Pyrrolobenzodiazepine conjugates

Abstract

A conjugate of formula (I), wherein L is a Ligand unit, D is a Drug Linker unit of formula (II), wherein either: (a) R10 and R11 form a nitrogen-carbon double bond between the nitrogen and carbon atoms to which they are bound; or (b) R10 is OH, and R11 is formula (A): p is an integer of from 1 to 20.

Description

PYRROLOBENZODIAZEPINE CONJUGATESThe present invention relates to conjugates comprising a specific pyrrolobenzodiazepine (PBD), and the precursor drug linker used to make such conjugates.Background to the inventionSome 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: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, InAntibiotics 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):(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 :and in WO2006 / 1 1 1759, bisulphites of such PBD compounds, for example SG2285 (ZC-These compounds have been shown to be highly useful cytotoxic agents (Howard, P.W., et al., Bioorg. Med. Chem. (2009), doi: 10.1016 / j.bmcl.2009.09.012).In an impact study submitted to the 2014 Research Excellence Framework (REF) in the United Kingdom by University College London (available athttp: / / impact.ref.ac.uk / casestudies2 / refservice.svc / GetCaseStudyPDF / 35393), it was commented that:"The next generation of PBD dimers, which are more potent than SG2000, have been developed, including SG2057 and SG2202. They exhibit picomolar / sub-picomolar activity against a range of human tumour cell lines and demonstrate curative activity in human tumour xenograft models." making reference to:Hartley JA, et al., DNA interstrand cross-linking and in vivo antitumor activity of the extended pyrrolo[2, 1 -c][1 , ^benzodiazepine dimer SG2057. Invest New Drugs. 2012 Jun; 30(3):950-8. http: / / dx.doi.org / 10.1007 / s10637-01 1-9647-z (herein after "Hartley et al (2012)")and:"The ability to generate such cytotoxic molecules that display exquisite potency suggested a potential role in strategies aimed at targeting and releasing highly cytotoxic agents directly at a tumour site. An example is as the 'warhead' component of an antibody drug conjugate (ADC). The fully synthetic PBD dimers are ideally suited for the role of warhead in an ADC approach."The Hartley et al (2012) paper comments in its summary that "SG2057 is therefore a highly active antiumour agent, with more potent in vitro activity and superior in vivo activity to SG2000, warranting further development".SG2057 has the structure:SG2057Antibody drug conjugates using SG2057 as a warhead were first disclosed in WO201 1 / 130598. For example, claim 54 of this application includes the formula:wherein n is from 1 to 24, more preferably 4 to 8. The following drug linkers were exemplified: n=4, 15c; n=8, 15d; n=24, 15e.Claim 54 of this application also includes the formula:wherein n is from 1 to 24, more preferably 4 to 8. The following drug linkers were exemplified: n=8, 58; n=24, 61.WO 201 1 / 130598 also discloses antibody-drug conjugates including these drug linkers, for example 1 10 (antiSteap1 -15d), example 1 14 (tastuzumab-15d) and example 1 15(tastuzumab-58).WO 2013 / 055987 discloses the drug linkers 14 and 22:and their use in antibody-drug con ugates.More recently, the warhead:has been used in drug linkers and antibody-drug conjugates. WO 2014 / 057074 discloses:WO2015 / 052322 discloses:Disclosure of the inventionThe present inventors have surprisingly found that although SG2000 is at least 10 times less cytotoxic than SG2057 (see Hartley et al 2012), particular antibody-drug conjugates appear to show at least comparable activity. These conjugates have been shown to have surprisingly well tolerated in toxicity studies in a variety of species. This leads to the conjugates exhibiting high therapeutic indices and thus are promising clinical candidates.In a first aspect, the present invention provides Conjugates of formula I :wherein L is a Li and unit (i.e., a targeting agent), D is a Drug Linker unit of formula I I :whereineither:(a) R10and R11form a nitrogen-carbon double bond between the nitrogen and carbon atoms to which they are bound; or(b R10is OH, and R11is: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:whereineither:(a) R10and R11form a nitrogen-carbon double bond between the nitrogen and carbon atoms to which they are bound; or(b R10is OH, and R11is: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 thetreatment 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 FiguresFigure 1 shows the effect on volume of a BT474 tumour following treatment with a conjugate of the present invention;Figure 2 shows the effect on volume of a BT474 tumour following treatment with a different conjugate of the present invention;Figure 3 shows the effect on volume of a NCI-N87 tumour following treatment with a conjugate of the present invention;Figure 4 shows the effect on volume of a NCI-N87 tumour following treatment with a different conjugate of the present invention.DLIn the first aspect DLis selected from DL-A and DL-B:Ligand UnitThe 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 x107M"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 AgentA 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. PeptidesIn 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 sequenceNAVXXXXXXXXXXXXXXXRTC.AntibodiesThe 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 determiningregion), 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 substantiallyhomogeneous 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. HumanisationTechniques 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 graftingIn 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 selectionThe 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 Vdomains 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 antibodiesIn 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 .DeimmunizationThis 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 establishedmethods such as Site Directed Mutagenesis. However, the use of protein chemistry or any other means of molecular alteration is also possible.ResurfacingThis 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).SuperhumanizationThe 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 OptimizationThis 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 MolecularImmunology, 44, (2007) 1986-1998).Framework ShufflingThe 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 inWO 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)NucleotideGenbank accession no. NM_001203Genbank version no. NM_001203.2 Gl:169790809Genbank record update date: Sep 23, 2012 02:06 PMPolypeptideGenbank accession no. NP 001 194Genbank version no. NP_001 194.1 Gl:4502431Genbank record update date: Sep 23, 2012 02:06 PMCross-referencesten 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)NucleotideGenbank accession no. NM_003486Genbank version no. NM_003486.5 Gl:71979931Genbank record update date: Jun 27, 2012 12:06 PMPolypeptideGenbank accession no. NP_003477Genbank version no. NP_003477.4 Gl:71979932Genbank record update date: Jun 27, 2012 12:06 PMCross referencesBiochem. 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)NucleotideGenbank accession no. NM_012449Genbank version no. NM_012449.2 Gl:22027487Genbank record update date: Sep 9, 2012 02:57 PMPolypeptideGenbank accession no. NP_036581Genbank version no. NP_036581 .1 Gl:9558759Genbank record update date: Sep 9, 2012 02:57 PMCross referencesCancer 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 (Fig1 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)NucleotideGenbank accession no. AF361486Genbank version no. AF361486.3 Gl:34501466Genbank record update date: Mar 1 1 , 2010 07:56 AMPolypeptideGenbank accession no. AAK74120Genbank version no. AAK74120.3 Gl:34501467Genbank record update date: Mar 1 1 , 2010 07:56 AMCross referencesJ. 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) NucleotideGenbank accession no. NM_005823Genbank version no. NM_005823.5 Gl:293651528Genbank record update date: Sep 2, 2012 01 :47 PMPolypeptideGenbank accession no. NP_005814Genbank version no. NP_005814.2 Gl:53988378Genbank record update date: Sep 2, 2012 01 :47 PMCross referencesYamaguchi, 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)NucleotideGenbank accession no. NM_006424Genbank version no. NM_006424.2 Gl:1 1061 1905Genbank record update date: Jul 22, 2012 03:39 PMPolypeptideGenbank accession no. NP_006415Genbank version no. NP_006415.2 Gl:1 1061 1906Genbank record update date: Jul 22, 2012 03:39 PMCross referencesJ. 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 (Claim1 ; 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)NucleotideGenbank accession no. AB040878Genbank version no. AB040878.1 G 7959148Genbank record update date: Aug 2, 2006 05:40 PMPolypeptideGenbank accession no. BAA95969Genbank version no. BAA95969.1 Gl:7959149Genbank record update date: Aug 2, 2006 05:40 PMCross referencesNagase T., et al (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 cDNA2700050C12 gene)NucleotideGenbank accession no. AY358628Genbank version no. AY358628.1 Gl:37182377Genbank record update date: Dec 1 , 2009 04:15 AMPolypeptideGenbank accession no. AAQ88991Genbank version no. AAQ88991 .1 Gl:37182378Genbank record update date: Dec 1 , 2009 04:15 AMCross referencesRoss etal (2002) Cancer Res.62:2546-2553; US2003 / 129192 (Claim 2); US2004 / 044180 (Claim 12); US2004 / 044179 (Claim 11); US2003 / 096961 (Claim 11); US2003 / 232056 (Example 5); WO2003 / 10575816 (Claim 12); US2003 / 206918 (Example 5); EP1347046 (Claim 1); WO2003 / 025148 (Claim 20); Gl:37182378.(9) ETBR (Endothelin type B receptor)NucleotideGenbank accession no. AY275463Genbank version no. AY275463.1 Gl:30526094Genbank record update date: Mar 11, 201002:26 AMPolypeptideGenbank accession no. AAP32295Genbank version no. AAP32295.1 Gl:30526095Genbank record update date: Mar 11, 201002:26 AMCross referencesNakamuta M., et al Biochem. Biophys. Res. Commun.177, 34-39, 1991; Ogawa Y., etalBiochem. 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., YanagisawaM., 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; SvenssonP.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 (Claim1;Page 124-125); EP0522868 (Claim 8; Fig 2); WO2001 / 77172 (Claim 1 ; Page 297-299); US2003 / 109676; US6518404 (Fig 3); US5773223 (Claim 1 a; Col 31 -34); WO2004 / 001004.(10) MSG783 (RNF124, hypothetical protein FLJ20315)NucleotideGenbank accession no. NM_017763Genbank version no. NM_017763.4 Gl:167830482Genbank record update date: Jul 22, 2012 12:34 AM PolypeptideGenbank accession no. NP_060233Genbank version no. NP_060233.3 Gl:5671 1322Genbank record update date: Jul 22, 2012 12:34 AM Cross referencesWO2003 / 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 cancerassociated gene 1, prostate cancer associated protein 1, six transmembrane epithelial antigen of prostate 2, six transmembrane prostate protein)NucleotideGenbank accession no. AF455138Genbank version no. AF455138.1 Gl:22655487Genbank record update date: Mar 1 1 , 2010 01 :54 AMPolypeptideGenbank accession no. AAN04080Genbank version no. AAN04080.1 Gl:22655488Genbank record update date: Mar 1 1 , 2010 01 :54 AMCross referencesLab. 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)NucleotideGenbank accession no. NM_017636Genbank version no. NM_017636.3 Gl:304766649Genbank record update date: Jun 29, 2012 1 1 :27 AMPolypeptideGenbank accession no. NP_060106Genbank version no. NP_060106.2 Gl:21314671Genbank record update date: Jun 29, 2012 1 1 :27 AMCross referencesXu, 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) NucleotideGenbank accession no. NM_003212Genbank version no. NM_003212.3 Gl:292494881Genbank record update date: Sep 23, 2012 02:27 PMPolypeptideGenbank accession no. NP_003203Genbank version no. NP_003203.1 Gl:4507425Genbank record update date: Sep 23, 2012 02:27 PMCross referencesCiccodicola, 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); Ml M: 187395.(14) CD21 (CR2 (Complement receptor 2) or C3DR (C3d / Epstein Barr virus receptor) or Hs.73792)NucleotideGenbank accession no M26004Genbank version no. M26004.1 GM 81939Genbank record update date: Jun 23, 2010 08:47 AMPolypeptideGenbank accession no. AAA35786Genbank version no. AAA35786.1 GM 81940Genbank record update date: Jun 23, 2010 08:47 AMCross referencesFujisaku 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., et al (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)NucleotideGenbank accession no NM_000626Genbank version no. NM_000626.2 Gl:90193589Genbank record update date: Jun 26, 2012 01 :53 PMPolypeptideGenbank accession no. NP_000617Genbank version no. NP 000617.1 Gl:1 1038674Genbank record update date: Jun 26, 2012 01 :53 PM Cross referencesProc. 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 (claim35 5, page 15); US5644033; WO2003 / 048202 (claim 1 , pages 306 and 309); WO99 / 58658,US6534482 (claim 13, Fig 17A / B); WO2000 / 55351 (claim 1 1 , pages 1 145-1 146);Ml M: 147245(16) FcRH2 (IFGP4, IRTA4, SPAP1A (SH2 domain containing phosphatase anchor protein 5 1a), SPAP1B, SPAP1C)NucleotideGenbank accession no NM_030764Genbank version no. NM_030764.3 Gl:227430280Genbank record update date: Jun 30, 2012 12:30 AMPolypeptideGenbank accession no. NP_1 10391Genbank version no. NP_1 10391 .2 GM 9923629Genbank record update date: Jun 30, 2012 12:30 AMCross referencesAY358130); 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)NucleotideGenbank accession no M1 1730Genbank version no. M1 1730.1 GM 83986Genbank record update date: Jun 23, 2010 08:47 AMPolypeptideGenbank accession no. AAA75493Genbank version no. AAA75493.1 Gl:306840Genbank record update date: Jun 23, 2010 08:47 AMCross referencesCoussens 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 1A-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 ; AAA35808.1ANTIBODIESAbbott: US201 10177095For 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 IDNO: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 1For example, ATCC accession numbers: PTA-10355, PTA-10356, PTA-10357, PTA-10358For 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 17097for 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.US20090285837US20090202546for example, ATCC accession numbers: HB-12215, HB-12216, CRL 10463,HB-12698.US20060088523- for example, ATCC accession numbers: HB-12215, HB-12216for 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 24US20060018899- 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 / 0159014for example, an antibody having a light chain variable domaincomprising 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.US20090187007Glycotope: TrasGEX antibody http: / / www.glycotope.com / pipelineFor example, see International Joint Cancer Institute and ChanghaiHospital Cancer Cent: HMTI-Fc Ab - Gao J., et al BMB Rep. 2009 Oct31 ;42(10):636-41 .Symphogen: US201 10217305 Union Stem Cell &Gene Engineering, China - Liu HQ., et al X / Bao Yu Fen Zi Mian YiXue Za Zhi. 2010 May;26(5):456-8.(18) NCA (CEACAM6)NucleotideGenbank accession no M18728Genbank version no. M18728.1 GM 89084Genbank record update date: Jun 23, 2010 08:48 AMPolypeptideGenbank accession no. AAA59907Genbank version no. AAA59907.1 GM 89085Genbank record update date: Jun 23, 2010 08:48 AMCross referencesBarnett 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 (DPEP1)NucleotideGenbank accession no BC017023Genbank version no. BC017023.1 GM 6877538Genbank record update date: Mar 6, 2012 01 :00 PMPolypeptideGenbank accession no. AAH17023Genbank version no. AAH17023.1 GM 6877539Genbank record update date: Mar 6, 2012 01 :00 PMCross referencesProc. 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); MIM:179780.(20) IL20R-alpha (IL20Ra, ZCYTOR7)NucleotideGenbank accession no AF184971Genbank version no. AF184971.1 Gl:6013324Genbank record update date: Mar 10, 2010 10:00 PMPolypeptideGenbank accession no. AAF01320Genbank version no. AAF01320.1 Gl:6013325Genbank record update date: Mar 10, 2010 10:00 PMCross referencesClark H.F., et al Genome Res. 13, 2265-2270, 2003; Mungall A.J., et al Nature 425, 805- 81 1 , 2003; Blumberg H., ei a / Ce / / 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 (Page20-21 ); 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)NucleotideGenbank accession no AF229053Genbank version no. AF229053.1 Gl:10798902Genbank record update date: Mar 1 1 , 2010 12:58 AMPolypeptideGenbank accession no. AAG23135Genbank version no. AAG23135.1 Gl:10798903Genbank record update date: Mar 1 1 , 2010 12:58 AMCross referencesGary 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)NucleotideGenbank accession no NM_004442Genbank version no. NM_004442.6 Gl:1 1 1 1 18979Genbank record update date: Sep 8, 2012 04:43 PMPolypeptideGenbank accession no. NP_004433Genbank version no. NP 004433.2 Gl:21396504Genbank record update date: Sep 8, 2012 04:43 PM Cross referencesChan,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)NucleotideGenbank accession no. AX092328Genbank version no. AX092328.1 Gl:13444478Genbank record update date: Jan 26, 201 1 07:37 AMCross referencesUS2004 / 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; Page205-207); 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)NucleotideGenbank accession no AJ297436Genbank version no. AJ297436.1 Gl:936721 1Genbank record update date: Feb 1 , 201 1 1 1 :25 AMPolypeptideGenbank accession no. CAB97347Genbank version no. CAB97347.1 Gl:9367212Genbank record update date: Feb 1 , 201 1 1 1 :25 AMCross referencesReiter 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) GEDANucleotideGenbank accession no AY260763Genbank version no. AY260763.1 Gl:30102448Genbank record update date: Mar 1 1 , 2010 02:24 AMPolypeptideGenbank accession no. AAP14954Genbank version no. AAP14954.1 Gl:30102449Genbank record update date: Mar 1 1 , 2010 02:24 AMCross referencesAP14954 lipoma HMGIC fusion-partnerlike protein / pid=AAP 14954.1 - 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)NucleotideGenbank accession no AF1 16456Genbank version no. AF1 16456.1 Gl:4585274Genbank record update date: Mar 10, 2010 09:44 PMPolypeptideGenbank accession no. AAD25356Genbank version no. AAD25356.1 Gl:4585275Genbank record update date: Mar 10, 2010 09:44 PMCross referencesBAFF 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 ;AF132600(27) CD22 (B-cell receptor CD22-B isoform, BL-CAM, Lyb-8, Lyb8, SIGLEC-2, FLJ22814) NucleotideGenbank accession no AK026467Genbank version no. AK026467.1 Gl:10439337Genbank record update date: Sep 1 1 , 2006 11 :24 PMPolypeptideGenbank accession no. BAB15489Genbank version no. BAB15489.1 Gl:10439338Genbank record update date: Sep 1 1 , 2006 1 1 :24 PMCross referencesWilson ef 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)NucleotideGenbank accession no X52785Genbank version no. X52785.1 Gl:29778Genbank record update date: Feb 2, 201 1 10:09 AMPolypeptideGenbank accession no. CAA36988Genbank version no. CAA36988.1 Gl:29779Genbank record update date: Feb 2, 201 1 10:09 AMCross referencesStamenkovic I. et al., Nature 345 (6270), 74-77 (1990)??Other informationOfficial Symbol: CD22Other Aliases: SIGLEC-2, SIGLEC2Other 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 2ANTIBODIESG5 / 44 (Inotuzumab): DiJoseph JF.,et al Cancer Immunol Immunother. 