Anti-lilrb2 binding molecules and uses thereof

Abstract

Checkpoint inhibitors (CPIs) targeting CTLA-4, PD-1, and PD-L1 have transformed treatment, especially for metastatic cancers. However, many patients do not respond or relapse, partly due to an immunosuppressive tumor microenvironment (TME). Myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) contribute to this suppression. Targeting Leukocyte immunoglobulin-like receptor B2 (LILRB2), an immunosuppressive receptor in the TME, could enhance CPI efficacy. The present disclosure relates to LILRB2 antibody products and methods of use thereof. The antibody products specifically bind to LILRB2 on cells such as myeloid cells or cancer cells. The antibody products can be used for the treatment of diseases, such as cancer, infectious diseases and autoimmune diseases.

Description

[0001] G16863-00031 -AD

[0002] 1

[0003] ANTI-LILRB2 BINDING MOLECULES AND USES THEREOF

[0004] CROSS REFERENCE TO RELATED APPLICATIONS

[0005] The present application claims the benefit of U.S. provisional patent application serial No. 63 / 681 ,594, filed on August 9, 2024, which is incorporated herein by reference in its entirety.

[0006] SEQUENCE LISTING

[0007] A sequence listing is submitted herewith as an XML file named G16863-00031-AD_Seq listing.xml, that was created on August 1 , 2025, and having a size of ~113,959 bytes. The content of the aforementioned file is hereby incorporated by reference in its entirety.

[0008] TECHNICAL FIELD

[0009] The present invention generally relates to the field of oncology, and more particularly to the treatment of cancers using immunotherapies.

[0010] BACKGROUND ART

[0011] Cancer is marked by genetic alterations that promote growth and the ability to evade the immune system. Immunotherapy aims to overcome this immune tolerance, enabling immune recognition and anti-tumor responses. Tumors, however, employ various mechanisms for immune evasion, such as reducing tumor antigenicity, evading immune detection, and creating a suppressive tumor microenvironment (TME) that inhibits CD8+T cells' ability to kill cancer cells.

[0012] The advent of antibodies targeting immune checkpoints has revolutionized the treatment of malignant solid tumors, offering hope for curing or achieving long-term remission in advanced disease. Checkpoint inhibitor (CPI) antibodies against CTLA-4, PD-1 , and PD-L1 have proven effective as first-line treatments for metastatic diseases in various cancers, including lung, melanoma, triple-negative breast cancer, and head and neck cancers.

[0013] Despite these advancements, most patients treated with CPIs either do not respond or eventually relapse. CPIs have also been ineffective in 'cold' tumors, which lack immune cell infiltration. This failure is partially due to an immunosuppressive TME. Myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) are key components of the TME, contributing to immune evasion and promoting a tumor-friendly environment. High levels of MDSCs and TAMs infiltration generally predict poor prognosis. Alleviating myeloid cell- mediated immune suppression in the TME could enhance T-cell responses, complementing CPI therapy.

[0014] Leukocyte immunoglobulin-like receptor B2 (LILRB2), also known as ILT4, LIR2, MIR- 10, or CD85d, is an immunosuppressive receptor found on myeloid lineage cells but not on lymphocytes. In the TME, LILRB2 is present on MDSCs and TAMs, playing a dual role as an immune checkpoint and a tumor-supporting factor. LILRB2 interactions with ligands, such as G16863-00031 -AD

[0015] 2 human leukocyte antigen G (HLA-G) and classical HLA class I molecules (HLA-A and HLA-B), mediate immune suppression and promote tumor immune evasion. Targeting this pathway could enhance the efficacy of T-cell checkpoint inhibitors. Additionally, ANGPTL2 and ANGPTL5 promote lung cancer via LILRB2 on tumor cells through SHP1 signaling. LILRB2 expression on myeloid cells or HLA-G expression by tumors correlates with poor survival in multiple cancers.

[0016] Antibodies targeting LILRB2 are under clinical evaluation for cancer treatment, including MK-4830 (Agenus and Merck) and JTX-8064 (Jounce). Initial data from trials with the first-in-class anti-LILRB2 antibody MK-4830 indicate that LILRB2 blockade can overcome PD-1 resistance in advanced solid tumors. MK-4830, administered alone or with pembrolizumab (anti-PD-1), was well tolerated and showed dose-related target engagement and anti-tumor activity in patients lacking biomarkers predictive of response to anti-PD-1 monotherapy. The combination treatment had an overall response rate of 24%. These findings support the development of anti-LILRB2 antibodies in combination with CPI therapy.

[0017] There remains a need in the art for LILRB2 antibody products and methods for their therapeutic use.

[0018] The present description refers to a number of documents, the content of which is herein incorporated by reference in their entirety.

[0019] SUMMARY OF THE INVENTION

[0020] In various aspects and embodiments, the present disclosure provides the following items 1 to 80:

[0021] 1. An anti-LILRB2 antibody or an antigen binding fragment thereof comprising one of the following combinations of complementarity determining regions (CDRs):

[0022] (a) a CDR-L1 comprising an amino acid sequence having at least 70% identity with the sequence SGSSGSYG (SEQ ID NO:7); a CDR-L2 comprising an amino acid sequence having at least 70% identity with the sequence DNTNRPS (SEQ ID NO:8); a CDR-L3 comprising an amino acid sequence having at least 70% identity with the sequence GSEDSSSSGGI (SEQ ID NO:9); a CDR-H1 comprising an amino acid sequence having at least 70% identity with the sequence GFTFSSY (SEQ ID NO:4); a CDR-H2 comprising an amino acid sequence having at least 70% identity with the sequence TNTGSS (SEQ ID NQ:10); and a CDR-H3 comprising an amino acid sequence having at least 70% identity with the sequence SPGGYCTAGGCGAAGLIDA (SEQ ID NO:11);

[0023] (b) a light chain CDR1 (CDR-L1) comprising an amino acid sequence having at least 70% identity with the sequence SGGSSIYGSAYG (SEQ ID NO:1); a light chain CDR2 (CDR-L2) comprising the sequence SNNQRPS (SEQ ID NO:2); a light chain CDR3 (CDR-L3) comprising an amino acid sequence having at least 70% identity with the sequence GSTDSSSGAA (SEQ ID NO:3); a heavy chain CDR1 (CDR-H1) comprising an amino acid sequence having at least 70% identity with the sequence GFTFSSY (SEQ ID NO:4); a heavy chain CDR2 (CDR-H2) comprising an G16863-00031 -AD

[0024] 3 amino acid sequence having at least 70% identity with the sequence TNSGSY (SEQ ID N0:5); and a heavy chain CDR3 (CDR-H3) comprising an amino acid sequence having at least 70% identity with the sequence SPGGYCTTGGGCGAAALIDA (SEQ ID N0:6);

[0025] (c) a CDR-L1 comprising an amino acid sequence having at least 70% identity with the sequence SGSSGSYG (SEQ ID N0:7); a CDR-L2 comprising an amino acid sequence having at least 70% identity with the sequence YNDKRPS (SEQ ID NO:12); a CDR-L3 comprising an amino acid sequence having at least 70% identity with the sequence GGWDSSAGYAGGI (SEQ ID NO: 13); a CDR-H1 comprising an amino acid sequence having at least 70% identity with the sequence GFTFSSY (SEQ ID NO:4); a CDR-H2 comprising an amino acid sequence having at least 70% identity with the sequence DDTGTF (SEQ ID NO:14); and a CDR-H3 comprising an amino acid sequence having at least 70% identity with the sequence TPWICGTWTCDAYVGNIDA (SEQ ID NO:15); or

[0026] (d) a CDR-L1 comprising an amino acid sequence having at least 70% identity with the sequence SGGSGYAYG (SEQ ID NO:16); a CDR-L2 comprising the sequence ESDKRPS (SEQ ID NO:17); a CDR-L3 comprising an amino acid sequence having at least 70% identity with the sequence GSYDSSDAI (SEQ ID NO:18); a CDR-H1 comprising an amino acid sequence having at least 70% identity with the sequence GFTFSSY (SEQ ID NO:4); a CDR-H2 comprising the sequence TSGGSS (SEQ ID NO:19); and a CDR-H3 comprising an amino acid sequence having at least 70% identity with the sequence SPGGYCTSGGCGAAGLIDA (SEQ ID NQ:20).

[0027] 2. The anti-LILRB2 antibody or antigen binding fragment thereof according to item 1 , which comprises the following combinations of CDRs: a CDR-L1 comprising the sequence SGGSSIYGSAYG (SEQ ID NO:1); a CDR-L2 comprising the sequence SNNQRPS (SEQ ID NO:2); a CDR-L3 comprising the sequence GSTDSSSGAA (SEQ ID NO:3); a CDR-H1 comprising the sequence GFTFSSY (SEQ ID NO:4); a CDR-H2 comprising the sequence TNSGSY (SEQ ID NO:5); and CDR-H3 comprising the sequence SPGGYCTTGGGCGAAALIDA (SEQ ID NO:6).

[0028] 3. The anti-LILRB2 antibody or an antigen binding fragment thereof according to item 1 , which comprises the following combinations of CDRs: a CDR-L1 comprising the sequence SGSSGSYG (SEQ ID NO:7); a CDR-L2 comprising the sequence DNTNRPS (SEQ ID NO:8); a CDR-L3 comprising the sequence GSEDSSSSGGI (SEQ ID NO:9); a CDR-H1 comprising the sequence GFTFSSY (SEQ ID NO:4); a CDR-H2 comprising the sequence TNTGSS (SEQ ID NQ:10); and a CDR-H3 comprising the sequence SPGGYCTAGGCGAAGLIDA (SEQ ID NO:11).

[0029] 4. The anti-LILRB2 antibody or an antigen binding fragment thereof according to item 1 , which comprises the following combinations of CDRs: a CDR-L1 comprising the sequence SGSSGSYG (SEQ ID NO:7); a CDR-L2 comprising the sequence YNDKRPS (SEQ ID NO:12); a CDR-L3 comprising the sequence GGWDSSAGYAGGI (SEQ ID NO:13); a CDR-H1 comprising G16863-00031 -AD

[0030] 4 the sequence GFTFSSY (SEQ ID NO:4); a CDR-H2 comprising the sequence DDTGTF (SEQ ID NO:14); and a CDR-H3 comprising the sequence TPWICGTWTCDAYVGNIDA (SEQ ID NO:15).

[0031] 5. The anti-LILRB2 antibody or an antigen binding fragment thereof according to item 1 , which comprises the following combinations of CDRs: a CDR-L1 comprising the sequence SGGSGYAYG (SEQ ID NO:16); a CDR-L2 comprising the sequence ESDKRPS (SEQ ID NO:17); a CDR-L3 comprising the sequence GSYDSSDAI (SEQ ID NO:18); a CDR-H1 comprising the sequence GFTFSSY (SEQ ID NO:4); a CDR-H2 comprising the sequence TSGGSS (SEQ ID NO:19); and a CDR-H3 comprising the sequence SPGGYCTSGGCGAAGLIDA (SEQ ID NQ:20).

[0032] 6. The anti-LILRB2 antibody or an antigen binding fragment thereof according to any one of items 1 to 5, which comprises the following combinations of framework regions (FRs): a light chain FR1 comprising an amino acid sequence having at least 70% identity with the sequence SYELTQPPSVSVSPGQTARITC (SEQ ID NO:21) or QSVLTQPPSVSAAPGQKVTISC (SEQ ID NO:22); a light chain FR2 comprising an amino acid sequence having at least 70% identity with the sequence WHQQKPGQAPVTVIY (SEQ ID NO:23) or WYQQLPGTAPKTVIY (SEQ ID NO:24); a light chain FR3 comprising an amino acid sequence having at least 70% identity with the sequence GIPERFSGSGSGSTATLTISGVQAEDEADYYC (SEQ ID NO:25) or GIPDRFSGSKSGSSGTLGITGLQTGDEADYYC (SEQ ID NO:26); and / or a light chain FR4 comprising an amino acid sequence having at least 70% identity with the sequence FGGGTQLTVL (SEQ ID NO:27) or FGGGTKLTVL (SEQ ID NO:28).

[0033] 7. The anti-LILRB2 antibody or an antigen binding fragment thereof according to item 6, which comprises the following combinations of FRs: a light chain FR1 comprising the amino acid sequence SYELTQPPSVSVSPGQTARITC (SEQ ID NO:21) or QSVLTQPPSVSAAPGQKVTISC (SEQ ID NO:22); a light chain FR2 comprising the amino acid sequence WHQQKPGQAPVTVIY (SEQ ID NO:23) or WYQQLPGTAPKTVIY (SEQ ID NO:24); a light chain FR3 comprising the amino acid sequence GIPERFSGSGSGSTATLTISGVQAEDEADYYC (SEQ ID NO:25) or GIPDRFSGSKSGSSGTLGITGLQTGDEADYYC (SEQ ID NO:26); and / or a light chain FR4 comprising the amino acid sequence FGGGTQLTVL (SEQ ID NO:27) or FGGGTKLTVL (SEQ ID NO:28).

[0034] 8. The anti-LILRB2 antibody or an antigen binding fragment thereof according to any one of items 1 to 7, which comprises the following combinations of FRs: a heavy chain FR1 comprising an amino acid sequence having at least 70% identity with the sequence EVQLVESGGGLVQPGGSLRLSCAAS (SEQ ID NO:29) or

[0035] EVQLLESGGGLVQPGGSLRLSCAAS (SEQ ID NQ:30); a heavy chain FR2 comprising an amino acid sequence having at least 70% identity with the sequence DMAWVRQAPGKGLEFVAEI (SEQ ID NO:31) or NMGWVRQAPGKGLEFVAII (SEQ ID NO:32); a heavy chain FR3 comprising an amino acid sequence having at least 70% identity with the sequence

[0036] TYYGAAVKGRATISRDNAKNSVYLQMNSLRAEDTAVYYCAR (SEQ ID NO:33) or G16863-00031 -AD

[0037] 5

[0038] THYGAAVKGRATISRDNSKNTVYLQMNSLRAEDTAVYYCTR (SEQ ID NO:34); and / or a heavy chain FR4 comprising an amino acid sequence having at least 70% identity with the sequence WGQGTLVTVSS (SEQ ID NO:35).

[0039] 9. The anti-LILRB2 antibody or an antigen binding fragment thereof according to item 8, which comprises the following combinations of FRs: a heavy chain FR1 comprising the sequence EVQLVESGGGLVQPGGSLRLSCAAS (SEQ ID NO:29) or

[0040] EVQLLESGGGLVQPGGSLRLSCAAS (SEQ ID NQ:30); a heavy chain FR2 comprising the sequence DMAWVRQAPGKGLEFVAEI (SEQ ID NO:31) or NMGWVRQAPGKGLEFVAII (SEQ ID NO:32); a heavy chain FR3 comprising the sequence TYYGAAVKGRATISRDNAKNSVYLQMNSLRAEDTAVYYCAR (SEQ ID NO:33) or THYGAAVKGRATISRDNSKNTVYLQMNSLRAEDTAVYYCTR (SEQ ID NO:34); and / or a heavy chain FR4 comprising the sequence WGQGTLVTVSS (SEQ ID NO:35).

[0041] 10. The antibody or antigen binding fragment thereof according to any one of items 1 to 9, which comprises the following combination of heavy chain and light chain variable regions: (a) a heavy chain variable region comprising an amino acid sequence having at least 70% identity with the sequence:

[0042] EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYDMAWVRQAPGKGLEFVAEITNSGSYTYYGA AVKGRATISRDNAKNSVYLQMNSLRAEDTAVYYCARSPGGYCTTGGGCGAAALIDAWGQGTL VTVSS (SEQ ID NO:36); and a light chain variable region comprising an amino acid sequence having at least 70% identity with the sequence: SYELTQPPSVSVSPGQTARITCSGGSSIYGSAYGWHQQKPGQAPVTVIYSNNQRPSGIPERFS GSGSGSTATLTISGVQAEDEADYYCGSTDSSSGAAFGGGTQLTVL (SEQ ID NO:37).

[0043] 11 . The antibody or antigen binding fragment thereof according to item 10, which comprises the following combination of heavy chain and light chain variable regions: (a) a heavy chain variable region comprising the sequence:

[0044] EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYDMAWVRQAPGKGLEFVAEITNSGSYTYYGA AVKGRATISRDNAKNSVYLQMNSLRAEDTAVYYCARSPGGYCTTGGGCGAAALIDAWGQGTL VTVSS (SEQ ID NO:36); and a light chain variable region comprising the sequence: SYELTQPPSVSVSPGQTARITCSGGSSIYGSAYGWHQQKPGQAPVTVIYSNNQRPSGIPERFS GSGSGSTATLTISGVQAEDEADYYCGSTDSSSGAAFGGGTQLTVL (SEQ ID NO:37).

[0045] 12. The antibody or antigen binding fragment thereof according to any one of items 1 to 11 , which comprises the following combination of heavy chain and light chain variable regions: (a) a heavy chain variable region comprising an amino acid sequence having at least 70% identity with the sequence:

[0046] EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYNMGWVRQAPGKGLEFVAIIDDTGTFTHYGAA VKGRATISRDNSKNTVYLQMNSLRAEDTAVYYCTRTPWICGTWTCDAYVGNIDAWGQGTLVT VSS (SEQ ID NO:38); and a light chain variable region comprising an amino acid sequence G16863-00031 -AD

[0047] 6 having at least 70% identity with the sequence: QSVLTQPPSVSAAPGQKVTISCSGSSGSYGWYQQLPGTAPKTVIYYNDKRPSGIPDRFSGSKS GSSGTLGITGLQTGDEADYYCGGWDSSAGYAGGIFGGGTKLTVL (SEQ ID NO:39).

[0048] 13. The antibody or antigen binding fragment thereof according to item 12, which comprises the following combination of heavy chain and light chain variable regions: (a) a heavy chain variable region comprising the sequence:

[0049] EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYNMGWVRQAPGKGLEFVAIIDDTGTFTHYGAA VKGRATISRDNSKNTVYLQMNSLRAEDTAVYYCTRTPWICGTWTCDAYVGNIDAWGQGTLVT VSS (SEQ ID NO:38); and a light chain variable region comprising the sequence: QSVLTQPPSVSAAPGQKVTISCSGSSGSYGWYQQLPGTAPKTVIYYNDKRPSGIPDRFSGSKS GSSGTLGITGLQTGDEADYYCGGWDSSAGYAGGIFGGGTKLTVL (SEQ ID NO:39).

[0050] 14. The antibody or antigen binding fragment thereof according to any one of items 1 to 13, which is an IgG antibody.

[0051] 15. The antibody or antigen binding fragment thereof according to item 14, which is an lgG4 antibody.

[0052] 16. The antibody or antigen binding fragment thereof according to any one of items 1 to 15, wherein the light chain constant region comprises the sequence GQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSN NKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS (SEQ ID NQ:40).

[0053] 17. The antibody or antigen binding fragment thereof according to any one of items 1 to 14, wherein the heavy chain constant region comprises the sequence ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY SLSSWTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPK PKDTLMISRTPEVTCWVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRWSVLTVL HQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGF YPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHN HYTQKSLSLSLGK (SEQ ID NO:41).

[0054] 18. A bispecific antibody comprising a first binding domain comprising the antibody or antigen binding fragment thereof according to any one of items 1 to 17, and a second binding domain that binds to a tumor antigen, an angiogenic factor, or a checkpoint inhibitor protein.

[0055] 19. The bispecific antibody of item 18, wherein the second binding domain is an antibody or antigen binding fragment thereof that binds to vascular endothelial growth factor (VEGF).

[0056] 20. A conjugate comprising the antibody or antigen binding fragment thereof of any one of items 1 to 19.

[0057] 21 . A nucleic acid comprising a sequence encoding the light and heavy chain of the antibody or antigen binding fragment thereof of any one of items 1 to 19; or a first nucleic acid comprising a sequence encoding the light chain of the antibody or antigen binding fragment thereof of any G16863-00031 -AD

[0058] 7 one of items 1 to 19 and a second nucleic acid comprising a sequence encoding the heavy chain of the antibody or antigen binding fragment thereof of any one of items 1 to 19.

[0059] 22. A host cell comprising the nucleic acid(s) of item 21 .

[0060] 23. A pharmaceutical composition comprising the antibody or antigen binding fragment thereof of any one of items 1 to 19, the conjugate of item 20, the nucleic acid(s) of item 21 , or the cell of item 22, and a pharmaceutically acceptable excipient.

[0061] 24. The pharmaceutical composition of item 23, wherein the pharmaceutical composition is in the form of an injectable solution.

[0062] 25. A method of inducing phagocytosis in a macrophage, the method comprising a step of contacting the macrophage with the antibody or antigen binding fragment thereof of any one of items 1 to 19, the conjugate of item 20, the nucleic acid(s) of item 21 , the cell of item 22, or the pharmaceutical composition of item 23 or 24.

[0063] 26. A method of inducing or enhancing M 1 -like macrophage phenotype in a target cell, the method comprising a step of contacting the target cell with the antibody or antigen binding fragment thereof of any one of items 1 to 19, the conjugate of item 20, the nucleic acid(s) of item 21 , the cell of item 22, or the pharmaceutical composition of item 23 or 24.

