Medicine

Martin Glennie

BSc, PhD

Primary position:
Professor of Immunochemistry
Other positions:
Head of Cancer Sciences

Background

The University of Southampton

Professor Glennie was appointed a personal chair in 1999 and became Head of the Cancer Sciences Unit in 2005. 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.

Qualifications

BSc, University of Southampton 1977
PhD, University of Southampton 1980

Appointments held

Professional Employment

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-present Head of Cancer Sciences Unit, Faculty of Medicine

Professor Martin Glennie's photo

Publications

The University of Southampton's electronic library (e-prints)

Article

Chowdhury, Ferdousi, Lode, Holger N., Cragg, Mark S., Glennie, Martin J. and Gray, Juliet C. (2014) Development of immunomonitoring of antibody-dependent cellular cytotoxicity against neuroblastoma cells using whole blood. Cancer Immunology, Immunotherapy, 63, (6), 559-569. (doi:10.1007/s00262-014-1534-y). (PMID:24658837).
Vaughan, A.T., Iriyama, C., Beers, S.A., Chan, C.H.T., Lim, S.H., Williams, E.L., Shah, V., Roghanian, A., Frendeus, B., Glennie, M.J. and Cragg, M.S. (2013) Inhibitory FcyRIIb (CD32b) becomes activated by therapeutic mAb in both cis and trans and drives internalization according to antibody specificity. Blood, 1-33. (doi:10.1182/blood-2013-04-490821).
Williams, E.L., Tutt, A.L., Beers, S.A., French, R.R., Chan, C.H.T., Cox, K.L., Roghanian, A., Penfold, C.A., Butts, C.L., Boross, P., Verbeek, J.S., Cragg, M.S. and Glennie, M.J. (2013) Immunotherapy targeting inhibitory Fcγ receptor IIB (CD32b) in the mouse is limited by monoclonal antibody consumption and receptor internalization. Journal of Immunology, 191, (8), 4130-4140. (doi:10.4049/jimmunol.1301430). (PMID:24026082).
Williams, Emily L., Dunn, Stuart N., James, Sonya, Johnson, Peter W., Cragg, Mark S., Glennie, Martin J. and Gray, Juliet C. (2013) Immunomodulatory monoclonal antibodies combined with peptide vaccination provide potent immunotherapy in an aggressive murine neuroblastoma model. Clinical Cancer Research, 19, (13), 3545-3555. (doi:10.1158/1078-0432.CCR-12-3226). (PMID:23649004).
King, Ben C., Hamblin, Angela D., Savage, Philip M., Douglas, Leon R., Hansen, Ted H., French, Ruth R., Johnson, Peter W.M. and Glennie, Martin J. (2013) Antibody-peptide-MHC fusion conjugates target non-cognate T cells to kill tumour cells. Cancer Immunology Immunotherapy, 62, (6), 1093-1105. (doi:10.1007/s00262-013-1408-8). (PMID:23604105).
Lee, Chern Siang, Cragg, Mark, Glennie, Martin and Johnson, Peter (2013) Novel antibodies targeting immune regulatory checkpoints for cancer therapy. British Journal of Clinical Pharmacology (doi:10.1111/bcp.12164). (PMID:23701301).
White, Ann L., Chan, H. T. Claude, French, Ruth R., Beers, Stephen A., Cragg, Mark S., Johnson, Peter W. M. and Glennie, Martin J. (2013) FcγRΙΙB controls the potency of agonistic anti-TNFR mAbs. Cancer Immunology and Immunotherapy (doi:10.1007/s00262-013-1398-6). (PMID:23543215).
Teeling, Jessica L., Carare, Roxana O., Glennie, Martin J. and Perry, V. Hugh (2012) Intracerebral immune complex formation induces inflammation in the brain that depends on Fc receptor interaction. Acta Neuropathologica, 124, (4), 479-490. (doi:10.1007/s00401-012-0995-3).
