WO2016038383A1 - Pyrrolobenzodiazepines and conjugates thereof - Google Patents

Pyrrolobenzodiazepines and conjugates thereof Download PDF

Info

Publication number
WO2016038383A1
WO2016038383A1 PCT/GB2015/052629 GB2015052629W WO2016038383A1 WO 2016038383 A1 WO2016038383 A1 WO 2016038383A1 GB 2015052629 W GB2015052629 W GB 2015052629W WO 2016038383 A1 WO2016038383 A1 WO 2016038383A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
conjugate according
antibody
conjugate
genbank
Prior art date
Application number
PCT/GB2015/052629
Other languages
English (en)
French (fr)
Inventor
Philip Wilson Howard
Stephen John Gregson
Jean-Noel LEVY
Original Assignee
Medimmune Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Medimmune Limited filed Critical Medimmune Limited
Priority to JP2017513438A priority Critical patent/JP6518321B2/ja
Priority to EP15766215.6A priority patent/EP3191490B1/en
Priority to US15/510,345 priority patent/US10420777B2/en
Priority to CN201580048691.5A priority patent/CN106687472B/zh
Publication of WO2016038383A1 publication Critical patent/WO2016038383A1/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • A61K31/5517—1,4-Benzodiazepines, e.g. diazepam or clozapine condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A61K47/68035—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a pyrrolobenzodiazepine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
    • A61K47/6855—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell the tumour determinant being from breast cancer cell
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
    • C07K16/3015—Breast
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
    • C07K16/3046—Stomach, Intestines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
    • C07K5/06052—Val-amino acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06139—Dipeptides with the first amino acid being heterocyclic
    • C07K5/06165—Dipeptides with the first amino acid being heterocyclic and Pro-amino acid; Derivatives thereof
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to pyrrolobenzodiazepines (PBDs), in particular
  • pyrroiobenzodiazepines having a linker group connected to a ceil binding agent.
  • PBDs pyrrolobenzodiazepines
  • Family members include abbeymycin (Hochiowski, et al., J. Antibiotics, 40, 145-148 (1987)), chicamycin (Konishi, et al., J. Antibiotics, 37, 200-206 (1984)), DC-81 (Japanese Patent 58-180 487; Thurston, et al., Chem. Brit, 28, 767-772 (1990); Bose, et al., Tetrahedron, 48, 751-758 (1992)), mazethramycin (Kuminoto, et al., J.
  • PBDs are of the general structure:
  • CH(OMe)) at the 10-C1 1 position which is the electrophiiic centre responsible for alkylating DNA.
  • Ail of the known natural products have an (S) ⁇ configurafion at the chiral C1 1a position vv'hich provides them with a right-handed twist when viewed from the C ring towards the A ring. This gives them the appropriate three-dimensional shape for isohelicity with the minor groove of B-form DNA, leading to a snug fit at the binding site (Kohn, In Antibiotics ///.
  • a particularly advantageous pyrrolobenzodiazepine compound is described by Gregson ei a!. ⁇ Chem, Commun. 1999, 797-798) as compound 1 , and by Gregson et a!. ⁇ J. Med. Chem. 2001 , 44, 181-1174) as compound 4a.
  • This compound also known as SJG-136, is shown below:
  • ADC antibody-drug conjugates
  • cytotoxic or cytostatic agents i.e. drugs to kill or inhibit tumor ceils in the treatment of cancer
  • cytotoxic or cytostatic agents i.e. drugs to kill or inhibit tumor ceils in the treatment of cancer
  • systemic administration of these unconjugated drug agents may result in unacceptable levels of toxicity to normal cells as well as the tumor cells sought to be eliminated (Xie ei / (2008) Expert. Opin. Biol. Ther.
  • Drug moieties may impart their cytotoxic and cytostatic effects by mechanisms including tubulin binding, DNA binding, or topoisomerase inhibition. Some cytotoxic drugs tend to be inactive or less active when conjugated to large antibodies or protein receptor ligands. PBDs in ADCs
  • Dimeric PBDs have been disclosed as the drugs in drug conjugates.
  • dimer PBD compounds having linker groups for connection to a cell binding agent, such as an antibody are disclosed where the linker group is attached to one of the available N10 positions, and are generally cleaved by action of an enzyme on the linker group.
  • dimer PBD compounds having linker groups for connection to a ceil binding agent, such as an antibody where the linker group is attached via an aromatic group at one of the C2 postions, and are generally cleaved by action of an enzyme on the linker group.
  • a ceil binding agent such as an antibody
  • Such antibody drug conjugates are also described in Fiygare, J., et ai, Chem. Biol. Drug Des. 81 : 113-121 (2013), which also describes other types of antibody drug conjugates.
  • tomamycin-iike dimers have a linker group for connection to a cell binding agent, such as an antibody, where the linker group is attached to the tether between the tomamycin units, and are generally cleaved by action of an enzyme on the linker group.
  • the present inventors have developed a novel approach to forming PBD conjugates with ceil binding agents, and in particular PBD antibody conjugates.
  • the present invention provides a conjugate comprising a PBD dimer compound with a linker for connecting to a cell binding agent, wherein the linker is attached in a deavabie fashion to a propargylene group itself attached to a phenylene or pyriydylene in the bridge linking the two PBD monomers.
  • the cell binding agent is preferably an antibody.
  • the present invention provides novel conjugate compounds of formula (A):
  • R 2 is selected from the group consisting of:
  • R 35a and R 35 are H and the other is selected from: phenyl, which phenyl is optionally substituted by a group selected from halo, methyl, met and thiophenyl; and
  • R 34 is selected from: H; C1-3 saturated alkyl; C2-3 alkenyl; C2-3 alkynyl; cyclopropyl; phenyl, which phenyl is optionally substituted by a group selected from halo, methyl, methoxy; pyridyl; and thiophenyl;
  • R 2 is , where R 36a and R 36b are independently selected from H, F, C1-4 saturated alkyl, C2-3 alkenyl, which alkyl and alkenyl groups are optionally substituted by a group selected from C1-4 alkyl amido and Ci -4 alkyl ester; or, when one of R 16a and R 16 is H, the other is selected from nitriie and a Ci -4 alkyl ester;
  • Z is N or CH
  • D " represents either grou D'1 or D'2:
  • R 6 and R 9 are independently selected from H, R, OH, OR, SH, SR, NH 2 , NHR, NRR ⁇ N0 2 , Me 3 Sn and halo;
  • R 7 is independently selected from H, R, OH, OR, SH, SR, NH 2 , NHR, NRR ⁇ N0 2 , esSn and halo;
  • Y is of formula A1 :
  • L is a linker connected to a cell binding agent
  • R N is selected from H and C1-4 a!ky!
  • CBA is the cell binding agent
  • n is an integer selected in the range of 0 to 48;
  • Q x is such that Q is an amino-acid residue, a dipeptide residue or a tripeptide residue
  • R 10 is H, and R 1 1 is OH, 0R A , where R A is C1-4 alkyl; or
  • R ! 0 and R 1 1 form a nitrogen-carbon double bond between the nitrogen and carbon atoms to which they are bound;
  • R 10 is H and R 1 1 is OSO z M, where z is 2 or 3 and M is a monovalent
  • R and R' are each independently selected from optionally substituted CMS alkyl, C3-20 heterocyclyl and C5-20 aryi groups, and optionally in relation to the group NRR', R and R ! together with the nitrogen atom to which they are attached form an optionally substituted 4-, 5-, 6- or 7-membered heterocyclic ring;
  • R 16 , R 17 , R 19 , R 20 , R 2 and R 22 are as defined for R 6 , R 7 , R 9 , R 0 , R 11 and R 2 respectively;
  • T and T " are independently selected from a single bond or a C1-9 aikyiene, which chain may be interrupted by one or more heteroatoms e.g. O, S, N(H), NMe, provided that the number of atoms in the shortest chain of atoms between X and X' is 3 to 12 atoms;
  • a second aspect of the present invention provides novel drug-linker compounds of formula (B):
  • Y L is of formula B1 :
  • a third aspect of the present invention provides compounds of formula (C) which may be used in the preparation of the compounds and conjugate compounds of the invention:
  • R 30 is H, and R 31 is OH, OR A , where R A is C -4 aikyi; or
  • R 30 and R 31 form a nitrogen-carbon double bond between the nitrogen and carbon atoms to which they are bound;
  • R 30 is H and R 31 is OSO z , where z is 2 or 3 and M is a monovalent
  • R 30 is a nitrogen protecting group and R 31 is OProt°, where Prof° is a hydroxy protecting group;
  • R 40 and R 4 are as defined for R 30 and R 31 respectively;
  • a fourth aspect of the present invention provides the use of a compound of the first aspect of the invention in a method of medical treatment.
  • the fourth aspect also provides a pharmaceutical composition comprising a compound of the first aspect, and a
  • a fifth aspect of the present invention provides a compound of the first aspect of the invention or a pharmaceutical composition of the fourth aspect of the invention for use in a method of treatment of a proliferative disease.
  • the fifth aspect also provides the use of a compound of the first aspect in a method of manufacture of a medicament for the treatment of a proliferative disease, and a method of treating a mammal having a proliferative disease, comprising administering an effective amount of a compound of the first aspect or a pharmaceutical composition of the fourth aspect.
  • a sixth aspect of the present invention provides a method of synthesis of a compound of the first aspect of the present invention, comprising the step of conjugating a drug-linker of the second aspect with a cell-binding agent.
  • the present invention also provides the synthesis of compounds of the second aspect of the invention from compounds of the third aspect of the invention by reacting them with suitable reagents.
  • a further aspect of the invention provides a compounf of formula D:
  • R N2 is Ci-4 aikyi
  • the present invention provides a conjugate comprising a PBD dimer connected through the dimer bridging portion via a specified linker to a cell binding agent.
  • the present invention is suitable for use in providing a PBD conjugate to a preferred site in a subject.
  • Nitrogen protecting groups are well known in the art.
  • Preferred nitrogen protecting groups for use in the present invention are carbamate protecting groups that have the general formula: wherein R' 30 is an optionally substituted aikyl (e.g. C1-20 a!ky!), aryi (e.g. C5-20 aryl) or heteroaryl (e.g. C3-20 heterocyclyi) group.
  • Particularly preferred protecting groups include Alloc, Troc, Teoc, BOC, TcBOC, Fmoc, 1- Adoc and 2-Adoc.
  • Hydroxyi protecting groups are well known in the art. A large number of suitable groups are described on pages 24 to 298 of of Greene's Protective Groups in Organic Synthesis, 4 th Edition, John Wiley & Sons, inc., 2007 (ISBN 978-0-471-89754-1), which is incorporated herein by reference. Classes of particular interest include silyl ethers, methyl ethers, aikyl ethers, benzyl ethers, esters, benzoates, carbonates, and sulfonates. Particularly preferred hydroxyi protecting groups include THP and TBS. Preferences
  • D is D1. in some embodiments, D is D2.
  • R N1 is H.
  • R N1 is R N2 , i.e. Ci -4 alkyl (e.g. methyl).
  • R 2 When R 2 is a C5.10 aryi group, in some embodiments it may be a C5-7 aryi group.
  • a C5.7 aryl group may be a phenyl group or a C5-7 heteroaryi group, for example furanyl, thiophenyl and pyridyi.
  • R 2 may be phenyl, in other embodiments, R 2 may be thiophenyl, for example, thiophen-2-y! and thiophen-3-yl.
  • R 2 is a C5-10 aryl group, it some embodiments it may be a Cs-io aryi, for example a quinolinyi or isoquinolinyl group.
  • the quinolinyl or isoquinoiinyl group may be bound to the PBD core through any available ring position.
  • the quinolinyl may be quinoiin-2- yl, quinolin-3-yl, quinolin-4yl, quinolin-5-yi, quinolin-6-yi, quinolin-7-yl and quinolin-8-yl. Of these quinoiin-3-yi and quinolin-6-yi may be preferred.
  • the isoquinolinyl may be isoquinolin- 1-yl, isoquinoiin-3-yl, isoquinoiin-4yi, isoquinolin-5-yi, isoquinolin-6-yl, isoquinolin-7-yl and isoquinolin-8-yl. Of these isoquinolin-3-yi and isoquinolin-6-yl may be preferred.
  • R 2 is a C5.10 ar ⁇ group, it may bear any number of substifuent groups. In some embodiments, it may bear from 1 to 3 substituent groups. In some embodiments, it may bear 1 or 2 substituent groups. In some embodiments, it may bear a single substituent group. The substituents may be any position.
  • R 2 is C5-7 aryl group
  • a single substituent may be on a ring atom that is not adjacent the bond to the remainder of the compound, i.e. it may be ⁇ or ⁇ to the bond to the remainder of the compound. Therefore, in embodiments where the C5-7 aryl group is phenyl, the substituent may be in the meta- or para- positions, or may be in the para- position.
  • R 2 is a Cs-io aryl group, for example quinolinyl or isoquinolinyl, in some embodiments there may be any number of substituents at any position of the quinoline or isoquinoline rings. In some embodiments, it bears one, two or three substituents, and these may be on either the proximal and distal rings or both (if more than one substituent).
  • R 2 when R 2 is a C5-10 aryl group is halo it may be F or CI, and in some of these embodiments CI.
  • a substituent on R 2 when R 2 is a C5-10 aryl group is ether, it may in some embodiments be an aikoxy group, for example, a C1-7 aikoxy group (e.g. methoxy, efhoxy) or it may in some embodiments be a C5-7 aryioxy group (e.g phenoxy, pyridyloxy, furanyioxy).
  • the aikoxy group may itself be further substituted, for example by an amino group (e.g. dimethylamino).
  • a substituent on R 2 when R 2 is is a C5-10 aryl group is C1-7 aikyi, it may be a C1-4 aikyi group (e.g. methyl, ethyl, propryl, butyl).
  • a substituent on R 2 when R 2 is a C5-10 aryl group is C3-7 heterocyclyi, it may be Ce nitrogen containing heterocyclyi group, e.g. morpholino, thiomorphoiino, piperidinyl, piperazinyl. These groups may be bound to the rest of the PBD moiety via the nitrogen atom. These groups may be further substituted, for example, by C1-4 aikyi groups, if the Ce nitrogen containing heterocyclyi group is piperazinyl, the said further substituent may be on the second nitrogen ring atom.
  • substituents when R 2 is a C5-10 aryl group is bis-oxy-Ci.3 alkylene, this may be bis-oxy-methylene or bis-oxy-ethylene. in embodiments where a substituent on R 2 when R 2 is a C5-10 aryl group is ester, this is preferably methyl ester or ethyl ester. in some embodiments, substituents when R 2 is a C5-10 ary!
  • group may include methoxy, ethoxy, fiuoro, chioro, cyano, bis-oxy-methy!ene, methyl-piperazinyl, morpho!ino, methyl- thiophenyl, dimethy!aminopropyioxy and carboxy.
  • R 2 may be selected from 4-methoxy-phenyl, 3-methoxyphenyl, 4- ethoxy-phenyl, 3-ethoxy-phenyi, 4-fluoro-phenyi, 4-chioro-phenyl, 3,4-bisoxymethylene- phenyl, 4-methylthiophenyl, 4-cyanophenyl, 4-phenoxyphenyi, quinolin-3-yl and quinolin-6-yl, isoquinolin-3-yl and isoquinoiin-6-yi, 2-thienyi, 2-furanyi, methoxynaphthyi, naphthyi, 4- nitrophenyi, 4-(4-methylpiperazin-1-yl)phenyl and 3,4-bisoxymefhyiene ⁇ phenyi.
  • R 2 When R 2 is -5 saturated aliphatic aikyi, it may be methyl, ethyl, propyl, butyl or pentyi. in some embodiments, it may be methyl, ethyl or propyl (n-pentyi or isopropyl). In some of these embodiments, it may be methyl. In other embodiments, it may be butyl or pentyi, which may be linear or branched.
  • R 2 When R 2 is C3-S saturated cycioaikyi, it may be cyciopropyl, cyclobutyi, cyciopentyl or cyciohexyi. In some embodiments, it may be cyciopropyl.
  • R 2 is , in some embodiments, the total number of carbon atoms in the
  • R 2 group is no more than 4 or no more than 3.
  • one of R 31 , R 32 and R 33 is H, with the other two groups being selected from H, C1-3 saturated alkyl, C2-3 aikenyl, C2-3 aikynyl and cyciopropyl.
  • two of R 31 , R 32 and R 33 are H, with the other group being selected from H, C1.3 saturated alkyl, C2-3 aikenyl, C2-3 aikynyl and cyciopropyl.
  • the groups that are not H are selected from methyl and ethyl. In some of these embodiments, the groups that are not H are methyl.
  • R 33 ⁇ 4 is H.
  • R 32 is H.
  • R 33 is H. in some embodiments, R 33 ⁇ 4 and R 32 are H, In some embodiments, R 31 and R 33 are H. in some embodiments, R 32 and R 33 are H.
  • a R 2 group of particular interest is:
  • R 2 is , in some embodiments, the group (R 35a or R 3 b ) vv'hich is not
  • H is optionally substituted phenyl. If the phenyl optional substifuent is halo, it may be fiuoro. in some embodiment, the phenyl group is unsubstituted.
  • R 2 is in some embodiments where R 34 is phenyl, it is unsubstituted. in other embodiments, the phenyl group bears a single fiuoro substituent.
  • R 14 is selected from H, methyl, ethyl, ethenyl and ethynyl. In some of these embodiments, R' 4 is selected from H and methyl.
  • R 2 is halo, in some embodiments, it is fiuoro.
  • R 2 is in some embodiments, R 36a and R 36b are both H. in other embodiments, R 3ea and R 3eb are both methyl. in further embodiments, one of R 3ea and R 3eb is H, and the other is selected from C1-4 saturated alkyl, C2-3 alkenyl, which alkyl and aikenyi groups are optionally substituted. In some of these further embodiment, the group which is not H may be selected from methyl and ethyl.
  • R 6 is independently selected from H, R, OH, OR, SH, SR, NHs, NHR, NRR ⁇ N0 2l e 3 Sn- and Halo. in one embodiment, R 6 is independently selected from H, OH, OR, SH, NH2, NO2 and Halo, in one embodiment, R 6 is independently selected from H and Halo,
  • R s is independently H, in one embodiment, R 6 and R 7 together form a group -0-(CH2) -0-, where p is 1 or 2.
  • R 7 is independently selected from H, R, OH, OR, SH, SR, NH 2 , NHR, NRR ⁇ N0 2 , e 3 Sn and halo.
  • R 7 is independently OR.
  • R 7 is independently OR 7A , where R 7A is independently optionally substituted C1-6 alkyl.
  • R 7A is independently optionally substituted saturated Ci-e aikyi.
  • R 7A is independently optionally substituted C2-4 aikenyi.
  • R 7A is independently Me. in one embodiment, R 7A is independentiy ChbPh,
  • R 7A is independently ally!.
  • R 9 is independentiy selected from H, R, OH, OR, SH, SR, NH 2 , NHR, NRR', N0 2> Me 3 Sn- and Halo. in one embodiment, R 9 is independently H.
  • R 9 is independently R or OR.
  • R 10 is H, and R 11 is OH, OR A , where R A is Ci -4 aikyi. In some of these embodiments, R 11 is OH. in others of these embodiments, R is OR A , where R A is C -4 aikyi. In some of these embodiments, R A is methyl. in some embodiments, R 0 and R form a nitrogen-carbon double bond between the nitrogen and carbon atoms to which they are bound.
  • R 10 is H and R 11 is OSO z M, where z is 2 or 3 and M is a monovalent pharmaceutically acceptable cation. In some of these embodiments, is a monovalent pharmaceutically acceptable cation, and may be Na*. Furthermore, in some embodiments z is 3.
  • R 30 is H, and R 31 is OH, OR A , where R A is Ci -4 alkyl. In some of these embodiments, R 31 is OH. in others of these embodiments, R 31 is OR A , where R A is Ci -4 alkyl. In some of these embodiments, R A is methyl. in some embodiments, R 30 and R 31 form a nitrogen-carbon double bond between the nitrogen and carbon atoms to which they are bound. in some embodiments, R 30 is H and R 31 is OSO z , where z is 2 or 3 and M is a monovalent pharmaceutically acceptable cation, in some of these embodiments, M is a monovalent pharmaceutically acceptable cation, and may be Na + . Furthermore, in some embodiments z is 3.
  • R 30 is a nitrogen protecting group and R 3 is OProt°, where Prot° is a hydroxy protecting group.
  • the nitrogen protecting group may be selected from Alloc, Troc, Teoc, BOG, TcBOC, Fmoc, 1-Adoc and 2-Adoc, and more preferably be Boc, in some of these embodiments, the nitrogen protecting group may be THP.
  • Each of T and T is independently selected from a single bond or a C1-9 aikyiene group, which chain may be interrupted by one or more heteroatoms, e.g. O, S, N(H) and/or N e, provided that the number of atoms in the shortest chain of atoms between X and X is 3 to 12 atoms.
  • heteroatoms e.g. O, S, N(H) and/or N e
  • each aikyiene group of T and T is optionally interrupted by one or more heteroatoms selected from O, S, and NMe. in one embodiment, each of T and T" is independently selected from a single bond and a C1.9 aikyiene group.
