The CD19 gene encodes a member of the immunoglobulin gene superfamily. As a key co-receptor in the B cell receptor (BCR) signaling pathway, it is crucial for B cell development, activation, and differentiation. CD19, a pan-B-cell marker exclusively expressed in the B cell lineage, remains stable throughout B cell development, from pro-B cells to mature and memory B cells. It acts as a positive regulator of BCR signal transduction by forming a B cell-specific signaling complex with CD21 (complement receptor 2), CD81 (tetraspanin), and CD225 (Leu13), which lowers the threshold for antigen-induced B cell activation ^[1]. Dysregulation of CD19 is strongly linked to autoimmune diseases such as systemic lupus erythematosus (SLE) and B cell malignancies like acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma. Mutations in this gene are associated with common variable immunodeficiency 3 (CVID3), characterized by impaired B cell differentiation and hypogammaglobulinemia. Owing to its B cell-specific expression, CD19 has become a pivotal target for immunotherapy. For example, anti-CD19 CAR-T cell therapy (e.g., Tisagenlecleucel) has shown remarkable efficacy in refractory or relapsed ALL ^[2]. Recent studies have also explored CD19-targeted bispecific antibodies (e.g., blinatumomab) to enhance tumor cell clearance ^[3]. B6-hCD19 mice are a humanized model generated by replacing the mouse endogenous Cd19 gene sequence from the ATG start codon to part of intron 4 with the corresponding human CD19 gene sequence using gene editing technology. This model is applicable for studying B cell development and function, as well as therapeutic research on autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), and B cell malignancies. It is an ideal research platform for preclinical efficacy evaluation of anti-human CD19 CAR-T cell therapy, and the development of bispecific antibodies and combination therapies.

Lipoprotein A (LPA) is a type of particle similar to low-density lipoprotein (LDL) that is considered one of the risk factors for cardiovascular disease (CVD), such as atherosclerosis, coronary heart disease, stroke, etc ^[1]. LP(a) is similar in size and lipid content to LDL (low-density lipoprotein) and also contains the lipoprotein ApoB-100. However, unlike LDL, LP(a) additionally contains a variable-length lipoprotein called Apo(a), which covalently binds to ApoB-100 through a single disulfide bond. LP(a) plays an important role in systemic lipid transport, guiding inflammatory cells into blood vessel walls and leading to smooth muscle cell proliferation. Furthermore, it is involved in wound healing and tissue repair, interacting with the components of blood vessel walls and the extracellular matrix ^[2]. However, LP(a) can also cause arterial narrowing by adhering to the arterial wall, accelerating the formation of blood clots, and thereby triggering a series of pathological changes related to coronary heart disease, cardiovascular disease, atherosclerosis, thrombus formation, and stroke ^[3]. The plasma concentration of LP(a) is closely related to genetic factors and is primarily regulated by the LPA gene. Therefore, the LPA gene is an important potential target for cardiovascular disease treatment. The LPA gene encodes a serine protease that inhibits the activity of tissue-type plasminogen activator I. Fragments of this protein, generated through protein hydrolysis, can adhere to atherosclerotic lesions in arteries, promoting blood clot formation. The LPA gene is expressed in both humans and non-human primates but is not expressed in mice. Constructing mouse models expressing the human LPA gene is of significant importance for developing lipid-lowering drugs, which can drive the development of novel therapies for cardiovascular diseases. Currently, various novel therapies targeting the transcription rate of the LPA gene are under development, including small interfering RNA (siRNA) and antisense oligonucleotides (ASO) ^[4]. Proprotein convertase subtilisin/kexin 9 (PCSK9) is a serine protease primarily produced in the liver but expressed in other tissues, including the intestine, heart, and neurons. The N-terminal domain of the PCSK9 protein is responsible for protein localization and stability, while the C-terminal domain is responsible for protein enzymatic activity ^[5]. The Low-density lipoprotein receptor (LDLR) is a receptor that is responsible for clearing low-density lipoprotein cholesterol (LDL-C) from the blood. PCSK9 cleaves the intracellular domain of LDLR on the cell surface, causing it to detach from the cell membrane and be transported to the lysosome for degradation, promoting LDLR degradation, and increasing plasma LDL-C. Overexpression or gain-of-function mutations of the PCSK9 gene can lead to LDL-C accumulation by reducing LDLR levels. This can cause hypercholesterolemia, which increases the risk of cardiovascular diseases, such as atherosclerosis and coronary heart disease, and neurodegenerative diseases, such as Alzheimer's disease ^[6]. PCSK9 has emerged as a key target for the development of lipid-lowering drugs. Several PCSK9-targeted antibodies or small nucleic acid drugs have been approved for marketing worldwide, including evolocumab from Amgen, alirocumab from Sanofi and Regeneron, and inclisiran from Novartis. These drugs primarily work by inhibiting PCSK9 activity or preventing PCSK9 protein from binding to LDLR, lowering LDL-C levels in the blood to treat hypercholesterolemia ^[7-8]. In addition, PCSK9 can promote tumor growth and development by regulating cell proliferation, migration, and invasion. It can also regulate the expression of inflammatory factors that contribute to inflammation. Therefore, targeting the expression of PCSK9 has been investigated in tumor immunotherapy and autoimmune disease therapy ^[9-10]. The B6-hLPA (CKI)/Alb-cre/hPCSK9 mouse model is generated by crossing B6-hLPA (CKI) mice (Catalog No.: C001521, a mouse strain with conditional expression of the human LPA gene), Alb-Cre mice (liver-specific Cre-expressing mice), and B6-hPCSK9 mice (Catalog No.: C001617). This model harbors two cardiovascular disease risk factors, namely Lp (a) (lipoprotein (a)) and PCSK9, making it suitable for research on hyperlipidemia, stroke, coronary heart disease, and other atherosclerotic cardiovascular diseases (ASCVD).

