Preclinical Validation of Tumor-Penetrating and Interfering Peptides against Chronic Lymphocytic Leukemia

• Published in: Molecular pharmaceutics Vol. 19; no. 3; pp. 895 - 903
• Main Authors: Simón-Gracia, Lorena, Loisel, Severine, Sidorenko, Valeria, Scodeller, Pablo, Parizot, Christophe, Savier, Eric, Haute, Tanguy, Teesalu, Tambet, Rebollo, Angelita
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 07.03.2022
• Subjects: Animals; Apoptosis; B-Lymphocytes - metabolism; Cancer; Humans; Leukemia, Lymphocytic, Chronic, B-Cell - drug therapy; Leukemia, Lymphocytic, Chronic, B-Cell - metabolism; Life Sciences; Mice; Peptides - pharmacology; Peptides - therapeutic use; Protein Phosphatase 2 - metabolism; Protein Phosphatase 2 - pharmacology; Protein Phosphatase 2 - therapeutic use; xenograft models; tumor-penetrating and interfering peptides; chronic lymphocytic leukemia
• ISSN: 1543-8384; 1543-8392
• DOI: 10.1021/acs.molpharmaceut.1c00837

Chronic lymphocytic leukemia (CLL) is the most common form of leukemia in adults. The disease is characterized by the accumulation of tumoral B cells resulting from a defect of apoptosis. We have and preclinically validated a tumor-penetrating peptide (named TT1) coupled to an interfering peptide (IP) that dissociates the interaction between the serine/threonine protein phosphatase 2A (PP2A) from its physiological inhibitor, the oncoprotein SET. This TT1-IP peptide has an antitumoral effect on CLL, as shown by the increased survival of mice bearing xenograft models of CLL, compared to control mice. The peptide did not show toxicity, as indicated by the mouse body weight and the biochemical parameters, such as renal and hepatic enzymes. In addition, the peptide-induced apoptosis of primary tumoral B cells isolated from CLL patients but not of those isolated from healthy patients. Finally, the peptide had approximately 5 h half-life in human serum and showed pharmacokinetic parameters compatible with clinical development as a therapeutic peptide against CLL.