85 results about "Therapeutic index" patented technology

The invention discloses application of ursolic acid in resisting fish ichthyophthiriasis. The ursolic acid has a remarkable killing effect on ichthyophthirius multifilis in an in-vitro stage, and the 4-hour half effective insecticidal concentration (4h-EC50) of the ursolic acid on a grazing body is 0.3774 mg / L; and the 22-hour half effective insecticidal concentration (22h-EC 50) on the capsule is 4.931 mg / L. An acute toxicity test shows that the 96-hour median lethal concentration (96h-LC50) of ursolic acid to goldfish is 9.358 mg / L, the therapeutic index (TI = 96h-LC50 / 4h-EC50) is up to 24.8, and the safety of ursolic acid is remarkably superior to that of a traditional medicine. Ursolic acid used in the invention is a plant-derived active component, has the characteristics of high environmental compatibility and low biological accumulation, meets the development requirements of green fishery, and has an industrialization basis for being developed into eco-friendly aquatic products.

The present invention relates to an antibody or an antigen-binding fragment thereof binding to CLDN18.2, an antibody-drug conjugate comprising same, and a use of the antibody and the antibody-drug conjugate. An anti-CLDN18.2 monoclonal antibody according to the present invention comprises a fully human antibody sequence, thereby having low in vivo immunogenicity, and exhibits excellent antigen affinity and binding ability specific to a low expression to a high expression level of the CLDN18.2 protein. Thus, the antibody is expected to exhibit high specificity and safety as an antibody-based therapeutic agent such as in the form of a monoclonal antibody and / or an antigen-binding fragment (scFv), an antibody-drug conjugate (ADC), an immune cell engager, a chimeric antigen receptor (CAR), a multispecific antibody, and the like. In addition, the antibody according to the present invention may undergo cellular internalization, enables an anti-CLDN18.2 antibody-drug conjugate comprising said antibodies to be conveniently prepared, and has excellent yield and quality and thus is expected to be highly likely to be developed as a drug. A drug conjugate comprising the anti-CLDN18.2 antibody according to the present invention has excellent in vivo anticancer efficacy and has an expanded therapeutic index (TI) and thus is expected to be usefully employable for the treatment and / or prevention of cancer diseases expressing CLDN18.2 and related diseases.

The present invention provides variant forms of anti-CTLA-4 antibodies, such as ipilimumab, that preferentially bind to CTLA-4 at low pH. Such antibody variants exhibit preferential activity in the tumor microenvironment, an enhanced ratio of anti-tumor response to side-effects, and an enhanced therapeutic index.

The invention discloses an aryl oxadiazole compound with a chemical structural formula as shown in the specification or pharmaceutically acceptable salt thereof. In-vitro experiment results show that the compound has a remarkable inhibition effect on DENV, the therapeutic index (TI) of the compound is far higher than that of a clinical reference substance ribavirin, the TI value of a preferred compound such as I-29 exceeds 1131.86, and the TI value of the preferred compound is far higher than that of the clinical reference substance ribavirin. The characteristics of high efficiency and low toxicity are highlighted. In addition, the preparation method is simple in process, high in yield, mild in reaction condition and suitable for large-scale production and clinical popularization.

The new compound 3-(1-(2,3-dichloro-4-methoxyphenyl)ethyl)-1-methyl-1-(1,3,3-trimethylpiperidin-4-yl)urea monohydrochloride salt has a high capability to permeate through the blood-brain barrier and to display, at central nervous system level, a consistent ghrelin agonist activity; the compound is effective in the treatment and / or prevention of a medical condition mediated by the ghrelin receptor in the central nervous system. In particular, in experimental tests, the compound has shown high efficacy in the treatment of neurotoxic damage, with a useful combined pattern of neuroprotective effects both at central and peripheral level. The compound is further useful in the treatment of conditions which require a reduction of the heart rate. The compound is pharmacologically active at low to moderate doses, thus showing a favourable therapeutic index.

