Integrase-derived peptides together with CD24-targeted lentiviral particles inhibit the growth of CD24 expressing cancer cells.

Abstract

The integration of viral DNA into the host genome is mediated by viral integrase, resulting in the accumulation of double-strand breaks. Integrase-derived peptides (INS and INR) increase the number of integration events, leading to escalated genomic instability that induces apoptosis. CD24 is a surface protein expressed mostly in cancer cells and is very rarely found in normal cells. Here, we propose a novel targeted cancer therapeutic platform based on the lentiviral integrase, stimulated by integrase-derived peptides, that are specifically delivered to cancerous cells via CD24 antigen-antibody targeting. INS and INR were synthesized and humanized and anti-CD24 antibodies were fused to the lentivirus envelope. The activity, permeability, stability, solubility, and toxicity of these components were analyzed. Cell death was measured by fluorescent microscopy and enzymatic assays and potency were tested in vitro and in vivo. Lentivirus particles, containing non-functional DNA led to massive cell death (40-70%). Raltegravir, an antiretroviral drug, inhibited the induction of apoptosis. In vivo, single and repeated administrations of INS/INR were well tolerated without any adverse effects. Tumor development in nude mice was significantly inhibited (by 50%) as compared to the vehicle arm. In summary, a novel and generic therapeutic platform for selective cancer cell eradication with excellent efficacy and safety are presented.

• Authors: Shiran Shapira, Eynat Finkelshtein, Dina Kazanov, Esmira Naftali, Irena Stepansky, Abraham Loyter, Daniel Elbirt, Mori Hay-Levy, Eli Brazowski, Faina Bedny, Roy Dekel, Dov Hershkovitz, Arye Blachar, Ido Wolf, Nadir Arber
• Journal: Oncogene (Oncogene) Vol. 40 Issue 22 Pg. 3815-3825 (06 2021) ISSN: 1476-5594 [Electronic] England
• PMID: 33958722 (Publication Type: Journal Article)

Chemical References

• Antibodies, Monoclonal
• CD24 Antigen
• CD24 protein, human
• Peptide Fragments
• Integrases

Topics

• Animals
• Antibodies, Monoclonal (immunology)
• Apoptosis (drug effects)
• CD24 Antigen (biosynthesis, immunology)
• Cell Line, Tumor
• Humans
• Integrases (chemistry, pharmacology)
• Lentivirus (enzymology, genetics, immunology)
• Mice
• Mice, Nude
• Neoplasms (genetics, metabolism, therapy, virology)
• Oncolytic Virotherapy (methods)
• Peptide Fragments (chemistry, pharmacology)
• Tissue Distribution
• Xenograft Model Antitumor Assays