Classifications

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  • 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
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  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
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  • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
  • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
  • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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  • 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
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  • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
  • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
  • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
  • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
  • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
  • A61K47/68031—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being an auristatin
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  • 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
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  • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
  • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
  • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
  • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
  • A61K47/6883—Polymer-drug antibody conjugates, e.g. mitomycin-dextran-Ab; DNA-polylysine-antibody complex or conjugate used for therapy
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
  • A61L27/14—Macromolecular materials
• • A—HUMAN NECESSITIES
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• • A—HUMAN NECESSITIES
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  • A61P35/02—Antineoplastic agents specific for leukemia
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
  • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
  • C07K16/32—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against translation products of oncogenes
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K19/00—Hybrid peptides, i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
  • C07K7/02—Linear peptides containing at least one abnormal peptide link
• • C—CHEMISTRY; METALLURGY
  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
  • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
  • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
  • C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
  • C08G65/32—Polymers modified by chemical after-treatment
  • C08G65/329—Polymers modified by chemical after-treatment with organic compounds
  • C08G65/331—Polymers modified by chemical after-treatment with organic compounds containing oxygen
  • C08G65/332—Polymers modified by chemical after-treatment with organic compounds containing oxygen containing carboxyl groups, or halides, or esters thereof
  • C08G65/3324—Polymers modified by chemical after-treatment with organic compounds containing oxygen containing carboxyl groups, or halides, or esters thereof cyclic
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  • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
  • C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
  • C08G65/32—Polymers modified by chemical after-treatment
  • C08G65/329—Polymers modified by chemical after-treatment with organic compounds
  • C08G65/334—Polymers modified by chemical after-treatment with organic compounds containing sulfur
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  • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
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  • C08G65/32—Polymers modified by chemical after-treatment
  • C08G65/329—Polymers modified by chemical after-treatment with organic compounds
  • C08G65/334—Polymers modified by chemical after-treatment with organic compounds containing sulfur
  • C08G65/3348—Polymers modified by chemical after-treatment with organic compounds containing sulfur containing nitrogen in addition to sulfur
• • A—HUMAN NECESSITIES
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  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
  • A61K39/44—Antibodies bound to carriers
• • A—HUMAN NECESSITIES
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  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
  • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
• • C—CHEMISTRY; METALLURGY
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  • C07K—PEPTIDES
  • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
  • C07K7/04—Linear peptides containing only normal peptide links
  • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
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  • C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
  • C08G65/32—Polymers modified by chemical after-treatment
• • C—CHEMISTRY; METALLURGY
  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
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  • C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
  • C08G65/32—Polymers modified by chemical after-treatment
  • C08G65/329—Polymers modified by chemical after-treatment with organic compounds
  • C08G65/333—Polymers modified by chemical after-treatment with organic compounds containing nitrogen
  • C08G65/33396—Polymers modified by chemical after-treatment with organic compounds containing nitrogen having oxygen in addition to nitrogen

Definitions

• One objective in the field of drug delivery systems is to deliver medications intact to specifically targeted areas of the body through a system that can stabilize the drug and control the in vivo transfer of the therapeutic agent utilizing either physiological or chemical mechanisms, or both.
• Antibody-drug conjugates have been developed as target- specific therapeutic agents. Antibodies against various cancer cell-surface antigens have been conjugated with different cytotoxic agents that inhibit various essential cellular targets such as microtubules (maytansinoids, auristatins, taxanes: U.S. Patent Nos. 5,208,020; 5,416,064; 6,333,410;
• the present invention relates to a protein-polymer-drug conjugate that is biodegradable, biocompatible and exhibits high drug load as well as strong binding to target antigen.
• the present invention also relates to a polymeric scaffold useful to conjugate with a protein based recognition-molecule (PBRM) so as to obtain the protein-polymer-drug conjugate.
• PBRM protein based recognition-molecule
• the invention features a polymeric scaffold useful to conjugate with a PBRM.
• the scaffold comprises a polymeric carrier, one or more -L D -D connected to the polymeric carrier, and one or more L p connected to the polymeric carrier which is suitable for connecting a PBRM to the polymeric carrier, wherein:
• each occurrence of D is independently a therapeutic agent having a molecular weight ⁇ 5 kDa;
• the polymeric carrier is a polyacetal or polyketal
• L is a linker having the structure: connected to an oxygen atom of the polymeric carrier and L D1 connected to D, and ⁇ denotes direct or indirect attachment of D to L D1 , and L D contains a biodegradable bond so that when the bond is broken, D is released from the polymeric carrier in an active form for its intended therapeutic effect;
• L D1 is a carbonyl-containing moiety
• each of R LI and R L2 independently is absent, alkyl, heteroalkyl, cycloalkyl, or
• L pl is a moiety containing a functional group that is capable of forming a covalent bond with a functional group of a PBRM.
• the polymeric scaffold can include one or more of the following features.
• L is a linker having the structure: in which L is a moiety containing a functional group that is capable of forming a covalent bond with a functional group of a PBRM, and ⁇ denotes direct or indirect attachment of L P2 to L D1 .
• the functional group of L pl or L P2 is selected from -SR P , -S-S-LG, maleimido, and halo, in which LG is a leaving group and R p is H or a sulfur protecting group.
• L pl or L P2 contains a biodegradable bond.
• R L1 and R L2 are absent.
• the polymeric carrier of the scaffold of the invention is a polyacetal, e.g., a PHF having a molecular weight (i.e., MW of the unmodified PHF) ranging from about 2 kDa to about 300 kDa.
• a polyacetal e.g., a PHF having a molecular weight (i.e., MW of the unmodified PHF) ranging from about 2 kDa to about 300 kDa.
• the polymeric carrier of the scaffold of the invention is a polyacetal, e.g., a PHF having a molecular weight (i.e., MW of the unmodified PHF) ranging from about 2 kDa to about 40 kDa (e.g., about 6-20 kDa or about 8-15 kDa).
• a PHF having a molecular weight i.e., MW of the unmodified PHF
• the polymeric carrier of the scaffold of the invention is a polyacetal, e.g., a PHF having a molecular weight (i.e., MW of the unmodified PHF) ranging from about 20 kDa to about 300 kDa (e.g., about 40-150 kDa or about 50-100 kDa).
• the scaffold is of Formula (la):
• n 1 to about 2200
• mi is an integer from 1 to about 660
• n 1 to about 300
• n 3 is an integer from 1 to about 110
• the sum of m, mi, m 2 and m 3 ranges from about 15 to about 2200 .
• the PHF in Formula (la) has a molecular weight ranging from about 2 kDa to about 40 kDa (i.e., the sum of m, mi, m 2 , and m ranging from about 15 to about 300), m 2 is an integer from 1 to about 40, m is an integer from 1 to about 18, and/or mi is an integer from 1 to about 140 (e.g, mi being about 1-90).
• m 2 is an integer from 2 to about 20
• m is an integer from 1 to about 9
• mi is an integer from 1 to about 75 (e.g, mi being about 4-45).
• the PHF in Formula (la) has a molecular weight ranging from about 8 kDa to about 15 kDa (i.e., the sum of m, mi, m 2 , and m ranging from about 60 to about 110), m 2 is an integer from 2 to about 15, m is an integer from 1 to about 7, and/or mi is an integer from 1 to about 55 (e.g, mi being about 4-30).
• m 2 is an integer from 3 to about 300
• m is an integer from 1 to about 110
• mi is an integer from 1 to about 660 (e.g, mi being about 10-250).
• PHF in Formula (la) has a molecular weight ranging from 40 kDa to
• 150 kDa i.e., the sum of m, mi, m 2 , and m 3 ranging from about 300 to about 1100
• m 2 is an integer from 4 to about 150
• m is an integer from 1 to about 75
• mi is an integer from 1 to about 330 (e.g, mi being about 15-100).
• the PHF in Formula (la) has a molecular weight ranging from about 50 kDa to about 100 kDa (i.e., the sum of m, mi, m 2 , and m 3 ranging from about 370 to about 740), m 2 is an integer from 5 to about 100, m is an integer from 1 to about 40, and/or mi is an integer from 1 to about 220 (e.g, mi being about 15-80).
• the scaffold further comprises a PBRM connected to the polymeric carrier via L p .
• One or more PBRMs are connected to one drug-carrying polymeric carrier.
• the scaffold e.g., a PBRM-polymer-drug conjugate
• the scaffold is of Formula (lb):
• ⁇ between L P2 and PBRM denotes direct or indirect attachment of PBRM to L P2 , each occurrence of PBRM independently has a molecular weight of less than 200 kDa, m is an integer from 1 to about 2200,
• mi is an integer from 1 to about 660
• n 1 + 2 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + (C) + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3 + 3
• n is an integer from 0 to about 110
• iri4 is an integer from 1 to about 60;
• the sum of m, mi, m 2 , m 3 and rri 4 ranges from about 150 to about 2200 .
• mi is an integer from about 10 to about 660 (e.g, about 10-250).
• PHF in Formula (lb) has a molecular weight ranging from 40 kDa to
• m 2 is an integer from 4 to about 150
• m is an integer from 1 to about 75
• m 4 is an integer from 1 to about 30
• mi is an integer from 1 to about 330 (e.g, mi being about 10-330 or about 15-100).
• m 2 is an integer from 5 to about 100
• m is an integer from 1 to about 40
• m 4 is an integer from 1 to about 20
• mi is an integer from 1 to about 220 (e.g, mi being about 15-80).
• one or more drug-carrying polymeric carriers are connected to one PBRM.
• the scaffold(e.g., a PBRM-polymer-drug conjugate) comprises a PBRM with a molecular weight of greater than 40 kDa and one or more D-carrying polymeric carriers connected to the PBRM, in which each of the D-carrying polymeric carrier
• terminal attached to L denotes direct or indirect attachment of L to PBRM such that the D-carrying polymeric carrier is connected to the PBRM,
• n 1 to 300
• mi is an integer from 1 to 140
• n 2 is an integer from 1 to 40
• n 3 is an integer from 0 to 18,
• mi is an integer from 1 to 10; and the sum of m, mi, m 2 , m 3 , and m 4 ranges from 15 to 300; provided that the total number of L P2 attached to the PBRM is 10 or less.
• mi is an integer from 1 to about 120 (e.g, about 1-90) and/or m is an integer from 1 to about 10 (e.g, about 1-8).
• m 2 is an integer from 2 to about 20
• m is an integer from 1 to about 9
• mi is an integer from 1 to about 75 (e.g, mi being about 4-45).
• m 2 is an integer from 2 to about 15
• m is an integer from 1 to about 7
• mi is an integer from 1 to about 55 (e.g, mi being about 4-30).
• Each occurrence of D independently is selected from vinca alkaloids, auristatins, tubulysins, duocarmycins, kinase inhibitors, MEK inhibitors, KSP inhibitors, and analogs thereof.
• each occurrence of R 2 , R 3 , and R 4 independently is hydrogen or an aliphatic, heteroaliphatic, carbocyclic, or heterocyclic moiety, or each occurrence of -NR 2 - or -NR 2 NR 3 - is a heterocycloalkyl moiety;
• R IK is a leaving group (e.g., halide or RC(0)0- in which R is hydrogen, an aliphatic, heteroaliphatic, carbocyclic, or heterocycloalkyl moiety)
• R 1A is a sulfur protecting group
• ring A is cycloalkyl or heterocycloalkyl
• R 1J is hydrogen, an aliphatic, heteroaliphatic, carbocyclic, or heterocycloalkyl moiety.
• R sl , R s2 , and R s3 is hydrogen, an aliphatic, heteroaliphatic, carbocyclic, or heterocycloalkyl moiety.
• Each ⁇ when connected to PBRM, independently is -X p -M pl -
• each occurrence of R 2 , R 3 , and R 4 independently is hydrogen or an aliphatic, heteroaliphatic, carbocyclic, or heterocyclic moiety, or each occurrence of -NR 2 - or -NR 2 NR 3 - is a heterocycloalkyl moiety;
• X P r , Y P r , Z P r , and Q p is not absent.
• Each of M D1 and M pl independently is C 1-6 alkyl or C 1-6 heteroalkyl.
• Each of M D2 , M D3 , M m , M P2 , M P3 , and M P4 independently is absent, C 1-6 alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, or a combination thereof.
• j has one of the following structures:
• q is an integer from 0 to 12 and each of p and t independently is an integer from 0 to 3.
• R 4 o is selected from the group consisting of
• a is an integer from 1 to 6;
• c is an integer from 0 to 3.
• the invention features a polymeric scaffold useful to conjugate with both a protein based recognition-molecule (PBRM) and a therapeutic agent (D).
• the scaffold i.e., the one free of any D
• the polymeric carrier is a polyacetal or polyketal
• R L1 is connected to an oxygen atom of the polymeric carrier
• L D1 is a linker suitable for connecting a D molecule to the polymeric carrier, in which each occurrence of D is independently a therapeutic agent having a molecular weight ⁇ 5 kDa;
• each of R LI and R L2 independently is absent, alkyl, heteroalkyl, cycloalkyl, or
• L D1 is a moiety containing a functional group that is capable of forming a covalent bond with a functional group of D
• L pl is a moiety containing a functional group that is capable of forming a covalent bond with a functional group of a PBRM.
• the D-free scaffold useful to conjugate with a PBRM and a D can have one or more of the following features.
• L is a linker having the structure: in which L is a moiety containing a functional group that is capable of forming a covalent bond with a functional group of a PBRM, and ⁇ denotes direct or indirect attachment of L P2 to L D1 .
• the functional group of L pl or L P2 is selected from -SR P , -S-S-LG, maleimido, and halo, in which LG is a leaving group and R p is H or a sulfur protecting group.
• L pl or L P2 contains a biodegradable bond.
• R L1 and R L2 are absent.
• the polymeric carrier of the D-free scaffold is a polyacetal, e.g., a PHF having a molecular weight (i.e., MW of the unmodified PHF) ranging from about 2 kDa to about 300 kDa.
• a polyacetal e.g., a PHF having a molecular weight (i.e., MW of the unmodified PHF) ranging from about 2 kDa to about 300 kDa.
• the polymeric carrier of the D-free scaffold is a polyacetal, e.g., a PHF having a molecular weight (i.e., MW of the unmodified PHF) ranging from about 2 kDa to about 40 kDa (e.g., about 6-20 kDa or about 8-15 kDa).
• a PHF having a molecular weight i.e., MW of the unmodified PHF
• the polymeric carrier of the D-free scaffold of the invention is a polyacetal, e.g., a PHF having a molecular weight (i.e., MW of the unmodified PHF) ranging from about 20 kDa to about 300 kDa (e.g., about 40-150 kDa or about 50-100 kDa).
• the D-free scaffold is of Formula (Id):
• n 1 to about 2200
• mi is an integer from 1 to about 660
• n 3 is an integer from 1 to about 110
• the sum of m, mi, and m ranges from about 15 to about 2200 .
• the PHF in Formula (Id) has a molecular weight ranging from about 2 kDa to about 40 kDa (i.e., the sum of m, mi, and m 3 ranging from about 15 to about 300), m 3 is an integer from 1 to about 18, and/or mi is an integer from 1 to about 140 (e.g, mi being about 2- 120).
• the PHF in Formula (Id) has a molecular weight ranging from about 6 kDa to about 20 kDa (i.e., the sum of m, mi, and m ranging from about 45 to about 150), m is an integer from 1 to about 9, and/or mi is an integer from 1 to about 75 (e.g, mi being about 6-60).
• the PHF in Formula (Id) has a molecular weight ranging from about 8 kDa to about 15 kDa (i.e., the sum of m, mi, and m ranging from about 60 to about 110), m is an integer from 1 to about 7, and/or mi is an integer from 1 to about 55 (e.g, mi being about 6-45).
• m is an integer from 1 to about 7
• mi is an integer from 1 to about 55 (e.g, mi being about 6-45).
• the PHF in Formula (Id) has a molecular weight ranging from 20 kDa to
• m 3 is an integer from 1 to about 110
• mi is an integer from 1 to about 660 (e.g, mi being about 13-550).