2005 Jan;54(1 ):1 1 - 24. Epratuzumab- Goldenberg DM., et al Expert Rev Anticancer Ther. 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 M35 molecules, transduces a signal involved in B-cell differentiation), pi: 4.84, MW: 25028 TM: 2[P] Gene Chromosome: 19q13.2).NucleotideGenbank accession no NM_001783Genbank version no. NM_001783.3 Gl:90193587Genbank record update date: Jun 26, 2012 01 :48 PMPolypeptideGenbank accession no. NP_001774Genbank version no. NP_001774.1 Gl:4502685Genbank record update date: Jun 26, 2012 01 :48 PMCross referencesWO2003 / 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 a10 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,NucleotideGenbank accession no NM_001716Genbank version no. NM_001716.4 Gl:342307092Genbank record update date: Sep 30, 2012 01 :49 PMPolypeptideGenbank accession no. NP_001707Genbank version no. NP_001707.1 Gl:4502415Genbank record update date: Sep 30, 2012 01 :49 PMCross referencesWO2004 / 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)NucleotideGenbank accession no NM_002120Genbank version no. NM_002120.3 Gl:1 18402587Genbank record update date: Sep 8, 2012 04:46 PMPolypeptideGenbank accession no. NP_0021 1 1Genbank version no. NP_0021 1 1 .1 Gl:4504403Genbank record update date: Sep 8, 2012 04:46 PMCross referencesTonnelle 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).NucleotideGenbank accession no NM_002561Genbank version no. NM_002561 .3 Gl:325197202Genbank record update date: Jun 27, 2012 12:41 AM PolypeptideGenbank accession no. NP_002552Genbank version no. NP_002552.2 Gl:28416933Genbank record update date: Jun 27, 2012 12:41 AM Cross referencesLe 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).NucleotideGenbank accession no NM_001782Genbank version no. NM_001782.2 GM 94018444Genbank record update date: Jun 26, 2012 01 :43 PMPolypeptideGenbank accession no. NP_001773Genbank version no. NP_001773.1 Gl:4502683Genbank record update date: Jun 26, 2012 01 :43 PMCross referencesWO2004042346 (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 associatedwith increased disease activity in patients with systemic lupus erythematosis); 661 aa, pi: 6.20, MW: 74147 TM: 1 [P] Gene Chromosome: 5q12).NucleotideGenbank accession no NM_005582Genbank version no. NM_005582.2 Gl:167555126Genbank record update date: Sep 2, 2012 01 :50 PMPolypeptideGenbank accession no. NP_005573Genbank version no. NP_005573.2 Gl:167555127Genbank record update date: Sep 2, 2012 01 :50 PMCross referencesUS2002 / 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 domainthat contains C2 type Ig-like and ITAM domains, may have a role in B-lymphocyte20 differentiation); 429 aa, pi: 5.28, MW: 46925 TM: 1 [P] Gene Chromosome: 1q21-1q22) NucleotideGenbank accession no NM_052938Genbank version no. NM_052938.4 Gl:226958543Genbank record update date: Sep 2, 2012 01 :43 PM PolypeptideGenbank accession no. NP_443170Genbank version no. NP_443170.1 Gl:16418419Genbank record update date: Sep 2, 2012 01 :43 PM Cross referencesWO2003 / 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)NucleotideGenbank accession no AF343662Genbank version no. AF343662.1 GM 3591709Genbank record update date: Mar 1 1 , 2010 01 :16 AMPolypeptideGenbank accession no. AAK31325Genbank version no. AAK31325.1 GM 3591710Genbank record update date: Mar 1 1 , 2010 01 :16 AMCross referencesAF343663, 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 transmembrane35 proteoglycan, related to the EGF / heregulin family of growth factors and follistatin); 374 aa)NucleotideGenbank accession no AF179274Genbank version no. AF179274.2 GM 2280939Genbank record update date: Mar 1 1 , 2010 01 :05 AMPolypeptideGenbank accession no. AAD55776Genbank version no. AAD55776.2 Gl:12280940Genbank record update date: Mar 1 1 , 2010 01 :05 AMCross referencesNCBI 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 (pages69-70); 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 et al (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)NucleotideGenbank accession no M99487Genbank version no. M99487.1 GM 90663Genbank record update date: Jun 23, 2010 08:48 AMPolypeptideGenbank accession no. AAA60209Genbank version no. AAA60209.1 GM 90664Genbank record update date: Jun 23, 2010 08:48 AMCross referencesIsraeli R.S., et al Cancer Res. 53 (2), 227-230 (1993)Other informationOfficial Symbol: FOLH1Other Aliases: GIG27, FGCP, FOLH, GCP2, GCPII, NAALAD1 , NAALAdase, PSM, PSMA, mGCPOther 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; glutamatecarboxypeptidase 2; glutamate carboxypeptidase II; membrane glutamatecarboxypeptidase; prostate specific membrane antigen variant F; pteroylpoly-gamma- glutamate carboxypeptidaseANTIBODIES 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 (Larchmt). 2007Dec;26(6):363-72).Cytogen: monoclonal antibodies 7E1 1 -C5 (ATCC accession No. HB 10494) and 9H10-A4 (ATCC accession No. HB1 1430) - US 5,763,202GlycoMimetics: 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. 97131Medarex: Anti-PSMA antibodies that lack fucosyl residues - US 7,875,278Mouse 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 (ATCCHB12490), 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 6,150,508PSMA 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 - US7,850,971PSMA 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)NucleotideGenbank accession no NM_001050Genbank version no. NM_001050.2 Gl:44890054Genbank record update date: Aug 19, 2012 01 :37 PMPolypeptideGenbank accession no. NP_001041Genbank version no. NP_001041 .1 Gl:4557859Genbank record update date: Aug 19, 2012 01 :37 PMCross referencesYamada 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 informationOfficial Symbol: SSTR2Other Designations: SRIF-1 ; SS2R; somatostatin receptor type 2(38.2) SSTR5 (Somatostatin receptor 5)NucleotideGenbank accession no D16827Genbank version no. D16827.1 Gl:487683Genbank record update date: Aug 1 , 2006 12:45 PMPolypeptideGenbank accession no. BAA04107Genbank version no. BAA04107.1 Gl:487684Genbank record update date: Aug 1 , 2006 12:45 PMCross referencesYamada,Y., et al Biochem. Biophys. Res. Commun. 195 (2), 844-852 (1993)Other informationOfficial Symbol: SSTR5Other Aliases: SS-5-ROther Designations: Somatostatin receptor subtype 5; somatostatin receptor type 5(38.3) SSTR1(38.4) SSTR3(38.5) SSTR4AvB6 - Both subunits (39+40)(39) ITGAV (Integrin, alpha V;NucleotideGenbank accession no M14648 J02826 M18365Genbank version no. M14648.1 Gl:340306Genbank record update date: Jun 23, 2010 08:56 AMPolypeptideGenbank accession no. AAA36808Genbank version no. AAA36808.1 Gl:340307Genbank record update date: Jun 23, 2010 08:56 AMCross referencesSuzuki S., et al Proc. Natl. Acad. Sci. U.S.A. 83 (22), 8614-8618 (1986)Other informationOfficial Symbol: ITGAVOther Aliases: CD51 , MSK8, VNRA, VTNROther 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)NucleotideGenbank accession no NM_000888Genbank version no. NM_000888.3 Gl:9966771Genbank record update date: Jun 27, 2012 12:46 AM PolypeptideGenbank accession no. NP_000879Genbank version no. NP_000879.2 Gl:9625002Genbank record update date: Jun 27, 2012 12:46 AM Cross referencesSheppard D.J., et al Biol. Chem. 265 (20), 1 1502-1 1507 (1990)Other informationOfficial Symbol: ITGB6Other Designations: integrin beta-6ANTIBODIESBiogen: 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; US7,163,681For 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(8Supplement): 4630)(41) CEACAM5 (Carcinoembryonic antigen-related cell adhesion molecule 5)NucleotideGenbank accession no M17303Genbank version no. M17303.1 GM 78676Genbank record update date: Jun 23, 2010 08:47 AMPolypeptideGenbank accession no. AAB59513Genbank version no. AAB59513.1 GM 78677Genbank record update date: Jun 23, 2010 08:47 AMCross referencesBeauchemin N., et al Mol. Cell. Biol. 7 (9), 3221 -3230 (1987)Other informationOfficial Symbol: CEACAM5Other Aliases: CD66e, CEAOther Designations: meconium antigen 100ANTIBODIESAstraZeneca-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.:US5,047,507Bayer Corporation: US6,013,772BioAlliance: US7,982,017; US7,674,605• US 7,674,605an 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, 877,293The Dow Chemical Company: US5,472,693; US6,417,337; US6,333,405US5,472,693 - for example, ATCC No. CRL-1 1215US6,417,337 - for example, ATCC CRL-12208US6,333,405 - for example, ATCC CRL-12208Immunomedics, Inc: US7.534.431 ; US7.230.084; US7.300.644; US6.730.300;US201 10189085an antibody having CDRs of the light chain variable region comprise: CDR1 comprises KASQDVGTSVA (SEQ ID NO: 20); CDR2 comprisesWTSTRHT (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)NucleotideGenbank accession no M35073Genbank version no. M35073.1 GM 87553Genbank record update date: Mar 6, 2012 1 1 :12 AM PolypeptideGenbank accession no. AAA59589Genbank version no. AAA59589.1 Gl:553531Genbank record update date: Mar 6, 2012 1 1 :12 AM Cross referencesDean M., et al Nature 318 (6044), 385-388 (1985)Other informationOfficial Symbol: METOther Aliases: AUTS9, HGFR, RCCP2, c-MetOther 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 ANTIBODIESAbgenix / Pfizer: US20100040629for 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: US20050054019for 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 acidsequence 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): US20060035907Eli Lilly: US20100129369 Genentech: US5,686,292; US20100028337; US20100016241 ; US20070129301 ;US20070098707; US20070092520, US20060270594; US20060134104; US20060035278; US20050233960; US20050037431US 5,686,292 - for example, ATCC HB-1 1894 and ATCC HB-1 1895US 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 1Apr;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: US20040166544Pierre Fabre: US201 10239316, US201 10097262, US201001 15639Sumsung: 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):36149-57Van Andel Research Institute: Jiao Y., et al Mol Biotechnol. 2005 Sep;31 (1 ):41 -54.(43) MUC1 (Mucin 1, cell surface associated)NucleotideGenbank accession no J05581Genbank version no. J05581.1 Gl:188869Genbank record update date: Jun 23, 2010 08:48 AM PolypeptideGenbank accession no. AAA59876Genbank version no. AAA59876.1 Gl:188870Genbank record update date: Jun 23, 2010 08:48 AM Cross referencesGendler S.J., et al J. Biol. Chem. 265 (25), 15286-15293 (1990)Other informationOfficial Symbol: MUC1Other Aliases: RP1 1 -263K19.2, CD227, EMA, H23AG, KL-6, MAM6, MUC-1 , MUC-1 / SEC, MUC-1 / X, MUC1 / ZD, PEM, PEMT, PUMOther 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 mucinANTIBODIESAltaRex- 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, 147,850CRT: 5E5 - S0rensen AL., et al Glycobiology 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 ATCCaccession 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-5302Immunomedics: US 6,653,104 Ramot Tel Aviv Uni: US7,897,351 Regents Uni. CA: US 7,183,388; US20040005647; US20030077676. Roche GlycArt: US8.021.856Russian National Cancer Research Center: Imuteran- Ivanov PK., et al Biotechnol J. 2007 Jul;2(7):863-70Technische 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)NucleotideGenbank accession no . X66839Genbank version no. X66839.1 Gl:1000701Genbank record update date: Feb 2, 201 1 10:15 AMPolypeptideGenbank accession no. CAA47315Genbank version no. CAA47315.1 Gl:1000702Genbank record update date: Feb 2, 201 1 10:15 AM Cross referencesPastorek J., et al Oncogene 9 (10), 2877-2888 (1994)Other informationOfficial Symbol: CA9Other Aliases: CAIX, MNOther 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 ANTIBODIESAbgenix / Amgen: US20040018198Affibody: Anti-CAIX Affibody molecules(http: / / www.affibody.com / en / Product-Portfolio / Pipeline / )Bayer: US7,462,696Bayer / 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):e9625Institute 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 1647Institute of Virology, Slovak Academy of Sciences: US7, 816,493for 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 theInternational 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; US20050031623Novartis: US20090252738Wilex: 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. 2003Feb;5(1 ):70-5Xencor: US20090162382(45) EGFRvlll ( Epidermal growth factor receptor (EGFR), transcript variant 3,NucleotideGenbank accession no. NM_201283Genbank version no. NM_201283.1 Gl:41327733Genbank record update date: Sep 30, 2012 01 :47 PM PolypeptideGenbank accession no. NP_958440Genbank version no. NP_958440.1 Gl:41327734Genbank record update date: Sep 30, 2012 01 :47 PM Cross-referencesBatra 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 regionamino 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 IDNO: 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 IDNO: 13), 318 (SEQ ID NO: 15), 342 (SEQ ID NO: 16), and 333 (SEQ ID NO: 17); andCDR3 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 chainpolypeptides 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 chainpolypeptide, 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 sequencesUS20070274991 (EMD72000, also known as matuzumab; Harvard University)For example, SEQ ID NOs: 3 & 9 for light chain and heavy chain respectivelyUS6,129,915 (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)NucleotideGenbank accession no. M_23197Genbank version no. NM_23197.1 GM 80097Genbank record update date: Jun 23, 2010 08:47 AMPolypeptideGenbank accession no. AAA51948Genbank version no. AAA51948.1 GM 88098Genbank record update date: Jun 23, 2010 08:47 AMCross-referencesSimmons D., et al J. Immunol. 141 (8), 2797-2800 (1988)Other informationOfficial Symbol: CD33Other Aliases: SIGLEC-3, SIGLEC3, p67Other Designations: CD33 antigen (gp67); gp67; myeloid cell surface antigen CD33; sialic acid binding Ig-like lectin 3; sialic acid-binding Ig-like lectinANTIBODIESH195 (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. 97521US7,557,189 (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 IDNOs: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)NucleotideGenbank accession no. NM_001 178098Genbank version no. NM_001 178098.1 Gl:296010920Genbank record update date: Sep 10, 2012 12:43 AM PolypeptideGenbank accession no. NP_001 171569Genbank version no. NP_001 171569.1 Gl:296010921Genbank record update date: Sep 10, 2012 12:43 AM Cross-referencesTedder TF., et al J. Immunol. 143 (2): 712-7 (1989)Other informationOfficial Symbol: CD19Other Aliases: B4, CVID3Other Designations: B-lymphocyte antigen CD19; B-lymphocyte surface antigen B4; T-cell surface antigen Leu-12; differentiation antigen CD19ANTIBODIESImmunogen: 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): 135-47For example, sequences in Fig. 3 of of Knappik, A. et al. J Mol Biol 2000Feb;296(1 ):57-86AstraZeneca / Medlmmune: MEDI-551 - Herbst R., et al J Pharmacol Exp Ther. 2010 Oct;335(1 ):213-22Glenmark Pharmaceuticals: GBR-401 - Hou S., et al Mol Cancer Ther November 201 1 (Meeting Abstract Supplement) C164US7,109,304 (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 ofSEQ 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. 2010Feb;59(2):257-65.MorphoSys / Xencor: MOR-208 / XmAb-5574 - Zalevsky J., et al Blood. 2009 Apr16;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 US20120082664Zhejiang University School of Medicine: 2E8 - Zhang J., et al J Drug Target. 2010Nov;18(9):675-8 (48) IL2RA (Interleukin 2 receptor, alpha); NCBI Reference Sequence: NM_000417.2); NucleotideGenbank accession no. NM_000417Genbank version no. NM_000417.2 Gl:269973860Genbank record update date: Sep 09, 2012 04:59 PMPolypeptideGenbank accession no. NP_000408Genbank version no. NP_000408.1 Gl:4557667Genbank record update date: Sep 09, 2012 04:59 PMCross-referencesKuziel W.A., et al J. Invest. Dermatol. 94 (6 SUPPL), 27S-32S (1990)Other informationOfficial Symbol: IL2RAOther Aliases: RP1 1 -536K7.1 , CD25, IDDM10, IL2R, TCGFROther Designations: FIL-2 receptor subunit alpha; IL-2-RA; IL-2R subunit alpha; IL2-RA; TAC antigen; interleukin-2 receptor subunit alpha; p55 ANTIBODIESUS6, 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)NucleotideGenbank accession no. M76125Genbank version no. M76125.1 Gl:292869Genbank record update date: Jun 23, 2010 08:53 AMPolypeptideGenbank accession no. AAA61243Genbank version no. AAA61243.1 Gl:29870Genbank record update date: Jun 23, 2010 08:53 AMCross-referencesO'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 informationOfficial Symbol: AXLOther Aliases: JTK1 1 , UFOOther Designations: AXL oncogene; AXL transforming sequence / gene; oncogene AXL; tyrosine-protein kinase receptor UFOANTIBODIESYW327.6S2 - 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)NucleotideGenbank accession no. M83554Genbank version no. M83554.1 Gl:180095Genbank record update date: Jun 23, 2010 08:53 AMPolypeptideGenbank accession no. AAA51947Genbank version no. AAA51947.1 Gl:180096Genbank record update date: Jun 23, 2010 08:53 AM Cross-referencesDurkop H., et al Ce / / 68 (3), 421 -427 (1992)Other informationOfficial Symbol: TNFRSF8Other Aliases: CD30, D1 S166E, Ki-1Other 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)NucleotideGenbank accession no. Z29574Genbank version no. Z29574.1 Gl:471244Genbank record update date: Feb 02, 201 1 10:40 AMPolypeptideGenbank accession no. CAA82690Genbank version no. CAA82690.1 Gl:471245Genbank record update date: Feb 02, 201 1 10:40 AMCross-referencesLaabi Y., et al Nucleic Acids Res. 22 (7), 1 147-1 154 (1994)Other informationOfficial Symbol: TNFRSF17Other Aliases: BCM, BCMA, CD269Other 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-referencesFratta 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)NucleotideGenbank accession no. NM000149Genbank version no. NM000149.3 Gl:148277008Genbank record update date: Jun 26, 2012 04:49 PMPolypeptideGenbank accession no. NP_000140Genbank version no. NP_000140.1 Gl:4503809Genbank record update date: Jun 26, 2012 04:49 PMCross-referencesKukowska-Latallo.J.F., et al Genes Dev. 4 (8), 1288-1303 (1990)Other informationOfficial Symbol: FUT3Other Aliases: CD174, FT3B, FucT-lll, LE, LesOther 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)NucleotideGenbank accession no. NM175060Genbank version no. NM175060.2 Gl:371 123930Genbank record update date: Apr 01 , 2012 03:34 PMPolypeptideGenbank accession no. NP_778230Genbank version no. NP_778230.1 Gl:28269707Genbank record update date: Apr 01 , 2012 03:34 PMOther informationOfficial Symbol: CLEC14AOther Aliases: UNQ236 / PR0269, C14orf27, CEG1 , EGFR-5Other 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 70kDa protein 5 (glucose-regulated protein, 78kDa) NucleotideGenbank accession no. NM005347Genbank version no. NM005347.4 Gl:305855105Genbank record update date: Sep 30, 2012 01 :42 PMPolypeptideGenbank accession no. NP_005338Genbank version no. NP_005338.1 GM 6507237Genbank record update date: Sep 30, 2012 01 :42 PMCross-referencesTing J., et al DNA 7 (4), 275-286 (1988)Other infromationOfficial Symbol: HSPA5Other Aliases: BIP, GRP78, MIF2Other Designations: 78 kDa