Final Report Summary - FUTURE-PHARMA (Exploiting plants for the production of future generation recombinant pharmaceuticals)
In 2011, the field of molecular pharming was still in its infancy. There were no commercial products, only a handful of drug candidates in clinical trial and few large pharmaceutical companies engaged in the technology. Against this background, the Future-Pharma project was proposed, to build on recent European success in the FP5-funded Pharma-Planta project. The proposal was to advance the field particularly for developing country use, by developing innovative ways to use plants for the economical, safe and sustainable production of combinations of active pharmaceutical ingredients (APIs) based on recombinant proteins. Key aspects of the project included optimised production of APIs both individually and as combinations in plants, including the development of technologies to allow predictable introduction of transgenes into the plant genome. We also proposed development of new purification concepts which would be transferrable to developing countries. And importantly, we proposed a Phase I clinical trial in human volunteers, to advance the field in a significant way, also by signifying third party regulatory approval of the plant manufacturing process for biologics.
There have been many achievements from this project. Our focus on biologics for prevention and treatment of HIV and rabies resulted in plant resources for 16 individual drug targets being developed – 8 HIV neutralising compounds, and 8 rabies neutralising monoclonal antibodies. We investigated production of HIV compounds in multiple combinations in the same plant, but concluded that individual manufacture in separate plant lines provides the best opportunity for product control and does not inflate the final product cost significantly. With the aim of introducing predictability into the transgene insertion event in plants, thereby reducing effort and cost involved in elite plant line screening, we successfully developed a recombinase-mediated cassette exchange approach. With the discovery of CRISPR/Cas9, we were among the first to develop gene editing tools for N. tabacum.
Recognising that drug product extraction and downstream processing represented the most significant cost in the manufacturing process, we have assessed a number of protocols to minimise effort required, resulting in the development of a number of simple, inexpensive approaches to reduce the load of contaminating plant process before entering affinity purification steps.
The biggest effort was placed into advancing an antibody product into Phase 1 Clinical trial. Although we have fallen short of this final objective, the following achievements were made:
1) Redesign of manufacturing process for tobacco derived monoclonal antibodies to accommodate increased yield requirement and increased regulatory requirement for intra-venous delivery.
2) Manufacture of over 20g HIV neutralising monoclonal antibody active drug substance at GMP.
3) Development and validation of all assays (in-house) for Quality Control of the drug product, including four new assays.
4) Pre-clinical toxicology study in Sprague Dawley rats, for P2G12 given as a single intravenous (bolus) injection administration at dose levels of 0, 7 and 35 mg/kg.
5) Pharmacokinetics study of P2G12 in rats.
6) Manufacture of final drug product ~100 doses in intra-venous infusion bags, stored in preparation for human Phase I clinical trial.
7) Product release data confirmed.
8) Ongoing drug stability study (currently at 12 months) to support the clinical trial.
9) Design of a Phase I single-blind, dose escalation trial of intra-venously delivered plant derived HIV mAb in humans completed.
10) Local ethics committee approval for the clinical trial.
This work over the last 8 years will not be lost. We still plan to complete the clinical trial and the underlying contribution of ERC’s Future-Pharma project is valued and will be acknowledged.
There have been many achievements from this project. Our focus on biologics for prevention and treatment of HIV and rabies resulted in plant resources for 16 individual drug targets being developed – 8 HIV neutralising compounds, and 8 rabies neutralising monoclonal antibodies. We investigated production of HIV compounds in multiple combinations in the same plant, but concluded that individual manufacture in separate plant lines provides the best opportunity for product control and does not inflate the final product cost significantly. With the aim of introducing predictability into the transgene insertion event in plants, thereby reducing effort and cost involved in elite plant line screening, we successfully developed a recombinase-mediated cassette exchange approach. With the discovery of CRISPR/Cas9, we were among the first to develop gene editing tools for N. tabacum.
Recognising that drug product extraction and downstream processing represented the most significant cost in the manufacturing process, we have assessed a number of protocols to minimise effort required, resulting in the development of a number of simple, inexpensive approaches to reduce the load of contaminating plant process before entering affinity purification steps.
The biggest effort was placed into advancing an antibody product into Phase 1 Clinical trial. Although we have fallen short of this final objective, the following achievements were made:
1) Redesign of manufacturing process for tobacco derived monoclonal antibodies to accommodate increased yield requirement and increased regulatory requirement for intra-venous delivery.
2) Manufacture of over 20g HIV neutralising monoclonal antibody active drug substance at GMP.
3) Development and validation of all assays (in-house) for Quality Control of the drug product, including four new assays.
4) Pre-clinical toxicology study in Sprague Dawley rats, for P2G12 given as a single intravenous (bolus) injection administration at dose levels of 0, 7 and 35 mg/kg.
5) Pharmacokinetics study of P2G12 in rats.
6) Manufacture of final drug product ~100 doses in intra-venous infusion bags, stored in preparation for human Phase I clinical trial.
7) Product release data confirmed.
8) Ongoing drug stability study (currently at 12 months) to support the clinical trial.
9) Design of a Phase I single-blind, dose escalation trial of intra-venously delivered plant derived HIV mAb in humans completed.
10) Local ethics committee approval for the clinical trial.
This work over the last 8 years will not be lost. We still plan to complete the clinical trial and the underlying contribution of ERC’s Future-Pharma project is valued and will be acknowledged.