• m 3 is an integer from 1 to about 75
• mi is an integer from 1 to about 330 (e.g, mi being about 20-250).
• the PHF in Formula (Id) has a molecular weight ranging from about 50 kDa to about 100 kDa (i.e., the sum of m, mi, and m ranging from about 370 to about 740), m is an integer from 1 to about 40, and/or mi is an integer from 1 to about 220 (e.g, mi being about 20- 180).
• the D-free scaffold further comprises a PBRM connected to the polymeric carrier via L p .
• One or more PBRMs are connected to one D-free polymeric carrier.
• ⁇ between L and PBRM denotes direct or indirect attachment of PBRM to L
• PBRM has a molecular weight of less than 200 kDa
• n 1 to 2200
• mi is an integer from 1 to 660
• n 3 is an integer from 0 to 110
• iri4 is an integer from 1 to about 60; and the sum of m, mi, m 2 , m 3 and ⁇ 4 ranges from about 150 to about 2200 .
• mi is an integer from about 10 to about 660 (e.g, about 14-550).
• m is an integer from 1 to about 75
• m 4 is an integer from 1 to about 30
• mi is an integer from 1 to about 330 (e.g, mi being about 20-250).
• the PHF in Formula (Ie) has a molecular weight ranging from about 50 kDa to about 100 kDa (i.e., the sum of m, mi, m , and m 4 ranging from about 370 to about 740), m is an integer from 1 to about 40, m 4 is an integer from 1 to about 20, and/or mi is an integer from 1 to about 220 (e.g, mi being about 20-180).
• one or more D-free polymeric carriers are connected to one PBRM.
• the scaffold comprises a PBRM with a molecular weight of greater than 40 kDa and one or more polymeric carriers connected to the PBRM, in which each of the polymeric carrier independently is of Formula (Hi):
• terminal attached to L denotes direct or indirect attachment of L to PBRM such that the D-carrying polymeric carrier is connected to the PBRM,
• n 1 to 300
• mi is an integer from 1 to 140
• n is an integer from 0 to 18,
• mi is an integer from 1 to 10; and the sum of m, mi, m 3 , and m 4 ranges from 15 to 300; provided that the total number of L P2 attached to the PBRM is 10 or less .
• mi is an integer from 2 to about 130 (e.g, about 3-120) and/or m is an integer from 1 to about 10 (e.g, about 1-8).
• m 3 is an integer from 1 to about 9
• mi is an integer from 6 to about 75 (e.g, mi being about 7- 60).
• the PHF in Formula (Hi) has a molecular weight ranging from about 8 kDa to about 15 kDa (i.e., the sum of m, mi, m 3 , and mi ranging from about 60 to about 110), m 3 is an integer from 1 to about 7, and/or mi is an integer from 6 to about 55 (e.g, mi being about 7- 45).
• conjugates are used interchangeably when the scaffold comprises one or more PBRM and one or more D molecules.
• the invention encompasses a conjugate comprising a polymeric carrier, one or more -L D -D connected to the polymeric carrier, and a protein based recognition-molecule (PBRM) connected to the polymeric carrier via L p , wherein:
• each occurrence of D is independently a therapeutic agent (e.g., a drug) having a molecular weight ⁇ 5 kDa;
• the polymeric carrier is a polyacetal or polyketal
• each of R LI and R L2 independently is absent, alkyl, cycloalkyl, heteroalkyl, or heterocyclo alkyl ;
• each occurrence of R 2 , R 3 , and R 4 independently is hydrogen or an aliphatic, heteroaliphatic, carbocyclic, or heterocyclic moiety, or each occurrence of -NR 2 - or -NR 2 NR 3 - is a heterocycloalkyl moiety;
• each L D at least one of X D , Y D , Z D , and Q D is not absent, and for each L p , at least one of X p , Y p , Z p , and Q p is not absent.
• the conjugate can include one or more of the following features.
• the polymeric carrier can be a polyacetal, e.g., PHF.
• M D1 is not absent when X D is absent.
• M pl is not absent when X p is absent.
• R is a sulfur protecting group
• each of ring A and B independently, is cycloalkyl or heterocycloalkyl
• R w is an aliphatic, heteroaliphatic, carbocyclic or heterocycloalkyl moiety
• ring D is heterocycloalkyl
• R 1J is hydrogen, an aliphatic, heteroaliphatic, carbocyclic, or
• R is a leaving group (e.g., halide or RC(0)0- in which R is hydrogen, an aliphatic, heteroaliphatic, carbocyclic, or heterocycloalkyl moiety).
• R is a leaving group (e.g., halide or RC(0)0- in which R is hydrogen, an aliphatic, heteroaliphatic, carbocyclic, or heterocycloalkyl moiety), R 1A is a sulfur protecting group, and ring A is cycloalkyl or heterocycloalkyl, and R 1J is hydrogen, an aliphatic, heteroaliphatic,
• R is a leaving group (e.g., halide or RC(0)0- in which R is hydrogen, an aliphatic, heteroaliphatic, carbocyclic, or heterocycloalkyl moiety)
• R 1A is a sulfur protecting group
• ring A is cycloalkyl or heterocycloalkyl
• R 1J is hydrogen, an aliphatic, heteroaliphatic
• R is
• R s , R s2 and R s is hydrogen, an aliphatic, heteroaliphatic, carbocyclic, or heterocycloalkyl moiety.
• Ring A can be C 3 _8 cycloalkyl or 5-19 membered heterocycloalkyl.
• Ring A can be any material
• Ring B can be C 3 _8 cycloalkyl or 3-12 membered heterocycloalkyl.
• Ring D can be piperazinyl or piperidinyl.
• Each of R sl , R s2 , and R s3 can be hydrogen or C 1-6 alkyl.
• Each PBRM independently can be a peptide, a peptide mimetic, an antibody, or an antibody fragment.
• Each of M D1 and M pl independently can be C 1-6 alkyl or C 1-6 heteroalkyl.
• Each of M D2 , M D3 , M m , M P2 , M P3 , and M P4 independently can be absent, C 1-6 alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, or a combination thereof.
• M D2 and M D3 can have one of the following structures:
• q is an integer from 0 to 12 and each of p and t independently is an integer from 0 to 3.
• M P2 and M P3 can have one of the following structures:
• q is an integer from 0 to 12 and each of p and t independently is an integer from 0 to 3.
• ring A or B independently is cycloalkyl or heterocycloalkyl;
• R is an aliphatic, heteroaliphatic, carbocyclic, or heterocycloalkyl moiety;
• R 1J is hydrogen, an aliphatic, heteroaliphatic, carbocyclic, or heterocycloalkyl moiety; and
• ring D is heterocycloalkyl.
• each of -M P2 -Z P -, -Z P -M P3 -, -Z P -M P2 -, and -M P3 -Z P - can have one of the following structures:
• ring A is cycloalkyl or heterocycloalkyl and R 1J is hydrogen, an aliphatic,
• Each of X D and X p independently can be absent.
• Each of Y and Y p independently can be -S-S-, -OCO-, -COO-, -CONH-, or
• Each of Q D and Q p independently can be absent, -S-S-, -OCO-, -COO-, -CONH-, -NHCO- OCONHNH- or -NHNHCOO-.
• this invention features a conjugate of Formula (I):
• the disconnection or gap between the polyacetal units indicates that the units can be connected to each other in any order.
• the appending groups that contain D, PBRM, W D , and W P can be randomly distributed along the polymer backbone.
• each D can be the same or different moiety and each PBRM can be the same or different moiety.
• the ratio between n 2 and n 4 can be greater than 1: 1, and up to 200: 1 (e.g., up to
• 100: 1) e.g., between 2: 1 and 40: 1; between 5: 1 and 20: 1; between 10: 1 and 50: 1, between 25: 1 and 50: 1, or between 30: 1 and 50: 1.
• the ratio between n 2 and n 4 can be about 50: 1, 40: 1, 25: 1, 20: 1, 10: 1, 5: 1 or 2: 1.
• the invention provides compositions comprising the conjugates, methods for their preparation, and methods of use thereof in the treatment of various disorders, including, but not limited to cancer.
• the invention also features a drug-polymer conjugate (e.g., therapeutic agent- polymer conjugate) that is similar to the protein-polymer-drug conjugate described above except that drug-polymer conjugate does not contain a PBRM.
• the polymer-drug conjugate may comprise a plurality of drug moieties in which each D can be the same or different.
• n 4 is 0 in the conjugate of Formula (I).
• the invention also features a protein-polymer conjugate (e.g., PBRM -polymer conjugate) that is similar to the protein-polymer-drug conjugate described above except that protein-polymer conjugate does not contain a drug.
• the protein-polymer conjugate may comprise a plurality of protein moieties in which each PBRM can be the same or different.
• n 2 is 0 in the conjugate of Formula (I).
• the target cancer can be anal, astrocytoma, leukemia, lymphoma, head and neck, liver, testicular, cervical, sarcoma, hemangioma, esophageal, eye, laryngeal, mouth, mesothelioma, skin, myeloma, oral, rectal, throat, bladder, breast, uterus, ovary, prostate, lung, colon, pancreas, renal, or gastric cancer.
• the invention further relates to a pharmaceutical composition
• a pharmaceutical composition comprising a polymeric scaffold or conjugate described herein and a pharmaceutically acceptable carrier.
• the invention relates to a method of diagnosing a disorder in a subject suspected of having the disorder.
• the method comprises administering an effective amount of the conjugate described herein to the subject suspected of having the disorder or performing an assay to detect a target antigen/receptor in a sample from the subject so as to determine whether the subject expresses target antigen or receptor.
• HPV:trastuzumab about 16: 1 to 18: 1) at 15.6 mg/kg, 5.2 mg/kg, 1.6 mg/kg and 0.5 mg/kg respectively and drug polymer conjugate PHF-GA-(HPV-Alanine)-SH (Example 6) (dosed at a Vinca dose that was equivalent to that present in Example 8 at 15.6 mg/kg) dosed once every week for 3 weeks on day 1, day 8 and day 15 respectively.
• HPV trastuzumab about 19: 1 to 22: 1) at 3.5 mg/kg dosed once every week for 3 weeks on day 1, day 8 and day 15 respectively;
• trastuzumab-MCC (Example 7, HPV: trastuzumab about 19: 1 to 22: 1) at 10 mg/kg dosed as a single dose on day 1; PBRM-drug polymer conjugates PHF-GA- (HPV- Alanine)- (Trastuzumab- MCC) (Example 7, HPV: trastuzumab about 19: 1 to 22: 1) at 10 mg/kg dosed once every week for 3 weeks on day 17, day 24 and day 31 respectively.
• Figure 6 is a graph showing the plasma PK for the conjugated HPV.
• trastuzumab after IV bolus administration of PBRM-drug-conjugate PHF-GA-(HPV-Alanine)- (Trastuzumab-M-(PEG) 12 ) as in Example 8 (HPV:trastuzumab about 16: 1 to 18: 1) at 15 mg/kg (based on trastuzumab).
• Figure 7 is a graph showing the accumulation of HPV in various organs of the mice after IV bolus administration of PBRM-drug-conjugate PHF-GA-(HPV-Alanine)-(Trastuzumab- M-(PEG) 12 ) as in Example 8 (HPV: trastuzumab about 16: 1 to 18: 1) at 15 mg/kg (based on trastuzumab).
• Figure 8 is a graph showing the tumor response in mice inoculated
• the present invention provides novel protein-polymer-drug conjugates, polymeric scaffolds for making the conjugates, synthetic methods for making the conjugates or polymeric scaffolds, pharmaceutical compositions containing them and various uses of the conjugates.
• the present invention also provides novel polymer-drug conjugates, synthetic methods for making the conjugates, pharmaceutical compositions containing them and various uses of the conjugates.
• the present invention further provides novel drug derivatives, synthetic methods for making the derivatives, pharmaceutical compositions containing them and various uses of the drug derivatives.
• protecting group means that a particular functional moiety, e.g., O, S, or N, is temporarily blocked so that a reaction can be carried out selectively at another reactive site in a multifunctional compound.
• a protecting group reacts selectively in good yield to give a protected substrate that is stable to the projected reactions; the protecting group must be selectively removed in good yield by readily available, preferably nontoxic reagents that do not attack the other functional groups; the protecting group forms an easily separable derivative (more preferably without the generation of new stereogenic centers); and the protecting group has a minimum of additional functionality to avoid further sites of reaction.
• oxygen, sulfur, nitrogen and carbon protecting groups may be utilized.
• oxygen protecting groups include, but are not limited to methyl ethers, substituted methyl ethers ⁇ e.g., MOM (methoxymethyl ether), MTM (methylthiomethyl ether), BOM (benzyloxymethyl ether), and PMBM (p- methoxybenzyloxymethyl ether)), substituted ethyl ethers, substituted benzyl ethers, silyl ethers ⁇ e.g., TMS (trimethylsilyl ether), TES (tnethylsilylether), TIPS (triisopropylsilyl ether), TBDMS (t-butyldimethylsilyl ether), tribenzyl silyl ether, and TBDPS (t-butyldiphenyl silyl ether), esters ⁇ e.g., formate, acetate, benzoate (Bz), trifluoroacetate, and dichloro a
• nitrogen protecting groups are utilized.
• Nitrogen protecting groups as well as protection and deprotection methods are known in the art.
• Nitrogen protecting groups include, but are not limited to, carbamates (including methyl, ethyl and substituted ethyl carbamates (e.g. , Troc), amides, cyclic imide derivatives, N- Alkyl and N-Aryl amines, imine derivatives, and enamine derivatives.
• certain exemplary sulphur protecting groups may be utilized.
• the sulfur protecting groups include, but are not limited to those oxygen protecting group describe above as well as aliphatic carboxylic acid (e.g., acrylic acid), maleimide, vinyl sulfonyl, and optionally substituted maleic acid.
• Certain other exemplary protecting groups are detailed herein, however, it will be appreciated that the present invention is not intended to be limited to these protecting groups; rather, a variety of additional equivalent protecting groups can be readily identified using the above criteria and utilized in the present invention. Additionally, a variety of protecting groups are described in "Protective Groups in Organic Synthesis" Third Ed. Greene, T.W. and Wuts, P.G., Eds., John Wiley & Sons, New York: 1999, the entire contents of which are hereby incorporated by reference.
• Leaving group refers to a molecular fragment that departs with a pair of electrons in heterolytic bond cleavage. Leaving groups can be anions or neutral molecules. Leaving groups include, but are not limited to halides such as Cl ⁇ , Br ⁇ , and ⁇ , sulfonate esters, such as /?ara-toluenesulfonate ("tosylate", TsO ⁇ ), and RC(0)0- in which R is hydrogen, an aliphatic, heteroaliphatic, carbocyclic, or heterocycloalkyl moiety.
• Antibody refers to an immunoglobulin molecule of the class IgG including but not limited to IgG subclasses (IgGl, 2, 3 and 4) and class IgM which is able to specifically bind to a specific epitope on an antigen.
• Antibodies can be intact immunoglobulins derived from natural sources or from recombinant sources and can be immunoreactive portions of intact immunoglobulins.
• Antibodies may exist in a variety of forms including, for example, polyclonal antibodies, monoclonal antibodies, camelized single domain antibodies, intracellular antibodies (“intrabodies”), recombinant antibodies, anti-idiotypic antibodies, domain antibodies, linear antibody, multispecific antibody, antibody fragments, such as, Fv, Fab, Fab', Fab'-SH, F(ab') 2 , single chain variable fragment antibodies (scFv), Fc, pFc', scFvFc, disulfide Fv (dsfv), bispecific antibodies (bc-scFv) such as BiTE antibodies; camelid antibodies, resurfaced antibodies, humanized antibodies, fully human antibodies, single-domain antibody (sdAb, also known as NANOBODY®), chimeric antibodies, chimeric antibodies comprising at least one human constant region, dual-affinity antibodies such as, dual-affinity retargeting proteins (DARTTM), divalent (or bivalent) single-chain variable fragments (di-scF
• Antibody fragment refers to at least a portion of the variable region of the immunoglobulin molecule that binds to its target, i.e., the antigen-binding region.
