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A novel anti gonorrhea immunotherapeutic

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 1R41AI129106-01
Agency Tracking Number: R41AI129106
Amount: $242,093.00
Phase: Phase I
Program: STTR
Solicitation Topic Code: NIAID
Solicitation Number: PA15-270
Solicitation Year: 2015
Award Year: 2017
Award Start Date (Proposal Award Date): 2017-02-13
Award End Date (Contract End Date): 2018-03-31
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
WORCESTER, MA 01655-0002
United States

 Nonprofit College or University

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 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 domains arranged in an extended head to tail fashion
Only the four N terminal domains domains possess C inhibiting activity the remainder of the molecule
is important for recognition of host surfaces Many pathogens including Ng bind FH through domains
and or A recombinant fusion of FH domains to IgG Fc FH Fc promotes C dependent
killing of Ng Domains and in the context of full length FH bind to host cells and protect them from
damage by C Introducing a D G amino acid mutation in domain of FH Fc to yield FH Fc
retained anti Ng efficacy but abrogated C mediated lysis of host cells Topically administered FH Fc
attenuated Ng infection in the mouse vaginal colonization model Planet Biotechnology Inc PBI has
pioneered the production of functional antibodies and Fc fusion proteins in tobacco plants Nicotiana
benthamiana Production of large quantities of functional FH Fc in plants at relatively low costs
compared to traditional mammalian cell culture systems constitutes an ideal platform for developing anti
infective immunotherapeutics In Aim PBI will produce four FH Fc molecules differing in their Fc
three with human Fc hFc for studies in vitro and one with mouse Fc mFc for studies in mice The three
different hFcandapos s fused to FH will be i Fc from IgG equivalent to what has been produced in CHO
cells ii a linear chimera comprising IgG Fc plus CH and CH from IgA and iii Fc from IgA We
expect human IgA Fc to increase ADCC by engaging Fc RI on human neutrophils In Aim UMass will
examine the ability of the three FH hFcandapos s described above to i bind to ii deposit C on iii effect C
dependent killing of and iv support opsonophagocytosis of drug resistant Ng The efficacy of FH mFc
against Ng will be tested in the mouse vaginal colonization model using human FH transgenic BALB c mice
The use of these novel mice will evaluate the therapeutic in the context of human FH as would occur in
humans We also speculate that FH Fc may guide bacteria to Fc receptors on antigen presenting cells
and elicit an immune response that may protect mice against reinfection This possibility will be addressed by
re infecting the mice following FH Fc or control treatment We envision the use of FH Fc
either as a topical prophylactic in women at high risk for gonorrhea or as a parenteral adjunctive anti infective
While this proposal focuses on Ng we believe FH Fc will be useful against several medically important
drug resistant pathogens that bind to human FH Gonorrhea a sexually transmitted infection that adversely affects the reproductive health of women worldwide
has become resistant to almost every conventional antibiotic In an effort to develop new therapies against
gonorrhea we have created a chimeric Fc fusion protein that activates complement on and kills gonococci In
this proposal we will develop additional chimeric molecules with novel Fc modifications and produce these
fusion proteins in tobacco plants which will provide an economical alternative to develop adjunctive
treatments against multidrug resistant gonorrhea

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

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