Humanized Anti-hepatocyte Growth Factor Monoclonal Antibody (YYB-101) Inhibits Ovarian Cancer Progression

Kim, Hyun Jung; Lee, Sukmook; Oh, Yong‐Seok; Chang, Ha Kyun; Kim, Young Sang; Hong, Sung Hee; Kim, Jung Yong; Park, Young-Whan; Lee, Song-Jae; Song, Seong-Won; Kim, Jung Ju; Heo, Kyun

doi:10.3389/fonc.2019.00571

Cited by 9 publications

(9 citation statements)

References 39 publications

(49 reference statements)

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“…It was shown to provide significant benefit in a phase I trial (NCT02296879) and to reduce invasion and migration of nasopharyngeal cancer cells (Bhatia et al , 2017). Migration and invasion of cancer cells were also inhibited by another monoclonal antibody targeting c‐MET, YYB‐001 (Kim et al , 2019). A phase I clinical trial with this antibody has just been completed for colorectal cancer (NCT04368507) (Kim et al , 2020), reflecting the potential of therapies targeting DRs for preventing metastatic spread.…”

Section: The Dependence Receptor Paradigmmentioning

confidence: 99%

Dependence receptors: new targets for cancer therapy

et al. 2021

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Dependence receptors are known to promote survival and positive signaling such as proliferation, migration, and differentiation when activated, but to actively trigger apoptosis when unbound to their ligand. Their abnormal regulation was shown to be an important feature of tumorigenesis, allowing cancer cells to escape apoptosis triggered by these receptors while promoting in parallel major aspects of tumorigenesis such as proliferation, angiogenesis, invasiveness, and chemoresistance. This involvement in multiple cancer hallmarks has raised interest in dependence receptors as targets for cancer therapy. Although additional studies remain necessary to fully understand the complexity of signaling pathways activated by these receptors and to target them efficiently, it is now clear that dependence receptors represent very exciting targets for future cancer treatment. This manuscript reviews current knowledge on the contribution of dependence receptors to cancer and highlights the potential for therapies that activate pro‐apoptotic functions of these proteins.

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Section: The Dependence Receptor Paradigmmentioning

confidence: 99%

Dependence receptors: new targets for cancer therapy

et al. 2021

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“…Our study offers new insights into the potential clinical use of sHGF as a discrete blood‐based biomarker, which may be used in combination with CA125 and could repeatedly be applied for prognostic stratification, for example, in terms of sHGF‐guided therapy monitoring. In addition, the potential of longitudinal sHGF levels as a dynamic biomarker for predicting/monitoring response to HGF/cMET targeting drugs could be explored in future [ 23 , 24 , 41 ].…”

Section: Discussionmentioning

confidence: 99%

Prognostic relevance of longitudinal HGF levels in serum of patients with ovarian cancer

et al. 2021

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The pleiotropic protein hepatocyte growth factor (HGF) is the only known ligand of the tyrosine kinase mesenchymal-epithelial transition (cMET) receptor The HGF-cMET pathway mediates invasion and migration of ovarian cancer cells, and upregulation of HGF-cMET pathway components has been associated with poor prognosis. This study investigated the clinical relevance of circulating HGF in serum of patients with ovarian cancer. Serum HGF (sHGF) was determined by enzyme-linked immunosorbent assay in a total of 471 serum samples from 82 healthy controls and 113 patients with ovarian cancer (88.5 % with ≥ FIGO III). Patient samples were collected at primary diagnosis and at four follow-up time points throughout treatment and at disease recurrence. Patients with ovarian cancer showed elevated median sHGF levels at primary diagnosis, and sHGF levels transiently increased after surgery and normalized with chemotherapy, even dropping below initial baseline. Higher levels of sHGF were an independent predictor for shorter overall survival (OS) i) at primary diagnosis (HR = 0.41, 95%CI: 0.22-0.78, p = 0.006), ii) at longitudinal follow-up time points (after surgery and before/during/after chemotherapy), iii) along the patients' individual dynamics (HR = 0.21, 95%CI: 0.07-0.63, p = 0.005), and iv) among a subgroup analysis of patients with BRCA1/2 wild type ovarian cancer. This is the first study proposing sHGF as an independent prognostic biomarker for ovarian cancer at primary diagnosis and in the course of platinum-based chemotherapy, irrespective of the postoperative residual disease after surgical debulking. sHGF could be implemented into clinical diagnostics as a CA125 auxiliary tumor marker for individualized prognosis stratification and sHGF-guided therapy monitoring.

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“…In ovarian cancer preclinical models, the efficacy of YYB101 efficiently blocked HGF leading to inhibition of the growth of ovarian cancer cells through downregulation of the MET axis. 22 In this phase I trial, we enrolled 10 ovarian cancer patients who failed to respond to at least four previous regimens. Although serum HGF levels were proficiently blocked, as shown in Figure 2c, none of the ovarian cancer patients responded to single-agent YYB101 treatment.…”

Section: Discussionmentioning

confidence: 99%

First-in-human phase I trial of anti-hepatocyte growth factor antibody (YYB101) in refractory solid tumor patients

et al. 2020

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Background: YYB101, a humanized monoclonal antibody against hepatocyte growth factor (HGF), has shown safety and efficacy in vitro and in vivo. This is a first-in-human trial of this antibody. Materials and Methods: YYB101 was administered intravenously to refractory cancer patients once every 4 weeks for 1 month, and then once every 2 weeks until disease progression or intolerable toxicity, at doses of 0.3, 1, 3, 5, 10, 20, 30 mg/kg, according to a 3+3 dose escalation design. Maximum tolerated dose, safety, pharmacokinetics, and pharmacodynamics were studied. HGF, MET, PD-L1, and ERK expression was evaluated for 9 of 17 patients of the expansion cohort (20 mg/kg). Results: In 39 patients enrolled, no dose-limiting toxicity was observed at 0.3 mg/kg, and the most commonly detected toxicity was generalized edema ( n = 7, 18.9%) followed by pruritis and nausea ( n = 5, 13.5%, each), fatigue, anemia, and decreased appetite ( n = 4, 10.8%, each). No patient discontinued treatment because of adverse events. YYB101 showed dose-proportional pharmacokinetics up to 30 mg/kg. Partial response in 1 (2.5%) and stable disease in 17 (43.5%) were observed. HGF, MET, PD-L1, and ERK proteins were not significant predictors for treatment response. However, serum HGF level was significantly lowered in responders upon drug administration. RNA sequencing revealed a mesenchymal signature in two long-term responders. Conclusion: YYB101 showed favorable safety and efficacy in patients with refractory solid tumors. Based on this phase I trial, a phase II study on the YYB101 + irinotecan combination in refractory metastatic colorectal cancer patients is planned. Conclusion: ClinicalTrials.gov Identifier: NCT02499224

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Humanized Anti-hepatocyte Growth Factor Monoclonal Antibody (YYB-101) Inhibits Ovarian Cancer Progression

Cited by 9 publications

References 39 publications

Dependence receptors: new targets for cancer therapy

Dependence receptors: new targets for cancer therapy

Prognostic relevance of longitudinal HGF levels in serum of patients with ovarian cancer

First-in-human phase I trial of anti-hepatocyte growth factor antibody (YYB101) in refractory solid tumor patients

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