glucose-regulated protein; endoplasmic reticulum lumenal Ca(2+)-binding protein grp78; immunoglobulin heavy chain-binding protein(56) CD70 (CD70 molecule) L08096NucleotideGenbank accession no. L08096Genbank version no. L08096.1 Gl:307127Genbank record update date: Jun 23, 2012 08:54 AMPolypeptideGenbank accession no. AAA36175Genbank version no. AAA36175.1 Gl:307128Genbank record update date: Jun 23, 2012 08:54 AMCross-referencesGoodwin R.G., et al Cell 73 (3), 447-456 (1993) Other informationOfficial Symbol: CD70Other Aliases: CD27L, CD27LG, TNFSF7Other 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 7ANTIBODIESMDX-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)• CD32o Polypeptide■Genbank accession no. ABK42161■Genbank version no. ABK42161.1 Gl:1 17616286 ■ Genbank record update date: Jul 25, 2007 03:00 PM• LGR5 / GPR49o Nucleotide■Genbank accession no. NM_003667■Genbank version no. NM_003667.2 Gl:24475886 ■ Genbank record update date: Jul 22, 2012 03:38 PMo 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 / CD133o Nucleotide■Genbank accession no. NM_006017■Genbank version no. NM_006017.2 Gl:224994187■Genbank record update date: Sep 30, 2012 01 :47 PMo 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-5Cross-references(Smith L.M., et.al AACR 2010 Annual Meeting (abstract #2590); Gudas J.M., et.al. AACR 2010 Annual Meeting (abstract #4393)ANTIBODIESAnti- AGS-5 Antibody: M6.131 (Smith, L.M., et.al AACR 2010 Annual Meeting (abstract #2590)(59) ENPP3 (Ectonucleotide pyrophosphatase / phosphodiesterase 3)NucleotideGenbank accession no. AF005632Genbank version no. AF005632.2 Gl. "4432589Genbank record update date: Mar 10, 2010 09:41 PMPolypeptideGenbank accession no. AAC51813Genbank version no. AAC51813.1 Gl:2465540Genbank record update date: Mar 10, 2010 09:41 PMCross-referencesJin-Hua P., et al Genomics 45 (2), 412-415 (1997)Other informationOfficial Symbol: ENPP3Other Aliases: RP5-988G15.3, B10, CD203c, NPP3, PD-IBETA, PDNP3Other Designations: E-NPP 3; dJ1005H1 1.3 (phosphodiesterase l / nucleotidepyrophosphatase 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))NucleotideGenbank accession no. NM_007244Genbank version no. NM_007244.2 GM 54448885Genbank record update date: Jun 28, 2012 12:39 PMPolypeptideGenbank accession no. NP_009175Genbank version no. NP_009175.2 GM 54448886Genbank record update date: Jun 28, 2012 12:39 PMCross-referencesDickinson D.P., et al Invest. Ophthalmol. Vis. Sci. 36 (10), 2020-2031 (1995)Other informationOfficial Symbol: PRR4Other Aliases: LPRP, PROL4Other 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)NucleotideGenbank accession no. NM_004963Genbank version no. NM_004963.3 Gl:222080082Genbank record update date: Sep 02, 2012 01 :50 PMPolypeptideGenbank accession no. NP_004954Genbank version no. NP_004954.2 Gl:222080083Genbank record update date: Sep 02, 2012 01 :50 PMCross-referencesDe 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 informationOfficial Symbol: GUCY2COther Aliases: DIAR6, GUC2C, MUCIL, STAROther 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)NucleotideGenbank accession no. U41060Genbank version no. U41060.2 Gl:1271 1792Genbank record update date: Nov 30, 2009 04:35 PMPolypeptideGenbank accession no. AAA96258Genbank version no. AAA96258.2 Gl:1271 1793Genbank record update date: Nov 30, 2009 04:35 PMCross-referencesTaylor KM., et al Biochim Biophys Acta. 2003 Apr 1 ;161 1 (1 -2):16-30Other informationOfficial Symbol: SLC39A6Other Aliases: LIV-1Other 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)NucleotideGenbank accession no. AJ012159Genbank version no. AJ012159.1 Gl:3805946Genbank record update date: Feb 01 , 201 1 10:27 AMPolypeptideGenbank accession no. CAA09930Genbank version no. CAA09930.1 Gl:3805947Genbank record update date: Feb 01 , 201 1 10:27 AMCross-referencesKing 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 trophoblastglycoprotein; 5T4 oncotrophoblast glycoprotein• See WO2015 / 155345(64) CD56 - NCMA 1 (Neural cell adhesion molecule 1)NucleotideGenbank accession no. NM_000615Genbank version no. NM_000615.6 Gl:336285433Genbank record update date: Sep 23, 2012 02:32 PMPolypeptideGenbank accession no. NP_000606Genbank version no. NP_000606.3 Gl:94420689Genbank record update date: Sep 23, 2012 02:32 PMCross-referencesDickson, G., et al, Ce / / 50 (7), 1 1 19-1 130 (1987) Other informationOfficial Symbol: NCAM1Other Aliases: CD56, MSK39, NCAMOther Designations: antigen recognized by monoclonal antibody 5.1 H1 1 ; neural cell adhesion molecule, NCAMANTIBODIESImmunogen: 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-referencesHaglund C, et al Br J Cancer 60:845-851 , 1989;Baeckstrom D., et al J Biol Chem 266:21537-21547, 1991 ANTIBODIEShuC242 (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) FOLR 1 (Folate Receptor 1 )NucleotideGenbank accession no. J05013Genbank version no. J05013.1 GM 82417Genbank record update date: Jun 23, 2010 08:47 AMPolypeptideGenbank accession no. AAA35823Genbank version no. AAA35823.1 GM 82418Genbank record update date: Jun 23, 2010 08:47 AMCross-referencesElwood P.C., et al J. Biol. Chem. 264 (25), 14893-14901 (1989)Other informationOfficial Symbol: FOLR1Other Aliases: FBP, FOLROther Designations: FR-alpha; KB cells FBP; adult folate-binding protein; folate binding protein; folate receptor alpha; folate receptor, adult; ovarian tumor-associated antigen MOv18ANTIBODIESM9346A - Whiteman KR., et al Cancer Res April 15, 2012; 72(8 Supplement): 4628 (Immunogen)(67) GPNMB (Glycoprotein (transmembrane) nmb)NucleotideGenbank accession no. X76534Genbank version no. X76534.1 Gl:666042Genbank record update date: Feb 02, 201 1 10:10 AM PolypeptideGenbank accession no. CAA54044Genbank version no. CAA54044.1 Gl:666043Genbank record update date: Feb 02, 201 1 10:10 AM Cross-referencesWeterman M.A., et al Int. J. Cancer 60 (1 ), 73-81 (1995)Other informationOfficial Symbol: GPNMBOther Aliases: UNQ1725 / PR09925, HGFIN, NMBOther Designations: glycoprotein NMB; glycoprotein nmb-like protein; osteoactivin;transmembrane glycoprotein HGFIN; transmembrane glycoprotein NMBANTIBODIESCelldex 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)NucleotideGenbank accession no. AF043724Genbank version no. AF043724.1 Gl:2827453Genbank record update date: Mar 10, 2010 06:24 PMPolypeptideGenbank accession no. AAC39862Genbank version no. AAC39862.1 Gl:2827454Genbank record update date: Mar 10, 2010 06:24 PM Cross-referencesFeigelstock D., et al J. Virol. 72 (8), 6621 -6628 (1998)Other informationOfficial Symbol: HAVCR1Other 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-1Cross-referencesParry R., et al Cancer Res. 2005 Sep 15;65(18):8397-405(70) B7-H4 - VTCN1 (V-set domain containing T cell activation inhibitor 1NucleotideGenbank accession no. BX648021Genbank version no. BX648021.1 Gl:34367180Genbank record update date: Feb 02, 201 1 08:40 AMCross-referencesSica GL, et al Immunity. 2003 Jun;18(6):849-61 Other informationOfficial Symbol: VTCN1Other 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)NucleotideGenbank accession no. AF447176Genbank version no. AF447176.1 Gl:17432420Genbank record update date: Nov 28, 2008 01 :51 PMPolypeptideGenbank accession no. AAL39062Genbank version no. AAL39062.1 GM 7432421Genbank record update date: Nov 28, 2008 01 :51 PMCross-referencesPark S.K.,et al J. Biochem. 1 19 (2), 235-239 (1996)Other informationOfficial Symbol: PTK7Other Aliases: CCK-4, CCK4Other Designations: colon carcinoma kinase 4; inactive tyrosine-protein kinase 7; pseudo tyrosine kinase receptor 7; tyrosine-protein kinase-like 7(72) CD37 (CD37 molecule)NucleotideGenbank accession no. NM_001040031Genbank version no. NM_001040031.1 Gl:91807109Genbank record update date: Jul 29, 2012 02:08 PMPolypeptideGenbank accession no. NP_001035120Genbank version no. NP_001035120.1 Gl:918071 10Genbank record update date: Jul 29, 2012 02:08 PMCross-referencesSchwartz-Albiez R., et al J. Immunol. 140 (3), 905-914 (1988)Other informationOfficial Symbol: CD37Other Aliases: GP52-40, TSPAN26Other Designations: CD37 antigen; cell differentiation antigen 37; leukocyte antigen CD37; leukocyte surface antigen CD37; tetraspanin-26; tspan-26ANTIBODIESBoehringer 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: 253Immunogen: K7153A (Deckert J., et al Cancer Res April 15, 2012; 72(8Supplement): 4625) (73) CD138 - SDC1 (syndecan 1)NucleotideGenbank accession no. AJ551 176Genbank version no. AJ551 176.1 Gl:29243141Genbank record update date: Feb 01 , 201 1 12:09 PMPolypeptideGenbank accession no. CAD80245Genbank version no. CAD80245.1 Gl:29243142Genbank record update date: Feb 01 , 201 1 12:09 PMCross-referencesO'Connell FP., et al Am J Clin Pathol. 2004 Feb;121 (2):254-63Other informationOfficial Symbol: SDC1Other Aliases: CD138, SDC, SYND1 , syndecanOther Designations: CD138 antigen; heparan sulfate proteoglycan fibroblast growth factor receptor; syndecan proteoglycan 1 ; syndecan-1 ANTIBODIESBiotest: 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)NucleotideGenbank accession no. NM_004355Genbank version no. NM_004355.1 Gl:343403784Genbank record update date: Sep 23, 2012 02:30 PMPolypeptideGenbank accession no. NP_004346Genbank version no. NP_004346.1 Gl:10835071Genbank record update date: Sep 23, 2012 02:30 PMCross-referencesKudo,J., et al Nucleic Acids Res. 13 (24), 8827-8841 (1985)Other informationOfficial Symbol: CD74Other Aliases: DHLAG, HLADG, II, la-GAMMAOther 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; p33ANTIBODIESImmunomedics: 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 24Genmab: HuMax-CD74 (see website)(75) Claudins - CLs (Claudins)Cross-referencesOffner 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)NucleotideGenbank accession no. NM_005228Genbank version no. NM_005228.3 Gl:41927737Genbank record update date: Sep 30, 2012 01 :47 PMPolypeptideGenbank accession no. NP_005219Genbank version no. NP_005219.2 Gl:29725609Genbank record update date: Sep 30, 2012 01 :47 PMCross-referencesDhomen NS., et al Crit Rev Oncog. 2012;17(1 ):31-50Other informationOfficial Symbol: EGFROther Aliases: ERBB, ERBB1 , HER1 , PIG61 , mENAOther 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-1ANTIBODIESBMS: Cetuximab (Erbitux) - Broadbridge VT., et al Expert Rev Anticancer Then 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 Then 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))NucleotideGenbank accession no. M34309Genbank version no. M34309.1 Gl:183990Genbank record update date: Jun 23, 2010 08:47 PMPolypeptideGenbank accession no. AAA35979Genbank version no. AAA35979.1 Gl:306841Genbank record update date: Jun 23, 2010 08:47 PMCross-referencesPlowman, G.D., et al., Proc. Natl. Acad. Sci. U.S.A. 87 (13), 4905-4909 (1990)Other informationOfficial Symbol: ERBB3Other Aliases: ErbB-3, HER3, LCCS2, MDA-BF-1 , c-erbB-3, c-erbB3, erbB3-S, p180- ErbB3, p45-sErbB3, p85-sErbB3Other Designations: proto-oncogene-like protein c-ErbB-3; receptor tyrosine-protein kinase erbB-3; tyrosine kinase-type cell surface receptor HER3ANTIBODIESMerimack 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)) NucleotideGenbank accession no. X70040Genbank version no. X70040.1 Gl:36109Genbank record update date: Feb 02, 201 1 10:17 PMPolypeptideGenbank accession no. CCA49634Genbank version no. CCA49634.1 Gl:361 10Genbank record update date: Feb 02, 201 1 10:17 PMCross-referencesRonsin C, et al Oncogene 8 {5), 1 195-1202 (1993)Other informationOfficial Symbol: MST1 ROther Aliases: CD136, CDw136, PTK8, RONOther 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)NucleotideGenbank accession no. BC037166Genbank version no. BC037166.2 Gl:33879863Genbank record update date: Mar 06, 2012 01 :59 PM PolypeptideGenbank accession no. AAH37166Genbank version no. AAH37166.1 Gl:22713539Genbank record update date: Mar 06, 2012 01 :59 PM Cross-referencesStrausberg R.L., et al Proc. Natl. Acad. Sci. U.S.A. 99 (26), 16899-16903 (2002)Other informationOfficial Symbol: EPHA2Other Aliases: ARCC2, CTPA, CTPP1 , ECKOther Designations: ephrin type-A receptor 2; epithelial cell receptor protein tyrosine kinase; soluble EPHA2 variant 1 ; tyrosine-protein kinase receptor ECKANTIBODIESMedimmune: 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)NucleotideGenbank accession no. M27394Genbank version no. M27394.1 GM 79307Genbank record update date: Nov 30, 2009 1 1 :16 AMPolypeptideGenbank accession no. AAA35581Genbank version no. AAA35581.1 GM 79308Genbank record update date: Nov 30, 2009 1 1 :16 AMCross-referencesTedder T.F., et al Proc. Natl. Acad. Sci. U.S.A. 85 (1 ), 208-212 (1988)Other informationOfficial Symbol: MS4A1Other Aliases: B1 , Bp35, CD20, CVID5, LEU-16, MS4A2, S7Other Designations: B-lymphocyte antigen CD20; B-lymphocyte cell-surface antigen B1 ; CD20 antigen; CD20 receptor; leukocyte surface antigen Leu-16ANTIBODIESGenentech / 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 1Oct;45(10):1248-55.For example, see US20090169550A1 SEQ ID NOs: 2, 4 and 5. Immunomedics: Veltuzumab - Goldenberg DM., et al Leuk Lymphoma. 2010May;51 (5):747-55.For example, see US7919273B2 SEQ ID NOs: 1 , 2, 3, 4, 5 and 6.(81) Tenascin C - TNC (Tenascin C)NucleotideGenbank accession no. NM 002160Genbank version no. NM_002160.3 Gl:340745336Genbank record update date: Sep 23, 2012 02:33 PMPolypeptideGenbank accession no. NP_002151Genbank version no. NP_002151.2 GM 53946395Genbank record update date: Sep 23, 2012 02:33 PMCross-referencesNies 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 informationOfficial Symbol: TNCOther Aliases: 150-225, GMEM, GP, HXB, Jl, TN, TN-COther Designations: GP 150-225; cytotactin; glioma-associated-extracellular matrix antigen; hexabrachion (tenascin); myotendinous antigen; neuronectin; tenascin; tenascin-C isoform 14 / AD1 / 16 ANTIBODIESPhilogen : 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)NucleotideGenbank accession no. U09278Genbank version no. U09278.1 Gl:1888315Genbank record update date: Jun 23, 2010 09:22 AMPolypeptideGenbank accession no. AAB49652Genbank version no. AAB49652.1 Gl:1888316Genbank record update date: Jun 23, 2010 09:22 AMCross-referencesScanlan,M.J.,et al Proc. Natl. Acad. Sci. U.S.A. 91 (12), 5657-5661 (1994)Other informationOfficial Symbol: FAPOther Aliases: DPPIV, FAPAOther Designations: 170 kDa melanoma membrane-bound gelatinase; integral membrane serine protease; seprase(83) DKK-1 (Dickkopf 1 homolog (Xenopus laevis)NucleotideGenbank accession no. NM_012242Genbank version no. NM_012242.2 Gl:61676924Genbank record update date: Sep 30, 2012 01 :48 PM PolypeptideGenbank accession no. NP_036374Genbank version no. NP_036374.1 Gl:71 10719Genbank record update date: Sep 30, 2012 01 :48 PM Cross-referencesFedi P. et al J. Biol. C em. 274 (27), 19465-19472 (1999)Other informationOfficial Symbol: DKK1Other Aliases: UNQ492 / PR01008, DKK-1 , SKOther Designations: dickkopf related protein-1 ; dickkopf-1 like; dickkopf-like protein 1 ; dickkopf-related protein 1 ; hDkk-1ANTIBODIESNovartis: 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)NucleotideGenbank accession no. NM_001803Genbank version no. NM 001803.2 Gl:68342029Genbank record update date: Sep 30, 2012 01 :48 PMPolypeptideGenbank accession no. NP_001794Genbank version no. NP_001794.2 Gl:68342030Genbank record update date: Sep 30, 2012 01 :48 PMCross-referencesXia M.Q., et al Eur. J. Immunol. 21 (7), 1677-1684 (1991 )Other informationOfficial Symbol: CD52Other Aliases: CDW52Other 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 5ANTIBODIESAlemtuzumab (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)NucleotideGenbank accession no. NM_021 181Genbank version no. NM_021 181.3 GM 993571Genbank record update date: Jun 29, 2012 1 1 :24 AMPolypeptideGenbank accession no. NP_067004Genbank version no. NP_067004.3 GM 9923572Genbank record update date: Jun 29, 2012 1 1 :24 AMCross-referencesBoles K.S., et al Immunogenetics 52 (3-4), 302-307 (2001 )Other informationOfficial Symbol: SLAMF7Other Aliases: UNQ576 / PR01 138, 19A, CD319, CRACC, CS1Other 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 19AANTIBODIESBMS: elotuzumab / HuLuc63 (Benson DM., et al 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)NucleotideGenbank accession no. AF035753Genbank version no. AF035753.1 Gl:3452260Genbank record update date: Mar 10, 2010 06:36 PMPolypeptideGenbank accession no. AAC32802Genbank version no. AAC32802.1 Gl:3452261Genbank record update date: Mar 10, 2010 06:36 PMCross-referencesRius C, et al Blood 92 (12), 4677-4690 (1998)Official Symbol: ENGOther informationOther Aliases: RP1 1 -228B15.2, CD105, END, HHT1 , ORW, ORW1Other Designations: CD105 antigen(87) Annexin A 1 - ANXA 1 (Annexin A1)NucleotideGenbank accession no. X05908Genbank version no. X05908.1 Gl:34387Genbank record update date: Feb 02, 201 1 10:02 AMPolypeptideGenbank accession no. CCA29338Genbank version no. CCA29338.1 Gl:34388Genbank record update date: Feb 02, 201 1 10:02 AMCross-referencesWallner B.P.,et al Nature 320 (6057), 77-81 (1986) Other informationOfficial Symbol: ANXA1Other Aliases: RP1 1 -71A24.1 , ANX1 , LPC1Other 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)NucleotideGenbank accession no. M60335Genbank version no. M60335.1 Gl:340193Genbank record update date: Jun 23, 2010 08:56 AMPolypeptideGenbank accession no. AAA61269Genbank version no. AAA61269.1 Gl:340194Genbank record update date: Jun 23, 2010 08:56 AMCross-referencesHession C, et al J. Biol. Chem. 266 (1 1 ), 6682-6685 (1991 ) Other informationOfficial Symbol VCAM1Other Aliases: CD106, INCAM-100Other Designations: CD106 antigen; vascular cell adhesion protein 1 Antibody SequencesAnti-lntegrin ανββRHAB6.2QVQLVQSGSELKKPGASVKISCKASGFAFTDSYMHWVRQAPGQGLEWMGWIDPENGDT EYAPKFQGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCTRGTPTAVPNLRGDLQVLAQKVA GPYPFDYWGQGTLVTVSSRHCB6.2QVQLVQSGAEVKKPGASVKVSCKASGYTFIDSYMHWVRQAPGQRLEWMGWIDPENGDTEYAPKFQGRVTITTDTSASTAYMELSSLRSEDTAVYYCARGTPTAVPNLRGDLQVLAQKVAGPYPFDYWGQGTLVTVSSRHFQVQLVQSGAEVKKPGASVKVSCKASGFNFIDSYMHWVRQAPGQRLEWMGWIDPENGD TEYAPKFQGRVTFTTDTSASTAYMELSSLRSEDTAVYYCNEGTPTGPYYFDYWGQGTLV TVSSRHFB6QVQLVQSGAEVKKPGASVKVSCKASGFNFIDSYMHWVRQAPGQRLEWMGWIDPENGDTEYAPKFQGRVTFTTDTSASTAYMELSSLRSEDTAVYYCNEGTPTAVPNLRGDLQVLAQKVAGPYYFDYWGQGTLVTVSSRHAYI OObPQVQLVQSGSELKKPGASVKISCKASGFAFTDSYMHWVRQAPGQGLEWMGWIDPENGDT EYAPKFQGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCTRGTPTGPYPFDYWGQGTLVTV SSRKFENVLTQSPGTLSLSPGERATLSCSASSSVSYMHWFQQKPGQAPRLLIYSTSNLASGIPDR FSGSGSGTDFTLTISRLEPEDFAVYYCQQRSSYPLTFGGGTKVEIK RKFL36L50ENVLTQSPGTLSLSPGERATLSCSASSSVSYMHWLQQKPGQAPRLLIYLTSNLASGIPDR FSGSGSGTDFTLTISRLEPEDFAVYYCQQRSSYPLTFGGGTKVEIKRKC EIVLTQSPGTLSLSPGERATLSCSASSSVSYMHWFQQKPGQAPRLLIYSTSNLASGIPDRF SGSGSGTDFTLTISRLEPEDFAVYYCQQRSSYPLTFGGGTKVEIKAnti-CD33CD33 Hum195 VHQVQLVQSGAEVKKPGSSVKVSCKASGYTFTDYNMHWVRQAPGQGLEWIGYIYPYNGGT GYNQKFKSKATITADESTNTAYMELSSLRSEDTAVYYCARGRPAMDYWGQGTLVTVSSCD33 Hum195 VKDIQMTQSPSSLSASVGDRVTITCRASESVDNYGISFMNWFQQKPGKAPKLLIYAASNQGS GVPSRFSGSGSGTDFTLTISSLQPDDFATYYCQQSKEVPWTFGQGTKVEIKAnti-CD19CD19 B4 resurfaced VHQVQLVQPGAEVVKPGASVKLSCKTSGYTFTSNWMHWVKQRPGQGLEWIGEIDPSDSYT NYNQNFKGKAKLTVDKSTSTAYMEVSSLRSDDTAVYYCARGSNPYYYAMDYWGQGTSV TVSSCD19 B4 resurfaced VKEIVLTQSPAIMSASPGERVTMTCSASSGVNYMHWYQQKPGTSPRRWIYDTSKLASGVPA