Bio

Honors & Awards


  • Royal College of Pathologists Specialty Research Medal, Royal College of Pathologists (UK) (2012)
  • Clinician Scientist Fellowship, Cancer Research UK (2012)
  • Catovsky Prize, UK CLL Forum (2011)
  • Academic Clinical Trainee Conference - Best Oral Presentation, University of Southampton, UK (2010)
  • Translation Research Conference - Poster Prize, University of Southampton & Southampton University Hospital NHS Trust (2010)
  • Clinical Research Training Fellowship, Medical Research Council, UK (2008)

Professional Education


  • Doctor of Medicine, University Of Bristol (2001)
  • Doctor of Philosophy, University Of Southampton (2011)

Stanford Advisors


Publications

Journal Articles


  • CHEMOTHERAPY Advanced Hodgkin lymphoma-balancing toxicity and cure NATURE REVIEWS CLINICAL ONCOLOGY Lim, S. H., Johnson, P. W. 2011; 8 (11): 634-636

    View details for DOI 10.1038/nrclinonc.2011.137

    View details for Web of Science ID 000296812500003

    View details for PubMedID 21894205

  • Fc gamma receptor IIb on target B cells promotes rituximab internalization and reduces clinical efficacy BLOOD Lim, S. H., Vaughan, A. T., Ashton-Key, M., Williams, E. L., Dixon, S. V., Chan, H. T., Beers, S. A., French, R. R., Cox, K. L., Davies, A. J., Potter, K. N., Mockridge, C. I., Oscier, D. G., Johnson, P. W., Cragg, M. S., Glennie, M. J. 2011; 118 (9): 2530-2540

    Abstract

    The anti-CD20 mAb rituximab is central to the treatment of B-cell malignancies, but resistance remains a significant problem. We recently reported that resistance could be explained, in part, by internalization of rituximab (type I anti-CD20) from the surface of certain B-cell malignancies, thus limiting engagement of natural effectors and increasing mAb consumption. Internalization of rituximab was most evident in chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), but the extent of internalization was heterogeneous within each disease. Here, we show that the inhibitory FcγRIIb on target B cells promotes this process and is largely responsible for the observed heterogeneity across a range of B-cell malignancies. Internalization correlated strongly with FcγRIIb expression on normal and malignant B cells, and resulted in reduced macrophage phagocytosis of mAb-coated targets. Furthermore, transfection of FcγRIIb into FcγRIIb negative Ramos cells increased internalization of rituximab in a dose-dependent manner. Target-cell FcγRIIb promoted rituximab internalization in a cis fashion and was independent of FcγRIIb on neighboring cells. It became phosphorylated and internalized along with CD20:anti-CD20 complexes before lysosomal degradation. In MCL patients, high FcγRIIb expression predicted less durable responses after rituximab-containing regimens. Therefore, target-cell FcγRIIb provides a potential biomarker of response to type I anti-CD20 mAb.

    View details for DOI 10.1182/blood-2011-01-330357

    View details for Web of Science ID 000294476400025

    View details for PubMedID 21768293

  • Novel type II anti-CD20 monoclonal antibody (GA101) evokes homotypic adhesion and actin-dependent, lysosome-mediated cell death in B-cell malignancies BLOOD Alduaij, W., Ivanov, A., Honeychurch, J., Cheadle, E. J., Potluri, S., Lim, S. H., Shimada, K., Chan, C. H., Tutt, A., Beers, S. A., Glennie, M. J., Cragg, M. S., Illidge, T. M. 2011; 117 (17): 4519-4529

    Abstract

    The anti-CD20 mAb rituximab has substantially improved the clinical outcome of patients with a wide range of B-cell malignancies. However, many patients relapse or fail to respond to rituximab, and thus there is intense investigation into the development of novel anti-CD20 mAbs with improved therapeutic efficacy. Although Fc-FcγR interactions appear to underlie much of the therapeutic success with rituximab, certain type II anti-CD20 mAbs efficiently induce programmed cell death (PCD), whereas rituximab-like type I anti-CD20 mAbs do not. Here, we show that the humanized, glycoengineered anti-CD20 mAb GA101 and derivatives harboring non-glycoengineered Fc regions are type II mAb that trigger nonapoptotic PCD in a range of B-lymphoma cell lines and primary B-cell malignancies. We demonstrate that GA101-induced cell death is dependent on actin reorganization, can be abrogated by inhibitors of actin polymerization, and is independent of BCL-2 overexpression and caspase activation. GA101-induced PCD is executed by lysosomes which disperse their contents into the cytoplasm and surrounding environment. Taken together, these findings reveal that GA101 is able to potently elicit actin-dependent, lysosomal cell death, which may potentially lead to improved clearance of B-cell malignancies in vivo.

