BIO 5192 / Biogen - LARVOL DELTA

Noncoding GATA2 Genetic Variation As a Determinant of Hematopoietic Stem/Progenitor Cell Activity and Mobilization Efficiency (ASH 2023) - "We tested whether Gata2 variation impairs mobilization in response to different stimuli, or if select pathways are impacted via disrupting the CXCR4/CXCL12 chemokine axis with the CXCR4 antagonist plerixafor, stromal/neutrophil CXCR2 activation with rhIL-8, or VLA-4/VCAM1 binding with VLA-4 inhibitor BIO5192. Our mobilization-defective system offers unique utility for elucidating fundamental HSPC mechanisms e.g., in the context of additional environmental and/or genetic insults. Future knowledge linking functionality of mobilization regimens in these contexts may unveil insights into mechanisms operational in poor mobilizers."

Aplastic Anemia • Bone Marrow Transplantation • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • Transplantation • CD34 • CD48 • CXCL12 • CXCL8 • CXCR2 • GATA2 • VCAM1

Unconventional design of mobilizer-resistant CXCR4 variants to enable chemotherapy-free conditioning in Hematopoietic Stem Cell Gene Therapy (ESGCT 2024) - "Previously, we demonstrated that using combinations of mobilizing agents such as G-CSF, AMD3100, and BIO5192 creates a window of opportunity for the seamless engraftment of corrected cells. We are now combining AMD3100-resistant CXCR4 variants with other engraftment enhancers to generate a potential synergistic effect. Our results have the potential to transform HSCT into a safer, more widely applicable therapy, extending its benefits to a broader demographic and diverse healthcare settings."

Gene therapy • Bone Marrow Transplantation • Gene Therapies • Immunology • Primary Immunodeficiency • CXCL12 • CXCR4

OVERCOMING TOXIC CONDITIONING IN HEMATOPOIETIC STEM CELL THERAPY LEVERAGING MOBILIZATION-RESISTANT CXCR4 VARIANTS (EHA 2025) - "Previously, we demonstrated that using mobilizing agents such as G-CSF, AMD3100 (plerixafor), and BIO5192 creates a window of opportunity by transiently depleting bone marrow niches, thus enabling the seamless engraftment of genetically corrected cells. Our work seeks to eliminate the need for toxic conditioning regimens in HSPC-GT, opening the door to safer, more effective therapies. By extending the infusion window, our approach could potentially enable simultaneous conditioning and transplantation, transforming hematopoietic stem cell therapy into a safer, more widely applicable treatment."

Bone Marrow Transplantation • Gene Therapies • Immunology • Primary Immunodeficiency • CD34 • CXCL12 • CXCR4

INCREASING THE EFFICACY OF NON-GENOTOXIC CONDITIONING REGIMENS IN DISTINCT IMMUNODEFICIENCIES (ID 1164) (ESID 2024) - "Methods We assessed the depletion activity, engraftment and immune reconstitution achieved by anti-CD45-mAb conjugated with saporin (CD45-SAP) combined with a low dose of Treosulfan/Fludarabine (Treo/Flu) in: Rag1- KO mice (T-B-SCID model), Rag1-F971L mice (recapitulating CID with granulomas and autoimmunity), and Wiskott-Aldrich Syndrome ( Was )- KO mice. To overcome the use of chemotherapy, a mobilization-based protocol including G-CSF, AMD3100 and Bio5192 (G7AB) was tested in Rag1-KO mice...Conclusions Antibody-based conditioning combined with low doses of chemotherapy represents a valuable alternative to genotoxic regimens, eventually broadening HSCT access to more patients and diseases. Interestingly, preliminary data on the use of a mobilization-based protocol encourage further studies to assess its therapeutical potential in immunodeficiencies."

Clinical • Immunology • Primary Immunodeficiency • RAG1

G-CSF-Free HSC Mobilization with WU-106/AMD3100 Allows for Safe and Efficient In Vivo HSC Transduction and In Vivo Prime Editing of the Sickle Cell Disease Mutation in a Mouse Model (ASGCT 2023) - "Recently, we developed a simpler, rapid, and more HSC-selective mobilization regimen using truncated GRO-β (MGTA-145), a CXCR2 agonist, and plerixafor/AMD3100...Among the alternative G-CSF-free mobilization protocols is also plerixafor plus small molecule VLA4 antagonists, such as BIO5192 or its improved derivatives (e.g. WU-106)...Analysis of the percentage of βS versus βA globin in erythrocytes and phenotypic correction in primary mice (spleen size, histology, blood smears) will be reported. These first data indicate that HSC in vivo gene therapy using the new mobilization approach is safer than GSCF/AMD3100, can be done on one day, and can achieve therapeutically relevant correction levels of the SCD mutation in a relevant mouse model."

