Targeting RON receptor tyrosine kinase for treatment of advanced solid cancers: antibody-drug conjugates as lead drug candidates for clinical trials

Abstract

The recepteur d'origine nantais (RON) receptor tyrosine kinase, belonging to the mesenchymal-to-epithelial transition proto-oncogene family, has been implicated in the pathogenesis of cancers derived from the colon, lung, breast, and pancreas. These findings lay the foundation for targeting RON for cancer treatment. However, development of RON-targeted therapeutics has not gained sufficient attention for the last decade. Although therapeutic monoclonal antibodies (TMABs) targeting RON have been validated in preclinical studies, results from clinical trials have met with limited success. This outcome diminishes pharmaceutical enthusiasm for further development of RON-targeted therapeutics. Recently, antibody-drug conjugates (ADCs) targeting RON have drawn special attention owing to their increased therapeutic activity. The rationale for developing anti-RON ADCs is based on the observation that cancer cells are not sufficiently addicted to RON signaling for survival. Thus, TMAB-mediated inhibition of RON signaling is ineffective for clinical application. In contrast, anti-RON ADCs combine a target-specific antibody with potent cytotoxins for cancer cell killing. This approach not only overcomes the shortcomings in TMAB-targeted therapies but also holds the promise for advancing anti-RON ADCs into clinical trials. In this review, we discuss the latest advancements in the development of anti-RON ADCs for targeted cancer therapy including drug conjugation profile, pharmacokinetic properties, cytotoxic effect in vitro, efficacy in tumor models, and toxicological activities in primates.

Keywords: antibody–drug conjugates; clinical trials; epithelial cancer; pharmacokinetic profile; receptor tyrosine kinase; therapeutic efficacy; therapeutic target; toxicological activity.

Figure 1.

Schematic representation of anti-RON ADCs conjugated with MMAE and DCM. Anti-RON mAbs Zt/g4 and PCM5B14 are selected as lead candidates for drug conjugation. Zt/g4 14 is conjugated with MMAE linked to the synthetic dipeptide linker Mc-Val-Cit-PABC to generate Zt/g4-MMAE. PCM5B14 is conjugated with DCM linked to the synthetic dipeptide linker MA-PEG4-VC-PAB-DMEA to generate PCM5B14-DCM. The conjugation is aimed to reach the drug to antibody ratio of 4:1.

Figure 2.

Schematic representation of generation of anti-RON ADC and its mechanism of action in killing cancer cells. Anti-RON MABs such as Zt/g4 and PCM5B14 are conjugated with cytotoxic drugs including MMAE and DCM through the thioether linkers and protease-sensitive linker, respectively, to form anti-RON ADCs with a drug to antibody ratio (DAR) of 3~4 to 1. Anti-RON ADCs bind to RON expressed by cancer cells, which leads to internalization of ADCs into the intracellular compartments. Intracellular cleavage of the linker by lysosomal enzymes results in the release of cytotoxic drugs, which either blocks tubulin polymerization or inhibits DNA synthesis leading to cancer cell death (direct killing effect). Dissociated free drugs also diffuse into neighboring cancer cells causing apoptosis (bystander killing effect).