Trastuzumab-dolaflexin: A Promising HER2-Targeted ADC with Enhanced Potency and Tolerability in Preclinical Toxicology

Antibody-drug conjugates (ADCs) are a type of medication that targets cancer cells by using antibodies to deliver chemotherapy drugs. A specific type of ADC, Fleximer-based, has shown to be more potent due to its high drug-antibody ratio. The study focused on trastuzumab-dolaflexin (T-dolaflexin), an ADC that targets HER2 and is linked to auristatin molecules. T-dolaflexin has shown excellent pharmacokinetics and efficacy in mice, being effective at a single dose of 0.67 mg/kg and even more so at 2 mg/kg in a HER2-low model that is resistant to other treatments.

To evaluate the tolerability of T-dolaflexin, tests were conducted on mice, rats, and non-human primates. In mice, doses of 20 and 30 mg/kg were well-tolerated with a therapeutic index greater than 40X. Female cynomolgus monkeys received doses of 0.67, 1.34, or 2.68 mg/kg, and all survived with limited weight loss. Clinical pathology showed temporary transaminase elevations and decreased platelet counts, with one animal showing signs of hepatic injury that resolved by Day 22. No evidence of myelosuppression or related findings in HER2-expressing organs was observed, indicating good tolerability.

Toxicokinetics showed the drug conjugate's stability in plasma with a half-life of approximately 5 days, similar to the antibody's half-life, and minimal exposure to free payload. The exposure in monkeys at the 2.68 mg/kg dose was several times higher than in mice at the minimally efficacious dose and comparable to the exposure associated with prolonged tumor-free survival.

The research concluded that trastuzumab-dolaflexin, a potent Fleximer-based ADC, has a favorable therapeutic index in models with low HER2 expression where current treatments are ineffective. The study was presented at the 106th Annual Meeting of the American Association for Cancer Research and published in Cancer Research.