Advantages of homologous recombination- over transposition-based systems
to generate recombinant baculovirus for AAV vector production
Abstract
Viral vectors have a great potential for gene delivery, but
manufacturing at pharmaceutical scale is a big challenge for the
industry. The baculovirus-insect cells system is one of the most
scalable platforms to produce clinical grade recombinant
Adeno-Associated Virus (rAAV) vectors, however, the standard procedure
to generate recombinant baculovirus based on Tn7 transposition is time
consuming and still suffers technical constraints. Indeed, we recently
shown that baculoviral sequences adjacent to the AAV ITRs are
preferentially encapsidated into the rAAV vector particles. This
observation raised concern about safety for clinical applications due to
the presence of bacterial and antibiotic resistance coding sequences
with Tn7-mediated system for the construction of recombinant
baculoviruses. Here, we investigated a faster and safer method to
generate baculovirus reagents based on homologous recombination (HR) for
its use in rAAV manufacturing compared to the Tn7-based system. First,
we confirmed the functionality of inserted cassette and the absence of
undesirable genes into HR-derived baculoviral genomes. Strikingly, we
found that the exogenous cassette shown an increased stability over
passages when using HR system. Finally, we tested these materials to
produce rAAV vectors. The baculoviruses originated from either system
lead to high rAAV vector genome yields, with the advantage for the HR
method being that the rAAV lots are exempted of undesirable gentamycin
and kanamycin genes derived sequences which provides an additional level
of safety for the manufacturing of rAAV vectors. Overall, this study
highlights the importance of the upstream process and starting biologic
materials to generate safer rAAV biotherapeutic products.