Article ; Online: Discovery and Preclinical Characterization of XMT-1660, an Optimized B7-H4-Targeted Antibody-Drug Conjugate for the Treatment of Cancer.
2023 Volume 22, Issue 9, Page(s) 999–1012
Abstract: Antibody-drug conjugates (ADC) achieve targeted drug delivery to a tumor and have demonstrated clinical success in many tumor types. The activity and safety profile of an ADC depends on its construction: antibody, payload, linker, and conjugation method, ...
| Abstract | Antibody-drug conjugates (ADC) achieve targeted drug delivery to a tumor and have demonstrated clinical success in many tumor types. The activity and safety profile of an ADC depends on its construction: antibody, payload, linker, and conjugation method, as well as the number of payload drugs per antibody [drug-to-antibody ratio (DAR)]. To allow for ADC optimization for a given target antigen, we developed Dolasynthen (DS), a novel ADC platform based on the payload auristatin hydroxypropylamide, that enables precise DAR-ranging and site-specific conjugation. We used the new platform to optimize an ADC that targets B7-H4 (VTCN1), an immune-suppressive protein that is overexpressed in breast, ovarian, and endometrial cancers. XMT-1660 is a site-specific DS DAR 6 ADC that induced complete tumor regressions in xenograft models of breast and ovarian cancer as well as in a syngeneic breast cancer model that is refractory to PD-1 immune checkpoint inhibition. In a panel of 28 breast cancer PDXs, XMT-1660 demonstrated activity that correlated with B7-H4 expression. XMT-1660 has recently entered clinical development in a phase I study (NCT05377996) in patients with cancer. |
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| MeSH term(s) | Humans ; Female ; Immunoconjugates/pharmacology ; Immunoconjugates/therapeutic use ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Antibodies ; Breast Neoplasms ; Cell Line, Tumor ; Xenograft Model Antitumor Assays | |||||
| Chemical Substances | Immunoconjugates ; Antineoplastic Agents ; Antibodies | |||||
| Language | English | |||||
| Publishing date | 2023-06-09 | |||||
| Publishing country | United States | |||||
| Document type | Clinical Trial, Phase I ; Journal Article ; Research Support, Non-U.S. Gov't | |||||
| ZDB-ID | 2063563-1 | |||||
| ISSN | 1538-8514 ; 1535-7163 | |||||
| ISSN (online) | 1538-8514 | |||||
| ISSN | 1535-7163 | |||||
| DOI | 10.1158/1535-7163.MCT-22-0786 | |||||
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| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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