Anti-TREM2 antibodies and methods of use thereof

1. 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-α 6 -F-Y-M-S (SEQ ID NO:28), wherein α 6 is D or N;

ii. a CDR-H2 sequence comprising the sequence of V-I-R-N-β 5 -β 6 -N-β 8 -Y-T-β 11 -β 12 -Y-N-P-S-V-K-G (SEQ ID NO:29), wherein β 5 is K or R; β 6 is A or P; β 8 is G or A; β 11 is A or T; and β 12 is G or D;

iii. a CDR-H3 sequence comprising the sequence of γ 1 -R-L-γ 4 -Y-G-F-D-Y (SEQ ID NO:30), wherein γ 1 is A or T; and γ 4 is T or S;

iv. a CDR-L1 sequence comprising the sequence of Q-S-S-K-S-L-L-H-S-δ 10 -G-K-T-Y-L-N (SEQ ID NO:31), wherein δ 10 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-ϕ 6 -P-F-T (SEQ ID NO:32), wherein ϕ 6 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.

2. The antibody of claim 1 , wherein:

i. the CDR-H1 sequence is selected from the group consisting of SEQ ID NOS:4 and 12;

ii. the CDR-H2 sequence is selected from the group consisting of SEQ ID NOS:5, 13, and 25;

iii. the CDR-H3 sequence is selected from the group consisting of SEQ ID NOS:6, 14, and 17;

iv. the CDR-L1 sequence is selected from the group consisting of SEQ ID NOS:7 and 23;

v. the CDR-L2 sequence comprises the sequence WMSTRAS (SEQ ID NO:8); and

vi. the CDR-L3 sequence is selected from the group consisting of SEQ ID NOS:9 and 18.

3. The antibody of claim 1 , wherein the variable region comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:4, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:25, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 17, a CDR-L1 comprising the amino acid sequence of SEQ ID NO:23, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:8, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 18.

4. The antibody of claim 1 , wherein the variable region comprises a V H sequence that has at least 85% sequence identity to SEQ ID NO:24 and a V L sequence has at least 85% sequence identity to SEQ ID NO:22.

5. The antibody of claim 1 , wherein the first Fc polypeptide 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.

6. The antibody of claim 5 , wherein:

(a) the first Fc polypeptide has a T366W substitution and the second Fc polypeptide has T366S, L368A, and Y407V substitutions, according to EU numbering;

(b) the first Fc polypeptide and/or the second Fc polypeptide comprises amino acid substitutions of Ala at position 234 and Ala at position 235, according to EU numbering; and/or

(c) the first Fc polypeptide and/or the second Fc polypeptide comprises amino acid substitutions of Leu at position 428 and Ser at position 434, according to EU numbering.

7. The antibody of claim 1 , wherein the first Fc polypeptide comprises the sequence of SEQ ID NO:41 or 64, and the second Fc polypeptide comprises the sequence of SEQ ID NO:39 or 63.

8. The antibody of claim 7 , comprising:

(i) a first heavy chain (HC) comprising a V H comprising SEQ ID NO:24 and the first Fc polypeptide comprising SEQ ID NO:41 or 64;

(ii) a second heavy chain (HC) comprising a V H comprising SEQ ID NO:24 and the second Fc polypeptide comprising SEQ ID NO:39 or 63; and

(iii) two light chains each comprising a V L comprising SEQ ID NO:22.

9. The antibody of claim 8 , comprising:

(i) a first heavy chain (HC) that comprises or consists of the amino acid sequence set forth in SEQ ID NO:42 or 65;

(ii) a second HC that comprises or consists of the amino acid sequence set forth in SEQ ID NO:53 or 73; and

(iii) a first and a second light chain (LC) that each comprises or consists of the amino acid sequence set forth in SEQ ID NO:54.

10. The antibody of claim 1 , wherein the first Fc polypeptide comprises the sequence of SEQ ID NO:44 or 66, and the second Fc polypeptide comprises the sequence of SEQ ID NO:39 or 63.