Williams, Emily, Tutt, Alison L., French, Ruth R., Chan, H.T. Claude, Lau, Betty, Penfold, Christine, Mockridge, C. Ian, Roghanian, A, Cox, K., Verbeek, Sjef, Glennie, Martin J. and Cragg, Mark S. (2012) Development and characterisation of monoclonal antibodies specific for the murine inhibitory Fc gamma receptor FcgRIIB (CD32B). European Journal of Immunology
Lim, Sean, Vaughan, Andrew, Ashton-Key, Margaret, Williams, E.L., Dixon, S., Chan, H.T. Claude, Beers, Stephen, French, R.R., Cox, K., Davies, AJ, Potter, Kathleen N., Mockridge, C.I., Oscier, David G., Johnson, P.W.M., Cragg, Mark and Glennie, Martin (2011) Fc gamma receptor IIb on target B cells promotes rituximab internalization and reduces clinical efficacy. Blood, 118, (9), 2530-2540. (doi:10.1182/blood-2011-01-330357 ). (PMID:21768293).
White, Ann L., Chan, H.T. Claude, Roghanian, Ali, French, Ruth R., Mockridge, C. Ian, Tutt, Alison L., Dixon, Sandra V., Ajona, Daniel, Verbeek, J. Sjef, Al-Shamkhani, Aymen, Cragg, Mark S., Beers, Stephen A. and Glennie, Martin J. (2011) Interaction with FcyRIIB is critical for the agonistic activity of anti-CD40 monoclonal antibody. The Journal of Immunology, 187, (4), 1754-1763. (doi:10.4049/jimmunol.1101135). (PMID:21742972).
Lunnon, Katie, Teeling, Jessica L., Tutt, Alison L., Cragg, Mark S., Glennie, Martin J. and Perry, V. Hugh (2011) Systemic inflammation modulates Fc receptor expression on microglia during chronic neurodegeneration. Journal of Immunology, 186, (12), 7215-7224. (doi:10.4049/jimmunol.0903833).
Alduaij, Waleed, Ivanov, Andrei, Honeychurch, Jamie, Cheadle, Eleanor, Potluri, Sandeep, Lim, Sean H., Shimada, Kazuyuki, Chan, Claude H.T., Tutt, Alison L., Beers, Stephen A., Glennie, Martin J., Cragg, Mark S. and Illidge, Tim M. (2011) Novel type II anti-CD20 monoclonal antibody (GA101) evokes homotypic adhesion and actin-dependent, lysosome-mediated cell death in B-cell malignancies. Blood, 117, (17), 4519-4529. (doi:10.1182/blood-2010-07-296913 ). (PMID: 21378274).
Chowdhury, F., Tutt, A.L., Chan, C., Glennie, M. and Johnson, P.W. (2010) Development, validation and application of ELISAs for pharmacokinetic and HACA assessment of a chimeric anti-CD40 monoclonal antibody in human serum. Journal of Immunological Methods, 363, (1), Winter Issue, 1-8. (doi:10.1016/j.jim.2010.09.023). (PMID:20869964).
Roberts, D.J., Franklin, N.A., Kingeter, L.M., Yagita, H., Tutt, Alison L, Glennie, Martin J. and Bullock, T.N. (2010) Control of established melanoma by CD27 stimulation is associated with enhanced effector function and persistence, and reduced PD-1 expression of tumor infiltrating CD8(+) T cells. Journal of Immunotherapy, 33, (8), Winter Issue, 769-779. (doi:10.1097/CJI.0b013e3181ee238f). (PMID:20842060).
Workman, P., Aboagye, E.O., Balkwill, F., Balmain, A., Bruder, G., Chaplin, D.J., Double, J.A., Everitt, J., Farningham, D.A., Glennie, M.J., Kelland, L.R., Robinson, V., Stratford, I.J., Tozer, G.M., Watson, S., Wedge, S.R. and Eccles, S.A. (2010) Guidelines for the welfare and use of animals in cancer research. British Journal of Cancer, 102, 1555-1577. (doi:10.1038/sj.bjc.6605642). (PMID:20502460).
