Thursday, October 17, 2024 10/17/2024

Rationally guided discovery platform for monoclonal antibodies against carbohydrate antigens using virus-like particle conjugate immunization and high throughput selection

Award Number: R21AI174001
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

Group Awards By:

View Award Abstract

This project will establish a protein engineering platform for evolving monoclonal antibody binding affinity and specificity to solve the notorious challenge of developing clinical mAbs against tumor associated carbohydrate antigens (TACAs). Our central hypothesis is that the merger of Qβ carrier protein-elicited mAb discovery and rationally-guided directed evolution will outpace existing methodologies for discovering powerful antibodies against challenging TACA glycosylated biomarkers. TACAs are unique biomarkers to multiple tumor types, yet they have been underutilized for molecular imaging and diagnostics because of challenges in developing selective, potent binders. Distinct glycosylation patterns of tumor cell surfaces are hallmark features that arise during oncogenesis through changes in expression levels of glyco-processing enzymes. Problematically, these aberrant tumorigenic features are usually undetected by the immune system and rarely identified as non-self. Even when recognized as an antigen, weak binding against monovalent glycans leads to an insufficient immune response. To address this need, we will apply our directed evolution methodology to develop lead candidate mAbs against TACAs selective to cancer with in vivo binding of KD<10nM and specificity >100-fold binding above control cells. This will be accomplished by first generating a diverse panel of TACA-specific antibodies via immunization of transgenic mice with multivalent Qβ vaccines. Dominant antibodies will be isolated and characterized for paratope diversity and the ability to selectively bind the glyco-targets. Next, we use rationally- guided directed evolution to achieve mAb binding affinity and specificity. Multiple TACA-specific mAbs obtained through immunization will undergo high-throughput yeast display directed evolution with site-wise diversification based on structural, stabilizing, and phylogenetic factors to overcome the routinely low affinity of anti-carbohydrate binders. Specificity and affinity will be evaluated against multiple human tumor cell lines. This project will: 1) establish a platform that drastically reduces initial discovery time for translatable molecular imaging and diagnostic tools against carbohydrate antigens; 2) significantly advance understanding of tumorigenic cell glycosylation patterns; and 3) mark a major step towards improving sensitivity and specificity of biomarker-based diagnosis of cancers including ovarian, breast, and pancreatic cancers.


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 = $188,003 )
2024	2024	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Allergy and Infectious Diseases Research	000	2	7/9/2024	NON-COMPETING CONTINUATION	$188,003
														Subtotal = $188,003

Issue Date FY: 2023 ( Subtotal = $227,571 )
2023	2023	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Allergy and Infectious Diseases Research	000	1	7/10/2023	NEW	$227,571
														Subtotal = $227,571

Grand Total All Awards = $415,574

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Rationally guided discovery platform for monoclonal antibodies against carbohydrate antigens using virus-like particle conjugate immunization and high throughput selection

Award Number: R21AI174001

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer