Protective effect of vaginal application of neutralizing and non-neutralizing inhibitory antibodies against vaginal HIV challenge in macaques

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) Fcc receptor (FccR)–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 FccR-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.Fil: Moog, C. Institute of Virology. Strasbourg; FranciaFil: Dereuddre Bosquet, N. Universite Paris Sud; FranciaFil: Teillaud, J-L. Paris Descartes University; FranciaFil: Biedma, Marina Elizabeth. Institute of Virology. Strasbourg; Francia. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Holl, V. Hematology and Flow Department. Ginebra; SuizaFil: Van Ham, G. Universidad de Amberes; BélgicaFil: Heyndrickx, L. Universidad de Amberes; BélgicaFil: Van Dorsselaer, A. UMR 7178; FranciaFil: Katinger, D. Polymun Scientific GmbH; AlemaniaFil: Vcelar, B. Polymun Scientific GmbH; AlemaniaFil: Zolla Pazner, S. School of Medicine and New York Veterans Affairs Medical Center; Estados UnidosFil: Mangeot, I. Universite Paris Sud; FranciaFil: Kelly, C. King's College; Reino UnidoFil: Shattock, R. J.. Imperial College London; Reino UnidoFil: Le Grand, R. Universite Paris Sud; Franci

Protective effect of vaginal application of neutralizing and non-neutralizing inhibitory antibodies against vaginal HIV challenge in macaques

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) Fcc receptor (FccR)–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 FccR-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.Fil: Moog, C. Institute of Virology. Strasbourg; FranciaFil: Dereuddre Bosquet, N. Universite Paris Sud; FranciaFil: Teillaud, J-L. Paris Descartes University; FranciaFil: Biedma, Marina Elizabeth. Institute of Virology. Strasbourg; Francia. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Holl, V. Hematology and Flow Department. Ginebra; SuizaFil: Van Ham, G. Universidad de Amberes; BélgicaFil: Heyndrickx, L. Universidad de Amberes; BélgicaFil: Van Dorsselaer, A. UMR 7178; FranciaFil: Katinger, D. Polymun Scientific GmbH; AlemaniaFil: Vcelar, B. Polymun Scientific GmbH; AlemaniaFil: Zolla Pazner, S. School of Medicine and New York Veterans Affairs Medical Center; Estados UnidosFil: Mangeot, I. Universite Paris Sud; FranciaFil: Kelly, C. King's College; Reino UnidoFil: Shattock, R. J.. Imperial College London; Reino UnidoFil: Le Grand, R. Universite Paris Sud; Franci

Regulatory approval and a first-in-human phase I clinical trial of a monoclonal antibody produced in transgenic tobacco plants

Although plant biotechnology has been widely investigated for the production of clinical-grade monoclonal antibodies, no antibody products derived from transgenic plants have yet been approved by pharmaceutical regulators for clinical testing. In the Pharma-Planta project, the HIV-neutralizing human monoclonal antibody 2G12 was expressed in transgenic tobacco (Nicotiana tabacum). The scientific, technical and regulatory demands of good manufacturing practice (GMP) were addressed by comprehensive molecular characterization of the transgene locus, confirmation of genetic and phenotypic stability over several generations of transgenic plants, and by establishing standard operating procedures for the creation of a master seed bank, plant cultivation, harvest, initial processing, downstream processing and purification. The project developed specifications for the plant-derived antibody (P2G12) as an active pharmaceutical ingredient (API) based on (i) the guidelines for the m anufacture of monoclonal antibodies in cell culture systems; (ii) the draft European Medicines Agency Points to Consider document on quality requirements for APIs produced in transgenic plants; and (iii) de novo guidelines developed with European national regulators. From the resulting process, a GMP manufacturing authorization was issued by the competent authority in Germany for transgenic plant-derived monoclonal antibodies for use in a phase I clinical evaluation. Following preclinical evaluation and ethical approval, a clinical trial application was accepted by the UK national pharmaceutical regulator. A first-in-human, double-blind, placebo-controlled, randomized, dose-escalation phase I safety study of a single vaginal administration of P2G12 was carried out in healthy female subjects. The successful completion of the clinical trial marks a significant milestone in the commercial development of plant-derived pharmaceutical proteins