Abstract
Small molecule-drug conjugates (SMDCs) represent an alternative to conventional anti-tumor chemotherapeutic agents, with the potential to improve the therapeutic window of cytotoxic payloads through active delivery at the site of the disease. In this article we describe novel combination therapies consisting of anti-Carbonic Anhydrase IX SMDCs combined with different immunomodulatory products. The therapeutic effect of the SMDCs was potentiated by combination with PD-1 blockade and with tumor-homing antibody-cytokine fusions in mouse models of renal cell carcinoma and colorectal cancer. The combination with L19-IL12, a fusion protein specific to the alternatively-spliced EDB domain of fibronectin containing the murine interleukin-12 moiety, was active also against large established tumors. Analysis of the microscopic structures of healthy organs performed three months after tumor eradication confirmed absence of pathological abnormalities in the healthy kidney, liver, lung, stomach and intestine. Our findings may be of clinical significance as they provide motivation for the development of combinations based on small molecule-drug conjugates and immunotherapy for the treatment of renal cell carcinoma and of hypoxic tumors.
Competing Interest Statement
D.N. is a co-founder and shareholder of Philogen (www.philogen.com), a Swiss-Italian Biotech company that operates in the field of ligand-based pharmacodelivery. J.M., S.D.P., A.V. and S.C. are employees of Philochem AG, daughter company of Philogen acting as discovery unit of the group.
Footnotes
Financial Support: D.N. acknowledges funding from ETH Zurich. This project has received funding from the Swiss National Science Foundation (Grant Nr. 310030_182003/1) and the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (grant agreement 670603).
Disclosure of Potential Conflict of Interest: D.N. is a co-founder and shareholder of Philogen (www.philogen.com), a Swiss-Italian Biotech company that operates in the field of ligand-based pharmacodelivery. J.M., S.D.P., A.V. and S.C. are employees of Philochem AG, daughter company of Philogen acting as discovery unit of the group.