High CD21 expression inhibits internalization of anti-CD19 antibodies and cytotoxicity of an anti-CD19-drug conjugate
High CD21 expression inhibits internalization of anti-CD19 antibodies and cytotoxicity of an anti-CD19-drug conjugate
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DOI：
10.1111/j.1365-2141.2007.06883.x
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发表时间：
2008-01-01
影响因子：
6.5
通讯作者：
Scales, Suzie J.
中科院分区：
文献类型：
--
作者：
Ingle, Gladys S.;Chan, Pamela;Scales, Suzie J.
CD 19和CD 21（CR2）是在B细胞和各种B细胞淋巴瘤（包括非霍奇金淋巴瘤）上发现的共受体。为了评价它们作为使用内化依赖性抗体-药物缀合物[如抗体-4-（N-马来酰亚胺基甲基）环己烷-1-羧酸酯，（N-2 ′-脱乙酰基-N-2 ′-（3-巯基-1-氧代丙基）-美登素）（MCC-DM 1）缀合物，其需要抗体部分的溶酶体降解以获得功效]，我们检测了一组B细胞系中CD 19和CD 21抗体的摄取。即使在表达最高CD 21的Raji细胞中，抗CD 21抗体也没有充分内化，导致抗CD 21-MCC-DM 1缀合物缺乏功效。抗-CD 19抗体摄取是可变的，并且与CD 21表达出乎意料地负相关。因此，高表达CD 21的Raji、ARH 77和原代B细胞仅非常缓慢地内化抗CD 19抗体，而CD 21阴性或低表达细胞，包括拉莫斯和Daudi，在网格蛋白包被的囊泡中快速内化这些抗体，随后进行溶酶体递送。抗CD 19-MCC-DM 1在更快的抗CD 19内化细胞系中引起更大的细胞毒性，这意味着溶酶体递送和随后的药物释放速率很重要。此外，用CD 21转染拉莫斯细胞阻碍了抗CD 19的摄取，降低了抗CD 19-MCC-DM 1的功效，表明CD 21阴性肿瘤对这种抗CD 19缀合物的反应更好。这可能具有临床意义，因为抗CD 21免疫组化显示54例弥漫性大B细胞淋巴瘤患者中仅约30%缺乏CD 21表达。
CD19 and CD21 (CR2) are co-receptors found on B-cells and various B-cell lymphomas, including non-Hodgkin lymphoma. To evaluate their suitability as targets for therapy of such lymphomas using internalization-dependent antibody-drug conjugates [such as antibody-4-(N-maleimidomethyl)cyclohexane-1-carboxylate, (N-2'-deacetyl-N-2'-(3-mercapto-1-oxopropyl)-maytansine) (MCC-DM1) conjugates, which require lysosomal degradation of the antibody moiety for efficacy], we examined uptake of antibodies to CD19 and CD21 in a panel of B-cell lines. Anti-CD21 antibodies were not sufficiently internalized even in the highest CD21-expressing Raji cells, resulting in lack of efficacy with anti-CD21-MCC-DM1 conjugates. Anti-CD19 antibody uptake was variable, and was unexpectedly negatively correlated with CD21 expression. Thus, high CD21-expressing Raji, ARH77 and primary B-cells only very slowly internalized anti-CD19 antibodies, while CD21-negative or low expressing cells, including Ramos and Daudi, rapidly internalized these antibodies in clathrin-coated vesicles followed by lysosomal delivery. Anti-CD19-MCC-DM1 caused greater cytotoxicity in the faster anti-CD19-internalizing cell lines, implying that the rate of lysosomal delivery and subsequent drug release is important. Furthermore, transfection of Ramos cells with CD21 impeded anti-CD19 uptake and decreased anti-CD19-MCC-DM1 efficacy, suggesting that CD21-negative tumours should respond better to such anti-CD19 conjugates. This may have possible clinical implications, as anti-CD21 immunohistochemistry revealed only approximately 30% of 54 diffuse large B-cell lymphoma patients lack CD21 expression.