The Monoclonal antibodies (mAbs): the beginning

Muromonab-CD3 (OKT3)

Anwardeen Sirajuddin*

Clinical Pharmacist-CST, Kauvery Hospitals, India

*Correspondence: Tel.: +91 9578038232; email: clinical.cst@kauveryhospital.com

Abstract

The objective of this paper is to present the first Monoclonal Antibody (MUROMONAB-CD3). In 1986, it was registered as OKT3, and was approved by the US FDA for inhibiting rejection in solid-organ transplantation. Moreover, OKT3 is a potent mitogen, promoting T-cell proliferation and cytokine secretion, triggering a wide spectrum of side effects that include ‘flu-like’, ‘cytokine-release’ or ‘first-dose’ syndrome.

Keywords: hybridoma technology, T lymphocytes, promoting T-cell proliferation and cytokine secretion, anti-CD3 mAb

Background

Since 1985, approximately 100 monoclonal antibodies (mAbs) have been designated as drugs [1]. The success story of monoclonal antibodies (mAbs) began with the discovery of hybridoma technology for production of murine mAbs. The first mAb recognizing CD3 surface antigen on human T cells was marketed under the name muromonab, OKT3 was the first monoclonal murine antibody to become available for therapy in humans. In 1986, OKT3 was approved by the US FDA for inhibiting rejection in solid-organ transplantation [2].

History

Muromonab-CD3 was approved by the U.S. Food and Drug Administration (FDA) in 1986, making it the first monoclonal antibody to be approved anywhere as a drug for humans [3].

In the European Communities, it was the first drug to be approved by the precursor of the European Medicines Agency (EMEA), the centralized approval system in the European Union. In Germany, it was approved in 1988 by the Paul Ehrlich Institute in Frankfurt.

However, the manufacturer of muromonab-CD3 voluntarily withdrew it from the United States market in 2010 due to numerous side effects, arrival of better-tolerated alternatives and declining usage [4].

Action

Murine monoclonal antibodies consist of mouse proteins, this mouse IgG2a is directed against the CD3 epsilon chain of the CD3/TCR complex that characterizes T lymphocytes and has been successfully used to treat allograft rejection in kidney, liver and heart transplantation.

Side effects

A clinical trial with patients suffering from multiple sclerosis (MS) also showed potential of this anti-CD3 mAb to inhibit relapse of disease. However, further clinical development of this antibody was halted due to its side effects. Being a mAb of murine origin, OKT3 is extremely immunogenic in humans, eliciting a high titer of antimouse antibodies in most patients. Moreover, OKT3 is a potent mitogen, promoting T-cell proliferation and cytokine secretion, triggering a wide spectrum of side effects that include fever, chills nausea, vomiting and headaches, summarized as ‘flu-like’, ‘cytokine-release’ or ‘first-dose’ syndrome. A small portion of patients suffered even more severe side effects such as cardiopulmonary distress, seizures, encephalopathy, meningitis, renal insufficiency and graft thrombosis [5].

Conclusion

For the pioneers involved at the dawn of the therapeutic mAb development, this was to be a journey characterized by substantial risks and personal sacrifices. Some idea of the roller coaster ride this involved can be gleaned from the experience from Muromonab-CD3.

References

  1. https://www.kauveryhospital.com/kauverian-scientific-journal/monoclonal-antibodies-mabs-the magic-bullets
  2. https://www.futuremedicine.com/doi/10.2217/imt-2016-0049.
  3. Smith SL. Ten years of Orthoclone OKT3 (muromonab-CD3): a review. J Transpl Coordinat. 1996;6(3):109-119.
  4. Reza A, et al. Immunosuppressive Strategies in Human Renal Transplantation – Induction Therapy” (PDF). Nephrol Rounds. 2009;7(4).
  5. https://reference.medscape.com/drug/orthoclone-okt3-muromonab-cd3-343197#10
Anwardeen-Sirajuddin

Anwardeen Sirajuddin

Clinical Pharmacist-CST

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