A fully human anti-c-Kit monoclonal antibody 2G4 inhibits proliferation and degranulation of human mast cells

Kim, Kwang-Hyeok; Kim, Jin-Ock; Park, Sang Gyu

doi:10.1007/s11010-022-04557-3

Cited by 5 publications

(4 citation statements)

References 70 publications

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“…Number of MCs may be reduced by the targeted induction of apoptosis or by blocking their recruitment, migration and differentiation. The therapeutic approach used in diseases in which mast cell number is increased includes tyrosine kinase inhibitors (midostaurin, nilotinib, imatinib and dasatinib) to target the cKIT receptor action and mast cell tryptase inhibitors (gabexatemesylate, nafamostat mesylate, and tranilast) ( 25 ). Moreover, mast cell stabilizing drugs inhibit the release of mediators are used to prevent allergic reactions to common allergens.…”

Section: Discussionmentioning

confidence: 99%

Nasal cytology and histology in CRSwNP: Two sides of the same coin

Gelardi

Giancaspro²,

Cassano³

et al. 2023

Front. Med.

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Knowledge of chronic rhinosinusitis with nasal polyps (CRSwNP) has increased rapidly over the past decade. However, the study of the histological features of nasal polyps has not gone hand in hand with the study of the inflammatory mechanisms underlying CRSwNP. Indeed, precisely because they are benign neoformations, nasal polyps have not attracted the attention of pathologists over the years. Nasal cytology has shown that CRSwNP, generally defined as a Type-2 disease, is characterized not only by eosinophilic but also mast cell inflammation and, in particular, the most severe forms of CRSwNP are precisely characterized by a mixed eosinophilic-mast cell inflammation. Interestingly, mast cells cannot be visualized by histology due to limitations in staining and magnification, and therefore are not commonly described in histological reports of nasal polyps. However, immunohistochemistry can highlight these latter cells and specifically this technique has recently demonstrated that mast cells are located in the lamina propria of almost all types of polyps and in the epithelial level of the most severe forms. Unfortunately, the latter technique is not commonly carried out in clinical practice by virtue of the high cost and time burden. On the other hand, nasal cytology is an easy-to-apply and economic diagnostic tool, commonly practiced in rhinological setting, which can effectively fill the gap between histology and immunohistochemistry, allowing to non-invasively establish the endotype of nasal polyps and to highlight all cytotypes, including mast cells, that cannot be visualized by the other two techniques. The recent demonstration of the close correlation between mast cell intraepithelial infiltrate and CRSwNP severity paves the way for new therapeutic possibilities aimed at reducing not only eosinophilic infiltration but also mast cell infiltration.

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Section: Discussionmentioning

confidence: 99%

Nasal cytology and histology in CRSwNP: Two sides of the same coin

Gelardi

Giancaspro²,

Cassano³

et al. 2023

Front. Med.

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“…113 Another significant discovery includes the 2G4 antibody, which, in the LAD2 human mast cell line, inhibited mast cell proliferation and degranulation. 114…”

Section: Clinical Trials On Kit Antibody Injections For Mast Cell Dis...mentioning

confidence: 99%

“…Non‐human studies echo this potential: in African Green monkeys, a KIT‐specific antibody markedly reduced mast cell presence in various tissues, 112 while in murine models, a monoclonal antibody against soluble KITLG attenuated anaphylactic indicators, underpinned by reduced mast cell and enhanced gut barrier integrity 113 . Another significant discovery includes the 2G4 antibody, which, in the LAD2 human mast cell line, inhibited mast cell proliferation and degranulation 114 …”

Section: Kitlg/kit Role In Cutaneous Disordersmentioning

confidence: 99%

Therapeutic modulation of KIT ligand in melanocytic disorders with implications for mast cell diseases

