WO2022040596A1 - Antibody-tlr agonist conjugates, methods and uses thereof - Google Patents

Antibody-tlr agonist conjugates, methods and uses thereof Download PDF

Info

Publication number
WO2022040596A1
WO2022040596A1 PCT/US2021/047009 US2021047009W WO2022040596A1 WO 2022040596 A1 WO2022040596 A1 WO 2022040596A1 US 2021047009 W US2021047009 W US 2021047009W WO 2022040596 A1 WO2022040596 A1 WO 2022040596A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
substituted
antibody
amino acid
linker
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.)
Ceased
Application number
PCT/US2021/047009
Other languages
English (en)
French (fr)
Inventor
Sung-Ju Moon
Brian LEON
Mingchao KANG
Nickolas KNUDSEN
Sukumar Sakamuri
Feng Tian
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.)
Ambrx Inc
Original Assignee
Ambrx Inc
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 Ambrx Inc filed Critical Ambrx Inc
Priority to KR1020237009263A priority Critical patent/KR20230073200A/ko
Priority to EP21772883.1A priority patent/EP4199968A1/en
Priority to CN202180071626.XA priority patent/CN116457023A/zh
Priority to JP2023511915A priority patent/JP2023538071A/ja
Priority to CA3190606A priority patent/CA3190606A1/en
Priority to US18/022,099 priority patent/US20230302150A1/en
Priority to AU2021327396A priority patent/AU2021327396A1/en
Publication of WO2022040596A1 publication Critical patent/WO2022040596A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/18—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 one oxygen and one nitrogen atom, e.g. guanine
    • 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
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K47/6835—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
    • A61K47/6849—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 receptor, a cell surface antigen or a cell surface determinant
    • 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
    • A61K47/6851—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
    • A61K47/6835—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
    • A61K47/6869—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 a cell of the reproductive system: ovaria, uterus, testes, prostate
    • 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
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • R2 is C 1 -C 6 alkylene, Ci-C 12 substituted alkylene, C 3 -Cs cycloalkylene, C 3 -Cs substituted cycloalkylene, arylene, substituted arylene, 5-12 membered heteroarylene comprising 1- 3 hetero atoms, substituted 5-12 membered heteroarylene comprising 1-3 hetero atoms, 5-12 membered heterocycloalkylene comprising 1-3 hetero atoms, substituted 5-12 membered heterocycloalkylene comprising 1-3 hetero atoms, or (OCH 2 CH 2 ) r , or combination thereof, or R2 is absent; wherein r is an integer from 1 to 12, wherein each hetero atom is independently N, O or S;
  • the targeting polypeptide comprises one or more amino acid substitution, addition or deletion that increases the stability or solubility of the composition. In another embodiment, the targeting polypeptide comprises one or more amino acid substitution, addition or deletion that enhances/reduces ADCP or ADCC activity. In another embodiment, the targeting polypeptide comprises one or more amino acid substitution, addition or deletion that increases pharmacokinetics of the composition. In other embodiments, the composition comprises one or more amino acid substitution, addition or deletion that increases the expression of the targeting polypeptide in a recombinant host cell or synthesized in vitro.
  • the TLR agonist comprising a structure according to Formula I or Formula II further comprising a PEG shield.
  • the anti-HER2 antibody or antibody fragment comprises a) SEQ ID NO: 18; and b) any one of SEQ ID NOs: 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15.
  • the anti- HER2 antibody or antibody fragment comprises a mutation in the heavy chain disclosed in Table 9A; and b) any one of SEQ ID NOs: 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15.
  • the anti-HER2 antibody or antibody fragment comprises SEQ ID NO: 1 and SEQ ID NO: 5.
  • the anti-HER2 antibody or antibody fragment comprises SEQ ID NO: 1 and SEQ ID NO: 6.
  • the anti-HER2 antibody or antibody fragment comprises SEQ ID NO: 1 and SEQ ID NO: 7.
  • Figure 1 depicts the general structures of TLR agonists
  • FIGs 20A-20B show additional Trop2 ISACs in vitro activities in Trop2 positive HCC1806 ( Figure 20A) and Trop2 negative HCC1395 ( Figure 20B) cell line by Raw-Blue coculture assay.
  • Figures 26A-26B show PK profiles of HER2-AXC879 (Figure 26A) and HER2- AXC863 ( Figure 26B) after repeated dose in C57/B6 mice.
  • alkyl groups examples include, but are not limited to, vinyl, 2-propenyl, crotyl, 2- isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(l,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3- butynyl, and the higher homologs and isomers.
  • alkyl unless otherwise noted, is also meant to include those derivatives of alkyl defined in more detail herein, such as “heteroalkyl”, “haloalkyl” and “homoalkyl”.
  • Amino acids may be referred to herein by either their name, their commonly known three letter symbols or by the one-letter symbols recommended by the IUPAC-IUB Biochemical Nomenclature Commission. Additionally, nucleotides, may be referred to by their commonly accepted single-letter codes.
  • tumor-targeting moiety conjugate As used herein, the term “tumor-targeting moiety conjugate” "tumor-targeting moiety-biologically active molecule conjugate” or “BTC” refers to a tumor targeting polypeptide or a portion, analog or derivative thereof that binds to a target present on tumor cells or subunit thereof conjugated to a biologically active molecule, a portion thereof or an analog thereof, including but not limited to a TLR7 and/or a TLR8 agonist. Unless otherwise indicated, the terms “compound of the invention” and “composition of the invention” are used as alternatives for the term “conjugate of the invention.”
  • “conservatively modified variants” applies to both natural and non-natural amino acid and natural and non-natural nucleic acid sequences, and combinations thereof.
  • “conservatively modified variants” refers to those natural and non-natural nucleic acids which encode identical or essentially identical natural and non-natural amino acid sequences, or where the natural and non-natural nucleic acid does not encode a natural and non-natural amino acid sequence, to essentially identical sequences.
  • the codons GCA, GCC, GCG and GCU all encode the amino acid alanine.
  • amino acid sequences individual substitutions, deletions or additions to a nucleic acid, peptide, polypeptide, or protein sequence which alters, adds or deletes a single natural and non-natural amino acid or a small percentage of natural and non-natural amino acids in the encoded sequence is a “conservatively modified variant” where the alteration results in the deletion of an amino acid, addition of an amino acid, or substitution of a natural and non-natural amino acid with a chemically similar amino acid. Conservative substitution tables providing functionally similar natural amino acids are well known in the art. Such conservatively modified variants are in addition to and do not exclude polymorphic variants, interspecies homologs, and alleles of the methods and compositions described herein.
  • cycloalkyl examples include, but are not limited to, cyclopentyl, cyclohexyl, 1 -cyclohexenyl, 3 -cyclohexenyl, cycloheptyl, and the like.
  • cyclodextrin refers to cyclic carbohydrates consisting of at least six to eight glucose molecules in a ring formation.
  • the outer part of the ring contains water- soluble groups; at the center of the ring is a relatively nonpolar cavity able to accommodate small molecules.
  • oxidizing agent refers to a compound or material which is capable of removing an electron from a compound being oxidized.
  • oxidizing agents include, but are not limited to, oxidized glutathione, cystine, cystamine, oxidized dithiothreitol, oxidized erythreitol, and oxygen.
  • oxidizing agents are suitable for use in the methods and compositions described herein.
  • the molecular weight of the branched chain PEG may be between about 1,000 Da and about 100,000 Da, including but not limited to, about 100,000 Da, about 95,000 Da, about 90,000 Da, about 85,000 Da, about 80,000 Da, about 75,000 Da, about 70,000 Da, about 65,000 Da, about 60,000 Da, about 55,000 Da, about 50,000 Da, about 45,000 Da, about 40,000 Da, about 35,000 Da, about 30,000 Da, about 25,000 Da, about 20,000 Da, about 15,000 Da, about 10,000 Da, about 9,000 Da, about 8,000 Da, about 7,000 Da, about 6,000 Da, about 5,000 Da, about 4,000 Da, about 3,000 Da, about 2,000 Da, and about 1,000 Da.
  • polypeptide refers to a polymer of amino acid residues. That is, a description directed to a polypeptide applies equally to a description of a peptide and a description of a protein, and vice versa. The terms apply to naturally occurring amino acid polymers as well as amino acid polymers in which one or more amino acid residues is a non-natural amino acid. Additionally, such “polypeptides,” “peptides” and “proteins” include amino acid chains of any length, including full length proteins, wherein the amino acid residues are linked by covalent peptide bonds.
  • Stringent hybridization conditions include, but are not limited to, (i) about 5-10 °C lower than the thermal melting point (Tm) for the specific sequence at a defined ionic strength and pH; (ii) the salt concentration is about 0.01 M to about 1.0 M at about pH 7.0 to about pH 8.3 and the temperature is at least about 30 °C for short probes (including but not limited to, about 10 to about 50 nucleotides) and at least about 60 °C for long probes (including but not limited to, greater than 50 nucleotides); (iii) the addition of destabilizing agents including, but not limited to, formamide, (iv) 50% formamide, 5X SSC, and 1% SDS, incubating at 42 °C, or 5X SSC, about 1% SDS, incubating at 65 °C, with wash in 0.2X SSC, and about 0.1% SDS at 65 °C for between about 5 minutes to about 120 minutes.
  • Tm thermal melting point
  • detection of selective or specific hybridization includes, but is not limited to, a positive signal at least two times background.
  • An extensive guide to the hybridization of nucleic acids is found in Tijssen, Laboratory Techniques in Biochemistry and Molecular Biology— Hybridization with Nucleic Probes, “Overview of principles of hybridization and the strategy of nucleic acid assays” (1993).
  • Compounds, (including, but not limited to non-natural amino acids, non-natural amino acid polypeptides, modified non-natural amino acid polypeptides, and reagents for producing the aforementioned compounds) presented herein include isotopically-labeled compounds, which are identical to those recited in the various formulas and structures presented herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • non-natural amino acids, non-natural amino acid polypeptides and modified non-natural amino acid polypeptides described herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like.
  • solvated forms of the non-natural amino acids, non-natural amino acid polypeptides and modified non-natural amino acid polypeptides presented herein are also considered to be disclosed herein.
  • TLR-agonist linker derivative and the targeting polypeptide, to be modified using the methods, compositions and techniques described herein.
  • the new TLR-agonist linker derivative and the targeting polypeptide may be designed de novo, including by way of example only, as part of high-throughput screening process (in which case numerous polypeptides may be designed, synthesized, characterized and/or tested) or based on the interests of the researcher.
  • the new TLR-agonist linker derivative and the targeting polypeptide may also be designed based on the structure of a known or partially characterized polypeptide.
  • Cysteinyl residues most commonly are reacted with a-haloacetates (and corresponding amines), such as chloroacetic acid or chloroacetamide, to give carboxymethyl or carboxyamidomethyl derivatives. Cysteinyl residues also are derivatized by reaction with bromotrifluoroacetone, alpha-bromo-P-(5-imidozoyl)propionic acid, chloroacetyl phosphate, N- alkylmaleimides, 3-nitro-2-pyridyl disulfide, methyl 2-pyridyl disulfide, p-chloromercuribenzoate, 2-chloromercuri-4-nitrophenol, or chloro-7-nitrobenzo-2-oxa-l,3-diazole.
  • a-haloacetates and corresponding amines
  • corresponding amines such as chloroacetic acid or chloroacetamide
  • Arginyl residues are modified by reaction with one or several conventional reagents, among them phenyl glyoxal, 2,3 -butanedione, 1 ,2-cyclohexanedione, and ninhydrin. Derivatization of arginine residues requires that the reaction be performed in alkaline conditions because of the high pKa of the guanidine functional group. Furthermore, these reagents may react with the groups of lysine as well as the arginine epsilon-amino group.
  • L is a bond.
  • targeting polypeptide and M are conjugated together by reacting a nucleophilic reactive moiety on targeting polypeptide with and electrophilic reactive moiety on M.
  • targeting polypeptide and M are conjugated together by reacting an electrophilic reactive moiety on targeting polypeptide with a nucleophilic moiety on M.
  • L is an amide bond that forms upon reaction of an amine on targeting polypeptide (e.g. an e-amine of a lysine residue) with a carboxyl group on M.
  • targeting polypeptide and or M is derivatized with a derivatizing agent before conjugation.
  • L can be any molecule with at least two reactive groups (before conjugation to targeting polypeptide and M) capable of reacting with each of targeting polypeptide and M. In some embodiments L has only two reactive groups and is bifunctional. L (before conjugation to the peptides) can be represented by Formula VI: wherein A and B are independently nucleophilic or electrophilic reactive groups. In some embodiments A and B are either both nucleophilic groups or both electrophilic groups. In some embodiments one of A or B is a nucleophilic group and the other of A or B is an electrophilic group. Nonlimiting combinations of A and B are shown below in Table 1.
  • the linking group is maleimido- polymer(20-40 kDa)-COOH, iodoacetyl-polymer(20-40 kDa)-COOH, maleimido-polymer(20-40 kDa)-NHS, or iodoacetyl-polymer(20-40 kDa)-NHS.
  • Any molecular mass for a polymer can be used as practically desired, including but not limited to, from about 100 Daltons (Da) to 100,000 Da or more as desired (including but not limited to, sometimes 0.1-50 kDa or 10-40 kDa).
