A podcast interview (Emory Pharma) where Dr. Audrey Reeves and Benjamin Ezeokoli discuss antibody–drug conjugates (ADCs): what ADCs are, how they target cancer cells, advantages over traditional chemotherapy, challenges in optimizing drug–antibody ratio (DAR), steps in conjugation, factors affecting yield (temperature, pH, time, solvent), and emerging ADC technologies such as multispecific antibodies and ADCs combined with tyrosine kinase inhibitors.
Chapters
Yeah.
So particularly here at Emory Pharma, one really challenging aspect is trying to find specifically the ratio of linker toxin to ADC or the antibody that you would want to have. And so if you have too low of a linker toxin to antibody ratio, you're not going to effectively be able to introduce the antibody into the cell and thus be able to kill that cell. If you have too high of a ratio amount, you will introduce cytotoxicity into the patient or whoever you're introducing this drug into.
Hi, welcome everyone, to our Emory Podcast series. My name is Dr. Audrey Reeves. I'm assistant director of Analytical chemistry here at Emory Pharma, and I'm here today with Benjamin Ezeokoli, and he's here to talk with us about antibody drug conjugates. Welcome to the podcast, Benjamin. Why don't you tell us a little bit about your background?
Thank you, Audrey. So I'm here at Emory Pharma as a scientist currently. In the past, I studied chemistry at Stanford University and graduated, and from then I worked in the CRISPR space. And now I find myself here at Emory Pharma. I've worked with ADCs here and been able to successfully conjugate them as well. So I'm really excited to Talk today about ADCs.
Awesome. We're really excited to have you. Let's get started. Just for everyone that might not be familiar, what is an adc? What does that stand for and what is it exactly?
Yeah, so an ADC is an antibody drug conjugate. What essentially you're going to have is an antibody linker as well as a linker toxin or a drug associated. And so you're going to have an antibody linked to a linker or covalently bonded to a linker, and then you're going to have the drug as well bonded to that linker. Together they all form this kind of molecule called the ADC or the antibody drug conjugate.
Very interesting. And these are used for, are they used for any sort of certain treatments to target certain diseases at all?
Yeah. So you're going to have an ADC target specific. Let's say someone has cancer and you're going to want to try to kill a certain cell. You're going to want to have an ADC target a certain cell. How that's going to work is that antibody drug conjugate will target a cell expressing a certain protein and from then on will latch onto that cell. From then on, it will accept, hopefully that ADC into the cell. And then the ADC will release the linker toxin and hopefully and effectively kill that cell.
Sounds really powerful. So you mentioned cancer. What are some of the advantages that would make someone want to use an ADC over something more standard like a chemotherapy?
Yeah, so you're going to have the linker toxin that's associated with the adc. And so you can kind of treat it as kind of a Trojan horse kind of situation where you're kind of going to take that adc. It can be in lower dose amounts, and it being covalently bonded to that ADC will introduce itself into the cell at really low dosage amounts or whatever you need in order to get into the cell, and it will be able to effectively kill that cell. That will also be much safer for the patients or whoever you're introducing that ADC into.
Very cool. It sounds like the ADCs are a lot more selective for the cancer cells. Then you can use a lot less of them.
Right. So you can use a lot less of them.
Okay. Very cool. Are there any challenges or limitations to ADCs in their development? Yeah.
So, particularly here at Emory Pharma, one really challenging aspect is trying to find specifically the ratio of linker toxin to ADC or the antibody that you would want to have. And so if you have too low of a linker toxin to antibody ratio, you're not going to effectively be able to introduce the antibody into the cell and thus be able to kill that cell. If you have too high of a ratio amount, you will introduce cytotoxicity into the patient or whoever you're introducing this drug into. And so that's one issue that you can have as well. Also, you may want to try to find ways to specifically target specific cells. So you're going to want to optimize the type of antibody that you're introducing into the host cells.
Yeah, that sounds pretty complicated, like a lot of work. But you definitely sound like you have experience in this area here at Emory, huh?
Yes.
How about, you've talked a lot about this chemistry that's going on with ADCs. What are some of the main steps involved in conjugating them?
Yeah, so. Well, first you're going to want to identify what type of antibody that you're going to use in order to introduce into the host cell. And second, once you have an antibody or you know what antibody it is, you're going to want to create it en masse and be able to purify it and isolate it. After you do that, you're going to want to synthesize a linker toxin that you want to associate with the antibody and you want that to be, how would you say, compatible with that antibody. And then from then on you're going to want to conjugate the two. In conjugating the two, you're going to want to introduce certain concentrations and ratio amounts. And I'll speak a little bit more about that later. But that ratio amount will come up in our next question.
Our next question is going to be can you give us more detail about dar? Now what is dar? Can you kind of explain what that is short for?
Yeah, so you're gonna have linker toxin and you have a certain number of linker toxins associated per antibody. That ratio of number of linker toxins to antibody is called DAR or drug antibody ratio.
Okay, so can you comment on some other factors that might affect the efficiency or the yield of the conjugation reaction?
Right, so you're gonna have different levels and different various amounts of your linker toxin, your linker as well as your antibody. And so you're going to want to be able to optimize all three of those in order to achieve the DAR that you want. If you're not able to get that, you can try to play around with things like temperature, ph, the time of the conjugation as well the solvent and hopefully all those things can come together and work out fine and you'll be able to achieve your darling.
Thanks so much for talking with us today, Benjamin. I've got one last question for you and that's really just asking whether you could enlighten us onto some exciting spaces that ad seq technology is entering lately.
Yeah. So you're going to be able to have currently engineered multi specific antibodies that can bind to just more than one target antigen as well as it can also enhance the, the selectivity and the efficacy of the ADCs. You're also going to have ADCs that also incorporate tyrosine kinase inhibitors. Those can block the activity of enzymes called tyrosine kinases which are involved with cell growth. And so in effect you can be able to target cells that may kind of fight or resist it's death. And so it can essentially target cancers that are a lot more rigorous or a lot more, how should I say.
I guess like hard to target with standard chemotherapies. Right, okay. Yeah, it sounds like ADCs have a lot of advantages over some of the standard cancer treatments. And like there's a lot of space for other diseases as well. It's a really fascinating area. Thank you so much for kind of commenting on it today during our podcast series. I've learned a lot from you, and I know that our listeners have as well. If you're interested in learning more about ADC generation, please feel free to check out our website, emorypharma.com if you're interested in speaking more, send us an email or reach out to us through our contact form. You can find that there. And thank you so much for listening.
