ANTI-HUMAN RESPIRATORY SYNCYTIAL VIRUS (RSV) ANTIBODIES AND METHODS OF USE

• US 20130177573A1
• Filed: 07/08/2011
• Published: 07/11/2013
• Est. Priority Date: 07/09/2010
• Status: Active Grant

• Current Assignee: Crucell Holland B.V (Johnson & Johnson)
• Original Assignee: Crucell Holland B.V (Johnson & Johnson)
• Inventors: Williamson, Robert Anthony, Wadia, Jehangir, Keogh, Elissa, Pascual, Gabriel
• Granted Patent: US 9,139,642 B2
• Time in Patent Office: Days
• US Class Current: 424/159.1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 2039/507 Comprising a combination of two or more separate antibodies
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/7056 containing five-membered rings with nitrogen as a ring hetero atom
• CPC Class Codes: A61K 39/42 viral
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: C07K 16/1027 Paramyxoviridae, e.g. respiratory syncytial virus
• CPC Class Codes: C07K 16/468 Immunoglobulins having two or more different antigen binding sites, e.g. multifunctional antibodies
• CPC Class Codes: C07K 2317/14 Specific host cells or culture conditions, e.g. components, pH or temperature
• CPC Class Codes: C07K 2317/21 from primates, e.g. man
• CPC Class Codes: C07K 2317/24 containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/31 multispecific
• CPC Class Codes: C07K 2317/33 Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
• CPC Class Codes: C07K 2317/35 Valency
• CPC Class Codes: C07K 2317/55 Fab or Fab'
• CPC Class Codes: C07K 2317/565 Complementarity determining region [CDR]
• CPC Class Codes: C07K 2317/76 Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• CPC Class Codes: C07K 2317/92 : Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
• CPC Class Codes: C12N 2760/18534 : Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
• CPC Class Codes: C12N 2760/18571 : Demonstrated in vivo effect
• CPC Class Codes: C12N 7/00 : Viruses; Bacteriophages; Compositions thereof; Preparation or purification thereof preparing medicinal viral antigen or antibody compositions, e.g. virus vaccines, A61K39/00
• CPC Class Codes: G01N 2333/135 : Respiratory syncytial virus
• CPC Class Codes: G01N 33/56983 : Viruses

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.

Claims

1-99. -99. (canceled)

100. An anti-Respiratory Syncytial Virus (RSV) antibody or antigen-binding fragment thereof, wherein:

RSV does not produce a virus that escapes neutralization by the antibody or antigen-binding fragment thereof after more than ten or more rounds of viral replication in the presence of the antibody or antigen-binding fragment thereof.

101. The anti-RSV antibody or antigen-binding fragment thereof of claim 100, comprising:

a variable heavy chain containing a VH CDR1 comprising SEQ ID NO;

405 or 437 or having at least or at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity to SEQ ID NO;

405 or 437;

a VH CDR2 comprising SEQ ID NO;

406 or having at least or at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity to SEQ ID NO;

406; and

a VH CDR3 comprising SEQ ID NO;

407 or having at least or at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity to SEQ ID NO;

407; and

a variable light chain containing a VL CDR1 comprising SEQ ID NO;

408 or having at least or at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity to SEQ ID NO;

408;

a VL CDR2 comprising SEQ ID NO;

409 or having at least or at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity to SEQ ID NO;

409; and

a VL CDR3 comprising SEQ ID NO;

410 or having at least or at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity to SEQ ID NO;

410; and

the antibody or antigen-binding fragment thereof immunospecifically binds to RSV fusion (F) protein and/or neutralizes RSV.

102. The anti-RSV antibody or antigen-binding fragment of claim 101, comprising:

a VH domain as set forth in amino acids 1-121 of SEQ ID NO;

396 or is at least or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to amino acids 1-121 of SEQ ID NO;

396; and

a VL domain as set forth in amino acids 1-110 of SEQ ID NO;

395 or is at least or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to amino acids 1-110 of SEQ ID NO;

395.