[0064] 27. The method of item 26, wherein the target cell is a monocyte or macrophage.

[0065] 28. The method of item 26 or 27, wherein the method comprises repolarization of an M2-like macrophage phenotype into an M 1-like macrophage phenotype.

[0066] 29. A method of reducing a biological activity of LILRB2 in a subject in need thereof, said method comprising administering a therapeutically effective amount of the antibody or antigen binding fragment thereof of any one of items 1 to 19, the conjugate of item 20, the nucleic acid(s) of item 21 , the cell of item 22, or the pharmaceutical composition of item 23 or 24.

[0067] 30. A method of promoting an immune response in a subject in need thereof, the method comprising administering a therapeutically effective amount of the antibody or antigen binding fragment thereof of any one of items 1 to 19, the conjugate of item 20, the nucleic acid(s) of item 21 , the cell of item 22, or the pharmaceutical composition of item 23 or 24.

[0068] 31. A method of treating a disease associated with LILRB2 expression in a subject in need thereof, the method comprising administering a therapeutically effective amount of the antibody or antigen binding fragment thereof of any one of items 1 to 19, the conjugate of item 20, the nucleic acid(s) of item 21 , the cell of item 22, or the pharmaceutical composition of item 23 or 24.

[0069] 32. The method of item 31 , wherein the disease is cancer, an autoimmune disease, or an infectious disease.

[0070] 33. The method of item 32, wherein the disease is cancer.

[0071] 34. The method of item 33, wherein the cancer comprises cells expressing or over-expressing a ligand of LILRB2. G16863-00031 -AD

[0072] 8

[0073] 35. The method of item 33 or 34, wherein the cancer is a sarcoma, carcinoma, or a hematological cancer.

[0074] 36. The method of any one of items 33 to 35, wherein the cancer is 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.

[0075] 37. The method of any one of items 33 to 36, further comprising administering to the subject an effective amount of an anticancer therapy.

[0076] 38. The method of item 37, wherein the anticancer therapy comprises an immune checkpoint inhibitor.

[0077] 39. The method of item 38, wherein the immune checkpoint inhibitor is a PD-1 antagonist.

[0078] 40. The method of item 32, wherein the disease is an autoimmune disease.

[0079] 41 . The method of item 40, wherein the autoimmune disease is rheumatoid arthritis, systemic lupus erythematosus, or multiple sclerosis.

[0080] 42. The method of item 32, wherein the disease is an infectious disease.

[0081] 43. The method of item 42, wherein the infectious disease is a viral infection, a bacterial infection, a parasitic infection, or a fungal infection.

[0082] 44. Use of the antibody or antigen binding fragment thereof of any one of items 1 to 19, the conjugate of item 20, the nucleic acid(s) of item 21 , the cell of item 22, or the pharmaceutical composition of item 23 or 24, for the manufacture of a medicament for inducing phagocytosis in a macrophage.

[0083] 45. Use of the antibody or antigen binding fragment thereof of any one of items 1 to 19, the conjugate of item 20, the nucleic acid(s) of item 21 , the cell of item 22, or the pharmaceutical composition of item 23 or 24, for the manufacture of a medicament for inducing or enhancing M1- like macrophage phenotype in a target cell.

[0084] 46. The use of item 45, wherein the target cell is a monocyte or macrophage.

[0085] 47. The use of item 45 or 46, wherein inducing or enhancing M 1 -like macrophage phenotype comprises repolarization of an M2-like macrophage phenotype into an M1-like macrophage phenotype.

[0086] 48. Use of the antibody or antigen binding fragment thereof of any one of items 1 to 19, the conjugate of item 20, the nucleic acid(s) of item 21 , the cell of item 22, or the pharmaceutical composition of item 23 or 24, for the manufacture of a medicament for reducing a biological activity of LILRB2 in a subject.

[0087] 49. Use of the antibody or antigen binding fragment thereof of any one of items 1 to 19, the conjugate of item 20, the nucleic acid(s) of item 21 , the cell of item 22, or the pharmaceutical G16863-00031 -AD

[0088] 9 composition of item 23 or 24, for treating a disease associated with LILRB2 expression in a subject.

[0089] 50. Use of the antibody or antigen binding fragment thereof of any one of items 1 to 19, the conjugate of item 20, the nucleic acid(s) of item 21 , the cell of item 22, or the pharmaceutical composition of item 23 or 24, for the manufacture of a medicament for treating a disease associated with LILRB2 expression in a subject.

[0090] 51. The use of item 49 or 50, wherein the disease is cancer, an autoimmune disease, or an infectious disease.

[0091] 52. The use of item 51 , wherein the disease is cancer.

[0092] 53. The use of item 52, wherein the cancer comprises cells expressing or over-expressing a ligand of LILRB2.

[0093] 54. The use of item 52 or 53, wherein the cancer is a sarcoma, carcinoma, or hematological cancer.

[0094] 55. The use of any one of items 52 to 54, wherein the cancer is 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.

[0095] 56. The use of any one of items 52 to 55, wherein the antibody or antigen binding fragment thereof, conjugate, nucleic acid(s), or pharmaceutical composition is for use with an anticancer therapy.

[0096] 57. The use of item 56, wherein the anticancer therapy comprises an immune checkpoint inhibitor.

[0097] 58. The use of item 57, wherein the immune checkpoint inhibitor is a PD-1 antagonist.

[0098] 59. The use of item 51 , wherein the disease is an autoimmune disease.

[0099] 60. The use of item 59, wherein the autoimmune disease is rheumatoid arthritis, systemic lupus erythematosus, or multiple sclerosis.

[0100] 61 . The use of item 51 , wherein the disease is an infectious disease.

[0101] 62. The use of item 61 , wherein the infectious disease is a viral infection, a bacterial infection, or a fungal infection.

[0102] 63. The antibody or antigen binding fragment thereof of any one of items 1 to 19, the conjugate of item 20, the nucleic acid(s) of item 21 , the cell of item 22, or the pharmaceutical composition of item 23 or 24, for use in inducing phagocytosis in a macrophage.

[0103] 64. The antibody or antigen binding fragment thereof of any one of items 1 to 19, the conjugate of item 20, the nucleic acid(s) of item 21 , the cell of item 22, or the pharmaceutical composition of item 23 or 24, for use in inducing or enhancing M 1-like macrophage phenotype in a target cell. G16863-00031 -AD

[0104] 10

[0105] 65. The antibody or antigen binding fragment thereof, conjugate, nucleic acid(s), or pharmaceutical composition for use of item 64, wherein the target cell is a monocyte or macrophage.

[0106] 66. The antibody or antigen binding fragment thereof, conjugate, nucleic acid(s), or pharmaceutical composition for use of item 64 or 65, wherein inducing or enhancing M1-like macrophage phenotype comprises repolarization of an M2-like macrophage phenotype into an M1-like macrophage phenotype.

[0107] 67. The antibody or antigen binding fragment thereof of any one of items 1 to 19, the conjugate of item 20, the nucleic acid(s) of item 21 , the cell of item 22, or the pharmaceutical composition of item 23 or 24, for use in reducing a biological activity of LILRB2 in a subject.

[0108] 68. The antibody or antigen binding fragment thereof of any one of items 1 to 19, the conjugate of item 20, the nucleic acid(s) of item 21 , the cell of item 22, or the pharmaceutical composition of item 23 or 24, for use in treating a disease associated with LILRB2 expression in a subject.

[0109] 69. The antibody or antigen binding fragment thereof, conjugate, nucleic acid(s), cell, or pharmaceutical composition for use of item 68, wherein the disease is cancer, an autoimmune disease, or an infectious disease.

[0110] 70. The antibody or antigen binding fragment thereof, conjugate, nucleic acid(s), cell, or pharmaceutical composition for use of item 69, wherein the disease is cancer.

[0111] 71. The antibody or antigen binding fragment thereof, conjugate, nucleic acid(s), cell, or pharmaceutical composition for use of item 70, wherein the cancer comprises cells expressing or over-expressing a ligand of LILRB2.

[0112] 72. The antibody or antigen binding fragment thereof, conjugate, nucleic acid(s), cell, or pharmaceutical composition for use of item 70 or 71 , wherein the cancer is a sarcoma, carcinoma, or hematological cancer.

[0113] 73. The antibody or antigen binding fragment thereof, conjugate, nucleic acid(s), cell, or pharmaceutical composition for use of any one of items 70 to 72, wherein the cancer is 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.

[0114] 74. The antibody or antigen binding fragment thereof, conjugate, nucleic acid(s), or pharmaceutical composition for use of any one of items 70 to 73, wherein the antibody or antigen binding fragment thereof, conjugate, nucleic acid(s), cell, or pharmaceutical composition is for use with an anticancer therapy.

[0115] 75. The antibody or antigen binding fragment thereof, conjugate, nucleic acid(s), or pharmaceutical composition for use of item 74, wherein the anticancer therapy comprises an immune checkpoint inhibitor. G16863-00031 -AD

[0116] 11

[0117] 76. The antibody or antigen binding fragment thereof, conjugate, nucleic acid(s), or pharmaceutical composition for use of item 75, wherein the immune checkpoint inhibitor is a PD- 1 antagonist.

[0118] 77. The antibody or antigen binding fragment thereof, conjugate, nucleic acid(s), or pharmaceutical composition for use of item 69, wherein the disease is an autoimmune disease.

[0119] 78. The antibody or antigen binding fragment thereof, conjugate, nucleic acid(s), or pharmaceutical composition for use of item 77, wherein the autoimmune disease is rheumatoid arthritis, systemic lupus erythematosus, or multiple sclerosis.

[0120] 79. The antibody or antigen binding fragment thereof, conjugate, nucleic acid(s), or pharmaceutical composition for use of item 69, wherein the disease is an infectious disease.

[0121] 80. The antibody or antigen binding fragment thereof, conjugate, nucleic acid(s), or pharmaceutical composition for use of item 79, wherein the infectious disease is a viral infection, a bacterial infection, or a fungal infection.

[0122] Other objects, advantages and features of the present invention will become more apparent upon reading of the following non-restrictive description of specific embodiments thereof, given by way of example only with reference to the accompanying drawings.

[0123] BRIEF DESCRIPTION OF DRAWINGS

[0124] In the appended drawings:

[0125] FIGs. 1A-B depict the results of non-regenerative surface plasmon resonance (SPR) kinetic assays. LILRB2 was injected as a 10-point, 2.5-fold serial dilution over the immobilized ligand IBS316 (FIG. 1A) or IBS336 (FIG. 1B). Kinetic parameters were determined through fitting with 1 :1 Langmuir binding model.

[0126] FIG. 2 depicts the results of a SPR competition assay between ligand MK-4830 and competitors MK-4830, IBS316, IBS336 or an anti-histidine tag control antibody following a 5- minute analyte (LILRB2-His) injection.

[0127] FIGs. 3A-B show the results of experiments measuring the capacity of anti-LILRB2 antibodies (IBS316, IBS336 and MK-4830) to block the interaction between LILRB2 and HLA-G (FIG. 3A) or to bind to cell-surface LILRB2 (FIG. 3B). Data is from a representative experiment performed in duplicate three times independently.

[0128] FIGs. 4A-B show the effect of anti-LILRB2 antibody treatment on M2 cells polarization in M-CSF differentiated macrophages. FIG. 4A: Dot plots CD163 vs. CD206 at a concentration of antibody of 0.002 pg / mL. FIG. 4B: Dose-response curves showing the frequency of CD163+CD206+ cells in the presence of increasing concentrations of the antibodies.

[0129] FIGs. 5A-D show the effect of anti-LILRB2 antibody treatment on GM-CSF (FIG. 5A), IL- 10 (FIG. 5B), TNF-a (FIG. 5C) and MCP-1 (FIG. 5D) cytokine secretion in PBMC induced with LPS. Frozen human PBMCs were thawed, resuspended in media (RPMI, L-glutamine, 10%FBS, G16863-00031 -AD

[0130] 12 pen / strep) and plated in 96-well plate U-bottom (100,000 cells / well). Cells were stimulated with LPS and a range of antibody concentration (5-fold serial dilution starting at 2,5 pg / ml) (FIGs. 5A- B) or a single dose of 15 pg / ml (FIGs. 5C-D) of isotypic lgG4 or anti-LILRB2 antibodies (MK- 4830, IBS316 or IBS336). Supernatants were then collected and stored at -80°C. Cytokine production were later analyzed using Luminex xMAP technology. Graphs were built using GraphPad Prism (10.2.2).

[0131] FIGs. 6A-B show the effect of anti-LILRB2 antibody treatment on IL-10 (FIG. 6A) and TNF-a (FIG. 6B) cytokine secretion in PBMC induced with LPS.

[0132] FIGs. 7A-B depict the results of dose-response experiments of the binding of anti- LILRB2 antibodies (IBS316 vs. MK-4830, FIG. 7A; IBS336 vs. MK-4830, FIG. 7B) at different pHs. LILRB2 protein was coated in Nunc 96-well plates and anti-LILRB2 antibodies (IBS316, IBS336 and MK-4830) were then added to the wells in a 3-fold serial dilution starting at 10 pg / mL. The revelation was done with TMB.

[0133] FIG. 8 depicts the results of dose-response experiments of the binding of anti-LILRB2 antibodies IBS336 and MK-4830 at different pHs. 250,000 HEK-293T cells overexpressing LILRB2 were incubated with a 12-points, 3-fold serial dilution curve starting a 150 pg / mL of anti- LILRB2 antibodies (IBS316, IBS336 and MK-4830) or isotypic control lgG4 at pH 7.4, 6.5 or 6. Then, samples were incubated with Alexa Fluor™ 647 anti-human IgG Fc recombinant secondary. The binding of the antibodies to LILRB2 was analyzed by flow cytometry (iQue3, Sartorius, Germany). Data was analysed using GraphPad Prism (10.2.2).

[0134] FIGs. 9A-B show the effects of the anti-LILRB2 antibodies on tumor growth in a mouse melanoma model. FIG. 9A: Tumor volume was measured for the different groups using a caliper as described in Example 2 below. FIG. 9B: Mouse body weight was also monitored for the different groups.

[0135] FIG. 10 depicts the protein sequence of human LILRB2 (NP_005865.3, SEQ ID NO: 105).

[0136] DISCLOSURE OF INVENTION

[0137] In the studies described herein, the present inventors have developed antibodies having high affinity (in the low nanomolar / picomolar ranges) for human LILRB2, but not to other members of the LILRB family. These antibodies were shown to be able to reprogram immunosuppressive macrophages toward an immunostimulatory phenotype, to decrease the expression of immunosuppressive cytokines and to increase the expression of pro-inflammatory cytokines. The binding of the antibodies to LILRB2 was not significantly affected at acidic pHs mimicking the tumor microenvironment, in contrast to an antibody currently being tested in clinical trials.

[0138] The present disclosure provides an anti-LILRB2 antibody or an antigen-binding fragment thereof that binds to LILRB2 with an equilibrium dissociation constant (KD) of 10 nM or less. In an embodiment, the KDis of 1 nM or less. In an embodiment, the KDis of 0.5 nM (500 pM) or less. G16863-00031 -AD

[0139] 13

[0140] In an embodiment, the KDis of 0.1 nM (100 pM) or less. In an embodiment, the KDis of 0.05 nM (50 pM) or less. In an embodiment, the KD is of 0.03 nM (30 pM) or less.

[0141] The term “antibody or antigen-binding fragment thereof’ as used herein refers to any type of antibody / antibody fragment including monoclonal antibodies (including full-length monoclonal antibodies), polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), humanized antibodies, CDR-grafted antibodies, chimeric antibodies and antibody fragments so long as they exhibit the desired antigenic specificity / binding activity. Antibody fragments comprise a portion of a full-length antibody, generally an antigen binding or variable region thereof. Examples of antibody fragments include Fab, Fab', F(ab')2, and Fv fragments, diabodies, linear antibodies, single-chain antibody molecules (e.g., single-chain FV, scFV), single domain antibodies (e.g., from camelids), shark NAR single domain antibodies, and multispecific antibodies formed from antibody fragments. Antibody fragments can also refer to binding moieties comprising CDRs or antigen binding domains including, but not limited to, VHregions ( H, VH-VH), anticalins, PepBodies, antibody-T-cell epitope fusions (Troybodies) or Peptibodies.

[0142] In an embodiment, the antibody is a monoclonal antibody. The term "monoclonal antibody" as used herein refers to an antibody from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are substantially similar and bind the same epitope(s), except for possible variants that may arise during production of the monoclonal antibody, such variants generally being present in minor amounts. Such monoclonal antibody typically includes an antibody comprising a variable region that binds a target, wherein the antibody was obtained by a process that includes the selection of the antibody from a plurality of antibodies. For example, the selection process can be the selection of a unique clone from a plurality of clones, such as a pool of hybridoma clones, phage clones or recombinant DNA clones. It should be understood that the selected antibody can be further altered, for example, to improve affinity for the target, to humanize the antibody, to improve its production in cell culture, to reduce its immunogenicity in vivo, to create a multispecific antibody, etc., and that an antibody comprising the altered variable region sequence is also a monoclonal antibody of this disclosure. In addition to their specificity, the monoclonal antibody preparations are advantageous in that they are typically uncontaminated by other immunoglobulins. The modifier "monoclonal" indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method. For example, the monoclonal antibodies to be used in accordance with the present disclosure may be made by a variety of techniques, including the hybridoma method (e.g., Kohler et al., Nature, 256:495 (1975); Harlow et al., Antibodies: A Laboratory Manual, (Cold Spring Harbor Laboratory Press, 2nd ed. 1988); Hammerling et al., in: Monoclonal Antibodies and T-Cell Hybridomas 563-681 , (Elsevier, N. Y., 1981), recombinant DNA methods (see, e.g., U.S. Patent No. 4,816,567), phage display technologies (see, e.g., Clackson et al., Nature, 352:624-628 G16863-00031 -AD

[0143] 14

[0144] (1991); Marks et al., J. Mol. Biol., 222:581-597 (1991); Sidhu et al., J. Mol. Biol. 338(2) :299-310 (2004); Lee et al., J. Mol. Biol. 340(5): 1073-1093 (2004); Fellouse, Proc. Nat. Acad. Sci. USA 101 (34): 12467-12472 (2004); and Lee et al. J. Immunol. Methods 284(1-2):119-132 (2004) and technologies for producing human or human-like antibodies from animals that have parts or all of the human immunoglobulin loci or genes encoding human immunoglobulin sequences (see, e.g., WO98 / 24893, WO96 / 34096, WO96 / 33735, and WO91 / 10741 , Jakobovits et al., Proc. Natl. Acad. Sci. USA, 90:2551 (1993); Jakobovits et al., Nature, 362:255-258 (1993); Bruggemann et al., Year in Immune, 7:33 (1993); U.S. Patent Nos. 5,545,806, 5,569,825, 5,591 ,669 (all of GenPharm); 5,545,807; WO 97 / 17852, U.S. Patent Nos. 5,545,807; 5,545,806; 5,569,825; 5,625,126; 5,633,425; and 5,661 ,016, and Marks et al., Bio / Technology, 10: 779-783 (1992); Lonberg et al., Nature, 368: 856-859 (1994); Morrison, Nature, 368: 812-813 (1994); Fishwild et al., Nature Biotechnology, 14: 845-851 (1996); Neuberger, Nature Biotechnology, 14: 826 (1996); and Lonberg and Huszar, Intern. Rev. Immunol., 13: 65-93 (1995).

[0145] The monoclonal antibodies herein specifically include "chimeric" or “recombinant” antibodies in which a portion of the light and / or heavy chain is identical with or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is identical with or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they exhibit the desired biological activity (U.S. Patent No. 4,816,567; and Morrison et al., Proc. Natl. Acad. Sci. USA, 81 :6851-6855 (1984)). Chimeric antibodies of interest herein include "humanized" antibodies. In an embodiment, the antibody is a monoclonal antibody, preferably a human antibody.

[0146] The antibody of the present disclosure may be of any class or isotype, e.g., IgG, IgM, IgA, IgD or IgE. In an embodiment, the antibody of the present disclosure is an IgA. In an embodiment, the antibody of the present disclosure is an IgG. The IgG may be of any subclass, e.g., lgG1 , lgG2, lgG3, or lgG4. In an embodiment, the antibody is an lgG1. In another embodiment, the antibody is an lgG4.

[0147] Affinity of the anti-LILRB2 antibody or antigen-binding fragment thereof can be measured by common methods known in the art (such as, for example, ELISA KD, KinExA, bio-layer interferometry (BLI), and / or surface plasmon resonance (SPR) devices (such as a BIACORE® device), including those described herein). The term “KD”, as used herein, refers to the equilibrium dissociation constant of an antibody-antigen interaction. In some embodiments, the “KD” of the antibody or antigen-binding fragment thereof is measured by using surface plasmon resonance (SPR) assay.

[0148] The protein sequence of human LILRB2 (NP_005865.3) is set out in FIG. 10. This gene is a member of the leukocyte immunoglobulin-like receptor (LIR) family, which is found in a gene G16863-00031 -AD

[0149] 15 cluster at chromosomal region 19ql3.4. The encoded protein belongs to the 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.

