H. Michael Shepard, Ph.D. Eugene, OR, U.S.A.

After completing a PhD in Cellular, Molecular and Developmental Biology at Indiana University (IU), Bloomington, and a successful Walter Winchell-Ramon Runyon postdoctoral fellowship also at the Biology Department of IU, Shepard joined Genentech in 1980. For his first few years at Genentech, Shepard participated in the projects that resulted in the closing of human interferons, plasminogen activators, and tumor necrosis factors. Later, Shepard initiated two critical programs at Genentech. One was the Open Innovation Initiative which ultimately led the way to FDA approval of interferon-gamma, another that helped in the discovery of TNF Blockers by Dr. Marc Feldmann at the Kennedy Institute, and a third with Dr. Hans Schreiber at the University of Chicago which established TNF as critical for surveillance against cancer progression. Shepard also started the first Translational Biology Group (“Target Discovery”) at Genentech. The research goal which gripped Shepard, and became the passion of his career, became the discovery of cancer therapeutics that disable tumor cells and leave normal cells intact. This started with work aimed at the role of stromal and tumor cell-derived cytokines and growth factors, and the role of tumor cell resistance to the tumor necrosis factors in tumor progression. The work culminated in the first biomarker-drive drug discovery effort in biotechnology, i.e., the discovery of Herceptin/trastuzumab, an antibody that has now been used to treat more than 2.3 million breast cancer patients characterized by the overexpression of the HER2 proto-oncogene/p185-HER2. Shepard shared the Warren Alert Prize from Harvard Medical School and later the Lasker Prize for this breakthrough. 

To continue his efforts to create breakthrough cancer therapeutics, Shepard left Genentech to help start the first successful gene therapy company, Canji, Inc. This company was the first to successfully travers the gene therapy regulatory framework (including the Recombinant DNA Activities Committee), to initiate a clinical trial with adenovirus-p53, a disabled adenovirus encoding the p53 tumor suppressor gene, for drug-resistant ovarian cancer. Later, an adenovirus encoding IFN-alpha was constructed, and has been recently approved (Adstiladrin®, nadofaragene firadenovec-vncg). Aldastiladrin modifies the tumor microenvironment and acts as an immune stimulator resulting in efficacious activity against transitional cell bladder carcinoma. Additional successful efforts included the founding of NewBiotics, Inc., where Shepard’s team invented a new class of therapeutics called Enzyme Catalyzed Therapeutic Agents. These are compounds that are activated by enzymes overexpressed in p53-inactivated tumor cells. Returning to the tumor microenvironment at Halozyme Therapeutics, Shepard directed research supporting successful Phase 2 clinical studies of the tumor microenvironment-modifying pegylated PH20 Hyaluronidase, an enzyme that depletes stromal hyaluronan, expands tumor vasculature and enables drug and immune cell infiltration of tumors. Shepard’s team at Halozyme also discovered that overexpression of adenosine deaminase, which degrades immunosuppressive adenosine, predicts longer survival in some breast and lung cancer patients. Shepard’s group engineered a tumor-activated form of adenosine deaminase (ADA2) that potentiates reactivation of T cell function within solid tumors by depletion of adenosine, which otherwise suppresses macrophage and T cell function.

Shepard’s current work focuses on 1) the common properties of the disease microenvironment in solid tumors and rheumatoid arthritis and means of leveraging these common properties to create novel therapies that can be used to treat both diseases; 2) consulting; 3) mentoring.

• Career focus: molecular and cellular biology, the tumor microenvironment (TME) and its role in tumor progression; the functional role of stromal immune cells, cytokines and growth factors in tumor progression
• In vivo proof of concept for pegylated PH20 to treat cancer (by remodeling of the tumor microenvironment).
• First clinical proof of concept that:
  • Monoclonal antibodies could be used to treat solid tumors (Herceptin/Trastuzumab)
  • Inhibition of tyrosine kinases is useful in treating cancer (Herceptin/trastuzumab)
  • Established the current paradigm of biomarker-driven drug discovery and clinical trials (Herceptin/trastuzumab) can lead to rapid clinical testing and commercial success
• Created recombinant adenoviruses encoding the p53 tumor suppressor gene (ovarian cancer) and interferon (bladder cancer, APPROVED).
• Created the first high affinity EGFR family ligand trap and showed broad anticancer activity (see Receptor Biologix, below). Proof of concept that targeting multiple members of the EGFR family could give better efficacy than targeting a single member of the family
• Described specialized phosphoramidate derivatives of nucleosides to target upregulated enzymes (e.g., thymidylate synthase) in cancer cells containing inactivated tumor suppressor genes (TP53, RB) resulting in their conversion to cytotoxic moieties specifically in tumor cells with unregulated thymidylate synthase
• Discovered novel method to identify alternative splice variants of pre-mRNAs that encode important regulatory proteins that can be used as receptor antagonists

