Preclinical safety assessment of a therapeutic human papillomavirus DNA vaccine combined with intravaginal interleukin-7 fused with hybrid Fc in female rats

• Published in: Toxicology and applied pharmacology 2021-02, Vol.413, p.115406, Article 115406
• Main Authors: Han, Kang-Hyun, Jang, Min Seong, Han, Hyoung-Yun, Im, Wan-Jung, Jung, Kyung Jin, Park, Ki Seok, Choi, Donghoon, Jeong, Hye Gwang, Kim, Sang Kyum, Moon, Kyoung-Sik
• Format: Article
• Language: English
• Subjects: Administration, Intravaginal; Animals; Biomarkers - blood; Biomarkers - urine; Dose-Response Relationship, Drug; Drug Therapy, Combination; Electroporation; Female; IL-7hyFc treatment; Immunoglobulin Fc Fragments - administration & dosage; Immunoglobulin Fc Fragments - toxicity; Interleukin-7 - administration & dosage; Interleukin-7 - toxicity; Neutrophils - drug effects; Neutrophils - metabolism; No observed adverse effect level; Papillomavirus Vaccines - administration & dosage; Papillomavirus Vaccines - toxicity; Rats; Rats, Sprague-Dawley; Recombinant Fusion Proteins - toxicity; Repeated toxicity study; Risk Assessment; T-Lymphocytes - drug effects; T-Lymphocytes - metabolism; Therapeutic HPV DNA vaccine; Time Factors; Vaccines, DNA - administration & dosage; Vaccines, DNA - toxicity
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2021.115406

This study was conducted to establish the toxicological profile of combination treatment with therapeutic HPV DNA vaccines (GX-188E) and the long-acting form of recombinant human interleukin-7 fused with hybrid Fc (IL-7hyFc). GX-188E was administered intramuscularly by electroporation with or without IL-7hyFc intravaginally once per 2 weeks for 8 weeks (five times) in female Sprague-Dawley rats. Because up-regulation of immune responses and migration of antigen-specific T cells in cervicoviginal tissue were predicted as therapeutic effects, we distinguished adverse effects from therapeutic effects based on the severity of the systemic immune response, reversibility of lymphoid tissue changes, target tissue damage, and off-target immune responses. We observed that the number of neutrophils was increased, and the number of lymphocytes was decreased in the blood. Further, myofiber degeneration, necrosis, fibroplasia, and cell infiltration were observed at the GX-188E administration site. These changes were fully or partially recovered over a 4-week period. Analysis of lymphocytes in spleen revealed that CD4+ T cells and total T cells decreased in rats treated with GX-188E in combination with a high dose of IL-7hyFc (1.25 mg/animal). However, these changes were not considered adverse because they were transient and may have been related to electroporation-mediated DNA delivery or the local migration of lymphocytes induced by IL-7. Therefore, the potential toxicity of the combination of GX-188E and IL-7hyFc treatment was comparable to that of GX-188E treatment alone, and the no observed adverse effect level for GX-188E with IL-7hyFc was considered as 320 μg/animal for GX-188E and 1.25 mg/animal for IL-7hyFc. [Display omitted] •Preclinical safety of therapeutic HPV DNA vaccine (GX-188E) and local IL-7hyFc combination treatment.•Potential adverse effects of this combination were comparable to HPV DNA vaccine alone.•The NOAEL for this combination is 320 μg/animal for GX-188E and 1.25 mg/animal for IL-7hyFc.