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Webinar: Challenges in Adapting Neutralizing and Anti-Drug Antibody Assays to Gene Therapies

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Upcoming Webinar

Thursday, October 10, 2019
11:00am – 12:00pm EDT

Challenges in Adapting Neutralizing and Anti-Drug Antibody Assays to Gene Therapies

This presentation summarizes a recently published whitepaper by Absorption Systems.

We will discuss the process of developing and validating tests for detecting ADAs and NAbs. Given that the host immune response may be triggered by the AAV vector capsid, the therapeutic gene/ RNA, and the translated protein, a multi-tiered approach is required.  There are numerous challenges in developing ADA tests. These include:

  • Selection of the optimal methodology
  • Choice of cell line for NAb assays
  • Determining the appropriate cut-off point
  • Utilizing appropriate positive controls

Here we share our experience in overcoming these challenges and set out best-practice criteria.

NAbbed Again: Challenges in Developing Neutralizing and Anti-drug Antibody Assays for Gene Therapy

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Abstract

Gene Therapy is one of the most recent and fast-growing fields of medicine, which promises to change the way we approach and treat different diseases, including many which were considered incurable even a decade ago.  Recombinant adeno-associated virus (rAAV) is the most commonly used vector for therapeutic gene/RNA delivery because of its safety profile, limited immunogenicity and broad tissue tropism. Despite being the least immunogenic therapeutic viral vector AAV can evoke anti-drug antibodies (ADAs), which may be either pre-existing or developed after the onset of treatment. The absence of ADAs, especially neutralizing antibodies (NAbs), is often a prerequisite for enrolment in gene therapy trials, therefore, developing sensitive and robust assays for these antibodies is crucial.

We discuss the process of developing and validating tests for detecting ADAs and NAbs. Given that the host immune response may be triggered by the AAV vector capsid, the therapeutic gene/ RNA, and the translated protein, a multi-tiered approach is required.  There are numerous challenges in developing ADA tests. These include: selection of the optimal methodology, choice of cell line for NAb assays, determining the appropriate cut-off point, and utilizing appropriate positive controls. Here we share our experience in overcoming these challenges and set out best-practice criteria.

Demand Exceeds Supply in Cell & Gene Therapy Workforce

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The recent rapid growth of cell and gene therapies (CGTs) has led to a gap in the talent market that represents both a challenge and opportunity for the sector.

Whilst the research base for CGTs is well-established, the last five years have seen a ramping up of therapies being brought to market and treating patients. In the US over half of FDA approved CGTs gained authorization since 2014, bringing the current total up to 17. With almost 300 CGTs currently in development, the UK Cell and Gene Therapy Catapult predicts tens of thousands of patients to be benefiting from CGTs in the coming decade.

Figure 1. Number of CGTs with market authorization (MA) from 2001-2018. Taken from Cuende et al. 2018

The increasing demand for current and upcoming therapies is placing significant strain on parts of the CGT pipeline. As the industry is young and highly specialized, this growth has exposed gaps in the talent pool. Several key areas include:

  • Manufacturing… Mass production of critical components of cell and gene therapies, such as viral vectors, is a critical bottleneck for CGT companies. Production of CGTs is complex and highly regulated, with sites having to comply with strict “current Good Manufacturing Practice” (cGMP) standards set by national regulators. Scientists with experience working in these environments are highly sought after, and decisions about production facility locations often hinge on the availability of manufacturing expertise. Allogene Therapeutics’ recent plans to build a new manufacturing site in the biotech hub in San Francisco’s Bay area highlight this. The UK (a world-leader in CGT manufacturing), has announced apprenticeship schemes to help meet the need for these skills.
  • Senior management… The correct senior management is critical to the success of CGT companies. A recent report by the RSA concluded that fast delivery times and technical challenge of CGTs required management teams with a broader skills-base than in other drug discovery companies. Analyzing 182 CGT companies, the report finds that the majority (72%) of founders have scientific/medical expertise with a significant minority (24%) having managerial experience. Ensuring that operational and commercial management are on-board early in development was highlighted as critical to company success.
  • Regulatory expertise… The regulatory environment for CGTs is constantly developing. In 2018, the FDA and EMA released new regulatory guidelines for design, manufacture and testing of gene therapies. Whilst only 4% of CGT company founders have regulatory experience, this skill set becomes critical in commercialization and/or exit phases of growth.

As the CGT market continues to expand, there will only be an increasing demand for those with the scientific, manufacturing and commercial experience to tackle the unique challenges facing the CGT sector. In the interim, many CGT companies are using CROs like Absorption Systems to outsource expertise in specialist areas such as analytical testing. These services are crucial to bridge the talent gap whilst training schemes, attractive career paths and continued investment help the market reach its full potential in the coming decade and beyond.

