The inhibin βC subunit (INHBC) is a member of the transforming growth factor-β (TGF-β) superfamily. Its encoded precursor protein undergoes hydrolytic processing to form homodimers or heterodimeric activin complexes with βA/βB subunits, which are involved in inhibiting the activin A signaling pathway and regulating multiple physiological processes. INHBC is abundantly expressed in the liver and also participates in the regulation of hormone secretion in the reproductive system ^[1-2]. Studies have confirmed that circulating INHBC is associated with reduced subcutaneous fat, dyslipidemia, and increased risks of coronary artery disease (CAD) and non-alcoholic fatty liver disease (NAFLD). Meanwhile, obesity, hypertriglyceridemia, type 2 diabetes mellitus, and other conditions positively regulate plasma INHBC levels. Recombinant INHBC (Act-C) can inhibit lipolysis in adipocytes by activating the ALK7-SMAD2/3 signaling pathway, further clarifying its role in metabolic regulation ^[3]. The inhibin βE subunit (INHBE) is also a member of the TGF-β superfamily, with highly specific expression in hepatocytes. The precursor protein of INHBE generates the inhibin β subunit after proteolytic processing. This protein is associated with various cellular processes, including cell proliferation, apoptosis, immune response, and hormone secretion. During the development of obesity and diabetes, the expression of INHBE protein inhibits the proliferation and growth of relevant cells in the pancreas and liver. Research has found a positive correlation between INHBE expression in the liver and insulin resistance and body mass index (BMI), suggesting that INHBE may be a liver factor in altering systemic metabolic status under conditions of obesity-related insulin resistance ^[4]. The studies conducted by Alnylam Pharmaceuticals and the Regeneron Genetics Center (RGC) revealed the close relationship between INHBE and fat regulation. The research demonstrated that rare loss-of-function variants in INHBE may protect the liver from the impact of inflammation, abnormal blood lipids, and type 2 diabetes by promoting healthy fat storage. Patients carrying such mutations exhibit more normal fat distribution, significantly reduced abdominal fat, improved metabolic conditions, and a decreased risk of cardiovascular diseases and type 2 diabetes ^[5-7]. These findings suggest that INHBE is a liver-specific negative regulator of fat storage. Inhibiting the expression of INHBE genes and proteins may be a promising strategy for treating metabolic disorders associated with improper fat distribution and storage. The huINHBC/huINHBE mouse is a dual-gene humanized model established via gene editing technology. In this model, the sequences from upstream of the mouse Inhbc exon 1 to the mouse Inhbe 3'UTR were replaced with the sequences from upstream of the human INHBC exon 1 to 3'UTR of the human INHBE. This model can be utilized for investigating the mechanisms and therapeutic approaches of fat distribution and storage, dyslipidemia, CAD, NAFLD, as well as for the development of INHBC/INHBE-targeted drugs.

Ces1c, the mouse carboxylesterase 1C (Carboxylesterase 1C) gene, encodes an enzyme highly expressed in rodent plasma, responsible for hydrolyzing various ester- or amide-containing drugs, particularly cleavable linkers (Linker) in antibody-drug conjugates (ADCs) such as Val-Cit (VC) linkers ^[1-2]. Mouse Ces1c causes non-specific hydrolysis of ADCs in plasma, accelerating drug clearance and severely deviating pharmacokinetic (PK) profiles from human reality ^[3-4]. In humans, CES1 and CES2 are mainly distributed in the liver and intestine, with negligible activity in plasma, whereas mouse Ces1c, lacking an endoplasmic reticulum retention signal, is secreted in large amounts into plasma ^[3-4]. Besides its role in drug metabolism, Ces1c is also involved in physiological processes such as lipid metabolism. Studies show that, in evaluating VC-based ADCs, Ces1c in mouse plasma miscleaves the VC-PABC structure, causing premature release of toxic payloads, resulting in systemic toxicity and underestimation of antitumor activity ^[5-9]. In preclinical evaluation of ADCs, differences in immunodeficient strain backgrounds affect the biodistribution, clearance rates, and reliability of PK/PD results for humanized antibodies ^[10-15]. For example, highly immunodeficient NOD-SCID and its derivative strains, due to enhanced Fc-FcγR interactions, lead to shortened serum half-life of ADCs and increased off-target organ trapping, thereby underestimating antitumor activity ^[10-15]. In contrast, the CB17-SCID background exhibits superior characteristics in maintaining antibody half-life and optimizing biodistribution, providing more reliable efficacy data ^[13-15]. The CB17-SCID-Ces1c-KO mouse is a gene knockout (KO) model, generated on the CB17-SCID immunodeficient background with excellent PK/PD properties, using gene editing technology to knock out the Ces1c gene in mice. This model can be used for ADC drug development, particularly for evaluating VC linker drugs, and to avoid non-specific interference in mouse plasma, provides more clinically predictive efficacy data.