[0150] As used herein, an anti-LILRB2 antibody or antigen-binding fragment thereof is said to be "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 or antigen-binding fragment thereof for unrelated amino acid sequences. The terms are also applicable where for example, an antibody or antigenbinding fragment thereof 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 antigenbinding domain will be able to specifically bind to the epitope found in the different antigens.

[0151] In an embodiment, the anti-LILRB2 antibody or an antigen binding fragment thereof is a neutralizing antibody or antigen binding fragment thereof. 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 or antigen-binding fragment thereof that bind to LILRB2, a neutralizing antibody product will diminish the ability of LILRB2 to bind to one or more of its ligands (e.g., HLA class I molecules such as HLA-G) thereby inhibiting LILRB2 activity. G16863-00031 -AD

[0152] 16

[0153] In an embodiment, the anti-LILRB2 antibody or an antigen binding fragment thereof comprising one of the following combinations of complementarity determining regions (CDRs):

[0154] (a) a light chain CDR1 (CDR-L1) comprising an amino acid sequence having at least 70%, 75%, 80%, 85%, 90% or 95% identity with the sequence SGGSSIYGSAYG (SEQ ID NO:1); a light chain CDR2 (CDR-L2) comprising the sequence SNNQRPS (SEQ ID NO:2); a light chain CDR3 (CDR-L3) comprising an amino acid sequence having at least 70%, 75%, 80%, 85%, 90% or 95% identity with the sequence GSTDSSSGAA (SEQ ID NO:3); a heavy chain CDR1 (CDR-H1) comprising an amino acid sequence having at least 70%, 75%, 80%, 85%, 90% or 95% identity with the sequence GFTFSSY (SEQ ID NO:4); a heavy chain CDR2 (CDR-H2) comprising an amino acid sequence having at least 70%, 75%, 80%, 85%, 90% or 95% identity with the sequence TNSGSY (SEQ ID NO:5); and a heavy chain CDR3 (CDR-H3) comprising an amino acid sequence having at least 70%, 75%, 80%, 85%, 90% or 95% identity with the sequence SPGGYCTTGGGCGAAALIDA (SEQ ID NO:6);

[0155] (b) a CDR-L1 comprising an amino acid sequence having at least 70%, 75%, 80%, 85%, 90% or 95% identity with the sequence SGSSGSYG (SEQ ID NO:7); a CDR-L2 comprising an amino acid sequence having at least 70%, 75%, 80%, 85%, 90% or 95% identity with the sequence DNTNRPS (SEQ ID NO:8); a CDR-L3 comprising the sequence GSEDSSSSGGI (SEQ ID NO:9); a CDR-H1 comprising the sequence GFTFSSY (SEQ ID NO:4); a CDR-H2 comprising the sequence TNTGSS (SEQ ID NQ:10); and a CDR-H3 comprising an amino acid sequence having at least 70%, 75%, 80%, 85%, 90% or 95% identity with the sequence SPGGYCTAGGCGAAGLIDA (SEQ ID NO: 11);

[0156] (c) a CDR-L1 comprising an amino acid sequence having at least 70%, 75%, 80%, 85%, 90% or 95% identity with the sequence SGSSGSYG (SEQ ID NO:7); a CDR-L2 comprising an amino acid sequence having at least 70%, 75%, 80%, 85%, 90% or 95% identity with the sequence YNDKRPS (SEQ ID NO:12); a CDR-L3 comprising an amino acid sequence having at least 70%, 75%, 80%, 85%, 90% or 95% identity with the sequence GGWDSSAGYAGGI (SEQ ID NO:13); a CDR-H1 comprising an amino acid sequence having at least 70%, 75%, 80%, 85%, 90% or 95% identity with the sequence GFTFSSY (SEQ ID NO:4); a CDR-H2 comprising an amino acid sequence having at least 70%, 75%, 80%, 85%, 90% or 95% identity with the sequence DDTGTF (SEQ ID NO:14); and a CDR-H3 comprising an amino acid sequence having at least 70%, 75%, 80%, 85%, 90% or 95% identity with the sequence TPWICGTWTCDAYVGNIDA (SEQ ID NO:15); or

[0157] (d) a CDR-L1 comprising an amino acid sequence having at least 70%, 75%, 80%, 85%, 90% or 95% identity with the sequence SGGSGYAYG (SEQ ID NO: 16); a CDR-L2 comprising the sequence ESDKRPS (SEQ ID NO: 17); a CDR-L3 comprising an amino acid sequence having at least 70%, 75%, 80%, 85%, 90% or 95% identity with the sequence GSYDSSDAI (SEQ ID NO:18); a CDR-H1 comprising an amino acid sequence having at least 70%, 75%, 80%, 85%, G16863-00031 -AD

[0158] 17

[0159] 90% or 95% identity with the sequence GFTFSSY (SEQ ID NO:4); a CDR-H2 comprising the sequence TSGGSS (SEQ ID NO: 19); and a CDR-H3 comprising an amino acid sequence having at least 70%, 75%, 80%, 85%, 90% or 95% identity with the sequence SPGGYCTSGGCGAAGLIDA (SEQ ID NQ:20).

[0160] In an embodiment, the anti-LILRB2 antibody or an antigen binding fragment thereof comprising the following combination of CDRs: a CDR-L1 comprising the sequence SGGSSIYGSAYG (SEQ ID NO:1); a CDR-L2 comprising the sequence SNNQRPS (SEQ ID NO:2); a CDR-L3 comprising the sequence GSTDSSSGAA (SEQ ID NO:3); a CDR-H1 comprising the sequence GFTFSSY (SEQ ID NO:4); a CDR-H2 comprising the sequence TNSGSY (SEQ ID NO:5); and CDR-H3 comprising the sequence SPGGYCTTGGGCGAAALIDA (SEQ ID NO:6).

[0161] In an embodiment, the anti-LILRB2 antibody or an antigen binding fragment thereof comprising the following combination of CDRs: a CDR-L1 comprising the sequence SGSSGSYG (SEQ ID NO:7); a CDR-L2 comprising the sequence DNTNRPS (SEQ ID NO:8); a CDR-L3 comprising the sequence GSEDSSSSGGI (SEQ ID NO:9); a CDR-H1 comprising the sequence GFTFSSY (SEQ ID NO:4); a CDR-H2 comprising the sequence TNTGSS (SEQ ID NQ:10); and a CDR-H3 comprising the sequence SPGGYCTAGGCGAAGLIDA (SEQ ID NO: 11).

[0162] In an embodiment, the anti-LILRB2 antibody or an antigen binding fragment thereof comprising the following combination of CDRs: a CDR-L1 comprising the sequence SGSSGSYG (SEQ ID NO:7); a CDR-L2 comprising the sequence YNDKRPS (SEQ ID NO:12); a CDR-L3 comprising the sequence GGWDSSAGYAGGI (SEQ ID NO:13); a CDR-H1 comprising the sequence GFTFSSY (SEQ ID NO:4); a CDR-H2 comprising the sequence DDTGTF (SEQ ID NO:14); and a CDR-H3 comprising the sequence TPWICGTWTCDAYVGNIDA (SEQ ID NO: 15).

[0163] In an embodiment, the anti-LILRB2 antibody or an antigen binding fragment thereof comprising the following combination of CDRs: a CDR-L1 comprising the sequence SGGSGYAYG (SEQ ID NO:16); a CDR-L2 comprising the sequence ESDKRPS (SEQ ID NO: 17); a CDR-L3 comprising the sequence GSYDSSDAI (SEQ ID NO: 18); a CDR-H1 comprising the sequence GFTFSSY (SEQ ID NO:4); a CDR-H2 comprising the sequence TSGGSS (SEQ ID NO: 19); and a CDR-H3 comprising the sequence SPGGYCTSGGCGAAGLIDA (SEQ ID NO:20).

[0164] The term "complementarity determining regions" or "CDRs" when used herein refers to parts of immunological receptors that make contact with a specific ligand and determine its specificity. The CDRs of immunological receptors are the most variable part of the receptor protein, giving receptors their diversity, and are carried on six loops at the distal end of the G16863-00031 -AD

[0165] 18 receptor's variable domains, three loops coming from each of the two variable domains of the receptor.

[0166] As used herein, the term "framework region" refers to those portions of immunoglobulin light and heavy chain variable regions that are relatively conserved (i.e., other than the CDRs) among different immunoglobulins in a single species, as defined by Kabat et al. (supra) or Chothia (Al-Lazikani et al., supra). As used herein, a "human framework region" is a framework region that is substantially identical to the framework region of a naturally occurring human antibody.

[0167] The sequences of the CDR and FR as defined herein are defined according to the Chothia numbering scheme. However, the skilled person would understand that the amino acids forming the CDRs and FRs regions in the sequences of the antibodies or antigen-bonding fragments thereof defined herein may vary depending on the numbering scheme used. Other numbering schemes include the AbM, Kabat, Contact and IMGT schemes. The sequences of the CDRs of the antibodies described herein according to the Kabat and IMGT schemes are depicted in Tables 2A-2B below.

[0168] In an embodiment, one or two residues in the above-noted CDRs sequences are substituted. In a further embodiment, one residue in the above-noted CDRs sequences are substituted. In another embodiment, the antibody or antigen-binding fragment thereof comprises the above-noted CDRs sequence.

[0169] In an embodiment, the anti-LILRB2 antibody or an antigen binding fragment thereof comprises the following combinations of framework regions (FRs): a light chain FR1 comprising an amino acid sequence having at least 70%, 75%, 80%, 85%, 90% or 95% identity with the sequence SYELTQPPSVSVSPGQTARITC (SEQ ID NO:21) or QSVLTQPPSVSAAPGQKVTISC (SEQ ID NO:22); a light chain FR2 comprising an amino acid sequence having at least 70%, 75%, 80%, 85%, 90% or 95% identity with the sequence WHQQKPGQAPVTVIY (SEQ ID NO:23) or WYQQLPGTAPKTVIY (SEQ ID NO:24); a light chain FR3 comprising an amino acid sequence having at least 70%, 75%, 80%, 85%, 90% or 95% identity with the sequence GIPERFSGSGSGSTATLTISGVQAEDEADYYC (SEQ ID NO:25) or GIPDRFSGSKSGSSGTLGITGLQTGDEADYYC (SEQ ID NO:26); and / or a light chain FR4 comprising an amino acid sequence having at least 70%, 75%, 80%, 85%, 90% or 95% identity with the sequence FGGGTQLTVL (SEQ ID NO:27) or FGGGTKLTVL (SEQ ID NO:28).

[0170] In an embodiment, the anti-LILRB2 antibody or an antigen binding fragment thereof comprises the following combinations of framework regions (FRs): a light chain FR1 the sequence SYELTQPPSVSVSPGQTARITC (SEQ ID NO:21) or QSVLTQPPSVSAAPGQKVTISC (SEQ ID NO:22); a light chain FR2 comprising the sequence WHQQKPGQAPVTVIY (SEQ ID NO:23) or WYQQLPGTAPKTVIY (SEQ ID NO:24); a light chain FR3 comprising the sequence GIPERFSGSGSGSTATLTISGVQAEDEADYYC (SEQ ID NO:25) or G16863-00031 -AD

[0171] 19

[0172] GIPDRFSGSKSGSSGTLGITGLQTGDEADYYC (SEQ ID NO:26); and / or a light chain FR4 comprising the sequence FGGGTQLTVL (SEQ ID NO:27) or FGGGTKLTVL (SEQ ID NO:28).

[0173] In an embodiment, the anti-LILRB2 antibody or an antigen binding fragment thereof comprises the following combinations of FRs: a heavy chain FR1 comprising an amino acid sequence having at least 70%, 75%, 80%, 85%, 90% or 95% identity with the sequence EVQLVESGGGLVQPGGSLRLSCAAS (SEQ ID NO:29) or

[0174] EVQLLESGGGLVQPGGSLRLSCAAS (SEQ ID NQ:30); a heavy chain FR2 comprising an amino acid sequence having at least 70%, 75%, 80%, 85%, 90% or 95% identity with the sequence DMAWVRQAPGKGLEFVAEI (SEQ ID NO:31) or NMGWVRQAPGKGLEFVAII (SEQ ID NO:32); a heavy chain FR3 comprising an amino acid sequence having at least 70%, 75%, 80%, 85%, 90% or 95% identity with the sequence

[0175] TYYGAAVKGRATISRDNAKNSVYLQMNSLRAEDTAVYYCAR (SEQ ID NO:33) or THYGAAVKGRATISRDNSKNTVYLQMNSLRAEDTAVYYCTR (SEQ ID NO:34); and / or a heavy chain FR4 comprising an amino acid sequence having at least 70%, 75%, 80%, 85%, 90% or 95% identity with the sequence WGQGTLVTVSS (SEQ ID NO:35).

[0176] In an embodiment, the anti-LILRB2 antibody or an antigen binding fragment thereof comprises the following combinations of FRs: a heavy chain FR1 comprising the sequence EVQLVESGGGLVQPGGSLRLSCAAS (SEQ ID NO:29) or

[0177] EVQLLESGGGLVQPGGSLRLSCAAS (SEQ ID NQ:30); a heavy chain FR2 comprising the sequence DMAWVRQAPGKGLEFVAEI (SEQ ID NO:31) or NMGWVRQAPGKGLEFVAII (SEQ ID NO:32); a heavy chain FR3 comprising the sequence TYYGAAVKGRATISRDNAKNSVYLQMNSLRAEDTAVYYCAR (SEQ ID NO:33) or THYGAAVKGRATISRDNSKNTVYLQMNSLRAEDTAVYYCTR (SEQ ID NO:34); and / or a heavy chain FR4 comprising the sequence WGQGTLVTVSS (SEQ ID NO:35).

[0178] In an embodiment, the anti-LILRB2 antibody or an antigen binding fragment thereof comprises the following combination of heavy chain and light chain variable regions: a heavy chain variable region comprising an amino acid sequence having at least 70%, 75%, 80%, 85%, 90% or 95% identity with the sequence:

[0179] EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYDMAWVRQAPGKGLEFVAEITNSGSYTYYGA AVKGRATISRDNAKNSVYLQMNSLRAEDTAVYYCARSPGGYCTTGGGCGAAALIDAWGQGTL VTVSS (SEQ ID NO:36); and a light chain variable region comprising an amino acid sequence having at least 70%, 75%, 80%, 85%, 90% or 95% identity with the sequence: SYELTQPPSVSVSPGQTARITCSGGSSIYGSAYGWHQQKPGQAPVTVIYSNNQRPSGIPERFS GSGSGSTATLTISGVQAEDEADYYCGSTDSSSGAAFGGGTQLTVL (SEQ ID NO:37).

[0180] In another embodiment, the anti-LILRB2 antibody or an antigen binding fragment thereof comprises the following combination of heavy chain and light chain variable regions: G16863-00031 -AD

[0181] 20 a heavy chain variable region comprising an amino acid sequence having at least 70%, 75%, 80%, 85%, 90% or 95% identity with the sequence:

[0182] EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYNMGWVRQAPGKGLEFVAIIDDTGTFTHYGAA VKGRATISRDNSKNTVYLQMNSLRAEDTAVYYCTRTPWICGTWTCDAYVGNIDAWGQGTLVT VSS (SEQ ID NO:38); and a light chain variable region comprising an amino acid sequence having at least 70%, 75%, 80%, 85%, 90% or 95% identity with the sequence: QSVLTQPPSVSAAPGQKVTISCSGSSGSYGWYQQLPGTAPKTVIYYNDKRPSGIPDRFSGSKS GSSGTLGITGLQTGDEADYYCGGWDSSAGYAGGIFGGGTKLTVL (SEQ ID NO:39)

[0183] In an embodiment, the anti-LILRB2 antibody or an antigen binding fragment thereof comprises the following combination of heavy chain and light chain variable regions: a heavy chain variable region comprising the sequence:

[0184] EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYDMAWVRQAPGKGLEFVAEITNSGSYTYYGA AVKGRATISRDNAKNSVYLQMNSLRAEDTAVYYCARSPGGYCTTGGGCGAAALIDAWGQGTL VTVSS (SEQ ID NO:36); and a light chain variable region comprising the sequence: SYELTQPPSVSVSPGQTARITCSGGSSIYGSAYGWHQQKPGQAPVTVIYSNNQRPSGIPERFS GSGSGSTATLTISGVQAEDEADYYCGSTDSSSGAAFGGGTQLTVL (SEQ ID NO:37).

[0185] In an embodiment, the anti-LILRB2 antibody or an antigen binding fragment thereof comprises the following combination of heavy chain and light chain variable regions: a heavy chain variable region comprising the sequence:

[0186] EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYNMGWVRQAPGKGLEFVAIIDDTGTFTHYGAA VKGRATISRDNSKNTVYLQMNSLRAEDTAVYYCTRTPWICGTWTCDAYVGNIDAWGQGTLVT VSS (SEQ ID NO:38); and a light chain variable region comprising the sequence: QSVLTQPPSVSAAPGQKVTISCSGSSGSYGWYQQLPGTAPKTVIYYNDKRPSGIPDRFSGSKS GSSGTLGITGLQTGDEADYYCGGWDSSAGYAGGIFGGGTKLTVL (SEQ ID NO:39).

[0187] The term "variable" refers to the fact that certain portions of the variable domains differ extensively in sequence among antibodies and are used in the binding and specificity of each particular antibody for its particular antigen. However, the variability is not evenly distributed throughout the variable domains of antibodies. It is concentrated in the complementaritydetermining regions (CDRs) or hypervariable regions (HVRs) both in the light-chain and heavychain variable domains. The more highly conserved portions of variable domains are called the framework region (FR). The variable domains of native heavy and light chains each comprise four FR regions, largely adopting a p-sheet configuration, connected by three CDRs, which form loops connecting, and in some cases forming part of, the p-sheet structure. The CDRs in each chain are held together in close proximity by the FR regions and, with the CDRs from the other chain, contribute to the formation of the antigen-binding site of antibodies. The constant domains are not involved directly in binding an antibody to an antigen, but exhibit various effector functions, such as participation of the antibody in antibody-dependent cellular cytotoxicity (ADCC). From N- G16863-00031 -AD

[0188] 21 terminal to C-terminal, both light and heavy chain variable regions comprise alternating FRs and CDRs: FR1 , CDR1 , FR2, CDR2, FR3, CDR3 and FR4. The assignment of amino acids to each region may be made in accordance with the definitions of Kabat, Chothia (Al-Lazikani et al., J Mol Biol. 1997; 273(4):927-48), or IMGT (Lefranc, M.-P., Immunology Today, 18, 509 (1997)), as disclosed above, for example. "Fv" is the minimum antibody fragment which contains a complete antigen-recognition and binding site. In a two-chain Fv species, this region consists of a dimer of one heavy- and one light-chain variable domain in tight, non-covalent association. In a singlechain Fv species, one heavy- and one light-chain variable domain can be covalently linked by a flexible peptide linker such that the light and heavy chains can associate in a "dimeric" structure analogous to that in a two-chain Fv species. It is in this configuration that the three CDRs of each variable domain interact to define an antigen-binding site on the surface of the VH-VLdimer. Collectively, the six CDRs are involved in conferring the antigen-binding specificity to the antibody. However, even a single variable domain (or half of an Fv comprising only three CDRs specific for an antigen) has the ability to recognize and bind antigen, although at a lower affinity than the entire binding site.

[0189] In some embodiments, the anti-LILRB2 antibody or an antigen binding fragment thereof described herein comprises one or more human constant regions or a fragment thereof. In some embodiments, the human heavy chain constant region is of an isotype selected from IgA, IgG, and IgD. In some embodiments, the human light chain constant region is of an isotype selected from kappa and lambda. In some embodiments, a chimeric antibody described herein comprises a human IgG constant region. In some embodiments, anti-LILRB2 antibody or an antigen binding fragment thereof described herein comprises a human lgG4 heavy chain constant region or a fragment thereof.

[0190] In an embodiment, the anti-LILRB2 antibody or an antigen binding fragment thereof described herein comprises a constant region having an effector function. Exemplary “effector functions” include Fc receptor binding; C1q binding; CDC; ADCC; and / or phagocytosis. Such effector functions generally require the Fc region to be combined with a binding domain (for example, an antibody variable domain) and can be assessed using various assays. In another embodiment, the anti-LILRB2 antibody or an antigen binding fragment thereof described herein comprises a constant region that lacks effector function. Whether or not effector function is desirable may depend on the particular treatment / use intended for the anti-LILRB2 antibody or an antigen binding fragment thereof. Thus, in some embodiments, when effector function is desirable, the anti-LILRB2 antibody or an antigen binding fragment thereof preferably comprises a human IgG 1 heavy chain constant region or a human lgG3 heavy chain constant region. In some embodiments, when effector function is not desirable, the anti-LILRB2 antibody or an antigen binding fragment thereof preferably comprises a human lgG4 or lgG2 heavy chain constant region. G16863-00031 -AD

[0191] 22

[0192] In an embodiment, the anti-LILRB2 antibody or an antigen binding fragment thereof comprises a native Fc region. A “native Fc region” comprises an amino acid sequence identical to the amino acid sequence of an Fc region found in nature. Native sequence human Fc regions include a native sequence human lgG1 Fc region (non-A and A allotypes); native sequence human lgG2 Fc region; native sequence human lgG3 Fc region; and native sequence human lgG4 Fc region as well as naturally occurring variants thereof.

