Q-2361，一种用于器官移植受者皮肤癌预防的治疗药物

Solid organ transplant recipients require life-long immunosuppression in order to prevent the immune-mediated rejection of their transplanted organs. Tacrolimus, a mainstay in immunosuppressive therapy, acts systemically to suppress the activity of T cells within and around transplanted organs. Consequently, however, these patients suffer a 65- to 250-fold increased risk of developing cutaneous malignancies including squamous cell carcinoma (SCC) and Kaposi's Sarcoma. SCC is the most prevalent cancer in solid organ transplant recipients, with a more aggressive clinical course compared to the general population and is a significant contributor to morbidity and mortality. We have identified a small molecule drug candidate (Q-2361), to locally inhibit the unwanted effects of tacrolimus on T cells and ketatinocyes in the skin. Q-2361 potently blocked the interaction between tacrolimus and FKBP12 and rescued both mouse and human T cell activation and proliferation in the presence of tacrolimus in vitro . Functional studies in multiple ‘regressor' mouse models of skin cancer showed that the local administration of Q-2361 induced tumor regression in mice that had been systemically immune-suppressed with tacrolimus. Mechanistically, Q-2361 treatment permitted CD8 T cell activation, proliferation, and effector function, and Q-2361 could not induce tumor regression when CD8 T cells were depleted, demonstrating that Q-2361 induces tumor regression through the reactivation of cytotoxic T cells. In separate studies, Q-2361 blocked multiple effects of tacrolimus on UV-damaged keratinocytes, and prevented the formation of SCC tumours in UV-treated nude mice fed a tacrolimus-diet. A simple solution-based Q-2361 topical formulation achieved high and sustained residence in skin with negligible drug in the blood. Thus, topically applied Q-2361 shows high potential for the reactivation of T cells and the rescue of keratinocyte function locally in the skin but not at other body sites, which paves the way to clinical trials of topical Q-2361 treatments for skin malignancies in immunosuppressed organ transplant recipients.