Antibody-Drug Conjugates Designed to Eradicate Tumors with Homogeneous and Heterogeneous Expression of the Target Antigen
Open accessAbstract
Conjugates of the anti-CanAg humanized monoclonal antibody huC242 with the microtubule-formation inhibitor DM1 (a maytansinoid), or with the DNA alkylator DC1 (a CC1065 analogue), have been evaluated for their ability to eradicate mixed cell populations formed from CanAg-positive and CanAg-negative cells in culture and in xenograft tumors in mice. We found that in culture, conjugates of either drug killed not only the target antigen-positive cells but also the neighboring antigen-negative cells. Furthermore, we showed that, in vivo, these conjugates were effective in eradicating tumors containing both antigen-positive and antigen-negative cells. The presence of antigen-positive cells was required for this killing of bystander cells. This target cell–activated killing of bystander cells was dependent on the nature of the linker between the antibody and the drug. Conjugates linked via a reducible disulfide bond were capable of exerting the bystander effect whereas equally potent conjugates linked via a nonreducible thioether bond were not. Our data offer a rationale for developing optimally constructed antibody-drug conjugates for treating tumors that express the target antigen either in a homogeneous or heterogeneous manner. (Cancer Res 2006; 66(6): 3214-21)
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- Authors
- Kovtun, Y. V., Audette, C. A., Ye, Y., Xie, H., Ruberti, M. F., Phinney, S. J., Leece, B. A., Chittenden, T., Blättler, W. A., & Goldmacher, V. S.
- Affiliations
- ImmunoGen (United States) (US)
- ImmunoGen, Inc., Cambridge, Massachusetts
- Venue
- Cancer Research
- Published
- 2006-03-15
- Volume
- 66
- Issue
- 6
- Pages
- 3214-3221
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2139761471
- Cited by
- 479
- References
- 22
- Citations by year
- 2026: 21 · 2025: 35 · 2024: 32 · 2023: 38 · 2022: 26 · 2021: 40 · 2020: 37 · 2019: 28 · 2018: 20 · 2017: 19 · 2016: 19 · 2015: 32 · 2014: 18 · 2013: 19 · 2012: 14
- FWCI
- 13.33
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Brigham and Women's Hospital
- Topics
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Monoclonal and Polyclonal Antibodies Research
- Life Sciences › Immunology and Microbiology › Immunology › Toxin Mechanisms and Immunotoxins
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- antibody-drug conjugates, bystander effect, DM1, maytansinoids, DC1, thioether linker, tumor xenografts, tumor eradication, targeted cancer therapy
- MeSH terms
- Animals, Antibodies, Monoclonal, Antigens, Neoplasm, Colonic Neoplasms, Cross-Linking Reagents, Female, Humans, Maytansine, Mice, SCID, Immunoconjugates, HT29 Cells, Xenograft Model Antitumor Assays, Cell Line, Tumor, Mice
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