Depletion of il23r expressing cells in the treatment of various diseases

Abstract

The present invention relates, for example, to depletion of IL23R expressing cells in the treatment of disease and, in an embodiment thereof, to bispecific constructs that specifically bind to immune effector cells and, simultaneously, to IL23R-carrying target cells, as well as nucleic acids, vectors, host cells, pharmaceutical compositions, and methods of production and use thereof, including such bispecific constructs for use in, for example, treating inflammatory and/or autoimmune diseases and/or cancer.

1 . A method for the treatment of a disease selected from the group consisting of: an inflammatory disease, an autoimmune disease and/or cancer, comprising, in a human patient in need thereof, depleting IL23R expressing cells. 
     
     
         2 . The method of  claim 1 , wherein the patient is refractory to treatment via inhibition of IL-1β, IL-6, TGF-β, IL-23, IL-22, IL-17, IL-8, GM-CSF, G-CSF, IFN-γ and/or TNFα signaling. 
     
     
         3 . The method of  claim 1 , wherein said patient has an inflammatory disease and/or an autoimmune disease and is refractory to treatment via inhibition of effector cytokine signaling of IL23R expressing cells and/or cytokine signaling that drives differentiation of IL23R expressing cells. 
     
     
         4 . The method of  claim 1 , wherein the depleting comprises administering to the human patient in need thereof a bispecific construct comprising at least one first binding moiety and at least one second binding moiety, wherein said first binding moiety specifically binds to a first antigen present on a cytotoxic effector cell, and said second binding moiety specifically binds to an IL-23 receptor specific subunit (IL23R) present on the surface of a target cell, wherein said bispecific construct is administered in an effective amount for the treatment of the disease in the patient. 
     
     
         5 . The method of  claim 4 , wherein the cytotoxic effector cell is selected from the group consisting of: a cytotoxic effector T (Tc) cell and a cytotoxic natural killer (NK) cells. 
     
     
         6 . The method of  claim 4 , wherein said first binding moiety specifically binds to an antigen selected from CD3 and CD28. 
     
     
         7 . The method of  claim 4 , wherein said first binding moiety specifically binds to an agonistic epitope of CD3ε. 
     
     
         8 . The method of  claim 4 , wherein said first binding moiety and/or said second binding moiety comprises a heavy chain variable domain (V H ) or binding fragment thereof and a light chain variable domain (V L ) or binding fragment thereof. 
     
     
         9 . The method of  claim 4 , wherein the bispecific construct is in a format selected from the group consisting of a single-chain diabody (scDb), a tandem scDb (Tandab), a linear dimeric scDb (LD-scDb), a circular dimeric scDb (CD-scDb), a bispecific T-cell engager (BiTE; tandem di-scFv), a tandem tri-scFv, a tri(a)body, bispecific Fab 2 , di-miniantibody, tetrabody, scFv-Fc-scFv fusion, di-diabody, DVD-Ig, IgG-scFab, scFab-dsscFv, Fv2-Fc, IgG-scFv fusions, including bsAb, Bs1Ab, Bs2Ab, Bs3Ab, Ts1Ab, Ts2Ab, and Knob-into-Holes (KiHs) and DuoBodies. 
     
     
         10 . The method of  claim 1 , wherein the cancer is cancer metastasis. 
     
     
         11 . The method of  claim 1 , wherein the cancer is selected from the group consisting of colorectal cancer, lung cancer, breast cancer, melanoma, brain cancer, nasopharyngeal cancer, oral cancer, esophageal cancer, pancreatic cancer, kidney cancer, B-cell lymphomas, and T-cell lymphomas, including adult T-cell lymphoma leukemia (ATLL), acute myeloid lymphoma (AML), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), pediatric acute lymphoblastic lymphoma (B-ALL), angioimmunoblastic T-cell lymphoma (AITL), anaplastic large-cell lymphoma (ALCL), T-/natural killer-cell lymphomas, and peripheral T-cell lymphoma (PTCL). 
     
     
         12 . The method of  claim 1 , wherein the inflammatory and/or autoimmune disease is selected from the group consisting of: rheumatoid arthritis, ankylosing spondylitis, psoriasis, psoriatic arthritis, ulcerative colitis, irritable bowel disease, Crohn's disease, systemic lupus erythematosus, juvenile diabetes, autoimmune uveitis, multiple sclerosis, neuromyelitis optica/Devic's disease, Parkinson's disease, Alzheimer's disease, clinically isolated syndrome and ischemia-reperfusion injury. 
     
     
         13 . The method of  claim 1 , wherein the treatment is in an amount to effective to treat recurrence of the inflammatory and/or autoimmune disease. 
     
     
         14 . The method of  claim 3 , wherein the effector cytokines are IL-17, IL-22, GM-CSF, G-CSF, TNF and/or IFN-gamma. 
     
     
         15 . The method of  claim 3 , wherein the cytokines that drive differentiation are IL-1 beta, TGF-beta, IL23, IFN-gamma and/or IL-6. 
     
     
         16 . The method of  claim 7 , wherein the IL23R binding moiety VL is: 
       
         
           
                 
               
                   (SEQ ID NO: 3) 
                 
                   DIQMTQSPSSLSASVGDRVTITCQASENIYSFLAWYQQKPGKAPKLLIYS 
                 
                     
                 
                   ASKLAAGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQTNRYSNPDIY 
                 
                     
                 
                   NVFGQGTKLTVLG; 
                 
             
                
                
                
                
                
                
               
            
           
         
       
       and the IL23R binding moiety VH is: 
       
         
           
                 
               
                   (SEQ ID NO: 4) 
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGIDFNSNYYMCWVRQAPGKGLEWIG 
                 
                     
                 
                   CIYVGSHVNTYYANWAKGRFTISRDNSKNTVYLQMNSLRAEDTAVYYCAT 
                 
                     
                 
                   SGSSVLYFKFWGQGTLVTVSS. 
                 
             
                
                
                
                
                
                
               
            
           
         
       
     
     
         17 . The method of  claim 16 , wherein the CD3 binding moiety VL is: 
       
         
           
                 
               
                   (SEQ ID NO: 5) 
                 
                   DIQMTQSPSSLSASVGDRVTITCQSSESVYNNKRLSWYQQKPGKAPKLLI 
                 
                     
                 
                   YTASSLASGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQGEFTCSNAD 
                 
                     
                 
                   CFTFGQGTKLTVLG; 
                 
             
                
                
                
                
                
                
               
            
           
         
       
       and the CD3 binding moiety VH is: 
       
         
           
                 
               
                   (SEQ ID NO: 6) 
                 
                   EVQLVESGGGLVQPGGSLRLSCAASGFPLSSYAMIWVRQAPGKGLEWIGM 
                 
                     
                 
                   ILRAGNIYYASWVKGRFTISRDNSKNTVYLQMNSLRAEDTAVYYCARRHY 
                 
                     
                 
                   NREGYPIGIGDLWGQGTLVTVSS.