  • T is selected from a single bond, Ci , C2, C3 and a C 4 aikyiene group and
  • T is selected from a single bond, Ci , C2, C3 and a G 4 aikyiene group.
  • T is selected from a single bond, Ci , and a C2 aikyiene group and T is selected from a single bond, C ⁇ , and a C2 aikyiene group.
  • T is selected from a single bond and a Ci aikyiene group and T is selected from a single bond and a Ci aikyiene group.
  • T is a single bond and T is a single bond.
  • T is a Ci aikyiene group and T is a Ci aikyiene group.
  • T and T are the same.
  • the aikyiene groups listed above may be optionally interrupted by one or more heteroatoms.
  • the alkylene groups listed above may be unsubstituted linear aliphatic alkylene groups, X
  • X is selected from O, S, or N(H).
  • X is O.
  • the groups R 22 , R 16 , R 17 , R 19 , R 20 and R 21 are the same as the groups R 2 , R 6 , R 9 , R 7 , R 10 and R 11 respectively, in these embodiments, the PBD monomer units have the same substituents.
  • Particularly preferred compounds of the first aspect of the present invention may be of formula la:
  • R 0 , R , R 20 , R 21 and Y are as defined above;
  • ti and t2 are an independently selected from 0, 1 and 2;
  • R 7a and R 7a are independently selected from methyl and phenyl
  • R 2a and R 2 a are independently selected from:
  • These compounds may preferably be symmetrical
  • Particularly preferred compounds of the first aspect of the present invention may be of formula lb:
  • R 10 , R 11 , R 20 , R 23 ⁇ 4 and Y are as defined above;
  • ti and ⁇ ?. are an independently selected from 0, 1 and 2;
  • R 7a and R 7a are independently selected from methyl and phenyl.
  • These compounds may preferably be symmetrical.
  • R 10 , R 11 , R 20 , R 21 and Y L are as defined above;
  • ti and ⁇ 2 are an independently selected from 0, 1 and 2;
  • R 7a and R 17a are independently selected from methyl and phenyl
  • R 2a and R 22a are independently selected from:
  • These compounds may preferably be symmetrical.
  • Particularly preferred compounds of the second aspect of the present invention may be of formula lib:
  • R 10 , R 11 , R 20 , R 21 and Y L are as defined above; ti and t2 are an independently selected from 0, 1 and 2; and
  • R 7a and R 17a are independently selected from methyl and phenyl.
  • These compounds may preferably be symmetrical.
  • Particularly preferred compounds of the third aspect of the present invention may be of formula I Ha:
  • R 0 , R , R 20 , R 21 and Y c are as defined above;
  • ti and t2 are an independently selected from 0, 1 and 2;
  • R 7a and R 7a are independently selected from methyl and phenyl
  • R 2a and R 22a are independently selected from:
  • Particularly preferred compounds of the third aspect of the present invention may be of formula II lb:
  • R 10 , R 11 , R 20 , R 21 and Y c are as defined above;
  • ti and t2 are an independently selected from 0, 1 and 2;
  • R 73 and R 173 are independently selected from methyl and phenyl.
  • n (in Y or Y L ) is an integer between 0 and in some embodiments, n (in Y or Y L ) is an integer between 0 and 12. in some embodiments, n (in Y or Y L ) is an integer between 0 and 8. in some embodiments, n (in Y or Y L ) is an integer between 0 and 6. in some embodiments, n (in Y or Y L ) is 0.
  • n (in Y or Y L ) is 1.
  • n (in Y or Y L ) is 2.
  • n (in Y or Y L ) is 3.
  • n (in Y or Y L ) is 4.
  • n (in Y or Y L ) is 5, in some embodiments, n (in Y or Y L ) is 6,
  • n (in Y or Y L ) is 7,
  • n (in Y or Y L ) is 8.
  • n (in Y or Y L ) is 9.
  • n (in Y or Y L ) is 10
  • n (in Y or Y L ) is 11
  • n (in Y or Y L ) is 12
  • n (in Y or Y L ) is 13
  • n (in Y or Y L ) is 14
  • n (in Y or Y L ) is 15
  • Q is an amino acid residue.
  • the amino acid may a natural amino acids or a non-natural amino acid.
  • Q is selected from: Phe, Lys, Val, Ala, Cit, Leu, lie, Arg, and Trp, where Cit is citruiline.
  • Q comprises a dipeptide residue.
  • the amino acids in the dipeptide may be any combination of natural amino acids and non-natural amino acids.
  • the dipeptide comprises natural amino acids.
  • the linker is a cathepsin labile linker
  • the dipeptide is the site of action for cathepsin-mediated cleavage. The dipeptide then is a recognition site for cathepsin.
  • Q is selected from:
  • Cit citruiline
  • Q is selected from:
  • dipeptide combinations of interest include:
  • Q is a tnpeptide residue.
  • the amino acids in the tnpeptide may be any combination of natural amino acids and non-natural amino acids, in some
  • the tripeptide comprises natural amino acids.
  • the linker is a cathepsin labile linker
  • the tripeptide is the site of action for cathepsin-mediated cleavage.
  • the tripeptide then is a recognition site for cathepsin.
  • the amino acid side chain is chemically protected, where appropriate.
  • the side chain protecting group may be a group as discussed above.
  • Protected amino acid sequences are cleavable by enzymes. For example, a dipeptide sequence comprising a Boc side chain-protected Lys residue is cleavable by cathepsin.
  • Protecting groups for the side chains of amino acids are well known in the art and are described in the Novabioehem Catalog, and as described above.
  • L is a linker connected to the cell binding agent in the conjugate conmpound.
  • G is a reactive group for connecting the PBD dimer to the ceil binding agent to form the conjugate compound.
  • the linker/reactive group contains an e!ectrophilic functional group for reaction with a nucleophilic functional group on the eel! binding agent.
  • Nucleophilic groups on antibodies include, but are not limited to: (i) N-terminal amine groups, (ii) side chain amine groups, e.g. lysine, (iii) side chain thiol groups, e.g. cysteine, and (iv) sugar hydroxy! or amino groups where the antibody is glycosylated. Amine, thiol, and hydroxy!
  • linker moieties and linker reagents including: (i) maleimide groups (ii) activated disulfides, (iii) active esters such as NHS (N-hydroxysuccinimide) esters, HOBt (N-hydroxybenzotriazole) esters, ha!oformates, and acid haiides; (iv) alky! and benzyl ha!ides such as haloacetamides; and v) aldehydes, ketones, carboxyl, and, some of which are exemplified as follows:
  • Certain antibodies have reducible interchain disulfides, i.e, cysteine bridges.
  • Antibodies may be made reactive for conjugation with linker reagents by treatment with a reducing agent such as DTT (dithiothreitoi).
  • a reducing agent such as DTT (dithiothreitoi).
  • DTT dithiothreitoi
  • Each cysteine bridge will thus form, theoretically, two reactive thiol nuc!eophiies.
  • Additional nucleophilic groups can be introduced into antibodies through the reaction of lysines with 2-iminothioiane (Traut's reagent) resulting in conversion of an amine into a thiol.
  • Reactive thiol groups may be introduced into the antibody (or fragment thereof) by introducing one, two, three, four, or more cysteine residues (e.g., preparing mutant antibodies comprising one or more non-native cysteine amino acid residues).
  • US 7521541 teaches engineering antibodies by introduction of reactive cysteine amino acids, in some embodiments, a Linker has a reactive nucleophilic group which is reactive with an eiectrophilic group present on an antibody.
  • Useful electrophiiic groups on an antibody include, but are not limited to, aldehyde and ketone carbonyl groups.
  • the heteroatom of a nucleophilic group of a Linker can react with an eiectrophilic group on an antibody and form a covending bond to an antibody unit.
  • Useful nucleophilic groups on a Linker include, but are not limited to, hydrazide, oxime, amino, hydroxy!, hydrazine, thiosemicarbazone, hydrazine carboxy!ate, and ary I hydrazide.
  • the electrophi!ic group on an antibody provides a convenient site for attachment to a Linker.
  • the group L is:
  • m is an integer selected from the range 0 to 6, In one embodiment, m is selected from 2, 3, 4 and 5, in one embodiment, the connection between the cell binding agent and L is through a thiol residue of the cell binding agent and a maleimide group of L,
  • connection ng agent and L is:
  • the S atom is typically derived from the cell binding agent.
  • an alternative functionality may be used in place of the maleimide-derived group shown below:
  • the maleimide-derived group is replaced with a group, which optionally together with the cell binding agent, is selected from:
  • the maleimide-derived group is replaced with a group, which optionally together with the cell binding agent, is selected from:
  • the wavy line indicates either the point of attachment to the cell binding agent or the bond to the remaining portion of the L group or the remaining portion of the Y group
  • the asterisk indicates the other of the point of attachment to the cell binding agent or the bond to the remaining portion of the L group or the remaining portion of the Y group.
  • L is of formula:
  • n is from 0 to 6;
  • L A is selected from:
  • Ar represents a Cs-e ary!ene group, e.g. phenylene.
  • m may be 2, 3 or 5.
  • L A may be L A1"1 .
  • L is of formula:
  • n is from 0 to 6;
  • L A is selected from the groups above.
  • such a group may be cleaved from the antibody such that the carbamate group yields a terminal amine.
  • L A may be L A3"2 .
  • m may in embodiments of the present invention, L is of formula:
  • L A is selected from the groups above.
  • such a group may be cleaved from the antibody such that the carbamate group yields the group: H2N-(CH2) P - (L3').
  • L is L3, q may be 1 , and p may be 2.
  • L A may be selected from L A7 , L A8 1 and L A8 2 .
  • G is of formula:
  • G A is selected from:
  • Ar represents a C5-6 arylene group, e.g. phenylene.
  • G In some embodiments where G is G1 , m may be 2, 3 or 5. in some embodiments where G is G1 , G A may be G A " 1 . in embodiments of the present invention, G is of formula:
  • n is from 0 to 6;
  • G A is selected from the groups above. in some embodiments where G is G2, G A may be G A3 ⁇ 2 . in some embodiments where G is G2, m may be 1. in embodiments of the present invention, G is of formula:
  • G A is selected from the groups above. in some embodiments where G is G3, q may be 1 , and p may be 2. In some embodiments where G is G3, G A may be selected from G A7 and G A8 . R and R'
  • R is independently selected from optionally substituted C1-12 alkyl, C3-20 heterocyclyl and C5-20 aryl groups. These groups are each defined in the substituents section below.
  • R is independently optionally substituted -12 alkyl.
  • R is independently optionally substituted C3-20 heterocyclyl. in one embodiment, R is independently optionally substituted C5-20 aryl.
  • R is independently optionally substituted C1-12 alkyl.
  • the preferences for R apply also to R ! .
  • a compound having a substituent group -NRR' In one embodiment, R and R' together with the nitrogen atom to which they are attached form an optionally substituted 4-, 5-, 8- or 7-membered heterocyclic ring.
  • the ring may contain a further heteroatom, for example N, O or S.
  • the heterocyclic ring is itself substituted with a group R. Where a further N heteroatom is present, the substituent may be on the N heteroatom.
  • a cell binding agent may be of any kind, and include peptides and non-peptides. These can include antibodies or a fragment of an antibody that contains at least one binding site, lymphokines, hormones, hormone mimetics, vitamins, growth factors, nutrient-transport molecules, or any other ceil binding molecule or substance.
  • the ceil binding agent is a linear or cyclic peptide comprising 4-30, preferably 6-20, contiguous amino acid residues.
  • one cell binding agent is linked to one monomer or dimer pyrrolobenzodiazepine compound.
  • the cell binding agent comprises a peptide that binds integrin ⁇ ⁇ ⁇ .
  • the peptide may be selective for ⁇ ⁇ ⁇ over XYS.
  • the cell binding agent comprises the A20F DV-Cys polypeptide.
  • the A20FMDV-Cys has the sequence: NAVPNLRGDLQVLAQKVARTC.
  • a variant of the A20FMDV-Cys sequence may be used wherein one, two, three, four, five, six, seven, eight, nine or ten amino acid residues are substituted with another amino acid residue.
  • polypeptide may have the sequence NAVXXXXXXXXXXXXXXXXXRTC.
  • antibody herein is used in the broadest sense and specifically covers monoclonal antibodies, polyclonal antibodies, dimers, multimers, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments, so long as they exhibit the desired biological activity (Miller ef a/ (2003) Jour, of immunology 170:4854-4861).
  • Antibodies may be murine, human, humanized, chimeric, or derived from other species.
  • An antibody is a protein generated by the immune system that is capable of recognizing and binding to a specific antigen.
  • a target antigen generally has numerous binding sites, also called epitopes, recognized by CDRs on multiple antibodies. Each antibody that specifically binds to a different epitope has a different structure. Thus, one antigen may have more than one corresponding antibody.
  • An antibody includes a full-length immunoglobulin molecule or an immunologically active portion of a full-length immunoglobulin molecule, i.e., a molecule that contains an antigen binding site that immunospecifica!ly binds an antigen of a target of interest or part thereof, such targets including but not limited to, cancer ceil or cells that produce autoimmune antibodies associated with an autoimmune disease.
  • a full-length immunoglobulin molecule or an immunologically active portion of a full-length immunoglobulin molecule i.e., a molecule that contains an antigen binding site that immunospecifica!ly binds an antigen of a target of interest or part thereof, such targets including but not limited to, cancer ceil or cells that produce autoimmune antibodies associated with an autoimmune disease.
  • immunoglobulin can be of any type (e.g. igG, IgE, IgM, igD, and IgA), class (e.g. lgG1 , lgG2, igG3, igG4, lgA1 and lgA2) or subclass of immunoglobulin molecule.
  • the immunoglobulins can be derived from any species, including human, murine, or rabbit origin.
  • Antibody fragments comprise a portion of a full length antibody, generally the antigen binding or variable region thereof.
  • Examples of antibody fragments include Fab, Fab', F(ab') 2 , and scFv fragments; diabodies; linear antibodies; fragments produced by a Fab expression library, anti-idiotypic (anti-id) antibodies, CDR (complementary determining region), and epitope-binding fragments of any of the above which immunospecificaily bind to cancer cell antigens, viral antigens or microbial antigens, single-chain antibody molecules; and mu!tispecific antibodies formed from antibody fragments.
  • monoclonal antibody refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e. the individual antibodies comprising the population are identical except for possible naturally occurring mutations that may be present in minor amounts. Monoclonal antibodies are highly specific, being directed against a single antigenic site. Furthermore, in contrast to polyclonal antibody preparations which include different antibodies directed against different determinants (epitopes), each monoclonal antibody is directed against a single determinant on the antigen. In addition to their specificity, the monoclonal antibodies are advantageous in that they may be
  • the modifier "monoclonal” indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method.
  • the monoclonal antibodies to be used in accordance with the present invention may be made by the hybridoma method first described by Kohier et a! (1975) Nature 256:495, or may be made by recombinant DNA methods (see, US 4816567).
  • the monoclonal antibodies may also be isolated from phage antibody libraries using the techniques described in Clackson et al (1991) Nature, 352:624-628; Marks et al (1991) J. Mol. Biol., 222:581-597 or from transgenic mice carrying a fully human immunoglobulin system (Lonberg (2008) Curr. Opinion 20(4):450-459).
  • the monoclonal antibodies herein specifically include "chimeric" antibodies in which a portion of the heavy and/or light chain is identical with or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is identical with or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they exhibit the desired biological activity (US 4816587; and Morrison et al (1984) Proc. Natl. Acad. Sci. USA, 81 :6851-6855).
  • Chimeric antibodies include "primatized” antibodies comprising variable domain antigen-binding sequences derived from a non-human primate (e.g. Old World Monkey or Ape) and human constant region sequences.
  • An "intact antibody” herein is one comprising a VL and VH domains, as well as a light chain constant domain (CL) and heavy chain constant domains, CH1 , CH2 and CHS.
  • the constant domains may be native sequence constant domains (e.g. human native sequence constant domains) or amino acid sequence variant thereof.
  • the intact antibody may have one or more "effector functions" which refer to those biological activities attributable to the Fc region (a native sequence Fc region or amino acid sequence variant Fc region) of an antibody. Examples of antibody effector functions include C1q binding; complement dependent cytotoxicity; Fc receptor binding; antibody-dependent cell-mediated cytotoxicity (ADCC); phagocytosis; and down regulation of cell surface receptors such as B ceil receptor and BCR.
  • intact antibodies can be assigned to different "classes," There are five major classes of intact antibodies: IgA, IgD, IgE, IgG, and igM, and several of these may be further divided into “subclasses” (isotypes), e.g., igG1 , lgG2, lgG3, lgG4, IgA, and lgA2.
  • the heavy-chain constant domains that correspond to the different classes of antibodies are called ⁇ , ⁇ , ⁇ , ⁇ , and ⁇ , respectively.
  • the subunit structures and three-dimensional configurations of different classes of immunoglobulins are well known.
  • a “humanized antibody” refers to a polypeptide comprising at least a portion of a modified variable region of a human antibody wherein a portion of the variable region, preferably a portion substantially less than the intact human variable domain, has been substituted by the corresponding sequence from a non-human species and wherein the modified variable region is linked to at least another part of another protein, preferably the constant region of a human antibody.
  • humanized antibodies includes human antibodies in which one or more complementarity determining region ("CDR") amino acid residues and/or one or more framework region ("FW or “FR”) amino acid residues are substituted by amino acid residues from analogous sites in rodent or other non-human antibodies.
  • CDR complementarity determining region
  • FW or "FR framework region
  • humanized antibody also includes an immunoglobulin amino acid sequence variant or fragment thereof that comprises an FR having substantially the amino acid sequence of a human immunoglobulin and a CDR having substantially the amino acid sequence of a non- human immunoglobulin.
  • Humanized forms of non-human (e.g., murine) antibodies are chimeric antibodies that contain minimal sequence derived from non-human immunoglobulin. Or, looked at another way, a humanized antibody is a human antibody that also contains selected sequences from non-human (e.g. murine) antibodies in place of the human sequences.
  • a humanized antibody can include conservative amino acid substitutions or non-natural residues from the same or different species that do not significantly alter its binding and/or biologic activity.
  • Such antibodies are chimeric antibodies that contain minimal sequence derived from non- human immunoglobulins.
  • humanisation techniques including 'CDR grafting', 'guided selection', 'deimmunization', 'resurfacing' (also known as Veneering'), 'composite antibodies', 'Human String Content Optimisation' and framework shuffling.
  • the humanized antibodies are human immunoglobulins (recipient antibody) in which residues from a complementary-determining region (CDR) of the recipient antibody are replaced by residues from a CDR of a non-human species (donor antibody) such as mouse, rat, camel, bovine, goat, or rabbit having the desired properties (in effect, the non- human CDRs are 'grafted' onto the human framework), in some instances, framework region (FR) residues of the human immunoglobulin are replaced by corresponding non-human residues (this may happen when, for example, a particular FR residue has significant effect on antigen binding).
  • CDR complementary-determining region