White, A., Tutt, A., James, S., Wilkinson, K., Castro, F., Dixon, S., Hitchcox, J., Kahn, M., Al-Shamkhani, A., Cunningham, A. and Glennie, M. (2010) Ligation of CD11c during vaccination promotes germinal centre induction and robust humoral responses without adjuvant. Immunology, 131, (1), 141-151. (PMID:20465572).
Beers, Stephen A., Chan, H.T. Claude, French, Ruth R., Cragg, Mark S. and Glennie, Martin J. (2010) CD20 as a Target for Therapeutic Type I and II Monoclonal Antibodies. Seminars in Hematology. Seminars in Hematology, 47, (2), 107-114. (doi:10.1053/j.seminhematol.2010.01.001 ).
Beers, Stephen A., French, Ruth R., Chan, Claude H.T., Lim, Sean H., Jarrett, Timothy C., Mora Vidal, Regina, Wijayaweera, Sahan S., Dixon, Sandra V., Kim, Hyung J. , Cox, Kerry L. , Kerr, Jonathan P. , Johnston, David A. , Johnson, Peter W.M. , Verbeek, Sjef , Glennie, Martin J. and Cragg, Mark S. (2010) Antigenic modulation limits the efficacy of anti-CD20 antibodies: implications for antibody selection. Blood, 115, (25), 5191-5201. (doi:10.1182/blood-2010-01-263533). (PMID:20223920).
Lim, Sean H., Beers, Stephen A., French, Ruth R., Johnson, Peter W., Glennie, Martin J. and Cragg, Mark S. (2010) Anti-CD20 monoclonal antibodies: historical and future perspectives. Haematologica, 95, (1), 135-143. (doi:10.3324/haematol.2008.001628). (PMID:19773256).
Walton, James A., Lydyard, Peter M., Nathwani, Amit, Emery, Vincent, Akbar, Arne, Glennie, Martin J. and Poraskishvili, Nino (2009) Patients with B cell chronic lymphocytic leukaemia have an expanded population of CD4 perforin expressing T cells enriched for human cytomegalovirus specificity and an effector-memory phenotype. British Journal of Haematology, 148, (2), 274-284. (doi:10.1111/j.1365-2141.2009.07964.x).
Ivanov, Andrei, Beers, Stephen A., Walshe, Claire A., Honeychurch, Jamie, Aldjuaij, Waleed, Cox, Kerry L., Potter, Kathleen N., Murray, Stephen, Chan, Claude H.T., Klymento, Tetyana, Erenpreisa, Jekatarina, Glennie, Martin J., Illidge, Tim M. and Cragg, Mark S. (2009) Monoclonal antibodies directed to CD20 and HLA-DR can elicit homotypic adhesion followed by lysosome-mediated cell death in human lymphoma and leukemia cells. Journal of Clinical Investigation, 119, (8), 2143-2159. (doi:10.1172/JCI37884).
Bournazos, Stylianos, Hart, Simon P., Chamberlain, Luke H., Glennie, M.J. and Dransfield, Ian (2009) Association of FcγRIIa (CD32a) with lipid rafts regulates ligand binding activity. The Journal of Immunology, 182, 8026 -8036 . (doi:10.4049/jimmunol.0900107 ).
Beers, Stephen A., Chan, Claude H.T., James, Sonya, French, Ruth R., Attfield, Katherine E., Brennan, Claire M., Ahuja, Anupama, Shlomchik, Mark J., Cragg, Mark S. and Glennie, Martin J. (2008) Type II (tositumomab) anti-CD20 monoclonal antibody out performs type 1 (rituximab-like) reagents in B-cell depletion regardless of complement activation. Blood, 112, (10), 4170-4177. (doi:10.1182/blood-2008-04-149161).
Gray, Juliet C., French, Ruth R., James, Sonya, Al-Shamkhani, Aymen, Johnson, Peter W. and Glennie, Martin J. (2008) Optimising anti-tumour CD8 T-cell responses using combinations of immunomodulatory antibodies. European Journal of Immunology, 38, (9), 2499-2511. (doi:10.1002/eji.200838208). (PMID:18792403).
