WO2017186894A1 - Pyrrolobenzodiazepine conjugates and their use for the treatment of cancer - Google Patents

Pyrrolobenzodiazepine conjugates and their use for the treatment of cancer Download PDF

Info

Publication number
WO2017186894A1
WO2017186894A1 PCT/EP2017/060150 EP2017060150W WO2017186894A1 WO 2017186894 A1 WO2017186894 A1 WO 2017186894A1 EP 2017060150 W EP2017060150 W EP 2017060150W WO 2017186894 A1 WO2017186894 A1 WO 2017186894A1
Authority
WO
WIPO (PCT)
Prior art keywords
antibody
genbank
seq
update date
record update
Prior art date
Application number
PCT/EP2017/060150
Other languages
French (fr)
Inventor
Philip Wilson Howard
Thais CAILLEAU
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 US16/096,631 priority Critical patent/US10543279B2/en
Priority to EP17721108.3A priority patent/EP3448858A1/en
Publication of WO2017186894A1 publication Critical patent/WO2017186894A1/en

Links

Classifications

    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/545—Heterocyclic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/32—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against translation products of oncogenes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered

Definitions

  • the present invention relates to conjugates comprising a specific pyrrolobenzodiazepine (PBD), and the precursor drug linker used to make such conjugates.
  • PBD specific pyrrolobenzodiazepine
  • PBDs pyrrolobenzodiazepines
  • the PBD dimers are thought to form sequence-selective DNA lesions such as the palindromic 5'-Pu-GATC-Py-3' interstrand cross-link (Smellie, M., et al., Biochemistry, 42, 8232-8239 (2003); Martin, C, et al, Biochemistry, 44, 4135-4147) which is thought to be mainly responsible for their biological activity.
  • sequence-selective DNA lesions such as the palindromic 5'-Pu-GATC-Py-3' interstrand cross-link (Smellie, M., et al., Biochemistry, 42, 8232-8239 (2003); Martin, C, et al, Biochemistry, 44, 4135-4147) which is thought to be mainly responsible for their biological activity.
  • -136 One example of -136):
  • Dimeric PBD compounds bearing C2 aryl substituents, such as SG2202 (ZC-207), are disclosed in WO 2005/085251 :
  • WO2010/043880 discloses PBD dimers bearing a anchor for the attachment of another moiety
  • WO201 1/130613 discloses the use of such modified PBD dimers in antibody drug conjugates.
  • SGN-CD33A is undergoing clinical trials in patients with CD33-Postiive Acute Myeloid Leukemia (AML).
  • AML CD33-Postiive Acute Myeloid Leukemia
  • the pre-clinical development of SGN-CD33A is described in Kung Sutherland, M., et al., Blood, 2013; 122(8) 1455-1463 (doi:10.1 182/blood-2013-03- 491506).
  • An initial report of the clinical trials was provided at the 56 th ASH Annual Meeting, 6-9 December 2014 (Stein, E., et al., Session 616 - Abstract 623).
  • the present inventors have developed a further drug linker and conjugate comprising said drug linker.
  • This drug linker has an additional aromatic fluoro atom on the C2
  • conjugates of the newly developed drug linker appear to show a reduced activity in vitro to those including the drug linker from SGN-CD33A, which would discourage further testing, but a surprising comparable in vivo activity.
  • L is a Li and unit (i.e., a targeting agent), D is a Drug Linker unit of formula II:
  • p is an integer of from 1 to 20.
  • the Ligand unit is a targeting agent that binds to a target moiety.
  • the Ligand unit can, for example, specifically bind to a cell component (a Cell Binding Agent) or to other target molecules of interest.
  • the Ligand unit can be, for example, a protein, polypeptide or peptide, such as an antibody, an antigen-binding fragment of an antibody, or other binding agent, such as an Fc fusion protein.
  • a second as ect of the present invention provides a compound of formula III:
  • a third aspect of the present invention provides the use of a conjugate of the first aspect of the invention in the manufacture of a medicament for treating a proliferative disease.
  • the third aspect also provides a conjugate of the first aspect of the invention for use in the treatment of a proliferative disease.
  • the third aspect also provides a method of treating a proliferative disease comprising administering a therapeutically effective amount of a conjugate of the first aspect of the invention to a patient in need thereof.
  • a fourth aspect of the present invention provides the synthesis of a conjugate of the first aspect of the invention comprising conjugating a compound (drug linker) of the second aspect of the invention with a Ligand Unit.
  • Figure 1 shows the effect on volume of a NCI-N87 tumour following treatment with a conjugate of the present invention
  • Figure 2 shows the effect on volume of a JIMT-1 tumour following treatment with a conjugate of the present invention
  • Figure 3 shows the effect on volume of a BT474 tumour following treatment with a conjugate of the present invention.
  • the Ligand Unit may be of any kind, and include a protein, polypeptide, peptide and a non- peptidic agent that specifically binds to a target molecule.
  • the Ligand unit may be a protein, polypeptide or peptide.
  • the Ligand unit may be a cyclic polypeptide.
  • These Ligand units can include antibodies or a fragment of an antibody that contains at least one target molecule-binding site, lymphokines, hormones, growth factors, or any other cell binding molecule or substance that can specifically bind to a target.
  • telomere binding refers to the binding of an antibody or other protein, polypeptide or peptide to a predetermined molecule (e.g., an antigen).
  • the antibody or other molecule binds with an affinity of at least about 1 x10 7 M "1 , and binds to the predetermined molecule with an affinity that is at least two-fold greater than its affinity for binding to a non-specific molecule (e.g., BSA, casein) other than the predetermined molecule or a closely-related molecule.
  • a non-specific molecule e.g., BSA, casein
  • Ligand units include those agents described for use in WO 2007/085930, which is incorporated herein.
  • the Ligand unit is a Cell Binding Agent that binds to an extracellular target on a cell.
  • a Cell Binding Agent can be a protein, polypeptide, peptide or a non- peptidic agent.
  • the Cell Binding Agent may be a protein, polypeptide or peptide.
  • the Cell Binding Agent may be a cyclic polypeptide.
  • the Cell Binding Agent also may be antibody or an antigen-binding fragment of an antibody.
  • the present invention provides an antibody-drug conjugate (ADC).
  • ADC antibody-drug conjugate
  • 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 cell binding molecule or substance.
  • the cell binding agent is a linear or cyclic peptide comprising 4-30, preferably 6-20, contiguous amino acid residues. In this embodiment, it is preferred that one cell binding agent is linked to one monomer or dimer pyrrolobenzodiazepine compound.
  • the cell binding agent comprises a peptide that binds integrin ⁇ ⁇ ⁇ 6.
  • the peptide may be selective for ⁇ ⁇ ⁇ 6 over XYS.
  • the cell binding agent comprises the A20FMDV-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.
  • the polypeptide may have the sequence
  • 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 et al (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. (Janeway, C, Travers, P., Walport, M., Shlomchik (2001 ) Immuno Biology, 5th Ed., Garland Publishing, New York).
  • 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 immunospecifically binds an antigen of a target of interest or part thereof, such targets including but not limited to, cancer cell or cells that produce autoimmune antibodies associated with an autoimmune disease.
  • the immunoglobulin can be of any type (e.g.
  • 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 immunospecifically bind to cancer cell antigens, viral antigens or microbial antigens, single-chain antibody molecules; and multispecific antibodies formed from antibody fragments.
  • the term "monoclonal antibody” as used herein 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 synthesized uncontaminated by other antibodies.
  • the modifier "monoclonal" indicates the character of the antibody as being obtained from a substantially
  • the monoclonal antibodies to be used in accordance with the present invention may be made by the hybridoma method first described by Kohler et al (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 4816567; 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.
  • a non-human primate e.g. Old World Monkey or Ape
  • human constant region sequences e.g. Old World Monkey or Ape
  • 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 CH3.
  • 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 C1 q binding; complement dependent cytotoxicity; Fc receptor binding; antibody-dependent cell-mediated cytotoxicity (ADCC); phagocytosis; and down regulation of cell surface receptors such as B cell 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., lgG1 , 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.
  • the expression “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.
  • the expression “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.
  • CDR grafting There are a range of humanisation techniques, including 'CDR grafting', 'guided selection', 'deimmunization', 'resurfacing' (also known as 'veneering'), 'composite antibodies', 'Human String Content Optimisation' and framework shuffling.
  • CDR grafting includes '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).
  • 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 binding).
  • humanized antibodies can comprise residues that are found neither in the recipient antibody nor in the imported CDR or framework sequences.
  • 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 VH or Vi_ domain of a given non-human antibody specific for a particular epitope with a human VH or Vi_ 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 cell 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-cell epitopes from the V regions of the therapeutic antibody (or other molecule).
  • the therapeutic antibodies V-region sequence is analysed for the presence of MHC 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 MHC 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-cell 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:
  • variable region of the non-human (e.g. rodent) antibody (or fragment thereof) by constructing a three-dimensional model of the non-human antibody variable region
  • 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).
  • 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-cell 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
  • the CDRs of the non-human antibody are fused in-frame to cDNA pools encompassing all 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).
  • cell binding agents include those agents described for use in
  • Tumour-associate antigens and cognate antibodies for use in embodiments of the present invention are listed below.
  • BMPR1B bone morphogenetic protein receptor-type IB
  • WO2002/92836 (Claim 6; Fig 12); WO2002/83866 (Claim 15; Page 1 16-121 );
  • MPF MPF, MSLN, SMR, megakaryocyte potentiating factor, mesothelin
  • Napi3b (NAPI-3B, NPTIIb, SLC34A2, solute carrier family 34 (sodium phosphate), member 2, type II sodium-dependent phosphate transporter 3b)
  • Sema 5b (FLJ10372, KIAA1445, Mm.42015, SEMA5B, SEMAG, Semaphorin 5b Hlog, 25 sema domain, seven thrombospondin repeats (type 1 and type 1-like), transmembrane domain (TM) and short cytoplasmic domain, (semaphorin) 5B)
  • 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 1 1 ); Accession: 30 Q9P283; Genew; HGNC:10737
  • PSCA hlg (2700050C12Rik, C530008O16Rik, RIKEN cDNA 2700050C12, RIKEN cDNA
  • Genbank record update date Mar 1 1 , 2010 02:26 AM
  • WO2004/048938 Example 2; WO2004/040000 (Claim 151); WO2003/087768 (Claim 1); 20 WO2003/016475 (Claim 1); WO2003/016475 (Claim 1); WO2002/61087 (Fig 1);
  • 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); LocuslD:54894.
  • STEAP2 (HGNC_8639, IPCA-1, PCANAP1, STAMP1, STEAP2, STMP, prostate cancer
  • 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
  • WO2003/104270 (Claim 1 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 (Claim 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 1 1 :27 AM
  • WO2003/042661 (Claim 12); WO2002/30268 (Claim 27; Page 391 ); US2003/219806 (Claim 4); WO2001/62794 (Claim 14; Fig 1A-D); MIM:606936.
  • CD21 CR2 (Complement receptor 2) or C3DR (C3d/Epstein Barr virus receptor) or Hs.73792)
  • WO2004/045520 (Example 4); US2004/005538 (Example 1 ); WO2003/062401 (Claim 9); WO2004/045520 (Example 4); WO91/02536 (Fig 9.1 -9.9); WO2004/020595 (Claim 1 ); Accession: P20023; Q13866; Q14212; EMBL; M26004; AAA35786.1 .
  • CD79b (CD79B, CD79 , IGb (immunoglobulin-associated beta), B29)
  • Genbank record update date Jun 26, 2012 01 :53 PM
  • Genbank record update date Jun 26, 2012 01 :53 PM
  • FcRH2 (IFGP4, IRTA4, SPAP1A (SH2 domain containing phosphatase anchor protein 5 1a), SPAP1B, SPAP1C)
  • WO2004/016225 (Claim 2); WO2003/077836; WO2001/38490 (Claim 5; Fig 18D-1 -18D-2); WO2003/097803 (Claim 12);
  • WO2003/089904 (Claim 9); WO2003/016475 (Claim 1 ); US2003/1 18592; WO2003/008537 (Claim 1 ); WO2003/055439 (Claim 29; Fig 1 A-B); WO2003/025228 (Claim 37; Fig 5C); 20 WO2002/22636 (Example 13; Page 95-107); WO2002/12341 (Claim 68; Fig 7);
  • WO2002/13847 (Page 71 -74); WO2002/14503 (Page 1 14-1 17); WO2001/53463 (Claim 2; Page 41 -46); WO2001/41787 (Page 15); WO2000/44899 (Claim 52; Fig 7);
  • 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 all six CDR's from an antibody selected from the group consisting of BIIB71 F10 (SEQ ID NOs:1 1 , 13), BIIB69A09 (SEQ ID NOs:15, 17); BIIB67F10 (SEQ ID NOs:19, 21 ); BIIB67F1 1 (SEQ ID NOs:23, 25), BIIB66A12 (SEQ ID NOs:27, 29), BIIB66C01
  • an antibody comprising the variable light and variable heavy amino acid sequences in SEQ ID Nos. 3 and 4, respectively, for example, an antibody comprising a light chain amino acid sequence selected from SEQ ID No. 15 and 23, and a heavy chain amino acid sequence selected from SEQ ID No. 16 and 24
  • an antibody comprising the amino acid sequence in SEQ ID No. 23, or a deamidated and/or oxidized variant thereof.
  • an antibody having a light chain variable domain comprising the hypervariable regions of SEQ ID NO: 1 ".
  • an antibody having a heavy chain variable domain For example, an antibody having a heavy chain variable domain
  • WO2002/86443 (Claim 27; Page 427); WO2002/60317 (Claim 2); Accession: P40199;
  • EphB2R (DRT, ERK, Hek5, EPHT3, Tyro5)
  • WO2002/102235 (Claim 13; Page 299); US2003/091580 (Example 2); WO2002/10187 (Claim 6; Fig 10); WO2001/94641 (Claim 12; Fig 7b); WO2002/02624 (Claim 13; Fig 1A- 1 B); US2002/034749 (Claim 54; Page 45-46); WO2002/06317 (Example 2; Page 320-321 , Claim 34; Page 321 -322); WO2002/71928 (Page 468-469); WO2002/02587 (Example 1 ; Fig 1 ); WO2001/40269 (Example 3; Pages 190-192); WO2000/36107 (Example 2; Page 205-207); WO2004/053079 (Claim 12); WO2003/004989 (Claim 1 ); WO2002/71928 (Page 233-234, 452-453); WO 01/16318.
  • PSCA Prostate stem cell antigen precursor
  • Genbank record update date Feb 1 , 201 1 1 1 :25 AM Polypeptide
  • Genbank record update date Feb 1 , 201 1 1 1 :25 AM Cross references
  • WO2001/40309 (Example 1 ; Fig 17); US2001/055751 (Example 1 ; Fig 1 b); WO2000/32752 (Claim 18; Fig 1 ); WO98/51805 (Claim 17; Page 97); W098/51824 (Claim 10; Page 94); WO98/40403 (Claim 2; Fig 1 B); Accession: 043653; EMBL; AF043498; AAC39607.1 (25) GEDA
  • Genbank record update date Mar 1 1 , 2010 02:24 AM Polypeptide
  • AP14954 lipoma HMGIC fusion-partnerlike protein /pid AAP14954.1 - Homo sapiens (human); WO2003/054152 (Claim 20); WO2003/000842 (Claim 1 ); WO2003/023013 (Example 3, Claim 20); US2003/194704 (Claim 45); Gl:30102449; (26) BAFF-R (B cell -activating factor receptor, BLyS receptor 3, BR3)
  • BAFF receptor /pid NP_443177.1 - Homo sapiens: Thompson, J.S., et al Science 293 (5537), 2108-21 1 1 (2001 ); WO2004/058309; WO2004/01 161 1 ; WO2003/045422
  • 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 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-cell receptor CD22 B-lymphocyte cell adhesion molecule
  • B-lymphocyte cell adhesion molecule B-lymphocyte cell adhesion molecule
  • CAM CD22 antigen
  • T-cell surface antigen Leu-14 sialic acid binding Ig-like lectin 2
  • CD79a (CD79A, CD79alpha), immunoglobulin-associated alpha, a B cell-specific protein that covalently interacts with Ig beta (CD79B) and forms a complex on the surface with Ig M
  • CXCR5 Bokitt's lymphoma receptor 1, a G protein-coupled receptor that is activated by the CXCL13 chemokine, functions in lymphocyte migration and humoral defense, plays a
  • HLA-DOB Beta subunit of MHC class II 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 ligand-gated ion channel 5, an ion channel gated by extracellular ATP, may be involved in synaptic transmission and neurogenesis, deficiency may contribute to the pathophysiology of idiopathic detrusor instability
  • 422 aa) pi: 7.63
  • CD72 B-cell differentiation antigen CD72, Lyb-2
  • Genbank record update date Jun 26, 2012 01 :43 PM
  • IRTA2 Immunoglobulin superfamily receptor translocation associated 2, a putative immunoreceptor with possible roles in B cell development and lymphomagenesis
  • Genbank record update date Mar 1 1 , 2010 01 :16 AM
  • Genbank record update date Mar 1 1 , 2010 01 :16 AM
  • TENB2 (TMEFF2, tomoregulin, TPEF, HPP1, TR, putative transmembrane
  • 35 proteoglycan related to the EGF/heregulin family of growth factors and follistatin); 374 aa)
  • Genbank record update date Mar 1 1 , 2010 01 :05 AM Polypeptide
  • Genbank record update date Mar 1 1 , 2010 01 :05 AM
  • PSMA - FOLH1 Falate hydrolase (prostate-specific membrane antigen) 1
  • N-acetylated alpha-linked acidic dipeptidase 1 N-acetylated-alpha- linked acidic dipeptidase I; NAALADase I; cell growth-inhibiting gene 27 protein; folylpoly- gamma-glutamate carboxypeptidase; glutamate carboxylase II; glutamate carboxypeptidase 2; glutamate carboxypeptidase II; membrane glutamate
  • 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, 3E1 1 , 17G1 , 29B4, 30C1 and 20F2 (US 7,81 1 ,564; Moffett S., et al Hybridoma (Larc mt). 2007
  • Cytogen monoclonal antibodies 7E1 1 -C5 (ATCC accession No. HB 10494) and 9H10-A4 (ATCC accession No. HB1 1430) - US 5,763,202
  • Mouse anti-PSMA antibodies include the 3F5.4G6, 3D7.1 .1 , 4E10-1 .14, 3E1 1 , 4D8, 3E6, 3C9, 2C7, 1 G3, 3C4, 3C6, 4D4, 1 G9, 5C8B9, 3G6, 4C8B9, and monoclonal antibodies.
  • Hybridomas secreting 3F5.4G6, 3D7.1 .1 , 4E10-1 .14, 3E1 1 , 4D8, 3E6, 3C9, 2C7, 1 G3, 3C4, 3C6, 4D4, 1 G9, 5C8B9, 3G6 or 4C8B9 have been publicly deposited and are described in U.S. Pat. No. 6,159,508.
  • 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 J591 , are described in further detail in PCT Publication WO 02/098897.
  • Other 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 al. (2003) Int. J. Urol. 10:439-444).
  • human anti-PSMA monoclonal antibodies include the 4A3, 7F12, 8C12, 8A1 1 , 16F9, 2A10, 2C6, 2F5 and 1 C3 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. 60/654,125, entitled “Human Monoclonal Antibodies to Prostate Specific Membrane Antigen (PSMA)", filed on Feb. 18, 2005.
  • the V.sub.H amino acid sequences of 4A3, 7F12, 8C12, 8A1 1 , 16F9, 2A10, 2C6, 2F5 and 1 C3 are shown in SEQ ID NOs: 1 -9, respectively.
  • the V.sub.L amino acid sequences of 4A3, 7F12, 8C12, 8A1 1 , 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 cell line selected from the group consisting of 3F5.4G6 having ATCC accession number HB12060, 3D7-1 .1, having ATCC accession number HB12309, 4E10-1.14 having ATCC accession number HB12310, 3E1 1 (ATCC HB12488), 4D8 (ATCC HB12487), 3E6 (ATCC HB12486), 3C9 (ATCC HB12484), 2C7 (ATCC
  • HB12490 1 G3 (ATCC HB12489), 3C4 (ATCC HB12494), 3C6 (ATCC HB12491 ), 4D4 (ATCC HB12493), 1 G9 (ATCC HB12495), 5C8B9 (ATCC HB12492) and 3G6 (ATCC HB12485) - see US 6,150,508 PSMA Development Company / Progenies / Cytogen - Seattle Genetics: mAb 3.9, produced by the hybridoma deposited under ATCC Accession No. PTA-3258 or mAb 10.3, produced by the hybridoma deposited under ATCC Accession No. PTA-3347 - US
  • antigen identified by monoclonal antibody L230 integrin alpha-V; integrin alphaVbeta3; 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, 7.1 G10, 7.7G5, or 7.1 C5.
  • CEACAM5 Carcinoembryonic antigen-related cell adhesion molecule 5
  • CDRs complementarity determining regions
  • heavy chain CDR1 - DNYMH, CDR2 - WIDPENGDTE YAPKFRG, CDR3 - LIYAGYLAMD Y; and light chain
  • an antibody having CDRs of the light chain variable region comprise: CDR1 comprises KASQDVGTSVA (SEQ ID NO: 20); CDR2 comprises WTSTRHT (SEQ ID NO: 21 ); and CDR3 comprises QQYSLYRS (SEQ ID NO: 22);
  • CDR1 comprises TYWMS (SEQ ID NO: 23);
  • CDR2 comprises EIHPDSSTINYAPSLKD (SEQ ID NO: 24); and
  • CDR3 comprises LYFGFPWFAY (SEQ ID NO: 25).
  • Genbank record update date Mar 6, 2012 1 1 :12 AM
  • Genbank record update date Mar 6, 2012 1 1 :12 AM
  • 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
  • ATCC American Type Culture Collection
  • an antibody comprising the sequences of CDR1 , CDR2 and CDR3 of heavy chain 4687, 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-MAB GT-MAB 2.5-GEX (Website:
  • antibody MJ-170 hybridoma cell line MJ-170 ATCC
  • Genbank record update date Feb 2, 201 1 10:15 AM
  • Genbank record update date Feb 2, 201 1 10:15 AM
  • CAIX, MN Other Designations: CA-IX; P54/58N; RCC-associated antigen G250; RCC-associated protein G250; carbonate dehydratase IX; carbonic anhydrase 9; carbonic dehydratase; membrane antigen MN; pMW1 ; renal cell carcinoma-associated antigen G250 ANTIBODIES
  • Affibody Anti-CAIX Affibody molecules
  • BCCM Belgian Coordinated Collection of Microorganisms
  • LMBP Laboratorium voor Mole Diagram Bioloqie-Plasmidencollectie
  • EGFRvlll Epidermal growth factor receptor (EGFR), transcript variant 3,
  • an antibody comprising a heavy chain amino acid sequence comprising:
  • CDR1 consisting of a sequence selected from the group consisting of the amino acid sequences for the CDR1 region of antibodies 13.1 .2 (SEQ ID NO: 138), 131 (SEQ ID NO: 2), 170 (SEQ ID NO: 4), 150 (SEQ ID NO: 5), 095 (SEQ ID NO: 7), 250 (SEQ ID NO: 9), 139 (SEQ ID NO: 10), 21 1 (SEQ ID NO: 12), 124 (SEQ ID NO: 13), 318 (SEQ ID NO: 15), 342 (SEQ ID NO: 16), and 333 (SEQ ID NO: 17);
  • CDR2 consisting of a sequence selected from the group consisting of the amino acid sequences for the CDR2 region of antibodies 13.1 .2 (SEQ ID NO: 138), 131 (SEQ ID NO: 2), 170 (SEQ ID NO: 4), 150 (SEQ ID NO: 5), 095 (SEQ ID NO: 7),
  • CDR3 consisting of a sequence selected from the group consisting of the amino acid sequences for the CDR3 region of antibodies 13.1 .2 (SEQ ID NO: 138), 131
  • SEQ ID NO: 2 170 (SEQ ID NO: 4), 150 (SEQ ID NO: 5), 095 (SEQ ID NO: 7), 250 (SEQ ID NO: 9), 139 (SEQ ID NO: 10), 21 1 (SEQ ID NO: 12), 124 (SEQ ID NO: 13), 318 (SEQ ID NO: 15), 342 (SEQ ID NO: 16), and 333 (SEQ ID NO: 17).
  • an antibody having at least one of the heavy or light chain having at least one of the heavy or light chain
  • polypeptides comprises an amino acid sequence that is at least 90% identical to the amino acid sequence selected from the group consisting of: SEQ ID NO: 2, SEQ ID NO: 19, SEQ ID NO: 142, SEQ ID NO: 144, and any combination thereof.
  • polypeptide wherein at least one of the heavy or light chain polypeptides comprises an amino acid sequence that is at least 90% identical to the amino acid sequence selected from the group consisting of: SEQ ID NO: 2, SEQ ID NO: 19, SEQ ID NO: 142, SEQ ID NO: 144, and any combination thereof.
  • an antibody heavy chain amino acid sequence selected from the group consisting of the heavy chain amino acid sequence of antibody 13.1 .2 (SEQ ID NO: 138), 131 (SEQ ID NO: 2), 170 (SEQ ID NO: 4), 150 (SEQ ID NO: 5), 095 (SEQ ID NO: 7), 250 (SEQ ID NO: 9), 139 (SEQ ID NO: 10), 21 1 (SEQ ID NO: 12), 124 (SEQ ID NO: 13), 318 (SEQ ID NO: 15), 342 (SEQ ID NO: 16), and 333 (SEQ ID NO: 138), 131 (SEQ ID NO: 2), 170 (SEQ ID NO: 4), 150 (SEQ ID NO: 5), 095 (SEQ ID NO: 7), 250 (SEQ ID NO: 9), 139 (SEQ ID NO: 10), 21 1 (SEQ ID NO: 12), 124 (SEQ ID NO: 13), 318 (SEQ ID NO: 15), 342 (SEQ ID NO: 16), and 333 (SEQ ID NO:
  • a variant antibody having the sequence of SEQ ID NO.18 with the substitutions S98P-T99Y in the CDR3 VH, and F92W in CDR3 VL.
  • SEQ ID NO:9 for antibody heavy chain variable region SEQ ID NO:9 for antibody heavy chain variable region
  • SEQ ID NO:9 for antibody heavy chain variable region SEQ ID NO:9 for antibody heavy chain variable region
  • SEQ ID NOs: 3 & 9 for light chain and heavy chain respectively
  • CD33 (CD33 molecule)
  • CD33 antigen gp67
  • gp67 myeloid cell surface antigen CD33
  • sialic acid binding Ig-like lectin 3 sialic acid-binding Ig-like lectin
  • an antibody or fragment thereof comprising a heavy chain variable region which comprises three CDRs having the amino acid sequences of SEQ ID NOs:1 -3 and a light chain variable region comprising three CDRs having the amino acid sequences of SEQ ID NOs:4-6.
  • B-lymphocyte antigen CD19 B-lymphocyte surface antigen B4; T-cell surface antigen Leu-12; differentiation antigen CD19 ANTIBODIES
  • an antibody comprising the sequence of hA19Vk (SEQ ID NO:7) and the sequence of hA19VH (SEQ ID NO:10) US7,902,338 (Immunomedics)
  • an antibody or antigen-binding fragment thereof that comprises the light chain complementarity determining region CDR sequences CDR1 of SEQ ID NO: 16 (KASQSVDYDGDSYLN); CDR2 of SEQ ID NO: 17 (DASNLVS); and CDR3 of SEQ ID NO: 18 (QQSTEDPWT) and the heavy chain CDR sequences CDR1 of SEQ ID NO: 16 (KASQSVDYDGDSYLN); CDR2 of SEQ ID NO: 17 (DASNLVS); and CDR3 of SEQ ID NO: 18 (QQSTEDPWT) and the heavy chain CDR sequences CDR1 of SEQ ID NO: 16 (KASQSVDYDGDSYLN); CDR2 of SEQ ID NO: 17 (DASNLVS); and CDR3 of SEQ ID NO: 18 (QQSTEDPWT) and the heavy chain CDR sequences CDR1 of SEQ ID NO: 16 (KASQSVDYDGDSYLN); CDR2 of SEQ ID NO: 17 (DA
  • SEQ ID NO: 19 SYWMN
  • CDR2 of SEQ ID NO: 20 QIWPGDGDTNYNGKFKG
  • CDR3 of SEQ ID NO: 21 RETTTVGRYYYAMDY
  • FR human antibody framework
  • substituted FR residues comprise the substitution of serine for phenylalanine at Kabat residue 91 of the heavy chain variable region.
  • MorphoSys /Xencor MOR-208/XmAb-5574 - Zalevsky J., et al Blood. 2009 Apr
  • IL2RA Interleukin 2 receptor, alpha
  • NCBI Reference Sequence NM_000417.2
  • FIL-2 receptor subunit alpha IL-2-RA; IL-2R subunit alpha; IL2-RA; TAC antigen; interleukin-2 receptor subunit alpha; p55 ANTIBODIES
  • an antibody having an antigen binding site comprises at least one domain which comprises CDR1 having the amino acid sequence in SEQ. ID. NO: 7,
  • CDR2 having the amino acid sequence in SEQ. ID. NO: 8, and CDR3 chaving the amino acid sequence in SEQ. ID. NO: 9; or said CDR1 , CDR2 and CDR3 taken in sequence as a whole comprise an amino acid sequence which is at least 90% identical to SEQ. ID. NOs: 7, 8 and 9 taken in sequence as a whole.
  • AXL AXL receptor tyrosine kinase
  • CD30 - TNFRSF8 Tumor necrosis factor receptor superfamily, member 8
  • CD30L receptor CD30L receptor
  • Ki-1 antigen CD30
  • cytokine receptor CD30 lymphocyte activation antigen CD30
  • lymphocyte activation antigen CD30 CD30
  • tumor necrosis factor receptor superfamily member 8 511
  • BCMA B-cell maturation antigen
  • TNFRSF17 Tumor necrosis factor receptor superfamily, member 17
  • Genbank record update date Feb 02, 201 1 10:40 AM
  • Genbank record update date Feb 02, 201 1 10:40 AM
  • B cell maturation antigen B-cell maturation factor
  • B-cell maturation protein B-cell maturation protein
  • CD174 (Lewis Y) - FUT3 (fucosyltransferase 3 (galactoside 3(4)-L-fucosyltransf erase, Lewis blood group)
  • CLEC14A C-type lectin domain family 14, member A; Genbank accession no. NM175060
  • Genbank record update date Apr 01 , 2012 03:34 PM
  • Genbank record update date Apr 01 , 2012 03:34 PM
  • C-type lectin domain family 14 member A CIECT and EGF-like domain containing protein
  • epidermal growth factor receptor 5 CIECT and EGF-like domain containing protein
  • GRP78 - HSPA5 heat shock lOkDa protein 5 (glucose-regulated protein, 78kDa) Nucleotide
  • CD27 ligand CD27-L; CD70 antigen; Ki-24 antigen; surface antigen CD70; tumor necrosis factor (ligand) superfamily, member 7; tumor necrosis factor ligand superfamily member 7 ANTIBODIES
  • pyrophosphatase 3 dJ914N13.3 (phosphodiesterase l/nucleotide pyrophosphatase 3); ectonucleotide pyrophosphatase/phosphodiesterase family member 3; gp130RB13-6; phosphodiesterase I beta; phosphodiesterase l/nucleotide pyrophosphatase 3;
  • Genbank record update date Sep 02, 2012 01 :50 PM
  • Genbank record update date Sep 02, 2012 01 :50 PM

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Immunology (AREA)
  • Oncology (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Peptides Or Proteins (AREA)

Abstract

A conjugate of formula (I): L -(DL)p, wherein L is a Ligand unit, D is a Drug Linker unit of formula (II), wherein p is an integer of from 1 to 20.

