Antibodies against lilrb4 and lilrb2 and uses thereof

Abstract

In certain aspects, the subject matter disclosed herein relates to high affinity monoclonal antibodies against LILRB4 and / or LILRB2 and their use in inhibiting myeloid-dependent, immune-suppressive signals and in cancer treatment. In certain aspects, the subject matter disclosed herein relates to bispecific molecules binding LILRB4 and LILRB2.

Description

ANTIBODIES AGAINST LILRB4 AND LILRB2 AND USES THEREOF

[0001] This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63 / 569,486, filed on March 25, 2024, the content of which is hereby incorporated by reference in its entirety.

[0002] This patent disclosure contains material that is subject to copyright protection. The copyright owner has no objection to the facsimile reproduction by anyone of the patent document or the patent disclosure as it appears in the U.S. Patent and Trademark Office patent file or records, but otherwise reserves any and all copyright rights.

[0003] All patents, patent applications and publications cited herein are hereby incorporated by reference in their entirety. The disclosure of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art as known to those skilled therein as of the date of the invention described herein.SEQUENCE LISTING

[0004] The instant application contains a Sequence Listing which has been submitted electronically in XML file format and is hereby incorporated by reference in its entirety. Said XML copy, created on March 21, 2025, is named 2220189_122WOl_SL.xml and is 351,206 bytes in size.BACKGROUND

[0005] The leukocyte immunoglobulin-like receptor (LILR) family comprises paired immunomodulatory receptors that can be divided into two classes: the inhibitory LILR subfamily B (LILRB 1-5) and the activating LILR subfamily A (LILRA1-6). The receptors are expressed in human myeloid and lymphocyte cells. LILR subfamily A (LILRA) members associate with membrane adaptors to signal via immunoreceptor tyrosine-based activating motifs (IT AM). LILR subfamily B (LILRB) members signal via multiple cytoplasmic immunoreceptor tyrosine-based inhibitory motifs (ITIM). LILRB receptors and the murine ortholog, paired immunoglobulin-like receptor B (PIRB), negatively regulate maturation of myeloid cells such as mast cells, neutrophils, dendritic cells, and B cells.SUMMARY OF THE INVENTION

[0006] In certain aspects, the subject matter disclosed herein provides a monoclonal antibody, or an antigen-binding fragment thereof, comprising (i) a heavy chain (HC) variabledomain (VH) and (ii) a light chain (LC) variable domain (VL); wherein the antibody, or antigen binding fragment thereof, binds leukocyte immunoglobulin-like receptor 4 (LILRB4).

[0007] In some embodiments, the antibody binds LILRB4 with an equilibrium dissociation constant (KD) from about 10- 7M to about 10-11M. In some embodiments, the antibody binds LILRB4 with an association constant from about 103Ms-1to about 106Ms-1. In some embodiments, the antibody binds LILRB4 with a dissociation constant from about 10-2s-1to about 10-5s-1.

[0008] In some embodiments, the LILRB4 is a human LILRB4. In some embodiments, the LILRB4 is a cynomolgus macaque LILRB4. In some embodiments, the LILRB4 is a mouse ortholog of LILRB4. In some embodiments, the anti-LILRB4 antibody inhibits a LILRB4-dependent immune checkpoint. In some embodiments, the antibody depletes LILRB4- monocytes. In some embodiments, the antibody does not deplete immune- supporting myeloid populations. In some embodiments, the antibody is engineered by B-cell cloning. In some embodiments, the antibody is a blocking antibody.

[0009] In some embodiments, the VH domain comprises a heavy chain CDR1 having a sequence identity of at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 4, a heavy chain CDR2 having a sequence identity of at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 5, a heavy chain CDR3 having a sequence identity of at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 6 and the VL domain comprises a light chain CDR1 having a sequence identity of at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 46, a light chain CDR2 having a sequence identity of at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 47, and a light chain CDR3 having a sequence identity of at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 48. In some embodiments, the VH domain comprises a heavy chain CDR1 having a sequence identity of SEQ ID NO: 4, a heavy chain CDR2 having a sequence identity of SEQ ID NO: 5, and a heavy chain CDR3 having a sequence identity to SEQ ID NO: 6 and the VL domain comprises a light chain CDR1 having a sequence identity of SEQ ID NO: 46, a light chain CDR2 having a sequence identity of SEQ ID NO: 47, and a light chain CDR3 having a sequence identity of SEQ ID NO: 48. In some embodiments, the HC VH domain further comprises framework regions (FRs) comprising an amino acid sequence 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99 % identical to the FRs of SEQ ID NO: 22 and wherein the LC VL domain further comprises framework regions (FRs) comprising an amino acid sequence 80,81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99 % identical to the FRs of SEQ ID NO: 64.

[0010] In some embodiments, the HC VH domain further comprises framework regions (FRs) of a human IGHV1 gene and wherein the LC VL domain further comprises FRs of a human IGKV1 gene. In some embodiments, the HC VH domain further comprises framework regions (FRs) of a human IGHV1-8 gene and wherein the LC VL domain further comprises FRs of a human IGKV1-17 gene. In some embodiments, the antibody comprises (a) a first arm comprising the HC VH domain and the LC VL domain wherein a portion of the first arm binds LILRB4 and (b) a second arm comprising the HC VH domain and the LC VL domain wherein a portion of the second arm binds LILRB4. In some embodiments, the first and second arms each further comprise a CHI domain, a hinge domain, a Fc domain (CH2-CH3) and a CL domain.

[0011] In some embodiments, the VH domain of the first arm is encoded by a first polypeptide chain; the VL domain of the first arm is encoded by a second polypeptide chain; the VH domain of the second arm is encoded by a third polypeptide chain; the VL domain of the second arm is encoded by a fourth polypeptide chain; and wherein the VH domain and VL domain of the first arm form a first LILRB4 binding site and wherein the VH domain and VL domain of the second arm form a second LILRB4 binding site, wherein the first and second LILRB4 binding sites are the same. In some embodiments, the first and third polypeptide chain each further encode a hinge domain, a CH I domain, and an Fc domain, and wherein the second and fourth polypeptide chain each further encode a CL domain. In some embodiments, the first and third polypeptide chains comprise the same sequence and the second and fourth polypeptide chains comprise the same sequence.

[0012] In some embodiments, the VH domain of the first arm and the second arm both comprise an amino acid sequence comprising SEQ ID NO: 22, and wherein the VL domain of the first arm and the second arm both comprise an amino acid sequence comprising SEQ ID NO: 64. In some embodiments, the first and third polypeptide chain each comprises an amino acid sequence comprising SEQ ID NO: 34 and the second and fourth polypeptide chain each comprises an amino acid sequence comprising SEQ ID NO: 76.

[0013] In some embodiments, the first and second polypeptide chains are linked by one or more covalent disulfide bonds and the third and fourth polypeptide chains are linked by one or more covalent disulfide bonds. In some embodiments, the first and third polypeptide chains are linked by one or more covalent disulfide bonds.

[0014] In certain aspects, the subject matter disclosed herein provides a monoclonal antibody, or an antigen-binding fragment thereof, comprising (i) a heavy chain (HC) variable domain (VH) and (ii) a light chain (LC) variable domain (VL); wherein the antibody is capable of binding to leukocyte immunoglobulin-like receptor 4 (LILRB4) and LILRB2.

[0015] In some embodiments, the antibody binds LILRB4 with an equilibrium dissociation constant (KD) from about 10-7M to about 10-11M and separately binds LILRB2 with an equilibrium dissociation constant (KD) from about 10‘ M to about 10'11M. In some embodiments, the antibody binds LILRB4 with an association constant of about 105Ms-1and separately binds LILRB2 with an association constant from about 10-5Ms-1. In some embodiments, the antibody binds LILRB4 with a dissociation constant from about 10-2s-1to about 10-5s-1and separately binds LILRB2 with a dissociation constant from about 10-2s-1to about 10-5s-1.

[0016] In some embodiments, the LILRB4 is a human LILRB4. In some embodiments, the LILRB4 is a cynomolgus macaque LILRB4. In some embodiments, the LILRB2 is a human LILRB2. In some embodiments, the LILRB2 is a cynomolgus macaque LILRB2. In some embodiments, the LILRB4 is a mouse ortholog of LILRB4. In some embodiments, the LILRB2 is a mouse ortholog of LILRB2. In some embodiments, the anti-LILRB4 antibody inhibits a LILRB4-dependent immune checkpoint. In some embodiments, the anti-LILRB2 antibody inhibits a LILRB2-dependent immune checkpoint. In some embodiments, the antibody depletes LILRB4+ monocytes. In some embodiments, the antibody depletes LILRB2+ monocytes. In some embodiments, the antibody does not deplete immune- supporting myeloid populations. In some embodiments, the antibody is engineered by B-cell cloning. In some embodiments, the antibody is a blocking antibody.

[0017] In some embodiments, the VH domain comprises a heavy chain CDR1 having a sequence identity of at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 13, a heavy chain CDR2 having a sequence identity of at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 14, a heavy chain CDR3 having a sequence identity of at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 15 and the VL domain comprises a light chain CDR1 having a sequence identity of at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 55, a light chain CDR2 having a sequence identity of at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 56, and a light chain CDR3 having a sequence identity of at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 57. In some embodiments, the VHdomain comprises a heavy chain CDR1 having a sequence identity of SEQ ID NO: 13, a heavy chain CDR2 having a sequence identity of SEQ ID NO: 14, and a heavy chain CDR3 having a sequence identity to SEQ ID NO: 15 and the VL domain comprises a light chain CDRl having a sequence identity of SEQ ID NO: 55, a light chain CDR2 having a sequence identity of SEQ ID NO: 56, and a light chain CDR3 having a sequence identity of SEQ ID NO: 57. In some embodiments, the HC VH domain further comprises framework regions (FRs) comprising an amino acid sequence 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99 % identical to the FRs of SEQ ID NO: 22 and wherein the EC VL domain further comprises framework regions (FRs) comprising an amino acid sequence 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99 % identical to the FRs of SEQ ID NO: 64.

[0018] In some embodiments, the HC VH domain further comprises framework regions (FRs) of a human IGHV 1 gene and wherein the EC VL domain further comprises FRs of a human IGKV1 gene. In some embodiments, the HC VH domain further comprises framework regions (FRs) of a human IGHV 1-8 gene and wherein the EC VL domain further comprises FRs of a human IGKV1-17 gene. In some embodiments, the antibody comprises (a) a first arm comprising the HC VH domain and the EC VL domain wherein a portion of the first arm binds LILRB4 and (b) a second arm comprising the HC VH domain and the LC VL domain wherein a portion of the second arm binds LILRB4. In some embodiments, the first and second arms each further comprise a CHI domain, a hinge domain, a Fc domain (CH2-CH3) and a CL domain.

[0019] In some embodiments, the VH domain of the first arm is encoded by a first polypeptide chain; the VL domain of the first arm is encoded by a second polypeptide chain; the VH domain of the second arm is encoded by a third polypeptide chain; the VL domain of the second arm is encoded by a fourth polypeptide chain; and wherein the VH domain and VL domain of the first arm form a first LILRB4 binding site and wherein the VH domain and VL domain of the second ami form a second LILRB4 binding site, wherein the first and second LILRB4 binding sites are the same.

[0020] In some embodiments, the first and third polypeptide chain each further encode a hinge domain, a CHI domain, and an Fc domain, and wherein the second and fourth polypeptide chain each further encode a CL domain. In some embodiments, the first and third polypeptide chains comprise the same sequence and the second and fourth polypeptide chains comprise the same sequence, In some embodiments, the VH domain of the first arm and the second arm both comprise an amino acid sequence comprising SEQ ID NO: 22, and whereinthe VL domain of the first arm and the second arm both comprise an amino acid sequence comprising SEQ ID NO: 64. In some embodiments, the first and third polypeptide chain each comprises an amino acid sequence comprising SEQ ID NO: 34 and the second and fourth polypeptide chain each comprises an amino acid sequence comprising SEQ ID NO: 76.

[0021] In some embodiments, the first and second polypeptide chains are linked by one or more covalent disulfide bonds and the third and fourth polypeptide chains are linked by one or more covalent disulfide bonds. In some embodiments, the first and third polypeptide chains are linked by one or more covalent disulfide bonds.

[0022] In certain aspects, the subject matter disclosed herein provides a pharmaceutical composition comprising any one of the monoclonal antibodies disclosed herein.

[0023] In certain aspects, the subject matter disclosed herein provides a pharmaceutical composition comprising any one of the monoclonal antibodies disclosed herein.

[0024] In some embodiments, the pharmaceutical composition further comprises one or more pharmaceutically-acceptable diluents, one or more pharmaceutically-acceptable carriers or one or more pharmaceutically-acceptable excipients.

[0025] In certain aspects, the subject matter disclosed herein provides a method of treating or preventing cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of any one of the monoclonal antibodies disclosed herein or any one of the pharmaceutical compositions disclosed herein.

[0026] In some embodiments, the cancer is kidney cancer, breast cancer, brain tumor, head and neck cancer, liver cancer, melanoma, non-small cell lung cancer (NSCLC), bladder cancer, cervical cancer, colon cancer, renal cell cancer, skin cancer, stomach cancer, rectal cancer, gastrointestinal, pancreatic cancer, lung cancer, thymic carcinoma, ovarian cancer, prostate cancer, or endometrial cancer, In some embodiments, the cancer is a liquid cancer, In some embodiments, the liquid cancer is leukemia, lymphoma, Hodgkin lymphoma, or myeloma. In some embodiments, the liquid cancer is acute myeloid leukemia (AML). In some embodiments, the liquid cancer is B-cell malignancy.

[0027] In some embodiments, the cancer is a cancer treated with immune therapies including, but not limited to, T-cell checkpoint inhibitors such as anti-PD-1 antibodies and anti-CTLA4 antibodies. In some embodiments, the anti-PPD-1 antibody is Pembrolizumab. In some embodiments, the anti-PPD-1 antibody is Nivolumab. In some embodiments, the anti-PPD-1 antibody is Cemiplimab. In some embodiments, the anti-PPD-1 antibody is Dostarlimab. In some embodiments, the anti-PPD-1 antibody is Retifanlimab. In some embodiments, the anti-PPD-1 antibody is Toripalimab. In some embodiments, the anti-CTLA4 antibody is Ipilimumab. In some embodiments, the anti-CTLA4 antibody Tremelimumab.

[0028] In some embodiments, the administration of the monoclonal antibody or the pharmaceutical composition is capable of inhibiting tumor growth.

[0029] In certain aspects, the subject matter disclosed herein provides a method of inhibiting myeloid-dependent immune suppression or promoting immune activation in a subject in need thereof the method comprising administering to the subject an effective amount of any of the monoclonal antibodies disclosed herein or any of the pharmaceutical composition disclosed herein.

[0030] In some embodiments, the subject is a human subject.

[0031] In certain aspects, the subject matter disclosed herein provides a polynucleotide encoding any one of the antibodies disclosed herein targeting LILRB4.

[0032] In certain aspects, the subject matter disclosed herein provides a polynucleotide encoding any one of the antibodies disclosed herein targeting LILRB2.

[0033] In certain aspects, the subject matter disclosed herein provides a genetically engineered cell comprising any of the antibodies disclosed herein targeting LILRB4.

[0034] In certain aspects, the subject matter disclosed herein provides a genetically engineered cell comprising any of the antibodies disclosed herein targeting LILRB2.

[0035] In certain aspects, the subject matter disclosed herein provides a kit for generating a monoclonal antibody or antigen-binding fragment thereof, the kit comprising one or more vectors comprising a polynucleotide sequence encoding any of the monoclonal antibodies disclosed herein.

[0036] In certain aspects, the subject matter disclosed herein provides a kit for generating a monoclonal antibody or antigen-binding fragment thereof, the kit comprising: a first vector comprising a polynucleotide sequence encoding the first polypeptide chain of any one of the monoclonal antibodies disclosed herein targeting LILRB4 or targeting LILRB4 and LILRB2; and a second vector comprising a polynucleotide sequence encoding the second polypeptide chain of any one of the monoclonal antibodies disclosed herein targeting LILRB4 or targeting LILRB4 and LILRB2.

[0037] In certain aspects, the subject matter disclosed herein provides one or more in vitro cultured cells comprising: one or more vectors comprising a polynucleotide sequence encoding any of the monoclonal antibodies disclosed herein.

[0038] In certain aspects, the subject matter disclosed herein provides one or more in vitro cultured cells comprising: a first vector comprising a polynucleotide sequence encodingthe first polypeptide chain of any one of the monoclonal antibodies disclosed herein targeting LILRB4 or targeting LILRB4 and LILRB2; and a second vector comprising a polynucleotide sequence encoding the second polypeptide chain of any one of the monoclonal antibodies disclosed herein targeting LILRB4 or targeting LILRB4 and LILRB2.

[0039] In certain aspects, the subject matter disclosed herein provides a method of making a monoclonal antibody or antigen-binding fragment thereof comprising: culturing the one or more in vitro cultured cells disclosed herein under conditions suitable for an expression of the one or more vectors; and recovering the monoclonal antibody or antigenbinding fragment thereof

[0040] In certain aspects, the subject matter disclosed herein provides a composition comprising: one or more vectors comprising a polynucleotide sequence encoding any of the monoclonal antibodies described herein.

[0041] In certain aspects, the subject matter disclosed herein provides a composition comprising: a first vector comprising a polynucleotide sequence encoding the first polypeptide chain of any of the monoclonal antibodies disclosed herein; and a second vector comprising a polynucleotide sequence encoding the second polypeptide chain of any of the monoclonal antibodies disclosed herein.

[0042] In certain aspects, the subject matter disclosed herein provides a monoclonal antibody means for binding LILRB4.

[0043] In some embodiments, the means comprises any one of the monoclonal antibodies disclosed herein targeting LILRB4.

[0044] In certain aspects, the subject matter disclosed herein provides a monoclonal antibody means for binding LILRB4 and LILRB2.

[0045] In some embodiments, the means is capable of treating or preventing cancer in a subject in need thereof or inhibiting myeloid-dependent immune suppression or promoting immune activation in a subject in need thereof.

[0046] In some embodiments, the means comprises any one of the monoclonal antibodies disclosed herein targeting LILRB4 and LILRB2. In some embodiments, the means is capable of treating or preventing cancer in a subject in need thereof or inhibiting myeloid-dependent immune suppression or promoting immune activation in a subject in need thereof.

[0047] In certain aspects, the subject matter disclosed herein provides a bispecific molecule comprising a first antigen binding region and a second antigen binding region, wherein the first antigen binding region binds a LILRB4 protein and the second antigen binding region binds a LILRB2 protein.

[0048] In some embodiments, the first antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1 ) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 46, a light chain CDR2 (CDRL2) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 47, a light chain CDR3 (CDRL3) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 48 and the VH domain comprises a heavy chain CDRI having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 4, a heavy chain CDR2 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 5, and a heavy chain CDR3 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 6. In some embodiments, the first antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDRI (CDRL1) of SEQ ID NO: 46, a light chain CDR2 (CDRL2) of SEQ ID NO: 47, a light chain CDR3 (CDRL3) of SEQ ID NO: 48 and the VH domain comprises a heavy chain CDRI of SEQ ID NO: 4, a heavy chain CDR2 of SEQ ID NO: 5, and a heavy chain CDR3 of SEQ ID NO: 6.

[0049] In some embodiments, the first antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDRI (CDRL1) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 52, a light chain CDR2 (CDRL2) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 53, a light chain CDR3 (CDRL3) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 54 and the VH domain comprises a heavy chain CDRI having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 10, a heavy chain CDR2 having asequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 11, and a heavy chain CDR3 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 12. In some embodiments, the first antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRLl) of SEQ ID NO: 52, a light chain CDR2 (CDRL2) of SEQ ID NO: 53, a light chain CDR3 (CDRL3) of SEQ ID NO: 54 and the VH domain comprises a heavy chain CDRl of SEQ ID NO: 10, a heavy chain CDR2 of SEQ ID NO: 11, and a heavy chain CDR3 of SEQ ID NO: 12.

[0050] In some embodiments, the first antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDRl (CDRLl) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 49, a light chain CDR2 (CDRL2) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 50, a light chain CDR3 (CDRL3) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 51 and the VH domain comprises a heavy chain CDRl having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 7, a heavy chain CDR2 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 8, and a heavy chain CDR3 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 9. In some embodiments, the first antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDRl (CDRLl) of SEQ ID NO: 49, a light chain CDR2 (CDRL2) of SEQ ID NO: 50, a light chain CDR3 (CDRL3) of SEQ ID NO: 51 and the VH domain comprises a heavy chain CDRl of SEQ ID NO: 7, a heavy chain CDR2 of SEQ ID NO: 8, and a heavy chain CDR3 of SEQ ID NO: 9.

[0051] In some embodiments, the second antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domaincomprises a light chain CDR1 (CDRL1) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 43, a light chain CDR2 (CDRL2) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 44, a light chain CDR3 (CDRL3) having a sequence identity' of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 45 and the VH domain comprises a heavy chain CDR1 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: I, a heavy chain CDR2 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2, and a heavy chain CDR3 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 3. In some embodiments, the second antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) of SEQ ID NO: 43, a light chain CDR2 (CDRL2) of SEQ ID NO: 44, a light chain CDR3 (CDRL3) of SEQ ID NO: 45 and the VH domain comprises a heavy chain CDR1 of SEQ ID NO: 1, a heavy chain CDR2 of SEQ ID NO: 2, and a heavy chain CDR3 of SEQ ID NO: 3.

[0052] In some embodiments, the second antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 58, a light chain CDR2 (CDRL2) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 59, a light chain CDR3 (CDRL3) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 60 and the VH domain comprises a heavy chain CDR1 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 16, a heavy chain CDR2 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 17, and a heavychain CDR3 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 18. In some embodiments, the second antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) of SEQ ID NO: 58, a light chain CDR2 (CDRL2) of SEQ ID NO: 59, a light chain CDR3 (CDRL3) of SEQ ID NO: 60 and the VH domain comprises a heavy chain CDR1 of SEQ ID NO: 16, a heavy chain CDR2 of SEQ ID NO: 17, and a heavy chain CDR3 of SEQ ID NO: 18.

[0053] In some embodiments, the second antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 55, a light chain CDR2 (CDRL2) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 56, a light chain CDR3 (CDRL3) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 57 and the VH domain comprises a heavy chain CDR1 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 13, a heavy chain CDR2 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 14, and a heavy chain CDR3 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 15. In some embodiments, the second antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) of SEQ ID NO: 55, a light chain CDR2 (CDRL2) of SEQ ID NO: 56, a light chain CDR3 (CDRL3) of SEQ ID NO: 57 and the VH domain comprises a heavy chain CDR1 of SEQ ID NO: 13, a heavy chain CDR2 of SEQ ID NO: 14, and a heavy chain CDR3 of SEQ ID NO: 15.

[0054] In some embodiments, the first antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%,98% or 99% identity to SEQ ID NO: 46, a light chain CDR2 (CDRL2) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 47, a light chain CDR3 (CDRL3) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 48 and the VH domain comprises a heavy chain CDR1 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 4, a heavy chain CDR2 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 5, and a heavy chain CDR3 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 6; and the second antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 43, a light chain CDR2 (CDRL2) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 44, a light chain CDR3 (CDRL3) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 45 and the VH domain comprises a heavy chain CDR1 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 1, a heavy chain CDR2 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2, and a heavy chain CDR3 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 3. In some embodiments, the first antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) of SEQ ID NO: 46, a light chain CDR2 (CDRL2) of SEQ ID NO: 47, a light chain CDR3 (CDRL3) of SEQ ID NO: 48 and the VH domain comprises a heavy chain CDR1 of SEQ ID NO: 4, a heavy chain CDR2 of SEQ ID NO: 5, and a heavy chain CDR3 of SEQ ID NO: 6; and the second antigen binding region comprisesa light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) of SEQ ID NO: 43, a light chain CDR2 (CDRL2) of SEQ ID NO: 44, a light chain CDR3 (CDRL3) of SEQ ID NO: 45 and the VH domain comprises a heavy chain CDR1 of SEQ ID NO: 1, a heavy chain CDR2 of SEQ ID NO: 2, and a heavy chain CDR3 of SEQ ID NO: 3.

[0055] In some embodiments, the first antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 46, a light chain CDR2 (CDRL2) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 47, a light chain CDR3 (CDRL3) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 48 and the VH domain comprises a heavy chain CDR1 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 4, a heavy chain CDR2 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 5, and a heavy chain CDR3 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 6; and the second antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 58, a light chain CDR2 (CDRL2) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 59, a light chain CDR3 (CDRL3) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 60 and the VH domain comprises a heavy chain CDR1 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 16, a heavy chain CDR2 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%,93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 17, and a heavy chain CDR3 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 18. In some embodiments, the first antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) of SEQ ID NO: 46, a light chain CDR2 (CDRL2) of SEQ ID NO: 47, a light chain CDR3 (CDRL3) of SEQ ID NO: 48 and the VH domain comprises a heavy chain CDR1 of SEQ ID NO: 4, a heavy chain CDR2 of SEQ ID NO: 5, and a heavy chain CDR3 of SEQ ID NO: 6; and the second antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) of SEQ ID NO: 58, a light chain CDR2 (CDRL2) of SEQ ID NO: 59, a light chain CDR3 (CDRL3) of SEQ ID NO: 60 and the VH domain comprises a heavy chain CDR1 of SEQ ID NO: 16, a heavy chain CDR2 of SEQ ID NO: 17, and a heavy chain CDR3 of SEQ ID NO: 18.

[0056] In some embodiments, the first antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 46, a light chain CDR2 (CDRL2) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 47, a light chain CDR3 (CDRL3) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 48 and the VH domain comprises a heavy chain CDR1 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 4, a heavy chain CDR2 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 5, and a heavy chain CDR3 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 6; and the second antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%identity to SEQ ID NO: 55, a light chain CDR2 (CDRL2) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 56, a light chain CDR3 (CDRL3) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 57 and the VH domain comprises a heavy chain CDR1 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 13, a heavy chain CDR2 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 14, and a heavy chain CDR3 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 15. In some embodiments, the first antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) of SEQ ID NO: 46, a light chain CDR2 (CDRL2) of SEQ ID NO: 47, a light chain CDR3 (CDRL3) of SEQ ID NO: 48 and the VH domain comprises a heavy chain CDR1 of SEQ ID NO: 4, a heavy chain CDR2 of SEQ ID NO: 5, and a heavy chain CDR3 of SEQ ID NO: 6; and the second antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) of SEQ ID NO: 55, a light chain CDR2 (CDRL2) of SEQ ID NO: 56, a light chain CDR3 (CDRL3) of SEQ ID NO: 57 and the VH domain comprises a heavy chain CDR1 of SEQ ID NO: 13, a heavy chain CDR2 of SEQ ID NO: 14, and a heavy chain CDR3 of SEQ ID NO: 15.

[0057] In some embodiments, the first antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 52, a light chain CDR2 (CDRL2) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 53, a light chain CDR3 (CDRL3) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 54 and the VH domain comprises a heavy chain CDR1 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%,95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 10, a heavy chain CDR2 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 11, and a heavy chain CDR3 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 12; and the second antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 43, a light chain CDR2 (CDRL2) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 44, a light chain CDR3 (CDRL3) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 45 and the VH domain comprises a heavy chain CDR1 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 1, a heavy chain CDR2 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2, and a heavy chain CDR3 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 3. In some embodiments, the first antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) of SEQ ID NO: 52, a light chain CDR2 (CDRL2) of SEQ ID NO: 53, a light chain CDR3 (CDRL3) of SEQ ID NO: 54 and the VH domain comprises a heavy chain CDR1 of SEQ ID NO: 10, a heavy chain CDR2 of SEQ ID NO: 11, and a heavy chain CDR3 of SEQ ID NO: 12; and the second antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) of SEQ ID NO: 43, a light chain CDR2 (CDRL2) of SEQ ID NO: 44, a light chain CDR3 (CDRL3) of SEQ ID NO: 45 and the VH domain comprises a heavy chain CDR1 of SEQ ID NO: 1, a heavy chain CDR2 of SEQ ID NO: 2, and a heavy chain CDR3 of SEQ ID NO: 3.

[0058] In some embodiments, the first antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domaincomprises a light chain CDR1 (CDRL1) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 52, a light chain CDR2 (CDRL2) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 53, a light chain CDR3 (CDRL3) having a sequence identity' of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 54 and the VH domain comprises a heavy chain CDR1 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 10, a heavy chain CDR2 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 11, and a heavy chain CDR3 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 12; and the second antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 58, a light chain CDR2 (CDRL2) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 59, a light chain CDR3 (CDRL3) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 60 and the VH domain comprises a heavy chain CDR1 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 16, a heavy chain CDR2 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 17, and a heavy chain CDR3 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 18.

[0059] In some embodiments, the first antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) of SEQ ID NO: 52, a light chain CDR2 (CDRL2) ofSEQ ID NO: 53, a light chain CDR3 (CDRL3) of SEQ ID NO: 54 and the VH domain comprises a heavy chain CDR1 of SEQ ID NO: 10, a heavy chain CDR2 of SEQ ID NO: 11, and a heavy chain CDR3 of SEQ ID NO: 12; and the second antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) of SEQ ID NO: 58, a light chain CDR2 (CDRL2) of SEQ ID NO: 59, a light chain CDR3 (CDRL3) of SEQ ID NO: 60 and the VH domain comprises a heavy chain CDR1 of SEQ ID NO: 16, a heavy chain CDR2 of SEQ ID NO: 17, and a heavy chain CDR3 of SEQ ID NO: 18.

[0060] In some embodiments, the first antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 52, a light chain CDR2 (CDRL2) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 53, a light chain CDR3 (CDRL3) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 54 and the VH domain comprises a heavy chain CDR1 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 10, a heavy chain CDR2 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 11, and a heavy chain CDR3 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 12; and the second antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 55, a light chain CDR2 (CDRL2) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 56, a light chain CDR3 (CDRL3) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 57 and the VH domain comprises a heavy chain CDR1 having a sequence identity of at least80%, 81%, 82%, 83%, 84%, 85%. 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 13, a heavy chain CDR2 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 14, and a heavy chain CDR3 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 15. In some embodiments, the first antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) of SEQ ID NO: 52, a light chain CDR2 (CDRL2) of SEQ ID NO: 53, a light chain CDR3 (CDRL3) of SEQ ID NO: 54 and the VH domain comprises a heavy chain CDR1 of SEQ ID NO: 10, a heavy chain CDR2 of SEQ ID NO: 11, and a heavy chain CDR3 of SEQ ID NO: 12; and the second antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) of SEQ ID NO: 55, a light chain CDR2 (CDRL2) of SEQ ID NO: 56, a light chain CDR3 (CDRL3) of SEQ ID NO: 57 and the VH domain comprises a heavy chain CDR1 of SEQ ID NO: 13, a heavy chain CDR2 of SEQ ID NO: 14, and a heavy chain CDR3 of SEQ ID NO: 15.

[0061] In some embodiments, the first antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 49, a light chain CDR2 (CDRL2) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 50, a light chain CDR3 (CDRL3) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 51 and the VH domain comprises a heavy chain CDR1 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 7, a heavy chain CDR2 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 8, and a heavy chain CDR3 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 9; and the second antigen binding region comprises a light chain variable (VL)domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 43, a light chain CDR2 (CDRL2) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 44, a light chain CDR3 (CDRL3) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 45 and the VH domain comprises a heavy chain CDR1 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 1, a heavy chain CDR2 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2, and a heavy chain CDR3 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 3. In some embodiments, the first antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) of SEQ ID NO: 49, a light chain CDR2 (CDRL2) of SEQ ID NO: 50, a light chain CDR3 (CDRL3) of SEQ ID NO: 51 and the VH domain comprises a heavy chain CDR1 of SEQ ID NO: 7, a heavy chain CDR2 of SEQ ID NO: 8, and a heavy chain CDR3 of SEQ ID NO: 9; and the second antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) of SEQ ID NO: 43, a light chain CDR2 (CDRL2) of SEQ ID NO: 44, a light chain CDR3 (CDRL3) of SEQ ID NO: 45 and the VH domain comprises a heavy chain CDR1 of SEQ ID NO: 1, a heavy chain CDR2 of SEQ ID NO: 2, and a heavy chain CDR3 of SEQ ID NO: 3.

