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Immunotherapy of MRSA Osteomyelitis

Award Number: R44AI155309
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: 05/12/2021
PERIOD OF PERFORMANCE END DATE: 04/30/2025

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Immunotherapy of MRSA Osteomyelitis - Methicillin-resistant Staphylococcus aureus (MRSA) causes invasive infections in about 80,000 Americans every year with a 14% overall mortality rate, despite the availability of drugs that are active against MRSA. In addition, a significant number of invasive diseases with treatment failure and mortality can occur as a result of methicillin- sensitive S. aureus (MSSA) infection in critically ill and immunosuppressed patients. S. aureus is the leading cause of prosthetic joint infections (PJI). Remarkably, infection rates following total joint arthroplasty (TJA) and trauma surgery have remained largely unchanged over the last 50 years. Treatment failure rate for PJIs caused by S. aureus is as high as 38%. Reinfection rates from MRSA are very high (15-40%), and often require a two- stage exchange arthroplasty. Treatment failure rates as high as 33-59% and mortality rates of 7%-24% have been reported after two-stage revision surgery. Thus, given the growing burden and the severity of disease and the high rate of treatment failure after antibiotics treatment, alternatives like adjunct immunotherapies that can increase the treatment success are urgently needed. We have demonstrated a key role for N- acetylglucosaminidase (Gmd), a key enzyme in binary fission during S. aureus cellular division, during the infection-mediated invasion of the bone, a critical step in osteomyelitis. We developed a potent anti-Gmd neutralizing monoclonal antibody, TPH-101, and demonstrated the efficacy of this fully human antibody in a murine model of implant-induced S. aureus osteomyelitis as well as its adjunct efficacy in a revision surgery model of implant-associated S. aureus infection in combination with vancomycin. Having already established the proof of concept in relevant animal models, under this Direct to Phase II SBIR application, we will complete rigorous safety, efficacy and pharmacokinetic (PK) studies in sophisticated murine and rabbit models of implant- associated osteomyelitis, complete cell line and process development, hold a pre-IND meeting with FDA, and complete the IND-enabling safety and pharmacokinetic studies. The proposal has fours Specific Aims. In Aim 1 we will remove any potential sequence liabilities and test the antibody in a rabbit model of orthopedic implant- associated infection. In Aim 2 we will develop bioanalytical methods for release, potency, PK, and stability, and conduct preliminary dose translation studies. A stable CHO cell line will be developed in Aim 3 for high yield manufacturing. In Aim 4, a scalable manufacturing process will be developed, a toxicology lot produced, and a pre-IND meeting will be held with FDA to seek feedback on pre-clinical and clinical safety plans. The toxicology lot will be used in GLP-safety pharmacology studies in animals and human tissue samples. Upon completion of this SBIR, the product is positioned for cGMP manufacturing, IND filing and initiation of clinical development.


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: 2025 ( Subtotal = -$376 )
2025	2023	ABVACC, INC.	4 RESEARCH CT	ROCKVILLE	MD	20850	MONTGOMERY	USA	Allergy and Infectious Diseases Research	000	3	9/9/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$376
														Subtotal = -$376

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2023	ABVACC, INC.	4 RESEARCH CT	ROCKVILLE	MD	20850	MONTGOMERY	USA	Allergy and Infectious Diseases Research	001	3	1/19/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$426,581
2024	2022	INTEGRATED BIOTHERAPEUTICS, LLC	4 RESEARCH CT STE 300	ROCKVILLE	MD	20850	MONTGOMERY	USA	Allergy and Infectious Diseases Research	000	2	1/19/2024	NON-COMPETING CONTINUATION	-$426,581
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $1,000,000 )
2023	2023	ABVACC, INC.	4 RESEARCH CT	ROCKVILLE	MD	20850	MONTGOMERY	USA	Allergy and Infectious Diseases Research	001	3	4/21/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$1,000,000
2023	2022	INTEGRATED BIOTHERAPEUTICS INC	4 RESEARCH CT	POTOMAC	MD	20850	MONTGOMERY	USA	Allergy and Infectious Diseases Research	000	2	4/21/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $1,000,000

Issue Date FY: 2022 ( Subtotal = $1,000,000 )
2022	2022	INTEGRATED BIOTHERAPEUTICS, INC.	4 RESEARCH COURT, SUITE 300	ROCKVILLE	MD	20850	MONTGOMERY	USA	Allergy and Infectious Diseases Research	000	2	3/22/2022	NON-COMPETING CONTINUATION	$1,000,000
														Subtotal = $1,000,000

Issue Date FY: 2021 ( Subtotal = $1,000,000 )
2021	2021	INTEGRATED BIOTHERAPEUTICS, INC.	4 RESEARCH COURT, SUITE 300	ROCKVILLE	MD	20850	MONTGOMERY	USA	Allergy and Infectious Diseases Research	000	1	5/11/2021	NEW	$1,000,000
														Subtotal = $1,000,000

Grand Total All Awards = $2,999,624

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Immunotherapy of MRSA Osteomyelitis

Award Number: R44AI155309

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: 05/12/2021

PERIOD OF PERFORMANCE END DATE: 04/30/2025

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