Evaluation of the human type 3 adenoviral dodecahedron as a vector to target acute myeloid leukemia

• Published in: Molecular therapy. Methods & clinical development 2021-03, Vol.20, p.181-190
• Main Authors: Caulier, Benjamin, Stofleth, Gaëlle, Hannani, Dalil, Guidetti, Mélanie, Josserand, Véronique, Laurin, David, Chroboczek, Jadwiga, Mossuz, Pascal, Plantaz, Dominique
• Format: Article
• Language: English
• Subjects: acute myeloid leukemia; adenoviral dodecahedron; Biotechnology; delivery vector; leukemic stem cells; Life Sciences; Original; virus-like particles
• ISSN: 2329-0501; 2329-0501
• DOI: 10.1016/j.omtm.2020.11.009

Intensive systemic chemotherapy is the gold standard of acute myeloid leukemia (AML) treatment and is associated with considerable off-target toxicities. Safer and targeted delivery systems are thus urgently needed. In this study, we evaluated a virus-like particle derived from the human type 3 adenovirus, called the adenoviral dodecahedron (Dd) to target AML cells. The vectorization of leukemic cells was proved very effective at nanomolar concentrations in a time- and dose-dependent manner, without vector toxicity. The internalization involved clathrin-mediated energy-dependent endocytosis and strongly correlated with the expression of αVβ3 integrin. The treatment of healthy donor peripheral blood mononuclear cells showed a preferential targeting of monocytes compared to lymphocytes and granulocytes. Similarly, monocytes but also AML blasts were the best-vectorized populations in patients while acute lymphoid leukemia blasts were less efficiently targeted. Importantly, AML leukemic stem cells (LSCs) could be addressed. Finally, Dd reached peripheral monocytes and bone marrow hematopoietic stem and progenitor cells following intravenous injection in mice, without excessive spreading in other organs. These findings reveal Dd as a promising myeloid vector especially for therapeutic purposes in AML blasts, LSCs, and progenitor cells. [Display omitted] Vectors targeting myeloid cells are scarce and yet crucial for the improvement of therapy efficacy and tolerability against myeloid neoplasia. This study highlights promising features of a non-infectious dodecahedral adenovirus-like nanoparticle to target preferentially acute myeloid leukemia blasts and hematopoietic stem and progenitor cells.