  • the molecular weight of polymer may be of a wide range, including but not limited to, between about 100 Da and about 100,000 Da or more.
  • the molecular weight of each chain of the branched chain polymer is between about 1,000 Da and about 40,000 Da. In some embodiments, the molecular weight of each chain of the branched chain polymer is between about 5,000 Da and about 40,000 Da. In some embodiments, the molecular weight of each chain of the branched chain polymer is between about 5,000 Da and about 20,000 Da.
  • a wide range of polymer molecules are described in, including but not limited to, the Shearwater Polymers, Inc. catalog, Nektar Therapeutics catalog, incorporated herein by reference.
  • cleavable linkages include but are not limited to ester, carbonate ester, carbamate, sulfate, phosphate, acyloxyalkyl ether, acetal, and ketal.
  • Such conjugates should possess a physiologically cleavable bond that is stable upon storage and upon administration.
  • a targeting polypeptide or modified targeting polypeptide linked to a polymer should maintain its integrity upon manufacturing of the final pharmaceutical composition, upon dissolution in an appropriate delivery vehicle, if employed, and upon administration irrespective of route.
  • Any of the cleavable linkers disclosed herein can be linked to a drug, a payload, a targeting polypeptide, or a modified targeting polypeptide of the invention.
  • Exemplary examples of linkages via a cleavable linkers include, but are not limited:
  • TLR-agonist derivatives with linkers comprising a hydroxylamine, aldehyde, protected aldehyde, ketone, protected ketone, thioester, ester, dicarbonyl, hydrazine, amidine, imine, diamine, keto-amine, keto-alkyne, and ene- dione hydroxylamine group, a hydroxylamine-like group (which has reactivity similar to a hydroxylamine group and is structurally similar to a hydroxylamine group), a masked hydroxylamine group (which can be readily converted into a hydroxylamine group), or a protected hydroxylamine group (which has reactivity similar to a hydroxylamine group upon deprotection).
  • the TLR-agonist derivatives with linkers comprise azides, alkynes or cycloalkynes.
  • At least one non-natural amino acid comprising at least one post-translational modification
  • the at least one post-translational modification comprises a saccharide moiety.
  • the post-translational modification is made in vivo in a eukaryotic cell or in a non-eukaryotic cell.
  • a linker, polymer, water-soluble polymer, or other molecule may attach the molecule to the polypeptide.
  • the linker attached to the TC is long enough to permit formation of a dimer.
  • the molecule may also be linked directly to the polypeptide.
  • the acetylene-containing PEG derivative can be prepared by attaching a linking agent that has the acetylene moiety at one terminus to a conventional activated polymer so that the resulting polymer has the acetylene moiety at its terminus.
  • a water- soluble polymer having at least one active hydroxyl moiety undergoes a reaction to produce a substituted polymer having a more reactive moiety, such as a mesylate, tresylate, tosylate or halogen leaving group, thereon.
  • a more reactive moiety such as a mesylate, tresylate, tosylate or halogen leaving group.
  • the preparation and use of PEG derivatives or TLR-linker derivatives containing sulfonyl acid halides, halogen atoms and other leaving groups are known to those of ordinary skill in the art.
  • the resulting substituted polymer then undergoes a reaction to substitute for the more reactive moiety an azide moiety at the terminus of the polymer.
  • a catalogue of bacteria and bacteriophages useful for cloning is provided, e.g., by the ATCC, e.g., The ATCC Catalogue of Bacteria and Bacteriophage (1992) Gherna et al. (eds) published by the ATCC. Additional basic procedures for sequencing, cloning and other aspects of molecular biology and underlying theoretical considerations are also found in Watson et al. (1992) Recombinant DNA Second Edition Scientific American Books, NY.
  • nucleic acid and virtually any labeled nucleic acid, whether standard or non-standard
  • CGGG and AGGU were used to simultaneously incorporate 2-naphthylalanine and an NBD derivative of lysine into streptavidin in vitro with two chemically acylated frameshift suppressor tRNAs. See, e.g., Hohsaka et al., (1999) J. Am. Chem. Soc., 121:12194.
  • cyclic amino acids such as proline analogues as well as 3, 4 ,6, 7, 8, and 9 membered ring proline analogues
  • P and y amino acids such as substituted P-alanine and y-amino butyric acid.
  • the present invention provides TC linked to a water-soluble polymer, e.g., a PEG, by an oxime bond.
  • a water-soluble polymer e.g., a PEG
  • many types of non-naturally encoded amino acids are suitable for formation of oxime bonds. These include, but are not limited to, non-naturally encoded amino acids containing a carbonyl, dicarbonyl, or hydroxylamine group.
  • Such amino acids are described in U.S. Patent Publication Nos. 2006/0194256, 2006/0217532, and 2006/0217289 and WO 2006/069246 entitled “Compositions containing, methods involving, and uses of non-natural amino acids and polypeptides,” which are incorporated herein by reference in their entirety.
  • Non- naturally encoded amino acids are also described in U.S. Patent No. 7,083,970 and U.S. Patent No. 7,045,337, which are incorporated by reference herein in their entirety.
  • B is optional, and when present is a linker selected from the group consisting of lower alkylene, substituted lower alkylene, lower alkenylene, substituted lower alkenylene, lower heteroalkylene, substituted lower heteroalkylene, -O-, -O-(alkylene or substituted alkylene)-, -S-, -S-(alkylene or substituted alkylene)-, -S(O)k- where k is 1, 2, or 3, -S(O) k (alkylene or substituted alkylene)-, -C(O)-, -C(O)-(alkylene or substituted alkylene)-, -C(S)-, -C(S)-(alkylene or substituted alkylene)-, -N(R’)-, -NR’ -(alkylene or substituted alkylene)-, -C(O)N(R’)-, -CON(R’)-(alkylene or substituted alky
  • R is H, alkyl, substituted alkyl, cycloalkyl, or substituted cycloalkyl
  • R 2 is optional, and when present, is OH, an ester protecting group, resin, amino acid, polypeptide, or polynucleotide; wherein each Ra is independently selected from the group consisting of H, halogen, alkyl, substituted alkyl, -N(R’)2, -C(O)kR’ where k is 1, 2, or 3, -C(O)N(R’)2, -OR’, and -S(O)kR’, where each R’ is independently H, alkyl, or substituted alkyl.
  • R2 is optional, and when present, is OH, an ester protecting group, resin, amino acid, polypeptide, or polynucleotide; each R a is independently selected from the group consisting of H, halogen, alkyl, substituted alkyl, - N(R’) 2 , -C(O)kR’ where k is 1, 2, or 3, -C(O)N(R’)2, -OR’, and -S(O)kR’, where each R’ is independently H, alkyl, or substituted alkyl; and n is 0 to 8.
  • R is H, alkyl, substituted alkyl, cycloalkyl, or substituted cycloalkyl
  • Ri is optional, and when present, is H, an amino protecting group, resin, amino acid, polypeptide, or polynucleotide;
  • R is H, alkyl, substituted alkyl, cycloalkyl, or substituted cycloalkyl; Ri is optional, and when present, is H, an amino protecting group, resin, amino acid, polypeptide, or polynucleotide; and
  • Xi is C, S, or S(O); and L is alkylene, substituted alkylene, N(R’)(alkylene) or N(R’)(substituted alkylene), where R’ is H, alkyl, substituted alkyl, cycloalkyl, or substituted cycloalkyl.
  • A is optional, and when present is lower alkylene, substituted lower alkylene, lower cycloalkylene, substituted lower cycloalkylene, lower alkenylene, substituted lower alkenylene, alkynylene, lower heteroalkylene, substituted heteroalkylene, lower heterocycloalkylene, substituted lower heterocycloalkylene, arylene, substituted arylene, heteroarylene, substituted heteroarylene, alkarylene, substituted alkarylene, aralkylene, or substituted aralkylene;
  • A is optional, and when present is lower alkylene, substituted lower alkylene, lower cycloalkylene, substituted lower cycloalkylene, lower alkenylene, substituted lower alkenylene, alkynylene, lower heteroalkylene, substituted heteroalkylene, lower heterocycloalkylene, substituted lower heterocycloalkylene, arylene, substituted arylene, heteroarylene, substituted heteroarylene, alkarylene, substituted alkarylene, aralkylene, or substituted aralkylene;
  • R is H, alkyl, substituted alkyl, cycloalkyl, or substituted cycloalkyl
  • R2 is optional, and when present, is OH, an ester protecting group, resin, amino acid, polypeptide, or polynucleotide;
  • L is alkylene, substituted alkylene, N(R’)(alkylene) or N(R’)(substituted alkylene), where R’ is H, alkyl, substituted alkyl, cycloalkyl, or substituted cycloalkyl.
  • L is alkylene, substituted alkylene, N(R’)(alkylene) or N(R’)(substituted alkylene), where R’ is H, alkyl, substituted alkyl, cycloalkyl, or substituted cycloalkyl.
  • A is optional, and when present is lower alkylene, substituted lower alkylene, lower cycloalkylene, substituted lower cycloalkylene, lower alkenylene, substituted lower alkenylene, alkynylene, lower heteroalkylene, substituted heteroalkylene, lower heterocycloalkylene, substituted lower heterocycloalkylene, arylene, substituted arylene, heteroarylene, substituted heteroarylene, alkarylene, substituted alkarylene, aralkylene, or substituted aralkylene; to the A group and (b) indicates bonding to respective carbonyl groups, R3 and R4 are independently chosen from H, halogen, alkyl, substituted alkyl, cycloalkyl, or substituted cycloalkyl, or R3 and R4 or two R3 groups or two R4 groups optionally form a cycloalkyl or a heterocycloalkyl;
  • T3 is a bond, C(R)(R), O, or S, and R is H, halogen, alkyl, substituted alkyl, cycloalkyl, or substituted cycloalkyl;
  • T 3 is a bond, C(R)(R), O, or S, and R is H, halogen, alkyl, substituted alkyl, cycloalkyl, or substituted cycloalkyl;
  • Exemplary carbonyl-containing amino acids can be represented as follows: wherein n is 0-10; Ri is an alkyl, aryl, substituted alkyl, or substituted aryl; R2 is H, alkyl, aryl, substituted alkyl, and substituted aryl; and R3 is H, an amino acid, a polypeptide, or an amino terminus modification group, and R4 is H, an amino acid, a polypeptide, or a carboxy terminus modification group.
  • n 1, Ri is phenyl and R2 is a simple alkyl (i.e., methyl, ethyl, or propyl) and the ketone moiety is positioned in the para position relative to the alkyl side chain.
  • n 1, Ri is phenyl and R2 is a simple alkyl (i.e., methyl, ethyl, or propyl) and the ketone moiety is positioned in the meta position relative to the alkyl side chain.
  • n is 4, Ri is not present, and X is N. In some embodiments, n is 2, Ri is not present, and X is not present. In some embodiments, n is 1, Ri is phenyl, X is O, and the oxygen atom is positioned para to the alphatic group on the aryl ring.
  • azide and alkyne functional groups make them extremely useful for the selective modification of polypeptides and other biological molecules.
  • Organic azides, particularly alphatic azides, and alkynes are generally stable toward common reactive chemical conditions.
  • both the azide and the alkyne functional groups are inert toward the side chains (i.e., R groups) of the 20 common amino acids found in naturally-occurring polypeptides.
  • R groups side chains
  • the “spring-loaded” nature of the azide and alkyne groups is revealed, and they react selectively and efficiently via Huisgen [3+2] cycloaddition reaction to generate the corresponding triazole.
  • the Huisgen cycloaddition reaction involves a selective cycloaddition reaction (see, e.g., Padwa, A., in COMPREHENSIVE ORGANIC SYNTHESIS, Vol. 4, (ed. Trost, B. M., 1991), p. 1069-1109; Huisgen, R. in 1,3-DlPOLAR CYCLOADDITION CHEMISTRY, (ed. Padwa, A., 1984) , p.
  • Cycloaddition reaction involving azide or alkyne-containing TC can be carried out at room temperature under aqueous conditions by the addition of Cu(II) (including but not limited to, in the form of a catalytic amount of CUSO4) in the presence of a reducing agent for reducing Cu(II) to Cu(I), in situ, in catalytic amount. See, e.g., Wang, Q., et al., J. Am. Chem. Soc.
  • the azide functional group can also be reacted selectively with a water-soluble polymer containing an aryl ester and appropriately functionalized with an aryl phosphine moiety to generate an amide linkage.
  • the aryl phosphine group reduces the azide in situ and the resulting amine then reacts efficiently with a proximal ester linkage to generate the corresponding amide. See, e.g., E. Saxon and C. Bertozzi, Science 287, 2007-2010 (2000).
  • the azide-containing amino acid can be either an alkyl azide (including but not limited to, 2-amino-6-azido-l -hexanoic acid) or an aryl azide (p-azido-phenylalanine).
  • Exemplary azide-containing amino acids can be represented as follows: wherein n is 0-10; Ri is an alkyl, aryl, substituted alkyl, substituted aryl or not present; X is O, N, S or not present; m is 0-10; R2 is H, an amino acid, a polypeptide, or an amino terminus modification group, and R3 is H, an amino acid, a polypeptide, or a carboxy terminus modification group.
  • n is 1, Ri is phenyl, X is not present, m is 0 and the azide moiety is positioned para to the alkyl side chain.
  • Aminoacylation may be accomplished by aminoacyl tRNA synthetases or by other enzymatic molecules, including but not limited to, ribozymes.
  • ribozyme is interchangeable with "catalytic RNA.” Cech and coworkers (Cech, 1987, Science, 236: 1532-1539; McCorkle et al., 1987, Concepts Biochem. 64:221-226) demonstrated the presence of naturally occurring RNAs that can act as catalysts (ribozymes). However, although these natural RNA catalysts have only been shown to act on ribonucleic acid substrates for cleavage and splicing, the recent development of artificial evolution of ribozymes has expanded the repertoire of catalysis to various chemical reactions.
  • the proportion of polyethylene glycol molecules to protein molecules will vary, as will their concentrations in the reaction mixture.
  • the optimum ratio in terms of efficiency of reaction in that there is minimal excess unreacted protein or polymer
  • molecular weight typically the higher the molecular weight of the polymer, the fewer number of polymer molecules which may be attached to the protein.
  • branching of the polymer should be considered when optimizing these parameters. Generally, the higher the molecular weight (or the more branches) the higher the polymerprotein ratio.