The invention relates to the technical field of biological pharmacy, in particular to an application of N-[(3-chlorphenyl) methyl]-5-methyl-4-[(morpholine-4-yl) methyl]-1, 2-azole-3-formamide in preparation of an anti-melanoma drug and a preparation method of the N-[(3-chlorphenyl) methyl]-5-methyl-4-[(morpholine-4-yl) methyl]-1, 2-azole-3-formamide. According to the invention, specific pharmacophore and hydrophobic / hydrophilic modification are introduced in structure, so that the combination selectivity and stability of the compound and a target spot are improved; on the action mechanism, the compound can effectively interfere with a Bcl-3 signal channel. In-vivo experiments prove that the compound disclosed by the invention has a good tumor inhibition effect in an animal model, meanwhile, no obvious systemic toxicity is observed, and a relatively high therapeutic index is shown. In addition, the compound has good physicochemical properties and synthesis process feasibility, is convenient for industrial production, and is expected to become a novel candidate drug for clinical melanoma resistance.

Provided is an antibody-drug conjugate (ADC) having a drug-linker conjugate (A) linked thereto and a preparation method therefor, including a combination of a camptothecin-based drug that degrades DDX5 protein with a DAR of 4 or more and either (i) an acid-sensitive linker or (ii) an enzyme-sensitive linker. The antibody-drug conjugate is designed to increase the therapeutic index of the camptotechin-based drug payload while suppressing the non-selective uptake of the camptothecin-based drug and / or ADC released from apoptotic cells. The ADC is designed and / or synthesized so that two types of drug-linker conjugates including: a drug-linker conjugate (A) composed of a combination of a camptothecin-based drug that degrades DDX5 protein with a DAR of 4 or more and either (i) an acid-sensitive linker or (ii) an enzyme-sensitive linker; and a drug-linker conjugate (B) composed of a combination of a non-camptothecin cytotoxic drug and an enzyme-sensitive linker are each linked to a single antibody.

The present invention relates to the treatment of locally advanced and metastatic muscle-invasive bladder cancers (MIBC). The present invention provides compositions to be used in immunotherapy of MIBC, especially in combination with an anti-PD-1 / PD-L1 / PD-L2 antibody-based therapy. The present invention also provides biomarkers of response to anti-PD-1 / PD-L1 / PD-L2 immune checkpoint blocking antibodies (ICBs), alone or together with anti-CTLA4 antibodies and / or chemotherapy, for best guiding their neoadjuvant use and avoid unefficient administration of potentially toxic drugs to patients with localized bladder cancers.

Disclosed herein are novel antimicrobial peptides with useful, improved, or superior properties such as antimicrobial activity, desirable levels of hemolytic activity, and therapeutic index against a broad range of microorganisms including gram-negative and gram-positive bacteria and other organisms having a cellular or structural component of a lipid bilayer membrane. Also provided are methods of making and using such peptides to control microbial growth and in pharmaceutical compositions for the treatment of infections caused by such microorganisms.

The invention discloses an anti-cancer oligopeptide designed based on threonine and analogues thereof and application of the anti-cancer oligopeptide, the anti-cancer oligopeptide is obtained by taking KLLKKLLKKLLKKKLLKW as a structural basis, replacing amino acids at different sites with hydroxyl-containing threonine or analogues thereof, and then amidating a C terminal; the structural general formula of the compound is as follows: KXmLKKLLKKLLKW-NH2, wherein X = T, pT, F, Y or pY, and p represents phosphorylation; and m is 2, 3, 6, 7, 10, 11 or 13. The anti-cancer oligopeptide has the advantages of high efficiency, low toxicity, short sequence and the like. In-vitro anti-tumor activity and toxicity experiment results show that the compound has a relatively strong killing effect on various tumor cells, and is low in hemolytic toxicity and high in therapeutic index. Serum stability experiments further show that the protein has relatively high enzymolysis stability. A scanning electron microscope experiment shows that the anti-cancer oligopeptide can quickly kill tumor cells through an effective membrane rupture mechanism. Therefore, the compound has a good application prospect in the aspects of research on novel high-efficiency low-toxicity polypeptide anti-cancer drugs, resistance to multidrug resistance and preparation of anti-cancer drugs.

