ANTIBODIES SPECIFIC FOR IMMUNOGLOBULIN-LIKE TRANSCRIPT 3 (ILT3) AND USES THEREOF
Humanized, non-promiscuous monoclonal antibodies specific for immunoglobulin-like transcript 3 (ILT3), also known as Leukocyte immunoglobulin-like receptor subfamily B member 4 (LILRB4), are described.
1 .- 18 . (canceled)
19 . A chimeric, humanized, or recombinant human antibody or antigen binding fragment that cross-blocks or competes with the binding of an antibody comprising a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 15 and a light chain comprising the amino acid sequence shown in SEQ ID NO: 16 from binding to human immunoglobulin-like transcript 3 (ILT3).
20 .- 30 . (canceled)
31 . The chimeric, humanized, or recombinant human antibody or antigen binding fragment of claim 19 , wherein the chimeric, humanized, or recombinant human antibody or antigen binding fragment binds to an epitope on human ILT3 comprising the amino acid sequences set forth in SEQ ID NOs: 3, 4, 5, 6, 7, and 8 as determined by hydrogen deuterium exchange mass spectrometry (HDX-MS) analysis.
32 . The chimeric, humanized, or recombinant human antibody or antigen binding fragment of claim 31 , wherein the epitope consists of the amino acid sequences set forth in SEQ ID NOs: 3, 4, 5, 6, 7, and 8.
33 . The chimeric, humanized, or recombinant human antibody or antigen binding fragment of claim 19 that comprises at least two heavy chains (HCs) and two light chains (LCs) inter-connected by disulfide bonds.
34 . The chimeric, humanized, or recombinant human antibody or antigen binding fragment of claim 19 that has a dissociation constant (K D ) of 10 −7 to 10 −11 M.
35 . The chimeric, humanized, or recombinant human antibody or antigen binding fragment of claim 34 that comprises at least two heavy chains (HCs) and two light chains (LCs) inter-connected by disulfide bonds.
36 . The chimeric, humanized, or recombinant human antibody or antigen binding fragment of claim 19 that has a dissociation constant (K D ) of 5×10 −9 M or less.
37 . The chimeric, humanized, or recombinant human antibody or antigen binding fragment of claim 36 that comprises at least two heavy chains (HCs) and two light chains (LCs) inter-connected by disulfide bonds.
38 . The chimeric, humanized, or recombinant human antibody or antigen binding fragment of claim 19 that does not bind with measurable binding to human ILT5, human ILT7, human ILT8, and human ILT11 as determined in a cell enzyme linked immunosorbent assay (ELISA) or Biacore assay using 10 μg/mL of the chimeric, humanized, or recombinant human antibody or antigen binding fragment.
39 . The chimeric, humanized, or recombinant human antibody or antigen binding fragment of claim 38 that comprises at least two heavy chains (HCs) and two light chains (LCs) inter-connected by disulfide bonds.
40 . The chimeric, humanized, or recombinant human antibody or antigen binding fragment of claim 19 that is a variant of an antibody or antigen binding fragment comprising
(a) a heavy chain complementarity determining region (HC-CDR) 1, wherein the HC-CDR1 has the amino acid sequence set forth in SEQ ID NO: 17; an HC-CDR2, wherein the HC-CDR2 has the amino acid sequence set forth in SEQ ID NO: 19, 20, or 21; an HC-CDR3, wherein the HC-CDR3 has the amino acid sequence set forth in SEQ ID NO: 23; and
(b) a light chain complementarity determining region (LC-CDR) 1, wherein the LC-CDR1 has the amino acid sequence set forth in SEQ ID NO: 34, 35, 36, 37, 38, 39, 40, 41, or 42; an LC-CDR2, wherein the LC-CDR2 has the amino acid sequence set forth in SEQ ID NO: 43; and an LC-CDR3, wherein the LC-CDR3 has the amino acid sequence set forth in SEQ ID NO: 44;
wherein the variation is one, two, or three amino acid substitutions, additions, deletions, or combinations thereof in one or more of the HC-CDRs or LC-CDRs.
41 . The chimeric, humanized, or recombinant human antibody or antigen binding fragment of claim 40 wherein the variation is one, two, or three conservative amino acid substitutions.