The FCGR3A gene (commonly known as CD16A) encodes the FcγRIIIA protein, a transmembrane receptor that binds the Fc portion of IgG with high functional affinity (particularly to immune complexes). This gene is primarily expressed in immune cells, most notably on Natural Killer (NK) cells, where it serves as a critical trigger for antibody-dependent cellular cytotoxicity (ADCC), as well as on subsets of monocytes and macrophages ^[1]. By binding to the Fc region of antibodies that have coated a target cell (such as a pathogen or tumor cell), the CD16A protein initiates intracellular signaling cascades that lead to the release of cytotoxic granules and pro-inflammatory cytokines ^[2]. While humans utilize FCGR3A, the mouse Fcgr4 gene serves as its functional ortholog, encoding the FcγRIV receptor that is essential for mediating similar IgG2-dependent effector functions in murine models ^[3]. In clinical contexts, polymorphisms in FCGR3A (such as the V158F variant) are significant because they influence the binding affinity for therapeutic antibodies, impacting the efficacy of monoclonal antibody treatments in oncology and autoimmune disorders ^[4]. Furthermore, dysregulation or mutations in this gene are associated with increased susceptibility to recurrent viral infections and systemic lupus erythematosus (SLE). The huCD16A(FCGR3A) mouse model was generated by replacing the sequences from upstream of exon 1 to downstream of exon 5 of mouse Fcgr4 gene with the sequences from upstream of exon 1 to downstream of exon 6 of the human FCGR3A gene. This model is suitable for the study of various autoimmune diseases, such as systemic lupus erythematosus (SLE), as well as for oncology research, and for the screening, development, and safety evaluation of CD16A-targeted drugs.

Interferons (IFNs) are potent cytokines that serve as a critical component of the body's first line of defense against viral infections, playing a key role in inflammation and immune control by directly inducing pathogen-inhibiting molecules that suppress viral replication ^[1]. Arthropod-borne viruses (arboviruses) like Dengue virus (DENV), Zika virus (ZIKV), and Yellow Fever virus (YFV) encode proteins that antagonize the IFN response, helping these viruses evade host immunity and maintain sufficient viral loads in the blood (viremia) to sustain the vector-host transmission. Arboviruses pose a significant public health threat, affecting around 3.9 billion people in tropical and subtropical regions. However, most preclinical studies suggest that arboviruses cannot inhibit IFN responses in mice, rendering immunocompetent mice resistant to infection, with low viral loads and limited circulation, thus limiting their use in infection research ^[2-3]. As a result, immunodeficient mouse models with defects in multiple IFN signaling pathways have become essential tools for studying arbovirus pathogenesis and vaccine development ^[2-4]. Studies have demonstrated that wild-type mice of strains like C57BL/6, CD-1, or 129 rarely exhibit clinical symptoms after infection with arboviruses such as ZIKV. However, the virus has been detected in the blood, ovaries, and spleen of ZIKV-infected 129 mice, suggesting that this strain may be more susceptible to arboviruses ^[5-6]. Because the virus can persist in the bloodstream without causing disease or death, the 129 strain can be used to evaluate the teratogenic effects of such viruses. Furthermore, the 129 strain is commonly used in interferon signaling-deficient models related to other viral infections ^[7-8]. The IFNAR1 gene encodes a key component of the type I IFN receptor, while the IFNGR1 gene encodes the ligand-binding chain (α) of the type II (γ) IFN receptor. AG129 mice, which are knockout models for both the type I (α/β) IFN receptor (Ifnar1) and the type II (γ) IFN receptor (Ifngr1), lack functional IFNAR1 and IFNGR1 proteins, resulting in deficiencies in α/β/γ interferon receptor signaling and heightened susceptibility to viral infections. Homozygous AG129 mice are viable and fertile, and exhibit increased sensitivity to arboviral infections, generating viremia similar to that seen in humans. Compared to IFNα/β/γR KO mice on the C57BL/6 background, the 129-background AG129 mice exhibit more pronounced neurological symptoms after infection ^[6,9].

The MASP2 gene encodes MASP-2, a serum serine protease that serves as a key mediator in complement system activation. MASP-2 initiates the lectin pathway by forming complexes with pattern recognition molecules such as mannose-binding lectin (MBL) and ficolins. Upon pathogen recognition by MBL, MASP-2 is activated and subsequently cleaves complement components C4 and C2, leading to the generation of C3 convertase and triggering downstream complement activation. Beyond its role in the complement cascade, MASP-2 also contributes to the coagulation pathway by cleaving prothrombin to generate thrombin, thereby linking innate immunity and hemostasis ^[1]. Emerging evidence highlights the clinical significance of MASP2 gene polymorphisms, which are associated with altered susceptibility to infectious diseases and immune-related disorders. Reduced plasma levels of MASP-2 have been linked to increased vulnerability to HIV infection, while elevated MASP-2 activity may exacerbate inflammatory responses ^[2]. Given its pivotal role in immune regulation, MASP-2 has emerged as a promising therapeutic target. Inhibition of MASP-2 is currently under investigation as a potential strategy for treating a range of conditions, including IgA nephropathy (IgAN) ^[3], atypical hemolytic uremic syndrome (aHUS), and transplant-associated thrombotic microangiopathy (TA-TMA) ^[4]. The B6-hMASP2 mouse model, generated through precise gene editing technology, features the in situ replacement of part of the endogenous mouse Masp2 gene with the coding sequence (CDS) of human MASP2. Homozygous B6-hMASP2 mice are viable and fertile, providing a robust platform for studying the pathophysiology of autoimmune and infectious diseases. This model also serves as a valuable tool for the development and preclinical evaluation of MASP-2-targeted therapeutics, offering insights into both mechanistic and translational aspects of complement-mediated diseases.