24 results about "Alternate pathway" patented technology

A spirocyclicalkenyl or azaalkenyl compound, and a pharmaceutical composition thereof, a preparation method therefor and the use thereof. Specifically, provided are a spirocyclicalkenyl or azaalkenyl compound as shown in formula (I), which can be used for preparing a drug, particularly for preparing a drug for preventing and / or treating a disease or condition by means of the alternative complement pathway. Each group in formula (I) is as defined in the description.

In one aspect, the invention provides methods of inhibiting the effects of MASP-2-dependent complement activation in a living subject. The methods comprise the step of administering, to a subject in need thereof, an amount of a MASP-2 inhibitory agent effective to inhibit MASP-2-dependent complement activation. In some embodiments, the MASP-2 inhibitory agent inhibits cellular injury associated with MASP-2-mediated alternative complement pathway activation, while leaving the classical (C1q-dependent) pathway component of the immune system intact. In another aspect, the invention provides compositions for inhibiting the effects of lectin-dependent complement activation, comprising a therapeutically effective amount of a MASP-2 inhibitory agent and a pharmaceutically acceptable carrier.

Provided herein are methods of ameliorating a disease or condition associated with a disorder of a complement bypass pathway by administering to a subject a complement factor B (CFB) specific inhibitor.

Provided is a CFB-targeting double-stranded RNA molecule, specifically an siRNA. The provided siRNA can effectively inhibit the CFB expression, and can be used for preventing and treating diseases caused by up-regulated CFB expression or diseases associated with abnormal activation of an alternative complement pathway.

The present invention provides an antibody or antigen-binding portion thereof that can bind to properdin (factor P). The antibody of the current invention leads to selective inhibition of alternative complement pathway while allowing the classical and lectin pathways to continue. Further, the antibody of the present invention may have modified or reduced binding to FcγRs to minimize its ADCC activity. The present invention provide an antibody that comprises an amino acid sequence to minimise its CDC activity. The antibody according to the present invention has higher FcRn binding affinity and therefore the antibody according to the present invention may have long circulating half-life in the body of the patient and it can be given at a reduced dosing frequency. The antibody according to the present invention can further be used in the preparation of a drug for treating diseases through inhibition of alternative complement pathway.

Described herein are isolated monovalent antibodies or antibody fragments thereof that bind human properdin. Such antibodies are useful in methods of treatment for diseases mediated by alternative complement pathway dysregulation.

Provided herein are methods of ameliorating a disease or disorder associated with dysregulation of the alternative complement pathway by administering a Complement Factor B (CFB) specific inhibitor to a subject.

The present invention relates to a crystal form of a multi-membered spiro compound, and a preparation method therefor and a medical use thereof, and in particular to a crystal form of a compound represented by general formula (I), a preparation method, and a pharmaceutical composition containing a therapeutically effective amount of the crystal form and a pharmaceutical use thereof for treating diseases or conditions related to alternative complement pathway activation.

The present invention relates generally to the field of disorders of complement activation. More specifically, the present invention provides methods and compositions useful for diagnosing and treating complementopathies and monitoring therapy in disease where complement inhibitors are used. In one aspect, the present invention provides a method for detecting dysregulation of the alternative pathway of complement in a patient. In one embodiment, the method comprises the steps of (a) contacting serum obtained from a patient with a composition comprising double CD46 / PIGA knockout (DKO) cells suspended in MgEGTA buffer; and (b) measuring luminescence continuously or serially over a period of time, wherein a lower luminescence related to a healthy control indicates dysregulation of the alternative pathway of complement in the patient.

The invention relates to a monoclonal antibody targeting human complement C5 and application thereof, the monoclonal antibody comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region comprises HCDR1, HCDR2 and HCDR3, and the light chain variable region comprises LCDR1, LCDR2 and LCDR3. The antibody or the antigen binding fragment thereof has very strong binding capacity with the human complement C5, and blocks the cleavage activation effect of C5 invertase on the complement C5. In addition, C5 activation mediated by complement classical pathway activation and alternative pathway activation can be blocked at the same time.

The present application relates to the field of drugs, and in particular to a double-stranded oligonucleotide and conjugate for inhibiting the expression of C3 genes, and uses thereof. The double-stranded oligonucleotide or the conjugate comprising same can obviously inhibit the expression of C3 mRNA in HepG2 cells, can obviously inhibit the expression of C3 mRNA in animal bodies, can obviously reduce the level of C3 protein in the serum of cynomolgus monkeys, the inhibition effect being able to last for 42 days, can obviously inhibit alternative complement pathways of the serum of cynomolgus monkeys, but has no effect on classical complement pathways of the serum, can reduce the levels of C3 mRNA and protein of CFA-IgA mice, can reduce C3 deposition in a renal tissue, and can ameliorate the disease course of a patient with C3 deposition in the renal tissue. Additionally, no obvious abnormality is found in hematology and blood biochemistry of animals. The double-stranded oligonucleotide or the conjugate comprising same is beneficial to alleviating, preventing and / or treating diseases or disorders mediated by C3 genes.

Provided herein are methods for ameliorating a disease or disorder associated with dysregulation of the alternative complement pathway by administering a complement factor B (CFB)-specific inhibitor to a subject.

