LBA for biomarker validation with Joel Mathews
LBA for biomarker validation with Joel Mathews
https://asa1cadmoremedia.blob.core.windows.net/asset-16e88809-342a-4bc9-9f27-a889ee1e1e61/WRIB 2019 - Joel Interview V3.mp4
Segment:1 LBA and biomarker validation with Joel Mathews.
JOEL MATHEWS: My name is Joel Mathews. I work at Ionis Pharmaceuticals in Carlsbad, California. There, I am in charge of developing biomarkers for all of our different programs. And my interest in biomarkers is-- I got first recruited into work on bioanalysis, and was working on PK and ADA and on biomarkers assays. And I realized very quickly that, although developing assays is interesting and fun, what I really missed was just the science of things.
JOEL MATHEWS: But you can get that by really developing biomarkers, because biomarkers is all about the science that's going on.
Segment:2 What are the basic principles of LBA?.
JOEL MATHEWS: Most LBAs are you going to use a capture and detection system-- sandwiches, as people like to call it. And your basic principle is, you want to be able to understand how this system works. How reproducible is it going to be over time? And it's-- again, as we talk in biomarkers, is that assay development is fit for purpose.
JOEL MATHEWS: If you're only running one assay and you're just going to look at it once, the scrutiny that you need to do for that assay is a lot less than if you're going to try to run this in a clinical trial where you'll be running it over 3 years, or over 10 years, is you really need that-- if you're going to run it that long, you need to understand that a lot more than if you're just running it once.
JOEL MATHEWS: So in an LBA, yeah, you have a detection and a capture system. And that can be-- that capture and detection system could be on a lot of different technologies. So exactly how you're detecting that sandwich formation can be very different. If it's on a Quanterix, for instance, you're taking a picture of a bead that's light. Or an ELISA, you're looking for color formation.
JOEL MATHEWS: But it's very different depending on that. And so then you have a standard curve, where you're going to have some sort of known concentration that you're going to compare-- that you need to develop a curve fit to. The standard curve's in a span, a range. And then you compare back your unknowns to that known, with the assumption that the amount of signal you get in your calibrator curve isn't going to be the same as you're getting in your unknown.
JOEL MATHEWS: So you can figure out, with somewhat relative accuracy, what your concentrations are and your unknowns.
Segment:3 How do you use LBA for biomarker validation?.
JOEL MATHEWS: To validate a biomarker for use in the clinic, you need to show that it has some-- its change or its-- either compared to healthy volunteer and a disease state, or its change after drug has some relevance clinically. That could be that it's correlated highly with some change clinically, or it's correlated to that people who have higher levels of this progress quicker on-- their disease progresses quicker.
JOEL MATHEWS: So you can get all sorts of biomarkers. You can get diagnostic biomarkers. You can get prognostic biomarkers. You can get pharmacodynamic biomarkers. All the biomarkers have use. So an LBA could be used for all of these different types of biomarkers, because-- for instance, in a diagnostic, it could be that if you're two times above the normal range, then you have disease X for this certain biomarker.
JOEL MATHEWS: Or it could be that if, after drug treatment, this biomarker Y changes by 50%, that's correlated well with a loss of disease-- a disease going away, and you're cured of the disease, or-- wouldn't use cured. But anyway-- and LBAs, how do they all fit into here? The LBA, I think, in a lot of senses is the driver behind a lot of biomarkers, because they're high throughput, and they have good sensitivity and they have good specificity.
JOEL MATHEWS: Now, there are other types of markers. There's other types of assays. You can have mass spec. You can have kinetic assays. And I think each one of these have their use. It's just, you have to understand-- again, going back, you have to understand the biology of your biomarker and understand the best way to actually measure it.
Segment:4 Compared to other techniques, what are the main advantages of LBA?.
JOEL MATHEWS: I think one is the throughput.
JOEL MATHEWS: If you're doing a-- you could run four ELISA plates, for instance, in a day, have 36 samples. That's a lot of samples you're running through, where if you're using a mass spec, for instance, the amount of-- they are getting much better at throughput, but they're still not as high throughput as LBAs are. And your reproducibility can be pretty good with LBAs, because you're basing everything off one lot of reagents or figure out some way to bridge those lots.
JOEL MATHEWS: But it does suffer in other things. It's not as specific. I mean that-- mass spec people like to say they have high specificity, because they know they're looking at certain peptides. But mass spec also suffers in other things, too. So I think there's advantage the technology. Again, it goes back to what is the biology and how best to actually measure.
JOEL MATHEWS: And so I don't think there's one answer that LBA is the way to go or mass spec is the way to go. No, because I think each one of them has their space.
Segment:5 What lessons have you learnt when using LBA for biomarker validation?.
JOEL MATHEWS: So I think the biggest lesson is, there are a lot of LBA kits that are available, and not all of them work, and not all of them are characterized as much as we would like them to be. And so there is going to be a lot of work, in trying to take a kit or even make your own assay, to get it validated to enough that you truly understand what you're measuring.
JOEL MATHEWS: And even when that is true, 10 years from now, there may be a better assay out there, and we have to be willing to switch. So it's being flexible and being accepting that it's going to be a trial and error. You might buy five kits, and maybe only one of them work. But that's how it is.
Segment:6 Where do you hope this field will be in 5–10 years’ time?.
JOEL MATHEWS: I think one of the biggest places where we are still trying to learn and grow is really understanding how to get quality samples and make sure that our samples are correct, that we really understand what we're measuring.
JOEL MATHEWS: So I think that-- so quality samples, I think, is one place where I hope that as we move along, we can figure out how best to harmonize the collection, processing of samples and making sure we're collecting the correct samples for that biomarker that we want to measure. Second, I think, is, there's still a lot of work needed to be done on how to best characterize and what sort of characterisations need to be done.
JOEL MATHEWS: I say this from a standpoint of, oftentimes we may have an assay for IL-6, but we don't really know what form of IL-6 we're actually measuring. I hope that, as we move further along and understand a little bit more, that we can get to a point where we are-- now it becomes part of our normal process to really try to tease apart, are we measuring IL-6 that's bound to some other thing?
JOEL MATHEWS: Or are we measuring IL-6 that's cleaved or not cleaved? And building more and more information on what are we actually measuring so that it can be-- we can interpret our results better. [MUSIC PLAYING]