470 Botensilimab, an Fc-enhanced CTLA-4 antibody, enhances innate and adaptive immune activation to promote superior anti-tumor immunity in cold and I-O refractory tumors

• DOI: 10.1136/jitc-2022-sitc2022.0470
• Publication Date: 2022-11-08T00:58:46Z
• Authors: Chloe Delepine; Daniel Levey; Shanmugarajan Kri...; Kwang-Soo Kim; Adam Sonabend; Margaret Wilkens; Antoine Tanne; Pilar Garcia-Brocano; Claire Galand; Haiyong Han; Christopher MacDe...; Jacky Chow; Sylvia Vincent; Shalu Karkwal; Yan Sun; Racehl Smith; Xavier Michelet; Kah Teong; Katherine Rosenthal; David Savitsky; Cailin Joyce; Steven O'Day; Joseph Grossman; Jaymin Patel; Dhan Chand; Daniel Levey
• Keywords: Priming (agriculture)

<h3>Background</h3> Botensilimab is a novel fragment crystallizable (Fc)-enhanced anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) antibody designed to promote superior immune activation and tumor killing relative first-generation IgG1 CTLA-4 antibodies. In patients with advanced solid tumors, botensilimab ± balstilimab (anti-PD-1), demonstrated durable clinical responses across nine different immunotherapy-resistant or poorly immunogenic types. The deep broad activity observed attributed its enhanced binding Fc gamma receptor IIIA (FcyRIIIA). This strengthens the synapse between CTLA-4-expressing T cells FcyRIIIA-expressing antigen-presenting (APC) natural killer (NK) cells, resulting in cell priming, memory formation, intratumoral regulatory (Treg) depletion, APC functionality. We show that this diversity of functions, distinct from anti-CTLA-4, correlates more effective control 'cold' tumors alone combination other therapies. <h3>Methods</h3> Human <i>ex vivo</i> peripheral blood mononuclear (PBMCs) assays were used assess effects on responses, Treg depletion. Pre- post-treatment biopsies PBMCs botensilimab-treated Phase 1 dose-escalation trial analyzed by next-generation sequencing (NGS), flow cytometry immunohistochemistry neoantigen burden, gene signatures, clonality CD8:Treg ratios tumor. efficacy mouse surrogate (ms) botensilimab, combined agents, was assessed anti-PD-1 refractory models. <h3>Results</h3> human cell-based assays, as measured IL-2 secretion, increased frequency activated FcyRIIIA+ CD11c+ myeloid determined CD40, HLA-DR CD86 expression, promoted depletion anti-CTLA-4 antibody. Tumor-bearing mice (CT26 colon carcinoma, MC38 CT2A orthotopic glioblastoma) treated botensilimab^ms showed shrinkage survival compared anti-CTLA-4. When chemotherapy, radiotherapy, vaccines, adoptive therapy, tumor-targeted ultrasound iNKT-activation, therapeutically several models including GL261 glioblastoma, KPC pancreatic cancer B16 melanoma. both preclinical studies, expansion clonotypes CD8/Treg ratio. Concordant observations, response cancers independent FcγR polymorphism burden. <h3>Conclusions</h3> demonstrates unprecedented consistent mechanism action.