NZ758047B2 - Pegylated drug-linkers for improved ligand-drug conjugate pharmacokinetics - Google Patents

Pegylated drug-linkers for improved ligand-drug conjugate pharmacokinetics Download PDF

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Publication number
NZ758047B2
NZ758047B2 NZ758047A NZ75804714A NZ758047B2 NZ 758047 B2 NZ758047 B2 NZ 758047B2 NZ 758047 A NZ758047 A NZ 758047A NZ 75804714 A NZ75804714 A NZ 75804714A NZ 758047 B2 NZ758047 B2 NZ 758047B2
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New Zealand
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drug
unit
linker compound
subscript
alkyl
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NZ758047A
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NZ758047A (en
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Patrick Burke
Joshua Hunter
Robert Lyon
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Seagen Inc
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Application filed by Seagen Inc filed Critical Seagen Inc
Publication of NZ758047A publication Critical patent/NZ758047A/en
Publication of NZ758047B2 publication Critical patent/NZ758047B2/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • 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
    • A61K47/549—Sugars, nucleosides, nucleotides or nucleic acids
    • 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
    • A61K47/56—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 macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—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 macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/60—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 macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
    • 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
    • A61K47/68031—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being an auristatin
    • 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
    • A61K47/6811—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a protein or peptide, e.g. transferrin or bleomycin
    • A61K47/6817—Toxins
    • 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
    • A61K47/6811—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a protein or peptide, e.g. transferrin or bleomycin
    • A61K47/6817—Toxins
    • A61K47/6819—Plant toxins
    • 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
    • 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
    • A61K47/6883—Polymer-drug antibody conjugates, e.g. mitomycin-dextran-Ab; DNA-polylysine-antibody complex or conjugate used for therapy
    • 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
    • A61K47/6883—Polymer-drug antibody conjugates, e.g. mitomycin-dextran-Ab; DNA-polylysine-antibody complex or conjugate used for therapy
    • A61K47/6885—Polymer-drug antibody conjugates, e.g. mitomycin-dextran-Ab; DNA-polylysine-antibody complex or conjugate used for therapy the conjugate or the polymer being a starburst, a dendrimer, a cascade
    • 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
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2878—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/94—Stability, e.g. half-life, pH, temperature or enzyme-resistance

Abstract

The present invention provides Ligand-Drug Conjugates comprising a PEG Unit in a parallel orientation to the Drug Unit. The invention provides inter alia, Ligand-Drug Conjugates (LDCs), methods of preparing and using them, and intermediates thereof. The Ligand-Drug Conjugates are stable in circulation, yet capable of inflicting cell death on targeted cells or inhibiting proliferation of targeted cells once its drug cargo is released in the vicinity or within targeted cells. In principle embodiments, an LDC of the present invention is represented by the structure of Formulae IV, V, and VI, preferably IV.

Claims (17)

