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February/March 2017 Volume 21, Number 1
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R&D News.......................... 1 Appointments..................... 6 Pharma Notes..................... 7 New Products................... 15 Calendar........................... 17 App Reviews...................... 18
Ottawa researchers kill brain cancer in mice with combination immunotherapies (L to R) Drs. Eric Lacasse, Shawn Beug and Robert Korneluk
OTTAWA, ON – A team of researchers from the Children’s Hospital of Eastern Ontario (CHEO) have published new data in Nature Communications showing that a promising combination of immunotherapies can deliver a one-two punch to brain cancer tumours in mice. As part of their study, Drs. Eric Lacasse, Shawn Beug and Robert Korneluk found that a combination of drugs known as SMAC Mimetics and immune checkpoint inhibitors (ICIs) were able to amplify the kill
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rates of cancer tumour cells. At the same time they discovered a new mechanism by which the combination promotes long-term immunity against glioblastoma tumours. The combination therapy also proved to be highly effective against breast cancer and multiple myeloma. “These findings represent a significant evolution in our research and the field of immunotherapy... we are the first in the world to show the synergistic tumour-killing impact of combining SMAC Mimetics
with immune checkpoint inhibitors for glioblastoma,” said Dr. Korneluk, a professor at the University of Ottawa and senior scientist at the CHEO Research Institute. “You could say it takes two to tango, that it takes a combination strategy to impact cancer cure rates,” he adds. In 2014, a team of scientists led by Dr. Korneluk discovered that combining SMAC Mimetics with immune stimulators, or live virus therapies, had a synergistic or amplified tumour-killing effect that was greater than either agent on its own. These latest findings show that SMAC Mimetics also have a powerful synergistic effect with ICIs, which are relatively new drugs that are showing great promise in the clinic. As part of this latest study, SMAC Mimetics known as LCL161 and Birinapant were combined with ICI antibodies targeting PD-1 and CTLA-4 immune checkpoints.
Dr. Lacasse, a scientist at the CHEO Research Institute, adds “Two drug companies have initiated human clinical trials this year to assess the impact of this combination of SMAC Mimetics and ICIs on patients with a variety of cancers.” Although it could be years before any clinical trials begin for adults or children with the deadly brain cancer, glioblastoma, he says the research team is looking forward to seeing how scientific evidence from these experimental treatments will impact future research initiatives. “It’s an exciting, exploratory field and we hope we’ve hit a home run,” he said. “This research heightens our understanding of the mechanics behind this double-whammy effect, which both enhances the immune response and weakens tumour cells to immune attack,” commented Beug, lead author of the 2014 and 2017 papers. “We’re hoping that more oncologists and biotech companies test out this combination in clinical trials as we continue to decipher how SMAC Mimetics encourage the immune system to kill cancer cells.” The research was funded by the Canadian Cancer Society Research Institute, Brain Canada (with financial support from Health Canada through the Canada Brain Research Fund) and the Canadian Institutes of Health Research. In addition, the work was supported by donations to the Ottawa Regional Cancer Foundation, the Kiwanis Medical Foundation and the CHEO Foundation. To see this story online visit http://laboratoryfocus.ca/ottawaresearchers-kill-brain-cancer-inmice-with-combination-immunotherapies/
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Princess Margaret Cancer Centre joins Roche’s global cancer research network MISSISSAUGA, ON – Toronto’s Princess Margaret Cancer Centre has joined Hoffmann-La Roche Limited’s (Roche Canada) global can-
cer immunotherapy Centres of Research Excellence (imCORE) Network. The new network hopes to bring together leading
scientific and clinical experts in cancer immunotherapy to collaborate on the investigation and development of promising new treatment
approaches for the disease. The goal of imCORE is to rapidly initiate pre-clinical Continued on page 3
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Continued from page 2 and clinical research based on the latest scientific discoveries in cancer immunotherapy and to aggregate, as well as share data to help accelerate cancer research. According to the Canadian Cancer Society, cancer is the leading cause of death in Canada and is responsible for 30 per cent of all deaths in the country. In fact, two out of five Canadians (45 per cent of men and 42 per cent of women) are expected to develop cancer during their lifetimes. “Cancer is a complex disease, and one that poses a significant burden
across the world,” said Ronnie Miller, president and CEO, Roche Canada. “As a research-driven organization, Roche is proud to have the Princess Margaret Cancer Centre join the imCORE Network to help us better understand immune biology and cancer, and to ultimately improve treatment options.” The imCORE Network is comprised of 21 academic centres, inclusive of Princess Margaret Cancer Centre, from nine countries across the globe, working together to access and share technology, data and expertise to advance science.
“The imCORE Network provides a great opportunity for academic centres like ours to collaborate and explore new concepts, both in the laboratory and in the clinic,” said Dr. Lillian Siu, medical oncologist at Princess Margaret Cancer Centre and site lead for the imCORE Network. “This type of collective learning is exactly what is needed to make important progress in a field as fast-moving as cancer immunotherapy.” As a part of a global announcement regarding the launch of the imCORE
Electrophysiology laboratory opens at Montréal Heart Institute
Dr. Denis Roy, Dr. Laurent Macle, Mr. Keeron Tom, Dr. Paul Khairy and Mrs. Melanie La Couture (CNW Group/Montréal Heart Institute Foundation)
MONTRéAL, QC – A new electrophysiology laboratory (EP Lab), equipped with robotic and magnetic navigation, and dedicated to studying congenital heart diseases in Canada has opened at the Montréal Heart Institute (MHI). Dr. Denis Roy, cardiologist and executive director of the Institute calls the addition of the EP lab an advancement that benefits patients from across Canada and beyond. He adds that just a few decades ago, most children presenting with serious forms of congenital heart diseases died during childhood; today however, more than 90 per cent survive until adulthood, which leads to a rapid increase in the patient population presenting with congenital heart diseases. Thanks to this new robotic magnetic navigation platform, and combined with the expertise of its medical team, Roy believes the MHI
has strengthened its international leadership position in the treatment of adult congenital heart diseases. “This Canadian first will benefit not only Québec patients and those hailing from other provinces, but it will also benefit patients from abroad,” he says. “Thanks to this new (EP) lab, we will be able to perform interventions to treat arrhythmia in patients presenting with the most complex forms of cardiac malformations,” adds Dr. Paul Khairy, cardiologist-electrophysiologist and director of the Adult Congenital Heart Centre at the MHI. He explains that robotic magnetic navigation enables complex interventions aimed at mitigating arrhythmia by destroying the responsible electric cells and thus restoring a normal cardiac rhythm. “Thanks to the robotic and mag-
netic system, we can effectively and accurately guide catheters in a safe manner through complex anatomies caused by cardiac malformations,” says Khairy. “The first patients we treated with this new modality presented with serious forms of congenital heart diseases. A catheter ablation would not have been a viable option in those cases if it weren’t for the sophisticated functionalities this robotic magnetic navigation platform offers.” Construction of the lab was made possible with the support of the Canada Foundation for Innovation, St-Jude Medical, Dalfen Family Foundation and the Montréal Heart Institute Foundation. To see this story online visit http://laboratoryfocus.ca/electrophysiology-laboratory-opens-at-Montréal-heart-institute
Network, Roche is investing up to 100 million Swiss Francs (more than $130 million Canadian dollars) to support basic and clinical research collaborations related to cancer immunotherapy. The investment is incremental to Roche’s on-going research and development of investigational medicines and treatment approaches in the field of cancer immunotherapy. To see this story online visit http://laboratoryfocus.ca/princessmargaret-cancer-centre-joins-rochesglobal-cancer-research-network
BioCanRx, and partners, announce funding to manufacture first made-inCanada CAR-T cells OTTAWA, ON – BioCanRx and its partners are funding 16 collaborative research projects aimed at developing clinical Chimeric Antigen Receptor modified T cell (CAR-T) manufacturing capabilities in Canada. According to the organization, CAR-Ts are a powerful new tool for treating cancer and have begun to provide hope to patients without other therapeutic options to treat and cure their disease. Such therapies are also considered on the cutting edge of cancer therapeutics and have shown promise in paediatric and adult patients with certain blood cancers such as acute lymphoblastic leukemia and lymphoma. While promising, the development of such therapies also require sophisticated manufacturing and expertise. Canada currently does have the basic laboratory infrastructure in place, but this new funding will be used to fully develop the expertise and capacity required to deliver this technology. Additionally, the research projects will advance several innovative engineered T cell designs, benefiting from this infrastructure and capacity investment, and accelerate delivery of these novel concepts into clinical testing in Canada. Dr. John Bell, scientific director, BioCanRx adds that this CAR-T manufacturing initiative is unique in that it shows that Canada’s academic community recognizes Continued on page 4
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Merck’s $15 million investment helps launch ONCOPOLE
