Monoclonal antibodies against lilrb1 for diagnostic and therapeutic use

Patent metadata

Field	Value
Publication number	US-2023235055-A1
Application number	US-202118007185-A
Country	US
Kind code	A1
Filing date	Jul 26, 2021
Priority date	Jul 28, 2020
Publication date	Jul 27, 2023
Grant date	—

Abstract

Provided herein are antibodies binding to LILRB1 and the uses of the antibodies in detecting and treating cancer and autoimmune diseases.

First claim

1 . An isolated monoclonal antibody or an antigen-binding fragment thereof comprising a heavy chain (HC) variable region (VH) and a light chain (LC) variable region (VL) comprising clone-paired CDR sequences as set forth in Tables 1 and 3; and variants thereof wherein one or more of the HC-CDRs and/or LC-CDRs has one, two, or three amino acid substitutions, additions, deletions, or combinations thereof.

2 . The isolated monoclonal antibody or an antigen binding fragment thereof of claim 1 , wherein the isolated monoclonal antibody is a murine, a rodent, a rabbit, a chimeric, a humanized, or a human antibody.

3 . The isolated monoclonal antibody or an antigen-binding fragment thereof of claim 1 , wherein the antigen-binding fragment is a recombinant ScFv (single chain fragment variable) antibody, a Fab fragment, a F(ab′)2 fragment, or a Fv fragment.

4 . The isolated monoclonal antibody or an antigen binding fragment thereof of claim 1 , wherein the isolated monoclonal antibody is a human antibody.

5 . The isolated monoclonal antibody or an antigen-binding fragment thereof of claim 1 , wherein the VH and VL chains have amino acid sequences at least 90% or 95% identical to clone-paired sequences of Tables 6 and 8, respectively.

6 . The isolated monoclonal antibody or an antigen-binding fragment thereof of claim 5 , wherein the VH and VL chains have amino acid sequences identical to clone-paired sequences of Tables 6 and 8, respectively.

7 . The isolated monoclonal antibody or an antigen-binding fragment thereof of claim 1 , wherein the VH and VL chains are encoded by nucleic acid sequences at least 80% or 90% identical to clone-paired sequences of Tables 5 and 7, respectively.

8 . The isolated monoclonal antibody or an antigen binding fragment thereof of claim 7 , wherein the VH and VL chains are encoded by nucleic acid sequences identical to clone-paired sequences of Tables 5 and 7, respectively.

9 . The isolated monoclonal antibody or an antigen binding fragment thereof of claim 1 , wherein the isolated monoclonal antibody is a humanized antibody.

10 . The isolated monoclonal antibody or an antigen binding fragment thereof of claim 9 , wherein the humanized antibody has VH and VL chains having amino acid sequences at least 90% or 95% identical to clone-paired sequences of Hu-176 VH-1 and Hu-176-K, as shown in Tables 6 and 8, respectively.

11 . The isolated monoclonal antibody or an antigen-binding fragment thereof of claim 10 , wherein the VH and VL chains have amino acid sequences identical to clone-paired sequences of Hu-176 VH-1 and Hu-176-K, as shown in Tables 6 and 8, respectively.

12 . The isolated monoclonal antibody or an antigen binding fragment thereof of claim 9 , wherein the humanized antibody has VH and VL chains having amino acid sequences at least 90% or 95% identical to clone-paired sequences of Hu-176 VH-1 (W48L) and Hu-176-K, as shown in Tables 6 and 8, respectively.

13 . The isolated monoclonal antibody or an antigen-binding fragment thereof of claim 10 , wherein the VH and VL chains have amino acid sequences identical to clone-paired sequences of Hu-176 VH-1 (W48L) and Hu-176-K, as shown in Tables 6 and 8, respectively.

14 . The isolated monoclonal antibody or an antigen-binding fragment thereof of claim 1 , comprising an IgG Fc region comprising an amino acid modification in one or more of amino acid positions 234, 235, 297, and 329.

