Targeting CD300f to enhance hematopoietic stem cell transplantation in acute myeloid leukemia

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 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 fludarabine, 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.

Pan‐cancer analysis identifies CD300 molecules as potential immune regulators and promising therapeutic targets in acute myeloid leukemia

“…Several studies have reported the pathological roles of CD300s in autoimmune diseases, 21–25 but there is still insufficient data for their involvement in human cancer development. To date, transcriptional dysregulations of CD300s , especially CD300A and CD300LF , have been reported mostly in patients with hematological malignancies, such as ALL, AML, and DLBCL 26–29,53,54 . Accordingly, our analyses showed that CD300A ‐ CD300LF were remarkably overexpressed in AML both in RNA‐seq (TCGA) and microarray (GSE63270) datasets.…”

Worked to the bone: antibody-based conditioning as the future of transplant biology

“…A novel target for conditioning could be CD300f. The receptor was expressed more than CD33, the target of GO, in AML blasts, and was expressed by HSCs and progenitors [ 72 ]. The ADC showed synergism with fludarabine, an agent used in many conditioning regimens, in cytotoxicity of AML cell lines, further indicating its potential for inclusion in RIC.…”

“…In vivo studies of AML xenografted mice showed that the ADC significantly depleted bone marrow HSPCs and peripheral blood myeloid cells, leading to ADC-treated mice showing an extended survival versus untreated and isotype control. Lymphoid cells were spared as these cells do not express CD300f, which may impact the risk of rejection in a HCT model [ 72 ]. Nevertheless, CD300f seems a promising target, and further research on HCT following CD300f-ADC conditioning is needed.…”

Therapy Development by Genome Editing of Hematopoietic Stem Cells

“…The same is also true for other PIDs, where alternative conditioning has to be evaluated on an individual basis [254], and for hemoglobinopathies [255,256]. For other disorders, such as FA, efficient therapy is possible without conditioning altogether [14], while innovative, selective conditioning methods, such as cell-type-specific drug delivery targeting CD117 or CD300f, and the use of non-genotoxic agents, such as saporin, are being investigated for a range of disorders to minimize the risk of treatment-related hematopoietic malignancies [55,[257][258][259].…”