Bispecific Constructs and Their Use in the Treatment of Various Diseases

Abstract

The present invention relates 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 treating inflammatory and/or autoimmune diseases and/or cancer.

1 . A method of treatment of an inflammatory and/or autoimmune disease or cancer comprising IL23R-expressing cells, comprising administering to a subject an effective amount of 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 T (Tc) cell, wherein said first antigen is CD3, and said second binding moiety specifically binds to the IL23R present on the surface of the IL23R-expressing cells, and wherein said first binding moiety and said second binding moiety are antibody-based binding moieties. 
     
     
         2 . The method according to  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, Crohn's disease, systemic lupus erythematosus, juvenile diabetes, autoimmune uveitis, and multiple sclerosis, Parkinson's disease, Alzheimer's disease, and ischemia-reperfusion injury. 
     
     
         3 . The method according to  claim 1 , wherein the cancer is selected from the group consisting of colorectal cancer, lung cancer, breast cancer, nasopharyngeal cancer, oral cancer, esophageal cancer, pancreatic 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). 
     
     
         4 . The method of  claim 1 , wherein the subject is a human patient. 
     
     
         5 . The method of  claim 1 , wherein the subject is a human patient, which has a high Th17 response. 
     
     
         6 . The method of  claim 1 , wherein said first binding moiety specifically binds to the epsilon chain of CD3 (CD3ε). 
     
     
         7 . The method of  claim 1 , wherein the construct allows for efficient killing of said IL23R-expressing cells by the Tc cell. 
     
     
         8 . The method of  claim 1 , wherein said Tc cell is a stimulated or an unstimulated Tc cell. 
     
     
         9 . The method of  claim 1 , wherein said first and second binding moieties are arranged relative to each other in such a manner that the part of the first binding moiety recognizing CD3ε and the part of the second binding moiety recognizing IL23R project, relative to the center of the bispecific construct, outward in essentially opposite directions. 
     
     
         10 . The method of  claim 1 , wherein said bispecific construct is in an antibody 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. 
     
     
         11 . The method of  claim 10 , wherein said bispecific construct is a single-chain diabody (scDb). 
     
     
         12 . The method of  claim 11 , wherein the bispecific scDb comprises two variable heavy chain domains (V H ) or fragments thereof and two variable light chain domains (V L ) or fragments thereof connected by linkers L1, L2 and L3 in the order V H A-L1-V S B-L2-V H B-L3-V L A, V H A-L1-V H B-L2-V S B-L3-V L A, V L A-L1-V S B-L2-V H B-L3-V H A, V L A-L1-V H B-L2-V S B-L3-V H A, V H B-L1-V L A-L2-V H A-L3-V S B, V H B-L1-V H A-L2-V L A-L3-V S B, V S B-L1-V L A-L2-V H A-L3-V H B or V S B-L1-V H A-L2-V L A-L3-V H B, wherein the V L A and V H A domains jointly form the antigen binding site for CD3ε, and V S B and V H B jointly form the antigen binding site for IL23R. 
     
     
         13 . The method of  claim 1 , wherein the bispecific construct is SEQ ID NO: 7, or a functionally active variant of the construct according to SEQ ID NO: 7.