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Conjugates of biomolecule and use thereof

A technology of biomolecules and conjugates, applied in medical preparations with non-active ingredients, medical preparations containing active ingredients, drug combinations, etc., can solve problems such as patient death and severe pneumonia

Pending Publication Date: 2020-09-15
YAFEI (SHANGHAI) BIOLOG MEDICINE SCI & TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

For example, during the treatment of non-small cell lung cancer with the current PD-1 antibody, Coreda and Opdivo, severe pneumonia may occur, which may even lead to the death of the patient

Method used

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  • Conjugates of biomolecule and use thereof
  • Conjugates of biomolecule and use thereof
  • Conjugates of biomolecule and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0177] Example 1: Synthesis of chemical structures for activatable and binding arms

[0178] When R2 has the amino acid sequence of Ala-Ala-Asn and R3 is PABC (R3-5), the synthetic route is as follows:

[0179]

[0180] When R1 and R4 are different substituents, the following compounds shown in Table 1 are obtained.

[0181] Table 1

[0182]

[0183]

[0184]

[0185]

[0186] As shown in S15, the specific synthesis process is as follows:

[0187]

[0188] 1) Fmoc-Asn(Trt)-OH (20g, 0.03mol),

[0189] Add 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (15g, 0.04mol) and DMF (200mL) into a three-necked flask and stir for 30 minutes. p-Aminobenzyl alcohol (4.1 g, 0.03 mol) and N,N-diisopropylethylamine (8.7 g, 0.06 mol) were added at 0°C, respectively, followed by stirring at room temperature for 3 hours. Most of the DMF was removed by rotary evaporation. The residue was dissolved in ethyl acetate (200 mL), washed successive...

Embodiment 2

[0230] Example 2: Analysis of the binding activity of the CDR mutation of the antibody variable region and screening for R4

[0231]The amino acid sequence of the anti-PD-1 antibody disclosed in WO200815712A1 and its DNA sequence were optimally expressed and synthesized in the host (Jinweizhi). The amino acid sequence and DNA sequence of the anti-PD-1 antibody 2 disclosed in WO2006121168A2 were optimally expressed and synthesized in the host (Jinweizhi). The amino acid sequence and DNA sequence of the anti-CTLA-4 antibody disclosed in US20150283234 were optimized for expression and synthesis in the host (Jinweizhi). The amino acid sequence of the anti-TNFα antibody disclosed in US009534046 and its DNA sequence were optimized for expression and synthesis in the host (Jinweizhi). The amino acid sequence of the anti-CD-28 antibody disclosed in US007939638 and its DNA sequence were optimally expressed and synthesized in the host (Jinweizhi). The synthetic DNA was digested and li...

Embodiment 3

[0277] Example 3: Analysis and Screening of Binding Activity of Mutants with High Homology Sequence Mutations in Non-CDRs of Variable Regions R1

[0278] An antibody consists of 4 peptide chains, including two identical light chains and identical heavy chains. Two chains form a single monomer through disulfide bonds and non-covalent bonds. There are two types of light chains, such as κ and λ, and 5 types of light chains, such as μ, δ, γ, ε, and α. An antibody, as a whole, is divided into constant and variable regions. The variable regions are located at the ends of the two arms of the Y-shaped structure. Humanized or humanized antibodies have a certain degree of universality, and they all contain 4 loops (attached image 3 ). The three loops are highly variable and can directly bind to the antigen. These regions in the loop are called CDR regions, where CDR1, CDR2 and CDR3 are respectively in the three loops. On the same side there is another loop where the antibody binds ...

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Abstract

Provided are conjugates of biomolecule and use thereof. The provided conjugates of biomoelculer contain a biomolecule and a functional moiety covalently linked to the biomolecule. The functional moiety contains a group that prevents the biomolecule from binding to its ligand or receptor, a cleavable linker arm that can be activated by proteolytic enzymes or can be acidically activated in a microenvironment of a disease, a linker arm that will automatically shed after the cleavable linker arm is cleaved, and a group that maintains or promotes the binding capacity of the biomolecule to its ligand or receptor. The conjugates of biomolecule can effectively reduce immunogenicity of the biomolecule, increase it's half-life, and breakthrough the immune barrier of an individual, reach a pathologicmicroenvironment and be activated and released in the pathologic microenvironment, selectively promoting proliferation or killing effect of T cells and the like in the tumor, thereby preventing on target off tumor toxicity or in the inflammatory microenvironment of autoimmune disease and achieving a low autoimmunity and high efficacy.

Description

technical field [0001] The invention relates to a biomolecule conjugate and its application. Background technique [0002] The widespread availability of coupling agents linked to antibodies via natural cystines has further expanded the use of antibodies. Molecules such as toxins or drugs have been conjugated to antibodies to form drug-antibody conjugates. Tumor-locally activatable precursors have been used by fusing cleavable masking peptide sequences to antibodies. However, the peptide is limited to the end of the antibody, and under the influence of the masking peptide, the activation efficiency of the activation sequence is reduced, and the immunogenicity of the conjugated complex is increased. [0003] A common side effect of current commercial macromolecular drugs is immunotoxicity. Includes: immunosuppression, immunogenicity, hypersensitivity, auto-reaction, adverse immune stimulation. These side reactions are mainly caused by foreign macromolecules. After enteri...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/60
CPCA61K47/60A61K38/00C07K14/52C07K16/2818C07K16/241C07K16/2878C07K16/32C07K16/2827C07K16/2887C07K16/2809C07K2317/565C07K2317/567C07K2317/92C07K2317/31A61K2039/505C07K2317/76A61K39/3955C07K2317/21C07K2317/94C07K2317/24C07K2317/622C07K2319/00A61K2300/00A61K47/545A61P35/00C07D207/444A61K39/395
Inventor 刘源王海洋李仁柯张蕊刘辰
Owner YAFEI (SHANGHAI) BIOLOG MEDICINE SCI & TECH CO LTD
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