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Molecular Cancer Therapeutics
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Large Molecule Therapeutics

Development of Novel Antibody–Camptothecin Conjugates

Ryan D. Lyski, Lauren B. Bou, Uland Y. Lau, David W. Meyer, Julia H. Cochran, Nicole M. Okeley, Kim K. Emmerton, Francisco Zapata, Jessica K. Simmons, Esther S. Trueblood, David J. Ortiz, Margo C. Zaval, Katie M. Snead, Steven Jin, Lauren M. Farr, Maureen C. Ryan, Peter D. Senter and Scott C. Jeffrey
Ryan D. Lyski
1Seagen Inc., Bothell, Seattle, Washington.
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Lauren B. Bou
1Seagen Inc., Bothell, Seattle, Washington.
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Uland Y. Lau
2Neoleukin Therapeutics, Inc., Seattle, Washington.
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  • ORCID record for Uland Y. Lau
David W. Meyer
1Seagen Inc., Bothell, Seattle, Washington.
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Julia H. Cochran
1Seagen Inc., Bothell, Seattle, Washington.
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Nicole M. Okeley
1Seagen Inc., Bothell, Seattle, Washington.
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Kim K. Emmerton
1Seagen Inc., Bothell, Seattle, Washington.
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Francisco Zapata
1Seagen Inc., Bothell, Seattle, Washington.
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Jessica K. Simmons
1Seagen Inc., Bothell, Seattle, Washington.
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Esther S. Trueblood
1Seagen Inc., Bothell, Seattle, Washington.
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  • ORCID record for Esther S. Trueblood
David J. Ortiz
1Seagen Inc., Bothell, Seattle, Washington.
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Margo C. Zaval
1Seagen Inc., Bothell, Seattle, Washington.
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Katie M. Snead
1Seagen Inc., Bothell, Seattle, Washington.
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Steven Jin
1Seagen Inc., Bothell, Seattle, Washington.
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Lauren M. Farr
1Seagen Inc., Bothell, Seattle, Washington.
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Maureen C. Ryan
1Seagen Inc., Bothell, Seattle, Washington.
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Peter D. Senter
1Seagen Inc., Bothell, Seattle, Washington.
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Scott C. Jeffrey
1Seagen Inc., Bothell, Seattle, Washington.
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  • For correspondence: sjeffrey@seagen.com
DOI: 10.1158/1535-7163.MCT-20-0526 Published February 2021
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Abstract

We have developed a highly active and well-tolerated camptothecin (CPT) drug-linker designed for antibody-mediated drug delivery in which the lead molecule consists of a 7-aminomethyl-10,11-methylenedioxy CPT (CPT1) derivative payload attached to a novel hydrophilic protease-cleavable valine–lysine–glycine tripeptide linker. A defined polyethylene glycol stretcher was included to improve the properties of the drug-linker, facilitating high antibody–drug conjugate (ADC) drug loading, while reducing the propensity for aggregation. A CPT1 ADC with 8 drug-linkers/mAb displayed a pharmacokinetic profile coincident with parental unconjugated antibody and had high serum stability. The ADCs were broadly active against cancer cells in vitro and in mouse xenograft models, giving tumor regressions and complete responses at low (≤3 mg/kg, single administration) doses. Pronounced activities were obtained in both solid and hematologic tumor models and in models of bystander killing activity and multidrug resistance. Payload release studies demonstrated that two CPTs, CPT1 and the corresponding glycine analog (CPT2), were released from a cAC10 ADC by tumor cells. An ADC containing this drug-linker was well tolerated in rats at 60 mg/kg, given weekly four times. Thus, ADCs comprised of this valine–lysine–glycine linker with CPT drug payloads have promise in targeted drug delivery.

Footnotes

  • Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

  • Mol Cancer Ther 2021;20:329–39

  • Received June 26, 2020.
  • Revision received August 14, 2020.
  • Accepted November 9, 2020.
  • Published first December 3, 2020.
  • ©2020 American Association for Cancer Research.
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Molecular Cancer Therapeutics: 20 (2)
February 2021
Volume 20, Issue 2
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Development of Novel Antibody–Camptothecin Conjugates
Ryan D. Lyski, Lauren B. Bou, Uland Y. Lau, David W. Meyer, Julia H. Cochran, Nicole M. Okeley, Kim K. Emmerton, Francisco Zapata, Jessica K. Simmons, Esther S. Trueblood, David J. Ortiz, Margo C. Zaval, Katie M. Snead, Steven Jin, Lauren M. Farr, Maureen C. Ryan, Peter D. Senter and Scott C. Jeffrey
Mol Cancer Ther February 1 2021 (20) (2) 329-339; DOI: 10.1158/1535-7163.MCT-20-0526

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Development of Novel Antibody–Camptothecin Conjugates
Ryan D. Lyski, Lauren B. Bou, Uland Y. Lau, David W. Meyer, Julia H. Cochran, Nicole M. Okeley, Kim K. Emmerton, Francisco Zapata, Jessica K. Simmons, Esther S. Trueblood, David J. Ortiz, Margo C. Zaval, Katie M. Snead, Steven Jin, Lauren M. Farr, Maureen C. Ryan, Peter D. Senter and Scott C. Jeffrey
Mol Cancer Ther February 1 2021 (20) (2) 329-339; DOI: 10.1158/1535-7163.MCT-20-0526
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Molecular Cancer Therapeutics
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