Targeting leukaemias with a therapeutic human antibody


Currently marketed anticancer monoclonal antibodies (mAbs) recognise extracellular proteins or those expressed on the cell surface. Generally these are not tumour-specific, as oncogenic proteins tend to be nuclear or cytoplasmic. These intracellular proteins can however, be presented on the cell surface as T cell epitopes by the major histocompatibility complex (MHC). These epitopes are recognised by T cell receptors (TCRs). Therefore, the generation of ‘TCR-like’ mAbs that can recognise cell surface epitopes that are derived from tumours are an exciting potential cancer therapy.

Dao et al., recently published a paper in Science Translational Medicine, in which they have exploited phage display technology to produce a specific mAb (ESK1) against Wilms tumor 1 (WT1), an oncoprotein that is overexpressed in both leukaemia and a range of solid tumours such as ovarian cancer and mesothelioma, but is rare in normal tissues. It was also recently ranked as a top cancer target for immunotherapy by the NIH. ESK1 targets a 9mer WT1 derived peptide (RMF) that is processed and presented by HLA-A0201. RMF induces cytotoxic T cells that are able to kill WT1+ tumour cells in vitro.

ESK1 was shown to bind to acute myeloid leukaemia (AML) CD34+/CD33+ cells expressing HLA-A02 and WT1 but not to normal peripheral blood mononuclear cells. The specificity of the binding was confirmed with other cell types with no general cross-reactivity to healthy or leukemic cells that do not express WT1. Radioimmunoassay experiments then demonstrated that there was adequate RMF expressed on the surface of many cancer and leukaemia cells, whilst the levels of epitope on WT1 negative healthy cells are low.

mAbs can cause cytotoxicity in four ways: antibody-dependent cell-mediated cytotoxicity (ADCC), complement-mediated cytotoxicity (CMC), antibody-dependent cellular phagocytosis (ADCP) and inducing apoptosis. ESK1 was shown to be active in ADCC assays against the following cell types: JMN mesothelioma, BV173 leukaemia, ovarian carcinoma, colon carcinoma cell lines and AML cells. No other form of mAb-mediated cytotoxicity was observed.

The efficacy of ESK1 was then tested in vivo in mice that had been xenografted with BV173 acute lymphoblastic leukaemia (ALL) cells or BA25 acute lymphocytic leukaemia. Two intravenous doses of 100ug of ESK1, when administered in conjunction with human effector cells, suppressed the growth of  leukemic cells in both animal models. Prolonged or, in some cases, leukaemia-free survival were observed. Two control studies confirmed that the RMF/A2 epitope was required for the therapeutic effect observed. Further, no evidence of toxicity was observed in transgenic mice when given therapeutic doses of ESK1.

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Survival of NSG mice with BV173 leukaemia. **P<0.01 for all treatment groups compared to untreated control animals or animals treated with isotype control hIgG (log-rank Mantel-Cox test).

The ESK1 antibody could therefore be promising as a new cancer drug, with a large clinical impact for those patients with WT1+ tumours or leukaemia with HLA-A02 expression.

 

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