Author: Blümli, Seraina ; Ahuja, Shreya ; Rees, D Gareth ; Glover, Matthew S ; Arnaldez, Fernanda ; Jones, Des C ; Mulgrew, Kathy ; Pryts, Stacy ; Rajan, Saravanan ; Songvilay, Saly ; Dovedi, Simon J ; Varkey, Reena ; Kierny, Michael ; Chatzopoulou, Elisavet I ; Wilkinson, Robert W ; Hess, Sonja ; Irving, Lorraine ; Bienkowska, Kamila ; Kayserian, Andrew ; Wolny, Marcin ; Dudley, Rebecca ; Sandercock, Alan M ; Bowyer, Georgina ; Cobbold, Mark

BackgroundImmune checkpoint inhibitors have revolutionized the treatment of solid tumors, enhancing clinical outcomes by releasing T cells from inhibitory effects of receptors like programmed cell death protein 1 (PD-1). Despite these advancements, achieving durable antitumor responses remains challenging, often due to additional immunosuppressive mechanisms within the tumor microenvironment (TME). Tumor-associated macrophages (TAMs) contribute significantly to the immunosuppressive TME and play a pivotal role in shaping T cell-mediated antitumor responses. Leukocyte immunoglobulin-like receptor subfamily B member 2 (LILRB2), expressed on myeloid cells, including TAMs, is an inhibitory receptor, which contributes to macrophage-mediated immunosuppression. In this study, we present AZD2796, a high-affinity anti-LILRB2 antibody designed to repolarize TAMs from an immunosuppressive to a proinflammatory phenotype.MethodsAnti-LILRB2 antibodies were identified using single-B-cell encapsulation Immune Replica technology. The ability of AZD2796 to enhance proinflammatory responses from macrophages treated with CD40 ligand or lipopolysaccharide was assessed using a macrophage stimulation assay. A tumor cell/macrophage/T cell co-culture assay was developed to evaluate the effect of AZD2796, as a single agent and in combination with an anti-PD-1 antibody, on the cytolytic activity of antigen-specific T cells. In vivo assessments were then carried out to determine the ability of AZD2796 to alter tumor growth rate in mice humanized with CD34 hematopoietic stem cells.ResultsIn preclinical assessments, AZD2796 skewed macrophage differentiation away from an immunosuppressive phenotype and enhanced the proinflammatory function of macrophages. AZD2796 significantly increased the anti-tumor response of T cells following PD-1 checkpoint blockade, while AZD2796 monotherapy reduced tumor growth in humanized mouse models.ConclusionsThese findings support the potential of AZD2796 as an anti-cancer therapy, with the ability to synergize with T-cell-based therapeutics.

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Indication	Highest Phase	Country/Location	Organization	Date
Lung Cancer	Preclinical	United Kingdom	AstraZeneca PLC	02 Nov 2023
Melanoma	Preclinical	United Kingdom	AstraZeneca PLC	02 Nov 2023

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