Targeting CD300f to enhance hematopoietic stem cell transplantation in acute myeloid leukemia
Open Access
- 14 April 2020
- journal article
- research article
- Published by American Society of Hematology in Blood Advances
- Vol. 4 (7), 1206-1216
- https://doi.org/10.1182/bloodadvances.2019001289
Abstract
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) significantly reduces the rate of relapse in acute myeloid leukemia (AML) but comes at the cost of significant treatment-related mortality. Despite the reduction in relapse overall, it remains common, especially in high-risk groups. The outcomes for patients who relapse after transplant remains very poor. A large proportion of the morbidity that prevents most patients from accessing allo-HSCT is due to toxic nonspecific conditioning agents that are required to remove recipient hematopoietic stem and progenitor cells (HSPCs), allowing for successful is donor engraftment. CD300f is expressed evenly across HSPC subtypes. CD300f has transcription and protein expression equivalent to CD33 on AML. We have developed an anti-CD300f antibody that efficiently internalizes into target cells. We have generated a highly potent anti-CD300f antibody-drug conjugate (ADC) with a pyrrolobenzodiazepine warhead that selectively depletes AML cell lines and colony forming units in vitro. The ADC synergizes with fiudarabine, making it a natural combination to use in a minimal toxicity conditioning regimen. Our ADC prolongs the survival of mice engrafted with human cell lines and depletes primary human AML engrafted with a single injection. In a humanized mouse model, a single injection of the ADC depletes CD34(+) HSPCs and CD34(+)CD38(-)CD90(+) hematopoietic stem cells. This work establishes an anti-CD300f ADC as an attractive potential therapeutic that, if validated in transplant models using a larger cohort of primary AML samples, will reduce relapse rate and toxicity for patients with AML undergoing allo-HSCT.This publication has 48 references indexed in Scilit:
- Next‐generation sequencing‐defined minimal residual disease before stem cell transplantation predicts acute myeloid leukemia relapseAmerican Journal of Hematology, 2019
- Minimal residual disease assessed with deep sequencing of NPM1 mutations predicts relapse after allogeneic stem cell transplant in AMLLeukemia & Lymphoma, 2018
- Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panelBlood, 2017
- Risk factors for relapse after allogeneic transplantation in acute myeloid leukemiaHaematologica, 2015
- Allogeneic stem cell transplantation for refractory acute myeloid leukemia: a single center analysis of long‐term outcomeEuropean Journal of Haematology, 2015
- Survival of Patients with Acute Myeloid Leukemia Relapsing after Allogeneic Hematopoietic Cell Transplantation: A Center for International Blood and Marrow Transplant Research StudyTransplantation and Cellular Therapy, 2014
- Comparison of conditioning regimens of various intensities for allogeneic hematopoietic SCT using HLA-identical sibling donors in AML and MDS with <10% BM blasts: a report from EBMTBone Marrow Transplantation, 2012
- Impact of Pretransplantation Minimal Residual Disease, As Detected by Multiparametric Flow Cytometry, on Outcome of Myeloablative Hematopoietic Cell Transplantation for Acute Myeloid LeukemiaJournal of Clinical Oncology, 2011
- Monosomal Karyotype in Acute Myeloid Leukemia: A Better Indicator of Poor Prognosis Than a Complex KaryotypeJournal of Clinical Oncology, 2008
- Immunotherapy of AML: future directionsJournal of Clinical Pathology, 2000