RFSGSGSGTSYSLTISSMEPEDAATYYCHQRGSYTFGGGTKLEIKAnti-Her2Herceptin VH chainEVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTR YADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQGTLVT VSSHerceptin VL chainDIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPS RFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIKAnti-CD25Simulect VK (also known as Basiliximab)QIVSTQSPAIMSASPGEKVTMTCSASSSRSYMQWYQQKPGTSPKRWIYDTSKLASGVPA RFSGSGSGTSYSLTISSMEAEDAATYYCHQRSSYTFGGGTKLEIKSimulect VHQLQQSGTVLARPGASVKMSCKASGYSFTRYWMHWIKQRPGQGLEWIGAIYPGNSDTSY NQKFEGKAKLTAVTSASTAYMELSSLTHEDSAVYYCSRDYGYYFDFWGQGTTLTVSSAnti-PSMADeimmunised VH ΊEVQLVQSGPEVKKPGATVKISCKTSGYTFTEYTIHWVKQAPGKGLEWIGNINPNNGGTTY NQKFEDKATLTVDKSTDTAYMELSSLRSEDTAVYYCAAGWNFDYWGQGTLLTVSSDeimmunised VK ΊDIQMTQSPSSLSTSVGDRVTLTCKASQDVGTAVDWYQQKPGPSPKLLIYWASTRHTGIPS RFSGSGSGTDFTLTISSLQPEDFADYYCQQYNSYPLTFGPGTKVDIKDeimmunised VH1 '5EVKLVESGGGLVQPGGSMKLSCVASGFTFSNYWMNWVRQAPGKGLEWVAEIRSQSNN FATHYAESVKGRVTISRDDSKSIVYLQMNNLRAEDTGVYYCTRRWNNFWGQGTTVTVSSDeimmunised VH2 '5EVKLVESGGGLVQPGGSLKLSCVASGFTFSNYWMNWVRQAPGKGLEWVAEIRSQSNNF ATHYAESVKGRVTISRDDSKSIVYLQMNNLRAEDTAVYYCTRRWNNFWGQGTTVTVSSDeimmunised VH3 '5EVQLVESGGGLVQPGGSLKLSCVASGFTFSNYWMNWVRQAPGKGLEWVAEIRSQSNNF ATHYAESVKGRVTISRDDSKSIVYLQMNNLRAEDTAVYYCTRRWNNFWGQGTTVTVSS Deimmunised VH4 '5EVQLVESGGGLVQPGGSLKLSCVASGFTFSNYWMNWVRQAPGKGLEWVAEIRSQSNNF ATHYAESVKGRFTISRDDSKSIVYLQMNNLRAEDTAVYYCTRRWNNFWGQGTTVTVSSDeimmunised VK1 '5NIVMTQFPSSMSASVGDRVTITCKASENVGTYVSWYQQKPDQSPKMLIYGASNRFTGVP DRFTGSGSATDFTLTISSLQTEDLADYYCGQSYTFPYTFGQGTKLEMKDeimmunised VK2 '5NIVMTQFPSSMSASVGDRVTITCKASENVGTYVSWYQQKPDQSPKMLIYGASNRFTGVP DRFSGSGSGTDFTLTISSLQAEDLADYYCGQSYTFPYTFGQGTKLEIKDeimmunised VK3 '5NIQMTQFPSAMSASVGDRVTITCKASENVGTYVSWYQQKPDQSPKMLIYGASNRFTGVP DRFSGSGSGTDFTLTISSLQAEDLADYYCGQSYTFPYTFGQGTKLEIK Deimmunised VK4 '5NIQMTQFPSAMSASVGDRVTITCKASENVGTYVSWYQQKPDQSPKMLIYGASNRFTGVP DRFSGSGSGTDFTLTISSLQAEDEADYYCGQSYTFPYTFGQGTKLEIKDeimmunised VK PI '5NIVMTQFPKSMSASAGERMTLTCKASENVGTYVSWYQQKPTQSPKMLIYGASNRFTGVP DRFSGSGSGTDFILTISSVQAEDLVDYYCGQSYTFPYTFGGGTKLEMKDeimmunised VH PI '5EVKLEESGGGLVQPGGSMKISCVASGFTFSNYWMNWVRQSPEKGLEWVAEIRSQSNNF ATHYAESVKGRVIISRDDSKSSVYLQMNSLRAEDTAVYYCTRRWNNFWGQGTTVTVSSHumanised RHA '5EVQLVESGGGLVQPGGSLKLSCAASGFTFSNYWMNWVRQASGKGLEWVGEIRSQSNNF ATHYAESVKGRFTISRDDSKNTAYLQMNSLKTEDTAVYYCTRRWNNFWGQGTTVTVSSHumanised RHB '5EVKLVESGGGLVQPGGSLKLSCAASGFTFSNYWMNWVRQASGKGLEWVAEIRSQSNNF ATHYAESVKGRVIISRDDSKNTVYLQMNSLRTEDTAVYYCTRRWNNFWGQGTTVTVSS Humanised RHC '5EVQLVESGGGLVQPGGSLKLSCAASGFTFSNYWMNWVRQASGKGLEWVAEIRSQSNNF ATHYAESVKGRVIISRDDSKNTVYLQMNSLRTEDTAVYYCTRRWNNFWGQGTTVTVSSHumanised RHP '5EVKLVESGGGLVQPGGSLKLSCAASGFTFSNYWMNWVRQASGKGLEWVGEIRSQSNNF ATHYAESVKGRVIISRDDSKNTVYLQMNSLRTEDTAVYYCTRRWNNFWGQGTTVTVSSHumanised RHE '5EVKLVESGGGLVQPGGSLKLSCAASGFTFSNYWMNWVRQASGKGLEWVAEIRSQSNNF ATHYAESVKGRFTISRDDSKNTVYLQMNSLRTEDTAVYYCTRRWNNFWGQGTTVTVSSHumanised RHF '5EVKLVESGGGLVQPGGSLKLSCAASGFTFSNYWMNWVRQASGKGLEWVAEIRSQSNNF ATHYAESVKGRVIISRDDSKNTAYLQMNSLRTEDTAVYYCTRRWNNFWGQGTTVTVSS Humanised RHG '5EVKLVESGGGLVQPGGSLKLSCAASGFTFSNYWMNWVRQASGKGLEWVAEIRSQSNNF ATHYAESVKGRVIISRDDSKNTAYLQMNSLRTEDTAVYYCTRRWNNFWGQGTTVTVSSHumanised RKA '5DIQMTQSPSSVSASVGDRVTITCKASENVGTYVSWYQQKPGTAPKLLIYGASNRFTGVPS RFSGSGSATDFTLTINNLQPEDFATYYCGQSYTFPYTFGQGTKVEIKHumanised RKB '5DIQMTQSPSSVSASVGDRVTITCKASENVGTYVSWYQQKPGTAPKLLIYGASNRFTGVPS RFSGSGSATDFTLTINNLQPEDFATYYCGQSYTFPYTFGQGTKVEIKHumanised RKC '5DIQMTQSPSSVSASVGDRVTITCKASENVGTYVSWYQQKPGTAPKMLIYGASNRFTGVPS RFSGSGSATDFTLTINNLQPEDFATYYCGQSYTFPYTFGQGTKVEIKHumanised RKD '5DIQMTQSPSSVSASVGDRVTITCKASENVGTYVSWYQQKPGTAPKMLIYGASNRFTGVPS RFSGSGSATDFTLTINNLQPEDFATYYCGQSYTFPYTFGQGTKVEIK Humanised RKE '5NIVMTQSPSSVSASVGDRVTITCKASENVGTYVSWYQQKPGTAPKLLIYGASNRFTGVPD RFTGSGSATDFILTINNLQPEDFATYYCGQSYTFPYTFGQGTKVEIKHumanised RKF '5NIVMTQSPSSVSASVGDRVTITCKASENVGTYVSWYQQKPGTAPKMLIYGASNRFTGVPS RFSGSGSATDFILTINNLQPEDFATYYCGQSYTFPYTFGQGTKVEIKHumanised RKG '5NIVMTQSPSSVSASVGDRVTITCKASENVGTYVSWYQQKPGTAPKMLIYGASNRFTGVPD RFTGSGSATDFTLTINNLQPEDFATYYCGQSYTFPYTFGQGTKVEIKThe 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; WO01 / 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 unitThe 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 TreatmentThe 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 lupuserythematosus, 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, lymphomatoidgranulomatosis, 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, relapsingpolychondritis, 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 perdose. 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 loadingThe 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 (A or B) . 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 (A or B) 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 antibodiesand 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 routesThe 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); andd) WO 2005 / 085251 (pages 30 to 39). Synthesis routeThe Drug Linker compounds of the present invention (A and B) may be synthesised according to the Examples.Synthesis of Drug ConjugatesConjugates can be prepared as previously described. Antibodies can be conjugated to the Drug Linker compounds (A or B) 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 μηη 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 PreferencesThe 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:In other embodiments, the C1 1 substituent may be in the following stereochemical arrangement relative to neighbouring groups:5In one embodiment of the present invention, the compound of formula III is A.In one embodiment of the present invention, the compound of formula III is B.In one embodiment of the present invention, the Drug Linker unit of formula III is DL-A. In one embodiment of the present invention, the Drug Linker unit of formula III is DL-B.ExamplesReaction 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 Acq uity UPLC BEH Shield RP18 1.7μηι 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.Example 1(a) (S)-2-(methoxycarbonyl)-4-methylenepyrrolidinium chloride (3)Commercially available proline derivative (1 ) was obtained from Omegachem(i) (S)-1 -tert-butyl 2-methyl 4-methylenepyrrolidine-1,2-dicarboxylate (2)Potassium carbonate (19.92 g, 14 mmol, 3.0 eq.) was added to a stirred solution of the carboxylic acid 1 (10.92 g, 48 mmol, 1 .0 eq.) in DMF (270 mL). The resulting white suspension was stirred at room temperature for 30 mins, at which point iodomethane(21.48 g, 9.5 mL, 151 mmol, 3.15 eq.) was added. The reaction mixture was allowed to stir at room temperature for 3 days. The DMF was removed by rotary evaporation under reduced pressure to afford a yellow residue which was partitioned between ethylacetate and water. The organic layer was separated and the aqueous phase was extracted with ethylacetate. The combined organic layers were washed with water brined and dried over magnesium sulphate. The ethylacetate was removed by rotary evaporation under reduced pressure to give the crude product as a yellow oil. The crude product was purified by flash chromatography [85% n-hexane / 15% ethylacetate] to afford the product as a colourless oil (10.74 g, 93%).(ΊΊ) (S)-2-(methoxycarbonyl)-4-methylenepyrrolidinium chloride (3)A solution of 4 M hydrochloric acid in dioxane (63 mL, 254.4 mmol, 4.5 eq.) was added to the Boc protected C-ring fragment 2 (13.67 g, 56.6 mmol, 1 .0 eq.) at room temperature. Effervescence was observed indicating liberation of CO2 and removal of the Boc group. The product precipitated as a white solid and additional dioxane was added to facilitate stirring the reaction mixture was allowed to stir for an hour and then diluted with diethyl ether. The precipitated product was collected by vacuum filtration and washed withadditional diethyl ether. Air drying afforded the desired product as a white powder (9.42 g, 94%).(b) terf-Butyl (5-(3-(5-amino-4-((S)-2-(((terf-butyldimethylsilyl)oxy)methyl)-4- methylenepyrrolidine-1 -carbonyl)-2-methoxyphenoxy)propoxy)-2-((S)-2-(((te f- butyldimethylsilyl)oxy)methyl)-4-methylenepyrrolidine-1 -carbonyl)-4- methoxyphenvDcarbamate (12)(i) 1 ',3'-Bis[2-methoxy-4-(methoxycarbonyl)phenoxy]propane (5)Diisopropyl azodicarboxylate (71.3 ml_, 73.2 g, 362 mmol) was added drop-wise over a period of 60 min to an overhead stirred solution of methyl vanillate 4 (60 g, 329 mmol) and Ph3P (129.4 g, 494 mmol) in anhydrous THF (800 mL) at 0-5 °C (ice / acetone) under a nitrogen atmosphere. The reaction mixture was allowed to stir at 0-5 °C for an additional 1 h after which time a solution of 1 ,3-propanediol (1 1 .4 mL, 12.0 g, 158 mmol) in THF (12 mL) was added drop-wise over a period of 20 min. The reaction mixture was allowed to warm to room temperature and stirred for 5 days. The resulting white precipitate 3 was collected by vacuum filtration, washed with THF and dried in a vacuum desiccator to constant weight. Yield = 54.68 g (84% based on 1 ,3-propanediol). Analytical Data: Purity satisfactory by LC / MS 3.20 min (ES+) m / z (relative intensity) 427 {[M + Na]+, 10);1H NMR (400 MHz, CDCIs) δ 57.64 (dd, 2H, J = 1 .8, 8.3 Hz), 7.54 (d, 2H, J = 1 .8 Hz), 6.93 (d, 2H, J = 8.5 Hz), 4.30 (t, 4H, J = 6.1 Hz), 3.90 (s, 6H), 3.89 (s, 6H), 2.40 (p, 2H, J = 6.0 Hz).(ii) 1 ',3'-Bis[2-methoxy-4-(methoxycarbonyl)-5-nitrophenoxy]propane (6)Solid Cu(N03)2.3H20 (81 .54 g, 337.5 mmol) was added slowly to an overhead stirred slurry of the b / s-ester 5 (54.68 g, 135 mmol) in acetic anhydride (650 mL) at 0-5 °C (ice / acetone). The reaction mixture was allowed to stir for 1 h at 0-5 °C and then allowed to warm to room temperature. A mild exotherm (c. 40-50 °C), accompanied by thickening of the mixture and evolution of NO2 was observed at this stage. Additional acetic anhydride (300 mL) was added and the reaction mixture was allowed to stir for 16 h at room temperature. The reaction mixture was poured onto ice (~ 1.5 L), stirred and allowed to return to room temperature. The resulting yellow precipitate was collected by vacuum filtration and dried in a desiccator to afford the desired b / 's-nitro compound 6 as a yellow solid. Yield = 66.7 g (100%). Analytical Data: Purity satisfactory by LC / MS 3.25 min (ES+) m / z (relative intensity) 517 {[M + Na]+, 40);1H NMR (400 MHz, CDCI3) δ 7.49 (s, 2H), 7.06 (s, 2H), 4.32 (t, 4H, J = 6.0 Hz), 3.95 (s, 6H), 3.90 (s, 6H), 2.45-2.40 (m, 2H). See ref Thurston 1996. (Hi) 1 ',3'-Bis(4-carboxy-2-methoxy-5-nitrophenoxy) propane (7)A slurry of the methyl ester 6 (66.7 g, 135 mmol) in THF (700 mL) was treated with 1 N NaOH (700 mL) and the reaction mixture was allowed to stir vigorously at roomtemperature. After 4 days stirring, the slurry became a dark coloured solution which was subjected to rotary evaporation under reduced pressure to remove THF. The resulting aqueous residue was acidified to pH 1 with concentrated HCI and the colourless precipitate 7 was collected and dried thoroughly in a vacuum oven (50 °C). Yield = 54.5 g (87%). Analytical Data: Purity satisfactory by LC / MS 2.65 min (ES+) m / z (relative intensity) 489 ([Af + Na]+, 30);1H NMR (400 MHz, DMSO-d6) δ 7.62 (s, 2H), 7.30 (s, 2H), 4.29 (t, 4H, J = 6.0 Hz), 3.85 (s, 6H), 2.30-2.26 (m, 2H).(iv) Dimethyl 1, 1 '-(4,4'-(propane-1,3-diylbis(oxy))bis(5-methoxy-2-nitrobenzoyl))(2S,2'S)- bis(4-methylenepyrrolidine-2-carboxylate) (8)A catalytic amount of anhydrous DMF (2.4 mL) was added to a stirred suspension of oxalyl chloride (14.7 g, 9.8 mL, 1 15.8 mmol, 3 eq.) and dimer core 7 (18 g, 38.6 mmol, 1 eq.) in anhydrous DCM (500 mL) at room temperature. Vigorous effervescence was observed after the addition of DMF and the reaction mixture was allowed to stir for 18 h in a round bottom flask fitted with a calcium chloride drying tube. The resulting clear solution was evaporated under reduced pressure and the solid triturated with ether. The solid product was collected by vacuum filtration, washed with additional ether and dried in vacuo at 40 °C for 1 .5 h. This solid was then added portion wise to a suspension of the C-ring 3 (15.1 g, 84.9 mmol, 2.2 eq.) and TEA (19.5 g, 27 ml, 1 19.6 mmol, 5 eq.) in dry DCM (375 mL),maintaining the temperature between -40 and -50 °C with the aid of a dry ice / acetonitrile bath. The reaction mixture was allowed to stir at -40 °C for 1 h and then allowed to warm to room temperature at which point LCMS indicated the complete consumption of the starting material. The reaction mixture was diluted with additional DCM and washed sequentially with aqueous hydrochloric acid (1 M, 2 x 200 mL), saturated aqueous sodium bicarbonate (2 x 250 mL), water (250 mL), brine (250 mL), dried (MgS04). DCM was removed by rotary evaporation under reduced pressure to afford the product as a yellow foam (25.72 g, 94 %). Analytical Data: RT 1.59 min; MS (ES+) m / z (relative intensity) 713 {[M + H]+, 100) (v) ((Propane-1,3-diylbis(oxy))bis(5-methoxy-2-nitro-4, 1 -phenylene))bis(((S)-2- (hydroxymethyl)-4-methylenepyrrolidin- 1 -yl)methanone) (9)Solid lithium borohydride (3.18 g, 146 mmol, 3 eq.) was added in one portion to a solution of the ester 8 (34.72 g, 48.7 mmol, 1 eq.) in dry THF (350 mL) under a nitrogenatmosphere at 0 °C (ice bath). The reaction mixture was allowed to stir at 0 °C for 30 mins and then allowed to warm to room temperature at which point precipitation of an orange gum was observed. The reaction mixture was allowed to stir at room temperature for a futher 2 hours and then cooled in an ice bath and treated with water to give a yellow suspension. Hydrochloric acid (1 M) was carefully added until effervescence ceased. The reaction mixture was extracted with ethylacetate (x 4) and the combined organic layers were washed with water (x 1 ), brine (x 1 ) and dried (MgS04). Ethylacetate was removed by rotary evaporation under reduced pressure to give a yellow foam. Purification by flash column chromatography [gradient elution DCM / MeOH 0% to 5% in 1 % increments] gave the product as a pale yellow foam (23.1 g, 72%). Analytical Data: RT 1 .23 min; MS (ES+) m / z (relative intensity) 657 {[M + H]+, 100)(vi) (( Propane- 1, 3-diylbis(oxy))bis(5-methoxy-2-nitro-4, 1 -phenylene))bis( ((S)-2-((( tert- butyldimethylsilyl)oxy)methyl)-4-methylenepyrrolidin- 1 -yl)methanone) (10)A solution of the b / 's-alcohol 9 (10 g, 15.2 mmol, 1 eq.), i-butyldimethylsilylchloride (5.97 g, 39.6 mmol, 2.6 eq.) and imidazole (5.38 g, 79 mmol, 5.2 eq.) in dry DMF (80 ml) was stirred at room temperature for 3h. The reaction mixture was poured into water (500 mL) to give a yellow precipitate. The mixture was extracted with DCM (4 x 100 mL) and the combined extracts were washed with water and brine, dried (MgS04) and evaporated under reduced pressure to give a viscous yellow oil. Purification by columnchromatography [biotage isolera, gradient elution hexane 60% / EtOAc 40% to EtOAc 100%, 8 column volumes 100 g snap ultra® cartridge] gave the product as a yellow foam (1 1 .8 g,88%). Analytical Data: RT 2.20 min; MS (ES+) m / z (relative intensity) 885 {[M + H]+, 100), 907 {[M + Na]+, 50)( vii) ( ( Propane-1, 3-diylbis(oxy))bis(2-amino-5-methoxy-4, 1 -phenylene))bis( ((S)-2-((( tert- butyldimethylsilyl)oxy)methyl)-4-methylenepyrrolidin- 1 -yl)methanone) (11)Zinc powder (31.9 g, 488 mmol, 40 eq.) was activated by stirring / sonication with 1 M HCI for 10 min. The Zinc was filtered washing with 1 M HCI, water (x 3) and MeOH (x 2). The activated Zinc was added to a solution of the nitro-TBS compound 10 (10.8 g, 12.2 mmol, 1 eq.) in MeOH (88 mL) and 5% formic acid / MeOH solution (440 ml_). The temperature rose to 37°C and the reaction mixture changed from a yellow to a colourless solution. Once the exotherm had subsided (20 min.) the reaction was shown to be complete by LCMS. The reaction mixture was filtered through celite washing with EtOAc. The EtOAc portion was washed with saturated bicarbonate solution (x 4) [caution effervescence!], water (x 1 ), brine (x 1 ), dried (MgS04) and evaporated under reduced pressure to give a yellow solid. Purification by flash column chromatography [n-hexane / EtOAc 50 / 50 v / v to EtOAc 100% in 10% increments] gave the product as a yellow foam (9.5 g, 86%). Analytical Data: RT 2.12 min; MS (ES+) m / z (relative intensity) 825 {[M + H]+, 60), 847 {[M + Na]+, 30)(viii) tert-Butyl (5-(3-(5-amino-4-((S)-2-(((tert-butyldimethylsilyl)o^methylenepyrrolidine- 1 -carbonyl)-2-methoxyphenoxy)propoxy)-2-( (S)-2-((( tert- butyldimethylsilyl)oxy)methyl)-4-methylenepyrrolidine-1-carbonyl)-4- methoxyphenyl)carbamate (12)A solution of the b / 's-aniline 11 (3.27 g, 3.96 mmol) and di-i-butyldicarbonate (0.85 g, 3.96 mmol) in dry THF (125 mL) were heated under reflux for 24h. The reaction mixture was cooled and the solvent evaporated under reduced pressure. The residue was purified by flash column chromatography [n-hexane / EtOAc 50 / 50 v / v to EtOAc 100% in 10% increments then EtOAc / MeOH 98 / 2 v / v] to give the desired product as a yellow foam (1 .63 g, 44%). Analytical Data: RT 2.28 min; MS (ES+) m / z (relative intensity) 925 ([M + H]+, 70), 947 {[M + Na]+, 100)(c) Alloc-Val-Ala-PABOH (17)17(i) Alloc-Val-OH (14)Allyl chloroformate (41 g, 36.2 mL, 0.34 mol, 1.2 eq.) was added dropwise to a stirred solution of L-valine 13 (33.25 g, 0.28 mol, 1 eq.) and potassium carbonate (58.9 g, 0.426 mol, 1 .5 eq.) in water (650 mL) and THF (650 mL). The reaction mixture was stirred at room temperature for 18h. The THF was evaporated under reduced pressure and the remaining solution was extracted with diethyl ether (or MTBE) (x 2). The aqueous portion was acidified to pH 2 with cone. HCI and extracted with DCM (x 3). The combined organic extracts were washed with brine (x 1 ), dried (MgS04) and evaporated under reduced pressure to give a colourless oil (57.1 g). This was used in the next step without further purification.(ii) Alloc-Val-OSu (15)To a stirred solution of compound 14 (57.1 g, 0.28 mol, 1 eq.) and N-hydroxysuccinimide (32.68 g, 0.28 mol, 1 eq.) in dry THF (800 mL) was added dicyclohexylcarbodiimide (58.6 g, 0.28 mol, 1 eq.). The reaction mixture was stirred at room temperature for 18h. The reaction mixture was filtered. The solid was washed with THF and the combined filtrate was concentrated under reduced pressure. The oil / solid residue was re-dissolved in DCM and left to stand at 0 °C for 30 min. The suspension was filtered washing with cold DCM. Evaporation of the filtrate under reduced pressure gave the succinimide ester as a white solid which was used in the next step without further purification.(Hi) Alloc-Val-Ala-OH (16)A solution of Alloc-Val-OSu 15 (1 1 .67 g, 39.0 mmol, 1 eq.) in THF (50 mL) was added to a solution of H-Ala-OH (3.66 g, 41 .08 mmoL, 1 .05 eq.) and NaHCOs (3.61 g, 43.03 mmol, 1 .1 eq.) in THF (100 mL) and H2O (100 mL). The mixture was stirred at room temperature for 72h and the THF was evaporated under reduced pressure. The pH was adjusted to 3 - 4 with citric acid to precipitate a white gum. This was extracted with ethylacetate (6 x 150 mL) and the combined extracts were washed with H2O (200 mL), brine (200 mL), dried (MgS04) and evaporated under reduced pressure to give a white solid. Trituration with diethyl ether (xs) afforded the pure product as a white powder (7.93 g, 74%). Analytical Data: RT 2.17 min; MS (ES+) m / z (relative intensity) 295 ([Af + Na]+, 63), 273 ([Af + 1 ]+, 60).