Long-Term Multiple-Dose Pharmacokinetics of Human Monoclonal Antibodies (MAbs) against Human Immunodeficiency Virus Type 1 Envelope gp120 (MAb 2G12) and gp41 (MAbs 4E10 and 2F5)

Abstract

While certain antibodies directed against the human immunodeficiency virus (HIV) envelope have the potential to suppress virus replication in vitro, the impact of neutralizing antibodies in vivo remains unclear. In a recent proof-of-concept study, the broadly neutralizing monoclonal antibodies 2G12, 4E10, and 2F5 exhibited inhibitory activities in vivo, as exemplified by a delay of the viral rebound following the interruption of antiretroviral therapy. Unexpectedly, the antiviral effect seen was most prominently due to 2G12 activity. To further investigate whether differential HIV-inhibitory activity was due to different pharmacokinetic properties of the antibodies, we performed a formal pharmacokinetic analysis with 14 patients. Repeated infusions at high dose levels were well tolerated by the patients and did not elicit an endogenous immune response against the monoclonal antibodies. ؎ 1.1 days). The comprehensive pharmacokinetic data from this long-term multiple-dose phase II study were coherent with those from previous short-term phase I studies, as assessed by compartmental and noncompartmental techniques. The anti-HIV type 1 antibodies studied showed distribution and elimination kinetics similar to those seen for other humanlike antibodies. Further studies examining tissue concentrations to explain the differential in vivo activity of the anti-gp120 antibody compared with those of the two anti-gp41 antibodies are warranted.

Closing the door to human immunodeficiency virus

“…Phase 1 clinical trial has confirmed that 2F5 is safe and well tolerated by injection (Armbruster et al, 2002). Consistent data have been obtained from a phase 2 long-term multiple-dose pharmacokinetics study conducted in HIV-1 infected patients (Joos et al, 2006). The antibody-dependent cell cytotoxicity (ADCC) induced by 2F5 contributes to the elimination of HIV-1 infected cells (Tudor and Bomsel, 2011).…”

“…To note, substitutions in the MPER contributed to the resistance to 4E10 (Gray et al, 2008;Nakamura et al, 2010). The safety and tolerability of 4E10 for clinical use have also been confirmed by a phase 2 clinical study (Joos et al, 2006). In rhesus macaques, passive immunization of 4E10 and 2F5 provides protection against intrarectal challenge with SHIV (Hessell et al, 2010) and delays the viral rebound in HIV-1 infected patients .…”

“…A study shows that 2G12 can effectively protect against SHIV challenge in macaque models even at a low serum concentration (Hessell et al, 2009). Moreover, combining with 4E10 and 2F5, 2G12 shows a protective ability to suppress HIV-1 replication in humans despite the selected viral escape mutants (Baba et al, 2000;Trkola et al, 2005), partially due to its long in vivo half-life (Joos et al, 2006).…”

The Role of Antibody Polyspecificity and Lipid Reactivity in Binding of Broadly Neutralizing Anti-HIV-1 Envelope Human Monoclonal Antibodies 2F5 and 4E10 to Glycoprotein 41 Membrane Proximal Envelope Epitopes

“…2F5 and 4E10 mAb reactivity has been administered to a number of HIV-1-infected patients with no thrombotic event noted (51), although when these mAbs are administered, patient sera become positive in anti-cardiolipin and lupus anti-coagulant Ab assays (52). However, the MPER mAbs, 2F5 and 4E10, were not the contributing factor in the minimal effect observed on viral load (51,53). Thus, while these Abs may not be pathogenic and not cause thrombotic disease when administered to HIV ϩ patients, the relevance of our study resides in the notion that 2F5 and 4E10 have polyreactivity for various self Ags, and have structural and reactivity pattern similarities to known autoantibodies.…”

HIV-1 Glycoprotein Immunogenicity

“…The 4E10 Ab has also a polyspecificity for autoantigens as histone or DNA in systemic lupus erythematosus. Several in vivo pharmacokinetic studies and phase I/II clinical trials phases I and II with combination of 4E10, 2F5 and 2G12 showed that these three Abs are able to maintain undetectable viral load in patients where the infection has been suppressed by antiviral therapy (Joos et al, 2006). These studies also showed that 4E10 administration is not highly immunogenic with rare IgM against 4E10 but no IgG.…”