Last update 21 Mar 2024

ARHGAP45

Rho GTPase-activating protein 45

Last update 21 Mar 2024

Basic Info

Synonyms

ARHGAP45, HA-1, histocompatibility (minor) HA-1

+ [6]

Introduction

Precursor of the histocompatibility antigen HA-1. More generally, minor histocompatibility antigens (mHags) refer to immunogenic peptide which, when complexed with MHC, can generate an immune response after recognition by specific T-cells. The peptides are derived from polymorphic intracellular proteins, which are cleaved by normal pathways of antigen processing. The binding of these peptides to MHC class I or class II molecules and its expression on the cell surface can stimulate T-cell responses and thereby trigger graft rejection or graft-versus-host disease (GVHD) after hematopoietic stem cell transplantation from HLA-identical sibling donor. GVHD is a frequent complication after bone marrow transplantation (BMT), due to mismatch of minor histocompatibility antigen in HLA-matched sibling marrow transplants. Specifically, mismatching for mHag HA-1 which is recognized as immunodominant, is shown to be associated with the development of severe GVHD after HLA-identical BMT. HA-1 is presented to the cell surface by MHC class I HLA-A*0201, but also by other HLA-A alleles. This complex specifically elicits donor-cytotoxic T-lymphocyte (CTL) reactivity against hematologic malignancies after treatment by HLA-identical allogenic BMT. It induces cell recognition and lysis by CTL. Contains a GTPase activator for the Rho-type GTPases (RhoGAP) domain that would be able to negatively regulate the actin cytoskeleton as well as cell spreading. However, also contains N-terminally a BAR-domin which is able to play an autoinhibitory effect on this RhoGAP activity.

Drugs associated with ARHGAP45

TSC-100

Target

ARHGAP45

Mechanism

ARHGAP45 inhibitors [+2]

Active Org.

TScan Therapeutics, Inc.

Originator Org.

TScan Therapeutics, Inc.

Active Indication

Acute Lymphoblastic Leukemia [+3]

Inactive Indication-

Drug Highest PhasePhase 1

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

HA-1-specific T cell receptor therapy(MediGene AG)

Target

ARHGAP45

Mechanism

ARHGAP45 inhibitors [+2]

Active Org.-

Originator Org.

MediGene AG

Active Indication-

Inactive Indication

Acute Lymphoblastic Leukemia [+9]

Drug Highest PhaseDiscontinued

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

Clinical Trials associated with ARHGAP45

NCT05473910 / RecruitingPhase 1

A Controlled Multi-Arm Ph1 Study Evaluating the Safety and Feasibility of TCR Engineered Donor TCells Targeting HA1 (TSC-100) or HA2 (TSC-101) in HLA-A0201 Positive Patients Undergoing Haploidentical Allogeneic Stem Cell Transplantation

This is a multi-center, non-randomized, concurrent controlled, multi-arm, Phase 1 interventional, open-label, biologic assignment-based umbrella study evaluating the feasibility, safety and preliminary efficacy of an escalating dose regimen of up to 2 doses of TSC-100 and TSC-101 in patients with AML, MDS, or ALL following HCT from a haploidentical donor.

Start Date01 Nov 2022

Sponsor / Collaborator

TScan Therapeutics, Inc.

NL-OMON55022 / RecruitingNot Applicable

A dose-escalation, open label phase I study to assess the safety, feasibility and preliminary efficacy of HA-1H TCR modified T cells, MDG1021, in patients with relapsed or persistent hematologic malignancies after allogeneic hematological stem cell transplantation with or without unmanipulated donor lymphocyte infusion. - CD-TCR-003

Start Date18 Nov 2020

Sponsor / Collaborator

Miltenyi Biomedicine GmbHStartup

NCT04464889 / WithdrawnPhase 1

A Dose-Escalation, Open Label Phase I Study to Assess the Safety, Feasibility and Preliminary Efficacy of HA-1H TCR Modified T Cells, MDG1021, in Patients With Relapsed or Persistent Hematologic Malignancies After Allogeneic HSCT With or Without Unmanipulated DLI

This is a non-randomised, open-label phase I study of an investigational medicinal product (IMP) consisting of a HLA-A*02:01 restricted HA-1H T cell receptor transduced T cell (MDG1021) immunotherapy for relapsed or persistent hematologic malignancies after allogeneic hematopoietic stem cell transplantation. The aim of the study is to determine the recommended phase II dose of MDG1021.

