WO2010017598A1 - Anti-il-12/il-23 antibodies - Google Patents
Anti-il-12/il-23 antibodies Download PDFInfo
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- WO2010017598A1 WO2010017598A1 PCT/AU2009/001047 AU2009001047W WO2010017598A1 WO 2010017598 A1 WO2010017598 A1 WO 2010017598A1 AU 2009001047 W AU2009001047 W AU 2009001047W WO 2010017598 A1 WO2010017598 A1 WO 2010017598A1
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Definitions
- the present invention relates to antibodies which bind to human IL- 12 and IL-23.
- Interleukin-12 also known as cytotoxic lymphocyte maturation factor or natural killer cell stimulatory factor
- Interleukin-12 is a 75-kDa heterodimeric protein. It consists of a p35 subunit which is comprised of a bundle of four alpha helicies that resembles the class I cytokines. The 11 amino acids C-terminal to C63 in p35 are termed the disulphide bond loop, as this region contains numerous residues that contact p40, the other subunit of IL- 12, including an interchain disulphide bond with C 177 in p40. The p40 subunit folds like the extracellular domain of other class I receptors, such as growth hormone receptor (GHR).
- GHR growth hormone receptor
- the p40 subunit has three domains labelled Dl, D2 and D3. Each domain is a ⁇ -sheet structure with the D2 domain containing the C177 interchain disulphide bond. There is also an N-linked glycosylation site (GlcNAc-GlcNAc-mannose, where GIcNAc is N-acetylglucosamine) on D2 (Yoon et al. 2000 Embo J 19 3530-41).
- Interleukin-23 was discovered more recently (2000) by searching sequence databases with a computationally derived profile of members of the interleukin-6 helical cytokine family. This search led to the discovery of a novel cytokine subunit which was named IL-23pl9 (pl9). This subunit was co-expressed with IL-12p40 leading to secretion of a heterodimeric protein called Interleukin-23 (IL-23). IL-23pl9 is thought to resemble IL-12p35 in that it contains a four helix bundle (Oppmann et al. 2000 Immunity 13 715-25).
- IL- 12R complex which consists of IL-12R ⁇ l(Chua et al. 1994 J Immunol 153 128-36) and IL-12R ⁇ 2 (Presky et al. 1996 Proc Natl Acad Sci U S A 93 14002-7).
- IL-23R complex which consists of IL-12R ⁇ l and IL-23R (Parham et al. 2002 J Immunol 168 5699-708).
- IL-12R ⁇ l binding to IL- 12 and IL-23 is mediated via the common p40 subunit. This was demonstrated using competition experiments in which a homodimer of the p40 subunit (p80) competed with IL-12 for binding to IL-12R ⁇ l. However p80 had no effect on the binding of IL-12 to IL-12R ⁇ 2 (Presky et al. 1996 Ann N Y Acad Sci 795 390-3).
- the signalling of the IL- 12R and IL-23R complex has been elucidated.
- the IL- 12R activates the Janus kinase (JAK) - signal transducer and activator of transcription (STAT) pathway of signal transduction.
- JK Janus kinase
- STAT activator of transcription
- the actual cellular effects of IL-12 are due mainly to STAT4 activation (Kaplan et al. 1996 Nature 382 174-7).
- STAT4 binding site on IL-12R ⁇ 2 indicating that this receptor is vital for signalling (Yao et al. 1999 Arch Biochem Biophys 368 147-55).
- IL-12 is secreted by activated inflammatory cells (monocytes, macrophages, neutrophils, microglia, dendritic cells). IL-12 has mainly been studied for its effects on lymphocytes, although it affects other types of cells also. During the inflammatory response, IL-12 induces NK cells and T cells to produce interferon- ⁇ (IFN- ⁇ ). Then IL-12, possibly in combination with IFN- ⁇ , induces T cells to differentiate into T H I cells.
- IFN- ⁇ interferon- ⁇
- IL-23 is secreted by activated human macrophages as well as dendritic cells (Verreck et al. 2004 Proc Natl Acad Sci U S A 101 4560-5). IL-23 predominantly acts on memory T-cells and has been postulated to promote autoimmune disease through the regulation of IL- 17A and IL- 17F as demonstrated in the ability of murine splenocytes to secrete IL- 17 in response to IL-23. In humans the IL-23/IL-17 pathway is present, and IL-23 has been shown to be an equally good inducer of IL-21, IL-22, IFN- ⁇ , TNF- ⁇ along with IL-17, all pro-inflammatory cytokines.
- IL-12 and IL-23 contain a common subunit, it has been difficult to attribute disease states solely to overproduction of one interleukin or the other.
- IL-23 dysregulation has been implicated in the following diseases: psoriasis (Lee et al. 2004 J Exp Med 199 125-30; Torti et al. 2007 J Am Acad Dermatol 57 1059-68), Crohn's disease (Neurath 2007 Nat Med 13 26-8) and Multiple Sclerosis (Cua et al. 2003 Nature 421 744-8) among other autoimmune diseases.
- IL-12p40 can be secreted as a monomer (IL-12p40) or as a homodimer (IL-12p80) which is two p40 subunits held together by a disulphide bond (Gillessen et al. 1995 Eur J Immunol 25 200-6). These p40 species are secreted at 50-fold excess compared with IL-12 in a murine shock model (Gillessen, Carvajal et al. 1995 Eur J Immunol 25 200-6) and 10-20 fold excess in human peripheral blood mononuclear cells (PBMCs) (D'Andrea et al. 1992 J Exp Med 176 1387-98).
- PBMCs peripheral blood mononuclear cells
- IL-12p80 can antagonise IL-12 activity in vitro 20-fold greater than that of IL-12p40 (Gillessen, Carvajal et al. 1995 Eur J Immunol 25 200-6). Recombinant IL-12p80 has been shown to bind to IL-12 ⁇ l (Wang et al. 1999 Eur J Immunol 29 2007-13).
- IL-12p40/p80 is considered an antagonist of the IL- 12/23 receptor complex because recombinant murine IL-12p80 (rmIL-12p80) has been shown to compete with IL- 12/23 binding to IL-12R ⁇ l in vivo and in vitro (Mattner et al. 1993 Eur J Immunol 23 2202-8; Gillessen, Carvajal et al. 1995 Eur J Immunol 25 200-6; Gately et al. 1996 Ann N Y Acad Sci 795 1-12). The homodimer has also been shown to prevent IL- 12 mediated shock in the murine model (Mattner et al. 1997 Infect Immun 65 4734-7).
- IL-12p40 impaired IL-23 induced cytokine production by competitive binding to the IL-12R ⁇ l (Shimozato et al. 2006 Immunology 117 22-8). More recently IL-12p40 or IL-12p80 has been implicated in other biological roles. One of the earliest established activities of IL-12p80 is as a chemoattractant for macrophages.
- IL-12R ⁇ l deficient macrophages but not IL-12R ⁇ 2 or IL-12p35 deficient macrophages, have reduced chemoattractive responses to rmIL-12p80, indicating that IL-12R ⁇ l can mediate responses to IL-12p80 in the absence of IL-12R ⁇ 2 and that IL-12p80 activity is independent of IL- 12 (Russell et al. 2003 J Immunol 171 6866-74).
- IL-12p80 can also act as an inducer of dendritic cell (DC) migration. IL-12p40-deficient DCs are unable to migrate from the lungs to the lymph nodes in response to mycobacteria.
- DC dendritic cell
- IL- 12 and IL-23 have been implicated in a variety of disorders several therapeutic strategies have been designed to inhibit IL- 12 and/or IL-23 activity.
- Some of the earliest described antibodies were murine monoclonal antibodies that were secreted by hybridomas of mice immunised with IL- 12 (Strober et al. PCT Publication No. WO
- HAMA human anti-mouse antibody
- the first class of antibodies are those that specifically interact with IL-12p40 present in IL-12 and IL-23, along with the IL-12p40 monomer and the IL-12p80 homodimer (FIGURE 1.1).
- the second class of antibodies are those that specifically interact with IL-12p35 (as exemplified by antibody G161-566 in Devergne et al. 2001 Am J Pathol 159 1763-76; FIGURE 1.2).
- the third class of antibodies are those that specifically interact with IL-12 but not with IL-23, IL-12p35, and IL-12p40 (as exemplified by antibody 20C2 in D'Andrea, Rengaraju et al. 1992 J Exp Med 176 1387-98; FIGURE 1.3).
- the fourth class of antibodies are those that specifically interact with IL-23pl9 (as exemplified by Presta et al. WO 2007/027714; FIGURE 1.4).
- the fifth class of antibodies are those that specifically interact with IL-23p40 but not with IL-12p40, exploiting sequence on the IL-12p40 subunit that is exposed on IL-23 but masked by the IL-12p35 subunit in IL- 12 (as exemplified by Benson et al. U.S. Pat. No. 7,247,711; FIGURE 1.5).
- This current invention describes novel forms of the first class of antibodies that specifically interact with IL-12p40, IL-12p80, IL-12 and IL-23 (FIGURE 1.1).
- the present invention describes antibodies that inhibit the IL- 12/23 receptor - ligand complex via a novel mechanism of action (FIGURE 2.3).
- novel mechanism of action involves the selective neutralisation of the IL-12/IL-12R ⁇ 2 interaction and the IL-23/IL-23R interaction. They differ from antibodies described previously (see above) in that they do not neutralise the binding of IL- 12/23 to IL-12R ⁇ l.
- These antibodies are also novel in that they do not inhibit IL-12p40/p80 binding to IL-12R ⁇ l and thus do not inhibit the role IL-12p40/80 plays in host defense, thereby potentially increasing the safety profile of these antibodies relative to other IL- 12/23 antibodies.
- Such antibodies with novel mechanisms of actions could lead to improvement in the treatment of diseases associated with IL- 12/23 but with reduced safety concerns. Additionally, these antibodies could have improved efficacy since they do not inhibit the natural antagonists of IL- 12 and IL-23, IL-12p40 or IL-12p80. This would allow both the antibody and IL-12p40 or IL-12p80 to function as antagonists thereby increasing the level of inhibition above that of administering the antibody alone.
- the present invention provides an antibody comprising an antigen binding domain which binds to human IL- 12 and human IL-23, wherein the antibody binds human IL-12p40 existing as a monomer (human IL-12p40) and as a homodimer (human IL-12p80) and wherein the antibody inhibits the binding of human IL- 12 to human IL-12R ⁇ 2 and human IL- 23 to human IL-23R but does not inhibit the binding of human IL- 12 or human IL-23 or human IL-12p40 or human IL-12p80 to human IL-12R ⁇ l.
- the present invention further provides a method for treating or reducing the symptoms of at least one IL- 12 and/or IL-23 disease in a cell, tissue, organ, animal or patient comprising the use of the antibody of the present invention or a specified portion or variant thereof.
- the antibody of the present invention may also be used in detecting or measuring the presence of IL- 12, IL-23, IL-12p40 or IL-12p80 in a sample.
- the method involves addition of the antibody to the sample and measuring the binding of the antibody to IL- 12, IL-23, IL- 12p40 or IL-12p80 present in the sample.
- FIGURE 1 The different classes of Anti-IL- 12/23 antibodies.
- FIGURE 1.1 An antibody that binds to the p40 subunit of IL- 12, IL-23, IL- 12p40 and IL- 12p80;
- FIGURE 1.2 An antibody that binds to p35 subunit of IL- 12;
- FIGURE 1.3 An antibody that binds to the p35 and p40 subunit of IL- 12 as a heterodimer;
- FIGURE 1.4 An antibody that binds to the pl9 subunit of IL-23;
- FIGURE 1.5 An antibody that binds to p40 present in IL-23, IL-12p40 and IL-12p80 but not IL- 12.
- FIGURE 2 IL- 12/23 receptor interactions.
- IL- 12 binds to IL- 12R ⁇ 1 and IL- 12R ⁇ 2.
- IL-23 binds to IL-12R ⁇ l and IL-23R.
- IL-12p40 binds to IL-12R ⁇ l.
- IL-12p80 binds to IL- 12R ⁇ l.
- FIGURE 2.1) Subunits of IL-12 and IL-23.
- FIGURE 3 PMA204 and Antibody 1 bind to IL-12 (A), IL-23 (B), IL-12p40 (C) and IL-12p80 (D) in a dose dependent manner as measured by ELISA.
- FIGURE 4 PMA204 and Antibody 1 neutralize the binding of IL-12 to IL- 12R ⁇ 2 (A) and IL-23 to IL-23R (B).
- FIGURE 5 PMA204 and Antibody 1 do not inhibit the binding of IL-12 to IL-12R ⁇ l (A) and IL-12p80 to IL-12R ⁇ l (B).
- FIGURE 6 PMA204 and Antibody 1 do not inhibit the binding of IL- 12p40 to IL-12R ⁇ l (A) and IL-23 to IL-12R ⁇ l (B).
- FIGURE 7 Antibody 1 does not inhibit the binding of IL- 12p40 (A), IL-12 (B), IL- 23 (C) to an IL-12R ⁇ l stably transfected Jurkat cell line.
- the positive control Antibody 202.1 inhibits the binding of IL-12p40, IL-12 and IL-23 to this cell line in a dose dependant manner.
- FIGURE 8 Antibody 1 binds to IL-12p40 (A), IL-12 (B) and IL-23 (C) bound to IL- 12R ⁇ l stably transfected Jurkat cell lines, forming a complex. Positive control antibody 202.1 was not capable of forming such a complex.
- FIGURE 9 ELISA data showing binding of various antibodies to IL-12 and IL-23.
- FIGURE 10 SDS-PAGE gel of Antibodies 1, 3, 4, 7 and comparator antibody, demonstrating different band patterns.
- FIGURE 11 PMA204, Antibody 1 , Antibody 50, Antibody 68 and Antibody 80 demonstrating inhibition of IL-12 induced IFN- ⁇ release by NK-92 cells.
- FIGURE 12 ELISA data showing binding of various antibodies to IL-12 and IL-23
- FIGURE 13 ELISA data showing binding of various antibodies to IL-12 and IL-23
- FIGURE 14 Antibody 80 and Antibody 136 demonstrate inhibition of IL-23 induced IL- 17 secretion by murine splenocytes.
- FIGURE 15 ELISA data showing binding of various antibodies to IL- 12 and IL-23.
- FIGURE 16 ELISA data showing binding of various antibodies to IL- 12 and IL-23.
- FIGURE 17 Antibody 80 and Antibody 136 demonstrate inhibition of IL- 12 induced IFN- ⁇ release by human PBMCs.
- FIGURE 18 ELISA data showing binding of various antibodies to IL- 12 and IL-23.
- FIGURE 19 ELISA data showing binding of various antibodies to IL- 12 and IL-23.
- FIGURE 20 ELISA data showing binding of various antibodies to IL- 12 and IL-23.
- FIGURE 21 Competition SPR experiments demonstrating that Antibody 136 and PMA204 compete for binding to IL- 12 (A) and IL-23 (B).
- FIGURE 22 Competition SPR experiments demonstrating that Antibody 136 and PMA202 do not compete for binding to IL- 12 (A) and IL-23 (B).
- FIGURE 23 Competition ELISA experiments demonstrating that PMA204 and Antibody 202.1 do not compete for binding to IL- 12 or IL-23. PMA204 and Antibody 136 compete for binding to IL- 12 and IL-23.
- FIGURE 24 Antibody 80 and Antibody 136 neutralize the binding of IL- 12 to IL- 12R ⁇ 2 (A) and IL-23 to IL-23R (B), compared to Antibody 202.1 which demonstrates no inhibition at the highest concentration of antibody tested.
- FIGURE 25 PMA204 and Antibody 1 do not neutralize the binding of IL- 12 to IL- 12R ⁇ l (A) and IL-23 to IL-12R ⁇ l (B).
- Antibody 202.1 displayed dose dependant inhibition of IL-12 binding to IL-12R ⁇ l (A) and IL-23 binding to IL-12R ⁇ l (B).
- FIGURE 26 Various humanized and affinity matured antibodies inhibited IL-23 induced IL- 17 release from murine splenocytes. Shown are two groups of affinity matured humanized lead antibodies, those based on Antibody 80 (A) and those based on Antibody 136 (B).
- FIGURE 27 After 6 days of IL-23 intradermal administration to mice they develop skin inflammation resembling psoriasis. A) Administration of an isotype control did not prevent skin inflammation, however Antibody 80 and Antibody 136 reduced inflammation in this model as evidenced by the lower clinical score. B) At the histological level, epidermal thickening occurs after IL-23 intradermal administration over 6 days. Treatment with Antibody 80 and Antibody 136 ameliorated this epidermal thickening, but treatment with the isotype control antibody did not.
- FIGURE 28 Various humanized and affinity matured antibodies inhibited chimeric IL- 12 induced IFN- ⁇ release from murine splenocytes. Shown are two groups of affinity matured humanized lead antibodies, those based on Antibody 80 (A) and those based on Antibody 136 (B).
- FIGURE 29 Mice given repeated injections of chimeric IL- 12 have elevated serum levels of IFN- ⁇ . When treated with Antibody 80 or Antibody 136 the levels of serum IFN- ⁇ decreased relative to treatment with an isotype control antibody.
- FIGURE 30 (A) Antibody 80 is capable of detecting recombinant IL-23 in a sandwich ELISA. (B) Antibody 80 is capable of detecting native produced IL-23 produced by SAC stimulated PBMCs, in a sandwich ELISA.
- FIGURE 31 Antibody 80 bound strongly to IL-23 WT protein but had reduced binding to IL-23 mutants D265A and R266A by ELISA.
- the present inventors raised a panel of antibodies against IL- 12.
- screening these antibodies it was surprisingly found that a particular subset of antibodies bound human IL- 12 and IL-23 and inhibited the binding of IL- 12 to IL-12R ⁇ 2 and IL-23 to IL-23R but did not inhibit the binding of IL- 12 or IL-23 or IL-12p40 or IL-12p80 to IL-12R ⁇ l.
- the activity of IL- 12 and IL-23 was therefore able to be modified in a manner which had not been previously achievable.
- the present invention provides an antibody comprising an antigen binding domain which binds to human IL- 12 and human IL-23, wherein the antibody binds human IL-12p40 existing as a monomer (human IL-12p40) and as a homodimer (human IL-12p80) and wherein the antibody inhibits the binding of human IL- 12 to human IL-12R ⁇ 2 and human IL-23 to human IL-23R but does not inhibit the binding of human IL- 12 or human IL-23 or human IL- 12p40 or human IL- 12p80 to human IL- 12R ⁇ 1.
- the antibody competes for binding to human IL- 12 and/or human IL-23 with an antibody comprising a heavy chain variable region having the sequence of PMA204 (SEQ ID NO. 6) and/or an antibody comprising a light chain variable region having the sequence of PMA204 (SEQ ID NO. 7).
- test antibody when used at the same concentration as PMA204 reduces the binding of PMA204 to IL- 12, IL-23 or IL-12p40 by at least 10% as tested by ELISA.
