Enhanced Therapeutic Activity of Non-Internalizing Small-Molecule-Drug Conjugates Targeting Carbonic Anhydrase IX in Combination with Targeted Interleukin-2.

Abstract

Purpose: Antibody-drug conjugates and small-molecule-drug conjugates have been proposed as alternatives to conventional anticancer cytotoxic agents, with the potential to deliver bioactive payloads to the site of disease, helping spare normal tissues.Experimental Design: Here, we describe a novel small-molecule-drug conjugate, based on a high-affinity ligand specific to carbonic anhydrase IX. The product featured a peptidic linker, suitable for cleavage in the tumor extracellular environment, and monomethyl auristatin E as cytotoxic payload.Results: A potent anticancer activity was observed in nude mice bearing SKRC-52 renal cell carcinoma xenografts, but no durable complete responses could be observed in this model. However, when the product was administered together with L19-IL2 (a clinical-stage fusion protein capable of delivering IL2 to the tumor neovasculature), all treated mice in the combination group could be rendered tumor free, in a process that favored the influx of natural killer cells into the tumor mass. The combination of L19-IL2 and the new small-molecule-drug conjugate also eradicated cancer in 100% of immunocompetent mice, bearing subcutaneously grafted CT26 colorectal cancer cells, which stably expressed carbonic anhydrase IX.Conclusions: These findings may be of clinical significance, because carbonic anhydrase IX is overexpressed in the majority of clear cell renal cell carcinomas and in approximately 30% of colorectal cancers. The targeted delivery of IL2 helps potentiate the action of targeted cytotoxics, leading to cancer eradication in models that cannot be cured by conventional chemotherapy. Clin Cancer Res; 24(15); 3656-67. ©2018 AACR.

• Authors: Samuele Cazzamalli, Barbara Ziffels, Fontaine Widmayer, Patrizia Murer, Giovanni Pellegrini, Francesca Pretto, Sarah Wulhfard, Dario Neri
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 24 Issue 15 Pg. 3656-3667 (08 01 2018) ISSN: 1557-3265 [Electronic] United States
• PMID: 29691298 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2018 American Association for Cancer Research.

Chemical References

• Antigens, Neoplasm
• Interleukin-2
• Ligands
• Peptides
• Small Molecule Libraries
• CA9 protein, human
• Carbonic Anhydrase IX

Topics

• Animals
• Antigens, Neoplasm (immunology)
• Carbonic Anhydrase IX (antagonists & inhibitors, immunology)
• Carcinoma, Renal Cell (drug therapy, genetics, immunology, pathology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Colorectal Neoplasms (drug therapy, genetics, immunology, pathology)
• Disease Models, Animal
• Gene Expression Regulation, Neoplastic (immunology)
• Humans
• Immunotherapy (methods)
• Interleukin-2 (antagonists & inhibitors, immunology)
• Ligands
• Mice
• Molecular Targeted Therapy
• Peptides (immunology, pharmacology)
• Small Molecule Libraries (pharmacology)
• Xenograft Model Antitumor Assays