Start Date02 Jul 2020

Sponsor / Collaborator

MediGene AG

100 Clinical Results associated with ARHGAP45

100 Translational Medicine associated with ARHGAP45

0 Patents (Medical) associated with ARHGAP45

Literatures (Medical) associated with ARHGAP45

10 May 2023·Aging and disease

Microglia Exhibit Distinct Heterogeneity Rather than M1/M2 Polarization within the Early Stage of Acute Ischemic Stroke.

Article

Author: Hongyu Ma ; He Li ; Yongxin Zhang ; Yu Zhou ; Hanchen Liu ; Hongye Xu ; Luojiang Zhu ; Guanghao Zhang ; Jing Wang ; Zifu Li ; Bo Hong ; Wang Zhou ; Pengfei Yang ; Jianmin Liu

The classification of microglial M1/M2 polarization in the acute phase of ischemic stroke remains controversial, which has limited further advances in neuroprotective strategy. To thoroughly assess the microglial phenotypes, we made the middle cerebral artery occlusion model in mice to simulate the acute pathological processes of ischemic stroke from normal conditions to acute cerebral ischemia and then to the early reperfusion period. The temporal changes in gene profiles, cell subtypes, and microglial function were comprehensively analyzed using single-cell RNA sequencing. We identified 37,614 microglial cells and divided them into eight distinct subpopulations. Mic_home, Mic_pre1, and Mic_pre2 subpopulations were three clusters mainly composed of cells from the control samples, in which Mic_home was a homeostatic subpopulation characterized by high expression of Hpgd and Tagap, and Mic_pre1 and Mic_pre2 were two clusters with preliminary inflammatory activation characteristics marked by P2ry13 and Wsb1 respectively. Mic_M1L1 and Mic_M1L2 subpopulations exhibited M1-like polarization manifested by the upregulation of inflammatory genes after ischemic stroke, while the intrinsic heterogeneity on the level of inflammatory responses and neurotrophic support properties was observed. Moreover, we identified three unique clusters of cells with low inflammation levels. Mic_np1, Mic_np2, and Mic_np3 were characterized by high expression of Arhgap45, Rgs10, and Pkm respectively. However, these cells did not show significant M2-like characteristics and their classic microglia function was also attenuated. These subpopulations exhibited higher activation of neuropeptide functional pathways. At last, we performed cell-cell communication analysis and identified major couplings contributing to the interaction between microglia and other cell populations. In summary, our study elucidated the temporal heterogeneity of microglia in the acute phase of ischemic stroke, which may facilitate the identification of effective neuroprotective targets to curb ischemic damage at an early stage.

20 Mar 2023·The Science of the total environment

Full-cycle greenhouse gas balance of a Sphagnum paludiculture site on former bog grassland in Germany.

Article

Author: Caroline Daun ; Vytas Huth ; Greta Gaudig ; Anke Günther ; Matthias Krebs ; Gerald Jurasinski

