Preclinical efficacy of an antibody of the IgE class against a melanoma-associated antigen

Cancer treatments which mobilise the patient's own immune system to fight cancerous cells (immunotherapy) are proving to be an exciting new approach in the fight against cancer. Antibodies are proteins that recognise alien entities in the body and trigger their destruction by immune cells. Antibodies recognising surface proteins (antigens) on cancer cells are now generated in the laboratory, designed to specifically seek out tumours displaying these surface antigens. To work, antibodies must also bind to immune cells, which in turn target those cancer cells. Antibodies come in five types, but only one, IgG, has been used in cancer therapy. Unfortunately, IgG binds relatively poorly to immune cells and works inefficiently in tissues, where tumours grow. Another antibody type, namely IgE, known as the key component of allergies, may be better suited to cancer therapy, because of its excellent binding to immune cells and ability to activate these cells in tissues. Our earlier work on designing IgE antibodies in relation to the therapy of ovarian cancer has already elicited encouraging results that engender optimism and we plan to test this antibody in patients soon.
We are now working to apply the same principles towards the treatment of the most lethal skin cancer, malignant melanoma. Melanoma cells are subject to immune scrutiny, that is they display on their surfaces antigens, the targets for an antibody. To investigate this, we produced CSPG4 IgE, an antibody specifically recognising melanoma cancer cells. When we tested this antibody in the laboratory, it was very effective in activating immune cells to destroy cancer. We now plan to complete these studies so that this therapy may benefit patients with malignant melanoma for whom few effective therapies are available.

The clinical landscape for the lethal skin cancer, melanoma, is transformed by novel agents including an antibody targeting T-cell regulatory pathways, which, despite moderate clinical responses and high toxicities, demonstrates promise for antibody therapies. Yet, there are presently no antibodies directly targeting melanoma cells. This strategy entails an antibody targeting melanoma antigens that is engineered with Fc regions of the IgE antibody class. Attributes of IgE such as natural tissue immune activatory functions and high affinity for cognate Fc receptors on frequently tumour-resident effector cells can translate into superior protection against solid tumours compared to conventionally-used IgGs. These advantages are demonstrated by efficacy and safety in three in vivo tumour models and remarkable progress through process development of our successful first IgE antibody targeting Folate Receptor alpha-expressing cancers, now approaching first-in-man clinical trials supported by the CRUK New Agents Committee. We engineered IgE and IgG1 antibodies recognising CSPG4, a cell surface tumour antigen over-expressed by 80% of melanomas; CSPG4 participates in melanoma pathogenesis and progression through activation of key signalling pathways. CSPG4 IgE demonstrated superior efficacy in targeting melanoma and direct and cell-mediated tumour-killing activities, suggesting a multifactorial mode of action. Background IP is owned by KCL through a PCT application filed in 2011. Here, we will evaluate efficacy and safety of this agent through functional assays on patient and healthy volunteer blood and in disease-relevant models, some of which will also serve to support future evaluations in the pre-clinical development and clinical study stages. Study design is based on expertise with our lead antibody, to directly progress CSPG4 IgE to process development and clinical trials.

Substantial knowledge on Th2 immunity in cancer and IgE functions in the context of cancer therapy is presently being acquired in conjunction with our parallel on-going research and development activities with our lead agent. These activities are fully supported from funds independent to this application and will contribute added-value to our existing activities. Collectively, our research and development activities and knowledge acquired as part of this proposed study towards the clinical application of the concept for a second target and in a different set of clinical indications are of paramount importance towards making this approach widely applicable for cancer therapy.
There are several options for the future progression of the programme, especially in relation to other cancer types known to express CSPG4. This would include expansion into larger indications such as breast cancer, including breast carcinomas termed "triple-negative." This latter programme, as part of our newly funded Breakthrough Breast Cancer Unit at King's College London/Guy's Hospital (5-year Unit headed by Prof. Andrew Tutt; co-PIs: Karagiannis, Nestle, Ng) will commence with in vitro and in vivo models of breast cancer. Application as a therapy for breast cancer and specifically for triple-negative breast carcinomas is expected to report results in parallel with data acquired as part of this proposed study and will provide added value to this study.
This study also stands to make a substantial impact in the wider field of immune and antibody therapeutics. Our research on Th2 immunity, IgE and cancer is receiving increasing attention from the academic, medical and biotechnology communities. We have been approached by three biotechnology companies (Novartis, Biotechnol, UCB) who have shown strong interest specifically in relation to IgE immunotherapy, for example toward a collaborative effort to develop IgE antibody fragments with multiple specificities including CSPG4
If successful this proposed study will: a) point to strategies by which Th2 immune responses could be harnessed to target tumours; b) provide a new therapeutic avenue to potentially benefit the majority of the 112,000 in the UK living with malignant melanoma; c) pave the way towards the development of a new class of therapeutic antibody agents with improved immune activatory functions which could be redirected against cancers of different origins.
If unsuccessful, this study will be informative in informing the design of novel immune activatory strategies, especially those aimed at overcoming tumour-induced immune escape mechanisms and those aimed at re-educating inflammatory cells to attack rather than promote tumour growth.