A novel platinum(II)-based bifunctional ADC linker benchmarked using 89Zr-Desferal and auristatin F-conjugated trastuzumab

Niels J. Sijbrandi, Eugen Merkul, Joey A. Muns, Dennis C.J. Waalboer, Kevin Adamzek, Marije Bolijn, Veronica Montserrat, Govert W. Somsen, Rob Haselberg, Paul J.G.M. Steverink, Hendrik Jan Houthoff, Guus A.M.S. Van Dongen

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Greater control is desirable in the stochastic conjugation technology used to synthesize antibody-drug conjugates (ADC). We have shown recently that a fluorescent dye can be stably conjugated to a mAb using a bifunctional platinum(II) linker. Here, we describe the general applicability of this novel linker technology for the preparation of stable and efficacious ADCs. The ethylenediamine platinum(II) moiety, herein called Lx, was coordinated to Desferal (DFO) or auristatin F (AF) to provide storable "semifinal" products, which were directly conjugated to unmodified mAbs. Conjugation resulted in ADCs with unimpaired mAb-binding characteristics, DAR in the range of 2.5 to 2.7 and approximately 85% payload bound to the Fc region, presumably to histidine residues. To evaluate the in vivo stability of Lx and its effect on pharmacokinetics and tumor targeting of an ADC, Lx-DFO was conjugated to the HER2 mAb trastuzumab, followed by radiolabeling with 89Zr. Trastuzumab-Lx-DFO-98Zr was stable in vivo and exhibited pharmacokinetic and tumor-targeting properties similar to parental trastuzumab. In a xenograft mouse model of gastric cancer (NCI-N87) or an ado-trastuzumab emtansine-resistant breast cancer (JIMT-1), a single dose of trastuzumab-Lx-AF outperformed its maleimide benchmark trastuzumab-Mal-AF and FDA-approved ado-trastuzumab emtansine. Overall, our findings show the potential of the Lx technology as a robust conjugation platform for the preparation of anticancer ADCs.

Original languageEnglish
Pages (from-to)257-267
Number of pages11
JournalCancer Research
Volume77
Issue number2
DOIs
Publication statusPublished - 15 Jan 2017

Cite this

Sijbrandi, Niels J. ; Merkul, Eugen ; Muns, Joey A. ; Waalboer, Dennis C.J. ; Adamzek, Kevin ; Bolijn, Marije ; Montserrat, Veronica ; Somsen, Govert W. ; Haselberg, Rob ; Steverink, Paul J.G.M. ; Houthoff, Hendrik Jan ; Van Dongen, Guus A.M.S. / A novel platinum(II)-based bifunctional ADC linker benchmarked using 89Zr-Desferal and auristatin F-conjugated trastuzumab. In: Cancer Research. 2017 ; Vol. 77, No. 2. pp. 257-267.
@article{b02a304ba2e54cb19a869bece190a041,
title = "A novel platinum(II)-based bifunctional ADC linker benchmarked using 89Zr-Desferal and auristatin F-conjugated trastuzumab",
abstract = "Greater control is desirable in the stochastic conjugation technology used to synthesize antibody-drug conjugates (ADC). We have shown recently that a fluorescent dye can be stably conjugated to a mAb using a bifunctional platinum(II) linker. Here, we describe the general applicability of this novel linker technology for the preparation of stable and efficacious ADCs. The ethylenediamine platinum(II) moiety, herein called Lx, was coordinated to Desferal (DFO) or auristatin F (AF) to provide storable {"}semifinal{"} products, which were directly conjugated to unmodified mAbs. Conjugation resulted in ADCs with unimpaired mAb-binding characteristics, DAR in the range of 2.5 to 2.7 and approximately 85{\%} payload bound to the Fc region, presumably to histidine residues. To evaluate the in vivo stability of Lx and its effect on pharmacokinetics and tumor targeting of an ADC, Lx-DFO was conjugated to the HER2 mAb trastuzumab, followed by radiolabeling with 89Zr. Trastuzumab-Lx-DFO-98Zr was stable in vivo and exhibited pharmacokinetic and tumor-targeting properties similar to parental trastuzumab. In a xenograft mouse model of gastric cancer (NCI-N87) or an ado-trastuzumab emtansine-resistant breast cancer (JIMT-1), a single dose of trastuzumab-Lx-AF outperformed its maleimide benchmark trastuzumab-Mal-AF and FDA-approved ado-trastuzumab emtansine. Overall, our findings show the potential of the Lx technology as a robust conjugation platform for the preparation of anticancer ADCs.",
author = "Sijbrandi, {Niels J.} and Eugen Merkul and Muns, {Joey A.} and Waalboer, {Dennis C.J.} and Kevin Adamzek and Marije Bolijn and Veronica Montserrat and Somsen, {Govert W.} and Rob Haselberg and Steverink, {Paul J.G.M.} and Houthoff, {Hendrik Jan} and {Van Dongen}, {Guus A.M.S.}",
year = "2017",
month = "1",
day = "15",
doi = "10.1158/0008-5472.CAN-16-1900",
language = "English",
volume = "77",
pages = "257--267",
journal = "Cancer Research",
issn = "0008-5472",
publisher = "American Association for Cancer Research Inc.",
number = "2",