[0193] In some embodiments, the anti-LILRB2 antibody or an antigen binding fragment thereof comprises a variant Fc region that has at least one amino acid substitution compared to the Fc region of a wild-type IgG or a wild-type antibody. In some embodiments, the variant Fc region has two or more amino acid substitutions in the Fc region of the wild-type antibody. In some embodiments, the variant Fc region has three or more amino acid substitutions in the Fc region of the wild-type antibody. In some embodiments, the variant Fc region has at least one, two or three or more Fc region amino acid substitutions described herein. In some embodiments, the variant Fc region herein will possess at least about 80% identity with a native sequence Fc region and / or with an Fc region of a parent polypeptide. In some embodiments, the variant Fc region herein will possess at least about 90% identity with a native sequence Fc region and / or with an Fc region of a parent polypeptide. In some embodiments, the variant Fc region herein will possess at least about 95% identity with a native sequence Fc region and / or with an Fc region of a parent polypeptide.

[0194] A “variant Fc region” comprises an amino acid sequence which differs from that of a native sequence Fc region by virtue of at least one amino acid modification. In some embodiments, a “variant Fc region” comprises an amino acid sequence which differs from that of a native sequence Fc region by virtue of at least one amino acid modification, yet retains at least one effector function of the native sequence Fc region. In some embodiments, the variant Fc region has at least one amino acid substitution compared to a native sequence Fc region or to the Fc region of a parent polypeptide, for example, from about one to about ten amino acid substitutions, and preferably, from about one to about five amino acid substitutions in a native sequence Fc region or in the Fc region of the parent polypeptide. In some embodiments, the variant Fc region herein will possess at least about 80% sequence identity with a native sequence Fc region and / or with an Fc region of a parent polypeptide, at least about 90% sequence identity therewith, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity therewith.

[0195] In an embodiment, the light chain constant region comprises the sequence GQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSN NKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS (SEQ ID NO: 40) or a sequence having at least 90% sequence identity therewith. G16863-00031 -AD

[0196] 23

[0197] In an embodiment, the heavy chain constant region comprises the sequence ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY SLSSWTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPK PKDTLMISRTPEVTCWVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRWSVLTVL HQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGF YPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHN HYTQKSLSLSLGK (SEQ ID NO:41) or a sequence having at least 90% sequence identity therewith.

[0198] In some embodiments, the anti-LILRB2 antibody or an antigen binding fragment thereof is altered to increase or decrease the extent to which the antibody or antigen binding fragment is glycosylated. Addition or deletion of glycosylation sites to an antibody may be conveniently accomplished by altering the amino acid sequence such that one or more glycosylation sites is created or removed.

[0199] In some embodiments, antibody variants are provided having a carbohydrate structure that lacks fucose attached (directly or indirectly) to an Fc region. For example, the amount of fucose in such antibody may be from 1 % to 80%, from 1 % to 65%, from 5% to 65% or from 20% to 40%. The amount of fucose is determined by calculating the average amount of fucose within the sugar chain at Asn297, relative to the sum of all glycostructures attached to Asn 297 (for example, complex, hybrid and high mannose structures) as measured by MALDI-TOF mass spectrometry, as described in WO 2008 / 077546, for example. Asn297 refers to the asparagine residue located at about position 297 in the Fc region (EU numbering of Fc region residues); however, Asn297 may also be located about ± 3 amino acids upstream or downstream of position 297, that is, between positions 294 and 300, due to minor sequence variations in antibodies. Such fucosylation variants may have improved ADCC function. See, for example, U.S. Patent Publication Nos. U.S. 2003 / 0157108 and U.S. 2004 / 0093621. Examples of publications related to “defucosylated” or “fucose-deficient” antibody variants include: U.S. 2003 / 0157108; WO 2000 / 61739; WO 2001 / 29246; U.S. 2003 / 0115614; U.S. 2002 / 0164328; U.S. 2004 / 0093621 ; U.S. 2004 / 0132140; U.S. 2004 / 0110704; U.S. 2004 / 0110282; U.S. 2004 / 0109865; WO 2003 / 085119; WO 2003 / 084570; WO 2005 / 035586; WO 2005 / 035778; WO 2005 / 053742; WO 2002 / 031140; Okazaki et al., J. Mol. Biol. 336:1239-1249 (2004); Yamane-Ohnuki et al., 2004, Biotech. Bioeng. 87: 614. Examples of cell lines capable of producing defucosylated antibodies include Led 3 CHO cells deficient in protein fucosylation (Ripka et al., 1986, Arch. Biochem. Biophys. 249: 533-545; U.S. Patent Application No. U.S. 2003 / 0157108 A1 (Presta, L); and WO 2004 / 056312 A1 , and knockout cell lines, such as alpha-1 ,6-fucosyltransferase gene, FUT8, knockout CHO cells (see, for example, Yamane-Ohnuki et al., 2004, Biotech. Bioeng. 87: 614; Kanda, Y. et al., 2006, Biotechnol. Bioeng., 94(4):680-688; and WO 2003 / 085107). G16863-00031 -AD

[0200] 24

[0201] Variations in the antibodies or antigen-binding fragments thereof described herein, can be made, for example, using any of the techniques and guidelines for conservative and nonconservative mutations set forth, for instance, in U.S. Patent No. 5,364,934. Variations may be a substitution, deletion or insertion of one or more codons encoding the antibody that results in a change in the amino acid sequence as compared with the native sequence antibody. Optionally the variation is by substitution of at least one amino acid with any other amino acid in one or more of the domains of the antibody or antigen-binding fragment thereof. Guidance in determining which amino acid residue may be inserted, substituted or deleted without adversely affecting the desired activity may be found by comparing the sequence of the antibody or antigen-binding fragment thereof with that of homologous known protein molecules and minimizing the number of amino acid sequence changes made in regions of high homology. Amino acid substitutions can be the result of replacing one amino acid with another amino acid having similar structural and / or chemical properties, such as the replacement of a leucine with a serine, i.e., conservative amino acid replacements. Insertions or deletions may optionally be in the range of about 1 to 5 amino acids. The variation allowed may be determined by systematically making insertions, deletions or substitutions of amino acids in the sequence and testing the resulting variants for activity exhibited by the full-length or mature native sequence. In embodiment, the variant exhibits at least 50%, 55% or 60%, preferably at least 65, 70, 75, 80, 90, 95, 96, 97, 98 or 99% sequence identity with the sequence of the antibody or antigen-binding fragment thereof described herein, and maintains the ability to specifically bind to LILRB2.

[0202] "Identity" refers to sequence identity between two polypeptides. Percent (%) sequence identity with respect to a reference polypeptide sequence is the percentage of amino acid residues in a candidate sequence that are identical with the amino acid residues in the reference polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways that are known for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN or Megalign (DNASTAR) software. Appropriate parameters for aligning sequences are able to be determined, including algorithms needed to achieve maximal alignment over the full length of the sequences being compared. For purposes herein, however, % amino acid sequence identity values are generated using the sequence comparison computer program ALIGN-2. The ALIGN-2 sequence comparison computer program was authored by Genentech, Inc., and the source code has been filed with user documentation in the U.S. Copyright Office, Washington D.C., 20559, where it is registered under U.S. Copyright Registration No. TXU510087. The ALIGN-2 program is publicly available from Genentech, Inc., South San Francisco, Calif., or may be compiled from the source code. The ALIGN-2 program should be compiled for use on a UNIX operating system, including G16863-00031 -AD

[0203] 25 digital UNIX V4.0D. All sequence comparison parameters are set by the ALIGN-2 program and do not vary.

[0204] In situations where ALIGN-2 is employed for amino acid sequence comparisons, the % amino acid sequence identity of a given amino acid sequence A to, with, or against a given amino acid sequence B (which can alternatively be phrased as a given amino acid sequence A that has or comprises a certain % amino acid sequence identity to, with, or against a given amino acid sequence B) is calculated as follows: 100 times the fraction X / Y, where X is the number of amino acid residues scored as identical matches by the sequence alignment program ALIGN-2 in that program's alignment of A and B, and where Y is the total number of amino acid residues in B. It will be appreciated that where the length of amino acid sequence A is not equal to the length of amino acid sequence B, the % amino acid sequence identity of A to B will not equal the % amino acid sequence identity of B to A. Unless specifically stated otherwise, all % amino acid sequence identity values used herein are obtained as described in the immediately preceding paragraph using the ALIGN-2 computer program.

[0205] In an embodiment, the affinity of the antibody or antigen-binding fragment for LILRB2 is reduced by 2-fold or less at pH 5, 5.5 or 6, relative to physiological pH (pH of about 7.2-7.4). In an embodiment, the affinity of the antibody or antigen-binding fragment for LILRB2 is reduced by less than 1.5-fold at pH 5, 5.5 or 6, relative to physiological pH (pH of about 7.2-7.4). In an embodiment, the affinity is measured using the methods described in Example 2 below.

[0206] In an embodiment, the antibody of the present disclosure is a multispecific antibody or antigen-binding fragment thereof, such as a bispecific antibody or antigen-binding fragment thereof. In such multispecific (e.g., bispecific) antibodies or antigen-binding fragments thereof, at least one of the antigen-binding domains comprise one of the combinations of CDRs or variable regions described herein. Examples of bispecific antibody or antigen-binding fragment formats include bispecific monoclonal antibodies (mab)2, "knob into hole" IgG, crossMab, ortho-Fab IgG, DVD-lg, two in one IgG, IgG-scFv, scFv2-Fc, bispecific F(mab’)2, quadroma, bispecific diabodies (BsDb), single-chain bispecific diabodies (scBsDb), single-chain bispecific tandem variable domain (scBsTaFv), dock-and-lock trivalent Fab (DNL-(Fab)3), bispecific single-domain antibodies (BssdAb), tandem Ab, tandem diabodies (TandAb), and tandem ScFv (see, e.g., Brinkmann and Kontermann, MAbs. 2017 Feb-Mar; 9(2): 182-212).

[0207] Bispecific antibodies are monoclonal, often human or humanized, antibodies that have binding specificities for two different epitopes on the same or different antigen. In the present disclosure, one of the binding specificities can be directed towards LILRB2, the other can be for any other antigen, e.g., for a cell-surface protein, receptor, receptor subunit, tissue-specific antigen, virally-derived protein, virally-encoded envelope protein, bacterially-derived protein, or bacterial surface protein, etc. In certain embodiments, the bispecific and other multispecific LILRB2 antibodies and antigen binding fragments specifically bind to a second LILRB2 epitope, G16863-00031 -AD

[0208] 26 an epitope on a protein co-expressed on cancer cells, or an epitope on another protein presented on a different cell, such as an activated T cell. Bispecific antibodies of the disclosure include IgG format bispecific antibodies and single chain-based bispecific antibodies. Single chain-based bispecific antibodies of the disclosure can be any of the various types of single chain-based bispecific antibodies known in the art, such as bispecific T-cell engagers (BiTEs), diabodies, tandem diabodies (tandabs), dual-affinity retargeting molecules (DARTs), and bispecific killer cell engagers. See, e.g., Lbffler ef al., 2000, Blood 95:2098-2103; Holliger ef al., 1993, Proc Natl Acad Sci USA, 90:6444-8; Kipriyanov et al., 1999, Mol. Biol. 293:41-56; Johnson etal., 2010, Mol. Biol. 399:436-49; Wiernik et al., 2013, Clin Cancer Res 19:3844 55; Liu et al., 2017, Front. Immunol. 8:38; and Yang et al., 2017, Int. J. Mol. Sci. 18:48.

[0209] In some embodiments, the bispecific antibodies of the disclosure are bispecific T-cell engagers (BiTEs). BiTEs are single polypeptide chain molecules that having two antigen-binding domains, one of which binds to a T-cell antigen and the second of which binds to an antigen present on the surface of a target, e.g., LILRB2 (see, PCT Publication WO 05 / 061547; Baeuerle et al., 2008, Drugs of the Future 33: 137-147; Bargou, et al., 2008, Science 321 :974-977). Thus, the BiTEs of the disclosure have an antigen binding domain that binds to a T-cell antigen, and a second antigen binding domain that is directed towards LILRB2. In some embodiments, the bispecific antibodies of the disclosure are dual-affinity retargeting molecules (DARTs). DARTs comprise at least two polypeptide chains that associate (especially through a covalent interaction) to form at least two epitope binding sites, which may recognize the same or different epitopes. Each of the polypeptide chains of a DART comprise an immunoglobulin light chain variable region and an immunoglobulin heavy chain variable region, but these regions do not interact to form an epitope binding site. Rather, the immunoglobulin heavy chain variable region of one (e.g., the first) of the DART polypeptide chains interacts with the immunoglobulin light chain variable region of a different (e.g., the second) DART™ polypeptide chain to form an epitope binding site. Similarly, the immunoglobulin light chain variable region of one (e.g., the first) of the DART polypeptide chains interacts with the immunoglobulin heavy chain variable region of a different (e.g., the second) DART polypeptide chain to form an epitope binding site. DARTs may be monospecific, bispecific, trispecific, etc., thus being able to simultaneously bind one, two, three or more different epitopes (which may be of the same or of different antigens). DARTs may additionally be monovalent, bivalent, trivalent, tetravalent, pentavalent, hexavalent, etc., thus being able to simultaneously bind one, two, three, four, five, six or more molecules. These two attributes of DARTs (i.e., degree of specificity and valency may be combined, for example to produce bispecific antibodies (i.e., capable of binding two epitopes) that are tetravalent (i.e., capable of binding four sets of epitopes), etc. DART molecules are disclosed in PCT Publications WO 2006 / 113665, WO 2008 / 157379, and WO 2010 / 080538. In some embodiments of the bispecific antibodies of the disclosure, one of the binding specificities is directed towards LILRB2, G16863-00031 -AD

[0210] 27 and the other is directed to an antigen expressed on immune effector cells. The term “immune effector cell” or “effector cell” as used herein refers to a cell within the natural repertoire of cells in the mammalian immune system which can be activated to affect the viability of a target cell. Immune effector cells include cells of the lymphoid lineage such as natural killer (NK) cells, T cells including cytotoxic T cells, or B cells, but also cells of the myeloid lineage can be regarded as immune effector cells, such as monocytes or macrophages, dendritic cells and neutrophilic granulocytes. Hence, said effector cell is preferably an NK cell, a T cell, a B cell, a monocyte, a macrophage, a dendritic cell or a neutrophilic granulocyte. Recruitment of effector cells to aberrant cells means that immune effector cells are brought in close vicinity to the aberrant target cells such that the effector cells can directly kill, or indirectly initiate the killing of the aberrant cells that they are recruited to. In order to avoid non-specific interactions it is preferred that the bispecific antibodies of the disclosure specifically recognize antigens on immune effector cells that are at least over- expressed by these immune effector cells compared to other cells in the body. Target antigens present on immune effector cells may include CD3, CD8, CD16, CD25, CD28, CD64, CD89, NKG2D and NKp46. Preferably, the antigen on immune effector cells is CD3 expressed on T cells.

[0211] The bispecific antibody of the present disclosure may include a binding domain that binds to another (i.e., a second) immune checkpoint inhibitor (ICI). The term "immune checkpoint inhibitor" or "ICI" generally refers to an agent that modulates (inhibits) an immune checkpoint protein (a "checkpoint protein"). A checkpoint inhibitor can partially or fully reduce, inhibit, or interfere with the activity of the immune checkpoint protein. It can also induce structural changes in the immune checkpoint protein that affect its binding to a ligand or impact a pathway related to the checkpoint protein's activity. This can be achieved, for instance, by acting as an antagonist to the immune checkpoint protein or its ligand. An immune checkpoint inhibitor can be a compound such as an antibody, antibody fragments or other proteins that bind and antagonize human programmed cell death protein 1 (PD-1 ; also known as PDCD1 , CD279) or programmed cell death ligand 1 (PD-L1 ; also known as BZ-H1 , CD274). These are referred to as PD-1 antagonists and PD-L1 antagonists, respectively.

[0212] As disclosed herein, immune checkpoint proteins can, in certain contexts and states, interfere with T-cell-mediated killing of cancer cells. Immune checkpoint inhibitors can reverse this interference, but in certain cancers (e.g., certain solid tumors), interference with a single immune checkpoint protein might not be sufficient. The present disclosure contemplates that combining an anti-LILRB2 antibody or antigen-binding fragment thereof disclosed herein with another immune checkpoint inhibitor can relieve macrophage-mediated T-cell exhaustion and stimulate T-cell effector function.

[0213] An ICI can target one or more immune checkpoint proteins such as PD-1 , CD28, CTLA- 4, ICOS, TMIGD2, 4-1 BB, BTLA, CD160, LIGHT, LAG3, 0X40, CD27, CD40L, CD47, GITR, G16863-00031 -AD

[0214] 28

[0215] DNAM-1 , TIGIT, CD96, PVRIG, 2B4, TIM-3, Galectin9, CEACAM1 , SIRP alpha, DC-SIGN, CD200R, DR3, CHK1 , CHK2, A2aR, and B-7 family proteins. An ICI can target a ligand of an immune checkpoint protein. Examples of such ligands include PD-L1 , PD-L2, ICOS ligand, VISTA, 4-1 BBL, Herpesvirus Entry Mediator (HVEM), tumor necrosis factor receptor superfamily member 14 (TNFRSF14), MHO class I, MHO class II, PVR, OX-40L, CD70, CD40, GITRL, CD155, CD48, GAL9, HMGB1 , CEASAM-1 , phosphatidylserine (PtdSer), IDO, TDO, CD47, BTN2A1 , CD200, TL1A, CD112, CD155, LSECtin, CHK1 , CHK2, A2aR, and B-7 family ligands (e.g., CD80 (B7-1), CD86 (B7-2), B7-H3, B7-H4, B7-H7 (HHLA2), etc.).

[0216] In an embodiment, the ICI is an inhibitor of PD-1. Exemplary PD-1 antibodies suitable for use include, without limitation, nivolumab, pembrolizumab, cemipilimab, dostarlimab, pimivalimab, spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalimab, INCMGA00012, AMP-224, AMP-514, and balstilimab.

[0217] In some embodiments, the ICI is a PD-L1 antagonist, such as a PD-L1 antibody. Examples of PD-L1 antibodies include avelumab, durvalumab, atezolizumab, envafolimab, cosibelimab, LY3300054, CA-170, and BMS-936559. Other PD-L1 antagonists may include AUNP-12 and BMS-986189.

[0218] In an embodiment, the ICI is an inhibitor of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) or its ligand. CTLA-4 antibodies block the interaction of CTLA-4 with its ligands CD80 / CD86, which are expressed on antigen-presenting cells, thereby preventing the negative downregulation of immune responses. CTLA-4 antibodies can include ipilimumab, tremelimumab, and quavonlimab.

[0219] In an embodiment, the ICI is an inhibitor of Lymphocyte-activation gene 3 (LAG-3, CD223), which is a CD4-related transmembrane protein that competitively binds MHC II and acts as a co-inhibitory checkpoint for T cell activation. LAG-3-binding proteins (e.g., antibodies), can include LAG525, MK-4280, REGN3767, relatlimab, and Bl 754111.

[0220] In an embodiment, the ICI is an inhibitor of T cell immunoglobulin mucin 3 (TIM-3, HAVCR2), which is a type I glycoprotein receptor that binds to Galectin-9 (Gal-9). TIM-3-binding antibodies, can include TSR-022 and MGB453.

[0221] In an embodiment, the ICI is an inhibitor of T cell immunoglobulin and ITIM domain (TIGIT), which is an inhibitory receptor on lymphocytes that interacts with CD155 on antigen- presenting or tumor cells. TIGIT antagonists can include Tiragolumab, AB154, vibostolimab, BMS-985207, and ASP8374.

[0222] The bispecific antibody of the present disclosure may include a binding domain that binds to a tumor antigen or angiogenic factor. The term "tumor antigen" refers to molecules expressed on the surface of tumor cells that are recognized by the immune system. These antigens can be proteins, glycoproteins, glycolipids, or other molecular structures. They are either uniquely expressed by tumor cells or are expressed at higher levels or in different forms than in normal G16863-00031 -AD

[0223] 29 cells. The term “angiogenic factor” refers to agents such as proteins that promote the formation and / or growth of new blood vessels.

