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Precision Delivery and Imaging to Enhance Solid Tumor Therapy

Award Number: P01CA221775
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/08/2019
PERIOD OF PERFORMANCE END DATE: 12/31/2024

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Precision Delivery and Imaging to Enhance Solid Tumor Therapy - PROJECT 1 SUMMARY Existing antibody-based interventions for cancer rely on passive delivery of the circulating drug that depends on a large concentration gradient across the semi-permeable wall of blood vessels to get inside tumors. The forces driving the drug from the bloodstream into tumors result in sub-optimal delivery and poor access to tumor cells, in part because endothelial cells (EC) forming the vascular wall constitute a significant, limiting barrier. We intend to boost precision delivery into primary and metastatic tumors by overcoming the vascular EC barrier through a highly precise, active transport pathway that we discovered through proteomic imaging and named the caveolae pumping system. The approach proposed here to enhance delivery goes well beyond typical so- called 'active targeting' of antibodies. Our lead humanized antibody against Annexin A1 (hAnnA1), a tumor- specific antibody concentrated in EC caveolae, not only binds its intended target but is actually the first antibody to penetrate solid tumors actively, rapidly and specifically. It does so even at very low dosages and reaches unprecedented intra-tumoral concentrations well beyond the highest blood levels after injection. It is now time to test this unprecedented immunotargeting in humans. We propose here to develop a radiolabeled humanized mAnnA1 to detect and destroy primary and metastatic lesions. Major aims of this project are to: 1-2) evaluate in vivo delivery and efficacy of novel caveolae-targeting radioimmunoconjugates in hard-to-treat metastatic tumor models of breast cancer; 3) test the effectiveness of caveolae pumping in human tumor blood vessels using PDX and novel human IVM tumor models; and translate hAnnA1 towards clinical testing. We will 4) determine here the degree to which caveolae can be targeted to pump radiolabeled antibodies across vascular EC to concentrate them inside solid tumors as means to improve image-guided drug delivery and enhance their efficacy. Antibodies will be provided by Core B and radiolabeled with assistance provided by Core D for preclinical work. Several mammary tumor models will be used to assess the ability of radiolabeled hAnnA1 to target primary and metastatic tumors via imaging services provided in Core C. We will study by intravenously injected hAnnA1 with advanced multimodality in vivo imaging to quantify and optimize precision transvascular delivery and tumor penetration. As the utility of caveolae targeting in humans requires AnnA1 expression in tumor EC caveolae, we will use Core C imaging services to compare vascular expression of AnnA1 in preclinical tumor models and human tumors. To translate our findings for clinical testing, we will test hAnnA1, humanize further if needed and partner with NCI's NExT program for cGMP production, quality control and toxicology of hAnnA1. With Core D, Project 3 will optimize hAnnA1 radiolabeling necessary to conduct a first-in-human imaging trial as a direct result of successful translation of our findings from Project 1 into the clinic.


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 = $0 )
2025	2023	PROTEOGENOMICS RESEARCH INSTITUTE FOR SYSTEMS MEDICINE	505 COAST BLVD S STE 209	LA JOLLA	CA	92037	SAN DIEGO	USA	Cancer Detection and Diagnosis Research	000	5	4/24/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $2,519,995 )
2023	2023	PROTEOGENOMICS RESEARCH INSTITUTE FOR SYSTEMS MEDICINE	505 COAST BLVD S	LA JOLLA	CA	92037	SAN DIEGO	USA	Cancer Detection and Diagnosis Research	000	5	6/29/2023	NON-COMPETING CONTINUATION	$2,519,995
														Subtotal = $2,519,995

Issue Date FY: 2022 ( Subtotal = $2,534,428 )
2022	2022	PROTEOGENOMICS RESEARCH INSTITUTE FOR SYSTEMS MEDICINE	505 COAST BLVD S STE 209	LA JOLLA	CA	92037	SAN DIEGO	USA	Cancer Detection and Diagnosis Research	000	4	6/28/2022	NON-COMPETING CONTINUATION	$2,534,428
														Subtotal = $2,534,428

Issue Date FY: 2021 ( Subtotal = $2,678,066 )
2021	2021	PROTEOGENOMICS RESEARCH INSTITUTE FOR SYSTEMS MEDICINE	505 COAST BLVD S STE 209	LA JOLLA	CA	92037	SAN DIEGO	USA	Cancer Detection and Diagnosis Research	000	3	7/12/2021	NON-COMPETING CONTINUATION	$2,678,066
														Subtotal = $2,678,066

Issue Date FY: 2020 ( Subtotal = $2,667,097 )
2020	2020	PROTEOGENOMICS RESEARCH INSTITUTE FOR SYSTEMS MEDICINE	505 COAST BLVD S STE 209	LA JOLLA	CA	92037	SAN DIEGO	USA	Cancer Detection and Diagnosis Research	000	2	8/31/2020	NON-COMPETING CONTINUATION	$2,667,097
														Subtotal = $2,667,097

Issue Date FY: 2019 ( Subtotal = $2,788,878 )
2019	2019	PROTEOGENOMICS RESEARCH INSTITUTE FOR SYSTEMS MEDICINE	505 COAST BLVD S STE 209	LA JOLLA	CA	92037	SAN DIEGO	USA	Cancer Detection and Diagnosis Research	000	1	7/8/2019	NEW	$2,788,878
2019	2019	PROTEOGENOMICS RESEARCH INSTITUTE FOR SYSTEMS MEDICINE	505 COAST BLVD S STE 209	LA JOLLA	CA	92037	SAN DIEGO	USA	Cancer Detection and Diagnosis Research	001	1	7/15/2019	NEW	$0
														Subtotal = $2,788,878

Grand Total All Awards = $13,188,464

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Precision Delivery and Imaging to Enhance Solid Tumor Therapy

Award Number: P01CA221775

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/08/2019

PERIOD OF PERFORMANCE END DATE: 12/31/2024

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