ATX-101, a cell-penetrating protein targeting PCNA, can be safely administered as intravenous infusion in patients and shows clinical activity in a Phase 1 study.

Autor: Lemech CR; Scientia Clinical Research, Randwick, Australia and Prince of Wales Clinical School, UNSW Sydney, Sydney, NSW, Australia., Kichenadasse G; Southern Oncology Clinical Research Unit, Bedford Park, SA, Australia., Marschner JP; Therapim Pty Ltd, Southport, QLD, Australia. jpmarschner@apimtherapeutics.com., Alevizopoulos K; Therapim Pty Ltd, Southport, QLD, Australia., Otterlei M; Therapim Pty Ltd, Southport, QLD, Australia.; Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, NTNU Norwegian University of Science and Technology, NO-7491, Trondheim, Norway., Millward M; Linear Clinical Research & School of Medicine, University of Western Australia, Nedlands, WA, Australia.
Jazyk: angličtina
Zdroj: Oncogene [Oncogene] 2023 Feb; Vol. 42 (7), pp. 541-544. Date of Electronic Publication: 2022 Dec 23.
DOI: 10.1038/s41388-022-02582-6
Abstrakt: Proliferating Cell Nuclear Antigen (PCNA) is a highly conserved protein essential for DNA replication, repair and scaffold functions in the cytosol. Specific inhibition of PCNA in cancer cells is an attractive anti-cancer strategy. ATX-101 is a first-in-class drug targeting PCNA, primarily in cellular stress regulation. Multiple in vivo and in vitro investigations demonstrated anti-cancer activity of ATX-101 in many tumor types and a potentiating effect on the activity of anti-cancer therapies. Healthy cells were less affected. Based on preclinical data, a clinical phase 1 study was initiated. Twenty-five patients with progressive, late-stage solid tumors were treated with weekly ATX-101 infusions at four dose levels (20, 30, 45, 60 mg/m 2 ). ATX-101 showed a favorable safety profile supporting that vital cellular functions are not compromised in healthy cells. Mild and moderate infusion-related reactions were observed in 64% of patients. ATX-101 was quickly cleared from blood with elimination half-lives of less than 30 min at all dose levels, probably due to both, a quick cell penetration and peptide digestion in serum, as demonstrated in vivo. No tumor responses were observed but stable disease was seen in 70% of the efficacy population (n = 20). Further studies have been initiated to provide evidence of efficacy. Trial registration numbers: ANZCTR 375262 and ANZCTR 375319.
(© 2022. The Author(s).)
Databáze: MEDLINE
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