[0224] Examples of tumor antigens and / or angiogenic factors include GD2 / GD3 gangliosides (which may be targeted by 3F8, Dinutuximab, Ecromeximab, Mitumomab, Naxitamab), EpCAM (which may be targeted by Adecatumumab, Citatuzumab, Edrecolomab), Carcinoembryonic antigen (CEA) (which may be targeted by Altumomab pentetate, Besilesomab, Labetuzumab), mesothelin (which may be targeted by Amatuximab, Anetumab), Tumor-associated glycoprotein 72 (TAG-72) (which may be targeted by Anatumomab mafenatox, Minretumomab), gelatinase B (which may be targeted by Andecaliximab), activin receptor-like kinase 1 (which may be targeted by Ascrinvacumab), EGFR (which may be targeted by Amivantamab, Cetuximab, Depatuxizumab, Futuximab, Imgatuzumab, Matuzumab, Modotuximab, Necitumumab, Nimotuzuma, Panitumumab), VEGF (which may be targeted by Bevacizumab, Ranibizumab), VEGFRAZEGFR2 (which may be targeted by Icrucumab, Ramucirumab), CD44v6 (which may be targeted by Bivatuzumab), CD30 (which may be targeted by Brentuximab vedotin), CD19 (which may be targeted by Blinatumomab, Coltuximab, Denintuzumab), B-cell maturation antigen (BCMA) (which may be targeted by Belantamab), CD22 (which may be targeted by Bectumomab, Moxetumomab), Notchl (which may be targeted by Brontictuzumab), CanAg (which may be targeted by Cantuzumab), Lewis-Y antigen (which may be targeted by cBR96), CEACAM5 (which may be targeted by Cibisatamab), CD221 (which may be targeted by Cixutumumab, Dalotuzumab, Figitumumab, Ganitumab), PTK7 (which may be targeted by Cofetuzumab), CD38 (which may be targeted by Daratumumab), DLL4 (which may be targeted by Demcizumab), CD20 (which may be targeted by Divozilimab, Ibritumomab), ERBB3 (HER3) (which may be targeted by Elgemtumab, Duligotuzumab, Lumretuzuma), HER2 / neu (which may be targeted by Pertuzumab, Trastuzumab), CSF1 R (which may be targeted by Emactuzumab), HGFR (which may be targeted by Emibetuzumab), folate receptor 1 (which may be targeted by Farletuzumab), Hepatocyte growth factor (HGF) (which may be targeted by Ficlatuzumab, Rilotumumab), TYRP1 (which may be targeted by Flanvotumab), MUC1 (which may be targeted by Gatipotuzumab), CD33 (which may be targeted by Gemtuzumab, Lintuzumab), carbonic anhydrase 9 (CA-IX) (which may be targeted by Girentuximab), GPNMB (which may be targeted by Glembatumumab), CA-125 (which may be targeted by Oregovoma, Sofituzumab), MUC1 (which may be targeted by Pemtumomab), and TROP-2 (which may be targeted by Sacituzumab).

[0225] Covalent modifications of antibodies or antigen-binding fragments thereof are included within the scope of this disclosure. Covalent modifications include reacting targeted amino acid residues of the antibody or antigen-binding fragment thereof with an organic derivatizing agent that is capable of reacting with selected side chains or the N- or C- terminal residues of the antibody or antigen-binding fragment thereof. Other modifications include deamidation of glutaminyl and asparaginyl residues to the corresponding glutamyl and aspartyl residues, G16863-00031 -AD

[0226] 30 respectively, hydroxylation of proline and lysine, phosphorylation of hydroxyl groups of seryl or threonyl residues, methylation of the a-amino groups of lysine, arginine, and histidine side chains (T.E. Creighton, Proteins: Structure and Molecular Properties, W.H. Freeman & Co., San Francisco, pp. 79-86 (1983)), acetylation of the N-terminal amine, and amidation of any C-terminal carboxyl group.

[0227] Other types of covalent modification of the antibody or antigen-binding fragment thereof included within the scope of this disclosure include altering the native glycosylation pattern of the antibody or antigen-binding fragment thereof (Beck et al., Curr. Pharm. Biotechnol. 9: 482-501 , 2008; Walsh, Drug Discov. Today 15: 773-780, 2010), and linking the antibody or antigen-binding fragment thereof to one of a variety of nonproteinaceous polymers, e.g., polyethylene glycol (PEG), polypropylene glycol, or polyoxyalkylenes, in the manner set forth in U.S. Patent Nos. 4,640,835; 4,496,689; 4,301 ,144; 4,670,417; 4,791 ,192 or 4,179,337.

[0228] The anti-LILRB2 antibody or antigen-binding fragment thereof may further comprise one or more modifications that confer additional biological properties to the antibody or antigenbinding fragment thereof such as protease resistance, plasma protein binding, increased plasma half-life, intracellular penetration, etc. Such modifications include, for example, covalent attachment of molecules / moiety to the antibody or antigen-binding fragment thereof such as fatty acids (e.g., C6-Ci8), attachment of proteins such as albumin (see, e.g., U.S. Patent No. 7,268,113); sugars / polysaccharides (glycosylation), biotinylation or PEGylation (see, e.g., U.S. Patent Nos. 7,256,258 and 6,528,485). The above description of modification of the antibody or antigen-binding fragment thereof does not limit the scope of the approaches nor the possible modifications that can be engineered. Thus, in another aspect, the present disclosure provides a conjugate comprising the antibody or antigen-binding fragment thereof described herein and one or more additional molecules or agents (hereinafter secondary molecules or agents). The antibody or antigen-binding fragment thereof may be conjugated to any type of synthetic or natural secondary molecules or agents, such as peptides, proteins, saccharides / polysaccharides, lipids, naturally-occurring or synthetic polymers / co-polymers, etc. to modify one or more properties of the antibody or antigen-binding fragment thereof.

[0229] In an embodiment, the conjugate comprises a covalent link or bond between the antibody or antigen-binding fragment thereof and the molecule / agent conjugated thereto. The molecule may be conjugated directly to the antigenic peptide, or indirectly via a linker. The linker may be a polypeptide linker comprising one or more amino acids or another type of chemical linker (e.g., a carbohydrate linker, a lipid linker, a fatty acid linker, a polyether linker, PEG, etc.

[0230] In another embodiment, the molecule may be conjugated / attached to the side chain of one the amino acids of the antibody or antigen-binding fragment thereof. Methods for conjugating moieties to side chains of amino acids are well known in the art. For example, chemical groups that react with primary amines (-NH2) present in the side chain of lysine residues such as G16863-00031 -AD

[0231] 31 isothiocyanates, isocyanates, acyl azides, NHS esters, sulfonyl chlorides, aldehydes, glyoxals, epoxides, oxiranes, carbonates, aryl halides, imidoesters, carbodiimides, anhydrides, and fluorophenyl esters may be used to conjugate the molecule to the antigenic peptide. Most of these groups conjugate to amines by either acylation or alkylation. Cysteine residues present in the antibody or antigen-binding fragment thereof may also be used to attach the molecule.

[0232] In an embodiment, the antibody or antigen-binding fragment thereof is labelled or conjugated with one or more moieties. The antibody or antigen-binding fragment thereof may be labeled with one or more labels such as a biotin label, a fluorescent label, an enzyme label, a coenzyme label, a chemiluminescent label, or a radioactive isotope label. In an embodiment, the antibody or antigen-binding fragment thereof is labelled with a detectable label, for example a fluorescent moiety (fluorophore). Useful detectable labels include fluorescent compounds (e.g., fluorescein isothiocyanate, Texas red, rhodamine, fluorescein, Alexa Fluor® dyes, and the like), radiolabels, enzymes (e.g., horseradish peroxidase, alkaline phosphatase and others commonly used in a protein detection assays), streptavidin / biotin, and colorimetric labels such as colloidal gold, colored glass or plastic beads (e.g., polystyrene, polypropylene, latex, etc.). Chemiluminescent compounds may also be used. Such labelled antibodies or antigen-binding fragments thereof may be useful, for example, for the detection of LILRB2-expressing cells in vivo or in vitro, e.g., by flow cytometry, immunohistochemistry, etc. The antibody or antigen-binding fragment thereof can also be conjugated to detectable or affinity tags that facilitate detection and / or purification of the antibody or antigen-binding fragment thereof. Such tags are well known in the art. Examples of detectable or affinity tags include polyhistidine tags (His-tags), polyarginine tags, polyaspartate tags, polycysteine tags, polyphenylalanine tags, glutathione S-transferase (GST) tags, Maltose binding protein (MBP) tags, calmodulin binding peptide (CBP) tags, Streptavidin / Biotin-based tags, HaloTag®, Profinity eXact® tags, epitope tags (such as FLAG, hemagglutinin (HA), HSV, S / S1 , c-myc, KT3, T7, V5, E2, and Glu-Glu epitope tags), reportertags such as p-galactosidase (P-gal), alkaline phosphatase (AP), chloramphenicol acetyl transferase (CAT), and horseradish peroxidase (HRP) tags (see, e.g., Kimple et al., Curr Protoc Protein Sci. 2013; 73: Unit-9.9).

[0233] The anti-LILRB2 antibody or antigen-binding fragment thereof according to the present disclosure may be conjugated to a diagnostic agent, such as an enzyme (e.g., HRP, AP), a fluorophore (FITC, PE, APC), a radioisotope (e.g., lodine-125 (125l), Technetium-99m (99mTc)), or nanoparticles (e.g., gold nanoparticles, quantum dots).

[0234] The anti-LILRB2 antibody or antigen-binding fragment thereof according to the present disclosure may be conjugated to a therapeutic agent (e.g., antitumor agent) to form an antibodydrug conjugate (ADC). The therapeutic agent (e.g., often referred to as the payload) may be directly conjugated to the antibody or antigen-binding fragment thereof, or may also be indirectly conjugated through a linker. The therapeutic agent may also be loaded on or encapsulated into a G16863-00031 -AD

[0235] 32 suitable vehicle, such as liposomes or other polymeric or lipid-based vesicles (e.g., lipid nanoparticles).

[0236] The antitumor agent may be any compound that has the ability to inhibit the growth and / or kill tumor cells and includes, for example, small molecules, peptides, proteins, oligonucleotides (e.g., siRNA, shRNA), radionuclide agents (e.g.,177Lu,18F,68Ga,90Y,99mTc,111ln,213Bi,221At,225Ac,227Th), antibodies, as well as drug delivery systems including nanoparticles, liposomes, nanotubes, graphene particles loaded with or encapsulating a therapeutic antitumor agent.

[0237] In an embodiment, the antitumor agent is a chemotherapeutic agent. The term “chemotherapeutic agent” refers to agents that kill tumor cells and / or inhibit their proliferation / growth. Examples in chemotherapeutic agents include alkylating agents (e.g., Cyclophosphamide, Ifosfamide, Mechlorethamine, Chlorambucil, Melphalan, Dacarbazine, Nitrosoureas, Temozolomide, Carmustine, Lomustine, Streptozocin, Busulfan, Procarbazine), anthracyclines (e.g., Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, Mitoxantrone, Valrubicin), Monomethyl auristatin E (MMAE), monomethyl auristatin F (MMAF), cytoskeletal disruptors (e.g., taxanes such as Paclitaxel, Docetaxel, Abraxane, Taxotere, cabazitaxel), histone deacetylase inhibitors (e.g., Vorinostat, Romidepsin), topoisomerase I inhibitors (e.g., camptothecin analogs such as Irinotecan, Topotecan, SN-38, Exotecan), topoisomerase II inhibitors (e.g., Etoposide, Teniposide, Tafluposide), kinase inhibitors (e.g., Bortezomib, Erlotinib, Gefitinib, Imatinib, Vemurafenib, Vismodegib, Dasatinib, Nilotinib, Osimertinib, Crizotinib, Dabrafenib, Vemurafenib, Trametinib, Ibrutinib), nucleotide analogs and precursor analogs (e.g., Azacitidine, Azathioprine, Capecitabine, Cytarabine, Doxifluridine, Fluorouracil (5-FU), Gemcitabine, Hydroxyurea, Mercaptopurine, Methotrexate, Tioguanine (Thioguanine)), peptide antibiotics (e.g., Bleomycin, Actinomycin), platinum-based agents (e.g., Carboplatin, Cisplatin, Oxaliplatin), retinoids (Tretinoin, Alitretinoin, Bexarotene), mitotic inhibitors such as vinca alkaloids and derivative (e.g., Vinblastine, Vincristine, Vindesine, Vinorelbine), toxins such as maytansinoids (e.g., DM1 , DM4), Auristatins, Calicheamicins, Amatoxin or Amanitin, as well as natural phytochemicals having antitumor properties such as curcumin, Alkaloids (e.g., Chlorogenic acid, Theobromine, Theophylline), Anthocyanins (e.g., Cyanidin, Malvidin, Carotenoids (Beta-Carotene, Lutein, Lycopene), Coumestans, Flavan-3-Ols, Flavonoids (e.g., Epicatechin, Hesperidin, Isorhamnetin, Kaempferol, Myricetin, Naringin, Nobiletin, Proanthocyanidins, Quercetin, Rutin, Tangeretin), Hydroxycinnamic Acids (e.g., Chicoric acid, Coumarin, Ferulic acid, Scopoletin), Isoflavones (e.g., Daidzein, Genistein), Lignans (e.g., Silymarin), Monoterpenes (e.g., Geraniol, Limonene), Organosulfides (e.g., Allicin, Glutathione, lndole-3-Carbinol, Isothiocyanates, Sulforaphane), Damnacanthal, Digoxin, Phytic acid, Phenolic Acids (e.g., Capsaicin, Ellagic Acid, Gallic acid, Rosmarinic acid, Tannic Acid), Phytosterols (e.g., Beta-Sitosterol), Saponins, Stylbenes (e.g., G16863-00031 -AD

[0238] 33

[0239] Pterostilbene, Resveratrol), Triterpenoids (e.g., Ursolic acid), Xanthophylls (e.g., Astaxanthin, Beta-Cryptoxanthin), and Monophenols (e.g., Hydroxytyrosol).

[0240] It is to be understood that some agents may be used for diagnostic and therapeutic applications (theranostic agents), for example radioisotopes (e.g.,131l,177Lu), photosensitizers (e.g., porphyrins, phthalocyanines), nanoparticles (e.g., gold nanoparticles, magnetic nanoparticles), and liposomes / micelles loaded with imaging agents and therapeutic drugs.

[0241] The diagnostic or therapeutic agent may be connected at a free amine of a lysine residue of the anti-LILRB2 antibody or antigen-binding fragment thereof according to the present disclosure, optionally via a linker, or at an N-terminal position of the antibody or antigen-binding fragment thereof according to the present disclosure, optionally via a linker. The diagnostic or therapeutic agent may be connected to the anti-LILRB2 antibody or antigen-binding fragment thereof according to the present disclosure (optionally via a linker) at a cysteine residue added to an end of the antibody or antigen-binding fragment thereof according to the present disclosure.

[0242] The term “linker” as used herein means a chemical structure connecting the anti-LILRB2 antibody or antigen-binding fragment thereof to at least one antitumor agent. The linker can be connected to the anti-LILRB2 antibody or antigen-binding fragment thereof at different functional groups on the anti-LILRB2 antibody or antigen-binding fragment thereof. For example, the linker can be connected to the anti-LILRB2 antibody or antigen-binding fragment thereof at the primary amines (amines (-NH2): this group exists at the N-terminus of each polypeptide chain (called the alpha-amine) and in the side chain of lysine (Lys, K) residues (called the epsilon-amine). For example, the linker can be connected to the anti-LILRB2 antibody or antigen-binding fragment thereof at the carboxyls (-COOH): this group exists at the C-terminus of each polypeptide chain and in the side chains of aspartic acid (Asp, D) and glutamic acid (Glu, E). For example, the linker can be connected to the anti-LILRB2 antibody or antigen-binding fragment thereof at the Sulfhydryls (-SH): This group exists in the side chain of cysteine (Cys, C). Often, as part of a protein's secondary or tertiary structure, cysteines are joined together between their side chains via disulfide bonds (-S-S-). These must be reduced to sulfhydryls to make them available for crosslinking by most types of reactive groups. For example, the linker can be connected to the antibody or antigen-binding fragment thereof at the carbonyls (-CHO): ketone or aldehyde groups can be created in glycoproteins by oxidizing the polysaccharide post-translational modifications (glycosylation) with sodium meta-periodate.

[0243] The linker can be an aliphatic linker (e.g., with an amide bond to the polypeptide and an ester bond to the antitumor agent). Where an aliphatic linker is used, it may vary with regard to length (e.g., C1-C20, C1-C12, Ci-C6) and the chemical moieties it includes (e.g., an amino group or carbamate).

[0244] The linker can be an amino acid or peptide linker. Examples of suitable amino acid linkers are succinic acid, Lys, Glu, and Asp, or a dipeptide such as Gly-Lys. When the linker is succinic G16863-00031 -AD

[0245] 34 acid, one carboxyl group thereof may form an amide bond with an amino group of the amino acid residue, and the other carboxyl group thereof may, for example, form an amide bond with an amino group of the peptide or substituent. When the linker is Lys, Glu, or Asp, the carboxyl group thereof may form an amide bond with an amino group of the amino acid residue, and the amino group thereof may, for example, form an amide bond with a carboxyl group of the substituent. When Lys is used as the linker, a further linker may be inserted between the E-amino group of Lys and the substituent. The further linker may be succinic acid, which can form an amide bond with the E- amino group of Lys and with an amino group present in the substituent. In one embodiment, the further linker is Glu or Asp (e.g., which forms an amide bond with the E-amino group of Lys and another amide bond with a carboxyl group present in the substituent), that is, the substituent is a N£-acylated lysine residue. The linker may be a cleavable linker, for example comprising a sequence recognized by a protease (e.g., cathepsins) or an ester cleavable by esterases.

[0246] Nucleic acid molecules comprising polynucleotides that encode one or more chains of the anti-LILRB2 antibody or antigen-binding fragment thereof disclosed herein are provided. In some embodiments, a nucleic acid molecule comprises a polynucleotide that encodes a heavy chain or a light chain of the anti-LILRB2 antibody or antigen-binding fragment. In some embodiments, a nucleic acid molecule comprises both a polynucleotide that encodes a heavy chain and a polynucleotide that encodes a light chain, of the anti-LILRB2 antibody or antigenbinding fragment. In some embodiments, a first nucleic acid molecule comprises a first polynucleotide that encodes a heavy chain and a second nucleic acid molecule comprises a second polynucleotide that encodes a light chain.

[0247] In some embodiments, the heavy chain and the light chain are expressed from one nucleic acid molecule, or from two separate nucleic acid molecules, as two separate polypeptides. In some embodiments, such as when an antibody is an scFv, a single polynucleotide encodes a single polypeptide comprising both a heavy chain and a light chain linked together.

[0248] In some embodiments, a nucleic acid encoding a heavy chain or light chain of the anti- LILRB2 antibody or antigen-binding fragment thereof comprises a nucleotide sequence that encodes at least one of the CDRs provided herein. In some embodiments, a polynucleotide encoding a heavy chain or light chain of the anti-LILRB2 antibody or antigen-binding fragment thereof comprises a nucleotide sequence that encodes at least 3 of the CDRs provided herein. In some embodiments, a polynucleotide encoding a heavy chain or light chain of the anti-LILRB2 antibody or antigen-binding fragment thereof comprises a nucleotide sequence that encodes at least 6 of the CDRs provided herein. In some embodiments, a polynucleotide encoding a heavy chain or light chain of the anti-LILRB2 antibody or antigen-binding fragment thereof comprises a nucleotide sequence that encodes a leader sequence, which, when translated, is located at the G16863-00031 -AD

[0249] 35

[0250] N terminus of the heavy chain or light chain. The leader sequence may be the native heavy or light chain leader sequence, or may be another heterologous leader sequence.

[0251] In an embodiment, the nucleic acid encoding the light chain comprises the nucleotide sequence of SEQ ID NO:97 or 98 and the nucleic acid encoding the heavy chain comprises the nucleotide sequence of SEQ ID NO:99 or 100. In an embodiment, the nucleic acid encoding the light chain comprises the nucleotide sequence of SEQ ID NQ:101 or 102 and the nucleic acid encoding the heavy chain comprises the nucleotide sequence of SEQ ID NO: 103 or 104. Of course, because of the degeneracy of the genetic code, the skilled person would understand that the heavy chain and the light chains of the antibodies or antigen-binding fragments thereof described herein may be encoded by variants of the above-noted nucleotides sequences encoding the same amino acid sequences.

[0252] Vectors comprising polynucleotides that encode the anti-LILRB2 antibody heavy chains and / or anti-LILRB2 antibody light chains are provided. Vectors comprising polynucleotides that encode anti-LILRB2 heavy chains and / or anti-LILRB2 light chains are also provided. Such vectors include, but are not limited to, DNA vectors, phage vectors, viral vectors, retroviral vectors, etc. In some embodiments, a vector comprises a first polynucleotide sequence encoding a heavy chain and a second polynucleotide sequence encoding a light chain. In some embodiments, the heavy chain and light chain are expressed from the vector as two separate polypeptides. In some embodiments, the heavy chain and light chain are expressed as part of a single polypeptide, such as, for example, when the antibody is an scFv.

[0253] In some embodiments, a first vector comprises a nucleic acid that encodes a heavy chain and a second vector comprises a polynucleotide that encodes a light chain. In some embodiments, the first vector and second vector are transfected into host cells in similar amounts (such as similar molar amounts or similar mass amounts). In some embodiments, a mole- or mass-ratio of between 5:1 and 1 :5 of the first vector and the second vector is transfected into host cells. In some embodiments, a mass ratio of between 1 :1 and 1 :5 for the vector encoding the heavy chain and the vector encoding the light chain is used. In some embodiments, a mass ratio of 1 :2 for the vector encoding the heavy chain and the vector encoding the light chain is used.

[0254] In some embodiments, a vector is selected that is optimized for expression of polypeptides in CHO or CHO-derived cells, or in NSO cells. Exemplary such vectors are described, for example, in Running Deer et al., 2004, Biotechnol. Prog. 20:880-889.

