Development of a facile antibody-drug conjugate platform for increased stability and homogeneity

被引：30

作者：

Gupta, Nimish ^{[1
,2
,4
]}

Kancharla, Johny ^{[1
]}

Kaushik, Shelly ^{[1
]}

Ansari, Aasif ^{[1
]}

Hossain, Samad ^{[1
,2
,4
]}

Goyal, Ravinder ^{[1
]}

Pandey, Manoj ^{[1
]}

Sivaccumar, Jwala ^{[1
]}

Hussain, Sazid ^{[1
]}

Sarkar, Arindam ^{[1
,2
,4
]}

Sengupta, Aniruddha ^{[1
,2
,4
]}

Mandal, Swadhin K. ^{[3
]}

Roy, Monideepa ^{[1
,2
,4
]}

Sengupta, Shiladitya ^{[1
,2
,5
,6
]}

机构：

[1] Invictus Oncol Pvt Ltd, Delhi 110092, India

[2] India Innovat Res Ctr, Delhi 110092, India

[3] Indian Inst Sci Educ & Res Kolkata, Dept Chem Sci, Kolkata 741252, Mohanpur, India

[4] Symbiosis Int Univ, Hlth & Biomed Sci, Pune 412115, Maharashtra, India

[5] Harvard Med Sch, Brigham & Womens Hosp, Boston, MA 02115 USA

[6] Harvard MIT, Div Hlth Sci & Technol, Cambridge, MA 02139 USA

来源：

CHEMICAL SCIENCE | 2017年 / 8卷 / 03期

关键词：

CANCER-THERAPY; BREAST-CANCER; CYTOTOXIC DRUG; LINKER; TRASTUZUMAB; COMPLEXES; ADC; PLATINUM(II); PAYLOADS; ALBUMIN;

D O I：

10.1039/c6sc05149a

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

Despite the advances in the design of antibody-drug conjugates (ADCs), the search is still ongoing for novel approaches that lead to increased stability and homogeneity of the ADCs. We report, for the first time, an ADC platform technology using a platinum(II)-based linker that can re-bridge the inter-chain cysteines in the antibody, post-reduction. The strong platinum-sulfur interaction improves the stability of the ADC when compared with a standard maleimide-linked ADC thereby reducing the linker-drug exchange with albumin significantly. Moreover, due to the precise conserved locations of cysteines, both homogeneity and site-specificity are simultaneously achieved. Additionally, we demonstrate that our ADCs exhibit increased anticancer efficacy in vitro and in vivo. The Pt-based ADCs can emerge as a simple and exciting proposition to address the limitations of the current ADC linker technologies.

引用

页码：2387 / 2395

页数：9

共 38 条

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