Growing Sphagnum on rewetted bogs (=Sphagnum paludiculture) is an alternative to drainage-based land use because it retains its value as productive land while mitigating greenhouse gas (GHG) emissions. However, studies on GHG exchange covering the full production system and cycle are missing. Here, we combined data of the establishment phase with newly recorded data of a 7-year old Sphagnum paludiculture site in Germany including partial Sphagnum harvest. GHGs were measured with closed chambers at all elements of the system (production fields, ditches, causeways). Over the full production cycle, the production fields were GHG sinks with -3.2 ± 4.2 t ha^-1 a^-1 (in CO₂-eq), while ditches represented sources emitting 13.8 ± 11.5 t ha^-1 a^-1. New measurements on the causeway indicated that it was a stronger GHG source with 29.3 ± 9.8 t ha^-1 a^-1 than previously assumed from literature values. Corrected for the area share of its elements and including the partial Sphagnum harvest (in dry mass) of ~13.8 ± 0.6 t ha^-1 (=average 7-year CO₂ emissions of 3.3 ± 0.1 t ha^-1 a^-1), the site was a GHG source of 10.7 ± 4.6 t ha^-1 a^-1, thus reducing emissions by ~20 t ha^-1 a^-1 compared to the German emission factor for grassland on drained organic soils. Per ton harvested dry biomass, the paludiculture site emitted 9.9 ± 4.6 t of CO₂-eq. The causeways were the major contributor to the warming, calling for reducing causeway area in Sphagnum paludicultures. Future 'best-practice' could realistically comprise areal shares of 80 % production fields, 5 % ditches, 15 % causeways and a full Sphagnum harvest with the uppermost 5 cm remaining on site for recovery. In this scenario the site would emit CO₂-eq emissions of 4.3 ± 1.9 t ha^-1 a^-1 or 0.9 ± 2.1 t per ton harvested dry mass.

01 Jan 2023·Frontiers in genetics

Predicting late-stage age-related macular degeneration by integrating marginally weak SNPs in GWA studies.

Article

Author: Xueping Zhou ; Jipeng Zhang ; Ying Ding ; Heng Huang ; Yanming Li ; Wei Chen

Introduction: Age-related macular degeneration (AMD) is a progressive neurodegenerative disease and the leading cause of blindness in developed countries. Current genome-wide association studies (GWAS) for late-stage age-related macular degeneration are mainly single-marker-based approaches, which investigate one Single-Nucleotide Polymorphism (SNP) at a time and postpone the integration of inter-marker Linkage-disequilibrium (LD) information in the downstream fine mappings. Recent studies showed that directly incorporating inter-marker connection/correlation into variants detection can help discover novel marginally weak single-nucleotide polymorphisms, which are often missed in conventional genome-wide association studies, and can also help improve disease prediction accuracy. Methods: Single-marker analysis is performed first to detect marginally strong single-nucleotide polymorphisms. Then the whole-genome linkage-disequilibrium spectrum is explored and used to search for high-linkage-disequilibrium connected single-nucleotide polymorphism clusters for each strong single-nucleotide polymorphism detected. Marginally weak single-nucleotide polymorphisms are selected via a joint linear discriminant model with the detected single-nucleotide polymorphism clusters. Prediction is made based on the selected strong and weak single-nucleotide polymorphisms. Results: Several previously identified late-stage age-related macular degeneration susceptibility genes, for example, BTBD16, C3, CFH, CFHR3, HTARA1, are confirmed. Novel genes DENND1B, PLK5, ARHGAP45, and BAG6 are discovered as marginally weak signals. Overall prediction accuracy of 76.8% and 73.2% was achieved with and without the inclusion of the identified marginally weak signals, respectively. Conclusion: Marginally weak single-nucleotide polymorphisms, detected from integrating inter-marker linkage-disequilibrium information, may have strong predictive effects on age-related macular degeneration. Detecting and integrating such marginally weak signals can help with a better understanding of the underlying disease-development mechanisms for age-related macular degeneration and more accurate prognostics.