Description

PYRROLOBENZODIAZEPINE CONJUGATES AND THEIR USE FOR THE TREATMENT OF CANCER
The present invention relates to conjugates comprising a specific pyrrolobenzodiazepine (PBD), and the precursor drug linker used to make such conjugates.
Background to the invention
Some pyrrolobenzodiazepines (PBDs) have the ability to recognise and bond to specific sequences of DNA; the preferred sequence is PuGPu. The first PBD antitumour antibiotic, anthramycin, was discovered in 1965 (Leimgruber, et al., J. Am. Chem. Soc, 87, 5793- 5795 (1965); Leimgruber, et al., J. Am. Chem. Soc, 87, 5791 -5793 (1965)). Since then, a number of naturally occurring PBDs have been reported, and over 10 synthetic routes have been developed to a variety of analogues (Thurston, et al., Chem. Rev. 1994, 433-465 (1994)). Family members include abbeymycin (Hochlowski, 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 a/., Chem. Brit, 26, 767-772 (1990); Bose, et al., Tetrahedron, 48, 751 -758 (1992)), mazethramycin (Kuminoto, et al., J. Antibiotics, 33, 665-667 (1980)), neothramycins A and B (Takeuchi, et al., J. Antibiotics, 29, 93-96 (1976)), porothramycin (Tsunakawa, et al., J. Antibiotics, 41 , 1366-1373 (1988)), prothracarcin (Shimizu, et al, J. Antibiotics, 29, 2492-2503 (1982); Langley and Thurston, J. Org. Chem., 52, 91 -97 (1987)), sibanomicin (DC-102)(Hara, et al., J. Antibiotics, 41 , 702-704 (1988); Itoh, et al., J. Antibiotics, 41 , 1281 -1284 (1988)), sibiromycin (Leber, et al., J. Am. Chem. Soc, 110, 2992-2993 (1988)) and tomamycin (Arima, et al., J. Antibiotics, 25, 437-444 (1972)). PBDs are of the general structure:
Figure imgf000002_0001
They differ in the number, type and position of substituents, in both their aromatic A rings and pyrrolo C rings, and in the degree of saturation of the C ring. In the B-ring there is either an imine (N=C), a carbinolamine(NH-CH(OH)), or a carbinolamine methyl ether (NH- CH(OMe)) at the N 10-C1 1 position which is the electrophilic centre responsible for alkylating DNA. All of the known natural products have an (S)-configuration at the chiral C1 1 a position which 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 III. Springer-Verlag, New York, pp. 3-1 1 (1975); Hurley and Needham- VanDevanter, Acc. Chem. Res., 19, 230-237 (1986)). Their ability to form an adduct in the minor groove, enables them to interfere with DNA processing, hence their use as antitumour agents.
It has been previously disclosed that the biological activity of this molecules can be potentiated by joining two PBD units together through their C8/C'-hydroxyl functionalities via a flexible alkylene linker (Bose, D.S., et al., J. Am. Chem. Soc, 114, 4939-4941 (1992); Thurston, D.E., et al., J. Org. Chem., 61 , 8141 -8147 (1996)). The PBD dimers are thought to form sequence-selective DNA lesions such as the palindromic 5'-Pu-GATC-Py-3' interstrand cross-link (Smellie, M., et al., Biochemistry, 42, 8232-8239 (2003); Martin, C, et al, Biochemistry, 44, 4135-4147) which is thought to be mainly responsible for their biological activity. One example of -136):
Figure imgf000003_0001
(Gregson, S., et al., J. Med. Chem., 44, 737-748 (2001 ); Alley, M.C., et al., Cancer Research, 64, 6700-6706 (2004); Hartley, J.A., et al., Cancer Research, 64, 6693-6699 (2004)) which has been involved in clinical trials as a standalone agent, for example, NCT02034227 investigating its use in treating Acute Myeloid Leukemia and Chronic Lymphocytic Leukemia (see: https://www.clinicaltrials.gov/ct2/show/NCT02034227).
Dimeric PBD compounds bearing C2 aryl substituents, such as SG2202 (ZC-207), are disclosed in WO 2005/085251 :
Figure imgf000003_0002
and in WO2006/1 1 1759, bisulphites of such PBD compounds, for example SG2285 (ZC-
Figure imgf000004_0001
These compounds have been shown to be highly useful cytotoxic agents (Howard, P.W., et ai, Bioorg. Med. Chem. (2009), doi: 10.1016/j.bmcl.2009.09.012).
WO2010/043880 discloses PBD dimers bearing a anchor for the attachment of another moiety, and WO201 1/130613 discloses the use of such modified PBD dimers in antibody drug conjugates. One of the conjugates disclosed, that comprising:
Figure imgf000004_0002
(termed SGN-CD33A) is undergoing clinical trials in patients with CD33-Postiive Acute Myeloid Leukemia (AML). The pre-clinical development of SGN-CD33A is described in Kung Sutherland, M., et al., Blood, 2013; 122(8) 1455-1463 (doi:10.1 182/blood-2013-03- 491506). An initial report of the clinical trials was provided at the 56th ASH Annual Meeting, 6-9 December 2014 (Stein, E., et al., Session 616 - Abstract 623).
More recent publications have described the following conjugates comprising PBD dimers, for example, WO2014/057073 describes:
Figure imgf000004_0003
Figure imgf000005_0001
Figure imgf000005_0002
Figure imgf000005_0003
Figure imgf000005_0004
Disclosure of the invention
The present inventors have developed a further drug linker and conjugate comprising said drug linker. This drug linker has an additional aromatic fluoro atom on the C2
methoxyphenyl group, which increases the Log P compared to the drug linker present in SGN-CD33A. Such an increase in Log P would be expected to make the drug linker and its conjugates more hydrophobic and more aggregative, and hence less active.
Surprisingly, this does not appear to be the case in vivo.
Furthermore, the conjugates of the newly developed drug linker appear to show a reduced activity in vitro to those including the drug linker from SGN-CD33A, which would discourage further testing, but a surprising comparable in vivo activity.
In a first aspect, the present invention provides Conjugates of formula I:
Figure imgf000006_0001
wherein L is a Li and unit (i.e., a targeting agent), D is a Drug Linker unit of formula II:
Figure imgf000006_0002
wherein p is an integer of from 1 to 20.
The Ligand unit, described more fully below, is a targeting agent that binds to a target moiety. The Ligand unit can, for example, specifically bind to a cell component (a Cell Binding Agent) or to other target molecules of interest. The Ligand unit can be, for example, a protein, polypeptide or peptide, such as an antibody, an antigen-binding fragment of an antibody, or other binding agent, such as an Fc fusion protein. A second as ect of the present invention provides a compound of formula III:
Figure imgf000006_0003
A third aspect of the present invention provides the use of a conjugate of the first aspect of the invention in the manufacture of a medicament for treating a proliferative disease. The third aspect also provides a conjugate of the first aspect of the invention for use in the treatment of a proliferative disease. The third aspect also provides a method of treating a proliferative disease comprising administering a therapeutically effective amount of a conjugate of the first aspect of the invention to a patient in need thereof.
One of ordinary skill in the art is readily able to determine whether or not a candidate conjugate treats a proliferative condition for any particular cell type. For example, assays which may conveniently be used to assess the activity offered by a particular compound are described in the examples below.
A fourth aspect of the present invention provides the synthesis of a conjugate of the first aspect of the invention comprising conjugating a compound (drug linker) of the second aspect of the invention with a Ligand Unit.
Brief Description of Figures
Figure 1 shows the effect on volume of a NCI-N87 tumour following treatment with a conjugate of the present invention;
Figure 2 shows the effect on volume of a JIMT-1 tumour following treatment with a conjugate of the present invention;
Figure 3 shows the effect on volume of a BT474 tumour following treatment with a conjugate of the present invention.
Ligand Unit
The Ligand Unit may be of any kind, and include a protein, polypeptide, peptide and a non- peptidic agent that specifically binds to a target molecule. In some embodiments, the Ligand unit may be a protein, polypeptide or peptide. In some embodiments, the Ligand unit may be a cyclic polypeptide. These Ligand units can include antibodies or a fragment of an antibody that contains at least one target molecule-binding site, lymphokines, hormones, growth factors, or any other cell binding molecule or substance that can specifically bind to a target.
The terms "specifically binds" and "specific binding" refer to the binding of an antibody or other protein, polypeptide or peptide to a predetermined molecule (e.g., an antigen).
Typically, the antibody or other molecule binds with an affinity of at least about 1 x107 M"1, and binds to the predetermined molecule with an affinity that is at least two-fold greater than its affinity for binding to a non-specific molecule (e.g., BSA, casein) other than the predetermined molecule or a closely-related molecule.
Examples of Ligand units include those agents described for use in WO 2007/085930, which is incorporated herein.
In some embodiments, the Ligand unit is a Cell Binding Agent that binds to an extracellular target on a cell. Such a Cell Binding Agent can be a protein, polypeptide, peptide or a non- peptidic agent. In some embodiments, the Cell Binding Agent may be a protein, polypeptide or peptide. In some embodiments, the Cell Binding Agent may be a cyclic polypeptide. The Cell Binding Agent also may be antibody or an antigen-binding fragment of an antibody. Thus, in one embodiment, the present invention provides an antibody-drug conjugate (ADC). Cell Binding Agent
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 cell binding molecule or substance.
Peptides
In one embodiment, the cell binding agent is a linear or cyclic peptide comprising 4-30, preferably 6-20, contiguous amino acid residues. In this embodiment, it is preferred that one cell binding agent is linked to one monomer or dimer pyrrolobenzodiazepine compound.
In one embodiment the cell binding agent comprises a peptide that binds integrin ανβ6. The peptide may be selective for ανβ6 over XYS. In one embodiment the cell binding agent comprises the A20FMDV-Cys polypeptide. The A20FMDV-Cys has the sequence: NAVPNLRGDLQVLAQKVARTC. Alternatively, 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. Furthermore, the polypeptide may have the sequence
NAVXXXXXXXXXXXXXXXRTC. Antibodies
The term "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 et al (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. (Janeway, C, Travers, P., Walport, M., Shlomchik (2001 ) Immuno Biology, 5th Ed., Garland Publishing, New York). 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 immunospecifically binds an antigen of a target of interest or part thereof, such targets including but not limited to, cancer cell or cells that produce autoimmune antibodies associated with an autoimmune disease. The immunoglobulin can be of any type (e.g. IgG, IgE, IgM, IgD, and IgA), class (e.g. lgG1 , lgG2, lgG3, lgG4, 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 immunospecifically bind to cancer cell antigens, viral antigens or microbial antigens, single-chain antibody molecules; and multispecific antibodies formed from antibody fragments.
The term "monoclonal antibody" as used herein 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 synthesized uncontaminated by other antibodies. 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. For example, the monoclonal antibodies to be used in accordance with the present invention may be made by the hybridoma method first described by Kohler et al (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 4816567; 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 CH3. 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 C1 q binding; complement dependent cytotoxicity; Fc receptor binding; antibody-dependent cell-mediated cytotoxicity (ADCC); phagocytosis; and down regulation of cell surface receptors such as B cell receptor and BCR. Depending on the amino acid sequence of the constant domain of their heavy chains, 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., lgG1 , lgG2, lgG3, lgG4, IgA, and lgA2. The heavy-chain constant domains that correspond to the different classes of antibodies are called α, δ, ε, γ, and μ, respectively. The subunit structures and three-dimensional configurations of different classes of immunoglobulins are well known.
Humanisation
Techniques to reduce the in vivo immunogenicity of a non-human antibody or antibody fragment include those termed "humanisation".
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. The expression "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. The expression "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. There are a range of humanisation techniques, including 'CDR grafting', 'guided selection', 'deimmunization', 'resurfacing' (also known as 'veneering'), 'composite antibodies', 'Human String Content Optimisation' and framework shuffling. CDR grafting
In this technique, 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). Furthermore, 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. Thus, in general, 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.
Guided selection
The method consists of combining the VH or Vi_ domain of a given non-human antibody specific for a particular epitope with a human VH or Vi_ 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.
Composite antibodies
In this method, 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 cell 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 .
Deimmunization
This method involves the removal of human (or other second species) T-cell epitopes from the V regions of the therapeutic antibody (or other molecule). The therapeutic antibodies V-region sequence is analysed for the presence of MHC 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). Alternatively, 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 MHC 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.
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-cell 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.
All alterations can be accomplished by recombinant DNA technology, so that the final molecule may be prepared by expression from a recombinant host using well established methods such as Site Directed Mutagenesis. However, the use of protein chemistry or any other means of molecular alteration is also possible.
Resurfacing
This method involves:
(a) determining the conformational structure of the variable region of the non- human (e.g. rodent) antibody (or fragment thereof) by constructing a three-dimensional model of the non-human antibody variable region;
(b) generating sequence alignments using relative accessibility distributions from x-ray crystallographic structures of a sufficient number of non-human and human antibody variable region heavy and light chains to give a set of heavy and light chain framework positions wherein the alignment positions are identical in 98% of the sufficient number of non-human antibody heavy and light chains;
(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);
(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;
(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);
(f) constructing a three-dimensional model of the variable region of the non-human antibody resulting from the substituting specified in step (e);
(g) identifying, by comparing the three-dimensional models constructed in steps (a) and (f), any amino acid residues from the sets identified in steps (c) or (d), that are within 5 Angstroms of any atom of any residue of the complementarity determining regions of the non-human antibodt to be humanized; and
(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). Superhumanization
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.
Human String Content Optimization
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-cell epitopes. 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).
Framework Shuffling
The CDRs of the non-human antibody are fused in-frame to cDNA pools encompassing all 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
(1) BMPR1B (bone morphogenetic protein receptor-type IB)
Nucleotide
Genbank accession no. NM_001203
Genbank version no. NM_001203.2 Gl:169790809
Genbank record update date: Sep 23, 2012 02:06 PM
Polypeptide
Genbank accession no. NP_001 194
Genbank version no. NP_001 194.1 Gl:4502431
Genbank record update date: Sep 23, 2012 02:06 PM
Cross-references
ten Dijke.P., et al Science 264 (5155): 101 -104 (1994), Oncogene 14 (1 1 ):1377-1382 (1997)); WO2004/063362 (Claim 2); WO2003/042661 (Claim 12);
US2003/134790-A1 (Page 38-39); WO2002/102235 (Claim 13; Page 296);
WO2003/055443
(Page 91 -92); WO2002/99122 (Example 2; Page 528-530); WO2003/029421 (Claim 6); WO2003/024392 (Claim 2; Fig 1 12); WO2002/98358 (Claim 1 ; Page 183); WO2002/54940 (Page 100-101 ); WO2002/59377(Page 349-350); WO2002/30268 (Claim 27; Page 376); 15 WO2001/48204 (Example; Fig 4); NP_001 194 bone morphogenetic protein receptor, type IB /pid=NP_001 194.1 .; MIM:603248; AY065994
(2) E16 (LAT1, SLC7A5)
Nucleotide
Genbank accession no. NM_003486
Genbank version no. NM_003486.5 Gl:71979931
Genbank record update date: Jun 27, 2012 12:06 PM Polypeptide
Genbank accession no. NP_003477
Genbank version no. NP_003477.4 Gl:71979932
Genbank record update date: Jun 27, 2012 12:06 PM Cross references
Biochem. Biophys. Res.
Commun. 255 (2), 283-288 (1999), Nature 395 (6699):288-291 (1998), Gaugitsch, H.W., et 20 al (1992) J. Biol. Chem. 267 (16):1 1267-1 1273); WO2004/048938 (Example 2);
WO2004/032842 (Example IV); WO2003/042661 (Claim 12); WO2003/016475 (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); WO2000/14228 (Claim 5; Page 133-136); US2003/224454 (Fig 3); 25 WO2003/025138 (Claim 12; Page 150); NP_003477 solute carrier family 7 (cationic amino acid transporter, y+system), member 5 /pid=NP_003477.3 - Homo sapiens;
MIM:600182;; NM_015923.
(3) STEAP1 (six transmembrane epithelial antigen of prostate)
Nucleotide
Genbank accession no. NM_012449
Genbank version no. NM_012449.2 Gl:22027487
Genbank record update date: Sep 9, 2012 02:57 PM
Polypeptide
Genbank accession no. NP_036581
Genbank version no. NP_036581 .1 Gl:9558759
Genbank record update date: Sep 9, 2012 02:57 PM Cross references
Cancer Res. 61 (15), 5857-5860 (2001 ), Hubert, R.S., ei a/ (1999) Proc. Natl.
Acad. Sci. U.S.A. 96 (25): 14523-14528); WO2004/065577 (Claim 6); WO2004/027049 (Fig 1 L); EP1394274 (Example 1 1 ); WO2004/016225 (Claim 2); WO2003/042661 (Claim 12); US2003/157089 (Example 5); US2003/185830 (Example 5); US2003/064397 (Fig 2); WO2002/89747 (Example 5; Page 618-619); WO2003/022995 (Example 9; Fig 13A, 35 Example 53; Page 173, Example 2; Fig 2A); six transmembrane epithelial antigen of the prostate; MIM:604415.
(4) 0772P (CA125, MUC16)
Nucleotide
Genbank accession no. AF361486
Genbank version no. AF361486.3 Gl:34501466
Genbank record update date: Mar 1 1 , 2010 07:56 AM
Polypeptide
Genbank accession no. AAK74120
Genbank version no. AAK74120.3 Gl:34501467
Genbank record update date: Mar 1 1 , 2010 07:56 AM
Cross references
J. Biol. Chem. 276 (29):27371 -27375 (2001 )); WO2004/045553 (Claim 14);
WO2002/92836 (Claim 6; Fig 12); WO2002/83866 (Claim 15; Page 1 16-121 );
US2003/124140 (Example 16); Gl:34501467;
(5) MPF (MPF, MSLN, SMR, megakaryocyte potentiating factor, mesothelin)
Nucleotide
Genbank accession no. NM_005823
Genbank version no. NM_005823.5 Gl:293651528
Genbank record update date: Sep 2, 2012 01 :47 PM
Polypeptide
Genbank accession no. NP_005814
Genbank version no. NP_005814.2 Gl:53988378
Genbank record update date: Sep 2, 2012 01 :47 PM Cross references
Yamaguchi, N., et al Biol. Chem. 269 (2), 805-808 (1994), Proc. Natl. Acad. Sci. U.S.A. 96 (20):1 1531 -1 1536 (1999), Proc. Natl. Acad. Sci. U.S.A. 93 (1 ):136-140 (1996), J. Biol. Chem. 270 (37):21984-21990 (1995)); WO2003/101283 (Claim 14); (WO2002/102235 (Claim 13; Page 287-288); WO2002/101075 (Claim 4; Page 308- 309); WO2002/71928 (Page 320-321 ); WO94/10312 (Page 52-57); IM:601051 .
(6) Napi3b (NAPI-3B, NPTIIb, SLC34A2, solute carrier family 34 (sodium phosphate), member 2, type II sodium-dependent phosphate transporter 3b)
Nucleotide
Genbank accession no. NM_006424
Genbank version no. NM_006424.2 Gl:1 1061 1905
Genbank record update date: Jul 22, 2012 03:39 PM
Polypeptide
Genbank accession no. NP_006415
Genbank version no. NP_006415.2 Gl:1 1061 1906
Genbank record update date: Jul 22, 2012 03:39 PM
Cross references
J. Biol. Chem. 277 (22): 19665-19672 (2002), Genomics 62 (2):281 -284 (1999), Feild, J.A., et al (1999) Biochem. Biophys. Res. Commun. 258 (3):578-582); WO2004/022778 (Claim 2); EP1394274 (Example 1 1 ); WO2002/102235 (Claim 13; Page 326); EP0875569 (Claim 1 ; Page 17-19); WO2001/57188 (Claim 20; Page 329); WO2004/032842 (Example IV); WO2001/75177 (Claim 24; Page 139-140); MIM:604217.
(7) Sema 5b (FLJ10372, KIAA1445, Mm.42015, SEMA5B, SEMAG, Semaphorin 5b Hlog, 25 sema domain, seven thrombospondin repeats (type 1 and type 1-like), transmembrane domain (TM) and short cytoplasmic domain, (semaphorin) 5B)
Nucleotide
Genbank accession no. AB040878
Genbank version no. AB040878.1 Gl:7959148
Genbank record update date: Aug 2, 2006 05:40 PM
Polypeptide Genbank accession no. BAA95969
Genbank version no. BAA95969.1 Gl:7959149
Genbank record update date: Aug 2, 2006 05:40 PM Cross references
Nagase T., ei a/ (2000) DNA Res. 7 (2):143-150); WO2004/000997 (Claim 1 );
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 1 1 ); Accession: 30 Q9P283; Genew; HGNC:10737
(8) PSCA hlg (2700050C12Rik, C530008O16Rik, RIKEN cDNA 2700050C12, RIKEN cDNA
2700050C12 gene)
Nucleotide
Genbank accession no. AY358628
Genbank version no. AY358628.1 Gl:37182377
Genbank record update date: Dec 1 , 2009 04:15 AM
Polypeptide
Genbank accession no. AAQ88991
Genbank version no. AAQ88991 .1 Gl:37182378
Genbank record update date: Dec 1 , 2009 04:15 AM
Cross references
Ross ei a/ (2002) Cancer Res. 62:2546-2553; US2003/129192 (Claim 2); US2004/044180 (Claim 12); US2004/044179 (Claim 1 1 ); US2003/096961 (Claim 1 1 ); US2003/232056 (Example 5); WO2003/105758 16 (Claim 12); US2003/206918 (Example 5); EP1347046 (Claim 1 ); WO2003/025148 (Claim 20); Gl:37182378. (9) ETBR (Endothelin type B receptor)
Nucleotide
Genbank accession no. AY275463
Genbank version no. AY275463.1 Gl:30526094
Genbank record update date: Mar 1 1 , 2010 02:26 AM
Polypeptide Genbank accession no. AAP32295
Genbank version no. AAP32295.1 Gl:30526095
Genbank record update date: Mar 11, 201002:26 AM Cross references
Nakamuta M., et al Bioc em. Biop ys. Res. Commun.177, 34-39, 1991; Ogawa Y., etal Biochem. Biophys. Res. Commun.178, 248-255, 1991; Arai H., etalJpn. Circ. J.56, 1303- 1307, 1992; Arai H., etal J. Biol. Chem.268, 3463-3470, 1993; Sakamoto A., Yanagisawa M., etal Biochem. Biophys. Res. Commun.178, 656-663, 1991; Elshourbagy N.A., etal J. Biol. Chem.268, 3873-3879, 1993; Haendler B., et al J. Cardiovasc. Pharmacol.20, s1-S4, 1992; Tsutsumi M., etal Gene 228, 43-49, 1999; Strausberg R.L., etalProc. Natl. Acad. Sci. U.S.A.99, 16899-16903, 2002; Bourgeois C, etal J. Clin. Endocrinol. Metab.82, 3116-3123, 1997; OkamotoY., etal Biol. Chem.272,21589-21596, 1997; Verheij J.B., et alAm. J. Med. Genet.108, 223-225, 2002; Hofstra R.M.W., etal Eur. J. Hum. Genet.5, 180-185, 1997; Puffenberger E.G., etal Cell 79, 1257-1266, 1994; Attie T., etal, Hum. Mol. Genet.4, 2407-2409, 1995; Auricchio A., et al Hum. Mol. Genet.5:351-354, 1996; Amiel J., et al Hum. Mol.
Genet.5, 355-357, 1996; Hofstra R.M.W., etal Nat. Genet.12, 445-447, 1996; Svensson P.J., etal Hum. Genet.103, 145-148, 1998; Fuchs S., etal Mol. Med.7, 115-124,2001; Pingault V., et al (2002) Hum. Genet.111, 198-206; WO2004/045516 (Claim 1);
WO2004/048938 (Example 2); WO2004/040000 (Claim 151); WO2003/087768 (Claim 1); 20 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 1a; Col 31-34); WO2004/001004.
(10) MSG783 (RNF124, hypothetical protein FLJ20315)
Nucleotide
Genbank accession no. NM_017763
Genbank version no. NM_017763.4 Gl:167830482
Genbank record update date: Jul 22, 201212:34 AM
Polypeptide
Genbank accession no. NP_060233
Genbank version no. NP 060233.3 Gl:56711322 Genbank record update date: Jul 22, 2012 12:34 AM Cross references
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); LocuslD:54894.
(11) 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)
Nucleotide
Genbank accession no. AF455138
Genbank version no. AF455138.1 Gl:22655487
Genbank record update date: Mar 1 1 , 2010 01 :54 AM
Polypeptide
Genbank accession no. AAN04080
Genbank version no. AAN04080.1 Gl:22655488
Genbank record update date: Mar 1 1 , 2010 01 :54 AM
Cross references
Lab. Invest. 82 (1 1 ):1573-1582 (2002)); WO2003/087306; US2003/064397 (Claim 1 ; Fig 1 ); WO2002/72596 (Claim 13; Page 54-55); WO2001/72962 (Claim 1 ; Fig 4B);
WO2003/104270 (Claim 1 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 (Claim 12; Fig 10); Gl:22655488.
(12) TrpM4 (BR22450, FLJ20041, TRPM4, TRPM4B, transient receptor potential cation 5 channel, subfamily M, member 4)
Nucleotide
Genbank accession no. NM_017636
Genbank version no. NM_017636.3 Gl:304766649
Genbank record update date: Jun 29, 2012 1 1 :27 AM
Polypeptide Genbank accession no. NP_060106
Genbank version no. NP_060106.2 Gl:21314671
Genbank record update date: Jun 29, 2012 1 1 :27 AM Cross references
Xu, X.Z., et al Proc. Natl. Acad. Sci. U.S.A. 98 (19):10692-10697 (2001 ), Cell 109 (3):397- 407 (2002), J. Biol. Chem. 278 (33):30813-30820 (2003)); US2003/143557 (Claim 4); WO2000/40614 (Claim 14; Page 100-103); WO2002/10382 (Claim 1 ; Fig 9A);
WO2003/042661 (Claim 12); WO2002/30268 (Claim 27; Page 391 ); US2003/219806 (Claim 4); WO2001/62794 (Claim 14; Fig 1A-D); MIM:606936.
(13) CRIPTO (CR, CR1, CRGF, CRIPTO, TDGF1, teratocarcinoma-derived growth factor) Nucleotide
Genbank accession no. NM_003212
Genbank version no. NM_003212.3 Gl:292494881
Genbank record update date: Sep 23, 2012 02:27 PM
Polypeptide
Genbank accession no. NP_003203
Genbank version no. NP_003203.1 Gl:4507425
Genbank record update date: Sep 23, 2012 02:27 PM
Cross references
Ciccodicola, A., et al EMBO J. 8 (7):1987-1991 (1989), Am. J. Hum. Genet. 49 (3):555-565 (1991 )); US2003/22441 1 (Claim 1 ); WO2003/083041 (Example 1 ); WO2003/034984 (Claim 12); WO2002/88170 (Claim 2; Page 52-53); WO2003/024392 (Claim 2; Fig 58); 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.
(14) CD21 (CR2 (Complement receptor 2) or C3DR (C3d/Epstein Barr virus receptor) or Hs.73792)
Nucleotide
Genbank accession no M26004
Genbank version no. M26004.1 GM 81939
Genbank record update date: Jun 23, 2010 08:47 AM Polypeptide
Genbank accession no. AAA35786
Genbank version no. AAA35786.1 Gl:181940
Genbank record update date: Jun 23, 2010 08:47 AM
Cross references
Fujisaku ei a/ (1989) J. Biol. Chem. 264 (4):21 18-2125); Weis J.J., et al J. Exp. Med. 167, 1047-1066, 1988; Moore M., et al Proc. Natl. Acad. Sci. U.S.A. 84, 9194-9198, 1987; Barel M., et al Mol. Immunol. 35, 1025-1031 , 1998; Weis J.J., et al Proc. Natl. Acad. Sci. U.S.A. 83, 5639-5643, 1986; Sinha S.K., ei a/ (1993) J. Immunol. 150, 531 1 -5320;
WO2004/045520 (Example 4); US2004/005538 (Example 1 ); WO2003/062401 (Claim 9); WO2004/045520 (Example 4); WO91/02536 (Fig 9.1 -9.9); WO2004/020595 (Claim 1 ); Accession: P20023; Q13866; Q14212; EMBL; M26004; AAA35786.1 .
(15) CD79b (CD79B, CD79 , IGb (immunoglobulin-associated beta), B29)
Nucleotide
Genbank accession no NM_000626
Genbank version no. NM_000626.2 Gl:90193589
Genbank record update date: Jun 26, 2012 01 :53 PM
Polypeptide
Genbank accession no. NP_000617
Genbank version no. NP_000617.1 Gl:1 1038674
Genbank record update date: Jun 26, 2012 01 :53 PM
Cross references
Proc. Natl. Acad. Sci. U.S.A. (2003) 100 (7):4126-
4131 , Blood (2002) 100 (9):3068-3076, Muller et al (1992) Eur. J. Immunol. 22 (6):1621 - 1625); WO2004/016225 (claim 2, Fig 140); WO2003/087768, US2004/101874 (claim 1 , page 102); WO2003/062401 (claim 9); WO2002/78524 (Example 2); US2002/150573 (claim
35 5, page 15); US5644033; WO2003/048202 (claim 1 , pages 306 and 309); WO
99/58658,
US6534482 (claim 13, Fig 17A/B); WO2000/55351 (claim 1 1 , pages 1 145-1 146);
MIM:147245 (16) FcRH2 (IFGP4, IRTA4, SPAP1A (SH2 domain containing phosphatase anchor protein 5 1a), SPAP1B, SPAP1C)
Nucleotide
Genbank accession no NM_030764
Genbank version no. NM_030764.3 Gl:227430280
Genbank record update date: Jun 30, 2012 12:30 AM
Polypeptide
Genbank accession no. NP_1 10391
Genbank version no. NP_1 10391 .2 GM 9923629
Genbank record update date: Jun 30, 2012 12:30 AM
Cross references
AY358130); Genome Res. 13 (10):2265-2270 (2003), Immunogenetics 54 (2):87-95
(2002), Blood 99 (8):2662-2669 (2002), Proc. Natl. Acad. Sci. U.S.A. 98 (17):9772-9777 (2001 ), Xu, M.J., et al (2001 ) Biochem. Biophys. Res. Commun. 280 (3):768-775;
WO2004/016225 (Claim 2); WO2003/077836; WO2001/38490 (Claim 5; Fig 18D-1 -18D-2); WO2003/097803 (Claim 12);
10 WO2003/089624 (Claim 25);: MIM:606509.
(17) HER2 (ErbB2)
Nucleotide
Genbank accession no M1 1730
Genbank version no. M1 1730.1 Gl:183986
Genbank record update date: Jun 23, 2010 08:47 AM
Polypeptide
Genbank accession no. AAA75493
Genbank version no. AAA75493.1 Gl:306840
Genbank record update date: Jun 23, 2010 08:47 AM
Cross references
Coussens L, et al Science (1985) 230(4730): 1 132-1 139); Yamamoto T., et al Nature 319, 230-234, 1986; Semba K., et al Proc. Natl. Acad. Sci. U.S.A. 82, 6497-6501 , 1985; Swiercz J.M., et al J. Cell Biol. 165, 869-880, 2004; Kuhns J.J., et al J. Biol. Chem. 274, 36422- 36427, 1999; Cho H.-S., et al Nature 421 , 756-760, 2003; Ehsani A., ei a/ (1993)
Genomics 15, 426-429; WO2004/048938 (Example 2); WO2004/027049 (Fig 11);
WO2004/009622; WO2003/081210;
WO2003/089904 (Claim 9); WO2003/016475 (Claim 1 ); US2003/1 18592; WO2003/008537 (Claim 1 ); WO2003/055439 (Claim 29; Fig 1 A-B); WO2003/025228 (Claim 37; Fig 5C); 20 WO2002/22636 (Example 13; Page 95-107); WO2002/12341 (Claim 68; Fig 7);
WO2002/13847 (Page 71 -74); WO2002/14503 (Page 1 14-1 17); WO2001/53463 (Claim 2; Page 41 -46); WO2001/41787 (Page 15); WO2000/44899 (Claim 52; Fig 7);
WO2000/20579
(Claim 3; Fig 2); US5869445 (Claim 3; Col 31 -38); WO9630514 (Claim 2; Page 56-61 ); EP1439393 (Claim 7); WO2004/043361 (Claim 7); WO2004/022709; WO2001/00244 25 (Example 3; Fig 4); Accession: P04626; EMBL; M1 1767; AAA35808.1. EMBL; M1 1761 ; AAA35808.1 ANTIBODIES
Abbott: US201 10177095