• antibody refers to both the full-length antibody and antibody fragments unless otherwise specified.
• PBRM Protein based recognition-molecule
• PBRMs include but are not limited to, antibodies (e.g., Trastuzumab, Cetuximab, Rituximab, Bevacizumab, Epratuzumab, Veltuzumab, Labetuzumab) or peptides (LHRH receptor targeting peptides, EC-1 peptide), lipocalins, such as, for example, anticalins, proteins such as, for example, interferons, lymphokines, growth factors, colony stimulating factors, and the like, peptides or peptide mimics, and the like.
• the protein based recognition molecule in addition to targeting the modified polymer conjugate to a specific cell, tissue or location, may also have certain therapeutic effect such as antiproliferative
• the protein based recognition molecule comprises or may be engineered to comprise at least one chemically reactive group such as, -COOH, primary amine, secondary amine -NHR, -SH, or a chemically reactive amino acid moiety or side chains such as, for example, tyrosine, histidine, cysteine, or lysine.
• Biocompatible as used herein is intended to describe compounds that exert minimal destructive or host response effects while in contact with body fluids or living cells or tissues.
• a biocompatible group refers to an aliphatic, cycloalkyl, heteroaliphatic, heterocycloalkyl, aryl, or heteroaryl moiety, which falls within the definition of the term biocompatible, as defined above and herein.
• Biocompatibility as used herein, is also taken to mean that the compounds exhibit minimal interactions with recognition proteins, e.g., naturally occurring antibodies, cell proteins, cells and other components of biological systems, unless such interactions are specifically desirable.
• substances and functional groups specifically intended to cause the above minimal interactions are considered to be biocompatible.
• compounds intended to be cytotoxic such as, e.g., antineoplastic agents
• compounds are "biocompatible" if their addition to normal cells in vitro, at concentrations similar to the intended systemic in vivo concentrations, results in less than or equal to 1% cell death during the time equivalent to the half-life of the compound in vivo ⁇ e.g., the period of time required for 50% of the compound administered in vivo to be eliminated/cleared), and their administration in vivo induces minimal and medically acceptable inflammation, foreign body reaction, immunotoxicity, chemical toxicity and/or other such adverse effects.
• the term "normal cells” refers to cells that are not intended to be destroyed or otherwise significantly affected by the compound being tested.
• Biodegradable As used herein, “biodegradable” polymers are polymers that are susceptible to biological processing in vivo. As used herein, “biodegradable” compounds or moieties are those that, when taken up by cells, can be broken down by the lysosomal or other chemical machinery or by hydrolysis into components that the cells can either reuse or dispose of without significant toxic effect on the cells.
• biocleavable as used herein has the same meaning of “biodegradable”. The degradation fragments preferably induce little or no organ or cell overload or pathological processes caused by such overload or other adverse effects in vivo. Examples of biodegradation processes include enzymatic and non-enzymatic hydrolysis, oxidation and reduction.
• Suitable conditions for non-enzymatic hydrolysis of the biodegradable protein-polymer-drug conjugates (or their components, e.g., the biodegradable polymeric carrier and the linkers between the carrier and the antibody or the drug molecule) described herein, for example, include exposure of the biodegradable conjugates to water at a temperature and a pH of lysosomal intracellular compartment.
• Biodegradation of some protein-polymer-drug conjugates or their components, e.g., the biodegradable polymeric carrier and the linkers between the carrier and the antibody or the drug molecule
• can also be enhanced extracellularly e.g. in low pH regions of the animal body, e.g.
• the effective size of the polymer carrier at pH ⁇ 7.5 does not detectably change over 1 to 7 days, and remains within 50% of the original polymer size for at least several weeks.
• the polymer carrier preferably detectably degrades over 1 to 5 days, and is completely transformed into low molecular weight fragments within a two-week to several- month time frame. Polymer integrity in such tests can be measured, for example, by size exclusion HPLC.
• the polymer degrades in cells with the rate that does not exceed the rate of metabolization or excretion of polymer fragments by the cells.
• the polymers and polymer biodegradation byproducts are biocompatible.
• Bioavailability The term “bioavailability” refers to the systemic availability
• Bioavailability is an absolute term that indicates measurement of both the time (rate) and total amount (extent) of drug or compound that reaches the general circulation from an administered dosage form.
• Hydrophilic The term “hydrophilic” as it relates to substituents on the polymer monomeric units does not essentially differ from the common meaning of this term in the art, and denotes chemical moieties which contain ionizable, polar, or polarizable atoms, or which otherwise may be solvated by water molecules.
• a hydrophilic group refers to an aliphatic, cycloalkyl, heteroaliphatic, heterocycloalkyl, aryl or heteroaryl moiety, which falls within the definition of the term hydrophilic, as defined above.
• hydrophilic organic moieties which are suitable include, without limitation, aliphatic or heteroaliphatic groups comprising a chain of atoms in a range of between about one and twelve atoms, hydroxyl, hydroxyalkyl, amine, carboxyl, amide, carboxylic ester, thioester, aldehyde, nitryl, isonitryl, nitroso, hydroxylamine, mercaptoalkyl, heterocycle, carbamates, carboxylic acids and their salts, sulfonic acids and their salts, sulfonic acid esters, phosphoric acids and their salts, phosphate esters, polyglycol ethers, polyamines, polycarboxylates, polyesters and polythioesters.
• At least one of the polymer monomeric units include a carboxyl group (COOH), an aldehyde group (CHO), a methylol (CH 2 OH) or a glycol (for example, CHOH-CH 2 OH or CH-(CH 2 OH) 2 ).
• hydrophilic as it relates to the polymers of the invention generally does not differ from usage of this term in the art, and denotes polymers comprising hydrophilic functional groups as defined above.
• hydrophilic polymer is a water- soluble polymer. Hydrophilicity of the polymer can be directly measured through determination of hydration energy, or determined through investigation between two liquid phases, or by chromatography on solid phases with known hydrophobicity, such as, for example, C4 or CI 8.
• Polymeric Carrier refers to a polymer or a modified polymer, which is suitable for covalently attaching to or can be covalently attached to one or more drug molecules with a designated linker and/or one or more PBRMs with a designated linker.
• physiological conditions relate to the range of chemical ⁇ e.g., pH, ionic strength) and biochemical ⁇ e.g., enzyme concentrations) conditions likely to be encountered in the extracellular fluids of living tissues.
• chemical ⁇ e.g., pH, ionic strength a chemical ⁇ e.g., sodium bicarbonate
• biochemical ⁇ e.g., enzyme concentrations e.g., enzyme concentrations
• polysaccharide “carbohydrate”, or “oligosaccharide” are known in the art and refer, generally, to substances having chemical formula (CH 2 0) n , where generally n>2, and their derivatives.
• Carbohydrates are polyhydroxyaldehydes or polyhydroxyketones, or change to such substances on simple chemical transformations, such as hydrolysis, oxidation or reduction.
• carbohydrates are present in the form of cyclic acetals or ketals (such as, glucose or fructose). These cyclic units (monosaccharides) may be connected to each other to form molecules with few (oligosaccharides) or several (polysaccharides) monosaccharide units. Often, carbohydrates with well defined number, types and positioning of monosaccharide units are called
• polysaccharides consisting of mixtures of molecules of variable numbers and/or positioning of monosaccharide units
• polysaccharides consisting of mixtures of molecules of variable numbers and/or positioning of monosaccharide units.
• polysaccharide consisting of mixtures of molecules of variable numbers and/or positioning of monosaccharide units
• polysaccharides consisting of mixtures of molecules of variable numbers and/or positioning of monosaccharide units.
• polysaccharide may include natural sugars ⁇ e.g., glucose, fructose, galactose, mannose, arabinose, ribose, and xylose) and/or derivatives of naturally occurring sugars ⁇ e.g., 2'- fluororibose, 2'-deoxyribose, and hexose).
• Small molecule refers to molecules, whether naturally- occurring or artificially created (e.g. , via chemical synthesis) that have a relatively low molecular weight. Preferred small molecules are biologically active in that they produce a local or systemic effect in animals, preferably mammals, more preferably humans.
• the small molecule is a drug and the small molecule is referred to as "drug molecule” or “drug” or “therapeutic agent”.
• the drug molecule has MW less than or equal to about 5 kDa. In other embodiments, the drug molecule has MW less than or equal to about 1.5 kDa.
• the drug molecule is selected from vinca alkaloids, auristatins, tubulysins, duocarmycins, kinase inhibitors, MEK inhibitors, KSP inhibitors, and analogs thereof.
• the drug is one that has already been deemed safe and effective for use by an appropriate governmental agency or body, e.g., the FDA.
• drugs for human use listed by the FDA under 21 C.F.R. ⁇ 330.5, 331 through 361, and 440 through 460; drugs for veterinary use listed by the FDA under 21 C.F.R. ⁇ 500 through 589, incorporated herein by reference, are all considered suitable for use with the present hydrophilic polymers.
• Classes of drug molecules that can be used in the practice of the present invention include, but are not limited to, anti-cancer substances, radionuclides, vitamins, anti-AIDS substances, antibiotics, immunosuppressants, anti-viral substances, enzyme inhibitors, neurotoxins, opioids, hypnotics, anti-histamines, lubricants, tranquilizers, anti-convulsants, muscle relaxants and anti-Parkinson substances, anti-spasmodics and muscle contractants including channel blockers, miotics and anti-cholinergics, anti-glaucoma compounds, anti-parasite and/or anti-protozoal compounds, modulators of cell-extracellular matrix interactions including cell growth inhibitors and anti-adhesion molecules, vasodilating agents, inhibitors of DNA, RNA or protein synthesis, anti-hypertensives, analgesics, anti-pyretics, steroidal and non-steroidal anti-inflammatory agents, anti-angiogenic factors, anti- secretory factors, anticoagulants and
• prostaglandins are also drugs.
• the drug may have a chemically reactive group such as, for example, -COOH, primary amine, secondary amine -NHR, -OH, -SH, -C(0)H, -C(0)R, -C(0)NHR 2b , C(S)OH, -S(0) 2 OR 2b , -P(0) 2 OR 2b , -CN, -NC or -ONO, in which R is an aliphatic, heteroaliphatic, carbocyclic or heterocycloalkyl moiety and R 2b is a hydrogen, an aliphatic, heteroaliphatic, carbocyclic, or heterocyclic moiety.
• a chemically reactive group such as, for example, -COOH, primary amine, secondary amine -NHR, -OH, -SH, -C(0)H, -C(0)R, -C(0)NHR 2b , C(S)OH, -S(0) 2 OR 2b , -P(0) 2 OR 2b , -CN,
• drug derivative or “modified drug” or the like as used herein, refers to a compound that comprises the drug molecule intended to be delivered by the conjugate of the invention and a functional group capable of attaching the drug molecule to the polymeric carrier.
• active form refers to a form of a compound that exhibits intended pharmaceutical efficacy in vivo or in vitro.
• the active form can be the drug itself or its derivatives, which exhibit the intended therapeutic properties.
• the release of the drug from the conjugate can be achieved by cleavage of a biodegradable bond of the linker which attaches the drug to the polymeric carrier.
• the active drug derivatives accordingly can comprise a portion of the linker.
• Diagnostic label refers to an atom, group of atoms, moiety or functional group, a nanocrystal, or other discrete element of a composition of matter, that can be detected in vivo or ex vivo using analytical methods known in the art. When associated with a conjugate of the present invention, such diagnostic labels permit the monitoring of the conjugate in vivo. Alternatively or additionally, constructs and
• compositions that include diagnostic labels can be used to monitor biological functions or structures.
• diagnostic labels include, without limitation, labels that can be used in medical diagnostic procedures, such as, radioactive isotopes (radionuclides) for gamma scintigraphy and Positron Emission Tomography (PET), contrast agents for Magnetic Resonance Imaging (MRI) (for example paramagnetic atoms and superparamagnetic nanocrystals), contrast agents for computed tomography and other X-ray-based imaging methods, agents for ultrasound- based diagnostic methods (sonography), agents for neutron activation (e.g., boron, gadolinium), fluorophores for various optical procedures, and, in general moieties which can emit, reflect, absorb, scatter or otherwise affect electromagnetic fields or waves (e.g. gamma-rays, X-rays, radiowaves, microwaves, light), particles (e.g. alpha particles, electrons, positrons, neutrons, protons) or other forms of radiation, e.g
• aliphatic in general, includes both saturated and unsaturated, straight chain (i.e., unbranched) or branched aliphatic hydrocarbons, which are optionally substituted with one or more functional groups.
• aliphatic is intended herein to include, but is not limited to, alkyl, alkenyl, alkynyl moieties.
• alkyl includes straight and branched alkyl groups.
• alkyl encompass both substituted and unsubstituted groups.
• lower alkyl is used to indicate those alkyl groups (substituted, unsubstituted, branched or unbranched) having about 1-6 carbon atoms.
• alkenyl the term alkenyl denotes a monovalent group derived from a hydrocarbon moiety having at least one carbon-carbon double bond by the removal of a single hydrogen atom.
• substituted alkenyl groups are substituted with one or more functional groups. Substituents include, but are not limited to, any of the substituents mentioned below, i.e., the substituents recited below resulting in the formation of a stable compound.
• Alkenyl groups include, for example, ethenyl, propenyl, butenyl, l-methyl-2-buten-l-yl, and the like.
• alkynyl the term alkynyl as used herein refers to a monovalent group derived from a hydrocarbon having at least one carbon-carbon triple bond by the removal of a single hydrogen atom.
• Substituted alkenyl groups are substituted with one or more functional groups. Substituents include, but are not limited to, any of the substituents mentioned below, i.e., the substituents recited below resulting in the formation of a stable compound.
• alkynyl groups include ethynyl, 2-propynyl (propargyl), 1-propynyl, and the like.
• the alkyl, alkenyl and alkynyl groups employed in the invention contain about 1-20 aliphatic carbon atoms. In certain other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the invention contain about 1-10 aliphatic carbon atoms. In yet other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the invention contain about 1-8 aliphatic carbon atoms. In still other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the invention contain about 1-6 aliphatic carbon atoms.
• the alkyl, alkenyl, and alkynyl groups employed in the invention contain about 1-4 carbon atoms.
• Illustrative aliphatic groups thus include, but are not limited to, for example, methyl, ethyl, n-propyl, isopropyl, allyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n- pentyl, sec-pentyl, isopentyl, tert-pentyl, n-hexyl, sec-hexyl, moieties and the like, which again, may bear one or more substituents.
• Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, l-methyl-2-buten-l-yl, and the like.
• Representative alkynyl groups include, but are not limited to, ethynyl, 2-propynyl (propargyl), 1-propynyl and the like.
• Alkylene as used herein, the term alkylene by itself or part of another term refers to a saturated, branched or straight chain having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkane.
• Alkylene radicals include, but are not limited to, methylene, 1,2, ethylene, 1,3-propyl, and the like.
• Suitable alkylenes include, but are not limited to methylene, ethylene, propylene, butylene, pentylene, hexylene, heptylene, ocytylene, nonylene, decalene, and the like.
• Cycloalkylene similarly refers to bivalent cycloalkyl.
• Cycloalkylene radicals include, but are not limited to, 1,1-cyclopentylene, 1,2-cyclopentylene, 1,1-cyclobutylene, 1,3- cyclobutylene, etc.
• Heteroaliphatic refers to aliphatic moieties in which one or more carbon atoms in the main chain have been substituted with a heteroatom.
• a heteroaliphatic group refers to an aliphatic chain which contains one or more oxygen, sulfur, nitrogen, phosphorus or silicon atoms, e.g., in place of carbon atoms.
• Heteroaliphatic moieties may be branched or linear unbranched.
