ADCs, consisting of an antibody designed against a specific antigen at the cell membrane linked with a cytotoxic agent, are an emerging class of therapeutics. Since ADC targets do not have to be drivers of tumor growth, ADCs are potentially relevant for a wide range of tumor types. Therefore, we aimed to define the landscape of ADC target expression in a broad range of tumor types.
PubMed and ClinicalTrials.gov were searched for ADCs that are or were evaluated in clinical cancer trials. Gene expression profiles of 18,055 patient derived tumor samples representing 60 tumor (sub)types and ≥ 3,520 samples representing 22 healthy tissue types were collected from the public domain. Next, we applied FGmRNA-profiling (Fehrmann et al. Nat Genet 2015;47:115-25) to predict per tumor type the overexpression rate at the protein level of ADC targets with healthy tissue samples as reference.
We identified 87 ADCs directed against 59 unique targets. 17 ADC targets showed predicted overexpression of ≥ 75% of samples in at least 1 tumor (sub)type, 38 ≥ 50% and 56 ≥ 25%. A predicted overexpression rate of ≥ 10% of samples for multiple ADC targets was observed for high incidence tumors like breast cancer (n = 31 with n = 23 in triple negative breast cancer), colorectal cancer (n = 18), lung adenocarcinoma (n = 18), squamous cell lung cancer (n = 16) and prostate cancer (n = 5). In rare tumor types we identified targets showing high predicted overexpression, for example in uveal melanomas we found 95% predicted overexpression for c-MET.
This study provides a data driven prioritisation of available ADCs for clinical evaluation in 60 tumor (sub)types. This comprehensive ADC target landscape can support clinicians and drug developers in trial design.
Clinical trial identification
Legal entity responsible for the study
European Research Council advanced grant OnQview to E.G.E. de Vries; the Dutch Cancer Society grant, the NWO-VENI grant and a Mandema Stipendium to R.S.N. Fehrmann
E.G.E. de Vries: Advisory board: Medivation, Merck and Synthon: payments to the institution. Research grants: Amgen, Genentech/Roche, Chugai, Servier, Novartis, Synthon, AstraZeneca, Radius Health, CytomX, Nordic Nanovector: payments to the institution. All other authors have declared no conflicts of interest.