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Factor H Fc fusions as novel therapeutics for Burkholderia pseudomallei infections

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 1R41AI177227-01A1
Agency Tracking Number: R41AI177227
Amount: $300,000.00
Phase: Phase I
Program: STTR
Solicitation Topic Code: NIAID
Solicitation Number: PA22-178
Timeline
Solicitation Year: 2022
Award Year: 2023
Award Start Date (Proposal Award Date): 2023-08-10
Award End Date (Contract End Date): 2025-07-31
Small Business Information
20980 Corsair Boulevard
Hayward, CA 94545-2740
United States
DUNS: 052917593
HUBZone Owned: No
Woman Owned: No
Socially and Economically Disadvantaged: No
Principal Investigator
 KEITH WYCOFF
 (510) 887-1461
 kwycoff@planetbiotechnology.com
Business Contact
 ELLIOTT FINEMAN
Phone: (510) 887-1461
Email: efineman@planetbiotechnology.com
Research Institution
 UNIVERSITY OF TOLEDO
 
2801 WEST BANCROFT STREET
TOLEDO, OH 43606-3390
United States

 Nonprofit College or University
Abstract

Burkholderia pseudomallei (Bp) is the causative agent of melioidosis, a major cause of morbidity and
septic death in tropical/subtropical regions worldwide. It is particularly virulent in diabetic patients and is also
considered a Tier 1 select agent due to its potential use as a bioweapon. These bacteria are naturally resistant
to many antibiotics and there are currently no vaccines available. Thus, there is a great interest in identifying
targets for curative/preventative therapies. Like many human pathogens, Bp is adept at evading killing by
complement, a critical arm of innate immunity. Preliminary data generated by a co-investigator on this grant
showed that virulent Bp are very efficient at binding host Factor H (FH), a regulatory protein that inhibits C3
deposition, thus preventing complement activation on host cells. FH comprises 20 domains called short
consensus repeats (SCR), but only the four N-terminal SCR (SCR 1-4) possess complement inhibiting activity.
The ability to bind host FH, either via SCR6-7 or SCR18-20, is a common mechanism used by several pathogens
(now including Bp) to escape complement-mediated killing.Planet Biotechnology Inc (PBI) is developing therapeutic recombinant proteins containing specific FH
SCRs (those that bind to pathogens) fused to IgG Fc. In preliminary experiments we have shown that a construct
with IgG3 Fc N-terminal to SCR18-20 (Fc3/SCR(18-20)), promotes complement deposition and show potential
for mediating killing of Bp. The goal of this proposal is to further modify Fc3/SCR(18-20) to become more effective
at promoting direct killing, phagocyte uptake and killing of Bp, and potentially activating host cell cytoplasmic
killing pathways.We will start by producing variants of Fc3/SCR(19-20) with both short and long hinges, intended to
optimize either direct complement-mediated killing or opsonophagocytosis, respectively. We will also produce a
construct with Fc modifications intended to improve binding to the intracellular Fc receptor, TRIM21, and thus
enhance antibody-dependent intracellular neutralization (ADIN). We will purify and characterize sufficient
amounts of these new FH-Fc variants to be tested in vitro and in vivo against virulent strains of Bp.We will test the ability of the new Fc3/SCR(19-20) variants to: 1) bind to Bp, 2) promote C3 deposition
and membrane attack complexes (MAC) formation on Bp, 3) promote direct killing in the presence of serum, 4)
promote uptake and intracellular killing by macrophages and neutrophils, and 5) promote killing of Bp in mice if
administered either before or after infection, so as to significantly decrease the development of melioidosis.To evaluate potential activity of Fc3/SCR(19-20) against the “normal” intranasal flora, we will obtain
cultures representative of human nasal commensal (non-pathogenic) species from ATCC and evaluate their
sensitivity to killing by complement in the presence and absence of Fc-SCR(19-20). We will also evaluate the
ability of Fc-SCR(19-20) to enhance complement deposition on normal human erythrocytes.

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

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