Glatt Dylan M, Beckford Vera Denis R, Parrott Matthew C, Luft J Christopher, Benhabbour S Rahima, Mumper Russell J
Division of Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill , Marsico Hall, 125 Mason Farm Road, Chapel Hill, North Carolina 27599, United States.
Department of Radiology, Biomedical Research Imaging Center, University of North Carolina at Chapel Hill , Marsico Hall, 125 Mason Farm Road, Chapel Hill, North Carolina 27599, United States.
Mol Pharm. 2016 Jun 6;13(6):1894-903. doi: 10.1021/acs.molpharmaceut.6b00063. Epub 2016 Apr 28.
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.
单克隆抗体（mAb）有望成为癌症治疗中有效的肿瘤靶向和药物递送剂。然而，靶向同一肿瘤相关抗原（TAA）的单克隆抗体的生物学和临床特征往往差异很大。本研究使用一组针对癌症相关细胞表面受体和癌症干细胞标志物CD44的单克隆抗体克隆，研究了影响肿瘤靶向的单克隆抗体的特征。筛选CD44单克隆抗体与细胞表面的结合、抗原亲和力、内化以及CD44阳性A549细胞对CD44介导的肿瘤摄取情况。研究假设高亲和力、快速内化的CD44单克隆抗体将导致高肿瘤摄取和延长肿瘤滞留时间。虽然高亲和力克隆在体外能快速与A549细胞结合并被内化，但在体内，一种中等亲和力克隆的肿瘤摄取和滞留明显高于高亲和力克隆。在携带A549肿瘤的小鼠中，全身暴露而非高抗原亲和力或快速内化，与CD44单克隆抗体的肿瘤靶向性最佳相关。
