BuildGoodThings posted this on reddit: Leronlim
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Posted On: 10/01/2024 11:22:42 AM
BuildGoodThings posted this on reddit:
You can see the posters by going to the following links and then clicking “e-poster.pdf” at the bottom right side of the page. Dr. Sacha was one of the authors.
https://plus.iasociety.org/e-posters/delivery...ab-aav-art
https://plus.iasociety.org/e-posters/ls-varia...on-against
Here are the abstracts:
Abstract
CCR5 blockade represents a scalable non-transplantation approach for long-term ART-free HIV remission. Here, we tested if AAV vectors could induce long-term expression of CCR5-blocking monoclonal antibody Leronlimab in a SHIV-infected rhesus macaques (RMs). Four SHIV-infected RMs received AAV9 encoding macaque Fc Leronlimab with stabilizing, silencing, and half-life extending mutations (AAV9-MacLSLeron).
Animals were monitored longitudinally for CCR5 receptor occupancy (RO), plasma Leronlimab concentrations, antidrug antibodies (ADAs), and SHIV plasma viral loads. All four AAV9-MacLSLeron-treated RMs reached 100% CCR5 RO on blood CD4+ T cells within 1 week and plasma Leronlimab was detected (>1ug/ml) within 2 weeks of AAV administration. In two of the RMs, SHIV viremia declined and reached undetectable levels between 10-40 weeks post-AAV, and those levels have remained undetectable through 70 weeks post-AAV. The remaining two RMs developed ADAs within 5-15 weeks post-AAV resulting in complete clearance of Leronlimab from plasma as well as a rapid decline in CCR5 RO. Spontaneous reemergence of CCR5 RO by Leronlimab was observed approximately 1 year post-AAV. One of the two animals has had full and sustained CCR5 RO, detectable plasma Leronlimab, and undetectable SHIV RNA in plasma for over 1 year post-reexpression. The second re-expressing animal has achieved and maintained 100% CCR5 RO for about 10 weeks, has detectable plasma Leronlimab, and has declined plasma viremia.
While further investigation is needed to develop AAV vectors and/or regimens that reduce the incidence of ADAs, the transgene reexpression phenomenon we have observed highlights the need to further investigate the interplay between AAV establishment and the development of ADAs. Overall, these data demonstrate the potential of AAV vectors for sustained antibody-based CCR5 blockade as a gene therapy approach for long term ART-free HIV remission.
Abstract
Background: Development of pre-exposure prophylaxis (PrEP) agents that provide long-acting, effective protection from HIV acquisition is a promising approach to bolster PrEP usage and adherence and slow the HIV epidemic. Anti-CCR5 monoclonal antibody Leronlimab blocks CCR5-mediated HIV entry, and has previously been shown to be an effective agent for HIV suppression in PLWH and for SHIV suppression and PrEP when administered to rhesus macaques weekly or biweekly. Here, we tested the ability of a long-acting variant of anti-CCR5 blocking antibody Leronlimab to protect against intrarectal SHIV acquisition in rhesus macaques.
Methods: A macaque-ized, long-acting, Fc-silenced, and heavy-chain-stabilized
version of anti-CCR5 monoclonal antibody Leronlimab, termed “macLS Leronlimab”, was developed by exchanging the human IgG4 Fc portion for rhesus IgG4 Fc and adding M428L and N434S (LS), L234A and L235A (LALA), and S131C (SC) mutations.
Rhesus macaques received either a single (n=6) or double (n=6) 10 mg/kg subcutaneous dose of macLS Leronlimab, or served as untreated controls (n=10). One week after the last macLS dosing, all 22 macaques underwent weekly intrarectal SHIVsf162p3 challenges until infection was confirmed in all study animals. Macaques were monitored for Leronlimab CCR5 receptor occupancy on blood CD4+ T cells, Leronlimab concentrations in plasma, Leronlimab-directed antibody drug antibodies (ADAs), and SHIV plasma viral loads.
Results: Three macLS-dosed macaques (2/6 single-dosed, 1/6 double-dosed)
developed Leronlimab-directed ADAs, resulting in incomplete CCR5 occupancy on blood CD4+ T cells, clearance of plasma Leronlimab, and subsequent SHIV acquisition. The remaining 9 macLS-dosed macaques retained complete blood CD4+ T cell CCR5 blockade for 12-18 weeks and detectable plasma Leronlimab for 10-22 weeks after dosing. SHIV acquisition was significantly delayed for macLS Leronlimab-dosed macaques (p=0.0142, log-rank test), with a median of 11 weekly challenges until viral acquisition in dosed macaques compared to 2.5 weekly challenges in control macaques. While there was a trend toward enhanced protection in the double-dosed
versus single-dosed macLS Leronlimab groups (median 13 versus 7.5 weekly
challenges), this did not reach statistical significance (p=0.5641, log-rank test).
Conclusions: These data demonstrate the ability of LS-variant Leronlimab to provide long-term protection against intrarectal SHIV acquisition and support development of long-acting CCR5 blockade for HIV PrEP.
Project supported by NIH R01 #AI154559
Quote:
Leronlimab AIDS 2024 full resolution posters now publicly available
There were two poster presentations about Leronlimab at the Aids 2024 conference in Munich July 22-26, 2024. According to the conference site, "Delegates can access content on the virtual platform immediately. IAS Members can access content 1 month after the conference ends and the general public 2 months after."
