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.