PY265, MARCO and activating anti-tumor immunity by reprogramming immunosuppressive myeloid cells
Pionyr Immunotherapeutics is developing PY265 for the treatment of advanced solid tumors refractory to or relapsed with the current standard of care (SOC). PY265 is a humanized monoclonal antibody (mAb) that specifically binds the macrophage receptor with collagenous structure (MARCO), leveraging a distinct mechanism of action from other myeloid-directed therapeutics currently in development and is expected to be first-in-class.
Why target MARCO on immunosuppressive myeloid cells?
Macrophage receptor with a collagenous structure (MARCO) is a trimeric membrane-bound type-II scavenger receptor expressed on a subset of tissue-resident macrophages in normal tissues. MARCO functions as a scavenger receptor, in anti-microbial host defense by binding various ligands, and as an immunomodulatory receptor playing key roles in toll like receptor-induced activation, signaling, and lymph node trafficking of dendritic cells (Kraal et al., 2000).
MARCO is highly and specifically expressed by tumor-associated macrophages (TAMs) and monocytic myeloid-derived suppressor cells (mMDSCs), infiltrating the tumor microenvironment (TME) of multiple solid tumor indications (Georgoudaki et al. 2016; La Fleur et al. 2018). Targeting MARCO with an anti-MARCO antibody blocks tumor growth and metastasis in syngeneic mouse tumor models, by reprogramming immunosuppressive M2-like TAMs to pro-inflammatory M1-like macrophages, switching their metabolic program, and enhacing NK-cell activation (Georgoudaki et al. 2016; Eisenger et al. 2020). In addition, targeting MARCO on human macrophages repolarizes TAMs and restores the cytotoxic, anti-tumor capacities of both NK and T cells (La Fleur et al. 2021; Eisenger et al. 2020). These findings support the immune therapeutic approach of targeting MARCO-expressing TAMs to remodel the immune-suppressive tumor microenvironment.
MARCO expression on TAMs and mMDSCs
MARCO is highly expressed in the tumor microenvironment in a variety of different tumor types and up-regulated in response to immunosuppressive factors such as IL-10, TGFb, and hypoxia. In the example above, MARCO (highlighted in red, right panel) is specifically expressed on tumor-associated macrophages (TAMs) and monocytes from single-cell immune profiling of a human ovarian tumor.
Targeting MARCO offers a promising therapeutic opportunity and a novel myeloid tuning approach. PY265 functions as an immunomodulatory mAb that reprograms MARCO+ immunosuppressive myeloid cells into pro-inflammatory cells, leading to immune activation and effective anti-tumor immunity.
High levels of MARCO on tumor cells correlate with reduced patient survival times
As shown below, in patients with renal cell carcinoma or colorectal cancer, those with tumors that expressed low levels of MARCO (green lines) had longer survival times than patients whose tumors expressed high levels of MARCO (red lines). Additionally, high MARCO levels are observed in CPI refractory melanoma patients and chemo-refractory patients from various solid tumors (data not shown).
PY265 Mechanism of Action
PY265 binds to the immune-regulatory receptor MARCO on monocytes and M2-like (immune-suppressive) TAMs to activate a signaling pathway that converts them into inflammatory cells. These cells produce factors that activate natural killer (NK) and T cells with cytolytic activities against cancer cells.
PY265m demonstrates single agent and combinatorial efficacy in preclinical models
Therapeutic administration of PY265m (mouse surrogate anti-MARCO mAb) alone or in combination with CPIs resulted in tumor growth inhibition and complete regression of tumors in multiple mouse syngeneic tumor models.