The present invention provides a modified BoNT/A for use in treating facial lines, wherein the modified BoNT/A is administered by intramuscular injection at a plurality of sites of the face of the subject, wherein the modified BoNT/A is administered by way of a unit dose of greater than 1754 pg (e.g. greater than 1800 pg) of modified BoNT/A per site, wherein the plurality of sites are selected from: up to two sites of a corrugator muscle and one site of a procerus muscle for treating glabellar lines, up to five sites of a frontalis muscle for treating forehead lines, and up to three sites of an orbicularis oculi muscle for treating lateral canthal lines, wherein the total dose of modified BoNT/A administered during the treatment is up to 88,000 pg, and wherein the modified BoNT/A comprises a BoNT/A light-chain and translocation domain (HN domain), and a BoNT/B receptor binding domain (HC domain).
The present invention is directed inter alia to a modified botulinum neurotoxin A (BoNT/A) for use in treating cervical dystonia, wherein the modified BoNT/A is administered by intramuscular injection to an affected neck muscle of a subject, wherein the modified BoNT/A is administered by way of a unit dose of greater than 17,000 pg of modified BoNT/A, wherein at least a single unit dose is administered to the affected neck muscle, wherein the total dose administered during the treatment is up to 400,000 pg of modified BoNT/A, and wherein the modified BoNT/A comprises a BoNT/A light-chain and translocation domain, and a BoNT/B receptor binding domain (HC domain). Also provided are corresponding methods, uses, unit dosage forms, and kits.
The present invention is directed to a modified botulinum neurotoxin A (BoNT/A) for use in treating a facial dystonia, including blepharospasm and hemifacial spasm, wherein the unit dose of the modified BoNT/A is at least 240 pg of modified BoNT/A, wherein the modified BoNT/A is administered by intramuscular injection to an affected muscle of a subject, wherein the total dose administered during the treatment is greater than 24,000 pg and up to 82,500 pg (e.g. up to 75,000 pg) of the modified BoNT/A, and wherein the modified BoNT/A comprises a BoNT/A light-chain and translocation domain (HN), and a BoNT/B receptor binding domain (HC domain).
A61K 38/16 - Peptides ayant plus de 20 amino-acidesGastrinesSomatostatinesMélanotropinesLeurs dérivés
A61P 21/02 - Relaxants musculaires, p. ex. pour la tétanie ou les crampes
C07K 14/33 - Peptides ayant plus de 20 amino-acidesGastrinesSomatostatinesMélanotropinesLeurs dérivés provenant de bactéries provenant de Clostridium (G)
The invention is directed to treatment of limb spasticity using a modified botulinum neurotoxin A (BoNT/A) comprising a BoNT/A light-chain and translocation domain, and a BoNT/B receptor binding domain (HC domain). Also provided are unit dosage forms of said modified BoNT/A and corresponding kits.
The present invention is directed inter alia to the treatment of pain. For example, there is provided a chimeric clostridial neurotoxin for use in treating pain by inhibiting release of a pain mediator from a neuron comprising an A? nerve fiber or a C nerve fiber, wherein the chimeric clostridial neurotoxin binds to the neuron comprising the A? nerve fiber or the C nerve fiber, respectively, and wherein the chimeric clostridial neurotoxin comprises a botulinum neurotoxin A (BoNT/A) light-chain and translocation domain (HN domain), and a BoNT/B receptor binding domain (He domain). Also provided are methods, uses, kits, and unit dosage forms.
A61K 38/48 - Hydrolases (3) agissant sur des liaisons peptidiques (3.4)
A61P 29/02 - Agents analgésiques, antipyrétiques ou anti-inflammatoires non centraux, p. ex. agents antirhumatismauxMédicaments anti-inflammatoires non stéroïdiens [AINS] sans effet anti-inflammatoire
7.
MODIFIED BONT/A FOR USE IN THE TREATMENT OF A DISORDER AFFECTING AN EYELID MUSCLE OF A SUBJECT
The present invention is directed to a modified botulinum neurotoxin A (BoNT/A) for use in a method of treating blepharospasm in a subject, wherein the modified BoNT/A is administered by intramuscular injection at a plurality of sites of the face of the subject, the method comprising: a) administering a unit dose of the modified BoNT/A to the lateral upper orbicularis oculi muscle proximal to a first eye of the subject; b) administering a unit dose of the modified BoNT/A to the medial upper orbicularis oculi muscle proximal to the first eye of the subject; and c) administering a unit dose of the modified BoNT/A to the lateral lower orbicularis oculi muscle proximal to the first eye of the subject, wherein the unit dose of the modified BoNT/A is at least 240 pg (preferably 240 pg to 8,000 pg) of modified BoNT/A, wherein the total dose administered during the treatment is up to 24,000 pg of the modified BoNT/A, and wherein the modified BoNT/A comprises a BoNT/A light-chain and translocation domain (HN), and a BoNT/B receptor binding domain (HC domain).
