A PTK7-targeted antibody-drug conjugate reduces tumor-initiating cells and induces sustained tumor regressions

  • Sci Transl Med. 2017 Jan 11;9(372):eaag2611. doi: 10.1126/scitranslmed.aag2611.
Marc Damelin  1 ,  Alexander Bankovich  2 ,  Jeffrey Bernstein  2 ,  Justin Lucas  3 ,  Liang Chen  3 ,  Samuel Williams  2 ,  Albert Park  2 ,  Jorge Aguilar  2 ,  Elana Ernstoff  3 ,  Manoj Charati  3 ,  Russell Dushin  4 ,  Monette Aujay  2 ,  Christina Lee  2 ,  Hanna Ramoth  2 ,  Milly Milton  2 ,  Johannes Hampl  2 ,  Sasha Lazetic  2 ,  Virginia Pulito  3 ,  Edward Rosfjord  3 ,  Yongliang Sun  4 ,  Lindsay King  4 ,  Frank Barletta  3 ,  Alison Betts  4 ,  Magali Guffroy  3 ,  Hadi Falahatpisheh  3 ,  Christopher J O'Donnell  4 ,  Robert Stull  2 ,  Marybeth Pysz  2 ,  Paul Escarpe  2 ,  David Liu  2 ,  Orit Foord  2 ,  Hans Peter Gerber  3 ,  Puja Sapra  1 ,  Scott J Dylla  5
Affiliations
  • 1. Pfizer Worldwide Research and Development (R&D), 401 North Middletown Road, Pearl River, NY 10965, USA. [email protected] [email protected] [email protected].
  • 2. AbbVie Stemcentrx LLC, 450 East Jamie Court, South San Francisco, CA 94080, USA.
  • 3. Pfizer Worldwide Research and Development (R&D), 401 North Middletown Road, Pearl River, NY 10965, USA.
  • 4. Pfizer Worldwide R&D, 445 Eastern Point Road, Groton, CT 06340, USA.
  • 5. AbbVie Stemcentrx LLC, 450 East Jamie Court, South San Francisco, CA 94080, USA. [email protected] [email protected] [email protected].
PMID: 28077676 DOI: 10.1126/scitranslmed.aag2611
Abstract

Disease relapse after treatment is common in triple-negative breast Cancer (TNBC), ovarian Cancer (OVCA), and non-small cell lung Cancer (NSCLC). Therapies that target tumor-initiating cells (TICs) should improve patient survival by eliminating the cells that can drive tumor recurrence and metastasis. We demonstrate that protein tyrosine kinase 7 (PTK7), a highly conserved but catalytically inactive receptor tyrosine kinase in the Wnt signaling pathway, is enriched on TICs in low-passage TNBC, OVCA, and NSCLC patient-derived xenografts (PDXs). To deliver a potent Anticancer drug to PTK7-expressing TICs, we generated a targeted antibody-drug conjugate (ADC) composed of a humanized anti-PTK7 monoclonal antibody, a cleavable valine-citrulline-based linker, and Aur0101, an Auristatin microtubule inhibitor. The PTK7-targeted ADC induced sustained tumor regressions and outperformed standard-of-care chemotherapy. Moreover, the ADC specifically reduced the frequency of TICs, as determined by serial transplantation experiments. In addition to reducing the TIC frequency, the PTK7-targeted ADC may have additional antitumor mechanisms of action, including the inhibition of angiogenesis and the stimulation of immune cells. Together, these preclinical data demonstrate the potential for the PTK7-targeted ADC to improve the long-term survival of Cancer patients.

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