Most antibody-based treatments for myeloid malignancies, including AML, result in myelotoxicity due to sharing of target antigens by human hematopoietic stem and progenitor cells (HSPCs). To shield HSPCs, Marone, Landmann, Devaux, and Lepore et al. engineered CD123 (IL-3Rα) variants with a single aa substitution in a mAb epitope. The variants were structurally and functionally similar to wtCD123, but were resistant to mAb-targeted ADCC, Ab–drug conjugates and CAR T cell therapy. Transplanted into mice, epitope-engineered HSPCs engrafted with long-term reconstitution potential, suggesting this approach could enable targeted immunotherapy while rebuilding a functional hematopoietic system.
Contributed by Katherine Turner
ABSTRACT: Targeted eradication of transformed or otherwise dysregulated cells using monoclonal antibodies (mAb), antibody-drug conjugates (ADC), T cell engagers (TCE), or chimeric antigen receptor (CAR) cells is very effective for hematologic diseases. Unlike the breakthrough progress achieved for B cell malignancies, there is a pressing need to find suitable antigens for myeloid malignancies. CD123, the interleukin-3 (IL-3) receptor alpha-chain, is highly expressed in various hematological malignancies, including acute myeloid leukemia (AML). However, shared CD123 expression on healthy hematopoietic stem and progenitor cells (HSPCs) bears the risk for myelotoxicity. We demonstrate that epitope-engineered HSPCs were shielded from CD123-targeted immunotherapy but remained functional, while CD123-deficient HSPCs displayed a competitive disadvantage. Transplantation of genome-edited HSPCs could enable tumor-selective targeted immunotherapy while rebuilding a fully functional hematopoietic system. We envision that this approach is broadly applicable to other targets and cells, could render hitherto undruggable targets accessible to immunotherapy, and will allow continued posttransplant therapy, for instance, to treat minimal residual disease (MRD).
Author Info: (1) Department of Biomedicine, Basel University Hospital and University of Basel, Basel, Switzerland. ROR: https://ror.org/02s6k3f65 Transplantation Immunology and Nephrology, Base
Author Info: (1) Department of Biomedicine, Basel University Hospital and University of Basel, Basel, Switzerland. ROR: https://ror.org/02s6k3f65 Transplantation Immunology and Nephrology, Basel University Hospital, Basel, Switzerland. ROR: https://ror.org/04k51q396 (2) Department of Biomedicine, Basel University Hospital and University of Basel, Basel, Switzerland. ROR: https://ror.org/02s6k3f65 Transplantation Immunology and Nephrology, Basel University Hospital, Basel, Switzerland. ROR: https://ror.org/04k51q396 (3) Department of Biomedicine, Basel University Hospital and University of Basel, Basel, Switzerland. ROR: https://ror.org/02s6k3f65 Transplantation Immunology and Nephrology, Basel University Hospital, Basel, Switzerland. ROR: https://ror.org/04k51q396 (4) Department of Biomedicine, Basel University Hospital and University of Basel, Basel, Switzerland. ROR: https://ror.org/02s6k3f65 Transplantation Immunology and Nephrology, Basel University Hospital, Basel, Switzerland. ROR: https://ror.org/04k51q396 Cimeio Therapeutics AG , Basel, Switzerland. Ridgeline Discovery GmbH , Basel, Switzerland. (5) Department of Biomedicine, Basel University Hospital and University of Basel, Basel, Switzerland. ROR: https://ror.org/02s6k3f65 Transplantation Immunology and Nephrology, Basel University Hospital, Basel, Switzerland. ROR: https://ror.org/04k51q396 (6) Department of Biomedicine, Basel University Hospital and University of Basel, Basel, Switzerland. ROR: https://ror.org/02s6k3f65 Transplantation Immunology and Nephrology, Basel University Hospital, Basel, Switzerland. ROR: https://ror.org/04k51q396 (7) Department of Biomedicine, Basel University Hospital and University of Basel, Basel, Switzerland. ROR: https://ror.org/02s6k3f65 Transplantation Immunology and Nephrology, Basel University Hospital, Basel, Switzerland. ROR: https://ror.org/04k51q396 (8) Department of Biomedicine, Basel University Hospital and University of Basel, Basel, Switzerland. ROR: https://ror.org/02s6k3f65 Transplantation Immunology and Nephrology, Basel University Hospital, Basel, Switzerland. ROR: https://ror.org/04k51q396 (9) Department of Biomedicine, Basel University Hospital and University of Basel, Basel, Switzerland. ROR: https://ror.org/02s6k3f65 Transplantation Immunology and Nephrology, Basel University Hospital, Basel, Switzerland. ROR: https://ror.org/04k51q396 (10) Department of Biomedicine, Basel University Hospital and University of Basel, Basel, Switzerland. ROR: https://ror.org/02s6k3f65 Transplantation Immunology and Nephrology, Basel University Hospital, Basel, Switzerland. ROR: https://ror.org/04k51q396 (11) Translational Research Centre in Onco-Hematology, Faculty of Medicine, University of Geneva, and Swiss Cancer Center Leman, Geneva, Switzerland. ROR: https://ror.org/01swzsf04 (12) Division of Hematology, Department of Oncology, Geneva University Hospitals, Geneva, Switzerland. Department of Medicine, Translational Research Center for Onco-Hematology, Faculty of Medicine, University of Geneva, Geneva, Switzerland. ROR: https://ror.org/01swzsf04 (13) Institute for Transfusion Medicine and Gene Therapy, Medical Center - University of Freiburg , Freiburg, Germany. ROR: https://ror.org/0245cg223 Center for Chronic Immunodeficiency, Faculty of Medicine, University of Freiburg, Freiburg, Germany. ROR: https://ror.org/0245cg223 (14) Institute for Transfusion Medicine and Gene Therapy, Medical Center - University of Freiburg , Freiburg, Germany. ROR: https://ror.org/0245cg223 Center for Chronic Immunodeficiency, Faculty of Medicine, University of Freiburg, Freiburg, Germany. ROR: https://ror.org/0245cg223 (15) Institute of Medical Bioinformatics and Systems Medicine, Medical Center-University of Freiburg , Freiburg, Germany. ROR: https://ror.org/0245cg223 (16) Department of Biology, Institute of Molecular Health Sciences, ETH Zrich, Zrich, Switzerland. ROR: https://ror.org/05a28rw58 (17) Department of Biology, Institute of Molecular Health Sciences, ETH Zrich, Zrich, Switzerland. ROR: https://ror.org/05a28rw58 (18) Ridgeline Discovery GmbH , Basel, Switzerland. (19) Ridgeline Discovery GmbH , Basel, Switzerland. (20) Cimeio Therapeutics AG , Basel, Switzerland. (21) Ridgeline Discovery GmbH , Basel, Switzerland. (22) Cimeio Therapeutics AG , Basel, Switzerland. (23) Ridgeline Discovery GmbH , Basel, Switzerland. (24) Cimeio Therapeutics AG , Basel, Switzerland. (25) Department of Pediatrics, School of Medicine, Stanford University, Stanford, CA, USA. (26) Biozentrum, University of Basel , Basel, Switzerland. ROR: https://ror.org/02s6k3f65 SIB Swiss Institute of Bioinformatics , Basel, Switzerland. (27) Biozentrum, University of Basel , Basel, Switzerland. ROR: https://ror.org/02s6k3f65 SIB Swiss Institute of Bioinformatics , Basel, Switzerland. (28) Department of Pediatrics, School of Medicine, Stanford University, Stanford, CA, USA. (29) Department of Medicine, Translational Research Center for Onco-Hematology, Faculty of Medicine, University of Geneva, Geneva, Switzerland. ROR: https://ror.org/01swzsf04 (30) Department of Biology, Institute of Molecular Health Sciences, ETH Zrich, Zrich, Switzerland. ROR: https://ror.org/05a28rw58 (31) Institute for Transfusion Medicine and Gene Therapy, Medical Center - University of Freiburg , Freiburg, Germany. ROR: https://ror.org/0245cg223 Center for Chronic Immunodeficiency, Faculty of Medicine, University of Freiburg, Freiburg, Germany. ROR: https://ror.org/0245cg223 (32) Institute for Transfusion Medicine and Gene Therapy, Medical Center - University of Freiburg , Freiburg, Germany. ROR: https://ror.org/0245cg223 Center for Chronic Immunodeficiency, Faculty of Medicine, University of Freiburg, Freiburg, Germany. ROR: https://ror.org/0245cg223 (33) Cimeio Therapeutics AG , Basel, Switzerland. Ridgeline Discovery GmbH , Basel, Switzerland. (34) Department of Biomedicine, Basel University Hospital and University of Basel, Basel, Switzerland. ROR: https://ror.org/02s6k3f65 Transplantation Immunology and Nephrology, Basel University Hospital, Basel, Switzerland. ROR: https://ror.org/04k51q396
