HRP20221280T1 - Spojevi i njihovi konjugati - Google Patents

Spojevi i njihovi konjugati Download PDF

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HRP20221280T1
HRP20221280T1 HRP20221280TT HRP20221280T HRP20221280T1 HR P20221280 T1 HRP20221280 T1 HR P20221280T1 HR P20221280T T HRP20221280T T HR P20221280TT HR P20221280 T HRP20221280 T HR P20221280T HR P20221280 T1 HRP20221280 T1 HR P20221280T1
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HRP20221280TT
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Philip Wilson Howard
Niall DICKINSON
Thais CAILLEAU
Luke Masterson
William Goundry
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Medimmune Limited
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First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=69960637&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=HRP20221280(T1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
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Publication of HRP20221280T1 publication Critical patent/HRP20221280T1/hr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
    • C07K5/06052—Val-amino 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • 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
    • A61K47/545—Heterocyclic compounds
    • 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
    • A61K47/62—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 a protein, peptide or polyamino acid
    • A61K47/65—Peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers
    • 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
    • A61K47/68—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 antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • 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
    • A61K47/68—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 antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A61K47/68037—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a camptothecin [CPT] or derivatives
    • 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
    • A61K47/68—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 antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—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 antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6851—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 antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
    • A61K47/6855—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 antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell the tumour determinant being from breast cancer cell
    • 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
    • A61K47/68—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 antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6889—Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • C07D491/22—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 four or more hetero rings
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
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Claims (17)

