Category: Contract Research (CRO)

Gastrointestinal (GI) issues are common side effects of many drugs. Anticipating such side effects before clinical trials is limited by a lack of effective models for evaluating preclinical candidates for their potential to cause diarrhea, nausea, and other gut-related side effects. With its RepliGut in vitro human intestinal model, Altis Biosystems is developing a system that could help pharma companies identify GI toxicity issues early in the drug development process.

GI Toxicity Challenges

Gut toxicities are fairly prevalent, comprising five of the top 12 adverse events of approved drugs. Even for healthy people with normally functioning intestinal systems, drugs can have a dramatic influence, leading to serious problems. Gut toxicities are one of the least likely reasons to halt development of a candidate drug.

Medicines from all different drug classes have been associated with gut toxicities. It is therefore difficult to predict if a drug substance will cause nausea, diarrhea, abdominal distress, constipation, or other symptoms resulting from gut toxicities.

The lack of data means there are no effective in silico models available, and there currently are no good in vitro models for testing either. Occasionally, pharma companies will conduct GI toxicity tests in animals, but the digestive systems of rats and dogs are significantly different from that of humans, and the results are not very predictive. Some correlations have been made in studies conducted with nonhuman primates, but there are ethical concerns with these tests, and they are expensive to run. In addition, they are generally conducted at a point in the development process where it is too late to redesign the molecule should gut toxicities be discovered.

As a result, candidates generally progress through the various development stages even if they are known to cause diarrhea, constipation, or other gut issues. Changes in dosage may eliminate some problems. Other drugs are administered in combination with a palliative treatment, like an antidiarrheal compound. 

Overall, however, gut toxicities affect quality of life and can create patient compliance issues, which in turn reduce the efficacy of medicines. There is consequently a real need for a model that can be used at the lead selection stage to determine whether drug candidates present gut toxicities.

Developing an In Vitro Model for GI Toxicities

Adverse gastrointestinal effects are more complicated and nuanced and require complex readouts than cannot be obtained from a simple planar model. There are some published studies on the use of test groups of compounds for assessing gut-based side effects, including nausea and diarrhea. The presence and concentrations of these compounds indicate the clinical incidence frequency for a given drug, as well as its maximum concentration in the bloodstream.

Using the test groups, it is possible to validate in vitro models and provide in vitro/in vivo correlations for the specific readouts of those models. First, appropriate readouts based on the mechanisms of gut side effects must be developed. 

Another challenge is the need for models to include representations of the luminal and serosal surfaces of the intestine to account for different interactions possible with orally administered drugs that pass through the GI tract and those administered via injection and thus delivered systemically. Oral drugs pass from the lumen of the intestine through the epithelial cells and then into the bloodstream. Drugs administered by IV enter the bloodstream directly and then come in contact with the intestine through the bottom (basal side).

Organoids are promising three-dimensional model systems, but unfortunately they are basically like cysts and the lumen is located in the interior, making it difficult to study the impact of direction.

RepliGut as a Model for Assessing GI Toxicity

The RepliGut model from Altis Biosystems as it currently exists is an effective in vitro model for assessing the potential of drug candidates to cause diarrhea. With polarized cells having apical and basal membrane domains, it can provide information about the impact of directional flow. RepliGut has also been developed with readouts based on the mechanisms involved in diarrhea, which essentially results from barrier disruption in the gut. Two examples include measurement of transepithelial electrical resistance (TEER) values and permeability (using fluorescently labeled molecules). 

For other GI issues, we do not yet know how nuanced the readouts from RepliGut may eventually become. The mechanisms of side effects like nausea are much more complex. While RepliGut has multiple cell types, they are only intestinal epithelial cell types. We do not yet have commercial systems that include immunomodulatory, nerve, and other cells that are involved in signal transmission and other important functions relevant to GI toxicities.

The potential for RepliGut is very promising, however, and Altis is working to develop models that contain many different 3-D structures and the various cell types present in the gut in vivo. Ultimately, the goal is to have different models for each of the different GI issues, enabling drug developers to determine if a candidate may potentially have problems in the clinic.

Practical Application

Using our current RepliGut system for screening drug candidates for their potential to cause diarrhea is fairly simple. It takes approximately 10 days to culture and run a set of studies. During the culture phase, cells are expanded on Transwell plates until confluent and then differentiated to recapitulate the barrier function in the gut. At this point, the system has tight junctions that behave as they would in vivo, and therefore, have low permeability and high TEER values.

