Acid-cleavable thiomaleamic acid linker for homogeneous antibody-drug conjugation

被引：60

作者：

Castaneda, Lourdes ^{[1
]}

Maruani, Antoine ^{[1
]}

Schumacher, Felix F. ^{[1
]}

Miranda, Enrique ^{[2
]}

Chudasama, Vijay ^{[1
]}

Chester, Kerry A. ^{[2
]}

Baker, James R. ^{[1
]}

Smith, Mark E. B. ^{[1
]}

Caddick, Stephen ^{[1
]}

机构：

[1] UCL, Dept Chem, London WC1H 0AJ, England

[2] UCL Canc Inst, London WC1E 6BT, England

来源：

CHEMICAL COMMUNICATIONS | 2013年 / 49卷 / 74期

基金：

英国惠康基金; 英国生物技术与生命科学研究理事会; 英国工程与自然科学研究理事会;

关键词：

MONOCLONAL-ANTIBODIES; THERAPEUTIC INDEX; BREAST-CANCER; FUTURE; BROMOMALEIMIDES; TRASTUZUMAB; DOXORUBICIN;

D O I：

10.1039/c3cc45220d

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

In this communication we describe a novel acid-cleavable linker strategy for antibody-drug conjugation. Functional disulfide bridging of the single interchain disulfide bond of a trastuzumab Fab fragment yields a homogeneous antibody-drug conjugate bearing a thiomaleamic acid linker. This linker is stable at physiological pH and temperature, but quantitatively cleaves at lysosomal pH to release the drug payload.

引用

收藏

页码：8187 / 8189

页数：3

相关论文

共 27 条

[1] Antibody-drug conjugates - a perfect synergy [J].

Adair, John R. ;

Howard, Philip W. ;

Hartley, John A. ;

Williams, David G. ;

Chester, Kerry A. .

EXPERT OPINION ON BIOLOGICAL THERAPY, 2012, 12 (09) :1191-1206

[2] Antibody-drug conjugates: targeted drug delivery for cancer [J].

Alley, Stephen C. ;

Okeley, Nicole M. ;

Senter, Peter D. .

CURRENT OPINION IN CHEMICAL BIOLOGY, 2010, 14 (04) :529-537

[3]

[Anonymous], J CHM SOC P2

[4] ADRIAMYCIN, 14-HYDROXYDAUNOMYCIN, A NEW ANTITUMOR ANTIBIOTIC FROM S-PEUCETIUS VAR CAESIUS [J].

ARCAMONE, F ;

CASSINEL.G ;

FANTINI, G ;

GREIN, A ;

OREZZI, P ;

POL, C ;

SPALLA, C .

BIOTECHNOLOGY AND BIOENGINEERING, 1969, 11 (06) :1101-&

[5] Monitoring papain digestion of a monoclonal antibody by electrospray ionization mass spectrometry [J].

Bennett, KL ;

Smith, SV ;

Truscott, RJW ;

Sheil, MM .

ANALYTICAL BIOCHEMISTRY, 1997, 245 (01) :17-27

[6] A mild synthesis of N-functionalised bromomaleimides, thiomaleimides and bromopyridazinediones [J].

Castaneda, Lourdes ;

Wright, Zoe V. F. ;

Marculescu, Cristina ;

Tran, Trang M. ;

Chudasama, Vijay ;

Maruani, Antoine ;

Hull, Elizabeth A. ;

Nunes, Joao P. M. ;

Fitzmaurice, Richard J. ;

Smith, Mark E. B. ;

Jones, Lyn H. ;

Caddick, Stephen ;

Baker, James R. .

TETRAHEDRON LETTERS, 2013, 54 (27) :3493-3495

[7] Therapeutic antibodies: successes, limitations and hopes for the future [J].

Chames, Patrick ;

Van Regenmortel, Marc ;

Weiss, Etienne ;

Baty, Daniel .

BRITISH JOURNAL OF PHARMACOLOGY, 2009, 157 (02) :220-233

[8]

Dimitrov Dimiter S., 2009, V525, P1, DOI 10.1007/978-1-59745-554-1_1

[9] Cathepsin B-labile dipeptide linkers for lysosomal release of doxorubicin from internalizing immunoconjugates: Model studies of enzymatic drug release and antigen-specific in vitro anticancer activity [J].

Dubowchik, GM ;

Firestone, RA ;

Padilla, L ;

Willner, D ;

Hofstead, SJ ;

Mosure, K ;

Knipe, JO ;

Lasch, SJ ;

Trail, PA .

BIOCONJUGATE CHEMISTRY, 2002, 13 (04) :855-869

[10] Antibody-Drug Conjugates: Linking Cytotoxic Payloads to Monoclonal Antibodies [J].

Ducry, Laurent ;

Stump, Bernhard .

BIOCONJUGATE CHEMISTRY, 2010, 21 (01) :5-13