T-Cell Redirecting Bispecific Antibodies for Treatment of Disease
The present invention concerns compositions and methods of use of T-cell redirecting complexes, with at least one binding site for a T-cell antigen and at least one binding site for an antigen on a diseased cell or pathogen. Preferably, the complex is a DNL™ complex. More preferably, the complex comprises a bispecific antibody (bsAb). Most preferably, the bsAb is an anti-CD3×anti-CD19 bispecific antibody, although antibodies against other T-cell antigens and/or disease-associated antigens may be used. The complex is capable of targeting effector T cells to induce T-cell-mediated cytotoxicity of cells associated with a disease, such as cancer, autoimmune disease or infectious disease. The the cytotoxic immune response is enhanced by co-administration of interfon-based agents that comprise interferon-α, interferon-β, interferon-λ1, interferon-λ2 or interferon-λ3.
1 . A method of inducing a T-cell mediated cytotoxic immune response against a MUC5ac positive human cancer cell comprising:
a) administering a T-cell redirecting complex, comprising at least one binding site for human CD3 and at least one binding site for human MUC5ac, to a subject to induce a T-cell mediated immune response against the MUC5ac positive human cancer cell and wherein the T-cell redirecting complex comprises (i) a first antibody moiety conjugated to an AD (anchoring domain) moiety from an AKAP protein; and (ii) a second antibody moiety conjugated to a DDD (dimerization and docking domain) moiety, wherein the amino acid sequence of said DDD moiety is residues 1-44 of human protein kinase A (PKA) RIIα wherein two copies of the DDD moiety form a dimer that binds to one copy of the AD moiety to form the complex.
2 . The method of claim 1 , further comprising administering interferon-a to the subject.
3 . The method of claim 2 , wherein the interferon is administered before, simultaneously with, or after the T-cell redirecting complex.
4 . The method of claim 2 , wherein the interferon is administered as free interferon, PEGylated interferon, an interferon fusion protein or interferon conjugated to an antibody.
5 . The method of claim 1 , wherein the T-cell redirecting complex is a bispecific antibody comprising a first antibody moiety that binds to CD3 and a second antibody moiety that binds to MUC5ac.
6 . The method of claim 5 , wherein the first and second antibody moieties are selected from the group consisting of an scFv, a Fab and a dAb.
7 . The method of claim 5 , wherein the second antibody moiety is hPAM4.
8 . The method of claim 1 , wherein the T-cell redirecting complex is administered intravenously.
9 . The method of claim 1 , wherein the T-cell redirecting complex is administered subcutaneously.