Constructs targeting afp peptide/mhc complexes and uses thereof

Abstract

The present application provides constructs comprising an antibody moiety that specifically binds to a complex comprising an AFP peptide and an MHC class I protein. Also provided are methods of making and using these constructs.

1 - 34 . (canceled) 
     
     
         35 : A method of directing effector cells to kill a target cell expressing a complex comprising an alpha-fetoprotein (AFP) peptide and a major histocompatibility (MHC) class I protein (an AFP/MHC class I complex, or AMC) in an individual, comprising administering to the individual an effective amount of an effector cell comprising an anti-AMC construct comprising an extracellular domain comprising an anti-AMC antibody moiety that specifically binds to the AFP/MHC class I complex, wherein the AFP peptide has the amino acid sequence of SEQ ID NO: 4. 
     
     
         36 : The method of  claim 35 , wherein the MHC class I protein is HLA-A02. 
     
     
         37 : The method of  claim 36 , wherein the MHC class I protein is the HLA-A*02:01 subtype of the HLA-A02 allele. 
     
     
         38 : The method of  claim 35 , wherein the anti-AMC construct binds to the AFP/MHC class I complex with a K d  from about 0.1 pM to about 500 nM. 
     
     
         39 : The method of  claim 35 , wherein the anti-AMC antibody moiety in monovalent scFv format binds to the AFP/MHC class I complex with a Kd from about 10 to about 500 nM. 
     
     
         40 : The method of  claim 35 , wherein the anti-AMC construct is a chimeric antigen receptor (CAR) comprising an extracellular domain comprising the antibody moiety, a transmembrane domain, and an intracellular signaling domain capable of activating the effector cell. 
     
     
         41 : The method of  claim 40 , wherein the intracellular signaling domain comprises a CD3ζ intracellular signaling sequence and a CD28 intracellular signaling sequence. 
     
     
         42 : The method of  claim 35 , wherein the effector cell is a T cell. 
     
     
         43 : A method of treating an AFP-positive cancer in an individual, comprising subjecting the individual to the method of  claim 35 . 
     
     
         44 : The method of  claim 43 , wherein the AFP-positive cancer is hepatocellular carcinoma, germ cell tumor, or breast cancer. 
     
     
         45 : The method of  claim 35 , wherein the effector cell is via intravenous route or intratumoral route. 
     
     
         46 : The method of  claim 43 , wherein the cancer is hepatocellular carcinoma. 
     
     
         47 : The method of  claim 43 , wherein the AFP-positive disease is hepatocellular carcinoma and metastasis is inhibited. 
     
     
         48 : A method of directing effector T cells to kill a target cell expressing an AFP/MHC class I complex in an individual, comprising administering to the individual an effective amount of a multi-specific anti-AMC construct comprising: a) an anti-AMC antibody moiety that specifically binds to the AFP/MHC class I complex, wherein the AFP peptide has the amino acid sequence of SEQ ID NO: 4, and b) a second binding moiety that specifically binds to an effector T cell. 
     
     
         49 : The method of  claim 48 , wherein the second binding moiety specifically binds to CD3ε. 
     
     
         50 : The method of  claim 49 , wherein the anti-AMC construct is a tandem scFv comprising an N-terminal scFv specific for the AFP/MHC class I complex and a C-terminal scFv specific for CD3ε. 
     
     
         51 : The method of  claim 48 , wherein the anti-AMC construct binds to the AFP/MHC class I complex with a K d  from about 0.1 pM to about 500 nM. 
     
     
         52 : The method of  claim 48 , wherein the anti-AMC antibody moiety in monovalent scFv format binds to the AFP/MHC class I complex with a Kd from about 10 to about 500 nM. 
     
     
         53 : The method of  claim 48 , wherein the MEW class I protein is HLA-A02. 
     
     
         54 : The method of  claim 50 , wherein the method treats an AFP-positive cancer in the individual.