AAV-mediated delivery of actoxumab and bezlotoxumab results in serum and mucosal antibody concentrations that provide protection from C. difficile toxin challenge

AAV-monoclonal antibody expression protects mice from Ebola virus without impeding the endogenous antibody response to heterologous challenge

“…ZMapp was dosed at 50 mg/kg over multi-day treatment courses in humans to maintain a therapeutic threshold 9 ; however, much lower but more consistent serum mAb concentrations mediated by AAV6.2FF should be able to maintain therapeutic efficacy without the peak and trough pharmacokinetics associated with repeat recombinant mAb administration. 45 There is strong evidence of the prophylactic efficacy of AAV6.2FF-mAb therapies, [26][27][28] allowing for post-exposure use to extend the potential applications of this therapy. Potential exposures to EBOV in a lab accident or health-care setting are realistic possibilities.…”

“…Finally, the fact that AAV-driven expression of human IgG1 Fc domain-containing mAbs persisted for the lifetime of a mouse, without any apparent immune-mediated destruction of AAV-transduced cells, suggests that it may be possible to use the same vector design when translating from small animal models to NHPs and ultimately humans without the need to re-engineer vectors to express species-specific IgG constant domains. Indeed, we have shown that AAV-mediated expression of human IgG1 mAbs is feasible in mice, 26 Syrian hamsters, 27 and sheep. 28 More recently, data from a phase 1, dose-escalation clinical trial (NCT03374202) evaluating AAV8-mediated expression of the broadly neutralizing anti-HIV mAb VRC07 from an expression cassette that we based our EBOV mAb expression platform on in this body of work is encouraging in that all eight individuals produced measurable amounts of serum VRC07, with maximal concentrations >1 mg/mL in three participants.…”

“…25 This capsid elicits long-term systemic expression of mAbs, which conferred protection in multiple infectious disease models, including at mucosal surfaces. [26][27][28] Here, we further explore the immunity mediated by this AAV6.2FF-mAb approach at reduced vector doses, and we use human IgG1 (hIgG1) filovirus mAbs in immunocompetent mice to expand the utility of our AAV6.2FF-mAb expression platform. In dose reduction experiments, we demonstrate AAV6.2FF vectors expressing murine IgG2a, and later hIgG1 mAbs, have the ability to prevent morbidity and mortality in the mouse-adapted EBOV challenge model, even with low level mAb expression.…”

Safety and Tolerability of the Adeno-Associated Virus Vector, AAV6.2FF, Expressing a Monoclonal Antibody in Murine and Ovine Animal Models

“…An alternative approach to passive immunization is vectorized antibody expression, in which an adeno-associated virus (AAV) vector is used to transfer a mAb gene to host cells that subsequently produce and secrete antibody into the blood [ 9 , 10 ]. In this manner, antibody expression is continuously manufactured within treated patients, providing immunity for much extended periods compared to passive antibody transfer.Vectorized antibody expression has been highly effective at protecting animal models from various infectious diseases including HIV, Influenza virus, Ebola virus and Clostridium difficile [ 11 , 12 , 13 , 14 ].…”

“…To the best of our knowledge, there are no published studies examining the toxicity of AAV vectorized antibody expression; however, there is an abundance of preclinical and clinical studies that underscore the safety and tolerability of AAV-based therapies [ 15 , 16 ]. In this study, we selected a triple mutant AAV6 capsid, AAV6.2FF, as our vector of choice, due to its superior ability to transduce both muscle and lung tissue, as shown in murine and hamster animal models [ 13 , 14 , 17 ]. Here, we use AAV6.2FF to evaluate the safety and tolerability of this approach through hematology, blood biochemistry and histopathology and the feasibility of vectorized antibody expression in murine and ovine animal models to reach potentially therapeutic plasma antibody concentrations.…”