A First-in-Human Study of MAU868, a Novel Neutralizing Antibody Against BK Virus

Background: Reactivation of BK virus (BKV) infection can cause significant kidney and bladder disease in immunocompromised patients, including patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT). Hemorrhagic cystitis is the most common BKV-related complication following HSCT and a significant contributor to post-HSCT morbidity and possibly mortality. There are currently no effective or BKV-specific therapies. MAU868 is a novel monoclonal human IgG1 that binds to the BKV major capsid protein (VP1) with potent in vitro neutralizing activity against the 4 major BKV genotypes (EC₅₀s ranging from 0.009 to 0.093 μg/ml).

Methods: MAU868 was administered i.v. (1, 3, 10, 30, and 100 mg/kg) or s.c. (3 mg/kg) to healthy adults in a randomized, placebo-controlled, blinded, single ascending dose design. Each i.v. cohort was 5 subjects (4 MAU868:1 placebo); the s.c. cohort was 8 subjects (6 MAU868:2 placebo). Subjects were observed for 24 h and followed for 106 d with routine safety monitoring and PK assessments. Ex vivo neutralizing activity of serum was measured before and 4 w after dosing. The range of doses included and exceeded the predicted clinically efficacious dose.

Results: 33 subjects completed the study. Adverse events were mild and infrequent; those occurring in more than 1 subject included nasal congestion (3, 9.1%), oropharyngeal pain (3, 9.1%), and injection site hemorrhage (ecchymosis after s.c. injection; 2, 6.1%). There were no infusion reactions. No subject discontinued the study due to an adverse event or developed anti-drug antibodies. MAU868 PK was typical of a human IgG with a half-life of 23 to 30 d. AUC and Cmax were dose-proportional, ranging from 9880 to 1060000 µg*hr/mL and 24.7 to 2740 µg/mL (ie, no evidence of FcRn saturation). Day 29 plasma MAU868 concentrations, adjusted for extravascular distribution to estimate parenchymal exposure, were approximately 7- to 751-fold higher than the highest in vitro EC₅₀ (0.093 µg/mL). Maximum ex vivo neutralizing activity of serum was achieved for doses >10 mg/kg. Bioavailability after s.c. injection was 57.6%.

Conclusions: MAU868 was safe and well tolerated with PK typical for a human IgG. The ex vivo neutralizing activity suggests where the therapeutic range may be for the treatment or prevention of BKV disease. These results warrant further clinical investigation of MAU868 in patients with or at risk for BKV disease.