Virologist, Immunologist, Molecular Biologist

Douglas Macmillan Powell, Ph.D.

** ***** **** **

Littleton, MA 01460

Phone: 978-***-****

Email: **********************@*****.***

Douglas M. Powell, Ph.D.

Professional Summary

Over 15 years research experience in pharmacology, in vivo models, vaccine development, immunology, immuno-oncology, virology, molecular and cellular biology in academia and industry

Experience in all areas of drug discovery from target ID, through preclinical development and clinical trials

Expertise in vaccines, innate and adaptive immunology, cytotoxicity, signaling pathways and cytokines

Detailed knowledge of the structure/function of tumor targeting receptors such as T cell receptors (TCR) and chimeric antigen receptors (CAR)

Extensive knowledge of the tumor microenvironment (TME) in vivo and modulation for therapeutic benefit

Program Lead for multiple preclinical biologic checkpoint blockade inhibitors, innate and adaptive immunity and stimulatory receptor agonists, immunocytokines and small molecule bromodomain, DNA damage repair, and kinase inhibitors

High degree of creativity and independence with broad spectrum of expertise.

Effective team builder and leader with track record of successful investigation of the immunological mechanisms of drug candidates both small molecules and biologics pharmacology

Excellent communicator, motivator and mentor with strong verbal and written presentation skills

Experience with writing clinical protocols and clinical regulatory filings in INDs and NDAs

Collaborative spirit; able to incorporate views from multiple complementary disciplines to improve the quality and relevance of work

Core Competencies

Immuno-oncology

siRNA inhibition

Vaccine development

Developing translational biomarker strategies

Murine models, syngeneic, PDX, humanized

Immune Modulation

Project Management, internal and through CROs

Novel target identification

Management and development of staff

Team leadership and Collaboration

Immunoassay development

In vivo pharmacology PD/PK

Gene expression analysis

Professional Experience

Scientific Consultant March 2019 to present

Artugen Therapeutics

Design, experimental protocols and execute through academic collaboration and CROs in vivo murine cancer models and to determine effects of proprietary beneficial microbiome bacterial strains impact on immuno-oncology, specifically checkpoint blockade therapeutics. T cells generated in mice immunized against tumor antigens are adoptively transferred (ACT) to naïve tumor bearing mice to determine tumor growth inhibition. Proprietary bacterial strains are transferred via gavage to germ free mice plus or minus antibodies to checkpoint molecules (PD-1 and CTLA-4). Results demonstrate superior tumor growth inhibition in mice receiving proprietary bacterial strains (intestinal microbiome) and checkpoint blockade when combined with ACT. Biomarkers for enhanced T cell effector function have been identified in murine models similar to those reported in clinical trials and can be used to stratify patients likely to respond to checkpoint blockade and therapeutic modification of the intestinal microbiome.

ClearB Therapeutics

Design, and execute experimental vaccine studies using optimized immune epitopes associated with hepatitis B virus (HBV) clearance using in vivo murine AAV HBV chronic infection model to analyze impact on HBV clearance. Recently identified immune epitopes located within the HBV surface antigen are administered as vaccines and demonstrate HBV clearance, whereas full length HBV surface antigen vaccines do not. These non-immunodominant epitopes fail to generate adequate immune responses during vaccination or infection with HBV using full length HBV surface antigen, however when administered as modified HBV surface antigen protein the immune response is capable of mediating viral clearance in the in vivo murine AAV HBV model. Biomarkers for liver function and HBV viral clearance in addition to immunologic functional assays will be used in an upcoming clinical trial.

Senior Principal Scientist Tesaro Discovery Pharmacology April 2017 to November 2018

Program Lead for several immuno-oncology small molecule and antibody Development Programs. Develop small molecules and biologics in immuno-oncology as single agents and in combination with immune checkpoint inhibitors and agonists for immune stimulatory receptors to maximize efficacy using in in vitro functional assays, vivo syngeneic, PDX and humanized mouse models and analysis of dendritic, T cell, Treg, NK, myeloid and MDSC populations. Plan, manage and execute internal and external drug discovery programs through academic collaborations and CROs. Evaluate value propositions from pharmaceutical companies and academic centers for in-license or partnership. Evaluate science feasibility, novelty, platform, competition, pipeline fit, risk, resource and time to IND. Experienced drug hunter and developer of translational biomarker strategies using multiple platforms including RNA-Seq, proteomics, and multicolor flow cytometry to identify novel targets for therapeutic intervention and biomarkers in oncology. Validation of novel therapeutic targets by siRNA inhibition in vivo and in vitro. Preclinical identification and clinical evaluation of biomarkers for pharmacodynamics, prognostic, resistance and response predictive. Deep knowledge of immuno-oncology and immunoassay development.