This application discloses a method for determining the functional activity of the alternative complement pathway (AP50) in animal serum and its application. The method includes: preparing a reaction buffer containing magnesium and calcium chelating agents; washing red blood cells with the reaction buffer and adjusting the red blood cell concentration to a preset range by measuring the absorbance value after complete lysis; serially diluting the animal serum to be tested with the reaction buffer, mixing it with a standardized red blood cell suspension, and incubating to induce a hemolytic reaction; after terminating the reaction, measuring the absorbance value of hemoglobin in the supernatant, calculating the hemolysis rate at each dilution, determining the serum dilution factor corresponding to 50% hemolysis, and using its reciprocal as the AP50 value. This application selectively activates the alternative pathway using a disclosed buffer formulation and eliminates batch-to-batch variability in red blood cells through absorbance standardization. It has advantages such as self-controllability, good reproducibility, low cost, and wide species adaptability, and can be widely used in immunological research and drug safety evaluation.

In one aspect, the invention provides methods of inhibiting the effects of MASP-2-dependent complement activation in a living subject. The methods comprise the step of administering, to a subject in need thereof, an amount of a MASP-2 inhibitory agent effective to inhibit MASP-2-dependent complement activation. In some embodiments, the MASP-2 inhibitory agent inhibits cellular injury associated with MASP-2-mediated alternative complement pathway activation, while leaving the classical (C1q-dependent) pathway component of the immune system intact. In another aspect, the invention provides compositions for inhibiting the effects of lectin-dependent complement activation, comprising a therapeutically effective amount of a MASP-2 inhibitory agent and a pharmaceutically acceptable carrier.

Certain embodiments of the present invention relate to regulation of the innate immune system and complement activation. In particular, but not exclusively certain embodiments relate to a complement regulator protein and pharmaceutical compositions thereof for use in the treatment of diseases associated with or mediated by the alternative complement pathway and methods of treating such diseases and other subject matter.

An alternative route to moroidin-type bicyclic peptide biosynthesis is presented. Also included herein, it is reported that such moroidin-type bicyclic peptides are ribosomally synthesized and post-translationally modified peptides (RiPPs) in plants. Whereas D. moroides and C. argentea entail a previously uncharacterized DUF2775 family protein as candidate precursor peptides for moroidin biosynthesis, Japanese kerria (Kerria japonica) employs a BURP-domain protein as a precursor peptide similar to that of the recently reported lyciumin biosyntheti system. Disclosed herein are compositions and methods related to the biosynthesis of moroidin. In some embodiments of the disclosure, the moroidin peptides are synthetic. In other embodiments, the moroidin peptides are heterogenous. A skilled artisan will readily appreciate that based on the data disclosed herein that the present disclosure provides for the production of moroidins in transgenic host cells.

Provided herein are substituted indole compounds. In certain embodiments, these compounds are inhibitors of the complement system bypass pathway, and in particular complement factor B (CFB) inhibitors. Compositions comprising these compounds and methods of use thereof are also provided. The provided compounds are useful for treating, preventing or ameliorating diseases, conditions or disorders by inhibiting the complement bypass pathway.

The dosages and methods described herein provide desirable pharmacokinetic (PK) and pharmacodynamics (PD) characteristics which inhibit alternative pathway complement activity, for example at least 85% or more inhibition of AP activity in vivo at dosages from about 120 mg to 200 mg BID that provides a plasma level Ctrough at least about 65 ng / ml, which provides sufficient AP inhibition to reduce the risk of complement breakthrough. In addition, the dosage form described herein provides a significantly low Cmax, providing additional safety margin and better dosing flexibility.

Described herein are isolated monovalent antibodies or antibody fragments thereof that bind human properdin. Such antibodies are useful in methods of treatment for diseases mediated by alternative complement pathway dysregulation.

The present invention relates to a multi-domain polypeptide comprising (i) a first complement control protein repeat (CCP)-comprising domain being a convertase decay accelerating domain for convertases of the classical and alternative pathways of complement activation, (ii) a host cell recognition domain, and (iii) a second CCP-comprising domains with cofactor activity. The present invention further relates to a polynucleotide encoding said multi-domain polypeptide, to a vector comprising said polynucleotide, and to a host cell comprising said polynucleotide and / or said vector. Further, the present invention relates to the multi-domain polypeptide, the polypeptide, and the vector for use in medicine and for treating and / or preventing inappropriate complement activation and / or a disease having inappropriate complement activation as a symptom. Moreover, the present invention relates to methods and uses related to multi-domain polypeptide, the polypeptide, and the vector.

The present invention discloses a piperidine-substituted benzoic acid compound, a pharmaceutical composition thereof, and its use. The piperidine-substituted benzoic acid compound of the present invention is a compound represented by Formula I, a stereoisomer thereof, a tautomer thereof, an isotope-labeled compound thereof, or a pharmaceutically acceptable salt of any of the foregoing. The compound has good inhibitory activity against complement factor B, good affinity for complement factor B, hemolytic activity in the alternative complement pathway, and inhibitory activity in the alternative complement pathway. TIFF2025541667000344.tif11998s

The present invention relates to a crystal form of a multi-membered spiro compound, and a preparation method therefor and a medical use thereof, and in particular to a crystal form of a compound represented by general formula (I), a preparation method, and a pharmaceutical composition containing a therapeutically effective amount of the crystal form and a pharmaceutical use thereof for treating diseases or conditions related to alternative complement pathway activation.

The application discloses methods and compositions for the inhibition of the alternative complement pathway. The methods and compositions involve the use of aptamers for inhibiting complement Factor D. The application further provides anti-Factor D aptamers for the treatment of dry age-related macular degeneration, geographic atrophy, wet age-related macular degeneration or Stargardt disease.