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Principal Investigator: Melissa Ariel Walsh
Organization: UNIVERSITY OF MINNESOTA
Fiscal Year: 2024
Award: $43,262
Funding agency: National Cancer Institute
PROJECT SUMMARY/ABSTRACT
Natural killer (NK) cell engagers are a promising anticancer therapy that potently leverages the immune system
while providing an exceptional safety profile. Trispecific killer cell engagers (TriKEs) are NK cell engagers that
mediate NK cell killing of tumor cells through multispecific binding. TriKEs contain a tumor binding domain, an
IL-15 cytokine, and a CD16 engager. The IL-15 and CD16 engager stimulate robust NK cell activation and
tumor cell killing while the tumor binding domain targets the therapy to the tumor microenvironment. Expansion
of the TriKE platform to target new tumor-associated antigens requires integration of novel TriKE tumor binding
domains. This process is bottlenecked by difficulties preserving TriKE functionality and developability (i.e.
sufficient stability, aggregation, and recombinant yield for therapeutic use) upon the addition of a new tumor
binding domain. This project will transform the TriKE discovery process by interrogating the impact of
specific tumor binding domain properties on the resultant TriKE’s functionality and developability,
including use of innovative hyperstable miniproteins. Specifically, Aim 1 will investigate the impact of
tumor binder scaffold architecture by comparing the performance of several different scaffolds within TriKEs,
including antibody fragments and hminiproteins. Aim 2 will investigate the impact of preemptively optimizing
tumor binder stability and recombinant yield before insertion into TriKEs. This will be accomplished by
systematically varying tumor binder stability and recombinant yield and quantifying the impact on TriKE
functionality and developability. These investigations will involve the production and characterization of
experimental tumor binding domains and TriKEs targeting B7-H3, an established tumor-associated antigen.
The primary goal of this work is to inform the design of TriKE tumor targeting domains, thereby streamlining the
expansion of the platform to new therapeutic targets. Furthermore, this project will advance the development of
TriKEs as a therapeutic option for B7-H3 positive cancers.
Terms: <Activated Natural Killer Cell><Advanced Cancer><Advanced Development><Advanced Malignant Neoplasm><Affinity><Antibodies><Antibody Fragments><Architecture><Assay><B7-H3><B7H3><Binding><Bioassay><Biological Assay><Bite><CD16><CD16B><CD276><CD276 gene><Cancer Model><Cancer Treatment><CancerModel><Cancers><Cell Body><Cells><Cytotoxic cell><Data><Development><Directed Molecular Evolution><Early-Stage Clinical Trials><Elements><Engineering><Engineering / Architecture><Esteroproteases><Evaluation><Exhibits><Experimental Neoplasms><Experimental Tumor><FCGR3B><FCGR3B gene><Fc Receptor III-1><Fc gamma IIIb receptor><Fc-Gamma RIII-Beta><Fc-Gamma RIIIB><FcRIIIB><Future><GP2><GP2 gene><Generations><Glycoprotein 2, Zymogen Granule Membrane><Goals><IL-15><IL15><IL15 Protein><IgG Fc Receptor IIIB><Immune><Immune system><Immunes><Immunoglobulin Fragments><In Vitro><Interleukin-15><Interleukin-15 Precursor><Investigation><K Cells><K lymphocyte><Killer Cells><Knowledge><Link><Low Affinity IgG Fc Receptor IIIB><Low Affinity Immunoglobulin Gamma Fc Region Receptor III-B><Lytotoxicity><MGC9721><Malignant Cell><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Tumor><Mediating><Molecular><Molecular Interaction><NK Cell Activation><NK Cells><Natural Killer Cell Activation><Natural Killer Cells><Patients><Peptidases><Peptide Hydrolases><Performance><Phase 1 Clinical Trials><Phase I Clinical Trials><Physicians><Process><Production><Proliferating><Property><Protease Gene><Proteases><Proteinases><Proteins><Proteolytic Enzymes><Recombinants><Research><Resistance><Safety><Scientist><Specificity><Structure><TM-MKR><Technology><Therapeutic><Therapeutic Uses><Training><TriKE><Tumor Antigens><Tumor Cell><Tumor Markers><Tumor Promotion><Tumor-Associated Antigen><Veins><Work><Yeasts><Zymogen Granule Membrane Glycoprotein 2><anti-cancer therapeutic><anti-cancer therapy><cancer antigens><cancer biomarkers><cancer cell><cancer markers><cancer microenvironment><cancer therapy><cancer-directed therapy><cell killing><cytokine><cytotoxicity><design><designing><developmental><dimer><directed evolution><engineered immune system><experience><immune engineering><immunoengineering><improved><in vivo><innovate><innovation><innovative><malignancy><mutant><nanobodies><nanobody><native protein drug><neoplasm/cancer><neoplastic cell><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><novel><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><pharmaceutical protein><phase I protocol><pre-clinical study><preclinical study><preservation><protein drug agent><protein-based drug><resistant><response><scaffold><scaffolding><sdAb><single domain antibodies><stem><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic protein><trispecific killer engager><tumor><tumor biomarker><tumor microenvironment><tumor specific biomarker><tumor-specific antigen>