Consultant Biotechnology/Pharmaceuticals September 2013-April 2017

Evaluate value propositions from biotech companies seeking funding from venture capital firms. Provide scientific expertise in immunology to companies involved in development of immuno-oncology therapeutics, vaccines for infectious disease and cancer, non-replicating virus-like vesicles (VLV) for delivery of vaccine antigens and siRNA, Director of R&D Operations and Corporate Development, CaroGen. Advise in formation of strategic alliances/ collaborations.

Zoetis Lincoln, NE Jan 2013 – Aug 2013

Director of Vaccine Development

Lead a group of 7 scientists in the development of vaccines for coronavirus, influenza and E. coli using a variety of adjuvants to maximize clinical responses

Antigen Express Worcester, MA Jan 2004 – Jan 2012

Director of Immunobiology

Recruited to build and lead a new team of PhD and non-PhD scientists

Identify MHC Class II epitopes using computational methods and confirm activity using T cell Elispot assays with PBMCs from normal, healthy donors and vaccine recipients

Developed MHC Class II peptide, protein and DNA based vaccines for HIV, influenza and HER2/neu cancer epitope vaccine

Initiated collaboration and recruited as a consultant vaccine expert John Treanor, MD, University of Rochester Medical Center

Conducted lethal challenge studies in mice with H5N1.

Conducted Phase I/II H5N1 vaccine clinical trial and analyzed vaccine elicited T cell responses from PBMCs isolated from participants

Filed IND applications with Health Canada, the FDA and the EMA and we have had pre-IND meetings with each organization.

Performed vaccine relevant cell-based immunoassays using human PBMCs isolated from vaccine recipients and murine cells including, Elispot, multicolor flow cytometry and RT-PCR analysis of PBMCs to analyze innate and adaptive immune response to vaccines and develop molecular diagnostic assays

Utilized siRNA and gene expression constructs expressing siRNA to inhibit cellular genes involved in antigen presentation

Evaluated the cytokine GM-CSF as well as proprietary and commercially available adjuvants for DNA, protein and peptide vaccines to maximize the immune responses to multiple vaccines including homologous as well as heterologous prime/boost immunizations.

Partners AIDS Research Center and Harvard Medical School May 2004 –May 2006

Visiting Scientist in Medicine, Dr. Bruce Walker’s Lab

Evaluated the cellular and molecular T cell responses in patients infected with HIV to develop HIV therapeutic and preventive vaccine strategies.

Used Affymetrix gene arrays and RT-PCR analysis to determine molecular mechanisms of HIV pathogenesis in patients with progressive disease.

In addition to the induction of inhibitory receptors CTLA-4 and PD-1, several novel inhibitory receptors and immune signaling pathways were discovered.

Identified inhibitory transcription factors that block expression of MHC class II, perforin, granzyme-b and other proteins that are essential to a controlling immune response.

Determine mechanisms contributing to HIV pathophysiology resulting in immunologic failure

Utilized siRNA and gene expression constructs expressing siRNA to inhibit cellular genes involved in T cell effector function

Millennium Pharmaceuticals, Cambridge, MA January 2002 – November 2003

Senior Scientist

Principal Investigator in charge of HIV program utilizing human genomic RNA expression methods and RT-PCR to identify cellular targets for therapeutic intervention

60 patents filed on methods and compositions for treating AIDS and HIV-related disorders

Identified numerous biomarkers of disease progression for development of molecular diagnostic assays

15 molecules formatted for high throughput screening or in assay development

Established multiple collaborative research programs with investigators at Harvard and Emory Universities, The University California, Irvine and The University Hospital Zurich, Switzerland that were critical for reaching and exceeding program goals.