Studies are conducted using 96-well plates, and each compound is typically run in triplicate. When the format of the final drug product has not been determined, the model is dosed on both the apical and basal sides separately and/or simultaneously. In some cases, multiple dosing levels are required. The total number of assays for a given compound determines how many different candidates can be screened on a given plate.

In addition to TEER and permeability readouts, which are nondestructive, we may also conduct destructive assays, such as for changes in gene expression, which requires cell lysis, and immunohistochemistry, which requires cell fixation. In some cases, we may also run ELISA assays on the supernatant and look for cytokine release in the basal or apical compartments and other tests. The types of readouts required determine the number of experiments (plates) that must be run simultaneously. Typically, results are obtained within two weeks of culture initiation but may extend to three weeks depending on the assays being performed.

Achieving Additional Physiological Results

Expanding beyond intestinal epithelial cells is important for broadening the applicability of the RepliGut system for drug screening. Altis is thus working on co-culturing other cell types that are also isolated from the same donors as the epithelial cells.

The overall intent is to make the results more physiological. Throughput is not our primary focus, because we are already using 96-well plates, and we are focused on application of the model at the preclinical stage where tens, rather than thousands of compounds, are being screened in order to identify a lead candidate. However, we are always evaluating the means to improve the quality of the data.

In addition to adding other cell types, we are also pursuing models to replicate the full 3D architecture of the intestine. One of our biomedical engineers is developing what we refer to as a “3D crypt model” that mimics the villi and crypts in the gut, creating texture. By forming gradients of nutrients from the top to the bottom in the crypt, we have been able to observe stem cells at the bottom and differentiated cells at the top, indicating that this model recapitulates the cell renewal and differentiation capacity of the gut in vivo. 

This approach differs from the planar model, where cell expansions and differentiation occur in two phases. The challenge now is to develop effective readouts for this three-dimensional model, which we are currently pursuing. While this approach would lead to an overall decrease in throughput, the granularity into the impacts of processes by having differentiated and expanding cells together has a very high value, because it should give in vitro results that correlate well with in vivo data.

Another project designed to access more physiological results involves development of a mucus model. The mucus layer protects the epithelial cells and may protect the gut from the toxicity of some drug compounds. In the current RepliGut system, liquid is on the top in the apical compartment, and when the cells secrete mucus, it tends to float away into the media. In the gut, the lumen is dry for the most part with no liquid flowing through it, because the mucus layer is robust. In our new air–liquid interface model, mucus secreted by the cells accumulates to form a mucus layer. This system could be helpful in modeling the absorption of drugs. We are hoping to be able to show a better correlation with uptake in humans by having this mucus layer present in the model. 

Altis is also developing a model that has an anaerobic apical compartment. In this system, once the cells are expanded and differentiated, the apical compartment is blocked off and becomes devoid of oxygen, allowing the co-culture of bacteria on top of the cells. The intestinal cells, however, still get oxygen through the basal compartment through oxygenated media at the bottom of the wells. We believe this system will be useful for microbiome research.

Working Toward Validation

RepliGut is mostly being used for one-time analysis and has not yet been widely applied to the screening of preclinical candidates. Altis is actively working towards this goal. We have collaborated with AstraZeneca to evaluate three chemotherapeutic agents, with RepliGut results showing good correlation with in vivo data. 

Our next steps include performing an exhaustive screen of compounds with known clinical incidences of diarrhea to determine how the change in barrier function in the RepliGut model demonstrates firm in vitro/in vivo correlation. Once we have established a stronger validation package, we expect uptake of the RepliGut system for preclinical candidate assessment.

Originally published on PharmasAlmanac.com on February 18, 2021.

WuXi AppTec has continued to build a comprehensive offering through organic growth and acquisition. Its Laboratory Testing Division is poised to play a key role in propelling the open-access capability and technology platform company forward with a full range of integrated testing services. As an organization, WuXi AppTec provides a broad and integrated portfolio of services to help our worldwide customers and partners shorten the discovery and development time and lower the cost of drug and medical device R&D through cost-effective and efficient solutions.

The Laboratory Testing Division

The Laboratory Testing Division covers nearly all testing capabilities involved in drug and medical device development, from early-stage R&D to clinical diagnostics. It was formed in December 2013, when all of WuXi’s testing capabilities were combined into one powerhouse unit, adding a full range of DMPK, toxicology, bioanalytical, analytical and clinical diagnostics services to create a vast portfolio of IND- and NDA-enabling services.