For example, 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.
Biogen: US201001 1951 1
For example, ATCC accession numbers: PTA-10355, PTA-10356, PTA-10357,
PTA-10358
For example, a purified antibody molecule that binds to HER2 comprising a all six CDR's from an antibody selected from the group consisting of BIIB71 F10 (SEQ ID NOs:1 1 , 13), BIIB69A09 (SEQ ID NOs:15, 17); BIIB67F10 (SEQ ID NOs:19, 21 ); BIIB67F1 1 (SEQ ID NOs:23, 25), BIIB66A12 (SEQ ID NOs:27, 29), BIIB66C01
(SEQ ID NOs:31 , 33), BIIB65C10 (SEQ ID NOs:35, 37), BIIB65H09 (SEQ ID NOs:39, 41 ) and BIIB65B03 (SEQ ID NOs:43, 45), or CDRs which are identical or which have no more than two alterations from said CDRs. Herceptin (Genentech) - US6, 054,297; ATCC accession no. CRL-10463 (Genentech)
Pertuzumab (Genentech) US201 101 17097
for example, see SEQ IDs No. 15&16, SEQ IDs No. 17&18, SEQ IDs No.
23&24 & ATCC accession numbers HB-12215, HB-12216, CRL 10463, HB-
12697.
US20090285837
US20090202546
for example, ATCC accession numbers: HB-12215, HB-12216, CRL 10463, HB-12698.
US20060088523
- for example, ATCC accession numbers: HB-12215, HB-12216
for example, an antibody comprising the variable light and variable heavy amino acid sequences in SEQ ID Nos. 3 and 4, respectively, for example, an antibody comprising a light chain amino acid sequence selected from SEQ ID No. 15 and 23, and a heavy chain amino acid sequence selected from SEQ ID No. 16 and 24
US20060018899
- for example, ATCC accession numbers: (7C2) HB-12215, (7F3) HB- 12216, (4D5) CRL-10463, (2C4) HB-12697.
for example, an antibody comprising the amino acid sequence in SEQ ID No. 23, or a deamidated and/or oxidized variant thereof.
US201 1/0159014
for example, an antibody having a light chain variable domain comprising the hypervariable regions of SEQ ID NO: 1 ".
- For example, an antibody having a heavy chain variable domain
comprising the hypervariable regions of SEQ ID NO: 2.
US20090187007
Glycotope: TrasGEX antibody http://www.glycotope.com/pipeline
For example, see International Joint Cancer Institute and Changhai
Hospital Cancer Cent: HMTI-Fc Ab - Gao J., et al BMB Rep. 2009 Oct
31 ;42(10):636-41 .
Symphogen: US201 10217305 Union Stem Cell &Gene Engineering, China - Liu HQ., et al Xi Bao Yu Fen Zi Mian YiXue Za Zhi. 2010 May;26(5):456-8.
(18) NCA (CEACAM6)
Nucleotide
Genbank accession no M18728
Genbank version no. M18728.1 Gl:189084
Genbank record update date: Jun 23, 2010 08:48 AM Polypeptide
Genbank accession no. AAA59907
Genbank version no. AAA59907.1 Gl: 189085
Genbank record update date: Jun 23, 2010 08:48 AM Cross references
Barnett T., et al Genomics 3, 59-66, 1988; Tawaragi Y., et al Biochem. Biophys. Res.
Commun. 150, 89-96, 1988; Strausberg R.L., et al Proc. Natl. Acad. Sci. U.S.A. 99:16899-
16903, 2002; WO2004/063709; EP1439393 (Claim 7); WO2004/044178 (Example 4);
WO2004/031238; WO2003/042661 (Claim 12); WO2002/78524 (Example 2);
WO2002/86443 (Claim 27; Page 427); WO2002/60317 (Claim 2); Accession: P40199;
Q14920; EMBL; M29541 ; AAA59915.1.
EMBL; M18728.
(19) MDP (DPEPI)
Nucleotide
Genbank accession no BC017023
Genbank version no. BC017023.1 Gl:16877538
Genbank record update date: Mar 6, 2012 01 :00 PM Polypeptide
Genbank accession no. AAH17023
Genbank version no. AAH17023.1 Gl:16877539
Genbank record update date: Mar 6, 2012 01 :00 PM
Cross references Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899-16903 (2002)); WO2003/016475 (Claim 1 ); WO2002/64798 (Claim 33; Page 85- 87); JP05003790 (Fig 6-8); W099/46284 (Fig 9); Ml M: 179780. (20) IL20R-alp a (IL20Ra, ZCYT0R7)
Nucleotide
Genbank accession no AF184971
Genbank version no. AF184971.1 Gl:6013324
Genbank record update date: Mar 10, 2010 10:00 PM
Polypeptide
Genbank accession no. AAF01320
Genbank version no. AAF01320.1 Gl:6013325
Genbank record update date: Mar 10, 2010 10:00 PM
Cross references
Clark H.F., et al Genome Res. 13, 2265-2270, 2003; Mungall A.J., et al Nature 425, 805- 81 1 , 2003; Blumberg H., et al Cell 104, 9-19, 2001 ; Dumoutier L, et al J. Immunol. 167, 3545-3549,
2001 ; Parrish-Novak J., et al J. Biol. Chem. 277, 47517-47523, 2002; Pletnev S., et al (2003)
10 Biochemistry 42: 12617-12624; Sheikh F., et a/ (2004) J. Immunol. 172, 2006-2010; EP1394274 (Example 1 1 ); US2004/005320 (Example 5); WO2003/029262 (Page 74-75); WO2003/002717 (Claim 2; Page 63); WO2002/22153 (Page 45-47); US2002/042366 (Page
20-21 ); WO2001/46261 (Page 57-59); WO2001/46232 (Page 63-65); W098/37193 (Claim 1 ;
Page 55-59); Accession: Q9UHF4; Q6UWA9; Q96SH8; EMBL; AF184971 ; AAF01320.1. (21) Brevican (BCAN, BEHAB)
Nucleotide
Genbank accession no AF229053
Genbank version no. AF229053.1 Gl:10798902
Genbank record update date: Mar 1 1 , 2010 12:58 AM
Polypeptide Genbank accession no. AAG23135
Genbank version no. AAG23135.1 Gl:10798903
Genbank record update date: Mar 1 1 , 2010 12:58 AM Cross references
Gary S.C., et al Gene 256, 139-147, 2000; Clark H.F., et al Genome Res. 13, 2265-2270, 2003; Strausberg R.L., et al Proc. Natl. Acad. Sci. U.S.A. 99, 16899-16903, 2002;
US2003/186372 (Claim 1 1 ); US2003/186373 (Claim 1 1 ); US2003/1 19131 (Claim 1 ; Fig 52); US2003/1 19122 (Claim 1 ; Fig 52); US2003/1 19126 (Claim 1 ); US2003/1 19121 (Claim 1 ; Fig 52); US2003/1 19129 (Claim 1 ); US2003/1 19130 (Claim 1 ); US2003/1 19128 (Claim 1 ; Fig 52); US2003/1 19125 (Claim 1 ); WO2003/016475 (Claim 1 ); WO2002/02634 (Claim 1 )
(22) EphB2R (DRT, ERK, Hek5, EPHT3, Tyro5)
Nucleotide
Genbank accession no NM_004442
Genbank version no. NM_004442.6 Gl:1 1 1 1 18979
Genbank record update date: Sep 8, 2012 04:43 PM
Polypeptide
Genbank accession no. NP_004433
Genbank version no. NP_004433.2 Gl:21396504
Genbank record update date: Sep 8, 2012 04:43 PM
Cross references
Chan,J. and Watt, V.M., Oncogene 6 (6), 1057-1061 (1991 ) Oncogene 10 (5):897-905 (1995), Annu. Rev. Neurosci. 21 :309-345 (1998), Int. Rev. Cytol. 196:177-244 (2000)); WO2003042661 (Claim 12); WO200053216 (Claim 1 ; Page 41 ); WO2004065576 (Claim 1 ); WO2004020583 (Claim 9); WO2003004529 (Page 128-132); WO200053216 (Claim 1 ; Page 42); MIM:600997.
(23) ASLG659 (B7h)
Nucleotide
Genbank accession no. AX092328
Genbank version no. AX092328.1 Gl:13444478 Genbank record update date: Jan 26, 201 1 07:37 AM Cross references
US2004/0101899 (Claim 2); WO2003104399 (Claim 1 1 ); WO2004000221 (Fig 3);
US2003/165504 (Claim 1 ); US2003/124140 (Example 2); US2003/065143 (Fig 60);
WO2002/102235 (Claim 13; Page 299); US2003/091580 (Example 2); WO2002/10187 (Claim 6; Fig 10); WO2001/94641 (Claim 12; Fig 7b); WO2002/02624 (Claim 13; Fig 1A- 1 B); US2002/034749 (Claim 54; Page 45-46); WO2002/06317 (Example 2; Page 320-321 , Claim 34; Page 321 -322); WO2002/71928 (Page 468-469); WO2002/02587 (Example 1 ; Fig 1 ); WO2001/40269 (Example 3; Pages 190-192); WO2000/36107 (Example 2; Page 205-207); WO2004/053079 (Claim 12); WO2003/004989 (Claim 1 ); WO2002/71928 (Page 233-234, 452-453); WO 01/16318.
(24) PSCA (Prostate stem cell antigen precursor)
Nucleotide
Genbank accession no AJ297436
Genbank version no. AJ297436.1 Gl:936721 1
Genbank record update date: Feb 1 , 201 1 1 1 :25 AM Polypeptide
Genbank accession no. CAB97347
Genbank version no. CAB97347.1 Gl:9367212
Genbank record update date: Feb 1 , 201 1 1 1 :25 AM Cross references
Reiter R.E., et al Proc. Natl. Acad. Sci. U.S.A. 95, 1735-1740, 1998; Gu Z., et al Oncogene 19,
1288-1296, 2000; Biochem. Biophys. Res. Commun. (2000) 275(3):783-788;
WO2004/022709; EP1394274 (Example 1 1 ); US2004/018553 (Claim 17); WO2003/008537 (Claim 1 ); WO2002/81646 (Claim 1 ; Page 164); WO2003/003906 (Claim 10; Page 288);
WO2001/40309 (Example 1 ; Fig 17); US2001/055751 (Example 1 ; Fig 1 b); WO2000/32752 (Claim 18; Fig 1 ); WO98/51805 (Claim 17; Page 97); W098/51824 (Claim 10; Page 94); WO98/40403 (Claim 2; Fig 1 B); Accession: 043653; EMBL; AF043498; AAC39607.1 (25) GEDA
Nucleotide Genbank accession no AY260763
Genbank version no. AY260763.1 Gl:30102448
Genbank record update date: Mar 1 1 , 2010 02:24 AM Polypeptide
Genbank accession no. AAP14954
Genbank version no. AAP14954.1 Gl:30102449
Genbank record update date: Mar 1 1 , 2010 02:24 AM Cross references
AP14954 lipoma HMGIC fusion-partnerlike protein /pid=AAP14954.1 - Homo sapiens (human); WO2003/054152 (Claim 20); WO2003/000842 (Claim 1 ); WO2003/023013 (Example 3, Claim 20); US2003/194704 (Claim 45); Gl:30102449; (26) BAFF-R (B cell -activating factor receptor, BLyS receptor 3, BR3)
Nucleotide
Genbank accession no AF1 16456
Genbank version no. AF1 16456.1 Gl:4585274
Genbank record update date: Mar 10, 2010 09:44 PM
Polypeptide
Genbank accession no. AAD25356
Genbank version no. AAD25356.1 Gl:4585275
Genbank record update date: Mar 10, 2010 09:44 PM
Cross references
BAFF receptor /pid=NP_443177.1 - Homo sapiens: Thompson, J.S., et al Science 293 (5537), 2108-21 1 1 (2001 ); WO2004/058309; WO2004/01 161 1 ; WO2003/045422
(Example; Page 32-33); WO2003/014294 (Claim 35; Fig 6B); WO2003/035846 (Claim 70; Page 615-616); WO2002/94852 (Col 136-137); WO2002/38766 (Claim 3; Page 133); WO2002/24909 (Example 3; Fig 3); MIM:606269; NP_443177.1 ; NM_052945_1 ;
AF 132600
(27) CD22 (B-cell receptor CD22-B isoform, BL-CAM, Lyb-8, Lyb8, SIGLEC-2, FLJ22814) Nucleotide
Genbank accession no AK026467 Genbank version no. AK026467.1 Gl:10439337
Genbank record update date: Sep 1 1 , 2006 1 1 :24 PM
Polypeptide
Genbank accession no. BAB15489
Genbank version no. BAB15489.1 GM 0439338
Genbank record update date: Sep 1 1 , 2006 1 1 :24 PM
Cross references
Wilson et al (1991 ) J. Exp. Med. 173:137-146; WO2003/072036 (Claim 1 ; Fig 1 );
IM:107266; NP_001762.1 ; NM_001771_1 .
(27a) CD22 (CD22 molecule)
Nucleotide
Genbank accession no X52785
Genbank version no. X52785.1 Gl:29778
Genbank record update date: Feb 2, 201 1 10:09 AM
Polypeptide
Genbank accession no. CAA36988
Genbank version no. CAA36988.1 Gl:29779
Genbank record update date: Feb 2, 201 1 10:09 AM
Cross references
Stamenkovic I. et al., Nature 345 (6270), 74-77 (1990)??
Other information
Official Symbol: CD22
Other Aliases: SIGLEC-2, SIGLEC2
Other Designations: B-cell receptor CD22; B-lymphocyte cell adhesion molecule; BL-
CAM; CD22 antigen; T-cell surface antigen Leu-14; sialic acid binding Ig-like lectin 2; sialic acid-binding Ig-like lectin 2
ANTIBODIES
G5/44 (Inotuzumab): Di Joseph JF.,et al Cancer Immunol Immunother. 2005 Jan;54(1 ):1 1 - 24. Epratuzumab- Goldenberg DM., et al Expert Rev Anticancer Then 6(10): 1341 -53, 2006.
(28) CD79a (CD79A, CD79alpha), immunoglobulin-associated alpha, a B cell-specific protein that covalently interacts with Ig beta (CD79B) and forms a complex on the surface with Ig M
35 molecules, transduces a signal involved in B-cell differentiation), pi: 4.84, MW: 25028 TM: 2
[P] Gene Chromosome: 19q13.2).
Nucleotide
Genbank accession no NM_001783
Genbank version no. NM_001783.3 Gl:90193587
Genbank record update date: Jun 26, 2012 01 :48 PM Polypeptide
Genbank accession no. NP_001774
Genbank version no. NP_001774.1 Gl:4502685
Genbank record update date: Jun 26, 2012 01 :48 PM Cross references
WO2003/088808, US2003/0228319; WO2003/062401 (claim 9); US2002/150573 (claim 4, pages 13-14); W099/58658 (claim 13, Fig 16); WO92/07574 (Fig 1 ); US5644033; Ha et al (1992) J. Immunol. 148(5):1526-1531 ; Muller et al (1992) Eur. J. Immunol.. 22:1621 -1625; Hashimoto et al (1994) Immunogenetics 40(4):287-295; Preud'homme et al (1992) Clin. Exp.
5 Immunol. 90(1 ):141 -146; Yu ei a/ (1992) J. Immunol. 148(2) 633-637; Sakaguchi et al (1988)
EMBO J. 7(1 1 ):3457-3464 (29) CXCR5 (Burkitt's lymphoma receptor 1, a G protein-coupled receptor that is activated by the CXCL13 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: 8.54 MW: 41959 TM: 7 [P] Gene Chromosome: 11q23.3,
Nucleotide
Genbank accession no NM 001716 Genbank version no. NM_001716.4 Gl:342307092
Genbank record update date: Sep 30, 2012 01 :49 PM
Polypeptide
Genbank accession no. NP_001707
Genbank version no. NP_001707.1 Gl:4502415
Genbank record update date: Sep 30, 2012 01 :49 PM
Cross references
WO2004/040000; WO2004/015426; US2003/105292 (Example 2); US6555339 (Example 2); WO2002/61087 (Fig 1 ); WO2001/57188 (Claim 20, page 269); WO2001/72830 (pages 12-13); WO2000/22129 (Example 1 , pages 152-153, Example 2, pages 254-256);
W099/28468 (claim 1 , page 38); US5440021 (Example 2, col 49-52); W094/28931 (pages 56-58); W092/17497 (claim 7, Fig 5); Dobner et al (1992) Eur. J. Immunol. 22:2795-2799; Barella et al (1995) Biochem. J. 309:773-779
(30) HLA-DOB (Beta subunit of MHC class II 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)
Nucleotide
Genbank accession no NM_002120
Genbank version no. NM_002120.3 Gl:1 18402587
Genbank record update date: Sep 8, 2012 04:46 PM Polypeptide
Genbank accession no. NP_0021 1 1
Genbank version no. NP_0021 1 1 .1 Gl:4504403
Genbank record update date: Sep 8, 2012 04:46 PM Cross references
Tonnelle et al (1985) EMBO J. 4(1 1 ):2839-2847; Jonsson et al (1989) Immunogenetics 29(6):41 1 -413; Beck et al (1992) J. Mol. Biol. 228:433-441 ; Strausberg et al (2002) P roc. Natl. Acad. Sci USA 99:16899- 16903; Servenius et al (1987) J. Biol. Chem. 262:8759- 8766; Beck et al (1996) J. Mol. Biol. 255:1 -13; Naruse ei a/ (2002) Tissue Antigens 59:512- 519; W099/58658 (claim 13, Fig 15); US6153408 (Col 35-38); US5976551 (col 168-170); US601 1 146 (col 145-146); Kasahara et al (1989) Immunogenetics 30(1 ):66-68; Larhammar et al (1985) J. Biol. Chem. 260(26): 141 1 1 -141 19
(31) P2X5 (Purinergic receptor P2X ligand-gated ion channel 5, an ion channel gated by extracellular ATP, 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 [P] Gene Chromosome: 17p13.3).
Nucleotide
Genbank accession no NM_002561
Genbank version no. NM_002561 .3 Gl:325197202
Genbank record update date: Jun 27, 2012 12:41 AM
Polypeptide
Genbank accession no. NP_002552
Genbank version no. NP_002552.2 Gl:28416933
Genbank record update date: Jun 27, 2012 12:41 AM
Cross references
Le et al (1997) FEBS Lett. 418(1 -2):195-199; WO2004/047749; WO2003/072035 (claim 10); Touchman ei a/ (2000) Genome Res. 10:165-173; WO2002/22660 (claim 20);
WO2003/093444 (claim 1 ); WO2003/087768 (claim 1 ); WO2003/029277 (page 82)
(32) CD72 (B-cell differentiation antigen CD72, Lyb-2); 359 aa, pi: 8.66, MW: 40225, TM: 1 5 [P] Gene Chromosome: 9p13.3).
Nucleotide
Genbank accession no NM_001782
Genbank version no. NM_001782.2 GM 94018444
Genbank record update date: Jun 26, 2012 01 :43 PM Polypeptide
Genbank accession no. NP_001773
Genbank version no. NP_001773.1 Gl:4502683
Genbank record update date: Jun 26, 2012 01 :43 PM
Cross references 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 et al (2002) Proc. Natl. Acad. Sci USA 99:16899-16903. (33) 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 erythematosis); 661 aa, pi: 6.20, MW: 74147 TM: 1 [P] Gene Chromosome: 5q12).
Nucleotide
Genbank accession no NM_005582
Genbank version no. NM_005582.2 Gl:167555126
Genbank record update date: Sep 2, 2012 01 :50 PM Polypeptide
Genbank accession no. NP_005573
Genbank version no. NP_005573.2 Gl:167555127
Genbank record update date: Sep 2, 2012 01 :50 PM Cross references
US2002/193567; WO97/07198 (claim 1 1 , pages 39-42); Miura ei a/ (1996) Genomics 38(3):299-304; Miura ei a/ (1998) Stood 92:2815-2822; WO2003/083047; W097/44452 (claim 8, pages 57-61 ); WO2000/12130 (pages 24-26). (34) FcRH1 (Fc receptor-like protein 1, a putative receptor for the immunoglobulin Fc domain
that contains C2 type Ig-like and ITAM domains, may have a role in B-lymphocyte
20 differentiation); 429 aa, pi: 5.28, MW: 46925 TM: 1 [P] Gene Chromosome: 1q21-1q22)
Nucleotide
Genbank accession no NM_052938
Genbank version no. NM_052938.4 Gl:226958543
Genbank record update date: Sep 2, 2012 01 :43 PM
Polypeptide
Genbank accession no. NP_443170
Genbank version no. NP 443170.1 GM 6418419 Genbank record update date: Sep 2, 2012 01 :43 PM Cross references
WO2003/077836; WO2001/38490 (claim 6, Fig 18E-1 -18-E-2); Davis et al (2001 ) Proc. Natl. Acad. Sci USA 98(17):9772-9777; WO2003/089624 (claim 8); EP1347046 (claim 1 ); WO2003/089624 (claim 7).
(35) IRTA2 (Immunoglobulin superfamily receptor translocation associated 2, a putative immunoreceptor with possible roles in B cell development and lymphomagenesis;
deregulation of the gene by translocation occurs in some B cell malignancies); 977 aa, pi: 6.88, MW: 106468, TM: 1 [P] Gene Chromosome: 1q21)
Nucleotide
Genbank accession no AF343662
Genbank version no. AF343662.1 GM 3591709
Genbank record update date: Mar 1 1 , 2010 01 :16 AM
Polypeptide
Genbank accession no. AAK31325
Genbank version no. AAK31325.1 GM 3591710
Genbank record update date: Mar 1 1 , 2010 01 :16 AM
Cross references
AF343663, AF343664, AF343665, AF369794, AF397453, AK090423, AK090475, AL834187, AY358085; Mouse:AK089756, AY158090, AY506558; NP_1 12571.1 ;
WO2003/024392 (claim 2, Fig 97); Nakayama et al (2000) Biochem. Biophys. Res.
Commun. 277(1 ): 124-127; WO2003/077836; WO2001/38490 (claim 3, Fig 18B-1 -18B-2).
(36) TENB2 (TMEFF2, tomoregulin, TPEF, HPP1, TR, putative transmembrane
35 proteoglycan, related to the EGF/heregulin family of growth factors and follistatin); 374 aa)
Nucleotide
Genbank accession no AF179274
Genbank version no. AF179274.2 GM 2280939
Genbank record update date: Mar 1 1 , 2010 01 :05 AM Polypeptide
Genbank accession no. AAD55776
Genbank version no. AAD55776.2 GM 2280940
Genbank record update date: Mar 1 1 , 2010 01 :05 AM
Cross references
NCBI Accession: AAD55776, AAF91397, AAG49451 , NCBI RefSeq: NP_057276; NCBI Gene: 23671 ; OMIM: 605734; SwissProt Q9UIK5; AY358907, CAF85723, CQ782436; WO2004/074320; JP20041 13151 ; WO2003/042661 ; WO2003/009814; EP1295944 (pages 69-70); WO2002/30268 (page 329); WO2001/90304; US2004/249130; US2004/022727; WO2004/063355; US2004/197325; US2003/232350; US2004/005563; US2003/124579; Horie et al (2000) Genomics 67:146-152; Uchida et al (1999) Biochem. Biophys. Res. Commun. 266:593-602; Liang ei a/ (2000) Cancer Res. 60:4907-12; Glynne-Jones et al (2001 ) I nt J Cancer. Oct 15; 94(2):178-84.
(37) PSMA - FOLH1 (Folate hydrolase (prostate-specific membrane antigen) 1)
Nucleotide
Genbank accession no M99487
Genbank version no. M99487.1 GM 90663
Genbank record update date: Jun 23, 2010 08:48 AM
Polypeptide
Genbank accession no. AAA60209
Genbank version no. AAA60209.1 GM 90664
Genbank record update date: Jun 23, 2010 08:48 AM
Cross references
Israeli R.S., et al Cancer Res. 53 (2), 227-230 (1993)
Other information
Official Symbol: FOLH1
Other Aliases: GIG27, FGCP, FOLH, GCP2, GCPII, NAALAD1 , NAALAdase, PSM, PSMA, mGCP
Other Designations: N-acetylated alpha-linked acidic dipeptidase 1 ; N-acetylated-alpha- linked acidic dipeptidase I; NAALADase I; cell growth-inhibiting gene 27 protein; folylpoly- gamma-glutamate carboxypeptidase; glutamate carboxylase II; glutamate carboxypeptidase 2; glutamate carboxypeptidase II; membrane glutamate
carboxypeptidase; prostate specific membrane antigen variant F; pteroylpoly-gamma- glutamate carboxypeptidase
ANTIBODIES US 7,666,425:
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, 3E1 1 , 17G1 , 29B4, 30C1 and 20F2 (US 7,81 1 ,564; Moffett S., et al Hybridoma (Larc mt). 2007
Dec;26(6):363-72).
Cytogen: monoclonal antibodies 7E1 1 -C5 (ATCC accession No. HB 10494) and 9H10-A4 (ATCC accession No. HB1 1430) - US 5,763,202
GlycoMimetics: NUH2 - ATCC accession No. HB 9762 (US 7,135,301 )
Human Genome Science: HP RAJ 70 - 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, 3E1 1 , 4D8, 3E6, 3C9, 2C7, 1 G3, 3C4, 3C6, 4D4, 1 G9, 5C8B9, 3G6, 4C8B9, and monoclonal antibodies. Hybridomas secreting 3F5.4G6, 3D7.1 .1 , 4E10-1 .14, 3E1 1 , 4D8, 3E6, 3C9, 2C7, 1 G3, 3C4, 3C6, 4D4, 1 G9, 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. Moreover, humanized anti-PSMA antibodies, including a humanized version of J591 , are described in further detail in PCT Publication WO 02/098897. Other 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 al. (2003) Int. J. Urol. 10:439-444). Examples of human anti-PSMA monoclonal antibodies include the 4A3, 7F12, 8C12, 8A1 1 , 16F9, 2A10, 2C6, 2F5 and 1 C3 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. 60/654,125, entitled "Human Monoclonal Antibodies to Prostate Specific Membrane Antigen (PSMA)", filed on Feb. 18, 2005. The V.sub.H amino acid sequences of 4A3, 7F12, 8C12, 8A1 1 , 16F9, 2A10, 2C6, 2F5 and 1 C3 are shown in SEQ ID NOs: 1 -9, respectively. The V.sub.L amino acid sequences of 4A3, 7F12, 8C12, 8A1 1 , 16F9, 2A10, 2C6, 2F5 and 1 C3 are shown in SEQ ID NOs: 10-18, respectively.
Other human anti-PSMA antibodies include the antibodies disclosed in PCT Publication WO 03/034903 and US Application No. 2004/0033229.
NW Biotherapeutics: A hybridoma cell line selected from the group consisting of 3F5.4G6 having ATCC accession number HB12060, 3D7-1 .1, having ATCC accession number HB12309, 4E10-1.14 having ATCC accession number HB12310, 3E1 1 (ATCC HB12488), 4D8 (ATCC HB12487), 3E6 (ATCC HB12486), 3C9 (ATCC HB12484), 2C7 (ATCC
HB12490), 1 G3 (ATCC HB12489), 3C4 (ATCC HB12494), 3C6 (ATCC HB12491 ), 4D4 (ATCC HB12493), 1 G9 (ATCC HB12495), 5C8B9 (ATCC HB12492) and 3G6 (ATCC HB12485) - see US 6,150,508 PSMA Development Company / Progenies / Cytogen - Seattle Genetics: mAb 3.9, produced by the hybridoma deposited under ATCC Accession No. PTA-3258 or mAb 10.3, produced by the hybridoma deposited under ATCC Accession No. PTA-3347 - US
7,850,971 PSMA Development Company- Compositions of PSMA antibodies (US 20080286284, Table 1 )
This application is a divisional of U.S. patent application Ser. No. 10/395,894, filed on Mar. 21 , 2003 (US 7,850,971 ) University Hospital Freiburg, Germany - mAbs 3/A12, 3/E7, and 3/F1 1 (Wolf P., et al Prostate. 2010 Apr 1 ;70(5):562-9). (38) SST ( Somatostatin Receptor; note that there are5 subtypes)
(38.1 ) SSTR2 (Somatostatin receptor 2)
Nucleotide
Genbank accession no NM_001050
Genbank version no. NM_001050.2 Gl:44890054
Genbank record update date: Aug 19, 2012 01 :37 PM
Polypeptide
Genbank accession no. NP_001041
Genbank version no. NP_001041 .1 Gl:4557859
Genbank record update date: Aug 19, 2012 01 :37 PM
Cross references
Yamada Y., et al Proc. Natl. Acad. Sci. U.S.A. 89 (1 ), 251 -255 (1992); Susini C, et al Ann Oncol. 2006 Dec; 17(12): 1733-42
Other information
Official Symbol: SSTR2
Other Designations: SRIF-1 ; SS2R; somatostatin receptor type 2
(38.2) SSTR5 (Somatostatin receptor 5)
Nucleotide
Genbank accession no D16827
Genbank version no. D16827.1 Gl:487683
Genbank record update date: Aug 1 , 2006 12:45 PM
Polypeptide
Genbank accession no. BAA04107
Genbank version no. BAA04107.1 Gl:487684
Genbank record update date: Aug 1 , 2006 12:45 PM
Cross references
Yamada,Y., et al Biochem. Biophys. Res. Commun. 195 (2), 844-852 (1993)
Other information Official Symbol: SSTR5
Other Aliases: SS-5-R
Other Designations: Somatostatin receptor subtype 5; somatostatin receptor type 5 (38.3) SSTR1
(38.4) SSTR3
(38.5) SSTR4
AvB6 - Both subunits (39+40)
(39) ITGAV (Integrin, alpha V;
Nucleotide
Genbank accession no M14648 J02826 M18365
Genbank version no. M14648.1 Gl:340306
Genbank record update date: Jun 23, 2010 08:56 AM
Polypeptide
Genbank accession no. AAA36808
Genbank version no. AAA36808.1 Gl:340307
Genbank record update date: Jun 23, 2010 08:56 AM
Cross references
Suzuki S., et al Proc. Natl. Acad. Sci. U.S.A. 83 (22), 8614-8618 (1986) Other information
Official Symbol: ITGAV
Other Aliases: CD51 , MSK8, VNRA, VTNR
Other Designations: antigen identified by monoclonal antibody L230; integrin alpha-V; integrin alphaVbeta3; integrin, alpha V (vitronectin receptor, alpha polypeptide, antigen CD51 ); vitronectin receptor subunit alpha
(40) ITGB6 (Integrin, beta 6)
Nucleotide
Genbank accession no NM_000888
Genbank version no. NM 000888.3 Gl:9966771 Genbank record update date: Jun 27, 2012 12:46 AM
Polypeptide
Genbank accession no. NP_000879
Genbank version no. NP_000879.2 Gl:9625002
Genbank record update date: Jun 27, 2012 12:46 AM
Cross references
Sheppard D.J., et al Biol. Chem. 265 (20), 1 1502-1 1507 (1990)
Other information
Official Symbol: ITGB6
Other Designations: integrin beta-6 ANTIBODIES
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.
Biogen: US7, 465,449 - In some embodiments, 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, 7.1 G10, 7.7G5, or 7.1 C5.
Centocor (J&J): US7,550,142; US7,163,681
For example in US 7,550,142 - an antibody having human heavy chain and human light chain variable regions comprising the amino acid sequences shown in SEQ ID
NO: 7 and SEQ ID NO: 8.
Seattle Genetics: 15H3 (Ryan MC, et al Cancer Res April 15, 2012; 72(8
Supplement): 4630)
(41) CEACAM5 (Carcinoembryonic antigen-related cell adhesion molecule 5)
Nucleotide
Genbank accession no M17303
Genbank version no. M17303.1 GM 78676
Genbank record update date: Jun 23, 2010 08:47 AM Polypeptide
Genbank accession no. AAB59513
Genbank version no. AAB59513.1 GM 78677
Genbank record update date: Jun 23, 2010 08:47 AM
Cross references
Beauchemin N., et al Mol. Cell. Biol. 7 (9), 3221 -3230 (1987)
Other information
Official Symbol: CEACAM5
Other Aliases: CD66e, CEA
Other Designations: meconium antigen 100
ANTIBODIES
AstraZeneca-Medlmmune:US 20100330103; US20080057063;
US20020142359
for example an antibody having complementarity determining regions (CDRs) with the following sequences: heavy chain; CDR1 - DNYMH, CDR2 - WIDPENGDTE YAPKFRG, CDR3 - LIYAGYLAMD Y; and light chain CDR1 - SASSSVTYMH, CDR2 - STSNLAS, CDR3 -
QQRSTYPLT.
Hybridoma 806.077 deposited as European Collection of Cell Cultures (ECACC) deposit no. 96022936. Research Corporation Technologies, lnc.:US5,047,507
Bayer Corporation: US6,013,772
BioAlliance: US7,982,017; US7,674,605
· US 7,674,605
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. Celltech Therapeutics Limited: US5,877,293
The Dow Chemical Company: US5,472,693; US6,417,337; US6,333,405
US5,472,693 - for example, ATCC No. CRL-1 1215
US6,417,337 - for example, ATCC CRL-12208
US6,333,405 - for example, ATCC CRL-12208
Immunomedics, Inc: US7.534.431 ; US7.230.084; US7.300.644; US6.730.300;
US201 10189085
an antibody having CDRs of the light chain variable region comprise: CDR1 comprises KASQDVGTSVA (SEQ ID NO: 20); CDR2 comprises WTSTRHT (SEQ ID NO: 21 ); and CDR3 comprises QQYSLYRS (SEQ ID NO: 22);
and the CDRs of the heavy chain variable region of said anti-CEA antibody comprise: CDR1 comprises TYWMS (SEQ ID NO: 23); CDR2 comprises EIHPDSSTINYAPSLKD (SEQ ID NO: 24); and CDR3 comprises LYFGFPWFAY (SEQ ID NO: 25).
US20100221 175; US20090092598; US20070202044; US201 10064653;
US20090185974; US20080069775.
(42) MET (met proto-oncogene; hepatocyte growth factor receptor)
Nucleotide
Genbank accession no M35073
Genbank version no. M35073.1 GM 87553
Genbank record update date: Mar 6, 2012 1 1 :12 AM
Polypeptide
Genbank accession no. AAA59589
Genbank version no. AAA59589.1 Gl:553531
Genbank record update date: Mar 6, 2012 1 1 :12 AM
Cross references
Dean M., et al Nature 318 (6044), 385-388 (1985)
Other information Official Symbol: MET
Other Aliases: AUTS9, HGFR, RCCP2, c-Met
Other Designations: 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
ANTIBODIES
Abgenix/Pfizer: US20100040629
for example, the antibody produced by hybridoma 13.3.2 having American Type Culture Collection (ATCC) accession number PTA-5026; the antibody produced by hybridoma 9.1.2 having ATCC accession number PTA-5027; the antibody produced by hybridoma 8.70.2 having ATCC accession number PTA-5028; or the antibody produced by hybridoma 6.90.3 having ATCC accession number PTA-5029.
Amgen/Pfizer: US20050054019
for example, an antibody comprising a heavy chain having the amino acid sequences set forth in SEQ ID NO: 2 where X2 is glutamate and X4 is serine and a light chain having the amino acid sequence set forth in SEQ ID NO: 4 where X8 is alanine, without the signal sequences; an antibody comprising a heavy chain having the amino acid sequences set forth in SEQ ID NO: 6 and a light chain having the amino acid sequence set forth in SEQ ID NO: 8, without the signal sequences; an antibody comprising a heavy chain having the amino acid sequences set forth in SEQ ID NO: 10 and a light chain having the amino acid sequence set forth in SEQ ID NO: 12, without the signal sequences; or an antibody comprising a heavy chain having the amino acid sequences set forth in SEQ ID NO 14 and a light chain having the amino acid sequence set forth in SEQ ID NO: 16, without the signal sequences.
Agouron Pharmaceuticals (Now Pfizer): US20060035907 Eli Lilly: US20100129369
Genentech: US5,686,292; US20100028337; US20100016241 ; US20070129301 ;
US20070098707; US20070092520, US20060270594; US20060134104; US20060035278; US20050233960; US20050037431
US 5,686,292 - for example, ATCC HB-1 1894 and ATCC HB-1 1895 US 20100016241 - for example, ATCC HB-1 1894 (hybridoma 1A3.3.13) or HB- 1 1895 (hybridoma 5D5.1 1 .6)
National Defense Medical Center, Taiwan: Lu RM., et al Biomaterials. 201 1
Apr;32(12):3265-74.
Novartis: US20090175860
- for example, an antibody comprising the sequences of CDR1 , CDR2 and CDR3 of heavy chain 4687, 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.
Pharmacia Corporation: US20040166544
Pierre Fabre: US201 10239316, US201 10097262, US201001 15639 Sumsung: US 201 10129481 - for example a monoclonal antibody produced from a hybridoma cell having accession number KCLRF-BP-00219 or accession number of KCLRF-BP-00223.
Samsung: US 201 10104176 - for example an antibody produced by a hybridoma cell having Accession Number: KCLRF-BP-00220.
University of Turin Medical School: DN-30 Pacchiana G., et al J Biol Chem. 2010 Nov 12;285(46):36149-57 Van Andel Research Institute: Jiao Y., et al Mol Biotechnol. 2005 Sep;31 (1 ):41 -54.
(43) MUC1 (Mucin 1, cell surface associated)
Nucleotide
Genbank accession no J05581
Genbank version no. J05581.1 Gl:188869
Genbank record update date: Jun 23, 2010 08:48 AM Polypeptide
Genbank accession no. AAA59876
Genbank version no. AAA59876.1 GM 88870
Genbank record update date: Jun 23, 2010 08:48 AM
Cross references
Gendler S.J., et al J. Biol. Chem. 265 (25), 15286-15293 (1990) Other information
Official Symbol: MUC1
Other Aliases: RP1 1 -263K19.2, CD227, EMA, H23AG, KL-6, MAM6, MUC-1 , MUC-1/SEC, MUC-1/X, MUC1/ZD, PEM, PEMT, PUM
Other Designations: DF3 antigen; H23 antigen; breast carcinoma-associated antigen DF3; carcinoma-associated mucin; episialin; krebs von den Lungen-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
ANTIBODIES
AltaRex- Quest Pharma Tech: US 6,716,966 - for example an Alt-1 antibody produced by the hybridoma ATCC No PTA-975.