The FGFR1 gene encodes fibroblast growth factor receptor 1 (FGFR1), a pivotal transmembrane receptor tyrosine kinase widely expressed across diverse cell types, including epithelial, mesenchymal, and neuronal lineages, playing fundamental roles in development, angiogenesis, cell proliferation, differentiation, and migration through activation of intracellular signaling cascades like MAPK/ERK, PI3K/AKT, and STAT ^[1]. Aberrant FGFR1 expression or mutations are associated with developmental syndromes and various cancers, driving tumor growth, metastasis, and therapeutic resistance; its expression is tightly regulated by diverse cellular signals ^[2]. A key splice isoform is FGFR1c, predominantly expressed in epithelial cells and characterized by a specific extracellular immunoglobulin-like domain III, conferring high-affinity binding to a subset of FGF ligands crucial for epithelial-mesenchymal interactions during development and adult tissue homeostasis ^[3]. Dysregulation of FGFR1c signaling is implicated in the pathogenesis of cancers such as breast, prostate, and lung carcinomas, contributing to tumor initiation, progression, angiogenesis, and potentially therapy resistance, highlighting the importance of understanding isoform-specific functions for targeted therapeutic interventions ^[3-4]. B6-hFGFR1c mice are humanized models generated by gene editing technology, in which the p.22R to partial intron 2 of the mouse Fgfr1 gene was replaced in situ with p.22R to 376E from the coding sequence of the human FGFR1 gene, p.377I to 823X from the coding sequence of the mouse Fgfr1 gene, and the 3'UTR of the mouse Fgfr1 gene. This model can be used to study the pathological mechanisms and therapeutic methods of cancers, metabolic diseases such as obesity, diabetes, and metabolic-associated steatohepatitis (MASH), as well as the screening and development of FGFR1c-targeted drugs, and preclinical efficacy and safety evaluations.

