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)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Molecular Biology (AREA)
• Genetics & Genomics (AREA)
• Proteomics, Peptides & Aminoacids (AREA)
• Biophysics (AREA)
• Biochemistry (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• Animal Behavior & Ethology (AREA)
• Pharmacology & Pharmacy (AREA)
• Immunology (AREA)
• Epidemiology (AREA)
• Cell Biology (AREA)
• Oncology (AREA)
• General Chemical & Material Sciences (AREA)
• Chemical Kinetics & Catalysis (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 That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Priority Applications (4)

Applications Claiming Priority (2)

Publications (1)

Family

ID=51869483

Family Applications (1)

Country Status (6)

Cited By (10)

Families Citing this family (16)

Citations (5)

Family Cites Families (390)

• 2014
  • 2014-09-12 GB GBGB1416112.9A patent/GB201416112D0/en not_active Ceased
• 2015
  • 2015-09-11 EP EP15766215.6A patent/EP3191490B1/en not_active Not-in-force
  • 2015-09-11 JP JP2017513438A patent/JP6518321B2/ja not_active Expired - Fee Related
  • 2015-09-11 US US15/510,345 patent/US10420777B2/en not_active Expired - Fee Related
  • 2015-09-11 WO PCT/GB2015/052629 patent/WO2016038383A1/en not_active Ceased
  • 2015-09-11 CN CN201580048691.5A patent/CN106687472B/zh not_active Expired - Fee Related

Patent Citations (5)

Non-Patent Citations (1)

Also Published As

Similar Documents

Legal Events