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12 | APRIL 1, 2015 | GENengnews.com | Genetic Engineering & Biotechnology News Toxicity's Portents Continued from page 1 DRUG DISCOVERY induced pluripotent stem cells (iPSCs). This approach was considered by Roche, in col- laboration with Cellular Dynamics Interna- tional (CDI), after the pharma giant's CCR5 inhibitor RO5657 was dropped. Although RO5657 progressed through hERG and pre- clinical cardiotoxicity assessment, it was ulti- mately dropped due to severe cardiotoxicity in primates. The setback led the collaborators to hy- pothesize that in vitro phenotypic screening could be more predictive of drug-induced cardiotoxicity. The collaborators subsequent- ly evaluated CDI's human iPSC-derived iCell Cardiomyocytes on a drug development plat- form marketed by Roche. In a related development, the FDA is now collaborating with the Health and Environ- mental Sciences Institute to develop a comple- ment of in vitro and in silico assays as a replace- ment for the thorough QT assessment clinical trial. This effort, called the Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative, represents a major shift in the regulatory ap- proach toward the utility of in vitro assays. "iCell Cardiomyocytes have utility at many points in the drug discovery process. A group at the Hospital for Sick Children (Sick- Kids) in Toronto previously identifed a new target, integrin-linked kinase, involved in di- lated cardiomyopathy and was able to use the cells to validate this target," commented Carter Cliff, business development, CDI. "In addition, scientists in Roche's car- diovascular program cultured the iCell Car- diomyocytes under diabetic conditions and were able to demonstrate a diabetic cardio- myopathy phenotype similar to that seen by cardiomyocytes made from a diabetic genet- ic background," Cliff continued. "In a small molecule screen, this model produced novel and chemically diverse leads worthy of ad- ditional development." Human iPSC-derived cells provide a more relevant human model that may enable bet- ter research, reduce drug attrition, and spur cell therapy development. Fundamentally, the question is not whether to use iPSCs or primary cells but about the shift from target- based screening in heterologous cell lines to phenotypic readouts in contextually relevant human models. iPSCs can be derived from any person in any quantity needed, providing control over the background genotype. Furthermore, new gene-editing tools make it possible to produce PSC models with specifc defects, or isogenic models from individuals with known genetic defects. Multiple efforts are underway to de- velop better cell culture conditions for sup- port of both primary and PSC models. Cytokine Storms A cytokine storm, or an instance of cyto- kine-release syndrome, most commonly occurs as part of the immune response to some viral infections but can also be frequently associated with monoclonal antibodies (mAbs). Some mAbs carry black box warnings about cyto- kine-release syndrome, which can affect a sig- nifcant portion of patients to varying degrees. The mAb-mediated cytokine-release syn- drome may be either a pharmacological ef- fect, or a secondary effect, such as immune stimulation mediated via Fc receptors. Other types of therapeutics, such as siRNA, also have the potential to stimulate immune func- tion by interacting with toll-like receptors. Given the exquisite specifcity of mAbs and differences between human and animal immune systems, animal models may fail to adequately predict cytokine-storm potential. A potential treatment for B-cell chronic lym- phocytic leukemia, the CD28-specifc mAb TGN1412, was intended to activate regula- tory T cells and dampen immune response, but a cytokine storm resulted in systemic or- gan failure in initial human volunteers. Studies in rodents and nonhuman primates showed no ill effects. Researchers later discov- ered that differences in CD28 expression on T-cell subsets between cynomolgus monkeys and humans might explain the vastly different outcomes in the two species. According to Travis Harrison, Ph.D., di- rector, immunology services, SRI Biosciences, in vitro assays typically use peripheral mono- nuclear cells (PBMCs) or whole blood, not monocyte-derived dendritic cells (DCs). Ob- taining blood from a large number of diverse donors spanning the most frequent HLA types and evaluating multiple cell types would make in vitro evaluation more robust. Working with compounds that may inter- act with toll-like receptors, the Harrison lab- oratory anticipated a greater response in DCs than in PBMCs but saw the opposite. Differ- ences between myeloid and plasmacytoid DC subsets may be the reason, and underscores the need for multiple cell type evaluation. Analyzing Directly in Tissue Inoviem Scientifc's nematic protein orga- nization technique (NPOT) is based on the Kirkwood-Buff molecular crowding and ag- gregation theory. NPOT enables the forma- tion and label-free identifcation of macromo- lecular complexes involved in physiological or pathological processes, and is particularly effective for identifying the on- and off-target