CCR5 Receptor Occupancy Analysis Reveals Increased Peripheral Blood CCR5+CD4+ T Cells Following Treatment With the Anti-CCR5 Antibody Leronlimab
| العنوان: | CCR5 Receptor Occupancy Analysis Reveals Increased Peripheral Blood CCR5+CD4+ T Cells Following Treatment With the Anti-CCR5 Antibody Leronlimab |
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| المؤلفون: | Joseph Hwang, Andrew W. Sylwester, Meenakshi Tiwary, Rachele M. Bochart, Gabriela M. Webb, Courtney Waytashek, Colette M. Hughes, Scott Kelly, Xiao L. Chang, Jason S. Reed, Carla Boyle, Scott G. Hansen, Miranda Fischer, Jeremy Smedley, Helen L. Wu, Nader Pourhassan, Cleiton Pessoa, Jonah B. Sacha, Christopher P. Recknor, David Morrow, Karina Belica |
| المصدر: | Frontiers in Immunology, Vol 12 (2021) Frontiers in Immunology |
| بيانات النشر: | Frontiers Media S.A., 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | CD4-Positive T-Lymphocytes, Primates, Receptors, CCR5, Chemokine receptor CCR5, T cell, viruses, Cell, Immunology, Simian Acquired Immunodeficiency Syndrome, Viremia, HIV Infections, Pharmacology, HIV Antibodies, Antibodies, Monoclonal, Humanized, Flow cytometry, In vivo, antibody, medicine, Immunology and Allergy, Animals, Humans, Original Research, medicine.diagnostic_test, biology, Chemistry, SARS-CoV-2, flow cytometry, virus diseases, HIV, RC581-607, medicine.disease, CD4, CD4 Lymphocyte Count, COVID-19 Drug Treatment, medicine.anatomical_structure, Treatment Outcome, Viral replication, receptor occupancy (RO), biology.protein, HIV-1, Female, Simian Immunodeficiency Virus, Antibody, Immunologic diseases. Allergy, CCR5, Protein Binding |
| الوصف: | CCR5 plays a central role in infectious disease, host defense, and cancer progression, thereby making it an ideal target for therapeutic development. Notably, CCR5 is the major HIV entry co-receptor, where its surface density correlates with HIV plasma viremia. The level of CCR5 receptor occupancy (RO) achieved by a CCR5-targeting therapeutic is therefore a critical predictor of its efficacy. However, current methods to measure CCR5 RO lack sensitivity, resulting in high background and overcalculation. Here, we report on two independent, flow cytometric methods of calculating CCR5 RO using the anti-CCR5 antibody, Leronlimab. We show that both methods led to comparable CCR5 RO values, with low background on untreated CCR5+CD4+ T cells and sensitive measurements of occupancy on both blood and tissue-resident CD4+ T cells that correlated longitudinally with plasma concentrations in Leronlimab-treated macaques. Using these assays, we found that Leronlimab stabilized cell surface CCR5, leading to an increase in the levels of circulating and tissue-resident CCR5+CD4+ T cells in vivo in Leronlimab-treated macaques. Weekly Leronlimab treatment in a chronically SIV-infected macaque led to increased CCR5+CD4+ T cells levels and fully suppressed plasma viremia, both concomitant with full CCR5 RO on peripheral blood CD4+ T cells, demonstrating that CCR5+CD4+ T cells were protected from viral replication by Leronlimab binding. Finally, we extended these results to Leronlimab-treated humans and found that weekly 700 mg Leronlimab led to complete CCR5 RO on peripheral blood CD4+ T cells and a statistically significant increase in CCR5+CD4+ T cells in peripheral blood. Collectively, these results establish two RO calculation methods for longitudinal monitoring of anti-CCR5 therapeutic antibody blockade efficacy in both macaques and humans, demonstrate that CCR5+CD4+ T cell levels temporarily increase with Leronlimab treatment, and facilitate future detailed investigations into the immunological impacts of CCR5 inhibition in multiple pathophysiological processes. |
| اللغة: | English |
| تدمد: | 1664-3224 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::b85e251ba657476ea33e5a7dee18f1da https://www.frontiersin.org/articles/10.3389/fimmu.2021.794638/full |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....b85e251ba657476ea33e5a7dee18f1da |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 16643224 |
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