When Are Less Potent Payloads More Effective Than Ultra Potent Payloads in ADCs?

Oftentimes, antibody-drug conjugates (ADCs) that are the most potent, have high levels of toxicity when administered to patients or animals. This effect is precisely why it’s important for researchers to optimize and identify the correct dose level for an ADC in the preclinical stages.

During the 16th Annual World ADC Summit in San Diego, CA, the top ADC experts gathered to discuss the hottest and most relevant topics in the field. At the Summit, CancerNetwork® spoke with Greg Thurber, PhD, a professor in chemical engineering at the University of Michigan School of Biomedical Engineering, about some of the counterintuitive results of ADC efficacy in animals and the clinic.

At the Summit, Thurber presented a seminar titled “Contextualizing learnings from translational profiles of approved ADCs to unlock best approaches to preclinical dosing in mouse models” and a workshop about ADCs.

In lieu of utilizing “ultra-potent” payloads, which can elicit high toxicity, lower potency payloads offer the ability to be dosed highly, such that they can achieve tumor penetration, according to Thurber. The topoisomerases enzymes/payloads were one of these lower-potency payloads that Thurber noted as having been successful.

Another example of counterintuitive efficacy that was highlighted was that rapid internalization can sometimes be detrimental to efficacy; at lower doses, fast internalization can lead to limited tissue penetration, thus not all the malignant/tumor cells are reached.

Transcript:

One of the things the field is learning more from these newer agents is that there’s no one-size-fits-all ADC that will work for any given target. You have to design it with purpose, for a given target. We’ve had a few different counterintuitive scenarios that we’ve shown in preclinical models where, for instance—and this also translates to the clinic—the most potent compound that kills cells easily in a petri dish when you’re just growing a monolayer of cells looks the best in vitro on cells, but that also comes with this liability of high toxicity. What might look good with some of the ultra-potent payloads, once you get to the clinic, you don’t end up with a therapeutic window. By selecting lower potency payloads—and this is one of the major reasons why the topoisomerases have been so successful—is that they have a low enough potency that you can dose high in the clinic. That allows you to penetrate the tumor tissue, reach all the cells, and drive much higher efficacy. There are other counterintuitive examples that we’ve shown in the past. Sometimes, very rapid internalization can hurt efficacy. Now, this is a unique case. This is not in all cases, but sometimes, at these lower doses, fast internalization can limit the tissue penetration, so you don’t reach all the cells. In other cases, we’ve shown that slower internalization allows the molecule to penetrate deeper and reach more cells, and you end up with higher efficacy.