- the present invention provides an antibody or variant thereof which binds IL- 12p40 present in IL- 12 and IL-23 having a sequence listed as SEQ ID No 1 and given below:
- the epitope bound by the antibody is within the sequence sequence VQVQGKSKREKKDRVFTDKTSATVICRKNASISV (SEQ ID NO: 65).
- the antibody binds to human IL-12p40 (SEQ ID No. 1) at Asp 265.
- the present invention provides an antibody comprising an antigen binding domain which binds to human IL-23 (SEQ ID NO: 66), wherein the level of binding of the antibody to human IL-23 (SEQ ID NO: 66) is greater than the level of binding of the antibody to mutant IL-23 D265A (SEQ ID NO: 75).
- This antibody can also bind human IL-12p40 existing as a monomer (human IL-12p40) and as a homodimer (human IL-12p80) and inhibits the binding of human IL- 12 to human IL-12R ⁇ 2 and human IL-23 to human IL-23R but does not inhibit the binding of human IL- 12 or human IL-23 or human IL-12p40 or human IL-12p80 to human IL-12R ⁇ l.
- the present invention provides antibodies that could be used to treat at least one IL- 12 and/or one IL-23 related condition by selectively neutralising IL- 12 binding to IL-12R ⁇ 2 and IL-23 binding to IL-23R.
- the present invention provides an antibody which comprises 3 heavy chain CDR sequences selected from:
- X 3 C, A, N, D, E, Q, G, H, I, L, P or V.
- the present invention provides an antibody which comprises 3 light chain CDR sequences selected from:
- the present invention provides an antibody which comprises 3 heavy chain CDR sequences selected from:
- X 3 C, A, N, D, E, Q, G, H, I, L, P or V.
- the present invention provides an antibody which comprises of an immunoglobulin heavy variable region consisting of one of the following sequences:
- SEQ ID NO: 6 SEQ ID NO: 62, SEQ ID NO: 114, SEQ ID NO: 142, SEQ ID NO: 28, SEQ ID NO: 87, SEQ ID NO: 115, SEQ ID NO: 143, SEQ ID NO: 29, SEQ ID NO: 88, SEQ ID NO: 116, SEQ ID NO: 144, SEQ ID NO: 30, SEQ ID NO: 90, SEQ ID NO: 117, SEQ ID NO: 145, SEQ ID NO: 31, SEQ ID NO: 91, SEQ ID NO: 118, SEQ ID NO: 146, SEQ ID NO: 33, SEQ ID NO: 92, SEQ ID NO: 119, SEQ ID NO: 147, SEQ ID NO: 34, SEQ ID NO: 93, SEQ ID NO: 120, SEQ ID NO: 148, SEQ ID NO: 35, SEQ ID NO: 94, SEQ ID NO: 122, SEQ ID NO: 149, SEQ ID NO: 36, SEQ ID NO: 95
- the present invention provides an antibody which comprises of an immunoglobulin light variable region consisting of one of the following sequences:
- SEQ ID NO: 7 SEQ ID NO: 169, SEQ ID NO: 181, SEQ ID NO: 193, SEQ ID NO: 32, SEQ ID NO: 170, SEQ ID NO: 182, SEQ ID NO: 194, SEQ ID NO: 37, SEQ ID NO: 171, SEQ ID NO: 183, SEQ ID NO: 195, SEQ ID NO: 42, SEQ ID NO: 172, SEQ ID NO: 184, SEQ ID NO: 196, SEQ ID NO: 46, SEQ ID NO: 173, SEQ ID NO: 185, SEQ ID NO: 197, SEQ ID NO: 47, SEQ ID NO: 174, SEQ ID NO: 186, SEQ ID NO: 198, SEQ ID NO: 48, SEQ ID NO: 175, SEQ ID NO: 187, SEQ ID NO: 199, SEQ ID NO: 49, SEQ ID NO: 176, SEQ ID NO: 188, SEQ ID NO: 200, SEQ ID NO: 50, SEQ ID NO: 177,
- the present invention provides an antibody which further comprises human heavy chain acceptor framework.
- acceptor framework comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 202, SEQ ID NO: 205, SEQ ID NO: 208, SEQ ID NO: 203, SEQ ID NO: 206, SEQ ID NO: 209, SEQ ID NO: 204 and SEQ ID NO: 207.
- the present invention provides an antibody which further comprises human light chain acceptor framework.
- acceptor framework comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 210, SEQ ID NO: 213, SEQ ID NO: 216, SEQ ID NO: 211, SEQ ID NO: 214, SEQ ID NO: 212 and SEQ ID NO: 215.
- the present invention provides an antibody which comprises two immunoglobulin variable regions, wherein the said two immunoglobulin variable regions are selected from a group consisting of:
- SEQ ID NO: 44 & SEQ ID NO: 52 SEQ ID NO: 119 & SEQ ID NO: 179 SEQ ID NO: 45 & SEQID NO: 179 SEQIDNO: 119 & SEQ ID NO: 51
- the present invention provides an antibody wherein said human acceptor framework comprises at least one Framework Region amino acid substitution at a key residue, said key residue selected from the group consisting of a residue adjacent to a CDR, a glycosylation site residue, a rare residue, a residue capable of interacting with a p40 subunit of human IL- 12, a residue capable of interacting with a CDR, a canonical residue, a contact residue between heavy chain variable region and light chain variable region; a residue within a Vernier zone and a residue in a region that overlaps between a Chothia-defined VH domain CDRl and a Kabat-defined first heavy chain framework.
- the said human acceptor framework comprises at least one Framework Region amino acid substitution, wherein the amino acid sequence of the framework is at least 65% identical to the sequence of said human acceptor framework and comprises at least 70 amino acid residues identical to said human acceptor framework.
- the present invention provides an antibody that is a consensus human VH domain. Additionally, the present invention provides for an antibody that is a consensus human VL domain. [0073] The present invention provides an antibody wherein said human acceptor framework comprises at least one Framework Region amino acid substitution, wherein the amino acid sequence of the framework is at least 65% identical to the sequence of said human acceptor framework and comprises at least 70 amino acid residues identical to said human acceptor framework.
- the present invention describes an antibody in which the antibody contains a human or non-human primate heavy chain immunoglobulin constant region selected from a group consisting of IgGl, IgG2, IgG3, IgG4, IgM, IgE and IgA.
- the present invention describes an antibody in which the antibody contains a human or non-human primate light chain immunoglobulin constant region selected from a group consisting of kappa or lambda.
- the present invention also provides a method of producing the antibody of the present invention the method comprising
- human IL-12p40 and as a homodimer (human IL-12p80) and which inhibit the binding of human IL- 12 to human IL-12R ⁇ 2 and human IL-23 to human IL-23R but do not inhibit the binding of human IL- 12 or human IL-23 or human IL-12p40 or human IL-12p80 to human IL-12R ⁇ l.
- This method may also comprise at step (ii) selecting antibodies which also bind a peptide having the sequence VQVQGKSKREKKDRVFTDKTSATVICRKNASISV (SEQ ID NO. 65).
- the present invention also provides another method of producing the antibody of the present invention the method comprising
- VQVQGKSKREKKDRVFTDKTSATVICRKNASISV (SEQ ID NO. 65) to obtain a first panel of antibodies; (ii) selecting from the first panel antibodies which bind to human IL- 12 and human IL-23 to form a second panel of antibodies; and
- human IL-12p40 and as a homodimer (human IL-12p80) and which inhibit the binding of human IL- 12 to human IL- 12R ⁇ 2 and human IL-23 to human IL-23R but do not inhibit the binding of human IL- 12 or human IL-23 or human IL-12p40 or human IL-12p80 to human IL-12R ⁇ l.
- the present invention also provides a further method of producing the antibody of the present invention the method comprising
- the present invention provides a nucleic acid molecule which encodes a VH domain of the present invention. It is preferred that the nucleic acid molecule has a sequence selected from:
- the present invention provides a nucleic acid molecule which encodes a VL domain of the present invention. It is preferred that the nucleic acid molecule has a sequence selected from:
- the present invention also provides a method of treating a disease in a subject comprising administering to the subject an antibody of the present invention wherein the disease is selected from the group consisting of rheumatoid arthritis, osteoarthritis, reactive arthritis, psoriatic arthritis, bone loss, airways hypersensitivity, chronic obstructive pulmonary disease, a demyelinating disorder, psoriasis, multiple sclerosis, dermal hypersensitivity, acute and chronic transplant rejection, allograft rejection, graft-versus host disease, systemic sclerosis, systemic lupus erythematosus, an autoimmune inflammatory bowel disease, a urological inflammatory disorder, a cardiovascular disease, a vasculitis, a periodic fever, a glucose metabolism disorder, a pulmonary disease, a cancer, peridontitis, hepatic stromal keratitis, an allergy, inflammatory pain, a spondyloarthropathy, septicaemia, septic or
- the present invention further provides at least one antibody, specified portion or variant thereof in a method or composition, when administered in a therapeutically effective amount, for modulation, for treating or reducing the symptoms of at least one IL- 12 and/or IL- 23 disease in a cell, tissue, organ, animal or patient and/or, as needed in many different conditions, such as but not limited to, prior to, subsequent to, or during a related disease or treatment condition, as known in the art and/or as described herein.
- the present invention further provides at least one antibody, specified portion or variant thereof in a method or composition, when administered in a therapeutically effective amount, for modulation, for treating or reducing the symptoms of immune, neurological and related disorders, such as, but not limited to, arthritis, osteoarthritis, rheumatoid arthritis, juvenile chronic arthritis, septic arthritis, Lyme arthritis, psoriatic arthritis, reactive arthritis, spondyloarthropathy, systemic lupus erythematosus, Crohn's disease, ulcerative colitis, inflammatory bowel disease, insulin dependent diabetes mellitus, thyroiditis, asthma, allergic diseases, psoriasis, dermatitis scleroderma, graft versus host disease, organ transplant rejection, acute or chronic immune disease associated with organ transplantation, sarcoidosis, atherosclerosis, disseminated intravascular coagulation, Kawasaki's disease, Grave's disease, nephrotic syndrome, chronic fatigue syndrome, Wegener's
- an anti-IL-12/IL-23 antibody which has been affinity matured.
- Mutagenesis is often performed at the DNA level, for example by error prone PCR (Thie 2009), by gene shuffling (Kolkman 2001), by use of mutagenic chemicals or irradiation, by use of 'mutator' strains with error prone replication machinery (Greener 1996) or by somatic hypermutation approaches that harness natural affinity maturation machinery (Peled 2008). Mutagenesis can also be performed at the RNA level, for example by use of Q ⁇ replicase (Kopsidas 2006).
- Library-based methods allowing screening for improved variant proteins can be based on various display technologies such as phage, yeast, ribosome, bacterial or mammalian cells, and are well known in the art (Benhar 2007).
- Affinity maturation can be achieved by more directed/predictive methods for example by site-directed mutagenesis or gene synthesis guided by findings from 3D protein modeling (see for example Queen 1989; or US Pat. Nos 6,180,370; or 5,225,539).
- the present invention provides a method for producing an antigen binding domain that binds human IL-12p40, the method comprising
- HCDR2 and HCDR3 are a set of CDRs defined above, a VH domain which is an amino acid sequence variant of the parent VH domain, and optionally combining the VH domain thus provided with one or more VL domains to provide one or more VH/VL combinations; and
- VH domain which is an amino acid sequence variant of the parent
- the parent VH domain has the VH domain amino acid sequence shown in SEQ ID NO: 6, SEQ ID NO: 62, SEQ ID NO: 114, SEQ ID NO: 142, SEQ ID NO: 28, SEQ ID NO: 87, SEQ ID NO: 115, SEQ ID NO: 143, SEQ ID NO: 29, SEQ ID NO: 88, SEQ ID NO: 116, SEQ ID NO: 144, SEQ ID NO: 30, SEQ ID NO: 90, SEQ ID NO: 117, SEQ ID NO: 145, SEQ ID NO: 31, SEQ ID NO: 91, SEQ ID NO: 118, SEQ ID NO: 146, SEQ ID NO: 33, SEQ ID NO: 92, SEQ ID NO: 119, SEQ ID NO: 147, SEQ ID NO: 34, SEQ ID NO: 93, SEQ ID NO: 120, SEQ ID NO: 148, SEQ ID NO: 35, SEQ ID NO: 94, SEQ ID NO: 122
- VH domain which is an amino acid sequence variant of the parent VH domain may be provided by CDR mutagenesis.
- the one or more VL domains are provided by way of addition, deletion, substitution or insertion of one or more amino acids in the amino acid sequence of a parent VL domain comprising LCDRl, LCDR2 and LCDR3, wherein the parent VL domain LCDRl, LCDR2 and LCDR3 are a VL set of CDRs as defined above, producing one or more VL domains each of which is an amino acid sequence variant of the parent VL domain.
- the parent VL domain has the VL domain amino acid sequence shown in SEQ ID NO: 7, SEQ ID NO: 169, SEQ ID NO: 181, SEQ ID NO: 193, SEQ ID NO: 32, SEQ ID NO: 170, SEQ ID NO: 182, SEQ ID NO: 194, SEQ ID NO: 37, SEQ ID NO: 171, SEQ ID NO: 183, SEQ ID NO: 195, SEQ ID NO: 42, SEQ ID NO: 172, SEQ ID NO: 184, SEQ ID NO: 196, SEQ ID NO: 46, SEQ ID NO: 173, SEQ ID NO: 185, SEQ ID NO: 197, SEQ ID NO: 47, SEQ ID NO: 174, SEQ ID NO: 186, SEQ ID NO: 198, SEQ ID NO: 48, SEQ ID NO: 175, SEQ ID NO: 187, SEQ ID NO: 199, SEQ ID NO: 49, SEQ ID NO: 176, SEQ ID NO: 188,
- TheVL domain which is an amino acid sequence variant of the parent VL domain may be provided by CDR mutagenesis.
- the antibody antigen-binding domain may be provided as a component of an IgG, scFv or Fab antibody molecule.
- the present invention also provides a method for producing an antigen binding domain that binds human IL-12p40 which method comprises: a. providing starting nucleic acid encoding a VH domain or a starting repertoire of nucleic acids each encoding a VH domain, wherein the VH domain is selected from the group consisting of SEQ ID NO: 6, SEQ ID NO: 62, SEQ ID NO: 114, SEQ ID NO: 142, SEQ ID NO: 28, SEQ ID NO: 87, SEQ ID NO: 115, SEQ ID NO: 143, SEQ ID NO: 29, SEQ ID NO: 88, SEQ ID NO: 116,
- SEQ ID NO: 95 SEQ ID NO: 124, SEQ ID NO: 150, SEQ ID NO: 38, SEQ ID NO: 96, SEQ ID NO: 125, SEQ ID NO: 151, SEQ ID NO: 39, SEQ ID NO: 97, SEQ ID NO: 126, SEQ ID NO: 152, SEQ ID NO: 40, SEQ ID NO: 99, SEQ ID NO: 127, SEQ ID NO: 153, SEQ ID NO: 41, SEQ ID NO: 100, SEQ ID NO: 128, SEQ ID NO: 154, SEQ ID NO: 42, SEQ ID NO: 101, SEQ
- SEQ ID NO: 160 SEQ ID NO: 55, SEQ ID NO: 107, SEQ ID NO: 135, SEQ ID NO: 161, SEQ ID NO: 56, SEQ ID NO: 108, SEQ ID NO: 136, SEQ ID NO: 162, SEQ ID NO: 57, SEQ ID NO: 109, SEQ ID NO: 137, SEQ ID NO: 163, SEQ ID NO: 58, SEQ ID NO: 110, SEQ ID NO: 138, SEQ ID NO: 164, SEQ ID NO: 59, SEQ ID NO: 111, SEQ ID NO: 139, SEQ ID NO: 165, SEQ ID NO:
- starting nucleic acid or starting repertoire with donor nucleic acid or donor nucleic acids encoding or produced by mutation of the amino acid sequence, such that said donor nucleic acid is or donor nucleic acids are inserted into the VH domain in the starting nucleic acid or starting repertoire, so as to provide a product repertoire of nucleic acids encoding VH domains; expressing the nucleic acids of said product repertoire to produce product VH domains;
- VH domains optionally combining said product VH domains with one or more VL domains; d. selecting a antigen binding domain for human IL-12p40,
- the antigen binding domain comprises a product VH domain and optionally a VL domain
- the present invention also provides a method for producing an antigen binding domain that binds human IL-12p40 which method comprises:
- VL domain is selected from the group consisting of SEQ ID NO: 7, SEQ ID NO: 169, SEQ ID NO: 181, SEQ ID NO: 193, SEQ ID NO: 32, SEQ ID NO: 170, SEQ ID NO: 182, SEQ ID NO: 194, SEQ ID NO: 37, SEQ ID NO: 171, SEQ ID NO:
- SEQ ID NO: 195 SEQ ID NO: 42, SEQ ID NO: 172, SEQ ID NO: 184, SEQ ID NO: 196, SEQ ID NO: 46, SEQ ID NO: 173, SEQ ID NO: 185, SEQ ID NO: 197, SEQ ID NO: 47, SEQ ID NO: 174, SEQ ID NO: 186, SEQ ID NO: 198, SEQ ID NO: 48, SEQ ID NO: 175, SEQ ID NO: 187, SEQ ID NO: 199, SEQ ID NO: 49, SEQ ID NO: 176, SEQ ID NO: 188, SEQ ID NO: 200,
- SEQ ID NO: 50 SEQ ID NO: 177, SEQ ID NO: 189, SEQ ID NO: 201, SEQ ID NO: 51, SEQ ID NO: 178, SEQ ID NO: 190, SEQ ID NO: 52, SEQ ID NO: 179 and SEQ ID NO: 192
- starting nucleic acid or starting repertoire with donor nucleic acid or donor nucleic acids encoding or produced by mutation of the amino acid sequence, such that said donor nucleic acid is or donor nucleic acids are inserted into the VL domain in the starting nucleic acid or starting repertoire, so as to provide a product repertoire of nucleic acids encoding VL domains; expressing the nucleic acids of said product repertoire to produce product VL domains;
- the donor nucleic acids may be produced by mutation of said HCDRI and/or HCDR2 and/or HCDR3.
- the donor nucleic acid may also be provided by random mutation of nucleic acid.
- the antibody of the present invention may be selected from a wide range of antibody molecules well known in the art.
- the antibody is selected from a group consisting of an immunoglobulin molecule, a monoclonal antibody (mAb), a chimeric antibody, a CDR-grafted antibody, a humanised antibody, a synhumanised antibody, a primatised antibody, a domain antibody, a camelid derived antibody fragment, a Fab, a Fab', a F(ab') 2 , a Fv, a scFv, a disulphide linked Fv, a diabody, a multivalent antibody, a dual specific antibody, a bispecific antibody, an immunoglobulin constant region binding domain and a protein scaffold into which antigen binding domains have been grafted (as exemplified in Qiu et al.
