or peptides that have theproperty of promoting oligomerization. Leucine zippers and certain polypeptides derived from antibodies are among the peptides that can promote oligomerization of LILRB2 antibody products attached thereto, as described in more detail below.

[0172] Oligomers can comprise from two to four LILRB2 antibody products. The LILRB2 product moieties of the oligomer can be in any of the forms described above, e.g., variants or fragments. The oligomers comprise LILRB2 antibody products that have LILRB2 binding activity.

[0173] Preparation of fusion proteins comprising heterologous polypeptides fused to various portions of antibody-derived polypeptides (including the Fc domain) has been described, e.g., by Ashkenazi eta / ., Proc Natl Acad Sci USA. 1991 88(23): 10535-9; Byrn et a!., Nature 1990 344(6267):677-670; and Hollenbaugh and Aruffo, Curr Protoc Immunol. 2002 48(l):10.19A.l-10.19A.il.

[0174] Dimers are provided comprising two fusion proteins created by fusing a LILRB2 binding fragment of an LILRB2 antibody to the Fc region of an antibody. The dimer can be made by, for example, inserting a gene fusion encoding the fusion protein into an appropriate expression vector, expressing the gene fusion in host cells transformed with the recombinant expression vector, and allowing the expressed fusion protein to assemble much like antibody molecules, whereupon interchain disulfide bonds form between the Fc moieties to yield the dimer.

[0175] The term "Fc polypeptide" as used herein includes native and mutein forms of polypeptides derived from the Fc region of an antibody. Truncated forms of such polypeptides containing the hinge region that promotes dimerization also are included. Fusion proteins comprising Fc moieties (and oligomers formed therefrom) offer the advantage of facile purification by affinity chromatography over Protein A or Protein G columns.

[0176] One exemplary Fc polypeptide, described in PCT Publication No. WO 93 / 10151 and U. S. Patent Nos. 5,426,048 and 5,262,522 (each of which is hereby incorporated by reference), is a single chain polypeptide extending from the N-terminal hinge region to the native C-terminus of the Fc region of a human IgGl antibody. Another exemplary Fc polypeptide is the Fc mutein described in U. S. Patent No. 5,457,035 and in Baum eta!., EMBOJ. 1994 13:3992-4001 (1994). The amino acid sequence of this mutein is identical to that of the native Fc sequence presented in PCT Publication No. WO 93 / 10151, except that amino acid 19 has been changed from Leu to Ala, amino acid 20 has been changed fromLeu to Glu, and amino acid 22 has been changed from Gly to Ala. The mutein exhibits reduced affinity for Fc receptors.

[0177] Alternatively, the oligomer is a fusion protein comprising multiple LILRB2 antibody polypeptides, with or without peptide linkers (spacer peptides). Among the suitable peptide linkers are those described in U. S. Patent Nos. 4,751,180 and 4,935,233.

[0178] Another method for preparing oligomeric LILRB2 antibody product derivatives involves use of a leucine zipper. Leucine zipper domains are peptides that promote oligomerization of the proteins in which they are found. Examples of leucine zipper domains suitable for producing soluble oligomeric proteins are described in PCT Publication No. WO 94 / 10308, and the leucine zipper derived from lung surfactant protein D (SPD) described in Hoppe eta!., FEBS Lett. 1994344:191-5. The use of a modified leucine zipper that allows for stable trimerization of a heterologous protein fused thereto is described in Fanslow eta / ., Semin Immunol. 19946:267-78. Generally, recombinant fusion proteins comprising an LILRB2 antibody fragment fused to a leucine zipper peptide are expressed in suitable host cells, and the soluble oligomeric LILRB2 antibody products that form are recovered from the culture supernatant.

[0179] LILRB2 antibody products described herein can also be derivatized or modified such that the products have a longer half-life as compared to the underivatized or unmodified antibody. For example, the antibody product can contain point mutations to increase serum half-life, such as described in PCT Publication No. WO 00 / 09560.Compositions

[0180] Compositions that include LILRB2 antibody products are also provided.Pharmaceutical compositions typically include one or more of a buffer, a pharmaceutically acceptable diluent, a carrier, a solubilizer, an emulsifier and a preservative. The use of the foregoing antibody products in the preparation of a pharmaceutical composition or medicament is also provided. Compositions are provided that comprise an LIRLB2 antibody product and at least one excipient.

[0181] Pharmaceutically acceptable excipients are the substances in a formulated product other than the active pharmaceutical ingredient. Acceptable excipients for pharmaceutical preparations are generally nontoxic to recipients at the dosages and concentrations employed. In addition to the antibody products, the compositions that are provided herein can contain components for modifying, maintaining or preserving the state of the composition, and especially the active antibody product, for example, the pH, osmolarity,viscosity, clarity, color, isotonicity, odor, sterility, stability, rate of dissolution or release, adsorption, or penetration of the composition. Suitable materials for formulating pharmaceutical compositions include, but are not limited to, amino acids (such as glycine, glutamine, asparagine, arginine or lysine); antimicrobials; antioxidants (such as ascorbic acid, sodium sulfite or sodium hydrogen-sulfite); buffers (such as acetate, borate, bicarbonate, Tris-HCI, citrates, phosphates or other organic acids); bulking agents (such as mannitol or glycine); chelating agents (such as ethylenediamine tetraacetic acid (EDTA)); complexing agents (such as caffeine, polyvinylpyrrolidone, beta-cyclodextrin or hydroxypropyl-beta-cyclodextrin); fillers; monosaccharides; disaccharides; and other carbohydrates (such as glucose, mannose or dextrins); proteins (such as serum albumin, gelatin or immunoglobulins); coloring, flavoring and diluting agents; emulsifying agents; hydrophilic polymers (such as polyvinylpyrrolidone); low molecular weight polypeptides; saltforming counterions (such as sodium); preservatives (such as benzalkonium chloride, benzoic acid, salicylic acid, thimerosal, phenethyl alcohol, methylparaben, propylparaben, chlorhexidine, sorbic acid or hydrogen peroxide); solvents (such as glycerin, propylene glycol or polyethylene glycol); sugar alcohols (such as mannitol or sorbitol); suspending agents; surfactants or wetting agents (such as pluronics, PEG, sorbitan esters, polysorbates such as polysorbate 20, polysorbate 80, triton, tromethamine, lecithin, cholesterol, tyloxapal); stability enhancing agents (such as sucrose or sorbitol); tonicity enhancing agents (such as alkali metal halides, preferably sodium or potassium chloride, mannitol sorbitol); delivery vehicles; diluents; excipients and / or pharmaceutical adjuvants, (see Remington's Pharmaceutical Sciences, 23rd ed., (Adejare, ed.), 2020, Elsevier Academic Press).

[0182] The primary vehicle or carrier in a pharmaceutical composition can be either aqueous or non-aqueous in nature. Suitable vehicles or carriers for such compositions include water for injection, physiological saline solution or artificial cerebrospinal fluid, possibly supplemented with other materials common in compositions for parenteral administration. Neutral buffered saline or saline mixed with serum albumin are further exemplary vehicles. Compositions comprising LILRB2 antibody product can be prepared for storage by mixing the selected composition having the desired degree of purity with optional formulation agents in the form of a lyophilized cake or an aqueous solution. Further, the LILRB2 antibody product can be formulated as a lyophilizate using appropriate excipients such as sucrose.

[0183] Formulation components are present in concentrations that are acceptable to the site of administration. Buffers are advantageously used to maintain the composition atphysiological pH or at a slightly lower pH, typically within a pH range of from about 4.0 to about 8.5, or alternatively, between about 5.0 to 8.0. Pharmaceutical compositions can comprise TRIS buffer of about pH 6.5-8.5, or acetate buffer to yield a solution of pH 4.0-5.5, which can further include sorbitol or a suitable substitute therefor.

[0184] Additional pharmaceutical compositions are in the form of sustained- or controlled-delivery formulations. Techniques for formulating a variety of other sustained- or controlled-delivery means, such as liposome carriers, bio-erodible microparticles or porous beads and depot injections can be used (see, e.g., PCT Publication No. WO 93 / 15722 Al, which describes the controlled release of porous polymeric microparticles for the delivery of pharmaceutical compositions). Sustained-release preparations can include semipermeable polymer matrices in the form of shaped articles, e.g., films, or microcapsules, polyesters, hydrogels, polylactides (U. S. Pat. No. 3,773,919 and EP 058,481), copolymers of L-glutamic acid and gamma ethyl -L-g I uta mate (Sidman et al., Biopolymers. 1983 22:547-56), poly (2-hydroxyethyl-methacrylate) (Langer eta / ., J Biomed Mater Res. 1981 15:167-277) and Langer, Chem Tech. 1982 12:98-105), ethylene vinyl acetate (Langer etai., ibid.) or poly-D(-)-3-hydroxybutyric acid (EP 133,988). Sustained release compositions can also include liposomes, which can be prepared by any of several methods known in the art. See, e.g., Eppstein etai., Proc Nat / Acad Sci USA. 1985 82:3688-92; EPO Publication Nos. EP 036676; EP 088046, and EP 143949.

[0185] Once the pharmaceutical composition has been formulated, it can be stored in sterile vials as a solution, suspension, gel, emulsion, solid, or as a dehydrated or lyophilized powder. Such formulations can be stored either in a ready-to-use form or in a form {e.g., lyophilized) that is reconstituted prior to administration.

[0186] The components used to formulate the pharmaceutical compositions are preferably of high purity and are substantially free of potentially harmful contaminants e.g., at least National Food (NF) grade, generally at least analytical grade, and more typically at least pharmaceutical grade). Moreover, compositions intended for in vivo use are usually sterile. To the extent that a given compound must be synthesized prior to use, the resulting product is typically substantially free of any potentially toxic agents, particularly any endotoxins, which may be present during the synthesis or purification process. Compositions for parental administration are also sterile, substantially isotonic and made under GMP conditions.

[0187] The disclosure provides a pharmaceutical composition comprising one or more of sodium acetate, sucrose and polysorbate 80. The disclosure provides a pharmaceutical composition comprising sodium acetate, sucrose and polysorbate 80. The disclosureprovides a pharmaceutical composition comprising 10 mM sodium acetate, 9% (w / v) sucrose, 0.015% (w / w) polysorbate 80, pH 5.2. Pharmaceutical compositions provided herein may comprise OR502 formulated at 50 mg / mL.

[0188] Kits are provided for multi-dose or single-dose administration units. For example, kits can each contain both a first container having a dried protein and a second container having an aqueous diluent, including for example single and multi-chambered pre-filled syringes e.g., liquid syringes, lyosyringes or needle-free syringes). As another example, a kit can contain a sterile, single-use, preservative-free solution in a vial containing OR502 formulated in sodium acetate, sucrose and polysorbate 80. The solution can be 10 mM sodium acetate, 9% (w / v) sucrose, 0.015% (w / w) polysorbate 80, pH 5.2. As yet another example, a kit can contain a sterile, single-use, preservative-free solution in a vial containing a nominal fill volume of about 4 mL comprising OR502 formulated at 50 mg / mL in sodium acetate, sucrose and polysorbate 80. The solution can be 10 mM sodium acetate, 9% (w / v) sucrose, 0.015% (w / w) polysorbate 80, pH 5.2.

[0189] The pharmaceutical compositions can be delivered parenterally, typically by injection. Injections can be intraocular, intraperitoneal, intraportal, intramuscular, intravenous, intrathecal, intracerebral (intra-parenchymal), intracerebroventricular, intraarterial, intralesional, perilesional, or subcutaneous. Eye drops can be used for intraocular administration. In some instances, injections can be localized to the vicinity of a particular bone or bones to which the treatment is targeted. For parenteral administration, the antibodies can be administered in a pyrogen-free, parenterally acceptable aqueous solution comprising the desired LILRB2 antibody product in a pharmaceutically acceptable vehicle. A particularly suitable vehicle for parenteral injection is sterile distilled water in which the LILRB2 antibody product is formulated as a sterile, isotonic solution, properly preserved.

[0190] Pharmaceutical compositions comprising the subject LILRB2 antibody products can be administered by bolus injection or continuously by infusion, by implantation device, sustained release systems or other means for accomplishing prolonged release. The pharmaceutical composition also can be administered locally via implantation of a membrane, sponge or another appropriate material onto which the desired molecule has been absorbed or encapsulated. Where an implantation device is used, the device can be implanted into any suitable tissue or organ, and delivery of the desired molecule can be via diffusion, timed-release bolus, or continuous release. The preparation can be formulated with agents, such as injectable microspheres, bio-erodible particles, polymeric compounds(such as polylactic acid; polyglycolic acid; or copoly (lactic / glycolic) acid (PLGA), beads or liposomes, that can provide controlled or sustained release of the product which can then be delivered via a depot injection. Formulation with hyaluronic acid has the effect of promoting sustained duration in the circulation.

[0191] Subject compositions comprising LILRB2 antibody product also can be used ex vivo. In such instances, cells, tissues, or organs that have been removed from the patient are exposed to or cultured with the LILRB2 antibody product. The cultured cells can then be implanted back into the patient or a different patient or used for other purposes.

[0192] LILRB2 antibody product can be delivered by implanting certain cells that have been genetically engineered, using methods such as those described herein, to express and secrete the polypeptide. Such cells can be animal or human cells, and can be autologous, heterologous, or xenogeneic, or can be immortalized. In order to decrease the chance of an immunological response, the cells can be encapsulated to avoid infiltration of surrounding tissues. Encapsulation materials are typically biocompatible, semi-permeable polymeric enclosures or membranes that allow the release of the protein product(s) but prevent the destruction of the cells by the patient's immune system or by other detrimental factors from the surrounding tissues.