News (Medical) associated with ARHGAP45

01 Mar 2023

·www.globenewswire.com

BlueSphere Bio to Present at the Next Generation CAR & T Cell Therapies Conference

PITTSBURGH, Pa., March 01, 2023 (GLOBE NEWSWIRE) -- BlueSphere Bio, a T-cell receptor (TCR) T-cell therapy company developing a powerful TCR discovery platform and novel therapeutic candidates for patients with hematologic malignancies and solid tumors, today announced Robert Keefe, Ph.D., Chief Development Officer of BlueSphere Bio, will present an overview of the Company’s anticipated first in human clinical candidate, BSB-1001, and its discovery using the TCXpress™ platform at the Next Generation CAR & T Cell Therapies Conference held in San Diego, CA from February 27 – March 3, 2023. BSB-1001, targeting the minor histocompatibility antigen-1 (HA-1) and part of BlueSphere’s TCX-101 Program, is the first TCR-based clinical candidate generated using TCXpress and is in development for the treatment of acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL) and myeloid dysplastic syndrome (MDS) in conjunction with allogeneic hematopoietic stem cell transplantation (alloSCT). BlueSphere anticipates filing its first Investigational New Drug Application (IND) for BSB-1001 in 2023. Presentation details:Title: A Powerful Platform to Find TCRs to Defined Targets: Applications in Allogeneic Stem Cell TransplantationDate: Thursday, March 2, 2023Time: 11:30 a.m. – 12:00 p.m. PSTLocation: San Diego Convention Center For more information about the Next Generation CAR & T Cell Therapies Conference, please refer to the conference website at https://informaconnect.com/car-t/. About BlueSphere Bio BlueSphere Bio is the first translational sciences stand-alone company formed by UPMC Enterprises, the innovation, commercialization, and venture capital arm of the Pittsburgh-based health system. The Company was founded upon the unique, advanced TCR discovery platform – TCXpress™, designed to isolate and functionally characterize TCRs with speed and efficiency. This platform can be used in various clinical settings to discover TCRs for use in either TCR-based cell therapy or in antibody-like molecules, such as bi-specific T cell engagers. While the Company’s initial focus is oncology, the platform could be deployed in other therapeutic areas, such as auto-immunity. BSB-1001, targeting the minor histocompatibility antigen-1 (HA-1) and part of BlueSphere’s TCX-101 Program, is the first TCR-based clinical candidate generated using TCXpress and is in development for the treatment of acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL) and myeloid dysplastic syndrome (MDS) in conjunction with allogeneic hematopoietic stem cell transplantation (alloSCT). BlueSphere anticipates filing its first IND application for BSB-1001 in 2023. In addition, the TCXpress platform has enabled the discovery of several new TCRs reactive against other clinically relevant miHAs, which will become part of the TCX-101 Program as a panel that positions the Company with best-in-class population coverage in these indications. In addition to TCX-101, BlueSphere is currently identifying a broad panel of TCRs to deploy in its first solid tumor program, which will be announced later this year. Concurrent with its use for shared antigens, BlueSphere is deploying TCXpress™ and NEOXpress™, a proprietary patient-specific neoantigen discovery platform, to develop its TCX-201 Program, which aims to identify TCRs reactive against patient-specific neoantigens. The Company anticipates virtual patient data from multiple solid tumor types this year. Company ContactKim JaffeSenior Vice President, Head of Business Development & Strategy+1- 609-306-7042kjaffe@bluespherebio.com Media ContactAndrew MielachLifeSci Communications+1-646-876-5868amielach@lifescicomms.com

