Carbonic anhydrase‐9‐targeted near‐infrared photoimmunotherapy as a theranostic modality for clear cell renal cell carcinoma

Carbonic anhydrase-9 (CA9) is highly expressed in clear cell renal cell carcinoma (ccRCC) cells despite no expression in normal kidney tissues. Thus, CA9 has been proposed as a theranostic target for radioligand therapy (RLT). However, ccRCC tends to be radioresistant and may not effectively respond to RLT. Alternatively, CA9 can be targeted for near-infrared photoimmunotherapy (NIR-PIT) of ccRCC. Here, we sought to test NIR-PIT using CA9 in a preclinical model of ccRCC to determine its potential as a therapeutic strategy. Tissue microarray analysis showed that membrane CA9 was expressed in the majority of ccRCC cases. In vitro, CA9-targeted NIR-PIT induced cell membrane damage and cell killing in all CA9-expressing ccRCC cell lines specifically, UOK154, UOK220, and UOK122. In vivo, CA9-targeted NIR-PIT significantly inhibited tumor growth and prolonged survival in UOK154 and UOK220 subcutaneous xenograft models. Notably, 70%-80% of mice achieved complete remission after a single treatment of NIR-PIT. Additionally, remaining tumors after the first NIR-PIT persistently expressed CA9, suggesting that remaining tumors can be treated with repeated NIR-PIT. Furthermore, CA9-targeted NIR-PIT induced significant cytoplasmic damages on ccRCC cells in UOK154 orthotopic xenograft models. In conclusion, CA9-targeted NIR-PIT, which allow for safe and repeated application on the same lesion, is a promising treatment for ccRCC, especially in the management of multiple primary ccRCC (e.g., von Hippel-Lindau syndrome) and oligometastatic ccRCC.