CD3 and IL-23 receptor binding bispecific constructs and their use in the treatment of various diseases
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 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 IL-23 receptor specific subunit (IL23R) present on the surface of a target cell,
wherein said bispecific construct is an antibody format selected from the group of a bispecific T-cell engager (BiTE; tandem di-scFv), a tandem tri-scFv, a tri(a)body, a single-chain diabody (scDb), a tandem scDb (Tandab), a linear dimeric scDb (LD-scDb) and a circular dimeric scDb (CD-scDb) and 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 L B-L2-V H B-L3-V L A, V H A-L1-V H B-L2-V L B-L3-V L A, V L A-L1-V L B-L2-V H B-L3-V H A, V L A-L1-V H B-L2-V L B-L3-V H A, V H B-L1-V L A-L2-V H A-L3-V L B, V H B-L1-V H A-L2-V L A-L3-V L B, V L B-L1-V L A-L2-V H A-L3-V H B or V L 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 the first antigen, and V L B and V H B jointly form the antigen binding site for IL23R.
2. The bispecific construct of claim 1 , wherein said first binding moiety specifically binds to the epsilon chain of CD3 (CD3ε).
3. The bispecific construct of claim 1 , wherein the construct allows for efficient killing of said target cell by the Tc cell, wherein said Tc cell is a stimulated or an unstimulated Tc cell.
4. The bispecific construct 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 the first antigen and the part of the second binding moiety recognizing IL23R project, relative to the center of the bispecific construct, outward in essentially opposite directions.
5. The bispecific construct of claim 1 , wherein the bispecific construct is PRO165 (SEQ ID NO: 7), or a functionally active variant of PRO165.
6. A method for producing the bispecific construct according to claim 1 , comprising (i) providing a nucleic acid or nucleic acids encoding the bispecific construct according to claim 1 or a vector or vectors comprising said nucleic acid or nucleic acids, expressing said nucleic acid or nucleic acids or said vector or vectors and collecting said bispecific construct from the expression system, or (ii) providing a host cell or host cells comprising said vector or vectors, culturing said host cell or said host cells; and collecting said bispecific construct from the cell culture.
7. A pharmaceutical composition comprising the bispecific construct according to claim 1 and a pharmaceutically acceptable carrier.
8. The bispecific construct according to claim 1 for use in the treatment of an inflammatory and/or autoimmune disease.
9. The bispecific construct of claim 1 , wherein said target cell is a pathogenic cell.
10. The bispecific construct of claim 9 , wherein the pathogenic cell is a cell selected from the group of an IL-17 producing T cell (Th17 cell), a γδ T cell, a natural killer T (NKT) cell, an invariant natural killer (iNK) cell and an IL23R expressing tumor cell.
11. The bispecific construct of claim 10 , wherein the pathogenic cell is a Th17 cell, a γδ T cell or an IL23R expressing tumor cell.
12. The bispecific construct of claim 1 , wherein said first binding moiety specifically binds to an agonistic epitope of (CD3ε).
13. The bispecific construct of claim 1 , wherein the bispecific construct is a bispecific monomeric scDb.
14. The bispecific construct of claim 1 , wherein linker L1 is a peptide of 2-10 amino acids.
15. The bispecific construct of claim 1 , wherein linker L3 is a peptide of 1-10 amino acids.
16. The bispecific construct of claim 1 , wherein linker L2 is a peptide of 10-40 amino acids.
17. The bispecific construct of claim 8 , for use in treatment of a human patient.
18. The bispecific construct of claim 8 , wherein the inflammatory and/or autoimmune disease is selected from the group of rheumatoid arthritis, ankylosing spondylitis, psoriasis, psoriatic arthritis, ulcerative colitis, Crohn's disease, systemic lupus erythematosus, juvenile diabetes, autoimmune uveitis, multiple sclerosis, Parkinson's disease, Alzheimer's disease, and ischemia-reperfusion injury.