Breaking through the limitations of stem cell therapy and taking stock of the multiple application directions of CD117 targets

May 2, 2022/eMedClub News/--Recently, Jasper Therapeutics Inc.
(Nasdaq: JSPR), a biotechnology company focused on hematopoietic stem cell therapy, has announced the development of its CD117 monoclonal antibody product candidate JSP191.
Data on the latest efficacy, safety and pharmacokinetics from a central phase 1 clinical trial
.

▲ Image source: Jasper's official website Acute myeloid leukemia (AML) is the most common type of leukemia in adults, with a high mortality rate in the past
.

With the deepening of medical research, the treatment of AML has developed rapidly in recent years
.

However, the treatment of patients with relapsed or refractory (R/R) AML still faces enormous challenges
.

Allogeneic hematopoietic stem cell transplantation (HSCT) remains a common treatment option for AML, and only a limited number of patients are eligible
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In addition, 50%-70% of patients experience relapse after chemotherapy and HSCT, and the 5-year survival rate is 27%
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AML patients urgently need newer treatment options to overcome the limitations of HSCT
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In addition to this, clinical studies of JSP191 as a novel disease treatment for low-risk MDS patients are also scheduled to begin in 2022
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Recommended reading: mRNA-engineered hematopoietic stem cell therapy receives US$100 million in supportYimai Meng broke the news that CD117-focused monoclonal antibody JSP191 therapy JSP191 is an anti-CD117 monoclonal antibody (a targeting humanized monoclonal antibody), currently is in clinical development
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It acts as a modulator to deplete hematopoietic stem cells from the bone marrow of hematopoietic cell transplant patients, and is designed to help those patients undergoing therapeutic hematopoietic stem cell transplantation and gene therapy to replace chemotherapy/radiotherapy to address the limitations of current regulation , so as to achieve safer and more effective allogeneic hematopoietic cell transplantation therapy and gene therapy
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Clinical studies of JSP191 as a novel disease-modifying treatment for patients with low-risk MDS are also planned to begin in 2022
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CD117 is a stem cell factor (SCF) receptor expressed on the surface of hematopoietic stem and progenitor cells
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The interaction of SCF and CD117 is required for stem cell survival, and the use of JSP191 prevents SCF from binding to CD117 and disrupts key survival signals, causing stem cells to undergo a process of cell death
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This result creates an empty space in the bone marrow for donor or gene-corrected transplant cells to engraft
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Since JSP191 itself does not carry any toxic payload and does not recruit immune cells to induce an immune response, the potential for off-target toxicity is significantly reduced
.

▲ JSP191 mechanism of action (Image source: Jasper official website) The company's drug research results on JSP191 before clinical trials also showed satisfactory results: JSP191 as a single drug can safely consume SCID, sickle cell disease and myeloproliferation Hematopoietic stem cells in an animal transplantation model of abnormal syndrome (MDS)
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· JSP191 can directly deplete MDS cells from patients
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· Treatment of JSP191 created a blank space for the successful transplantation of both normal donor and gene-corrected hematopoietic stem cells involved in transplantation into the host's bone marrow
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Based on the development of hematopoietic stem cell therapy technology, the market popularity of biological products targeting CD117 has also continued to rise, attracting the attention of many research institutions and companies, and international pharmaceutical giants have deployed this promising target
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CD117-targeted therapy>>>>CD117 CAR-T Patients undergoing bone marrow transplants usually require intensive chemotherapy and sometimes intensive radiotherapy before surgery, and this preconditioning is not suitable for many patients
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Using CAR-T therapy targeting CD117, a team of scientists and doctors from the University of Zurich (UZH), the University Hospital Zurich (USZ) and the ETH Zurich Hospital (ETH Zurich) succeeded in selecting selective in animal models in May 2020 Leukemia and hematopoietic stem cells are eliminated, and mature blood cells and other tissues are preserved
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Acute myeloid leukemia (AML) is a cancer of the myeloid cell line characterized by the rapid growth of abnormal cells that accumulate in the bone marrow and blood, interfering with normal blood cell production
.

