EP3448393A1 - Nouveaux complexes de composés immunostimulateurs, et leurs utilisations - Google Patents

Nouveaux complexes de composés immunostimulateurs, et leurs utilisations

Info

Publication number
EP3448393A1
EP3448393A1 EP17723284.0A EP17723284A EP3448393A1 EP 3448393 A1 EP3448393 A1 EP 3448393A1 EP 17723284 A EP17723284 A EP 17723284A EP 3448393 A1 EP3448393 A1 EP 3448393A1
Authority
EP
European Patent Office
Prior art keywords
cdn
complex
cells
pharmaceutical composition
formula
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP17723284.0A
Other languages
German (de)
English (en)
Inventor
Fabienne Vernejoul
Cédric BOULARAN
Daniel Drocourt
Thierry Lioux
Grégory QUSHAIR
Jésus ROMO
Gérard TIRABY
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Invivogen SAS
Original Assignee
Invivogen SAS
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Invivogen SAS filed Critical Invivogen SAS
Publication of EP3448393A1 publication Critical patent/EP3448393A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7084—Compounds having two nucleosides or nucleotides, e.g. nicotinamide-adenine dinucleotide, flavine-adenine dinucleotide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
    • A61K31/708—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid having oxo groups directly attached to the purine ring system, e.g. guanosine, guanylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/543—Lipids, e.g. triglycerides; Polyamines, e.g. spermine or spermidine
    • A61K47/544—Phospholipids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions

