In 2013, the CDC listed Neisseria gonorrhoeae (Ng) is listed as one of the three multidrug-resistant pathogens that represented ?urgent? threats to human health worldwide. Ng has become resistant to almost every antibi-otic and has achieved ?superbug? status. Complications of gonorrhea include pelvic inflammatory disease, which may lead to infertility and ectopic pregnancy. Novel therapeutics against this pathogen are urgently needed. This collaboration between industry and academia seeks to further preclinical development of two immunotherapeutics against drug-resistant Ng. Each molecule targets a distinct epitope on Ng; both are im-portant for pathogenesis and thus ubiquitously expressed in vivo. Advantages of targeting distinct epitopes im-portant for virulence include i) synergistic activity and ii) raising the barrier for the development of drug re-sistance, if it were to occur. A chimeric mAb targets Ng and mediates complement (C?)-dependent killing of Ng in vivo. Several pathogens including Ng evade C? by binding to a host C? inhibitor called factor H (FH). FH comprises 20 domains, arranged in an extended head-to-tail fashion. FH domains 18-20 (lacks C? inhibitory function) fused to IgG Fc effects C?-dependent killing of Ng. FH domains 19 and 20 are important to limit un-wanted C? activation on host tissue. We introduced a D?G amino acid point mutation in domain 19 of FH18-20/Fc. This protein, called FH*/Fc, retains its efficacy against Ng in vitro and in vivo but does not lyse host cells.
In Aim 1 Planet Biotechnology, Inc. will produce the chimeric mAb and FH*/Fc in tobacco plants. This will permit efficient and low cost production. The efficacy of plant-produced FH*/Fc and the chimeric mAb against Ng in vitro and in mice will be tested by UMass in Aim 2. The drugs will be administered: i) systemically (mod-eling adjunctive treatment of established infection in men and women) or ii) intravaginally (modeling topical immunoprophylaxis in high-risk women). Each molecule will be tested individually and in combination for syn-ergy and to raise the barrier for drug resistance. Efficacy will also be assessed in novel transgenic (Tg) mice that express the human C? inhibitors, FH and C4b-binding protein, which Ng bind to in a human-specific man-ner to evade C?, and therefore represent barriers to the drugs that may be encountered in humans.
In Aim 3, Oak Crest Institute will formulate both drugs in combination in slow-release vaginal rings for use as topical im-munoprophylactics.
In Aim 4 Xenometrics will perform toxicology and toxicokinetic (TK) studies in rats and cynomolgus monkeys and Comparative Biosciences will perform tissue-cross reactivity studies.
In Aim 5, the mechanism of action of the chimeric mAb and FH*/Fc and will be defined in vivo using mice that lack C3, C5, PMNs and/or macrophages to define correlates of protection in vivo. These studies may lead to preparation for and participation in a pre-IND meeting with FDA (Aim 6).
In 2013, the CDC listed Neisseria gonorrhoeae (Ng) is listed as one of the three multidrug-resistant pathogens that represented `urgent' threats to human health worldwide. Ng has become resistant to almost every antibiotic and has achieved ?superbug? status. Complications of gonorrhea include pelvic inflammatory disease, which may lead to infertility and ectopic pregnancy. Novel therapeutics against this pathogen are urgently needed. This collaboration between industry and academia seeks to further preclinical development of two immunotherapeutics against drug-resistant Ng.
| Shaughnessy, Jutamas; Lewis, Lisa A; Zheng, Bo et al. (2018) Human Factor H Domains 6 and 7 Fused to IgG1 Fc Are Immunotherapeutic against Neisseria gonorrhoeae. J Immunol 201:2700-2709 |
| Ermert, David; Weckel, Antonin; Magda, Michal et al. (2018) Human IgG Increases Virulence of Streptococcus pyogenes through Complement Evasion. J Immunol 200:3495-3505 |
| Ram, Sanjay; Gulati, Sunita; Lewis, Lisa A et al. (2018) A Novel Sialylation Site on Neisseria gonorrhoeae Lipooligosaccharide Links Heptose II Lactose Expression with Pathogenicity. Infect Immun 86: |
| Blom, Anna M; Magda, Michal; Kohl, Lisa et al. (2017) Factor H-IgG Chimeric Proteins as a Therapeutic Approach against the Gram-Positive Bacterial Pathogen Streptococcus pyogenes. J Immunol 199:3828-3839 |
