# Nangibotide

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**Nangibotide** is an inhibitor of [TREM-1](/source/TREM-1), a receptor found on certain [white blood cells](/source/Granulocyte). Activation of TREM-1 stimulates [inflammation](/source/Systemic_inflammatory_response_syndrome). Nangibotide is therefore being investigated as a treatment for the overwhelming inflammation typically seen in severe [sepsis](/source/Sepsis).

## Chemistry

Nangibotide is a 12-amino-acid polypeptide derived from [TLT-1](/source/TREML1).[1]

## Mode of action

[TREM-1](/source/TREM-1) is a receptor found on [neutrophils](/source/Neutrophil), [macrophages](/source/Macrophage) and [monocytes](/source/Monocyte), key elements of the [immune system](/source/Immune_system). Activation of TREM-1 results in expression of [NF-κB](/source/NF-%CE%BAB), which promotes systemic [inflammation](/source/Inflammation). Nangibotide inhibits TREM-1, thereby preventing the inflammatory activation. Absence of TREM-1 results in vastly reduced inflammation without impairing the ability to fight infection.[2]

## Animal models

LR17, a mouse equivalent of nangibotide, improves survival in mouse models of severe sepsis.[3] In a pig model of sepsis, LR12 - another animal equivalent of nangibotide - resulted in significantly improved [haemodynamics](/source/Haemodynamics) and less [organ failure](/source/Organ_failure).[4] In monkeys, LR12 also reduced the inflammatory and hypotensive effects of sepsis.[5]

## Human studies

Nangibotide has demonstrated safety in Phase 1 (healthy volunteers)[6] and Phase 2 (sick patients with septic shock)[7] studies. The ASTONISH trial will examine clinical efficacy in 450 patients with septic shock.[8]

## References

1. Cuvier V, Lorch U, Witte S, Olivier A, Gibot S, Delor I, Garaud JJ, Derive M, Salcedo-Magguilli M (2018). "A first-in-man safety and pharmacokinetics study of nangibotide, a new modulator of innate immune response through TREM-1 receptor inhibition.". *British Journal of Clinical Pharmacology*. **84** (10): 2270–2279. [doi:10.1111/bcp.13668](https://doi.org/10.1111/bcp.13668). [PMC 6138490](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6138490). [PMID 29885068](https://pubmed.ncbi.nlm.nih.gov/29885068)

1. Weber B, Schuster S, Zysset D, Rihs S, Dickgreber N, Schürch C, Riether C, Siegrist M, Schneider C, Pawelski H, Gurzeler U, Ziltener P, Genitsch V, Tacchini-Cottier F, Ochsenbein A, Hofstetter W, Kopf M, Kaufmann T, [Oxenius A](/source/Annette_Oxenius), Reith W, Saurer L, Mueller C (2014). "TREM-1 deficiency can attenuate disease severity without affecting pathogen clearance.". *PLOS Pathog.*. **10** (1). [doi:10.1371/journal.ppat.1003900](https://doi.org/10.1371/journal.ppat.1003900). [PMC 3894224](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3894224). [PMID 24453980](https://pubmed.ncbi.nlm.nih.gov/24453980)

1. Derive M, Bouazza Y, Sennoun N, Marchionni S, Quigley L, Washington V, Massin F, Max JP, Ford J, Alauzet C, Levy B, McVicar DW, Gibot S (1 June 2012). "Soluble TREM-like transcript-1 regulates leukocyte activation and controls microbial sepsis.". *Journal of Immunology*. **188** (11): 5585–5592. [doi:10.4049/jimmunol.1102674](https://doi.org/10.4049/jimmunol.1102674). [PMC 6382278](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6382278). [PMID 22551551](https://pubmed.ncbi.nlm.nih.gov/22551551)

1. Derive M, Boufenzer A, Bouazza Y, Groubatch F, Alauzet C, Barraud D, Lozniewski A, Leroy P, Tran N, Gibot S (Feb 2013). "Effects of a TREM-like transcript 1-derived peptide during hypodynamic septic shock in pigs.". *Shock*. **39** (2): 176–182. [doi:10.1097/SHK.0b013e31827bcdfb](https://doi.org/10.1097/SHK.0b013e31827bcdfb). [PMID 23324887](https://pubmed.ncbi.nlm.nih.gov/23324887). [S2CID 23583753](https://api.semanticscholar.org/CorpusID:23583753)

1. Derive M, Boufenzer A, Gibot S (April 2014). "Attenuation of responses to endotoxin by the triggering receptor expressed on myeloid cells-1 inhibitor LR12 in nonhuman primate.". *Anesthesiology*. **120** (4): 935–942. [doi:10.1097/ALN.0000000000000078](https://doi.org/10.1097/ALN.0000000000000078). [PMID 24270127](https://pubmed.ncbi.nlm.nih.gov/24270127). [S2CID 10347527](https://api.semanticscholar.org/CorpusID:10347527)

1. Cuvier V, Lorch U, Witte S, Olivier A, Gibot S, Delor I, Garaud JJ, Derive M, Salcedo-Magguilli M (2018). "A first-in-man safety and pharmacokinetics study of nangibotide, a new modulator of innate immune response through TREM-1 receptor inhibition.". *Br J Clin Pharmacol*. **84** (10): 2270–2279. [doi:10.1111/bcp.13668](https://doi.org/10.1111/bcp.13668). [PMC 6138490](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6138490). [PMID 29885068](https://pubmed.ncbi.nlm.nih.gov/29885068)

1. François B, Wittebole X, Ferrer R, Mira JP, Dugernier T, Gibot S, Derive M, Olivier A, Cuvier V, Witte S, Pickkers P, Vandenhende F, Garaud JJ, Sánchez M, Salcedo-Magguilli M, Laterre PF (July 2020). "Nangibotide in patients with septic shock: a Phase 2a randomized controlled clinical trial.". *Intensive Care Medicine*. **46** (7): 1425–1437. [doi:10.1007/s00134-020-06109-z](https://doi.org/10.1007/s00134-020-06109-z). [hdl:2078.1/242176](https://hdl.handle.net/2078.1/242176). [PMID 32468087](https://pubmed.ncbi.nlm.nih.gov/32468087). [S2CID 218912723](https://api.semanticscholar.org/CorpusID:218912723)

1. ["Efficacy, Safety and Tolerability of Nangibotide in Patients With Septic Shock (ASTONISH)"](https://clinicaltrials.gov/ct2/show/NCT04055909). *ClinicalTrials.gov*. US National Library of Medicine. Retrieved 13 July 2020.

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Adapted from the Wikipedia article [Nangibotide](https://en.wikipedia.org/wiki/Nangibotide) by Wikipedia contributors ([contributor history](https://en.wikipedia.org/wiki/Nangibotide?action=history)). Available under [Creative Commons Attribution-ShareAlike 4.0 International](https://creativecommons.org/licenses/by-sa/4.0/). Changes may have been made.