IF 4.5 2区 医学 Q2 MEDICINE, RESEARCH & EXPERIMENTAL
Abbigael Harthorn, Tse-Han Kuo, Sarah W Torres, Roy R Lobb, Benjamin J Hackel
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引用次数: 0

摘要

通过与肿瘤选择性细胞表面生物标记物结合,选择性地向肿瘤细胞输送治疗模式,使癌症治疗取得了重大进展。然而,肿瘤细胞通常缺乏真正特异的生物标记物,这种标记物在肿瘤组织中高密度存在,而在健康组织中却完全不存在。相反,在健康组织中低表达但非零表达会导致靶上、瘤外活性,产生有害副作用,从而限制治疗窗口期或完全无法使用。我们迫切需要先进的技术来提高肿瘤靶向的选择性。我们已设计出一种结合平台,它通过亲和力驱动的特异性,定量地依赖于表达水平,而不是二元依赖于生物标记物的存在与否。我们针对癌胚抗原相关细胞粘附分子 5(CEACAM5)和叶酸受体 1(FolR1)设计了亲和抗体,从而系统地改变了单体的结合亲和力。两个相同的亲和体配体以不同的多肽连接长度与结合 Alfa 肽的纳米抗体相连,从而产生了一种双特异性三价蛋白质,用于预靶向放射性配体治疗。这两种系统都实现了表达依赖性靶向:与CEACAM5的单体亲和力为110 nM,带有两个氨基酸连接体;与FolR1的单体亲和力为250 nM,带有10个氨基酸连接体。后者的双特异性三价在混合培养中实现了 25 倍以上的 FolR1 高和 FolR1 低细胞之间的分化。缺乏中心纳米抗体的高效二价分子也实现了类似的选择性。此外,亲和性双价抗体分子对可溶性抗原的抑制作用极小,而高亲和性双价抗体的抑制率为 97 ± 2%,这表明血清对脱落抗原有抑制作用。这项工作推进了通过低亲和力、高活性配体实现表达依赖性肿瘤靶向的设计原则。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Expression-Dependent Tumor Pretargeting via Engineered Avidity.

Selective delivery of therapeutic modalities to tumor cells via binding of tumor-selective cell-surface biomarkers has empowered substantial advances in cancer treatment. Yet, tumor cells generally lack a truly specific biomarker that is present in high density on tumor tissue while being completely absent from healthy tissue. Rather, low but nonzero expression in healthy tissues results in on-target, off-tumor activity with detrimental side effects that constrain the therapeutic window or prevent use altogether. Advanced technologies to enhance the selectivity for tumor targeting are sorely needed. We have engineered a binding platform that is quantitatively dependent upon expression levels, via avidity-driven specificity, rather than binarily reliant on the presence or absence of a biomarker. We systematically varied monomeric binding affinity by engineering affibodies to target carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) and folate receptor 1 (FolR1). Two identical affibody ligands were tethered, with varying polypeptide linker lengths, to a nanobody that binds Alfa peptide to create a bispecific, trivalent protein for use in pretargeted radioligand therapy. Expression-dependent targeting was achieved in both systems: with 110 nM monomeric affinity to CEACAM5 with a two-amino-acid linker or with 250 nM monomeric affinity for FolR1 and a 10 amino acid linker. The latter bispecific, trivalent achieved over 25-fold differentiation between FolR1high and FolR1low cells in a mixed culture. Similar selectivity was achieved in a size-efficient bivalent molecule lacking a central nanobody. Moreover, the avid bivalent affibody molecule exhibited minimal inhibition by soluble antigen, whereas high-affinity bivalent antibody was inhibited by 97 ± 2%, which is indicative of serum inhibition of shed antigen. This work advances design principles for achieving expression-dependent tumor targeting via low-affinity, high-avidity ligands.

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来源期刊
Molecular Pharmaceutics
Molecular Pharmaceutics 医学-药学
CiteScore
8.00
自引率
6.10%
发文量
391
审稿时长
2 months
期刊介绍: Molecular Pharmaceutics publishes the results of original research that contributes significantly to the molecular mechanistic understanding of drug delivery and drug delivery systems. The journal encourages contributions describing research at the interface of drug discovery and drug development. Scientific areas within the scope of the journal include physical and pharmaceutical chemistry, biochemistry and biophysics, molecular and cellular biology, and polymer and materials science as they relate to drug and drug delivery system efficacy. Mechanistic Drug Delivery and Drug Targeting research on modulating activity and efficacy of a drug or drug product is within the scope of Molecular Pharmaceutics. Theoretical and experimental peer-reviewed research articles, communications, reviews, and perspectives are welcomed.
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