Drug Conjugates Specific to Fibroblast Activation Protein and Carbonic Anhydrase IX for Applications in Oncology

Despite the different therapeutic options available, more than 10 million deaths every year are caused by cancer, thus representing one of the majors’ causes of death worldwide. Lung cancer (1.8 million), breast cancer (700’000), colorectal cancer (950’000), and liver cancer (830’000) represent half of the global cancer incidence. Common approaches for the treatment of cancer include surgery, radiotherapy (external beam radiation and Radioligand Therapy, RLT), chemotherapy and immunotherapy. While radiotherapy indistinctively targets all cells within the tumor environment, chemotherapeutic agents can interfere with the growth of rapidly dividing cancer cells. Both conventional therapeutic modalities lack selectivity, can affect healthy cells and elicit drug-resistance mechanisms that further reduce efficacy. To overcome the limitations of conventional treatments, pharmaceutical industries focused on the discovery of therapeutic agents which can be selectively active at the site of tumors. A strategy to generate targeted therapeutics consist in the use of active delivery vehicles of bioactive payloads including cytotoxic agents, radiations, and immunomodulatory agents. An increased number of products based on tumor targeting like monoclonal antibodies, peptides, and small molecules have been recently approved (e.g., ZynlontaTM, an Antibody-Drug Conjugate approved in 2021, and Sunitinib, a multikinase inhibitor approved in 2006), or are being studied in clinical trials. This thesis is focused on the design and development of Small Molecule-Drug Conjugates (SMDCs) and Small Molecule-Radio Conjugates (SMRCs) for the imaging and treatment of solid tumors. Some of the results presented in this thesis have been published in our paper “Immunotherapy with Immunocytokines and PD-1 blockade enhances the anticancer activity of Small Molecule-Drug Conjugates targeting Carbonic Anhydrase IX” (Molecular Cancer Therapeutics; 2021) and in our article “An Ultra-High Affinity Small Organic Ligand of Fibroblast Activation Protein for Tumor Targeting Applications” ( Proceedings of National Academy of Sciences; 2021).