Definitions

  • the present invention is related to the fields of molecular biology, cell biology, immunology and organic chemistry.
  • Human STING is activated three ways: via binding of the exogenous (3',3) cyclic dinucleotides (CDNs) c-diGMP, c-diAMP and c-GAMP, which are released by invading bacteria or archaea (see (Gomelsky, 201 1 ) and references therein); via binding of the (2',3') CDN cyclic guanosine monophosphate-adenosine monophosphate (2',3')c-GAMP), a recently discovered endogenous cyclic dinucleotide that is produced by the enzyme cyclic GMP-AMP synthase (cGAS; also known as C6orf150 or MB21D1) in the presence of exogenous double-stranded DNA (e.g.
  • viruses that have been employed to deliver CDN STING agonists into cells include virus-like particles (US/2017/0074507); PEGylated phosphatidylcholine nanoparticles (Hanson ef a/., 2015); linear polyethyleneimine/hyaluronic acid (PEI/HA) hydrogels (Lee ef a/., 2016); and an Arg(9) cell- penetrating peptide (Yildiz ef a/., 2015).
  • the delivery vehicle or complexing agent comprises multiple molecules, rather than a single molecule.
  • Lipid formulations of therapeutic molecules can exhibit immunogenicity, which can be advantageous (e.g. by boosting the immune system) or disadvantageous (e.g. by causing unwanted immune responses such as acute inflammation), depending on the context.
  • EP/212501 1/B1 relates to the use of cationic lipid formulations of diverse antigens to deliberately generate an immunostimulatory therapeutic response via MAP-kinase signaling, as a strategy for therapeutic modulation of T cells; and
  • WO2008/148057 proposes lipid-based adjuvants for nucleic acid vaccines that encode immunogens, in which the adjuvants enable enhanced in vivo immune responses to the immunogens.
  • WO/2014/182661 proposes an itinerated dosing approach for administration of lipid-formulated nucleic acids as a strategy to avoid the adverse acute immune responses (known as "infusion-related reactions") that are often observed shortly after treatment.
  • cationic lipids used for delivery of nucleic acids can show toxicity, which inventors have sought to reduce.
  • US/2017/0009637 relates to the delivery of nucleic acids (siRNAs, aptamers or plasmids) using biodegradable cationic lipids that, relative to other cationic lipids, purportedly offer specific pharmacologic benefits (e.g. faster clearance) and consequently, lower toxicity.
  • ⁇ - ⁇ and B 2 are purine bases independently chosen from adenine, guanine or hypoxanthine;
  • Y-i and Y 2 are independently chosen from H, OH or F;
  • Y 3 and Y 4 are independently chosen from O or S;
  • X " can be chosen from chloride, acetate, benzenesulfonate, benzoate, bromide, carbonate, citrate, fluoride, formate, fumarate, galacturonate, gluconate, glutarate, lactate, nitrate, succinate, tartrate, maleate, phosphate, pyruvate, sulfate, tosylate, trifluoroacetate or any other pharmaceutically acceptable anion.
  • the cyclic purine dinucleotide of Formula II is chosen from the following compounds (as defined in Table 1 ), in which the internucleotide linkages in the CDN are two phosphodiester linkages: CL592, CL603, CL605, CL657, CL614, CL674.
  • the pharmaceutical composition further comprises a surfactant.
  • surfactant means any compound having both a lipophilic portion and a hydrophilic portion in particular a ionic or non-ionic surfactant, which confers to the complex an enhancement of a particular aspect of formulation such as, but not limited to, solubility.
  • the concentration of each of the constituent solutions is adjusted prior to mixing such that the desired final compound of Formula l/compound of Formula II ratio and the desired final concentration of compound of Formula II is obtained upon mixing the two solutions.
  • CDNs used in the present invention and their corresponding code numbers (format: CL###) shown below in table 1.
  • CDNs CL592, CL655, CL603, CL632, CL614, CL656, CL674 and CL702 were synthesized in the form of a sodium salt according to a procedure similar to the one described in PCT/EP2015/070635.
  • the remaining CDNs were obtained from InvivoGen:
  • HEK-BlueTM IL-28 This HEK293 cell line is derived from HEK-BlueTM ISG cells (InvivoGen catalog code: hkb-isg). It enables detection of bioactive Type III IFNs (IL-28A [IFN- 2], IL-28B [IFN- 3] and IL- 29 [IFN- ⁇ ]) through monitoring of activation of the ISG54 pathway.
