IP Library › Granted Patent US 11,840,572

Granted Patent B2

US 11,840,572 · App. 17/378,377 · Granted Dec 12, 2023

Therapeutic antibodies and their uses

Inventors: James Reasoner Apgar (Newton, MA); Andrea Therese Hooper (Port Chester, NY); Malgorzata Agnieszka Nocula-Lugowska (Brighton, MA); Lei Wu (New York, NY)

Assignee: Pfizer Inc.

C07K16/2827 A61P35/00 C07K16/2809 A61K2039/505 C07K2317/31 C07K2317/73 C07K2317/92

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Quick Facts

Patent No.: US 11,840,572
App. No.: 17/378,377
Granted: Dec 12, 2023
Kind: B2

External Links

USPTO Patent Center↗ Full Patent PDF↗

Abstract

The present invention relates to antibodies that specifically bind to B7-H4 (B7 Homology 4, encoded by gene VTCN1) and bispecific antibodies that specifically bind to both B7-H4 and CD3 (Cluster of Differentiation 3), and polynucleotides, pharmaceutical compositions and methods and uses thereof.

Claims (75)

1. A bispecific antibody that specifically binds to both B7-H4 and CD3, comprising a first heavy chain and a first light chain, and a second heavy chain and a second light chain, wherein the first heavy chain and the first light chain form a first arm which comprises a first antigen binding domain that binds to B7-H4, and the second heavy chain and the second light chain form a second arm which comprises a second antigen binding domain that binds to CD3, wherein

(a) the first heavy chain comprises a VH CDR1 having the amino acid sequence of SEQ ID NO: 20; a VH CDR2 having the amino acid sequence of SEQ ID NO:21, a VH CDR3 having the amino acid sequence of SEQ ID NO:160, and the first light chain comprises a VL CDR1 having the amino acid sequence of SEQ ID NO: 166, a VL CDR2 having the amino acid sequence of SEQ ID NO:25 and a VL CDR3 having the amino acid sequence of SEQ ID NO:153;

(b) the first heavy chain comprises a VH CDR1 having the amino acid sequence of SEQ ID NO: 205; a VH CDR2 having the amino acid sequence of SEQ ID NO:21, a VH CDR3 having the amino acid sequence of SEQ ID NO:160, and the first light chain comprises a VL CDR1 having the amino acid sequence of SEQ ID NO: 166, a VL CDR2 having the amino acid sequence of SEQ ID NO:25 and a VL CDR3 having the amino acid sequence of SEQ ID NO:153;

(c) the first heavy chain comprises a VH CDR1 having the amino acid sequence of SEQ ID NO: 206; a VH CDR2 having the amino acid sequence of SEQ ID NO:207, a VH CDR3 having the amino acid sequence of SEQ ID NO:160, and the first light chain comprises a VL CDR1 having the amino acid sequence of SEQ ID NO: 166, a VL CDR2 having the amino acid sequence of SEQ ID NO:25 and a VL CDR3 having the amino acid sequence of SEQ ID NO:153;

(d) the first heavy chain comprises a VH CDR1 having the amino acid sequence of SEQ ID NO: 5; a VH CDR2 having the amino acid sequence of SEQ ID NO:6, a VH CDR3 having the amino acid sequence of SEQ ID NO:7, and the first light chain comprises a VL CDR1 having the amino acid sequence of SEQ ID NO: 9, a VL CDR2 having the amino acid sequence of SEQ ID NO:10 and a VL CDR3 having the amino acid sequence of SEQ ID NO:138;

(e) the first heavy chain comprises a VH CDR1 having the amino acid sequence of SEQ ID NO: 200; a VH CDR2 having the amino acid sequence of SEQ ID NO:201, a VH CDR3 having the amino acid sequence of SEQ ID NO:7, and the first light chain comprises a VL CDR1 having the amino acid sequence of SEQ ID NO: 9, a VL CDR2 having the amino acid sequence of SEQ ID NO:10 and a VL CDR3 having the amino acid sequence of SEQ ID NO:138;

