UCLA researchers from the Department of Molecular and Medical Pharmacology and the Department of Microbiology, Immunology and Molecular Genetics have developed a panel of human antibodies and chimeric antigen receptors targeting Trop-2, providing diagnostic and therapeutic resources for targeting Trop2-driven cancer.
BACKGROUND: Trophoblast cell surface antigen 2 (Trop-2) is a type-I transmembrane protein that has emerged as a clinically relevant oncogenic driver in nearly all epithelial cancers. Prior studies have demonstrated that Trop2 undergoes regulated intramembrane proteolysis, releasing its extracellular domain and producing a nuclear-localized intracellular domain that promotes tumor initiation and self-renewal. Although several pharmaceutical companies have developed anti-Trop-2 antibodies with preclinical efficacy, these constructs are typically murine or chimeric, which increases the likelihood of immunogenicity and limits their long-term therapeutic utility. Currently, two FDA-approved Trop2-targeting ADCs are available for breast cancer: sacituzumab govitecan (SG/Trodelvy®) and datopotamab deruxtecan (Dato-DXd/Datroway®)7,8. However, they have modest efficacy or concerning safety profiles and both have TOP1 inhibitors as payloads, and emergence of TOP1 mutations can confer therapeutic resistance. Thus, there is an unmet need for a fully human antibody platform with improved specificity, efficacy, minimal side effects and reduced immunogenicity.
INNOVATION: Dr. Tanya Stoyanova at the Department of Molecular and Medical Pharmacology and Dr. Owen Witte at the Department of Microbiology, Immunology and Molecular Genetics at UCLA, together with collaborators have generated the first fully human anti-Trop-2extracellular domain antibodies through high-throughput phage display technology. Using a human single-fold scFv library developed at UCLA, the inventors isolated 23 unique antibody clones that specifically bind the Trop2 extracellular domain with varying affinities. These antibodies were expressed as scFv-Fc fusion proteins in mammalian cells, purified, and quantitatively ranked for binding strength using FACS analysis across prostate cancer cell lines expressing different Trop2 levels. These antibodies exhibit high specificity and potent inhibition of Trop2 activation and downstream signaling. Further, researchers conjugated antibodies to indocyanine green (ICG), an FDA-approved optical imaging dye, to generate anti-Trop2 antibody fragment ICG conjugates that can provide low cost, high-sensitivity optical detection and intraoperative guidance in Trop2+ cancers. Additionally, five representative antibodies with distinct binding strengths were incorporated into chimeric antigen receptor (CAR) constructs. Two of these Trop2-CARs exhibited potent and selective cytotoxicity toward Trop2-overexpressing tumor cells while sparing those with endogenous expression levels. Collectively, this platform provides a versatile group of human antibody, CAR, and imaging modalities for Trop2 targeted therapy, diagnostics, and surgical applications.
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ADVANTAGES:
DEVELOPMENT-TO-DATE: UCLA researchers have developed 23 anti-human Trop-2 extracellular domain antibodies using phage display technology and shown that they can be used to detect human Trop-2 on the cell surface of cancer cells. The naked anti-human Trop-2 antibodies exhibit strong efficacy in pre-clinical models with no measurable side effects. They have also generated 5 Trop-2 chimeric antigen receptors that may be used for cancer immunotherapies, as well as Trop-2 antibody-ICG conjugates for intraoperative optical guidance.
Related Papers (from the inventors only):
TDG Keywords:
Diagnostic Markers > Cancer
Diagnostic Markers > Targets and Assays
Life Science Research Tools > Antibodies
Therapeutics > Oncology
Therapeutics > Immunology and Immunotherapy
Keywords: Trop-2, antibody, CAR-T, imaging, ICG, epithelial cancer, phage display, immunotherapy, prostate cancer, antibody-drug conjugate, therapeutic antibody, cancer diagnostics