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An immunotherapeutic to prevent gonorrhea

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 4R44AI147930-02
Agency Tracking Number: R44AI147930
Amount: $1,727,108.00
Phase: Phase II
Program: SBIR
Solicitation Topic Code: NIAID
Solicitation Number: PA18-574
Solicitation Year: 2018
Award Year: 2020
Award Start Date (Proposal Award Date): 2020-03-11
Award End Date (Contract End Date): 2022-02-28
Small Business Information
Hayward, CA 94545-2740
United States
DUNS: 052917593
HUBZone Owned: No
Woman Owned: No
Socially and Economically Disadvantaged: No
Principal Investigator
 (510) 887-1461
Business Contact
Phone: (510) 887-1461
Research Institution

Antimicrobial resistance is a major public health problem worldwide. Neisseria gonorrhoeae (Ng), the
causative agent of the sexually transmitted infection gonorrhea, has become multidrug-resistant and has achieved
“superbug” status. In addition, between 6% and 12% of women successfully treated for gonorrhea are re-infected
within three months. Novel therapeutics against Ng are urgently needed. Complement (C′) is a key arm of innate
immune defenses. A mechanism used by several pathogens, including Ng, to escape C′ is to bind to a host C′
inhibitor called factor H (FH). FH comprises 20 domains, arranged in an extended head-to-tail fashion. Only the
four N-terminal domains (domains 1-4) possess C′ inhibiting activity; the remainder of the molecule is important
for recognition of host surfaces. Many pathogens, including Ng, have evolved to bind FH through domains 6-7
and/or 18-20. A recombinant fusion of FH domains 18-20 (with a point mutation in domain 19 to abrogate binding
to host cells) to IgG Fc (FH*/Fc) binds to and promotes C′-dependent killing of Ng. Topically administered FH*/Fc
attenuates Ng infection in the mouse vaginal colonization model.We have produced, in our plant expression system, variant FH*/Fc molecules with different Fc or different
linkers between FH and Fc. We demonstrated the functional superiority of plant-made FH*/Fc variants
incorporating flexible linkers, (GGGGS)2 or (GGGGS)3, both in vitro and in a mouse vaginal infection prophylactic
model. We have also shown that the functionality of these molecules depends on the ability of the Fc to activate
complement on the Ng surface.We envision using FH*/GS-hFc to prevent re-infection in women treated for uncomplicated gonorrhea. In
this Fast-Track project we seek to further preclinical development of this promising immunotherapeutic against
drug-resistant Ng. In Phase I we will produce and test in vitro five new FH*/GS-hFc variants where the Fc is
modified to improve C´-mediated killing of Ng and identify two lead variants with the greatest potency. In Phase
II we will compare the potency of these FH*/GS-hFc lead variants in vivo against four divergent Ng isolates,
determining the minimum effective dose. We will test their in vitro potency against 50 diverse Ng clinical isolates.We will scale up purification and evaluate the ability of the two lead variants to undergo spray-drying and
retain in vitro potency. Based on the sum of all the above experiments, we will select one variant as a lead for
commercialization. We will formulate the lead FH*/GS-hFc variant in an intravaginal ring designed for sustained,
controlled release over several weeks, and evaluate its PK and safety in rhesus macaques. We will perform a
six-month drug substance stability study in anticipation of a future Phase 1 clinical trial. With the help of a large
contract manufacturer of plant-made proteins, we will conduct a technoeconomic analysis to determine the
commercial viability of plant-made FH*/GS-hFc, and seek the guidance of the FDA on future FH*/GS-hFc non-
clinical and clinical development.Gonorrhea, a sexually transmitted infection that adversely affects the
reproductive health of women worldwide, has become resistant to almost every
conventional antibiotic. We have produced, in a plant expression system, a chimeric Fc
fusion protein that activates complement on and kills gonococci. In this proposal, we will
test variants of this protein for enhanced activity in vivo and in vivo and will conduct
additional nonclinical studies designed to progress the product toward a Phase 1 clinical
trial and commercial development as an immunoprophylactic or as an adjunctive
treatment against multidrug-resistant gonorrhea.

* Information listed above is at the time of submission. *

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