103. The antibody or antigen-binding fragment of claim 100, wherein the antibody or antigen-binding fragment has an EC₅₀ of less than 2 nM for neutralization of RSV in an in vitro plaque reduction assay or an affinity of at least 10⁸ M⁻

1 for isolated RSV F protein or for RSV virus.

109. A multivalent antibody, comprising:

a first antigen-binding portion comprising an antibody or antigen-binding fragment of claim 100 or an antigen-binding fragment thereof conjugated to a multimerization domain; and

a second antigen-binding portion comprising an antigen-binding fragment of an antiviral antibody conjugated to a second multimerization domain, wherein;

the first multimerization domain and the second multimerization domain are complementary or the same, wherein the first antigen-binding portion and second antigen-binding portion form a multivalent antibody.

110. A pharmaceutical composition comprising:

the antibody or antigen-binding fragment of claim 100, and

a pharmaceutically acceptable carrier or excipient.

111. A method of treating or inhibiting one or more symptoms of a RSV infection, or for preventing a RSV infection, the method comprising:

utilizing the antibody or antigen-binding fragment of claim 100 for treating or inhibiting one or more symptoms of a RSV infection, or for preventing a RSV infection.

112. A method of detecting RSV infection, the method comprising:

assaying the level of RSV antigen in a fluid, cell, or tissue sample utilizing the antibody or antigen-binding fragment of claim 100;

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 a RSV infection.

113. An isolated nucleic acid that encodes the antibody or antigen-binding fragment of claim 100.

104. An anti-Respiratory Syncytial Virus (RSV) antibody or antigen-binding fragment thereof comprising:

a variable heavy chain containing a VH CDR1 comprising SEQ ID NO;

464 or 483 or having at least or at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity to SEQ ID NO;

464 or 483;

a VH CDR2 comprising SEQ ID NO;

465 or having at least or at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity to SEQ ID NO;

465; and

a VH CDR3 comprising SEQ ID NO;

466 or having at least or at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity to SEQ ID NO;

466; and

a variable light chain containing a VL CDR1 comprising SEQ ID NO;

467 or having at least or at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity to SEQ ID NO;

467;

a VL CDR2 comprising SEQ ID NO;

468 or having at least or at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity to SEQ ID NO;

468; and

a VL CDR3 comprising SEQ ID NO;

469 or having at least or at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity to SEQ ID NO;

469; and

the antibody or antigen-binding fragment immunospecifically binds to RSV fusion (F) protein and/or neutralizes RSV.

105. The anti-RSV antibody or antigen-binding fragment of claim 104, 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 or is at least or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to 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 or is at least or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to amino acids 1-107 of SEQ ID NO;

455.

106. An anti-Respiratory Syncytial Virus (RSV) antibody or antigen-binding fragment thereof comprising:

a variable heavy chain containing a VH CDR1 comprising SEQ ID NO;

458 or 482 or having at least or at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity to SEQ ID NO;

458 or 482;

a VH CDR2 comprising SEQ ID NO;

459 or having at least or at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity to SEQ ID NO;

459; and

a VH CDR3 comprising SEQ ID NO;

460 or having at least or at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity to SEQ ID NO;

460; and

a variable light chain containing a VL CDR1 comprising SEQ ID NO;

461 or having at least or at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity to SEQ ID NO;

461;

a VL CDR2 comprising SEQ ID NO;

462 or having at least or at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity to SEQ ID NO;

462; and

a VL CDR3 comprising SEQ ID NO;

463 or having at least or at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity to SEQ ID NO;

463; and

the antibody or antigen-binding fragment immunospecifically binds to RSV fusion (F) protein and/or neutralizes RSV.

107. The anti-RSV antibody or antigen-binding fragment of claim 106, comprising:

a VH domain as set forth in amino acids 1-124 of SEQ ID NO;

452 or is at least or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to amino acids 1-124 of SEQ ID NO;

452; and

a VL domain as set forth in amino acids 1-111 of SEQ ID NO;

453 or is at least or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to amino acids 1-111 of SEQ ID NO;

453.

