Session: 701. Experimental Transplantation: Basic and Translational: Poster III
Hematology Disease Topics & Pathways:
Research, Fundamental Science, Translational Research, Drug development, Treatment Considerations, Biological therapies, Transplantation (Allogeneic and Autologous)
To achieve effective and more tolerable conditioning for HSCT we used our designed ankyrin repeat protein (DARPin) platform to generate MP0621, a cKit x CD16a x CD47 multi-specific Switch-DARPin candidate. MP0621 contains a masked CD47 blocker that is released only upon binding to cKit and triggers conditional immune cell-mediated killing of HSCs by engaging macrophages and natural killer (NK) cells via CD16a.
In vitro, MP0621 elicited potent macrophage-mediated phagocytosis of cKit+ AML cell lines, comparable to a combination of anti-cKit and anti-CD47 antibodies with functionally active Fc-domain, showing that the anti-CD47 DARPin moiety was engaged in the presence of cKit+ cells. In contrast, no phagocytosis was observed on cKit– CD47+ Raji cells, indicating that the anti-CD47 moiety remained effectively masked in the absence of cKit. Cytotoxicity assays using allogeneic NK cells and human ex vivo samples showed that MP0621 induced killing of CD34+ HSCs from healthy human donors as well as cKit+ tumor blasts from bone marrow samples of patients with AML. In CD34+ humanized NSG mice, MP0621 was able to target human cKit+ cells in the bone marrow and reduce HSCs without direct negative impact on overall frequency of mature human immune cells in the blood. In contrast, the combination of anti-cKit and anti-CD47 antibodies led to a strong reduction in total human blood cells in these mice due to the unconditional engagement of CD47.
In summary, our preclinical results indicate that combining cKit-targeting with conditional blockade of CD47 in a single molecule via the DARPin switch platform might render the combination treatment a viable approach for HSC depletion in patients. The blockade of CD47 exclusively on target cells allows MP0621 to enhance efficacy of cKit-targeting, while reducing off-target effects seen with systemic anti-CD47 blockade. Thus, MP0621 represents a potential novel targeted treatment approach for conditioning that could improve the benefit/risk profile of current HSCT strategies for patients.
Disclosures: Link: Molecular Partners AG: Current Employment, Current equity holder in publicly-traded company. Frasconi: Molecular Partners AG: Current Employment, Current equity holder in publicly-traded company. Wullschleger: Molecular Partners AG: Current Employment, Current equity holder in publicly-traded company. Venetz: Molecular Partners AG: Current Employment, Current equity holder in publicly-traded company. Ribeiro: Molecular Partners AG: Current Employment, Current equity holder in publicly-traded company. Schlegel: Molecular Partners AG: Current Employment, Current equity holder in publicly-traded company. Kaufmann: Molecular Partners AG: Current Employment, Current equity holder in publicly-traded company. Auge: Molecular Partners AG: Current Employment, Current equity holder in publicly-traded company. Ali: Molecular Partners AG: Current Employment, Current equity holder in publicly-traded company. Fic: Molecular Partners AG: Current Employment, Current equity holder in publicly-traded company. Siddiqui: Molecular Partners AG: Current Employment, Current equity holder in publicly-traded company. Eggenschwiler: Molecular Partners AG: Current Employment, Current equity holder in publicly-traded company. Jetzer: Molecular Partners AG: Current Employment, Current equity holder in publicly-traded company. Häberle: Molecular Partners AG: Current Employment, Current equity holder in publicly-traded company. Prekajski: Molecular Partners AG: Current Employment, Current equity holder in publicly-traded company. De Winter: Molecular Partners AG: Current Employment, Current equity holder in publicly-traded company. Dawson: Molecular Partners AG: Current Employment, Current equity holder in publicly-traded company. Croset: Molecular Partners AG: Current Employment, Current equity holder in publicly-traded company. Goubier: Molecular Partners AG: Current Employment, Other: Current stock holder.
See more of: Oral and Poster Abstracts