• heteroaliphatic moieties are substituted ("substituted heteroaliphatic") by independent replacement of one or more of the hydrogen atoms thereon with one or more moieties including, but not limited to aliphatic; heteroaliphatic; cycloalkyl; heterocycloalkyl; aryl; heteroaryl;
• SQ 2 N independently includes, but is not limited to, hydrogen, halogen, or an optionally substituted aliphatic, heteroaliphatic, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, or alkylheteroaryl moiety. Additional examples of generally applicable substituents are illustrated by the specific embodiments shown in the Examples that are described herein.
• Cycloalkyl refers to a saturated or unsaturated nonaromatic hydrocarbon mono-or multi-ring system having 3 to 30 carbon atoms (e.g., C3-Q0).
• Suitable cycloalkyls include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cycloheptynyl, adamantyl, and the like.
• Heterocycloalkyl refers to a saturated or unsaturated
• heterocycloalkyl refers to a non-aromatic 5-, 6-, 7- or 8- membered ring or a polycyclic group, including, but not limited to a bi- or tri-cyclic group comprising fused six-membered rings having between one and three heteroatoms independently selected from oxygen, sulfur and nitrogen, wherein (i) each 5-membered ring has 0 to 2 double bonds and each 6-membered ring has 0 to 2 double bonds, (ii) the nitrogen and sulfur
• heteroatoms may optionally be oxidized, (iii) the nitrogen heteroatom may optionally be quaternized, and (iv) any of the above heterocycloalkyl; rings may be fused to an aryl or heteroaryl ring.
• heterocycloalkyl groups include, but are not limited to, piperidinyl, piperazinyl, pyrrolidinyl, dioxanyl, tetrahydrofuranyl, tetrahydrothienyl, isoindolinyl, indolinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, tetrahyrofuranyl, oxiranyl, azetidinyl, oxetanyl, thietanyl, 1,2,3,6-tetrahydropyridinyl, tetrahydro-2H-pyranyl, 3,6
• Aryl refers to groups with aromaticity, including “conjugated,” or multicyclic systems with at least one aromatic ring and do not contain any heteroatom in the ring structure. Examples include phenyl, benzyl, 1,2,3,4-tetrahydronaphthalenyl, etc.
• Heteroaryl refers to aryl groups, as defined above, except having from one to four heteroatoms in the ring structure, and may also be referred to as “aryl heterocycles” or “heteroaromatics.”
• heteroaryl is intended to include a stable 5-, 6-, or 7-membered monocyclic or 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic aromatic heterocyclic ring which consists of carbon atoms and one or more heteroatoms, e.g. , 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, or e.g. ⁇ l, 2, 3, 4, 5, or 6 heteroatoms,
• the nitrogen atom may be substituted or unsubstituted (i.e. , N or NR wherein R is H or other substituents, as defined).
• heteroaryl examples include pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, tetrazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, tetrazolyl, pyridazinyl, quinazolinyl, dihydroquinazolyl, and tetrahydroquinazolyl and the like.
• aryl and heteroaryl include multicyclic aryl and heteroaryl groups, e.g. , tricyclic, bicyclic, e.g. , naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzoimidazole, benzothiophene, methylenedioxyphenyl, quinoline, isoquinoline, naphthrydine, indole, benzofuran, purine, benzofuran, deazapurine, indolizine.
• Carbocycle or “carbocyclic moiety” as used herein, is intended to include any stable monocyclic, bicyclic or tricyclic ring having the specified number of carbons, any of which may be saturated, unsaturated, or aromatic.
• Carbocycle includes cycloalkyl and aryl.
• a C3-C 14 carbocycle is intended to include a monocyclic, bicyclic or tricyclic ring having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms.
• carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl,
• Bridged rings are also included in the definition of carbocycle, including, for example,
• a bridged ring occurs when one or more carbon atoms link two non-adjacent carbon atoms.
• bridge rings are one or two carbon atoms. It is noted that a bridge always converts a monocyclic ring into a tricyclic ring. When a ring is bridged, the substituents recited for the ring may also be present on the bridge. Fused (e.g., naphthyl, tetrahydronaphthyl) and spiro rings are also included.
• Heterocycle or “heterocyclic moiety” as used herein, includes any ring structure (saturated, unsaturated, or aromatic) which contains at least one ring heteroatom (e.g., N, O or S). Heterocycle includes heterocycloalkyl and heteroaryl. Examples of heterocycles include, but are not limited to, morpholine, pyrrolidine, tetrahydrothiophene, piperidine, piperazine and tetrahydrofuran.
• heterocyclic groups include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-l,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, lH-indazoly
• the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring can be substituted at one or more ring positions (e.g., the ring-forming carbon or heteroatom such as N) with such substituents as described above, for example, aliphatic; heteroaliphatic; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; alkylaryl; alkylheteroaryl; alkoxy; aryloxy; heteroalkoxy; heteroaryloxy; alkylthio; arylthio; heteroalkylthio; heteroarylthio; F; CI; Br; I; -N0 2 ; -CN; -CF 3 ; -CH 2 CF 3 ; -CHC1 2 ; -CH 2 OH; - CH 2 CH 2 OH; -CH 2 NH 2 ; -CH 2 S0 2 CH 3 ; -
• alkoxy refers to an alkyl group, as previously defined, attached to the parent molecular moiety through an oxygen atom (“alkoxy").
• alkoxy refers to an alkyl group, as previously defined, attached to the parent molecular moiety through an oxygen atom (“alkoxy").
• the alkyl group contains about 1-20 aliphatic carbon atoms.
• the alkyl group contains about 1-10 aliphatic carbon atoms.
• the alkyl group contains about 1-8 aliphatic carbon atoms.
• the alkyl group contains about 1-6 aliphatic carbon atoms.
• the alkyl group contains about 1-4 aliphatic carbon atoms.
• alkoxy groups include but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, tert- butoxy, neopentoxy and n-hexoxy.
• aryloxy refers to an aryl group, as defined herein, attached to the parent molecular moiety through an oxygen atom.
• aryloxy groups include but are not limited to phenoxy and napthyloxy.
• Heteroaryloxy refers to a heteroaryl group, as defined herein, attached to the parent molecular moiety through an oxygen atom.
• heteroaryloxy groups include but are not limited to, quinolyloxy and
• alkylamino refers to a group having the structure -NHR' wherein R' is alkyl, as defined herein.
• aminoalkyl refers to a group having the structure NH 2 R'-, wherein R' is alkyl, as defined herein.
• the alkyl group contains about 1-20 aliphatic carbon atoms.
• the alkyl group contains about 1-10 aliphatic carbon atoms.
• the alkyl, alkenyl, and alkynyl groups employed in the invention contain about 1-8 aliphatic carbon atoms.
• the alkyl group contains about 1-6 aliphatic carbon atoms.
• the alkyl group contains about 1-4 aliphatic carbon atoms.
• alkylamino include, but are not limited to, methylamino, ethylamino, iso-propylamino and the like.
• Alkylthio (or “thioalkyl”) means an alkyl group as defined herein with the indicated number of carbon atoms attached through a sulfur atom.
• C 1-6 alkylthio is intended to include C 1; C 2 , C 3 , C 4 , C 5 , and C 6 alkylthio groups.
• Ci_8 alkylthio is intended to include C 1; C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , and alkylthio groups.
• the thioalkyl groups can be substituted with groups such as alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, carboxyacid, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, amino (including alkylamino, dialkylamino, arylamino, diarylamino and
• alkylarylamino examples include alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl alkylaryl, or an aryl or heteroaryl moieties.
• Thiocarbonyl or "thiocarboxy” includes compounds and moieties which contain a carbon connected with a double bond to a sulfur atom.
• Thioether includes moieties which contain a sulfur atom bonded to two carbon atoms or heteroatoms.
• thioethers include, but are not limited to alkthioalkyls, alkthioalkenyls and alkthioalkynyls.
• alkthioalkyls include moieties with an alkyl, alkenyl or alkynyl group bonded to a sulfur atom which is bonded to an alkyl group.
• alkthioalkenyls refers to moieties wherein an alkyl, alkenyl or alkynyl group is bonded to a sulfur atom which is covalently bonded to an alkenyl group
• alkthioalkynyls refers to moieties wherein an alkyl, alkenyl or alkynyl group is bonded to a sulfur atom which is covalently bonded to an alkynyl group.
• Arylthio (or “thioaryl”) means an aryl group as defined herein with the indicated number of carbon atoms attached through a sulfur atom.
• Carboxylic acid refers to a compound comprising a group of formula -C0 2 H.
• Dicarboxylic acid refers to a compound comprising two groups of formula -
• Halo, halide and halogen refer to an atom selected from fluorine, chlorine, bromine, and iodine.
• methylol refers to an alcohol group of the structure -CH 2 OH.
• hydroxyalkyl refers to an alkyl group, as defined above, bearing at least one OH group.
• mercaptoalkyl refers to an alkyl group, as defined above, bearing at least one SH group
• Acyl includes moieties that contain the acyl radical (-C(O)-) or a carbonyl group.
• substituted acyl includes acyl groups where one or more of the hydrogen atoms are replaced by, for example, alkyl groups, alkynyl groups, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including
• Hydrocarbon refers to any chemical group comprising hydrogen and carbon.
• the hydrocarbon may be substituted or unsubstituted.
• the hydrocarbon may be unsaturated, saturated, branched, unbranched, cyclic, polycyclic, or heterocyclic.
• Illustrative hydrocarbons include, for example, methyl, ethyl, n-propyl, iso-propyl, cyclopropyl, allyl, vinyl, n-butyl, tert-butyl, ethynyl, cyclohexyl, methoxy, diethylamino, heterocycloalkyl, aryl, heteroaryl, thioalkyl, and the like. As would be known to one skilled in this art, all valencies must be satisfied in making any substitutions.
• Alkylaryl refers to an aryl group substituted with one or more alkyl groups (e.g., methylphenyl).
• Alkylarylamino refers to -N R G4 R G5 , wherein R G4 is alkyl, as defined herein, and R G5 is an aryl, as defined herein, or at least one of R G w 4 and R G U 5 J is an alkylaryl as defined herein.
• substituted refers to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent. When more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position.
• substituted is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds.
• Heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valencies of the heteroatoms.
• substituents include, but are not limited to aliphatic; heteroaliphatic; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; alkylaryl; alkylheteroaryl; alkoxy; aryloxy;
• Animal refers to humans as well as non- human animals, at any stage of development, including, for example, mammals, birds, reptiles, amphibians, fish, worms and single cells. Cell cultures and live tissue samples are considered to be pluralities of animals.
• the non-human animal is a mammal (e.g., a rodent, a mouse, a rat, a rabbit, a monkey, a dog, a cat, a primate, or a pig).
• An animal may be a transgenic animal or a human clone.
• subject encompasses animals.
• “Efficient amount” In general, as it refers to an active agent or drug delivery device, the term “efficient amount” refers to the amount necessary to elicit the desired biological response. As will be appreciated by those of ordinary skill in this art, the efficient amount of an agent or device may vary depending on such factors as the desired biological endpoint, the agent to be delivered, the composition of the encapsulating matrix, the target tissue, etc. For example, the efficient amount of microparticles containing an antigen to be delivered to immunize an individual is the amount that results in an immune response sufficient to prevent infection with an organism having the administered antigen.
• Natural amino acid refers to any one of the common, naturally occurring L-amino acids found in naturally occurring proteins: glycine (Gly), alanine (Ala), valine (Val), leucine (Leu), isoleucine (He), lysine (Lys), arginine (Arg), histidine (His), proline (Pro), serine (Ser), threonine (Thr), phenylalanine (Phe), tyrosine (Tyr), tryptophan (Trp), aspartic acid (Asp), glutamic acid (Glu), asparagine (Asn), glutamine (Gin), cysteine (Cys) and methionine (Met).
• Unnatural amino acid refers to any amino acid which is not a natural amino acid. This includes, for example, amino acids that comprise ⁇ -, ⁇ -, CO-, D-, L- amino acyl residues. More generally, the unnatural amino acid comprises a residue of the
• exemplary unnatural amino acids include, but are not limited to, sarcosine (N-methylglycine) , citrulline (cit), homocitrulline, ⁇ -ureidoalanine, thiocitrulline,
• amino acyl More generally, the term amino acyl, as used herein, encompasses natural amino acid and unnatural amino acids.
• Polyamide refers to homo- or hetero- polymers of natural amino acid and unnatural amino acids.
• Illustrative homo-polymers include, but are not limited to, poly-lysine, poly-arginine, poly-y-glutaric acid, and the like.
• Illustrative hetero- polymers include, but are not limited to, polymers comprising peptides fragments selected from peptidases, lysozymes, metalloproteinases, and the like.
• PEF poly(l-hydroxymethylethylene hydroxymethyl-formal).
• the present invention is intended to include all isotopes of atoms occurring in the present compounds.
• Isotopes include those atoms having the same atomic number but different mass numbers.
• isotopes of hydrogen include tritium and deuterium.
• isotopes of carbon include C-13 and C-14.
• the present invention is intended to include all isomers of the compound, which refers to and includes, optical isomers, and tautomeric isomers, where optical isomers include enantiomers and diastereomers, chiral isomers and non-chiral isomers, and the optical isomers include isolated optical isomers as well as mixtures of optical isomers including racemic and non-racemic mixtures; where an isomer may be in isolated form or in a mixture with one or more other isomers.
• the conjugates of the invention find use in biomedical applications, such as drug delivery and tissue engineering, and the carrier is biocompatible and biodegradable.
• the carrier is a soluble polymer, nanoparticle, gel, liposome, micelle, suture, implant, etc.
• the term "soluble polymer” encompasses biodegradable biocompatible polymer such as a polyal (e.g., hydrophilic polyacetal or polyketal).
• the carrier is a fully synthetic, semi- synthetic or naturally-occurring polymer.
• the carrier is hydrophilic.
• the carriers used in the present invention are biodegradable biocompatible polyals comprising at least one hydrolysable bond in each monomer unit positioned within the main chain. This ensures that the degradation process (via hydrolysis/cleavage of the monomer units) will result in fragmentation of the polymer conjugate to the monomeric components (i.e., degradation), and confers to the polymer conjugates of the invention their biodegradable properties.
• the properties (e.g., solubility, bioadhesivity and hydrophilicity) of biodegradable biocompatible polymer conjugates can be modified by subsequent substitution of additional hydrophilic or hydrophobic groups. Examples of biodegradable biocompatible polymers suitable for practicing the invention can be found inter alia in U.S.
• Guidance on the significance, preparation, and applications of this type of polymers may be found in the above-cited documents. In certain embodiments, it is anticipated that the present invention will be particularly useful in combination with the above- referenced patent documents, as well as U.S. Patent Nos. 5,582,172 and 6,822,086, each of the above listed patent documents is incorporated herein by reference in its entirety.
• the conjugates of this invention are hydrophilic, hydrolysable and comprise drug molecules (e.g., vinca alkaloids or derivatives, non-natural camptothecin compounds or derivatives, auristatins, tubulysins, duocarmycins, PI3 kinases, MEK inhibitors, KSP inhibitors, and analogs thereof) and antibodies (e.g., Trastuzumab, Cetuximab, Rituximab, Bevacizumab, Epratuzumab, Veltuzumab, Labetuzumab) or peptides (LHRH receptor targeting peptides, EC-1 peptide) covalently attached to the polymer carrier via linkages that contain one or more biodegradable bonds.
• drug molecules e.g., vinca alkaloids or derivatives, non-natural camptothecin compounds or derivatives, auristatins, tubulysins, duocarmycins, PI3 kinases, ME
• carriers suitable for practicing the present invention are polyals having at least one acetal/ketal oxygen atom in each monomer unit positioned within the main chain. As discussed above, this ensures that the degradation process (via hydrolysis/cleavage of the polymer acetal/ketal groups) will result in fragmentation of the polyal conjugate to low molecular weight components (i.e., degradation).
• biodegradable biocompatible polymer carriers used for preparation of polymer conjugates of the invention, are naturally occurring polysaccharides, glycopolysaccharides, and synthetic polymers of polyglycoside, polyacetal, polyamide, polyether, and polyester origin and products of their oxidation, fictionalization, modification, cross-linking, and conjugation.
