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

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, 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. Both hSA and FcRn have already been shown to be expressed and enable half-life extension of compounds with enhanced binding to hFcRn and hSA in genO-hSA/hFcRn mice (Viuff et al. , 2016). Humanization has been confirmed by the detection of circulating human IgG1 levels in mice. Other immunoglobulins are also present in their serum, with only minor differences relative to WT mice, and suggesting no impairment on class switch. To test the tolerance to hIgG1, mice received a weekly injection of Teropavimab (anti-gp120- hIgG1κ) for 7 weeks. Blood was collected 2 hours after each injection for quantification of circulating Teropavimab. Expression of hIgG1 in mice leads to better tolerance to multiple cycles of Teropavimab compared to WT and genO-hSA/hFcRn mice. Indeed, one week after the last injection (day 49), Teropavimab is not detected in genO-hSA/hFcRn mice, whereas is detected in 2/5 WT mice, and in 5/5 mice expressing hIgG1 mice. Taken together, these results indicate that constitutive expression of hIgG1 promotes immunological tolerance to repeated administrations of therapeutic hIgG1 in murine models. Moreover, hIgG1 expression has been integrated into advanced mouse models such as genO-PanhCD3 and genO-FcgammaR to enable tolerance induction in experimental systems designed for the evaluation of T-cell engagers and Fc-mediated effector functions, respectively. In addition, an hIgG1-expressing variant of genO-TFRC model is available to support the characterization of hIgG1-based antibodies engineered for TFRC-mediated transcytosis, facilitating targeted delivery of therapeutic antibodies across the blood-brain barrier.