Design and Assembly
SMIPs are single-chain polypeptides containing three basic units—a binding domain, hinge domain, and an effector domain. Trubion maintains combinatorial libraries from which desired features are selected for each of the three modular units. Each SMIP therapeutic is designed to meet predetermined specifications for binding and biological activity based on an assessment of a validated target for a proposed indication. The modular design allows the process to be “carried out with significant time and capital efficiency,” notes Dr. Thompson.
SMIPs are assembled through combinatorial chemistry by first combining a hinge domain and effector domain that will produce a specific biological action such as killing the immune system cell that carries the target antigen. Cell killing takes place through the induction of complement dependent cytotoxicity (CDC), or promotion of antibody-dependent cellular cytotoxicity (ADCC) mediated activity, or an orchestrated balance of both types of immune action.
In addition, the hinge and effector domains can be designed to generate cellular signals that lead to cell death via apoptosis. Trubion selects specific effector domains based on the molecular target and desired clinical outcome.
In the next step, the hinge and effector domain combo is paired with an appropriate binding domain selected from the polypeptide library. The binding domain recognizes and attaches to a specific target antigen such as a cell surface receptor on B cells resulting in the desired biological activity. Binding domains can be hormones, cytokines, chemokines, cell surface receptors, or immunoglobulin molecules. The customized SMIPs have controlled biological activity that makes them potentially safer and more effective than other first-generation immunopharmaceuticals, Dr. Thompson maintains.
“SMIPs also are engineered to have an optimal half-life, making them more suitable for treating acute and chronic diseases. Moreover, the small size of SMIPs allows them to reach tissue sites that are inaccessible to larger antibodies. The mechanism of action is intentionally designed into the compound,” says Dr. Thompson, whereas in standard mAbs “the mechanism of action is inherent in the antibody.”
Just 24 months after launching Trubion, the streamlined SMIP technology allowed the company to file its first IND application with the FDA. The lead product candidate, TRU-015, is designed to deplete B cells in autoimmune and inflammatory conditions such as rheumatoid arthritis and B-cell malignancies.