Nonclinical Development of Next Generation Site-Specific HER2 Targeting Antibody Drug Conjugate (ARX788) for Breast Cancer Treatment.

Conventional antibody drug conjugates (ADC) utilize native surface-exposed lysines or cysteines on the antibody of interest to conjugate cytotoxic payload. The non-specific conjugation results in a mixture with variable drug-to-antibody ratios (DARs), conjugation sites, and ADCs that are often unstable in systemic circulation. ARX788 is an ADC consisting of a HER2-targeting antibody site-specifically conjugated with a potent anti-tubulin cytotoxic drug-linker, AS269. The site-specific conjugation is achieved by first incorporating the non-natural amino acid, para-acetyl phenylalanine (pAF), into the antibody, followed by covalent conjugation of AS269 to the pAF to form a highly stable oxime bond resulting in a DAR2 ADC. ARX788 exhibits significant, dose-dependent anti-tumor activity against HER2 expressing breast and gastric xenograft tumors. Pharmacokinetic (PK) studies in multiple species showed the highly stable nature of ARX788 with overlapping PK profiles for the intact ADC and total antibody. Metabolism studies demonstrated pAF-AS269 was the sole major metabolite of ARX788, with no evidence for the release of free drug often observed in conventional ADCs and responsible for adverse side effects. Furthermore, ARX788 demonstrated a favorable safety profile in monkeys with a Highest Non-Severely Toxic Dose (HNSTD) of 10 mg/kg, which was well above the efficacious dose level observed in preclinical tumor models, thus supporting clinical development of ARX788.