Claims for Patent: 9,403,900

Summary for Patent: 9,403,900

Title:	Anti-human respiratory syncytial virus (RSV) antibodies and methods of use
Abstract:	Provided herein are antibodies or antigen-binding fragments thereof that immunospecifically bind to the fusion (F) protein of Respiratory Syncytial Virus (RSV). Also provided are methods for of prevention, treatment and diagnosis of viral infection and/or the treatment of one more symptoms of RSV-mediated disease. Methods of generating antibodies that immunospecifically bind RSV F protein also are provided.
Inventor(s):	Williamson; Robert Anthony (London, GB), Wadia; Jehangir (San Diego, CA), Pascual; Gabriel (San Diego, CA), Keogh; Elissa (San Diego, CA)
Assignee:	Crucell Holland B.V. (Leiden, NL)
Application Number:	14/297,486
Patent Claims:	1. An anti-Respiratory Syncytial Virus (RSV) antigen-binding fragment of an antibody, wherein: the antigen-binding fragment comprises: a variable heavy (VH) chain containing a complementary region 1 (CDR1) comprising SEQ ID NO: 464 or 483; a complementary region 2 (CDR2) comprising SEQ ID NO: 465; and a complementary region 3 (CDR3) comprising SEQ ID NO: 466; and a variable light (VL) chain containing a CDR1 comprising SEQ ID NO: 467; a CDR2 comprising SEQ ID NO: 468; and a CDR3 comprising SEQ ID NO: 469; and wherein the antigen-binding fragment immunospecifically binds to Respiratory Syncytial Virus (RSV) fusion (F) protein and/or neutralizes RSV, and wherein the fragment is non-human, humanized, chimeric, and/or camelised. 2. The anti-RSV antigen-binding fragment of claim 1, wherein said fragment is selected from the group consisting of a Fab, Fab', F(ab')2, single-chain Fv (scFv), Fv, dsFv, diabody, Fd and Fd' fragments. 3. The anti-RSV antigen-binding fragment of claim 1, wherein said fragment is a Fab or scFv. 4. The anti-RSV antigen-binding fragment of claim 1, comprising: a VH domain, wherein the amino acid sequence of the VH domain comprises amino acids 1-133 of SEQ ID NO:454; and a VL domain, wherein the amino acid sequence of the VL domain comprises amino acids 1-107 of SEQ ID NO:455. 5. The anti-RSV antigen-binding fragment of claim 1, comprising: a VH domain, wherein the amino acid sequence of the VH domain is set forth in amino acids 1-133 of SEQ ID NO:454; and a VL domain, wherein the amino acid sequence of the VL domain is set forth in amino acids 1-107 of SEQ ID NO:455. 6. The anti-RSV antigen-binding fragment of claim 1, comprising: a heavy chain comprising the peptide of SEQ ID NO:454; and a light chain comprising the peptide of SEQ ID NO:455. 7. An antigen-binding fragment of an antibody, wherein: the antigen-binding fragment is selected from the group consisting of an antigen binding fragment comprising: a) a variable heavy chain (VH) containing a complementary region 1 (CDR1) comprising SEQ ID NO: 411 or 438; a complementary region 2 (CDR2) comprising SEQ ID NO: 412; and a complementary region 3 (CDR3) comprising SEQ ID NO: 413; and a variable light chain (VL) containing a CDR1 comprising SEQ ID NO: 414; a CDR2 comprising SEQ ID NO: 415; and a CDR3 comprising SEQ ID NO: 416; b) a variable heavy chain containing a CDR1 comprising SEQ ID NO: 417 or 439; a CDR2 comprising SEQ ID NO: 418; and a CDR3 comprising SEQ ID NO: 419; and a variable light chain containing a CDR1 comprising SEQ ID NO: 420; a CDR2 comprising SEQ ID NO: 421; and a CDR3 comprising SEQ ID NO: 422; c) a variable heavy chain containing a CDR1 comprising SEQ ID NO: 423 or 440; a CDR2 comprising SEQ ID NO: 424; and a CDR3 comprising