[0062] In some embodiments, the first antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 49, a light chain CDR2 (CDRL2) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 50, a light chain CDR3 (CDRL3) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%,88%, 89%, 90%, 91%, 92%, 93%. 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 51 and the VH domain comprises a heavy chain CDR1 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 7, a heavy chain CDR2 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 8, and a heavy chain CDR3 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 9; and the second antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) having a sequence identity' of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 58, a light chain CDR2 (CDRL2) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 59, a light chain CDR3 (CDRL3) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 60 and the VH domain comprises a heavy chain CDR1 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 16, a heavy chain CDR2 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 17, and a heavy chain CDR3 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 18. In some embodiments, the first antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) of SEQ ID NO: 49, a light chain CDR2 (CDRL2) of SEQ ID NO: 50, a light chain CDR3 (CDRL3) of SEQ ID NO: 51 and the VH domain comprises a heavy chain CDR1 of SEQ ID NO: 7, a heavy chain CDR2 of SEQ ID NO: 8, and a heavy chain CDR3 of SEQ ID NO: 9; and the second antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) of SEQ ID NO: 58, a light chain CDR2 (CDRL2) of SEQ ID NO: 59, a light chain CDR3 (CDRL3) of SEQ ID NO: 60 and the VHdomain comprises a heavy chain CDR1 of SEQ ID NO: 16, a heavy chain CDR2 of SEQ ID NO: 17, and a heavy chain CDR3 of SEQ ID NO: 18.

[0063] In some embodiments, the first antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 49, a light chain CDR2 (CDRL2) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 50, a light chain CDR3 (CDRL3) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 51 and the VH domain comprises a heavy chain CDR1 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 7, a heavy chain CDR2 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 8, and a heavy chain CDR3 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 9; and the second antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 55, a light chain CDR2 (CDRL2) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 56, a light chain CDR3 (CDRL3) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 57 and the VH domain comprises a heavy chain CDR1 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 13, a heavy chain CDR2 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 14, and a heavy chain CDR3 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ IDNO: 15. In some embodiments, the first antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1 ) of SEQ ID NO: 49, a light chain CDR2 (CDRL2) of SEQ ID NO: 50, a light chain CDR3 (CDRL3) of SEQ ID NO: 51 and the VH domain comprises a heavy chain CDR1 of SEQ ID NO: 7, a heavy chain CDR2 of SEQ ID NO: 8, and a heavy chain CDR3 of SEQ ID NO: 9; and the second antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) of SEQ ID NO: 55, a light chain CDR2 (CDRL2) of SEQ ID NO: 56, a light chain CDR3 (CDRL3) of SEQ ID NO: 57 and the VH domain comprises a heavy chain CDR1 of SEQ ID NO: 13, a heavy chain CDR2 of SEQ ID NO: 14, and a heavy chain CDR3 of SEQ ID NO: 15.

[0064] In some embodiments, the first antigen binding region of the bispecific molecule binds LILRB4 with an equilibrium dissociation constant (KD) from about 10-7M to about 10’11M. In some embodiments, the first antigen binding region of the bispecific molecule binds LILRB4 with an association constant from about 105Ms-1to about 106Ms'’. In some embodiments, the first antigen binding region of the bispecific molecule binds LILRB4 with a dissociation constant from about 10-2s-1to about 10-5s-1.

[0065] In some embodiments, the LILRB4 is a human LILRB4. In some embodiments, the LILRB4 is a cynomolgus macaque LILRB4. In some embodiments, the LILRB4 is a mouse ortholog of LILRB4. In some embodiments, the bispecific molecule inhibits a LILRB4-dependent immune checkpoint. In some embodiments, the bispecific molecule depletes LILRB4+ monocytes. In some embodiments, the bispecific molecule does not deplete immune-supporting myeloid populations. In some embodiments, the bispecific molecule is a blocking molecule.

[0066] In some embodiments, VH domain further comprises framework regions (FRs) of a human IGHV gene and wherein the VL domain further comprises FRs of a human IGKV gene.

[0067] In some embodiments, the bispecific molecule comprises (a) a first arm comprising the first antigen binding region wherein the first antigen binding region binds LILRB4 and (b) a second arm comprising the second antigen binding region wherein the second antigen binding region binds LILRB2. In some embodiments, the first and second arms each further comprise a CHI domain, a hinge domain, a Fc domain (CH2-CH3) and a CL domain. In some embodiments, the VH domain of the first arm is encoded by a first polypeptide chain: the VL domain of the first arm is encoded by a second polypeptide chain;the VH domain of the second arm is encoded by a third polypeptide chain; the VL domain of the second arm is encoded by a fourth polypeptide chain; and wherein the VH domain and VL domain of the first arm form the first antigen binding region, wherein the first antigen binding region binds LILRB4, and wherein the VH domain and VL domain of the second arm form the second antigen binding region, wherein the second antigen binding region binds LILRB2.

[0068] In some embodiments, the first and third polypeptide chain each further encode a hinge domain, a CHI domain, and an Fc domain, and wherein the second and fourth polypeptide chain each further encode a CL domain. In some embodiments, the first, second, third, and fourth polypeptide chains comprise different amino acid sequences. In some embodiments, the VH domain of the first arm comprises an amino acid sequence comprising SEQ ID NO: 22, SEQ ID NO: 26, or SEQ ID NO: 24 and the VH domain of the second arm comprises an amino acid sequence comprising SEQ ID NO: 28, SEQ ID NO: 30, or SEQ ID NO: 20. In some embodiments, the VL domain of the first arm comprises an amino acid sequence comprising SEQ ID NO: 64, SEQ ID NO: 68, or SEQ ID NO: 66 and the VL domain of the second arm comprises an amino acid sequence comprising SEQ ID NO: 70, SEQ ID NO: 72, or SEQ ID NO: 62. In some embodiments, the first arm comprises an amino acid sequence comprising SEQ ID NO: 34, SEQ ID NO: 38, or SEQ ID NO: 36 and the second comprises an amino acid sequence comprising SEQ ID NO: 40, SEQ ID NO: 42, or SEQ ID NO: 32. In some embodiments, the first arm comprises an amino acid sequence comprising SEQ ID NO: 76, SEQ ID NO: 80, or SEQ ID NO: 78 and the second comprises an amino acid sequence comprising SEQ ID NO: 82, SEQ ID NO: 84, or SEQ ID NO: 74.

[0069] In some embodiments, the first and second polypeptide chains are linked by one or more covalent disulfide bonds and the third and fourth polypeptide chains are linked by one or more covalent disulfide bonds. In some embodiments, the first and third polypeptide chains are linked by one or more covalent disulfide bonds.

[0070] In some embodiments, the bispecific molecule binds LILRB2 with an equilibrium dissociation constant (KD) from about 10-7M to about 10-11M. In some embodiments, the bispecific molecule binds LILRB2 with an association constant from about 10-5Ms-1. In some embodiments, the bispecific molecule binds LILRB2 with a dissociation constant from about 10-2s-1to about 10-5s-1.

[0071] In some embodiments, the LILRB2 is a human LILRB2. In some embodiments, the LILRB2 is a cynomolgus macaque LILRB2. In some embodiments, the LILRB2 is a mouse ortholog of LILRB2. In some embodiments, the anti-LILRB2 antibody inhibits aLILRB2-dependent immune checkpoint. In some embodiments, the bispecific molecule depletes LILRB2+ monocytes. In some embodiments, the bispecific molecule does not deplete immune-supporting myeloid populations. In some embodiments, the bispecific molecule is a blocking bispecific.

[0072] In certain aspects, the subject matter disclosed herein provides a pharmaceutical composition comprising any of the bispecific molecules described herein.

[0073] In some embodiments, the pharmaceutical composition described herein further comprising one or more pharmaceutically-acceptable diluents, one or more pharmaceutically- acceptable carriers or one or more pharmaceutically-acceptable excipients.

[0074] In certain aspects, the subject matter disclosed herein provides a method of treating or preventing cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of any of the bispecific molecules described herein or any of the pharmaceutical compositions described herein.

[0075] In some embodiments, the cancer is kidney cancer, breast cancer, brain tumor, head and neck cancer, liver cancer, melanoma, non-small cell lung cancer (NSCLC), bladder cancer, cervical cancer, colon cancer, renal cell cancer, skin cancer, stomach cancer, rectal cancer, gastrointestinal, pancreatic cancer, lung cancer, thymic carcinoma, ovarian cancer, prostate cancer, or endometrial cancer. In some embodiments, the cancer is a liquid cancer. In some embodiments, the liquid cancer is leukemia, lymphoma, Hodgkin lymphoma, or myeloma. In some embodiments, the liquid cancer is acute myeloid leukemia (AML). In some embodiments, the liquid cancer is B-cell malignancy.

[0076] In some embodiments, the cancer is a cancer treated with immune therapies including, but not limited to, T-cell checkpoint inhibitors such as anti-PD-1 antibodies and anti-CTLA4 antibodies. In some embodiments, the anti-PPD-1 antibody is Pembrolizumab. In some embodiments, the anti-PPD-1 antibody is Nivolumab. In some embodiments, the anti-PPD-1 antibody is Cemiplimab. In some embodiments, the anti-PPD-1 antibody is Dostarlimab. In some embodiments, the anti-PPD-1 antibody is Retifanlimab. In some embodiments, the anti-PPD-1 antibody is Toripalimab. In some embodiments, the anti- CTLA4 antibody is Ipilimumab. In some embodiments, the anti-CTLA4 antibody Tremelimumab.

[0077] In certain aspects, the subject matter disclosed herein provides a method of inhibiting myeloid-dependent immune suppression or promoting immune activation in a subject in need thereof, the method comprising administering to the subject an effectiveamount of any of the bispecific molecules described herein or any of the pharmaceutical compositions described herein.

[0078] In some embodiments, the subject is a human subject.

[0079] In certain aspects, the subject matter disclosed herein provides a polynucleotide encoding at least a portion of any one of the bispecific molecules described herein.

[0080] In certain aspects, the subject matter disclosed herein provides a genetically engineered cell comprising any of the bispecific molecules described herein.

[0081] In certain aspects, the subject matter disclosed herein provides a composition comprising: one or more vectors comprising one or more polynucleotide sequences encoding any of the bispecific molecules described herein.

[0082] In certain aspects, the subject matter disclosed herein provides a composition comprising: a first set of one or more vectors comprising one or more polynucleotide sequences encoding the first antigen binding region of any of the bispecific molecules described herein: and a second set of one or more vectors comprising one or more polynucleotide sequences encoding the antigen binding region of any of the bispecific molecules described herein.

[0083] In certain aspects, the subject matter disclosed herein provides a bispecific molecule means for binding LILRB4 and LILRB2.

[0084] In some embodiments, the means comprises any one of the bispecific molecules described herein. In some embodiments, the means is capable of treating or preventing cancer in a subject in need thereof or inhibiting myeloid-dependent immune suppression or promoting immune activation in a subject in need thereof.BRIEF DESCRIPTION OF FIGURES

[0085] The patent or application file contains at least one drawing executed in color. To conform to the requirements for PCT patent applications, many of the figures presented herein are black and white representations of images originally created in color.

[0086] FIG. 1 shows a summary of key characteristics of monoclonal antibodies (mAb) BT-2652 against LILRB4 and BT-2671 cross-reactive against LILRB2 and LILRB4. Note: the antibody designations prefix “ATX” and “BT” are used interchangeably throughout the present application.

[0087] FIGS 2A-C show a diverse panel of high affinity selective anti-LILRB4 mAbs. FIG. 2 A shows a panel of high affinity mAbs targeting human LILRB4. FIG. 2B shows mAbs’ binding to target overtime. Standard methods for surface plasma resonance were used,each line represents a different antibody concentration. FIG. 2C shows association rate, dissociation rate, and biding affinity. Calculated average rates are shown.

[0088] FIG. 3 shows that the mAbs of the present disclosure bind endogenous LILRB4 on the surface of BL2-H cells.

[0089] FIG. 4 shows diverse clusters of the mAbs of the present disclosure. Diversity of mAbs was evaluated by epitope binning and cluster analysis. The mAbs in the same bin are mutually competitive for binding to LILRB4.

[0090] FIGS. 5A-D shows a biochemical characterization of anti-LILRB4 mAbs. FIG.5 A shows human LILRB4 binding affinity, epitope bin and method of mAb generation. FIG. 5B shows human LILRB4 binding affinity. FIG. 5C shows binding affinity for BT-2652 mAb. FIG. 5D shows binding affinity for BT-2671 mAb. Binding to recombinant human LILRB4-AviHis determined by high-throughput SPR using Carterra LSA.

[0091] FIG. 6 shows that anti-LILRB4 mAbs inhibit myeloid immune suppressive signals and promote immune activating signals via NF-kB. ZM4.1 includes effector function and reduces myeloid signaling overall. BTx mAbs lack effector function and affect LILRB4 checkpoint activity to restore immune supportive activity. In vitro screen on large scale preps of the 8 selected mAbs: LILRB4 agonism in reporter cell lines. Relative light units (RLU).

[0092] FIGS. 7A-B show effects of treatment with anti-LILRB4 mAbs. FIG. 7A shows that anti-LILRB4 mAbs rescue T-cell activity from myeloid-dependent suppression. Data from 4 independent donors; 1:1 ratio of MDSC:T-cells, biased toward suppression. ZM4.1 includes effector function, reduces myeloid signaling overall and does not rescue T-cell activity. 6101 is a benchmark mAb (h52B8 surrogate). BTx mAbs lack effector function, activate pro-immune functions and rescue T-cell activity. FIG. 7B shows that monotherapy with anti-LILRB4 mAbs inhibits tumor growth as well or better than benchmark antibody.

[0093] FIG. 8 shows that monotherapy with anti-LILRB4, non-depleting antibodies inhibits tumor growth more effectively than a benchmark antibody, h52B8. SK-Mel-5 cells in Hu-NSG-SGM3 mice.

[0094] FIG. 9 shows that monotherapy with anti-LILRB4 selective mAbs inhibits tumor growth as well or better than a benchmark antibody. Monotherapy with anti-LILRB4 selective mAbs inhibits tumor growth as well or better than benchmark antibody.

[0095] FIG. 10 shows that monotherapy anti-LILRB2 / anti-LILRB4 cross reactive mAbs inhibits tumor growth more effectively than benchmark antibody.

[0096] FIGS. 11A-B show that soluble LILRB4 is a PD marker for anti-LILRB4 mAbs inhibition of tumor growth in vivo. SK-MEL5 tumors in CD34- reconstituted NSG-SGM3human immune mice. Treatments initiated when tumors reached ~70mm3, i.p. Tx weekly with the indicated mAb (10 mg / kg). FIG. 11 A shows that anti-LILRB4 mAbs inhibit tumor growth in vivo in mice with a humanized immune system. SK-MEL5 tumors in CD34+ reconstitutedNSG-SGM3 human immune mice. Treatments initiated when tumors reached ~70mm3, i.p. Tx weekly with the indicated mAb (10 mg / kg). FIG. 1 IB shows that soluble LILRB4 is reduced in mice treated with anti-LILRB4 mAbs.

[0097] FIG. 12 shows immune suppressive LILRB4+ myeloid cells are reduced in mice treated with anti-LILRB4 mAbs.

[0098] FIG. 13 shows human LILRB family receptors and their ligands.

[0099] FIG. 14 shows antibody sequences.

[0100] FIGS. 15A-C show that antibodies BTX-2006 and BTX-2666 are both LILRB2 / LILRB4 cross-reactive monoclonal antibodies. FIG. 15A shows antibody epitope bin, method of generation, and binding affinity to human LILRB4 as determined by SPR. FIG. 15B shows antibody binding affinity to cyno LILRB4 as determined by SPR. FIG. 15C shows antibody binding to recombinant LILRB4 from human, cynomolgus monkey and mouse compared to binding to human LILRB2 as determined by Carterra LSA.DETAILED DESCRIPTION OF THE INVENTION

[0101] All patent applications, published patent applications, issued and granted patents, texts, and literature references cited in this specification are hereby incorporated herein by reference in their entirety to more fully describe the state of the art to which the present disclosed subject matter pertains.

[0102] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Methods and materials are described herein for use in the present invention; other, suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and not intended to be limiting.

[0103] The singular forms “a”, “an” and “the” include plural reference unless the context clearly dictates otherwise.

[0104] Myeloid suppression in cancer

[0105] Cancer is often characterized by tumor-promoting inflammation and avoidance of tumor destruction by the immune system. Tumor-promoting inflammation can disturb normal myelopoiesis. This disturbance leads to the generation of immunosuppressive myeloid cells,such as myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs). Immunosuppressive myeloid cells can be an important barrier to cancer immunotherapy due to their potent suppressive activities against effector lymphocytes and their abundance in the tumor microenvironment. Immune checkpoint molecules expressed on tumor-infiltrating myeloid cells have emerged as potential therapeutic targets to redirect these cells to eliminate tumor cells. There is a complex crosstalk between cancer-related inflammation and immunosuppressive myeloid cells, which provides a possible therapeutic strategy to take advantage of antitumor immune responses.

[0106] Immunotherapy is a pillar of cancer therapy. Immune checkpoint blockade (ICB) therapies have significantly improved outcomes in patients with melanoma, non-small-cell lung cancer, and other types of tumors with high tumor mutational burden. However, durable clinical responses in most cancer patients have yet to be achieved. One major hurdle to overcome is that the tumor microenvironment (TME) acts as a major barrier for the recruitment and activation of effector lymphocytes to battle cancer cells. It has recently been appreciated that inflammation not only directly fuels tumor growth but also critically contributes to the generation of TME with proangiogenic and immunosuppressive features.

[0107] Immunosuppressive cells can be induced by cancer-related inflammation. Cancer- related inflammation can trigger myeloid-dependent immunosuppression. A wide variety of growth factors and proinflammatory cytokines can alter myelopoiesis leading to the generation of immature myeloid cells with potent immunosuppressive activities (i.e., MDSCs). MDSCs can be recruited into tumor tissues in response to chemokine signaling, where they further undergo dynamic alteration, such as differentiation into TAMs from monocytic MDSCs. MDSCs and TAMs can act as a key barrier for anti-tumor immunity. A broad range of inflammatory stimuli can trigger the generation of MDSCs such as growth factors that are required for expansion (e.g., G-CSF, M-CSF, GM-CSF and S-CSF); cytokines for functional maturation (IL-1 family cytokines, IL -4, IL-6, IL- 13, and TNF); and chemoattractants for mobilization into the TME (IL-8, CCL2, and CXCL12). Downstream signaling and transcriptional factors are involved in each step. For instance, C / EBPp, a key transcriptional factor for emergency granulopoiesis, plays a crucial role in the expansion of MDSCs. The C / EBPP-driven expansion of MDSCs is positively regulated by retinoic acid- related orphan receptor C (RORC1) expressed on immature myeloid cells under cancer- related inflammation. By contrast, interferon regulatory factor-8 (IRF8) acts as a negative regulator of the generation of MDSCs. Mice deficient in IRF8 harbor MDSC-like cells evenunder tumor- free conditions and that transgenic overexpression of IRF8 reduces the accumulation of MDSCs under tumor-bearing conditions.

[0108] Immune checkpoints

[0109] Immune checkpoints are a regulatory point in the development of immune cells. They prevent an immune response to a stimulus from becoming so strong that it destroys healthy cells in the body or progresses to an autoimmune disorder or blood cancer. Immune checkpoints occur when cell surface proteins on immune cells recognize and bind to their partners on other cells, such as some tumor cells. These immune cell surface proteins are immune checkpoint proteins. When the checkpoint protein and the partner protein bind each other, they can send an “off’ signal to the immune cell, such as a T cell, expressing the immune checkpoint protein. This can prevent the immune system from destroying the cancer cell and allowing the cancer to develop and metastasize.

[0110] Immunotherapy drugs have been developed to inhibit the immune checkpoint proteins. These immune checkpoint inhibitors block the immune checkpoint proteins from binding with their partner proteins on the cancer cells. Thus, the checkpoint inhibition prevents the “off’ signal from being sent, allowing the T cells to kill cancer cells and prevent further disease.

[0111] In some embodiments, the subject matter described herein relates to the inhibition of immune checkpoints. In some embodiments, the subject matter described herein relates to inhibition of myeloid-dependent immune suppression. In some embodiments, the subject matter described herein relates to promoting myeloid cell maturation. In some embodiments, the subject matter described here relates to cancer treatment or prevention. In some embodiments, the cancer is blood cancer. In some embodiments, the cancer comprises a solid tumor.

[0112] In some embodiments, the subject matter described herein relates to monoclonal antibodies as inhibitors of myeloid-dependent immune suppression, In some embodiments, the subject matter described herein relates to monoclonal antibodies as promoters of myeloid cell maturation. In some embodiments, the subject matter described herein relates to use of monoclonal antibodies in the treatment or prevention of cancer.

[0113] In some embodiments, the monoclonal antibodies described here bind LILRB4, an immune checkpoint protein. In some embodiments, the monoclonal antibodies described here bind LILRB4 with high affinity. In some embodiments, the monoclonal antibodies described here bind LILRB2. In some embodiments, the monoclonal antibodies described here bindLILRB2 with high affinity. In some embodiments, the antibodies described herein both LILRB4 and LILRB2 with high affinity.

[0114] In some embodiments, the subject matter described herein relates to monoclonal antibodies against LILRB4 as inhibitors of myeloid-dependent immune suppression. In some embodiments, the subject matter described herein relates to monoclonal antibodies against LILRB4 as promoters of myeloid cell maturation, In some embodiments, the subject matter described herein relates to use of monoclonal antibodies against LILRB4 in the treatment or prevention of cancer.

[0115] In some embodiments, the subject matter described herein relates to monoclonal antibodies with high affinity against both LILRB4 and LILRB2 as inhibitors of myeloid- dependent immune suppression. In some embodiments, the subject matter described herein relates to monoclonal antibodies with high affinity against both LILRB4 and LILRB2 as promoters of myeloid cell maturation, In some embodiments, the subject matter described herein relates to use of monoclonal antibodies with high affinity against LILRB4 and LILRB2 in the treatment or prevention of cancer.

[0116] In some embodiments, the LILRB2 / LILRB4 cross-reactive antibodies disclosed herein show improved in vivo activity over LILRB4 selective monoclonal antibodies. In some embodiments, the LILRB2 / LILRB4 cross-reactive antibodies disclosed herein show improved in vivo activity over antibody h52b8. In some embodiments, the LILRB4 selective monoclonal antibodies disclosed herein show improvement in tumor growth inhibition compared to antibody h52B8. In some embodiments, antibodies disclosed herein show improvement over h52B8 in cell-based assays, such as in reducing immune suppressive LILRB4+ myeloid cells following treatment with one or more of the antibodies disclosed herein.LILRB4

[0117] LILRB4 is an inhibitory receptor and a member of the LILR family. LILRB4 is mainly expressed on normal and malignant human myeloid cells. LILRB4 can be activated following ligand binding, which leads to recruitment of adaptor proteins to the cytoplasmic immunoreceptor tyrosine inhibitory motifs of LILRB4. These adaptors initiate various downstream signaling cascades playing an important role in physiological and pathological conditions, including autoimmune diseases, cancers, and infections.

[0118] In healthy myeloid cells, LILRB4 regulates intrinsic cell activation and differentiation by binding to partner proteins. In disease-associated or malignant myeloid cells, LILRB4 activation suppresses T cell development, thereby participating in thepathogenesis of various diseases including, but not limited to, cancer. LILRB4 activation in the context of disease is correlated with disease severity or patient survival. Therefore, regulating LILRB4 activity and or expression may be a promising therapeutic target for various human immune diseases, especially for cancer immunotherapy.

[0119] The leukocyte immunoglobulin-like receptor (LILR) family comprises inhibitory and activating receptors expressed in human myeloid cells. The LILR family has 13 members - six activating receptors (LILRA1-ILLRA6), five inhibitory receptors (LILRB1-LILRB5), and two pseudogenes. The extracellular structures of LILRAs and LILRBs are highly similar to C2-type Ig-like domains. LILRAs have a shorter cytoplasmic tail without an intrinsic signaling capacity but with a positively charged arginine residue (R) in the transmembrane domain. This arginine residue enables association with the FcyR chain that contains immunoreceptor tyrosine-based activation motifs (IT AMs). LILRBs have a long cytoplasmic tail with immunoreceptor tyrosine-based inhibition motifs (ITIMs). LILRs are mainly expressed on the myeloid lineage cells, such as monocytes, macrophages, neutrophils and dendritic cells. Some LILRs are also found on B cells, NK cells and T cells.

[0120] LILRB4 is one of the inhibitory receptors in the LILR family. LILRB4 is known as ILT3, LIR5, CD85K, and HM18. It was identified in the late 1990s as an inhibitory receptor on monocytes and was considered to be a homolog of mouse glycoprotein (gp49B). While most family members contain four Ig domains, the LILRB4 protein has two extracellular C2-type Ig domains and three cytoplasmic ITIMs which can recruit phosphatases for downstream signal transduction. Unlike other LILRBs, LILRB4 is not conformationally and electrostatically suitable for interaction with major histocompatibility complex (MHC), hormone, virus products. Thus, LILRB4 may not be directly involved in regulation of MHC -mediated antigen-specific T cell activation.

[0121] The intracellular ITIMS of LILRB4 inhibitory receptors attenuate crosslinkdependent activation of ITAM-containing activated receptors. By co-ligation with activating receptors, ITIMs are phosphorylated by Src-family tyrosine kinases, which enables them to recruit Src homology 2(SH2) domain phosphatases (SHPs), such as SHP-1 or SHP-2, and SH2 -containing inositol phosphatase (SHIP-1). This signaling cascade can inhibit the activation of Syk and PI3K signals, thus terminating the activation signals induced by ITAM- containing receptors. Subsequently, co-ligation of LILRB4 and FcyRI inhibits production of the key pro-inflammatory cytokine TNFa induced by FcyRI by reducing FcyRLmediated phosphorylation of Lek, Syk, LAT, Erk and c-Cbl. Conversely, treatment with the SHP-1- specific phosphatase inhibitor sodium stibogluconate reverses the inhibitory effect ofLILRB4 on TNFa production. In addition to inhibiting cytokine production, LILRB4 inhibits FcyRI-dependent endocytosis through SHP-dependent dephosphorylation of Syk, clathrin, and the E3 ubiquitin protein ligase Cbl. LILRB4 is an inhibitor of monocyte activation and plays an important role in immune regulation by abrogating FcyRI-dependent monocyte activation.

[0122] LILRB4 is expressed in macrophages, which are derived from blood monocytes and are a key component of the innate immune system responding to tissue invasion by infectious microorganisms and tissue injury. As an endogenous negative regulator of macrophage activation, co-ligation of LILRB4 and FcyRI inhibits the FcyRI-mediated production of TNFa. In Toxoplasma gondii infection during pregnancy, LILRB4 expression is downregulated on macrophages, which results in downregulation of the arginine catabolism enzyme arginase- 1 (ARG-1) and upregulation of inducible nitric oxide synthase (iNOS) to suppress placental vascular development, which contributes to abnormal pregnancy outcomes. In atherosclerosis, LILRB4 is expressed on macrophages located in atherosclerotic plaque atherosclerotic lesions of human coronary arteries. Overall, LILRB4 plays an important role in the activation, differentiation, and polarization of macrophages during disease pathogenesis.

[0123] In the tumor immune microenvironment, myeloid-derived suppressor cells (MDSCs) are strongly expanded and can inhibit the activity of T cells. In non-small-cell lung cancer (NSCLC), LILRB4 is expressed on both PMN-MDSCs and M-MDSCs. Particularly in PMN-MDSCs, the expression of LILRB4 is correlated with poor outcomes in NSCLC patients. M-MDSCs may exhibit a stronger immunosuppressive potential than PMN-MDSCs. Treatment of these M-MDSCs with anti-LILRB4 antibodies impairs the ability to induce T cell suppression, In addition, the fibronectin expressed by stromal cells in tumor microenvironment binds and activates LILRB4 on MDSCs. The fibronectin-LILRB4 interaction recruits SHP-1 to inhibit Syk-mediated FcyR signaling and immunosuppressive activities of MDSCs. Thus, MDSCs may inhibit the activity of T cells via LILRB4 in cancer development and progression and LILRB4 expressed on MDSCs can be a target for cancer immunotherapy.

[0124] In addition to MDSCs, monocytes in patient blood circulation can be recruited to the tumor microenvironment and further differentiate into tumor-associated macrophages (TAMs) TAMs, lack phagocytotic activities and promote tumor cell evasion from immune surveillance. They also promote metastasis to other tissues and organs. LILRB4 is expressed on TAMs in human lung cancer, melanoma, colon carcinoma, pancreatic carcinoma, mousemelanoma and colon cancer models. Blocking LILRB4 with antibodies or protein deficiency increases the infiltration of anti-tumor immune cells into the tumor microenvironment. Thus, LILRB4 expressed on TAMs can be a target for cancer immunotherapy.

[0125] LILRB4 is expressed in a variety of cancer cells, including on solid tumors and hematological tumors. LILRB4 is specifically expressed on monocytic acute myeloid leukemia (AML) cells. In AML, apolipoprotein E (APOE) binds to LILRB4, recruiting SHP- 2 to the intracellular ITIMs of LILRB4 and activating the NFKB signaling pathway to promote leukemia cell infiltration. Mutation analyses have shown that phosphorylation of tyrosine 412 and 441 in LILRB4 ITIMs by Src-family tyrosine kinases controls T cell suppression and leukemia cell infiltration. Treatment with anti-LILRB4 antibodies, which interrupts the APOE-LILRB4 interaction, releases T cell suppression and inhibits leukemia cell infiltration as well as AML development.

[0126] LILRB4 expression is regulated at multiple levels, including the transcriptional, posttranscriptional and epigenetic levels. Vitamin D3 and its nuclear receptor can bind to the promoter region of LILRB4 and drive LILRB4 expression. Fat mass and obesity-related protein (FTO), an RNA N6-methyladenosine (m6A) demethylase, positively regulates the expression of LILRB4 in monocytic AML cells by inhibiting YTH N6-methyladenosine RNA binding protein 2 (YTHDF2)-mediated decay of LILRB4 mRNA m6A modification. FTO-specific inhibitors reduce the expression of LILRB4 on AML cells, increasing the sensitivity of AML cells to activated T cells. LILRB4 expression is upregulated by PRMT5 in AML cells, which results in activation of the mTOR pathway to enhance the invasion ability of AML cells. LILRB4 is specifically expressed on monocytic AML cells but not on normal hematopoietic progenitor cells and anti-tumor T cells, which makes LILRB4 a promising therapeutic target evading toxicity. Thus, LILRB4 can be a target for AML immunotherapy.

[0127] Several therapeutic strategies have been developed based on LILRB4 inhibition. These include anti-LILRB4 humanized monoclonal antibodies, anti-LILRB4 chimeric antigen receptor (CAR)-T cells, anti-LILRB4 antibody-drug conjugates (ADCs), and biomimetic inhibitors. Some of these therapeutics have shown anti-tumor efficacy in pre- clinical experiments. LILRB4 is also expressed on solid cancer cells. In NSCLC, LILRB4 is activated by APOE binding and further recruits SHP-2 and SHIP-1 to activate ERK1 / 2 signaling. This increases the expression of vascular endothelial growth factor (VEGF) and promotes cancer metastasis.

[0128] LILRB2

[0129] Blocking inmrunoinhibitory receptor LILRB2 can also reprogram tumor- associated myeloid cells in the treatment of cancer. LILRB2 antagonism inhibits receptor- mediated activation of SHP1 / 2, thus, enhancing proinflammatory responses. Transcriptome analysis has shown that LILRB2 inhibition alters genes involved in cell cytoskeleton remodeling, lipid / cholesterol metabolism, and endosomal sorting pathways, as well as changed differentiation gene networks associated with inflammatory myeloid cells as opposed to their alternatively activated phenotype. LILRB2 blockade suppresses MDSC and Treg infiltration and promotes in vivo antitumor effects of T cell immune checkpoint inhibitors.

[0130] Anti-LILRB4 and Anti-LILRB4 / LILRB2 Antibodies

[0131] Disclosed herein are novel monoclonal antibodies that, in some embodiments, are useful for preventing or treating disease (e.g., cancer).

[0132] Unless otherwise indicated, the practice of aspects of the present invention can employ conventional techniques of cell biology, cell culture, molecular biology, transgenic biology, microbiology, recombinant DNA, and immunology, which are within the skill of the art. Such techniques are explained fully in the literature.

[0133] A protein is encoded by a nucleic acid (including, for example, genomic DNA, complementary DNA (cDNA), synthetic DNA, as well as any form of corresponding RNA). One skilled in the art can obtain a protein in several ways, including, but not limited to isolating the protein via biochemical means or expressing a nucleotide sequence encoding the protein of interest. The nucleic acids encoding a protein can be produced via recombinant DNA technology and such recombinant nucleic acids can be prepared by conventional techniques, including chemical synthesis, genetic engineering, enzymatic techniques, or a combination thereof.

[0134] Protein variants can include amino acid sequence modifications. For example, amino acid sequence modifications fall into one or more of three classes: substitutional, insertional or deletional variants. Insertions can include amino and / or carboxyl terminal fusions as well as intrasequence insertions of single or multiple amino acid residues. Ordinarily, insertions will be smaller than those of amino or carboxyl terminal fusions, for example, on the order of one to four residues. Deletions are characterized by the removal of one or more amino acid residues from the protein sequence. These variants ordinarily are prepared by site-specific mutagenesis of nucleotides in the DNA encoding the protein, thereby producing DNA encoding the variant, and thereafter expressing the DNA in recombinant cell culture or using cell-free methods known in the art.

