Photo by Einar Fredriksen
Rhesus macaque
ORLANDO, FL—A 2-drug combination is “an exceptional candidate for clinical translation” as prophylaxis for graft-vs-host disease (GVHD), according to a presenter at the 2017 BMT Tandem Meetings.
The combination consists of sirolimus and KY1005, a monoclonal antibody that binds to OX40L and stops it from activating OX40, a protein that induces prolonged responses in T cells.
Experiments in rhesus macaques showed that KY1005 alone can have a modest effect on GVHD, but the combination of KY1005 and sirolimus can provide long-term, GVHD-free survival.
Victor Tkachev, PhD, of Seattle Children’s Research Institute in Washington, presented these results as one of the “Best Abstracts” at the recent BMT Tandem Meetings (abstract 3). This research was supported by Kymab, the company developing KY1005.
Dr Tkachev and his colleagues tested KY1005 alone and in combination with sirolimus in a previously described model of GVHD. In this model, rhesus macaques that do not receive prophylaxis develop severe GVHD after haploidentical hematopoietic stem cell transplant (HSCT).
For the current study, the animals received no prophylaxis, KY1005 alone, sirolimus alone, or KY1005 plus sirolimus.
When compared to no prophylaxis, KY1005 delayed the progression of acute GVHD and significantly prolonged the survival of HSCT recipients. However, all KY1005-treated animals eventually developed lethal GVHD.
Dr Tkachev noted that KY1005 provided partial control of T-cell activation, decreasing CD4 T-cell proliferation but having no significant effect on CD8 T-cell expansion.
As with KY1005 alone, sirolimus alone delayed GVHD progression and prolonged survival when compared to no GVHD prophylaxis.
However, all animals treated with sirolimus monotherapy eventually developed GVHD and died, and sirolimus alone wasn’t able to control T-cell proliferation.
On the other hand, the combination of KY1005 and sirolimus provided long-term, GVHD-free survival. All of the animals that received this combination survived, without developing GVHD, through day 100 after HSCT.
Dr Tkachev noted that, when given together, KY1005 and sirolimus synergistically controlled both CD4 and CD8 T-cell proliferation. However, this effect did not result in a lack of engraftment. In fact, animals that received the combination “displayed robust hematopoietic reconstitution” and maintained a high number of donor T cells.
Further investigation revealed that combination treatment with KY1005 and sirolimus preserves the reconstitution of regulatory T cells after HSCT and prevents both Th1- and Th17-driven alloimmunity.
Dr Tkachev and his colleagues also found that KY1005 plus sirolimus demonstrates an “unprecedented capacity” to protect against acute GVHD. Results with this combination were superior to those observed with tacrolimus and methotrexate in combination as well as abatacept and sirolimus in combination.
“Taken together, these data suggest that combined prophylaxis with KY1005 plus sirolimus represents an exceptional candidate for clinical translation,” Dr Tkachev concluded.
Kymab has said it will begin testing KY1005 in clinical trials this year.
