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Growing Impact of Biologics in Drug Discovery and Therapeutics

“Biologics make up an estimated 25 to 30 percent of therapeutic agents on the market today. This demand for therapeutic biologics has exceeded what can be provided by traditional manual laboratory methods and has opened the door for the development of automation and miniaturization to accelerate the discovery process and offer new therapeutic opportunities,” says Daniel Sipes, M.S., director of automation at Genomics Institute, Novartis Research Foundation, (San Diego, CA).

To help explore these new opportunities, Sipes and Rob Howes, Ph.D., director of reagents and assay development at AstraZeneca (Gothenburg, Sweden) are co co-chairing the new Biologics Discovery track at SLAS2018. Howes, who chaired a session on assay platforms for biologics at SLAS2017 is excited to be involved in the new track. He says, “At SLAS2017 we were barely able to scratch the surface. By having this as a full track, we're able to get into much more detail on biologics drug discovery in the form of antibodies and therapeutic proteins, and we're able to delve into other areas that are critical for the success of the industry, such as biobanking, automation and miniaturization.”

According to Sipes the biologic revolution started in the 1970s and 1980s with the discovery of synthetic insulin. But the approach to developing these therapeutic agents has evolved in recent years. “In the '70s and '80s there were just a couple of biotech companies around that were really pursuing biologics, but over time, they've become much more mainstream and the efforts to discover these therapeutic proteins and other entities have become much more deliberate.”

Dan Lightwood, Ph.D., director, antibody discovery at UCB Pharma (Brussels) demonstrates this effort in his presentation of a platform for identifying rare antibodies from single primary cells. He describes how techniques such as a high-throughput automated B cell culture screening, fluorescence-based secretion assay and microfluidics can be used to mine the memory B cell repertoire.

Sipes says developments like this are important because “That’s something you're always wondering about when you run these types of assays: are you efficiently mining the whole b cell repertoire to try to get to the best epitopes for your antibody?”

Another example of how far the development of antibodies as therapeutic agents has come is Wendy Williams’s presentation on the development of an antibody to a ligand-gated ion channel for the treatment of neuropathic pain. According to Williams, Ph.D., scientist II at MedImmune (Cambridge, UK) the complex structure of ion channels makes them a challenging target for antibodies. She describes how she uses phage display and hybridoma technologies to isolate specific modulating antibodies with high affinity and specificity for their target. Howes says, “This is a great story! This is a functional antibody and it’s one of the first examples of developing biologics to ion channels.”

The track isn’t limited to traditional proteins. Patricia MacDonald, Ph.D., associate professor, molecular medicine at The Scripps Research Institute (Jupiter, FL) says peptides as therapeutic agents and diagnostic tools are on the rise. Peptides have historically been challenging to develop as therapeutics due to their instability and lack of oral bioavailability. But thanks to advanced peptide modification techniques and new drug delivery systems, MacDonald says these challenges may soon be a thing of the past. She describes how her lab uses a high-throughput autocrine-based functional assay to screen large peptide libraries, a system that led to the discovery of a potent and selective GLP-1R G-protein biased agonist that may prove useful in the treatment of type 2 diabetes. She believes “studies like this pave the way to identify new ligands for cell surface receptors that may be useful for de-convolution of signal transduction pathways and discovery of new mechanisms of receptor activation.”   

What’s In Store for Biologics Discovery?

Sipes thinks miniaturization will be a key component of biologics discovery in the future. He says, “Miniaturization allows scientists to perform experiments not otherwise possible, such as screening individual cells for therapeutic proteins of interest then directly isolating their DNA or RNA for cloning.” 

As an example, Steven Wiltgen, Ph.D., product manager at Molecular Devices (Sunnyvale, CA) discusses how his lab uses microfluidic technology for screening clones to improve single-cell viability. As he explains in his session abstract, the FDA requires evidence that host cell lines used in the production of monoclonal antibodies is derived from a single cell. But, he says, conventional techniques for isolating single cells are plagued by inefficiencies. Because microfluidic-based methods enable scientists to sort single cells in a low stress environment, he believes these methods hold promise for overcoming traditional limitations. Sipes says this type of research is opening the door for using biologics in personalized medicine, the use of genomics to tailor therapy to an individual.

At Berkeley Lights, Inc. (BLI) (Emeryville, CA) scientists are already focusing on single cells to develop individualized therapies. Hayley Bennett, Ph.D., single cell genomics scientist at BLI, describes how they are using their proprietary OptoSelect microfluidic technology to isolate and analyze individual cells for real-time genotyping. Using next gen sequencing, they are able to link phenotype to genotype.

