title: A PTK7-targeted antibody-drug conjugate reduces tumor-initiating cells and induces sustained tumor regressions.
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.
authors.affiliation: Pfizer Worldwide Research and Development (R&D), 401 North Middletown Road, Pearl River, NY 10965, USA. marc.damelin@pfizer.com puja.sapra@pfizer.com scott.dylla@abbvie.com.
authors.forename: Marc
authors.initials: M
authors.lastname: Damelin
authors.affiliation: AbbVie Stemcentrx LLC, 450 East Jamie Court, South San Francisco, CA 94080, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Bankovich
authors.affiliation: AbbVie Stemcentrx LLC, 450 East Jamie Court, South San Francisco, CA 94080, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Bernstein
authors.affiliation: Pfizer Worldwide Research and Development (R&D), 401 North Middletown Road, Pearl River, NY 10965, USA.
authors.forename: Justin
authors.initials: J
authors.lastname: Lucas
authors.affiliation: Pfizer Worldwide Research and Development (R&D), 401 North Middletown Road, Pearl River, NY 10965, USA.
authors.forename: Liang
authors.initials: L
authors.lastname: Chen
authors.affiliation: AbbVie Stemcentrx LLC, 450 East Jamie Court, South San Francisco, CA 94080, USA.
authors.forename: Samuel
authors.initials: S
authors.lastname: Williams
authors.affiliation: AbbVie Stemcentrx LLC, 450 East Jamie Court, South San Francisco, CA 94080, USA.
authors.forename: Albert
authors.initials: A
authors.lastname: Park
authors.affiliation: AbbVie Stemcentrx LLC, 450 East Jamie Court, South San Francisco, CA 94080, USA.
authors.forename: Jorge
authors.initials: J
authors.lastname: Aguilar
authors.affiliation: Pfizer Worldwide Research and Development (R&D), 401 North Middletown Road, Pearl River, NY 10965, USA.
authors.forename: Elana
authors.initials: E
authors.lastname: Ernstoff
authors.affiliation: Pfizer Worldwide Research and Development (R&D), 401 North Middletown Road, Pearl River, NY 10965, USA.
authors.forename: Manoj
authors.initials: M
authors.lastname: Charati
authors.affiliation: Pfizer Worldwide R&D, 445 Eastern Point Road, Groton, CT 06340, USA.
authors.forename: Russell
authors.initials: R
authors.lastname: Dushin
authors.affiliation: AbbVie Stemcentrx LLC, 450 East Jamie Court, South San Francisco, CA 94080, USA.
authors.forename: Monette
authors.initials: M
authors.lastname: Aujay
authors.affiliation: AbbVie Stemcentrx LLC, 450 East Jamie Court, South San Francisco, CA 94080, USA.
authors.forename: Christina
authors.initials: C
authors.lastname: Lee
authors.affiliation: AbbVie Stemcentrx LLC, 450 East Jamie Court, South San Francisco, CA 94080, USA.
authors.forename: Hanna
authors.initials: H
authors.lastname: Ramoth
authors.affiliation: AbbVie Stemcentrx LLC, 450 East Jamie Court, South San Francisco, CA 94080, USA.
authors.forename: Milly
authors.initials: M
authors.lastname: Milton
authors.affiliation: AbbVie Stemcentrx LLC, 450 East Jamie Court, South San Francisco, CA 94080, USA.
authors.forename: Johannes
authors.initials: J
authors.lastname: Hampl
authors.affiliation: AbbVie Stemcentrx LLC, 450 East Jamie Court, South San Francisco, CA 94080, USA.
authors.forename: Sasha
authors.initials: S
authors.lastname: Lazetic
authors.affiliation: Pfizer Worldwide Research and Development (R&D), 401 North Middletown Road, Pearl River, NY 10965, USA.
authors.forename: Virginia
authors.initials: V
authors.lastname: Pulito
authors.affiliation: Pfizer Worldwide Research and Development (R&D), 401 North Middletown Road, Pearl River, NY 10965, USA.
authors.forename: Edward
authors.initials: E
authors.lastname: Rosfjord
authors.affiliation: Pfizer Worldwide R&D, 445 Eastern Point Road, Groton, CT 06340, USA.
