Immune-checkpoint targeting drug conjugates: a novel class of promising therapeutic agents for cancer treatment

Abstract

Immune-checkpoint targeting Drug Conjugates (IDCs) are a novel class of therapeutics that combine an immune checkpoint-targeting moiety, a cleavable linker, and a cytotoxic payload. By integrating features and functions of antibody-drug conjugates and immunotherapy, IDCs represent a promising strategy to remodel the tumor microenvironment and enhance antitumor efficacy. Several IDCs targeting checkpoints such as PD-L1, B7-H3, and B7-H4 are in early-phase clinical trials. This review summarizes available data on IDC efficacy and toxicity in human. Although current evidence is limited, ongoing phase III trials and biomarker studies will clarify their optimal clinical role, including potential for tumor-agnostic use.

Fig. 1. IDCs targets and mechanism of action within tumor microenvironment.

IDCs recognize immune checkpoints such as PD-L1 (B7-H1), B7-H3, B7-H4, CD70, and CD56, expressed on the surface of tumor and tumor microenvironment cells. Upon binding to their target, IDCs are internalized and degraded within lysosomes, leading to the release of the cytotoxic payload inside the target cell. This results in direct tumor cell killing by microtubule disruption or DNA strand breakage, depending on the payload type. IDCs’ payload can also induce a bystander effect, impacting closer antigen-negative tumor cells. Additionally, IDCs may disrupt checkpoint interactions with effector immune cells, enhancing antitumor immune responses within tumor microenvironment.

Fig. 2. IDCs under investigation.

MMAE monomethyl auristatin E, dHBD heterocycle-fused benzodiazepine dimer, F-HPA auristatin F-HPA, MMAF monomethyl auristatin phenylalanine, NA non available.