Walshe, Claire A., Beers, S.A., French, Ruth R., Chan, H.T. Claude, Johnson, P. W., Packham, Graham, Glennie, Martin J. and Cragg, Mark S. (2008) Induction of cytosolic calcium flux by CD20 Is dependent upon B cell antigen receptor signaling. Journal of Biological Chemistry, 283, (25), 16971-16984. (doi:10.1074/jbc.M708459200).
Bleeker, Wim K., Munk, Martin E., Mackus, Wendy J.M., van den Brakel, Jeroen H.N., Pluyter, Marielle, Glennie, Martin J., van de Winkel, Jan G.J. and Parren, Paul W.H.L. (2008) Estimation of dose requirements for sustained in vivo activity of a therapeutic human anti-CD20 antibody. British Journal of Haematology, 140, (3), 303-312. (doi:10.1111/j.1365-2141.2007.06916.x ).
Taraban, Vadim Y., Martin, Sonya, Attfield, Kathrine E., Glennie, Martin J., Elliott, Tim, Elewaut, Dirk, Van Calenbergh, Serge, Linclau, Bruno and Al-Shamkhani, Aymen (2008) Invariant NKT cells promote CD8(+) cytotoxic T cell responses by inducing CD70 expression on dendritic cells. Journal of Immunology, 180, (7), 4615-4620. (PMID:18354184).
Castro, Fernanda V.V., Tutt, Alison L., White, Ann L., Teeling, Jessica L., James, Sonya, French, Ruth R. and Glennie, Martin J. (2008) CD11c provides an effective immunotarget for the generation of both CD4 and CD8 T cell responses. European Journal of Immunology, 38, (8), 2263 -2273. (doi:10.1002/eji.200838302). (PMID:18651710).
Glennie, Martin J., French, Ruth R., Cragg, Mark S. and Taylor, Ronald P. (2007) Mechanisms of killing by anti-CD20 monoclonal antibodies. Molecular Immunology, 44, (16), 3823-3837. (doi:10.1016/j.molimm.2007.06.151).
Savage, Phillip, Dyson, Julian, Milrain, Maggie, Mathews, Douglas, King, Ben, Chan, H.T. Claude, Barber, Linda, Epenetos, Agamemnon, Ogg, Graham, McMichael, Andrew, Glennie, Martin J. and French, Ruth R. (2007) Immunotherapy with antibody-targeted HLA class I complexes: results of in vivo tumour cell killing and therapeutic vaccination. Tumor Biology, 28, (4), 205-211. (doi:10.1159/000107416). (PMID:17709989).
Horner, Heike, Frank, Carola, Dechant, Claudia, Repp, Roland, Glennie, Martin, Herrmann, Martin and Stockmeyer, Bernhard (2007) Intimate cell conjugate formation and exchange of membrane lipids precede apoptosis induction in target cells during antibody-dependent, granulocyte-mediated cytotoxicity. Journal of Immunology, 179, (1), 337-345. (PMID:17579054).
Melero, Ignatio, Hervas-Stubbs, Sandra, Glennie, Martin, Pardoll, Drew M. and Chen, Lieping P. (2007) Immunostimulatory monoclonal antibodies for cancer therapy. Nature Reviews Cancer, 7, (2), 95-106. (doi:10.1038/nrc2051).
Du, Yong, Honeychurch, Jamie, Glennie, Martin, Johnson, Peter and Illidge, Tim (2007) Microscopic intratumoral dosimetry of radiolabeled antibodies is a critical determinant of successful radioimmunotherapy in B-cell lymphoma. Cancer Research, 67, (3), 1335-1343. (doi:10.1158/0008-5472.CAN-06-2495).
French, Ruth R., Taraban, Vadim Y., Crowther, Graham R., Rowley, Tania F., Gray, Juliet C., Johnson, Peter W., Tutt, Alison L., Al-Shamkhani, Aymen and Glennie, Martin J. (2007) Eradication of lymphoma by CD8 T cells following anti-CD40 monoclonal antibody therapy is critically dependent on CD27 costimulation. Blood, 109, (11), 4810-4815. (doi:10.1182/blood-2006-11-057216).
