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

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.