title: Llama antibody fragments have good potential for application as HIV type 1 topical microbicides.
abstract: There is an urgent global need for preventive strategies against HIV-1 infections. Llama heavy-chain antibody fragments (VHH) are a class of molecules recently described as potent cross-clade HIV-1 entry inhibitors. We studied the potential of a VHH-based microbicide in an application-oriented fashion. We show that VHH can be inexpensively produced in high amounts in the GRAS organism Saccharomyces cerevisiae, resulting in a very pure and endotoxin free product. VHH are very stable under conditions they might encounter during transport, storage, or use by women. We developed active formulations of VHH in aqueous gel and compressed and lyophilized tablets for controlled release from an intravaginal device. The release profile of the VHH from, e.g., a vaginal ring suggests sufficient bioavailability and protective concentration of the molecule at the mucosal site at the moment of the infection. The ex vivo penetration kinetics through human tissues show that the VHH diffuse into the mucosal layer and open the possibility to create a second defense layer either by blocking the HIV receptor binding sites or by blocking the receptors of immune cells in the mucosa. In conclusion, our data show that VHH have a high potential for HIV-1 microbicide application because of their low production costs, their high stability, and their favorable release and tissue penetration properties.
authors.affiliation: Cellular Architecture and Dynamics, Department of Biology, Faculty of Science, Utrecht University, The Netherlands.
authors.forename: Andrea
authors.initials: A
authors.lastname: Gorlani
authors.forename: Joachim
authors.initials: J
authors.lastname: Brouwers
authors.forename: Christopher
authors.initials: C
authors.lastname: McConville
authors.forename: Pieter
authors.initials: P
authors.lastname: van der Bijl
authors.forename: Karl
authors.initials: K
authors.lastname: Malcolm
authors.forename: Patrick
authors.initials: P
authors.lastname: Augustijns
authors.forename: Anna Forsman
authors.initials: AF
authors.lastname: Quigley
authors.forename: Robin
authors.initials: R
authors.lastname: Weiss
authors.forename: Hans
authors.initials: H
authors.lastname: De Haard
authors.forename: Theo
authors.initials: T
authors.lastname: Verrips
mesh_terms: D000818:Animals; D000891:Anti-Infective Agents, Local / Q000494:pharmacology*; D000915:Antibody Affinity / Q000276:immunology; D002161:Camelids, New World / Q000276:immunology; D003274:Contraceptive Devices, Female; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006679:HIV Seropositivity / Q000188:drug therapy / Q000276:immunology*; D015497:HIV-1 / Q000187:drug effects* / Q000276:immunology; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000276:immunology* / Q000302:isolation & purification; D012441:Saccharomyces cerevisiae / Q000276:immunology*; D014622:Vaginal Creams, Foams, and Jellies
chemical_list: D000891:Anti-Infective Agents, Local; D007143:Immunoglobulin Heavy Chains; D014622:Vaginal Creams, Foams, and Jellies