  • donor antibody such as mouse, rat, camel, bovine, goat, or rabbit having the desired properties (in effect, the non- human CDRs are 'grafted' onto the human framework)
  • framework region (FR) residues of the human immunoglobulin are replaced by corresponding non-human residues (this may happen when, for example, a particular FR residue has significant effect on antigen
  • humanized antibodies can comprise residues that are found neither in the recipient antibody nor in the imported CDR or framework sequences. These modifications are made to further refine and maximize antibody performance.
  • a humanized antibody will comprise all of at least one, and in one aspect two, variable domains, in which all or all of the hypervariable loops correspond to those of a non-human immunoglobulin and all or substantially all of the FR regions are those of a human immunoglobulin sequence.
  • the humanized antibody optionally also will comprise at least a portion of an immunoglobulin constant region (Fc), or that of a human immunoglobulin.
  • the method consists of combining the V H or V L domain of a given non-human antibody specific for a particular epitope with a human VH or VL library and specific human V domains are selected against the antigen of interest. This selected human VH is then combined with a VL library to generate a completely human VHxVL combination.
  • the method is described in Nature Biotechnology (N.Y.) 12, (1994) 899-903.
  • two or more segments of amino acid sequence from a human antibody are combined within the final antibody molecule. They are constructed by combining multiple human VH and VL sequence segments in combinations which limit or avoid human T cell epitopes in the final composite antibody V regions. Where required, T ceil epitopes are limited or avoided by, exchanging V region segments contributing to or encoding a T cell epitope with alternative segments which avoid T cell epitopes. This method is described in US 2008/0206239 A1.
  • This method involves the removal of human (or other second species) T ⁇ ceil epitopes from the V regions of the therapeutic antibody (or other molecule).
  • the therapeutic antibodies V-region sequence is analysed for the presence of HC class II- binding motifs by, for example, comparison with databases of MHC-binding motifs (such as the "motifs" database hosted at www.wehi.edu.au).
  • MHC class II- binding motifs may be identified using computational threading methods such as those devised by Altuvia et al. (J. Mol. Biol. 249 244-250 (1995)); in these methods, consecutive overlapping peptides from the V-region sequences are testing for their binding energies to HC class II proteins.
  • This data can then be combined with information on other sequence features which relate to successfully presented peptides, such as amphipathicity, Rothbard motifs, and cleavage sites for cathepsin B and other processing enzymes.
  • T-cell epitopes Once potential second species (e.g. human) T-cell epitopes have been identified, they are eliminated by the alteration of one or more amino acids.
  • the modified amino acids are usually within the T-ceil epitope itself, but may also be adjacent to the epitope in terms of the primary or secondary structure of the protein (and therefore, may not be adjacent in the primary structure). Most typically, the alteration is by way of substitution but, in some circumstances amino acid addition or deletion will be more appropriate.
  • This method involves:
  • step (c) defining for the non-human antibody to be humanized, a set of heavy and light chain surface exposed amino acid residues using the set of framework positions generated in step (b);
  • step (d) identifying from human antibody amino acid sequences a set of heavy and light chain surface exposed amino acid residues that is most closely identical to the set of surface exposed amino acid residues defined in step (c), wherein the heavy and light chain from the human antibody are or are not naturally paired;
  • step (e) substituting, in the amino acid sequence of the non-human antibody to be humanized, the set of heavy and light chain surface exposed amino acid residues defined in step (c) with the set of heavy and light chain surface exposed amino acid residues identified in step (d);
  • step (f) constructing a three-dimensional model of the variable region of the non-human antibody resulting from the substituting specified in step (e);
  • step (h) changing any residues identified in step (g) from the human to the original non- human amino acid residue to thereby define a non-human antibody humanizing set of surface exposed amino acid residues; with the proviso that step (a) need not be conducted first, but must be conducted prior to step (g).
  • the method compares the non-human sequence with the functional human germline gene repertoire. Those human genes encoding canonical structures identical or closely related to the non-human sequences are selected. Those selected human genes with highest homology within the CDRs are chosen as FR donors. Finally, the non-human CDRs are grafted onto these human FRs. This method is described in patent WO 2005/079479 A2.
  • This method compares the non-human (e.g. mouse) sequence with the repertoire of human germline genes and the differences are scored as Human String Content (HSC) that quantifies a sequence at the level of potential MHC/T-cel I epitopes.
  • HSC Human String Content
  • the target sequence is then humanized by maximizing its HSC rather than using a global identity measure to generate multiple diverse humanized variants (described in Molecular Immunology, 44, (2007) 1986-1998).
  • the CDRs of the non-human antibody are fused in-frame to cDNA pools encompassing ail known heavy and light chain human germline gene frameworks. Humanised antibodies are then selected by e.g. panning of the phage displayed antibody library. This is described in Methods 36, 43-60 (2005). Examples of cell binding agents include those agents described for use in WO 2007/085930, which is incorporated herein. Tumour-associate antigens and cognate antibodies for use in embodiments of the present invention are listed below. TUMOR-ASSOCIATED ANTIGENS AND COGNATE ANTIBODIES
  • BMPR1B bone morphogenetic protein receptor-type IB
  • WO2002/99122 (Example 2; Page 528-530); WO2003/029421 (Claim 6); WO2003/024392 (Claim 2; Fig 12); WO2002/98358 (Claim 1 ; Page 183); WO2002/54940 (Page 100-101); WO2002/59377(Page 349-350); WO2002/30268 (Claim 27; Page 376); WO2001/48204 (Example; Fig 4); NP__001194 bone morphogenetic protein receptor, type IB
  • WO2004/032842 (Example IV); WO2003/042661 (Claim 12); WG2003/G 16475 (Claim 1); WO2002/78524 (Example 2); WO2002/99074 (Claim 19; Page 127-129); WO2002/86443 (Claim 27; Pages 222, 393); WO2003/003906 (Claim 10; Page 293); WO2002/64798 (Claim 33; Page 93-95); WO2Q00/14228 (Claim 5; Page 133-136); US2003/224454 (Fig 3);
  • NP_003477 solute carrier family 7 cationic amino acid transporter, y+system
  • member 5 /pid : NP m Q03477.3 - Homo sapiens
  • Example 53 Page 173, Example 2; Fig 2A); six transmembrane epithelial
  • MPF MPF, MSLN, SMR, megakaryocyte potentiating factor, mesothetin
  • Napi3b (NAPI-3B, NPTUb, SLC34A2, solute carrier family 34 (sodium phosphate), member 2, type I! sodium-dependent phosphate transporter 3b)
  • WO2003/003984 (Claim 1); WO2002/06339 (Claim 1 ; Page 50); WO2001/88133 (Claim 1 ; Page 41-43, 48-58); WO2003/054152 (Claim 20); WO2003/101400 (Claim 11); Accession: 30 Q9P283; Genew; HGNC: 10737
  • PSCA hlg (2700050C12Rik, C530008O16Rik, RIKEN cDNA 2700050C12, RIKEN cDNA 2700050C12 gene)
  • Genbank record update date Mar 1 1 , 2010 02:26 AM
  • Genbank record update date Mar 1 1 , 2010 02:26 AM
  • WO2004/048938 Example 2
  • WO2004/040000 (Claim 151); WO2003/087768 (Claim 1); WO2003/016475 (Claim 1); WO2003/016475 (Claim 1 ); WO2002/61087 (Fig 1);
  • WO2003/016494 (Fig 6); WO2003/025138 (Claim 12; Page 144); WO2001/98351 (Claim 1 ; Page 124-125); EP0522868 (Claim 8; Fig 2); WO2001/77172 (Claim 1 ; Page 297-299); US2003/109676; US6518404 (Fig 3); US5773223 (Claim 1 a; Col 31-34); WO2004/00 004.
  • WO2003/104275 (Claim 1); WO2004/046342 (Example 2); WO2003/042661 (Claim 12); WO2003/083074 (Claim 14; Page 61); WO2003/018621 (Claim 1); WO2003/024392 (Claim 2; Fig 93); WO2001/66689 (Example 6); Locus! D:54894.
  • STEAP2 (HGNC 8639, IPCA-1, PCANAP1 , STAMP1 , STEAP2, STMP, prostate cancer associated gene 1 , prostate cancer associated protein 1, six transmembrane epithelial antigen of prostate 2, six transmembrane prostate protein)
  • Genbank record update date Mar 1 1 , 2010 01 :54 AM
  • Genbank record update date Mar 1 1 , 2010 01 :54 AM Cross references
  • WO2003/104270 (Claim 1); WO2003/104270 (Claim 16); US2004/005598 (Claim 22); WO2003/042661 (Claim 12); US2003/060612 (Claim 12; Fig 10); WO2002/26822 (Claim 23; Fig 2); WO2002/16429 (Ciaim 12; Fig 10); Gl:22655488.
  • TrpM4 (BR22450, FLJ20041, TRPM4, TRPM4B, transient receptor potential cation 5 channel, subfamily M, member 4)
  • Genbank record update date Jun 29, 2012 11 :27 AM
  • Genbank record update date Jun 29, 2012 11 :27 AM
  • WO2000/40614 (Ciaim 14; Page 100-103); WO2GQ2/10382 (Ciaim 1 ; Fig 9A);
  • WO2003/042661 (Claim 12); WO2002/30268 (Claim 27; Page 391); US2003/219806 (Claim 4); WO2001/62794 (Claim 10 14; Fig 1A-D); MI :606936.
  • WO2002/16413 (Claim 1 ; Page 94-95, 105); WO2002/22808 (Claim 2; Fig 1); US5854399 (Example 2; Col 17-18); US5792616 (Fig 2); MIM: 187395.
  • CD21 CR2 (Complement receptor 2) or C3DR (C3d/Epstein Barr virus receptor) or Hs.73792)
  • CD79b CD79B, ⁇ 79 ⁇ , IGb (immunoglobuiin-associated beta), B29
  • FcRH2 (IFGP4, IRTA4, SPAP1A (SH2 domain containing phosphatase anchor protein 5 1a), SPAP1B, SPAP1C)
  • WO2002/13847 (Page 71-74); WO2002/14503 (Page 114-1 7); WO2001/53463 (Claim 2;
  • an antibody comprising CDRs having overall at least 80% sequence identity to CDRs having amino acid sequences of SEQ ID NO:3 (CDR-H1), SEQ ID NO:4 (CDR-H2), SEQ ID NO:5 (CDR-H3), SEQ ID NO: 104 and/or SEQ ID NO:6 (CDR-L1), SEQ ID NO:7 (CDR-L2), and SEQ ID NO:8 (CDR-L3), wherein the anti- HER2 antibody or anti-HER2 binding fragment has reduced immunogenicity as compared to an antibody having a VH of SEQ ID NO: 1 and a VL of SEQ ID NO:2.
  • a purified antibody molecule that binds to HER2 comprising a ail six
  • Herceptin (Genentech) - US6,054,297; ATCC accession no, CRL-10463 (Genentech) Pertuzumab (Genentech)
  • an antibody comprising the variable light and variable heavy amino acid sequences in SEQ !D Nos. 3 and 4, respectively,
  • an antibody comprising a light chain amino acid
  • an antibody having a light chain variable domain for example, an antibody having a light chain variable domain
  • an antibody having a heavy chain variable domain comprising the hypervariabie regions of SEQ ID NO: 2.
  • NCA (CEACAM6)
  • EphB2R (DRT, ERK, Hek5, EPHT3, Tyro5)
  • WO2003042661 (Claim 12); WO200053216 (Claim 1 ; Page 41); WO2004065576 (Claim 1); WO2004020583 (Claim 9); WO2003004529 (Page 128-132); WO200053216 (Claim 1 ; Page 42); MI :600997.
  • Genbank record update date Feb , 201 11 :25 AM
  • Genbank record update date Feb 1 , 201 1 11 :25 AM
  • Genbank record update date Mar 1 , 2010 02:24 AM Polypeptide
  • AP14954 lipoma HMGIC fusion-partneriike protein /pid AAP 14954.1 - Homo sapiens (human); WO2003/054152 (Claim 20); WO2003/000842 (Claim 1); WO2003/023013 (Example 3, Ciaim 20); US2003/194704 (Ciaim 45); GL30102449; (26) BAFF-R (B eel! -activating factor receptor, BLyS receptor 3, BR3)
  • WO2002/24909 (Example 3; Fig 3); M I M: 606269; NP_443177.1 ; NM_052945_1 ; AF132600
  • CD22 B-cell receptor CD22-B isoform, BL-CAM, Lyb-8, Lyb8, SIGLEC-2, FLJ22814) Nucleotide
  • Genbank record update date Sep 1 1 , 2006 1 1 :24 PM
  • Genbank record update date Sep 1 1 , 2006 1 :24 PM
  • Genbank record update date Feb 2, 201 1 10:09 AM
  • Genbank record update date Feb 2, 201 1 10:09 AM
  • SIGLEC-2 SIGLEC2
  • B-cel! receptor CD22 B-lymphocyte cell adhesion molecule
  • BL-CAM B-lymphocyte cell adhesion molecule
  • CD22 antigen T-ceil surface antigen Leu-14
  • sialic acid binding ig-iike lectin 2 sialic acid-binding Ig-like lectin 2
  • CD79a (CD79A, CD79alpha), immunogiobuiin-associated alpha, a B cell-specific protein that covalently interacts with Ig beta (CD79B) and forms a complex on the surface with Ig M
  • Genbank record update date Jun 26, 2012 01 :48 PM
  • Genbank record update date Jun 26, 2012 01 :48 PM
  • CXCR5 Bokitt's lymphoma receptor 1, a G protein-coupled receptor that is activated by the CXCL 13 chemokine, functions in lymphocyte migration and humoral defense, plays a 10 role in HIV-2 infection and perhaps development of AIDS, lymphoma, myeloma, and leukemia); 372 aa, pi: 3,54 MW: 41959 I ' M: 7 [P] Gene Chromosome: 1 1q23.3,
  • HLA-DOB Beta subunit of MHC class // molecule (la antigen) that binds peptides and 20 presents them to CD4+ T lymphocytes); 273 aa, pi: 6.56, MW: 30820.
  • TM 1 [P] Gene Chromosome: 6p21.3)
  • P2X5 Purinergic receptor P2X iigand-gated ion channel 5, an ion channel gated by extracellular A TP, may be involved in synaptic transmission and neurogenesis, deficiency may contribute to the pathophysiology of idiopathic detrusor instability
  • 422 aa pi: 7.63, MW: 47206 TM: 1
  • Gene Chromosome 17 pi 3.3).
  • CD72 B-cell differentiation antigen CD72, Lyb-2
  • Genbank record update date Jun 26, 2012 01 :43 PM
  • WO2004042346 (claim 65); WO2003/026493 (pages 51-52, 57-58); WO2000/75655 (pages 105-106); Von Hoegen ei a/ (1990) J. Immunol. 144(12):4870-4877; Strausberg ef a/ (20Q2) Proc. Nail. Acad. Sci USA 99: 16899-16903.
  • LY64 Lymphocyte antigen 64 (RP105), type I membrane protein of the leucine rich repeat (LRR) family; regulates B-cell activation and apoptosis, loss of function is associated with increased disease activity in patients with systemic lupus erythematosus); 661 aa, pi: 6.20, MW: 74147 TM: 1 [P] Gene Chromosome: 5q12).
  • RP105 Lymphocyte antigen 64
  • LRR leucine rich repeat
  • FcRH1 Fc receptor-like protein 1, a putative receptor for the immunoglobulin Fc domain that contains C2 type Ig-like and !TAM domains, may have a role in B-lymphocyte
  • WO2003/089624 (claim 7). (35) IRTA2 (Immunoglobulin superfamily receptor translocation associated 2, a putative immunorecepfor with possible roles in B ceil development and iymphomagenesis;
  • Genbank record update date Mar 1 1 , 2010 01 :16 AM
  • Genbank record update date Mar 1 1 , 2010 01 : 16 AM
  • TENB2 tomoregulin, TPEF, HPP1, TR, putative transmembrane
  • Genbank record update date Mar 1 1 , 2010 01 :05 AM
  • PSMA - FOLH1 Falate hydrolase (prostate-specific membrane antigen) 1
  • growth-inhibiting gene 27 protein fo!y!poly- gamma-glutamate carboxypeptidase; glutamate carboxylase II; glutamate carboxypeptidase 2; glutamate carboxypeptidase II; membrane glutamate carboxypeptidase; prostate specific membrane antigen variant F; pteroy!poly-gamma-g!utamate carboxypeptidase
  • Antibodies produces by Hybridomas having the following ATCC references:ATCC accession No. HB-12101 , ATCC accession No. HB-12109, ATCC accession No. HB-12127 and ATCC accession No. HB-12126.
  • Proscan a monoclonal antibody selected from the group consisting of 8H12, 3E11 , 17G1 , 29B4, 30C1 and 20F2 (US 7,81 1 , 564; Moffett S., et al Hybridoma (Larchmt). 2007
  • Cytogen monoclonal antibodies 7E1 1-C5 (ATCC accession No. HB 10494) and 9H10-A4 (ATCC accession No. HB11430) - US 5,763,202
  • Glyco imetics NUH2 - ATCC accession No. HB 9762 (US 7, 135,301)
  • HPRAJ70 Human Genome Science: HPRAJ70 - ATCC accession No. 97131 (US 6,824,993); Amino acid sequence encoded by the cDNA clone (HPRAJ70) deposited as American Type Culture Collection (“ATCC”) Deposit No. 97131
  • Medarex Anti-PSMA antibodies that lack fucosyl residues - US 7,875,278
  • Mouse anti-PSMA antibodies include the 3F5.4G6, 3D7.1.1 , 4E10-1.14, 3E11 , 4D8, 3E6, 3C9, 2C7, 1G3, 3C4, 3C6, 4D4, 1 G9, 5C8B9, 3G6, 4C8B9, and monoclonal antibodies.
  • Hybridomas secreting 3F5.4G6, 3D7.1.1 , 4E10-1.14, 3E11 , 4D8, 3E6, 3C9, 2C7, 1G3, 3C4, 3C6, 4D4, 1G9, 5C8B9, 3G6 or 4C8B9 have been publicly deposited and are described in U.S. Pat. No. 6, 159,508. Relevant hybridomas have been publicly deposited and are described in U.S. Pat. No. 6, 107,090.
  • humanized anti-PSMA antibodies, including a humanized version of J59 are described in further detail in PCT Publication WO
  • mouse anti-human PSMA antibodies have been described in the art, such as mAb 107-1A4 (Wang, S. et al. (2001) int. J. Cancer 92:871-876) and mAb 2C9 (Kato, K. et ai. (2003) Int. J. Urol. 10:439-444).
  • human anti-PSMA monoclonal antibodies inciude the 4A3, 7F12, 8C 2, 8A11 , 16F9, 2A10, 2C6, 2F5 and 1C3 antibodies, isolated and structurally characterized as originally described in PCT Publications WO 01/09192 and WO 03/064606 and in U.S. Provisional Application Ser. No.
  • V.sub.H amino acid sequences of 4A3, 7F12, 8C12, 8A11 , 16F9, 2A10, 2C6, 2F5 and 1C3 are shown in SEQ ID NOs: 1-9, respectively.
  • V.sub.L amino acid sequences of 4A3, 7F12, 8C12, 8A11 , 16F9, 2A10, 2C6, 2F5 and 1 C3 are shown in SEQ ID NOs: 10-18, respectively.
  • human anti-PSMA antibodies include the antibodies disclosed in PCT Publication WO 03/034903 and US Application No. 2004/0033229.
  • NW Biotherapeutics A hybridoma ceil line selected from the group consisting of 3F5.4G6 having ATCC accession number HB12060, 3D7-1.I. having ATCC accession number HB12309, 4E10-1.14 having ATCC accession number HB12310, 3E11 (ATCC HB12488), 4D8 (ATCC HB12487), 3E6 (ATCC HB12486), 3C9 (ATCC HB12484), 2C7 (ATCC
  • PSMA Development Company-- Compositions of PSMA antibodies (US 20080286284, Table 1)
  • antigen identified by monoclonal antibody L230 integrin alpha-V; integrin alphaVbetaS; integrin, alpha V (vitronectin receptor, alpha polypeptide, antigen CD51); vitronectin receptor subunit alpha
  • Biogen US 7,943,742 - Hybridoma clones 6.3G9 and 6.8G6 were deposited with the ATCC, accession numbers ATCC PTA-3649 and -3645, respectively.
  • the antibody comprises the same heavy and light chain polypeptide sequences as an antibody produced by hybridoma 6.1A8, 6.3G9, 6.8G6, 6.2B1 , 6.2B10, 6.2A1 , 6.2E5, 7.1G10, 7.7G5, or 7.1 C5.
  • CEACAM5 Cardnoembryonic antigen-related cell adhesion molecule 5 ⁇
  • CDRs with the following sequences: heavy chain; CDR1 - D!MYMH, CDR2 - W!DPEIMGDTE YAPKFRG, CDR3 - LIYAGYLA D Y; and light chain CDR1 - SASSSVTYIV1H, CDR2 -
  • an antibody comprising the heavy chain variable region sequence from the amino acid sequence of SEQ ID NO: 1 , and the light chain variable region sequence from the amino acid sequence of SEQ ID NO:2.
  • an antibody comprising the heavy chain variable region sequence from the amino acid sequence of SEQ ID NO:5, and the light chain variable region sequence from the amino acid sequence of SEQ ID NO:6.
  • CDR1 comprises KASQDVGTSVA (SEQ ID NO: 20);
  • CDR2 comprises WTSTRHT (SEQ ID NO: 21 ): and
  • CDRS comprises QQYSLYRS (SEQ ID NO: 22);
  • CDR1 comprises TY MS (SEQ ID NO: 23);
  • CDR2 comprises EIHPDSSTINYAPSLKD (SEQ ID NO: 24); and CDRS comprises LYFGFPWFAY (SEQ ID NO: 25).
  • HGF receptor HGF/SF receptor
  • SF receptor hepatocyte growth factor receptor
  • met proto-oncogene tyrosine kinase proto-oncogene c-Met
  • scatter factor receptor tyrosine-protein kinase Met
  • an antibody comprising the sequences of CDR1 ,
  • CDR2 and CDR3 of heavy chain 4887 wherein the sequences of CDR1 , CDR2, and CDR3 of heavy chain 4687 are residues 26-35, 50-65, and 98-102, respectively, of SEQ ID NO: 58; and the sequences of CDR1 , CDR2, and CDR3 of light chain 5097, wherein the sequences of CDR1 , CDR2, and CDR3 oflight chain 5097 are residues 24-39,55-61 , and 94-100 of SEQ ID NO: 37.
  • DF3 antigen H23 antigen; breast carcinoma-associated antigen DF3; carcinoma-associated mucin; episialin; krebs von den Lept-6; mucin 1 , transmembrane; mucin-1 ; peanut-reactive urinary mucin; polymorphic epithelial mucin; tumor associated epithelial mucin; tumor-associated epithelial membrane antigen; tumor-associated mucin
  • AltaRex- Quest Pharma Tech US 6,716,966 - for example an Alt-1 antibody produced by the hybridoma ATCC No PTA-975.
  • GT- AB GT- AB 2.5-GEX (Website:
  • antibody M J-170 hybridoma cell line M J-170 ATCC accession no.
  • PTA-5286Monoclonai antibody M J-171 hybridoma cell line M J-171 ATCC accession no.
  • monoclonal antibody MJ-172 hybridoma ceil line M J-172 ATCC accession no.
  • PTA-5288; or monoclonal antibody J-173 hybridoma ceil line MJ- 173 ATCC accession no. PTA-5302
  • Genbank record update date Feb 2, 201 1 10:15 AM
  • Affibody Anti-CAIX Affibody molecules

