Albumin-binding 177Lu-DOTA-Fab-ABD radioconjugate reduces toxicity, overcomes trastuzumab resistance in HER2 tumors.

Current therapeutic antibodies and antibody-drug conjugates (ADCs) face limitations in cancer therapy, including large molecular size, poor tumor penetration, and the development of signaling-adaptive resistance. Specifically, treatments for HER2-positive cancers can encounter issues like intrinsic trastuzumab resistance, where tumors no longer respond to receptor blockade. There is a critical need for strategies that improve tumor dosimetry, reduce off-target radiation, and enhance efficacy against resistant forms of the disease, particularly by rebalancing pharmacokinetics for better therapeutic indices.

Researchers developed 177Lu-DOTA-Fab-ABD, an engineered radiotherapeutic antibody fragment, by integrating a 177Lu-labeled Fab fragment with an albumin-binding domain (ABD). This design aimed to rebalance molecular size and pharmacokinetics, facilitating rapid tumor penetration alongside albumin-mediated extended systemic circulation. The efficacy and safety of 177Lu-DOTA-Fab-ABD were evaluated in HER2 tumor models, where its performance was directly compared against full-length 177Lu-DOTA-pertuzumab. The study assessed tumor dosimetry, off-target retention, hematologic toxicity, and the ability to overcome trastuzumab resistance.

The novel 177Lu-DOTA-Fab-ABD radioconjugate demonstrated strong HER2 and albumin binding, effectively integrating rapid tumor penetration with extended circulation. This led to improved tumor dosimetry and reduced off-target radiation compared to traditional approaches. Critically, in HER2 tumor models, 177Lu-DOTA-Fab-ABD exhibited substantially lower hematologic toxicity than full-length 177Lu-DOTA-pertuzumab, while maintaining potent β-particle tumor control. The radioconjugate also overcame intrinsic trastuzumab resistance by bypassing receptor blockade and inducing DNA double-strand breaks. This mechanism displayed mechanistic complementarity with trastuzumab, suggesting potential for combination therapies. The engineering strategy provides a generalizable framework for fragment-based radiotherapeutics. > 177Lu-DOTA-Fab-ABD showed substantially lower hematologic toxicity than 177Lu-DOTA-pertuzumab while maintaining potent tumor control and overcoming trastuzumab resistance.