  • Typical reactive groups can include those reactive groups that are commonly used to react with the functional groups found in the 20 common amino acids (including but not limited to, maleimide groups, activated carbonates (including but not limited to, p-nitrophenyl ester), activated esters (including but not limited to, N- hydroxysuccinimide, p-nitrophenyl ester) and aldehydes) as well as functional groups that are inert to the 20 common amino acids but that react specifically with complementary functional groups present in non-naturally encoded amino acids (including but not limited to, azide groups, alkyne groups).
  • the molecular weight of each chain of the branched chain PEG may be between about 1,000 Da and about 100,000 Da, including but not limited to, 100,000 Da, 95,000 Da, 90,000 Da, 85,000 Da, 80,000 Da, 75,000 Da, 70,000 Da, 65,000 Da, 60,000 Da, 55,000 Da, 50,000 Da, 45,000 Da, 40,000 Da, 35,000 Da, 30,000 Da, 25,000 Da, 20,000 Da, 15,000 Da, 10,000 Da, 9,000 Da, 8,000 Da, 7,000 Da, 6,000 Da, 5,000 Da, 5,000 Da, 4,000 Da, 3,000 Da, 2,000 Da, and 1,000 Da. In some embodiments, the molecular weight of each chain of the branched chain PEG is between about 1,000 Da and about 50,000 Da.
  • the PEG molecule is available for reaction with the non-naturally-encoded amino acid.
  • PEG derivatives or TLR-linker derivatives bearing alkyne and azide moieties for reaction with amino acid side chains can be used to attach PEG to non-naturally encoded amino acids as described herein.
  • the non-naturally encoded amino acid comprises an azide
  • the PEG will typically contain either an alkyne moiety to effect formation of the [3+2] cycloaddition product or an activated PEG species (i.e., ester, carbonate) containing a phosphine group to effect formation of the amide linkage.
  • the PEG will typically contain an azide moiety to effect formation of the [3+2] Huisgen cycloaddition product.
  • the PEG will typically comprise a potent nucleophile (including but not limited to, a hydrazide, hydrazine, hydroxylamine, or semicarbazide functionality) in order to effect formation of corresponding hydrazone, oxime, and semicarbazone linkages, respectively.
  • the TC polypeptide with a PEG derivative contains a chemical functionality that is reactive with the chemical functionality present on the side chain of the non-naturally encoded amino acid.
  • the invention provides in some embodiments, azide- and acetylene-containing polymer derivatives comprising a water-soluble polymer backbone having an average molecular weight from about 800 Da to about 100,000 Da.
  • the polymer backbone of the water-soluble polymer can be poly(ethylene glycol).
  • water-soluble polymers including but not limited to poly(ethylene)glycol and other related polymers, including poly(dextran) and polypropylene glycol), are also suitable for use in the practice of this invention and that the use of the term PEG or poly(ethylene glycol) is intended to encompass and include all such molecules.
  • PEG conjugates tend not to produce a substantial immune response or cause clotting or other undesirable effects.
  • PEG having a molecular weight of from about 800 Da to about 100,000 Da are in some embodiments of the present invention particularly useful as the polymer backbone.
  • the molecular weight of PEG may be of a wide range, including but not limited to, between about 100 Da and about 100,000 Da or more.
  • the molecular weight of PEG may be between about 100 Da and about 100,000 Da, including but not limited to, 100,000 Da, 95,000 Da, 90,000 Da, 85,000 Da, 80,000 Da, 75,000 Da, 70,000 Da, 65,000 Da, 60,000 Da, 55,000 Da, 50,000 Da, 45,000 Da, 40,000 Da, 35,000 Da, 30,000 Da, 25,000 Da, 20,000 Da, 15,000 Da, 10,000 Da, 9,000 Da, 8,000 Da, 7,000 Da, 6,000 Da, 5,000 Da, 5,000 Da, 4,000 Da, 3,000 Da, 2,000 Da, 1,000 Da, 900 Da, 800 Da, 700 Da, 600 Da, 500 Da, 400 Da, 300 Da, 200 Da, and 100 Da. In some embodiments, the molecular weight of PEG is between about 100 Da and about 50,000 Da.
  • the molecular weight of PEG is between about 100 Da and about 40,000 Da. In some embodiments, the molecular weight of PEG is between about 1,000 Da and about 40,000 Da. In some embodiments, the molecular weight of PEG is between about 5,000 Da and about 40,000 Da. In some embodiments, the molecular weight of PEG is between about 10,000 Da and about 40,000 Da.
  • the polymer backbone can be linear or branched.
  • Branched polymer backbones are generally known in the art.
  • a branched polymer has a central branch core moiety and a plurality of linear polymer chains linked to the central branch core.
  • PEG is commonly used in branched forms that can be prepared by addition of ethylene oxide to various polyols, such as glycerol, glycerol oligomers, pentaerythritol and sorbitol.
  • the central branch moiety can also be derived from several amino acids, such as lysine.
  • the polymer can also be prepared with weak or degradable linkages in the backbone.
  • PEG can be prepared with ester linkages in the polymer backbone that are subject to hydrolysis. As shown below, this hydrolysis results in cleavage of the polymer into fragments of lower molecular weight:
  • poly(ethylene glycol) or PEG represents or includes all the forms known in the art including but not limited to those disclosed herein.
  • polymer backbones that are water-soluble, with from 2 to about 300 termini, are particularly useful in the invention.
  • suitable polymers include, but are not limited to, other poly(alkylene glycols), such as polypropylene glycol) (“PPG”), copolymers thereof (including but not limited to copolymers of ethylene glycol and propylene glycol), terpolymers thereof, mixtures thereof, and the like.
  • PPG polypropylene glycol
  • the molecular weight of each chain of the polymer backbone can vary, it is typically in the range of from about 800 Da to about 100,000 Da, often from about 6,000 Da to about 80,000 Da.
  • the molecular weight of each chain of the polymer backbone may be between about 100 Da and about 100,000 Da, including but not limited to, 100,000 Da, 95,000 Da, 90,000 Da, 85,000 Da, 80,000 Da, 75,000 Da, 70,000 Da, 65,000 Da, 60,000 Da, 55,000 Da, 50,000 Da, 45,000 Da, 40,000 Da, 35,000 Da, 30,000 Da, 25,000 Da, 20,000 Da, 15,000 Da, 10,000 Da, 9,000 Da, 8,000 Da, 7,000 Da, 6,000 Da, 5,000 Da, 5,000 Da, 4,000 Da, 3,000 Da, 2,000 Da, 1,000 Da, 900 Da, 800 Da, 700 Da, 600 Da, 500 Da, 400 Da, 300 Da, 200 Da, and 100 Da.
  • the molecular weight of each chain of the polymer backbone is between about 100 Da and about 50,000 Da. In some embodiments, the molecular weight of each chain of the polymer backbone is between about 100 Da and about 40,000 Da. In some embodiments, the molecular weight of each chain of the polymer backbone is between about 1,000 Da and about 40,000 Da. In some embodiments, the molecular weight of each chain of the polymer backbone is between about 5,000 Da and about 40,000 Da. In some embodiments, the molecular weight of each chain of the polymer backbone is between about 10,000 Da and about 40,000 Da.
  • the chemically reactive group is a carboxylic acid, such as butanoic or propionic acid, or a hydroxyl group
  • the protecting group can be benzyl or an alkyl group such as methyl, ethyl, or tert-butyl.
  • Other protecting groups known in the art may also be used in the present invention.
  • terminal functional groups in the literature include, but are not limited to, N-succinimidyl carbonate (see e g., U.S. Pat. Nos. 5,281,698, 5,468,478), amine (see, e.g., Buckmann et al. Makromol. Chem. 182: 1379 (1981), Zalipsky et al. Eur. Polym. J. 19:1177 (1983)), hydrazide (See, e.g., Andresz et al. Makromol. Chem. 179:301 (1978)), succinimidyl propionate and succinimidyl butanoate (see, e g., Olson et al.
  • succinimidyl succinate See, e.g., Abuchowski et al. Cancer Biochem. Biophys. 7: 175 (1984) and Joppich et al. Makromol. Chem. 180:1381 (1979), succinimidyl ester (see, e g., U.S. Pat. No. 4,670,417), benzotriazole carbonate (see, e.g., U.S. Pat. No.
  • PEGylation i.e, addition of any water-soluble polymer
  • TC polypeptides containing a non-naturally encoded amino acid such as j>-azido-L-pheny 1 alanine
  • the aqueous solution is buffered with a buffer having a pK a near the pH at which the reaction is to be carried out (generally about pH 4-10).
  • a buffer having a pK a near the pH at which the reaction is to be carried out generally about pH 4-10.
  • suitable buffers for PEGylation at pH 7.5 include, but are not limited to, HEPES, phosphate, borate, TRIS-HC1, EPPS, and TES.
  • the pH is continuously monitored and adjusted if necessary.
  • the reaction is typically allowed to continue for between about 1-48 hours.
  • the eluent containing the desired conjugates is concentrated by ultrafiltration and desalted by diafiltration.
  • Substantially purified PEG-TC can be produced using the elution methods outlined above where the PEG-TC produced has a purity level of at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, specifically, a purity level of at least about 75%, 80%, 85%, and more specifically, a purity level of at least about 90%, a purity level of at least about 95%, a purity level of at least about 99% or greater as determined by appropriate methods such as SDS/PAGE analysis, RP-HPLC, SEC, and capillary electrophoresis.
  • the PEGylated TC polypeptide obtained from the hydrophobic chromatography can be purified further by one or more procedures known to those of ordinary skill in the art including, but are not limited to, affinity chromatography; anion- or cation-exchange chromatography (using, including but not limited to, DEAE SEPHAROSE); chromatography on silica; reverse phase HPLC; gel filtration (using, including but not limited to, SEPHADEX G-75); hydrophobic interaction chromatography; sizeexclusion chromatography, metal-chelate chromatography; ultrafiltration/diafiltration; ethanol precipitation; ammonium sulfate precipitation; chromatofocusing; displacement chromatography; electrophoretic procedures (including but not limited to preparative isoelectric focusing), differential solubility (including but not limited to ammonium sulfate precipitation), or extraction.
  • affinity chromatography anion- or cation-exchange chromatography (using, including but not limited to, DEAE SEPHAROSE); chromatography on silic
  • Apparent molecular weight may be estimated by GPC by comparison to globular protein standards (Preneta, AZ in PROTEIN PURIFICATION METHODS, A PRACTICAL APPROACH (Harris & Angal, Eds.) IRL Press 1989, 293-306).
  • the purity of the TC-PEG conjugate can be assessed by proteolytic degradation (including but not limited to, trypsin cleavage) followed by mass spectrometry analysis.
  • proteolytic degradation including but not limited to, trypsin cleavage
  • the azide-terminal PEG derivative will have the structure: RO-(CH 2 CH 2 O)n -O-(CH 2 ) m -NH-C(O)-(CH 2 ) p -N 3 where R is a simple alkyl (methyl, ethyl, propyl, etc.), m is 2-10, p is 2-10 and n is 100-1,000 (i.e., average molecular weight is between 5-40 kDa).
  • R is a simple alkyl (methyl, ethyl, propyl, etc.)
  • m is 2-10
  • n is 100-1,000 (i.e., average molecular weight is between 5-40 kDa).
  • the alkyne-terminal PEG derivative will have the following structure:
  • the PEG derivative will have the structure: wherein X can be O, N, S or not present, Ph is phenyl, W is a water-soluble polymer and R can be H, alkyl, aryl, substituted alkyl and substituted aryl groups.
  • the invention includes TC polypeptides incorporating one or more non-naturally encoded amino acids bearing saccharide residues.
  • the saccharide residues may be either natural (including but not limited to, N-acetylglucosamine) or non-natural (including but not limited to, 3- fluorogalactose).
  • the saccharides may be linked to the non-naturally encoded amino acids either by an N- or O-linked glycosidic linkage (including but not limited to, N-acetylgalactose-L-serine) or a non-natural linkage (including but not limited to, an oxime or the corresponding C- or S-linked glycoside).
  • Linkers may be used to provide a desired spatial relationship or conformation between TC and the linked entity or between TC and its receptor, or between the linked entity and its binding partner, if any.
  • Linkers having longer or shorter molecular length may also be used to provide a desired space or flexibility between TC and the linked entity, or between the linked entity and its binding partner, if any.
  • the invention provides water-soluble bifunctional linkers that have a dumbbell structure that includes: a) an azide, an alkyne, a hydrazine, a hydrazide, a hydroxylamine, or a carbonyl-containing moiety on at least a first end of a polymer backbone; and b) at least a second functional group on a second end of the polymer backbone.
  • the second functional group can be the same or different as the first functional group.
  • the second functional group in some embodiments, is not reactive with the first functional group.
  • the invention provides, in some embodiments, water-soluble compounds that comprise at least one arm of a branched molecular structure.
  • the branched molecular structure can be dendritic.
  • TC polypeptides may be analyzed for their ability to activate TC-sensitive signal transduction pathways.
  • ISRE interferon-stimulated response element
  • Cells which constitutively express the TC receptor are transiently transfected with an ISRE- luciferase vector (pISRE-luc, Clontech). After transfection, the cells are treated with a targeting polypeptide of the TC. A number of protein concentrations, for example from 0.0001-10 ng/mL, are tested to generate a dose-response curve. If the TC polypeptide binds and activates the TC receptor, the resulting signal transduction cascade induces luciferase expression. Luminescence can be measured in a number of ways, for example by using a TopCountTM or FusionTM microplate reader and Steady-Glo R Luciferase Assay System (Promega).
  • TC polypeptides may be analyzed for their ability to bind to the TC receptor
  • affinity of TC for its receptor can be measured by using a BIAcoreTM biosensor (Pharmacia).
  • BIAcoreTM biosensor Pharmacia
  • Suitable binding assays include, but are not limited to, BIAcore assays (Pearce et al., Biochemistry 38:81-89 (1999)) and AlphaScreenTM assays (PerkinElmer).
  • the potency and functional in vivo half-life of a targeting polypeptide of the TC comprising a non-naturally encoded amino acid can be determined according to protocols known to those of ordinary skill in the art.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Immunology (AREA)
  • Cell Biology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Oncology (AREA)
  • Reproductive Health (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Peptides Or Proteins (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
PCT/US2021/047009 2020-08-20 2021-08-20 Antibody-tlr agonist conjugates, methods and uses thereof Ceased WO2022040596A1 (en)