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Genetics & Genomics (AREA)
  • Biochemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Immunology (AREA)
  • Epidemiology (AREA)
  • Cell Biology (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Hematology (AREA)
  • Peptides Or Proteins (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
PCT/GB2015/052629 2014-09-12 2015-09-11 Pyrrolobenzodiazepines and conjugates thereof WO2016038383A1 (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
JP2017513438A JP6518321B2 (ja) 2014-09-12 2015-09-11 ピロロベンゾジアゼピン及びそのコンジュゲート
EP15766215.6A EP3191490B1 (en) 2014-09-12 2015-09-11 Pyrrolobenzodiazepines and conjugates thereof
US15/510,345 US10420777B2 (en) 2014-09-12 2015-09-11 Pyrrolobenzodiazepines and conjugates thereof
CN201580048691.5A CN106687472B (zh) 2014-09-12 2015-09-11 吡咯并苯并二氮杂卓及其缀合物

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB1416112.9 2014-09-12
GBGB1416112.9A GB201416112D0 (en) 2014-09-12 2014-09-12 Pyrrolobenzodiazepines and conjugates thereof

Publications (1)

Publication Number Publication Date
WO2016038383A1 true WO2016038383A1 (en) 2016-03-17

Family

ID=51869483

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB2015/052629 WO2016038383A1 (en) 2014-09-12 2015-09-11 Pyrrolobenzodiazepines and conjugates thereof

Country Status (6)

Country Link
US (1) US10420777B2 (US07943609-20110517-C00101.png)
EP (1) EP3191490B1 (US07943609-20110517-C00101.png)
JP (1) JP6518321B2 (US07943609-20110517-C00101.png)
CN (1) CN106687472B (US07943609-20110517-C00101.png)
GB (1) GB201416112D0 (US07943609-20110517-C00101.png)
WO (1) WO2016038383A1 (US07943609-20110517-C00101.png)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017201132A2 (en) 2016-05-18 2017-11-23 Mersana Therapeutics, Inc. Pyrrolobenzodiazepines and conjugates thereof
US10188746B2 (en) 2014-09-10 2019-01-29 Medimmune Limited Pyrrolobenzodiazepines and conjugates thereof
WO2021080608A1 (en) 2019-10-25 2021-04-29 Medimmune, Llc Branched moiety for use in conjugates
WO2022053651A2 (en) 2020-09-10 2022-03-17 Precirix N.V. Antibody fragment against fap
WO2022228494A1 (zh) 2021-04-29 2022-11-03 上海汇连生物医药有限公司 抗体偶联药物的制备方法及应用
US11524969B2 (en) 2018-04-12 2022-12-13 Medimmune Limited Pyrrolobenzodiazepines and conjugates thereof as antitumour agents
WO2023203135A1 (en) 2022-04-22 2023-10-26 Precirix N.V. Improved radiolabelled antibody
WO2023213801A1 (en) 2022-05-02 2023-11-09 Precirix N.V. Pre-targeting

