Sathe, Atul, Wrobel, Matthias, Knapp, Mark, Zhao, Lihong, Kim, Peter, Leber, Xavier Charles, Hein, Andreas, Scharenberg, Meike, Shaul, Jacob, Ornelas, Elizabeth, Wong, Kelly, Pietzonka, Thomas, Kovacs, Steven, Traggiai, Elisabetta, Patick, Amy and Abend, Johanna (2024) Nonclinical and clinical characterization of MAU868, a novel human-derived monoclonal neutralizing antibody targeting BK polyomavirus VP1. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. ISSN 1600-6143

Abstract

Reactivation of BK polyomavirus (BKPyV) can cause significant kidney and bladder disease in immunocompromised patients. There are currently no effective, BKPyV-specific therapies. MAU868 is a novel, human immunoglobulin (Ig) G1 monoclonal antibody that binds the major capsid protein, VP1, of BKPyV with picomolar affinity, neutralizes infection by the 4 major BKPyV genotypes (EC50 ranging from 0.009-0.093 μg/mL; EC90 ranging from 0.102-4.160 μg/mL), and has comparable activity against variants with highly prevalent VP1 polymorphisms. No resistance-associated variants were identified in long-term selection studies, indicating a high in vitro barrier-to-resistance. The high-resolution crystal structure of MAU868 in complex with VP1 pentamer identified 3 key contact residues in VP1 (Y169, R170, and K172). A first-in-human study was conducted to assess the safety, tolerability, and pharmacokinetics of MAU868 following intravenous and subcutaneous administration to healthy adults in a randomized, placebo-controlled, double-blinded, single ascending dose design. MAU868 was safe and well-tolerated. All adverse events were grade 1 and resolved. The pharmacokinetics of MAU868 was typical of a human IgG, with dose-proportional systemic exposure and an elimination half-life ranging between 23 and 30 days. These results demonstrate the potential of MAU868 as a first-in-class therapeutic agent for the treatment or prevention of BKPyV disease.

Item Type:	Article
Date Deposited:	17 Sep 2024 00:45
Last Modified:	17 Sep 2024 00:45
URI:	https://oak.novartis.com/id/eprint/50324