Molecular Partners has identified “suboptimal exposure” to its tetra-specific T-cell engager as the potential cause of the limited response rate in its early-phase trial, prompting the Swiss biotech to change the protocol to try to dial up the impact of the compound.
The candidate, MP0533, features six binding domains. Three of the domains engage CD33, CD123 and CD70 on the target tumor cells. One domain targets CD3 to engage T cells, and the final two domains are there to prolong the half-life of the candidate in circulation. Molecular Partners picked the tumor targets to kill cancer cells that express two or more antigens while sparing healthy, single-expressing cells.
Investigators are testing the candidate in a phase 1/2a study that is enrolling patients with relapsed or refractory acute myeloid leukemia and myelodysplastic syndrome. As of July 29, the biotech had seen four clinical responses in the 28 patients treated in the first six dose cohorts.
Philippe Legenne, M.D., fresh from his appointment as Molecular Partners’ permanent chief medical officer, walked through the interim data on an earnings call Tuesday. After discussing the number of responses, Legenne concluded that the company “need[s] to have more than that to be completely satisfied and to qualify that we would unlock the potential of that compound.”
Molecular Partners has identified “suboptimal exposure” as a barrier to realizing the full potential of the candidate. That observation led the biotech to prepare to change the protocol to allow higher and more frequent dosing in pursuit of improved response rate, depth of response and durability. Investigators are now enrolling patients in the eighth dose cohort and could go up to the eleventh dose level.
“What we hope is that we are going to … reduce the tumor … burden. We see that we have more responses in the lower tumor burden than in the higher,” Legenne said. “We also want to avoid by design having chronic exposure, because we are also conscious of that concept of T-cell exhaustion. So we wouldn’t want to be continuous all the time. Then the question is how little is enough.”
One outstanding question is whether increasing the dose will improve the responses. Molecular Partners saw one complete response on the fourth dose and one case of morphologic leukemia-free state at the third, fifth and sixth doses. The biotech is still collecting data on the seventh dose, but, at this stage, there is no clear dose response.