Continued from page 3
Québec City, QC – Various public and private sector stakeholders in Québec, including Merck & Co. Inc. and the Fonds de recherche du Québec – Santé (FRQS), have teamed up to launch a new research, development and investment hub in the hopes of accelerating the fight against cancer. The hub, called Oncopole, is being backed by a $15-million investment by Merck that will be administered over three years and overseen by the FRQS. Oncopole will aspire to strengthen the research and innovation ecosystem in the province and bring together various stakeholders under one flagship hub in oncology. “Thanks to its energy and effervescence, and its many high-level research universities and infrastructures, Québec has become the ideal site for large-scale projects,” said Dominique Anglade, Québec Minister
of Economy, Science and Innovation. “The Oncopole will be a major highcalibre hub that will help position and support Québec experts as we propel our innovations on the Canadian and international scene,” she adds. The creation and planning of the new centre included the involvement of more than 50 experts from Québec’s scientific community, who also provided key insight into helping to identify what its priorities should be going forward. According to Merck and FRQS, these priorities will include incubating and creating new companies, capitalizing on innovation and cancer care in Québec, and better positioning cancer care in the province in terms of clinical outcome, patient experience and system efficiency. “Merck is delighted to have found
Solving cancer’s biggest questions: OICR researchers to be part of Cancer Research UK’s Grand Challenge
Joining Dr. Stein in this initiatve is Dr. Gallinger, head of Hepatobiliary/Pancreatic Surgical Oncology Program at University Health Network and Mount Sinai Hospital and leader of OICR’s PanCuRx Translational Research Initiative. “Dr.Gallinger and I are proud to participate in this groundbreaking project by contributing scientific expertise and samples collected from Canadians across several cancer types,” adds Stein. “Cancer Research UK set up the Grand Challenge awards to bring a renewed focus and energy to the fight against cancer,” said Sir Harpal Kumar, Cancer Research UK’s chief executive. “We want to shine a light on the toughest questions that stand in the way of progress. We’re incredibly excited to be able to support these exceptional teams as they help us achieve our ambition.” Cancer Research UK set up Grand Challenge in 2015 and committed up to £100 million (CDN$164 million) to this new approach to help increase the pace of research. Phase two of the Grand Challenge, when Cancer Research UK plans to issue a set of second challenges, will launch this summer.
the gap and stepping up to drive Canadian is solutions to meet grassroots efforts taking place in the U.S., China and Europe. To help ensure CAR-T cell therapy is brought to patients safely and effectively, BioCanRx is also funding a companion Clinical, Social, and Economic Impact project. It will review the existing base of knowledge and involve patient
Dr. Steven Gallinger
TORONTO, ON – Two Ontario Institute for Cancer Research (OICR) researchers, Drs. Lincoln Stein and Steven Gallinger, have been selected as members of one of the first global research teams to receive Cancer Research UK’s Grand Challenge grants. The Grand Challenge aims to help overcome the biggest challenges fac-
consultation to design a rigorous CAR-T clinical trial protocol ready to implement once the products are ready for a Phase 1 clinical trial. To see this story online visit http://laboratoryfocus.ca/biocanrxand-partners-announce-fundingto-manufacture-first-made-incanada-car-t-cells
Dr. Lincoln Stein
ing cancer research in a global effort to beat cancer sooner. Stein and Gallinger’s pioneering team will study samples from five continents to understand the DNA damage associated with different cancers, to understand what causes them and if they can be prevented. The project will be led by Professor
Mike Stratton at the Wellcome Trust Sanger Institute, Cambridge, with collaborators from France, the U.S. and U.K. According to Grand Challenge, the winning projects are set to revolutionize our understanding of cancer, and how to better prevent, diagnose and treat the disease. The international, multidisciplinary teams will bring together people, technology and knowledge on a scale that has not previously been undertaken in cancer. The international, multidisciplinary teams will bring together people, technology and knowledge on a scale that has not previously been undertaken in cancer. “One of the most intriguing aspects of cancer is how much the rate and types of cancer differ from one part of the world to another,” said Stein, who is interim scientific director of OICR and director of OICR’s Informatics and Bio-computing Program. “This project is the first large-scale attempt to systematically study how geography influences cancer at the genomic level, and will lead to new understandings of how diet, lifestyle, the environment and genetics interact to cause these regional differences,” he said.
Continued on page 5
To see this story online visit http://laboratoryfocus.ca/ oicrresearchers-to-be-part-of-cancer-research-uks-grand-challenge-trying-toanswer-cancers-biggest-questions
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news Continued from page 4 in Québec the fertile environment needed to build this unique alliance between public and private partners,” said Chirfi Guindo, president and managing director of Merck Canada Inc. Additionally, the FRQS and Merck hope that this initial investment will attract other partners to join the Oncopole and make it a truly collaborative initiative. “We may be the first private partner but we hope that other businesses will join us so that we may combine
our strengths and reach ambitious well-being goals for our patients,” adds Guindo. The Institute for Research in Immunology and Cancer (IRIC) of the Université de Montréal has been selected to host Oncopole’s coordinating offices. To see this story online visit http://www.laboratoryfocus.ca/cpdcteams-with-dana-farber-cancer-institute-on-cancer-research-initiative/
(L to R) Adam H. Schechter, president, Global Human Health, Merck, Mr. Rémi Quirion, Québec Chief Scientist and Chairman of the boards of directors of the Fonds de recherche du Québec, Mr. Chirfi Guindo, President and Managing Director of Merck Canada Inc. and Mr. Jacques Simard, Oncopole leader – axis 2
Immune therapy scientists discover distinct cells that block cancer-fighting immune cells TORONTO, ON – Princess Margaret Cancer Centre scientists have discovered a distinct cell population in tumours that inhibits the body’s immune response to fight cancer. The findings, published online in Nature Medicine, could prove critical to understanding more about why patients will or will not respond to immune therapies, says principal investigator Pamela Ohashi, director, Tumour Immunotherapy Program at the cancer centre, University Health Network. “We’ve uncovered a potential new approach to modulate the immune response to cancer,” says Dr. Ohashi. “By looking at tumour biology from this different perspective we’ll have a better understanding of the barriers that prevent a strong immune response. This can help advance drug development to target these barriers.” The research team with international collaborators analyzed more than 100 patient samples from ovarian and other cancer types to discover a distinct population of cells found in some tumours. This population of cells suppresses the growth of cancer-fighting immune cells, thereby limiting the ability of the immune system to fight off cancer. For patients, down the road Dr. Ohashi envisions a new era of combined therapies to simultaneously target and kill these suppressive cells while augmenting the immune response against cancer. “This would really strengthen the way clinicians can treat cancer using immune therapy, which holds so much promise for patients.”
Dr. Pamela Ohashi, Director, Tumour Immunotherapy Program at the Princess Margaret Cancer Centre, University Health Network (Photo credit: UHN)
The team’s next avenue of research will be focused on identifying a “biomarker” that can identify this distinct suppressive cell elsewhere in the body – for example, in blood or other samples – as a potential predictive clinical tool to determine when these cells are present in patients, which currently cannot be done.
“That knowledge will guide clinical decisions to personalize cancer treatment to unleash an individual’s immune response,” says Dr. Ohashi. “We need to identify ways to track these cells and find another source and ways to grow these cells for further study.” Dr. Ohashi’s research was funded
by the Canadian Institutes of Health Research and The Princess Margaret Cancer Foundation. To see this story online visit http://laboratoryfocus.ca/immunetherapy-scientists-discover-distinctcells-that-block-cancer-fightingimmune-cells/
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Appointments
Dr. Lesley Esford has been named executive director of Life Sciences BC. Since 2006, Esford has worked as an ITA with the National Research Council - Industrial Research Assistance Program,
Dr. Lesley Esford helping over 100 entrepreneurs develop a wide array of products and services. Her career path has taken her from B.C. to Boston developing insights, observations and a broad knowledge base in human life sciences along the way. She received her PhD in Microbiology and Immunology from UBC and has a M.Sc. from Brock University. The Centre for Drug Research and Development (CDRD) appoints Gordon McCauley as president and CEO. A Vancouver-based life sciences leader with international experience in the industry, McCauley has been a director of CDRD since 2012, assumed the position of Interim CEO last summer, and will now lead the organization going forward. McCauley’s past roles include: president and CEO of Viable Healthworks Corp., president and CEO of Allon Therapeutics Inc., co-founder of NDI Capital, and he was a senior advisor to a number of Canadian political leaders. He is also a past-chair of LifeSciences British Columbia, a director of BIOTECanada, and was the first Canadian appointed to the Board of the Biotechnology Industry Organization (BIO) in Washington D.C. where he served in leadership positions until 2013. Aurinia Pharmaceuticals Inc. has appointed its founder and chairman of the board Dr. Richard M. Glickman CEO of the company.