}

Sijbrandi, NJ, Merkul, E, Muns, JA, Waalboer, DCJ, Adamzek, K, Bolijn, M, Montserrat, V, Somsen, GW, Haselberg, R, Steverink, PJGM, Houthoff, HJ & Van Dongen, GAMS 2017, 'A novel platinum(II)-based bifunctional ADC linker benchmarked using 89Zr-Desferal and auristatin F-conjugated trastuzumab' Cancer Research, vol. 77, no. 2, pp. 257-267. https://doi.org/10.1158/0008-5472.CAN-16-1900

A novel platinum(II)-based bifunctional ADC linker benchmarked using 89Zr-Desferal and auristatin F-conjugated trastuzumab. / Sijbrandi, Niels J.; Merkul, Eugen; Muns, Joey A.; Waalboer, Dennis C.J.; Adamzek, Kevin; Bolijn, Marije; Montserrat, Veronica; Somsen, Govert W.; Haselberg, Rob; Steverink, Paul J.G.M.; Houthoff, Hendrik Jan; Van Dongen, Guus A.M.S.

In: Cancer Research, Vol. 77, No. 2, 15.01.2017, p. 257-267.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - A novel platinum(II)-based bifunctional ADC linker benchmarked using 89Zr-Desferal and auristatin F-conjugated trastuzumab

AU - Sijbrandi, Niels J.

AU - Merkul, Eugen

AU - Muns, Joey A.

AU - Waalboer, Dennis C.J.

AU - Adamzek, Kevin

AU - Bolijn, Marije

AU - Montserrat, Veronica

AU - Somsen, Govert W.

AU - Haselberg, Rob

AU - Steverink, Paul J.G.M.

AU - Houthoff, Hendrik Jan

AU - Van Dongen, Guus A.M.S.

PY - 2017/1/15

Y1 - 2017/1/15

N2 - Greater control is desirable in the stochastic conjugation technology used to synthesize antibody-drug conjugates (ADC). We have shown recently that a fluorescent dye can be stably conjugated to a mAb using a bifunctional platinum(II) linker. Here, we describe the general applicability of this novel linker technology for the preparation of stable and efficacious ADCs. The ethylenediamine platinum(II) moiety, herein called Lx, was coordinated to Desferal (DFO) or auristatin F (AF) to provide storable "semifinal" products, which were directly conjugated to unmodified mAbs. Conjugation resulted in ADCs with unimpaired mAb-binding characteristics, DAR in the range of 2.5 to 2.7 and approximately 85% payload bound to the Fc region, presumably to histidine residues. To evaluate the in vivo stability of Lx and its effect on pharmacokinetics and tumor targeting of an ADC, Lx-DFO was conjugated to the HER2 mAb trastuzumab, followed by radiolabeling with 89Zr. Trastuzumab-Lx-DFO-98Zr was stable in vivo and exhibited pharmacokinetic and tumor-targeting properties similar to parental trastuzumab. In a xenograft mouse model of gastric cancer (NCI-N87) or an ado-trastuzumab emtansine-resistant breast cancer (JIMT-1), a single dose of trastuzumab-Lx-AF outperformed its maleimide benchmark trastuzumab-Mal-AF and FDA-approved ado-trastuzumab emtansine. Overall, our findings show the potential of the Lx technology as a robust conjugation platform for the preparation of anticancer ADCs.

AB - Greater control is desirable in the stochastic conjugation technology used to synthesize antibody-drug conjugates (ADC). We have shown recently that a fluorescent dye can be stably conjugated to a mAb using a bifunctional platinum(II) linker. Here, we describe the general applicability of this novel linker technology for the preparation of stable and efficacious ADCs. The ethylenediamine platinum(II) moiety, herein called Lx, was coordinated to Desferal (DFO) or auristatin F (AF) to provide storable "semifinal" products, which were directly conjugated to unmodified mAbs. Conjugation resulted in ADCs with unimpaired mAb-binding characteristics, DAR in the range of 2.5 to 2.7 and approximately 85% payload bound to the Fc region, presumably to histidine residues. To evaluate the in vivo stability of Lx and its effect on pharmacokinetics and tumor targeting of an ADC, Lx-DFO was conjugated to the HER2 mAb trastuzumab, followed by radiolabeling with 89Zr. Trastuzumab-Lx-DFO-98Zr was stable in vivo and exhibited pharmacokinetic and tumor-targeting properties similar to parental trastuzumab. In a xenograft mouse model of gastric cancer (NCI-N87) or an ado-trastuzumab emtansine-resistant breast cancer (JIMT-1), a single dose of trastuzumab-Lx-AF outperformed its maleimide benchmark trastuzumab-Mal-AF and FDA-approved ado-trastuzumab emtansine. Overall, our findings show the potential of the Lx technology as a robust conjugation platform for the preparation of anticancer ADCs.

UR - http://www.scopus.com/inward/record.url?scp=85018660497&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-16-1900

DO - 10.1158/0008-5472.CAN-16-1900

M3 - Article

VL - 77

SP - 257

EP - 267

JO - Cancer Research

JF - Cancer Research

SN - 0008-5472

IS - 2

ER -