Savage, Philip, Dyson, Julian, French, Ruth and Glennie, Martin (2006) Immunotherapy with antibody targeted MHC complexes: results of in vivo tumour cell killing and therapeutic vaccination. Journal of Immunotherapy, 29, (6), 636-637. (doi:10.1097/01.cji.0000211343.73588.59).
Teeling, Jessica L., Mackus, Wendy J.M., Wiegman, Luus J.J.M., van den Brakel, Jeroen H.N., Beers, Stephen A., French, Ruth R., van Meerten, Tom, Ebeling, Saskia, Vink, Tom, Slootstra, Jerry W., Parren, Paul W.H.I., Glennie, Martin J. and van den Winkel, Jan G.J. (2006) The biological activity of human CD20 monoclonal antibodies is linked to unique epitopes on CD20. Journal of Immunology, 177, (1), 362-371.
Gray, J.C., Johnson, P.W.M. and Glennie, M.J. (2006) Therapeutic potential of immunostimulatory monoclonal antibodies. Clinical Science, 111, (2), 93-106.
Teeling, Jessica L., Mackus, Wendy J. M., Wiegman, Luus J. J. M., van den Brakel, Jeroen H. N., Beers, Stephen A., French, Ruth R., van Meerten, Tom, Ebeling, Saskia, Vink, Tom, Slootstra, Jerry W., Parren, Paul W. H. I., Glennie, Martin J. and van de Winkel, Jan G. J. (2006) The biological activity of human CD20 monoclonal antibodies is linked to unique epitopes on CD2013. Journal of Immunology, 177, (1), 362-371.
Gidron, Yori, Perry, Hugh and Glennie, Martin (2005) Does the vagus nerve inform the brain about preclinical tumours and modulate them? Lancet Oncology, 6, (4), 245-248. (doi:10.1016/S1470-2045(05)70096-6). (PMID:15811620).
Honeychurch, Jamie, Glennie, Martin J. and Illidge, Timothy M. (2005) Cyclophosphamide inhibition of anti-CD40 monoclonal antibody-based therapy of B cell lymphoma is dependent on CD11b+ cells. Cancer Research, 65, (16), 7493-7501. (doi:10.1158/0008-5472.CAN-04-3808).
Cragg, M.S., Walshe, C.A., Ivanov, A.O. and Glennie, M.J. (2005) The biology of CD20 and its potential as a target for mAb therapy. Current directions in autoimmunity, 8, 140-174. (doi:10.1159/000082102).
Porakishvili, N., Kardava, L., Jewell, A. P., Yong, K., Glennie, M. J., Akbar, A. and Lydyard, P. M. (2004) Cytotoxic CD4+ T cells in patients with B cell chronic lymphocytic leukemia kill via a perforin-mediated pathway. Haematologica, 89, (4), 435-443.
Teeling, J.L., French, R.R., Cragg, M.S., Van den Brakel, J., Pluyter, M., Huang, H., Chan, C., Parren, P.W., Hack, C.E., Dechant, M., Valerius, T., Van de Winkel, J.G. and Glennie, M.J. (2004) Characterization of new human CD20 monoclonal antibodies with potent cytolytic activity against non-Hodgkin lymphomas. Blood, 104, (6), 1793-1800. (doi:10.1182/blood-2004-01-0039).
Du, Yong, Honeychurch, Jamie, Cragg, Mark S., Bayne, Mike, Glennie, Martin J., Johnson, Peter W.M. and Illidge, Tim M. (2004) Antibody-induced intracellular signaling works in combination with radiation to eradicate lymphoma in radioimmunotherapy. Blood, 103, (4), 1485-1494. (doi:10.1182/blood-2003-06-2037).
Cragg, Mark S. and Glennie, Martin J. (2004) Antibody specificity controls in vivo effector mechanisms of anti-CD20 reagents. Blood, 103, (7), 2738-2743. (doi:10.1182/blood-2003-06-2031).
Cragg, M. S., Bayne, M. C., Illidge, T. M., Valerius, T., Johnson, P. W. and Glennie, M. J. (2004) Apparent modulation of CD20 by rituximab: an alternative explanation. Blood, 103, (10), 3989-3991.
