CD3 Bi-specific Platform

The concept of using T-cell retargeting against cancer stretches back to the 1970s. Unlike macrophages, dendritic cells, and other accessory cells, T-cells are present in copious numbers, expand rapidly upon activation, give robust and durable cytotoxic responses, attack tumors from the outside and infiltrate them, and have the potential to generate immunologic memory. These features make T-cells optimal therapeutic effectors for cancer.

First Generation T-cell Engagers: BiTEs

Bispecific T-cell engagers (BiTEs) are a new class of immunotherapy drugs designed to target cancer. BiTes are constructed of two single chain variable fragments (scFv) connected by a flexible linker. This configuration allows the BiTE to physically bridge two cells, by binding one scFv to an antigen on one cell and another scFv to an antigen on a different cell. Typically, the BiTE will bind to CD3 on the T-cell and to a tumor-associated antigen on the tumor cell. Binding to CD3 will bypass the requirement of a second stimulatory signal required for full T-cell activation, resulting in tumor killing and cytokine production. Despite its therapeutic potential, current BiTEs have two limitations. First, they have a narrow therapeutic window due to low-affinity binding to tumor antigen and antigen-independent T-cell activation. Second, they have poor pharmacokinetics (PK) due to the lack of an Fc domain.

Immunowake: CD3 Bi-specific Antibody

Similar to BiTEs, our CD3 bi-specific antibodies bind to both CD3 and tumor-associated antigens to redirect T-cells to target tumor cells. However, our CD3 bi-specific antibodies can overcome limitations of current BiTEs through two strategies. First, our CD3 antibody has a unique characteristic: it has low affinity to CD3 but retains the ability to activate T-cells. When this CD3 antibody is incorporated into our bi-specific platform, our bi-specific antibodies can activate T-cells in an antigen-dependent manner. In the presence of tumor cells, low concentrations (pg/ml) of our bi-specific antibody was found to efficiently facilitate T-cell killing against cancer cells. Conversely, in the absence of tumor cells, high concentrations of our bi-specific antibody (1ug /ml) were unable to activate T-cells. Our data suggests that antigen binding is required for biological activity of the bi-specific CD3 antibody. Second, our CD3 bi-specific antibody retains the integral IgG structure, containing two Fabs and a FcRn. This design targets tumor cells in the bivalent manner, which has increased binding affinity relative to monovalent binding in BiTEs. Furthermore, inclusion of the integral Fc domain allows our bi-specific antibody to retain similar PKs to the traditional monoclonal antibodies.