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Latest guides
Mouse models for the assessment of cGAS/STING therapeutics: practical considerations for translational research
Summary:
- The cGAS-STING pathway detects misplaced double-stranded DNA and connects DNA sensing to type I interferon and inflammatory signaling.
- cGAS and STING are distinct pharmacological targets:
- cGAS inhibitors prevent the production of 2′3′-cGAMP.
- STING inhibitors block signaling downstream of cGAMP.
- STING agonists activate innate immune signaling independently of upstream DNA detection.
- Pathway activation can support antitumor immunity, antiviral responses and vaccine adjuvanticity.
- Excessive or chronic activation can contribute to autoinflammatory, autoimmune and neuroinflammatory disease.
- Wild-type mice are valuable for pathway biology but may not predict the activity of compounds designed specifically for human cGAS or human STING.
- STING pharmacology is particularly species- and allele-dependent. Activity should be confirmed against the exact human STING variant being modelled.
Mouse models for the assessment of therapeutics targeting the PD-1/PD-L1 axis: practical considerations for translational research
Summary:
- The PD-1/PD-L1 pathway is one of the most clinically validated immune checkpoints in oncology.
- Most clinical anti-PD-1 and anti-PD-L1 antibodies bind human targets and do not fully cross-react with mouse PD-1 or PD-L1.
- Wild-type mice often require surrogate anti-mouse antibodies and cannot directly evaluate human-specific therapeutics.
- Humanized PD-1 and PD-L1 knock-in mice enable direct testing of human therapeutics in an immunocompetent setting.
- Physiological expression of humanized targets is critical for generating translatable efficacy and pharmacodynamic data.
- Model selection depends on whether the objective is target engagement, efficacy testing, mechanism-of-action studies, candidate ranking, combination therapy assessment, or evaluation in a human immune system.
- Humanized immune system (HIS) models provide access to human immune cells but introduce additional variability, cost, and complexity.
Mice with a human immune system (HIS mice) for the assessment of therapeutics: practical considerations for translational research
Summary:
- HIS mice are immunodeficient mice engrafted with human cells (such as HSCs and PBMCs) or human tissue (bone marrow, liver, thymus), enabling the in vivo development of many components of the human immune system.
- HIS mice are particularly useful when the research question depends on human immune-cell biology, such as checkpoint blockade, T-cell engagers, cell therapies, cytokine-driven toxicity, or complex tumor-immune interactions.
- A key limitation of conventional HIS models such as NSG-HIS is that myeloid and NK-cell reconstitution is often incomplete, which can reduce translational relevance for mechanisms involving ADCC, phagocytosis, cytokine release, or myeloid immune suppression.
- The BRGSF background was developed to support efficient human engraftment through the introduction of NOD Sirpα polymorphism (Yamauchi et al., 2013) while avoiding some broader NOD-strain abnormalities; BRGSF mice preserve normal C5 complement function, supporting complement-relevant antibody studies better than some NOD-based hosts.
- The genO-BRGSF-HIS model is a human immune system model used for translational immunology and antibody testing. It is especially useful when researchers need to study human immune cell interactions rather than just target binding or pharmacokinetics.
- Model selection matters: choosing the wrong HIS model can lead to false efficacy signals, missed toxicity, poor biomarker interpretation, or limited translation to the clinic.
Humanized FcγR mouse models for the assessment of therapeutic antibodies – practical considerations for translational research
Summary:
- Fcγ receptors (FcγRs) are critical determinants of antibody efficacy and safety, especially for IgG-based therapeutics.
- Species differences between murine and human FcγRs significantly impact antibody binding, effector function, and PK/PD interpretation.
- Wild-type mice often provide misleading results for Fc-mediated functions (e.g., ADCC, ADCP).
- Humanized FcγR mouse models enable translationally relevant evaluation of: Effector function, Fc-engineering strategies, and safety (e.g., cytokine release, immune activation).
- Model selection directly impacts data interpretation and candidate ranking.
- Using an inappropriate model can lead to: False efficacy signals, under- or over-estimation of toxicity, and incorrect Fc-optimization decisions.
Mouse models for the assessment of T-cell engagers: Practical considerations for translational research
Summary:
- CD3 engagement is the core mechanism of action of T-cell engagers (TCEs) and must be relevant for humans.
- Species differences in the CD3 sequence and structure between mice and humans, as well as their limited antibody cross-reactivity, may result in inaccurate findings when using wild-type (WT) mouse data.
- Humanized CD3 mouse models enable mechanistic, efficacy, and safety‑relevant TCE assessment.
- Model choice strongly impacts T-cell activation strength, cytokine release, and translational value.
- Using the wrong model can lead to false negatives, incorrect toxicity, or misleading potency ranking.
Mouse models for pharmacokinetics assessment of therapeutic antibodies – Practical considerations for translational research
Summary:
- FcRn biology is the main driver of IgG half‑life and must be human‑relevant for translational PK.
- Human FcRn is required to rank human IgGs and evaluate Fc‑engineered antibodies.
- Albumin recycling is frequently underestimated but can strongly influence antibody exposure.
- hFcRn‑only models (e.g., Tg32) fail for albumin‑binding therapeutics and can mis‑rank candidates.
- Models expressing both human FcRn and human albumin at physiological levels provide the most decision‑grade PK data.
