Accelerating the Commercialization of COVID-19 Neutralizing Antibodies With Plant-Based Manufacturing

The biotechnology company Angany recently announced the successful production of neutralizing monoclonal antibodies (NAbs) derived from the plasma of COVID-19 patients using its plant-based system. Angany has now joined forces with global technology company Phylloceuticals to leverage its PhAAST^TM (Pharmaceuticals as a Service Technology), plant-made commercial production system, to rapidly scale up commercial manufacturing.

Technology Networks spoke with Phylloceuticals’ chief science officer Dr Barry Holtz and Angany’s senior vice president Guy Tropper to learn more about key considerations when scaling up manufacturing, the benefits of a plant-based production system and how this approach is helping to accelerate the development of NAbs against SARS-CoV-2 and its variants.

Q: Could you comment on some of the key challenges encountered when scaling up the production of biopharmaceuticals, particularly considering the exceptional need for preventives and treatments to combat COVID-19?

A: Time to construct and commission, capital expenditures (CapEx) and personnel training are all key challenges to bringing on a new production facility. To frame any of these issues in the need to address epidemic and pandemic disease presupposes that there is a constant and vigilant effort to identify new viruses and other microbial threats. It also presupposes that preemptive vaccine and antiviral product development efforts are proactive and not reactive. Regional facilities will have to be created proactively and commissioned to make vaccines and antibodies for current needs. These facilities will need to be designed to pivot quickly to produce vaccines, antivirals and other products to address an outbreak. These facilities need to be in constant use so that personnel are trained and ready to pivot to a new product. Technologies that can address rapid product development and innovative scale-up and purification should replace or augment hardware heavy systems that require a long scale-up cycle to produce a consistent product. Response time is paramount. The trillions that COVID-19 has cost the global economy could have been greatly diminished by even a 6-month faster response to a vaccine and useful antiviral monoclonal antibodies (mAbs).

Plant-made pharmaceutical (PMP) manufacture can cut capital expense by 75% and operating expenses (OpEx) by 66%. PMPs have been around for a long time, but most new biopharmaceuticals are developed out of culture-based systems, likely due to familiarity with the approach. Adopting a “know how it’s done", established way of practice, rather than a conscious decision to truly examine other methods. However, there is an alternative way to mass-produce biopharmaceuticals that is not only able to achieve levels of production required to address a pandemic, but also to reorient current means of bioproduction that will be more efficient. We see a future where biotech start-ups order their prototype medicines so that from the get-go development is established in plant-based production systems.

Q: What are the benefits to plant-based production? Can you tell us more about Phylloceuticals’ plant-based pharmaceutical production system?

A: Using plants as bioreactors assures the drug developer that they have a generic bioreactor that is always the same. Plants possess all of the appropriate cellular machinery required to make complex human proteins. Transfection of these generic bioreactors by bacterial vectors introduces a new gene into plants and temporarily “hijacks” the protein production machinery to make the product of choice. These vectors can be made and tested in weeks instead of months. Bioreactors can always be “in production” and no cold start is necessary. The plant system assures rapid process development and rapid change-over from product to product.

At Phylloceuticals we can deliver a facility to make 100 kg of monoclonal antibodies or 2.5 billion doses of a sub-unit or VLP vaccines for less than $100 M of CapEx. Biologics can be delivered at much lower OpEx. The investment in preemptive manufacturing facilities using plants would be “budget dust” compared to the cost of the current pandemic.

Q: How is this system helping to accelerate the development of neutralizing monoclonal antibodies (NAbs) against SARS-CoV-2 and its variants?

A: Plants make antibodies at high yields and accuracy with very homogeneous glycosylation. Glycoforms can be humanized rapidly if needed. A recent technoeconomic study¹ showed that antibodies can be manufactured at less than $200 per gram in a facility designed for 300 kg of output per year. The development time to make a new antibody in plants is 25% of the time necessary to scale-up a typical Chinese hamster ovary (CHO)-based, large-scale bioreactor system. This fact will allow rapid response to new variants of current threats and threats from viruses that become pathogenic in the future.

Q: While the pandemic has resulted in a strain to existing production processes globally, the unprecedented need to develop strategies to combat SARS-CoV-2 has hopefully helped to streamline and innovate in this area. Could you comment on this?

A: The COVID-19 pandemic has focused the biopharma manufacturing community on the current lack of global resources to fight pandemic infection. Existing facilities have been repurposed, sometimes at the expense of the production of other drugs. Supply chains of common items (e.g., pipette tips) have dried up. These deficiencies must be addressed proactively to have any real effect on response time and the saving of lives. New facilities have to be built and staffed globally to effectively deal with epidemics and pandemics. These facilities have to be kept “warm” by continuously making useful vaccines and antivirals so they can effectively pivot rapidly to a new pandemic threat. This is a global investment and a globally collaborative effort. There is a great disparity between “haves” and “have nots” that could be addressed by lower cost plant-made biologics facilities.

Under current mammalian cell culture, there has been very little innovation, perhaps with the exception of single-use technology. We may be at the junction of a paradigm shift – until now we have relied on a technique using stainless steel bioreactors and mammalian cell culture that has proven very useful over the last twenty years. But there is now great incentive to take advantage of PMP production systems, which have been around for over twenty years. The technology is excellent but due to inertia and a comfort level with existing approaches, has not been applied and has not been that visible. Now, in the context of the pandemic, it has pushed the plant-made technology to the forefront, for a new generation of technologists and engineers to use.

Q: Before joining the fight against COVID-19 Angany was working to combat the “allergy pandemic”, can you provide an overview of allergy prevalence and discuss some of the work the company is doing in this area?

A: Allergy currently affects close to one in three persons and by 2050, this could reach 50% of people if nothing changes. Angany is developing a new generation of treatments for allergy. To address the specific challenges of allergy, Angany had to invent a biosynthetic, auto-adjuvanted immunomodulatory vector. In short, Angany aims to treat people with, say an allergy to cats or peanuts through a short, safe course of treatment. The goal is to protect people from the risk of allergic reactions for several months, perhaps several years with booster doses. Beyond this vaccinal platform called the eBioparticle™, Angany’s other major innovation consists in its plant-based bioproduction platform. Only an evolved vegetal production platform could realistically meet the global need considered in allergy and the specific quality required (“natural-like”) of the diagnostic proteins and allergen-bearing bioparticles. The COVID-19 pandemic compelled Angany’s team to contribute. Collaborating with researchers from Amsterdam UMC and with Phylloceuticals, Angany is convinced that neutralizing mAbs against SARS-CoV-2 and variants can be made available in short order and in quantities that can make a real difference in pandemic response. mAbs are a necessary complement to vaccines in our fight against pandemics; we must appropriate the biomanufacturing capacity to meet the needs of a population-wide emergency. 

Reference

1. Nandi S, Kwong AT, Holtz BR, Erwin RL, Marcel S, McDonald KA. Techno-economic analysis of a transient plant-based platform for monoclonal antibody production. MAbs. 2016;8(8):1456-1466. doi: 10.1080/19420862.2016.1227901

Dr Barry Holtz and Guy Tropper were speaking to Laura Elizabeth Lansdowne, Managing Editor for Technology Networks.