(f) the first heavy chain comprises a VH CDR1 having the amino acid sequence of SEQ ID NO: 199; a VH CDR2 having the amino acid sequence of SEQ ID NO:6, a VH CDR3 having the amino acid sequence of SEQ ID NO:7, and the first light chain comprises a VL CDR1 having the amino acid sequence of SEQ ID NO: 9, a VL CDR2 having the amino acid sequence of SEQ ID NO:10 and a VL CDR3 having the amino acid sequence of SEQ ID NO:138;

(g) the first heavy chain comprises a VH CDR1 having the amino acid sequence of SEQ ID NO: 20; a VH CDR2 having the amino acid sequence of SEQ ID NO:21, a VH CDR3 having the amino acid sequence of SEQ ID NO:160, and the first light chain comprises a VL CDR1 having the amino acid sequence of SEQ ID NO: 152, a VL CDR2 having the amino acid sequence of SEQ ID NO:41 and a VL CDR3 having the amino acid sequence of SEQ ID NO:153;

(h) the first heavy chain comprises a VH CDR1 having the amino acid sequence of SEQ ID NO: 5; a VH CDR2 having the amino acid sequence of SEQ ID NO:6, a VH CDR3 having the amino acid sequence of SEQ ID NO:7, a VL CDR1 having the amino acid sequence of SEQ ID NO: 9, and the first light chain comprises a VL CDR2 having the amino acid sequence of SEQ ID NO:10 and a VL CDR3 having the amino acid sequence of SEQ ID NO:138; or

(i) the first heavy chain comprises a VH CDR1 having the amino acid sequence of SEQ ID NO: 5; a VH CDR2 having the amino acid sequence of SEQ ID NO:130, a VH CDR3 having the amino acid sequence of SEQ ID NO:7, and the first light chain comprises a VL CDR1 having the amino acid sequence of SEQ ID NO: 9, a VL CDR2 having the amino acid sequence of SEQ ID NO:10 and a VL CDR3 having the amino acid sequence of SEQ ID NO:138.

2. The bispecific antibody of claim 1 , wherein

(a) the first heavy chain comprises a VH having the amino acid sequence of SEQ ID NO:161, and the first light chain comprises a VL having the amino acid sequence of SEQ ID NO:167;

(b) the first heavy chain comprises a VH having the amino acid sequence of SEQ ID NO:172, and the first light chain comprises a VL having the amino acid sequence of SEQ ID NO:139;

(c) the first heavy chain comprises a VH having the amino acid sequence of SEQ ID NO:155; and the first light chain comprises a VL having the amino acid sequence of SEQ ID NO:139;

(d) the first heavy chain comprises a VH having the amino acid sequence of SEQ ID NO:156; and the first light chain comprises a VL having the amino acid sequence of SEQ ID NO:139;

(e) the first heavy chain comprises a VH having the amino acid sequence of SEQ ID NO:157; and the first light chain comprises a VL having the amino acid sequence of SEQ ID NO:141;

(f) the first heavy chain comprises a VH having the amino acid sequence of SEQ ID NO:155; and the first light chain comprises a VL having the amino acid sequence of SEQ ID NO:141;

(g) the first heavy chain comprises a VH having the amino acid sequence of SEQ ID NO:156; and the first light chain comprises a VL having the amino acid sequence of SEQ ID NO:141;

(h) the first heavy chain comprises a VH having the amino acid sequence of SEQ ID NO:159; and the first light chain comprises a VL having the amino acid sequence of SEQ ID NO:27;

(i) the first heavy chain comprises a VH having the amino acid sequence of SEQ ID NO:161; and the first light chain comprises a VL having the amino acid sequence of SEQ ID NO:27;

(j) the first heavy chain comprises a VH having the amino acid sequence of SEQ ID NO:163; and the first light chain comprises a VL having the amino acid sequence of SEQ ID NO:27;

(k) the first heavy chain comprises a VH having the amino acid sequence of SEQ ID NO:165; and the first light chain comprises a VL having the amino acid sequence of SEQ ID NO:27;