Our progress since then has remained constant. Over the last four years, the Laboratory Testing Division has evolved to become a fully-integrated testing platform supporting customers across the full scope of drug discovery and development. We are continuously evolving to meet the ever-changing needs of our clients and global patient populations.

Acquisition is a key component of our expansion strategy. One of the most recent changes to our division has been the addition of the Medical Device Testing Unit, formerly referred to as AppTec. The company, which specialized in medical device testing, was acquired by WuXi in January 2008. At the time of its acquisition, it was one of the top three medical device testing companies in the US. In October 2017, WuXi AppTec acquired ResearchPoint Global, a US-based CRO, in order to continue to build a more robust clinical CRO offering.

Platform to Patient

At its core, WuXi is a platform company that is committed to enabling innovative therapies to benefit patients. The Laboratory Testing Division offers comprehensive solutions that stem from this commitment, enabling customers to take their projects from lab to patient on an accelerated timeline. Our “Platform to Patient” philosophy speaks to the many layers that comprise the organization’s vision, as it emphasizes the value of consistently delivering high-quality study data from early through late phases of development, while also serving to connect the Laboratory Testing Division to the other areas of the WuXi business.

As an integrated testing platform, the Laboratory Testing Division is uniquely positioned to aid our customers in all of their testing and development needs. Our goal is to ensure our clients are able to deliver innovative medicines faster and more cost-effectively. To best address any request, the Laboratory Testing Division is divided into three key platforms—preclinical drug development, clinical drug development and medical device testing.

When customers work with us, they are working with a partner fully committed to the success of their project.

WuXi Plus IND Form WIND

Our preclinical drug development services support the testing, document preparation and regulatory submission for Investigational New Drug (IND) applications. Our commitment to meeting all goals within an accelerated timeline and hands-on program management, coupled with extensive expertise in both US and China-specific regulations, makes us fully equipped to support the full scope of any drug development program. WuXi and IND combine together to form our “WIND” program, which takes customers from the initial steps of document preparation all the way through to submission. Our IND-enabling services include CMC and analytical development, bioanalytical solutions, full-scale in vitro and in vivo ADME and PK/PD, as well as preclinical and clinical toxicology safety assessments.

WIND combines our open-access capability and technology platform, program management and regulatory support services to facilitate our customers’ global IND applications, designing customized solutions that fit the needs of each individual project. Our team of regulatory experts support IND submissions to global regulatory bodies, including the CFDA and FDA.

Complete Clinical Development

The transition from preclinical to clinical studies should be seamless. As we provide support at all levels and across all phases, our goal is to ensure that regardless of when we take on a project, we are able to successfully progress it though each development stage, leveraging our vast range of technical capabilities. Our clinical development services include, but are not limited to: small molecule and biologics quantitation, generic/biosimilar and innovator study support, biomarker testing, PK Met ID, mass balance (hot & cold), CYP, Phase II enzyme and transporter substrate phenotyping, chronic and subchronic toxicology, Seg I-III DART studies, carcinogenicity studies, juvenile toxicology, four-week batch impurity testing, late-phase commercial analytical development, stability studies, regulatory CMC and project management.

Our commitment to meeting all goals within an accelerated timeline and hands-on program management, coupled with extensive expertise in both US and China-specific regulations, makes us fully equipped to support the full scope of any drug development program.

Partnering through Medical Device Testing

When customers work with us, they are working with a partner fully committed to the success of their project. We understand the challenges associated with getting a medical device to market, and our scientists have the expertise and experience to proactively support this endeavor within an ever-changing regulatory environment.

What definitively sets us apart — as an organization, business unit and testing platform — is our people. Our medical device testing experts not only serve on international standards committees as active participants, but as leaders. In addition to keeping us in tune with the shifting regulatory environment, our leading chemists work alongside our toxicologists to provide comprehensive toxicological risk assessments. We not only provide guidance but adopt a customized strategy for each individual program. The vast number of diverse products that our experts have tested makes us an unquestionable authority in this space.

A Forward Looking Joint Venture: WuXi and the Mayo Clinic

As part of our commitment to delivering value to patients worldwide and our vision that ‘every drug can be made and every disease can be treated’, in January 2018 WuXi AppTec Group formed a joint venture with the Mayo Clinic to introduce testing capabilities and clinical diagnostic services to the Chinese market. This venture will bring novel esoteric tests to market faster, benefiting patients in both China and the US.

