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A Brain Penetrating Bi-functional Transferrin Receptor Antibody-TNF-alpha Decoy Receptor Fusion Protein for Alzheimer's Disease

Award Number: R01AG062840
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2019
PERIOD OF PERFORMANCE END DATE: 04/30/2025

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A Brain Penetrating Bi-functional Transferrin Receptor Antibody-TNF-alpha Decoy Receptor Fusion Protein for Alzheimer's Disease - PROJECT SUMMARY / ABSTRACT Alzheimers disease (AD) clinical trials have primarily been anti-Aβ and anti-tau centric, however this single-target therapeutic approach has not been successful so far. The idea that AD can be stopped, or delayed by targeting a single pathological event, needs revision and a multi-level therapeutic approach is needed for AD. Limited multi-level approaches have been tested for AD but have failed primarily due to inappropriate time of treatment, side-effects and lack of brain penetration. A promising multi-level therapeutic approach is to target TNF-α which plays a central role at multiple stages of AD pathology. Existing biologic TNF-α inhibitors (TNFIs) are thus a potential treatment for AD, however, do not cross the blood-brain barrier (BBB). No study still date has developed a BBB-penetrating biologic TNFI for AD and this application aims to fill this gap, and focuses on the development of a BBB-penetrating biologic TNFI for AD. The model biologic TNFI in the current application is etanercept, which is a type-II TNF-α decoy receptor (TNFR)-Fc fusion protein. We have fused TNFR to a chimeric antibody against the mouse transferrin receptor (cTfRMAb), wherein the cTfRMAb domain acts as a molecular Trojan horse to ferry the TNFR into the brain non-invasively via the transvascular route. We have recently shown that this BBB-penetrating cTfRMAb-TNFR fusion protein results in better therapeutic indices than etanercept (non-BBB-penetrating TNFI) in AD mice, underscoring the need for brain delivery of the biologic TNFI. Our central hypothesis is that systemic administration of cTfRMAb- TNFR, which modulates both peripheral and neural TNF-α, intervenes at multiple levels of AD pathology and is thus therapeutic in AD. In the proposed studies, we will utilize two different AD mice (APPswe, PSEN1dE9 double and 3xTg triple transgenic mice), ages 4- and 12-months to mimic early- and late-stage AD, and treat with vehicle, cTfRMAb-TNFR, etanercept or cTfRMAb systemically 3 days/week for 12-weeks. The following specific aims will be addressed: Aim 1: Optimize dose-response and therapeutic time-window of the BBB- penetrating biologic TNFI. The effect on neuropathological hallmarks (Aβ and tau), and clinical hallmark (cognitive deficit) will be studied using three doses (1mg/kg, 3mg/kg and 6 mg/kg). Aim 2: Characterize the mechanisms involved in the therapeutic effects of the BBB-penetrating biologic TNFI. The effects on markers of inflammation, BBB function, oxidative stress and synaptic/neuronal loss will be determined. Aim 3: Evaluate the adverse effects associated with chronic dosing of the BBB-penetrating biologic TNFI. Both cTfRMAb- and TNF-α inhibition-relevant adverse-effects will be studied. These studies will help optimize the lowest dose that results in a high efficacy to toxicity ratio, outline the therapeutic time-window for TNF-α inhibition, identify mechanisms involved in the therapeutic effects of cTfRMAb-TNFR which may enable the identification of new targets, and will provide the necessary pre-clinical results that will advance the development of cTfRMAb-TNFR for AD in humans.


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: 2024 ( Subtotal = $245,000 )
2024	2024	CHAPMAN UNIVERSITY	1 UNIVERSITY DR	ORANGE	CA	92866	ORANGE	USA	Aging Research	000	6	4/17/2024	NON-COMPETING CONTINUATION	$245,000
														Subtotal = $245,000

Issue Date FY: 2023 ( Subtotal = $377,708 )
2023	2023	CHAPMAN UNIVERSITY	1 UNIVERSITY DR	ORANGE	CA	92866	ORANGE	USA	Aging Research	001	5	4/26/2023	NON-COMPETING CONTINUATION	$377,708
2023	2022	CHAPMAN UNIVERSITY	1 UNIVERSITY DR	ORANGE	CA	92866	ORANGE	USA	Aging Research	000	4	3/16/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $377,708

Issue Date FY: 2022 ( Subtotal = $377,708 )
2022	2022	CHAPMAN UNIVERSITY	ONE UNIVERSITY DR	ORANGE	CA	92866	ORANGE	USA	Aging Research	003	4	4/28/2022	NON-COMPETING CONTINUATION	$377,708
2022	2021	CHAPMAN UNIVERSITY	1 UNIVERSITY DR	ORANGE	CA	92866	ORANGE	USA	Aging Research	002	3	2/28/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$234,733
2022	2020	KECK GRADUATE INSTITUTE OF APPLIED LIFE SCIENCES	535 WATSON DR	CLAREMONT	CA	91711	LOS ANGELES	USA	Aging Research	001	2	2/28/2022	NON-COMPETING CONTINUATION	-$162,296
2022	2019	KECK GRADUATE INSTITUTE OF APPLIED LIFE SCIENCES	535 WATSON DR	CLAREMONT	CA	91711	LOS ANGELES	USA	Aging Research	000	1	2/28/2022	NEW	-$72,437
														Subtotal = $377,708

Issue Date FY: 2021 ( Subtotal = $162,296 )
2021	2021	CHAPMAN UNIVERSITY	ONE UNIVERSITY DR	ORANGE	CA	92866	ORANGE	USA	Aging Research	001	3	8/12/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$198,312
2021	2021	CHAPMAN UNIVERSITY	ONE UNIVERSITY DR	ORANGE	CA	92866	ORANGE	USA	Aging Research	002	3	9/24/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$179,396
2021	2020	KECK GRADUATE INSTITUTE OF APPLIED LIFE SCIENCES	535 WATSON DR	CLAREMONT	CA	91711	LOS ANGELES	USA	Aging Research	000	2	8/12/2021	NON-COMPETING CONTINUATION	-$215,412
														Subtotal = $162,296

Issue Date FY: 2020 ( Subtotal = $377,708 )
2020	2020	KECK GRADUATE INSTITUTE OF APPLIED LIFE SCIENCES	535 WATSON DR	CLAREMONT	CA	91711	LOS ANGELES	USA	Aging Research	000	2	6/3/2020	NON-COMPETING CONTINUATION	$377,708
														Subtotal = $377,708

Issue Date FY: 2019 ( Subtotal = $390,183 )
2019	2019	KECK GRADUATE INSTITUTE OF APPLIED LIFE SCIENCES	535 WATSON DR	CLAREMONT	CA	91711	LOS ANGELES	USA	Aging Research	001	1	9/6/2019	NEW	$0
2019	2019	KECK GRADUATE INSTITUTE OF APPLIED LIFE SCIENCES	535 WATSON DR	CLAREMONT	CA	91711	LOS ANGELES	USA	Aging Research	000	1	7/26/2019	NEW	$390,183
														Subtotal = $390,183

Grand Total All Awards = $1,930,603

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A Brain Penetrating Bi-functional Transferrin Receptor Antibody-TNF-alpha Decoy Receptor Fusion Protein for Alzheimer's Disease

Award Number: R01AG062840

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2019

PERIOD OF PERFORMANCE END DATE: 04/30/2025

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