IP Library › Granted Patent US 11,623,958

Granted Patent B2

US 11,623,958 · App. 16/773,806 · Granted Apr 11, 2023

Single chain variable fragment CD3 binding proteins

Inventors: Robert B. Dubridge (Belmont, CA); Pui Seto (San Carlos, CA); Richard J. Austin (San Francisco, CA); Luke Evnin (San Francisco, CA); Jeanmarie Guenot (San Francisco, CA); Bryan Lemon (Mountain View, CA)

Assignee: HARPOON THERAPEUTICS, INC.

C07K16/2809 C07K16/18 C07K16/2887 C07K2317/31 C07K2317/565 C07K2317/622 C07K2317/73 C07K2317/92 C07K2317/94

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Quick Facts

Patent No.: US 11,623,958
App. No.: 16/773,806
Granted: Apr 11, 2023
Kind: B2

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Abstract

Disclosed herein are single chain variable fragment CD3 binding proteins with improved binding affinities, and robust aggregation profiles. Also described are multispecific binding proteins comprising a single chain variable fragment CD3 binding protein according to the instant disclosure. Pharmaceutical compositions comprising the binding proteins disclosed herein and methods of using such formulations are provided.

Claims (71)

1. A method of treating a cancer, the method comprising administering to a subject a protein, wherein the protein comprises a single chain variable fragment CD3 binding protein comprising a variable heavy chain region (VH), a variable light chain region (VL), and a linker, wherein the protein further comprises a cancer antigen binding domain,

wherein the VH comprises complementarity determining regions HC CDR1, HC CDR2, and HC CDR3, wherein the VL comprises complementarity determining regions LC CDR1, LC CDR2, and LC CDR3, wherein the single chain variable fragment CD3 binding protein is at least eighty percent identical to SEQ ID NO: 22, wherein

(a) the amino acid sequence of HC CDR1 is as set forth in SEQ ID NO. 29, SEQ ID NO. 30, SEQ ID NO. 31, SEQ ID NO. 32, SEQ ID NO. 33, SEQ ID NO. 34, SEQ ID NO. 35, SEQ ID NO. 36, SEQ ID NO. 37, SEQ ID NO. 38, SEQ ID NO. 39, or SEQ ID NO. 40;

(b) the amino acid sequence of HC CDR2 is as set forth in SEQ ID NO. 41, SEQ ID NO. 42, SEQ ID NO. 43, SEQ ID NO. 44, SEQ ID NO. 45, SEQ ID NO. 46, SEQ ID NO. 47, SEQ ID NO. 48, SEQ ID NO. 49, or SEQ ID NO. 50;

(c) the amino acid sequence of HC CDR3 is as set forth in SEQ ID NO. 51, SEQ ID NO. 52, SEQ ID NO. 53, SEQ ID NO. 54, SEQ ID NO. 55, SEQ ID NO. 56, SEQ ID NO. 57, SEQ ID NO. 58, SEQ ID NO. 59, or SEQ ID NO. 60;

(d) the amino acid sequence of LC CDR1 is as set forth in SEQ ID NO. 61, SEQ ID NO. 62, SEQ ID NO. 63, SEQ ID NO. 64, SEQ ID NO. 65, SEQ ID NO. 66, SEQ ID NO. 67, SEQ ID NO. 68, SEQ ID NO. 69, SEQ ID NO. 70, SEQ ID NO. 71, SEQ ID NO. 72, or SEQ ID NO: 73;

(e) the amino acid sequence of LC CDR2 is as set forth in SEQ ID NO. 74, SEQ ID NO. 75, SEQ ID NO. 76, SEQ ID NO. 77, SEQ ID NO. 78, SEQ ID NO. 79, SEQ ID NO. 80, SEQ ID NO. 81, SEQ ID NO. 82, SEQ ID NO. 83, SEQ ID NO. 84, SEQ ID NO. 85, or SEQ ID NO. 86; and

(f) the amino acid sequence of LC CDR3 is as set forth in SEQ ID NO. 87, SEQ ID NO: 88, SEQ ID NO. 89, SEQ ID NO. 90, SEQ ID NO. 91, SEQ ID NO. 92, or SEQ ID NO. 93, and

wherein said single chain variable fragment CD3 binding protein has an amino acid sequence that is at least 95% identical to a sequence selected from the group consisting of: SEQ ID NO. 8, SEQ ID NO. 9, SEQ ID NO. 10, SEQ ID NO. 11, SEQ ID NO. 12, SEQ ID NO. 13, SEQ ID NO. 14, SEQ ID NO. 15, SEQ ID NO. 16, SEQ ID NO. 17, SEQ ID NO. 18, SEQ ID NO. 19, SEQ ID NO. 20, SEQ ID NO. 21, SEQ ID NO. 94, and SEQ ID NO. 95.

