Title: Immunomodulating Monoclonal Ab for the Promotion of Anti-Cancer T-cell Immunity
Funder: Cancer Research UK

Abstract: Immunostimulatory monoclonal antibodies which promote immune recognition of cancer have shown exciting clinical responses especially when given with a specific cancer vaccine. However, therapeutic outcomes to date have been unpredictable and problematic. This programme will rationalise the discovery of new immunostimulatory mAb using sophisticated models that predict clinical activity. Background and relevance to cancer The success of monoclonal antibodies (mAb), such as rituximab and trastuzumab, in the treatment of cancer has encouraged an intense search for new reagents. Immunomodulatory monoclonal antibodies (mAb), such as anti-CD40 and anti-CTLA-4, constitute a new class of clinical reagent designed to promote either endogenous or vaccine mediated anti-cancer T-cell immunity. Early clinical observations are compelling, with objective responses seen during single agent phase I studies in melanoma and lymphoma. However, there have also been negative studies and autoimmune toxicity is a genuine hazard. Unfortunately the drive to develop clinical applications has by-passed a detailed analysis of the properties required for an effective immunomodulatory mAb, either in terms of epitope specificity or Fc?R dependency. The importance of understanding such issues is underlined by the unpredicted and serious clinical consequences of the anti-CD28 mAb, TGN1412, and the recent difficulties encountered in the development of anti-CTLA-4 reagents. Specific Aims We propose a programme of research to deliver immunomodulatory mAb into the clinic, with detailed analysis of binding and Fc?R interactions introduced as key selection criteria for clinical candidates. The programme will focus on targeting a subset of receptors that belong to the tumour necrosis factor receptor superfamily (TNFRSF). It will benefit from antibody expertise at Southampton (Cancer Sciences Division) and Oxford (The Sir William Dunn School of Pathology), with the planning and strategy overseen by an international Scientific Steering Committee of experts in the field. Plan of Research: 1) MAb production and characterisation MAb will be produced to each of the cysteine-rich repeats (CRR) within the extracellular region of 4-1BB, OX40 and HVEM, all members of the TNFRSF. Detailed characterisation of affinity, kinetics of interactions with the receptors and epitopes will be carried out. MAb will also be assessed in vitro to quantitate signalling activity and dependency on interaction with Fc gamma receptors (FcgR). 2) Mouse models Knock-in mice will be established for the chosen human TNFRSF targets and mouse mAb will be assessed for immunomodulatory activity in vivo. 3) Humanised mAb Selected mAb (2-4 per target) will be humanised to IgG1 and IgG2 isotypes and assessed for immunostimulatory activity in mice deficient in endogenous FcgR (FcgR-IV KO), but carrying the humananised TNFRSF members and selected human FcgR. 4) Clinical trials Selected clinical candidates will be developed to phase I trials and beyond, in collaboration with the CRUK DDO. Last updated 21/07/2010


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: CANCER AND NEOPLASMS