An excerpt from Article... 4.1.3 Development of
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An excerpt from Article...
4.1.3 Development of Monoclonal Antibodies
In addition to small molecule inhibitors, monoclonal antibodies targeting the CCR5 receptor are being developed and investigated for use in treatment of HIV-1 infection and pre-exposure prophylaxis (PrEP). These antibodies are intended to bind the CCR5 receptor to inhibit gp120 interacting with the co-receptor (Figure 2). The drug Leronlimab is a humanized anti-CCR5 IgG4 monoclonal antibody that is delivered subcutaneously or intravenously (Table 1) (115). Preliminary studies have shown that contrary to natural antibodies, Leronlimab is able to bind the N-terminal domain of EL2 on the CCR5 receptor, the same binding site used by gp120 (Figure 2). This loop is thought to be a well conserved area of CCR5 encoding genes (108). Another CCR5 antibody HGS004 directed at the same area of CCR5 has also show in vitro and in vivo efficacy in infected patients. However, a linear dose-dependent response was not observed and only about 50% of patients showed a viral load decrease of greater than one log two weeks after a single dose (116).
Studies in rhesus macaques showed dose-dependent protection from CCR5-utilizing infection following injections of Leronlimab subcutaneously. Additionally, 50 mg/kg prevented HIV-1 infection in all sites for all subjects, while just 10 mg/kg prevented infection in rectal tissue in all but one subject (117). In Phase 2 clinical trials in individuals with solely CCR5-utilizing HIV-1 intravenous Leronlimab infusion was well tolerated. Dosage as low as 5 mg/kg elicited maximum antiviral effects around 14 days post injection with greater than 1.8 log viral load reduction (118). In this same study, viral load rebounded to near baseline in all dosages around day 40 post-injection, highlighting a need for sustained treatment. No evidence of resistance or switched tropism was observed while only mild side effects were encountered with this medication, and it has been given a fast track status by the US Food and Drug Administration (FDA) (119).
Of the monoclonal antibodies directed at CCR5 that have been investigated, Leronlimab has achieved the most sustained receptor occupancy. Promising infection prevention and antiviral data has been gathered from clinical trial and macaque studies. Patients exhibited 85% receptor occupancy through day 29 post-infusion of both 5 and 10 mg/kg doses (106). Additionally, while Leronlimab could benefit other neurological diseases, the issue of the viral reservoir will likely not be well addressed by these monoclonal antibody treatments. Studies report 70-75% receptor occupancy in Leronlimab-treated macaques (120). Long-term treatment sustainability and standardized treatment protocols have yet to be determined, though several patients have seen continuous suppression for over two years.
4.1.3 Development of Monoclonal Antibodies
In addition to small molecule inhibitors, monoclonal antibodies targeting the CCR5 receptor are being developed and investigated for use in treatment of HIV-1 infection and pre-exposure prophylaxis (PrEP). These antibodies are intended to bind the CCR5 receptor to inhibit gp120 interacting with the co-receptor (Figure 2). The drug Leronlimab is a humanized anti-CCR5 IgG4 monoclonal antibody that is delivered subcutaneously or intravenously (Table 1) (115). Preliminary studies have shown that contrary to natural antibodies, Leronlimab is able to bind the N-terminal domain of EL2 on the CCR5 receptor, the same binding site used by gp120 (Figure 2). This loop is thought to be a well conserved area of CCR5 encoding genes (108). Another CCR5 antibody HGS004 directed at the same area of CCR5 has also show in vitro and in vivo efficacy in infected patients. However, a linear dose-dependent response was not observed and only about 50% of patients showed a viral load decrease of greater than one log two weeks after a single dose (116).
Studies in rhesus macaques showed dose-dependent protection from CCR5-utilizing infection following injections of Leronlimab subcutaneously. Additionally, 50 mg/kg prevented HIV-1 infection in all sites for all subjects, while just 10 mg/kg prevented infection in rectal tissue in all but one subject (117). In Phase 2 clinical trials in individuals with solely CCR5-utilizing HIV-1 intravenous Leronlimab infusion was well tolerated. Dosage as low as 5 mg/kg elicited maximum antiviral effects around 14 days post injection with greater than 1.8 log viral load reduction (118). In this same study, viral load rebounded to near baseline in all dosages around day 40 post-injection, highlighting a need for sustained treatment. No evidence of resistance or switched tropism was observed while only mild side effects were encountered with this medication, and it has been given a fast track status by the US Food and Drug Administration (FDA) (119).
Of the monoclonal antibodies directed at CCR5 that have been investigated, Leronlimab has achieved the most sustained receptor occupancy. Promising infection prevention and antiviral data has been gathered from clinical trial and macaque studies. Patients exhibited 85% receptor occupancy through day 29 post-infusion of both 5 and 10 mg/kg doses (106). Additionally, while Leronlimab could benefit other neurological diseases, the issue of the viral reservoir will likely not be well addressed by these monoclonal antibody treatments. Studies report 70-75% receptor occupancy in Leronlimab-treated macaques (120). Long-term treatment sustainability and standardized treatment protocols have yet to be determined, though several patients have seen continuous suppression for over two years.
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