Optimization of Affibody Affinity to Improve Distribution in Tumor Models

IF 5.9 2区化学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biomacromolecules Pub Date : 2026-09-14 Epub Date: 2026-09-17 DOI:10.1021/acs.biomac.6c01111

Bryce M. Bower, Gabrielle M. Ho, Sven A. Saemundsson, Andrew P. Goodwin, Jennifer N. Cha

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Abstract

Poor distribution is often a limiting factor when using affinity targeted treatments. High affinity creates a barrier to transport because proteins cannot diffuse throughout the tissue while bound to the cell surface. Lowering the affinity can help with transport throughout a tumor but can also result in a loss of total delivery and specificity for the target. In this research, we used point mutations to create affibodies with a range of different affinities for epidermal growth factor receptor (EGFR) and measured their penetration through tumor spheroids. Mutants in the range of ∼7–12 nM K _D were able to distribute more evenly throughout 3D tumor spheroids without losing total accumulation or receptor specificity. Lower affinity mutants showed both low target specificity and accumulation in 3D tumor spheroids. This work shows the effects of affinity on distribution and how slightly reducing binding affinity can improve transport.

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优化词缀亲和力以改善肿瘤模型的分布

当使用亲和力靶向治疗时，不良分布往往是一个限制因素。高亲和力产生了运输障碍，因为蛋白质在结合到细胞表面时不能扩散到整个组织。降低亲和力有助于整个肿瘤的转运，但也可能导致靶蛋白的总递送和特异性的丧失。在这项研究中，我们使用点突变来创建具有一系列不同亲和力的表皮生长因子受体（EGFR）的粘附体，并测量它们在肿瘤球体中的渗透。在~ 7-12 nM KD范围内的突变体能够更均匀地分布在整个三维肿瘤球体中，而不会失去总积累或受体特异性。低亲和力突变体在三维肿瘤球体中表现出低靶标特异性和积累。这项工作显示了亲和性对分布的影响，以及轻微降低结合亲和性如何改善转运。

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来源期刊

Biomacromolecules 化学-高分子科学

CiteScore

10.60

自引率

4.80%

发文量

417

审稿时长

1.6 months

期刊介绍： Biomacromolecules is a leading forum for the dissemination of cutting-edge research at the interface of polymer science and biology. Submissions to Biomacromolecules should contain strong elements of innovation in terms of macromolecular design, synthesis and characterization, or in the application of polymer materials to biology and medicine. Topics covered by Biomacromolecules include, but are not exclusively limited to: sustainable polymers, polymers based on natural and renewable resources, degradable polymers, polymer conjugates, polymeric drugs, polymers in biocatalysis, biomacromolecular assembly, biomimetic polymers, polymer-biomineral hybrids, biomimetic-polymer processing, polymer recycling, bioactive polymer surfaces, original polymer design for biomedical applications such as immunotherapy, drug delivery, gene delivery, antimicrobial applications, diagnostic imaging and biosensing, polymers in tissue engineering and regenerative medicine, polymeric scaffolds and hydrogels for cell culture and delivery.