Human Antibodies to Respiratory Syncytial Virus F Protein and Methods of Use Thereof

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.

1 - 59 . (canceled) 
     
     
         60 . 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 a heavy chain variable region (HCVR) comprising an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 274; and comprises three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within a light chain variable region (LCVR) comprising an amino acid sequence with at least 90% sequence identity to SEQ ID NOs: 282. 
     
     
         61 . The isolated human antibody or antigen-binding fragment of  claim 60 , comprising:
 (a) a HCDR3 domain having the amino acid sequence of SEQ ID NO: 280; and   (b) a LCDR3 domain having the amino acid sequence of SEQ ID NO: 288.   
     
     
         62 . The isolated antibody or antigen-binding fragment of  claim 61 , comprising a HCVR comprising an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 274, and a LCVR comprising an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 282. 
     
     
         63 . The isolated antibody or antigen-binding fragment of  claim 60 , wherein the HCVR and the LCVR comprise amino acid sequences with at least 95% sequence identity to SEQ ID NOs: 274 and 282, respectively. 
     
     
         64 . The isolated antibody or antigen-binding fragment of  claim 60 , wherein the HCVR and the LCVR comprise amino acid sequences with at least 98% sequence identity to SEQ ID NOs: 274 and 282, respectively. 
     
     
         65 . The isolated antibody or antigen-binding fragment of  claim 60 , wherein the HCVR and the LCVR comprise amino acid sequences with at least 99% sequence identity to SEQ ID NOs: 274 and 282, respectively. 
     
     
         66 . An isolated nucleic acid molecule encoding the antibody or antigen-binding fragment of  claim 60 . 
     
     
         67 . An expression vector comprising the nucleic acid molecule of  claim 63 . 
     
     
         68 . A host cell comprising the expression vector of  claim 67 . 
     
     
         69 . A method for treating a respiratory syncytial virus (RSV) infection, the method comprising administering an antibody or antigen-binding fragment of  claim 60 , or a composition comprising an antibody or antigen-binding fragment of  claim 60 , to a patient in need thereof. 
     
     
         70 . The method of  claim 69 , wherein:
 (a) the RSV infection is caused by a subtype A or a subtype B respiratory syncytial virus; and/or   (b) the patient in need thereof is a patient at high risk of acquiring an RSV infection, or a patient who may experience a more severe form of the RSV infection due to an underlying or pre-existing medical condition.   
     
     
         71 . The method of  claim 70 , wherein:
 (a) the patient is a pre-term infant, a full term infant, a child greater than or equal to one year of age with or without an underlying medical condition (e.g. congenital heart disease, chronic lung disease, cystic fibrosis, immunodeficiency, a neuromuscular disorder), an institutionalized or hospitalized patient, or an elderly adult (greater than 65 years of age) with or without an underlying medical condition such as congestive heart failure or chronic obstructive pulmonary disease); or   (b) the patient suffers from a condition resulting from a compromised pulmonary, cardiovascular, neuromuscular, or immune system.   
     
     
         72 . The method of  claim 71 , wherein the condition is selected from the group consisting of an abnormality of the airway, a chronic lung disease, a chronic heart disease, a neuromuscular disease that compromises the handling of respiratory secretions and immunosuppression. 
     
     
         73 . The method of  claim 72 , wherein:
 (a) the chronic lung disease is chronic obstructive pulmonary disease (COPD), cystic fibrosis, or bronchopulmonary dysplasia, optionally wherein the chronic heart disease is congestive heart failure (CHF), or congenital heart disease; and/or   (b) the immunosuppression is a result of severe combined immunodeficiency or severe acquired immunodeficiency, or is a result of any other infectious disease or cancerous condition that leads to immunosuppression, or is a result of treatment with immunosuppressant drug therapy or radiation therapy.   
     
     
         74 . The method of  claim 69 , wherein:
 (a) the antibody or antigen-binding fragment thereof is administered via a route selected from the group consisting of intravenously, intramuscularly, and subcutaneously; and/or   (b) the antibody or antigen-binding fragment is administered to the patient in combination with a second therapeutic agent.   
     
     
         75 . A pharmaceutical composition comprising the antibody or antigen binding fragment thereof of  claim 60  and a pharmaceutically acceptable carrier. 
     
