Abstract
TROP-2 is a glycoprotein first described as a surface marker of trophoblast cells, but subsequently shown to be increased in many solid cancers, with lower expression in certain normal tissues. It regulates cancer growth, invasion and spread by several signaling pathways, and has a role in stem cell biology and other diseases. This review summarizes TROP-2's properties, especially in cancer, and particularly its role as a target for antibody-drug conjugates (ADC) or immunotherapy. When the irinotecan metabolite, SN-38, is conjugated to a humanized anti-TROP-2 antibody (sacituzumab govitecan), it shows potent broad anticancer activity in human cancer xenografts and in patients with advanced triple-negative breast, non-small cell and small-cell lung, as well as urothelial cancers.
Highlights
The challenge of cancer treatment remains selectivity - attacking the cancer while minimizing collateral damage to normal cells
Even before the era of precision medicine, many proteins produced in elevated quantities by tumor cells, such as Bence-Jones protein, beta human chorionic gonadotrophin (β-HCG), alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA), prostatic acid phosphatase, and human epidermal growth factor receptor (EGFR), and EGFR-2 (HER2), were used as circulating biomarkers of disease activity aiding in immunodiagnosis [4] or even as targets for radionuclide- or drug-conjugated antibodies [5, 6]
The results clearly indicate that (i) transfection of the MDA-MB-231 with human TROP-2 cDNA does not appreciable alter its sensitivity to IRI, and (ii) increasing TROP-2 expression ~4 fold significantly enhances sacituzumab govitecan’s therapeutic activity
Summary
The challenge of cancer treatment remains selectivity - attacking the cancer while minimizing collateral damage to normal cells. Grade >3 diarrhea was lower (~9%) than typically found with IRI therapy Summarizing, this Trop-2 ADC appears to have good activity as a monotherapy in several cancer types expressing TROP-2, and represents a paradigmchange in the ADC technology by: (i) using a moderatelytoxic drug, SN-38; (ii) conjugation of the drug to the antibody at a high ratio (~8:1) without affecting targeting and pharmacokinetics; (iii) use of a pH-sensitive, cleavable linker; (iv) administering repeated, high doses of ADC over prolonged times without provoking an immune response; and (v) reduced and manageable toxicities related only to the drug, such as neutropenia and diarrhea. The highly stable, more potent auristatin-derived ADC appears to have toxicities that are likely associated with TROP-2 targeting, while the less potent and less stable SN-38 conjugate has a safety profile related to its parent drug, IRI, but with an improved therapeutic window [66]
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