• the carrier is a hydrophilic biodegradable polymer selected from the group consisting of carbohydrates, glycopolysaccharides, glycolipids, glycoconjugates, polyacetals, polyketals, and derivatives thereof.
• the carrier is a naturally occurring linear and/or branched biodegradable biocompatible homopolysaccharide selected from the group consisting of cellulose, amylose, dextran, levan, fucoidan, carraginan, inulin, pectin,
• amylopectin, glycogen and lixenan amylopectin, glycogen and lixenan.
• the carrier is a naturally occurring linear and branched biodegradable biocompatible heteropolysaccharide selected from the group consisting of agarose, hyluronan, chondroitinsulfate, dermatansulfate, keratansulfate, alginic acid and heparin.
• the polymeric carrier comprises a copolymer of a polyacetal/polyketal and a hydrophilic polymer selected from the group consisting of polyacrylates, polyvinyl polymers, polyesters, polyorthoesters, polyamides, polypeptides, and derivatives thereof.
• the polymeric carrier is dextrin that is produced by the hydrolysis of a starch obtained from various natural products such as, for example, wheat, rice, maize and tapioca.
• each dextrin comprises a unique distribution of a- 1,4 linkages and a- 1,6 linkages. Since the rate of biodegradability of a- 1,6 linkages is typically less than that for a- 1,4 linkages, preferably the percentage of a-1,6 linkages is less than 10% and more preferably less than 5%.
• the molecular weight of the dextrin is in the range of about 1 kDa to about 200 kDa, more preferably from about 2 kDa to about 55 kDa.
• the carrier comprises polysaccharides activated by selective oxidation of cyclic vicinal diols of 1,2-, 1,4-, 1,6-, and 2,6-pyranosides, and 1,2-, 1,5-, 1,6-furanosides, or by oxidation of lateral 6-hydroxy and 5,6-diol containing polysaccharides prior to conjugation with drug molecules or PBRMs.
• the polymeric carrier comprises a biodegradable biocompatible polyacetal wherein at least a subset of the polyacetal repeat structural units have the following chemical structure:
• one of Ri and R 2 is hydrogen, and the other is a biocompatible group and includes a carbon atom covalently attached to C 1 ;
• R x is a carbon atom covalently attached to C ;
• n" is an integer; each occurrence of R 3 , R 4 , R5 and R 6 is a biocompatible group and is independently hydrogen or an organic moiety; and for each occurrence of the bracketed structure n, at least one of R 1; R 2 , R , R 4 , R5 and R 6 comprises a functional group suitable for coupling.
• the functional group is a hydroxyl moiety.
• the polymeric carrier comprises activated hydrophilic biodegradable biocompatible polymers comprising from 0.1% to 100% polyacetal moieties whose backbone is represented by the following chemical structure:
• R 7 and R 8 are independently hydrogen, hydroxyl, hydroxy alkyl (e.g., -CH 2 OH,
• o is an integer from 20 to 2000.
• the polymeric carrier comprises a biodegradable biocompatible polyketal wherein at least a subset of the polyketal repeatable structural units have the following chemical structure:
• R and R 2 are as defined herein
• the ketal units are monomers of Formula (Ila) or (lib):
• the polymeric carrier can be obtained from partially oxidized dextran ( l ⁇ 6)-D-glucose) followed by reduction.
• the polymer comprises a random mixture of the unmodified dextran (A), partially oxidized dextran acetal units (B) and exhaustively dextran acetal units (C) of the following structures:
• the polymeric carrier comprises unmodified acetal units, i.e., polyacetal segments.
• the polyacetals can be derived from
• the unmodified polyacetal polymer is a
• poly(hydroxymethylethylene hydroxymethyl formal) polymer PHF
• the backbone of the polymeric carrier can also comprise co-polymers of
• poly(hydroxymethylethylene hydroxymethyl formal) blocks and other acetal or non-acetal monomers or polymers are useful as a stealth agent in the polymer backbone because they can decrease interactions between polymer side chains of the appended functional groups. Such groups can also be useful in limiting interactions such as between serum factors and the modified polymer.
• Other stealth agent monomers for inclusion in the polymer backbone include, for example, ethyleneimine, methacrylic acid, acrylamide, glutamic acid, and combinations thereof.
• the acetal or ketal units are present in the modified polymer in an amount effective to promote biocompatibility.
• the unmodified acetal or ketal unit can be described as a "stealth agent" that provides biocompatibility and solubility to the modified polymers.
• conjugation to a polyacetal or polyketal polymer can modify the susceptibility to metabolism and degradation of the moieties attached to it, and influence biodistribution, clearance and degradation.
• the unmodified acetal units are monomers of Formula (III):
• the molar fraction, n, of unmodified polyacetal units is the molar fraction available to promote biocompatibility, solubility and increase half-life, based on the total number of polymer units in the modified polymer.
• the molar fraction n may be the minimal fraction of unmodified monomer acetal units needed to provide biocompatibility, solubility, stability, or a particular half-life, or can be some larger fraction.
• the most desirable degree of cytotoxicity is substantially none, i.e., the modified polymer is substantially inert to the subject. However, as is understood by those of ordinary skill in the art, some degree of cytotoxicity can be tolerated depending on the severity of disease or symptom being treated, the efficacy of the treatment, the type and degree of immune response, and like considerations.
• the modified polymer backbone comprises units of Formula
• each polyacetal unit has a single hydroxyl group attached to the glycerol moiety of the unit and an X' group (or another substituent such as -L D -D) attached to the glycolaldehyde moiety of the unit.
• the polymer having units of Formula (IV) and other formulae described herein can contain a random distribution of units having a X' group (or another substituent such as -L D -D) attached to the glycolaldehyde moiety of the units and those having a single X' group (or another substituent such as -L D -D) attached to the glycerol moiety of the units as well as units having two X' groups (or other substituents such as -L D -D) with one attached to the glycolaldehyde moiety and the other attached to the glycerol moiety of the units.
• biodegradable biocompatible polyals suitable for practicing the present invention have a molecular weight of between about 0.5 and about 300 kDa.
• the biodegradable biocompatible polyals have a molecular weight of between about 1 and about 300 kDa (e.g., between about 1 and about 200 kDa, between about 2 and about 300 kDa, between about 2 and about 200 kDa, between about 5 and about 100 kDa, between about 10 and about 70 kDa, between about 20 and about 50 kDa, between about 20 and about 300 kDa, between about 40 and about 150 kDa, between about 50 and about 100 kDa, between about 2 and about 40 kDa, between about 6 and about 20 kDa, or between about 8 and about 15 kDa).
• the biodegradable biocompatible polyals suitable for practicing the present invention are modified before conjugating with a drug or a PBRM.
• Table A below provides some examples of the modified polyals suitable for conjugating with a drug or PBRM or derivatives thereof. Unless otherwise specified, reference numbers in Tables A through E below correspond to the Example numbers described herein; the term "ND" means not determined; and X is CH 2 , O, or NH. Table A
• the therapeutic agent is a small molecule having a molecular weight preferably ⁇ about 5 kDa, more preferably ⁇ about 4 kDa, more preferably about 3 kDa, most preferably ⁇ about 1.5 kDa or ⁇ about 1 kDa.
• about 0.1 to about 25 % monomers comprise a therapeutic agent, more preferably about 0.5 to about 20%, more preferably about 1 to about 15%, and even more preferably about 2 to about 10%.
• the small molecule therapeutic agents used in this invention e.g.,
• antiproliferative (cytotoxic and cytostatic) agents capable of being linked to a polymer carrier) include cytotoxic compounds (e.g., broad spectrum), angiogenesis inhibitors, cell cycle progression inhibitors, PBK/m-TOR/AKT pathway inhibitors, MAPK signaling pathway inhibitors, kinase inhibitors, protein chaperones inhibitors, HDAC inhibitors, PARP inhibitors, Wnt/Hedgehog signaling pathway inhibitors and RNA polymerase inhibitors.
• Broad spectrum cytotoxins include, but are not limited to, DNA-binding or alkylating drugs, microtubule stabilizing and destabilizing agents, platinum compounds, and topoisomerase I inhibitors.
• Exemplary DNA-binding or alkylating drugs include, CC-1065 and its analogs, anthracyclines (doxorubicin, epirubicin, idarubicin, daunorubicin) and its analogs, alkylating agents, such as calicheamicins, dactinomycines, mitromycines, pyrrolobenzodiazepines, and the like.
• anthracyclines doxorubicin, epirubicin, idarubicin, daunorubicin
• alkylating agents such as calicheamicins, dactinomycines, mitromycines, pyrrolobenzodiazepines, and the like.
• Exemplary CC-1065 analogs include duocarmycin SA, duocarmycin CI, duocarmycin C2, duocarmycin B2, DU-86, KW-2189, bizelesin, seco-adozelesin, and those described in U.S. Patent Nos. 5,475,092; 5,595,499; 5,846,545; 6,534,660; 6,586,618; 6,756,397 and 7,049,316.
• Doxorubicin and its analogs include those described in U.S. Patent No.
• Calicheamicins include those described in U.S. Patent Nos. 5,714,586 and 5,739,116.
• Duocarmycins include those described in U.S. Patent Nos.5,070,092; 5,101,038; 5,187,186; 6,548,530; 6,660,742; and 7,553,816 B2; and Li et al., Tet Letts., 50:2932 - 2935 (2009).
• Pyrrolobenzodiazepines include those described in Denny, Exp. Opin. Ther. Patents., 10(4):459-
• microtubule stabilizing and destabilizing agents include taxane compounds, such as paclitaxel, docetaxel; maytansinoids, auristatins and analogs thereof, tubulysin A and B derivatives, vinca alkaloid derivatives, epothilones and cryptophycins.
• Exemplary maytansinoids or maytansinoid analogs include maytansinol and maytansinol analogs, maytansine or DM-1 and DM-4 are those described in U.S. Patent Nos. 5,208,020; 5,416,064; 6,333.410; 6,441,163; 6,716,821; RE39,151 and 7,276,497.
• the cytotoxic agent is a maytansinoid, another group of anti-tubulin agents (ImmunoGen, Inc.; see also Chari et al., 1992, Cancer Res. 52: 127-131), maytansinoids or maytansinoid analogs.
• suitable maytansinoids include maytansinol and maytansinol analogs. Suitable maytansinoids are disclosed in U.S. Patent Nos. 4,424,219;
• Exemplary auristatins include auristatin E (also known as a derivative of dolastatin-10), auristatin EB (AEB), auristatin EFP (AEFP), monomethyl auristatin E (MMAE), monomethyl auristatin F (MMAF), auristatin F and dolastatin.
• Suitable auristatins are also described in U.S. Publication Nos. 2003/0083263, 2011/0020343, and 2011/0070248; PCT Application Publication Nos. WO 09/117531, WO 2005/081711, WO 04/010957; WO
• Exemplary tubulysin compounds include compounds described in U.S. Patent Nos. 7,816,377; 7,776,814; 7,754,885; U.S. Publication Nos. 2011/0021568; 2010/004784;
• Exemplary vinca alkaloids include vincristine, vinblastine, vindesine, and navelbine (vinorelbine).
• Suitable Vinca alkaloids that can be used in the present invention are also disclosed in U.S. Publication Nos. 2002/0103136 and 2010/0305149, and in U.S. Patent No. 7,303,749 Bl, the disclosures of which are incorporated herein by reference in their entirety.
• Exemplary epothilone compounds include epothilone A, B, C, D, E and F, and derivatives thereof. Suitable epothilone compounds and derivatives thereof are described, for example, in U.S. Patent Nos.
• Exemplary cryptophycin compounds are described in U.S. Patent Nos. 6,680,311 and 6,747,021.
• Exemplary platinum compounds include cisplatin (PLATINOL®), carboplatin
• PARAPLATIN® oxaliplatin
• ELOX ATINE® oxaliplatin
• iproplatin ormaplatin
• tetraplatin oxaliplatin
• Exemplary topoisomerase I inhibitors include camptothecin, camptothecin, derivatives, camptothecin analogs and non-natural camptothecins, such as, for example, CPT-11 (irinotecan), SN-38, topotecan, 9-aminocamptothecin, rubitecan, gimatecan, karenitecin, silatecan, lurtotecan, exatecan, diflomotecan, belotecan, lurtotecan and S39625.
• Other camptothecin compounds that can be used in the present invention include those described in, for example, J. Med. Chem., 29:2358-2363 (1986); J. Med. Chem., 23:554 (1980); J. Med. Chem., 30: 1774 (1987).
• Angiogenesis inhibitors include, but are not limited, MetAP2 inhibitors.
• MetAP2 inhibitors include fumagillol analogs, meaning any compound that includes the fumagillin core structure, including fumagillamine, that inhibits the ability of MetAP-2 to remove NH 2 -terminal methionines from proteins as described in Rodeschini et al., /. Org.
• Exemplary cell cycle progression inhibitors include CDK inhibitors such as, for example, BMS-387032 and PD0332991; Rho-kinase inhibitors such as, for example
• GSK429286 checkpoint kinase inhibitors such as, for example, AZD7762; aurora kinase inhibitors such as, for example, AZD1152, MLN8054 and MLN8237; PLK inhibitors such as, for example, BI 2536, BI6727 (Volasertib), GSK461364, ON-01910 (Estybon); and KSP inhibitors such as, for example, SB 743921, SB 715992 (ispinesib), MK-0731, AZD8477, AZ3146 and ARRY-520.
• checkpoint kinase inhibitors such as, for example, AZD7762
• aurora kinase inhibitors such as, for example, AZD1152, MLN8054 and MLN8237
• PLK inhibitors such as, for example, BI 2536, BI6727 (Volasertib), GSK461364, ON-01910 (Estybon)
• Exemplary PI3K/m-TOR/AKT signaling pathway inhibitors include
• PI3K phosphoinositide 3-kinase
• Exemplary PI3 kinases are disclosed in U.S. Patent No. 6,608,053, and include BEZ235, BGT226, BKM120, CAL101, CAL263, demethoxyviridin, GDC-0941, GSK615, IC87114, LY294002, Palomid 529, perifosine, PF-04691502, PX-866, SAR245408, SAR245409, SF1126, Wortmannin, XL147 and XL765.
• Exemplary AKT inhibitors include, but are not limited to AT7867.
• Exemplary MAPK signaling pathway inhibitors include MEK, Ras, JNK, B-Raf and p38 MAPK inhibitors .
• Exemplary MEK inhibitors are disclosed in U.S. Patent No. 7,517,994 and include GDC-0973, GSK1120212, MSC1936369B, AS703026, R05126766 and R04987655, PD0325901, AZD6244, AZD 8330 and GDC-0973.
• Exemplary B-raf inhibitors include CDC-0879, PLX-4032, and SB590885.
• Exemplary B p38 MAPK inhibitors include BIRB 796, LY2228820 and SB
• RTK Receptor tyrosine kinases
• Exemplary inhibitors of ErbB2 receptor include but not limited to
• AEE788 (NVP-AEE 788), BIBW2992, (Afatinib), Lapatinib, Erlotinib (Tarceva), and Gefitinib (Iressa).
• multitargeted kinase inhibitors include AP24534 (Ponatinib) that targets FGFR, FLT-3, VEGFR-PDGFR and Bcr-Abl receptors; ABT-869 (Linifanib) that targets FLT-3 and VEGFR- PDGFR receptors; AZD2171 that targets VEGFR-PDGFR, Flt-1 and VEGF receptors; CHR-258 (Dovitinib) that targets VEGFR-PDGFR, FGFR, Flt-3, and c-Kit receptors.
• AP24534 Panatinib
• ABT-869 Liifanib
• AZD2171 that targets VEGFR-PDGFR, Flt-1 and VEGF receptors
• CHR-258 Dovitinib
• Exemplary protein chaperon inhibitors include HSP90 inhibitors.
• Exemplary amino acids include HSP90 inhibitors.
• HSP90 inhibitors include 17AAG derivatives, BIIB021, BIIB028, SNX-5422, NVP-AUY-922 and KW-2478.
