Method for in vivo generation of multispecific antibodies from monospecific antibodies

An antibody and specific technology, applied in the direction of antibodies, chemical instruments and methods, specific peptides, etc., can solve difficult problems such as high throughput and contamination of bsAb products, and achieve efficient production effects

Pending Publication Date: 2020-07-03
F HOFFMANN LA ROCHE & CO AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Due to the high similarity between the input and bsAb, complex procedures are required for quantitative removal (hard to achieve high throughput), otherwise the remaining bivalent input and polymer will contaminate the final bsAb preparation to some extent

Method used

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  • Method for in vivo generation of multispecific antibodies from monospecific antibodies
  • Method for in vivo generation of multispecific antibodies from monospecific antibodies
  • Method for in vivo generation of multispecific antibodies from monospecific antibodies

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Embodiment Construction

[0578] The present invention is based at least in part on the discovery that multispecific antibodies can be obtained by half-antibody exchange reactions using as starting materials incomplete antibodies such as 2 / 3-IgGs or 2 / 3-BiFabs comprising antibody light chains, anti- Heavy chains and antibody heavy chain fragments, wherein the heavy chain-heavy chain interaction is destabilized by an asymmetric interfering mutation, preferably in the heavy chain fragment, wherein the interfering mutation on the one hand facilitates the dissolution of the initial incomplete antibody On the other hand, it promotes the production of correctly assembled full-length bi / multispecific antibodies. It was further found that the method of the invention can be carried out even without a reducing agent using the starting compound if the heavy chain-heavy chain disulfide bond in the starting incomplete antibody is removed (the generation of the starting material and exchange reactions and generation...

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Abstract

Herein is reported a method for the generation of multispecific antibodies directly on the cell-surface at the site of action by a half-antibody exchange reaction between two 2 / 3-IgGs or two 2 / 3-BiFabs destabilized in one half by asymmetric perturbing mutations fostering the generation of correctly assembled full length bi-or multi-specific antibodies. The method is performed in the absence hingeregion disulfide bonds in the starting 2 / 3-IgGs or 2 / 3-BiFabs.

Description

[0001] The present invention discloses methods for the in vivo assembly of multispecific (eg, bispecific) antibodies on cells using novel half-antibody exchange methods. This approach is even applicable to full antibodies, ie antibodies comprising CH2-CH3 domains and thus possessing effector functions. [0002] Background of the invention [0003] In the current state of the art, methods for obtaining assembled bispecific antibodies through biochemical conversion of monospecific antibody derivatives use (i) half-antibody complementation reaction and (i) IgG-IgG exchange reaction. [0004] These techniques are disclosed, for example, in WO 2015 / 046467; Rispens et al., J. Biol. Chem. 289 (2014) 6098-6109; US 9,409,989; WO 2013 / 060867; WO 2011 / 131746; WO 2011 / 133886; WO 2010 / 151792; Gunasekaran et al., J. Biol. Chem. 285 (2010) 19637-19646; WO 2009 / 041613; WO 2009 / 089004; WO 2008 / 119353; WO 2007 / 114325; / 047340; WO 2006 / 106905; WO 2005 / 042582; WO 2005 / 062916; WO 2005 / 000898; US 7...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K16/00C07K16/06C07K16/46
CPCC07K16/00C07K16/065C07K16/461C07K16/468C07K2317/14C07K2317/31A61K2039/505C07K16/2809C07K2317/24C07K2317/526C07K2317/55C07K2317/569
Inventor U·布林克曼K·迈尔S·迪科普夫
Owner F HOFFMANN LA ROCHE & CO AG
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