Name:
Lipid nanoparticles: immunogenicity, assessment, challenges and regulations
Description:
Lipid nanoparticles: immunogenicity, assessment, challenges and regulations
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T00H06M41S
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Upload Date:
2020-03-04T00:00:00.0000000
Transcript:
Language: EN.
Segment:0 .
[MUSIC PLAYING]
Segment:1 What are lipid nanoparticle drug products? How are they given and how do they work?.
UMA KAVITA: Lipid nanoparticles are essentially small ball-like structures that are anywhere from 1 nanometer to 100 nanometers in size. The name comes from the fact that they're composed of various different kinds of lipids that come together to form a vessel or a vehicle to carry various kinds of drug substances into the body. And these drugs substances could be anything such as small molecules for cancer therapy.
UMA KAVITA: They could be vaccines. Or they could even be gene therapeutics like DNA or RNA molecules. So in a traditional sense, you can think of lipid nanoparticles as a formulation material. Except in this case, it has a definite structure. And because of the definition and structure, there are certain advantages. You can, for example, insert targeting agents in the outer surface membrane of the lipid nanoparticle that will allow you to deliver the drug product to specific cells within the body.
UMA KAVITA: You can also, for example, put molecules such as polyethylene glycol on the surface. Things like PEG will allow your drug to hang around the body for an extended period of time and give it time to work. So this, in essence, is how a lipid nanoparticle works. In our case with Bristol-Myers Squibb for example, we have a lipid nanoparticle drug called BMS 986263 that is meant for the treatment of liver and lung fibrosis. So we have essentially inserted a targeting molecule in the outer surface membrane. And because the drug is targeted to liver hepatic cells which contains specific receptors for the retinoid moiety we are able to get the drug substance which is located inside, and in this case, it happens to be a small interfering RNA molecule, directly to the hepatic stellate cells in the liver where the drug is needed. Now the drug can be administered in various different ways. There is subq-- subcutaneous administration You can give it by IV infusion sometimes orally and sometimes also via pulmonary administration.
Segment:2 Why is it important to conduct immunogenicity assessments?.
UMA KAVITA: For the same reason that, when a bacteria or a virus enters your body, for example, your immune system recognizes it as foreign or non-self substance. And so it reacts in defense to protect you from the invader. Now lipid nanoparticles are most often composed of synthetic lipids and the drug substances that they carry have several different modifications which the body has never seen before.
UMA KAVITA: So the immune system will immediately recognize the lipid nanoparticle and the drug substance that it is carrying as a foreign substance. So as soon as it does that, it's going to mount an immune response. And there are two aspects to this. There might be safety issues where the immune cells that are trying to protect you can go into overdrive and start secreting inflammatory proteins such as interleukin 1 and interleukin 6, which can make the patient receiving the drug very sick. The second aspect to this, is you can have an antibody response to the drug product because of all the foreign components that it carries.
UMA KAVITA: So antibodies, once made against these components, can neutralize the drug and eliminate the drug from the body. So there is an efficacy issue that comes along with an immune response. So by doing an immunogenicity assessment you can address the safety profile of the lipid nanoparticle drug product. You can build a safety profile rather, as well as adjust your dosing regimen in the future to counteract the antibody mediated elimination of the drug from the body.
Segment:3 What are the challenges of assessing immunogenicity?.
UMA KAVITA: Speaking from my own experience, the first time you look at the lipid nanoparticle drug product, it looks so complex and it has so many different components as opposed to the simpler protein therapeutics that the industry has been working with in the last decade or so. So as soon as you see those various components, for example, the targeting agent, the various novel lipids that form the drug product, as well as the intracellular drug substance and the polyethylene glycol that is used to make the drug more stable, the first thought that crosses your mind is, wow, how to set up multiple anti-drug antibody assays to really understand the immunogenicity profile of this drug product. But, because resources are most often limited and there are no positive controls to begin with, it becomes a challenge as far as setting up these various assays that may be required. That I would say is one immediate challenge. The second challenge which the industry as a whole needs to address is, how do we address immunogenicity in the first place? So far we have been looking at anti-drug antibody responses to protein therapeutics.
UMA KAVITA: But now that this lipid nanoparticle comes in looking complex and with various different components, we need to understand whether we have to follow the innate immune system activation within the body and this is different from an antibody response. We now have to begin to understand whether we want to look at cytokine production, innate immune cell stimulation and so on and so forth.
UMA KAVITA: So the way we assess immunogenicity is going to change and the challenge is understanding what exactly what needs to be done.
Segment:4 Could you explain relevant regulatory guidelines – are there any challenges with these?.
UMA KAVITA: Currently there are no specific regulatory guidelines for lipsomal nanoparticles, per se. Definitely there is no FDA guidance for immunogenicity assessment of lipid nanoparticles. But there is an existing FDA guidance that came out in 2019 for immunogenicity method development and validation for protein therapeutics.
UMA KAVITA: Many of the principles that are explained within that guidance are applicable to immunogenicity assessment for lipid nanoparticle drug products. So we can use that existing guidance to begin developing and validating methods for lipid nanoparticle immunogenicity. [MUSIC PLAYING]
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