HA binding agents

Patent metadata

Field	Value
Publication number	US-9969794-B2
Application number	US-201313830367-A
Country	US
Kind code	B2
Filing date	Mar 14, 2013
Priority date	May 10, 2012
Publication date	May 15, 2018
Grant date	May 15, 2018

Abstract

This disclosure relates to novel peptide agents, e.g., antibodies and antigen-binding fragments thereof, that bind hemagglutinin protein of influenza viruses, and methods of their use.

First claim

We claim:

1. An antibody molecule capable of binding to hemagglutinin (HA), comprising:
(a) a heavy chain (HC) immunoglobulin variable region segment comprising:
an HC CDR1 comprising the sequence S-Y-A-M-H (SEQ ID NO:68), or a sequence that differs therefrom at the 3 rd position (A to G substitution);
an HC CDR2 comprising the sequence V-V-S-Y-D-G-N-Y-K-Y-Y-A-D-S-V-Q-G (SEQ ID NO:69) or a sequence that differs therefrom at the 2 nd position (V to I substitution), the 7 th residue (N to S substitution), the 8 th position (Y to N substitution), or a combination thereof;
an HC CDR3 comprising the sequence D-S-R-L-R-S-L-L-Y-F-E-W-L-S-Q-G-Y-F-N-P (SEQ ID NO:70), or a sequence that differs therefrom at the 2 nd position (S to T substitution), the 3 rd position (R to K substitution), the 15 th position (Q to S substitution), the 17 th position (Y to L substitution), the 18 th position (F to L substitution), the 19 th position (N to D substitution), the 20 th position (P to Y substitution), or a combination thereof; and

(b) a light chain (LC) immunoglobulin variable region segment comprising:
an LC CDR1 comprising the sequence Q-S-I-T-F-N-Y-K-N-Y-L-A (SEQ ID NO:71), or a sequence that differs therefrom at the 2 nd position (S to T substitution), the 3 rd position (I to V substitution), the 5 th position (F to Y substitution), the 6 th position (N to S or N to D substitution), the 12 th position (A to G substitution), or a combination thereof;
an LC CDR2 comprising the sequence W G S Y L E S (SEQ ID NO:72), or a sequence that differs therefrom at the 2 nd position (G to A substitution), the 4 th position (Y to T substitution), the 5 th position (L to R substitution), or a combination thereof;
an LC CDR3 comprising the sequence Q-Q-H-Y-R-T-P-P-S (SEQ ID NO:73), or a sequence that differs therefrom at the 3 rd position (H to Y substitution), the 9 th position (S to T substitution), or both,

wherein the HC CDR1-3 and LC CDR1-3, collectively, comprise sequences that differ by 0, 1 or 2 amino acids from SEQ ID NOS: 68-73.

2. The antibody molecule of claim 1 , wherein, said antibody has one or both of the following properties:
(i) it fails to produce any escape mutants as determined by the failure of a viral titer to recover following at least 5 rounds of serial infections in cell culture with a mixture of the antibody molecule and an influenza A virus; and
(ii) it produces fewer escape mutants than does a reference anti-HA antibody selected from Ab 67-11, FI6, FI28, C179, F10, CR9114, or CR6261, when tested by the method described in (i).

3. The antibody molecule of claim 1 , wherein:
a) the heavy chain (HC) immunoglobulin variable region segment further comprises one or more or all of:
an HC FR1 comprising the sequence Q-V-Q-L-L-E-T-G-G-G-L-V-K-P-G-Q-S-L-K-L-S-C-A-A-S-G-F-T-F-T (SEQ ID NO:74);
an HC FR2 comprising the sequence W-V-R-Q-P-P-G-K-G-L-E-W-V-A (SEQ ID NO:75);
an HC FR3 comprising the sequence R-F-T-I-S-R-D-N-S-K-N-T-L-Y-L-Q-M-N-S-L-R-A-E-D-T-A-V-Y-Y-C-A-K (SEQ ID NO:76); and
an HC FR4 comprising the sequence W-G-Q-G-T-T-L-T-V-S-S (SEQ ID NO:77); and
b) the light chain (LC) immunoglobulin variable region segment further comprises one or more or all of:
an LC FR1 comprising the sequence D-I-Q-M-T-Q-S-P-S-S-L-S-A-S-V-G-D-R-V-T-I-T-C-R-S-S(SEQ ID NO:78);
an LC FR2 comprising the sequence W-Y-Q-Q-K-P-G-K-A-P-K-L-L-I-Y (SEQ ID NO:79);
an LC FR3 comprising the sequence G-V-P-S-R-F-S-G-S-G-S-G-T-D-F-T-L-T-I-S-S-L-Q-P-E-D-F-A-T-Y-Y-C (SEQ ID NO:80); and
an LC FR4 comprising the sequence F-G-Q-G-T-K-V-E-I-K (SEQ ID NO:81).