Symptoms may include feeling tired, short of breath, easy bruising and bleeding, and an increased risk of infection
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Occasionally, it may spread to the brain, skin, or gums
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As an acute leukemia, AML progresses rapidly and is often fatal within weeks or months if left untreated
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Often, the patient needs to receive intensive chemotherapy with drugs or sometimes radiation therapy, after which hematopoietic stem cells from a healthy donor are transplanted into the patient's bone marrow
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But chemotherapy and radiation not only destroy cancer cells and blood stem cells, but also affect all dividing cells, that is, nearly all tissues
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Therefore, it is not suitable for most patients
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▲ Image source: The new CAR-T cell therapy used by Nature researchers genetically modifies human immune cells to have a special receptor through which they can systematically dock only with leukemia stem cells and healthy hematopoietic stem cells and destroy it
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This creates empty space for new donor cells to be transplanted
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To prevent the genetically modified immune cells from simultaneously attacking the donor's hematopoietic stem cells, CAR-T cells are deactivated after their work is done and before transplantation by using antibodies against surface markers of CAR-T cells
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After donor stem cells are transplanted, they take up space in the bone marrow and rebuild the hematopoietic and immune systems
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Such results were obtained in laboratory cell cultures and in vivo human blood and cancer cell cultures in mice, but project leader Markus Manz believes the treatment could work in humans as well: "The principle is the same, the high Precise elimination of leukemia and hematopoietic stem cells in organisms
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” Researchers are currently investigating whether the therapy is suitable for cells other than CAR-T cells, aiming to address the limitations of current therapies, such as T-cell activating antibodies
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With the preclinical work completed, Manz sought to test the new immunotherapy in a human clinical study
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"If our method is also applicable to humans, and it can avoid the serious side effects of chemotherapy and radiotherapy, it will greatly benefit patients with acute myeloid leukemia or other hematopoietic stem cell diseases
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" >>>>CD117+HSC allogeneic Hematopoietic stem cell transplantation (allo-HSCT) is mainly used for the treatment of myelopoietic stem and progenitor cell (HS(P)C)-derived malignancies
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The success of allo-HSCT relies on 2 elements, sustained engraftment of physiologically functional replacement HSCs and co-transferred immune cells, and eradication of underlying hematological malignancies
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However, conventional HSCT conditioning regimens targeting most hematopoietic cells, including healthy and malignant HS(P)C, also produce non-hematopoietic environmental damage, resulting in transient cytopenias and non-hematopoietic toxicity
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In May 2019, Markus Manz and Norman et al.
at the University of Zurich (UZH) successfully addressed some of these challenges by using a monoclonal antibody targeting c-Kit (CD117).
Using CD117+HSCs, the researchers demonstrated Generation of HSC niche space, eradication of host malignant HS(P)C, and continued engraftment of donor HSCs
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They demonstrated that HSCs can be "niche-cleared" with a CD117-blocking anti-mouse antibody (ACK2) that allows engraftment of congenital HSCs in immunocompromised recipients
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And the researchers found that, in immunocompetent mice, a single dose of the drug combined with the CD117 antibody followed by full donor chimerism by HSCT did not impair immune function or mature blood counts
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▲ Image source: Blood commentary However, there are still some problems to be solved in this method: researchers have not yet fully discovered the precise in vivo mode of action of anti-CD117+ targeted therapy; in different clinical situations, the optimal effect of immune methods is also unknown.
In addition, the targeted toxicity of this method to other hematopoietic and non-hematopoietic cells has not been clarified, and although the toxicity of non-hematopoietic systems has not been pointed out in the reports of in vivo models, there may be species-specific expression and response differences
.

>>>>CD117 ADC US-based Magenta Therapeutics, Inc.
has developed an ADC drug targeting the CD117 receptor (MGTA-117), which aims to replace traditional non-targeted cytotoxic myeloablative drugs and expand patients scope of application
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MGTA-117 targets CD117, and the CD117 receptor is highly expressed on the surface of hematopoietic stem cells and leukemia cells, making it an ideal target for a wide range of diseases.
Great benefit
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▲ Image source: Magenta official website On April 14, 2022, Magenta announced its latest progress and disclosed the early data of the MGTA-117 Phase 1/2 target conditioning clinical trial
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The company's most important near-term clinical milestone is the study of early data from the Phase 1/2 clinical trial of MGTA-117 in multiple patients already taking the drug in Cohort 1 of the ongoing clinical trial.
The signal was positive for pharmacodynamic activity, MGTA-117 was well tolerated, and there were no reports of unexpected or major drug-related adverse events
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Recommended reading: ADC drug helps AIDS gene-editing therapy, Magenta received funding from the US National Institutes of HealthYimai Meng broke the news that Magenta is currently translating the data from this clinical trial for future use in transplant-eligible patients
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In its first-quarter 2022 earnings report scheduled for early May 2022, Magenta also plans to disclose a summary of clinical observations for these initial patients on CD117-targeted binding, drug clearance, cell depletion, and tolerability
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>>>>CD117 Gene therapyIn June 2021, Jasper Therapeutics and Aruvant announced a research collaboration to evaluate JSP191 (Jasper's anti-CD117 monoclonal antibody) and Aruvant's lentiviral gene therapy ARU for SCD (sickle cell disease) - Use of 1801 as a targeted, non-toxic modulator
.

JSP191, a potent and more tolerable modulator, could increase the number of patients treated with ARU-1801, a potential treatment for SCD, and the collaboration was designed to assess the level of action of the former
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Sickle cell disease (SCD) is an inherited blood disorder caused by mutations in the HBB gene, which gives cells the genetic instructions they need to make hemoglobin
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Hemoglobin is the protein in red blood cells that binds oxygen
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Mutations in the HBB gene can lead to incorrect production of hemoglobin
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This causes the red blood cells to take a "sickle" shape instead of the usual disc shape
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Sickle cells stick to each other, blocking blood flow -- especially in small blood vessels
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As a result, SCD can frequently cause severe pain, weakness, and other serious complications
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▲ Image credit: Aruvant's official website Gene therapy and gene editing techniques typically require the removal of a patient's own blood-forming stem cells from the bone marrow, followed by a process known as conditioning to facilitate the engraftment of new genetically modified stem cells
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Other investigational gene therapy and gene editing approaches in SCD often use high-dose chemotherapy, such as busulfan, as a conditioning regimen, which puts patients at long-term risk for infection, bleeding, secondary malignancies, and infertility
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Gene therapy through targeted modulation of CD117 can effectively reduce these risks in patients.
Based on the fact that JSP191 itself does not carry any toxic payload, nor does it recruit immune cells to induce immune responses, gene therapy methods using ARU-1801 have off-target toxicity is significantly reduced
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Recommended reading: Using CD117 monoclonal antibody as a pretreatment of gene therapy to reduce side effects and improve efficacy A potential one-time therapy that can be administered in the safest way possible
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By evaluating the use of JSP191 with ARU-1801, we are one step closer to developing a more patient-friendly next-generation definitive treatment regimen
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We believe This combination may further expand the number of patients benefiting from ARU-1801 in the future, including those likely to have more moderate disease
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" Reference: 1.
https:// 2.
https://aruvant .
com/research#sickle-cell-disease3.
https:// .
org/blood/article/133/19/2007/273811/Selective-CD117-HSC-exchange-therapy6.
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