IP Library › Granted Patent US 9,879,083
Granted Patent B2
US 9,879,083 · App. 14/653,684 · Granted Jan 30, 2018

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.
C07K16/28A61K39/3955C12N15/09C12N15/63A61K2039/505C07K16/2863C07K2317/14C07K2317/24C07K2317/515C07K2317/56C07K2317/565C07K2317/76C07K2317/92C12N5/10C12N5/12C12N5/16
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Quick Facts
Patent No.
US 9,879,083
App. No.
14/653,684
Granted
Jan 30, 2018
Kind
B2
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 (96)

1. An isolated antibody that binds human Notch3 comprising an immunoglobulin heavy chain variable region and an immunoglobulin light chain variable region selected from the group consisting of:

(a) (i) an immunoglobulin heavy chain variable region comprising a CDR H1 comprising the amino acid sequence of SEQ ID NO:51, a CDR H2 comprising the amino acid sequence of SEQ ID NO:53, and a CDR H3 comprising the amino acid sequence of SEQ ID NO:7; and

(ii) an immunoglobulin light chain variable region comprising a CDR L1 comprising the amino acid sequence of SEQ ID NO:62, a CDR L2 comprising the amino acid sequence of SEQ ID NO:9, and a CDR L3 comprising the amino acid sequence of SEQ ID NO:10;

(b) (i) an immunoglobulin heavy chain variable region comprising a CDR H1 comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 5 and SEQ ID NO:11; a CDR H2 comprising the amino acid sequence of SEQ ID NO: 6; and a CDR H3 comprising the amino acid sequence of SEQ ID NO: 7; and

(ii) an immunoglobulin light chain variable region comprising a CDR L1 comprising the amino acid sequence of SEQ ID NO: 8; a CDR L2 comprising the amino acid sequence of SEQ ID NO: 9; and a CDR L3 comprising the amino acid sequence of SEQ ID NO: 10;

(c) (i) an immunoglobulin heavy chain variable region comprising a CDR H1 comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 5 and SEQ ID NO:11; a CDR H2 comprising the amino acid sequence of SEQ ID NO: 6; and a CDR H3 comprising the amino acid sequence of SEQ ID NO: 7; and

(ii) an immunoglobulin light chain variable region comprising a CDR L1 comprising the amino acid sequence of SEQ ID NO: 62; a CDR L2 comprising the amino acid sequence of SEQ ID NO: 9; and a CDR L3 comprising the amino acid sequence of SEQ ID NO: 10;

(d) (i) an immunoglobulin heavy chain variable region comprising a CDR H1 comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 5 and SEQ ID NO:11; a CDR H2 comprising the amino acid sequence of SEQ ID NO: 6; and a CDR H3 comprising the amino acid sequence of SEQ ID NO: 7; and

(ii) an immunoglobulin light chain variable region comprising a CDR L1 comprising the amino acid sequence of SEQ ID NO: 63; a CDR L2 comprising the amino acid sequence of SEQ ID NO: 9; and a CDR L3 comprising the amino acid sequence of SEQ ID NO: 10;

(e) (i) an immunoglobulin heavy chain variable region comprising a CDR H1 comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 5 and SEQ ID NO:11; a CDR H2 comprising the amino acid sequence of SEQ ID NO: 6; and a CDR H3 comprising the amino acid sequence of SEQ ID NO: 7; and

(ii) an immunoglobulin light chain variable region comprising a CDR L1 comprising the amino acid sequence of SEQ ID NO: 64; a CDR L2 comprising the amino acid sequence of SEQ ID NO: 9; and a CDR L3 comprising the amino acid sequence of SEQ ID NO: 10;

(f) (i) an immunoglobulin heavy chain variable region comprising a CDR H1 comprising the amino acid sequence of SEQ ID NO:51, a CDR H2 comprising the amino acid sequence of SEQ ID NO:53, and a CDR H3 comprising the amino acid sequence of SEQ ID NO:7; and

(ii) an immunoglobulin light chain variable region comprising a CDR L1 comprising the amino acid sequence of SEQ ID NO:8, a CDR L2 comprising the amino acid sequence of SEQ ID NO:9, and a CDR L3 comprising the amino acid sequence of SEQ ID NO:10;

(g) (i) an immunoglobulin heavy chain variable region comprising a CDR H1 comprising the amino acid sequence of SEQ ID NO:51, a CDR H2 comprising the amino acid sequence of SEQ ID NO:53, and a CDR H3 comprising the amino acid sequence of SEQ ID NO:7; and

