Drucker DJ. Advances in oral peptide therapeutics. Nat Rev Drug Discov. 2020;19(4):277–89. https://doi.org/10.1038/s41573-019-0053-0.

Article  PubMed  CAS  Google Scholar 

Zhu Q, Chen Z, Paul PK, Lu Y, Wu W, Qi J. Oral delivery of proteins and peptides: challenges, status quo and future perspectives. Acta Pharm Sin B. 2021;11(8):2416–48. https://doi.org/10.1016/j.apsb.2021.04.001.

Article  PubMed  PubMed Central  CAS  Google Scholar 

Zhang Y, Thanou M, Vllasaliu D. Exploiting disease-induced changes for targeted oral delivery of biologics and nanomedicines in inflammatory bowel disease. Eur J Pharm Biopharm. 2020;155:128–38. https://doi.org/10.1016/j.ejpb.2020.08.017.

Article  PubMed  CAS  Google Scholar 

Brayden DJ, Hill TA, Fairlie DP, Maher S, Mrsny RJ. Systemic delivery of peptides by the oral route: formulation and medicinal chemistry approaches. Adv Drug Deliv Rev. 2020;157:2–36. https://doi.org/10.1016/j.addr.2020.05.007.

Article  PubMed  CAS  Google Scholar 

Buckley ST, Bækdal TA, Vegge A, Maarbjerg SJ, Pyke C, Ahnfelt-Rønne J, et al. Transcellular stomach absorption of a derivatized glucagon-like peptide-1 receptor agonist. Sci Transl Med. 2018;10(467): eaar7047. https://doi.org/10.1126/scitranslmed.aar7047.

Article  PubMed  CAS  Google Scholar 

Tuvia S, Atsmon J, Teichman SL, Katz S, Salama P, Pelled D, et al. Oral octreotide absorption in human subjects: comparable pharmacokinetics to parenteral octreotide and effective growth hormone suppression. J Clin Endocrinol Metab. 2012;97(7):2362–9. https://doi.org/10.1210/jc.2012-1179.

Article  PubMed  CAS  Google Scholar 

Mrsny RJ, Mahmood TA. Re-assessing PK/PD issues for oral protein and peptide delivery. Pharmaceutics. 2021;13(7):1006. https://doi.org/10.3390/pharmaceutics13071006.

Article  PubMed  PubMed Central  CAS  Google Scholar 

Moroz E, Matoori S, Leroux JC. Oral delivery of macromolecular drugs: where we are after almost 100 years of attempts. Adv Drug Deliv Rev. 2016;101:108–21. https://doi.org/10.1016/j.addr.2016.01.010.

Article  PubMed  CAS  Google Scholar 

Bak A, Ashford M, Brayden DJ. Local delivery of macromolecules to treat diseases associated with the colon. Adv Drug Deliv Rev. 2018;136–137:2–27. https://doi.org/10.1016/j.addr.2018.10.009.

Article  PubMed  CAS  Google Scholar 

Layer P, Stanghellini V. Review article: Linaclotide for the management of irritable bowel syndrome with constipation. Aliment Pharmacol Ther. 2014;39(4):371–84. https://doi.org/10.1111/apt.12604.

Article  PubMed  PubMed Central  CAS  Google Scholar 

Braga Emidio N, Tran HNT, Andersson A, Dawson PE, Albericio F, Vetter I, et al. Improving the gastrointestinal stability of linaclotide. J Med Chem. 2021;64(12):8384–90. https://doi.org/10.1021/acs.jmedchem.1c00380.

Article  PubMed  PubMed Central  CAS  Google Scholar 

Johnston JM, Shiff SJ, Quigley EM. A review of the clinical efficacy of linaclotide in irritable bowel syndrome with constipation. Curr Med Res Opin. 2013;29(2):149–60. https://doi.org/10.1185/03007995.2012.754743.

Article  PubMed  CAS  Google Scholar 

Waldman SA, Camilleri M. Guanylate cyclase-C as a therapeutic target in gastrointestinal disorders. Gut. 2018;67(8):1543–52. https://doi.org/10.1136/gutjnl-2018-316029.

Article  PubMed  CAS  Google Scholar 

Rao SSC. Plecanatide: a new guanylate cyclase agonist for the treatment of chronic idiopathic constipation. Ther Adv Gastroenterol. 2018;11:1756284818777945. https://doi.org/10.1177/1756284818777945.

Article  CAS  Google Scholar 

Weinberg DS, Foster NR, Della’Zanna G, McMurray RP, Kraft WK, Pallotto A, et al. Phase I double-blind, placebo-controlled trial of dolcanatide (SP-333) 27 mg to explore colorectal bioactivity in healthy volunteers. Cancer Biol Ther. 2021;22(10–12):544–53. https://doi.org/10.1080/15384047.2021.1967036.

Article  PubMed  PubMed Central  CAS  Google Scholar 

Rosario M, French J, Dirk NL, Sankoh S, Parikh A, Yang H, et al. Exposure–efficacy relationships for vedolizumab induction therapy in patients with ulcerative colitis or Crohn’s disease. J Crohns Colitis. 2017;11:921–9.

Article  Google Scholar 

Bhandari A, Patel DV, Zemede G, Mattheakis LC, Liu D. α4β7 peptide monomer and dimer antagonists. USP 9,809,623.

Sandborn WJ, Mattheakis LC, Modi NB, Pugatch D, Bressler B, Lee S, et al. PTG-100, an Oral α4β7 antagonist peptide: preclinical development and Phase I and 2a Studies in ulcerative colitis. Gastroenterology. 2021;161(6):1853-1864.e10. https://doi.org/10.1053/j.gastro.2021.08.045.

Article  PubMed  CAS  Google Scholar 

Solitano V, Parigi TL, Ragaini E, Danese S. Anti-integrin drugs in clinical trials for inflammatory bowel disease (IBD): insights into promising agents. Expert Opin Investig Drugs. 2021;30(10):1037–46. https://doi.org/10.1080/13543784.2021.1974396.

Article  PubMed  CAS  Google Scholar 

Mattheakis L, Tang T, Venkataraman S, Rao N, Li Wang L, Zhao L, et al. The oral α4β7 integrin specific antagonist PN-10943 is more effective than PTG-100 in multiple preclinical studies. Gastroenterology. 2019;156:S80–1.

Article  Google Scholar 

Modi NB, Cheng X, Mattheakis L, Hwang CC, Nawabi R, Liu D, et al. Single- and multiple-dose pharmacokinetics and pharmacodynamics of PN-943, a gastrointestinal-restricted oral peptide antagonist of α4β7, in healthy volunteers. Clin Pharmacol Drug Dev. 2021;10(11):1263–78. https://doi.org/10.1002/cpdd.946.

Article  PubMed  PubMed Central  CAS  Google Scholar 

https://www.protagonist-inc.com/investors-media/press-releases/news-details/2022/Protagonist-Therapeutics-Announces-Topline-Data-from-Phase-2-IDEAL-Study-of-PN-943-in-Ulcerative-Colitis/default.aspx. Accessed 10 Oct 2022.

Maaser C, Kannengiesser K, Specht C, Lügering A, Brzoska T, Luger TA, et al. Crucial role of the melanocortin receptor MC1R in experimental colitis. Gut. 2006;55(10):1415–22.

Article  CAS  Google Scholar 

Spana C, Taylor AW, Yee DG, Makhlina M, Yang W, Dodd J. Probing the role of melanocortin type 1 receptor agonists in diverse immunological diseases. Front Pharmacol. 2018;9:1535.

Article  CAS  Google Scholar 

Dhingra P, Obr A, Spana C, Dodd JH, Kayne PS. Cellular and molecular impact of the Melanocortin receptor agonist PL8177 in dextran sulfate sodium (DSS)-induced colitis in rats. In: Crohns and Colitis Congress (2022). https://palatin.com/wp-content/uploads/2022/01/PAL-G21PL8.2008-CCC-2021-Dhingra-DSS-Rat-Genomic-Poster-0119-2.pdf. Accessed 10 Oct 2022.

Ip WKE, Hoshi N, Shouval DS, Snapper S, Medzhitov R. Anti-inflammatory effect of IL-10 mediated by metabolic reprogramming of macrophages. Science. 2017;356(6337):513–9. https://doi.org/10.1126/science.aal353.