  • HEK-BlueTM IL-28 cells were generated by inactivation of the IFNAR2 and IFNGR1 genes, to abolish (i.e. reduce to undetectable levels) the Type I and Type II IFN response, followed by stable transfection with the human IFNLR1 and IL10R genes, to obtain a strong Type III IFN response.
  • the other genes of the (shared Type I/Type III) IFN pathway are naturally expressed in sufficient amounts.
  • the resultant cells were then transfected with a SEAP reporter gene under control of a promoter that comprises five IFN-stimulated response elements (ISREs) fused to a minimal promoter of the human ISG54 gene, which is unresponsive to activators of the NF- ⁇ or AP-1 pathways.
  • ISREs IFN-stimulated response elements
  • RAW-LuciaTM ISG (InvivoGen catalog code: rawl-isg): These cells were generated from the RAW 264.7 murine macrophage cell line (ATCC ® TIB-71TM).
  • HEK293-T-ISG These cells were generated from the HEK-293T human embryonic kidney cell line (ATCC ® CRL-3216TM).
  • THP1 -DualTM-KO-STING InvivoGen catalog code: thpd-kostg: These cells were generated from the human monocyte THP-1-DualTM, through stable homozygote knockout of the STING gene. Biallelic STING knockout was verified by functional assays, PCR and DNA sequencing. Cytokine quantification
  • Example 2.1 Comparison of CDN/CL338 complexes to the corresponding CDN alone, for STING pathway-dependent cytokine induction in cell cultures
  • test concentration 0 ⁇ g/mL
  • test concentration 0 ⁇ g/mL
  • the level of ISG54 activity (as an indicator of Type I IFN induction) was indirectly quantified using QUANTI-LucTM, which was prepared and used according to the manufacturer's instructions.
  • the level of NF-Kb pathway activation was measured using QUANTI-BlueTM, which was prepared and used according to the manufacturer's instructions.
  • the figures show that: firstly, most of the CDN/CL338 complex provides greater induction of ISG-induced IRF pathway (Type IFNs) and of the NF- ⁇ pathway (proinflammatory cytokines) than does the corresponding CDN alone; and secondly, among the various complexes, those using CL338 gave the strongest response for both activities.
  • ISG-induced IRF pathway Type IFNs
  • NF- ⁇ pathway proinflammatory cytokines
  • Each blood sample was diluted (1 :2 [v/v]) in RPMI medium and aliquoted into 96-well plates (180- ⁇ _ wells) containing either a CDN at one of seven different concentrations (20 ⁇ g mL, 6.7 ⁇ g mL, 2.2 ⁇ g mL, 0.7 ⁇ g mL, 0.2 ⁇ g mL, 0.08 ⁇ g mL or 0.03 ⁇ g mL), or a CDN/CL338 complex (2:5 [w/w]) at one of seven different (CDN) concentrations (20 ⁇ g mL, 2 ⁇ g mL, 200 ng/mL, 20 ng/mL, 2ng/ml_, 200 pg/mL or 20 pg/mL).
  • CDN CDN/CL338 complex
  • CDN ( g mL) CDN/CL338 (Mg/mL)
  • CDN ( g mL) CDN/CL338 (Mg/mL) Fold increase
  • Example 2.4 Comparison of CDNs alone with their corresponding CDN/CL338 complexes for in vitro antiviral activity
  • CDNs and their corresponding CDN/CL338 complexes were tested for their possible effects on infection of human retinal cells by human cytomegalovirus (CMV).
  • CMV cytomegalovirus
  • the anti-CMV drug ganciclovir which is a standard of care for retinal CMV infection (reference: http://www.merckmanuals.com/professional/infectious-diseases/herpesviruses/cytomegalovirus- %28cmv%29-infection), was used as positive control.
  • ARPE19 human retinal pigment epithelial (RPE) cells (reference: ATCC ® CRL-2302 TM ) were seeded in 96-well plates (5,000 cells/well) and treated with the indicated CDN (10 Mg/mL), CDN/CL338 complex (10 ⁇ g/mL CDN cone; 2:5 [w/w]), saline or ganciclovir (3 ⁇ g/mL [12.5 ⁇ ]). Immediately after treatment, the cells were infected with the autofluorescent ANCHORTM strain of human CMV (see Gros ef a/. , ACS Infect Dis, 2015) at a multiplicity-of-infection (MOI) of 1 .
  • MOI multiplicity-of-infection
  • Figure 4 Comparison of transfection agents for NF- ⁇ pathway activation by complexes containing either CL632 (Fig. 4A) or CL702 (Fig. 4B), in ⁇ -DualTM cells.
  • Figure 5. Comparison of CDNs alone with their corresponding CDN/CL338 complexes for ex vivo cytokine induction in human blood: (A) CL614 vs. CL614/CL338 for induction of Type I IFNs; (B) CL614 vs. CL614/CL338 for induction of TNF-a (CL614); (C) CL614 vs. CL614/CL338 for induction of IL-1 ; and (D) f CL656 vs. CL656/CL338 or induction of IFN- ⁇ .
  • Figure 6. Comparison of CDNs alone with their corresponding CDN/CL338 complexes for in vitro antiviral (anti-hCMV) activity in human retinal cells.
  • anti-hCMV antiviral
  • Nanoparticulate STING agonists are potent lymph node-targeted vaccine adjuvants. The Journal of clinical investigation 125, 2532-2546, doi: 10.1 172/JCI79915 (2015).