(l) the first heavy chain comprises a VH having the amino acid sequence of SEQ ID NO:23; and the first light chain comprises a VL having the amino acid sequence of SEQ ID NO:167;

(m) the first heavy chain comprises a VH having the amino acid sequence of SEQ ID NO:171; and the first light chain comprises a VL having the amino acid sequence of SEQ ID NO:141;

(n) the first heavy chain comprises a VH having the amino acid sequence of SEQ ID NO:172; and the first light chain comprises a VL having the amino acid sequence of SEQ ID NO:141;

(o) the first heavy chain comprises a VH having the amino acid sequence of SEQ ID NO:171; and the first light chain comprises a VL having the amino acid sequence of SEQ ID NO:139;

(p) the first heavy chain comprises a VH having the amino acid sequence of SEQ ID NO:173; and the first light chain comprises a VL having the amino acid sequence of SEQ ID NO:139;

(q) the first heavy chain comprises a VH having the amino acid sequence of SEQ ID NO:174; and the first light chain comprises a VL having the amino acid sequence of SEQ ID NO:139;

(r) the first heavy chain comprises a VH having the amino acid sequence of SEQ ID NO:175; and the first light chain comprises a VL having the amino acid sequence of SEQ ID NO:139;

(s) the first heavy chain comprises a VH having the amino acid sequence of SEQ ID NO:161; and a VL having the amino acid sequence of SEQ ID NO:168;

(t) the first heavy chain comprises a VH having the amino acid sequence of SEQ ID NO:161; and the first light chain comprises a VL having the amino acid sequence of SEQ ID NO:169;

(u) the first heavy chain comprises a VH having the amino acid sequence of SEQ ID NO:161; and the first light chain comprises a VL having the amino acid sequence of SEQ ID NO:170; or

(v) the first heavy chain comprises a VH having the amino acid sequence of SEQ ID NO:172; and the first light chain comprises a VL having the amino acid sequence of SEQ ID NO:139.

3. The bispecific antibody of claim 1 , wherein

(a) the second heavy chain comprises a VH CDR1 having the amino acid sequence of SEQ ID NO: 28, a VH CDR2 having the amino acid sequence of SEQ ID NO:105, a VH CDR3 having the amino acid sequence of SEQ ID NO:30, and the second light chain comprises a VL CDR1 having the amino acid sequence of SEQ ID NO: 107, a VL CDR2 having the amino acid sequence of SEQ ID NO:33 and a VL CDR3 having the amino acid sequence of SEQ ID NO:34;

(b) the second heavy chain comprises a VH CDR1 having the amino acid sequence of SEQ ID NO: 202, a VH CDR2 having the amino acid sequence of SEQ ID NO:105, a VH CDR3 having the amino acid sequence of SEQ ID NO:30, and the second light chain comprises a VL CDR1 having the amino acid sequence of SEQ ID NO: 107, a VL CDR2 having the amino acid sequence of SEQ ID NO:33 and a VL CDR3 having the amino acid sequence of SEQ ID NO:34;

(c) the second heavy chain comprises a VH CDR1 having the amino acid sequence of SEQ ID NO: 203, a VH CDR2 having the amino acid sequence of SEQ ID NO:204, a VH CDR3 having the amino acid sequence of SEQ ID NO:30, and the second light chain comprises a VL CDR1 having the amino acid sequence of SEQ ID NO: 107, a VL CDR2 having the amino acid sequence of SEQ ID NO:33 and a VL CDR3 having the amino acid sequence of SEQ ID NO:34;

(d) the second heavy chain comprises a VH CDR1 having the amino acid sequence of SEQ ID NO: 28, a VH CDR2 having the amino acid sequence of SEQ ID NO:105, a VH CDR3 having the amino acid sequence of SEQ ID NO:30, and the second light chain comprises a VL CDR1 having the amino acid sequence of SEQ ID NO: 107, a VL CDR2 having the amino acid sequence of SEQ ID NO:33 and a VL CDR3 having the amino acid sequence of SEQ ID NO:116;