[0193] As used herein, "substantially pure" means that the described species of molecule is the predominant species present, that is, on a molar basis it is more abundant than any other individual species in the same mixture. A substantially pure molecule can be a composition in which the object species comprises at least 50% (on a molar basis) of all macromolecular species present. A substantially pure composition can comprise at least 80%, 85%, 90%, 95%, or 99% of all macromolecular species present in the composition. The object species can also be purified to essential homogeneity in which contaminating species cannot be detected in the composition by conventional detection methods and thus the composition consists of a single detectable macromolecular species.Dosages

[0194] The pharmaceutical compositions that are provided can be administered for prophylactic and / or therapeutic treatment.

[0195] As used herein, the terms "treatment," "treating," "providing cancer immunotherapy," and the like, refer to administering an agent or carrying out a procedure, for the purposes of obtaining an effect. The effect is prophylactic in terms of completely or partially preventing disease or symptom thereof in a subject at risk for cancer and / or istherapeutic in terms of effecting a partial or complete cure for a disease and / or symptoms of the disease in a subject having (suffering from) cancer. "Treatment," as used herein, includes treatment of a disease or disorder e.g., cancer) in a mammal, particularly in a human, and includes: (a) prophylactic treatment, that is preventing the disease or a symptom of a disease from occurring in a subject which is predisposed to the disease but has not yet been diagnosed as having it e.g., including diseases that are associated with or caused by a primary disease); (b) therapeutic treatment inhibiting the disease, i.e., arresting its development; and (c) therapeutic treatment relieving the disease, i.e., causing regression of the disease. Treating refers to any clinical indicia of success in the treatment or amelioration or prevention, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the disease condition more tolerable to the patient; slowing in the rate of degeneration or decline; or making the final point of degeneration less debilitating. The treatment or amelioration of symptoms is based on one or more objective or subjective parameters, including the results of an examination by a physician. Accordingly, the term "treating" includes the administration of the compounds or agents of the present disclosure to prevent or delay, to alleviate, or to arrest or inhibit development of the symptoms or conditions associated with diseases e.g., cancer). The term "therapeutic effect" refers to the reduction, elimination, or prevention of the disease, symptoms of the disease, or side effects of the disease in the subject. For example, a subject is "treated" for a disease or disorder if, after receiving a therapeutic amount of a combination of a LILRB2 antibody product provided herein, the patient shows one or more observable and / or measurable changes in an endpoint or symptom of the disease condition.

[0196] An "effective response" in accordance with the present disclosure is achieved when the subject experiences partial or total alleviation or reduction of signs or symptoms of illness and, in the case of the treatment of cancer, specifically includes, without limitation, amelioration of symptoms, retarding progression, cure, remission, prolongation of survival, or other objective responses. The expected progression-free survival times can be measured in months to years, depending on prognostic factors including the number of relapses, stage of disease, and other factors. Prolonging survival includes without limitation times of at least 1 month (mo.), about at least 2 mos., about at least 3 mos., about at least 4 mos., about at least 6 mos., about at least 1 year, about at least 2 years, about at least 3 years, etc.Overall survival is also measured, for example, in months to years. Alternatively, an effective response can be that a subject's symptoms remain static.

[0197] Administration of a therapeutic agent in a prophylactic method occurs prior to the manifestation of symptoms of an undesired disease or disorder, such that the disease or disorder is prevented or, alternatively, delayed in its progression. Thus, when used in conjunction with prophylactic methods, the term "therapeutically effective" means that, after treatment, a smaller number of subjects (on average) develop the undesired disease or disorder or progress in severity of symptoms.

[0198] The terms "recipient," "individual," "subject," "host," and "patient," are used interchangeably herein and refer to any mammalian subject for whom diagnosis, treatment, or therapy is desired, particularly humans. "Mammal" for purposes of treatment refers to any animal classified as a mammal, including humans, domestic and farm animals, and laboratory, zoo, sports, or pet animals, such as dogs, horses, cats, cows, sheep, goats, pigs, mice, rats, rabbits, guinea pigs, monkeys, etc. The mammal can be a human.

[0199] In general, toxicity and therapeutic efficacy of the antibody product can be determined according to standard pharmaceutical procedures in cell cultures and / or experimental animals, including, for example, determining the LD5o (the dose lethal to 50% of the population) and the ED5o (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD50 / ED50. Compositions that exhibit large therapeutic indices are preferred.

[0200] The data obtained from cell culture and / or animal studies can be used in formulating a range of dosages for humans. The dosage of the active ingredient typically lines within a range of circulating concentrations that include the ED50 with little or no toxicity. The dosage can vary within this range depending upon the dosage form employed and the route of administration utilized.

[0201] The effective amount of a pharmaceutical composition comprising LILRB2 antibody product to be employed therapeutically or prophylactically will depend, for example, upon the therapeutic context and objectives. One skilled in the art will appreciate that the appropriate dosage levels for treatment will thus vary depending, in part, upon the molecule delivered, the indication for which the LILRB2 antibody is being used, the route of administration, and the size (body weight, body surface or organ size) and / or condition (the age and general health) of the patient. A clinician can titer the dosage and modify the route of administration to obtain the optimal therapeutic effect. Typical dosages range from about 1 mg to up to about 1600 mg or more, depending on the factors mentioned above. The dosage can range from 1 mg up to about 200 mg; or 1 mg up to about 1200 mg; or 1 ug / kgup to about 1600 mg. The dosage can be about 100 mg to about 800 mg. The dosage can be about 100 mg, about 200 mg, about 400 mg, about 800 mg or about 1600 mg. The dosage can be about 800 mg.

[0202] The dosage of the LILRB2 antibody product can be sufficient to obtain more than 90% occupancy of LILRB2 in the subject for at least 21 days.

[0203] The dosage of the LILRB2 antibody product can be sufficient to obtain blood concentration in the subject to achieve at least 90% maximal pharmacological active concentration e.g., EC90=19.1 pg / mL) for at least 21 days.

[0204] The dosing frequency will depend upon the pharmacokinetic parameters of the LILRB2 antibody product in the formulation. For example, a clinician will administer the composition until a dosage is reached that achieves the desired effect. The composition can therefore be administered as a single dose, or as two or more doses (which can contain the same amount of the desired molecule) over time, or as a continuous infusion via an implantation device or catheter. Treatment can be continuous over time or intermittent, e.g., periodic or occasional. Further refinement of the appropriate dosage is routinely made by those of ordinary skill in the art and is within the ambit of tasks routinely performed by them. Appropriate dosages can be ascertained through use of appropriate dose-response data. An exemplary dosing schedule is every 2 to 3 weeks. A dosing schedule can be every 3 weeks, i.e., every 21 days.

[0205] To treat a disease condition by targeting LILRB2, a composition comprising the subject LILRB2 antibody product is administered to the patient in an amount and for a time sufficient to induce a sustained improvement in at least one indicator that reflects the severity of the disorder. An improvement is considered "sustained" if the patient exhibits the improvement on at least two occasions separated by at least one to seven days, or in some instances one to six weeks. The appropriate interval will depend to some extent on what disease condition is being treated; it is within the purview of the skilled physician to determine the appropriate interval for determining whether the improvement is sustained. The degree of improvement is determined based on signs or symptoms, and can also employ questionnaires that are administered to the patient, such as quality-of-life questionnaires.

[0206] Various indicators that reflect the extent of the patient's illness can be assessed for determining whether the amount and time of the treatment is sufficient. The baseline value for the chosen indicator or indicators is established by examination of the patient prior toadministration of the first dose of antibody. Preferably, the baseline examination is done within about 60 days of administering the first dose. If the antibody is being administered to treat acute symptoms, such as for example to treat a broken bone, the first dose is administered as soon as practically possible after the injury has occurred.

[0207] Improvement is induced by administering the subject LILRB2 antibody product until the patient manifests an improvement over baseline for the chosen indicator or indicators. In treating chronic conditions, this degree of improvement is obtained by repeatedly administering this medicament over a period of at least a month or more, e.g., for one, two, or three months or longer, or indefinitely. A period of one to six weeks, or even a single dose, often is sufficient for treating acute conditions. For injuries or acute conditions, a single dose can be sufficient.

[0208] Although the extent of the patient's illness after treatment may appear improved according to one or more indicators, treatment can be continued indefinitely at the same level or at a reduced dose or frequency. Once treatment has been reduced or discontinued, it later can be resumed at the original level if symptoms should reappear.Methods of Use

[0209] The LILRB2 antibody products disclosed herein have a variety of utilities. In methods provided herein, the antibody products can be used to treat various diseases that are associated with the activity of LILRB2.

[0210] The LILRB2 antibody products provided herein are useful for the immunotherapy of cancers.

[0211] Thus, LILRB2 antibody products described herein can be used for the treatment of cancer, either alone or in combination with another anti-cancer therapeutic. Cancers to be treated are those where the cancer cells are known to express LILRB2 or are of a type that has previously been observed to express LILRB2. Certain cancers that are EGFR-mutant have been found to more highly express LILRB2, and so are contemplated for treatment using the antibodies disclosed herein. In contrast, expression of LILRB2 in cancer cells has also been found to be inversely related to expression of PD-L1. Anti-LILRB2 treatment as described herein is thus also contemplated in cases where PD-L1 expression by the cancer cells is not observed. Such treatment is indicated when therapeutic intervention in the PD-1 / PD-L1 axis is, or is expected to be, ineffective.

[0212] Provided herein are methods of providing immunotherapy and treating a patient having a cancer, in which a LILRB2 antibody product mediates killing of the cells of the cancer.

[0213] As used herein, the term "cancer" has its general meaning in the art and includes, but is not limited to, solid tumors and blood-borne tumors. The term cancer includes diseases of the skin, tissues, organs, bone, cartilage, blood and vessels. The term "cancer" further encompasses both primary and metastatic cancers.

[0214] Examples of cancers that can be treated by methods and compositions provided herein include, but are not limited to, cancers of the bladder, blood, bone, bone marrow, brain, breast, cervix, colon, esophagus, gastrointestinal tract, rectum, head and neck, kidney, larynx, liver, lung, mouth nasopharynx, neck, ovary, pancreas, prostate, skin, stomach, testis, thyroid, tongue, and uterus.

[0215] Cancers to be treated include, for example, acute lymphoblastic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, myelodysplastic syndrome, chronic myelogenous leukemia, Hodgkin's disease; Hodgkin's lymphoma, non-Hodgkin's lymphoma, Burkitt lymphoma, bladder cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, esophageal cancer, gallbladder cancer, hepatocellular cancer, head and neck cancer, kidney cancer, melanoma, malignant mesothelioma, nasopharyngeal cancer, neuroblastoma, glioblastoma, pancreatic cancer, multiple myeloma, prostate cancer, small cell lung cancer, non-small cell lung cancer, and metastatic cancers. Cancers to be treated include, for example, glioblastoma multiforme, head and neck cancer, kidney renal clear cell cancer, acute myeloid leukemia, pancreatic adenocarcinoma, skin cutaneous melanoma, stomach adenocarcinoma, testicular germ cell cancer, gastric cancer, Merkel cell carcinoma, dendritic sarcoma, non-small cell lung cancer, papillary thyroid cancer, cutaneous squamous cell carcinoma, or ovarian cancer. The cancer treated can be melanoma. The cancer treated can be non-small cell lung cancer.

