In Vitro and In Vivo Evaluation of Cysteine Rebridged Trastuzumab-MMAE Antibody Drug Conjugates with Defined Drug-to-Antibody Ratios

被引：95

作者：

Bryant, Penny ^{[1
]}

Pabst, Martin ^{[1
]}

Badescu, George ^{[1
]}

Bird, Matthew ^{[1
]}

McDowell, William ^{[1
]}

Jamieson, Estera ^{[1
]}

Swierkosz, Julia ^{[1
]}

Jurlewicz, Kosma ^{[1
]}

Tommasi, Rita ^{[1
]}

Henseleit, Korinna ^{[1
]}

Sheng, XiaoBo ^{[1
]}

Camper, Nicolas ^{[1
]}

Manin, Anais ^{[2
]}

Kozakowska, Katarzyna ^{[1
]}

Peciak, Karolina ^{[1
]}

Laurine, Emmanuelle ^{[1
]}

Grygorash, Ruslan ^{[1
]}

Kyle, Andrew ^{[1
]}

Morris, David ^{[1
]}

Parekh, Vimal ^{[1
]}

Abhilash, Amrita ^{[1
]}

Choi, Ji-won ^{[1
]}

Edwards, Jeff ^{[1
]}

Frigerio, Mark ^{[1
]}

Baker, Matthew P. ^{[1
,2
]}

Godwin, Antony ^{[1
]}

机构：

[1] PolyTher Ltd, Cambridge CB22 3AT, England

[2] Antitope Ltd, Cambridge CB22 3AT, England

来源：

MOLECULAR PHARMACEUTICS | 2015年 / 12卷 / 06期

关键词：

antibody drug conjugates (ADC); drug loading; disulfide rebridging; bis-sulfone; bis-alkylation; trastuzumab; auristatin; MMAE; JIMT-1 xenograft model; BREAST-CANCER; ANTITUMOR-ACTIVITY; THERAPEUTIC INDEX; CYTOTOXIC DRUG; STABILITY; RESISTANCE; TRANSGLUTAMINASE; MECHANISMS; POTENCY; IMPACT;

D O I：

10.1021/acs.molpharmaceut.5b00116

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

The conjugation of monomethyl auristatin E (MMAE) to trastuzumab using a reduction bis-alkylation approach that is capable of rebridging reduced (native) antibody interchain disulfide bonds has been previously shown to produce a homogeneous and stable conjugate with a drug-to-antibody ratio (DAR) of 4 as the major product. Here, we further investigate the potency of the DAR 4 conjugates prepared by bis-alkylation by comparing to lower drug loaded variants to maleimide linker based conjugates possessing typical mixed DAR profiles. Serum stability, HER2 receptor binding, internalization, in vitro potency, and in vivo efficacy were all evaluated. Greater stability compared with maleimide conjugation was observed with no significant decrease in receptor/FcRn binding. A clear dose-response was obtained based on drug loading (DAR) with the DAR 4 conjugate showing the highest potency in vitro and a much higher efficacy in vivo compared with the lower DAR conjugates. Finally, the DAR 4 conjugate demonstrated superior efficacy compared to trastuzumab-DM1 (T-DM1, Kadcyla), as evaluated in a low HER2 expressing JIMT-1 xenograft model.

引用

页码：1872 / 1879

页数：8

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