Presence Of C-met Research Articles

Abstract ND01: ABBV-303: A novel NK and CD8 T cell engager specific for c-Met-expressing tumors

Abstract Natural killer (NK) cell redirecting therapies are emerging as promising “off the shelf” treatments for cancer without the safety issues associated with T cell directed therapies. ABBV-303 is a novel c-Met targeted multispecific NK cell engager based on Dragonfly Therapeutics’ TriNKET® technology. ABBV-303 includes three functional arms: (1) a c-Met binding scFv based on ABT-700, common to c-Met-targeting antibody-drug conjugates ABBV-400 and Teliso-V; (2) a Fab arm that binds NKG2D, a stimulatory receptor expressed by NK cells and activated CD8+ T cells; and (3) a heterodimeric IgG1 Fc which binds CD16a on NK cells and links the other two binding moieties. ABBV-303 binding to NKG2D and CD16a results in redirection of both innate (NK cells) and adaptive (CD8+ T cells) immune cells to lyse c-Met expressing tumor cells. Treatment of peripheral blood mononuclear cells (PBMCs) from healthy donors and cancer patients with ABBV-303 in the presence of c-Met+ tumor cells stimulates NK and CD8+ T cells as demonstrated by modulation of activation-associated surface proteins and release of soluble factors. ABBV-303 drives sub-nanomolar redirected killing potency against tumor cells expressing a broad range of c-Met. Additionally, anti-tumor activity of ABBV-303 has been demonstrated against established xenografts in CD34 humanized NSG mice. NK and CD8+ T cell activity in response to ABBV-303 has been observed in c-Met-expressing fresh patient tumor explants. A benign safety profile was observed in non-human primates through three repeat doses up to 150 mg/kg given every two weeks, with antibody-like exposures and a serum half-life around 8 days. Based on these findings, the First in Human ABBV-303 study will initiate in 1H 2024 in solid tumors as a monotherapy and in combination with an anti-PD-1 checkpoint inhibitor. All authors are current employees of AbbVie. The design, study conduct, and financial support for this research were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the publication. Citation Format: Jennifer Stone, Kamonwan Pear Fish, Devika Ashok, Laura McKay, Saeed Akhand, Weilong Zhao, Si Wu, Amani Makkouk, Cormac Cosgrove, Paul Ellis, David Peetz, Stephanie Shee, Richard Peterson II, Shelby Anderson, Adam Chervin, Claudina Stevenson, Tamar Uziel, Edward Reilly. ABBV-303: A novel NK and CD8 T cell engager specific for c-Met-expressing tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr ND01.

HGF/c-MET Signaling in Melanocytes and Melanoma.

Hepatocyte growth factor (HGF)/ mesenchymal-epithelial transition factor (c-MET) signaling is involved in complex cellular programs that are important for embryonic development and tissue regeneration, but its activity is also utilized by cancer cells during tumor progression. HGF and c-MET usually mediate heterotypic cell–cell interactions, such as epithelial–mesenchymal, including tumor–stroma interactions. In the skin, dermal fibroblasts are the main source of HGF. The presence of c-MET on keratinocytes is crucial for wound healing in the skin. HGF is not released by normal melanocytes, but as melanocytes express c-MET, they are receptive to HGF, which protects them from apoptosis and stimulates their proliferation and motility. Dissimilar to melanocytes, melanoma cells not only express c-MET, but also release HGF, thus activating c-MET in an autocrine manner. Stimulation of the HGF/c-MET pathways contributes to several processes that are crucial for melanoma development, such as proliferation, survival, motility, and invasiveness, including distant metastatic niche formation. HGF might be a factor in the innate and acquired resistance of melanoma to oncoprotein-targeted drugs. It is not entirely clear whether elevated serum HGF level is associated with low progression-free survival and overall survival after treatment with targeted therapies. This review focuses on the role of HGF/c-MET signaling in melanoma with some introductory information on its function in skin and melanocytes.