[0216] In addition, the cancer can specifically be of the following histological type, though it is not limited to these: neoplasm, malignant; carcinoma; carcinoma, undifferentiated; giant and spindle cell carcinoma; small cell carcinoma; papillary carcinoma; squamous cell carcinoma; lymphoepithelial carcinoma; basal cell carcinoma; pilomatrix carcinoma; transitional cell carcinoma; papillary transitional cell carcinoma; adenocarcinoma; gastrinoma, malignant; cholangiocarcinoma; hepatocellular carcinoma; combined hepatocellular carcinoma and cholangiocarcinoma; trabecular adenocarcinoma; adenoid cystic carcinoma; adenocarcinoma in adenomatous polyp; adenocarcinoma, familialadenomatous polyposis; solid carcinoma; carcinoid tumor, malignant; bronchiolo-alveolar adenocarcinoma; papillary adenocarcinoma; chromophobe carcinoma; acidophil carcinoma; oxyphilic adenocarcinoma; basophil carcinoma; clear cell adenocarcinoma; granular cell carcinoma; follicular adenocarcinoma; papillary and follicular adenocarcinoma; nonencapsulating sclerosing carcinoma; adrenal cortical carcinoma; endometroid carcinoma; skin appendage carcinoma; apocrine adenocarcinoma; sebaceous adenocarcinoma; ceruminous adenocarcinoma; mucoepidermoid carcinoma; cystadenocarcinoma; papillary cystadenocarcinoma; papillary serous cystadenocarcinoma; mucinous cystadenocarcinoma; mucinous adenocarcinoma; signet ring cell carcinoma; infiltrating duct carcinoma; medullary carcinoma; lobular carcinoma; inflammatory carcinoma; Paget's disease, mammary; acinar cell carcinoma; adenosquamous carcinoma; adenocarcinoma w / squamous metaplasia; thymoma, malignant; ovarian stromal tumor, malignant; thecoma, malignant; granulosa cell tumor, malignant; androblastoma, malignant; Sertoli cell carcinoma; Leydig cell tumor, malignant; lipid cell tumor, malignant; paraganglioma, malignant; extra-mammary paraganglioma, malignant; pheochromocytoma; glomangiosarcoma; malignant melanoma; amelanotic melanoma; superficial spreading melanoma; malignant melanoma in giant pigmented nevus; epithelioid cell melanoma; malignant cellular blue nevus; sarcoma; fibrosarcoma; fibrous histiocytoma, malignant; myxosarcoma; liposarcoma; leiomyosarcoma; rhabdomyosarcoma; embryonal rhabdomyosarcoma; alveolar rhabdomyosarcoma; stromal sarcoma; mixed tumor, malignant; Mullerian mixed tumor; nephroblastoma; hepatoblastoma; carcinosarcoma; mesenchymoma, malignant; Brenner tumor, malignant; phyllodes tumor, malignant; synovial sarcoma; mesothelioma, malignant; dysgerminoma; embryonal carcinoma; teratoma, malignant; struma ovarii, malignant; choriocarcinoma; mesonephroma, malignant; hemangiosarcoma; hemangioendothelioma, malignant; Kaposi's sarcoma; hemangiopericytoma, malignant; lymphangiosarcoma; osteosarcoma; juxtacortical osteosarcoma; chondrosarcoma; chondroblastoma, malignant; mesenchymal chondrosarcoma; giant cell tumor of bone; Ewing's sarcoma; odontogenic tumor, malignant; ameloblastic odontosarcoma; ameloblastoma, malignant; ameloblastic fibrosarcoma; pinealoma, malignant; chordoma; glioma, malignant; ependymoma; astrocytoma; protoplasmic astrocytoma; fibrillary astrocytoma; astroblastoma; glioblastoma; oligodendroglioma; oligodendroblastoma; primitive neuroectodermal; cerebellar sarcoma; ganglioneuroblastoma; neuroblastoma; retinoblastoma; olfactory neurogenic tumor; meningioma, malignant; neurofibrosarcoma; neurilemmoma, malignant; granular cell tumor, malignant; malignant lymphoma; Hodgkin's disease; Hodgkin's lymphoma; paragranuloma; malignant lymphoma, small lymphocytic; malignant lymphoma, large cell, diffuse; malignantlymphoma, follicular; mycosis fungoides or cutaneous T-cell lymphoma; other specified nonHodgkin's lymphomas; malignant histiocytosis; multiple myeloma; mast cell sarcoma; immunoproliferative small intestinal disease; leukemia; lymphoid leukemia; plasma cell leukemia; erythroleukemia; lymphosarcoma cell leukemia; myeloid leukemia; basophilic leukemia; eosinophilic leukemia; monocytic leukemia; mast cell leukemia; megakaryoblastic leukemia; myeloid sarcoma; and hairy cell leukemia.

[0217] As an example, a method is provided for the treatment of a subject suffering from melanoma. As used herein, "melanoma" refers to a condition characterized by the growth of a tumor arising from the melanocytic system of the skin and other organs. Most melanocytes occur in the skin, but are also found in the meninges, digestive tract, lymph nodes and eyes. When melanoma occurs in the skin, it is referred to as cutaneous melanoma. Melanoma can also occur in the eyes and is called ocular or intraocular melanoma. Melanoma occurs rarely in the meninges, the digestive tract, lymph nodes or other areas where melanocytes are found.

[0218] Cells of a cancer treated in methods provided herein can express LILRB2. Cells of the cancer can overexpress LILRB2.

[0219] A way by which a LILRB2 antibody product can mediate cancer cell killing is through antibody-dependent cellular toxicity C'ADCC"). ADCC is the process by which antibodies coat a target cell e.g., a cancer cell or bacterial cell) and recruit effector cells to induce target cell death via non-phagocytic mechanisms.

[0220] As noted above, in treatment methods the LILRB2 antibody products provided herein can be used as a monotherapy or in a combination therapy. A "combination" therapy refers to administration of one treatment agent before, during, or after administration of the other treatment agent to the subject.

[0221] In a combination treatment for cancer, the LILRB2 antibody product is used in combination with one or more other anticancer modalities for the treatment of a cancer in a subject. The anticancer modality can be a chemotherapeutic or biologic molecule. The anticancer modality can be an immunotherapeutic molecule.

[0222] Provided herein are methods of treating a patient having a cancer, comprising administering to the patient an LILRB2 antibody product as described herein in combination with an immunotherapy.

[0223] As an example of a combination with an immunotherapy, methods of treating a patient having a cancer are provided, comprising administering to the patient atherapeutically effective amount of a LILRB2 antibody product and one or more immune checkpoint inhibitors that inhibit PD-1. Programmed cell death 1 (PD-1) is a key checkpoint receptor expressed by activated T and B cells, and mediates immunosuppression. Among other things, PD-1 limits activity of T cells in peripheral tissues during an inflammatory response to infection. In addition, as a checkpoint protein, PD-1 blockade can enhance T-cell proliferation and cytokine production in response to a challenge by specific antigen targets or by allogeneic cells in mixed lymphocyte reactions.

[0224] Without intending to be bound by theory, it is believed that blockade of PD-1, in combination with a LILRB2 antibody product as disclosed herein, relieves macrophage-mediated T cell suppression / exhaustion, increases T cell proliferation and cytokine production, and improves immune cell effector function. PD-1 blockade can be accomplished by a variety of mechanisms. For instance, PD-1 blockade can be achieved by blocking PD-1 binding to its ligands. PD-1 can be blocked with a checkpoint inhibitor that is a PD-1 antagonist. For instance, a PD-1 antagonist can be a PD-1 antibody {e.g., nivolumab, pembrolizumab, etc.). A PD-1 antagonist can be a small molecule \e.g., INCB-086550 (Incyte) or small molecules disclosed in, e.g., Wu eta / ., Acta Pharmacol Sin. 2021 42:1-9; Jiao etai., Curr Pharm Des. 2018 24(41):4911-20; and Liu etai., Cancer Cell I nt. 2021 21(1):239]. A PD-1 antagonist can be or can comprise rationally-designed peptide {e.g., APi2568). A PD-1 antagonist can be or can comprise a cell or cell preparation e.g., cells that express a PD-1 binding agent, e.g., a PD-1 antibody, e.g., HerinCAR-PDl).

[0225] Exemplary PD-1 antibody products (and compositions thereof) suitable for use in the methods include, without limitation, nivolumab {e.g., ONO-4538, BMS-936558, MDX1106, Opdivo®; Bristol-Myers Squibb), pembrolizumab {e.g., MK-3475, Keytruda®; Merck), cemiplimab {e.g., cemiplimab-rwlc, Libtayo®; Regeneron), dostarlimab {e.g., dostarlimab-gxly, Jemperli®; GlaxoSmithKline), pimivalimab (IgG4)(e.., JTX-4014; Jounce Therapeutics), spartalizumab (IgG4)(e.., PDR001; Novartis), camrelizumab {e.g., SHR1210; Jiangsu HengRui Medicine), sintilimab (IgG4)(e.., IBI308, Tyvyt®; Innovent and Eli Lilly), tislelizumab {e.g., BGBA317, tislelizumab-jsgr, (Tevimbra®); BeiGene), toripalimab {e.g., JS 001, toripalimab-tpzi, Loqtorzi®; Coherus Biosciences and Shanghai Junshi Bioscience), MEDI0680 (IgG4K) {e.g., AMP-514; AstraZeneca), balstilimab {e.g., AGEN2034; Agenus); retifanlimab {e.g., retifanlimab-dlwr, INCMGA00012, MGA012, Zynyz®; Incyte), zimberelimab {e.g., GLS-010; Gloria Pharmaceuticals, WuXi Biologies, Arcus); and / or a PD-1 binding domain of any of them. In some embodiments, the PD-1 antibody product or composition is selected from those already approved by a regulatory agency for use (aloneor in combination) in the treatment of cancers of the type of concern in the subject being treated.

[0226] Treatment methods provided herein can include administration of cemiplimab to a subject. The dosage of cemiplimab can be about 350 mg / kg administered by IV.

[0227] Another exemplary PD-1 antagonist is a rationally designed peptide such as, e.g., APi2568, which comprises a B-cell epitope (amino acids 92-110 from PD-1) linked to a promiscuous T-cell epitope (amino acid residues 288-302 from measles virus fusion protein) via a 4-amino acid linker, and combined with Water for Injection (WFI) forms the drug product, IMU-201, which becomes PDl-Vaxx when emulsified with excipient Montanide ISA 720 VG.

[0228] Another exemplary PD-1 antagonist is a cell expressing a PD-1 antibody, for example, PD-1 anti body-exp ressi ng -CAR-T cells e.g., HerinCAR-PDl cells).

[0229] In some embodiments, the checkpoint inhibitor is a PD-L1 antagonist, such as a PD-L1 antibody. In some embodiments, the PD-L1 antibody is selected from the group consisting of avelumab, durvalumab, atezolizumab, envafolimab, cosibelimab, LY3300054 CA-170, BMS-936559, and PD-Ll-binding fragments or combinations thereof. In some embodiments, the PD-L1 antagonist comprises AUNP-12, BMS-986189, a PD-L1 binding domain comprising CDRs of an antibody selected from the group consisting of avelumab, durvalumab, atezolizumab, envafolimab, cosibelimab (CK-301), LY3300054, CA-170, and BMS-936559, and active fragments thereof, or combinations thereof.

[0230] Methods of treating a disease condition in a subject, in which the disease condition is characterized by or mediated through LILRB2 expression by myeloid cells, are also provided. The myeloid cell can be macrophages. The myeloid cells can be osteoclasts or osteoclast precursors. The methods comprise administering to the subject a therapeutically effective amount of an LILRB2 antibody product disclosed herein.

[0231] Methods of treatment or prophylaxis of a bone-metabolism disorder in a subject are also provided. The bone-metabolism disorder can be osteoporosis, bone destruction accompanying rheumatoid arthritis, cancerous hypercalcemia, bone destruction accompanying multiple myeloma or cancer metastasis to bone, giant cell tumor, osteopenia, tooth loss due to periodontitis, osteolysis around a prosthetic joint, bone destruction in chronic osteomyelitis, bone Paget's disease, renal osteodystrophy, or osteogenesis imperfecta. The bone metabolism disorder can be osteoporosis. The osteoporosis can be postmenopausal osteoporosis, senile osteoporosis, secondary osteoporosis due to the use ofa therapeutic agent such as a steroid or an immunosuppressant, or osteoporosis accompanying rheumatoid arthritis.Other Terminology and Disclosure

[0232] As used herein and in the appended claims, the singular forms "a," "an," and "the" mean "one or more" unless the context unambiguously requires a more restricted meaning. Thus, for example, reference to "an antibody" includes multiple antibodies. It is further noted that the claims may be drafted to exclude any element, e.g., any optional element. As such, this sentence is intended to serve as antecedent basis for use of such exclusive terminology as "solely," "only" and the like in connection with the recitation of claim elements, or use of a "negative" limitation.

[0233] Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integer or step. When used herein the term "comprising" can be substituted with the term "containing" or "including" or sometimes when used herein with the term "having." When used herein, "consisting of excludes any element, step, or ingredient not specified in the claim. When used herein, "consisting essentially of does not exclude materials or steps that do not materially affect the basic and novel characteristics of the subject matter of a claim.

[0234] As used herein, all numerical values or numerical ranges include whole integers within or encompassing such ranges and fractions of the values or the integers within or encompassing ranges unless the context clearly indicates otherwise. Thus, for example, reference to a range of 90-100%, includes 91%, 92%, 93%, 94%, 95%, 95%, 97%, etc., as well as 91.1%, 91.2%, 91.3%, 91.4%, 91.5%, etc., 92.1%, 92.2%, 92.3%, 92.4%, 92.5%, etc., and so forth. In another example, reference to a range of 1-5,000-fold includes 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-, 13-, 14-, 15-, 16-, 17-, 18-, 19-, or 20-fold, etc., as well as 1.1-, 1.2-, 1.3-, 1.4-, or 1.5-fold, etc., 2.1-, 2.2-, 2.3-, 2.4-, or 2.5-fold, etc., and so forth.

[0235] "About" a number, as used herein, refers to range including the number and ranging from 10% below that number to 10% above that number. "About" a range refers to 10% below the lower limit of the range, spanning to 10% above the upper limit of the range.

[0236] This entire document is intended to be read as a unified disclosure, and it should be understood that all combinations of features described herein are contemplated, even if the combination of features is not found together in the same sentence, or paragraph, or section of this document. The disclosure also includes, for instance, all embodiments of the disclosure narrower in scope in any way than the embodiments specifically mentioned. With respect to aspects of the disclosure described as a genus, all individual species are considered separate aspects of the disclosure.

[0237] All documents mentioned in this application are hereby incorporated herein by reference in their entirety to disclose and describe the methods and / or materials for the purpose for which the documents are cited. To the extent the material incorporated by a document contradicts or is inconsistent with this specification, the specification will supersede any such material.EXAMPLES

[0238] While the following examples describe specific embodiments, variations and modifications will occur to those skilled in the art. Accordingly, only such limitations as appear in the claims should be placed on the invention.

