A major asset of many monoclonal antibody (mAb)-based biologics is their persistence in circulation. The MHC class I family Fc receptor, FCGRT, is primarily responsible for this extended pharmacokinetic behavior. Engagement of FCGRT with the crystallizable fragment (Fc) domain protects IgG from catabolic elimination, thereby extending the persistence and bioavailability of IgG and related Fc-based biologics. There is a need for reliable in vivo models to facilitate the preclinical development of novel IgG-based biologics. FcRn-humanized mice have been widely accepted as translationally relevant surrogates for IgG-based biologics evaluations. Although such FCGRT-humanized mice, especially the mouse strain, B6.Cg-Fcgrt tm1Dcr Tg(FCGRT)32Dcr (abbreviated Tg32), have been substantially validated for modeling humanized IgG-based biologics, there is a recognized caveat – they lack an endogenous source of human IgG that typifies the human competitive condition. Here, we used CRISPR/Cas9-mediated homology-directed repair to equip the hFCGRT Tg32 strain with a human IGHG1 Fc domain. This replacement now results in mice that produce human IgG1 Fc-mouse IgG Fab 2 chimeric antibodies at physiologically relevant levels, which can be further heightened by immunization. This endogenous chimeric IgG1 significantly dampens the serum half-life of administered humanized mAbs in an hFCGRT-dependent manner. Thus, such IgG1-Fc humanized mice may provide a more physiologically relevant competitive hFCGRT-humanized mouse model for the preclinical development of human IgG-based biologics.

Improved mouse models for type 1 diabetes (T1D) therapy development are needed. T1D susceptibility is restored to normally resistant NOD.β2m mice transgenically expressing human disease-associated HLA-A*02:01 or HLA-B*39:06 class I molecules in place of their murine counterparts. T1D is dependent on pathogenic CD8 T-cell responses mediated by these human class I variants. NOD.β2m-A2.1 mice were previously used to identify β-cell autoantigens presented by this human class I variant to pathogenic CD8 T cells and for testing therapies to attenuate such effectors. However, NOD.β2m mice also lack nonclassical MHC I family members, including FcRn, required for antigen presentation, and maintenance of serum IgG and albumin, precluding therapies dependent on these molecules. Hence, we used CRISPR/Cas9 to directly ablate the NOD H2-K and H2-D classical class I variants either individually or in tandem (cMHCI). Ablation of the H2-A class II variant in the latter stock created NOD mice totally lacking in classical murine MHC expression (cMHCI/II). NOD-cMHCI mice retained nonclassical MHC I molecule expression and FcRn activity. Transgenic expression of HLA-A2 or -B39 restored pathogenic CD8 T-cell development and T1D susceptibility to NOD-cMHCI mice. These next-generation HLA-humanized NOD models may provide improved platforms for T1D therapy development.

Background Suicide is one of the leading causes of preventable death in the USA, representing a critical public health threat. Suicide risks differ for different populations. In particular, the sexual and gender minority (SGM) population remains at increased risk for suicide. One of the circumstances that may differ for SGM and non-SGM individuals is the propensity to leave a suicide note. Information regarding note-leaving may be helpful in informing suicide prevention and intervention. Aims This study documents the differences in note-leaving in SGM individuals compared with non-SGM individuals, using recent data from the National Violent Death Reporting System (N = 98 515) and accounting for important covariates. Method We fit a logistic regression model with SGM status and covariates predicting note-leaving in suicide. Results SGM decedents were 1.508 times more likely to leave a note than their non-SGM counterparts, controlling for demographic, mental health and substance use covariates. Conclusions These findings highlight the importance of tailoring suicide prevention and intervention efforts to meet the needs of SGM populations.

No abstract

Preclinical assessment is required for the growing number of immunotherapeutics in development. Clinically relevant pharmacokinetic analysis can be achieved by using transgenic mice that uniquely express the human Fc receptor neonatal (hFcRn). To demonstrate the utility of the human FcRn Tg mouse model platform, three immunotherapeutics (pembrolizumab, ipilimumab, and belatacept) were administered IV to Tg32, Tg276, FcRn null, and B6 wild type mice. The mice were blood sampled (25 µL) at 1, 3, 5, 7, 9, 12, 16, 19, 22, 26, and 30 days. Immunotherapeutic plasma concentations, assessed by human IgG ELISA, were pharmacokinetically analyzed. Tg32 mice yielded half-life values for these immunotherapeutics with ranges that mimicked patient data. Though reduced in scale, Tg276 mice also produced half-life data that correlated with the established human half-life data for pembrolizumab, ipilimumab, and belatacept. These results confirm that the human FcRn Tg model platform can be broadly applied to preclinical pharmacokinetic screening of mAb and Fc-fusion based immunotherapeutics. Citation Format: Gregory J. Christianson, Emily Lowell, Cat Lutz. Utility of human FcRn transgenic mice for preclinical screening of immunotherapeutics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4905.