Unlock instant, AI-driven research and patent intelligence for your innovation.

A drug design method and the obtained drug and its application

A technology of drugs and biologically active drugs, which is applied in the field of drug design and development and pharmaceutical preparations, and can solve problems such as unsatisfactory effects, congestive heart failure, and liver toxicity

Active Publication Date: 2021-06-04
HEFEI LIFEON PHARMA
View PDF8 Cites 0 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although anti-tumor antibody drugs with high hopes have brought hope to cancer patients, the effect is still unsatisfactory
For example, antibody drugs developed against human epidermal growth factor receptor 2 (HER2), such as Herceptin, have achieved good results in the treatment of breast cancer. May increase cardiovascular toxicity, cause congestive heart failure, mild or even moderate to severe hypocardia (Nemeth,B.T.,et al.(2016).Br JPharmacol.doi:10.1111 / bph.13643), this is the drug target Side effects due to poor organ specificity of dot protein distribution
Antibody-conjugated drug (ADC) drugs targeting HER2, such as T-DM1 (trastuzumab-maytansinoid DM1), carry highly effective cytotoxic drugs that can inhibit tubulin polymerization and microtubule tube dynamics, but also because the distribution of HER2 in the heart tissue can lead to cardiotoxicity, and the metabolism of T-DM1 in non-lesional sites can also produce liver toxicity, etc. (Yan,H.,etal.(2016).Mol Cancer Ther 15 (3): 480-490)

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • A drug design method and the obtained drug and its application
  • A drug design method and the obtained drug and its application
  • A drug design method and the obtained drug and its application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0147] Embodiment 1: detect the ED-B protein in the blood

[0148] (A) Expression and purification of ED-B protein antibody

[0149]The DNA sequence of the single-chain antibody (scFv) structure of B5 and L19 was synthesized respectively (see patent application number CN201480001324.5, Pini, Viti et al. (1998). J Biol Chem.273:21769-21776 and Borsi, Balza et al . (2002). Int J Cancer. 102:75-85). Add a DNA sequence encoding a signal peptide at the 5' end of the antibody DNA sequence and a DNA sequence encoding an IgG1 Fc tag at the 3' end (Cao, Cao et al. (2009). Appl Biochem Biotechnol.157:562-574) . The N-terminal and C-terminal of the sequence were respectively digested with Nhe I and Not I restriction endonucleases and cloned into pCI-neo vector to form pCI-neo-B5-Fc vector and pCI-neo-L19-Fc vector. The vector construction and expression method of antibody protein can be found in (Borsi, Balza et al. (2002). Int J Cancer. 102:75-85.).

[0150] The vector containing th...

Embodiment 2

[0158] Example 2: Design and expression of biologically inert and biologically active drugs

[0159] 1) Design and expression of biologically inert drug B5-Fc fusion protein (SEQ ID NO: 5)

[0160] The B5 antibody heavy chain (VH) (SEQ ID NO: 1) and light chain (VL) (SEQ ID NO: 2) are connected with a long linker fragment (SEQ ID NO: 7) to form a single-chain antibody B5-ScFv ( SEQ ID NO: 3), the Fc fragment of antibody IgG4 (SEQ ID NO: 4) is fused to the back end, and the hinge region of the Fc fragment is retained, that is, cysteine ​​is retained to form a dimer, and the flexibility of the protein is improved (B5 For antibodies, see patent publication WO2014 / 194784). The carboxy-terminal of the B5 antibody is connected to the amino-terminal hinge region sequence of Fc with three alanine residues. The fusion forms protein B5-Fc (SEQ ID NO: 5).

[0161] 2) Design and expression of bioactive drug B5-IL2 fusion protein (SEQ ID NO: 6)

[0162] The B5 antibody heavy chain (VH)...

Embodiment 3

[0167] Embodiment 3: animal modeling, grouping and administration method

[0168] Solution preparation: in PBS (NaCl 8g / L, KCl 0.2g / L, NaCl 2 HPO 4 1.42g / L,KH 2 PO 4 0.27g / L, pH=7.4) the B5-Fc and B5-IL2 fusion proteins prepared in Example 1 were prepared into 0.4mg / ml solutions respectively.

[0169] Establishment of mouse xenograft tumor model: Healthy Balb / c nu nude mice were raised in SPF level barrier system until 8 weeks old, and mouse teratoma cells (F9) were subcutaneously inoculated on the back of the mice (Shanghai Fuxiang Biotechnology Co., Ltd.) , 2.5×10 per injection point 6 cells. On the 6th day of inoculation, the tumor volume was selected to be about 60mm 3 mice for group experiments. According to 8 groups per group, set up groups A, B, C, D, and E, and administer them through tail vein injection on the 6th day, 7th day, and 8th day after inoculation, wherein:

[0170] Group A was the negative control group, and they were given normal saline twice a d...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

PropertyMeasurementUnit
molecular weightaaaaaaaaaa
Login to View More

Abstract

The present invention provides methods for drug system design comprising selecting a targeting moiety that specifically binds a target of interest; linking the targeting moiety to a biologically active moiety; and / or linking the targeting moiety to a biologically inert moiety. The present invention also provides a kit, kit or pharmaceutical composition comprising a biologically inert drug comprising a targeting moiety and a biologically inert part and a biologically active drug comprising a targeting moiety and a biologically active part, wherein the biologically inert drug is combined with the The bioactive drugs described above can target the same target. The present invention also provides a method for using the medicament or the pharmaceutical composition to treat diseases such as ED-B-related diseases.

Description

[0001] field of invention [0002] The present invention relates to the field of drug design and development and the field of pharmaceutical preparations, in particular to the field of drug design and development for ED-B-related diseases, and also relates to drugs and therapeutic applications. [0003] Background of the invention [0004] Organs, tissues, cells, and biomacromolecules that can exert active effects when drugs enter the human body and their specific drug binding sites are called target organs, target tissues, target cells, and targets, respectively. Targets can be proteins, nucleic acids or other substances, including genetic sites, receptors, enzymes, ion channels, nucleic acids and other biomacromolecules, and generally have important physiological or pathological functions. The drug can specifically act on the target, but some drug targets are distributed on the unintended drug-acting organs or tissues, or fall off in the blood, which will compete with the dru...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
Patent Type & Authority Patents(China)
IPC IPC(8): A61K45/06A61K38/20C07K19/00
CPCA61K38/20A61K45/06C07K19/00A61P35/00C07K14/55C07K2317/54C07K2317/55C07K2317/565C07K2317/622C07K2319/01
Inventor 张美季俊虬高美华陈军
Owner HEFEI LIFEON PHARMA