ABSTRACT
Definition of antibody (Ab) functions capable of preventing mucosal HIV transmission may be critical to both effective vaccine development and the prophylactic use of monoclonal Abs. Although direct antibody-mediated neutralization is highly effective against cell-free virus, increasing evidence suggests an important role for immunoglobulin G (IgG) Fcγ receptor (FcγR)-mediated inhibition of HIV replication. Thus, a panel of well-known neutralizing (NAbs) and nonneutralizing Abs (NoNAbs) were screened for their ability to block HIV acquisition and replication in vitro in either an independent or FcγR-dependent manner. Abs displaying the highest Fc-mediated inhibitory activity in various in vitro assays were selected, formulated for topical vaginal application in a microbicide gel, and tested for their antiviral activity against SHIVSF162P3 vaginal challenge in non-human primates (NHPs). A combination of three NAbs, 2G12, 2F5, and 4E10, fully prevented simian/human immunodeficiency virus (SHIV) vaginal transmission in 10 out of 15 treated NHPs, whereas a combination of two NoNAbs, 246-D and 4B3, although having no impact on SHIV acquisition, reduced plasma viral load. These results indicate that anti-HIV Abs with distinct neutralization and inhibitory functions differentially affect in vivo HIV acquisition and replication, by interfering with early viral replication and dissemination. Therefore, combining diverse Ab properties may potentiate the protective effects of anti-HIV-Ab-based strategies.
Subject(s)
Antibodies, Monoclonal/immunology , HIV Antibodies/immunology , Simian Acquired Immunodeficiency Syndrome/immunology , Simian Acquired Immunodeficiency Syndrome/prevention & control , Simian Immunodeficiency Virus/immunology , Vagina/immunology , Vagina/virology , Animals , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal/metabolism , Antibodies, Neutralizing/administration & dosage , Antibodies, Neutralizing/immunology , Antibodies, Neutralizing/metabolism , Antibody-Dependent Cell Cytotoxicity , Female , HIV Antibodies/administration & dosage , HIV Antibodies/metabolism , Immunoglobulin Fc Fragments/immunology , Immunoglobulin Fc Fragments/metabolism , Macaca fascicularis , Macrophages/immunology , Macrophages/virology , Neutralization Tests , Protein Binding/immunology , Receptors, IgG/metabolism , Simian Acquired Immunodeficiency Syndrome/virology , Virus Replication/immunologyABSTRACT
OBJECTIVE: To assess the efficacy and safety of liposomally encapsulated recombinant human superoxide dismutase (lrhSOD) for the treatment of Peyronie's disease. METHODS: In an uncontrolled phase-2 study, 20 patients with Peyronie's disease were treated with a gel containing lrhSOD (1.5 mg/g). Patients with penile deviation of >45 degrees or plaque calcifications of >5 mm were regarded as candidates for surgical correction and excluded from this study. RESULTS: Elimination of pain was observed in 7/13 patients (in 2 patients after only 3 days of therapy), and an almost complete resolution of pain was reported by the remaining 6/13 patients. Plaque size was reduced in 8/14 patients. Minimal improvement of penile deviation was observed in 3/12 patients. Post-therapeutic improvement of sexual function, mainly due to cessation of pain, was reported by 12/15 patients. No systemic or local side effects were observed. CONCLUSION: In the present study, 100% pain relief as well as a plaque size reduction in 56% of Peyronie's disease patients were observed after a maximum of 6 weeks of lrhSOD therapy. The convenience and safety of lrhSOD gel therapy were superior compared to other current regimens. The present results suggest that lrhSOD gel is a promising treatment for patients with early stage Peyronie's disease. Early institution of lrhSOD therapy may prevent disease progression to penile deviation. The present preliminary results are the basis of a placebo-controlled randomized study.
