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The University of Southampton
Medicine
Email:
alw1@soton.ac.uk

Dr Ann White PhD

Senior Research Fellow

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Dr Ann White is Senior Research Fellow within Medicine at the University of Southampton.

Ann White obtained her PhD from the MRC Clinical Research Centre, Harrow in 1991. She then spent 10 years in the United States working on lipoprotein metabolism first as a post-doc at the Southwest Foundation for Biomedical Research, San Antonio, Texas, then as a tenure-track Assistant Professor in Internal Medicine at the University of Texas Southwestern Medical Center in Dallas. After returning to the UK in 2001 and a career break with her young children, Ann joined Professor Martin Glennie at the University of Southampton in 2005, where she is now an established researcher in the Antibody and Vaccine Group of the Cancer Sciences Unit

Ann’s research in Southampton is focused in the area of cancer immunotherapy. Her studies are aimed at understanding the molecular mechanisms that drive the therapeutic effects of anti-cancer monoclonal antibodies. In particular, she is interested in exploring the roles that antibody isotype and Fc receptor interactions play in determining the efficacy of agonistic antibodies. Her work has been pivotal in delineating the molecular pathways that contribute to the contrasting mechanisms of action of different antibody drugs with direct implication for drug development.

As a member of the ‘Antibody Discovery’ team, Ann’s work is primarily funded by Cancer Research UK (CRUK) as well as a collaborative EU initiative with the goal of translating laboratory based research discovery into improved therapeutics for clinical trials. Ann also has industrial links and is principal investigator on a research contract with a large pharmaceutical company. As well as basic research, Ann is involved in the supervision and examination of undergraduate students, medical students and PhD students in the laboratory.

Qualifications

BSc (Hons), Applied Biology, University of Hertfordshire, 1987.
PhD, Molecular and Cellular Biology, MRC Clinical Research Centre, 1991.

Appointments held

1991-1993 Postdoctoral Scientist, Department of Virology and Immunology, Southwest Foundation for Biomedical Research, San Antonio, Texas.

1993-1997 Staff Scientist, Department of Virology and Immunology, Southwest Foundation for Biomedical Research, San Antonio, Texas.

1997-2001 Assistant Professor, Department of Internal Medicine, University of Texas Southwestern Medical Centre, Dallas, Texas.

2005-present Senior Research Fellow, Cancer Sciences Unit, Faculty of Medicine, University of Southampton.

Research interests

Dr White’s research is focused on the optimisation of immunostimulatory monoclonal antibody (mAb) based anti-cancer drugs designed to induce anti-cancer immunity. One target in development is the TNF receptor superfamily member, CD40, an essential co-stimulatory receptor found on a number of key immune cells. CD40 mAb can exert agonistic (stimulatory) or antagonistic (inhibitory) effects on CD40 signaling to stimulate or dampen immune responses, respectively. However, the mechanisms mediating these contrasting effects are unclear.

Like other TNF receptors, CD40 is believed to require clustering in the membrane to recruit intracellular signaling molecules and promote immune stimulation. Ann’s research showed that CD40 mAb usually require cross-linking in vivo by the inhibitory Fc receptor, FcγRIIB, to be active. More recently she also demonstrated that FcγR independent activity can be conferred by the human IgG2 isotype due to a unique configuration of disulphide bonds in its hinge region. In addition, ‘superagonistic’ mAb have also been identified that are active independent of isotype and FcγR interaction, which presumably reflects fine epitope binding specificity.

Current ongoing projects are as follows:

Structural and mechanistic basis for mAb agonistic activity. Through a collaboration with Dr Ivo Tews in the Institute for Life Sciences, Professor Jon Essex in Chemistry and Professor Mark Cragg in Medicine, this project aims to understand, at the molecular level, the basis for different types of receptor agonism and antagonism. A combination of protein crystallography, SAXS analysis and molecular modelling/dynamics are being used to define mAb-receptor interactions and conformational changes that these interactions precipitate. In addition, in collaboration with Dr Marisa Martin-Fernandez at the STFC central laser facility in Oxford, high resolution microscopy will be used to determine events in the cell membrane associated with different types of mAb activity. Understanding at the most basic level the mechanisms by which these agents achieve their defined activities will contribute to the design of the next generation of antibody therapeutics.

Agonistic mechanism, therapeutic efficacy and toxicity. Toxicity has been limiting for some immunostimulatory mAb in patients, and a key question is whether therapeutic efficacy and toxicity can be uncoupled. Detailed studies aim to address the relative potency and efficacy of mAb that deliver agonistic activity through distinct molecular mechanisms and their associated side effects. The goal is to determine the optimum type of agent to take forward into human subjects.

Translation of basic research into patients. The primary goal of the Antibody and Vaccine Group in the Cancer Sciences Unit is to deliver mAb drugs into clinical trials. As part of a European Consortium funded through Framework 7, ChiLob7/4, a human CD40 mAb developed in Southampton that has just completed phase I clinical trial, is now being taken into trials in pancreatic cancer patients.

Department(s)

Cancer Sciences

Student supervision

Medical student intercalated projects: Susan Tam and Ali Dohdy.
Integrated PhD rotation project: Yifang Gao
Bath University 6 month undergraduate placement students: Betty Lau and Kane Moss
Undergraduate placement student (Germany): Sandra Lehnert
Work experience school students: Natalie Kanda and Aaron Bush
Current supervisor of 4 year PhD student Christian Orr

National and International Responsibilities

Article reviewer for a number of immunology journals.

External examiner for PhD thesis, University of Malaya

Member of the British Society of Immunology

Undergraduate research projects

BMedSc/MMedSc

Integrated PhD Cancer Pathway

Dr Ann White
Tel:+44-2381-20-6590 Fax: +44-2380-70-4061 Email: A.L.White@soton.ac.uk

Email:alw1@soton.ac.uk

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