(e) the second heavy chain comprises a VH CDR1 having the amino acid sequence of SEQ ID NO: 28, a VH CDR2 having the amino acid sequence of SEQ ID NO:109, a VH CDR3 having the amino acid sequence of SEQ ID NO:30, and the second light chain comprises a VL CDR1 having the amino acid sequence of SEQ ID NO: 111, a VL CDR2 having the amino acid sequence of SEQ ID NO:112 and a VL CDR3 having the amino acid sequence of SEQ ID NO:34; or

(f) the second heavy chain comprises a VH CDR1 having the amino acid sequence of SEQ ID NO: 28, a VH CDR2 having the amino acid sequence of SEQ ID NO:29, a VH CDR3 having the amino acid sequence of SEQ ID NO:30, and the second light chain comprises a VL CDR1 having the amino acid sequence of SEQ ID NO: 32, a VL CDR2 having the amino acid sequence of SEQ ID NO:33 and a VL CDR3 having the amino acid sequence of SEQ ID NO:34.

4. The bispecific antibody of claim 1 , wherein

(a) the second heavy chain comprises a VH having the amino acid sequence of SEQ ID NO: 106, and the second light chain comprises a VL having the amino acid sequence of SEQ ID NO: 108;

(b) the second heavy chain comprises a VH having the amino acid sequence of SEQ ID NO: 115, and the second light chain comprises a VL having the amino acid sequence of SEQ ID NO: 117;

(c) the second heavy chain comprises a VH having the amino acid sequence of SEQ ID NO: 110, and the second light chain comprises a VL having the amino acid sequence of SEQ ID NO: 113; or

(d) the second heavy chain comprises a VH having the amino acid sequence of SEQ ID NO: 31, and the second light chain comprises a VL having the amino acid sequence of SEQ ID NO: 35.

5. The bispecific antibody of claim 1 , wherein

(b) the second heavy chain comprises a VH CDR1 having the amino acid sequence of SEQ ID NO: 28, a VH CDR2 having the amino acid sequence of SEQ ID NO:105, a VH CDR3 having the amino acid sequence of SEQ ID NO:30, and the second light chain comprises a VL CDR1 having the amino acid sequence of SEQ ID NO: 107, a VL CDR2 having the amino acid sequence of SEQ ID NO:33 and a VL CDR3 having the amino acid sequence of SEQ ID NO:34.

6. The bispecific antibody of claim 1 , wherein (a) the first heavy chain comprises a VH CDR1 having the amino acid sequence of SEQ ID NO: 5; a VH CDR2 having the amino acid sequence of SEQ ID NO:6, a VH CDR3 having the amino acid sequence of SEQ ID NO:7, and the first light chain comprises a VL CDR1 having the amino acid sequence of SEQ ID NO: 9, a VL CDR2 having the amino acid sequence of SEQ ID NO:10 and a VL CDR3 having the amino acid sequence of SEQ ID NO:138; and

7. A bispecific antibody that specifically binds to both B7-H4 and CD3, comprising a first heavy chain and a first light chain, and a second heavy chain and a second light chain, wherein the first heavy chain and the first light chain form a first arm which comprises a first antigen binding domain that binds to B7-H4, and the second heavy chain and the second light chain form a second arm which comprises a second antigen binding domain that binds to CD3, and wherein

(a) the first heavy chain comprises a VH having the amino acid sequence of SEQ ID NO:161, and the first light chain comprises a VL having the amino acid sequence of SEQ ID NO:167; and

(b) the second heavy chain comprises a VH having the amino acid sequence of SEQ ID NO: 106, and the second light chain comprises a VL having the amino acid sequence of SEQ ID NO:108.

8. The bispecific antibody of claim 1 , wherein

(c) the first heavy chain comprises a VH having the amino acid sequence of SEQ ID NO:172, and the first light chain comprises a VL having the amino acid sequence of SEQ ID NO:139; and

(d) the second heavy chain comprises a VH having the amino acid sequence of SEQ ID NO: 106, and the second light chain comprises a VL having the amino acid sequence of SEQ ID NO:108.

9. The bispecific antibody of claim 1 , wherein the first arm further comprises human IgG2ΔA constant region with substitutions D265A, C223E, P228E, and L368E, the second arm further comprises a human IgG2ΔA constant region with substitutions D265A, C223R, E225R, P228R, and K409R, wherein the numbering is according to the human wildtype IgG2 and EU numbering schemes.

10. A bispecific antibody that specifically binds to both B7-H4 and CD3, comprising a first heavy chain and a first light chain, and a second heavy chain and a second light chain, wherein the first heavy chain and the first light chain form a first antibody arm which comprises a first antigen binding domain that binds to B7-H4, and the second heavy chain and the second light chain form a second antigen binding domain that binds to CD3, wherein

(a) the first heavy chain having the amino acid sequence of SEQ ID NO: 190; and the first light chain having the amino acid sequence of SEQ ID NO: 191; and

(b) the second heavy chain having the amino acid sequence of SEQ ID NO:188, and the second light chain having the amino acid sequence of SEQ ID NO: 189.

11. A bispecific antibody that specifically binds to both B7-H4 and CD3, comprising a first heavy chain and a first light chain, and a second heavy chain and a second light chain, wherein the first heavy chain and the first light chain form a first antibody arm which comprises a first antigen binding domain that binds to B7-H4, and the second heavy chain and the second light chain forms a second antigen binding domain that binds to CD3, wherein

(a) the first heavy chain having the amino acid sequence of SEQ ID NO: 186; and the first light chain having the amino acid sequence of SEQ ID NO: 187; and

(b) the second heavy chain having the amino acid sequence of SEQ ID NO:188, and the second light chain having the amino acid sequence of SEQ ID NO:189.

12. A bispecific antibody that specifically binds to B7-H4 and CD3, comprising a first heavy chain and a first light chain, and a second heavy chain and a second light chain, wherein the first heavy chain and the first light chain form a first antibody arm which comprises a first antigen binding domain that binds to B7-H4, and the second heavy chain and the second light chain form a second antigen binding domain that binds to CD3, wherein

(a) the first heavy chain comprises the amino acid sequence of the full-length polypeptide encoded by the open reading frame (ORF) deposited under ATCC Accession No. PTA-126779, and the first light chain comprises the amino acid sequence of the full-length polypeptide encoded by the open reading frame (ORF) deposited under ATCC Accession No. PTA-126781; and

(b) the second heavy chain comprises the amino acid sequence of the full-length polypeptide encoded by the open reading frame (ORF) deposited under ATCC Accession No. PTA-126780, and the second light chain comprises the amino acid sequence of the full-length polypeptide encoded by the open reading frame (ORF) deposited under ATCC Accession No. PTA-126782.

13. An isolated polynucleotide molecule encoding (i) a heavy chain of the antibody of claim 1 or (ii) a light chain of the antibody of claim 1 .

14. A vector comprising the polynucleotide molecule of claim 13 .

15. A host cell comprising the vector of claim 14 .

16. A method of treating cancer in a subject in need comprising administering to the subject the bispecific antibody claim 1 .

17. A pharmaceutical composition comprising the bispecific antibody of claim 1 .

18. A method of treating a condition associated with malignant cells expressing B7-H4 in a subject comprising administering to the subject in need thereof a therapeutically effective amount of the pharmaceutical composition of claim 17 .

19. The method of claim 18 , wherein the condition is a cancer.

20. A method of inhibiting tumor growth or progression in a subject who has malignant cells expressing B7-H4, comprising administering to the subject in need thereof a therapeutically effective amount of the pharmaceutical composition of claim 17 .

21. A method of inducing tumor regression in a subject who has malignant cells expressing B7-H4, comprising administering to the subject in need thereof an effective amount of the pharmaceutical composition of claim 17 .

Assignments (1)

ASSIGNEE ADDRESS CORRECTION Recorded Mar 20, 2023

From: PFIZER INC.

To: PFIZER INC.

Reel/Frame 063119/0087 →