Cragg, Mark S., Bayne, Mike B., Tutt, Alison L, French, Ruth R., Beers, Stephen, Glennie, Martin J. and Illidge, Timothy M. (2004) A new anti-idiotype antibody capable of binding rituximab on the surface of lymphoma cells. Blood, 104, (8), 2540-2542. (doi:10.1182/blood-2004-05-1733).
Chan, H.T. Claude, Hughes, David, French, Ruth R., Tutt, Alison L., Walshe, Claire A., Teeling, Jessica L., Glennie, Martin J. and Cragg, Mark S. (2003) CD20-induced lymphoma cell death is independent of both caspases and its redistribution into triton X-100 insoluble membrane rafts. Cancer Research, 63, (17), 5480-5489.
Chan, H.T.C., Hughes, David, French, Ruth.R., Tutt, Alison.L., Walshe, Claire.A., Teeling, Jessica.L., Glennie, Martin.J. and Cragg, Mark.S. (2003) CD20-induced lymphoma cell death is independent of both caspases and its redistribution into Triton X-100 insoluble membrane rafts. Cancer Research, 63, 5480-5489.
Prodhomme, Emmanuel J.F., Tutt, Alison L., Glennie, Martin J. and Bugg, Timothy D.H. (2003) Multivalent conjugates of poly-γ-D-glutamic acid from Bacillus licheniformis with antibody F(ab') and glycopeptide ligands. Bioconjugate Chemistry, 14, (6), 1148-1155. (doi:10.1021/bc020019m S1043-1802(02)00019-8).
Cragg, Mark S., Morgan, Suzanne M., Chan, H.T. Claude, Morgan, B. Paul, Filatov, A.V., Johnson, Peter W.M., French, Ruth R. and Glennie, Martin J. (2003) Complement-mediated lysis by anti-CD20 mAb correlates with segregation into lipid rafts. Blood, 101, (3), 1045-1052. (doi:10.1182/blood-2002-06-1761).
Glennie, Martin J. and van de Winkel, Jan G.J. (2003) Renaissance of cancer therapeutic antibodies. Drug Discovery Today, 8, (11), 503-510. (doi:10.1016/S1359-6446(03)02714-4).
Honeychurch, Jamie, Glennie, Martin J., Johnson, Peter W.M. and Illidge, Timothy M. (2003) Anti-CD40 monoclonal antibody therapy in combination with irradiation results in a CD8 T-cell-dependent immunity to B-cell lymphoma. Blood, 102, (4), 1449-1457. (doi:10.1182/blood-2002-12-3717.).
Cragg, Mark S., Chan, H.T. Claude, Fox, Matthew D., Tutt, Alison, Smith, Aaimée, Oscier, David G., Hamblin, Terry J. and Glennie, Martin J. (2002) The alternative transcript of CD79b is overexpressed in B-CLL and inhibits signaling for apoptosis. Blood, 100, (9), 3068-3076. (doi:10.1182/blood.V100.9.3068).
Tutt, Alison L., O'Brien, Lyn, Hussain, Akmal, Crowther, Graham R., French, Ruth R. and Glennie, Martin J. (2002) T cell immunity to lymphoma following treatment with anti-CD40 monoclonal antibody. Journal of Immunology, 168, (6), 2720-2728.
Stadick, H., Stockmeyer, B., Kuhn, R., Schrott, K.M., Kalden, J.R., Glennie, M.J., Van de Winkel, J.G., Gramatzki, M., Valerius, T. and Elsasser, D. (2002) Epidermal growth factor receptor and g250: useful target antigens for antibody mediated cellular cytotoxicity against renal cell carcinoma? The Journal of Urology, 167, (2 Pt 1), 707-712.
Taraban, Vadim Y., Rowley, Tania F., O'Brien, Lyn, Chan, H.T. Claude, Haswell, Linsey E., Green, Michael H.A, Tutt, Alison L., Glennie, Martin J. and Al-Shamkhani, Aymen (2002) Expression and costimulatory effects of the TNF receptor superfamily members CD134 (OX40) and CD137 (4-1BB), and their role in the generation of anti-tumor immune responses. European Journal of Immunology, 32, (12), 3617-3627. (doi:10.1002/1521-4141(200212)32:12<3617::AID-IMMU3617>3.0.CO;2-M).
