Data from The CD33xCD123xCD70 Multispecific CD3-Engaging DARPin MP0533 Induces Selective T Cell–Mediated Killing of AML Leukemic Stem Cells Article Swipe

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Matteo Bianchi , Christian Reichen , Amelie Croset , Stefanie Fischer , Aline Eggenschwiler , Yvonne Grübler , Rajlakshmi Marpakwar , Thamar Looser , Patricia Spitzli , Christel Herzog , Denis Villemagne , Dieter Schiegg , Liridon Abduli , Chloé Iss , Alexandra Neculcea , Marco Franchini , Tamara Lekishvili , Simone Ragusa , Christof Zitt , Yvonne Kaufmann , Alienor Auge , Martin Hänggi , Waleed Ali , Teresa M. Frasconi , Stephan Wullschleger , Iris Schlegel , Mirela Matzner , Ursina Lüthi , Bernd Schlereth , Keith M. Dawson , Vladimir Kirkin , Adrian F. Ochsenbein , Sebastian Grimm , Nina Reschke , Carsten Riether , Daniel Steiner , Nicolas Leupin , Anne Goubier ·

YOU? · · 2024 · Open Access · · DOI: https://doi.org/10.1158/2326-6066.c.7311391.v1

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).

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Stem cell Cancer research CD3 Cell biology Chemistry Biology Immunology CD8 Antigen

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Type: preprint
Language: en
Landing Page: https://doi.org/10.1158/2326-6066.c.7311391.v1
OA Status: gold
Related Works: 10
OpenAlex ID: https://openalex.org/W4400250975

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DOI: https://doi.org/10.1158/2326-6066.c.7311391.v1

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Title: Data from The CD33xCD123xCD70 Multispecific CD3-Engaging DARPin MP0533 Induces Selective T Cell–Mediated Killing of AML Leukemic Stem Cells

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Type: preprint

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Language: en

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Publication year: 2024

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Publication date: 2024-07-02

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Authors: Matteo Bianchi, Christian Reichen, Amelie Croset, Stefanie Fischer, Aline Eggenschwiler, Yvonne Grübler, Rajlakshmi Marpakwar, Thamar Looser, Patricia Spitzli, Christel Herzog, Denis Villemagne, Dieter Schiegg, Liridon Abduli, Chloé Iss, Alexandra Neculcea, Marco Franchini, Tamara Lekishvili, Simone Ragusa, Christof Zitt, Yvonne Kaufmann, Alienor Auge, Martin Hänggi, Waleed Ali, Teresa M. Frasconi, Stephan Wullschleger, Iris Schlegel, Mirela Matzner, Ursina Lüthi, Bernd Schlereth, Keith M. Dawson, Vladimir Kirkin, Adrian F. Ochsenbein, Sebastian Grimm, Nina Reschke, Carsten Riether, Daniel Steiner, Nicolas Leupin, Anne Goubier

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Landing page: https://doi.org/10.1158/2326-6066.c.7311391.v1

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OA URL: https://doi.org/10.1158/2326-6066.c.7311391.v1

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Concepts: Stem cell, Cancer research, CD3, Cell biology, Chemistry, Biology, Immunology, CD8, Antigen

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