Cell TherapyINDImmunotherapyClinical Study

06 Feb 2023

·www.globenewswire.com

BlueSphere Bio to Present at the 25th Annual BIO CEO & Investor Conference

PITTSBURGH, Feb. 06, 2023 (GLOBE NEWSWIRE) -- BlueSphere Bio, a T-cell receptor (TCR) T-cell therapy company developing a powerful TCR discovery platform and novel therapeutic candidates for patients with hematologic malignancies and solid tumors, today announced Keir Loiacono, Chief Executive Officer of BlueSphere Bio, will present a corporate overview at the 2023 BIO CEO & Investor Conference held in New York City, NY from February 6-9, 2023. The in-person presentation will highlight the Company’s first and lead product candidate, BSB-1001, currently being developed for the treatment of acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL) and myeloid dysplastic syndrome (MDS) in conjunction with allogeneic hematopoietic stem cell transplantation (alloSCT). The Company anticipates filing its first investigational new drug application later this year. Presentation details:Date: Tuesday, February 7, 2023Time: 10:30 a.m. ETLocation: Marriott Marquis Times Square For more information about the BIO CEO & Investor Conference, please refer to the conference website at www.bio.org/events/bio-ceo-investor-conference. About BlueSphere Bio BlueSphere Bio is the first translational sciences stand-alone company formed by UPMC Enterprises, the innovation, commercialization, and venture capital arm of the Pittsburgh-based health system. The Company was founded upon the unique, advanced TCR discovery platform – TCXpress™, designed to isolate and functionally characterize TCRs with speed and efficiency. This platform can be used in various clinical settings to discover TCRs for use in either TCR-based cell therapy or in antibody-like molecules, such as bi-specific T cell engagers. While the Company’s initial focus is oncology, the platform could be deployed in other therapeutic areas, such as auto-immunity. BSB-1001, targeting the minor histocompatibility antigen-1 (HA-1) and part of BlueSphere’s TCX-101 Program, is the first TCR-T cell therapy candidate generated using TCXpress and is in development for the treatment of acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL) and myeloid dysplastic syndrome (MDS) in conjunction with allogeneic hematopoietic stem cell transplantation (alloSCT). BlueSphere anticipates filing its first IND application for BSB-1001 in 2023. In addition, the TCXpress platform has enabled the discovery of several new TCRs reactive against other clinically relevant miHAs, which will become part of the TCX-101 Program as a panel that positions the Company with best-in-class population coverage in these indications. In addition to TCX-101, BlueSphere is currently identifying a broad panel of TCRs to deploy in its first solid tumor program, which will be announced later this year. Concurrent with its use for shared antigens, BlueSphere is deploying TCXpress™ and NEOXpress™, a proprietary patient-specific neoantigen discovery platform, to develop its TCX-201 Program, which aims to identify TCRs reactive against patient-specific neoantigens. The Company anticipates virtual patient data from multiple solid tumor types this year. Company ContactKim JaffeSenior Vice President, Head of Business Development & Strategy+1- 609-306-7042kjaffe@bluespherebio.com Media ContactAndrew MielachLifeSci Communications+1-646-876-5868amielach@lifescicomms.com

