%0 Journal Article %A Stephen P. Persaud %A Julie K. Ritchey %A Jaebok Choi %A Peter G. Ruminski %A Matthew L. Cooper %A Michael P. Rettig %A John F. DiPersio %T Antibody-drug conjugates targeting CD45 plus Janus kinase inhibitors effectively condition for allogeneic hematopoietic stem cell transplantation %D 2020 %R 10.1101/2020.10.02.324475 %J bioRxiv %P 2020.10.02.324475 %X Despite the curative potential of hematopoietic stem cell transplantation (HSCT), transplant conditioning-associated toxicities preclude broader clinical application. Antibody-drug conjugates (ADC) provide an attractive approach to HSCT conditioning that minimizes toxicity while retaining efficacy. Initial studies of ADC conditioning have largely involved syngeneic HSCT; however, for treatment of acute leukemias or tolerance induction for solid organ transplantation, strategies for allogeneic HSCT (allo-HSCT) are needed. Using murine allo-HSCT models, we show that combining CD45-targeted ADCs with the Janus kinase inhibitor baricitinib enables multilineage alloengraftment with >80-90% donor chimerism. Mechanistically, baricitinib impaired T and NK cell survival, proliferation and effector function, with NK cells being particularly susceptible due to inhibited IL-15 signaling. Unlike irradiated mice, CD45-ADC-conditioned mice did not manifest graft-versus-host alloreactivity when challenged with mismatched T cells. Our studies demonstrate novel allo-HSCT conditioning strategies that exemplify the promise of immunotherapy to improve the safe application of HSCT for treating hematologic diseases.Competing Interest StatementS.P.P.: None to declare J.K.R: None to declare J.C.: Consultancy: Daewoong Pharmaceutical; Research support: Mallinckrodt Pharmaceuticals, Incyte Corporation. P.G.R.: None to declare M.L.C.: None to declare M.P.R.: None to declare J.F.D.: Consulting/Advisory Committees: Rivervest; Research support: Macrogenics, BioLine, NeoImmuneTech, Incyte Corporation; Ownership Investment: Magenta Therapeutics, Wugen. 7-AAD7-aminoactinomycin DAllo-HSCTallogeneic hematopoietic stem cell transplantationACKAmmonium chloride-potassium bicarbonateADCantibody-drug conjugateAMLacute myeloid leukemiaAPCantigen presenting cellBSAbovine serum albuminCBCComplete blood countCDCluster of differentiationCFUcolony forming unitFBSfetal bovine serumEDTAethylenediaminetetraacetic acidFACSfluorescence-activated cell sortingGFPgreen fluorescent proteinvGHDgraft-versus-host diseaseGvLgraft-versus-leukemiaHcthematocritHEPESA-2-hydroxyethylpiperazine-N′-2-ethanesulfonic acidHSC/HSCThematopoietic stem cell/hematopoietic stem cell transplantationIFNInterferonIgimmunoglobulinILInterleukinIMDMIscove’s Modified Dulbecco’s MediaJAKJanus kinaseLKLineage-Sca1-cKit+LSKLineage-Sca1+cKit+miHAminor histocompatibility antigenMHCmajor histocompatibility complexMLRmixed leukocyte reactionPLTSplateletsPBSphosphate buffered salineRunning bufferPBS + 0.5% BSA + 2 mM EDTANKnatural killer cellRAGrecombinase activating geneRPMI-1640Roswell Park Memorial Institute-1640 mediasAVstreptavidinSAPsaporin-conjugatedStatsignal transducer and transactivatorTBITotal body irradiationTCDT cell depletion/depletedTNFTumor necrosis factorWBCwhite blood cells %U https://www.biorxiv.org/content/biorxiv/early/2020/10/03/2020.10.02.324475.full.pdf