Genetic Engineering & Biotechnology News

AUG 2018

Genetic Engineering & Biotechnology News (GEN) is the world's most widely read biotech publication. It provides the R&D community with critical information on the tools, technologies, and trends that drive the biotech industry.

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Gareth John Macdonald When developing, configuring, or operating a bioreac- tor, one should avoid "pulling out all the stops," as the saying goes. To understand why, one needs to know that in this saying, "the stops" originally referred to the control elements of another instrument, the pipe organ. Pulling different stops directs pressurized air through different sets of pipes, producing different sounds, not all of which work well together. Similarly, proper ad- justment of a bioreactor's controls, or manipulation of the variables that influence an upstream process, re- quires something like a good ear. Some combinations may produce pleasing harmonies in the form of high yields, batch by batch, or consistent output from dense- ly packed but highly viable cell cultures. Other combi- nations, however, may clash, jarringly—or even worse, expensively. GEN asked recently asked a Bioreactors Pull Out Some of the Stops But it is still an emerging field and not without its technologi- cal and biological challenges. Industry experts regularly meet at annual scientific conferences to discuss epitope mapping and how its translational potential may be realized. For ex- ample they consider how mutations accrue in dividing tumor cells and result in modified peptide sequences, tumor-specif- ic neoepitopes that can be the unique tumor-specific antigens by which the adaptive immune system can selectively target cancer cells. Historically, epitope mapping experiments were very labor intensive, instrumentation lacked the needed sensitivity, and material requirements were high. As data patterns emerged, predictive algorithms became the principle way to identify new epitopes. Although good at predicting the biophysics of the peptide–receptor interaction, these algorithms do a poor job of predicting cellular processing and regulation. From Prediction to Observation "If you cannot predict what will be presented, the bio- physics is irrelevant. A more effective approach is to cap- ture the major histocompatibility complex receptors, elute the peptides, and measure what has actually been pre- sented. Current improvements in mass spectrometers, mass accuracy, and bioinformatics have made looking directly into patient samples practical. This shift toward observa- tion is also the challenge," stated Eustache Paramithio- tis, Ph.D., vice president, discovery, Caprion Biosciences. Quality of mass spectrometry data varies widely; strong expertise in informatics is also required to define acceptable data. Overall, epitope mapping is a multidisciplinary activity that requires commitment and infrastructure. Caprion Bio- sciences has developed an industrialized, robust, reproducible process, and expertise in numerous sample types. In the past, neoepitopes were assumed to be point muta- tions. Yet Caprion Biosciences' data consistently demonstrate multiple mutation types presented on the tumor cells: inherited and somatic point mutations at a rate of about 25%, frame shifts at a similar proportion, and other splicing errors and fu- sion peptides. Afterward, identification targets must see page 10 MaryAnn Labant Epitope mapping, which identifies antigen regions that serve as binding sites for antibodies, is starting to inform the discovery and de- velopment of new therapeutics, vaccines, and diagnostics for a myriad of afflictions including cancer, infectious diseases, and allergic diseases. Epitope Mapping Orients Immune Interventions see page 18 Caroline Seydel Television writers portray DNA evidence as a slam dunk, sealing the fate of many a villain in a fast-paced game of cat and mouse. The reality, however, is that a single DNA sample requires days to analyze, and many samples never get processed at all. DNA profil- ing has come a long way since its debut in 1986, but in many ways, it's still in its infancy. Here are four ways researchers are breaking new ground with forensic uses of genetic analysis. Whose Cell Is It Anyway? A DNA sample can indeed put a criminal behind bars or exonerate an innocent suspect—but only if it gets tested. If it stays in a neglected rape kit, for exam- ple, DNA won't serve the cause of justice. Thousands of rape kits stay on shelves for years simply because each kit takes so long to process. The first big hold-up occurs when the rape kit's sperm cells are separated from the victim's own cells. This process, which re- quires multiple rounds of washing and centrifugation, can last eight hours. "We can reduce that multistep process to a one-step process that takes just an hour," says Utkan Demirci, Ph.D., professor of radiology at Stanford University. Dr. Demirci worked with Fatih Inci, a graduate student in his lab, to You Can Run, but Your DNA Can't Hide see page 25 MedImmune, the global biologics research and development arm of AstraZeneca, recently conducted a study on MEDI4276, an antibody-drug conjugate composed of a bispecific antibody against the extracellular domain of human epidermal growth factor receptor 2 (HER2). According to MedImmune scientists, MEDI4276 binds to two distant and non-overlapping epitopes on HER2. Forensics Technologies $12.7 billion 2016 $19.2 billion Source: BCC Research (CAGR 7.7%) 2022 August 2018 The Scoop Tissue Engineering Covers Wide Range of Applications 6 New CRISPR Startups Get a Leg Up 14 Outsourcing Drives Growth at Almac 8 Commercializing Gene Therapies 24 Demonstrating Process Scalability 22

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