Discovery and Preclinical Characterization of XMT-1660, an Optimized B7-H4-Targeted Antibody-Drug Conjugate for the Treatment of Cancer

被引：18

作者：

Toader, Dorin ^{[1
,2
]}

Fessler, Shawn P. ^{[1
]}

Collins, Scott D. ^{[1
]}

Conlon, Patrick R. ^{[1
]}

Bollu, Reddy ^{[1
]}

Catcott, Kalli C. ^{[1
]}

Chin, Chen-Ni ^{[1
]}

Dirksen, Anouk ^{[1
]}

Du, Bingfan ^{[1
]}

Duvall, Jeremy R. ^{[1
]}

Higgins, Stacy ^{[1
]}

Kozytska, Mariya V. ^{[1
]}

Bellovoda, Kamela ^{[1
]}

Faircloth, Chelsey ^{[1
]}

Lee, David ^{[1
]}

Li, Fu ^{[1
]}

Qin, Liuliang ^{[1
]}

Routhier, Caitlin ^{[1
]}

Shaw, Pamela ^{[1
]}

Stevenson, Cheri A. ^{[1
]}

Wang, Jason ^{[1
]}

Wongthida, Phonphimon ^{[1
]}

Ter-Ovanesyan, Elena ^{[1
]}

Ditty, Elizabeth ^{[1
]}

Bradley, Stephen P. ^{[1
]}

Xu, Ling ^{[1
]}

Yin, Mao ^{[1
]}

Yurkovetskiy, Alexandr V. ^{[1
]}

Mosher, Rebecca ^{[1
]}

Damelin, Marc ^{[1
]}

Lowinger, Timothy B. ^{[1
,2
]}

机构：

[1] Mersana Therapeut Inc, 840 Mem Dr, Cambridge, MA USA

[2] 840 Mem Dr, Cambridge, MA 02139 USA

来源：

MOLECULAR CANCER THERAPEUTICS | 2023年 / 22卷 / 09期

关键词：

B7; FAMILY; B7-H4; BREAST; EXPRESSION; PHARMACOKINETICS; IMPROVES;

D O I：

10.1158/1535-7163.MCT-22-0786

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Antibody-drug conjugates (ADC) achieve targeted drug delivery to a tumor and have demonstrated clinical success in many tumor types. The activity and safety profile of an ADC depends on its construction: antibody, payload, linker, and conjugation method, as well as the number of payload drugs per antibody [drug-to-antibody ratio (DAR)]. To allow for ADC optimization for a given target antigen, we developed Dolasynthen (DS), a novel ADC platform based on the payload auristatin hydroxypropylamide, that enables precise DAR-ranging and site-specific conjugation. We used the new platform to optimize an ADC that targets B7-H4 (VTCN1), an immune-suppressive protein that is overexpressed in breast, ovarian, and endometrial cancers. XMT-1660 isa site-specific DS DAR 6 ADC that induced complete tumor regressions in xenograft models of breast and ovarian cancer as well as in a syngeneic breast cancer model that is refractory to PD-1 immune checkpoint inhibition. In a panel of 28 breast cancer PDXs, XMT-1660 demonstrated activity that correlated with B7-H4 expression. XMT-1660 has recentlyentered clinical development in a phase I study (NCT05377996) in patients with cancer.

引用

页码：999 / 1012

页数：14

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