- the present invention also extends to antibody compositions,nucleic acids encoding the antibody and complementary nucleic acids, vectors, host cells, compositions, formulations, devices, transgenic animals, transgenic plants and methods of making and using thereof, as described and enabled herein, in combination with what is known in the art.
- the present invention provides isolated nucleic acid molecules comprising, complementary or hybridising to a polynucleotide encoding specific antibodies or variants thereof, comprising at least one specified sequence, domain, portion or variant thereof.
- the present invention provides recombinant vectors comprising said antibody derived nucleic acid molecules, host cells containing such nucleic acids and/or recombinant vectors, as well as methods of making and/or using such antibody nucleic acids, vectors and/or host cells.
- the present invention also provides at least one composition
- a composition comprising (a) an isolated antibody, specified portion or variant thereof encoding nucleic acid and/or antibody as described herein; and (b) a suitable carrier or diluent.
- the carrier or diluent can optionally be pharmaceutically acceptable, according to known methods.
- the composition can optionally further comprise at least one other compound, protein or composition.
- the present invention also provides at least one method for expressing the antibodies or variants thereof in a host cell, comprising culturing a host cell as described herein and/or as known in the art under conditions in which the antibody or variant thereof is expressed in recoverable amounts.
- the present invention provides at least one antibody encoding nucleic acid, comprising a nucleic acid that hybridises under stringent conditions, or has at least 95% identity, to a nucleic acid encoding an antibody.
- the invention further provides an isolated antibody encoded by such nucleic acid.
- the invention further provides an antibody vector, comprising such a nucleic acid, wherein the vector optionally further comprises at least one promoter selected from the group consisting of a late or early SV40 promoter, a CMV promoter, an HSV tk promoter, a pgk promoter, a human immunoglobulin promoter, and an EF- l ⁇ promoter.
- Such a vector can optionally further comprise at least one selection gene or portion thereof selected from at least one of methotrexate (MTX), dihydrofolate reductase (DHFR), green fluorescent protein (GFP), neomycin (G418), or glutamine synthetase (GS).
- the invention further comprises a mammalian host cell comprising such an isolated nucleic acid, optionally, wherein said host is at least one selected from COS-I, COS-7, HEK293, BHK21, CHO, BSC-I, HwpG2, PerCP, 653, SP2/0, 293, HeLa, myeloma, or lymphoma cells, or any derivative, immortalised or transformed cell thereof.
- the invention also provides at least one method for producing at least one antibody composition, comprising at least one antibody and a carrier or diluent, optionally, further wherein said carrier or diluent is pharmaceutically acceptable, and/or further comprising at least one compound or protein selected from a TNF antagonist, an antirheumatic, a muscle relaxant, a narcotic, a non-steroid anti-inflammatory drug (NSAID), an analgesic, an anesthetic, a sedative, a local anesthetic, a neuromuscular blocker, an antimicrobial, an antipsoriatic, a corticosteriod, an anabolic steroid, an IL-23 agent, an IL- 12 agent, a mineral, a nutritional, a thyroid agent, a vitamin, a calcium related hormone, an antidiarrheal, an antitussive, an antiemetic, an antiulcer, a laxative, an anticoagulant, an erythropoie
- the present invention also provides at least one method for treating an IL- 12/23 condition in a cell, tissue, organ or animal, comprising contacting or administering a immune related- or infectious related-condition modulating effective amount of at least one antibody with, or to, said cell, tissue, organ or animal, optionally, wherein said animal is a primate, optionally a monkey or a human.
- the method can further optionally include wherein said effective amount is about 0.001-100 mg/kilogram of said cells, tissue, organ or animal.
- Such a method can further include wherein said contacting or said administrating is by at least one mode selected from intravenous, intramuscular, bolus, intraperitoneal, subcutaneous, respiratory, inhalation, topical, nasal, vaginal, rectal, buccal, sublingual, intranasal, subdermal, and transdermal.
- Such a method can further comprise administering, prior, concurrently or after said contacting or administering, at least one composition comprising a therapeutically effective amount of at least one compound or protein selected from at least one of a TNF antagonist, an antirheumatic, a muscle relaxant, a narcotic, a non-steroid anti- inflammatory drug (NSAID), an analgesic, an anesthetic, a sedative, a local anesthetic, a neuromuscular blocker, an antimicrobial, an antipsoriatic, a corticosteriod, an anabolic steroid, an IL-23 agent, and IL- 12 agent, a mineral, a nutritional, a thyroid agent, a vitamin, a calcium related hormone, an antidiarrheal, an antitussive, an antiemetic, an antiulcer, a laxative, an anticoagulant, an erythropoietin, a filgrastim, a sargramostim, an
- the invention also includes at least one formulation comprising at least one antibody, and at least one formulating agent selected from sterile water, sterile buffered water, or at least one preservative selected from the group consisting of phenol, m-cresol, p-cresol, o- cresol, chlorocresol, benzyl alcohol, alkylparaben, benzalkonium chloride, benzethonium chloride, sodium dehydroacetate and thimerosal, or mixtures thereof in an aqueous diluent, optionally, wherein the concentration of protein is about 0.1 mg/ml to about 100 mg/ml, further comprising at least one isotonicity agent or at least one physiologically acceptable buffer.
- at least one formulating agent selected from sterile water, sterile buffered water, or at least one preservative selected from the group consisting of phenol, m-cresol, p-cresol, o- cresol, chlorocresol, benzyl alcohol, alkyl
- the invention also provides at least one article of manufacture for human pharmaceutical use, comprising packaging material and a container comprising a solution or a lyophilised form of at least one antibody of the invention, optionally, further wherein said container is a glass or plastic container having a stopper for multi-use administration, optionally, further wherein said container is a blister pack, capable of being punctured and used in intravenous, intramuscular, bolus, intraperitoneal, subcutaneous, topical, respiratory, inhalation, nasal, vaginal, rectal, buccal, sublingual, intranasal, subdermal, or transdermal administration; said container is a component of an intravenous, intramuscular, bolus, intraperitoneal, subcutaneous, respiratory, inhalation, nasal, vaginal, topical, rectal, buccal, sublingual, intranasal, subdermal, or transdermal delivery device or system; said container is a component of an injector or pen-injector device or system for intravenous, intramus
- the invention also provides at least one method for producing at least one antibody of the invention, comprising providing a host cell, transgenic animal, transgenic plant or plant cell capable of expressing in recoverable amounts said human antibody, optionally, further wherein said host cell is a mammalian cell, a plant cell or a yeast cell; said transgenic animal is a mammal; said transgenic mammal is selected from a goat, a cow, a sheep, a horse, and a non-human primate.
- the invention further provides at least one method for treating at least one IL- 12/23 mediated disorder, comprising at least one of (a) administering an effective amount of a composition or pharmaceutical composition comprising at least one binding protein to a cell, tissue, organ, animal or patient in need of such modulation, treatment or therapy; and (b) further administering, before, concurrently, and/or after said administering in (a) above, at least one selected from an immune related therapeutic, a TNF antagonist, an antirheumatic, a muscle relaxant, a narcotic, a non-steroid anti-inflammatory drug (NSAID), an analgesic, an anesthetic, a sedative, a local anesthetic, a neuromuscular blocker, an antimicrobial, an antipsoriatic, a corticosteriod, an anabolic steroid, a neurological agent, a mineral, a nutritional, a thyroid agent, a vitamin, a calcium related hormone, an antidiarrheal, an
- IL-12p40 is present in the proteins IL- 12 and IL-23 and exists as an IL-12p40 monomer and an IL-12p80 homodimer.
- the present invention describes an antibody that binds to IL- 12, IL-23, IL-12p40, IL-12p80, and will likely bind to any newly discovered proteins which contain the IL-12p40 subunit.
- the antibody specifically binds to IL-12p40 but not IL-12p35 or IL-23pl9.
- the present invention further provides compositions, formulations, methods, devices and uses of such antibodies, including therapeutic uses.
- the antibody is able to neutralise IL- 12 to IL-12R ⁇ 2 which this thought to bind to IL- 12 at the p40/p35 interface.
- the antibody is able to inhibit the binding of IL-23 to IL-23R which is likely thought to be mediated through interactions at the pl9/p40 interface.
- the antibody is able to inhibit the binding of IL- 12 to IL-12R ⁇ 2 and IL-23 binding to IL-23R.
- the antibody is inhibiting the binding of the relevant receptors to IL- 12 and/or IL-23.
- This invention describes antibodies that bind to both IL-12p40/80, but not neutralise the binding of IL-12p40 or IL-12p80 to IL-12R ⁇ l. Regulation of IL- 12 or IL-23 systems can still be accomplished via the IL-12p40/80 subunit in the presence of the antibody, since these proteins are still free to bind to IL-12R ⁇ l.
- the advantage of the following method of action is that it will allow the natural regulators of the IL-12 and IL-23 system (IL-12p40/p80) to continue to compete along with the antibody which also acts as an antagonist of IL-12 and IL-23. Hence a dual antagonist system could be established via this method of action leading to greater efficacy of the antibody when used as a therapeutic.
- IL-12p40/80 has recently been shown to have divergent roles in addition to serving as an antagonist and regulating the IL-12/IL-23 pathways. The antibody will not prevent
- IL-12p40/80 acting as a chemoattractant for macrophages and as an inducer of DC migration in response to a pathogen challenge. This could lead to improvements in the safety profile of the antibody when administered as a therapeutic agent.
- polypeptide refers to any polymeric chain of amino acids.
- peptide and protein are used interchangeably with the term polypeptide and also refer to a polymeric chain of amino acids.
- polypeptide encompasses native or artificial proteins, protein fragments and polypeptide analogues of a protein sequence.
- a polypeptide may be monomeric or polymeric.
- isolated protein or "isolated polypeptide” is a protein or polypeptide that by virtue of its origin or source of derivation is not associated with naturally associated components that accompany it in its native state; is substantially free of other proteins from the same species; is expressed by a cell from a different species; or does not occur in nature.
- a polypeptide that is chemically synthesised or synthesised in a cellular system different from the cell from which it naturally originates will be “isolated” from its naturally associated components.
- a protein may also be rendered substantially free of naturally associated components by isolation, using protein purification techniques well known in the art.
- recovery refers to the process of rendering a chemical species, such as a polypeptide, substantially free of naturally associated components by isolation, e.g., using protein purification techniques well known in the art.
- human IL- 12 (abbreviated herein as hIL-12, or IL- 12), as used herein, includes a human cytokine that is secreted primarily by antigen presenting cells such as monocytes, macrophages and dendritic cells.
- the term includes a heterodimeric protein comprising a 35 kD subunit (p35) and a 40 kD subunit (p40) which are both linked together with a disulfide bridge.
- the heterodimeric protein is referred to as a "p70 protein”.
- human IL- 12 is intended to include recombinant human IL- 12 (rhIL-12), which can be prepared by standard recombinant expression methods.
- IL- 12 belongs to a family of interleukins the newest member being IL-35, which shares the IL-12p35 subunit (Niedbala et al. 2007 Eur J Immunol 37 3021-9). The recent discovery of IL-35 indicates that there are likely to be more forms of both the IL-12p40 and IL-12p35 that are yet to be discovered. It is logical to assume that antibodies described in the present invention would bind to all newly discovered proteins that contain forms of IL-12p40.
- human IL-23 (abbreviated herein as hIL-23, or IL-23), as used herein, includes a heterodimeric human cytokine belonging to a family of five such heterodimeric cytokines including IL- 12 and IL-27 (Trinchieri et al. 2003 Immunity 19 641-4).
- the term includes a heterodimeric protein comprising of the subunits pl9 and p40 which are both linked together with a disulfide bridge.
- human IL-23 is intended to include recombinant human IL-23 (rh IL-23), which can be prepared by standard recombinant expression methods.
- IL- 12/23 refers to human IL- 12 and IL-23 collectively.
- IL-12p40 identicial to "IL-23p40”, and also referred to simply as “p40” and "p40 subunit”, as used herein, includes the 40 kD subunit of the human cytokine IL- 12 (p40) and the 40 kD subunit of the human cytokine IL-23.
- IL-12p80 includes 2 monomeric 40 kD subunits of the human cytokine IL- 12 (p40) linked together by a disulphide bond to form a dimeric protein.
- IL-12p35 also referred to simply as “p35”, as used herein, includes the 35 kD subunit of the human cytokines, IL-12 (p70) and IL-35.
- IL-23pl9 also referred to simply as “pi 9”, as used herein, includes the 19 kD subunit of the human cytokine IL-23.
- the IL- 12R complex is composed of two subunits, named IL-12 receptor beta 1, used herein as IL-12R ⁇ l, and IL-12 receptor beta 2, used herein as IL-12R ⁇ 2, both of which are required for high affinity binding of IL-12 and signalling.
- This IL- 12R was initially characterised on PHA-activated lymphoblasts and IL-2 activated NK cells (Chizzonite et al. 1992 J Immunol 148 3117-24; Chua et al. 1994 J Immunol 153 128-36).
- IL- 12R ⁇ 2 is responsible for signalling via the Tyk2/JAK2 and STAT4 pathway leading cells down a T n I pathway (IFN- ⁇ secreting) (Presky et al. 1996 Proc Natl Acad Sci U S A 93 14002-7; Watford et al. 2004 Immunol Rev 202 139-56).
- IL-12R ⁇ l has since been shown to be involved in signalling by phosphorylating Tyk2 and STAT3 (Zou et al. 1997 J Biol Chem 272 6073-7).
- the IL-23R complex is composed of two subunits, IL- 12R ⁇ l which is present in the IL- 12R complex, and the IL-23 receptor, used herein as IL-23R.
- the engagement of IL-23R by IL-23 results in JAK2 autophosphorylation and phosphorylation of IL-23R. This results in the localisation and phosphorylation of STAT3, as well as STATl, STAT4 and STAT5 (Parham et al. 2002 J Immunol 168 5699-708).
- Biological activity refers to all inherent biological properties of the cytokine.
- Biological properties of IL-12 include but are not limited to binding IL-12R ⁇ l and/or IL- 12R ⁇ 2; induction of IFN- ⁇ secretion and regulation of balance between antigen- specific T helper type 1 (T H I) and type 2 (T R 2) lymphocytes.
- Biological properties of IL-23 include but are not limited to binding IL-12R ⁇ l and/or IL-23R, inducing IFN- ⁇ production, inducing IL- 17 production, inducing IL-21 production, inducing IL- 22 production, T H 17 cell differentiation and activating the antigen-presenting functions of dendritic cells, and selectively inducing proliferation of memory T cells.
- telomere binding in reference to the interaction of an antibody, a protein, or a peptide with a second chemical species, mean that the interaction is dependent upon the presence of a particular structure (e.g., an antigenic determinant or epitope) on the chemical species; for example, an antibody recognises and binds to a specific protein structure rather than to proteins generally. If an antibody is specific for epitope "A”, the presence of a molecule containing epitope A (or free, unlabeled A), in a reaction containing labeled "A” and the antibody, will reduce the amount of labeled A bound to the antibody.
- a particular structure e.g., an antigenic determinant or epitope
- antibody broadly refers to any immunoglobulin (Ig) molecule comprised of four polypeptide chains, two heavy (H) chains and two light (L) chains, or any functional fragment, mutant, variant, or derivation thereof, which retains the essential epitope binding features of an Ig molecule.
- Ig immunoglobulin
- Such mutant, variant, or derivative antibody formats are known in the art. Non-limiting embodiments of which are discussed below.
- each heavy chain is comprised of a heavy chain variable region (abbreviated herein as HCVR or VH) and a heavy chain constant region.
- the heavy chain constant region is comprised of three domains, CHl, CH2 and CH3.
- Each light chain is comprised of a light chain variable region (abbreviated herein as LCVR or VL) and a light chain constant region.
- the light chain constant region is comprised of one domain, CL.
- the VH and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with regions that are more conserved, termed framework regions (FR).
- CDR complementarity determining regions
- Each VH and VL is composed of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FRl, CDRl, FR2, CDR2, FR3, CDR3, FR4.
- Immunoglobulin molecules can be of any type (e.g., IgG, IgE, IgM, IgD, IgA and IgY), class (e.g., IgGl, IgG2, IgG 3, IgG4, IgAl and IgA2) or subclass.
- antigen binding domain or "antigen binding portion” of an antibody, as used herein, refers to one or more fragments of an antibody or protein that retain the ability to specifically bind to an antigen (e.g., IL-12). It has been shown that the antigen-binding function of an antibody can be performed by fragments of a full-length antibody. Such antibody embodiments may also be bispecific, dual specific, or multi- specific formats; specifically binding to two or more different antigens.
- binding fragments encompassed within the term "antigen- binding portion" of an antibody include (i) a Fab fragment, a monovalent fragment consisting of the VL, VH, CL and CHl domains; (ii) a F(ab')2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; (iii) a Fd fragment consisting of the VH and CHl domains; (iv) a Fv fragment consisting of the VL and VH domains of a single arm of an antibody , (v) a dAb fragment (Ward et al.
- VL and VH are coded for by separate genes, they can be joined, using recombinant methods, by a synthetic linker that enables them to be made as a single protein chain in which the VL and VH regions pair to form monovalent molecules (known as single chain Fv (scFv); (see e.g.,Bird et al. 1988 Science 242 423-6; Huston et al. 1988 Proc Natl Acad Sci U S A 85 5879-83).
- scFv single chain Fv
- single chain antibodies are also intended to be encompassed within the term "antigen-binding portion" of an antibody.
- Other forms of single chain antibodies, such as diabodies are also encompassed.
- Diabodies are bivalent, bispecific antibodies in which VH and VL domains are expressed on a single polypeptide chain, but using a linker that is too short to allow for pairing between the two domains on the same chain, thereby forcing the domains to pair with complementary domains of another chain and creating two antigen binding sites (see e.g., Holliger, P., et al., 1993, Proc. Natl. Acad. Sci. USA 90:6444-6448; Poljak, R. J., et al., 1994, Structure 2:1121-1123).
- Such antibody binding portions are known in the art (Kontermann and Dubel eds., Antibody Engineering 2001 Springer- Verlag. New York. 790 pp., ISBN 3-540-41354-5).
- antibody construct refers to a polypeptide comprising one or more antigen binding portions of the invention linked to a linker polypeptide or an immunoglobulin constant domain.
- Linker polypeptides comprise two or more amino acid residues joined by peptide bonds and are used to link one or more antigen binding portions.
- Such linker polypeptides are well known in the art (see e.g. Holliger et al. 1993 Proc Natl Acad Sci U S A 90 6444-8).
- An immunoglobulin constant domain refers to a heavy or light chain constant domain.
- Human IgG heavy chain and light chain constant domain amino acid sequences are known in the art and examples are represented below.
- Human heavy chain IgG 1 constant domain (or derivatives thereof like NCBI Accession No: PO 1857)
- an antibody or antigen-binding portion thereof may be part of a larger immunoadhesion molecule, formed by covalent or noncovalent association of the antibody or antibody portion with one or more other proteins or peptides.
- immunoadhesion molecules include use of the streptavidin core region to make a tetrameric scFv molecule (Kipriyanov et al.
