Review: Local Tumor Necrosis Factor-α Inhibition in Inflammatory Bowel Disease
Abstract
:1. Introduction
2. Methods
3. Preclinical Studies on Local TNF-α Inhibition
3.1. Considerations
3.2. Antibodies
3.3. Antisense Oligonucleotides
3.4. microRNA
3.5. Small Interfering RNA
3.6. Prokaryotes
3.7. Eukaryotes
4. Clinical Studies on Local TNF-α Inhibition
4.1. Considerations
4.2. Local Injections
4.3. Topical Treatment
4.4. Oral Therapy
5. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Treatment | Formulation | ROA | Animal Model | TNF-α a | Cytokines a | Measured Effects | Histology | Reference |
---|---|---|---|---|---|---|---|---|
Antibodies | ||||||||
IFX-Enema | Enema containing an IFX solution | Rec. | Mice, DSS acute colitis | – | – | Body weight, colon length, DAI, Rachmilewitz score | H&E staining | [90] |
V565 | Anti-TNF-α single domain antibody | PO | Mice, DSS acute colitis | – | – | – | – | [92] |
V565 tablet | Anti-TNF-α single domain antibody coated with pH sensitive polymer (pH threshold ≥6) | PO | Cynomolgus monkeys, healthy | – | – | – | – | [94] |
Avian-anti-TNF-α | Avian antibody against TNF-α | PO | Rats, TNBS acute colitis | – | – | Colon morphology, colon weight, MPO | H&E staining, histopathology score, IgY staining | [109] |
Rats, TNBS chronic colitis | – | – | Colon morphology, colon weight, MPO | Histopathology score, IgY staining | ||||
AVX-470 | Bovine colostral antibody against TNF-α | PO | Mice, DSS acute colitis | – | – | Endoscopy score | – | [105] |
Mice, DSS chronic colitis | mRNA | IL-1β, IL-6, IL-12p40 | Endoscopy score, colon length, colon weight, IHC score | Histopathology score, IHC staining | ||||
Mice, TNBS acute colitis | – | – | Endoscopy score | – | ||||
Antisense Oligonucleotides | ||||||||
ISIS 25302 | ASO against TNF-α | SC | Mice, DSS chronic colitis | Protein, mRNA | – | DAI | Histopathology score | [110] |
ISIS 25302 | ASO against TNF-α | IP | Mice, db/db | mRNA | – | - | – | [112] |
IV | Mice, DSS acute colitis | – | – | Colon length, DAI | – | |||
SC | Mice, DSS chronic colitis | Northern blot | – | DAI | Histopathology score | |||
Mice, IL-10−/− colitis prophylaxis | Colon organ culture, basal and LPS stimulated | – | – | Histopathology score | ||||
Mice, IL-10−/− colitis therapy | Colon organ culture, basal and LPS stimulated | IFN-γ | – | Histopathology score | ||||
Gal–LMWC–ASO | Nanocomplex of ASO against TNF-α (ISIS 25302) associated with galactosylated low molecular weight chitosan | IC | Mice, TNBS acute colitis | Protein, mRNA | IFN-γ, IL-1β, IL-6, IL-12, IL-17, IL-23, | AAT, body weight, DAI, mortality, MPO | H&E staining, histopathology score, TNF-α staining | [113] |
Mice, CD4+ CD45RBhi chronic colitis | Protein, mRNA | IFN-γ, IL-1β, IL-6, IL-12, IL-17, IL-23 | AAT, body weight, DAI, mortality, MPO | H&E staining, histopathology score. TNF-α staining | ||||
GGG-ASO | Colon-targeted microspheres containing ASO (ISIS 25302) against TNF-α complexed with a mixture of glucomannan-gellan gum | PO | Mice, DSS acute colitis | Protein | IL-1β, IL-6, IL-12p70, IL-23 | Body weight, colon length, DAI, mortality, MPO | H&E staining, histopathology score | [131] |
CAL-ASO | ASO against TNF-α (ISIS 25302) complexed with lentinan encapsulated in chitosan–alginate | PO | Mice, DSS acute colitis | Protein | – | Body weight, colon length, MDA, MPO, spleen size | – | [116] |
SPG-ASO | Enema containing schizophyllan–ASO complex against TNF-α | Rec. | Mice, DSS acute colitis | mRNA | IL-1β, IL-6 | Body weight, colon length, endoscopy | H&E staining, histopathology score | [117] |
ASO-miR-301a | Enema containing ASO against miR-301a | IC | Mice, TNBS acute colitis | mRNA | IFN-γ, IL-4, IL-10, IL17A | Body weight, colon length, DAI | H&E staining, histopathology score | [119] |
MicroRNA | ||||||||
Gal-LMWC-pre-miR-16 | Precursor of miR-16 complexed with galactosylated low molecular weight chitosan | IC | Mice, TNBS acute colitis | Protein, mRNA | IFN-γ, IL-1β, IL-6, IL-12p40, IL-17A, IL-23 | Body weight, DAI, mortality, MPO | H&E staining, histopathology score, IL-12p40 staining, TNF-α staining | [122] |
