501 AZD2796, a myeloid checkpoint inhibitor targeting LILRB2 that promotes pro-inflammatory responses by macrophages and enhances T cell anti-tumor activity

Background

Inhibition of T cell immune checkpoints has revolutionized cancer therapy. However, responses are not uniformly positive, and many patients develop resistance. Myeloid cells are an abundant component of the tumor microenvironment able to promote cancer progression and suppress immune responses. Consequently, targeting these cells may be an avenue to optimize immune-based cancer therapies. LILRB2 is an inhibitory member of the leukocyte immunoglobulin-like receptor (LILR) family that is expressed on the surface of myeloid cells, including key suppressive myeloid subsets such as macrophages and myeloid-derived suppressor cells (MDSCs) found in tumors. LILRB2 signalling contributes to the suppressive phenotype of myeloid cells by inhibiting the activity of pro-inflammatory signalling pathways.

Methods

AZD2796 is a fully humanised monoclonal antibody that binds LILRB2. AZD2796 was assessed for target specificity, binding affinity and antagonism of ligand binding. The ability of AZD2796 to enhance proinflammatory responses of macrophages was determined by the release of pro inflammatory cytokines from monocyte derived macrophages in vitro, and enhancement of tumor cell lysis by T cells when co-cultured in the presence of macrophages. The anti-tumor effect of AZD2796 was explored in vivo using two xenograft models of human cancer in humanised mice.

Results

AZD2796 is highly specific to LILRB2 and does not bind other members of the LILR family. It binds LILRB2 with high affinity and blocks binding of LILRB2 to its major histocompatibility complex (MHC) class I ligands. In functional assays, AZD2796 enhanced the production of the proinflammatory cytokines TNF-α and GM-CSF from human macrophages stimulated with CD40L, while reducing the production of VEGF, an important driver of angiogenesis. In addition, AZD2796 increased tumor cell killing by T cells when co-cultured with macrophages. In vivo, AZD2796 significantly reduced tumor growth rate of NCI-H358 lung cancer cells and SK-MEL-5 melanoma cancer cells in humanised mice.

Conclusions

AZD2796 is a high affinity anti-LILRB2 monoclonal antibody that promotes pro-inflammatory responses by macrophages and enhances anti-tumor activity of T cells. Our pre-clinical data support the potential of AZD2796 as an anti-cancer therapy with opportunities to combine with T-cell-based therapeutics.

Ethics Approval

All animal studies are run under the Institutional Animal Care and Use Committee (IACUC) approved in vivo protocol number AUP-22–17. AstraZeneca’s US site IACUC committee oversees the specific use of animals by conducting a formal review of the animal use, ethics and protocols and grants approval prior to the work commencing.