“…We have addressed this question by assessing changes in transcriptomic profiles of HSCs and progenitors by single-cell RNA sequencing (scRNA-seq) analysis as well as genotoxicity and systemic toxicity in response to anti-mCD117 mAb -ACK2 treatment in wild-type (WT) C57BL/6N mice, as well as FA complementation group D2 knockout (FANCD2 -/-) mice -which model the disease and display a hematopoietic phenotype. While prior studies have showcased the utility of antagonistic anti-CD117 mAbs in this and other FA mouse models 13,14 , our study underscores the safety of this treatment in FA mice, both in the short and long term, with no evidence of DNA damage induction. Moreover, our investigation into potential downstream effects reveals intriguing disruptions various regulatory pathways including the MAPK pathway with downregulation of Fos, opening avenues for further exploration of antagonistic anti-mCD117 mAbs as therapeutic agents in the context of BMF and other conditions.…”
Section: Introductionmentioning
confidence: 52%
“…Subsequently, we created Venn diagrams for each cluster to investigate if genes were commonly upregulated or downregulated following antagonistic anti-mCD117 mAb treatment (supplementary figures 7-20). Interestingly, we observed across clusters that Fos was significantly downregulated 1-week after treatment in both WT and FANCD2 -/mice whereas at 24-weeks post-treatment in WT mice Fos was upregulated (supplementary figures [7][8][9][10][11][12][13][14][15][16][17][18][19][20].…”
Section: Scrna-seq Analysis Highlights the Involvement Of Mapk Pathwa...mentioning
confidence: 87%
“…Recently our laboratory conducted similar experiments to assess the conditioning capacity of antagonistic anti-mCD117 ACK2 mAb in combination with GK1.5 in FANCD2 -/animals 14 . We chose the FANCD2 -/model for these studies due to its well-established severe hematopoietic phenotype, which aligns with prior investigations.…”
Anti-CD117 monoclonal antibody (mAb) agents have emerged as exciting alternative conditioning strategies to traditional genotoxic irradiation or chemotherapy conditioning for both allogeneic and autologous gene-modified hematopoietic stem cell transplantation. Further, these agents are concurrently being explored in the treatment of mast cell disorders. Despite promising results in animal models and more recently in patients, the short-term and long-term effects of these treatments have not been fully explored. We conducted rigorous assessments to evaluate the effects of antagonistic anti-mCD117 mAb, ACK2, on hematopoiesis in wild-type (WT) and Fanconi Anemia (FA) mice. Importantly, we found no evidence of short-term DNA damage in either setting following this treatment suggesting that ACK2 does not induce immediate genotoxicity, providing crucial insights into its safety profile. Surprisingly, FA mice exhibited an increase in colony formation post-ACK2 treatment without accompanying DNA damage, indicating a potential targeting of hematopoietic stem cells (HSCs) and expansion of hematopoietic progenitor cells. Moreover, the long-term phenotypic and functional changes in hematopoietic stem and progenitor cells did not significantly differ between the ACK2-treated and control groups, in either setting, supporting that ACK2 does not adversely affect hematopoietic capacity. These finding underscore the safety of these agents when utilized as a short-course treatment in the conditioning context, as they did not induce significant changes in DNA damage amongst hematopoietic stem or progenitor cells. However, through a comparison of gene expression via single-cell RNA sequencing between untreated and treated mice, it was revealed that the ACK2 mAb, via c-Kit downregulation, effectively modulated the MAPK pathway with Fos down-regulation in WT and FA mice. Importantly, this modulation was achieved without causing prolonged disruptions. These findings validate the safety of the treatment and also enhance our understanding of its intricate mode of action at the molecular level.
“…We have addressed this question by assessing changes in transcriptomic profiles of HSCs and progenitors by single-cell RNA sequencing (scRNA-seq) analysis as well as genotoxicity and systemic toxicity in response to anti-mCD117 mAb -ACK2 treatment in wild-type (WT) C57BL/6N mice, as well as FA complementation group D2 knockout (FANCD2 -/-) mice -which model the disease and display a hematopoietic phenotype. While prior studies have showcased the utility of antagonistic anti-CD117 mAbs in this and other FA mouse models 13,14 , our study underscores the safety of this treatment in FA mice, both in the short and long term, with no evidence of DNA damage induction. Moreover, our investigation into potential downstream effects reveals intriguing disruptions various regulatory pathways including the MAPK pathway with downregulation of Fos, opening avenues for further exploration of antagonistic anti-mCD117 mAbs as therapeutic agents in the context of BMF and other conditions.…”
Section: Introductionmentioning
confidence: 52%
“…Subsequently, we created Venn diagrams for each cluster to investigate if genes were commonly upregulated or downregulated following antagonistic anti-mCD117 mAb treatment (supplementary figures 7-20). Interestingly, we observed across clusters that Fos was significantly downregulated 1-week after treatment in both WT and FANCD2 -/mice whereas at 24-weeks post-treatment in WT mice Fos was upregulated (supplementary figures [7][8][9][10][11][12][13][14][15][16][17][18][19][20].…”
Section: Scrna-seq Analysis Highlights the Involvement Of Mapk Pathwa...mentioning
confidence: 87%
“…Recently our laboratory conducted similar experiments to assess the conditioning capacity of antagonistic anti-mCD117 ACK2 mAb in combination with GK1.5 in FANCD2 -/animals 14 . We chose the FANCD2 -/model for these studies due to its well-established severe hematopoietic phenotype, which aligns with prior investigations.…”
