Adnectin–drug conjugates for Glypican-3-specific delivery of a cytotoxic payload to tumors

Daša Lipovšek; Irvith Carvajal; Alban J Allentoff; Anthony Barros; John Brailsford; Qiang Cong; Pete Cotter; Sanjeev Gangwar; Cris Hollander; Virginie Lafont; Wai Leung Lau; Wenying Li; Miguel Moreta; Steven O’Neil; Jason Pinckney; Michael J Smith; Julie Su; Christina Terragni; Michael A Wallace; Lifei Wang; Martin Wright; H Nicholas Marsh; James W Bryson

doi:10.1093/protein/gzy013

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Adnectin–drug conjugates for Glypican-3-specific delivery of a cytotoxic payload to tumors

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Adnectin–drug conjugates for Glypican-3-specific delivery of a cytotoxic payload to tumors

Daša Lipovšek, Irvith Carvajal, Alban J Allentoff, Anthony Barros, John Brailsford, Qiang Cong, Pete Cotter, Sanjeev Gangwar, Cris Hollander, Virginie Lafont, …

Protein engineering, design and selection, Vol.31(5), pp.159-171

01/05/2018

DOI: https://doi.org/10.1093/protein/gzy013

PMID: 30247737

Résumé

Original

Tumor-specific delivery of cytotoxic agents remains a challenge in cancer therapy. Antibody–drug conjugates (ADC) deliver their payloads to tumor cells that overexpress specific tumor-associated antigens—but the multi-day half-life of ADC leads to high exposure even of normal, antigen-free, tissues and thus contributes to dose-limiting toxicity. Here, we present Adnectin–drug conjugates, an alternative platform for tumor-specific delivery of cytotoxic payloads. Due to their small size (10 kDa), renal filtration eliminates Adnectins from the bloodstream within minutes to hours, ensuring low exposure to normal tissues. We used an engineered cysteine to conjugate an Adnectin that binds Glypican-3, a membrane protein overexpressed in hepatocellular carcinoma, to a cytotoxic derivative of tubulysin, with the drug-to-Adnectin ratio of 1. We demonstrate specific, nanomolar binding of this Adnectin–drug conjugate to human and murine Glypican-3; its high thermostability; its localization to target-expressing tumor cells in vitro and in vivo, its fast clearance from normal tissues and its efficacy against Glypican-3-positive mouse xenograft models.