(ii) an immunoglobulin light chain variable region comprising a CDR L1 comprising the amino acid sequence of SEQ ID NO:63, a CDR L2 comprising the amino acid sequence of SEQ ID NO:9, and a CDR L3 comprising the amino acid sequence of SEQ ID NO:10;

(h) (i) an immunoglobulin heavy chain variable region comprising a CDR H1 comprising the amino acid sequence of SEQ ID NO:51, a CDR H2 comprising the amino acid sequence of SEQ ID NO:53, and a CDR H3 comprising the amino acid sequence of SEQ ID NO:7; and

(ii) an immunoglobulin light chain variable region comprising a CDR L1 comprising the amino acid sequence of SEQ ID NO:64, a CDR L2 comprising the amino acid sequence of SEQ ID NO:9, and a CDR L3 comprising the amino acid sequence of SEQ ID NO:10;

(i) (i) an immunoglobulin heavy chain variable region comprising a CDR H1 comprising an amino acid sequence selected from the group consisting of SEQ ID NO:52 and SEQ ID NO: 56, a CDR H2 comprising the amino acid sequence of SEQ ID NO:53, and a CDR H3 comprising the amino acid sequence of SEQ ID NO:7; and

(ii) an immunoglobulin light chain variable region comprising a CDR L1 comprising the amino acid sequence of SEQ ID NO:8, a CDR L2 comprising the amino acid sequence of SEQ ID NO:9, and a CDR L3 comprising the amino acid sequence of SEQ ID NO:10;

(j) (i) an immunoglobulin heavy chain variable region comprising a CDR H1 comprising an amino acid sequence selected from the group consisting of SEQ ID NO:52 and SEQ ID NO: 56, a CDR H2 comprising the amino acid sequence of SEQ ID NO:53, and a CDR H3 comprising the amino acid sequence of SEQ ID NO:7; and

(ii) an immunoglobulin light chain variable region comprising a CDR L1 comprising the amino acid sequence of SEQ ID NO:62, a CDR L2 comprising the amino acid sequence of SEQ ID NO:9, and a CDR L3 comprising the amino acid sequence of SEQ ID NO:10;

(k) (i) an immunoglobulin heavy chain variable region comprising a CDR H1 comprising an amino acid sequence selected from the group consisting of SEQ ID NO:52 and SEQ ID NO: 56, a CDR H2 comprising the amino acid sequence of SEQ ID NO:53, and a CDR H3 comprising the amino acid sequence of SEQ ID NO:7; and

(ii) an immunoglobulin light chain variable region comprising a CDR L1 comprising the amino acid sequence of SEQ ID NO:63, a CDR L2 comprising the amino acid sequence of SEQ ID NO:9, and a CDR L3 comprising the amino acid sequence of SEQ ID NO:10;

(l) (i) an immunoglobulin heavy chain variable region comprising a CDR H1 comprising an amino acid sequence selected from the group consisting of SEQ ID NO:52 and SEQ ID NO: 56, a CDR H2 comprising the amino acid sequence of SEQ ID NO:53, and a CDR H3 comprising the amino acid sequence of SEQ ID NO:7; and

(ii) an immunoglobulin light chain variable region comprising a CDR L1 comprising the amino acid sequence of SEQ ID NO:64, a CDR L2 comprising the amino acid sequence of SEQ ID NO:9, and a CDR L3 comprising the amino acid sequence of SEQ ID NO:10;

(m) (i) an immunoglobulin heavy chain variable region comprising a CDR H1 comprising an amino acid sequence selected from the group consisting of SEQ ID NO:5 and SEQ ID NO: 57, a CDR H2 comprising the amino acid sequence of SEQ ID NO:53, and a CDR H3 comprising the amino acid sequence of SEQ ID NO:7; and

(ii) an immunoglobulin light chain variable region comprising a CDR L1 comprising the amino acid sequence of SEQ ID NO:8, a CDR L2 comprising the amino acid sequence of SEQ ID NO:9, and a CDR L3 comprising the amino acid sequence of SEQ ID NO:10;

(n) (i) an immunoglobulin heavy chain variable region comprising a CDR H1 comprising an amino acid sequence selected from the group consisting of SEQ ID NO:5 and SEQ ID NO: 57, a CDR H2 comprising the amino acid sequence of SEQ ID NO:53, and a CDR H3 comprising the amino acid sequence of SEQ ID NO:7; and

(ii) an immunoglobulin light chain variable region comprising a CDR L1 comprising the amino acid sequence of SEQ ID NO:62, a CDR L2 comprising the amino acid sequence of SEQ ID NO:9, and a CDR L3 comprising the amino acid sequence of SEQ ID NO:10;

