Oral delivery of therapeutic proteins bioencapsulated in plant cells: preclinical and clinical advances

Abstract

Oral delivery of protein drugs (PDs) made in plant cells could revolutionize current approaches of their production and delivery. Expression of PDs reduces their production cost by elimination of prohibitively expensive fermentation, purification, cold transportation/storage, and sterile injections and increases their shelf life for several years. Ability of plant cell wall to protect PDs from digestive acids/enzymes, commensal bacteria to release PDs in gut lumen after lysis of plant cell wall and role of GALT in inducing tolerance facilitate prevention or treatment allergic, autoimmune diseases or anti-drug antibody responses. Delivery of functional proteins facilitate treatment of inherited or metabolic disorders. Recent advances in making PDs free of antibiotic resistance genes in edible plant cells, long-term storage at ambient temperature maintaining their efficacy, production in cGMP facilities, IND enabling studies for clinical advancement and FDA approval of orally delivered PDs augur well for advancing this novel drug delivery platform technology.

Keywords: Molecular farming; autoimmune diseases; chloroplast; metabolic disorders; oral tolerance; protein drugs; transplastomic plants.

Figure-1:. Mechanism of tolerance induction by oral delivery of antigens bioencapsulated in plant cells.

A. The gene gun used to shoot gold particles coated with genes into plant cells. B. Lettuce plant regenerated after selection and expressing antigens in chloroplasts. C. Lyophilized plant cells powder and capsules. D. Intact plant cells (PC) with GFP protected from digestion and GFP in the gut epithelial cell (EC) after lysis of plant cells and GFP uptake (Xiao et al., 2016). E. Antigen taken up by tolerogenic CD103⁺ DCs (white arrows). F. Induction of antigen specific regulatory T cells. G. Induced Tregs suppress B cell and T cell responses against the antigen. H, I. The disease prevention via oral tolerance of autoimmune diseases.

Figure-2:. Oral delivery of functional protein drugs in lettuce lyophilized cells.

A. Lyophilization, grinding and capsule made from lettuce biomass containing protein drugs. B. Oral delivery of plant made PDs capsules . C. Intact plant cells (PC) with GFP avoided degradation and GFP in the gut epithelial cell (EC) after lysis of plant cells and GFP uptake (Xiao et al., 2016). D. Chloroplast bioencapsulated lettuce biomass expressing ACE2 (SARS-Cov-2 spike protein receptor) and Ang 1–7 in Renin-Angiotensin System (RAS) is potential therapeutic to treat SARS-Cov-2 infection (data not published) E. Bone regeneration in diabetic fracture healing in mice model via oral delivery of lettuce made Pro-IGF-1 (Park et al., 2019). F. Pulmonary vascular remodeling in mice model via oral delivery of ACE-2/Ang1–7 bioencaspsulated in lettuce cells (Daniell et al., 2020).