Mice are the most commonly used animal model for scientific research, covering wide-ranging areas in life science, such as cancer, metabolism, and neurology. However, due to the obvious species differences between humans and mice, the results of preclinical testing, obtained using conventional mouse models, are often inapplicable to humans. Therefore, the humanized mouse models were generated to resolve the issue. Applicable therapeutic target-humanized mouse models can not only improve the validity of our preclinical data, but also greatly shorten the preclinical development cycle.

In order to meet diversified requirements on humanized mice, we have launched U-HuDTMbase®, a resource library of therapeutic target-humanized mouse models, after years of independent research and development, relying on an experienced gene editing team. At present, U-HuDTMbase® is composed of more than 600 therapeutic target-humanized mouse models, including multiple background strains, such as C57BL/6, BALB/c, NMG, etc., and has basically covered all commonly studied areas, such as oncology, metabolism, immunity, inflammation and more. In this article, we will take you to learn more about all aspects of therapeutic target-humanized mice.

What Therapeutic Target-Humanized Mice are

The genome of mice is highly similar to that of humans and easy to be genetically engineered, making mice ideal for mimicking human biology. At present, most of the novel drugs are developed by targeting certain molecules, but the differences in the homology of molecular targets between mice and humans may produce unreliable results of drug efficacy testing. Therefore, in order to improve the reliability of preclinical results, it is necessary to use animal models that are more "close" to humans. For example, using a therapeutic target-humanized mouse model.

Broadly speaking, humanized mice refer to the mouse models carrying functional human genes, cells, tissues, organs, immune systems, or microorganisms. Our U-HuDTMbase® resource library mainly provides therapeutic target-humanized mouse models, constructed by using gene editing technologies, such as ES cell targeting and CRISPR/Cas9-mediated gene editing, to knock human-derived target genes into the mouse genome. Thus, these mouse models can express human genes or specific human gene variants, and even exhibit similar phenotype to human in some respects.

Why We Need Therapeutic Target-Humanized Mice

Humanized mice can be used to study the function of human genes, related diseases, advance personalized medicine research, and can also be used to delve into the biomedical areas to facilitate the development of therapeutics.

Gene Function Studies

Humanized mice can be used to study the function of specific human genes and understand their molecular mechanisms in physiology and pathology.

Disease Research

Humanized mice can simulate human conditions, such as cancer, genetic diseases, cardiovascular disorders, to help to study pathogenic mechanisms, and test new treatments, and guide the direction of drug development.

Pharmacodynamics and Pharmacokinetics Studies

Humanized mice can be applied to efficacy evaluation and safety assessment of drugs, pharmacokinetics testing, and discovery of novel drugs.

Immunological Research

Humanized mice can help to elucidate the function of the immune system and improve the immune reconstitution in mice.

Personalized Medicine Research

Humanized mice can serve as the powerful tools to study the impact of individual genetic variation on drug response and disease incidence, thereby providing preclinical evidence for personalized medicine.

Currently, most of the novel drugs under development are targeted drugs. Identifying target molecules is the foundation ofnew drug development. The following are some of the hot targets in recent years.

CD40/CD40L

CD40 is a type I transmembrane protein that is an important immune cell communication mediator that connects innate and adaptive immunity. CD40 is mainly expressed in B cells and myeloid cells, and also found in endothelial cells, fibroblasts, smooth muscle cells, certain types of tumor cells, etc. CD40L is a natural trimer ligand for CD40.

As a pair of costimulatory molecules, CD40/CD40L interact on the cell surface and promote intracellular signaling by recruiting intracellular TNFR-related factors, thereby activating different signaling pathways. They are involved in the humoral and cellular immune responses of the body: they play key roles in the activation, proliferation and differentiation of B cells, and the production of antibodies. Besides, they participate in the activation of T cells and the regulation of the secretion of effector cytokines. Meanwhile, they also contribute to the differentiation of memory cells, the production of antibodies, and regulate the immune responses.

