Ultra high affinity neutralizing antibodies

Abstract

Ultra high affinity antibodies with binding affinities in the range of 10 10 M −1 , and even 10 11 M −1 are disclosed. Such antibodies include antibodies having novel high affinity complementarity determining regions (CDRs), especially those with framework and constant regions derived from either humans or mice. Methods of preparing and screening such antibodies, as well as methods of using them to prevent and/or treat disease, especially virus-induced diseases, are also disclosed.

1 .- 48 . (canceled) 
     
     
         49 . An isolated high affinity neutralizing immunoglobulin that specifically binds to a respiratory syncytial virus (RSV) F antigen with an affinity constant (K a ) of at least 10 10  M −1  as measured by surface plasmon resonance, wherein the high affinity neutralizing immunoglobulin binds to the same epitope on the RSV F antigen as an antibody comprising a heavy chain variable region (VH) having an amino acid sequence SEQ ID NO:2 ( FIG. 1B ) and a light chain variable region (VL) having the amino acid sequence SEQ ID NO:1 ( FIG. 1A ), and wherein the high affinity neutralizing immunoglobulin comprises: (a) a VH comprising a VH complementarity determining region (CDR)1 having the amino acid sequence TAGMSVG (SEQ ID NO: 9); and (b) a VL comprising a VL CDR2 having the amino acid sequence DTSKLAS (SEQ ID NO: 4) and a VL CDR3 having the amino acid sequence FQGSGYPFT (SEQ ID NO 5). 
     
     
         50 . The high affinity neutralizing immunoglobulin of  claim 49 , wherein the immunoglobulin has a K a  of at least 10 11  M −1 . 
     
     
         51 . The high affinity neutralizing immunoglobulin of  claim 49 , wherein the immunoglobulin has a K a  is 10 10  M −1  or 10 11  M −1 . 
     
     
         52 . The high affinity neutralizing immunoglobulin of  claim 49 , wherein the immunoglobulin neutralizes RSV as measured by a microneutralization assay. 
     
     
         53 . The high affinity neutralizing immunoglobulin of  claim 52 , wherein the immunoglobulin has an IC 50  in the microneutralization assay that is less than the IC 50  of the IX-493 antibody. 
     
     
         54 . The high affinity neutralizing immunoglobulin of  claim 49 , wherein the immunoglobulin is a tetrameric antibody, a Fab fragment, an F(ab)′ 2 , a heavy-light chain dimer, or a single chain structure. 
     
     
         55 . The high affinity neutralizing immunoglobulin of  claim 49 , wherein the immunoglobulin is a monoclonal antibody. 
     
     
         56 . The high affinity neutralizing immunoglobulin of  claim 49 , wherein the immunoglobulin is a humanized antibody. 
     
     
         57 . The high affinity neutralizing immunoglobulin of  claim 49 , wherein the immunoglobulin further comprises framework regions of a VL having the amino acid sequence of SEQ ID NO:1 and framework regions of a VH having the amino acid of SEQ ID NO:2. 
     
     
         58 . A composition comprising the high affinity neutralizing immunoglobulin of  claim 49 , and a pharmacologically acceptable diluent or excipient. 
     
     
         59 . A method for preventing a disease associated with RSV in a patient at risk of such disease or afflicted with such disease, comprising administering the high affinity neutralizing immunoglobulin of  claim 49  to the patient. 
     
     
         60 . A method for treating a disease associated with RSV in a patient at risk of such disease or afflicted with such disease, comprising administering the high affinity neutralizing immunoglobulin of  claim 49  to the patient.