AltaRex- Quest Pharma Tech: US7, 147,850 CRT: 5E5 - S0rensen AL., et al Glycobiology vo\. 16 no. 2 pp. 96-107, 2006; HMFG2 - Burchell J., et al Cancer Res., 47, 5476-5482 (1987); see WO2015/159076
Glycotope GT-MAB: GT-MAB 2.5-GEX (Website:
http://www.glycotope.com/pipeline/pankomab-gex)
Immunogen: US7,202,346
- for example, antibody MJ-170: hybridoma cell line MJ-170 ATCC
accession no. PTA-5286Monoclonal antibody MJ-171 : hybridoma cell line MJ-171 ATCC accession no. PTA-5287; monoclonal antibody MJ- 172: hybridoma cell line MJ-172 ATCC accession no. PTA-5288; or monoclonal antibody MJ-173: hybridoma cell line MJ-173 ATCC accession no. PTA-5302
Immunomedics: US 6,653,104
Ramot Tel Aviv Uni: US7,897,351
Regents Uni. CA: US 7,183,388; US20040005647; US20030077676. Roche GlycArt: US8,021 ,856
Russian National Cancer Research Center: Imuteran- Ivanov PK., et al Biotechnol J. 2007 Jul;2(7):863-70 Technische Univ Braunschweig: (IIB6, HT186-B7, HT186-D1 1 , HT186-G2, HT200-3A-C1 , HT220-M-D1 , HT220-M-G8) - Thie H., et al PLoS One. 201 1 Jan 14;6(1 ):e15921
(44) CA9 (Carbonic anhydrase IX)
Nucleotide
Genbank accession no . X66839
Genbank version no. X66839.1 Gl:1000701
Genbank record update date: Feb 2, 201 1 10:15 AM
Polypeptide
Genbank accession no. CAA47315
Genbank version no. CAA47315.1 Gl:1000702
Genbank record update date: Feb 2, 201 1 10:15 AM
Cross references
Pastorek J., et al Oncogene 9 (10), 2877-2888 (1994)
Other information
Official Symbol: CA9
Other Aliases: CAIX, MN Other Designations: CA-IX; P54/58N; RCC-associated antigen G250; RCC-associated protein G250; carbonate dehydratase IX; carbonic anhydrase 9; carbonic dehydratase; membrane antigen MN; pMW1 ; renal cell carcinoma-associated antigen G250 ANTIBODIES
Abgenix/Amgen: US20040018198
Affibody: Anti-CAIX Affibody molecules
(http://www.affibody.com/en/Product-Portfolio/Pipeline/)
Bayer: US7,462,696
Bayer/Morphosys: 3ee9 mAb - Petrul HM., et al Mol Cancer Ther. 2012 Feb;1 1 (2):340-9 Harvard Medical School: Antibodies G10, G36, G37, G39, G45, G57, G106, G1 19, G6, G27, G40 and G125. Xu C, et al PLoS One. 2010 Mar 10;5(3):e9625
Institute of Virology, Slovak Academy of Sciences (Bayer) - US5,955,075
- for example, M75- ATCC Accession No. HB 1 1 128 or MN12 - ATCC Accession No. HB 1 1647
Institute of Virology, Slovak Academy of Sciences: US7, 816,493
for example the M75 monoclonal antibody that is secreted from the hybridoma VU-M75, which was deposited at the American Type Culture Collection under ATCC No. HB 1 1 128; or the V/10 monoclonal antibody secreted from the hybridoma V/10-VU, which was deposited at the International Depository Authority of the Belgian Coordinated Collection of Microorganisms (BCCM) at the Laboratorium voor Moleculaire Bioloqie-Plasmidencollectie (LMBP) at the Universeit Gent in Gent, Belgium, under Accession No. LMBP 6009CB.
Institute of Virology, Slovak Academy of Sciences US20080177046; US20080176310; US20080176258; US20050031623 Novartis: US20090252738 Wilex: US7,691 ,375 - for example the antibody produced by the hybridoma cell line DSM ASC 2526.
Wilex: US201 10123537; Rencarex: Kennett RH., et al Curr Opin Mol Ther. 2003
Feb;5(1 ):70-5
Xencor: US20090162382
(45) EGFRvlll ( Epidermal growth factor receptor (EGFR), transcript variant 3,
Nucleotide
Genbank accession no. NM_201283
Genbank version no. NM_201283.1 Gl:41327733
Genbank record update date: Sep 30, 2012 01 :47 PM Polypeptide
Genbank accession no. NP_958440
Genbank version no. NP_958440.1 Gl:41327734
Genbank record update date: Sep 30, 2012 01 :47 PM Cross-references
Batra SK., et al Cell Growth Differ 1995;6:1251-1259.
ANTIBODIES:
US7,628,986 and US7,736,644 (Amgen)
For example, a heavy chain variable region amino acid sequence selected from the group consisting of SEQ ID NO: 142 and variants & a light chain variable region amino acid sequence selected from the group consisting of: SEQ ID NO: 144 and variants. US201001 1 1979 (Amgen)
For example, an antibody comprising a heavy chain amino acid sequence comprising:
CDR1 consisting of a sequence selected from the group consisting of the amino acid sequences for the CDR1 region of antibodies 13.1 .2 (SEQ ID NO: 138), 131 (SEQ ID NO: 2), 170 (SEQ ID NO: 4), 150 (SEQ ID NO: 5), 095 (SEQ ID NO: 7), 250 (SEQ ID NO: 9), 139 (SEQ ID NO: 10), 21 1 (SEQ ID NO: 12), 124 (SEQ ID NO: 13), 318 (SEQ ID NO: 15), 342 (SEQ ID NO: 16), and 333 (SEQ ID NO: 17); CDR2 consisting of a sequence selected from the group consisting of the amino acid sequences for the CDR2 region of antibodies 13.1 .2 (SEQ ID NO: 138), 131 (SEQ ID NO: 2), 170 (SEQ ID NO: 4), 150 (SEQ ID NO: 5), 095 (SEQ ID NO: 7),
250 (SEQ ID NO: 9), 139 (SEQ ID NO: 10), 21 1 (SEQ ID NO: 12), 124 (SEQ ID NO: 13), 318 (SEQ ID NO: 15), 342 (SEQ ID NO: 16), and 333 (SEQ ID NO: 17); and
CDR3 consisting of a sequence selected from the group consisting of the amino acid sequences for the CDR3 region of antibodies 13.1 .2 (SEQ ID NO: 138), 131
(SEQ ID NO: 2), 170 (SEQ ID NO: 4), 150 (SEQ ID NO: 5), 095 (SEQ ID NO: 7), 250 (SEQ ID NO: 9), 139 (SEQ ID NO: 10), 21 1 (SEQ ID NO: 12), 124 (SEQ ID NO: 13), 318 (SEQ ID NO: 15), 342 (SEQ ID NO: 16), and 333 (SEQ ID NO: 17).
US20090240038 (Amgen)
For example, an antibody having at least one of the heavy or light chain
polypeptides comprises an amino acid sequence that is at least 90% identical to the amino acid sequence selected from the group consisting of: SEQ ID NO: 2, SEQ ID NO: 19, SEQ ID NO: 142, SEQ ID NO: 144, and any combination thereof.
US20090175887 (Amgen)
For example, an antibody having a heavy chain amino acid sequence selected from the group consisting of the heavy chain amino acid sequence of antibody 13.1 .2 (SEQ ID NO: 138), 131 (SEQ ID NO: 2), 170 (SEQ ID NO: 4), 150 (SEQ ID NO: 5), 095 (SEQ ID NO: 7), 250 (SEQ ID NO: 9), 139 (SEQ ID NO: 10), 21 1 (SEQ ID NO: 12), 124 (SEQ ID NO: 13), 318 (SEQ ID NO: 15), 342 (SEQ ID NO: 16), and 333 (SEQ ID NO: 17).
US20090156790 (Amgen)
For example, antibody having heavy chain polypeptide and a light chain
polypeptide, wherein at least one of the heavy or light chain polypeptides comprises an amino acid sequence that is at least 90% identical to the amino acid sequence selected from the group consisting of: SEQ ID NO: 2, SEQ ID NO: 19, SEQ ID NO: 142, SEQ ID NO: 144, and any combination thereof.
US20090155282, US20050059087 and US20050053608 (Amgen) For example, an antibody heavy chain amino acid sequence selected from the group consisting of the heavy chain amino acid sequence of antibody 13.1 .2 (SEQ ID NO: 138), 131 (SEQ ID NO: 2), 170 (SEQ ID NO: 4), 150 (SEQ ID NO: 5), 095 (SEQ ID NO: 7), 250 (SEQ ID NO: 9), 139 (SEQ ID NO: 10), 21 1 (SEQ ID NO: 12), 124 (SEQ ID NO: 13), 318 (SEQ ID NO: 15), 342 (SEQ ID NO: 16), and 333 (SEQ
ID NO: 17).
MR1 -1 (US7,129,332; Duke)
For example, a variant antibody having the sequence of SEQ ID NO.18 with the substitutions S98P-T99Y in the CDR3 VH, and F92W in CDR3 VL.
L8A4, H10, Y10 (Wikstrand CJ., et al Cancer Res. 1995 Jul 15;55(14):3140-8; Duke)
US2009031 1803 (Harvard University)
For example, SEQ ID NO:9 for antibody heavy chain variable region, and SEQ ID
NO: 3 for light chain variable region amino acid sequences
US20070274991 (EMD72000, also known as matuzumab; Harvard University)
For example, SEQ ID NOs: 3 & 9 for light chain and heavy chain respectively
US6,129,915 (Schering)
For example, SEQ. ID NOs: 1 , 2, 3, 4, 5 and 6. mAb CH12 - Wang H., et al FASEB J. 2012 Jan;26(1 ):73-80 (Shanghai Cancer Institute).
RAbDMvlll - Gupta P., et al BMC Biotechnol. 2010 Oct 7;10:72 (Stanford University Medical Center). mAb Ua30 - Ohman L, et al Tumour Biol. 2002 Mar-Apr;23(2):61 -9 (Uppsala University).
Han DC, et al Nan Fang Yi Ke Da Xue Xue Bao. 2010 Jan;30(1 ):25-9 (Xi'an Jiaotong University).
(46) CD33 (CD33 molecule)
Nucleotide
Genbank accession no. M 23197 Genbank version no. NM_23197.1 GM 80097
Genbank record update date: Jun 23, 2010 08:47 AM
Polypeptide
Genbank accession no. AAA51948
Genbank version no. AAA51948.1 GM 88098
Genbank record update date: Jun 23, 2010 08:47 AM
Cross-references
Simmons D., et al J. Immunol. 141 (8), 2797-2800 (1988)
Other information
Official Symbol: CD33
Other Aliases: SIGLEC-3, SIGLEC3, p67
Other Designations: CD33 antigen (gp67); gp67; myeloid cell surface antigen CD33; sialic acid binding Ig-like lectin 3; sialic acid-binding Ig-like lectin
ANTIBODIES
H195 (Lintuzumab)- Raza A., et al Leuk Lymphoma. 2009 Aug;50(8):1336-44;
US6, 759,045 (Seattle Genetics/lmmunomedics) mAb OKT9: Sutherland, D.R. et al. Proc Natl Acad Sci USA 78(7): 4515-4519 1981 , Schneider.C., et al J Biol Chem 257, 8516-8522 (1982) mAb E6: Hoogenboom,H.R., et al J Immunol 144, 321 1 -3217 (1990)
US6,590,088 (Human Genome Sciences)
For example, SEQ ID NOs: 1 and 2 and ATCC accession no. 97521 US7,557,189 (Immunogen)
For example, an antibody or fragment thereof comprising a heavy chain variable region which comprises three CDRs having the amino acid sequences of SEQ ID NOs:1 -3 and a light chain variable region comprising three CDRs having the amino acid sequences of SEQ ID NOs:4-6.
(47) CD19 (CD19 molecule) Nucleotide
Genbank accession no. NM_001 178098
Genbank version no. NM_001 178098.1 Gl:296010920
Genbank record update date: Sep 10, 2012 12:43 AM
Polypeptide
Genbank accession no. NP_001 171569
Genbank version no. NP_001 171569.1 Gl:296010921
Genbank record update date: Sep 10, 2012 12:43 AM
Cross-references
Tedder TF., et al J. Immunol. 143 (2): 712-7 (1989)
Other information
Official Symbol: CD19
Other Aliases: B4, CVID3
Other Designations: B-lymphocyte antigen CD19; B-lymphocyte surface antigen B4; T-cell surface antigen Leu-12; differentiation antigen CD19 ANTIBODIES
Immunogen: HuB4 - Al-Katib AM., et al Clin Cancer Res. 2009 Jun 15;15(12):4038-45.
4G7: Kugler M., et al Protein Eng Des Sel. 2009 Mar;22(3): 135-47
For example, sequences in Fig. 3 of of Knappik, A. et al. J Mol Biol 2000
Feb;296(1 ):57-86
AstraZeneca /Medlmmune: MEDI-551 - Herbst R., et al J Pharmacol Exp Ther. 2010 Oct;335(1 ):213-22 Glenmark Pharmaceuticals: GBR-401 - Hou S., et al Mol Cancer Ther November 201 1 (Meeting Abstract Supplement) C164
US7, 109,304 (Immunomedics)
For example, an antibody comprising the sequence of hA19Vk (SEQ ID NO:7) and the sequence of hA19VH (SEQ ID NO:10) US7,902,338 (Immunomedics)
For example, an antibody or antigen-binding fragment thereof that comprises the light chain complementarity determining region CDR sequences CDR1 of SEQ ID NO: 16 (KASQSVDYDGDSYLN); CDR2 of SEQ ID NO: 17 (DASNLVS); and CDR3 of SEQ ID NO: 18 (QQSTEDPWT) and the heavy chain CDR sequences CDR1 of
SEQ ID NO: 19 (SYWMN); CDR2 of SEQ ID NO: 20 (QIWPGDGDTNYNGKFKG) and CDR3 of SEQ ID NO: 21 (RETTTVGRYYYAMDY) and also comprises human antibody framework (FR) and constant region sequences with one or more framework region amino acid residues substituted from the corresponding framework region sequences of the parent murine antibody, and wherein said substituted FR residues comprise the substitution of serine for phenylalanine at Kabat residue 91 of the heavy chain variable region.
Medarex: MDX-1342 - Cardarelli PM., et al Cancer Immunol Immunother. 2010
Feb;59(2):257-65.
MorphoSys /Xencor: MOR-208/XmAb-5574 - Zalevsky J., et al Blood. 2009 Apr
16;1 13(16):3735-43 US7,968,687 (Seattle Genetics)
An antibody or antigen-binding fragment comprising a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO:9 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 24. 4G7 chim - Lang P., et al Blood. 2004 May 15;103(10):3982-5 (University of Tubingen) For example, fig. 6 and SEQ ID No: 80 of US20120082664
Zhejiang University School of Medicine: 2E8 - Zhang J., et al J Drug Target. 2010
Nov;18(9):675-8
(48) IL2RA (Interleukin 2 receptor, alpha); NCBI Reference Sequence: NM_000417.2); Nucleotide
Genbank accession no. NM_000417
Genbank version no. NM_000417.2 Gl:269973860
Genbank record update date: Sep 09, 2012 04:59 PM Polypeptide
Genbank accession no. NP_000408
Genbank version no. NP_000408.1 Gl:4557667
Genbank record update date: Sep 09, 2012 04:59 PM
Cross-references
Kuziel W.A., et al J. Invest. Dermatol. 94 (6 SUPPL), 27S-32S (1990)
Other information
Official Symbol: I L2RA
Other Aliases: RP1 1 -536K7.1 , CD25, IDDM10, IL2R, TCGFR
Other Designations: FIL-2 receptor subunit alpha; IL-2-RA; IL-2R subunit alpha; IL2-RA; TAC antigen; interleukin-2 receptor subunit alpha; p55 ANTIBODIES
US6,383,487 (Novartis/UCL: Baxilisimab [Simulect])
US6,521 ,230 (Novartis/UCL: Baxilisimab [Simulect])
For example, an antibody having an antigen binding site comprises at least one domain which comprises CDR1 having the amino acid sequence in SEQ. ID. NO: 7,
CDR2 having the amino acid sequence in SEQ. ID. NO: 8, and CDR3 chaving the amino acid sequence in SEQ. ID. NO: 9; or said CDR1 , CDR2 and CDR3 taken in sequence as a whole comprise an amino acid sequence which is at least 90% identical to SEQ. ID. NOs: 7, 8 and 9 taken in sequence as a whole.
Daclizumab - Rech AJ., et al Ann N Y Acad Sci. 2009 Sep;1 174:99-106 (Roche)
(49) AXL (AXL receptor tyrosine kinase)
Nucleotide
Genbank accession no. M76125
Genbank version no. M76125.1 Gl:292869
Genbank record update date: Jun 23, 2010 08:53 AM
Polypeptide
Genbank accession no. AAA61243
Genbank version no. AAA61243.1 Gl:29870 Genbank record update date: Jun 23, 2010 08:53 AM Cross-references
O'Bryan J. P., et al Mol. Cell. Biol. 1 1 (10), 5016-5031 (1991 ); Bergsagel P.L., et al J. Immunol. 148 (2), 590-596 (1992)
Other information
Official Symbol: AXL
Other Aliases: JTK1 1 , UFO
Other Designations: AXL oncogene; AXL transforming sequence/gene; oncogene AXL; tyrosine-protein kinase receptor UFO
ANTIBODIES
YW327.6S2 - Ye X., et al Oncogene. 2010 Sep 23;29(38):5254-64. (Genentech)
BergenBio: BGB324 (http://www.bergenbio.com/BGB324)
(50) CD30 - TNFRSF8 (Tumor necrosis factor receptor superfamily, member 8)
Nucleotide
Genbank accession no. M83554
Genbank version no. M83554.1 Gl:180095
Genbank record update date: Jun 23, 2010 08:53 AM
Polypeptide
Genbank accession no. AAA51947
Genbank version no. AAA51947.1 Gl:180096
Genbank record update date: Jun 23, 2010 08:53 AM
Cross-references
Durkop H., et al Ce// 68 (3), 421 -427 (1992)
Other information
Official Symbol: TNFRSF8
Other Aliases: CD30, D1 S166E, Ki-1
Other Designations: CD30L receptor; Ki-1 antigen; cytokine receptor CD30; lymphocyte activation antigen CD30; tumor necrosis factor receptor superfamily member 8 (51) BCMA (B-cell maturation antigen) - TNFRSF17 (Tumor necrosis factor receptor superfamily, member 17)
Nucleotide
Genbank accession no. Z29574
Genbank version no. Z29574.1 Gl:471244
Genbank record update date: Feb 02, 201 1 10:40 AM
Polypeptide
Genbank accession no. CAA82690
Genbank version no. CAA82690.1 Gl:471245
Genbank record update date: Feb 02, 201 1 10:40 AM
Cross-references
Laabi Y., et al Nucleic Acids Res. 22 (7), 1 147-1 154 (1994)
Other information
Official Symbol: TNFRSF17
Other Aliases: BCM, BCMA, CD269
Other Designations: B cell maturation antigen; B-cell maturation factor; B-cell maturation protein; tumor necrosis factor receptor superfamily member 17
(52) CTAgs - CTA (Cancer Testis Antigens)
Cross-references
Fratta E., et al. Mol Oncol. 201 1 Apr;5(2): 164-82; Lim SH., at al Am J Blood Res. 2012;2(1 ):29-35.
(53) CD174 (Lewis Y) - FUT3 (fucosyltransferase 3 (galactoside 3(4)-L-fucosyltransf erase, Lewis blood group)
Nucleotide
Genbank accession no. NM000149
Genbank version no. NM000149.3 Gl:148277008
Genbank record update date: Jun 26, 2012 04:49 PM
Polypeptide Genbank accession no. NP_000140
Genbank version no. NP_000140.1 Gl:4503809
Genbank record update date: Jun 26, 2012 04:49 PM Cross-references
Kukowska-Latallo,J.F., et al Genes Dev. 4 (8), 1288-1303 (1990)
Other information
Official Symbol: FUT3
Other Aliases: CD174, FT3B, FucT-lll, LE, Les
Other Designations: Lewis FT; alpha-(1 ,3/1 ,4)-fucosyltransferase; blood group Lewis alpha-4-fucosyltransferase; fucosyltransferase III; galactoside 3(4)-L-fucosyltransferase
(54) CLEC14A (C-type lectin domain family 14, member A; Genbank accession no. NM175060)
Nucleotide
Genbank accession no. NM175060
Genbank version no. NM175060.2 Gl:371 123930
Genbank record update date: Apr 01 , 2012 03:34 PM
Polypeptide
Genbank accession no. NP_778230
Genbank version no. NP_778230.1 Gl:28269707
Genbank record update date: Apr 01 , 2012 03:34 PM
Other information
Official Symbol: CLEC14A
Other Aliases: UNQ236/PR0269, C14orf27, CEG1 , EGFR-5
Other Designations: C-type lectin domain family 14 member A; CIECT and EGF-like domain containing protein; epidermal growth factor receptor 5
(55) GRP78 - HSPA5 (heat shock lOkDa protein 5 (glucose-regulated protein, 78kDa) Nucleotide
Genbank accession no. NM005347
Genbank version no. NM005347.4 Gl:305855105
Genbank record update date: Sep 30, 2012 01 :42 PM Polypeptide
Genbank accession no. NP_005338
Genbank version no. NP_005338.1 GM 6507237
Genbank record update date: Sep 30, 2012 01 :42 PM
Cross-references
Ting J., et al DNA 7 (4), 275-286 (1988) Other infromation
Official Symbol: HSPA5
Other Aliases: BIP, GRP78, MIF2
Other Designations: 78 kDa glucose-regulated protein; endoplasmic reticulum lumenal Ca(2+)-binding protein grp78; immunoglobulin heavy chain-binding protein
(56) CD70 (CD70 molecule) L08096
Nucleotide
Genbank accession no. L08096
Genbank version no. L08096.1 Gl:307127
Genbank record update date: Jun 23, 2012 08:54 AM
Polypeptide
Genbank accession no. AAA36175
Genbank version no. AAA36175.1 Gl:307128
Genbank record update date: Jun 23, 2012 08:54 AM
Cross-references
Goodwin R.G., et al Ce// 73 (3), 447-456 (1993) Other information
Official Symbol: CD70
Other Aliases: CD27L, CD27LG, TNFSF7
Other Designations: CD27 ligand; CD27-L; CD70 antigen; Ki-24 antigen; surface antigen CD70; tumor necrosis factor (ligand) superfamily, member 7; tumor necrosis factor ligand superfamily member 7 ANTIBODIES
MDX-141 1 against CD70 (Medarex) h1 F6 (Oflazoglu, E., et al, Clin Cancer Res. 2008 Oct 1 ;14(19):6171 -80; Seattle Genetics) For example, see US20060083736 SEQ ID NOs: 1 , 2, 1 1 and 12 and Fig. 1.
(57) Stem Cell specific antigens. For example:
• 5T4 (see entry (63) below)
• CD25 (see entry (48) above)
. CD32
o Polypeptide
■ Genbank accession no. ABK42161
■ Genbank version no. ABK42161.1 Gl:1 17616286
■ Genbank record update date: Jul 25, 2007 03:00 PM
•LGR5/GPR49
o Nucleotide
■ Genbank accession no. NM_003667
■ Genbank version no. NM_003667.2 Gl:24475886
■ Genbank record update date: Jul 22, 2012 03:38 PM
o Polypeptide
■ Genbank accession no. NP_003658
■ Genbank version no. NP_003658.1 Gl:4504379
■ Genbank record update date: Jul 22, 2012 03:38 PM
• Prominin/CD133
o Nucleotide
■ Genbank accession no. NM_006017
■ Genbank version no. NM_006017.2 Gl:224994187
■ Genbank record update date: Sep 30, 2012 01 :47 PM
o Polypeptide
■ Genbank accession no. NP_006008
■ Genbank version no. NP_006008.1 Gl:5174387
■ Genbank record update date: Sep 30, 2012 01 :47 PM
(58) ASG-5
Cross-references (Smith L.M., et.al AACR 2010 Annual Meeting (abstract #2590); Gudas J.M., et.al. AACR 2010 Annual Meeting (abstract #4393)
ANTIBODIES
Anti- AGS-5 Antibody: M6.131 (Smith, L.M., et.al AACR 2010 Annual Meeting (abstract #2590)
(59) ENPP3 (Ectonucleotide pyrophosphatase/phosphodiesterase 3)
Nucleotide
Genbank accession no. AF005632
Genbank version no. AF005632.2 Gl:4432589
Genbank record update date: Mar 10, 2010 09:41 PM
Polypeptide
Genbank accession no. AAC51813
Genbank version no. AAC51813.1 Gl:2465540
Genbank record update date: Mar 10, 2010 09:41 PM
Cross-references
Jin-Hua P., et al Genomics 45 (2), 412-415 (1997)
Other information
Official Symbol: ENPP3
Other Aliases: RP5-988G15.3, B10, CD203c, NPP3, PD-IBETA, PDNP3
Other Designations: E-NPP 3; dJ1005H1 1.3 (phosphodiesterase l/nucleotide
pyrophosphatase 3); dJ914N13.3 (phosphodiesterase l/nucleotide pyrophosphatase 3); ectonucleotide pyrophosphatase/phosphodiesterase family member 3; gp130RB13-6; phosphodiesterase I beta; phosphodiesterase l/nucleotide pyrophosphatase 3;
phosphodiesterase-l beta
(60) PRR4 (Proline rich 4 (lacrimal))
Nucleotide
Genbank accession no. NM_007244
Genbank version no. NM_007244.2 Gl:154448885
Genbank record update date: Jun 28, 2012 12:39 PM Polypeptide
Genbank accession no. NP_009175
Genbank version no. NP_009175.2 GM 54448886
Genbank record update date: Jun 28, 2012 12:39 PM
Cross-references
Dickinson D.P., et al Invest. Ophthalmol. Vis. Sci. 36 (10), 2020-2031 (1995)
Other information
Official Symbol: PRR4
Other Aliases: LPRP, PROL4
Other Designations: lacrimal proline-rich protein; nasopharyngeal carcinoma-associated proline-rich protein 4; proline-rich polypeptide 4; proline-rich protein 4 (61) GCC - GUCY2C (guanylate cyclase 2C (heat stable enterotoxin receptor)
Nucleotide
Genbank accession no. NM_004963
Genbank version no. NM_004963.3 Gl:222080082
Genbank record update date: Sep 02, 2012 01 :50 PM
Polypeptide
Genbank accession no. NP_004954
Genbank version no. NP_004954.2 Gl:222080083
Genbank record update date: Sep 02, 2012 01 :50 PM
Cross-references
De Sauvage F.J., et al J. Biol. Chem. 266 (27), 17912-17918 (1991 ); Singh S., et al Biochem. Biophys. Res. Commun. 179 (3), 1455-1463 (1991 ) Other information
Official Symbol: GUCY2C
Other Aliases: DIAR6, GUC2C, MUCIL, STAR
Other Designations: GC-C; STA receptor; guanylyl cyclase C; hSTAR; heat-stable enterotoxin receptor; intestinal guanylate cyclase
(62) Liv-1 - SLC39A6 (Solute carrier family 39 (zinc transporter), member 6) Nucleotide
Genbank accession no. U41060
Genbank version no. U41060.2 Gl:1271 1792
Genbank record update date: Nov 30, 2009 04:35 PM
Polypeptide
Genbank accession no. AAA96258
Genbank version no. AAA96258.2 Gl:1271 1793
Genbank record update date: Nov 30, 2009 04:35 PM
Cross-references
Taylor KM., et al Biochim Biophys Acta. 2003 Apr 1 ;161 1 (1 -2):16-30
Other information
Official Symbol: SLC39A6
Other Aliases: LIV-1
Other Designations: LIV-1 protein, estrogen regulated; ZIP-6; estrogen-regulated protein LIV-1 ; solute carrier family 39 (metal ion transporter), member 6; solute carrier family 39 member 6; zinc transporter ZIP6; zrt- and Irt-like protein 6
(63) 5T4, Trophoblast glycoprotein, TPBG - TPBG (trophoblast glycoprotein)
Nucleotide
Genbank accession no. AJ012159
Genbank version no. AJ012159.1 Gl:3805946
Genbank record update date: Feb 01 , 201 1 10:27 AM
Polypeptide
Genbank accession no. CAA09930
Genbank version no. CAA09930.1 Gl:3805947
Genbank record update date: Feb 01 , 201 1 10:27 AM
Cross-references
King K.W.,et al Biochim. Biophys. Acta 1445 (3), 257-270 (1999)
Other information
• Official Symbol: TPBG • Other Aliases: 5T4, 5T4AG, M6P1
• Other Designations: 5T4 oncofetal antigen; 5T4 oncofetal trophoblast
glycoprotein; 5T4 oncotrophoblast glycoprotein
• See WO2015/155345
(64) CD56 - NCMA 1 (Neural cell adhesion molecule 1)
Nucleotide
Genbank accession no. NM_000615
Genbank version no. NM_000615.6 Gl:336285433
Genbank record update date: Sep 23, 2012 02:32 PM
Polypeptide
Genbank accession no. NP_000606
Genbank version no. NP_000606.3 Gl:94420689
Genbank record update date: Sep 23, 2012 02:32 PM
Cross-references
Dickson, G., et al, Ce// 50 (7), 1 1 19-1 130 (1987) Other information
Official Symbol: NCAM1
Other Aliases: CD56, MSK39, NCAM
Other Designations: antigen recognized by monoclonal antibody 5.1 H1 1 ; neural cell adhesion molecule, NCAM
ANTIBODIES
Immunogen: HuN901 (Smith SV., et al Curr Opin Mol Ther. 2005 Aug;7(4):394-401 )
For example, see humanized from murine N901 antibody. See Fig. 1 b and 1 e of Roguska, M.A., et al. Proc Natl Acad Sci USA Feb 1994;91 :969-973.
(65) CanAg (Tumor associated antigen CA242)
Cross-references
Haglund C, et al Br J Cancer 60:845-851 , 1989;Baeckstrom D., et al J Biol Chem 266:21537-21547, 1991
ANTIBODIES huC242 (Tolcher AW et al., J Clin Oncol. 2003 Jan 15;21 (2):21 1 -22; Immunogen) For example, see US20080138898A1 SEQ ID NO: 1 and 2
(66) FOLR1 (Folate Receptor 1)
Nucleotide
Genbank accession no. J05013
Genbank version no. J05013.1 GM 82417
Genbank record update date: Jun 23, 2010 08:47 AM
Polypeptide
Genbank accession no. AAA35823
Genbank version no. AAA35823.1 GM 82418
Genbank record update date: Jun 23, 2010 08:47 AM
Cross-references
Elwood P.C., et al J. Biol. Chem. 264 (25), 14893-14901 (1989)
Other information
Official Symbol: FOLR1
Other Aliases: FBP, FOLR
Other Designations: FR-alpha; KB cells FBP; adult folate-binding protein; folate binding protein; folate receptor alpha; folate receptor, adult; ovarian tumor-associated antigen MOv18
ANTIBODIES
M9346A - Whiteman KR., et al Cancer Res April 15, 2012; 72(8 Supplement): 4628 (Immunogen) (67) GPNMB (Glycoprotein (transmembrane) nmb)
Nucleotide
Genbank accession no. X76534
Genbank version no. X76534.1 Gl:666042
Genbank record update date: Feb 02, 201 1 10:10 AM
Polypeptide Genbank accession no. CAA54044
Genbank version no. CAA54044.1 Gl:666043
Genbank record update date: Feb 02, 201 1 10:10 AM Cross-references
Weterman M.A., et al Int. J. Cancer 60 (1 ), 73-81 (1995)
Other information
Official Symbol: GPNMB
Other Aliases: UNQ1725/PR09925, HGFIN, NMB
Other Designations: glycoprotein NMB; glycoprotein nmb-like protein; osteoactivin;
transmembrane glycoprotein HGFIN; transmembrane glycoprotein NMB
ANTIBODIES
Celldex Therapeutics: CR01 1 (Tse KF., et al Clin Cancer Res. 2006 Feb 15; 12(4): 1373-82) For example, see EP1827492B1 SEQ ID NO: 22, 24, 26, 31 , 33 and 35
(68) TIM-1 - HAVCR1 (Hepatitis A virus cellular receptor 1)
Nucleotide
Genbank accession no. AF043724
Genbank version no. AF043724.1 Gl:2827453
Genbank record update date: Mar 10, 2010 06:24 PM
Polypeptide
Genbank accession no. AAC39862
Genbank version no. AAC39862.1 Gl:2827454
Genbank record update date: Mar 10, 2010 06:24 PM
Cross-references
Feigelstock D., et al J. Virol. 72 (8), 6621 -6628 (1998)
Other information
Official Symbol: HAVCR1
Other Aliases: HAVCR, HAVCR-1 , KIM-1 , KIM1 , TIM, TIM-1 , TIM1 , TIMD-1 , TIMD1 Other Designations: T cell immunoglobin domain and mucin domain protein 1 ; T-cell membrane protein 1 ; kidney injury molecule 1 (69) RG-1 /Prostate tumor target Mindin - Mindin/RG-1
Cross-references
Parry R., et al Cancer Res. 2005 Sep 15;65(18):8397-405
(70) B7-H4 - VTCN1 (V-set domain containing T cell activation inhibitor 1
Nucleotide
Genbank accession no. BX648021
Genbank version no. BX648021.1 Gl:34367180
Genbank record update date: Feb 02, 201 1 08:40 AM
Cross-references
Sica GL, et al Immunity. 2003 Jun;18(6):849-61 Other information
Official Symbol: VTCN1
Other Aliases: RP1 1 -229A19.4, B7-H4, B7H4, B7S1 , B7X, B7h.5, PR01291 , VCTN1 Other Designations: B7 family member, H4; B7 superfamily member 1 ; T cell costimulatory molecule B7x; T-cell costimulatory molecule B7x; V-set domain-containing T-cell activation inhibitor 1 ; immune costimulatory protein B7-H4
(71) PTK7 (PTK7 protein tyrosine kinase 7)
Nucleotide
Genbank accession no. AF447176
Genbank version no. AF447176.1 Gl:17432420
Genbank record update date: Nov 28, 2008 01 :51 PM
Polypeptide
Genbank accession no. AAL39062
Genbank version no. AAL39062.1 GM 7432421
Genbank record update date: Nov 28, 2008 01 :51 PM
Cross-references
Park S.K.,et al J. Biochem. 1 19 (2), 235-239 (1996) Other information
Official Symbol: PTK7
Other Aliases: CCK-4, CCK4
Other Designations: colon carcinoma kinase 4; inactive tyrosine-protein kinase 7; pseudo tyrosine kinase receptor 7; tyrosine-protein kinase-like 7
(72) CD37 (CD37 molecule)
Nucleotide
Genbank accession no. NM_001040031
Genbank version no. NM_001040031.1 Gl:91807109
Genbank record update date: Jul 29, 2012 02:08 PM
Polypeptide
Genbank accession no. NP_001035120
Genbank version no. NP_001035120.1 Gl:918071 10
Genbank record update date: Jul 29, 2012 02:08 PM
Cross-references
Schwartz-Albiez R., et al J. Immunol. 140 (3), 905-914 (1988)
Other information
Official Symbol: CD37
Other Aliases: GP52-40, TSPAN26
Other Designations: CD37 antigen; cell differentiation antigen 37; leukocyte antigen CD37; leukocyte surface antigen CD37; tetraspanin-26; tspan-26
ANTIBODIES
Boehringer Ingelheim: mAb 37.1 (Heider KH., et al Blood. 201 1 Oct 13;1 18(15):4159-68) Trubion: CD37-SMIP (G28-1 scFv-lg) ((Zhao X., et al Blood. 2007;1 10: 2569-2577)
For example, see US201 10171208A1 SEQ ID NO: 253
Immunogen: K7153A (Deckert J., et al Cancer Res April 15, 2012; 72(8
Supplement): 4625)
(73) CD138 - SDC1 (syndecan 1) Nucleotide
Genbank accession no. AJ551 176
Genbank version no. AJ551 176.1 Gl:29243141
Genbank record update date: Feb 01 , 201 1 12:09 PM
Polypeptide
Genbank accession no. CAD80245
Genbank version no. CAD80245.1 Gl:29243142
Genbank record update date: Feb 01 , 201 1 12:09 PM
Cross-references
O'Connell FP., et al Am J Clin Pathol. 2004 Feb;121 (2):254-63
Other information
Official Symbol: SDC1
Other Aliases: CD138, SDC, SYND1 , syndecan
Other Designations: CD138 antigen; heparan sulfate proteoglycan fibroblast growth factor receptor; syndecan proteoglycan 1 ; syndecan-1 ANTIBODIES
Biotest: chimerized MAb (nBT062) - (Jagannath S., et al Poster ASH #3060, 2010; WIPO Patent Application WO/2010/128087)
For example, see US20090232810 SEQ ID NO: 1 and 2 Immunogen: B-B4 (Tassone P., et al Blood 104_3688-3696)
For example, see US20090175863A1 SEQ ID NO: 1 and 2
(74) CD74 (CD74 molecule, major histocompatibility complex, class II invariant chain) Nucleotide
Genbank accession no. NM_004355
Genbank version no. NM_004355.1 Gl:343403784
Genbank record update date: Sep 23, 2012 02:30 PM
Polypeptide
Genbank accession no. NP_004346
Genbank version no. NP 004346.1 Gl:10835071 Genbank record update date: Sep 23, 2012 02:30 PM Cross-references
Kudo,J., et al Nucleic Acids Res. 13 (24), 8827-8841 (1985)
Other information
Official Symbol: CD74
Other Aliases: DHLAG, HLADG, II, la-GAMMA
Other Designations: CD74 antigen (invariant polypeptide of major histocompatibility complex, class II antigen-associated); HLA class II histocompatibility antigen gamma chain; HLA-DR antigens-associated invariant chain; HLA-DR-gamma; la-associated invariant chain; MHC HLA-DR gamma chain; gamma chain of class II antigens; p33
ANTIBODIES
Immunomedics: hLL1 (Milatuzumab,) - Berkova Z., et al Expert Opin Investig Drugs. 2010 Jan;19(1 ):141 -9)
For example, see US200401 15193 SEQ ID NOs: 19, 20, 21 , 22, 23 and 24 Genmab: HuMax-CD74 (see website)
(75) Claudins - CLs (Claudins)
Cross-references
Offner S., et al Cancer Immunol Immunother. 2005 May; 54(5):431 -45, Suzuki H., et al Ann N YAcad Sci. 2012 Jul;1258:65-70)
