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WO2007038868A2 - Nouveau compose d'enediyne et ses utilisations - Google Patents

Nouveau compose d'enediyne et ses utilisations Download PDF

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Publication number
WO2007038868A2
WO2007038868A2 PCT/CA2006/001634 CA2006001634W WO2007038868A2 WO 2007038868 A2 WO2007038868 A2 WO 2007038868A2 CA 2006001634 W CA2006001634 W CA 2006001634W WO 2007038868 A2 WO2007038868 A2 WO 2007038868A2
Authority
WO
WIPO (PCT)
Prior art keywords
analogue
antibody
compound
carbon
uncialamycin
Prior art date
Application number
PCT/CA2006/001634
Other languages
English (en)
Other versions
WO2007038868A3 (fr
Inventor
Julian E. Davies
Raymond J. Anderson
Hao Wang
Koaru Warabi
Xin Hui Huang
Original Assignee
The University Of British Columbia
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 The University Of British Columbia filed Critical The University Of British Columbia
Publication of WO2007038868A2 publication Critical patent/WO2007038868A2/fr
Publication of WO2007038868A3 publication Critical patent/WO2007038868A3/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/08—Bridged systems
    • 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
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • This application relates to a novel enediyne compound, analogues of the compound, compositions containing the compound, and uses thereof.
  • Antibiotic resistance is an increasing problem in the treatment of bacterial infections. Hospital-acquired (nosocomial) infections are particularly difficult to treat due to bacteria acquiring resistance to commonly used drugs, often as a result of continued exposure of bacteria to multiple antibiotics. Such infections can be particularly troubling for patients who are immunocompromised or otherwise weakened from illness. As many bacteria are increasingly becoming resistant to known drugs, the need for novel antibiotics is also increasing.
  • the invention relates to the enediyne compound uncialamycin having the formula:
  • the invention relates to analogues of uncialamycin having the following formula:
  • an analogue of uncialamycin comprises the formula
  • the invention relates to salts and prodrugs of uncialamycin and its analogues.
  • the invention also relates to methods of making analogues of uncialamycin.
  • the invention relates to compositions comprising an effective amount of uncialamycin, or analogues, salts, or prodrugs thereof, and a pharmaceutically acceptable carrier.
  • Such compositions include orally administrable, injectable, and topically applicable compositions.
  • Such compositions also include antibody conjugates comprising uncialamycin, or analogues, salts, or prodrugs thereof, conjugated to an antibody through a linker.
  • Such compositions also include other useful forms of uncialamycin, or analogues, salts, or prodrugs thereof, such as powders and solutions.
  • the invention relates to methods of administering the compositions by administering effective amounts of uncialamycin.
  • the invention relates to methods of using the compound or compositions thereof as antibiotics.
  • the invention also relates to methods of using the compound or compositions as bacteriostatic or bactericidal agents to inhibit bacterial growth or to kill bacteria.
  • the bacteria include Staphylococcus aureus, Escherichia coli, and Burkholderia cepacia complex.
  • the compound or compositions can also be used against multidrug resistant bacteria.
  • the invention relates to methods of using the compound or compositions thereof as antitumor and anticancer agents.
  • Figure 1 depicts HMBC correlations used to identify two major fragments A and B of uncialamycin (1).
  • Figure 2 is a photograph of pBR322 plasmid DNA samples incubated with uncialamycin for 15 minutes, analyzed by polyacrylamide gel electrophoresis.
  • Figure 3 is a photograph of pBR322 plasmid DNA samples incubated with uncialamycin for 3 hours, analyzed by polyacrylamide gel electrophoresis.
  • the invention relates to a novel enediyne compound.
  • the compound is uncialamycin and has the following structure:
  • the invention relates to analogues of uncialamycin having the following formula:
  • X can be H and Y can
  • the analogue comprises the formula
  • the analogue comprises the formula
  • R 1 , R 2 , and R 4 are acetyl groups (Ac) and R 3 is H.
  • Ri and R 4 are acetyl groups (Ac), and R 2 and R 3 are H.
  • R 2 and R 4 are acetyl groups (Ac), and Ri and R 3 are H.
  • R 4 is an acetyl group (Ac), and Ri , R 2 and R 3 are H.