The partnership with the Mayo Clinic elevates our portfolio of diagnostic services and will serve to accelerate research in the lab. The outcome will be the transformation of discovery tests and the diagnostic landscape, as well as precision medicine — not only in China but also worldwide. Through the collaboration with Mayo, we’re committed to building a leading diagnostic services operation in China and co-developing in ways that will benefit our patients, doctors, and innovative collaborators in all corners of the world.

At its core, WuXi is a platform company that is committed to enabling innovative therapies to benefit patients.

Life, Technology, and Discovery

The Laboratory Testing Division is commonly referred to as “LTD” for short. We have made use of this internal acronym, developing it into the meaningful slogan: “Life, Technology and Discovery” — an all-embracing reflection of our capabilities as a testing platform. We stand for these three tenets, which truly summarize where we see our company in the future. Our focus is strongly on the US and China, and we have expansion plans for both. Specifically, the expansion of our New Jersey facility for DMPK and Bioanalytical services, with the opening of a new building in Cranbury, is taking place in early 2018.

Overcoming the Challenges of a Rapidly Progressing Organization

Although our organization’s growth is overwhelmingly positive, one of the challenges of growing so rapidly is addressing any doubts concerning where everyone fits, and how we can all work together to accomplish one overarching goal. Of course, our evolution is an ongoing process. Internally, we are relying on program management to play a key role in how our divisions are perceived.

Ultimately, the Laboratory Testing Division — or LTD — stands for just what we are capable of — our testing capabilities are limitless. Regardless of whether a client comes to us with one single compound, or hundreds of thousands of compounds, LTD can do the testing, evaluate that the targets are druggable, go through all the necessary preclinical testing and eventually conduct testing in clinical trials. It has been tremendously exciting to watch our Laboratory Testing Division’s growth over the last four years into the integrated testing powerhouse it is today, and we are wholeheartedly looking forward to what lies ahead in the coming years. 

Originally published on PharmasAlmanac.com on March 12, 2018.

Advanced microphysiological systems can replicate aspects of intestinal complexity, such as epithelium self-renewal by stem cells in in vitro crypts or the interactions of microbes and intestinal epithelium mediated by a mucus layer. Availability of such models is key to progress in compound screening, disease modeling, and microbiome research.

Defining a Niche

A niche is a multidimensional space of resources and conditions that define where an organism can survive and grow. One might typically think about an ecological niche — where a certain species can live and reproduce, as well as how it impacts its environment. Within the intestine, it refers to where specific cell types or microbes reside and how their interactions and relative proportions in the population impact survival and maintenance of the microenviroment. There are multiple intestinal niches of interest, including the local environment of the intestinal crypt that enables maintenance of the intestinal stem cell population, distinct gut regions, and the various microbial ecosystems across or within individuals. Key questions in intestinal health and disease require an understanding of how changes in intestinal niches cause, perpetuate, or allow recovery from injury.

Niches in the Gut

Throughout the entirety of the intestine, stem cells reside in pockets referred to as crypts. Gradients in extracellular matrix components, as well as matrix stiffness and the presence of physical binding sites, allow the stem cells to establish themselves within these niches in the intestine and coexist with differentiated cells. Intestinal stem cells divide rapidly, continually replacing differentiated cells which, in the human colon, live only around five days. 

There are distinct regions within the gastrointestinal tract, which starts with the mouth and ends with the anus. Within the gut specifically, there are important differences between the small and large intestines. The small intestine comprises three distinct regions: duodenum, jejunum, and ileum. The large intestine, or colon, comprises the ascending, transverse, and descending colon. The small intestine is covered in projections called villi, which expand the surface area of absorptive enterocytes in order to facilitate nutrient absorption. The colon, on the other hand, is mostly flat, except for the crypts where intestinal stem cells reside. Oxygen concentration and pH vary along the length of the gut. High luminal acidity at the beginning of the small intestine gradually decreases as the distance from the stomach itself increases. Likewise, oxygen levels are comparatively high at the duodenum and decrease along the length of the intestine. The differentiated, absorptive cells found in the colon receive oxygen from the basal side via the vasculature, but are adapted to living in a low-oxygen environment. 

