ASH 2023 | A Phase I trial of Hu8F4, an anti-PR1/HLA-A2 monoclonal antibody, in R/R myeloid malignancies

This was in the poster session. It’s a Phase I study of a T-cell receptor-like antibody, Hu8F4, in patients with relapsed or refractory myeloid malignancies. So as a background, one of the challenges in AML has been to find the right immune therapy to target AML blasts beyond just chemotherapy and targeted agents, so to bring antibody therapy into this treatment paradigm. In ALL we have things like rituximab, we have blinatumomab, which can target surface receptors and lead to remissions. The challenge in AML has been to find the right antigen.

So what we did in this particular study is to fashion a T-cell receptor-like antibody. So what this does is it is an antibody that’s designed to detect an epitope of a protein called PR1 that’s present in AML cells almost exclusively on the AML blasts in a differential way to normal cells. And so it’s an antigen that’s presented inside the AML blast. It’s a part of the peptide that’s presented on the surface of MHC protein. And because it’s presented in the context of an MHC protein, the only thing that could recognize it well is a T-cell receptor-like antibody. So it’s essentially a monoclonal antibody where the target portion is like a T-cell receptor, so it recognizes this epitope on AML blasts. And then we’re using that in patients with relapsed/refractory AML to get a dose and schedule.

What we found very nicely, number one is that almost 100% of the blasts and all of these AML patients that we treated had strong expression of this peptide and therefore had the target expressed very strongly. We gave this antibody in a dose-escalation fashion starting from 0.01mg/kg, all the way up to 10mg/kg, in a dose-escalation fashion. We found that with each antibody dose, the drug was very well tolerated at the higher dose levels, around one milligram or higher. We started noticing some infusion reactions. These were very mild, similar to what you would get with other monoclonal antibodies such as rituximab, which were treated well with holding the drug, giving some hydrocortisone or benadryl and then restarting the infusion with no other issues.

In terms of activity, again, this was in many highly pretreated, relapsed/refractory AML patients with bad karyotype and bad mutations. And what we found is that, interestingly, with each dose of the antibody, which is given on days 1 and 15 of a 28-day cycle, we saw a quick and prompt drop in the blast count in the peripheral blood with the antibody, and then after a few days, the blast would recover, another dose was given on day 15 and we’d see blast count drop. And so we found that clearly there was some pharmacodynamic effect of the antibody where we saw in the peripheral blood a quick drop in the blast count after the antibody was infused with increasing LDH, some tumor lysis labs suggesting that there was some activity in the blast, but we saw a recovery with the blast in-between and the bone marrow, we saw very little objective response. And so that tells us that potentially that the dosing strategy may need to be altered, potentially a more frequent dosing strategy where we can actually stay on top of the blast and avoid saturation of the macrophage sites, we could potentially lead to better activity. And so we’re studying some alternate dosing schedules, such as three times a week or twice a week, as well as combination strategies. And again, this is one of the newer ways as an immune therapy to target acute myeloid leukemia, since antigen recognition and appropriate antigens have been available.