Abstract: This invention discloses a bifunctional TGF-B/immune checkpoint fusion gene and protein with anti-inflammatory activity that represents a new class of therapy for Immune disorders, immune dysregulation, and autoimmune diseases. The bifunctional TGF-B/immune checkpoint fusion gene and protein include: (i) a TGF-B domain consists of TGF-B1 (ii) an immune checkpoint consisting of PD-L1, (iii) a flexible peptide linker that links two TGF-B domains resulting in a dimeric TGF-B construct wherein the dimeric form of the TGF-B ligand is important for its binding and functional activity, and (iv) a rigid peptide linker, wherein the dimeric TGF-B ligand is linked to the immune checkpoint ligand. A unique feature of this invention is the engineering of a dimeric TGF-B1 domain in the TGF-B1/PD-L1 fusion protein which was experimentally shown to be important in its binding to its TFGBR1 receptor and its functional activity.

Abstract: This invention discloses a bifunctional TGF-B/immune checkpoint fusion gene and protein with anti-inflammatory activity that represents a new class of therapy for Immune disorders, immune dysregulation, and autoimmune diseases. The bifunctional TGF-B/immune checkpoint fusion gene and protein include: (i) a TGF-B domain is selected from the group consisting of TGF-B1, TGF-B2, and TGF-B3, (ii) an immune checkpoint domain selected from the group of immune checkpoints consisting of PD-L1, PD-L2, and CTLA-4, (iii) a flexible peptide linker that links two TGF-B domains resulting in a dimeric TGF-B construct wherein the dimeric form of the TGF-B ligand is important for its binding and functional activity, and (iv) a rigid peptide linker, wherein the dimeric TGF-B ligand is linked to the immune checkpoint ligand. The functional domains of the fusion protein act in concert to maintain tolerance for self-antigens by stimulating regulatory cells and to regulate the activities of effector cells, respectively.