Theranostic pairing: ABY-025/251 targeting HER2 with ⁶⁸Ga and ¹⁸⁸Re—Minimized radioligands using Affibody peptide scaffold technology.

3093 Background: HER2 expressing tumors such as subsets of metastatic breast cancer and gastro-esophageal tumors can be targeted using specific antibodies or antibody-drug-conjugates (ADCs). However, some tumors remain refractory to treatment. External radiation therapy is unsuited to advanced metastatic disease. Targeted molecular radiation therapy has proven useful in other tumors such as neuroendocrine tumors or prostate cancer using 177Lu. 188Re is a beta emitting isotope that when chelated to the ABY-251 Affibody molecule has the potential to precisely target HER2 expressing tumors locally. The ABY-251 Affibody molecule is a very small, structured protein scaffold with a molecular weight of only 7 kDa targeting HER2 with high affinity (KD = 100pM). ABY-251 can be manufactured by chemical synthesis. A diagnostic analog molecule ABY-025 was also developed with chelation to 68Ga ideal for PET visualization. Methods: A pre-clinical study in mice was conducted to investigate tumor/tissue uptake, followed by a clinical diagnostic study for visualization in HER+ patients with metastatic breast cancer, to be followed by a theranostic study in humans. Results: Pre-clinical Study: A preclinical study in mice has previously demonstrated high contrast uptake in HER2 tumor tissue using the diagnostic analog ABY-025. Off target accumulation was seen in kidney tissue using the diagnostic ABY-025, which in the ABY-251 therapeutic molecule has been reduced by further engineering of the molecule. This molecule has now been proven to increase survival in mice bearing HER2+ tumors. Median survival in the treated animals was 68 days as compared to 29 and 27.5 days in animals treated with vehicle and non-labelled peptide respectively. Clinical diagnostic study ph1/2: ABY-025 was studied in HER2+ patients with metastatic breast cancer. In a study of 16 women with refractory metastatic breast cancer (>2 prior lines of therapy, 12 IHC positive and 4 IHC negative) 9 out of 10 patients showed high HER2 expression levels as measured with ABY-025 PET despite ongoing treatment with HER2 targeted therapy. Persistent high 68Ga-ABY-025 tumor uptake in patients despite treatment with standard HER2-targeted therapies is a sign of therapeutic drug resistance. These patients would be eligible for treatment with the therapeutic analog ABY-251 using 188Re generated beta radiation for tumor eradication. Clinical therapeutic study (planned): ABY-251 is in development to soon enter therapeutic clinical Ph1/2a trials in patients with refractory HER2+ tumors and positive tumor imaging using ABY-025 as a theranostic pair. Conclusions: A radiopharmaceutical theranostic approach diagnosing HER2+ patients with metastatic disease using 68Ga-ABY-025 for targetability and subsequent treatment using 188Re-ABY-251 seems feasible and is currently in clinical trials. Clinical trial information: NCT01858116.