SEQ ID NO: 425; and a variable light chain containing a CDR1 comprising SEQ ID NO: 426; a CDR2 comprising SEQ ID NO: 427; and a CDR3 comprising SEQ ID NO: 428; d) a variable heavy chain containing a CDR1 comprising the peptide of SEQ ID NO: 429 or 441 ; a CDR2 comprising the peptide of SEQ ID NO: 430 ; and a CDR3 comprising SEQ ID NO: 431; and a variable light chain containing a CDR1 comprising SEQ ID NO: 432; a CDR2 comprising SEQ ID NO: 433; and a CDR3 comprising SEQ ID NO: 434; e) a variable heavy chain containing a CDR1 comprising SEQ ID NO: 458 or 482; a CDR2 comprising SEQ ID NO: 459; and a CDR3 comprising SEQ ID NO: 460; and a variable light chain containing a CDR1 comprising SEQ ID NO: 461; a CDR2 comprising SEQ ID NO: 462; and a CDR3 comprising SEQ ID NO: 463; and f) a variable heavy chain containing a CDR1 comprising SEQ ID NO: 470 or 484; a CDR2 comprising SEQ ID NO: 471; and a CDR3 comprising SEQ ID NO: 472; and a variable light chain containing a CDR1 comprising SEQ ID NO: 473; a CDR2 comprising SEQ ID NO: 474; and a CDR3 comprising SEQ ID NO: 475; wherein the antigen-binding fragment immunospecifically binds to Respiratory Syncytial Virus (RSV) fusion (F) protein and/or neutralizes RSV, and wherein the fragment is non-human, humanized, chimeric, and/or camelised. 8. The antigen-binding fragment of claim 7, wherein said antigen-binding fragment is selected from the group consisting of a Fab, Fab', F(ab')2, single-chain Fv (scFv), Fv, dsFv, diabody, Fd and Fd' fragments. 9. The antigen-binding fragment of claim 8, wherein said fragment is a Fab or scFv. 10. The antigen-binding fragment of claim 7, wherein the antigen-binding fragment is selected from the group consisting of an antigen binding fragment comprising: a) a VH domain, wherein the amino acid sequence of the VH domain is amino acids 1-125 of SEQ ID NO: 398; and a VL domain, wherein the amino acid sequence of the VL domain is amino acids 1-107 of SEQ ID NO: 397; b) a VH domain, wherein the amino acid sequence of the VH domain is amino acids 1-124 of SEQ ID NO:400; and a VL domain, wherein the amino acid sequence of the VL domain is amino acids 1-108 of SEQ ID NO:399; c) a VH domain, wherein the amino acid sequence of the VH domain is amino acids 1-125 of SEQ ID NO: 402; and a VL domain, wherein the amino acid sequence of the VL domain is amino acids 1-113 of SEQ ID NO: 401; d) a VH domain, wherein the amino acid sequence of the VH domain is amino acids 1-123 of SEQ ID NO: 404; and a VL domain, wherein the amino acid sequence of the VL domain is amino acids 1-107 of SEQ ID NO: 403; e) a VH domain, wherein the amino acid sequence of the VH domain is amino acids 1-124 of SEQ ID NO: 452; and a VL domain, wherein the amino acid sequence of the VL domain is amino acids 1-111 of SEQ ID NO: 453; and f) a VH domain, wherein the amino acid sequence of the VH domain is amino acids 1-118 of SEQ ID NO:456; and a VL domain, wherein the amino acid sequence of the VL domain is amino acids 1-109 of SEQ ID NO:457. 11. The antigen-binding fragment of claim 7, wherein the antigen-binding fragment is selected from the group consisting of an antigen-binding fragment comprising: a) a heavy chain comprising SEQ ID NO: 398; and a light chain comprising amino acids 1-107 of SEQ ID NO: 397; b) a heavy chain comprising SEQ ID NO: 400; and a light chain comprising SEQ ID NO: 399; c) a heavy chain comprising SEQ ID NO: 402; and a light chain comprising SEQ ID NO: 401; d) a heavy chain comprising SEQ ID NO: 404; and a light chain comprising a peptide set forth in SEQ ID NO: 403; e) a heavy chain comprising SEQ ID NO: 452; and a light chain comprising SEQ ID NO: 453; and f) a heavy chain comprising SEQ ID NO: 456; and a light chain comprising SEQ ID NO: 457. 