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Merck

Human anti-nucleolin recombinant immunoagent for cancer therapy.

Proceedings of the National Academy of Sciences of the United States of America (2015-07-15)
Dario Palmieri, Timothy Richmond, Claudia Piovan, Tyler Sheetz, Nicola Zanesi, Fulvia Troise, Cindy James, Dorothee Wernicke, Fata Nyei, Timothy J Gordon, Jessica Consiglio, Francesco Salvatore, Vincenzo Coppola, Flavia Pichiorri, Claudia De Lorenzo, Carlo M Croce
RESUMEN

Nucleolin (NCL) is a nucleocytoplasmic protein involved in many biological processes, such as ribosomal assembly, rRNA processing, and mRNA stabilization. NCL also regulates the biogenesis of specific microRNAs (miRNAs) involved in tumor development and aggressiveness. Interestingly, NCL is expressed on the surface of actively proliferating cancer cells, but not on their normal counterparts. Therefore, NCL is an attractive target for antineoplastic treatments. Taking advantage of phage-display technology, we engineered a fully human single-chain fragment variable, named 4LB5. This immunoagent binds NCL on the cell surface, it is translocated into the cytoplasm of target cells, and it abrogates the biogenesis of NCL-dependent miRNAs. Binding of 4LB5 to NCL on the cell surface of a variety of breast cancer and hepatocellular carcinoma cell lines, but not to normal-like MCF-10a breast cells, dramatically reduces cancer cell viability and proliferation. Finally, in orthotopic breast cancer mouse models, 4LB5 administration results in a significant reduction of the tumor volume without evident side effects. In summary, here we describe, to our knowledge, the first anti-NCL single-chain fragment variable displaying antineoplastic activity against established solid tumors, which could represent the prototype of novel immune-based NCL-targeting drugs with clinical potential as diagnostic and therapeutic tools in a wide variety of human cancers.

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