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Mark Dennis Senior Scientist: Antibody Engineering |
"I can not imagine a more exciting, supportive and collaborative environment than the one I have witnessed over the last 30 years at Genentech. Starting from the humble beginnings of recombinant DNA technology, I have helped to pioneer phage display technology as a means to enhance and modify protein-protein interactions, utilized peptide phage display to generate novel peptide ligands, and developed a technology for enhancing the pharmacokinetics of proteins.
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.
Over the last several years, as a member of the Antibody Engineering Department, I have had the opportunity to collaborate with scientists throughout the research organization to facilitate the development of novel antibody generation technologies and the generation of exciting new antibody therapeutics."
Current Projects "The delivery of antibodies across the blood-brain barrier presents a formidable challenge. In collaboration with Neurobiology and PK/PD Sciences, we are generating reagents to examine how the BBB forms and functions, with a particular focus on antibody dynamics at the BBB. Our efforts have focused on generating antibodies that target specific brain endothelial targets to enable receptor-mediated transport as a means to deliver antibodies across the BBB.
Our lab also 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.' These humanized antibodies are directed towards tumor antigens, infectious agents and various other immunologic, neurologic and angiogenic targets in support of innovative therapies.
Synthetic antibody phage libraries have become an increasingly important source for novel antibodies and we are continuously evolving the design of these libraries. We also continue to explore the AB.Fab technology as a means to enhance tumor delivery for imaging and therapy. 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, Infectious Disease, Neurobiology and many 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 and creativity. 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."