[0239] A list of various abbreviations used herein follows.List of abbreviations>

[0240] Tumor-associated macrophages (TAMs) are important components of the tumor microenvironment (TME) and inhibit anti-tumor responses by several mechanisms (Mantovani eta / ., 2011, Nat Rev Immunol, 11: 519-31; Cassetta and Pollard, 2018, Nat Rev Drug Discov, 17: 887-904; Garvin eta / ., 2018, J Cancer Res CH n Oncol, 144: 1253-63; Chen eta / ., 2019, J Biomed Sci, 26: 78; Mantovani eta / ., 2022, Nat Rev Drug Discov, 21: 799-820). They directly inhibit T-cell activation by engaging immune checkpoints, producing immunosuppressive cytokines e.g., interleukin (IL)-10 and transforming growth factor beta rTGFP]), and promoting T-cell skewing toward a pro-cancer Th2 phenotype. High levels of tumor infiltration by TAMs generally predict an unfavorable prognosis in patients with solid tumors (Chen etai., 2018, J Clin Invest, 128: 5647-62). Relieving the immunosuppression of TAMs in the TME to improve T-cell-mediated responses is a rational adjunct to immune checkpoint inhibitor (CPI) therapy.

[0241] Leukocyte immunoglobulin-like receptor B2 (LILRB2) is an inhibitory receptor that binds to human leukocyte antigen (HLA) class I proteins and is expressed on myeloid cells, including TAMs and myeloid-derived suppressor cells (MDSCs), but not lymphocytes (Chen etai., 2018, J din Invest 128(12): 5647-5662). LILRB2 expression on myeloid cells in the TME or expression of its ligand HLA-G by tumors correlates with poor survival in multiple cancers (Cai eta / ., 2019, Int J Oncol 54(6): 1943-1954; Li eta / ., 2020, Biomark Res 8: 11; Lin and Yan, 2021,

[0242] "OR502" used herein is a humanized immunoglobulin G1 (IgGl) antibody that binds specifically to LILRB2. OR502 reverses and prevents LILRB2-mediated immune suppression by myeloid cells and restores T cell functions. OR502 showed preclinical anti-tumor activity alone and in combination with anti-PD-l(Bouchlaka eta!., 2023, J Immunother Cancer, 1 l(Suppl 1): A556).

[0243] OR502 binds to human LILRB2 protein with an equilibrium dissociation constant (KD) of 1.18 nM as measured by biolayer interferometry (BLI) analysis. OR502 binds to human LILRB2 and has minimal to no binding to cynomolgus LILRB2 protein nor cynomolgus monocytes. OR502 binds specifically to LILRB2 without binding to other LILR family members. In whole blood, OR502 preferentially binds LILRB2 expressing CD14+monocytes and CD15+neutrophils with no off-target binding to lymphocyte populations. The mean OR502 concentrations to reach 90% receptor occupancy (RO) for human monocytes and M2c macrophages were equivalent and calculated at 0.43 pg / mL and 0.49 pg / mL, respectively.

[0244] The primary pharmacology studies demonstrate that OR502 reverses LILRB2-mediated immune suppression in at least 4 different assay settings.-OR502 potentiated a Thl-like innate immune response by enhancinginterferon gamma (IFN-y) secretion by lipopolysaccharide (LPS)-stimulated human peripheral blood mononuclear cells (PBMCs) and increased tumor necrosis factor alpha (TNF-o) release by CD40L-activated macrophages.-Treatment with OR502 reduced the immunosuppressive phenotype ofexisting M2c macrophages and reversed their inhibition of human T-cell activation and proliferation.-OR502 prevented formation of new immunosuppressive M2c macrophages and thereby maintained T-cell effector function in macrophage / T cell coculture assays.-OR502 reversed macrophage-mediated immune suppression of exhausted T cells as a monotherapy and amplified anti-programmed cell death protein-1(PD-1) activity.

[0245] In vitro M2c macrophage / T cell coculture assays showed that OR502 reversed M2c-mediated T-cell suppression with half-maximal effective concentrations (ECso) of 7.81, 6.83, and 5.12 pg / mL forT cell proliferation, IFN-y, and perforin release, respectively. The mean ECso biological activity (~6.6 pg / mL across all assay readouts) was used to guide selection of the starting clinical dose.

[0246] Single-dose PK were characterized in transgenic mice expressing the human neonatal fragment crystallizable (Fc) receptor (FcRn) and cynomolgus monkeys. In human FcRn mice following a single intraperitoneal (IP) dose at 10 mg / kg, the maximum serumconcentration (Cmax) was 108 pg / mL, the area under the concentration / time curve from 0 to 240 hours (AUC(0-240)) was 15,664 pg / mL*hr, the half-life (ti / 2) was 231 hours and the time to maximum concentration (Tmax) occurred at 2 hours post dose. The PK of OR502 was evaluated in a non-Good Laboratory Practice (GLP) single intravenous (IV) dose-range finding study in male cynomolgus monkeys. Animals were administered single IV bolus injections of OR502 at 0.1, 1.0, or 5.0 mg / kg. The highest exposure was observed immediately after the OR502 IV dose at the first PK sampling time point of 0.0833 hours across all dose levels. The mean Cmax values for 0.1, 1, and 5 mg / kg OR502 dose groups were 4.03, 46.8, and 208 pg / mL. The mean AUC(o-264) for the 0.1, 1, and 5 mg / kg OR502 dose groups were 447, 4100, and 20,300 hr*pg / mL, respectively, and the mean ti / 2values were 297, 246, and 241 hours, respectively.

[0247] In vitro secondary pharmacology and nonclinical toxicology studies demonstrated that OR502 bound to myeloid cells in a tissue cross-reactivity study with limited crossreactivity to other cells in human tissues and induced only minimal to no cytokine release in soluble or plate bound assay formats at concentrations up to 150 pg / mL. Additionally, OR502 did not cause activation nor depletion of neutrophils at concentrations up to 100 pg / mL. These data, in combination with the in vitro primary pharmacology studies, suggest a minimal risk of cytokine release syndrome (CRS) by OR502 and support the use of OR502 in humans.Example 1OR502 physical, chemical, and pharmaceutical properties and formulation

[0248] Sequences

[0249] The protein sequences for the heavy and light chain of OR502 are shown below with domain boundary annotations based on the International ImMunoGeneTics Information System® (IMGT) database (Lefranc, Cold Spring Harb Protoc 2011(6): 595-603) and the complementarity-determining regions (CDR) region annotations based on the Honegger (AHo) numbering scheme (Honegger and Pluckthun, 2001, J Mol Biol 309(3): 657-670). The CDR regions are indicated by underlined text and the domain boundaries (heavy chain VH, CHI, hinge, CH2, CH3; light chain VK, CK1) by a symbol.OR502 Heavy Chain Sequence (SEQ ID NO: 3) EVOLLESGGGLVOPGTSLTLSCAASGFSLSTYAMSWVROAPGKGLEWIGWIYNDGSTYYAAWAKGRF TISKDTSKTTLYLOITSLRAEDTATYFCAREGDYIGYFNIWGOGTLVTVSS | ASTKGPSVFPLAPSSKST SGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTQTYICNVNH KPSNTKVDKRV | EPKSCDKTHTCPPCP | APELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPE VKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAK| GQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYS KLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK OR502 Light Chain Sequence (SEQ ID NO: 4) DWMTOTPSSVSAALGGTVTIKCOASOSIGSNLAWYOIKPGORPKLLIYAAATLASGGSSRFKGSGSGT DFTLTISSLEPADAATYYCOSYVSGSSDVAFGGGTEWVK | RTVAAPSVFIFPPSDEQLKSGTASWCLL NNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSP VTKSFNRGEC

[0250] Pharmaceutical PropertiesTable 3: OR502 Physicochemical Characteristics

[0251] Formulation and storage

[0252] OR502 is supplied as a sterile, single-use, preservative-free solution for IV infusion in a vial containing a nominal fill volume of about 4 mL (200 mg). The drug product is formulated at 50 mg / mL in 10 mM sodium acetate, 9% (w / v) sucrose, 0.015% (w / w) polysorbate 80, pH 5.2. The final container is a 6 mL USP Type I glass vial with a gray Flurotec®-coated plug and flip-off top seal. The recommended storage conditions are at -20°C protected from light.Example 2Pharmacokinetic Profile of OR502 in Cynomolgus Monkeys

[0253] The PK of OR502 was evaluated in a single IV dose range-finding study in male cynomolgus monkeys. Animals received a single IV bolus dose of OR502 at 0.1, 1.0, or 5.0 mg / kg (n=4 / group). Dose levels were chosen based on equivalent doses in rodent studies that yielded useful PK data and did not cause notable adverse effects. No significant body weight changes or signs of distress or pain were associated with OR502 treatment. PK samples were collected up to 264 hours post dosing.

[0254] Serum OR502 concentrations decreased in a multi-exponential manner following a single IV bolus administration of OR502 (Fig. 1). Concentrations generally stayed above the lower limit of quantification up to 264 hours post-dose for all treated groups.

[0255] Non-compartmental PK analysis was conducted on serum-concentration time data from each animal and used to determine the PK of OR502. The resulting PK parameters estimated for OR502 are shown in Table 4 below. OR502 mean Cmax values for the 0.1, 1, and 5 mg / kg OR502 dose groups were 4.03, 46.8, and 208 pg / mL, respectively. The mean AUCo-t for the 0.1, 1, and 5 mg / kg OR502 dose groups were 447, 4100, and 20300 hr*pg / mL, respectively. OR502 mean ti / 2 values were 297, 246, and 241 hours, respectively. Overall, exposure increased in a dose-proportional manner over the dose range tested. Table 4: Summary of Mean (CV%) PK Parameters of OR502 in Cynomolgus MonkeysaMedian. Co=Back-extrapolated concentration at time 0. DN Co =Dose normalized Co calculated as Co / dose level. Tmax=time of maximum concentration. Cmax=maximum concentration. DN Cmax=dose normalized Cmax, calculated as Cmax / dose level. AUCo-t =area under the concentration-time curve from hour 0 to the last measurable concentration, estimated by the linear trapezoidal rule. DN AUCo-t=dose normalized AUCo-t, calculated as AUCo-t / dose level. AUCo-int =area under the concentration-time curve from hour 0 to infinity for Day 1 only. DN AUCo-int =area under the concentration-time curve from hour 0 to infinity for Day 1 only. DN AUCo-int =Dose normalized AUCo-int, calculated as AUCo-int / dose level. ti / 2=elimination half-life, determined by ln(2) / λz, where λz is the elimination rate constant estimated using log-linear regression during the terminal elimination phase. The number of points used in λzcalculation was determined by visual inspection of the data describing the terminal phase.At least the last 3 timepoints with measurable values excluding Cmax were used in lzcalculation and the r-squared adjusted value for the regression was > 0.8. CL=clearance; Vz=volume of clearance; Vss=volume of distribution at steady-state; CV=coefficient of variation.Example 3Tissue Cross-Reactivity of OR502 in Normal Human Tissues

[0256] The cross-reactivity of OR502 was assessed in a non-GLP study utilizing a panel of 38 normal human tissues at Charles River Laboratories.

[0257] OR502 (or positive or negative control antibodies) were applied to cryosections of normal human tissues (at least 1 donor per tissue) at two concentrations (10 and 1 pg / mL). Assessed using immunohistochemistry (IHC) OR502 stained the membrane and cytoplasm of leukocytes in the kidney (intravascular, interstitium), thyroid (intravascular, interstitium), tonsil (associated with crypts), and uterus endometrium (interstitium). The staining was weak-to-moderate or weak-to-strong and rare or rare-to-occasional at the higher concentration with comparable or reduced staining at the lower concentration. The leukocyte binding observed with OR502 was consistent with the reported expression of LILRB2 on myeloid cells, including monocytes, macrophages, dendritic cells, and granulocytes (Colonna, eta / ., 1997, J Exp Med 186(11): 1809-1818; Baudhuin, eta / ., 2013, Proc Natl Acad Sci USA 110(44): 17957-17962; Gao, eta!., 2018, Biochim Biophys Acta Rev Cancer 1869(2): 278-285).Example 4Cytokine Release in Whole Blood and Human PBMCs

[0258] To assess if OR502 triggers cytokine release in whole blood, samples from healthy human donors were incubated with OR502, anti-CD52 (alemtuzumab), human IgGl (negative control), or LPS (positive control). Anti-CD52 antibody is known to induce cytokine release in whole blood and was included as a reference antibody (Wing eta / ., 1996, J Clin Invest 98(12): 2819-2826; Vessillier et al., 2020, Cytokine X 2(1): 100042). Plasma was collected 24 hours post-incubation and IFN-y, IL-ip, IL-2, IL-6, and TNF o and were quantified by MSD ELISA.

[0259] As shown in Fig. 2, soluble OR502 did not induce significant cytokine release in whole blood compared to IgGl isotype control, except for a small increase in TNF-o at the highest OR502 concentration (150 pg / mL). Anti-CD52 induced a significant release of IFN-y and IL-6 when compared to isotype control, and the positive control LPS induced the releaseof IFN-y, IL-1 p, IL 6, and TNF-o. Similar results were obtained when human PBMCs were incubated with plate-bound OR502 (data not shown).

[0260] Overall, these data show that soluble or plate bound OR502, at concentrations up to 150 pg / mL, induces minimal to no cytokine release, which is contemplated herein to indicate a minimal risk of clinical CRS by OR502.Example 5Clinical Study Protocol

[0261] Given the near-ubiquitous use of CPIs in modern oncology therapy, potentiation of their activity and broadening the scope of tumors in which they are active is a critical component of improving outcomes for patients with metastatic solid tumors. Relieving the immune suppression of TAMs in the TME to improve T-cell-mediated responses is a rational adjunct to CPI therapy. OR502 binds specifically to LILRB2 and targets the differentiation and immune suppressive activities of TAMs to restore T-cell effector function and promote activation of innate responses.