Priority Applications (7)

Application Number Priority Date Filing Date Title
KR1020237009263A KR20230073200A (ko) 2020-08-20 2021-08-20 항체-tlr 작용제 접합체, 그 방법 및 용도
EP21772883.1A EP4199968A1 (en) 2020-08-20 2021-08-20 Antibody-tlr agonist conjugates, methods and uses thereof
CN202180071626.XA CN116457023A (zh) 2020-08-20 2021-08-20 抗体-tlr激动剂缀合物、方法及其用途
JP2023511915A JP2023538071A (ja) 2020-08-20 2021-08-20 抗体－ｔｌｒアゴニストコンジュゲート、その方法及び使用
CA3190606A CA3190606A1 (en) 2020-08-20 2021-08-20 Antibody-tlr agonist conjugates, methods and uses thereof
US18/022,099 US20230302150A1 (en) 2020-08-20 2021-08-20 Antibody-tlr agonist conjugates, methods and uses thereof
AU2021327396A AU2021327396A1 (en) 2020-08-20 2021-08-20 Antibody-TLR agonist conjugates, methods and uses thereof

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US202063068342P 2020-08-20 2020-08-20
US63/068,342 2020-08-20
US202063118365P 2020-11-25 2020-11-25
US63/118,365 2020-11-25

Publications (1)

Publication Number Publication Date
WO2022040596A1 true WO2022040596A1 (en) 2022-02-24

Family

ID=77802239

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2021/047009 Ceased WO2022040596A1 (en) 2020-08-20 2021-08-20 Antibody-tlr agonist conjugates, methods and uses thereof

Country Status (8)

Country Link
US (1) US20230302150A1 (https=)
EP (1) EP4199968A1 (https=)
JP (1) JP2023538071A (https=)
KR (1) KR20230073200A (https=)
AU (1) AU2021327396A1 (https=)
CA (1) CA3190606A1 (https=)
TW (1) TW202227449A (https=)
WO (1) WO2022040596A1 (https=)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024020684A1 (en) * 2022-07-26 2024-02-01 Zymeworks Bc Inc. Immunomodulator purine-derived compounds, conjugates thereof, and methods of use thereof
WO2024077277A1 (en) 2022-10-07 2024-04-11 Ambrx, Inc. Drug linkers and antibody conjugates thereof
JP2024524213A (ja) * 2021-06-22 2024-07-05 タクシス ファーマシューティカルズ， インコーポレイテッド 治療化合物
WO2024155627A1 (en) 2023-01-16 2024-07-25 Ambrx, Inc. Anti-cd70 antibody-drug conjugates
WO2024178310A1 (en) 2023-02-23 2024-08-29 Ambrx, Inc. Trop2-directed antibody-drug conjugates and uses thereof
US12133884B2 (en) 2018-05-11 2024-11-05 Beam Therapeutics Inc. Methods of substituting pathogenic amino acids using programmable base editor systems
WO2025038646A1 (en) * 2023-08-14 2025-02-20 Intellia Therapeutics, Inc. Cd70 car-t compositions and methods for cell-based therapy

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20250161096A (ko) * 2024-05-07 2025-11-17 바이티디 주식회사 Vista 및 msln에 특이적으로 결합하는 이중특이적 항체 및 이의 용도
WO2025250885A1 (en) * 2024-05-31 2025-12-04 Oncotelic, Inc. In situ tumor-infiltrating lymphocyte therapeutics for cancer