108. An anti-Respiratory Syncytial Virus (RSV) antibody or antigen-binding fragment thereof selected from among an antibody or antigen binding fragment comprising:

a) a variable heavy chain containing a VH CDR1 comprising SEQ ID NO;

411 or 438 or having at least or at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity to SEQ ID NO;

411 or 438;

a VH CDR2 comprising SEQ ID NO;

412 or having at least or at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity to SEQ ID NO;

412; and

a VH CDR3 comprising SEQ ID NO;

413 or having at least or at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity to SEQ ID NO;

413; and

a variable light chain containing a VL CDR1 comprising SEQ ID NO;

414 or having at least or at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity to SEQ ID NO;

414;

a VL CDR2 comprising SEQ ID NO;

415 or having at least or at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity to SEQ ID NO;

415; and

a VL CDR3 comprising SEQ ID NO;

416 or having at least or at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity to SEQ ID NO;

416;

b) a variable heavy chain containing a VH CDR1 comprising SEQ ID NO;

417 or 439 or having at least or at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity to SEQ ID NO;

417 or 439;

a VH CDR2 comprising SEQ ID NO;

418 or having at least or at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity to SEQ ID NO;

418; and

a VH CDR3 comprising SEQ ID NO;

419 or having at least or at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity to SEQ ID NO;

419; and

a variable light chain containing a VL CDR1 comprising SEQ ID NO;

420 or having at least or at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity to SEQ ID NO;

420;

a VL CDR2 comprising SEQ ID NO;

421 or having at least or at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity to SEQ ID NO;

421; and

a VL CDR3 comprising SEQ ID NO;

422 or having at least or at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity to SEQ ID NO;

422;

c) a variable heavy chain containing a VH CDR1 comprising SEQ ID NO;

423 or 440 or having at least or at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity to SEQ ID NO;

423 or 440;

a VH CDR2 comprising SEQ ID NO;

424 or having at least or at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity to SEQ ID NO;

424; and

a VH CDR3 comprising SEQ ID NO;

425 or having at least or at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity to SEQ ID NO;

425; and

a variable light chain containing a VL CDR1 comprising SEQ ID NO;

426 or having at least or at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity to SEQ ID NO;

426;

a VL CDR2 comprising SEQ ID NO;

427 or having at least or at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity to SEQ ID NO;

427; and

a VL CDR3 comprising SEQ ID NO;

428 or having at least or at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity to SEQ ID NO;

428;

d) a variable heavy chain containing a VH CDR1 comprising SEQ ID NO;

429 or 441 or having at least or at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity to SEQ ID NO;

429 or 441;

a VH CDR2 comprising SEQ ID NO;

430 or having at least or at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity to SEQ ID NO;

430; and

a VH CDR3 comprising SEQ ID NO;

431 or having at least or at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity to SEQ ID NO;

431; and

a variable light chain containing a VL CDR1 comprising SEQ ID NO;

432 or having at least or at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity to SEQ ID NO;

432;

a VL CDR2 comprising SEQ ID NO;

433 or having at least or at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity to SEQ ID NO;

433; and

a VL CDR3 comprising SEQ ID NO;

434 or having at least or at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity to SEQ ID NO;

434; and

e) a variable heavy chain containing a VH CDR1 comprising SEQ ID NO;

470 or 484 or having at least or at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity to SEQ ID NO;

470 or 484;

a VH CDR2 comprising SEQ ID NO;

471 or having at least or at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity to SEQ ID NO;

471; and

a VH CDR3 comprising SEQ ID NO;

472 or having at least or at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity to SEQ ID NO;

472; and

a variable light chain containing a VL CDR1 comprising SEQ ID NO;

473 or having at least or at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity to SEQ ID NO;

473;

a VL CDR2 comprising SEQ ID NO;

474 or having at least or at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity to SEQ ID NO;

474; and

a VL CDR3 comprising SEQ ID NO;

475 or having at least or at least about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity to SEQ ID NO;

475; and

wherein the antibody or antigen-binding fragment immunospecifically binds to RSV fusion (F) protein and/or neutralizes RSV.