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Posted On: 02/16/2023 3:55:07 PM
Post# of 148892
There is a new article in "Frontiers in Microbiology" that mentions Leronlimab. I will post excerpts and link below.
Strategies to overcome HIV drug resistance - current and future perspectives
Introduction
In 2021, 38.4 million people were living with HIV infections and 1.5 million people became newly infected with HIV according to the recent update from The Joint United Nations Programme on HIV/AIDS.1 The availability of combined antiretroviral therapy (cART) has revolutionized the course of HIV infection, suppressing HIV viremia, restoring the immune system, and improving the quality of life of HIV infected patients (Samji et al., 2013). Current HIV treatment includes five different classes of antiretrovirals targeting multiple steps of the HIV life cycle (Figure 1): entry inhibitors that block (1) the attachment of HIV envelope glycoprotein gp120 to CCR5 co-receptors (maraviroc) or (2) the cell fusion mediated by HIV gp41 (enfuvirtide), (3) nucleoside reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs) that block the reverse transcription of viral RNA to cDNA, (4) integrase strand transfer inhibitors (INSTIs) that inhibit the integration of proviral DNA into host genome, and (5) protease inhibitors (PIs) that inhibit the protease-mediated cleavage of gag and gag-pol precursors, resulting in the production of non-infectious virus particles (De Clercq and Li, 2016). However, the emergence of drug resistant and multidrug resistant strains remains an important contributor to cART failure, associated with a higher risk of HIV-disease progression and mortality (Galli et al., 2020). Cross-resistance between drugs within the same class can occur and affects all major classes of antiretroviral drugs (Puertas et al., 2020). According to the latest WHO HIV Drug Resistance Report, the prevalence of acquired and transmitted HIV drug resistance in ART naive individuals has exponentially increased in the recent years, being an important obstacle in ending HIV-1 epidemic as a public health threat by 2030.
Antibody-based strategies
Monoclonal antibodies are becoming attractive strategies for HIV treatment, with good resistance profile, ability to restore CD4 T-cell count and lack of toxicity.
Leronlimab (Pro 140)-long-acting CCR5 antagonist
Leronlimab (PRO 140), a humanized IgG4 monoclonal antibody (mAb), acts as an HIV-1 CCR5 antagonist; it binds to hydrophilic extracellular domains on CCR5, inhibiting HIV-1 viral entry in a competitive manner (Thompson, 2018).
The safety and effectiveness of leronlimab is currently, evaluated in phase IIb/III clinical trials. In CD 02 trial (PRO 140_CD 02; NCT02483078), leronlimab was tested in treatment-experienced patients with multidrug resistant HIV. In the first week, participants received 350 mg of PRO 140 subcutaneously or placebo together with their regular medication and 1 week later, they received PRO 140 with an optimized regimen. The primary endpoint of the trial was achieved: patients in the PRO 140 arm showed a statistically significant reduction in HIV RNA viral load of greater than 0.5log from baseline versus patients in the placebo arm.4 A recent report showed that all CCR5-tropic strains were fully susceptible to PRO 140 in a group of heavily treatment-experienced HIV-1-positive patients harboring 4-class drug-resistance to NRTIs, NNRTIs, PIs, and InSTIs; current exposure to maraviroc (68% of the participants) was not associated with different PRO 140 activity (Rusconi et al., 2022).
CD03 clinical trial has evaluated weekly subcutaneous PRO 140 as monotherapy maintenance in patients with viral suppression (PRO 140_CD03; NCT02859961). The rate of virological failure was lower in the group of participants receiving 700 mg dose comparing with 525 mg and 350 mg dose groups (13.8, 33 and 65.9%, respectively); no evidence of treatment-emergent resistance to leronlimab was observed. A report published on March 31, 2022, showed that weekly injections of Leronlimab (700 mg dose) maintained viral suppression in the five HIV+ participants for over seven years (ClinicalTrials.gov NCT02175680 and NCT02355184).