2. The method of claim 1 , wherein HC CDR1 is SEQ ID NO. 39, HC CDR2 is SEQ ID NO. 49, HC CDR3 is SEQ ID NO. 51, LC CDR1 is SEQ ID NO. 61, LC CDR2 is SEQ ID NO. 86, and LC CDR3 is SEQ ID NO. 87.

3. The method of claim 1 , wherein HC CDR1 is SEQ ID NO. 30, HC CDR2 is SEQ ID NO. 43, LC CDR1 is SEQ ID NO. 64, and LC CDR3 is SEQ ID NO. 89.

4. The method of claim 1 , wherein HC CDR3 is SEQ ID NO. 55, LC CDR1 is SEQ ID NO. 67, LC CDR2 is SEQ ID NO. 77, and LC CDR3 is SEQ ID NO. 92.

5. The method of claim 1 , wherein HC CDR1 is SEQ ID NO. 31, HC CDR2 is SEQ ID NO. 42, HC CDR3 is SEQ ID NO. 60, LC CDR1 is SEQ ID NO. 64, LC CDR2 is SEQ ID NO. 79, and LC CDR3 is SEQ ID NO. 91.

6. The method of claim 1 , wherein HC CDR1 is SEQ ID NO. 35, HC CDR2 is SEQ ID NO. 46, HC CDR3 is SEQ ID NO. 56, LC CDR1 is SEQ ID NO. 68, and LC CDR3 is SEQ ID NO. 75.

7. The method of claim 1 , wherein HC CDR1 is SEQ ID NO. 29, HC CDR2 is SEQ ID NO. 44, HC CDR3 is SEQ ID NO. 52, LC CDR1 is SEQ ID NO. 73, and LC CDR2 is SEQ ID NO. 76.

8. The method of claim 1 , wherein HC CDR1 is SEQ ID NO. 33, HC CDR2 is SEQ ID NO. 48, HC CDR3 is SEQ ID NO. 57, LC CDR1 is SEQ ID NO. 69, and LC CDR2 is SEQ ID NO. 74.

9. The method of claim 1 , wherein HC CDR1 is SEQ ID NO. 37, HC CDR3 is SEQ ID NO. 53, LC CDR1 is SEQ ID NO. 70, LC CDR2 is SEQ ID NO. 82, and LC CDR3 is SEQ ID NO. 88.

10. The method of claim 1 , wherein HC CDR1 is SEQ ID NO. 34, HC CDR2 is SEQ ID NO. 47, HC CDR3 is SEQ ID NO. 56, LC CDR1 is SEQ ID NO. 68 and LC CDR2 is SEQ ID NO. 75.

11. The method of claim 1 , wherein HC CDR1 is SEQ ID NO. 29, HC CDR3 is SEQ ID NO. 54, LC CDR1 is SEQ ID NO. 71 and LC CDR2 is SEQ ID NO. 83.

12. The method of claim 1 , wherein HC CDR1 is SEQ ID NO. 33, HC CDR2 is SEQ ID NO. 41, LC CDR1 is SEQ ID NO. 63, LC CDR2 is SEQ ID NO. 84, and LC CDR1 is SEQ ID NO. 90 or wherein HC CDR1 is SEQ ID NO. 30, HC CDR2 is SEQ ID NO. 44, HC CDR3 is SEQ ID NO. 58, LC CDR1 is SEQ ID NO. 66 and LC CDR2 is SEQ ID NO. 85.

13. The method of claim 1 , wherein HC CDR1 is SEQ ID NO. 40, HC CDR2 is SEQ ID NO. 45, HC CDR3 is SEQ ID NO. 56, LC CDR2 is SEQ ID NO. 78 and LC CDR3 is SEQ ID NO. 93 or wherein HC CDR1 is SEQ ID NO. 36, HC CDR2 is SEQ ID NO. 50, HC CDR3 is SEQ ID NO. 59, LC CDR1 is SEQ ID NO. 72 and LC CDR2 is SEQ ID NO. 75.