(iv) Alloc-Val-Ala-PABOH (17)EEDQ (4.79 g, 19.3 mmol, 1 .05 eq.) was added to a solution of p-aminobenzyl alcohol (2.38 g, 19.3 mmol, 1 .05 eq.) and Alloc-Val-Ala-OH 16 (5.02 g, 18.4 mmol, 1 .0eq) in dry THF (100 mL). The mixture was stirred at room temperature for 72h. The solvent was evaporated under reduced pressure to give a pale brown solid. The solid was triturated with diethyl ether and filtered washing with an excess of diethyl ether. This afforded the product as a white solid (6.2 g, 89%). Analytical Data: RT 2.50 min; MS (ES+) m / z (relative intensity) 400.6 ([Af + Na]+, 50), 378.6 {[M + 1 ]+, 60).(d) 4-((2S,5S)-37-(2,5-dioxo-2,5-dihydro-1 H-pyrrol-1 -yl)-5-isopropyl-2-methyl-4,7,35-trioxo- 10, 13, 16,19,22,25,28,31 -octaoxa-3,6,34-triazaheptatriacontanamido)benzyl (1 1 S,1 1 aS)- 1 1 -hvdroxy-7-methoxy-8-(3-(((S)-7-methoxy-2-methylene-5-oxo-2,3,5,1 1 a-tetrahydro-1 H- benzo[elpyrrolo[1 ,2-alH ,4ldiazepin-8-yl)oxy)propoxy)-2-methylene-5-oxo-2,3,1 1 ,1 1 a- tetrah dro-1 H-benzo[elpyrrolo[1 ,2-alH ,4ldiazepine-10(5H)-carboxylate (23)(i) tert-butyl (5-(3-(5-((((4-((S)-2-((S)-2-(((allylomethylbutanamido)propanamido)benzyl)oxy) carbonyl)amino)-4-( (S)-2-((( tert- butyldimethylsilyl)oxy)methyl)-4-methylenepyrrolidine-1-carbonyl)-2- methoxyphenoxy)propoxy)-2-( (S)-2-((( tert-butyldimethylsilyl)oxy)methyl)-4- methylenepyrrolidine-1-carbonyl)-4-methoxyphenyl)carbamate (18)Triethylamine (0.38 g, 0.53 mL, 3.8 mmol, 2.2 eq.) was added to a stirred solution of the mono-boc protected b / 's-aniline (12) (1 .6 g, 1 .72 mmol, 1.0 eq.) and triphosgene (0.184 g, 0.62 mmol, 0.36 eq.) in dry THF (25 mL) under a nitrogen atmosphere at roomtemperature. The reaction mixture was heated to 40°C, after 5 min a sample was treated with methanol and analysed by LCMS as the methyl carbamate. Analytical Data: RT 2.32 min; MS (ES+) m / z (relative intensity) 983 ([Af + H]+, 55), 1005 ([Af + Na]+, 100)A solution / suspension of the benzyl-alcohol (17) (1 .52 g, 2.35 mmol, 1 .4 eq.) and triethylamine (0.26 g, 0.36 ml. 2.6 mmol, 1 .5 eq.) in dry THF (40 ml.) was run in from a dropping funnel to the freshly prepared isocyanate. The reaction mixture was stirred at 40°C for 2.5h. The reaction mixture was allowed to cool, filtered and the filtrate evaporated to dryness to afford the crude product as a yellow oil which was purified by flash column chromatography [n-hexane / EtOAc 50 / 50 v / v] which gave the product as a yellow glass (1 .192 g). The mixed fractions were purified by flash column chromatography[CHC / MeOH 0% to 1 %] to give a further amount of product (0.22 g). The material was combined to give the product as a yellow foam (1 .41 g, 63%). Analytical Data: RT 2.27 min; MS (ES+) m / z (relative intensity) 1328 ([Af + H]+,30), 1350 {[M + Na]+, 100) (ii) tert-butyl (5-(3-(5-((((4-((S)-2-((S)-2-(((allyloxy)carbonyl)am^methylbutanamido)propanamido)benzyl)oxy)carbonyl)amino)-4-((S)-2-(hydroxymethyl)-4- methylenepyrrolidine- 1 -carbonyl)-2-methoxyphenoxy)propoxy)-2-( (S)-2-(hydroxymethyl)-4- methylenepyrrolidine-1-carbonyl)-4-methoxyphenyl)carbamate (19)A 1 .0M solution of TBAF in THF (2.34 ml_, 2.34 mmol, 2.2 eq.) was added to a solution of the b / 's-TBS compound (18) (1 .41 g, 1 .06 mmol, 1 .0 eq.) in anhydrous THF (12 ml_). The mixture was stirred at room temperature for 30 min., the solvent was removed under reduced pressure and the residue purified by flash column chromatography [CHC / MeOH 0% to 4% in 1 % increments] to give the desired product as a white foam (0.98 g, 84%). Analytical Data: RT 1 .62 min; MS (ES+) m / z (relative intensity) 1 100 ([M + H]+,60), 1 122 ([Af + Na]+, 100)(Hi) 4-((S)-2-((S)-2-(((allyloxy)carbonyl)amino)-3-methylbutanamido)propanamido)benzyl (11S, 11aS)-8-(3-(((11S, 11 aS)-10-(tert-butoxycarbonyl)-11-hydroxy-7-methoxy-2- methylene-5-oxo-2,3,5, 10, 11, 11a-hexahydro-1 H-benzo[e]pyrrolo[1 ,2-a][1 ,4]diazepin-8- yl)oxy)propoxy)-11-hydroxy-7-methoxy-2-methylene-5-oxo-2,3, 11, 11 a-tetrahydro-1 H- benzo[e]pyrrolo[1 ,2-a][1 ,4]diazepine-10(5H)-carboxylate (20)I BX (45 wt%, 1 .3 g, 2.09 mmol, 2.4 eq.) was added to a solution of the b / 's-alcohol 19(0.959 g, 0.87 mmol, 1 .0 eq.) in anhydrous DMSO (25 ml_). The solution was stirred at 30°C for 18h. LCMS analysis indicated the presence of a small amount of partially cyclised material. A further portion of IBX (45 wt%, 0.049 g, 0.17 mmol, 0.2 eq.) was added and the reaction was continued for a further 18h. The reaction mixture was poured into water (200mL) and the resultant precipitate was collected by filtration washing with water. The precipitate was dissolved in DCM (150 mL) and washed with saturated NaHCC>3 (100 mL), water (100 mL) and brine (100 mL). The organic portion was dried (MgS04) andevaporated to give a white solid. Purification by flash column chromatography[CHC / MeOH 0% to 4% in 1 % increments] gave the product as a white solid (0.696 g, 73%). Analytical Data: RT 1 .55 min; MS (ES+) m / z (relative intensity) 1096 {[M + H]+,20), 1 1 18 {[M + Na]+, 100)(iv) 4-((S)-2-((S)-2-amino-3-methylbutanamido)propanamido)benzyl (11S, 11aS)-8-(3- (((11S, 11 aS)-10-(tert-butoxycarbonyl)-11 -hydroxy-7-methoxy-2-methylene-5-oxo-2,3,5, 10, 11, 11 a-hexahydro-1 H-benzo[e]pyrrolo[1 ,2-a][1 ,4]diazepin-8-yl)oxy)propoxy)-11- hydroxy-7-methoxy-2-methylene-5-oxo-2,3, 11, 11 a-tetrahydro-1 H-benzo[e]pyrrolo[1 ,2- a][1 ,4]diazepine-10(5H)-carboxylate (21)Pd(PPh3)4(14 mg, 12.28 μηιοΙ, 0.02 eq.) was added to a solution of the cyclised product 20 (0.673 g, 0.61 mmol, 1 .0 eq.) and pyrrolidine (55 mg, 63 μί, 0.8 mmol, 1 .25 eq.)in anhydrous DCM (30 mL). The solution was stirred at room temperature for 30 min. The reaction mixture was diluted with DCM (70 mL) and washed with saturated NH4CI (100 mL), saturated brine (100 mL), dried (MgS04) and evaporated to give an off white foam. The product was triturated with diethyl ether and dried to give the product (0.62 g, 100%) which was used without further purification. Analytical Data: RT 1 .16 min; MS (ES+) m / z (relative intensity) 1012 {[M + H]+,80), 1034 {[M + Na]+, 20)(v) tert-butyl (11S, 11aS)-8-(3-(((11S, 11aS)-10-(((4-((2S,5S)-37-(2,5-dioxo-2,5-dihydro-1H- pyrrol- 1 -yl)-5-isopropyl-2-methyl-4, 7, 35-trioxo- 10, 13, 16, 19, 22, 25, 28, 31 -octaoxa-3, 6, 34- triazaheptatriacontanamido)benzyl)oxy)carbonyl)-11-hydroxy-7-methoxy-2-methylene-5- oxo-2,3,5, 10, 11, 11 a-hexahydro-1 H-benzo[e]pyrrolo[1 ,2-a][1 ,4]diazepin-8-yl)oxy)propoxy)- 11-hydroxy-7-methoxy-2-methylene-5-oxo-2,3, 11, 11 a-tetrahydro-1 H-benzo[e]pyrrolo[1 ,2- a][1,4]diazepine-10(5H)-carboxylate (22)EDCI .HCI (0.13 g, 0.66 mmol, 1 .1 eq.) was added to a cloudy solution of compound 21 (0.61 g, 0.6 mmol, 1 .0 eq.) and Mal-dPEG8®-OH (0.393 g, 0.66 mmol, 1 .1 eq.) in CHCI3(25 mL). The clear solution was stirred at room temperature for 1 .5h., diluted with CHC (100 mL) washed with brine (2 x 100 mL), dried (MgS04) and evaporated under reduced pressure to give a yellow foam. Purification by flash column chromatography [CHCb / MeOH 0% to 6% in 1 % increments gave the product as a white foam (0.786 g, 82%). Analytical Data: RT 1 .44 min; MS (ES+) m / z (relative intensity) 1586 {[M + H]+,40), 1609 {[M + Na]+, 100)(vi) 4-((2S, 5S)-37-(2, 5-dioxo-2, 5-dihydro- 1 H-pyrrol- 1 -yl)-5-isopropyl-2-methyl-4, 7, 35-trioxo- 10, 13, 16, 19,22,25,28,31-octaoxa-3,6,34-triazaheptatriacontanamido)benzyl (11S, 11aS)- 11-hydroxy-7-methoxy-8-(3-(((S)-7-methoxy-2-methylene-5-oxo-2,3,5, 11 a-tetrahydro-1 H- benzo[e]pyrrolo[1, 2-a][1,4]diazepin-8-yl)oxy)propoxy)-2-methylene-5-oxo-2, 3, 11, 11a- tetrahydro-1 H-benzo[e]pyrrolo[1 ,2-a][1 ,4]diazepine-10(5H)-carboxylate (23)Ice cold 95% TFA(aq) solution (10 mL) was added to the Boc protected compound 22 (0.759 g, 0.48 mmol, 1 .Oeq) which had been cooled to 0°C (ice bath). The yellow solution was stirred at 0°C for 1 h. The reaction mixture was poured onto ice / water (200 mL) and the mixture was basified to pH 8 with solid NaHCC>3. The mixture was extracted with DCM (4 x 50 mL) and the combined extracts washed with brine (100 mL), dried (MgSCU) and evaporated under reduced pressure. The product was purified by flash columnchromatography [CHC / MeOH 0% to 8% in 1 % increments] to give a pale yellow foam (0.445 g, 65%). Analytical Data: RT 1 .37 min; MS (ES+) m / z (relative intensity) 1468 {[M + H]+,40)Example 2Alternate synthesis of tert-butyl (5-(3-(5-((((4-((S)-2-((S)-2-(((allyloxy)carbonyl)amino)-3- methylbutanamido)propanamido)benzyl)oxy)carbonyl)amino)-4-((S)-2-(hydroxymethyl)-4- methylenepyrrolidine-1 -carbonyl)-2-methoxyphenoxy)propoxy)-2-((S)-2-(hydroxymethyl)-4- meth lenepyrrolidine-1 -carbonyl)-4-methoxyphenyl)carbamate (19)24(i)((2S,2^)-(4,4'-(propane-1,3 liylbis(oxy))bis(5-methoxy-2-nitrob bis(4- methylenepyrrolidine-1,2-diyl))bis(methylene) diacetate (24)A solution of acetyl chloride (21 .1 mL, 23.3 g, 297 mmol) in DCM (100 mL) was added drop-wise over a period of 20 min to a stirred solution of bis-alcohol (9) (75 g, 1 14 mmol) and triethylamine (34.7 g, 343 mmol) in anhydrous DCM (900 mL) at 0-5 °C under a nitrogen atmosphere. The reaction mixture was allowed to warm to room temperature and stirred for a further 60 mins. The reaction mixture was washed with ice cold 0.5M HCI (500 mL), saturated aqueous sodium hydrogen carbonate (250 mL), brine (100 mL) and dried (MgSC ). Removal of the solvent by rotary evaporation gave a pale yellow foam which was used in the next step without further purification. Yield = 66.7 g (79%). Analytical Data:Purity satisfactory by LC / MS (7.60 min (ES+) m / z (relative intensity) 741 .2 {[M + 1 ]+, 60) 763.3 {[M + Na]+, 100) );1H NMR (400 MHz, CDCI3) δ 57.73 (s, 2H), 6.83 (s,2H), 5.12 (d, 2H, J = 12 Hz), 5.02 (s, 2H), 4.89 (s, 2H), 4.79 (m, 2H), 4.61 (m, 1 H), 4.35 (m, 6H), 3.98 (s, 6H), 3.87 (d, 1 H, J = 4.0 Hz), 3.76 (m, 3H), 2.87-2.83 (m, 2H), 2.56-2.43 (m, 4H), 2.05 (s, 4H), 1 .96 (s, 2H).(ii) ((2S!2'S)-(4,4'-(propane-1,3-diylbis(oxy))bis(2-amino-5-met oxybenzoyl)) bis(4- methylenepyrrolidine-1,2-diyl))bis(methylene) diacetate (25)A 10% solution of formic acid in methanol (500 mL) was added in one go, via a separating funnel, to a solution of the bis-alcohol (24) (66 g, 0.09 mol) in methanol (1000 mL) containing zinc* (145 g, 2.22 mol) at room temperature. The temperature of the reaction mixture rapidly rose to 42°C and was then cooled back to room temperature with the aid of a cold water bath. The excess zinc was removed by filtering through a short bed of celite, which was then washed with ethyl acetate (100 mL). The filtrate was diluted with ethyl acetate (1400 mL) and washed with saturated sodium hydrogen carbonate (1500 mL), water (500 mL), brine (100 mL) and dried (MgSC ). Removal of the solvent by rotary evaporation gave a yellow solid which was purified by column chromatography (4% methanol / DCM) to give the product as a pale yellow foam. Yield = 38.1 g (63%).Analytical Data: Purity satisfactory by LC / MS (6.61 min (ES+) m / z (relative intensity) 681 .2 {[M + 1 ]+, 100));1H NMR (400 MHz, CDCI3) δ 6.74 (s, 2H), 6.31 (s, 2H), 5.02 (bs, 2H), 4.97 (bs, 2H), 4.80 (s, 2H), 4.33-4.10 (m, 16H), 3.78 (s, 3H), 2.78 (m, 2H), 2.46 (m, 2H), 2.34 (m, 2H), 2.04 (s, 6H).(Hi) ((S)-1-(4-(3-(4-((S)-2-(acetoxymethyl)-4-methylenepyrrolidine-1-c^butoxycarbonyl)amino)-2-methoxyphenoxy)propoxy)-2-amino-5-methoxybenzoyl)-4- methylenepyrrolidin-2-yl)methyl acetate (26)Boc anhydride (21 .6 g, 31 .7 mmol) was added to a solution of the diamine (25) (6.92 g 31 .7 mmol) in THF (200 mL) at room temperature. The resulting solution was then heated at reflux for 3 hours, cooled and evaporated to dryness under reduced pressure. The resulting residue was purified by column chromatography (70-100% ethyl acetate / hexane) to give the product as a pale yellow solid. Yield = 8.4 g (34%).Analytical Data: Purity satisfactory by LC / MS (3min run) (1 .64 min (ES+) m / z (relative intensity) 781 .2 {[M + Na]+, 30));1H NMR (400 MHz, CDC ) δ 8.32 (bs, 1 H), 7.87 (s, 1 H), 6.80 (s, 1 H), 6.73 (s, 1 H), 5.02 (m, 3H), 4.79 (3H), 4.34-4.09 (m, 14H), 3.83 (s, 3H), 3.78 (s, 3H), 2.81 -2.74 (m, 2H), 2.48-2.36 (m, 4H), 2.04 (m, 7H), 1 .49 (s, 9H).(iv) ((S)-1-(4-(3-(4-((S)-2-(acetoxymethyl)^-methylenepyrm((S)-2-(((allyloxy)carbonyl)amino)-3-methylbutanamido)propanamido)benzyl)oxy)carbonyl)amino)-2-methoxyphenoxy)propoxy)-2-((tert-butoxycarbonyl)amino)-5- methoxybenzoyl)-4-methylenepyrrolidin-2-yl)methyl acetate (27)Triethyl amine (0.57 g, 5.6 mmol) was added in one go to a solution of the amine (26) (2 g, 2.56 mmol) and triphosgene (0.27 g, 0.92 mmol) in THF (30 mL) under nitrogen. The resulting mixture was heated at 40°C for 5 min. A small aliquot was quenched with methanol, and LCMS indicated complete conversion to the methyl carbamate (m / z 983, M+1 ). A slurry of SG3366 (2.25 g, 3.48 mmol) and triethyl amine (0.39 g, 3.84 mmol) in THF (50 mL) was added in one go and the resulting mixture heated at 40°C for 4 hours. After cooling, the white solid was removed by filtration and the filtrate evaporated to dryness under reduced pressure, and purified by column chromatography (1 -3% methanol / DCM) to give the product as a pale yellow solid. Yield = 2.1 g (69%). Analytical Data: Purity satisfactory by LC / MS (8.26 min (ES+) m / z (relative intensity) 1 184.3 ([M+1]+, 70), 1206.3 {[M + Na]+, 100));1H NMR (400 MHz, DMSO-de) δ 7.62 (s, 2H), 7.30 (s, 2H), 4.29 (t, 4H, J = 6.0 Hz), 3.85 (s, 6H), 2.30-2.26 (m, 2H).(v) ((S)-1-(4-(3-(4-((S)-2-(acetoxymethyl)-4-methylenepyrrolidine-^((S)-2-(((allyloxy)carbonyl)amino)-3-methylbutanamido)propanamido)benzyl)oxy)carbonyl)amino)-2-methoxyphenoxy)propoxy)-2-((tert-butoxycarbonyl)amino)-5- methoxybenzoyl)-4-methylenepyrrolidin-2-yl)methyl acetate (19)Potassium carbonate (1.16 g, 8.44 mmol) was dissolved in water (8.4 mL) and added to a solution of the diacetate (27) (2.0 g, 1.69 mmol) in methanol (40 mL). The resulting mixture was stirred at 25°C for 30 mins, then evaporated to dryness under reduced pressure. The resulting residue was taken up in water (100 mL), acidified (pH 3) with 1 M citric acid and extracted with ethyl acetate (3 x 100 mL). The combined extracts were washed with water (100 mL), brine (30 mL) and dried (MgSC ). Removal of the solvent under reduced pressure left the product as an off-white solid which was used in the next step without further purification. Yield = 1 .6 g (87%). Analytical Data: Purity satisfactory by LC / MS (7.32 min (ES+) m / z (relative intensity) 1 100.7 ([M+1]+, 50), 1 122.3 {[M + Na]+, 100));1H NMR (400 MHz, DMSO-d6) 59.98 (bs, 1 H), 9.09 (bs, 1 H), 8.73 (bs, 1 H), 8.14 (d, J = 8 Hz, 1 H), 7.59 (d, J = 8 Hz, 2H), 7.33 (d, J = 8 Hz, 2H), 7.21 (m, 3H), 6.90 (bs, 2H), 5.91 (m, 1 H), 5.30 (d, J = 4 Hz, 1 H), 5.19 (d, J = 4 Hz, 1 H), 5.00 (m, 6H), 4.70 - 4.35 (m, 6H), 4.15 - 3.88 (m, 12H), 3.77 (s, 3H), 3.67 (s, 3H), 2.82 - 2.67 (m, 2H), 2.42 (m, 3H), 2.21 (t, J = 4Hz, 2H), 1 .98 (m, 6H), 1.42 (s, 9H), 1.31 (d, J = 8 Hz, 3H), 0.90 (d, J = 4 Hz, 3H), 0.84 (d, J = 4Hz, 3H).(a) Allyl (5-(3-(5-amino-4-((S)-2-(((tert-butyldimethylsilyl)oxy)methylenepyrrolidine- 1 -carbonyl)-2-methoxyphenoxy)propoxy)-2-( (S)-2-( ((tert- butyldimethylsilyl)oxy)methyl)-4-methylenepyrrolidine- 1 -carbonyl)-4- methoxyphenyl)carbamate (28)A solution of allyl chloroformate (1.05 g, 0.9 mL, 8.7 mmol, 0.9 eq.) was added drop wise to a solution of bis aniline (11 )(8.02 g, 9.7 mmol, 1 eq.) and pyridine (1.15 g, 1.2 mL, 14.55 mmol, 1.9 eq.) in dry DCM (350 mL) at -78 °C (dry ice / acetone bath). The reaction mixture was stirred at -78°C for 1 hour and then allowed to reach room temperature. The reaction mixture was washed with saturated aqueous copper sulphate solution (250 mL), water (250 mL), saturated sodium bicarbonate (250 mL), brine (250 mL) and dried(MgS04). Rotary evaporation under reduced pressure afforded the crude product.Purification by flash chromatography [50% n-hexane / 50% ethyl acetate, to 20% n-hexane / 80% ethyl acetate to 100% ethyl acetate to 1 % methanol / 99% ethyl acetate] gave the bis-a\\oc product (2.066 g), the desired mono-alloc product (4.33 g, 49%) and recovered b / 's-aniline (1 .96 g). Analytical Data: RT 2.26 min; MS (ES+) m / z (relative intensity) 909 {[M + 1]+, 100); 931 {[M + Na]+, 100)(b) 4-((S)-2-((S)-2-(((allyloxy)carbonyl)amino)-3-methylbutanamido (5- (3-(5-(((allyloxy)carbonyl)amino)-4-((S)-2-(((tert-butyldimethytemethylenepyrrolidine- 1 -carbonyl)-2-methoxyphenoxy)propoxy)-2-( (S)-2-( ((tert- butyldimethylsilyl)oxy)methyl)-4-methylenepyrrolidine-1-carbonyl)-4- methoxyphenyl)carbamate (29)Triethylamine (1 .22 g, 1.7 mL, 12.1 mmol, 2.2 eq.) was added to a stirred solution of the mono-boc protected b / 's-aniline (28) (5.0 g, 5.5 mmol, 1.0 eq.) and triphosgene (0.59 g, 1 .98 mmol, 0.36 eq.) in dry THF (75 mL) under a nitrogen atmosphere at roomtemperature. The reaction mixture was heated to 40 °C, after 5 min a sample was treated with methanol and analysed by LCMS as the methyl carbamate. Analytical Data: RT 2.30 min; MS (ES+) m / z (relative intensity) 967 {[M + H]+, 25), 989 {[M + Na]+, 100)A solution / suspension of the benzyl-alcohol (17) (3.1 1 g, 8.25 mmol, 1 .5 eq.) and triethylamine (0.83 g, 1.1 mL 2.6 mmol, 1.5 eq.) in dry THF (75 mL) was run in from a dropping funnel to the freshly prepared isocyanate. The reaction mixture was stirred at 40°C for 5h. then overnight at room temperature The reaction mixture was allowed to cool, filtered and the filtrate evaporated to dryness to afford the crude product as a yellow oil which was purified by flash column chromatography [50% n-hexane / 50% ethyl acetate to 40% n-hexane / 60% ethyl acetate] which gave the product as a yellow glass (1 .25 g, 17%). Analytical Data: RT 2.26 min; MS (ES+) m / z (relative intensity) 1312 {[M + H]+, 25), 1335 {[M + Na]+, 35)(c) 4-((S)-2-((S)-2-(((allyloxy)carbonyl)amino)-3-methylbutanamido)propanamido)benzyl (5- (3-(5-(((allyloxy)carbonyl)amino)-4-((S)-2-(hydroxymethyl)-4-methylenepyrrolidine-1- carbonyl)-2-methoxyphenoxy)propoxy)-2-( (S)-2-(hydroxymethyl)-4-methylenepyrrolidine- 1 - carbonyl)-4-methoxyphenyl)carbamate (30)A 1 .0M solution of TBAF in THF (5.2 mL, 5.2 mmol, 2.2 eq.) was added to a solution of the bis TBS compound (29) (3.096 g, 2.36 mmol, 1 .0 eq.) in anhydrous THF (25 mL). The mixture was stirred at room temperature for 30 min., the solvent was removed under reduced pressure and the residue purified by flash column chromatography [ethyl acetate / methanol 0% to 6% in 1 % increments] which gave the desired product as a whitefoam (1 .91 g, 75%). Analytical Data: RT 1 .56 min; MS (ES+) m / z (relative intensity) 1084 {[M + H]+, 100), 1 106 {[M + Na]+, 90)(d) Allyl (11S, 11aS)-8-(3-(((11S, 11aS)-10-(((4-((S)-2-((S)-2-(((allyloxy)carbonyl)amino)-3- methylbutanamido)propanamido)benzyl)oxy) carbonyl)- 11 -hydroxy- 7-methoxy-2-methylene- 5-oxo-2,3,5, 10, 11, 11 a-hexahydro-1 H-pyrrolo[2, 1 -c][1 ,4]benzodiazepin-8-yl)oxy)propoxy)- 11-hydroxy-7-methoxy-2-methylene-5-oxo-2,3, 11, 11 a-tetrahydro-1 H-pyrrolo[2, 1 - c][1 , ^benzodiazepine- 10( 