The application discloses a high-safety tumor treatment preparation based on a prodrug-enzyme-neutralizing antibody three-system, and a preparation method and application thereof. The preparation comprises three core components: (a) a prodrug, which is coupled by an anti-tumor drug (such as doxorubicin) and cephalosporin; (b) an activating enzyme, such as beta-lactamase, which is specifically expressed in the tumor by phage, catalyzes the hydrolysis of the prodrug, and releases the active drug; and (c) a neutralizing antibody, such as an anti-doxorubicin monoclonal antibody, which can specifically bind and neutralize the active drug overflowing into the blood circulation. The application first integrates the precise killing strategy of "prodrug-local activation" and the safety strategy of "neutralizing antibody-systematic protection" into a complete treatment closed loop, utilizes the "differential neutralization" characteristics of the anti-doxorubicin antibody, effectively protects normal tissues from toxic damage under the premise of not affecting the local efficacy of the tumor, and significantly improves the therapeutic index of the chemotherapy drug, reduces the side effects such as cardiotoxicity and bone marrow suppression, and provides a new paradigm with high efficiency and safety for tumor treatment.

The invention discloses an application of (5R)-5-hydroxytriptolide in preparation of a medicine, in particular to an application in preparation of a medicine for treating and / or preventing abnormal immune activation of AIDS (acquired immune deficiency syndrome) or immune reconstitution insufficiency related to the abnormal immune activation of the AIDS. Experiments carried out by using (5R)-5-hydroxytriptolide (T8) show that the (5R)-5-hydroxytriptolide (T8) has immunosuppressive activity in abnormal immune activation of AIDS or immune reconstitution insufficiency related to the abnormal immune activation of AIDS, and has the advantages of high efficiency, low toxicity and very good safe therapeutic index.

V1a RECEPTOR PARTIAL AGONISTS AND METHODS OF USE SOLUTION: The present invention provides novel partial V1a agonists for partial activation of V1a receptors. The partial V1a agonists have therapeutic indices of at least 20 (e.g., at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, at least 100). Also provided is a method of treating liver fibrosis, hepatocirrhosis, portal hypertension, peritoneal fluid, esophageal varices, fundic varices, hemorrhage, arterial hypotension, and / or hepatorenal syndrome, comprising administering to a subject in need thereof a therapeutically effective dose of a composition comprising one or more of the disclosed partial V1a agonists, optionally in combination with a V2 antagonist.SELECTED DRAWING: None

The problem to be solved by the present invention is to provide cationic lipids for oligonucleotide delivery which can provide a high drug: lipid ratio, which protect the nucleic acid from degradation and clearance in serum, which are suitable for systemic delivery, which can result in intracellular delivery of the nucleic acid, and which are well tolerated, provide an adequate therapeutic index, and treatment of patients with an effective dose of the nucleic acid is not associated with significant toxicity and / or risk to the patient.SOLUTION: The present invention relates to cationic lipids having one or more biodegradable groups located in the lipid portion (e.g., hydrophobic chain) of the cationic lipid. These cationic lipids can be incorporated into lipid particles for the delivery of active agents such as nucleic acids. The present invention also relates to a lipid particle comprising a neutral lipid, a lipid capable of reducing aggregation, a cationic lipid of the invention and optionally a sterol. The lipid particles may further comprise a therapeutic agent, such as a nucleic acid.SELECTED DRAWING: None

The present invention discloses a lactic acid bacteria-derived antimicrobial peptide and a database-assisted construction method and application thereof, belonging to the field of bioengineering. The amino acid sequence of the antimicrobial peptide is shown in SEQ NO.1. The present invention utilizes bioinformatics resources and computational tools to assist in peptide design and a database prediction model to predict peptide activity, thereby screening the optimal candidate peptide sequence in the shortest time and at the lowest cost. The peptide is a non-natural peptide based on a lactic acid bacteria-derived antimicrobial peptide database that can effectively inhibit Gram-positive and Gram-negative bacteria, has good biological activity and low hemolytic toxicity, and has a therapeutic index of up to 168.98, thereby having good application prospects.

Antibodies against the CD3 complex are being tested in bispecific and trispecific antibody formats that further recognize a tumor-associated antigen. Such antibodies are commonly associated with on-target toxicities, however. It is discovered herein that the toxicities can be reduced or avoided if the bispecific and trispecific antibody adopts a suitable structure and uses an anti-CD3 unit having a suitably balanced T cell activation activity level. Provided are such bispecific and trispecific antibody structures. Also provided is a broad spectrum of anti-CD3 antibodies having different levels of T cell activation activities that can be readily used in different scenarios.

