PLT012, a humanized CD36-blocking antibody, is effective for unleashing anti-tumor immunity against liver cancer and liver metastasis

Tumor cells develop various strategies to evade immune surveillance, one of which is the modulation of the metabolic state of the tumor microenvironment (TME). In response to metabolic stress in the TME, several tumor-infiltrating immune subsets upregulate CD36 to take up lipids. This leads to impaired anti-tumor immunity, as intratumoral regulatory T cells (Tregs) exhibit increased survival and suppressive activity, while CD8+ T cells become more susceptible to ferroptosis and exhaustion. Here, we develop a humanized anti-CD36 IgG4 antibody, PLT012, against the lipid-binding domain of CD36 with excellent safety and favorable pharmacokinetic features in mice and cynomolgus monkey. PLT012 alone or in combination with PD-L1 blockade or standard-of-care immunotherapy results in robust anti-tumor immunity in both immunotherapy-sensitive and -resistant hepatocellular carcinomas (HCCs). Notably, PLT012 also reprograms immune landscape of human HCC ex vivo. Our findings provide proof-of-concept evidence that PLT012 effectively reprograms anti-tumor immunity in HCC, positioning it as a first-in-class immunotherapy targeting CD36. Overall design: To investigate the immune response to PLT012 treatment, we isolated CD45+ tumor-infiltrating cells from liver tumors and subjected them to single-cell RNA sequencing (scRNA-seq). Liver tissues were finely minced and enzymatically digested in RPMI medium containing 2% FBS, 1% penicillin-streptomycin, DNase I (1 µg/mL), and collagenase (0.5 mg/mL) at 37°C for 40 minutes. The digested suspension was filtered through a 70-µm strainer, treated with RBC Lysing Buffer, and washed with FACS buffer. Tumor-infiltrating leukocytes were enriched using Percoll density gradient centrifugation (800g, 20 minutes, room temperature). CD45+ cells were then isolated for scRNA-seq analysis, comparing transcriptional profiles between PLT012-treated and control groups.