Differences observed in the various gut regions contribute to and are impacted by the different bacterial ecosystems they contain. Facultative anaerobes, which prefer anerobic environments but can survive in the presence of some oxygen, are found in the small intestine. Meanwhile, obligate anaerobes can typically only establish a presence in the large intestine, where generally higher biomass contributes to the maintenance of anaerobic conditions. Nutrient availability directly influences the composition of the gut microbiome, as different microbial species require different nutrients to become established. Diet plays an important role in nutrient availability, which is then modulated by both the organism’s nutrient absorption and microbial nutrient utilization. The mucous layer in the gut plays an important role in gut health by protecting the intestinal epithelium and supporting the many microbes that reside in and feed on the mucus itself. Disruptions to the established microbiome enable competitor microbes to displace resident microbes. This may be caused by the introduction of a new nutrient or changes in the mucous layer, which could occur as the result of inflammation due to disease or consumption of antibiotics or other medicines.

Using a Microphysiological System

Many open questions pertaining to health and disease of the intestinal epithelium are challenging to address, owing to the complexity of the tissue and its multitude of niches. Monolayer cultures of Caco-2 cells, a commonly used human colorectal tumor cell line, are not capable of replicating this complexity. While animal models possess system complexity, it is frequently difficult to modulate and control the desired experimental parameters in in vivo studies. Additionally, the intestinal systems and diets of most animals differ dramatically from those of humans. The use of inappropriate model systems in drug development can result in ineffective drugs reaching clinical trials and the failure to investigate potentially useful therapeutics.

RepliGut Advantages

Altis Biosystems is developing in vitro human gut models for use in various applications. These RepliGut models are derived from human donor stem cells. One of the big advantages we have is access to a bank of human intestinal systems from multiple donors. In addition to the ability to compare cells from different donors, we are also able to grow cells from multiple gut regions from each donor. While differentiated monolayers from all gut regions express absorptive markers and goblet cells as expected, we do observe differences in terms of morphology and transepithelial electrical resistance (TEER; a measure of barrier function) profiles between monolayers derived from small intestine and colon stem cells. Models based on Caco-2 cells do not provide any opportunity to probe regional differences as they pertain to a given hypothesis or effect. With RepliGut, however, we can investigate how a compound (or microbe) impacts the epithelium in a certain region of the intestine. That makes it possible to study variation across the length of the entire intestine within and between individuals. All RepliGut platforms use Transwell-style inserts, which allows for multiple treatments on each plate and side-specific (apical or basal) testing. This approach also makes our platforms simple to use; no pumps or complex systems are required, as with microfluidic devices.

RepliGut Planar

Our workhorse platform is a planar model (RepliGut Planar) based on human stem cells that are expanded and then differentiated to recreate the human small intestine or colonic epithelium for compound screening. Thus, it is possible to study cells in the stem or differentiated state independently. This planar system enables numerous assays on primary human gut epithelium, such as permeability, transport, toxicity, gene expression, protein expression, and high-content imaging. This platform is available as a kit in 12- and 96-well plate formats.

RepliGut 3D

Some applications may require additional features beyond what is achieved with RepliGut Planar. Altis’ RepliGut 3D platform involves replication of the three-dimensional complexity of the gut epithelium in which multiple different cell types (including stem, absorptive, and goblet cells) coexist in a physiologically relevant spatial scale and configuration. RepliGut 3D uses micro-molded collagen gel to make crypt-like structures. This architecture allows for the establishment of growth factor gradients along the length of the crypt. As a result, we can maintain a stem cell population at the base of the in vitro crypts, while simultaneously supporting a self-renewing, differentiated monolayer on the top surface of the scaffold. The migration of differentiating cells up the walls of the crypts also mimics what is observed in vivo.

This model allows quantification of different cell types by zone along the crypt using confocal imaging and is of interest to drug developers with candidates that may influence stem cell differentiation pathways or for which long-term toxicity information is needed. Indeed, the U.S. FDA would like to see microphysiological systems with six-month cultures to enable long-term toxicology studies. The 3D geometry also allows for apical compound application in which differentiated and stem cells will receive slightly different dosing in a more biomimetic fashion, as a result of compound metabolism along the length of the crypt. This is useful for identifying effective dosing levels that also minimize undesired effects on the stem or differentiated cell compartment.