[0255] In some embodiments, the anti-LILRB2 antibody heavy chains and / or anti-LILRB2 antibody light chains may be expressed in prokaryotic cells, such as bacterial cells; or in eukaryotic cells, such as fungal cells (such as yeast), plant cells, insect cells, and mammalian cells. Such expression may be carried out, for example, according to procedures known in the art. Exemplary eukaryotic cells that may be used to express polypeptides include, but are not limited to, COS cells, including COS 7 cells; 293 cells, including 293-6E cells; CHO cells, including G16863-00031 -AD

[0256] 36

[0257] CHO-S, DG44. Led 3 CHO cells, and FUT8 CHO cells; PER. C6® cells (Crucell); and NSO cells. In some embodiments, anti-LILRB2 antibody heavy chains and / or anti-LILRB2 antibody light chains may be expressed in yeast. See, for example, U.S. Publication No. 2006 / 0270045 A1. In some embodiments, a particular eukaryotic host cell is selected based on its ability to make desired post-translational modifications to the anti-LILRB2 antibody heavy chains and / or anti- LILRB2 antibody light chains. For example, in some embodiments, CHO cells produce polypeptides that have a higher level of sialylation than the same polypeptide produced in 293 cells.

[0258] Introduction of one or more nucleic acids into a desired host cell may be accomplished by any method, including but not limited to, calcium phosphate transfection, DEAE-dextran mediated transfection, cationic lipid-mediated transfection, electroporation, transduction, infection, etc. Nonlimiting exemplary methods are described, for example, in Sambrook et al., Molecular Cloning, A Laboratory Manual, 3rded. Cold Spring Harbor Laboratory Press (2001). Nucleic acids may be transiently or stably transfected in the desired host cells, according to any suitable method.

[0259] In other embodiments, the nucleic acid(s) encoding the may be incorporated into a cell using gene-editing technologies such as CRISPR-Cas9, TALE nucleases, and zinc-finger nucleases. Thus, the present disclosure provides a host cell, such as a mammalian cell, comprising the nucleic acid(s) encoding the anti-LILRB2 antibody or antigen-binding fragment thereof described herein within its genome.

[0260] In embodiment, the nucleic acid(s) (DNA, mRNA) encoding the antibody or antigenbinding fragment described herein of the disclosure is comprised within a vesicle such as lipid nanoparticles (e.g., liposomes) or any other suitable vehicle. In an embodiment, the nucleic acid(s) is / are mRNA and is / are encapsulated into nanoparticulate delivery vehicles (see, e.g., Van Hoecke and Roose (2019) How mRNA therapeutics are entering the monoclonal antibody field, J. Transl. Med. 17, 54. https: / / doi.org / 10.1186 / s12967-019-1804-8; Sanz and Alvarez-Vallina (2021) Engineered mRNA and the Rise of Next-Generation Antibodies, Antibodies 10(4):37. https: / / doi.org / 10.3390 / antib10040037).

[0261] In various embodiments, the anti-LILRB2 antibody or antigen-binding fragment thereof disclosed herein exhibit one or more biological or binding activities.

[0262] In an embodiment, the anti-LILRB2 antibody or antigen-binding fragment thereof disclosed herein promotes immunogenicity (e.g., as exhibited by M1-like macrophages) to respond to a pathology, e.g., cancer. Additionally or alternatively, the anti-LILRB2 antibody or antigen-binding fragment thereof disclosed herein inhibits an immunoregulatory (e.g., immunosuppressive) response, e.g., as exhibited by M2-like macrophages. G16863-00031 -AD

[0263] 37

[0264] In an embodiment, the anti-LILRB2 antibody or antigen-binding fragment thereof disclosed herein inhibits or disrupts the binding between LILRB2 and classical MHC class I molecules, such as HLA-G and / or HLA-A2.

[0265] In an embodiment, the anti-LILRB2 antibody or antigen-binding fragment thereof disclosed herein converts an M2-like macrophage population to an M1-like macrophage population.

[0266] The present disclosure provides pharmaceutical compositions comprising the anti- LILRB2 antibody or antigen-binding fragment thereof as described herein. The pharmaceutical compositions of the disclosure are formulated with suitable diluents, carriers, excipients, and other agents that provide improved transfer, delivery, tolerance, and the like. The compositions may be formulated for specific uses, such as for veterinary uses or pharmaceutical uses in humans. The form of the composition and the excipients, diluents and / or carriers used will depend upon the intended uses of the antibody and, for therapeutic and in situ diagnostic uses, the mode of administration. A multitude of appropriate formulations can be found in the formulary known to pharmaceutical chemists: Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa. These formulations Include, for example, powders, pastes, ointments, jellies, waxes, oils, lipids, lipid- (cationic or anionic) containing vesicles (such as LIPOFECTIN™, Life Technologies, Carlsbad, Calif.), DNA conjugates, anhydrous absorption pastes, oil-in-water and water-in-oil emulsions, emulsions carbowax (polyethylene glycols of various molecular weights), semi-solid gels, and semi-solid mixtures containing carbowax. See also Powell et al. "Compendium of excipients for parenteral formulations" PDA (1998) J Pharm Sci Technol 52:238- 311.

[0267] The dose of anti-LILRB2 antibody or antigen-binding fragment thereof administered to a patient may vary depending upon the age and the size of the patient, target disease, conditions, route of administration, and the like. The preferred dose is typically calculated according to body weight or body surface area. When an antibody of the present disclosure is used for treating a condition or disease associated with LILRB2 in an adult patient, it may be advantageous to intravenously administer the anti-LILRB2 antibody or antigen-binding fragment thereof of the present disclosure. Depending on the severity of the condition, the frequency and the duration of the treatment can be adjusted. Effective dosages and schedules for administering the anti-LILRB2 antibody or antigen-binding fragment thereof may be determined empirically; for example, patient progress can be monitored by periodic assessment, and the dose adjusted accordingly. Moreover, interspecies scaling of dosages can be performed using well-known methods in the art (e.g., Mordenti et al., 1991 , Pharmaceut. Res. 8:1351).

[0268] Various delivery systems are known and can be used to administer the pharmaceutical composition of the disclosure, e.g., encapsulation in liposomes, microparticles, microcapsules, recombinant cells capable of expressing the mutant viruses, receptor mediated endocytosis (see, G16863-00031 -AD

[0269] 38 e.g,, Wu et al., 1987, J. Biol. Chem. 262:4429-4432). Methods of introduction include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral routes. The composition may be administered by any convenient route, for example by Infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa, etc.) and may be administered together with other biologically active agents. Administration can be systemic or local.

[0270] A pharmaceutical composition of the present disclosure can be delivered subcutaneously or intravenously with a standard needle and syringe. In addition, with respect to subcutaneous delivery., a pen delivery device readily has applications in delivering a pharmaceutical composition of the present disclosure. Such a pen delivery device can be reusable or disposable, A reusable pen delivery device generally utilizes a replaceable cartridge that contains a pharmaceutical composition. Once all of the pharmaceutical composition within the cartridge has been administered and the cartridge is empty, the empty cartridge can readily be discarded and replaced with a new cartridge that contains the pharmaceutical composition. The pen delivery device can then be reused. In a disposable pen delivery device, there is no replaceable cartridge. Rather, the disposable pen delivery device comes prefilled with the pharmaceutical composition held in a reservoir within the device. Once the reservoir is emptied of the pharmaceutical composition, the entire device is discarded.

[0271] In certain situations, the pharmaceutical composition can be delivered in a controlled release system. In one embodiment, a pump may be used (see Sefton, 1987, CRC Crit. Ref. Biomed. Eng. 14:201). In another embodiment, polymeric materials can be used; see, Medical Applications of Controlled Release, Langer and Wise (eds.), 1974, CRC Pres., Boca Raton, Fla. In yet another embodiment, a controlled release system can be placed in proximity of the composition's target, thus requiring only a fraction of the systemic dose (see, e.g., Goodson, 1984, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115-138). Other controlled release systems are discussed in the review by Langer, 1990, Science 249:1527-1533.

[0272] The injectable preparations may include dosage forms for intravenous, subcutaneous, intracutaneous and intramuscular injections, drip infusions, etc. These injectable preparations may be prepared by methods publicly known. For example, the injectable preparations may be prepared, e.g., by dissolving, suspending or emulsifying the anti-LILRB2 antibody or antigenbinding fragment thereof in a sterile aqueous medium or an oily medium conventionally used for injections. As the aqueous medium for injections, there are, for example, physiological saline, an isotonic solution containing glucose and other auxiliary agents, etc., which may be used in combination with an appropriate solubilizing agent such as an alcohol (e.g., ethanol), a polyalcohol (e.g., propylene glycol, polyethylene glycol), a nonionic surfactant (e.g., polysorbate 80, HCO-50 (polyoxyethylene (50 mol) adduct of hydrogenated castor oil)), etc. As the oily medium, there are employed, e.g., sesame oil, soybean oil, etc., which may be used in G16863-00031 -AD

[0273] 39 combination with a solubilizing agent such as benzyl benzoate, benzyl alcohol, etc. The injection thus prepared is preferably filled in an appropriate ampoule.

[0274] Advantageously, the pharmaceutical compositions for oral or parenteral use described above are prepared into dosage forms in a unit dose suited to fit a dose of the active ingredients. Such dosage forms in a unit dose include, for example, tablets, pills, capsules, injections (ampoules), suppositories, etc.

[0275] The anti-LILRB2 antibody or antigen-binding fragment thereof disclosed herein can specifically bind human LILRB2 expressed by myeloid cells or cells, such as LILRB2-expressing cells, of a cancer. The antibody product can specifically bind to a human immunosuppressive myeloid cell. The immunosuppressive myeloid cell can be in a tumor microenvironment. The immunosuppressive myeloid cell can be a macrophage, a myeloid dendritic cell, or a myeloid- derived suppressor cell. The immunosuppressive myeloid cell can be a M2a, M2b, M2c, or M2d macrophage.

[0276] The term “M2 macrophages” or M2-like macrophages” refers to macrophages that are involved in anti-inflammatory responses, tissue repair, and immunoregulation. They produce antiinflammatory cytokines like IL-10 and TGF-p, which help suppress inflammatory responses and promote tissue healing. Induced by signals such as IL-4, IL-13, and glucocorticoids, M2 macrophages exhibit efficient phagocytosis of cellular debris and apoptotic cells, aiding in the cleanup process after tissue damage. M2 macrophages can be further categorized:

[0277] • M2a: Induced by IL-4 and IL-13, involved in tissue repair and fibrosis.

[0278] • M2b: Induced by immune complexes and TLR ligands, playing roles in immune regulation.

[0279] • M2c: Induced by IL-10 and TGF-p, associated with immunosuppression and tissue remodeling.

[0280] • M2d: Induced following stimulation with Toll-like receptor (TLR) agonists and adenosine, and / or tumor-associated factors. Common in the tumor microenvironment.

[0281] Clinically, M2 macrophages are implicated in various pathological conditions. They can promote tumor growth and metastasis by creating an immunosuppressive environment in cancers.

[0282] The anti-LILRB2 antibody or antigen-binding fragment thereof disclosed herein may be used in a variety of applications. Some of the antibodies and fragments, for instance, are useful for specific binding assays, affinity purification of LILRB2 or its ligands, and screening assays to identify other antagonists of LILRB2 activity. The anti-LILRB2 antibody or antigen-binding fragment thereof can be used to treat various diseases that are associated with the activity of LILRB2.

[0283] The anti-LILRB2 antibody or antigen-binding fragment thereof disclosed herein may be used to detect LILRB2 in biological samples. This capability facilitates the identification of cells or G16863-00031 -AD

[0284] 40 tissues producing the protein and serves as a diagnostic tool for detecting pathological conditions associated with LILRB2 overproduction or underproduction. The expression of LILRB2 by macrophages, osteoclasts, and other myeloid cells can indicate the activity of these cells. Therefore, detecting LILRB2 expression on myeloid cells can serve as a marker for diseases or disorders characterized by these cell types. Similarly, detecting LILRB2 expression in cancer cells can help identify patients whose cancer may respond to treatment with the anti-LILRB2 antibody or antigen-binding fragment thereof disclosed herein.

[0285] Accordingly, methods are provided for detecting cell activity in a biological sample, which can be an in vitro medium, a biological (e.g., tissue, blood) sample from a subject, or in vivo within a subject. The method involves contacting a cell expressing LILRB2 with the anti-LILRB2 antibody or antigen-binding fragment thereof disclosed herein. The anti-LILRB2 antibody or antigenbinding fragment thereof disclosed herein can be conjugated to a detectable moiety, allowing for direct detection of the moiety. Alternatively, the method can involve detecting the binding of the anti-LILRB2 antibody or antigen-binding fragment thereof to the cell indirectly through a detectable moiety that binds to the antibody. For instance, an IgG antibody conjugated to a detectable moiety can be used to bind to the LILRB2 antibody presented as an IgG isotype. The cell can be a tumor cell or a myeloid cell (e.g., a monocyte, dendritic cell, macrophage, myeloid- derived suppressor cell, tumor-associated macrophage, immunosuppressive macrophage, or M2- like macrophage) or an osteoclast.

[0286] The anti-LILRB2 antibody or antigen-binding fragment thereof disclosed herein are useful for the treatment of human diseases, including cancers.

[0287] The anti-LILRB2 antibody or antigen-binding fragment thereof disclosed herein can be used for cancer treatment, either as a monotherapy or in combination with other anti-cancer therapeutics. These treatments are applicable to cancers where the cancer cells are known to express LILRB2 or are of a type previously observed to express LILRB2. Notably, certain EGFR- mutant cancers have been found to express higher levels of LILRB2 and are therefore considered suitable for treatment with these antibodies. Conversely, LILRB2 expression in cancer cells has been found to inversely correlate with PD-L1 expression. Consequently, anti-LILRB2 treatment is also considered in cases where cancer cells do not express PD-L1 . This treatment is particularly indicated when therapeutic intervention targeting the PD-1 / PD-L1 axis is, or is anticipated to be, ineffective, i.e. a cancer resistant to treatment with PD-1 and / or PD-L1 inhibitors.

[0288] As used herein, the term "cancer" has its general meaning in the art and includes, but is not limited to, solid tumors and blood cancers. 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.

[0289] Cancers that may be treated with the anti-LILRB2 antibody or antigen-binding fragment thereof disclosed herein include, for example, acute lymphoblastic leukemia, chronic lymphocytic G16863-00031 -AD

[0290] 41 leukemia, acute myeloid leukemia, myelodysplastic syndrome, chronic myelogenous leukemia, Hodgkin's disease; Hodgkin's lymphoma, non-Hodgkin's lymphoma, Burkitt lymphoma, bladder cancer, kidney cancer (e.g., renal cell carcinoma, e.g., papillary renal cell carcinoma), 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.

[0291] In some embodiment, the cancers to be treated include, for example, glioblastoma multiforme, head and neck cancer, kidney renal clear cell cancer, acute myeloid leukemia, pancreatic adenocarcinoma, melanoma (e.g., 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.

[0292] In an embodiment, the cancer is a solid cancer.

[0293] Cells of a cancer treated in methods provided herein can express or overexpress LILRB2. Studies have demonstrated an association between upregulation of LILRB2 and a diverse number of tumors, such as endometrial cancer, colorectal cancer, non-small cell lung cancer (NSCLC), lung adenocarcinoma, hepatocellular carcinoma, breast cancer, renal cell carcinoma and ovarian cancer (Cao et al., Oncol Lett. 2025 Feb 12;29(4):181).

[0294] The anti-LILRB2 antibody or antigen-binding fragment thereof can be administered as needed to subjects. Determination of the frequency of administration can be made by persons skilled in the art, such as an attending physician based on considerations of the condition being treated, age of the subject being treated, severity of the condition being treated, general state of health of the subject being treated and the like. In some embodiments, an effective dose of an anti-LILRB2 antibody is administered to a subject one or more times. In some embodiments, an effective dose of an anti-LILRB2 antibody is administered to the subject once a month, less than once a month, such as, for example, every two months or every three months.

[0295] The therapeutically effective amount is typically dependent on the weight of the subject being treated, his or her physical or health condition, the extensiveness of the condition to be treated, or the age of the subject being treated. In general, the anti-LILRB2 antibody or antigenbinding fragment thereof may be administered in an amount in the range of about 10 pg / kg body weight to about 100 mg / kg body weight per dose. In some embodiments, the anti-LILRB2 antibody or antigen-binding fragment thereof may be administered in an amount in the range of about 50 pg / kg body weight to about 5 mg / kg body weight per dose. In some embodiments, the anti-LILRB2 antibody or antigen-binding fragment thereof may be administered in an amount in the range of about 100 pg / kg body weight to about 10 mg / kg body weight per dose. In some embodiments, G16863-00031 -AD

[0296] 42 the anti-LILRB2 antibody or antigen-binding fragment thereof may be administered in an amount in the range of about 100 pg / kg body weight to about 20 mg / kg body weight per dose. In some embodiments, the anti-LILRB2 antibody or antigen-binding fragment thereof may be administered in an amount in the range of about 0.5 mg / kg body weight to about 20 mg / kg body weight per dose.

[0297] In some embodiments, the anti-LILRB2 antibody or antigen-binding fragment thereof disclosed herein may be used to stimulate the immune response against an infection, e.g., a viral infection, a bacterial infection, a parasitic infection or a fungal infection.

[0298] The anti-LILRB2 antibody or antigen-binding fragment thereof disclosed 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.

[0299] The anti-LILRB2 antibody or antigen-binding fragment thereof disclosed herein may be used in combination with one or more other anticancer therapy for the treatment of a cancer in a subject. The anticancer therapy can be a chemotherapeutic agent, a biologic agent (e.g., an antibody, antibody-drug conjugate), a cancer vaccine, radiotherapy, and / or surgery. In an embodiment, the anticancer therapy is an immunotherapeutic molecule, such as an immune checkpoint inhibitor (ICI), as described above.

[0300] In some embodiments, the anti-LILRB2 antibody or antigen-binding fragment thereof disclosed herein and an immune checkpoint inhibitor are co-formulated. In others, they are in separate formulations. For example, the anti-LILRB2 antibody or antigen-binding fragment thereof could be administered with a coformulation of a PD-1 antagonist (e.g., a PD-1 antibody) and a CTLA-4 antagonist (e.g., a CTLA-4 antibody), with dosages controlled to provide a safe and effective treatment. In some cases, the anti-LILRB2 antibody or antigen-binding fragment thereof is administered with a coformulation of pembrolizumab / quavonlimab (Merck).

[0301] In some embodiments, the anti-LILRB2 antibody or antigen-binding fragment thereof disclosed herein is administered with a PD-1 therapy, such as anti-PD1 and / or PD-L1 antibodies. Exemplary PD-1 therapies include, but are not limited to, nivolumab, pidilizumab, lambrolizumab / pembrolizumab, durvalumab; RG-7446; avelumab, AMP-224, BMS-936559, AMP-514, MDX-1105; ANB-011 , anti-LAG-3 / PD-1 , anti-PD-1 Ab (CoStim), anti-PD-1 Ab (Kadmon Pharm.), anti-PD-1 Ab (Immunovo), anti-TIM-3 / PD-1 Ab (AnaptysBio); anti-PD-L1 Ab (CoStim / Novartis), MEDI-4736, RG7446 / MPDL3280A, KD-033, PD-1 antagonist (Agenus), STI- A1010, STI-A1110, TSR-042, atezolizumab, and other antibodies and other agents that are directed against PD-1 or PD-L1.

[0302] The present disclosure also provides kits, medicines, compositions, and unit dosage forms for use in any of the methods described herein. Kits can include one or more containers comprising the anti-LILRB2 antibody or antigen-binding fragment thereof disclosed herein (or unit G16863-00031 -AD

[0303] 43 dosage forms and / or articles of manufacture). In some embodiments, a unit dosage is provided wherein the unit dosage contains a predetermined amount of a composition comprising the anti- LILRB2 antibody or antigen-binding fragment thereof disclosed herein, with or without one or more additional agents. In some embodiments, such a unit dosage is supplied in single use prefilled syringe for injection. In some embodiments, the composition contained in the unit dosage can comprise saline, sucrose, orthe like; a buffer, such as phosphate, orthe like; and / or be formulated within a stable and effective pH range. In some embodiments, the composition can be provided as a lyophilized powder that may be reconstituted upon addition of an appropriate liquid, for example, sterile water. In some embodiments, the composition comprises one or more substances that inhibit protein aggregation, including, but not limited to, sucrose and arginine. In some embodiments, a composition comprises heparin and / or a proteoglycan.

[0304] In some embodiments, the amount of the anti-LILRB2 antibody or antigen-binding fragment thereof disclosed herein used in the unit dose can be any of the amounts provided herein for the various methods and / or compositions described.

[0305] In some embodiments, kits further comprise instructions for use in the treatment of cancer in accordance with any of the methods described herein. The kit may further comprise a description of selection an individual suitable or treatment. Instructions supplied in the kits are typically written instructions on a label or package insert (for example, a paper sheet included in the kit), but machine-readable instructions (for example, instructions carried on a magnetic or optical storage disk) are also acceptable. In some embodiments, the kit further comprises another therapeutic agent.

