Impact of Drug Conjugation on Pharmacokinetics and Tissue Distribution of Anti-STEAP1 Antibody-Drug Conjugates in Rats
Impact of Drug Conjugation on Pharmacokinetics and Tissue Distribution of Anti-STEAP1 Antibody-Drug Conjugates in Rats
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DOI：
10.1021/bc200212a
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发表时间：
2011-10-01
影响因子：
4.7
通讯作者：
Lin, Kedan
中科院分区：
文献类型：
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作者：
Boswell, C. Andrew;Mundo, Eduardo E.;Lin, Kedan
抗体药物结合物(ADC)的设计目的是将针对肿瘤抗原的抗体的高度特异性与化疗药物的细胞毒力结合起来。除了连接物的一般化学稳定性外，彻底了解ADC组成和生物处置之间的关系是必要的，以确保治疗窗口不会受到改变的药代动力学(PK)、组织分布和/或潜在的器官毒性的影响。前列腺I型六跨膜上皮抗原(STEAM)正被视为肿瘤抗原靶点。为了评估ADC成分在PK中的作用，我们评估了单剂量人源化抗STEAP1 IgG1抗体、硫代抗STEAP1(ThioMab)变异体和两种相应的分别通过链间二硫代半胱氨酸残基(ADC)和工程半胱氨酸(TDC)修饰的硫醚连接的单甲基尿毒素E(MMAE)药物结合物在大鼠血浆和组织PK谱中的作用。酶联免疫吸附试验(EL ISA)检测总抗体的血浆PK显示，ADC的清除速度比亲本抗体快45%，但TDC和未结合的亲本ThioMab的清除率没有明显差异。两种未结合抗体的总抗体清除量相似，表明半胱氨酸突变对PK的影响很小。MMAE偶联抗体的酶联免疫吸附试验表明，ADC的清除速度比TDC快，但总抗体ELISA法对两种药物的清除能力相当。此外，与相对药物负荷一致，就血浆游离MMAE水平而言，ADC比TDC具有更大的药物去结合力。抗体结合对组织分布有明显的影响，尽管影响很小，总体趋势是肝脏摄取增加，其他高度血管化的器官水平降低。ADC和TDC在注射后5天的肝脏摄取量分别是未修饰抗体的2倍和1.3倍。综上所述，这些结果表明，抗STEAP1-MMAE结合物的整体结构修饰程度对PK和组织分布都有相应程度的影响。
Antibody drug conjugates (ADCs) are designed to combine the exquisite specificity of antibodies to target tumor antigens with the cytotoxic potency of chemotherapeutic drugs. In addition to the general chemical stability of the linker, a thorough understanding of the relationship between ADC composition and biological disposition is necessary to ensure that the therapeutic window is not compromised by altered pharmacokinetics (PK), tissue distribution, and/or potential organ toxicity. The six-transmembrane epithelial antigen of prostate I (STEAM) is being pursued as a tumor antigen target. To assess the role of ADC composition in PK, we evaluated plasma and tissue PK profiles in rats, following a single dose, of a humanized anti-STEAP1 IgG1 antibody, a thio-anti-STEAP1 (ThioMab) variant, and two corresponding thioether-linked monomethylauristatin E (MMAE) drug conjugates modified through interchain disulfide cysteine residues (ADC) and engineered cysteines (TDC), respectively. Plasma PK of total antibody measured by enzyme-linked immunosorbent assay (ELISA) revealed similar to 45% faster clearance for the ADC relative to the parent antibody, but no apparent difference in clearance between the TDC and unconjugated parent ThioMab. Total antibody clearances of the two unconjugated antibodies were similar, suggesting minimal effects on PK from cysteine mutation. An ELISA specific for MMAE-conjugated antibody indicated that the ADC cleared more rapidly than the TDC, but total antibody ELISA showed comparable clearance for the two drug conjugates. Furthermore, consistent with relative drug load, the ADC had a greater magnitude of drug deconjugation than the TDC in terms of free plasma MMAE levels. Antibody conjugation had a noticeable, albeit minor, impact on tissue distribution with a general trend toward increased hepatic uptake and reduced levels in other highly vascularized organs. Liver uptakes of ADC and TDC at 5 days postinjection were 2-fold and 1.3-fold higher, respectively, relative to the unmodified antibodies. Taken together, these results indicate that the degree of overall structural modification in anti-STEAP1-MMAE conjugates has a corresponding level of impact on both PK and tissue distribution.