- Antibody portions such as Fab and F(ab')2 fragments, can be prepared from whole antibodies using conventional techniques, such as papain or pepsin digestion, respectively, of whole antibodies. Moreover, antibodies, antibody portions and immunoadhesion molecules can be obtained using standard recombinant DNA techniques, as described herein.
- an "isolated antibody”, as used herein, is intended to refer to an antibody that is substantially free of other antibodies having different antigenic specificities (e.g., an isolated antibody that specifically binds hIL-12 is substantially free of antibodies that specifically bind antigens other than hIL-12).
- An isolated antibody that specifically binds hIL-12 may, however, have cross-reactivity to other antigens, such as IL- 12 molecules from other species.
- an isolated antibody may be substantially free of other cellular material and/or chemicals.
- the term "human antibody”, as used herein, is intended to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences.
- human antibodies of the invention may include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo), for example in the CDRs and in particular CDR3.
- human antibody as used herein, is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences.
- recombinant human antibody is intended to include all human antibodies that are prepared, expressed, created or isolated by recombinant means, such as antibodies expressed using a recombinant expression vector transfected into a host cell, antibodies isolated from a recombinant, combinatorial human antibody library (Hoogenboom 1997 Trends Biotechnol 15 62-70; Azzazy et al. 2002 Clin Biochem 35 425- 45; Gavilondo et al. 2000 Biotechniques 29 128-32, 134-6, 138 passim Hoogenboom et al.
- antibodies isolated from an animal e.g., a mouse
- that is transgenic for human immunoglobulin genes see e.g., Taylor et al. 1992 Nucleic Acids Res 20 6287-95, Little et al. 2000 Immunol Today 21 364-70
- Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences.
- such recombinant human antibodies are subjected to in vitro mutagenesis (or, when an animal transgenic for human Ig sequences is used, in vivo somatic mutagenesis) and thus the amino acid sequences of the VH and VL regions of the recombinant antibodies are sequences that, while derived from and related to human germline VH and VL sequences, may not naturally exist within the human antibody germline repertoire in vivo.
- chimeric antibody refers to antibodies which comprise heavy and light chain variable region sequences from one species and constant region sequences from another species, such as antibodies having murine heavy and light chain variable regions linked to
- CDR-grafted antibody refers to antibodies which comprise heavy and light chain variable region sequences from one species but in which the sequences of one or more of the CDR regions of VH and/or VL are replaced with CDR sequences of another species, such as antibodies having murine heavy and light chain variable regions in which one or more of the murine CDRs (e.g., CDR3) has been replaced with human CDR sequences.
- humanised antibody refers to antibodies which comprise heavy and light chain variable region sequences from a non-human species (e.g., a mouse) but in which at least a portion of the VH and/or VL sequence has been altered to be more "human-like", ie, more similar to human germline variable sequences.
- a non-human species e.g., a mouse
- human CDR-grafted antibody in which human CDR sequences are introduced into non-human VH and VL sequences to replace the corresponding non-human CDR sequences.
- Kabat numbering “Kabat definitions” and “Kabat labeling” are used interchangeably herein. These terms, which are recognised in the art, refer to a system of numbering amino acid residues which are more variable (ie. hypervariable) than other amino acid residues in the heavy and light chain variable regions of an antibody, or an antigen binding portion thereof (Kabat et al. 1971 Ann N Y Acad Sci 190 382-93 and Kabat, E.A., et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242).
- the hypervariable region ranges from amino acid positions 31 to 35 for CDRl, amino acid positions 50 to 65 for CDR2, and amino acid positions 95 to 102 for CDR3.
- the hypervariable region ranges from amino acid positions 24 to 34 for CDRl, amino acid positions 50 to 56 for CDR2, and amino acid positions 89 to 97 for CDR3.
- the terms “acceptor” and “acceptor antibody” refer to the antibody or nucleic acid sequence providing or encoding at least 80%, at least 85%, at least 90%, at least 95%, at least 98% or 100% of the amino acid sequences of one or more of the framework regions.
- the term “acceptor” refers to the antibody amino acid or nucleic acid sequence providing or encoding the constant region(s).
- the term “acceptor” refers to the antibody amino acid or nucleic acid sequence providing or encoding one or more of the framework regions and the constant region(s).
- the term "acceptor” refers to a human antibody amino acid or nucleic acid sequence that provides or encodes at least 80%, preferably, at least 85%, at least 90%, at least 95%, at least 98%, or 100% of the amino acid sequences of one or more of the framework regions.
- an acceptor may contain at least 1, at least 2, at least 3, least 4, at least 5, or at least 10 amino acid residues that does (do) not occur at one or more specific positions of a human antibody.
- An acceptor framework region and/or acceptor constant region(s) may be, e.g., derived or obtained from a germline antibody gene, a mature antibody gene, a functional antibody (e.g., antibodies well-known in the art, antibodies in development, or antibodies commercially available).
- CDR refers to the complementarity determining region within antibody variable sequences. There are three CDRs in each of the variable regions of the heavy chain and the light chain, which are designated CDRl, CDR2 and CDR3, for each of the variable regions.
- CDR set refers to a group of three CDRs that occur in a single variable region capable of binding the antigen.
- canonical residue refers to a residue in a CDR or framework that defines a particular canonical CDR structure as defined by Chothia et al (Chothia and Lesk 1987 J MoI Biol 196 901-17; Chothia et al. 1992 J MoI Biol 227 799-817) and are incorporated herein by reference. According to Chothia et al., critical portions of the CDRs of many antibodies have nearly identical peptide backbone confirmations despite great diversity at the level of amino acid sequence. Each canonical structure specifies primarily a set of peptide backbone torsion angles for a contiguous segment of amino acid residues forming a loop.
- the terms “donor” and “donor antibody” refer to an antibody providing one or more CDRs.
- the donor antibody is an antibody from a species different from the antibody from which the framework regions are obtained or derived.
- the term “donor antibody” refers to a non- human antibody providing one or more CDRs.
- the term “framework” or “framework sequence” refers to the remaining sequences of a variable region minus the CDRs. Because the exact definition of a CDR sequence can be determined by different systems, the meaning of a framework sequence is subject to correspondingly different interpretations.
- the six CDRs also divide the framework regions on the light chain and the heavy chain into four sub-regions (FRl, FR2, FR3 and FR4) on each chain, in which CDRl is positioned between FRl and FR2, CDR2 between FR2 and FR3, and CDR3 between FR3 and FR4.
- a framework region represents the combined FRs within the variable region of a single, naturally occurring immunoglobulin chain.
- a FR represents one of the four sub-regions
- FRs represents two or more of the four sub-regions constituting a framework region.
- germline antibody gene or “gene fragment” refers to an immunoglobulin sequence encoded by non-lymphoid cells that have not undergone the maturation process that leads to genetic rearrangement and mutation for expression of a particular immunoglobulin.
- a particular immunoglobulin See, e.g., Shapiro et al. 2002 Crit Rev Immunol 22 183-200; Marchalonis et al. 2001 Adv Exp Med Biol 484 13-30).
- One of the advantages provided by various embodiments of the present invention stems from the recognition that germline antibody genes are more likely than mature antibody genes to conserve essential amino acid sequence structures characteristic of individuals in the species, hence less likely to be recognised as from a foreign source when used therapeutically in that species.
- key residues refer to certain residues within the variable region that have more impact on the binding specificity and/or affinity of an antibody, in particular a humanised antibody.
- a key residue includes, but is not limited to, one or more of the following: a residue that is adjacent to a CDR, a potential glycosylation site (can be either N- or O-glycosylation site), a rare residue, a residue capable of interacting with the antigen, a residue capable of interacting with a CDR, a canonical residue, a contact residue between heavy chain variable region and light chain variable region, a residue within the Vernier zone, and a residue in the region that overlaps between the Chothia definition of a VH domain CDRl and the Kabat definition of the first heavy chain framework.
- the term "humanised antibody” is an antibody or a variant, derivative, analog or fragment thereof which immunospecifically binds to an antigen of interest and which comprises a framework (FR) region having substantially the amino acid sequence of a human antibody and a complementarity determining region (CDR) having substantially the amino acid sequence of a non-human antibody .
- FR framework
- CDR complementarity determining region
- the term “substantially” in the context of a CDR refers to a CDR having an amino acid sequence at least 80%, preferably at least 85%, at least 90%, at least 95%, at least 98% or at least 99% identical to the amino acid sequence of a non-human antibody CDR.
- a humanised antibody comprises substantially all of at least one, and typically two, variable domains (Fab, Fab', F(ab')2, FabC, Fv) in which all or substantially all of the CDR regions correspond to those of a non-human immunoglobulin (i.e., donor antibody) and all or substantially all of the framework regions are those of a human immunoglobulin consensus sequence.
- a humanised antibody also comprises at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin.
- a humanised antibody contains both the light chain as well as at least the variable domain of a heavy chain.
- the antibody also may include the C H I, hinge, C H 2, C H 3, and C H 4 regions of the heavy chain.
- a humanised antibody only contains a humanised light chain. In some embodiments, a humanised antibody only contains a humanised heavy chain. In specific embodiments, a humanised antibody only contains a humanised variable domain of a light chain and/or humanised heavy chain.
- the humanised antibody can be selected from any class of immunoglobulins, including IgM, IgG, IgD, IgA and IgE, and any isotype, including without limitation IgGl, IgG2, IgG3 and IgG4.
- the humanised antibody may comprise sequences from more than one class or isotype, and particular constant domains may be selected to optimise desired effector functions using techniques well-known in the art.
- the framework and CDR regions of a humanised antibody need not correspond precisely to the parental sequences, e.g., the donor antibody CDR or the consensus framework may be mutagenised by substitution, insertion and/or deletion of at least one amino acid residue so that the CDR or framework residue at that site does not correspond to either the donor antibody or the consensus framework. In a preferred embodiment, such mutations, however, will not be extensive. Usually, at least 80%, preferably at least 85%, more preferably at least 90%, and most preferably at least 95% of the humanised antibody residues will correspond to those of the parental FR and CDR sequences.
- the term "consensus framework" refers to the framework region in the consensus immunoglobulin sequence.
- the term "consensus immunoglobulin sequence” refers to the sequence formed from the most frequently occurring amino acids (or nucleotides) in a family of related immunoglobulin sequences (See e.g., Winnaker, From Genes to Clones, Verlagsgesellschaft, Weinheim, Germany 1987). In a family of immunoglobulins, each position in the consensus sequence is occupied by the amino acid occurring most frequently at that position in the family. If two amino acids occur equally frequently, either can be included in the consensus sequence.
- "Vernier" zone refers to a subset of framework residues that may adjust CDR structure and fine-tune the fit to antigen as described by Foote et al. 1992 J MoI Biol 224 487-99.
- Vernier zone residues form a layer underlying the CDRs and may impact on the structure of CDRs and the affinity of the antibody.
- neutralising refers to neutralisation of biological activity of a cytokine when an antibody specifically binds the cytokine.
- a neutralising antibody is a neutralising antibody whose binding to IL- 12 and/or IL-23 results in inhibition of a biological activity of IL- 12 and/or IL-23.
- the neutralising antibody binds IL- 12 and/or IL-23 and reduces a biologically activity of IL- 12 and/or IL-23 by at least about 50%, 60%, 80%, 85% or more.
- the term "inhibition” refers to the reduction of a biological activity of a cytokine when an antibody specifically binds the cytokine. Inhibition of a biological activity of IL- 12 and/or IL-23 by a neutralising antibody can be assessed by measuring one or more indicators of IL- 12 and/or IL-23 biological activity well known in the art. For example inhibition of human phytohemagglutinin blast proliferation in a in-vitro IL- 12 PHA assay or inhibition of receptor binding in a human IL- 12 receptor binding assay (See Example).
- the term "activity" includes activities such as the binding specificity/affinity of an antibody for an antigen, for example, an anti-IL-12 antibody that binds to an IL- 12 antigen and/or the neutralising potency of an antibody , for example, an anti-IL-12 antibody whose binding to IL- 12 inhibits the biological activity of hIL-12, e.g. inhibition of PHA blast proliferation or inhibition of receptor binding in a human IL- 12 receptor binding assay, or an in vitro IL- 12 PHA assay.
- activities such as the binding specificity/affinity of an antibody for an antigen, for example, an anti-IL-12 antibody that binds to an IL- 12 antigen and/or the neutralising potency of an antibody , for example, an anti-IL-12 antibody whose binding to IL- 12 inhibits the biological activity of hIL-12, e.g. inhibition of PHA blast proliferation or inhibition of receptor binding in a human IL- 12 receptor binding assay, or an in vitro IL- 12 PHA assay.
- epitope includes any polypeptide determinant capable of specific binding to an immunoglobulin or T-cell receptor.
- epitope determinants include chemically active surface groupings of molecules such as amino acids, sugar side chains, phosphoryl, or sulfonyl, and, in certain embodiments, may have specific three dimensional structural characteristics, and/or specific charge characteristics.
- An epitope is a region of an antigen that is bound by an antibody.
- an antibody is said to specifically bind an antigen when it preferentially recognises its target antigen in a complex mixture of proteins and/or macromolecules.
- the present invention also provides an antibody that inhibits IL- 12/23 activity in antigen presenting cells (APCs), such as but not limited to, macrophages, microglia, mesangial phagocytes, synovial A cells, stem cell precursors, Langerhans cells, Kupffer cells, dendritic cells, B cells, and the like.
- APCs antigen presenting cells
- Such APCs can be present in different tissues, e.g., but not limited to, skin, epidermis, liver, spleen, brain, spinal cord, thymus, bone marrow, joint synovial fluid, kidneys, blood, and the like.
- Such APCs can also be limited to outside or inside the blood brain barrier.
- the present invention provides isolated, recombinant and/or synthetic antibodies, specified portions or variants thereof, as well as compositions and encoding nucleic acid molecules comprising at least one polynucleotide encoding at least one antibody.
- Such antibodies, specified portions or variants thereof of the present invention comprise specific full length antibody sequences, domains, fragments and specified variants thereof, and methods of making and using said nucleic acids and antibodies, specified portions or variants thereof, including therapeutic compositions, methods and devices.
- the antibodies that can be used in the invention are optionally characterised by their ability to treat patients for extended periods with good to excellent alleviation of symptoms and low toxicity.
- Low immunogenicity and/or high affinity, as well as other suitable properties, may contribute to the therapeutic results achieved.
- Low immunogenicity is defined herein as raising significant HAHA, HACA or HAMA responses in less than about 75%, or preferably less than about 50% of the patients treated and/or raising low titres in the patient treated (less than about 300, preferably, less than about 100 measured with a double antigen enzyme immunoassay; Elliott et al. 1994 Lancet 344 1125-7).
- the isolated nucleic acids of the present invention can be used for production of at least one antibody, fragment or specified variant thereof, which can be used in a cell, tissue, organ or animal (including mammals and humans), to modulate, treat, alleviate, help prevent the incidence of, or reduce the symptoms of, at least one IL- 12 and/or IL-23 condition.
- Such a method can comprise administering an effective amount of a composition or a pharmaceutical composition comprising at least one antibody or specified portion or variant to a cell, tissue, organ, animal or patient in need of such modulation, treatment, alleviation, prevention, or reduction in symptoms, effects or mechanisms.
- the effective amount can comprise an amount of about 0.001 to 500 mg/kg per single or multiple administration, or to achieve a serum concentration of 0.01-5000 ⁇ g/ml serum concentration per single or multiple administration, or any effective range or value therein, as done and determined using known methods, as described herein or known in the relevant arts.
- Antibodies that are specific for the IL-12p40 subunit can be raised against an appropriate immunogenic antigen, such as isolated IL-12p40, IL- 12 or IL-23 protein or a portion thereof (including synthetic molecules, such as synthetic peptides).
- an appropriate immunogenic antigen such as isolated IL-12p40, IL- 12 or IL-23 protein or a portion thereof (including synthetic molecules, such as synthetic peptides).
- Preparation of immunogenic antigens and monoclonal antibody production can be performed using any suitable technique. A variety of methods have been described (see e.g., Kohler et al. 1975 Nature 256 495-7 and Kohler et al. 1976 Eur J Immunol 6 511-9; Galfre et al. 1977 Nature 266 550-2; Koprowski et al., U.S. Pat. No. 4,172,124; Harlow, E. and D.
- a hybridoma is produced by fusing a suitable immortal cell line (e.g., a myeloma cell line such as, but not limited to, Sp2/0, Sp2/0-AG14, NSO, NSl, NS2, AE-I, L.5, >243, P3X63Ag8.653, Sp2 SA3, Sp2 MAI, Sp2 SSl, Sp2 SA5, U937, MLA 144, ACT IV, MOLT4, DA-I, JURKAT, WEHI, K-562, COS, RAJI, NIH 3T3, HL-60, MLA 144, NAMAIWA, NEURO 2A, or the like, or heteromyelomas, fusion products thereof, or any cell or fusion cell derived therefrom, or any other suitable cell line as known in the art, see, e.g., www.atcc.org, www.lifetech.com., and the like, each of which is entirely incorporated herein by reference) with antibody producing cells
- Antibody producing cells can be obtained from the peripheral blood or, preferably, the spleen or lymph nodes, of humans or other suitable animals that have been immunised with the antigen of interest. Any other suitable host cell can also be used for expressing heterologous or endogenous nucleic acid encoding an antibody, specified fragment or variant thereof, of the present invention.
- the fused cells (hybridomas) or recombinant cells can be isolated using selective culture conditions or other suitable known methods, and cloned by limiting dilution or cell sorting, or other known methods. Cells which produce antibodies with the desired specificity can be selected by a suitable assay (e.g., ELISA).
- Suitable methods of producing or isolating antibodies of the requisite specificity can be used, including, but not limited to, methods that select recombinant antibody from a peptide or protein library (e.g., but not limited to, a bacteriophage, ribosome, oligonucleotide, RNA, cDNA, or the like, display library; e.g., as available from Cambridge Antibody Technologies, Cambridgeshire, UK; MorphoSys, Martinsreid/Planegg, DE; Biovation, Aberdeen, Scotland, UK; Biolnvent, Lund, Sweden; Dyax Corp., Enzon, Affymax/Biosite; Xoma, Berkeley, Calif.; Ixsys.
- a peptide or protein library e.g., but not limited to, a bacteriophage, ribosome, oligonucleotide, RNA, cDNA, or the like, display library; e.g., as available from Cambridge Antibody Technologies,
- a chimeric antibody is a molecule in which different portions of the antibody are derived from different animal species, such as antibodies having a variable region derived from a murine monoclonal antibody and a human immunoglobulin constant region.
- Methods for producing chimeric antibodies are known in the art. See e.g., Morrison (1985); Oi (1986); Gillies (1989); U.S. Pat. Nos. 5,807,715; 4,816,567; and 4,816,397.
- de-immunized antibodies that have sequence variations produced using methods described in, for example, Patent Publication Nos. EP 0983303A1, WO 2000/34317, and WO 98/52976.
