| Autor: |
Volker Schellenberger, David Fischer, Bing Zheng, Thomas H. Pillow, Amrita V. Kamath, Carl Ng, Jan Marik, Corinna Lei, Dorothea Reilly, Shabkhaiz Masih, Kelly M. Loyet, Vladimir N. Podust, Kimberly Kajihara, Maciej Paluch, Andrew Polson, Gail Dianne Phillips, Summer Park, Luna Liu, Morisaki John Hiroshi, Kai Zheng, Guangmin Li, Dian Su, Douglas D. Leipold, Josefa Chuh, Victor Yip, Emily Dong, Shang-Fan Yu, Wouter L. W. Hazenbos, Jack Sadowsky, Geoffrey Del Rosario, Rebecca K. Rowntree, Jeff N. Tinianow, Neelie Zacharias, Min Xu, William S. Sawyer, Katherine R. Kozak, Hilda Hernandez-Barry, Jintang He, Cong Wu, Keyang Xu, Ben-Quan Shen |
| Rok vydání: |
2021 |
| Předmět: |
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| DOI: |
10.21203/rs.3.rs-356231/v1 |
| Popis: |
Antibody-drug conjugates (ADCs) enable cell-specific delivery of small molecules and are validated anti-cancer therapeutics. One factor limiting ADC advancement and broader application is the drug-to-antibody ratio (DAR), which dictates the number of payloads that can be delivered per antibody. With few exceptions, efficacious ADCs with DAR > 4 are inaccessible due to aggregation or rapid clearance in vivo. Here, we report a versatile platform for the generation of homogeneous ADCs with DAR up to 18, combining Cys-engineered THIOMAB antibodies and XTEN polypeptides to give “TXCs”. We show that high-DAR TXCs are stable biochemically and in vivo. We demonstrate that two different cytotoxic TXCs directed toward a tumor xenograft and one TXC targeting Staphylococcus aureus have comparable pharmacokinetics, but significantly enhanced efficacy in vivo versus conventional low-DAR ADCs. Our data suggest that high-DAR TXCs may ultimately offer several advantages versus conventional ADCs, including increased therapeutic index and efficacious delivery of less potent payloads. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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