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Curative Properties of Noninternalizing Antibody–Drug Conjugates Based on Maytansinoids
Published version of a preprint
Abstract
It is generally thought that the anticancer efficacy of antibody–drug conjugates (ADC) relies on their internalization by cancer cells. However, recent work on an ADC that targets fibronectin in the tumor microenvironment suggests this may not be necessary. The alternatively spliced extra domains A and B (EDA and EDB) of fibronectin offer appealing targets for ADC development, because the antigen is strongly expressed in many solid human tumors and nearly undetectable in normal tissues except for the female reproductive system. In this study, we describe the properties of a set of ADCs based on an antibody targeting the alternatively spliced EDA of fibronectin coupled to one of a set of potent cytotoxic drugs (DM1 or one of two duocarmycin derivatives). The DM1 conjugate SIP(F8)-SS-DM1 mediated potent antitumor activity in mice bearing DM1-sensitive F9 tumors but not DM1-insensitive CT26 tumors. Quantitative biodistribution studies and microscopic analyses confirmed a preferential accumulation of SIP(F8)-SS-DM1 in the subendothelial extracellular matrix of tumors, similar to the pattern observed for unmodified antibody. Notably, we found that treatments were well tolerated at efficacious doses that were fully curative and compatible with pharmaceutical development. Our findings offer a preclinical proof-of-concept for curative ADC targeting the tumor microenvironment that do not rely upon antigen internalization. Cancer Res; 74(9); 2569–78. ©2014 AACR.
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“They bind to cell surface receptors that are upregulated by mutant RAS and exhibit potent antitumor activity, demonstrating their efficacy in targeting undruggable proteins outside the cell.645–649”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [648]
In the citing paper
“They bind to cell surface receptors that are upregulated by mutant RAS and exhibit potent antitumor activity, demonstrating their efficacy in targeting undruggable proteins outside the cell.645–649”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [648]
In the citing paper
“They bind to cell surface receptors that are upregulated by mutant RAS and exhibit potent antitumor activity, demonstrating their efficacy in targeting undruggable proteins outside the cell.645–649”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [648]
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Metadata
- Authors
- Perrino, E., Steiner, M., Krall, N., Bernardes, G. J. L., Pretto, F., Casi, G., & Neri, D.
- Affiliations
- University of Lisbon (PT)
- Venue
- Cancer Research
- Published
- 2014-04-30
- Volume
- 74
- Issue
- 9
- Pages
- 2569-2578
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2073629335
- Cited by
- 130
- References
- 51
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 6 · 2023: 7 · 2022: 10 · 2021: 9 · 2020: 7 · 2019: 16 · 2018: 17 · 2017: 15 · 2016: 16 · 2015: 17 · 2014: 6
- FWCI
- 14.05
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Cambridge University Engineering Department Publications Database (submittedVersion)
- Funders
- Novartis Foundation
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- Kommission für Technologie und Innovation
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Monoclonal and Polyclonal Antibodies Research
- Life Sciences › Immunology and Microbiology › Immunology › Toxin Mechanisms and Immunotoxins
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Keywords
- antibody-drug conjugates, maytansinoids, DM1, fibronectin, tumor microenvironment, curative treatment, antigen uptake, extracellular matrix, tumor targeting, CT26 tumor, tissue distribution
- MeSH terms
- Animals, Antibodies, Antineoplastic Agents, Cricetulus, Female, Cricetinae, Humans, Maytansine, Mice, Inbred BALB C, Mice, Nude, Tissue Distribution, CHO Cells, Xenograft Model Antitumor Assays, Cell Line, Tumor, Mice, Embryonal Carcinoma Stem Cells, Mice, 129 Strain
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