2. Academic Validation
  3. A homogeneous high-DAR antibody-drug conjugate platform combining THIOMAB antibodies and XTEN polypeptides

A homogeneous high-DAR antibody-drug conjugate platform combining THIOMAB antibodies and XTEN polypeptides

  • Chem Sci. 2022 Jan 28;13(11):3147-3160. doi: 10.1039/d1sc05243h.
Neelie Zacharias 1,  Vladimir N Podust 2,  Kimberly K Kajihara 1,  Douglas Leipold 1,  Geoffrey Del Rosario 1,  Desiree Thayer 2,  Emily Dong 1,  Maciej Paluch 1,  David Fischer 1,  Kai Zheng 1,  Corinna Lei 1,  Jintang He 1,  Carl Ng 1,  Dian Su 1,  Luna Liu 1,  Shabkhaiz Masih 1,  William Sawyer 1,  Jeff Tinianow 1,  Jan Marik 1,  Victor Yip 1,  Guangmin Li 1,  Josefa Chuh 1,  J Hiroshi Morisaki 1,  Summer Park 1,  Bing Zheng 1,  Hilda Hernandez-Barry 1,  Kelly M Loyet 1,  Min Xu 1,  Katherine R Kozak 1,  Gail Lewis Phillips 1,  Ben-Quan Shen 1,  Cong Wu 1,  Keyang Xu 1,  Shang-Fan Yu 1,  Amrita Kamath 1,  Rebecca K Rowntree 1,  Dorothea Reilly 1,  Thomas Pillow 1,  Andrew Polson 1,  Volker Schellenberger 2,  Wouter L W Hazenbos 1,  Jack Sadowsky 1
Affiliations

Affiliations

  • 1 Genentech, Inc. 1 DNA Way South San Francisco CA 94080 USA whazenbos@vir.bio jack.sadowsky@gmail.com.
  • 2 Amunix Pharmaceuticals, Inc. 2 Tower Place South San Francisco CA 94080 USA vschellenberger@amunix.com.
PMID: 35414872 DOI: 10.1039/d1sc05243h
Abstract

The antibody-drug conjugate (ADC) is a well-validated modality for the cell-specific delivery of small molecules with impact expanding rapidly beyond their originally-intended purpose of treating Cancer. However, antibody-mediated delivery (AMD) remains inefficient, limiting its applicability to targeting highly potent payloads to cells with high antigen expression. Maximizing the number of payloads delivered per antibody is one key way in which delivery efficiency can be improved, although this has been challenging to carry out; with few exceptions, increasing the drug-to-antibody ratio (DAR) above ∼4 typically destroys the biophysical properties and in vivo efficacy for ADCs. Herein, we describe the development of a novel bioconjugation platform combining cysteine-engineered (THIOMAB) Antibodies and recombinant XTEN polypeptides for the unprecedented generation of homogeneous, stable "TXCs" with DAR of up to 18. Across three different bioactive payloads, we demonstrated improved AMD to tumors and Staphylococcus aureus bacteria for high-DAR TXCs relative to conventional low-DAR ADCs.

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