In humans, 24 members of the family have been described - see literature reference.
(76) EGFR (Epidermal growth factor receptor)
Nucleotide
Genbank accession no. NM_005228
Genbank version no. NM_005228.3 Gl:41927737
Genbank record update date: Sep 30, 2012 01 :47 PM
Polypeptide
Genbank accession no. NP_005219
Genbank version no. NP 005219.2 Gl:29725609 Genbank record update date: Sep 30, 2012 01 :47 PM
Cross-references
Dhomen NS., et al Crit Rev Oncog. 2012;17(1 ):31-50
Other information
Official Symbol: EGFR
Other Aliases: ERBB, ERBB1 , HER1 , PIG61 , mENA
Other Designations: avian erythroblastic leukemia viral (v-erb-b) oncogene homolog; cell growth inhibiting protein 40; cell proliferation-inducing protein 61 ; proto-oncogene c-ErbB-1 ; receptor tyrosine-protein kinase erbB-1
ANTIBODIES
BMS: Cetuximab (Erbitux) - Broadbridge VT., et al Expert Rev Anticancer Ther. 2012 May;12(5):555-65.
For example, see US6217866 - ATTC deposit No. 9764.
Amgen: Panitumumab (Vectibix) - Argiles G., et al Future Oncol. 2012 Apr;8(4):373-89 For example, see US6235883 SEQ ID NOs: 23-38.
Genmab: Zalutumumab - Rivera F., et al Expert Opin Biol Ther. 2009 May;9(5):667-74.
YM Biosciences: Nimotuzumab - Ramakrishnan MS., et al MAbs. 2009 Jan-Feb;1 (1 ):41 -8.
For example, see US5891996 SEQ ID NOs: 27-34.
(77) Her3 (ErbB3) - ERBB3 (v-erb-b2 erythroblastic leukemia viral oncogene homolog 3
(avian))
Nucleotide
Genbank accession no. M34309
Genbank version no. M34309.1 GM 83990
Genbank record update date: Jun 23, 2010 08:47 PM
Polypeptide
Genbank accession no. AAA35979
Genbank version no. AAA35979.1 Gl:306841
Genbank record update date: Jun 23, 2010 08:47 PM Cross-references
Plowman,G.D., et al., Proc. Natl. Acad. Sci. U.S.A. 87 (13), 4905-4909 (1990) Other information
Official Symbol: ERBB3
Other Aliases: ErbB-3, HER3, LCCS2, MDA-BF-1 , c-erbB-3, c-erbB3, erbB3-S, p180- ErbB3, p45-sErbB3, p85-sErbB3
Other Designations: proto-oncogene-like protein c-ErbB-3; receptor tyrosine-protein kinase erbB-3; tyrosine kinase-type cell surface receptor HER3
ANTIBODIES
Merimack Pharma : MM-121 (Schoeberl B., et al Cancer Res. 2010 Mar 15;70(6):2485- 2494)
For example, see US201 1028129 SEQ ID NOs: 1 , 2, 3, 4, 5, 6, 7 and 8.
(78) RON - MST1R (macrophage stimulating 1 receptor (c-met-related tyrosine kinase)) Nucleotide
Genbank accession no. X70040
Genbank version no. X70040.1 Gl:36109
Genbank record update date: Feb 02, 201 1 10:17 PM
Polypeptide
Genbank accession no. CCA49634
Genbank version no. CCA49634.1 Gl:361 10
Genbank record update date: Feb 02, 201 1 10:17 PM
Cross-references
Ronsin C, et al Oncogene 8 {5), 1 195-1202 (1993)
Other information
Official Symbol: MST1 R
Other Aliases: CD136, CDw136, PTK8, RON
Other Designations: MSP receptor; MST1 R variant RON30; MST1 R variant RON62; PTK8 protein tyrosine kinase 8; RON variant E2E3; c-met-related tyrosine kinase; macrophage- stimulating protein receptor; p185-Ron; soluble RON variant 1 ; soluble RON variant 2; soluble RON variant 3; soluble RONvariant 4
(79) EPHA2 (EPH receptor A2)
Nucleotide
Genbank accession no. BC037166
Genbank version no. BC037166.2 Gl:33879863
Genbank record update date: Mar 06, 2012 01 :59 PM Polypeptide
Genbank accession no. AAH37166
Genbank version no. AAH37166.1 Gl:22713539
Genbank record update date: Mar 06, 2012 01 :59 PM Cross-references
Strausberg R.L., et al Proc. Natl. Acad. Sci. U.S.A. 99 (26), 16899-16903 (2002)
Other information
Official Symbol: EPHA2
Other Aliases: ARCC2, CTPA, CTPP1 , ECK
Other Designations: ephrin type-A receptor 2; epithelial cell receptor protein tyrosine kinase; soluble EPHA2 variant 1 ; tyrosine-protein kinase receptor ECK
ANTIBODIES
Medimmune: 1 C1 (Lee JW., et al Clin Cancer Res. 2010 May 1 ;16(9):2562-2570) For example, see US20090304721A1 Fig. 7 and 8.
(80) CD20 - MS4A 1 (membrane-spanning 4-domains, subfamily A, member 1)
Nucleotide
Genbank accession no. M27394
Genbank version no. M27394.1 GM 79307
Genbank record update date: Nov 30, 2009 1 1 :16 AM
Polypeptide
Genbank accession no. AAA35581
Genbank version no. AAA35581.1 GM 79308 Genbank record update date: Nov 30, 2009 1 1 :16 AM
Cross-references
Tedder T.F., et al Proc. Natl. Acad. Sci. U.S.A. 85 (1 ), 208-212 (1988)
Other information
Official Symbol: MS4A1
Other Aliases: B1 , Bp35, CD20, CVID5, LEU-16, MS4A2, S7
Other Designations: B-lymphocyte antigen CD20; B-lymphocyte cell-surface antigen B1 ; CD20 antigen; CD20 receptor; leukocyte surface antigen Leu-16
ANTIBODIES
Genentech/Roche: Rituximab - Abdulla NE., et al BioDrugs. 2012 Apr 1 ;26(2):71 -82.
For example, see US5736137, ATCC deposit No. HB-691 19.
GSK/Genmab: Ofatumumab - Nightingale G., et al Ann Pharmacother. 201 1
Oct;45(10):1248-55.
For example, see US20090169550A1 SEQ ID NOs: 2, 4 and 5. Immunomedics: Veltuzumab - Goldenberg DM., et al Leuk Lymphoma. 2010
May;51 (5):747-55.
For example, see US7919273B2 SEQ ID NOs: 1 , 2, 3, 4, 5 and 6.
(81) Tenascin C - TNC (Tenascin C)
Nucleotide
Genbank accession no. NM_002160
Genbank version no. NM_002160.3 Gl:340745336
Genbank record update date: Sep 23, 2012 02:33 PM
Polypeptide
Genbank accession no. NP_002151
Genbank version no. NP_002151.2 Gl:153946395
Genbank record update date: Sep 23, 2012 02:33 PM
Cross-references Nies D.E., et al J. Biol. Chem. 266 (5), 2818-2823 (1991 ); Siri A., et al Nucleic Acids Res. 19 (3), 525-531 (1991 )
Other information
Official Symbol: TNC
Other Aliases: 150-225, GMEM, GP, HXB, Jl, TN, TN-C
Other Designations: GP 150-225; cytotactin; glioma-associated-extracellular matrix antigen; hexabrachion (tenascin); myotendinous antigen; neuronectin; tenascin; tenascin-C isoform 14/AD1/16
ANTIBODIES
Philogen : G1 1 (von Lukowicz T., et al J Nucl Med. 2007 Apr;48(4):582-7) and F16 (Pedretti M., et al Lung Cancer. 2009 Apr;64(1 ):28-33)
For example, see US7968685 SEQ ID NOs: 29, 35, 45 and 47.
(82) FAP (Fibroblast activation protein, alpha)
Nucleotide
Genbank accession no. U09278
Genbank version no. U09278.1 Gl:1888315
Genbank record update date: Jun 23, 2010 09:22 AM
Polypeptide
Genbank accession no. AAB49652
Genbank version no. AAB49652.1 Gl:1888316
Genbank record update date: Jun 23, 2010 09:22 AM
Cross-references
Scanlan,M.J.,et al Proc. Natl. Acad. Sci. U.S.A. 91 (12), 5657-5661 (1994) Other information
Official Symbol: FAP
Other Aliases: DPPIV, FAPA
Other Designations: 170 kDa melanoma membrane-bound gelatinase; integral membrane serine protease; seprase
(83) DKK-1 (Dickkopf 1 homolog (Xenopus laevis) Nucleotide
Genbank accession no. NM_012242
Genbank version no. NM_012242.2 Gl:61676924
Genbank record update date: Sep 30, 2012 01 :48 PM
Polypeptide
Genbank accession no. NP_036374
Genbank version no. NP_036374.1 Gl:71 10719
Genbank record update date: Sep 30, 2012 01 :48 PM
Cross-references
Fedi P. et al J. Biol. C em. 274 (27), 19465-19472 (1999)
Other information
Official Symbol: DKK1
Other Aliases: UNQ492/PRO1008, DKK-1 , SK
Other Designations: dickkopf related protein-1 ; dickkopf-1 like; dickkopf-like protein 1 ; dickkopf-related protein 1 ; hDkk-1 ANTIBODIES
Novartis: BHQ880 (Fulciniti M., et al Blood. 2009 Jul 9;1 14(2):371 -379)
For example, see US20120052070A1 SEQ ID NOs: 100 and 108.
(84) CD52 (CD52 molecule)
Nucleotide
Genbank accession no. NM_001803
Genbank version no. NM_001803.2 Gl:68342029
Genbank record update date: Sep 30, 2012 01 :48 PM Polypeptide
Genbank accession no. NP_001794
Genbank version no. NP_001794.2 Gl:68342030
Genbank record update date: Sep 30, 2012 01 :48 PM Cross-references
Xia M.Q., et al Eur. J. Immunol. 21 (7), 1677-1684 (1991 ) Other information
Official Symbol: CD52
Other Aliases: CDW52
Other Designations: CAMPATH-1 antigen; CD52 antigen (CAMPATH-1 antigen); CDW52 antigen (CAMPATH-1 antigen); Cambridge pathology 1 antigen; epididymal secretory protein E5; he5; human epididymis-specific protein 5
ANTIBODIES
Alemtuzumab (Campath) - Skoetz N., et al Cochrane Database Syst Rev. 2012 Feb 15;2:CD008078.
For example, see Drugbank Acc. No. DB00087 (BIOD00109, BTD00109)
(85) CS1 - SLAMF7 (SLAM family member 7)
Nucleotide
Genbank accession no. NM_021 181
Genbank version no. NM_021 181.3 GM 993571
Genbank record update date: Jun 29, 2012 1 1 :24 AM Polypeptide
Genbank accession no. NP_067004
Genbank version no. NP_067004.3 Gl:19923572
Genbank record update date: Jun 29, 2012 1 1 :24 AM Cross-references
Boles K.S., et al Immunogenetics 52 (3-4), 302-307 (2001 )
Other information
Official Symbol: SLAMF7
Other Aliases: UNQ576/PR01 138, 19A, CD319, CRACC, CS1
Other Designations: 19A24 protein; CD2 subset 1 ; CD2-like receptor activating cytotoxic cells; CD2-like receptor-activating cytotoxic cells; membrane protein FOAP-12; novel LY9 (lymphocyte antigen 9) like protein; protein 19A ANTIBODIES BMS: elotuzumab/HuLuc63 (Benson DM., et a I J Clin Oncol. 2012 Jun 1 ;30(16):2013- 2015)
For example, see US201 10206701 SEQ ID NOs: 9, 10, 1 1 , 12, 13, 14, 15 and 16. (86) Endoglin - ENG (Endoglin)
Nucleotide
Genbank accession no. AF035753
Genbank version no. AF035753.1 Gl:3452260
Genbank record update date: Mar 10, 2010 06:36 PM
Polypeptide
Genbank accession no. AAC32802
Genbank version no. AAC32802.1 Gl:3452261
Genbank record update date: Mar 10, 2010 06:36 PM
Cross-references
Rius C, et al Blood 92 (12), 4677-4690 (1998)
Official Symbol: ENG Other information
Other Aliases: RP1 1 -228B15.2, CD105, END, HHT1 , ORW, ORW1
Other Designations: CD105 antigen
(87) Annexin A 1 - ANXA 1 (Annexin A1)
Nucleotide
Genbank accession no. X05908
Genbank version no. X05908.1 Gl:34387
Genbank record update date: Feb 02, 201 1 10:02 AM Polypeptide
Genbank accession no. CCA29338
Genbank version no. CCA29338.1 Gl:34388
Genbank record update date: Feb 02, 201 1 10:02 AM Cross-references
Wallner B.P.,et al Nature 320 (6057), 77-81 (1986) Other information
Official Symbol: ANXA1
Other Aliases: RP1 1 -71A24.1 , ANX1 , LPC1
Other Designations: annexin I (lipocortin I); annexin-1 ; calpactin II; calpactin-2;
chromobindin-9; lipocortin I; p35; phospholipase A2 inhibitory protein
(88) V-CAM (CD106) - VCAM1 (Vascular cell adhesion molecule 1)
Nucleotide
Genbank accession no. M60335
Genbank version no. M60335.1 Gl:340193
Genbank record update date: Jun 23, 2010 08:56 AM
Polypeptide
Genbank accession no. AAA61269
Genbank version no. AAA61269.1 Gl:340194
Genbank record update date: Jun 23, 2010 08:56 AM
Cross-references
Hession C, et al J. Biol. Chem. 266 (1 1 ), 6682-6685 (1991 )
Other information
Official Symbol VCAM1
Other Aliases: CD106, INCAM-100
Other Designations: CD106 antigen; vascular cell adhesion protein 1
Antibody Sequences
Anti-lntegrin ανββ
RHAB6.2
QVQLVQSGSELKKPGASVKISCKASGFAFTDSYMHWVRQAPGQGLEWMGWIDPENGDT EYAPKFQGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCTRGTPTAVPNLRGDLQVLAQKVA GPYPFDYWGQGTLVTVSS
RHCB6.2 QVQLVQSGAEVKKPGASVKVSCKASGYTFIDSYMHWVRQAPGQRLEWMGWIDPENGDT
EYAPKFQGRVTITTDTSASTAYMELSSLRSEDTAVYYCARGTPTAVPNLRGDLQVLAQKV
AGPYPFDYWGQGTLVTVSS RHF
QVQLVQSGAEVKKPGASVKVSCKASGFNFIDSYMHWVRQAPGQRLEWMGWIDPENGD TEYAPKFQGRVTFTTDTSASTAYMELSSLRSEDTAVYYCNEGTPTGPYYFDYWGQGTLV TVSS RHFB6
QVQLVQSGAEVKKPGASVKVSCKASGFNFIDSYMHWVRQAPGQRLEWMGWIDPENGD
TEYAPKFQGRVTFTTDTSASTAYMELSSLRSEDTAVYYCNEGTPTAVPNLRGDLQVLAQK
VAGPYYFDYWGQGTLVTVSS RHAYI OObP
QVQLVQSGSELKKPGASVKISCKASGFAFTDSYMHWVRQAPGQGLEWMGWIDPENGDT EYAPKFQGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCTRGTPTGPYPFDYWGQGTLVTV SS RKF
ENVLTQSPGTLSLSPGERATLSCSASSSVSYMHWFQQKPGQAPRLLIYSTSNLASGIPDR FSGSGSGTDFTLTISRLEPEDFAVYYCQQRSSYPLTFGGGTKVEIK
RKFL36L50
ENVLTQSPGTLSLSPGERATLSCSASSSVSYMHWLQQKPGQAPRLLIYLTSNLASGIPDR FSGSGSGTDFTLTISRLEPEDFAVYYCQQRSSYPLTFGGGTKVEIK
RKC
EIVLTQSPGTLSLSPGERATLSCSASSSVSYMHWFQQKPGQAPRLLIYSTSNLASGIPDRF SGSGSGTDFTLTISRLEPEDFAVYYCQQRSSYPLTFGGGTKVEIK
Anti-CD33
CD33 Hum195 VH
QVQLVQSGAEVKKPGSSVKVSCKASGYTFTDYNMHWVRQAPGQGLEWIGYIYPYNGGT GYNQKFKSKATITADESTNTAYMELSSLRSEDTAVYYCARGRPAMDYWGQGTLVTVSS CD33 Hum195 VK
DIQMTQSPSSLSASVGDRVTITCRASESVDNYGISFMNWFQQKPGKAPKLLIYAASNQGS GVPSRFSGSGSGTDFTLTISSLQPDDFATYYCQQSKEVPWTFGQGTKVEIK Anti-CD19
CD19 B4 resurfaced VH
QVQLVQPGAEWKPGASVKLSCKTSGYTFTSNWMHWVKQRPGQGLEWIGEIDPSDSYT NYNQNFKGKAKLTVDKSTSTAYMEVSSLRSDDTAVYYCARGSNPYYYAMDYWGQGTSV TVSS
CD19 B4 resurfaced VK
EIVLTQSPAIMSASPGERVTMTCSASSGVNYMHWYQQKPGTSPRRWIYDTSKLASGVPA RFSGSGSGTSYSLTISSMEPEDAATYYCHQRGSYTFGGGTKLEIK Anti-Her2
Herceptin VH chain
EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTR YADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQGTLVT VSS
Herceptin VL chain
DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPS RFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIK Anti-CD25
Simulect VK (also known as Basiliximab)
QIVSTQSPAIMSASPGEKVTMTCSASSSRSYMQWYQQKPGTSPKRWIYDTSKLASGVPA RFSGSGSGTSYSLTISSMEAEDAATYYCHQRSSYTFGGGTKLEIK Simulect VH
QLQQSGTVLARPGASVKMSCKASGYSFTRYWMHWIKQRPGQGLEWIGAIYPGNSDTSY NQKFEGKAKLTAVTSASTAYMELSSLTHEDSAVYYCSRDYGYYFDFWGQGTTLTVSS
Anti-PSMA
Deimmunised VH Ί EVQLVQSGPEVKKPGATVKISCKTSGYTFTEYTIHWVKQAPGKGLEWIGNINPNNGGTTY NQKFEDKATLTVDKSTDTAYMELSSLRSEDTAVYYCAAGWNFDYWGQGTLLTVSS
Deimmunised VK Ί
DIQMTQSPSSLSTSVGDRVTLTCKASQDVGTAVDWYQQKPGPSPKLLIYWASTRHTGIPS RFSGSGSGTDFTLTISSLQPEDFADYYCQQYNSYPLTFGPGTKVDIK
Deimmunised VH1 '5
EVKLVESGGGLVQPGGSMKLSCVASGFTFSNYWMNWVRQAPGKGLEWVAEIRSQSNN FATHYAESVKGRVTISRDDSKSIVYLQMNNLRAEDTGVYYCTRRWNNFWGQGTTVTVSS
Deimmunised VH2 '5
EVKLVESGGGLVQPGGSLKLSCVASGFTFSNYWMNWVRQAPGKGLEWVAEIRSQSNNF ATHYAESVKGRVTISRDDSKSIVYLQMNNLRAEDTAVYYCTRRWNNFWGQGTTVTVSS
Deimmunised VH3 '5
EVQLVESGGGLVQPGGSLKLSCVASGFTFSNYWMNWVRQAPGKGLEWVAEIRSQSNNF ATHYAESVKGRVTISRDDSKSIVYLQMNNLRAEDTAVYYCTRRWNNFWGQGTTVTVSS Deimmunised VH4 '5
EVQLVESGGGLVQPGGSLKLSCVASGFTFSNYWMNWVRQAPGKGLEWVAEIRSQSNNF ATHYAESVKGRFTISRDDSKSIVYLQMNNLRAEDTAVYYCTRRWNNFWGQGTTVTVSS
Deimmunised VK1 '5
NIVMTQFPSSMSASVGDRVTITCKASENVGTYVSWYQQKPDQSPKMLIYGASNRFTGVP DRFTGSGSATDFTLTISSLQTEDLADYYCGQSYTFPYTFGQGTKLEMK
Deimmunised VK2 '5
NIVMTQFPSSMSASVGDRVTITCKASENVGTYVSWYQQKPDQSPKMLIYGASNRFTGVP DRFSGSGSGTDFTLTISSLQAEDLADYYCGQSYTFPYTFGQGTKLEIK
Deimmunised VK3 '5
NIQMTQFPSAMSASVGDRVTITCKASENVGTYVSWYQQKPDQSPKMLIYGASNRFTGVP DRFSGSGSGTDFTLTISSLQAEDLADYYCGQSYTFPYTFGQGTKLEIK
Deimmunised VK4 '5 NIQMTQFPSAMSASVGDRVTITCKASENVGTYVSWYQQKPDQSPKMLIYGASNRFTGVP DRFSGSGSGTDFTLTISSLQAEDEADYYCGQSYTFPYTFGQGTKLEIK
Deimmunised VK PI '5
NIVMTQFPKSMSASAGERMTLTCKASENVGTYVSWYQQKPTQSPKMLIYGASNRFTGVP DRFSGSGSGTDFILTISSVQAEDLVDYYCGQSYTFPYTFGGGTKLEMK
Deimmunised VH PI '5
EVKLEESGGGLVQPGGSMKISCVASGFTFSNYWMNWVRQSPEKGLEWVAEIRSQSNNF ATHYAESVKGRVIISRDDSKSSVYLQMNSLRAEDTAVYYCTRRWNNFWGQGTTVTVSS
Humanised RHA '5
EVQLVESGGGLVQPGGSLKLSCAASGFTFSNYWMNWVRQASGKGLEWVGEIRSQSNNF ATHYAESVKGRFTISRDDSKNTAYLQMNSLKTEDTAVYYCTRRWNNFWGQGTTVTVSS
Humanised RHB '5
EVKLVESGGGLVQPGGSLKLSCAASGFTFSNYWMNWVRQASGKGLEWVAEIRSQSNNF ATHYAESVKGRVIISRDDSKNTVYLQMNSLRTEDTAVYYCTRRWNNFWGQGTTVTVSS Humanised RHC '5
EVQLVESGGGLVQPGGSLKLSCAASGFTFSNYWMNWVRQASGKGLEWVAEIRSQSNNF ATHYAESVKGRVIISRDDSKNTVYLQMNSLRTEDTAVYYCTRRWNNFWGQGTTVTVSS
Humanised RHP '5
EVKLVESGGGLVQPGGSLKLSCAASGFTFSNYWMNWVRQASGKGLEWVGEIRSQSNNF ATHYAESVKGRVIISRDDSKNTVYLQMNSLRTEDTAVYYCTRRWNNFWGQGTTVTVSS
Humanised RHE '5
EVKLVESGGGLVQPGGSLKLSCAASGFTFSNYWMNWVRQASGKGLEWVAEIRSQSNNF ATHYAESVKGRFTISRDDSKNTVYLQMNSLRTEDTAVYYCTRRWNNFWGQGTTVTVSS
Humanised RHF '5
EVKLVESGGGLVQPGGSLKLSCAASGFTFSNYWMNWVRQASGKGLEWVAEIRSQSNNF ATHYAESVKGRVIISRDDSKNTAYLQMNSLRTEDTAVYYCTRRWNNFWGQGTTVTVSS
Humanised RHG '5 EVKLVESGGGLVQPGGSLKLSCAASGFTFSNYWMNWVRQASGKGLEWVAEIRSQSNNF ATHYAESVKGRVIISRDDSKNTAYLQMNSLRTEDTAVYYCTRRWNNFWGQGTTVTVSS
Humanised RKA '5
DIQMTQSPSSVSASVGDRVTITCKASENVGTYVSWYQQKPGTAPKLLIYGASNRFTGVPS RFSGSGSATDFTLTINNLQPEDFATYYCGQSYTFPYTFGQGTKVEIK
Humanised RKB '5
DIQMTQSPSSVSASVGDRVTITCKASENVGTYVSWYQQKPGTAPKLLIYGASNRFTGVPS RFSGSGSATDFTLTINNLQPEDFATYYCGQSYTFPYTFGQGTKVEIK
Humanised RKC '5
DIQMTQSPSSVSASVGDRVTITCKASENVGTYVSWYQQKPGTAPKMLIYGASNRFTGVPS RFSGSGSATDFTLTINNLQPEDFATYYCGQSYTFPYTFGQGTKVEIK
Humanised RKD '5
DIQMTQSPSSVSASVGDRVTITCKASENVGTYVSWYQQKPGTAPKMLIYGASNRFTGVPS RFSGSGSATDFTLTINNLQPEDFATYYCGQSYTFPYTFGQGTKVEIK Humanised RKE '5
NIVMTQSPSSVSASVGDRVTITCKASENVGTYVSWYQQKPGTAPKLLIYGASNRFTGVPD RFTGSGSATDFILTINNLQPEDFATYYCGQSYTFPYTFGQGTKVEIK
Humanised RKF '5
NIVMTQSPSSVSASVGDRVTITCKASENVGTYVSWYQQKPGTAPKMLIYGASNRFTGVPS RFSGSGSATDFILTINNLQPEDFATYYCGQSYTFPYTFGQGTKVEIK
Humanised RKG '5
NIVMTQSPSSVSASVGDRVTITCKASENVGTYVSWYQQKPGTAPKMLIYGASNRFTGVPD RFTGSGSATDFTLTINNLQPEDFATYYCGQSYTFPYTFGQGTKVEIK
The parent antibody may also be a fusion protein comprising an albumin-binding peptide (ABP) sequence (Dennis et al. (2002) "Albumin Binding As A General Strategy For Improving The Pharmacokinetics Of Proteins" J Biol Chem. 277:35035-35043; WO 01/45746). Antibodies of the invention include fusion proteins with ABP sequences taught by: (i) Dennis et al (2002) J Biol Chem. 277:35035-35043 at Tables III and IV, page 35038; (ii) US 2004/0001827 at [0076]; and (iii) WO 01/45746 at pages 12-13, and all of which are incorporated herein by reference. In one embodiment, the antibody has been raised to target specific the tumour related antigen ανβ6.
The cell binding agent may be labelled, for example to aid detection or purification of the agent either prior to incorporation as a conjugate, or as part of the conjugate. The label may be a biotin label. In another embodiment, the cell binding agent may be labelled with a radioisotope.
Connection of Linker unit to Ligand unit
The Ligand unit is connected to the Linker unit through a disulfide bond.
In one embodiment, the connection between the Ligand unit and the Drug Linker is formed between a thiol group of a cysteine residue of the Ligand unit and a maleimide group of the Drug Linker unit. The cysteine residues of the Ligand unit may be available for reaction with the functional group of the Linker unit to form a connection. In other embodiments, for example where the Ligand unit is an antibody, the thiol groups of the antibody may participate in interchain disulfide bonds. These interchain bonds may be converted to free thiol groups by e.g. treatment of the antibody with DTT prior to reaction with the functional group of the Linker unit.
In some embodiments, the cysteine residue is an introduced into the heavy or light chain of an antibody. Positions for cysteine insertion by substitution in antibody heavy or light chains include those described in Published U.S. Application No. 2007-0092940 and International Patent Publication WO2008070593, which are incorporated herein.
Methods of Treatment
The compounds of the present invention may be used in a method of therapy. Also provided is a method of treatment, comprising administering to a subject in need of treatment a therapeutically-effective amount of a conjugate of formula I. The term
"therapeutically effective amount" is an amount sufficient to show benefit to a patient. Such benefit may be at least amelioration of at least one symptom. The actual amount administered, and rate and time-course of administration, will depend on the nature and severity of what is being treated. Prescription of treatment, e.g. decisions on dosage, is within the responsibility of general practitioners and other medical doctors.
A conjugate may be administered alone or in combination with other treatments, either simultaneously or sequentially dependent upon the condition to be treated. Examples of treatments and therapies include, but are not limited to, chemotherapy (the administration of active agents, including, e.g. drugs; surgery; and radiation therapy.
Pharmaceutical compositions according to the present invention, and for use in accordance with the present invention, may comprise, in addition to the active ingredient, i.e. a conjugate of formula I, a pharmaceutically acceptable excipient, carrier, buffer, stabiliser or other materials well known to those skilled in the art. Such materials should be non-toxic and should not interfere with the efficacy of the active ingredient. The precise nature of the carrier or other material will depend on the route of administration, which may be oral, or by injection, e.g. cutaneous, subcutaneous, or intravenous.
Pharmaceutical compositions for oral administration may be in tablet, capsule, powder or liquid form. A tablet may comprise a solid carrier or an adjuvant. Liquid pharmaceutical compositions generally comprise a liquid carrier such as water, petroleum, animal or vegetable oils, mineral oil or synthetic oil. Physiological saline solution, dextrose or other saccharide solution or glycols such as ethylene glycol, propylene glycol or polyethylene glycol may be included. A capsule may comprise a solid carrier such a gelatin.
For intravenous, cutaneous or subcutaneous injection, or injection at the site of affliction, the active ingredient will be in the form of a parenterally acceptable aqueous solution which is pyrogen-free and has suitable pH, isotonicity and stability. Those of relevant skill in the art are well able to prepare suitable solutions using, for example, isotonic vehicles such as Sodium Chloride Injection, Ringer's Injection, Lactated Ringer's Injection. Preservatives, stabilisers, buffers, antioxidants and/or other additives may be included, as required.
The Conjugates can be used to treat proliferative disease and autoimmune disease. The term "proliferative disease" pertains to an unwanted or uncontrolled cellular proliferation of excessive or abnormal cells which is undesired, such as, neoplastic or hyperplastic growth, whether in vitro or in vivo. Examples of proliferative conditions include, but are not limited to, benign, pre-malignant, and malignant cellular proliferation, including but not limited to, neoplasms and tumours (e.g., histocytoma, glioma, astrocyoma, osteoma), cancers (e.g. lung cancer, small cell lung cancer, gastrointestinal cancer, bowel cancer, colon cancer, breast carinoma, ovarian carcinoma, prostate cancer, testicular cancer, liver cancer, kidney cancer, bladder cancer, pancreatic cancer, brain cancer, sarcoma, osteosarcoma, Kaposi's sarcoma, melanoma), leukemias, psoriasis, bone diseases, fibroproliferative disorders (e.g. of connective tissues), and atherosclerosis. Other cancers of interest include, but are not limited to, haematological; malignancies such as leukemias and lymphomas, such as non-Hodgkin lymphoma, and subtypes such as DLBCL, marginal zone, mantle zone, and follicular, Hodgkin lymphoma, AML, and other cancers of B or T cell origin.
Examples of autoimmune disease include the following: rheumatoid arthritis, autoimmune demyelinative diseases (e.g., multiple sclerosis, allergic encephalomyelitis), psoriatic arthritis, endocrine ophthalmopathy, uveoretinitis, systemic lupus erythematosus, myasthenia gravis, Graves' disease, glomerulonephritis, autoimmune hepatological disorder, inflammatory bowel disease (e.g., Crohn's disease), anaphylaxis, allergic reaction, Sjogren's syndrome, type I diabetes mellitus, primary biliary cirrhosis, Wegener's granulomatosis, fibromyalgia, polymyositis, dermatomyositis, multiple endocrine failure, Schmidt's syndrome, autoimmune uveitis, Addison's disease, adrenalitis, thyroiditis,
Hashimoto's thyroiditis, autoimmune thyroid disease, pernicious anemia, gastric atrophy, chronic hepatitis, lupoid hepatitis, atherosclerosis, subacute cutaneous lupus
erythematosus, hypoparathyroidism, Dressler's syndrome, autoimmune thrombocytopenia, idiopathic thrombocytopenic purpura, hemolytic anemia, pemphigus vulgaris, pemphigus, dermatitis herpetiformis, alopecia areata, pemphigoid, scleroderma, progressive systemic sclerosis, CREST syndrome (calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia), male and female autoimmune infertility, ankylosing spondolytis, ulcerative colitis, mixed connective tissue disease, polyarteritis nedosa, systemic necrotizing vasculitis, atopic dermatitis, atopic rhinitis, Goodpasture's syndrome, Chagas' disease, sarcoidosis, rheumatic fever, asthma, recurrent abortion, anti- phospholipid syndrome, farmer's lung, erythema multiforme, post cardiotomy syndrome, Cushing's syndrome, autoimmune chronic active hepatitis, bird-fancier's lung, toxic epidermal necrolysis, Alport's syndrome, alveolitis, allergic alveolitis, fibrosing alveolitis, interstitial lung disease, erythema nodosum, pyoderma gangrenosum, transfusion reaction, Takayasu's arteritis, polymyalgia rheumatica, temporal arteritis, schistosomiasis, giant cell arteritis, ascariasis, aspergillosis, Sampter's syndrome, eczema, lymphomatoid granulomatosis, Behcet's disease, Caplan's syndrome, Kawasaki's disease, dengue, encephalomyelitis, endocarditis, endomyocardial fibrosis, endophthalmitis, erythema elevatum et diutinum, psoriasis, erythroblastosis fetalis, eosinophilic faciitis, Shulman's syndrome, Felty's syndrome, filariasis, cyclitis, chronic cyclitis, heterochronic cyclitis, Fuch's cyclitis, IgA nephropathy, Henoch-Schonlein purpura, graft versus host disease, transplantation rejection, cardiomyopathy, Eaton-Lambert syndrome, relapsing
polychondritis, cryoglobulinemia, Waldenstrom's macroglobulemia, Evan's syndrome, and autoimmune gonadal failure. In some embodiments, the autoimmune disease is a disorder of B lymphocytes (e.g., systemic lupus erythematosus, Goodpasture's syndrome, rheumatoid arthritis, and type I diabetes), Th1 -lymphocytes (e.g., rheumatoid arthritis, multiple sclerosis, psoriasis, Sjogren's syndrome, Hashimoto's thyroiditis, Graves' disease, primary biliary cirrhosis, Wegener's granulomatosis, tuberculosis, or graft versus host disease), or Th2-lymphocyt.es (e.g., atopic dermatitis, systemic lupus erythematosus, atopic asthma, rhinoconjunctivitis, allergic rhinitis, Omenn's syndrome, systemic sclerosis, or chronic graft versus host disease). Generally, disorders involving dendritic cells involve disorders of Th1 - lymphocytes or Th2-lymphocytes. In some embodiments, the autoimmunie disorder is a T cell-mediated immunological disorder.
In some embodiments, the amount of the Conjugate administered ranges from about 0.01 to about 10 mg/kg per dose. In some embodiments, the amount of the Conjugate administered ranges from about 0.01 to about 5 mg/kg per dose. In some embodiments, the amount of the Conjugate administerd ranges from about 0.05 to about 5 mg/kg per dose. In some embodiments, the amount of the Conjugate administerd ranges from about 0.1 to about 5 mg/kg per dose. In some embodiments, the amount of the Conjugate administered ranges from about 0.1 to about 4 mg/kg per dose. In some embodiments, the amount of the Conjugate administered ranges from about 0.05 to about 3 mg/kg per dose. In some embodiments, the amount of the Conjugate administered ranges from about 0.1 to about 3 mg/kg per dose. In some embodiments, the amount of the Conjugate administered ranges from about 0.1 to about 2 mg/kg per dose.
Drug loading
The drug loading (p) is the average number of PBD drugs per cell binding agent, e.g. antibody. Where the compounds of the invention are bound to cysteines, drug loading may range from 1 to 8 drugs (D) per cell binding agent, i.e. where 1 , 2, 3, 4, 5, 6, 7, and 8 drug moieties are covalently attached to the cell binding agent. Compositions of conjgates include collections of cell binding agents, e.g. antibodies, conjugated with a range of drugs, from 1 to 8. Where the compounds of the invention are bound to lysines, drug loading may range from 1 to 80 drugs (D) per cell binding agent, although an upper limit of 40, 20, 10 or 8 may be preferred. Compositions of conjgates include collections of cell binding agents, e.g. antibodies, conjugated with a range of drugs, from 1 to 80, 1 to 40, 1 to 20, 1 to 10 or 1 to 8.
The average number of drugs per antibody in preparations of ADC from conjugation reactions may be characterized by conventional means such as UV, reverse phase HPLC, HIC, mass spectroscopy, ELISA assay, and electrophoresis. The quantitative distribution of ADC in terms of p may also be determined. By ELISA, the averaged value of p in a particular preparation of ADC may be determined (Hamblett et al (2004) Clin. Cancer Res. 10:7063-7070; Sanderson et al (2005) Clin. Cancer Res. 1 1 :843-852). However, the distribution of p (drug) values is not discernible by the antibody-antigen binding and detection limitation of ELISA. Also, ELISA assay for detection of antibody-drug conjugates does not determine where the drug moieties are attached to the antibody, such as the heavy chain or light chain fragments, or the particular amino acid residues. In some instances, separation, purification, and characterization of homogeneous ADC where p is a certain value from ADC with other drug loadings may be achieved by means such as reverse phase HPLC or electrophoresis. Such techniques are also applicable to other types of conjugates.
For some antibody-drug conjugates, p may be limited by the number of attachment sites on the antibody. For example, an antibody may have only one or several cysteine thiol groups, or may have only one or several sufficiently reactive thiol groups through which a linker may be attached. Higher drug loading, e.g. p >5, may cause aggregation, insolubility, toxicity, or loss of cellular permeability of certain antibody-drug conjugates. Typically, fewer than the theoretical maximum of drug moieties are conjugated to an antibody during a conjugation reaction. An antibody may contain, for example, many lysine residues that do not react with the Drug Linker. Only the most reactive lysine groups may react with an amine-reactive linker reagent. Also, only the most reactive cysteine thiol groups may react with a thiol-reactive linker reagent. Generally, antibodies do not contain many, if any, free and reactive cysteine thiol groups which may be linked to a drug moiety. Most cysteine thiol residues in the antibodies of the compounds exist as disulfide bridges and must be reduced with a reducing agent such as dithiothreitol (DTT) or TCEP, under partial or total reducing conditions. The loading (drug/antibody ratio) of an ADC may be controlled in several different manners, including: (i) limiting the molar excess of Drug Linker relative to antibody, (ii) limiting the conjugation reaction time or temperature, and (iii) partial or limiting reductive conditions for cysteine thiol modification.
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 (dithiothreitol). Each cysteine bridge will thus form, theoretically, two reactive thiol nucleophiles. Additional nucleophilic groups can be introduced into antibodies through the reaction of lysines with 2-iminothiolane (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 engineering 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.
