Macomics Ltd, a company specialising in macrophage drug discovery, has unveiled details of its lead programme MACO-355: a first-in-class ligand independent-pan-LILRB monoclonal antibody for the treatment of cancer.
Key data was presented at the American Association for Cancer Research Annual Meeting (AACR 2024) in San Diego1.
MACO-355 is a novel, non-ligand blocking, pan-LILR targeting antibody capable of mediating macrophage reprogramming under immune suppressive conditions. It's the first ligand independent antibody that has been reported, which does not block interaction between LIL-receptors and MHC Class I molecules.
This new mode of action results in increased antibody activity as measured by macrophage reprogramming (cytokine release) and T cell activation. The antibody also induces tumour cell phagocytosis and NK cell tumour kill independent of the ligand status of the tumour cells, unlike ligand blocking antibodies.
Tested head-to-head against reference antibodies, MACO-355 was the only antibody able to activate highly immune-suppressed macrophages. Data presented also showed that it reverts M2 (TGFβ/IL-10/IL-4) macrophage mediated suppression of T cell activity in vitro and slows tumour growth in vivo.
MACO-355 binds to selected members of LILRB and targets a unique, membrane proximal epitope. It requires engagement of Fc receptor(s) for full activity and rewires the macrophage kinase network in a novel mode of action. Macomics hypothesises that by having activity independent of the ligand status of the tumour and the ability to activate highly immunosuppressed macrophages will translate into increased efficacy in clinic and provide opportunity for biomarker-led patient stratification.
MACO-355 has a favourable developability and safety profile and is currently in CMC and IND enabling studies with the novel soluble biomarker hypothesis guiding patient selection.
Dr Krzysztof Wicher SVP Drug Discovery and Development of Macomics, who presented the poster, said: “To date, therapeutic approaches to targeting LILRB1 and LILRB2 have blocked receptor – ligand interaction to relieve ligand-mediated immune suppression. In this study, surprisingly, the most active antibodies for macrophage reprogramming were non-ligand blocking and our new lead antibody, MACO-355, demonstrated wide potentially clinically-relevant effects across a range of measures. It was also unique in being able to re-programme immune suppressed macrophages. We believe these data are a compelling basis for the clinical evaluation of MACO-355 as a cancer therapeutic.”
Bibliography
1 AACR 2024 – Poster 10625 - Discovery of MACO355: a first in mechanism ligand-blocking independent LILRB1/2/3 antibody for cancer therapy - Krzysztof B. Wicher, Moritz Haneklaus, Alicia Poindron, Martha Lopez-Yrigoyen, Carmen Rodriguez Seoane, Maikel Fransen, Chantell Payton, Stephane Guillame, Luca Cassetta, Stephen Myatt, and Carola Ries
