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Immune cell targeting of corticosteroids transforms the treatment of severe, chronic inflammatory diseases

Award Number: R44AI165119
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Immune cell targeting of corticosteroids transforms the treatment of severe, chronic inflammatory diseases - Glucocorticoids (GC) are a class of drugs with overwhelming anti-inflammatory activities. However, dose limiting toxicities (DLT) caused by systemic GC exposure prevent GC from being a true panacea in the management of inflammatory disease. This Direct SBIR Phase 2 proposal requests support for a novel therapeutic that targets delivery of GC to the immune system, which will reduce DLT and allow for the long term and high dose use of GC in the treatment of inflammation. ImmuNext has established the technical merit, feasibility, proof of concept and commercial potential of this antibody-targeted, immune-specific steroid conjugate. We have achieved specific and direct targeting of GC to the immune system with INX200, an antibody-drug conjugate (ADC) of an Fc-silent, fully humanized immune-targeting mAb conjugated through a cleavable linker to budesonide. Importantly, targeting GC with INX200 results in superior potency and reduced toxicity when compared to free GC. We have shown that INX200: 1) broadly targets the immune system with minimal exposure outside the hematopoietic compartment, 2) leverages an immune-targeting mAb that itself (unconjugated) possesses no known immunologic activities and acts exclusively as a targeting agent, 3) rapidly internalizes allowing for robust and efficient uptake of the GC thereby providing superior loading of GC into immune cells, 4) is therapeutically equivalent at 1/10th the dose, and has substantially longer PD compared to free GC, 5) has minimal off target activity and reduced toxicity compared to free GC due to its specific immune system targeting, 6) is suitable for SC administration and 7) is an attractive therapeutic for the treatment of GC- dependent asthma because of the unmet GC need in this patient population. The Specific Aims of this Phase 2 application are as follows. 1) Assess the lead ADC INX200 and multiple backups for immunogenicity and stability for commercial development. 2) Define the immunologic and toxicologic GC biomarkers of INX200. These biomarkers will be measured and compared to the definitive pharmacological signatures known to be specifically altered by systemic exposure to GC. INX200-dependent modulation of cytokines and induction of steroid-specific transcripts will be assessed as immunologic and toxicity biomarkers, respectively. 3) Conduct non-GLP Tox/PK/PD studies in cynomolgus monkeys in order to confirm safety and guide the development of a subsequent IND-enabling GLP tox study. 4) Review and assess the regulatory path to IND. The data generated in aims (1)-(3), in particular non-GLP non-human primate (NHP) studies, will be reviewed to design (a) a single ascending dose Phase 1 trial in healthy volunteers, and (b) a multiple ascending dose Phase 2 trial in GC-dependent asthma patients. Based on this clinical program outline, a GLP toxicology study in NHP will be designed to support an IND. The successful targeting of GC to the immune system with the sparing of non-hematopoietic toxicities, offers a transformative advance in GC-based drugs for the treatment of severe, chronic inflammatory disease.


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	LIFORDI IMMUNOTHERAPEUTICS, INC.	1 VAN DE GRAAFF DR	BURLINGTON	MA	01803	MIDDLESEX	USA	Allergy and Infectious Diseases Research	001	4	1/21/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$112
2025	2023	IMMUNEXT PHARMACEUTICALS	1 MEDICAL CENTER DR	LEBANON	NH	03756	GRAFTON	USA	Allergy and Infectious Diseases Research	000	3	1/21/2025	NON-COMPETING CONTINUATION	-$112
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2023	LIFORDI IMMUNOTHERAPEUTICS, INC.	C/O 5AM VENTURES 200 CLARENDON STREET, 22ND FLOOR	BOSTON	MA	02116	SUFFOLK	USA	Allergy and Infectious Diseases Research	001	4	6/25/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$993,646
2024	2023	IMMUNEXT PHARMACEUTICALS	1 MEDICAL CENTER DR	LEBANON	NH	03756	GRAFTON	USA	Allergy and Infectious Diseases Research	000	3	6/25/2024	NON-COMPETING CONTINUATION	-$993,646
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $993,758 )
2023	2023	IMMUNEXT, INC.	1 MEDICAL CENTER DR	LEBANON	NH	03756	GRAFTON	USA	Allergy and Infectious Diseases Research	000	3	6/14/2023	NON-COMPETING CONTINUATION	$993,758
														Subtotal = $993,758

Issue Date FY: 2022 ( Subtotal = $974,853 )
2022	2022	IMMUNEXT, INC.	1 MEDICAL CENTER DR	LEBANON	NH	03756	GRAFTON	USA	Allergy and Infectious Diseases Research	000	2	5/20/2022	NON-COMPETING CONTINUATION	$974,853
														Subtotal = $974,853

Issue Date FY: 2021 ( Subtotal = $990,946 )
2021	2021	IMMUNEXT, INC.	1 MEDICAL CENTER DR	LEBANON	NH	03756	GRAFTON	USA	Allergy and Infectious Diseases Research	000	1	6/21/2021	NEW	$990,946
														Subtotal = $990,946

Grand Total All Awards = $2,959,557

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Immune cell targeting of corticosteroids transforms the treatment of severe, chronic inflammatory diseases

Award Number: R44AI165119

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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