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Détails

Titre: Adnectin–drug conjugates for Glypican-3-specific delivery of a cytotoxic payload to tumors
Créateurs - sans rôle: Daša Lipovšek - Molecular Discovery Technologies, Bristol-Myers Squibb, Waltham, MA, USA Radiochemistry, Bristol-Myers Squibb, Lawrenceville, NJ, USA Preclinical Candidate Optimization, Bristol-Myers Squibb, Lawrenceville, NJ, USA Discovery Chemistry Oncology, Bristol-Myers Squibb, Redwood City, CA, USA Molecular Discovery Technologies, Bristol-Myers Squibb, Lawrenceville, NJ, USA Chemical and Synthetic Development, Bristol-Myers Squibb, New Brunswick, NJ, USA
Irvith Carvajal - Molecular Discovery Technologies, Bristol-Myers Squibb, Waltham, MA, USA Radiochemistry, Bristol-Myers Squibb, Lawrenceville, NJ, USA Preclinical Candidate Optimization, Bristol-Myers Squibb, Lawrenceville, NJ, USA Discovery Chemistry Oncology, Bristol-Myers Squibb, Redwood City, CA, USA Molecular Discovery Technologies, Bristol-Myers Squibb, Lawrenceville, NJ, USA Chemical and Synthetic Development, Bristol-Myers Squibb, New Brunswick, NJ, USA
Alban J Allentoff - Molecular Discovery Technologies, Bristol-Myers Squibb, Waltham, MA, USA Radiochemistry, Bristol-Myers Squibb, Lawrenceville, NJ, USA Preclinical Candidate Optimization, Bristol-Myers Squibb, Lawrenceville, NJ, USA Discovery Chemistry Oncology, Bristol-Myers Squibb, Redwood City, CA, USA Molecular Discovery Technologies, Bristol-Myers Squibb, Lawrenceville, NJ, USA Chemical and Synthetic Development, Bristol-Myers Squibb, New Brunswick, NJ, USA
Anthony Barros - Molecular Discovery Technologies, Bristol-Myers Squibb, Waltham, MA, USA Radiochemistry, Bristol-Myers Squibb, Lawrenceville, NJ, USA Preclinical Candidate Optimization, Bristol-Myers Squibb, Lawrenceville, NJ, USA Discovery Chemistry Oncology, Bristol-Myers Squibb, Redwood City, CA, USA Molecular Discovery Technologies, Bristol-Myers Squibb, Lawrenceville, NJ, USA Chemical and Synthetic Development, Bristol-Myers Squibb, New Brunswick, NJ, USA
John Brailsford - Molecular Discovery Technologies, Bristol-Myers Squibb, Waltham, MA, USA Radiochemistry, Bristol-Myers Squibb, Lawrenceville, NJ, USA Preclinical Candidate Optimization, Bristol-Myers Squibb, Lawrenceville, NJ, USA Discovery Chemistry Oncology, Bristol-Myers Squibb, Redwood City, CA, USA Molecular Discovery Technologies, Bristol-Myers Squibb, Lawrenceville, NJ, USA Chemical and Synthetic Development, Bristol-Myers Squibb, New Brunswick, NJ, USA
Qiang Cong - Molecular Discovery Technologies, Bristol-Myers Squibb, Waltham, MA, USA Radiochemistry, Bristol-Myers Squibb, Lawrenceville, NJ, USA Preclinical Candidate Optimization, Bristol-Myers Squibb, Lawrenceville, NJ, USA Discovery Chemistry Oncology, Bristol-Myers Squibb, Redwood City, CA, USA Molecular Discovery Technologies, Bristol-Myers Squibb, Lawrenceville, NJ, USA Chemical and Synthetic Development, Bristol-Myers Squibb, New Brunswick, NJ, USA
Pete Cotter - Molecular Discovery Technologies, Bristol-Myers Squibb, Waltham, MA, USA Radiochemistry, Bristol-Myers Squibb, Lawrenceville, NJ, USA Preclinical Candidate Optimization, Bristol-Myers Squibb, Lawrenceville, NJ, USA Discovery Chemistry Oncology, Bristol-Myers Squibb, Redwood City, CA, USA Molecular Discovery Technologies, Bristol-Myers Squibb, Lawrenceville, NJ, USA Chemical and Synthetic Development, Bristol-Myers Squibb, New Brunswick, NJ, USA
Sanjeev Gangwar - Molecular Discovery Technologies, Bristol-Myers Squibb, Waltham, MA, USA Radiochemistry, Bristol-Myers Squibb, Lawrenceville, NJ, USA Preclinical Candidate Optimization, Bristol-Myers Squibb, Lawrenceville, NJ, USA Discovery Chemistry Oncology, Bristol-Myers Squibb, Redwood City, CA, USA Molecular Discovery Technologies, Bristol-Myers Squibb, Lawrenceville, NJ, USA Chemical and Synthetic Development, Bristol-Myers Squibb, New Brunswick, NJ, USA