DuPont Pharmaceutical Company Wilmington, DE June 1997 – October 2001

Principal Research Scientist

Recruited to build and lead a new team of PhD and non-PhD scientists in a new program to identify novel inhibitors of HIV

replication

Developed program utilizing genetically engineered cell lines to identify small molecule inhibitors of HIV-1 Tat protein and discovered multiple compounds that inhibited Tat function in in vitro transcription, RNA binding and human cell based infectivity assays.

Developed stable human cell lines using viral and non-viral vectors expressing cellular and viral genes for use in disease relevant human cell biology experiments. Quantitative gene expression was determined by GFP fluorescence and Q-PCR

Performed cell based binding assays to identify small molecule inhibitors of CCR5 to block entry of HIV into target cells. Selected compounds were then evaluated in human cell based assays including binding, competition, and HIV infectivity assays. Identified 20 molecules that selectively inhibited ligand binding and HIV entry in the low nanomolar and picomolar range

Participated in preclinical development and FDA approval of Efavirenz, a non-nucleoside reverse transcriptase inhibitor (NNRTI)

Evaluated lead synthesis optimized small molecules with a focus on resistance mutations and determined potency and synergistic activity in combination with other antiviral compounds

Gladstone Institute of Virology and Immunology, San Francisco, CA1 1993-1997

Postdoctoral Fellow

Conducted research on mechanisms of regulation of alternative splicing of HIV pre-mRNA using in vitro splicing and RNA gel shift assays with recombinant Rev protein and nuclear extract from human cells.

Demonstrated ASF/SF2 splicing factor binding to the Rev responsive element (RRE) of HIV and proposed a mechanism for Rev mediated regulation of alternative splicing in viral replication.

George Washington University 1987-1993

Genetics Department Ph.D. Candidate

Dissertation: ”Structure and Function of the Rev-Responsive Element and Target Sequence For the Rev Protein of HIV-1”

National Institutes of Health, National Institute of Allergy and Infectious 1984-1993

Diseases Laboratory of Immunoregulation, Bethesda, Maryland

Biologist

Research concentrated on HIV immunology, cell and molecular biology

Preformed viral infection of human PBMCs and multiple T cell lines with HIV

Conducted cell based assays with PBMCs isolated from HIV infected patients including mixed lymphocyte reaction (MLR), cytotoxic T cell (CTL), antibody dependent cell mediated cytotoxicity (ADCC), antigen proliferation and flow cytometry

Demonstrated that HIV could exist in a latent state in T cells

Characterization of immunologic profiles in patients infected with HIV

National Institutes of Health, Clinical Hematology, Bethesda, Maryland 1980-84

Student (while in college) part time during semesters and full-time summers

Performed complete blood counts, (CBC) differential white blood counts, erythrocyte sedimentation rates and coagulation tests and collected blood from patients

Saw the first HIV infected patients begin to arrive at the NIH and became interested in HIV research

Worked on a research project with Dr. Cliff Lane in the Laboratory of Immunoregulation which led to a full-time position in the lab upon graduation

Education

George Washington University

Ph.D., Genetics

University of Maryland

B.S., Microbiology

Honors and Other Special Scientific Recognition

Inventor U.S. Patent #4,752,565 "A cell line producing HIV proteins without production of infectious virus particles".

Inventor U.S. Patent #5,459,056 "Human T lymphocyte clone which can be induced to produce infectious viral particles".

Inventor Methods and Compositions for Treating AIDS and HIV related Disorders Using Molecules (60 cellular target proteins) Serial number 10/366,288 Pending

Special Interests and Skills:

HIV molecular virology, PCR, cloning, mutagenesis.

Cell and virus culture, transient transfections, selection of stable cell lines with protein encoding plasmids as well as plasmids encoding siRNA and synthetic siRNA.

Protein purification and analysis, Western blot, metabolic labeling, immunoprecipitations. DNA and RNA gel mobility shift assays.

Antiviral assays to determine activity of HIV-1 reverse transcriptase and protease inhibitors.

In vitro transcription, in vitro RNA splicing.

GPCR assay development, screening and antiviral assays for CCR5 inhibitors.

Analysis of gene arrays for identification of novel targets for therapeutic intervention in HIV.

Identification of biomarkers and pharmacodynamic markers for inflammatory diseases.

Development of preclinical and clinical vaccines for HIV and pandemic influenza models including H5N1 and H1N1 swine origin influenza (S-OIV).

