Exploring Plant-Based Bioreactors for Developing COVID-19 Therapeutics and Vaccines

Biologics company iBio, is focused on developing therapeutics and vaccines using a novel plant-based system. It recently announced a worldwide licensing agreement with Planet Biotech to develop and manufacture a novel COVID-19 therapeutic called ACE2-Fc.

Technology Networks spoke with iBio’s CEO and Chairman of the Board Thomas Isett, to learn more about the company’s efforts to develop ACE2-Fc as well as two vaccine candidates IBIO-200 and IBIO-201 against SARS-CoV-2. Isett also discusses the key benefits of plant-based manufacturing and highlights additional disease areas that they are working to develop biotherapeutics for.

Molly Campbell (MC): Please can you talk to us about the FastPharming System, how it works and how it differs from the typical biopharmaceutical manufacturing process?

Thomas Isett (TI): iBio is a global leader in plant-based biologics manufacturing. We develop our own biologic therapeutics and vaccines as well as offer contract development and manufacturing services to others. The primary benefits of our FastPharming System® are speed, consistent quality, yield and cost. Compared with traditional mammalian cell culture processes, plant-based production is faster and easier and produces consistently high-quality biologics in an eco-friendly way.

The process is fairly simple. A plant-specific expression vector containing the gene of interest is transfected into Agrobacterium, which are then vacuum infiltrated into the leaves of iBio’s proprietary Nicotiana benthamiana plants. The target protein is expressed in the leaves as the plants grow. The leaves are then harvested and the protein is isolated, purified and formulated into the desired final product.

The FastPharming System combines vertical farming, automated hydroponics and glycan engineering technologies to rapidly deliver gram quantities of high-quality monoclonal antibodies, vaccines, bioinks and other proteins. Unlike traditional cell culture bioprocesses that are performed in stainless steel or single-use bioreactors, iBio’s FastPharming System uses plants as bioreactors.

Plant-based production saves months in initial setup time compared with competing methods. There is, for instance, no need for expensive, labor-intensive cell-line development. The risks and delays associated with scale-up are also reduced. Scale-up is achieved by simply growing more plants. The material obtained during the research stage is highly comparable to the material obtained at a commercial scale.

iBio's FastPharming System is designed for the rapid scale-up of vaccines and therapeutics. We operate a 130,000-square-foot manufacturing facility in Texas that was initially funded by the Department of Defense as part of its Blue Angel program. The Blue Angel Program commissioned the build-out of our two-story vertical farming operation for the controlled growing of plants to provide medical countermeasures to a pandemic.

The FastPharming System has been used to produce vaccines such as ones against H5N1 and H1N1 influenza viruses.

MC: Does the regulatory and approval process for a biotherapeutic manufactured in a plant-based system differ from the process for a biotherapeutic produced in a bacterial cell system, for example?

TI: The regulatory process is the same for all biologics, regardless of the expression system utilized; however, as noted plant-based production provides several advantages. One in particular, from a regulatory perspective, is the avoidance of the use of raw materials with components that have an animal origin and may present a risk of viral contamination or transmissible spongiform encephalopathies, like bovine spongiform encephalopathy or “Mad Cow Disease”.

MC: iBio has announced an agreement with Planet Biotech to develop and manufacture ACE2-Fc, a novel COVID-19 therapeutic. Please can you tell us more about the therapeutic? What preclinical data has been obtained thus far?

TI: This therapeutic is a novel immunoadhesin molecule that we believe may be effective against SARS-CoV-2 and could potentially address mutations in the current virus as well as future coronavirus diseases.

More specifically, ACE2-Fc is a recombinant protein comprised of human angiotensin-converting enzyme 2 (ACE2) fused to a human immunoglobulin G Fc fragment (Fc). It works by targeting the coronavirus virions directly by using the ACE2 extracellular domain as a decoy to bind the spike protein and block infection of healthy cells, while the fused Fc domain prolongs the life of the protein in circulation. The design is expected to bring the benefit of a traditional monoclonal antibody while prospectively limiting the potential for "viral escape" – a process that can lead to the development of resistance to antiviral antibodies.

We are in the early stages of the partnership and have not yet completed preclinical work.

