PRO 140, a monoclonal antibody targeting CCR5, as a long-acting, single-agent maintenance therapy for HIV-1 infection

Abstract

Background PRO 140 is a humanized monoclonal antibody targeting CCR5 with potent antiviral activity in patients with CCR5-tropic HIV-1 infection. In phase 2b studies, we evaluated the long-term efficacy, safety, and tolerability of PRO 140 monotherapy in maintaining viral suppression for over 24 months in patients who were stable on combination antiretroviral therapy on entry into the trials. Methods and Results Forty-one adult patients, infected exclusively with CCR5-tropic HIV-1 with viral loads <50 copies/mL, were switched from daily oral combination ART regimens to weekly PRO 140 monotherapy for 12 weeks. Participants who completed 12 weeks of treatment without experiencing virologic rebound were allowed to self-administer PRO 140 as a 350 mg subcutaneous injection weekly, for up to an additional 160 weeks. Participants were monitored bi-weekly for one year, and every four weeks thereafter for virologic rebound. PRO 140 provided virologic suppression in 23/41 (56.1%) participants for 12 weeks and was well tolerated. Ten (10) participants are currently ongoing, of which nine participants have completed more than two years of monotherapy treatment (47-129 weeks). Participants experiencing virologic rebound achieved full viral suppression upon re-initiation of oral combination ART regimen. Anti-PRO 140 antibodies were not detected in any patient, and no drug-related major adverse events or treatment discontinuations were reported. Conclusions PRO 140 has a potential to address an unmet need for a long-acting, single-agent, maintenance regimen for HIV infection in selected patients. Studies are underway to determine host and/or virologic factors that may predict treatment success on PRO 140 monotherapy. Moreover, it has sufficient potency for a prolonged period of monotherapy that it would be an excellent component of a multi long-acting drug combination.

Emerging Therapeutic Modalities against COVID-19

“…Leronlimab or PRO 140 is an investigational C-C chemokine receptor type 5 (CCR5) antibody found to be efficacious in a phase 3 clinical trial for the treatment of R5 HIV patients [ 181 ]. A recent study reported that leronlimab reduced the inflammation, plasma viremia levels, and T cell lymphocytopenia via blocking the CCL5/RANTES-CCR5 pathway in COVID-19 patients [ 179 ].…”

CCR5 inhibition in critical COVID-19 patients decreases inflammatory cytokines, increases CD8 T-cells, and decreases SARS-CoV2 RNA in plasma by day 14

“…Because SARS-CoV-infected airway epithelial cells and macrophages express high levels of CCL5 (Law et al, 2005, Yen et al, 2006 , a chemotactic molecule able to amplify inflammatory responses towards immunopathology, we hypothesized that disrupting the CCL5-CCR5 axis via leronlimab-mediated CCR5 blockade might prevent pulmonary trafficking of proinflammatory leukocytes and dampen pathogenic immune activation in Leronlimab, formerly PRO 140, is a CCR5-specific human IgG4 monoclonal antibody in development for HIV therapy as a once-weekly, at-home subcutaneous injection. In five completed and four ongoing HIV clinical trials where over 800 individuals have received leronlimab, no drug related deaths, serious injection site reactions, or drug-drug interactions were reported (Jacobson et al, 2008, Jacobson et al, 2010a, Jacobson et at., 2010b, Dhody et al, 2018. Subcutaneous, self-administration of leronlimab by patients facilitates simple, onceweekly dosing.…”

“…Leronlimab, formerly PRO 140, is a CCR5-specific human IgG4 monoclonal antibody in development for HIV therapy as a once-weekly, at-home subcutaneous injection. In five completed and four ongoing HIV clinical trials where over 800 individuals have received leronlimab, no drug related deaths, serious injection site reactions, or drug-drug interactions were reported ( Jacobson et al, 2008 , Jacobson et al, 2010a , Jacobson et al, 2010b , Dhody et al, 2018 ). Subcutaneous, self-administration of leronlimab by patients facilitates simple, once-weekly dosing.…”

Antibody-based strategies in HIV therapy

“…Forty-three subjects were enrolled, but two subjects were removed because they had mixed tropism prior to leronlimab receipt. 35 Thus, 41 subjects were studied through three cohorts: one (n=11), two (n=28), and three (n=2). More than half of the enrolled subjects maintained virologic suppression at 12 weeks.…”