Site-specific chelator-antibody conjugation for PET and SPECT imaging with radiometals

Q1 Pharmacology, Toxicology and Pharmaceutics Drug Discovery Today: Technologies Pub Date : 2018-12-01 DOI:10.1016/j.ddtec.2018.10.002

Mauricio Morais, Michelle T. Ma

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引用次数: 45

Abstract

Antibodies and their derivatives radiolabelled with positron- and gamma-emitting radiometals enable sensitive and quantitative molecular Positron Emission Tomography (PET) and Single Photon Emission Computed Tomography (SPECT) imaging of antibody distribution in vivo. Chelators that are covalently attached to antibodies allow radiolabelling with metallic PET and SPECT radioisotopes. Conventional strategies for chelator-protein conjugation generate heterogeneous mixtures of bioconjugates that can exhibit reduced affinity for their receptor targets, and undesirable biodistribution and pharmacokinetics. Recent advances in bioconjugation technology enable site-specific modification to generate well-defined constructs with superior properties. Herein we survey existing site-specific chelator-protein conjugation methods. These include chelator attachment to cysteines/disulfide bonds or the glycan region of the antibody, enzyme-mediated chelator conjugation, and incorporation of sequences of amino acids that chelate the radiometal. Such technology will allow better use of PET and SPECT imaging in the development of antibody-based therapies.

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位点特异性螯合剂-抗体偶联PET和SPECT成像与放射性金属

用发射正电子和伽马射线的放射性金属对抗体及其衍生物进行放射性标记，可以实现分子正电子发射断层扫描(PET)和单光子发射计算机断层扫描(SPECT)对体内抗体分布的敏感和定量成像。与抗体共价连接的螯合剂允许用金属PET和SPECT放射性同位素进行放射性标记。传统的螯合剂-蛋白质偶联策略会产生异质的生物偶联物混合物，这些生物偶联物对受体靶点的亲和力降低，并且不希望出现生物分布和药代动力学。生物偶联技术的最新进展使位点特异性修饰能够产生具有优越性能的定义良好的结构体。本文综述了现有的位点特异性螯合剂-蛋白偶联方法。这些包括螯合剂附着于半胱氨酸/二硫键或抗体的聚糖区，酶介导的螯合剂偶联，以及与放射性金属螯合的氨基酸序列的结合。这种技术将允许更好地利用PET和SPECT成像来开发基于抗体的疗法。

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Drug Discovery Today: Technologies Pharmacology, Toxicology and Pharmaceutics-Drug Discovery

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期刊介绍： Discovery Today: Technologies compares different technological tools and techniques used from the discovery of new drug targets through to the launch of new medicines.