[0262] MK-4830 (Merck) is currently the most advanced clinical-stage blocking antibody targeting LILRB2. As a monotherapy in patients with advanced solid tumors, response rates to MK-4830 alone were negligible, but combination treatment of MK-4830 with pembrolizumab (an anti-PD-1 monoclonal antibody) produced responses in 8 of 34 subjects; an objective response rate of 24% (Siu, eta / ., 2022, Clinical Cancer Research, 28: 57-70.). Importantly, when MK-4830 and pembrolizumab were administered in combination, responses were seen in 5 of 11 subjects who had previously received anti-PD-1 therapy. It is contemplated herein that these results suggest that blockade of LILRB2 can overcome resistance mechanisms in the TME to enhance cytolytic T-cell responses to anti-PD-1 therapy and support further development of OR502 as an anti-cancer therapy.

[0263] Study Objectives and End pointsTable 5

[0264] The study was an open-label, multicenter, dose-escalation and expansion Phase 1 / 2 study designed to determine the safety, tolerability, PK, pharmacodynamics, and preliminary anti-tumor activity of OR502 administered alone and in combination with cemiplimab to subjects with advanced solid tumors. The study consisted of 2 parts:• Part A: a dose-escalation phase to determine the maximum tolerated dose (MTD), maximum achievable dose, or optimal doses of OR502 for further evaluation as monotherapy and in combination with cemiplimab in a maximum of approximately 48 subjects.• Part B: an expansion phase in subjects with advanced solid tumors treated with OR502 at 2 separate doses as monotherapy followed by combination with cemiplimab, and in subjects with previously treated PROC or CSCC treated with OR502 at 2 separate doses in combination with cemiplimab. Up to approximately 20 subjects will be treated in each arm of the 3 Part B cohorts to further characterize safety, help determine the recommended Phase 2 dose (RP2D) for further development and determine preliminary anti-tumor activity. Up to approximately 120 subjects total will be treated in Part B.

[0265] Additional expansion cohorts of up to 20 subjects each with specific tumor histology and / or biomarker-defined status may be included in Part B, if supported based on the efficacy signals observed during the dose escalation phase or during other Part B expansion cohorts.

[0266] The expansion cohorts may be opened in parallel, or sequentially.

[0267] Part A (OR502 Dose-escalation Phase)

[0268] Part A evaluated escalating repeated doses of OR502 as monotherapy and in combination with cemiplimab in subjects with advanced solid tumors for which no existing options are known to provide clinical benefit. Part A identified the doses of OR502 for further evaluation alone and in combination up to the MTD or maximum achievable dose, based on safety, PK, pharmacodynamics, anti-tumor activity, and if appropriate, biomarker data.Additional dosing regimens may also be evaluated based on analyses of emerging data. Two separate cohorts of subjects will be enrolled in Part A as outlined below.

[0269] Cohort A1 (OR502 monotherapy): employed a modified toxicity probability interval-2 (mTPI-2) design targeting a DLT rate of 25% with an equivalence interval of 20% to 30%. For all dose levels, subjects may be enrolled in cohorts of 2 to 4 (the target size of each cohort will be 3 subjects).

[0270] The mTPI-2 method relies upon a statistical probability algorithm, calculated using all subjects treated in prior and current cohorts at the same dose level to determine whether future cohorts should be on dose-escalation, no change in dose, or dose de-escalation. The algorithm will stop if either of the following criteria is met:• The maximum sample size has been achieved.• At least 9 subjects have received a dose that is predicted to be the MTD.

[0271] All the dose-escalation decisions were pre-calculated under the mTPI-2 design and presented in a 2-way decision matrix table.

[0272] The starting dose cohort received 100 mg OR502 every 3 weeks (q3W). The planned escalation dose levels are 200 mg, 400 mg, 800 mg, and 1600 mg (with the option for higher / intermediate dose levels based on emerging data). The mTPI-2 method guided dose escalation / de-escalation among the planned dose levels. Intermediate doses may also be evaluated based on emerging data and informed using a 3-parameter Bayesian logistic regression model (BLRM) with overdose control.

[0273] After the last subject in each cohort completed 21 days of follow-up from the first dose (the "DLT period"), the safety information was assessed. AEs were assessed per the NCI-CTCAE version 5.0.

[0274] During dose-escalation, lower dose cohorts determined to be safe (dose level N-l) may be backfilled to a maximum of 10 subjects per cohort to obtain additional information to support the selection of the doses to be further evaluated in the dose expansion phase.

[0275] Cohort A2 (OR502 plus cemiplimab): determined the dose(s) of OR502 to be used in combination with cemiplimab, the same mTPI-2 design as used in Cohort Al will be applied. The initial dose of OR502 was 1 dose level below the dose determined to be safe in Cohort Al, i.e., if Dose Level 2 has been determined to be safe, combination treatment can begin at Dose Level 1. The combination dose level may not exceed a dose determined to be safe as monotherapy.

[0276] Dose escalation in combination with cemiplimab may start at a dose level above the initial monotherapy starting dose if, for example, the monotherapy starting dose is set below 100 mg or cemiplimab supply is delayed, provided that the OR502 dose level has been determined to be safe. Intermediate doses of OR502 in combination with cemiplimab may be evaluated according to the BRLM with overdose control criteria used for the monotherapy dose escalation in Cohort Al.

[0277] Escalation will continue until the MTD is reached or the highest dose level that has been evaluated in monotherapy is complete. Similar to Cohort Al, dose levels already determined to be safe in Cohort A2 may be backfilled up to approximately 10 subjects. Cohort A2 may enroll concurrently with Cohort Al.

[0278] Choosing doses for further evaluation: as described below, 2 doses of OR502 will be evaluated in the Part B expansion phase. If an MTD is reached in Part A, the 2 doses to be evaluated will be the MTD and a second, lower dose level. If an MTD is not reached in Part A and there are no significant safety concerns, the OR502 dose to be evaluated will be chosen based on available data, including RO, safety, PK, pharmacodynamic markers, and anti-tumor activity. One additional dose to be determined using all available data will also be further evaluated. The 2 doses chosen for further evaluation should have non-overlapping PK characteristics.

[0279] Part B (OR502 Expansion Phase)

[0280] Part B will explore OR502 at 2 different dose levels in subjects with advanced solid tumors and in specific tumor types to further document the safety and preliminary anti-tumor activity of OR502 and determine the dose for further development. OR502 will be given alone and in combination with cemiplimab at the 2 doses identified in Part A to subjects with advanced solid tumors, CSCC, or PROC in 3 separate cohorts as described below. A total of up to approximately 120 subjects will be enrolled in Part B.• Cohort Bl: Subjects with advanced solid tumors will be randomized 1: 1 to 1 of 2 doses of OR502 as monotherapy. Subjects 21-40 of Cohort Bl will be required to consent to tumor biopsies before and during the first cycle of treatment. This requirement may be waived by the Sponsor at any time. Subjects with stable disease (SD) or better after 2 cycles of therapy may, at the discretion of the Investigator and in consultation with the Medical Monitor, be treated in combination with cemiplimab in subsequent cycles. A total of approximately 40 subjects will be treated in this cohort: 20 subjects treated with each dose of OR502.• Cohort B2: Subjects with CSCC who have received prior anti-programmed cell death protein-l / programmed death ligand-1 (PD(L)-l) therapy for advanced or metastatic disease will be randomized 1:1 to receive 1 of 2 doses of OR502 in combination with cemiplimab. A total of approximately 40 subjects will be treated in this cohort:20 treated with each dose of OR502.• Cohort B3: Subjects with ovarian cancer who have experienced disease progression on or within 6 months of completion of platinum-based chemotherapy will be randomized 1:1 to receive 1 of 2 doses of OR502 in combination with cemiplimab. A total of approximately 40 subjects will be treated in this cohort: 20 treated with each dose of OR502.

[0281] In addition to confirming the safety of OR502 as monotherapy and in combination with cemiplimab, the study design of Part B is intended to investigate preliminary anti-tumor activity and aid in choosing the dose recommended for further development, the RP2D.

[0282] Subjects in cohorts Bl through B3 will be randomized to 1 of the 2 OR502 dose levels to ensure adequate enrollment in all arms, but each cohort will be analyzed separately and no formal comparison between arms is planned. Randomization will be stratified by number of lines of prior therapy as follows:• Cohort Bl: up to 3 vs more than 3• Cohort B2: 1 vs more than 1Cohort B3: up to 1 vs more than 1 post-platinum therapiesThe ORR in each cohort may be evaluated during the course of enrollment.

[0283] Additional Expansion Cohorts in Part B (Cohorts B4 and B5)

[0284] Additional expansion cohorts of up to 20 subjects each with specific tumor histology and / or biomarker-defined status may be included in Part B. The expansion cohorts may be opened in parallel, or sequentially.

[0285] Cohort B4: Subjects in Cohort B4 must have a histological diagnosis of cutaneous melanoma with advanced / metastatic disease. Subjects must have progressed with > 2 lines of treatment, > 12 weeks of prior PD-(L)l-based therapy, either alone or in combination with other anti-cancer agents, for at least 12 weeks. Subjects may not have received other immunotherapy but may have received additional anti-cancer therapies after failure of a PD-(L) 1 inhibitor. Subjects in this cohort will be treated with OR502 as monotherapy.

[0286] Cohort B5: Subjects in Cohort B5 must have a histological diagnosis of non-small cell lung cancer (NSCLC) with advanced / metastatic disease. Subjects must have progressed with > 2 lines of treatment. Subjects must have progressed after at least 12 weeks of prior PD-(L)l-based therapy, either alone or in combination with other anti-cancer agents.Subjects may not have received other immunotherapy but may have received additional anti-cancer therapies after failure of a PD-(L) 1 inhibitor. Subjects in this cohort will be treated with OR502 in combination with cemiplimab.

[0287] Method of Assigning Subjects to Treatment Groups

[0288] The study included both non-randomized and randomized cohorts. Subjects in the non-randomized portions were assigned to treatment in one of the dose cohorts.

[0289] Subjects in Part B will be randomized 1:1 to 1 of 2 doses of OR502 alone or in combination with cemiplimab. Randomization will be stratified by number of lines of prior therapy as follows.Cohort Bl: up to 3 vs more than 3Cohort B2: 1 vs more than 1Cohort B3: up to 1 vs more than 1 post-platinum therapies.

[0290] Selection of Dose

[0291] Selection of the starting dose of OR502 (100 mg OR502 q3W) was informed by in vitro and ex vivo pharmacology results, a non-GLP cynomolgus monkey PK study, a human tissue cross-reactivity study, and soluble and plate-bound cytokine release assays.

[0292] The PK parameters of OR502 in humans were estimated by means of allometric scaling using body surface area and PK data generated in cynomolgus monkeys at the doses of 0.1, 1, and 5 mg / kg. Human exposures were simulated to maintain a minimal concentration (Cmin) of approximately 5 pg / mL without exceeding a maximum concentration (Cmax) of 150 pg / mL over a dosing interval of 21 days.

[0293] A fixed dose of 100 mg OR502 q3W was contemplated to achieve a Cmax of approximately 90 pg / mL. The minimal to absent inflammatory cytokine release in whole blood treated ex vivo with up to 150 pg / mL OR502 suggests the 100 mg dose is unlikely to cause a significant degree of cytokine release. The projected minimum exposure (Cmin) of approximately 5 pg / mL is justified by concentrations of OR502 required to enable immune responses in pharmacology co-culture assays designed to mimic an immunosuppressive tumor microenvironment (mean ECso = 6.6 pg / mL across all assay readouts).

[0294] OR502 binds specifically to myeloid cells and demonstrated limited cross-reactivity to other cells in human tissues. Given that OR502 is not a direct immune agonist, the proposed initial regimen of 100 mg OR502 once every 3 weeks was determined to be optimal for both patient safety and potential for enabling anti-tumor responses.

