Glypican-3 (GPC3) / Topoisomerase I

Class

Antibody-drug conjugate: GPC3-directed antibody conjugated to a topoisomerase I inhibitor payload

Pathway

GPC3 is a cell-surface protein overexpressed in hepatocellular carcinoma and lung cancers; ADC internalization releases the topoisomerase I inhibitor payload to induce DNA damage and tumor cell death

Glypican-3 (GPC3) is a protein anchored to the outer surface of cells via a lipid tail; it is normally expressed at high levels only during fetal development but becomes re-expressed on many hepatocellular carcinoma (liver cancer) cells and some lung tumors, while remaining largely absent from healthy adult tissue. This restricted expression pattern makes GPC3 an attractive docking site for a targeted therapy. The mechanism described here is an antibody-drug conjugate (ADC): an antibody engineered to bind GPC3 is chemically linked to a small-molecule payload that inhibits topoisomerase I, an enzyme cells need to unwind DNA during replication. After the antibody binds GPC3 on the tumor cell surface, the complex is drawn inside the cell, where the linker is broken down and the topoisomerase I inhibitor is released internally, causing DNA damage that leads to cell death. This design allows the cytotoxic payload to be concentrated inside cancer cells rather than circulating freely throughout the body, which is the general rationale for ADC approaches across many solid tumors. GPC3-directed ADCs are studied primarily in liver cancer, where few targeted surface antigens exist, and in other GPC3-expressing malignancies.