Current Professional Associations

• Oregon Health Sciences University Center for Experimental Therapeutics
• World Laureates Association
• Adjunct Professor, Dept. Biological Sciences, Indiana University, Bloomington, IN.
• Adjunct Professor, Shanghai Jiao Tong University
• Advisor: Multiple biotechnology companies

Enosi Therapeutics 2019-2024

Chief Executive Officer and Chief Scientific Officer

Novel biologics for cancer and autoimmune disease by targeting overlapping molecular pathologies

Halozyme Therapeutics, Inc., San Diego, CA 2009-2017

Halozyme Research Fellow; Vice President, Research and Chief Scientific Officer

• Focus on targeting the tumor microenvironment for therapeutic effect in malignancy and other diseases
• Solved problems in preclinical and clinical trials of PEGPH20, Halozyme’s lead anticancer molecule
• Co-inventor of digital IHC companion diagnostic for PEGPH20
• Co-inventor of overall strategy of how to take advantage of the tumor microenvironment to discover new drugs: tumor selective anti-EGFR MAb, and conditionally active adenosine deaminase that restores T cell anticancer activity in the tumor microenvironment
• EMEA and FDA approval of three drugs

Receptor BioLogix, Inc., Palo Alto, CA 2003-2008

Founder/President/Chief Scientific Officer

• Established Receptor BioLogix, Inc. to explore the potential of alternative splicing variants of receptors and ligands to act as antagonists of stromal or autocrine produced cytokines and growth factors
• Created heterodimeric receptor:Fc fusion protein (extracellular domains of EGFR and HER3) that targets 9/11 of the ligands that drive the EGFR family. Improved concept is now being developed by Enosi Therapeutics

New Biotics, Inc., San Diego, CA 1997-2002

Founder and Chief Scientific Officer

• Development of a targeted drug for fluoropyrimidine-resistant cancer
• Fluoropyrimidine-resistant cancers can utilize several mechanisms to overcome the toxicity of this chemotherapeutic. A major mechanism is the over-expression of thymidylate synthase, a principal target of this class of drugs. Thymidylate synthase and pathway-related enzymes (like dihydrofolate reductase) are, additionally, upregulated as a result of the loss of tumor suppressor genes. Shepard developed the concept of using thymidylate synthase as an ‘engine’ to preferentially produce alkylating agent in target cells. This new concept allows for the design of drugs which target tumor cell selective biochemical pathways. This family of compounds is now called Thymectacin, and is the subject of active research and development as a model for other enzyme-catalyzed therapeutic agents.

Canji/Shering-Plough Research Institute 1992-1997

Vice President, Research and Development; Chief Scientific Officer; Senior Director, Technology Evaluation

• Adnovirus/Interferon for superficial bladder cancer
• Development of p53 adenovirus for ovarian cancer
• Multiple Schering partnerships

Genentech, Inc., South San Francisco, CA 1980-1992

Scientist, Molecular Biology; Scientific Manager, Department of Pharmacological Sciences; Senior Scientist, Developmental Biology; Project Team Leader, Herceptin Development Project

• Discovery and development of Herceptin
• Led the Genentech team which identified 4D5 as the most broadly antiproliferative antibody with respect to breast tumor cells which overexpress p185HER2. Following initial proof of principal clinical trials with murine 4D5, it was later humanized to produce Herceptin. Herceptin was the first proof of principle that an antibody can be used to treat solid tumors, as well as the first demonstration that tyrosine kinases are valid targets for cancer treatment

Postdoctoral Training - 1977-1980

Damon Runyon-Walter Winchell Research Fellow

Indiana University, Bloomington, IN, USA

• Topic: Regulation of DNA replication
• Main Finding: First proof of trans-acting small RNA molecules regulating DNA replication
• Laboratory of Dr. Barry Polinsky

Ph.D., Molecular, Cellular and Developmental Biology - 1977

Indiana University, Bloomington, IN

• Thesis: The role of maternal mRNA-protein complexes (mRNPs) in early development of sea urchin embryos
• Laboratory of George Malacinski and Rudolph Raff

B.S., University of California, Davis, CA - 1973

• Major: Zoology (Honors)
• Minor: Chemistry

 Lasker Award: Recognizing Herceptin/trastuzumab as the fist monoclonal antibody therapy targeting oncogene

Warren Alpert Prize: Harvard School of Medicine: Recognizing the Herceptin work

First appointed Fellow of the Kennedy Institute of Rheumatology, University of Oxford, U.K: Recognizing contributions to the discovery of TNF Blockade to treat rheumatoid arthritis

 Spouse: Regina Hocson Sideris

Children: Two sons and three daughters

Current Residence: Eugene, Oregon, USA