Demibodies: dimerization-activated therapeutic agents
The present invention relates generally to a set of synthetic immunointeractive molecules referred to herein as “demibodies” which are useful in targeting particular cells in a subject. More particularly, the present invention provides a set of demibodies wherein at least two molecules from within the set, each specific for a different antigen on a target cell, are required to interact together at the cell surface in order to form an active complex which directs demibody-mediated cellular or complement mediated cytotoxicity and/or reporter function and/or therapeutic activity. The demibodies of the present invention are useful in the targeting of particular cells such as cancer cells including leukemic cells, pathogens including malarial, bacterial and viral agents, and stem cells including embryonic and adult stem cells and pathogen cells. The present invention provides, therefore, methods of treatment, diagnosis and undertaking research and compositions comprising demibodies useful for same.
1. An isolated pair of demibodies comprising a first demibody and a second demibody, said first demibody comprising:
an antigen-binding portion of a first immunoglobulin that interacts with a first antigen on a target cell;
a first non-cytotoxic portion of an Fc domain; and
a first member of a complementary leucine zipper pair;
said second demibody comprising:
an antigen-binding portion of a second immunoglobulin that interacts with a second antigen on the target cell;
a second non-cytotoxic portion of an Fc domain; and
a second member of a complementary leucine zipper pair;
wherein the pair of demibodies is configured so that the first and second non-toxic portions of said first and second demibodies are only able to combine to generate a cytotoxic Fc domain after the first and second demibodies are bound to the first and second antigens on the target cell.
2. The pair of demibodies of claim 1 wherein the antigen-binding portions of the first and second immunoglobulins are single chain variable fragments (scFv).
3. The pair of demibodies of claim 1 wherein at least one of said antigen-binding portions of said first or second immunoglobulins is specific for a cluster of differentiation (CD) antigen.
4. The pair of demibodies of claim 1 , wherein said cytotoxic Fc domain mediates complement-dependent cytotoxicity (CDC) or antibody-dependent cellular cytotoxicity (ADCC).
5. The pair of demibodies of claim 1 , wherein said target cell is a cancer cell.