A61K 38/48 - Hydrolases (3) agissant sur des liaisons peptidiques (3.4)
A61P 21/02 - Relaxants musculaires, p. ex. pour la tétanie ou les crampes
C07K 14/33 - Peptides ayant plus de 20 amino-acidesGastrinesSomatostatinesMélanotropinesLeurs dérivés provenant de bactéries provenant de Clostridium (G)
8.
MODIFIED BONT/A FOR USE IN THE TREATMENT OF CERVICAL DYSTONIA
The present invention is directed to treatment of cervical dystonia using a modified BoNT/A, including a modified botulinum neurotoxin A (BoNT/A) for use in treating cervical dystonia, wherein the modified BoNT/A is administered by intramuscular injection to an affected neck muscle of a subject, wherein the modified BoNT/A is administered by way of a unit dose of 750 pg to 17,000 pg of modified BoNT/A, wherein at least a single unit dose is administered to the affected neck muscle, wherein the total dose administered during the treatment is up to 170,000 pg of modified BoNT/A, and wherein the modified BoNT/A comprises a BoNT/A light- chain and translocation domain, and a BoNT/B receptor binding domain (HC domain). Also provided are associated methods, uses, unit dosage forms, and kits.
C07K 14/33 - Peptides ayant plus de 20 amino-acidesGastrinesSomatostatinesMélanotropinesLeurs dérivés provenant de bactéries provenant de Clostridium (G)
The present invention is directed to a polypeptide for use in treating pain or an inflammatory disorder, wherein the polypeptide comprises a clostridial neurotoxin light-chain (L-chain), a clostridial neurotoxin translocation domain (HN domain) and/or a clostridial neurotoxin receptor binding domain (HC domain), wherein when the polypeptide comprises a clostridial neurotoxin L-chain, the L-chain is catalytically inactive. Also provided are corresponding methods of treatment and uses.
The present invention relates to a clostridial neurotoxin for use in treating post-operative surgical pain in a patient, said method comprising administering to a patient a clostridial neurotoxin more than 5 days prior to surgery and wherein the clostridial neurotoxin is administered: i) intradermally; or ii) intrathecally. Also provided are corresponding methods of treatment and administration dosages of a clostridial neurotoxin.
A61P 29/02 - Agents analgésiques, antipyrétiques ou anti-inflammatoires non centraux, p. ex. agents antirhumatismauxMédicaments anti-inflammatoires non stéroïdiens [AINS] sans effet anti-inflammatoire
The present invention relates to a modified botulinum neurotoxin A (BoNT/A) for use in treating limb spasticity or paediatric limb spasticity, wherein the modified BoNT/A is administered by intramuscular injection to a plurality of affected muscles of a subject, wherein the modified BoNT/A is administered by way of a unit dose of 53 Units to 948 Units or 26.5 Units to 474 Units of modified BoNT/A at the plurality of affected muscles.
The present invention relates to a modified BoNT/A for use in treating facial lines, wherein the modified BoNT/A is administered by intramuscular injection at a plurality of sites of the face of the subject, wherein the modified BoNT/A is administered by way of a unit dose of Units to 41 Units of modified BoNT/A per site and wherein 1 Unit is an amount of the modified BoNT/A that corresponds to the calculated median lethal dose (LD50) in mice, wherein the plurality of sites are selected from: up to two sites of a corrugator muscle and one site of a procerus muscle for treating glabellar lines, up to five sites of a frontalis muscle for treating forehead lines; and up to three sites at the external part of an orbicularis oculi muscle for treating lateral canthal lines, wherein the total dose of modified BoNT/A administered during the treatment is up to 574 Units, and wherein the modified BoNT/A comprises a modification at one or more amino acid residue(s) selected from: ASN 886, ASN 905, GLN 915, ASN 918, GLU 920, ASN 930, ASN 954, SER 955, GLN 991, GLU 992, GLN 995, ASN 1006, ASN 1025, ASN 1026, ASN 1032, ASN 1043, ASN 1046, ASN 1052, ASP 15 1058, HIS 1064, ASN 1080, GLU 1081, GLU 1083, ASP 1086, ASN 1188, ASP 1213, GLY 1215, ASN 1216, GLN 1229, ASN 1242, ASN 1243, SER 1274, and THR 1277, wherein the modification is selected from: i. substitution of an acidic surface exposed amino acid residue with a basic amino acid residue; ii. substitution of an acidic surface exposed amino acid residue with an uncharged amino acid residue; iii. substitution of an uncharged surface exposed amino acid residue with a basic amino acid residue; iv. insertion of a basic amino acid residue; and v. deletion of an acidic surface exposed amino acid residue. Also provided are corresponding methods of treatment and uses, as well as unit dosage forms, and kits.