miR-195 | Agomir of miR-195 | NS | Rats, TNBS acute colitis | Protein, mRNA | IL-1β, IL-6 | DAI | H&E staining | [132] |
Small interfering RNA | ||||||||
PACC-siRNA-TACE | Poly arginine–cysteine complex containing siRNA against TACE | IV | Mice, DSS acute colitis | Protein | IL-1β, IL-6 | Body weight, colitis score, colon length, mortality, MPO, NADPH | H&E staining, histopathology score | [130] |
Mice, DSS chronic colitis | – | – | Body weight, colitis score, mortality | H&E staining, histopathology score | ||||
GTC-siRNA | Nanoparticle containing siRNA against TNF-α complex with galactosylated tri-methyl-chitosan–cysteine | IC | Mice, DSS acute colitis | Protein, mRNA | – | Body weight, MPO | H&E staining | [133] |
Lipoplex-siRNA-1 | Enema containing liposomal siRNA against TNF-α | Rec. | Mice, DSS acute colitis | mRNA | – | – | H&E staining | [134] |
Lipoplex-siRNA-2 | Enema containing liposomal siRNA against TNF-α | Rec. | Mice, DSS acute colitis | mRNA | Gene analysis of 25,000 genes | DAI, mortality, MPO, weight-over-length ratio colon | H&E staining, histopathology score | [135] |
CycD-siRNA | Enema containing nanocomplex of cationic cyclodextrin complexed with siRNA against TNF-α | Rec. | Mice, DSS acute colitis | mRNA | IL-6 | Body weight, colon length, colon weight | – | [136] |
CaP-siRNA | Enema containing nanoparticles of siRNA loaded on calcium phosphate and encapsulated in PLGA | Rec. | Mice, DSS acute colitis | Protein, mRNA | – | Body weight, colon length, DAI, hematocrit | H&E staining, histopathology score | [137] |
US-siRNA | Enema containing siRNA against TNF-α delivered by ultrasound | Rec. | Mice, DSS acute colitis | Protein | – | Fecal score | Histopathology score | [138] |
ROS-siRNA | Nanoparticle containing siRNA against TNF-α encapsulated in a ROS-sensitive polymer | PO | Mice, DSS acute colitis | Protein, mRNA | IFN-γ, IL-1, IL-6, IL-12 | Body weight, MPO | H&E staining | [139] |
GalC-siRNA | Galactosylated chitosan-coated nanoparticle containing siRNA against TNF-α loaded on PLGA | PO | Mice, DSS acute colitis | Protein, mRNA | IFN-γ, IL-6 | Body weight, colon length, DAI, MPO | H&E staining | [140] |
NiMOS-siRNA | Nanoparticle in microsphere containing siRNA against TNF-α | PO | Mice, DSS acute colitis | Protein, mRNA | GM-CSF, IFN-γ, IL-1β, IL-2, IL-5, IL-6, IL-12p70, MCP-1, MIP-1α | Body weight, colon length, MPO | H&E staining | [141] |
CA-siRNA | Colon-targeted nanoparticle containing siRNA against TNF-α encapsulated in chitosan–alginate | PO | Mice, LPS-induced acute inflammation | Protein | – | – | – | [142] |
CA-Fab’-siRNA | Colon-targeted nanoparticle containing siRNA against TNF-α bearing Fab’ of F4/80 antibody encapsulated in chitosan–alginate | PO | Mice, DSS acute colitis | – | – | Body weight, IκB-α, MPO | Ly6 g staining | [143] |
NiMOS-siRNA-CyD1 | Nanoparticle in microsphere containing siRNA against TNF-α and CyD1 | PO | Mice, DSS acute colitis | Protein, mRNA | CyD1, GM-CSF, IFN-γ, IL-1α, IL-1β, IL-2, IL-5, IL-6, IL-17, MCP-1, MIP-1α | Body weight, colon length, MPO | H&E staining | [144] |
Gal-siRNA-IL-22 | Nanoparticle containing IL-22 and siRNA against TNF-α in galactosylated PLGA encapsulated chitosan–alginate hydrogel | PO | Mice, DSS acute colitis | mRNA | –- | Body weight, colon length, MPO, spleen weight | H&E staining, histopathology score | [145] |
Prokaryotes | ||||||||
Lacto-scFv | Lactococcus lactis carrying eukaryotic vector coding for a scFv anti-TNF-α | PO | Mice, DSS acute colitis | mRNA | IL-1β, IL-6, IL-10, IL-17A, TGF-β | Body weight, colon length, CRP, DAI | H&E staining, histopathology score | [146] |
Lacto-Nanobody | Lactococcus lactis secreting bivalent nanobodies against TNF-α | PO | Mice, DSS chronic colitis | – | – | - | H&E staining, histopathology score | [147] |
PO | Mice, IL-10−/−, chronic colitis | – | – | MPO | H&E staining, histopathology score | |||
Eukaryotes | ||||||||
PRX-106 | Plant-cell expressed anti-TNF-α fusion protein consisting of sTNFR2 fused to human Fc of human IgG1 | PO | Mice, TNBS acute colitis | – | – | Body weight | H&E staining, histopathology score, IκB-α pSer32/Ser36 staining | [148] |