The invention discloses D-type mannosylerythritol lipid as well as a preparation method and application thereof. According to the invention, the green and bio-friendly D-type mannosylerythritol lipid is used as a biological bacteriostatic agent and is independently used or combined with other bacteriostatic agents (cefaclor, gentamicin or erythromycin and the like); effective inhibition and even killing of various pathogenic microorganisms (methicillin-resistant staphylococcus aureus, bacillus subtilis or bacillus cereus and the like) are realized. The novel bacteriostatic strategy of the D-type mannosylerythritol lipid provided by the invention not only can effectively realize efficient bacteriostasis, reduce the dosage of an antibacterial agent and reduce the graded bacteriostatic concentration index to 0.09, but also shows good biocompatibility, has a therapeutic index as high as 44.81, and has a wide application prospect.

The invention provides an application of children Danqing Shuanglian granules in preparation of drugs for treating acute inflammation. The acute inflammation comprises acute upper respiratory tract infection, bronchitis, amygdalitis and pneumonia caused by virus infection (H1N1, H3N2, FluB and HRSV) or abnormal immunoreaction. Raw materials of the granules comprise nauclea officinalis, artemisia apiacea, scutellaria baicalensis and other traditional Chinese medicinal materials and anti-inflammatory regulatory peptide. The preparation process comprises the following steps: extracting volatile oil by steam distillation, extracting effective components by combining microwave assistance and ultrasonic enhancement, carrying out beta-cyclodextrin inclusion on polypeptide to enhance the stability, and finally granulating to obtain granules with the water content of less than or equal to 6%. Experiments show that the inhibition rate of the drug to HRSV under the maximum non-toxic concentration reaches 81.8% + / -2.0%, and the therapeutic index is SIgt; 2, the latency period of ammonia water induced mouse cough can be remarkably prolonged, the cough frequency is reduced, the antiviral, anti-inflammatory and antitussive effects are achieved, and a safe and effective traditional Chinese medicine choice is provided for clinical treatment of viral acute inflammation.

The invention discloses an aryl bishydrazide compound with a structural formula shown in the following formula: in-vitro experiment results show that the compound has remarkable inhibitory activity on dengue virus (DENV), the therapeutic index (TI) of the compound is remarkably higher than that of a clinical positive control drug ribavirin, and in addition, the compound can be used for preparing an aryl bishydrazide compound with the structural formula shown in the specification. The preparation method disclosed by the invention is simple and efficient in process, good in yield and mild in reaction condition, has good large-scale production potential, and provides a feasible synthesis basis for further clinical transformation and application.

The present invention concerns antibody-conjugate having general structure (2):wherein AB is an antibody capable of targeting Trop-2-expressing tumours and D is selected from the group consisting of taxanes, anthracyclines, camptothecins, epothilones, mytomycins, combretastatins, vinca alkaloids, maytansinoids, enediynes such as calicheamicins, duocarmycins, tubulysins, amatoxins, bleomycins, dolastatins and auristatins, pyrrolobenzodiazepine dimers, indolinobenzodiazepine dimers, radioisotopes, therapeutic proteins and peptides (or fragments thereof), kinase inhibitors, MEK inhibitors, KSP inhibitors, and analogues or prodrugs thereof. These antibody-conjugates exhibit an improved therapeutic index. The invention further concerns a process for preparing the antibody-conjugate according to the invention, a method for targeting Trop-2-expressing cells, medical uses of the antibody-conjugates according to the invention.

The present invention belongs to the field of pharmaceutical chemistry technology, and specifically relates to a near-infrared light-releasing binuclear ruthenium complex, its preparation, and its application in combating drug resistance in non-small cell lung cancer. The binuclear ruthenium complex disclosed in the present invention has the structural formula shown below. The complex has a strong photochemotherapy effect on cisplatin-resistant human non-small cell lung cancer cell lines. Under light conditions, it has a strong growth and proliferation inhibition ability (IC 50 The phototoxicity of the metallo-photosensitive material was 0.22 μM, while in the dark, its cytotoxicity was only 75.6 μM, and the phototherapy index (PI) was as high as 343, which is of great significance for the study of metallo-medicines for anti-drug-resistant tumors. It is expected to be used to prepare anti-tumor photoactivated drugs or drugs for anti-proliferation of cisplatin-resistant strains of human non-small cell lung cancer, and even anti-tumor metal photosensitizers.

