A Potent Anti-CD70 Antibody-Drug Conjugate Combining a Dimeric Pyrrolobenzodiazepine Drug with Site-Specific Conjugation Technology

Scott C. Jeffrey; Patrick J. Burke; Robert P. Lyon; David W.  Meyer; Django Sussman; Martha  Anderson; Joshua H. Hunter; Chris I. Leiske; Jamie B. Miyamoto; Nicole D. Nicholas; Nicole M. Okeley; Russell J. Sanderson; Ivan J. Stone; Weiping Zeng; Stephen J. Gregson; Luke Masterson; Arnaud C. Tiberghien; Philip W. Howard; David E Thurston; Che-Leung Law; Peter D. Senter

doi:10.1021/bc400217g

A Potent Anti-CD70 Antibody-Drug Conjugate Combining a Dimeric Pyrrolobenzodiazepine Drug with Site-Specific Conjugation Technology

Scott C. Jeffrey, Patrick J. Burke, Robert P. Lyon, David W. Meyer, Django Sussman, Martha Anderson, Joshua H. Hunter, Chris I. Leiske, Jamie B. Miyamoto, Nicole D. Nicholas, Nicole M. Okeley, Russell J. Sanderson, Ivan J. Stone, Weiping Zeng, Stephen J. Gregson, Luke Masterson, Arnaud C. Tiberghien, Philip W. Howard, David E Thurston, Che-Leung LawPeter D. Senter

Institute of Pharmaceutical Science

Research output: Contribution to journal › Article › peer-review

223 Citations (Scopus)

Abstract

A highly cytotoxic DNA cross-linking pyrrolobenzodiazepine (PBD) dimer with a valine-alanine dipeptide linker was conjugated to the anti-CD70 h1F6 mAb either through endogenous interchain cysteines or, site-specifically, through engineered cysteines at position 239 of the heavy chains. The h1F6239C-PBD conjugation strategy proved to be superior to interchain cysteine conjugation, affording an antibody–drug conjugate (ADC) with high uniformity in drug-loading and low levels of aggregation. In vitro cytotoxicity experiments demonstrated that the h1F6239C-PBD was potent and immunologically specific on CD70-positive renal cell carcinoma (RCC) and non-Hodgkin lymphoma (NHL) cell lines. The conjugate was resistant to drug loss in plasma and in circulation, and had a pharmacokinetic profile closely matching that of the parental h1F6239C antibody capped with N-ethylmaleimide (NEM). Evaluation in CD70-positive RCC and NHL mouse xenograft models showed pronounced antitumor activities at single or weekly doses as low as 0.1 mg/kg of ADC. The ADC was tolerated at 2.5 mg/kg. These results demonstrate that PBDs can be effectively used for antibody-targeted therapy.

Original language	English
Pages (from-to)	1256−1263
Number of pages	8
Journal	Bioconjugate Chemistry
Volume	24
Issue number	7
DOIs	https://doi.org/10.1021/bc400217g
Publication status	Published - 17 Jul 2013

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Jeffrey, S. C., Burke, P. J., Lyon, R. P., Meyer, D. W., Sussman, D., Anderson, M., Hunter, J. H., Leiske, C. I., Miyamoto, J. B., Nicholas, N. D., Okeley, N. M., Sanderson, R. J., Stone, I. J., Zeng, W., Gregson, S. J., Masterson, L., Tiberghien, A. C., Howard, P. W., Thurston, D. E., ... Senter, P. D. (2013). A Potent Anti-CD70 Antibody-Drug Conjugate Combining a Dimeric Pyrrolobenzodiazepine Drug with Site-Specific Conjugation Technology. Bioconjugate Chemistry, 24 (7), 1256−1263 . https://doi.org/10.1021/bc400217g

@article{facb50ee826d4679b667aaa4b0c95fcd,

title = "A Potent Anti-CD70 Antibody-Drug Conjugate Combining a Dimeric Pyrrolobenzodiazepine Drug with Site-Specific Conjugation Technology",

abstract = "A highly cytotoxic DNA cross-linking pyrrolobenzodiazepine (PBD) dimer with a valine-alanine dipeptide linker was conjugated to the anti-CD70 h1F6 mAb either through endogenous interchain cysteines or, site-specifically, through engineered cysteines at position 239 of the heavy chains. The h1F6239C-PBD conjugation strategy proved to be superior to interchain cysteine conjugation, affording an antibody–drug conjugate (ADC) with high uniformity in drug-loading and low levels of aggregation. In vitro cytotoxicity experiments demonstrated that the h1F6239C-PBD was potent and immunologically specific on CD70-positive renal cell carcinoma (RCC) and non-Hodgkin lymphoma (NHL) cell lines. The conjugate was resistant to drug loss in plasma and in circulation, and had a pharmacokinetic profile closely matching that of the parental h1F6239C antibody capped with N-ethylmaleimide (NEM). Evaluation in CD70-positive RCC and NHL mouse xenograft models showed pronounced antitumor activities at single or weekly doses as low as 0.1 mg/kg of ADC. The ADC was tolerated at 2.5 mg/kg. These results demonstrate that PBDs can be effectively used for antibody-targeted therapy.",