     
         76 . 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 a heavy chain variable region (HCVR) comprising an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 338; and comprises three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within a light chain variable region (LCVR) comprising an amino acid sequence with at least 90% sequence identity to SEQ ID NOs: 346. 
     
     
         77 . The isolated human antibody or antigen-binding fragment of  claim 76 , comprising:
 (a) a HCDR3 domain having the amino acid sequence of SEQ ID NO: 344; and   (b) a LCDR3 domain having the amino acid sequence of SEQ ID NO: 352.   
     
     
         78 . The isolated antibody or antigen-binding fragment of  claim 77 , comprising a HCVR comprising an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 338, and a LCVR comprising an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 346. 
     
     
         79 . The isolated antibody or antigen-binding fragment of  claim 76 , wherein the HCVR and the LCVR comprise amino acid sequences with at least 95% sequence identity to SEQ ID NOs: 338 and 346, respectively. 
     
     
         80 . The isolated antibody or antigen-binding fragment of  claim 76 , wherein the HCVR and the LCVR comprise amino acid sequences with at least 98% sequence identity to SEQ ID NOs: 338 and 346, respectively. 
     
     
         81 . The isolated antibody or antigen-binding fragment of  claim 76 , wherein the HCVR and the LCVR comprise amino acid sequences with at least 99% sequence identity to SEQ ID NOs: 338 and 346, respectively. 
     
     
         82 . An isolated nucleic acid molecule encoding an antibody or antigen-binding fragment of  claim 76 . 
     
     
         83 . An expression vector comprising the nucleic acid molecule of  claim 82 . 
     
     
         84 . A host cell comprising the expression vector of  claim 83 . 
     
     
         85 . A method for treating a respiratory syncytial virus (RSV) infection, the method comprising administering an antibody or antigen-binding fragment of  claim 76 , or a composition comprising an antibody or antigen-binding fragment of  claim 76 , to a patient in need thereof. 
     
     
         86 . The method of  claim 85 , wherein:
 (a) the RSV infection is caused by a subtype A or a subtype B respiratory syncytial virus; and/or   (b) the patient in need thereof is a patient at high risk of acquiring an RSV infection, or a patient who may experience a more severe form of the RSV infection due to an underlying or pre-existing medical condition.   
     
     
         87 . The method of  claim 86 , wherein:
 (a) the patient is a pre-term infant, a full term infant, a child greater than or equal to one year of age with or without an underlying medical condition (e.g. congenital heart disease, chronic lung disease, cystic fibrosis, immunodeficiency, a neuromuscular disorder), an institutionalized or hospitalized patient, or an elderly adult (greater than 65 years of age) with or without an underlying medical condition such as congestive heart failure or chronic obstructive pulmonary disease); or   (b) the patient suffers from a condition resulting from a compromised pulmonary, cardiovascular, neuromuscular, or immune system.   
     
     
         88 . The method of  claim 87 , wherein the condition is selected from the group consisting of an abnormality of the airway, a chronic lung disease, a chronic heart disease, a neuromuscular disease that compromises the handling of respiratory secretions and immunosuppression. 
     
     
         89 . The method of  claim 88 , wherein:
 (a) the chronic lung disease is chronic obstructive pulmonary disease (COPD), cystic fibrosis, or bronchopulmonary dysplasia, optionally wherein the chronic heart disease is congestive heart failure (CHF), or congenital heart disease; and/or   (b) the immunosuppression is a result of severe combined immunodeficiency or severe acquired immunodeficiency, or is a result of any other infectious disease or cancerous condition that leads to immunosuppression, or is a result of treatment with immunosuppressant drug therapy or radiation therapy.   
     
     
         90 . The method of  claim 85 , wherein:
 (a) the antibody or antigen-binding fragment thereof is administered via a route selected from the group consisting of intravenously, intramuscularly, and subcutaneously; and/or   (b) the antibody or antigen-binding fragment is administered to the patient in combination with a second therapeutic agent.   
     
     
         91 . A pharmaceutical composition comprising the antibody or antigen binding fragment thereof of  claim 76  and a pharmaceutically acceptable carrier.