Phase 1/2 study of MP0533, a tetra-specific T cell engager (CD33 x CD123 x CD70 x CD3), in patients with relapsed/refractory AML or MDS/AML: Initial results from optimized treatment regimen including densified MP0533 dosing and adapted premedication

Abstract

Abstract BACKGROUND: MP0533 is a tetra-specific CD3-engaging DARPin designed for avidity-driven T cell-mediated killing of acute myeloid leukemia (AML) cells expressing ≥2 of the 3 leukemia-associated antigens CD33, CD123, and CD70, while sparing healthy cells. MP0533 is evaluated for the treatment of adults with AML or myelodysplastic syndrome (MDS)/AML. The results of the Phase 1/2a dose-escalating dosing regimens (DR) 1–7 showed an acceptable safety profile with evidence of target engagement, T cell activation, and preliminary antitumor activity. However, serum pharmacokinetics (PK) suggested that MP0533 exposure is impacted by target-mediated drug disposition and anti-drug antibodies (ADA) (Jongen-Lavrencic et al. ASH 2024). To mitigate these effects and optimize exposure to treatment, initial MP0533 dose-densification in cycle 1 was introduced in DR 8. Encouraging preliminary antitumor activity was observed (Bories et al. EHA 2025). DR 9 comprises further dose-densification plus anti-CD20 pretreatment. AIM We report the latest results of this first-in-human, multicenter, open-label, Phase 1/2a study of MP0533 (NCT05673057) with focus on the outcomes of DR 8 and 9. METHODS Safety, PK, pharmacodynamics (PD), ADA, and antileukemic activity of MP0533 are assessed. Whilst DR 1–7 utilized MP0533 step-up dosing (SUD) on day 1, 5, 8, followed by target dose (TD) on day 15, DR 8 implemented a higher starting dose and earlier TD administration on day 12. Across DR 1–8, TD on day 15 was followed by weekly dosing (28-day cycles). For DR 9, MP0533 is administered with higher frequency vs DR 8 in cycle 1 and beyond, reaching the TD on day 3, and obinutuzumab is given >3 days prior to the first MP0533 dose. Treatment-emergent adverse events (TEAEs) are assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events v5.0. Response is evaluated at weeks 4, 8, and 12 using 2022 European Leukemia Net (ELN) criteria, with additional bone marrow assessment (BMA) on day 14 in DR 9. Centralized molecular measurable residual disease (MRD) is conducted using next-generation sequencing and polymerase chain reaction. RESULTS As of 21 Jul 2025, 52 patients with relapsed/refractory disease were treated (DR 1=1, DR 2=1; DR 3=3; DR 4=6, DR 5=8, DR 6=9, DR 7=9, DR 8=10, DR 9=5). Median baseline age was 73 years (range 22–82). ELN genetic risk was adverse in 35 patients (67%) and intermediate in 14 (27%). Thirty-one patients (60%) received ≥2 prior treatment lines. Patients received a median of 6 TDs (range 1–21) in DR 1–7 (complete) and 6 TDs (range 1–40) in DR 8 (1 patient still on treatment). DR 9 is ongoing, with a median of 13 TDs (range 8–21) administered; 2 patients completed the 28-day dose-limiting toxicity (DLT) period to date. In addition to the 3 DLTs reported previously (DR7: proctitis, muscular weakness; DR 8: fatal pulmonary hemorrhage in context of disseminated intravascular coagulation, resulting in TD decrease for subsequent patients), 1 DLT of grade 4 liver enzyme elevation was observed in DR 9. The most frequent MP0533-related TEAEs across DR 1–9 were cytokine release syndrome (CRS, 35 patients [67%]) and infusion-related reactions (IRRs, 25 patients [48%]). Three CRS and 6 IRRs transiently reached grade 3 (DR 5–8); all others, including those reported in DR 9, remained of grade ≤2. In DR 8, 3 of 8 evaluable patients achieved a response (1 complete remission [CR]; 2 CR with partial hematologic recovery) vs 4 of 33 in DR 1–7 (1 CR, 3 morphologic leukemia-free state). Two patients in DR 8 maintained response for ≥12 weeks, including 1 in ongoing CR for >9 months. One of the 3 responders in DR 8 showed transient MRD negativity and the 2 others a decrease of variant allele frequency from baseline mutations. In DR 9 to date, 1 of 4 patients with available BMA up to day 14 responded (1 CR) and 2 further showed initial signs of blast count reduction. Serum PK data from DR 8 showed higher drug exposure in cycle 1 vs previous DRs; PK and ADA assessments of DR 9 to confirm expected levels of MP0533 exposure with densified treatment regimen and anti-CD20 pre-treatment is ongoing. SUMMARY MP0533 shows an acceptable safety profile across DR 1–9. Based on initial data, densified MP0533 dosing and anti-CD20 pre-treatment appear tolerable. Preliminary antitumor activity signs with the densified treatment regimens are encouraging. Further efficacy and PK/PD data for DR 9 are currently being collected.