author = "Jeffrey, {Scott C.} and Burke, {Patrick J.} and Lyon, {Robert P.} and Meyer, {David W.} and Django Sussman and Martha Anderson and Hunter, {Joshua H.} and Leiske, {Chris I.} and Miyamoto, {Jamie B.} and Nicholas, {Nicole D.} and Okeley, {Nicole M.} and Sanderson, {Russell J.} and Stone, {Ivan J.} and Weiping Zeng and Gregson, {Stephen J.} and Luke Masterson and Tiberghien, {Arnaud C.} and Howard, {Philip W.} and Thurston, {David E} and Che-Leung Law and Senter, {Peter D.}",

year = "2013",

month = jul,

day = "17",

doi = "10.1021/bc400217g",

language = "English",

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Jeffrey, SC, Burke, PJ, Lyon, RP, Meyer, DW, Sussman, D, Anderson, M, Hunter, JH, Leiske, CI, Miyamoto, JB, Nicholas, ND, Okeley, NM, Sanderson, RJ, Stone, IJ, Zeng, W, Gregson, SJ, Masterson, L, Tiberghien, AC, Howard, PW, Thurston, DE, Law, C-L & Senter, PD 2013, 'A Potent Anti-CD70 Antibody-Drug Conjugate Combining a Dimeric Pyrrolobenzodiazepine Drug with Site-Specific Conjugation Technology', Bioconjugate Chemistry, vol. 24 , no. 7, pp. 1256−1263 . https://doi.org/10.1021/bc400217g

TY - JOUR

T1 - A Potent Anti-CD70 Antibody-Drug Conjugate Combining a Dimeric Pyrrolobenzodiazepine Drug with Site-Specific Conjugation Technology

AU - Jeffrey, Scott C.

AU - Burke, Patrick J.

AU - Lyon, Robert P.

AU - Meyer, David W.

AU - Sussman, Django

AU - Anderson, Martha

AU - Hunter, Joshua H.

AU - Leiske, Chris I.

AU - Miyamoto, Jamie B.

AU - Nicholas, Nicole D.

AU - Okeley, Nicole M.

AU - Sanderson, Russell J.

AU - Stone, Ivan J.

AU - Zeng, Weiping

AU - Gregson, Stephen J.

AU - Masterson, Luke

AU - Tiberghien, Arnaud C.

AU - Howard, Philip W.

AU - Thurston, David E

AU - Law, Che-Leung

AU - Senter, Peter D.

PY - 2013/7/17

Y1 - 2013/7/17

N2 - A highly cytotoxic DNA cross-linking pyrrolobenzodiazepine (PBD) dimer with a valine-alanine dipeptide linker was conjugated to the anti-CD70 h1F6 mAb either through endogenous interchain cysteines or, site-specifically, through engineered cysteines at position 239 of the heavy chains. The h1F6239C-PBD conjugation strategy proved to be superior to interchain cysteine conjugation, affording an antibody–drug conjugate (ADC) with high uniformity in drug-loading and low levels of aggregation. In vitro cytotoxicity experiments demonstrated that the h1F6239C-PBD was potent and immunologically specific on CD70-positive renal cell carcinoma (RCC) and non-Hodgkin lymphoma (NHL) cell lines. The conjugate was resistant to drug loss in plasma and in circulation, and had a pharmacokinetic profile closely matching that of the parental h1F6239C antibody capped with N-ethylmaleimide (NEM). Evaluation in CD70-positive RCC and NHL mouse xenograft models showed pronounced antitumor activities at single or weekly doses as low as 0.1 mg/kg of ADC. The ADC was tolerated at 2.5 mg/kg. These results demonstrate that PBDs can be effectively used for antibody-targeted therapy.

AB - A highly cytotoxic DNA cross-linking pyrrolobenzodiazepine (PBD) dimer with a valine-alanine dipeptide linker was conjugated to the anti-CD70 h1F6 mAb either through endogenous interchain cysteines or, site-specifically, through engineered cysteines at position 239 of the heavy chains. The h1F6239C-PBD conjugation strategy proved to be superior to interchain cysteine conjugation, affording an antibody–drug conjugate (ADC) with high uniformity in drug-loading and low levels of aggregation. In vitro cytotoxicity experiments demonstrated that the h1F6239C-PBD was potent and immunologically specific on CD70-positive renal cell carcinoma (RCC) and non-Hodgkin lymphoma (NHL) cell lines. The conjugate was resistant to drug loss in plasma and in circulation, and had a pharmacokinetic profile closely matching that of the parental h1F6239C antibody capped with N-ethylmaleimide (NEM). Evaluation in CD70-positive RCC and NHL mouse xenograft models showed pronounced antitumor activities at single or weekly doses as low as 0.1 mg/kg of ADC. The ADC was tolerated at 2.5 mg/kg. These results demonstrate that PBDs can be effectively used for antibody-targeted therapy.

U2 - 10.1021/bc400217g

DO - 10.1021/bc400217g

M3 - Article

SN - 1043-1802

VL - 24

SP - 1256−1263

JO - Bioconjugate Chemistry

JF - Bioconjugate Chemistry

IS - 7

ER -

A Potent Anti-CD70 Antibody-Drug Conjugate Combining a Dimeric Pyrrolobenzodiazepine Drug with Site-Specific Conjugation Technology

Abstract

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