He replaces Charles Rowland who resigned from the role and as an executive member of the board, effective immediately. Dr. Glickman brings over 30 years of experience and has founded and co-founded numerous companies during his career. As the co-founder, chairman and CEO of Aspreva Pharmaceuticals, he played an integral role in developing and establishing CellCept®, or MMF, as the current standard of care for the treatment of lupus nephritis (LN). He currently serves as founding chairman of Essa Pharmaceuticals Inc., chairman of the board for Engene Corporation and a director of Cardiome Pharma. He is also a partner at Lumira Capital. Additionally, he has served on numerous biotechnology and community boards, including as a member of the federal government’s National Biotechnology Advisory Committee, director of the Canadian Genetic Disease Network, chairman of Life Sciences B.C. and a member of the British Columbia Innovation Council. Kennet Brysting has been appointed general manager of Gilead Sciences Canada, Inc. The former general manager of Gilead Nordics (Sweden, Norway,
Kennet Brysting
Denmark, Finland and Iceland), Kennet Brysting also joins Gilead’s North America Commercial Senior Leadership Team. He succeeds Ed Gudaitis, who left the company in October for another opportunity. Brysting has nearly 20 years of industry experience, including prior pharmaceutical industry general
manager experience, and was the general manager for Gilead Nordics, for four years. He has an EMBA from Cranfield University, UK, and a Bachelor’s Degree in Management Accounting from Copenhagen Business School. B.F. Francis Ouellette has joined Génome Québec as vice president of scientific affairs. He previously worked for the Ontario Institute for Cancer Research (OICR) in Toronto for 10 years, as an associate director of the Informatics and Biocomputing platform and as a lead investigator. Before his arrival in Toronto in 2007, he had served as associate professor in the department of Medical Genetics at the University of British Columbia (UBC) and director of the UBC Bioinformatics Centre (UBiC) at the Michael Smith Laboratories. He was trained at McGill University, the University of Calgary and Simon Fraser University. He was also employed by the National Institutes of Health (NIH), where he coordinated GenBank, the world’s largest open DNA sequence database. He also sits on various advisory boards and editorial boards, including as education editor for PLOS Computational Biology and associate editor for DATABASE journal (an Oxford University Press open access publication). He currently works as associate professor, adjunct in the department of Cell and Systems Biology at the University of Toronto. Mark T. Crane is stepping in as vice president of business development for ITR Laboratories Canada Inc. Crane joins ITR in Montréal from SNBL USA where he served as vice president of business development and marketing. He has held similar positions at Ricerca Biosciences, Bridge Pharmaceuticals (formerly Gene Logic), Quest Pharmaceutical Services and MDS Pharma Services. XiteBio announces the addition of Don Sanders and Julia Cann as the newest members to its Innovation, Research & Development (IRD) team. Sanders joins the team as a research associate and Cann is joining as a lab technician at XiteBio’s IRD Centre in Winnipeg, MB. Sanders recently completed his M.Sc.
from the Department of Plant Science at the University of Manitoba and has previously been employed by the University of Manitoba, Cargill Canada & Kackenhoff Nurseries. Cann has a Bachelors degree from the University of Winnipeg and has previously been employed by Haplotech Inc. and the University of Winnipeg. Oncolytics Biotech® Inc. appoints Dr. Matt Coffey to the role of president and CEO. Dr. Coffey had been serving as the company’s interim president and CEO since early November 2016. A cofounder of the company, Dr. Coffey completed his doctorate degree in oncology at the University of Calgary with a focus on the oncolytic capabilities of the reovirus. The results of his research have been published in various respected scientific journals, including Science, Human Gene Therapy, and The EMBO Journal. Dr. Coffey has held progressively senior roles with Oncolytics including: chief operating officer since December 2008, chief scientific officer, vice-president of Product Development and chief financial officer. Canadian health sciences accelerator Accel-Rx has elected David J. Main as its new board chairman. Currently Main is chairman, president and CEO of Aquinox, and recently, he completed a three-year term as chairman of BIOTECanada. As a co-founder of Aquinox, he has overseen the advancement of the company’s lead product, AQX-1125, from a target validation program to a Phase 3 clinical trial candidate. During this time, he has also been responsible for the transition of Aquinox from a private to a NASDAQlisted public company having raised over US$300 million in equity. Other past roles include INEX Pharmaceuticals Corp. president and CEO, and QLT Inc. vice president. The University of Waterloo has appointed Charmaine Dean vicepresident, university research, beginning July 1. Dr. Dean is currently a professor and dean of the faculty of science at Western University. She was previously associate dean at Simon Fraser University and has served as president of the Statistical Society of Canada.
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Pharma Notes Zymeworks Inc. (Vancouver, BC) reports that the U.S. Food and Drug Administration has granted its lead product candidate ZW25 an orphan drug designation as a treatment for gastric cancer, including cancer of the gastroesophageal junction. ZW25 is currently being evaluated in an adaptive Phase 1 clinical trial in the U.S. It is a bispecific antibody that the company says can simultaneously bind two non-overlapping epitopes, known as biparatopic binding, of HER2 resulting in dual HER2 signal blockade, increasing binding and removal of HER2 protein from the cell surface, and enhancing effector function. These combined mechanisms of action have led to significant anti-tumour activity in preclinical models. Gastric cancer represents ZW25’s second orphan drug designation, in addition to ovarian cancer, which was granted last year. Aequus Pharmaceuticals (Vancouver, BC) has completed the treatment phase of its multi-dose proof of concept clinical trial evaluating the bioavailability and safety of its once-weekly transdermal patch for aripiprazole, AQS1301. Aripiprazole is an atypical antipsychotic and the active ingredient in Abilify®, a leading medication in the U.S. used for the treatment of a number of psychiatric disorders including bipolar I disorder, schizophrenia, major depressive disorder and irritability associated with autistic disorder. Aequus’ once-weekly formulation is designed to provide patients with an easy to use and convenient longacting alternative to the once a day oral pill. This 28-day, multi-dose Proof of Concept study was supported by a grant of up to $100,000 from the National Research Council of Canada Industrial Research Assistance Program. The company hopes to report topline results from this multi-dose study in the first quarter of 2017. Avivagen Inc. (Ottawa, ON), a life sciences company commercializing products intended to replace the antibiotics added to livestock feeds, has launched a new project to explore the potential application of its OxC-beta™ technology in human health. With the help of the National Research Council of Canada (NRC), the company plans to evaluate the efficacy of OxC-beta in an established research model of a yet to be announced human infectious disease. Avivagen says it is not disclosing the specific disease target at this time to help ensure the patentability of the new application. However, the company does say that the disease
target is one of the top 18 urgent, serious or concerning drug-resistance threats listed by the U.S. Centers for Disease Control. As part of the project, work will be conducted by NRC experts at its facilities based upon a jointly developed protocol and is expected to be completed in 2017. The OxC-beta™ technology is derived from Avivagen discoveries about carotenoids, compounds that give certain fruits and vegetables their bright colors and is a non-antibiotic
means of maintaining optimal health and growth.
ongoing 10-cohort Phase 1b study in patients with relapsed or refractory hematologic malignancies. The twopart clinical trial is designed as a multi-center, open-label Phase 1a/1b trial, and is evaluating TTI-621 as a single-agent. The escalation phase will include single or multiple doses of TTI-621 delivered by intratumoral injections, which will be followed by an expansion phase during which one or more selected dose levels of TTI-621 will be tested.
