Genetic Engineering & Biotechnology News

DEC 2017

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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12 | DECEMBER 2017 | | Genetic Engineering & Biotechnology News Rohan Thakurr Over the last few decades, matrix-assisted laser desorption/ionization mass spectrom- etry (MALDI-MS) has proven its usefulness and robustness in many applications. Recent innovations in MALDI-MS utilize advances in two detection schemes being applied to accelerate preclinical drug discovery: one in ultra-high-throughput screening (uHTS) programs, the other in drug-distribution MALDI imaging studies. The recurring principle—fail early, fail cheap—drives innovation in pharma who seek to rapidly generate more compound leads or "hits" as well as involve ADME/ TOX (absorption, distribution, metabolism, excretion/toxicity) earlier in the discovery process to quickly eliminate candidates. New initiatives have undoubtedly driven the growth (2015–2016) in drug pipelines to an estimated 11.5 %. 1 Ultra-High-Throughput Screening The ideal analytical tool for small- molecule R&D is label-free characteriza- tion and mapping along with the abil- ity to measure directly and quantitatively. Rapid, robust, easy-to-use, cost-effective, and automation-ready are also features on most wish lists. New generation mass spectrometry inherently delivers on many of these criteria, and opened up a new are- na for MALDI–MS within the last years. MALD-MS is helping researchers identify the most promising small-molecule leads, and is now expanding into the ultra-high- throughput, compound-screening pro- grams that Big Pharma relies on. When configured for uHTS, as with Bruker's rapifleX MALDI-PharmaPulse TM instrument, the result is a system that is up to 50 times faster than a traditional instru- ment, with improved robustness, sensitivity, and extended mass range. Presented at the ASMS conference in 2016, a poster from Dr. Peter Marshall et al. (GlaxoSmithKline, Stevenage, U.K.) described how their use of MALDI-PharmaPulse, coupled with nanoli- ter liquid handling, enabled them to screen more than 1 million samples per week. 2 The work was possible in large part because of the revolutionary 10 kHz laser in rapifleX MALDI–PharmaPulse. Mass spectra were acquired in the range of either m/z 80–400 or 700–3,500, with 200 laser shots per sample. Under these ex- perimental conditions, the system processed a 1,536-well plate in 7.36 minutes. With a vast in-house collection of candidate com- pounds, simple scale-up calculations indicate that to analyze 2 million compounds would require 7.85 days. An assessment of the ro- bustness of the system and the methodology was made—with good correlation of results before and after 108 measurements. They conclude that the technology and approach for uHTS is robust and can de- liver very fast analysis times. The group has measured more than 1 million samples in a week and found that it is possible to mea- sure more than 2 million samples without having to clean the instrument lens stack. Finally, looking forward to even higher throughput, the group achieved similar as- say performance using 6,144-well plates. If adopted into routine, this could cut the time required to screen 2 million compounds to 2.39 days. Valuable Tool in Small-Molecule R&D Pharma companies are increasingly aware of the disconnection between out- comes in clinical programs and early-stage development work. As part of the industry's response, ADME/TOX investigations are now integrated as early as possible, in order to understand essential details of drug dis- tribution, metabolism, and toxicology while still in preclinical phase. The current best practice methods for Novel Method to Finding New Drug Candidates with Promisting Therapeutic Applications MALDI-MS Detection Schemes Hasten Drug Development Drug Discovery Tutorial Insights Discovery & Development Microbiome research has been on a tear lately, mov- ing from revelation to revelation—bacterial fats accu- mulate in human atherosclerotic plaque, microbiome composition affects patient responses to melanoma immunotherapy, and unexpected connections keep appearing between gut bacteria and conditions as di- verse as multiple sclerosis, post-traumatic stress disor- der, and chronic fatigue syndrome. Although advances in microbiome research have been conspicuous, recent progress in microbiome drug development, though less dramatic, is nothing to overlook. Kaleido Biosciences and CoreBiome have part- nered to integrate genomics and informatics, and thereby enhance the study of structure-function rela- tionships and the design of microbiome-modulating therapeutics. Symbiotix Biotherapeutics has received $5 million in financing to develop microbiome-derived therapeutics to modulate regulatory T-cell activity. And Vedanta Biosciences is advancing cancer immuno- therapy candidates based on microbiome-derived live biotherapeutics that induce CD8+ T cells. Putting such advances in context, market research firms note that the study of the human microbiome is still in its infancy. "Lack of comprehensive research, minimal awareness regarding the beneficial use of microbiome-based products, and stringent govern- ment regulations are turning out to be restraints for the market," states Research and Markets. The firm also indicates that fecal microbiota transplant is the only commercially available microbiome-based therapy. Nonetheless, the microbiome therapeutic pipeline has several promising candidates. According to Re- search and Markets, over 170 microbiome therapeutics and close to 25 microbiome diagnostics are in various stages of development. Another analyst, Transparency Market Research, estimates that the therapeutics and diagnostics markets will have growth rates of 9.2% and 8.6%, respectively, as the year 2024 approaches. By that time, the agency estimates, the worldwide market could be worth $3.2 billion. Other parties that are bullish about the microbi- ome's commercial prospects participated in the recent Microbiome Drug Development Summit. One of the presenters, Janssen R&D's Dirk Gevers, Ph.D., charac- terized the emerging microbiome industry as "a nice balance between bacterial mixtures, computational platforms, single strains, diagnostic approaches, and engineered bacteria." A post-event report emphasized that developers were willing to try nontraditional approaches, including the use of a human-first drug discovery platform for FMT, technologies for "culturing the unculturable," and microbiome surveys focused on metabolomics. n Drug Development Teems with Microbiome Activity Figure 1. Images from histology and MALDI–MSI correlate to show that a specific metabolite is localized to areas of inflammation in a dosing study. 2

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