Cris Hollander - Molecular Discovery Technologies, Bristol-Myers Squibb, Waltham, MA, USA Radiochemistry, Bristol-Myers Squibb, Lawrenceville, NJ, USA Preclinical Candidate Optimization, Bristol-Myers Squibb, Lawrenceville, NJ, USA Discovery Chemistry Oncology, Bristol-Myers Squibb, Redwood City, CA, USA Molecular Discovery Technologies, Bristol-Myers Squibb, Lawrenceville, NJ, USA Chemical and Synthetic Development, Bristol-Myers Squibb, New Brunswick, NJ, USA
Virginie Lafont - Molecular Discovery Technologies, Bristol-Myers Squibb, Waltham, MA, USA Radiochemistry, Bristol-Myers Squibb, Lawrenceville, NJ, USA Preclinical Candidate Optimization, Bristol-Myers Squibb, Lawrenceville, NJ, USA Discovery Chemistry Oncology, Bristol-Myers Squibb, Redwood City, CA, USA Molecular Discovery Technologies, Bristol-Myers Squibb, Lawrenceville, NJ, USA Chemical and Synthetic Development, Bristol-Myers Squibb, New Brunswick, NJ, USA
Wai Leung Lau - Molecular Discovery Technologies, Bristol-Myers Squibb, Waltham, MA, USA Radiochemistry, Bristol-Myers Squibb, Lawrenceville, NJ, USA Preclinical Candidate Optimization, Bristol-Myers Squibb, Lawrenceville, NJ, USA Discovery Chemistry Oncology, Bristol-Myers Squibb, Redwood City, CA, USA Molecular Discovery Technologies, Bristol-Myers Squibb, Lawrenceville, NJ, USA Chemical and Synthetic Development, Bristol-Myers Squibb, New Brunswick, NJ, USA
Wenying Li - Molecular Discovery Technologies, Bristol-Myers Squibb, Waltham, MA, USA Radiochemistry, Bristol-Myers Squibb, Lawrenceville, NJ, USA Preclinical Candidate Optimization, Bristol-Myers Squibb, Lawrenceville, NJ, USA Discovery Chemistry Oncology, Bristol-Myers Squibb, Redwood City, CA, USA Molecular Discovery Technologies, Bristol-Myers Squibb, Lawrenceville, NJ, USA Chemical and Synthetic Development, Bristol-Myers Squibb, New Brunswick, NJ, USA
Miguel Moreta - Molecular Discovery Technologies, Bristol-Myers Squibb, Waltham, MA, USA Radiochemistry, Bristol-Myers Squibb, Lawrenceville, NJ, USA Preclinical Candidate Optimization, Bristol-Myers Squibb, Lawrenceville, NJ, USA Discovery Chemistry Oncology, Bristol-Myers Squibb, Redwood City, CA, USA Molecular Discovery Technologies, Bristol-Myers Squibb, Lawrenceville, NJ, USA Chemical and Synthetic Development, Bristol-Myers Squibb, New Brunswick, NJ, USA
Steven O’Neil - Molecular Discovery Technologies, Bristol-Myers Squibb, Waltham, MA, USA Radiochemistry, Bristol-Myers Squibb, Lawrenceville, NJ, USA Preclinical Candidate Optimization, Bristol-Myers Squibb, Lawrenceville, NJ, USA Discovery Chemistry Oncology, Bristol-Myers Squibb, Redwood City, CA, USA Molecular Discovery Technologies, Bristol-Myers Squibb, Lawrenceville, NJ, USA Chemical and Synthetic Development, Bristol-Myers Squibb, New Brunswick, NJ, USA
Jason Pinckney - Molecular Discovery Technologies, Bristol-Myers Squibb, Waltham, MA, USA Radiochemistry, Bristol-Myers Squibb, Lawrenceville, NJ, USA Preclinical Candidate Optimization, Bristol-Myers Squibb, Lawrenceville, NJ, USA Discovery Chemistry Oncology, Bristol-Myers Squibb, Redwood City, CA, USA Molecular Discovery Technologies, Bristol-Myers Squibb, Lawrenceville, NJ, USA Chemical and Synthetic Development, Bristol-Myers Squibb, New Brunswick, NJ, USA
Michael J Smith - Molecular Discovery Technologies, Bristol-Myers Squibb, Waltham, MA, USA Radiochemistry, Bristol-Myers Squibb, Lawrenceville, NJ, USA Preclinical Candidate Optimization, Bristol-Myers Squibb, Lawrenceville, NJ, USA Discovery Chemistry Oncology, Bristol-Myers Squibb, Redwood City, CA, USA Molecular Discovery Technologies, Bristol-Myers Squibb, Lawrenceville, NJ, USA Chemical and Synthetic Development, Bristol-Myers Squibb, New Brunswick, NJ, USA
