Human IgG1-expressing mouse models for tolerance induction and reliable assessment of IgG1-based therapeutic antibodies

Background: Mouse models expressing human targets offer strong translational relevance for evaluating human antibody-based therapies in IO. However, when treated with human antibodies, these models frequently develop anti-drug antibodies (ADA), which can compromise the interpretation of preclinical data. ADA formation may alter pharmacokinetics (PK), reduce therapeutic efficacy, and introduce immune-related artifacts that do not reflect human responses. This immune recognition limits the duration and reliability of treatment studies, especially for repeated dosing or long-term efficacy assessments. Therefore, careful selection and engineering of preclinical models that minimize ADA formation are essential to accurately predict clinical performance and support the development of safe and effective biologics. We generated a model expressing humanized IgG1, the most used isotype in clinical development, which was designed to induce tolerance to human IgG1-based therapies. Herein, we describe the investigation of the tolerance induced by the expression of hIgG1 in a mouse model humanized for serum albumin, FcRn, which was developed to investigate PK profile of antibodies in a context of tolerance to hIgG1.