Cluster of Differentiation 3 (CD3) is a protein complex that acts as a co-receptor for T cells and is involved in the activation of cytotoxic T cells (CTLs) and helper T cells (THs). CD3 consists of five polypeptide chains: γ, δ, ε, ζ, and η, all of which are transmembrane proteins. The transmembrane regions of CD3 molecules connect with the transmembrane regions of TCR's two polypeptide chains through salt bridges, forming the TCR-CD3 complex, which is essential for T cell antigen recognition ^[1-2]. After TCR recognizes an antigen, the activation signal is transduced by CD3 into the T cell. CD3 is highly specific at all developmental stages of T cells, thus it is considered a T cell-specific immunohistochemical marker. Additionally, CD3 is present in almost all T cell lymphomas and leukemias and can be used to distinguish between morphologically similar B cell and bone marrow tumors. Due to its significant role in T cell activation and antigen recognition, CD3 is an important drug target in immunosuppressive therapy for type 1 diabetes and other autoimmune diseases ^[3]. The EPCAM gene encodes a transmembrane glycoprotein, Epithelial Cell Adhesion Molecule (EPCAM), also known as CD326 or Trop-1, which mediates calcium-independent homotypic cell adhesion and participates in fundamental processes including cell adhesion, migration, proliferation, and signal transduction, thereby maintaining epithelial tissue integrity ^[4]. While normally expressed on the surface of epithelial cells in organs such as the gastrointestinal tract, lungs, and skin, EPCAM is frequently overexpressed in various cancers, including colorectal, breast, and pancreatic carcinomas, but is largely absent or weakly expressed in healthy squamous epithelia ^[4]. Structurally, EPCAM comprises an extracellular domain (EpEX) mediating intercellular adhesion, a transmembrane domain, and a short intracellular domain (EpICD). Upon proteolytic cleavage by ADAM17 and γ-secretase, EpICD translocates to the nucleus, activating oncogenic pathways such as Wnt/β-catenin, ERK, and FAK-AKT, which promotes epithelial-mesenchymal transition (EMT), tumor progression, and metastasis ^[5]. Notably, EPCAM serves as a marker for circulating tumor cells (CTCs) and cancer stem cells, and its downregulation during EMT can complicate advanced cancer detection ^[5-6]. Furthermore, dysregulated EPCAM expression is associated with congenital tufting enteropathy (CTE), a severe intestinal epithelial dysfunction ^[5]. Given its involvement in tumor metastasis through interaction with HGFR (c-Met), targeting EPCAM with strategies like the neutralizing antibody EpAb2-6 in combination with HGFR inhibitors has shown promising preclinical efficacy ^[7]. The B6-hCD3/hEPCAM mouse is obtained by crossbreeding B6-hCD3 mice (Catalog No.: C001325) with B6-hEPCAM mice. It can be used for the development of CD3/EPCAM-targeted drugs, as well as for research in tumor immunotherapy and autoimmune disease-related drugs.

The CRBN gene, located on chromosome 3, exhibits broad expression across diverse tissues, including the brain, kidney, muscle, and immune cell populations such as monocytes, macrophages, dendritic cells, and B lymphocytes ^[1]. This gene encodes cereblon, a protein that functions as a key substrate receptor within the CRL4-CRBN E3 ubiquitin ligase complex. This complex mediates the ubiquitination and subsequent proteasomal degradation of specific target proteins, thereby regulating crucial cellular processes encompassing protein homeostasis, ion transport, and AMPK signaling ^[1-2]. Notably, mutations in CRBN are implicated in autosomal recessive nonsyndromic intellectual disability ^[2]. Furthermore, Cereblon protein serves as a primary molecular target for targeted protein degradation (TBD) therapy by specifically modulating the enzymatic activity of the CRL4-CRBN complex and altering its substrate recognition properties, thereby enabling the selective degradation of specific transcription factors. This molecular mechanism has emerged as a critical theoretical foundation for the clinical treatment of malignant hematological malignancies such as multiple myeloma, leading to the development of diverse therapeutic modalities including molecular glues and proteolysis targeting chimeras (PROTACs) ^[3-5]. B6-hCRBN mice are humanized models generated by gene editing technology, in which the exon 2 to partial intron 2 of the mouse Crbn gene was replaced in situ with the Exon 2~11 of the coding sequence (CDS) of human CRBN gene. This model can be used to study the pathological mechanisms and therapeutic methods of autosomal recessive nonsyndromic intellectual disability and multiple myeloma and other hematological cancers, as well as the screening, development, and preclinical efficacy and safety evaluation of CRBN-based targeted protein degradation (TBD) therapies.

The CRBN gene, located on chromosome 3, exhibits broad expression across diverse tissues, including the brain, kidney, muscle, and immune cell populations such as monocytes, macrophages, dendritic cells, and B lymphocytes ^[1]. This gene encodes cereblon, a protein that functions as a key substrate receptor within the CRL4-CRBN E3 ubiquitin ligase complex. This complex mediates the ubiquitination and subsequent proteasomal degradation of specific target proteins, thereby regulating crucial cellular processes encompassing protein homeostasis, ion transport, and AMPK signaling ^[1-2]. Notably, mutations in CRBN are implicated in autosomal recessive nonsyndromic intellectual disability ^[2]. Furthermore, Cereblon protein serves as a primary molecular target for targeted protein degradation (TBD) therapy by specifically modulating the enzymatic activity of the CRL4-CRBN complex and altering its substrate recognition properties, thereby enabling the selective degradation of specific transcription factors. This molecular mechanism has emerged as a critical theoretical foundation for the clinical treatment of malignant hematological malignancies such as multiple myeloma, leading to the development of diverse therapeutic modalities including molecular glues and proteolysis targeting chimeras (PROTACs) ^[3-5]. BALB/c-hCRBN mice are humanized models generated by gene editing technology, in which the exon 2 to partial intron 2 of the mouse Crbn gene was replaced in situ with the Exon 2~11 of the coding sequence (CDS) of human CRBN gene. This model can be used to study the pathological mechanisms and therapeutic methods of autosomal recessive nonsyndromic intellectual disability and multiple myeloma and other hematological cancers, as well as the screening, development, and preclinical efficacy and safety evaluation of CRBN-based targeted protein degradation (TBD) therapies.