(o) (i) an immunoglobulin heavy chain variable region comprising a CDR H1 comprising an amino acid sequence selected from the group consisting of SEQ ID NO:5 and SEQ ID NO: 57, a CDR H2 comprising the amino acid sequence of SEQ ID NO:53, and a CDR H3 comprising the amino acid sequence of SEQ ID NO:7; and

(ii) an immunoglobulin light chain variable region comprising a CDR L1 comprising the amino acid sequence of SEQ ID NO:63, a CDR L2 comprising the amino acid sequence of SEQ ID NO:9, and a CDR L3 comprising the amino acid sequence of SEQ ID NO:10; and

(p) (i) an immunoglobulin heavy chain variable region comprising a CDR H1 comprising an amino acid sequence selected from the group consisting of SEQ ID NO:5 and SEQ ID NO: 57, a CDR H2 comprising the amino acid sequence of SEQ ID NO:53, and a CDR H3 comprising the amino acid sequence of SEQ ID NO:7; and

(ii) an immunoglobulin light chain variable region comprising a CDR L1 comprising the amino acid sequence of SEQ ID NO:64, a CDR L2 comprising the amino acid sequence of SEQ ID NO:9, and a CDR L3 comprising the amino acid sequence of SEQ ID NO:10.

2. The antibody of claim 1 , wherein the CDR sequences are interposed between human or humanized framework sequences.

3. An isolated nucleic acid comprising a nucleotide sequence encoding an immunoglobulin heavy chain variable region of claim 1 .

4. An expression vector comprising the nucleic acid of claim 3 .

5. A host cell comprising the expression vector of claim 4 .

6. An isolated nucleic acid comprising a nucleotide sequence encoding an immunoglobulin light chain variable region of claim 1 .

7. An expression vector comprising the nucleic acid of claim 6 .

8. The expression vector of claim 6 , further comprising the nucleic acid of claim 3 .

9. A host cell comprising the expression vector of claim 8 .

10. 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 9 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.

11. A host cell comprising the expression vector of claim 7 .

12. A host cell of claim 11 , further comprising the expression vector of claim 4 .

13. 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 12 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.

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

(a) growing the host cell of claim 5 or 11 under conditions so that the host cell expresses the polypeptide comprising the immunoglobulin heavy chain variable region or the immunoglobulin light chain variable region; and

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

15. A method of inhibiting or reducing proliferation of a tumor cell comprising exposing the cell to an effective amount of the antibody of claim 1 to inhibit or reduce proliferation of the tumor cell.

16. A method of inhibiting or reducing tumor growth in a mammal, the method comprising exposing the mammal to an effective amount of the antibody of claim 1 to inhibit or reduce proliferation of the tumor.

17. A method of treating cancer in a human subject, the method comprising administering to the subject an effective amount of the antibody of claim 1 to a human subject in need thereof.

18. The antibody of claim 1 , wherein the antibody has a K D of 35 nM or lower as measured by surface plasmon resonance.

19. The isolated antibody of claim 1 , wherein the antibody comprises:

(i) an immunoglobulin heavy chain variable region comprising a CDR H1 comprising the amino acid sequence of SEQ ID NO:51, a CDR H2 comprising the amino acid sequence of SEQ ID NO:53, and a CDR H3 comprising the amino acid sequence of SEQ ID NO:7; and

(ii) an immunoglobulin light chain variable region comprising a CDR L1 comprising the amino acid sequence of SEQ ID NO:62, a CDR L2 comprising the amino acid sequence of SEQ ID NO:9, and a CDR L3 comprising the amino acid sequence of SEQ ID NO:10.

20. An isolated antibody that binds human Notch3 comprising 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).

21. The isolated antibody of claim 20 , wherein the antibody comprises 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).

22. An isolated antibody that binds human Notch3 comprising an immunoglobulin heavy chain and an immunoglobulin light 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), and an immunoglobulin light chain comprising the amino acid sequence of SEQ ID NO: 90 (Hu4F11 Kv2D-29 N28H Kappa);

(b) 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);

(c) 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);

(d) 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);

(e) 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);

(f) 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);

(g) 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);

(h) 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);

(i) 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);

(j) 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);

(k) 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);

(l) 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);

(m) 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);

(n) 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);

(o) 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);

(p) 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

(q) 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).

23. The isolated antibody of claim 22 , wherein the antibody comprises 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).

Continuity (3)
Provisional Application 61739435 · Dec 19, 2012
Provisional Application 61866787 · Aug 16, 2013
Related Publication 20160185852A1 · Jun 30, 2016