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ISTAb- A novel therapy to target staphylococcal toxins at the site of infections

Award Number: R43AI136143
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2019
PERIOD OF PERFORMANCE END DATE: 03/31/2022

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ISTAb- A novel therapy to target staphylococcal toxins at the site of infections - Project Summary Many bacterial pathogens secrete exotoxins to modify the host-pathogen interactions in a manner that benefits the bacteria. There are several examples of successful prophylaxis and treatment by targeting bacterial toxins as evident by decades-long history of vaccines for tetanus, diphtheria, and pertussis. Staphylococcus aureus (SA) is a major human pathogen responsible for several hundred thousand of hospitalizations and over 12,000 death in the US every year. SA produces a plethora of toxins including pore-forming toxins (PFTs) that play a key role in pathogenesis and immune evasion. While neutralization of these toxins by monoclonal antibodies (mAbs) is expected to reduce clinical disease, it is unlikely to uproot invasive disease, as suggested by recent failure of a PFT mAb cocktail to prevent SA ventilator associated pneumonia (Arsanis clinical trial). We have devised a novel approach to target neutralizing anti-toxin mAbs specifically to the site of infection enabling instant toxin neutralization and mediating opsonophagocytic killing (OPK) at the same time. The approach exploits the cell wall targeting domains (CWT) of a phage-derived bacteriolysin which binds with species-specificity and high affinity to cell wall components of specific bacteria. The CWT is fused to specific anti-toxin mAbs to generate Infection Site Targeted Antitoxin antibodies (ISTAbs). We have successfully applied this to B. anthracis and C. difficile under NIAID support. In this proposal we aim to develop ISTAbs for S. aureus using the isolated CWT of lysostaphin along with potent PFT neutralizing mAbs. ISTAbs are expected to accumulate where they are needed most, i.e. at the site of infection; they capture and sequester the toxins, thus immediately neutralizing the immune suppressive effects of the toxins and preventing their release into circulation. Bacterium-ISTAb-toxin complex is then cleared by phagocytes. Concurrent toxin neutralization and bacterial clearance is a unique advantage of the ISTAb technology over mere antitoxin treatment. In this proposal, we will use a set of broadly neutralizing S. aureus PFT mAbs to generate ISTAbs with lysostaphin CWT. However, because IgG binding to protein A on the surface of S. aureus interferes with opsonophagocytic killing and may even cause immunopathology, we will create and test mutant ISTAbs that do not bind protein A. In Aim 1, these ISTAbs will be generated and characterized for biophysical and functional properties, including neutralization and OPK activity, to select a short list for in vivo efficacy studies. In Aim 2, we will evaluate the efficacy of ISTAbs in different mouse models of S. aureus infection including pneumonia, sepsis and surgical wound infection. Upon completion of the Phase I SBIR we anticipate a Phase II project to expand the efficacy studies to invasive infection models in rabbits including sepsis, prosthetic joint infection, ventilator associated pneumonia, and endocarditis models as well as IND-enabling studies.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2020	INTEGRATED BIOTHERAPEUTICS, LLC	4 RESEARCH CT STE 300	ROCKVILLE	MD	20850	MONTGOMERY	USA	Allergy and Infectious Diseases Research	000	2	6/20/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $300,000 )
2020	2020	INTEGRATED BIOTHERAPEUTICS, INC.	4 RESEARCH COURT, SUITE 300	ROCKVILLE	MD	20850	MONTGOMERY	USA	Allergy and Infectious Diseases Research	000	2	3/11/2020	NON-COMPETING CONTINUATION	$300,000
														Subtotal = $300,000

Issue Date FY: 2019 ( Subtotal = $300,000 )
2019	2019	INTEGRATED BIOTHERAPEUTICS, INC.	4 RESEARCH COURT, SUITE 300	ROCKVILLE	MD	20850	MONTGOMERY	USA	Allergy and Infectious Diseases Research	001	1	7/18/2019	NEW	$0
2019	2019	INTEGRATED BIOTHERAPEUTICS, INC.	4 RESEARCH COURT, SUITE 300	ROCKVILLE	MD	20850	MONTGOMERY	USA	Allergy and Infectious Diseases Research	000	1	3/11/2019	NEW	$300,000
														Subtotal = $300,000

Grand Total All Awards = $600,000

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ISTAb- A novel therapy to target staphylococcal toxins at the site of infections

Award Number: R43AI136143

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 04/01/2019

PERIOD OF PERFORMANCE END DATE: 03/31/2022

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