Making advancements in a scientific field requires continual learning, extreme curiosity and just plain old hard work. To fuel their interest in the expanding field of biologics in drug discovery, Rob Howes, Ph.D., and Joseph G. McGivern, Ph.D., took on volunteer roles as Journal of Biomolecular Screening (JBS) guest editors for the April 2015 Special Issue on Therapeutic Antibody Discovery and Development.
They were not disappointed.
Howes, associate director of Antibody Discovery and Protein Engineering at MedImmune in Cambridge, U.K., and McGivern, research director in Discovery Technologies at Amgen in Thousand Oaks, CA, both have small molecule drug discovery backgrounds. Howes, with MedImmune since September 2013, is responsible for biologics high-throughput screening including assay development, lead discovery and profiling across a range of target classes. McGivern, with Amgen since February 2000, is focused on bioassay and profiling, including assay development, lead discovery, in vitro pharmacology and profiling of small and large molecules with multiple classes of targets including ion channels, GPCRs, transporters, kinases and other enzymes. He also manages external collaborations.
"I thought serving as JBS guest editor would be an exciting way to compare and contrast and to bring together learnings from the small molecule arena to this special issue," Howes says. "I also thought it would be really exciting to work with someone else in the industry as we survey the field."
McGivern echoes Howes' thoughts and adds he thought it would be an opportunity to make a contribution to sharing knowledge in the large molecule antibody drug discovery field.
"I've been a small molecule drug discovery scientist for most of my career but have gotten into large molecules in the last five years or so," McGivern says. "This was a good opportunity for me to gain perspective from contributors from other companies."
"I, too, have a small molecule background," Howes adds. "I haven't done biologics; and biologics seem to be a very impressive type of therapeutic with some great examples of successful drugs. The speed and progress within biologics – the ability to take a project from idea to pre-clinical and into clinics – is really amazing."
As guest editors, their goal from the beginning was to assemble – in a single special issue of JBS – work that exemplifies and discusses various aspects and challenges associated with the discovery, development and manufacture of biologics.
"We wanted the articles to tell a story that follows the logical process of drug discovery," McGivern notes. "First the articles would talk about specific targets, then screening methods and then areas beyond research like patenting and formulations."
"The goal of pharmaceutical and biotechnology companies is to discover and develop safe and efficacious drugs that either alleviate the symptoms of a disease or preferably halt or reverse its progression often by modulating the function of a known validated target," state Howes and McGivern in their From the Guest Editor column in the April issue. "After targets have been selected, an increasingly common question that must be asked during the early life of a drug discovery effort is the choice of therapeutic modality."
Small molecule drug discovery emerged more than 100 years ago with the introduction of important medicines such as morphine, aspirin and penicillin, and "today more than 90 percent of all drugs on the market are formulations of small molecule chemical entities." However, biologic drug discovery and development has advanced in the last couple of decades and "in a major show of force, a majority (seven) of the 10 best-selling drugs worldwide in 2013 were biologics."
The guest editors say the 12 papers selected for this special issue focus on how large, protein-based molecules can enable more complex biological targets and more complex therapeutics than originally thought.
In one of four reviews that appear in the special issue, Allison J. Smith summarizes what antibody therapeutics have achieved to date and what opportunities and challenges lie ahead in "New Horizons in Therapeutic Antibody Discovery: Opportunities and Challenges versus Small-Molecule Therapeutics."
"The expanding pipeline of antibody-drug conjugates offers the potential to combine small molecule and large molecule modalities in a variety of creative ways, and antibodies also offer exciting potential to build bi- and multispecific molecules," states the author. "The ability to pursue more challenging targets can also be further exploited but highlights the need for earlier screening in functional cell-based assays. I discuss how this might be addressed given the practical constraints imposed by high-throughput screening sample type and process differences in antibody primary screening."
Smith concludes, "There is significant further potential for targeting complex multimembrane-spanning receptors and protein-protein interactions with selective antibody drugs, and there is a rich landscape of additional potential targets, including intracellular ones and those that lie behind the blood-brain barrier."
Another review article in the special issue is "Accelerated Formulation Development of Monoclonal Antibodies (mAbs) and mAb-Based Modalities: Review of Methods and Tools." Author Vladimir I. Razinkov and his team find "Biotherapeutic products based on monoclonal antibodies (mAbs) are the fastest growing category of therapeutics entering clinical study." They tell the story of process, and how the latest advances in formulation screening methods combined with automation technologies and high-throughput assays point to a future of "accelerated formulation development of both typical antibodies and complex modalities derived from them."
Howes says another key paper in the issue is "Discovery of Functional Antibodies Targeting Ion Channels" by Trevor C.I. Wilkinson et al. Here the authors conclude that "although no therapeutic ion channel antibodies are described to date," the wealth of recent studies on functional monoclonal antibodies signal hope for effective drugs in the near future. The last decade's advances in ion channel biochemistry and structural understanding along with advances in antibody discovery and screening technologies "strongly suggest that effective functional antibodies may be developed with significant opportunities for therapeutic treatment of diseases covering a wide spectrum of pathophysiologies."