• HDAC inhibitors include Belinostat (PXD101), CUDC-101,
• Droxinostat ITF2357 (Givinostat, Gavinostat), JNJ-26481585, LAQ824 (NVP-LAQ824, Dacinostat), LBH-589 (Panobinostat), MC1568, MGCD0103 (Mocetinostat), MS-275 (Entinostat), PCI-24781, Pyroxamide (NSC 696085), SB939, Trichostatin A and Vorinostat (SAHA).
• Exemplary PARP inhibitors include iniparib (BSI 201), olaparib (AZD-2281),
• ABT-888 (Veliparib), AG014699, CEP 9722, MK 4827, KU-0059436 (AZD2281), LT-673, 3- aminobenzamide, A-966492, and AZD2461
• Exemplary Wnt/Hedgehog signaling pathway inhibitors include vismodegib
• Exemplary RNA polymerase inhibitors include amatoxins.
• Exemplary amatoxins include a- amanitins, ⁇ - amanitins, ⁇ - amanitins, ⁇ -amanitins, amanullin, amanullic acid, amaninamide, amanin, and proamanullin.
• the drug of the invention is a non-natural camptothecin compound, vinca alkaloid, kinase inhibitor (e.g., PI3 kinase inhibitor (GDC-0941 and PI- 103)), MEK inhibitor, KSP inhibitor, RNA polymerse inhibitor, PARP inhibitor, docetaxel, paclitaxel, doxorubicin, duocarmycin, tubulysin, auristatin or a platinum compound.
• kinase inhibitor e.g., PI3 kinase inhibitor (GDC-0941 and PI- 103)
• MEK inhibitor e.g., PI3 kinase inhibitor (GDC-0941 and PI- 103)
• MEK inhibitor e.g., PI3 kinase inhibitor (GDC-0941 and PI- 103)
• KSP inhibitor e.g., PI3 kinase inhibitor (GDC-0941 and PI- 103)
• KSP inhibitor
• the drug is a derivative of SN-38, vindesine, vinblastine, PI- 103, AZD 8330, auristatin E, auristatin F, a duocarmycin compound, tubulysin compound, or ARRY-520.
• the drug used in the invention is a combination of two or more drugs, such as, for example, PI3 kinases and MEK inhibitors; broad spectrum cytotoxic compounds and platinum compounds; PARP inhibitors and platinum compounds; broad spectrum cytotoxic compounds and PARP inhibitors.
• drugs such as, for example, PI3 kinases and MEK inhibitors; broad spectrum cytotoxic compounds and platinum compounds; PARP inhibitors and platinum compounds; broad spectrum cytotoxic compounds and PARP inhibitors.
• Vinca alkaloid is a compound of Formula (V),:
• R 14 is hydrogen, -C(0)-C 1 _3 alkyl or -C(0)-chloro substituted C 1-3 alkyl;
• R 15 is hydrogen, -CH 3 or -CHO
• R 18 is hydrogen, and either R 16 or R 17 is ethyl and the other is hydroxyl;
• R 16 is ethyl
• Rig is hydrogen, OH, amino group, alkyl amino or -[C(R 2 oR 2 i)] a -R 22 ;
• each of R 20 and R 21 independently is hydrogen, C 1-6 alkyl, C 6-10 aryl, hydroxylated C 6-10 aryl, polyhydroxylated C 6 -io aryl, 5 to 12-membered heterocycle, C 3 _ 8 cycloalkyl, hydroxylated C 3 _ 8 cycloalkyl, polyhydroxylated C 3 _ 8 cycloalkyl or a side chain of a natural or unnatural amino acid;
• R 22 is -OH, -NH 2 , -COOH, -R 82 -C(0)(CH 2 ) c -C(H)(R 23 )-N(H)(R 23 ), -R 82 -C(0)(CH 2 ) d -(0
• each R 23 independently is hydrogen, Ci_6 alkyl, C 6 -io aryl, C 3 _ 8 cycloalkyl, -COOH, or -COO-Ci_6 alkyl;
• X is a side chain of a natural or unnatural amino acid
• R 77 is hydrogen or X and NR 77 form a nitrogen containing heterocyclic moiety;
• R-82 is -NH or oxygen;
• a is an integer from 1 to 6;
• c is an integer from 0 to 3;
• d is an integer from 1 to 3;
• f is an integer from 1 to 12.
• Vinca alkaloid of Formula (V) is a compound of Formula
• a is an integer from 1 to 6;
• R 40 is
• non-natural camptothecin is a compound of Formula
• R24 is -H, -CI, -F, -OH or alkyl; or R 24 and R 25 , may be taken together to form a five- or six-membered ring;
• R 29 is -NH 2 , -R 28 -C 1 _6 alkyl-R 22 , 5 to 12-membered heterocycloalkyl, R 28 -C 5 - 12 heterocycloalkyl-Ci-6 alkyl-R 22 or -R 28 -C 1 _6 alkyl-C6-i 2 aryl-Ci-6 alkyl-R 22 ;
• R 26 is -H, -CH 2 -N(CH 3 ) 2 , NH 2 , or N0 2 ;
• R 27 is ethyl, N-methyl piperidine, cycloalkyl, -CH 2 CH 2 NHCH(CH 3 ) 2 , or
• R 79 is -H or -C(O)-R 28 -[C(R 20 R 2 i)] a -R 22 ;
• each of R 20 and R 21 independently is hydrogen, C 1-6 alkyl, C 6 -io aryl, hydroxylated C 6 -io aryl, polyhydroxylated C 6 -io aryl, 5 to 12-membered heterocycle, C 3 _8 cycloalkyl, hydroxylated C 3 -8 cycloalkyl, polyhydroxylated C 3 _8 cycloalkyl or a side chain of a natural or unnatural amino acid;
• R 22 is -OH, -NH 2 , -COOH, -R 82 -C(0)(CH 2 ) c -C(H)(R 23 )-N(H)(R 23 ), -R 82 -C(0)(CH 2 ) d -(0 CH 2 -CH 2 ) f -N(H)(R 23 ), or -R 82 -(C(0)-CH(X 2 )-NH) d -R 77 ;
• each R 23 independently is hydrogen, Ci_6 alkyl, C 6 -io aryl, C 3 _ 8 cycloalkyl, -COOH, or -COO-Ci_6 alkyl;
• X is a side chain of a natural or unnatural amino acid
• R 77 is a hydrogen or X and NR 77 form a nitrogen containing cyclic compound
• R 82 is -NH or oxygen; or R 2 6 and R 27 when taken together with the two carbon atoms to which they attach and the third carbon atom connecting the two carbon atoms form an optionally substituted six-membered ring;
• R 2 8 is absent, NH or oxygen
• a is an integer from 1 to 6;
• c is an integer from 0 to 3;
• d is an integer from 1 to 3;
• f is an integer from 1 to 12;
• u is an integer 0 or 1 ;
• w is an integer 0 or 1 ;
• non-natural camptothecin compound of Formula (VII) is a compound of Formula (VIII) or Formula (XXV):
• R30 is -NH 2 , -R 2 8-C 1-6 alkyl-R 22 , 5 to 12-membered heterocycloalkyl, R 28 -C 5 - 12 heterocycloalkyl-Ci-6 alkyl-R 22 or -R 2 g-C 1-6 alkyl-C6-i 2 aryl-C 1-6 alkyl-R 22 ;
• R 28 is absent, NH or oxygen
• R 22 is -OH, -NH 2 , -COOH, -R 82 -C(0)(CH 2 ) c -C(H)(R 23 )-N(H)(R 23 ), -R 82 -C(0)(CH 2 ) d -(0 CH 2 -CH 2 ) f -N(H)(R 23 ) or -R 82 -(C(0)-CH(X 2 )-NH) d -R 77 ;
• each R 2 independently is hydrogen, C 1-6 alkyl, C 6-10 aryl, C 3 _ 8 cycloalkyl, -COOH, or -COO-Ci-6 alkyl;
• X is a side chain of a natural or unnatural amino acid
• R 77 is a hydrogen or X and NR 77 form a nitrogen containing cyclic compound
• R 82 is -NH or oxygen
• c is an integer from 0 to 3;
• d is an integer from 1 to 3;
• f is an integer from 1 to 12.
• R 3 o is any one of the following structures:
• a is an integer from 1 to 6;
• c is an integer from 0 to 3;
• g is an integer from 2 to 6.
• the PI3 kinase is a com ound of Formula (IX):
• R 47 is an amino group, -R 9 -[C(R 2 oR 2 i)] a -Rio, -R9-C 5 - 12 heterocycloalkyl-Ci-6 alkyl-R 10 or 5 to 12-membered heterocycloalkyl;
• each of R 20 and R 21 independently is hydrogen, C 1-6 alkyl, C 6-10 aryl, hydroxylated C 6-10 aryl, polyhydroxylated C 6 -io aryl, 5 to 12-membered heterocycle, C3-8 cycloalkyl, hydroxylated C 3 _ 8 cycloalkyl, polyhydroxylated C 3 _ 8 cycloalkyl or a side chain of a natural or unnatural amino acid;
• R 10 is -OH, -NHR 83 , -N-(R 83 )Rn, -COOH, -R 82 -C(0)(CH 2 ) c -C(H)(R 23 )-N(H)(R 23 ), -R 82 - C(0)(CH 2 ) d -(0 CH 2 -CH 2 ) f -N(H)(R 23 ), -R 82 -(C(0)-CH(X 2 )-NH) d -R 77 or -R 82 -C(0)- [C(R 20 R 2 i )] a-R8 2 -R8 3 ;
• each R 2 independently is hydrogen, C 1-6 alkyl, C 6-10 aryl, C 3 _ 8 cycloalkyl, -COOH, or -COO-Ci-6 alkyl;
• X is a side chain of a natural or unnatural amino acid
• R 77 is a hydrogen or X and NR 77 form a nitrogen containing cyclic compound
• R 82 is -NH or oxygen
• R 9 is absent, N-(R 83 ) or oxygen
• R 83 is hydrogen or CH ;
• Rn is: each R 12 independently is hydrogen, chloride, -C3 ⁇ 4 or -OCH 3 ;
• Ri3 is hydrogen or -C(0)-(CH 2 ) d -(0-CH 2 -CH 2 ) f -NH 2 ;
• X 4 is the side chain of lysine, arginine, citrulline, alanine or glycine;
• X5 is the side chain of phenylalanine, valine, leucine, isoleucine or tryptophan;
• each of X 6 and X 7 is independently the side chain of glycine, alanine, serine, valine or proline;
• a is an integer from 1 to 6;
• c is an integer from 0 to 3;
• d is an integer from 1 to 3;
• f is an integer from 1 to 12;
• each u independently is an integer 0 or 1.
• citrulline-valine is citrulline-valine; lysine-phenylalanine; citrulline-phenylalanine; citrulline-leucine; citrulline- valine-glycine-glycine; glycine -phenylalanine-glycine-glycine; valine; proline; leucine or isoleucine.
• Rn is any one of the following structures:
• R 47 is any one of the following structures:
• auristatin is a compound of Formula (X):
• each of R 31 and R 2 independently is hydrogen or C 8 alkyl and at most one of R 1 and R 2 is hydrogen;
• R 33 is hydrogen, Cr 8 alkyl, C 3 - 8 carbocycle, C 6 -io aryl, C 8 alkyl-C 6 -io aryl, X ⁇ -s carbocycle), C 3 - 8 heterocycle or ⁇ ⁇ - ⁇ 3 - 8 heterocycle);
• R 34 is hydrogen, C 8 alkyl, C 3 - 8 carbocycle, C 6 -io aryl, X ⁇ Ce-io aryl, X l -(C 3 -s carbocycle), C 3 - 8 heterocycle or ⁇ ⁇ - ⁇ 3 - 8 heterocycle);
• R 3 5 is hydrogen or methyl
• R 34 and R 35> together with the carbon atom to which they attach form a carbocyclic ring having the formula -(CRssR-u wherein each of R55 and R 41 independently is hydrogen or Ci- 8 alkyl and b is an integer from 3 to 7;
• R 3 6 is hydrogen or C 8 alkyl
• R 37 is hydrogen, C 8 alkyl, C 3 - 8 carbocycle, C 6 -io aryl, -X ⁇ Ce-io aryl, -X ⁇ C ⁇ carbocycle), C 3 - 8 heterocycle or - ⁇ ⁇ - ⁇ 3 - 8 heterocycle);
• each R 8 independently is hydrogen, OH, C 8 alkyl, C 3 - 8 carbocycle or 0-(Ci- 8 alkyl);
• R 3 9 is H, C 1-8 alkyl, C 6 -io aryl, -X ⁇ Ce-io aryl, C 3 _ 8 carbocycle, C 3 _ 8 heterocycle, -X ⁇ C ⁇ heterocycle, -C 1-8 alkylene-NH 2 , or (CH 2 ) 2 SCH 3
• each X 1 independently is C 1-10 alkylene or C 3-1 o cycloalkylene
• R ⁇ is hydrogen or C 1-8 alkyl
• R 45 is X 3 -Re or NH-R 19 ; X 3 is O or S;
• R 9 is hydrogen, OH, amino group, alkyl amino or -[C(R2oR2i)] a -R22;
• R 42 is an amino group, Ci_6 alkyl amino or -[C(R2oR2i)] a -R22;
• each of R 20 and R 21 independently is hydrogen, C 1-6 alkyl, C 6-10 aryl, hydroxylated C 6-10 aryl, polyhydroxylated C 6 -io aryl, 5 to 12-membered heterocycle, C 3 -8 cycloalkyl, hydroxylated C 3 -8 cycloalkyl, polyhydroxylated C 3 -8 cycloalkyl or a side chain of a natural or unnatural amino acid;
• R22 is -OH, -NHR23, -COOH, -R82-C(0)(CH 2 ) C -C(H)(R23)-N(H)(R23), -R 8 2-C(0)(CH 2 )d (O CH 2 -CH 2 )f -N(H)(R23) or -R 82 -(C(0)-CH(X 2 )-NH) d -R 77 ;
• each R 2 3 independently is hydrogen, C 1-6 alkyl, C 6 -io aryl, C 3 _s cycloalkyl, -COOH, or -COO-Ci-6 alkyl;
• X is a side chain of a natural or unnatural amino acid
• R 77 is a hydrogen or X and NR 77 form a nitrogen containing cyclic compound
• R82 is -NH or oxygen
• R 54 is -C(R 5 6)2-C(R56)2-C 6 -io aryl, -C(R 5 6)2-C(R56)2-C 3 -8 heterocycle or -C(R 56 ) 2 - C(R 5 6)2-C 3 -8 carbocycle;
• R56 is independently selected from H, OH, Ci-g alkyl, C 3 _s carbocycle, -O-Ci-g alkyl, -O C(0)-R 29 and -O-Ras-O-Q-e alkyl-NH 2 ;
• R29 is an amino group, 5 to 12-membered heterocycloalkyl, -R 2 8-C 1 _6 alkyl-R 2 2, R28-C5-i2 heterocycloalkyl-Ci-6 alkyl-R 22 , -[C(R 20 R2i)] a -R22, or -R 28 -C 1 _ 6 alkyl-C 6 -i2 aryl-Ci_6 alkyl-R 22 ;
• R 2 8 is absent, NH or oxygen
• a is an integer from 1 to 6;
• c is an integer from 0 to 3;
• d is an integer from 1 to 3;
• f is an integer from 1 to 12.
• R 39 is benzyl or ;
• R44 is hydrogen
• auristatin of Formula (X) is a compound of Formula (XI),
• a is an integer from 1 to 6;
• c is an integer from 0 to 3;
• a is an integer from 1 to 6;
• c is an integer from 0 to 3.