Trillium Therapeutics (Toronto, ON) has initiated dosing in its second Phase 1 clinical trial for TTI-621 (SIRPaFc) in patients with relapsed or refractory percutaneously-accessible solid tumours and mycosis fungoides. Trillium is developing TTI621 as a checkpoint inhibitor of the innate immune system, and the drug is currently being evaluated in an
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feature
b y Jennif er Fournier , Wil liam R . Alley, Jr . and Mat thew L a u ber
Can Improved Technology for Glycosylation Analysis Expedite
Biosimilar Development?
G
eneric versions of innovator drug molecules make medicines more affordable. Nearly eight out of 10 prescriptions filled in the U.S. are for generic drugs and they cost on average 80 to 85 per cent less than their brand-name counterparts. Over the last three decades, significant effort has been devoted to the development and engineering of proteins, including monoclonal antibodies (mAbs), as pharmaceutical products. Similar to small-molecule generics, numerous companies are now beginning to offer generic alternatives to the innovator protein therapeutics, commonly referred to as biosimilars. Regardless of the type of molecule, the main attributes important for similarity are identity, quality and purity, potency1 and method of action. In the small molecule drug manufacturing space, these quality attributes are relatively straightforward to test. However, in the biotherapeutic space, defining similarity is significantly more complicated. The complexity of the task is, in part, due to the heterogeneous nature of these drugs.2 Regardless of the size of the drug, the journey to the market is very similar. Innovator molecules must undergo extensive animal and clinical trials to prove safety, efficacy, and effectiveness. It is generally intended for biosimilars to circumvent the extensive trials required of an innovator drug and their cost to be minimized through a shorter drug application process. However, their time to market is very critical because of the competitive landscape surrounding drugs with expiring patent protection. Undoubtedly, the biosimilar industry is becoming increasingly more competitive as the number of potential manufacturers continues to grow and as the patents for several proteinbased biologic drugs are set to expire in the coming years, with relevant examples being listed in Table 1.3 The race to get to market first is a critical one to win. Therefore, it is advantageous when developing biosimilar products to be sharply focused on how to get to market faster without compromising the safety and efficacy of the drug. To prove that a biosimilar drug is comparable to the innovator molecule, it is subjected to a battery of
analytical tests, which may include primary sequence confirmation by intact mass analysis and peptide mapping experiments, elucidation of higher order structure, analyses of product impurities (host-cell proteins) and characterization of posttranslation modifications, including glycosylation patterns.4-5 These analyses were previously performed on the innovator molecule during its development and manufacturing. However, companies producing biosimilar products are not required to perform exactly the same analyses as those used by the innovator company.1 This allows the biosimilar companies to utilize new technologies which can decrease the time invested in each test, while increasing the analytical measurement sensitivity, which ultimately will provide a “high definition” picture of the minor differences that occur and need to be well characterized and tracked for bioactivity and safety. A pertinent example of a test that may slow a drug’s entrance onto the market is glycan profiling. Traditionally, this is one of the more complicated and time-consuming product quality attributes to characterize. Yet, glycosylation, the enzyme-mediated attachment of saccharides to a pro-
tein backbone, can influence a number of physicochemical properties of a therapeutic glycoprotein, including its serum half-life, effector functions like complement-dependent cytotoxicity (CDC) and antibody-dependent cell cytotoxicity (ADCC).6 Glycosylation may also induce immunogenic responses if non-human epitopes, like N-glycolylneuraminic acids7 or α-linked galactose pairs8 are present at sufficient
Table 1
abundance levels. It is, therefore, important to characterize and control glycosylation during the development and manufacturing of therapeutic glycoproteins. In this article, we present a case study that demonstrates the advantages that new analytical approaches for glycan profiling can have on facilitating the comparability testing of an innovator versus biosimilar monoclonal antibody.
Biologic Drugs with Expiring Patent Protection
US Innovator Drug Dollars* Humira (adalimumab) $12.50 Rituxan (Rituximab) $8.70 Remicade (infliximab) $9.20 Enbrel (etanercept) $8.50 Avas n (bevacizumab) $7.00 Avonex, Rebif (interferon Beta-1A) $3 Hercep n (trastuzumab) $6.80 Neulasta (Pegfilgras m) $5.90 * in billions for 2014 global revenues1
US Patent Expira�on Date# 2016 2016 2018 2028 2017 2026 2019 2014
(Top 10 Best-Selling Biotech Drugs, http://www.biospace. com/News/top-10-best-selling-biotech-drugs/393360) # The Next Frontier for Improved Access to Medicines: Biosimilars and Interchangable Biologic Products
1
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Figure 1
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Laboratory Focus February/March 2017
Schematic outline of the N-linked glycan sample preparation protocol used in this study.
Figure 2
The fluorescence (FLR) and mass spectrometric (MS) performance of various N-linked glycan labels. Reprinted with permission from Lauber, MA, Yu YQ, Brousmiche DW, Hua Z, Koza SM, Magnelli P, Guthrie E, Taron CH, Fountain KJ. Rapid Preparation of Released N-glycans for HILIC Analysis Using a Labeling Reagent that Facilitates Sensitive Fluorescence and ESI-MS Detection. Anal Chem 2015; 87: 5401-5409. Copyright 2015 American Chemical Society.
The technological advances that enabled this comparison were made in both sample preparation and in analytical workflow including informatics. These advances enabled fast sample processing combined with highly automated data processing, annotation and reporting. Traditional glycan sample preparation protocols for LCMS are time consuming and often require overnight PNGase F digestions followed by extended labeling times and sample purification procedures. This methodology can be quite labour intensive and lengthy and when high throughput is required, for example during clone selection, such procedures can hinder the overall progress of bringing a product to market. This
is clearly not advantageous for companies developing biosimilar products. To address these time-consuming areas, a new higher throughput platform was developed to streamline and simplify N-linked glycan sample preparation (Figure 1)9. In this approach, biotherapeutic samples are denatured with 1% RapiGest® SF surfactant at a temperature of at least 90o C for 5 minutes and then cooled to room temperature. The N-linked glycans are then released using Rapid PNGase F through a 5-minute incubation at 55O C. A short incubation is essential to preserving a form of released N-glycans, known as glycosylamines, which can be derivatized with a highly active amine labeling
reagent, RapiFluor-MS (RFMS). Complete labeling is achieved in 5 minutes. Subsequently, the samples are purified by μ-elution solid phase extraction (SPE) and analyzed by hydrophilic interaction chromatography (HILIC). Beyond trimming the turn-around time of N-linked glycan sample preparation to less than an hour, RFMS uniquely facilitates both fluorescence (FLR) and mass spectrometric (MS) detection. As depicted in Figure 2, RFMS provides significantly enhanced MS signal intensities while maintaining sensitive FLR detection, making it possible to detect, characterize, and quantify even the low abundance glycans that typically are missed when using conventional la-
Feature bels such as 2-aminobenzamide. To further streamline the task of Nlinked glycan profiling, a dedicated glycan analysis workflow was developed within the Waters UNIFI Scientific Information System to automate the analytical process using combined FLR and MS data from a single injection (FLR and MS detectors are in tandem). One of the key features of this workflow is the ability to perform glycan library searches based on the calibrated HILIC retention time in Glucose Units (GU) and accurate mass values. For this, each glycan component is matched and assigned by the glycan entries from the scientific library that have close GU values and matched m/z values within the analytical standard deviation set by the user. In addition, the integrated FLR peaks are used to quantify the relative amount of each glycan. In the comparability study presented here, the RFMS Glycan GU Scientific Library was used. This library was co-developed with the National Institute for Bioprocessing Research and Training (NIBRT) in Dublin, Ireland and has experimental GU values for over 160 N-glycans derived from nine different glycoproteins. Combining the RFMS sample preparation platform with the above glycan analysis workflow provides a high throughput, yet powerful, approach to glycan analysis. The capabilities of this approach can be seen in a case study that compares the N-linked glycans of the innovator mAb infliximab (Remicade®), produced in an SP2/0 mouse cell line, to those from a biosimilar equivalent (Inflectra®) produced by a Chinese hamster ovary (CHO) cell line. Three different lots of the innovator drug and one biosimilar sample were studied. For the innovator molecule, 23 mass confirmed N-linked glycans were identified, and 21 of these were observed from the biosimilar mAb. The majority of the glycans were neutral complex type, though eight glycans with N-glycolylneuraminic acid were also observed. Six glycans with α-linked galactose pairs were also identified. To initially evaluate the N-linked glycan profiles, fluorescence traces were stacked, as shown in Figure 3. The trace for the biosimilar mAb is shown in red, and the innovator sample traces are show in blue, black, and purple. The glycan profiles of the innovator mAb and biosimilar appeared to be quite comparable, though some differences could be observed for low abundance species. This was confirmed by summary plots that compare normalized abundance levels (Figure 4). Such a plot made it possible to visualize an increased relative amount of a glycan with N-glycolylneuraminic acid (Figure 4a) and a decreased relative
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amount of a glycan with α-linked galactose on the biosimilar (Figure 4b). Derivatizing the glycans from these samples with RFMS was critical to achieving suitable MS sensitivity to mass confirm these lower abundance glycans with immunogenic properties. Proving bioequivalency is critical for the development and approval processes of biosimilars. As many potential biosimilars are glycoproteins, there is an analytical burden to demonstrate the comparability of glycosylation. The noted advances in glycan profiling technology can help biosimilar drug manufacturers overcome this hurdle faster. In particular, HILIC-FLR-MS can be used as a powerful analytical tool for resolving and identifying critical low abundance glycans. Moreover, advances in sample preparation, such as the RapiFluor-MS™ kit, combined with bioinformatics platforms, such as UNIFI, can help biosimilar companies quickly detail their glycan profiles and to more efficiently access deeper levels of information on their candidate biologics. When combined, these tech-
Figure 3
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Fluorescence N-glycan profiles for the three innovator samples (blue, black, and purple) compared to that of the biosimilar sample (red). Reprinted with permission from Fang, J, Doneanu CE, Alley WR, Yu YQ, Beck A, Chen W. Advanced Assessment of the Physicochemical Characteristics of Remicade® and Inflectra® by Sensitive LC/MS Techniques. mAbs 2016; 8: 1021-1034. Copyright 2016 Taylor and Francis Group.