Citations (138)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3773919A (en) 1969-10-23 1973-11-20 Du Pont Polylactide-drug mixtures
US4289872A (en) 1979-04-06 1981-09-15 Allied Corporation Macromolecular highly branched homogeneous compound based on lysine units
EP0036676A1 (en) 1978-03-24 1981-09-30 The Regents Of The University Of California Method of making uniformly sized liposomes and liposomes so made
EP0052322A2 (de) 1980-11-10 1982-05-26 Gersonde, Klaus, Prof. Dr. Verfahren zur Herstellung von Lipid-Vesikeln durch Ultraschallbehandlung, Anwendung des Verfahrens und Vorrichtung zur Durchführung des Verfahrens
EP0058481A1 (en) 1981-02-16 1982-08-25 Zeneca Limited Continuous release pharmaceutical compositions
US4414148A (en) 1981-04-15 1983-11-08 Sanofi Anti-cancer drugs for the treatment of melanomas and method for preparing thereof
DE3218121A1 (de) 1982-05-14 1983-11-17 Leskovar, Peter, Dr.-Ing., 8000 München Arzneimittel zur tumorbehandlung
EP0102324A2 (de) 1982-07-29 1984-03-07 Ciba-Geigy Ag Lipide und Tenside in wässriger Phase
US4485045A (en) 1981-07-06 1984-11-27 Research Corporation Synthetic phosphatidyl cholines useful in forming liposomes
EP0133988A2 (de) 1983-08-02 1985-03-13 Hoechst Aktiengesellschaft Regulatorische Peptide enthaltende pharmazeutische Präparate mit protrahierter Freisetzung und Verfahren zu deren Herstellung
US4511503A (en) 1982-12-22 1985-04-16 Genentech, Inc. Purification and activity assurance of precipitated heterologous proteins
US4511502A (en) 1982-12-22 1985-04-16 Genentech, Inc. Purification and activity assurance of precipitated heterologous proteins
US4512922A (en) 1982-12-22 1985-04-23 Genentech, Inc. Purification and activity assurance of precipitated heterologous proteins
EP0143949A1 (en) 1983-11-01 1985-06-12 TERUMO KABUSHIKI KAISHA trading as TERUMO CORPORATION Pharmaceutical composition containing urokinase
EP0154316A2 (en) 1984-03-06 1985-09-11 Takeda Chemical Industries, Ltd. Chemically modified lymphokine and production thereof
US4542225A (en) 1984-08-29 1985-09-17 Dana-Farber Cancer Institute, Inc. Acid-cleavable compound
US4544545A (en) 1983-06-20 1985-10-01 Trustees University Of Massachusetts Liposomes containing modified cholesterol for organ targeting
EP0183503A2 (en) 1984-11-30 1986-06-04 Beecham Group Plc Conjugates of pharmaceutically useful proteins
EP0188256A2 (en) 1985-01-14 1986-07-23 NeoRx Metal radionuclide labeled proteins for diagnosis and therapy
US4619794A (en) 1982-02-17 1986-10-28 Ciba-Geigy Corporation Spontaneous preparation of small unilamellar liposomes
US4625014A (en) 1984-07-10 1986-11-25 Dana-Farber Cancer Institute, Inc. Cell-delivery agent
US4659839A (en) 1984-10-10 1987-04-21 Mallinckrodt, Inc. Coupling agents for radiolabeled antibody fragments
WO1987002670A1 (en) 1985-10-25 1987-05-07 Mackay Vivian L Method of using bar1 for secreting foreign proteins
US4670417A (en) 1985-06-19 1987-06-02 Ajinomoto Co., Inc. Hemoglobin combined with a poly(alkylene oxide)
US4671958A (en) 1982-03-09 1987-06-09 Cytogen Corporation Antibody conjugates for the delivery of compounds to target sites
US4680338A (en) 1985-10-17 1987-07-14 Immunomedics, Inc. Bifunctional linker
EP0229108A1 (en) 1985-06-26 1987-07-22 Cetus Corp PROTEIN SOLUBILIZATION FOR PHARMACEUTICAL COMPOSITIONS USING A POLYMER CONJUGATION.
WO1987005330A1 (en) 1986-03-07 1987-09-11 Michel Louis Eugene Bergh Method for enhancing glycoprotein stability
US4699784A (en) 1986-02-25 1987-10-13 Center For Molecular Medicine & Immunology Tumoricidal methotrexate-antibody conjugate
US4820352A (en) 1983-01-10 1989-04-11 Bausch & Lomb Incorporated Cleaning and conditioning solutions for contact lenses and methods of use
US4870008A (en) 1983-08-12 1989-09-26 Chiron Corporation Secretory expression in eukaryotes
US4902502A (en) 1989-01-23 1990-02-20 Cetus Corporation Preparation of a polymer/interleukin-2 conjugate
EP0400472A2 (en) 1989-05-27 1990-12-05 Sumitomo Pharmaceuticals Company, Limited Process for preparing polyethylene glycol derivatives and modified protein.
EP0402378A1 (en) 1988-01-20 1990-12-19 Cetus Corp CONJUGATION OF THE POLYMERS ON COLONIZING FACTOR.
US5021234A (en) 1983-09-26 1991-06-04 Udo Ehrenfeld Agent and product for the diagnosis and treatment of tumors and for the treatment of weaknesses of the cellular and humoral immune defense
EP0439508A1 (en) 1988-10-20 1991-08-07 PolyMASC Pharmaceuticals plc Polyethylene glycolcol (peg)-protein adducts and process for their fractionation
US5047335A (en) 1988-12-21 1991-09-10 The Regents Of The University Of Calif. Process for controlling intracellular glycosylation of proteins
US5122614A (en) 1989-04-19 1992-06-16 Enzon, Inc. Active carbonates of polyalkylene oxides for modification of polypeptides
WO1992016555A1 (en) 1991-03-18 1992-10-01 Enzon, Inc. Hydrazine containing conjugates of polypeptides and glycopolypeptides with polymers
EP0510356A1 (en) 1991-03-25 1992-10-28 F. Hoffmann-La Roche Ag Polyethylene glycol protein conjugates
US5219564A (en) 1990-07-06 1993-06-15 Enzon, Inc. Poly(alkylene oxide) amino acid copolymers and drug carriers and charged copolymers based thereon
US5229490A (en) 1987-05-06 1993-07-20 The Rockefeller University Multiple antigen peptide system
US5252714A (en) 1990-11-28 1993-10-12 The University Of Alabama In Huntsville Preparation and use of polyethylene glycol propionaldehyde
WO1993021259A1 (en) 1992-04-14 1993-10-28 Cornell Research Foundation Inc. Dendritic based macromolecules and method of production
US5281698A (en) 1991-07-23 1994-01-25 Cetus Oncology Corporation Preparation of an activated polymer ester for protein conjugation
WO1994004193A1 (en) 1992-08-21 1994-03-03 Enzon, Inc. Novel attachment of polyalkylene oxides to bio-effecting substances
US5324844A (en) 1989-04-19 1994-06-28 Enzon, Inc. Active carbonates of polyalkylene oxides for modification of polypeptides
WO1994014758A1 (en) 1992-12-22 1994-07-07 Enzon, Inc. Aryl imidate activated polyalkylene oxides
EP0605963A2 (en) 1992-12-09 1994-07-13 Ortho Pharmaceutical Corporation Peg hydrazone and peg oxime linkage forming reagents and protein derivatives thereof
WO1994017039A1 (en) 1993-01-19 1994-08-04 Enzon, Inc. Cyclic imide thione activated polyalkylene oxides
WO1994018247A1 (en) 1993-02-02 1994-08-18 Enzon, Inc. Azlactone activated polyalkylene oxides
WO1994028024A1 (en) 1993-06-01 1994-12-08 Enzon, Inc. Carbohydrate-modified polymer conjugates with erythropoietic activity
WO1995000162A1 (en) 1993-06-21 1995-01-05 Enzon, Inc. Site specific synthesis of conjugated peptides
US5382657A (en) 1992-08-26 1995-01-17 Hoffmann-La Roche Inc. Peg-interferon conjugates
WO1995006058A1 (en) 1993-08-24 1995-03-02 Polymasc Pharmaceuticals Plc Polymer modification
WO1995011924A1 (en) 1993-10-27 1995-05-04 Enzon, Inc. Non-antigenic branched polymer conjugates
WO1995013090A1 (en) 1993-11-10 1995-05-18 Enzon, Inc. Improved interferon polymer conjugates
WO1995013312A1 (en) 1993-11-12 1995-05-18 Shearwater Polymers, Inc. Water soluble active sulfones of poly(ethylene glycol)
US5468478A (en) 1987-08-03 1995-11-21 Oxis International, Inc. Conjugates of superoxide dismutage coupled to high molecular weight polyalkylene glycols
US5473034A (en) 1994-03-18 1995-12-05 Hyogo Prefectural Government Method for producing protein-synthetic polymer conjugate and said conjugate produced thereby
WO1995033490A1 (en) 1994-06-02 1995-12-14 Enzon, Inc. Method of solubilizing substantially water insoluble materials
US5476653A (en) 1992-06-17 1995-12-19 Amgen Inc. Polyoxymethylene-oxyethylene copolymers in conjuction with biomolecules
WO1996000080A1 (en) 1994-06-24 1996-01-04 Enzon, Inc. Non-antigenic amine derived polymers and polymer conjugates
WO1996007670A1 (en) 1994-09-09 1996-03-14 Surface Engineering Technologies, Division Of Innerdyne, Inc. Electrophilic polyethylene oxides for the modification of polysaccharides, polypeptides (proteins) and surfaces
US5516673A (en) 1993-02-15 1996-05-14 Bar Ilan University Bioactive conjugates of cellulose with amino compounds
WO1996021469A1 (en) 1995-01-10 1996-07-18 Shearwater Polymers, Inc. Multi-armed, monofunctional, and hydrolytically stable derivatives of poly(ethylene glycol) and related polymers for modification of surfaces and molecules
WO1996040791A1 (en) 1995-06-07 1996-12-19 Novo Nordisk A/S Modification of polypeptides
WO1996041813A2 (en) 1994-11-09 1996-12-27 Offord Robin E Functionalized polymers for site-specific attachment
WO1997003106A1 (en) 1995-07-07 1997-01-30 Shearwater Polymers, Inc. Poly(ethylene glycol) and related polymers monosubstituted with propionic or butanoic acids and functional derivatives thereof for biotechnical applications
US5629384A (en) 1994-05-17 1997-05-13 Consiglio Nazionale Delle Ricerche Polymers of N-acryloylmorpholine activated at one end and conjugates with bioactive materials and surfaces
WO1997018832A1 (en) 1995-11-21 1997-05-29 Enzon, Inc. Interferon-polymer conjugates and process for preparing the same
WO1997032607A2 (en) 1996-03-06 1997-09-12 Amgen Inc. Activated linkers and methods for making and purifying the same
EP0809996A2 (en) 1996-05-31 1997-12-03 F. Hoffmann-La Roche Ag Interferon conjugates
WO1998005363A2 (en) 1996-08-02 1998-02-12 Ortho-Mcneil Pharmaceutical, Inc. Polypeptides having a single covalently bound n-terminal water-soluble polymer
US5736625A (en) 1990-11-14 1998-04-07 Cargill, Incorporated Method for stabilizing proteins with saccharide linked protein polymer conjugates
WO1998032466A1 (en) 1997-01-29 1998-07-30 Polymasc Pharmaceuticals Plc Pegylation process
WO1998041562A1 (en) 1997-03-20 1998-09-24 Enzon, Inc. Non-antigenic branched polymer conjugates
US5824778A (en) 1988-12-22 1998-10-20 Kirin-Amgen, Inc. Chemically-modified G-CSF
US5824784A (en) 1994-10-12 1998-10-20 Amgen Inc. N-terminally chemically modified protein compositions and methods
WO1998048837A1 (en) 1997-04-30 1998-11-05 Enzon, Inc. Polyalkylene oxide-modified single chain polypeptides
EP0921131A1 (en) 1997-06-06 1999-06-09 Kyowa Hakko Kogyo Co., Ltd. Chemically modified polypeptides
WO1999032134A1 (en) 1997-12-19 1999-07-01 Enzon, Inc. Substantially pure histidine-linked protein polymer conjugates
WO1999032140A1 (en) 1997-12-19 1999-07-01 Enzon, Inc. Alpha-interferon-polymer-conjugates having enhanced biological activity and methods of preparing the same
WO1999032139A1 (en) 1997-12-19 1999-07-01 Shering Corporation Improved interferon polymer conjugates
US5980948A (en) 1996-08-16 1999-11-09 Osteotech, Inc. Polyetherester copolymers as drug delivery matrices
US5990237A (en) 1997-05-21 1999-11-23 Shearwater Polymers, Inc. Poly(ethylene glycol) aldehyde hydrates and related polymers and applications in modifying amines
US6001800A (en) 1994-12-16 1999-12-14 Ortho Pharmaceutical Corp. Spray dried erythropoietin
US6004573A (en) 1997-10-03 1999-12-21 Macromed, Inc. Biodegradable low molecular weight triblock poly(lactide-co-glycolide) polyethylene glycol copolymers having reverse thermal gelation properties
US6129912A (en) 1997-09-26 2000-10-10 Uab Research Foundation Polyethylene glycol-protein compositions which reduce the antigenic display of red blood cells
US6201072B1 (en) 1997-10-03 2001-03-13 Macromed, Inc. Biodegradable low molecular weight triblock poly(lactide-co- glycolide) polyethylene glycol copolymers having reverse thermal gelation properties
US6214966B1 (en) 1996-09-26 2001-04-10 Shearwater Corporation Soluble, degradable poly(ethylene glycol) derivatives for controllable release of bound molecules into solution
US6281211B1 (en) 1999-02-04 2001-08-28 Euro-Celtique S.A. Substituted semicarbazides and the use thereof
US6306821B1 (en) 1999-04-16 2001-10-23 Wm. Marsh Rice University Functionalized poly(propylene fumarate) and poly(propylene fumarate-co-ethylene glycol)
US20010044526A1 (en) 2000-02-22 2001-11-22 Shearwater Corporation N-maleimidyl polymer derivatives
US20010056171A1 (en) 1999-12-22 2001-12-27 Shearwater Corporation Method for the preparation of 1-benzotriazolyl carbonate esters of poly(ethylene glycol)
US20020002250A1 (en) 1999-12-22 2002-01-03 Shearwater Corporation Sterically hindered poly(ethylene glycol) alkanoic acids and derivatives thereof
US20020037949A1 (en) 1998-03-12 2002-03-28 Shearwater Corporation Poly(ethylene glycol) derivatives with proximal reactive groups
US20020052009A1 (en) 1997-11-03 2002-05-02 Hans Hornauer Polyethylene glycol-derivatized biomolecules and their use in heterogeneous detection methods
US20020072573A1 (en) 1997-11-06 2002-06-13 Shearwater Corporation Heterobifunctional poly(ethylene glycol) derivatives and methods for their preparation
US20020082345A1 (en) 2000-12-18 2002-06-27 Shearwater Corporation Synthesis of high molecular weight non-peptidic polymer derivatives
US6420339B1 (en) 1998-10-14 2002-07-16 Amgen Inc. Site-directed dual pegylation of proteins for improved bioactivity and biocompatibility
US6423685B1 (en) 1998-03-05 2002-07-23 Chiron Corporation Method for increasing the serum half-life of a biologically active molecule
US6436386B1 (en) 2000-11-14 2002-08-20 Shearwater Corporation Hydroxyapatite-targeting poly (ethylene glycol) and related polymers
US6451346B1 (en) 1998-12-23 2002-09-17 Amgen Inc Biodegradable pH/thermosensitive hydrogels for sustained delivery of biologically active agents
US6461603B2 (en) 2000-02-28 2002-10-08 Shearwater Corporation Water-soluble polymer conjugates of artelinic acid
US20020156047A1 (en) 2001-01-19 2002-10-24 Shearwater Corporation Multi-arm block copolymers as drug delivery vehicles
WO2002085923A2 (en) 2001-04-19 2002-10-31 The Scripps Research Institute In vivo incorporation of unnatural amino acids
US20030023023A1 (en) 1999-12-10 2003-01-30 Shearwater Corporation Hydrolytically degradable polymers and hydrogels made therefrom
US6521427B1 (en) 1997-09-16 2003-02-18 Egea Biosciences, Inc. Method for the complete chemical synthesis and assembly of genes and genomes
US6552167B1 (en) 1998-08-28 2003-04-22 Gryphon Therapeutics, Inc. Polyamide chains of precise length
US20030105224A1 (en) 2001-10-09 2003-06-05 Shearwater Corporation Thioester polymer derivatives and method of modifying the N-terminus of a polypeptide therewith
US20030143596A1 (en) 2001-11-07 2003-07-31 Shearwater Corporation Branched polymers and their conjugates
US6608183B1 (en) 1997-07-14 2003-08-19 Bolder Biotechnology, Inc. Derivatives of growth hormone and related proteins
US6646110B2 (en) 2000-01-10 2003-11-11 Maxygen Holdings Ltd. G-CSF polypeptides and conjugates
US6656389B2 (en) 2001-06-29 2003-12-02 International Business Machines Corporation Thermal paste for low temperature applications
US6656398B2 (en) 2001-06-19 2003-12-02 Corning Incorporated Process of making a pattern in a film
US20030228593A1 (en) 2002-02-15 2003-12-11 Hiraoki Suga Ribozymes with broad tRNA aminoacylation activity
WO2003101972A1 (en) 2002-05-30 2003-12-11 The Scripps Research Institute Copper-catalysed ligation of azides and acetylenes
US6667312B2 (en) 2000-12-08 2003-12-23 3M Innovative Properties Company Thioether substituted imidazoquinolines
US20040001838A1 (en) 2001-12-21 2004-01-01 Immunogen, Inc. Cytotoxic agents bearing a reactive polyethylene glycol moiety, cytotoxic conjugates comprising polyethylene glycol linking groups, and methods of making and using the same
US6677347B2 (en) 2000-12-08 2004-01-13 3M Innovative Properties Company Sulfonamido ether substituted imidazoquinolines
US20040013637A1 (en) 1999-12-23 2004-01-22 Nektar Therapeutics Al, Corportion Hydrolytically degradable carbamate derivatives of poly(ethylene glycol)
US6683088B2 (en) 2000-12-08 2004-01-27 3M Innovative Properties Company Sulfonamido ether substituted imidazoquinolines
US6756382B2 (en) 1999-06-10 2004-06-29 3M Innovative Properties Company Amide substituted imidazoquinolines
US6825350B2 (en) 1999-06-10 2004-11-30 3M Innovative Properties Company Sulfonamide and sulfamide substituted imidazoquinolines and methods for the treatment of periodontal disease using these and other immune response modifiers
WO2006069246A2 (en) 2004-12-22 2006-06-29 Ambrx, Inc. Compositions containing, methods involving, and uses of non-natural amino acids and polypeptides
US7144574B2 (en) 1999-08-27 2006-12-05 Maxygen Aps Interferon β variants and conjugates
JP2008118008A (ja) 2006-11-07 2008-05-22 Nippon Telegr & Teleph Corp <Ntt> シリコン化合物薄膜の形成方法
EP1939202A1 (en) * 2005-09-22 2008-07-02 Dainippon Sumitomo Pharma Co., Ltd. Novel adenine compound
US7598382B2 (en) 2002-12-20 2009-10-06 Coley Pharmaceutical Group, Inc. Aryl substituted imidazoquinolines
US7807619B2 (en) 2004-11-01 2010-10-05 The Regents Of The University Of California Compositions and methods for modification of biomolecules
US20120295847A1 (en) 2005-03-18 2012-11-22 Novo Nordisk A/S Acylated GLP-1 Compounds
WO2012168430A2 (en) 2011-06-10 2012-12-13 Novo Nordisk A/S Polypeptides
WO2013004607A1 (en) 2011-07-01 2013-01-10 Bayer Intellectual Property Gmbh Relaxin fusion polypeptides and uses thereof
US8673932B2 (en) 2003-08-12 2014-03-18 3M Innovative Properties Company Oxime substituted imidazo-containing compounds
US20170182181A1 (en) 2014-04-04 2017-06-29 Merck Sharp & Dohme Corp. Phosphate based linkers for intracellular delivery of drug conjugates
WO2020056192A1 (en) * 2018-09-12 2020-03-19 Silverback Therapeutics, Inc. Antibody conjugates of toll-like receptor agonists
WO2020168017A1 (en) * 2019-02-12 2020-08-20 Ambrx, Inc. Compositions containing, methods and uses of antibody-tlr agonist conjugates

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB0624500D0 (en) * 2006-12-07 2007-01-17 Istituto Superiore Di Sanito A novel passive vaccine for candida infections
AR065784A1 (es) * 2007-03-20 2009-07-01 Dainippon Sumitomo Pharma Co Derivados de 8-oxo adenina,medicamentos que los contienen y usos como agentes terapeuticos para enfermedades alergicas, antivirales o antibacterianas.
CN112587671A (zh) * 2012-07-18 2021-04-02 博笛生物科技有限公司 癌症的靶向免疫治疗
CA2874083C (en) * 2014-12-05 2024-01-02 Universite Laval Tdp-43-binding polypeptides useful for the treatment of neurodegenerative diseases
TN2018000112A1 (en) * 2015-10-29 2019-10-04 Novartis Ag Antibody conjugates comprising toll-like receptor agonist

