General Updates | GPRC5D-directed ADCs for multiple myeloma: ongoing research in the field

Hi, my name is Sridevi Rajeeve and I’m a physician at Memorial Sloan Kettering Cancer Center focusing on multiple myeloma and cellular therapies for multiple myeloma. It’s a pleasure to be here and this is being recorded as part of the inaugural International Working Group of GPRC5D, which is being held in New York City. So we had a lot of discussions today regarding all types of classes of drugs for this particular target, which is GPRC5D. And specifically, my talk was really focusing on highlighting a new and emerging drug class called antibody-drug conjugates or GPRC5D-directed antibody-drug conjugates. Now, there’s not a lot of data in this space. In fact, it’s a completely data-free zone, which is why it’s exciting, because we are really interested to see whether this class of drugs will have some of the efficacy that the counterparts in bispecific antibodies and CAR-Ts directed against GPRC5D have, and most importantly, whether they will have similar or a different profile of toxicities that we have found to be limiting for CAR-T as well as bispecific antibodies. Now, you know, we only have probably a few folks around the world who really looked into developing GPRC5D antibody-drug conjugates, and one group was from China, a biotech company that really developed a molecule which was then acquired by AstraZeneca and is now a clinical trial which we have at MSK and also it’s open at other sites in Europe and the US that’s really looking at the GPRCD-directed ADC as a monotherapy in relapsed/refractory multiple myeloma. Patients who are eligible include patients who have had multiple different kinds of treatments, those who’ve been exposed to triple classes, anti-CD38 monoclonal antibodies, proteasome inhibitors, IMiDs, and can also have had a CAR-T prior BCMA exposure is allowed. However, we do not include patients who have had a prior GPRCD-directed therapy, so really they have to be GPRCD-naive to be eligible for this trial. And the reason is we are trying to understand the efficacy of the GPRCD-directed ADC, so we really do not want a prior exposure to this drug while being considered to be eligible for this trial. Another important aspect to highlight, the antibody drug conjugate is usually made up of a couple of critical elements. The target is important, the target we already defined, which is GPRC5D. And then coming to the drug itself, it is an antibody. So it’s a Y-shaped antibody, immunoglobulin, on which there is a payload or the drug which actually does the cytotoxic cell killing. In case of this AZD0305, it is MMAE or monomethyl auristatin E. That is the payload of the drug that actually does the myeloma killing that’s attached to the antibody with a cleavable linker. And there’s also a conjugation process that puts the whole thing together as a molecule. So looking at this drug in general, the way it acts is that it comes and attaches to the GPRC5D target on the myeloma cell, the myeloma cell internalizes it, and then there’s a structure inside the cell called a lysosome that takes in the antibody. There are enzymes within the lysosome that cleave away the drug away from the antibody. The drug then is now free to act and the drug goes and effectively kills the myeloma cells. So that is how the mechanism of action of this particular drug is, which we are testing in a clinical trial. And the reason I mentioned this mechanism of action is because this cytotoxic medication, MMAE, in other antibody-drug conjugates that have been studied and FDA approved for other cancers, it has been shown to have a characteristic three or four toxicities, most prominent of which is neuropathy, neutropenia, anemia, as well as some skin changes, but neuropathy being the most debilitating. So if a patient who is coming to us with grade two or above neuropathy, we again try to not enroll them in this trial because we fear that there will be additive neuropathy that can be quite detrimental. So again, if it’s a patient coming to us who hasn’t had GPRC5D directed therapies, relapsed/refractory myeloma, no grade two or above neuropathy, and no interstitial lung disease, no COPD, we try to actively put them on this trial. This trial, again, is at the Phase I level right now at the time of recording of this video. We are not at any point in which we can elucidate an efficacy or safety signal yet. I think we are still months away from really fully recruiting enough for that and analyzing the data, but it is something that we are really excited about and it’s a completely new class of medication, very different from bispecifics and CAR-Ts and purportedly, there might be some advantages similar to belantamab in the BCMA space for this particular ADC because this is a standalone antibody, right? It’s not dependent on T-cell fitness to exert its action. So there may not be immunologic toxicities, the safety profile might be different, we may not see the significant dysgeusia or cerebellar toxicities of CAR-Ts with this ADC and that is promising as well as availability. This is an antibody drug. From the time you conceive the idea of giving someone the drug, you can just give it to them in one to two weeks instead of waiting for a step-up dosing for bispecific or four to eight weeks for apheresis, for CAR-T, etc. So immediate availability, safety profile, toxicity profile all might be potentially an advantage that this antibody-drug conjugate may have over other classes, provided we see that the efficacy is non-inferior to the others. So, more in this space, we’re really excited about this drug class, and we hope that we can bring it to the market to our patients who really need a new target for their myeloma after they have seen many different kinds of therapies.

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