Ganesha, Thanks for the link to Dr. Sacha's pre
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Posted On: 03/08/2023 2:07:33 PM
Ganesha,
Thanks for the link to Dr. Sacha's presentation. I did a little investigating and saw that he had 2 abstracts at the 10th International Workshop on HIV Persistence During Therapy in Miami on December 13 - 16, 2022.
This is a link to the workshop:
https://www.hiv-persistence.com/
I downloaded the PDF file of abstracts and will post his 2 abstracts. Nice to see a discussion of long-acting Leronlimab .
Session 2: In Vitro and Animal Model Studies of HIV Persistence
OP 2.1 CCR5 in HIV Prevention and Cure
Helen L. Wu, Gabriela M. Webb, Jonah B. Sacha
Vaccine & Gene Therapy Institute and Oregon National Primate Research Center, Oregon Health & Science University, Portland, OR, USA
Background:CCR5 plays a critical role in HIV infection as the major viral co-receptor. Individuals naturally lacking surfaceCCR5 expression through a homozygous 32 base pair deletion(CCR5Δ32/Δ32) are highly resistant to HIV infection, and the only documented cases of HIV cure occurred following allogeneic stem cell transplantation from CCR5Δ32/Δ32donors. Mimicking the CCR5Δ32/Δ32 phenotype is therefore an attractive avenue for both HIV prevention and cure.
Methods: Leronlimab is a CCR5-specific monoclonal anti-body that binds to the extracellular loop-2 and N-terminus domains of CCR5, thereby directly outcompeting HIV for CCR5 engagement and blocking entry to CD4+ T cells. We generated long-acting leronlimab and administered it to rhesus macaques prior to weekly rectal challenge with CCR5-tropic SHIV. To test use of leronlimab in functional cure, an AAV vector expressing long-acting leronlimab was administered to macaques with established SHIV infection
Results: A single dose of long-acting Leronlimab achieved full CCR5 receptor occupancy (RO) on CD4+ T cells isolated from both peripheral blood and rectal biopsies for >12 weeks. A single dose of long-acting leronlimab also significantly protected against acquisition following repeated, low dose rectal challenge with CCR5-tropic SHIV. In macaques with established CCR5-tropic SHIV infection, resolution of plasma viremia occurred following the emergence of full CCR5 RO on CD4+ T cells in peripheral blood. Of note, we observed viral blips concomitant with transient loss of full CCR5 RO on CD4+ T cells in blood.
Conclusions: Given the safety and protective efficacy of the naturally occurring CCR5Δ32/Δ32 phenotype, leronlimab is an attractive addition to the growing arsenal of long-acting injectables for HIV prevention. AAV vectored delivery of leronlimab demonstrated proof of concept that the CCR5Δ32/Δ32 phenotype can be phenocopied by gene therapy delivery of CCR5blockade.
OP 6.3–00150
Delivery and long-term expression of CCR5-blocking monoclonal antibody Leronlimab with AAV for ART-free remission from SHIV viremia
G. Webb, H.Wu, C. Waytashek, C. Boyle, J. Smedley, J. Zikos, D. Magnani, S. Fuchs, R. Desrosiers, J. Sacha
Background: CCR5 blockade represents a scalable non-trans-plantation 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 macaque (RM) and Mauritian cynomolgus macaque (MCM).
Methods: One RM received AAV9 encoding macaque FcLeronlimab with stabilizing, silencing, and half-life extending mutations (AAV9-MacLSLeron) with no immune suppression. One MCM received AAV9 encoding human Fc Leronlimab (AAV9-HuLeron), and to limit immune activation, received three doses of dexamethasone (−12,−1, and 5 hours post-AAV) and daily tacrolimus (days−8 to 28 post-AAV).
Results: The AAV9-MacLSLeron-treated RM reached 100% CCR5 receptor occupancy (RO) on blood CD4+ T cells within 1week and plasma Leronlimab was detected (>1 ug/ml) within 2 weeks of administration. Antidrug antibodies (ADA) developed 4 weeks post-AAV, but then resolved by 6 weeks post-AAV. Consequently, SHIV viremia became undetectable shortly after resolution of ADA at 9 weeks post-AAV. The AAV9-HuLeron-treated MCM achieved 100% CCR5 RO on blood CD4+ T-cells within 2 weeks and possessed detectable plasma Leronlimab(>1 ug/mL) within 3 weeks without ADA, with CCR5 RO and plasma Leronlimab maintained through 33 weeks post-AAV. Mesenteric lymph node and spleen CD4+ T-cells from week 13 post-AAV exhibited >98% RO. SHIV viremia became undetectable within 4 weeks post-AAV and remained undetectable through 33 weeks post-AAV with the exception of 3 blips of plasma viremia, which coincided with small transient dips in blood CD4+ T-cell CCR5 RO.
