背景:抗体-药物缀合物(ADC)代表了有效的癌症疗法,可以精确地将高毒性药物传递给肿瘤细胞,从而允许靶向治疗并显著降低脱靶效应。尽管他们的有效性,ADC可能由于获得的抗性和潜在的副作用而面临限制。
目的:本研究关注各种ADC成分的进展,以提高这些药物的疗效和安全性,并包括对几种新颖的ADC格式的分析。这项工作评估了VHHs的独特功能-比如它们的小尺寸,增强组织渗透,稳定性,和成本效益-使它们成为ADC常规抗体的可行替代品,并回顾了它们在ADC开发中的现状。
方法:遵循PRISMA指南,这项研究的重点是VHHs作为ADC的组成部分,审查2014年1月1日至2024年6月30日的进展和前景。搜索是在PubMed中进行的,科克伦图书馆,ScienceDirect和LILACS使用与ADC和单结构域抗体相关的特定术语。检索到的文章经过严格评估,不包括重复和不合格的研究。对选定的同行评审文章进行了质量分析和综合,以突出进步,方法,有效载荷,以及未来ADC研究的方向。
结果:与常规抗体相比,VHH在药物缀合方面具有显著优势,这增强了组织的穿透性,并能够接近以前无法接近的表位。它们优越的稳定性,溶解度,和可制造性有助于成本有效的生产并扩大可靶向抗原的范围。此外,一些VHH可以自然地穿过血脑屏障或容易被修改以促进其渗透,使它们有望靶向脑肿瘤和转移瘤。虽然目前没有VHH-药物缀合物(nADC或nanoADC)在临床领域,临床前研究已经探索了各种缀合方法和接头。
结论:虽然ADC正在改变癌症治疗,它们独特的机制和相关的毒性挑战了传统的生物利用度观点,并因不同的肿瘤类型而异.严重的毒性,通常与复合不稳定有关,脱靶效应,和非特异性血细胞相互作用,强调需要更好地理解。相反,快速分配,肿瘤渗透,清除VHHs可能是有利的,通过最大限度地减少长期暴露来降低毒性。这些属性使单结构域抗体成为下一代ADC的强候选物,可能提高疗效和安全性。
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.
OBJECTIVE: 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.