TROP-2 is an ideal candidate for targeted therapeutics due to it being a transmembrane protein with an extracellular domain overexpressed on a wide variety of tumors as well as its upregulated expression relative to normal cells. With the development of anti-TROP-2 antibodies, BOC Sciences has worked to develop TROP-2-targeting antibody-drug conjugates (ADCs). We provide comprehensive ADC development services for TROP-2 targeted therapies. Our unique antibody discovery and leading bioconjugation programs help customers access the best ADC candidates.
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TROP-2, also known as epithelial glycoprotein-1, gastrointestinal antigen 733-1, membrane component surface marker-1, and tumor-associated calcium signal transducer-2, is the protein product of the TACSTD2 gene. This transmembrane glycoprotein functions in a variety of cell signaling pathways and was first elucidated as a transducer of an intracellular calcium signal. TROP-2 may play a role in tumor progression given the involvement in several molecular pathways traditionally associated with cancer development. High TROP-2 expression correlates with poor prognosis in pancreatic, hilar cholangiocarcinoma, cervical cancer, gastric cancer, and others. In a meta-analysis including 2569 patients, increased TROP-2 expression was associated with poor overall and disease-free survival outcomes across several solid tumors. Given TROP-2's expression pattern and associated poor prognostic outcomes, TROP-2 is a rational prognostic marker and therapeutic target.
Fig. 1. TROP-2 processing, cell signaling and its effects (Genes Cancer. 2015; 6: 84-105).
Two different ADCs targeting the TROP-2 protein have been synthesized, including Sacituzumab govitecan (SG) and RN927C. SG is a novel, third generation of ADCs. It is composed of a humanized anti-TROP-2 immunoglobulin (Ig)G antibody that is conjugated through a hydrolyzable linker to SN-38, which is an active metabolite of irinotecan. Irinotecanis a camptothecin that inhibits the nuclear topoisomerase I enzyme, thereby inducing double-stranded DNA breaks during the S-phase of the cell cycle. 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.
Fig. 2. Representation of structure of the CL2A linker used to bind SN-38 to the anti-TROP-2 IgG to form sacituzumab govitecan (Oncotarget. 2018, 9(48): 28989).
Unlike sacituzumab govitecan, RN927C is an ADC composed of a different humanized anti-TROP-2 antibody conjugated to a more potent auristatin derivative that is a microtubule inhibitor at a maximum substitution of 2.0. In rats that do not express human TROP-2, the toxicity of the conjugate was primarily hematological, but in monkeys that are cross-reactive with human TROP-2, reversible toxicity was observed in multiple epithelial tissues, including the skin, upper alimentary track, and vagina.
Breast cancer is the most common cancer in women worldwide. TROP-2 is expressed in all breast cancer subtypes, and has been linked with poor prognosis and decreased survival.
Lung cancer is one of the most common types of cancer throughout the world and is responsible for 18% of all cancer deaths. TROP2 is a transmembrane glycoprotein expressed by NSCLC and other malignancies.
Bladder cancer is the most common malignancy of the urinary tract and develops from the tissues of the urinary bladder. TROP2 expression across molecular subtypes of urothelial carcinoma and enfortumab vedotin-resistant cells.
With years of experience in bioconjugation, BOC Sciences overcomes the toxicity challenges associated with many current treatments, improving the efficacy and safety of combination regimens for the treatment of cancer. We can help developers screen the range of possible drug targets unavailable with traditional antibody-drug conjugates, thereby providing new and more powerful therapeutic options. In addition to providing customized breast, bladder and lung cancer ADC development services to our global customers, we also provide target screening and ADC development process support for other solid tumors. Click here for more targeted ADC development services.