Clinical significance of chemokine receptor antagonists

ABSTRACT

Introduction: Chemokine receptors are important therapeutic targets for the treatment of many human diseases. This study will provide an overview of approved chemokine receptor antagonists and promising candidates in advanced clinical trials.

Areas covered: We will describe clinical aspects of chemokine receptor antagonists regarding their clinical efficacy, mechanisms of action, and re-purposed applications.

Expert opinion: Three chemokine antagonists have been approved: (i) plerixafor is a small-molecule CXCR4 antagonist that mobilizes hematopoietic stem cells; (ii) maraviroc is a small-molecule CCR5 antagonist for anti-HIV treatment; and (iii) mogamulizumab is a monoclonal-antibody CCR4 antagonist for the treatment of mycosis fungoides or Sézary syndrome. Moreover, phase 3 trials are ongoing to evaluate many potent candidates, including CCR5 antagonists (e.g. leronlimab), dual CCR2/CCR5 antagonists (e.g. cenicriviroc), and CXCR4 antagonists (e.g. balixafortide, mavorixafor, motixafortide). The success of chemokine receptor antagonists depends on the selective blockage of disease-relevant chemokine receptors which are indispensable for disease progression. Although clinical translation has been slow, antagonists targeting chemokine receptors with multifaced functions offer the potential to treat a broad spectrum of human diseases.

KEYWORDS:

• Maraviroc
• plerixafor
• mogamulizumab
• leronlimab
• cenicriviroc

Article highlights

• Plerixafor (Mozobil®) designed for anti-HIV treatment is a potent CXCR4 antagonist that mobilizes hematopoietic stem cells. Under the treatment of plerixafor plus G-CSF, a collection of ≥2×10⁶ CD34+ cells/kg within 4 apheresis days could be achieved in more than 80% of patients with non-Hodgkin’s lymphoma or multiple myeloma.

• Maraviroc (Selzentry®, Celsentri®) is a noncompetitive CCR5 antagonist that prevents the binding of HIV envelope glycoprotein to CCR5. In the treatment of HIV-infected patients with CCR5 tropism, the maraviroc-based regimen offers 73% to 78% of virologic response (HIV-1 RNA <50 copies/mL at week 48).

• Mogamulizumab (Poteligeo®) is a defucosylated humanized monoclonal antibody that acts as a CCR4 antagonist. Clinical efficacy of mogamulizumab was approximately 21% and 37% to treat mycosis fungoides and Sézary syndrome, respectively.

• There is an increasing number of experimental chemokine antagonists against almost all chemokine receptors, supporting the potential of chemokine receptor antagonists to treat a broad spectrum of human diseases.

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 work was supported by the National Natural Science Foundation of China (grant numbers 31571368, 31871324, 81730064), the National Science and Technology Major Project of the Ministry of Science and Technology of China (grant number 2018ZX10715004), the Natural Science Foundation of Hunan Province (grant number 2018JJ3713), and the Hunan Youth Elite Project (grant number 2018RS3006).