Enhancing Anticancer Therapy: The Development and Efficacy of CBX-12, a Tumor-Targeting Topoisomerase Inhibitor Conjugate

Topoisomerase inhibitors are recognized for their potential in treating various solid tumors, yet their clinical use is hindered by toxic side effects such as bone marrow suppression and stomach toxicity. To address these issues, a new approach has been introduced using the alphalexTM platform, which employs a pH-Low Insertion Peptide variant that homes in on the low pH environment common to all tumors due to the Warburg effect. This technology enables the selective delivery of drugs to cancer cells without the need for antigen targeting.

The alphalexTM platform has led to the creation of CBX-12, a conjugate of the topoisomerase inhibitor exatecan. CBX-12 has shown significant tumor-targeting capabilities in preclinical studies, with enhanced stability in plasma and minimal drug release over time. It demonstrates high selectivity for tumor tissues over normal ones and has been shown to effectively deliver exatecan to tumors, thanks to an optimized cleavable linker. This results in remarkable efficacy in treating HER2-negative tumors without antigen dependency.

In preclinical trials, CBX-12 has been shown to almost completely inhibit the growth of human colorectal tumors in mice at a dosage of 10 mg/kg, without affecting bone marrow, unlike the free exatecan which, at an equimolar dosage, led to tumor growth, neutropenia, and weight loss. The alphalexTM platform's CBX-12 has demonstrated both safety and potent anti-tumor activity, paving the way for its advancement into clinical development as a leading candidate for cancer treatment.