α₄β₇ integrin inhibitors: a patent review

ABSTRACT

Introduction: The α₄β₇ integrin is heterodimeric cell surface receptors expressed on most leukocytes. Mucosal addressing cell adhesion molecule 1(MAdCAM-1) is an exclusive ligand for α₄β₇ integrin.

Areas covered: This article will highlight the progress that has been made in the discovery and development of α₄β₇ integrin inhibitors, and their use in the treatment of inflammatory bowel diseases, multiple sclerosis, asthma, hepatic disorders, human immunodeficiency virus, allergic conjunctivitis and type 1 diabetes.

Expert opinion: α₄β₇ integrin inhibitors have attracted much interest for their clinical implication. Natalizumab and Vedolizumab are monoclonal antibodies (mAbs) successfully utilized clinically. Natalizumab is a mAbs of α₄-subunit blocking both α₄β₁ and α₄β₇ integrin. Vedolizumab selectively targets the α₄β₇ integrin. Several mAbs are still in the process of research and development. Among these mAbs, etrolizumab selectively against the β₇-subunit and AMG-181 specifically against the α₄β₇ integrin are the most promising anti-α₄β₇ integrin antibodies. Despite the unclear development stage of TR-14035 and R411, several low molecular compounds show bright future of further development, such as AJM300 and CDP323. In addition, results from laboratory data show that peptide inhibitors, such as peptide X, are effective α₄β₇ integrin inhibitors.

KEYWORDS:

• α₄β₇ integrin
• inhibitor
• inflammatory bowel diseases
• multiple sclerosis
• asthma
• hepatic disorders
• human immunodeficiency virus
• allergic conjunctivitis
• type 1 diabetes

Article highlights

• α₄β₇ integrin inhibitors can be used in the treatment of inflammatory bowel diseases (IBD), multiple sclerosis (MS), asthma, hepatic disorders, human immunodeficiency virus (HIV), allergic conjunctivitis, and type 1 diabetes.

• Etrolizumab and AMG-181 are the most promising anti-α₄β₇ integrin antibodies.

• Low molecular compounds of α₄β₇ integrin inhibitors still have a very attractive prospect, such as AJM300 and CDP323.

• Peptide X is a potent effective α₄β₇ integrin inhibitor.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

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

Additional information

Funding

This project was sponsored by the grants from National Major Scientific, Technological Special Project for ‘Significant New Drugs Development’ [2011ZX09302-003-02]; the Fundamental Research Funds for the Central Universities [17JCYB11].