Cell TherapyImmunotherapyIND

30 Jan 2023

·www.biospace.com

BlueSphere Bio Appoints Erkut Bahceci, M.D., as Chief Medical Officer

Dr. Bahceci brings more than two decades of combined clinical and drug development experience PITTSBURGH, Pa., Jan. 30, 2023 (GLOBE NEWSWIRE) -- BlueSphere Bio, a T-cell receptor (TCR) T-cell therapy company developing a powerful TCR discovery platform and novel therapeutic candidates for patients with hematologic malignancies and solid tumors, today announced the appointment of Erkut Bahceci, M.D., as Chief Medical Officer. “Dr. Bahceci has a wide breadth of experience in clinical trial design across all stages of development that will prove to be invaluable as we approach our entrance into the clinic with BSB-1001, the first candidate from our TCX-101 Program, later this year,” said Keir Loiacono, Chief Executive Officer of BlueSphere Bio. “Beyond industry experience, Dr. Bahceci has a deep understanding of the needs of patients and the treatment landscape from his years as a clinician, focused on allogeneic stem cell transplants.” BSB-1001 is the first TCR-T cell therapy candidate generated using the Company’s TCXpress™ platform and is in development for the treatment of acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL) and myeloid dysplastic syndrome (MDS) in conjunction with allogeneic hematopoietic stem cell transplantation (alloSCT). BSB-1001 targets the minor histocompatibility antigen-1 (HA-1), whose expression is largely limited to hematopoietic cells. Dr. Bahceci added, “This is an incredibly exciting time to join BlueSphere Bio. Despite the effectiveness of allogeneic stem cell transplants for a broad range of hematological malignancies, a significant number of patients relapse. BSB-1001 is designed to provide durable remission by eradicating residual cancer cells after transplant and could potentially transform the treatment landscape. As a part of the broader TCX-101 Program, which aims to provide best-in-class population coverage in these indications, BSB-1001 represents only a fraction of TCXpress’s potential to provide new therapeutics for a broad range of cancers and I look forward to working closely with the team to help realize the promise of TCR T-cell therapies for treating patients.” Dr. Bahceci holds more than 20 years of combined clinical and drug development experience. Most recently, he served as the Senior Vice President and Head of Oncology Development at Takeda Pharmaceuticals. Prior to Takeda, he worked at Astellas in roles of increasing responsibility up to the Head of Clinical Science, Hematologic Malignancies. While at Astellas, he led the development of gilteritinib from first-in-human studies to worldwide approval in relapsed or refractory AML. Before joining Astellas, he worked at Bristol-Myers-Squib, leading the U.S. team for dasatinib. He began his career in the pharmaceutical industry at Bayer, where he served as Associate Director of Medical Sciences-Oncology. Dr. Bahceci received his M.D. degree from Marmara University in Istanbul, Turkey and conducted his residency training in Internal Medicine at Mercy Hospital in Chicago and National Heart Lung and Blood Institute, National Institutes of Health in Bethesda, Maryland, followed by fellowship in Hematology and Oncology at National Heart Lung and Blood Institute. He was appointed to the faculty of the Yale University School of Medicine in 2000, where he performed allogeneic and autologous stem cell transplants and conducted research on immunotherapy, including chimeric activating receptor (CAR) T cell therapy, until 2007. About BlueSphere Bio BlueSphere Bio is the first translational sciences stand-alone company formed by UPMC Enterprises, the innovation, commercialization, and venture capital arm of the Pittsburgh-based health system. The Company was founded upon the unique, advanced TCR discovery platform – TCXpress™, designed to isolate and functionally characterize TCRs with speed and efficiency. This platform can be used in various clinical settings to discover TCRs for use in either TCR-based cell therapy or in antibody-like molecules, such as bi-specific T cell engagers. While the Company’s initial focus is oncology, the platform could be deployed in other therapeutic areas, such as auto-immunity. BSB-1001, targeting the minor histocompatibility antigen-1 (HA-1) and part of BlueSphere’s TCX-101 Program, is the first TCR-T cell therapy candidate generated using TCXpress and is in development for the treatment of acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL) and myeloid dysplastic syndrome (MDS) in conjunction with allogeneic hematopoietic stem cell transplantation (alloSCT). BlueSphere anticipates filing its first IND application for BSB-1001 in 2023. In addition, the TCXpress platform has enabled the discovery of several new TCRs reactive against other clinically relevant miHAs, which will become part of the TCX-101 Program as a panel that positions the Company with best-in-class population coverage in these indications. In addition to TCX-101, BlueSphere is currently identifying a broad panel of TCRs to deploy in its first solid tumor program, which will be announced later this year. Concurrent with its use for shared antigens, BlueSphere is deploying TCXpress™ and NEOXpress™, a proprietary patient-specific neoantigen discovery platform, to develop its TCX-201 Program, which aims to identify TCRs reactive against patient-specific neoantigens. The Company anticipates virtual patient data from multiple solid tumor types this year. Company Contact Kim Jaffe Senior Vice President, Head of Business Development & Strategy +1- 609-306-7042 kjaffe@bluespherebio.com Media Contact Andrew Mielach LifeSci Communications +1-646-876-5868 amielach@lifescicomms.com

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ARHGAP45

Rho GTPase-activating protein 45

Basic Info

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