[0135] An antibody can by expressing DNA encoding the antibody in recombinant cell culture or using cell-free methods known in the art followed by purification. Non-limiting purification methods include size exclusion chromatography, ammonium sulfate fractionation, ion exchange chromatography, affinity chromatography, and preparative gel electrophoresis.

[0136] In some embodiments, the antibody may be post-translationally modified. In some embodiments, polypeptides or proteins can be modified enzymatically or chemically, by addition or removal of a post-translational modification. For example, a polypeptide or protein can be glycosylated or deglycosylated enzymatically. Similarly, polypeptides can be phosphorylated using a purified kinase, such as a MAP kinase (e.g, p38, ERK, or JNK) or a tyrosine kinase (e.g., Src or erbB2). A polypeptide or protein can also be modified through synthetic chemistry. Alternatively, one can isolate the antibody from a cell or tissue that expresses the polypeptide with the desired post-translational modification, In another embodiment, a nucleic acid molecule encoding the polypeptide or protein of interest is introduced into a host cell that is capable of post-translationally modifying the encoded polypeptide(s) in the desired fashion. If the polypeptide or protein does not contain a motif for a desired post-translational modification, one can alter the post-translational modification by mutating the nucleic acid sequence of a nucleic acid molecule encoding the polypeptide(s) so that it contains a site for the desired post-translational modification. The nucleic acid molecule can also be introduced into a host cell that is capable of post-translationally modifying the encoded polypeptide(s). Similarly, one can delete sites that are post- translationally modified by mutating the nucleic acid sequence so that the encoded polypeptide(s) does not contain the post-translational modification motif, or by introducing the native nucleic acid molecule into a host cell that is not capable of post-translationally modifying the encoded polypeptide(s).

[0137] Useful post-synthetic (and post-translational) modifications include conjugation to chemical moieties. A wide variety of amine-reactive and thiol-reactive fluorophore derivatives have been synthesized that react under nondenaturing conditions with N-terminal amino groups and epsilon amino groups of lysine residues, on the one hand, and with free thiol groups of cysteine residues, on the other. Chemical moieties that usefully can be conjugated to antibodies disclosed herein include radioactive labels, echosonographic contrast reagents, and MRI contrast agents. Kits are available commercially that permit conjugation of proteins to a variety of amine-reactive or thiol-reactive chemical moieties.

[0138] There are five classes of human antibodies (i.e., IgA, IgD, IgE, IgG, and IgM) and each have various isotypes (e.g., IgGl, IgG2, IgG3, IgG4, IgAl, and IgA2). In some embodiments, the antibodies disclosed herein belong to the IgG class. IgG can be divided into four subclasses: IgGl, IgG2, IgG3, and IgG4. Each subclass has a unique profile with respect to antigen binding, immune complex formation, complement activation, triggering of effector cells, half-life, and placental transport. E.g., see Gestur Vidarsson, et al., IgG Subclasses and Allotypes: From Structure to Effector Functions, 5 Frontiers in Immunology 520 (2014), incorporated by reference herein in its entirety. In some embodiments, the antibodies disclosed herein belong to the IgGl class. The term “immunoglobulin” (Ig) is used interchangeably with “antibody” herein.

[0139] The IgG immunoglobulin molecule consists of four polypeptide chains, two identical light (L) chains and two identical heavy (H) chains. Disulfide bonds join the four chains in a “Y” configuration wherein the light chains bracket the heavy chains starting at the mouth of the “Y” and continuing through the variable region to the dual ends of the “Y”. Each L chain is linked to an H chain by one covalent disulfide bond, while the two H chains are linked to each other by one or more disulfide bonds depending on the H chain isotype. Each H and L chain also has regularly spaced intrachain disulfide bridges. Each heavy chain consists of an N-terminal variable domain (VH) and three constant domains (CHI, CH2, CH3), with an additional “hinge region” between CHI and CH2. Similarly, the light chains consist of an N-terminal variable domain (VL) and a constant domain (CL). The variable domains of the heavy chain and light chain may be referred to as “VH” and “VL”, respectively. These domains are generally the most variable parts of the antibody (relative to other antibodies of the same class) and contain the antigen binding sites. The VL is aligned with the VH and the CL is aligned with the first constant domain of the heavy chain (CHI). The pairing of a VH and VL together forms a single antigen-binding site. The part of the antibody formed by the lower hinge region and the CH2 / CH3 domains of the heavy chain is called “Fc” (“fragment crystalline”). See e.g., Basic and Clinical Immunology, 8th Edition, Daniel P. Sties, Abba I. Terr and Tristram G. Parsolw (eds), Appleton & Lange, Norwalk, CT, 1994, page 71 and Chapter 6, incorporated by reference herein in its entirety.

[0140] The variability in an antibody sequence is concentrated in three segments called complementarity determining regions (CDRs) (also called hypervariable regions (HVRs)) both in the light-chain and the heavy-chain v ariable domains. The more highly conserved portions of variable domains are called the framework regions (FR). The variable domains of native heavy and light chains each comprise four FR regions, largely adopting a beta-sheetconfiguration, connected by three CDRs, which form loops connecting, and in some cases forming part of, the beta-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. See Kabat et al, Sequences of Immunological Interest, Fifth Edition, National Institute of Health, Bethesda, MD (1991), incorporated by reference in its entirety herein. The constant domains are not involved directly in the binding of antibodies to an antigen but exhibit various effector functions, such as the participation of the antibody in antibody-dependent cellular toxicity.

[0141] By way of example, CDRs may be defined using the nomenclature described by Kabat et al. (1991, NIH Publication 91-3242, National Technical Information Service, Springfield, Va.), incorporated by reference in its entirety herein.

[0142] The antibodies disclosed herein (e.g., monoclonal antibodies) includes, but is not limited to, full-length antibodies and also includes other immunologically reactive / antigen- binding molecules. The antibodies of the various embodiments disclosed herein can include one or more of synthetic antibodies, monoclonal antibodies, oligoclonal or polyclonal antibodies, multiclonal antibodies, recombinantly produced antibodies, intrabodies, monospecific antibodies, monovalent antibodies, multispecific antibodies, multivalent antibodies, bispecific antibodies, bivalent antibodies, tetravalent antibodies, human antibodies, humanized antibodies, chimeric antibodies, CDR-grafted antibodies, primatized antibodies, Fab fragments, F(ab’) fragments, F(ab’)2 fragments, Fv fragments, single-chain FvFcs (scFv-Fc), single-chain Fvs (scFv), Dabs, nanobodies, anti-idiotypic (anti-Id) antibodies, and any other immunologically-reactive / antigen-binding molecules. In some embodiments, the antibody is a monoclonal antibody.

[0143] In some embodiments, the monoclonal antibody comprises a first, second, third and fourth chain. In some embodiments, the first and third chains each comprise a VH domain and the second and fourth chains each comprise a VL domain. In some embodiments, the first and third chains each further comprise a CHI domain, a hinge domain, and a Fc domain. In some embodiments, the second and fourth chains each further comprise a CL domain. The pairing of the VH and VL of the first and second chains together forms a single antigen-binding site that binds to LILRB4, and optionally to LILRB2, and the pairing of the VH and VL of the third and fourth chains together forms a single antigen-binding site specific for the same epitope(s). In some embodiments, the first and second chains are linked by one or more covalent disulfide bonds and the third and fourth chains are linked by one ormore covalent disulfide bonds. In some embodiments, the first and third chains are linked by one or more disulfide bonds.

[0144] However, the antibodies disclosed herein are not limited to full-length IgG like antibodies. Other immunologically reactive / antigen-binding molecules are also contemplated herein and a person of skill in the art can readily synthesize such molecules using the sequences and identified domains of the heavy and light chains of the antibodies disclosed herein. For example, in some embodiments, the monoclonal antibody comprises a first and second chain that associate together. In some embodiments, the first chain and second chain each comprises an scFv with specificity for an epitope on LILRB4, and optionally on LILRB2. An scFv comprises a variable heavy domain and variable light chain domain separated by a linker. In some embodiments, the linker is a glycine-serine linker. In some embodiments, the Fc domain of the first chain comprises knob mutations and the Fc domain of the second chain comprise hole mutations, or vice versa.

[0145] In some embodiments, the monoclonal antibodies disclosed herein contain various modifications, substitutions, additions, or deletions to the variable or binding regions of one or more arms of an antibody disclosed herein. In some embodiments, the monoclonal antibodies disclosed herein may contain substitutions or modifications of the constant region (i.e., the Fc domain). The antibodies disclosed herein may contain one or more additional amino acid residue substitutions, mutations and / or modifications, which result in a compound with preferred characteristics including, but not limited to: altered pharmacokinetics, increased serum half-life, increased binding affinity, reduced binding affinity, reduced immunogenicity; increased production, altered Fc ligand binding, enhanced or reduced ADCC or CDC activity, altered glycosylation and / or disulfide bonds and modified binding specificity.

[0146] Amino Acid Sequences of Anti-LILRB4 Antibodies

[0147] In certain aspects, the subject matter disclosed herein provides a monoclonal antibody, or an antigen-binding fragment thereof, comprising (i) a heavy chain (HC) variable domain (VH) and (ii) a light chain (LC) variable domain (VL); wherein the antibody binds leukocyte immunoglobulin-like receptor 4 (LILRB4). In some embodiments, the antibody is also capable of binding leukocyte immunoglobulin-like receptor 2 (LILRB2). In some embodiments, the LILRB2 / LILRB4 cross-reactive antibodies disclosed herein show improved in vivo activity over LILRB4 selective monoclonal antibodies. In some embodiments, the LILRB2 / LILRB4 cross-reactive antibodies disclosed herein show improved in vivo activity over antibody h52b8. In some embodiments, the LILRB4 selectivemonoclonal antibodies disclosed herein show improvement in tumor growth inhibition compared to h52B8. In some embodiments, antibodies disclosed herein show improvement over h52B8 in cell-based assays, such as in reducing immune suppressive LILRB4+ myeloid cells following treatment with one or more of the antibodies disclosed herein.

[0148] In some embodiments, the antibody comprises two polypeptide heavy chains each comprising a variable heavy chain (VH) domain, CHI domain, a hinge domain, a Fc domain (CH2-CH3), and two polypeptide light chains comprising a variable light chain (VL) domain and a CL domain.

[0149] In some embodiments, the amino acid sequence of the antibody VH domain comprises SEQ ID NO: 22. In some embodiments, the amino acid sequence of the antibody heavy chain comprises a signal peptide immediately followed by SEQ ID NO: 22. In some embodiments, the signal peptide is cleaved during post-translational modifications that occur in vitro or in vivo, In some embodiments, a nucleic acid sequence encoding the amino acid sequence of the antibody heavy chain comprises a nucleic acid sequence encoding a signal peptide immediately followed by a nucleic acid sequence encoding SEQ ID NO: 22.

[0150] In some embodiments, the antibody comprises a polypeptide heavy chain comprising a variable heavy chain (VH) domain comprising SEQ ID NO: 22 followed by a constant region comprising a CHI domain, a hinge domain, a Fc domain (CH2-CH3). In some embodiments the constant region comprises a CHI domain, a hinge domain, and a Fc domain (CH2-CH3) of a human IgGI, IgG2, IgG3, or IgG4 constant region. In some embodiments the constant region comprises a CHI domain, a hinge domain, and a Fc domain (CH2-CH3) of a human IgGI constant region. In some embodiments, the antibody comprises a polypeptide heavy chain comprising SEQ ID NO: 34.

[0151] In some embodiments, the amino acid sequence of the antibody VL domain comprises SEQ ID NO: 64. In some embodiments, the amino acid sequence of the antibody light chain comprises a signal peptide immediately followed by SEQ ID NO: 64. In some embodiments, the signal peptide is cleaved during post-translational modifications that occur in vitro or in vivo. In some embodiments, a nucleic acid sequence encoding the amino acid sequence of the antibody light chain comprises a nucleic acid sequence encoding a signal peptide immediately followed by a nucleic acid sequence encoding SEQ ID NO: 64.

[0152] In some embodiments, the antibody comprises a polypeptide light chain comprising a variable light chain (VL) domain comprising SEQ ID NO: 64 followed by a constant region comprising a CL domain. In some embodiments the constant region comprises a CL domain of a human Ig kappa chain or Ig lambda chain. In someembodiments the constant region comprises a CL of a human Ig kappa chain. In some embodiments, the antibody comprises a polypeptide light chain comprising SEQ ID NO: 76.

[0153] In some embodiments, the monoclonal antibody comprises a first and third chain each comprising SEQ ID NO: 22 and a second and fourth chains each comprising SEQ ID NO: 64. In some embodiments, the monoclonal antibody comprises a first and third chain each comprising SEQ ID NO: 22 followed by a constant region comprising a CHI domain, a hinge domain, a Fc domain (CH2-CH3) and a second and fourth chains each comprising SEQ ID NO: 64 followed by a constant region comprising a CL domain, wherein the constant region of the first and third chain comprises a CHI domain, a hinge domain, and a Fc domain (CH2-CH3) of a human IgGl, IgG2, IgG3, or IgG4 constant region and the constant region of the second and fourth chain comprises a CL domain of a human Ig kappa chain or Ig lambda chain. In some embodiments, the monoclonal antibody comprises a first and third chain each comprising SEQ ID NO: 34 and a second and fourth chains each comprising SEQ ID NO: 76. In some embodiments, the first and second chains are linked by one or more covalent disulfide bonds and the third and fourth chains are linked by one or more covalent disulfide bonds. In some embodiments, the first and third chains are linked by one or more disulfide bonds.

[0154] In some embodiments, the antibody heavy chain comprises a VH domain comprising an amino acid sequence 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94,95, 96, 97, 98 or 99 % identical to SEQ ID NO: 22. In some embodiments, the antibody light chain comprises a VL domain comprising an amino acid sequence 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99 % identical to SEQ ID NO: 64. In some embodiments, the antibody heavy chain comprises an amino acid sequence 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99 % identical to SEQ ID NO: 34. In some embodiments, the antibody light chain comprises an amino acid sequence 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99 % identical to SEQ ID NO: 76.

[0155] In some embodiments, the antibody heavy' chain comprises a VH domain comprising CDR sequences SEQ ID NO: 4 (CDR-H1), SEQ ID NO: 5 (CDR-H2), and SEQ ID NO: 6 (CDR-H3). In some embodiments, the framework regions (FRs) of the VH domain comprise an amino acid sequence 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95,96, 97, 98 or 99 % identical to the FRs of SEQ ID NO: 22. In some embodiments, the VH domain comprises FRs of a human IGHV 1 gene, In some embodiments, the VH domain comprises FRs of a human IGHV 1-8 gene. In some embodiments, the antibody heavy chainfurther comprises a constant region comprising a CHI domain, a hinge domain, a Fc domain (CH2-CH3). In some embodiments the constant region comprises a CHI domain, a hinge domain, and a Fc domain (CH2-CH3) of a human IgGl, IgG2, IgG3, or IgG4 constant region. In some embodiments the constant region comprises a CHI domain, a hinge domain, and a Fc domain (CH2-CH3) of a human IgGl constant region. In some embodiments, the antibody comprises a constant region comprising a CHI domain, a hinge domain, a Fc domain (CH2-CH3) of SEQ ID NO: 34.

[0156] In some embodiments, the antibody light chain comprises a VL domain comprising CDR sequences SEQ ID NO: 46 (CDR-L1), SEQ ID NO: 47 (CDR-L2), and SEQ ID NO: 48 (CDR-L3). In some embodiments, the framework regions (FRs) of the VL domain comprise an amino acid sequence 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99 % identical to the FRs of SEQ ID NO: 64. In some embodiments, the VL domain comprises FRs of a human IGKV1 gene. In some embodiments, the VL domain comprises FRs of a human IGKV1-17 gene. In some embodiments, the antibody light chain further comprises a constant region comprising a CL domain. In some embodiments the constant region comprises a CL domain of a human Ig kappa chain or Ig lambda chain. In some embodiments the constant region comprises a CL of a huma Ig kappa chain. In some embodiments, the antibody comprises a CL domain of SEQ ID NO: 76.

[0157] In some embodiments, the antibody heavy chain comprises a VH domain comprising CDR sequences SEQ ID NO: 4 (CDR-H1), SEQ ID NO: 5 (CDR-H2), and SEQ ID NO: 6 (CDR-H3) and the antibody light chain comprises a VL domain comprising CDR sequences SEQ ID NO: 46 (CDR-L1), SEQ ID NO: 47 (CDR-L2), and SEQ ID NO: 48 (CDR-L3). In some embodiments, the framework regions (FRs) of the VH domain and the FRs of the variable light chain domain of the antibody comprise an amino acid sequence 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99 % identical to the FRs of SEQ ID NO: 22 and SEQ ID NO: 64, respectively, In some embodiments, the VH domain comprises FRs of a human IGHV1 gene and FRs of a human IGKV1 gene. In some embodiments, the VH domain comprises FRs of a human IGHV1-8 gene and FRs of a human IGKV1-17 gene. In some embodiments, the antibody heavy chain further comprises a constant region comprising a CHI domain, a hinge domain, a Fc domain (CH2-CH3). In some embodiments the constant region comprises a CHI domain, a hinge domain, and a Fc domain (CH2-CH3) of a human IgGl, IgG2, IgG3, or IgG4 constant region. In some embodiments the constant region comprises a CHI domain, a hinge domain, and a Fc domain (CH2-CH3) of a human IgGl constant region. In some embodiments, the antibody comprisesa constant region comprising a CHI domain, a hinge domain, a Fc domain (CH2-CH3) of SEQ ID NO: 34. In some embodiments, the antibody light chain further comprises a constant region comprising a CL domain. In some embodiments the constant region comprises a CL domain of a human Ig kappa chain or Ig lambda chain. In some embodiments the constant region comprises a CL of a huma Ig kappa chain. In some embodiments, the antibody comprises a CL domain of SEQ ID NO: 76.

[0158] In some embodiments, the monoclonal antibody comprises a first and third chain each comprising a VH domain comprising CDR sequences SEQ ID NO: 4 (CDR-H1), SEQ ID NO: 5 (CDR-H2), and SEQ ID NO: 6 (CDR-H3) and a second and fourth chains each comprising a VL domain comprising CDR sequences SEQ ID NO: 46 (CDR-L1), SEQ ID NO: 47 (CDR-L2), and SEQ ID NO: 48 (CDR-L3). In some embodiments, the monoclonal antibody comprises a first and third chain each comprising a VH domain comprising CDR sequences SEQ ID NO: 4 (CDR-H1), SEQ ID NO: 5 (CDR-H2), and SEQ ID NO: 6 (CDR- H3) followed by a constant region comprising a CHI domain, a hinge domain, a Fc domain (CH2-CH3) and a second and fourth chains each comprising a VL domain comprising CDR sequences SEQ ID NO: 46 (CDR-L1), SEQ ID NO: 47 (CDR-L2), and SEQ ID NO: 48 (CDR-L3) followed by a constant region comprising a CL domain, wherein the constant region of the first and third chain comprises a CHI domain, a hinge domain, and a Fc domain (CH2-CH3) of a human IgGl, IgG2, IgG3, or IgG4 constant region and the constant region of the second and fourth chain comprises a CL domain of a human Ig kappa chain or Ig lambda chain. In some embodiments, the framework regions (FRs) of the VH domains comprise an amino acid sequence 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99 % identical to the FRs of SEQ ID NO: 22. In some embodiments, the VH domains comprises FRs of a human IGHV1 gene. In some embodiments, the VH domains comprises FRs of a human IGHV1-8 gene. In some embodiments, the framework regions (FRs) of the VL domains comprise an amino acid sequence 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99 % identical to the FRs of SEQ ID NO: 64. In some embodiments, the VL domains comprises FRs of a human IGKV1 gene. In some embodiments, the VL domains comprises FRs of a human IGKV1-17 gene. In some embodiments, the first and second chains are linked by one or more covalent disulfide bonds and the third and fourth chains are linked by one or more covalent disulfide bonds, In some embodiments, the first and third chains are linked by one or more disulfide bonds.

[0159] In some embodiments, one or more amino acids of an amino acid sequence encoding one or more CDRs of SEQ ID NO: 22 or SEQ ID NO: 64 is substituted. In someembodiments, one or more amino acids of an amino acid sequence encoding one or more variable heavy chain CDRs of SEQ ID NO: 22 is substituted. In some embodiments, one or more amino acids of an amino acid sequence encoding one or more variable light chain CDRs of SEQ ID NO: 64 is substituted.

[0160] In some embodiments, the antibody heavy chain comprises a VH comprising a heavy' chain CDR1 having a sequence identity of at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 4, a heavy chain CDR2 having a sequence identity of at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 5, a heavy chain CDR3 having a sequence identity of at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 6 and the antibody light chain comprises a VL comprising a light chain CDR1 having a sequence identity of at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 46, a light chain CDR2 having a sequence identity of at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 47, and a light chain CDR3 having a sequence identity of at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 48.

[0161] In some embodiments, the antibody lacks effector function. In some embodiments, the antibody is a blocking antibody.

[0162] In some embodiments, the antibodies disclosed herein bind LILRB4 with an equilibrium dissociation constant (KD) from about 10-7M to about 10-11M. In some embodiments, the KD is 1 O'9to about 10-10. In some embodiments, the antibody binds LILRB4 with an association constant from about 105Ms-1to about 106Ms’i. In some embodiments, the antibody binds LILRB4 with a dissociation constant from about 10-2s-1to about 10-5s-1. In some embodiments, the antibody binds LILRB4 with a dissociation constant from about 10'3s-1to about 10'4s-1.

[0163] In some embodiments, the LILRB4 is a human LILRB4. In some embodiments, the LILRB4 is a cynomolgus macaque LILRB4. In some embodiments, the LILRB4 is a mouse ortholog of LILRB4. In some embodiments, the anti-LILRB4 antibody inhibits a LILRB4-dependent immune checkpoint. In some embodiments, the antibody depletes LILRB4- monocytes. In some embodiments, the antibody does not deplete immune- supporting myeloid populations. In some embodiments, the antibody is engineered by B-cell cloning.

[0164] In certain embodiments described and depicted in this disclosure, an antibody comprising a dimer of the heterodimer comprising SEQ ID NO: 34 and SEQ ID NO: 76 is represented by antibody “ATX-P-2652” or “BT-2652”.

[0165] Exemplary nucleic acid sequences encoding the antibodies described herein, or portions thereof are provided as SEQ ID NOs: 21 (VH), 33 (HC), 63 (VL) and 75 (LC). A person skilled in the art can identify the nucleic acid sequences encoding the features identified in the corresponding amino acid sequences (e.g., CDRs, variable heavy domain, variable light domain, CHI domain, hinge domain, Fc domain, CL domain) by translating the nucleic acid sequences into amino acid sequences. In some embodiments, the nucleic acid sequences may be codon optimized.

[0166] In some embodiments, the nucleic acid sequence encoding an VH domain comprise a nucleic acid sequence 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99 % identical to SEQ ID NO: 21. In some embodiments, the nucleic acid sequence encoding an heavy chain comprise a nucleic acid sequence 80, 81, 82, 83, 84, 85,86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99 % identical to SEQ ID NO: 33. In some embodiments, the nucleic acid sequence encoding an VL domain comprise a nucleic acid sequence 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99 % identical to SEQ ID NO: 63. In some embodiments, the nucleic acid sequence encoding a light chain comprise a nucleic acid sequence 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99 % identical to SEQ ID NO: 75. In some embodiments, the nucleic acid sequence encoding framework regions (FRs) of the VH domain and the FRs of the VL domain of the antibody comprise a nucleic acid sequence 80, 81, 82, 83, 84, 85, 86,87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99 % identical to the sequence encoding the FRs of SEQ ID NO: 21 and SEQ ID NO: 63, respectively.

[0167] A person of ordinary skill in the art would readily recognize that a monoclonal antibody of the present invention is comprised of any of the antibodies disclosed in FIG. 14. In some embodiments, the amino acid sequence of the antibody VH domain comprises SEQ ID NO: 24, 26, 104, 106, 110, or 114. In some embodiments, the amino acid sequence of the antibody heavy chain comprises a signal peptide immediately followed by SEQ ID NO: 24, 26, 104, 106, 110, or 114. In some embodiments, the signal peptide is cleaved during post- translational modifications that occur in vitro or in vivo. In some embodiments, a nucleic acid sequence encoding the amino acid sequence of the antibody heavy chain comprises a nucleic acid sequence encoding a signal peptide immediately followed by a nucleic acid sequence encoding SEQ ID NO: 24, 26, 104, 106, 110, or 114.

[0168] In some embodiments, the antibody comprises a polypeptide heavy chain comprising a variable heavy chain (VH) domain comprising SEQ ID NO: 24, 26, 104, 106, 110, or 114 followed by a constant region comprising a CHI domain, a hinge domain, a Fc domain (CH2-CH3). In some embodiments the constant region comprises a CHI domain, a hinge domain, and a Fc domain (CH2-CH3) of a human IgGl, IgG2, IgG3, or IgG4 constant region. In some embodiments the constant region comprises a CHI domain, a hinge domain, and a Fc domain (CH2-CH3) of a human IgGl constant region. In some embodiments, the antibody comprises a polypeptide heavy chain comprising SEQ ID NO: 36, 38, 116, 118, 122, or 126.

[0169] In some embodiments, the amino acid sequence of the antibody VL domain comprises SEQ ID NO: 66, 68, 146, 148, 152, or 156. In some embodiments, the amino acid sequence of the antibody light chain comprises a signal peptide immediately followed by SEQ ID NO: 66, 68, 146, 148, 152, or 156. In some embodiments, the signal peptide is cleaved during post-translational modifications that occur in vitro or in vivo. In some embodiments, a nucleic acid sequence encoding the amino acid sequence of the antibody light chain comprises a nucleic acid sequence encoding a signal peptide immediately followed by a nucleic acid sequence encoding SEQ ID NO: 66, 68, 146, 148, 152, or 156.

[0170] In some embodiments, the antibody comprises a polypeptide light chain comprising a variable light chain (VL) domain comprising SEQ ID NO: 66, 68, 146, 148, 152, or 156 followed by a constant region comprising a CL domain. In some embodiments the constant region comprises a CL domain of a human Ig kappa chain or Ig lambda chain. In some embodiments the constant region comprises a CL of a human Ig kappa chain. In some embodiments, the antibody comprises a polypeptide light chain comprising SEQ ID NO: 78, 80, 158, 160, 164, or 168.

[0171] In some embodiments, the monoclonal antibody comprises a first and third chain each comprising SEQ ID NO: 24, 26, 104, 106, 110, or 114 and a second and fourth chains each comprising SEQ ID NO: 66, 68, 146, 148, 152, or 156. In some embodiments, the monoclonal antibody comprises a first and third chain each comprising SEQ ID NO: 24, 26, 104, 106, 110, or 114 followed by a constant region comprising a CHI domain, a hinge domain, a Fc domain (CH2-CH3) and a second and fourth chains each comprising SEQ ID NO: 66, 68, 146, 148, 152, or 156 followed by a constant region comprising a CL domain, wherein the constant region of the first and third chain comprises a CHI domain, a hinge domain, and a Fc domain (CH2-CH3) of a human IgGl, IgG2, IgG3, or IgG4 constant region and the constant region of the second and fourth chain comprises a CL domain of a human Igkappa chain or Ig lambda chain. In some embodiments, the monoclonal antibody comprises a first and third chain each comprising SEQ ID NO: 36, 38, 116, 118, 122, or 126 and a second and fourth chains each comprising SEQ ID NO: 78, 80, 158, 160, 164, or 168. In some embodiments, the first and second chains are linked by one or more covalent disulfide bonds and the third and fourth chains are linked by one or more covalent disulfide bonds. In some embodiments, the first and third chains are linked by one or more disulfide bonds. A person of skill in the art understands the sequences used for the first and third and second and fourth chains are paired according to their antibody designation in FIG. 14 (e.g., SEQ ID NOs: 24 and 66 etc.)

[0172] In some embodiments, the antibody heavy chain comprises a VH domain comprising an amino acid sequence 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99 % identical to SEQ ID NO: 24, 26, 104, 106, 110, or 114. In some embodiments, the antibody light chain comprises a VL domain comprising an amino acid sequence 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99 % identical to SEQ ID NO: 66, 68, 146, 148, 152, or 156. In some embodiments, the antibody heavy chain comprises an amino acid sequence 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91,92, 93, 94, 95, 96, 97, 98 or 99 % identical to SEQ ID NO: 36, 38, 116, 118, 122, or 126. In some embodiments, the antibody light chain comprises an amino acid sequence 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99 % identical to SEQ ID NO: 78, 80, 158, 160, 164, or 168.

[0173] In some embodiments, the antibody heavy chain comprises a VH domain comprising CDR sequences designated in FIG. 14 (e.g., SEQ ID NOs 7-9, 10-12, 85-87, 88- 90, 94-96, or 100-102). In some embodiments, the framework regions (FRs) of the VH domain comprise an amino acid sequence 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92,93, 94, 95, 96, 97, 98 or 99 % identical to the FRs of SEQ ID NO: 24, 26, 104, 106, 110, or114 for the VH corresponding to the antibody designation in FIG.14. In some embodiments, the VH domain comprises FRs of a human IGH gene corresponding to the antibody designation in FIG.14. In some embodiments, the antibody heavy chain further comprises a constant region comprising a CHI domain, a hinge domain, a Fc domain (CH2-CH3). In some embodiments the constant region comprises a CHI domain, a hinge domain, and a Fc domain (CH2-CH3) of a human IgGl, IgG2, IgG3, or IgG4 constant region. In some embodiments the constant region comprises a CH 1 domain, a hinge domain, and a Fc domain (CH2-CH3) of a human IgG l constant region. In some embodiments, the antibody comprises a constant region comprising a CHI domain, a hinge domain, a Fc domain (CH2-CH3) ofSEQ ID NO: 36, 38, 116, 118, 122, or 126 corresponding to the antibody designation in FIG.14.

[0174] In some embodiments, the antibody light chain comprises a VL domain comprising CDR sequences designated in FIG. 14 (e.g., SEQ ID NOs 49-51, 52-54, 127-129, 130-132, 136-138, 142-144). In some embodiments, the framework regions (FRs) of the VL domain comprise an amino acid sequence 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99 % identical to the FRs of SEQ ID NO: 66, 68, 146, 148, 152, or 156 for the VL corresponding to the antibody designation in FIG.14. In some embodiments, the VL domain comprises FRs of a human IGK gene corresponding to the antibody designation in FIG.14. In some embodiments, the antibody light chain further comprises a constant region comprising a CL domain. In some embodiments the constant region comprises a CL domain of a human Ig kappa chain or Ig lambda chain. In some embodiments the constant region comprises a CL of a human Ig kappa chain. In some embodiments, the antibody comprises a CL domain of SEQ ID NO: 78, 80, 158, 160, 164, or 168 corresponding to the antibody designation in FIG.14.

[0175] In some embodiments, the antibody heavy chain comprises a VH domain comprising CDR sequences designated in FIG. 14 (e.g., SEQ ID NOs 7-9, 10-12, 85-87, 88- 90, 94-96, or 100-102) and the antibody light chain comprises a VL domain comprising CDR sequences designated in FIG. 14 (e.g., SEQ ID NOs 49-51, 52-54, 127-129, 130-132, BOBS, 142-144). In some embodiments, the framework regions (FRs) of the VH domain and the FRs of the variable light chain domain of the antibody comprise an amino acid sequence 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99 % identical to the FRs of SEQ ID NO: 24, 26, 104, 106, 110, or 114 for the VH corresponding to the antibody designation in FIG.14 and SEQ ID NO: 66, 68, 146, 148, 152, or 156 for the VL corresponding to the antibody designation in FIG. 14, respectively. In some embodiments, the VH domain comprises FRs of a human IGH gene and FRs of a human IGK gene corresponding to the antibody designation in FIG.14. In some embodiments, the antibody heavy chain further comprises a constant region comprising a CHI domain, a hinge domain, a Fc domain (CH2-CH3). In some embodiments the constant region comprises a CHI domain, a hinge domain, and a Fc domain (CH2-CH3) of a human IgGl, IgG2, IgG3, or IgG4 constant region. In some embodiments the constant region comprises a CHI domain, a hinge domain, and a Fc domain (CH2-CH3) of a human IgGl constant region. In some embodiments, the antibody comprises a constant region comprising a CHI domain, a hinge domain, a Fc domain (CH2-CH3) of SEQ ID NO: 36, 38, 116, 118, 122, or 126corresponding to the antibody designation in FIG.14. In some embodiments, the antibody light chain further comprises a constant region comprising a CL domain. In some embodiments the constant region comprises a CL domain of a human Ig kappa chain or Ig lambda chain. In some embodiments the constant region comprises a CL of a huma Ig kappa chain. In some embodiments, the antibody comprises a CL domain of SEQ ID NO: 78, 80, 158, 160, 164, or 168 corresponding to the antibody designation in FIG.14.

