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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 (EC 50 ranging from 0.009-0.093 μg/mL; EC 90 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., Competing Interests: Declaration of competing interest The authors of this manuscript have conflicts of interest to disclose as described by the American Journal of Transplantation. J. R. Abend, A. Sathe, M. B. Wrobel, M. Knapp, L. Xu, L. Zhao, P. Kim, S. Desai, A. Nguyen, X.-C. Leber, A. Hein, M. Scharenberg, J. Shaul, E. Ornelas, K. Wong, T. Pietzonka, P. Pertel, E. Traggiai, and S. J. Kovacs are or were employees of Novartis and shareholders of Novartis stock when the study was performed. L. M. Sterling was an employee of Celerion when the study was performed. MAU868 was discovered at Novartis Institutes for BioMedical Research and was then acquired by Amplyx Pharmaceuticals, Inc, which became a wholly owned subsidiary of Pfizer. MAU868 was most recently acquired and continues to be held by Vera Therapeutics., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)