Genetic Engineering & Biotechnology News

OCT15 2017

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28 | OCTOBER 15, 2017 | | Genetic Engineering & Biotechnology News ing human cytokines, and cell-humanized NOG mice such as hematopoietic stem cell (HSC) human immune system (HIS)–en- grafted mouse models (Figure 3). A key challenge is to understand the limita- tions of each technology and to select the best model for a particular application, according to Dr. Tanaka. "Use a syngeneic model first to understand the mechanism of action, the target, and the cells involved in an experi- mental therapy," she advises. "Once you have identified the specific cell target (e.g., T cells, myeloid cells), then select a humanized model that allows reconstitution of that particular cell type to study a protein of interest. For example, targeting a myeloid cell requires a transgenic mouse that expresses human GM-CSF and IL-3 cytokines, and study- ing multiple myeloma may call for a model that expresses human IL-6. [Taconic's] HIS- engrafted models include the HSC-engrafted mice that transgenically express human GM- CSF and hIL-3, called huNOG-EXL ™ ." Among the advantages of using mice as models for drug discovery and development is the ability to create syngeneic and human- ized animals, and their relatively small size and fast reproduction rate, making it easier and less costly to generate larger populations to perform high-throughput testing. Dr. Azusa describes the advantages of using humanized mice to study immuno- therapeutic approaches for cancer that has metastasized to the bone. Bone metastasis is especially difficult to target and treat, due in part to the development of drug resistance, and because HSCs reside in the bone mar- row. HSC-engrafted (HIS) mice can mimic the coexistence of HSCs and cancer metas- tasis in the bone, allow researchers to study the crosstalk between human immune-cell populations, HSCs in the bone marrow, and the tumor and bone microenvironment, and enable studies of immuno-oncology drugs. While T cells have largely been the focus of immuno-oncology drug discovery to date, researchers are increasingly looking closely at natural killer (NK) cells as targets and as the basis for cell and gene therapy. Human NK cells require human IL-15 for survival, and Taconic provides a human transgenic super-immunodeficient mouse that expresses human IL-15 to promote the expansion of human NK cells. Matching Immune and Tumor Cells "There are a lot of different versions of humanized mouse models, which can make it confusing for consumers," says Marcus W. Bosenberg, M.D., Ph.D., associate profes- sor at Yale University. One issue to consider is how the human immune system is intro- duced into the mouse. Dr. Bosenberg studies melanoma and typically uses a more primitive mouse mod- el, the NSG ™ immunodeficient mouse strain from The Jackson Laboratory, into which he remakes the human immune system us- ing lymphocytes removed from the same tu- mor that he transplants into the mouse. As the tumor-infiltrating lymphocytes (TILs) and the tumor are derived from the same patient, the interaction between immune cells and the tumor will more closely mir- ror what occurs in the patient. Similarly, the response to an immunotherapeutic drug— such as an immune-checkpoint inhibitor— in mice with matched TILs and tumor cells is anticipated to be more predictive of the response in humans. Another advantage of using TILs, instead of HSCs derived from umbilical cord blood or some other source to rebuild the immune system of immunodeficient mouse models, is a reduced risk of graft-versus-host disease, which can limit the lifespan of the animals. Most of Dr. Bosenberg's research relies on syngeneic mouse models, which "have been the workhorse for industry because they are relatively fast, cheap, and easy to use," he says. At present, though, only approximately 5% of cancer drugs that make it into Phase I testing are approved for commercial use. The hope is that "humanized mice will improve the predictive value of preclinical testing," says Dr. Bosenberg. In the meantime, re- searchers are also exploring faster, less costly alternatives that will allow them to avoid the use of animal models. How predictive these complex, in vitro three-dimensional tissue models—such as spheroids—are, also re- mains to be determined. REGISTER NOW LIFE SCIENCES SHORT COURSES: FEBRUARY 3-4 | CONFERENCE: FEBRUARY 3-7 | EXHIBITS: FEBRUARY 5-7 | SLAS2018.ORG Keynote Speakers O P E N I N G K E Y N O T E Benjamin F. Cravatt C L O S I N G K E Y N O T E Marc Abrahams Educational Tracks SLAS2018 offers participants a world-class scientific program that showcases the top life sciences discovery and technology education from industry leaders. Podium and poster presentations offer SLAS2018 participants compelling content, best practice and new perspectives on emerging scientific technologies from a broad range of industries and academic research perspectives. The SLAS2018 scientific program features 10 educational tracks, including three tracks making their debut in San Diego: z Advances in Bioanalytics and Biomarkers z Assay Development and Screening z Automation and High-Throughput Technologies z Biologics Discovery (NEW!) z Cellular Technologies z Chemical Biology (NEW!) z Data Analysis and Informatics z Drug Target Strategies z High-Definition Biotechnology (NEW!) z Micro- and Nanotechnologies Complete information on SLAS2018 can be found at SLAS2018.ORG . Register by October 31 to take advantage of the deepest-discounted early-bird rates. Animal Models Continued from page 27 Translational Medicine

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