Regioselective and Stoichiometrically Controlled Conjugation of Photodynamic Sensitizers to a HER2 Targeting Antibody Fragment
Regioselective and Stoichiometrically Controlled Conjugation of Photodynamic Sensitizers to a HER2 Targeting Antibody Fragment
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DOI：
10.1021/bc5000324
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发表时间：
2014-03-01
影响因子：
4.7
通讯作者：
Boyle, Ross W.
中科院分区：
文献类型：
--
作者：
Bryden, Francesca;Maruani, Antoine;Boyle, Ross W.
对合成抗体-药物缀合物作为强有力的靶向抗癌剂的兴趣迅速增加，证明了对抗体和抗体片段作为高度选择性靶向部分的能力的日益重视。这种靶向能力在光动力疗法领域中特别令人感兴趣，因为目前临床光敏剂的适用性受到其在靶组织中与健康组织相比相对较差的积累的限制。虽然卟啉-抗体偶联物的合成以前已经被证明，在这一领域的现有工作已被传统的抗体偶联方法的局限性所阻碍。这项工作描述了通过一种新的缀合方法将叠氮化物官能化的水溶性卟啉连接到曲妥珠单抗Fab片段上。该方法允许合成均质产物，而不会损失与二硫化物修饰的常规方法相关的结构稳定性。合成的缀合物的生物学评价证明了相对于对照，对HER 2阳性细胞系的优异选择性，在任一情况下均未观察到暗毒性。
The rapidly increasing interest in the synthesis of antibody-drug conjugates as powerful targeted anticancer agents demonstrates the growing appreciation of the power of antibodies and antibody fragments as highly selective targeting moieties. This targeting ability is of particular interest in the area of photodynamic therapy, as the applicability of current clinical photosensitizers is limited by their relatively poor accumulation in target tissue in comparison to healthy tissue. Although synthesis of porphyrin-antibody conjugates has been previously demonstrated, existing work in this area has been hindered by the limitations of conventional antibody conjugation methods. This work describes the attachment of azide-functionalized, water-soluble porphyrins to a tratuzumab Fab fragment via a novel conjugation methodology. This method allows for the synthesis of a homogeneous product without the loss of structural stability associated with conventional methods of disulfide modification. Biological evaluation of the synthesized conjugates demonstrates excellent selectivity for a HER2 positive cell line over the control, with no dark toxicity observed in either case.