CD47, also known as Integrin Associated Protein (IAP), is a transmembrane protein that belongs to the immunoglobulin superfamily. It is widely expressed on the surface of almost all normal cells and is highly expressed in tumor cells ^[1]. SIRPα, a signal regulatory protein mainly expressed on macrophages, inhibits their phagocytosis of target cells by transmitting inhibitory signals when binding to CD47 on other cells. However, some tumor cells can evade phagocytosis and cause tumor immune escape by highly expressing CD47 and binding to SIRPα on macrophages, sending a “don’t eat me” signal. Targeting CD47 antibodies can initiate anti-tumor T cell immune responses and promote cancer-specific lymphocyte activation through macrophage-mediated phagocytosis of tumors. As a result, the CD47-SIRPα signaling pathway has great therapeutic potential and is a highly competitive target in tumor immunotherapy after PD-1/PD-L1 ^[1-2]. CD47 is a transmembrane protein with its extracellular domain serving as the receptor/ligand binding region and its intracellular domain responsible for signal transduction ^[3]. B6-hCD47 mice are obtained by replacing the fragment encoding the extracellular domain of CD47 protein in the mouse Cd47 gene with the corresponding human CD47 gene sequence, resulting in a model expressing the extracellular domain of human CD47 protein and the intracellular domain of mouse CD47 protein. This ensures normal binding with human antibodies and other protein drugs while completely retaining the intracellular part of mouse CD47 protein, maintaining normal intracellular signal transduction. B6-hCD47 mice can successfully express human CD47 protein and can be used for research on CD47-targeted inhibitors or antibody drug development and screening, pharmacology and safety evaluation, tumor immunotherapy evaluation, and mechanisms of tumor immune escape systems.

The Growth Differentiation Factor 15 (GDF15) gene encodes a secreted ligand of the Transforming Growth Factor-β (TGF-β) superfamily protein. This protein plays a crucial role in the TGFβ signaling pathway, which is integral to various cellular processes ^[1]. GDF15 is involved in the body’s response to stress following cell damage. It is associated with tissue hypoxia, inflammation, acute injury, and oxidative stress, among other disease states. Elevated levels of GDF15 in the serum are considered a potential biomarker for the progression of cancer, as it is overexpressed in various types of tumor cells, including colon, prostate, pancreatic, breast, and thyroid cancers ^[2-3]. Interestingly, GDF15 is not solely a pathological biomarker. Despite its association with disease states, it also exhibits high expression under various non-pathological conditions. Studies suggest that GDF15 may exert a protective effect on the heart, liver, kidney, and lungs following inflammation and injury, highlighting its potential role in tissue repair and recovery ^[4]. GDF15 is an important biomarker for metabolic diseases, cardiovascular diseases, tumors, and more, and holds potential as a therapeutic target. It can induce anorexia by activating the GFRAL-RET receptor in the brainstem, making it a promising target for anti-obesity therapy ^[5]. Furthermore, GDF15 neutralization could potentially alleviate anorexia and weight loss, common side effects of platinum-based chemotherapy ^[6]. Research has shown that a therapeutic antagonistic monoclonal antibody can inhibit RET signal transduction by blocking the interaction between GDF15-driven RET and cell surface GFRAL. This could reverse excessive lipid oxidation in tumor-bearing mice and prevent cancer cachexia ^[7]. The potential of GDF15 as a therapeutic target is being increasingly recognized in the scientific community. In this context, the construction of animal gene humanization models for this target is of significant importance, providing a crucial tool for further research and development in this area. This strain is a mouse Gdf15 gene humanized model expressing human GDF15 protein obtained by replacing the sequence encoding the endogenous structural domain in the mouse Gdf15 gene with the sequence encoding the structural domain in the human GDF15 gene. B6-hGDF15 mice can be used for research on metabolic diseases, cardiovascular diseases, tumor occurrence and development, etc., to assist in the preclinical evaluation of GDF15-targeted drugs.

