For this episode of the Microsamplify Podcast, we spoke with Mike Wright, Scientific Director, Drug Development Solutions at LGC. LGC, also known as LGC Group, is an international life sciences measurement and testing company that provides reference materials, genomics solutions and analytical testing products and services. The Drug Development Solution division within LGC is a contract research organization, based in Fordham, Cambridgeshire, England that has more than 20 years’ experience working to GLP and GCP on a wide range of species and matrices and includes LGC’s Immunogenicity Centre of Excellence. Most recently, the Centre developed the first commercially available SARS-CoV-2 Antibody Test in the UK that is compatible with Neoteryx’s Mitra® microsampling device for at-home blood collection, and Mr. Wright played a key role in that effort.
Neoteryx: Hello Mike, and welcome to the Microsamplify Podcast from Neoteryx. Thanks for taking the time to speak with us about your work at LGC’s Immunogenicity Centre of Excellence.
Wright: Thank you for inviting me on this podcast. I’m happy to speak with you about how we use microsampling within the drug development solutions division at LGC, and about our new COVID-19 assay.
Neoteryx: Can you tell us a little bit about yourself and your role at LGC?
Wright: Sure! After completing my studies in my home town of Perth, Western Australia I began my career in clinical research groups, first in Australia and later in Germany. By 2001, I had moved to the UK and I took a position working with Professor Neil Dalton and Charles Turner in their Inherited metabolic disease laboratory which, at the time, was at Guys Hospital in London, now moved to the Evelina Children’s Hospital. This was a defining period in my career as the laboratory was one of the early adopters and promoters of quantitative LC-MS/MS in clinical diagnostics, particularly in the screening of PKU and MCADD in newborns but also in the measurement of a range of biomarkers as part of the assessment of inherited diseases. This was also my first exposure to the use of microsampling, as our samples were typically dried blood spots from newborn babies.
After a number of years working in clinical diagnostics, therapeutic drug monitoring and clinical trials I joined the Drug Development Solutions division at LGC in the UK, first as a principal scientist and then for the last 2 ½ years as scientific director. My team oversee all the LC-MS, Ligand Binding Assay and Flow Cytometry methods being deployed in our Bioanalytical laboratories in Cambridgeshire.
Neoteryx: Can you give us an overview of the services that LGC Group provides, and specifically, the services that your Immunogenicity Centre of Excellence provides?
Wright: The Drug Development Solutions division supports our pharmaceutical industry partners in developing life-saving and life-improving drugs. The motto of LGC is “science for a safer world” and I like to think that the work we do epitomizes that slogan. Our bioanalytical laboratories are among the largest in Europe and we support large and small molecule drug development through the lifecycle of preclinical through to Phase I, II and III clinical trials.
The Immunogenicity Centre of Excellence sits within our large molecule bioanalysis group, which comprises approximately 70 scientists and regulatory project managers based at our Fordham laboratories. The Centre has over 10 years’ experience in developing and validating assays to support clinical and pre-clinical immunogenicity programs. In doing so, we use gold-standard technologies for method development (e.g., MSD, AlphaLISA and Gyrolab) but also cutting-edge approaches to drug and target tolerance requirements, and we are an industry leader in the implementation of SAS for statistical analysis and Labware LIMS for data management.
Neoteryx: Your team at LGC’s Centre in Fordham has a reputation for operating to the highest scientific and quality standards. I understand that your operating capacity, rapid turnaround and logistics support large, complex protocols. Can you discuss the types of projects your group tackles? How does microsampling fit into those projects?
Wright: Our Bioanalysis laboratories have been a GLP/GCP accredited laboratory for over 20 years and we support many large trials, in some cases coordinating as many as 140 different sites, to deliver PK, biomarker and immunogenicity studies. Because we work with so many different pharmaceutical and biotech partners, we see a huge variety in the types of trials and the diseases being targeted. Microsampling can play a role in many of these.
For preclinical work, the move by the industry to microsampling has been driven by 3R principles for more humane animal research. The 3Rs being Replacement, Reduction and Refinement of animal testing.
For clinical trials, microsampling is usually considered when working with vulnerable patient types, such as newborns, or for diseases that are acute in nature, such as headaches or indigestion where it is impractical to try to have the patients in a clinic while you wait for symptoms appear. You don’t know when you will have a migraine, and you need the medication when it happens, so these studies benefit from a sampling device that can be operated at home.
A number of years ago I performed phlebotomy as part of my job and it quickly became apparent to me that for a number of patients a venipuncture [blood draw] can be a very invasive procedure. For example, it can be challenging to perform a blood draw on someone with extreme anorexia. Some people suffer from needle phobia, which can be very distressing, and if you are working with recovering or recovered drug addicts, the psychological impact of putting a needle in their vein can be profound. Whereas performing a finger-prick capillary blood draw combined with a device like the Mitra® circumvents these issues. In my opinion, as healthcare and bioanalytical communities, we have a duty of care to provide the most appropriate and ethical options we have available for studies involving vulnerable patient groups.
Neoteryx: Your team at LGC recently developed a SARS-CoV-2 antibody assay that is the first in the UK to utilize Mitra microsampling with VAMS® technology from Neoteryx. Can you tell us more about your COVID-19 assay and how you developed it?
