Researchers techniques for Immunology and Inflammation Research

I am Vice President and Clinical Portfolio Leader in the Pfizer Inflammation and Immunology Research Unit in Cambridge, Massachusetts. I joined Pfizer in 1995 to lead the Gastrointestinal Discovery Biology group at the Sandwich site in the UK and then joined the Experimental Medicine group in 2002. Prior to this I worked for Glaxo as a Research Leader in the Gastrointestinal Pharmacology Group. Since joining the clinical world I have led early clinical development and translational medicine activities from first-into-human to clinical proof-of-concept across a range of diverse diseases in gastroenterology and hepatology. Since 2008, I have been leading clinical development activities across several areas of internal medicine, including nephrology, as either RPL or Clinical Lead. I currently have responsibility for early clinical development activities in Inflammatory Bowel Disease.

RESEARCH AREA(S)

My research focuses on the early clinical development of novel medicines, primarily in the field of gastroenterology, but also nephrology, skin scarring, complications of diabetes and women’s health. The scope of my research is Phase 1 to Phase 2b and includes biomarker-based and translational medicine-based approaches to decision making.

PUBLICATIONS

1. Scheele W, Diamond S, Gale J, Clerin V, Tamimi N, Le V, Walley R, Grover-Páez F, Perros-Huguet C, Rolph T and El Nahas M (2016) Selective inhibition of phosphodiesterase type 5 reduces albuminuria in subjects with type 2 diabetes and overt nephropathy. J Am Soc Nephrol 27(11):3459-3468. https://www.ncbi.nlm.nih.gov/pubmed/27113485
2. Walley R.J, Birch C.L, Gale J.D and Woodward P (2015) Advantages of a wholly Bayesian approach to assessing efficacy in early drug development: a case study. Pharm Stat 14: 205-215. https://www.ncbi.nlm.nih.gov/pubmed/25865949
3. Manousou P, Burroughs A.K, Tsochatzis E, Isgro G, Hall A, Green A, Calvaruso V, Ma G.L, Gale J, Burgess G, O'Beirne J, Patch D, Thorburn D, Leandro G, and Dhillon A.P. (2013) Digital image analysis of collagen assessment of progression of fibrosis in recurrent HCV after liver transplantation. J Hepatol 58(5): 962-8. https://www.ncbi.nlm.nih.gov/pubmed/23262247
4. Gale, J.D and Houghton L.A (2011) Alpha2delta (2) ligands, gabapentin and pregabalin: What’s the evidence for potential use of these ligands in irritable bowel syndrome. Frontiers Gastrointestinal Pharmacology 2:1-9 https://www.ncbi.nlm.nih.gov/pubmed/21713059
5. Ferens D.M, Yin L, Ohashi-Doi K, Habgood M, Bron R, Gale J.D. and Furness J.B (2010) Evidence for functional ghrelin receptors on parasympathetic preganglionic neurons of micturition control pathways in the rat. Clin Exp Pharmacol Physiol 37: 926-932. https://www.ncbi.nlm.nih.gov/pubmed/20497419
6. Neubert H, Gale J, Muirhead D (2010) Quantitative Protein Bioanalysis by Online High Flow Peptide Immunoaffinity Enrichment and Nanoflow LC-MS/MS: Assay Development for Measuring Total Salivary Pepsin/Pepsinogen. Clin Chem 56: 1413-1423.https://www.ncbi.nlm.nih.gov/pubmed/20472821/

EDUCATION

European Confederation of the Upper Rhine Universities, Basel, Freiburg & Strasbourg, Diploma and University Professional of Advanced Studies in Pharmaceutical Medicine, European Center of Pharmaceutical Medicine, 2015
University of Warwick, 2011
University of London, Royal Free Hospital School of Medicine, Ph.D: “Morphological and pharmacological studies of 5-HT in sympathetic nerve fibres,” 1988
Sunderland Polytechnic, Sunderland, Pharmacology, Class II (i), B.S. (Honors), 1985