[0176] In some embodiments, the monoclonal antibody comprises a first and third chain each comprising a VH domain comprising CDR sequences designated in FIG. 14 (e.g., SEQ ID NOs 7-9, 10-12, 85-87, 88-90, 94-96, or 100-102) and a second and fourth chains each comprising a VL domain comprising CDR sequences designated in FIG. 14 (e.g., SEQ ID NOs 49-51, 52-54, 127-129, 130-132, 136-138, 142-144). In some embodiments, the monoclonal antibody comprises a first and third chain each comprising a VH domain comprising CDR sequences designated in FIG. 14 (e.g., SEQ ID NOs 7-9, 10-12, 85-87, 88- 90, 94-96, or 100-102) followed by a constant region comprising a CHI domain, a hinge domain, a Fc domain (CH2-CH3) and a second and fourth chains each comprising a VL domain comprising CDR sequences designated in FIG. 14 (e.g., SEQ ID NOs 49-51, 52-54, 127-129, 130-132, 136-138, 142-144) followed by a constant region comprising a CL domain, wherein the constant region of the first and third chain comprises a CHI domain, a hinge domain, and a Fc domain (CH2-CH3) of a human IgGl, IgG2, IgG3, or IgG4 constant region and the constant region of the second and fourth chain comprises a CL domain of a human Ig kappa chain or Ig lambda chain. In some embodiments, the framework regions (FRs) of the VH domains comprise an amino acid sequence 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99 % identical to the FRs of SEQ ID NO: 24, 26, 104, 106, 110, or 114 for the VH corresponding to the antibody designation in FIG.14. In some embodiments, the VH domains comprises FRs of a human IGH gene corresponding to the antibody designation in FIG.14. In some embodiments, the framework regions (FRs) of the VL domains comprise an amino acid sequence 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99 % identical to the FRs of SEQ ID NO: 66, 68, 146, 148, 152, or 156 for the VL corresponding to the antibody designation in FIG.14. In some embodiments, the VL domains comprises FRs of a human IGK gene corresponding to the antibody designation in FIG.14. In some embodiments, the first and second chains are linked by one or more covalent disulfide bonds and the third and fourth chains are linked by one or more covalent disulfide bonds, In some embodiments, the first and third chains are linked by one or more disulfide bonds.

[0177] In some embodiments, one or more amino acids of an amino acid sequence encoding one or more CDRs of FIG. 14 is substituted. In some embodiments, one or more amino acids of an amino acid sequence encoding one or more variable heavy chain CDRs of FIG. 14 is substituted. In some embodiments, one or more amino acids of an amino acid sequence encoding one or more variable light chain CDRs of FIG. 14 is substituted.

[0178] In some embodiments, the antibody heavy chain comprises a VH comprising a heavy chain CDR1, CDR2, and / or CDR3 having a sequence identity of at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to HCDR sequences designated in FIG. 14 (e.g., SEQ ID NOs 7-9, 10-12, 85-87, 88-90, 94-96, or 100-102) and the antibody light chain comprises a VL comprising a light chain CDR1, CDR2, and / or CDR3 having a sequence identity of at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to LCDR sequences designated in FIG. 14 (SEQ ID NOs 49-51, 52-54, 127-129, 130-132, 136-138, 142-144).

[0179] In some embodiments, the antibody lacks effector function. In some embodiments, the antibody is a blocking antibody.

[0180] In some embodiments, the antibodies disclosed herein bind LILRB4 with an equilibrium dissociation constant (KD) from about 10-7M to about 10-11M. In some embodiments, the KD is 10'9to about 10-10. In some embodiments, the antibody binds LILRB4 with an association constant from about 105Ms-1to about 106Ms-1. In some embodiments, the antibody binds LILRB4 with a dissociation constant from about 10-2s-1to about 10-5s-1. In some embodiments, the antibody binds LILRB4 with a dissociation constant from about 10-3s-1to about 10-4s-1.

[0181] In some embodiments, the LILRB4 is a human LILRB4. In some embodiments, the LILRB4 is a cynomolgus macaque LILRB4. In some embodiments, the LILRB4 is a mouse ortholog of LILRB4. In some embodiments, the anti-LILRB4 antibody inhibits a LILRB4-dependent immune checkpoint. In some embodiments, the antibody depletes LILRB4+ monocytes. In some embodiments, the antibody does not deplete immune- supporting myeloid populations, In some embodiments, the antibody is engineered by B-cell cloning.

[0182] Exemplary nucleic acid sequences encoding the antibodies described herein, or portions thereof are provided in FIG. 14. A person skilled in the art can identify the nucleic acid sequences encoding the features identified in the corresponding amino acid sequences (e.g., CDRs, variable heavy domain, variable light domain, CHI domain, hinge domain, Fcdomain, CL domain) by translating the nucleic acid sequences into amino acid sequences. In some embodiments, the nucleic acid sequences may be codon optimized.

[0183] In some embodiments, the nucleic acid sequence encoding an VH domain comprise a nucleic acid sequence 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99 % identical to the nucleotide sequences provided in FIG. 14. In some embodiments, the nucleic acid sequence encoding an heavy chain comprise a nucleic acid sequence 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99 % identical to the nucleotide sequences provided in FIG. 14. In some embodiments, the nucleic acid sequence encoding an VL domain comprise a nucleic acid sequence 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99 % identical to the nucleotide sequences provided in FIG. 14. In some embodiments, the nucleic acid sequence encoding a light chain comprise a nucleic acid sequence 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99 % identical to the nucleotide sequences provided in FIG. 14.

[0184] Amino Acid Sequences of Anti-LILRB4 / LILRB2 Antibodies

[0185] In certain aspects, the subject matter disclosed herein provides a monoclonal antibody, or an antigen-binding fragment thereof, comprising (i) a heavy chain (HC) variable domain (VH) and (ii) a light chain (LC) variable domain (VL); wherein the antibody is capable of binding to leukocyte immunoglobulin-like receptor 4 (LILRB4) and LILRB2. In some embodiments, the antibody is cross-reactive to LILRB4 and LILRB2, which refers to the ability of an antibody to react with similar antigenic sites on different proteins. For example, a cross-reactive antibody can mean that such an antibody can cross-react (i.e., bind to an epitope) on LILRB4 and LILRB2, rather than specifically binding only LILRB4 or LILRB2. Thus, in some embodiments, the antibody binds to LILRB4 and in some embodiments, the antibody binds to LILRB2.

[0186] In some embodiments, the antibody comprises two polypeptide heavy chains each comprising a variable heavy chain (VH) domain, CHI domain, a hinge domain, a Fc domain (CH2-CH3), and two polypeptide light chains comprising a variable light chain (VL) domain and a CL domain.

[0187] In some embodiments, the amino acid sequence of the antibody VH domain comprises SEQ ID NO: 28. In some embodiments, the amino acid sequence of the antibody heavy chain comprises a signal peptide immediately followed by SEQ ID NO: 28. In some embodiments, the signal peptide is cleaved during post-translational modifications that occur in vitro or in vivo. In some embodiments, a nucleic acid sequence encoding the amino acidsequence of the antibody heavy chain comprises a nucleic acid sequence encoding a signal peptide immediately followed by a nucleic acid sequence encoding SEQ ID NO: 28.

[0188] In some embodiments, the antibody comprises a polypeptide heavy chain comprising a variable heavy chain (VH) domain comprising SEQ ID NO: 28 followed by a constant region comprising a CHI domain, a hinge domain, a Fc domain (CH2-CH3). In some embodiments the constant region comprises a CHI domain, a hinge domain, and a Fc domain (CH2-CH3) of a human IgGl, IgG2, IgG3, or IgG4 constant region. In some embodiments the constant region comprises a CHI domain, a hinge domain, and a Fc domain (CH2-CH3) of a human IgGl constant region. In some embodiments, the antibody comprises a polypeptide heavy chain comprising SEQ ID NO: 40.

[0189] In some embodiments, the amino acid sequence of the antibody VL domain comprises SEQ ID NO: 70. In some embodiments, the amino acid sequence of the antibody light chain comprises a signal peptide immediately followed by SEQ ID NO: 70. In some embodiments, the signal peptide is cleaved during post-translational modifications that occur in vitro or in vivo. In some embodiments, a nucleic acid sequence encoding the amino acid sequence of the antibody light chain comprises a nucleic acid sequence encoding a signal peptide immediately followed by a nucleic acid sequence encoding SEQ ID NO: 70.

[0190] In some embodiments, the antibody comprises a polypeptide light chain comprising a variable light chain (VL) domain comprising SEQ ID NO: 70 followed by a constant region comprising a CL domain. In some embodiments the constant region comprises a CL domain of a human Ig kappa chain or Ig lambda chain. In some embodiments the constant region comprises a CL of a human Ig kappa chain. In some embodiments, the antibody comprises a polypeptide light chain comprising SEQ ID NO: 82.

[0191] In some embodiments, the monoclonal antibody comprises a first and third chain each comprising SEQ ID NO: 28 and a second and fourth chains each comprising SEQ ID NO: 70. In some embodiments, the monoclonal antibody comprises a first and third chain each comprising SEQ ID NO: 28 followed by a constant region comprising a CHI domain, a hinge domain, a Fc domain (CH2-CH3) and a second and fourth chains each comprising SEQ ID NO: 70 followed by a constant region comprising a CL domain, wherein the constant region of the first and third chain comprises a CHI domain, a hinge domain, and a Fc domain (CH2-CH3) of a human IgGl, IgG2, IgG3, or IgG4 constant region and the constant region of the second and fourth chain comprises a CL domain of a human Ig kappa chain or Ig lambda chain. In some embodiments, the monoclonal antibody comprises a first and third chain each comprising SEQ ID NO: 40 and a second and fourth chains each comprising SEQ ID NO: 82.In some embodiments, the first and second chains are linked by one or more covalent disulfide bonds and the third and fourth chains are linked by one or more covalent disulfide bonds. In some embodiments, the first and third chains are linked by one or more disulfide bonds.

[0192] In some embodiments, the antibody heavy chain comprises a VH domain comprising an amino acid sequence 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99 % identical to SEQ ID NO: 28. In some embodiments, the antibody light chain comprises a VL domain comprising an amino acid sequence 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99 % identical to SEQ ID NO: 70. In some embodiments, the antibody heavy chain comprises an amino acid sequence 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99 % identical to SEQ ID NO: 40. In some embodiments, the antibody light chain comprises an amino acid sequence 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99 % identical to SEQ ID NO: 82.

[0193] In some embodiments, the antibody heavy chain comprises a VH domain comprising CDR sequences SEQ ID NO: 13 (CDR-H1), SEQ ID NO: 14 (CDR-H2), and SEQ ID NO: 15 (CDR-H3). In some embodiments, the framework regions (FRs) of the VH domain comprise an amino acid sequence 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99 % identical to the FRs of SEQ ID NO: 28. In some embodiments, the VH domain comprises FRs of a human IGHV6 gene. In some embodiments, the VH domain comprises FRs of a human IGHV6-1 gene. In some embodiments, the antibody heavy chain further comprises a constant region comprising a CHI domain, a hinge domain, a Fc domain (CH2-CH3). In some embodiments the constant region comprises a CHI domain, a hinge domain, and a Fc domain (CH2-CH3) of a human IgGl , IgG2, IgG3, or IgG4 constant region. In some embodiments the constant region comprises a CHI domain, a hinge domain, and a Fc domain (CH2-CH3 ) of a human IgGl constant region. In some embodiments, the antibody comprises a constant region comprising a CHI domain, a hinge domain, a Fc domain (CH2-CH3) of SEQ ID NO: 40.

[0194] In some embodiments, the antibody light chain comprises a VL domain comprising CDR sequences SEQ ID NO: 55 (CDR-L1), SEQ ID NO: 56 (CDR-L2), and SEQ ID NO: 57 (CDR-L3). In some embodiments, the framework regions (FRs) of the VL domain comprise an amino acid sequence 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99 % identical to the FRs of SEQ ID NO: 70. In some embodiments, the VL domain comprises FRs of a human IGKV1 gene. In some embodiments, the VLdomain comprises FRs of a human IGKV1-5 gene. In some embodiments, the antibody light chain further comprises a constant region comprising a CL domain. In some embodiments the constant region comprises a CL domain of a human Ig kappa chain or Ig lambda chain. In some embodiments the constant region comprises a CL of a huma Ig kappa chain. In some embodiments, the antibody comprises a CL domain of SEQ ID NO: 82.

[0195] In some embodiments, the antibody heavy chain comprises a VH domain comprising CDR sequences SEQ ID NO: 13 (CDR-H1), SEQ ID NO: 14 (CDR-H2), and SEQ ID NO: 15 (CDR-H3) and the antibody light chain comprises a VL domain comprising CDR sequences SEQ ID NO: 55 (CDR-L1), SEQ ID NO: 56 (CDR-L2), and SEQ ID NO: 57 (CDR-L3). In some embodiments, the framework regions (FRs) of the VH domain and the FRs of the variable light chain domain of the antibody comprise an amino acid sequence 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99 % identical to the FRs of SEQ ID NO: 28 and SEQ ID NO: 70, respectively. In some embodiments, the VH domain comprises FRs of a human IGHV6 gene and FRs of a human IGKV1 gene. In some embodiments, the VH domain comprises FRs of a human IGHV6-1 gene and FRs of a human IGKV1-5 gene. In some embodiments, the antibody heavy chain further comprises a constant region comprising a CHI domain, a hinge domain, a Fc domain (CH2-CH3). In some embodiments the constant region comprises a CHI domain, a hinge domain, and a Fc domain (CH2-CH3) of a human IgGl, IgG2, IgG3, or IgG4 constant region. In some embodiments the constant region comprises a CHI domain, a hinge domain, and a Fc domain (CH2-CH3) of a human IgGl constant region. In some embodiments, the antibody comprises a constant region comprising a CHI domain, a hinge domain, a Fc domain (CH2-CH3) of SEQ ID NO: 40. In some embodiments, the antibody light chain further comprises a constant region comprising a CL domain. In some embodiments the constant region comprises a CL domain of a human Ig kappa chain or Ig lambda chain. In some embodiments the constant region comprises a CL of a huma Ig kappa chain. In some embodiments, the antibody comprises a CL domain of SEQ ID NO: 82.

[0196] In some embodiments, the monoclonal antibody comprises a first and third chain each comprising a VH domain comprising CDR sequences SEQ ID NO: 13 (CDR-H1), SEQ ID NO: 14 (CDR-H2), and SEQ ID NO: 15 (CDR-H3) and a second and fourth chains each comprising a VL domain comprising CDR sequences SEQ ID NO: 55 (CDR-Ll), SEQ ID NO: 56 (CDR-L2), and SEQ ID NO: 57 (CDR-L3). In some embodiments, the monoclonal antibody comprises a first and third chain each comprising a VH domain comprising CDR sequences SEQ ID NO: 13 (CDR-H1), SEQ ID NO: 14 (CDR-H2), and SEQ ID NO: 15(CDR-H3) followed by a constant region comprising a CHI domain, a hinge domain, a Fc domain (CH2-CH3) and a second and fourth chains each comprising a VL domain comprising CDR sequences SEQ ID NO: 55 (CDR-L1), SEQ ID NO: 56 (CDR-L2), and SEQ ID NO: 57 (CDR-L3) followed by a constant region comprising a CL domain, wherein the constant region of the first and third chain comprises a CHI domain, a hinge domain, and a Fc domain (CH2-CH3) of a human IgGl, IgG2, IgG3, or IgG4 constant region and the constant region of the second and fourth chain comprises a CL domain of a human Ig kappa chain or Ig lambda chain, In some embodiments, the framework regions (FRs) of the VH domains comprise an amino acid sequence 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99 % identical to the FRs of SEQ ID NO: 28. In some embodiments, the VH domains comprises FRs of a human IGHV6 gene. In some embodiments, the VH domains comprises FRs of a human IGHV6-1 gene. In some embodiments, the framework regions (FRs) of the VL domains comprise an amino acid sequence 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99 % identical to the FRs of SEQ ID NO: 70. In some embodiments, the VL domains comprises FRs of a human IGKV1 gene, In some embodiments, the VL domains comprises FRs of a human IGKV1-5 gene. In some embodiments, the first and second chains are linked by one or more covalent disulfide bonds and the third and fourth chains are linked by one or more covalent disulfide bonds. In some embodiments, the first and third chains are linked by one or more disulfide bonds.

[0197] In some embodiments, one or more amino acids of an amino acid sequence encoding one or more CDRs of SEQ ID NO: 28 or SEQ ID NO: 70 is substituted. In some embodiments, one or more amino acids of an amino acid sequence encoding one or more variable heavy chain CDRs of SEQ ID NO: 28 is substituted. In some embodiments, one or more amino acids of an amino acid sequence encoding one or more variable light chain CDRs of SEQ ID NO: 70 is substituted.

[0198] In some embodiments, the antibody heavy chain comprises a VH comprising a heavy chain CDR1 having a sequence identity of at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 13, a heavy chain CDR2 having a sequence identity of at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 14, a heavy chain CDR3 having a sequence identity of at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 15 and the antibody light chain comprises a VL comprising a light chain CDR1 having a sequence identity of at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 55, a light chain CDR2 having a sequence identity of at least 90%, 91%, 92%, 93%, 94%, 95%,96%, 97%, 98%, or 99% identity to SEQ ID NO: 56, and a light chain CDR3 having a sequence identity of at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 57.

[0199] In some embodiments, the antibody lacks effector function. In some embodiments, the antibody is a blocking antibody.

[0200] In some embodiments, the antibody binds LILRB4 with an equilibrium dissociation constant (KD) from about 10' ' M to about 10-11M and separately binds LILRB2 with an equilibrium dissociation constant (KD) from about 10-7M to about 10-11M. In some embodiments, the KD of binding LILRB4 or LILRB2 is from about 10’9M to about 10-10M. In some embodiments, the antibody binds LILRB4 with an association constant of about 105Ms-1and separately binds LILRB2 with an association constant of about ICC Ms-1. In some embodiments, the antibody binds LILRB4 with a dissociation constant from about 10-2s-1to about 10-5s-1and separately binds LILRB2 with a dissociation constant from about 10-2s-1to about 10-5s-1.

[0201] In some embodiments, the LILRB4 is a human LILRB4. In some embodiments, the LILRB4 is a cynomolgus macaque LILRB4. In some embodiments, the LILRB2 is a human LILRB2. In some embodiments, the LILRB2 is a cynomolgus macaque LILRB2. In some embodiments, the LILRB4 is a mouse ortholog of LILRB4. In some embodiments, the LILRB2 is a mouse ortho log of LILRB2.

[0202] In some embodiments, the anti-LILRB4 antibody inhibits a LILRB4-dependent immune checkpoint. In some embodiments, the anti-LILRB2 antibody inhibits a LILRB2- dependent immune checkpoint. In some embodiments, the antibody depletes LILRB4+ monocytes. In some embodiments, the antibody depletes LILRB2+ monocytes. In some embodiments, the antibody does not deplete immune-supporting myeloid populations.

[0203] In certain embodiments described and depicted in this disclosure, an antibody comprising a dimer of the heterodimer comprising SEQ ID NO: 40 and SEQ ID NO: 82 is represented by antibody “ATX-P-2671” or “BT-2671”.

[0204] Exemplary nucleic acid sequences encoding the antibodies described herein, or portions thereof are provided as SEQ ID NOs: 27 (VH), 39 (HC), 69 (VL) and 81 (EC). A person skilled in the art can identify the nucleic acid sequences encoding the features identified in the corresponding amino acid sequences (e.g., CDRs, variable heavy domain, variable light domain, CHI domain, hinge domain, Fc domain, CL domain) by translating the nucleic acid sequences into amino acid sequences. In some embodiments, the nucleic acid sequences may be codon optimized.

[0205] In some embodiments, the nucleic acid sequence encoding an VH domain comprise a nucleic acid sequence 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99 % identical to SEQ ID NO: 27. In some embodiments, the nucleic acid sequence encoding an heavy chain comprise a nucleic acid sequence 80, 81, 82, 83, 84, 85,86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99 % identical to SEQ ID NO: 39. In some embodiments, the nucleic acid sequence encoding an VL domain comprise a nucleic acid sequence 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99 % identical to SEQ ID NO: 69. In some embodiments, the nucleic acid sequence encoding a light chain comprise a nucleic acid sequence 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99 % identical to SEQ ID NO: 81. In some embodiments, the nucleic acid sequence encoding framework regions (FRs) of the VH domain and the FRs of the VL domain of the antibody comprise a nucleic acid sequence 80, 81, 82, 83, 84, 85, 86,87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99 % identical to the sequence encoding the FRs of SEQ ID NO: 27 and SEQ ID NO: 69, respectively.

[0206] A person of ordinary skill in the art would readily recognize that a monoclonal antibody of the present invention is comprised of any of the antibodies disclosed in FIG. 14. In some embodiments, the amino acid sequence of the antibody VH domain comprises SEQ ID NO: 20, 30, 108, or 112. In some embodiments, the amino acid sequence of the antibody heavy chain comprises a signal peptide immediately followed by SEQ ID NO: 20, 30, 108, or 112. In some embodiments, the signal peptide is cleaved during post-translational modifications that occur in vitro or in vivo. In some embodiments, a nucleic acid sequence encoding the amino acid sequence of the antibody heavy chain comprises a nucleic acid sequence encoding a signal peptide immediately followed by a nucleic acid sequence encoding SEQ ID NO: 20, 30, 108, or 112.

[0207] In some embodiments, the antibody comprises a polypeptide heavy chain comprising a variable heavy chain (VH) domain comprising SEQ ID NO: 20, 30, 108, or 112 followed by a constant region comprising a CHI domain, a hinge domain, a Fc domain (CH2-CH3). In some embodiments the constant region comprises a CHI domain, a hinge domain, and a Fc domain (CH2-CH3) of a human IgGl, IgG2, IgG3, or IgG4 constant region. In some embodiments the constant region comprises a CH 1 domain, a hinge domain, and a Fc domain (CH2-CH3) of a human IgGl constant region. In some embodiments, the antibody comprises a polypeptide heavy chain comprising SEQ ID NO: 32, 42, 120, or 124.

[0208] In some embodiments, the amino acid sequence of the antibody VL domain comprises SEQ ID NO: 62, 72, 150, or 154. In some embodiments, the amino acid sequenceof the antibody light chain comprises a signal peptide immediately followed by SEQ ID NO: 62, 72, 150, or 154. In some embodiments, the signal peptide is cleaved during post- translational modifications that occur in vitro or in vivo. In some embodiments, a nucleic acid sequence encoding the amino acid sequence of the antibody light chain comprises a nucleic acid sequence encoding a signal peptide immediately followed by a nucleic acid sequence encoding SEQ ID NO: 62, 72, 150, or 154.

[0209] In some embodiments, the antibody comprises a polypeptide light chain comprising a variable light chain (VL) domain comprising SEQ ID NO: 62, 72, 150, or 154 followed by a constant region comprising a CL domain. In some embodiments the constant region comprises a CL domain of a human Ig kappa chain or Ig lambda chain. In some embodiments the constant region comprises a CL of a human Ig kappa chain. In some embodiments, the antibody comprises a polypeptide light chain comprising SEQ ID NO: 74, 84, 162, or 166.

[0210] In some embodiments, the monoclonal antibody comprises a first and third chain each comprising SEQ ID NO: 20, 30, 108, or 112 and a second and fourth chains each comprising SEQ ID NO: 62, 72, 150, or 154. In some embodiments, the monoclonal antibody comprises a first and third chain each comprising SEQ ID NO: 20, 30, 108, or 112 followed by a constant region comprising a CHI domain, a hinge domain, a Fc domain (CH2-CH3) and a second and fourth chains each comprising SEQ ID NO: 62, 72, 150, or 154 followed by a constant region comprising a CL domain, wherein the constant region of the first and third chain comprises a CHI domain, a hinge domain, and a Fc domain (CH2-CH3) of a human IgGl, IgG2, IgG3, or IgG4 constant region and the constant region of the second and fourth chain comprises a CL domain of a human Ig kappa chain or Ig lambda chain. In some embodiments, the monoclonal antibody comprises a first and third chain each comprising SEQ ID NO: 32, 42, 120, or 124 and a second and fourth chains each comprising SEQ ID NO: 74, 84, 162, or 166. In some embodiments, the first and second chains are linked by one or more covalent disulfide bonds and the third and fourth chains are linked by one or more covalent disulfide bonds. In some embodiments, the first and third chains are linked by one or more disulfide bonds. A person of skill in the art understands the sequences used for the first and third and second and fourth chains are paired according to their antibody designation in FIG. 14 (e.g., SEQ ID NOs: 20 and 62 etc.)

[0211] In some embodiments, the antibody heavy chain comprises a VH domain comprising an amino acid sequence 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99 % identical to SEQ ID NO: 20, 30, 108, or 112. In some embodiments,the antibody light chain comprises a VL domain comprising an amino acid sequence 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99 % identical to SEQ ID NO: 62, 72, 150, or 154. In some embodiments, the antibody heavy chain comprises an amino acid sequence 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99 % identical to SEQ ID NO: 32, 42, 120, or 124. In some embodiments, the antibody light chain comprises an amino acid sequence 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99 % identical to SEQ ID NO: 74, 84, 162, or 166.

[0212] In some embodiments, the antibody heavy chain comprises a VH domain comprising CDR sequences designated in FIG. 14 (e.g., SEQ ID NOs 1-3, 16-18, 91-93, 97- 99). In some embodiments, the framework regions (FRs) of the VH domain comprise an amino acid sequence 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99 % identical to the FRs of SEQ ID NO: 20, 30, 108, or 112 for the VH corresponding to the antibody designation in FIG.14. In some embodiments, the VH domain comprises FRs of a human IGH gene corresponding to the antibody designation in FIG.14. In some embodiments, the antibody heavy chain further comprises a constant region comprising a CHI domain, a hinge domain, a Fc domain (CH2-CH3). In some embodiments the constant region comprises a CHI domain, a hinge domain, and a Fc domain (CH2-CH3) of a human IgGl, IgG2, IgG3, or IgG4 constant region. In some embodiments the constant region comprises a CHI domain, a hinge domain, and a Fc domain (CH2-CH3) of a human IgGl constant region. In some embodiments, the antibody comprises a constant region comprising a CHI domain, a hinge domain, a Fc domain (CH2-CH3) of SEQ ID NO: 32, 42, 120, or 124 corresponding to the antibody designation in FIG.14.

[0213] In some embodiments, the antibody light chain comprises a VL domain comprising CDR sequences designated in FIG. 14 (e.g., SEQ ID NOs 43-45, 58-60, 133-135, 139-141). In some embodiments, the framework regions (FRs) of the VL domain comprise an amino acid sequence 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99 % identical to the FRs of SEQ ID NO: 62, 72, 150, or 154 for the VL corresponding to the antibody designation in FIG.14. In some embodiments, the VL domain comprises FRs of a human IGK gene corresponding to the antibody designation in FIG.14. In some embodiments, the antibody light chain further comprises a constant region comprising a CL domain. In some embodiments the constant region comprises a CL domain of a human Ig kappa chain or Ig lambda chain. In some embodiments the constant region comprises a CL of a human Ig kappa chain. In some embodiments, the antibody comprises a CL domain of SEQ ID NO: 74, 84, 162, or 166 corresponding to the antibody designation in FIG.14.

[0214] In some embodiments, the antibody heavy chain comprises a VH domain comprising CDR sequences designated in FIG. 14 (e.g., SEQ ID NOs 1-3, 16-18, 91-93, 97- 99) and the antibody light chain comprises a VL domain comprising CDR sequences designated in FIG. 14 (e.g., SEQ ID NOs 43-45, 58-60, 133-135, 139-141). In some embodiments, the framework regions (FRs) of the VH domain and the FRs of the variable light chain domain of the antibody comprise an amino acid sequence 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99 % identical to the FRs of SEQ ID NO: 20, 30, 108, or 112 for the VH corresponding to the antibody designation in FIG.14 and SEQ ID NO: 62, 72, 150, or 154 for the VL corresponding to the antibody designation in FIG.14, respectively. In some embodiments, the VH domain comprises FRs of a human IGH gene and FRs of a human IGK gene corresponding to the antibody designation in FIG.14. In some embodiments, the antibody heavy chain further comprises a constant region comprising a CHI domain, a hinge domain, a Fc domain (CH2-CH3). In some embodiments the constant region comprises a CHI domain, a hinge domain, and a Fc domain (CH2-CH3) of a human IgGl, IgG2, IgG3, or IgG4 constant region. In some embodiments the constant region comprises a CHI domain, a hinge domain, and a Fc domain (CH2-CH3) of a human IgGl constant region. In some embodiments, the antibody comprises a constant region comprising a CHI domain, a hinge domain, a Fc domain (CH2-CH3) of SEQ ID NO: 32, 42, 120, or 124 corresponding to the antibody designation in FIG.14. In some embodiments, the antibody light chain further comprises a constant region comprising a CL domain. In some embodiments the constant region comprises a CL domain of a human Ig kappa chain or Ig lambda chain. In some embodiments the constant region comprises a CL of a huma Ig kappa chain. In some embodiments, the antibody comprises a CL domain of SEQ ID NO: 74, 84, 162, or 166 corresponding to the antibody designation in FIG.14.

[0215] In some embodiments, the monoclonal antibody comprises a first and third chain each comprising a VH domain comprising CDR sequences designated in FIG. 14 (e.g., SEQ ID NOs 1-3, 16-18, 91-93, 97-99) and a second and fourth chains each comprising a VL domain comprising CDR sequences designated in FIG. 14 (e.g., SEQ ID NOs 43-45, 58-60, 133-135, 139-141). In some embodiments, the monoclonal antibody comprises a first and third chain each comprising a VH domain comprising CDR sequences designated in FIG. 14 (e.g., SEQ ID NOs 1-3, 16-18, 91-93, 97-99) followed by a constant region comprising a CHI domain, a hinge domain, a Fc domain (CH2-CH3) and a second and fourth chains each comprising a VL domain comprising CDR sequences designated in FIG. 14 (e.g., SEQ ID NOs 43-45, 58-60, 133-135, 139-141) followed by a constant region comprising a CLdomain, wherein the constant region of the first and third chain comprises a CH 1 domain, a hinge domain, and a Fc domain (CH2-CH3) of a human IgGl, IgG2, IgG3, or IgG4 constant region and the constant region of the second and fourth chain comprises a CL domain of a human Ig kappa chain or Ig lambda chain. In some embodiments, the framework regions (FRs) of the VH domains comprise an amino acid sequence 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99 % identical to the FRs of SEQ ID NO: 20, 30, 108, or 112 for the VH corresponding to the antibody designation in FIG.14. In some embodiments, the VH domains comprises FRs of a human IGH gene corresponding to the antibody designation in FIG.14. In some embodiments, the framework regions (FRs) of the VL domains comprise an amino acid sequence 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99 % identical to the FRs of SEQ ID NO: 62, 72, 150, or 154 for the VL corresponding to the antibody designation in FIG.14. In some embodiments, the VL domains comprises FRs of a human IGK gene corresponding to the antibody designation in FIG.14. In some embodiments, the first and second chains are linked by one or more covalent disulfide bonds and the third and fourth chains are linked by one or more covalent disulfide bonds. In some embodiments, the first and third chains are linked by one or more disulfide bonds.

[0216] In some embodiments, one or more amino acids of an amino acid sequence encoding one or more CDRs of FIG. 14 is substituted. In some embodiments, one or more amino acids of an amino acid sequence encoding one or more variable heavy chain CDRs of FIG. 14 is substituted. In some embodiments, one or more amino acids of an amino acid sequence encoding one or more variable light chain CDRs of FIG. 14 is substituted.

[0217] In some embodiments, the antibody heavy chain comprises a VH comprising a heavy chain CDR1, CDR2, and / or CDR3 having a sequence identity of at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to HCDR sequences designated in FIG. 14 (e.g., SEQ ID NOs 1-3, 16-18, 91-93, 97-99) and the antibody light chain comprises a VL comprising a light chain CDR1, CDR2, and / or CDR3 having a sequence identity of at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to LCDR sequences designated in FIG. 14 (SEQ ID NOs 43-45, 58-60, 133-135, 139-141).

[0218] In some embodiments, the antibody lacks effector function. In some embodiments, the antibody is a blocking antibody.

[0219] In some embodiments, the antibody binds LILRB4 with an equilibrium dissociation constant (KD) from about 10-7M to about 10-11M and separately binds LILRB2 with an equilibrium dissociation constant (KD) from about 10-7M to about 10- 11M. In someembodiments, the KD of binding LILRB4 or LILRB2 is from about 10-9M to about 10-10M. In some embodiments, the antibody binds LILRB4 with an association constant of about 105Ms-1and separately binds LILRB2 with an association constant of about 10' Ms-1. In some embodiments, the antibody binds LILRB4 with a dissociation constant from about 10-2s-1to about 10-5s-1and separately binds LILRB2 with a dissociation constant from about 10-2s-1to about 10-5s-1.

