American Association for Cancer Research
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Supplementary Materials and Methods from ABT-165, a Dual Variable Domain Immunoglobulin (DVD-Ig) Targeting DLL4 and VEGF, Demonstrates Superior Efficacy and Favorable Safety Profiles in Preclinical Models

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posted on 2023-04-03, 15:10 authored by Yingchun Li, Jonathan A. Hickson, Dominic J. Ambrosi, Deanna L. Haasch, Kelly D. Foster-Duke, Lucia J. Eaton, Enrico L. DiGiammarino, Sanjay C. Panchal, Fang Jiang, Sarah R. Mudd, Catherine Zhang, Surekha S. Akella, Wenqing Gao, Sherry L. Ralston, Louie Naumovski, Jijie Gu, Susan E. Morgan-Lappe

This file describes the binding assay details of surface plasmon resonance technology, ligand and receptor binding competition assays, western blot detection of DLL4 protein down-regulation, and the methods to measure total circulating soluble DLL4 and VEGF in cynomolgus monkey plasma.

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ARTICLE ABSTRACT

Antiangiogenic therapy is a clinically validated modality in cancer treatment. To date, all approved antiangiogenic drugs primarily inhibit the VEGF pathway. Delta-like ligand 4 (DLL4) has been identified as a potential drug target in VEGF-independent angiogenesis and tumor-initiating cell (TIC) survival. A dual-specific biologic targeting both VEGF and DLL4 could be an attractive strategy to improve the effectiveness of anti-VEGF therapy. ABT-165 was uniquely engineered using a proprietary dual-variable domain immunoglobulin (DVD-Ig) technology based on its ability to bind and inhibit both DLL4 and VEGF. In vivo, ABT-165 induced significant tumor growth inhibition compared with either parental antibody treatment alone, due, in part, to the disruption of functional tumor vasculature. In combination with chemotherapy agents, ABT-165 also induced greater antitumor response and outperformed anti-VEGF treatment. ABT-165 displayed nonlinear pharmacokinetic profiles in cynomolgus monkeys, with an apparent terminal half-life > 5 days at a target saturation dose. In a GLP monkey toxicity study, ABT-165 was well-tolerated at doses up to 200 mg/kg with non-adverse treatment–related histopathology findings limited to the liver and thymus. In summary, ABT-165 represents a novel antiangiogenic strategy that potently inhibits both DLL4 and VEGF, demonstrating favorable in vivo efficacy, pharmacokinetic, and safety profiles in preclinical models. Given these preclinical attributes, ABT-165 has progressed to a phase I study. Mol Cancer Ther; 17(5); 1039–50. ©2018 AACR.

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