  • R 4 is an acyl group, and R 1 , R 2 and R 3 are H.
  • R 4 is a linker to an antibody, and R 1 , R 2 and R 3 are H.
  • R 4 is a linker to an antibody
  • Ri and R 2 are acetyl groups (Ac)
  • R 3 is H.
  • R b R 2 , and R 4 are acetyl groups (Ac)
  • R 3 is a linker to an antibody.
  • an analogue of uncialamycin comprises the formula
  • the invention in another aspect, relates to salts and prodrugs of uncialamycin and its analogues.
  • the invention includes organometallic derivatives of uncialamycin and its analogues.
  • the invention also relates to methods of making analogues of uncialamycin.
  • Various analogues of uncialamycin can be derived from uncialamycin using any of the following schemes or any combinations thereof.
  • R may be methyl or a simple alkyl such as ethyl, propyl, butyl, etc. Many other R substituents are also possible.
  • R 3 may be as defined above, for example.
  • analogues with different acyl or alkyl groups can be created by using different acylation or alkylation reagents.
  • compositions comprising an effective amount of uncialamycin and pharmaceutically acceptable carriers.
  • Such compositions include compositions comprising analogues, salts, or prodrugs of uncialamycin and pharmaceutically acceptable carriers.
  • An effective amount of uncialamycin is an amount that is effective to treat a bacterial infection, to inhibit bacterial growth, to kill bacteria, to treat tumors, to inhibit growth of tumor cells, to kill tumor cells, to treat cancer, to inhibit cancers cells, or to kill cancer cells.
  • Suitable pharmaceutically acceptable carriers are also known to persons skilled in the art, including, but not limited to, suspending agents, flavorings, sweeteners, colorants, coatings, etc.
  • compositions can be orally administrable, injectable, topically applied, or supplied in other suitable forms.
  • Orally administrable compositions include compositions in the form of a tablet, a powder, a suspension, an emulsion, a capsule, a granule, a lozenge, a pill, a liquid, a syrup, or any other appropriate orally administrable form.
  • the injectable compositions include compositions in the form of a liquid, a suspension, a solution, or any other suitable injectable form.
  • the topical compositions include compositions in the form of a paste, an ointment, a liquid, a powder, a plaster, a suppository, an aerosol, a liniment, a lotion, an enema, an emulsion, or any other suitable topical form.
  • Other forms of administering or otherwise providing the compositions are also contemplated, such as powder forms and solutions.
  • compositions also include antibody conjugates comprising uncialamycin, or analogues, salts, or prodrugs thereof, conjugated to an antibody.
  • the antibodies of these conjugates can be monoclonal antibodies, or any other suitable antibodies, which target bacterial antigens, tumor cell antigens, cancer cell antigens, or any other suitable antigens.
  • Such conjugates can assist in delivering uncialamycin, or analogues, salts, or prodrugs thereof, to sites of infection or sites of tumor or cancer growth.
  • Uncialamycin, or analogues, salts, or prodrugs thereof can be bonded to antibodies by any bonding method known to persons skilled in the art including, but not limited to, non-covalent bonds and covalent bonds, including cleavable and non-cleavable linkers. Such bonds include, but are not limited to, peptide linkers, saccharide linkers, sulfide linkers, etc. [0030] In another aspect, the invention relates to methods of using uncialamycin or compositions thereof. Uncialamycin demonstrates inhibitory activity against both gram positive and gram negative bacteria, but does not exhibit inhibitory activity against yeasts.
  • the invention relates to methods of using uncialamycin, or compositions thereof, as an antibiotic to treat bacterial infections in humans or other animals having a bacterial infection.
  • uncialamycin, or compositions thereof can be used as a bacteriostatic agent to inhibit bacterial growth, either in vitro or in vivo.
  • uncialamycin, or compositions thereof can be used as a bactericidal agent to kill bacteria, either in vitro or in vivo.
  • the bacteria can comprise gram positive or gram negative bacteria, including, but not limited to, Staphylococcus aureus, Escherichia coli and Burkholderia cepacia.