[0220] In some embodiments, the LILRB4 is a human LILRB4. In some embodiments, the LILRB4 is a cynomolgus macaque LILRB4. In some embodiments, the LILRB2 is a human LILRB2. In some embodiments, the LILRB2 is a cynomolgus macaque LILRB2. In some embodiments, the LILRB4 is a mouse ortholog of LILRB4. In some embodiments, the LILRB2 is a mouse ortho log of LILRB2.

[0221] In some embodiments, the anti-LILRB4 antibody inhibits a LILRB4-dependent immune checkpoint, In some embodiments, the anti-LILRB2 antibody inhibits a LILRB2- dependent immune checkpoint. In some embodiments, the antibody depletes LILRB4+ monocytes. In some embodiments, the antibody depletes LILRB2+ monocytes. In some embodiments, the antibody does not deplete immune-supporting myeloid populations.

[0222] Exemplary nucleic acid sequences encoding the antibodies described herein, or portions thereof are provided in FIG. 14. A person skilled in the art can identify the nucleic acid sequences encoding the features identified in the corresponding amino acid sequences (e.g., CDRs, variable heavy domain, variable light domain, CHI domain, hinge domain, Fc domain, CL domain) by translating the nucleic acid sequences into amino acid sequences. In some embodiments, the nucleic acid sequences may be codon optimized.

[0223] In some embodiments, the nucleic acid sequence encoding an VH domain comprise a nucleic acid sequence 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99 % identical to the nucleotide sequences provided in FIG. 14. In some embodiments, the nucleic acid sequence encoding an heavy chain comprise a nucleic acid sequence 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99 % identical to the nucleotide sequences provided in FIG. 14. In some embodiments, the nucleic acid sequence encoding an VL domain comprise a nucleic acid sequence 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99 % identical to the nucleotide sequences provided in FIG. 14. In some embodiments, the nucleic acid sequence encoding a light chain comprise a nucleic acid sequence 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99 % identical to the nucleotide sequences provided in FIG. 14.

[0224] Pharmaceutical Compositions

[0225] In some embodiments, the subject matter disclosed herein provides a pharmaceutical composition comprising any of the anti-LILRB4 or anti-LILRB4 / LILRB2 antibodies disclosed herein, including without limitation antibodies described in sections entitled “Amino Acid Sequences of Anti-LILRB4 Antibodies” and “Amino Acid Sequences of Anti-LILRB4 / LILRB2 Antibodies.”

[0226] In some embodiments, the pharmaceutical composition disclosed herein further comprises one or more pharmaceutically-acceptable diluents, one or more pharmaceutically- acceptable carriers, or one or more pharmaceutically-acceptable excipients.

[0227] In some embodiments, the subject matter disclosed herein provides a polynucleotide encoding the any of the anti-LILRB4 or anti-LILRB4 / LILRB2 antibodies disclosed herein, including without limitation antibodies described in sections entitled “Amino Acid Sequences of Anti-LILRB4 Antibodies” and “Amino Acid Sequences of Anti- LILRB4 / LILRB2 Antibodies.” In some embodiments, the subject matter disclosed herein provides a genetically engineered cell comprising any of the anti-LILRB4 or anti- LILRB4 / LILRB2 antibodies disclosed herein, including without limitation antibodies described in sections entitled “Amino Acid Sequences of Anti-LILRB4 Antibodies” and “Amino Acid Sequences of Anti-LILRB4 / LILRB2 Antibodies.” In some embodiments, the subject matter disclosed herein provides a genetically engineered cell comprising a polynucleotide encoding the any of the anti-LILRB4 or anti-LILRB4 / LILRB2 antibodies disclosed herein, including without limitation antibodies described in sections entitled “Amino Acid Sequences of Anti-LILRB4 Antibodies” and “Amino Acid Sequences of Anti- LILRB4 / LILRB2 Antibodies.”

[0228] In certain aspects, also herein provided are pharmaceutical compositions comprising the above-described antibodies (or one or more polynucleotides encoding one or more antibodies). In some embodiments, the subject matter described herein relates to a pharmaceutical composition comprising an effective amount of the antibodies (or one or more polynucleotides encoding one or more antibodies) described herein and a pharmaceutically-acceptable diluent, carrier or excipient. In certain embodiments, the antibodies are conjugated with other molecules to increase their effectiveness as is known by those practiced in the art.

[0229] As used herein, “pharmaceutical composition” means a therapeutically effective formulation according to the invention. A “therapeutically effective amount,” or “effective amount,” or “therapeutically effective,” as used herein, refers to that amount which provides a therapeutic effect for a given condition and administration regimen. A therapeuticallyeffective amount can be determined by a skilled person based on patient characteristics, such as age, weight, sex, condition, complications, other diseases, etc., as is well known in the art.

[0230] In some embodiments, the pharmaceutical compositions described herein can be administered as solid compositions. In some embodiments, the solid compositions comprise excipients including but not limited to lactose, starch, cellulose, milk sugar or high molecular weight polyethylene glycols. In some embodiments, the pharmaceutical compositions described herein can be administered as aqueous suspensions and / or elixirs. In some embodiments, the pharmaceutical compositions described herein may be combined with various sweetening or flavouring agents, coloring matter or dyes, with emulsifying and / or suspending agents and with diluents such as water, ethanol, propylene glycol and glycerin, and combinations thereof.

[0231] In some embodiments, the pharmaceutical compositions described herein can be administered parenterally, for example, intravenously, intra-arterially, intraperitoneally, intra- thecally, intraventricularly, intrastemally, intracranially, intra-muscularly or subcutaneously, or they may be administered by infusion techniques. In some embodiments, the pharmaceutical compositions described herein can be administered in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood. The preparation of suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques well- known to those skilled in the art.

[0232] In some embodiments, pharmaceutical compositions suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The pharmaceutical compositions can be presented in unit-dose or multi-dose containers. The pharmaceutical compositions can be sealed ampoules or vials. The pharmaceutical compositions can be stored in a freeze-dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, such as water for injections, immediately prior to use.

[0233] The compounds and pharmaceutical compositions of the present invention can be employed in combination therapies, that is, the compounds and pharmaceutical compositions can be administered concurrently with, prior to, or subsequent to, one or more other desired therapeutics or medical procedures (e.g.. antibodies can be used in combination treatment with another treatment). The particular combination of therapies (therapeutics or procedures)to employ in a combination regimen will take into account compatibility of the desired therapeutics and / or procedures and the desired therapeutic effect to be achieved. It will also be appreciated that the therapies employed may achieve a desired effect for the same disorder (for example, the compound of the present invention may be administered concurrently with another therapeutic or prophylactic).

[0234] The invention also provides a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the invention. Optionally associated with such container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use or sale for human administration.

[0235] Compositions can be formulated with appropriate carriers and adjuvants using techniques to yield compositions suitable for prophylaxis or treatment. The compositions can include an adjuvant, such as, for example but not limited to, alum, poly IC, MF-59, squalene- based adjuvants, or liposomal based adjuvants suitable for prophylaxis or treatment.

[0236] In some embodiments, the antibodies described herein are encoded by nucleic acids which are prepared in a mRNA-LNP or a DNA-LNP formulation for administration to a subject.

[0237] Antibody Production

[0238] The antibodies disclosed herein can be produced by any method known in the art. In some embodiments, the antibodies disclosed herein are produced by culturing a cell transfected or transformed with a vector comprising nucleic acid sequences encoding an antibody described herein and isolating the antibody.

[0239] hr some embodiments, antibodies are synthesized by methods which results in antibodies that are not contaminated by other immunoglobulins. The modifier monoclonal does not require production of the antibody by any particular method. For example, the monoclonal antibodies to be used in accordance with the present invention may be made by a variety of techniques known in the art, including, for example, the hybridoma method, recombinant DNA methods, phage-display technologies, B-cell discovery methods, and technologies for producing human or human-like antibodies in animals that have parts or all of the human immunoglobulin loci or genes encoding human immunoglobulin sequences.

[0240] In some embodiments, expression of an antibody comprises expression vector(s) containing a polynucleotide that encodes an anti-LILRB4 or anti-LILRB4 / LILRB2 antibody. Methods that are well known to those skilled in the art can be used to construct expressionvectors comprising antibody coding sequences and appropriate transcriptional and translational control signals. These methods include, for example, in vitro recombinant DNA techniques, synthetic techniques, and in vivo genetic recombination. Particular embodiments provide replicable vectors comprising a nucleotide sequence encoding an anti-LILRB4 or anti-LILRB4 / LILRB2 antibody disclosed herein operably linked to a promoter. In preferred embodiments, such vectors may include a nucleotide sequence encoding the heavy chain of an antibody molecule (or fragment thereof), a nucleotide sequence encoding the light chain of an antibody (or fragment thereof), or a nucleotide sequence encoding both the heavy and light chain of an antibody molecule (or fragment thereof).

[0241] The polynucleotide encoding the antibody may be modified, for example, by substituting the coding sequence for human heavy- and light-chain constant domains or by covalently joining to the immunoglobulin coding sequence all or part of the coding sequence for a non-immunoglobulin polypeptide. Typically, such non-immunoglobulin polypeptides are substituted for the constant domains of an antibody. The monoclonal antibodies described herein may by monovalent, the preparation of which is well known in the art. For example, one method involves recombinant expression of an immunoglobulin light chain and a modified heavy chain. The heavy chain is generally truncated at any point in the Fc domain so as to prevent heavy chain crosslinking. Alternatively, the relevant cysteine residues may be substituted with another amino acid residue or are deleted so as to prevent crosslinking. In vitro methods are also suitable for preparing monovalent antibodies. Antibiotic ingestion to produce fragments, particularly Fab fragments, can be accomplished using routine techniques known in the art. Chimeric or hybrid antibodies also may be prepared in vitro using known methods in synthetic protein chemistry, including those involving crosslinking agents.

[0242] Various expression systems for producing antibodies are known in the art, and include, prokaryotic (e.g., bacteria), plant, insect, yeast, and mammalian expression systems. Suitable cell lines, can be transformed, transduced, or transfected with nucleic acids containing coding sequences for antibodies or portions of antibodies disclosed herein in order to produce the antibody of interest. Expression vectors containing such nucleic acid sequences, which can be linked to at least one regulatory sequence in a manner that allows expression of the nucleotide sequence in a host cell, can be introduced via methods known in the art. Practitioners in the art understand that designing an expression vector can depend on factors, such as the choice of host cell to be transfected and / or the type and / or amount of desired protein to be expressed. Enhancer regions, which are those sequences found upstream or downstream of the promoter region in non-coding DNA regions, are also knownin the art to be important in optimizing expression. If needed, origins of replication from viral sources can be employed, such as if a prokaryotic host is utilized for introduction of plasmid DNA. However, in eukaryotic organisms, chromosome integration is a common mechanism for DNA replication. For stable transfection of mammalian cells, a small fraction of cells can integrate introduced DNA into their genomes. The expression vector and transfection method utilized can be factors that contribute to a successfill integration event. For stable amplification and expression of a desired protein, a vector containing DNA encoding a protein of interest (e.g., antibodies and fragments thereof) is stably integrated into the genome of eukaryotic cells (for example mammalian cells), resulting in the stable expression of transfected genes. A gene that encodes a selectable marker (for example, resistance to antibiotics or drugs) can be introduced into host cells along with the gene of interest in order to identify and select clones that stably express a gene encoding a protein of interest. Cells containing the gene of interest can be identified by drug selection wherein cells that have incorporated the selectable marker gene will survive in the presence of the drug. Cells that have not incorporated the gene for the selectable marker die. Surviving cells can then be screened for the production of the desired antibody molecule.

[0243] In some embodiments, the antibodies disclosed herein are encoded in a vector for expression in a cell line. In some embodiments, a vector comprises a polynucleotide sequence that encodes an anti-LILRB4 or anti-LILRB4 / LILRB2 antibody and the vector is transfected into one or more cell lines for expression. In some embodiments, one or more vectors comprise polynucleotide sequences encoding a light chain and a heavy chain of the antibody. For example, in some embodiments, a first vector may comprise a polynucleotide sequence encoding a light chain, a second vector may comprise a polynucleotide sequence encoding a heavy chain, of an anti-LILRB4 or anti-LILRB4 / LILRB2 antibody, In some embodiments, both vectors are transfected into one or more cell lines for expression. A host cell strain, which modulates the expression of the inserted sequences, or modifies and processes the nucleic acid in a specific fashion desired also may be chosen. Such modifications (for example, glycosylation and other post-translational modifications) and processing (for example, cleavage) of protein products may be important for the function of the antibody. Different host cell strains have characteristic and specific mechanisms for the post- translational processing and modification of proteins and gene products. As such, appropriate host systems or cell lines can be chosen to ensure the correct modification and processing of the foreign antibody expressed. Thus, eukaryotic host cells possessing thecellular machinery for proper processing of the primary transcript, glycosylation, and phosphorylation of the gene product may be used.

[0244] In some embodiments, the antigen binding portions of the anti-LILRB4 or anti- LILRB4 / LILRB2 antibodies described herein can be expressed as part of a chimeric antigen receptor (CAR) expressed on T cells. Thus, in certain aspects provided herein is a CAR comprising a VH domain and a VL domain of any one of the anti-LILRB4 or anti- LILRB4 / LILRB2 antibodies described herein. In some embodiments, provided herein is a CAR comprising a VH domain comprising the HCDRs of any one of the anti-LILRB4 or anti-LILRB4 / LILRB2 antibodies described herein and a VL domain comprising the LCDRs of any one of the anti-LILRB4 or anti-LILRB4 / LILRB2 antibodies described herein. In some embodiments, provided herein is a T cell or population of T cells comprising a CAR comprising a VH domain and a VL domain of any one of the anti-LILRB4 or anti- LILRB4 / LILRB2 antibodies described herein. In some embodiments, provided herein is a T cell or population of T cells comprising CAR comprising a VH domain comprising the HCDRs of any one of the anti-LILRB4 or anti-LILRB4 / LILRB2 antibodies described herein and a VL domain comprising the LCDRs of any one of the anti-LILRB4 or anti- LILRB4 / LILRB2 antibodies described herein.

[0245] Various culturing parameters can be used with respect to the host cell being cultured. Appropriate culture conditions for mammalian cells are well known in the art or can be determined by the skilled artisan (see, for example, Animal Cell Culture: A Practical Approach 2ndEd., Rickwood, D. and Hames, B. D., eds. (Oxford University Press: New York, 1992)). Cell culturing conditions can vary according to the type of host cell selected. Commercially available media can be utilized.

[0246] Antibodies disclosed herein can be purified from any human or non-human cell that expresses the antibody, including those that have been transfected with expression constructs that express the antibody or fragments thereof. For antibody recovery, isolation and / or purification, the cell culture medium or cell lysate is centrifuged to remove particulate cells and cell debris. The desired antibody molecule is isolated or purified away from contaminating soluble proteins and polypeptides by suitable purification techniques. Nonlimiting purification methods for proteins / antibodies include: size exclusion chromatography, affinity chromatography, ion exchange chromatography, ethanol precipitation; reverse phase HPLC; chromatography on a resin, such as silica, or cation exchange resin, e.g.. DEAE; chromatofocusing; SDS-PAGE; ammonium sulfate precipitation; gel filtration using, e.g, Sephadex G-75, Sepharose; protein A sepharose chromatography for removal ofimmunoglobulin contaminants; and the like. Other additives, such as protease inhibitors (e.g., PMSF or proteinase K) can be used to inhibit proteolytic degradation during purification. Purification procedures that can select for carbohydrates can also be used, e.g., ion-exchange soft gel chromatography, or HPLC using cation- or anion-exchange resins, in which the more acidic fraction(s) is / are collected.

[0247] Methods of Treatment

[0248] In one embodiment, the subject matter disclosed herein relates to a preventive medical treatment started after following diagnosis of a disease (e.g., cancer) in order to prevent the disease from worsening or curing the disease. In one embodiment, the subject matter disclosed herein relates to prophylaxis of subjects who are believed to be at risk for moderate or severe disease associated with cancer or have previously been diagnosed with another disease, such as cancer. In one embodiment, the subjects can be administered the pharmaceutical composition described herein. The invention contemplates using any of the antibodies produced by the systems and methods described herein. In one embodiment, the compositions described herein can be administered subcutaneously via syringe or any other suitable method know in the art.

[0249] The compound(s) (e.g., anti-LILRB4 or anti-LILRB4 / LILRB2 antibodies) disclosed herein, or pharmaceutical compositions may be administered to a cell, mammal, or human by any suitable means. In some embodiments, one or more antibodies disclosed herein are prepared in a cocktail of DNA-encoding antibodies or mRNA-encoding antibodies and delivered to a subject for in vivo expression of the encoded antibodies.

[0250] As will be readily apparent to one skilled in the art, the effective in vivo dose to be administered and the particular mode of administration will vary depending upon the age, weight and species treated, and the specific use for which the compound or combination of compounds disclosed herein are employed. The determination of effective dose levels, that is the dose levels necessary to achieve the desired result, can be accomplished by one skilled in the art using routine pharmacological methods. Typically, human clinical applications of products are commenced at lower dose levels, with dose level being increased until tire desired effect is achieved. Alternatively, acceptable in vitro studies can be used to establish useful doses and routes of administration of the compositions identified by the present methods using established pharmacological methods. Effective animal doses from in vivo studies can be converted to appropriate human doses using conversion methods known in the art.

[0251] In certain aspects, the subject matter disclosed herein provides a method of treating or preventing cancer in a subject in need thereof, the method comprising administering to the subject any of the anti-LILRB4 or anti-LILRB4 / LILRB2 antibodies disclosed herein, including without limitation antibodies described in sections entitled “Amino Acid Sequences of Anti-LILRB4 Antibodies” and “Amino Acid Sequences of Anti- LILRB4 / LILRB2 Antibodies.”

[0252] In some embodiments, the cancer is kidney cancer, breast cancer, brain tumor, head and neck cancer, liver cancer, melanoma, non-small cell lung cancer (NSCLC), bladder cancer, cervical cancer, colon cancer, renal cell cancer, skin cancer, stomach cancer, rectal cancer, gastrointestinal, pancreatic cancer, lung cancer, thymic carcinoma, ovarian cancer, prostate cancer, or endometrial cancer. In some embodiments, the cancer is a liquid cancer. In some embodiments, the liquid cancer is leukemia, lymphoma, Hodgkin lymphoma, or myeloma. In some embodiments, the liquid cancer is acute myeloid leukemia (AML). In some embodiments, the liquid cancer is B-cell malignancy.

[0253] In some embodiments, the cancer is a cancer treated with immune therapies including, but not limited to, T-cell checkpoint inhibitors such as anti-PD-1 antibodies and anti-CTLA4 antibodies, In some embodiments, the anti-PPD-1 antibody is Pembrolizumab. In some embodiments, the anti-PPD-1 antibody is Nivolumab. In some embodiments, the anti-PPD-1 antibody is Cemiplimab. In some embodiments, the anti-PPD-1 antibody is Dostarlimab. In some embodiments, the anti-PPD-1 antibody is Retifanlimab. In some embodiments, the anti-PPD-1 antibody is Toripalimab. In some embodiments, the anti- CTLA4 antibody is Ipilimumab. In some embodiments, the anti-CTLA4 antibody Tremelimumab.

[0254] In some embodiments, the antibody lacks effector function. In some embodiments, the antibody is a blocking antibody. In some embodiments, the antibody stimulates NF-KB activity, In some embodiments, the antibody stimulates T-cell activity. In some embodiments, the antibody stimulates T-cell proliferation. In some embodiments, the antibody stimulates T-cell division.

[0255] In certain aspects, the subject matter disclosed herein provides a method of inhibiting myeloid-dependent immune suppression or promoting immune activation in a subject in need thereof, the method comprising administering to the subject any of the anti- LILRB4 or anti-LILRB4 / LILRB2 antibodies disclosed herein, including without limitation antibodies described in sections entitled “Amino Acid Sequences of Anti-LILRB4 Antibodies” and “Amino Acid Sequences of Anti-LILRB4 / LILRB2 Antibodies.”

[0256] In some embodiments, the antibody lacks effector function. In some embodiments, the antibody is a blocking antibody. In some embodiments, the antibody stimulates NF-KB activity. In some embodiments, the antibody stimulates T-cell activity. In some embodiments, the antibody stimulates T-cell proliferation. In some embodiments, the antibody stimulates T-cell division.

[0257] In some embodiments, in the methods disclosed herein the subject is a human subject.

[0258] Kits of the Invention

[0259] In one embodiment, the subject matter disclosed herein relates to a kit for generating anti-LILRB4 or anti-LILRB4 / LILRB2 antibodies comprising an antibody composition of the present invention and instructions for use. In one embodiment, the subject matter disclosed herein relates to a kit for generating anti-LILRB4 or anti-LILRB4 / LILRB2 antibodies comprising one or more vectors comprising a polynucleotide sequence of any of the anti-LILRB4 or anti-LILRB4 / LILRB2 antibodies described above targeting LILRB4 or LILRB4 / LILRB2. The kit can further include at least one additional reagent or one or more antibodies of the present invention. The kit usually has a label indicating the intended use of the kit contents. The term label includes all documents and is attached to the kit or with the kit, or otherwise attached to the kit.

[0260] Non-limiting Embodiments of the Subject Matter

[0261] In certain aspects, the subject matter disclosed herein provides a monoclonal antibody, or an antigen-binding fragment thereof, comprising (i) a heavy chain (HC) variable domain (VH) and (ii) a light chain (LC) variable domain (VL); wherein the antibody, or antigen binding fragment thereof, binds leukocyte immunoglobulin-like receptor 4 (LILRB4).

[0262] In some embodiments, the antibody binds LILRB4 with an equilibrium dissociation constant (KD) from about 10-7M to about 10-11M. In some embodiments, the antibody binds LILRB4 with an association constant from about 105Ms-1to about 106Ms'’. In some embodiments, the antibody binds LILRB4 with a dissociation constant from about 10-2s-1to about 10-5s-1.

[0263] In some embodiments, the LILRB4 is a human LILRB4. In some embodiments, the LILRB4 is a cynomolgus macaque LILRB4. In some embodiments, the LILRB4 is a mouse ortholog of LILRB4. In some embodiments, the anti-LILRB4 antibody inhibits a LILRB4-dependent immune checkpoint. In some embodiments, the antibody depletes LILRB4+ monocytes. In some embodiments, the antibody does not deplete immune-supporting myeloid populations. In some embodiments, the antibody is engineered by B-cell cloning. In some embodiments, the antibody is a blocking antibody.

[0264] In some embodiments, the VH domain comprises a heavy chain CDR1 having a sequence identity of at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 4, a heavy chain CDR2 having a sequence identity of at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 5, a heavy chain CDR3 having a sequence identity of at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 6 and the VL domain comprises a light chain CDRl having a sequence identity of at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 46, a light chain CDR2 having a sequence identity of at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 47, and a light chain CDR3 having a sequence identity of at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 48. In some embodiments, the VH domain comprises a heavy chain CDRl having a sequence identity of SEQ ID NO: 4, a heavy chain CDR2 having a sequence identity of SEQ ID NO: 5, and a heavy chain CDR3 having a sequence identity to SEQ ID NO: 6 and theVL domain comprises a light chain CDRl having a sequence identity of SEQ ID NO: 46, a light chain CDR2 having a sequence identity of SEQ ID NO: 47, and a light chain CDR3 having a sequence identity of SEQ ID NO: 48. In some embodiments, the HC VH domain further comprises framework regions (FRs) comprising an amino acid sequence 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99 % identical to the FRs of SEQ ID NO: 22 and wherein the EC VL domain further comprises framework regions (FRs) comprising an amino acid sequence 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99 % identical to the FRs of SEQ ID NO: 64.

[0265] In some embodiments, the HC VH domain further comprises framework regions (FRs) of a human IGHV1 gene and wherein the EC VL domain further comprises FRs of a human IGKV1 gene. In some embodiments, the HC VH domain further comprises framework regions (FRs) of a human IGHV1-8 gene and wherein the LC VL domain further comprises FRs of a human IGKV1-17 gene. In some embodiments, the antibody comprises (a) a first arm comprising the HC VH domain and the LC VL domain wherein a portion of the first arm binds LILRB4 and (b) a second arm comprising the HC VH domain and the LC VL domain wherein a portion of the second arm binds LILRB4. In some embodiments, the first and second arms each further comprise a CH I domain, a hinge domain, a Fc domain (CH2-CH3) and a CL domain.

[0266] In some embodiments, the VH domain of the first arm is encoded by a first polypeptide chain; the VL domain of the first arm is encoded by a second polypeptide chain; the VH domain of the second arm is encoded by a third polypeptide chain; the VL domain of the second arm is encoded by a fourth polypeptide chain; and wherein the VH domain and VL domain of the first arm form a first LILRB4 binding site and wherein the VH domain and VL domain of the second arm form a second LILRB4 binding site, wherein the first and second LILRB4 binding sites are the same. In some embodiments, the first and third polypeptide chain each further encode a hinge domain, a CHI domain, and an Fc domain, and wherein the second and fourth polypeptide chain each further encode a CL domain. In some embodiments, the first and third polypeptide chains comprise the same sequence and the second and fourth polypeptide chains comprise the same sequence.

[0267] In some embodiments, the VH domain of the first arm and the second arm both comprise an amino acid sequence comprising SEQ ID NO: 22, and wherein the VL domain of the first arm and the second arm both comprise an amino acid sequence comprising SEQ ID NO: 64. In some embodiments, the first and third polypeptide chain each comprises an amino acid sequence comprising SEQ ID NO: 34 and the second and fourth polypeptide chain each comprises an amino acid sequence comprising SEQ ID NO: 76.

[0268] In some embodiments, the first and second polypeptide chains are linked by one or more covalent disulfide bonds and the third and fourth polypeptide chains are linked by one or more covalent disulfide bonds. In some embodiments, the first and third polypeptide chains are linked by one or more covalent disulfide bonds.

[0269] In certain aspects, the subject matter disclosed herein provides a monoclonal antibody, or an antigen-binding fragment thereof, comprising (i) a heavy chain (HC) variable domain (VH) and (ii) a light chain (LC) variable domain (VL); wherein the antibody is capable of binding to leukocyte immunoglobulin-like receptor 4 (LILRB4) and LILRB2.

[0270] In some embodiments, the antibody binds LILRB4 with an equilibrium dissociation constant (KD) from about 10-7M to about 10-11M and separately binds LILRB2 with an equilibrium dissociation constant (KD) from about 10-7M to about 10-11M. In some embodiments, the antibody binds LILRB4 with an association constant of about 105Ms-1and separately binds LILRB2 with an association constant from about 10-5Ms-1. In some embodiments, the antibody binds LILRB4 with a dissociation constant from about 10-2s-1to about 10-5s-1and separately binds LILRB2 with a dissociation constant from about 10-2s-1to about I0-5s-1.

[0271] In some embodiments, the LILRB4 is a human LILRB4. In some embodiments, the LILRB4 is a cynomolgus macaque LILRB4. In some embodiments, the LILRB2 is a human LILRB2. In some embodiments, the LILRB2 is a cynomolgus macaque LILRB2. In some embodiments, the LILRB4 is a mouse ortholog of LILRB4. In some embodiments, the LILRB2 is a mouse ortho log of LILRB2. In some embodiments, the anti-LILRB4 antibody inhibits a LILRB4-dependent immune checkpoint. In some embodiments, the anti-LILRB2 antibody inhibits a LILRB2-dependent immune checkpoint. In some embodiments, the antibody depletes LILRB4+ monocytes. In some embodiments, the antibody depletes LILRB2+ monocytes. In some embodiments, the antibody does not deplete immune- supporting myeloid populations. In some embodiments, the antibody is engineered by B-cell cloning. In some embodiments, the antibody is a blocking antibody.

[0272] In some embodiments, the VH domain comprises a heavy chain CDR1 having a sequence identity of at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 13, a heavy chain CDR2 having a sequence identity of at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 14, a heavy chain CDR3 having a sequence identity of at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 15 and the VL domain comprises a light chain CDR1 having a sequence identity of at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 55, a light chain CDR2 having a sequence identity of at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 56, and a light chain CDR3 having a sequence identity of at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 57. In some embodiments, the VH domain comprises a heavy chain CDR1 having a sequence identity of SEQ ID NO: 13, a heavy chain CDR2 having a sequence identity of SEQ ID NO: 14, and a heavy chain CDR3 having a sequence identity to SEQ ID NO: 15 and the VL domain comprises a light chain CDR1 having a sequence identity of SEQ ID NO: 55, a light chain CDR2 having a sequence identity of SEQ ID NO: 56, and a light chain CDR3 having a sequence identity of SEQ ID NO: 57. In some embodiments, the HC VH domain further comprises framework regions (FRs) comprising an amino acid sequence 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99 % identical to the FRs of SEQ ID NO: 22 and wherein the LC VL domain further comprises framework regions (FRs) comprising an amino acid sequence 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99 % identical to the FRs of SEQ ID NO: 64.

[0273] In some embodiments, the HC VH domain further comprises framework regions (FRs) of a human IGHV 1 gene and wherein the LC VL domain further comprises FRs of a human IGKV1 gene. In some embodiments, the HC VH domain further comprises framework regions (FRs) of a human IGHV 1-8 gene and wherein the LC VL domain further comprises FRs of a human IGKV1-17 gene. In some embodiments, the antibody comprises (a) a first arm comprising the HC VH domain and the LC VL domain wherein a portion of the first arm binds LILRB4 and (b) a second ami comprising the HC VH domain and the LC VL domain wherein a portion of the second arm binds LILRB4. In some embodiments, the first and second arms each further comprise a CHI domain, a hinge domain, a Fc domain (CH2-CH3) and a CL domain.

[0274] In some embodiments, the VH domain of the first arm is encoded by a first polypeptide chain; the VL domain of the first arm is encoded by a second polypeptide chain; the VH domain of the second arm is encoded by a third polypeptide chain; the VL domain of the second ami is encoded by a fourth polypeptide chain; and wherein the VH domain and VL domain of the first arm form a first LILRB4 binding site and wherein the VH domain and VL domain of the second arm form a second LILRB4 binding site, wherein the first and second LILRB4 binding sites are the same.

[0275] In some embodiments, the first and third polypeptide chain each further encode a hinge domain, a CHI domain, and an Fc domain, and wherein the second and fourth polypeptide chain each further encode a CL domain. In some embodiments, the first and third polypeptide chains comprise the same sequence and the second and fourth polypeptide chains comprise the same sequence. In some embodiments, the VH domain of the first arm and the second arm both comprise an amino acid sequence comprising SEQ ID NO: 22, and wherein the VL domain of the first arm and the second arm both comprise an amino acid sequence comprising SEQ ID NO: 64. In some embodiments, the first and third polypeptide chain each comprises an amino acid sequence comprising SEQ ID NO: 34 and the second and fourth polypeptide chain each comprises an amino acid sequence comprising SEQ ID NO: 76.

[0276] In some embodiments, the first and second polypeptide chains are linked by one or more covalent disulfide bonds and the third and fourth polypeptide chains are linked by one or more covalent disulfide bonds. In some embodiments, the first and third polypeptide chains are linked by one or more covalent disulfide bonds.

[0277] In certain aspects, the subject matter disclosed herein provides a pharmaceutical composition comprising any one of the monoclonal antibodies disclosed herein.

[0278] In certain aspects, the subject matter disclosed herein provides a pharmaceutical composition comprising any one of the monoclonal antibodies disclosed herein.

[0279] In some embodiments, the pharmaceutical composition further comprises one or more pharmaceutically-acceptable diluents, one or more pharmaceutically-acceptable carriers or one or more pharmaceutically-acceptable excipients.

[0280] In certain aspects, the subject matter disclosed herein provides a method of treating or preventing cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of any one of the monoclonal antibodies disclosed herein or any one of the pharmaceutical compositions disclosed herein.

[0281] In some embodiments, the cancer is kidney cancer, breast cancer, brain tumor, head and neck cancer, liver cancer, melanoma, non-small cell lung cancer (NSCLC), bladder cancer, cervical cancer, colon cancer, renal cell cancer, skin cancer, stomach cancer, rectal cancer, gastrointestinal, pancreatic cancer, lung cancer, thymic carcinoma, ovarian cancer, prostate cancer, or endometrial cancer. In some embodiments, the cancer is a liquid cancer. In some embodiments, the liquid cancer is leukemia, lymphoma, Hodgkin lymphoma, or myeloma. In some embodiments, the liquid cancer is acute myeloid leukemia (AML). In some embodiments, the liquid cancer is B-cell malignancy.

