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Antibody-drug conjugates targeting TROP-2: Clinical development in metastatic breast cancer

Antibody drug conjugates (ADCs) combine the potent cytotoxicity of chemotherapy with the antigen -specific targeted approach of antibodies into one single molecule. Trophoblast cell surface antigen 2 (TROP-2) is a transmembrane glycoprotein involved in calcium signal transduction and is expressed in...

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Autores principales: Shastry, Mythili, Jacob, Saya, Rugo, Hope S., Hamilton, Erika
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9614644/
https://www.ncbi.nlm.nih.gov/pubmed/36302269
http://dx.doi.org/10.1016/j.breast.2022.10.007
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author Shastry, Mythili
Jacob, Saya
Rugo, Hope S.
Hamilton, Erika
author_facet Shastry, Mythili
Jacob, Saya
Rugo, Hope S.
Hamilton, Erika
author_sort Shastry, Mythili
collection PubMed
description Antibody drug conjugates (ADCs) combine the potent cytotoxicity of chemotherapy with the antigen -specific targeted approach of antibodies into one single molecule. Trophoblast cell surface antigen 2 (TROP-2) is a transmembrane glycoprotein involved in calcium signal transduction and is expressed in multiple tumor types. TROP-2 expression is higher in HER2-negative breast tumors (HR+/HR-) and is associated with worse survival. Sacituzumab govitecan (SG) is a first-in-class TROP-2-directed ADC with an anti-TROP-2 antibody conjugated to SN-38, a topoisomerase inhibitor via a hydrolysable linker. This hydrolysable linker permits intracellular and extracellular release of the membrane permeable payload enabling the “bystander effect” contributing to the efficacy of this agent. There was significant improvement in progression free survival (PFS) and overall survival (OS) with SG versus chemotherapy in pretreated metastatic triple negative breast cancer (TNBC), resulting in regulatory approval. Common adverse events (AE) reported were neutropenia and diarrhea. SG also demonstrated clinical activity versus chemotherapy in a phase III trial of HR+/HER2-metastatic breast cancer (MBC) and is under evaluation in first-line metastatic and early stage TNBC as well. Datopotamab deruxtecan (Dato-DXd) is a TROP-2 ADC that differs from SG in that it has a cleavable tetrapeptide linker and a more potent topoisomerase inhibitor payload. This construct is highly stable in circulation with a longer half-life than SG, and undergoes cleavage in presence of intracellular lysosomal proteases. Dato-DXd demonstrated preliminary efficacy in unselected metastatic TNBC, with common AEs of low-grade nausea and stomatitis. Dato-DXd is being investigated in phase III studies in metastatic TNBC and HR+/HER2- MBC. These novel TROP-2 ADCs have the potential to deliver enhanced efficacy with reduced toxicity in MBC and possibly in early stage breast cancer (EBC).
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spelling pubmed-96146442022-10-29 Antibody-drug conjugates targeting TROP-2: Clinical development in metastatic breast cancer Shastry, Mythili Jacob, Saya Rugo, Hope S. Hamilton, Erika Breast Article(s) from the Special Issue on: Antibody-drug Conjugates; Edited by Giuseppe Curigliano, Hope Rugo Antibody drug conjugates (ADCs) combine the potent cytotoxicity of chemotherapy with the antigen -specific targeted approach of antibodies into one single molecule. Trophoblast cell surface antigen 2 (TROP-2) is a transmembrane glycoprotein involved in calcium signal transduction and is expressed in multiple tumor types. TROP-2 expression is higher in HER2-negative breast tumors (HR+/HR-) and is associated with worse survival. Sacituzumab govitecan (SG) is a first-in-class TROP-2-directed ADC with an anti-TROP-2 antibody conjugated to SN-38, a topoisomerase inhibitor via a hydrolysable linker. This hydrolysable linker permits intracellular and extracellular release of the membrane permeable payload enabling the “bystander effect” contributing to the efficacy of this agent. There was significant improvement in progression free survival (PFS) and overall survival (OS) with SG versus chemotherapy in pretreated metastatic triple negative breast cancer (TNBC), resulting in regulatory approval. Common adverse events (AE) reported were neutropenia and diarrhea. SG also demonstrated clinical activity versus chemotherapy in a phase III trial of HR+/HER2-metastatic breast cancer (MBC) and is under evaluation in first-line metastatic and early stage TNBC as well. Datopotamab deruxtecan (Dato-DXd) is a TROP-2 ADC that differs from SG in that it has a cleavable tetrapeptide linker and a more potent topoisomerase inhibitor payload. This construct is highly stable in circulation with a longer half-life than SG, and undergoes cleavage in presence of intracellular lysosomal proteases. Dato-DXd demonstrated preliminary efficacy in unselected metastatic TNBC, with common AEs of low-grade nausea and stomatitis. Dato-DXd is being investigated in phase III studies in metastatic TNBC and HR+/HER2- MBC. These novel TROP-2 ADCs have the potential to deliver enhanced efficacy with reduced toxicity in MBC and possibly in early stage breast cancer (EBC). Elsevier 2022-10-18 /pmc/articles/PMC9614644/ /pubmed/36302269 http://dx.doi.org/10.1016/j.breast.2022.10.007 Text en © 2022 The Authors. Published by Elsevier Ltd. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Article(s) from the Special Issue on: Antibody-drug Conjugates; Edited by Giuseppe Curigliano, Hope Rugo
Shastry, Mythili
Jacob, Saya
Rugo, Hope S.
Hamilton, Erika
Antibody-drug conjugates targeting TROP-2: Clinical development in metastatic breast cancer
title Antibody-drug conjugates targeting TROP-2: Clinical development in metastatic breast cancer
title_full Antibody-drug conjugates targeting TROP-2: Clinical development in metastatic breast cancer
title_fullStr Antibody-drug conjugates targeting TROP-2: Clinical development in metastatic breast cancer
title_full_unstemmed Antibody-drug conjugates targeting TROP-2: Clinical development in metastatic breast cancer
title_short Antibody-drug conjugates targeting TROP-2: Clinical development in metastatic breast cancer
title_sort antibody-drug conjugates targeting trop-2: clinical development in metastatic breast cancer
topic Article(s) from the Special Issue on: Antibody-drug Conjugates; Edited by Giuseppe Curigliano, Hope Rugo
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9614644/
https://www.ncbi.nlm.nih.gov/pubmed/36302269
http://dx.doi.org/10.1016/j.breast.2022.10.007
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