The application discloses a cannabidiol derivative and application thereof, and belongs to the technical field of medicinal chemistry. The structural general formula of the cannabidiol derivative is shown as formula (I): (I) R1 is selected from one of hydrogen, chlorine, bromine, a hydroxyl group, a cyano group, an acetoxy group, an acryloyloxy group, a benzoyl group, an acetamide group, an acrylamide group, a propiolamide group, an ethyl thiourea group, a 3-chloro-2,2-dimethylpropionyl group, a 2-ethylsulfonamide acetyl group, a 2-ethylsulfonamide-N-(2-amino-2-oxoethyl) acetyl group, a methylsulfonyl group, an ethylsulfonyl group, a vinylsulfonyl group, an alkyne propylsulfonyl group, a phenylsulfonyl group and a styrylsulfonyl group; and R2 is selected from one of C2-C5 alkyl groups. The cannabidiol derivative disclosed by the application has significantly improved anti-neuroinflammatory activity, significantly reduced cytotoxicity, and a generally improved treatment index of more than 10 times, or even more than 260 times, compared with cannabidiol.

The present disclosure provides novel V1a partial agonists for partially activating a V1a receptor. The partial V1a agonist has a therapeutic index of at least 20 (e.g., at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, at least 100). Also provided are method of treating liver fibrosis, cirrhosis, portal hypertension, ascites, esophageal varices, fundal varices, bleeding, arterial hypotension, and / or hepatorenal syndrome, including administering to a subject in need thereof a therapeutically effective dose of a composition including the V1a partial agonist(s) of the present disclosure, optionally in combination with a V2 antagonist.

The invention belongs to the technical field of biological medicines, and discloses a fusion polypeptide of tachyplesin antibacterial peptide and carrier protein and a preparation method of the fusion polypeptide. The fusion polypeptide is formed by sequentially connecting an N-terminal tachyplesin antibacterial peptide, an intermediate microenvironment response type connection module and a C-terminal carrier protein, wherein the connection module is a GFLGVR sequence with both acid sensitivity and MMP-9 cleavability or a chemical equivalent structure of the GFLGVR sequence. Through a bionically designed double-response connection module, the fusion polypeptide is highly stable under physiological conditions, active components are efficiently released in an infected microenvironment, and the therapeutic index is remarkably improved; the in-vivo half-life period of the tachyplesin antibacterial peptide is prolonged from the minute level to the hour level by utilizing the natural long-cycle characteristic of the carrier protein, so that the defect of rapid removal of the tachyplesin antibacterial peptide is overcome; lesion targeted activation is realized by depending on infection microenvironment specific signals, and whole body exposure and potential toxicity are reduced; the preparation process is mature and controllable, is suitable for large-scale production, and lays a foundation for clinical transformation.

The application discloses application of BMS-833923 and derivatives thereof and a medicine, and belongs to the technical field of antibiotics. The BMS-833923 and the derivatives thereof can be used as colistin adjuvants to jointly inhibit or eliminate gram-negative bacteria, and can also independently inhibit or eliminate gram-positive bacteria. The gram-negative bacteria can include at least one of Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, pan-drug-resistant strains BAA-1800, BAA-1794 and BAA-1792, and the gram-positive bacteria can include at least one of Staphylococcus aureus and Bacillus subtilis. By taking the BMS-833923 and the derivatives thereof as adjuvants of colistin, the therapeutic index of the colistin can be effectively expanded, and lower, non-toxic doses of the colistin can be used in clinical treatment of effective treatment of drug-resistant bacterial infections.