Publications:

1.Folks, T., Powell, D.M., Lightfoot, M.M., Benn, S., Martin, M.A. and Fauci, A.S.: Induction of HTLV-III/LAV from a nonvirus - producing T cell line: Implications for latency. Science 231:600, 1986.

2.Folks, T. Powell, D.M., Lightfoot, M.M., Koenig, S., Fauci, A.S., Rabson, A., Daugherty, D., Hogan, D.M. and Martin, M.A.: Biological and biochemical characterization of a cloned Leu-3 cell surviving infection with the acquired immune deficiency syndrome retrovirus. J. Exp. Med. 164:280, 1986.

3.Koenig, S., Earl, P., Powell, D., Pantaleo, G., Merli, S. Moss, B. and Fauci, A.S.: Group specific, major histocompatibility complex class I-restricted cytotoxic responses to human immunodeficiency virus I (HIV-I) envelope proteins by cloned peripheral blood T cells from an HIV-I infected individual. Proc. Natl. Acad. Sci. USA 88:8638, 1988.

4.Clouse, K., Powell, D.M., Washington, I., Poli, G., Strebel, K. Farrar, W., Barstad, P., Kovacs, J., Fauci, A.S. and Folks, T.: Monokine regulation of human immunodeficiency virus-I expression in chronically infected human T cell clone. J. Immunol. 142:431, 1989.

5.Koenig, S., Hirsch, U.M., Olmsted, R.A., Powell, D., Maury, W., Rabson, A., Fauci, A.S., Purcell, R.H. and Johnson, P.R.: Selective infection of human CD4+ cells by simian immunodeficiency virus: Productive infection associated with envelope glycoprotein-induced fusion. Proc. Natl. Acad. Sci. USA 86:2443, 1989.

6.Dayton, E.T., Powell, D.M. and Dayton, A.I.: Functional Analysis of CAR, the target sequence for the rev protein of HIV-1.Science, 246:1625-1629, 1989.

7.Dayton, E.T., Konings, D.A., Powell, D.M., Shapiro, B.A, Butini, L., Maizel, J.V. and Dayton, A.I.: Extensive sequence-specific information throughout the CAR/RRE, the target sequence of the human immunodeficiency virus type 1 rev protein. J. Virol. 66:1139-1151, 1992.

8.Powell, D.M., Zhang, M.J., Konings, D.A.M., Wingfield, P.T., Dayton, E.T., and Dayton, A.I.:Sequence-specificity in the higher order interaction of the Rev protein of HIV-1 with its target sequence, the RRE J. Acq. Immune Deficiency Syndromes 10: 317-323, 1995

9.Powell, D. M., Amaral, K.A., Wu, J.Y., Maniatis, T., and Greene, W.C.:HIV Rev dependent binding of SF2/ASF to the Rev response element: Possible role in Rev- dependent inhibition of HIV RNA splicing Proc. Natl.Acad. Sci.USA 94:973-978, 1997

10.Shailesh K. Choudharya, 1, Russell M. Walkerb, Douglas M. Powellb, Vicente Planellesc, Craig Walshd and David Camerinia, CXCR4 tropic human immunodeficiency virus type 1 induces an apoptotic cascade in immature infected thymocytes that resembles thymocyte negative selection Virology 2006 Sep 1;352(2):268-84

11.Audige A, Urosevic M, Schlaepfer E, Walker R, Powell D, Hallenberger S, Joller H, Simon HU, Dummer R, Speck RF. Anti-HIV state but not apoptosis depends on IFN signature in CD4+ T cells. J Immunol. 2006 Nov 1;177(9):6227-37.

12.Zinckgraf J.W, Sposato M, Zielinski V, Powell D, Treanor J, von Hofe E. Identification of HLA class II H5N1 Hemagglitinin epitopes following subvirion influenza A (H5N1) vaccination. Vaccine (2009) doi:1016/j.vaccine.2009.06.081 In press

13. Kallinteris NL1, Powell D, Blackwell CE, Kim M, Lu X, Wu S, Humphreys RE, Xu M, von Hofe E. Ii-Key/MHC class II epitope peptides as helper T cell vaccines for cancer and infectious disease. Front Biosci. 2006 Jan 1;11:46-58.

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