- Veneering refers to the selective replacement of framework region residues from, for example, a mouse heavy or light chain variable region with human framework region residues in order to provide a xenogeneic molecule comprising an antigen- binding site which retains substantially all of the native framework region folding structure.
- Veneering techniques are based on the understanding that the ligand-binding characteristics of an antigen-binding site are determined primarily by the structure and relative disposition of the heavy and light chain CDR sets within the antigen-binding surface (Davies (1990)). Thus, antigen-binding specificity can be preserved in a humanized antibody only wherein the CDR structures, their interaction with each other, and their interaction with the rest of the V region domains are carefully maintained.
- exterior (e.g. solvent accessible) framework region residues which are readily encountered by the immune system, are selectively replaced with human residues to provide a hybrid molecule that comprises either a weakly immunogenic, or substantially non-immunogenic, veneered surface.
- humanized anti-IL-12/IL-23 antibodies By “humanized” is intended forms of anti-IL-12/IL-23 antibodies that contain minimal sequence derived from non-human immunoglobulin sequences.
- humanized antibodies are human immunoglobulins (recipient antibody) in which residues from a hypervariable region (also known as complementarity determining region or CDR) of the recipient are replaced by residues from a hypervariable region of a non-human species (donor antibody) such as mouse, rat, rabbit, or nonhuman primate having the desired specificity, affinity, and capacity.
- donor antibody such as mouse, rat, rabbit, or nonhuman primate having the desired specificity, affinity, and capacity.
- Humanized antibodies within the scope, and suitable for use in the methods, of the present invention may, for example, have binding characteristics similar to those exhibited by non-humanized antibodies, such as, for example the PMA204 monoclonal antibody described herein.
- Humanization can be essentially performed following the method of Winter and co- workers (Jones (1986); Riechmann (1988); Verhoeyen (1988)), by substituting rodent or mutant rodent CDRs or CDR sequences for the corresponding sequences of a human antibody. See also U.S. Pat. Nos. 5,225,539; 5,585,089; 5,693,761; 5,693,762; and 5,859,205.
- Antibodies can be humanized using a variety of techniques known in the art including, for example, CDR-grafting (EP 239400; PCT publication WO 91/09967; U.S. Pat. Nos.
- Superhumanization is a humanization approach where the CDRs conferring antigen specificity ('donor') are grafted to human germline framework sequences ('acceptor') that are known to be expressed with human CDRs that are structurally identical or similar to the 'donor' CDRs (Tan 2002, see also International Publication No. WO 2004/006955 ).
- frameworks encoded by human genomic V gene sequences rather than sequences that can include somatic mutations, this approach has enhanced potential for reduced immunogenicity.
- this approach also has enhanced potential for affinity retention.
- humanized antibodies may comprise residues that are not found in the recipient antibody or in the donor antibody. These modifications are made to further refine antibody performance (e.g., to obtain desired affinity).
- the humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the hypervariable regions correspond to those of a non-human immunoglobulin and all or substantially all of the framework 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), typically that of a human immunoglobulin.
- Fc immunoglobulin constant region
- Such "humanized” antibodies may include antibodies wherein substantially less than an intact human variable domain has been substituted by the corresponding sequence from a non- human species.
- humanized antibodies are typically human antibodies in which some CDR residues and possibly some framework residues are substituted by residues from analogous sites in rodent antibodies. See, for example, U.S. Pat. Nos. 5,225,539; 5,585,089; 5,693,761; 5,693,762; 5,859,205. See also U.S. Pat. No. 6,180,370, and International Publication No. WO 2001/27160 where humanized antibodies and techniques for producing humanized antibodies having improved affinity for a predetermined antigen are disclosed.
- Human antibodies can be made by a variety of methods known in the art including phage display methods described above using antibody libraries derived from human immunoglobulin sequences. See also, U.S. Pat. Nos. 4,444,887 and 4,716,111; and PCT publications WO 98/46645, WO 98/50433, WO 98/24893, WO 98/16654, WO 96/34096, WO [0166] Completely human antibodies which recognize a selected epitope can be generated using a technique referred to as "guided selection.” In this approach a selected non-human monoclonal antibody, e.g., a mouse antibody, is used to guide the selection of a completely human antibody recognizing the same epitope (Jespers (1988)).
- Human antibodies can also be produced using transgenic animals which are incapable of expressing functional endogenous immunoglobulins, but which can express human immunoglobulin genes.
- the human heavy and light chain immunoglobulin gene complexes may be introduced randomly or by homologous recombination into mouse embryonic stem cells.
- the human variable region, constant region, and diversity region may be introduced into mouse embryonic stem cells in addition to the human heavy and light chain genes.
- variable domains both light and heavy
- the choice of human variable domains, both light and heavy, to be used in making the humanised antibodies can be used to reduce antigenicity.
- sequence of the variable domain of a rodent antibody is screened against the entire library of known human variable-domain sequences.
- the human sequence that is closest to that of the rodent is then accepted as the human framework (FR) for the humanised antibody (Chothia and Lesk 1987 J MoI Biol 196 901-17; Sims et al. 1993 J Immunol 151 2296-308, each of which is entirely incorporated herein by reference).
- Another method uses a particular framework derived from the consensus sequence of all human antibodies of a particular subgroup of light or heavy chains.
- Antibodies can also optionally be humanised with retention of high affinity for the antigen and other favorable biological properties.
- humanised antibodies are prepared by a process of analysis of the parental sequences and various conceptual humanised products using three-dimensional models of the parental and humanised sequences. Three-dimensional immunoglobulin models are commonly available and are familiar to those skilled in the art. Computer programs are available which illustrate and display probable three-dimensional conformational structures of selected candidate immunoglobulin sequences. Inspection of these displays permits analysis of the likely role of the residues in the functioning of the candidate immunoglobulin sequence, i.e., the analysis of residues that influence the ability of the candidate immunoglobulin to bind its antigen. In this way, FR residues can be selected and combined from the consensus and import sequences so that the desired antibody characteristic, such as increased affinity for the target antigen(s), is achieved. In general, the CDR residues are directly and most substantially involved in influencing antigen binding.
- Human antibodies can be made by the hybridoma method.
- Human myeloma and mouse-human heteromyeloma cell lines for the production of human monoclonal antibodies have been described, for example, by Kozbor, J. Immunol. 133:3001 (1984); Brodeur et al., Monoclonal Antibody Production Techniques and Applications, pp. 51-63 (Marcel Dekker, Inc., New York, 1987); and Boerner et al., J. Immunol. 147:86 (1991), each of which is entirely incorporated herein by reference.
- phage display technology in addition to that presented above, can be used to produce human antibodies and antibody fragments in vitro, from immunoglobulin variable (V) domain gene repertoires from unimmunised donors.
- V domain genes are cloned in-frame into either a major or minor coat protein gene of a filamentous bacteriophage, such as M 13 or fd, and displayed as functional antibody fragments on the surface of the phage particle. Because the filamentous particle contains a single- stranded DNA copy of the phage genome, selections based on the functional properties of the antibody also result in selection of the gene encoding the antibody exhibiting those properties.
- the phage mimics some of the properties of the B-cell.
- Phage display can be performed in a variety of formats; for their review see, Johnson 1993 Current Opinions in Structural Biology 3 564-571, each of which is entirely incorporated herein by reference.
- V-gene segments can be used for phage display.
- Clackson et al. (Clackson et al. 1991 Nature 352 624-8) isolated a diverse array of anti-oxazolone antibodies from a small random combinatorial library of V genes derived from the spleens of immunised mice.
- a repertoire of V genes from unimmunised human donors can be constructed and antibodies to a diverse array of antigens (including self-antigens) can be isolated essentially following the techniques described by Marks et al. 1991 J MoI Biol 222 581-97, or Griffiths et al. 1993 Embo J 12 725-34, each of which is entirely incorporated herein by reference.
- Bispecific antibodies can also be used that are monoclonal, preferably human or humanised, antibodies that have binding specificities for at least two different antigens.
- one of the binding specificities is for at least one IL- 12 and/or IL-23 protein; the other one is for any other antigen.
- bispecific antibodies specifically binding an IL- 12/23 protein and at least one neurotrophic factor, or two different types of IL- 12/23 polypeptides are within the scope of the present invention.
- bispecific antibodies Methods for making bispecific antibodies are known in the art. Traditionally, the recombinant production of bispecific antibodies is based on the co-expression of two immunoglobulin heavy chain-light chain pairs, where the two heavy chains have different specificities (Milstein et al. 1983 Nature 305 537-40). Because of the random assortment of immunoglobulin heavy and light chains, these hybridomas (quadromas) produce a potential mixture of 10 different antibody molecules, of which only one has the correct bispecific structure. The purification of the correct molecule, which is usually done by affinity chromatography steps, is rather cumbersome, and the product yields are low. Similar procedures are disclosed in WO 93/08829, and in Traunecker et al. 1991 Embo J 10 3655-9 entirely incorporated herein by reference.
- antibody-variable domains with the desired binding specificities are fused to immunoglobulin constant-domain sequences.
- the fusion preferably is with an immunoglobulin heavy-chain constant domain, comprising at least part of the hinge, the second heavy chain constant region (C H 2), and the third heavy chain constant region (C H 3). It is preferred to have the first heavy-chain constant region (C H I), containing the site necessary for light-chain binding, present in at least one of the fusions.
- DNA encoding the immunoglobulin heavy chain fusions and, if desired, the immunoglobulin light chain are inserted into separate expression vectors, and are co-transfected into a suitable host organism.
- the bispecific antibodies are composed of a hybrid immunoglobulin heavy chain with a first binding specificity in one arm, and a hybrid immunoglobulin heavy chain-light chain pair (providing a second binding specificity) in the other arm.
- This asymmetric structure facilitates the separation of the desired bispecific compound from unwanted immunoglobulin chain combinations, as the presence of an immunoglobulin light chain in only one half of the bispecific molecule provides for a facile way of separation.
- bispecific antibodies see, for example Suresh et al. 1986 Methods Enzymol 121 210-28.
- Antibodies are bifunctional molecules, the N-terminal variable segments from the heavy and light chains associate together in a specific manner to generate a three-dimensional structure with affinity for a particular epitope on the surface of an antigen.
- the constant region segments are responsible for prolonged serum half-life and the effector functions of the antibody and relate to complement binding, stimulation of phagocytosis, antibody-dependent cellular cytotoxicity (ADCC) and triggering of granulocyte granule release.
- ADCC antibody-dependent cellular cytotoxicity
- an anti-IL- 12/23 antibody would be capable of performing effector functions like ADCC or CDC (complement direted cytotoxicity). This is due to the discovery that IL- 12 could exist as a membrane bound form (Quinones et al.
- an antibody could bind and recruit effector cells.
- the present antibody could bind to IL- 12 or IL-23 bound to the surface of cells and thus form a complex capable of recruiting effector cells to the target cell surface (Vogel et al. 1996 Int Immunol 8 1955-62).
- a number of methods for modulating antibody serum half-life and biodistribution are based on modifying the interaction between antibody and the neonatal Fc receptor (FcRn), a receptor with a key role in protecting IgG from catabolism, and maintaining high serum antibody concentration.
- FcRn neonatal Fc receptor
- Dall'Acqua et al (2002) describe substitutions in the Fc region of IgGl that enhance binding affinity to FcRn, thereby increasing serum half-life, and further demonstrate enhanced bioavailability and modulation of ADCC activity with triple substitution of M252Y/S254T/T256E (DaIl' Acqua 2006). See also U.S Pat. Nos 6,277,375; 6,821,505; and 7,083,784.
- Hinton et al (2004, 2005) have described constant domain amino acid substitutions at positions 250 and 428 that confer increased in vivo half-life. See also U.S Pat. No 7,217,797. Petkova et al (2006) have described constant domain amino acid substitutions at positions 307, 380 and 434 that confer increased in vivo half-life. See also Shields et al (2001) and WO 2000/42072. Other examples of constant domain amino acid substitutions which modulate binding to Fc receptors and subsequent function mediated by these receptors, including FcRn binding and serum half-life, are described in U.S Pat. Application Nos 20090142340; 20090068175; and 20090092599.
- the glycans linked to antibody molecules are known to influence interactions of antibody with Fc receptors and glycan receptors and thereby influence antibody activity, including serum half-life (Kaneko Y et al, 2006; Jones AJ et al, 2007; Kanda Y et al, 2007).
- certain glycoforms that modulate desired antibody activities can confer therapeutic advantage.
- Methods for generating engineered glycoforms are known in the art and include but are not limited to those described in U.S. Pat. Nos 6,602,684; 7,326,681; 7,388,081; and WO 2008/006554.
- Heteroconjugate antibodies are also within the scope of the present invention.
- Heteroconjugate antibodies are composed of two covalently joined antibodies. Such antibodies have, for example, been proposed to target immune system cells to unwanted cells (U.S. Pat. No. 4,676,980), and for treatment of HIV infection (WO 91/00360; WO 92/00373; and EP 03089).
- Heteroconjugate antibodies can be made using any convenient cross-linking methods. Suitable cross-linking agents are well known in the art, and are disclosed in U.S. Pat. No. 4,676,980, along with a number of cross -linking techniques.
- At least one antibody or specified portion or variant of the present invention is produced by a cell line, a mixed cell line, an immortalised cell or clonal population of immortalised cells.
- Immortalised binding producing cells can be produced using suitable methods, for example, fusion of a human antibody-producing cell and a heteromyeloma or immortalisation of an activated human B cell via infection with Epstein Barr virus (Gustafsson et al. 1991 Hum Antibodies Hybridomas 2 26-32; Zanella et al. 1992 J Immunol Methods 156 205-15; Niedbala et al. 1998 Hybridoma 17 299-304).
- the human anti-human IL- 12/23 proteins, fragments, specified portions or variants are generated by immunisation of a transgenic animal (e.g., mouse, rat, hamster, non-human primate, and the like) capable of producing a repertoire of human antibodies, as described herein and/or as known in the art.
- a transgenic animal e.g., mouse, rat, hamster, non-human primate, and the like
- Cells that produce a human antibody can be isolated from such animals and immortalised using suitable methods, such as the methods described herein.
- Transgenic mice that can produce a repertoire of human antibodies that bind to human antigens can be produced by known methods (e.g., but not limited to, U.S. Pat. Nos. 5,770,428, 5,569,825, 5,545,806, 5,625,126, 5,625,825, 5,633,425, 5,661,016 and 5,789,650 issued to Lonberg et al.; Jakobovits et al. WO 98/50433, Jakobovits et al. WO 98/24893, Lonberg et al. WO 98/24884, Lonberg et al. WO 97/13852, Lonberg et al.
- mice comprise at least one transgene comprising DNA from at least one human immunoglobulin locus that is functionally rearranged, or which can undergo functional rearrangement.
- the endogenous immunoglobulin loci in such mice can be disrupted or deleted to eliminate the capacity of the animal to produce antibodies encoded by endogenous genes.
- the term "functionally rearranged,” as used herein refers to a segment of DNA from an immunoglobulin locus that has undergone V(D)J recombination, thereby producing an immunoglobulin gene that encodes an immunoglobulin chain (e.g., heavy chain, light chain), or any portion thereof.
- a functionally rearranged immunoglobulin gene can be directly or indirectly identified using suitable methods, such as, for example, nucleotide sequencing, hybridization (e.g., Southern blotting, Northern blotting) using probes that can anneal to coding joints between gene segments or enzymatic amplification of immunoglobulin genes (e.g., polymerase chain reaction) with primers that can anneal to coding joints between gene segments.
- Whether a cell produces an antibody comprising a particular variable region or a variable region comprising a particular sequence can also be determined using suitable methods.
- mRNA can be isolated from an antibody- producing cell (e.g., a hybridoma or recombinant cell or other suitable source) and used to produce cDNA encoding the antibody or specified portion or variant thereof.
- the cDNA can be cloned and sequenced or can be amplified (e.g., by polymerase chain reaction or other known and suitable methods) using a first primer that anneals specifically to a portion of the variable region of interest (e.g., CDR, coding joint) and a second primer that anneals specifically to non-variable region sequences (e.g., C H I, V H ).
- a first primer that anneals specifically to a portion of the variable region of interest (e.g., CDR, coding joint) and a second primer that anneals specifically to non-variable region sequences (e.g., C H I, V H ).
- Screening antibodies, specified portions or variants thereof for specific binding to similar proteins or fragments can be conveniently achieved using peptide display libraries.
- This method involves the screening of large collections of peptides for individual members having the desired function or structure.
- Antibody screening of peptide display libraries is well known in the art.
- the displayed peptide sequences can be from 3 to 5000 or more amino acids in length, frequently from 5-100 amino acids long, and often from about 8 to 25 amino acids long.
- several recombinant DNA methods have been described.
- One type involves the display of a peptide sequence on the surface of a bacteriophage or cell.
- Each bacteriophage or cell contains the nucleotide sequence encoding the particular displayed peptide sequence.
- Such methods are described in PCT Patent Publication Nos. WO 91/17271, WO 91/18980, WO 91/19818, and WO 93/08278.
- Other systems for generating libraries of peptides have aspects of both in vitro chemical synthesis and recombinant methods. See, PCT Patent Publication Nos. WO 92/05258, WO 92/14843, and WO 96/19256. See also, U.S. Pat. Nos. 5,658,754; and 5,643,768.
- Peptide display libraries, vector, and screening kits are commercially available from such suppliers as Invitrogen (Carlsbad, Calif.), and Cambridge Antibody Technologies (Cambridgeshire, UK). See, e.g., U.S. Pat. Nos. 4,704,692, 4,939,666, 4,946,778, 5,260,203, 5,455,030, 5,518,889, 5,534,621, 5,656,730, 5,763,733, 5,767,260, 5,856,456, assigned to Enzon; U.S. Pat. Nos. 5,223,409, 5,403,484, 5,571,698, 5,837,500, assigned to Dyax, U.S. Pat. Nos.
- Antibodies, specified portions and variants thereof of the present invention can also be prepared by providing at least one antibody, specified portion or variant thereof encoding nucleic acid to transgenic animals or mammals, such as goats, cows, horses, sheep, and the like, that produce such antibodies, specified portions or variants thereof in their milk.
- transgenic animals or mammals such as goats, cows, horses, sheep, and the like, that produce such antibodies, specified portions or variants thereof in their milk.
- Such animals can be provided using known methods. See, e.g., but not limited to, U.S. Pat. Nos. 5,827,690; 5,849,992; 4,873,316; 5,849,992; 5,994,616; 5,565,362; 5,304,489, each of which is entirely incorporated herein by reference.
- Antibodies, specified portions and variants thereof of the present invention can additionally be prepared using at least one antibody or specified portion or variant encoding nucleic acid to provide transgenic plants and cultured plant cells (e.g., but not limited to, tobacco, maize and bryophytes) that produce such antibodies, specified portions or variants thereof in the plant parts or in cells cultured therefrom.