14. The method of claim 1 , wherein the single chain variable fragment CD3 binding protein comprises a sequence that is at least 80% identical to SEQ ID NO. 22.

15. The method of claim 1 , wherein the single chain variable fragment CD3 binding protein comprises a sequence selected from the group consisting of SEQ ID NO. 8, SEQ ID NO. 9, SEQ ID NO. 10, SEQ ID NO. 11, SEQ ID NO. 12, SEQ ID NO. 13, SEQ ID NO. 14, SEQ ID NO. 15, SEQ ID NO. 16, SEQ ID NO. 17, SEQ ID NO. 18, SEQ ID NO. 19, SEQ ID NO. 20, SEQ ID NO. 21, SEQ ID NO. 94, and SEQ ID NO. 95.

16. The method of claim 15 , wherein the single chain variable fragment CD3 binding protein comprises the sequence of SEQ ID No. 8.

17. The method of claim 1 , wherein the linker has a sequence selected from those of SEQ ID NO. 1 and SEQ ID NO. 96-104.

18. The method of claim 1 , wherein the cancer comprises a hematological cancer.

19. The method of claim 1 , wherein the cancer comprises a solid tumor cancer.

20. A method of treating a cancer, the method comprising administering a protein,

wherein the protein comprises a single chain variable fragment CD3 binding protein comprising a variable heavy chain region (VH) and a variable light chain region (VL),

wherein the VH comprises complementarity determining regions HC CDR1, HC CDR2, and HC CDR3,

wherein the VL comprises complementarity determining regions LC CDR1, LC CDR2, and LC CDR3,

wherein the HC-CDR1, the HC-CDR2, the HC-CDR3, the LC-CDR1, the LC-CDR1, and the LC-CDR3 are not simultaneously SEQ ID NO. 23, SEQ ID NO. 24, SEQ ID NO. 25, SEQ ID NO. 26, SEQ ID NO. 27, and SEQ ID NO. 28,

wherein the single chain variable fragment CD3 binding protein is at least 80% identical to SEQ ID NO. 22,

wherein the protein further comprises a cancer antigen binding domain, and

wherein the CD3 binding CDRs are selected from:

(i) HC CDR1 is SEQ ID NO. 39, HC CDR2 is SEQ ID NO. 49, HC CDR3 is SEQ ID NO. 51, LC CDR1 is SEQ ID NO. 61, LC CDR2 is SEQ ID NO. 86, and LC CDR3 is SEQ ID NO. 87;

(ii) HC CDR1 is SEQ ID NO. 30, HC CDR2 is SEQ ID NO. 43, HC CDR3 is SEQ ID NO. 25, LC CDR1 is SEQ ID NO. 64, LC CDR2 is SEQ ID NO. 27, and LC CDR3 is SEQ ID NO. 89;

(iii) HC CDR1 is SEQ ID NO. 23, HC CDR2 is SEQ ID NO. 24, HC CDR3 is SEQ ID NO. 55, LC CDR1 is SEQ ID NO. 67, LC CDR2 is SEQ ID NO. 77, and LC CDR3 is SEQ ID NO. 92;

(iv) HC CDR1 is SEQ ID NO. 31, HC CDR2 is SEQ ID NO. 42, HC CDR3 is SEQ ID NO. 60, LC CDR1 is SEQ ID NO. 64, LC CDR2 is SEQ ID NO. 79, and LC CDR3 is SEQ ID NO. 91;

(v) HC CDR1 is SEQ ID NO. 35, HC CDR2 is SEQ ID NO. 46, HC CDR3 is SEQ ID NO. 56, LC CDR1 is SEQ ID NO. 68, LC CDR2 is SEQ ID NO. 75, and LC CDR3 is SEQ ID NO. 28;

(vi) HC CDR1 is SEQ ID NO. 32, HC CDR2 is SEQ ID NO. 47, HC CDR3 is SEQ ID NO. 56, LC CDR1 is SEQ ID NO. 65, LC CDR2 is SEQ ID NO. 80, and LC CDR3 is SEQ ID NO. 87;

