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 cytotoxic immune response is enhanced by co-administration of interferon-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 Trop-2 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 Trop-2, to a subject to induce a T-cell mediated immune response against the Trop-2 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 after “human cancer cell”.
2. The method of claim 1 , further comprising administering interferon-α to the subject.
3. The method of claim 2 , wherein the combination of interferon and T-cell redirecting complex is more effective than interferon alone and T-cell redirecting complex alone.
4. The method of claim 2 , wherein the interferon is administered before, simultaneously with, or after the T-cell redirecting complex.
5. 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.
6. 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 Trop-2.
7. The method of claim 6 , wherein the first and second antibody moieties are selected from the group consisting of an scFv, a Fab and a dAb.
8. The method of claim 6 , wherein the second antibody moiety is hRS7.
9. The method of claim 1 , wherein the T-cell redirecting complex is administered intravenously.
10. The method of claim 1 , wherein the T-cell redirecting complex is administered subcutaneously.