Abstract

La présente invention concerne la préparation de complexes formés entre un lipide cationique et au moins un des divers agonistes dinucléotidiques cycliques (CDN) de STING, et des utilisations desdits complexes. Plus spécifiquement, ces complexes peuvent être utilisés pour obtenir des activités biologiques améliorées ou distinctes in vitro, ex vivo ou in vivo, par rapport à l'utilisation du composant CDN correspondant seul.
EP17723284.0A 2016-04-25 2017-04-25 Nouveaux complexes de composés immunostimulateurs, et leurs utilisations Withdrawn EP3448393A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP16305481 2016-04-25
PCT/EP2017/059781 WO2017186711A1 (fr) 2016-04-25 2017-04-25 Nouveaux complexes de composés immunostimulateurs, et leurs utilisations

Publications (1)

Publication Number Publication Date
EP3448393A1 true EP3448393A1 (fr) 2019-03-06

Family

ID=55969073

Family Applications (1)

Application Number Title Priority Date Filing Date
EP17723284.0A Withdrawn EP3448393A1 (fr) 2016-04-25 2017-04-25 Nouveaux complexes de composés immunostimulateurs, et leurs utilisations

Country Status (2)

Country Link
EP (1) EP3448393A1 (fr)
WO (1) WO2017186711A1 (fr)

