Phase 1 Study of Monotherapy with KHK2866, an Anti-Heparin-Binding Epidermal Growth Factor-Like Growth Factor Monoclonal Antibody, in Patients with Advanced Cancer

Sarantopoulos, John; Mita, Monica; Birrer, Michael J.; Cranmer, Lee D.; Campos, Luis T.; Zhang, Xiaoping; Bristow, Penelope; Kaito, Hidekuni; Strout, Vincent; Camacho, Luis H.

doi:10.1007/s11523-015-0394-5

Cited by 13 publications

(12 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Targeting of HB-EGF has been aimed to inhibit growth and metastasis of various cancers [ 36 , 63 – 72 ]. Diverse approaches for HB-EGF targeting have been tested including blocking antibodies [ 63 , 65 , 66 , 70 ] and inert diphtheria toxin derivatives [ 71 , 73 ]. Unexpectedly, the HB-EGF blocking antibodies caused neurological side effects, which caused discontinuation of human trial [ 70 ].…”

Section: Discussionmentioning

confidence: 99%

“…Diverse approaches for HB-EGF targeting have been tested including blocking antibodies [ 63 , 65 , 66 , 70 ] and inert diphtheria toxin derivatives [ 71 , 73 ]. Unexpectedly, the HB-EGF blocking antibodies caused neurological side effects, which caused discontinuation of human trial [ 70 ]. Similar neurological effect was also shown in mice with brain-specific HB-EGF knockout [ 74 ].…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Targeting hepatic heparin-binding EGF-like growth factor (HB-EGF) induces anti-hyperlipidemia leading to reduction of angiotensin II-induced aneurysm development

Kim¹,

Yang²,

Kim³

et al. 2017

PLoS ONE

View full text Add to dashboard Cite

ObjectiveThe upregulated expression of heparin binding EGF-like growth factor (HB-EGF) in the vessel and circulation is associated with risk of cardiovascular disease. In this study, we tested the effects of HB-EGF targeting using HB-EGF-specific antisense oligonucleotide (ASO) on the development of aortic aneurysm in a mouse aneurysm model.Approach and resultsLow-density lipoprotein receptor (LDLR) deficient mice (male, 16 weeks of age) were injected with control and HB-EGF ASOs for 10 weeks. To induce aneurysm, the mice were fed a high fat diet (22% fat, 0.2% cholesterol; w/w) at 5 week point of ASO administration and infused with angiotensin II (AngII, 1,000ng/kg/min) for the last 4 weeks of ASO administration. We confirmed that the HB-EGF ASO administration significantly downregulated HB-EGF expression in multiple tissues including the liver. Importantly, the HB-EGF ASO administration significantly suppressed development of aortic aneurysms including thoracic and abdominal types. Interestingly, the HB-EGF ASO administration induced a remarkable anti-hyperlipidemic effect by suppressing very low density lipoprotein (VLDL) level in the blood. Mechanistically, the HB-EGF targeting suppressed hepatic VLDL secretion rate without changing heparin-releasable plasma triglyceride (TG) hydrolytic activity or fecal neutral cholesterol excretion rate.ConclusionThis result suggested that the HB-EGF targeting induced protection against aneurysm development through anti-hyperlipidemic effects. Suppression of hepatic VLDL production process appears to be a key mechanism for the anti-hyperlipidemic effects by the HB-EGF targeting.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Targeting hepatic heparin-binding EGF-like growth factor (HB-EGF) induces anti-hyperlipidemia leading to reduction of angiotensin II-induced aneurysm development

Kim¹,

Yang²,

Kim³

et al. 2017

PLoS ONE

View full text Add to dashboard Cite

show abstract

“…HB-EGF-targeted agents have been tested in two phase I clinical trials, which investigated the safety, tolerability, and efficacy of the inhibitory monoclonal antibody to HB- EGF KHK2866 in patients with advanced ovarian cancer and of BK-UM in patients with recurrent ovarian cancer (21,23). Companion diagnostics for each agent were also developed (8,24).…”

Section: Discussionmentioning

confidence: 99%

“…Companion diagnostics for each agent were also developed (8,24). The studies found that serum HB-EGF levels were reduced by intravenous injection of KHK2866 (23), and significantly reduced by intraperitoneal administration of BK-UM in patients with high levels of serum HB-EGF (>125 pg/ml by ELISA) (21). However, the KHK2866 antibody caused reversible neuropsychiatric toxicity and its development has been discontinued (23).…”