Anti-CD117 monoclonal antibody (mAb) agents have emerged as exciting alternative conditioning strategies to traditional genotoxic irradiation or chemotherapy conditioning for both allogeneic and autologous gene-modified hematopoietic stem cell transplantation. Further, these agents are concurrently being explored in the treatment of mast cell disorders. Despite promising results in animal models and more recently in patients, the short-term and long-term effects of these treatments have not been fully explored. We conducted rigorous assessments to evaluate the effects of antagonistic anti-mCD117 mAb, ACK2, on hematopoiesis in wild-type (WT) and Fanconi Anemia (FA) mice. Importantly, we found no evidence of short-term DNA damage in either setting following this treatment suggesting that ACK2 does not induce immediate genotoxicity, providing crucial insights into its safety profile. Surprisingly, FA mice exhibited an increase in colony formation post-ACK2 treatment without accompanying DNA damage, indicating a potential targeting of hematopoietic stem cells (HSCs) and expansion of hematopoietic progenitor cells. Moreover, the long-term phenotypic and functional changes in hematopoietic stem and progenitor cells did not significantly differ between the ACK2-treated and control groups, in either setting, supporting that ACK2 does not adversely affect hematopoietic capacity. These finding underscore the safety of these agents when utilized as a short-course treatment in the conditioning context, as they did not induce significant changes in DNA damage amongst hematopoietic stem or progenitor cells. However, through a comparison of gene expression via single-cell RNA sequencing between untreated and treated mice, it was revealed that the ACK2 mAb, via c-Kit downregulation, effectively modulated the MAPK pathway with Fos down-regulation in WT and FA mice. Importantly, this modulation was achieved without causing prolonged disruptions. These findings validate the safety of the treatment and also enhance our understanding of its intricate mode of action at the molecular level.
“…A panel of antigens, including CD117, CD123, CD33, and others, are considered potential targets for HSCT conditioning. Data on an anti-CD117 antibody and an ADC were recently reported, and early clinical experience suggests that they have high potential as engraftment-facilitating agents 50,51 . Notably, monotherapy with anti-CD117 might not provide sufficient immune suppression for the engraftment of allogeneic hematopoietic cells beyond the cohort of severe combined immune deficiency patients.…”
Hematopoietic stem cell transplantation (HSCT) is widely used to treat patients with life-threatening hematologic and immune system disorders. The currently used nontargeted chemo- /radiotherapy conditioning regimens cause tissue injury and induce an array of immediate and delayed adverse effects, which limits the use of this potentially curative treatment. The growing demand to replace canonical conditioning regimens has led to the development of alternative approaches based on antibody‒drug conjugates, naked antibodies and CAR T cells. Here, we propose a preconditioning strategy based on targeting CD45 on hematopoietic cells with CAR45 T cells. To avoid fratricide of CD45 CAR T cells, targeted genomic disruption of the CD45 gene was performed in human CD45 CAR T cells in combination with dasatinib treatment. CD45DCAR45 T cells showed impressive activity in terms of target cell elimination in vitro and depletion of tumor cells in vivo or human hematopoietic cells in humanized immunodeficient mice engrafted with human blood-derived HSCs. CD45DCAR45 NK cells also exhibited potent killing activity against tumor cell lines and human hematopoietic cells. Therefore, fratricide-resistant CAR45 T and NK cells have the potential to provide the benefits of full myeloablative conditioning and therapy for hematologic malignancies. Thus, we provide the proof of concept for the generation and preclinical efficacy of CAR T cells directed against CD45-expressing cells.
“…The more patient friendly regimens under development (i.e. hematopoietic stem cell depletion of the host by treatment with anti-cKIT antibodies) 72–74 may make now this approach feasible even in IPF patients. The fact that reduced conditioning in transplanted patients with myelofibrosis, a population as fragile as that affected by IPF, gave satisfactory results supports the feasibility of transplants with this regiment in older patients 75 .…”
Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disorder with limited therapeutic options. Insufficient understanding of driver mutations and poor fidelity of currently available animal models has limited the development of effective therapies. Since GATA1deficient megakaryocytes sustain myelofibrosis, we hypothesized that they may also induce fibrosis in lungs. We discovered that lungs from IPF patients and Gata1low mice contain numerous GATA1negative immune-poised megakaryocytes that, in mice, have defective RNA-seq profiling and increased TGF-β1, CXCL1 and P-selectin content. With age, Gata1low mice develop fibrosis in lungs. Development of lung fibrosis in this model is prevented by P-selectin deletion and rescued by P-selectin, TGF-β1 or CXCL1 inhibition. Mechanistically, P-selectin inhibition decreases TGF-β1 and CXCL1 content and increases GATA1positive megakaryocytes while TGF-β1 or CXCL1 inhibition decreased CXCL1 only. In conclusion, Gata1low mice are the first genetic-driven model for IPF and provide a link between abnormal immune-megakaryocytes and lung fibrosis.
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