05/06/2018
Published in Primary Care and
News · June 05, 2018
DDW 2018: Integrase-Derived Peptides + CD24-Targeted Lentivirus Therapy Promotes Killing and Removal of a Wide Range of Cancer Cells
PracticeUpdate Editorial Team
June 5, 2018—Washington, DC—Integrase-derived peptides + CD24-targeted lentivirus therapy has been found to promote killing and removal of a wide range of cancer cells.
This outcome of a murine analysis of the experimental drug Gammora (integrase-derived peptide + targeted lentiviruses) that employed high-performance liquid chromatography/mass spectrometry, MTD antibodies, fluorescent microscopy, and the enzymatic MTT assay, was presented at Digestive Disease Week (DDW) 2018, from June 2 – 5.
Nadir Arber, MD, of the Tel-Aviv Sourasky Medical Center, Israel, explained that the HIV integrase is important in the integration of viral DNA into the host genome. Such integration results in double-stranded breaks.
Only 1 to 2 copies are integrated, due to inhibition of HIV-1 Rev protein, rendering the cells invisible to the immune system. CD24 is expressed mostly on cancer and not normal cells.
Dr. Arber and colleagues hypothesized that specific targeting of viral particles using a monoclonal antibody to CD24, together with enzyme stimulation and a rise in frequency of integration events, would increase the occurrence of double-stranded breaks. This increased occurrence, would, in turn, lead to genomic instability, and ultimately to apoptosis of target cells.
The team developed a therapeutic platform for selective eradication of cancer cells. The platform consists of targeted lentivirus particles and integrase-derived peptides.
Dr. Arber told Elsevier’s PracticeUpdate, “In 2016, Abraham Loyter, PhD, and colleagues at the Hebrew University of Jerusalem, Israel, found that combination of specific peptides, derived from HIV-1 integrase, together with lentiviruses, promote killing of a variety of cultured cells, among them, cancer cells.”
Integrase-derived peptides (designated INR2 and INS) were synthesized. Humanized anti-CD24 antibody was engineered and fused to the lentivirus envelope. “We have been studying CD24 for over a decade. We have confirmed it to be expressed mostly on cancer cells,” Dr. Arber said.
Peptide stability and solubility were analyzed by high-performance liquid chromatography/mass spectrometry. Their activity and permeability into cells were also analyzed.
In addition, an acute intravenous toxicity study was performed. Both peptides, INS and INR2, were found to be well tolerated without adverse effects. Cell death was measured qualitatively using fluorescent microscopy and quantified using the enzymatic MTT assay.
Colorectal, pancreatic, and lung cancer cells were used to evaluate the potency of the lentiviral-based system. Efficacy was assessed in vivo, in n**e mice bearing xenografts of lung cancer. The mice were treated systemically twice weekly.
INS and INR2 stimulated viral integrase in vitro. Single IV administration of INR2 and INS was well tolerated without adverse effects. Unlike other gene therapies, these lentivirus particles contained nonfunctional DNA with flanked long terminal repeats.
Such nonfunctional DNA with flanked long terminal repeats allowed for integration into target cell DNA and formation of double-stranded breaks. Integrase, whose activity was stimulated by integrase-derived peptides, caused cell integration.
Massive cell death (40% - 70%) was achieved dose-dependently.
Raltegravir, an approved antiretroviral drug, was able to inhibit cell death 2 to 3 times. In vivo, the combination of NR2 + INS led to significant reduction (50%) in tumor volume.
Live imaging using an IVIS device of tumors and selected organs confirmed that the viruses indeed reached the tumor after systemic injection and that anti-CD24 enhanced the selectivity of infection.
Dr. Arber concluded that the use of integrase-derived peptides + the CD24-targeted lentiviral therapy approach suggests a novel strategy that specifically promotes killing and removal of a wide range of cancer cells.