Why Cell & Gene Therapy Focuses on the Eye

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Many companies are developing cell and gene therapy for ocular diseases.

There are more than 25 companies developing cell and gene therapy (CGT) for ocular diseases with more than 60 active clinical studies.  The reasons for this focus on the eye are not limited to but include the following:

  • Improved understanding … Significant progress has recently been made in the understanding of the pathogenesis and molecular mechanisms of diseases of the eye.  This knowledge and understanding has allowed scientists to correct mutations and underlying causes of diseases with cell and gene therapy approaches.  For example; the RPE65 protein is produced in a thin layer of cells at the back of the eye and is essential for normal vision.  There are more than 30 known mutations to the RPE65 gene, which make it one of the hottest molecular targets in the eye for cell and gene therapy.
  • Safety and delivery … The eye itself is a safe target organ for gene therapy because the therapy can be directly delivered to the appropriate tissue without systemic exposure.  Also, the eye is considered immune privileged due to the blood-ocular barrier.  In addition regarding the design of clinical studies, the subjects’ other eye can be used as a control.  Another safety and delivery factor for gene therapy for the eye is the fact that a commonly used vector, adeno-associated virus (AAV), can be engineered to deliver DNA to many cell types in the eye.  AAV is considered a safe vector because it can be engineered to not integrate into the hosts’ genome, it normally causes a mild immune response, and it is not known to cause disease or be pathogenic.
  • Important sense … Vision is arguably the most important sense for a safe and happy life.  The human eye is a gateway through which environmental light is sensed then sent to the brain for interpretation.  We perceive up to 80% of all impressions by means of our sight.  People with limited or no vision are willing to try new and experimental therapies to restore their sight.  Also many societies are willing to invest in these new and experimental treatments for ocular diseases.
  • Recent success … In December 2017 Spark Therapeutics’ Luxturna became the first directly administered gene therapy product approved by the U.S. FDA.  Luxturna treats an inherited retinal disease due to mutations in both copies of the RPE65 gene.  In January 2018 Novartis licensed this gene therapy from Spark for all markets outside of the US.  More recently the UK’s National Health Service announced that they plan to make Luxturna accessible to patients.  This success continues to inspire other companies developing therapy for ocular diseases to focus on using cell and gene therapy technologies.

With all this recent focus on CGT development for ocular diseases ACF Bioservices has expanded its services to help these companies.  ACF offers specialized preclinical in vivo ocular models, GLP and non-GLP bioanalysis, pre-existing immunity & ADA testing, and a full suite of analytical services including potency for CGT products.

 

Gut Reactions: An ADME-Centric View of the Gut Microbiome

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Did you know that, although we’re 100% human at birth, by adulthood we’re 90% bacteria?  That’s because we harbor ten times more bacterial cells in our microbiome (most of which are in the gut) than our own cells.  So much so that the total mass of our microbiome is about the same as that of our liver.

Did you know that the large inter-individual variability in hepatic CYP3A4 expression may be largely accounted for by differences in the gut microbiome?  That’s because different bacteria produce different metabolites, many of which are substrates of uptake transporters in the gut and are inducers of CYP3A4 in the liver.

Did you know that transfer of gut bacteria from an obese animal or a diabetic animal or an animal with an inflammatory bowel to a normal animal can transfer the phenotype?  Maybe we should avoid using sledgehammers such as antibiotics and learn how to selectively modulate our gut microbiome to treat diseases.

Learn about research findings such as these at the symposium “Gut Reactions: An ADME-Centric View of the Gut Microbiome,” presented by the Delaware Valley Drug Metabolism Discussion Group on Tuesday, September 17 at the Sheraton Bucks County Hotel in Langhorne, PA.  For details, go to http://www.dvdmdg.org/event/gut-microbiome/.

Andrew Goodman (Yale), Jason Boer (Incyte Pharmaceuticals), Aaron Wright (Pacific Northwest National Lab and Washington State University), and Peter Spanogiannopoulos (UCSF) will speak on different aspects of bacterial drug metabolism.  Julia Cui and her student Joe Dempsey (University of Washington) will focus on the gut-liver axis.  Seth Walk (Montana State University) will talk about modulation of arsenic toxicity by gut bacteria.  And David Shen (University of Pennsylvania) will cover modulation of the human gut microbiome by a bile acid derivative.

Come and learn!  Lunch and refreshments are included in the registration ($175 in general, $75 for academic faculty, free for students), along with a very full scientific program.

Want to speak with one of our Transporter Experts at the show, contact us at contact@absorption.com