Figure 4 A
B
Summary plots for a) a glycan terminated with N-glycolylneuraminic acid that appears to be elevated in its abundance level on the biosimilar mAb, and b) a glycan with α-linked galactose units that may be elevated on the innovator drug. The data are reported as “% amount” where the FLR peak area for each glycan is expressed as percent of the total peak area summed for all glycans identified.
niques afford a competitive advantage for biosimilar development.
References: 1. US Food and Drug Administration. What are biosimilar drugs? http://www.fda.gov/Drugs/ResourcesForYou/Consumers/ BuyingUsingMedicineSafely/ UnderstandingBiosimilarDrugs/ ucm167991.htm (accessed November 14, 2016). 2. Consalvo, AP, Bio E. Pharmaceutical Manufactoring. Five Questions Large Molecule CMOs Want to Be Asked. http://www. pharmamanufacturing.com/ articles/2016/five-questionslarge-molecule-cmos-want-to-beasked/. 3. Drug Store News. Generic Drug Report 2016. https://www.drugstorenews.com/sites/drugstorenews.Com/files/GenericReport_2016.pdf. 4. Xie, H, Chakraborty A, Ahn J, Yu YQ, Dakshinamoorthy DP, Gilar M, Chen W, Skilton SJ, Mazzeo JR. Rapid Comparison of a Candidate Biosimilar to an Innovator Monoclonal Antibody with Advanced Liquid Chromatography and Mass Spectrometry Technologies. MAbs 2010; 2: 379-394. 5. Fang, J, Doneanu CE, Alley WR, Yu YQ, Beck A, Chen W. Advanced Assessment of the Physicochemical Characteristics of Remicade® and Inflectra® by Sensitive LC/MS Techniques. mAbs 2016; 8: 1021-1034. 6. Shields, RL, Lai J, Keck R, O’Connell LY, Hong K, Meng YG, Weikert SH, Presta LG. Lack of Fucose on Human IgG1 N-linked
Oligosaccharide Improves Binding to Human Fc Gamma RIII and Antibody-dependent Cellular Toxicity. J Biol Chem 2002; 277: 26733-26740. 7. Noguchi, A, Mukuria CJ, Suzuki E, Naiki M. Immunogenicity of N-glycolylneuraminic Acid-containing Carbohydrate Chains of Recombinant Human Erythropoietin Expressed in Chinese Hamster Ovary Cells. J Biochem 1995; 117: 59-62. 8. Chung, CH, Mirakhur B, Chan E, Le QT, Berlin J, Morse M, Murphy BA, Satinover SM, Hosen J, Mauro D, Slebos RJ, Zhou Q, Gold D, Hatley T, Hicklin DJ, Platts-Mills TA. Cetuximab-induced Anaphylaxis and IgE Specific for Galactose-alpha-1,3-galactose. N Engl J Med 2008; 358: 1109-1117. 9. Lauber, MA, Yu YQ, Brousmiche DW, Hua Z, Koza SM, Magnelli P, Guthrie E, Taron CH, Fountain KJ. Rapid Preparation of Released N-glycans for HILIC Analysis Using a Labeling Reagent that Facilitates Sensitive Fluorescence and ESI-MS Detection. Anal Chem 2015; 87: 54015409.
To see this story online visit http://laboratory focus.ca/can-improvedtechnology-for-glycosylationanalysis-expedite-biosimilardevelopment/
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Laboratory Focus February/March 2017
Feature
b y G o r d o n P. S h a rp, F o u n d e r, A i r cu i t y I n c. , M e mb er ASHRA E
New Technology and Approaches to Significantly Cut
Lab & Commercial Building Energy Use
L
ab research facilities are energy intense building types due to the vast amounts of 100 per cent outside air required. With today’s concerns over high energy expenses, reducing carbon footprints, plus efforts to make facilities green and provide a better indoor environment, reducing both new and existing lab and vivarium facility energy expenses has become a critical challenge. The primary reason behind many labs’ high energy expenses is the minimum ventilation or air change requirements that often dominate the amount of outside air required by these facilities. To date very little objective data has been avail-
Figure 1
able on the environmental and energy savings impact of both reducing and varying air change rates. To address this gap a major research study was conducted that generated a significant amount of objective data on the indoor environmental quality (IEQ) conditions of labs and vivariums that are using dynamic control of air change rate.
Opportunity for Optimization In a large majority of labs (particularly life sciences labs) and vivariums the air flow is often dictated by the minimum air change rate for the space- which might be six to 12 ACH in a lab room or 12 to 20 ACH in a vivarium. If the air in these rooms is
“clean”, or free of any harmful or irritating contaminants, then a high air change rate is not needed. One approach that has been shown to effectively and safely vary air change rates in labs and vivariums is to sense the quality of the air for such contaminants as volatile organic compounds (VOC’s), ammonia, plus some other chemical vapors and odors, as well as particulates. When the room air is free of these contaminants then the air change rates can possibly be reduced to 4, or in cases 2 ACH, in a lab and 4 to 6 ACH in a vivarium.
Study Methodology The study is believed to be the largest one done of laboratory and vi-
Multiplexed sensing architecture for Demand Based Control
varium IEQ conditions covering over 1,500,000 hours of lab operation from over 300 lab areas at 18 different facilities labs. In total over 20 million sensor values were collected and analyzed including data on TVOC’s, Particles of a size range of 0.3 to 2.5 microns, carbon dioxide, and dewpoint (absolute humidity). These sites consisted primarily of life sciences and biology related areas as well as a smaller amount of chemistry and physical sciences lab areas. In order to economically and reliably accomplish this sensing of environmental conditions in many labs and vivarium rooms within one facility multiplexed sensing was used. With this approach, one central set of sensors is used in a multiplexed fashion to sense many different rooms or areas. Every 40 to 50 seconds a sample of air from a different area is routed through a common air sampling backbone consisting of a hollow structured cable to the centralized set of sensors, known as a sensor suite, for measurement. These sequential measurements are then “de-multiplexed” for each sampled area to create distinct sensor signals used for traditional monitoring and control. Typically, 20 to 30 areas can be sampled with one set of sensors approximately every 15 minutes depending on the requirements for those spaces. A variety of different types of sensors can be used to analyze the air samples for multiple air parameters. Figure 1 shows an example of the architecture of the multiplexed sensing system used to implement the study. In addition to dramatically reducing the number of sensors needed to implement this concept by a factor of nearly 30, this multiplexed sensing concept can measure different contaminant or parameter level much more accurate. Typically for controlling the lab room space airflow and IEQ it is best to look at the contaminant levels in the room differentially- subtracting the contaminants in the supply airflow from the exhaust or room levels. Any offset drift error of the sen-
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February/March 2017 Laboratory Focus www.laboratoryfocus.ca
feature Figure 2
Average TVOC level percentages over threshold (1.5M hours of lab operation).