12. The antigen-binding fragment of claim 1, wherein the antigen-binding fragment has an EC.sub.50 of less than 2 nM for neutralization of RSV in an in vitro plaque reduction assay or an affinity of at least 10.sup.8 M.sup.-1 for isolated Respiratory Syncytial Virus (RSV) Fusion (F) protein or for RSV virus. 13. The antigen-binding fragment of claim 1, wherein the antigen-binding fragment has an EC.sub.50 for neutralization of RSV in an in vitro plaque reduction assay of less than or about 2 nM to less than or about 0.005 nM; less than or about 1 nM to less than or about 0.005 nM; less than or about 0.5 nM to less than or about 0.005 nM; less than or about 1 nM to less than or about 0.01 nM; less than or about 1 nM to less than or about 0.05 nM; or less than or about 0.5 nM to less than or about 0.05 nM. 14. The antigen-binding fragment of claim 1, wherein the antigen-binding fragment immunospecifically binds to an epitope of a Respiratory Syncytial Virus (RSV) Fusion (F) protein wherein said epitope is within amino acids 1-544 of SEQ ID NO:25. 15. The antigen-binding fragment of claim 1, wherein said fragment neutralizes RSV. 16. The antigen-binding fragment of claim 1, wherein said fragment neutralizes RSV subtypes A and B. 17. The antigen-binding fragment of claim 1, wherein said fragment is a chimeric antigen-binding fragment. 18. A multivalent antibody comprising: a first antigen-binding portion comprising the antigen-binding fragment of claim 1 conjugated to a multimerization domain; and a second antigen-binding portion comprising an antiviral antibody or antigen-binding fragment thereof conjugated to a second multimerization domain, wherein: the first multimerization domain and the second multimerization domain are complementary or the same, whereby the first antigen-binding portion and second antigen-binding portion form a multivalent antibody. 19. The multivalent antibody of claim 18, wherein the second antigen-binding portion comprises an anti-RSV antibody or antigen-binding fragment thereof. 20. The multivalent antibody of claim 19, wherein the anti-RSV antibody or antigen-binding fragment is selected from the group consisting of palivizumab, motavizumab, AFFF, P12f2, Pt2f4, P11d4, A1e9, A12a6, A13c4, A17d4, A4B4, A8c7, 1X-493L1, FR H3-3F4, M3H9, Y10H6, DG, AFFF(1), 6H8, L1-7E5, L2-15B10, A13a11, A1h5, A4B4(1), A4B4L1FR-S28R, A4B4-F52S, rsv6, rsv11, rsv13, rsv19, rsv21, rsv22, rsv23, RF-1, RF-2, and antigen-binding fragments thereof. 21. The multivalent antibody of claim 18, wherein the second antigen-binding portion comprises an antigen-binding fragment of an antiviral antibody that immunospecifically binds an antigen of parainfluenza virus (PIV) or human metapneumovirus (hMPV). 22. A composition comprising: the antigen-binding fragment of claim 1, and an antiviral agent. 23. The composition of claim 22, wherein the antiviral agent is ribavirin. 24. The composition of claim 22, wherein the antiviral agent is an additional antiviral antibody that differs from the first antigen binding fragment. 25. The composition of claim 24, wherein the additional antiviral antibody is selected from the group consisting of palivizumab, motavizumab, AFFF, P12f2, P12f4, P11d4, A1e9, A12a6, A13c4, A17d4, A4B4, A8c7, 1X-493L1, FR H3-3F4, M3H9, Y10H6, DG, AFFF(1), 6H8, L1-7E5, L2-15B10, A13a11, A1h5, A4B4(1), A4B4L1FR-S28R, A4B4-F52S, rsv6, rsv11, rsv13, rsv19, rsv21, rsv22, rsv23, RF-1, RF-2, and an antigen-binding fragment of thereof. 