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Promoting immunity against acute myeloid leukemia through Fc effector-optimized antibody inhibitory of MICA/B shedding

Award Number: R37CA269982
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/06/2023
PERIOD OF PERFORMANCE END DATE: 11/30/2027

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Promoting immunity against acute myeloid leukemia through Fc effector-optimized antibody inhibitory of MICA/B shedding - SUMMARY Acute myeloid leukemia (AML) is a clonal hematopoietic stem and progenitor cell malignancy characterized by poor clinical outcomes. Malignant transformation triggers expression of surface proteins that serve as “danger signals”, such as MICA and MICB (MICA/B) that are commonly expressed by leukemia cells in response to cellular stress pathways. Natural killer (NK) cells and cytotoxic T lymphocytes recognize MICA/B with the NKG2D receptor, which in turn induces cytotoxic functions against leukemia cells. However, they often escape recognition by shedding MICA/B via an intriguing post-translational modification called proteolytic cleavage. In previous and revolutionary study, we developed a series of MICA/B-targeted monoclonal antibodies that inhibit the shedding of MICA/B by blocking the extracellular domain that undergoes an unfolding by disulfide isomerase, which enables subsequent cleavage by metalloproteases. One of them was further characterized, and it promotes NK cell-mediated immunity against solid tumors by dual signaling of NKG2D and Fc receptors. Recently, we discovered that the antibody also promotes macrophage-driven immunity in AML models, by enabling antibody-dependent phagocytosis of leukemia cells in the blood and bone marrow. In this setting, MICA/B serve as “leukemia antigens” for Fc receptor-driven immunity, although contributions by NKG2D, NK cells, and T cells were also detected. Now we developed a new version of this antibody, with three point mutations in the Fc domain to increase the binding affinity to all three Fc activating receptors while maintaining low affinity to the Fc inhibitory receptor. This new version is humanized and induces potent NK cell effector functions against human AML cells, compared to the humanized wild type version. We also established mouse models of human Fc receptor biology and both murine and human AML models, to establish the anti-leukemia activity of our now enhanced molecule in vivo. Furthermore, we propose a mechanism-driven drug combination regimen, whereby a histone deacetylase inhibitor (romidepsin) induces human leukemia cells to express MICA/B mRNAs that are then translated to MICA/B proteins, which are followed by stabilization on cellular surface by our antibody that inhibits the shedding. We propose that immunotherapy for AML can be achieved via this drug combination, which increases the innate immunogenicity of leukemia cells. For these reasons, our studies will generate important information about how to induce protective immunity against AML. Antibody-mediated inhibition of MICA/B shedding is a new immunotherapeutic opportunity pioneered by us and now validated independently by multiple pharmaceutical companies, one of which has recently began phase-I clinical trial testing an antibody analog to ours, but the wild type version, in patients with advanced solid tumors. Therefore, our studies will generate compelling rationale to test MICA/B-targeted antibodies in AML trials, by pharmaceutical companies, ourselves in academia, or both by working in collaboration.


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: 2026 ( Subtotal = $520,895 )
2026	2026	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Cancer Treatment Research	001	4	1/20/2026	NON-COMPETING CONTINUATION	$0
2026	2026	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Cancer Treatment Research	000	4	12/8/2025	NON-COMPETING CONTINUATION	$468,806
2026	2026	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Cancer Treatment Research	002	4	4/16/2026	NON-COMPETING CONTINUATION	$52,089
														Subtotal = $520,895

Issue Date FY: 2025 ( Subtotal = $520,895 )
2025	2025	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Cancer Treatment Research	000	3	11/14/2024	NON-COMPETING CONTINUATION	$468,806
2025	2025	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Cancer Treatment Research	001	3	6/2/2025	NON-COMPETING CONTINUATION	$52,089
														Subtotal = $520,895

Issue Date FY: 2024 ( Subtotal = $468,199 )
2024	2024	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Cancer Treatment Research	000	2	11/28/2023	NON-COMPETING CONTINUATION	$443,557
2024	2024	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Cancer Treatment Research	001	2	4/17/2024	NON-COMPETING CONTINUATION	$24,642
														Subtotal = $468,199

Issue Date FY: 2023 ( Subtotal = $492,841 )
2023	2023	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Cancer Treatment Research	000	1	2/6/2023	NEW	$492,841
														Subtotal = $492,841

Grand Total All Awards = $2,002,830

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Promoting immunity against acute myeloid leukemia through Fc effector-optimized antibody inhibitory of MICA/B shedding

Award Number: R37CA269982

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/06/2023

PERIOD OF PERFORMANCE END DATE: 11/30/2027

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