• R29 is an amino group, 5 to 12-membered heterocycloalkyl, -R ⁇ -Ci-6 alkyl-R 22 , R 2 8-C 5 -i2 heterocycloalkyl-Ci-e alkyl-R 22 , -R 2 8-[C(R 20 R 2 i)] a -R 22 , or -R 28 -C 1-6 alkyl-C 6 - 12 aryl-Q. 6 alkyl-R 22 ;
• each of R 20 and R 21 independently is hydrogen, C 1-6 alkyl, C 6-10 aryl, hydroxylated C 6-10 aryl, polyhydroxylated C 6 -io aryl, 5 to 12-membered heterocycle, C 3 _ 8 cycloalkyl, hydroxylated C 3 _8 cycloalkyl, polyhydroxylated C 3 _ 8 cycloalkyl or a side chain of a natural or unnatural amino acid;
• R 22 is -OH, -NHR 2 , -COOH, -R 82 -C(0)(CH 2 ) c -C(H)(R 23 )-N(H)(R 23 ), -R 82 -C(0)(CH 2 ) d -
• each R 2 independently is hydrogen, C 1-6 alkyl, C 6-10 aryl, C 3 _ 8 cycloalkyl, -COOH, or -COO-Ci_6 alkyl;
• X is a side chain of a natural or unnatural amino acid
• R 77 is a hydrogen or X and NR 77 form a nitrogen containing cyclic compound
• R 82 is -NH or oxygen
• R 28 is absent, NH or oxygen
• a is an integer from 1 to 6;
• c is an integer from 0 to 3;
• d is an integer from 1 to 3;
• R 4 o is
• R29 is -NH 2 , 5 membered heterocycloalkyl, -R 28 -C 1-6 alkyl-R 2 2, R 2 8-C5- 12 heterocycloalkyl-Ci-6 alkyl-R 22 or -R 2 8-C 1 _6 alkyl-C6-i2 aryl-Ci-6 alkyl-R 22; ;
• R 2 8 is absent, NH or oxygen
• R 22 is -OH, -NHR 23 , -COOH, -R 82 -C(0)(CH 2 ) c -C(H)(R 23 )-N(H)(R 23 ), -R 82 -C(0)(CH 2 ) d - (O CH 2 -CH 2 ) f -N(H)(R 23 ) or -R 82 -(C(0)-CH(X 2 )-NH) d -R 77 ;
• each R 23 independently is hydrogen, C 1-6 alkyl, C 6 -io aryl, C 3 _ 8 cycloalkyl, -COOH, or -COO-Ci_6 alkyl;
• X is a side chain of a natural or unnatural amino acid
• R 77 is a hydrogen or X and NR 77 form a nitrogen containing cyclic compound
• R 82 is -NH or oxygen
• c is an integer from 0 to 3;
• d is an integer from 1 to 3;
• f is an integer from 1 to 12.
• R 2 g is any one of the following structures:
• a is an integer from 1 to 6;
• c is an integer from 0 to 3;
• g is an integer from 2 to 6.
• the MEK inhibitor is a compound of Formula (XIV):
• R 43 is H or -R 46 -R 47 ;
• each of R 2 o and R 21 independently is hydrogen, C 1-6 alkyl, C 6 -io aryl, hydroxylated C 6 -io aryl, polyhydroxylated C 6 -io aryl, 5 to 12-membered heterocycle, C 3 _8 cycloalkyl, hydroxylated C 3 _8 cycloalkyl, polyhydroxylated C 3 _s cycloalkyl or a side chain of a natural or unnatural amino acid;
• R 22 is -OH, -NH 2 , -COOH, -R 82 -C(0)(CH 2 ) c -C(H)(R 23 )-N(H)(R 23 ), -R 82 -C(0)(CH 2 ) d -(0 CH 2 -CH 2 ) f -N(H)(R 23 ) or -R 82 -(C(0)-CH(X 2 )-NH) d -R 77 ;
• each R 2 independently is hydrogen, C 1-6 alkyl, C 6 -io aryl, C 3 _g cycloalkyl, -COOH, or
• X is a side chain of a natural or unnatural amino acid
• R 77 is a hydrogen or X and NR 77 form a nitrogen containing cyclic compound
• Rg 2 is -NH or oxygen
• R 46 is -C(O)-; -C(0)-0-, -C(0)-NH-, or absent;
• R 47 is as defined herein;
• a is an integer from 1 to 6;
• c is an integer from 0 to 3;
• d is an integer from 1 to 3; and f is an integer from 1 to 12.
• R 43 is -C(0)-(CH 2 ) a -NH 2 , or -C(0)-C(H)(CH 3 )-(CH 2 ) c -
• the duocarmycin compound is a compound of Formula
• R 47 is as defined herein;
• R 48 is hydrogen, -COOCi_ 6 alkyl, -COOH, -NH 2 or -CH 3 ;
• R 49 is CI, Br or -OH
• R50 is hydrogen, -OCH 3 ,
• each of R 51 and R 52 independently is hydrogen or -OCH 3 ;
• ring A A is either a phenyl or pyrrolyl ring.
• duocarmycin compounds are disclosed in US 7,553,816.
• R 49 is CI, Br or -OH
• R47 is as defined herein.
• the duocaraiycin compound is a duocaraiycin compound of Formula XX): US 5101038; or (XXI):
• R 42 is Ci_ 6 alkyl amino or -[C(R 20 R2i)] a -R22;
• each of R 20 and R 21 independently is hydrogen, C 1-6 alkyl, C 6-10 aryl, hydroxylated C 6-10 aryl, polyhydroxylated C 6 -io aryl, 5 to 12-membered heterocycle, C 3 -8 cycloalkyl, hydroxylated C 3 -8 cycloalkyl, polyhydroxylated C 3 -8 cycloalkyl or a side chain of a natural or unnatural amino acid;
• R 22 is -OH, -NH 2 , -COOH, -R 82 -C(0)(CH 2 ) C -C(H)(R 2 3)-N(H)(R 23 ), -R 82 -C(0)(CH 2 ) d -(0
• each R 23 independently is hydrogen, C 1-6 alkyl, C 6 -io aryl, C3_s cycloalkyl, -COOH, or -COO-Ci-6 alkyl;
• X is a side chain of a natural or unnatural amino acid
• R 77 is a hydrogen or X and NR 77 form a nitrogen containing cyclic compound
• R8 2 is -NH or oxygen
• a is an integer from 1 to 6;
• c is an integer from 0 to 3;
• d is an integer from 1 to 3;
• f is an integer from 1 to 12.
• R 42 is any one of the following structures: a is an integer from 1 to 6; and
• c is an integer from 0 to 3.
• tubulysin is a compound of Formula (XXII):
• R 57 is Ci- 4 alkyl or -C(0)R 5 8;
• R 5 8 is Ci-6 alkyl, CF 3 or C 6 -io aryl
• R 59 is Ci-6 alkyl
• R 6 o is hydrogen, Ci-6 alkyl, C 2 - 7 alkenyl, -CH 2 -phenyl, CH 2 OR 65 or CH 2 OCOR 66 ;
• R65 is hydrogen, Ci-6 alkyl, C 2 - 7 alkenyl, C6-10 aryl or C(0)R6 7 ;
• R 67 is Ci-6 alkyl, C 2 -6 alkenyl, C 6 -10 aryl or heteroaryl;
• R 66 is Ci-6 alkyl, -C 6 H 5 or -CH 2 -phenyl
• R 6 i is Ci-6 alkyl
• R 62 is hydrogen, OH, 0-Ci- 4 alkyl or 0-C(0)-Ci_ 4 alkyl;
• R 63 is hydrogen, OH, 0-Ci- 4 alkyl, 0-C(0)-Ci_ 4 alkyl, halogen or Ci-6 alkyl; e is an integer between 1 and 3 inclusive;
• R 64 is:
• R 68 is hydrogen or C1-C 6 alkyl
• R 69 is CO2R70, C(0)-R 78 , CONHNH2, OH, NH 2 , SH or optionally substituted alkyl, cycloalkyl, heteroalkyl or heterocycloalkyl group;
• R 70 is an optionally substituted alkyl (i.e. Ci_6 alkyl amine), heteroalkyl or
• each of R 71 and R73 independently is hydrogen, halo, -NO2, -CN, -NHR74, C 1-6 alkyl, haloalkyl, alkoxy, and haloalkoxy;
• R 72 is hydrogen, OR 43 , alkoxy, halogen, -NHR 74 , -0-C(0)-R 47 , N0 2 , -CN, C 6-10 aryl, Ci_ 6 alkyl, amino or dialkylamino;
• R 74 is hydrogen, -CHO, -C(0)-C 1 _ 4 alkyl, OH, amino group, alkyl amino or -
• R 43 is H or -R 46 — R 47 ;
• R 46 is -C(O)-; -C(0)-0-, -C(0)-NH-, or absent;
• R 47 is as defined herein;
• R 78 is X 3 -R 7 5 or NH-R 19 ;
• X 3 is O or S
• R 19 is hydrogen, OH, amino group, alkyl amino or -[C(R2oR2i)] a -R22;
• R75 is a hydrogen, an amino group, C 1-6 alkyl amino or -[C(R2oR2i)] a -R22;
• each of R20 and R21 independently is hydrogen, C 1-6 alkyl, C 6 -io aryl, hydroxylated C 6 -io aryl, polyhydroxylated C 6 -io aryl, 5 to 12-membered heterocycle, C 3 _ 8 cycloalkyl, hydroxylated C 3 _8 cycloalkyl, polyhydroxylated C 3 _ 8 cycloalkyl or a side chain of a natural or unnatural amino acid;
• R 22 is -OH, -NH 2 , -COOH, -R 82 -C(0)(CH 2 ) C -C(H)(R2 3 )-N(H)(R2 3 ), -R 82 -C(0)(CH 2 ) d -(0 CH 2 -CH 2 ) f -N(H)(R 23 ), or -R 82 -(C(0)-CH(X 2 )-NH) d -R 77 ;
• each R 23 independently is hydrogen, C 1-6 alkyl, C 6-10 aryl, C 3 _ 8 cycloalkyl, -COOH, or -COO-Ci-6 alkyl;
• X is a side chain of a natural or unnatural amino acid
• R 77 is a hydrogen or X and NR 77 form a nitrogen containing cyclic compound
• R 8 2 is -NH or oxygen
• R 47 is as defined herein;
• d is an integer from 1 to 3;
• f is an integer from 1 to 12;
• R 6 9 is C(0)-X -R75 or C(0)-NH-R 19
• one or both of R 71 and R 73 are -NHR 74
• R 72 is OR 43> -NHR 74 or -0-C(0)-R 47
• at least one of R 19> R43, R 74 and R 75 cannot be hydrogen.
• R 57 is -CH 3 ;
• R59 is sec-butyl
• R 6 o is hydrogen, methyl, ethyl, propyl, iso-propyl or iso-butyl;
• R 61 is iso-propyl
• R 62 is hydrogen
• R 63 is hydrogen, OH, -0-C 3 H 7 , 0-C(0)-CH 3 ;
• R 6 8 is hydrogen or -CH 3 ;
• R 69 is C0 2 H, CO 2 R 70 or C(0)-R 78 ;
• R 7 o is Ci_6 alkyl amine
• each of R 71 and R 73 independently is hydrogen
• R 72 is hydrogen, -OR 43, OH, F, -CH 3 or -OCH 3 ;
• R 78 is OH, -OR 75 or -NHR 40 ;
• e is the integer 2;
• R 4 o is hydrogen, -OH, -NH 2 , or any of the following structures:
• a is an integer from 1 to 6;
• c is an integer from 0 to 3;
• R75 is any one of the following structures:
• a is an integer from 1 to 6;
• c is an integer from 0 to 3;
• R43 is hydrogen, -C(0)-(CH 2 ) a -NH 2 , or -C(0)-C(H)(CH 3 )-(CH 2 ) c -NH 2 ; wherein:
• R47 is any one of the following structures:
• a is an integer from 1 to 6;
• c is an integer from 0 to 3;
• g is an integer from 2 to 6;
• R 72 is -OH, then R 7 5 cannot be hydrogen; if R 6 9 is COOH then R 72 must be -OR 43 or -0-C(0)-R 47 .
• tubulysin of Formula (XXII) is a compound of
• R 76 is hydrogen , OH, OCH 3 , F, -OR 43 or -0-C(0)-R 47 ;
• R 78 , R 7 5, R 19 , R ⁇ 7 and R 4 are as defined herein;
• R 76 is -OH, OCH 3 or F, then R 75 and R 19 cannot be hydrogen.
• R 47 is
• the KSP inhibitor compound is a compound of Formula
• R 30 is as defined herein.
• R 0 is:
• a is an integer from 1 to 6;
• c is an integer from 0 to 3;
• g is an integer from 2 to 6.
• the KSP inhibitor compound is a compound of Formula
• Rn is as defined herein.
• therapeutic agents described herein can be modified in such a manner that the resulting compound still retains the specificity and/or activity of the original compound.
• therapeutic agents of the present invention include analogues and derivatives of the compounds described herein.
• Table B below provides more examples of the therapeutic agents and derivatives thereof suitable for conjugation to form the polymer-drug-protein conjugates or polymer-drug scaffolds of the invention. Spectral data of certain compounds are also provided (ND in the table means "not determined”). These examples may also be the active form of the drug when it is released from the conjugates in vitro or in vivo.
• PBRMs Protein-Based Recognition Molecules
• the protein-based recognition molecule directs the drug-polymer carrier conjugates to specific tissues, cells, or locations in a cell.
• the protein-based recognition molecule can direct the modified polymer in culture or in a whole organism, or both.
• the protein-based recognition molecule has a ligand that is present on the cell surface of the targeted cell(s) to which it binds with an effective specificity, affinity and avidity.
• the protein-based recognition molecule targets the modified polymer to tissues other than the liver.
• the protein-based recognition molecule targets the modified polymer to a specific tissue such as the liver, kidney, lung or pancreas.
• the protein- based recognition molecule can target the modified polymer to a target cell such as a cancer cell, such as a receptor expressed on a cell such as a cancer cell, a matrix tissue, or a protein associated with cancer such as tumor antigen.
• a target cell such as a cancer cell, such as a receptor expressed on a cell such as a cancer cell, a matrix tissue, or a protein associated with cancer such as tumor antigen.
• cells comprising the tumor vasculature may be targeted.
• Protein-based recognition molecules can direct the polymer to specific types of cells such as specific targeting to hepatocytes in the liver as opposed to Kupffer cells. In other cases, protein-based recognition molecules can direct the polymer to cells of the reticular endothelial or lymphatic system, or to professional phagocytic cells such as
• the polymer itself might also be an effective delivery system, without the need for specific targeting).
• the protein based recognition molecule can target the modified polymer to a location within the cell, such as the nucleus, the cytoplasm, or the endosome, for example.
• the protein based recognition molecule can enhance cellular binding to receptors, or cytoplasmic transport to the nucleus and nuclear entry or release from endosomes or other intracellular vesicles.
• the protein based recognition molecules include antibodies, proteins and peptides or peptide mimics.
• Exemplary antibodies or antibodies derived from Fab, Fab2, scFv or camel antibody heavy-chain fragments specific to the cell surface markers include, but are not limited to, 5T4, AOC3, C242, CA-125, CCL11, CCR 5, CD2, CD3, CD4, CD5, CD15, CD18, CD19, CD20, CD22, CD23, CD25, CD28, CD30, CD31, CD33, CD37, CD38, CD40, CD41, CD44, CD51, CD52, CD54, CD56, CD62E, CD62P, CD62L, CD70, CD74, CD80, CD125, CD138, CD141, CD147, CD152, CD 154, CD326, CEA, clumping factor, CTLA-4, EGFR, ErbB2, ErbB3, EpCAM, folate receptor, FAP, GD2, GD3, GPNMB, HGF, HER2, ICAM, IGF-1 receptor, VEGFR1, EphA2, TRPV1, CFTR,
• RANKL respiratory syncytial virus
• Rhesus factor Rhesus factor
• SLAMF7 sphingosine-1 -phosphate
• TAG- 72 T-cell receptor
• tenascin C TGF-1, TGF ⁇ 2, TGF- ⁇ , TNF-a, TRAIL-R1, TRAIL-R2, tumor antigen CTAA16.88, VEGF-A, VEGFR2, vimentin, and the like.
