Macomics Unveils its Lead First-in-Class Anti-Pan-LILRB Monoclonal Antibody Programme with Positive Pre-clinical Data Presented at AACR 2024

• Macomics’ lead programme, MACO-355, in IND enabling studies is a ligand-blocking independent pan-LILR monoclonal antibody for the treatment of cancer
• Data presented at AACR 2024 shows MACO-355 is highly potent in macrophage reprogramming under tumour-like immune suppressed conditions
• Data demonstrated Macomics’ ENIGMAC™ platform at-scale CRISPR screening for macrophage target discovery

Edinburgh and Cambridge, UK, 11 April 2024 - Macomics Ltd, a leader in macrophage drug discovery, has unveiled details of its lead programme, a first-in-class ligand independent-pan-LILRB monoclonal antibody for the treatment of cancer, having presented key data on MACO-355 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 is 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 hypothesizes 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.”

Stephen Myatt, CEO of Macomics said, “We are now focused on advancing MACO-355 with the aim of rapidly advancing this novel first in class antibody as a potential therapy to improve the long-term outcome for cancer patients. In parallel we are leveraging our unique discovery platform across disease areas including fibrosis and inflammation where we believe targeting of disease specific macrophage populations will provide exciting new therapeutic approaches to improve patient outcomes.”

Macomics presented data on its macrophage drug discovery platform, ENIGMAC™ at AACR2. The results of a pooled CRISPRi screen, aiming to identify regulators of IFNγ-mediated PD-L1 upregulation on macrophages, provided technical proof of concept for the ENIGMAC platform to perform screens at scale and to identify novel hits in macrophages, a cell type that is inherently difficult to gene edit. The platform which includes proprietary human induced Pluripotent Stem Cell (hiPSC) lines that stably express CRISPRi and CRISPRa expression constructs represents a unique tool for gene to function studies using human macrophages. ENIGMAC, used in the discovery of MACO-355 is disease agnostic and can be integrated with a variety of disease-specific conditions and phenotypic readouts.

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

2. AACR 2024 – Poster 10619 – ENIGMAC™ platform enables at-scale CRISPR screening for macrophage target discovery - Thomas W. M. Crozier, Martha Lopez-Yrigoyen, Helena Engman, Moritz Haneklaus, Samuel Witham, Krzysztof B. Wicher, Steven Myatt, Luca Cassetta and Carola Ries.

About Macomics – www.macomics.com

Macomics Ltd is a macrophage drug discovery company with a world-leading macrophage drug discovery platform, developing first-in-class medicines to deliver transformational impact for patients with macrophage-driven diseases: Macrophages are key to multiple diseases of high unmet medical need, including as key mediators of solid tumour immunosuppression and pathological inflammation in chronic inflammatory disorders.
The company is progressing a diversified portfolio of therapies targeting disease specific macrophages towards the clinic. Its ENIGMAC macrophage drug discovery platform enables identification and validation of novel macrophage therapeutic targets and provides a translationally relevant path to clinic through the development of more physiologically relevant human macrophage models combined with proprietary gene editing technology.
The company was co-founded in 2020 by Prof. Jeffrey Pollard and Dr. Luca Cassetta, University of Edinburgh, internationally recognised leaders in macrophage biology. It has R&D and office facilities in Edinburgh and Cambridge, UK. The company’s financing was led by Epidarex Capital and the company is backed by Scottish Enterprise, LifeLink Ventures and Caribou Property Limited.

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