Monovalent anti-mertk antibodies and methods of use thereof

Patent metadata

Field	Value
Publication number	US-2024279358-A1
Application number	US-202218570888-A
Country	US
Kind code	A1
Filing date	Jun 15, 2022
Priority date	Jun 16, 2021
Publication date	Aug 22, 2024
Grant date	—

Abstract

The present disclosure is generally directed to compositions that include monovalent antibodies, e.g., monoclonal monovalent antibodies that specifically bind a MerTK polypeptide, e.g., a mammalian MerTK polypeptide or human MerTK polypeptide, and use of such compositions in treating an individual in need thereof.

First claim

What is claimed is:

1 . An antibody that binds to human Mer Tyrosine Kinase (MerTK), wherein the antibody contains no more than one antigen-binding domain that binds to human MerTK.

2 . The antibody of claim 1 , wherein the antigen-binding domain that binds to human MerTK binds to the Ig1 domain of MerTK protein.

3 . The antibody of claim 1 or 2 , wherein the antigen-binding domain that binds to human MerTK competitively inhibits binding to human MerTK of an antibody comprising a variable heavy chain comprising the amino acid sequence of SEQ ID NO:9 and a variable light chain comprising the amino acid sequence of SEQ ID NO:10.

4 . The antibody of any one of claims 1-3 , wherein the antigen-binding domain that binds to human MerTK binds to the same epitope of human MerTK as an antibody comprising a variable heavy chain comprising the amino acid sequence of SEQ ID NO:9 and a variable light chain comprising the amino acid sequence of SEQ ID NO:10.

5 . The antibody of any one of claims 1-4 , wherein the antigen-binding domain that binds to human MerTK comprises an HVR-H1 comprising amino acids 31-35 of SEQ ID NO:9, an HVR-H2 comprising amino acids 50-66 of SEQ ID NO:9, an HVR-H3 comprising amino acids 99-109 of SEQ ID NO:9, an HVR-L1 comprising amino acids 24-34 of SEQ ID NO:10, an HVR-L2 comprising amino acids 50-56 of SEQ ID NO:10, and an HVR-L3 comprising amino acids 89-97 of SEQ ID NO:10.

6 . The antibody of any one of claims 1-4 , wherein the antibody comprises the HVRs of the 16.2 antibody, optionally wherein the HVRs are the Kabat-defined HVRs, the Chothia-defined HVRs, the AbM-defined HVRs, or the contact-defined HVRs.

7 . The antibody of any one of claims 1-6 , wherein the antigen-binding domain that binds to human MerTK comprises a variable heavy chain comprising an amino acid sequence that is at least 85%, at least 90%, or at least 95% identical to the amino acid sequence of SEQ ID NO:9.

8 . The antibody of any one of claims 1-7 , wherein the antigen-binding domain that binds to human MerTK comprises a variable light chain comprising an amino acid sequence that is at least 85%, at least 90%, or at least 95% identical to the amino acid sequence of SEQ ID NO:10.

9 . The antibody of any one of claims 1-8 , wherein the antigen-binding domain that binds to human MerTK comprises a variable heavy chain comprising the amino acid sequence of SEQ ID NO:9 and/or a variable light chain comprising the amino acid sequence of SEQ ID NO:10.

10 . The antibody of claim 1 or 2 , wherein the antigen-binding domain that binds to human MerTK competitively inhibits binding to human MerTK of an antibody comprising a variable heavy chain comprising the amino acid sequence of SEQ ID NO:13 and a variable light chain comprising the amino acid sequence of SEQ ID NO: 14.

11 . The antibody of any one of claims 1, 2 and 10 , wherein the antigen-binding domain that binds to human MerTK binds to the same epitope of human MerTK as an antibody comprising a variable heavy chain comprising the amino acid sequence of SEQ ID NO:13 and a variable light chain comprising the amino acid sequence of SEQ ID NO:14.

12 . The antibody of any one of claims 1, 2, 10, and 11 , wherein the antigen-binding domain that binds to human MerTK comprises an HVR-H1 comprising amino acids 31-35 of SEQ ID NO:13, an HVR-H2 comprising amino acids 50-66 of SEQ ID NO:13, an HVR-H3 comprising amino acids 99-108 of SEQ ID NO:13, an HVR-L1 comprising amino acids 24-34 of SEQ ID NO:14, an HVR-L2 comprising amino acids 50-56 of SEQ ID NO:14, and an HVR-L3 comprising amino acids 89-97 of SEQ ID NO: 14.

