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dc.contributor.authorChan, Yan Y.
dc.contributor.authorHo, Pui Y.
dc.contributor.authorDib, Carla
dc.contributor.authorSwartzrock, Leah
dc.contributor.authorRayburn, Maire
dc.contributor.authorWillner, Hana
dc.contributor.authorKo, Ethan
dc.contributor.authorHo, Katie
dc.contributor.authorDown, Julian D.
dc.contributor.authorWilkinson, Adam C.
dc.contributor.authorNakauchi, Hiro
dc.contributor.authorDenis, Morgane
dc.contributor.authorCool, Taylor
dc.contributor.authorCzechowicz, Agnieszka
dc.date.accessioned2024-11-08T17:05:44Z
dc.date.available2024-11-08T17:05:44Z
dc.date.issued2024-10-29
dc.identifier.urihttps://hdl.handle.net/1721.1/157518
dc.description.abstractAbstract Background Hematopoietic stem cell transplantation (HSCT) is a curative treatment for many diverse blood and immune diseases. However, HSCT regimens currently commonly utilize genotoxic chemotherapy and/or total body irradiation (TBI) conditioning which causes significant morbidity and mortality through inducing broad tissue damage triggering infections, graft vs. host disease, infertility, and secondary cancers. We previously demonstrated that targeted monoclonal antibody (mAb)-based HSC depletion with anti(α)-CD117 mAbs could be an effective alternative conditioning approach for HSCT without toxicity in severe combined immunodeficiency (SCID) mouse models, which has prompted parallel clinical αCD117 mAbs to be developed and tested as conditioning agents in clinical trials starting with treatment of patients with SCID. Subsequent efforts have built upon this work to develop various combination approaches, though none are optimal and how any of these mAbs fully function is unknown. Methods To improve efficacy of mAb-based conditioning as a stand-alone conditioning approach for all HSCT settings, it is critical to understand the mechanistic action of αCD117 mAbs on HSCs. Here, we compare the antagonistic properties of αCD117 mAb clones including ACK2, 2B8, and 3C11 as well as ACK2 fragments in vitro and in vivo in both SCID and wildtype (WT) mouse models. Further, to augment efficacy, combination regimens were also explored. Results We confirm that only ACK2 inhibits SCF binding fully and prevents HSC proliferation in vitro. Further, we verify that this corresponds to HSC depletion in vivo and donor engraftment post HSCT in SCID mice. We also show that SCF-blocking αCD117 mAb fragment derivatives retain similar HSC depletion capacity with enhanced engraftment post HSCT in SCID settings, but only full αCD117 mAb ACK2 in combination with αCD47 mAb enables enhanced donor HSC engraftment in WT settings, highlighting that the Fc region is not required for single-agent efficacy in SCID settings but is required in immunocompetent settings. This combination was the only non-genotoxic conditioning approach that enabled robust donor engraftment post HSCT in WT mice. Conclusion These findings shed new insights into the mechanism of αCD117 mAb-mediated HSC depletion. Further, they highlight multiple approaches for efficacy in SCID settings and optimal combinations for WT settings. This work is likely to aid in the development of clinical non-genotoxic HSCT conditioning approaches that could benefit millions of people world-wide.en_US
dc.publisherBioMed Centralen_US
dc.relation.isversionofhttps://doi.org/10.1186/s13287-024-03981-0en_US
dc.rightsCreative Commons Attributionen_US
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/en_US
dc.sourceBioMed Centralen_US
dc.titleTargeted hematopoietic stem cell depletion through SCF-blockadeen_US
dc.typeArticleen_US
dc.identifier.citationChan, Y.Y., Ho, P.Y., Dib, C. et al. Targeted hematopoietic stem cell depletion through SCF-blockade. Stem Cell Res Ther 15, 387 (2024).en_US
dc.contributor.departmentKoch Institute for Integrative Cancer Research at MITen_US
dc.relation.journalStem Cell Research & Therapyen_US
dc.identifier.mitlicensePUBLISHER_CC
dc.eprint.versionFinal published versionen_US
dc.type.urihttp://purl.org/eprint/type/JournalArticleen_US
eprint.statushttp://purl.org/eprint/status/PeerRevieweden_US
dc.date.updated2024-11-03T04:18:02Z
dc.language.rfc3066en
dc.rights.holderThe Author(s)
dspace.date.submission2024-11-03T04:18:02Z
mit.journal.volume15en_US
mit.licensePUBLISHER_CC
mit.metadata.statusAuthority Work and Publication Information Neededen_US


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