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
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 N. Torrey Pines Rd, La Jolla, CA 92037 (USA).
Angew Chem Int Ed Engl. 2014 Oct 27;53(44):11863-7. doi: 10.1002/anie.201408103. Epub 2014 Sep 11.
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.
合成了一种化学定义的抗CXCR4-奥瑞他汀抗体药物偶联物（ADC），其可选择性消除过表达CXCR4受体的肿瘤细胞。将非天然氨基酸对乙酰苯丙氨酸（pAcF）位点特异性地掺入抗CXCR4免疫球蛋白G（IgG）中，并通过稳定的、不可裂解的肟键与奥瑞他汀偶联，以得到化学性质均一的ADC。全长抗CXCR4 ADC在体外对CXCR4(+)癌细胞具有选择性细胞毒性（半数最大效应浓度（EC50）≈80 - 100 pM）。此外，在小鼠肺种植瘤模型中，抗CXCR4 ADC消除了人骨肉瘤细胞的肺部病变。未观察到明显的明显毒性，但骨髓来源的CXCR4(+)细胞群体略有减少。由于CXCR4在大多数转移性癌症中高表达，CXCR4-奥瑞他汀ADC可能对治疗多种转移性恶性肿瘤有用。
