Abstract
BACKGROUND: The HER2 targeted therapy paradigm has increasingly shifted in recent years from focussed treatment of only cancers with high HER2 expression towards those with also low HER2 expression, unlocking a larger subset of patients, in either single or combination treatment strategies. Radiotherapeutic HER2-targeting single-domain antibody (sdAb) 2Rs15d has been previously developed and characterised (pre-)clinically for HER2 high-expressing tumours. The current study explores the use of [(131)I]I-GMIB- and [(225)Ac]Ac-DOTA-labelled sdAb 2Rs15d as single treatments or as combinations with the PARP-inhibitor Olaparib in HER2 low-expressing xenografts. RESULTS: [(131)I]I-GMIB-2Rs15d and [(225)Ac]Ac-DOTA-2Rs15d specifically bound to HER2-low-expressing DLD-1 BRCA2(−/−) cells in vitro, inflicted DNA damage (elevated γH2AX) and decreased cell viability as a single agent, an effect that was invigorated upon combination with Olaparib. Radiotracers showed specific tumour uptake in DLD-1 BRCA2(−/−) tumour xenografts, correlating with the low HER2 expression in this model. Clear antitumour effects were observed in mice treated with fractionated [(131)I]I-GMIB-2Rs15d (8 × 37 MBq, p’=0.00232) and [(225)Ac]Ac-DOTA-2Rs15d (8 × 20 kBq, p’=0.0149) compared to vehicle control. In combination with Olaparib (28 × 75 mg/kg), synergistic effects were observed for both [(131)I]I-GMIB-2Rs15d and [(225)Ac]Ac-DOTA-2Rs15d. CONCLUSION: [(131)I]I-GMIB-2Rs15d and [(225)Ac]Ac-DOTA-2Rs15d showed therapeutic efficacy in tumour xenografts expressing low levels of HER2. Furthermore, when treatment was combined with Olaparib both radiopharmaceuticals prolonged survival further, underlining a synergistic effect. GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12967-025-07572-2.