AWARDS & HONORS

Honorary Professorship, University of Liverpool, 2015 – 2018
Postgraduate Award in Management of Chronic Kidney Disease (Obtained a 67% overall), University of Warwick, 2011
Graduated in top 25% of class in 4/5 modules, European Confederation of the Upper Rhine Universities, Basel, Freiburg & Strasbourg, 2003-2005

I lead the Preclinical Group within Inflammation & Immunology, responsible for the portfolio from the point we invest in screening through to delivering the regulatory package for first in human studies. I joined Pfizer in 1996 and since then have had the opportunity to work across the pipeline from target hunting through to Ph2 development. The majority of this time has been focused on anti-inflammatory therapies across a range of chronic conditions, in disease areas including rheumatology, dermatology, gastroenterology and respiratory indications.

I have worked on both large and small molecules, delivered by various different routes including oral, inhaled, topical and injectable therapies. Of note, I have a specific interest in inflammatory signaling pathways and personally led a number of kinase inhibitor projects to the clinic including IRAK4, JAK and p38 programs in addition to other non-kinase small and large molecule programs. Throughout my career at Pfizer I have enjoyed working closely with academic or industrial key opinion leaders, both through direct collaboration and as part of industrial academic consortia.

I am an advocate for a primary focus on understanding human pathophysiology of inflammatory diseases by working with primary patient samples and have a keen interest in building translational understanding of the targets we invest in.

RESEARCH AREA(S)

The preclinical group supports both large and small molecule programs across our core diseases areas of rheumatology, dermatology and gastroenterology. We are interested in anti-inflammatory approaches in innate and adaptive immunity as well as well targets that would address the end stage fibrotic manifestations of many autoimmune diseases. Mechanistic areas of interest include cytokine signaling, innate receptor signaling, immunometabolism, tolerance induction, epithelial barrier function, modulation of checkpoint signaling and drivers of fibrosis.

Where possible, we focus on primary patient cells or biofluids to build understanding of our targets of interest and have also invested in complex in vitro and humanized in vivo models. In choosing targets we are somewhat modality agnostic and have access to core expertise in medicinal chemistry and biomedical design. Of note, we are currently working on oral, topical and systemically delivered therapies. There is a keen focus on translational strategies to support crisp clinical decision making as we transition our programs into development.

