A Novel Anti-Human HB-EGF Monoclonal Antibody with Multiple Antitumor Mechanisms against Ovarian Cancer Cells

Miyamoto, Shingo; Iwamoto, Ryo; Furuya, Akiko; Takahashi, Kumiko; Sasaki, Yuka; Ando, Hiroshi; Yotsumoto, Fusanori; Yoneda, Tomoko; Hamaoka, Miki; Yagi, Hiroshi; Murakami, Takuya; Hori, Shigeru; Shitara, Kenya; Mekada, Eisuke

doi:10.1158/1078-0432.ccr-11-1029

Cited by 31 publications

(36 citation statements)

References 26 publications

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“…Given the extreme metastatic capability and dependence upon the VEGF-signaling pathway in OVCA [41], PG545 may be considered an ideal drug candidate for testing in this cancer indication. Moreover, increasing evidence has suggested a critical role for HB-EGF in ovarian cancer progression [43] as a negative prognostic factor [44]. Furthermore HB-EGF might be involved in tumour resistance against paclitaxel [45].…”

Section: Discussionmentioning

confidence: 99%

PG545 enhances anti-cancer activity of chemotherapy in ovarian models and increases surrogate biomarkers such as VEGF in preclinical and clinical plasma samples

Winterhoff¹,

Freyer²,

Hammond³

et al. 2015

European Journal of Cancer

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Background Despite the utility of antiangiogenic drugs in ovarian cancer, efficacy remains limited due to resistance linked to alternate angiogenic pathways and metastasis. Therefore, we investigated PG545, an anti-angiogenic and anti-metastatic agent which is currently in Phase I clinical trials, using preclinical models of ovarian cancer. Methods PG545's anti-cancer activity was investigated in vitro and in vivo as a single agent, and in combination with paclitaxel, cisplatin or carboplatin using various ovarian cancer cell lines and tumour models. Results PG545, alone, or in combination with chemotherapeutics, inhibited proliferation of ovarian cancer cells, demonstrating synergy with paclitaxel in A2780 cells. PG545 inhibited growth factor-mediated cell migration and reduced HB-EGF-induced phosphorylation of ERK, AKT and EGFR in vitro and significantly reduced tumour burden which was enhanced when combined with paclitaxel in an A2780 model or carboplatin in a SKOV-3 model. Moreover, in the immunocompetent ID8 model, PG545 also significantly reduced ascites in vivo. In the A2780 maintenance model, PG545 initiated with, and following paclitaxel and cisplatin treatment, significantly improved overall survival. PG545 increased plasma VEGF levels (and other targets) in preclinical models and in a small cohort of advanced cancer patients which might represent a potential biomarker of response. Conclusion Our results support clinical testing of PG545, particularly in combination with paclitaxel, as a novel therapeutic strategy for ovarian cancer.

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Section: Discussionmentioning

confidence: 99%

PG545 enhances anti-cancer activity of chemotherapy in ovarian models and increases surrogate biomarkers such as VEGF in preclinical and clinical plasma samples

Winterhoff¹,

Freyer²,

Hammond³

et al. 2015

European Journal of Cancer

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“…To date, few anti-HB-EGF antibodies with biological activity against HB-EGF have been reported in the literature [29], [32], [33]. However, the results of this study show that Y-142 has unique properties with its potent neutralizing activity in multiple HB-EGF signaling events.…”

Section: Discussionmentioning

confidence: 63%

“…An HB-EGF inhibitor of the diphtheria toxin mutant, CRM197, is in Phase I clinical development for the treatment of advanced ovarian cancers [28]. Anti-HB-EGF antibodies U3-1565 and KHK2866 are currently in Phase I clinical trials for solid cancers [29]. An anti-HB-EGF therapeutic monoclonal antibody is expected to have a longer half-life compared to CRM197 [30], [31], but the generation of potent anti-HB-EGF antibodies has been challenging and few anti-HB-EGF monoclonal antibodies with a functional activity have been reported [29], [32], [33].…”

