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Large Molecule Therapeutics

ABT-165, a Dual Variable Domain Immunoglobulin (DVD-Ig) Targeting DLL4 and VEGF, Demonstrates Superior Efficacy and Favorable Safety Profiles in Preclinical Models

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 and Susan E. Morgan-Lappe
Yingchun Li
1Oncology Discovery, AbbVie Inc., North Chicago, Illinois.
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Jonathan A. Hickson
1Oncology Discovery, AbbVie Inc., North Chicago, Illinois.
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Dominic J. Ambrosi
2AbbVie Bioresearch Center, Worcester, Massachusetts.
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Deanna L. Haasch
1Oncology Discovery, AbbVie Inc., North Chicago, Illinois.
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Kelly D. Foster-Duke
1Oncology Discovery, AbbVie Inc., North Chicago, Illinois.
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Lucia J. Eaton
2AbbVie Bioresearch Center, Worcester, Massachusetts.
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Enrico L. DiGiammarino
3Global Protein Sciences, AbbVie Inc., North Chicago, Illinois.
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Sanjay C. Panchal
3Global Protein Sciences, AbbVie Inc., North Chicago, Illinois.
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Fang Jiang
1Oncology Discovery, AbbVie Inc., North Chicago, Illinois.
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Sarah R. Mudd
4Translational Imaging, AbbVie Inc., North Chicago, Illinois.
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Catherine Zhang
5Drug Metabolism and Pharmacokinetics - Bioanalysis, AbbVie Biotherapeutics, Redwood City, California.
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Surekha S. Akella
6Preclinical Safety, AbbVie Biotherapeutics, Redwood City, California.
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Wenqing Gao
7Drug Metabolism and Pharmacokinetics, AbbVie Inc., North Chicago, Illinois.
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Sherry L. Ralston
8Preclinical Safety, AbbVie Inc., North Chicago, Illinois.
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Louie Naumovski
9Oncology Early Development, AbbVie Inc., Redwood City, California.
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Jijie Gu
2AbbVie Bioresearch Center, Worcester, Massachusetts.
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Susan E. Morgan-Lappe
1Oncology Discovery, AbbVie Inc., North Chicago, Illinois.
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  • For correspondence: susan.morgan-lappe@abbvie.com
DOI: 10.1158/1535-7163.MCT-17-0800 Published May 2018
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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.

Footnotes

  • Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

  • Received August 21, 2017.
  • Revision received December 28, 2017.
  • Accepted March 8, 2018.
  • Published first March 28, 2018.
  • ©2018 American Association for Cancer Research.
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Molecular Cancer Therapeutics: 17 (5)
May 2018
Volume 17, Issue 5
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ABT-165, a Dual Variable Domain Immunoglobulin (DVD-Ig) Targeting DLL4 and VEGF, Demonstrates Superior Efficacy and Favorable Safety Profiles in Preclinical Models
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 and Susan E. Morgan-Lappe
Mol Cancer Ther May 1 2018 (17) (5) 1039-1050; DOI: 10.1158/1535-7163.MCT-17-0800

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ABT-165, a Dual Variable Domain Immunoglobulin (DVD-Ig) Targeting DLL4 and VEGF, Demonstrates Superior Efficacy and Favorable Safety Profiles in Preclinical Models
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 and Susan E. Morgan-Lappe
Mol Cancer Ther May 1 2018 (17) (5) 1039-1050; DOI: 10.1158/1535-7163.MCT-17-0800
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