1. Spoj s formulom I: [image] i njegove soli i solvati, pri čemu je RL poveznica za spajanje s protutijelom ili antigen-vezujući fragment protutijela, koji je odabran od: (Ia): [image] pri čemu Q je: [image] gdje Qx je takav da je Q aminokiselinski ostatak, dipeptidni ostatak, tripeptidni ostatak ili tetrapeptidni ostatak, i pri čemu oznake gornjih indeksa C(=O) i NH označavaju skupinu na koju su atomi vezani; X je: [image] , gdje a = 0 do 5, b1 = 0 do 16, b2 = 0 do 16, c1 = 0 ili 1, c2 = 0 ili 1, d = 0 do 5, pri čemu najmanje b1 ili b2 = 0 i najmanje c1 ili c2 = 0; GL je poveznica za spajanje na protutijelo ili fragment protutijela koji veže antigen, pri čemu je GL odabran od [image] gdje Ar predstavlja C5-6 arilensku skupinu, i X' predstavlja C1-4 alkil; (Ib): [image] gdje su RL1 i RL2 neovisno odabrani između H i metila, ili zajedno s atomom ugljika na koji su vezani tvore ciklopropilensku ili ciklobutilensku skupinu; i e je 0 ili 1.
2. Spoj prema zahtjevu 1, naznačen time što RL je s formulom Ia, i pri čemu Q je: (a) aminokiselinski ostatak odabran od: Phe, Lys, Val, Ala, Cit, Leu, Ile, Arg, i Trp; ili (b) dipeptidni ostatak odabran od: NH-Phe-Lys-C=O, NH-Val-Ala- c=o, NH-Val-Lys- c=o, NHAla-Lys- c=o, NH-Val-Cit- c=o, NH-Phe-Cit- c=o, NH-Leu-Cit- c=o, NH-Ile-Cit- c=o, NH-Phe-Arg- c=o, HH-Trp-Cit- c=o, i NH-Gly-Val- c=o; ili (c) tripeptidni ostatak odabran od: NH-Glu-Val-Ala-c=o, NH-Glu-Val-Cit-c=o, NH-αGlu-Val-Ala-c=o, i NH-αGlu-Val-Cit-c=o; ili (d) tetrapeptidni ostatak odabran od: NH-Gly-Gly-Phe-Gly- c=o; i NH-Gly-Phe-Gly-Gly- c=o., pri čemu NH-predstavlja N-terminalni kraj, i -c=o predstavlja C-terminalni kraj ostatka.
3. Spoj prema zahtjevu 2, naznačen time što a je: (a) 0 do 3; ili (b) 0 ili 1; ili (c) 0, i dalje po izboru pri čemu b1 je: (a) 0 do 8; ili (b) 0; ili (c) 2; ili (d) 3; ili (e) 4; ili (f) 5; ili (g) 8. i još dalje po izboru pri čemu b2 je: (a) 0 do 8; ili (b) 0; ili (c) 2; ili (d) 3; ili (e) 4; ili (f) 5; ili (g) 8.
4. Spoj prema zahtjevu 2 ili zahtjevu 3, naznačen time što (i) c1 je: (a) 0; ili (b) 1; i (ii) c2 je: (a) 0; ili (b) 1; pri čemu najmanje jedan od c1 i c2 je 0, i po izboru pri čemu d je: (a) 0 do 3; ili (b) 1 ili 2; ili (c) 2; ili (d) 5.
5. Spoj prema bilo kojem od patentnih zahtjeva 2 do 4, naznačen time što: (a) a je 0, b1 je 0, c1 je 1, c2 je 0 i d je 2, i b2 je 0, 2, 3, 4, 5 ili 8; ili (b) a je 1, b2 je 0, c1 je 0, c2 je 0 i d je 0, i b1 je 0, 2, 3, 4, 5 ili 8; ili (c) a je 0, b1 je 0, c1 je 0, c2 je 0 i d je 1, i b2 je 0, 2, 3, 4, 5 ili 8; ili (d) b1 je 0, b2 je 0, c1 je 0, c2 je 0, jedan od a i d je 0, i drugi od a i d je 1 ili 5; ili (e) a je 1, b2 je 0, c1 je 0, c2 je 1, d je 2, i b1 je 0, 2, 3, 4, 5 ili 8.
6. Spoj prema bilo kojem od zahtjeva 1 do 5, naznačen time što je GL odabran od GL1-1 i GL1-2.
7. Spoj prema zahtjevu 1, naznačen time što RL je s formulom Ib, i: (a) oba RL1 i RL2 su H; ili (b) RL1 je H i RL2 je metil; ili (c) oba RL1 i RL2 su metil; ili (d) pri čemu RL1 i RL2 zajedno s atomom ugljika za koji su oni vezani tvore ciklopropilensku skupinu; ili (e) pri čemu RL1 i RL2 zajedno s atomom ugljika za koji su oni vezani tvore ciklobutilensku skupinu.
8. Spoj prema zahtjevu 1 naznačen time što je 1-(3-(2,5-diokso-2,5-dihidro-1H-pirol-1-il)propanamido)-N-((S)-1-(((S)-1-(((S)-9-etil-9-hidroksi-10,13-diokso-2,3,9,10,13,15-heksahidro-1H,12H-benzo[de]pirano[3',4':6,7]indolizino[1,2-b]kinolin-4-il)amino)-1-oksopropan-2-il)amino)-3-metil-1-oksobutan-2-il)-3,6,9,12,15,18,21,24-oktaoksaheptakozan-27-amid.
9. Spoj prema zahtjevu 1 naznačen time što je (S)-2-(2-(2-(2-(2-azidoetoksi)etoksi)etoksi)acetamido)-N-((S)-1-(((S)-9-etil-9-hidroksi-10,13-diokso-2,3,9,10,13,15-heksahidro-1H,12H-benzo[de]pirano[3',4':6,7]indolizino[1,2-b]kinolin-4-il)amino)-1-oksopropan-2-il)-3-metilbutanamid.
10. Spoj prema zahtjevu 1 naznačen time što je N-((S)-1-(((S)-1-(((S)-9-etil-9-hidroksi-10,13-diokso-2,3,9,10,13,15-heksahidro-1H,12H-benzo[de]pirano[3',4':6,7]indolizino[1,2-b]kinolin-4-il)amino)-1-oksopropan-2-il)amino)-3-metil-1-oksobutan-2-il)-4,7,10,13,16-pentaoksanonadek-18-inamid.
11. Konjugat s formulom IV: L -(DL)p (IV) ili njegova farmaceutski prihvatljiva sol ili solvat, pri čemu L je jedinica liganda, DL je jedinica za povezivanje lijeka koja ima formulu III: [image] RLL je poveznica spojena s jedinicom liganda odabranom od (Ia'): [image] gdje Q i X su kako je definirano u bilo kojem od zahtjeva 1 do 5 i GLL je poveznica spojena s jedinicom liganda, pri čemu je GLL odabran od: [image] gdje Ar predstavlja C5-6 arilensku skupinu i X' predstavlja C1-4 alkil; i (Ib'): [image] gdje su RL1 i RL2 definirani u bilo kojem zahtjevu 1 ili zahtjevu 7; i p je cijeli broj od 1 do 20, i pri čemu jedinica liganda je protutijelo ili njegov aktivni fragment.
12. Konjugat prema zahtjevu 11, naznačen time što GLL je odabran od GLL1-1 i GLL1-2.
13. Konjugat prema zahtjevu 11, naznačen time što Q je dipeptidni ostatak koji je NH -Val-Ala-C=O, a je 0, b1 je 0, c1 je 1, c2 je 0 i d je 2, b2 je 8 i GLL je GLL1-1, pri čemu NH-predstavlja N-terminalni kraj, i -C=O predstavlja C-terminalni kraj ostatka.
14. Konjugat prema bilo kojem od patentnih zahtjeva 11 do 13, naznačen time što je opterećenje lijeka (p) lijekova (D) na antitijelo (Ab) cijeli broj od 1 do 10.
15. Farmaceutski pripravak naznačen time što sadrži konjugat prema bilo kojem od zahtjeva 11 do 14 i farmaceutski prihvatljiv razrjeđivač, nosač ili pomoćna tvar.
16. Konjugat prema bilo kojem od patentnih zahtjeva 11 do 14, ili farmaceutski pripravak prema zahtjevu 15, naznačen time što je za upotrebu u liječenju raka kod subjekta.
17. Spoj s formulom VI: [image] gdje Q je kao u bilo kojem od zahtjeva 1 ili 2.
HRP20221280TT 2019-03-29 2020-03-23 Spojevi i njihovi konjugati HRP20221280T1 (hr)

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EP20713873.6A EP3946464B1 (en) 2019-03-29 2020-03-23 Compounds and conjugates thereof
PCT/EP2020/057984 WO2020200880A1 (en) 2019-03-29 2020-03-23 Compounds and conjugates thereof

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