Figure 3
Percentage of Time Lab TVOC Levels over Threshold
Average TVOC level percentages for multiple lab sites. Percentage of Time Lab TVOC Levels over Threshold
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sor will be the same for both measurements since the sensor is the same for both measurements and the offset drift error of each is cancelled out.
Results Figure 2 shows a cumulative graph of the average TVOC levels over all of the lab locations, representing about 1,500,000 hours of operating data. It demonstrates that labs are typically “clean” of most chemical contaminants about 99.2 per cent of the time! Based on this, energy can be saved by operating at reduced minimum air change rates the majority of the time with respect to the TVOC sensor. When looking at each site separately (Figure 3), even the site with
the greatest amount of TVOC activity, the dynamic control concept can still save energy about 97per cent of the time. Another parameter that can cause an increase in the minimum air change rate is particles in the lab. This could be due to a reaction that goes out of control or an acid spill that causes an evolution of smoke or perhaps an aerosol into the lab room. Figure 3 shows a graph of the average level of 0.3 to 2.5-micron particle counts (PM2.5) that exceeded a background level of the lab room’s supply air for all the different sites of the study. Figure 4 depicts the average lab room (dotted black line) is above
The study showed that that particle and TVOC events occur only a few hours a week and require high ventilation rates, however much lower flow rates can be utilized with an automatic ACH rate control system for well over 97% of the time. the 1M pcf threshold almost 0.5 per cent of the time, or about 30 minutes a week on average. The individual sites show a range of values from near zero up to about 1.5 per cent of the time that airflow should be increased based on a particle event. If this amount of time is added to the time that TVOC’s are above the control threshold, this adds up to only 1.2 per cent of the time on average. In other words, minimum air change rates of between 2 to 4 ACH can be achieved from 97 per cent to in excess 99.0 per cent of the time due to the presence of either TVOC or particle events occurring on average up to about 5 hours a week.
Conclusions The study showed that that particle and TVOC events occur only a few hours a week and require high ventilation rates, however much lower flow rates can be utilized with an automatic ACH rate control system for well over 97 per cent of the time. With the current challenges many organizations are facing concerning reducing their carbon footprint and their usage of energy, this research and the case study provide evidence of the significant contribution that the demand based control of lab air change rates can make towards safely meeting these goals and creating measurably better environments.
References 1. American Industrial Hygiene Association (AIHA). 2012. Laboratory ventilation. ANSI/AIHA Standard Z9.5-2012. American Industrial Hygiene Association, Fairfax, VA. 2. American Society of Heating, Refrigeration, and Air-Condition Engineers (ASHRAE). (2011). ASHRAE handbook - HVAC applications Chapter 16, Laboratories (pp. 16.1 to 16.22)., Atlanta, GA: ASHRAE, Inc.
To see this story online visit http://laboratory focus.ca/new-technology-andapproaches-to-significantlycut-lab-commercial-buildingenergy-use/
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Laboratory Focus February/March 2017
feature
b y L i s a S app & S t e v e M u rp hy, A g i l e n t Te ch n o l o g i es
Automation:
A more reliable and scalable way to process samples in the biopharmaceutical lab
O
ver the past two decades, pharmaceutical companies have expanded their focus in new drug development efforts beyond small molecules to include large molecules or biopharmaceuticals. In a September 2016 publication by EvaluatePharma 1, they estimated by 2022, biologic drugs will contribute 50 per cent of the top 100 pharmaceutical product sales. Biopharmaceuticals have been called the most sophisticated and elegant achievements of modern science (Otto et al, 20142). They are complex macromolecules with intricate three dimen-
sional structures that are often isolated from living sources. Primarily composed of amino acids or nucleic acids, biopharmaceuticals often have modifications such as sugar moieties that are critical for proper function. One area of intense focus is the development of biologic drugs that combine the specificity of large molecules and the potency of small molecules. These biologic drugs perform their jobs remarkably well and offer high efficacy with few side effects (Sekhon et al, 20103). With this new sophistication and enhanced performance comes added complexity in development and manufacturing. Therefore,
a tremendous number of potential bio therapeutic proteins need to be rapidly and accurately characterized, so that data driven decisions can be made that move the best candidates through the drug discovery and development process. The characterization and analysis of protein biotherapies requires robust and highly reproducible sample preparation techniques. For purposes of this article, sample preparation will be defined as the preparation of proteins from complex biological matrices for analysis using liquid chromatography with detection by mass spectrometry (LC-MS), tandem mass
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February/March 2017 Laboratory Focus www.laboratoryfocus.ca
Feature The liquid handling of the AssayMAP Bravo provides precise flow control through 8-96 microchromatrography cartridges allowing sample preparation to be performed in a highly parallel format that enables high reproducibility, reduced hands on time, excellent sample recovery, efficient washing, and very low elution volumes. spectrometry (MS-MS), conventional detectors, or a combination of these. Today’s analytical instrumentation offers performance advantages in terms of specificity, acquisition rate, and sensitivity. Scientist are now able to acquire reproducible, accurate data faster than ever before. Instrumental analysis is no longer the bottleneck in reporting a sample. The time needed for sample preparation and data analysis are often the largest contributor to the overall time and effort it takes to complete sample analysis. In the analysis of protein therapeutics, there are many approaches to sample preparation. Three common techniques that are often used in the biopharmaceutical lab either alone or in combination are: affinity purification, in-solution digestion and peptide cleanup. Affinity purification is a method of separating biochemical mixtures based on a highly specific interaction such as that between antigen and antibody, enzyme and substrate, or receptor and ligand. Typical steps involved are purification and concentration of a substance from a mixture, such as cell culture supernatants, cell lysates, and serum into a buffering solution (Morris et al, 20144). In-solution digestion is another common method of preparing protein samples for detailed analytical characterization. Proteins in-solution are usually denatured by using chaotropic agents or detergents. During this step, the disulfide bonds must also be reduced, and the sulfhydryl groups must be alkylated to prevent the disulfides from re-forming. Before adding protease, usually trypsin, the denaturants must be either diluted or removed so the denaturing reagents do not interfere with subsequent enzymatic digestion. The protein samples are then incubated with protease for several hours before the resulting peptides can be analyzed by MS (Medzihradszky, 20055). Peptide analysis can present a number of issues that affect detector response, due to the presence of unwanted interferences from either the matrix or from reagents and other additives used to facilitate protein digestion. Peptide cleanup techniques employed to remove these interferences
are required to be quick, effective and simple. Because of the effectiveness at sample cleanup, ease of use, and ability to have a generic methodology solid-phase extraction (SPE) is commonly employed to remove unwanted reagents and particulates from the digested sample prior to MS analysis (Henion, 19996). This method typically provides a high recovery of the peptides and can be highly reproducible. Reproducibility is important as this enables users to confidently assign data differences to the sample and not the methodological conditions used. An additional concentration step such as dry down may also be necessary before analysis. Historically the bulk of work done to prepare protein samples for analysis has been performed by LC-MS or LC-MS/MS analysis, manually on a relatively small number of samples. These sample preparation steps consist of a series of complex, time-consuming, and potentially error-prone tasks that can lead to operator fatigue due to repetitive movement. Due to improved technology and lower costs, laboratories now have the option of transitioning to automated sample preparation. Automation provides improved consistency, reduction in human error, scalability, and reduction in labor costs. Agilent Technologies has created a cartridge-based system, the Agilent AssayMAP Bravo platform, that automates a wide variety of LC/MS sample prep workflows such as affinity purification, in-solution digestion, peptide cleanup, phosphopeptide enrichment, and N-glycan preparation, on a single, easy to use instrument that can meet the increasing requirements for high-throughput, robust, and reproducible sample preparation (Russell et al, 20177). The liquid handling of the AssayMAP Bravo provides precise flow control through 8-96 microchromatrography cartridges allowing sample preparation to be performed in a highly parallel format that enables high reproducibility, reduced hands on time, excellent sample recovery, efficient washing, and very low elution volumes. To manage the transition from manual to automated sample preparation, a laboratory should be clear
about its specific needs. Space requirements, the type of automation required, and the level of automation expertise required in the lab should all be considerations. Available space is also an important consideration as there are a very wide range of options from compact to very large systems. A compact system is ideal for laboratories with bench space restrictions and/or tight budgets. It provides the benefit of reduced hands on time by automating the most tedious liquid handling steps. A compact system may however, require frequent walkups so that operators can change tips boxes or introduce reagents. Scientists should also consider the type of work that needs to be done. Deciding if the instrument will be a dedicated, single-purpose instrument, or a system capable of adapting to different processes will be key to selection. Determining what sample prep should be automated and whether to take an online or offline approach is also central to successfully automating sample preparation. Sample preparation methods that require high-throughput, reproducibility and robustness, will benefit greatly from automation. Finally, a lab should also consider how much programming they are willing to learn. In the past, one of the challenges of implementing automation in a biopharma lab was the requirement for a specialized robotics expert to program the instrumentation to perform routine tasks. There are varying levels in complexity of software offered by automation providers. If ease-ofuse is a priority, selection of an automation platform with user-friendly software and flexibility would be a preference. The most straightforward way to automate a sample preparation protocol is to work with a vendor that has preprogrammed methods for the type of analysis that a lab requires. There are a variety of automation choices available in the market today that increase throughput, provide consistency in results, streamline workflows, and potentially provide walkaway time to researchers so that they can perform other tasks. By automating sample preparation, biopharma laboratories can rapidly and accurately characterize more bio
therapeutic proteins that could eventually benefit more patients and improve overall health outcomes. Automation increases throughput, boosts productivity and reduces variability so that data driven decisions about the best possible therapies can be made more quickly.