Families Citing this family (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9242013B2 (en) 2010-04-15 2016-01-26 Seattle Genetics Inc. Targeted pyrrolobenzodiazapine conjugates
KR101819404B1 (ko) 2012-10-12 2018-02-28 메디뮨 리미티드 피롤로벤조디아제핀 및 그의 컨주게이트
GB201416112D0 (en) 2014-09-12 2014-10-29 Medimmune Ltd Pyrrolobenzodiazepines and conjugates thereof
GB201601431D0 (en) 2016-01-26 2016-03-09 Medimmune Ltd Pyrrolobenzodiazepines
GB201602359D0 (en) 2016-02-10 2016-03-23 Medimmune Ltd Pyrrolobenzodiazepine Conjugates
GB201602356D0 (en) 2016-02-10 2016-03-23 Medimmune Ltd Pyrrolobenzodiazepine Conjugates
GB201607478D0 (en) 2016-04-29 2016-06-15 Medimmune Ltd Pyrrolobenzodiazepine Conjugates
GB201617466D0 (en) 2016-10-14 2016-11-30 Medimmune Ltd Pyrrolobenzodiazepine conjugates
GB201702031D0 (en) 2017-02-08 2017-03-22 Medlmmune Ltd Pyrrolobenzodiazepine-antibody conjugates
PL3544636T3 (pl) 2017-02-08 2021-12-06 Adc Therapeutics Sa Koniugaty pirolobenzodiazepina-przeciwciało
RS63502B1 (sr) 2017-04-18 2022-09-30 Medimmune Ltd Konjugati pirolobenzodiazepina
NZ761175A (en) 2017-08-18 2024-07-26 Medimmune Ltd Pyrrolobenzodiazepine conjugates
CN107746424A (zh) * 2017-10-30 2018-03-02 上海药明生物技术有限公司 一种IgG4抗体的生物偶联方法
GB201803342D0 (en) 2018-03-01 2018-04-18 Medimmune Ltd Methods
US20210380605A1 (en) * 2018-10-19 2021-12-09 Medimmune Limited Pyrrolobenzodiazepine conjugates
AU2020329191A1 (en) 2019-08-12 2022-03-31 Regeneron Pharmaceuticals, Inc. Macrophage stimulating 1 receptor (MST1R) variants and uses thereof

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011130616A1 (en) * 2010-04-15 2011-10-20 Spirogen Limited Pyrrolobenzodiazepines used to treat proliferative diseases
WO2014057113A1 (en) * 2012-10-12 2014-04-17 Adc Therapeutics Sarl Pyrrolobenzodiazepine - anti-psma antibody conjugates
WO2014096368A1 (en) * 2012-12-21 2014-06-26 Spirogen Sàrl Pyrrolobenzodiazepines and conjugates thereof
WO2014140862A2 (en) * 2013-03-13 2014-09-18 Spirogen Sarl Pyrrolobenzodiazepines and conjugates thereof
WO2014159981A2 (en) * 2013-03-13 2014-10-02 Spirogen Sarl Pyrrolobenzodiazepines and conjugates thereof