    View details for DOI 10.1182/blood-2010-07-296913

    View details for Web of Science ID 000289984800017

    View details for PubMedID 21378274

  • Antigenic modulation limits the efficacy of anti-CD20 antibodies: implications for antibody selection BLOOD Beers, S. A., French, R. R., Chan, H. T., Lim, S. H., Jarrett, T. C., Vidal, R. M., Wijayaweera, S. S., Dixon, S. V., Kim, H., Cox, K. L., Kerr, J. P., Johnston, D. A., Johnson, P. W., Verbeek, J. S., Glennie, M. J., Cragg, M. S. 2010; 115 (25): 5191-5201

    Abstract

    Rituximab, a monoclonal antibody that targets CD20 on B cells, is now central to the treatment of a variety of malignant and autoimmune disorders. Despite this success, a substantial proportion of B-cell lymphomas are unresponsive or develop resistance, hence more potent anti-CD20 monoclonal antibodies (mAbs) are continuously being sought. Here we demonstrate that type II (tositumomab-like) anti-CD20 mAbs are 5 times more potent than type I (rituximab-like) reagents in depleting human CD20 Tg B cells, despite both operating exclusively via activatory Fcgamma receptor-expressing macrophages. Much of this disparity in performance is attributable to type I mAb-mediated internalization of CD20 by B cells, leading to reduced macrophage recruitment and the degradation of CD20/mAb complexes, shortening mAb half-life. Importantly, human B cells from healthy donors and most cases of chronic lymphatic leukemia and mantle cell lymphoma, showed rapid CD20 internalization that paralleled that seen in the Tg mouse B cells, whereas most follicular lymphoma and diffuse large B-cell lymphoma cells were far more resistant to CD20 loss. We postulate that differences in CD20 modulation may play a central role in determining the relative efficacy of rituximab in treating these diseases and strengthen the case for focusing on type II anti-CD20 mAb in the clinic.

    View details for DOI 10.1182/blood-2010-01-263533

    View details for Web of Science ID 000279113100012

    View details for PubMedID 20223920

  • Anti-CD20 monoclonal antibodies: historical and future perspectives HAEMATOLOGICA-THE HEMATOLOGY JOURNAL Lim, S. H., Beers, S. A., French, R. R., Johnson, P. W., Glennie, M. J., Cragg, M. S. 2010; 95 (1): 135-143

    Abstract

    Antibodies to CD20 have confirmed the hypothesis that monoclonal reagents can be given in vivo to alleviate human diseases. The targeting of CD20 on normal, malignant and auto-immune B-lymphocytes by rituximab has demonstrated substantial benefits for patients with a variety of B-cell lymphomas, as well as some with autoimmune disorders. There has been a notable increase in the survival rates from B-cell lymphoma in the decade since anti-CD20 therapy was introduced.

    View details for DOI 10.3324/haematol.2008.001628

    View details for Web of Science ID 000273869800022

    View details for PubMedID 19773256

  • Life-threatening bleeding in a patient with a lupus inhibitor and probable acquired factor VII deficiency BLOOD COAGULATION & FIBRINOLYSIS Lim, S., Zuha, R., Burt, T., Chacko, J., Scott, R., Mainwaring, C. J. 2006; 17 (8): 667-671

    Abstract

    We report the case of a 71-year-old man on warfarin for chronic atrial fibrillation presenting with a massive spontaneous soft tissue bleed. Despite reversing the effects of warfarin with large doses of intravenous vitamin K and fresh frozen plasma, bleeding continued, and his prothrombin time and activated partial thromboplastin time remained prolonged. The prothrombin time and activated partial thromboplastin time failed to correct with 50% normal plasma. Further investigations confirmed a lupus inhibitor with low levels of factors II, V, VII and XI. Factor II, V and XI levels normalized, however, when the patient's plasma was diluted 1:16 in buffer, suggesting the lupus inhibitor may have been interfering with these factor assays causing artefactual low results. Factor VII levels remained consistently low at all dilutions. The patient subsequently died following a massive left haemothorax despite surgical intervention and treatment with activated recombinant factor VII concentrate. We presumed the primary problem was bleeding from a local vascular lesion but the patient was never well enough to undergo confirmatory angiography. This case highlights the fact that patients with lupus inhibitors can develop severe haemorrhagic complications, and illustrates the complexities involved in both the investigation and treatment of abnormal bleeding in these patients.

    View details for Web of Science ID 000242672700010

    View details for PubMedID 17102654

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