Mixtures of antibodies

A technology of antibody mixture and mixture, applied in the direction of antibodies, antibody medical components, anti-animal/human immunoglobulin, etc.

Active Publication Date: 2019-03-15
QILU PUGET SOUND BIOTHERAPEUTICS CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Similarly, both binding entities will have the same in vivo half-life in a bispecific antibody, which may not be optimal in some cases

Method used

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  • Mixtures of antibodies
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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0569] Example 1: Designing HC Partner Orientation Changes and LC Partner Orientation Changes

[0570] Preventing non-cognate HC / LC pairing would greatly limit the number of antibody species produced by host cells transfected with DNA encoding multiple full-length antibodies. see for example Figure 4 . To ensure that only homologous LC / HC pairs form, it is critical to find efficient ways to control the kinetics of the HC / LC assembly process such that each LC strongly favors pairing with its cognate HC and disfavors pairing with noncognate HC. Since both the VH / VL interface and the CH1 / CL interface are involved in HC / LC recognition and engagement (see Knarr et al. (1995), J. Biol. Chem. 270:27589-27594; Feige et al. (2009), Mol. Cell 34 (2004), J.Mol.Biol.342:665-679; Rothlisberger et al. (2005), J .Mol.Biol.347:773-789, all of which are incorporated herein by reference in their entirety), so both interfaces were engineered to force homologous HC / LC pairing, as explained in...

Embodiment 2

[0587] Example 2: Design and testing of disulfide bridges added in the HC / LC interface

[0588] We hypothesized that changes that generate additional HC / LC interchain disulfide bridges might enhance the association of homologous HC / LC pairs. In unmodified antibodies, interchain disulfide bonds are solvent-exposed, while intra-chain disulfide bonds are embedded between two antiparallel β-sheet structures within each domain, ie, are not exposed to solvent. For example, the interchain disulfide bonds in the hinge region are solvent exposed, as are the disulfide bonds between HC and LC. Cysteine ​​residues exposed to solvent were found to be more reactive than unexposed cysteine ​​residues. Therefore, when performing cysteine ​​substitutions, we try to generate disulfide bridges that are partially or fully solvent exposed.

[0589] The introduced disulfide bridge has been shown to stabilize the Fv fragment by stabilizing the VH / VL interaction, resulting in higher yield and solub...

Embodiment 3

[0609] Example 3: Testing Antibody Cocktails Containing Altered LC Partner Orientation and Altered HC Partner Orientation That Are Charge Pair Substitutions and / or Cysteine ​​Substitutions

[0610] The identity of many residue contact pairs in HC and LC suitable for charge pair substitutions or cysteine ​​substitutions (Example 1 and Example 2) has been determined by analysis of published tertiary structures and has been performed A number of cysteine ​​substitutions were tested and a number of such substitutions and their combinations were made and tested to determine their effect on homologous HC / LC pairing. To quickly assess the effectiveness of various LC partner orientation changes and HC partner orientation changes in forcing homologous HC / LC pairing, a "chain-off" experiment was performed as described below.

[0611] Antibody-encoding DNA constructs were prepared using methods similar to those described in Example 2. A DNA fragment encoding the human IgG1 HC of the hum...

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Abstract

Described herein are antibodies and mixtures of antibodies optionally produced by a host cell line, nucleic acids encoding the antibodies and mixtures of antibodies, host cells containing such nucleicacids, and methods of treatment using the antibodies, mixtures of antibodies, or nucleic acids encoding the antibodies or mixtures of antibodies. Also described are methods of producing mixtures of antibodies in host cells.

Description

technical field [0001] The compositions and methods described herein are in the field of recombinant antibodies and methods for their preparation. Background technique [0002] Over the past 20 years, recombinant monoclonal antibodies have become a very successful class of biologic drugs for the treatment of many different diseases. They have been used with and without co-administration of small molecule drugs. Due to the biological complexity of some diseases, antibody mixtures or bispecific antibodies targeting more than one antigen or epitope are more effective than single antibodies in treating certain conditions. See eg Lindzen et al., (2010), Proc. Natl. Acad. Sci. 107(28): 12550-12563; Nagorsen and Baeuerle (2011), Exp. CellRes. 317(9): 1255-60. [0003] Antibody mixtures allow for the flexibility of dosing two different binding entities. This is not the case for IgG bispecific antibodies, as each of the two binding entities is present in the same amount, since the...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K39/395C07K16/18C07K16/30A61K39/00
CPCC07K16/32A61K2039/507C07K2317/10C07K2317/14C07K2317/24C07K2317/51C07K2317/515C07K2317/73C07K2317/76C07K2317/94C07K16/2818A61P35/00A61K9/0019C07K16/2887C07K16/2896C07K2317/21C07K2317/31C07K2317/40C07K2317/522C07K2317/55C07K2317/56C07K2317/732C07K2317/734C07K2317/92
Inventor 阎炜刘智M·J·彭托尼
Owner QILU PUGET SOUND BIOTHERAPEUTICS CORP
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