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Image-guided, intra-arterial delivery of antibodies to the central nervous system

Award Number: R01NS120929
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/15/2021
PERIOD OF PERFORMANCE END DATE: 02/28/2026

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Image-guided, intra-arterial delivery of antibodies to the central nervous system - Central nervous system (CNS) diseases including neurological, oncological and psychiatric conditions are the biggest healthcare expense worldwide. Biotechnological drugs such as antibodies are a frontline of therapeutic progress elsewhere in the body, but the CNS diseases rarely benefit from them mostly due blood brain barrier (BBB) limiting their penetration to the brain, as they have relatively large size. The benefit of macromolecules mostly comes from higher specificity and safety over traditional small molecule approaches. Intra-arterial route of delivery of therapeutic agents to the brain is an intuitive approach and it has been attempted for years but so far it has been plagued by the variability. We have recently shown that real-time MRI guidance is capable to overcome these limitations. Moreover, macromolecules such as antibodies can be far easier tagged and imaged than small molecules in majority of circumstances, which provides a unique opportunity to be even more precise. Radiolabeling of antibodies can be performed by chelation of radiometals, which is relatively simple process to be completed even by a biologist, and radionuclides can be easily shipped from all over the country so no need for on-site cyclotron is needed. We have been first to show the feasibility of merging technologies of antibody radiolabeling and intra-arterial delivery and observed impressive benefits of this route of delivery. While, our early results are quite compelling there are still many puzzles to be put together to better understand the advantages of intra-arterial route as they might be crucial for a proper design of intra-arterial injections in patients, not only to eradicate variability but also to learn what are the optimal conditions to take the most of the procedure. First, here we will learn how the antibody concentration in cerebral vasculature contributes to their extravasation as well as we will look into the potential role of plasma-antibody interaction as a factor limiting extravasation of intravenously administered antibody. This knowledge will provide clear guidelines on a positioning catheter during intra-arterial infusions in patients, as if high concentration and no exposure of antibody to blood are contribution factors, then the catheter should be placed quite distally in the cerebral vessels to maximize the benefit of intra-arterial route. Then, we will learn what is the optimal concentration to perform procedure safely while to maximize the brain uptake of antibodies. While, the direct numbers will apply to mice only, it will also give a context to considerations to clinical translation. Then, we will study in detail the potential impact of antibody delivery to the CNS on essential brain processes through getting insight into transcriptomics and proteomics to detect potential negative consequences, which would then serve as a basis for finding countermeasures. Ultimately, we will look into antibody clearance from the brain and the role of targets for brain retention of antibodies. This part will also allow to assess the difference in antibody extravasation to the brain cancer as well as will provide preliminary data on their therapeutic activity.


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 = $386,250 )
2025	2025	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	5	8/5/2025	NON-COMPETING CONTINUATION	$38,625
2025	2025	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	3/4/2025	NON-COMPETING CONTINUATION	$347,625
														Subtotal = $386,250

Issue Date FY: 2024 ( Subtotal = $374,663 )
2024	2024	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	4/9/2024	NON-COMPETING CONTINUATION	$27,038
2024	2024	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	3/5/2024	NON-COMPETING CONTINUATION	$347,625
														Subtotal = $374,663

Issue Date FY: 2023 ( Subtotal = $386,250 )
2023	2023	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	5/12/2023	NON-COMPETING CONTINUATION	$386,250
2023	2023	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	8/17/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $386,250

Issue Date FY: 2022 ( Subtotal = $386,250 )
2022	2022	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	4/6/2022	NON-COMPETING CONTINUATION	$386,250
2022	2021	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	4/6/2022	NEW	$0
														Subtotal = $386,250

Issue Date FY: 2021 ( Subtotal = $386,250 )
2021	2021	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	4/5/2021	NEW	$386,250
														Subtotal = $386,250

Grand Total All Awards = $1,919,663

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Image-guided, intra-arterial delivery of antibodies to the central nervous system

Award Number: R01NS120929

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/15/2021

PERIOD OF PERFORMANCE END DATE: 02/28/2026

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