Section: Discussionmentioning

confidence: 99%

“…The studies found that serum HB-EGF levels were reduced by intravenous injection of KHK2866 (23), and significantly reduced by intraperitoneal administration of BK-UM in patients with high levels of serum HB-EGF (>125 pg/ml by ELISA) (21). However, the KHK2866 antibody caused reversible neuropsychiatric toxicity and its development has been discontinued (23). However, the trial of BK-UM showed not only that it was safe and tolerable, but also that high serum HB-EGF concentrations were associated with poor clinical prognosis (21).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Serum Heparin-binding Epidermal Growth Factor-like Growth Factor (HB-EGF) as a Biomarker for Primary Ovarian Cancer

Miyata

Yotsumoto

Fukagawa

et al. 2017

View full text Add to dashboard Cite

Ovarian cancer is the most lethal malignancy among gynaecological cancers. Although many anticancer agents have been developed for the treatment of ovarian cancer, it continues to have an extremely poor prognosis. Heparin-binding epidermal growth factor-like grown factor (HB-EGF) has been reported to be a rational therapeutic target for ovarian cancer. Here, we evaluated the clinical significance of serum HB-EGF by examining the association between prognosis and serum HB-EGF levels in patients with primary ovarian cancer. We found that high serum HB-EGF concentrations were significantly associated with poor prognosis in a combined cohort of patients with all stages of ovarian cancer, as well as in a subset of patients with advanced disease. In addition, serum HB-EGF levels increased as the cancer advanced. These data suggest that serum HB-EGF may be a target for the design of novel therapies for ovarian cancer.

show abstract

First-in-human study of the anti-HB-EGF antibody U3-1565 in subjects with advanced solid tumors

et al. 2018

View full text Add to dashboard Cite

U3-1565 is a monoclonal antibody directed against heparin-binding epidermal growth factor-like growth factor (HB-EGF), which mediates angiogenesis via induction of vascular endothelial growth factor (VEGF-A). This first-in-human study characterized the safety, tolerability, efficacy, pharmacokinetics, and pharmacodynamics of U3-1565 in subjects with advanced solid tumors. In Part 1 (dose escalation following a modified 3 + 3 design), Cohorts 1-4, U3-1565 was administered at 2, 8, 16, and 24 mg/kg every 3 weeks for Cycle 1 and every 2 weeks thereafter. In Part 1, Cohort 5, and in Part 2 (dose expansion), U3-1565 was administered at 24 mg/kg every week. Thirty-six subjects were enrolled and treated (15 in Part 1; 21 in Part 2). No subject experienced dose limiting toxicity and maximum tolerated dose was not reached. All drug-related events were Grade 1 or 2 in severity, with fatigue and rash predominating. Following treatment with U3-1565, 1 subject with metastatic colorectal cancer experienced partial response and 6 subjects achieved stable disease. Four subjects completed the study main phase (first 12 cycles) and entered the extension phase. Of the 6/36 subjects with high (> 1500 pg/ml) baseline VEGF-A levels, all showed a decrease in VEGF-A (median - 60% [-22% to -97%]). Of the remaining subjects, only 19/30 showed a decrease (median - 18% [-2% to -82%]). Subjects with high VEGF-A baseline levels remained on treatment longer (3/6 entered study extension phase versus 1/30), and were more likely to show disease control (3/6 versus 4/30). In conclusion, U3-1565 demonstrates both proof of mechanism and clinical activity across different tumor types.

show abstract

Phase 1 Study of Monotherapy with KHK2866, an Anti-Heparin-Binding Epidermal Growth Factor-Like Growth Factor Monoclonal Antibody, in Patients with Advanced Cancer

Cited by 13 publications

References 41 publications

Targeting hepatic heparin-binding EGF-like growth factor (HB-EGF) induces anti-hyperlipidemia leading to reduction of angiotensin II-induced aneurysm development

Targeting hepatic heparin-binding EGF-like growth factor (HB-EGF) induces anti-hyperlipidemia leading to reduction of angiotensin II-induced aneurysm development

Serum Heparin-binding Epidermal Growth Factor-like Growth Factor (HB-EGF) as a Biomarker for Primary Ovarian Cancer

First-in-human study of the anti-HB-EGF antibody U3-1565 in subjects with advanced solid tumors

Contact Info

Product

Resources

About