4. The antibody molecule of claim 1 , comprising:
a) a heavy chain immunoglobulin variable region segment comprising SEQ ID NO: 25; and
b) a light chain immunoglobulin variable region segment comprising SEQ ID NO: 45.

5. The antibody molecule of claim 1 , wherein the antibody molecule has one or more or all of the following properties:
(a) it fails to produce any escape mutants as determined by the failure of a viral titer to recover following at least 5 rounds of serial infections in cell culture with a mixture of the antibody molecule and an influenza A virus;
(b) it produces fewer escape mutants than does a reference anti-HA antibody selected from Ab 67-11, FI6, FI28, C179, F10, CR9114, or CR6261, when tested by the method described in (a);
(c) it binds with high affinity to a hemagglutinin (HA) of at least one influenza subtype of Group 1 and at least one influenza subtype of Group 2;
(d) it prevents infection by at least one influenza subtype of Group 1, and by at least one influenza subtype of Group 2;
(e) it inhibits fusogenic activity of the targeted HA;
(f) it treats or prevents infection by a Group 1 influenza virus, wherein the virus is an H1, H5, or H9 virus; and treats or prevents infection by a Group 2 influenza virus, wherein the virus is an H3 or H7 virus;
(g) it treats or prevents infection by influenza A strains H1N1 and H3N2; and
(j) it binds an epitope which comprises or consists of the hemagglutinin trimer interface.

6. The antibody molecule of claim 1 , wherein the antibody molecule is a single chain antibody (scFv), a F(ab′) 2 fragment, a Fab fragment, or an Fd fragment.

7. The antibody molecule of claim 1 , wherein the antibody molecule is an IgG1 antibody.

8. The antibody molecule of claim 1 , wherein the antibody molecule binds an epitope that has one, two, three, four, five, or all of, the following properties a)-f):
a) it comprises one, two, or all of, H3 HA1 residues N38, I278, and D291;
b) it comprises H3 HA2 residue N12;
c) it does not comprise one, two or all of, H3 HA1 residues Q327, T328, and R329;
d) it does not comprise one, two, three, four, or all of, H3 HA2 residues G1, L2, F3, G4, and D46;
e) it comprises one, two, or all of, H3 HA1 residues T318, R321, and V323; or
f) it comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or all of, H3 HA2 residues A7, E11, I18, D19, G20, W21, L38, K39, T41, Q42, A43, I45, I48, N49, L52, N53, I56, and E57.

9. The antibody molecule of claim 8 , comprising properties: c) and d).

10. The antibody molecule of claim 8 , which binds an epitope that does not comprise one or both of:
cc) one or both of H1 HA1 residues Q328 and S329; and
dd) one, two, three, four, or all of, H1 HA2 residues G1, L2, F3, G4, and D46.

11. The antibody molecule of claim 8 , comprising properties: a) or b); and c) or d).

12. A pharmaceutical composition comprising the antibody molecule of claim 1 and a pharmaceutically acceptable carrier.

13. A kit comprising a container having disposed therein the antibody molecule of claim 1 ; and a pharmaceutically acceptable delivery vehicle or buffer, a delivery device, or both.

14. The antibody molecule of claim 1 , comprising:
(a) a heavy chain (HC) immunoglobulin variable region segment comprising:
an HC CDR1 comprising the sequence S-Y-A-M-H (SEQ ID NO:68);
an HC CDR2 comprising the sequence V-V-S-Y-D-G-N-Y-K-Y-Y-A-D-S-V-Q-G (SEQ ID NO:69);
an HC CDR3 comprising the sequence D-S-R-L-R-S-L-L-Y-F-E-W-L-S-Q-G-Y-F-N-P (SEQ ID NO:70); and

(b) a light chain (LC) immunoglobulin variable region segment comprising:
an LC CDR1 comprising the sequence Q-S-I-T-F-N-Y-K-N-Y-L-A (SEQ ID NO:71);
an LC CDR2 comprising the sequence W-G-S-Y-L-E-S (SEQ ID NO:72); and
an LC CDR3 comprising the sequence Q-Q-H-Y-R-T-P-P-S (SEQ ID NO:73).

15. The antibody molecule of claim 1 , comprising a heavy chain immunoglobulin variable region segment comprises a sequence that is at least 98% homologous to the sequence of SEQ ID NO: 25.

Assignees

• Visterra Inc

Inventors

• Shriver Zachary
• Viswanathan Karthik
• Subramanian Vidya
• Raguram Sasisekharan

Classifications

• A61P31/16

  for influenza or rhinoviruses · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P37/04

  Immunostimulants · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P31/12

  Antivirals · CPC title