Delivery of passive immunity against HIV using commensal vaginal Lactobacillus bioengineered to secrete broadly neutralizing domain antibodies

DESCRIPTION Women bear the brunt of the global AIDS epidemic due in part to their inherent social and biological vulnerability Biologically the cervical and vaginal mucosae are vulnerable targets for HIV transmission In healthy women of childbearing age mucosal antibodies and microbiota including Lactobacillus jensenii help protect these surfaces and serve to block the colonization and infection by intruding pathogens Epidemiological studies suggest that the loss of vaginal lactobacilli is associated with an increased risk of heterosexual HIV transmission and other sexually transmitted infections Osel Inc has used the properties of these natural protective agents by engineering a native human vaginal Lactobacillus L jensenii to express potent and broadly neutralizing single domain antibodies directed against HIV termed MucoCept Ab Osel recently showed proof of concept for this recombinant Lactobacillus approach by expressing an HIV entry inhibitor mCV N from L jensenii which reduced SHIV virus transmission in macaques by Lagenaur et al Mucosal Immunol Jul Phase II studies will advance MucoCept Ab through preclinical development These studies will focus on developing a safe efficacious and stable MucoCept Ab product and will include strain optimization formulation process development manufacturing preclinical safety testing and efficacy testing in a nonhuman primate NHP viral challenge model The goal of this Phase II is to develop a Lactobacillus strain capable of delivering an antibody locally to prevent HIV infection at the vaginal or rectal mucosa This strain will be formulated into a cost effective product capable of persistent protection that is coitally independent and controlled by women Aim MucoCept Ab API optimization and characterization A Complete MucoCept Ab strain optimization maximize promoter strength optimize codons for L jensenii remove epitope tag and test two genomic integration sites B Complete microbiological characterization of the MucoCept Ab strain genetic stability sequence chromosomal insertion site of expression cassette biochemical profiling antibiotic susceptibility resistant profiling AP m expressio levels C Establish ability of the MucoCept Ab strain to vaginally colonize female rhesus macaques Aim MucoCept Ab method development A Develop antibodies and ELISA to detect and measure AP m levels B Develop qPCR assay to measure levels of the MucoCept Ab strain Aim MucoCept Ab formulation process development and manufacturing A Develop formulation and lyophilization process for production of a stable MucoCept Ab product B Transfer MucoCept Ab strain and technology to GMP manufacturer for production of MCB and WCB scale up process development and production of MucoCept Ab for preclinical safety studies Aim MucoCept Ab preclinical safety and efficacy A Evaluate acute toxicity and systemic exposure of the MucoCept Ab strain and purified AP m protein following vaginal administration in mice B Evaluate acute toxicity of formulated MucoCept Ab in the rabbit vaginal irritation model C Evaluate subchronic toxicity vaginal colonization and AP m levels following vaginal administration of the MucoCept Ab product in female rhesus macaques D Evaluate efficacy of the MucoCept Ab product in female rhesus macaques using a repeated vaginal SHIV challenge protocol If successful this approach could provide a safe yet inexpensive means to deliver passive immunity against HIV to the vaginal mucosa and to address the urgent need for female controlled approaches to prevent sexually transmitted viral infection PUBLIC HEALTH RELEVANCE We are harnessing the vaginal microbiota to develop a fundamentally new female controlled and coital independent HIV preventative Technologies have been developed to bioengineer a human vaginal Lactobacillus strain to express a potent single domain antibody against HIV creating a live self renewing microbicide that can be formulated as a novel fast dissolving vaginal tablet This product is mechanistically different from other microbicides and has the potential to greatly impact global HIV AIDS acquisition in women of childbearing age