Dechant, Michael, Vidarsson, Gestur, Stockmeyer, Bernhard, Repp, Roland, Glennie, Martin J., Gramatzki, Martin, van de Winkel, G.J and Valerius, Thomas (2002) Chimeric IgA antibodies against HLA class II effectively trigger lymphoma cell killing. Blood, 100, (13), 4574-4580. (doi:10.1182/blood-2002-03-0687).
Lee-MacAry, Alice E., Ross, Elizabeth L., Davies, Derek, Laylor, Ruthline, Honeychurch, Jamie, Glennie, Martin J., Snary, David and Wilkinson, Robert W. (2001) Development of a novel flow cytometric cell-mediated cytotoxicity assay using the fluorophores PKH-26 and TO-PRO-3 iodide. Journal of Immunological Methods, 252, (1-2), 83-92. ( doi:10.1016/S0022-1759(01)00336-2).
Stockmeyer, Bernhard, Elsässer, David, Dechant, Michael, Repp, Roland, Gramatzki, Martin, Glennie, Martin J., van de Winkel, Jan G.J. and Valerius, Thomas (2001) Mechanisms of G-CSF- or GM-CSF-stimulated tumor cell killing by Fc receptor-directed bispecific antibodies. Journal of Immunological Methods, 248, (1-2), 103-111. (doi:10.1016/S0022-1759(00)00346-X).
Todryk, Stephen M., Tutt, Alison L., Green, Michael H.A., Smallwood, J.A., Halanek, Nicole, Dalgleish, Angus G. and Glennie, Martin J. (2001) CD40 ligation for immunotherapy of solid tumours. Journal of Immunological Methods, 248, (1-2), 139-147. (doi:10.1016/S0022-1759(00)00349-5).
Johnson, P.W.M. and Glennie, M.J. (2001) Rituximab: mechanisms and applications. British Journal of Cancer, 85, (11), 1619-1623. (doi:10.1054/bjoc.2001.2127).
Haswell, Linsey E., Glennie, Martin J. and Al-Shamkhani, Aymen (2001) Analysis of the oligomeric requirement for signaling by CD40 using soluble multimeric forms of its ligand, CD154. European Journal of Immunology, 31, (10), 3094-3100. (doi:10.1002/1521-4141(2001010)31:10<3094::AID-IMMU3094>3.0.CO;2-F).
Honeychurch, Jamie, Tutt, Alison L., Heijnen, Ingmar A.F.M., van de Winkel, Jan G.J. and Glennie, Martin J. (2000) Therapeutic efficacy of FcgammaRI/CD64-directed bispecific antibodies in B-cell lymphoma. Blood, 96, (10), 3544-3552. (PMID:11071653).
Glennie, M.J. (2000) Signalling antibodies for the treatment of neoplastic disease. Disease Markers, 16, (1-2), 63-63. (PMID:11360830).
French, R.R., Chan, H.T.C., Tutt, A.L. and Glennie, M.J. (1999) CD40 antibody evokes a cytotoxic T-cell response that eradicates lymphoma and bypasses T-cell help. Nature Medicine, 5, (5), 549-553. (doi:10.1038/8426). (PMID:10229232).
 

Research

Research Interests

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.

Academic unit:  Cancer Sciences

Research project

Improving immunotherapy for Alzheimer’s diseases by modulating FcR interaction: an antibody engineering approach.

This MRC funded CASE studenship aims to understanding the role of FcγR in immunotherapy for neurodegenerative diseases. This work is done in collaboration with Lundbeck.

Figure 1

Effector function of mAb therapy

Figure 1

Figure 2

Anti-tumour effector mechanism

Figure 2

Responsibilities

Head of Cancer Sciences Unit

Teaching Responsibilities

Postgraduate School Programme, Taught course: including, antibody structure/function and cancer immunotherapy.

Contact

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

Room Number: SGH/Tenovus/MP88