- transgenic tobacco leaves expressing recombinant proteins have been successfully used to provide large amounts of recombinant proteins, e.g., using an inducible promoter. See, e.g., Cramer et al. 1999 Curr Top Microbiol Immunol 240 95-118 and references cited therein.
- transgenic maize have been used to express mammalian proteins at commercial production levels, with biological activities equivalent to those produced in other recombinant systems or purified from natural sources. See, e.g Hood et al. 1999 Adv Exp Med Biol 464 127-47 and references cited therein. Antibodies have also been produced in large amounts from transgenic plant seeds including tobacco seeds and potato tubers. See, e.g., Conrad et al. 1998 Plant MoI Biol 38 101-9 and references cited therein.
- Antibodies have also been transiently expressed and secreted by such genetically modified moss protoplasts and show an unaltered antigen- binding affinity and, in extensive tests, revealed up to 40-fold enhanced ADCC (Schuster, Jost et al. 2007 Biotechnol J 2 700-8).
- antibodies, specified portions and variants thereof of the present invention can also be produced using transgenic plants, according to known methods. See also, e.g., Whitelam et al. 1994 Biochem Soc Trans 22 940-4; Ma et al. 1995 Trends Biotechnol 13 522-7; Ma et al. 1995 Plant Physiol 109 341-6 and references cited therein. Each of the above references is entirely incorporated herein by reference.
- the antibodies of the invention can bind human IL- 12/23 with a wide range of affinities (K D ).
- at least one antibody of the present invention can optionally bind human IL- 12/23 with high affinity.
- an antibody can bind human IL- 12/23 proteins with a K D equal to or less than about 10 ⁇ 9 M or, more preferably, with a K D equal to or less than about 0.1-9.9 (or any range or value therein) X 10 "10 M, 10 "11 , 10 "12 , 10 "13 or any range or value therein.
- the affinity or avidity of an antibody for an antigen can be determined experimentally using any suitable method.
- the measured affinity of a particular antibody with its binding partner can vary if measured under different conditions (e.g., salt concentration, pH).
- affinity and other antigen-binding parameters e.g., K D , K a , K d
- K D , K a , K d are preferably made with standardised solutions of antibody and binding partner, and a standardised buffer, such as the buffer described herein.
- Isolated nucleic acid molecules of the present invention can include nucleic acid molecules comprising an open reading frame (ORF), optionally with one or more introns, e.g., but not limited to, at least one specified portion of at least one CDR, as CDRl, CDR2 and/or CDR3 of at least one heavy chain or light chain, respectively; nucleic acid molecules comprising the coding sequence for an antibody, specified portion or variant thereof; and nucleic acid molecules which comprise a nucleotide sequence substantially different from those described above but which, due to the degeneracy of the genetic code, still encode at least one antibody as described herein and/or as known in the art.
- ORF open reading frame
- introns e.g., but not limited to, at least one specified portion of at least one CDR, as CDRl, CDR2 and/or CDR3 of at least one heavy chain or light chain, respectively
- nucleic acid molecules comprising the coding sequence for an antibody, specified portion or variant thereof
- nucleic acid variants that code for specific antibody, specified portion or variants thereof of the present invention. See, e.g., Ausubel, et al., supra, and such nucleic acid variants are included in the present invention.
- nucleic acid molecules of the present invention which comprise a nucleic acid encoding an antibody or specified portion or variant can include, but are not limited to, those encoding the amino acid sequence of an antibody fragment, by itself; the coding sequence for the entire antibody or a portion thereof; the coding sequence for an antibody, fragment or portion, as well as additional sequences, such as the coding sequence of at least one signal leader or fusion peptide, with or without the aforementioned additional coding sequences, such as at least one intron, together with additional, non-coding sequences, including but not limited to, non-coding 5' and 3' sequences, such as the transcribed, non- translated sequences that play a role in transcription, mRNA processing, including splicing and polyadenylation signals (for example - ribosome binding and stability of mRNA); an additional coding sequence that codes for additional amino acids, such as those that provide additional functionalities.
- the sequence encoding an antibody or specified portion or variant can be fused to
- the present invention provides isolated nucleic acids that hybridise under selective hybridisation conditions to a polynucleotide encoding an antibody of the present invention.
- the polynucleotides of this embodiment can be used for isolating, detecting, and/or quantifying nucleic acids comprising such polynucleotides.
- polynucleotides of the present invention can be used to identify, isolate, or amplify partial or full-length clones in a deposited library.
- the polynucleotides are genomic or cDNA sequences isolated, or otherwise complementary to, a cDNA from a human or mammalian nucleic acid library.
- the cDNA library comprises at least 80% full-length sequences, preferably at least 85% or 90% full-length sequences, and more preferably at least 95% full- length sequences.
- the cDNA libraries can be normalised to increase the representation of rare sequences.
- Low or moderate stringency hybridisation conditions are typically, but not exclusively, employed with sequences having a reduced sequence identity relative to complementary sequences.
- Moderate and high stringency conditions can optionally be employed for sequences of greater identity.
- Low stringency conditions allow selective hybridisation of sequences having about 70% sequence identity and can be employed to identify orthologous or paralogous sequences.
- polynucleotides of this invention will encode at least a portion of an antibody or specified portion or variant encoded by the polynucleotides described herein.
- the polynucleotides of this invention embrace nucleic acid sequences that can be employed for selective hybridisation to a polynucleotide encoding an antibody or specified portion or variant of the present invention. See, e.g., Ausubel, supra; Colligan, supra, each entirely incorporated herein by reference.
- the isolated nucleic acids of the present invention can be made using (a) recombinant methods, (b) synthetic techniques, and (c) purification techniques, or combinations thereof, as well-known in the art.
- the nucleic acids can conveniently comprise sequences in addition to a polynucleotide of the present invention.
- a multi-cloning site comprising one or more endonuclease restriction sites can be inserted into the nucleic acid to aid in isolation of the polynucleotide.
- translatable sequences can be inserted to aid in the isolation of the translated polynucleotide of the present invention.
- a hexa-histidine marker sequence provides a convenient means to purify the proteins of the present invention.
- the nucleic acid of the present invention, excluding the coding sequence is optionally a vector, adapter, or linker for cloning and/or expression of a polynucleotide of the present invention.
- Additional sequences can be added to such cloning and/or expression sequences to optimise their function in cloning and/or expression, to aid in isolation of the polynucleotide, or to improve the introduction of the polynucleotide into a cell.
- Use of cloning vectors, expression vectors, adapters, and linkers is well known in the art. (See, e.g., Ausubel, supra; or Sambrook, supra)
- RNA, cDNA, genomic DNA, or any combination thereof can be obtained from biological sources using any number of cloning methodologies known to those of skill in the art.
- oligonucleotide probes that selectively hybridise, under stringent conditions, to the polynucleotides of the present invention are used to identify the desired sequence in a cDNA or genomic DNA library.
- the isolation of RNA, and construction of cDNA and genomic libraries, is well known to those of ordinary skill in the art. (See, e.g., Ausubel, supra; or Sambrook, supra)
- a cDNA or genomic library can be screened using a probe based upon the sequence of a polynucleotide of the present invention, such as those disclosed herein. Probes can be used to hybridise with genomic DNA or cDNA sequences to isolate homologous genes in the same or different organisms.
- Probes can be used to hybridise with genomic DNA or cDNA sequences to isolate homologous genes in the same or different organisms.
- degrees of stringency of hybridisation can be employed in the assay; and either the hybridisation or the wash medium can be stringent. As the conditions for hybridisation become more stringent, there must be a greater degree of complementarity between the probe and the target for duplex formation to occur.
- the degree of stringency can be controlled by one or more of temperature, ionic strength, pH and the presence of a partially denaturing solvent, such as formamide.
- the stringency of hybridisation is conveniently varied by changing the polarity of the reactant solution through, for example, manipulation of the concentration of formamide within the range of 0% to 50%.
- the degree of complementarity (sequence identity) required for detectable binding will vary in accordance with the stringency of the hybridisation medium and/or wash medium.
- the degree of complementarity will optimally be 100%, or 90- 100%, or any range or value therein.
- minor sequence variations in the probes and primers can be compensated for by reducing the stringency of the hybridisation and/or wash medium.
- RNA or DNA Methods of amplification of RNA or DNA are well known in the art and can be used according to the present invention without undue experimentation, based on the teaching and guidance presented herein.
- Known methods of DNA or RNA amplification include, but are not limited to, polymerase chain reaction (PCR) and related amplification processes (see, e.g., U.S. Pat. Nos. 4,683,195, 4,683,202, 4,800,159, 4,965,188, to Mullis, et al; U.S. Pat. Nos. 4,795,699 and 4,921,794 to Tabor, et al; U.S. Pat. No. 5,142,033 to Innis; U.S. Pat. No.
- PCR polymerase chain reaction
- PCR technology can be used to amplify the sequences of polynucleotides of the present invention and related genes directly from genomic DNA or cDNA libraries.
- PCR and other in vitro amplification methods can also be useful, for example, to clone nucleic acid sequences that code for proteins to be expressed, to make nucleic acids to use as probes for detecting the presence of the desired mRNA in samples, for nucleic acid sequencing, or for other purposes.
- examples of techniques sufficient to direct persons of skill through in vitro amplification methods are found in Berger, supra, Sambrook, supra, and Ausubel, supra, as well as Mullis, et al., U.S. Pat. No.
- kits for genomic PCR amplification are known in the art. See, e.g., Advantage®-GC Genomic PCR Kit (Clontech).
- the T4 gene 32 protein (Boehringer Mannheim) can be used to improve yield of long PCR products.
- the isolated nucleic acids of the present invention can also be prepared by direct chemical synthesis by known methods (see, e.g., Ausubel, et al., supra). Chemical synthesis generally produces a single-stranded oligonucleotide, which can be converted into double- stranded DNA by hybridisation with a complementary sequence, or by polymerisation with a DNA polymerase using the single strand as a template.
- Chemical synthesis of DNA can be limited to sequences of about 100 or more bases, longer sequences can be obtained by the ligation of shorter sequences.
- the present invention further provides recombinant expression cassettes comprising a nucleic acid of the present invention.
- a nucleic acid sequence of the present invention for example, a cDNA or a genomic sequence encoding an antibody or specified portion or variant of the present invention, can be used to construct a recombinant expression cassette that can be introduced into at least one desired host cell.
- a recombinant expression cassette will typically comprise a polynucleotide of the present invention operably linked to transcriptional initiation regulatory sequences that will direct the transcription of the polynucleotide in the intended host cell. Both heterologous and non-heterologous (i.e., endogenous) promoters can be employed to direct expression of the nucleic acids of the present invention.
- isolated nucleic acids that serve as promoter, enhancer, or other elements can be introduced in the appropriate position (upstream, downstream or in intron) of a non-heterologous form of a polynucleotide of the present invention so as to up or down regulate expression of a polynucleotide of the present invention.
- endogenous promoters can be altered in vivo or in vitro by mutation, deletion and/or substitution.
- the present invention also relates to vectors that include isolated nucleic acid molecules of the present invention, host cells that are genetically engineered with the recombinant vectors, and the production of at least one antibody or specified portion or variant by recombinant techniques, as is well known in the art. See, e.g., Sambrook, et al., supra; Ausubel, et al., supra, each entirely incorporated herein by reference.
- the polynucleotides can optionally be joined to a vector containing a selectable marker for propagation in a host.
- a plasmid vector is introduced in a precipitate, such as a calcium phosphate precipitate, or in a complex with a charged lipid. If the vector is a virus, it can be packaged in vitro using an appropriate packaging cell line and then transduced into host cells.
- the DNA insert should be operatively linked to an appropriate promoter.
- the expression constructs will further contain sites for transcription initiation, termination and, in the transcribed region, a ribosome binding site for translation.
- the coding portion of the mature transcripts expressed by the constructs will preferably include a translation initiating at the beginning and a termination codon (e.g., UAA, UGA or UAG) appropriately positioned at the end of the mRNA to be translated, with UAA and UAG preferred for mammalian or eukaryotic cell expression.
- Expression vectors will preferably but optionally include at least one selectable marker.
- markers include, e.g., but not limited to, methotrexate (MTX), dihydrofolate reductase (DHFR, U.S. Pat. Nos. 4,399,216; 4,634,665; 4,656,134; 4,956,288; 5,149,636; and 5,179,017), ampicillin, neomycin (G418), mycophenolic acid, or glutamine synthetase (GS, U.S. Pat. Nos.
- At least one antibody, specified portion or variant of the present invention can be expressed in a modified form, such as a fusion protein, and can include not only secretion signals, but also additional heterologous functional regions.
- a region of additional amino acids, particularly charged amino acids can be added to the N-terminus of an antibody, specified portion or variant to improve stability and persistence in the host cell, during purification, or during subsequent handling and storage.
- peptide moieties can be added to an antibody, specified portion or variant of the present invention to facilitate purification. Such regions can be removed prior to final preparation of an antibody or at least one fragment thereof.
- nucleic acids of the present invention can be expressed in a host cell by turning on (by manipulation) in a host cell that contains endogenous DNA encoding an antibody, specified portion or variant of the present invention.
- Such methods are well known in the art, e.g., as described in U.S. Pat. Nos. 5,580,734, 5,641,670, 5,733,746, and 5,733,761, entirely incorporated herein by reference.
- mammalian cells useful for the production of the antibodies, specified portions or variants thereof, are mammalian cells. Mammalian cell systems often will be in the form of monolayers of cells although mammalian cell suspensions or bioreactors can also be used.
- COS-I e.g., ATCC CRL 1650
- COS-7 e.g., ATCC CRL- 1651
- HEK293, BHK21 e.g., ATCC CRL-IO
- CHO e.g., ATCC CRL 1610
- BSC-I e.g., ATCC CRL-26 cell lines
- COS-7 cells CHO cells
- hep G2 cells hep G2 cells
- HeLa cells and the like which are readily available from, for example, American Type Culture Collection, Manassas, Va.
- Preferred host cells include cells of lymphoid origin, such as myeloma and lymphoma cells.
- Particularly preferred host cells are P3X63Ag8.653 cells (ATCC Accession Number CRL- 1580) and SP2/0-Agl4 cells (ATCC Accession Number CRL-1851).
- the recombinant cell is a P3X63Ab8.653 or a SP2/0-Agl4 cell.
- Expression vectors for these cells can include one or more of the following expression control sequences, such as, but not limited to, an origin of replication; a promoter (e.g., late or early SV40 promoters, the CMV promoter; U.S. Pat. Nos. 5,168,062; 5,385,839), an HSV tk promoter, a pgk (phosphoglycerate kinase) promoter, an EF-I alpha promoter (U.S. Pat. No.
- an origin of replication e.g., a promoter (e.g., late or early SV40 promoters, the CMV promoter; U.S. Pat. Nos. 5,168,062; 5,385,839), an HSV tk promoter, a pgk (phosphoglycerate kinase) promoter, an EF-I alpha promoter (U.S. Pat. No.
- At least one human immunoglobulin promoter at least one human immunoglobulin promoter; an enhancer, and/or processing information sites, such as ribosome binding sites, RNA splice sites, polyadenylation sites (e.g., an SV40 large T Ag poly A addition site), and transcriptional terminator sequences.
- an enhancer, and/or processing information sites such as ribosome binding sites, RNA splice sites, polyadenylation sites (e.g., an SV40 large T Ag poly A addition site), and transcriptional terminator sequences.
- polyadenlyation or transcription terminator sequences are typically incorporated into the vector.
- An example of a terminator sequence is the polyadenlyation sequence from the bovine growth hormone gene. Sequences for accurate splicing of the transcript can also be included.
- An example of a splicing sequence is the VPl intron from SV40 (Sprague et al. 1983 J Virol 45 773-81). Additionally, gene sequences to control replication in the host cell can be incorporated into the vector, as known in the art.
- An antibody, specified portion or variant can be recovered and purified from recombinant cell cultures by well-known methods, including, but not limited to, protein A purification, ammonium sulfate or ethanol precipitation, acid extraction, anion or cation exchange chromatography, phosphocellulose chromatography, hydrophobic interaction chromatography, affinity chromatography, hydroxylapatite chromatography and lectin chromatography. High performance liquid chromatography (“HPLC”) can also be employed for purification.
- HPLC high performance liquid chromatography
- Antibodies, specified portions or variants thereof of the present invention include naturally purified products, products of chemical synthetic procedures, and products produced by recombinant techniques from a eukaryotic host, including, for example, yeast, higher plant, insect and mammalian cells. Depending upon the host employed in a recombinant production procedure, the antibody, specified portion or variant of the present invention can be glycosylated or can be non-glycosylated, with glycosylated preferred. Such methods are described in many standard laboratory manuals, such as Sambrook, supra, Sections 17.37- 17.42; Ausubel, supra, Chapters 10, 12, 13, 16, 18 and 20, Colligan, Protein Science, supra, Chapters 12-14, all entirely incorporated herein by reference.
- the isolated antibodies of the present invention comprise an antibody or specified portion or variant encoded by any one of the polynucleotides of the present invention as discussed more fully herein, or any isolated or prepared antibody, specified portion or variant thereof.
- the antibody or antigen-binding fragment binds human IL- 12/23 proteins and, thereby substantially neutralises the biological activity of the proteins.
- neutralising antibody refers to an antibody that can inhibit human IL-12p40 protein or fragment related-dependent activity by about 20-120%, preferably by at least about 60, 70, 80, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100% or more depending on the assay.
- the capacity of the antibody or specified portion or variant to inhibit human IL- 12/23 related- dependent activity is preferably assessed by at least one suitable antibody or protein assay, as described herein and/or as known in the art.
- An antibody, specified portion or variant of the invention can be of any class (IgG, IgA, IgM, IgE, IgD, etc.) or isotype and can comprise a kappa or lambda light chain.
- the antibody or specified portion or variant comprises an IgG heavy chain or defined fragment, for example, at least one of isotypes,
- Antibodies of this type can be prepared by employing a transgenic mouse or other trangenic non-human mammal comprising at least one human light chain (e.g., IgG, IgA and IgM; e.g., ⁇ l, ⁇ 2, ⁇ 3, ⁇ 4) transgene as described herein and/or as known in the art.
- the antibody, specified portion or variant thereof comprises an IgGl heavy chain and an IgGl light chain.
- At least one antibody, specified portion or variant of the invention binds at least one specified epitope specific to IL-12p40 protein, fragment, portion or any combination thereof.
- an antibody, specified portion or variant specifically binds at least one epitope comprising at least 1-3 amino acids of the entire amino acid sequence of IL- 12p40 subunit.
- the at least one specified epitope can comprise any combination of at least one amino acid of IL-12p40 such as, but not limited to, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 amino acids of at least one of, 1-10, 10-20, 20-30, 30-40, 40-50, 50-60, 60-70, 70-80, 80-90, 90-100, 100-110, 110-120, 120-130, 130-140, 140-150, 150-160, 160-170, 170-180, 180-190, 190-200, 200-210, 210-220, 220-230, 230-240, 240-250, 250-260, 260-270, 280- 290, 290-300, 300-306, 1-7, 14-21, 29-52, 56-73, 83-93, 96-105, 156-175, 194-204
- the antibody can comprise at least one of a heavy or light chain variable region having a defined amino acid sequence.
