A first‐in‐man safety and pharmacokinetics study of nangibotide, a new modulator of innate immune response through TREM‐1 receptor inhibition

Cuvier, Valerie; Lorch, Ulrike; Witte, Stephan; Olivier, Aurélie; Gibot, Sébastien; Delor, Isabelle; Garaud, Jean–Jacques; Derive, Marc; Salcedo-Magguilli, Margarita

doi:10.1111/bcp.13668

Cited by 27 publications

(17 citation statements)

References 46 publications

(74 reference statements)

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“…So far, however, the therapeutic use of TREM-1 inhibitors has been limited to preclinical models, and only studies designed to measure the prognostic/diagnostic value of TREM-1 expression and/or sTREM-1 levels in samples from patients with inflammation-associated cancer have been carried out [37,157]. Recently, a phase I clinical trial has been run to evaluate the safety, tolerability, and pharmacokinetics of the synthetic peptide nangibotide (LR12), the first drug candidate targeting TREM-1 to reach clinical stage development [239], and future assessment of this agent for cancer therapy is expected.…”

Section: Discussionmentioning

confidence: 99%

Targeting Mononuclear Phagocyte Receptors in Cancer Immunotherapy: New Perspectives of the Triggering Receptor Expressed on Myeloid Cells (TREM-1)

Raggi

Bosco

2020

Cancers

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Inflammatory cells are major players in the onset of cancer. The degree of inflammation and type of inflammatory cells in the tumor microenvironment (TME) are responsible for tilting the balance between tumor progression and regression. Cancer-related inflammation has also been shown to influence the efficacy of conventional therapy. Mononuclear phagocytes (MPs) represent a major component of the inflammatory circuit that promotes tumor progression. Despite their potential to activate immunosurveillance and exert anti-tumor responses, MPs are subverted by the tumor to support its growth, immune evasion, and spread. MP responses in the TME are dictated by a network of stimuli integrated through the cross-talk between activatory and inhibitory receptors. Alterations in receptor expression/signaling can create excessive inflammation and, when chronic, promote tumorigenesis. Research advances have led to the development of new therapeutic strategies aimed at receptor targeting to induce a tumor-infiltrating MP switch from a cancer-supportive toward an anti-tumor phenotype, demonstrating efficacy in different human cancers. This review provides an overview of the role of MP receptors in inflammation-mediated carcinogenesis and discusses the most recent updates regarding their targeting for immunotherapeutic purposes. We focus in particular on the TREM-1 receptor, a major amplifier of MP inflammatory responses, highlighting its relevance in the development and progression of several types of inflammation-associated malignancies and the promises of its inhibition for cancer immunotherapy.

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Section: Discussionmentioning

confidence: 99%

Targeting Mononuclear Phagocyte Receptors in Cancer Immunotherapy: New Perspectives of the Triggering Receptor Expressed on Myeloid Cells (TREM-1)

Raggi

Bosco

2020

Cancers

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“…LR12 peptide (LQEEDAGEYGCM, international non‐proprietary name: nangibotide) is a specific, clinical stage, functional inhibitor of TREM‐1 . LR12‐scr is a scrambled control peptide composed of the same amino acids from LR12 but in a random sequence (YQDVELCETGED).…”

Section: Methodsmentioning

confidence: 99%

“…We, and others, have shown that genetic invalidation of TREM‐1 or its pharmacological inhibition by the use of a synthetic peptide conferred protection in various models of acute (septic shock, myocardial infarction) or chronic (atherosclerosis, rheumatoid arthritis, inflammatory bowel diseases) inflammatory disorders . Furthermore, the LR12 peptide is currently in a Phase 2 clinical trial in humans for the treatment of septic shock . Intriguingly, TREM‐1 inhibition was associated with a dampening of coagulation abnormalities and thrombocytopenia constantly observed during acute inflammation, especially sepsis …”

Section: Introductionmentioning

confidence: 99%

Inhibition of triggering receptor expressed on myeloid cells‐1 impairs thrombin generation

