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Mark Dennis Senior Scientist: Antibody Engineering |
"I am proud to have been part of Genentech for more than 25 years. As an original member of what has become the Protein Engineering Department, I have helped to pioneer phage display technology as a means for engineering protein-protein interactions.
Initially, we altered the specificity of Kunitz domain inhibitors to inhibit specific proteases and later, using peptide phage libraries, identified novel peptide inhibitors that specifically inhibit factor VIIa. A thorough biochemical and structural characterization of these peptides helped to elucidate their unique allosteric mechanisms of inhibition. Utilizing the same technology, I identified a class of peptides that bind specifically to albumin. These peptides, fused to a Fab, generate an albumin-binding Fab (AB.Fab) with dramatically increased half-life in vivo. The ability to associate with albumin also greatly enhances tumor deposition of the AB.Fab as compared to other small immunoglobulin fragments.
As a member of the Antibody Engineering Department for the last 4 years, I have had the opportunity to collaborate with a great team of scientists to facilitate the development of novel antibody generation technologies and the generation of exciting new antibody therapeutics."
Current Projects "Our lab focuses on the humanization of antibodies for clinical development with an eye towards enhancing humanization methods. In this role, we have developed a new and rapid method for humanizing antibodies called 'CDR repair.' Many of the humanized antibodies are directed towards tumor antigens and angiogenic targets in support of innovative cancer therapies.
Synthetic antibody phage libraries have become an increasingly important source for novel antibodies and we are continuously trying to improve the design of these libraries. We also continue to explore the AB.Fab technology as a means to enhance tumor delivery. An AB.Fab offers distinct advantages over an IgG, scFv or other immunoglobulin fragments for targeting tumors."
Collaborations "My lab collaborates with Immunology, Molecular Oncology and other groups throughout Research as a result of our antibody humanization work. Antibodies have become important tools for the development of new therapies. In addition our pursuit of the AB.Fab for tumor targeting has led to fruitful collaborations with Molecular Oncology, Pathology and PK/PD Sciences for imaging, efficacy and pharmacokinetic studies."
Inspiration/Vision "The founders of Genentech, Bob Swanson and Herb Boyer created a collaborative University-style environment that nurtures a passion for excellent science. This environment encourages teamwork and provides the freedom to follow creative impulses thus combining innovative ideas and state of the art technologies with the resources to move those ideas forward.
My hope is that we shall develop far better treatments for cancer and other devastating diseases. The development of the AB.Fab, for example, may lead to improved tumor targeting by providing efficient and tumor specific delivery of cytotoxic agents, thus potentially reducing overall toxicity associated with chemotherapies. The opportunity to make such an impact on important medical problems offers tremendous satisfaction and incentive."