Human antibodies to respiratory syncytial virus F protein and methods of use thereof

Patent metadata

Field	Value
Publication number	US-9447173-B2
Application number	US-201414207797-A
Country	US
Kind code	B2
Filing date	Mar 13, 2014
Priority date	Mar 14, 2013
Publication date	Sep 20, 2016
Grant date	Sep 20, 2016

Abstract

The present invention provides fully human antibodies that bind to respiratory syncytial virus F protein, compositions comprising the antibodies and methods of use. The antibodies of the invention are useful for preventing fusion of the virus with the cell membrane and preventing cell to cell spread of the virus, thereby providing a means of preventing the infection, or treating a patient suffering from the infection and ameliorating one or more symptoms or complications associated with the viral infection. The antibodies may also be useful for diagnosis of an infection by RSV.

First claim

What is claimed is:

1. An isolated human antibody or antigen-binding fragment thereof that binds specifically to RSV-F, wherein the antibody or antigen-binding fragment comprises three heavy chain complementarity determining regions (CDRs) (HCDR1, HCDR2 and HCDR3) contained within any one of the heavy chain variable region (HCVR) amino acid sequences selected from the group consisting of SEQ ID NO: 2, 18, 34, 50, 66, 82, 98, 114, 130, 146, 162, 178, 194, 210, 226, 242, 258, 274, 290, 306, 322 and 338; and comprises three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within any one of the light chain variable region (LCVR) amino acid sequences selected from the group consisting of SEQ ID NOs: 10, 26, 42, 58, 74, 90, 106, 122, 138, 154, 170, 186, 202, 218, 234, 250, 266, 282, 298, 314, 330 and 346.

2. The isolated human antibody or antigen-binding fragment of claim 1 , comprising:
(a) a HCDR1 domain having an amino acid sequence selected from the group consisting of SEQ ID NOs: 4, 20, 36, 52, 68, 84, 100, 116, 132, 148, 164, 180, 196, 212, 228, 244, 260, 276, 292, 308, 324 and 340;
(b) a HCDR2 domain having an amino acid sequence selected from the group consisting of SEQ ID NOs: 6, 22, 38, 54, 70, 86, 102, 118, 134, 150, 166, 182, 198, 214, 230, 246, 262, 278, 294, 310, 326 and 342;
(c) a HCDR3 domain having an amino acid sequence selected from the group consisting of SEQ ID NOs: 8, 24, 40, 56, 72, 88, 104, 120, 136, 152, 168, 184, 200, 216, 232, 248, 264, 280, 296, 312, 328, and 344;
(d) a LCDR1 domain having an amino acid sequence selected from the group consisting of SEQ ID NOs: 12, 28, 44, 60, 76, 92, 108, 124, 140, 156, 172, 188, 204, 220, 236, 252, 268, 284, 300, 316, 332 and 348;
(e) a LCDR2 domain having an amino acid sequence selected from the group consisting of SEQ ID NOs: 14, 30, 46, 62, 78, 94, 110, 126, 142, 158, 174, 190, 206, 222, 238, 254, 270, 286, 302, 318, 334 and 350; and
(f) a LCDR3 domain having an amino acid sequence selected from the group consisting of SEQ ID NOs: 16, 32, 48, 64, 80, 96, 112, 128, 144, 160, 176, 192, 208, 224, 240, 256, 272, 288, 304, 320, 336 and 352.

3. An isolated antibody or antigen-binding fragment thereof that competes for specific binding to RSV-F with an antibody or antigen-binding fragment comprising heavy and light chain sequence pairs selected from the group consisting of SEQ ID NOs: 2/10, 18/26, 34/42, 50/58, 66/74, 82/90, 98/106, 114/122, 130/138, 146/154, 162/170, 178/186, 194/202, 210/218, 226/234, 242/250, 258/266, 274/282, 290/298, 306/314, 322/330 and 338/346, wherein the antibody that competes for specific binding to RSV-F interacts with an epitope comprising an amino acid sequence ranging from about position 161 to about position 188 of SEQ ID NO:354, or interacts with the serine at position 173 of SEQ ID NO: 354, and/or the threonine at position 174 of SEQ ID NO: 354.

4. An isolated antibody or antigen-binding fragment thereof that binds the same epitope on RSV-F that is recognized by an antibody comprising heavy and light chain sequence pairs selected from the group consisting of SEQ ID NOs: 2/10, 18/26, 34/42, 50/58, 66/74, 82/90, 98/106, 114/122, 130/138, 146/154, 162/170, 178/186, 194/202, 210/218, 226/234, 242/250, 258/266, 274/282, 290/298, 306/314, 322/330 and 338/346, wherein the epitope comprises an amino acid sequence ranging from about position 161 to about position 188 of SEQ ID NO:354.

