Development of VNX-101, an adeno-associated virus with less immunogenicity and efficient long-term expression of a...

We previously described the use of recombinant adeno-associated virus (AAV) gene therapy to achieve off-the-shelf, long-term in vivo T cell engagement for CD19+ B cell malignancies following a single dose by expressing a transgene encoding a bispecific diabody termed GP101. Here we describe the selection and development of a clinical lead construct, VNX-101, with enhanced safety and efficacy features. A single dose of the virus was effective at eliminating B cell malignancies in humanized mouse xenograft models. We observed a linear dose-dependent increase in serum concentrations of GP101 over a three-log range in mice, with transduction and serum levels lower in females than males. There were no concerning safety signals and the No Observed Adverse Event Level was determined to be >2.7E13 vg/kg. We also conducted a 12-week study to evaluate the pharmacokinetics, biodistribution, in-life safety, gross pathology, and histopathology in hamadryas baboon monkeys. VNX-101 treatment was well tolerated with no significant changes in body weight or clinical signs reported. Collectively, these preclinical data support the efficacy and safety of VNX-101 as a potential AAV-based treatment for cancer. A phase 1/2 clinical trial of VNX-101 for relapsed or refractory B cell malignancies is under way.