The CD33xCD123xCD70 Multispecific CD3-Engaging DARPin MP0533 Induces Selective T Cell–Mediated Killing of AML Leukemic Stem Cells
Author:
Bianchi Matteo1ORCID, Reichen Christian1ORCID, Croset Amelie1ORCID, Fischer Stefanie1ORCID, Eggenschwiler Aline1ORCID, Grübler Yvonne1ORCID, Marpakwar Rajlakshmi1ORCID, Looser Thamar1ORCID, Spitzli Patricia1ORCID, Herzog Christel1ORCID, Villemagne Denis1ORCID, Schiegg Dieter1ORCID, Abduli Liridon1ORCID, Iss Chloé1ORCID, Neculcea Alexandra1ORCID, Franchini Marco1ORCID, Lekishvili Tamara1ORCID, Ragusa Simone1ORCID, Zitt Christof1ORCID, Kaufmann Yvonne1ORCID, Auge Alienor1ORCID, Hänggi Martin1ORCID, Ali Waleed1ORCID, Frasconi Teresa M.1ORCID, Wullschleger Stephan1ORCID, Schlegel Iris1ORCID, Matzner Mirela1ORCID, Lüthi Ursina2ORCID, Schlereth Bernd1ORCID, Dawson Keith M.1ORCID, Kirkin Vladimir1ORCID, Ochsenbein Adrian F.2ORCID, Grimm Sebastian1ORCID, Reschke Nina1ORCID, Riether Carsten2ORCID, Steiner Daniel1ORCID, Leupin Nicolas1ORCID, Goubier Anne1ORCID
Affiliation:
1. Molecular Partners AG, Zurich-Schlieren, Switzerland. 1 2. Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland. 2
Abstract
Abstract
The prognosis of patients with acute myeloid leukemia (AML) is limited, especially for elderly or unfit patients not eligible for hematopoietic stem cell (HSC) transplantation. The disease is driven by leukemic stem cells (LSCs), which are characterized by clonal heterogeneity and resistance to conventional therapy. These cells are therefore believed to be a major cause of progression and relapse. We designed MP0533, a multispecific CD3-engaging designed ankyrin repeat protein (DARPin) that can simultaneously bind to three antigens on AML cells (CD33, CD123, and CD70), aiming to enable avidity-driven T cell–mediated killing of AML cells coexpressing at least two of the antigens. In vitro, MP0533 induced selective T cell–mediated killing of AML cell lines, as well as patient-derived AML blasts and LSCs, expressing two or more target antigens, while sparing healthy HSCs, blood, and endothelial cells. The higher selectivity also resulted in markedly lower levels of cytokine release in normal human blood compared to single antigen–targeting T-cell engagers. In xenograft AML mice models, MP0533 induced tumor-localized T-cell activation and cytokine release, leading to complete eradication of the tumors while having no systemic adverse effects. These studies show that the multispecific-targeting strategy used with MP0533 holds promise for improved selectivity toward LSCs and efficacy against clonal heterogeneity, potentially bringing a new therapeutic option to this group of patients with a high unmet need. MP0533 is currently being evaluated in a dose-escalation phase 1 study in patients with relapsed or refractory AML (NCT05673057).
Funder
Molecular Partners AG
Publisher
American Association for Cancer Research (AACR)
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