Table 2 Summary of main pre-clinical and clinical studies with oral anti-tumor necrosis factor-α treatment in inflammatory bowel diseases

Worledge et al. (2000) [26]

Avian anti-TNF-α antibody

Solution of polyclonal yolk IgY anti-TNF-α antibody diluted in carbonate buffer

Animal study (TNBS-induced colitis in rats)

Oral anti-TNF-α (600 mg/kg/day) therapy was significantly more effective in decreasing the colonic inflammatory activity assessed by gross morphology score, histology score, and tissue myeloperoxidase activity when compared to sulphasalazine (200 mg/kg/day) and dexamethasone (2 mg/kg/day)

Vandenbroucke et al. (2010) [27]

Monovalent and bivalent murine mTNF-neutralizing nanobody

Genetically modified Lactococcus lactis strain, secreting anti-mTNF nanobodies

Animal study (DSS-induced colitis and enterocolitis in IL-10^−/− mice)

Orally administered L. lactis secreting anti-mTNF nanobodies were effective in ameliorating experimental enterocolitis assessed histologically when compared with controls

Bhol et al. (2013) [75]

AVX-470—a polyclonal antibody specific for human TNF-α isolated from the colostrum of dairy cows

AVX-470 solution diluted in saline

Animal study (TNBS- and DSS-induced colitis in mice)

Orally administered AVX-470 significantly reduced colonic inflammation assessed endoscopically, histologically—comparably to prednisolone or parenteral etanercept, as well as decreased colonic expression of multiple pro-inflammatory proteins and mRNA levels of cytokines

Harris et al. (2016) [29] and Hartman et al. (2016) [28]

AVX-470—a polyclonal antibody specific for human TNF-α isolated from the colostrum of dairy cows

AVX-470-containing capsules

Randomized double-blind and placebo-controlled trial in patients with active moderate-to-severe ulcerative colitis

Oral administration of AVX-470 capsules for 4 weeks resulted in numerically higher percentages of patients achieving clinical, biochemical (CRP, IL-6), and endoscopic improvement when compared with placebo. AVX-470 also decreased the expressions of TNF and myeloperoxidase in the mucosa and diminished the apoptotic loss of epithelial cells. The therapy was safe and well-tolerated. No immunogenicity was detected

Maurer et al. (2016) [30] and Gareb et al. (2019) [31]

IFX

pH-sensitive ColoPulse tablets enabling drug release in the ileocolonic region

Gastrointestinal in vitro model (GISS) study, simulating gastrointestinal transit

ColoPulse-IFX tablets were stable in long-term storage conditions at room temperature and showed complete release in a simulated model of the ileocolonic region

Crowe et al. (2018) [32]

V565—a TNF-α-inhibiting antibody heavy chain variable domain

V565 solution loaded in a gastroprotective vehicle (NaHCO₃ containing Marvel milk)

Animal study (DSS-induced colitis in mice) and in vitro study on human IBD tissue culture model

Oral administration of V565 led to a high drug concentration in colonic tissue and detectable drug serum levels in DSS-colitis mice. V565 decreased the production of proinflammatory cytokines to a similar extent as infliximab in ex vivo model of human IBD tissue

Crowe et al. (2019) [33]

V565—a TNF-α-inhibiting antibody heavy chain variable domain

Eudragit® enteric-coated V565 mini-tablets

Animal study (cynomolgus monkeys)

Enteric-coated V565 minitablets effectively transported the anti-TNF-α-acting molecule to the intestines, which was detected in the intestinal wall and faeces with a very low systemic exposure

Nurbhai et al. (2019) [34]

V565—a TNF-α-inhibiting antibody heavy chain variable domain

Eudragit® enteric-coated V565 mini-tablets

Human IBD study

Enteric-coated V565 minitablets were detected in ileal fluid and faeces of patients with IBD. After a 7-day oral therapy, V565 was detected in colonic biopsies and resulted in a decrease of tissue phosphoprotein levels, reflecting its anti-inflammatory properties. There were no serious adverse events (AE) or withdrawals due to AE

Kim et al. (2020) [40]

IFX

Nanocomposite formulations: IFX-L, AC-IFX-L, and EAC-IFX-L

Animal study (DSS-induced colitis in mice) and in vitro study on PBMC of IBD patients

Nanocomposites-based IFX oral therapy targeted to inflamed colonic tissues with minimal systemic exposure in animal models of IBD, leading to clinical and histomorphological improvement. The most significant improvement was seen in the case of AC-IFX-L, and EAC-IFX-L. These nanocomposite carriers loaded with IFX also significantly decreased the pro-inflammatory cytokine expression

Wang et al. (2020) [41]

IFX

IFX@PPNP given as drinking water

Animal study (DSS-induced colitis in mice)

The synthesis of IFX@PPNP was feasible. Oral administration of IFX@PPNP resulted in a high drug concentration locally in the inflamed intestines and low systemic exposure. Treatment with IFX@PPNP was highly effective in terms of clinical, histomorphological parameters, as well it led to a decrease in pro-inflammatory parameters in colonic tissue and serum

Almon et al. (2021) [35]

Recombinant TNFR2-Fc fusion protein (OPRX-106)

A lyophilized Nicotiana tabacum (BY2) tobacco plant expressing OPRX-106

Open-label clinical trial in patients with active mild-to-moderate ulcerative colitis

Oral administration of OPRX-106 for 8 weeks resulted in an almost 70% rate of clinical response. One-third of patients were in clinical remission. A decrease in fecal calprotectin and histologic activity was observed