  • uncialamycin is effective against Burkholderia cepacia complex (Bcc), a group of nine species of Gram-negative non-sporulating bacilli that have emerged as serious opportunistic human pathogens in cystic fibrosis and immunocompromised patients. Because uncialamycin is a novel antibiotic, in another aspect of the invention, uncialamycin, or compositions thereof, are also useful to treat antibiotic resistant bacteria, including multidrug resistant (MDR) bacteria.
  • Mcc Burkholderia cepacia complex
  • the invention also relates to methods of using uncialamycin or compositions thereof to treat tumors in humans or other animals in need of treatment, to inhibit growth of tumor cells in vivo or in vitro, to kill tumor cells in vivo or in vitro, to treat cancer in humans or other animals in need of treatment, to inhibit growth of cancer cells in vivo or in vitro, or to kill cancer cells in vivo or in vitro.
  • the invention also relates to methods of administering the compositions such that uncialamycin, or analogues, salts, or prodrugs thereof, are administered in a therapeutically effective dose. Such doses would be well within the skill of a physician or other persons skilled in the art to determine.
  • the producing strain was extracted from the surface of the lichen Cladonia uncialis collected near Pitt River, British Columbia. Characterisation by 16S RNA sequencing showed the strain to be related, but not identical, to Streptomyces cyanogenus. Antibiotic activity of the strain was assayed by cutting plugs from solid agar cultures of the strain and placing them on lawns of tester strains of bacteria. Good inhibitory activity was detected against Gram-positive and Gram-negative bacteria (including Bcc), but not against yeasts.
  • the EtOAc soluble material was fractionated by sequential application of flash C- 18 reversed-phase chromatography (eluent: step gradient from H 2 O to MeOH) and reversed-phase HPLC (column-Inertsil ODS-2; eluent: CH 3 CN/H 2 O 40:60) to give pure uncialamycin (1) ( ⁇ 300 ⁇ g) as a bright purple [UV(MeOH): ⁇ max nm ( ⁇ ) 206 (25,000), 254 (33,000), 280 (shoulder), 320 (shoulder), 539 (9,400)], optically active ([ ⁇ ] D +3,300 (c 0.005, MeOH)) oil.
  • This set of four HMBC correlations indicated that the two oxygenated carbons bridged the C- 17 and C-24 carbons to form a ten membered ring (C- 16 to C-25) containing the enediyne substructure.
  • HMBC correlations observed between the proton resonance at ⁇ 8.23 (H-6) and a carbon resonance at 187.0 (C-4) and between the proton resonance at 8.24 (H-8) and a carbon resonance at 182.2 (C-11) suggested that the other two subsituents on the benzene ring were quinone carbonyls.
  • Fragments A and B shown in Figure 1 accounted for all of the carbon, hydrogen, and nitrogen atoms in the molecular formula of uncialamycin (1), but contained one extra oxygen atom.
  • the two carbonyl carbons of fragment B (C-4 and C-I l) had to be attached to the two substituted aromatic carbons (C-3 and C- 12) of fragment A.
  • the two oxygentated carbons C- 16 and C-25 had to be bridged by an epoxide to account for the number of oxygen atoms and sites of unsaturation required by the molecular formula of 1. This implied that the C- 13 oxygen substituent had to be part of a phenol functionality that would engage in intramolecular hydrogen bonding with the C-I l carbonyl consistent with the observed OH chemical shift of ⁇ 13.2.
  • Comparison of the additional NMR assigments reported for dynemicin A (2) and its triacetate derivative provided further strong support for the assigned structure of uncialamycin
  • Uncialamycin (1) shows potent in vitro antibacterial activity against Staphylococcus aureus (Minimal Inhibitory Concentration (MIC) 0.0000064 ⁇ g/mL), Escherichia coli (MIC 0.002 ⁇ g/mL) and Burkholderia cepacia (MIC 0.001 ⁇ g/mL).
  • MIC Minimum Inhibitory Concentration
  • B. cepacia K56-2, C2822, CEP559, C3430, and CEP1016 were sensitive to uncialamycin at low concentrations.
  • Candida albicans and Sacchromyces cerevisiae were not sensitive at relatively high concentrations of uncialamycin.
  • MICs were determined as follows.
