CCR5 Receptor Occupancy Analysis Reveals Increased Peripheral Blood CCR5+CD4+ T Cells Following Treatment With the Anti-CCR5 Antibody Leronlimab
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 (...
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Frontiers Media S.A.
2021
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oai:doaj.org-article:90d1587b8e514b8db82121653a4bb63e2021-11-19T07:53:08ZCCR5 Receptor Occupancy Analysis Reveals Increased Peripheral Blood CCR5+CD4+ T Cells Following Treatment With the Anti-CCR5 Antibody Leronlimab1664-322410.3389/fimmu.2021.794638https://doaj.org/article/90d1587b8e514b8db82121653a4bb63e2021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fimmu.2021.794638/fullhttps://doaj.org/toc/1664-3224CCR5 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.Xiao L. ChangHelen L. WuGabriela M. WebbMeenakshi TiwaryColette HughesJason S. ReedJoseph HwangCourtney WaytashekCarla BoyleCleiton PessoaAndrew W. SylwesterDavid MorrowKarina BelicaMiranda FischerScott KellyNader PourhassanRachele M. BochartJeremy SmedleyChristopher P. RecknorScott G. HansenJonah B. SachaJonah B. SachaFrontiers Media S.A.articleCCR5CD4HIVreceptor occupancy (RO)flow cytometryantibodyImmunologic diseases. AllergyRC581-607ENFrontiers in Immunology, Vol 12 (2021) |
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DOAJ |
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EN |
| topic |
CCR5 CD4 HIV receptor occupancy (RO) flow cytometry antibody Immunologic diseases. Allergy RC581-607 |
| spellingShingle |
CCR5 CD4 HIV receptor occupancy (RO) flow cytometry antibody Immunologic diseases. Allergy RC581-607 Xiao L. Chang Helen L. Wu Gabriela M. Webb Meenakshi Tiwary Colette Hughes Jason S. Reed Joseph Hwang Courtney Waytashek Carla Boyle Cleiton Pessoa Andrew W. Sylwester David Morrow Karina Belica Miranda Fischer Scott Kelly Nader Pourhassan Rachele M. Bochart Jeremy Smedley Christopher P. Recknor Scott G. Hansen Jonah B. Sacha Jonah B. Sacha CCR5 Receptor Occupancy Analysis Reveals Increased Peripheral Blood CCR5+CD4+ T Cells Following Treatment With the Anti-CCR5 Antibody Leronlimab |
| description |
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. |
| format |
article |
| author |
Xiao L. Chang Helen L. Wu Gabriela M. Webb Meenakshi Tiwary Colette Hughes Jason S. Reed Joseph Hwang Courtney Waytashek Carla Boyle Cleiton Pessoa Andrew W. Sylwester David Morrow Karina Belica Miranda Fischer Scott Kelly Nader Pourhassan Rachele M. Bochart Jeremy Smedley Christopher P. Recknor Scott G. Hansen Jonah B. Sacha Jonah B. Sacha |
| author_facet |
Xiao L. Chang Helen L. Wu Gabriela M. Webb Meenakshi Tiwary Colette Hughes Jason S. Reed Joseph Hwang Courtney Waytashek Carla Boyle Cleiton Pessoa Andrew W. Sylwester David Morrow Karina Belica Miranda Fischer Scott Kelly Nader Pourhassan Rachele M. Bochart Jeremy Smedley Christopher P. Recknor Scott G. Hansen Jonah B. Sacha Jonah B. Sacha |
| author_sort |
Xiao L. Chang |
| title |
CCR5 Receptor Occupancy Analysis Reveals Increased Peripheral Blood CCR5+CD4+ T Cells Following Treatment With the Anti-CCR5 Antibody Leronlimab |
| title_short |
CCR5 Receptor Occupancy Analysis Reveals Increased Peripheral Blood CCR5+CD4+ T Cells Following Treatment With the Anti-CCR5 Antibody Leronlimab |
| title_full |
CCR5 Receptor Occupancy Analysis Reveals Increased Peripheral Blood CCR5+CD4+ T Cells Following Treatment With the Anti-CCR5 Antibody Leronlimab |
| title_fullStr |
CCR5 Receptor Occupancy Analysis Reveals Increased Peripheral Blood CCR5+CD4+ T Cells Following Treatment With the Anti-CCR5 Antibody Leronlimab |
| title_full_unstemmed |
CCR5 Receptor Occupancy Analysis Reveals Increased Peripheral Blood CCR5+CD4+ T Cells Following Treatment With the Anti-CCR5 Antibody Leronlimab |
| title_sort |
ccr5 receptor occupancy analysis reveals increased peripheral blood ccr5+cd4+ t cells following treatment with the anti-ccr5 antibody leronlimab |
| publisher |
Frontiers Media S.A. |
| publishDate |
2021 |
| url |
https://doaj.org/article/90d1587b8e514b8db82121653a4bb63e |
| work_keys_str_mv |
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