Family Cites Families (390)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3361742A (en) 1964-12-07 1968-01-02 Hoffmann La Roche 5-oxo-1h-pyrrolo-[2, 1-c][1, 4]-benzodiazepin-2-crylamides
US3523941A (en) 1967-03-06 1970-08-11 Hoffmann La Roche Benzodiazepine compounds and process for their preparation
US3524849A (en) 1967-10-27 1970-08-18 Hoffmann La Roche Process for the preparation of pyrrolo-benzodiazepine acrylamides and intermediates useful therein
DE1965304A1 (de) 1968-12-30 1970-07-23 Fujisawa Pharmaceutical Co Benzdiazepinon-Verbindungen und Verfahren zu ihrer Herstellung
IL33558A (en) 1968-12-30 1973-10-25 Fujisawa Pharmaceutical Co Antibiotic pyrrolo-benzodiazepine compound,its derivatives and processes for their production
JPS4843755B1 (US07943609-20110517-C00101.png) 1969-06-26 1973-12-20
JPS6053033B2 (ja) 1976-12-28 1985-11-22 財団法人微生物化学研究会 新制癌抗生物質マゼスラマイシン及びその製造方法
JPS585916B2 (ja) 1977-12-27 1983-02-02 株式会社ミドリ十字 新規ベンゾジアゼピン系化合物
JPS5615289A (en) 1979-07-17 1981-02-14 Green Cross Corp:The Novel benzodiazepinnbased compound 3
JPS57131791A (en) 1980-12-31 1982-08-14 Fujisawa Pharmaceut Co Ltd Benzodiazepine derivative and its preparation
CA1185602A (en) 1981-02-27 1985-04-16 Emilio Kyburz Imidazodiazepines
CA1173441A (en) 1981-02-27 1984-08-28 Hoffmann-La Roche Limited Imidazodiazepines
CA1184175A (en) 1981-02-27 1985-03-19 Walter Hunkeler Imidazodiazepines
JPS58180487A (ja) 1982-04-16 1983-10-21 Kyowa Hakko Kogyo Co Ltd 抗生物質ｄｃ−８１およびその製造法
US4427588A (en) 1982-11-08 1984-01-24 Bristol-Myers Company Process for conversion of oxotomaymycin to tomaymycin
US4427587A (en) 1982-11-10 1984-01-24 Bristol-Myers Company Total synthesis of antitumor antibiotics BBM-2040A and BBM-2040B
JPS59152329A (ja) 1983-02-17 1984-08-31 Green Cross Corp:The 局所障害抑制剤
US4816567A (en) 1983-04-08 1989-03-28 Genentech, Inc. Recombinant immunoglobin preparations
FR2586683B1 (fr) 1985-08-29 1988-07-01 Centre Nat Rech Scient Nouveaux derives de neothramycine, leur procede de preparation et leur application en tant que medicaments
US5583024A (en) 1985-12-02 1996-12-10 The Regents Of The University Of California Recombinant expression of Coleoptera luciferase
JP2660201B2 (ja) 1988-08-05 1997-10-08 塩野義製薬株式会社 新規ピロロ［１，４］ベンゾジアゼピン誘導体および老人性痴呆薬
WO1991002536A1 (en) 1989-08-23 1991-03-07 Scripps Clinic And Research Foundation Compositions and methods for detection and treatment of epstein-barr virus infection and immune disorders
JPH053790A (ja) 1990-04-19 1993-01-14 Fujisawa Pharmaceut Co Ltd デヒドロペプチダーゼ−ｉ
US5256643A (en) 1990-05-29 1993-10-26 The Government Of The United States Human cripto protein
WO1992007574A1 (en) 1990-10-25 1992-05-14 Tanox Biosystems, Inc. Glycoproteins associated with membrane-bound immunoglobulins as antibody targets on b cells
US5440021A (en) 1991-03-29 1995-08-08 Chuntharapai; Anan Antibodies to human IL-8 type B receptor
CA2105998C (en) 1991-03-29 2003-05-13 James Lee Human pf4a receptors and their use
US5543503A (en) 1991-03-29 1996-08-06 Genentech Inc. Antibodies to human IL-8 type A receptor
FR2676230B1 (fr) 1991-05-07 1993-08-27 Centre Nat Rech Scient Nouveaux derives de pyrrolo [1,4]-benzodiazepines, leur procede de preparation et medicaments les contenant.
JP3050424B2 (ja) 1991-07-12 2000-06-12 塩野義製薬株式会社 ヒトエンドセリンリセプター
US5264557A (en) 1991-08-23 1993-11-23 The United States Of America As Represented By The Department Of Health And Human Services Polypeptide of a human cripto-related gene, CR-3
US5362852A (en) 1991-09-27 1994-11-08 Pfizer Inc. Modified peptide derivatives conjugated at 2-hydroxyethylamine moieties
US6011146A (en) 1991-11-15 2000-01-04 Institut Pasteur Altered major histocompatibility complex (MHC) determinant and methods of using the determinant
US6153408A (en) 1991-11-15 2000-11-28 Institut Pasteur And Institut National De La Sante Et De La Recherche Medicale Altered major histocompatibility complex (MHC) determinant and methods of using the determinant
GB9205051D0 (en) 1992-03-09 1992-04-22 Cancer Res Campaign Tech Pyrrolobenzodiazepine derivatives,their preparation,and compositions containing them
FR2696176B1 (fr) 1992-09-28 1994-11-10 Synthelabo Dérivés de pipéridine, leur préparation et leur application en thérapeutique.
IL107366A (en) 1992-10-23 2003-03-12 Chugai Pharmaceutical Co Ltd Genes coding for megakaryocyte potentiator
US5644033A (en) 1992-12-22 1997-07-01 Health Research, Inc. Monoclonal antibodies that define a unique antigen of human B cell antigen receptor complex and methods of using same for diagnosis and treatment
US5801005A (en) 1993-03-17 1998-09-01 University Of Washington Immune reactivity to HER-2/neu protein for diagnosis of malignancies in which the HER-2/neu oncogene is associated
US5869445A (en) 1993-03-17 1999-02-09 University Of Washington Methods for eliciting or enhancing reactivity to HER-2/neu protein
US6214345B1 (en) 1993-05-14 2001-04-10 Bristol-Myers Squibb Co. Lysosomal enzyme-cleavable antitumor drug conjugates
GB9316162D0 (en) 1993-08-04 1993-09-22 Zeneca Ltd Fungicides
US5773223A (en) 1993-09-02 1998-06-30 Chiron Corporation Endothelin B1, (ETB1) receptor polypeptide and its encoding nucleic acid methods, and uses thereof
EP0647450A1 (en) 1993-09-09 1995-04-12 BEHRINGWERKE Aktiengesellschaft Improved prodrugs for enzyme mediated activation
US5750370A (en) 1995-06-06 1998-05-12 Human Genome Sciences, Inc. Nucleic acid encoding human endothlein-bombesin receptor and method of producing the receptor
JPH08336393A (ja) 1995-04-13 1996-12-24 Mitsubishi Chem Corp 光学活性なγ−置換−β−ヒドロキシ酪酸エステルの製造法
US5707829A (en) 1995-08-11 1998-01-13 Genetics Institute, Inc. DNA sequences and secreted proteins encoded thereby
US20020193567A1 (en) 1995-08-11 2002-12-19 Genetics Institute, Inc. Secreted proteins and polynucleotides encoding them
JP3646191B2 (ja) 1996-03-19 2005-05-11 大塚製薬株式会社 ヒト遺伝子
US6218519B1 (en) 1996-04-12 2001-04-17 Pro-Neuron, Inc. Compounds and methods for the selective treatment of cancer and bacterial infections
AU722499B2 (en) 1996-05-17 2000-08-03 Schering Corporation Human B-cell antigens, related reagents
WO1998013059A1 (en) 1996-09-27 1998-04-02 Bristol-Myers Squibb Company Hydrolyzable prodrugs for delivery of anticancer drugs to metastatic cells
US6759509B1 (en) 1996-11-05 2004-07-06 Bristol-Myers Squibb Company Branched peptide linkers
US5945511A (en) 1997-02-20 1999-08-31 Zymogenetics, Inc. Class II cytokine receptor
US7033827B2 (en) 1997-02-25 2006-04-25 Corixa Corporation Prostate-specific polynucleotide compositions
US20030185830A1 (en) 1997-02-25 2003-10-02 Corixa Corporation Compositions and methods for the therapy and diagnosis of prostate cancer
US6541212B2 (en) 1997-03-10 2003-04-01 The Regents Of The University Of California Methods for detecting prostate stem cell antigen protein
US6261791B1 (en) 1997-03-10 2001-07-17 The Regents Of The University Of California Method for diagnosing cancer using specific PSCA antibodies
JP4404381B2 (ja) 1997-03-10 2010-01-27 ザ リージェンツ オブ ザ ユニバーシティ オブ カリフォルニア Ｐｓｃａ：前立腺幹細胞抗原
US6555339B1 (en) 1997-04-14 2003-04-29 Arena Pharmaceuticals, Inc. Non-endogenous, constitutively activated human protein-coupled receptors
US6319688B1 (en) 1997-04-28 2001-11-20 Smithkline Beecham Corporation Polynucleotide encoding human sodium dependent phosphate transporter (IPT-1)
WO1998051824A1 (en) 1997-05-15 1998-11-19 Abbott Laboratories Reagents and methods useful for detecting disease of the urinary tract
WO1998051805A1 (en) 1997-05-15 1998-11-19 Abbott Laboratories Reagents and methods useful for detecting diseases of the prostate
US6602677B1 (en) 1997-09-19 2003-08-05 Promega Corporation Thermostable luciferases and methods of production
US20030060612A1 (en) 1997-10-28 2003-03-27 Genentech, Inc. Compositions and methods for the diagnosis and treatment of tumor
US20020034749A1 (en) 1997-11-18 2002-03-21 Billing-Medel Patricia A. Reagents and methods useful for detecting diseases of the breast
US6110695A (en) 1997-12-02 2000-08-29 The Regents Of The University Of California Modulating the interaction of the chemokine, B Lymphocyte Hemoattractant, and its Receptor, BLR1
JP4603157B2 (ja) 1998-03-13 2010-12-22 ザ バーナム インスティチュート 種々の選択された器官または組織にホーミングする分子
CA2685270C (en) 1998-05-13 2014-07-29 Pharmexa Inc. Expression vectors for stimulating an immune response and methods of using the same
US20030064397A1 (en) 1998-05-22 2003-04-03 Incyte Genomics, Inc. Transmembrane protein differentially expressed in prostate and lung tumors
US6835807B1 (en) 1998-05-22 2004-12-28 Daiichi Pharmaceuticals Co., Ltd. Drug complex and drug delivery system
US20020187472A1 (en) 2001-03-09 2002-12-12 Preeti Lal Steap-related protein
ATE276536T1 (de) 1998-07-08 2004-10-15 E Ink Corp Verfahren zur verbesserung der farbwiedergabe in elektrophoretischen vorrichtungen, welche mikrokapseln verwenden
GB9818731D0 (en) 1998-08-27 1998-10-21 Univ Portsmouth Compounds
AU757510C (en) 1998-08-27 2003-09-11 Medimmune Limited Pyrrolobenzodiazepines
WO2000012130A1 (en) 1998-08-27 2000-03-09 Smithkline Beecham Corporation Rp105 agonists and antagonists
GB9818730D0 (en) 1998-08-27 1998-10-21 Univ Portsmouth Collections of compounds
GB9818732D0 (en) 1998-08-27 1998-10-21 Univ Portsmouth Collection of compounds
JP4689781B2 (ja) 1998-09-03 2011-05-25 独立行政法人科学技術振興機構 アミノ酸輸送蛋白及びその遺伝子
WO2000020579A1 (en) 1998-10-02 2000-04-13 Mcmaster University Spliced form of erbb-2/neu oncogene
US6962980B2 (en) 1999-09-24 2005-11-08 Corixa Corporation Compositions and methods for the therapy and diagnosis of ovarian cancer
US6468546B1 (en) 1998-12-17 2002-10-22 Corixa Corporation Compositions and methods for therapy and diagnosis of ovarian cancer
US6858710B2 (en) 1998-12-17 2005-02-22 Corixa Corporation Compositions and methods for the therapy and diagnosis of ovarian cancer
US20030091580A1 (en) 2001-06-18 2003-05-15 Mitcham Jennifer L. Compositions and methods for the therapy and diagnosis of ovarian cancer
US20020119158A1 (en) 1998-12-17 2002-08-29 Corixa Corporation Compositions and methods for the therapy and diagnosis of ovarian cancer
US20030187196A1 (en) 1998-12-30 2003-10-02 Genentech, Inc. Secreted and transmembrane polypeptides and nucleic acids encoding the same
WO2000040614A2 (en) 1998-12-30 2000-07-13 Beth Israel Deaconess Medical Center, Inc. Characterization of the soc/crac calcium channel protein family
CN1201004C (zh) 1999-01-29 2005-05-11 考丽克萨有限公司 HER－2/neu融合蛋白
GB9905124D0 (en) 1999-03-05 1999-04-28 Smithkline Beecham Biolog Novel compounds
AU3395900A (en) 1999-03-12 2000-10-04 Human Genome Sciences, Inc. Human lung cancer associated gene sequences and polypeptides
US7312303B2 (en) 1999-05-11 2007-12-25 Genentech, Inc. Anti-PRO4980 antibodies
US6268488B1 (en) 1999-05-25 2001-07-31 Barbas, Iii Carlos F. Prodrug activation using catalytic antibodies
AU4952600A (en) 1999-06-03 2000-12-28 Takeda Chemical Industries Ltd. Screening method with the use of cd100
BRPI0012196B8 (pt) 1999-06-25 2021-05-25 Genentech Inc artigo industrializado
US6302318B1 (en) 1999-06-29 2001-10-16 General Electric Company Method of providing wear-resistant coatings, and related articles
US20030119113A1 (en) 1999-07-20 2003-06-26 Genentech, Inc. Secreted and transmembrane polypeptides and nucleic acids encoding the same
US7297770B2 (en) 1999-08-10 2007-11-20 Genentech, Inc. PRO6496 polypeptides
US7294696B2 (en) 1999-08-17 2007-11-13 Genentech Inc. PRO7168 polypeptides
US6909006B1 (en) 1999-08-27 2005-06-21 Spirogen Limited Cyclopropylindole derivatives
CA2380355A1 (en) 1999-09-01 2001-03-08 Genentech, Inc. Secreted and transmembrane polypeptides and nucleic acids encoding the same
US20030206918A1 (en) 1999-09-10 2003-11-06 Corixa Corporation Compositions and methods for the therapy and diagnosis of ovarian cancer
US20030129192A1 (en) 1999-09-10 2003-07-10 Corixa Corporation Compositions and methods for the therapy and diagnosis of ovarian cancer
US20030232056A1 (en) 1999-09-10 2003-12-18 Corixa Corporation Compositions and methods for the therapy and diagnosis of ovarian cancer
DK1226177T3 (da) 1999-10-29 2008-10-06 Genentech Inc Antistofsammensætninger mod anti-prostata stamcelle-antigen (PSCA) og anvendelser deraf
CA2393126C (en) 1999-11-29 2016-05-24 The Trustees Of Columbia University In The City Of New York Isolation of five novel genes coding for new fc receptors-type melanoma involved in the pathogenesis of lymphoma/melanoma
AU1807401A (en) 1999-11-30 2001-06-12 Corixa Corporation Compositions and methods for therapy and diagnosis of breast cancer
EP1568373A3 (en) 1999-12-10 2005-12-21 Epimmune Inc. Inducing cellular immune responses to HER2/neu using peptide and nucleic acid compositions
JP4741139B2 (ja) 1999-12-23 2011-08-03 ザイモジェネティクス， インコーポレイテッド 可溶性インターロイキン−２０レセプター
NZ502058A (en) 1999-12-23 2003-11-28 Ovita Ltd Isolated mutated nucleic acid molecule for regulation of ovulation rate
DE60030769T2 (de) 1999-12-23 2007-10-25 Zymogenetics, Inc., Seattle Verfahren zur behandlung von entzündungen
US6610286B2 (en) 1999-12-23 2003-08-26 Zymogenetics, Inc. Method for treating inflammation using soluble receptors to interleukin-20
US20040001827A1 (en) 2002-06-28 2004-01-01 Dennis Mark S. Serum albumin binding peptides for tumor targeting
PT1240337E (pt) 1999-12-24 2007-01-31 Genentech Inc Métodos e composições para prolongar as meias-vidas de eliminação de compostos bioactivos
US7294695B2 (en) 2000-01-20 2007-11-13 Genentech, Inc. PRO10268 polypeptides
WO2001053463A2 (en) 2000-01-21 2001-07-26 Corixa Corporation COMPOUNDS AND METHODS FOR PREVENTION AND TREATMENT OF HER-2/neu ASSOCIATED MALIGNANCIES
US20030224379A1 (en) 2000-01-21 2003-12-04 Tang Y. Tom Novel nucleic acids and polypeptides
AU2001243142A1 (en) 2000-02-03 2001-08-14 Hyseq, Inc. Novel nucleic acids and polypeptides
US20020142377A1 (en) 2000-02-22 2002-10-03 Glucksmann Maria Alexandra 18607, a novel human calcium channel
US20030219806A1 (en) 2000-02-22 2003-11-27 Millennium Pharmaceuticals, Inc. Novel 18607, 15603, 69318, 12303, 48000, 52920, 5433, 38554, 57301, 58324, 55063, 52991, 59914, 59921 and 33751 molecules and uses therefor
US20040052793A1 (en) 2001-02-22 2004-03-18 Carter Paul J. Caspase activivated prodrugs therapy
US20040002068A1 (en) 2000-03-01 2004-01-01 Corixa Corporation Compositions and methods for the detection, diagnosis and therapy of hematological malignancies
US20040005561A1 (en) 2000-03-01 2004-01-08 Corixa Corporation Compositions and methods for the detection, diagnosis and therapy of hematological malignancies
EP1261743A2 (en) 2000-03-07 2002-12-04 Hyseq, Inc. Novel nucleic acids and polypeptides
AU2001249411B2 (en) 2000-03-24 2007-02-15 Fahri Saatcioglu Novel prostate-specific or testis-specific nucleic acid molecules, polypeptides,and diagnostic and therapeutic methods
WO2004043361A2 (en) 2002-11-08 2004-05-27 Genentech, Inc. Compositions and methods for the treatment of natural killer cell related diseases
AU2001250412A1 (en) 2000-03-31 2001-10-08 Ipf Pharmaceuticals Gmbh Diagnostic and medicament for analysing the cell surface proteome of tumour and inflammatory cells and for treating tumorous and inflammatory diseases, preferably using specific chemokine receptor analysis and the chemokine receptor-ligand interaction
WO2001075177A2 (en) 2000-04-03 2001-10-11 The Government Of The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Tumor markers in ovarian cancer
JP2003532057A (ja) 2000-04-07 2003-10-28 アリーナ・フアーマシユーチカルズ・インコーポレーテツド 非内因性の、構成的に活性化される既知ｇタンパク質−共役受容体
US20030119115A1 (en) 2000-05-17 2003-06-26 Genentech, Inc. Secreted and transmembrane polypeptides and nucleic acids encoding the same
WO2001088133A2 (en) 2000-05-18 2001-11-22 Lexicon Genetics Incorporated Human semaphorin homologs and polynucleotides encoding the same
WO2001090304A2 (en) 2000-05-19 2001-11-29 Human Genome Sciences, Inc. Nucleic acids, proteins, and antibodies
WO2001094641A2 (en) 2000-06-09 2001-12-13 Idec Pharmaceuticals Corporation Gene targets and ligands that bind thereto for treatment and diagnosis of ovarian carcinomas
EP1297130A2 (en) 2000-06-16 2003-04-02 Incyte Genomics, Inc. G-protein coupled receptors
EP1383892A2 (en) 2000-06-30 2004-01-28 Incyte Genomics, Inc. Human extracellular matrix and cell adhesion polypeptides
WO2002002587A1 (en) 2000-06-30 2002-01-10 Human Genome Sciences, Inc. B7-like polynucleotides, polypeptides, and antibodies
MXPA02012749A (es) 2000-06-30 2003-10-06 Amgen Inc Moleculas semejantes a b7 y sus usos.
WO2002006339A2 (en) 2000-07-03 2002-01-24 Curagen Corporation Proteins and nucleic acids encoding same
US20040044179A1 (en) 2000-07-25 2004-03-04 Genentech, Inc. Secreted and transmembrane polypeptides and nucleic acids encoding the same
AU2001283507A1 (en) 2000-07-27 2002-02-13 Mayo Foundation For Medical Education And Research B7-h3 and b7-h4, novel immunoregulatory molecules
ATE396266T1 (de) 2000-07-28 2008-06-15 Ulrich Wissenbach Trp8 krebsmarker
US7229623B1 (en) 2000-08-03 2007-06-12 Corixa Corporation Her-2/neu fusion proteins
WO2002014503A2 (en) 2000-08-14 2002-02-21 Corixa Corporation Compositions and methods for the therapy and diagnosis of her-2/neu-associated malignancies
WO2002013847A2 (en) 2000-08-14 2002-02-21 Corixa Corporation Methods for diagnosis and therapy of hematological and virus-associated malignancies
EP1445318A2 (en) 2000-08-24 2004-08-11 Genetech, Inc. Compositions and methods for the diagnosis and treatment of tumor
GB0020953D0 (en) 2000-08-24 2000-10-11 Smithkline Beecham Biolog Vaccine
EP1346040A2 (en) 2000-09-11 2003-09-24 Nuvelo, Inc. Novel nucleic acids and polypeptides
US6613567B1 (en) 2000-09-15 2003-09-02 Isis Pharmaceuticals, Inc. Antisense inhibition of Her-2 expression
EP1803733B1 (en) 2000-09-15 2010-03-10 ZymoGenetics, Inc. Polypeptides comprising the extracellular domains of IL-20RA and/or IL-20RB
US7582293B2 (en) 2000-09-15 2009-09-01 Genentech, Inc. Anti-PRO6308 antibodies
UA83458C2 (uk) 2000-09-18 2008-07-25 Байоджен Айдек Ма Інк. Виділений поліпептид baff-r (рецептор фактора активації в-клітин сімейства tnf)
AU2001292724B2 (en) 2000-09-18 2005-05-26 Biogen Idec Ma Inc. CRIPTO mutant and uses thereof
ES2254492T3 (es) 2000-09-19 2006-06-16 Moses Lee Composiciones y procedimientos de uso de analogos aquirales de cc-1065 y de duocarmicinas.
WO2002030268A2 (en) 2000-10-13 2002-04-18 Eos Biotechnology, Inc. Methods of diagnosis of prostate cancer, compositions and methods of screening for modulators of prostate cancer
CA2428242A1 (en) 2000-11-07 2002-05-16 Zymogenetics, Inc. Human tumor necrosis factor receptor
US20020150573A1 (en) 2000-11-10 2002-10-17 The Rockefeller University Anti-Igalpha-Igbeta antibody for lymphoma therapy
US20040018194A1 (en) 2000-11-28 2004-01-29 Francisco Joseph A. Recombinant anti-CD30 antibodies and uses thereof
WO2002061087A2 (en) 2000-12-19 2002-08-08 Lifespan Biosciences, Inc. Antigenic peptides, such as for g protein-coupled receptors (gpcrs), antibodies thereto, and systems for identifying such antigenic peptides
WO2002054940A2 (en) 2001-01-12 2002-07-18 University Of Medicine & Dentistry Of New Jersey Bone morphogenetic protein-2 in the treatment and diagnosis of cancer
US20030119119A1 (en) 2001-01-16 2003-06-26 Genentech, Inc. Secreted and transmembrane polypeptides and nucleic acids encoding the same
US20030119126A1 (en) 2001-01-16 2003-06-26 Genentech, Inc. Secreted and transmembrane polypeptides and nucleic acids encoding the same
US7754208B2 (en) 2001-01-17 2010-07-13 Trubion Pharmaceuticals, Inc. Binding domain-immunoglobulin fusion proteins
WO2002059377A2 (en) 2001-01-24 2002-08-01 Protein Design Labs Methods of diagnosis of breast cancer, compositions and methods of screening for modulators of breast cancer
US20030073144A1 (en) 2001-01-30 2003-04-17 Corixa Corporation Compositions and methods for the therapy and diagnosis of pancreatic cancer
WO2002064775A1 (en) 2001-02-12 2002-08-22 Bionomics Limited Identification of genes involved in the tumourigenic process
WO2002071928A2 (en) 2001-03-14 2002-09-19 Millennium Pharmaceuticals, Inc. Nucleic acid molecules and proteins for the identification, assessment, prevention, and therapy of ovarian cancer
EP1243276A1 (en) 2001-03-23 2002-09-25 Franciscus Marinus Hendrikus De Groot Elongated and multiple spacers containing activatible prodrugs
WO2002078524A2 (en) 2001-03-28 2002-10-10 Zycos Inc. Translational profiling
WO2003008537A2 (en) 2001-04-06 2003-01-30 Mannkind Corporation Epitope sequences
US6820011B2 (en) 2001-04-11 2004-11-16 The Regents Of The University Of Colorado Three-dimensional structure of complement receptor type 2 and uses thereof
AU2002254615A1 (en) 2001-04-17 2002-10-28 The Board Of Trustees Of The University Of Arkansas Repeat sequences of the ca125 gene and their use for diagnostic and therapeutic interventions
EP1463928A2 (en) 2001-04-18 2004-10-06 Protein Design Labs Methods of diagnosis of lung cancer, compositions and methods of screening for modulators of lung cancer
EE200300528A (et) 2001-04-26 2004-08-16 Biogen, Inc. Cripto valku blokeerivad antikehad ja nende kasutamine
WO2003083041A2 (en) 2002-03-22 2003-10-09 Biogen, Inc. Cripto-specific antibodies
US6884869B2 (en) 2001-04-30 2005-04-26 Seattle Genetics, Inc. Pentapeptide compounds and uses related thereto
WO2002089747A2 (en) 2001-05-09 2002-11-14 Corixa Corporation Compositions and methods for the therapy and diagnosis of prostate cancer
WO2002092836A2 (en) 2001-05-11 2002-11-21 Sloan-Kettering Institute For Cancer Research Nucleic acid sequence encoding ovarian antigen, ca125, and uses thereof
ATE542545T1 (de) 2001-05-24 2012-02-15 Zymogenetics Inc Taci-immunoglobulin-fusionsproteine
US7157558B2 (en) 2001-06-01 2007-01-02 Genentech, Inc. Polypeptide encoded by a polynucleotide overexpresses in tumors
AU2002314901A1 (en) 2001-06-04 2002-12-16 Eos Biotechnology, Inc. Methods of diagnosis and treatment of androgen-dependent prostate cancer, prostate cancer undergoing androgen-withdrawal, and androgen-independent prostate cancer
WO2003000842A2 (en) 2001-06-04 2003-01-03 Curagen Corporation Novel proteins and nucleic acids encoding same
JP2005501528A (ja) 2001-06-05 2005-01-20 エクセリクシス・インコーポレイテッド ｐ５３経路のモディファイヤーとしてのＧＦＡＴｓおよび使用方法
EP1402053A4 (en) 2001-06-05 2005-05-11 Exelixis Inc CHDS AS MODULATORS OF THE MECHANISM OF ACTION OF P53 AND USES THEREOF
US7235358B2 (en) 2001-06-08 2007-06-26 Expression Diagnostics, Inc. Methods and compositions for diagnosing and monitoring transplant rejection
US7125663B2 (en) 2001-06-13 2006-10-24 Millenium Pharmaceuticals, Inc. Genes, compositions, kits and methods for identification, assessment, prevention, and therapy of cervical cancer
US7189507B2 (en) 2001-06-18 2007-03-13 Pdl Biopharma, Inc. Methods of diagnosis of ovarian cancer, compositions and methods of screening for modulators of ovarian cancer
AU2002347428A1 (en) 2001-06-18 2003-01-02 Eos Biotechnology Inc. Methods of diagnosis of ovarian cancer, compositions and methods of screening for modulators of ovarian cancer
US7705120B2 (en) 2001-06-21 2010-04-27 Millennium Pharmaceuticals, Inc. Compositions, kits, and methods for identification, assessment, prevention, and therapy of breast cancer
WO2003002717A2 (en) 2001-06-28 2003-01-09 Schering Corporation Biological activity of ak155
WO2003004529A2 (en) 2001-07-02 2003-01-16 Licentia Ltd. Ephrin-tie receptor materials and methods
