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Compound comprising substance with affinity for antibody, cleavage site and reactive group, or salt thereof

A reactive group and affinity technology, applied in the direction of antibody mimics/scaffolds, medical preparations of non-active ingredients, hybrid peptides, etc., can solve the problems of decreased total yield, decreased antibody expression efficiency, and antibody expression system long wait

Pending Publication Date: 2021-08-06
AJINOMOTO CO INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Regarding the genetic engineering modification method, although position selectivity and number selectivity can be controlled, it is pointed out that there are problems such as a decrease in the expression efficiency of the antibody itself (a decrease in the overall yield when preparing ADC)
In addition, there is also a problem that it takes a long time to construct an antibody expression system (Non-Patent Documents 5 to 7)

Method used

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  • Compound comprising substance with affinity for antibody, cleavage site and reactive group, or salt thereof
  • Compound comprising substance with affinity for antibody, cleavage site and reactive group, or salt thereof
  • Compound comprising substance with affinity for antibody, cleavage site and reactive group, or salt thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[1419] (Example 1) Design of modified protein A and its secretory expression in Corynebacterium glutamicum (C. glutamicum) (1-1) Outline of design of modified protein A

[1420] In the present invention, it is necessary to bind the linker to the protein. That is, in order to realize the specific binding of the linker to a specific amino acid residue in the protein, it needs to be designed under the condition that there is only one amino group in the protein that can react with the linker. The following mutations have been implemented in consideration of this matter;

[1421] A) All K (lysine) in the protein is mutated into R (arginine);

[1422] B) Pyroglutamylation of the N-terminal amino acid by Q (glutamine) and conversion of the N-terminal amino group to an amide;

[1423] The actual modified protein A was designed following the rules of A) and B) above.

[1424] (1-2) Preparation of modified protein A

[1425] The following modified protein A was prepared;

[1426] (...

Embodiment 2

[1486] (Example 2) Design of modified Fc-III and its secretory expression in Corynebacterium glutamicum (C. glutamicum) (2-1) Outline of design of modified Fc-III

[1487] Fc-III having the amino acid sequence of DCAWHLGELVWCT (SEQ ID NO: 54) has been reported as a peptide having the ability to bind to human IgG (WO2001 / 045746). Fc-III was modified according to rules A) and B) described in Example (1-1) and rule C) described in Example (1-3), and the following modified Fc-III was designed.

[1488] (2-2) Preparation of modified Fc-III

[1489] The following modified Fc-IIIs were prepared;

[1490] (g) QET-LV

[1491] QETRGNCAYHKGQLVWCTYH (SEQ ID NO: 24)

[1492] (h) QET-II

[1493] QETRGNCAYHKGQIIWCTYH (SEQ ID NO: 25).

[1494] (2-3) Construction of secretory expression plasmids of QET-LV and QET-II

[1495] As the modified Fc-III, the above two amino acid sequences of QET-LV and QET-II were respectively designed, and the base sequences encoding these proteins were desig...

Embodiment 3

[1513] (Example 3) Preparation of Compounds Having Affinity Substances for Antibodies, Cleavage Moieties, and Reactive Groups In order to remove impurity components in the culture medium, the expressed proteins were purified once by reverse-phase preparative HPLC. A disulfide linker is bound to the purified protein. Specifically, it was performed as follows.

[1514] (3-1) Preparation of compound having an affinity substance for antibody (CspB6Tev-QZ34C), a cleavage moiety, and a reactive group CspB6Tev-QZ34C was used as the affinity substance for antibody. Dissolve QETNPTENLYFQQKNMQCQRRF YEALHDPNLNEEQRNARIRSIRDDC (SEQ ID NO: 7) (13.0 mg, 2.24 μmol, wherein the two cysteines at the 18th and 47th positions respectively form a disulfide bond in the molecule) in N,N-dimethyl Dithiodipropionic acid di(N-succinimid yl)) ( 18.0 mg, 44.8 μmol) in N,N-dimethylformamide (0.40 mL) and stirred at room temperature for 24 hours. After removing acetonitrile by concentrating under reduced...

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Abstract

The invention provides a compound that comprises a substance with an affinity for an antibody, a cleavage site and a reactive group, or a salt of the compound. The compound is represented by formula (I): A-L-B-R (I) [wherein: A stands for a substance with an affinity for an antibody; L stands for a cleaving linker that is a divalent group having a cleavage site; B stands for (a) a divalent group having a bioorthogonal functional group or (b) a divalent group having no bioorthogonal functional group; and R stands for a reactive group to the antibody. The substance with an affinity for an antibody is a polypeptide having a glutamine residue (Q) at the N-terminus.

Description

technical field [0001] The present invention relates to compounds or salts thereof having an affinity substance for antibodies, a cleavage moiety, and a reactive group. Background technique [0002] In recent years, a large amount of research and development of antibody drug conjugates (Antibody Drug Conjugation: ADC) has been carried out. As its name suggests, ADC is a drug obtained by coupling a drug (such as an anticancer agent) to an antibody, and has direct cell killing activity against cancer cells and the like. As a representative ADC, there is T-DM1 (trade name: Kadcyla (registered trademark)) jointly developed by Immunogene and Roche (Non-Patent Documents 1 to 3). [0003] The ADC represented by T-DM1 had the problem of its inhomogeneity from the early stage of development. That is, since a low-molecular-weight drug is randomly reacted with about 70 to 80 Lys residues in an antibody, the drug antibody ratio (Drug Antibody Ratio: DAR) and the coupling position are ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/31C07K14/315C07K16/00C07K19/00
CPCC07K14/31C07K14/315A61K47/6889C07K16/44C07K16/32C07K2319/00A61K47/6855A61K47/6811C07K2319/50C07K2317/24
Inventor 山田慧松田吉彦高桥一敏敷田奈都纪新保和高长野隼人
Owner AJINOMOTO CO INC
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