Conclusions: While further investigation is needed to develop AAV vectors and/or regimens that reduce the incidence of ADA, 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.
Thanks for the link to Dr. Sacha's presentation. I did a little investigating and saw that he had 2 abstracts at the 10th International Workshop on HIV Persistence During Therapy in Miami on December 13 - 16, 2022.
This is a link to the workshop:
https://www.hiv-persistence.com/
I downloaded the PDF file of abstracts and will post his 2 abstracts. Nice to see a discussion of long-acting Leronlimab .
Session 2: In Vitro and Animal Model Studies of HIV Persistence
OP 2.1 CCR5 in HIV Prevention and Cure
Helen L. Wu, Gabriela M. Webb, Jonah B. Sacha
Vaccine & Gene Therapy Institute and Oregon National Primate Research Center, Oregon Health & Science University, Portland, OR, USA
Background:CCR5 plays a critical role in HIV infection as the major viral co-receptor. Individuals naturally lacking surfaceCCR5 expression through a homozygous 32 base pair deletion(CCR5Δ32/Δ32) are highly resistant to HIV infection, and the only documented cases of HIV cure occurred following allogeneic stem cell transplantation from CCR5Δ32/Δ32donors. Mimicking the CCR5Δ32/Δ32 phenotype is therefore an attractive avenue for both HIV prevention and cure.
Methods: Leronlimab is a CCR5-specific monoclonal anti-body that binds to the extracellular loop-2 and N-terminus domains of CCR5, thereby directly outcompeting HIV for CCR5 engagement and blocking entry to CD4+ T cells. We generated long-acting leronlimab and administered it to rhesus macaques prior to weekly rectal challenge with CCR5-tropic SHIV. To test use of leronlimab in functional cure, an AAV vector expressing long-acting leronlimab was administered to macaques with established SHIV infection
Results: A single dose of long-acting Leronlimab achieved full CCR5 receptor occupancy (RO) on CD4+ T cells isolated from both peripheral blood and rectal biopsies for >12 weeks. A single dose of long-acting leronlimab also significantly protected against acquisition following repeated, low dose rectal challenge with CCR5-tropic SHIV. In macaques with established CCR5-tropic SHIV infection, resolution of plasma viremia occurred following the emergence of full CCR5 RO on CD4+ T cells in peripheral blood. Of note, we observed viral blips concomitant with transient loss of full CCR5 RO on CD4+ T cells in blood.
Conclusions: Given the safety and protective efficacy of the naturally occurring CCR5Δ32/Δ32 phenotype, leronlimab is an attractive addition to the growing arsenal of long-acting injectables for HIV prevention. AAV vectored delivery of leronlimab demonstrated proof of concept that the CCR5Δ32/Δ32 phenotype can be phenocopied by gene therapy delivery of CCR5blockade.
OP 6.3–00150
Delivery and long-term expression of CCR5-blocking monoclonal antibody Leronlimab with AAV for ART-free remission from SHIV viremia
G. Webb, H.Wu, C. Waytashek, C. Boyle, J. Smedley, J. Zikos, D. Magnani, S. Fuchs, R. Desrosiers, J. Sacha
Background: CCR5 blockade represents a scalable non-trans-plantation 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 macaque (RM) and Mauritian cynomolgus macaque (MCM).
Methods: One RM received AAV9 encoding macaque FcLeronlimab with stabilizing, silencing, and half-life extending mutations (AAV9-MacLSLeron) with no immune suppression. One MCM received AAV9 encoding human Fc Leronlimab (AAV9-HuLeron), and to limit immune activation, received three doses of dexamethasone (−12,−1, and 5 hours post-AAV) and daily tacrolimus (days−8 to 28 post-AAV).
Results: The AAV9-MacLSLeron-treated RM reached 100% CCR5 receptor occupancy (RO) on blood CD4+ T cells within 1week and plasma Leronlimab was detected (>1 ug/ml) within 2 weeks of administration. Antidrug antibodies (ADA) developed 4 weeks post-AAV, but then resolved by 6 weeks post-AAV. Consequently, SHIV viremia became undetectable shortly after resolution of ADA at 9 weeks post-AAV. The AAV9-HuLeron-treated MCM achieved 100% CCR5 RO on blood CD4+ T-cells within 2 weeks and possessed detectable plasma Leronlimab(>1 ug/mL) within 3 weeks without ADA, with CCR5 RO and plasma Leronlimab maintained through 33 weeks post-AAV. Mesenteric lymph node and spleen CD4+ T-cells from week 13 post-AAV exhibited >98% RO. SHIV viremia became undetectable within 4 weeks post-AAV and remained undetectable through 33 weeks post-AAV with the exception of 3 blips of plasma viremia, which coincided with small transient dips in blood CD4+ T-cell CCR5 RO.
Conclusions: While further investigation is needed to develop AAV vectors and/or regimens that reduce the incidence of ADA, 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.
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