Novel t cell receptors and immune therapy using the same

Abstract

The present invention relates to antigen recognizing constructs against a tumor associated antigen (TAA) derived from the target protein DDB1 and CUL4 associated factor 4-like 2 (DCAF4L2). The invention in particular provides novel T cell receptor (TCR) based molecules which are selective and specific for the TAA of the invention. The TCR of the invention, and TAA binding fragments derived therefrom, are of use for the diagnosis, treatment and prevention of TAA expressing cancerous diseases. Further provided are nucleic acids encoding the antigen recognizing constructs of the invention, vectors comprising these nucleic acids, recombinant cells expressing the antigen recognizing constructs and pharmaceutical compositions comprising the compounds of the invention.

1 . A soluble antigen recognizing construct, comprising SEQ ID NO: 25, SEQ ID NO: 27, SEQ ID NO: 31, and SEQ ID NO: 33,
 wherein each of SEQ ID NO: 25, SEQ ID NO: 27, SEQ ID NO: 31, and SEQ ID NO: 33 comprises at most one conservative amino acid substitution.   
     
     
         2 . The soluble antigen recognizing construct of  claim 1 , wherein the soluble antigen recognizing construct binds to a peptide of SEQ ID NO: 49 in a complex with an MHC class I molecule. 
     
     
         3 . The soluble antigen recognizing construct of  claim 1 , wherein the soluble antigen recognizing construct does not selectively bind any of similar DCAF4L2-001 peptides set forth in SEQ ID NO: 59 to 68. 
     
     
         4 . The soluble antigen recognizing construct of  claim 1 , further comprising SEQ ID NO: 26 and SEQ ID NO: 32. 
     
     
         5 . The soluble antigen recognizing construct of  claim 1 , wherein the soluble antigen recognizing construct comprises
 a CDR1α chain comprising SEQ ID NO: 25,   a CDR2α chain comprising SEQ ID NO: 26,   a CDR3α chain comprising SEQ ID NO: 27,   a CDR1β chain comprising SEQ ID NO: 31,   a CDR2β chain comprising SEQ ID NO: 32, and   a CDR3β chain comprising SEQ ID NO: 33,   wherein each of SEQ ID NOs: 25 and 31 comprise at most one conservative amino acid substitution.   
     
     
         6 . The soluble antigen recognizing construct of  claim 1 , wherein the soluble antigen recognizing construct comprises
 a CDR1α chain comprising SEQ ID NO: 25,   a CDR2α chain comprising SEQ ID NO: 26,   a CDR3α chain comprising SEQ ID NO: 27,   a CDR1β chain comprising SEQ ID NO: 31,   a CDR2β chain comprising SEQ ID NO: 32, and   a CDR3β chain comprising SEQ ID NO: 33,   wherein each of SEQ ID NOs: 26 and 32 comprise at most one conservative amino acid substitution.   
     
     
         7 . The soluble antigen recognizing construct of  claim 1 , wherein the soluble antigen recognizing construct comprises
 a CDR1α chain comprising SEQ ID NO: 25,   a CDR2α chain comprising SEQ ID NO: 26,   a CDR3α chain comprising SEQ ID NO: 27,   a CDR1β chain comprising SEQ ID NO: 31,   a CDR2β chain comprising SEQ ID NO: 32, and   a CDR3β chain comprising SEQ ID NO: 33,   wherein each of SEQ ID NOs: 27 and 33 comprises at most one conservative amino acid substitution.   
     
     
         8 . The soluble antigen recognizing construct of  claim 1 , wherein the soluble antigen recognizing construct comprises
 a CDR1α chain consisting of SEQ ID NO: 25,   a CDR2α chain consisting of SEQ ID NO: 26,   a CDR3α chain comprising SEQ ID NO: 27,   a CDR1β chain consisting of SEQ ID NO: 31,   a CDR2β chain consisting of SEQ ID NO: 32, and   a CDR3β chain comprising SEQ ID NO: 33.   
     
     
         9 . The soluble antigen recognizing construct of  claim 1 , wherein the soluble antigen recognizing construct comprises
 a CDR1α chain comprising SEQ ID NO: 25,   a CDR2α chain consisting of SEQ ID NO: 26,   a CDR3α chain comprising SEQ ID NO: 27,   a CDR1β chain comprising SEQ ID NO: 31,   a CDR2β chain consisting of SEQ ID NO: 32, and   a CDR3β chain comprising SEQ ID NO: 33.   
     
     
         10 . The soluble antigen recognizing construct of  claim 1 , wherein the soluble antigen recognizing construct comprises
 a CDR1α chain consisting of SEQ ID NO: 25,   a CDR2α chain comprising SEQ ID NO: 26,   a CDR3α chain consisting of SEQ ID NO: 27,   a CDR1β chain consisting of SEQ ID NO: 31,   a CDR2β chain comprising SEQ ID NO: 32, and   a CDR3β chain consisting of SEQ ID NO: 33.   
     
     
         11 . The soluble antigen recognizing construct of  claim 1 , wherein the soluble antigen recognizing construct comprises
 a CDR1α chain comprising SEQ ID NO: 25,   a CDR2α chain comprising SEQ ID NO: 26,   a CDR3α chain consisting of SEQ ID NO: 27,   a CDR1β chain comprising SEQ ID NO: 31,   a CDR2β chain comprising SEQ ID NO: 32, and   a CDR3β chain consisting of SEQ ID NO: 33.   
     
     
         12 . The soluble antigen recognizing construct of  claim 1 , wherein the soluble antigen recognizing construct comprises
 a CDR1α chain consisting of SEQ ID NO: 25,   a CDR2α chain consisting of SEQ ID NO: 26,   a CDR3α chain consisting of SEQ ID NO: 27,   a CDR1β chain consisting of SEQ ID NO: 31,   a CDR2β chain consisting of SEQ ID NO: 32, and   a CDR3β chain consisting of SEQ ID NO: 33.   
     
     
         13 . The soluble antigen recognizing construct of  claim 1 , wherein the soluble antigen recognizing construct is an antibody or derivative or fragment thereof, or an αβ-T cell receptor (TCR) or a derivative or fragment thereof, or a γδ TCR or a derivative or fragment thereof. 
     
     
         14 . The soluble antigen recognizing construct of  claim 12 , wherein the antibody is a bispecific antibody. 
     
     
         15 . The soluble antigen recognizing construct of  claim 1 , comprising a TCR variable chain region having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 28 or SEQ ID NO: 34. 
     
     
         16 . The soluble antigen recognizing construct of  claim 1 , comprising a TCR variable chain region comprising the amino acid sequence of SEQ ID NO: 28 or SEQ ID NO: 34. 
     
     
         17 . A nucleic acid encoding the soluble antigen recognizing construct of  claim 1 . 
     
     
         18 . An expression vector comprising the nucleic acid of  claim 17  operably linked to at least one promoter sequence. 
     
     
         19 . A host cell transformed with the expression vector of  claim 18 . 
     
     
         20 . A pharmaceutical composition comprising the soluble antigen recognizing construct of  claim 1 .