Section: Introductionmentioning

confidence: 99%

A Potent Anti-HB-EGF Monoclonal Antibody Inhibits Cancer Cell Proliferation and Multiple Angiogenic Activities of HB-EGF

et al. 2012

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Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is a member of the epidermal growth factor family and has a variety of physiological and pathological functions. Modulation of HB-EGF activity might have a therapeutic potential in the oncology area. We explored the therapeutic possibilities by characterizing the in vitro biological activity of anti-HB-EGF monoclonal antibody Y-142. EGF receptor (EGFR) ligand and species specificities of Y-142 were tested. Neutralizing activities of Y-142 against HB-EGF were evaluated in EGFR and ERBB4 signaling. Biological activities of Y-142 were assessed in cancer cell proliferation and angiogenesis assays and compared with the anti-EGFR antibody cetuximab, the HB-EGF inhibitor CRM197, and the anti-vascular endothelial growth factor (VEGF) antibody bevacizumab. The binding epitope was determined with alanine scanning. Y-142 recognized HB-EGF as well as the EGFR ligand amphiregulin, and bound specifically to human HB-EGF, but not to rodent HB-EGF. In addition, Y-142 neutralized HB-EGF-induced phosphorylation of EGFR and ERBB4, and blocked their downstream ERK1/2 and AKT signaling. We also found that Y-142 inhibited HB-EGF-induced cancer cell proliferation, endothelial cell proliferation, tube formation, and VEGF production more effectively than cetuximab and CRM197 and that Y-142 was superior to bevacizumab in the inhibition of HB-EGF-induced tube formation. Six amino acids in the EGF-like domain were identified as the Y-142 binding epitope. Among the six amino acids, the combination of F115 and Y123 determined the amphiregulin cross-reactivity and that F115 accounted for the species selectivity. Furthermore, it was suggested that the potent neutralizing activity of Y-142 was derived from its recognition of R142 and Y123 and its high affinity to HB-EGF. Y-142 has a potent HB-EGF neutralizing activity that modulates multiple biological activities of HB-EGF including cancer cell proliferation and angiogenic activities. Y-142 may have a potential to be developed into a therapeutic agent for the treatment of HB-EGF-dependent cancers.

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“…Thus, HB-EGF is recognised as a possible target for cancer therapy. An antibody against HB-EGF ( Miyamoto et al, 2011) and CRM197 (a nontoxic mutant form of diphtheria toxin that neutralises HB-EGF activity) are undergoing clinical development as anticancer drugs (Nam et al, 2014). However, such blocking therapies also have potential side effects associated with the inhibition of the physiological functions of HB-EGF.…”

Section: Discussionmentioning

confidence: 99%

ErbB1 and ErbB4 generate opposing signals regulating mesenchymal cell proliferation during valvulogenesis

Iwamoto¹,

Mine²,

Mizushima³

et al. 2017

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Heparin-binding EGF-like growth factor (HB-EGF) plays an indispensable role in suppression of cell proliferation during mouse valvulogenesis. However, ligands of the EGF receptor (EGFR/ErbB1), including HB-EGF, are generally considered as growth-promoting factors, as shown in cancers. HB-EGF binds to and activates ErbB1 and ErbB4. We investigated the role of ErbB receptors in valvulogenesis in vivo using ErbB1-and ErbB4-deficient mice, and an ex vivo model of endocardial cushion explants. We show that HB-EGF suppresses valve mesenchymal cell proliferation through a heterodimer of ErbB1 and ErbB4, and an ErbB1 ligand (or ligands) promotes cell proliferation through a homodimer of ErbB1. Moreover, a rescue experiment with cleavable or uncleavable isoforms of ErbB4 in ERBB4-null cells indicates that the cleavable JM-A, but not the uncleavable JM-B, splice variant of ErbB4 rescues the defect of the null cells. These data suggest that the cytoplasmic intracellular domain of ErbB4, rather than the membrane-anchored tyrosine kinase, achieves this suppression. Our study demonstrates that opposing signals generated by different ErbB dimer combinations function in the same cardiac cushion mesenchymal cells for proper cardiac valve formation.

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A Novel Anti-Human HB-EGF Monoclonal Antibody with Multiple Antitumor Mechanisms against Ovarian Cancer Cells

Cited by 31 publications

References 26 publications

PG545 enhances anti-cancer activity of chemotherapy in ovarian models and increases surrogate biomarkers such as VEGF in preclinical and clinical plasma samples

PG545 enhances anti-cancer activity of chemotherapy in ovarian models and increases surrogate biomarkers such as VEGF in preclinical and clinical plasma samples

A Potent Anti-HB-EGF Monoclonal Antibody Inhibits Cancer Cell Proliferation and Multiple Angiogenic Activities of HB-EGF

ErbB1 and ErbB4 generate opposing signals regulating mesenchymal cell proliferation during valvulogenesis

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