Without a doubt, mAbs have been a therapeutic and marketing success for the treatment of cancer and inflammatory illnesses. Nonetheless, their large size creates challenges such as limited tissue penetration and suboptimal antigen binding or biological response.
Researchers at Trubion Pharmaceuticals (www.trubion.com) are designing compounds called SMIP™ therapeutics, short for small modular immunopharmaceutical, that reportedly advance mAb technology. SMIP therapeutics, which are one-third to one-half the size of conventional therapeutic mAbs, are engineered to specifically bind and activate a disease target. “The technology is broadly applicable across a range of targets, and we can create customized biotherapeutics with different mechanisms of action,” says Peter A. Thompson, M.D., CEO, chairman, and president of Trubion.
In 2002, Dr. Thompson cofounded Trubion Pharmaceuticals with Jeffrey Ledbetter, who was a principal investigator at the Pacific Northwest Research Institute in Seattle, and Kendall Mohler, Ph.D., vp of biology at the former Seattle-based Immunex.
After Amgen purchased Immunex, many former employees of that company joined Trubion. “The joke around town was that Trubion should be renamed Immunext,” says Dr. Thompson. The SMIP platform was invented in Ledbetter’s laboratory at the Pacific Northwest Research Institute and broadened and perfected at Trubion.
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.
TRU-015 is directed at CD-20, a validated clinical target on B cells. Rituxan®, sold by Genentech, also targets CD-20, and both drugs deplete B cells. However, TRU-015 is engineered to produce potent ADCC activity and attenuated CDC activity, compared to Rituxan, according to Dr. Thompson. “The higher CDC activity of Rituxan has been linked to side effects, particularly infusion site reactions. The reduced CDC activity built into TRU-015 may overcome this adverse reaction,” he adds.
In December 2005, Trubion and Wyeth Pharmaceuticals entered into a collaboration to develop and commercialize TRU-015. Wyeth paid Trubion $40 million in upfront fees, and financial rewards for meeting milestones could reach up to $800 million.
“We chose Wyeth because the manufacturing of SMIPs is similar to monoclonal antibodies, and Wyeth has a monoclonal antibody production system in place. In addition, there’s lots of trust between the two organizations,” Dr. Thompson says. Wyeth and Immunex developed Enbrel, an anti-TNF alpha biologic used to treat rheumatoid arthritis. Now many of the same team members are working together again to develop TRU-015. “There’s a strong incentive to find a successor to Enbrel and the next blockbuster drug,” concludes Dr. Thompson.