Cysteine amino acids may be engineered at reactive sites in an antibody and which do not form intrachain or intermolecular disulfide linkages (Junutula, et al., 2008b Nature Biotech., 26(8):925-932; Dornan et al (2009) Blood 1 14(13):2721 -2729; US 7521541 ; US 7723485; WO2009/052249). The engineered cysteine thiols may react with linker reagents or the drug-linker reagents of the present invention which have thiol-reactive, electrophilic groups such as maleimide or alpha-halo amides to form ADC with cysteine engineered antibodies and the PBD drug moieties. The location of the drug moiety can thus be designed, controlled, and known. The drug loading can be controlled since the engineered cysteine thiol groups typically react with thiol-reactive linker reagents or drug-linker reagents in high yield. Engineering an IgG antibody to introduce a cysteine amino acid by substitution at a single site on the heavy or light chain gives two new cysteines on the symmetrical antibody. A drug loading near 2 can be achieved with near homogeneity of the conjugation product ADC.
Where more than one nucleophilic or electrophilic group of the antibody reacts with a drug- linker intermediate, or linker reagent followed by drug moiety reagent, then the resulting product is a mixture of ADC compounds with a distribution of drug moieties attached to an antibody, e.g. 1 , 2, 3, etc. Liquid chromatography methods such as polymeric reverse phase (PLRP) and hydrophobic interaction (HIC) may separate compounds in the mixture by drug loading value. Preparations of ADC with a single drug loading value (p) may be isolated, however, these single loading value ADCs may still be heterogeneous mixtures because the drug moieties may be attached, via the linker, at different sites on the antibody.
Thus the antibody-drug conjugate compositions of the invention include mixtures of antibody-drug conjugate compounds where the antibody has one or more PBD drug moieties and where the drug moieties may be attached to the antibody at various amino acid residues.
In one embodiment, the average number of dimer pyrrolobenzodiazepine groups per cell binding agent is in the range 1 to 20. In some embodiments the range is selected from 1 to 8, 2 to 8, 2 to 6, 2 to 4, and 4 to 8. In some embodiments, there is one dimer pyrrolobenzodiazepine group per cell binding agent.
General synthetic routes
The synthesis of PBD compounds is extensively discussed in the following references, which discussions are incorporated herein by reference:
a) WO 00/12508 (pages 14 to 30);
b) WO 2005/023814 (pages 3 to 10);
c) WO 2004/043963 (pages 28 to 29); and
d) WO 2005/085251 (pages 30 to 39).
Synthesis route
The Drug Linker compound of the present invention may be synthesised according to the Examples. Synthesis of Drug Conjugates
Conjugates can be prepared as previously described. Antibodies can be conjugated to the Drug Linker compound as described in Doronina et al., Nature Biotechnology, 2003, 21 , 778-784). Briefly, antibodies (4-5 mg/mL) in PBS containing 50 mM sodium borate at pH 7.4 are reduced with tris(carboxyethyl)phosphine hydrochloride (TCEP) at 37 °C. The progress of the reaction, which reduces interchain disulfides, is monitored by reaction with 5,5'-dithiobis(2-nitrobenzoic acid) and allowed to proceed until the desired level of thiols/mAb is achieved. The reduced antibody is then cooled to 0°C and alkylated with 1 .5 equivalents of maleimide drug-linker per antibody thiol. After 1 hour, the reaction is quenched by the addition of 5 equivalents of N-acetyl cysteine. Quenched drug-linker is removed by gel filtration over a PD-10 column. The ADC is then sterile-filtered through a 0.22 μηι syringe filter. Protein concentration can be determined by spectral analysis at 280 nm and 329 nm, respectively, with correction for the contribution of drug absorbance at 280 nm. Size exclusion chromatography can be used to determine the extent of antibody aggregation, and RP-HPLC can be used to determine the levels of remaining NAC- quenched drug-linker.
Further Preferences
The following preferences may apply to all aspects of the invention as described above, or may relate to a single aspect. The preferences may be combined together in any combination.
In some embodiments, the C1 1 substituent may be in the following stereochemical arrangement relative to neighbouring groups:
Figure imgf000094_0001
In other embodiments, the C1 1 substituent may be in the following stereochemical arrangement relative to neighbouring groups:
Figure imgf000094_0002
Examples
Reaction progress was monitored by thin-layer chromatography (TLC) using Merck Kieselgel 60 F254 silica gel, with fluorescent indicator on aluminium plates. Visualisation of TLC was achieved with UV light or iodine vapour unless otherwise stated. Flash chromatography was performed using Merck Kieselgel 60 F254 silica gel. Extraction and chromatography solvents were bought and used without further purification from VWR, U.K. All chemicals were purchased from Aldrich.
Proton NMR chemical shift values were measured on the delta scale at 400 MHz using a Bruker AV400. The following abbreviations have been used: s, singlet; d, doublet; t, triplet; q, quartet; quin, quintet; m, multiplet; br, broad. Coupling constants are reported in Hz. Column chromatography was performed on an Isolera (Biotage) automated system using normal phase SNAP cartridges. The LC/MS conditions were as follow:
LCMS data were obtained using a Shimadzu Nexera series LC/MS with a Shimadzu LCMS-2020 quadrupole MS, with Electrospray ionisation. Mobile phase A - 0.1 % formic acid in water. Mobile phase B - 0.1 % formic acid in acetonitrile. Short run gradient: initial composition was 5% B held over 0.25 min, then increase from 5% B to 100% B over a 2 min period. The composition was held for 0.50 min at 100% B, then returned to 5% B in 0.05 minutes and hold there for 0.05 min. Total gradient run time equals 3 min. Flow rate 0.8 mL/min. Wavelength detection range: 190 to 800 nm. Oven temperature: 50°C. Column: Waters Acquity UPLC BEH Shield RP18 1.7μιτι 2.1 x50mm.
Long run gradient: initial composition 5% B held over 1 min, then increase from 5% B to 100% B over a 9 min period. The composition was held for 2 min at 100% B, then returned to 5% B in 0.10 minutes and hold there for 3 min. Total gradient run time equals 15 min. Flow rate 0.6 mL/min. Wavelength detection range: 190 to 800 nm. Oven temperature: 50°C. Column: ACE Excel 2 C18-AR, 2 μ, 3.0 x 100mm.
Exam le 1
Figure imgf000096_0001
Compound 1 is compound 13 of WO 2014/057073. (a) (S)-2-(4-aminophenyl)-8-(3-(((S)-2-(3-fluoro-4-methoxyphenyl)-7-methoxy-5J
10-((2-(trimethylsilyl)ethoxy)methyl)-5, 10,1 1 ,1 1 a-tetrahydro-1 H-benzoielpyrrolon ,2- al[1 ,4ldiazepin-8-yl)oxy)propoxy)-7-methoxy-10-((2-(trimethylsilyl)ethoxy)methyl)-1 ,1 1 a- dihydro-5/-/-benzorelpyrrolori ,2-ain ,4ldiazepine-5,1 1 (10H)-dione (2)
Pd(PPh3)4 (21 mg, 0.018 mmol) was added to a stirred mixture of the aniline-triflate 1
(981 .2 mg, 0.92 mmol), boronic ester (287.8 mg, 1 .1 1 mmol) and Na2C03 (451 mg, 4.2 mmol) in a 2:1 :1 mixture of toluene/MeOH/h O (20 ml_). The reaction mixture was allowed to stir at 30 °C under a nitrogen atmosphere for 2 hours after which time all of triflate 1 has reacted. The reaction mixture was then evaporated to dryness before the residue was taken up in CH2CI2 (50 mL) and washed with H2O (2 x 50 ml_), brine (50 ml_), dried
(MgS04), filtered and evaporated under reduced pressure to provide the crude product. Purification by flash chromatography (gradient elution: 1 :1 v/v Hexane/EtOAc to 100% EtOAc) afforded product 2 as a yellow foam (845.9 mg, 88%). LC/MS 2.01 min (ES+) m/z (relative intensity) 1036.45 {[M + H]+ , 60%).
(b) (9H-fluoren-9-yl)methyl ((S)-1 -(((S)-1 -((4-((S)-8-(3-(((S)-2-(3-fluoro-4-methoxyphenyl)-7- methoxy-5,1 1 -dioxo-10-((2-(trimethylsilyl)ethoxy)methyl)-5,10, 1 1 ,1 1 a-tetrahydro-1 H- benzo[elpyrrolo[1 ,2-alH ,4ldiazepin-8-yl)oxy)propoxy)-7-methoxy-5,1 1 -dioxo-10-((2- (trimethylsilyl)ethoxy)methyl)-5, 10,1 1 ,1 1 a-tetrahydro-1 /-/-benzo[elpyrrolo[1 ,2- alH ,4ldiazepin-2-yl)phenyl)amino)-1 -oxopropan-2-yl)amino)-3-methyl-1 -oxobutan-2- vDcarbamate (3)
To a solution of 2 (845.9 mg, 0.81 mmol) in dry CH2CI2 (25 mL) was added the protected peptide (368 g, 0.89 mmol) and EEDQ (222 mg, 0.89 mmol). The mixture was stirred at room temperature until completion (16 hours). The reaction mixture was then washed with H2O (2 x 25 mL), brine (25 mL), dried (MgS04), filtered and evaporated under reduced pressure to provide the crude product. Purification by flash chromatography (gradient elution: 100% CHCI3 to 93/7 CHC /MeOH) afforded product 3 as a yellow foam (987 mg, 84%). LC/MS 2.16 min (ES+) m/z (relative intensity) 1428.50 {[M + H]+ , 5%) ; 1450.90 ([M+Na])+ , 50%).
(c) (9H-fluoren-9-yl)methyl ((S)-1 -(((S)-1 -((4-((S)-8-(3-(((S)-2-(3-fluoro-4-methoxyphenyl)-7- methoxy-5-oxo-5,1 1 a-dihydro-1 /-/-benzo[elpyrrolo[1 ,2-al[1 ,41diazepin-8-yl)oxy)propoxy)-7- methoxy-5-oxo-5,1 1 a-dihydro-1 /-/-benzo[elpyrrolo[1 ,2-al[1 ,4ldiazepin-2-yl)phenyl)amino)-1 - oxopropan-2-yl)amino)-3-methyl-1 -oxobutan-2-yl)carbamate (4)
A solution of Super-Hydride® (1.75 mL, 1 M in THF) was added dropwise to a solution of SEM-dilactam 3 (987 mg, 0.7 mmol) in dry THF (3 mL) at -78 °C under an argon atmosphere. The addition was completed over 5 minutes in order to maintain the internal temperature of the reaction mixture constant. After 40 minutes, an aliquot was quenched with water for LC/MS analysis, which revealed that the reaction was complete. Water (20 mL) was added to the reaction mixture and the cold bath was removed. The organic layer was extracted with CH2CI2 (3 x 50 mL) and the combined organics were washed with brine (100 mL), dried with MgSC>4, filtered and the solvent removed by rotary evaporation under reduced pressure. The crude product was dissolved in MeOH (9 mL), CH2CI2 (3 mL), water (1 mL) and enough silica gel to form a thick stirring suspension. After 5 days, the suspension was filtered through a sintered funnel and washed with Ch C /MeOH (9:1 ) (100 mL) until the elution of the product was complete. The organic layer was washed with brine (2 x 50 mL), dried with MgSC>4, filtered and the solvent removed by rotary evaporation under reduced pressure. Purification by silica gel column chromatography (isolera, CHC /MeOH 98:2 to 80:20) afforded product 4 as a yellow solid (563 mg, 71 %). LC/MS 1 .73min (ES+) m/z (relative intensity) 1336.35 {[M + H]+ , 10%).
(d) (S)-2-amino-/V-((S)-1 -((4-((S)-8-(3-(((S)-2-(3-fluoro-4-methoxyphenyl)-7-methoxy-5-oxo- 5,1 1 a-dihydro-1 /-/-benzo[elpyrrolo[1 ,2-al[1 ,41diazepin-8-yl)oxy)propoxy)-7-methoxy-5-oxo- 5,1 1 a-dihydro-1 /-/-benzo[elpyrrolo[1 ,2-al[1 ,4ldiazepin-2-yl)phenyl)amino)-1 -oxopropan-2- yl)-3-methylbutanamide (5)
Excess piperidine was added (0.2 mL) to a solution of PBD 4 (563 mg, 0.49 mmol) in DMF (3 mL). The mixture was allowed to stir at room temperature for 20 min, at which point the reaction had gone to completion (as monitored by LC/MS). The reaction mixture was diluted with CH2CI2 (50 mL) and the organic phase was washed with H2O (2 x 50 mL) until complete piperidine removal. The organic phase was dried over MgS04, filtered and excess solvent removed by rotary evaporation under reduced pressure to afford crude product 5 which was used as such in the next step. LC/MS 1.15 min (ES+) m/z (relative intensity) 914.40 {[M + H]+ , 10%).
(e) 6-(2,5-dioxo-2,5-dihvdro-1 H-pyrrol-1 -yl)-/V-((S)-1 -(((S)-1 -((4-((S)-8-(3-(((S)-2-(3-fluoro-4- methoxyphenyl)-7-methoxy-5-oxo-5,1 1 a-dihydro-1 /-/-benzo[elpyrrolo[1 ,2-al[1 ,41diazepin-8- yl)oxy)propoxy)-7-methoxy-5-oxo-5,1 1 a-dihydro-1 /-/-benzo[elpyrrolo[1 ,2-alH ,41diazepin-2- yl)phenyl)amino)-1 -oxopropan-2-yl)amino)-3-methyl-1 -oxobutan-2-yl)hexanamide (6)
EDCI hydrochloride (94 mg, 0.49 mmol) and 6-maleimidohexanoic acid (104 mg, 0.49 mmol) were added to a solution of crude 5 in dry CH2CI2 (15 mL) under an argon atmosphere. Stirring was maintained until the reaction was complete (4h). The reaction was diluted with CH2Cl2 (50 mL) and the organic phase was washed with H2O (2 x 50 mL) and brine before being dried over MgSC>4, filtered and excess solvent removed by rotary evaporation under reduced pressure by rotary evaporation under reduced pressure. The product was purified by silica gel chromatography column (100% CHC to 95:5
CHC /MeOH) affording 6 (82.9 mg, 15%). LC/MS 1 .50 min (ES+) m/z (relative intensity) 1 107.80 {[M + H]+ , 80%). LC/MS (long run) 6.90 min (ES+) m/z (relative intensity) 1 107.80 {[M + H]+ , 50%).
Example 2 - Conjugation
Conjugate Tratuzumab-6
A 50 mM solution of tris(2-carboxyethyl)phosphine hydrochloride (TCEP) in phosphate- buffered saline pH 7.4 (PBS) was added (50 molar equivalent/antibody, 30 micromoles, 600 μΙ_) to a 21 mL solution of antibody, Trastuzumab, (90 mg, 600 nanomoles) in reduction buffer containing PBS and 1 mM ethylenediaminetetraacetic acid (EDTA) and a final antibody concentration of 4.35 mg/mL. The reduction mixture was heated at +37 °C for 3 hours (or until full reduction is observed by UHPLC) in an incubator with gentle (135 rpm) shaking. After cooling down to room temperature, the reduced antibody was buffer exchanged, via spin filter centrifugation, into a reoxidation buffer containing PBS pH 7.4 and 1 mM EDTA to remove all the excess reducing agent. A 50 mM solution of
dehydroascorbic acid (DHAA, 13 molar equivalent/antibody, 7.8 micromoles, 156 μί) in DMSO was added and the reoxidation mixture was allowed to react for 16 hours at room temperature with gentle (< 150 rpm) shaking at an antibody concentration of 2 mg/mL (or more DHAA added and reaction left for longer until full reoxidation of the cysteine thiols to reform the inter-chain cysteine disulfides is observed by UHPLC). The reoxidation mixture was then sterile-filtered and diluted in a conjugation buffer containing PBS pH 7.4, 1 mM EDTA for a final antibody concentration of 1.0-1.5 mg/mL. Compound 6 was added as a DMSO solution (20 molar equivalent/antibody, 2.0 micromole, in 1 .0 mL DMSO) to 9 mL of this reoxidised antibody solution (15 mg, 100 nanomoles) for a 10% {v/v) DMSO
concentration, followed by addition of propylene glycol (~ 15% final v/v) after 10-15 minutes to solubilise the payload. The solution was mixed for 5 hours at room temperature, after which the conjugation was quenched by addition of /V-acetyl-L-cysteine (6 micromoles, 60 μ\- at 100 mM). The conjugation mixture was purified by spin filtration using a 15 mL Amicon Ultracell 50 kDa MWCO spin filter, then further purified by tangential flow filtration (TFF) to >50 diavolumes using a Spectrum Labs KrosFlo Research IN system with a 30 kDa MWCO, 1 15 cm2 surface area hollow fibre filter module at 50 mL/min in PBS with a transmembrane pressure (TMP) of 0.5-1 .0 bar, and sterile-filtered and analysed. UHPLC analysis on a Shimadzu Prominence system using a Phenomenex Aeris 3.6u XB- C18 150 mm x 2.1 mm column eluting with a gradient of water and acetonitrile on a reduced sample of Conjugate Tratusumab-6 at 280 nm and 330 nm (Compound 6 specific) shows unconjugated light chains and a mixture of unconjugated heavy chains and heavy chains attached to a single molecule of Compound 6, consistent with a drug-per-antibody ratio (DAR) of 1 .67 molecules of Compound 6 per antibody.
UHPLC analysis on a Shimadzu Prominence system using a Tosoh Bioscience TSKgel G3000SWXL 5 μηη 7.8 x 300 mm column (with a 7 μηη 6.0 x 40 mm guard column) eluting with sterile-filtered SEC buffer containing 200 mM potassium phosphate pH 6.95, 250 mM potassium chloride and 10% isopropanol {v/v) on a sample of Conjugate Tratusumab-6 at 280 nm shows a monomer purity of 96%. UHPLC SEC analysis gives a concentration of final Conjugate Tratusumab-6 at 0.44 mg/mL in 19.0 mL, obtained mass of Conjugate Tratusumab-6 is 8.3 mg (56% yield).
Example 3 - in vitro testing
Medium from sub-confluent (80-90% confluency) cell culture in a T75 flask was aspirated and the flask rinsed with PBS (about 20ml) and emptied. Trypsin-EDTA (5ml) was added, the flask returned to the 37°C gassed incubator for up to about 5 minutes, then rapped sharply to dislodge and dissociate cells from the plastic. The cell suspension was transferred to a sterile 50ml screw-top centrifuge tube, diluted with growth medium to a final volume of 15ml, then centrifuged (400g for 5 min). The supernatant was aspirated and the pellet re-suspended in 10ml culture medium. Repeated pipetting may be necessary to produce monodisperse cell suspensions. The cell concentration and viability are measured of trypan blue cell stained cells, using a haemocytometer. Cells were diluted to 2x105/ml, dispensed (50μΙ /well) into 96 well flat bottom plates and incubated overnight before use. A stock solution (1 ml) of antibody drug conjugate (ADC) (20pg/ml) was made by dilution of filter-sterilised ADC into cell culture medium. A set of 8x 10-fold dilutions of stock ADC were made in a 24 well plate by serial transfer of 100μΙ onto 900μΙ of cell culture medium.
ADC dilution was dispensed (50μΙ/ well) into 4 replicate wells of the 96-well plate, containing 50μΙ cell suspension seeded the previous day. Control wells received 50μΙ cell culture medium. The 96-well plate containing cells and ADCs was incubated at 37°C in a CC>2-gassed incubator for the exposure time.
At the end of the incubation period, cell viability was measured by MTS assay. MTS (Promega) was dispensed (20μΙ per well) into each well and incubated for 4 hours at 37°C in the C02-gassed incubator. Well absorbance was measured at 490nm. Percentage cell survival was calculated from the mean absorbance in the 4 ADC-treated wells compared to the mean absorbance in the 4 control untreated wells (100%). I C50 was determined from the doses-response data using GraphPad Prism using the non-linear curve fit algorithm: sigmoidal, 4PL X is log(concentration).
Figure imgf000101_0001
Figure imgf000101_0002
Example 4 - Xenograft testing
Mice
Female severe combined immune-deficient mice (Fox Chase SCID®, C.B-M/\cr-Prkdcscid, Charles River) were ten weeks old with a body weight (BW) range of 16.2 to 21.9 grams on Day 1 of the study. The animals were fed ad libitum water (reverse osmosis, 1 ppm CI), and NIH 31 Modified and Irradiated Lab Diet® consisting of 18.0% crude protein, 5.0% crude fat, and 5.0% crude fibre. The mice were housed on irradiated Enricho'cobs™ Laboratory Animal Bedding in static micro-isolators on a 12-hour light cycle at 20-22°C (68-72°F) and 40-60% humidity. CR Discovery Services specifically complies with the recommendations of the Guide for Care and Use of Laboratory Animals with respect to restraint, husbandry, surgical procedures, feed and fluid regulation, and veterinary care. The animal care and use program at CR Discovery Services is accredited by the
Association for Assessment and Accreditation of Laboratory Animal Care International (AAALAC), which assures compliance with accepted standards for the care and use of laboratory animals. NCI-N87 Xenografts
Tumour Cell Culture
Human NCI-N87 gastric carcinoma lymphoma cells were cultured in RPMI-1640 medium supplemented with 10% fetal bovine serum, 2 mM glutamine, 100 units/mL penicillin, 100 μg mL streptomycin sulfate and 25 μg mL gentamicin. The cells were grown in tissue culture flasks in a humidified incubator at 37 °C, in an atmosphere of 5% C02 and 95% air.
In Vivo Implantation and Tumour Growth
The NCI-N87 cells used for implantation were harvested during log phase growth and Re- suspended in phosphate buffered saline (PBS) containing 50% Matrigel™ (BD
Biosciences). On the day of tumour implant, each test mouse was injected subcutaneously in the right flank with 1 x 107 cells (0.1 mL cell suspension), and tumour growth was monitored as the average size approached the target range of 100 to 150 mm3. Fourteen days later, designated as Day 1 of the study, mice were sorted according to calculated tumour size into groups each consisting of ten animals with individual tumour volumes ranging from 108 to 172 mm3 and group mean tumour volumes of 133 mm3.
Tumours were measured in two dimensions using calipers, and volume was calculated using the formula:
Tumour Volume (mm3 ) = ^—il
i
where w = width and / = length, in mm, of the tumour. Tumour weight may be estimated with the assumption that 1 mg is equivalent to 1 mm3 of tumour volume.
Treatment
Treatment began on Day 1 in groups of 10 mice (n=10) with established subcutaneous NCI-N87 tumours (108-172 mm3). Trastuzumab-6 was administered intravenously once on Day 1 (qd x 1 ). A vehicle-treated group served as the control group for efficacy analysis. Tumours were measured twice per week until the study was ended on Day 78. Each mouse was euthanized when its tumour reached the endpoint volume of 800 mm3 or on the final day, whichever came first. The time to endpoint (TTE) was calculated for each mouse. Treatment outcome was determined from percent tumour growth delay (%TGD), defined as the percent increase in median TTE for treated versus control mice, with differences between groups deemed statistically significant at P≤ 0.05 using logrank survival analysis. Mice were monitored for complete regression (CR) and partial regression (PR) responses. Treatment tolerability was assessed by body weight measurements and frequent observation for signs of treatment-related side effects. Treatment tolerability was assessed by body weight measurements and frequent observation for signs of treatment-related side effects. All regimens were well tolerated. The median TTE for vehicle-treated controls was 45.2 days, establishing a maximum possible TGD of 32.8 days (72%) for the 78-day study. All ADC regimens tested produced significant survival benefit compared to vehicle-treated controls (P < 0.01 ) and eleven of thirteen resulted in the maximum possible TGD.
The minimum effective dose was defined as the minimum dosage required to produce tumour stasis for twenty-eight days after test article administration. Based on visual inspection of the mean and median tumour volume plots and percent change of tumour volume from Day 1 , trastuzumab-6 at 0.4 mg/kg, appeared to be the dosage that achieved a response consistent with the minimum effective dose
Trastuzumab-6 at 0.4 mg/kg produced one partial regression (PR) and at 0.6 mg/kg produced three partial regressions (PRs). The results are illustrated in Figure 1.
JIMT-1 Xenografts
Tumour Cell Culture
JIMT-1 human breast carcinoma cells were grown in DMEM containing 10% fetal bovine serum, 100 units/mL penicillin G sodium, 100 μg/mL streptomycin sulphate, 25 μg/mL gentamicin, and 2 mM glutamine. Cell cultures were maintained in tissue culture flasks in a humidified incubator at 37 °C, in an atmosphere of 5% C02 and 95% air.
In Vivo Implantation and Tumour Growth
The JIMT-1 cells used for implantation were harvested during exponential growth and re- suspended in 50% Matrigel (BD Biosciences): 50% phosphate buffered saline at a concentration of 5 x 107 cells/mL. On the day of tumour implant, each test mouse was injected subcutaneously in the right flank with 1 x 107 cells (0.2 ml. cell suspension), and tumour growth was monitored as the average size approached the target range of 100 to 150 mm3. Tumours were measured in two dimensions using calipers, and volume was calculated using the formula:
Tumour Volume (mnr ) =— where w = width and / = length, in mm, of the tumour. Tumour weight may be estimated with the assumption that 1 mg is equivalent to 1 mm3 of tumour volume.
Treatment
Treatment began on Day 1 in groups of 10 mice (n=10) with established subcutaneous JIMT-1 tumours (75-162 mm3). Trastuzumab-6 was administered intravenously once on Day 1 (qd x 1 ). A vehicle-treated group served as the control group for efficacy analysis. Tumours were measured twice per week until the study was ended on Day 64. Each mouse was euthanized when its tumour reached the endpoint volume of 1000 mm3 or on the final day, whichever came first. The time to endpoint (TTE) was calculated for each mouse.
Treatment outcome was determined from percent tumour growth delay (%TGD), defined as the percent increase in median TTE for treated versus control mice, with differences between groups deemed statistically significant at P≤ 0.05 using logrank survival analysis. Mice were monitored for complete regression (CR) and partial regression (PR) responses.
Treatment tolerability was assessed by body weight measurements and frequent observation for signs of treatment-related side effects. Treatment tolerability was assessed by body weight measurements and frequent observation for signs of treatment-related side effects. All regimens were well tolerated. The median TTE for vehicle-treated controls was 55.7 days, establishing a maximum possible TGD of 8.3 days (13%) for the 64-day study. All ADC regimens tested produced significant survival benefit compared to vehicle-treated controls (P < 0.01 ) and eleven of thirteen resulted in the maximum possible TGD.
The minimum effective dose was defined as the minimum dosage required to produce tumour stasis for twenty-eight days after test article administration. Based on visual inspection of the mean and median tumour volume plots and percent change of tumour volume from Day 1 , trastuzumab-6 at 0.3 mg/kg, appeared to be the dosage that achieved a response consistent with the minimum effective dose. Trastuzumab-6 at 0.3 mg/kg produced one partial regression (PR) and at 1.0 mg/kg produced two partial regressions (PRs) and three complete regressions (CRs) which remained tumour-free survivors (TFSs) at study end. The results are illustrated in Figure 2.
BT474 Xenografts
In Vivo Implantation and Tumour Growth
Xenografts were initiated with BT474 human breast carcinomas maintained at CR
Discovery Services by serial subcutaneous transplantation in SCID mice. On the day of tumor implant, each test mouse received a 1 mm3 BT474 fragment implanted
subcutaneously in the right flank, and tumor growth was monitored as the average size approached the target range of 100 to 150 mm3. Thirty-five days after tumor implantation, designated as Day 1 of the study, the animals were sorted into groups each consisting of ten mice with individual tumor volumes of 75 to 196 mm3 and group mean tumor volumes of 1 17-1 18 mm3. Tumors were measured in two dimensions using calipers, and volume was calculated using the formula:
Tumour Volume (mm3 ) =— where w = width and / = length, in mm, of the tumour. Tumour weight may be estimated with the assumption that 1 mg is equivalent to 1 mm3 of tumour volume.
Treatment
Treatment began on Day 1 in groups of mice (n=10) with established subcutaneous BT474 tumors (75-196 mm3). Trastuzumab-6 was were administered intravenously once on Day 1 (qd x 1 ) at two dosages (0.3 and 1 mg/kg). The dosing volume was 0.2 mL per 20 grams of body weight (10 mL/kg), and was scaled to the body weight of each individual animal. A vehicle-treated group served as the control group for efficacy analysis. Tumors were measured twice per week until the study was ended on Day 60. Each mouse was euthanized when its tumor reached the endpoint volume of 1000 mm3 or on the final day, whichever came first. The time to endpoint (TTE) was calculated for each mouse.
Treatment outcome was determined from percent tumor growth delay (%TGD), defined as the percent increase in median TTE for treated versus control mice, with differences between groups deemed statistically significant at P < 0.05 using logrank survival analysis. Mice were monitored for complete regression (CR) and partial regression (PR) responses. Treatment tolerability was assessed by body weight measurements and frequent observation for signs of treatment-related side effects. Treatment tolerability was assessed by body weight measurements and frequent observation for signs of treatment-related side effects. All regimens were acceptably tolerated. The median TTE for vehicle-treated controls was 44.4 days, establishing a maximum possible TGD of 15.6 days (35%) for the 60-day study.
The minimum effective dose was defined as the minimum dosage required to produce tumour stasis for twenty-eight days after test article administration. Based on visual inspection of the mean and median tumour volume plots and percent change of tumour volume from Day 1 , trastuzumab-6 at 0.3 mg/kg, appeared to be the dosage that achieved a response consistent with the minimum effective dose.
Trastuzumab-6 at 0.3 mg/kg produced four partial regressions (PRs) and at 1.0 mg/kg produced seven partial regressions (PRs) and one complete regressions (CR) which remained a tumour-free survivor (TFS) at study end. The results are illustrated in Figure 3.
Example 5 - Toxicity studies/Therapeutic Index
Rat study:
A single dose toxicity study was used to determine the maximum tolerated dose (MTD) and safety profile of Trastuzumab-6. Male Sprague Dawley rats (Harlan, Inc) were dosed once by slow bolus intravenous injection via the tail vein with vehicle control (25 mM Histidine- HCI, 7% sucrose, 0.02% Polysorbate 80, pH 6.0) or test material (Trastuzumab-6).
Parameters evaluated during the study included mortality, physical examinations, cageside observations, body weights, body weight changes, clinical pathology (clinical chemistry, hematology, and coagulation), and gross pathology findings. All animals were terminated on Study Day (SD) 29.
Figure imgf000106_0001
Control = 25 mM Histidine-HCI, 7% sucrose, 0.02% Polysorbate 80, pH 6.0
Tolerability was determined based on toxicity end points, including body weight loss (>10%) and bone marrow suppression. Based on minimal adverse findings in the 1 .5 mg/kg high dose group, the maximum tolerated dose (MTD) in the rat after a single dose of Trastuzumab-6 was determined to be 0.5 mg/kg.
Therapeutic Index
The Therapeutic Index can be calculated by dividing the maximum tolerated single dose (MTD) of non-targeted ADC in rat, by the minimal effective single dose (MED) of the a targeted ADC. The MED is the single dose necessary to achieve tumour stasis in an in vivo model at 28 days (for NCI-N87 xenograft). Thus for conjugates of compound 6, the therapeutic index is the MTD of 0.5 mg/kg divided by the MED which is 0.4 mg/kg (see above), giving a Therapeutic Index of 1 .25.
All documents and other references mentioned above are herein incorporated by reference.

