Tandem Meetings 2023 | Advantages & concerns associated with the use of ADC-based conditioning in SCT recipients

So I think this is a very important concept to pursue. We’re not there yet, meaning that there’s a lot of work to be done. The issues with fully ablative conditioning that are antibody based has to do with the toxicity of the ADC, the drug conjugate that’s the payload for the antibodies. So this is really one of the really downsides of ADCs. They’ve probably been 500 different ADCs and different ADC programs that have been underdevelopment over the past 20 years or more. And only a few have actually reached a clinic and a fewer have actually gotten approved.

And the problem is that there’s acute, known, and there’s chronic unknown long-term toxicities of ADCs. So that’s the downside. But they’re very attractive in that you can expose patients to antibodies without any chemotherapy and radiation therapy. So the potential for DNA damage is reduced. It’s probably not eliminated, but it’s reduced. And so with reduction in potential DNA damage then some of these secondary events such as myelodysplasia and acute leukemia are in theory less likely to occur. So that’s one of the strengths.

The second is some of the payloads are the toxins attached to the antibodies are so effective that only one or two molecules delivered to a cell is sufficient to kill a cell. And so in many ways, it can be even more potent than chemotherapy or radiation therapy. You just have to target the right cells, and so there can’t be any off-target effects, et cetera. So the myeloablative nature of these conditioning regimens depends upon the toxins. Some of the toxins are more potent than others. Some of them are more effective at ablating, the target population, some of them have some short-term and long-term toxicities which have to be established. The common toxicities for a lot of these ADCs are skin toxicity, liver toxicity, and obviously if you’re targeting a hematopoietic stem cell, it’s hematopoietic toxicity. But there’s been, now, as you know, there’s been a number of ADCs that have these crazy toxicities like ocular toxicities and resulting in decreased vision and retinal toxicities and CNS toxicities and Parkinsonism and all this crazy stuff. And so these things have to be followed closely and it’s going to take time to really find the ideal toxin that’s both effective, myeloablative, and not toxic.

Now, that brings me into one other realm, which is not been explored much, and that is the use of antibodies without ADCs. Could antibodies without ADCs be used to ablate someone’s bone marrow or to provide conditioning for transplant across MHC barriers, or even within MHC barriers? So that’s something that needs to be developed as well. And so again, in principle, we need some proof of principle experiments that this can be done. So in the case of immune-deficient children, an unconjugated [inaudible] antibody can be used to condition those children because they have no immune response. And so there is some evidence that just a naked antibody can be a conditioning agent. So that’s the kind of thing that really needs to be developed in the future so that you don’t have any toxicities from chemotherapy radiation therapy, or the ADC itself.