For related drug development, CD40 has become a therapeutic target for B-cell lymphoma. For example, the CD40 monoclonal antibody, Lucatumumab, has some inhibitory effects on advanced Hodgkin lymphoma and non-Hodgkin lymphoma. In B-cell lymphoma, Dacetuzumab (SGN-40) exhibited potent anti-proliferative and pro-apoptotic efficacy against malignant cells in both in vitro and in vivo experiments. CD40-targeted immunotherapeutics have emerged as promising anti-cancer treatment strategies. 

PD-1/PD-L1

The well-known PD-1 and PD-L1 still exhibit extraordinary popularity. PD-1 (programmed death molecule-1) is a receptor protein commonly found on T cells, B cells, and other immune cells of human immune system. One of the main physiological effects of PD-1 is to inhibit the excessive immune responses.

PD-1 and PD-L1 are a pair of costimulatory molecules. PD-1 can inhibit the activity of T cells by binding to its ligand, PD-L1, thereby preventing excessive immune responses. PD-L1 is also used by certain tumor cells and pathogens to evade the detection and attack by the immune system. They can interact with PD-1 receptors by expressing PD-L1, so as to inhibit the immune system's attack on them.

The mechanism of PD-1 is particularly important in anti-tumor immunotherapeutics. Anti-PD-1 drugs, such as Palulizumab and Nibertamide, can block the interaction between PD-1 and PD-L1, thereby relieving T cell inhibition and enhancing their attack on tumor cells. These drugs have exhibited significant anti-tumor efficacy in a variety of cancer types and become important advances in anti-tumor immunotherapeutics. By removing the inhibitory effects of PD-1, anti-PD-1 drugs help to enhance the immune system's response to cancer cells, thereby improving the efficacy of treatment.

IL-33/ST2

In addition to the immune checkpoint mentioned above, cytokines also play important roles in the development of targeted drugs. For example, interleukin-33 (IL-3) is a tissue-derived nuclear cytokine from the IL-1 family that is involved in the regulation of homeostasis and the development of inflammation. The primary targets of IL-33 in vivo are tissue immune cells, such as mast cells, type 2 innate lymphoid cells (ILC2), and regulatory T cells (Tregs). ST2 is its specific receptor.

IL-33/ST2 plays a role in intercellular signaling, and participate in the occurrence and development of a variety of conditions, such as allergies, atopic dermatitis, severe asthma, ulcerative colitis, and chronic obstructive pulmonary disease. In terms of anti-tumor drug research, the researchers found IL-33 can achieve tumor growth promotion or inhibition by affecting the tumor microenvironment (TME). In recent years, the development of anti-IL-33 monoclonal antibodies such as Itepekimab and Torudokimab, and anti-ST2 antibody 9MW1911 have begun to emerge.

We are Committed to Providing Cutting-edge Therapeutic Target-Humanized Mouse Models

Focusing on the field of model organisms, with more than 20 years of experience in animal modeling, Shanghai Model Organisms has developed wide-ranging therapeutic target-humanized mouse models, which are widely applied to the efficacy evaluation in preclinical pharmacodynamics and pharmacokinetics studies.

The U-HuDTMbase® covers the hottest therapeutic targets of anti-tumor immunotherapy, including dual-target and multiple-target humanized mice. We also provide custom therapeutic target-humanized mouse models, intended for the humanization of more immune checkpoint genes or specified domains of genes as requested, which serve as the most reliable tools for your targeted drug discovery.

References

Vonderheide RH, Flaherty KT, et al. Clinical activity and immune modulation in cancer patients treated with CP-870,893, a novel CD40 agonist monoclonal antibody. J Clin Oncol. 2007 Mar 1;25(7):876-83. doi: 10.1200/JCO.2006.08.3311. PMID: 17327609.

Bardhan K, Anagnostou T, Boussiotis VA. The PD1:PD-L1/2 Pathway from Discovery to Clinical Implementation. Front Immunol. 2016 Dec 12;7:550. doi: 10.3389/fimmu.2016.00550. PMID: 28018338; PMCID: PMC5149523.

Yeoh WJ, Vu VP, Krebs P. IL-33 biology in cancer: An update and future perspectives. Cytokine. 2022 Sep;157:155961. doi: 10.1016/j.cyto.2022.155961. Epub 2022 Jul 14. PMID: 35843125.