Opsonic monoclonal and chimeric antibodies specific for lipoteichoic acid of gram positive bacteria

Abstract

The present invention encompasses monoclonal antibodies that bind to lipoteichoic acid (LTA) of Gram positive bacteria. The antibodies also bind to whole bacteria and enhance phagocytosis and killing of the bacteria in vitro. The invention also provides antibodies having human sequences (chimeric, humanized and human antibodies). The invention also sets forth the variable regions of three antibodies within the invention and presents the striking homology between them.

1 . An isolated monoclonal antibody, or antigen-binding fragment thereof, that binds to lipoteichoic acid (LTA) of Gram positive bacteria, wherein at least a portion of the antibody variable region is obtained from a phage display library comprising human antibody sequences or is obtained from a cell comprising a human antibody sequence. 
     
     
         2 . The isolated monoclonal antibody of  claim 1  wherein at least a portion of the antibody variable region has been identified as binding to a peptide mimetic of an LTA epitope,  Staphylococcus , or a  Staphylococcus  antigen. 
     
     
         3 . The isolated monoclonal antibody of  claim 1  wherein the phage display library comprising human antibody sequences is derived from sequences from a  Staphylococcus  seropositive human or human immunized with a  Staphylococcus  antigen or mimetic thereof. 
     
     
         4 . (canceled) 
     
     
         5 . The isolated monoclonal antibody of  claim 1 , wherein the cell is a human B-cell or a transgenic B-cell comprising a human antibody sequence. 
     
     
         6 . The isolated monoclonal antibody of  claim 5  wherein the transgenic B-cell is obtained from a transgenic animal comprising a human antibody sequence. 
     
     
         7 . The isolated monoclonal antibody of  claim 6  wherein the transgenic animal is a mouse that has been immunized with Gram positive bacteria, an antigen thereof, or mimetic thereof. 
     
     
         8 . The isolated monoclonal antibody of  claim 1 , wherein the antibody is a fully human antibody. 
     
     
         9 . An isolated human monoclonal antibody or fragment thereof that specifically binds to lipoteichoic acid (LTA) of Gram positive bacteria. 
     
     
         10 . (canceled) 
     
     
         11 . The isolated monoclonal antibody of  claim 1 , wherein the antibody specifically binds to LTA of Gram positive bacteria that are coagulase positive, coagulase negative, or both coagulase positive and coagulase negative Gram positive bacteria. 
     
     
         12 . The isolated monoclonal antibody of  claim 1 , wherein the antibody specifically binds to LTA of Gram positive bacteria that are  Staphylococcus epidermidis.    
     
     
         13 . The isolated monoclonal antibody of  claim 1 , wherein the antibody specifically binds to LTA of Gram positive bacteria that are  Staphylococcus epidermidis, Staphylococcus aureus , or both  Staphylococcus epidermidis  and  Staphylococcus aureus.    
     
     
         14 . The isolated monoclonal antibody of  claim 1 , wherein the antibody specifically binds to LTA of the Gram positive bacteria  Staphylococcus epidermidis  and  Staphylococcus aureus.    
     
     
         15 . The isolated monoclonal antibody of  claim 1 , wherein the antibody specifically binds to LTA of Gram positive bacteria that are multiple serotypes of  Staphylococcus epidermidis, Staphylococcus aureus , or both  Staphylococcus epidermidis  and  Staphylococcus aureus.    
     
     
         16 . The isolated monoclonal antibody of  claim 15 , wherein the multiple serotypes of  Staphylococcus aureus  are serotype 5, serotype 8, or both serotype 5 and serotype 8. 
     
     
         17 . The isolated monoclonal antibody of  claim 1 , wherein the antibody specifically binds to LTA of Gram positive bacteria that are  Staphylococcus epidermidis  and one or more Gram positive bacteria selected from the group consisting of  Staphylococcus aureus, Streptococcus mutans, Streptococcus faecalis , and  Streptococcus pyogenes.    
     
     
         18 . The isolated monoclonal antibody of  claim 1 , wherein the antibody recognizes the peptide sequence WRMYFSHRHAHLRSP (SEQ ID NO:23), the peptide sequence WHWRHRIPLQLAAGR (SEQ ID NO:24), a peptide sequence having substantial identity to the peptide sequence WRMYFSHRHAHLRSP (SEQ ID NO:23), a peptide sequence having substantial identity to the peptide sequence WHWRHRIPLQLAAGR (SEQ ID NO:24), or combination thereof. 
     
     
         19 . The isolated monoclonal antibody of  claim 1 , wherein the antibody recognizes LTA of Gram positive bacteria which are coagulase positive, or coagulase negative, or recognizes both coagulase positive and coagulase negative Gram positive bacteria. 
     
     
         20 . The isolated monoclonal antibody of  claim 1 , wherein the antibody recognizes Gram positive bacteria which are  Staphylococcus epidermis, Staphylococcus aureus, Streptococcus mutans, Streptococcus faecalis, Streptococcus pyogenes , or a combination thereof. 
     
     
         21 .- 28 . (canceled) 
     
     
         29 . The isolated antigen-binding antibody fragment of  claim 1 , wherein the fragment is a Fab, Fab′, F(ab′)2, SFv, light chain, heavy chain, or combination thereof. 
     
     
         30 . A polynucleotide encoding an antibody, or fragment thereof, of  claim 1 . 
     
     
         31 . A vector comprising the polynucleotide of  claim 30 . 
     
     
         32 . A cell comprising the vector of  claim 31 . 
     
     
         33 . An antibody, or antigen-binding fragment thereof, produced by the cell of  claim 32 . 
     
     
         34 . A composition comprising an isolated monoclonal antibody or antigen-binding fragment thereof, and a pharmaceutically acceptable carrier, wherein the antibody specifically binds to lipoteichoic acid (LTA) of Gram positive bacteria and comprises a portion of a human antibody sequence.