[0306] The kits are in suitable packaging. Suitable packaging includes, but is not limited to, vials, bottles, jars, flexible packaging (for example, sealed Mylar or plastic bags), and the like. Kits may optionally provide additional components such as buffers and interpretative information. The present application thus also provides articles of manufacture, which include vials (such as sealed vials), bottles, jars, flexible packaging, and the like.

[0307] MODE(S) FOR CARRYING OUT THE INVENTION

[0308] The present invention is illustrated in further details by the following non-limiting examples.

[0309] Example 1: Immunization and selection of anti-LILRB2 antibodies

[0310] Animals (hens) were immunized with the LILRB2 protein and by DNA using electroporation with plasmid DNA. Candidates were selected via phage display and B cell screening. Hundreds of antibody candidates were assessed for specificity, binding, and affinity using the LSA™ platform (Carterra). Non-Regenerative surface plasmon resonance (SPR) kinetic assays were performed on an LSA instrument (Carterra, Salt Lake City, UT). Antibodies were prepared at a concentration of 2.5 pg / mL and captured for 15 minutes on a previously conditioned linear polycarboxylate SPR surface. Following ligand immobilization, the analyte LILRB2 was G16863-00031 -AD injected as a 10-point, 2.5-fold serial dilution over the surface. For each analyte injection, an 8- minute association phase and 10-minute dissociation phase were performed. Binding data were fitted to a 1 :1 Langmuir binding model to determine on-rate (fe) and off-rate ( / ). Binding affinity, KD, was calculated following the equation KD= kdI ka. These assays led to the selection of 24 antibody candidates, shown in Table 1A.

[0311] Subsequent functional assays, including HLA-G blocking and cytokine profiling, were conducted to identify antibody candidates having the ability to interfere with LILRB2 activity. The top four antibody candidates, IBS032, IBS039, IBS068 and IBS099 (in bold in Table 1A), were humanized by CDR grafting based on the closest germline sequences and / or using the BioPhi antibody design platform (David Prihoda, Jad Maamary, Andrew Waight, Veronica Juan, Laurence Fayadat-Dilman, Daniel Svozil & Danny A. Bitton (2022). BioPhi: A platform for antibody design, humanization, and humanness evaluation based on natural antibody repertoires and deep learning, mAbs, 14:1). After further validation, two of the humanized candidates (IBS316 and IBS336) were selected for further characterization (Table 1B). The properties of these two candidates were compared to those of the anti-LILRB2 antibody MK-4830 (described in PCT publication No. WO 2018 / 187518), which is currently under clinical development (see, e.g., Siu et al., Clin Cancer Res. 2022 Jan 1 ;28(1):57-70. doi: 10.1158 / 1078-0432.CCR-21 -2160.

[0312] Table 1A G16863-00031 -AD

[0313] Table 1B

[0314] FIGs. 1A-B depict the results of non-regenerative SPR kinetic assays for IBS316 (FIG. 1A) and IBS336 (FIG. 1B). LILRB2 was injected as a 10-point, 2.5-fold serial dilution over the immobilized ligand IBS316 or IBS336. Kinetic parameters were determined through fitting with 1 :1 Langmuir binding model.

[0315] The amino acid sequences of domains and chains of antibodies IBS032, IBS039, IBS068, IBS099, IBS316 and IBS336 are depicted in Table 2A, and the nucleotide sequences encoding IBS032, IBS039, IBS068, IBS099, IBS316 and IBS336 are depicted in Table 2B.

[0316] Table 2A G16863-00031 -AD

[0317] 46 G16863-00031 -AD

[0318] 47 G16863-00031 -AD

[0319] 48 G16863-00031 -AD

[0320] 49 G16863-00031 -AD

[0321] 50 G16863-00031 -AD

[0322] 51 G16863-00031 -AD

[0323] 52

[0324] Table 2B G16863-00031 -AD

[0325] 53 G16863-00031 -AD

[0326] 54 G16863-00031 -AD

[0327] 55 G16863-00031 -AD

[0328] 56 G16863-00031 -AD

[0329] 57

[0330] The amino acid sequences of additional putative humanized versions of IBS032 and

[0331] IBS068 predicted by BioPhi are depicted in Table 3A and Table 3B, respectively.

[0332] Table 3A Table 3B G16863-00031 -AD

[0333] 58

[0334] Example 2: Characterization of IBS316 and IBS336

[0335] The specificity and affinity between the humanized antibodies IBS316 and IBS336 and various members of the leukocyte immunoglobulin-like receptor (LILR) family was assessed. Antigens of interest (human LILRB1 , human LILRB2, human LILRB3, human LILRB4, human LILRB5, murine PIR-B, human LILRA1 or BSA) were immobilized at a concentration of 1 pg / mL (except BSA at 0.2 mg / ml) in carbonate buffer 50 mM pH 9,6 to the surface of 96-well Nunc plates by incubating overnight at 4 °C. After washing with PBS + 0.05% Tween™-20 and blocking with 3% milk PBS for 1 hour at room temperature, plates containing the immobilized antigens were incubated with anti-LILRB2 antibodies (MK-4830, NGM707, IBS316 or IBS336) of isotypic lgG4 at various antibody concentrations (3-fold serial dilution starting at 20 pg / ml). The plates were then washed again with PBS + 0.05% Tween™-20 and the secondary antibody Goat Anti-Human IgG Fc (HRP) (abeam, ab98624) was added at 1 :10 000 concentration and incubated for 1 hour at room temperature. The plates were then washed with PBS + 0.05% Tween™-20 and revealed by adding TMB substrate and incubated for 30 minutes at room temperature. The reaction was stopped by adding 0,18M H3PO4 and optical density was read at 450nm. The analysis was performed with nonlin fit, log(inhibitor) vs. response, variable slope (four parameter). As shown in Table 4, IBS316, IBS336 and MK-4830 specifically binds to LILRB2, with no detectable binding to any of the other LILR family members. In contrast, the known dual LILRB1 / LILRB2 antagonist monoclonal antibody NGM707 was shown to bind to both LILRB1 and LILRB2, as well as to LILRA1 .

[0336] Table 4

[0337] It was next assessed whether antibodies IBS316 and IBS336 compete with MK-4830 for binding to LILRB2. To do so, SPR competition assay were performed on an LSA instrument (Carterra, Salt Lake City, UT). Ligand MK-4830 was prepared at a concentration of 5 pg / mL and G16863-00031 -AD

[0338] 59 captured for 15 minutes on a previously conditioned linear polycarboxylate SPR surface. Following ligand immobilization, the analyte LILRB2-His was injected on the SPR surface at a concentration of 0.25 pM for 5 minutes. Competitor antibodies (MK-4830, IBS316, IBS336 and an anti-histidine tag control antibody) were prepared at a concentration of 10 pg / mL and injected for 5 minutes before surface regeneration. Binding responses (RUs) have been relativized to value at Time = 290 seconds. Binding affinity (KD) have been determined through previous SPR kinetic experiments. The results depicted in FIG. 2 show that antibodies IBS316 and IBS336 compete with MK-4830 for binding to LILRB2, as evidenced by the loss of signal when IBS316 and IBS336 were used as competitor antibodies. As expected, a loss of signal was also detected when MK-4830 was used as competitor antibodies, whereas the negative control anti-histidine tag antibody did not compete with MK-4830 for binding to LILRB2.

[0339] In the next series of experiments, the ability of IBS316 and IBS336 to interfere with the interaction between LILRB2 and its ligand HLA-G was assessed. 250,000 HEK-293T cells overexpressing LILRB2 were incubated with 2 pg / mL of fluorescent tetrameric BV421-HLA-G (Creative Biolabs, USA) for 1 h at 4°C. HEK-293T cells were washed and subsequently incubated for 1 h at 4° C with a 10-points, 3-fold serial dilution curve starting a 150 pg / mL of anti-LILRB2 antibodies (IBS316, IBS336 and MK-4830) or isotypic control lgG4. Then, samples were split in two before analysis by flow cytometry (iQue3, Sartorius, Germany). One half was used to determine the binding of HLA-G to LILRB2 and the other half was incubated with Alexa Fluor™ 647 anti-human IgG Fc recombinant secondary antibody (Biolegend, 366914) at a concentration of 1 pg / mL for 1 h at 4° C to determine the binding of antibodies (IBS316, IBS336, MK-4830 and lgG4) to LILRB2. Geomean results were normalized using a control with no antibody as 100% of binding HLA-G / LILRB2 or using individual antibody controls (each Ab at 150 pg / mL) with no HLA- G as 100% of binding Ab / LILRB2. Data was analysed using GraphPad™ Prism (10.2.2). The results depicted in FIG. 3A show that IBS316, IBS336 and MK-4830, but not the isotype control, inhibit the binding of LILRB2 to its ligand HLA-G in a dose-dependent manner, with IBS336 being the most potent. The results depicted in FIG. 3B show that IBS316, IBS336 and MK-4830, but not the isotype control, binds to LILRB2 at the surface of the cells in a dose-dependent manner, with IBS336 being again the most potent.

[0340] The ability of the antibodies to modulate the polarization of macrophages was assessed. Frozen human PBMCs were thawed, resuspended in media (RPMI, L-glutamine, 10% FBS, pen / strep), plated in 24-well plate (400,000 cells / well) and incubated for 24h at 37° C, 5% CO2. Next, M-CSF (50 ng / ml) and isotypic lgG4 or anti-LILRB2 antibodies (MK-4830, IBS316 or IBS336) were added to each well at a concentration of 1 pg / ml. After 6 days, cells were harvested, stained with anti-CD163 Alexa Fluor™ 488, anti-CD206 eFluor™ 450 and LIVE / DEAD Near IR (780) dye and samples were analyzed by flow cytometry. Cells were gated on live macrophages and CD163 / CD206 expression was assessed. Dot plots including the percentage of G16863-00031 -AD

[0341] 60

[0342] CD163+ / CD206+ populations are shown. Data was analyzed with FlowJo™ (10.10.0) and graph was built using GraphPad™ Prism (10.2.2). As shown in FIG. 4, IBS316, IBS336 and MK-4830, but not the isotype control, led to a dose-dependent reduction in the expression of the immunosuppressive M2 phenotype markers CD163 and CD206, providing evidence that the antibodies are able to reprogram immunosuppressive macrophages toward an immunostimulatory phenotype. Antibody IBS316 was more potent than IBS336 and MK-4830 at reducing the expression of CD163 and CD206 in macrophages.

[0343] The ability of the antibodies at modulating the expression of pro-inflammatory and anti- inflammatory / immunosuppressive cytokines by immune cells was next tested. Frozen human PBMCs were thawed, resuspended in media (RPMI, L-glutamine, 10% FBS, pen / strep) and plated in 96-well plate U-bottom (100,000 cells / well). Cells were stimulated for 24h with 50 ng / ml LPS and a range of antibody concentration (5-fold serial dilution starting at 2,5 pg / ml) (FIGs. 5A- B) or a single dose of 15 pg / ml (FIGs. 5C-D) of isotypic lgG4 or anti-LILRB2 antibodies (MK- 4830, IBS316 or IBS336). Supernatants were then collected and stored at -80°C for future analyses. Cytokine production was analyzed using Luminex™ xMAP technology according to the manufacturer’s instructions. Graphs were built using GraphPad™ Prism (10.2.2). The results depicted in FIGs. 5A-B show that IBS316, IBS336 and MK-4830, but not the isotype control, led to an increase in the expression of the pro-inflammatory cytokine GM-CSF (FIG. 5A) and a decrease in the expression of the immunosuppressive cytokine IL-10 (FIG. 5B) by the LPS- stimulated PBMCs in a dose-dependent manner, with antibody IBS336 being the most potent. Incubation of the LPS-stimulated PBMCs in the presence of the antibodies also led to an increase in the expression of the pro-inflammatory cytokine TNF-alpha (TNF-a) (FIG. 5C) and to a decrease in the expression of MCP-1 (FIG. 5D). Additional experiments were performed to assess IL-10 and TNF-a expression in the presence of the antibodies. Thawed and cultured PBMCs were stimulated with 50 ng / mL LPS for 24hrs before treatment with isotypic lgG4 or anti-LILRB2 antibodies (MK-4830, IBS316, IBS336) in a dose-response assay starting at 2.5 ug / mL in an 8- points, 5-fold dilution curve. Cytokines secretion dosage was conducted using Sartorius QBeads PlexScreen Secreted Protein Assay Kit on IQue3 Plus cytometer according to the manufacturer’s instructions. The results depicted in FIGs. 6A and 6B confirm that MK-4830, IBS316 and IBS336 decrease in the expression of the immunosuppressive cytokine IL-10 and increase in the expression of the pro-inflammatory cytokine TNF-a in a dose-dependent manner.

[0344] The binding of the antibodies to LILRB2 at physiological and acidic pHs (mimicking the acidic conditions prevailing in the tumor microenvironment (TME)) was assessed. LILRB2 protein (0.1 pg) or BSA (2 mg) was coated overnight at 4°C in Nunc 96-well plate in 50 mM carbonate buffer pH 9.6. The following day, PBS-Milk 3% pH 7.3 was used to block the wells 1 h at RT. Anti- LILRB2 antibodies (IBS316, IBS336 and MK-4830) were then added to the wells diluted in PBS- Milk 1% at different pH (5.0 to 7.3), in a 3-fold serial dilution starting at 10 pg / mL, 1 h at RT. Then, G16863-00031 -AD

[0345] 61

[0346] Goat Anti-Human IgG Fc (HRP) was added to the wells in PBS-Milk 1% pH 7.3 in a dilution of 1 :10,000. The revelation was done with TMB for 7 minutes and stopped with 0.18M phosphoric acid. The results depicted in FIGs. 7A-B and Table 5 demonstrate that whereas the binding of IBS336 to LILRB2 is similar across all pH tested (5.0, 5.5, 6.0, 6.5, 7.0 and 7.3), there was a significant decrease in the binding of MK-4830 and IBS316 to LILRB2 at acidic pHs.

[0347] Table 5

[0348] Additional experiments were performed to assess the binding of the antibodies to LILRB2 at the surface of cells at different pHs. 250,000 HEK-293T cells overexpressing LILRB2 were incubated with a 12-points, 3-fold serial dilution curve starting a 150 pg / mL of anti-LILRB2 antibodies (IBS316, IBS336 and MK-4830) or isotypic control lgG4 at pH 7.4, 6.5 or 6.0. Then, samples were incubated with Alexa Fluor™ 647 anti-human IgG Fc recombinant secondary antibody (Biolegend, 366914) at a concentration of 2 pg / mL for 1 h at 4° C. The binding of antibodies (IBS316, IBS336, MK-4830 and lgG4) to LILRB2 was analyzed by flow cytometry (iQue3, Sartorius, Germany). Data was analysed using GraphPad™ Prism (10.2.2).

[0349] The results depicted in FIG. 8 show that whereas the binding of IBS336 to cell-surface LILRB2 was only slightly affected at more acidic pH (6.0 and 6.5), there was a significant decrease in the binding of MK-4830 and IBS336 to LILRB2 at acidic pHs, with a ~2-fold reduction in affinity at pH 6.0 relative to physiological pH (7.4).

[0350] The ability of anti-LILRB2 antibodies (IBS316, IBS336 and MK-4830) to alter tumor growth rate in vivo was assessed in NSG-SGM3 mice humanized with CD34 hematopoietic stem cells (2 donors). Human xenograft tumours were established in Female 14-16-week-old NSG- SGM3 mice intravenously engrafted with CD34+ haematopoietic stem cells (HSC) from cord blood (mice supplied by Jackson Laboratory, USA) by subcutaneous (SC) injection of 3.0 x 106SK-Mel-5 (melanoma cell line), suspended in 0.1 mL PBS into the right hind flank. Injected tumour cells grew to a volume of approximately 100 mm3before randomization of mice into specific study groups consisting of 7 mice. Randomisation was performed using matched distribution setting. All mice planned for this study had measurable tumours and were included. Mice were then administered, by intraperitoneal injection, with 20 mg / kg of IBS316, IBS336, MK-4830 or isotype (lgG4) control antibody in a total volume of 200 pL once weekly for 3 weeks. Tumours were monitored in every animal on study at an interval of one or two times per week by caliper, and the volumes of tumours were calculated using the following formula: (mm3) = (length [mm] x width [mm] x width [mm]) / 2. Euthanasia occurred when tumour volume reached 1000 mm3or for welfare reasons, e.g. , ulceration of tumour or loss of body weight greater than 20% from baseline. G16863-00031 -AD

[0351] 62

[0352] The results depicted in FIG. 9A show that all tested anti-LILRB2 antibodies (IBS316, IBS336 and MK-4830) inhibited tumor growth relative to the isotype (lgG4) control antibody. No effect specific to antibody treatment was observed on body weight (FIG. 9B).

[0353] Although the present invention has been described hereinabove by way of specific embodiments thereof, it can be modified, without departing from the spirit and nature of the subject invention as defined in the appended claims. In the claims, the word "comprising" is used as an open-ended term, substantially equivalent to the phrase "including, but not limited to". The singular forms "a", "an" and "the" include corresponding plural references unless the context clearly dictates otherwise.

Claims

G16863-00031 -AD63WHAT IS CLAIMED IS:

1. An anti-LILRB2 antibody or an antigen binding fragment thereof comprising one of the following combinations of complementarity determining regions (CDRs):(a) a CDR-L1 comprising an amino acid sequence having at least 70% identity with the sequence SGSSGSYG (SEQ ID NO:7); a CDR-L2 comprising an amino acid sequence having at least 70% identity with the sequence DNTNRPS (SEQ ID NO:8); a CDR-L3 comprising an amino acid sequence having at least 70% identity with the sequence GSEDSSSSGGI (SEQ ID NO:9); a CDR-H1 comprising an amino acid sequence having at least 70% identity with the sequence GFTFSSY (SEQ ID NO:4); a CDR-H2 comprising an amino acid sequence having at least 70% identity with the sequence TNTGSS (SEQ ID NQ:10); and a CDR-H3 comprising an amino acid sequence having at least 70% identity with the sequence SPGGYCTAGGCGAAGLIDA (SEQ ID NO:11);(b) a light chain CDR1 (CDR-L1) comprising an amino acid sequence having at least 70% identity with the sequence SGGSSIYGSAYG (SEQ ID NO:1); a light chain CDR2 (CDR-L2) comprising the sequence SNNQRPS (SEQ ID NO:2); a light chain CDR3 (CDR-L3) comprising an amino acid sequence having at least 70% identity with the sequence GSTDSSSGAA (SEQ ID NO:3); a heavy chain CDR1 (CDR-H1) comprising an amino acid sequence having at least 70% identity with the sequence GFTFSSY (SEQ ID NO:4); a heavy chain CDR2 (CDR-H2) comprising an amino acid sequence having at least 70% identity with the sequence TNSGSY (SEQ ID NO:5); and a heavy chain CDR3 (CDR-H3) comprising an amino acid sequence having at least 70% identity with the sequence SPGGYCTTGGGCGAAALIDA (SEQ ID NO:6);(c) a CDR-L1 comprising an amino acid sequence having at least 70% identity with the sequence SGSSGSYG (SEQ ID NO:7); a CDR-L2 comprising an amino acid sequence having at least 70% identity with the sequence YNDKRPS (SEQ ID NO: 12); a CDR-L3 comprising an amino acid sequence having at least 70% identity with the sequence GGWDSSAGYAGGI (SEQ ID NO:13); a CDR-H1 comprising an amino acid sequence having at least 70% identity with the sequence GFTFSSY (SEQ ID NO:4); a CDR-H2 comprising an amino acid sequence having at least 70% identity with the sequence DDTGTF (SEQ ID NO:14); and a CDR-H3 comprising an amino acid sequence having at least 70% identity with the sequence TPWICGTWTCDAYVGNIDA (SEQ ID NO:15); or(d) a CDR-L1 comprising an amino acid sequence having at least 70% identity with the sequence SGGSGYAYG (SEQ ID NO:16); a CDR-L2 comprising the sequence ESDKRPS (SEQ ID NO:17); a CDR-L3 comprising an amino acid sequence having at least 70% identity with the sequence GSYDSSDAI (SEQ ID NO:18); a CDR-H1 comprising an amino acid sequence having at least 70% identity with the sequence GFTFSSY (SEQ ID NO:4); a CDR-H2 comprising the sequenceG16863-00031 -AD64TSGGSS (SEQ ID NO:19); and a CDR-H3 comprising an amino acid sequence having at least 70% identity with the sequence SPGGYCTSGGCGAAGLIDA (SEQ ID NO:20).

2. The anti-LILRB2 antibody or antigen binding fragment thereof according to claim 1 , which comprises the following combinations of CDRs: a CDR-L1 comprising the sequence SGGSSIYGSAYG (SEQ ID NO:1); a CDR-L2 comprising the sequence SNNQRPS (SEQ ID NO:2); a CDR-L3 comprising the sequence GSTDSSSGAA (SEQ ID NO:3); a CDR-H1 comprising the sequence GFTFSSY (SEQ ID NO:4); a CDR-H2 comprising the sequence TNSGSY (SEQ ID NO:5); and CDR-H3 comprising the sequence SPGGYCTTGGGCGAAALIDA (SEQ ID NO:6).