11. The antibody of claim 10 , comprising:

(i) a first heavy chain (HC) comprising a V H comprising SEQ ID NO:24 and the first Fc polypeptide comprising SEQ ID NO:44 or 66;

(ii) a second heavy chain (HC) comprising a V H comprising SEQ ID NO:24 and the second Fc polypeptide comprising SEQ ID NO:39 or 63; and

(iii) two light chains each comprising a V L comprising SEQ ID NO:22.

12. The antibody of claim 11 , comprising:

(i) a first heavy chain (HC) that comprises or consists of the amino acid sequence set forth in SEQ ID NO:45 or 67;

(ii) a second HC that comprises or consists of the amino acid sequence set forth in SEQ ID NO:53 or 73; and

(iii) a first and a second light chain (LC) that each comprises or consists of the amino acid sequence set forth in SEQ ID NO:54.

13. The antibody of claim 1 , wherein the first Fc polypeptide comprises the sequence of SEQ ID NO:47 or 68, and the second Fc polypeptide comprises the sequence of SEQ ID NO:39 or 63.

14. The antibody of claim 13 , comprising:

(i) a first heavy chain (HC) comprising a V H comprising SEQ ID NO:24 and the first Fc polypeptide comprising SEQ ID NO:47 or 68;

(ii) a second heavy chain (HC) comprising a V H comprising SEQ ID NO:24 and the second Fc polypeptide comprising SEQ ID NO:39 or 63; and

(iii) two light chains each comprising a V L comprising SEQ ID NO:22.

15. The antibody of claim 14 , comprising:

(i) a first heavy chain (HC) that comprises or consists of the amino acid sequence set forth in SEQ ID NO:48 or 69;

(ii) a second HC that comprises or consists of the amino acid sequence set forth in SEQ ID NO:53 or 73; and

(iii) a first and a second light chain (LC) that each comprises or consists of the amino acid sequence set forth in SEQ ID NO:54.

16. The antibody of claim 1 , wherein the first Fc polypeptide comprises the sequence of SEQ ID NO:47 or 68, and the second Fc polypeptide comprises the sequence of SEQ ID NO:61 or 84.

17. The antibody of claim 16 , comprising:

(i) a first heavy chain (HC) comprising a V H comprising SEQ ID NO:24 and the first Fc polypeptide comprising SEQ ID NO:47 or 68;

(ii) a second heavy chain (HC) comprising a V H comprising SEQ ID NO:24 and the second Fc polypeptide comprising SEQ ID NO:61 or 84; and

(iii) two light chains each comprising a V L comprising SEQ ID NO:22.

18. The antibody of claim 17 , comprising:

(i) a first heavy chain (HC) that comprises or consists of the amino acid sequence set forth in SEQ ID NO:48 or 69;

(ii) a second HC that comprises or consists of the amino acid sequence set forth in SEQ ID NO:52 or 72; and

(iii) a first and a second light chain (LC) that each comprises or consists of the amino acid sequence set forth in SEQ ID NO:54.

19. The antibody of claim 1 , wherein the first Fc polypeptide comprises the sequence of SEQ ID NO:50 or 70, and the second Fc polypeptide comprises the sequence of SEQ ID NO:39 or 63.

20. The antibody of claim 19 , comprising:

(i) a first heavy chain (HC) comprising a V H comprising SEQ ID NO:24 and the first Fc polypeptide comprising SEQ ID NO:50 or 70;

(ii) a second heavy chain (HC) comprising a V H comprising SEQ ID NO:24 and the second Fc polypeptide comprising SEQ ID NO:39 or 63; and

(iii) two light chains each comprising a V L comprising SEQ ID NO:22.

21. The antibody of claim 20 , comprising:

(i) a first heavy chain (HC) that comprises or consists of the amino acid sequence set forth in SEQ ID NO:51 or 71;

(ii) a second HC that comprises or consists of the amino acid sequence set forth in SEQ ID NO:53 or 73; and

(iii) a first and a second light chain (LC) that each comprises or consists of the amino acid sequence set forth in SEQ ID NO:54.