References: 1. EvaluatePharma® World Preview 2016, Outlook to 2022 9th Edition – September 2016 2. Otto, Ralf, Santagostino, Alberto, Schrader, Ulf. Rapid Growth in biopharma: Challenges and Opportunities. McKinsey & Company Home: Pharmaceuticals & Medical Products. December 2014 3. Sekhon, Bhupinder Singh. Biopharmaceuticals: An Overview. Thai. J. Pharm. Sci. 34: 1-19. 2010 4. Morris, John, M Knudsen, Giselle, Verschuerer, Erik, Johnson, Jeffrey, Cimermancic, Peter, Greninger, Alexander, Pico, Alexander. Affinity purification– mass spectrometry and network analysis to understand proteinprotein interactions. Nature Protocols Volume: 9, Pages: 2539– 2554.201 5. Medzihradsky, Katalin. Mass Spectrometry: Modified Proteins and Glycoconjugates In-Solution Digestion of Proteins for Mass Spectrometry. Methods in Enzymology. Volume 405, 2005, Pages 50–65 6. Hennion, Marie-Claire, Solidphase extraction: method development, sorbents, and coupling with liquid chromatography. Journal of Chromatography. Volume 856, Issues 1–2, 24 September 1999, Pages 3–54 7. Jason D. Russell, Zachary Van Den Heuvel, Michael Bovee, Steve Murphy. Workflow Automation for LC/MS: In‑Solution Protein Digestion, Peptide Cleanup, and Strong Cation-Exchange Fractionation of Peptides Enabled by AssayMAP Technology. Agilent Technologies, Inc., 2013.
Lisa Sapp is the Biopharma Market Manager for Agilent Technologies, Inc. Steve Murphy, Ph.D., Director of Development-BioPharma Solutions and AssayMAP, Agilent Technologies, Inc.
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Laboratory Focus February/March 2017
Liquid Handling
New Products Pipettes Hamilton Company has expanded its pipetting family with the introduction of the ZEUS LT OEM pipetting module. Like the original ZEUS® module, the ZEUS LT is an ideal complement to analytical instruments and clinical diagnostic systems. Unlike the original pipetting module, the ZEUS LT does not come with an integrated z-axis, but rather offers the option for integrators to custom design the z-axis. More than a simple pipette module, it also incorporates Hamilton’s intelligent air displacement pipetting technology including; Qualitative Pipette Monitoring™ (QPM) for monitoring clogged tips or foam aspiration, Anti-Droplet Control (ADC™) for pipetting of volatile liquids, capacitive and pressure based level detection, tip detection and liquid class definitions. Easy mounting hardware enables attachment to an existing XYZ system, or development of an application-specific z-axis to accommodate space constraints or other design considerations.
Web: www.hamiltoncompany.com Beckman Coulter Life Sciences introduces its Biomek i-Series Automated Workstations, the first major additions to the company’s family of liquid handling platforms in more than 13 years. The new i-Series enables a broader range of solutions for genomics, pharmaceutical, and academic customers. Notable features and accessories include an exterior status light bar that simplifies a user’s ability to monitor progress during operation, a Biomek light curtain that provides a key safety feature during operation and method development, and an internal LED light that improves visibility during manual intervention and method start-up. Additionally, an off-set, rotating gripper optimizes access to high-density decks leading to more efficient workflows. Further, the workstations large-volume, 1 mL multichannel pipetting head streamlines sample transfers and enables more efficient mixing steps. The workstation’s open-platform design also offers users access from all sides, making it easy to integrate adjacent-to-deck, and offdeck processing elements (such as analytical devices, external storage/ incubation units, and labware feeders).
Web: www.biomek.beckman.com
Spectrometry IRsweep announces the release of the IRspectrometer, a table-top frequency dualcomb spectrometer that provides microsecond time resolution, large spectral bandwidth and high spectral resolution. The IRspectrometer can be used in a variety of applications, including biological sample and chemical composition analysis. The device excels where fast time resolution or high throughput and superior brightness is required — including applications that involve a complex background matrix or where multiple similar molecules must be simultaneously quantified. Unique features of the IRspectrometer include: fast time resolution (as low as 1 µs for a full spectrum), the ability to monitor high-throughput applications without relying on techniques like step-scan in FT-IRs and brightness advantages that significantly ease sample preparation for liquid and solid analytes. The device also delivers microsecond resolution at high bandwidths, with center wavelengths between 6 µm (1700 cm-1) and 9.5 µm (1050 cm-1), covering fundamental amid absorption bands, are available.
Web: http://irsweep.com.
Cell Culture Irvine Scientific, a provider of cell culture media, introduces PRIME-XV® T Cell CDM, a chemically-defined, animal component-free medium for T cell culture. The new medium has been developed to maximize consistent growth of T cells while maintaining their functionality and therapeutic potential. An increasingly important trend in cell culture media for gene therapies and immunotherapies is the move away from animal-derived and undefined components to serum and animal component-free, chemicallydefined culture conditions. When working with T cells the advantage of this is two-fold: animal-derived components are variable between lots; and the naturally occurring cytokines and growth factors in them can result in undesirable effects. For example, cytokines and growth factors have been shown to impact growth, phenotype and the potential of T cells to polarize into therapeutic subtypes. PRIME-XV T Cell CDM removes this variability to provide more consistency between lots.
Web: www.irvinesci.com
Sample Handling EcoTensil® disposable paper sampling spoons by Bel-Art® are made of a coated paperboard that stands up to powders, gels and semi-solids. Suitable for any laboratory or testing facility, the spoons are easily stored flatly and in one simple step fold into a functional spoon for sampling and retrieving materials. They are also compostable and recyclable.
Web: www.belart.com/EcoTensilSample
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New Products Pipettes
Hot Plates
The Eppendorf epMotion 96 is an easy to use bench top system for high precision pipetting in 96- and 384-well or deep-well plates within life science research, pharmaceutical and industry laboratories. Overcoming the limits of manual multichannel pipetting, it allows easy, rapid handling with high precision and accuracy compared to multichannel manual pipettes. Moreover, thanks to its ability to dispense into all 96 wells at the same time, users can simultaneously start or stop a biological assay for all wells in a plate. An added feature is its a large volume range, between 0.5 and 300µL, using only one head or system so there is no need to switch pipette heads or employ a second device to achieve all volumes. Workflows benefiting from the epMotion 96 include but are not limited to: solid phase extraction, DNA extractions from blood and tissue, sequencing and PCR clean-up, total RNA isolation, NGS library preparation, distributing reagents and serial dilutions, media change, other cell culture applications and more.
Web: www.eppendorf.com.
Liquid Handling The BrandTech® Scientific Liquid Handling Station (LHS) pipetting robot reduces repetitive manual pipetting and increases laboratory efficiency and reproducibility through automation. An extremely compact benchtop instrument, it has seven working positions and five available liquid ends with single channel volumes up to 1000µL and multichannel volumes up to 300µL. With a wide variety of accessories, this flexible system moves liquids between reservoirs, tubes and plates; and is ideal for plate reformatting, ELISA and PCR setup, cherry picking, etc.
