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Nonclinical Efficacy and Safety of CX-2029, an Anti-CD71 Probody–Drug Conjugate
Probody therapeutics (Pb-Txs) are conditionally activated antibody–drug conjugates (ADCs) designed to remain inactive until proteolytically activated in the tumor microenvironment, enabling safer targeting of antigens expressed in both tumor and normal tissue. Previous attempts to target CD71, a hig...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Association for Cancer Research
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9662867/ https://www.ncbi.nlm.nih.gov/pubmed/35666803 http://dx.doi.org/10.1158/1535-7163.MCT-21-0193 |
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author | Singh, Shweta Serwer, Laura DuPage, Amy Elkins, Kristi Chauhan, Niharika Ravn, Matthew Buchanan, Fritz Wang, Leyu Krimm, Michael Wong, Ken Sagert, Jason Tipton, Kimberly Moore, Stephen J. Huang, Yuanhui Jang, Andrew Ureno, Eric Miller, Adam Patrick, Sarah Duvur, Shanti Liu, Shouchun Vasiljeva, Olga Li, Yingchun Henriques, Tracy Badagnani, Ilaria Jeffries, Shawn Schleyer, Siew Leanna, Rob Krebber, Claus Viswanathan, Sridhar Desnoyers, Luc Terrett, Jonathan Belvin, Marcia Morgan-Lappe, Susan Kavanaugh, W. Michael Richardson, Jennifer |
author_facet | Singh, Shweta Serwer, Laura DuPage, Amy Elkins, Kristi Chauhan, Niharika Ravn, Matthew Buchanan, Fritz Wang, Leyu Krimm, Michael Wong, Ken Sagert, Jason Tipton, Kimberly Moore, Stephen J. Huang, Yuanhui Jang, Andrew Ureno, Eric Miller, Adam Patrick, Sarah Duvur, Shanti Liu, Shouchun Vasiljeva, Olga Li, Yingchun Henriques, Tracy Badagnani, Ilaria Jeffries, Shawn Schleyer, Siew Leanna, Rob Krebber, Claus Viswanathan, Sridhar Desnoyers, Luc Terrett, Jonathan Belvin, Marcia Morgan-Lappe, Susan Kavanaugh, W. Michael Richardson, Jennifer |
author_sort | Singh, Shweta |
collection | PubMed |
description | Probody therapeutics (Pb-Txs) are conditionally activated antibody–drug conjugates (ADCs) designed to remain inactive until proteolytically activated in the tumor microenvironment, enabling safer targeting of antigens expressed in both tumor and normal tissue. Previous attempts to target CD71, a highly expressed tumor antigen, have failed to establish an acceptable therapeutic window due to widespread normal tissue expression. This study evaluated whether a probody–drug conjugate targeting CD71 can demonstrate a favorable efficacy and tolerability profile in preclinical studies for the treatment of cancer. CX-2029, a Pb-Tx conjugated to maleimido-caproyl-valine-citrulline-p-aminobenzyloxycarbonyl-monomethyl auristatin E, was developed as a novel cancer therapeutic targeting CD71. Preclinical studies were performed to evaluate the efficacy and safety of this anti-CD71 PDC in patient-derived xenograft (PDX) mouse models and cynomolgus monkeys, respectively. CD71 expression was detected at high levels by IHC across a broad range of tumor and normal tissues. In vitro, the masked Pb-Tx form of the anti-CD71 PDC displayed a >50-fold reduced affinity for binding to CD71 on cells compared with protease-activated, unmasked anti-CD71 PDC. Potent in vivo tumor growth inhibition (stasis or regression) was observed in >80% of PDX models (28/34) at 3 or 6 mg/kg. Anti-CD71 PDC remained mostly masked (>80%) in circulation throughout dosing in cynomolgus monkeys at 2, 6, and 12 mg/kg and displayed a 10-fold improvement in tolerability compared with an anti-CD71 ADC, which was lethal. Preclinically, anti-CD71 PDC exhibits a highly efficacious and acceptable safety profile that demonstrates the utility of the Pb-Tx platform to target CD71, an otherwise undruggable target. These data support further clinical development of the anti-CD71 PDC CX-2029 as a novel cancer therapeutic. |
format | Online Article Text |
id | pubmed-9662867 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Association for Cancer Research |
record_format | MEDLINE/PubMed |
