Targeting AXL-Expressing Tumors with ADCT-601: A Promising Pyrrolobenzodiazepine-Dimer Based Antibody-Drug Conjugate

The receptor AXL, part of the TAM family of tyrosine kinase receptors, is known to be overexpressed in a range of cancers including solid tumors and blood cancers. This overexpression is linked to a poor prognosis and resistance to treatments. Given these characteristics, AXL is a promising target for developing antibody-drug conjugates (ADCs) to combat cancers where it is expressed.

ADCT-601 is an ADC that includes a humanized IgG1 antibody specific to AXL, conjugated using GlycoconnectTM technology to the cytotoxin SG3199, which is connected through a cleavable linker. The study aimed to explore the efficacy and safety of ADCT-601 in various cancer cell lines and animal models, as well as its tolerability in rats.

In cell culture studies, ADCT-601 showed significant cytotoxicity against cell lines with varying levels of AXL expression, with its effectiveness being notably diminished in AXL-negative lines. In animal models, the drug exhibited strong anti-tumor effects. For instance, in a triple-negative breast cancer model with moderate AXL expression, a single dose of 1 mg/kg led to considerable tumor reduction and complete tumor eradication in a subset of animals. Similarly, in a renal cell carcinoma model with high AXL expression, ADCT-601 demonstrated dose-dependent anti-tumor activity, with the highest dose leading to a high rate of complete responders and tumor-free survivors. In a pancreatic cancer model with heterogeneous AXL levels, the drug also showed complete eradication of tumors at the tested doses.

Furthermore, ADCT-601 was found to be stable and well-tolerated in rats, with a half-life of 9 days and a maximum tolerated dose of 6 mg/kg. The study concludes that ADCT-601 has shown potent and specific anti-tumor activity in different cancer models with varying AXL expression levels and is stable and well-tolerated in rats, supporting further development towards clinical use.

The citation for this study is as follows: Francesca Zammarchi et al. Preclinical activity of ADCT-601, a novel pyrrolobenzodiazepine (PBD) dimer-based antibody-drug conjugate (ADC) targeting AXL-expressing tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2792A.