Structurally Defined αMHC-II Nanobody-Drug Conjugates: A Therapeutic and Imaging System for B-Cell Lymphoma.
Structurally Defined αMHC-II Nanobody-Drug Conjugates: A Therapeutic and Imaging System for B-Cell Lymphoma.
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DOI：
10.1002/anie.201509432
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发表时间：
2016-02-12
期刊：
影响因子：
--
通讯作者：
Ploegh HL
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文献类型：
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作者：
Fang T;Duarte JN;Ling J;Li Z;Guzman JS;Ploegh HL
结构明确的抗体-药物偶联物（adc）在癌症治疗中具有很大的前景，但进一步的进展受到全尺寸抗体复杂结构的限制。骆驼衍生的单域抗体片段（VHHs或纳米体）通过在成像和治疗之间穿梭提供快速的靶标筛选/验证，为这一挑战提供了可能的解决方案。在这里，我们使用了一种针对小鼠MHC-II的纳米体（VHH7），并使sortasready用于引入低聚甘氨酸修饰的细胞毒性有效载体或近红外荧光团。VHH7偶联物在内化方面优于市售单克隆抗体，对A20小鼠b细胞淋巴瘤表现出高特异性和细胞毒性。使用vhh7 -荧光基团偶联物的非侵入性近红外成像显示，在局部和转移性淋巴瘤模型上都能快速靶向肿瘤。随后使用纳米-药物偶联物有效地控制了肿瘤的生长和转移，没有明显的全身毒性。
Antibody-drug conjugates (ADCs) of defined structure hold great promise for cancer therapies, but further advances are constrained by the complex structures of full-sized antibodies. Camelid-derived single domain antibody fragments (VHHs or nanobodies) offer possible solutions to this challenge by providing expedited target screening/validation through shuttling between imaging and therapy. Here, we used a nanobody (VHH7) specific for murine MHC-II and rendered sortase-ready for introduction of oligoglycine-modified cytotoxic payloads or NIR fluorophores. The VHH7 conjugates outcompeted commercial mAbs for internalization and exhibited high specificity and cytotoxicity against the A20 murine B-cell lymphoma. Non-invasive NIR imaging with a VHH7-fluorophore conjugate showed rapid tumor targeting on both localized and metastatic lymphoma models. Subsequent treatment with the nanobody-drug conjugate efficiently controlled tumor growth and metastasis without obvious systemic toxicity.