Anti-ASGR-1 monoclonal inhibitory antibodies

Patent metadata

Field	Value
Publication number	US-12331122-B2
Application number	US-202016987237-A
Country	US
Kind code	B2
Filing date	Aug 6, 2020
Priority date	Sep 29, 2015
Publication date	Jun 17, 2025
Grant date	Jun 17, 2025

Abstract

Antigen binding proteins that interact with ASGR, ASGR-1 and/or ASGR-2 are described as well as methods of making and using such antigen binding proteins. Methods of treating and preventing cardiovascular disease by administering a pharmaceutically effective amount of ASGR, ASGR-1 and/or ASGR-2 antigen binding proteins. Methods of treating and preventing cardiovascular disease by administering a pharmaceutically effective amount of interfering RNA compositions that reduce expression of ASGR, ASGR-1 and/or ASGR-2 are described.

First claim

What is claimed is:

1. An isolated monoclonal antibody or antigen binding fragment thereof, wherein the isolated monoclonal antibody or antigen binding fragment thereof specifically binds to human asialoglycoprotein receptor 1 (“ASGR-1”) and comprises
a heavy chain variable domain comprising a VH CDR1, a VH CDR2 and a VH CDR3 and a light chain variable domain comprising a VL CDR1, a VL CDR2 and a VL CDR3, wherein:
(i) VH CDR1, VH CDR2, and VH CDR3 comprise the sequences of SEQ ID NOs: 4880, 12892, and 20904, respectively; and VL CDR1, VL CDR2 and VL CDR3 comprise the sequences of SEQ ID NOs: 872, 8884, and 16896, respectively;
(ii) VH CDR1, VH CDR2, and VH CDR3 comprise the sequences of SEQ ID NOs: 4700, 12712, and 20724, respectively; and VL CDR1, VL CDR2 and VL CDR3 comprise the sequences of SEQ ID NOs: 692, 8704, and 16716, respectively;
(iii) VH CDR1, VH CDR2, and VH CDR3 comprise the sequences of SEQ ID NOs: 5150, 13162, and 21174, respectively; and VL CDR1, VL CDR2 and VL CDR3 comprise the sequences of SEQ ID NOs: 1144, 9156, and 17168, respectively;
(iv) VH CDR1, VH CDR2, and VH CDR3 comprise the sequences of SEQ ID NOs: 7382, 15394, and 23406, respectively; and VL CDR1, VL CDR2 and VL CDR3 comprise the sequences of SEQ ID NOs: 3378, 11390, and 19402, respectively;
(v) VH CDR1, VH CDR2, and VH CDR3 comprise the sequences of SEQ ID NOs: 7822, 15834, and 23846, respectively; and VL CDR1, VL CDR2 and VL CDR3 comprise the sequences of SEQ ID NOs: 3818, 11830, and 19842, respectively;
(vi) VH CDR1, VH CDR2, and VH CDR3 comprise the sequences of SEQ ID NOs: 5378, 13390, and 21402, respectively; and VL CDR1, VL CDR2 and VL CDR3 comprise the sequences of SEQ ID NOs: 1372, 9384, and 17396, respectively;
(vii) VH CDR1, VH CDR2, and VH CDR3 comprise the sequences of SEQ ID NOs: 7500, 15512 and 23524, respectively; and VL CDR1, VL CDR2 and VL CDR3 comprise the sequences of SEQ ID NOs: 3496, 11508, and 19520, respectively;
(viii) VH CDR1, VH CDR2, and VH CDR3 comprise the sequences of SEQ ID NOs: 4846, 12858, and 20870, respectively; and VL CDR1, VL CDR2 and VL CDR3 comprise the sequences of SEQ ID NOs: 838, 8850, and 16862, respectively;
(ix) VH CDR1, VH CDR2, and VH CDR3 comprise the sequences of SEQ ID NOs: 6138, 14150, and 22162, respectively; and VL CDR1, VL CDR2 and VL CDR3 comprise the sequences of SEQ ID NOs: 2132, 10144, and 18156, respectively;
(x) VH CDR1, VH CDR2, and VH CDR3 comprise the sequences of SEQ ID NOs: 6884, 14896, and 22908, respectively; and VL CDR1, VL CDR2 and VL CDR3 comprise the sequences of SEQ ID NOs: 2878, 10890, and 18902, respectively;
(xi) VH CDR1, VH CDR2, and VH CDR3 comprise the sequences of SEQ ID NOs: 6898, 14910, and 22922, respectively; and VL CDR1, VL CDR2 and VL CDR3 comprise the sequences of SEQ ID NOs: 2892, 10904, and 18916, respectively;
(xii) VH CDR1, VH CDR2, and VH CDR3 comprise the sequences of SEQ ID NOs: 7296, 15308, and 23320, respectively; and VL CDR1, VL CDR2 and VL CDR3 comprise the sequences of SEQ ID NOs: 3292, 11304, and 19316, respectively;
(xiii) VH CDR1, VH CDR2, and VH CDR3 comprise the sequences of SEQ ID NOs: 7298, 15310, and 23322, respectively; and VL CDR1, VL CDR2 and VL CDR3 comprise the sequences of SEQ ID NOs: 3294, 11306, and 19318, respectively;
(xiv) VH CDR1, VH CDR2, and VH CDR3 comprise the sequences of SEQ ID NOs: 7308, 15320, and 23332, respectively; and VL CDR1, VL CDR2 and VL CDR3 comprise the sequences of SEQ ID NOs: 3304, 11316, and 19328, respectively; or
(xv) VH CDR1, VH CDR2, and VH CDR3 comprise the sequences of SEQ ID NOs: 6508, 14520, and 22532, respectively; and VL CDR1, VL CDR2 and VL CDR3 comprise the sequences of SEQ ID NOs: 2502, 10514, and 18526, respectively.