US20040076955A1 (en) 2001-07-03 2004-04-22 Eos Biotechnology, Inc. Methods of diagnosis of bladder cancer, compositions and methods of screening for modulators of bladder cancer
WO2003003984A2 (en) 2001-07-05 2003-01-16 Curagen Corporation Novel proteins and nucleic acids encoding same
WO2003055439A2 (en) 2001-07-18 2003-07-10 The Regents Of The University Of California Her2/neu target antigen and use of same to stimulate an immune response
US20030108963A1 (en) 2001-07-25 2003-06-12 Millennium Pharmaceuticals, Inc. Novel genes, compositions, kit, and methods for identification, assessment, prevention and therapy of prostate cancer
HUP0500992A3 (en) 2001-08-03 2007-11-28 Genentech Inc Tacis and br3 polypeptides and uses thereof
EP1478772A2 (en) 2001-08-14 2004-11-24 The General Hospital Corporation Nucleic acid and amino acid sequences involved in pain
US20030092013A1 (en) 2001-08-16 2003-05-15 Vitivity, Inc. Diagnosis and treatment of vascular disease
AU2002313559A1 (en) 2001-08-23 2003-03-10 Oxford Biomedica (Uk) Limited Genes
US6902930B2 (en) 2001-08-29 2005-06-07 Vanderbilt University Human Mob-5 (IL-24) receptors and uses thereof
US20030124579A1 (en) 2001-09-05 2003-07-03 Eos Biotechnology, Inc. Methods of diagnosis of ovarian cancer, compositions and methods of screening for modulators of ovarian cancer
WO2003022995A2 (en) 2001-09-06 2003-03-20 Agensys, Inc. Nucleic acid and corresponding protein entitled steap-1 useful in treatment and detection of cancer
CA2459219A1 (en) 2001-09-17 2003-03-27 Protein Design Labs, Inc. Methods of diagnosis of cancer compositions and methods of screening for modulators of cancer
IL160933A0 (en) 2001-09-18 2004-08-31 Proteologics Inc Methods and compositions for treating ?cap associated diseases
NZ531674A (en) 2001-09-18 2009-03-31 Genentech Inc Compositions and methods for the diagnosis and treatment of tumor
WO2003025148A2 (en) 2001-09-19 2003-03-27 Nuvelo, Inc. Novel nucleic acids and polypeptides
WO2003026577A2 (en) 2001-09-24 2003-04-03 Seattle Genetics, Inc. P-amidobenzylethers in drug delivery agents
US7091186B2 (en) 2001-09-24 2006-08-15 Seattle Genetics, Inc. p-Amidobenzylethers in drug delivery agents
US20030077644A1 (en) 2001-09-28 2003-04-24 Bing Yang Diagnosis and treatment of diseases caused by mutations in CD72
US20050130117A1 (en) 2001-10-03 2005-06-16 Davis Cong L. Modulators of lymphocyte activation and migration
WO2003029421A2 (en) 2001-10-03 2003-04-10 Origene Technologies, Inc. Regulated breast cancer genes
JP2005522986A (ja) 2001-10-19 2005-08-04 ジェネンテック・インコーポレーテッド 炎症性腸疾患の診断と治療のための組成物と方法
US20050123925A1 (en) 2002-11-15 2005-06-09 Genentech, Inc. Compositions and methods for the diagnosis and treatment of tumor
EP1525213B1 (en) 2001-10-24 2012-06-27 National Jewish Health Three-dimensional structures of tall-1 and its cognate receptors and modified proteins and methods related thereto
KR101072867B1 (ko) 2001-10-31 2011-10-17 유니버시티 오브 노스 텍사스 헬스 사이언스 센터 뼈 형태발생 단백질(ｂｍｐ), ｂｍｐ 수용체 및 ｂｍｐ 결합 단백질 및 녹내장 진단 및 치료에서 그의 용도
WO2003042661A2 (en) 2001-11-13 2003-05-22 Protein Design Labs, Inc. Methods of diagnosis of cancer, compositions and methods of screening for modulators of cancer
US20030232350A1 (en) 2001-11-13 2003-12-18 Eos Biotechnology, Inc. Methods of diagnosis of cancer, compositions and methods of screening for modulators of cancer
CA2467242A1 (en) 2001-11-20 2003-05-30 Seattle Genetics, Inc. Treatment of immunological disorders using anti-cd30 antibodies
US7344843B2 (en) 2001-11-29 2008-03-18 Serono Genetics Institute S.A. Agonists and antagonists of prolixin for the treatment of metabolic disorders
JP4723810B2 (ja) 2001-12-03 2011-07-13 アレクシオン ファーマシューティカルズ， インコーポレイテッド ハイブリッド抗体
AU2002349784A1 (en) 2001-12-03 2003-06-17 Asahi Kasei Pharma Corporation Nf-kappab activating genes
WO2003054152A2 (en) 2001-12-10 2003-07-03 Nuvelo, Inc. Novel nucleic acids and polypeptides
US20030134790A1 (en) 2002-01-11 2003-07-17 University Of Medicine And Dentistry Of New Jersey Bone Morphogenetic Protein-2 And Bone Morphogenetic Protein-4 In The Treatment And Diagnosis Of Cancer
US7452675B2 (en) 2002-01-25 2008-11-18 The Queen's Medical Center Methods of screening for TRPM4b modulators
WO2003072036A2 (en) 2002-02-21 2003-09-04 Duke University Treatment methods using anti-cd22 antibodies
US20040258678A1 (en) 2002-02-22 2004-12-23 Genentech, Inc. Compositions and methods for the treatment of immune related diseases
US20030219795A1 (en) 2002-03-01 2003-11-27 Marcia Belvin SCDs as modifiers of the p53 pathway and methods of use
US6660856B2 (en) 2002-03-08 2003-12-09 Kaohsiung Medical University Synthesis of pyrrolo[2,1-c][1,4]benzodiazepine analogues
EP2258712A3 (en) 2002-03-15 2011-05-04 Multicell Immunotherapeutics, Inc. Compositions and Methods to Initiate or Enhance Antibody and Major-histocompatibility Class I or Class II-restricted T Cell Responses by Using Immunomodulatory, Non-coding RNA Motifs
CA2486490A1 (en) 2002-03-19 2003-12-31 Curagen Corporation Therapeutic polypeptides, nucleic acids encoding same, and methods of use
EP1579186A4 (en) 2002-03-21 2008-10-08 Sunesis Pharmaceuticals Inc IDENTIFICATION OF KINASE INHIBITORS
US7193069B2 (en) 2002-03-22 2007-03-20 Research Association For Biotechnology Full-length cDNA
CA2480404A1 (en) 2002-03-25 2003-10-30 Uab Research Foundation Fc receptor homolog, reagents, and uses thereof
WO2003083074A2 (en) 2002-03-28 2003-10-09 Idec Pharmaceuticals Corporation Novel gene targets and ligands that bind thereto for treatment and diagnosis of colon carcinomas
US20030194704A1 (en) 2002-04-03 2003-10-16 Penn Sharron Gaynor Human genome-derived single exon nucleic acid probes useful for gene expression analysis two
JP2005534287A (ja) 2002-04-05 2005-11-17 アジェンシス， インコーポレイテッド 癌の処置および検出において有用な９８ｐ４ｂ６との名称の核酸および対応するタンパク質
AU2003223520A1 (en) 2002-04-12 2003-10-27 Mitokor Targets for therapeutic intervention identified in the mitochondrial proteome
AU2003230874A1 (en) 2002-04-16 2003-11-03 Genentech, Inc. Compositions and methods for the diagnosis and treatment of tumor
AU2003239158A1 (en) 2002-04-17 2003-11-03 Baylor College Of Medicine Aib1 as a prognostic marker and predictor of resistance to encocrine therapy
WO2003093444A2 (en) 2002-05-03 2003-11-13 Incyte Corporation Transporters and ion channels
EP1572925A4 (en) 2002-05-15 2007-08-15 Avalon Pharmaceuticals CANCER-RELATED GENE AS A TARGET FOR CHEMOTHERAPY
AU2003232453A1 (en) 2002-05-30 2003-12-19 David K. Bol Human solute carrier family 7 member 11 (hslc7a11)
AU2003239969A1 (en) 2002-06-04 2003-12-19 Avalon Pharmaceuticals, Inc. Cancer-linked gene as target for chemotherapy
WO2003101283A2 (en) 2002-06-04 2003-12-11 Incyte Corporation Diagnostics markers for lung cancer
KR101031025B1 (ko) 2002-06-06 2011-04-25 온코세라피 사이언스 가부시키가이샤 사람 결장암에 관계하는 유전자 및 폴리펩티드
AU2003242633A1 (en) 2002-06-06 2003-12-22 Molecular Engines Laboratories Dudulin genes, non-human animal model: uses in human hematological disease
EP1576111A4 (en) 2002-06-07 2006-10-18 Avalon Pharmaceuticals CANCER-ASSOCIATED GENE AS A TARGET FOR CHEMOTHERAPY
AU2003245441A1 (en) 2002-06-12 2003-12-31 Avalon Pharmaceuticals, Inc. Cancer-linked gene as target for chemotherapy
WO2003106659A2 (en) 2002-06-18 2003-12-24 Archemix Corp. Aptamer-toxin molecules and methods for using same
US20040249130A1 (en) 2002-06-18 2004-12-09 Martin Stanton Aptamer-toxin molecules and methods for using same
US7304149B2 (en) 2002-06-20 2007-12-04 Washington University In St. Louis BTLA nucleic acids
WO2004001004A2 (en) 2002-06-21 2003-12-31 Johns Hopkins University School Of Medicine Membrane associated tumor endothelium markers
DE10229834A1 (de) 2002-07-03 2004-01-29 Zinser Textilmaschinen Gmbh Streckwerk für Spinnmaschinen mit nachgeordneter Verdichtungsvorrichtung
WO2004009622A2 (en) 2002-07-19 2004-01-29 Cellzome Ag Protein complexes of cellular networks underlying the development of cancer and other diseases
US20050043516A1 (en) 2002-07-25 2005-02-24 Genentech, Inc. TACI antibodies and uses thereof
US20050180972A1 (en) 2002-07-31 2005-08-18 Wahl Alan F. Anti-CD20 antibody-drug conjugates for the treatment of cancer and immune disorders
US7659241B2 (en) 2002-07-31 2010-02-09 Seattle Genetics, Inc. Drug conjugates and their use for treating cancer, an autoimmune disease or an infectious disease
JP2004121218A (ja) 2002-08-06 2004-04-22 Jenokkusu Soyaku Kenkyusho:Kk 気管支喘息または慢性閉塞性肺疾患の検査方法
AU2003251471A1 (en) 2002-08-06 2004-02-25 Bayer Healthcare Ag Diagnostics and therapeutics for diseases associated with human cxc chemokine receptor 5(cxcr5)
KR20050048615A (ko) 2002-08-19 2005-05-24 제넨테크, 인크. 종양의 진단 및 치료를 위한 조성물 및 방법
JP2006515742A (ja) 2002-08-27 2006-06-08 ブリストル−マイヤーズ　スクイブ　カンパニー 乳癌細胞でのプロテインチロシンキナーゼおよび／またはプロテインチロシンキナーゼ経路と相互作用および／またはモデュレートする化合物の活性を予測するためのポリヌクレオチドの同定
WO2004020595A2 (en) 2002-08-29 2004-03-11 Five Prime Therapeutics, Inc. Novel human polypeptides encoded by polynucleotides
WO2004019993A1 (en) 2002-08-30 2004-03-11 Ramot At Tel Aviv University Ltd. Self-immolative dendrimers releasing many active moieties upon a single activating event
AU2002951346A0 (en) 2002-09-05 2002-09-26 Garvan Institute Of Medical Research Diagnosis of ovarian cancer
CA2496888A1 (en) 2002-09-06 2004-03-18 Mannkind Corporation Epitope sequences
AU2003300776A1 (en) 2002-09-09 2004-05-25 Omeros Corporation G protein coupled receptors and uses thereof
JP2004113151A (ja) 2002-09-27 2004-04-15 Sankyo Co Ltd 癌遺伝子及びその用途
CA2500978A1 (en) 2002-10-03 2004-04-15 Mcgill University Antibodies and cyclic peptides which bind cea (carcinoembryonic antigen) and their use as cancer therapeutics
US20060183120A1 (en) 2002-10-04 2006-08-17 Teh Bin T Molecular sub-classification of kidney tumors and the discovery of new diagnostic markers
US20040138269A1 (en) 2002-10-11 2004-07-15 Sugen, Inc. Substituted pyrroles as kinase inhibitors
US20040146907A1 (en) 2002-11-13 2004-07-29 Genentech, Inc. Methods and compositions for detecting dysplasia
JP2006507322A (ja) 2002-11-14 2006-03-02 シンタルガ・ビーブイ 多重自己脱離放出スペーサーとして構築されたプロドラッグ
GB0226593D0 (en) 2002-11-14 2002-12-24 Consultants Ltd Compounds
CA2505919A1 (en) 2002-11-15 2004-06-03 The Board Of Trustees Of The University Of Arkansas Ca125 gene and its use for diagnostic and therapeutic interventions
ES2392511T3 (es) 2002-11-15 2012-12-11 Musc Foundation For Research Development Moduladores de complemento dianas sobre el receptor 2 de complemento
AU2003297300A1 (en) 2002-11-20 2004-06-15 Biogen Idec Inc. Novel gene targets and ligands that bind thereto for treatment and diagnosis of carcinomas
AU2003294462C1 (en) 2002-11-21 2011-06-30 University Of Utah Research Foundation Purinergic modulation of smell
US20040253606A1 (en) 2002-11-26 2004-12-16 Protein Design Labs, Inc. Methods of detecting soft tissue sarcoma, compositions and methods of screening for soft tissue sarcoma modulators
EP1581641A4 (en) 2002-12-06 2006-11-15 Diadexus Inc COMPOSITIONS, SPREADING VARIATIONS AND METHODS RELATED TO OVARAL SPECIFIC GENES AND PROTEINS
US20040157278A1 (en) 2002-12-13 2004-08-12 Bayer Corporation Detection methods using TIMP 1
ES2388280T3 (es) 2002-12-20 2012-10-11 Abbott Biotherapeutics Corp. Anticuerpos que reaccionan frente a GPR64 y utilización de los mismos
WO2004058309A1 (en) 2002-12-23 2004-07-15 Human Genome Sciences, Inc. Neutrokine-alpha conjugate, neutrokine-alpha complex, and uses thereof
WO2004063709A2 (en) 2003-01-08 2004-07-29 Bristol-Myers Squibb Company Biomarkers and methods for determining sensitivity to epidermal growth factor receptor modulators
US20050181375A1 (en) 2003-01-10 2005-08-18 Natasha Aziz Novel methods of diagnosis of metastatic cancer, compositions and methods of screening for modulators of metastatic cancer
US20050227301A1 (en) 2003-01-10 2005-10-13 Polgen Cell cycle progression proteins
WO2004065577A2 (en) 2003-01-14 2004-08-05 Bristol-Myers Squibb Company Polynucleotides and polypeptides associated with the nf-kb pathway
US7258971B2 (en) 2003-01-15 2007-08-21 Bayer Healthcare Ag Methods and compositions for treating urological disorders using carboxypeptidase Z identified as 8263
CA2516128A1 (en) 2003-02-14 2004-09-02 Sagres Discovery, Inc. Therapeutic targets in cancer
US20030224411A1 (en) 2003-03-13 2003-12-04 Stanton Lawrence W. Genes that are up- or down-regulated during differentiation of human embryonic stem cells
GB0321295D0 (en) 2003-09-11 2003-10-15 Spirogen Ltd Synthesis of protected pyrrolobenzodiazepines
GB0416511D0 (en) 2003-10-22 2004-08-25 Spirogen Ltd Pyrrolobenzodiazepines
ATE516288T1 (de) 2003-10-22 2011-07-15 Us Gov Health & Human Serv Pyrrolobenzodiazepinderivate, zusammensetzungen, die diese enthalten, und damit in zusammenhang stehende verfahren
US20050288491A1 (en) 2004-02-17 2005-12-29 Wilson David S Super-humanized antibodies against respiratory syncytial virus
JP5064037B2 (ja) 2004-02-23 2012-10-31 ジェネンテック， インコーポレイテッド 複素環式自壊的リンカーおよび結合体
CA2558195C (en) 2004-03-01 2012-11-06 Spirogen Limited 11-hydroxy-5h-pyrrolo[2,1-c][1,4]benzodiazepin-5-one derivatives as key intermediates for the preparation of c2 substituted pyrrolobenzodiazepines
GB0404574D0 (en) 2004-03-01 2004-04-07 Spirogen Ltd Amino acids
GB0404578D0 (en) 2004-03-01 2004-04-07 Spirogen Ltd Pyrrolobenzodiazepines
DE102004010943A1 (de) 2004-03-03 2005-09-29 Degussa Ag Verfahren zur Herstellung von N-geschützten 4-Ketprolinderivaten
EP1723152B1 (en) 2004-03-09 2015-02-11 Spirogen Sàrl Pyrrolobenzodiazepines
FR2869231B1 (fr) 2004-04-27 2008-03-14 Sod Conseils Rech Applic Composition therapeutique contenant au moins un derive de la pyrrolobenzodiazepine et la fludarabine
CA2565849C (en) 2004-05-11 2013-01-29 The General Hospital Corporation Dba Massachusetts General Hospital Methods for making oxidation resistant polymeric material
GB0410725D0 (en) 2004-05-13 2004-06-16 Spirogen Ltd Pyrrolobenzodiazepine therapeutic agents
CA2580141C (en) 2004-09-23 2013-12-10 Genentech, Inc. Cysteine engineered antibodies and conjugates
JP2006203186A (ja) 2004-12-24 2006-08-03 Showa Denko Kk 熱電半導体合金の製造方法および熱電変換モジュールならびに熱電発電装置
EP1844074B1 (en) 2005-02-03 2013-04-24 Antitope Limited Human antibodies and proteins
CA2605507C (en) 2005-04-19 2016-06-28 Seattle Genetics, Inc. Humanized anti-cd70 binding agents and uses thereof
CA2604805C (en) 2005-04-21 2014-05-27 Spirogen Limited Pyrrolobenzodiazepines
GB0508084D0 (en) 2005-04-21 2005-06-01 Spirogen Ltd Pyrrolobenzodiazepines
US20070154906A1 (en) 2005-10-05 2007-07-05 Spirogen Ltd. Methods to identify therapeutic candidates
WO2007039752A1 (en) 2005-10-05 2007-04-12 Spirogen Limited Alkyl 4- [4- (5-oxo-2, 3, 5, 11a-tetrahyd0-5h-pyrr0l0 [2, 1-c] [1, 4] benzodiazepine-8-yloxy) -butyrylamino]-1h-pyrrole-2-carboxylate derivatives and related compounds for the treatment of a proliferative disease
EP1934174B1 (en) 2005-10-07 2011-04-06 Exelixis, Inc. Azetidines as mek inhibitors for the treatment of proliferative diseases
ATE527262T1 (de) 2006-01-25 2011-10-15 Sanofi Sa Neue tomaymycin derivate enhaltende zytotoxische mittel
EP2044122B1 (en) 2006-07-18 2018-03-28 Sanofi Antagonist antibody against epha2 for the treatment of cancer
ES2402591T3 (es) 2006-08-14 2013-05-07 Xencor Inc. Anticuerpos optimizados que seleccionan como diana CD19
US20080112961A1 (en) 2006-10-09 2008-05-15 Macrogenics, Inc. Identification and Engineering of Antibodies with Variant Fc Regions and Methods of Using Same
EP1914242A1 (en) 2006-10-19 2008-04-23 Sanofi-Aventis Novel anti-CD38 antibodies for the treatment of cancer
WO2008050140A2 (en) 2006-10-27 2008-05-02 Spirogen Limited Compounds for treatment of parasitic infection
PT2099823E (pt) 2006-12-01 2014-12-22 Seattle Genetics Inc Agentes de ligação ao alvo variantes e suas utilizações
PE20090245A1 (es) 2007-05-08 2009-03-17 Genentech Inc Anticuerpos anti-muc16 disenados con cisteina y conjugados de anticuerpos y farmacos
ES2435779T3 (es) 2007-07-19 2013-12-23 Sanofi Agentes citotóxicos que comprenden nuevos derivados de tomaimicina y su uso terapéutico
KR101622412B1 (ko) 2007-10-19 2016-05-18 제넨테크, 인크. 시스테인 조작된 항-ｔｅｎｂ２ 항체 및 항체 약물 접합체
GB0722088D0 (en) 2007-11-09 2007-12-19 Spirogen Ltd Pyrrolobenzodiazepines
GB0722087D0 (en) 2007-11-09 2007-12-19 Spirogen Ltd Polyamides
US8609105B2 (en) 2008-03-18 2013-12-17 Seattle Genetics, Inc. Auristatin drug linker conjugates
US8236319B2 (en) 2008-04-30 2012-08-07 Immunogen, Inc. Cross-linkers and their uses
NZ589880A (en) 2008-06-16 2012-10-26 Immunogen Inc Use of synergistic anti-cancer compositions comprising lenalidomide, at least one corticosteroid and at least one immunoconjugate
GB0813432D0 (en) 2008-07-22 2008-08-27 Spirogen Ltd Pyrrolobenzodiazepines
GB0819095D0 (en) 2008-10-17 2008-11-26 Spirogen Ltd Pyrrolobenzodiazepines
GB0819097D0 (en) 2008-10-17 2008-11-26 Spirogen Ltd Pyrrolobenzodiazepines
RU2545080C2 (ru) 2009-02-05 2015-03-27 Иммьюноджен, Инк. Новые производные бензодиазепина
US8679492B2 (en) 2009-02-23 2014-03-25 Glenmark Pharmaceuticals S.A. Humanized antibodies that bind to CD19 and their uses
JP5382792B2 (ja) 2009-08-14 2014-01-08 独立行政法人理化学研究所 光２次非線形薄膜における１次及び２次光感受率異方性同時測定方法、当該方法を実行する装置及び当該方法をコンピュータに実行させるプログラム
FR2949469A1 (fr) 2009-08-25 2011-03-04 Sanofi Aventis Derives anticancereux, leur preparation et leur application en therapeutique
NZ598929A (en) 2009-09-01 2014-05-30 Abbvie Inc Dual variable domain immunoglobulins and uses thereof
US20110070248A1 (en) 2009-09-24 2011-03-24 Seattle Genetics, Inc. Dr5 ligand drug conjugates
ES2449379T3 (es) 2010-02-09 2014-03-19 Bristol-Myers Squibb Company Derivados de bencilpirrolidinona como moduladores de la actividad de receptores de quimiocinas
TW201129383A (en) 2010-02-10 2011-09-01 Immunogen Inc CD20 antibodies and uses thereof
CN105001334A (zh) 2010-02-10 2015-10-28 伊缪诺金公司 Cd20抗体及其用途
US9242013B2 (en) 2010-04-15 2016-01-26 Seattle Genetics Inc. Targeted pyrrolobenzodiazapine conjugates
PE20130342A1 (es) 2010-04-15 2013-04-20 Spirogen Sarl Pirrolobenzodiacepinas y conjugados de las mismas
WO2011130615A2 (en) 2010-04-15 2011-10-20 Dr. Reddy's Laboratories Ltd. Preparation of lacosamide
GB201006340D0 (en) 2010-04-15 2010-06-02 Spirogen Ltd Synthesis method and intermediates
PL3056203T3 (pl) 2010-04-21 2018-06-29 Syntarga B.V. Koniugaty analogów CC-1065 i łączników dwufunkcyjnych
FR2963007B1 (fr) 2010-07-26 2013-04-05 Sanofi Aventis Derives anticancereux, leur preparation et leur application therapeutique
PL2675479T3 (pl) 2011-02-15 2016-09-30 Cytotoksyczne pochodne benzodiazepiny
US9135118B2 (en) 2011-03-07 2015-09-15 Aptare, Inc. System to catalog and search point-in-time instances of a file system
KR101860174B1 (ko) 2011-09-20 2018-05-21 메디뮨 리미티드 표적 접합체 내의 내포를 위한 비대칭 이량체 pbd 화합물로서 피롤로벤조디아제핀
US9526798B2 (en) 2011-10-14 2016-12-27 Seattle Genetics, Inc. Pyrrolobenzodiazepines and targeted conjugates
CN104011018B (zh) 2011-10-14 2016-12-14 麦迪穆有限责任公司 可用于制备吡咯并苯并二氮杂卓的合成方法和中间体
US9399073B2 (en) 2011-10-14 2016-07-26 Seattle Genetics, Inc. Pyrrolobenzodiazepines
EP2750713B1 (en) 2011-10-14 2015-09-16 Spirogen Sàrl Pyrrolobenzodiazepines and conjugates thereof
CN110183470A (zh) 2011-10-14 2019-08-30 麦迪穆有限责任公司 吡咯并苯并二氮杂卓
BR112014009055B1 (pt) 2011-10-14 2021-12-14 Seattle Genetics, Inc. Compostos pirrolobenzodiazepinas, conjugados alvos, ligante de fármaco e uso dos ditos conjugados para tratar uma doença proliferativa
JP2013194140A (ja) 2012-03-19 2013-09-30 Fuji Xerox Co Ltd トナー用ポリエステル樹脂、静電荷像現像用トナー、静電荷像現像剤、トナーカートリッジ、プロセスカートリッジ、画像形成装置及び画像形成方法
WO2013164593A1 (en) 2012-04-30 2013-11-07 Spirogen Sàrl Pyrrolobenzodiazepines
CN104540827B (zh) 2012-04-30 2018-03-23 Ucl商业有限公司 吡咯并苯并二氮杂卓
WO2013177481A1 (en) 2012-05-25 2013-11-28 Immunogen, Inc. Benzodiazepines and conjugates thereof
SG11201500087VA (en) 2012-07-09 2015-02-27 Genentech Inc Immunoconjugates comprising anti-cd22 antibodies
JP2015523380A (ja) 2012-07-09 2015-08-13 ジェネンテック， インコーポレイテッド 抗ｃｄ７９ｂ抗体を含む免疫複合体
BR112015002193A2 (pt) 2012-08-02 2017-07-04 Genentech Inc anticorpos anti-etbr e imunoconjugados
EP2887965A1 (en) 2012-08-22 2015-07-01 ImmunoGen, Inc. Cytotoxic benzodiazepine derivatives
WO2014057072A1 (en) 2012-10-12 2014-04-17 Spirogen Sàrl Synthesis and intermediates of pyrrolobenzodiazepine derivatives for conjugation
MX364329B (es) 2012-10-12 2019-04-23 Medimmune Ltd Conjugados del anticuerpo pirrolobenzodiazepina.
ES2660029T3 (es) 2012-10-12 2018-03-20 Medimmune Limited Conjugados de anticuerpo-pirrolobenzodiazepinas
EP2906250B1 (en) 2012-10-12 2018-05-30 ADC Therapeutics SA Pyrrolobenzodiazepine-anti-psma antibody conjugates
WO2014057118A1 (en) 2012-10-12 2014-04-17 Adc Therapeutics Sarl Pyrrolobenzodiazepine-anti-cd22 antibody conjugates
CN105102068B (zh) 2012-10-12 2018-06-01 Adc疗法责任有限公司 吡咯并苯并二氮杂卓-抗体结合物
KR101819404B1 (ko) 2012-10-12 2018-02-28 메디뮨 리미티드 피롤로벤조디아제핀 및 그의 컨주게이트
AU2013328628B2 (en) 2012-10-12 2016-12-15 Adc Therapeutics Sa Pyrrolobenzodiazepine-anti-CD22 antibody conjugates
CA2885315C (en) 2012-10-12 2020-06-23 Spirogen Sarl Pyrrolobenzodiazepines and conjugates thereof
CA2887896A1 (en) 2012-10-12 2014-04-17 Adc Therapeutics Sarl Pyrrolobenzodiazepine-anti-her2 antibody conjugates
WO2014080251A1 (en) 2012-11-24 2014-05-30 Hangzhou Dac Biotech Co., Ltd. Hydrophilic linkers and their uses for conjugation of drugs to cell binding molecules
CA2894959C (en) 2012-12-21 2022-01-11 Spirogen Sarl Unsymmetrical pyrrolobenzodiazepines-dimers for use in the treatment of proliferative and autoimmune diseases
HUE043851T2 (hu) 2013-02-22 2019-09-30 Abbvie Stemcentrx Llc Anti-DLL3-antitest-PBD konjugátumok és alkalmazásuk
JP6444902B2 (ja) 2013-03-13 2018-12-26 メドイミューン・リミテッドＭｅｄＩｍｍｕｎｅ Ｌｉｍｉｔｅｄ ピロロベンゾジアゼピン及びその結合体
WO2014174111A1 (en) 2013-04-26 2014-10-30 Pierre Fabre Medicament Axl antibody-drug conjugate and its use for the treatment of cancer
NL2011583C2 (en) 2013-10-10 2015-04-13 Wwinn B V Module, system and method for detecting acoustical failure of a sound source.
US9950078B2 (en) 2013-10-11 2018-04-24 Medimmune Limited Pyrrolobenzodiazepine-antibody conjugates
EP3054984A1 (en) 2013-10-11 2016-08-17 Medimmune Limited Pyrrolobenzodiazepine-antibody conjugates
DE102013220528B4 (de) 2013-10-11 2015-05-07 Continental Automotive Gmbh Einspritzventil und Verfahren zum Betreiben eines Einspritzventils
US10010624B2 (en) 2013-10-11 2018-07-03 Medimmune Limited Pyrrolobenzodiazepine-antibody conjugates
GB201317981D0 (en) 2013-10-11 2013-11-27 Spirogen Sarl Pyrrolobenzodiazepines and conjugates thereof
GB201318069D0 (en) 2013-10-11 2013-11-27 Maersk Olie & Gas Seismic data processing method and apparatus
GB201317982D0 (en) 2013-10-11 2013-11-27 Spirogen Sarl Pyrrolobenzodiazepines and conjugates thereof
WO2015052535A1 (en) 2013-10-11 2015-04-16 Spirogen Sàrl Pyrrolobenzodiazepine-antibody conjugates
AU2014333776B2 (en) 2013-10-11 2021-01-28 Cellectis Methods and kits for detecting nucleic acid sequences of interest using DNA-binding protein domain
CA2931798C (en) 2013-12-16 2023-06-27 Genentech, Inc. Peptidomimetic compounds and antibody-drug conjugates thereof
GB201406767D0 (en) 2014-04-15 2014-05-28 Cancer Rec Tech Ltd Humanized anti-Tn-MUC1 antibodies anf their conjugates
CN106687141A (zh) 2014-09-10 2017-05-17 麦迪穆有限责任公司 吡咯并苯并二氮杂卓及其缀合物
AR101846A1 (es) 2014-09-12 2017-01-18 Genentech Inc Anticuerpos anti-cll-1 e inmunoconjugados
GB201416112D0 (en) 2014-09-12 2014-10-29 Medimmune Ltd Pyrrolobenzodiazepines and conjugates thereof
AU2015317653A1 (en) 2014-09-17 2017-04-06 Genentech, Inc. Pyrrolobenzodiazepines and antibody disulfide conjugates thereof

