Scardovi, AL;
Bartolucci, D;
Montemurro, L;
Bortolotti, S;
Angelucci, S;
Amadesi, C;
Nieddu, G;
... Tonelli, R; + view all
(2024)
Preclinical Pharmacokinetics in Tumors and Normal Tissues of the Antigene PNA Oligonucleotide MYCN-Inhibitor BGA002.
Nucleic Acid Therapeutics
10.1089/nat.2024.0005.
(In press).
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Abstract
Although MYCN has been considered an undruggable target, MYCN alterations confer poor prognosis in many pediatric and adult cancers. The novel MYCN-specific inhibitor BGA002 is an antigene peptide nucleic acid oligonucleotide covalently bound to a nuclear localization signal peptide. In the present study, we characterized the pharmacokinetics (PK) of BGA002 after single and repeated administration to mice using a novel specific enzyme-linked immunosorbent assay. BGA002 concentrations in plasma showed linear PK, with dose proportional increase across the tested dose levels and similar exposure between male and female and between intravenous and subcutaneous route of administration. Repeated dosing resulted in no accumulation in plasma. Biodistribution up to 7 days after single subcutaneous administration of [14C]-radiolabeled BGA002 showed broad tissues and organ distribution (suggesting a potential capability to reach primary tumor and metastasis in several body sites), with high concentrations in kidney, liver, spleen, lymph nodes, adrenals, and bone marrow. Remarkably, we demonstrated that BGA002 concentrates in tumors after repeated systemic administrations in three mouse models with MYCN amplification (neuroblastoma, rhabdomyosarcoma, and small-cell lung cancer), leading to a significant reduction in tumor weight. Taking into account the available safety profile of BGA002, these data support further evaluation of BGA002 in patients with MYCN-positive tumors.
| Type: | Article |
|---|---|
| Title: | Preclinical Pharmacokinetics in Tumors and Normal Tissues of the Antigene PNA Oligonucleotide MYCN-Inhibitor BGA002 |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1089/nat.2024.0005 |
| Publisher version: | http://dx.doi.org/10.1089/nat.2024.0005 |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. |
| Keywords: | Science & Technology, Life Sciences & Biomedicine, Biochemistry & Molecular Biology, Chemistry, Medicinal, Medicine, Research & Experimental, Pharmacology & Pharmacy, Research & Experimental Medicine, MYCN-positive tumors, antigene PNA-peptide, pharmacokinetics, biodistribution, pharmacodynamics, HUMAN NEUROBLASTOMA-CELLS, PEPTIDE NUCLEIC-ACID, C-MYC, GENE-EXPRESSION, CANCER, ONCOGENE, PHOSPHOROTHIOATE, AMPLIFICATION, THERAPEUTICS, SEQUENCE |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy > Pharmacology |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10195615 |
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