[Development of Antibody-polymer Conjugates for the Treatment of Intractable Cancers].

Abstract

Antibody therapeutics have become a major modality for cancer treatment. Particularly, immune checkpoint inhibitors have shown remarkable efficacy against various cancers. However, similar to other antibody therapeutics, they have not demonstrated clinical efficacy against malignant brain tumors. The primary reason for this is the presence of the blood-brain tumor barrier (BBTB) in the endothelial cells of malignant brain tumors, which prevents antibodies from entering the tumor parenchyma. Additionally, treatment with immune checkpoint inhibitors is clinically challenged by the occurrence of immune-related adverse events (irAEs) owing to non-specific and excess activation of the immune system. To address these issues, we integrated synthetic polymer-based drug delivery systems with immune checkpoint inhibitors. Specifically, we modified anti-PD-L1 antibodies with multiple glucosylated poly(ethylene glycol) (PEG) chains via disulfide bonds. This glucose-PEG-conjugated anti-PD-L1 antibody effectively accumulates in glioblastoma by penetrating the BBTB through the interaction of glucose ligands with glucose transporter-1, which is overexpressed in glioblastoma endothelial cells. Subsequently, the PEG chains detach from the antibodies in response to the reductive environment within the glioblastoma, thereby blocking PD-L1 expression. Conversely, the PEG chains remain conjugated to antibodies in the bloodstream and normal tissues, masking their functions. The glucose-PEG-conjugated anti-PD-L1 antibody demonstrated significant efficacy against glioblastoma, while reducing the risk of irAEs in normal tissues. This technology is applicable to various antibody therapeutics and can be adapted to target other organs or specific cell types by exchanging ligand molecules, offering broad potential therapeutic applications.