[0295] Inclusion Criteria

[0296] Subjects met the following enrollment criteria.1. Informed consent signed by the subject prior to conducting study-specific procedures. 2. Male or female subjects > 18 years of age.3. Histological diagnosis as follows:a. Parts A and B (Cohorts Al, A2, and Bl): subjects must have a histological diagnosis of any type of carcinoma, sarcoma, or melanoma with progressive metastatic disease, or progressive locally advanced disease not amenable to local therapy with curative intent.b. Part B (Expansion Cohorts B2-B3): subjects must have a histological diagnosis of the relevant tumor type (CSCC or PROC) with advanced / metastatic disease not amenable to local therapy with curative intent.4. Prior therapies:a. Part A (dose-escalation) and Cohort Bl (monotherapy expansion)i. Subjects must have experienced progressive disease (PD) on an established standard systemic anti-cancer therapy for the treatment of metastatic or locallyadvanced disease for a given tumor type or have been intolerant to such therapy, or in the opinion of the Investigator have been considered ineligible for a particular form of standard therapy on medical grounds. Subjects must have no available proven curative or life-prolonging therapies.b. Cohorts B2 and B3 (dose-expansion)i. Cohort B2 subjects (CSCC) must have received a PD-(L)1 inhibitor. Subjects may not have received an additional immunotherapy.ii. Cohort B3 subjects (PROC) must have received platinum-based therapy and experienced disease progression on or within 6 months of completion of such therapy. Subjects may have received prior anti-PD-1 therapy. Subjects may have received additional therapies after failure of platinum-based therapy.c. Cohorts B4 and B5 (additional expansion)i. Cohort B4 subjects (cutaneous melanoma) must have progressed with > 2 lines of treatment. Subjects must have progressed after at least 12 weeks of prior PD-(L)1- based therapy, either alone or in combination with other anti-cancer agents.Subjects may not have received other immunotherapy but may have received additional anti-cancer therapies after failure of a PD-(L)1 inhibitor. Subjects must have resolved prior toxicity with a 2- to 4-week washout, adequate organ function, ECOG < 2, and no significant ascites, pleural effusion or CNS metastases, recent infections or autoimmune disease requiring steroids or immunosuppressants.Subjects in this cohort will be treated with OR502 as monotherapy.ii. Cohort B5 subjects (NSCLC all histologies) must have progressed with > 2 lines of treatment. Subjects must have progressed after at least 12 weeks of prior PD-(L)1- based therapy, either alone or in combination with other anti-cancer agents.Subjects may not have received other immunotherapy but may have received additional anti-cancer therapies after failure of a PD-(L)1 inhibitor. Subjects must have resolved prior toxicity with a 2- to 4-week washout, adequate organ function, ECOG < 2, and no significant ascites, pleural effusion or CNS metastases, recent infections or autoimmune disease requiring steroids or immunosuppressants.Subjects in this cohort will be treated with OR502 in combination with cemiplimab. Subjects must have measurable disease per RECIST vl.l.People of childbearing potential, if not postmenopausal (defined as no menses for at least 12 continuous months prior to study entry) or surgically sterile, must be willing topractice at least one of the highly effective methods of birth control for at least a menstrual cycle (or partner's menstrual cycle, for male subjects) before and for 4 months after study medication administration.Resolution of prior clinically significant therapy-related AEs (excluding alopecia and < Grade 2 peripheral neuropathy) to < Grade 1 per NCI-CTCAE version 5.0, and no treatment for these AEs for at least 2 weeks prior to the time of enrollment. Electrolyte and hormonal supplementation may be used to treat these AEs provided the subject is stable on these supplements.Minimum of 2 weeks since the last dose of other hormone therapy and 3 weeks since the last dose of other systemic cancer therapy or radiotherapy (> 4 weeks in case of nitrosoureas or radio-immuno conjugate therapy). Adjuvant hormonal therapy e.g., tamoxifen) is allowed provided the original tumor diagnosis was more than 3 years before the first dose of study medication. Subjects with prostate cancer on stable doses of anti-hormone treatment may remain on therapy for this trial.Subjects must have adequate organ function as indicated by the following laboratory values.Table 610. Biopsy specimens:a. All subjects must be able to supply an archival tumor tissue specimen. If an archival specimen is not available, subjects may remain eligible with approval of the medical monitor.b. Subjects 21-40 in Cohort Bl must consent to pre- and on-treatment biopsies. Tissue obtained for the biopsy must not be previously irradiated. No systemic anti-neoplastic therapy may be received by the subject between the time of the biopsy and the first administration of study medication. The requirement for biopsy in this cohort may be waived by the Sponsor at any time.c. Subjects in all other cohorts will be asked to consent to pre- and on-treatment biopsies for biomarker analysis of the acquired tissue. These biopsies are optional and not required for study participation. Tissue obtained for the biopsy must not be previously irradiated. No systemic anti-neoplastic therapy may be received by the subject between the time of the biopsy and the first administration of studymedication.11. Subject is able and willing to comply with the protocol and the restrictions and assessments therein.12. As required by local regulations or law, subjects must fulfill the obligation of affiliation or beneficiary of a social security or similar scheme.

[0297] Exclusion Criteria1. Subject previously had a severe hypersensitivity reaction to treatment with another monoclonal antibody (mAb).2. Life expectancy < 12 weeks.3. Subject has an Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) > 2.4. Prior organ or stem cell transplant.5. Subjects with symptomatic ascites or pleural effusion. Subjects who are clinically stable for at least 2 weeks following treatment for these conditions (including therapeutic thoraco- or paracentesis) are eligible.6. Subject has a known active central nervous system (CNS) primary tumor or metastases and / or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are clinically stable for at least 4 weeks prior to study entry, have no radiological evidence of new or enlarging brain metastases, and are off steroids or on a stable dose up to an equivalent of prednisone 10 mg / day for at least 15 days prior to first dose of study medication. Subjects who have symptoms consistent with CNS metastasis must have a negative magnetic resonance imaging (MRI) scan during the screening period.7. Subject has a known history of a hematologic malignancy, malignant primary brain tumor, or another malignant primary solid tumor (other than that under study), unless the subject has undergone potentially curative therapy with no evidence of recurrent disease for at least 3 years before the start of treatment.a. Subjects with a known history of AJCC Stage 1 cancer that has undergone potentially curative therapy with no evidence of recurrent disease for at least 1 year before the start of treatment may be eligible.b. Subjects who underwent successful definitive resection of basal cell carcinoma of the skin, superficial bladder cancer, squamous cell carcinoma of the skin, in situ cervical cancer, or other in situ cancers at any time before the start of treatment, and have no evidence of recurrent disease, are eligible.Recent or ongoing serious infection including the following:a. Any uncontrolled Grade 3 or higher (per NCI-CTCAE version 5.0) viral, bacterial, or fungal infection within 2 weeks prior to the first dose of OR502. Routine antimicrobial prophylaxis is allowed.b. Uncontrolled infection with human immunodeficiency virus (HIV). Subjects on stable highly active antiretroviral therapy (HAART) with undetectable viral load and normal CD4 counts for at least 6 months prior to study entry are eligible. Serological testing for HIV at screening is not required.c. Known to be positive for hepatitis B virus (HBV) surface antigen, or any other positive test for hepatitis B indicating acute or chronic infection. Subjects who are or have received anti-HBV therapy and have undetectable HBV DNA for at least 6 months prior to study entry are eligible. Serological testing for hepatitis B at screening is not required.d. Known active hepatitis C as determined by positive serology and confirmed by polymerase chain reaction (PCR). Subjects on or having received anti-retroviral therapy are eligible provided they are virus-free by PCR for at least 6 months prior to study entry. Serological testing for hepatitis C at screening is not required.e. Known active or latent tuberculosis (testing at screening is not required).Autoimmune disease or inflammatory condition requiring systemic anti-inflammatory therapy with exceptions. Subjects on hormone replacement therapy for autoimmune-induced endocrinopathies are eligible.Use of systemic corticosteroids within 15 days or other immunosuppressive drugs within 30 days prior to start of the study, with the exception of corticosteroids as replacement therapy up to an equivalent of prednisone 10 mg / day, which are allowed.QTcF interval > 470 msec by electrocardiogram (ECG).Subject has received an investigational product or been treated with an investigational device within 30 days prior to first administration of study medication.Subject has received a live vaccine within 30 days prior to first administration of study medication.For Cohorts A2, Bl, B2, and B3 only:a. Known hypersensitivity to cemiplimab or any of its excipients or contraindicated to cemiplimab per approved local labeling.b. Interstitial lung disease.c. Prior pneumonitis requiring systemic corticosteroid therapy.d. Receiving immunosuppressive therapy, with exceptions as noted in Exclusion Criterion 10.e. A history of severe immune-related adverse reactions from treatment with ipilimumab, defined as any Grade 4 toxicity or Grade 3 toxicity requiring corticosteroid treatment (> 10 mg / day prednisone or equivalent) for more than 12 weeks.15. Concurrent therapy with anti-cancer or anti-neoplastic drugs, with the exception of adjuvant hormonal therapy, which is allowed as outlined in Inclusion Criterion 8.16. History or clinical evidence of any surgical or medical condition that the Investigator judges as likely to interfere with the results of the study or pose an additional risk in participating, e.g., rapidly progressive or uncontrolled disease involving a major organ system— vascular, cardiac, pulmonary, gastrointestinal, gynecologic, hematologic, neurologic, neoplastic, renal, endocrine, autoimmune or an immunodeficiency, or clinically significant active psychiatric or abuse disorders.17. Subjects who, at the time of signing informed consent, had a recent history (within the last year) of chronic substance abuse.18. Subject is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study.19. Vulnerable persons: subjects under judicial safeguard, subjects deprived of their liberty by judicial or administrative decision, subjects under psychiatric care without their consent, subjects admitted to a health or social institution for purposes other than research, adults subject to a measure of legal protection (guardianship or curatorship), and subjects unable to express their consent.

[0298] Treatments

[0299] The treatments included the investigational drug product, OR502, or a combination of OR502 and the combination agent cemiplimab (LIBTAYO®). All information for cemiplimab is provided in the LIBTAYO® package insert (2023, LIBTAYO®, summary of product characteristics. In. Dublin, Ireland: Regeneron Pharmaceuticals, Inc.).

[0300] OR502 was diluted prior to administration as IV infusion.

[0301] In all parts of the study, OR502 was administered as a 60-minute IV infusion.

[0302] Part A (monotherapy dose-escalation cohorts): OR502 administered q3w at doses of 100 mg (starting dose cohort), 200 mg, 400, 800, and 1600 mg (with the option for higher / intermediate dose levels based on emerging data). During dose-escalation, lower dose cohorts determined to be safe (dose level N-l) may be backfilled to a maximum ofapproximately 10 subjects per cohort to obtain additional PK and pharmacodynamic information to support the selection of the RP2D.

[0303] Part A (cemiplimab combination dose escalation): OR502 starting at a minimum dose of 100 mg once determined to be safe, followed by cemiplimab 350 mg IV q3w.Combination dose escalation may begin at a higher dose of OR502 if necessary (for example if cemiplimab delivery is delayed) once that dose has been deemed acceptable. If no DLTs are observed at this dose level, and the next dose level of OR502 (200 mg) has been determined to be safe, OR502 will be administered at 200 mg, followed by cemiplimab 350 mg IV. Dose escalation will continue in this manner until the maximum OR502 dose is reached or the MTD is determined.

[0304] Expansion Part B4 (monotherapy): OR502 by IV infusion at 1 of 2 doses identified in Part A.

[0305] Expansion Part B5 (combination therapy): OR502 by IV infusion at 1 of 2 doses identified in Part A, followed by cemiplimab 350 mg IV.

[0306] Treatment Period

[0307] During the treatment period, OR502 was administered IV on Day 1 of every 21-day cycle. Subjects in combination cohorts will also receive cemiplimab on Day 1 of every 21-day cycle.

[0308] Study Assessments

[0309] The schedule of assessments (Table 7) lists all assessments performed during the study.Table 7: Schedule of Events / AssessmentsWhen both OR502 and cemiplimab are administered, the terms 'predose' and 'postdose' refer to the OR502 infusion1. Subjects 21-40 in Cohort Bl must consent to pre- and on-treatment biopsies. The requirement for biopsy in this cohort may be waived. Subjects in all other cohorts will be asked to consent to optional pre- and on-treatment biopsies for biomarker analysis. If performed, pre-treatment biopsy to be taken after informed consent; post-treatment biopsies to be performed within 7 days from Cycle 2, Day 1 infusion.2. Complete physical examination required at screening. Abbreviated physical examination is acceptable at subsequent visits (to be completed in a targeted manner covering related body systems).3. Height will be measured only at screening.4. May be done -1 week.5. Vital sign measurements (blood pressure, heart rate, pulse oximetry, and body temperature) to be obtained with subject in sitting or semi-recumbent position. To be done prior to infusion and 1 hour (±15 minutes) after the end of infusion.6. ECGs will be recorded at Screening, Day 1 of Cycles 1, 2, 3, 5, 7, 9, pre-dose (within 1 hour before the start of infusion), post-infusion (± 5 minutes after the end of infusion) and at the EOT visit. On Cycle 1 Day 1, ECGs are performed pre-infusion, at end of infusion, and 4 hours after end of infusion. For all subsequent cycles, ECGs should be performed pre- and post-infusion on Day 1. ECGs will be read on-site.7. Perform pregnancy test (per institutional standards) at start of every cycle in women of reproductive potential. If cycle length changes, perform at least monthly. Pregnancy testing should be continued for 4 months following the last dose of OR502 or cemiplimab, whichever is later. At a minimum, pregnancy tests should be done once at 4 months after the last dose of OR502 or cemiplimab, whichever is later.8. Hematology / chemistry panel only required on Days 8 and 15 of Cycle 1. Coagulation assessed at screening only. Urinalysis can be done 3 days prior to Day 1.9. SAEs / AEs are to be collected from the time of informed consent through 120 days after last dose of study medication.10. Sampling TimepointsWhen OR502 and cemiplimab are administered, the terms 'predose' and 'postdose' refer to the OR502 infusion.a NOT applicable for dose-escalation cohorts (Cohort Al and Cohort A2) in Part A.b Cycle 1 onlyc Cycle 2 and 4 onlyd N American subjects only11. ctDNA to be collected on Cycles 1, 3, and 5 on Day 1 pre-infusion.12. Cemiplimab 350 mg IV if enrolled on combination treatment cohorts.13. Efficacy will be evaluated as per RECIST vl.l every 6 weeks (- 7 days) for 6 months after the first dose of study medication, then every 12 weeks (± 7 days) for the next 6 months, and then every 6 months (± 2 weeks) thereafter. If PD is seen at first evaluation, immune-related response criteria may be used to continue therapy in the presence of pseudo progression or tumor flare with clinical stability as appropriate and per the guidelines for immunotherapies of solid tumors.14. For all subjects.15. Contact the subject for survival status and collection of first subsequent anticancer treatment information until death or study closure.16. N American subjects only.17. 7-day window prior to dosing permitted for Cycle 3 and beyond.18. 72-hour window prior to dosing permitted.19. NOT applicable for dose-escalation cohorts in Part A (Cohort Al and Cohort A2).

