title: A CXCR4-targeted site-specific antibody-drug conjugate.
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 pM). 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.
authors.affiliation: Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 N. Torrey Pines Rd, La Jolla, CA 92037 (USA).
authors.forename: Sumith A
authors.initials: SA
authors.lastname: Kularatne
authors.forename: Vishal
authors.initials: V
authors.lastname: Deshmukh
authors.forename: Jennifer
authors.initials: J
authors.lastname: Ma
authors.forename: Virginie
authors.initials: V
authors.lastname: Tardif
authors.forename: Reyna K V
authors.initials: RK
authors.lastname: Lim
authors.forename: Holly M
authors.initials: HM
authors.lastname: Pugh
authors.forename: Ying
authors.initials: Y
authors.lastname: Sun
authors.forename: Anthony
authors.initials: A
authors.lastname: Manibusan
authors.forename: Aaron J
authors.initials: AJ
authors.lastname: Sellers
authors.forename: Richard S
authors.initials: RS
authors.lastname: Barnett
authors.forename: Shailaja
authors.initials: S
authors.lastname: Srinagesh
authors.forename: Jane S
authors.initials: JS
authors.lastname: Forsyth
authors.forename: Wolf
authors.initials: W
authors.lastname: Hassenpflug
authors.forename: Feng
authors.initials: F
authors.lastname: Tian
authors.forename: Tsotne
authors.initials: T
authors.lastname: Javahishvili
authors.forename: Brunhilde
authors.initials: B
authors.lastname: Felding-Habermann
authors.forename: Brian R
authors.initials: BR
authors.lastname: Lawson
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Kazane
authors.forename: Peter G
authors.initials: PG
authors.lastname: Schultz
mesh_terms: D000911:Antibodies, Monoclonal / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000737:chemistry*; D045744:Cell Line, Tumor; D006801:Humans; D018796:Immunoconjugates / Q000737:chemistry*; D007167:Immunotherapy / Q000379:methods*; D019718:Receptors, CXCR4 / Q000737:chemistry*
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; C527276:CXCR4 protein, human; D018796:Immunoconjugates; D019718:Receptors, CXCR4
keywords: antibody engineering; antibody-drug conjugates; cancer; immunotherapy; unnatural amino acids