Anti-trem2 antibodies and methods of use thereof
AssigneeDenali Therapeutics Inc.
InventorsMark S. Dennis, Zhenyu Gu, Mihalis Kariolis, Cathal Mahon, Kathryn M. Monroe, Joshua I. Park, Rachel Prorok, Adam P. Silverman, Bettina Van Lengerich
Life of this patent
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Abstract
In one aspect, antibodies that specifically bind to a human triggering receptor expressed on myeloid cells 2 (TREM2) protein are provided. In some embodiments, the antibody decreases levels of soluble TREM2 (sTREM2). In some embodiments, the antibody enhances TREM2 activity.
Claims35
1-88. (canceled)
A method of treating a neurodegenerative disease in a subject, comprising administering to the subject an isolated antibody that specifically binds to a human triggering receptor expressed on myeloid cells 2 (TREM2), wherein the antibody comprises:
- (a) a variable region comprising:
- i. a CDR-H1 sequence comprising the sequence of G-F-T-F-T-α6-F-Y-M-S (SEQ ID NO:28), wherein α6 is D or N;
- ii. a CDR-H2 sequence comprising the sequence of V-I-R-N-β5-β6-N-β8-Y-T-β11-β12-Y-N-P-S-V-K-G (SEQ ID NO:29), wherein β5 is K or R;
- β6 is A or P;
- β8 is G or A;
- β11 is A or T;
- and β12 is G or D;
- iii. a CDR-H3 sequence comprising the sequence of γ1-R-L-γ4-Y-G-F-D-Y (SEQ ID NO:30), wherein γ1 is A or T;
- and γ4 is T or S;
- iv. a CDR-L1 sequence comprising the sequence of Q-S-S-K-S-L-L-H-S-δ10-G-K-T-Y-L-N (SEQ ID NO:31), wherein δ10 is N or T;
- v. a CDR-L2 sequence comprising the sequence WMSTRAS (SEQ ID NO:8);
- and
- vi. a CDR-L3 sequence comprising the sequence of Q-Q-F-L-E-ϕ6-P-F-T (SEQ ID NO:32), wherein ϕ6 is Y or F:
- (b) a first Fc polypeptide that specifically binds to human transferrin receptor 1 and comprises a sequence having at least 90% sequence identity to SEQ ID NO:49;
- and
- (c) a second Fc polypeptide.
A method of decreasing levels of sTREM2 in a subject having a neurodegenerative disease, comprising administering to the subject an isolated antibody that specifically binds to a human triggering receptor expressed on myeloid cells 2 (TREM2), wherein the antibody comprises:
- (a) a variable region comprising:
- i. a CDR-H1 sequence comprising the sequence of G-F-T-F-T-α6-F-Y-M-S (SEQ ID NO:28), wherein α6 is D or N;
- ii. a CDR-H2 sequence comprising the sequence of V-I-R-N-β5-β6-N-β8-Y-T-β11-β12-Y-N-P-S-V-K-G (SEQ ID NO:29), wherein β5 is K or R;
- β6 is A or P;
- β8 is G or A;
- β11 is A or T;
- and β12 is G or D;
- iii. a CDR-H3 sequence comprising the sequence of γ1-R-L-γ4-Y-G-F-D-Y (SEQ ID NO:30), wherein γ1 is A or T;
- and γ4 is T or S;
- iv. a CDR-L1 sequence comprising the sequence of Q-S-S-K-S-L-L-H-S-δ10-G-K-T-Y-L-N (SEQ ID NO:31), wherein δ10 is N or T;
- v. a CDR-L2 sequence comprising the sequence WMSTRAS (SEQ ID NO:8);
- and
- vi. a CDR-L3 sequence comprising the sequence of Q-Q-F-L-E-ϕ6-P-F-T (SEQ ID NO:32), wherein ϕ6 is Y or F:
- (b) a first Fc polypeptide that specifically binds to human transferrin receptor 1 and comprises a sequence having at least 90% sequence identity to SEQ ID NO:49;
- and
- (c) a second Fc polypeptide.