Sevilla,

Grichnik

2024

Experimental Dermatology

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KIT ligand and its associated receptor KIT serve as a master regulatory system for both melanocytes and mast cells controlling survival, migration, proliferation and activation. Blockade of this pathway results in cell depletion, while overactivation leads to mastocytosis or melanoma. Expression defects are associated with pigmentary and mast cell disorders. KIT ligand regulation is complex but efficient targeting of this system would be of significant benefit to those suffering from melanocytic or mast cell disorders. Herein, we review the known associations of this pathway with cutaneous diseases and the regulators of this system both in skin and in the more well‐studied germ cell system. Exogenous agents modulating this pathway will also be presented. Ultimately, we will review potential therapeutic opportunities to help our patients with melanocytic and mast cell disease processes potentially including vitiligo, hair greying, melasma, urticaria, mastocytosis and melanoma.

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“…10 Mast cells highly express Fc epsilon receptor 1 (FcεRI), the receptor for immunoglobulin E (IgE), and c-Kit, a type III receptor tyrosine kinase and activation of both receptor results in degranulation of mediators. 11, 12 A multipotent growth factor that plays an important role in the formation of mast cells is the c-Kit ligand stem cell factor (SCF). SCF causes immature mast cells to proliferate and differentiate from CD34+ progenitors, as well as chemotaxis and mast cell existence.…”

Section: Introductionmentioning

confidence: 99%

Modulation of Stem Cell Factor by Forskolin Inhibits the Progression of Tubule Interstitial Fibrosis

Vadnal,

Babu,

Manikantha

et al. 2024

Journal of Pharmacology and Pharmacotherapeutics

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Purpose: Forskolin is primarily found in the roots of the Coleus forskohlii plant, historically employed in Southeast Asian and Indian Ayurvedic medicine. Mast cells play a crucial role in fibrosis progression, yet their activation and inhibition in animal models are understudied; thus, we explored forskolin’s impact on kidney fibrosis. Materials and Methods: Forskolin was evaluated in a mouse model for stem cell factor-induced histamine release, and plasma histamine levels were measured using the enzyme-linked immunosorbent assay. Kidney fibrosis was developed by unilateral ureteral obstruction (UUO). Renal function was assessed by spectrophotometric measurements of serum blood urea nitrogen (BUN) and creatinine. The gene expression of collagen, transforming growth factor-beta (TGF-β), α-smooth muscle actin (α-SMA), interleukin-1 beta (IL-1β), and mast cell protease-5 (MCPT-5) in the kidney was analyzed by reverse transcription polymerase chain reaction (RT-PCR). Histopathological changes in the renal tissues were examined by hematoxylin and eosin (H&E) and Masson’s trichome stain. Results: Our results showed that 3 mg/kg forskolin inhibited SCF-induced plasma histamine release in a mouse model. In the 7-day UUO model, forskolin significantly showed inhibition of serum creatinine and blood urea nitrogen compared with the disease group. Forskolin significantly inhibited elevated expression of collagen, TGF-β, α-SMA, IL-1β, and MCPT-5 in the kidneys. Histopathological observation of H&E and Masson trichome-stained kidney forskolin demonstrated a reduction in inflammatory cells, pelvic and tubular dilation, and fibrosis. Conclusion: Forskolin showed an anti-fibrotic effect in UUO-induced renal fibrotic mice. Most significantly, forskolin administration showed a decrease in the expression of the mast cell protease MCPT5 in the kidneys. These results imply that forskolin, through modifying SCF activity, may be a viable potential treatment for the attenuation of tubule-interstitial fibrosis.

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A fully human anti-c-Kit monoclonal antibody 2G4 inhibits proliferation and degranulation of human mast cells

Cited by 5 publications

References 70 publications

Nasal cytology and histology in CRSwNP: Two sides of the same coin

Nasal cytology and histology in CRSwNP: Two sides of the same coin

Therapeutic modulation of KIT ligand in melanocytic disorders with implications for mast cell diseases

Modulation of Stem Cell Factor by Forskolin Inhibits the Progression of Tubule Interstitial Fibrosis

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