细胞毒性
药理学
结合
体外
抗体
毒性
体内
人源化抗体
耐受性
癌症
抗体-药物偶联物
化学
癌症研究
医学
免疫学
生物
内科学
生物化学
单克隆抗体
不利影响
生物技术
数学分析
数学
作者
Thomas M. Cardillo,Serengulam V. Govindan,Robert M. Sharkey,Preeti Trisal,David M. Goldenberg
标识
DOI:10.1158/1078-0432.ccr-10-2939
摘要
Evaluate the efficacy of an SN-38-anti-Trop-2 antibody-drug conjugate (ADC) against several human solid tumor types, and to assess its tolerability in mice and monkeys, the latter with tissue cross-reactivity to hRS7 similar to humans.Two SN-38 derivatives, CL2-SN-38 and CL2A-SN-38, were conjugated to the anti-Trop-2-humanized antibody, hRS7. The immunoconjugates were characterized in vitro for stability, binding, and cytotoxicity. Efficacy was tested in five different human solid tumor-xenograft models that expressed Trop-2 antigen. Toxicity was assessed in mice and in Cynomolgus monkeys.The hRS7 conjugates of the two SN-38 derivatives were equivalent in drug substitution (∼ 6), cell binding (K(d) ∼ 1.2 nmol/L), cytotoxicity (IC(50) ∼ 2.2 nmol/L), and serum stability in vitro (t/(½) ∼ 20 hours). Exposure of cells to the ADC demonstrated signaling pathways leading to PARP cleavage, but differences versus free SN-38 in p53 and p21 upregulation were noted. Significant antitumor effects were produced by hRS7-SN-38 at nontoxic doses in mice bearing Calu-3 (P ≤ 0.05), Capan-1 (P < 0.018), BxPC-3 (P < 0.005), and COLO 205 tumors (P < 0.033) when compared to nontargeting control ADCs. Mice tolerated a dose of 2 × 12 mg/kg (SN-38 equivalents) with only short-lived elevations in ALT and AST liver enzyme levels. Cynomolgus monkeys infused with 2 × 0.96 mg/kg exhibited only transient decreases in blood counts, although, importantly, the values did not fall below normal ranges.The anti-Trop-2 hRS7-CL2A-SN-38 ADC provides significant and specific antitumor effects against a range of human solid tumor types. It is well tolerated in monkeys, with tissue Trop-2 expression similar to humans, at clinically relevant doses, and warrants clinical investigation.
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