PUBLICATIONS

1. Hill, A., Loh, P., Bharadwaj, R., Guinan, E., Lakhani, K., Kilty, I.and Jelinsky, J. (2017) “Stepwise Distributed Open Innovation Contests for Software Development - Acceleration of Genome-Wide Association Analysis” GigaScience doi: 10.1093/gigascience/gix009 https://www.ncbi.nlm.nih.gov/pubmed/28327993
2. Jones, P., Storer, R, Sabnis, Y., Wakenhut, F., Whitlock, G., England, K., Mukaiyama, T., Dehnhardt, C., Coe, J., Kortum, S., Chrencik, J., Brown, D., Jones, R., Murphy, J., Yeoh, T., Morgan, P. and Kilty, I. (2017) "Design and Synthesis of a pan-JAK Kinase Inhibitor Clinical Candidate (PF-06263276) Suitable for Inhaled and Topical Delivery for the Treatment of Inflammatory Diseases of the Lungs and Skin" J.Med.Chem doi: 10.1021/acs.jmedchem.6b01634 https://www.ncbi.nlm.nih.gov/pubmed/2798383
3. Lee, K., Ambler, C., Anderson, D., Boscoe, B., Brodfuehrer, J.,Bree, A.,Chang, J., Choi, C., Chung, S., Curran, K.,Day, J., Dehnhardt, C.,Dower, K.,Drozda, S., Frisbie, R., Gavrin, L., Goldberg, J.,Han, S.,Hegen, M.,Hepworth, D., Hope, H.,┴ Kamtekar, S., Kilty, IC, Lee, A., Lin, L.L., Lovering, F., Lowe, M.D., Mathias, J., Morgan, H., Murphy, E., Papaioannou, N.,Patny, A., Pierce, B.,Ramsey, S.,Rao, V., Saiah, E., Samardjiev, I.,Samas, B., Shen, M., Shin, J., Soutter, H., Strohbach, J.,Symanowicz, P.,Thomason, J.,Trzupek, J., Vargas, R., Vincent, F., Wrightstone, A., Yan, J.,Zapf, C.and Wright, S. (2017) “Discovery of Clinical Candidate 1{[(2S,3S,4S)-3-Ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide (PF-06650833), a Potent, Selective Inhibitor of Interleukin1 Receptor Associated Kinase 4 (IRAK4), by Fragment-Based Drug Design” J.Med.Chem doi: 10.1021/acs.jmedchem.7b00231 https://www.ncbi.nlm.nih.gov/pubmed/28498658
4. Singh, D., Siew, L., Christensen, J., Plumb, J., Clarke, G., Greenaway, S., Clarke, N., Kilty, I. and Tan, L. (2015) “Different effects of oral and inhaled P38 MAPK inhibitors on corticosteroid resistant neutrophilic inflammation after inhaled LPS challenge in healthy subjects.” Eur.J.Clin.Pharm. doi:10.1007/s00228-015-1920-1 https://www.ncbi.nlm.nih.gov/pubmed/26265232
5. Nicholson, G., Leaker, B., Holloway, R., Donnelly, L., Kilty, I.C. and Barnes P.J. (2016) “A novel flow cytometric based method to measure kinase inhibition in sputum from COPD subjects” B.M.J.Open Resp. Res. 3:e000140 doi:10.1136/bmjresp-2016-000140 https://www.ncbi.nlm.nih.gov/pubmed/27403320</li>

EDUCATION

University of Liverpool, PhD: “The Development of Two Distinct Differentiated Cell Lines with a Thermolabile Form of SV40 Large T Antigen,” 1996
University of Cambridge, Jesus College, Cantab Biochemistry, M.A., 1993
University of Cambridge, Jesus College, Cantab Biochemistry, B.A., 1992

AWARDS & HONORS

Pfizer Team Achievement Award for the (Topical JAK Program), 2016
Senior Editor Journal of Inflammation
Member of the Organizational Committee for the British Inflammation Research Association (BIRAs)
Member of the UK Government Asthma Advisory Group

In July 2017, I joined Pfizer to lead the Discovery effort in the Inflammation and Immunology Research Unit at Pfizer located in Cambridge, MA. Prior to joining Pfizer, I was a Senior Investigator and Chief of the Immunopathogenesis Section of the Laboratory of Parasitic Disease, in the National Institute of Allergy and Infectious Diseases, NIH in Bethesda, MD. I received my Ph.D. from the Department of Medical Microbiology and Immunology at the University of Wisconsin, in Madison, Wisconsin. I have published over 200 research papers, reviews, and book chapters in many prestigious journals including Nature, Science, and Nature Immunology and have made important contributions to our understanding of the role of cytokines and growth factors in the progression and resolution of chronic inflammation, tissue regeneration, and fibrosis. At Pfizer, I’m leading our discovery efforts in the areas of immune tolerance, epithelial cell biology, immunometabolism, innate immunity, and fibrosis. For the past three years, I have been included on Thomson Reuters’ list of Highly Cited Researchers.

RESEARCH AREA(S)

The discovery group in the Inflammation and Immunology Research Unit focuses on core mechanisms that drive tissue damaging inflammation in important rheumatic, gastrointestinal, and dermatological diseases, including rheumatoid arthritis, systemic lupus erythematosus, ulcerative colitis, Crohn’s disease, non-alcoholic steatohepatitis, fibrosis, psoriasis, atopic dermatitis, alopecia, and vitiligo. Our work on immune tolerance is focused on identifying novel strategies to induce durable disease remission by harnessing endogenous regulatory mechanisms including immunosuppressive T cells. Epithelial cells have emerged as key drivers of several important chronic inflammatory diseases including atopic dermatitis, psoriasis, and IBD.