A method of enhancing TREM2 activity in a subject having a neurodegenerative disease, comprising administering to the subject an isolated antibody that specifically binds to a human triggering receptor expressed on myeloid cells 2 (TREM2), wherein the antibody comprises:
- (a) a variable region comprising:
- i. a CDR-H1 sequence comprising the sequence of G-F-T-F-T-α6-F-Y-M-S (SEQ ID NO:28), wherein α6 is D or N;
- ii. a CDR-H2 sequence comprising the sequence of V-I-R-N-β5-β6-N-β8-Y-T-β11-β12-Y-N-P-S-V-K-G (SEQ ID NO:29), wherein β5 is K or R;
- β6 is A or P;
- β8 is G or A;
- β11 is A or T;
- and β12 is G or D;
- iii. a CDR-H3 sequence comprising the sequence of γ1-R-L-γ4-Y-G-F-D-Y (SEQ ID NO:30), wherein γ1 is A or T;
- and γ4 is T or S;
- iv. a CDR-L1 sequence comprising the sequence of Q-S-S-K-S-L-L-H-S-δ10-G-K-T-Y-L-N (SEQ ID NO:31), wherein δ10 is N or T;
- v. a CDR-L2 sequence comprising the sequence WMSTRAS (SEQ ID NO:8);
- and
- vi. a CDR-L3 sequence comprising the sequence of Q-Q-F-L-E-ϕ6-P-F-T (SEQ ID NO:32), wherein ϕ6 is Y or F;
- (b) a first Fc polypeptide that specifically binds to human transferrin receptor 1 and comprises a sequence having at least 90% sequence identity to SEQ ID NO:49;
- and
- (c) a second Fc polypeptide.
93-102. (canceled)
A method of treating a neurodegenerative disease in a subject, comprising administering to the subject an isolated antibody that specifically binds to a human triggering receptor expressed on myeloid cells 2 (TREM2), wherein the antibody comprises:
- (i) a first heavy chain (HC) comprising a VH comprising SEQ ID NO:24 and a first Fc polypeptide comprising SEQ ID NO:47;
- (ii) a second heavy chain (HC) comprising a VH comprising SEQ ID NO:24 and a second Fc polypeptide comprising SEQ ID NO:39;
- and
- (iii) two light chains each comprising a VL comprising SEQ ID NO:22.
A method of treating a neurodegenerative disease in a subject, comprising administering to the subject an isolated antibody that specifically binds to a human triggering receptor expressed on myeloid cells 2 (TREM2), wherein the antibody comprises:
- (i) a first heavy chain (HC) comprising a VH comprising SEQ ID NO:24 and a first Fc polypeptide comprising SEQ ID NO:68;
- (ii) a second heavy chain (HC) comprising a VH comprising SEQ ID NO:24 and a second Fc polypeptide comprising SEQ ID NO:63;
- and
- (iii) two light chains each comprising a VL comprising SEQ ID NO:22.
A method of treating a neurodegenerative disease in a subject, comprising administering to the subject an isolated antibody that specifically binds to a human triggering receptor expressed on myeloid cells 2 (TREM2), wherein the antibody comprises:
- (a) a variable region comprising:
- i. a CDR-H1 sequence comprising the sequence of G-F-T-F-T-α6-F-Y-M-S (SEQ ID NO:28), wherein α6 is D or N;
- ii. a CDR-H2 sequence comprising the sequence of V-I-R-N-β5-β6-N-β8-Y-T-β11-β12-Y-N-P-S-V-K-G (SEQ ID NO:29), wherein β5 is K or R;
- β6 is A or P;
- β8 is G or A;
- Δ11 is A or T;
- and β12 is G or D;
- iii. a CDR-H3 sequence comprising the sequence of γ1-R-L-γ4-Y-G-F-D-Y (SEQ ID NO:30), wherein γ1 is A or T;
- and γ4 is T or S;
- iv. a CDR-L1 sequence comprising the sequence of Q-S-S-K-S-L-L-H-S-δ10-G-K-T-Y-L-N (SEQ ID NO:31), wherein δ10 is N or T;
- v. a CDR-L2 sequence comprising the sequence WMSTRAS (SEQ ID NO:8);
- and
- vi. a CDR-L3 sequence comprising the sequence of Q-Q-F-L-E-ϕ6-P-F-T (SEQ ID NO:32), wherein ϕ6 is Y or F;
- (b) a first Fc polypeptide that specifically binds to human transferrin receptor 1 and comprises:
- Trp, Leu, or Glu at position 380;
- Tyr or Phe at position 384;
- Thr at position 386;
- Glu at position 387;
- Trp at position 388;
- Ser, Ala, or Val at position 389;
- Ser or Asn at position 390;
- Thr or Ser at position 413;
- Glu or Ser at position 415;
- Glu at position 416;
- and Phe at position 421, according to EU numbering;
- and
- (c) a second Fc polypeptide.
A method of treating Alzheimer's disease in a subject, comprising administering to the subject an isolated antibody that specifically binds to a human triggering receptor expressed on myeloid cells 2 (TREM2), wherein the antibody comprises:
- (i) a first heavy chain (HC) comprising a VH comprising SEQ ID NO:24 and a first Fc polypeptide comprising SEQ ID NO:47;
- (ii) a second heavy chain (HC) comprising a VH comprising SEQ ID NO:24 and a second Fc polypeptide comprising SEQ ID NO:39;
- and
- (iii) two light chains each comprising a VL comprising SEQ ID NO:22.
Dependencies are inferred from the claim text.