The following content is available through searching by the presentation titles at https://plus.iasociety.org/search/resources/convening/172
Delivery and long-term expression of CCR5-blocking monoclonal antibody Leronlimab with AAV for ART-free remission from SHIV viremia
LS-variant anti-CCR5 monoclonal antibody provides long-lasting protection against intrarectal SHIV acquisition in rhesus macaques
You can see the posters by going to the following links and then clicking “e-poster.pdf” at the bottom right side of the page. Dr. Sacha was one of the authors.
https://plus.iasociety.org/e-posters/delivery...ab-aav-art
https://plus.iasociety.org/e-posters/ls-varia...on-against
Here are the abstracts:
Abstract
CCR5 blockade represents a scalable non-transplantation approach for long-term ART-free HIV remission. Here, we tested if AAV vectors could induce long-term expression of CCR5-blocking monoclonal antibody Leronlimab in a SHIV-infected rhesus macaques (RMs). Four SHIV-infected RMs received AAV9 encoding macaque Fc Leronlimab with stabilizing, silencing, and half-life extending mutations (AAV9-MacLSLeron).
Animals were monitored longitudinally for CCR5 receptor occupancy (RO), plasma Leronlimab concentrations, antidrug antibodies (ADAs), and SHIV plasma viral loads. All four AAV9-MacLSLeron-treated RMs reached 100% CCR5 RO on blood CD4+ T cells within 1 week and plasma Leronlimab was detected (>1ug/ml) within 2 weeks of AAV administration. In two of the RMs, SHIV viremia declined and reached undetectable levels between 10-40 weeks post-AAV, and those levels have remained undetectable through 70 weeks post-AAV. The remaining two RMs developed ADAs within 5-15 weeks post-AAV resulting in complete clearance of Leronlimab from plasma as well as a rapid decline in CCR5 RO. Spontaneous reemergence of CCR5 RO by Leronlimab was observed approximately 1 year post-AAV. One of the two animals has had full and sustained CCR5 RO, detectable plasma Leronlimab, and undetectable SHIV RNA in plasma for over 1 year post-reexpression. The second re-expressing animal has achieved and maintained 100% CCR5 RO for about 10 weeks, has detectable plasma Leronlimab, and has declined plasma viremia.
While further investigation is needed to develop AAV vectors and/or regimens that reduce the incidence of ADAs, the transgene reexpression phenomenon we have observed highlights the need to further investigate the interplay between AAV establishment and the development of ADAs. Overall, these data demonstrate the potential of AAV vectors for sustained antibody-based CCR5 blockade as a gene therapy approach for long term ART-free HIV remission.
Abstract
Background: Development of pre-exposure prophylaxis (PrEP) agents that provide long-acting, effective protection from HIV acquisition is a promising approach to bolster PrEP usage and adherence and slow the HIV epidemic. Anti-CCR5 monoclonal antibody Leronlimab blocks CCR5-mediated HIV entry, and has previously been shown to be an effective agent for HIV suppression in PLWH and for SHIV suppression and PrEP when administered to rhesus macaques weekly or biweekly. Here, we tested the ability of a long-acting variant of anti-CCR5 blocking antibody Leronlimab to protect against intrarectal SHIV acquisition in rhesus macaques.
Methods: A macaque-ized, long-acting, Fc-silenced, and heavy-chain-stabilized
version of anti-CCR5 monoclonal antibody Leronlimab, termed “macLS Leronlimab”, was developed by exchanging the human IgG4 Fc portion for rhesus IgG4 Fc and adding M428L and N434S (LS), L234A and L235A (LALA), and S131C (SC) mutations.
Rhesus macaques received either a single (n=6) or double (n=6) 10 mg/kg subcutaneous dose of macLS Leronlimab, or served as untreated controls (n=10). One week after the last macLS dosing, all 22 macaques underwent weekly intrarectal SHIVsf162p3 challenges until infection was confirmed in all study animals. Macaques were monitored for Leronlimab CCR5 receptor occupancy on blood CD4+ T cells, Leronlimab concentrations in plasma, Leronlimab-directed antibody drug antibodies (ADAs), and SHIV plasma viral loads.
Results: Three macLS-dosed macaques (2/6 single-dosed, 1/6 double-dosed)
developed Leronlimab-directed ADAs, resulting in incomplete CCR5 occupancy on blood CD4+ T cells, clearance of plasma Leronlimab, and subsequent SHIV acquisition. The remaining 9 macLS-dosed macaques retained complete blood CD4+ T cell CCR5 blockade for 12-18 weeks and detectable plasma Leronlimab for 10-22 weeks after dosing. SHIV acquisition was significantly delayed for macLS Leronlimab-dosed macaques (p=0.0142, log-rank test), with a median of 11 weekly challenges until viral acquisition in dosed macaques compared to 2.5 weekly challenges in control macaques. While there was a trend toward enhanced protection in the double-dosed
versus single-dosed macLS Leronlimab groups (median 13 versus 7.5 weekly
challenges), this did not reach statistical significance (p=0.5641, log-rank test).
Conclusions: These data demonstrate the ability of LS-variant Leronlimab to provide long-term protection against intrarectal SHIV acquisition and support development of long-acting CCR5 blockade for HIV PrEP.
Project supported by NIH R01 #AI154559
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