The epithelial biology group is using novel human cell based assays to better understand the role of the epithelium in disease pathogenesis and to test new therapeutics. The innate immunity is group is focused on understanding the role of danger sensing mechanisms and checkpoint (co-regulatory) receptor pathways in the initiation and maintenance of tissue damaging inflammatory responses. Similarly, the immunometabolism group is developing unique strategies to target metabolic pathways in important immune cells such as T cells and macrophages to restore immune homeostasis. Finally, the fibrosis groups is elucidating mechanisms that transform fat accumulation in the liver (steatosis) into a chronic inflammatory response (steatohepatitis) that can lead to fibrosis, cirrhosis, and ultimately organ failure that is rapidly becoming a leading cause of liver transplantation. A better understanding of the mechanisms that drive hepatic fibrosis could also reveal improved strategies to treat a variety of important fibrotic diseases including lupus nephritis, cardiovascular fibrosis, radiation induced fibrosis, and idiopathic pulmonary fibrosis.

PUBLICATIONS

1. Type 2 immunity in tissue repair and fibrosis.
   Nat Rev Immunol. 2018 Jan;18(1):62-76.
   Gieseck RL 3rd, Wilson MS, Wynn TA.
   https://www.ncbi.nlm.nih.gov/pubmed/28853443
2. Type 2 immunity is protective in metabolic disease but exacerbates NAFLD collaboratively with TGF-β.
   Sci Transl Med. 2017 Jun 28;9(396).
   Hart KM, Fabre T, Sciurba JC, Gieseck RL 3rd, Borthwick LA, Vannella KM, Acciani TH, de Queiroz Prado R, Thompson RW, White S, Soucy G, Bilodeau M, Ramalingam TR, Arron JR, Shoukry NH, Wynn TA.
   https://www.ncbi.nlm.nih.gov/pubmed/28659437
3. Inflammation and metabolism in tissue repair and regeneration.
   Science. 2017 Jun 9;356(6342):1026-1030.
   Eming SA, Wynn TA, Martin P.
   https://www.ncbi.nlm.nih.gov/pubmed/2859633
4. Interleukin-13 Activates Distinct Cellular Pathways Leading to Ductular Reaction, Steatosis, and Fibrosis.
   Immunity. 2016 Jul 19;45(1):145-58.
   Gieseck RL 3rd, Ramalingam TR, Hart KM, Vannella KM, Cantu DA, Lu WY, Ferreira-González S,
   Forbes SJ, Vallier L, Wynn TA.
   https://www.ncbi.nlm.nih.gov/pubmed/27421703
5. Combinatorial targeting of TSLP, IL-25, and IL-33 in type 2 cytokine-driven inflammation and fibrosis.
   Sci Transl Med. 2016 May 4;8(337):337ra65.
   Vannella KM, Ramalingam TR, Borthwick LA, Barron L, Hart KM, Thompson RW, Kindrachuk KN,
   Cheever AW, White S, Budelsky AL, Comeau MR, Smith DE, Wynn TA.
   https://www.ncbi.nlm.nih.gov/pubmed/27147589

EDUCATION

National Institutes of Health, Postdoctoral Fellow, 1995
University of Wisconsin – Madison, PhD, 1991
Miami University, B.A., 1986

AWARDS & HONORS

Thomson Reuters Highly Cited Researcher. 2014 – 2017
Elected to Fellowship in the American Academy of Microbiology, 2012
National Institutes of Health Merit Award, 2011
Bailey K. Ashford Medal, American Society of Tropical Medicine and Hygiene, 2006
Oswaldo Cruz Medal, Oswaldo Cruz Foundation, 2002

QUOTE

“I joined Pfizer so I could more effectively move basic science discoveries into the clinic so patient lives will be improved”