Families Citing this family (55)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3366691A1 (fr) 2015-12-03 2018-08-29 GlaxoSmithKline Intellectual Property Development Limited Dinucléotides cycliques de purine utilisés comme modulateurs de sting
EP3402498A1 (fr) 2016-01-11 2018-11-21 Synlogic, Inc. Microorganismes programmés pour produire des immunomodulateurs et des agents thérapeutiques anticancéreux dans des cellules tumorales
MA43827A (fr) 2016-03-18 2018-11-28 Immune Sensor Llc Composés di-nucléotides cycliques et leurs procédés d'utilisation
KR20230010826A (ko) 2016-10-14 2023-01-19 프리시젼 바이오사이언시스 인코포레이티드 B형 간염 바이러스 게놈 내의 인식 서열에 대해 특이적인 조작된 메가뉴클레아제
JOP20170192A1 (ar) 2016-12-01 2019-01-30 Takeda Pharmaceuticals Co داي نوكليوتيد حلقي
AU2018212788A1 (en) 2017-01-27 2019-07-25 Janssen Biotech, Inc. Cyclic dinucleotides as STING agonists
AU2018212787B2 (en) 2017-01-27 2023-10-26 Janssen Biotech, Inc. Cyclic dinucleotides as sting agonists
JP7311514B2 (ja) * 2017-08-30 2023-07-19 ベイジン シュエンイー ファーマサイエンシズ カンパニー， リミテッド インターフェロン遺伝子刺激因子調節薬としての環状ジヌクレオチド
CA3074232A1 (fr) * 2017-08-31 2019-03-07 Sperovie Biosciences, Inc. Composes, compositions et methodes pour le traitement d'une maladie
TW201922263A (zh) 2017-11-10 2019-06-16 日商武田藥品工業股份有限公司 干擾素基因刺激蛋白之調節化合物，及製造和使用方法
KR102492115B1 (ko) 2017-12-20 2023-01-27 인스티튜트 오브 오가닉 케미스트리 앤드 바이오케미스트리 에이에스 씨알 브이.브이.아이. Sting 어댑터 단백질을 활성화하는 포스포네이트 결합을 가진 2'3' 사이클릭 다이뉴클레오티드
US11685761B2 (en) 2017-12-20 2023-06-27 Merck Sharp & Dohme Llc Cyclic di-nucleotide compounds as sting agonists
WO2019123340A1 (fr) 2017-12-20 2019-06-27 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. Dinucléotides 3'3' cycliques ayant une liaison phosphonate activant la protéine adaptatrice de sting
CN111788204B (zh) 2018-02-26 2023-05-05 吉利德科学公司 作为hbv复制抑制剂的取代吡咯嗪化合物
WO2019170912A1 (fr) 2018-03-09 2019-09-12 Lidds Ab Compositions biorésorbables à libération contrôlée comprenant des molécules modulant sting
US11874276B2 (en) 2018-04-05 2024-01-16 Dana-Farber Cancer Institute, Inc. STING levels as a biomarker for cancer immunotherapy
EP3774883A1 (fr) 2018-04-05 2021-02-17 Gilead Sciences, Inc. Anticorps et leurs fragments qui se lient à la protéine x du virus de l'hépatite b
AU2019247905B2 (en) 2018-04-06 2023-10-05 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. 3'3'-cyclic dinucleotides
TWI818007B (zh) 2018-04-06 2023-10-11 捷克科學院有機化學與生物化學研究所 2'3'-環二核苷酸
TW202005654A (zh) 2018-04-06 2020-02-01 捷克科學院有機化學與生物化學研究所 ２，２，─環二核苷酸
US11142750B2 (en) 2018-04-12 2021-10-12 Precision Biosciences, Inc. Optimized engineered meganucleases having specificity for a recognition sequence in the Hepatitis B virus genome
TW202014193A (zh) 2018-05-03 2020-04-16 捷克科學院有機化學與生物化學研究所 包含碳環核苷酸之2’3’－環二核苷酸
EP3802534B1 (fr) 2018-05-25 2022-07-13 Incyte Corporation Composés hétérocycliques tricycliques en tant qu'activateurs de sting
WO2020028566A1 (fr) 2018-07-31 2020-02-06 Incyte Corporation Composés amides hétéroaryles en tant qu'activateurs de sting
WO2020028565A1 (fr) 2018-07-31 2020-02-06 Incyte Corporation Composés hétéroaryles tricycliques en tant qu'activateurs de sting
WO2020028097A1 (fr) 2018-08-01 2020-02-06 Gilead Sciences, Inc. Formes solides d'acide (r)-11-(méthoxyméthyl)-12-(3-méthoxypropoxy)-3,3-diméthyl-8-0 x0-2,3,8,13b-tétrahydro-1h-pyrido[2,1-a] pyrrolo[1,2-c]phtalazine-7-carboxylique
MA53659A (fr) 2018-09-21 2022-02-23 Shanghai De Novo Pharmatech Co Ltd Analogue dinucléotidique cyclique, composition pharmaceutique associée et utilisation
TW202028212A (zh) 2018-10-11 2020-08-01 日商小野藥品工業股份有限公司 Ｓｔｉｎｇ促效化合物
JP7460644B2 (ja) 2018-10-31 2024-04-02 ギリアード サイエンシーズ， インコーポレイテッド Ｈｐｋ１阻害剤としての置換６－アザベンゾイミダゾール化合物
EP3873608A1 (fr) 2018-10-31 2021-09-08 Gilead Sciences, Inc. Composés 6-azabenzimidazole substitués ayant une activité inhibitrice de hpk1
AU2019376140A1 (en) * 2018-11-08 2021-06-03 Synlogic Operating Company, Inc. Combination therapies of microorganisms and immune modulators for use in treating cancer
US11596692B1 (en) 2018-11-21 2023-03-07 Incyte Corporation PD-L1/STING conjugates and methods of use
KR20210137518A (ko) 2019-03-07 2021-11-17 인스티튜트 오브 오가닉 케미스트리 앤드 바이오케미스트리 에이에스 씨알 브이.브이.아이. 3'3'-사이클릭 다이뉴클레오티드 및 이의 프로드럭
US11766447B2 (en) 2019-03-07 2023-09-26 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. 3′3′-cyclic dinucleotide analogue comprising a cyclopentanyl modified nucleotide as sting modulator
CN113543851A (zh) 2019-03-07 2021-10-22 捷克共和国有机化学与生物化学研究所 2’3’-环二核苷酸及其前药
TW202212339A (zh) 2019-04-17 2022-04-01 美商基利科學股份有限公司 類鐸受體調節劑之固體形式
TW202210480A (zh) 2019-04-17 2022-03-16 美商基利科學股份有限公司 類鐸受體調節劑之固體形式
CA3137119A1 (fr) 2019-05-09 2020-11-12 Aligos Therapeutics, Inc. Composes di-nucleosidiques cycliques modifies servant de modulateurs sting
TWI826690B (zh) 2019-05-23 2023-12-21 美商基利科學股份有限公司 經取代之烯吲哚酮化物及其用途
JP7295283B2 (ja) 2019-06-25 2023-06-20 ギリアード サイエンシーズ， インコーポレイテッド Ｆｌｔ３ｌ－ｆｃ融合タンパク質及び使用方法
EP4017476A1 (fr) 2019-08-19 2022-06-29 Gilead Sciences, Inc. Formulations pharmaceutiques de ténofovir alafénamide
US20220305048A1 (en) 2019-08-26 2022-09-29 Dana-Farber Cancer Institute, Inc. Use of heparin to promote type 1 interferon signaling
CR20220129A (es) 2019-09-30 2022-05-06 Gilead Sciences Inc Vacunas para vhb y métodos de tratamiento de vhb
US20230031465A1 (en) 2019-12-06 2023-02-02 Precision Biosciences, Inc. Optimized engineered meganucleases having specificity for a recognition sequence in the hepatitis b virus genome
WO2021188959A1 (fr) 2020-03-20 2021-09-23 Gilead Sciences, Inc. Promédicaments de nucléosides de 4'-c-substitué-2-halo-2'-désoxyadénosine et leurs procédés de fabrication et d'utilisation
KR20220167275A (ko) 2020-04-10 2022-12-20 오노 야꾸힝 고교 가부시키가이샤 암 치료 방법
EP4134134A4 (fr) 2020-04-10 2023-12-27 ONO Pharmaceutical Co., Ltd. Composé agoniste de sting
CR20230071A (es) 2020-08-07 2023-04-11 Gilead Sciences Inc Profármacos de análogos de nucleótidos de fosfonamida y su uso farmacéutico
KR20230106606A (ko) 2020-11-09 2023-07-13 다케다 야쿠힌 고교 가부시키가이샤 항체 약물 접합체
WO2022241134A1 (fr) 2021-05-13 2022-11-17 Gilead Sciences, Inc. Combinaison d'un composé de modulation de tlr8 et agent thérapeutique anti-arnsi de vhb
US20220389394A1 (en) 2021-05-18 2022-12-08 Gilead Sciences, Inc. METHODS OF USING FLT3L-Fc FUSION PROTEINS
CR20230585A (es) 2021-06-23 2024-02-19 Gilead Sciences Inc Compuestos Moduladores de Diacilglicerol Quinasa.
AU2022299051A1 (en) 2021-06-23 2023-12-07 Gilead Sciences, Inc. Diacylglyercol kinase modulating compounds
AU2022298639A1 (en) 2021-06-23 2023-12-07 Gilead Sciences, Inc. Diacylglyercol kinase modulating compounds
KR20240005901A (ko) 2021-06-23 2024-01-12 길리애드 사이언시즈, 인코포레이티드 디아실글리세롤 키나제 조절 화합물