Julie Su - Molecular Discovery Technologies, Bristol-Myers Squibb, Waltham, MA, USA Radiochemistry, Bristol-Myers Squibb, Lawrenceville, NJ, USA Preclinical Candidate Optimization, Bristol-Myers Squibb, Lawrenceville, NJ, USA Discovery Chemistry Oncology, Bristol-Myers Squibb, Redwood City, CA, USA Molecular Discovery Technologies, Bristol-Myers Squibb, Lawrenceville, NJ, USA Chemical and Synthetic Development, Bristol-Myers Squibb, New Brunswick, NJ, USA
Christina Terragni - Molecular Discovery Technologies, Bristol-Myers Squibb, Waltham, MA, USA Radiochemistry, Bristol-Myers Squibb, Lawrenceville, NJ, USA Preclinical Candidate Optimization, Bristol-Myers Squibb, Lawrenceville, NJ, USA Discovery Chemistry Oncology, Bristol-Myers Squibb, Redwood City, CA, USA Molecular Discovery Technologies, Bristol-Myers Squibb, Lawrenceville, NJ, USA Chemical and Synthetic Development, Bristol-Myers Squibb, New Brunswick, NJ, USA
Michael A Wallace - Molecular Discovery Technologies, Bristol-Myers Squibb, Waltham, MA, USA Radiochemistry, Bristol-Myers Squibb, Lawrenceville, NJ, USA Preclinical Candidate Optimization, Bristol-Myers Squibb, Lawrenceville, NJ, USA Discovery Chemistry Oncology, Bristol-Myers Squibb, Redwood City, CA, USA Molecular Discovery Technologies, Bristol-Myers Squibb, Lawrenceville, NJ, USA Chemical and Synthetic Development, Bristol-Myers Squibb, New Brunswick, NJ, USA
Lifei Wang - Molecular Discovery Technologies, Bristol-Myers Squibb, Waltham, MA, USA Radiochemistry, Bristol-Myers Squibb, Lawrenceville, NJ, USA Preclinical Candidate Optimization, Bristol-Myers Squibb, Lawrenceville, NJ, USA Discovery Chemistry Oncology, Bristol-Myers Squibb, Redwood City, CA, USA Molecular Discovery Technologies, Bristol-Myers Squibb, Lawrenceville, NJ, USA Chemical and Synthetic Development, Bristol-Myers Squibb, New Brunswick, NJ, USA
Martin Wright - Molecular Discovery Technologies, Bristol-Myers Squibb, Waltham, MA, USA Radiochemistry, Bristol-Myers Squibb, Lawrenceville, NJ, USA Preclinical Candidate Optimization, Bristol-Myers Squibb, Lawrenceville, NJ, USA Discovery Chemistry Oncology, Bristol-Myers Squibb, Redwood City, CA, USA Molecular Discovery Technologies, Bristol-Myers Squibb, Lawrenceville, NJ, USA Chemical and Synthetic Development, Bristol-Myers Squibb, New Brunswick, NJ, USA
H Nicholas Marsh - Molecular Discovery Technologies, Bristol-Myers Squibb, Waltham, MA, USA Radiochemistry, Bristol-Myers Squibb, Lawrenceville, NJ, USA Preclinical Candidate Optimization, Bristol-Myers Squibb, Lawrenceville, NJ, USA Discovery Chemistry Oncology, Bristol-Myers Squibb, Redwood City, CA, USA Molecular Discovery Technologies, Bristol-Myers Squibb, Lawrenceville, NJ, USA Chemical and Synthetic Development, Bristol-Myers Squibb, New Brunswick, NJ, USA
James W Bryson - Molecular Discovery Technologies, Bristol-Myers Squibb, Waltham, MA, USA Radiochemistry, Bristol-Myers Squibb, Lawrenceville, NJ, USA Preclinical Candidate Optimization, Bristol-Myers Squibb, Lawrenceville, NJ, USA Discovery Chemistry Oncology, Bristol-Myers Squibb, Redwood City, CA, USA Molecular Discovery Technologies, Bristol-Myers Squibb, Lawrenceville, NJ, USA Chemical and Synthetic Development, Bristol-Myers Squibb, New Brunswick, NJ, USA
Détails de publication: Protein engineering, design and selection, Vol.31(5), pp.159-171
Éditeur: Oxford University Press
Nombre de pages: 13
Note de subvention: ;
Identifiants: 99162924209311
Unité académique: Institut de Recherche en Cancérologie de Montpellier - IRCM
Langue: English
Type de ressource: Journal article