  • Lane 1 control (no drug) + DTT
  • Lane 2 control (no drug) +NADPH
  • Lane 3 20 ⁇ M drug
  • Lane 4 20 ⁇ M drug +NADPH
  • Lane 5 20 ⁇ M drug + DTT
  • lane 6 10 ⁇ M drug + DTT
  • lanes 7 and 8 contain size standard markers. Lanes 4, 5, and 6 show degradation of DNA.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Cette invention concerne un nouveau composé d'énédiyne, l'uncialamycine, et ses analogues. Elle concerne également des méthodes d'utilisation du composé pour traiter des infections bactériennes, inhiber la croissance bactérienne, et tuer des bactéries. Le composé de l'invention peut également être utilisé pour traiter des tumeurs, empêcher la croissance de cellules tumorales, tuer des cellules tumorales, traiter des cancers, empêcher la croissance de cellules cancéreuses, et tuer des cellules cancéreuses. L'invention concerne aussi des méthodes de production d'analogues d'uncialamycine. Elle concerne en outre des compositions comprenant l'uncialamycine et des méthodes d'administration des compositions de l'invention.
PCT/CA2006/001634 2005-10-03 2006-10-03 Nouveau compose d'enediyne et ses utilisations WO2007038868A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US72240705P 2005-10-03 2005-10-03
US60/722,407 2005-10-03

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WO2007038868A2 true WO2007038868A2 (fr) 2007-04-12
WO2007038868A3 WO2007038868A3 (fr) 2007-11-08

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Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013122823A1 (fr) 2012-02-13 2013-08-22 Bristol-Myers Squibb Company Composés d'ènediyne, leurs conjugués ainsi qu'utilisations et procédés s'y rattachant
WO2015023879A1 (fr) * 2013-08-14 2015-02-19 William Marsh Rice University Dérivés de l'uncialamycine, procédés de synthèse et leur utilisation comme agents anti-tumoraux
WO2015143156A1 (fr) 2014-03-20 2015-09-24 Bristol-Myers Squibb Company Molécules de charpente à base de fibronectine stabilisée
WO2016081748A2 (fr) 2014-11-21 2016-05-26 Bristol-Myers Squibb Company Anticorps anti-cd73 et leurs utilisations
WO2016086021A1 (fr) 2014-11-25 2016-06-02 Bristol-Myers Squibb Company Nouveaux polypeptides fixant pd-l1 pour l'imagerie
WO2016112282A1 (fr) * 2015-01-08 2016-07-14 The Scripps Research Institute Candidats médicamenteux anticancéreux
WO2016144608A1 (fr) 2015-03-10 2016-09-15 Bristol-Myers Squibb Company Anticorps pouvant être conjugués par la transglutaminase et conjugués ainsi obtenus
WO2016196228A1 (fr) 2015-05-29 2016-12-08 Bristol-Myers Squibb Company Anticorps anti-ox40 et leurs utilisations
WO2017049139A3 (fr) * 2015-09-17 2017-05-04 The Scripps Research Institute Immunoconjugués à double domaine variable et leurs utilisations
WO2017112624A1 (fr) 2015-12-21 2017-06-29 Bristol-Myers Squibb Company Anticorps variants pour conjugaison spécifique à un site
WO2017152085A1 (fr) 2016-03-04 2017-09-08 Bristol-Myers Squibb Company Polythérapie avec des anticorps anti-cd73
WO2018048975A1 (fr) 2016-09-09 2018-03-15 Bristol-Myers Squibb Company Utilisation d'un anticorps anti-pd-1 en combinaison avec un anticorps anti-mésothéline dans le traitement du cancer
WO2018218056A1 (fr) 2017-05-25 2018-11-29 Birstol-Myers Squibb Company Anticorps comprenant des régions constantes de chaîne lourde modifiées
