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Drug with prolonged half-life period, library thereof, preparation method and application thereof

A half-life and drug technology, applied in the field of drugs with prolonged half-life and their libraries, can solve the problems of poor PEG molecular homogeneity, difficult quality control of PEGylated drugs, and limited half-life improvement effect.

Pending Publication Date: 2021-05-04
ASSEMBLY MEDICINE LLC
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] PEG modification is the main method of chemical modification to increase the half-life of protein or polypeptide drugs. The advantage is that PEG has strong biocompatibility and can increase the solubility and stability of drugs. The disadvantage is that PEG modification will greatly affect the activity of biological enzymes, etc. Protein activity, high molecular weight PEG is immunogenic, poor homogeneity of PEG molecules makes quality control of PEGylated drugs difficult, etc.
In addition, chemical modification methods such as PEG increase the half-life of protein or peptide drugs depending on the increase in molecular weight, so the half-life improvement effect is limited
[0005] Although Fc or HSA fusion protein can prolong the half-life, the method of prolonging the half-life of Fc or HSA fusion protein will generate a new epitope at the fusion site between the target protein or polypeptide and Fc / HSA
In addition, Fc can only be fused to the C-terminus, while HSA can only be fused to the N-terminal or C-terminal of the target protein or polypeptide
In addition, this method is not applicable to natural proteins or peptides

Method used

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  • Drug with prolonged half-life period, library thereof, preparation method and application thereof
  • Drug with prolonged half-life period, library thereof, preparation method and application thereof
  • Drug with prolonged half-life period, library thereof, preparation method and application thereof

Examples

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preparation example Construction

[0203] 2. Preparation method of antibody-L-nucleic acid complex

[0204] First, the 5' or 3' end of the L-nucleic acid is replaced by NH 2 Modification, and then according to the difference of the linker, the following main preparation methods can be used, wherein the functional group at one end of the linker is NHS (N-hydroxysuccinimide) or Sulfo-NHS (N-hydroxysuccinimide sulfonic acid sodium salt ), for rapid coupling of NH at one end of the L-nucleic acid 2group. Linkers containing bispecific functional groups are first combined with the NH of the L-nucleic acid 2 Reaction, followed by reducing the sulfhydryl group on the antibody, the group at the other end reacts with the sulfhydryl group to form a stable chemical bond.

[0205] 2.1 Maleimide. The linker used to conjugate the sulfhydryl group on the antibody is maleimide. Maleimides can rapidly react with free sulfhydryl groups on antibodies to form thioether bonds. Common linkers include SMCC (4-(N-maleimidomethyl)...

Embodiment 1 4

[0221] The design of embodiment 1 tetramer DNA framework

[0222] Design four L-nucleic acids that can be paired according to the quadrilateral shape (such as figure 2 shown). Wherein, any one L-nucleic acid single strand can perform specific complementary pairing with the other two L-nucleic acid single strands, but not pair with the fourth one. And the absolute value of the Gibbs energy change ΔG of the specific complementary pairing is much greater than that of the non-specific pairing, and the absolute value of the Gibbs energy change ΔG of the specific complementary pairing of each arm is greater than 25 kilocalories per mole (kcal / mole), while the non-specific pairings are all less than 7 kcal / mole (kcal / mole), which means that the tetramer assembly is easier to occur than the non-specific pairwise pairing, and the tetramer form is in the reaction system most stable.

[0223] The four L-DNA single-strand sequences designed according to the above principles are as fo...

Embodiment 2 4

[0233] Synthesis and Verification of Example 2 Tetramer DNA Framework

[0234] Synthesize 5'-terminal NH by biotechnology service companies (such as Chemgene Inc., Biosyn Inc., etc.) 2 Modified L-DNA single strands, the sequences of the four single strands are as shown in Example 1.

[0235] Phosphate buffer (50mM NaH 2 PO 4 , 150mM NaCl, pH 7.0) to dissolve the L-DNA single strand, and prepare a stock solution with a final concentration of 200uM. Dissolve SMCC powder with dimethyl sulfoxide (DMSO), and freshly prepare 250 mM SMCC stock solution. Add 10-50 times molar amount of SMCC mother solution to the L-DNA single-strand mother solution, mix rapidly and react at room temperature for 30min-2h. After the reaction was completed, 10% volume of 1M Tris-HCl (pH 7.0) was added to the reaction solution, mixed and incubated at room temperature for 20 minutes to terminate excess SMCC and continue the reaction. After the incubation, add 2 times the volume of 100% absolute ethano...

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Abstract

The invention provides a drug with prolonged half-life period and a library thereof, and a preparation method and an application thereof. Specifically, the present invention provides a drug library comprising: (a) a drug unit; and (b) n half-life extending units; wherein the drug unit comprises a drug element part and a first nucleic acid element part connected with the drug element part; the half-life extending unit comprises a half-life period prolonging element part and a second nucleic acid element part connected with the half-life extending element part; the first nucleic acid element part of the drug unit and the second nucleic acid element part of at least one half-life period prolonging unit can form a base complementary pairing structure, so that a drug unit-half-life extending unit compound is formed; wherein n is a positive integer greater than or equal to 1. The drug with prolonged half-life period can be quickly and efficiently assembled at low cost and high yield according to requirements.

Description

technical field [0001] The invention relates to the field of biotechnology medicine. In particular, it relates to drugs with extended half-life and libraries thereof, as well as preparation methods and applications thereof. Background technique [0002] For protein or protein-based drugs, prolonging their half-life is beneficial to improve efficacy and reduce drug dosage. [0003] In order to prolong the half-life of protein or polypeptide drugs, existing methods include preparing them into: Fc-fusion protein, HSA-fusion protein; using chemical coupling to prepare Fc-protein / polypeptide conjugates, HSA-protein / polypeptide conjugates; and replacing HSA in the above fusion protein or conjugates with proteins or polypeptides (such as anti-HSA antibodies), small molecules, nucleic acids (such as aptamer) that can bind to HSA; PEG, glycosylation , sialic acid and other chemical modification methods. [0004] PEG modification is the main method of chemical modification to incr...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C40B40/06A61K38/02A61K38/37A61K39/395A61K47/54A61K47/64A61K47/68
CPCC40B40/06A61K47/64A61K47/6801A61K47/549A61K38/02A61K38/37A61K39/395C40B40/10C07K19/00C07K2319/30C07K2317/569C07K16/18A61K47/6811A61K47/6843A61K47/6889A61K38/00C07K14/765C07K14/755A61K47/68C40B40/08
Inventor 周界文潘利强闰长青周柳娟
Owner ASSEMBLY MEDICINE LLC
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