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Nanobodies against Lymphocyte Activation Gene 3 for Inflammation Regulation and Cancer Immunotherapy

Award Number: R21AI199951
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/21/2026
PERIOD OF PERFORMANCE END DATE: 06/30/2028

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Nanobodies against Lymphocyte Activation Gene 3 for Inflammation Regulation and Cancer Immunotherapy - Project Summary/Abstract Lymphocyte activation gene 3 (Lag3) is an inhibitory co-receptor expressed on activated T cells facilitating their exhaustion and on regulatory T cells (Tregs) controlling their immunosuppressive functions. Effective anti-tumor cytotoxic T cell responses are frequently inhibited by multiple mechanisms, including T cell exhaustion, a state in which tumor-infiltrating lymphocytes (TILs) express high levels of inhibitory receptors such as PD1, CTLA4, Lag3, and TIM3. Immune checkpoint blockade targeting PD1 and CTLA4 has revolutionized cancer immunotherapy by restoring the cytotoxic function of exhausted CD8⁺ T cells, leading to significantly prolonged survival in subsets of patients, particularly those with melanoma. Despite these advances, several limitations remain, including highly variable clinical response rates, intrinsic resistance in many tumor types, and systemic chronic inflammation due to reactivation of the adaptive immune system. We have recently developed a novel cell type–specific Lag3 knockout mouse model and demonstrated that Lag3 expression on Foxp3⁺ Tregs is essential for maintaining their suppressive function and for regulating both inflammatory and anti-tumor immune responses. Although Lag3 blockade alone has shown limited efficacy, our preliminary data reveal that T cell–specific Lag3 deficiency alone is sufficient to elicit robust anti-tumor immunity in both lung metastasis and subcutaneous melanoma models. These findings support our central hypothesis that Lag3, when appropriately targeted, represents a compelling therapeutic checkpoint in cancer immunotherapy and a novel treatment for controlling chronic inflammation. To this end, we propose to develop a novel class of anti-Lag3 nanobodies (Nbs) with enhanced specificity and efficacy. Nbs offer distinct advantages over conventional antibodies, including superior stability, enhanced tissue penetration, reduced immunogenicity, and the ability to target epitopes that may be inaccessible to full-length antibodies. We have previously established innovative platforms for Nb generation, including the Nanomouse model and a fully human nanobody library, which we successfully applied to produce Nbs targeting various viral proteins. Leveraging these platforms, we will generate Lag3- specific Nbs and evaluate their therapeutic efficacy in preclinical cancer models and autoimmune model. Antagonistic Nbs capable of blocking Lag3’s interaction with its ligands have the potential to reactivate anti-tumor activity of exhausted T cells without the need for combination therapy, reducing the risk of off-target autoimmune inflammation. On the other hand, agonistic Nbs may directly activate downstream inhibitory signaling of Lag3 to alleviate chronic inflammation. Successful completion of this study will enable the development of next- generation, tissue-penetrant immunotherapeutics with enhanced specificity and potency, broadening the scope and effectiveness of cancer immunotherapy and chronic inflammation regulation.


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 = $281,620 )
2026	2026	THE WISTAR INSTITUTE OF ANATOMY AND BIOLOGY	3601 SPRUCE ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	1	7/21/2026	NEW	$281,620
														Subtotal = $281,620

Grand Total All Awards = $281,620

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Nanobodies against Lymphocyte Activation Gene 3 for Inflammation Regulation and Cancer Immunotherapy

Award Number: R21AI199951

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/21/2026

PERIOD OF PERFORMANCE END DATE: 06/30/2028

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