13 . The antibody of any one of claims 1, 2, 10, and 11 , wherein the antibody comprises the HVRs of the 13.11 antibody, optionally wherein the HVRs are the Kabat-defined HVRs, the Chothia-defined HVRs, the AbM-defined HVRs, or the contact-defined HVRs.

14 . The antibody of any one of claims 1, 2, and 10-13 , wherein the antigen-binding domain that binds to human MerTK comprises a variable heavy chain comprising an amino acid sequence that is at least 85%, at least 90%, or at least 95% identical to the amino acid sequence of SEQ ID NO:13.

15 . The antibody of any one of claims 1, 2, and 10-14 , wherein the antigen-binding domain that binds to human MerTK comprises a variable light chain comprising an amino acid sequence that is at least 85%, at least 90%, or at least 95% identical to the amino acid sequence of SEQ ID NO:14.

16 . The antibody of any one of claims 1, 2, and 10-15 , wherein the antigen-binding domain that binds to human MerTK comprises a variable heavy chain comprising the amino acid sequence of SEQ ID NO:13 and/or a variable light chain comprising the amino acid sequence of SEQ ID NO:14.

17 . The antibody of any one of claims 1-16 , wherein the antibody is of the IgG class, the IgM class, or the IgA class.

18 . The antibody of claim 17 , wherein the antibody is of the IgG class, optionally wherein the antibody has an IgG1, an IgG2, or an IgG4 isotype.

19 . The antibody of claim 17 , wherein the antibody is an IgG1 antibody.

20 . The antibody of claim 17 , wherein the antibody is an IgG4 antibody.

21 . The antibody of any one of claims 1-20 , wherein the antibody comprises (a) a first heavy chain or a fragment thereof and a first light chain or a fragment thereof, wherein the first heavy chain or fragment there of and the first light chain or fragment thereof together form the antigen-binding domain that binds to human MerTK and (b) a second heavy chain or fragment thereof and/or a second light chain or fragment thereof, wherein the second heavy chain or fragment thereof and/or the second light chain or fragment thereof do not form an antigen-binding domain that binds to human MerTK.

22 . The antibody of claim 21 , wherein the second heavy chain or fragment thereof does not contain a variable heavy chain.

23 . The antibody of claim 21 or 22 , wherein the second light chain or fragment thereof does not contain a variable light chain.

24 . The antibody of any one of claims 21-23 , wherein the antibody does not comprise a second light chain or fragment thereof.

25 . The antibody of any one of claims 21-24 , wherein the second heavy chain or fragment thereof comprises a CH2 domain and a CH3 domain, optionally wherein the second heavy chain or fragment thereof further comprises a hinge domain.

26 . The antibody of any one of claims 1-25 , wherein the antibody comprises an Fc region comprising a first polypeptide and a second polypeptide wherein:
(a) the first polypeptide comprises the amino acid substitution T366Y, and the second polypeptide comprises the amino acid substation Y407T; (b) the first polypeptide comprises the amino acid substitution T366W, and the second polypeptide comprises the amino acid substitutions T366S, L368W, and Y407V; (c) the first polypeptide comprises the amino acid substitution T366W, and the second polypeptide comprises the amino acid substitutions T366S, L368A, and Y407V; (d) the first polypeptide comprises the amino acid substitutions T366W, and S354C and the second polypeptide comprises the amino acid substitutions T366S, L368A, Y407V, and Y349C; (e) the first polypeptide comprises the amino acid substitutions T350V, L351Y, F405A, Y407V, and the second polypeptide comprises the amino acid substitutions T350V, T366L, K392L, and T394W; (f) the first polypeptide comprises the amino acid

Assignees

• Alector Llc

Inventors

• Lee Seung-Joo
• Nivitchanyong Tarangsri
• Ho Wei-Hsien
• Li Wei
• Roell Marina K
• Liang Spencer

Classifications

• C07K2317/92

  Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value · CPC title

• C07K2317/76

  Antagonist effect on antigen, e.g. neutralization or inhibition of binding · CPC title

• C07K2317/53

  Hinge · CPC title

• C07K2317/35

  Valency · CPC title

• C07K2317/24

  containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered · CPC title