5H)-carboxylate (31)IBX (45 wt%, 2.06 g, 3.3 mmol, 2.4 eq.) was added to a solution of the b / 's-alcohol 30 (1 .49 g, 1 .38 mmol, 1 .0 eq.) in anhydrous DMSO (40 mL). The solution was stirred at 30°C for 18h. LCMS analysis indicated the presence of a small amount of partially cyclised material. A further portion of IBX (45 wt%, 0.171 g, 0.275 mmol, 0.2 eq.) was added and the reaction was continued for a further 24h. The reaction mixture was poured into water (200 mL) and the resultant precipitate was collected by filtration washing with water. The precipitate was dissolved in DCM (150 mL) and washed with saturated NaHCOs (100 mL), water (100 mL) and brine (100 mL). The organic portion was dried (MgS04) and evaporated to give a white solid. Purification by flash column chromatography [CHC / MeOH 0% to 3% in 1 % increments] gave the product as a white solid (1.06 g, 72%). Analytical Data: RT 6.88 min; MS (ES+) m / z (relative intensity) 1080 {[M + H]+, 50), 1 102 {[M + Na]+, 100)(e) 4-((S)-2-((S)-2-amino-3-methylbutanamido)propanamido)benzyl (11S, 11aS)-11- hydroxy- 7-methoxy-8-(3-( ( (S)-7-methoxy-2-methylene-5-oxo-2, 3,5, 11 a-tetrahydro- 1 H- pyrrolo[2, 1-c][1,4]benzodiazepin-8-yl)oxy)propoxy)-2-methylene-5-oxo-2,3, 11, 11a- tetrahydro- 1 H-pyrrolo[2, 1 -c][1 ,4]benzodiazepine- 10( 5H)-carboxylate (32)Pd(PPh3)4 (44 mg, 38.5 μηιοΙ, 0.04 eq.) was added to a solution of the cyclised product 31 (1 .04 g, 0.96 mmol, 1.0 eq.) and pyrrolidine (0.171 mg, 196 μί, 2.4 mmol, 2.5 eq.) in anhydrous DCM (30 mL). The solution was stirred at room temperature for 30 min. The reaction mixture was diluted with DCM (30 mL) and washed with saturated NH4CI (100 mL), saturated brine (100 mL), dried (MgS04) and evaporated to give an off white foam. The product was triturated with diethyl ether and dried to give the product (0.86 g, 100%) which was used without further purification. Analytical Data: RT 1 .10 min; MS (ES+) m / z (relative intensity) 894 ([M + H]+, 30)(f) 4-((2S, 5S)-37-(2, 5-dioxo-2, 5-dihydro- 1 H-pyrrol- 1 -yl)-5-isopropyl-2-methyl-4, 7, 35-trioxo- 10, 13, 16, 19,22,25,28,31-octaoxa-3,6,34-triaza eptatriacontanamido)benzyl (11S, 11aS)- 11-hydroxy-7-methoxy-8-(3-(((S)-7-methoxy-2-methylene-5-oxo-2,3,5, 11a-tetrahydro-1H- pyrrolo[2, 1-c][1,4]benzodiazepin-8-yl)oxy)propoxy)-2-methylene-5-oxo-2,3, 11, 11a- tetrahydro-1 H-pyrrolo[2, 1 -c][1 ,4]benzodiazepine-10(5H)-carboxylate (23)EDCI .HCI (0.203 g, 1 .06 mmol, 1 .1 eq.) was added to a solution of compound 32 (0.86 g, 0.96 mmol, 1 .0 eq.) and Mal-dPEG8®-OH (0.57 g, 0.96 mmol, 1 .1 eq.) in dry DCM (30 mL) and CHC (to give a clear solution). The clear solution was stirred at room temperature for 18h. then a further portion of EDCI.HCI (0.037 g, 0.19 mmol, 0.2 eq.) was added and reaction continued for a further 24h. The reaction mixture was diluted with DCM (70 mL) washed with water (100 mL), brine (100 mL), dried (MgS04) and evaporated under reduced pressure to give a yellow foam. Purification by flash column chromatography[CHC / MeOH 0% to 6% in 1 % increments] gave the product as an off white foam (0.56 g, 40%). Analytical Data: RT 6.13 min; MS (ES+) m / z (relative intensity) 1468 {[M + H]+, 20)Example 4(a) Allyl (2-((R)-2-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylenepyrrolidin5-(3-(4-((R)-2-( ((tert-butyldimethylsilyl)oxy)methyl)-4-methylenepyrrolidine- 1 -carbonyl)-5- ((((4-((10S, 13S)-10-isopropyl-13-methyl-8, 11-dioxo-2,5-dioxa-9, 12-diazatetradecan-14- amido)benzyl)oxy)carbonyl)amino)-2-methoxyphenoxy)propoxy)-4- methoxyphenyl)carbamate (34)Triethylamine (0.049 g, 0.07 mL, 0.48 mmol, 2.2 eq.) was added to a stirred solution of the mono-alloc protected b / 's-aniline (23) (0.2 g, 0.22 mmol, 1 .0 eq.) and triphosgene (0.024 g, 0.079 mmol, 0.36 eq.) in dry THF (5 mL) under an argon atmosphere at room temperature. The reaction mixture was heated to 40°C, after 5 min a sample was treated with methanol and analysed by LCMS as the methyl carbamate. Analytical Data: RT 2.27 min; MS (ES+) m / z (relative intensity) 967 {[M + H]+, 80), 989 {[M + Na]+, 100)A solution / suspension of the benzyl-alcohol (33) (0.121 g, 0.29 mmol, 1 .3 eq.) and triethylamine (0.029 g, 0.04 mL 0.29 mmol, 1 .3 eq.) in dry THF (5 mL) was run in from a dropping funnel to the freshly prepared isocyanate. The reaction mixture was stirred at 40°C for 4h. then overnight at room temperature The reaction mixture was allowed to cool, filtered and the filtrate evaporated to dryness to afford the crude product which was purified by flash column chromatography [Biotage Isolera™ CHC / MeOH 2% to 4%, gradient elution]. This gave the product (0.237 g, 79%). Analytical Data: RT 2.19 min; MS (ES+) m / z (relative intensity) 1358 {[M + H]+, 30), 1380 {[M + Na]+, 15) (b) 4-((10S, 13S)-10-isopropyl-13-met yl-8, 11-dioxo-2,5-dioxa-9, 12-diazatetradecan-14- amido)benzyl (5-(3-(5-amino-4-((R)-2-(((tert-butyldimethylsilyl)oxy)methyl)-4- methylenepyrrolidine- 1 -carbonyl)-2-methoxyphenoxy)propoxy)-2-((R)-2-( ( (tert- butyldimethylsilyl)oxy)methyl)-4-methylenepyrrolidine-1-carbonyl)-4- methoxyphenyl)carbamate (35)Pd(PPh3)4(0.3 g, 0.25 mmol, 0.06 eq.) was added to a solution of the alloc protected intermediate 34 (5.89 g, 4.3 mmol, 1.0 eq.) and pyrrolidine (0.46 g, 530 μΙ_, 6.5 mmol, 1 .5 eq.) in anhydrous DCM (50 mL). The solution was stirred at room temperature for 1 h. The reaction mixture was diluted with DCM and washed with saturated NH4CI, saturated brine, dried (MgS04) and evaporated to give crude product. The product was purified by flash column chromatography [Biotage Isolera™ DCM / MeOH 1 % to 3%] to give the product(4.53 g, 83%) which had an overall purity of 80% and was used without further purification. Analytical Data: RT 2.10 min; MS (ES+) m / z (relative intensity) 1275 {[M + H]+, 40).(c) 4-((S)-2-((S)-2-(((allyloxy)carbonyl)amino)-3-methylbutanamido)propanamido)benzyl (2- ((S)-2-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylenepyrrolidine-2-( ((tert-butyldimethylsilyl)oxy)methyl)-4-methylenepyrrolidine- 1 -carbonyl)-5-( (((4- ((10S, 13S)-10-isopropyl-13-methyl-8, 11-dioxo-2,5-dioxa-9, 12-diazatetradecan-14- amido)benzyl)oxy)carbonyl)amino)-2-methoxyphenoxy)propoxy)-4- methoxyphenyl)carbamate (36)Triethylamine (0.35 g, 48 μΙ_, 0.34 mmol, 2.2 eq.) was added to a stirred solution of the aniline (35) (0.2 g, 0.157 mmol, 1.0 eq.) and triphosgene (0.017 g, 57 μηηοΙ, 0.36 eq.) in dry THF (5 mL) under an argon atmosphere at room temperature. The reaction mixture was heated to 40°C, after 5 min a sample was treated with methanol and analysed by LCMS as the methyl carbamate. Analytical Data: RT 2.15 min; MS (ES+) m / z (relative intensity) 1333 {[M + H]+, 40), 1354 {[M + Na]+, 35).A solution / suspension of the benzyl-alcohol (17) (0.071 g, 0.19 mmol, 1.2 eq.) and triethylamine (19 mg, 26 μΙ_ 0.19 mmol, 1.2 eq.) in dry THF (5 ml_) was run in from a dropping funnel to the freshly prepared isocyanate. The reaction mixture was stirred at 40°C for 4h. then overnight at room temperature The reaction mixture was filtered and the filtrate evaporated to dryness to afford the crude product which was purified by flash column chromatography [Biotage Isolera™ CHC / MeOH 2% to 3%, gradient elution] which gave the product (0.152 g, 58%). Analytical Data: RT 2.12 min; MS (ES+) m / z (relative intensity) 1677 ([Af + H]+, 30), 1700 ([Af + Na]+, 100). (d) 4-((S)-2-((S)-2-(((allyloxy)carbonyl)amino)-3-methylbutanamido)pro (2- ( (S)-2-(hydroxymethyl)-4-methylenepyrrolidine- 1 -carbonyl)-5-(3-(4-( (S)-2-(hydroxymethyl)- 4-methylenepyrrolidine-1 -carbonyl)-5-((((4-((1 OS, 13S)-10-isopropyl-13-methyl-8, 11-dioxo- 2, 5-dioxa-9, 12-diazatetradecan- 14-amido)benzyl)oxy)carbonyl)amino)-2- methoxyphenoxy)propoxy)-4-methoxyphenyl)carbamate (37)A 1 .0M solution of TBAF in THF (3.4 mL, 3.4 mmol, 2.0 eq.) was added to a solution of the bis TBS compound (36) (2.86 g, 1.7 mmol, 1.0 eq.) in anhydrous THF (30 mL) under an argon atmosphere. The mixture was stirred at room temperature for 6h., the reaction mixture was diluted with CHC and washed with water, brine, dried (MgSC ) and evaporated under reduced pressure to give a yellow solid. The residue was purified by flash column chromatography [Biotage Isolera™ CHC / MeOH, gradient elution with the product eluting at 4% MeOH] which gave the desired product (1 .365 g) and mixed fractions which were further purified by flash column chromatography [CHC / MeOH 1 % to 5%] to give further product (0.562 g) this gave a combined yield of desired product (1.93 g, 75%). Analytical Data: RT 1 .55 min; MS (ES+) m / z (relative intensity) 1449 ([Af + 1]+, 25); 1471 {[M + Na]+, 20).(e) 4-((S)-2-((S)-2-(((allyloxy)carbonyl)amino)-3-methylbutanamido)propanamido)benzyl (11S, 11aS)-11-hydroxy-8-(3-(((S)-10-(((4-((10S, 13S)-10-isopropyl-13-methyl-8, 11-dioxo- 2,5-dioxa-9, 12-diazatetradecan-14-amido)benzyl)oxy)carbonyl)-7-methoxy-2-methylene-5- oxo-2,3,5, 10, 11, 11 a-hexahydro-1 H-pyrrolo[2, 1 -c][1 ,4]benzodiazepin-8-yl)oxy)propoxy)-7- methoxy-2-methylene-5-oxo-2,3, 11, 11a-tetrahydro-1 H-pyrrolo[2, 1-c][1 ,4]benzodiazepine- 10(5H)-carboxylate (38)IBX (45 wt%, 0.236 g, 0.38 mmol, 2.2 eq.) was added to a solution of the b / 's-alcohol 37 (0.25 g, 0.17 mmol, 1.0 eq.) in anhydrous DMSO (12 mL). The solution was stirred at 30°C for 3.5d. The reaction mixture was poured into water (100 mL) and the resultant precipitate was collected by filtration washing with water. The precipitate was extracted with DCM (5 x30 mL) and the combined fractions were washed with saturated NaHCC>3 (60 mL), water (60 mL) and brine (60 mL). The organic portion was dried (MgS04) and evaporated to give crude product. Purification by flash column chromatography [CHC / MeOH 1 % to 5%] gave the product as a white solid (0.158 g, 64%). Analytical Data: RT 1.53 min; MS (ES+) m / z (relative intensity) 1445 ([Af + 1]+, 20); 1467 {[M + Na]+, 30).(f) 4-((S)-2-((S)-2-amino-3-methylbutanamido)propanamido)benzyl (11 S, 11aS)-11-hydroxy- 8-(3-(((11S, 11aS)-11-hydroxy-10-(((4-((10S, 13S)-10-isopropyl-13-methyl-8, 11-dioxo-2,5- dioxa-9, 12-diazatetradecan-14-amido)benzyl)oxy)carbonyl)-7-methoxy-2-methylene-5-oxo- 2,3,5, 10, 11, 11 a-hexahydro-1 H-benzo[e]pyrrolo[1 ,2-a][1 ,4]diazepin-8-yl)oxy)propoxy)-7- methoxy-2-methylene-5-oxo-2,3, 11, 11a-tetrahydro-1 H-benzo[e]pyrrolo[1 ,2- a ][ 1 ,4]diazepine- 10(5H)-carboxylate (39)Pd(PPh3)4(8 mg, 6.9 μηιοΙ, 0.06 eq.) was added to a solution of the cyclised product 38 (0.158 g, 0.109 mmol, 1.0 eq.) and pyrrolidine (0.01 g, 12 μί, 0.15 mmol, 1 .5 eq.) in anhydrous DCM (10 mL). The solution was stirred at room temperature for 15 min. The reaction mixture was diluted with CHC and washed with saturated sodium bicarbonate solution, saturated brine, dried (MgS04) and evaporated to give crude product. The product was triturated with diethyl ether (x 3) and dried to give the product (0.136 g, 100%) which was used without further purification. Analytical Data: RT 1.21 min; MS (ES+) m / z (relative intensity) 1361 {[M + 1]+, 50); 1384 {[M + Na]+, 10).(g) 4-((2S, 5S)-37-(2, 5-dioxo-2, 5-dihydro- 1 H-pyrrol- 1 -yl)-5-isopropyl-2-methyl-4, 7, 35-trioxo- 10, 13, 16, 19,22,25,28,31-octaoxa-3,6,34-triazaheptatriacontanamido)benzyl (11S, 11aS)-11-hydroxy-8-(3-(((11S, 11aS)-11-hydroxy-10-(((4-((10S, 13S)-10-isopropyl-13-methyl-8, 11- dioxo-2,5-dioxa-9, 12-diazatetradecan-14-amido)benzyl)oxy)carbonyl)-7-methoxy-2- methylene-5-oxo-2,3,5, 10, 11, 11 a-hexahydro-1 H-pyrrolo[2, 1-c][1 ,4]benzodiazepin-8- yl)oxy)propoxy)-7-methoxy-2-methylene-5-oxo-2,3, 11, 11 a-tetrahydro-1 H-pyrrolo[2, 1 - c][1 ,4]benzodiazepine- 10(5H)-carboxylate (40)A solution of compound 39 (0.136 g, 0.1 mmol, 1 .0 eq.), Mal-dPEG8®-OH (0.066 g, 0.1 1 mmol, 1.1 eq.) and EDCI.HCI (0.022 g, 0.1 1 mmol, 1.1 eq.) in dry DCM (10 mL) and MeOH (1 drop) was stirred at room temperature for 1.45h. The reaction mixture was diluted with CHC and washed with water, brine, dried (MgS04) and evaporated under reduced pressure to give the crude product. Purification by flash column chromatography[CHC / MeOH 1 % to 9%] gave the product as a white solid (0.123 g, 63%). Analytical Data: [a]21D= +1 12.5° (c = 0.4, hplc CHCI3); RT 6.37 min; MS (ES+) m / z (relative intensity) 1936 {[M + 1]+, 35); 1958 {[M + Na]+, 15).Example 5 - ConjugationConjugate trastuzumab-23A 50 mM solution of tris(2-carboxyethyl)phosphine hydrochloride (TCEP) in phosphate- buffered saline pH 7.4 (PBS) was added (50 molar equivalent / antibody, 35 micromoles, 700 μΙ_) to a 24.14 mL solution of antibody, trastuzumab, (105 mg, 700 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 (<150 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 ofdehydroascorbic acid (DHAA, 10 molar equivalent / antibody, 7 micromoles, 140 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 2.3 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 23 (SG3400) was added as a DMSO solution (10 molar equivalent / antibody, 1 micromole, in 1 .0 mL DMSO) to 9 mL of this reoxidised antibody solution (15 mg, 100 nanomoles) for a 10% (v / v) final DMSO concentration. The solution was mixed for 1.5 hours at room temperature, then the conjugation was quenched by addition of / V-acetyl cysteine (4 micromoles, 40 μ\- at 100 mM), diluted to >50 mL in PBS and conjugate trastuzumab-23 was purified by spin filtration using a 15 mL Amicon Ultracell 50 kDa MWCO spin filter, 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 trastuzumab-A at 280 nm and 330 nm (Compound A specific) shows unconjugated light chains and a mixture of unconjugated heavy chains and heavy chains attached to a single molecule of compound 23, consistent with a drug-per-antibody ratio (DAR) of 1.71 molecules of compound 23 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 pm 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 trastuzumab-23 at280 nm shows a monomer purity of 94%. UHPLC SEC analysis gives a concentration of final conjugate trastuzumab-23 at 0.84 mg / mL in 15 mL, obtained mass of conjugate trastuzumab-23 is 12.7 mg (84% yield). Conjugate trastuzumab-40A 50 mM solution of tris(2-carboxyethyl)phosphine hydrochloride (TCEP) in phosphate- buffered saline pH 7.4 (PBS) was added trastuzumab, (50 molar equivalent / antibody, 50 micromoles, 1.0 mL) to a 34.5 mL solution of antibody (150 mg, 1 .0 micromole) in reduction buffer containing PBS and 1 mM ethylenediaminetetraacetic acid (EDTA) at 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 (<150 rpm) shaking. After cooling down to room temperature, the reduced antibody was buffer exchanged, via spin filter centrifugation, into a reoxidation buffer containing PBS and 1 mM EDTA to remove excess reducing agent. A 50 mM solution of dehydroascorbic acid (DHAA, 50 molar equivalent / antibody, 50 micromoles, 1.0 mL) in DMSO was added and the reoxidation mixture was allowed to react for 2 hours at room temperature (or until full reoxidation of the cysteine thiols to reform the inter-chain cysteine disulfides is observed by UHPLC) with gentle (< 150 rpm) shaking at an antibody concentration of 2-3 mg / mL. The reoxidation mixture was then sterile-filtered and diluted in a conjugation buffer containing PBS and 1 mM EDTA to a final antibody concentration of ~1 .5 mg / mL. Compound 40 was added as a DMSO solution (10 molar equivalent / antibody, 1 micromole, in 0.9 mL DMSO) to 9 mL of this reoxidised antibody solution (15 mg, 100 nanomoles). The solution was mixed for 1 .25 hours at room temperature, after which the conjugation reaction was quenched by addition of / V-acetyl cysteine (4 micromoles, 40 μ\- at 100 mM) and diluted to >50 mL in PBS. The conjugation mixture was purified by spin filtration using a 15 mL Amicon Ultracell 50 kDa MWCO spin filter, sterile-filtered, analysed and stored at +4 °C. The reduction and reoxidation steps are monitored by comparison of the relative amounts of individual light and heavy chains with full length antibody as observed by UHPLC analysis on a Shimadzu Prominence system using a Phenomenex Aeris 3.6u XB-C18 150 x 2.1 mm column eluting with a gradient of water and acetonitrile. UHPLC analysis on a Shimadzu Prominence system using a Phenomenex Aeris 3.6u XB-C18 150 x 2.1 mm column eluting with a gradient of water and acetonitrile on a reduced sample of conjugate trastuzumab-B at 280 nm and 330 nm (Compound 40 specific) shows unconjugated light chains and a mixture of unconjugated heavy chains and heavy chains attached to a single molecule of Compound 40, consistent with a drug-per-antibody ratio (DAR) of 1.68 molecules of Compound 40 per antibody.UHPLC analysis on a Shimadzu Prominence system using a Tosoh Bioscience TSKgel SuperSW mAb HTP 4 μηη 4.6 x 150 mm column (with a 4 pm 3.0 x 20 mm guard column) eluting with 0.3 mL / minute 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 trastuzumab-40 at 280 nm shows a monomer purity of 93% with no impurity detected. UHPLC SEC analysis gives a concentration of final conjugate trastuzumab-B at 0.74 mg / mL in 17 mL, obtained mass of conjugate trastuzumab-40 is 12.5 mg (83% yield). Conjugate R347-23A 50 mM solution of tris(2-carboxyethyl)phosphine hydrochloride (TCEP) in phosphate- buffered saline pH 7.4 (PBS) was added (42 molar equivalent / antibody, 56 micromoles, 1 .12 mL at 50 mM) to a 14.09 mL solution of antibody (200 mg, 1.33 micromoles) in reduction buffer containing PBS and 1 mM ethylenediaminetetraacetic acid (EDTA) and a final antibody concentration of 4.0 mg / mL. The reduction mixture was heated at +25°C for 24 hours (or until full reduction observed by UHPLC) in an incubator with gentle (<100 rpm) shaking. After cooling down to room temperature, the reduced antibody was buffer exchanged, via Tangential Flow Filtration unit (TFF) using mPES, MidiKros®30 kDa fiber filter with 1 15 cm2surface area, into a reoxidation buffer containing PBS pH 7.4 and 1 mM EDTA to remove all the excess reducing agent. The reduced antibody was centrifuged for 3 min at 4000 rpm and then filtered using 0.45 μΜ membrane filter. A 50 mM solution of dehydroascorbic acid (DHAA, 15 molar equivalent / antibody, 20 micromoles, 400 μί at 50 mM) in DMSO was added and the reoxidation mixture was allowed to react for 16 hours at room temperature with gentle (<100 rpm) shaking at an antibody concentration of 2.5 mg / mL (or until full reoxidation of the cysteine thiols to reform the inter-chain cysteine disulfides is observed by UHPLC). The reoxidation mixture was centrifuged for 3 min at 4000 rpm and then sterile-filtered using 0.2 μΜ membrane filter. Compound 23 was added as a DMSO solution (10 molar equivalent / antibody, 13.3 micromoles, in 6.6 mL DMSO) to 80 mL of this reoxidised antibody solution (200 mg, 1.33 micromoles) for a 10% (v / v) final DMSO concentration. The solution was shaken for 3 hours at +25°C and then the conjugation was quenched with / V-acetyl cysteine (72.3 micromoles, 0.72 mL at 100 mM).Excess free drug was removed via Tangential Flow Filtration unit (TFF) using mPES, MidiKros®30 kDa fiber filter with 1 15 cm2surface area, into buffer containing PBS pH 7.4. Extent of free drug removal was monitored by UHPLC-RP using neat conjugate. After complete removal of free drug, ADC