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Molecular Cancer Therapeutics

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Large Molecule Therapeutics

Characterization of ABBV-221, a Tumor-Selective EGFR-Targeting Antibody Drug Conjugate

Andrew C. Phillips, Erwin R. Boghaert, Kedar S. Vaidya, Hugh D. Falls, Michael J. Mitten, Peter J. DeVries, Lorenzo Benatuil, Chung-Ming Hsieh, Jonathan A. Meulbroek, Sanjay C. Panchal, Fritz G. Buchanan, Kenneth R. Durbin, Martin J. Voorbach, David R. Reuter, Sarah R. Mudd, Lise I. Loberg, Sherry L. Ralston, Diana Cao, Hui K. Gan, Andrew M. Scott and Edward B. Reilly
Andrew C. Phillips
AbbVie Inc., North Chicago, Illinois.
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Erwin R. Boghaert
AbbVie Inc., North Chicago, Illinois.
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Kedar S. Vaidya
AbbVie Inc., North Chicago, Illinois.
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Hugh D. Falls
AbbVie Inc., North Chicago, Illinois.
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Michael J. Mitten
AbbVie Inc., North Chicago, Illinois.
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Peter J. DeVries
AbbVie Inc., North Chicago, Illinois.
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Lorenzo Benatuil
AbbVie Bioresearch Center, Worcester, Massachusetts.
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Chung-Ming Hsieh
AbbVie Bioresearch Center, Worcester, Massachusetts.
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Jonathan A. Meulbroek
AbbVie Inc., North Chicago, Illinois.
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Sanjay C. Panchal
AbbVie Inc., North Chicago, Illinois.
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Fritz G. Buchanan
AbbVie Inc., North Chicago, Illinois.
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Kenneth R. Durbin
AbbVie Inc., North Chicago, Illinois.
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Martin J. Voorbach
AbbVie Inc., North Chicago, Illinois.
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David R. Reuter
AbbVie Inc., North Chicago, Illinois.
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Sarah R. Mudd
AbbVie Inc., North Chicago, Illinois.
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Lise I. Loberg
AbbVie Inc., North Chicago, Illinois.
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Sherry L. Ralston
AbbVie Inc., North Chicago, Illinois.
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Diana Cao
Olivia Newton-John Cancer Research Institute, and La Trobe University Austin Hospital, Heidelberg, Victoria, Australia.
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Hui K. Gan
Olivia Newton-John Cancer Research Institute, and La Trobe University Austin Hospital, Heidelberg, Victoria, Australia.
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Andrew M. Scott
Olivia Newton-John Cancer Research Institute, and La Trobe University Austin Hospital, Heidelberg, Victoria, Australia.
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Edward B. Reilly
AbbVie Inc., North Chicago, Illinois.
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  • For correspondence: ed.reilly@abbvie.com
DOI: 10.1158/1535-7163.MCT-17-0710 Published April 2018
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Abstract

Depatuxizumab mafodotin (depatux-m, ABT-414) is a tumor-selective antibody drug conjugate (ADC) comprised of the anti-EGFR antibody ABT-806 and the monomethyl auristatin F (MMAF) warhead. Depatux-m has demonstrated promising clinical activity in glioblastoma multiforme (GBM) patients and is currently being evaluated in clinical trials in first-line and recurrent GBM disease settings. Depatux-m responses have been restricted to patients with amplified EGFR, highlighting the need for therapies with activity against tumors with nonamplified EGFR overexpression. In addition, depatux-m dosing has been limited by corneal side effects common to MMAF conjugates. We hypothesized that a monomethyl auristatin E (MMAE) ADC utilizing an EGFR-targeting antibody with increased affinity may have broader utility against tumors with more modest EGFR overexpression while mitigating the risk of corneal side effects. We describe here preclinical characterization of ABBV-221, an EGFR-targeting ADC comprised of an affinity-matured ABT-806 conjugated to MMAE. ABBV-221 binds to a similar EGFR epitope as depatux-m and retains tumor selectivity with increased binding to EGFR-positive tumor cells and greater in vitro potency. ABBV-221 displays increased tumor uptake and antitumor activity against wild-type EGFR-positive xenografts with a greatly reduced incidence of corneal side effects relative to depatux-m. ABBV-221 has similar activity as depatux-m against an EGFR-amplified GBM patient derived xenograft (PDX) model and is highly effective alone and in combination with standard-of-care temozolomide in an EGFRvIII-positive GBM xenograft model. Based on these results, ABBV-221 has advanced to a phase I clinical trial in patients with advanced solid tumors associated with elevated levels of EGFR. Mol Cancer Ther; 17(4); 795–805. ©2018 AACR.

Footnotes

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

  • Received July 31, 2017.
  • Revision received December 7, 2017.
  • Accepted February 6, 2018.
  • Published first February 26, 2018.
  • ©2018 American Association for Cancer Research.
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Molecular Cancer Therapeutics: 17 (4)
April 2018
Volume 17, Issue 4
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Characterization of ABBV-221, a Tumor-Selective EGFR-Targeting Antibody Drug Conjugate
Andrew C. Phillips, Erwin R. Boghaert, Kedar S. Vaidya, Hugh D. Falls, Michael J. Mitten, Peter J. DeVries, Lorenzo Benatuil, Chung-Ming Hsieh, Jonathan A. Meulbroek, Sanjay C. Panchal, Fritz G. Buchanan, Kenneth R. Durbin, Martin J. Voorbach, David R. Reuter, Sarah R. Mudd, Lise I. Loberg, Sherry L. Ralston, Diana Cao, Hui K. Gan, Andrew M. Scott and Edward B. Reilly
Mol Cancer Ther April 1 2018 (17) (4) 795-805; DOI: 10.1158/1535-7163.MCT-17-0710

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Characterization of ABBV-221, a Tumor-Selective EGFR-Targeting Antibody Drug Conjugate
Andrew C. Phillips, Erwin R. Boghaert, Kedar S. Vaidya, Hugh D. Falls, Michael J. Mitten, Peter J. DeVries, Lorenzo Benatuil, Chung-Ming Hsieh, Jonathan A. Meulbroek, Sanjay C. Panchal, Fritz G. Buchanan, Kenneth R. Durbin, Martin J. Voorbach, David R. Reuter, Sarah R. Mudd, Lise I. Loberg, Sherry L. Ralston, Diana Cao, Hui K. Gan, Andrew M. Scott and Edward B. Reilly
Mol Cancer Ther April 1 2018 (17) (4) 795-805; DOI: 10.1158/1535-7163.MCT-17-0710
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Molecular Cancer Therapeutics
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