Muronomab: The First Approved Monoclonal Antibody

Muronomab-CD3, also known by its trade name Orthoclone OKT3, is historically significant as it was the first monoclonal antibody approved by the U.S. Food and Drug Administration (FDA) for use in humans in 1986, for the prevention of kidney transplant rejection. This groundbreaking development not only demonstrated the potential of mAbs in clinical practice but also set the foundation for future research and therapeutic strategies. 

Development of Muronomab 

Muronomab-CD3 is a mouse IgG2 developed via hybridoma technology, a method pioneered by Georges Köhler and César Milstein in 1975, which later earned them the Nobel Prize. The antibody was specifically designed to bind to the CD3 receptor on T cells, which plays a crucial role in the cellular immune response. 

The primary action of muronomab is immunosuppression, achieved by binding to the epsilon unit of the CD3 complex on the surface of T cells. This binding leads to the modulation and eventual depletion of T cells, thereby preventing the cellular immune response responsible for organ rejection. The mechanism involves both the blocking of antigen recognition and the direct induction of T-cell apoptosis.¹

Clinical Applications and Efficacy 

Initially approved for preventing acute rejection in renal transplantation, muronomab was a cornerstone drug in transplant immunology. It showed remarkable efficacy in reducing the incidence of reversing acute renal, hepatic, cardiac and combined kidney-pancreas transplant rejection episodes, thus improving graft survival rates. However, its use was often limited by significant side effects, including cytokine release syndrome, which resulted from the massive T-cell activation and subsequent release of cytokines. These cytokines caused flu-like symptoms, fever, and in severe cases, could be life-threatening.²

Unfortunately, in 2010, muromonab was withdrawn from use due to the frequency of those severe adverse reactions and mild and transient serum enzyme elevations during therapy, although it was not linked to cases of clinically apparent liver injury. Since muromonab is a potent immunosuppressive agent, it could cause the reactivation of hepatitis B in susceptible patients.³

Impact and Legacy 

The approval of muronomab not only validated the clinical utility of monoclonal antibodies but also encouraged the pharmaceutical industry to invest in this technology. Following muronomab, several other monoclonal antibodies have been developed and approved, targeting diseases like cancer, rheumatoid arthritis, and multiple sclerosis. 

References: 

1. Strohl, W. R., & Strohl, L. M. (2012). Variable chain engineering – humanization and optimization approaches. Therapeutic Antibody Engineering, 111-595. https://doi.org/10.1533/9781908818096.111

2. Todd, P.A., Brogden, R.N. (1989). Muromonab CD3. Drugs 37, 871–899. https://doi.org/10.2165/00003495-198937060-00004

3. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. (2012). Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases. Available from: https://www.ncbi.nlm.nih.gov/books/NBK548590/