Long-acting Leronlimab poster also at the Aids2024 conference this week. Jonas Sacha and his colleagues are on a roll IMO
https://programme.aids2024.org/Abstract/Abstr...actid=9872
Title
LS-variant anti-CCR5 monoclonal antibody provides long-lasting protection against intrarectal SHIV acquisition in rhesus macaques
Presenter
Helen Wu
Authors
H. Wu1, J. Zikos2, C. Waytakshek1, C. Boyle1, J. Hwang1, H. Fisher1, A. McCullen1, C. Shriver-Munsch1, K. Armantrout1, H. Crank1, M. Fischer1, J. Smedley1, M. Axthelm1, D. Magnani2, J. Sacha1
Institutions
1Oregon Health & Science University, Beaverton, United States, 2University of Massachusetts Medical School, Boston, United States
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.
https://programme.aids2024.org/Abstract/Abstr...actid=9872
Title
LS-variant anti-CCR5 monoclonal antibody provides long-lasting protection against intrarectal SHIV acquisition in rhesus macaques
Presenter
Helen Wu
Authors
H. Wu1, J. Zikos2, C. Waytakshek1, C. Boyle1, J. Hwang1, H. Fisher1, A. McCullen1, C. Shriver-Munsch1, K. Armantrout1, H. Crank1, M. Fischer1, J. Smedley1, M. Axthelm1, D. Magnani2, J. Sacha1
Institutions
1Oregon Health & Science University, Beaverton, United States, 2University of Massachusetts Medical School, Boston, United States
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.
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