were formulated onto 25 mM Histidine, 200 mMSucrose, pH 6.0, via TFF using mPES, MidiKros®30 kDa fiber filter with 1 15 cm2surface area. The whole process of R347 conjugation with Compound 23 was repeated with 400 mg antibody and also purified using TFF. ADC from both batches were combined and then filtered using Mustang filter under sterile atmosphere and then further stored at -78°C.UHPLC analysis on a Shimadzu Prominence system using a Phenomenex Aeris 3.6u XB- C18 150 x 2.1 mm column eluting with a gradient of water and acetonitrile on a reduced sample of Conjugate at 214 nm and 330 nm (Compound 23 specific) shows a mixture of light and heavy chains attached to several molecules of Compound 23, consistent with a drug-per-antibody ratio (DAR) of 1.71 molecules of Compound 23 per antibody.UHPLC analysis on a Shimadzu Prominence system using a Tosoh Bioscience TSKgel SuperSW mAb HTP 4 μηη 4.6 x 150 mm column (with a 4 pm 3.0 x 20 mm guard column) eluting with 0.3 mL / minute 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 ADC at 280 nm shows a monomer purity of greater than 97%. UHPLC SEC analysis gives a concentration of final ADC at 1 .92 mg / mL in 265 mL, obtained mass of ADC is 509 mg (85% yield). Conjugate R347-40A 50 mM solution of tris(2-carboxyethyl)phosphine hydrochloride (TCEP) in phosphate- buffered saline pH 7.4 (PBS) was added (50 molar equivalent / antibody, 20 micromoles, 0.4 mL) to a 13.25 mL solution of antibody (60 mg, 0.4 micromoles) in reduction buffer containing PBS and 1 mM ethylenediaminetetraacetic acid (EDTA) at a final antibody concentration of 4.5 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 (<150 rpm) shaking. After cooling down to room temperature, the reduced antibody was buffer exchanged, via spin filter centrifugation, into a reoxidation buffer containing PBS and 1 mM EDTA to remove excess reducing agent. A 50 mM solution of dehydroascorbic acid (DHAA, 12 molar equivalent / antibody, 4.8 micromoles, 96 μί) in DMSO was added and the reoxidation mixture was allowed to react for 17 hours at room temperature (or until full reoxidation of the cysteine thiols to reform the inter-chain cysteine disulfides is observed by UHPLC) with gentle (< 150 rpm) shaking at an antibody concentration of ~1 .6 mg / mL. The reoxidation mixture was then sterile-filtered and diluted in a conjugation buffer containing PBS and 1 mM EDTA to a final antibody concentration of ~1 .5 mg / mL. Compound 40 was added as a DMSO solution (1 1 molar equivalent / antibody, 0.44 micromoles, in 0.45 mL DMSO) to 4.05mL of this reoxidised antibody solution (6 mg, 40 nanomoles). The solution was mixed for 1 .25 hours at room temperature, after which the conjugation reaction was quenched by addition of / V-acetyl cysteine (1.76 micromoles, 17.6 μΙ_ at 100 mM). The conjugation mixture was purified by spin filtration with PBS using a 15 mL Amicon Ultracell 50 kDa MWCO spin filter, sterile-filtered, analysed and stored at +4 °C.The reduction and reoxidation steps are monitored by comparison of the relative amounts of individual light and heavy chains with full length antibody as observed by UHPLC analysis on a Shimadzu Prominence system using a Phenomenex Aeris 3.6u XB-C18 150 x 2.1 mm column eluting with a gradient of water and acetonitrile. UHPLC analysis on a Shimadzu Prominence system using a Phenomenex Aeris 3.6u XB-C18 150 x 2.1 mm column eluting with a gradient of water and acetonitrile on a reduced sample of Conjugate R347-40 at 280 nm and 330 nm (Conjugate 40 specific) shows unconjugated light chains and a mixture of unconjugated heavy chains and heavy chains attached to a single molecule of Compound 40, consistent with a drug-per-antibody ratio (DAR) of 1.86 molecules of Compound 40 per antibody.UHPLC analysis on a Shimadzu Prominence system using a Tosoh Bioscience TSKgel G3000SWXL 5 μηι 7.8 x 300 mm column (with a 7 μηι 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 R347-40 at 280 nm shows a monomer purity of 97% with no impurity detected. UHPLC SEC analysis gives a concentration of final Conjugate R347-40 at 0.87 mg / mL in 5.5 mL, obtained mass of Conjugate R347-40 is 4.8 mg (80% yield).Conjugate HLL2-23A 50 mM solution of DTT (Dithiothreitol) in phosphate-buffered saline pH 7.4 (PBS) was added (40 molar equivalent / antibody, 40 micromoles, 825μί) to a 37.5 mL solution of antibody HLL2 (150mg, 1 micromol) in reduction buffer containing PBS and 1 mM ethylenediaminetetraacetic acid (EDTA) and a final antibody concentration of 4 mg / mL. The reduction mixture was incubated at room temperature overnight with gentle (135 rpm) shaking. The reduced antibody was buffer-exchanged against PBS+1 mM EDTA (to remove the excess of DTT) using TFF (Tangential Flow Filtration, Spectrum Labs 1 15 cm2hollow fibre cassette with 50kDa molecular weight cut off). The sample was filtered using a 0.4μηι syringe filter to remove any debris from the TFF step and antibody concentration brought to 1 .5mg / mL before reoxidation. A 50 mM solution of dehydroascorbic acid (DHAA,15 molar equivalent / antibody, 13.9 micromoles, 0.28 ml.) in DMSO was added and the reoxidation mixture was allowed to react for 16 hours at room temperature under gentle (< 150 rpm) shaking. The reoxidation mixture was then sterile-filtered; 139mg of antibody (92.6ml_ as 1 .5 mg / mL solution) was obtained, 14ml_ of which was taken forward for conjugation with Compound 23 (estimated ca. 21 mg antibody, 0.14 micromoles).Compound 23 was added as a DMSO solution (10 molar equivalent / antibody, 0.33 micromoles in 0.133 ml. DMSO) to 14 mL of the reoxidised antibody solution. The conjugation mixture was topped with 1.27ml of DMSO to bring the final DMSOconcentration to 10% (v / v) and incubated for 3 hours at room temperature under gentle agitation (135rpm). Free drug was then removed from the antibody-drug conjugate by extensive diafiltration in PBS using a spin filter device (Amicon Ultra-30K centrifugal filter, Millipore). The resulting conjugation mixture was sterile-filtered and analysed by UHPLC.UHPLC analysis on a Shimadzu Prominence system using a Phenomenex Aeris 3.6u XB- C18 150 x 2.1 mm column eluting with a gradient of water and acetonitrile on a reduced sample of Conjugate at 214 nm (ADC) and 330 nm (Compound 23 specific) shows a mixture of heavy chains either unconjugated or attached to 1 molecule of Compound 23, consistent with a drug-per-antibody ratio (DAR) of 1 .64 molecules of Compound 23 per antibody.UHPLC analysis on a Shimadzu Prominence system using a Tosoh Bioscience TSKgel SuperSW mAb HTP 4 μηι 4.6 x 150 mm column (with a 4 μηι 3.0 x 20 mm guard column) eluting with 0.3 mL / minute 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 ADC at 280 nm shows a monomer purity greater than 97%. UHPLC SEC analysis gives a concentration of final ADC at 2.06 mg / mL in 10 mL, obtained mass of ADC is 20.6 mg.Conjugate AntiCD79b-23A 50 mM solution of DL-dithiothreitol (DTT) in phosphate-buffered saline pH 7.4 (PBS) was added (80 molar equivalent / antibody, 53.3 micromoles, 1 .07 mL) to a 25 mL solution of antibody CD79b (100mg, 667 nmol) in reduction buffer containing PBS and 1 mM ethylenediaminetetraacetic acid (EDTA) and a final antibody concentration of 4 mg / mL. The reduction mixture was allowed to react at room temperature overnight with gentle shaking. The reduced antibody was buffer exchanged, via spin filter centrifugation, into a reoxidation buffer containing PBS and 1 mM EDTA to remove all the excess reducing agent. A 50 mM solution of dehydroascorbic acid (DHAA, 15 molar equivalent / antibody,9.28 micromoles, 185 μΙ_) in DMSO was added and the reoxidation mixture was allowed to react for 16 hours at room temperature under gentle (< 150 rpm) shaking. The reoxidation mixture was then sterile-filtered; Compound 23 was added as a DMSO solution (15 molar equivalent / antibody, 1 .8 micromoles in 1 .0 ml. DMSO) to 9 ml. of this reoxidised antibody solution (18 mg, 120 nanomoles) for a 10% (v / v) final DMSO concentration and a final antibody concentration of 1 .8 mg / mL in PBS + 1 mM EDTA. The solution was mixed for 2 hours at room temperature under gentle agitation (135 rpm), then the conjugation was quenched by addition of / V-acetyl cysteine (7.2 micromoles, 72 μΙ_ at 100 mM), then purified by spin filtration using a 15 mL Amicon Ultracell 50 kDa MWCO spin filter, sterile-filtered and analysed.UHPLC analysis on a Shimadzu Prominence system using a Phenomenex Aeris 3.6u XB- C18 150 x 2.1 mm column eluting with a gradient of water and acetonitrile on a reduced sample of Conjugate at 280 nm (ADC) and 330 nm (Compound 23 specific) unconjugated light chains and a mixture of unconjugated heavy chains and heavy chains attached to 1 or 2 molecules of Compound 23, consistent with a drug-per-antibody ratio (DAR) of 2.08 molecules of Compound 23 per antibody.UHPLC analysis on a Shimadzu Prominence system using a Tosoh Bioscience TSKgel SuperSW mAb HTP 4 μηι 4.6 x 150 mm column (with a 4 m 3.0 x 20 mm guard column) eluting with 0.3 mL / minute 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 ADC at 280 nm shows a monomer purity of greater than 98%. UHPLC SEC analysis gives a concentration of final ADC at 1 .62 mg / mL in 7.6 mL, obtained mass of ADC is 12.28 mg.Example 5 - in vitro testingMedium 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 dilutedto 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 10ΟμΙ 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).Cell Line Description ADC Exposure Cell growth mediumSKBR3 Breast carcinoma 4 days McCoys with Glutamax, 10%FBSBT474 Breast carcinoma 5 days DMEM with glutamax, 10% FBSNCIN87 Gastric carcinoma 7 days RPMI 1640 with glutamax, 10%FBSICso (Mg / ml) in:ADC DARBT474 NCI-N87 SKBR3trastuzumab-40 1 .68 >1 0.019 0.019 trastuzumab-23 1 .71 >1 0.030 0.022Testing of AntiCD79b-23The concentration and viability of cells from a sub-confluent (80-90% confluency) T75 flask are measured by trypan blue staining, and counted using the LUNA-II™ Automated Cell Counter. Cells were diluted to 2x105 / ml, dispensed (50 μΙ / well) into 96-well flat-bottom plates.A stock solution (1 ml) of antibody drug conjugate (ADC) (20 Mg / 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 100 μΙ into 900 μΙ of cell culture medium. ADC dilution was dispensed (50 μΙ / well) into 4 replicate wells of the 96-well plate, containing 50 μΙ cell suspension seeded the previously. Control wells received 50 μΙ 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 (20 μΙ per well) into each well and incubated for 4 hours at 37°C in the C02-gassed incubator. Well absorbance was measured at 490 nm. 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 dose-response data using GraphPad Prism using the non-linear curve fit algorithm: sigmoidal dose-response curve with variable slope.ADC incubation times were 4 days with WSUDLCL2 (B-cell non-Hodgkin lymphoma) and SUDHL4 (B-lymphocyte), 5 days for Granta519 (B-cell non-Hodgkin lymphoma) and 6 days for BJAB (Burkitt lymphoma). WSUDLCL2 and SUDHL4 were cultured in RPMI 1640 with Glutamax + 10% (v / v) HyClone™ Fetal Bovine Serum, Granta519 in DMEM + Glutamax with 10% (v / v) HyClone™ Fetal Bovine Serum and BJAB in RPMI 1640 + Glutamax with 20% (v / v) HyClone™ Fetal Bovine Serum.EC5o (Mg / ml) in:ADCSUDHL4 WSUDLCL2 GRANTA519 BJABAntiCD79b-23 0.05387 0.9268 0.04957 0.003158Example 6MiceFemale 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 theAssociation for Assessment and Accreditation of Laboratory Animal Care International (AAALAC), which assures compliance with accepted standards for the care and use of laboratory animals. In Vivo Implantation and Tumour GrowthXenografts were initiated with BT474 human breast carcinomas maintained at CRDiscovery Services by serial subcutaneous transplantation into the SCID mice (see above). On the day of tumour implant, each test mouse received a 1 -mm3BT474 fragment implanted subcutaneously in the right flank, and tumour growth was monitored as the average size approached the target range of 100 to 150 mm3. Thirty-three days after tumour implantation, designated as Day 1 of the study, the animals were sorted into nine groups each consisting of ten mice with individual tumour volumes of 75 to 144 mm3and group mean tumour volumes of 1 1 1 to 1 12 mm3. Tumours were measured in two dimensions using calipers, and volume was calculated using the formula:Tumour Volume (mm3) = 0.5( w2x 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 mm3of tumour volume.Treatment 1Treatment began on Day 1 in groups of mice (n=10) with established subcutaneous BT474 tumors (75-196 mm3). Trastuzumab-23 was administered intravenously once on Day 1 (qd x 1 ) at two dosages (0.3 and 1 mg / kg). 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 800 mm3or 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. ADC regimens resulted in the maximum possible TGD, produced survival benefit that was statistically significantly different from vehicle-treated controls (P < 0.01 ) and could not be distinguished based on logrank analysis (P > 0.05). Differences within ADC treatments were only evident in the MTV on the final day and numbers and types of regression responses produced by each regimen.Trastuzumab-23 at 1 mg / kg produced four partial regressions (PRs). The results are illustrated in Figure 1.Treatment 2Treatment began on Day 1 in groups of mice (n = 9 or 10) with established subcutaneous BT474 tumors (108-196 mm3). Trastuzumab-40 was administered intravenously once on Day 1 (qd x 1 ) at two dosages (0.3 and 1 mg / kg). A vehicle-treated group served as the control group for efficacy analysis. Tumors were measured twice per week until the studywas ended on Day 62. Each mouse was euthanized when its tumor reached the endpoint volume of 1000 mm3or 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 52.9 days, establishing a maximum possible TGD of 9.1 days (17%) for the 62-day study. ADC treatment resulted in the maximum possible TGD, however only the 1 mg / kg treatment produced survival benefit that was statistically significantly different from vehicle- treated controls (P < 0.001 ).Trastuzumab-40, at 1 mg / kg produced four partial regressions (PRs) and one complete regression (CR) which remained a tumour-free survivor (TFS) at study end. The results are shown in Figure 2. Example 7Tumor Cell CultureHuman 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% CO2 and 95% air.In Vivo Implantation and Tumor GrowthThe NCI-N87 cells used for implantation were harvested during log phase growth and resuspended in phosphate buffered saline (PBS) containing 50% Matrigel™ (BDBiosciences). On the day of tumor implant, each test mouse (SCID mice as in Example 6) was injected subcutaneously in the right flank with 1 x 107cells (0.1 mL cell suspension),and tumor growth was monitored as the average size approached the target range of 100 to 150 mm3. Eleven days later, designated as Day 1 of the study, mice were sorted according to calculated tumor size into eleven groups each consisting of ten animals with individual tumor volumes ranging from 88 to 144 mm3and group mean tumor volumes of 1 19-121 mm3. Tumors were measured in two dimensions using calipers, and volume was calculated using the formula:Tumour Volume (mm3) = 0.5 {w2x 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 mm3of tumour volumeTreatment 1Treatment began on Day 1 in groups of mice (n=10) with established subcutaneous NCI- N87 tumors (88-144 mm3). Trastuzumab-23 was administered intravenously once on Day 1 (qd x 1 ) at two dosages (0.3 and 1 mg / kg). 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 81. Each mouse was euthanized when its tumor reached the endpoint volume of 800 mm3or 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 53.4 days, establishing a maximum possible TGD of 27.6 days (52%) for the 81 -day study. Trastuzumab-23 tested at 1 mg / kg produced survival benefit that was statistically significantly different from vehicle-treated controls (P < 0.001 ) and resulted in the maximum possible TGD. At 0.3 mg / kg, the median TTE was 80.5 days, which corresponds to TGD of 27.1 days (51 %).Trastuzumab-23, at 1 mg / kg produced one partial regressions (PR). The results are illustrated in Figure 3.Treatment 2Treatment began on Day 1 in groups of mice (n=10) with established subcutaneous NCI- N87 tumors (75-126 mm3). Trastuzumab-40 was administered intravenously once on Day 1 (qd x 1 ) at two dosages (0.3 and 1 mg / kg). 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 83. Each mouse was euthanized when its tumor reached the endpoint volume of 800 mm3or 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 44.9 days, establishing a maximum possible TGD of 38.1 days (85%) for the 83-day study. Trastuzumab-40 (0.3mg / kg) had a median TTE of 54.2 days corresponding to a TGD of 9.3 days (21 %). Trastuzumab-40 (1 mg / kg) had a median TTE of 61 .6 days corresponding to a TGD of 16.7 days (37%).The results are illustrated in Figure 4.Example 8 - Toxicity studies / Therapeutic IndexRat study:A single dose toxicity study was used to determine the maximum tolerated dose (MTD) and safety profile of Trastuzumab-23. 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-23).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.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 at the high dose, the maximum tolerated dose (MTD) in the rat after a single dose of Trastuzumab-23 was determined to be >7mg / kg, which was the highest dose level evaluated. Therapeutic IndexThe 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 23, the therapeutic index is the MTD of greater than 7 mg / kg divided by the MED which is less than 1 mg / kg (see Fig 3 at 28 days), giving a Therapeutic Index of greater than 7.Cynomolgus Macaque Study:A Single-Dose Toxicity study was performed in male Cynomolgus macaques monkeys (Macaca fascicularis) of Cambodian origin following a single intravenous (IV) bolus injection of ADC-SG3400. The study was conducted in 2 phases. In phase 1 , animals (n=1 ) were treated at dose levels of 1 , 3, or 6 mg / kg to determine the optimal dose level to explore in phase 2. Animals were dosed by slow bolus intravenous injection via the saphenous vein with vehicle control (25 mM Histidine, 200 mM Sucrose, pH 6.0) or test material (Trastuzumab-23). Based on observations of significant body weight loss at 6mg / kg, a dose level of 4.5 mg / kg was chosen for phase 2 of the study. In phase 2, animals (n=3) were administered a single dose of 4.5 mg / kg Trastuzumab-23 on Day 1 and necropsied on Days 71 or 72.Tolerability was determined based on toxicity end points, including body weight loss (>10%) and bone marrow suppression. There was no unscheduled mortality in any animal administered Trastuzumab-23. The major findings were body weight loss and bone marrow suppression at the highest tested dose of 6 mg / kg. Based on these data, and minimal signs of toxicity at next lowest dose, the MTD of Trastuzumab-23 in cynos was 4.5 mg / kg.All documents and other references mentioned above are herein incorporated by reference.