Family Cites Families (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2565633C (fr) 2004-05-05 2016-04-26 Atugen Ag Lipides, complexes lipidiques et utilisations correspondantes
EP1782826A1 (fr) 2005-11-08 2007-05-09 GBF Gesellschaft für Biotechnologische Forschung mbH PQS, c-diGMP et leurs conjugués utilisés comme adjuvants et leur emploi dans des compositions pharmaceutiques
US8877206B2 (en) 2007-03-22 2014-11-04 Pds Biotechnology Corporation Stimulation of an immune response by cationic lipids
WO2008148057A2 (fr) 2007-05-23 2008-12-04 Vical Incorporated Compositions et procédés pour améliorer la réponse immunitaire à des vaccins
FR2925491B1 (fr) 2007-12-19 2010-09-03 Oz Biosciences Sas Nouvelle classe de lipides cationiques pour le transport d'agents actifs dans les cellules
CA2743139C (fr) 2008-11-10 2019-04-02 Alnylam Pharmaceuticals, Inc. Nouveaux lipides et compositions pour l'administration d'agents therapeutiques
EP2448954A1 (fr) 2009-07-01 2012-05-09 Rutgers, The State University of New Jersey Synthèse de monophosphate de diguanosine cyclique et de leurs analogues thiophosphate
KR101967411B1 (ko) 2010-06-03 2019-04-10 알닐람 파마슈티칼스 인코포레이티드 활성제의 전달을 위한 생분해성 지질
AU2012234259A1 (en) 2011-03-31 2013-10-03 Libera-Korner, Jeanette Perfluorinated compounds for the non-viral transfer of nucleic acids
SG10201610251PA (en) 2012-06-08 2017-01-27 Aduro Biotech Compositions and methods for cancer immunotherapy
EP2674170B1 (fr) 2012-06-15 2014-11-19 Invivogen Nouvelles compositions d'agonistes TLR7 et/ou TLR8 conjugués à des lipides
EP3527579A1 (fr) 2012-12-13 2019-08-21 Aduro BioTech, Inc. Compositions comprenant des dinucléotides cycliques de purine présentant des stéréochimies définies et procédés pour leur préparation et leur utilisation
CA2888286C (fr) 2013-03-06 2020-03-24 Biomics Biotechnologies Co., Ltd. Preparation de lipidosomes, leur procede de preparation et leur application
WO2014152211A1 (fr) 2013-03-14 2014-09-25 Moderna Therapeutics, Inc. Formulation et administration de compositions de nucléosides, de nucléotides, et d'acides nucléiques modifiés
WO2014179335A1 (fr) 2013-04-29 2014-11-06 Memorial Sloan Kettering Cancer Center Compositions et procédés pour altérer la signalisation par un second messager
US10246708B2 (en) 2013-05-06 2019-04-02 Alnylam Pharmaceuticals, Inc. Dosages and methods for delivering lipid formulated nucleic acid molecules
US9549944B2 (en) 2013-05-18 2017-01-24 Aduro Biotech, Inc. Compositions and methods for inhibiting “stimulator of interferon gene”—dependent signalling
US10010607B2 (en) 2014-09-16 2018-07-03 Institut Curie Method for preparing viral particles with cyclic dinucleotide and use of said particles for inducing immune response
US10011630B2 (en) * 2014-12-16 2018-07-03 Invivogen Cyclic dinucleotides for cytokine induction