26. The composition of claim 24, wherein the additional antiviral antibody is either an antibody or antigen-binding fragment that immunospecifically binds an antigen of parainfluenza virus (PIV) or human metapneumovirus (hMPV). 27. A pharmaceutical composition comprising: the antigen-binding fragment of claim 1; and a pharmaceutically acceptable carrier or excipient. 28. The pharmaceutical composition of claim 27 formulated as a gel, ointment, liquid, suspension, aerosol, tablet, pill or powder. 29. The pharmaceutical composition of claim 27 formulated as a nasal spray. 30. The pharmaceutical composition of claim 27, formulated for pulmonary, intranasal, or parenteral administration. 31. The pharmaceutical composition of claim 27, formulated for single dosage administration. 32. The pharmaceutical composition of claim 27 that is a sustained release formulation. 33. A method of treating a RSV infection in a subject, the method comprising: administering to the subject a therapeutically effective amount of the pharmaceutical composition of claim 27. 34. A method of treating or inhibiting one or more symptoms of a RSV infection in a subject, the method comprising: administering to the subject a therapeutically effective amount of the pharmaceutical composition of claim 27. 35. The method of claim 33, further comprising administration of one or more antiviral agents. 36. The method of claim 35, wherein the antiviral agent is ribavirin. 37. The method of claim 33, further comprising administration of one or more additional antiviral antibodies or antigen-binding fragments thereof. 38. The method of claim 37, wherein the one or more additional anti-RSV antibodies are selected from the group consisting of palivizumab, motavizumab, AFFF, P12f2, P12f4, P11d4, A1e9, A12a6, A13c4, A17d4, A4B4, A8c7, 1X-493L1, FR H3-3F4, M3H9, Y10H6, DG, AFFF(1), 6H8, L1-7E5, L2-15B10, A13a11, A1h5, A4B4(1), A4B4L1FR- S28R, A4B4-F52S, rsv6, rsv11, rsv13, rsv19, rsv21, rsv22, rsv23, RF-1, RF-2, and antigen-binding fragments thereof. 39. A method of detecting RSV infection, the method comprising: (a) assaying the level of RSV antigen in a fluid, cell, or tissue sample using the antigen-binding fragment of claim 1; and (b) comparing the assayed level of RSV antigen with a control level whereby an increase in the assayed level of RSV antigen compared to the control level of the RSV antigen is indicative of a RSV infection. 40. A kit comprising the antigen-binding fragment of claim 1 in one or more containers, and instructions for use. 41. A humanized monoclonal anti-Respiratory Syncytial Virus (anti-RSV) anti-body comprising: a VH chain containing a CDR1 comprising SEQ ID NO: 464, a CDR2 comprising SEQ ID NO: 465, and a CDR3 comprising SEQ ID NO: 466; and a VL chain containing a CDR1 comprising SEQ ID NO: 467, a CDR2 comprising SEQ ID NO: 468, and a CDR3 comprising SEQ ID NO: 469; wherein the humanized monoclonal antibody immunospecifically binds to RSV fusion (F) protein and/or neutralizes RSV. 42. The antibody of claim 41, comprising: a VH domain comprising amino acids 1-133 of SEQ ID NO: 454; and a VL domain comprising amino acids 1-107 of SEQ ID NO: 455. 