5. The isolated antibody of claim 1 , wherein the antibody does not cross-compete for binding to RSV-F with palivizumab, or AM-22.

6. The isolated human antibody of claim 1 , wherein the antibody does not bind to an epitope on RSV-F ranging from amino acid residue 255 to amino acid residue 276 of SEQ ID NO: 354.

7. The isolated antibody or antigen-binding fragment thereof of claim 1 , wherein the antibody is a human recombinant monoclonal antibody.

8. The isolated antibody or antigen-binding fragment thereof of claim 1 , wherein the antibody or antigen-binding fragment thereof interacts with an amino acid sequence comprising amino acid residues ranging from about position 161 to about position 188 of SEQ ID NO: 354.

9. The isolated antibody or antigen-binding fragment thereof of claim 1 , wherein the antibody or antigen-binding fragment thereof interacts with either the serine at position 173 of SEQ ID NO: 354, or the threonine at position 174 of SEQ ID NO: 354, or both the serine at position 173 of SEQ ID NO: 354 and the threonine at position 174 of SEQ ID NO: 354.

10. The isolated antibody or antigen-binding fragment thereof of claim 1 , wherein the antibody or antigen-binding fragment comprises a heavy chain variable region (HCVR) amino acid sequence selected from the group consisting of SEQ ID NO: 2, 18, 34, 50, 66, 82, 98, 114, 130, 146, 162, 178, 194, 210, 226, 242, 258, 274, 290, 306, 322 and 338.

11. The isolated antibody or antigen-binding fragment thereof of claim 1 , wherein the antibody or antigen-binding fragment comprises a light chain variable region (LCVR) amino acid sequence selected from the group consisting of SEQ ID NOs: 10, 26, 42, 58, 74, 90, 106, 122, 138, 154, 170, 186, 202, 218, 234, 250, 266, 282, 298, 314, 330 and 346.

12. The isolated antibody or antigen-binding fragment of claim 1 , comprising a HCVR/LCVR amino acid sequence pair selected from the group consisting of SEQ ID NOs: 2/10, 18/26, 34/42, 50/58, 66/74, 82/90, 98/106, 114/122, 130/138, 146/154, 162/170, 178/186, 194/202, 210/218, 226/234, 242/250, 258/266, 274/282, 290/298, 306/314, 322/330 and 338/346.

13. The isolated antibody or antigen-binding fragment of claim 12 , comprising a HCVR/LCVR amino acid sequence pair selected from the group consisting of SEQ ID NOs: 274/282 and 338/346.

14. The isolated antibody or antigen-binding fragment of claim 13 , comprising the HCVR/LCVR amino acid sequence pair of SEQ ID NOs: 274/282.

15. The isolated antibody or antigen-binding fragment thereof of claim 1 , wherein the antibody or the antigen-binding fragment thereof demonstrates the ability to significantly reduce the lung viral load in a mouse model of RSV infection when administered at a dose ranging from about 0.05 mg/kg to about 0.15 mg/kg.

16. The isolated antibody or an antigen-binding fragment thereof of claim 1 , wherein the antibody or the antigen-binding fragment thereof demonstrates a 1-2 logs greater reduction of nasal and/or lung viral titers as compared to palivizumab in a cotton rat model of RSV infection when administered at a dose ranging from about 0.62 mg/kg to about 5.0 mg/kg.

17. The isolated antibody or an antigen-binding fragment thereof of claim 1 , wherein the antibody or the antigen-binding fragment thereof demonstrates an ED 99 of about 0.15 mg/kg or less when administered in a mouse model of RSV subtype A infection.

18. The isolated antibody or an antigen-binding fragment thereof of claim 1 , wherein the antibody or the antigen-binding fragment thereof demonstrates an ED 99 of about 0.62 mg/kg or less when administered in a cotton rat model of RSV subtype A infection.

19. The isolated antibody or an antigen-binding fragment thereof of claim 1 , wherein the antibody or the antigen-binding fragment thereof demonstrates an ED 99 of about 2.5 mg/kg or less when administered in a cotton rat model of RSV subtype B infection.

20. The isolated antibody or an antigen-binding fragment thereof of claim 1 , wherein the antibody or the antigen-binding fragment thereof demonstrates an ED 99 that is about 2 to 3 fold lower than the ED 99 for palivizumab or motavizumab.

Assignees

• Regeneron Pharma

Inventors

• Gurnett-Bander Anne
• Perez-Caballero David
• Sivapalasingam Sumathi
• Duan Xunbao
• Macdonald Douglas

Classifications

• A61K39/155 Primary

  Paramyxoviridae, e.g. parainfluenza virus · CPC title

• C07K2317/24

  containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• G01N2333/135

  Respiratory syncytial virus · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title