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

Abstract

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.

ADAM17-mediated EGFR ligand shedding directs macrophage-promoted cancer cell invasion

“…It became evident that soluble HB-EGF (sHB-EGF) promotes tumor progression ( 57 ), and HB-EGF inhibition has been validated in vitro as a possible therapeutic target in ovarian, breast, bladder, and gastric cancer cells ( 58 ). Different sHB-EGF–blocking strategies have been developed to inhibit its binding to EGFR, including monoclonal antibodies ( 59 , 60 ), a nontoxic mutant of diphtheria toxin ( 61 ), the recombinant prodomain of ADAM12 ( 62 ), and small inhibitory peptides ( 63 ). A first-in-human study with the anti–HB-EGF antibody U3-1565, conducted in a small patient cohort with solid tumors, demonstrated an antitumor response and no dose-limited toxicity ( 60 ).…”

“…Different sHB-EGF–blocking strategies have been developed to inhibit its binding to EGFR, including monoclonal antibodies ( 59 , 60 ), a nontoxic mutant of diphtheria toxin ( 61 ), the recombinant prodomain of ADAM12 ( 62 ), and small inhibitory peptides ( 63 ). A first-in-human study with the anti–HB-EGF antibody U3-1565, conducted in a small patient cohort with solid tumors, demonstrated an antitumor response and no dose-limited toxicity ( 60 ). In the future, it would be interesting to analyze the effect of U3-1565 on the TME and evaluate whether this treatment could enhance the effect of immune checkpoint inhibitors.…”

s-HBEGF/SIRT1 circuit-dictated crosstalk between vascular endothelial cells and keratinocytes mediates sorafenib-induced hand–foot skin reaction that can be reversed by nicotinamide

“…Our study confirmed that HBEGF neutralizing antibody could attenuate sorafenib-induced stratum corneum thickening in mice. However, the HBEGF antibody is still under phase I trial, 71 and the date of its clinical approval is yet undetermined. Meanwhile, the combined usage of EGFR inhibitor and sorafenib may lead to severe adverse reactions including pulmonary toxicity and hepatotoxicity, 72,73 and no specific JNK2-inhibiting compound has yet been identified.…”