Lilrb2-specific monoclonal antibodies and methods of their use

Patent metadata

Field	Value
Publication number	US-2024392001-A1
Application number	US-202218691249-A
Country	US
Kind code	A1
Filing date	Sep 13, 2022
Priority date	Sep 13, 2021
Publication date	Nov 28, 2024
Grant date	—

Abstract

Isolated or recombinant anti-LILRB2 monoclonal antibodies are provided. In some embodiments, the antibodies herein can be used for the detection, diagnosis and/or therapeutic treatment of human diseases, such as Alzheimer's Disease. In further aspects, the LILRB2-binding antibodies can affect cellular signaling mediated through at least the oA and PS-mediated TREM2 and LILRB2 co-ligation signaling pathway and can be used to modulate microglia function.

First claim

1 . An isolated monoclonal antibody, wherein the antibody specifically binds to LILRB2 and wherein the antibody competes for binding of the LILRB2 epitopes with a NeuB2-8, NeuB2-9, NeuB2-13, NeuB2-19, NeuB2-29, NeuB2-37, NeuB2-40, NeuB2-55, NeuB2-60, NeuB2-80, NeuB2-93, NeuB2-110, or NeuB2-128 monoclonal antibody.

2 . The antibody of claim 1 , or antigen-binding fragment thereof, wherein the antibody comprises:
(a) a first V H CDR at least 80% identical to the V H CDR1 (SEQ ID NO: 1) of NeuB2-8, at least 80% identical to V H CDR1 (SEQ ID NO: 4) of NeuB2-9, at least 80% identical to the V H CDR1 (SEQ ID NO: 7) of NeuB2-13, at least 80% identical to the V H CDR1 (SEQ ID NO: 10) of NeuB2-19, at least 80% identical to the V H CDR1 (SEQ ID NO: 13) of NeuB2-29, at least 80% identical to the V H CDR1 (SEQ ID NO: 16) of NeuB2-37, at least 80% identical to the V H CDR1 (SEQ ID NO: 19) of NeuB2-40, at least 80% identical to the V H CDR1 (SEQ ID NO: 22) of NeuB2-55, at least 80% identical to the V H CDR1 (SEQ ID NO: 25) of NeuB2-60, at least 80% identical to the V H CDR1 (SEQ ID NO: 28) of NeuB2-80, at least 80% identical to the V H CDR1 (SEQ ID NO: 31) of NeuB2-93, at least 80% identical to the V H CDR1 (SEQ ID NO: 34) of NeuB2-110, or at least 80% identical to the V H CDR1 (SEQ ID NO: 37) of NeuB2-128; (b) a second V H CDR at least 80% identical to the V H CDR2 (SEQ ID NO: 2) of NeuB2-8, at least 80% identical to the V H CDR2 (SEQ ID NO: 5), at least 80% identical to the V H CDR2 (SEQ ID NO: 8), at least 80% identical to the V H CDR2 (SEQ ID NO: 11), at least 80% identical to the V H CDR2 (SEQ ID NO: 14), at least 80% identical to the V H CDR2 (SEQ ID NO: 17), at least 80% identical to the V H CDR2 (SEQ ID NO: 20), at least 80% identical to the V H CDR2 (SEQ ID NO: 23), at least 80% identical to the V H CDR2 (SEQ ID NO: 26), at least 80% identical to the V H CDR2 (SEQ ID NO: 29), at least 80% identical to the V H CDR2 (SEQ ID NO: 32), at least 80% identical to the V H CDR2 (SEQ ID NO: 35), or at least 80% identical to the V H CDR2 (SEQ ID NO: 38); (c) a third V H CDR at least 80% identical to V H CDR3 (SEQ ID NO: 3) of NeuB2-8, at least 80% identical to V H CDR3 (SEQ ID NO: 6) of NeuB2-9, at least 80% identical to V H CDR3 (SEQ ID NO: 9) of NeuB2-13, at least 80% identical to V H CDR3 (SEQ ID NO: 12) of NeuB2-19, at least 80% identical to V H CDR3 (SEQ ID NO: 15) of NeuB2-29, at least 80% identical to V H CDR3 (SEQ ID NO: 18) of NeuB2-37, at least 80% identical to V H CDR3 (SEQ ID NO: 21) of NeuB2-40, at least 80% identical to V H CDR3 (SEQ ID NO: 24) of NeuB2-55, at least 80% identical to V H CDR3 (SEQ ID NO: 27) of NeuB2-60, at least 80% identical to V H CDR3 (SEQ ID NO: 30) of NeuB2-80, at least 80% identical to V H CDR3 (SEQ ID NO: 33) of NeuB2-93, at least 80% identical to V H CDR3 (SEQ ID NO: 36) of NeuB2-110, or at least 80% identical to V H CDR3 (SEQ ID NO: 39) of NeuB2-128; (d) a first V L CDR at least 80% identical to V L CDR1 (SEQ ID NO: 40) of NeuB2-8, at least 80% identical to V L CDR1 (SEQ ID NO: 42) of NeuB2-9, at least 80% identical to V L CDR1 (SEQ ID NO: 44) of NeuB2-13, at least 80% identical to V L CDR1 (SEQ ID NO: 46) of NeuB2-19, at least 80% identical to V L CDR1 (SEQ ID NO: 48) of NeuB2-29, at least 80% identical to V L CDR1 (SEQ ID NO: 50) of NeuB2-37, at least 80% identical to V L CDR1 (SEQ ID NO: 52) of NeuB2-40, at least 80% identical to V L CDR1 (SEQ ID NO: 54) of NeuB2-55, at least 80% identical to V L CDR1 (SEQ ID NO: 56) of NeuB2-60, at least 80% identical to V L CDR1 (SEQ ID NO: 58) of NeuB2-80, at least 80% identical to V L CDR1 (SEQ ID NO: 60) of NeuB2-93, at least 80% identical to V L CDR1 (SEQ ID NO: 62) of NeuB2-110, or at least 80% identical to V L CDR1 (SEQ ID NO: 64) of NeuB2-128; (e) a second V L CDR at least 80% identical to V L CDR2 (tripeptide GVS) of NeuB2-8, at least 80% identical to V L CDR2 (tripeptide SNN) of NeuB2-9, at least 80% identical to V L CDR2 (tripeptide GAS) of NeuB2-13, at least 80% identical to V L CDR2 (tripeptide DNN) of NeuB2-19, at least 80% identical to V L CDR2 (tripeptide YDD) of NeuB2-29, at least 80% identical to V L CDR2 (tripeptide SNN) of NeuB2-37, at least 80% identical to V L CDR2 (tripeptide YDD) of NeuB2-40, at least 80% identical to V L CDR2 (Tripeptide DVS) of NeuB2-55, at least 80% identical to V L CDR2 (Tripeptide YDD) of NeuB2-60, at least 80% identical to V L CDR2 (Tripeptide NNS) of NeuB2-80, at least 80% identical to V L CDR2 (Tripeptide EVS) of NeuB2-93, at least 80% identical to V L CDR2 (Tripeptide EVS) of NeuB2-110, or at least 80% identical to V L CDR2 (Tripeptide DAS) of NeuB2-128; and (f) a third V L CDR at least 80% identical to V L CDR3 (SEQ ID NO: 41) of NeuB2-8, at least 80% identical to V L CDR3 (SEQ ID NO: 43) of NeuB2-9, at least 80% identical to V L CDR3 (SEQ ID NO: 45) of NeuB2-13, at least 80% identical to V L CDR3 (SEQ ID NO: 47) of NeuB2-19, at least 80% identical to V L CDR3 (SEQ ID NO: 80) of NeuB2-29, at least 80% identical to V L CDR3 (SEQ ID NO: 51) of NeuB2-37, at least 80% identical to V L CDR3 (SEQ ID NO: 53) of NeuB2-40, at least 80% identical to V L CDR3 (SEQ ID NO: 55) of NeuB2-55, at least 80% identical to V L CDR3 (SEQ ID NO: 57) of NeuB2-60, at least 80% identical to V L CDR3 (SEQ ID NO: 59) of NeuB2-80, at least 80% identical to V L CDR3 (SEQ ID NO: 61) of NeuB2-93, at least 80% identical to V L CDR3 (SEQ ID NO: 63) of NeuB2-110, or at least 80% identical to V L CDR3 (SEQ ID NO: 65) of NeuB2-128.