Article  PubMed  PubMed Central  CAS  Google Scholar 

Taverner A, MacKay J, Laurent F, Hunter T, Liu K, Mangat K, et al. Cholix protein domain I functions as a carrier element for efficient apical to basal epithelial transcytosis. Tissue Barriers. 2020;8(1):1710429. https://doi.org/10.1080/21688370.2019.1710429.

Article  PubMed  PubMed Central  CAS  Google Scholar 

Keubler LM, Buettner M, Häger C, Bleich A. A multihit model: colitis lessons from the interleukin-10-deficient mouse. Inflamm Bowel Dis. 2015;21(8):1967–75. https://doi.org/10.1097/MIB.0000000000000468.

Article  PubMed  Google Scholar 

Buruiana FE, Solà I, Alonso-Coello P. Recombinant human interleukin 10 for induction of remission in Crohn’s disease. Cochrane Database Syst Rev. 2010;2010(11):CD005109. https://doi.org/10.1002/14651858.CD005109.

Article  PubMed Central  Google Scholar 

Liu K, Hunter T, Taverner A, Yin K, MacKay J, Colebrook K, et al. GRP75 as a functional element of cholix transcytosis. Tissue Barriers. 2022. https://doi.org/10.1080/21688370.2022.2039003.

Article  PubMed  Google Scholar 

Fay NC, Muthusamy BP, Nyugen LP, Desai RC, Taverner A, MacKay J, et al. A novel fusion of IL-10 engineered to traffic across intestinal epithelium to treat colitis. J Immunol. 2020;205(11):3191–204. https://doi.org/10.4049/jimmunol.2000848.

Article  PubMed  PubMed Central  CAS  Google Scholar 

https://www.appliedmt.com/pipeline/amt-101/. Accessed 10 Oct 2022.

https://ir.appliedmt.com/news-releases/news-release-details/applied-molecular-transport-announces-top-line-phase-2-results. Accessed 10 Oct 2022.

Ilan Y, Gingis-Velitski S, Ben Ya’aco A, Shabbat Y, Zolotarov L, Almon E, et al. A plant cell-expressed recombinant anti-TNF fusion protein is biologically active in the gut and alleviates immune-mediated hepatitis and colitis. Immunobiology. 2017;222(3):544–51. https://doi.org/10.1016/j.imbio.2016.11.001.

Article  PubMed  CAS  Google Scholar 

Ilan Y, Ben Ya’acov A, Shabbat Y, Gingis-Velitski S, Almon E, Shaaltiel Y. Oral administration of a non-absorbable plant cell-expressed recombinant anti-TNF fusion protein induces immunomodulatory effects and alleviates nonalcoholic steatohepatitis. World J Gastroenterol. 2016;22(39):8760–9. https://doi.org/10.3748/wjg.v22.i39.8760.

Article  PubMed  PubMed Central  CAS  Google Scholar 

Almon E, Khoury T, Drori A, Gingis-Velitski S, Alon S, Chertkoff R, et al. An oral administration of a recombinant anti-TNF fusion protein is biologically active in the gut promoting regulatory T cells: results of a phase I clinical trial using a novel oral anti-TNF alpha-based therapy. J Immunol Methods. 2017;446:21–9. https://doi.org/10.1016/j.jim.2017.03.023.

Article  PubMed  CAS  Google Scholar 

Almon E, Shaaltiel Y, Sbeit W, Fich A, Schwartz D, Waterman M, et al. Novel orally administered recombinant anti-TNF alpha fusion protein for the treatment of ulcerative colitis: results from a phase IIa clinical trial. J Clin Gastroenterol. 2021;55(2):134–40. https://doi.org/10.1097/MCG.0000000000001314.

Article  PubMed  CAS  Google Scholar 

https://protalix.com/pipeline/. Accessed 5 July 2022.

Bhol KC, Tracey DE, Lemos BR, Lyng GD, Erlich EC, Keane DM, et al. AVX-470: a novel oral anti-TNF antibody with therapeutic potential in inflammatory bowel disease. Inflamm Bowel Dis. 2013;19(11):2273–81. https://doi.org/10.1097/MIB.0b013e3182a11958.