Minimal functional activity and presence of an antigen sink limit CD36 blockade as a macrophage-targeted cancer immunotherapy

Targeting macrophages in the tumor microenvironment offers potential to relieve immune-suppression and improve anti-tumor immune responses. Unfortunately, a range of tumor-associated macrophage (TAM)-targeting agents in development has not yet translated into clinical benefit. We sought to identify novel targets on primary human macrophages through an unbiased phenotypic selection campaign. This work identified the scavenger receptor and lipid transporter CD36 as a potential target associated with anti-inflammatory phenotypes on macrophages. We first confirmed the ability of in-house generated and commercially available anti-CD36 monoclonal antibodies (mAbs) to inhibit CD36 binding and cellular uptake of oxidized lipids, both in cell-free settings and in engineered cell lines. However, we were unable to observe consistent or robust responses to CD36 blockade in primary human macrophages using a range of TAM-like and lipid-induced in vitro models. In vivo , CD36-KO mice showed reduced tumor growth, which implicated a CD36-dependent host impact on tumor progression. Importantly, anti-CD36 mAb failed to phenocopy this effect. Pharmacokinetic assessments revealed considerable target-mediated drug disposition with anti-CD36 mAb, limiting free plasma concentrations of the drug. A modified dosing regimen managed to increase drug concentration in plasma but still failed to elicit meaningful activity across primary tumor models, with/without anti-PD-L1. Although it remains clear that lipid uptake and metabolism is a key feature in TAM that can drive their immunosuppressive activities, our investigation raises concerns regarding the therapeutic targeting of CD36 due to redundancy in the lipid scavenging receptor family and a broad tissue expression profile. Together, these findings suggest that conventional monoclonal antibody blockade of CD36 has limited therapeutic potential in solid tumors, although outcomes may vary in different biological contexts.