3. The anti-LILRB2 antibody or an antigen binding fragment thereof according to claim 1 , which comprises the following combinations of CDRs: a CDR-L1 comprising the sequence SGSSGSYG (SEQ ID NO:7); a CDR-L2 comprising the sequence DNTNRPS (SEQ ID NO:8); a CDR-L3 comprising the sequence GSEDSSSSGGI (SEQ ID NO:9); a CDR-H1 comprising the sequence GFTFSSY (SEQ ID NO:4); a CDR-H2 comprising the sequence TNTGSS (SEQ ID NQ:10); and a CDR-H3 comprising the sequence SPGGYCTAGGCGAAGLIDA (SEQ ID NO:11).

4. The anti-LILRB2 antibody or an antigen binding fragment thereof according to claim 1 , which comprises the following combinations of CDRs: a CDR-L1 comprising the sequence SGSSGSYG (SEQ ID NO:7); a CDR-L2 comprising the sequence YNDKRPS (SEQ ID NO:12); a CDR-L3 comprising the sequence GGWDSSAGYAGGI (SEQ ID NO: 13); a CDR-H1 comprising the sequence GFTFSSY (SEQ ID NO:4); a CDR-H2 comprising the sequence DDTGTF (SEQ ID NO:14); and a CDR-H3 comprising the sequence TPWICGTWTCDAYVGNIDA (SEQ ID NO:15).

5. The anti-LILRB2 antibody or an antigen binding fragment thereof according to claim 1 , which comprises the following combinations of CDRs: a CDR-L1 comprising the sequence SGGSGYAYG (SEQ ID NO:16); a CDR-L2 comprising the sequence ESDKRPS (SEQ ID NO:17); a CDR-L3 comprising the sequence GSYDSSDAI (SEQ ID NO:18); a CDR-H1 comprising the sequence GFTFSSY (SEQ ID NO:4); a CDR-H2 comprising the sequence TSGGSS (SEQ ID NO:19); and a CDR-H3 comprising the sequence SPGGYCTSGGCGAAGLIDA (SEQ ID NQ:20).

6. The anti-LILRB2 antibody or an antigen binding fragment thereof according to any one of claims 1 to 5, which comprises the following combinations of framework regions (FRs): a light chain FR1 comprising an amino acid sequence having at least 70% identity with the sequence SYELTQPPSVSVSPGQTARITC (SEQ ID NO:21) or QSVLTQPPSVSAAPGQKVTISC (SEQ ID NO:22); a light chain FR2 comprising an amino acid sequence having at least 70% identity with the sequence WHQQKPGQAPVTVIY (SEQ ID NO:23) or WYQQLPGTAPKTVIY (SEQ ID NO:24); a light chain FR3 comprising an amino acid sequence having at least 70% identity with the sequence GIPERFSGSGSGSTATLTISGVQAEDEADYYC (SEQ ID NO:25) orG16863-00031 -AD65GIPDRFSGSKSGSSGTLGITGLQTGDEADYYC (SEQ ID NO:26); and / or a light chain FR4 comprising an amino acid sequence having at least 70% identity with the sequence FGGGTQLTVL (SEQ ID NO:27) or FGGGTKLTVL (SEQ ID NO:28).

7. The anti-LILRB2 antibody or an antigen binding fragment thereof according to claim 6, which comprises the following combinations of FRs: a light chain FR1 comprising the amino acid sequence SYELTQPPSVSVSPGQTARITC (SEQ ID NO:21) or QSVLTQPPSVSAAPGQKVTISC (SEQ ID NO:22); a light chain FR2 comprising the amino acid sequence WHQQKPGQAPVTVIY (SEQ ID NO:23) or WYQQLPGTAPKTVIY (SEQ ID NO:24); a light chain FR3 comprising the amino acid sequence GIPERFSGSGSGSTATLTISGVQAEDEADYYC (SEQ ID NO:25) or GIPDRFSGSKSGSSGTLGITGLQTGDEADYYC (SEQ ID NO:26); and / or a light chain FR4 comprising the amino acid sequence FGGGTQLTVL (SEQ ID NO:27) or FGGGTKLTVL (SEQ ID NO:28).

8. The anti-LILRB2 antibody or an antigen binding fragment thereof according to any one of claims 1 to 7, which comprises the following combinations of FRs: a heavy chain FR1 comprising an amino acid sequence having at least 70% identity with the sequence EVQLVESGGGLVQPGGSLRLSCAAS (SEQ ID NO:29) orEVQLLESGGGLVQPGGSLRLSCAAS (SEQ ID NQ:30); a heavy chain FR2 comprising an amino acid sequence having at least 70% identity with the sequence DMAWVRQAPGKGLEFVAEI (SEQ ID NO:31) or NMGWVRQAPGKGLEFVAII (SEQ ID NO:32); a heavy chain FR3 comprising an amino acid sequence having at least 70% identity with the sequence TYYGAAVKGRATISRDNAKNSVYLQMNSLRAEDTAVYYCAR (SEQ ID NO:33) or THYGAAVKGRATISRDNSKNTVYLQMNSLRAEDTAVYYCTR (SEQ ID NO:34); and / or a heavy chain FR4 comprising an amino acid sequence having at least 70% identity with the sequence WGQGTLVTVSS (SEQ ID NO:35).

9. The anti-LILRB2 antibody or an antigen binding fragment thereof according to claim 8, which comprises the following combinations of FRs: a heavy chain FR1 comprising the sequence EVQLVESGGGLVQPGGSLRLSCAAS (SEQ ID NO:29) orEVQLLESGGGLVQPGGSLRLSCAAS (SEQ ID NQ:30); a heavy chain FR2 comprising the sequence DMAWVRQAPGKGLEFVAEI (SEQ ID NO:31) or NMGWVRQAPGKGLEFVAII (SEQ ID NO:32); a heavy chain FR3 comprising the sequence TYYGAAVKGRATISRDNAKNSVYLQMNSLRAEDTAVYYCAR (SEQ ID NO:33) or THYGAAVKGRATISRDNSKNTVYLQMNSLRAEDTAVYYCTR (SEQ ID NO:34); and / or a heavy chain FR4 comprising the sequence WGQGTLVTVSS (SEQ ID NO:35).

10. The antibody or antigen binding fragment thereof according to any one of claims 1 to 9, which comprises the following combination of heavy chain and light chain variable regions: (a) aG16863-00031 -AD66 heavy chain variable region comprising an amino acid sequence having at least 70% identity with the sequence:EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYDMAWVRQAPGKGLEFVAEITNSGSYTYYGA AVKGRATISRDNAKNSVYLQMNSLRAEDTAVYYCARSPGGYCTTGGGCGAAALIDAWGQGTL VTVSS (SEQ ID NO:36); and a light chain variable region comprising an amino acid sequence having at least 70% identity with the sequence: SYELTQPPSVSVSPGQTARITCSGGSSIYGSAYGWHQQKPGQAPVTVIYSNNQRPSGIPERFS GSGSGSTATLTISGVQAEDEADYYCGSTDSSSGAAFGGGTQLTVL (SEQ ID NO:37).11 . The antibody or antigen binding fragment thereof according to claim 10, which comprises the following combination of heavy chain and light chain variable regions: (a) a heavy chain variable region comprising the sequence:EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYDMAWVRQAPGKGLEFVAEITNSGSYTYYGA AVKGRATISRDNAKNSVYLQMNSLRAEDTAVYYCARSPGGYCTTGGGCGAAALIDAWGQGTL VTVSS (SEQ ID NO:36); and a light chain variable region comprising the sequence: SYELTQPPSVSVSPGQTARITCSGGSSIYGSAYGWHQQKPGQAPVTVIYSNNQRPSGIPERFS GSGSGSTATLTISGVQAEDEADYYCGSTDSSSGAAFGGGTQLTVL (SEQ ID NO:37).

12. The antibody or antigen binding fragment thereof according to any one of claims 1 to 11 , which comprises the following combination of heavy chain and light chain variable regions: (a) a heavy chain variable region comprising an amino acid sequence having at least 70% identity with the sequence:EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYNMGWVRQAPGKGLEFVAIIDDTGTFTHYGAA VKGRATISRDNSKNTVYLQMNSLRAEDTAVYYCTRTPWICGTWTCDAYVGNIDAWGQGTLVT VSS (SEQ ID NO:38); and a light chain variable region comprising an amino acid sequence having at least 70% identity with the sequence: QSVLTQPPSVSAAPGQKVTISCSGSSGSYGWYQQLPGTAPKTVIYYNDKRPSGIPDRFSGSKS GSSGTLGITGLQTGDEADYYCGGWDSSAGYAGGIFGGGTKLTVL (SEQ ID NO:39).

13. The antibody or antigen binding fragment thereof according to claim 12, which comprises the following combination of heavy chain and light chain variable regions: (a) a heavy chain variable region comprising the sequence:EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYNMGWVRQAPGKGLEFVAIIDDTGTFTHYGAA VKGRATISRDNSKNTVYLQMNSLRAEDTAVYYCTRTPWICGTWTCDAYVGNIDAWGQGTLVT VSS (SEQ ID NO:38); and a light chain variable region comprising the sequence: QSVLTQPPSVSAAPGQKVTISCSGSSGSYGWYQQLPGTAPKTVIYYNDKRPSGIPDRFSGSKS GSSGTLGITGLQTGDEADYYCGGWDSSAGYAGGIFGGGTKLTVL (SEQ ID NO:39).G16863-00031 -AD6714. The antibody or antigen binding fragment thereof according to any one of claims 1 to 13, which is an IgG antibody.

15. The antibody or antigen binding fragment thereof according to claim 14, which is an lgG4 antibody.

16. The antibody or antigen binding fragment thereof according to any one of claims 1 to 15, wherein the light chain constant region comprises the sequence GQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSN NKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS (SEQ ID NO:40).

17. The antibody or antigen binding fragment thereof according to any one of claims 1 to 14, wherein the heavy chain constant region comprises the sequence ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY SLSSWTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPK PKDTLMISRTPEVTCWVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRWSVLTVL HQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGF YPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHN HYTQKSLSLSLGK (SEQ ID NO:41).

18. A bispecific antibody comprising a first binding domain comprising the antibody or antigen binding fragment thereof according to any one of claims 1 to 17, and a second binding domain that binds to a tumor antigen, an angiogenic factor, or a checkpoint inhibitor protein.

19. The bispecific antibody of claim 18, wherein the second binding domain is an antibody or antigen binding fragment thereof that binds to vascular endothelial growth factor (VEGF).

20. A conjugate comprising the antibody or antigen binding fragment thereof of any one of claims 1 to 19.21 . A nucleic acid comprising a sequence encoding the light and heavy chain of the antibody or antigen binding fragment thereof of any one of claims 1 to 19; or a first nucleic acid comprising a sequence encoding the light chain of the antibody or antigen binding fragment thereof of any one of claims 1 to 19 and a second nucleic acid comprising a sequence encoding the heavy chain of the antibody or antigen binding fragment thereof of any one of claims 1 to 19.

22. A host cell comprising the nucleic acid(s) of claim 21 .

23. A pharmaceutical composition comprising the antibody or antigen binding fragment thereof of any one of claims 1 to 19, the conjugate of claim 20, the nucleic acid(s) of claim 21 , or the cell of claim 22, and a pharmaceutically acceptable excipient.

24. The pharmaceutical composition of claim 23, wherein the pharmaceutical composition is in the form of an injectable solution.G16863-00031 -AD6825. A method of inducing phagocytosis in a macrophage, the method comprising a step of contacting the macrophage with the antibody or antigen binding fragment thereof of any one of claims 1 to 19, the conjugate of claim 20, the nucleic acid(s) of claim 21 , the cell of claim 22, or the pharmaceutical composition of claim 23 or 24.

26. A method of inducing or enhancing M 1 -like macrophage phenotype in a target cell, the method comprising a step of contacting the target cell with the antibody or antigen binding fragment thereof of any one of claims 1 to 19, the conjugate of claim 20, the nucleic acid(s) of claim 21 , the cell of claim 22, or the pharmaceutical composition of claim 23 or 24.

27. The method of claim 26, wherein the target cell is a monocyte or macrophage.

28. The method of claim 26 or 27, wherein the method comprises repolarization of an M2-like macrophage phenotype into an M 1-like macrophage phenotype.

29. A method of reducing a biological activity of LILRB2 in a subject in need thereof, said method comprising administering a therapeutically effective amount of the antibody or antigen binding fragment thereof of any one of claims 1 to 19, the conjugate of claim 20, the nucleic acid(s) of claim 21 , the cell of claim 22, or the pharmaceutical composition of claim 23 or 24.

30. A method of promoting an immune response in a subject in need thereof, the method comprising administering a therapeutically effective amount of the antibody or antigen binding fragment thereof of any one of claims 1 to 19, the conjugate of claim 20, the nucleic acid(s) of claim 21 , the cell of claim 22, or the pharmaceutical composition of claim 23 or 24.

31. A method of treating a disease associated with LILRB2 expression in a subject in need thereof, the method comprising administering a therapeutically effective amount of the antibody or antigen binding fragment thereof of any one of claims 1 to 19, the conjugate of claim 20, the nucleic acid(s) of claim 21 , the cell of claim 22, or the pharmaceutical composition of claim 23 or 24.

32. The method of claim 31 , wherein the disease is cancer, an autoimmune disease, or an infectious disease.

33. The method of claim 32, wherein the disease is cancer.

34. The method of claim 33, wherein the cancer comprises cells expressing or overexpressing a ligand of LILRB2.

35. The method of claim 33 or 34, wherein the cancer is a sarcoma, carcinoma, or a hematological cancer.G16863-00031 -AD6936. The method of any one of claims 33 to 35, wherein the cancer is 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.

37. The method of any one of claims 33 to 36, further comprising administering to the subject an effective amount of an anticancer therapy.

38. The method of claim 37, wherein the anticancer therapy comprises an immune checkpoint inhibitor.

39. The method of claim 38, wherein the immune checkpoint inhibitor is a PD-1 antagonist.

40. The method of claim 32, wherein the disease is an autoimmune disease.41 . The method of claim 40, wherein the autoimmune disease is rheumatoid arthritis, systemic lupus erythematosus, or multiple sclerosis.

42. The method of claim 32, wherein the disease is an infectious disease.

43. The method of claim 42, wherein the infectious disease is a viral infection, a bacterial infection, a parasitic infection, or a fungal infection.

44. Use of the antibody or antigen binding fragment thereof of any one of claims 1 to 19, the conjugate of claim 20, the nucleic acid(s) of claim 21 , the cell of claim 22, or the pharmaceutical composition of claim 23 or 24, for the manufacture of a medicament for inducing phagocytosis in a macrophage.

45. Use of the antibody or antigen binding fragment thereof of any one of claims 1 to 19, the conjugate of claim 20, the nucleic acid(s) of claim 21 , the cell of claim 22, or the pharmaceutical composition of claim 23 or 24, for the manufacture of a medicament for inducing or enhancing M 1 -like macrophage phenotype in a target cell.

46. The use of claim 45, wherein the target cell is a monocyte or macrophage.

47. The use of claim 45 or 46, wherein inducing or enhancing M 1 -like macrophage phenotype comprises repolarization of an M2-like macrophage phenotype into an M1-like macrophage phenotype.

48. Use of the antibody or antigen binding fragment thereof of any one of claims 1 to 19, the conjugate of claim 20, the nucleic acid(s) of claim 21 , the cell of claim 22, or the pharmaceutical composition of claim 23 or 24, for the manufacture of a medicament for reducing a biological activity of LILRB2 in a subject.G16863-00031 -AD7049. Use of the antibody or antigen binding fragment thereof of any one of claims 1 to 19, the conjugate of claim 20, the nucleic acid(s) of claim 21 , the cell of claim 22, or the pharmaceutical composition of claim 23 or 24, for treating a disease associated with LILRB2 expression in a subject.

50. Use of the antibody or antigen binding fragment thereof of any one of claims 1 to 19, the conjugate of claim 20, the nucleic acid(s) of claim 21 , the cell of claim 22, or the pharmaceutical composition of claim 23 or 24, for the manufacture of a medicament for treating a disease associated with LILRB2 expression in a subject.51 . The use of claim 49 or 50, wherein the disease is cancer, an autoimmune disease, or an infectious disease.

52. The use of claim 51 , wherein the disease is cancer.

53. The use of claim 52, wherein the cancer comprises cells expressing or over-expressing a ligand of LILRB2.

54. The use of claim 52 or 53, wherein the cancer is a sarcoma, carcinoma, or hematological cancer.

55. The use of any one of claims 52 to 54, wherein the cancer is 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.

56. The use of any one of claims 52 to 55, wherein the antibody or antigen binding fragment thereof, conjugate, nucleic acid(s), or pharmaceutical composition is for use with an anticancer therapy.

57. The use of claim 56, wherein the anticancer therapy comprises an immune checkpoint inhibitor.

58. The use of claim 57, wherein the immune checkpoint inhibitor is a PD-1 antagonist.

59. The use of claim 51 , wherein the disease is an autoimmune disease.

60. The use of claim 59, wherein the autoimmune disease is rheumatoid arthritis, systemic lupus erythematosus, or multiple sclerosis.61 . The use of claim 51 , wherein the disease is an infectious disease.

62. The use of claim 61 , wherein the infectious disease is a viral infection, a bacterial infection, or a fungal infection.G16863-00031 -AD7163. The antibody or antigen binding fragment thereof of any one of claims 1 to 19, the conjugate of claim 20, the nucleic acid(s) of claim 21 , the cell of claim 22, or the pharmaceutical composition of claim 23 or 24, for use in inducing phagocytosis in a macrophage.

64. The antibody or antigen binding fragment thereof of any one of claims 1 to 19, the conjugate of claim 20, the nucleic acid(s) of claim 21 , the cell of claim 22, or the pharmaceutical composition of claim 23 or 24, for use in inducing or enhancing M 1 -like macrophage phenotype in a target cell.

65. The antibody or antigen binding fragment thereof, conjugate, nucleic acid(s), or pharmaceutical composition for use of claim 64, wherein the target cell is a monocyte or macrophage.

66. The antibody or antigen binding fragment thereof, conjugate, nucleic acid(s), or pharmaceutical composition for use of claim 64 or 65, wherein inducing or enhancing M1-like macrophage phenotype comprises repolarization of an M2-like macrophage phenotype into an M1-like macrophage phenotype.

67. The antibody or antigen binding fragment thereof of any one of claims 1 to 19, the conjugate of claim 20, the nucleic acid(s) of claim 21 , the cell of claim 22, or the pharmaceutical composition of claim 23 or 24, for use in reducing a biological activity of LILRB2 in a subject.

68. The antibody or antigen binding fragment thereof of any one of claims 1 to 19, the conjugate of claim 20, the nucleic acid(s) of claim 21 , the cell of claim 22, or the pharmaceutical composition of claim 23 or 24, for use in treating a disease associated with LILRB2 expression in a subject.

69. The antibody or antigen binding fragment thereof, conjugate, nucleic acid(s), cell, or pharmaceutical composition for use of claim 68, wherein the disease is cancer, an autoimmune disease, or an infectious disease.

70. The antibody or antigen binding fragment thereof, conjugate, nucleic acid(s), cell, or pharmaceutical composition for use of claim 69, wherein the disease is cancer.

71. The antibody or antigen binding fragment thereof, conjugate, nucleic acid(s), cell, or pharmaceutical composition for use of claim 70, wherein the cancer comprises cells expressing or over-expressing a ligand of LILRB2.

72. The antibody or antigen binding fragment thereof, conjugate, nucleic acid(s), cell, or pharmaceutical composition for use of claim 70 or 71 , wherein the cancer is a sarcoma, carcinoma, or hematological cancer.G16863-00031 -AD7273. The antibody or antigen binding fragment thereof, conjugate, nucleic acid(s), cell, or pharmaceutical composition for use of any one of claims 70 to 72, wherein the cancer is 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.

74. The antibody or antigen binding fragment thereof, conjugate, nucleic acid(s), or pharmaceutical composition for use of any one of claims 70 to 73, wherein the antibody or antigen binding fragment thereof, conjugate, nucleic acid(s), cell, or pharmaceutical composition is for use with an anticancer therapy.

75. The antibody or antigen binding fragment thereof, conjugate, nucleic acid(s), or pharmaceutical composition for use of claim 74, wherein the anticancer therapy comprises an immune checkpoint inhibitor.

76. The antibody or antigen binding fragment thereof, conjugate, nucleic acid(s), or pharmaceutical composition for use of claim 75, wherein the immune checkpoint inhibitor is a PD- 1 antagonist.

77. The antibody or antigen binding fragment thereof, conjugate, nucleic acid(s), or pharmaceutical composition for use of claim 69, wherein the disease is an autoimmune disease.

78. The antibody or antigen binding fragment thereof, conjugate, nucleic acid(s), or pharmaceutical composition for use of claim 77, wherein the autoimmune disease is rheumatoid arthritis, systemic lupus erythematosus, or multiple sclerosis.

79. The antibody or antigen binding fragment thereof, conjugate, nucleic acid(s), or pharmaceutical composition for use of claim 69, wherein the disease is an infectious disease.

80. The antibody or antigen binding fragment thereof, conjugate, nucleic acid(s), or pharmaceutical composition for use of claim 79, wherein the infectious disease is a viral infection, a bacterial infection, or a fungal infection.

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