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- Title
Anti-cancer pro-inflammatory effects of an IgE antibody targeting the melanoma-associated antigen chondroitin sulfate proteoglycan 4.
- Authors
Chauhan, Jitesh; Grandits, Melanie; Palhares, Lais C. G. F.; Mele, Silvia; Nakamura, Mano; López-Abente, Jacobo; Crescioli, Silvia; Laddach, Roman; Romero-Clavijo, Pablo; Cheung, Anthony; Stavraka, Chara; Chenoweth, Alicia M.; Sow, Heng Sheng; Chiaruttini, Giulia; Gilbert, Amy E.; Dodev, Tihomir; Koers, Alexander; Pellizzari, Giulia; Ilieva, Kristina M.; Man, Francis
- Abstract
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. IgE antibodies targeting cancer antigens can be used for immunotherapy. Here the authors present an IgE antibody targeting the melanoma-associated antigen, chondroitin sulphate proteoglycan 4, that recognises human melanoma, stimulates tumour cell cytotoxicity, and restricts tumour growth in humanised mouse models.
- Subjects
CHONDROITIN sulfate proteoglycan; MONOCLONAL antibodies; IMMUNOGLOBULIN E; BRAF genes; ANTIBODY-dependent cell cytotoxicity; ANTINEOPLASTIC agents; PROGRAMMED cell death 1 receptors; IMMUNOGLOBULINS
- Publication
Nature Communications, 2023, Vol 14, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-023-37811-3