Preclinical synergistic effects when combining a radiolabelled HER2-targeting single domain antibody with PARP inhibitor Olaparib

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 [131I]I-GMIB- and [225Ac]Ac-DOTA-labelled sdAb 2Rs15d as single treatments or as combinations with the PARP-inhibitor Olaparib in HER2 low-expressing xenografts. [131I]I-GMIB-2Rs15d and [225Ac]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 [131I]I-GMIB-2Rs15d (8 × 37 MBq, p’=0.00232) and [225Ac]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 [131I]I-GMIB-2Rs15d and [225Ac]Ac-DOTA-2Rs15d. [131I]I-GMIB-2Rs15d and [225Ac]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.