Automation is another area that is changing the face of biologics discovery, particularly in downstream cell line development. Making stable clones of CHO cells is one of the key steps in establishing a production cell line that will produce a biologic in large quantities. As Howes points out, it’s currently a very labor-intensive, manual process. He’s looking forward to hearing Paul Anderson, M.S., senior automation engineer at Genomics Institute of the Novartis Research Foundation (San Diego, CA) describe how he and his colleagues are combining newly developed software with existing technology in the form of AutoFlasks and a non-invasive flask density reader to automate this process. As Anderson states in the session abstract, this innovative approach “enables cost-effective, facile production of proteins at quantities and quality useful for early stage drug discovery tasks such as screening, protein engineering and even in vivo studies.”

Melissa Crisp, Ph.D., senior research scientist, automation at Eli Lilly and Company (Indianapolis, IN) is also using automated workflows to develop a high-throughput mammalian expression platform. This approach incorporates both integrated automation systems and stand-alone equipment which allows for maximum flexibility, quality control and cost savings. In her session summary, she describes the careful considerations required to minimize downtime in an “Islands of Automation” system. She also notes that by streamlining their workflows, they have increased efficiency, reduced staff time and lowered reagent costs. And, as Sipes points out, reducing costs through automation may be crucial to the success of the biologics industry.

New Therapies Bring New Challenges

The cost to produce biologics can reach the hundreds of thousands of dollars, and Sipes thinks this may be the biggest perceived obstacle to biologics discovery. On the other hand, biologics are very effective, often not only treating a patient, but actually curing their disease. “In that sense, they're a bargain, when you look at the total cost of health care,” says Sipes. He attributes much of that success to precision medicine. “By doing genomic analysis on these biospecimens, we’re able to determine precisely who will be able to respond to which therapy.”

Storage of biospecimens is the subject of “Biobanking: At the Intersection of Biospecimens and Discovery,” a session within the Biologics Discovery track. Andy Zaayenga, managing director at SmarterLab (Martinsville, NJ) and chair of the session, says using biospecimens for biomarker discovery provides a pathway to personalized medicine and facilitates efficient, and potentially less expensive, drug development.

During this session Rostislav Chernomorsky, M.A., MBA, director, DNA Core and Automation Technologies at Regeneron Pharmaceuticals (Tarrytown, NY) is speaking about how Regeneron uses automated biobanks at various locations to efficiently process several thousand unique samples of tissues, proteins and nucleic acids per week for research purposes. As Chernomorsky states in the session summary, “without the aid of an automated biobank, this step would consume precious and expensive hours of human resources, lead to sample tracking errors and result in unpredictable downstream problems in data analysis.”

Christina Glazier, M.S., M.B.A., senior associate scientist at Amgen, Inc. (Thousand Oaks, CA) explores how the tools used by Amgen’s research materials management group to expand their existing small molecule research collection may also be used in tracking biologics samples to reduce staffing requirements.

One of the most exciting challenges Howes sees is the intra-cellular delivery of biologics. He points out that while scientists can develop biologics against a range of targets, traditionally they’ve only been able to get them to cell surface receptors and secreted proteins. “If we could actually deliver an antibody or a peptide into a cell, then we would be able to drug a whole range of different targets and open up a lot of the undruggable space.”

Researchers at AstraZeneca are attempting to address this issue using antibody-drug, as Johan Meuller, Ph.D., senior research scientist at AstraZeneca (Gothenburg, Sweden) describes. As he explains in his study abstract, antisense oligonucleotides (ASOs) show promise in the treatment of type 2 diabetes because they have the potential to reverse beta-cell loss by targeting known genetic targets. The problem lies in uptake of the ASOs by pancreatic beta cells.

Who Should Attend?

With 15 sessions spanning two days, Sipes says the SLAS2018 Biologics Discovery track offers a diverse representation of approaches and technologies that are likely to appeal to a wide audience. “The track offers a lot to engineers who are interested in how to most efficiently discover these activities as well as to scientists who are looking at making the discoveries,” says Sipes. He also thinks higher level executives in organizations would benefit by getting an idea on the state of the art and developing strategies.

Howes adds that even people interested in small molecule discovery will find there are lessons they can learn from biologics. “As an industry, we're going beyond the development of just small molecules,” he says. “A lot of small molecules that we want to design will end up being too big to get into the cells by passive diffusion. They'll need an active mechanism. The mechanisms that we will identify for biologics delivery will be applicable to small molecule drug discovery as well.”

View the full SLAS2018 schedule and register today.

 

Photo courtesy of AstraZeneca.

January 15, 2018