Also Published As

Publication number Publication date
WO2017186711A1 (fr) 2017-11-02

Similar Documents

Publication Publication Date Title
EP3448393A1 (fr) Nouveaux complexes de composés immunostimulateurs, et leurs utilisations
JP6948313B2 (ja) 治療剤の細胞内送達のための化合物および組成物
JP6990176B2 (ja) メッセンジャーリボ核酸薬物の治療投与のための方法
JP2020532528A (ja) 脂質ナノ粒子の生成方法
CA2853689C (fr) Procede de fabrication de nanoparticules lipidiques pour une administration de medicament
CN110522918B (zh) 靶向元件及其制备方法和运用
JP7066632B2 (ja) 親油性抗炎症剤を含む脂質ナノ粒子およびその使用方法
JP2022519557A (ja) 脂質ナノ粒子の調製方法
ES2872377T3 (es) Nanopartículas de protamina/ARN para inmunoestimulación
US20120157500A1 (en) Jak inhibition blocks rna interference associated toxicities
JP2014532071A (ja) カーゴの経皮送達を含む標的送達用の多孔性ナノ粒子に担持された脂質二重層（プロトセル）及びその方法
JP7379325B2 (ja) 組織特異的送達用のカチオン性脂質組成物
Du et al. Cytosolic delivery of the immunological adjuvant Poly I: C and cytotoxic drug crystals via a carrier-free strategy significantly amplifies immune response
KR20110112305A (ko) 베시클 제제
JP2022531010A (ja) 薬物送達キャリア及びそれを用いた医薬製剤
CN105873941A (zh) 生存素导向的癌症疫苗治疗
WO2021113365A1 (fr) Nanomatériaux
Huang et al. Intracellular delivery of messenger RNA to macrophages with surfactant-derived lipid nanoparticles
JP2022075622A (ja) 薬物送達キャリア及びそれを用いて多種類の治療剤を共同送達する医薬製剤
TW200836762A (en) Polymeric short interfering RNA conjugates
WO2021216572A1 (fr) Compositions lipidiques pour l'administration de composés agonistes de sting et leurs utilisations
US9970002B2 (en) Compositions and methods for functional nucleic acid delivery
US9540638B2 (en) Lipid particle, nucleic acid transfer carrier, compound for manufacturing nucleic acid transfer carrier, method for manufacturing lipid particle, and gene transfer method
US20180298379A1 (en) Small interfering rna modification method by combining with isonucleoside modification, terminal peptide conjugation and cationic liposomes, and preparation
US20240016940A1 (en) Long-acting and long-circulating delivery vehicles

Legal Events

Date Code Title Description
STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: UNKNOWN

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE INTERNATIONAL PUBLICATION HAS BEEN MADE

PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: REQUEST FOR EXAMINATION WAS MADE

17P Request for examination filed

Effective date: 20181122

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

AX Request for extension of the european patent

Extension state: BA ME

DAV Request for validation of the european patent (deleted)
DAX Request for extension of the european patent (deleted)
GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: GRANT OF PATENT IS INTENDED

INTG Intention to grant announced

Effective date: 20191106

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20200603