Professor of Immunochemistry, Head of Antibody and Vaccine Group
Professor Martin Glennie is Professor of Immunochemistry within Medicine at the University of Southampton.
Professor Glennie was appointed a personal chair in 1999 and was Head of the Cancer Sciences Unit from 2005 to 2015. Having graduated from the University of Southampton in 1977, he embarked on a PhD with Profs Freda and George Stevenson investigating the therapeutic application of antibodies to the treatment of cancer. In 1980 he moved to Cambridge to work with Prof Arnold Feinstein on the structure and function of pentameric IgM, before returning to Southampton to take up a ‘New Blood’ lectureship in cancer immunotherapy.
Throughout his career Professor Glennie has focused on understanding and improving how antibodies can be used therapeutically. He was one of the first to undertake antibody engineering and to show that structural changes, such as reducing antibody valency, could have profound benefits on therapeutic efficacy. Prof Glennie now leads a team of clinical and non-clinical scientists and students investigating many aspects of antibody immunotherapy. Understanding antibody biology, including target specificity, effector function, half-life, and agonistic activity in cell signalling, has proved critical in developing clinical reagents. Prof Glennie and colleagues (Profs Cragg, Johnson, Al-Shamkhani and Drs Beers, Davies and White) are particularly focused on the role of Fc receptors (FcR), myeloid cells and tumour environment and how these can be modulated to promote antibody activity. They are also investigating the therapeutic potential of immune stimulating antibodies, which stimulate the body’s anti-cancer immunity to provide long-lasting protection against the disease. These reagents are being developed both in preclinical models and in the clinic in Southampton.
Professor Glennie is an adjunct Professor to the Dartmouth Medical School, NH, a visiting Professor at the Scripps Research Institute, CA, and consults for the biotech industry in Europe and the US. He is also a frequent reviewer for a wide range of scientific journals and granting bodies, and sits on review panels and advisory boards for Cancer Research UK and the NIH.
BSc, University of Southampton 1977 PhD, University of Southampton 1980
1981-83 Research Fellow, Department of Immunology, Babraham, Cambridge.
1983-86 "New Blood" Lecturer, School of Medicine, University of Southampton.
1999-present Professor of Immunochemistry, School of Medicine, University of Southampton
1998-2001 Director of Research, School of Medicine, University of Southampton
2005-2015 Head of Cancer Sciences Unit, Faculty of Medicine
In recent years monoclonal antibodies have become front runners in the fight against cancer. The Antibody and Vaccine Group in the Cancer Sciences Unit works on understanding the structure and function of antibodies and uses this mechanistic insight to inform cancer treatments. They focus on two main areas: 1) improving the potency of monoclonal antibodies that target cancer cells directly, via FcR-expressing effector cells and complement activation; and 2) developing immunostimulatory antibodies that promote the body’s immune system to provide long-lasting cancer immunity. These latter reagents are also being developed, in collaboration with colleagues in Southampton, for use in combination with cancer vaccines such as RNA and other adjuvants. The field of immunostimulation has been given a major boost by the recent success of anti-PD-1, anti-CTLA-4 and anti-CD40 in ‘difficult to treat’ cancers such as metastatic melanoma.
1) Improving the effectiveness of anti-cancer mAb
Antibodies such a rituximab, ofatumumab and alemtuzumab which target lymphomas directly rely mainly on FcR-expressing myeloid cells to deliver their killing activity. It is known that the balance of activatory and inhibitory FcR on these effector cells is one of the factors in determining how effectively they control cancer. The Antibody and Vaccine Group, including Profs Glennie, Johnson, and Cragg and Dr Beers, is looking at this issue in detail, asking which are the important effectors in therapy, how important different FcR are, how FcR expression changes in a mature tumour environment and how FcR expression can be manipulated to favour antibody therapy. By changing the activation status of effector cells in the tumour, they envisage being able to influence the ratio of activatory to inhibitory receptors and thereby improve antibody therapy.
