公开(公告)号：EP3359194A2

公开(公告)日：2018-08-15

申请号：EP16854112.6

申请日：2016-09-30

申请人： Merck Sharp & Dohme Corp. ,  Ambrx, Inc.

发明人： BRANDISH, Philip, E. ,  GARBACCIO, Robert, M. ,  KERN, Jeffrey ,  LIANG, Linda ,  SHAH, Sanjiv ,  ZALLER, Dennis ,  BECK, Andrew ,  GATELY, Dennis ,  KNUDSEN, Nick ,  MANIBUSAN, Anthony ,  WANG, Jianing ,  SUN, Ying

IPC分类号： A61K39/44 ,  C07K17/06 ,  A61K47/24 ,  A61K39/395

CPC分类号： C07K16/2833 ,  A61K47/6803 ,  A61K47/6849 ,  A61K47/6889 ,  C07K16/2866 ,  C07K16/2875

摘要： Antibody drug conjugates (ADCs) comprising an antibody conjugated to an anti-inflammatory therapeutic agent via a phosphate-based linker with tunable extracellular and intracellular stability are described.

公开(公告)号：EP3125943A1

公开(公告)日：2017-02-08

申请号：EP15773458.3

申请日：2015-03-30

申请人： Merck Sharp & Dohme Corp. ,  Ambrx, Inc.

发明人： GARBACCIO, Robert M. ,  KERN, Jeffrey ,  BRANDISH, Philip E. ,  SHAH, Sanjiv ,  LIANG, Linda ,  SUN, Ying ,  WANG, Jianing ,  KNUDSEN, Nick ,  BECK, Andrew ,  MANIBUSAN, Anthony ,  GATELY, Dennis

IPC分类号： A61K47/24

CPC分类号： C07K16/2866 ,  A61K47/6803 ,  A61K47/6817 ,  A61K47/6849 ,  A61K47/6889 ,  A61K51/1045 ,  C07F9/091 ,  C07F9/098 ,  C07F9/12 ,  C07F9/2458 ,  C07F9/5721 ,  C07F9/65517 ,  C07F9/65583 ,  C07F9/65586 ,  C07F9/6561 ,  C07H19/10

摘要： Phosphate-based linkers with tunable stability for intracellular delivery of drug conjugates are described. The phosphate-based linkers comprise a monophosphate, diphosphate, triphosphate, or tetraphosphate group (phosphate group) and a linker arm comprising a tuning element and optionally a spacer. A payload is covalently linked to the phosphate group at the distal end of the linker arm and the functional group at the proximal end of the linker arm is covalently linked to a cell-specific targeting ligand such as an antibody. These phosphate-based linkers have a differentiated and tunable stability in blood vs. an intracellular environment (e.g. lysosomal compartment).

摘要翻译： 描述了具有用于细胞内递送药物偶联物的可调节稳定性的磷酸酯接头。 基于磷酸盐的连接体包含单磷酸盐，二磷酸盐，三磷酸盐或四磷酸盐基团（磷酸酯基团）和包含调谐元件和任选的间隔基的连接臂。 有效载荷与连接臂末端的磷酸基团共价连接，并且连接臂近端的官能团与细胞特异性靶向配体如抗体共价连接。 这些基于磷酸酯的接头在血液中相对于细胞内环境（例如溶酶体隔室）具有分化和可调节的稳定性。

公开(公告)号：EP2633066A1

公开(公告)日：2013-09-04

申请号：EP11836900.8

申请日：2011-10-21

申请人： Merck Sharp & Dohme Corp.

发明人： HAYASHI, Ikuo ,  MAJERCAK, John ,  SHAH, Sanjiv

IPC分类号： C12Q1/37

CPC分类号： C12Q1/37 ,  C12Q1/66 ,  G01N33/5023

摘要： The invention herein provides a method for identifying a Notch-sparing γ-secretase inhibitor (NS-GSI) by evaluating ε- and γ-cleavage in a single APP-based substrate. The inventive assay utilizes ε-cleavage as surrogate for S3-cleavage of Notch and a substrate comprising the C99 fragment of APP fused to a Gal4/VP16 transcription factor to evaluate the inhibitory activity of compounds on ε and γ-cleavage simultaneously and for the identification of ε -sparing inhibitors that decrease Aβ production without affecting AICD production. In another embodiment, the APP-based substrate incorporates a mutated α-secretase cleavage site for enhanced Aβ production which allows for greater sensitivity of the assay.