[0310] Outcome Measures / Analyses

[0311] Some outcome Measures / Analyses related to safety and tolerability.Safety and Tolerability• DLT(s)• Recording of AEs by CTCAE version 5.0• Recording of IRRs• Results of monitoring vital signs• Occurrence of late or cumulative AEs• Occurrence of autoimmune AEs• Results of clinical chemistry, hematology / coagulation, and urine analysis tests • ECG results• Changes in physical examination• Markers of inflammation and immunogenicity• Need for concomitant medications

[0312] Some outcome measures / analyses related to efficacy.

[0313] Efficacy AnalysesORR was calculated overall and by cohort and dose using both RECIST vl.l and, when data are available, iRECIST vl.l. See below. Either may be used to trigger decisions in the expansion cohorts. ORR and its 95% CI were calculated and presented.DOR per RECIST vl.l is defined as the time from first response subsequently confirmed to disease progression, death, or loss to follow up. DOR and its 95% CI were calculated and presented.DCR, per RECIST vl.l, is defined as the percentage of subjects with a confirmed CR or PR, or SD for at least 24 weeks. DCR and its 95% CI were calculated and presented.PFS was calculated from Cycle 1 Day 1 for all subjects and by cohort and dose, per RECIST vl.l, as above using the Kaplan-Meier method. The quartiles of PFS and percentage of subjects remaining progression-free at landmark timepoints (6, 12, 18, 24 months, etc.) may also be reported.OS was calculated from Cycle 1 Day 1 for all subjects and by cohort and dose using the Kaplan-Meier method. The quartiles of OS and percentage of subjects alive at landmark timepoints (6, 12, 18, 24 months etc.) may also be reported.

[0314] RECIST Response CriteriaResponse and progression were evaluated in this study using the international criteria proposed by the RECIST committee (Eisenhauer, eta / ., 2009, Eur J Cancer, 45: 228-47). Changes in only the largest diameter (unidimensional measurement) of the tumor lesions are used in the RECIST vl.l criteria.Measurable DiseaseTumor lesions: Must be accurately measured in at least one dimension (longest diameter in the plane of measurement is to be recorded) with a minimum size as follows:10 mm by CT scan (CT scan slice thickness recommended to be < 5 mm) and MRI (no less than double the slice thickness and at least 10 mm).10 mm caliper measurement by clinical examination (when superficial).20 mm by chest X-ray (if clearly defined and surrounded by aerated lung).Lymph Nodes: To be considered pathologically enlarged and measurable, a lymph node must be > 15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended to be < 5 mm). At baseline and follow-up, only the short axis will be measured and followed.Lytic Bone Lesions or mixed lytic-blastic lesions, with identifiable soft tissue components that can be evaluated by CT or MRI, can be considered as measurable lesions if the soft tissue component meets the definition of measurability. Blastic bone lesions are non-measurable. All tumor measurements must be recorded in millimeters (or decimal fractions of centimeters). Tumor lesions situated in a previously irradiated area are not considered measurable unless there has been demonstrated progression in the lesion.Non-measurable DiseaseAll other lesions (or sites of disease), including small lesions (longest diameter < 10 mm or pathological lymph nodes with310 to < 15 mm short axis) are considered non-measurable disease. Leptomeningeal disease, ascites, pleural or pericardial effusion, lymphangitic involvement of skin or lung, inflammatory breast disease, abdominal masses / abdominal organomegaly identified by physical examination that is not measurable by reproducible imaging techniques and blastic bone lesions are all non-measurable.Target LesionsAll measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total should be identified as target lesions and be recorded and measured at baseline. These 5 lesions should be selected because of their size (lesions with the longest diameter), represent all involved organs, and be suitable for reproducible RM. A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target lesions will be calculated and reported as the baseline sum of diameters. The baseline sum of diameters will be used as reference to further characterize any objective tumor regression of the measurable dimension of the disease. If there are > 5 measurable lesions, those not selected as target lesions will be considered together with non-measurable disease as non-target lesions.Non-target LesionsAll non-measurable lesions (or sites of disease) plus any measurable lesions over and above the five listed as target lesions. Measurements are not required, but these lesions should be noted at baseline and should be followed as "present," "absent," or in rare cases "unequivocal progression".It is possible to record multiple non-target lesions involving the same organ as a single item on the case record form e.g., "multiple enlarged pelvic lymph nodes" or "multiple liver metastases").Best Response (BR)All subjects will have their best response on study classified as outlined below.Complete Response (CR)Disappearance of all clinical and radiological evidence of tumor (both target and non-target). Any pathological lymph nodes (whether target or non-target) must have a reduction in short axis to < 10 mm.Partial Response (PR)At least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum, no unequivocal progression of existing non-target lesions and no appearance of new lesions.SDSteady state of disease. Neither enough shrinkage to qualify for PR nor enough increase to qualify for PD, no unequivocal progression of existing non-target lesions, and no appearance of new lesions.PDAt least a 20% increase in the sum of diameters of target lesions taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Unequivocal progression of existing non-target lesions or the appearance of 1 or more new lesions will also constitute PD.Table 8 andTable summarize the assessment of best response according to the RECIST vl.l criteria. Table 8: Assessment of Best Response According to the RECIST Vl.l Criteria for Subjects with Target and Non-Target LesionsSubjects with a global deterioration of health status requiring discontinuation of treatment without objective evidence of disease progression at that time should be reported as "symptomatic deterioration". Every effort should be made to document the objective progression even after discontinuation of treatment.Table 9: Assessment of Best Response According to the RECIST vl.l Criteria for Subjects with Non-target Lesions OnlyA "Non-complete response / non-PD" is preferred over "SD" for non-target lesions.

[0315] Methods of MeasurementThe same method of assessment and the same technique should be used to characterize each identified and reported lesion at baseline (if available, previous CT / MRI scans may be assessed additionally) and during follow-up.• Clinical Lesions - Clinical lesions will only be considered measurable when they are superficial e.g., skin nodules, palpable lymph nodes) and > 1 0 mm diameter as assessed using calipers. For the case of skin lesions, documentation by color photography including a ruler to estimate the size of the lesion is recommended. • Chest X-ray - Lesions on chest X-ray are acceptable as measurable lesions when they are clearly defined and surrounded by aerated lung. However, chest CT is preferable.• CT / MRI - CT is the best currently available and reproducible method to measure target lesions selected for response assessment. CT scans should be performed with cuts of 5 mm or less in slice thickness. When CT scans have slice thickness greater than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness. MRI is also acceptable. This applies to the chest, abdomen, and pelvis. Head and neck and extremities usually require specific protocols.• Ultrasound - Ultrasound is not useful in assessment of lesion size and should not be used as method of measurement. If new lesions are identified by ultrasound during the study, confirmation by CT or MRI is advised.• Endoscopy / Laparoscopy - The use of these techniques for objective tumor evaluation is not advised.• Cytology / Histology - These techniques can be used to differentiate between PR and CR in rare cases e.g., residual lesions in tumor types such as germ cell tumors, where known residual benign tumors can remain).The cytological confirmation of the neoplastic origin of any effusion that appears or worsens during treatment when the measurable tumor has met criteria for responseor SD is mandatory to differentiate between response or SD (an effusion may be a side effect of the treatment) and PD.

[0316] Some outcome measures / analyses related to pharmacokinetics.

[0317] Serum concentration-time data for OR502 from all evaluable subjects was analyzed by non-compartmental methods using the software package Phoenix WinNonlin® (Certara, Princeton NJ) and PKanalix® (Simulations Plus, Lancaster, Lancaster, CA).

[0318] The following PK parameters were evaluated: Cmax, time to reach maximum concentration (Tmax), AUCo-t, AUCo-co, AUCtau, Ctrough, CL, Vss, and Vz. The PK parameters obtained in the analysis will be stratified by dose group, and summary statistics will be generated. Dose proportionality will be assessed based on dose-normalized Cmax and AUCs.

[0319] In addition, the serum concentration-time data for OR502 may be evaluated using compartmental or mixed effects methods as the data permit.Example 6PK and Receptor Occupancy

[0320] PK

[0321] Dose-proportional PK with 10-14-day half-life was observed on serum samples from a limited number of patients (Table 10A below). Subsequently, PK analysis was performed on all evaluable subjects from both the OR502 monotherapy (n=17) and the OR502 monotherapy and cemiplimab combination cohorts (n=18) (Table 10B below). PK was dose-proportional with a half-life of 7.6-15.9-days observed for the OR502 monotherapy and a half-life of 8.4-12.4 days for the OR502 + cemiplimab combination. The calculated half-lives, Cmax, and AUCo-t < for OR502 are summarized in Table 10B below.Table 10AOR502 Dose (mg) T1 / 2 (days)100 9.8200 9.2400 14.4800 12.71600 14.2Table 10B

[0322] As shown in Fig. 3A, OR502 dose > 400 mg predicts G™ levels to achieve 90% maximal pharmacological activity (EC90). In Cycle 1, OR502 demonstrated a doseproportional increase in Cmax (maximal concentrations) and AUC (total drug exposure over time). Fig.3B below is an update to Fig.3A with data from all the evaluable patients fromboth the OR502 monotherapy and the OR502 and cemiplimab combination cohort. In both cohorts, an OR502 dose > 400 mg predicts Cmin levels to achieve 90% maximal pharmacological activity (EC90) (Fig. 3B). Combination with cemiplimab did not affect PK profile of OR502 (Fig.3B and Table 10B).

[0323] Receptor occupancy (RO)

[0324] As shown in Fig. 4A-C, near-complete (97%) peripheral receptor occupancy was observed at all doses, 100% at higher doses.

[0325] Receptor occupancy on circulating monocytes and neutrophils on d21 post-cycle 1 was dose-proportional and near-complete for all dose levels (Table 11 below). RO was maintained with repeat dosing. The 800 mg dose was selected for melanoma monotherapy mini-expansion cohort B4 as well as for the Expansion B5 cohort for OR502 (800 mg) in combination with cemiplimab for NSCLC.Table 11 - Percent RO on Day 21 post Cycle 1 (mean ± SEM

[0326] As shown in Fig. 5A-C and Table 12 below, combination with cemiplimab (350 mg) did not affect OR502 RO at tested dose levels.Table 12 - %RO on Day 21 post Cycle 1 (mean ± SEMExample 7Clinical Safety Data

[0327] Safety population in Cohorts Al and A2 was 39 treated subjects, 19 subjects in Cohort Al and 20 subjects in Cohort A2. Thirty-five subjects (90%) were evaluable for RECIST 1.1 assessment.

[0328] OR502 monotherapy safety

[0329] Nineteen patients (6 sarcoma / soft tissue, 4 lung, 2 urothelial, 1 melanoma, 6 other) were: 63% females, median age 62 years (47-82), median 3 prior systemic treatments (0-11) and median ECOG 1 (0-1). Seventeen patients were evaluable by RECIST1.1. There were no DLTs or G>3 treatment-related AEs (TRAE). Ten patients (53%) experienced Gl-2 TRAE, unrelated to exposure. Three patients (16%) had Gl-2 infusion related reactions (IRR): 1 at 800 mg (2 IRRs) and 2 at 1600 mg. All IRRs resolved with standard management within <6 hours. Secondary prophylaxis (acetaminophen, diphenhydramine) implemented after IRR. We subsequently extended the infusion to 60 minutes with premedication. One patient at 400 mg had 2 immune-related TRAEs (G2 hypothyroidism and G2 pneumonitis; both resolved). There were no treatment-related deaths / SAEs.

[0330] All dose levels were well tolerated with manageable IRRs at higher doses.

[0331] OR502 and cemiplimab safety

[0332] Twenty patients (3 NSCLC, 3 sarcoma / soft tissue, 3 colon, 2 thyroid, 1 melanoma, 8 other) were: 50% females, median age 64 years (23-85), median 3 prior systemic treatments (0-7) and median ECOG 1 (0-1). Eighteen patients were evaluable by RECISIT 1.1. Six patients (30%) experienced G1-G2 AEs. There were no DLTs or G>3 TRAE, no treatment-related deaths or SAEs.

[0333] The most common AE type: IRR occurred in 2 patients (10%) (1 at 800 mg and 1 at 1600 mg in combo with cemiplimab). No other AE was reported more than once. All IRRs were grade < 2 and were mitigated by extending infusion duration to 60 minutes, with secondary prophylaxis if necessary (acetaminophen, diphenhydramine). The IRRs were deemed to be related to OR502 and not related to cemiplimab. All other AEs were deemed to be related to both agents in combination.Example 8Anti-Tumor Efficacy Data

[0334] Early efficacy signals were observed among response-evaluable patients with advanced and metastatic solid tumors.

[0335] Of 19 enrolled subjects in the monotherapy cohort, 17 (89.5%) were evaluable for efficacy assessment as per RECIST 1.1. Of the 20 enrolled subjects in the OR502 and cemiplimab combination cohort, 18 (90%) were evaluable for efficacy assessment as per RECIST 1.1. Tables 13A and 13B below summarize the best objective response per RECIST 1.1 in the subjects.Table 13ATable 13B

[0336] In the Al monotherapy cohort, one subject with melanoma had a confirmed PR (cPR) and is still on treatment after 24 doses (Figs. 6A and 6B). Fig. 6A depicts efficacy (% change in the sum of tumor target lesions from baseline) in the Al monotherapy up to week 36 post first dose with OR502. Fig. 6B has the same subjects shown in Fig. 6A, except Fig.6B depicts efficacy up to week 72 post first dose with OR502. In Fig. 6B, melanoma patient M05 showed a -74% change in tumor size at week 72 post dose, while at week 36, this same patient showed a -57% change in tumor size (Fig. 6A).