authors.forename: Yongliang
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Pfizer Worldwide R&D, 445 Eastern Point Road, Groton, CT 06340, USA.
authors.forename: Lindsay
authors.initials: L
authors.lastname: King
authors.affiliation: Pfizer Worldwide Research and Development (R&D), 401 North Middletown Road, Pearl River, NY 10965, USA.
authors.forename: Frank
authors.initials: F
authors.lastname: Barletta
authors.affiliation: Pfizer Worldwide R&D, 445 Eastern Point Road, Groton, CT 06340, USA.
authors.forename: Alison
authors.initials: A
authors.lastname: Betts
authors.affiliation: Pfizer Worldwide Research and Development (R&D), 401 North Middletown Road, Pearl River, NY 10965, USA.
authors.forename: Magali
authors.initials: M
authors.lastname: Guffroy
authors.affiliation: Pfizer Worldwide Research and Development (R&D), 401 North Middletown Road, Pearl River, NY 10965, USA.
authors.forename: Hadi
authors.initials: H
authors.lastname: Falahatpisheh
authors.affiliation: Pfizer Worldwide R&D, 445 Eastern Point Road, Groton, CT 06340, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: O'Donnell
authors.affiliation: AbbVie Stemcentrx LLC, 450 East Jamie Court, South San Francisco, CA 94080, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Stull
authors.affiliation: AbbVie Stemcentrx LLC, 450 East Jamie Court, South San Francisco, CA 94080, USA.
authors.forename: Marybeth
authors.initials: M
authors.lastname: Pysz
authors.affiliation: AbbVie Stemcentrx LLC, 450 East Jamie Court, South San Francisco, CA 94080, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Escarpe
authors.affiliation: AbbVie Stemcentrx LLC, 450 East Jamie Court, South San Francisco, CA 94080, USA.
authors.forename: David
authors.initials: D
authors.lastname: Liu
authors.affiliation: AbbVie Stemcentrx LLC, 450 East Jamie Court, South San Francisco, CA 94080, USA.
authors.forename: Orit
authors.initials: O
authors.lastname: Foord
authors.affiliation: Pfizer Worldwide Research and Development (R&D), 401 North Middletown Road, Pearl River, NY 10965, USA.
authors.forename: Hans Peter
authors.initials: HP
authors.lastname: Gerber
authors.affiliation: Pfizer Worldwide Research and Development (R&D), 401 North Middletown Road, Pearl River, NY 10965, USA. marc.damelin@pfizer.com puja.sapra@pfizer.com scott.dylla@abbvie.com.
authors.forename: Puja
authors.initials: P
authors.lastname: Sapra
authors.affiliation: AbbVie Stemcentrx LLC, 450 East Jamie Court, South San Francisco, CA 94080, USA. marc.damelin@pfizer.com puja.sapra@pfizer.com scott.dylla@abbvie.com.
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Dylla
mesh_terms: D062365:Aminobenzoates / Q000627:therapeutic use; D000818:Animals; D000906:Antibodies / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000276:immunology / Q000628:therapy; D015815:Cell Adhesion Molecules / Q000737:chemistry* / Q000276:immunology; D045744:Cell Line, Tumor; D002986:Clinical Trials as Topic; D005260:Female; D006801:Humans; D018796:Immunoconjugates / Q000627:therapeutic use*; D007167:Immunotherapy / Q000379:methods; D008175:Lung Neoplasms / Q000276:immunology / Q000628:therapy; D008252:Macaca fascicularis; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008870:Microtubules / Q000737:chemistry; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D009842:Oligopeptides / Q000627:therapeutic use; D010051:Ovarian Neoplasms / Q000276:immunology / Q000628:therapy; D020794:Receptor Protein-Tyrosine Kinases / Q000737:chemistry* / Q000276:immunology; D064726:Triple Negative Breast Neoplasms / Q000276:immunology / Q000628:therapy; D023041:Xenograft Model Antitumor Assays
chemical_list: D062365:Aminobenzoates; D000906:Antibodies; D000970:Antineoplastic Agents; D015815:Cell Adhesion Molecules; D018796:Immunoconjugates; D009842:Oligopeptides; C543533:auristatin; C096905:PTK7 protein, human; D020794:Receptor Protein-Tyrosine Kinases