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Much-improved mouse models
HUDSON, N.Y.—According to Dr. Michael Seiler, associate director of genetically engineered models design and precision research models at Taconic Biosciences, “The major challenge in bridging clinical efficacy in drug development is predicting efficacy from animal models. We need a model that predicts human immunology, so we have created a uniquely suitable host for human immune cells to grow, repopulate and become functional within a human system.”
Taconic, a global provider of genetically engineered rodent models and services, has launched the huNOG-EXL to meet this challenge. The extended lineage mouse model could greatly improve immuno-oncology, allergy and inflammation research, according to the company, which was founded in 1952. The huNOG-EXL incorporates an engrafted human immune system to recapitulate myeloid lineages that are known to play a key role in innate immune responses, resulting in a more complete reflection of human immunity.
Taconic developed a mouse model in 2002. In 2014, the company began releasing off-the-shelf models of these animals for bioresearch and drug discovery. According to Seiler, they “changed the landscape for oncology drugs with a new class of immunotherapies, giving us a living system method to exploit new targets.” Now, he said, the newest company offering “provides a clearer representation of human immune response and reflects years of development of new in-vivo rodent models with more complete immune development, enabling investigators to perform studies that were not feasible in the past.”
The development of animal models capable of mimicking human immune responses is crucial to study the pathophysiology of disease and to generate new therapeutic methodologies. Significant advances in immunology modeling have been made utilizing the super immune-deficient CIEA NOG mouse, but the full application of engrafted human immune models depends upon overcoming some cross-species differences.
Since the early days of producing mouse models, Taconic has learned a great deal about these cross-species issues. While huNOG-EXL is still a mouse host, it has been engineered to produce human stem cells and address other limitations, Seiler pointed out.
As explained by the company, the huNOG-EXL combines the background of the CIEA NOG mouse with transgenic low-level expression of two human cytokines (GM-CSF and IL-3), both known to limit myeloid lineage commitment due to cross-species limitations. When engrafted with human hematopoietic stem cells, the hGM-CSF/hIL3 transgenic-NOG host results in a human-like immune system that includes mature granulocytes, monocytes, macrophages, B cells and T cells, extending the limits of existing engrafted human immune system models. This precision research model enables the study of key innate mechanisms with direct correlates to safety and efficacy, and is especially useful for immuno-oncology applications.
“The extended reconstitution of immune cell lineages of the huNOG-EXL will allow improved modeling of the complex, heterogeneous tumor microenvironment by favoring the differentiation of cells that can infiltrate the tumor and participate in the immuno-modulatory tumor niche, all of which are high-value targets for immuno-oncology drug discovery,” Seiler remarked. Because the huNOG-EXL is more reflective of innate human immunity than previously available models, it will enable better predictability of clinical outcomes and help speed time-to-market with efficacious therapies.
The huNOG-EXL, available to the research community worldwide, has commercial potential driven by the growth of immuno-oncology and the need to do combination drug studies.
“For instance, in the case of Jimmy Carter, who had stage 4 metastatic melanoma in the brain and liver, new and combinatorial oncology therapeutics were a game-changer for the drug development industry. We can use his dramatic recovery to measure the remarkable success of developing drugs by using xenograpft specimens with animal models,” said Seiler.