Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 600.00K | Year: 2012
DESCRIPTION (provided by applicant): The ultimate goal of this proposal and any subsequent phase II proposal is to develop a unique protein agent to prevent Clostridium difficile associated diseases in those patients at high risk rather than wait to treattheir dangerous and costly infections. We aim in this SBIR phase I project to determine the feasibility of oral delivery of a lead, specifically targeted bactericidal protein to eliminate C. difficile cariage without untended collateral damage to the intestinal microbiota. The lead candidate, termed a diffocin , kills 27 of a collection of 28 BI/NAP1/027 strains; and Lawley et al (2010) have described a mouse model of C. difficile carriage. We have recently shown that another engineered R-type bacteriocin administered orally to rabbits can transit the GI tract to act as a specific bactericidal agent killing another bacterial pathogen in the terminal ileum and colon. Thus, after improving the lab scale production of this lead recombinant protein in B. subtilis and conducting preliminary pharmacology and pharmacodynamic studies to guide dosing, we shall evaluate the efficacy of diffocins in C57Bl/6 mice that are asymptomatic carriers and shedders of a sensitive strain of C. difficile. If diffocins eliminateC. difficile from carrier mice, the efect of oral diffocins on the mouse intestinal microbiota will be determined by ribotyping the fecal microbiome of normal and C. difficile carrier mice after diffocin administration. PUBLIC HEALTH RELEVANCE: Clostridium difficile is a bacterium that can reside in human intestines and not cause disease until the healthy bacteria sharing the intestinal space are damaged by antibiotics. Because Clostridium difficile bacteria are usually resistant to antibiotics they can then proliferate, make potent toxins, and cause severe diarrhea and potentially lethal inflammation of the colon. Such infections are now more common in hospitals than MRSA. We have discovered, cloned and made a protein that specifically kills the most toxic form of Clostridium difficile bacteria. We intend to determine whether this agent, a diffocin , when administered orally is capable of eliminating Clostridium difficile bacteria residing innocuously i the intestine of a mouse model of the humaninfection. If so, we plan to develop this bacteria-killing protein as an agent to kill Clostridium difficile present in patients before they receive antibiotics and thereby prevent the severe, recurring infections without damaging the healthy bacteria ofthe gut.
Avidbiotics Corporation | Date: 2011-05-27
This disclosure relates to the discovery and isolation of the entire cluster of genes encoding R-type high molecular weight bacteriocins that specifically kill
Avidbiotics Corporation | Date: 2014-06-20
This invention describes soluble, monovalent, non-natural protein molecules that can activate NK cells and certain T-cells to attack specific cellular target cells by attaching the NKG2D-binding portions of monovalent MICA or MICB protein, i.e. their 1-2 platform domain, to the intended target cell specifically. The 1-2 domain is contiguous with a heterologous 3 domain that has been genetically modified to bind directly or indirectly to the extracellular aspect of the target cell, thereby serving as the targeting domain. The genetic modification to create a non-natural and non-terminal targeting motif within the 3 domain can include a portion of an antibody, another protein molecule or portion thereof, a peptide, or a non-natural, modified 3 domain of a MIC protein.
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 1.07M | Year: 2009
DESCRIPTION (provided by applicant): In our Phase 1 project we have developed R-type pyocins, targetable bactericidal proteins, that kill the plague bacterium, Yersinia pestis, in vitro and are not sensitive to the mechanisms that bacteria use to resist antibiotics. Thus, these agents are candidates for protecting or treating humans exposed to plague, particularly strains that have been engineered to be broadly resistant to traditional antibiotics. The same R-type pyocins that can kill Y. pestis in vitro have efficacy when administered intraperitoneally or intravenously to mice infected systemically with Pseudomonas aeruginosa. This Phase 2 application proposes to characterize the immunogenicity of R-type pyocins in mice and then determine whether PEGylation of pyocins can reduce their immunogenicity without compromising potency. In addition, we shall complete pharmacokinetic (PK) characterizations of R-type pyocins in mice and rats and establish antimicrobial pharmacodynamic (PD) parameters in mice. These latter studies are necessary to generate PK and PD parameters to guide an efficacy study of R-type pyocins in mice with virulent pneumonic plague under BSL-3 containment. Allometric scaling parameters derived from the PK studies in 2 rodent species will provide guidance for the eventual Phase 1 IND safety and PK studies in humans, not part of this application. The proposed studies will provide critical information about: (1) the immunogenicity of R-type pyocins in mice and modulation of their immunogenicity by selective PEGylation. (2) the pharmacokinetic parameters of these potent bactericidal proteins in mice and rats (3) the antimicrobial pharmacodynamic parameters of R-type pyocins in mice lethally infected with Pseudomonas aeruginosa (4) the efficacy of R-type pyocins in murine pneumonic plague. PUBLIC HEALTH RELEVANCE: Yersinia pestis (plague bacteria) is a Category A pathogen that is deemed a significant threat to the U.S. as a biowarfare agent. If weaponized in an aerosol form, plague can easily gain access to the human respiratory system to cause pneumonia, shock and death within one day. Pneumonic plague, with its rapid progression and fatality rates over 80%, is much more difficult to treat than bubonic plague. Furthermore, this form of plague is highly contagious, being easily passed from human to human or animal to human. Because much of the biology of how bacteria develop drug resistance now is known and a clinical isolate of Y. pestis resistant to 9 antibiotics has been described, weaponized plague bacteria resistant to most front-line antibiotics is a real threat, i.e. a superweapon. We have discovered and designed R-type pyocins that kill plague bacteria in the tube and are not sensitive to the multiple mechanisms bacteria deploy to resist antibiotics. We propose to conduct the pharmacologic studies necessary for the development of R-type pyocins as targetable bactericidal proteins against plague and to demonstrate the efficacy of these R-type pyocins in an animal model of pneumonic plague.
Avidbiotics Corporation | Date: 2013-03-12
Recombinant P4 bacteriophage containing modified tail fibers having a base plate attachment region (BPAR) from a P2 bacteriophage gene H product and a heterologous receptor binding domain (RBD) are disclosed. Methods for the use of the recombinant P4 bacteriophage, such as to detect the presence of a target bacterium in a sample, are also described.