2. The isolated monoclonal antibody or antigen binding fragment thereof of claim 1 , comprising a heavy chain variable domain having at least 80% identity to any of the VH domain amino acid sequences set forth in SEQ ID NOs: 28734, 29184, 31418, 31858, 29412, 31536, 28914, 28880, 30172, 31332, 31334, 31344, 30542, 30918, and 30932.

3. The isolated monoclonal antibody or antigen binding fragment thereof of claim 1 , comprising a heavy chain variable domain having at least 90% identity to any of the VH domain amino acid sequences set forth in SEQ ID NOs: 28734, 29184, 31418, 31858, 29412, 31536, 28914, 28880, 30172, 31332, 31334, 31344, 30542, 30918, and 30932.

4. The isolated monoclonal antibody or antigen binding fragment thereof of claim 1 , comprising a light chain variable domain having at least 80% identity to any of the VL domain amino acid sequences set forth in SEQ ID NOs: 24728, 25178, 27412, 27852, 25406, 27530, 24908, 24874, 26166, 27326, 27328, 27338, 26536, 26912, and 26926.

5. The isolated monoclonal antibody or antigen binding fragment thereof of claim 1 , comprising a light chain variable domain having at least 90% identity to any of the VL domain amino acid sequences set forth in SEQ ID NOs: 24728, 25178, 27412, 27852, 25406, 27530, 24908, 24874, 26166, 27326, 27328, 27338, 26536, 26912, and 26926.

6. The isolated monoclonal antibody or antigen binding fragment thereof of claim 1 , wherein the heavy chain variable domain and the light chain variable domain are selected from one of the following paired VH and VL sequences, respectively:
SEQ ID NOs: 28734 and 24728;
SEQ ID NOs: 29184 and 25178;
SEQ ID NOs: 31418 and 27412;
SEQ ID NOs: 31858 and 27852;
SEQ ID NOs: 29412 and 25406;
SEQ ID NOs: 31536 and 27530;
SEQ ID NOs: 28914 and 24908;
SEQ ID NOs: 28880 and 24874;
SEQ ID NOs: 30172 and 26166;
SEQ ID NOs: 31332 and 27326;
SEQ ID NOs: 31334 and 27328;
SEQ ID NOs: 31344 and 27338;
SEQ ID NOs: 30542 and 26536;
SEQ ID NOs: 30918 and 26912; and
SEQ ID NOs: 30932 and 26926.

7. The isolated monoclonal antibody or antigen binding fragment thereof of claim 1 that is a humanized or a human monoclonal antibody or antigen binding fragment thereof.

8. An isolated neutralizing monoclonal antibody that binds to human asialoglycoprotein receptor 1 (“ASGR-1”) comprising the amino acid sequence of SEQ ID NO:5 but has a statistically significant reduction in binding to a variant human ASGR-1, wherein the variant human ASGR-1 comprises a single mutation of a residue selected from the group consisting of: R170, S171, G172, R183, L184, W195, E196, K199, H203, H204, P207, V208, N209, H215, D216, P220, D225, D228, R237, P238, E239, P241, D242, D243, Y245, G246, H247, G248, L249, G251, E253, T259, D260, R263, N265, Q270, R271, P272, R274 and E280 as shown in SEQ ID NO:5.

9. The isolated neutralizing monoclonal antibody of claim 8 , wherein the single mutation is selected from the group consisting of: W195, E196, K199, H203, H204, P207, P220, G251, and R263 as shown in SEQ ID NO:5.

10. The isolated monoclonal antibody of claim 8 , wherein the single mutation comprises a substitution of a non-arginine residue with arginine, or a substitution of an arginine residue to glutamic acid.

11. The isolated monoclonal antibody of claim 9 , wherein the single mutation comprises a substitution of a non-arginine residue with arginine, or a substitution of an arginine residue to glutamic acid.

12. An isolated humanized or human monoclonal antibody that binds to human asialoglycoprotein receptor 1 (“ASGR-1”) comprising the amino acid sequence of SEQ ID NO: 5, wherein the binding of the monoclonal antibody to human ASGR-1 is reduced at a pH of 5.6 as compared to its binding at a pH of 7.4, and wherein the monoclonal antibody inhibits ASGR-1 ligand binding.

13. The isolated humanized or human monoclonal antibody of claim 12 , wherein the binding of the monoclonal antibody to human ASGR-1 is reduced in the abse

Assignees

• Amgen Inc

Inventors

• Nioi Paul
• Coward Peter
• Murawsky Christopher
• Piper Derek E
• Garces Fernando
• Chan Brian Mingtung

Classifications

• C07K2317/94

  Stability, e.g. half-life, pH, temperature or enzyme-resistance · CPC title

• 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

• A61K2039/507

  Comprising a combination of two or more separate antibodies · CPC title

• A61K2039/505

  comprising antibodies · CPC title