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RESEARCH AREA: Autoimmune Cardiovascular Disease Cell and Gene Therapy Infectious Disease Metabolism Neurology Oncology Other Rare Disease

December 20, 2024

Mouse Models of anti-PD-1 Resistance Reveals Insights into Resistance Mechanisms

The immune checkpoint molecule PD-1 and its ligand PD-L1 play a pivotal role in tumor immune evasion and progression by thwarting apoptosis induced by the immune system. Despite the significant efficacy of anti-PD-1/PD-L1 therapy against solid tumors, durable responses are observed in only a minority of patients. Many patients fail to experience the full benefits of therapy, with a notable proportion eventually developing acquired resistance. Therefore, establishing robust preclinical models of PD-1 resistance is crucial for unraveling resistance mechanisms and devising novel treatment strategies. Common mechanisms contributing to anti-PD-1/anti-PD-L1 resistance include the absence of suitable tumor antigens, tumor surface MHC molecules inactivation, dysregulated IFN-γ signaling pathways, and the immunosuppressive tumor microenvironment.
December 08, 2024

Spontaneous Systemic Lupus Erythematosus Mouse Model Based on TLR7Y264H Genetic Mutation

Toll-like receptor 7(TLR7) variant Y264H has recently been identified to cause Systemic Lupus Erythematosus (SLE) in human patients. Mice harboring TLR7Y264H mutation in the C57BL/6NCrL background developed spontaneous SLE-like symptoms and organ damage. In order to create clinically relevant mouse models of SLE to evaluate novel therapeutics (especially targeting TLR7), we developed TLR7Y264H mutant mice in both the BALB/c and C57BL/6J background.
November 30, 2024

Chromosome 1 substitution strains, a new resource for pre-clinical MASLD mouse model development

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common cause of chronic liver disease and is the leading cause of liver-related morbidity and mortality. However, neither the diet induction model nor the monogenic model based on the laboratory mice could fully imitate human MASH due to the genetic background of existing inbred mice have limitations, such as the lack of genetic diversity and reduced disease susceptibility. Comparing with the laboratory mice, wild mice harbor more genetic polymorphisms to adapt to the natural environment, therefore, introducing the genetic material from wild mice into inbred mice would provide new experiments resources for the complex trait researches. Therefore, GemPharmatech has launched “Wild Mouse” project to develop a complete set of consomics covering all 19 autosomes of mouse, and each chromosome replacement panel will be represented by a population of chromosome substitution strains using captured wild mice across China as chromosome donors. Given that chromosome 1 (Chr1) includes multiple gene loci related to lipid metabolism, we first screened Chr1 substitution strains to search for more appropriate mice model for MASLD research.
November 30, 2024

A persistent hypertension model developed on the AGT humanized mice

As a condition of metabolic syndrome, the prevalence of hypertension increased rapidly in the past three decades and consistent hypertension causes various complications,which impair life quality and even be life-threatening. Angiotensinogen, also known as AGT, is the sole precursor of angiotensin peptides in the RAAS pathway, which is the most carefully studied mechanism of blood pressure and volume regulation. RNAi therapies targeting AGT is a promising approach to treat hypertension and related organ damages. Given that the action of RNA interference drugs based on the complementary base pairing, mouse models for preclinical evaluation on AGT target are limited. In this study, we initially generated AGT humanized mice by introducing the entire AGT gene into the Rosa26 site. Despite the presence of a large amount of human AGT in hAGT mice,the inability of rodent RENIN to convert human AGT to AngI prevents the spontaneous development of hypertension. Therefore, we developed a modified human RENIN virus as a flexible tool to induce the persistence hypertension on our novel AGT humanized mice.
November 27, 2024

PDX Models with Differential HER2 Expression for preclinical evaluation of HER2-targeted therapy

