Background: Antibody–drug conjugates (ADCs) represent potent cancer therapies that deliver highly toxic drugs to tumor cells precisely, thus allowing for targeted treatment and significantly reducing off-target effects. Despite their effectiveness, ADCs can face limitations due to acquired resistance and potential side effects. Objectives: This study focuses on advances in various ADC components to improve both the efficacy and safety of these agents, and includes the analysis of several novel ADC formats. This work assesses whether the unique features of VHHs—such as their small size, enhanced tissue penetration, stability, and cost-effectiveness—make them a viable alternative to conventional antibodies for ADCs and reviews their current status in ADC development. Methods: Following PRISMA guidelines, this study focused on VHHs as components of ADCs, examining advancements and prospects from 1 January 2014 to 30 June 2024. Searches were conducted in PubMed, Cochrane Library, ScienceDirect and LILACS using specific terms related to ADCs and single-domain antibodies. Retrieved articles were rigorously evaluated, excluding duplicates and non-qualifying studies. The selected peer-reviewed articles were analyzed for quality and synthesized to highlight advancements, methods, payloads, and future directions in ADC research. Results: VHHs offer significant advantages for drug conjugation over conventional antibodies due to their smaller size and structure, which enhance tissue penetration and enable access to previously inaccessible epitopes. Their superior stability, solubility, and manufacturability facilitate cost-effective production and expand the range of targetable antigens. Additionally, some VHHs can naturally cross the blood–brain barrier or be easily modified to favor their penetration, making them promising for targeting brain tumors and metastases. Although no VHH–drug conjugates (nADC or nanoADC) are currently in the clinical arena, preclinical studies have explored various conjugation methods and linkers. Conclusions: While ADCs are transforming cancer treatment, their unique mechanisms and associated toxicities challenge traditional views on bioavailability and vary with different tumor types. Severe toxicities, often linked to compound instability, off-target effects, and nonspecific blood cell interactions, highlight the need for better understanding. Conversely, the rapid distribution, tumor penetration, and clearance of VHHs could be advantageous, potentially reducing toxicity by minimizing prolonged exposure. These attributes make single-domain antibodies strong candidates for the next generation of ADCs, potentially enhancing both efficacy and safety.
背景：抗体药物偶联物（ADC）是一类强效的癌症疗法，能将高毒性药物精准递送至肿瘤细胞，从而实现靶向治疗并显著降低脱靶效应。尽管ADC疗效显著，但其应用可能因获得性耐药和潜在副作用而受限。目的：本研究重点关注ADC各组成部分的进展，以提升此类药物的疗效与安全性，并分析多种新型ADC形式。本研究评估了VHH（单域抗体）的独特特性——如体积小、组织穿透性强、稳定性高及成本效益好——是否使其成为ADC中传统抗体的可行替代选择，并综述了其在ADC开发中的现状。方法：本研究遵循PRISMA指南，聚焦于作为ADC组成部分的VHH，考察了2014年1月1日至2024年6月30日期间的相关进展与前景。在PubMed、Cochrane Library、ScienceDirect和LILACS数据库中，使用与ADC及单域抗体相关的特定术语进行检索。对检索到的文献进行严格评估，排除重复及不符合条件的研究。对筛选出的同行评议文章进行质量分析，并综合归纳ADC研究中的进展、方法、有效载荷及未来方向。结果：与传统抗体相比，VHH因其更小的体积和结构，在药物偶联方面具有显著优势，可增强组织穿透性并触及以往难以接近的表位。其优异的稳定性、溶解性和可生产性有助于实现成本效益高的生产，并扩大了可靶向抗原的范围。此外，部分VHH能天然穿过血脑屏障或易于修饰以增强其穿透能力，使其在靶向脑肿瘤和转移瘤方面前景广阔。尽管目前尚无VHH-药物偶联物（nADC或纳米ADC）进入临床阶段，但临床前研究已探索了多种偶联方法和连接子。结论：尽管ADC正在改变癌症治疗格局，但其独特的作用机制及相关毒性挑战了关于生物利用度的传统认知，且随肿瘤类型不同而变化。严重毒性通常与化合物不稳定性、脱靶效应及非特异性血细胞相互作用相关，这凸显了深入理解的必要性。相反，VHH的快速分布、肿瘤穿透和清除特性可能具有优势，通过减少长期暴露可能降低毒性。这些特性使单域抗体成为下一代ADC的有力候选者，有望同时提升疗效与安全性。
Single-Domain Antibodies as Antibody–Drug Conjugates: From Promise to Practice—A Systematic Review
肿瘤(癌症)患者之家