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

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 tar...

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Published inChemical science (Cambridge) Vol. 13; no. 11; pp. 3147 - 3160
Main Authors Zacharias, Neelie, Podust, Vladimir N., Kajihara, Kimberly K., Leipold, Douglas, Del Rosario, Geoffrey, Thayer, Desiree, Dong, Emily, Paluch, Maciej, Fischer, David, Zheng, Kai, Lei, Corinna, He, Jintang, Ng, Carl, Su, Dian, Liu, Luna, Masih, Shabkhaiz, Sawyer, William, Tinianow, Jeff, Marik, Jan, Yip, Victor, Li, Guangmin, Chuh, Josefa, Morisaki, J. Hiroshi, Park, Summer, Zheng, Bing, Hernandez-Barry, Hilda, Loyet, Kelly M., Xu, Min, Kozak, Katherine R., Phillips, Gail Lewis, Shen, Ben-Quan, Wu, Cong, Xu, Keyang, Yu, Shang-Fan, Kamath, Amrita, Rowntree, Rebecca K., Reilly, Dorothea, Pillow, Thomas, Polson, Andrew, Schellenberger, Volker, Hazenbos, Wouter L. W., Sadowsky, Jack
Format Journal Article
LanguageEnglish
Published England Royal Society of Chemistry 16.03.2022
The Royal Society of Chemistry
Subjects
Antibodies
Antigens
Chemistry
Conjugates
Payloads
Polypeptides
Online AccessGet full text
ISSN2041-6520
2041-6539
DOI10.1039/D1SC05243H

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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.
AbstractList 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.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.
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.
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 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 bacteria for high-DAR TXCs relative to conventional low-DAR ADCs.
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.
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. Efficiency of targeted cell delivery of small molecules was enhanced in cells and animals via a novel well-defined bioconjugation platform combining site-specific antibody conjugation and XTEN polypeptides to enable high payload loading.
Author Wu, Cong
Shen, Ben-Quan
Phillips, Gail Lewis
Kajihara, Kimberly K.
Del Rosario, Geoffrey
Xu, Min
Fischer, David
Zacharias, Neelie
Morisaki, J. Hiroshi
Schellenberger, Volker
Zheng, Kai
Xu, Keyang
Reilly, Dorothea
Dong, Emily
He, Jintang
Hernandez-Barry, Hilda
Sadowsky, Jack
Yip, Victor
Rowntree, Rebecca K.
Kozak, Katherine R.
Sawyer, William
Hazenbos, Wouter L. W.
Chuh, Josefa
Marik, Jan
Liu, Luna
Yu, Shang-Fan
Masih, Shabkhaiz
Ng, Carl
Leipold, Douglas
Tinianow, Jeff
Zheng, Bing
Park, Summer
Polson, Andrew
Paluch, Maciej
Kamath, Amrita
Pillow, Thomas
Podust, Vladimir N.
Lei, Corinna
Loyet, Kelly M.
Thayer, Desiree
Su, Dian
Li, Guangmin
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Present address: Carmot Therapeutics, 740 Heinz Avenue, Berkeley, CA 94710.
Present address: Atomwise, 717 Market Street, San Francisco, CA 94103. Email: desiree.thayer@gmail.com.
These authors contributed equally.
Current address: Vir Biotechnology, 499 Illinois St, San Francisco, CA 94158.
Present address: Ambys Medicines, 131 Oyster Point Blvd, South San Francisco, CA 94080.
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  text: 2022-03-16
  day: 16
PublicationDecade 2020
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PublicationTitle Chemical science (Cambridge)
PublicationTitleAlternate Chem Sci
PublicationYear 2022
Publisher Royal Society of Chemistry
The Royal Society of Chemistry
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Snippet The antibody–drug conjugate (ADC) is a well-validated modality for the cell-specific delivery of small molecules with impact expanding rapidly beyond their...
The antibody-drug conjugate (ADC) is a well-validated modality for the cell-specific delivery of small molecules with impact expanding rapidly beyond their...
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SubjectTerms Antibodies
Antigens
Chemistry
Conjugates
Payloads
Polypeptides
Title A homogeneous high-DAR antibody–drug conjugate platform combining THIOMAB antibodies and XTEN polypeptides
URI https://www.ncbi.nlm.nih.gov/pubmed/35414872
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