Disease | Drug | ROA | Dosage | Therapy | Follow-up | Response a | Remarks | Reference |
---|---|---|---|---|---|---|---|---|
CD, perianal fistulas (n = 9) | IFX | Local injection | 20 mg | 0, 1, 3 weeks | 6 months | 78% | ADA did not develop during follow-up | [169] |
CD, perianal fistulas (n = 15) | IFX | Local injection | 15–21 mg | 0, 4, 8, 12, 16, 20 weeks | 18.2 (3–30) months b | 67% | Combined with surgical treatment; included nonresponders to IV IFX and patients with contraindication for IFX | [171] |
CD, perianal fistulas (n = 11) | IFX | Local injection | 20 mg | Every 4–16 weeks | 10.5 (7–18) months b | 73% | Including patients not responding to conventional systemic therapy | [170] |
CD, perianal fistulas (n = 12) | IFX | Local injection | 20–25 mg | Every 4–6 weeks | 35 (19–43) months c | 88% | Combined with surgical treatment; included nonresponders to IV IFX | [172] |
CD, perianal fistulas (n = 16) | adalimumab | Local injection | 40 mg | Every 15 days | NS | NS, but response was observed | Combined with surgical treatment and including patient who did not respond to local IFX therapy | [173] |
CD, perianal fistulas (n = 33) | adalimumab | Local injection | 40 mg | Every 15 days | 11 (7–14) months c | 40% | Combined with surgical treatment | [174] |
CD, perianal fistulas (n = 12) | adalimumab | Local injection | 20 mg | Every 2 weeks | 17.5 (5–30) months b | 100% | Including surgical therapy | [175] |
CD, perianal fistulas (n = 9) | adalimumab | Local injection | 10 mg | Every 2 weeks | NS | 100% | Investigated different T cell phenotypes in peripheral blood and fistulas | [176] |
CD, postoperative localized recurrent (n = 8) | IFX | Local injection | 8–60 mg | variable | 20 (14–21) months c | 38% | Endoscopy-guided injections into localized regions of <5 cm | [177] |
CD, isolated symptomatic regions (n = 4) | IFX | Local injection | 20–30 mg | variable | NS | 75% | Endoscopy-guided injections into local regions | [178] |
CD, colonic strictures (n = 3) | IFX | Local injection | 90–120 mg | variable | 5–8 months | 100% | Manual dilation in 1 patient | [179] |
CD, rectal stenosis (n = 2) | IFX | Local injection | 25 mg | variable | NS | 100% | Combined with balloon dilation | [180] |
CD, small bowel strictures (n = 6) | IFX | Local injection | 40 mg | 0, 2, 6 weeks | 6 months | 100% | Combined with balloon dilation | [181] |
UC, refractory proctitis (n = 1) | IFX | Enema | 100 mg | 6 days | NS | 100% | Patient with subtotal colectomy and ileorectal anastomosis | [182] |
Healthy volunteers (n = 14) | PRX-106 | PO | 2–16 mg | 5 days | 10 days | NA | PRX-106 was not systemically absorbed and no clear in vivo effects were seen | [167] |
UC, colonic involvement (n = 37) | AVX-470, capsule | PO | 0.2–3.5 g | 4 weeks | 7 weeks | 14% d | Colonic biopsies were analyzed in a separate study [107] | [108] |
CD (n = 6) | V565, enteric coated tablet | PO | 555–1665 mg | Single dose | No follow-up | NA | PK study | [104] |
UC (n = 5) | 1110 mg | 7 days | Tissue penetration study | |||||
Non–CD Ileostomy (n = 4) | 1665 mg | Single dose | Ileal fluid recovery study |
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Gareb, B.; Otten, A.T.; Frijlink, H.W.; Dijkstra, G.; Kosterink, J.G.W. Review: Local Tumor Necrosis Factor-α Inhibition in Inflammatory Bowel Disease. Pharmaceutics 2020, 12, 539. https://doi.org/10.3390/pharmaceutics12060539
Gareb B, Otten AT, Frijlink HW, Dijkstra G, Kosterink JGW. Review: Local Tumor Necrosis Factor-α Inhibition in Inflammatory Bowel Disease. Pharmaceutics. 2020; 12(6):539. https://doi.org/10.3390/pharmaceutics12060539
Chicago/Turabian StyleGareb, Bahez, Antonius T. Otten, Henderik W. Frijlink, Gerard Dijkstra, and Jos G. W. Kosterink. 2020. "Review: Local Tumor Necrosis Factor-α Inhibition in Inflammatory Bowel Disease" Pharmaceutics 12, no. 6: 539. https://doi.org/10.3390/pharmaceutics12060539
APA StyleGareb, B., Otten, A. T., Frijlink, H. W., Dijkstra, G., & Kosterink, J. G. W. (2020). Review: Local Tumor Necrosis Factor-α Inhibition in Inflammatory Bowel Disease. Pharmaceutics, 12(6), 539. https://doi.org/10.3390/pharmaceutics12060539