Claims

1 . A conjugate of formula I :
Figure imgf000108_0001
wherein L is a Ligand unit, D is a Drug Linker unit of formula II :
Figure imgf000108_0002
wherein p is an integer of from 1 to 20.
2. A conjugate according to claim 1 , wherein the Ligand Unit is an antibody or an active fragment thereof.
3. The conjugate according to claim 2, wherein the antibody or antibody fragment is an antibody or antibody fragment for a tumour-associated antigen. 4. The conjugate according to claim 3 wherein the antibody or antibody fragment is an antibody which binds to one or more tumor-associated antigens or cell-surface receptors selected from (1 )-(88):
(1 ) BMPR1 B;
(2) E16;
(3) STEAP1 ;
(4) 0772P;
(5) MPF;
(6) Napi3b;
(7) Sema 5b;
(8) PSCA hlg;
(9) ETBR;
(10) MSG783;
(11 ) STEAP2;
(12) TrpM4; (13) CRIPTO;
(14) CD21;
(15) CD79b;
(16) FcRH2;
(17) HER2;
(18) NCA;
(19) MDP;
(20) IL20R-alpha;
(21) Brevican;
(22) EphB2R;
(23) ASLG659;
(24) PSCA;
(25) GEDA;
(26) BAFF-R;
(27) CD22;
(28) CD79a;
(29) CXCR5;
(30) HLA-DOB;
(31) P2X5;
(32) CD72;
(33) LY64;
(34) FcRH1;
(35) IRTA2;
(36) TENB2;
(37) PSMA- FOLH1;
(38) SST;
(38.1) SSTR2;
(38.2) SSTR5;
(38.3) SSTR1;
(38.
4) SSTR3;
(38.5) SSTR4;
(39) ITGAV;
(40) ITGB6;
(41) CEACAM5;
(42) MET;
(43) MUC1; (44) CA9;
(45) EGFRvlll;
(46) CD33;
(47) CD19;
(48) IL2RA;
(49) AXL;
(50) CD30 - TNFRSF8;
(51) BCMA - TNFRSF17;
(52) CT Ags - CTA;
(53) CD174 (Lewis Y) - FUT3;
(54) CLEC14A;
(55) GRP78 - HSPA5;
(56) CD70;
(57) Stem Cell specific antigens;
(58) ASG-5;
(59) ENPP3;
(60) PRR4;
(61) GCC - GUCY2C;
(62) Liv-1 - SLC39A6;
(63) 5T4;
(64) CD56- NCMA1;
(65) CanAg;
(66) F0LR1;
(67) GPNMB;
(68) TIM-1 - HAVCR1;
(69) RG-1/Prostate tumor target Mindin - Mindin/RG-1 ;
(70) B7-H4- VTCN1;
(71) PTK7;
(72) CD37;
(73) CD138-SDC1;
(74) CD74;
(75) Claudins - CLs;
(76) EGFR;
(77) Her3;
(78) RON - MST1R;
(79) EPHA2;
(80) CD20 - MS4A1 ; (81 ) Tenascin C - TNC;
(82) FAP;
(83) DKK-1 ;
(84) CD52;
(85) CS1 - SLAMF7;
(86) Endoglin - ENG;
(87) Annexin A1 - ANXA1 ;
(88) V-CAM (CD106) - VCAM1.
5. The conjugate of any one of claims 2 to 4 wherein the antibody or antibody fragment is a cysteine-engineered antibody.
6. The conjugate according to any one of claims 1 to 5 wherein p is an integer from 1 to 8.
7. The conjugate according to claim 6, wherein p is 1 , 2, 3, or 4.
8. A composition comprising a mixture of conjugates according to any one of claims 1 to 7, wherein the average p in the mixture of conjugate compounds is about 1 to about 8.
9. The conjugate according to any one of claims 1 to 7, for use in therapy.
10. A pharmaceutical composition comprising the conjugate of any one of claims 1 to 7 a pharmaceutically acceptable diluent, carrier or excipient.
1 1 . The conjugate according to any one of claims 1 to 7 or the pharmaceutical composition according to claim 10, for use in the treatment of a proliferative disease in a subject.
12. The conjugate for use according to claim 1 1 , wherein the disease treated is cancer.
13. Use of a conjugate according to any one of claims 1 to 7 or a pharmaceutical according to claim 10 in a method of medical treatment.
14. A method of medical treatment comprising administering to a patient the
pharmaceutical composition of claim 10.
15. The method of claim 14 wherein the method of medical treatment is for treating cancer.
16. The method of claim 15, wherein the patient is administered a chemotherapeutic agent, in combination with the conjugate.
17. Use of a conjugate according to any one of claims 1 to 7 in a method of manufacture of a medicament for the treatment of a proliferative disease.
18. A method of treating a mammal having a proliferative disease, comprising administering an effective amount of a conjugate according to any one of claims 1 to 7 or a pharmaceutical composition according to claim 10. 1
Figure imgf000112_0001
20. A method of synthesis of a conjugate according to any one of claims 1 to 7 comprising the step of conjugating a compound according to claim 19 with a cell-binding agent.
PCT/EP2017/060150 2016-04-29 2017-04-28 Pyrrolobenzodiazepine conjugates and their use for the treatment of cancer WO2017186894A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US16/096,631 US10543279B2 (en) 2016-04-29 2017-04-28 Pyrrolobenzodiazepine conjugates and their use for the treatment of cancer
EP17721108.3A EP3448858A1 (en) 2016-04-29 2017-04-28 Pyrrolobenzodiazepine conjugates and their use for the treatment of cancer

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB1607478.3A GB201607478D0 (en) 2016-04-29 2016-04-29 Pyrrolobenzodiazepine Conjugates
GB1607478.3 2016-04-29

Publications (1)

Publication Number Publication Date
WO2017186894A1 true WO2017186894A1 (en) 2017-11-02

Family

ID=56234105

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2017/060150 WO2017186894A1 (en) 2016-04-29 2017-04-28 Pyrrolobenzodiazepine conjugates and their use for the treatment of cancer

Country Status (4)

Country Link
US (1) US10543279B2 (en)
EP (1) EP3448858A1 (en)
GB (1) GB201607478D0 (en)
WO (1) WO2017186894A1 (en)

Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019034764A1 (en) 2017-08-18 2019-02-21 Medimmune Limited Pyrrolobenzodiazepine conjugates
WO2019096788A1 (en) 2017-11-14 2019-05-23 Medimmune Limited Pyrrolobenzodiazepine conjugates
WO2019224340A1 (en) 2018-05-25 2019-11-28 Medimmune Limited Pyrrolobenzodiazepine conjugates
WO2020025108A1 (en) 2018-07-31 2020-02-06 Astrazeneca Ab Linkers and conjugates
WO2020079239A1 (en) 2018-10-19 2020-04-23 Medimmune Limited Pyrrolobenzodiazepine conjugates
WO2020079229A1 (en) 2018-10-19 2020-04-23 Medimmune Limited Pyrrolobenzodiazepine conjugates
WO2020187721A1 (en) 2019-03-15 2020-09-24 Medimmune Limited Azetidobenzodiazepine dimers and conjugates comprising them for use in the treatment of cancer
WO2020200880A1 (en) 2019-03-29 2020-10-08 Medimmune Limited Compounds and conjugates thereof
WO2021080608A1 (en) 2019-10-25 2021-04-29 Medimmune, Llc Branched moiety for use in conjugates
WO2021148500A1 (en) 2020-01-22 2021-07-29 Medimmune Limited Compounds and conjugates thereof
WO2021148501A1 (en) 2020-01-22 2021-07-29 Medimmune Limited Compounds and conjugates thereof
WO2022053651A2 (en) 2020-09-10 2022-03-17 Precirix N.V. Antibody fragment against fap
US11352324B2 (en) 2018-03-01 2022-06-07 Medimmune Limited Methods
WO2022218973A2 (en) 2021-04-12 2022-10-20 Medimmune Limited Pyrrolobenzodiazepine conjugates
WO2022218970A2 (en) 2021-04-12 2022-10-20 Medimmune Limited Pyrrolobenzodiazepine conjugates
US11524969B2 (en) 2018-04-12 2022-12-13 Medimmune Limited Pyrrolobenzodiazepines and conjugates thereof as antitumour agents
WO2023006782A1 (en) 2021-07-26 2023-02-02 Cambridge Enterprise Limited Conjugating reagents and conjugates thereof
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
WO2023227757A1 (en) 2022-05-25 2023-11-30 Cambridge Enterprise Limited Quinone protected forms and conjugates
US12060427B2 (en) 2018-03-28 2024-08-13 Mitsubishi Tanabe Pharma Corporat Drug conjugates of cMET monoclonal binding agents, and uses thereof

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2020329191A1 (en) 2019-08-12 2022-03-31 Regeneron Pharmaceuticals, Inc. Macrophage stimulating 1 receptor (MST1R) variants and uses thereof

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011130613A1 (en) * 2010-04-15 2011-10-20 Seattle Genetics, Inc. Targeted pyrrolobenzodiazapine conjugates
WO2014057073A1 (en) * 2012-10-12 2014-04-17 Spirogen Sàrl Pyrrolobenzodiazepines and conjugates thereof

Family Cites Families (397)

