AAVrh.10 immunogenicity in mice and humans. Relevance of antibody cross-reactivity in human gene therapy

Abstract

Simian adeno-associated virus (AAV) serotype rh.10 is a promising gene therapy tool, achieving safe, sustained transgene expression in the nervous system, lung, liver and heart in animal models. To date, preexisting immunity in humans has not been confirmed, though exposure is unexpected. We compared the humoral immune response with serotypes AAVrh.10 and AAV9 in mice, and AAVrh.10, AAV9 and AAV2 in 100 healthy humans. Mice, injected-intravenously, raised significantly more anti-AAV9 than anti-AAVrh.10 IgG (immunoglobulins), and sera demonstrated greater neutralizing capacity, correspondingly. Antibody cross-binding studies in mice showed negligible cross-recognition between AAVrh.10, AAV9 and AAV2. In humans, IgG prevalence against the most common human serotype, AAV2, was 72%; AAV9, 47% and AAVrh.10, a surprising, 59%. Yet, neutralizing-antibody seroprevalences were 71% for AAV2, 18% for AAV9 and 21% for AAVrh.10. Thus, most anti-AAV9 and anti-AAVrh.10 IgG were nonneutralizing. Indeed, sera generally neutralized AAV2 more strongly than AAVrh.10. Further, all samples neutralizing AAVrh.10 or AAV9 also neutralized AAV2, suggesting antibody cross-recognition. This contrasts with the results in mice, and highlights the complexity of tailoring gene therapy to minimize the immune response in humans, when multiple-mixed infections during a lifetime evoke a broad repertoire of preexisting antibodies capable of cross reacting with non-human serotypes.

AAV natural infection induces broad cross-neutralizing antibody responses to multiple AAV serotypes in chimpanzees

“…12,15,16 These findings differ from observations in gene therapy trials, in which a replication-deficient serotypespecific AAV vector is injected into subjects with no preexisting AAV NAbs, in which the ensuing NAb response is limited to the AAV serotype that was injected. 17,18 To further understand the phenomenon of naturally occurring broadly cross-neutralizing NAb responses observed in nonhuman primates, we conducted a longitudinal study designed to analyze serum samples collected from captive housed chimpanzees over 10 years for AAV NAbs.…”

Gene therapy for monogenic liver diseases: clinical successes, current challenges and future prospects

“…The cumulative safety experience with the rapidly growing number of AAV-based trials targeting the human liver, combined with the low rate of HCC-associated AAV integrations despite the high seroprevalence of wild type AAV in the human population (e.g. >50% for AAV2) (Thwaite et al 2015) are consistent with a favourable safety profile of AAV vectors. Nevertheless the findings of Nault et al warrant further studies and mandate close monitoring in ongoing human trials.…”

High-Density Recombinant Adeno-Associated Viral Particles are Competent Vectors forIn VivoTransduction

“…Studies in humans have found that antibodies to some AAV serotypes are less prevalent than others. 50 AAV serotype switching and capsid engineering strategies have produced promising results. 51,52 Because the capsid composition is different between rAAV RD and rAAV HD particles, it can be hypothesized that humoral immunity may also have some difference.…”