The present invention relates to the treatment of skin conditions with neurotoxins, and non-therapeutic uses for cosmetic treatment of the skin. Administration of the neurotoxin induces secretion of one or more sebaceous lipid(s) selected from a squalene, a fatty acid, a cholesterol, and a wax ester to an epidermal layer of skin.
A61K 8/00 - Cosmétiques ou préparations similaires pour la toilette
A61K 8/99 - Cosmétiques ou préparations similaires pour la toilette caractérisés par la composition contenant des produits de constitution indéterminée ou leurs dérivés à base de micro-organismes autres que des algues ou des champignons, p. ex. à base de protozoaires ou de bactéries
A61K 9/00 - Préparations médicinales caractérisées par un aspect particulier
The present technology relates to commercial-scale methods for purifying botulinum toxin compositions obtained from cell cultures. Purification methods according to the present disclosure are based on a series of filtration and chromatographic separation steps that produce a high-purity botulinum toxin composition, which comprises botulinum toxin protein molecules (~150 kDa) in solution, which is free, essentially free, or substantially free of botulinum toxin complexes and animal products, and without precipitating or lyophilizing botulinum toxin protein molecules. The purification method according to the present disclosure uses no precipitation, lyophilization, or centrifugation steps, permitting production of highly pure, highly active, free botulinum toxin protein molecules (~150 kDa) in solution, without the need for reconstitution by the end user.
C07K 14/33 - Peptides ayant plus de 20 amino-acidesGastrinesSomatostatinesMélanotropinesLeurs dérivés provenant de bactéries provenant de Clostridium (G)
The present disclosure relates generally to the field of producing botulinum toxin. More specifically, the present disclosure relates to a method for producing botulinum toxin in a culture medium free or substantially free of animal product. The present disclosure also relates to the culture medium for producing botulinum toxin that is free or substantially free of animal product.
Disclosed herein are methods of treatment of moderate to severe and very severe glabellar lines and lateral canthal lines using liquid botulinum neurotoxin compositions. Also disclosed are liquid compositions of botulinum neurotoxin.
The present invention relates to a method for proteolytically processing a single-chain clostridial neurotoxin into a corresponding di-chain clostridial neurotoxin, the method comprising: providing a single-chain clostridial neurotoxin; and contacting the single-chain clostridial neurotoxin with enterokinase or factor Xa; wherein the single-chain clostridial neurotoxin has an activation loop comprising the polypeptide sequence Cys-(Xaa)a -Ile- Asp/Glu-Gly-Arg-(Yaa)b -Cys (SEQ ID NO: 1), wherein a = 1-10 and b = 4-15; and wherein enterokinase or factor Xa hydrolyses a peptide bond of the activation loop thereby producing a di-chain clostridial neurotoxin. The invention also relates to engineered clostridial neurotoxins and methods for manufacturing the same, as well as related pharmaceutical compositions, nucleotide sequences, and therapeutic uses.
INSTITUTE OF MOLECULAR AND CELL BIOLOGY, BIOMEDICAL SCIENCES INSTITUTES (Singapour)
Inventeur(s)
Foster, Keith
Beard, Matthew
Yeo Changyu, Jeremy
Bard, Frederic Andre Jean
Tay, Pei Ling Felicia
Abrégé
The present invention is directed to a method for identifying a gene that regulates clostridial neurotoxin activity, the method comprising: a. providing a sample of human neuronal cells expressing a polypeptide that comprises a C-terminal detectable label, wherein the polypeptide is cleavable by a clostridial neurotoxin; b. altering expression of a target gene of the cells; c. contacting the cells with the clostridial neurotoxin; d. measuring an amount of C-terminal detectable label, thereby quantifying clostridial neurotoxin activity; and e. identifying the target gene as a regulator of clostridial neurotoxin activity when the quantified clostridial neurotoxin activity is different to the quantified clostridial neurotoxin activity when expression of the target gene is unaltered; or f. identifying that the target gene is not a regulator of clostridial neurotoxin activity when the quantified clostridial neurotoxin activity is equivalent to the quantified clostridial neurotoxin activity when expression of the target gene is unaltered. Also provided are related methods for identifying an agent that regulates clostridial neurotoxin activity, as well as human neuronal cells, nucleotides, vectors, polypeptides, kits, and compositions suitable for use in the methods of the invention.