2D Crypt Model

To supplement RepliGut 3D, we are also developing a 2D model that can be conceptualized as a flattened version of the intestinal epithelium, with its crypt-like structures. This model consists of an array of proliferating spots surrounded by differentiated cells. To achieve this goal, we are using a patterned substrate that has holes in it. Cells above the holes are exposed to expansion media and stem cell cues from the bottom, while cells physically distant on the surface from those holes are only exposed to differentiation media in the top compartment. In this manner, a self-renewing culture is generated with both differentiating and differentiated cells, while easier imaging renders the platform more high-throughput.

Disease Modeling Potential 

It is difficult to model something you don’t understand and hard to understand something you can’t study. The stem cell niche/crypt plays an important role in controlling homeostasis and regeneration after injury or inflammation. There is a lot of interest in using cells from an inflammatory bowel disease (IBD) donor in the RepliGut model, but since IBD is not well understood, there is no assurance that the cells would continue to have an IBD phenotype.

A 3D model that presents a more complex view of the intestine and can be manipulated more easily than an in vivo study could potentially be useful for investigating changes that occur after injury, such as changes in the percentage of the crypt that is proliferative. The 3D RepliGut model could thus be interesting to developers looking at disease models for IBD.

Anaerobic Chamber with Mucous Layer 

Our anaerobic platform incorporates an oxygen gradient and mucous layer into the RepliGut Planar model to more accurately recapitulate the environment in which the intestinal epithelium resides in vivo. The goal is to design a system within which cells can be cultured with a wide variety of bacteria. The anaerobic system we have established to date allows us to culture differentiated cells in an anaerobic chamber, and we have shown that facultative and some obligate anaerobes can survive under these conditions.

One of the big challenges has been developing a physiologically relevant mucous layer. Having that layer is essential, because many bacteria of interest kill the epithelial layer when in direct contact with it. One of the common methods for generating a mucous layer in a culture is to create an air–liquid interface. Yet, a layer of media is required to grow many relevant bacteria. We are therefore focusing on identifying solutions for generating more robust, impermeable mucous layers that will allow longer-term cultures with multiple bacteria.

Our approach in its current form has some important advantages. It is in fact fairly self-sufficient, straightforward, and easy to use. It does not require any external gas source, pump for media flow, or external anaerobic chambers to perform cell culture. Ultimately readouts common for RepliGut Planar will be available for this system, including TEER, permeability, gene expression, protein secretion, and various immunostaining assays.

Many Options to Meet Pharma Industry Needs 

Overall, our goal at Altis is to provide drug developers with a suite of human in vitro gut models for many different applications. By offering multiple platforms, we will be maximally leveraging our donor bank. RepliGut Planar is the simplest tool and can answer many fundamental research questions. For clients with more complex needs, our anaerobic or crypt-based 2D and 3D models may be more appropriate, with the 2D option offering a more high-throughput but simpler option. Ultimately, our ability to effectively address research questions and to assess approaches for improving human health depends on the availability of useful model systems.

Originally published on PharmasAlmanac.com on March 11, 2021.

Drug discovery, development, and manufacturing are complex, time-consuming, and expensive activities that are essential to innovations in healthcare. Knowledge of the human genome combined with an increased understanding of disease mechanisms has led to the generation of vast volumes of data, much of which cannot be fully leveraged with conventional statistical or other computational capabilities. Artificial intelligence (AI), by its nature, is designed to analyze and learn from large data sets and thus has tremendous potential to improve many aspects of the drug development process and other activities across biopharma. By applying AI to antibody design, Sino Biological is dramatically reducing the time and cost required to generate more effective vaccines and therapeutics.

Complex Drug Development Challenges Benefit from Advanced Solutions

The drug development process can be divided into three different stages: target discovery, candidate identification, and process development and scale-up for commercial manufacturing. Target discovery involves evaluating the genomics of a disease to determine how genetic mutations affect proteomics — the full complement of proteins produced in the relevant tissue. Enormous volumes of data are generated, much of which is not analyzed using conventional methods and are therefore not available for use, such as in correlating symptoms associated with the target disease to similar symptoms appearing in other diseases.

During the candidate identification stage, molecules that may potentially modulate the target identified in stage one are sought. That process involves extensive in vitro and in vivo screening of huge numbers of molecules, both of which are time-consuming and expensive. In addition, the identified molecules are often not easily translatable into clinical candidates.

On the manufacturing side, extensive process optimization is required to develop processes that are robust, efficient, and practically scalable. Formulation optimization is also necessary to generate a drug product with high efficacy that is safe to administer to patients.

