Apelgren L D, Bailey D L, Briggs S L, Barton R L, Guttman-Carlisle D, Koppel G A, Nichols C L, Scott W L, Lindstrom T D, Baker A L
Lilly Research Laboratories, Indianapolis, Indiana 46285.
Bioconjug Chem. 1993 Mar-Apr;4(2):121-6. doi: 10.1021/bc00020a003.
Preclinical efficacy studies are presented in a human ovarian carcinoma model utilizing several novel conjugation strategies with the KS1/4 monoclonal antibody and derivatives of the vinca alkaloid desacetylvinblastine hydrazide. The chemoimmunoconjugates KS1/4-beta-alanine-methylenemalonic acid ethyl ester-4-decacetylvinblastine 23-hydrazide (KS1/4-BAMME-DAVLB-HY), KS1/4-beta-alanine-5-formylpyrrole-2-carboxylic acid-4-desacetylvinblastine 23-hydrazide (KS1/4-BAP-DAVLB-HY), and KS1/4-4-desacetylvinblastine 23-hydrazide were explored in the OVCAR-3 human ovarian carcinoma xenograft model. These conjugates, constructed with variable linker stability between the vinca alkaloid and the antibody, were studied by comparing the route of administration and the treatment schedule. Under these conditions a mean survival time from 28 to 35 days in untreated control animals was observed. Significant increases in survival (i.e. 3-9-fold over untreated control animals) were observed with all the immunoconjugates tested but with varying potency and efficacy dependent on linker strategy. Parallel therapy with equivalent doses of free DAVLB-HY or a non-antigen-binding immunoconjugate did not significantly increase the survival of the animals. These results suggest several chemoimmunoconjugate strategies for site-directed therapy of human ovarian cancer.
在人卵巢癌模型中开展了临床前疗效研究，该研究利用了几种与KS1/4单克隆抗体及长春花生物碱去乙酰长春花碱酰肼衍生物的新型偶联策略。在OVCAR-3人卵巢癌异种移植模型中探究了化学免疫偶联物KS1/4-β-丙氨酸-亚甲基丙二酸乙酯-4-去乙酰长春花碱23-酰肼（KS1/4-BAMME-DAVLB-HY）、KS1/4-β-丙氨酸-5-甲酰基吡咯-2-羧酸-4-去乙酰长春花碱23-酰肼（KS1/4-BAP-DAVLB-HY）以及KS1/4-4-去乙酰长春花碱23-酰肼。这些偶联物在长春花生物碱与抗体之间构建了具有可变连接稳定性的结构，通过比较给药途径和治疗方案对其进行了研究。在这些条件下，观察到未治疗的对照动物的平均存活时间为28至35天。在所测试的所有免疫偶联物中均观察到存活率显著提高（即比未治疗的对照动物高出3至9倍），但效力和疗效因连接策略而异。用等量的游离DAVLB-HY或非抗原结合免疫偶联物进行平行治疗并未显著提高动物的存活率。这些结果提示了几种用于人卵巢癌定点治疗的化学免疫偶联物策略。