C12Q 1/37 - Procédés de mesure ou de test faisant intervenir des enzymes, des acides nucléiques ou des micro-organismesCompositions à cet effetProcédés pour préparer ces compositions faisant intervenir une hydrolase faisant intervenir une peptidase ou une protéinase
G01N 33/50 - Analyse chimique de matériau biologique, p. ex. de sang ou d'urineTest par des méthodes faisant intervenir la formation de liaisons biospécifiques par ligandsTest immunologique
G01N 33/542 - Tests immunologiquesTests faisant intervenir la formation de liaisons biospécifiquesMatériaux à cet effet avec formation d'un complexe immunologique en phase liquide avec inhibition stérique ou modification du signal, p. ex. extinction de fluorescence
G01N 33/569 - Tests immunologiquesTests faisant intervenir la formation de liaisons biospécifiquesMatériaux à cet effet pour micro-organismes, p. ex. protozoaires, bactéries, virus
The present invention provides a modified botulinum neurotoxin A (BoNT/A) L-chain protease that demonstrates enhanced cleavage of human SNAP-23 (hSNAP-23) relative to unmodified (wild-type) BoNT/A L-chain protease, together with the use thereof for cleaving hSNAP-23.
A61K 38/48 - Hydrolases (3) agissant sur des liaisons peptidiques (3.4)
A61K 47/64 - Conjugués médicament-peptide, médicament-protéine ou médicament-acide polyaminé, c.-à-d. l’agent de modification étant un peptide, une protéine ou un acide polyaminé lié par covalence ou complexé à un agent thérapeutiquement actif
A61K 47/69 - Préparations médicinales caractérisées par les ingrédients non actifs utilisés, p. ex. les supports ou les additifs inertesAgents de ciblage ou de modification chimiquement liés à l’ingrédient actif l’ingrédient non actif étant chimiquement lié à l’ingrédient actif, p. ex. conjugués polymère-médicament le conjugué étant caractérisé par sa forme physique ou sa forme galénique, p. ex. émulsion, particule, complexe d’inclusion, stent ou kit
The present invention provides a modified botulinum neurotoxin A (BoNT/A) L-chain protease that demonstrates enhanced cleaveage of human SNAP-23 (hSNAP-23) relative to unmodified (wild-type) BoNT/A L-chain protease, together with the use thereof for cleaving hSNAP-23.
A61K 39/08 - Clostridium, p. ex. Clostridium tetani
C07K 14/33 - Peptides ayant plus de 20 amino-acidesGastrinesSomatostatinesMélanotropinesLeurs dérivés provenant de bactéries provenant de Clostridium (G)
Combination therapy regimens including liposomal irinotecan, oxaliplatin and 5-fluorouracil are useful in the treatment of gastric cancer, including treatment of patients diagnosed with previously untreated gastric cancer. The combination therapy can include the administration of liposomal irinotecan, oxaliplatin, leucovorin and 5-fluorouracil once every two weeks.
A61K 9/127 - Vecteurs à bicouches synthétiques, p. ex. liposomes ou liposomes comportant du cholestérol en tant qu’unique agent tensioactif non phosphatidylique
A61K 31/4745 - QuinoléinesIsoquinoléines condensées en ortho ou en péri avec des systèmes hétérocycliques condensées avec des systèmes cycliques ayant l'azote comme hétéro-atome d'un cycle, p. ex. phénanthrolines
A61K 31/513 - PyrimidinesPyrimidines hydrogénées, p. ex. triméthoprime ayant des groupes oxo liés directement à l'hétérocycle, p. ex. cytosine
A61K 31/519 - PyrimidinesPyrimidines hydrogénées, p. ex. triméthoprime condensées en ortho ou en péri avec des hétérocycles
A61K 31/555 - Composés hétérocycliques contenant des métaux lourds, p. ex. hémine, hématine, mélarsoprol
The invention relates to stable liquid neurotoxin formulations which are free of animal proteins, comprising a surfactant, an amino acid selected from tryptophan and tyrosine, a buffer comprising sodium, chloride and phosphate ions, which have a pH between 5.5 and 8, and which are stable for 2 months. These compositions are suitable for use in therapy and in particular for administration to a patient to achieve a desired therapeutic or aesthetic effect. The invention also relates to the use of an amino acid selected from tryptophan and tyrosine to protect a proteinaceous neurotoxin from degradation in a liquid composition which is free of animal derived proteins.
