Abstract 2524: Antibodies of the IgG and IgE classes against the melanoma-associated antigen HMW-MAA: Investigating a new therapeutic approach

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Melanoma, the fastest rising cancer in the UK, is a major therapeutic challenge and effective treatments are urgently needed. The human high molecular weight melanoma associated antigen (HMW-MAA), a membrane-bound protein over-expressed in > 90% of melanomas, is thought to contribute to melanoma growth and metastasis. A number of studies indicate the merit of blocking these tumor-promoting functions by antibodies. Most antibodies for cancer therapy in clinical use belong to the IgG class, the most prevalent class in blood. IgE antibodies, characterised for their role in allergic responses and protection against parasites, function through high-affinity Fc receptors. IgE antibodies, naturally reside in tissues where they exert immunological surveillance, a different spectrum of effector cells, and offer a novel therapeutic approach by targeting solid tumors such as melanoma. Previous studies, suggest that IgE antibodies are more effective than the corresponding IgGs in eliciting anti-tumural immune responses, with our lead antibody candidate against the tumour antigen Folate Receptor alpha (FRa) presently in clinical development. We wished to elucidate whether this concept can be applied to the treatment of melanoma. To test this, we engineered IgG1, IgG4 and IgE antibodies of the same specificity against HMW-MAA and examined their functionality in activating immune effector cells against cancer cells. IgG1 and IgE antibodies induced significant tumor cell death by two mechanisms: antibody-dependent cell-mediated phagocytosis and antibody-dependent cell-mediated cytotoxicity in vitro, using patient-derived monocytes and monocytes from healthy volunteers. These results suggest different antibody classes may harbor complementary functional properties against cancer cells, by activating different families of Fc receptors on immune effector cells. Furthermore, we compared the therapeutic efficacy of these antibodies in tumor-bearing NOD/SCID/IL-2 receptor ≤ chain-/- mice engrafted with human lymphocytes. We demonstrate, that IgE antibodies are superior compared to IgG1 (p<0.05) and non-specific antibody controls (p<0.001). Moreover, immunohistological and transcriptomic analyses revealed an increased lymphocyte infiltrate within the treatment groups. The data indicate, infiltrating immune cells interactions with the tumor microenviroment to reduce tumor growth. We are currently undertaking additional functional validation to identify the in vivo signaling mechanisms involved. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2524. doi:1538-7445.AM2012-2524