"Characterization of Bispecific T-cell Engager (BiTE) Antibodies with a High-Capacity T-cell Dependent Cellular Cytotoxicity (TDCC) Assay" by Aaron A. Nazarian and team explain a specific approach to targeting tumors. "BiTE antibodies are derived from the variable domains of two distinct monoclonal antibodies that (1) bind to T-cells with one arm (anti-CD3?) and (2) bind to a specific surface antigen expressed on the tumor cell with the other arm [i.e., anti-EGFR (epidermal growth factor receptor)]." The authors describe selection and development of an in vitro cellular-based bioassay to screen for functional activity against multiple target-positive tumor cell lines with multiple T-cell donors.
They state, "Our primary focus was to develop a robust method that is rapid, scalable, and reproducible. Ideally, it is desirable to have a cell-based assay that can be performed in a homogeneous format, in which reagents are simply added, and signal is detected without the need to remove supernatant or to wash the assay plate. Here, we describe a successful TDCC screening assay that is validated for precise and accurate in vitro assessment of BiTE antibody molecule potency and efficacy, and also has the capacity to evaluate multiple tumor cell lines and with multiple T-cell donors. Furthermore, characterization of TDCC activity will support the rapid identification of discovery research BiTE antibodies against various targets and drive lead selection for additional characterization and further preclinical development."
Howes and McGivern indicate the JBS Special Issue on Therapeutic Antibody Discovery and Development also includes papers on a variety of assay technologies used to detect binding of antibodies to isolated proteins.
"Unlike small molecule starting points that emerge from HTS campaigns, active antibodies are often very potent (pM-levels of affinity) and extremely selective for the target of interest; so selective in fact that they often do not cross-react with homologous targets in species such as rodents, dogs or non-human primates that are most commonly used for in vivo efficacy, pharmacokinetic and toxicologic studies," state Howes and McGivern.
Ensuring coverage of the full spectrum of this emerging area of science, the JBS Special Issue on Therapeutic Antibody Discovery and Development looks beyond the research phase. For example in "CHO-S Antibody Titers >1 Gram/Liter Using Flow Electroporation-Mediated Transient Gene Expression followed by Rapid Migration to High-Yield Stable Cell Lines," Krista Steger et al. discuss how production cell lines must be created, selected, characterized, stored and banked for future use during the entire lifecycle of the product. In "High-Throughput Screening of Formulations to Optimize the Thermal Stability of a Therapeutic Monoclonal Antibody," a team led by Anita Niedziela-Majka reviews thermal stability.
The issue also includes high-level insight into intellectual property concerns. "How to Successfully Patent Therapeutic Antibodies" by Fritz Lahrtz, an attorney with the law firm Isenbruck Bösl Hörschler in Munich, Germany, explains that "the mere production of yet another therapeutic antibody is in many jurisdictions not considered as a patentable invention. In contrast, antibodies with novel structural features and/or improved properties may be patentable. When drafting the claims, care should be taken to obtain a broad patent scope which protects both the antibody of interest and related antibodies having the same functional features, thereby preventing competitors from marketing a functionally equivalent antibody. Furthermore, the application should contain experimental evidence showing the improved properties of the claimed antibody. After the filing of a priority patent application, patent protection should be initiated at least in countries which are of particular commercial importance. Subsequent inventions relating to novel uses, formulations, dosage regimens and combinations with other treatment modalities should be protected by further patent applications in order to extend patent term."
Howes and McGivern are not newcomers to the scientific publishing process. They both have published papers, reviewed manuscripts and assisted team members prepare material for publication. As special issue guest editors, however, their eyes were opened to the business of publishing and all the steps required to complete a journal issue.
Howes talks of enjoying the sharing of ideas during issue development and the 'Wizard of Oz' syndrome – peeking behind the curtain and seeing what's actually involved in getting the papers out. "I've always been involved as an author and reviewer but not really seeing the nuts and bolts of the editorial process.
"Editing a journal is a lot more work than I thought it might be," he continues. "Much of that was garnering the number of papers submitted and the breadth for the particular issue. The other was trying to understand some of the challenges in biologics drug discovery that are outside of my usual area, which is high-throughput screening."
He pointed to fantastic support from JBS Editor-in-chief Robert M. Campbell, Ph.D. and SLAS Director of Publishing Nan Hallock.
"They are so good at shaping it up to get things done on time and to keep the issue running and to meet the deadlines," Howes notes. "For us, all of the manuscripts came in during summer vacation time. It was a huge challenge to get them all in, send them out to reviewers, gather the first reviews back and send out for second reviews – all on time. They did a great job with that."
McGivern, too, was appreciative of Campbell and Hallock, saying simply, "they get things done." He enjoyed the experience and learned from it.
"Participating as a special issue guest editor was an opportunity to see what was beyond what we do in the early stages of drug discovery in the lab and learn how a journal is put together," McGivern says. "It's hard to believe it was a year in the making."
When not busy with their day jobs, family and serving as journal guest editors, both men enjoy biking. For McGivern, it's on a mountain bike in the beautiful Santa Monica Mountains of southern California. For Howes, it's the local roads of Cambridge – now with his first full carbon bike weighing less than 8 kilos.
The April 2015 Journal of Biomolecular Screening Special Issue on Therapeutic Antibody Discovery and Development is available now at JBS Online for SLAS Biomolecular Sciences Section members and JBS subscribers. Articles become open access one year after publication.
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April 27, 2015