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Heterodimeric proteins

A heterodimer and antibody technology, applied in the direction of immunoglobulin, hybrid immunoglobulin, antibody, etc., can solve the problems of non-specific activation and toxicity

Pending Publication Date: 2020-05-12
XENCOR INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] Thus, while bispecific antibodies generated from antibody fragments encounter biophysical and pharmacokinetic hurdles, those constructs with full-length antibody-like formats have the disadvantage that they are multivalent in the absence of a primary target antigen. Engage common target antigens efficiently, leading to non-specific activation and potential toxicity

Method used

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Examples

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Embodiment 1

[0380] Example 1. Design of unnatural charge displacements to reduce pI

[0381] The antibody constant chain is modified with a lower pi by engineered substitutions in the constant domain. A reduced pi can be engineered by substituting a basic amino acid (K or R) for an acidic amino acid (D or E), which results in a maximal decrease in pi. Mutations from basic to neutral amino acids and from neutral to acidic amino acids will also result in a decrease in pi. A list of amino acid pK values ​​can be found in Table 1 of Bjellqvist et al., 1994, Electrophoresis 15:529-539.

[0382] We chose to develop substitutions in the CH1 (Cγ1) and CL (Ckappa or CK) regions of the antibody (sequences shown in Figure 13 middle) because, unlike the Fc region, they do not interact with natural ligands that affect the pharmacological properties of the antibody. In deciding which position to mutate, consideration is given to the surrounding environment and the number of contact points of the WT...

Embodiment 2

[0388] Embodiment 2. Transformation method of constant region pI transformation

[0389] Reduction of the pi of a protein or antibody can be performed in a number of ways. At the highest basic level, residues with high pKa (lysine, arginine and to some extent histidine) are replaced by neutral or negatively charged residues, and / or neutral residues are replaced by low pKa residues (aspartic acid and glutamic acid) were replaced. The particular substitution may depend on many factors, including position in structure, position in function, and immunogenicity.

[0390] Because immunogenicity is an issue, some effort can be made to minimize the risk that pI-lowering substitutions will cause immunogenicity. One way to reduce risk is to minimize the mutational load of the variant, ie, reduce the pi with the smallest number of mutations. Charge exchange mutations, in which K, R, or H are replaced by D or E, have the greatest effect on reducing pi, so these substitutions are prefer...

Embodiment 3

[0394] Example 3. Isotype light chain constant region variants

[0395] The homology between CK and Cλ is not as high as that between IgG subclasses, however the sequence and structural homology that exists is still used to guide substitutions to form the isotype low-pi light chain constant region. exist Figure 56 In , positions with residues contributing to higher pi (K, R and H) or lower pi (D and E) are highlighted in bold. Gray indicates lysine, arginine and histidine that can be replaced, preferably with aspartic acid or glutamic acid, to lower the isoelectric point. These variants, alone or in combination, can be combined independently and optionally with all other heavy chain variants in the backbone having at least one light chain.

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Abstract

In one aspect, the present invention provides a heterodimer antibody. The heterodimer antibody comprises a first monomer comprising a first heavy chain constant domain comprising a first variant Fc domain and a first antigen binding domain, and a second monomer comprising a second heavy chain constant domain and a second antigen binding domain, and the second heavy chain constant domain comprisesa second variant Fc domain. In other aspects, the heterodimeric antibody comprises the first monomer comprising a heavy chain, and the heavy chain comprises a first Fc domain and a single chain Fv region (scFv) binding to a first antigen, wherein the scFv comprises a charged scFv linker. The heterodimer antibody further comprises a second monomer comprising a first heavy chain and a first light chain, and the first heavy chain comprises a second Fc domain and a first variable heavy chain.

Description

[0001] This application is a divisional application of the Chinese patent application with application number 201480014664.1. [0002] This application is based on International Patent Application No. PCT / US14 / 11549, filed January 14, 2014, U.S. Patent Application No. 14 / 155,334, filed January 14, 2014, 14 / 205,248 and continuation-in-part of 14 / 207,489 filed March 12, 2014. Additionally, this application claims U.S. Patent Application Nos. 61 / 818,513, filed May 1, 2013, 61 / 818,344, filed May 1, 2013, 61 / 794,896, filed March 15, 2013, 61 / 818,401 filed May 1, 61 / 913,879 filed December 9, 2013, 61 / 913,832 filed December 9, 2013, 61 / 938,095 filed February 10, 2014 and Priority of 61 / 913,870 filed December 9, 2013, all of which are specifically incorporated by reference in their entirety, particularly for all figures and legends disclosed herein, and for the amino acid variations disclosed herein. body. [0003] Background of the invention [0004] Antibody-based therapies have ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K16/46C12N15/62C12N5/10
CPCC07K16/28A61P37/02C07K1/18C07K16/2809C07K16/2896A61K2039/505C07K2317/31C07K2317/622C07K16/468C07K2317/64C07K2317/94C07K16/065C07K16/2803C07K2317/60C07K2317/71C07K2317/72C07K16/00C07K2317/526C07K16/18C07K2317/55
Inventor G·摩尔J·戴斯扎拉斯R·拉施德M·J·伯内特
Owner XENCOR INC
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