Antibody-drug conjugates plus Janus kinase inhibitors enable MHC-mismatched allogeneic hematopoietic stem cell transplantation
Stephen P. Persaud, … , Jaebok Choi, John F. DiPersio
Stephen P. Persaud, … , Jaebok Choi, John F. DiPersio
Published November 2, 2021
Citation Information: J Clin Invest. 2021;131(24):e145501. https://doi.org/10.1172/JCI145501.
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Research Article Immunology

Antibody-drug conjugates plus Janus kinase inhibitors enable MHC-mismatched allogeneic hematopoietic stem cell transplantation

Abstract

Despite the curative potential of hematopoietic stem cell transplantation (HSCT), conditioning-associated toxicities preclude broader clinical application. Antibody-drug conjugates (ADCs) provide an attractive approach to HSCT conditioning that minimizes toxicity while retaining efficacy. Initial studies of ADC conditioning have largely focused on syngeneic HSCT. However, to treat acute leukemias or induce tolerance for solid organ transplantation, this approach must be expanded to allogeneic HSCT (allo-HSCT). Using murine allo-HSCT models, we show that pharmacologic Janus kinase 1/2 (JAK1/2) inhibition combined with CD45- or cKit-targeted ADCs enables robust multilineage alloengraftment. Strikingly, myeloid lineage donor chimerism exceeding 99% was achievable in fully MHC-mismatched HSCT using this approach. Mechanistic studies using the JAK1/2 inhibitor baricitinib revealed marked impairment of T and NK cell survival, proliferation, and effector function. NK cells were exquisitely sensitive to JAK1/2 inhibition due to interference with IL-15 signaling. Unlike irradiated mice, ADC-conditioned mice did not develop pathogenic graft-versus-host alloreactivity when challenged with mismatched T cells. Finally, the combination of ADCs and baricitinib balanced graft-versus-host disease and graft-versus-leukemia responses in delayed donor lymphocyte infusion models. Our allo-HSCT conditioning strategy exemplifies the promise of immunotherapy to improve the safety of HSCT for treating hematologic diseases.

Authors

Stephen P. Persaud, Julie K. Ritchey, Sena Kim, Sora Lim, Peter G. Ruminski, Matthew L. Cooper, Michael P. Rettig, Jaebok Choi, John F. DiPersio

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Figure 1

CD45-SAP and cKit-SAP are similarly effective as conditioning agents for syngeneic HSCT.

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CD45-SAP and cKit-SAP are similarly effective as conditioning agents for...
(A) Inhibition of B6 bone marrow colony formation in vitro by ADCs or control conjugates. Mean colony counts (from duplicate plates) from 1 representative of 3 experiments are shown. (B) In vivo depletion of bone marrow CD150+CD48– LSK cells (HSC) and CFUs 7 days after infusion with the indicated conjugates. Mice were pooled from 2 to 4 experiments; the same cohort of untreated mice was used to compare with the CD45-SAP and cKit-SAP treatment groups. (C and D) Schematic and results for syngeneic HSCT in mice conditioned with the indicated conjugates. Donor chimerism overall and by lineage (C) and CBCs (D) are displayed and were pooled from 2 to 3 experiments. (E) Secondary HSCT using whole marrow from B6-GFP→B6 primary recipients that were conditioned with the indicated ADCs, analyzed at 4 months after HSCT. The percentage of GFP+ HSCs (donor-derived HSCs from primary recipients) infused to the secondary recipients is shown; mice were pooled from 2 experiments. Data points and error bars represent mean ± SEM. Student’s t test (B, CD45-SAP), 1-way ANOVA (B, cKit-SAP), and repeated measures ANOVA (C) were used for statistical comparisons. *P < 0.05; ***P < 0.001; ****P < 0.0001.