3 . The antibody of claim 2 , wherein the antibody comprises:
(i) a V H domain at least about 80% identical to the V H domain (SEQ ID NO: 66) of NeuB2-8 or the humanized V H domain of NeuB2-8 mAb; and a V L domain at least about 80% identical to the V L domain (SEQ ID NO: 79) of NeuB2-8 or the humanized V L domain of NeuB2-8 mAb; (ii) a V H domain at least about 80% identical to the V H domain (SEQ ID NO: 67) of NeuB2-9 or the humanized V H domain of NeuB2-9 mAb; and a V L domain at least about 80% identical to the V L domain (SEQ ID NO: 80) of NeuB2-9 or the humanized V L domain of NeuB2-9 mAb; (iii) a V H domain at least about 80% identical to the V H domain (SEQ ID NO: 68) of NeuB2-13 or the humanized V H domain of NeuB2-13 mAb; and a V L domain at least about 80% identical to the V L domain (SEQ ID NO: 81) of NeuB2-13 or the humanized V L domain of NeuB2-13 mAb; (iv) a V H domain at least about 80% identical to the V H domain (SEQ ID NO: 69) of NeuB2-19 or the humanized V H domain of NeuB2-19 mAb; and a V L domain at least about 80% identical to the V L domain (SEQ ID NO: 82) of NeuB2-19 or the humanized V L domain of NeuB2-19 mAb; (v) a V H domain at least about 80% identical to the V H domain (SEQ ID NO: 70) of NeuB2-29 or the humanized V H domain of NeuB2-29 mAb; and a V L domain at least about 80% identical to the V L domain (SEQ ID NO: 83) of NeuB2-29 or the humanized V L domain of NeuB2-29 mAb; (vi) a V H domain at least about 80% identical to the V H domain (SEQ ID NO: 71) of NeuB2-37 or the humanized V H domain of NeuB2-37 mAb; and a V L domain at least about 80% identical to the V L domain (SEQ ID NO: 84) of NeuB2-37 or the humanized V L domain of NeuB2-37 mAb; (vii) a V H domain at least about 80% identical to the V H domain (SEQ ID NO: 72) of NeuB2-40 or the humanized V H domain of NeuB2-40 mAb; and a V L domain at least about 80% identical to the V L domain (SEQ ID NO: 85) of NeuB2-40 or the humanized V L domain of NeuB2-40 mAb; (viii) a V H domain at least about 80% identical to the V H domain (SEQ ID NO: 73) of NeuB2-55 or the humanized V H domain of NeuB2-55 mAb; and a V L domain at least about 80% identical to the V L domain (SEQ ID NO: 86) of NeuB2-55 or the humanized V L domain of NeuB2-55 mAb; (ix) a V H domain at leas

Assignees

• Univ Texas

Inventors

• An Zhiqiang
• Zhang Ningyan
• Zhao Peng

Classifications

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title

• C07K16/2896

  against molecules with a "CD"-designation, not provided for elsewhere · CPC title

• C07K2317/21

  from primates, e.g. man · CPC title

• C07K2317/92

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

• C07K2317/33

  Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity · CPC title