Claims

CLAIMS1 . A conjugate of formula I:wherein L is a Li and unit, D is a Drug Linker unit of formula II:whereineither:(a) R10and R11form a nitrogen-carbon double bond between the nitrogen and carbon atoms to which they are bound; or(b R10is OH, and R11is:p is an integer of from 1 to 20.

3. A conjugate according to claim 1 , wherein DLis DL-B:

4. A conjugate according to according to any one of claims 1 to 3, wherein the Ligand Unit is an antibody or an active fragment thereof.

5. The conjugate according to claim 4, wherein the antibody or antibody fragment is an antibody or antibody fragment for a tumour-associated antigen.

6. The conjugate according to claim 4 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) H LA-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.

7. The conjugate according to any one of claims 4 to 6 wherein the antibody or antibody fragment is a cysteine-engineered antibody.

8. The conjugate according to any one of claims 1 to 7 wherein p is an integer from 1 to 8.

9. The conjugate according to claim 8, wherein p is 1 , 2, 3, or 4.

10. A composition comprising a mixture of conjugates according to any one of claims 1 to 9, wherein the average p in the mixture of conjugate compounds is about 1 to about 8. 1 1 . The conjugate according to any one of claims 1 to 9, for use in therapy.

12. A pharmaceutical composition comprising the conjugate of any one of claims 1 to 9 a pharmaceutically acceptable diluent, carrier or excipient.

13. The conjugate according to any one of claims 1 to 9 or the pharmaceutical composition according to claim 12, for use in the treatment of a proliferative disease in a subject.

14. The conjugate for use according to claim 13, wherein the disease treated is cancer.

15. Use of a conjugate according to any one of claims 1 to 9 or a pharmaceutical according to claim 12 in a method of medical treatment.

16. A method of medical treatment comprising administering to a patient thepharmaceutical composition of claim 12.

17. The method of claim 16 wherein the method of medical treatment is for treating cancer.

18. The method of claim 17, wherein the patient is administered a chemotherapeutic agent, in combination with the conjugate.

19. Use of a conjugate according to any one of claims 1 to 9 in a method of manufacture of a medicament for the treatment of a proliferative disease.

20. 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 9 or a pharmaceutical composition according to claim 12.A com ound of formula IIIeither:(a) R10and R11form a nitrogen-carbon double bond between the nitrogen and carbon atoms to which they are bound; or(b) R10is OH, and R11is:

24. A method of synthesis of a conjugate according to any one of claims 1 to 9 comprising the step of conjugating a compound according to any one of claims 21 to 23 with a cell-binding agent.

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