Bulk production of the antiviral lectin griffithsin

Fuqua, Joshua L.; Hamorsky, Krystal; Khalsa, Guruatma; Matoba, Nobuyuki; Palmer, Kenneth E.

The outlook on development of additional PMP products to clinically relevant therapeutics is currently favourable, but this is much more related to positive outcomes in clinical development than a validation of PMPs. GRFT has been shown to be safe and effective in in vivo and in vitro models and warrants further clinical development. For the continued clinical development of GRFT, a bulk production system is needed and has been developed in parallel to GRFT's clinical development. There are unique challenges associated with the development of every protein biopharmaceutical and the relative immaturity of PMPs, as a bulk production platform, provides additional challenges. Plant systems seem to be optimum for the production of GRFT, which may be related to its inherent stability and natural production in red alga. In this review, we have updated the field on challenges associated with the bulk production of GRFT and the progress made in addressing those challenges. Systems have been developed and are currently in place for the monitoring and use of rTMV-based expression systems. Programs for the qualification and assessment of the long-term stability of GRFT have been developed and implemented. The GRFT API has demonstrated to be stable and robust with no significant changes in purity or activity over 3 months. The potential remains with GRFT rectal microbicide, like many biologics, that molecular heterogeneity and immunogenicity could become an issue in either the API, formulated product or upon delivery. Systems are being developed and preliminary data collected to overcome issues related to the oxidation of GRFT; assessing formulation and direct molecular alteration solutions. Successful development of GRFT as a safe and effective microbicide in the current clinical trials will then necessitate its availability to at-risk populations. The logistics of acquiring enough GRFT to provide it prophylactically to those at high risk for HIV exposure will require increased production infrastructure, both in the USA and abroad. The current infrastructure in the USA is not sufficient to provide GRFT to the large population of individuals who would potentially benefit from it. Therefore, a further expansion of production infrastructure of current facilities is necessary along with expansion of production into regions heavily affected by HIV. The optimization of production systems for GRFT provides a platform for further economic analysis of the viability of PMPs and comparison of upstream production systems. Although any economic analysis is product and process specific, it is likely that GRFT would represent a best-case scenario for nonvaccine PMPs because of its high expression levels, stability, potency and its current indication for topical deliverymeaning some of the qualification assays may not be as stringent as they are for injectables.