Sexually transmitted infections, such as HIV and gonorrhea, are a major threat to human health worldwide. Antibiotic-resistant N. gonorrhoeae have emerged in all parts of the world. Safe and effective vaccines against gonorrhea and HIV remain elusive. Further, gonorrhea can increase transmission of HIV about 5-fold. Thus, there is an urgent need to develop novel methods to prevent these STIs. We have identified a murine monoclonal antibody (mAb) called 2C7 that is directed against a gonococcal lipooligosaccharide (LOS) epitope that is expressed by ~95% of clinical isolates, has complement-dependent bactericidal and opsonic activity and attenuates gonococcal infection in the mouse model. A chimeric version of mAb 2C7 (Ximab 2C7), created in an ongoing collaboration with Genmab, was also efficacious when administered intravaginally to mice. Introduction of a mutation in human IgG1 Fc that increases IgG hexamerization and enhances complement activation further enhanced activity of Ximab 2C7. This collaborative proposal between UMass, Planet Biotechnology, Inc., Oak Crest Institute of Science and MassBiologics seeks to develop intravaginal rings (IVRs) to deliver fully humanized mAb 2C7 in combination with tenofovir disoproxil fumarate (intravaginal TDF; proven efficacious in preventing HIV transmission to women) to prevent gonorrhea and HIV infections. In the R61 phase (years 1 and 2) of this proposal, we will i) fully humanize mAb 2C7 that contains the complement-enhancing Fc mutation (Humab 2C7), ii) produce functional Humab 2C7 at a relatively low cost in tobacco plants, iii) formulate Humab 2C7 along with the tenofovir into IVRs for local vaginal delivery and iv) prepare for and participate in a pre-IND meeting with the FDA. In the R33 phase (years 3-5) we will i) perform PK, release and toxicity studies following tenofovir and Humab 2C7 delivery via IVR in an ovine model, ii) test the efficacy of Humab 2C7 against contemporary clinical multidrug-resistant isolates in novel human factor H (FH) and C4b-binding protein (C4BP) dual transgenic mice (gonococci bind these complement inhibitors in a human specific manner, thus these mice will provide the `obstacles' that Humab 2C7 will have to surmount in humans), iii) elucidate the mechanism of action of Humab 2C7 in vivo using mice that lack complement components (C1q, C3, C5, C5aR) and /or phagocytes (PMNs, macrophages) and iv) develop a scalable purification process and a set of drug product release assays appropriate for technology transfer to a contract manufacturing organization. Successful completion of the proposed work will result in a clinically effective deliverable to prevent HIV and gonorrhea at the end of the funding period.
Sexually transmitted infections, such as HIV and gonorrhea, are a major threat to human health worldwide. Antibiotic-resistant N. gonorrhoeae have emerged in all parts of the world. Safe and effective vaccines against gonorrhea and HIV remain elusive. Further, gonorrhea can increase transmission of HIV about 5-fold. Thus, there is an urgent need to develop novel methods to prevent these STIs simultaneously.
| 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 |
