Learning from the failure of Nebacumab

Vinoth Rajendran*

Clinical Pharmacist- CST, Kauvery Hospital, India

*Correpondence: Tel: 9487387680; [email protected]

Background

In our series of articles on Monoclonal Antibodies, we now present the second one, on Nebacumab, a human monoclonal antibody (mAb).

Nebacumab, also known as HA-1A, was a human IgM monoclonal antibody that could bind to the lipid A domain of endotoxin produced by Gram Negative bacteria. It was developed for the treatment of Gram-negative sepsis [1]. Sepsis is a condition that is known to be an important cause of morbidity and mortality death in intensive care units [2,3].

Mechanism of action

learning-from-the-failure-of-nebacumab-1

Fig. 1. Mechanism of action of Nebacumab [4].

Lipopolysaccharide (LPS, endotoxin) is the main surface antigen (O-antigen) and important virulence factor of most of the Gram-negative bacteria pathogenic for humans and animals. LPS contributes greatly to the structural integrity of the bacterial cell wall and constitutes a “pathogen-associated molecular pattern” for host infection.

Most of the known structures of LPS are smooth-type molecules built of O-specific polysaccharide, core oligosaccharide, and lipid A.

Among all these defined regions, the glycolipid part of LPS called lipid A constitutes a center of biological activity of the endotoxin that stimulates different cells of the immune system.

The hexa-acylated lipid A displays the highest immunostimulatory or endotoxic activity in the mammalian host and it was identified for the first time in Escherichia coli LPS.

Interaction of such asymmetric, hexa-acylated lipid A region of LPS with mCD14/TLR4/MD-2 receptor complex on the surface of monocytes/macrophages constitutes a major mechanism responsible for innate immune response to Gram-negative infection.

High levels of inflammatory mediators, as a response of the immune system to a large amount of LPS released into the bloodstream, have profound effects on the cardiovascular system, kidneys, lungs, liver, and central nervous system and trigger the coagulation cascade.

Excessive inflammatory response of the innate immune system finally leads to sepsis and septic shock.

Nebacumab is primarily a human IgM monoclonal antibody that binds to the lipid A region of endotoxin and reduces circulating levels of endotoxin [lipopolysaccharide (LPS)] and tumour necrosis factor in vivo.

The Rise and Fall of Nebacumab

In March 1991, the European Committee for Proprietary Medicinal Products recommended the Mab for the treatment of Gram-negative sepsis. Based on this recommendation, it was subsequently approved in the Netherlands, Britain, Germany and France between March and December 1991 [5,6]. In September 1991, the FDA Vaccines and Related Biological Advisory Committee, although expressing some reservations about the validity of results showing the drug increased survival rates in septic shock, unanimously advised FDA approval with restrictive labelling for the drug.

In late November 1991, the FDA was alerted to a trial undertaken by the US National Institutes of Health (NIH) Clinical Center’s Department of Critical Care Medicine. The study showed the drug to be potentially lethal and unable to protect against sepsis. Finally, it has been withdrawn in 1993 because it failed to reduce mortality in clinical trials [7,8]. And therein lies the cautionary tale!

Conclusion

Although therapy for the illness remains complex and Nebacumab’s failure represented the first commercial disappointment of MAbs in the sepsis sector, research on the drug gave important biological insights.

This came as a cautionary tale, reminding us to create mAbs as therapies from greater knowledge of the disease processes, a deeper understanding of medication development, and the need for careful regulation.

The history of failure of Nebacumab spurred greater research and precision into the emergence of subsequent mAbs as both safe and effective tools in medical therapeutics.

Reference

[1] Shaw D. FDA, Wall Street brings bad tidings to Centocor. The Philadelphia Inquirer 1992: B11.

[2] Momich B. Building something significant at Centocor. Pennsylvania Technology Second Quarter 1990; 25-31.

[3] Gutin KAC. The infection unto death. Discovery Magazine 1993.

[4] Nebacumab Overview. Creativebiolabs.net. Accessed November 5, 2022. https://www.creativebiolabs.net/nebacumab-overview.htm

[5] Fisher CJ, et al. Initial evaluation of human monoclonal anti-lipid A antibody (HA-1A) in patients with sepsis syndrome. Crit Care Med. 1990;18(12):1311-5.

[6] Ziegler EJ, et al. Treatment of gram-negative bacteremia and septic shock with HA-1A human monoclonal antibody against endotoxin. A randomized, double-blind, placebo-controlled trial. The HA-1A Sepsis Study Group. N Engl J Med. 1991;324:429-36.

[7] Quezado ZM, et al. A controlled trial of HA-1A in a canine model of gram-negative septic shock. JAMA 1993;269:2221-7.

[8] Leff DN. Animal study showed mortality with HA-1A. BioWorld Today 1991;1993:5.

Vinoth Rajendran,

Clinical Pharmacist – CST

Learning from the failure of Nebacumab

Learning from the failure of Nebacumab

Vinoth Rajendran,

Journals