43. A multivalent antibody comprising: a first antigen-binding portion comprising a VH containing a CDR1 comprising SEQ ID NO: 464, a CDR2 comprising SEQ ID NO: 465, and a VH CDR3 comprising SEQ ID NO: 466; and a VL containing a CDR1 comprising SEQ ID NO: 467, a CDR2 comprising SEQ ID NO: 468, and a CDR3 comprising SEQ ID NO: 469, and a second antigen-binding portion comprising an antigen-binding fragment of an antiviral antibody conjugated to a second multimerization domain, wherein the multivalent antibody immunospecifically binds to Respiratory Syncytial Virus (RSV) fusion (F) protein and/or neutralizes RSV, wherein the first multimerization domain and the second multimerization domain are complementary or the same, and wherein the first antigen-binding portion and second antigen-binding portion form a multivalent antibody, and wherein the first and/or the second antigen-binding portion is non-human, humanized, chimeric, and/or camelised. 44. A pharmaceutical composition comprising: 1) a humanized monoclonal antibody of a non-human species comprising: a VH chain containing a CDR1 comprising SEQ ID NO: 464, a CDR2 comprising SEQ ID NO: 465; and a CDR3 comprising SEQ ID NO: 466; and a VL chain containing a CDR1 comprising SEQ ID NO: 467, a CDR2 comprising SEQ ID NO: 468, and a CDR3 comprising SEQ ID NO: 469, wherein the humanized monoclonal antibody of a non-human species immunospecifically binds to Respiratory Syncytial Virus (RSV) fusion (F) protein and/or neutralizes RSV, and 2) a pharmaceutically acceptable carrier or excipient. 45. A conjugate comprising: (a) an anti-Respiratory Syncytial Virus (anti-RSV) antibody that immunospecifically binds to RSV fusion (F) protein, the anti-RSV antibody comprising: a VH containing a CDR1comprising SEQ ID NO: 464, a CDR2comprising SEQ ID NO: 465, and a CDR3comprising SEQ ID NO: 466; and a VL containing a CDR1 comprising SEQ ID NO: 467, a CDR2 comprising SEQ ID NO: 468, and a CDR3 comprising SEQ ID NO: 469; and (b) a moiety conjugated to the anti-RSV antibody, wherein the moiety is selected from the group consisting of a high molecular weight polyethylene glycol (PEG), a detectable moiety, and a therapeutic moiety. 46. The conjugate of claim 45, wherein the moiety is polyethylene glycol (PEG). 47. The conjugate of claim 45, wherein the moiety is a detectable moiety comprising a label. 48. The conjugate of claim 45, wherein the moiety is a therapeutic polypeptide. 49. A method of reducing one or more symptoms of a Respiratory Syncytial Virus (RSV) infection, or for inhibiting an RSV infection in a subject, the method comprising: administering to the subject the humanized monoclonal anti-RSV antibody of claim 41, so as to reduce one or more symptoms of a RSV infection, or so as to inhibit an RSV infection in the subject. 50. A method of detecting Respiratory Syncytial Virus (RSV) infection in a subject, the method comprising: assaying the level of RSV antigen in a fluid cell, or tissue sample from the subject with the humanized monoclonal anti-RSV antibody of claim 41; comparing the assayed level of RSV antigen with a control level wherein an increase in the assayed level of RSV antigen compared to the control level of the RSV antigen is indicative of an RSV infection.

Details for Patent 9,403,900

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Swedish Orphan Biovitrum Ab (publ)	SYNAGIS	palivizumab	For Injection	103770	06/19/1998		2029-08-13
Swedish Orphan Biovitrum Ab (publ)	SYNAGIS	palivizumab	Injection	103770	07/23/2004		2029-08-13
Hoffmann-la Roche Inc.	PEGASYS COPEGUS COMBINATION PACK	peginterferon alfa-2a and ribavirin		125083	06/04/2004		2029-08-13
Schering Corporation A Subsidiary Of Merck & Co., Inc.	PEGINTRON/ REBETOL COMBO PACK	peginterferon alfa-2b and ribavirin		125196	06/13/2008		2029-08-13