Hamann Philip R, Hinman Lois M, Beyer Carl F, Greenberger Lee M, Lin Clara, Lindh Delores, Menendez Ana T, Wallace Rosalyn, Durr Frederick E, Upeslacis Janis
Wyeth Research, 401 N. Middletown Road, Pearl River, New York 10965, USA.
Bioconjug Chem. 2005 Mar-Apr;16(2):346-53. doi: 10.1021/bc049795f.
The anti-MUC1 antibody, CTM01, has been chosen to target the potently cytotoxic calicheamicin antitumor antibiotics to solid tumors of epithelial origin that express this antigen. Earlier calicheamicin conjugates relied on the attachment of a hydrazide derivative to the oxidized carbohydrates that occur naturally on antibodies. This produced a "carbohydrate conjugate" capable of releasing active drug by hydrolysis in the lysosomes where the pH is low. Conjugates have now been made that are formed by reacting a calicheamicin derivative containing an activated ester with the lysines of antibodies. This gives an "amide conjugate" that is stable to hydrolysis, leaving the disulfide that is present in all calicheamicin conjugates as the only likely site of drug release from the conjugate. As previously shown for the carbohydrate conjugate, this amide conjugate of CTM01 produces complete regressions of xenograft tumors at doses of 300 microg/kg (calicheamicin equivalents) given three times. This indicates that hydrolytic drug release is not necessary for potent, selective cytotoxicity for calicheamicin conjugates of CTM01. Although the unconjugated calicheamicins are in general less active in cells expressing the multidrug resistance phenotype, both in vitro and in vivo results of studies reported here suggest that the efficacy of the calicheamicins toward such tumors is unexpectedly enhanced by antibody conjugation, especially for the "amide conjugate". These hydrolytically stable conjugates are also active toward cisplatin-resistant ovarian carcinoma cells as well. Such studies indicate that the calicheamicin amide conjugate of CTM01 may have potential for the treatment of MUC1-positive solid tumors, including some types of resistant tumors.
抗MUC1抗体CTM01已被选定，用于将具有强细胞毒性的刺孢霉素抗肿瘤抗生素靶向至表达该抗原的上皮源性实体瘤。早期的刺孢霉素缀合物依赖于酰肼衍生物与抗体上天然存在的氧化碳水化合物相连。这产生了一种“碳水化合物缀合物”，能够在pH值较低的溶酶体中通过水解释放活性药物。现在已经制备出了通过使含活化酯的刺孢霉素衍生物与抗体的赖氨酸反应而形成的缀合物。这得到了一种对水解稳定的“酰胺缀合物”，使得所有刺孢霉素缀合物中存在的二硫键成为缀合物中药物释放的唯一可能位点。如先前针对碳水化合物缀合物所显示的那样，CTM01的这种酰胺缀合物在以300微克/千克（刺孢霉素当量）的剂量给药三次时，可使异种移植肿瘤完全消退。这表明水解药物释放对于CTM01的刺孢霉素缀合物产生强效、选择性细胞毒性并非必要。尽管未缀合的刺孢霉素在表达多药耐药表型的细胞中通常活性较低，但此处报道的体外和体内研究结果均表明，抗体缀合意外地增强了刺孢霉素对此类肿瘤的疗效，尤其是对于“酰胺缀合物”。这些水解稳定的缀合物对顺铂耐药的卵巢癌细胞也有活性。此类研究表明，CTM01的刺孢霉素酰胺缀合物可能具有治疗MUC1阳性实体瘤的潜力，包括某些类型的耐药肿瘤。
