MP0533 (CD33 x CD123 x CD70 x CD3), a Tetra-Specific CD3-Engaging Darpin for the Treatment of Patients with Relapsed/Refractory AML or MDS/AML: Results of an Ongoing Phase 1/2a Study
Authors: Jongen-Lavrencic Mojca , Pabst Thomas , Bories Pierre , Griškevičius Laimonas , Huls Gerwin , de Leeuw David C. , Boettcher Steffen , Pigneux Arnaud , Boissel Nicolas , Dymkowska Mariola , Andrieu Christiane , Schönborn-Kellenberger Oliver , Baverel Paul G. , Arany Zita , Fernandez Elena , Florescu Ana-Maria , Sanderson Michael P. , Goubier Anne , Kirkin Vladimir , Legenne Philippe , Subklewe Marion 
Published: December 2024

BACKGROUND: The development of targeted immunotherapy for acute myeloid leukemia (AML) faces significant challenges due to clonal heterogeneity and the absence of a single, specific target antigen on AML cells. MP0533 is a tetra-specific CD3-engaging DARPin (Designed Ankyrin Repeat Protein) that simultaneously targets CD33, CD123, and CD70, leading to avidity-driven T cell-mediated killing of AML blasts and leukemic stem cells. MP0533's affinity to each target is calibrated to preferentially kill malignant cells co-expressing at least two of the three antigens. Healthy cells expressing only one or none of these antigens are spared.
AIM: To report data of the first 7 dose regimens (DR) from the first-in-human, multicenter, single-arm, open-label, phase 1/2a study of MP0533 in adults with relapsed/refractory AML or myelodysplastic syndrome (MDS)/AML (NCT05673057).
METHODS: This ongoing trial assesses the safety/tolerability, pharmacokinetics (PK), and preliminary antileukemic activity of MP0533 monotherapy. In addition, exploratory outcome measures include pharmacodynamics and immunogenicity. After initial step-up dosing on days 1, 5, and 8, patients receive their MP0533 target dose weekly from day 15 in 28-day cycles until disease progression or unacceptable toxicity. Dose escalation follows a Bayesian logistic regression model, considering both cytokine release syndrome (CRS) and non-CRS dose-limiting toxicities (DLTs). Treatment-emergent adverse events (TEAEs) are assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0. Response is assessed at weeks 4, 8, and 12 using the 2022 European Leukemia Net (ELN) criteria. T-cell activation is measured by cytokine secretion and flow cytometry in peripheral blood samples, evaluating intracellular and surface activation markers on CD4+ and CD8+ subsets of T cells. MP0533 target engagement is monitored by assessing changes in sCD33, sCD27, and IL3.
RESULTS: As of data cut-off (July 4, 2024), 37 patients have been enrolled in the dose-escalation part of the trial and completed the DLT assessment period, including 16 women and 21 men (1 patient each in DR 1/2; 3, 6 and 8 in DR 3-5, respectively; and 9 patients each in DR 6/7). The median age at enrolment was 73 years (range 22-82). ELN genetic risk was adverse in 27 patients (73%) and intermediate in 8 (27%). Twenty-nine patients (78%) received 1 or 2 previous treatment lines and 8 patients (22%) ≥3. Thirteen patients (35%) received prior hematopoietic stem cell transplantation. On average, patients received 6 target doses of MP0533 (range 1-21 doses, average of 2 cycles), with 6 patients continuing for at least 4 cycles. No DLTs have been observed so far. The most frequent MP0533-related TEAEs were CRS (24 patients [65%]) and infusion-related reactions (IRR, 21 patients [57%]); 7 events (3 CRSs and 4 IRRs) transiently reached Grade 3, all others remained Grade ≤2, and all resolved. To date, of 30 patients evaluable for response, 3 reached a morphologic leukemia-free state (1 each in DR 3, 5, and 6), and 1 patient in DR 4 achieved complete remission with a duration of up to 8 weeks. Fifteen of these 30 patients (50%) showed a reduction in bone marrow blasts during treatment, including 8 patients experiencing at least a 50% decrease. Serum PK data confirmed that all patients were exposed to MP0533 and showed nonlinearity suggestive of target-mediated drug disposition consistent with the proposed MP0533 multi-target mechanism of action. An association was observed between low tumor burden (≤20% of bone marrow blasts) at baseline, MP0533 serum exposure, and blast reduction during treatment. Initial pharmacodynamic analyses indicated the presence of MP0533 on AML cells in the bone marrow, and target engagement in periphery through increase in soluble biomarkers. Activation of T cells was observed in peripheral blood as evidenced by Granzyme B degranulation of CD8+ T cells, upregulation of their activation markers (CD25, CD69), and secretion of cytokines (e.g., IFNγ, TNFα) and chemokines (e.g., CXCL9, CXCL10). The study currently enrolls patients in DR 8.
SUMMARY/CONCLUSION: MP0533 dosed weekly showed an acceptable safety profile in the first 7 DRs of this ongoing phase 1/2a study. Preliminary antileukemic activity and pharmacodynamics data are encouraging, with 4 responders and evidence of target engagement and T-cell activation.