At each of these three stages, human capabilities are limited to a certain degree. Artificial intelligence (AI) has the potential to expand those capabilities.

Leveraging Large Data Sets

The main way in which AI is expanding those capabilities is by processing the unimaginably large data sets now being generated at all phases of drug discovery, development, and manufacturing. The quantity and complexity of data generated today are beyond the ability of humans to fully process, even with traditional computational tools.

Following the sequencing of the human genome, a transition began to advance the field from genomics to proteomics and metabolomics. These areas are all extremely data intensive. Conventional statistical methods are limited in their ability to extract valuable information. With AI models, machine learning, “high-powered gardens,” and other advanced digital tools, it is possible to identify relationships and uncover patterns and correlations that previously would have remained hidden.

Important De-Risking Tool

Numerous benefits can be realized by applying AI and other digital tools — enhanced speed, reduced cost, lower workloads and thus labor requirements, increased throughput, and greater accuracy. Beyond these quantified advantages are less tangible but equally valuable benefits, including the ability to use types of data — for example, real-world data — that could not be adequately leveraged in the past.

Combined, these benefits of using AI contribute to a simplification of drug discovery, development, and manufacturing while also de-risking all three phases. Compound screening for candidate selection can be simplified using AI; in silico screening of large quantities of possible compounds using highly advanced predictive models (e.g., virtual cells, virtual animals) can rapidly identify those with the greatest likelihood of providing efficacy and safety and being industrializable. Only those compounds need to be subjected to in vitro and in vivo screening, dramatically reducing the time and cost of drug discovery while also increasing the chances of identifying candidates with high potential for success. We expect, in fact, that in the next five to eight years, approximately 20–30% of drug candidates reaching the clinic will have been designed using AI as part of the discovery process or in the preclinical development stage.

Many Successes

While the adoption of AI in the biopharmaceutical industry is a relatively recent phenomenon, there have already been many examples of its successful application. It is regularly used today in the recombinant protein and antibody space for sequence design, antibody affinity maturation, antibody humanization, and even manufacturing process optimization. AI also finds growing use in the diagnostics field, particularly for image analysis to determine whether cells are healthy or diseased and to detect various cancers. In these areas, AI can help companies overcome manpower and resource challenges and speed up the evaluation process.

Many success stories involve collaborations between pharmaceutical companies and AI software developers. The most well-known involve Big Pharma firms (e.g., Roche, Pfizer, GlaxoSmithKline) partnering with leading tech companies (e.g., IBM, Google). For example, Pfizer has partnered with IBM to advance its drug discovery process for cancer therapies.

Increasing Collaboration

The trend toward collaboration is a hallmark of AI adoption by the biopharmaceutical sector. Most major pharmaceutical companies are investigating ways to implement AI across drug discovery, development, and manufacturing, often in partnership with tech companies specializing in AI technology, from startups to well-established technology providers.

Some of the AI firms are focused specifically on pharmaceutical applications, while others are generalist AI companies working across multiple industries. Both approaches have their advantages for pharma and biotech developers looking for assistance with AI implementation. The former has more knowledge of drug discovery, development, and manufacturing, while the latter brings broader knowledge and experience to pharma projects, sharing insights from other contexts that have value for pharma applications.

It is also worth noting that some pharma companies choose to license AI technology that is implemented and managed by their in-house AI groups rather than forming deep relationships with tech companies. Others establish internal AI expertise through the acquisition of their AI partners. Still, others may outsource AI activities to a contract research organization that specializes in these activities.

Different Platforms for Different Domains

It is not only strategies for the pursuit of AI projects that vary. Many different AI platforms have been adopted in the pharma industry to meet specific needs in different domains. In precision medicine, for instance, AI systems are used that can rapidly match specific therapies to individual patients. In manufacturing, meanwhile, AI platforms designed to select the best buffer solutions for the optimization of the entire production process are appropriate. Image screening and diagnostics applications require AI systems designed for rapid image processing. Platforms for use in clinical trials must be designed for comprehensive, compliant, and efficient clinical trial data management.

The need for specific AI solutions for different applications is perhaps one of the biggest challenges to leveraging the technology. Each system should be optimized for each application and project. Numerous platforms have been developed; unfortunately, sufficient data has yet to be generated to validate many of these systems. Validation is essential to ensure that generated results have real-world applicability and are part of the optimization process. Collecting data to support optimization and validation is therefore a current critical need.

