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Design and Development of Immunotolerant S. aureus Biotherapies

Award Number: R42AI118133
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: 02/15/2015
PERIOD OF PERFORMANCE END DATE: 01/31/2020

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Design and Development of Immunotolerant S. aureus Biotherapies - The increasing incidence of multi-drug resistance in Staphylococcus aureus and other bacteria represents a public health crisis. Two thirds of hospital-associated S. aureus infections and ~50% of those acquired in the community are now methicillin-resistant (MRSA). MRSA causes >450,000 infections in the US each year, and it is responsible for half of all US deaths caused by drug-resistant bacteria. This threat to public health is creating demand for new therapeutic agents, but traditional antibiotic development pipelines are not keeping pace with the escalating problem. Moreover, antibacterial chemotherapies have proven widely susceptible to rapid evolution of bacterial resistance. Bacteriolytic enzymes, such as Staphylococcus simulans lysostaphin, are an innovative new class of antibiotics that catalytically dismantle cell wall peptidoglycan causing bacterial lysis and death. Due to peptidoglycan’s conserved nature and complex biosynthesis, such enzymes have proven less susceptible to emergent resistance. Unfortunately, lysostaphin elicits anti-drug antibodies in vivo, and this immunogenicity and associated toxicity are barriers to clinical translation. Supported by a successful Phase I STTR grant, Stealth Biologics has re-engineered lysostaphin for reduced immunogenicity in humans. The pivotal outcomes of the Phase I STTR project were: 1) design and construction of F12, a globally deimmunized variant of lysostaphin; 2) in vitro validation of F12’s anti-MRSA potency; 3) preliminary quantification of F12 synergy with FDA approved antibiotics; 4) demonstration of reduced immunogenicity in human cellular immunoassays; and 5) confirmation of reduced in vivo immunogenicity and consequent enhanced therapeutic efficacy in humanized HLA transgenic mice. Collectively, these data suggest that F12 is a promising therapeutic for drug-resistant S. aureus infections. In the proposed Phase II STTR, we have designed a systematic and focused strategy for constructing an F12 target product profile (TPP). In Aim 1, F12 manufacturing and purification will be optimized and scaled up. In Aim 2, an initial clinical indication will be selected based on F12’s in vivo efficacy in two well-established models: rabbit bacteremia/endocarditis and murine skin infection. Efficacy studies will be supported by rigorous experimental analyses of in vitro potency, in vitro resistance susceptibility, in vivo maximum tolerated dose, and in vivo pharmacokinetics. Aim 3 will yield a preliminary toxicity and immunogenicity profile in rabbits and humanized mice that have received escalating single or repeated doses of F12. The resulting data package will enable construction of a TPP that will guide design and execution of comprehensive IND-enabling studies. We anticipate that F12-based antibacterial therapies will prove to be potent, safe, and amenable to repeated dosing. As such, F12 will benefit from competitive advantages relative to more immunogenic phage endolysins, and ultimately it may represent a breakthrough drug for life-threatening MRSA infections.


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: 2021 ( Subtotal = $0 )
2021	2018	LYTICON LLC	16 CAVENDISH CT	LEBANON	NH	03766	GRAFTON	USA	Allergy and Infectious Diseases Research	000	3	10/19/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2018 ( Subtotal = $609,888 )
2018	2018	LYTICON LLC	16 CAVENDISH CT	LEBANON	NH	03766	GRAFTON	USA	Allergy and Infectious Diseases Research	000	3	1/17/2018	NON-COMPETING CONTINUATION	$609,888
														Subtotal = $609,888

Issue Date FY: 2017 ( Subtotal = $868,526 )
2017	2017	LYTICON LLC	201 DORCHESTER RD	LYME	NH	03768	GRAFTON	USA	Allergy and Infectious Diseases Research	001	2	7/25/2017	COMPETING CONTINUATION	$0
2017	2017	LYTICON LLC	201 DORCHESTER RD	LYME	NH	03768	GRAFTON	USA	Allergy and Infectious Diseases Research	000	2	1/24/2017	COMPETING CONTINUATION	$868,526
														Subtotal = $868,526

Grand Total All Awards = $1,478,414

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Design and Development of Immunotolerant S. aureus Biotherapies

Award Number: R42AI118133

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: 02/15/2015

PERIOD OF PERFORMANCE END DATE: 01/31/2020

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