[0282] In some embodiments, the cancer is a cancer treated with immune therapies including, but not limited to, T-cell checkpoint inhibitors such as anti-PD-1 antibodies and anti-CTLA4 antibodies. In some embodiments, the anti-PPD-1 antibody is Pembrolizumab. In some embodiments, the anti-PPD-1 antibody is Nivolumab. In some embodiments, the anti-PPD-1 antibody is Cemiplimab. In some embodiments, the anti-PPD-1 antibody is Dostarlimab. In some embodiments, the anti-PPD-1 antibody is Retifanlimab. In some embodiments, the anti-PPD-1 antibody is Toripalimab. In some embodiments, the anti- CTLA4 antibody is Ipilimumab. In some embodiments, the anti-CTLA4 antibody Tremelimumab.

[0283] In some embodiments, the administration of the monoclonal antibody or the pharmaceutical composition is capable of inhibiting tumor growth.

[0284] In certain aspects, the subject matter disclosed herein provides a method of inhibiting myeloid-dependent immune suppression or promoting immune activation in a subject in need thereof, the method comprising administering to the subject an effective amount of any of the monoclonal antibodies disclosed herein or any of the pharmaceutical composition disclosed herein.

[0285] In some embodiments, the subject is a human subject.

[0286] In certain aspects, the subject matter disclosed herein provides a polynucleotide encoding any one of the antibodies disclosed herein targeting LILRB4.

[0287] In certain aspects, the subject matter disclosed herein provides a polynucleotide encoding any one of the antibodies disclosed herein targeting LILRB2.

[0288] In certain aspects, the subject matter disclosed herein provides a genetically engineered cell comprising any of the antibodies disclosed herein targeting LILRB4.

[0289] In certain aspects, the subject matter disclosed herein provides a genetically engineered cell comprising any of the antibodies disclosed herein targeting LILRB2.

[0290] In certain aspects, the subject matter disclosed herein provides a kit for generating a monoclonal antibody or antigen-binding fragment thereof, the kit comprising one or more vectors comprising a polynucleotide sequence encoding any of the monoclonal antibodies disclosed herein.

[0291] In certain aspects, the subject matter disclosed herein provides a kit for generating a monoclonal antibody or antigen-binding fragment thereof, the kit comprising: a first vector comprising a polynucleotide sequence encoding the first polypeptide chain of any one of the monoclonal antibodies disclosed herein targeting LILRB4 or targeting LILRB4 and LILRB2; and a second vector comprising a polynucleotide sequence encoding the second polypeptide chain of any one of the monoclonal antibodies disclosed herein targeting LILRB4 or targeting LILRB4 and LILRB2.

[0292] In certain aspects, the subject matter disclosed herein provides one or more in vitro cultured cells comprising: one or more vectors comprising a polynucleotide sequence encoding any of the monoclonal antibodies disclosed herein.

[0293] In certain aspects, the subject matter disclosed herein provides one or more in vitro cultured cells comprising: a first vector comprising a polynucleotide sequence encoding the first polypeptide chain of any one of the monoclonal antibodies disclosed herein targeting LILRB4 or targeting LILRB4 and LILRB2; and a second vector comprising a polynucleotide sequence encoding the second polypeptide chain of any one of the monoclonal antibodies disclosed herein targeting LILRB4 or targeting LILRB4 and LILRB2.

[0294] In certain aspects, the subject matter disclosed herein provides a method of making a monoclonal antibody or antigen-binding fragment thereof comprising: culturing the one or more in vitro cultured cells disclosed herein under conditions suitable for an expression of the one or more vectors; and recovering the monoclonal antibody or antigenbinding fragment thereof.

[0295] In certain aspects, the subject matter disclosed herein provides a composition comprising: one or more vectors comprising a polynucleotide sequence encoding any of the monoclonal antibodies described herein.

[0296] In certain aspects, the subject matter disclosed herein provides a composition comprising: a first vector comprising a polynucleotide sequence encoding the first polypeptide chain of any of the monoclonal antibodies disclosed herein; and a second vector comprising a polynucleotide sequence encoding the second polypeptide chain of any of the monoclonal antibodies disclosed herein.

[0297] In certain aspects, the subject matter disclosed herein provides a monoclonal antibody means for binding LILRB4.

[0298] In some embodiments, the means comprises any one of the monoclonal antibodies disclosed herein targeting LILRB4.

[0299] In certain aspects, the subject matter disclosed herein provides a monoclonal antibody means for binding LILRB4 and LILRB2.

[0300] In some embodiments, the means is capable of treating or preventing cancer in a subject in need thereof or inhibiting myeloid-dependent immune suppression or promoting immune activation in a subject in need thereof.

[0301] In some embodiments, the means comprises any one of the monoclonal antibodies disclosed herein targeting LILRB4 and LILRB2. In some embodiments, the means is capable of treating or preventing cancer in a subject in need thereof or inhibiting myeloid-dependent immune suppression or promoting immune activation in a subject in need thereof.

[0302] A person of ordinary skill in the art would readily recognize that a monoclonal antibody of the present invention is comprised of any of the antibodies disclosed in FIG. 14.

[0303] In some embodiments, the VH domain comprises a heavy chain CDR1 having a sequence identity of at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NOS: 1, 4, 7, 10, 13, 16, 85, 88, 91, 94, 97, or 100, a heavy chain CDR2 having a sequence identity of at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NOs: 2, 5, 8, 11, 14, 17, 86, 89, 92, 95, 98, or 101, a heavy chain CDR3 having a sequence identity of at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NOs: 3, 6, 9, 12, 15, 18, 87, 90, 93, 96, 99, or 102, and the VL domain comprises a light chain CDR1 having a sequence identity of at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NOs: 43, 46, 49, 52, 55, 58, 127, 130, 133, 136, 139, or 142, a light chain CDR2 having a sequence identity of at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NOs: 44, 47,50, 53, 56, 59, 128, 131, 134, 137, 140, or 143, and a light chain CDR3 having a sequence identity of at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NOs: 45, 48, 51, 54, 57, 60, 129, 132, 135, 138, 141, or 144. In some embodiments, the VH domain comprises a heavy chain CDR1 having a sequence identity of SEQ ID NOs: 1, 4, 7, 10, 13, 16, 85, 88, 91, 94, 97, or 100, a heavy' chain CDR2 having a sequence identity of SEQ ID NOs: 2, 5, 8, 11, 14, 17, 86, 89, 92, 95, 98, or 101, and a heavy chain CDR3 having a sequence identity to SEQ ID NOs: 3, 6, 9, 12, 15, 18, 87, 90, 93, 96, 99, or 102, and the VL domain comprises a light chain CDR1 having a sequence identity of SEQ ID NOs: 43, 46, 49, 52, 55, 58, 127, 130, 133, 136, 139, or 142, a light chain CDR2 having a sequence identity of SEQ ID NOs: 44, 47. 50, 53, 56, 59, 128. 131 , 134. 137, 140. or 143, and a light chain CDR3 having a sequence identity' of SEQ ID NOs: 45, 48, 51, 54, 57, 60, 129, 132, 135, 138, 141, or 144. In some embodiments, the HC VH domain further comprises framework regions (FRs) comprising an amino acid sequence 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99 % identical to the FRs of SEQ ID NOs: 20, 22, 24, 26, 28, 30, 104, 106, 108, 110, 112, or 114 and wherein the EC VL domain further comprises framework regions (FRs) comprising an amino acid sequence 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99 % identical to the FRs of SEQ ID NOs: 62, 64, 66, 68, 70, 72, 146, 148, 150, 152, 154, or 156. In some embodiments, the HCDRsl-3 and LCDRsl-3 and FR regions are from the same antibody (e.g. HCDRsl-3 and LCDRsl-3, and optionally FRs are all from BT-1992) as provided in FIG. 14.

[0304] In some embodiments, the HC VH domain further comprises framework regions (FRs) of a human heavy chain gene provided in FIG. 14 and wherein the EC VL domain further comprises FRs of a human light chain gene provided in FIG. 14.

[0305] In some embodiments, the VH domain of the first arm and the second arm both comprise an amino acid sequence comprising SEQ ID NOs: 20, 22, 24, 26, 28, 30, 104, 106, 108, 110, 112, or 114, and wherein the VL domain of the first arm and the second arm both comprise an amino acid sequence comprising SEQ ID NOs: 62, 64, 66, 68, 70, 72, 146, 148, 150, 152, 154, or 156. In some embodiments, the first and third polypeptide chain each comprises an amino acid sequence comprising SEQ ID NOs: 20, 22, 24, 26, 28, 30, 104, 106, 108, 110, 112, or 114 and the second and fourth polypeptide chain each comprises an amino acid sequence comprising SEQ ID NOs: 62, 64, 66, 68, 70, 72, 146, 148, 150, 152, 154, or 156. In some embodiments, the VH and VL are from the same antibody (e.g. VH and VL are from BT-1992) as provided in FIG. 14.

[0306] Bispecifi c Molecules

[0307] In some embodiments, the subject matter described herein relates to bispecific antibodies, functional equivalent thereof, antigen binding fragment thereof, a derivative thereof, an antibody-like bispecific molecule that binds to two different antigens, etc., which are collectively referred to herein as “bispecific molecules.” Bispecific molecules are engineered hybrid molecules with two different binding domains, which distinguishes them from monoclonal antibodies which have two identical binding domains, In some embodiments, the bispecific molecule binds to two different antigens - a first antigen and a second antigen. In some embodiments, the first antigen is LILRB4. In some embodiments the second antigen is LILRB2. It should be noted that in any of the bispecific molecule embodiments disclosed herein the second antigen binding domain that binds LILRB2 may also bind LILRB4 (i.e. it is cross-reactive with LILRB2 and LILRB4). In some embodiments, the bispecific molecules described herein are a class of therapeutics useful in the field of oncology and improving cancer treatment responses.

[0308] In some embodiments, the bispecific molecules of the present disclosure are bispecific antibodies comprising an Fc domain. In some embodiments, the bispecific molecules of the present disclosure are non-IgG-like molecules without an Fc domain. The Fc domain may play a role in the stability, solubility, and half-life of the bispecific molecules. The Fc domain may also play a role the bispecific molecules’ ability to kill cancer cells via complement-dependent and antibody-dependent cytotoxicity.

[0309] Bispecific molecules with an Fc domain, such as bispecific antibodies, can be produced by any methods know in the art such as knobs-into-holes, CrossMab, and DuoBody technologies. The knobs-into-holes method may be the most widely utilized method of bispecific antibody production. Using this method, the bispecific antibody is produced by engineering the CH3 domains of the two antibody Fc domains to express certain amino acids forming a “knob” or “hole” structures. The “knob” and “hole” structures interact with each other to promote heterozygous dimerization of the bispecific antibody, thus, assembling the chains of the bispecific antibody into the familiar “Y” shape. One challenge with this knobs- into-holes method is the occasional inaccurate light-chain binding to respective heavy chains. This challenge can be addressed by the CrossMab method of bispecific antibody production. The CrossMab technology uses an inter-arm cross-exchange of bispecific IgG antibodies and heterodimerization of heavy chains via knob-into-hole configuration. The inter-arm crossexchange involves swapping the location of the light chain variable domain with corresponding heavy chain variable domain. More details on the knob-in-hole and CrossMab formats can be found in Klein, C., et al. “Engineering therapeutic bispecific antibodies usingCrossMab technology,” Methods, Volume 154, 2019, pg 21-31, the content of which is incorporated herein by reference in its entirety. The DuoBody method of producing bispecific antibodies involves a Fab-arm exchange. The parental monoclonal antibodies undergo a selective reduction of their disulfide bonds at the hinge region. Chains are then recombined through amino acid substitutions to form a bispecific antibody. This method maintains the structural integrity of the antibody. More details on the DuoBody methodology can be found in Labrijn, A.F., et al., “Efficient generation of stable bispecific IgGl by controlled Fab-arm exchange,” PNAS 110(13): 5145-5150 (2013) and Labrijn, A.F., et al., “Efficient Generation of Bispecific Murine Antibodies for Pre-Clinical Investigations in Syngeneic Rodent Models,” Sei Report 7(1) (2017), the contents of each of which are incorporated herein by reference in their entirety.

[0310] In some embodiments, a non-IgG fragment-based bispecific molecule comprises a single-chain variable fragment (scFv), with VL and VH regions. In some embodiments, a peptide linker of amino acids couples the VL and VH regions to each other. Due to the lack of an Fc fragment, this type of bispecific molecule can have superior tumor tissue penetration, weak immunogenicity allowing for administration of a low drug dose, preserved binding activity of the parental antibody. However, there may be structure instability, a short half-life, and low expression. In some embodiments, the bispecific molecule comprises two tandem scFv molecules (ta-scFvs) comprising two scFvs chains that can be fused by a peptide linker. In some embodiments, an exemplary ta-scFv comprises a VLmAbA-VHmAbA- VLmAbB-VHmAbB. The structure of these bivalent scFv molecules contain a first binding region binding a first antigen and a second binding region binding a second antigen. In some embodiments, the bispecific molecule described herein is a ta-scFv. In some embodiments, the first antigen is LILRB4. In some embodiments, the second antigen is LILRB2.

[0311] In some embodiments, ta-scFv comprises a bispecific T cell engager (BiTE), which consists of two scFvs. One of the ta-scFv can bind to CD3 on T cells and the second one can bind to an antigen on the tumor cell. This concurrent binding of the BiTE to the T cell and the tumor cell can induce a cascade of immune events, such as T cells activation, release of cytokines, and secretion of perforin and granzyme B, leading to the tumor cell apoptosis. In some embodiments, the bispecific molecule described herein is a BiTE.

[0312] In some embodiments, the bispecific molecule disclosed herein is a diabody. In some embodiments, the diabody has a first polypeptide chain and a second polypeptide chain. In some embodiments, the first polypeptide chain comprises the VH domain of a first monoclonal antibody coupled to a VL domain of a second monoclonal antibody. In someembodiments, the second polypeptide chain comprises a VH domain of the second monoclonal antibody coupled to the VL domain of the first monoclonal antibody A. An exemplary diabody comprises a VHmAbl-VLmAb2 / VHmAb2-VLmAbl. In some embodiments, the diabody molecule has a VLmAbl-VHmAb2 / VLmAb2-VHmAbl configuration. In some embodiments, each variable domain is connected to another one by a peptide linker. In some embodiments, the diabody comprises a disulfide bond between the domains of one polypeptide chain. In some embodiments, two polypeptide chains are fused by one or more flexible peptide linkers. In some embodiments, a dimeric molecule can be generated with four binding sites based on the single-chain diabody format, the tandem diabody.

[0313] In some embodiments, the diabody-based bispecific molecule is a Dual-Affinity Re-Targeting Molecules (DART). In some embodiments, the DART comprises two polypeptide chains (VLmAbl-VHmAb2 / VLmAb2-VHmAbl). In some embodiments, the two polypeptide chains are linked by one or more disulfide bonds. In some embodiments, the disulfide bonds provide the molecule with greater stability. In some embodiments, the disulfide bonds may be formed due to the presence of a cysteine residue at the C-terminus. In some embodiments, the bispecific molecule described herein is a DART. More details on scFv-Based bispecific molecules can be found in Ahamadi-Fesharaki, R., et al., “SingleChain Variable Fragment-Based Bispecific Antibodies: Hitting Two Targets with One Sophisticated Arrow,” Mol Ther Oncolytics. 2019 Sep 27; 14: 38-56, the content of which is incorporated herein by reference in its entirety.

[0314] In some embodiments, the bispecific antibody comprises a first and second chain. In some embodiments, the first chain comprises an scFv with specificity for a first antigen and the second chain comprises an scFv with specificity for a second antigen. In some embodiments, the first and second chains each further comprise a Fc domain. In some embodiments, the bispecific antibody comprises a first and a second heavy chain and a first and a second light chain. The pairing of the first VH and first VL chains together can form a single antigen-binding site specific for a first antigen and the pairing of the second VH and second VL together forms a single antigen-binding site specific for a second antigen. In some embodiments, the first antigen is a LILRB4 protein. In some embodiments, the second antigen is a LILRB2 protein.

[0315] In some embodiments, the bispecific antibodies disclosed herein may contain substitutions or modifications of the constant region (i.e., the Fc region). The antibodies disclosed herein may contain one or more additional amino acid residue substitutions,mutations and / or modifications, which result in a compound with preferred characteristics including, but not limited to: altered pharmacokinetics, increased serum half-life, increase binding affinity, reduced binding affinity, reduced immunogenicity, increased production, altered Fc ligand binding, altered glycosylation and / or disulfide bonds and modified binding specificity.

[0316] Various bispecific molecule formats are known in the art, for example, as described in FIG. 2 of Konterman R.E. et al., Bispecific Antibodies, Drug Discov. Today 20 (July (7)) (2015) 838-847 and FIG. 1 of Suurs F.V., et al., A review of bispecific antibodies and antibody constructs in oncology and clinical challenges, Pharmacol. Tlier. 2019 Sep; 201 : 103 - 119, the contents of each of which is hereby incorporated by reference in their entirety.

[0317] In certain aspects, the subject matter disclosed herein provides a bispecific molecule comprising a first antigen binding region and a second antigen binding region, wherein the first antigen binding region binds a LILRB4 protein and the second antigen binding region binds a LILRB2 protein.

[0318] In some embodiments, the first antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 46, a light chain CDR2 (CDRL2) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 47, a light chain CDR3 (CDRL3) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 48 and the VH domain comprises a heavy chain CDR1 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 4, a heavy chain CDR2 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 5, and a heavy chain CDR3 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 6. In some embodiments, the first antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) of SEQ ID NO: 46, a light chain CDR2 (CDRL2) ofSEQ ID NO: 47, a light chain CDR3 (CDRL3) of SEQ ID NO: 48 and the VH domain comprises a heavy chain CDR1 of SEQ ID NO: 4, a heavy chain CDR2 of SEQ ID NO: 5, and a heavy chain CDR3 of SEQ ID NO: 6.

[0319] In some embodiments, the first antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) having a sequence identity' of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 52, a light chain CDR2 (CDRL2) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 53, a light chain CDR3 (CDRL3) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 54 and the VH domain comprises a heavy chain CDR1 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 10, a heavy chain CDR2 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 11, and a heavy chain CDR3 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 12. In some embodiments, the first antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) of SEQ ID NO: 52, a light chain CDR2 (CDRL2) of SEQ ID NO: 53, a light chain CDR3 (CDRL3) of SEQ ID NO: 54 and the VH domain comprises a heavy chain CDR1 of SEQ ID NO: 10, a heavy chain CDR2 of SEQ ID NO: 11 , and a heavy chain CDR3 of SEQ ID NO: 12.

[0320] In some embodiments, the first antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 49, a light chain CDR2 (CDRL2) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 50, a light chain CDR3 (CDRL3) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ IDNO: 51 and the VH domain comprises a heavy chain CDR1 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 7, a heavy chain CDR2 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 8, and a heavy chain CDR3 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 9. In some embodiments, the first antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) of SEQ ID NO: 49, a light chain CDR2 (CDRL2) of SEQ ID NO: 50, a light chain CDR3 (CDRL3) of SEQ ID NO: 51 and the VH domain comprises a heavy chain CDR1 of SEQ ID NO: 7, a heavy chain CDR2 of SEQ ID NO: 8, and a heavy chain CDR3 of SEQ ID NO: 9.

[0321] In some embodiments, the second antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 43, a light chain CDR2 (CDRL2) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 44, a light chain CDR3 (CDRL3) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 45 and the VH domain comprises a heavy chain CDR1 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 1, a heavy chain CDR2 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2, and a heavy chain CDR3 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 3. In some embodiments, the second antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) of SEQ ID NO: 43, a light chain CDR2 (CDRL2) of SEQ ID NO: 44, a light chain CDR3 (CDRL3) of SEQ ID NO: 45 and the VH domaincomprises a heavy chain CDR1 of SEQ ID NO: 1, a heavy chain CDR2 of SEQ ID NO: 2, and a heavy chain CDR3 of SEQ ID NO: 3.

[0322] In some embodiments, the second antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRLl) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 58, a light chain CDR2 (CDRL2) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 59, a light chain CDR3 (CDRL3) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 60 and the VH domain comprises a heavy chain CDR1 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 16, a heavy chain CDR2 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 17, and a heavy chain CDR3 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 18. In some embodiments, the second antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRLl ) of SEQ ID NO: 58, a light chain CDR2 (CDRL2) of SEQ ID NO: 59, a light chain CDR3 (CDRL3) of SEQ ID NO: 60 and the VH domain comprises a heavy chain CDR1 of SEQ ID NO: 16, a heavy chain CDR2 of SEQ ID NO: 17, and a heavy chain CDR3 of SEQ ID NO: 18.

[0323] In some embodiments, the second antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRLl) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 55, a light chain CDR2 (CDRL2) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 56, a light chain CDR3 (CDRL3) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 57 and the VH domain comprises a heavy chain CDR1 having a sequence identity of atleast 80%, 81%, 82%, 83%, 84%, 85%. 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 13, a heavy chain CDR2 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 14, and a heavy chain CDR3 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 15. In some embodiments, the second antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) of SEQ ID NO: 55, a light chain CDR2 (CDRL2) of SEQ ID NO: 56, a light chain CDR3 (CDRL3) of SEQ ID NO: 57 and the VH domain comprises a heavy chain CDRI of SEQ ID NO: 13, a heavy chain CDR2 of SEQ ID NO: 14, and a heavy chain CDR3 of SEQ ID NO: 15.

[0324] In some embodiments, the first antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDRI (CDRL1) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 46, a light chain CDR2 (CDRL2) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 47, a light chain CDR3 (CDRL3) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 48 and the VH domain comprises a heavy chain CDRI having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 4, a heavy chain CDR2 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 5, and a heavy chain CDR3 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 6; and the second antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDRI (CDRL1) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 43, a light chain CDR2 (CDRL2 ) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%,95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 44, a light chain CDR3 (CDRL3) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 45 and the VH domain comprises a heavy chain CDR1 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 1, a heavy chain CDR2 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2, and a heavy chain CDR3 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 3. In some embodiments, the first antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) of SEQ ID NO: 46, a light chain CDR2 (CDRL2) of SEQ ID NO: 47, a light chain CDR3 (CDRL3) of SEQ ID NO: 48 and the VH domain comprises a heavy chain CDR1 of SEQ ID NO: 4, a heavy chain CDR2 of SEQ ID NO: 5, and a heavy chain CDR3 of SEQ ID NO: 6; and the second antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) of SEQ ID NO: 43, a light chain CDR2 (CDRL2) of SEQ ID NO: 44, a light chain CDR3 (CDRL3) of SEQ ID NO: 45 and the VH domain comprises a heavy chain CDR1 of SEQ ID NO: 1, a heavy chain CDR2 of SEQ ID NO: 2, and a heavy chain CDR3 of SEQ ID NO: 3.

[0325] In some embodiments, the first antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 46, a light chain CDR2 (CDRL2) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 47, a light chain CDR3 (CDRL3) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 48 and the VH domain comprises a heavy chain CDR1 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 4, a heavy chain CDR2 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%,91%, 92%, 93%, 94%, 95%, 96%. 97%, 98% or 99% identity to SEQ ID NO: 5, and a heavy chain CDR3 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 6; and the second antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 58, a light chain CDR2 (CDRL2) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 59, a light chain CDR3 (CDRL3) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 60 and the VH domain comprises a heavy chain CDR1 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 16, a heavy chain CDR2 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 17, and a heavy chain CDR3 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 18. In some embodiments, the first antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) of SEQ ID NO: 46, a light chain CDR2 (CDRL2) of SEQ ID NO: 47, a light chain CDR3 (CDRL3) of SEQ ID NO: 48 and the VH domain comprises a heavy chain CDR1 of SEQ ID NO: 4, a heavy chain CDR2 of SEQ ID NO: 5, and a heavy chain CDR3 of SEQ ID NO: 6; and the second antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) of SEQ ID NO: 58, a light chain CDR2 (CDRL2) of SEQ ID NO: 59, a light chain CDR3 (CDRL3) of SEQ ID NO: 60 and the VH domain comprises a heavy chain CDR1 of SEQ ID NO: 16, a heavy chain CDR2 of SEQ ID NO: 17, and a heavy chain CDR3 of SEQ ID NO: 18.

[0326] In some embodiments, the first antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%,98% or 99% identity to SEQ ID NO: 46, a light chain CDR2 (CDRL2) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 47, a light chain CDR3 (CDRL3) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 48 and the VH domain comprises a heavy chain CDR1 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 4, a heavy chain CDR2 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 5, and a heavy chain CDR3 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 6; and the second antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 55, a light chain CDR2 (CDRL2) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 56, a light chain CDR3 (CDRL3) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 57 and the VH domain comprises a heavy chain CDR1 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 13, a heavy chain CDR2 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 14, and a heavy chain CDR3 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 15. In some embodiments, the first antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) of SEQ ID NO: 46, a light chain CDR2 (CDRL2) of SEQ ID NO: 47, a light chain CDR3 (CDRL3) of SEQ ID NO: 48 and the VH domain comprises a heavy chain CDR1 of SEQ ID NO: 4, a heavy chain CDR2 of SEQ ID NO: 5, and a heavy chain CDR3 of SEQ ID NO: 6; and the second antigen binding region comprisesa light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) of SEQ ID NO: 55, a light chain CDR2 (CDRL2) of SEQ ID NO: 56, a light chain CDR3 (CDRL3) of SEQ ID NO: 57 and the VH domain comprises a heavy chain CDR1 of SEQ ID NO: 13, a heavy chain CDR2 of SEQ ID NO: 14, and a heavy chain CDR3 of SEQ ID NO: 15.

[0327] In some embodiments, the first antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 52, a light chain CDR2 (CDRL2) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 53, a light chain CDR3 (CDRL3) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 54 and the VH domain comprises a heavy chain CDR1 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 10, a heavy chain CDR2 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 11, and a heavy chain CDR3 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 12; and the second antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 43, a light chain CDR2 (CDRL2) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 44, a light chain CDR3 (CDRL3) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 45 and the VH domain comprises a heavy chain CDR1 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 1, a heavy chain CDR2 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%,93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2, and a heavy chain CDR3 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 3. In some embodiments, the first antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) of SEQ ID NO: 52, a light chain CDR2 (CDRL2) of SEQ ID NO: 53, a light chain CDR3 (CDRL3) of SEQ ID NO: 54 and the VH domain comprises a heavy chain CDR1 of SEQ ID NO: 10, a heavy chain CDR2 of SEQ ID NO: 11, and a heavy chain CDR3 of SEQ ID NO: 12; and the second antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) of SEQ ID NO: 43, a light chain CDR2 (CDRL2) of SEQ ID NO: 44, a light chain CDR3 (CDRL3) of SEQ ID NO: 45 and the VH domain comprises a heavy chain CDR1 of SEQ ID NO: 1, a heavy chain CDR2 of SEQ ID NO: 2, and a heavy chain CDR3 of SEQ ID NO: 3.

[0328] In some embodiments, the first antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 52, a light chain CDR2 (CDRL2) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 53, a light chain CDR3 (CDRL3) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 54 and the VH domain comprises a heavy chain CDR1 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 10, a heavy chain CDR2 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 11, and a heavy chain CDR3 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 12; and the second antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%identity to SEQ ID NO: 58, a light chain CDR2 (CDRL2) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 59, a light chain CDR3 (CDRL3) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 60 and the VH domain comprises a heavy chain CDR1 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 16, a heavy chain CDR2 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 17, and a heavy chain CDR3 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 18.

[0329] In some embodiments, the first antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRLl) of SEQ ID NO: 52, a light chain CDR2 (CDRL2) of SEQ ID NO: 53, a light chain CDR3 (CDRL3) of SEQ ID NO: 54 and the VH domain comprises a heavy chain CDR1 of SEQ ID NO: 10, a heavy chain CDR2 of SEQ ID NO: 11 , and a heavy chain CDR3 of SEQ ID NO: 12; and the second antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRLl ) of SEQ ID NO: 58, a light chain CDR2 (CDRL2) of SEQ ID NO: 59, a light chain CDR3 (CDRL3) of SEQ ID NO: 60 and the VH domain comprises a heavy chain CDR1 of SEQ ID NO: 16, a heavy chain CDR2 of SEQ ID NO: 17, and a heavy chain CDR3 of SEQ ID NO: 18.

[0330] In some embodiments, the first antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRLl) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 52, a light chain CDR2 (CDRL2) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 53, a light chain CDR3 (CDRL3) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 54 and the VH domain comprises a heavy chain CDR1 having a sequence identity of atleast 80%, 81%, 82%, 83%, 84%, 85%. 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 10, a heavy chain CDR2 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 11, and a heavy chain CDR3 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 12; and the second antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 55, a light chain CDR2 (CDRL2) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 56, a light chain CDR3 (CDRL3) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 57 and the VH domain comprises a heavy chain CDR1 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 13, a heavy chain CDR2 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 14, and a heavy chain CDR3 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 15. In some embodiments, the first antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) of SEQ ID NO: 52, a light chain CDR2 (CDRL2) of SEQ ID NO: 53, a light chain CDR3 (CDRL3) of SEQ ID NO: 54 and the VH domain comprises a heavy chain CDR1 of SEQ ID NO: 10, a heavy chain CDR2 of SEQ ID NO: 11 , and a heavy chain CDR3 of SEQ ID NO: 12; and the second antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRLl ) of SEQ ID NO: 55, a light chain CDR2 (CDRL2) of SEQ ID NO: 56, a light chain CDR3 (CDRL3) of SEQ ID NO: 57 and the VH domain comprises a heavy chain CDR1 of SEQ ID NO: 13, a heavy chain CDR2 of SEQ ID NO: 14, and a heavy chain CDR3 of SEQ ID NO: 15.

[0331] In some embodiments, the first antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1 ) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 49, a light chain CDR2 (CDRL2) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 50, a light chain CDR3 (CDRL3) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 51 and the VH domain comprises a heavy chain CDRI having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 7, a heavy chain CDR2 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 8, and a heavy chain CDR3 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 9; and the second antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDRI (CDRL1) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 43, a light chain CDR2 (CDRL2) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 44, a light chain CDR3 (CDRL3) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 45 and the VH domain comprises a heavy chain CDR I having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 1, a heavy chain CDR2 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2, and a heavy chain CDR3 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 3. In some embodiments, the first antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domaincomprises a light chain CDR1 (CDRL1) of SEQ ID NO: 49, a light chain CDR2 (CDRL2) of SEQ ID NO: 50, a light chain CDR3 (CDRL3) of SEQ ID NO: 51 and the VH domain comprises a heavy chain CDR1 of SEQ ID NO: 7, a heavy chain CDR2 of SEQ ID NO: 8, and a heavy chain CDR3 of SEQ ID NO: 9; and the second antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) of SEQ ID NO: 43, a light chain CDR2 (CDRL2) of SEQ ID NO: 44, a light chain CDR3 (CDRL3) of SEQ ID NO: 45 and the VH domain comprises a heavy chain CDR1 of SEQ ID NO: 1, a heavy chain CDR2 of SEQ ID NO: 2, and a heavy chain CDR3 of SEQ ID NO: 3.

[0332] In some embodiments, the first antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRLl ) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 49, a light chain CDR2 (CDRL2) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 50, a light chain CDR3 (CDRL3) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 51 and the VH domain comprises a heavy chain CDR1 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 7, a heavy chain CDR2 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 8, and a heavy chain CDR3 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 9; and the second antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRLl) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 58, a light chain CDR2 (CDRL2) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 59, a light chain CDR3 (CDRL3) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 60and the VH domain comprises a heavy chain CDR1 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 16, a heavy chain CDR2 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 17, and a heavy chain CDR3 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 18. In some embodiments, the first antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) of SEQ ID NO: 49, a light chain CDR2 (CDRL2) of SEQ ID NO: 50, a light chain CDR3 (CDRL3) of SEQ ID NO: 51 and the VH domain comprises a heavy chain CDR1 of SEQ ID NO: 7, a heavy chain CDR2 of SEQ ID NO: 8, and a heavy chain CDR3 of SEQ ID NO: 9; and the second antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) of SEQ ID NO: 58, a light chain CDR2 (CDRL2) of SEQ ID NO: 59, a light chain CDR3 (CDRL3) of SEQ ID NO: 60 and the VH domain comprises a heavy chain CDR1 of SEQ ID NO: 16, a heavy chain CDR2 of SEQ ID NO: 17, and a heavy chain CDR3 of SEQ ID NO: 18.

[0333] In some embodiments, the first antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRLl ) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 49, a light chain CDR2 (CDRL2) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 50, a light chain CDR3 (CDRL3) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 51 and the VH domain comprises a heavy chain CDR1 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 7, a heavy chain CDR2 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 8, and a heavy chain CDR3 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQID NO: 9; and the second antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 55, a light chain CDR2 (CDRL2) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 56, a light chain CDR3 (CDRL3) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 57 and the VH domain comprises a heavy chain CDR1 having a sequenc e identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 13, a heavy chain CDR2 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 14, and a heavy chain CDR3 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 15. In some embodiments, the first antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) of SEQ ID NO: 49, a light chain CDR2 (CDRL2) of SEQ ID NO: 50, a light chain CDR3 (CDRL3) of SEQ ID NO: 51 and the VH domain comprises a heavy chain CDR1 of SEQ ID NO: 7, a heavy chain CDR2 of SEQ ID NO: 8, and a heavy chain CDR3 of SEQ ID NO: 9; and the second antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) of SEQ ID NO: 55, a light chain CDR2 (CDRL2) of SEQ ID NO: 56, a light chain CDR3 (CDRL3) of SEQ ID NO: 57 and the VH domain comprises a heavy chain CDR1 of SEQ ID NO: 13, a heavy chain CDR2 of SEQ ID NO: 14, and a heavy chain CDR3 of SEQ ID NO: 15.

