Abstract LB040: MACO-355, a unique pan-LILR monoclonal antibody for cancer therapy, re-programs and stimulates immuno-suppressive macrophages in a novel ligand-binding blocking independent manner

Abstract Macrophages populate most solid tumors in large numbers and limit effective anti-tumoral immune responses. The leukocyte immunoglobulin-like receptors (LILR) such as e. g. LILRB1, LILRB2, and others are expressed on tumor associated macrophages. Despite sharing multiple ligands such as major histocompatibility complex class I G (HLA-G), these receptors regulate different macrophage functions such as phagocytosis or cytokine release. To date, therapeutic approaches to targeting LILRs have concentrated on blocking receptor-ligand interactions to relieve ligand-mediated immune suppression. MACO-355 is a fully human antibody binding multiple LILRA (activating) and LILRB (inhibiting) family members including LILRB1, LILRB2, LILRB3, LILRA4 and LILRA6, that does not neutralize ligand (HLA-G, HLA-A, HLA-E) binding to either LILRB1 or to LILRB2. Nevertheless, MACO-355 mediates macrophage reprogramming even under strong immune suppressive conditions, as measured e. g. by stimulation of the TLR agonist induced pro-inflammatory cytokine release in CSF1, TGFβ, IL-10, and IL-4 treated cells. Concordantly, stimulation of immuno-suppressive macrophages with MACO-355 also resulted in significantly higher levels of T cell expansion, proliferation, and INFγ release in a co-culture suppression assay compared to ligand blocking antibodies. Additionally, MACO-355 enhances macrophage phagocytosis irrespective of tumor cell HLA-G ligand status and NK tumor cell killing. All these in vitro activities translate into in vivo activity in A375 melanoma CDX tumor model comparable to that of anti-PD-1 and anti-PD-L1 Abs in humanized mice. Safety studies showed that despite its potent immune stimulatory activity, MACO-355 does not lead to spurious pro-inflammatory cytokine production in in vitro cytokine storm assays. Molecular studies showed MACO-355 binds a novel epitope distant from a ligand binding pocket on LILRs and requires both bi-valent binding and Fc effector function for full activity. This results in pronounced modulation of intracellular kinase signaling. MACO-355 is a unique receptor-ligand non-blocking pan-LILR antibody highly potent in pro-inflammatory reprogramming of immuno-suppressive macrophages, both in vitro and in vivo. This appears to occur via a novel mode of action in which MACO-355 clusters multiple LILRs with Fc-receptors into unconventional signaling hubs. Altogether the data support the future clinical evaluation of MACO-355 as a cancer therapeutic. Citation Format: Krzysztof B. Wicher, Moritz Haneklaus, Martha Lopez-Yrigoyen, Alicia Poindron, Carmen Rodriguez-Seoane, Maikel Fransen, Chantell Payton, Stephane M. Guillame, Luca Cassetta, Stephen Myatt, Carola Ries. MACO-355, a unique pan-LILR monoclonal antibody for cancer therapy, re-programs and stimulates immuno-suppressive macrophages in a novel ligand-binding blocking independent manner abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (7Suppl): Abstract nr LB040.