* 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
FR2027356A1 (en) 1968-12-30 1970-09-25 Fujisawa Pharmaceutical Co Benzodiazepinone antibiotics
IL33558A (en) 1968-12-30 1973-10-25 Fujisawa Pharmaceutical Co Antibiotic pyrrolo-benzodiazepine compound,its derivatives and processes for their production
JPS4843755B1 (en) 1969-06-26 1973-12-20
JPS6053033B2 (en) 1976-12-28 1985-11-22 財団法人微生物化学研究会 New anticancer antibiotic mazethramycin and its production method
JPS585916B2 (en) 1977-12-27 1983-02-02 株式会社ミドリ十字 New benzodiazepine compounds
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
CA1184175A (en) 1981-02-27 1985-03-19 Walter Hunkeler Imidazodiazepines
CA1173441A (en) 1981-02-27 1984-08-28 Hoffmann-La Roche Limited Imidazodiazepines
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 (en) 1983-02-17 1984-08-31 Green Cross Corp:The Local disorder inhibitor
US4816567A (en) 1983-04-08 1989-03-28 Genentech, Inc. Recombinant immunoglobin preparations
FR2586683B1 (en) 1985-08-29 1988-07-01 Centre Nat Rech Scient NOVEL NEOTHRAMYCIN DERIVATIVES, THEIR PREPARATION PROCESS AND THEIR APPLICATION AS MEDICAMENTS
US5583024A (en) 1985-12-02 1996-12-10 The Regents Of The University Of California Recombinant expression of Coleoptera luciferase
JP2660201B2 (en) 1988-08-05 1997-10-08 塩野義製薬株式会社 Novel pyrrolo [1,4] benzodiazepine derivatives and senile dementia drugs
AU6355090A (en) 1989-08-23 1991-04-03 Scripps Clinic And Research Foundation Compositions and methods for detection and treatment of epstein-barr virus infection and immune disorders
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
US5543503A (en) 1991-03-29 1996-08-06 Genentech Inc. Antibodies to human IL-8 type A receptor
ES2149772T5 (en) 1991-03-29 2008-02-16 Genentech, Inc. HUMAN RECEPTORS PF4A AND ITS USE.
FR2676230B1 (en) 1991-05-07 1993-08-27 Centre Nat Rech Scient NOVEL PYRROLO [1,4] -BENZODIAZEPINES DERIVATIVES, PROCESS FOR THEIR PREPARATION AND MEDICAMENTS CONTAINING THEM.
JP3050424B2 (en) 1991-07-12 2000-06-12 塩野義製薬株式会社 Human endothelin receptor
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
US5976551A (en) 1991-11-15 1999-11-02 Institut Pasteur And Institut Nationale De La Sante Et De La Recherche Medicale Altered major histocompatibility complex (MHC) determinant and method 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 (en) 1992-09-28 1994-11-10 Synthelabo Piperidine derivatives, their preparation and their therapeutic application.
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 (en) 1995-04-13 1996-12-24 Mitsubishi Chem Corp Production of optically active gamma-substituted-beta-hydroxybutyric ester
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 (en) 1996-03-19 2005-05-11 大塚製薬株式会社 Human gene
US6218519B1 (en) 1996-04-12 2001-04-17 Pro-Neuron, Inc. Compounds and methods for the selective treatment of cancer and bacterial infections
SK157498A3 (en) 1996-05-17 1999-10-08 Schering Corp Isolated and recombinant nucleic acid, bas-1 protein or peptide thereof, and agent, antibody, expression vector, host cell and method of their use
AU739028B2 (en) 1996-09-27 2001-10-04 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
US20030185830A1 (en) 1997-02-25 2003-10-02 Corixa Corporation Compositions and methods for the therapy and diagnosis of prostate cancer
US7033827B2 (en) 1997-02-25 2006-04-25 Corixa Corporation Prostate-specific polynucleotide compositions
EP2343085B1 (en) 1997-03-10 2014-12-10 The Regents of The University of California Antibody against prostate stem cell antigen (PSCA)
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
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
CA2323071C (en) 1998-03-13 2011-06-21 The Burnham Institute Molecules that home to various selected organs or tissues
US6534482B1 (en) 1998-05-13 2003-03-18 Epimmune, Inc. Expression vectors for stimulating an immune response and methods of using the same
KR100581443B1 (en) 1998-05-22 2006-05-23 다이이찌 세이야꾸 가부시기가이샤 Drug Composites
US20030064397A1 (en) 1998-05-22 2003-04-03 Incyte Genomics, Inc. Transmembrane protein differentially expressed in prostate and lung tumors
US20020187472A1 (en) 2001-03-09 2002-12-12 Preeti Lal Steap-related protein
WO2002016429A2 (en) 2000-08-24 2002-02-28 Genentech, Inc. Compositions and methods for the diagnosis and treatment of tumor
CA2336596A1 (en) 1998-07-08 2000-01-20 E Ink Corporation Methods for achieving improved color in microencapsulated electrophoretic devices
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
GB9818731D0 (en) 1998-08-27 1998-10-21 Univ Portsmouth Compounds
GB9818732D0 (en) 1998-08-27 1998-10-21 Univ Portsmouth Collection of compounds
ES2244210T3 (en) 1998-08-27 2005-12-01 Spirogen Limited PIRROLOBENZODIAZEPINAS.
JP4689781B2 (en) 1998-09-03 2011-05-25 独立行政法人科学技術振興機構 Amino acid transport protein and its gene
AU5963699A (en) 1998-10-02 2000-04-26 Mcmaster University Spliced form of (erb)b-2/neu oncogene
WO2001057188A2 (en) 2000-02-03 2001-08-09 Hyseq, Inc. Novel nucleic acids and polypeptides
US6858710B2 (en) 1998-12-17 2005-02-22 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
US6962980B2 (en) 1999-09-24 2005-11-08 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
ATE407949T1 (en) 1998-12-30 2008-09-15 Beth Israel Hospital CHARACTERIZATION OF THE PROTEIN FAMILY OF SOC/CRAC CALCIUM CHANNELS
US20030009013A1 (en) 1998-12-30 2003-01-09 Genentech, Inc. Secreted and transmembrane polypeptides and nucleic acids encoding the same
TR200102191T2 (en) 1999-01-29 2001-12-21 Corixa Corporation HER-2 / neu fusion proteins.
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
ES2466715T3 (en) 1999-06-25 2014-06-11 Immunogen, Inc. Treatment methods using anti-ErbB-maitansinoid antibody conjugates
US6302318B1 (en) 1999-06-29 2001-10-16 General Electric Company Method of providing wear-resistant coatings, and related articles
US7589172B2 (en) 1999-07-20 2009-09-15 Genentech, Inc. PRO256 polypeptides
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
JP3951035B2 (en) 1999-09-01 2007-08-01 ジェネンテック・インコーポレーテッド Secreted and transmembrane polypeptides and nucleic acids encoding them
US20030232056A1 (en) 1999-09-10 2003-12-18 Corixa Corporation Compositions and methods for the therapy and diagnosis of ovarian cancer
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
IL149116A0 (en) 1999-10-29 2002-11-10 Genentech Inc Anti-prostate stem cell antigen (psca) antibody compositions and methods of use
EP2404927B1 (en) 1999-11-29 2016-05-11 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
WO2001040269A2 (en) 1999-11-30 2001-06-07 Corixa Corporation Compositions and methods for therapy and diagnosis of breast cancer
WO2001041787A1 (en) 1999-12-10 2001-06-14 Epimmune Inc. INDUCING CELLULAR IMMUNE RESPONSES TO HER2/neu USING PEPTIDE AND NUCLEIC ACID COMPOSITIONS
NZ502058A (en) 1999-12-23 2003-11-28 Ovita Ltd Isolated mutated nucleic acid molecule for regulation of ovulation rate
JP4741139B2 (en) 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 Soluble interleukin-20 receptor
US6610286B2 (en) 1999-12-23 2003-08-26 Zymogenetics, Inc. Method for treating inflammation using soluble receptors to interleukin-20
AU2458001A (en) 1999-12-23 2001-07-03 Zymogenetics Inc. Method for treating inflammation
US20040001827A1 (en) 2002-06-28 2004-01-01 Dennis Mark S. Serum albumin binding peptides for tumor targeting
CA2390691C (en) 1999-12-24 2016-05-10 Genentech, Inc. Methods and compositions for prolonging elimination half-times of bioactive compounds
US7294695B2 (en) 2000-01-20 2007-11-13 Genentech, Inc. PRO10268 polypeptides
US20020039573A1 (en) 2000-01-21 2002-04-04 Cheever Martin A. 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
US20030104562A1 (en) 2000-02-11 2003-06-05 Genentech, Inc. Secreted and transmembrane polypeptides and nucleic acids encoding the same
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
AU2001238596A1 (en) 2000-02-22 2001-09-03 Millennium Pharmaceuticals, Inc. 18607, a novel human calcium channel
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
AU2001245280A1 (en) 2000-03-07 2001-09-17 Hyseq, Inc. Novel nucleic acids and polypeptides
EP1268526A4 (en) 2000-03-24 2004-09-08 Fahri Saatcioglu Novel prostate-specific or testis-specific nucleic acid molecules, polypeptides, and diagnostic and therapeutic methods
EP1268554A2 (en) 2000-03-31 2003-01-02 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 a specific chemokine receptor analysis and the chemokine receptor-ligand interaction
AU2001253140A1 (en) 2000-04-03 2001-10-15 The Government Of The United States Of America, As Represented By The Secretary Of The Department Of Health And Human Services Tumor markers in ovarian cancer
EP1301594A2 (en) 2000-04-07 2003-04-16 Arena Pharmaceuticals, Inc. Non-endogenous, consstitutively activated known g protein-coupled receptors
WO2001088133A2 (en) 2000-05-18 2001-11-22 Lexicon Genetics Incorporated Human semaphorin homologs and polynucleotides encoding the same
AU2001274888A1 (en) 2000-05-19 2001-12-03 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
AU2001271714A1 (en) 2000-06-30 2002-01-14 Human Genome Sciences, Inc. B7-like polynucleotides, polypeptides, and antibodies
AU2001273151A1 (en) 2000-06-30 2002-01-14 Incyte Genomics, Inc. Human extracellular matrix and cell adhesion polypeptides
MXPA02012749A (en) 2000-06-30 2003-10-06 Amgen Inc B7-like molecules and uses thereof.
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
WO2002010187A1 (en) 2000-07-27 2002-02-07 Mayo Foundation For Medical Education And Research B7-h3 and b7-h4, novel immunoregulatory molecules
US7205108B2 (en) 2000-07-28 2007-04-17 Ulrich Wissenbach Trp8, Trp9 and Trp10, novel markers for cancer
US7229623B1 (en) 2000-08-03 2007-06-12 Corixa Corporation Her-2/neu fusion proteins
WO2002013847A2 (en) 2000-08-14 2002-02-21 Corixa Corporation Methods for diagnosis and therapy of hematological and virus-associated malignancies
JP2004522412A (en) 2000-08-14 2004-07-29 コリクサ コーポレイション Compositions and methods for the treatment and diagnosis of HER-2 / NEU-related malignancies
GB0020953D0 (en) 2000-08-24 2000-10-11 Smithkline Beecham Biolog Vaccine
WO2002022660A2 (en) 2000-09-11 2002-03-21 Hyseq, Inc. Novel nucleic acids and polypeptides
US20030119121A1 (en) 2000-09-15 2003-06-26 Genentech, Inc. Secreted and transmembrane polypeptides and nucleic acids encoding the same
CA2422033A1 (en) 2000-09-15 2002-03-21 Zymogenetics, Inc. Method for treating inflammation
US6613567B1 (en) 2000-09-15 2003-09-02 Isis Pharmaceuticals, Inc. Antisense inhibition of Her-2 expression
CA2422814A1 (en) 2000-09-18 2002-03-21 Biogen, Inc. Cripto mutant and uses thereof
UA83458C2 (en) 2000-09-18 2008-07-25 Байоджен Айдек Ма Інк. The isolated polypeptide baff-r (the receptor of the factor of activation of b-cells of the family tnf)
CN1315805C (en) 2000-09-19 2007-05-16 斯皮罗根公司 Compositions and methods of use thereof achiral analogues of CC-1065 and duocarmycins
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
DE60138927D1 (en) 2000-11-07 2009-07-16 Zymogenetics Inc HUMAN RECIPE FOR TUMOR NECROSIS FACTOR
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
AU2002243495A1 (en) 2001-01-12 2002-07-24 University Of Medicine And Dentistry Of New Jersey Bone morphogenetic protein-2 in the treatment and diagnosis of cancer
US20030119133A1 (en) 2001-01-16 2003-06-26 Genentech, Inc. Secreted and transmembrane polypeptides and nucleic acids encoding the same
US20030119125A1 (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
EP1425302A2 (en) 2001-01-24 2004-06-09 Protein Design Labs Methods of diagnosis of breast cancer, compositions and methods of screening for modulators of breast cancer
WO2002060317A2 (en) 2001-01-30 2002-08-08 Corixa Corporation Compositions and methods for the therapy and diagnosis of pancreatic cancer
US20040170994A1 (en) 2001-02-12 2004-09-02 Callen David Frederick DNA sequences for human tumour suppressor genes
US20030087250A1 (en) 2001-03-14 2003-05-08 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
US20040236091A1 (en) 2001-03-28 2004-11-25 Chicz Roman M. Translational profiling
US6362331B1 (en) 2001-03-30 2002-03-26 Council Of Scientific And Industrial Research Process for the preparation of antitumor agents
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
MXPA03009510A (en) 2001-04-17 2005-04-29 Univ Arkansas Repeat sequences of the ca125 gene and their use for diagnostic and therapeutic interventions.
JP2005527180A (en) 2001-04-18 2005-09-15 プロテイン デザイン ラブス， インコーポレイテッド Lung cancer diagnosis method, composition of lung cancer modifier and screening method
SK14432003A3 (en) 2001-04-26 2004-07-07 Biogen, Inc. Cripto blocking antibodies and uses thereof
AU2002334799B2 (en) 2001-04-26 2009-05-07 Biogen Ma Inc. Cripto-specific antibodies
US6884869B2 (en) 2001-04-30 2005-04-26 Seattle Genetics, Inc. Pentapeptide compounds and uses related thereto
CA2446788A1 (en) 2001-05-09 2002-11-14 Corixa Corporation Compositions and methods for the therapy and diagnosis of prostate cancer
US20030078399A1 (en) 2001-05-11 2003-04-24 Sloan-Kettering Institute For Cancer Research Nucleic acid sequence encoding ovarian antigen, CA125, and uses thereof
ATE542545T1 (en) 2001-05-24 2012-02-15 Zymogenetics Inc TACI-IMMUNOGLOBULIN FUSION PROTEINS
WO2003000842A2 (en) 2001-06-04 2003-01-03 Curagen Corporation Novel proteins and nucleic acids encoding same
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
US20050170344A1 (en) 2001-06-05 2005-08-04 Lori Friedman Chds as modifiers of the p53 pathway and methods of use
WO2002099140A1 (en) 2001-06-05 2002-12-12 Exelixis, Inc. GLRAs AS MODIFIERS OF THE p53 PATHWAY AND METHODS OF USE
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
MXPA03011979A (en) 2001-06-18 2005-04-08 Eos Biotechnology Inc Methods of diagnosis of ovarian cancer, compositions and methods of screening for modulators of ovarian 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
AU2002322280A1 (en) 2001-06-21 2003-01-21 Millennium Pharmaceuticals, Inc. Compositions, kits, and methods for identification, assessment, prevention, and therapy of breast cancer
US20030108958A1 (en) 2001-06-28 2003-06-12 Rene De Waal Malefyt Biological activity of AK155
US20030120040A1 (en) 2001-06-29 2003-06-26 Genentech, Inc. Secreted and Transmembrane polypeptides and nucleic acids encoding the same
AU2002314433A1 (en) 2001-07-02 2003-01-21 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
AU2002337657A1 (en) 2001-07-25 2003-02-17 Millennium Pharmaceuticals, Inc. Novel genes, compositions, kits, and methods for identification, assessment, prevention, and therapy of prostate cancer
US20050070689A1 (en) 2001-08-03 2005-03-31 Genentech, Inc. Taci and br3 polypeptides and uses thereof
CA2457819A1 (en) 2001-08-14 2003-02-27 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
WO2003018621A2 (en) 2001-08-23 2003-03-06 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
ES2537074T3 (en) 2001-09-06 2015-06-02 Agensys, Inc. Nucleic acid and corresponding protein called STEAP-1 useful in the treatment and detection of cancer
JP2005518782A (en) 2001-09-17 2005-06-30 プロテイン デザイン ラブス， インコーポレイテッド Cancer diagnosis method, cancer modulator screening composition and method
WO2003025228A1 (en) 2001-09-18 2003-03-27 Proteologics, Inc. Methods and compositions for treating hcap associated diseases
AU2002330015B2 (en) 2001-09-18 2008-02-07 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
WO2003026493A2 (en) 2001-09-28 2003-04-03 Bing Yang Diagnosis and treatment of diseases caused by mutations in cd72
US20040249144A1 (en) 2001-10-03 2004-12-09 Zairen Sun Regulated breast cancer genes
US20050130117A1 (en) 2001-10-03 2005-06-16 Davis Cong L. Modulators of lymphocyte activation and migration
US20050123925A1 (en) 2002-11-15 2005-06-09 Genentech, Inc. Compositions and methods for the diagnosis and treatment of tumor
WO2003034984A2 (en) 2001-10-19 2003-05-01 Genentech, Inc. Compositions and methods for the diagnosis and treatment of inflammatory bowel disorders
WO2003035846A2 (en) 2001-10-24 2003-05-01 National Jewish Medical And Research Center Structure of tall-1 and its cognate receptor
WO2003055443A2 (en) 2001-10-31 2003-07-10 Alcon, Inc. Bone morphogenic proteins (bmp), bmp receptors and bmp binding proteins and their use in the diagnosis and treatment of glaucoma
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
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
AU2002363939A1 (en) 2001-11-20 2003-06-10 Seattle Genetics, Inc. Treatment of immunological disorders using anti-cd30 antibodies
EP1448226A1 (en) 2001-11-29 2004-08-25 Genset S.A. Agonists and antagonists of prolixin for the treatment of metabolic disorders
AU2002349784A1 (en) 2001-12-03 2003-06-17 Asahi Kasei Pharma Corporation Nf-kappab activating genes
EP2298817A1 (en) 2001-12-03 2011-03-23 Alexion Pharmaceuticals, Inc. Hybrid antibodies
EP1504099A4 (en) 2001-12-10 2006-05-10 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
WO2003060612A1 (en) 2002-01-16 2003-07-24 Japan Science And Technology Agency Moving image holography reproducing device and color moving image holography reproducing device
US7452675B2 (en) 2002-01-25 2008-11-18 The Queen's Medical Center Methods of screening for TRPM4b modulators
US20040001828A1 (en) 2002-02-21 2004-01-01 Joseph Tuscano Treatment methods using anti-CD22 antibodies
JP2005535290A (en) 2002-02-22 2005-11-24 ジェネンテック・インコーポレーテッド Compositions and methods for the treatment of immune related diseases
WO2003083047A2 (en) 2002-03-01 2003-10-09 Exelixis, Inc. MP53s AS MODIFIERS OF THE p53 PATHWAY AND METHODS OF USE
US20050220798A1 (en) 2002-06-04 2005-10-06 Reinhard Ebner Cancer-linked gene as target for chemotherapy
WO2003104399A2 (en) 2002-06-07 2003-12-18 Avalon Pharmaceuticals, Inc Cancer-linked gene as target for chemotherapy
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
AU2003228345B2 (en) 2002-03-21 2009-02-05 Sunesis Pharmaceuticals, Inc. Identification of kinase inhibitors
US7193069B2 (en) 2002-03-22 2007-03-20 Research Association For Biotechnology Full-length cDNA
EP1490085A2 (en) 2002-03-25 2004-12-29 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
BR0308953A (en) 2002-04-05 2006-03-14 Agensys Inc compositions, protein, polynucleotide, method of generating an immune response, detection method, pharmaceutical composition, antibody or fragment thereof, transgenic animal, hybridoma, method of providing a cytotoxic agent or diagnostic agent and method of inhibiting cell growth cancerous
WO2003087768A2 (en) 2002-04-12 2003-10-23 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
US20030224467A1 (en) 2002-04-17 2003-12-04 Osborne C. Kent AIB1 as a prognostic marker and predictor of resistance to endocrine therapy
AU2003228869A1 (en) 2002-05-03 2003-11-17 Incyte Corporation Transporters and ion channels
AU2003229294A1 (en) 2002-05-15 2003-12-02 Avalon Pharmaceuticals Cancer-linked gene as target for chemotherapy
AU2003232453A1 (en) 2002-05-30 2003-12-19 David K. Bol Human solute carrier family 7 member 11 (hslc7a11)
WO2003101283A2 (en) 2002-06-04 2003-12-11 Incyte Corporation Diagnostics markers for lung cancer
KR101031025B1 (en) 2002-06-06 2011-04-25 온코세라피 사이언스 가부시키가이샤 Genes and polypeptides relating to human colon cancers
AU2003242633A1 (en) 2002-06-06 2003-12-22 Molecular Engines Laboratories Dudulin genes, non-human animal model: uses in human hematological disease
AU2003245441A1 (en) 2002-06-12 2003-12-31 Avalon Pharmaceuticals, Inc. Cancer-linked gene as target for chemotherapy
US20040249130A1 (en) 2002-06-18 2004-12-09 Martin Stanton Aptamer-toxin molecules and methods for using same
AU2003247576A1 (en) 2002-06-18 2003-12-31 Archemix Corp. Aptamer-toxin molecules and methods for using same
CA2489803A1 (en) 2002-06-20 2003-12-31 The Regents Of The University Of California Compositions and methods for modulating lymphocyte activity
AU2003278161A1 (en) 2002-06-21 2004-01-06 Johns Hopkins University School Of Medicine Membrane associated tumor endothelium markers
DE10229834A1 (en) 2002-07-03 2004-01-29 Zinser Textilmaschinen Gmbh Drafting system for spinning machines with a downstream compacting device
WO2004009622A2 (en) 2002-07-19 2004-01-29 Cellzome Ag Protein complexes of cellular networks underlying the development of cancer and other diseases
MXPA05000940A (en) 2002-07-25 2005-05-16 Genentech Inc Taci antibodies and uses thereof.
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
WO2004032828A2 (en) 2002-07-31 2004-04-22 Seattle Genetics, Inc. Anti-cd20 antibody-drug conjugates for the treatment of cancer and immune disorders
WO2004015426A1 (en) 2002-08-06 2004-02-19 Bayer Healthcare Ag Diagnostics and therapeutics for diseases associated with human cxc chemokine receptor 5(cxcr5)
JP2004121218A (en) 2002-08-06 2004-04-22 Jenokkusu Soyaku Kenkyusho:Kk Method for testing bronchial asthma or chronic obstructive pulmonary disease
MXPA05001933A (en) 2002-08-19 2005-04-28 Genentech Inc Compositions and methods for the diagnosis and treatment of tumor.
US7504211B2 (en) 2002-08-27 2009-03-17 Bristol-Myers Squibb Company Methods of using EPHA2 for predicting activity of compounds that interact with and/or modulate protein tyrosine kinases and/or protein tyrosine kinase pathways in breast cells
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
JP2005537800A (en) 2002-09-06 2005-12-15 マンカインド コーポレイション Epitope sequence
JP2006513702A (en) 2002-09-09 2006-04-27 ヌラ インコーポレーティッド G protein-coupled receptor and use thereof
JP2004113151A (en) 2002-09-27 2004-04-15 Sankyo Co Ltd Oncogene and its application
AU2003278002A1 (en) 2002-10-03 2004-04-23 Mcgill Univeristy Antibodies and cyclic peptides which bind cea (carcinoembryonic antigen) and their use as cancer therapeutics
WO2004032842A2 (en) 2002-10-04 2004-04-22 Van Andel Research Institute 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
JP2006516094A (en) 2002-11-08 2006-06-22 ジェネンテック・インコーポレーテッド Compositions and methods for treatment of natural killer cell related diseases
AU2003295511A1 (en) 2002-11-13 2004-06-03 Genentech, Inc. Methods and compositions for diagnosing dysplasia
WO2004043493A1 (en) 2002-11-14 2004-05-27 Syntarga B.V. Prodrugs built as multiple self-elimination-release spacers
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
CN100594037C (en) 2002-11-15 2010-03-17 Musc研究发展基金会 Complement receptor 2 targeted complement modulators
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
WO2004047749A2 (en) 2002-11-21 2004-06-10 University Of Utah Research Foundation Purinergic modulation of smell
WO2004048938A2 (en) 2002-11-26 2004-06-10 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, splice variants and methods relating to ovarian specific genes and proteins
JP2004198419A (en) 2002-12-13 2004-07-15 Bayer Healthcare Llc Detection method using timp1
WO2004058171A2 (en) 2002-12-20 2004-07-15 Protein Design Labs, Inc. Antibodies against gpr64 and uses thereof
AU2003299819A1 (en) 2002-12-23 2004-07-22 Human Genome Sciences, Inc. Neutrokine-alpha conjugate, neutrokine-alpha complex, and uses thereof
EP1597558A2 (en) 2003-01-08 2005-11-23 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
EP1583820A4 (en) 2003-01-14 2007-07-18 Bristol Myers Squibb Co 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
JP2009520459A (en) 2003-02-14 2009-05-28 サイグレス ディスカバリー， インコーポレイテッド Therapeutic target 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
DE60326060D1 (en) 2003-03-31 2009-03-19 Council Scient Ind Res Non-Crosslinking PYRROLOA2,1-CÜ1,4ÜBENZODIAZEPINE AS POTENTIAL ANTITUMOR AGENTS AND THEIR PREPARATION
GB0321295D0 (en) 2003-09-11 2003-10-15 Spirogen Ltd Synthesis of protected pyrrolobenzodiazepines
ATE516288T1 (en) 2003-10-22 2011-07-15 Us Gov Health & Human Serv PYRROLOBENZODIAZEPINE DERIVATIVES, COMPOSITIONS CONTAINING SAME AND RELATED METHODS
GB0416511D0 (en) 2003-10-22 2004-08-25 Spirogen Ltd Pyrrolobenzodiazepines
WO2005079479A2 (en) 2004-02-17 2005-09-01 Absalus, Inc. Super-humanized antibodies against respiratory syncytial virus
JP5064037B2 (en) 2004-02-23 2012-10-31 ジェネンテック， インコーポレイテッド Heterocyclic self-destructive linkers and conjugates
GB0404578D0 (en) 2004-03-01 2004-04-07 Spirogen Ltd Pyrrolobenzodiazepines
GB0404574D0 (en) 2004-03-01 2004-04-07 Spirogen Ltd Amino acids
SI2270010T1 (en) 2004-03-01 2012-05-31 Spirogen Ltd 11-hydroxy-5h-pyrrolo?á2,1-c?å?á1,4?åbenzodiazepin-5-one derivatives as key intermediates for the preparation of c2 substituted pyrrolobenzodiazepins
GB0404577D0 (en) 2004-03-01 2004-04-07 Spirogen Ltd Pyrrolobenzodiazepines
DE102004010943A1 (en) 2004-03-03 2005-09-29 Degussa Ag Process for the preparation of N-protected 4-ketproline derivatives
JP5166861B2 (en) 2004-03-09 2013-03-21 スピロゲン リミティッド Pyrrolobenzodiazepine
FR2869231B1 (en) 2004-04-27 2008-03-14 Sod Conseils Rech Applic THERAPEUTIC COMPOSITION CONTAINING AT LEAST ONE PYRROLOBENZODIAZEPINE DERIVATIVE AND 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
NZ553500A (en) 2004-09-23 2009-11-27 Genentech Inc Genentech Inc Cysteine engineered antibodies and conjugates withCysteine engineered antibodies and conjugates with a free cysteine amino acid in the heavy chain a free cysteine amino acid in the heavy chain
RU2364643C2 (en) 2004-12-24 2009-08-20 Сова Денко К.К. Method of obtaining thermoelectric semiconductor alloy, module of thermoelectric treansformation and thermoelectric device for electric energy generation
ES2417133T3 (en) 2005-02-03 2013-08-06 Antitope Limited Antibodies and human proteins
AU2006236225C1 (en) 2005-04-19 2013-05-02 Seagen Inc. Humanized anti-CD70 binding agents and uses thereof
GB0508084D0 (en) 2005-04-21 2005-06-01 Spirogen Ltd Pyrrolobenzodiazepines
PT1879901E (en) 2005-04-21 2010-03-29 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
BRPI0617165B1 (en) 2005-10-07 2023-10-03 Exelixis Inc MEK INHIBITOR COMPOUNDS, PHARMACEUTICAL COMPOSITIONS CONTAINING THEM AND METHODS OF USE THEREOF
RS52060B (en) 2006-01-25 2012-04-30 Sanofi Cytotoxic agents comprising new tomaymycin derivatives
MX2009000709A (en) 2006-07-18 2009-02-04 Sanofi Aventis Antagonist antibody against epha2 for the treatment of cancer.
PL2059536T3 (en) 2006-08-14 2014-07-31 Xencor Inc Optimized antibodies that target 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
ES2523915T5 (en) 2006-12-01 2022-05-26 Seagen Inc Variant Target Binding Agents and Uses Thereof
WO2008141044A2 (en) 2007-05-08 2008-11-20 Genentech, Inc. Cysteine engineered anti-muc16 antibodies and antibody drug conjugates
PL2019104T3 (en) 2007-07-19 2014-03-31 Sanofi Sa Cytotoxic agents comprising new tomaymycin derivatives and their therapeutic use
US8937161B2 (en) 2007-10-19 2015-01-20 Genentech, Inc. Cysteine engineered anti-TENB2 antibodies and antibody drug conjugates
GB0722088D0 (en) 2007-11-09 2007-12-19 Spirogen Ltd Pyrrolobenzodiazepines
GB0722087D0 (en) 2007-11-09 2007-12-19 Spirogen Ltd Polyamides
PL2842575T3 (en) 2008-03-18 2018-02-28 Seattle Genetics, Inc. Auristatin drug linker conjugates
EP2109244A1 (en) 2008-04-09 2009-10-14 Siemens Aktiengesellschaft Method for security-oriented transmission, security switch device and control unit
LT2281006T (en) 2008-04-30 2017-11-27 Immunogen, Inc. Cross-linkers and their uses
AU2009271401A1 (en) 2008-06-16 2010-01-21 Immunogen Inc. Novel synergistic effects
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
SG173152A1 (en) 2009-02-05 2011-08-29 Immunogen Inc Novel benzodiazepine derivatives
AP2011005859A0 (en) 2009-02-23 2011-10-31 Glenmark Pharmaceuticals Sa Humanized antibodies that bind to CD19 and their uses.
JP5382792B2 (en) 2009-08-14 2014-01-08 独立行政法人理化学研究所 Method for simultaneously measuring primary and secondary photosensitivity anisotropy in optical second-order nonlinear thin film, apparatus for executing the method, and program for causing computer to execute the method
FR2949469A1 (en) 2009-08-25 2011-03-04 Sanofi Aventis ANTICANCER DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION
SG178602A1 (en) 2009-09-01 2012-04-27 Abbott Lab Dual variable domain immunoglobulins and uses thereof
WO2011038159A2 (en) 2009-09-24 2011-03-31 Seattle Genetics, Inc. Dr5 ligand drug conjugates
ES2449379T3 (en) 2010-02-09 2014-03-19 Bristol-Myers Squibb Company Benzylpyrrolidinone derivatives as modulators of chemokine receptor activity
AR080155A1 (en) 2010-02-10 2012-03-14 Immunogen Inc ANTI-CD20 ANTIBODIES AND ITS USE
WO2011100403A1 (en) 2010-02-10 2011-08-18 Immunogen, Inc Cd20 antibodies and uses thereof
WO2011130616A1 (en) 2010-04-15 2011-10-20 Spirogen Limited Pyrrolobenzodiazepines used to treat proliferative diseases
WO2011130615A2 (en) 2010-04-15 2011-10-20 Dr. Reddy's Laboratories Ltd. Preparation of lacosamide
JP5972864B2 (en) 2010-04-15 2016-08-17 メディミューン リミテッド Pyrrolobenzodiazepines and their conjugates
GB201006340D0 (en) 2010-04-15 2010-06-02 Spirogen Ltd Synthesis method and intermediates
DK3056203T3 (en) 2010-04-21 2018-01-29 Syntarga Bv CONJUGATES OF CC-1065 ANALOGS AND BIFUNCTIONAL LINKERS.
FR2963007B1 (en) 2010-07-26 2013-04-05 Sanofi Aventis ANTICANCER DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION
EP3666289A1 (en) 2011-02-15 2020-06-17 ImmunoGen, Inc. Cytotoxic benzodiazepine derivatives
US9135118B2 (en) 2011-03-07 2015-09-15 Aptare, Inc. System to catalog and search point-in-time instances of a file system
CN103987718A (en) 2011-09-20 2014-08-13 斯皮罗根有限公司 Pyrrolobenzodiazepines as unsymmetrical dimeric PBD compounds for inclusion in targeted conjugates
EP3388435B1 (en) 2011-10-14 2023-05-03 Seagen Inc. Pyrrolobenzodiazepines and targeted conjugates
BR112014008981A2 (en) 2011-10-14 2017-05-02 Spirogen Sàrl pyrrolobenzodiazepines
EA036202B1 (en) 2011-10-14 2020-10-14 Сиэтл Дженетикс, Инк. Pyrrolobenzodiazepines and targeted conjugates
KR101877598B1 (en) 2011-10-14 2018-07-11 메디뮨 리미티드 Pyrrolobenzodiazepines and conjugates thereof
EA028457B1 (en) 2011-10-14 2017-11-30 Медимьюн Лимитед Pyrrolobenzodiazepines
JP6166728B2 (en) 2011-10-14 2017-07-19 メドイミューン・リミテッドＭｅｄＩｍｍｕｎｅ Ｌｉｍｉｔｅｄ Synthetic methods and intermediates useful for the preparation of pyrrolobenzodiazepines
JP2013194140A (en) 2012-03-19 2013-09-30 Fuji Xerox Co Ltd Polyester resin for toner, electrostatic charge image development toner, electrostatic charge image developer, toner cartridge, process cartridge, image forming apparatus and image forming method
US9321774B2 (en) 2012-04-30 2016-04-26 Medimmune Limited Pyrrolobenzodiazepines
BR112014027143B1 (en) 2012-04-30 2020-06-09 Medimmune Ltd pyrrolobenzodiazepines
US9062577B2 (en) 2012-05-14 2015-06-23 Southwest Research Institute Diesel engine operation for fast transient response and low emissions
WO2013177481A1 (en) 2012-05-25 2013-11-28 Immunogen, Inc. Benzodiazepines and conjugates thereof
US20140030279A1 (en) 2012-07-09 2014-01-30 Spirogen Sarl Anti-cd22 antibodies and immunoconjugates
JP2015523380A (en) 2012-07-09 2015-08-13 ジェネンテック， インコーポレイテッド Immune complex comprising anti-CD79B antibody
KR20150039818A (en) 2012-08-02 2015-04-13 제넨테크, 인크. Anti-etbr antibodies and immunoconjugates
EP2887965A1 (en) 2012-08-22 2015-07-01 ImmunoGen, Inc. Cytotoxic benzodiazepine derivatives
WO2014057120A1 (en) 2012-10-12 2014-04-17 Adc Therapeutics Sàrl Pyrrolobenzodiazepine-antibody conjugates
PT2906296T (en) 2012-10-12 2018-06-01 Medimmune Ltd Pyrrolobenzodiazepine-antibody conjugates
WO2014057118A1 (en) 2012-10-12 2014-04-17 Adc Therapeutics Sarl Pyrrolobenzodiazepine-anti-cd22 antibody conjugates
SI2906298T1 (en) 2012-10-12 2018-12-31 Adc Therapeutics Sa Pyrrolobenzodiazepine-antibody conjugates
EP2906250B1 (en) 2012-10-12 2018-05-30 ADC Therapeutics SA Pyrrolobenzodiazepine-anti-psma antibody conjugates
DK2906252T3 (en) 2012-10-12 2017-09-11 Adc Therapeutics Sa Pyrrolobenzodiazepine Anti-Her2 antibody conjugates
SI2906251T1 (en) 2012-10-12 2018-01-31 Adc Therapeutics Sa Pyrrolobenzodiazepine-anti-cd22 antibody conjugates
AU2013328580B2 (en) 2012-10-12 2016-01-21 Medimmune Limited Pyrrolobenzodiazepines and conjugates thereof
KR101986404B1 (en) 2012-10-12 2019-06-07 에이디씨 테라퓨틱스 에스에이 Pyrrolobenzodiazepine - anti-psma antibody conjugates
WO2014057072A1 (en) 2012-10-12 2014-04-17 Spirogen Sàrl Synthesis and intermediates of pyrrolobenzodiazepine derivatives for conjugation
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
CN105246894A (en) 2012-12-21 2016-01-13 斯皮罗根有限公司 Unsymmetrical pyrrolobenzodiazepines-dimers for use in the treatment of proliferative and autoimmune diseases
EP2935268B2 (en) 2012-12-21 2021-02-17 MedImmune Limited Pyrrolobenzodiazepines and conjugates thereof
ME03394B (en) 2013-02-22 2020-01-20 Medimmune Ltd Antidll3-antibody-pbd conjugates and uses thereof
AU2014230735B2 (en) 2013-03-13 2018-03-15 Medimmune Limited Pyrrolobenzodiazepines and conjugates thereof
NZ710745A (en) 2013-03-13 2019-03-29 Genentech Inc Pyrrolobenzodiazepines and conjugates thereof
US9649390B2 (en) 2013-03-13 2017-05-16 Medimmune Limited Pyrrolobenzodiazepines and conjugates thereof
US20160106861A1 (en) 2013-04-26 2016-04-21 Spirogen Sarl 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.
GB201318069D0 (en) 2013-10-11 2013-11-27 Maersk Olie & Gas Seismic data processing method and apparatus
EP3054985B1 (en) 2013-10-11 2018-12-26 Medimmune Limited Pyrrolobenzodiazepine-antibody conjugates
US9956299B2 (en) 2013-10-11 2018-05-01 Medimmune Limited Pyrrolobenzodiazepine—antibody conjugates
EP3055423B1 (en) 2013-10-11 2019-12-25 Cellectis Method for detecting nucleic acid sequences of interest using talen protein
WO2015052533A1 (en) 2013-10-11 2015-04-16 Spirogen Sàrl Pyrrolobenzodiazepine-antibody conjugates
DE102013220528B4 (en) 2013-10-11 2015-05-07 Continental Automotive Gmbh Injection valve and method for operating an injection valve
WO2015052532A1 (en) 2013-10-11 2015-04-16 Spirogen Sàrl Pyrrolobenzodiazepine-antibody conjugates
GB201317981D0 (en) 2013-10-11 2013-11-27 Spirogen Sarl Pyrrolobenzodiazepines and conjugates thereof
GB201317982D0 (en) 2013-10-11 2013-11-27 Spirogen Sarl Pyrrolobenzodiazepines and conjugates thereof
KR102405762B1 (en) 2013-12-16 2022-06-07 제넨테크, 인크. 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
EP3193940A1 (en) 2014-09-10 2017-07-26 Medimmune Limited Pyrrolobenzodiazepines and conjugates thereof
GB201416112D0 (en) 2014-09-12 2014-10-29 Medimmune Ltd Pyrrolobenzodiazepines and conjugates thereof
EP3693391B1 (en) 2014-09-12 2024-08-21 Genentech, Inc. Anti-cll-1 antibodies and immunoconjugates
CR20170099A (en) 2014-09-17 2017-07-19 Genentech Inc PIRROLOBENZODIAZEPINAS AND CONJUGADOS DE ANTIBERPOS-DISULFURO DE LAS SISAS

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011130613A1 (en) * 2010-04-15 2011-10-20 Seattle Genetics, Inc. Targeted pyrrolobenzodiazapine conjugates
WO2014057073A1 (en) * 2012-10-12 2014-04-17 Spirogen Sàrl Pyrrolobenzodiazepines and conjugates thereof

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
PURSER SOPHIE ET AL: "Fluorine in medicinal chemistry", CHEMICAL SOCIETY REVIEWS, CHEMICAL SOCIETY, LONDON, GB, vol. 37, no. 2, 1 February 2008 (2008-02-01), pages 320 - 330, XP002596910, ISSN: 0306-0012, [retrieved on 20071213], DOI: 10.1039/B610213C *
SCOTT C. JEFFREY ET AL: "A Potent Anti-CD70 Antibody-Drug Conjugate Combining a Dimeric Pyrrolobenzodiazepine Drug with Site-Specific Conjugation Technology", BIOCONJUGATE CHEMISTRY, vol. 24, no. 7, 17 July 2013 (2013-07-17), pages 1256 - 1263, XP055124636, ISSN: 1043-1802, DOI: 10.1021/bc400217g *

Cited By (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019034764A1 (en) 2017-08-18 2019-02-21 Medimmune Limited Pyrrolobenzodiazepine conjugates
US11649250B2 (en) 2017-08-18 2023-05-16 Medimmune Limited Pyrrolobenzodiazepine conjugates
WO2019096788A1 (en) 2017-11-14 2019-05-23 Medimmune Limited Pyrrolobenzodiazepine conjugates
US11352324B2 (en) 2018-03-01 2022-06-07 Medimmune Limited Methods
US12060427B2 (en) 2018-03-28 2024-08-13 Mitsubishi Tanabe Pharma Corporat Drug conjugates of cMET monoclonal binding agents, and uses thereof
US11524969B2 (en) 2018-04-12 2022-12-13 Medimmune Limited Pyrrolobenzodiazepines and conjugates thereof as antitumour agents
WO2019224340A1 (en) 2018-05-25 2019-11-28 Medimmune Limited Pyrrolobenzodiazepine conjugates
WO2020025108A1 (en) 2018-07-31 2020-02-06 Astrazeneca Ab Linkers and conjugates
WO2020079239A1 (en) 2018-10-19 2020-04-23 Medimmune Limited Pyrrolobenzodiazepine conjugates
WO2020079229A1 (en) 2018-10-19 2020-04-23 Medimmune Limited Pyrrolobenzodiazepine conjugates
WO2020187721A1 (en) 2019-03-15 2020-09-24 Medimmune Limited Azetidobenzodiazepine dimers and conjugates comprising them for use in the treatment of cancer
WO2020200880A1 (en) 2019-03-29 2020-10-08 Medimmune Limited Compounds and conjugates thereof
US11446292B2 (en) 2019-03-29 2022-09-20 Medimmune Limited Compounds and conjugates thereof
EP4176904A1 (en) 2019-03-29 2023-05-10 MedImmune Limited Compounds and conjugates thereof
WO2021080608A1 (en) 2019-10-25 2021-04-29 Medimmune, Llc Branched moiety for use in conjugates
WO2021148501A1 (en) 2020-01-22 2021-07-29 Medimmune Limited Compounds and conjugates thereof
WO2021148500A1 (en) 2020-01-22 2021-07-29 Medimmune Limited Compounds and conjugates thereof
WO2022053651A2 (en) 2020-09-10 2022-03-17 Precirix N.V. Antibody fragment against fap
WO2022218973A2 (en) 2021-04-12 2022-10-20 Medimmune Limited Pyrrolobenzodiazepine conjugates
WO2022218970A2 (en) 2021-04-12 2022-10-20 Medimmune Limited Pyrrolobenzodiazepine conjugates
WO2023006782A1 (en) 2021-07-26 2023-02-02 Cambridge Enterprise Limited Conjugating reagents and conjugates thereof
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
WO2023227757A1 (en) 2022-05-25 2023-11-30 Cambridge Enterprise Limited Quinone protected forms and conjugates

Also Published As

Publication number Publication date
US20190134205A1 (en) 2019-05-09
GB201607478D0 (en) 2016-06-15
US10543279B2 (en) 2020-01-28
EP3448858A1 (en) 2019-03-06

Similar Documents

Publication Publication Date Title
US10543279B2 (en) Pyrrolobenzodiazepine conjugates and their use for the treatment of cancer
US20230143309A1 (en) Pyrrolobenzodiazepine antibody conjugates
US10799595B2 (en) Pyrrolobenzodiazepine conjugates
KR102138220B1 (en) Pyrrolobenzodiazepines and conjugates thereof
JP6448632B2 (en) Pyrrolobenzodiazepines and their complexes
US10695439B2 (en) Pyrrolobenzodiazepine conjugates
KR20190098275A (en) Pyrrolobenzodiazepines and conjugates thereof
US20190307890A1 (en) Pyrrolobenzodiazepine conjugates
US10392393B2 (en) Pyrrolobenzodiazepines
EP3525829A1 (en) Antibody-drug conjugates with immune-mediated therapy agents

Legal Events

Date Code Title Description
NENP Non-entry into the national phase

Ref country code: DE

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

Ref document number: 17721108

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 2017721108

Country of ref document: EP

ENP Entry into the national phase

Ref document number: 2017721108

Country of ref document: EP

Effective date: 20181129