The Insulin-like Growth Factor 1 Receptor (IGF-1R), encoded by the IGF1R gene, is a receptor tyrosine kinase expressed in most tissues and cells. Its expression is developmentally regulated and influenced by nutrition, hormones, and intracellular factors, with high expression during growth and development, declining in adulthood ^[1]. The IGF1R protein is a heterotetramer (α2β2) of α and β subunits derived from a precursor protein, forming transmembrane αβ chains. The α chain is located extracellularly, while the β chain spans the cell membrane and is responsible for intracellular signal transduction after ligand stimulation. IGF1R binds Insulin-like Growth Factor-1 (IGF-1) with high affinity, mediating IGF-1's growth-promoting effects and regulating cell growth, differentiation, survival, and metabolism ^[1-4], and IGF1R defects are linked to growth retardation and diabetes ^[2-4]. Furthermore, IGF1R overexpression in tumors promotes proliferation, invasion, and metastasis, making it a cancer therapy target ^[3]. In thyroid eye disease (TED), an autoimmune disorder, activating IGF1R antibodies can be detected. IGF1R is overexpressed in T cells, B cells, and orbital fibroblasts of patients, forming a signal transduction complex with the thyroid-stimulating hormone receptor, thereby enhancing the effect of thyroid-stimulating hormone ^[5]. Therefore, Targeting IGF1R to inhibit thyroid-stimulating hormone action is a therapeutic strategy for TED, improving exophthalmos ^[6]. B6-hIGF1R mice are humanized models generated using gene editing technology by integrating the protein-coding sequence (CDS) encoding the extracellular domain of human IGF1R protein and the intracellular domain of mouse IGF1R protein into the mouse Igf1r gene locus, while retaining the endogenous gene sequence encoding the signal peptide of mouse IGF1R protein. Homozygous B6-hIGF1R mice are viable and fertile, and can be used for studying the pathological mechanisms and treatments of growth retardation, diabetes, and cancer, as well as for screening, developing, and preclinical efficacy and safety evaluation of IGF1R-targeted drugs.

PD-1 and CTLA-4 are checkpoint receptors that critically modulate T cell immunity. The genes PDCD1 and CTLA4 encode PD-1 and CTLA-4 respectively, with CTLA4 expression largely restricted to T cells, while PDCD1 is evident in activated T cells, B cells, and myeloid populations ^[1]. These transmembrane proteins function as key negative regulators of T cell activation ^[2]. CTLA-4 primarily operates in lymphoid tissues during early immune responses to restrain T cell proliferation, whereas PD-1 predominantly acts in peripheral tissues during the effector phase to dampen T cell activity and limit immunopathology, particularly in chronically stimulated or ‘exhausted’ T cells ^[2-3]. Aberrant regulation of PD-1 and CTLA-4 is implicated in the pathogenesis of cancers, including melanoma, non-small cell lung cancer, and renal cell carcinoma, as well as chronic viral infections such as hepatitis B and C ^[1][4]. Clinically, monoclonal antibodies targeting CTLA-4 (e.g., ipilimumab) and PD-1 (e.g., nivolumab, pembrolizumab) are established immunotherapeutic agents that enhance anti-tumor responses. By blocking these negative signaling pathways, these monoclonal antibodies restore the anti-tumor activity of T cells, significantly enhancing anti-tumor responses ^[1-2]. These drug applications have not only improved the treatment outcomes for various cancers but also offer new strategies for the treatment of chronic viral infections. B6-hPD-1/hCTLA4 mouse is a dual humanized model of PD1 and CTLA4 constructed by humanizing the mouse Pdcd1 gene based on the CTLA4 humanized mouse model (Catalog No. C001413), due to the fact that the mouse Pdcd1 gene and Ctla4 gene are on the same chromosome. These mice express human CTLA4 and PDCD1 genomic sequences under the control of mouse promoters. This model is capable of reproducing the human PD-1/CTLA4 signaling pathway and is a valuable tool for studying cancers and chronic viral infections. Furthermore, this model provides a powerful preclinical research platform for evaluating the efficacy and mechanism of therapeutic drugs targeting the PD-1/CTLA4 signaling pathway.