A CXCR4‐Targeted Site‐Specific Antibody–Drug Conjugate1. (11th September 2014)

• Record Type: Journal Article
• Authors: Kularatne, Sumith A.; Deshmukh, Vishal; Ma, Jennifer; Tardif, Virginie; Lim, Reyna K. V.; Pugh, Holly M.; Sun, Ying; Manibusan, Anthony; Sellers, Aaron J.; Barnett, Richard S.; Srinagesh, Shailaja; Forsyth, Jane S.; Hassenpflug, Wolf; Tian, Feng; Javahishvili, Tsotne; Felding‐Habermann, Brunhilde; Lawson, Brian R.; Kazane, Stephanie A.; Schultz, Peter G.
• Is Part Of: Angewandte Chemie. Volume 126:Number 44(2014)
• Page Start: 12057
• Page End: 12061
• Publication Date: 2014-09-11
• Subjects: Chemistry -- Periodicals; 540
• DOI: 10.1002/ange.201408103
• Languages: English
• ISSNs: 0044-8249

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <p>A chemically defined anti‐CXCR4–auristatin antibody–drug conjugate (ADC) was synthesized that selectively eliminates tumor cells overexpressing the CXCR4 receptor. The unnatural amino acid <italic>p</italic>‐acetylphenylalanine (pAcF) was site‐specifically incorporated into an anti‐CXCR4 immunoglobulin G (IgG) and conjugated to an auristatin through a stable, non‐cleavable oxime linkage to afford a chemically homogeneous ADC. The full‐length anti‐CXCR4 ADC was selectively cytotoxic to CXCR4⁺ cancer cells in vitro (half maximal effective concentration (EC₅₀)≈80–100 p<sc>M</sc>). Moreover, the anti‐CXCR4 ADC eliminated pulmonary lesions from human osteosarcoma cells in a lung‐seeding tumor model in mice. No significant overt toxicity was observed but there was a modest decrease in the bone‐marrow‐derived CXCR4⁺ cell population. Because CXCR4 is highly expressed in a majority of metastatic cancers, a CXCR4–auristatin ADC may be useful for the treatment of a variety of metastatic malignancies.</p> </abstract>