15 . The isolated monoclonal antibody or an antigen-binding fragment thereof of claim 14 , wherein the IgG Fc region comprises an amino acid substitution N to A at amino acid position 297.

16 . The isolated monoclonal antibody or an antigen-binding fragment thereof of claim 14 , wherein the IgG Fc region comprises the amino acid substitutions L to A at amino acid position 234, L to A at amino acid position 235, and P to G at amino acid position 329.

17 . The isolated monoclonal antibody or an antigen binding fragment thereof of claim 1 , wherein the antibody is a chimeric antibody.

18 . The isolated monoclonal antibody or an antigen binding fragment thereof of claim 1 , which induces the activation of LILRB1.

19 . The isolated monoclonal antibody or an antigen binding fragment thereof of claim 1 , which suppresses the activation of LILRB1.

20 . An isolated monoclonal antibody or an antigen binding fragment thereof, which competes for binding to the same epitope as the isolated monoclonal antibody or an antigen-binding fragment thereof according to claim 1 .

21 . An isolated monoclonal antibody or an antigen binding fragment thereof, that binds to an epitope on LILRB1 recognized by an antibody of claim 1 .

22 . An isolated monoclonal antibody or an antigen binding fragment thereof, wherein, when bound to LILRB1, the monoclonal antibody binds to residues Y76 and R84 of LILRB1.

23 . The isolated monoclonal antibody or an antigen binding fragment thereof of claim 1 , wherein the antibody or fragment thereof is conjugated or fused to an imaging agent or a cytotoxic agent.

24 . The isolated monoclonal antibody or an antigen binding fragment thereof of, wherein the antibody or fragment thereof is labeled.

25 . The isolated monoclonal antibody or an antigen binding fragment thereof of claim 24 , wherein the label is a fluorescent label, an enzymatic label, or a radioactive label.

26 . A pharmaceutical composition comprising the isolated monoclonal antibody or an antigen-binding fragment thereof according to claim 1 , and a pharmaceutically acceptable carrier.

27 . An isolated nucleic acid that encodes the isolated monoclonal antibody according to claim 1 .

28 . A vector comprising the isolated nucleic acid of claim 27 .

29 . A host cell comprising the vector of claim 28 .

30 . The host cell of claim 29 , wherein the host cell is a mammalian cell.

31 . The host cell of claim 29 , wherein the host cell is a CHO cell.

32 . A hybridoma or engineered cell encoding and/or producing the isolated monoclonal antibody according to claim 1 .

33 . A process of producing an antibody, comprising culturing the host cell of claim 29 under conditions suitable for expressing the antibody, and recovering the antibody.

34 . A chimeric antigen receptor (CAR) protein comprising an antigen-binding fragment according to claim 1 .

35 . An isolated nucleic acid that encodes a CAR protein of claim 34 .

36 . A vector comprising the isolated nucleic acid of claim 35 .

37 . An engineered cell comprising the isolated nucleic acid of claim 35 .

38 . The engineered cell of claim 37 , wherein the cell is a T cell, NK cell, or macrophage.

39 . A method of treating or ameliorating the effect of a cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of the antibody or an antigen-binding fragment thereof according to claim 1 .

40 . The method of claim 39 , wherein the method reduces or eradicates the tumor burden in the subject.

41 . The method of claim 39 , wherein the method reduces the number of tumor cells.

42 . The method of claim 39 , wherein the method reduces

Assignees

• Univ Texas

Inventors

• An Zhiqiang
• Zhang Chengcheng
• Zhang Ningyan
• Chen Yuanzhi
• Chen Heyu

Classifications

• G01N33/5758

  involving compounds serving as markers for tumours, cancers or neoplasias, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides or metabolites · CPC title

• C07K16/2803 Primary

  against the immunoglobulin superfamily · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• G01N33/57484

  Physics · mapped topic

• A61K39/3955

  against proteinaceous materials, e.g. enzymes, hormones, lymphokines · CPC title