WO2020112588A1 (fr) 2018-11-30 2020-06-04 Bristol-Myers Squibb Company Anticorps comprenant une extension c-terminale de chaîne légère contenant de la glutamine, conjugués de celui-ci, et méthodes et utilisations
WO2020112781A1 (fr) 2018-11-28 2020-06-04 Bristol-Myers Squibb Company Anticorps comprenant des régions constantes de chaîne lourde modifiées
WO2020123425A2 (fr) 2018-12-12 2020-06-18 Bristol-Myers Squibb Company Anticorps modifiés pour la conjugaison de la transglutaminase, conjugués associés, et méthodes et utilisations
EP3733698A1 (fr) 2015-09-23 2020-11-04 Bristol-Myers Squibb Company Molécules à échafaudage à base de fibronectine se liant à la glypicane-3
EP3789399A1 (fr) 2014-11-21 2021-03-10 Bristol-Myers Squibb Company Anticorps comprenant des régions constantes de chaîne lourde modifiées
WO2021055306A1 (fr) 2019-09-16 2021-03-25 Bristol-Myers Squibb Company Méthode de capture double d'analyse de conjugués anticorps-médicament
CN116813627A (zh) * 2023-06-15 2023-09-29 哈药慈航制药股份有限公司 一种天赐霉素类似物及其制备方法和应用

Citations (1)

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US5849750A (en) * 1994-07-27 1998-12-15 California Institute Of Technology Dynemicin analogs

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5849750A (en) * 1994-07-27 1998-12-15 California Institute Of Technology Dynemicin analogs

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DAVIES ET AL.: 'UNCIALAMYCIN, A NEW ENEDIYNE ANTIBIOTIC' ORGANIC LETTERS vol. 7, no. 23, 13 October 2005, pages 5233 - 5236 *

Cited By (39)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013122823A1 (fr) 2012-02-13 2013-08-22 Bristol-Myers Squibb Company Composés d'ènediyne, leurs conjugués ainsi qu'utilisations et procédés s'y rattachant
US9156850B2 (en) 2012-02-13 2015-10-13 Bristol-Myers Squibb Company Enediyne compounds, conjugates thereof, and uses and methods therefor
CN104220441A (zh) * 2012-02-13 2014-12-17 百时美施贵宝公司 烯二炔化合物、其缀合物及其用途和方法
EA027925B1 (ru) * 2012-02-13 2017-09-29 Бристол-Майерс Сквибб Компани Ендиины, их конъюгаты и способы их получения и применения
JP2015508074A (ja) * 2012-02-13 2015-03-16 ブリストル−マイヤーズ スクイブ カンパニーＢｒｉｓｔｏｌ−Ｍｙｅｒｓ Ｓｑｕｉｂｂ Ｃｏｍｐａｎｙ エンジイン化合物、その抱合体、ならびにその使用および方法
CN104220441B (zh) * 2012-02-13 2017-03-29 百时美施贵宝公司 烯二炔化合物、其缀合物及其用途和方法
US8709431B2 (en) 2012-02-13 2014-04-29 Bristol-Myers Squibb Company Enediyne compounds, conjugates thereof, and uses and methods therefor
JP2016534105A (ja) * 2013-08-14 2016-11-04 ウィリアム マーシュ ライス ユニバーシティＷｉｌｌｉａｍ Ｍａｒｓｈ Ｒｉｃｅ Ｕｎｉｖｅｒｓｉｔｙ ウンシアラマイシン誘導体、合成方法、および抗腫瘍薬としてのそれらの使用
US9777013B2 (en) 2013-08-14 2017-10-03 William Marsh Rice University Derivatives of uncialamycin, methods of synthesis and their use as antitumor agents
US10233192B2 (en) 2013-08-14 2019-03-19 William Marsh Rice University Derivatives of uncialamycin, methods of synthesis and their use as antitumor agents
CN105899515A (zh) * 2013-08-14 2016-08-24 威廉马歇莱思大学 uncialamycin的衍生物、合成方法及其作为抗肿瘤剂的用途
WO2015023879A1 (fr) * 2013-08-14 2015-02-19 William Marsh Rice University Dérivés de l'uncialamycine, procédés de synthèse et leur utilisation comme agents anti-tumoraux
AU2014306592B2 (en) * 2013-08-14 2019-04-04 Bristol-Myers Squibb Company Derivatives of uncialamycin, methods of synthesis and their use as antitumor agents
