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Novel multi-specific binding proteins

A technology for binding proteins and binding regions, which can be used in hybrid immunoglobulins, immunoglobulins, anti-growth factor immunoglobulins, etc., and can solve problems such as low activity, indistinguishability, and stability problems

Inactive Publication Date: 2019-10-25
Y BIOLOGICS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, for these heterodimerization-based bispecific antibodies, it is difficult to distinguish the homotype and heterotype present in the expression medium simultaneously in the production of recombinant proteins using animal cells to obtain bispecific antibodies, and with Lower activity compared to conventional parental bivalent antibodies
[0004] Additionally, mutations introduced with respect to selective heterodimerization of heavy and light chains may cause stability issues such as immunogenicity

Method used

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Examples

Experimental program
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Effect test

Embodiment 1

[0102] Example 1. Structure of a new bispecific antibody format (Fv2mab)

[0103] Fv2mab is a bispecific antibody with a variable domain (Fv ) The tandem structure of fragments. Two or more kinds of variable regions connected in different series have the ability to bind different antigens independently or simultaneously, and have a form in which the heavy chain CH1 domain, kappa or lambda and light chain CL domain are removed ( Figure 1a ).

[0104] To guarantee binding affinity for a single antigen corresponding to two tandem-linked variable domains (Fv), the short linker (VH: ASTKGP SEQ; ID NO: 1, VL: TVAAP; SEQ ID NO: 4), the long linker (VH: ASTKGPSVFPLAP; SEQ ID NO: 2, VL: TVAAPSVFIFPP; SEQ ID NO: 5) and G4S linker (VH: GGGGSGGGGS; SEQ ID NO: 3, VL: GGSGGGGSG; SEQ ID NO: 6) for external variable structures Domains and internal variable domains to ensure the structural independence of each variable domain ( figure 2 ).

[0105] Parental antibodies used as proof of co...

Embodiment 2

[0106] Example 2. Fv2mab Engineering for Thermodynamic Stability

[0107] The structure of the Fv2mab bispecific antibody is H with two or more consecutive Fv (VH and VL) 2 L 2 multivalent tetramer. In order to tetramer (H 2 L 2 ) structure exists, and the CH domain of the heavy chain and the CL domain of the light chain of the universal antibody are connected by an interchain disulfide bridge (covalent bond). However, in the case of Fv2mabs lacking CH1 and CL, the structure and stability are governed by the binding forces (hydrophobic, ionic, hydrogen-bonded, etc.), and in contrast to universal antibodies, there are no intrachain disulfide bridges (covalent bonds) between the heavy and light chains. Therefore, the binding force to determine the structure of the heavy and light chains at low concentrations is expected to be lower than that of a generic antibody, and therefore, the pK / pD is also expected to be lower than in the case of a generic antibody.

[0108] Therefo...

Embodiment 3

[0112] The preparation of embodiment 3.Fv2mab

[0113] By using Humira (adalimumab, AbbVie), KOSENTYX (secukinumab, Novartis), anti-VEGFA (in-house antibody) and ABT-122 (DVD-Ig, AbbVie) heavy chain variable region and light chain Sequences of variable regions Proof-of-concept (POC) parental antibodies were prepared for various combinations of bispecific Fv2 mabs. The pFE expression vector prepared by the applicant is used as an animal cell expression vector for the production of the recombinant protein of the bispecific antibody Fv2mab. The heavy and light chain variable regions of antibodies consist of hypervariable regions (CDRs) and frameworks (FRs). Since FR1 as the starting point and FR4 as the ending point in the variable region consist of similar amino acid sequences in most antibodies, it is difficult to connect two kinds of variable regions in tandem by a method such as PCR. This is because it is difficult to prepare and use specific binding primers due to the simi...

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Abstract

The present disclosure relates to a novel multi-specific binding protein, specifically, a novel multi-specific binding protein prepared by supplementing drawbacks of various conventionally disclosed multi-specific binding proteins, for example, a bispecific binding protein, more specifically, a novel multi-specific binding protein including a polypeptide, wherein heavy chain CH1 domain and CL domain of an antibody constant region are not included but a heavy chain variable region and / or a light chain variable region are consecutively linked in the polypeptide.

Description

technical field [0001] The present disclosure relates to a novel multispecific binding protein, in particular to a novel multispecific binding protein prepared by overcoming the shortcomings of various conventionally disclosed multispecific binding proteins such as bispecific binding proteins, more specifically It relates to a novel multispecific binding protein comprising a polypeptide wherein the heavy chain CH1 domain and CL domain of the antibody constant region are not included in the polypeptide, but the heavy chain variable region and / or the light chain variable region are contiguous connected. Background technique [0002] With the ease of production of genetically recombinant proteins and screening of human antibody libraries based on phage display technology, development of therapeutic agents using antibodies has been initiated. Therapeutics using antibodies work based on the unique immune system of the human body by using specific antigen-antibody binding, and th...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K16/46C07K16/24A61K47/50
CPCC07K16/22C07K16/241C07K16/244C07K16/468C07K2317/31C07K2317/524C07K2317/526C07K2317/53C07K2317/56C07K2317/624C07K2317/64C07K2317/76C07K2317/92C07K2317/94C07K2319/00C07K2317/21C07K2317/35A61K47/68C07K2317/567
Inventor 张世逸朴荣祐朴范灿
Owner Y BIOLOGICS INC
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