公开(公告)号：US20230398224A1

公开(公告)日：2023-12-14

申请号：US17760081

申请日：2021-02-04

Applicant: Novartis AG

Inventor： Martin Allan ,  Jeffrey T. BAGDANOFF ,  David Weninger Barnes ,  Kevin Clairmont ,  Thomas Smith ,  Shuangxi Wang

IPC: A61K47/54 ,  C07K7/64

CPC classification number: A61K47/549 ,  C07K7/64

Abstract: The present invention is directed to the bifunctional compounds and the use of such bifunctional compounds to lower plasma levels of extracellular target molecules by lysosomal degradation. Such bifunctional compounds have a cell surface receptor ligand covalently linked to a ligand that is capable of binding to an extracellular target molecule (such as a ligand for a growth factor, a cytokine, a chemokine, a hormone, a neurotransmitter, a capsid, a soluble receptor, an extracellular secreted protein, an antibody, a lipoprotein, an exosome, a virus, a cell, or a plasma membrane protein), where the cell surface receptor is associated with receptor mediated endocytosis, including asialoglycoprotein receptor (ASGPR) mediated lysosomal degradation and mannose-6-phosphate (M6PR) mediated lysosomal degradation. Pharmaceutical compositions comprising such bifunctional compounds and methods of treating a disease or disorder mediated by an extracellular molecule using such bifunctional compounds are also provided herein.

公开(公告)号：US10406198B2

公开(公告)日：2019-09-10

申请号：US15312267

申请日：2015-05-22

Applicant: NOVARTIS AG

Inventor： Qi-Ying Hu ,  Martin Allan

IPC: A61K9/00 ,  A61K38/05 ,  A61K47/68

Abstract: The invention provides methods to prepare protein conjugates from proteins having at least four accessible cysteine residues. In one embodiment, an antibody with four reducible disulfide linkages is reduced to provide four pairs of free cysteines. Each pair of free cysteines is reacted with a 1,3-dihaloacetone or similar reactant, linking the sulfur atoms of each pair together though a 3-carbon tether with a reactive ketone. A pair of these reactive ketones are linked together with and used to attach a single payload molecule, thus conjugating the antibody to two payload groups. This method gives a stabilized antibody conjugate with high selectivity for a ratio of two payloads per antibody.