https://www.frontiersin.org/articles/10.3389/...PPanyb6rVU
Strategies to overcome HIV drug resistance - current and future perspectives
Introduction
In 2021, 38.4 million people were living with HIV infections and 1.5 million people became newly infected with HIV according to the recent update from The Joint United Nations Programme on HIV/AIDS.1 The availability of combined antiretroviral therapy (cART) has revolutionized the course of HIV infection, suppressing HIV viremia, restoring the immune system, and improving the quality of life of HIV infected patients (Samji et al., 2013). Current HIV treatment includes five different classes of antiretrovirals targeting multiple steps of the HIV life cycle (Figure 1): entry inhibitors that block (1) the attachment of HIV envelope glycoprotein gp120 to CCR5 co-receptors (maraviroc) or (2) the cell fusion mediated by HIV gp41 (enfuvirtide), (3) nucleoside reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs) that block the reverse transcription of viral RNA to cDNA, (4) integrase strand transfer inhibitors (INSTIs) that inhibit the integration of proviral DNA into host genome, and (5) protease inhibitors (PIs) that inhibit the protease-mediated cleavage of gag and gag-pol precursors, resulting in the production of non-infectious virus particles (De Clercq and Li, 2016). However, the emergence of drug resistant and multidrug resistant strains remains an important contributor to cART failure, associated with a higher risk of HIV-disease progression and mortality (Galli et al., 2020). Cross-resistance between drugs within the same class can occur and affects all major classes of antiretroviral drugs (Puertas et al., 2020). According to the latest WHO HIV Drug Resistance Report, the prevalence of acquired and transmitted HIV drug resistance in ART naive individuals has exponentially increased in the recent years, being an important obstacle in ending HIV-1 epidemic as a public health threat by 2030.
Antibody-based strategies
Monoclonal antibodies are becoming attractive strategies for HIV treatment, with good resistance profile, ability to restore CD4 T-cell count and lack of toxicity.
Leronlimab (Pro 140)-long-acting CCR5 antagonist
Leronlimab (PRO 140), a humanized IgG4 monoclonal antibody (mAb), acts as an HIV-1 CCR5 antagonist; it binds to hydrophilic extracellular domains on CCR5, inhibiting HIV-1 viral entry in a competitive manner (Thompson, 2018).
The safety and effectiveness of leronlimab is currently, evaluated in phase IIb/III clinical trials. In CD 02 trial (PRO 140_CD 02; NCT02483078), leronlimab was tested in treatment-experienced patients with multidrug resistant HIV. In the first week, participants received 350 mg of PRO 140 subcutaneously or placebo together with their regular medication and 1 week later, they received PRO 140 with an optimized regimen. The primary endpoint of the trial was achieved: patients in the PRO 140 arm showed a statistically significant reduction in HIV RNA viral load of greater than 0.5log from baseline versus patients in the placebo arm.4 A recent report showed that all CCR5-tropic strains were fully susceptible to PRO 140 in a group of heavily treatment-experienced HIV-1-positive patients harboring 4-class drug-resistance to NRTIs, NNRTIs, PIs, and InSTIs; current exposure to maraviroc (68% of the participants) was not associated with different PRO 140 activity (Rusconi et al., 2022).
CD03 clinical trial has evaluated weekly subcutaneous PRO 140 as monotherapy maintenance in patients with viral suppression (PRO 140_CD03; NCT02859961). The rate of virological failure was lower in the group of participants receiving 700 mg dose comparing with 525 mg and 350 mg dose groups (13.8, 33 and 65.9%, respectively); no evidence of treatment-emergent resistance to leronlimab was observed. A report published on March 31, 2022, showed that weekly injections of Leronlimab (700 mg dose) maintained viral suppression in the five HIV+ participants for over seven years (ClinicalTrials.gov NCT02175680 and NCT02355184).
https://www.frontiersin.org/articles/10.3389/...PPanyb6rVU
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