Prec-O2-02 - Anti-tumor effect of anti-apoptosis clone 11 protein-derived peptides on Sézary syndrome malignant CD4+ T lymphocytes

Abstract

Sézary syndrome (SS) is a rare, aggressive leukemic form of cutaneous T-cell lymphoma characterized by generalized erythroderma, lymphadenopathy and circulating malignant CD4+ T cells (Sézary cells). Sézary syndrome evolves very quickly, patients are severely immunocompromised and their quality of life is drastically impaired. SS prognosis remains dismal despite recent therapeutic advances. AAC-11 (Anti-Apoptosis Clone 11, also known as Api5) is a survival scaffold protein that is widely expressed in cancer cells. Recent data indicate that AAC-11 might to be one of the central molecules involved in cancer cell progression and survival. Therefore, its inactivation might constitute an attractive approach for developing novel cancer therapeutics. AAC-11 contains a heptad leucine repeat domain that constitutes a protein-protein interaction motif, allowing its interaction with several apoptosis regulatory proteins. Loss-of-function mutations of the heptad leucine repeat motif are responsible for a defect in the interaction with its binding partners and associated with an abolition of the survival properties of AAC-11. We have recently described cell penetrating peptides based on the fusion of penetratin and a portion of the heptad leucine repeat region of AAC-11 that can induce cancer cells death. This effect is not observed in normal cells, suggesting high therapeutic indices. Here we evaluated the anti-tumor effect of a novel AAC-11-derived peptide, termed RT39, in the context of Sézary syndrome. Our results demonstrate that RT39 exerts an efficient and specific cytotoxic activity towards Sézary cells, while sparring the other immune cell populations, both <i>ex vivo</i> on primary patient cells and <i>in vivo</i> in preclinical Sézary syndrome murine models. Mechanistic studies revealed that RT39 induces membranolysis of Sézary cells by means of binding to p21-activated kinase 1 (PAK1) in the context of Sézary cells plasma membrane, where PAK1 is overexpressed. Preliminary pharmacokinetic studies in mice indicated that, after intravenous, subcutaneous or intraperitoneal administration, the half-life of the peptide is of the order of 30 minutes, but the elimination phase is very prolonged with high AUCs, indicative of durable exposure. Along with excellent tolerability in mice, our preclinical results support the development of RT39 as a new therapeutic strategy in Sézary syndrome.