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A CXCR4‐Targeted Site‐Specific Antibody–Drug Conjugate
Author(s) -
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,
FeldingHabermann Brunhilde,
Lawson Brian R.,
Kazane Stephanie A.,
Schultz Peter G.
Publication year - 2014
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201408103
Subject(s) - cxcr4 , conjugate , medicine , cancer research , cytotoxicity , population , cxcr4 antagonist , in vitro , cytotoxic t cell , pharmacology , chemistry , immunology , immune system , biochemistry , mathematical analysis , chemokine , mathematics , environmental health
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 (EC 50 )≈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.