• the antibodies or antibody derived from Fab, Fab2, scFv or camel antibody heavy-chain fragments specific to the cell surface markers include CA-125, C242, CD3, CD19, CD22, CD25, CD30, CD31, CD33, CD37, CD40, CD44, CD51, CD54, CD56, CD62E, CD62P, CD62L, CD70, CD138, CD141, CD326, CEA, CTLA-4, EGFR, ErbB2, ErbB3, FAP, folate receptor, IGF-1 receptor, GD3, GPNMB, HGF, HER2, VEGF-A, VEGFR2, VEGFR1, EphA2, EpCAM, 5T4, TAG-72, tenascin C, TRPV1, CFTR, gpNMB, CA9, Cripto, ACE, APP, PDGFR a, phosphatidylserine, prostatic carcinoma cells, adrenergic receptor-beta2, Claudine
• Exemplary antibodies include 3F8, abagovomab, abciximab (REOPRO), adalimumab (HUMIRA), adecatumumab, afelimomab, afutuzumab, alacizumab, ALD518, alemtuzumab (CAMPATH), altumomab, amatuximab, anatumomab, anrukinzumab, apolizumab, arcitumomab (CEA-SCAN), aselizumab, atlizumab (tocilizumab, Actemra, RoActemra), atorolimumab, bapineuzumab, basiliximab (Simulect), bavituximab, bectumomab
• maslimomab matuzumab, mepolizumab (BOSATRIA), metelimumab, milatuzumab, minretumomab, mitumomab, morolimumab, motavizumab (NUMAX), muromonab-CD3 (ORTHOCLONE OKT3), nacolomab, naptumomab, natalizumab (TYSABRI), nebacumab, necitumumab, nerelimomab, nimotuzumab (THERACIM), nofetumomab, ocrelizumab, odulimomab, ofatumumab (ARZERRA), olaratumab, omalizumab (XOLAIR), ontecizumab, oportuzumab, oregovomab (OVAREX), otelixizumab, pagibaximab
• ruplizumab (ANTOVA), satumomab pendetide, sevirumab, sibrotuzumab, sifalimumab, siltuximab, siplizumab, solanezumab, sonepcizumab, thankuzumab, stamulumab, sulesomab (LEUKOSCAN), tacatuzumab (AFP-CIDE), tetraxetan, tadocizumab, talizumab, tanezumab, taplitumomab paptox, tefibazumab (AUREXIS), telimomab, tenatumomab, teneliximab, teplizumab, TGN1412, ticilimumab (tremelimumab), tigatuzumab, TNX-650, tocilizumab (at
• vapaliximab vapaliximab, vedolizumab, veltuzumab, vepalimomab, visilizumab (NUVION), volociximab (HUMASPECT), votumumab, zalutumumab (HuMEX-EGFr), zanolimumab (HuMAX-CD4), ziralimumab and zolimomab.
• the antibodies are directed to cell surface markers for 5T4,
• the antibodies are abagovomab, adecatumumab, alacizumab, altumomab, anatumomab, arcitumomab, bavituximab, bevacizumab (AVASTIN), bivatuzumab, blinatumomab, brentuximab, cantuzumab,
• catumaxomab capromab , cetuximab, citatuzumab, clivatuzumab, conatumumab, dacetuzumab, edrecolomab, epratuzumab, ertumaxomab, etaracizumab, farletuzumab, figitumumab, gemtuzumab, glembatumumab, ibritumomab, igovomab, intetumumab, inotuzumab,
• labetuzumab lexatumumab, lintuzumab, lucatumumab, matuzumab, mitumomab, naptumomab estafenatox, necitumumab, oportuzumab, oregovomab, panitumumab, pemtumomab,
• pertuzumab pertuzumab, pritumumab, rituximab (RrfUXAN), rilotumumab, robatumumab, satumomab, sibrotuzumab, taplitumomab , tenatumomab, tenatumomab, ticilimumab (tremelimumab), tigatuzumab, trastuzumab (HERCEPTIN), tositumomab, tremelimumab, tucotuzumab celmoleukin, volociximab and zalutumumab.
• the antibodies directed to cell surface markers for HER2 are pertuzumab or trastuzumab and for EGFR the antibody is cetuximab and for CD20 the antibody is rituximab and for VEGF-A is bevacizumab and for CD-22 the antibody is
• epratuzumab or veltuzumab and for CEA the antibody is labetuzumab.
• Exemplary peptides or peptide mimics include integrin targeting peptides (RGD peptides), LHRH receptor targeting peptides, ErbB2 (HER2) receptor targeting peptides, prostate specific membrane bound antigen (PSMA) targeting peptides, lipoprotein receptor LRP1 targeting, ApoE protein derived peptides, ApoA protein peptides, somatostatin receptor targeting peptides, chlorotoxin derived peptides, and bombesin.
• RGD peptides integrin targeting peptides
• LHRH receptor targeting peptides LHRH receptor targeting peptides
• ErbB2 (HER2) receptor targeting peptides ErbB2 (HER2) receptor targeting peptides
• PSMA prostate specific membrane bound antigen
• lipoprotein receptor LRP1 targeting
• ApoE protein derived peptides ApoA protein peptides
• somatostatin receptor targeting peptides chlorotoxin derived peptid
• the peptides or peptide mimics are LHRH receptor targeting peptides and ErbB2 (HER2) receptor targeting peptides
• Exemplary proteins comprise insulin, transferrin, fibrinogen-gamma fragment, thrombospondin, claudin, apolipoprotein E, Affibody molecules such as, for example, ABY-025, Ankyrin repeat proteins, ankyrin-like repeats proteins and synthetic peptides.
• the protein drug polymer conjugates comprise broad spectrum cytotoxins in combination with cell surface markers for HER2 such as pertuzumab or trastuzumab; for EGFR such as cetuximab; for CEA such as labetuzumab; for CD20 such as rituximab; for VEGF-A such as bevacizumab; or for CD-22 such as epratuzumab or veltuzumab.
• HER2 such as pertuzumab or trastuzumab
• EGFR such as cetuximab
• CEA such as labetuzumab
• CD20 such as rituximab
• VEGF-A such as bevacizumab
• CD-22 such as epratuzumab or veltuzumab.
• the protein-drug-polymer conjugates or protein-polymer conjugates used in the invention comprise combinations of two or more protein based recognition molecules, such as, for example, combination of bispecific antibodies directed to the EGF receptor (EGFR) on tumor cells and to CD3 and CD28 on T cells; combination of antibodies or antibody derived from Fab, Fab2, scFv or camel antibody heavy-chain fragments and peptides or peptide mimetics; combination of antibodies or antibody derived from Fab, Fab2, scFv or camel antibody heavy-chain fragments and proteins; combination of two bispecific antibodies such as CD3 x CD 19 plus CD28 x CD22 bispecific antibodies.
• EGFR EGF receptor
• Table C below provides more examples of the PBRM described hereof, which are suitable for conjugation to form the polymer-drug-protein conjugates or polymer- PBRM scaffolds of the invention.
• the drug or PBRM is connected to the polymeric carrier via a linker L D or L p .
• the linker is biocleavable/biodegradable under intracellular conditions, such that the cleavage of the linker releases the drug or PBRM from the polymer unit in the intracellular environment.
• a linker is any chemical moiety that is capable of linking a drug or a PBRM to a polymer backbone through chemical bonds such that the drug or PBRM and the polymer are chemically coupled (e.g., covalently bonded) to each other.
• the linker comprises a biodegradable linker moiety (e.g., a biodegradable bond such as an ester or amide bond).
• the linker L D or L p is biodegradable under mild conditions, i.e., conditions within a cell under which the activity of the drug is not affected.
• suitable biodegradable linker moiety include disulfide linkers, acid labile linkers, photolabile linkers, peptidase labile linkers, and esterase labile linkers.
• the linker L D or L p is biocleavable under reducing conditions (e.g., a disulfide linker).
• the drug or PBRM moiety is linked to the polymer through a disulfide bond.
• the linker molecule comprises a reactive chemical group that can react with the drug. Preferred reactive chemical groups for reaction with the drug or
• PBRM moiety are N-succinimidyl esters and N-sulfosuccinimidyl esters. Additionally the linker molecule comprises a reactive chemical group, preferably a dithiopyridyl group that can react with the drug to form a disulfide bond.
• the linker molecules include, for example, N-succinimidyl 3-(2-pyridyldithio)propionate (SPDP), N-succinimidyl 4- (2- pyridyldithio)butanoate (SPDB), N-succinimidyl 4-(2-pyridyldithio)pentanoate (SPP), N- succinimidyl-S-acetylthioacetate (SATA) and N-succinimidyl-oxycarbonyl-alpha-methyl-alpha- (2-pyridyl-dithio)toluene or 2,5-dioxopyrrolidin- 1-yl 4-(l-(pyridin-2-yldisulfanyl)ethyl)benzoate (SMPT).
• SPDP N-succinimidyl 3-(2-pyridyldithio)propionate
• SPDB N-succinimidyl
• the biocleavable linker L D or L p is pH-sensitive, i.e., sensitive to hydrolysis at certain pH values.
• the pH-sensitive linker is hydrolysable under acidic conditions.
• an acid-labile linker that is hydrolysable in the lysosome or endosome e.g., a hydrazone, semicarbazone, thiosemicarbazone, cis-aconitic amide, orthoester, acetal, ketal, or the like
• Such linkers are relatively stable under neutral pH conditions, such as those in the blood, but are unstable at below pH 5.5 or 5.0, the
• the hydrolysable linker is a thioether linker (such as, e.g., a thioether attached to the therapeutic agent via an acylhydrazone bond.
• the linker L D or L p is photo-labile and is useful at the body surface and in many body cavities that are accessible to light. Furthermore, L D or L p is biocleavable by infrared light which can penetrate tissue. Accordingly, L D or L p is useful for both applications on the body surface and in the tissue. [00302] In some embodiments, the linker L D or L p is biocleavable by a cleaving agent that is present in the intracellular environment (e.g., within a lysosome or endosome or caveolea).
• the linker can be, for example, a peptidyl linker that is cleaved by an intracellular peptidase or protease enzyme, including, but not limited to, a lysosomal or endosomal protease.
• the linker L D or L p is cleaved by esterases. Only certain esters can be cleaved by esterases present inside or outside cells. Esters are formed by the condensation of a carboxylic acid and an alcohol. Simple esters are esters produced with simple alcohols, such as aliphatic alcohols, and small cyclic and small aromatic alcohols.
• the linker L D or L p is not biocleavable and the drug is released by antibody degradation. See, for example, U.S. Patent No. 7,498,298, which is incorporated by reference herein in its entirety and for all purposes.
• the linker L D or L p is not substantially sensitive to the extracellular environment.
• “not substantially sensitive to the extracellular environment,” in the context of a linker means that no more than about 20%, typically no more than about 15%, more typically no more than about 10%, and even more typically no more than about 5%, no more than about 3%, or no more than about 1% of the linkers, in a sample of Polymer Drug Conjugate, are cleaved when the Polymer Drug Conjugate presents in an extracellular environment (e.g., in plasma) for 24 hours.
• Whether a linker is not substantially sensitive to the extracellular environment can be determined, for example, by incubating the Polymer Drug Conjugate with plasma for a predetermined time period (e.g., 2, 4, 8, 16, or 24 hours) and then quantitating the amount of free drug present in the plasma.
• a predetermined time period e.g. 2, 4, 8, 16, or 24 hours
• the linker L D has the structure:
• the linker L p has the structure:
• each of R L1 and R L2 independently is absent, alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, aryl, or heteroaryl.
• each of R L1 and R L2 independently is absent, alkyl, cycloalkyl, heteroalkyl, or heterocycloalkyl.
• R is absent.
• R L2 is absent.
• non-biodegradable linker moiety selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, heteroalkenyl, heteroalkynyl,
• heterocycloalkyl aryl, heteroaryl, and a combination thereof and each of M D1 , M D2 , M D3 , M pl ,
• each of M D1 , M D2 , M D3 , M D4 , M pl , M P2 , M P3 and M P4 independently is Ci-6 alkyl, C 1-6 alkyl-C(O)-C 0 - 6 alkyl, C 1-6 alkyl-NH-C 0 - 6 alkyl, C 1-6 alkyl-O-C 0 - 6 alkyl, Ci-6 alkyl-S-Co-6 alkyl, C 1-6 alkyl-C(0)-C 1-6 alkyl-NH, C 1-6 alkyl-C(0)-C 1-6 alkyl-O, C 1-6 alkyl- C(0)-Ci-6 alkyl-S, C3-10 cycloalkyl-C(O)-C 0 - 6 alkyl, 3-19 membered heterocycloalkyl-C(O)-C 0 - 6 alkyl, aryl-C(O)-C 0 - 6 alkyl, aryl-C(
• M D1 is not absent when X D is absent.
• M pl is not absent when X p is absent.
• each of M D1 and M pl independently is Ci_6 alkyl or C 1-6 heteroalkyl.
• each of M D2 , M D3 , M m , M P2 , M P3 , and M P4 independently is absent,
• M D u 2 and M D U 3 J has one of the following structures:
• q is an integer from 0 to 12 and each of p and t independently is an integer from 0 to 3, and the other of M D2 or M D3 is either absent or a moiety different from the above, such as Ci_6 alkyl.
• M P r 2 and M P r 3 j has one of the following structures:
• q is an integer from 0 to 12 and each of p and t independently is an integer from 0 to 3, and the other of M P2 or M P3 is either absent or a moiety different from the above, such as C 1-6 alkyl.
• p is 2.
• q is 0 or 12.
• t is 0 or 1.
• each of -M D2 -Z D -, -Z D -M D3 -, -Z D -M D2 -, or -M D3 -Z D - independently has one of the following structures:
• ring A or B independently is cycloalkyl or heterocycloalkyl;
• R is an aliphatic, heteroaliphatic, carbocyclic, or heterocycloalkyl moiety;
• R 1J is hydrogen, an aliphatic, heteroaliphatic, carbocyclic, or heterocycloalkyl moiety; and
• ring D is heterocycloalkyl.
• each of -M P2 -Z P -, -Z P -M P3 -, -Z P -M P2 -, and -M P3 -Z P - independently, has one of the following structures:
• ring A is cycloalkyl or heterocycloalkyl and R is hydrogen, an aliphatic, heteroaliphatic, carbocyclic, or heterocycloalkyl moiety.
• ring A is 5-19 membered heterocycloalkyl, e.g.,
• ring A is C 3 _g cycloalkyl.
• ring D is piperazinyl or piperidinyl.
• R w is C 1-6 alkyl.
• R 1J is hydrogen or Ci_6 alkyl.
• Z is
• X is absent, O or NH.
• X p is absent, O or NH.
• each of X D and X p independently is
• each of Y D and Y p independently is -S-S-, -OCO-, -COO-, -CONH- or -NHCO-
• each of Q D and Q p independently is absent,-S-S-, -OCO-, -COO-, -CONH-, -NHCO-, -OCONHNH-, or -NHNHCOO-.
• -L D -D can have one of the following structures below, in which the wavy bond indicates that D (i.e. Drug) is either connected to the functional linker directly or via another moiety:
• R 80 is CH 2 , -NH, or oxygen
• R 82 is -NH or oxygen.
• polymeric carrier-L p -PBRM can have one of the following structures below:

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• Inorganic Chemistry (AREA)
• Hematology (AREA)
• Medicinal Preparation (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Peptides Or Proteins (AREA)
• Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Polyethers (AREA)
• Other Resins Obtained By Reactions Not Involving Carbon-To-Carbon Unsaturated Bonds (AREA)

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Publications (1)

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Cited By (40)

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Citations (115)

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• 2012
  • 2012-06-11 RU RU2014100171A patent/RU2617402C2/ru active
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  • 2012-06-11 EP EP17159707.3A patent/EP3228325A1/en not_active Withdrawn
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• 2013
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• 2014
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• 2016
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• 2017
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• 2018
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• 2019
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• 2020
  • 2020-10-28 JP JP2020180205A patent/JP7305604B2/ja active Active
• 2023
  • 2023-06-28 JP JP2023106308A patent/JP2023120427A/ja active Pending