A61K 47/18 - AminesAmidesUréesComposés d’ammonium quaternaireAcides aminésOligopeptides ayant jusqu’à cinq acides aminés
A61K 47/26 - Hydrates de carbone, p. ex. polyols ou sucres alcoolisés, sucres aminés, acides nucléiques, mono-, di- ou oligosaccharidesLeurs dérivés, p. ex. polysorbates, esters d’acide gras de sorbitan ou glycyrrhizine
23.
CHIMERIC NEUROTOXINS COMPRISING A LHN DOMAIN FROM A FIRST NEUROTOXIN LINKED TO A HC DOMAIN FROM A SECOND NEUROTOXIN, AND THEIR USE IN THERAPY
The present invention relates to chimeric neurotoxins comprising a LHn domain from a first neurotoxin linked to a He domain from a second neurotoxin, wherein (a) the C-terminal of said LHn domain corresponds to the first amino acid residue of the 3io helix separating the LHn and He domains in said first neurotoxin, (b) the N-terminal of said He domain corresponds to the second amino acid residue of the 3io helix separating the LHn and He domains in said second neurotoxin, and (c) said first and second neurotoxins are different and said first neurotoxin is a Botulinum Neurotoxin (BoNT) serotype A, serotype B, serotype C, serotype D, serotype E, serotype F or serotype G or a Tetanus Neurotoxin (TeNT), and said second neurotoxin is a BoNT serotype A, B, C, D, E, F or G or a TeNT. It also relates to these chimeric neurotoxins' use in therapy.
A61K 38/00 - Préparations médicinales contenant des peptides
C07K 14/33 - Peptides ayant plus de 20 amino-acidesGastrinesSomatostatinesMélanotropinesLeurs dérivés provenant de bactéries provenant de Clostridium (G)
Irinotecan phospholipid liposomes with improved storage stability are provided, with related methods of treatment and manufacture. The irinotecan liposomes can have reduced formation of lyso-phosphatidylcholine (lyso-PC) during storage, and prior to administration to a patient.
A61K 31/4745 - QuinoléinesIsoquinoléines condensées en ortho ou en péri avec des systèmes hétérocycliques condensées avec des systèmes cycliques ayant l'azote comme hétéro-atome d'un cycle, p. ex. phénanthrolines
25.
METHODS FOR TREATING METASTATIC PANCREATIC CANCER USING COMBINATION THERAPIES COMPRISING LIPOSOMAL IRINOTECAN AND OXALIPLATIN
Combination therapy regimens including liposomal irinotecan, oxaliplatin and 5-fluorouracil are useful in the treatment of pancreatic cancer, including treatment of patients diagnosed with previously untreated metastatic adenocarcinoma of the pancreas. The combination therapy can include the administration of liposomal irinotecan, oxaliplatin, leucovorin and 5-fluorouracil once every two weeks.
A61K 9/127 - Vecteurs à bicouches synthétiques, p. ex. liposomes ou liposomes comportant du cholestérol en tant qu’unique agent tensioactif non phosphatidylique
A61K 31/436 - Composés hétérocycliques ayant l'azote comme hétéro-atome d'un cycle, p. ex. guanéthidine ou rifamycines ayant des cycles à six chaînons avec un azote comme seul hétéro-atome d'un cycle condensés en ortho ou en péri avec des systèmes hétérocycliques le système hétérocyclique contenant un cycle à six chaînons ayant l'oxygène comme hétéro-atome du cycle, p. ex. rapamycine
A61K 31/4745 - QuinoléinesIsoquinoléines condensées en ortho ou en péri avec des systèmes hétérocycliques condensées avec des systèmes cycliques ayant l'azote comme hétéro-atome d'un cycle, p. ex. phénanthrolines
A61K 31/475 - QuinoléinesIsoquinoléines ayant un cycle indole, p. ex. yohimbine, réserpine, strychnine, vinblastine
A61K 31/513 - PyrimidinesPyrimidines hydrogénées, p. ex. triméthoprime ayant des groupes oxo liés directement à l'hétérocycle, p. ex. cytosine
A61K 31/519 - PyrimidinesPyrimidines hydrogénées, p. ex. triméthoprime condensées en ortho ou en péri avec des hétérocycles
A61P 35/04 - Agents anticancéreux spécifiques pour le traitement des métastases
brevets
