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.

• My Focus

  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.

• Publications

  • Addressing Safety Liabilities of TfR Bispecific Antibodies That Cross the Blood-Brain Barrier

    Science Translational Medicine, 2013, ISSN: 1946-6234

    Couch, Jessica A; Yu, Y Joy; Zhang, Yin; Tarrant, Jacqueline M; Fuji, Reina N; Meilandt, William J; Solanoy, Hilda; Tong, Raymond K; Hoyte, Kwame; Luk, Wilman; Lu, Yanmei; Gadkar, Kapil; Prabhu, Saileta; Ordonia, Benjamin A; Nguyen, Quyen; Lin, Yuwen; Lin, Zhonghua; Balazs, Mercedesz; Scearce-Levie, Kimberly; Ernst, James A; Dennis, Mark S; Watts, Ryan J

     View on PubMed

  • Bispecific antibodies for delivery into the brain

    Current Opinion in Chemical Biology, 2013, ISSN: 1367-5931

    Watts, Ryan J; Dennis, Mark S

     View on PubMed

  • Highly specific off-target binding identified and eliminated during the humanization of an antibody against FGF receptor 4

    mAbs, 1 Jul2011, V3, N4, p.376-86, ISSN: 1942-0870.

    Bumbaca, Daniela; Wong, Anne; Drake, Elizabeth; Reyes, Arthur; Lin, Benjamin C; Stephan, Jean Philippe; Desnoyers, Luc; Shen, Ben Quan; Dennis, Mark S

     View on PubMed

  • Antibodies specific for a segment of human membrane IgE deplete IgE-producing B cells in humanized mice.

    Journal of Clinical Investigation, 2010, ISSN: 1558-8238

    Brightbill, H.; Jeet, S.; Lin, Z.; Yan, D.; Zhou, M.; Tan, M.; Nguyen, A.; Yeh, S.; Delarosa, D.; Leong, S.; Wong, T.; Chen, Y.; Ultsch, M.; Luis, E.; Ramani, S.; Jackman, J.; Gonzalez, L.; Dennis, M.; Chuntharapai, A.; DeForge, L.; Meng, Y.; Xu, M.; Eigenbrot, C.; Lee, W.; Refino, C.; Balazs, M.; Wu, L.

  • Therapeutic potential of an anti-CD79b antibody-drug conjugate, anti-CD79b-vc-MMAE, for the treatment of non-Hodgkin's lymphoma.

    Blood, 2009, ISSN: 1528-0020

    Dornan, D.; Bennett, F.; Chen, Y.; Dennis, M.; Eaton D.; Elkins, K.; French, D.; Go, M.A.T.; Jack, A.; Junutula, J.R.; Koeppen, H.; Lau, J.; McBride, J.; Rawstron, A.; Shi, X.; Yu, N.; Yu, S.-F.; Yue, P.; Zheng, B.; Ebens, A.; Polson, A.G.

  • CDR repair: a novel approach to antibody humanization.

    , 2010, ISSN:

    Dennis, M.

  • Engineering as a Means to Improve the Pharmacokinetics of Injected Therapeutic Proteins

    , 2010, ISSN:

    Dennis, Mark S; Yeung, Yik Andy; Kelley, Robert F; Lowman, Henry B

  • Selection and Screening Strategies.

    , 2005, ISSN:

    Dennis, Mark S

     View on PubMed

  • Cloning and Sequencing of the cDNA Encoding the Rubber Elongation Factor of Hevea brasiliensis.

    Plant Physiology, 1991, ISSN:

    Elisabeth Goyvaerts; Dennis, Mark; David Light; Nam-Hai Chua

     View on PubMed

• Education
  • Texas A&M University, Department of Biochemistry, M.S. – 1980
  • Texas A&M University, Department of Biochemistry, B.S. – 1978