spelling | pubmed-96628672023-01-05 Nonclinical Efficacy and Safety of CX-2029, an Anti-CD71 Probody–Drug Conjugate Singh, Shweta Serwer, Laura DuPage, Amy Elkins, Kristi Chauhan, Niharika Ravn, Matthew Buchanan, Fritz Wang, Leyu Krimm, Michael Wong, Ken Sagert, Jason Tipton, Kimberly Moore, Stephen J. Huang, Yuanhui Jang, Andrew Ureno, Eric Miller, Adam Patrick, Sarah Duvur, Shanti Liu, Shouchun Vasiljeva, Olga Li, Yingchun Henriques, Tracy Badagnani, Ilaria Jeffries, Shawn Schleyer, Siew Leanna, Rob Krebber, Claus Viswanathan, Sridhar Desnoyers, Luc Terrett, Jonathan Belvin, Marcia Morgan-Lappe, Susan Kavanaugh, W. Michael Richardson, Jennifer Mol Cancer Ther Large Molecule Therapeutics Probody therapeutics (Pb-Txs) are conditionally activated antibody–drug conjugates (ADCs) designed to remain inactive until proteolytically activated in the tumor microenvironment, enabling safer targeting of antigens expressed in both tumor and normal tissue. Previous attempts to target CD71, a highly expressed tumor antigen, have failed to establish an acceptable therapeutic window due to widespread normal tissue expression. This study evaluated whether a probody–drug conjugate targeting CD71 can demonstrate a favorable efficacy and tolerability profile in preclinical studies for the treatment of cancer. CX-2029, a Pb-Tx conjugated to maleimido-caproyl-valine-citrulline-p-aminobenzyloxycarbonyl-monomethyl auristatin E, was developed as a novel cancer therapeutic targeting CD71. Preclinical studies were performed to evaluate the efficacy and safety of this anti-CD71 PDC in patient-derived xenograft (PDX) mouse models and cynomolgus monkeys, respectively. CD71 expression was detected at high levels by IHC across a broad range of tumor and normal tissues. In vitro, the masked Pb-Tx form of the anti-CD71 PDC displayed a >50-fold reduced affinity for binding to CD71 on cells compared with protease-activated, unmasked anti-CD71 PDC. Potent in vivo tumor growth inhibition (stasis or regression) was observed in >80% of PDX models (28/34) at 3 or 6 mg/kg. Anti-CD71 PDC remained mostly masked (>80%) in circulation throughout dosing in cynomolgus monkeys at 2, 6, and 12 mg/kg and displayed a 10-fold improvement in tolerability compared with an anti-CD71 ADC, which was lethal. Preclinically, anti-CD71 PDC exhibits a highly efficacious and acceptable safety profile that demonstrates the utility of the Pb-Tx platform to target CD71, an otherwise undruggable target. These data support further clinical development of the anti-CD71 PDC CX-2029 as a novel cancer therapeutic. American Association for Cancer Research 2022-08-02 2022-06-06 /pmc/articles/PMC9662867/ /pubmed/35666803 http://dx.doi.org/10.1158/1535-7163.MCT-21-0193 Text en ©2022 The Authors; Published by the American Association for Cancer Research https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) license. |
spellingShingle | Large Molecule Therapeutics Singh, Shweta Serwer, Laura DuPage, Amy Elkins, Kristi Chauhan, Niharika Ravn, Matthew Buchanan, Fritz Wang, Leyu Krimm, Michael Wong, Ken Sagert, Jason Tipton, Kimberly Moore, Stephen J. Huang, Yuanhui Jang, Andrew Ureno, Eric Miller, Adam Patrick, Sarah Duvur, Shanti Liu, Shouchun Vasiljeva, Olga Li, Yingchun Henriques, Tracy Badagnani, Ilaria Jeffries, Shawn Schleyer, Siew Leanna, Rob Krebber, Claus Viswanathan, Sridhar Desnoyers, Luc Terrett, Jonathan Belvin, Marcia Morgan-Lappe, Susan Kavanaugh, W. Michael Richardson, Jennifer Nonclinical Efficacy and Safety of CX-2029, an Anti-CD71 Probody–Drug Conjugate |
title | Nonclinical Efficacy and Safety of CX-2029, an Anti-CD71 Probody–Drug Conjugate |
title_full | Nonclinical Efficacy and Safety of CX-2029, an Anti-CD71 Probody–Drug Conjugate |
title_fullStr | Nonclinical Efficacy and Safety of CX-2029, an Anti-CD71 Probody–Drug Conjugate |
title_full_unstemmed | Nonclinical Efficacy and Safety of CX-2029, an Anti-CD71 Probody–Drug Conjugate |
title_short | Nonclinical Efficacy and Safety of CX-2029, an Anti-CD71 Probody–Drug Conjugate |
title_sort | nonclinical efficacy and safety of cx-2029, an anti-cd71 probody–drug conjugate |
topic | Large Molecule Therapeutics |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9662867/ https://www.ncbi.nlm.nih.gov/pubmed/35666803 http://dx.doi.org/10.1158/1535-7163.MCT-21-0193 |
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