Universal chimeric antigen expressing immune cells for targeting of diverse multiple antigens and method of manufacturing the same and use of the same for treatment of cancer, infections and autoimmune disorders

Abstract

The present invention relates to immune cell-based anti-cancer therapeutics and methods of using the therapeutics in the treatment of cancer.

1 . A nucleic acid encoding a universal chimeric antigen receptor, wherein the receptor comprises three domains, wherein
 the first domain is a tag-binding domain,   the second domain is an extracellular hinge and a transmembrane domain and   the third domain is a signal transduction domain,   wherein the tag-binding domain binds to a tag derived from any human nuclear protein.   
     
     
         2 . The nucleic acid according to  claim 1 , wherein the tag is a short linear epitope from the human nuclear La protein (E5B9) according to SEQ ID NO:14. 
     
     
         3 . The nucleic acid according to  claim 1 , wherein the tag-binding domain is an antibody or an antigen-binding fragment thereof, whereas the tag-binding domain constitutes an anti-La epitope scFv, preferably an anti-La epitope scFv according to SEQ ID NO:3 and SEQ ID NO:4. 
     
     
         4 . The nucleic acid according to  claim 1 , wherein the hinge and transmembrane region is selected from hinge and transmembrane regions of human CD28 molecule, CD8a chain, NK cell receptors, preferably natural killer group NKG2D, or parts of the constant region of an antibody as well as combinations of different hinge and transmembrane domains thereof. 
     
     
         5 . The nucleic acid according to  claim 1 , wherein the signal transduction domain is selected from cytoplasmic regions of CD28, CD137 (41 BB), CD134 (OX40), DAP10 and CD27, programmed cell death-1 (PD-1), cytotoxic T-lymphocyte antigen 4 (CTLA-4) and cytoplasmic regions CD3 chains, DAP12 and T cell activation inducing Fc receptors. 
     
     
         6 . The nucleic acid according to  claim 1 , wherein the receptor comprises a fourth domain which is a short peptide linker in the extracellular portion of the receptor. 
     
     
         7 . The nucleic acid according to  claim 1 , wherein said nucleic acid has a nucleotide sequence of SEQ ID NO:1. 
     
     
         8 . A target module composed of a binding moiety specific for a certain human cell surface protein or protein complex and a tag, wherein the tag is derived from any human nuclear protein, preferably from human nuclear La protein. 
     
     
         9 . The target module according to  claim 8 , wherein binding moiety of target modules include antibodies or fragments thereof that binds to surface antigens CD2, CD3, CD4, CD8, CD10, CD19, CD20, CD22, CD23, CD33, CD38, CD44, CD52, CD99, CD123, CD274, TIM-3, members of the epidermal growth factor receptor family and mutants thereof, members of the ephrin receptor family, prostate specific antigens PSCA or PSMA, embryonic antigens, members of the vascular endothelia growth factor family, epithelia cell adhesion molecule EpCAM, alphafetoprotein AFP, members of the mucin protein family, follicle stimulating hormone receptor, human high molecular weight- melanoma-associated antigen, folate binding protein FBP, a-Folate receptor, ligands of the NKG2D receptor, members of the epithelia glycoprotein family, diasialogangliosides, members of the carbonic anhydrase family, members of the carbohydrate antigen family, members of the Rho family of GTPases, members of the high mobility group proteins and mutants thereof and wherein binding moiety of target modules is composed of the alpha and beta or the gamma and delta chains of a T cell receptor or fragments thereof, including auto-reactive T cell receptor-derived receptors, wherein such T cell receptor-derived binding moieties recognize and bind to peptides presented by human leukocyte antigen class I and II protein complexes. 
     
     
         10 . The target module according to  claim 8 , wherein the binding moiety of target modules comprise ligands to proteins and protein complexes, which bind to, cytokine receptors, ligands of the NKG2D receptor or ligands to the EGFR family members. 
     
     
         11 . The target module according to  claim 8 , wherein the binding moiety of target modules comprise bi- and multispecific antigen specificities include binding to PSCA and PSMA antigen, CD19 and CD20 antigen, CD19, CD20, and CD22 antigen, CD33 and CD123 antigen, CD33 and CD99, CD33 and TIM-3, erb-1 and -2, PSCA and erb-2. 
     
     
         12 . The target module according to  claim 8 , wherein binding moiety of target modules include antibodies or fragments thereof that binds to the La/SSB antigen, preferably according to SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31 and SEQ ID NO:32. 
     
     
         13 . A nucleic acid encoding a target module according to  claim 8 , wherein said nucleic acid has a sequence selected from the group consisting of SEQ ID NO:10, SEQ ID NO:17, SEQ ID NO:20, SEQ ID NO:23 and SEQ ID NO:26. 
     
     
         14 . A cell or vector comprising a nucleic acid according to  claim 1 . 
     
     
         15 . The cell according to  claim 14 , wherein the cell is selected from the group of immune cells including T cell, a Natural Killer cell, a cytotoxic T lymphocyte, and a regulatory T cell. 
     
     
         16 . A kit comprising:
 a vector according to  claim 14  and   a target module composed of a binding moiety specific for a certain human cell surface protein or protein complex and a tag, wherein the tag is derived from any human nuclear protein, preferably from human nuclear La protein and/or a vector encoding a nucleic acid having a sequence selected from the group consisting of SEQ ID NO:10, SEQ ID NO:17, SEQ ID NO:20, SEQ ID NO:23, and SEQ ID NO:26.   
     
     
         17 . A formulation comprising UniCAR expressing immune cells according to  claim 14  and/or a target module for administration to a subject, said target module being composed of a binding moiety specific for a certain human cell surface protein or protein complex and a tag, wherein the tag is derived from any human nuclear protein, preferably from human nuclear La protein. 
     
     
         18 . Use of a cell according to  claim 14  and a target module for stimulating an universal chimeric antigen receptor mediated immune response in a mammal, wherein said target module is composed of a binding moiety specific for a certain human cell surface protein or protein complex and a tag, wherein the tag is derived from any human nuclear protein, preferably from human nuclear La protein.