- the antibody comprises at least one of at least one heavy chain variable region and/or at least one light chain variable region.
- Human antibodies that bind to human IL- 12/23 proteins and/or fragments and that comprise a defined heavy or light chain variable region can be prepared using suitable methods, such as phage display (Katsube et al. 1998 Int J MoI Med 1 863-8) or methods that employ transgenic animals, as known in the art and/or as described herein.
- a transgenic mouse comprising a functionally rearranged human immunoglobulin heavy chain transgene and a transgene comprising DNA from a human immunoglobulin light chain locus that can undergo functional rearrangement, can be immunised with human IL- 12 and/or IL-23 proteins, receptors, and/or fragments thereof to elicit the production of antibodies.
- the antibody producing cells can be isolated and hybridomas or other immortalised antibody-producing cells can be prepared as described herein and/or as known in the art.
- the antibody, specified portion or variant can be expressed using the encoding nucleic acid or portion thereof in a suitable host cell.
- the invention also relates to antibodies, antigen-binding fragments, immunoglobulin chains and CDRs comprising amino acids in a sequence that is substantially the same as an amino acid sequence described herein.
- antibodies or antigen-binding fragments and antibodies comprising such chains or CDRs can bind human IL- 12/23 proteins, and/or fragments with high affinity (e.g., K oless than or equal to about 10 "9 M).
- Amino acid sequences that are substantially the same as the sequences described herein include sequences comprising conservative amino acid substitutions, as well as amino acid deletions and/or insertions.
- a conservative amino acid substitution refers to the replacement of a first amino acid by a second amino acid that has chemical and/or physical properties (e.g., charge, structure, polarity, hydrophobicity/hydrophilicity) that are similar to those of the first amino acid.
- Conservative substitutions include replacement of one amino acid by another within the following groups: lysine (K), arginine (R) and histidine (H); aspartate (D) and glutamate (E); asparagine (N), glutamine (Q), serine (S), threonine (T), tyrosine (Y), K, R, H, D and E; alanine (A), valine (V), leucine (L), isoleucine (I), proline (P), phenylalanine (F), tryptophan (W), methionine (M), cysteine (C) and glycine (G); F, W and Y; C, S and T.
- An antibody or specified portion or variant of the present invention can include one or more amino acid substitutions, deletions or additions, either from natural mutations or human manipulation, as specified herein.
- amino acid substitutions a skilled artisan would make depends on many factors, including those described above. Generally speaking, the number of amino acid substitutions, insertions or deletions for any given binding polypeptide will not be more than 40, 30, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, such as 1-30 or any range or value therein, as specified herein.
- Amino acids in antibody, specified portion or variant of the present invention that are essential for function can be identified by methods known in the art, such as site-directed mutagenesis or alanine- scanning mutagenesis (e.g., Ausubel, supra, Chapters 8, 15; Cunningham et al. 1989 Science 244 1081-5). The latter procedure introduces single alanine mutations at every residue in the molecule. The resulting mutant molecules are then tested for biological activity, such as, but not limited to, at least one IL- 12/23 neutralising activity. Sites that are critical for an antibody, specified portion or variant binding can also be identified by structural analysis such as crystallisation, nuclear magnetic resonance or photoaffinity labeling (de Vos et al. 1992 Science 255 306-12; Smith et al. 1992 J MoI Biol 224 899-904).
- the invention relates to antibodies and antigen-binding fragments, as described herein, which are modified by the covalent attachment of an organic moiety.
- modification can produce an antibody or antigen-binding fragment with improved pharmacokinetic properties (e.g., increased in vivo serum half-life).
- the organic moiety can be a linear or branched hydrophilic polymeric group, fatty acid group, or fatty acid ester group.
- the hydrophilic polymeric group can have a molecular weight of about 800 to about 120,000 Daltons and can be a polyalkane glycol (e.g., polyethylene glycol (PEG), polypropylene glycol (PPG)), carbohydrate polymer, amino acid polymer or polyvinyl pyrolidone, and the fatty acid or fatty acid ester group can comprise from about eight to about forty carbon atoms.
- a polyalkane glycol e.g., polyethylene glycol (PEG), polypropylene glycol (PPG)
- carbohydrate polymer e.g., amino acid polymer or polyvinyl pyrolidone
- the fatty acid or fatty acid ester group can comprise from about eight to about forty carbon atoms.
- the modified antibodies and antigen-binding fragments of the invention can comprise one or more organic moieties that are covalently bonded, directly or indirectly, to the antibody, specified portion or variant.
- Each organic moiety that is bonded to an antibody or antigen-binding fragment of the invention can independently be a hydrophilic polymeric group, a fatty acid group or a fatty acid ester group.
- fatty acid encompasses mono-carboxylic acids and di-carboxylic acids.
- Hydrophilic polymers suitable for modifying antibodies of the invention can be linear or branched and include, for example, polyalkane glycols (e.g., PEG, monomethoxy- polyethylene glycol (mPEG), PPG and the like), carbohydrates (e.g., dextran, cellulose, oligosaccharides, polysaccharides and the like), polymers of hydrophilic amino acids (e.g., polylysine, polyarginine, polyaspartate and the like), polyalkane oxides (e.g., polyethylene oxide, polypropylene oxide and the like) and polyvinyl pyrolidone.
- polyalkane glycols e.g., PEG, monomethoxy- polyethylene glycol (mPEG), PPG and the like
- carbohydrates e.g., dextran, cellulose, oligosaccharides, polysaccharides and the like
- polymers of hydrophilic amino acids e.g., polylysine, polyarg
- the hydrophilic polymer that modifies the antibody of the invention has a molecular weight of about 800 to about 150,000 Daltons as a separate molecular entity.
- PEG5000 and PEG 2 O 1 OOo wherein the subscript is the average molecular weight of the polymer in Daltons, can be used.
- the hydrophilic polymeric group can be substituted with one to about six alkyl, fatty acid or fatty acid ester groups.
- Hydrophilic polymers that are substituted with a fatty acid or fatty acid ester group can be prepared by employing suitable methods.
- a polymer comprising an amine group can be coupled to a carboxylate of the fatty acid or fatty acid ester, and an activated carboxylate (e.g., activated with N,N-carbonyl diimidazole) on a fatty acid or fatty acid ester can be coupled to a hydroxyl group on a polymer.
- Fatty acids and fatty acid esters suitable for modifying antibodies of the invention can be saturated or can contain one or more units of unsaturation.
- Fatty acids that are suitable for modifying antibodies of the invention include, for example, n-dodecanoate (C 12 , laurate), n-tetradecanoate (C 14 , myristate), n-octadecanoate (C 18 , stearate), n-eicosanoate (C 2 o, arachidate), n-docosanoate (C 22 , behenate), n-triacontanoate (C30), n-tetracontanoate (C 4 o), cis- ⁇ 9-octadecanoate (C 18 , oleate), all cis- ⁇ 5,8,l l,14-eicosatetraenoate (C 2 o, arachidonate), octanedioic acid, tetradecane
- the modified antibodies and antigen-binding fragments can be prepared using suitable methods, such as by reaction with one or more modifying agents.
- An “activating group” is a chemical moiety or functional group that can, under appropriate conditions, react with a second chemical group thereby forming a covalent bond between the modifying agent and the second chemical group.
- amine-reactive activating groups include electrophilic groups, such as tosylate, mesylate, halo (chloro, bromo, fluoro, iodo), N-hydroxysuccinimidyl esters (NHS), and the like.
- Activating groups that can react with thiols include, for example, maleimide, iodoacetyl, acrylolyl, pyridyl disulfides, 5-thiol-2-nitrobenzoic acid thiol (TNB- thiol), and the like.
- An aldehyde functional group can be coupled to amine- or hydrazide- containing molecules, and an azide group can react with a trivalent phosphorous group to form phosphoramidate or phosphorimide linkages.
- Suitable methods to introduce activating groups into molecules are known in the art (see for example, Hermanson, G. T., Bioconjugate Techniques , Academic Press: San Diego, Calif. (1996)).
- An activating group can be bonded directly to the organic group (e.g., hydrophilic polymer, fatty acid, fatty acid ester), or through a linker moiety, for example, a divalent C 1 -C 12 group wherein one or more carbon atoms can be replaced by a heteroatom, such as oxygen, nitrogen or sulfur.
- Suitable linker moieties include, for example, tetraethylene glycol, — (CH 2 ) 3 — , — NH — (CH 2 ) 6 — NH — , — (CH 2 ) 2 — NH- and — CH 2 -O-CH 2 -CH 2 -O-CH 2 -CH 2 -O-CH-NH-.
- Modifying agents that comprise a linker moiety can be produced, for example, by reacting a mono-Boc- alkyldiamine (e.g., mono-Boc-ethylenediamine, mono-Boc-diaminohexane) with a fatty acid in the presence of l-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) to form an amide bond between the free amine and the fatty acid carboxylate.
- a mono-Boc- alkyldiamine e.g., mono-Boc-ethylenediamine, mono-Boc-diaminohexane
- EDC l-ethyl-3-(3-dimethylaminopropyl) carbodiimide
- the Boc protecting group can be removed from the product by treatment with trifluoroacetic acid (TFA) to expose a primary amine that can be coupled to another carboxylate as described, or can be reacted with maleic anhydride and the resulting product cyclised to produce an activated maleimido derivative of the fatty acid, (see, for example, Thompson, et al., WO 92/16221, the entire teachings of which are incorporated herein by reference.)
- TFA trifluoroacetic acid
- the modified antibodies of the invention can be produced by reacting an antibody or antigen-binding fragment with a modifying agent.
- the organic moieties can be bonded to the antibody in a non-site specific manner by employing an amine-reactive modifying agent, for example, an NHS ester of PEG.
- Modified antibodies or antigen-binding fragments can also be prepared by reducing disulfide bonds (e.g., intra-chain disulfide bonds) of an antibody or antigen-binding fragment. The reduced antibody or antigen-binding fragment can then be reacted with a thiol-reactive modifying agent to produce the modified antibody of the invention.
- Modified antibodies and antigen-binding fragments comprising an organic moiety that is bonded to specific sites of an antibody, specified portion or variant of the present invention can be prepared using suitable methods, such as reverse proteolysis (Fisch et al. 1992 Bioconjug Chem 3 147-53; Werlen et al. 1994 Bioconjug Chem 5 411-7; Capellas et al. 1997 Biotechnol Bioeng 56 456-63; Kumaran et al. 1997 Protein Sci 6 2233-41 and the methods described in Hermanson, G. T., Bioconjugate Techniques , Academic Press: San Diego, Calif. (1996)).
- suitable methods such as reverse proteolysis (Fisch et al. 1992 Bioconjug Chem 3 147-53; Werlen et al. 1994 Bioconjug Chem 5 411-7; Capellas et al. 1997 Biotechnol Bioeng 56 456-63; Kumaran et al. 1997 Protein Sci 6 2233-41 and the methods described in Her
- the antibody compositions of the invention can optionally further comprise an effective amount of at least one compound or protein selected from at least one of an anti- infective drug, a cardiovascular (CV) system drug, a central nervous system (CNS) drug, an autonomic nervous system (ANS) drug, a respiratory tract drug, a gastrointestinal (GI) tract drug, a hormonal drug, a drug for fluid or electrolyte balance, a hematologic drug, an antineoplastic, an immunomodulation drug, an ophthalmic, otic or nasal drug, a topical drug, a nutritional drug or the like.
- CV cardiovascular
- CNS central nervous system
- ANS autonomic nervous system
- a respiratory tract drug a gastrointestinal (GI) tract drug
- GI gastrointestinal
- a hormonal drug a drug for fluid or electrolyte balance
- a hematologic drug an antineoplastic
- an immunomodulation drug an ophthalmic, otic or nasal drug
- topical drug a nutritional drug or the like.
- Such drugs are well known in the art, including formulations, indications, dosing and administration for each presented herein (see, e.g., Nursing 2001 Handbook of Drugs, 21 st edition, Springhouse Corp., Springhouse, Pa., 2001; Health Professional's Drug Guide 2001, ed., Shannon, Wilson, Stang, Prentice-Hall, Inc, Upper Saddle River, NJ. ; Pharmcotherapy Handbook, Wells et al., ed., Appleton & Lange, Stamford, Conn., each entirely incorporated herein by reference).
- Antibody, specified portion or variant compositions of the present invention can further comprise at least one of any suitable auxiliary, such as, but not limited to, diluent, binder, stabiliser, buffers, salts, lipophilic solvents, preservative, adjuvant or the like.
- any suitable auxiliary such as, but not limited to, diluent, binder, stabiliser, buffers, salts, lipophilic solvents, preservative, adjuvant or the like.
- auxiliaries are preferred.
- Non-limiting examples of, and methods of preparing such sterile solutions are well known in the art, such as, but not limited to,
- Pharmaceutically acceptable carriers can be routinely selected that are suitable for the mode of administration, solubility and/or stability of the antibody composition as well known in the art or as described herein.
- compositions include but are not limited to proteins, peptides, amino acids, lipids, and carbohydrates (e.g., sugars, including monosaccharides, di-, tri-, tetra-, and oligosaccharides; derivatised sugars such as alditols, aldonic acids, esterified sugars and the like; and polysaccharides or sugar polymers), which can be present singly or in combination, comprising alone or in combination 1-99.99% by weight or volume.
- Exemplary protein excipients include serum albumin, such as human serum albumin (HSA), recombinant human albumin (rHA), gelatin, casein, and the like.
- One preferred amino acid is glycine.
- Carbohydrate excipients suitable for use in the invention include, for example, monosaccharides, such as fructose, maltose, galactose, glucose, D-mannose, sorbose, and the like; disaccharides, such as lactose, sucrose, trehalose, cellobiose, and the like; polysaccharides, such as raffinose, melezitose, maltodextrins, dextrans, starches, and the like; and alditols, such as mannitol, xylitol, maltitol, lactitol, xylitol sorbitol (glucitol), myoinositol and the like.
- Preferred carbohydrate excipients for use in the present invention are mannitol, trehalose, and raffinose.
- Antibody compositions can also include a buffer or a pH adjusting agent; typically, the buffer is a salt prepared from an organic acid or base.
- Representative buffers include organic acid salts, such as salts of citric acid, ascorbic acid, gluconic acid, carbonic acid, tartaric acid, succinic acid, acetic acid, or phthalic acid; Tris, tromethamine hydrochloride, or phosphate buffers.
- Preferred buffers for use in the present compositions are organic acid salts, such as citrate.
- the antibody, specified portion or variant compositions of the invention can include polymeric excipients/additives, such as polyvinylpyrrolidones, ficolls (a polymeric sugar), dextrates (e.g., cyclodextrins, such as 2-hydroxypropyl- ⁇ -cyclodextrin), polyethylene glycols, flavoring agents, antimicrobial agents, sweeteners, antioxidants, antistatic agents, surfactants (e.g., polysorbates such as "TWEEN® 20" and "TWEEN® 80"), lipids (e.g., phospholipids, fatty acids), steroids (e.g., cholesterol), and chelating agents (e.g., EDTA).
- polymeric excipients/additives such as polyvinylpyrrolidones, ficolls (a polymeric sugar), dextrates (e.g., cyclodextrins, such as 2-hydroxypropyl- ⁇ -cyclodextrin), poly
- the invention provides for stable formulations, which comprise preferably a phosphate buffer with saline or a chosen salt, as well as preserved solutions and formulations containing a preservative, as well as multi-use preserved formulations suitable for pharmaceutical or veterinary use, comprising at least one antibody, specified portion or variant in a pharmaceutically acceptable formulation.
- Preserved formulations contain at least one known preservative or optionally selected from the group consisting of at least one phenol, m-cresol, p-cresol, o-cresol, chlorocresol, benzyl alcohol, phenylmercuric nitrite, phenoxyethanol, formaldehyde, chlorobutanol, magnesium chloride (e.g., hexahydrate), alkylparaben (methyl, ethyl, propyl, butyl and the like), benzalkonium chloride, benzethonium chloride, sodium dehydroacetate and thimerosal, or mixtures thereof in an aqueous diluent.
- Any suitable concentration or mixture can be used as known in the art, such as 0.001-5%, or any range or value therein, such as, but not limited to 0.001, 0.003, 0.005, 0.009, 0.01, 0.02, 0.03, 0.05, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.3, 4.5, 4.6, 4.7, 4.8, 4.9, or any range or value therein.
- Non-limiting examples include, no preservative, 0.1-2% m-cresol (e.g., 0.2, 0.3, 0.4, 0.5, 0.9, 1.0%), 0.1-3% benzyl alcohol (e.g., 0.5, 0.9, 1.1., 1.5, 1.9, 2.0, 2.5%), 0.001-0.5% thimerosal (e.g., 0.005, 0.01), 0.001-2.0% phenol (e.g., 0.05, 0.25, 0.28, 0.5, 0.9, 1.0%), 0.0005-1.0% alkylparaben(s) (e.g., 0.00075, 0.0009, 0.001, 0.002, 0.005, 0.0075, 0.009, 0.01, 0.02, 0.05, 0.075, 0.09, 0.1, 0.2, 0.3, 0.5, 0.75, 0.9, 1.0%), and the like.
- 0.1-2% m-cresol e.g., 0.2, 0.3, 0.4, 0.5, 0.9
- Any method of the present invention can comprise administering an effective amount of a composition or phannaceutical composition comprising at least one antibody, specified portion or variant to a cell, tissue, organ, animal or patient in need of such modulation, treatment or therapy.
- Such a method can optionally further comprise co-administration or combination therapy for treating such immune diseases, wherein the administering of said at least one antibody, specified portion or variant thereof further comprises administering, before, concurrently, and/or after, at least one selected from at least one multiple sclerosis therapeutic (including but not limited to, beta-interferon Ia and beta-interferon Ib (e.g., AvonexTM, RebiF M , BetaseonTM), glutiramer acetate (e.g., Copaxone), cyclophasphamide, azathioprine, glucocorticosteroids, methotrexate, Paclitaxel, 2-chlorodeoxyadenosine, mitoxantrone, IL-10, TGBb, CD
- Suitable dosages are well known in the art. See, e.g., Wells et al., eds., Pharmacotherapy Handbook, 2nd Edition, Appleton and Lange, Stamford, Conn. (2000); PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, Deluxe Edition, Tarascon Publishing, Loma Linda, Calif. (2000), each of which references are entirely incorporated herein by reference.