Patent Citations (172)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3773919A (en) 1969-10-23 1973-11-20 Du Pont Polylactide-drug mixtures
EP0036676A1 (en) 1978-03-24 1981-09-30 The Regents Of The University Of California Method of making uniformly sized liposomes and liposomes so made
US4289872A (en) 1979-04-06 1981-09-15 Allied Corporation Macromolecular highly branched homogeneous compound based on lysine units
EP0052322A2 (de) 1980-11-10 1982-05-26 Gersonde, Klaus, Prof. Dr. Verfahren zur Herstellung von Lipid-Vesikeln durch Ultraschallbehandlung, Anwendung des Verfahrens und Vorrichtung zur Durchführung des Verfahrens
EP0058481A1 (en) 1981-02-16 1982-08-25 Zeneca Limited Continuous release pharmaceutical compositions
US4414148A (en) 1981-04-15 1983-11-08 Sanofi Anti-cancer drugs for the treatment of melanomas and method for preparing thereof
US4485045A (en) 1981-07-06 1984-11-27 Research Corporation Synthetic phosphatidyl cholines useful in forming liposomes
US4619794A (en) 1982-02-17 1986-10-28 Ciba-Geigy Corporation Spontaneous preparation of small unilamellar liposomes
US4671958A (en) 1982-03-09 1987-06-09 Cytogen Corporation Antibody conjugates for the delivery of compounds to target sites
DE3218121A1 (de) 1982-05-14 1983-11-17 Leskovar, Peter, Dr.-Ing., 8000 München Arzneimittel zur tumorbehandlung
EP0102324A2 (de) 1982-07-29 1984-03-07 Ciba-Geigy Ag Lipide und Tenside in wässriger Phase
US4511503A (en) 1982-12-22 1985-04-16 Genentech, Inc. Purification and activity assurance of precipitated heterologous proteins
US4511502A (en) 1982-12-22 1985-04-16 Genentech, Inc. Purification and activity assurance of precipitated heterologous proteins
US4512922A (en) 1982-12-22 1985-04-23 Genentech, Inc. Purification and activity assurance of precipitated heterologous proteins
US4820352A (en) 1983-01-10 1989-04-11 Bausch & Lomb Incorporated Cleaning and conditioning solutions for contact lenses and methods of use
US4544545A (en) 1983-06-20 1985-10-01 Trustees University Of Massachusetts Liposomes containing modified cholesterol for organ targeting
EP0133988A2 (de) 1983-08-02 1985-03-13 Hoechst Aktiengesellschaft Regulatorische Peptide enthaltende pharmazeutische Präparate mit protrahierter Freisetzung und Verfahren zu deren Herstellung
US4870008A (en) 1983-08-12 1989-09-26 Chiron Corporation Secretory expression in eukaryotes
US5021234A (en) 1983-09-26 1991-06-04 Udo Ehrenfeld Agent and product for the diagnosis and treatment of tumors and for the treatment of weaknesses of the cellular and humoral immune defense
EP0143949A1 (en) 1983-11-01 1985-06-12 TERUMO KABUSHIKI KAISHA trading as TERUMO CORPORATION Pharmaceutical composition containing urokinase
EP0154316A2 (en) 1984-03-06 1985-09-11 Takeda Chemical Industries, Ltd. Chemically modified lymphokine and production thereof
US4625014A (en) 1984-07-10 1986-11-25 Dana-Farber Cancer Institute, Inc. Cell-delivery agent
US4569789A (en) 1984-08-29 1986-02-11 Dana-Farber Cancer Institute, Inc. Acid-cleavable compound, use in protein conjugates and drug delivery systems
US4618492A (en) 1984-08-29 1986-10-21 Dana-Farber Cancer Institute, Inc. Acid-cleavable compound
US4542225A (en) 1984-08-29 1985-09-17 Dana-Farber Cancer Institute, Inc. Acid-cleavable compound
US4659839A (en) 1984-10-10 1987-04-21 Mallinckrodt, Inc. Coupling agents for radiolabeled antibody fragments
EP0183503A2 (en) 1984-11-30 1986-06-04 Beecham Group Plc Conjugates of pharmaceutically useful proteins
EP0188256A2 (en) 1985-01-14 1986-07-23 NeoRx Metal radionuclide labeled proteins for diagnosis and therapy
US4670417A (en) 1985-06-19 1987-06-02 Ajinomoto Co., Inc. Hemoglobin combined with a poly(alkylene oxide)
EP0229108A1 (en) 1985-06-26 1987-07-22 Cetus Corp PROTEIN SOLUBILIZATION FOR PHARMACEUTICAL COMPOSITIONS USING A POLYMER CONJUGATION.
US4680338A (en) 1985-10-17 1987-07-14 Immunomedics, Inc. Bifunctional linker
WO1987002670A1 (en) 1985-10-25 1987-05-07 Mackay Vivian L Method of using bar1 for secreting foreign proteins
US4699784A (en) 1986-02-25 1987-10-13 Center For Molecular Medicine & Immunology Tumoricidal methotrexate-antibody conjugate
WO1987005330A1 (en) 1986-03-07 1987-09-11 Michel Louis Eugene Bergh Method for enhancing glycoprotein stability
US5229490A (en) 1987-05-06 1993-07-20 The Rockefeller University Multiple antigen peptide system
US5468478A (en) 1987-08-03 1995-11-21 Oxis International, Inc. Conjugates of superoxide dismutage coupled to high molecular weight polyalkylene glycols
EP0402378A1 (en) 1988-01-20 1990-12-19 Cetus Corp CONJUGATION OF THE POLYMERS ON COLONIZING FACTOR.
EP0439508A1 (en) 1988-10-20 1991-08-07 PolyMASC Pharmaceuticals plc Polyethylene glycolcol (peg)-protein adducts and process for their fractionation
US5047335A (en) 1988-12-21 1991-09-10 The Regents Of The University Of Calif. Process for controlling intracellular glycosylation of proteins
US5824778A (en) 1988-12-22 1998-10-20 Kirin-Amgen, Inc. Chemically-modified G-CSF
US4902502A (en) 1989-01-23 1990-02-20 Cetus Corporation Preparation of a polymer/interleukin-2 conjugate
US5612460A (en) 1989-04-19 1997-03-18 Enzon, Inc. Active carbonates of polyalkylene oxides for modification of polypeptides
US5122614A (en) 1989-04-19 1992-06-16 Enzon, Inc. Active carbonates of polyalkylene oxides for modification of polypeptides
US5808096A (en) 1989-04-19 1998-09-15 Enzon, Inc. Process for preparing active carbonates of polyalkylene oxides for modification of polypeptides
US5324844A (en) 1989-04-19 1994-06-28 Enzon, Inc. Active carbonates of polyalkylene oxides for modification of polypeptides
EP0400472A2 (en) 1989-05-27 1990-12-05 Sumitomo Pharmaceuticals Company, Limited Process for preparing polyethylene glycol derivatives and modified protein.
US5219564A (en) 1990-07-06 1993-06-15 Enzon, Inc. Poly(alkylene oxide) amino acid copolymers and drug carriers and charged copolymers based thereon
US5736625A (en) 1990-11-14 1998-04-07 Cargill, Incorporated Method for stabilizing proteins with saccharide linked protein polymer conjugates
US5252714A (en) 1990-11-28 1993-10-12 The University Of Alabama In Huntsville Preparation and use of polyethylene glycol propionaldehyde
WO1992016555A1 (en) 1991-03-18 1992-10-01 Enzon, Inc. Hydrazine containing conjugates of polypeptides and glycopolypeptides with polymers
US5834594A (en) 1991-03-25 1998-11-10 Hoffman-La Roche Inc. Polyethylene-protein conjugates
US5849860A (en) 1991-03-25 1998-12-15 Hoffmann-La Roche Inc. Polyethylene-protein conjugates
US5747646A (en) 1991-03-25 1998-05-05 Hoffmann-La Roche Inc. Polyethylene-protein conjugates
EP0510356A1 (en) 1991-03-25 1992-10-28 F. Hoffmann-La Roche Ag Polyethylene glycol protein conjugates
US5559213A (en) 1991-03-25 1996-09-24 Hoffmann-La Roche Inc. Polyethylene-protein conjugates
US5281698A (en) 1991-07-23 1994-01-25 Cetus Oncology Corporation Preparation of an activated polymer ester for protein conjugation
WO1993021259A1 (en) 1992-04-14 1993-10-28 Cornell Research Foundation Inc. Dendritic based macromolecules and method of production
US5476653A (en) 1992-06-17 1995-12-19 Amgen Inc. Polyoxymethylene-oxyethylene copolymers in conjuction with biomolecules
WO1994004193A1 (en) 1992-08-21 1994-03-03 Enzon, Inc. Novel attachment of polyalkylene oxides to bio-effecting substances
US5382657A (en) 1992-08-26 1995-01-17 Hoffmann-La Roche Inc. Peg-interferon conjugates
EP0605963A2 (en) 1992-12-09 1994-07-13 Ortho Pharmaceutical Corporation Peg hydrazone and peg oxime linkage forming reagents and protein derivatives thereof
WO1994014758A1 (en) 1992-12-22 1994-07-07 Enzon, Inc. Aryl imidate activated polyalkylene oxides
WO1994017039A1 (en) 1993-01-19 1994-08-04 Enzon, Inc. Cyclic imide thione activated polyalkylene oxides
WO1994018247A1 (en) 1993-02-02 1994-08-18 Enzon, Inc. Azlactone activated polyalkylene oxides
US5516673A (en) 1993-02-15 1996-05-14 Bar Ilan University Bioactive conjugates of cellulose with amino compounds
WO1994028024A1 (en) 1993-06-01 1994-12-08 Enzon, Inc. Carbohydrate-modified polymer conjugates with erythropoietic activity
WO1995000162A1 (en) 1993-06-21 1995-01-05 Enzon, Inc. Site specific synthesis of conjugated peptides
WO1995006058A1 (en) 1993-08-24 1995-03-02 Polymasc Pharmaceuticals Plc Polymer modification
WO1995011924A1 (en) 1993-10-27 1995-05-04 Enzon, Inc. Non-antigenic branched polymer conjugates
US5643575A (en) 1993-10-27 1997-07-01 Enzon, Inc. Non-antigenic branched polymer conjugates
WO1995013090A1 (en) 1993-11-10 1995-05-18 Enzon, Inc. Improved interferon polymer conjugates
US6610281B2 (en) 1993-11-12 2003-08-26 Shearwater Corporation Water soluble activated polymers containing an active ethyl sulfone moiety for modification of surfaces and molecules
US5739208A (en) 1993-11-12 1998-04-14 Shearwater Polymers, Inc. Isolatable, water soluble, and hydrolytically stable active sulfones of poly(ethylene glycol) and related polymers for modification of surfaces and molecules
WO1995013312A1 (en) 1993-11-12 1995-05-18 Shearwater Polymers, Inc. Water soluble active sulfones of poly(ethylene glycol)
US5900461A (en) 1993-11-12 1999-05-04 Shearwater Polymers, Inc. Isolatable, water soluble, and hydrolytically stable active sulfones of poly(ethylene glycol) and related polymers for modification of surfaces and molecules
US5446090A (en) 1993-11-12 1995-08-29 Shearwater Polymers, Inc. Isolatable, water soluble, and hydrolytically stable active sulfones of poly(ethylene glycol) and related polymers for modification of surfaces and molecules
US5473034A (en) 1994-03-18 1995-12-05 Hyogo Prefectural Government Method for producing protein-synthetic polymer conjugate and said conjugate produced thereby
US5629384A (en) 1994-05-17 1997-05-13 Consiglio Nazionale Delle Ricerche Polymers of N-acryloylmorpholine activated at one end and conjugates with bioactive materials and surfaces
WO1995033490A1 (en) 1994-06-02 1995-12-14 Enzon, Inc. Method of solubilizing substantially water insoluble materials
WO1996000080A1 (en) 1994-06-24 1996-01-04 Enzon, Inc. Non-antigenic amine derived polymers and polymer conjugates
US5650234A (en) 1994-09-09 1997-07-22 Surface Engineering Technologies, Division Of Innerdyne, Inc. Electrophilic polyethylene oxides for the modification of polysaccharides, polypeptides (proteins) and surfaces
WO1996007670A1 (en) 1994-09-09 1996-03-14 Surface Engineering Technologies, Division Of Innerdyne, Inc. Electrophilic polyethylene oxides for the modification of polysaccharides, polypeptides (proteins) and surfaces
US5824784A (en) 1994-10-12 1998-10-20 Amgen Inc. N-terminally chemically modified protein compositions and methods
WO1996041813A2 (en) 1994-11-09 1996-12-27 Offord Robin E Functionalized polymers for site-specific attachment
US6235710B1 (en) 1994-12-16 2001-05-22 Ortho Pharmaceutical Corporation Spray dried erythropoietin
US6001800A (en) 1994-12-16 1999-12-14 Ortho Pharmaceutical Corp. Spray dried erythropoietin
WO1996021469A1 (en) 1995-01-10 1996-07-18 Shearwater Polymers, Inc. Multi-armed, monofunctional, and hydrolytically stable derivatives of poly(ethylene glycol) and related polymers for modification of surfaces and molecules
US5932462A (en) 1995-01-10 1999-08-03 Shearwater Polymers, Inc. Multiarmed, monofunctional, polymer for coupling to molecules and surfaces
