Albumin binding improves the pharmacokinetics and therapeutic efficacy of a ¹⁷⁷Lu-labeled HER2 Fab radioconjugate.

Authors

Peifei Liu, Yizhen Pang, Cuicui Li, Yuqi Hua, Wenyao Zhen, Tianzhi Zhao, Xiaobin Zhao, Jie Liu, Bingyu Li, Jinming Yu, Xiaoyuan Chen, Jingjing Zhang

Published in

Science advances. Volume 12. Issue 29. Pages eaee4052. Jul 17, 2026. Epub Jul 17, 2026.

Abstract

Therapeutic antibodies and antibody-drug conjugates are limited by large molecular size, poor tumor penetration, and signaling-adaptive resistance. We introduce an engineering strategy for radiotherapeutic antibody fragments in which an albumin-binding domain (ABD) rebalances molecular size and pharmacokinetics. Using human epidermal growth factor receptor 2 (HER2) as a proof of concept, we developed ¹⁷⁷Lu-DOTA-Fab-ABD, which integrates rapid tumor penetration with albumin-mediated extended circulation, improving tumor dosimetry while reducing off-target radiation. In HER2 tumor models, ¹⁷⁷Lu-DOTA-Fab-ABD showed strong HER2 and albumin binding, reduced off-target retention, and substantially lower hematologic toxicity than full-length ¹⁷⁷Lu-DOTA-pertuzumab while maintaining potent β-particle tumor control. It also overcame intrinsic trastuzumab resistance by bypassing receptor blockade and inducing DNA double-strand breaks and displayed mechanistic complementarity with trastuzumab. Overall, ¹⁷⁷Lu-DOTA-Fab-ABD represents a generalizable framework for engineering fragment-based radiotherapeutics.

PMID:
42467791
Bibliographic data and abstract were imported from PubMed on 18 Jul 2026.

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