Human antibodies to respiratory syncytial virus F protein and methods of use thereof
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. 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 the amino acid sequence of SEQ ID NO: 274; and comprises three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NOs: 282, wherein the CDRs are identified by the Kabat definition, the Chothia definition, or the AbM definition.
2. The isolated human antibody or antigen-binding fragment of claim 1 , comprising:
(a) a HCDR1 domain having the amino acid sequence of SEQ ID NO: 276;
(b) a HCDR2 domain having the amino acid sequence of SEQ ID NO: 278;
(c) a HCDR3 domain having the amino acid sequence of SEQ ID NO: 280;
(d) a LCDR1 domain having the amino acid sequence of SEQ ID NO: 284;
(e) a LCDR2 domain having the amino acid sequence of SEQ ID NO: 286; and
(f) a LCDR3 domain having the amino acid sequence of SEQ ID NO: 288.
3. The isolated antibody or antigen-binding fragment of claim 2 , comprising the HCVR/LCVR amino acid sequence pair of SEQ ID NOs: 274/282, wherein the antibody or antigen-binding fragment binds to RSV-F within amino acids 161-188of SEQ ID NO: 354.
4. An isolated nucleic acid molecule encoding the antibody or antigen-binding fragment of claim 1 .
5. An expression vector comprising the nucleic acid molecule of claim 4 .
6. A host cell comprising the expression vector of claim 5 .
7. A method for treating a respiratory syncytial virus (RSV) infection, the method comprising administering an antibody or antigen-binding fragment of claim 1 , or a composition comprising an antibody or antigen-binding fragment of claim 1 , to a patient in need thereof.
8. The method of claim 7 , 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.
9. The method of claim 8 , 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.
10. The method of claim 9 , 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.
11. The method of claim 10 , 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.
12. The method of claim 7 , 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.
13. A pharmaceutical composition comprising the antibody or antigen binding fragment thereof of claim 1 and a pharmaceutically acceptable carrier.
14. 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 the amino acid sequence of SEQ ID NO: 338; and comprises three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NOs: 346, wherein the CDRs are identified by the Kabat definition, the Chothia definition, or the AbM definition.
15. The isolated human antibody or antigen-binding fragment of claim 14 , comprising:
(a) a HCDR1 domain having the amino acid sequence of SEQ ID NO: 340;
(b) a HCDR2 domain having the amino acid sequence of SEQ ID NO: 342;
(c) a HCDR3 domain having the amino acid sequence of SEQ ID NO: 344;
(d) a LCDR1 domain having the amino acid sequence of SEQ ID NO: 348;
(e) a LCDR2 domain having the amino acid sequence of SEQ ID NO: 350; and
(f) a LCDR3 domain having the amino acid sequence of SEQ ID NO: 352.
16. The isolated antibody or antigen-binding fragment of claim 15 , comprising the HCVR/LCVR amino acid sequence pair of SEQ ID NOs: 338/346.
17. An isolated nucleic acid molecule encoding an antibody or antigen-binding fragment of claim 14 .
18. An expression vector comprising the nucleic acid molecule of claim 17 .
19. A host cell comprising the expression vector of claim 18 .
20. A method for treating a respiratory syncytial virus (RSV) infection, the method comprising administering an antibody or antigen-binding fragment of claim 14 , or a composition comprising an antibody or antigen-binding fragment of claim 14 , to a patient in need thereof.
21. The method of claim 20 , 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.
22. The method of claim 21 , 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.
23. The method of claim 22 , 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.
24. The method of claim 23 , 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.
25. The method of claim 20 , 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.
26. A pharmaceutical composition comprising the antibody or antigen binding fragment thereof of claim 14 and a pharmaceutically acceptable carrier.