US20030114647A1 (en) 1995-01-10 2003-06-19 Shearwater Corporation Multi-armed, monofunctional, and hydrolytically stable derivatives of poly (ethylene glycol) and related polymers for modification of surfaces and molecules
WO1996040791A1 (en) 1995-06-07 1996-12-19 Novo Nordisk A/S Modification of polypeptides
US5672662A (en) 1995-07-07 1997-09-30 Shearwater Polymers, Inc. Poly(ethylene glycol) and related polymers monosubstituted with propionic or butanoic acids and functional derivatives thereof for biotechnical applications
WO1997003106A1 (en) 1995-07-07 1997-01-30 Shearwater Polymers, Inc. Poly(ethylene glycol) and related polymers monosubstituted with propionic or butanoic acids and functional derivatives thereof for biotechnical applications
WO1997018832A1 (en) 1995-11-21 1997-05-29 Enzon, Inc. Interferon-polymer conjugates and process for preparing the same
WO1997032607A2 (en) 1996-03-06 1997-09-12 Amgen Inc. Activated linkers and methods for making and purifying the same
EP0809996A2 (en) 1996-05-31 1997-12-03 F. Hoffmann-La Roche Ag Interferon conjugates
WO1998005363A2 (en) 1996-08-02 1998-02-12 Ortho-Mcneil Pharmaceutical, Inc. Polypeptides having a single covalently bound n-terminal water-soluble polymer
US5980948A (en) 1996-08-16 1999-11-09 Osteotech, Inc. Polyetherester copolymers as drug delivery matrices
US6515100B2 (en) 1996-09-26 2003-02-04 Shearwater Corporation Soluble, degradable poly (ethylene glycol) derivatives for controllable release of bound molecules into solution
US20010021763A1 (en) 1996-09-26 2001-09-13 Shearwater Corporation Soluble, degradable poly (ethylene glycol) derivatives for controllable release of bound molecules into solution
US20030220447A1 (en) 1996-09-26 2003-11-27 Shearwater Corporation Soluble, degradable poly (ethylene glycol) derivatives for controllable release of bound molecules into solution
US6214966B1 (en) 1996-09-26 2001-04-10 Shearwater Corporation Soluble, degradable poly(ethylene glycol) derivatives for controllable release of bound molecules into solution
WO1998032466A1 (en) 1997-01-29 1998-07-30 Polymasc Pharmaceuticals Plc Pegylation process
WO1998041562A1 (en) 1997-03-20 1998-09-24 Enzon, Inc. Non-antigenic branched polymer conjugates
WO1998048837A1 (en) 1997-04-30 1998-11-05 Enzon, Inc. Polyalkylene oxide-modified single chain polypeptides
US5990237A (en) 1997-05-21 1999-11-23 Shearwater Polymers, Inc. Poly(ethylene glycol) aldehyde hydrates and related polymers and applications in modifying amines
EP0921131A1 (en) 1997-06-06 1999-06-09 Kyowa Hakko Kogyo Co., Ltd. Chemically modified polypeptides
US6608183B1 (en) 1997-07-14 2003-08-19 Bolder Biotechnology, Inc. Derivatives of growth hormone and related proteins
US20030162949A1 (en) 1997-07-14 2003-08-28 Bolder Biotechnology, Inc. Cysteine variants of granulocyte-macrophage colony-stimulating factor
US6521427B1 (en) 1997-09-16 2003-02-18 Egea Biosciences, Inc. Method for the complete chemical synthesis and assembly of genes and genomes
US6129912A (en) 1997-09-26 2000-10-10 Uab Research Foundation Polyethylene glycol-protein compositions which reduce the antigenic display of red blood cells
US6004573A (en) 1997-10-03 1999-12-21 Macromed, Inc. Biodegradable low molecular weight triblock poly(lactide-co-glycolide) polyethylene glycol copolymers having reverse thermal gelation properties
US6201072B1 (en) 1997-10-03 2001-03-13 Macromed, Inc. Biodegradable low molecular weight triblock poly(lactide-co- glycolide) polyethylene glycol copolymers having reverse thermal gelation properties
US20020052009A1 (en) 1997-11-03 2002-05-02 Hans Hornauer Polyethylene glycol-derivatized biomolecules and their use in heterogeneous detection methods
US20020072573A1 (en) 1997-11-06 2002-06-13 Shearwater Corporation Heterobifunctional poly(ethylene glycol) derivatives and methods for their preparation
WO1999032139A1 (en) 1997-12-19 1999-07-01 Shering Corporation Improved interferon polymer conjugates
WO1999032134A1 (en) 1997-12-19 1999-07-01 Enzon, Inc. Substantially pure histidine-linked protein polymer conjugates
WO1999032140A1 (en) 1997-12-19 1999-07-01 Enzon, Inc. Alpha-interferon-polymer-conjugates having enhanced biological activity and methods of preparing the same
US6423685B1 (en) 1998-03-05 2002-07-23 Chiron Corporation Method for increasing the serum half-life of a biologically active molecule
US20020040076A1 (en) 1998-03-12 2002-04-04 Shearwater Corporation Poly(ethylene glycol) derivatives with proximal reactive groups
US20020037949A1 (en) 1998-03-12 2002-03-28 Shearwater Corporation Poly(ethylene glycol) derivatives with proximal reactive groups
US20020052430A1 (en) 1998-03-12 2002-05-02 Shearwater Corporation Poly (ethylene glycol) derivatives with proximal reactive groups
US20030228274A1 (en) 1998-08-28 2003-12-11 Gryphon Sciences Polyamide chains of precise length
US6552167B1 (en) 1998-08-28 2003-04-22 Gryphon Therapeutics, Inc. Polyamide chains of precise length
US6420339B1 (en) 1998-10-14 2002-07-16 Amgen Inc. Site-directed dual pegylation of proteins for improved bioactivity and biocompatibility
US6451346B1 (en) 1998-12-23 2002-09-17 Amgen Inc Biodegradable pH/thermosensitive hydrogels for sustained delivery of biologically active agents
US6281211B1 (en) 1999-02-04 2001-08-28 Euro-Celtique S.A. Substituted semicarbazides and the use thereof
US6306821B1 (en) 1999-04-16 2001-10-23 Wm. Marsh Rice University Functionalized poly(propylene fumarate) and poly(propylene fumarate-co-ethylene glycol)
US6825350B2 (en) 1999-06-10 2004-11-30 3M Innovative Properties Company Sulfonamide and sulfamide substituted imidazoquinolines and methods for the treatment of periodontal disease using these and other immune response modifiers
US6756382B2 (en) 1999-06-10 2004-06-29 3M Innovative Properties Company Amide substituted imidazoquinolines
US7144574B2 (en) 1999-08-27 2006-12-05 Maxygen Aps Interferon β variants and conjugates
US20030023023A1 (en) 1999-12-10 2003-01-30 Shearwater Corporation Hydrolytically degradable polymers and hydrogels made therefrom
US20020086939A1 (en) 1999-12-22 2002-07-04 Shearwater Corporation Method for the preparation of 1-benzotriazolyl carbonate esters of poly(ethylene glycol)
US20030105275A1 (en) 1999-12-22 2003-06-05 Shearwater Corporation Sterically hindered poly(ethylene glycol) alkanoic acids and derivatives thereof
US20020002250A1 (en) 1999-12-22 2002-01-03 Shearwater Corporation Sterically hindered poly(ethylene glycol) alkanoic acids and derivatives thereof
US20010056171A1 (en) 1999-12-22 2001-12-27 Shearwater Corporation Method for the preparation of 1-benzotriazolyl carbonate esters of poly(ethylene glycol)
US20020099133A1 (en) 1999-12-22 2002-07-25 Shearwater Corporation Method for the preparation of 1-benzotriazolyl carbonate esters of poly(ethylene glycol)
US20040013637A1 (en) 1999-12-23 2004-01-22 Nektar Therapeutics Al, Corportion Hydrolytically degradable carbamate derivatives of poly(ethylene glycol)
US6646110B2 (en) 2000-01-10 2003-11-11 Maxygen Holdings Ltd. G-CSF polypeptides and conjugates
US20010044526A1 (en) 2000-02-22 2001-11-22 Shearwater Corporation N-maleimidyl polymer derivatives
US6461603B2 (en) 2000-02-28 2002-10-08 Shearwater Corporation Water-soluble polymer conjugates of artelinic acid
US6436386B1 (en) 2000-11-14 2002-08-20 Shearwater Corporation Hydroxyapatite-targeting poly (ethylene glycol) and related polymers
US6667312B2 (en) 2000-12-08 2003-12-23 3M Innovative Properties Company Thioether substituted imidazoquinolines
US6683088B2 (en) 2000-12-08 2004-01-27 3M Innovative Properties Company Sulfonamido ether substituted imidazoquinolines
US6677347B2 (en) 2000-12-08 2004-01-13 3M Innovative Properties Company Sulfonamido ether substituted imidazoquinolines
US20020082345A1 (en) 2000-12-18 2002-06-27 Shearwater Corporation Synthesis of high molecular weight non-peptidic polymer derivatives
US20020156047A1 (en) 2001-01-19 2002-10-24 Shearwater Corporation Multi-arm block copolymers as drug delivery vehicles
US7083970B2 (en) 2001-04-19 2006-08-01 The Scripps Research Institute Methods and compositions for the production of orthogonal tRNA-aminoacyl tRNA synthetase pairs
US7045337B2 (en) 2001-04-19 2006-05-16 The Scripps Research Institute In vivo incorporation of unnatural amino acids
WO2002085923A2 (en) 2001-04-19 2002-10-31 The Scripps Research Institute In vivo incorporation of unnatural amino acids
US6656398B2 (en) 2001-06-19 2003-12-02 Corning Incorporated Process of making a pattern in a film
US6656389B2 (en) 2001-06-29 2003-12-02 International Business Machines Corporation Thermal paste for low temperature applications
US20030105224A1 (en) 2001-10-09 2003-06-05 Shearwater Corporation Thioester polymer derivatives and method of modifying the N-terminus of a polypeptide therewith
US20030158333A1 (en) 2001-10-09 2003-08-21 Shearwater Corporation Thioester-terminated water soluble polymers and method of modifying the N-terminus of a polypeptide therewith
US20030143596A1 (en) 2001-11-07 2003-07-31 Shearwater Corporation Branched polymers and their conjugates
US20040001838A1 (en) 2001-12-21 2004-01-01 Immunogen, Inc. Cytotoxic agents bearing a reactive polyethylene glycol moiety, cytotoxic conjugates comprising polyethylene glycol linking groups, and methods of making and using the same
US20030228593A1 (en) 2002-02-15 2003-12-11 Hiraoki Suga Ribozymes with broad tRNA aminoacylation activity
WO2003101972A1 (en) 2002-05-30 2003-12-11 The Scripps Research Institute Copper-catalysed ligation of azides and acetylenes
US7598382B2 (en) 2002-12-20 2009-10-06 Coley Pharmaceutical Group, Inc. Aryl substituted imidazoquinolines
US8673932B2 (en) 2003-08-12 2014-03-18 3M Innovative Properties Company Oxime substituted imidazo-containing compounds
US7807619B2 (en) 2004-11-01 2010-10-05 The Regents Of The University Of California Compositions and methods for modification of biomolecules
WO2006069246A2 (en) 2004-12-22 2006-06-29 Ambrx, Inc. Compositions containing, methods involving, and uses of non-natural amino acids and polypeptides
US20060194256A1 (en) 2004-12-22 2006-08-31 Ambrx, Inc. Compositions containing, methods involving, and uses of non-natural amino acids and polypeptides
US20060217289A1 (en) 2004-12-22 2006-09-28 Ambrx, Inc. Compositions containing, methods involving, and uses of non-natural amino acids and polypeptides
US20060217532A1 (en) 2004-12-22 2006-09-28 Ambrx, Inc. Compositions containing, methods involving, and uses of non-natural amino acids and polypeptides
US20120295847A1 (en) 2005-03-18 2012-11-22 Novo Nordisk A/S Acylated GLP-1 Compounds
EP1939202A1 (en) * 2005-09-22 2008-07-02 Dainippon Sumitomo Pharma Co., Ltd. Novel adenine compound
JP2008118008A (ja) 2006-11-07 2008-05-22 Nippon Telegr & Teleph Corp <Ntt> シリコン化合物薄膜の形成方法
WO2012168430A2 (en) 2011-06-10 2012-12-13 Novo Nordisk A/S Polypeptides
WO2013004607A1 (en) 2011-07-01 2013-01-10 Bayer Intellectual Property Gmbh Relaxin fusion polypeptides and uses thereof
US20170182181A1 (en) 2014-04-04 2017-06-29 Merck Sharp & Dohme Corp. Phosphate based linkers for intracellular delivery of drug conjugates
WO2020056192A1 (en) * 2018-09-12 2020-03-19 Silverback Therapeutics, Inc. Antibody conjugates of toll-like receptor agonists
WO2020168017A1 (en) * 2019-02-12 2020-08-20 Ambrx, Inc. Compositions containing, methods and uses of antibody-tlr agonist conjugates