Laura Lansdowne (LL): In addition to the ACE2-Fc therapeutic, iBio is also developing two COVID-19 vaccine candidates (IBIO-200 and IBIO-201). Could you tell us more about these two candidates?

TI: Earlier this month, we announced that we intend to advance IBIO-201 as our lead vaccine candidate for the prevention of SARS-CoV-2 infection. IBIO-201, our LicKM^TM- subunit vaccine candidate, is based on a subunit platform that combines antigens derived from the SARS-CoV-2 spike protein fused with iBio's patented LicKM booster molecule to enhance the immune response. We believe our LicKM technology could potentially strengthen and extend the immune response to the antigen, possibly lowering vaccine antigen dose requirements or enabling fewer doses to establish prolonged immunity.

Preclinical immunization studies with both IBIO-200 and IBIO-201, combined with select adjuvants from the Infectious Disease Research Institute, induced SARS-CoV-2 immune responses. Additional cell-based pseudovirus neutralization assay testing demonstrated that IBIO-201 induced the production of more anti-spike neutralizing antibodies than IBIO-200 in immunized mice. Our plan is to conduct toxicology studies on IBIO-201 before proceeding to clinical studies.

We are also encouraged by the potential of IBIO-200, our virus-like particle (VLP) platform, as a potential plug and play vaccine development system and we plan to conduct more focused studies on it. IBIO-200 employs a VLP that is amenable to production scale-up, highly flexible for antigen display and adaptable to new viral strains. VLP vaccines interact with immune cells differently than soluble antigens and trigger both humoral and cellular responses. The safety and effectiveness of several VLP vaccines have been well documented since the first one was approved in 1998.

LL: What is the lichenase booster molecule (LicKM) and what key advantages does the technology offer in terms of designing vaccine candidates?

TI: The LicKM Booster^TM is a modified thermostable variant of the lichenase protein from the thermophilic bacterium Clostridium thermocellum. LicKM may be effective in addressing issues with subunit vaccines, which have a track record of protecting humans against deadly diseases but are often insufficiently stable and typically require the use of a strong adjuvant to boost their immunogenicity. IBio’s LicKM protein fusions have been shown to be more soluble and expressed at higher levels than antigens alone. They also can confer thermostability on fusion proteins, allowing for easy and cost-effective recovery of target proteins following heat treatment. With three available insertion sites, N-terminus, C-terminus and internal loop, LicKM allows the integration of three antigens (or multiple copies of the same antigen) within a single stable fusion protein as well as identification of the optimal insertion location.

MC: IBio is also working in disease areas outside of COVID-19. Can you discuss some of the other biotherapeutics that are in the company's pipeline?

TI: Our pipeline also includes treatment candidates for fibrotic diseases as well as classical swine fever.

Our lead asset for fibrotic diseases is IBIO-100. This product candidate has been granted orphan-drug designation by the US Food and Drug Administration (FDA) for the treatment of systemic scleroderma and is also being evaluated for other indications. It is a fusion of the endostatin-derived E4 antifibrotic peptide to the hinge and heavy chain of a human immunoglobulin G1. IBIO-100 has been shown to be effective using infusion and oral administration schemes in animal models. Preclinical studies have demonstrated a reduction of fibrotic symptoms. We are conducting additional studies to support an IND filing. The next steps are toxicology and cGMP manufacturing in our Texas facility. More information on this program may be found here.

IBIO-400 is our candidate for classical swine fever, a highly contagious, often fatal, disease affecting pigs. We are collaborating with the Institute of Infectious Animal Diseases at Texas A&M University and Kansas State University to develop a potentially safe and protective differentiating infected from vaccinated animals (DIVA)-capable subunit vaccine using our FastPharming system. This means that this vaccine candidate allows diagnostic tests to differentiate vaccinate from infected pigs, important for both economic and disease-control reasons. Formulated in cost-effective oil-in-water emulsion adjuvants, IBIO-400 studies have shown that after a single dose, the adjuvanted, plant-made CSF E2 subunit vaccine provides complete protection in challenged pigs and is accompanied by strong virus neutralization antibody responses. More information on this program may be found here.

Thomas Isett was speaking with Molly Campbell and Laura Lansdowne, Science Writers for Technology Networks.