Overexpression of the human epidermal growth factor receptor 2 (HER2) is increasingly recognized as a common molecular abnormality in gastric and gastroesophageal cancer. Drugs targeting the HER2 protein have shown promise in treating these cancers. Additionally, there is evidence to suggest that DS-8201a, a HER2-targeted antibody-drug conjugate (ADC), may be effective and safe in treating patients with heterogeneous or low HER2 expression. To aid in the design of personalized or precision drug treatment strategies for HER2-targeted therapies in clinical trials, GemPharmatech offers suitable patient-derived xenograft (PDX) gastric cancer models.
November 20, 2024

NCG-XM Humanized Mice - An Improved Model for Human HSC Immune Reconstitution Without Irradiation

Severely immunodeficient mice engrafted with human hematopoietic stem cells (HSCs) are widely used in immuno-oncology studies to evaluate cancer therapies. GemPharmatech has developed the NCG-XM model, which expresses human granulocyte-macrophage colony-stimulating factor 2 (GM-CSF), interleukin-3 (IL-3), and stem cell factor (SCF), along with a W41/W41 inactivation mutation in the Kit gene. The goal of this model is to support multilineage human immune cell differentiation without the need for irradiation. The HSC-NCG-XM model enables better reconstitution of human T cells, B cells, NK cells, and myeloid cells (such as granulocytes, monocytes, neutrophils, macrophages, and dendritic cells) without requiring murine myeloablation prior to HSC engraftment, typically achieved through sublethal radiation or chemoablation. Furthermore, HSC-NCG-XM mice can survive for over 22 weeks post-engraftment, making them ideal for long-term immuno-oncology studies.
November 20, 2024

Development of a Novel Murine Model, NCG-M/hIL15, for Enhanced Post-HSC Transplantation Immunoreconstruction

Advances in immunology and hematopoietic stem cell (HSC) transplantation have led to the development of murine models that faithfully recapitulate human immune responses. GemPharmatech has developed the NCG-M/hIL15 model, which expresses human granulocyte-macrophage colony-stimulating factor 2 (GM-CSF), interleukin-3 (IL-3), stem cell factor (SCF), and interleukin-15 (IL-15) in the severely immunodeficient NCG mouse. The goal of developing this model is to support a broader reconstitution of the human immune system, including T cells, myeloid cells, and NK cells, following HSC engraftment.
November 20, 2024

An Improved PBMC Humanized Xenograft Model for Preclinical Evaluation of Immune Checkpoint Inhibitors

Immuno-oncology (I-O) therapies have been extensively explored in recent years, particularly immune checkpoint inhibitors (ICIs) such as programmed cell death protein 1 (PD-1) and PD-ligand 1 (PD-L1) inhibitors. Robust and stable animal models are essential for advancing preclinical research and addressing challenges such as low response rates to anti-PD-1/PD-L1 therapies and drug resistance.
GemPharmatech has developed a human peripheral blood mononuclear cell (PBMC)-based humanized xenograft model. In this newly established model, human PBMCs are mixed with human tumor cell lines (including A-431 epidermoid carcinoma) and inoculated subcutaneously into the right flank of immunodeficient NCG mice. This PBMCs-cancer cell lines mixed injection model of NCG mice provides a valuable opportunity to evaluate the in vivo efficacy of immune checkpoint inhibitors.
November 20, 2024

BALB/C-hIL12RB1/hIL12RB2 Serves as a Robust Mouse Model to Evaluate Novel Human IL-12 Therapeutics

Interleukin-12 (IL-12) is a multifunctional cytokine predominantly produced by activated inflammatory cells. IL-12 plays a pivotal role in orchestrating the immune response of Th1 cells, promoting interferon (IFN-γ) production, and enhancing the activation of cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells. Preclinical investigations have highlighted IL-12's ability to stimulate T cells and NK cells within the tumor microenvironment, leading to potent anti-tumor effects, thereby positioning IL-12 as a promising therapeutic target. GemPharmatech developed a novel mouse model expressing human IL-12RB1 and IL-12RB2 (BALB/c-hIL-12RB1/hIL-12RB2), providing a powerful tool to evaluate novel human IL-12 therapeutics.

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