Pillo

Carrasco²,

Brustolin

et al. 2020

Journal of Thrombosis and Haemostasis

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Background:New evidence has shown the link between inflammation and thrombosis. Triggering receptor expressed on myeloid cells-1 (TREM-1) is an immunoreceptor expressed mostly on neutrophils and monocytes/macrophages. TREM-1 acts as an amplifier of the inflammatory response, and its pharmacological inhibition displays protective effects in various models of inflammatory disorders, in particular by dampening coagulation abnormalities and thrombocytopenia observed during acute inflammation.Objectives: We aimed to decipher the role of TREM-1 in fostering thrombin generation. Methods:We measured thrombin generation (TG) by the use of calibrated automated thrombography with whole blood, and isolated primary human neutrophils and monocytes upon stimulation with lipopolysaccharide (LPS). Tissue factor (TF) expression was measured by flow cytometry and its activity by ELISA. Phosphatidylserine (PtdSer) exposure was determined by flow cytometry. A dodecapeptide (LR12) was used as a specific inhibitor of TREM-1. Results: LPS increased TG, TF expression, and activity, as well as the exposure of PtdSer on the surface of monocytes. LR12 dampened TF activity through the decrease of PtdSer exposure, leading to a reduction of thrombin generation. Conclusions: TREM-1 inhibition decreases thrombin generation and could be an interesting target for the development of new inhibitors of leukocyte-associated thrombotic activity. K E Y W O R D S monocytes, thrombin generation, TREM-1 | 455 di PiLLO et aL.

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“…Study MOT-C-104 was the first administration of nangibotide in healthy volunteers to assess its safety, tolerability and pharmacokinetics [69]. Nangibotide was safe and well tolerated up to the highest dose tested (5 mg/kg bolus followed by 6.0 mg/kg/h continuous infusion for 7.75 h).…”

Section: Soluble Trem-1 and Nangibotidementioning

confidence: 99%

“…No pharmacodynamic effects of MOT-C-104 were observed since the TREM-1 signalling pathway is only active in an activated immune system. Nangibotide had a short half-life (≈ 3 min) and a clearance rate compatible with extensive enzymatic metabolism in blood [69].…”

Section: Soluble Trem-1 and Nangibotidementioning

confidence: 99%

New Agents in Development for Sepsis: Any Reason for Hope?

Vignon

Laterre

Daix

et al. 2020

Drugs

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Sepsis is a syndrome which is defined as a dysregulated host response to infection leading to organ failure. Since it remains one of the leading causes of mortality worldwide, numerous drug candidates have already been tested, and continue to be developed, as potential adjunct therapies. Despite convincing mechanisms of action and robust pre-clinical data, almost all drug candidates in the field of sepsis have failed to demonstrate clinical efficacy in the past two decades. Accordingly, the development of new sepsis drugs has markedly decreased in the past few years. Nevertheless, thanks to a better understanding of sepsis pathophysiology and pathways, new promising drug candidates are currently being developed. Instead of a unique sepsis profile as initially suspected, various phenotypes have been characterised. This has resulted in the identification of multiple targets for new drugs together with relevant biomarkers, and a better understanding of the most appropriate time to intervention. Within the entire sepsis drugs portfolio, those targeting the immune response are probably the most promising. Monoclonal antibodies targeting either cytokines or infectious agents are undoubtedly part of the potential successful therapeutic classes to come.

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A first‐in‐man safety and pharmacokinetics study of nangibotide, a new modulator of innate immune response through TREM‐1 receptor inhibition

Abstract: The novel immunomodulator nangibotide displayed favourable safety and PK profiles at all doses, including expected pharmacologically active doses, and warrants further clinical development.

Cited by 27 publications

References 46 publications

Targeting Mononuclear Phagocyte Receptors in Cancer Immunotherapy: New Perspectives of the Triggering Receptor Expressed on Myeloid Cells (TREM-1)

Targeting Mononuclear Phagocyte Receptors in Cancer Immunotherapy: New Perspectives of the Triggering Receptor Expressed on Myeloid Cells (TREM-1)

Inhibition of triggering receptor expressed on myeloid cells‐1 impairs thrombin generation

New Agents in Development for Sepsis: Any Reason for Hope?

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