The Interplay of Antigen Affinity, Internalization, and Pharmacokinetics on CD44-Positive Tumor Targeting of Monoclonal Antibodies
The Interplay of Antigen Affinity, Internalization, and Pharmacokinetics on CD44-Positive Tumor Targeting of Monoclonal Antibodies
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DOI：
10.1021/acs.molpharmaceut.6b00063
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发表时间：
2016-06-01
影响因子：
4.9
通讯作者：
Mumper, Russell J.
中科院分区：
文献类型：
--
作者：
Glatt, Dylan M.;Vera, Denis R. Beckford;Mumper, Russell J.
单克隆抗体（mAb）提供了作为用于癌症治疗的有效肿瘤靶向和药物递送剂的前景。然而，靶向相同肿瘤相关抗原（TAA）的mAb的比较生物学和临床特征通常差异很大。本研究使用一组对癌症相关细胞表面受体和癌症干细胞标志物CD44具有特异性的mAb克隆，检查了影响肿瘤靶向的mAb的特征。筛选CD44 mAb的细胞表面结合、抗原亲和力、内化和CD44阳性A549细胞对CD44介导的肿瘤摄取。假设高亲和力、快速内化的CD44 mAb将导致高肿瘤摄取和延长的肿瘤保留。尽管高亲和力克隆在体外快速结合并被A549细胞内化，但中等亲和力克隆在体内表现出比高亲和力克隆显著更大的肿瘤摄取和保留。全身暴露，而不是高抗原亲和力或快速内化，与CD44 mAb在A549荷瘤小鼠中的肿瘤靶向最相关。
Monoclonal antibodies (mAbs) offer promise as effective tumor targeting and drug delivery agents for cancer therapy. However, comparative biological and clinical characteristics of mAbs targeting the same tumor-associated antigen (TAA) often differ widely. This study examined the characteristics of mAbs that impact tumor targeting using a panel of mAb clones specific to the cancer-associated cell-surface receptor and cancer stem cell marker CD44. CD44 mAbs were screened for cell-surface binding, antigen affinity, internalization, and CD44-mediated tumor uptake by CD44-positive A549 cells. It was hypothesized that high-affinity, rapidly internalizing CD44 mAbs would result in high tumor uptake and prolonged tumor retention. Although high-affinity clones rapidly bound and were internalized by A549 cells in vitro, an intermediate-affinity clone demonstrated significantly greater tumor uptake and retention than high-affinity clones in vivo. Systemic exposure, rather than high antigen affinity or rapid internalization, best associated with tumor targeting of CD44 mAbs in A549 tumor-bearing mice.