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Anti-cancer pro-inflammatory effects of an IgE antibody targeting the melanoma-associated antigen chondroitin sulfate proteoglycan 4

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posted on 2023-05-15, 11:05 authored by J Chauhan, M Grandits, LCGF Palhares, S Mele, M Nakamura, J López-Abente, S Crescioli, R Laddach, P Romero-Clavijo, A Cheung, C Stavraka, AM Chenoweth, HS Sow, G Chiaruttini, AE Gilbert, T Dodev, A Koers, G Pellizzari, KM Ilieva, F Man, N Ali, C Hobbs, S Lombardi, DA Lionarons, HJ Gould, AJ Beavil, JLC Geh, AD MacKenzie Ross, C Healy, E Calonje, J Downward, FO Nestle, S Tsoka, DH Josephs, PJ Blower, P Karagiannis, KE Lacy, J Spicer, SN Karagiannis, HJ Bax
Outcomes for half of patients with melanoma remain poor despite standard-of-care checkpoint inhibitor therapies. The prevalence of the melanoma-associated antigen chondroitin sulfate proteoglycan 4 (CSPG4) expression is ~70%, therefore effective immunotherapies directed at CSPG4 could benefit many patients. Since IgE exerts potent immune-activating functions in tissues, we engineer a monoclonal IgE antibody with human constant domains recognizing CSPG4 to target melanoma. CSPG4 IgE binds to human melanomas including metastases, mediates tumoricidal antibody-dependent cellular cytotoxicity and stimulates human IgE Fc-receptor-expressing monocytes towards pro-inflammatory phenotypes. IgE demonstrates anti-tumor activity in human melanoma xenograft models engrafted with human effector cells and is associated with enhanced macrophage infiltration, enriched monocyte and macrophage gene signatures and pro-inflammatory signaling pathways in the tumor microenvironment. IgE prolongs the survival of patient-derived xenograft-bearing mice reconstituted with autologous immune cells. No ex vivo activation of basophils in patient blood is measured in the presence of CSPG4 IgE. Our findings support a promising IgE-based immunotherapy for melanoma.

Funding

Crick (Grant ID: CC2097, Grant title: Downward CC2097)

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