Wright: Not long after the COVID-19 pandemic began, the scientists in our Immunogenicity Centre of Excellence began working on a SARS-CoV-2 antibody test, which we are pleased to announce has recently completed validation. The drive at LGC was to create an assay that could be used for both traditional serum samples, and also with the Mitra devices to enable home or remote sampling. In this current era of social distancing, we recognized the importance of removing the need for a patient to come into a clinic to see a phlebotomist.
The first step was to develop and validate the serum antibody assay and ensure it demonstrated sufficient sensitivity and specificity, while also meeting the performance criteria set out in both government guidance and recommendations from the Royal College of Pathologists. We did this by analyzing a large cohort of pre-pandemic patient samples as our negative control group. Included in this control group were up to 40 patient samples that were positive for antibodies against four other coronaviruses, along with a number of other confounding interferences and disease states.
As our positive control group, we analyzed samples from COVID-19 patients where the presence of the SARS-CoV-2 virus had been confirmed by the PCR test. From these assessments, our assay demonstrated sensitivity of 98% and specificity of 100%. Interestingly, the one COVID-19 sample that tested negative for antibodies in our assay also tested negative on the Roche Elecsys and the Siemens Total antibody assays suggesting that this patient may not have seroconverted, or that the PCR test was a false positive.
We were also interested in looking at how our assay performed compared to other commercial assays. We exchanged cohorts of samples with our collaborators, who ran them using the SARS-CoV-2 assays on the Roche, Abbott and Siemens platforms in their own laboratories. In each case, there was a high level of agreement, with only one sample giving a slightly positive result by the Abbot assay and a negative result on ours.
Once we were confident in the performance of our serum assay, we then validated the assay for use with the Mitra device and subsequently tested it for concordance. To characterize the assay, we created surrogate samples using the positive and negative control serum that I described earlier, combined with fresh-packed red cells from healthy volunteers. Once we were happy that the assay gave the same results in the surrogate samples as it did in the serum, we ran a study using volunteers who had both venous blood drawn for serum and a fingerpick capillary blood sample collected onto a Mitra device. The paired samples matched perfectly, giving identical results.
Lastly, we needed to test stability of the antibodies on the devices. We were pleased to find that dried blood Mitra samples were stable when stored at room temperature or even 35°C, meaning that they can be transported in the post.
Neoteryx: Can you explain from a drug development & testing perspective what you are looking for in a high-quality blood sample for lab analysis, and how the Mitra® microsampling device helps fulfill that?
Wright: Firstly, we needed a device that is approved as a CE marked IVD. Secondly, we assessed a number of devices for the “patient experience” as we wanted to use a device that is easy for people to use unaided. Thirdly, while the assay is qualitative, we wanted to know what our measurement of uncertainty was at the cut-off index, and so we wanted a volumetric sampler to reduce variability. The Mitra device met all of these requirements.
Finally, we already have extensive experience over a number of years using the Mitra device for small molecule applications at LGC and have developed our own workflows for handling them. So the Mitra was an obvious choice.
Neoteryx: What equipment is LGC using in the lab at the Immunogenicity Centre of Excellence and did you have to adjust your setup to be compatible with Mitra microsampling and VAMS technology?
Wright: We employ a number of technologies such as MSD, AlphaLISA and Gyrolab in our immunogenicity workflows. This particular assay was developed on the MSD platform using viral spike protein as a capture and detection. The one downside of using dried samples like the Mitra instead of serum is the impact of dilution. For example, our assay uses a 20µL Mitra sampler and we then reconstitute the dried blood in 200µL of extraction buffer, so there is a 10-fold dilution before you even think about the hematocrit. However, our serum assay on the MSD already uses a large dilution step prior to measurement, so this dilution using the Mitra is of little concern.
Another benefit of the Mitra device is that it is compatible with a 96-well plate format so, once we have performed the extraction step, we can leverage our liquid handling capabilities in the same way as we would for typical liquid samples.
What this opens up is the possibility of running large clinical immunogenicity studies using Mitra devices, which could be very beneficial for clinical trials in the COVID-19 era. It also links nicely to recent technological advancements in the biomarker arena. Earlier this year, we validated the new Simoa HD-X platform from Quanterix for use in regulated studies. This is a highly sensitive technology, and the sensitivities that can be achieved with this platform can potentially offset the impact of dilution when using Mitra devices for biomarker programs.
Neoteryx: Is there anything you would like to add about what makes the LGC Centre unique from other CROs or labs in England or elsewhere?
Wright: We have a unique heritage as a pharmaceutical contract laboratory that was developed from the world’s leading sports drug surveillance laboratory and is now part of a large, worldwide, multidisciplinary group. This breadth of knowledge across LGC is leveraged through our internal “science families” that bring together specialists from across the company where we can discuss new innovations and current challenges. In addition to that, our method development team at Fordham is multidisciplinary, so we have LC-MS specialists working alongside Flow Cytometry and Ligand Binding assay specialists. This enables us to select the best technology for the application and provides us with additional insight when adopting new technologies for the measurement of drugs and biomarkers in biological fluids.
If you combine our proven track record in bioanalysis, biomarkers and immunogenicity with our data management, PK, sample kits and logistics services, it gives you access to a broad-based laboratory capability and customized service to help you get the most from your samples.
Neoteryx: Thank you, Mike, for speaking with us about how you use microsampling in your Centre of Excellence and also about the service capabilities of LGC Group. We wish you great success with your SARS-CoV-2 Antibody Testing and your many other projects!
And, thanks to our audience for listening to this episode of the Microsamplify Podcast, a partner to The Microsampling Blog from Neoteryx.
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