22. 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 V H comprising SEQ ID NO:24 and a first Fc polypeptide comprising SEQ ID NO:47;

(ii) a second heavy chain (HC) comprising a V H comprising SEQ ID NO:24 and a second Fc polypeptide comprising SEQ ID NO:39; and

(iii) two light chains each comprising a V L comprising SEQ ID NO:22.

23. The antibody of claim 22 , comprising:

(i) a first heavy chain (HC) that consists of the amino acid sequence set forth in SEQ ID NO:48;

(ii) a second HC that consists of the amino acid sequence set forth in SEQ ID NO:53; and

(iii) a first and a second light chain (LC) that each consists of the amino acid sequence set forth in SEQ ID NO:54.

24. 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 V H comprising SEQ ID NO:24 and a first Fc polypeptide comprising SEQ ID NO:68;

(ii) a second heavy chain (HC) comprising a V H comprising SEQ ID NO:24 and a second Fc polypeptide comprising SEQ ID NO:63; and

(iii) two light chains each comprising a V L comprising SEQ ID NO:22.

25. The antibody of claim 24 , comprising:

(i) a first heavy chain (HC) that consists of the amino acid sequence set forth in SEQ ID NO:69;

(ii) a second HC that consists of the amino acid sequence set forth in SEQ ID NO:73; and

(iii) a first and a second light chain (LC) that each consists of the amino acid sequence set forth in SEQ ID NO:54.

26. A pharmaceutical composition comprising the isolated antibody of claim 1 and a pharmaceutically acceptable carrier.

27. An isolated polynucleotide comprising:

(a) a nucleotide sequence encoding the antibody of claim 1 ; or

(b) a nucleotide sequence encoding SEQ ID NOS:42, 53, and 54; or

(c) a nucleotide sequence encoding SEQ ID NOS:45, 53, and 54; or

(d) a nucleotide sequence encoding SEQ ID NOS:48, 53, and 54; or

(e) a nucleotide sequence encoding SEQ ID NOS:48, 52, and 54; or

(f) a nucleotide sequence encoding SEQ ID NOS:51, 53, and 54.

28. A vector or host cell comprising the polynucleotide of claim 27 .

29. A method of expressing an antibody that specifically binds to a human triggering receptor expressed on myeloid cells 2 (TREM2), comprising: culturing the host cell of claim 28 under conditions suitable for expression of the antibody.

30. 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-α 6 -F-Y-M-S(SEQ ID NO:28), wherein α 6 is D or N;

ii. a CDR-H2 sequence comprising the sequence of V-I-R-N-β 5 -β 6 -N-β 8 -Y-T-β 11 -β 12 -Y-N-P-S-V-K-G (SEQ ID NO:29), wherein β 5 is K or R; β 6 is A or P; β 8 is G or A; β 11 is A or T; and β 12 is G or D;

iii. a CDR-H3 sequence comprising the sequence of γ 1 -R-L-γ 4 -Y-G-F-D-Y (SEQ ID NO:30), wherein γ 1 is A or T; and γ 4 is T or S;

iv. a CDR-L1 sequence comprising the sequence of Q-S-S-K-S-L-L-H-S-δ 10 -G-K-T-Y-L-N(SEQ ID NO:31), wherein δ 10 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-ϕ 6 -P-F-T (SEQ ID NO:32), wherein ϕ 6 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.

31. The antibody of claim 30 , wherein:

(a) the first Fc polypeptide has a T366W substitution and the second Fc polypeptide has T366S, L368A, and Y407V substitutions, according to EU numbering;

(b) the first Fc polypeptide and/or the second Fc polypeptide comprises amino acid substitutions of Ala at position 234 and Ala at position 235, according to EU numbering; and/or

(c) the first Fc polypeptide and/or the second Fc polypeptide comprises amino acid substitutions of Leu at position 428 and Ser at position 434, according to EU numbering.