actions of therapeutic molecules. Protein-protein interactions can be ana- lyzed directly in human tissue, from complex mixtures, without disrupting the native mo- lecular conformation. Homogenates are prepared from human normal or pathologic tissues in the absence of any detergent, reducing agent, or protease or phosphatase inhibitors. Dilutions and washes are performed in a buffer with equal osmolal- ity, trace elements, vitamins, and salts, in con- centrations as close as possible to those of the interstitial medium or cytoplasm. The label-free ligand of interest, which is unmodifed chemically or molecularly, is put in contact with the total tissue material. Then the macromolecular assemblies related to the ligand are separated using a proprietary dif- > Denovo Licenses Failed Schizophrenia Candidate from Lilly Denovo Biopharma has exclusively licensed pomaglume- tad methionil (mGlu2/3 receptor agonist), a late-stage neuro- science drug, from Eli Lilly. The deal comes nearly two and a half years after Lilly halted Phase III development of pomaglu- metad (DB103, formerly LY2140023) as a schizophrenia treat- ment, after an independent analysis of data from a second Phase III study (designated HBBN) concluded that the drug simply didn't seem to work. Pomaglumetad was primarily developed and tested in schizophrenia, including in Phase II and Phase III clinical trials. While pomaglumetad did not meet the primary endpoint in the intent-to-treat population in Phase III studies, Denovo said "a meaningful subset" of patients who showed signifcantly im- proved outcomes had been identifed through predefned sub- population analysis and post hoc analysis across multiple studies. Under the licensing deal, Denovo gains all rights to devel- op, manufacture, and commercialize pomaglumetad globally, including transfer of all intellectual property and other rights, data, and information. Lilly has an option to reacquire poma- glumetad upon a successful clinical trial. > Chugai to Co-Develop Athersys' Cell Therapy in Japan in Up-to-$205M Partnership Athersys will co-develop and co-commercialize its Multi- Stem® cell therapy for ischemic stroke in Japan by bringing in a partner, Chugai Pharmaceutical, in a deal that could net Athersys up to $205 million-plus. MultiStem is under Phase II clinical study for ischemic stroke in the United States and Eu- rope. Chugai will oversee the development and commercial- ization of MultiStem for ischemic stroke in Japan, with Ather- sys having responsibility for product supply. Athersys says MultiStem has potential for treating multiple disease conditions, including cardiovascular, infammatory, and immune diseases, as well as neurological disorders such as isch- emic stroke. MultiStem is designed as an "of the shelf" stem cell product that can be manufactured in a scalable manner, may be stored for years in frozen form, and is administered without tissue matching or the need for immune suppression. According to the company, preclinical research to date has shown that administration of MultiStem has resulted in reduc- tion of infammation and immune system modulation in the ischemic area, and the protection and rescue of damaged or injured cells, including neuronal tissue. > Bavarian Nordic Could Reap $975M in Prostate Cancer Deal with BMS Bristol-Myers Squibb (BMS) obtained an exclusive option to license and commercialize Prostvac®, Bavarian Nordic's Phase III prostate-specifc antigen-targeting cancer immu- notherapy in development for the treatment of asymptom- atic or minimally symptomatic metastatic castration-resis- tant prostate cancer. Bavarian Nordic is scheduled to receive an up-front pay- ment of $60 million. BMS can exercise that option within a designated time after data is available from the ongoing trial. Bavarian Nordic would be entitled to a payment of $80 million upon exercise of the option plus additional incremental pay- ments starting at $50 million, but with a potential to exceed $230 million should the median overall survival beneft of Prostvac exceed the efcacy seen in Phase II results. Bavarian Nordic also could receive regulatory milestone payments of $110 million, up to $495 million in sales mile- stones, as well as tiered double-digit royalties on future sales of Prostvac. The parties have also agreed to enter into a sup- ply contract, under which Bavarian Nordic will undertake the future commercial manufacturing of Prostvac. n News DISCOVERY & DEVELOPMENT Using HCA, researchers at University College Dublin subjected fne needle aspirates of canine lymph glands to morphometric analysis and immunophenotyping. Conventional light microscopy requires a certifed pathologist and is less objective and less quantitative. A cancerous lymph gland (upper left) is shown alongside three fuorescent, microscopic HCA images. HCA is used to measure nuclear and cytoplasmic areas, nuclear displacement, and cell roundness to diagnose cancer from normal cells. For prognosis, immunophenotyping is performed using fuorescent antibodies to cell-surface proteins specifc for cell type; for example, cancer of T-lymphocytes is 3× more lethal than that of B-lymphocytes.