This group defined the Type I and II classification of anti-CD20 monoclonal antibodies and contributed to the production and approval of ofatumumab and obinutuzumab. They were also the first to show that the inhibitory FcR, FcγRIIb, expressed on B-cell malignancies may play a critical role in determining the effectiveness of the anti-CD20 mAb, rituximab and other Type I mAb. Despite rituximab’s success in the treatment of B-cell malignancies, tumour resistance remains a significant problem, and the work of the Southampton team shows that internalization of rituximab from the surface of certain B-cell malignancies limits engagement of natural effectors and increases mAb consumption. This internalization is most evident in diseases such as chronic lymphocytic leukaemia (CLL) and mantle cell lymphoma (MCL) which remain relatively unresponsive to rituximab. They have now demonstrated that the inhibitory FcγRIIb on target B cells promotes rituximab internalisation and that the level FcγRIIb expression is inversely related to the rate and extent of rituximab internalisation. Early results show that in MCL patients, high FcγRIIb expression may actually predict less durable responses following rituximab-containing regimens. Therefore, FcγRIIb expression provides a potential biomarker of response to rituximab and identifies patients for which treatment with non-internalising, so-called type II, anti-CD20 monoclonal antibodies may be preferable.
2) Generating the most potent immunostimulatory monoclonal antibodies
Immunostimulatory monoclonal antibodies became newsworthy when the drug ipilimumab proved effective against metastatic melanoma and was approved for patients by the Food and Drug Administration. The Antibody and Vaccine Group first discovered this class of reagent back in the late 1990s when they showed that an agonistic antibody against CD40, a member of the TNFR superfamily (TNFRSF), could promote a powerful anti-cancer CD8 T-cell response that cleared tumours and provided long-lasting tumour immunity. They have gone on to develop an engineered anti-CD40 monoclonal antibody (ChiLob7-4), which has now completed phase I trials. It appears that these reagents work primarily by binding to CD40 on antigen presenting cells such as dendritic cells, but probably also B cells, and activating them to a level that allows the generation of effective tumour-specific T cells. Often this is achieved without the need for T-cell help, allowing responses in the absence of the rare helper epitopes. Dr White, also part of the Southampton team, has recently shown a critical role for FcγRIIb as a promoter of the agonistic activity of certain anti-CD40 mAb. This opens up the possibility of refining agonistic activity by engineering reagents which bind with the correct affinity to this receptor.
In 2009 Profs Glennie and Al-Shamkhani, together with collaborators in Southampton (Profs Cragg, Johnson, and Ottensmeier) and Oxford (Professor N Barclay and Dr M Brown) were awarded a Cancer Research UK Discovery Programme to develop reagents to various other members of the TNF receptor superfamily (TNFRSF). This programme has now produced agonistic reagents recognising OX40 and 4-1BB, for clinical use, and is also providing selected reagents for a consortium of four cancer immunology centres and four SMEs across Europe focused on developing agonistic antibodies for use in difficult to treat cancers. This work is supported by the EU framework 7 until 2017. Finally, the Antibody and Vaccine Group are working with collaborators in the USA (Dr T Bullock (Virginia) and Celldex Therapeutics) to develop immunostimulatory monoclonal antibodies against the TNFRSF molecule CD27. The patent for this target was awarded to Southampton/Celldex in 2013.
Antagonistic Human FcγRIIB (CD32B) antibodies have anti-tumor activity and overcome resistance to antibody therapy in vivo. - Roghanian, Ali, Teige, Ingrid, Mårtensson, Linda, Cox, Kerry L., Kovacek, Mathilda, Ljungars, Anne, Mattson, Jenny, Sundberg, Annika, Vaughan, Andrew T., Shah, Vallari, Smyth, Neil R., Sheth, Bhavwanti, Chan, H.T. Claude, Li, Zhan-Chun, Williams, Emily L., Manfredi, Giusi, Oldham, Robert J., Mockridge, C. Ian, James, Sonya A., Dahal, Lekh N., Hussain, Khiyam, Nilsson, Björn, Verbeek, J. Sjef, Juliusson, Gunnar, Hansson, Markus, Jerkeman, Mats, Johnson, Peter W.M., Davies, Andrew, Beers, Stephen A., Glennie, Martin J., Frendéus, Björn and Cragg, Mark S.
Postgraduate School Programme, Taught course: including, antibody structure/function and cancer immunotherapy.
Professor Martin Glennie Antibody and Vaccine Group Cancer Sciences Unit Faculty of Medicine University of Southampton Southampton General Hospital Mailpoint 88 Tremona Road Southampton SO16 6YD Tel: 023 8120 6593 Email: M.J.Glennie@soton.ac.uk