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Setting High Standards for Antibody Production Using Nucleosomes

A unique approach to antibody production that exposes antibody candidates to nucleosomes is revolutionizing best practices.

Fortis Life Sciences
Michael-Christopher Keogh, PhD, Chief Scientific Officer, EpiCypher Inc.
Michael-Christopher Keogh, PhD, Chief Scientific Officer, EpiCypher Inc.
Michael-Christopher Keogh, PhD

Michael-Christopher Keogh’s passion for epigenetics and chromatin biology helps scientists tackle complex research questions and overcome the challenges of health science advancement. A former academic scientist himself, Keogh is now the chief scientific officer at EpiCypher, a biotechnology company that supports transformative clinical breakthroughs across the complete cycle of innovation and commercialization—from academics engaged in fundamental explorative work to companies delivering cutting-edge health innovations. 

What has your journey as a scientist been like?

At the beginning, I was interested in transcription and gene expression. Everybody in the field at the time was largely working with naked DNA, a bit of genetics, and a lot of bucket biochemistry. We would all ignore the fact that transcription takes place not on a naked DNA template, but inside cells. This process is chromatinized—bundled with histones into nucleosomes. When the first transcriptional activator was definitively identified as a histone modifier, I immediately started working on chromatin and epigenetics, and then became more broadly interested in all DNA transactions, including gene expression, damage repair, telomere maintenance and chromosome transmission.

I was an assistant professor at Albert Einstein College of Medicine in New York for a few years and then decided I wasn’t suited for the academic track. Some colleagues invited me to join their new company, EpiCypher, and I’ve loved it ever since. EpiCypher is an epigenetics and technology development company. We support academics who do early-stage research to identify new protein families and uncover the associations between mutation and disease, as well as drug developers who have already delivered multiple clinically-approved drugs against different epigenetic targets. EpiCypher supports the entire ecosystem, using nucleosomes as substrates and genomic mapping controls. 

What is a key research challenge that your work addresses?

One focus was to build an independent testing platform to identify whether the antibodies to histone post-translational modifications (PTMs) that everybody was spending millions of dollars on were fit for purpose. We discovered that most are not, and in many cases even if an antibody does what it promises there can be difficulty securing a consistent supply. Antibodies are generally developed by immunizing rabbits and are launched to the world as a single catalog number. The field has largely ignored the inherent biological variability between different lots of these reagents, even for recombinant monoclonals. We assess the performance of these reagents, demonstrating that a given anti-PTM antibody is fit for the approaches that we have directly tested to nucleosome standards. We select the best-in-class to enable transformative genomic technologies, with a focus on epigenetics and chromatin. We make no promises outside of that. We know that antibodies are not universally capable. We are open with end users about how each antibody has been validated for a specific application, using defined and fully transparent criteria that can be independently validated.

How are you using Fortis (Bethyl) antibodies to help address this challenge?

Everybody knows how to make anti-PTM antibodies. They are a commodity developed and sold by multiple companies. But we often see profound differences in ability because these reagents are generally raised, tested, and validated to histone peptides only. The nucleosome is never considered. Bethyl has taken a different approach by implementing our tech with theirs, and what they’re doing is working. Bethyl immunizes and initially screens rabbits with peptides, then exposes the candidates to our nucleosomes to determine how they deal with these chromatin subunits. Clone products are then shipped to EpiCypher for further testing to panels of PTM-defined nucleosome controls, after which the best-performing candidates are selected for scale-up and final validation in approaches of interest. EpiCypher will then release all of the data that went into creating these reagents—essentially, we will show exactly what each antibody can do and will check every single lot with comparable stringency. We’ve been consistently pleased by Bethyl’s initial candidate success rate. They are creative in their workflows, responsive to our inputs, and a great group to work with overall. We’re now engaged in multiple projects, with multiple anti-PTM clones about to be launched as formal genomic mapping reagents. 

This interview has been edited and condensed for clarity.

Fortis
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