Hla-restricted, peptide-specific binding proteins

Abstract

Antigen binding proteins with TCR-like paratopes, that is, with an antigen binding region specific for an HLA-A2 restricted peptide are disclosed. The antigen binding proteins encompass antibodies in a variety of forms, including full-length antibodies, substantially intact antibodies, Fab fragments, F(ab′)2 fragments, and single chain Fv fragments. Fusion proteins, such as scFv fusions with immunoglobulin or T-cell receptor domains, incorporating the specificity of the antigen binding region for each peptide are also contemplated by the invention. Furthermore, immunoconjugates may include antibodies to which is linked a radioisotope, fluorescent or other detectable marker, cytotoxin, or other molecule are also encompassed by the invention. Among other things, immunoconjugates can be used for delivery of an agent to elicit a therapeutic effect or to facilitate an immune effector function.

1 . (canceled) 
     
     
         2 . The isolated antigen-binding protein of  claim 6 , wherein the isolated antigen-binding protein is an antibody. 
     
     
         3 . The isolated antigen-binding protein of  claim 6 , wherein the antigen-binding protein is a chimeric antigen receptor (CAR). 
     
     
         4 . The isolated antigen-binding protein of  claim 2 , wherein the antibody is a full-length antibody, a substantially intact antibody, a Fab fragment, a F(ab′) 2  fragment or a single chain variable fragment (scFv). 
     
     
         5 . The isolated antigen-binding protein of  claim 6 , wherein the antigen-binding protein specifically binds to an epitope on an HLA/peptide complex. 
     
     
         6 . The isolated antigen-binding protein of  claim 5 , comprising one of:
 (A) an antigen binding region having the amino acid sequence of SEQ ID NO: 2;   (B) an antigen binding region comprising a V H  and a V L  respectively, with the amino acid sequences SEQ ID NOs: 22 and 23; or   (C))(i)
 (a) a light chain(LC) complementarity determining region 1 (CDR1) comprising the amino acid sequence of SEQ ID NO: 56; 
 (b) a LC CDR2 comprising the amino acid sequence of SEQ ID NO: 57; and 
 (c) a LC CDR3 comprising the amino acid sequence of SEQ ID NO: 64; and 
 (ii) 
 (a) a heavy chain (HC) complementarity determining region 1 (CDR1) comprising the amino acid sequence of SEQ ID NO: 38; 
 (b) a HC CDR2 comprising the amino acid sequence of SEQ ID NO: 40; and 
 (c) a HC CDR3 comprising the amino acid sequence of SEQ ID NO: 48. 
   
     
     
         7 . The isolated antigen-binding protein of  claim 6 , wherein the peptide of the HLA /peptide complex has the amino acid sequence RMFPNAPYL (SEQ ID NO:1). 
     
     
         8 .- 18 . (canceled) 
     
     
         19 . The isolated antigen-binding protein of  claim 6 , wherein the HLA of the HLA/peptide complex is HLA-A2. 
     
     
         20 . A fusion protein comprising an antigen-binding protein of  claim 6 . 
     
     
         21 . An isolated single-chain variable fragment (scFv) comprising one of the amino acid sequences set forth in SEQ ID NOS: 2. 
     
     
         22 . An isolated scFv comprising a V H  and a V L  linked by an amino acid spacer, wherein the V H  and V L  respectively comprise the amino acid sequences set forth in SEQ ID NOS: (i) 22 and 23. 
     
     
         23 . An immunoconjugate comprising a first component which is an antigen-binding protein or fragment thereof of  claim 6 . 
     
     
         24 . The immunoconjugate of  claim 23 , comprising a second component having a second amino acid sequence. 
     
     
         25 . The immunoconjugate according to  claim 24 , further comprising a cytotoxin. 
     
     
         26 . The immunoconjugate of  claim 24 , wherein the second component is a binding protein or antibody having a binding specificity for a target that is different from the HLA-peptide complex. 
     
     
         27 . A bispecific antibody comprising an antigen-binding protein of  claim 6 . 
     
     
         28 . A pharmaceutical composition comprising a compound of  claim 6 .