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 interfon-based agents that comprise interferon-α, interferon-β, interferon-λ1, interferon-λ2 or interferon-λ3.
1. A complex comprising:
a) a first antibody or antigen-binding fragment thereof conjugated to an AD (anchoring domain) moiety from an AKAP protein, wherein the first antibody or fragment thereof binds to human CD3, wherein amino acid sequence of the first antibody or fragment thereof conjugated to an AD moiety comprises the amino acid sequences of SEQ ID NO:96, SEQ ID NO:97, SEQ ID NO:98, SEQ ID NO:99, SEQ ID NO:100 and SEQ ID NO:101; and
b) a second antibody or antigen-binding fragment 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 the second antibody or fragment thereof binds to human MUC5ac and is an hPAM4 antibody;
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 complex of claim 1 , wherein the first antigen-binding antibody fragment is a scFv.
3. The complex of claim 1 , wherein the second antibody is an IgG antibody.
4. An antibody fragment comprising the amino acid sequence of SEQ ID NO:98.
5. An anti-CD3 antibody fragment comprising the amino acid sequences of SEQ ID NO:96, SEQ ID NO:97, SEQ ID NO:98, SEQ ID NO:99, SEQ ID NO:100 and SEQ ID NO:101.
6. A bispecific antibody comprising an anti-CD3 antibody fragment according to claim 5 .