[0334] In some embodiments, the first antigen binding region of the bispecific molecule binds LILRB4 with an equilibrium dissociation constant (KD) from about 10-7M to about 10'11M. In some embodiments, the first antigen binding region of the bispecific molecule binds LILRB4 with an association constant from about 105Ms-1to about 106Ms-1. In some embodiments, the first antigen binding region of the bispecific molecule binds LILRB4 with a dissociation constant from about 10-2s-1to about 10-5s-1.

[0335] In some embodiments, the LILRB4 is a human LILRB4. In some embodiments, the LILRB4 is a cynomolgus macaque LILRB4. In some embodiments, the LILRB4 is a mouse ortholog of LILRB4. In some embodiments, the bispecific molecule inhibits a LILRB4-dependent immune checkpoint. In some embodiments, the bispecific molecule depletes LILRB4+ monocytes. In some embodiments, the bispecific molecule does not deplete immune-supporting myeloid populations. In some embodiments, the bispecific molecule is a blocking molecule.

[0336] In some embodiments, VH domain further comprises framework regions (FRs) of a human IGHV gene and wherein the VL domain further comprises FRs of a human IGKV gene.

[0337] In some embodiments, the bispecific molecule comprises (a) a first arm comprising the first antigen binding region wherein the first antigen binding region binds LILRB4 and (b) a second arm comprising the second antigen binding region wherein the second antigen binding region binds LILRB2. In some embodiments, the first and second arms each further comprise a CHI domain, a hinge domain, a Fc domain (CH2-CH3) and a CL domain. In some embodiments, the VH domain of the first arm is encoded by a first polypeptide chain; the VL domain of the first arm is encoded by a second polypeptide chain; the VH domain of the second arm is encoded by a third polypeptide chain; the VL domain of the second arm is encoded by a fourth polypeptide chain; and wherein the VH domain and VL domain of the first arm form the first antigen binding region, wherein the first antigen binding region binds LILRB4, and wherein the VH domain and VL domain of the second arm form the second antigen binding region, wherein the second antigen binding region binds LILRB2.

[0338] In some embodiments, the first and third polypeptide chain each further encode a hinge domain, a CHI domain, and an Fc domain, and wherein the second and fourth polypeptide chain each further encode a CL domain, In some embodiments, the first, second, third, and fourth polypeptide chains comprise different amino acid sequences. In some embodiments, the VH domain of the first arm comprises an amino acid sequence comprising SEQ ID NO: 22, SEQ ID NO: 26, or SEQ ID NO: 24 and the VH domain of the second arm comprises an amino acid sequence comprising SEQ ID NO: 28, SEQ ID NO: 30, or SEQ ID NO: 20. In some embodiments, the VL domain of the first arm comprises an amino acid sequence comprising SEQ ID NO: 64, SEQ ID NO: 68, or SEQ ID NO: 66 and the VL domain of the second arm comprises an amino acid sequence comprising SEQ ID NO: 70, SEQ ID NO: 72, or SEQ ID NO: 62. In some embodiments, the first arm comprises an aminoacid sequence comprising SEQ ID NO: 34, SEQ ID NO: 38, or SEQ ID NO: 36 and the second comprises an amino acid sequence comprising SEQ ID NO: 40, SEQ ID NO: 42, or SEQ ID NO: 32. In some embodiments, the first arm comprises an amino acid sequence comprising SEQ ID NO: 76, SEQ ID NO: 80, or SEQ ID NO: 78 and the second comprises an amino acid sequence comprising SEQ ID NO: 82, SEQ ID NO: 84, or SEQ ID NO: 74.

[0339] hr some embodiments, the first and second polypeptide chains are linked by one or more covalent disulfide bonds and the third and fourth polypeptide chains are linked by one or more covalent disulfide bonds. In some embodiments, the first and third polypeptide chains are linked by one or more covalent disulfide bonds.

[0340] In some embodiments, the bispecific molecule binds LILRB2 with an equilibrium dissociation constant (KD) from about 10-7M to about 10-11M. In some embodiments, the bispecific molecule binds LILRB2 with an association constant from about 10-5Ms-1. In some embodiments, the bispecific molecule binds LILRB2 with a dissociation constant from about 10-2s-1to about 10-5s-1.

[0341] In some embodiments, the LILRB2 is a human LILRB2. In some embodiments, the LILRB2 is a cynomolgus macaque LILRB2. In some embodiments, the LILRB2 is a mouse ortholog of LILRB2. In some embodiments, the anti-LILRB2 antibody inhibits a LILRB2-dependent immune checkpoint. In some embodiments, the bispecific molecule depletes LILRB2+ monocytes. In some embodiments, the bispecific molecule does not deplete immune-supporting myeloid populations. In some embodiments, the bispecific molecule is a blocking bispecific.

[0342] In certain aspects, the subject matter disclosed herein provides a pharmaceutical composition comprising any of the bispecific molecules described herein.

[0343] In some embodiments, the pharmaceutical composition described herein further comprising one or more pharmaceutically-acceptable diluents, one or more pharmaceutically- acceptable carriers or one or more pharmaceutically-acceptable excipients.

[0344] In certain aspects, the subject matter disclosed herein provides a method of treating or preventing cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of any of the bispecific molecules described herein or any of the pharmaceutical compositions described herein.

[0345] In some embodiments, the cancer comprises a solid tumor. In some embodiments, the cancer is kidney cancer, breast cancer, brain tumor, head and neck cancer, liver cancer, melanoma, non-small cell lung cancer (NSCLC), bladder cancer, cervical cancer, colon cancer, renal cell cancer, skin cancer, stomach cancer, rectal cancer, gastrointestinal,pancreatic cancer, lung cancer, thymic carcinoma, ovarian cancer, prostate cancer, or endometrial cancer. In some embodiments, the cancer is a liquid cancer. In some embodiments, the liquid cancer is leukemia, lymphoma, Hodgkin lymphoma, or myeloma. In some embodiments, the liquid cancer is acute myeloid leukemia (AML). In some embodiments, the liquid cancer is B-cell malignancy. In some embodiments, the administration of the bispecific molecule or the pharmaceutical composition is capable of inhibiting tumor growth.

[0346] In certain aspects, the subject matter disclosed herein provides a method of inhibiting myeloid-dependent immune suppression or promoting immune activation in a subject in need thereof, the method comprising administering to the subject an effective amount of any of the bispecific molecules described herein or any of the pharmaceutical compositions described herein.

[0347] In some embodiments, the subject is a human subject.

[0348] In certain aspects, the subject matter disclosed herein provides a polynucleotide encoding at least a portion of any one of the bispecific molecules described herein.

[0349] In certain aspects, the subject matter disclosed herein provides a genetically engineered cell comprising any of the bispecific molecules described herein.

[0350] In certain aspects, the subject matter disclosed herein provides a composition comprising: one or more vectors comprising one or more polynucleotide sequences encoding any of the bispecific molecules described herein.

[0351] In certain aspects, the subject matter disclosed herein provides a composition comprising: a first set of one or more vectors comprising one or more polynucleotide sequences encoding the first antigen binding region of any of the bispecific molecules described herein; and a second set of one or more vectors comprising one or more poly nucleotide sequences encoding the antigen binding region of any of the bispecific molecules described herein.

[0352] In certain aspects, the subject matter disclosed herein provides a bispecific molecule means for binding LILRB4 and LILRB2.

[0353] In some embodiments, the means comprises any one of the bispecific molecules described herein. In some embodiments, the means is capable of treating or preventing cancer in a subject in need thereof or inhibiting myeloid-dependent immune suppression or promoting immune activation in a subject in need thereof.

[0354] Pharmaceutical Compositions of the Bispecific Molecules

[0355] In some embodiments, the subject matter disclosed herein provides a pharmaceutical composition comprising any of the bispecific molecules described herein. In some embodiments, the subject matter disclosed herein provides a pharmaceutical composition comprising any if the bispecific antibodies described here. In some embodiments, the subject matter disclosed herein provides a pharmaceutical composition comprising any of the anti-LILRB4 and anti- LILRB2 bispecific antibodies disclosed herein. In some embodiments, the pharmaceutical composition disclosed herein further comprises one or more pharmaceutically-acceptable diluents, one or more pharmaceutically-acceptable carriers, or one or more pharmaceutically-acceptable excipients.

[0356] In some embodiments, the subject matter disclosed herein provides a polynucleotide encoding the any of the bispecific molecules described herein. In some embodiments, the subject matter disclosed herein provides a polynucleotide encoding the any of bispecific antibodies described here. In some embodiments, the subject matter disclosed herein provides a polynucleotide encoding the any of anti-LILRB4 and anti-LILRB2 bispecific antibodies disclosed herein. In some embodiments, the subject matter disclosed herein provides a genetically engineered cell comprising any of the bispecific molecules described herein. In some embodiments, the subject matter disclosed herein provides a genetically engineered cell comprising any of the bispecific antibodies described herein. In some embodiments, the subject matter disclosed herein provides a genetically engineered cell comprising any of anti-LILRB4 and anti-LILRB2 antibodies disclosed herein. In some embodiments, the subject matter disclosed herein provides a genetically engineered cell comprising a polynucleotide encoding the any of the bispecific molecules described herein. In some embodiments, the subject matter disclosed herein provides a genetically engineered cell comprising a polynucleotide encoding the any of the bispecific antibodies described herein. In some embodiments, the subject matter disclosed herein provides a genetically engineered cell comprising a polynucleotide encoding the any of theanti-LILRB4 and anti- LILRB2 bispecific antibodies disclosed herein.

[0357] In certain aspects, also herein provided are pharmaceutical compositions comprising the above-described bispecific molecules (or one or more polynucleotides encoding one or more molecules). In some embodiments, the subject matter described herein relates to a pharmaceutical composition comprising an effective amount of the bispecific molecules (or one or more polynucleotides encoding one or more bispecific molecules) described herein and a pharmaceutically-acceptable diluent, carrier or excipient, In certainembodiments, the bispecific molecules are conjugated with other molecules to increase their effectiveness as is known by those practiced in the art.

[0358] As used herein, “pharmaceutical composition” means a therapeutically effective formulation according to the invention. A “therapeutically effective amount,” or “effective amount,” or “therapeutically effective,” as used herein, refers to that amount which provides a therapeutic effect for a given condition and administration regimen. A therapeutically effective amount can be determined by a skilled person based on patient characteristics, such as age, weight, sex, condition, complications, other diseases, etc., as is well known in the art.

[0359] In some embodiments, the pharmaceutical compositions described herein can be administered as solid compositions. In some embodiments, the solid compositions comprise excipients including but not limited to lactose, starch, cellulose, milk sugar or high molecular weight polyethylene glycols. In some embodiments, the pharmaceutical compositions described herein can be administered as aqueous suspensions and / or elixirs, In some embodiments, the pharmaceutical compositions described herein may be combined with various sweetening or flavouring agents, coloring matter or dyes, with emulsifying and / or suspending agents and with diluents such as water, ethanol, propylene glycol and glycerin, and combinations thereof.

[0360] In some embodiments, the pharmaceutical compositions described herein can be administered parenterally, for example, intravenously, intra-arterially, intraperitoneally, intra- thecally, intraventricularly, intrastemally, intracranially, intra-muscularly or subcutaneously, or they may be administered by infusion techniques. In some embodiments, the pharmaceutical compositions described herein can be administered in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood. The preparation of suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques well- known to those skilled in the art.

[0361] In some embodiments, pharmaceutical compositions suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The pharmaceutical compositions can be presented in unit-dose or multi-dose containers. The pharmaceutical compositions can be sealed ampoules or vials. The pharmaceutical compositions can bestored in a freeze-dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, such as water for injections, immediately prior to use.

[0362] The compounds and pharmaceutical compositions of the present invention can be employed in combination therapies, that is, the compounds and pharmaceutical compositions can be administered concurrently with, prior to, or subsequent to, one or more other desired therapeutics or medical procedures (e.g.. bispecific antibodies can be used in combination treatment with another treatment). The particular combination of therapies (therapeutics or procedures) to employ in a combination regimen will take into account compatibility of the desired therapeutics and / or procedures and the desired therapeutic effect to be achieved. It will also be appreciated that the therapies employed may achieve a desired effect for the same disorder (for example, the compound of the present invention may be administered concurrently with another therapeutic or prophylactic).

[0363] The invention also provides a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the invention. Optionally associated with such container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use or sale for human administration.

[0364] Compositions can be formulated with appropriate carriers and adjuvants using techniques to yield compositions suitable for prophylaxis or treatment. The compositions can include an adjuvant, such as, for example but not limited to, alum, poly IC, MF-59, squalene- based adjuvants, or liposomal based adjuvants suitable for prophylaxis or treatment.

[0365] In some embodiments, the antibodies described herein are encoded by nucleic acids which are prepared in a mRNA-LNP or a DNA-LNP formulation for administration to a subject.

[0366] Production of Bispecific Molecules

[0367] The bispecific molecules disclosed herein can be produced by any method known in the art. In some embodiments, the bispecific antibodies disclosed herein are produced by culturing a cell transfected or transformed with one or more vectors comprising nucleic acid sequences encoding a bispecific molecule described herein. In some embodiments the method of production comprises isolating the bispecific molecule.

[0368] In some embodiments, the bispecific molecules are synthesized by methods which result in molecules that are not contaminated by other immunoglobulins. In some embodiments, the parental monoclonal antibodies to be used in accordance with the presentinvention may be made by a variety of techniques known in the art, including, for example, the hybridoma method, recombinant DNA methods, phage-display technologies, B-cell discovery methods, and technologies for producing human or human-like antibodies in animals that have parts or all of the human immunoglobulin loci or genes encoding human immunoglobulin sequences.

[0369] In some embodiments, expression of a bispecific molecule comprises expression vector(s) containing a polynucleotide that encodes an anti-LILRB4 or anti-LILRB4 / LILRB2 antibody. Methods that are well known to those skilled in the art can be used to construct expression vectors comprising bispecific molecules coding sequences and appropriate transcriptional and translational control signals. These methods include, for example, in vitro recombinant DNA techniques, synthetic techniques, and in vivo genetic recombination. Particular embodiments provide replicable vectors comprising a nucleotide sequence encoding an anti-LILRB4 and anti- LILRB2 bispecific molecule disclosed herein operably linked to a promoter. In preferred embodiments, such vectors may include one or more nucleotide sequences encoding the heavy chain of a bispecific antibody (or fragment thereof), a nucleotide sequence encoding the light chain of a bispecific antibody (or fragment thereof), or a nucleotide sequence encoding both the heavy and light chain of a bispecifc antibody (or fragment thereof).

[0370] The polynucleotide(s) encoding the bispecific antibody may be modified, for example, by substituting the coding sequence for human heavy- and light-chain constant domains or by covalently joining to the immunoglobulin coding sequence all or part of the coding sequence for a non-immunoglobulin polypeptide chain. Typically, such nonimmunoglobulin polypeptides are substituted for the constant domains of an antibody.

[0371] Various expression systems for producing antibodies are known in the art, and include, prokaryotic (e.g., bacteria), plant, insect, yeast, and mammalian expression systems. Suitable cell lines, can be transformed, transduced, or transfected with nucleic acids containing coding sequences for antibodies or portions of antibodies disclosed herein in order to produce the antibody of interest. Expression vectors containing such nucleic acid sequences, which can be linked to at least one regulatory sequence in a manner that allows expression of the nucleotide sequence in a host cell, can be introduced via methods known in the art. Practitioners in the art understand that designing an expression vector can depend on factors, such as the choice of host cell to be transfected and / or the type and / or amount of desired protein to be expressed. Enhancer regions, which are those sequences found upstream or downstream of the promoter region in non-coding DNA regions, are also knownin the art to be important in optimizing expression. If needed, origins of replication from viral sources can be employed, such as if a prokaryotic host is utilized for introduction of plasmid DNA. However, in eukaryotic organisms, chromosome integration is a common mechanism for DNA replication. For stable transfection of mammalian cells, a small fraction of cells can integrate introduced DNA into their genomes. The expression vector and transfection method utilized can be factors that contribute to a successfill integration event. For stable amplification and expression of a desired protein, a vector containing DNA encoding a protein of interest (e.g., antibodies and fragments thereof) is stably integrated into the genome of eukaryotic cells (for example mammalian cells), resulting in the stable expression of transfected genes. A gene that encodes a selectable marker (for example, resistance to antibiotics or drugs) can be introduced into host cells along with the gene of interest in order to identify and select clones that stably express a gene encoding a protein of interest. Cells containing the gene of interest can be identified by drug selection wherein cells that have incorporated the selectable marker gene will survive in the presence of the drug. Cells that have not incorporated the gene for the selectable marker die. Surviving cells can then be screened for the production of the desired antibody molecule. A person of skill in the art would recognize that methods for producing antibodies know in the art can be adapted to produce bispecific antibodies and or any bispecific molecules without an Fc domain.

[0372] In some embodiments, the bispecific molecules disclosed herein are encoded in one or more vectors for expression in a cell line. In some embodiments, the one or more vectors comprise one or more polynucleotide sequences that encode an anti-LILRB4 and anti-LILRB2 bispecific molecule. In some embodiments, the one or more vectors are transfected into one or more cell lines for expression. In some embodiments, the one or more vectors comprise polynucleotide sequences encoding one or more light chains and one or more heavy chains of the bispecific antibodies described here. For example, in some embodiments, a first vector may comprise a polynucleotide sequence encoding a first light chain, a second vector may comprise a polynucleotide sequence encoding a first heavy chain, of an anti-LILRB4 and anti-LILRB2 bispecific antibody while a third vector may comprise a polynucleotide sequence encoding a second light chain, a fourth vector may comprise a polynucleotide sequence encoding a second heavy chain, of an anti-LILRB4 and anti- LILRB2 bispecific antibody. In some embodiments, all four vectors are transfected into one or more cell lines for expression. A host cell strain, which modulates the expression of the inserted sequences, or modifies and processes the nucleic acid in a specific fashion desired also may be chosen. Such modifications (for example, glycosylation and other post-translational modifications) and processing (for example, cleavage) of protein products may be important for the function of the bispecific molecules. Different host cell strains have characteristic and specific mechanisms for the post-translational processing and modification of proteins and gene products. As such, appropriate host systems or cell lines can be chosen to ensure the correct modification and processing of the foreign antibody expressed. Thus, eukaryotic host cells possessing the cellular machinery for proper processing of the primary transcript, glycosylation, and phosphorylation of the gene product may be used.

[0373] Various culturing parameters can be used with respect to the host cell being cultured. Appropriate culture conditions for mammalian cells are well known in the art or can be determined by the skilled artisan (see, for example, Animal Cell Culture: A Practical Approach 2ndEd., Rickwood, D. and Hames, B. D., eds. (Oxford University Press: New York, 1992)). Cell culturing conditions can vary according to the type of host cell selected. Commercially available media can be utilized.

[0374] The bispecific molecules disclosed herein can be purified from any human or nonhuman cell that expresses the molecule, including those that have been transfected with expression constructs that express the molecule or fragments thereof. For molecule recovery, isolation and / or purification, the cell culture medium or cell lysate is centrifuged to remove particulate cells and cell debris. The desired molecule is isolated or purified away from contaminating soluble proteins and polypeptides by suitable purification techniques. Nonlimiting purification methods for proteins / molecules / antibodies include: size exclusion chromatography, affinity chromatography, ion exchange chromatography, ethanol precipitation; reverse phase HPLC; chromatography on a resin, such as silica, or cation exchange resin, e.g., DEAE; chromatofocusing; SDS-PAGE; ammonium sulfate precipitation; gel filtration using, e.g., Sephadex G-75, Sepharose; protein A sepharose chromatography for removal of immunoglobulin contaminants; and the like. Other additives, such as protease inhibitors (e.g. , PMSF or proteinase K) can be used to inhibit proteolytic degradation during purification. Purification procedures that can select for carbohydrates can also be used, e.g., ion-exchange soft gel chromatography, or HPLC using cation- or anion- exchange resins, in which the more acidic fraction(s) is / are collected.

[0375] Methods of Treatment with Bispecific Molecules

[0376] In one embodiment, the subject matter disclosed herein relates to a preventive medical treatment started after following diagnosis of a disease (e.g., cancer) in order to prevent the disease from worsening or curing the disease. In one embodiment, the subject matter disclosed herein relates to prophylaxis of subjects who are believed to be at risk formoderate or severe disease associated with cancer or have previously been diagnosed with another disease, such as cancer. In one embodiment, the subjects can be administered the pharmaceutical composition described herein comprising one or more bispecific molecule. The invention contemplates using any of the bispecific molecules produced by the systems and methods described herein. In one embodiment, the compositions described herein can be administered subcutaneously via syringe or any other suitable method known in the art.

[0377] The compound(s) (e.g., anti-LILRB4 and anti-LILRB2 bispecific molecules) disclosed herein, or pharmaceutical compositions may be administered to a cell, mammal, or human by any suitable means. In some embodiments, one or more bispecific molecules disclosed herein are prepared in a cocktail of DNA-encoding molecules or niRNA-encoding molecules and delivered to a subject for in vivo expression of the encoded bispecific antibodies.

[0378] As will be readily apparent to one skilled in the art, the effective in vivo dose to be administered and the particular mode of administration will vary depending upon the age, weight and species treated, and the specific use for which the compound or combination of compounds disclosed herein are employed. The determination of effective dose levels, that is the dose levels necessary to achieve the desired result, can be accomplished by one skilled in the art using routine pharmacological methods. Typically, human clinical applications of products are commenced at lower dose levels, with dose level being increased until the desired effect is achieved. Alternatively, acceptable in vitro studies can be used to establish useful doses and routes of administration of the compositions identified by the present methods using established pharmacological methods. Effective animal doses from in vivo studies can be converted to appropriate human doses using conversion methods known in the art.

[0379] In certain aspects, the subject matter disclosed herein provides a method of treating or preventing cancer in a subject in need thereof, the method comprising administering to the subject any of the anti-LILRB4 and anti-LILRB2 bispecific molecules disclosed herein.

[0380] In some embodiments, the cancer comprises a solid tumor. In some embodiments, the cancer is kidney cancer, breast ca...

Claims

CLAIMSWhat is claimed is:

1. A monoclonal antibody, or an antigen-binding fragment thereof, comprising (i) a heavy chain (HC) variable domain (VH) and (ii) a light chain (LC) variable domain (VL); wherein the antibody, or antigen binding fragment thereof, binds leukocyte immunoglobulin-like receptor 4 (LILRB4). The monoclonal antibody of claim 1, wherein the antibody binds LILRB4 with an equilibrium dissociation constant (KD) from about 10-7M to about 10’11M. The monoclonal antibody of claim 1, wherein the antibody binds LILRB4 with an association constant from about 105Ms-1to about 106Ms-1. The monoclonal antibody of claim 1, wherein the antibody binds LILRB4 with a dissociation constant from about 10-2s-1to about 10-5s-1.5 The monoclonal antibody of claim 1 , wherein the LILRB4 is a human LILRB4. The monoclonal antibody of claim 1, wherein the LILRB4 is a cynomolgus macaque LILRB4. The monoclonal antibody of claim 1 , wherein the LILRB4 is a mouse ortholog of LILRB4.8 The monoclonal antibody of claim 1, wherein the anti-LILRB4 antibody inhibits a LILRB4-dependent immune checkpoint. The monoclonal antibody of claim 1, wherein the antibody depletes LILRB4+ monocytes.10 The monoclonal antibody of claim 1, wherein the antibody does not deplete immune- supporting myeloid populations.11 The monoclonal antibody of claim 1 , wherein the antibody is engineered by B-cell cloning.12 The monoclonal antibody of claim 1 , wherein the antibody is a blocking antibody.

13. The monoclonal antibody of claims 1-12, wherein the VH domain comprises a heavy chain CDR1 having a sequence identity of at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 4, a heavy chain CDR2 having a sequence identity of at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 5, a heavy chain CDR3 having a sequence identity of at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 6 and the VL domain comprises a light chain CDR1 having a sequence identity of at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 46, a light chain CDR2 having a sequence identity of at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 47, and a light chain CDR3 having a sequence identity of at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 48.

14. The monoclonal antibody of claim 13, wherein the VH domain comprises a heavy chain CDR1 having a sequence identity of SEQ ID NO: 4, a heavy chain CDR2 having a sequence identity of SEQ ID NO: 5, and a heavy chain CDR3 having a sequence identity to SEQ ID NO: 6 and the VL domain comprises a light chain CDR1 having a sequence identity of SEQ ID NO: 46, a light chain CDR2 having a sequence identity of SEQ ID NO: 47, and a light chain CDR3 having a sequence identity of SEQ ID NO: 48.

15. The monoclonal antibody of claims 13 or 14, wherein the HC VH domain further comprises framework regions (FRs) comprising an amino acid sequence 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99 % identical to the FRs of SEQ ID NO: 22 and wherein the LC VL domain further comprises framework regions (FRs) comprising an amino acid sequence 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99 % identical to the FRs of SEQ ID NO: 64.

16. The monoclonal antibody of claims 13 or 14, wherein the HC VH domain further comprises framework regions (FRs) of a human IGHV1 gene and wherein the LC VL domain further comprises FRs of a human IGKV1 gene.

17. The monoclonal antibody of claim 16, wherein the HC VH domain further comprises framework regions (FRs) of a human IGHV1-8 gene and wherein the LC VL domain further comprises FRs of a human IGKV1-17 gene.

18. The monoclonal antibody of claims 13-17, wherein the antibody comprises (a) a first arm comprising the HC VH domain and the LC VL domain wherein a portion of the first arm binds LILRB4 and (b) a second arm comprising the HC VH domain and the LC VL domain wherein a portion of the second arm binds LILRB4.

19. The monoclonal antibody of claim 18, wherein the first and second arms each further comprise a CHI domain, a hinge domain, a Fc domain (CH2-CH3) and a CL domain.

20. The monoclonal antibody of claims 18-19, wherein: the VH domain of the first arm is encoded by a first polypeptide chain; the VL domain of the first arm is encoded by a second polypeptide chain; the VH domain of the second arm is encoded by a third polypeptide chain; theVL domain of the second arm is encoded by a fourth polypeptide chain; and wherein the VH domain and VL domain of the first arm form a first LILRB4 binding site and wherein the VH domain and VL domain of the second arm form a second LILRB4 binding site, wherein the first and second LILRB4 binding sites are the same.

21. The monoclonal antibody of claim 20, wherein the first and third polypeptide chain each further encode a hinge domain, a CHI domain, and an Fc domain, and wherein the second and fourth polypeptide chain each further encode a CL domain.

22. The monoclonal antibody of claim 21 , wherein the first and third polypeptide chains comprise the same sequence and the second and fourth polypeptide chains comprise the same sequence.

23. The monoclonal antibody of claims 18-22, wherein the VH domain of the first arm and the second arm both comprise an amino acid sequence comprising SEQ ID NO: 22, and wherein the VL domain of the first arm and the second arm both comprise an amino acid sequence comprising SEQ ID NO: 64.

24. The monoclonal antibody of claim 20-22, wherein the first and third polypeptide chain each comprises an amino acid sequence comprising SEQ ID NO: 34 and thesecond and fourth polypeptide chain each comprises an amino acid sequence comprising SEQ ID NO: 76.

25. The monoclonal antibody of claims 20-24, wherein the first and second polypeptide chains are linked by one or more covalent disulfide bonds and the third and fourth polypeptide chains are linked by one or more covalent disulfide bonds.

26. The monoclonal antibody of claims 20-25, wherein the first and third polypeptide chains are linked by one or more covalent disulfide bonds.

27. A monoclonal antibody, or an antigen-binding fragment thereof, comprising (i) a heavy chain (HC) variable domain (VH) and (ii) a light chain (LC) variable domain (VL); wherein the antibody is capable of binding to leukocyte immunoglobulin-like receptor 4 (LILRB4) and LILRB2.

28. The monoclonal antibody of claim 27, wherein the antibody binds LILRB4 with an equilibrium dissociation constant (KD) from about 10-7M to about 10- 11M and separately binds LILRB2 with an equilibrium dissociation constant (KD) from about 10-7M to about 10-11M.

29. The monoclonal antibody of claim 27, wherein the antibody binds LILRB4 with an association constant of about 105Ms-1and separately binds LILRB2 with an association constant from about 10-5Ms-1.

30. The monoclonal antibody of claim 27, wherein the antibody binds LILRB4 with a dissociation constant from about 10-2s'1to about 10-5s-1and separately binds LILRB2 with a dissociation constant from about 10-2s-1to about 10-5s-1.

31. The monoclonal antibody of claim 27, wherein the LILRB4 is a human LILRB4.

32. The monoclonal antibody of claim 27, wherein the LILRB4 is a cynomolgus macaque LILRB4.

33. The monoclonal antibody of claim 27, wherein the LILRB2 is a human LILRB2.

34. The monoclonal antibody of claim 27, wherein the LILRB2 is a cynomolgus macaque LILRB2.

35. The monoclonal antibody of claim 27, wherein the LILRB4 is a mouse ortholog of LILRB4.

36. The monoclonal antibody of claim 27, wherein the LILRB2 is a mouse ortholog of LILRB2.

37. The monoclonal antibody of claim 27, wherein the anti-LILRB4 antibody inhibits a LILRB4-dependent immune checkpoint.

38. The monoclonal antibody of claim 27, wherein the anti-LILRB2 antibody inhibits a LILRB2-dependent immune checkpoint.

39. The monoclonal antibody of claim 27, wherein the antibody depletes LILRB4+ monocytes.

40. The monoclonal antibody of claim 27, wherein the antibody depletes LILRB2+ monocytes.

41. The monoclonal antibody of claim 27, wherein the antibody does not deplete immune-supporting myeloid populations.

42. The monoclonal antibody of claim 27, wherein the antibody is engineered by B-cell cloning.

43. The monoclonal antibody of claim 27, wherein the antibody is a blocking antibody.

44. The monoclonal antibody of claim 27, wherein the VH domain comprises a heavy chain CDR1 having a sequence identity of at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 13, a heavy chain CDR2 having a sequence identity of at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 14, a heavy chain CDR3 having a sequence identity of at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 15 and the VL domain comprises a light chain CDR1 having a sequence identity of at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 55, a light chain CDR2 having a sequence identity of at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 56, and a lightchain CDR3 having a sequence identity of at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 57.

45. The monoclonal antibody of claim 44, wherein the VH domain comprises a heavy chain CDR1 having a sequence identity of SEQ ID NO: 13, a heavy chain CDR2 having a sequence identity of SEQ ID NO: 14, and a heavy chain CDR3 having a sequence identity to SEQ ID NO: 15 and the VL domain comprises a light chain CDR1 having a sequence identity of SEQ ID NO: 55, a light chain CDR2 having a sequence identity of SEQ ID NO: 56, and a light chain CDR3 having a sequence identity of SEQ ID NO: 57.

46. The monoclonal antibody of claims 44 or 45, wherein the HC VH domain further comprises framework regions (FRs) comprising an amino acid sequence 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99 % identical to the FRs of SEQ ID NO: 22 and wherein the EC VL domain further comprises framework regions (FRs) comprising an amino acid sequence 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99 % identical to the FRs of SEQ ID NO: 64.

47. The monoclonal antibody of claims 44 or 45, wherein the HC VH domain further comprises framework regions (FRs) of a human IGHV 1 gene and wherein the EC VL domain further comprises FRs of a human IGKV1 gene.

48. The monoclonal antibody of claim 27, wherein the HC VH domain further comprises framework regions (FRs) of a human IGHV 1-8 gene and wherein the LC VL domain further comprises FRs of a human IGKV1-17 gene.

49. The monoclonal antibody of claims 44-48, wherein the antibody comprises (a) a first arm comprising the HC VH domain and the LC VL domain wherein a portion of the first arm binds LILRB4 and (b) a second arm comprising the HC VH domain and the LC VL domain wherein a portion of the second arm binds LILRB4.

50. The monoclonal antibody of claim 49, wherein the first and second arms each further comprise a CHI domain, a hinge domain, a Fc domain (CH2-CH3) and a CL domain.

51. The monoclonal antibody of claims 49-50, wherein: the VH domain of the first arm is encoded by a first polypeptide chain;the VL domain of the first arm is encoded by a second polypeptide chain; the VH domain of the second arm is encoded by a third polypeptide chain; the VL domain of the second arm is encoded by a fourth polypeptide chain; and wherein the VH domain and VL domain of the first arm form a first LILRB4 binding site and wherein the VH domain and VL domain of the second arm form a second LILRB4 binding site, wherein the first and second LILRB4 binding sites are the same.