Ready for Prime Time

Aside from the need for more data to populate AI systems, the technology itself is perhaps 80–90% ready for use in biopharma applications, with only moderate additional innovation in the technology itself needed to realize its potential. It is already revolutionizing fields such as physics and chemistry, and, with certain conventional theories, AI has actually surpassed human capabilities. The next step in the pharma sector will be feeding more data into the different systems in order to optimize and validate them. Going forward, we anticipate the continued improvement of systems targeting different pharma domains.

Looking at the industry as a whole, at least 60–70% of biopharma companies are bringing some sort of AI into their development programs. That includes smaller companies and startups, as well as Big Pharma firms. Some are leveraging AI to analyze phenotypic and genotypic data for target identification, while others are applying AI for drug screening to identify candidate molecules. As mentioned previously, it is also being widely applied in image analysis for diagnostic applications. Smaller firms with limited resources particularly benefit from the reduced time and cost that AI affords.

More Application Waves to Come

During the past 30 years, two to three different waves of AI implementation have occurred in different industrial sectors. In the pharma industry, the past few years have experienced the greatest acceleration of AI adoption, largely to address the unique situations created by the COVID-19 pandemic. The need to rapidly develop vaccines against the SARS-CoV-2 virus, for instance, led many to consider how AI can accelerate drug discovery, development, and manufacturing to benefit mankind.

In parallel, AI is seeing expanding use in other industries, with software, computers, and robotics in the lead. Robotics is potentially the largest opportunity at present, considering the ongoing development of self-driving cars and other similar technologies. As advances are made in these areas outside biopharma, an understanding of new ways in which AI can be applied and provide benefits is emerging, and this new knowledge will ultimately be leveraged for drug discovery, development, and manufacturing as well, driving future application waves in the pharmaceutical industry.

AI at Sino Biological: A Partnership Approach

Sino Biological offers the world’s largest selection of bioactive recombinant proteins (nearly 6,500) and antibodies (monoclonal, polyclonal, and multispecific), as well as custom manufacturing and research services. AI is leveraged for drug discovery through a partnership with Ainnocence,^a which has developed SentinusAI™ and CarbonAI™, self-evolving AI platforms specifically for the acceleration of large molecule and small molecule drug discovery, respectively.

Sino Biological and Ainnocence have joined forces to establish an AI-enabled platform for antibody affinity maturation. Powered by a self-evolving AI engine, Ainnocence’s SentinusAI™ is revolutionizing affinity maturation processes. SentinusAI™ can effectively rank up to 10¹⁰ antibody sequences based on their predicted affinity toward one or more antigens within a few days. Sino Biological then performs physical screening of only the top candidates, fully expressing the selected antibody sequences and performing affinity validation studies based on its high-throughput platform for recombinant antibody development and advanced technologies for biomolecular interaction analysis.

The closed-loop nature of SentinusAI™ guarantees that the model creates better antibodies by learning from each cycle of the experimental results. A higher hit rate will be achieved on subsequent computation by incorporating wet-lab data. The AI-powered affinity maturation platform can deliver affinity-matured antibody sequences with an average hit rate of 15% and develop 10³ increased affinity-matured antibodies within four weeks.

The Ainnocence AI platform is attractive because it only requires sequence data; no structural information must be provided. This approach dramatically reduces wet lab work, saving significant time and money. Through the partnership with Ainnocence and by leveraging its AI technology, Sino Biological has been able to further enhance its antibody development CRO services offering, thus saving customers precious development time and ensuring antibody–antigen binding affinities that meet their strict demands.

As the global leader in recombinant technology, Sino Biological has extensive experience in producing recombinant proteins and antibodies for research and drug discovery needs and can provide one-stop custom antibody services covering the initial antigen design to final scale-up antibody production. Sino Biological’s proprietary expression platforms and methodologies, as well as high-throughput and scale-up capabilities, ensure the highest chances of success for producing proteins and antibodies that are difficult to develop. Working with Ainnocence to offer next-generation antibody design and development CRO services, Sino Biological now has high expectations that AI can be leveraged to develop antibodies that will be effective in actual, real-life scenarios, even for applications in which the target is complex and/or continuously changing.

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a Acknowledgment: The author acknowledges Dr. Lurong Pan, CEO of Ainnocence, for her invaluable input and contribution to this article.

Originally published on PharmasAlmanac.com on January 10, 2023