Macrophages are major constituents of the microenvironment in many cancers, promoting carcinogenesis, malignant progression and resistance to therapy making them attractive targets for therapeutic intervention. Macrophage Pharma’s approach in cancer is to manipulate tumour associated macrophages to inhibit the immunosuppression that they generate, leading to more effective anti-tumour immune responses. Esterase Sensitive Motif™ technology represents a strategy of highly selective delivery of small molecule inhibitors to tumour macrophages such that the function of other important anti-tumour immune cells is not impacted. Macrophage Pharma believes that development of these highly novel therapeutics will lead to optimal anti-tumour macrophage activities providing maximal therapeutic responses.
Macrophage Pharma’s initial clinical focus is to develop a new generation of powerful small-molecule oncology drugs which inhibit the ability of tumour polarised macrophages to release immunosuppressive cytokines. This in turn is expected to lead to an increase in anti-tumour T-cell numbers and function. This “re-programming” of the tumour immune system is necessary to enhance the activity of both cytotoxic and immuno-oncology therapies such as the checkpoint antibodies. The company therefore intends to pursue development programmes aimed at blocking the activity of macrophage derived immunosuppressive cytokines such as IL-10 and restoring levels of stimulatory molecules such as IL-12 and IFN-γ.
Our lead programme involves utilisation of Esterase Sensitive Motif™ technology to provide macrophage targeted inhibition of p38 MAP kinase. Extended activation of p38 MAP kinase in tumour macrophages indicates this is a key regulatory mechanism in the tumour microenvironment contributing to T-cell “exhaustion”. p38 MAP kinase has been extensively characterised as a master regulator of cytokine production such as IL-10 in macrophages leading to tumour mediated immunosuppression and impaired immunosurveillance. Inhibition of p38 MAPK reverses this immunosuppression and restores anti-tumour T-cell function by restoring levels of IL-12. In addition, p38 MAPK is an important signalling element in suppressing tumour dendritic cells and impairing antigen presentation. Because the p38 MAPK pathway is important in key anti-tumour immune cells such as effector T-cells and NK cells selective delivery to the macrophage is crucial to ensure the maximum benefit of target inhibition.
Through focussing on additional elements of the immune system by targeting the macrophage the company expects to be able to address a wider range of tumour types (e.g. where T cells are not anti-PD-1 responsive due to macrophage repression mechanisms) and broader patient populations. Macrophage Pharma’s drug discovery and development efforts will thus focus outside checkpoint inhibition on mechanisms that enable cancer cells to escape detection and eradication by the immune system. Macrophage Pharma’s molecules are also expected to improve the effectiveness of antigen presentation and block the activity of suppressor cells in the tumour microenvironment. The company is advancing a focused pipeline based on these approaches.