Torrey Pines Scientific introduces its EchoTherm™ Programmable Corrosion Resistant Digital Stirring Hot Plates for use with aggressive chemicals in environments where other stirring hot plates would be quickly destroyed by vapors or spills. The hot plates are designed to be purged using an inert gas through a fitting on the rear of the chassis. Purging provides a positive pressure inside the unit to prevent corrosive gasses from entering the chassis and attacking the electronics or stirring mechanism. These units feature 10-program memory with 10 steps per program, temperature ramping, RS232 I/O port, membrane keyboard, and full function liquid crystal display where all parameters are continuously visible. Heater tops are 8″ square solid ceramic with 600 watts of power. Temperatures can be set to 450°C. The units are readable and settable to 1°C. Temperature control is by PID software and is controlled to ±1°C or ±1ºF. Stirrer speeds can be set from 100 to 1500 rpm. Temperature ramping can be set from 1ºC/hour to 450ºC/hour in 1ºC increments. The built-in timer is settable to 99 hours and is readable to 1 second. It has an audible alarm with user settable auto-off for turning off the heater and stirrer when the timer counts down to zero. The units are supplied with a 6” Teflon immersion probe for controlling solution temperatures directly. All units are available in 100, 115, and 230 VAC, 50/60 Hz models.
Web: www.torreypinesscientific.com.
Imaging solutions
Web: www.brandtech.com.
Mixers MilliporeSigma’s Mobius® Power MIX single-use mixing systems are engineered with advanced technology to effectively handle difficult-to-mix buffers, culture media powders and other pharmaceutical ingredients. The system achieves a strong vortex using an impeller design and motor based on magneticallycoupled NovAseptic® technology-a proven mixing technology in stainless steel tanks. Sterile zero deadleg sampling can be performed directly from the mixing container. A probe port allows for insertion of either a reusable probe for nonaseptic processes or a pre-sterilized, single-use sensor for in-process pH measurement of aseptic processes. The 100, 200 and 500 litre models are available in both jacketed stainless steel and high-density polyethylene HDPE, providing the flexibility needed for both buffers and media mixing. Innovative design features make the mixing system easy to use, enabling loading of bags by a single person and offering an optional integrated hoist for powder delivery (2000 L only).
Web: emdmillipore.com/powermix
Web: www.andor.com/ixon
Andor Technology (Andor), an Oxford Instruments company, has released its ultrasensitive iXon Life Electron Multiplying CCD (EMCCD) camera platform for fluorescence microscopy. The iXon Life is available in 1024 x 1024 and 512 x 512 sensor formats, back-illuminated to deliver the highest and broadest QE of any microscopy camera and deep cooled down to -80°C for minimal darkcurrent. It’s suitable for single molecule biophysics and low-light live cell microscopy.
Mass Spectrometry Mass Spec Analytical is now shipping its Thermal Extraction Ion Source Sciex™ 3200 Triple Quadrupole Mass Spectrometer and other V-Series models to customers. The Mass Spec TEIS-3200 is ideal for applications where the method requires a large quantity of sample measurements in a relatively short period of time or where automation is required. When coupled with Mass Spec Analytical’s analysis software, results can be provided in as little as 4 seconds. The TEIS-3200 uses a patented thermal extraction sample introduction device. Compounds amenable to thermal desorption, such as many pesticides, drugs and explosives, can be rapidly analysed in this way without the need for any sample pre-treatment, solvents or glassware.
Web: www.msaltd.co.uk
Laboratory Focus February/March 2017
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Web: http://www.labvolution.de/home Web: http://www.biotechnica.de
MARCH 2017 March 14-15 BC Tech Summit Venue: Vancouver, BC Hashtag: #BCTECH Summit Email: info@bctechsummit.ca Web: http://bctechsummit.ca/
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Calendar June 19-22 Bio International Conference Venue: San Diego, CA Email: convention@bio.org Web: http://convention.bio.org/2017/
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June 26-27 WIN 2017 Symposium : Expediting Global Innovation in Precision Cancer Medicine Venue: Paris, France Email: vladimir.lazar@winconsortium.org Web: www.winsymposium.org
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BIO Europe Spring Venue: Barcelona, Spain Web: https://ebdgroup.knect365.com/ bioeurope-spring/
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APRIL 2017 April 3-7 Toronto Health Innovation Week Venue: Toronto, ON Email: info@tohealth.ca Web: http://healthinnovationweek.ca/
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app review Mr. BioChem
http://apple.co/1KY6DNZ
Canada-Wide Science Fair comes to Regina this spring The Canada-Wide Science Fair, Canada’s largest youth science competition, will bring together the country’s top young scientists in Regina this spring. The fair kicks off May 14 and runs until the 20, with students vying for nearly $1 million in cash awards and scholarships. In all, the event now in its 56th year, will feature 500 students from Grades 7 to 12 and their 400 plus projects that have earned top marks at regional science fairs across the country. Many of these projects will address the pressing issues of our time: from climate change and food security to declining natural resources and environmental degradation – and much more. The event is expected to attract about 6,000 visitors to the Regina area, making this Canada’s largest youth science competition. Visitors will include 500 volunteers, 350 judges, 200 chaperones made up of professional scientists, researchers, engineers and the public. “It’s a thrill to host this showcase of finalists from our regional fairs across the country,” says Jim Jo, vice-president at Saskatchewan Association of Science Fairs. “Everyone involved is committed to supporting youth as they develop solutions that will help humanity in the years and generations to come.” The Saskatchewan Association of Science Fairs, a non-profit organization dedicated to promoting and encouraging youth in Saskatchewan to develop scientific literacy and participate in science fairs, is the local host organization in Regina. The group has worked with Youth Science Canada for two years to organize this year’s event. “It takes 10 to 15 years to ‘grow’ a scientist or engineer,” says Reni Barlow, Managing Director at Youth Science Canada, of which the fair is its flagship program. “We are proud to help sow the seeds as we help youth pursue satisfying careers that will enhance Canada’s ability to fulfil its potential in science, technology and innovation.” Alongside the competition, the fair will also feature STEAM 2017, a festival of learning in science, technology, engineering, arts and mathematics. The event serves as the Regina stop for Innovation150, an interactive nationwide tour by five leading science organizations that celebrates Canada’s innovative past and sparks the ideas and ingenuity that will propel our future. It’s also part of Innovation Festival: Saskatchewan, a three-month celebration of innovation across the province organized by Innovation150 partners and the Saskatchewan Science Centre. You can stay up to date on the competition, the projects and check back for the winners by following the Canada-Wide Science Fair on Facebook and Twitter.
The Mr. BioChem app gives its users access to a whole suite of useful laboratory tools accessible from five different sections: Calculators, Recipes, Safety, Enzymes, and Extra. The Calculators section includes sequencing tools, such as one for finding restriction sites within a user-inputted DNA sequence, a codon table, detailed periodic table and a translation tool. Additionally, through the calculator, users can convert DNA sequences into their reverse, complement or reversecomplement, as well as translate DNA sequences into proteins. The calculator section is also relevant to solution preparation. Whether its dilution, serial dilution, molarity, normality, concentration etc. it can help you. And if you want to know the protein concentration in your sample, the app can find that through the absorbance and the extinction coefficient of your protein. Other features include the recipes section for buffers and common laboratory solutions that comes with pre-loaded recipes and allows users to add new ones and select favorites. Within other sections of the app, users will also find a glossary of laboratory safety phrases and symbols. The app “extras” include links in the field.
Complete Anatomy (iOS: Free, $4.99 to unlock) https://3d4medical.com/apps/complete-anatomy
Available on iPad, Mac and Windows, 3D4Medical’s Complete Anatomy app is a mobile resource that allows you to explore human anatomy anywhere. The ideal tool for medical students, teachers and doctors, it features accurate 3D model renderings of the human body and its various system with over 6,200 high resolution anatomical structures. In terms of its usability, its simple gesture control system makes it a snap to navigate the human body as users simply tap on individual body parts for greater information. Additionally, there are audio and interactive lectures, cloud sharing for groups that are studying together, 3D recordings, screens, stickies, quizzes and much more. Unfortunately, while the free demo does allow you to explore the skeletal system and connective tissues, there are in-app purchases that need to be made to get all of this apps’ features. The total cost to unlock the whole package is $4.99.
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