Proof-of-Concept of CAIX-Targeted α-Particle Delivery in a Patient-Derived Hypoxic Head and Neck Squamous Cell Carcinoma Model.

Abstract

PurposeTumor hypoxia correlates with a poor prognosis in many solid tumors, including head and neck squamous cell carcinoma (HNSCC). Carbonic anhydrase IX (CAIX) is an endogenous hypoxia-related marker and can be targeted using the humanized monoclonal antibody girentuximab (hG250). A potential new therapy to treat hypoxic tumors is CAIX-targeted α therapy (CAIX-TAT) as α-particles cause complex DNA damage independent of oxygen levels. Here, we investigate the targeting potential of CAIX-TAT in patient-derived HNSCC SCCNij153 xenografts.MethodsDOTA-hG250 was labeled with indium-111 (111In) or actinium-225 (225Ac), and in vivo biodistribution was assessed in SCCNij153 tumor-bearing mice. The spatial distribution of radiolabeled hG250 was correlated to CAIX expression using autoradiography and immunofluorescence. Absorbed doses of [225Ac]Ac-DOTA-hG250 in healthy tissue and CAIX-positive (CAIX+) tumor regions were calculated from ex vivo biodistribution data and quantitative longitudinal SPECT imaging. Finally, SCCNij153 tumor sections from mice injected with [225Ac]Ac-DOTA-hG250 were stained for the DNA damage marker γH2AX.Results[111In]In-DOTA-hG250 accumulates in SCCNij153 tumors 3 days after injection (25.4 ± 5.0 %IA/g). Autoradiography and CAIX immunofluorescence of ex vivo tumor tissue shows that this uptake is predominantly present in the CAIX+ tumor areas. Dosimetry calculations indicated that treatment with 15 kBq [225Ac]Ac-DOTA-hG250 would result in an absorbed dose of 92.5 ± 35.4 Gy for CAIX+ tumor areas. Tumor sections obtained 7 days after [225Ac]Ac-DOTA-hG250 showed that 225Ac colocalized with CAIX expression and a trend was observed towards more γH2AX foci compared with DOTA-hG250 injected mice.ConclusionRadiolabeled hG250 binds to CAIX+ tumor regions in SCCNij153 tumor-bearing mice. Additional studies are required to assess the therapeutic potential and underlying mechanism-of-action of CAIX-TAT for hypoxic tumors.