US10889590B2 (en) 2013-08-14 2021-01-12 William Marsh Rice University Derivatives of uncialamycin, methods of synthesis and their use as antitumor agents
WO2015143156A1 (fr) 2014-03-20 2015-09-24 Bristol-Myers Squibb Company Molécules de charpente à base de fibronectine stabilisée
EP3647322A1 (fr) 2014-03-20 2020-05-06 Bristol-Myers Squibb Company Molécules de charpente à base de fibronectine stabilisée
EP3725808A1 (fr) 2014-11-21 2020-10-21 Bristol-Myers Squibb Company Anticorps anti-cd73 et leurs utilisations
EP3789399A1 (fr) 2014-11-21 2021-03-10 Bristol-Myers Squibb Company Anticorps comprenant des régions constantes de chaîne lourde modifiées
WO2016081748A2 (fr) 2014-11-21 2016-05-26 Bristol-Myers Squibb Company Anticorps anti-cd73 et leurs utilisations
EP3702367A1 (fr) 2014-11-25 2020-09-02 Bristol-Myers Squibb Company Nouveaux polypeptides de liaison pd-l1 pour imagerie
WO2016086021A1 (fr) 2014-11-25 2016-06-02 Bristol-Myers Squibb Company Nouveaux polypeptides fixant pd-l1 pour l'imagerie
WO2016112282A1 (fr) * 2015-01-08 2016-07-14 The Scripps Research Institute Candidats médicamenteux anticancéreux
CN107531720A (zh) * 2015-01-08 2018-01-02 斯克利普斯研究院 抗癌症候选药物
WO2016144608A1 (fr) 2015-03-10 2016-09-15 Bristol-Myers Squibb Company Anticorps pouvant être conjugués par la transglutaminase et conjugués ainsi obtenus
WO2016196228A1 (fr) 2015-05-29 2016-12-08 Bristol-Myers Squibb Company Anticorps anti-ox40 et leurs utilisations
CN108025071A (zh) * 2015-09-17 2018-05-11 斯克利普斯研究院 双重可变结构域免疫缀合物及其用途
CN108025071B (zh) * 2015-09-17 2022-11-01 斯克利普斯研究院 双重可变结构域免疫缀合物及其用途
WO2017049139A3 (fr) * 2015-09-17 2017-05-04 The Scripps Research Institute Immunoconjugués à double domaine variable et leurs utilisations
EP3733698A1 (fr) 2015-09-23 2020-11-04 Bristol-Myers Squibb Company Molécules à échafaudage à base de fibronectine se liant à la glypicane-3
WO2017112624A1 (fr) 2015-12-21 2017-06-29 Bristol-Myers Squibb Company Anticorps variants pour conjugaison spécifique à un site
WO2017152085A1 (fr) 2016-03-04 2017-09-08 Bristol-Myers Squibb Company Polythérapie avec des anticorps anti-cd73
WO2018048975A1 (fr) 2016-09-09 2018-03-15 Bristol-Myers Squibb Company Utilisation d'un anticorps anti-pd-1 en combinaison avec un anticorps anti-mésothéline dans le traitement du cancer
WO2018218056A1 (fr) 2017-05-25 2018-11-29 Birstol-Myers Squibb Company Anticorps comprenant des régions constantes de chaîne lourde modifiées
EP4098662A1 (fr) 2017-05-25 2022-12-07 Bristol-Myers Squibb Company Anticorps comprenant des régions constantes de chaîne lourde modifiées
WO2020112781A1 (fr) 2018-11-28 2020-06-04 Bristol-Myers Squibb Company Anticorps comprenant des régions constantes de chaîne lourde modifiées
WO2020112588A1 (fr) 2018-11-30 2020-06-04 Bristol-Myers Squibb Company Anticorps comprenant une extension c-terminale de chaîne légère contenant de la glutamine, conjugués de celui-ci, et méthodes et utilisations
WO2020123425A2 (fr) 2018-12-12 2020-06-18 Bristol-Myers Squibb Company Anticorps modifiés pour la conjugaison de la transglutaminase, conjugués associés, et méthodes et utilisations
WO2021055306A1 (fr) 2019-09-16 2021-03-25 Bristol-Myers Squibb Company Méthode de capture double d'analyse de conjugués anticorps-médicament
CN116813627A (zh) * 2023-06-15 2023-09-29 哈药慈航制药股份有限公司 一种天赐霉素类似物及其制备方法和应用

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