WHAT IS CLAIMED IS:
1. A Drug-Linker Compound, wherein the Drug-Linker compound is represented by the structure of formula (IV), (V), or (VI): or a pharmaceutically acceptable salt thereof, wherein D is a Drug Unit, wherein D is a cytotoxic, cytostatic, or immunosuppressive hydrophobic drug; PEG is a Polyethylene Glycol Unit, wherein the PEG Unit comprises a total of 8 to 72 (OCH CH ) subunits and has the structure of: wherein the wavy line indicates a site of attachment of the PEG Unit to L ; R is a PEG Attachment Unit selected from the group consisting of –C(O)-, -O-, -S-, -S(O)-, -NH-, and -C(O)O-,; each R is independently a PEG Capping Unit selected from the group consisting of -C alkyl, and -C alkyl-CO H; 1-10 2-10 2 each R is independently a PEG Coupling Unit selected from the group consisting of -C alkyl-C(O)-NH-, -C alkyl-NH-C(O)-, -C alkyl-NH-, -C alkyl-O- , 1-10 1-10 2-10 2-10 -C alkyl-S-, and –C alkyl-NH-; 1-10 2-10 each subscript n is independently an integer selected from 8 to 72; each subscript e is independently an integer selected from 2 to 5; each subscript n' is independently an integer selected from 6 to 72; Z' is a Stretcher Unit with the structure optionally protected by a tert-butyloxycarbonyl group, wherein the wavy line indicates covalent attachment to the remainder of the Drug-Linker structure; X is a Releasable Assembly Unit, wherein each Releasable Assembly Unit is capable of releasing free drug upon enzymatic cleavage of the Releasable Assembly Unit and has the structure of: wherein Q is an optional Covalent Attachment Unit and, when present, has the structure of: , or , wherein one wavy line indicates covalent attachment to the Cleavable Unit and the other wavy line indicates covalent attachment to L , A, or AD; and R is -C -C alkylene-, -C -C carbocyclo-, -arylene-, -C -C heteroalkylene-, 1 6 3 8 1 10 -C3-C8 heterocyclo-; Q is an optional Spacer Unit; Q is a Cleavable Unit; the asterisk indicates the site of covalent attachment to the Drug Unit; and the wavy line indicates covalent attachment to L or A, wherein the Cleavable Unit is a peptide Cleavable Unit comprising an amino acid or is a peptide sequence with a cleavable bond to Q or D, depending on the presence or absence, respectively, of Q , wherein said cleavable bond is capable of enzymatic cleavage by a tumor associated protease for said releasing of free drug; and wherein the Spacer Unit, when present, has the formula of: wherein Q is -C1-C8 alkyl, -O-(C1-C8 alkyl), -halogen, -nitro, or -cyano; and subscript m is an integer selected from 0-4; and the wavy line adjacent to the nitrogen atom indicates the site of covalent attachment to the dipeptide of the peptide Cleavable Unit and the wavy line adjacent to carbonyl carbon atom indicates the site of covalent attachment to an oxygen or nitrogen atom of the Drug Unit, wherein the Cleavable Unit has the formula of: or , wherein Su is a Sugar moiety; -O'- represents an oxygen glycosidic bond that is capable of enzymatic cleavable by a glycosidase for said free drug release; each R is independently hydrogen, a halogen, -CN, or -NO ; and wherein the wavy line indicates the site of covalent attachment to L or A, depending on the absence or presence of A, respectively, either directly or indirectly through the Covalent Attachment Unit; the asterisk indicates the site of covalent attachment to the Drug Unit, either directly or indirectly through the Spacer Unit; the Spacer Unit when present is –C(=O)-; L is a Parallel Connector Unit, wherein L connects Z to PEG and D such that PEG and D are in a parallel orientation, wherein L has the structure of: , or , wherein the wavy lines indicate the sites of covalent attachment within the Drug-Linker Compound; subscript n is an integer from 1 to 4; X is selected from the group consisting of –O-, -NH-, -S-, -S(=O)-, -C(=O)-, and -C2-C8 heterocyclo-; R and R are independently selected from the group consisting of -H, -C -C alkyl, -phenyl and -C -C heterocycle; A is an optional Branching Unit, wherein each A, when present, is one to 10 independently selected amino acid, amino alcohol, amino aldehyde, or polyamine residues, or a combination thereof, covalently bonded to one another; AD is a Drug Attachment Unit, wherein each AD, when present, is one to 10 independently selected amino acid, amino alcohol, amino aldehyde, or polyamine residues, or a combination thereof, covalently bonded to one another; subscript m is an integer ranging from 1 to 4; and subscript s is 0 or 1, with the proviso that when s is 0, m is 1 and when s is 1, m is 2, 3 or
2. The Drug-Linker Compound of claim 1, wherein the Drug-Linker Compound has the structure of : or a pharmaceutically acceptable salt thereof.
3. The Drug-Linker Compound of claim 1 or 2, wherein subscript s is zero (i.e., A is absent).
4. The Drug-Linker Compound of any one of claims 1 to 3, wherein subscript s is 1 and subscript m is 2 to 4.
5. The Drug-Linker Compound of claim 1, wherein the Drug-Linker has the structure represented by formula IVa, IVb, Va, Vb, Vc, VIa or VIb: or a pharmaceutically acceptable salt thereof.
6. The Drug-Linker Compound of claim 1, wherein the Drug-Linker compound has the structure of: or a pharmaceutically acceptable salt thereof.
7. The Drug-Linker Compound of claim 1, wherein the Drug-Linker Compound has the structure of: or a pharmaceutically acceptable salt thereof.
8. The Drug-Linker Compound of claim 1, wherein the Drug-Linker Compound has the structure of: -O. .N. >\''N ,NH h2n. ,0 or a pharmaceutically acceptable salt thereof.
9. The Drug-Linker Compound of claim 1, wherein the Drug-Linker Compound has the structure of: or a pharmaceutically acceptable salt thereof, wherein R is a PEG Capping Unit and n is an integer ranging from 6 to 72, 8 to 72, or 8 to 24.
10. The Drug-Linker Compound of claim 1, wherein the Drug-Linker Compound has the structure of: or a pharmaceutically acceptable salt thereof wherein R is a PEG Capping Unit and n is 6 to 72, or 8 to 72, or 8 to 24.
11. The Drug-Linker Compound of claim 9 or 10, wherein n is 8, 12, or 24.
12. The Drug-Linker Compound of any one of claims 9 to 11, wherein R is methyl, ethyl or propyl.
13. The Drug-Linker compound of claim 1, wherein the Drug-Linker compound has the structure of: or a pharmaceutically acceptable salt thereof, wherein R is hydrogen or a tert-butyloxycarbonyl protecting group; and n is 8, 10, 12, or 24.
14. The Drug-Linker compound of claim 1, wherein the Drug-Linker compound has the structure of:
15. The Drug-Linker compound of claim 1, wherein the Drug-Linker compound has the structure of:
16. A Ligand-Linker Compound according to claim 1, wherein subscript m is 1 or 2.
17. A Drug-Linker compound as claimed in any one of claims 1 to 16, substantially as herein described and exemplified. Untreated cAC10-1, 2 mg/kg cAC10-4, 2 mg/kg cAC10-10, 2 mg/kg schedule: once, day 10 0 10 20 30 40 50 60 DAYS POST TUMOR IMPLANT
NZ758047A 2014-10-14 Pegylated drug-linkers for improved ligand-drug conjugate pharmacokinetics NZ758047B2 (en)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US201361891320P 2013-10-15 2013-10-15
US201461941904P 2014-02-19 2014-02-19
US201461947742P 2014-03-04 2014-03-04
US201461975318P 2014-04-04 2014-04-04
NZ717668A NZ717668B2 (en) 2014-10-14 Pegylated drug-linkers for improved ligand-drug conjugate pharmacokinetics

Publications (2)

Publication Number Publication Date
NZ758047A NZ758047A (en) 2024-03-22
NZ758047B2 true NZ758047B2 (en) 2024-06-25

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