Fc-mediated immune stimulating, pro-inflammatory and antitumor effects of anti-HER2 IgE against HER2-expressing and trastuzumab-resistant tumors

• DOI: 10.1136/jitc-2024-010945
• Publication Date: 2025-03-13T16:54:05Z
• Authors: Melanie Grandits; Lais C G F Palhares; Gabriel Osborn; Jitesh Chauhan; Katie Stoker; Heng Sheng Sow; Rebecca Adams; Alex J McCraw; Alicia Chenoweth; Sofia Vlasova; Jacobo López-Abente; Kristina M Ilieva; James Birtley; Sophia Tsoka; Elizabeth Hardaker; Kevin FitzGerald; Sophia N Karagiannis; Heather J Bax
• Keywords: Pertuzumab

Background Anti-human epidermal growth factor receptor 2 (HER2) IgG1-based antibody therapies significantly improve cancer prognosis, yet intrinsic or acquired resistance to fragment antigen-binding (Fab)-mediated direct effects commonly occurs. Most resistant tumors retain antigen expression and therefore remain potentially targetable with anti-HER2 that promote immune-mediated responses. Tumor-antigen-specific IgE class antibodies can mediate powerful immune cell-mediated against different cancers have been shown activate Fc receptor-expressing monocytes. We previously reported the engineering of a trastuzumab-equivalent showed early evidence Fc-mediated cell-targeting effects. In present study, we evaluated anti-tumoral functions two IgEs, trastuzumab pertuzumab IgE. Methods vitro functionality was assessed by HER2 phosphorylation ligand-independent viability assays, as well basophil (RBL-SX38) degranulation, antibody-dependent cellular cytotoxicity/antibody-dependent phagocytosis(ADCC/ADCP) assays primary monocyte stimulation assays. The potential trigger hypersensitivity type I reaction investigated using activation test (BAT). efficacy in humanized HER2+, trastuzumab-resistant models vivo. Changes tumor microenvironment were flow cytometry bulk RNA sequencing. Results demonstrate immunostimulatory IgEs derived from variable region sequences clinically available IgG1 antibodies. engagement monocytes via induced cell cytotoxicity pro-inflammatory shift upregulation immune-stimulatory CD40, CD80 CD86, downregulation scavenger CD163, surface molecules. This accompanied enhanced necrosis (TNF)-α, interleukin (IL)-6, IL-1β cytokine production. absence ex vivo whole blood points safe administration humans. HER2+ xenograft immunodeficient mice reconstituted human cells, restricted growth. Treatment associated enriched classical (CD14 + CD16 – ) lower alternatively-activated (CD163 CD206 macrophage infiltration, higher densities activated CD4 (CD127 lo CD25 hi T cells favorable effector cell(Teff) regulatory (Treg) ratios tumors. Conclusion Collectively, maintains Fab-mediated antitumor activity, induces HER2-expressing stimulates remodeling phenotypes which could translate improved outcomes for patients.