Nonclinical pharmacology and toxicology studies of LY01620, a therapeutic mRNA vaccine against human papillomavirus 16-related cancers

Human papillomavirus (HPV) infection and related cancers remain significant public health concerns worldwide. Among high-risk HPV genotypes, HPV16 demonstrates the highest epidemiological prevalence. The viral oncoproteins E6 and E7 are crucial drivers of HPV16-associated carcinogenesis and have become key therapeutic targets for treating HPV16-related cervical intraepithelial neoplasia and cancers. HPV prophylactic vaccines have been widely implemented in clinical practice; however, effective therapeutic interventions for infected individuals remain limited. Therefore, the development of therapeutic HPV vaccines is urgently needed. LY01620 is an investigational mRNA therapeutic vaccine targeting HPV16 E6/E7 antigens. To support LY01620’s clinical trial application and development, comprehensive nonclinical studies were conducted, including immunogenicity evaluations in mice and rats, anti-tumor activity and mechanistic studies in C3.43 tumor-bearing mice, single-dose tissue distribution study in rats, and a GLP-compliant repeated-dose toxicity study in rats combined with toxicokinetics, local irritation, and immunotoxicity assessments. LY01620 demonstrated strong immunogenicity in mice and rats and exhibited significant anti-tumor activity through inducing a strong Th1-polarized immune response, increasing frequency of antigen-specific T cells, and enhancing infiltration of CD8 + T cells and mature macrophages into tumors. LY01620 mRNA exhibited sustained accumulation in inguinal lymph nodes and spleens, potentially facilitating persistent antigen presentation and prolonged immunological effects. In the repeated-dose toxicity study in SD rats, LY01620 exhibited a favorable safety profile, with the no observed adverse effect level was the highest dose of 300 μg/animal. In conclusion, preclinical studies have demonstrated that LY01620 exhibited favorable mechanism of action-related efficacy and a well-tolerated safety profile, supporting its further development.