(vii) HC CDR1 is SEQ ID NO. 29, HC CDR2 is SEQ ID NO. 44, HC CDR3 is SEQ ID NO. 52, LC CDR1 is SEQ ID NO. 73, LC CDR2 is SEQ ID NO. 76, and LC CDR3 is SEQ ID NO. 28;

(viii) HC CDR1 is SEQ ID NO. 33, HC CDR2 is SEQ ID NO. 48, HC CDR3 is SEQ ID NO. 57, LC CDR1 is SEQ ID NO. 69, LC CDR2 is SEQ ID NO. 74, and LC CDR3 is SEQ ID NO. 28;

(ix) HC CDR1 is SEQ ID NO. 38, HC CDR2 is SEQ ID NO. 24, HC CDR3 is SEQ ID NO. 25, LC CDR1 is SEQ ID NO. 62, LC CDR2 is SEQ ID NO. 81, and LC CDR3 is SEQ ID NO. 28;

(x) HC CDR1 is SEQ ID NO. 37, HC CDR2 is SEQ ID NO. 24, HC CDR3 is SEQ ID NO. 53, LC CDR1 is SEQ ID NO. 70, LC CDR2 is SEQ ID NO. 82, and LC CDR3 is SEQ ID NO. 88;

(xi) HC CDR1 is SEQ ID NO. 34, HC CDR2 is SEQ ID NO. 47, HC CDR3 is SEQ ID NO. 56, LC CDR1 is SEQ ID NO. 68, LC CDR2 is SEQ ID NO. 75, and LC CDR3 is SEQ ID NO. 28;

(xii) HC CDR1 is SEQ ID NO. 29, HC CDR2 is SEQ ID NO. 24, HC CDR3 is SEQ ID NO. 54, LC CDR1 is SEQ ID NO. 71, LC CDR2 is SEQ ID NO. 83, and LC CDR3 is SEQ ID NO. 28;

(xiii) HC CDR1 is SEQ ID NO. 33, HC CDR2 is SEQ ID NO. 41, HC CDR3 is SEQ ID NO. 25, LC CDR1 is SEQ ID NO. 63, LC CDR2 is SEQ ID NO. 84, and LC CDR3 is SEQ ID NO. 90;

(xiv) HC CDR1 is SEQ ID NO. 30, HC CDR2 is SEQ ID NO. 44, HC CDR3 is SEQ ID NO. 58, LC CDR1 is SEQ ID NO. 66, LC CDR2 is SEQ ID NO. 85, and LC CDR3 is SEQ ID NO. 28;

(xv) HC CDR1 is SEQ ID NO. 94, HC CDR2 is SEQ ID NO. 45, HC CDR3 is SEQ ID NO. 56, LC CDR1 is SEQ ID NO. 26, LC CDR2 is SEQ ID NO. 78, and LC CDR3 is SEQ ID NO. 93; or

(xvi) HC CDR1 is SEQ ID NO. 36, HC CDR2 is SEQ ID NO. 50, HC CDR3 is SEQ ID NO. 59, LC CDR1 is SEQ ID NO. 72, LC CDR2 is SEQ ID NO. 75, and LC CDR3 is SEQ ID NO. 28.

21. The method of claim 20 , wherein the single chain variable fragment CD3 binding protein comprises a sequence that is at least 80% identical to a sequence selected from the group consisting of SEQ ID NO. 8, SEQ ID NO. 9, SEQ ID NO. 10, SEQ ID NO. 11, SEQ ID NO. 12, SEQ ID NO. 13, SEQ ID NO. 14, SEQ ID NO. 15, SEQ ID NO. 16, SEQ ID NO. 17, SEQ ID NO. 18, SEQ ID NO. 19, SEQ ID NO. 20, SEQ ID NO. 21, SEQ ID NO. 94, and SEQ ID NO. 95.

22. The method of claim 20 , wherein the cancer comprises a hematological cancer.

23. The method of claim 20 , wherein the cancer comprises a solid tumor cancer.

24. A method of treating a cancer comprising administering a multispecific protein comprising: (a) a single chain variable fragment CD3 binding protein, (b) a domain that specifically binds to a serum albumin, and (c) a cancer antigen binding domain, wherein the CD3 binding protein comprising a variable heavy chain region (VH), a variable light chain region (VL), wherein VH comprises complementarity determining regions HC CDR1, HC CDR2, and HC CDR3, wherein VL comprises complementarity determining regions LC CDR1, LC CDR2, and LC CDR3, and wherein