Site-Specifically Labeled Immunoconjugates for Molecular Imaging--Part 1: Cysteine Residues and Glycans.
Site-Specifically Labeled Immunoconjugates for Molecular Imaging--Part 1: Cysteine Residues and Glycans.
复制标题
DOI：
10.1007/s11307-015-0919-4
复制
发表时间：
2016-02
影响因子：
3.1
通讯作者：
Zeglis BM
中科院分区：
文献类型：
--
作者：
Adumeau P;Sharma SK;Brent C;Zeglis BM
由于其对癌症生物标志物的显着选择性和特异性，免疫缀合物已成为向恶性组织递送诊断放射性同位素和荧光团的极有前途的载体。然而，矛盾的是，这些精准医学工具的合成方式非常不精确。事实上，绝大多数免疫偶联物是通过双功能探针（例如 DOTA-NCS）与抗体内的氨基酸（例如赖氨酸）随机偶联而产生的。然而，抗体在其整个大分子结构中具有这些残基的多个拷贝，使得无法控制缀合反应的位置。这种位点特异性的缺乏可能导致形成不明确的、异质的免疫缀合物，其体内行为不理想。在过去的十年中，人们对位点特异性标记的免疫偶联物（包括抗体-药物偶联物以及体内成像构建体）的合成和开发兴趣急剧增加，许多报告表明，与随机修饰的同类相比，这些定义更明确、更均一的构建体在体内表现出更好的性能。在这篇由两部分组成的综述中，我们试图概述已开发的各种方法，用于创建用于正电子发射断层扫描、单光子发射计算机断层扫描和荧光成像的位点特异性修饰的免疫缀合物。我们首先介绍抗体和抗体片段的结构。接下来是工作的核心：详细介绍基于半胱氨酸残基、聚糖、肽标签和非天然氨基酸的位点特异性修饰策略的四种不同方法的部分。这些讨论将分为两部分：半胱氨酸残基和聚糖将在综述的第 1 部分中详细介绍，而肽标签和非天然氨基酸将在第 2 部分中讨论。最终，我们真诚地希望这篇综述能够激发核医学和分子成像界对位点特异性免疫缀合物的兴趣和热情。
Due to their remarkable selectivity and specificity for cancer biomarkers, immunoconjugates have emerged as extremely promising vectors for the delivery of diagnostic radioisotopes and fluorophores to malignant tissues. Paradoxically, however, these tools for precision medicine are synthesized in a remarkably imprecise way. Indeed, the vast majority of immunoconjugates are created via the random conjugation of bifunctional probes (e.g., DOTA-NCS) to amino acids within the antibody (e.g., lysines). Yet antibodies have multiple copies of these residues throughout their macromolecular structure, making control over the location of the conjugation reaction impossible. This lack of site specificity can lead to the formation of poorly defined, heterogeneous immunoconjugates with suboptimal in vivo behavior. Over the past decade, interest in the synthesis and development of site-specifically labeled immunoconjugates—both antibody-drug conjugates as well as constructs for in vivo imaging—has increased dramatically, and a number of reports have suggested that these better defined, more homogeneous constructs exhibit improved performance in vivo compared to their randomly modified cousins. In this two-part review, we seek to provide an overview of the various methods that have been developed to create site-specifically modified immunoconjugates for positron emission tomography, single photon emission computed tomography, and fluorescence imaging. We will begin with an introduction to the structure of antibodies and antibody fragments. This is followed by the core of the work: sections detailing the four different approaches to site-specific modification strategies based on cysteine residues, glycans, peptide tags, and unnatural amino acids. These discussions will be divided into two installments: cysteine residues and glycans will be detailed in Part 1 of the review, while peptide tags and unnatural amino acids will be addressed in Part 2. Ultimately, we sincerely hope that this review fosters interest and enthusiasm for site-specific immunoconjugates within the nuclear medicine and molecular imaging communities.