Hepatocyte growth factor activates several transduction pathways in rat pancreatic acini

The receptor of hepatocyte growth factor (HGF), c-met induces different physiological responses in several cell types. Little is known about the role of HGF in exocrine pancreas. However, abnormal HGF signaling has been strongly implicated in pancreatic tumorigenesis and association of HGF with pancreatitis has been demonstrated. We have studied the presence of c-met and activation of their intracellular pathways associated in rat pancreatic acini in comparison with cholecystokinin (CCK) and epidermal growth factor (EGF). C-met expression in rat exocrine pancreas was identified by immunohistochemistry and immunoprecipitation followed by Western analysis. Tyrosine phosphorylation of c-met is strongly stimulated as well as kinase pathways leading to ERK1/2 cascade. HGF, but not CCK or EGF, selectively caused a consistent increase in the amount of p85 regulatory subunit of PI3-K present in anti-phosphotyrosine immunoprecipitates. Downstream of PI3-K, HGF increased Ser473 phosphorylation of Akt selectively, as CCK or EGF did not affect it. HGF selectively stimulated tyrosine phosphorylation of phosphatase PTP1D. HGF failed to promote the well-known CCK effects in pancreatic acini such as amylase secretion and intracellular calcium mobilization. Although HGF shares activation of ERK1/2 with CCK, we demonstrate that it promotes the selective activation of intracellular pathways not regulated by CCK or EGF. Our results suggest that HGF is an in vivo stimulus of pancreatic acini and provide novel insight into the transduction pathways and effects of c-met/HGF in normal pancreatic acinar cells.

The receptor encoded by the human C-MET oncogene is expressed in testicular tissue and on human spermatozoa.

Because of its distinctive ability to act as a mitogen, a mitogen and a morphogen, hepatocyte growth factor/scatter factor (HGF/SF) has all the characteristics of a molecule able to function in regulatory networks of motility, such as the spermatogenic epithelium, and this through binding of its receptor p190MET (C-MET). In this study we report the expression of C-MET in the human seminiferous epithelium and on spermatozoa from men being treated for infertility and sperm donors. The presence of C-MET was demonstrated by immunochemistry on the cell membrane of spermatogonia, spermatocytes, spermatids and on spermatozoa, whereas Sertoli cells and Leydig cells did not show expression. Comparison of C-MET expression on spermatozoa of the 90% Percoll layer of subfertile patients and donors revealed clearly two distinct groups (unpaired t-test, P < 0.001), whereas comparison of C-MET expression on spermatozoa in the 47% Percoll layer was not significantly different between patients and donors. In addition, there was a significant inverse correlation between sperm concentration and the C-MET expression of spermatozoa in the 90% Percoll layer (r = -0.80, 95% confidence interval, -0.92 to -0.55; P < 0.0001), but not with the C-MET expression of spermatozoa in the 47% Percoll layer. In conclusion, the presence of C-MET was demonstrated in the seminiferous epithelium and on mature and immature spermatozoa, indicating a role for this growth factor receptor in the differentiation and/or migration that occurs during human spermatogenesis.

Hepatocyte growth factor activates quiescent skeletal muscle satellite cells in vitro

The effect of hepatocyte growth factor (HGF) on the activation of quiescent rat skeletal muscle satellite cells was evaluated in vitro. Satellite cells from 9-month-old adult rats are quiescent in vivo and when cultured, display a protracted lag phase prior to division that is not present in satellite cells from neonatal or regenerating muscle. Under normal growth conditions, satellite cells divide for the first time between 42 and 60 hr. Hepatocyte growth factor increased proliferation in a dose-dependent fashion prior to 48 hr with half-maximal stimulation at approximately 3 ng/ml; in addition, heparin enhanced this activity. The time course of cyclin-D1 and proliferating cell nuclear antigen (PCNA) expression was accelerated in HGF-treated satellite cells, indicating that cells entered the cell cycle earlier. No significant effects on muscle-derived fibroblast proliferation was observed. The signalling receptor for HGF is the product of the c-met protooncogene, and rtPCR analysis of satellite cells 0-72 hr in culture demonstrated the presence of this message throughout this time period. The presence of c-met in quiescent satellite cells, the ability of HGF to stimulate precocious entry into the cell cycle, and the previously described localization of HGF message in regenerating muscle (Jennische et al., 1993) indicate that HGF could act as an activator of quiescent satellite cells in vivo.