Preclinical • Beta-Thalassemia • Gene Therapies • Genetic Disorders • Hematological Disorders • Sickle Cell Disease • Transplantation • CD46 • CXCR2 • CXCR4 • IFNG • IL6 • KIT

Mobilization-Based Chemotherapy-Free Conditioning for Hematopoietic Stem and Progenitor Cells Gene Therapy in the Non-Human Primate Model (ASGCT 2023) - "However, the chemo/radiotherapy-based conditioning procedures currently used in clinics may have severe acute and long-term side effects.To overcome this limitation and advance toward a chemotherapy-free non-genotoxic conditioning regimen, we previously reported that HSPC mobilization with G-CSF, AMD3100, and BIO5192, efficiently depletes the BM niche, creating a window of opportunity for the engraftment of ex vivo-cultured cells in a human hematochimeric mouse model. Our current results in this model are consistent with observations in human cells, showing that CXCR4 expression is rescued during ex vivo culture of NHP HSPC harvested by G-CSF and AMD3100 mediated mobilization and transient overexpression of this molecule increases SDF-1 dependent migration efficiency in in vitro assays. Moreover, we show that base editing at the CD33 locus and CXCR4 overexpression can be combined without impacting the efficiency of each procedure, conferring edited cells a migration..."

Gene therapy • Preclinical • Gene Therapies • Oncology • Transplantation • CD33 • CXCL12 • ITGA4

Investigating cytoskeletal and adhesion dynamics associated with dementia risk factors arising from toxin exposures and seizure-related neuronal activity (Neuroscience 2022) - "Note that Pxn-mediated synaptopathy was not evident when the insult was applied after brain explants were treated with the β1 integrin inhibitor BIO 5192, thus supporting the idea that integrin responses play a role in governing synaptic vulnerability and toxicity. These comparative assessments indicate that while OP toxin exposures and other military-related vulnerabilities have been linked to an increase in dementia risk later in life, disparate impacts on cytoskeletal and adhesion chemistries in the brain are evident among the different risk factors."

Clinical • Alzheimer's Disease • CNS Disorders • Dementia • Epilepsy

Development of New Potential Inhibitors of β1 Integrins through In Silico Methods-Screening and Computational Validation. (PubMed, Life (Basel)) - "Furthermore, the significance of retaining the pyrrolidine core of the ligand and increasing the therapeutic potential of the new compounds is emphasized. Finally, one novel molecule (1592) was identified as a potential drug candidate, with appropriate pharmacokinetic profiles, similar dynamic behavior at the integrin interaction site compared with BIO5192, and a higher predicted affinity to VLA-4."

Journal

Modulated integrin signaling plays a role in anticholinesterase-induced synaptopathy in hippocampal explants (Neuroscience 2021) - "Here, hippocampal tissue cultures were exposed to the OP toxin paraoxon (Pxn) to decipher if the evident synaptic vulnerability is influenced by integrins, using the β1-integrin inhibitor (BIO 5192)...Additionally, the synaptic compromise observed in Pxn-exposed explants was not exhibited after the application of the β1-integrininhibitor, suggesting that blocking β1 integrin signaling appears to attenuate the unique synaptotoxicity mediated by Pxn. These findings postulate that integrins can respond to excitotoxic insults and induce distinct cell signaling that influences synaptic integrity and maintece.; Grant Support: ARO W911NF-15-1-0432; NIH 5R25GM077634"

CNS Disorders • Epilepsy • NCAM1

Bone marrow-derived mesenchymal stem cells propagate immunosuppressive/anti-inflammatory macrophages in cell-to-cell contact-independent and -dependent manners under hypoxic culture. (PubMed, Exp Cell Res) - "Intriguingly, an inhibitor for intercellular adhesion molecule (ICAM)-1 receptor/lymphocyte function-associated antigen (LFA)-1, Rwj50271, partially suppressed expression of CD206 in the Lin+ blood cells but an inhibitor for VCAM-1 receptor/VLA-4, BIO5192, did not, suggesting that the cell-to-cell adhesion through LFA-1 on pre-M2-Mφs and ICAM-1 on MSCs was supposed to promoted the M2-Mφ polarization. Thus, the co-culture system consisting of bone marrow-derived Lin+ blood cells and MSCs under hypoxic condition was a beneficial supplier of a number of M2-Mφs, which could be clinically applicable to inflammatory diseases."

Journal • Biosimilar

Targeting CXCR4, VLA4, and CXCR2 for Hematopoietic Stem Cell Mobilization (ASH 2019) - "Two examples of previously described drugs that target mechanisms of stem cell retention are Plerixafor (a CXCR4 inhibitor already in clinical use), and truncated Gro-Beta (tGroβ; a CXCR2 agonist). Firetagrast and BIO5192 are previously characterized VLA4i that have been administered to humans for indications unrelated to HSC mobilization. Our best VLA4i to date, LGB-2019, exhibited similar potency as BIO5192 in preventing the binding of sVCAM-1 to VLA-4 (IC50: 1.7nM) and was >200-fold more potent than firategrast. LGB-2019 showed increased aqueous solubility and mobilized 1.5-fold more murine LSK cells for a longer time period (peak HSC mobilization maintained for 4 hours) than BIO5192 when administered alone."

CXCR2 • CXCR4

Early synaptopathology in organophosphate-exposed hippocampal explants is governed by neuron-specific β1 integrin responses (Neuroscience 2019) - "...When the β1 integrin was blocked in hippocampal slices with the highly potent α4β1 inhibitor BIO 5192, the tissue exhibited enhanced vulnerability to paraoxon...These findings suggest that anticholinesterase toxins mediate distinct synaptic damage, and the integrin signaling pathway plays an important compensatory role. Synaptic compromise in the hippocampus can be detrimental to many brain functions and integrin-linked responses activated by toxic insults appear to govern the extent of the synaptotoxicity."