Rational and clinical development of the anti-MAdCAM monoclonal antibody for the treatment of IBD

ABSTRACT

Introduction: Mucosal addressin cell adhesion molecule-1 (MAdCAM-1) expression in gut-associated lymphoid tissue is upregulated in patients with inflammatory bowel disease (IBD). Blocking adhesion molecules and thereby inhibiting migration of lymphocytes into sites of inflammation in the gut is an attractive new treatment target in drug development for IBD.

Areas covered: This review discusses the preclinical and clinical experience on SHP647 (previously called PF-00547659 and PF-00547,659), a fully human IgG2K monoclonal antibody that binds to MAdCAM-1 to selectively reduce lymphocyte homing to the intestinal tract.

Expert opinion: Blocking endothelial adhesion molecule MAdCAM−1 could represent an attractive target for the treatment of IBD. In the next years, the results from the phase III studies as well as data to support therapeutic drug monitoring based on drug levels to guide and optimize individual therapy will become available. Furthermore, much effort is put in the development of clinical prediction models to predict which drug is optimal for an individual patient.

Trial registration: ClinicalTrials.gov identifier: NCT03259334.

Trial registration: ClinicalTrials.gov identifier: NCT03259308.

Trial registration: ClinicalTrials.gov identifier: NCT03559517.

Trial registration: ClinicalTrials.gov identifier: NCT03566823.

Trial registration: ClinicalTrials.gov identifier: NCT01298492.

KEYWORDS:

• Crohn’s disease
• ulcerative colitis
• inflammatory bowel disease
• therapy
• integrins
• anti-MadCAM

Article highlights

• Gut homing CD4+ and CD8+ T lymphocytes express the α₄β₇ integrin, and binding of this integrin to MAdCAM allows lymphocyte migration to the gut.

• Blocking MAdCAM reduces lymphocyte recruitment, colon inflammation and clinical deterioration in several preclinical colitis models.

• SHP647 (previously called PF-00547659 and PF-00547,659) is a fully human IgG2K monoclonal antibody that binds to MAdCAM-1 to selectively reduce lymphocyte homing to the intestinal tract.

• SHP647 was well tolerated in phase II studies in UC as well as CD, and clinical efficacy was clearly demonstrated in patients with UC.

• Phase III studies to evaluate the efficacy and safety of SHP647 in UC as well as CD are ongoing.

This box summarizes key points contained in the article.

Declaration of interest

M Duijvestein has served as an advisor for Echo pharma and Robarts Clinical Trials, reports nonfinancial support from Dr. Falk Pharma, and received speaker fees from Janssen, Merck & Co. Inc., Pfizer, Takeda, and Tillotts Pharma. G D’Haens has served as advisor for Abbvie, Ablynx, Amakem, AM Pharma, Avaxia, Biogen, Bristol Meiers Squibb, Boerhinger Ingelheim, Celgene, Celltrion, Cosmo, Covidien, Ferring, DrFALK Pharma, Engene, Galapagos, Gilead, Glaxo Smith Kline, Hospira, Immunic, Johnson and Johnson, Lycera, Medicmetrics, Millenium/Takeda, Mitsubishi Pharma, Merck Sharp Dome, Mundipharma, Novonordis, Pfizer, Prometheus laboratories/Nestle, Protagonist, Receptos, Robarts Clinical Trials, Salix, Sandoz, Setpoint, Shire, Teva, Tigenix, Tillotts, Topivert, Versant and Vifor and received speaker fees from Abbvie, Ferring, Johnson and Johnson, Merck Sharp & Dohme, Mundipharma, Norgine, Pfizer, Shire, Millenium/Takeda, Tillotts and Vifor. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was not funded.