[0337] One subject with NSCLC in the 800 mg monotherapy cohort had a PR but, after 6 doses, discontinued due to PD. Target lesions in the NSCLC subject continued to decrease; PD was diagnosed due to a new intramural bronchial lesion.

[0338] Seven (41%) subjects had durable stable disease (SD) for > 12 weeks and nine (53%) subjects had stable disease for 4-8 cycles for a disease control rate of 65% in the monotherapy groups (Table 13A and Table 13B above).

[0339] In the A2 combination cohort, one patient (C34) with soft tissue sarcoma (1600 mg) had a cPR (Fig. 6C). Four (22%) had durable SD > 12 weeks and eight (44%) had SD for 4-8 cycles for a disease control rate of 50% (Fig. 6C and Table 13B).

[0340] In the OR502 monotherapy and combination (OR502 + cemiplimab) dose escalation, there were 13 deaths due to progressive disease. Durable SD was seen in sarcomas, cutaneous squamous cell carcinoma, thymoma, thyroid, melanoma, hepatocellular carcinoma and colorectal cancer.

[0341] OR502 showed dose-proportional PK with t1 / 2 8-16 days (Fig. 3A and Fig. 3B). Peripheral RO and PK results supports 800 mg dose as the RP2D.

[0342] Peripheral RO was dose-proportional, near-complete across doses, and 100% at doses >400 mg (Fig. 4A-C, Fig. 5A-C, Table 11 and Table 12).

[0343] Al monotherapy cohorts are shown in Fig. 6A, Fig. 6B and Fig. 7.

[0344] A2 combination cohorts are shown in Fig. 6C.

Claims

CLAIMSWhat is claimed is:

1. A method of providing cancer immunotherapy to a human subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of an LILRB2 antibody product, the antibody product comprising;(a) a CDR-H1 set forth in SEQ ID NO: 1, a CDR-H2 set forth in SEQ ID NO: 2, a CDR-H3 set forth in SEQ ID NO: 3 a CDR-L1 set forth in SEQ ID NO: 4, a CDR-L2 set forth in SEQ ID NO: 5, and a CDR-L3 set forth in SEQ ID NO: 6, as determined by the IMGT method; or(b) a CDR-H1 set forth in SEQ ID NO: 7, a CDR-H2 set forth in SEQ NO: 8, a CDR-H3 set forth in SEQ ID NO: 9, a CDR-L1 set forth in SEQ ID NO: 10, a CDR-L2 set forth in SEQ ID NO: 11, and a CDR-L3 set forth in SEQ ID NO: 12 as determined by the Kabat method.

2. The method of claim 1, in which the antibody product comprises a heavy chain variable region having a sequence comprising SEQ ID NO: 13.

3. The method of claim 1, in which the antibody product comprises a light chain variable region having a sequence comprising SEQ ID NO: 14.

4. The method of any of claims 1 to 3, in which the antibody product comprises an IgGl heavy chain.

5. The method of any of claims 1 to 3, in which the antibody product comprises a kappa light chain.

6. The method of any of claims 1 to 5, in which antibody product comprises a heavy chain having a sequence comprising SEQ ID NO: 15.

7. The method of any of claims 1 to 5, in which antibody product comprises a light chain having a sequence comprising SEQ ID NO: 16.

8. A method of providing cancer immunotherapy to a human subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of an antibody product that recognizes human LILRB2, in which the antibody product consists essentially of a bivalent, monospecific, IgG antibody comprising a heavy chain variable region comprising SEQ ID NO: 13 and a light chain variable region comprising SEQ ID NO: 14.

9. A method of providing cancer immunotherapy to a human subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of an antibody product that recognizes human LILRB2, in which the antibody product consists essentially of a bivalent, monospecific, humanized IgGl antibody comprising a heavy chain having a sequence comprising SEQ ID NO: 15 and a light chain having a sequence comprising SEQ ID NO: 16.

10. The method of claim 1, in which the antibody product is bound by an Fc receptor expressed on an immunosuppressive macrophage or other myeloid cell of the subject.

11. The method of claim 1, in which the antibody product is bound by CD16 (FcyRIIIa), CD32 (FcyRII), or CD64 (FcyRI) expressed on an immunosuppressive macrophage or other myeloid cell of the subject.

12. The method of claim 1, in which the antibody product binds to LILRB2 expressed on a myeloid cell and is bound by CD16 (FcyRIIIa), CD32 (FcyRII), or CD64 (FcyRI) expressed on the same myeloid cell of the subject.

13. The method of claim 1, in which the antibody product binds to LILRB2 on a first cell of the subject and is bound by CD16 (FcyRIIIa), CD32 (FcyRII), or CD64 (FcyRI) expressed on a second cell of the subject.

14. The method of claim 1, in which the cancer comprises a solid tumor.

15. The method of claim 1, in which the cancer is a sarcoma or carcinoma.

16. The method of claim 1, in which the cancer is glioblastoma multiforme, head and neck cancer, kidney renal clear cell cancer, acute myeloid leukemia, pancreatic adenocarcinoma, cutaneous melanoma, stomach adenocarcinoma, testicular germ cell cancer, gastric cancer, Merkel cell carcinoma, dendritic sarcoma, non-small cell lung cancer, papillary thyroid cancer, cutaneous squamous cell carcinoma, liposarcoma, leiomyosarcoma, endometrial cancer, urothelial cancer, pleomorphic sarcoma, or ovarian cancer.

17. The method of claim 1, in which the cells of the cancer express or overexpress LILRB2.

18. The method of claim 1, further comprising administering to the subject an effective amount of a PD-1 antagonist.

19. The method of claim 18, in which the PD-1 antagonist comprises an anti-PD-1 antibody product.

20. The method of claim 19, in which the PD-1 antibody product comprises nivolumab, pembrolizumab, cemiplimab, dostarlimab, pimivalimab, spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalimab, MEDI0680, balstilimab, retifanlimab, or zimberelimab, or a PD-1 binding domain of any of them.

21. The method of claim 18, in which the PD-1 antagonist comprises cemiplimab or a PD-1 binding domain thereof.

22. A method of providing cancer immunotherapy to a human subject in need thereof, the method comprising administering to the subject a combination comprising:(a) a dose of an LILRB2 antibody product comprising:(i) a CDR-H1 set forth in SEQ ID NO: 1, a CDR-H2 set forth in SEQ ID NO: 2, a CDR-H3 set forth in SEQ ID NO: 3 a CDR-L1 set forth in SEQ ID NO: 4, a CDR-L2 set forth in SEQ ID NO: 5, and a CDR-L3 set forth in SEQ ID NO: 6, as determined by the IMGT method; or(ii) a CDR-H1 set forth in SEQ ID NO: 7, a CDR-H2 set forth in SEQ NO: 8, a CDR-H3 set forth in SEQ ID NO: 9, a CDR-L1 set forth in SEQ ID NO: 10, a CDR-L2 set forth in SEQ ID NO: 11, and a CDR-L3 set forth in SEQ ID NO: 12 as determined by the Kabat method; and(b) a dose of a PD-1 antagonist;wherein the dose of the LILRB2 antibody product and the dose of the PD-1 antagonist are selected to provide a therapeutic effect in the subject.

23. The method of claim 1 or 22, in which the dose of the LILRB2 antibody product is sufficient to obtain more than 90% occupancy of LILRB2 in the subject for at least 21 days.

24. The method of claim23, in which the dose of the LILRB2 antibody product is sufficient to obtain blood concentration in the subject of at least the EC90for at least 21 days.

25. The method of claim 23, in which the dose of the LILRB2 antibody product is between about 100 mg and about 1,600 mg.

26. The method of claim 1 or 22, in which the dose of the LILRB2 antibody product is between about 200 mg and about 1,600 mg.

27. The method of claim 26, in which the dose of the LILRB2 antibody product is about 200 mg, about 400 mg, about 800 mg, or about 1,600 mg.

28. The method of claim 26, in which the dose of the PD-1 antibody product is about 800 mg.

29. The method of claim 26, in which the dose of the PD-1 antibody product is about 350 mg / kg.

30. A method of providing cancer immunotherapy to a human subject in need thereof, the method comprising administering to the subject a combination comprising:(a) a dose of about 100 mg to about 1,600 mg of a bivalent, monospecific, humanized IgGl LILRB2 antibody, in which the antibody comprises a heavy chain having a sequence comprising SEQ ID NO: 15 and a light chain having a sequence comprising SEQ ID NO: 16; and(b) a dose of about 350 mg of cemiplimab.

31. The method of claim 30, in which the LILRB2 antibody is administered by IV infusion over about 30 to about 60 minutes.

32. The method of claim 30, in which the cemiplimab is administered by IV infusion over about 60 minutes.

33. The method of claim 30, in which the LILRB2 antibody and the cemiplimab are administered q3w in 21-day cycles.

34. A method of providing cancer immunotherapy to a human subject in need thereof, in which cells of the cancer express or overexpress LILRB2, the method comprising administering to the subject a therapeutically effective amount of an LILRB2 antibody product that recognizes human LILRB2, in which the antibody product consists essentially of a bivalent, monospecific, humanized IgGl antibody comprising a heavy chain having a sequence comprising SEQ ID NO: 15 and a light chain having a sequence comprising SEQ ID NO: 16.

35. The method of 34, in which the administering of the antibody product comprises administering an amount the antibody product effective to mediate killing of cells of the cancer through antibody-dependent cellular toxicity.

36. The method of claim 34, in which the administering of the antibody product comprises administering an amount of the antibody product effective to relieve LILRB2-mediated suppression of T cells in the subject.

37. The method of claim 34, further comprising administering to the subject a PD-1 antagonist in an amount sufficient to relieve PD-1 / PD-L1 axis-mediated immunosuppression of T cells in the subject.

38. The method of any one of claims 34-37, in which the antibody product increases an immune response, slows or prevents tumor growth, inhibits tumor-mediated immune suppression, eliminates a tumor, depletes or blocks an activity of tumor-associated macrophages, decreases tumor-associated macrophage-mediated immune suppression, reduces or reverses T cell suppression, or a combination thereof.

39. An aqueous pharmaceutical composition adapted for intravenous administration of an LILRB2 antibody product to a recipient subject, in which the antibody product comprises a bivalent, monospecific, humanized IgGl antibody comprising a heavy chain having a sequence comprising SEQ ID NO: 15 and a light chain having a sequence comprising SEQ ID NO: 16, the composition comprising about 20 mg / mL to about 70 mg / mL of the antibody product in a pharmaceutically acceptable buffer, and having a pH of about 5.0 to about 5.4.

40. An aqueous pharmaceutical composition of claim 39, the composition comprising about 50 mg / mL of the antibody product, about 10 mM sodium acetate, about 9% (w / v) sucrose, and about 0.015% (w / w) polysorbate 80, and having a pH of about 5.2.

41. A method of treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of the pharmaceutical composition of any one of claims 39-40.

42. The method of claim 41, comprising administering to the subject an amount of the composition sufficient to deliver a dose of about 100 mg to about 1,600 mg of the antibody product.

43. The method of claim 41, comprising administering to the subject an amount of the composition sufficient to deliver a dose of about 100 mg, about 200 mg, about 400 mg, about 800 mg, or about 1,600 mg of the antibody product.

44. A pharmaceutical product comprising a glass vial containing about 2 mL to about 25 mL of the composition of any of claims 39-40 and a closure means affixed to the vial, enabling stable maintenance of the composition at -20 °C protected from light for at least 18 months.

45. A kit comprising solution in a vial containing an LILRB2 antibody product formulated in sodium acetate, sucrose and polysorbate 80.

46. The Kit of claim 45, wherein the solution consists of 10 mM sodium acetate, 9% (w / v) sucrose, 0.015% (w / w) polysorbate 80, pH 5.2.

47. The kit of claim 46 wherein the vial contains a nominal fill volume of about 4 mL comprising the antibody product formulated at 50 mg / mL in 10 mM sodium acetate, 9% (w / v) sucrose, 0.015% (w / w) polysorbate 80, pH 5.2.

48. The kit of claim 47, wherein the antibody product comprises:(a) a CDR-H1 set forth in SEQ ID NO: 1, a CDR-H2 set forth in SEQ ID NO: 2, a CDR-H3 set forth in SEQ ID NO: 3 a CDR-L1 set forth in SEQ ID NO: 4, a CDR-L2 set forth in SEQ ID NO: 5, and a CDR-L3 set forth in SEQ ID NO: 6, as determined by the IMGT method; or(b) a CDR-H1 set forth in SEQ ID NO: 7, a CDR-H2 set forth in SEQ NO: 8, a CDR-H3 set forth in SEQ ID NO: 9, a CDR-L1 set forth in SEQ ID NO: 10, a CDR-L2 set forth in SEQ ID NO: 11, and a CDR-L3 set forth in SEQ ID NO: 12 as determined by the Kabat method.

49. The kit of claim 48, wherein the antibody product comprises a heavy chain variable region having a sequence comprising SEQ ID NO: 13.

50. The kit of claim 48, wherein the antibody product comprises a light chain variable region having a sequence comprising SEQ ID NO: 14.

51. The kit of claim 48, wherein the antibody product comprises an IgGl heavy chain.

52. The kit of claim 48, wherein the antibody product comprises a kappa light chain.

53. The kit of claim 51, wherein the antibody product comprises a heavy chain having a sequence comprising SEQ ID NO: 15.

54. The kit of claim 52, wherein the antibody product comprises a light chain having a sequence comprising SEQ ID NO: 16.

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