RT Journal Article
SR Electronic
T1 Antibody-drug conjugates targeting CD45 plus Janus kinase inhibitors effectively condition for allogeneic hematopoietic stem cell transplantation
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.10.02.324475
DO 10.1101/2020.10.02.324475
A1 Stephen P. Persaud
A1 Julie K. Ritchey
A1 Jaebok Choi
A1 Peter G. Ruminski
A1 Matthew L. Cooper
A1 Michael P. Rettig
A1 John F. DiPersio
YR 2020
UL http://biorxiv.org/content/early/2020/10/03/2020.10.02.324475.abstract
AB 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