PO.ET01.05 · 实验与分子治疗
一种克服抗体类治疗药物结合位点屏障的通用方法
A general method to overcome the binding site barrier in antibody-based therapeutics
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摘要 Abstract
中文摘要
背景：肿瘤内穿透不足仍是抗体类治疗药物在实体瘤中的一项主要局限。结合位点屏障（BSB）由血管周围区域附近的高亲和力相互作用所驱动，限制了ADC和双特异性抗体在组织中更深层的分布，从而限制了它们的治疗指数。当前策略，如与亲代抗体共同给药或对更低亲和力的变体进行工程改造，受制于靶点特异性，且需要对每种治疗药物进行重新设计。人们需要一种广泛适用的新方法，能够在不改变抗体结构的情况下短暂地调节BSB以改善肿瘤穿透。
方法：我们评估了DSPE-PEG2000——一种FDA批准的两亲性磷脂-聚合物偶联物——作为一种通用的BSB调节剂。使用HER2、TROP2以及PD-1/VEGF靶向治疗药物，我们通过流式细胞术、共聚焦显微镜和活细胞成像，在多种癌细胞模型中定量测定了细胞表面结合、受体可及性和内化的变化。在皮下异种移植模型中，我们使用纵向IVIS成像和肿瘤切片的空间分析评估了Cy3标记的ADC和一种PD-1/VEGF双特异性抗体的肿瘤内分布。抗肿瘤疗效通过肿瘤生长抑制、疗效持久性和生存期进行评估。生物安全性评估包括血清生化和主要器官的组织病理学。
结果：DSPE-PEG2000迅速掺入肿瘤细胞膜并生成一个短程PEG层，在多种不同靶点（如HER2、TROP2和PD-1/VEGF）中短暂地将抗体-抗原相互作用降低40%-60%。这种表面调节未损害抗体的内化或下游运输。在体内，DSPE-PEG2000显著拓宽了ADC和双特异性抗体的肿瘤内分布，使其能够穿透至血管周围区域以外的更深处。这种改善的空间递送转化为更强的肿瘤生长抑制和延长的生存期，且在多种ADC载荷和抗体结构中表现一致。共同给药未增加全身暴露或肿瘤外组织蓄积，也未观察到与治疗相关的毒性。
结论：DSPE-PEG2000提供了一种可推广的、不依赖靶点的策略，以克服结合位点屏障并增强抗体类治疗药物在实体瘤中的分布和功能性疗效。通过在不改变抗体亲和力或结构的情况下经膜锚定PEG接枝短暂调节BSB，DSPE-PEG2000为改善当前及下一代抗体治疗药物的肿瘤穿透提供了一种实用且与临床兼容的方法。
查看英文原文 English abstract
Background: Insufficient intratumoral penetration remains a major limitation of antibody-based therapeutics in solid tumors. The binding site barrier (BSB), driven by high-affinity interactions near perivascular regions, restricts deeper tissue distribution of ADCs and bispecific antibodies and thereby limits their therapeutic index. Current strategies such as co-dosing with parental antibodies or engineering lower-affinity variants are constrained by target specificity and require redesign of each therapeutic. A broadly applicable, novel approaches that transiently modulates BSB without altering antibody structure is needed to improve tumor penetration.
Methods: We evaluated DSPE-PEG2000, an FDA-approved amphiphilic phospholipid-polymer conjugate, as a general BSB modulator. Using HER2-, TROP2-, and PD-1/VEGF-targeted therapeutics, we quantified changes in cell-surface engagement, receptor accessibility, and internalization across multiple cancer cell models via flow cytometry, confocal microscopy, and live-cell imaging. In subcutaneous xenograft models, we assessed the intratumoral distribution of Cy3-labeled ADCs and a PD-1/VEGF bispecific antibody using longitudinal IVIS imaging and spatial analysis of tumor sections. Antitumor efficacy was evaluated by tumor growth suppression, treatment durability, and survival. Biosafety assessments included serum chemistry and histopathology of major organs.
Results: DSPE-PEG2000 rapidly incorporated into tumor cell membranes and generated a short-range PEG layer that transiently reduced antibody-antigen interactions by 40-60% across diverse targets (e.g., HER2, TROP2, and PD-1/VEGF). This surface modulation did not impair antibody internalization or downstream trafficking. In vivo, DSPE-PEG2000 substantially broadened the intratumoral distribution of ADCs and bispecific antibodies, enabling deeper penetration beyond perivascular regions. The improved spatial delivery translated into greater tumor growth inhibition and prolonged survival, consistent across multiple ADC payloads and antibody architectures. Co-administration did not increase systemic exposure or off-tumor tissue accumulation, and no treatment-related toxicity was observed.
Conclusions: DSPE-PEG2000 provides a generalizable, target-independent strategy to overcome the binding site barrier and enhance the distribution and functional efficacy of antibody-based therapeutics in solid tumors. By transiently modulating BSB through membrane-anchored PEG grafting without modifying antibody affinity or structure, DSPE-PEG2000 offers a practical and clinically compatible approach to improve tumor penetration of current and next-generation antibody therapeutics.
利益披露 Disclosure
Y. Li, None..
S. Yao, None..
P. Guo, None.