52. The monoclonal antibody of claim 51 , wherein the first and third polypeptide chain each further encode a hinge domain, a CHI domain, and an Fc domain, and wherein the second and fourth polypeptide chain each further encode a CL domain.

53. The monoclonal antibody of claim 52, wherein the first and third polypeptide chains comprise the same sequence and the second and fourth polypeptide chains comprise the same sequence.

54. The monoclonal antibody of claims 49-53, wherein the VH domain of the first arm and the second arm both comprise an amino acid sequence comprising SEQ ID NO: 22, and wherein the VL domain of the first arm and the second arm both comprise an amino acid sequence comprising SEQ ID NO: 64.

55. The monoclonal antibody of claim 51-53, wherein the first and third polypeptide chain each comprises an amino acid sequence comprising SEQ ID NO: 34 and the second and fourth polypeptide chain each comprises an amino acid sequence comprising SEQ ID NO: 76.

56. The monoclonal antibody of claims 51-55, wherein the first and second polypeptide chains are linked by one or more covalent disulfide bonds and the third and fourth polypeptide chains are linked by one or more covalent disulfide bonds.

57. The monoclonal antibody of claims 51-56, wherein the first and third polypeptide chains are linked by one or more covalent disulfide bonds.

58. A pharmaceutical composition comprising the monoclonal antibody of any one of claims 1-26.

59. A pharmaceutical composition comprising the monoclonal antibody of any one of claims 27-57.

60. The pharmaceutical composition of claim 58 or 59 further comprising one or more pharmaceutically-acceptable diluents, one or more pharmaceutically-acceptable carriers or one or more pharmaceutically-acceptable excipients.

61. A method of treating or preventing cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of the monoclonal antibody of any one of claims 1-57 or the pharmaceutical composition of claims 58- 59.

62. The method of claim 61, wherein the cancer comprises a solid tumor.

63. The method of claim 61, wherein the cancer is kidney cancer, breast cancer, brain tumor, head and neck cancer, liver cancer, melanoma, non-small cell lung cancer (NSCLC), bladder cancer, cervical cancer, colon cancer, renal cell cancer, skin cancer, stomach cancer, rectal cancer, gastrointestinal, pancreatic cancer, lung cancer, thymic carcinoma, ovarian cancer, prostate cancer, or endometrial cancer.

64. The method of claim 61, wherein the cancer is a liquid cancer.

65. The method of claim 64, wherein the liquid cancer is leukemia, lymphoma, Hodgkin lymphoma, or myeloma.

66. The method of claim 64, wherein the liquid cancer is acute myeloid leukemia (AML).

67. The method of claim 64, wherein the liquid cancer is B-cell malignancy.

68. The method of claim 61, wherein the administration of the monoclonal antibody or the pharmaceutical composition is capable of inhibiting tumor growth.

69. A method of inhibiting myeloid-dependent immune suppression or promoting immune activation in a subject in need thereof, the method comprising administering to the subject an effective amount of the monoclonal antibody of any one of claims 1- 57 or the pharmaceutical composition of claims 58-59.

70. The method of claims 61-69, wherein the subject is a human subject.

71. A polynucleotide encoding the antibody of any one of claims 1 -26.

72. A polynucleotide encoding the antibody of any one of claims 27-57.

73. A genetically engineered cell comprising the antibody of any one of claims 1-26.

74. A genetically engineered cell comprising the antibody of any one of claims 27-57.

75. A kit for generating a monoclonal antibody or antigen-binding fragment thereof, the kit comprising one or more vectors comprising a polynucleotide sequence encoding any of the monoclonal antibodies of any of claims 1-57.

76. A kit for generating a monoclonal antibody or antigen-binding fragment thereof, the kit comprising: a first vector comprising a polynucleotide sequence encoding the first polypeptide chain of the monoclonal antibody of claims 20 or 51 ; and a second vector comprising a polynucleotide sequence encoding the second polypeptide chain of the monoclonal antibody of claims 20 or 51.

77. One or more in vitro cultured cells comprising: one or more vectors comprising a polynucleotide sequence encoding any of the monoclonal antibodies of any of claims 1-57.

78. One or more in vitro cultured cells comprising: a first vector comprising a polynucleotide sequence encoding the first polypeptide chain of the monoclonal antibody of claims 20 or 51 ; and a second vector comprising a polynucleotide sequence encoding the second polypeptide chain of the monoclonal antibody of claims 20 or 51.

79. A method of making a monoclonal antibody or antigen-binding fragment thereof comprising: culturing the one or more in vitro cultured cells of claim 78 under conditions suitable for an expression of the one or more vectors; and recovering the monoclonal antibody or antigen-binding fragment thereof.

80. A composition comprising: one or more vectors comprising a polynucleotide sequence encoding any of the monoclonal antibodies of any of claims 1-57.

81. A composition comprising: a first vector comprising a polynucleotide sequence encoding the first polypeptide chain of the monoclonal antibody of claims 1-57; and a second vector comprising a polynucleotide sequence encoding the second polypeptide chain of the monoclonal antibody of claims 1-57.

82. A monoclonal antibody means for binding LILRB4.

83. The means of claim 82, wherein the means comprises any one of the monoclonal antibodies of claims 1-26.

84. A monoclonal antibody means for binding LILRB4 and LILRB2.

85. The means of claim 84, wherein the means comprises any one of the monoclonal antibodies of claims 27-57.

86. The means of claims 82-85, wherein the means is capable of treating or preventing cancer in a subject in need thereof or inhibiting myeloid-dependent immune suppression or promoting immune activation in a subject in need thereof.

87. A bispecific molecule comprising a first antigen binding region and a second antigen binding region, wherein the first antigen binding region binds a LILRB4 protein and the second antigen binding region binds a LILRB2 protein.

88. The bispecific molecule of claim 87, wherein the first antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 46, a light chain CDR2 (CDRL2) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 47, a light chain CDR3 (CDRL3) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 48 and the VH domain comprises a heavy chain CDR1 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%,90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 4, a heavy chain CDR2 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 5, and a heavy chain CDR3 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 6 The bispecific molecule of claim 87, wherein the first antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) of SEQ ID NO: 46, a light chain CDR2 (CDRL2) of SEQ ID NO: 47, a light chain CDR3 (CDRL3) of SEQ ID NO: 48 and the VH domain comprises a heavy chain CDR1 of SEQ ID NO: 4, a heavy chain CDR2 of SEQ ID NO: 5, and a heavy chain CDR3 of SEQ ID NO:

6. The bispecific molecule of claim 87, wherein the first antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 52, a light chain CDR2 (CDRL2) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 53, a light chain CDR3 (CDRL3) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 54 and the VH domain comprises a heavy chain CDR1 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 10, a heavy chain CDR2 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 11, and a heavy chain CDR3 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 12.

91. The bispecific molecule of claim 87, wherein the first antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) of SEQ ID NO: 52, a light chain CDR2 (CDRL2) of SEQ ID NO: 53, a light chain CDR3 (CDRL3) of SEQ ID NO: 54 and the VH domain comprises a heavy chain CDR1 of SEQ ID NO: 10, a heavy chain CDR2 of SEQ ID NO: 11, and a heavy chain CDR3 of SEQ ID NO: 12.

92. The bispecific molecule of claim 87, wherein the first antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 49, a light chain CDR2 (CDRL2) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 50, a light chain CDR3 (CDRL3) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 51 and the VH domain comprises a heavy chain CDR1 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 7, a heavy chain CDR2 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 8, and a heavy chain CDR3 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 9.

93. The bispecific molecule of claim 87, wherein the first antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) of SEQ ID NO: 49, a light chain CDR2 (CDRL2) of SEQ ID NO: 50, a light chain CDR3 (CDRL3) of SEQ ID NO: 51 and the VH domain comprises a heavy chain CDR1 of SEQ ID NO: 7, a heavy chain CDR2 of SEQ ID NO: 8, and a heavy chain CDR3 of SEQ ID NO: 9.

94. The bispecific molecule of claim 87, wherein the second antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 43, a light chain CDR2 (CDRL2) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 44, a light chain CDR3 (CDRL3) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 45 and the VH domain comprises a heavy chain CDR1 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 1, a heavy chain CDR2 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2, and a heavy chain CDR3 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 3.

95. The bispecific molecule of claim 87, wherein the second antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) of SEQ ID NO: 43, a light chain CDR2 (CDRL2) of SEQ ID NO: 44, a light chain CDR3 (CDRL3 ) of SEQ ID NO: 45 and the VH domain comprises a heavy chain CDR1 of SEQ ID NO: 1 , a heavy chain CDR2 of SEQ ID NO: 2, and a heavy chain CDR3 of SEQ ID NO: 3.

96. The bispecific molecule of claim 87, wherein the second antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 58, a light chain CDR2 (CDRL2) having a sequence identity of at least 80%, 81 %, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%,96%, 97%, 98% or 99% identity to SEQ ID NO: 59, a light chain CDR3 (CDRL3) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 60 and the VH domain comprises a heavy chain CDR1 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 16, a heavy chain CDR2 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 17, and a heavy chain CDR3 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:

18. The bispecific molecule of claim 87, wherein the second antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDRl (CDRL1) of SEQ ID NO: 58, a light chain CDR2 (CDRL2) of SEQ ID NO: 59, a light chain CDR3 (CDRL3) of SEQ ID NO: 60 and the VH domain comprises a heavy chain CDRl of SEQ ID NO: 16, a heavy chain CDR2 of SEQ ID NO: 17, and a heavy chain CDR3 of SEQ ID NO:

18. The bispecific molecule of claim 87, wherein the second antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDRl (CDRL1) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 55, a light chain CDR2 (CDRL2) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 56, a light chain CDR3 (CDRL3) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 57 and the VH domain comprises a heavy chain CDRl having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 13, a heavy chain CDR2 having a sequence identity of at least 80%, 81%, 82%, 83%,84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 14, and a heavy chain CDR3 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 15.

99. The bispecific molecule of claim 87, wherein the second antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) of SEQ ID NO: 55, a light chain CDR2 (CDRL2) of SEQ ID NO: 56, a light chain CDR3 (CDRL3) of SEQ ID NO: 57 and the VH domain comprises a heavy chain CDR1 of SEQ ID NO: 13, a heavy chain CDR2 of SEQ ID NO: 14, and a heavy chain CDR3 of SEQ ID NO:

15.

00. The bispecific molecule of claim 87, wherein: the first antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 46, a light chain CDR2 (CDRL2) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 47, a light chain CDR3 (CDRL3) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 48 and the VH domain comprises a heavy chain CDR1 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 4, a heavy chain CDR2 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 5, and a heavy chain CDR3 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%. 89%, 90%, 91%, 92%, 93%, 94%, 95%. 96%, 97%, 98% or 99% identity to SEQ ID NO: 6; andthe second antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 43, a light chain CDR2 (CDRL2) having a sequence identity' of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 44, a light chain CDR3 (CDRL3) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 45 and the VH domain comprises a heavy chain CDR1 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 1, a heavy chain CDR2 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2, and a heavy chain CDR3 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:

3.

01. The bispecific molecule of claim 87, wherein: the first antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) of SEQ ID NO: 46, a light chain CDR2 (CDRL2) of SEQ ID NO: 47, a light chain CDR3 (CDRL3) of SEQ ID NO: 48 and the VH domain comprises a heavy chain CDR1 of SEQ ID NO: 4, a heavy chain CDR2 of SEQ ID NO: 5, and a heavy chain CDR3 of SEQ ID NO: 6; and the second antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) of SEQ ID NO: 43, a light chain CDR2 (CDRL2) of SEQ ID NO: 44, a light chain CDR3 (CDRL3) of SEQ ID NO: 45 and the VH domain comprises a heavy chain CDR1 of SEQ ID NO: 1, a heavy chain CDR2 of SEQ ID NO: 2, and a heavy chain CDR3 of SEQ ID NO: 3.

02. The bispecific molecule of claim 87, wherein: the first antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 46, a light chain CDR2 (CDRL2) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 47, a light chain CDR3 (CDRL3) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 48 and the VH domain comprises a heavy chain CDR1 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 4, a heavy chain CDR2 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 5, and a heavy chain CDR3 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 6; and the second antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 58, a light chain CDR2 (CDRL2) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 59, a light chain CDR3 (CDRL3) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 60 and the VH domain comprises a heavy chain CDR1 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 16, a heavy chain CDR2 having a sequence identity of at least80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 17, and a heavy chain CDR3 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%. 88%, 89%. 90%, 91%, 92%, 93%, 94%. 95%, 96%. 97%, 98% or 99% identity to SEQ ID NO: 18.

103. The bispecific molecule of claim 87, wherein: the first antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) of SEQ ID NO: 46, a light chain CDR2 (CDRL2) of SEQ ID NO: 47, a light chain CDR3 (CDRL3) of SEQ ID NO: 48 and the VH domain comprises a heavy chain CDR1 of SEQ ID NO: 4, a heavy chain CDR2 of SEQ ID NO: 5, and a heavy chain CDR3 of SEQ ID NO: 6; and the second antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) of SEQ ID NO: 58, a light chain CDR2 (CDRL2) of SEQ ID NO: 59, a light chain CDR3 (CDRL3) of SEQ ID NO: 60 and the VH domain comprises a heavy chain CDR1 of SEQ ID NO: 16, a heavy chain CDR2 of SEQ ID NO: 17, and a heavy chain CDR3 of SEQ ID NO:

18.

04. The bispecific molecule of claim 87, wherein: the first antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 46, a light chain CDR2 (CDRL2) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 47, a light chain CDR3 (CDRL3) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 48 and the VH domain comprises a heavy chain CDR1 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%identity to SEQ ID NO: 4, a heavy chain CDR2 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 5, and a heavy chain CDR3 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 6; and the second antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 55, a light chain CDR2 (CDRL2) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 56, a light chain CDR3 (CDRL3) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 57 and the VH domain comprises a heavy chain CDR1 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 13, a heavy chain CDR2 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 14, and a heavy chain CDR3 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:

15.

05. The bispecific molecule of claim 87, wherein: the first antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) of SEQ ID NO: 46, a light chain CDR2 (CDRL2) of SEQ ID NO: 47, a light chain CDR3 (CDRL3) of SEQ ID NO: 48 and the VH domain comprises a heavy chain CDR1 of SEQ ID NO: 4, a heavy chain CDR2 of SEQ ID NO: 5, and a heavy chain CDR3 of SEQ ID NO: 6; andthe second antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) of SEQ ID NO: 55, a light chain CDR2 (CDRL2) of SEQ ID NO: 56, a light chain CDR3 (CDRL3) of SEQ ID NO: 57 and the VH domain comprises a heavy chain CDR1 of SEQ ID NO: 13, a heavy chain CDR2 of SEQ ID NO: 14, and a heavy chain CDR3 of SEQ ID NO:

15.

06. The bispecific molecule of claim 87, wherein: the first antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 52, a light chain CDR2 (CDRL2) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 53, a light chain CDR3 (CDRL3) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 54 and the VH domain comprises a heavy chain CDR1 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 10, a heavy chain CDR2 having a sequence identity of at least 80%, 81%, 82%. 83%, 84%, 85%, 86%, 87%, 88%, 89%. 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 11, and a heavy chain CDR3 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 12; and the second antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%. 87%, 88%, 89%, 90%, 91%, 92%, 93%. 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 43, a light chain CDR2 (CDRL2) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 44, alight chain CDR3 (CDRL3) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 45 and the VH domain comprises a heavy chain CDR1 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity' to SEQ ID NO: 1, a heavy chain CDR2 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2, and a heavy chain CDR3 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:

3.

07. The bispecific molecule of claim 87, wherein: the first antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) of SEQ ID NO: 52, a light chain CDR2 (CDRL2) of SEQ ID NO: 53, a light chain CDR3 (CDRL3) of SEQ ID NO: 54 and the VH domain comprises a heavy chain CDR1 of SEQ ID NO: 10, a heavy chain CDR2 of SEQ ID NO: 11, and a heavy chain CDR3 of SEQ ID NO: 12; and the second antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDRl (CDRL1) of SEQ ID NO: 43, a light chain CDR2 (CDRL2) of SEQ ID NO: 44, a light chain CDR3 (CDRL3) of SEQ ID NO: 45 and the VH domain comprises a heavy chain CDRl of SEQ ID NO: 1 , a heavy chain CDR2 of SEQ ID NO: 2, and a heavy chain CDR3 of SEQ ID NO:

3.

08. The bispecific molecule of claim 87, wherein: the first antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDRl (CDRL1) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 52, a light chain CDR2 (CDRL2) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%,91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 53, a light chain CDR3 (CDRL3) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 54 and the VH domain comprises a heavy chain CDR1 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 10, a heavy chain CDR2 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 11, and a heavy chain CDR3 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 12; and the second antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 58, a light chain CDR2 (CDRL2) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 59, a light chain CDR3 (CDRL3) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 60 and the VH domain comprises a heavy chain CDR1 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 16, a heavy chain CDR2 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 17, and a heavy chain CDR3 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:

18.

09. The bispecific molecule of claim 87, wherein:the first antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) of SEQ ID NO: 52, a light chain CDR2 (CDRL2) of SEQ ID NO: 53, a light chain CDR3 (CDRL3) of SEQ ID NO: 54 and the VH domain comprises a heavy chain CDR1 of SEQ ID NO: 10, a heavy chain CDR2 of SEQ ID NO: 11, and a heavy chain CDR3 of SEQ ID NO: 12; and the second antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) of SEQ ID NO: 58, a light chain CDR2 (CDRL2) of SEQ ID NO: 59, a light chain CDR3 (CDRL3) of SEQ ID NO: 60 and the VH domain comprises a heavy chain CDR1 of SEQ ID NO: 16, a heavy chain CDR2 of SEQ ID NO: 17, and a heavy chain CDR3 of SEQ ID NO:

18.

10. The bispecific molecule of claim 87, wherein: the first antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 52, a light chain CDR2 (CDRL2) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 53, a light chain CDR3 (CDRL3) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 54 and the VH domain comprises a heavy chain CDR1 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 10, a heavy chain CDR2 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 11, and a heavy chain CDR3 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%. 88%, 89%. 90%, 91%, 92%, 93%, 94%. 95%, 96%. 97%, 98% or 99% identity to SEQ ID NO: 12; andthe second antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 55, a light chain CDR2 (CDRL2) having a sequence identity' of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 56, a light chain CDR3 (CDRL3) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 57 and the VH domain comprises a heavy chain CDR1 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 13, a heavy chain CDR2 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 14, and a heavy chain CDR3 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:

15.

11. The bispecific molecule of claim 87, wherein: the first antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) of SEQ ID NO: 52, a light chain CDR2 (CDRL2) of SEQ ID NO: 53, a light chain CDR3 (CDRL3) of SEQ ID NO: 54 and the VH domain comprises a heavy chain CDR1 of SEQ ID NO: 10, a heavy chain CDR2 of SEQ ID NO: 11 , and a heavy chain CDR3 of SEQ ID NO: 12; and the second antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) of SEQ ID NO: 55, a light chain CDR2 (CDRL2) of SEQ ID NO: 56, a light chain CDR3 (CDRL3) of SEQ ID NO: 57 and the VH domain comprises a heavy chain CDR1 of SEQ ID NO: 13, a heavy chain CDR2 of SEQ ID NO: 14, and a heavy chain CDR3 of SEQ ID NO: 15.

12. The bispecific molecule of claim 87, wherein: the first antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 49, a light chain CDR2 (CDRL2) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 50, a light chain CDR3 (CDRL3) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 51 and the VH domain comprises a heavy chain CDR1 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 7, a heavy chain CDR2 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 8, and a heavy chain CDR3 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 9; and the second antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 43, a light chain CDR2 (CDRL2) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 44, a light chain CDR3 (CDRL3) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 45 and the VH domain comprises a heavy chain CDR1 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 1, a heavy chain CDR2 having a sequence identity of at least80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%,94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2, and a heavy chain CDR3 hav ing a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%. 88%, 89%. 90%, 91%, 92%, 93%, 94%. 95%, 96%. 97%, 98% or 99% identity to SEQ ID NO: 3.

113. The bispecific molecule of claim 87, wherein: the first antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) of SEQ ID NO: 49, a light chain CDR2 (CDRL2) of SEQ ID NO.- SO, a light chain CDR3 (CDRL3) of SEQ ID NO: 51 and the VH domain comprises a heavy chain CDR1 of SEQ ID NO: 7, a heavy chain CDR2 of SEQ ID NO: 8, and a heavy chain CDR3 of SEQ ID NO: 9; and the second antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) of SEQ ID NO: 43, a light chain CDR2 (CDRL2) of SEQ ID NO: 44, a light chain CDR3 (CDRL3) of SEQ ID NO: 45 and the VH domain comprises a heavy chain CDR1 of SEQ ID NO: 1 , a heavy chain CDR2 of SEQ ID NO: 2, and a heavy chain CDR3 of SEQ ID NO:

3.

14. The bispecific molecule of claim 87, wherein: the first antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 49, a light chain CDR2 (CDRL2) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 50, a light chain CDR3 (CDRL3) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 51 and the VH domain comprises a heavy chain CDR1 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%identity to SEQ ID NO: 7, a heavy chain CDR2 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 8, and a heavy chain CDR3 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 9; and the second antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 58, a light chain CDR2 (CDRL2) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 59, a light chain CDR3 (CDRL3) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 60 and the VH domain comprises a heavy chain CDR1 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 16, a heavy chain CDR2 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 17, and a heavy chain CDR3 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:

18.

15. The bispecific molecule of claim 87, wherein: the first antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) of SEQ ID NO: 49, a light chain CDR2 (CDRL2) of SEQ ID NO: 50, a light chain CDR3 (CDRL3) of SEQ ID NO: 51 and the VH domain comprises a heavy chain CDR1 of SEQ ID NO: 7, a heavy chain CDR2 of SEQ ID NO: 8, and a heavy chain CDR3 of SEQ ID NO: 9; andthe second antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) of SEQ ID NO: 58, a light chain CDR2 (CDRL2) of SEQ ID NO: 59, a light chain CDR3 (CDRL3) of SEQ ID NO: 60 and the VH domain comprises a heavy chain CDR1 of SEQ ID NO: 16, a heavy chain CDR2 of SEQ ID NO: 17, and a heavy chain CDR3 of SEQ ID NO:

18.

16. The bispecific molecule of claim 87, wherein: the first antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 49, a light chain CDR2 (CDRL2) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 50, a light chain CDR3 (CDRL3) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 51 and the VH domain comprises a heavy chain CDR1 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 7, a heavy chain CDR2 having a sequence identity of at least 80%, 81%, 82%. 83%, 84%, 85%, 86%, 87%, 88%, 89%. 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 8, and a heavy chain CDR3 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 9; and the second antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%. 87%, 88%, 89%, 90%, 91%, 92%, 93%. 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 55, a light chain CDR2 (CDRL2) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 56, alight chain CDR3 (CDRL3) having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 57 and the VH domain comprises a heavy chain CDR1 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity' to SEQ ID NO: 13, a heavy chain CDR2 having a sequence identity' of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 14, and a heavy chain CDR3 having a sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 15.

117. The bispecific molecule of claim 87, wherein: the first antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDR1 (CDRL1) of SEQ ID NO: 49, a light chain CDR2 (CDRL2) of SEQ ID NO: 50, a light chain CDR3 (CDRL3) of SEQ ID NO: 51 and the VH domain comprises a heavy chain CDR1 of SEQ ID NO: 7, a heavy chain CDR2 of SEQ ID NO: 8, and a heavy chain CDR3 of SEQ ID NO: 9; and the second antigen binding region comprises a light chain variable (VL) domain and a heavy chain variable (VH) domain, wherein the VL domain comprises a light chain CDRl (CDRL1) of SEQ ID NO: 55, a light chain CDR2 (CDRL2) of SEQ ID NO: 56, a light chain CDR3 (CDRL3) of SEQ ID NO: 57 and the VH domain comprises a heavy chain CDRl of SEQ ID NO: 13, a heavy chain CDR2 of SEQ ID NO: 14, and a heavy chain CDR3 of SEQ ID NO: 15.

118. The bispecific molecule of any one of claims 87-93, 100-117, wherein the first antigen binding region of the bispecific molecule binds LILRB4 with an equilibrium dissociation constant (KD) from about 10-7M to about 10-11M.

119. The bispecific molecule of any one of claims 87-93, 100-117, wherein the first antigen binding region of the bispecific molecule binds LILRB4 with an association constant from about 105Ms-1to about 106Ms-1.

120. The bispecific molecule of any one of claims 87-93, 100-117, wherein the first antigen binding region of the bispecific molecule binds LILRB4 with a dissociation constant from about 10’2s-1to about I O' - s-1.

121. The bispecific molecule of any one of claims 87-93, 100-120, wherein the LILRB4 is a human LILRB4.

122. The bispecific molecule of any one of claims 87-93, 100-120, wherein the LILRB4 is a cynomolgus macaque LILRB4.

123. The bispecific molecule of any one of claims 87-93, 100-120, wherein the LILRB4 is a mouse ortholog of LILRB4.

124. The bispecific molecule of any one of claims 87-93, 100-120, wherein the bispecific molecule inhibits a LILRB4-dependent immune checkpoint.

125. The bispecific molecule of any one of claims 87-93, 100-120, wherein the bispecific molecule depletes LILRB4+ monocytes.

126. The bispecific molecule of any one of claims 87-93, 100-120, wherein the bispecific molecule does not deplete immune-supporting myeloid populations.

127. The bispecific molecule of any one of claims 87-93, 100-120, wherein the bispecific molecule is a blocking molecule.

128. The bispecific molecule of claims 88-117, wherein the VH domain further comprises framework regions (FRs) of a human IGHV gene and wherein the VL domain further comprises FRs of a human IGKV gene.

129. The bispecific molecule of claims 88-117, wherein the bispecific molecule comprises (a) a first arm comprising the first antigen binding region wherein the first antigen binding region binds LILRB4 and (b) a second arm comprising the second antigen binding region wherein the second antigen binding region binds LILRB2.

130. The bispecific molecule of claim 129, wherein the first and second arms each further comprise a CHI domain, a hinge domain, a Fc domain (CH2-CH3) and a CL domain.

131. The bispecific molecule of claims 129-130, wherein:the VH domain of the first arm is encoded by a first polypeptide chain; the VL domain of the first arm is encoded by a second polypeptide chain; the VH domain of the second arm is encoded by a third polypeptide chain; the VL domain of the second arm is encoded by a fourth polypeptide chain; and wherein the VH domain and VL domain of the first arm form the first antigen binding region, wherein the first antigen binding region binds LILRB4, and wherein the VH domain and VL domain of the second arm form the second antigen binding region, wherein the second antigen binding region binds LILRB2.

132. The bispecific molecule of claim 131, wherein the first and third polypeptide chain each further encode a hinge domain, a CHI domain, and an Fc domain, and wherein the second and fourth polypeptide chain each further encode a CL domain.

133. The bispecific molecule of claim 132, wherein the first, second, third, and fourth polypeptide chains comprise different amino acid sequences.

134. The bispecific molecule of claims 131-133, wherein the VH domain of the first arm comprises an amino acid sequence comprising SEQ ID NO: 22, SEQ ID NO: 26, or SEQ ID NO: 24 and the VH domain of the second arm comprises an amino acid sequence comprising SEQ ID NO: 28, SEQ ID NO: 30, or SEQ ID NO: 20.

135. The bispecific molecule of claims 131-133, wherein the VL domain of the first arm comprises an amino acid sequence comprising SEQ ID NO: 64, SEQ ID NO: 68, or SEQ ID NO: 66 and the VL domain of the second arm comprises an amino acid sequence comprising SEQ ID NO: 70, SEQ ID NO: 72, or SEQ ID NO: 62.

136. The bispecific molecule of claim 129-133, wherein the first arm comprises an amino acid sequence comprising SEQ ID NO: 34, SEQ ID NO: 38, or SEQ ID NO: 36 and the second comprises an amino acid sequence comprising SEQ ID NO: 40, SEQ ID NO: 42, or SEQ ID NO: 32.

137. The bispecific molecule of claim 129-133, wherein the first arm comprises an amino acid sequence comprising SEQ ID NO: 76, SEQ ID NO: 80, or SEQ ID NO: 78 andthe second comprises an amino acid sequence comprising SEQ ID NO: 82, SEQ ID NO: 84, or SEQ ID NO: 74.

138. The bispecific molecule of claims 131-133, wherein the first and second polypeptide chains are linked by one or more covalent disulfide bonds and the third and fourth polypeptide chains are linked by one or more covalent disulfide bonds.

139. The bispecific molecule of claims 131-133, wherein the first and third polypeptide chains are linked by one or more covalent disulfide bonds.

140. The bispecific molecule of any one of claims 87-93, 100-117, wherein the bispecific molecule binds LILRB2 with an equilibrium dissociation constant (KD) from about 10-7M to about 10-11M.

141. The bispecific molecule of any one of claims 87-93, 100-117, wherein the bispecific molecule binds LILRB2 with an association constant from about 10-5Ms-1.

142. The bispecific molecule of any one of claims 87-93, 100-117, wherein the bispecific molecule binds LILRB2 with a dissociation constant from about 10-2s-1to about 10-5s-1.

143. The bispecific molecule of any one of claims 87-93, 100-120, wherein the LILRB2 is a human LILRB2.

144. The bispecific molecule of any one of claims 87-93, 100-120, wherein the LILRB2 is a cynomolgus macaque LILRB2.

145. The bispecific molecule of any one of claims 87-93, 100-120, wherein the LILRB2 is a mouse ortholog of LILRB2.

146. The bispecific molecule of any one of claims 87-93, 100-120, wherein the anti- LILRB2 antibody inhibits a LILRB2-dependent immune checkpoint.

147. The bispecific molecule of any one of claims 87-93, 100-120, wherein the bispecific molecule depletes LILRB2+ monocytes.

148. The bispecific molecule of any one of claims 87-93, 100-120, wherein the bispecific molecule does not deplete immune-supporting myeloid populations.

149. The bispecific molecule of any one of claims 87-93, 100-120, wherein the bispecific molecule is a blocking bispecific.

150. A pharmaceutical composition comprising the bispecific molecule of any one of claims 87-149.

151. The pharmaceutical composition of claim 150 further comprising one or more pharmaceutically-acceptable diluents, one or more pharmaceutically-acceptable carriers or one or more pharmaceutically-acceptable excipients.

152. A method of treating or preventing cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of the bispecific molecule of any one of claims 87-149 or the pharmaceutical composition of claims 150-151.

153. The method of claim 152, wherein the cancer comprises a solid tumor.

154. The method of claim 152, wherein the cancer is kidney cancer, breast cancer, brain tumor, head and neck cancer, liver cancer, melanoma, non-small cell lung cancer (NSCLC), bladder cancer, cervical cancer, colon cancer, renal cell cancer, skin cancer, stomach cancer, rectal cancer, gastrointestinal, pancreatic cancer, lung cancer, thymic carcinoma, ovarian cancer, prostate cancer, or endometrial cancer.

155. The method of claim 152, wherein the cancer is a liquid cancer.

156. The method of claim 155, wherein the liquid cancer is leukemia, lymphoma, Hodgkin lymphoma, or myeloma.

157. The method of claim 175, wherein the liquid cancer is acute myeloid leukemia (AML).

158. The method of claim 155, wherein the liquid cancer is B-cell malignancy.

159. The method of claim 152, wherein the administration of the bispecific molecule or the pharmaceutical composition is capable of inhibiting tumor growth.

160. A method of inhibiting myeloid-dependent immune suppression or promoting immune activation in a subject in need thereof, the method comprising administeringto the subject an effective amount of the bispecific molecule of any one of claims 87- 149 or the pharmaceutical composition of claims 150-151.

161. The method of claims 152-160, wherein the subject is a human subject.

162. A polynucleotide encoding at least a portion of the bispecific molecule of any one of claims 87-149.

163. A genetically engineered cell comprising the bispecific molecule of any one of claims 87-149.

164. A composition comprising: one or more vectors comprising one or more polynucleotide sequences encoding any of the bispecific molecules of any of claims 87-149.

165. A composition comprising: a first set of one or more vectors comprising one or more polynucleotide sequences encoding the first antigen binding region of the bispecific molecule of claims 87-149; and a second set of one or more vectors comprising one or more polynucleotide sequences encoding the antigen binding region of the bispecific molecule of claims 87-149.

166. A bispecific molecule means for binding LILRB4 and LILRB2.

167. The means of claim 166, wherein the means comprises any one of the bispecific molecules of claims 87-149.

168. The means of claims 166-167 wherein the means is capable of treating or preventing cancer in a subject in need thereof or inhibiting myeloid-dependent immune suppression or promoting immune activation in a subject in need thereof.

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