Non-Patent Citations (119)

* Cited by examiner, † Cited by third party
Title
"MEDICAL APPLICATIONS OF LIPOSOMES", 1998
ABUCHOWSKI ET AL., CANCER BIOCHEM. BIOPHYS., vol. 7, 1984, pages 175 - 176
ANDERSON ET AL.: "Exploring the Limits of Codon and Anticodon Size", CHEMISTRY AND BIOLOGY, vol. 9, 2002, pages 237 - 244, XP055506543, DOI: 10.1016/S1074-5521(02)00094-7
ANDRESZ ET AL., MAKROMOL. CHEM., vol. 179, 1978, pages 301
APLINWRISTON, CRC CRIT. REV. BIOCHEM., 1981, pages 259 - 306
ARAKAWA ET AL., PHARM. RES., vol. 8, no. 3, 1991, pages 285 - 291
BAIN, J. D. ET AL., NATURE, vol. 356, 1992, pages 537
BAIN, J. D.GLABE, C. G.DIX, T. A.CHAMBERLIN, A. R., J. AM. CHEM. SOC., vol. 111, 1989, pages 8013
BAIN, J.D.GLABE, C.G.DIX, T.A.CHAMBERLIN, A.R.DIALA, E.S.: "Biosynthetic site-specific Incorporation of a non-natural amino acid into a polypeptide", J. AM CHEM SOC, vol. 111, 1989, pages 8013 - 8014
BARANY ET AL., PROC. NATL. ACAD. SCI., vol. 88, 1991, pages 1069 - 1109
BATZER ET AL., NUCLEIC ACID RES., vol. 19, 1991, pages 5081
BEAUCHAMP ET AL., ANAL. BIOCHEM., vol. 131, 1983, pages 25
BLACKWELL ET AL., ANGEW, CHEM., INT. ED., vol. 37, 1998, pages 3281 - 3284
BROADHEAD, J. ET AL.: "The Spray Drying of Pharmaceuticals", DRUG DEV. IND. PHARM, vol. 18, 1992, pages 1169 - 1206, XP009030193, DOI: 10.3109/03639049209046327
BUCHNER ET AL., ANAL. BIOCHEM., vol. 205, 1992, pages 263 - 270
BUCKMANN ET AL., MAKROMOL. CHEM., vol. 182, 1981, pages 1379 - 161
CECH, SCIENCE, vol. 236, 1987, pages 1532 - 1539
CHAN ET AL., ORG. LETT., vol. 6, 2004, pages 2853
CHEMISTRY AND BIOLOGY, vol. 10, 2003, pages 1077 - 1084
CHIN J. ET AL., SCIENCE, vol. 301, 2003, pages 964 - 7
CHIN, J. W. ET AL., J. AM. CHEM. SOC., vol. 124, 2002, pages 14626 - 14630
COLOMA, M: "152", J. IMM. METHODS, 1992
CORNISH, V. W. ET AL., J. AM. CHEM. SOC., vol. 118, 1996, pages 8150 - 8151
CORNISH, V. W.MENDEL, D.SCHULTZ, P. G., ANGEW. CHEM. INT. ED. ENGL., vol. 34, 1995, pages 621
CURRENT PROTOCOLS IN MOLECULAR BIOLOGY, 1994
DEBINSKI ET AL., J. BIOL. CHEM., vol. 268, 1993, pages 14065 - 14070
DEITERS, A. ET AL., J. AM. CHEM. SOC., vol. 125, 2003, pages 11782 - 11783
E. SAXONC. BERTOZZI, SCIENCE, vol. 287, 2000, pages 2007 - 2010
ELLING ET AL., BIOTECH. APPL. BIOCHEM., vol. 13, 1991, pages 354
ELLMAN, J.A.MENDEL, D.ANTHONY-CAHILL, S.NOREN, C.J.SCHULTZ, P.G.: "Biosynthetic method for introducing unnatural amino acids site-specifically into proteins", METHODS IN ENZ., vol. 202, 1992, pages 301 - 336, XP009072078, DOI: 10.1016/0076-6879(91)02017-4
ELLMAN, J.A.MENDEL, D.SCHULTZ, P.G.: "Site-specific incorporation of novel backbone structures into proteins", SCIENCE, vol. 255, no. 5041, 1992, pages 197 - 200
EPPSTEIN ET AL., PROC. NATL. ACAD. SCI. U.S.A., vol. 82, 1985, pages 3688 - 3692
GAERTNER ET AL., J. BIOL. CHEM., vol. 269, 1994, pages 7224 - 7230
GALLIVAN, J. P.LESTER, H. A.DOUGHERTY, D. A., CHEM. BIOL., vol. 4, 1997, pages 740
GEOGHEGAN, K. F.STROH, J. G., BIOCONJUG. CHEM., vol. 3, 1992, pages 262 - 268
GILLAMSMITH, GENE, vol. 8, 1979, pages 81
GOODSON ET AL., BIOTECHNOLOGY (NY, vol. 8, 1990, pages 343
GUCKIANKOOL, ANGEW. CHEM. INT. ED. ENGL., vol. 36, 1998, pages 2825
H. HANGC. BERTOZZI, ACC. CHEM. RES., vol. 34, no. 9, 2001, pages 727 - 736
HARRIS ET AL., J. POLYM. SCI. CHEM. ED., vol. 22, 1984, pages 341
HECHT, S. M., ACC. CHEM. RES., vol. 25, 1992, pages 545
HECHT, S. M.ALFORD, B. L.KURODA, Y.KITANO, S., J. BIOL. CHEM., vol. 253, 1978, pages 4517
HECKLER, T. G.ROESSER, J. R.XU, C.CHANG, P.HECHT, S. M., BIOCHEMISTRY, vol. 27, 1988, pages 7254
HIRAO ET AL.: "An unnatural base pair for incorporating amino acid analogues into protein", NATURE BIOTECHNOLOGY, vol. 20, 2002, pages 177 - 182
HOHSAKA, T. ET AL., J. AM. CHEM. SOC., vol. 121, 1999, pages 11585 - 6
HU ET AL., CANCER RESEARCH, vol. 56, 1996, pages 3055 - 3061
HUDSON, CURR. OPIN. BIOTECHNOL., vol. 9, 1998, pages 395 - 402
HWANG ET AL., PROC. NATL. ACAD. SCI. U.S.A., vol. 77, 1980, pages 4030 - 4034
ILLANGAKEKARE ET AL., SCIENCE, vol. 268, 1995, pages 439 - 647
JENCKS, W. P., J. AM. CHEM. SOC., vol. 123, 1959, pages 7439 - 481
JOPPICH ET AL., MAKROMOL. CHEM., vol. 180, 1979, pages 1381
KAYSER, B. ET AL., TETRAHEDRON, vol. 53, no. 7, 1997, pages 2475 - 2484
KIICK ET AL.: "Incorporation of azides into recombinant proteins for chemoselective modification by the Staudinger ligation", PNAS, vol. 99, 2002, pages 19 - 24, XP002904363, DOI: 10.1073/pnas.012583299
KOBAYASHI ET AL., NATURE STRUCTURAL BIOLOGY, vol. 10, no. 6, 2003, pages 425 - 432
KOGAN, SYNTHETIC COMM, vol. 22, 1992, pages 2417
KOLB ET AL., ANGEW. CHEM. INT. ED., vol. 40, 2001, pages 2004
KOLB ET AL., DRUG DISCOVERY TODAY, vol. 8, 2003, pages 1128
KOOL, CURR. OPIN. CHEM. BIOL., vol. 4, 2000, pages 602
KREITMANPASTAN, BIOCONJUG. CHEM., vol. 4, 1993, pages 581 - 585
KRIEGLER, GENE TRANSFER AND EXPRESSION: A LABORATORY MANUAL, 1990
L. A. VALLS ET AL., CELL, vol. 48, 1987, pages 887 - 897
LANGER ET AL., J. BIOMED. MATER. RES., vol. 15, 1981, pages 267 - 277
LANGER, CHEM. TECH., vol. 12, 1982, pages 98 - 105
LOHSE ET AL., NATURE, vol. 381, 1996, pages 442 - 444
M. CARRASCOR. BROWN, J. ORG. CHEM., vol. 68, 2003, pages 8853 - 8858
M. EGEL-MITANI ET AL., YEAST, vol. 6, 1990, pages 127 - 137
MA ET AL., BIOCHEMISTRY, vol. 32, 1993, pages 7939
MAGLIERY: "Expanding the Genetic Code: Selection of Efficient Suppressors of Four-base Codons and Identification of ''Shifty'' Four-base Codons with a Library Approach in Escherichia coli", J. MOL. BIOL., vol. 307, 2001, pages 755 - 769, XP004464163, DOI: 10.1006/jmbi.2001.4518
MAHAL, L. K. ET AL., SCIENCE, vol. 276, 1997, pages 1125 - 1128
MAMOT C ET AL., CANCER RES., vol. 63, 2003, pages 3154 - 3161
MANETSCH ET AL., J. AM. CHEM. SOC., vol. 126, 2004, pages 12809
MAYNARDGEORGIOU, ANNU. REV. BIOMED. ENG., vol. 2, 2000, pages 339 - 76
MCCORKLE ET AL., CONCEPTS BIOCHEM, vol. 64, 1987, pages 221 - 226
MEHVAR, R., J. PHARM SCI., vol. 3, no. 1, 2000, pages 125 - 136
MENDEL, D.CORNISH, V.W.SCHULTZ, P.G.: "Site-Directed Mutagenesis with an Expanded Genetic Code", ANNU REV BIOPHYS. BIOMOL STRUCT., vol. 24, 1995, pages 435 - 62, XP009036460, DOI: 10.1146/annurev.bb.24.060195.002251
MOORE ET AL., J. MOL. BIOL., vol. 298, 2000, pages 195
MOSBACH ET AL., NATURE, vol. 302, 1983, pages 543 - 545
N. BUDISA ET AL., FASEB J., vol. 13, 1999, pages 41 - 51
NIELSEN UB ET AL., BIOCHIM. BIOPHYS. ACTA, vol. 1591, no. 1-3, 2002, pages 109 - 118
NOREN, C. J.ANTHONY-CAHILL, S. J.GRIFFITH, M. C.SCHULTZ, P. G., SCIENCE, vol. 244, 1989, pages 182
NOREN, C.J.ANTHONY-CAHILL, GRIFFITH, M.C.SCHULTZ, P.G.: "A general method for site-specific incorporation of unnatural amino acids into proteins", SCIENCE, vol. 244, 1989, pages 182 - 188
O. HAGENBUCHLE ET AL., NATURE, vol. 289, 1981, pages 643 - 646
OHTSUKA ET AL., J. BIOL. CHEM., vol. 260, 1985, pages 2605 - 2608
OLSON ET AL.: "Poly(ethylene glycol) Chemistry & Biological Applications", 1997, ACS, pages: 170 - 181
PADWA, A., COMPREHENSIVE ORGANIC SYNTHESIS, vol. 4, 1991, pages 1069 - 1109
PALVA ET AL., GENE, vol. 22, 1983, pages 229 - 235
PARK JW ET AL., CLIN. CANCER RES., vol. 8, 2002, pages 1172 - 1181
PARK JW ET AL., PROC. NATL. ACAD. SCI. USA, vol. 92, 1995, pages 1327 - 1331
PEARCE ET AL., BIOCHEMISTRY, vol. 38, 1999, pages 81 - 89
PEPINSKY RB. ET AL., J. PHARMCOL. & EXP. THER., vol. 297, no. 3, 2001, pages 1059 - 66
PICCIRILLI ET AL., NATURE, vol. 343, 1990, pages 33
PIKAL, M., BIOPHARM., vol. 3, no. 9, 1990, pages 26 - 30
PITHA ET AL., EUR. J BIOCHEM., vol. 94, 1979, pages 11
PRENETA, AZ: "PROTEIN PURIFICATION METHODS, A PRACTICAL APPROACH", 1989, IRL PRESS, pages: 293 - 306
ROBERTS ET AL., NATURE, vol. 328, 1987, pages 731
ROBERTSON, S. A.ELLMAN, J. A.SCHULTZ, P. G., J. AM. CHEM. SOC., vol. 113, 1991, pages 2722
ROMANI ET AL., CHEMISTRY OF PEPTIDES AND PROTEINS, vol. 2, 1984, pages 29
ROSENTHAL, G., LIFE SCI, vol. 60, 1997, pages 1635 - 1641
ROSSOLINI ET AL., MOL. CELL. PROBES, vol. 8, 1994, pages 91 - 98
ROSTOVTSEV ET AL., ANGEW. CHEM. INT. ED., vol. 41, 2002, pages 2596 - 2599
SAKS, M. E. ET AL., J. BIOL. CHEM., vol. 271, 1996, pages 23169
SAMBROOK ET AL., MOLECULAR CLONING, A LABORATORY MANUAL, 2001
SARTORE ET AL., APPL. BIOCHEM. BIOTECH., vol. 27, 1991, pages 45
SAWHNEY ET AL., MACROMOLECULES, vol. 26, 1993, pages 581
SAYERS, J.R. ET AL.: "5 '-3' Exonucleases in phosphorothioate-based oligonucleotide-directed mutagenesis", NUCLEIC ACIDS RES, vol. 16, 1988, pages 791 - 802, XP001314878
SAYERS, J.R.SCHMIDT, W. ECKSTEIN: "F. 5'-3' Exonucleases in phosphorothioate-based oligonucleotide-directed mutagenesis", NUCLEIC ACIDS RES, vol. 16, no. 3, 1988, pages 791 - 802, XP001314878
SCHAFMEISTER ET AL., J. AM. CHEM. SOC., vol. 122, 2000, pages 10714 - 5892
SCHNEIDER, E. ET AL., PROTEIN EXPR. PURIF.
SHAO, J.TAM, J. P., J. AM. CHEM. SOC., vol. 117, no. 14, 1995, pages 3893 - 3899
SIDMAN ET AL., BIOPOLYMERS, vol. 22, 1983, pages 547 - 556
TIJSSEN: "Laboratory Techniques in Biochemistry and Molecular Biology--Hybridization with Nucleic Probes", OVERVIEW OF PRINCIPLES OF HYBRIDIZATION AND THE STRATEGY OF NUCLEIC ACID ASSAYS, 1993
TONDELLI ET AL., J. CONTROLLED RELEASE, vol. 1, 1985, pages 251
TORNOE, C. W. ET AL., J. ORG. CHEM., vol. 67, 2002, pages 3057 - 3064
VERONESE ET AL., APPL. BIOCHEM. BIOTECH., vol. 11, 1985, pages 141
WALENSKY ET AL., SCIENCE, vol. 305, 2004, pages 1466 - 1470
WASER ET AL., J. AM. CHEM. SOC., vol. 127, 2005, pages 15998
WOGHIREN ET AL., BIOCONJ. CHEM., vol. 4, 1993, pages 314
ZALIPSKY ET AL., EUR. POLYM. J., vol. 19, 1983, pages 1177
ZHANG, Z. ET AL., BIOCHEMISTRY, vol. 42, 2003, pages 6735 - 6746

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12133884B2 (en) 2018-05-11 2024-11-05 Beam Therapeutics Inc. Methods of substituting pathogenic amino acids using programmable base editor systems
JP2024524213A (ja) * 2021-06-22 2024-07-05 タクシス ファーマシューティカルズ， インコーポレイテッド 治療化合物
EP4359416A4 (en) * 2021-06-22 2025-05-14 Taxis Pharmaceuticals, Inc. THERAPEUTIC COMPOUNDS
WO2024020684A1 (en) * 2022-07-26 2024-02-01 Zymeworks Bc Inc. Immunomodulator purine-derived compounds, conjugates thereof, and methods of use thereof
WO2024077277A1 (en) 2022-10-07 2024-04-11 Ambrx, Inc. Drug linkers and antibody conjugates thereof
WO2024155627A1 (en) 2023-01-16 2024-07-25 Ambrx, Inc. Anti-cd70 antibody-drug conjugates
WO2024178310A1 (en) 2023-02-23 2024-08-29 Ambrx, Inc. Trop2-directed antibody-drug conjugates and uses thereof
WO2025038646A1 (en) * 2023-08-14 2025-02-20 Intellia Therapeutics, Inc. Cd70 car-t compositions and methods for cell-based therapy

Also Published As

Publication number Publication date
TW202227449A (zh) 2022-07-16
JP2023538071A (ja) 2023-09-06
US20230302150A1 (en) 2023-09-28
KR20230073200A (ko) 2023-05-25
EP4199968A1 (en) 2023-06-28
AU2021327396A1 (en) 2023-03-23
CA3190606A1 (en) 2022-02-24

Similar Documents

Publication Publication Date Title
AU2024205610B2 (en) Compositions containing, methods and uses of antibody-TLR agonist conjugates
US20230302150A1 (en) Antibody-tlr agonist conjugates, methods and uses thereof
US12049485B2 (en) Interleukin-2 polypeptide conjugates and their uses
US20250161471A1 (en) Anti-her2 antibody-drug conjugates and uses thereof
US20220009986A1 (en) Interleukin-10 polypeptide conjugates, dimers thereof, and their uses
US20230226152A1 (en) Interleukin-2 polypeptide conjugates and methods of use thereof
CN116457023A (zh) 抗体-tlr激动剂缀合物、方法及其用途
CN117440833A (zh) 抗-her2抗体-药物缀合物及其用途
HK40062074A (en) Compositions containing, methods and uses of antibody-tlr agonist conjugates
HK40106268A (zh) 抗-her2抗体-药物缀合物及其用途
HK40096444A (zh) 抗体-tlr激动剂缀合物、方法及其用途
HK40062074B (zh) 包含抗体-tlr激动剂缀合物的组合物、方法和用途

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 21772883

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 3190606

Country of ref document: CA

ENP Entry into the national phase

Ref document number: 2023511915

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2021327396

Country of ref document: AU

Date of ref document: 20210820

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 2021772883

Country of ref document: EP

Effective date: 20230320

WWE Wipo information: entry into national phase

Ref document number: 202180071626.X

Country of ref document: CN