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011130616A1 (en) * 2010-04-15 2011-10-20 Spirogen Limited Pyrrolobenzodiazepines used to treat proliferative diseases
WO2014057113A1 (en) * 2012-10-12 2014-04-17 Adc Therapeutics Sarl Pyrrolobenzodiazepine - anti-psma antibody conjugates
WO2014096368A1 (en) * 2012-12-21 2014-06-26 Spirogen Sàrl Pyrrolobenzodiazepines and conjugates thereof
WO2014140862A2 (en) * 2013-03-13 2014-09-18 Spirogen Sarl Pyrrolobenzodiazepines and conjugates thereof
WO2014159981A2 (en) * 2013-03-13 2014-10-02 Spirogen Sarl Pyrrolobenzodiazepines and conjugates thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
S. C. JEFFREY ET. AL.: "A Potent Anti-CD70 Antibody-Drug Conjugate Combining a Dimeric Pyrrolobenzodiazepine Drug with Site-Specific Conjugation.", BIOCONJUGATE CHEMISTRY, vol. 24, 12 June 2013 (2013-06-12), pages 1256 - 1263, XP055124636, DOI: 10.1021/bc400217g *

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10188746B2 (en) 2014-09-10 2019-01-29 Medimmune Limited Pyrrolobenzodiazepines and conjugates thereof
WO2017201132A2 (en) 2016-05-18 2017-11-23 Mersana Therapeutics, Inc. Pyrrolobenzodiazepines and conjugates thereof
US11524969B2 (en) 2018-04-12 2022-12-13 Medimmune Limited Pyrrolobenzodiazepines and conjugates thereof as antitumour agents
WO2021080608A1 (en) 2019-10-25 2021-04-29 Medimmune, Llc Branched moiety for use in conjugates
WO2022053651A2 (en) 2020-09-10 2022-03-17 Precirix N.V. Antibody fragment against fap
WO2022228494A1 (zh) 2021-04-29 2022-11-03 上海汇连生物医药有限公司 抗体偶联药物的制备方法及应用
WO2022228495A1 (zh) 2021-04-29 2022-11-03 上海汇连生物医药有限公司 抗体偶联药物的制备方法及应用
WO2022228493A1 (zh) 2021-04-29 2022-11-03 上海汇连生物医药有限公司 抗体偶联药物的制备方法及应用
WO2023203135A1 (en) 2022-04-22 2023-10-26 Precirix N.V. Improved radiolabelled antibody
WO2023213801A1 (en) 2022-05-02 2023-11-09 Precirix N.V. Pre-targeting

Also Published As

Publication number Publication date
CN106687472A (zh) 2017-05-17
CN106687472B (zh) 2019-01-08
EP3191490A1 (en) 2017-07-19
JP6518321B2 (ja) 2019-05-22
EP3191490B1 (en) 2019-08-07
JP2017528467A (ja) 2017-09-28
US20170239365A1 (en) 2017-08-24
GB201416112D0 (en) 2014-10-29
US10420777B2 (en) 2019-09-24

Similar Documents

Publication Publication Date Title
US10420777B2 (en) Pyrrolobenzodiazepines and conjugates thereof
AU2014230735B2 (en) Pyrrolobenzodiazepines and conjugates thereof
EP2935268B1 (en) Pyrrolobenzodiazepines and conjugates thereof
JP6531166B2 (ja) ピロロベンゾジアゼピン及びそのコンジュゲート
AU2013366490B9 (en) Unsymmetrical pyrrolobenzodiazepines-dimers for use in the treatment of proliferative and autoimmune diseases
ES2931051T3 (es) Conjugados de pirrolobenzodiacepina y anticuerpo
CA3039832A1 (en) Pyrrolobenzodiazepine conjugates
EP3283120A1 (en) Site-specific antibody-drug conjugates

Legal Events

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

Ref document number: 15766215

Country of ref document: EP

Kind code of ref document: A1

REEP Request for entry into the european phase

Ref document number: 2015766215

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 2015766215

Country of ref document: EP

ENP Entry into the national phase

Ref document number: 2017513438

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE