IP Library › Granted Patent US 10,745,476

Granted Patent B2

US 10,745,476 · App. 15/864,710 · Granted Aug 18, 2020

Anti-NOTCH3 antibodies

Inventors: Heidi Okamura (Brookline, MA); Sandra Abbott (Boston, MA); Alisa C. Bell (Bedford, MA); Kelly Kreuter (Arvada, CO); Ronan O'Hagan (Arlington, MA); Samantha Perino (Brighton, MA); Hamid Tissire (Abington, MA); William M. Winston, Jr. (Marlborough, MA); Jeno Gyuris (Lincoln, MA)

Assignee: AVEO Pharmaceuticals, Inc.

C07K16/28 A61K39/3955 C12N15/09 C12N15/63 A61K2039/505 C07K16/2863 C07K2317/14 C07K2317/24 C07K2317/515 C07K2317/56 C07K2317/565 C07K2317/76 C07K2317/92 C12N5/10 C12N5/12 C12N5/16

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Quick Facts

Patent No.: US 10,745,476
App. No.: 15/864,710
Granted: Aug 18, 2020
Kind: B2

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Abstract

Monoclonal antibodies that bind and inhibit activation of human Notch3 are disclosed. The antibodies can be used to treat cell proliferative diseases and disorders, including certain forms of cancer, associated with activation of Notch3.

Claims (170)

1. An isolated nucleic acid comprising a nucleotide sequence encoding

an immunoglobulin heavy chain variable region selected from the group consisting of:

(a) an immunoglobulin heavy chain variable region comprising the amino acid sequence of SEQ ID NO:36 (Sh4F11 Hv3-23 A28T S31H T62S);

(b) an immunoglobulin heavy chain variable region comprising the amino acid sequence of SEQ ID NO:2 (4F11, Ch4F11 Chimeric);

(d) an immunoglobulin heavy chain variable region comprising the amino acid sequence of SEQ ID NO:38 (Sh4F11 Hv3-23 S31H T62S);

(e) an immunoglobulin heavy chain variable region comprising the amino acid sequence of SEQ ID NO:40 (Sh4F11 Hv3-23 A28T S31N T62S); and

(f) an immunoglobulin heavy chain variable region comprising the amino acid sequence of SEQ ID NO:42 (Sh4F11 Hv3-23 A28T T62S).

2. An expression vector comprising the nucleic acid of claim 1 .

3. A host cell comprising the expression vector of claim 2 .

4. A method of producing a polypeptide comprising an immunoglobulin heavy chain variable region, the method comprising:

(a) growing the host cell of claim 3 under conditions so that the host cell expresses the polypeptide comprising the immunoglobulin heavy chain variable region; and

(b) purifying the polypeptide comprising the immunoglobulin heavy chain variable region.

5. A method of inhibiting or reducing proliferation of a tumor cell comprising exposing the cell to an effective amount of an antibody that binds human Notch3 to inhibit or reduce proliferation of the tumor cell, wherein the antibody comprises:

an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region selected from the group consisting of:

(a) an immunoglobulin heavy chain variable region comprising the amino acid sequence of SEQ ID NO:36 (Sh4F11 Hv3-23 A28T S31H T62S), and an immunoglobulin light chain variable region comprising the amino acid sequence of SEQ ID NO:46 (Hu4F11 Kv2D-29 N28H);

(b) an immunoglobulin heavy chain variable region comprising the amino acid sequence of SEQ ID NO:2 (4F11, Ch4F11 Chimeric), and an immunoglobulin light chain variable region comprising the amino acid sequence of SEQ ID NO:4 (4F11, Ch4F11 Chimeric);

(c) an immunoglobulin heavy chain variable region comprising the amino acid sequence of SEQ ID NO:2 (4F11, Ch4F11 Chimeric), and an immunoglobulin light chain variable region comprising the amino acid sequence of SEQ ID NO:44 (Hu4F11 Kv2D-29);

(d) an immunoglobulin heavy chain variable region comprising the amino acid sequence of SEQ ID NO:34 (Sh4F11 Hv3-23), and an immunoglobulin light chain variable region comprising the amino acid sequence of SEQ ID NO:4 (4F11, Ch4F11 Chimeric);

(e) an immunoglobulin heavy chain variable region comprising the amino acid sequence of SEQ ID NO:34 (Sh4F11 Hv3-23), and an immunoglobulin light chain variable region comprising the amino acid sequence of SEQ ID NO:44 (Hu4F11 Kv2D-29);

(f) an immunoglobulin heavy chain variable region comprising the amino acid sequence of SEQ ID NO:38 (Sh4F11 Hv3-23 S31H T62S), and an immunoglobulin light chain variable region comprising the amino acid sequence of SEQ ID NO:46 (Hu4F11 Kv2D-29 N28H),

(g) an immunoglobulin heavy chain variable region comprising the amino acid sequence of SEQ ID NO:40 (Sh4F11 Hv3-23 A28T S31N T62S), and an immunoglobulin light chain variable region comprising the amino acid sequence of SEQ ID NO:46 (Hu4F11 Kv2D-29 N28H),

(h) an immunoglobulin heavy chain variable region comprising the amino acid sequence of SEQ ID NO:42 (Sh4F11 Hv3-23 A28T T62S), and an immunoglobulin light chain variable region comprising the amino acid sequence of SEQ ID NO:46 (Hu4F11 Kv2D-29 N28H),

(i) an immunoglobulin heavy chain variable region comprising the amino acid sequence of SEQ ID NO:36 (Sh4F11 Hv3-23 A28T S31H T62S), and an immunoglobulin light chain variable region comprising the amino acid sequence of SEQ ID NO:48 (Hu4F11 Kv2D-29 N28Q),

(j) an immunoglobulin heavy chain variable region comprising the amino acid sequence of SEQ ID NO:38 (Sh4F11 Hv3-23 S31H T62S), and an immunoglobulin light chain variable region comprising the amino acid sequence of SEQ ID NO:48 (Hu4F11 Kv2D-29 N28Q),

(k) an immunoglobulin heavy chain variable region comprising the amino acid sequence of SEQ ID NO:40 (Sh4F11 Hv3-23 A28T S31N T62S), and an immunoglobulin light chain variable region comprising the amino acid sequence of SEQ ID NO:48 (Hu4F11 Kv2D-29 N28Q),

(l) an immunoglobulin heavy chain variable region comprising the amino acid sequence of SEQ ID NO:42 (Sh4F11 Hv3-23 A28T T62S), and an immunoglobulin light chain variable region comprising the amino acid sequence of SEQ ID NO:48 (Hu4F11 Kv2D-29 N28Q),

(m) an immunoglobulin heavy chain variable region comprising the amino acid sequence of SEQ ID NO:36 (Sh4F11 Hv3-23 A28T S31H T62S), and an immunoglobulin light chain variable region comprising the amino acid sequence of SEQ ID NO:50 (Hu4F11 Kv2D-29 N28Y);

(n) an immunoglobulin heavy chain variable region comprising the amino acid sequence of SEQ ID NO:38 (Sh4F11 Hv3-23 S31H T62S), and an immunoglobulin light chain variable region comprising the amino acid sequence of SEQ ID NO:50 (Hu4F11 Kv2D-29 N28Y);

(o) an immunoglobulin heavy chain variable region comprising the amino acid sequence of SEQ ID NO:40 (Sh4F11 Hv3-23 A28T S31N T62S), and an immunoglobulin light chain variable region comprising the amino acid sequence of SEQ ID NO:50 (Hu4F11 Kv2D-29 N28Y); and

(p) an immunoglobulin heavy chain variable region comprising the amino acid sequence of SEQ ID NO:42 (Sh4F11 Hv3-23 A28T T62S), and an immunoglobulin light chain variable region comprising the amino acid sequence of SEQ ID NO:50 (Hu4F11 Kv2D-29 N28Y); or

an immunoglobulin heavy chain and an immunoglobulin light chain selected from the group consisting of:

(q) an immunoglobulin heavy chain comprising the amino acid sequence of SEQ ID NO: 78 (Sh4F11 Hv3-23 A28T S31H T62S), and an immunoglobulin light chain comprising the amino acid sequence of SEQ ID NO: 90 (Hu4F11 Kv2D-29 N28H Kappa);

(r) an immunoglobulin heavy chain comprising the amino acid sequence of SEQ ID NO: 27 (4F11), and an immunoglobulin light chain comprising the amino acid sequence of SEQ ID NO: 29 (4F11);

(s) an immunoglobulin heavy chain comprising the amino acid sequence of SEQ ID NO: 74 (Ch4F11), and an immunoglobulin light chain comprising the amino acid sequence of SEQ ID NO: 86 (Ch4F11);

(t) an immunoglobulin heavy chain comprising the amino acid sequence of SEQ ID NO: 74 (Ch4F11), and an immunoglobulin light chain comprising the amino acid sequence of SEQ ID NO: 88 (Hu4F11 Kv2D-29);

(u) an immunoglobulin heavy chain comprising the amino acid sequence of SEQ ID NO: 76 (Sh4F11 Hv3-23), and an immunoglobulin light chain comprising the amino acid sequence of SEQ ID NO: 86 (Ch4F11);

(v) an immunoglobulin heavy chain comprising the amino acid sequence of SEQ ID NO: 76 (Sh4F11 Hv3-23), and an immunoglobulin light chain comprising the amino acid sequence of SEQ ID NO: 88 (Hu4F11 Kv2D-29);

(w) an immunoglobulin heavy chain comprising the amino acid sequence of SEQ ID NO: 80 (Sh4F11 Hv3-23 S31H T62S), and an immunoglobulin light chain comprising the amino acid sequence of SEQ ID NO: 90 (Hu4F11 Kv2D-29 N28H Kappa);

(x) an immunoglobulin heavy chain comprising the amino acid sequence of SEQ ID NO: 82 (Sh4F11 Hv3-23 A28T S31N T62S), and an immunoglobulin light chain comprising the amino acid sequence of SEQ ID NO: 90 (Hu4F11 Kv2D-29 N28H Kappa);

(y) an immunoglobulin heavy chain comprising the amino acid sequence of SEQ ID NO: 84 (Sh4F11 Hv3-23 A28T T62S), and an immunoglobulin light chain comprising the amino acid sequence of SEQ ID NO: 90 (Hu4F11 Kv2D-29 N28H Kappa);

(z) an immunoglobulin heavy chain comprising the amino acid sequence of SEQ ID NO: 78 (Sh4F11 Hv3-23 A28T S31H T62S), and an immunoglobulin light chain comprising the amino acid sequence of SEQ ID NO: 92 (Hu4F11 Kv2D-29 N28Q Kappa);

(aa) an immunoglobulin heavy chain comprising the amino acid sequence of SEQ ID NO: 80 (Sh4F11 Hv3-23 S31H T62S), and an immunoglobulin light chain comprising the amino acid sequence of SEQ ID NO: 92 (Hu4F11 Kv2D-29 N28Q Kappa);

(bb) an immunoglobulin heavy chain comprising the amino acid sequence of SEQ ID NO: 82 (Sh4F11 Hv3-23 A28T S31N T62S), and an immunoglobulin light chain comprising the amino acid sequence of SEQ ID NO: 92 (Hu4F11 Kv2D-29 N28Q Kappa);

(cc) an immunoglobulin heavy chain comprising the amino acid sequence of SEQ ID NO: 84 (Sh4F11 Hv3-23 A28T T62S), and an immunoglobulin light chain comprising the amino acid sequence of SEQ ID NO: 92 (Hu4F11 Kv2D-29 N28Q Kappa);

(dd) an immunoglobulin heavy chain comprising the amino acid sequence of SEQ ID NO: 78 (Sh4F11 Hv3-23 A28T S31H T62S), and an immunoglobulin light chain comprising the amino acid sequence of SEQ ID NO: 94 (Hu4F11 Kv2D-29 N28Y Kappa);

(ee) an immunoglobulin heavy chain comprising the amino acid sequence of SEQ ID NO: 80 (Sh4F11 Hv3-23 S31H T62S), and an immunoglobulin light chain comprising the amino acid sequence of SEQ ID NO: 94 (Hu4F11 Kv2D-29 N28Y Kappa);

(ff) an immunoglobulin heavy chain comprising the amino acid sequence of SEQ ID NO: 82 (Sh4F11 Hv3-23 A28T S31N T62S), and an immunoglobulin light chain comprising the amino acid sequence of SEQ ID NO: 94 (Hu4F11 Kv2D-29 N28Y Kappa); and

(gg) an immunoglobulin heavy chain comprising the amino acid sequence of SEQ ID NO: 84 (Sh4F11 Hv3-23 A28T T62S), and an immunoglobulin light chain comprising the amino acid sequence of SEQ ID NO: 94 (Hu4F11 Kv2D-29 N28Y Kappa).

6. A method of inhibiting or reducing tumor growth in a mammal, the method comprising exposing the mammal to an effective amount of an antibody that binds human Notch3 to inhibit or reduce growth of the tumor, wherein the antibody comprises:

an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region selected from the group consisting of:

an immunoglobulin heavy chain and an immunoglobulin light chain selected from the group consisting of:

(r) an immunoglobulin heavy chain comprising the amino acid sequence of SEQ ID NO: 27 (4F11), and an immunoglobulin light chain comprising the amino acid sequence of SEQ ID NO: 29 (4F11);

(s) an immunoglobulin heavy chain comprising the amino acid sequence of SEQ ID NO: 74 (Ch4F11), and an immunoglobulin light chain comprising the amino acid sequence of SEQ ID NO: 86 (Ch4F11);

(t) an immunoglobulin heavy chain comprising the amino acid sequence of SEQ ID NO: 74 (Ch4F11), and an immunoglobulin light chain comprising the amino acid sequence of SEQ ID NO: 88 (Hu4F11 Kv2D-29);

(u) an immunoglobulin heavy chain comprising the amino acid sequence of SEQ ID NO: 76 (Sh4F11 Hv3-23), and an immunoglobulin light chain comprising the amino acid sequence of SEQ ID NO: 86 (Ch4F11);

7. A method of treating cancer in a human subject, the method comprising administering to the subject an effective amount of an antibody that binds human Notch3 to a human subject in need thereof, wherein the antibody comprises:

an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region selected from the group consisting of:

an immunoglobulin heavy chain and an immunoglobulin light chain selected from the group consisting of:

(r) an immunoglobulin heavy chain comprising the amino acid sequence of SEQ ID NO: 27 (4F11), and an immunoglobulin light chain comprising the amino acid sequence of SEQ ID NO: 29 (4F11);

(s) an immunoglobulin heavy chain comprising the amino acid sequence of SEQ ID NO: 74 (Ch4F11), and an immunoglobulin light chain comprising the amino acid sequence of SEQ ID NO: 86 (Ch4F11);

(t) an immunoglobulin heavy chain comprising the amino acid sequence of SEQ ID NO: 74 (Ch4F11), and an immunoglobulin light chain comprising the amino acid sequence of SEQ ID NO: 88 (Hu4F11 Kv2D-29);

(u) an immunoglobulin heavy chain comprising the amino acid sequence of SEQ ID NO: 76 (Sh4F11 Hv3-23), and an immunoglobulin light chain comprising the amino acid sequence of SEQ ID NO: 86 (Ch4F11);

8. An isolated antibody that competes with an antibody comprising an immunoglobulin heavy chain variable region comprising the amino acid sequence of SEQ ID NO:36 (Sh4F11 Hv3-23 A28T S31H T62S) and an immunoglobulin light chain variable region comprising the amino acid sequence of SEQ ID NO:46 (Hu4F11 Kv2D-29 N28H) for binding to EGF-like repeats 1-11 of human Notch3, wherein the isolated antibody comprises an immunoglobulin heavy chain variable region comprising an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:36 (Sh4F11 Hv3-23 A28T S31H T62S) and an immunoglobulin light chain variable region comprising an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:46 (Hu4F11 Kv2D-29 N28H).

9. The isolated antibody of claim 8 , wherein the isolated antibody comprises an immunoglobulin heavy chain variable region comprising an amino acid sequence that is at least 98% identical to the amino acid sequence of SEQ ID NO:36 (Sh4F11 Hv3-23 A28T S31H T62S) and an immunoglobulin light chain variable region comprising an amino acid sequence that is at least 98% identical to the amino acid sequence of SEQ ID NO:46 (Hu4F11 Kv2D-29 N28H)).

10. The isolated antibody of claim 8 , wherein the isolated antibody comprises an immunoglobulin heavy chain variable region comprising an amino acid sequence that is at least 99% identical to the amino acid sequence of SEQ ID NO:36 (Sh4F11 Hv3-23 A28T S31H T62S) and an immunoglobulin light chain variable region comprising an amino acid sequence that is at least 99% identical to the amino acid sequence of SEQ ID NO:46 (Hu4F11 Kv2D-29 N281).

11. An isolated nucleic acid comprising a nucleotide sequence encoding an immunoglobulin light chain variable region selected from the group consisting of:

(a) an immunoglobulin light chain variable region comprising the amino acid sequence of SEQ ID NO:46 (Hu4F11 Kv2D-29 N28H);

(b) an immunoglobulin light chain variable region comprising the amino acid sequence of SEQ ID NO:4 (4F11, Ch4F11 Chimeric);

(d) an immunoglobulin light chain variable region comprising the amino acid sequence of SEQ ID NO:48 (Hu4F11 Kv2D-29 N28Q); and

(e) an immunoglobulin light chain variable region comprising the amino acid sequence of SEQ ID NO:50 (Hu4F11 Kv2D-29 N28Y).

12. An expression vector comprising the nucleic acid of claim 11 .

13. A host cell comprising the expression vector of claim 12 .

14. A method of producing a polypeptide comprising an immunoglobulin light chain variable region, the method comprising:

(a) growing the host cell of claim 13 under conditions so that the host cell expresses the polypeptide comprising the immunoglobulin light chain variable region; and

(b) purifying the polypeptide comprising the immunoglobulin light chain variable region.

15. The expression vector of claim 2 , further comprising the nucleic acid of claim 11 .

16. A host cell comprising the expression vector of claim 15 .

17. A method of producing an antibody that binds human Notch3 or an antigen-binding fragment of the antibody, the method comprising:

(a) growing the host cell of claim 16 under conditions so that the host cell expresses a polypeptide or polypeptides comprising the immunoglobulin heavy chain variable region and the immunoglobulin light chain variable region, thereby producing the antibody or the antigen binding-fragment of the antibody; and

(b) purifying the antibody or the antigen-binding fragment of the antibody.

18. An isolated nucleic acid comprising a nucleotide sequence encoding an immunoglobulin heavy chain selected from the group consisting of:

(a) an immunoglobulin heavy chain comprising the amino acid sequence of SEQ ID NO: 78 (Sh4F11 Hv3-23 A28T S31H T62S);

(b) an immunoglobulin heavy chain comprising the amino acid sequence of SEQ ID NO: 27 (4F11);

(d) an immunoglobulin heavy chain comprising the amino acid sequence of SEQ ID NO: 76 (Sh4F11 Hv3-23);

(e) an immunoglobulin heavy chain comprising the amino acid sequence of SEQ ID NO: 80 (Sh4F11 Hv3-23 S31H T62S);

(f) an immunoglobulin heavy chain comprising the amino acid sequence of SEQ ID NO: 82 (Sh4F11 Hv3-23 A28T S31N T62S); and

(g) an immunoglobulin heavy chain comprising the amino acid sequence of SEQ ID NO: 84 (Sh4F11 Hv3-23 A28T T62S).

19. An expression vector comprising the nucleic acid of claim 18 .

20. A host cell comprising the expression vector of claim 19 .

21. A method of producing a polypeptide comprising an immunoglobulin heavy chain, the method comprising:

(a) growing the host cell of claim 20 under conditions so that the host cell expresses the polypeptide comprising the immunoglobulin heavy chain; and

(b) purifying the polypeptide comprising the immunoglobulin heavy chain.

22. An isolated nucleic acid comprising a nucleotide sequence encoding an immunoglobulin light chain selected from the group consisting of:

(a) an immunoglobulin light chain comprising the amino acid sequence of SEQ ID NO: 90 (Hu4F11 Kv2D-29 N28H Kappa);

(b) an immunoglobulin light chain comprising the amino acid sequence of SEQ ID NO: 29 (4F11);

(d) an immunoglobulin light chain comprising the amino acid sequence of SEQ ID NO: 88 (Hu4F11 Kv2D-29);

(e) an immunoglobulin light chain comprising the amino acid sequence of SEQ ID NO: 92 (Hu4F11 Kv2D-29 N28Q Kappa); and

(f) an immunoglobulin light chain comprising the amino acid sequence of SEQ ID NO: 94 (Hu4F11 Kv2D-29 N28Y Kappa).

23. An expression vector comprising the nucleic acid of claim 22 .

24. A host cell comprising the expression vector of claim 23 .

25. A method of producing a polypeptide comprising an immunoglobulin light chain, the method comprising:

(a) growing the host cell of claim 24 under conditions so that the host cell expresses the polypeptide comprising the immunoglobulin light chain; and

(b) purifying the polypeptide comprising the immunoglobulin light chain.

26. The expression vector of claim 19 , further comprising the nucleic acid of claim 22 .

27. A host cell comprising the expression vector of claim 26 .

28. A method of producing an antibody that binds human Notch3 or an antigen-binding fragment of the antibody, the method comprising:

(a) growing the host cell of claim 27 under conditions so that the host cell expresses a polypeptide or polypeptides comprising the immunoglobulin heavy chain and the immunoglobulin light chain, thereby producing the antibody or the antigen-binding fragment of the antibody; and

(b) purifying the antibody or the antigen-binding fragment of the antibody.

Assignments (1)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 8, 2020

From: OKAMURA, HEIDI; ABBOTT, SANDRA; BELL, ALISA C.; KREUTER, KELLY; O'HAGAN, RONAN; PERINO, SAMANTHA; TISSIRE, HAMID; WINSTON, WILLIAM M., JR.; GYURIS, JENO

To: AVEO PHARMACEUTICALS, INC.

Reel/Frame 052867/0354 →

Continuity (4)

Continuation 14653684

Provisional Application 61866787 · Aug 16, 2013

Provisional Application 61739435 · Dec 19, 2012

Related Publication 20180230213A1 · Aug 16, 2018

Cited By (2)

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