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Background Trophoblast cell-surface antigen-2 (Trop-2) protein as a target for antibody-drug conjugates (ADC). Trop-2 is a 40-kDa glycoprotein that was the first described transducer of intracellular calcium signaling. Trop-2 expression was originally described in trophoblasts (placenta) and fetal tissues (e.g. lungs). Its expression was subsequently described in the normal stratified squamous epithelium of the skin, uterine cervix, esophagus, and tonsil crypts. However, many normal tissues lack or show low Trop-2 protein expression (e.g. colon, kidney, liver, lung, prostate, and breast). Aberrant Trop-2 overexpression has been described in various solid cancers, including those with low Trop-2 expression in their normal counterparts (e.g. colorectal, renal, lung, and breast carcinomas). High Trop-2 expression usually confers a poor outcome.
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Methods N/A - Review article
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Results Two different ADCs targeting the Trop-2 protein have been synthesized, including Sacituzumab govitecan (SG) and RN927C. SG is the first in the class that has been clinically validated and approved by the FDA for heavily pretreated metastatic triple-negative breast and urothelial carcinomas. SG (IMMU-132) is a novel, third generation of ADCs composed of a humanized anti-Trop-2 immunoglobulin (Ig)G antibody. Trop-2 expression has also been described in some rare and aggressive malignancies, such as salivary duct carcinomas, anaplastic thyroid carcinomas, uterine/ovarian carcinosarcomas, and neuroendocrine carcinoma of the prostate.
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Data Summary In a meta-analysis by Zeng et al. that included 2569 cancer patients (reflecting 13 common solid malignancies), increased Trop-2 expression was particularly associated with poor overall survival (OS) and disease-free survival outcomes in patients with gastrointestinal and gynecological malignancies. Lower Trop-2 expression has been described in pulmonary and thyroid neuroendocrine neoplasms. We recently reported Trop-2 in ~20% of mammary NEC. Our study on cervical NEC revealed marginal (<5% of tested samples) Trop-2 protein expression.
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Conclusions The authors concluded that a frequent Trop-2 expression in the majority of solid tumors and its association with a poor prognosis provided a good rationale to target Trop-2 for therapeutic purposes. Sacituzumab govitecan (SG), a conjugate of anti-Trop-2 antibody and SN-38 payload, is the first in the class that has been clinically validated and approved by the Food and Drug Administration for the treatment of metastatic triple-negative breast (2020) and urothelial carcinomas (2021).
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Practical Significance Two recently approved indications of anti-Trop-2 ADCs are discussed in the following paragraphs. SG is the first in the class that has been clinically validated and approved by the FDA for heavily pretreated metastatic triple-negative breast and urothelial carcinomas. ADCs represent a new generation of highly potent antineoplastic drugs, with nine ADCs having already entered clinical practice.