A PEGylated ICD inducer-IDO inhibitor nanoconjugate and a preparation method and use thereof. The nanoconjugate has a structural formula as follows:where R is H orwith a weight-average molecular weight of 1000-5000. For the PEGylated ICD inducer-IDO inhibitor nanoconjugate provided in an aqueous medium, the PEGylated drug conjugate can self-assemble into a drug-based nanoconjugate, which can not only reduce non-specific accumulation in MPS-related organs, but also improve the passive targeting capability to solid tumors through the enhanced permeability and retention effect, thereby increasing the therapeutic index.

The invention belongs to the technical field of biological medicines, discloses a ganoderma lucidum oligopeptide for inhibiting tumor cell growth and a preparation method and application thereof, and aims to overcome the technical defects of unknown active ingredients, low yield, poor purity and high toxicity of the existing ganoderma lucidum oligopeptide. The sequence of the ganoderma lucidum oligopeptide is Trp-Gly-Ala-Pro-Arg, the molecular weight is 623.7 Da, the isoelectric point is 8.92, and the ganoderma lucidum oligopeptide plays a tumor inhibition role by reducing a PI3K / Akt / mTOR signal channel in a targeted manner. The preparation method comprises the following steps: carrying out superfine grinding on a lucid ganoderma raw material, carrying out composite enzymatic hydrolysis by using papain, alkaline protease and flavourzyme (5: 3: 2), and carrying out ultrafiltration, gel chromatography and RP-HPLC (Reverse Phase-High Performance Liquid Chromatography) purification, so that the yield is 1.16-1.20%, and the purity is greater than or equal to 98%. The ICs of the peptide to six tumor cells such as lung cancer A549 are 0.8-1.4 [mu] mol / L, and the ICs of the peptide to normal cells are ICgt; the therapeutic index is greater than or equal to 15.4; the cells PPappgt of Caco-2 are subjected to cell culture; 1 * 10 cm / s, the plasma protein binding rate is 65%-68%, LDgt; the density is 500 mg / kg. The compound can be prepared into dosage forms such as injections and the like, and the tumor inhibition rate reaches 85% when the compound is combined with cis-platinum, and CI is equal to 0.65. The process is stable, and the product is high in activity, safe, suitable for tumor treatment and adjuvant therapy and good in industrialization prospect.

The present disclosure relates to the application of antibodies and bispecific antibodies targeting human Cadherin-17 and CD3 as an effective and tissue-specific treatment of CDH17-mediated diseases or disorders such as breast, lung, pancreatic, gastric, and other CDH17 overexpressed cancers. The bispecific antibodies may contain masking domains to minimize systemic toxicity. The masking domains are fused via protease-cleavable linkers to the Fab domains targeting human Cadherin-17 and CD3. The unmasking of the shielded bispecific antibodies occurs predominantly by proteases and enzymes in the tumor microenvironment. The application of such bispecific antibodies thereby minimizes systemic toxicity and expands the therapeutic index.

This invention provides a liver-targeting glycoligand molecule modified with dual-antenna GalNAc and its drug delivery system. This liver-targeting glycoligand molecule and its drug delivery system, through ASGPR recognition, can maximize the concentration of therapeutic drugs in liver tumor parenchymal cells, thereby improving the targeting of drug distribution, increasing the therapeutic index, reducing systemic toxicity, and improving patient survival time and quality of life. The liver-targeting glycoligand molecule of this invention is synthesized using an enzymatic synthesis method, which involves fewer synthesis steps, mild enzymatic reaction conditions, high regioselectivity, high reaction efficiency, is environmentally friendly, and has low production costs, making it highly promising for industrialization.

The new compound 3-(1-(2,3-dichloro-4-methoxyphenyl) ethyl)-1-methyl-l-(l,3,3-trimethylpiperidin-4-yl)urea monohydrochloride salt has a high capability to permeate through the blood-brain barrier and to display, at central nervous system level, a consistent ghrelin agonist activity; the compound is effective in the treatment and / or prevention of a medical condition mediated by the ghrelin receptor in the central nervous system. In particular, in experimental tests, the compound has shown high efficacy in the treatment of neurotoxic damage, with a useful combined pattern of neuroprotective effects both at central and peripheral level. The compound is further useful in the treatment of conditions which require a reduction of the heart rate. The compound is pharmacologically active at low to moderate doses, thus showing a favourable therapeutic index.