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- Title
A CXCR4-Targeted Site-Specific Antibody-Drug Conjugate.
- 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.
- Abstract
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 p-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 M). 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.
- Subjects
CXCR4 receptors; ANTIBODY-drug conjugates; CANCER cells; AMINO acids; IMMUNOGLOBULIN G; ANTINEOPLASTIC agents
- Publication
Angewandte Chemie International Edition, 2014, Vol 53, Issue 44, p11863
- ISSN
1433-7851
- Publication type
Article
- DOI
10.1002/anie.201408103