The small molecule antibody mimic SH7139 targets a family of HLA-DRs expressed by B-cell lymphomas and other solid cancers.
The small molecule antibody mimic SH7139 targets a family of HLA-DRs expressed by B-cell lymphomas and other solid cancers.
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小分子抗体模拟物 SH7139 靶向 B 细胞淋巴瘤和其他实体癌表达的 HLA-DR 家族。
DOI：
10.1080/1061186x.2020.1787418
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发表时间：
2020
影响因子：
4.5
通讯作者：
Rebhun,RobertB
中科院分区：
文献类型：
--
作者：
Balhorn,Rod;Balhorn,MoniqueCosman;Balakrishnan,Karuppiah;Rebhun,RobertB
选择性高亲和力配体（SHAL）属于一类新型的小分子癌症治疗剂，其作为靶向前药发挥作用。SH 7139是最先进的SHAL药物，旨在结合位于HLA-DR 10上的独特β亚基结构表位，已表现出卓越的临床前疗效和安全性。SH 7139和SH 7129（开发用于诊断的药物的生物素衍生物）的比较显示，生物素标签的掺入不会改变SHAL靶向或杀死表达HLA-DR 10的Raji细胞的能力。在免疫组织化学类型测定中使用SH 7129对从表达特异性HLA-DRB 1等位基因的个体获得的外周血单核细胞（PBMC）进行染色，也揭示了除了HLA-DR 10之外，该药物还靶向其他七种更常见表达的HLA-DR。SHAL的识别配体与许多HLA-DR结构的计算对接部分地解释了为什么SH 7129和SH 7139的靶向结构域与一些HLA-DR结合，而不与其他结合。结果还证实了SH 7129的选择性，并表明它可能被证明是有用的，作为预筛选活检样本的伴随诊断，以确定那些肿瘤应该响应SH 7139治疗的患者。
Selective high-affinity ligands (SHALs) belong to a novel class of small-molecule cancer therapeutics that function as targeted prodrugs. SH7139, the most advanced of the SHAL drugs designed to bind to a unique β-subunit structural epitope located on HLA-DR10, has exhibited exceptional preclinical efficacy and safety profiles. A comparison of SH7139 and SH7129, a biotin derivative of the drug developed for use as a diagnostic, showed the incorporation of a biotin tag did not alter the SHALs ability to target or kill HLA-DR10 expressing Raji cells. The use of SH7129 in an immuno-histochemical type assay to stain peripheral blood mononuclear cells (PBMCs) obtained from individuals expressing specific HLA-DRB1 alleles has also revealed that in addition to HLA-DR10, seven other more commonly expressed HLA-DRs are targeted by the drug. Computational dockings of the SHAL’s recognition ligands to a number of HLA-DR structures explain, in part, why the targeting domains of SH7129 and SH7139 bind to some HLA-DRs but not others. The results also substantiate the selectivity of SH7129 and suggest it may prove useful as a companion diagnostic for pre-screening biopsy samples to identify those patients whose tumours should respond to SH7139 therapy.