- TNF antagonists suitable for compositions, combination therapy, co-administration, devices and/or methods of the present invention include, but are not limited to, anti-TNF antibodies, antigen-binding fragments thereof, and receptor molecules which bind specifically to TNF; compounds which prevent and/or inhibit TNF synthesis, TNF release or its action on target cells, such as thalidomide, tenidap, phosphodiesterase inhibitors (e.g., pentoxifylline and rolipram), A2b adenosine receptor agonists and A2b adenosine receptor enhancers; compounds which prevent and/or inhibit TNF receptor signalling, such as mitogen activated protein (MAP) kinase inhibitors; compounds which block and/or inhibit membrane TNF cleavage, such as metalloproteinase inhibitors; compounds which block and/or inhibit TNF activity, such as angiotensin converting enzyme
- MAP mitogen activated protein
- a "tumor necrosis factor antibody,” “TNF antibody,” “TNF ⁇ antibody,” or fragment and the like decreases, blocks, inhibits, abrogates or interferes with TNF ⁇ activity in vitro, in situ and/or preferably in vivo.
- a suitable TNF human antibody of the present invention can bind TNF ⁇ and includes anti-TNF antibodies, antigen- binding fragments thereof, and specified mutants or domains thereof that bind specifically to TNF ⁇ .
- a suitable TNF antibody or fragment can also decrease block, abrogate, interfere, prevent and/or inhibit TNF RNA, DNA or protein synthesis, TNF release, TNF receptor signaling, membrane TNF cleavage, TNF activity, TNF production and/or synthesis.
- Preferred TNF receptor molecules useful in the present invention are those that bind TNF ⁇ with high affinity (see, e.g., Feldmann et al., International Publication No. WO 92/07076; Loetscher et al. 1990 Cell 61 351-9; Schall et al. 1990 Cell 61 361-70, which references are entirely incorporated herein by reference) and optionally possess low immunogenicity.
- the 55 kDa (p55 TNF-R) and the 75 kDa (p75 TNF-R) TNF cell surface receptors are useful in the present invention.
- Truncated forms of these receptors comprising the extracellular domains (ECD) of the receptors or functional portions thereof (see, e.g., Corcoran et al. 1994 Eur J Biochem 223 831-40), are also useful in the present invention.
- Truncated forms of the TNF receptors, comprising the ECD have been detected in urine and serum as 30 kDa and 40 kDa TNF ⁇ inhibitory antibodies (Engelmann et al. 1990 J Biol Chem 265 1531-6).
- TNF receptor multimeric molecules and TNF immunoreceptor fusion molecules, and derivatives and fragments or portions thereof, are additional examples of TNF receptor molecules which are useful in the methods and compositions of the present invention.
- TNF receptor molecules which can be used in the invention are characterised by their ability to treat patients for extended periods with good to excellent alleviation of symptoms and low toxicity. Low immunogenicity and/or high affinity, as well as other undefined properties, may contribute to the therapeutic results achieved.
- treatment of pathologic conditions is effected by administering an effective amount or dosage of at least one antibody composition that total, on average, a range from at least about 0.01 to 500 milligrams of at least one antibody, specified portion or variant/kilogram of patient per dose, and, preferably, from at least about 0.1 to 100 milligrams of an antibody, specified portion or variant/kilogram of patient per single or multiple administration, depending upon the specific activity of antibody, specified portion or variant contained in the composition.
- the effective serum concentration can comprise 0.1-5000 ⁇ g/ml serum concentration per single or multiple administration. Suitable dosages are known to medical practitioners and will, of course, depend upon the particular disease state, specific activity of the composition being administered, and the particular patient undergoing treatment.
- Preferred doses can optionally include 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20,
- 97, 98, 99 and/or 100 mg/kg/administration or any range, value or fraction thereof, or to achieve a serum concentration of 0.1, 0.5, 0.9, 1.0, 1.1, 1.2, 1.5, 1.9, 2.0, 2.5, 2.9, 3.0, 3.5, 3.9, 4.0, 4.5, 4.9, 5.0, 5.5, 5.9, 6.0, 6.5, 6.9, 7.0, 7.5, 7.9, 8.0, 8.5, 8.9, 9.0, 9.5, 9.9, 10, 10.5, 10.9,
- the dosage administered can vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent, and its mode and route of administration; age, health, and weight of the recipient; nature and extent of symptoms, kind of concurrent treatment, frequency of treatment, and the effect desired.
- a dosage of active ingredient can be about 0.1 to 100 milligrams per kilogram of body weight.
- 0.1 to 50, and, preferably, 0.1 to 10 milligrams per kilogram per administration or in sustained release form is effective to obtain desired results.
- treatment of humans or animals can be provided as a one-time or periodic dosage of at least one antibody, specified portion or variant of the present invention, 0.1 to 100 mg/kg, such as 0.5, 0.9, 1.0, 1.1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,
- Dosage forms (composition) suitable for internal administration generally contain from about 0.1 milligram to about 500 milligrams of active ingredient per unit or container.
- the active ingredient will ordinarily be present in an amount of about 0.5-99.999% by weight based on the total weight of the composition.
- the antibody, specified portion or variant can be formulated as a solution, suspension, emulsion or lyophilised powder in association, or separately provided, with a pharmaceutically acceptable parenteral vehicle.
- a pharmaceutically acceptable parenteral vehicle examples include water, saline, Ringer's solution, dextrose solution, and 1-10% human serum albumin. Liposomes and nonaqueous vehicles, such as fixed oils, may also be used.
- the vehicle or lyophilised powder may contain additives that maintain isotonicity (e.g., sodium chloride, mannitol) and chemical stability (e.g., buffers and preservatives).
- the formulation is sterilised by known or suitable techniques.
- Suitable pharmaceutical carriers are described in the most recent edition of Remington's Pharmaceutical Sciences, A. Osol, a standard reference text in this field.
- a dosage form can contain a pharmaceutically acceptable non-toxic salt of the compounds that has a low degree of solubility in body fluids, for example, (a) an acid addition salt with a polybasic acid, such as phosphoric acid, sulfuric acid, citric acid, tartaric acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalene mono- or di-sulfonic acids, polygalacturonic acid, and the like; (b) a salt with a polyvalent metal cation, such as zinc, calcium, bismuth, barium, magnesium, aluminium, copper, cobalt, nickel, cadmium and the like, or with an organic cation formed from e.g., N,N'-d
- the compounds of the present invention or, preferably, a relatively insoluble salt, such as those just described can be formulated in a gel, for example, an aluminium monostearate gel with, e.g. sesame oil, suitable for injection.
- Particularly preferred salts are zinc salts, zinc tannate salts, pamoate salts, and the like.
- Another type of slow release depot formulation for injection would contain the compound or salt dispersed for encapsulation in a slow degrading, nontoxic, non-antigenic polymer, such as a polylactic acid/polyglycolic acid polymer, for example, as described in U.S. Pat. No. 3,773,919.
- the compounds or, preferably, relatively insoluble salts, such as those described above, can also be formulated in cholesterol matrix silastic pellets, particularly for use in animals.
- Additional slow release, depot or implant formulations, e.g., gas or liquid liposomes, are known in the literature (U.S. Pat. No. 5,770,222 and "Sustained and Controlled Release Drug Delivery Systems", J. R. Robinson ed., Marcel Dekker, Inc., N.Y., 1978).
- RNA from the cell lines, PMA202 and PMA204, and using PCR techniques the sequences of the murine heavy chain and light chain variable regions were obtained. These sequences are as follows, with the CDRs underlined and defined according to Kabat (Kabat et al. 1971 Ann N Y Acad Sci 190 382-93 and Kabat, E.A., et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242). Note all subsequent protein sequences encoding variable regions of antibodies are numbered according to the Kabat numbering system.
- TVTVSS PMA204 Murine Light Chain variable region (SEQ ID NO: 7)
- Antibody 202.1 heavy chain (SEQ ID NO: 10)
- Antibody 202.1 light chain (SEQ ID NO: 11)
- Antibody 1 light chain (SEQ ID NO: 13)
- Both antibodies were produced transiently in a HEK cell line and purified using Protein A chromatography.
- Antibody 1 was tested in ELISA (FIGURE 3) and Surface Plasmon Resonance (SPR) (TABLE 1) assays against IL-12, IL-23, IL-12p40 and shown to be specific for the p40 subunit of IL- 12/23.
- the binding profile was similar to that of the original mouse antibody PMA204 (FIGURE 3).
- PMA204 and Antibody 1 do not neutralize IL-12, IL-12p40, IL-12p80 or IL-23 binding to IL-12R ⁇ l
- PMA204 and Antibody 1 do not neutralize the binding of IL-12 and IL- 12p80 to IL-12R ⁇ l(SEQ ID NO: 14) (FIGURE 5). IL-12p40 and IL-23 binding to IL-12R ⁇ l was not inhibited by PMA204 or Antibody 1 (FIGURE 6).
- Antibody 1 does not inhibit the binding of IL- 12/23 to IL-12R ⁇ l transfected cell lines
- a stably transfected Jurkat cell line overexpressing IL-12R ⁇ l was generated. This cell line was negative for IL- 12R ⁇ 2 and IL-23R as determined by flow cytometry. Binding of IL- 12p40, IL-12 and IL-23 to the cell line was confirmed using flow cytometry. In an experiment in which Antibody 1 and Antibody 202.1 were titrated with IL-12p40, IL-12 or IL-23, Antibody 202.1 demonstrated titratable inhibition of cytokine binding to the IL-12R ⁇ l Jurkat cell line (FIGURE 7).
- Antibody 1 did not appreciably neutralize binding of either IL-12, IL-23 or the IL-12p40 chain alone to the IL-12R ⁇ l Jurkat cell line (FIGURE 7).
- the mean fluorescence intensity of both IL-12 and IL-23 increased with increasing Antibody 1 concentration up to l ⁇ g/ml, reflecting the formation of antibody-cytokine-receptor complexes (FIGURE 7).
- 2.5 Antibody 1 forms a complex with IL-12, IL-23 bound to IL-12R ⁇ l on transfected cell lines.
- Antibody 1 bound strongly to IL-12, IL-23 or the IL- 12p40 chain bound to IL- 12R ⁇ l on the surface of transfected cells (FIGURE 8). It could be envisioned that this complex could occur in biological systems and present the antibody in such an orientation as to allow the Fc region of the antibody to interact with Fc binding receptors. Such receptors could be present on effector cells and induce ADCC and CDC activity thereby exhibiting cytotoxic effects on the target cell on which the antibody-cytokine-receptor complex is formed. In contrast, Antibody 202.1, showed negligible binding to cytokine-receptor complexes.
- Antibody 50 which had the following heavy and light chain variable regions:
- Antibody 50 VH domain (SEQ ID NO: 112)
- any of the germline sequences shown (SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19) in combination with any of the six known human germline JH sequences could supply the framework regions for making a humanized heavy chain.
- the following JH region sequence was chosen based on primary sequence similiarity:
- Antibodies 37, 39 and 44 Three antibodies were selected Antibodies 37, 39 and 44. Based on the optimization of Antibody 1, the 3 point mutations that enhanced the biophysical properties of Antibody 1 (Light Chain W94F, Heavy Chain M34L, Heavy Chain C95N) were introduced into Antibodies 37, 39 and 44. A combination approach mixing the heavy chains and light chains of the optimized variants was performed generating a panel of antibodies (Antibodies 76, 77, 78, 79, 80, 81). Of these antibodies all bound to IL- 12 and IL-23 in ELISA (FIGURE 13). Antibody 80 displayed strong binding to IL-12 as measured via SPR and was chosen for further analysis using the NK92 cell based assay
- FIGURE 11 the human PBMC IL-12 induced IFN- ⁇ assay (FIGURE 17) and the murine splenocyte assay (FIGURE 14).
- the construct Antibody 80 demonstrated strong inhibition of IL-12 induced IFN- ⁇ secretion in NK-92 assay and IL-23 induced IL- 17 secretion in the murine splenocyte assay.
- PMA204 was also humanized using human framework sequences that are closely homologous in linear peptide sequence to framework sequences of the original mouse antibody.
- a close human homologue to the heavy chain variable region of PMA204 was 1RZ7HC variable region (SEQ ID NO: 25) as shown below:
- the heavy chain variable region of Antibody 68 was aligned with the heavy chain variable region of the optimized chimeric antibody Antibody 50. At each position in which Antibody 68 differed from Antibody 50 the residue from Antibody 50 at that position was introduced into Antibody 68.
- the light chain variable region of Antibody 68 was aligned with the light chain variable region of the optimized chimeric Antibody 50. At each position in which Antibody 68 differed from Antibody 50 the residue from Antibody 50 at that position was introduced into Antibody 68. These variants were gene synthesized, paired with Antibody 68 heavy chain and expressed (Antibodies 126, 127, 128, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148). An ELISA was performed on all the heavy chain and light chain antibodies. Some retained binding activity for both IL- 12 and IL-23, while others showed no binding to either cytokine (FIGURE 19).
- Antibodies 127, 130, 136, 140, 146, 147 and 148 were selected based on their strong binding to IL-12 and IL-23 to be screened in the cell based assays.
- Antibody 136 displayed strong inhibition of IL-12 human PBMC IL-12 induced IFN- ⁇ assay (FIGURE 17) and IL-23 induced IL- 17 secretion in the murine splenocyte assay (FIGURE 14).
- Antibody 80 was reformatted for expression as a scFv (scFv-80) (SEQ ID NO: 27) and sub-cloned into the pEGX448 expression vector.
- the scFv was expressed with a FLAG tag to allow for affinity purification.
- the scFv was then expressed in E. coli and purified by affinity- chromatography and gel filtration. Expression was confirmed by SDS-PAGE and immunoblotting.
- the scFv retained binding activity against both IL-12 and IL-23 with similar kinetics to the parental IgG, as confirmed by SPR.
- the coding sequence for scFv-80 was sub-cloned into the pEGX412 mutagenesis/ribosome display vector and random mutations were introduced into the scFv sequence using Q-Beta replicase (Kopsidas et al., 2007, BMC Biotechnology, 7: 18).
- the resulting pool of DNA constructs encoding mutant scFv-80 variants was transcribed to single- stranded mRNA in a T7 RNA polymerase reaction and then used to conduct ribosome display.
- IL-23 A commercial preparation of IL-23 was biotinylated for use in ribosome display experiments. An SPR experiment was performed to confirm that biotinylated IL-23 bound well to streptavidin and retained binding against scFv-80 within minimal loss in binding affinity.
- the mRNA pool encoding the scFv-80 variants was translated using an in vitro expression system and the resulting scFv library was panned for IL-23 binders using the ribosome display protocol described by Kopsidas et al. (2007). The selective pressure of the system was adjusted to bias for binders with low dissociation constants (k d ).
- the coding sequences for the enriched scFvs were amplified by PCR and sub-cloned into the pEGX448 expression vector. Twenty random clones from the sub-cloned scFv pool were sequenced to confirm their identity as variants of scFv-80. The remaining clones were subjected to high throughput screening against IL-23.
- scFvs that showed the highest binding affinities in SPR assays were reformatted for IgG expression by subcloning the V H and V L domains into separate mammalian expression vectors (i.e. one construct for the antibody heavy chain, one for the light chain).
- CU-A6 was converted to Antibody 183
- CP- A6 was converted to Antibody 184
- AW- F2 was converted to Antibody 207 by addition of a human heavy chain Fc region (SEQ ID NO: 8) and a constant kappa light chain region (SEQ ID NO: 9).
- IgG molecules were expressed by co-transfecting the heavy and light chain construct for each antibody into HEK 293E cultures.
- the expressed IgGs were purified by affinity chromatography and gel exclusion and the resulting monomeric molecules were tested for IL- 12 and IL-23 binding by SPR (TABLE 6).
- AU three IgG variants retained binding activity against both analytes with a visible improvement in k d compared to the parental wild- type IgG. Based on this, it is reasonable to expect that scFv variants described in TABLE 4 could be converted to the IgG format and retain improved binding characteristics against IL- 12 and IL-23.
- Antibody 80 Based on the affinity maturation of Antibody 80 several key mutations in the heavy chain variable region (Y59S, Y59H and F29L) that enhanced affinity to IL-12 and IL- 23 were introduced into Antibody 136 (Antibodies 175, 176, 177, 178, 179, 180, 181, 182). These were expressed and screened in ELISA (FIGURE 20). All antibodies showed binding to IL-12 and IL-23.
- Affinity matured variants of Antibody 80 heavy chain containing a substitution at position 93 were paired with their corresponding light chains (Antibodies 199, 200, 201, 202, 203, 204, 205, 206) (FIGURE 20). This substitution was introduced to return position 93 back to the human germline which most frequently contains an Ala at this position. Affinity matured variants of Antibody 80 heavy chain containing the N93A substitution were also expressed with Antibody 136 light chain in order to identify higher affinity variants (Antibodies 190, 191, 192, 193, 194, 195, 196, 197, 198) (FIGURE 20).
- a competition assay was established using SPR to verify that the chimeric and humanized antibodies described above maintained the same binding specificity as PMA204.
- Antibody 136 was captured on a Protein A coated surface leading to an increase in the response units (RU) and then loaded with IL- 12 or IL-23 (leading to another increase in response units). PMA204 was then loaded but did not bind to the surface IL- 12 or IL-23 - Antibody 136 complex (FIGURE 21) (no increase in response units). This indicates that Antibody 136 binds IL- 12 and IL-23 in such as way as to prevent PMA204 binding and that the two antibodies share an overlapping epitope on IL- 12 and IL-23.
- Antibody 80 and Antibody 136 neutralize IL-12 binding to IL-12R ⁇ 2 and IL-23 binding to IL-23R [0304] Using receptor neutralization assays it was demonstrated that Antibody 80 and Antibody 136 neutralized the binding of IL-12 to IL-12R ⁇ 2 (FIGURE 24A) and the binding of IL-23 to IL-23R (FIGURE 24B). The control Antibody 202.1 displayed no inhibition of IL- 12 binding to IL-12R ⁇ 2 or IL-23 binding to IL-23R.
- Antibody 80 and Antibody 136 do not neutralize IL-12 or IL-23 binding to IL- 12R ⁇ l
- Antibody 80 and Antibody 136 did not neutralize the binding of IL-12 to IL- 12R ⁇ l (FIGURE 25A). IL-23 binding to IL-12R ⁇ l was not inhibited by Antibody 80 and Antibody 136 (FIGURE 25B) but rather complex formation occurred as evidenced by the increase in the bound IL-23 above that of just IL-23 and receptor alone. The control Antibody 202.1 inhibited the binding IL- 12 and IL-23 to IL-12R ⁇ l.
- Antibody 136 showed a trend towards decreased epidermal thickness as compared to isotype control, only Antibody 80 caused a statistically significant decrease in epidermal thickness (FIGURE 27B). This correlates well with the clinical scoring, where although both Antibody 136 and Antibody 80 significantly reduced erythema and induration caused by IL-23, Antibody 80 was more effective.
- chimeric IL-12 human IL-12p40 chain with mouse IL-12 p35 chain (SEQ ID NO: 63) for five consecutive days induced a robust serum IFN- ⁇ response with no apparent toxicity.
- Antibodies were tested for their ability to neutralize the chimeric IL-12 and hence abrogate the IFN ⁇ response at a dose of 5mg/kg with either a single dose on the first day of cytokine treatment or three doses on alternate days concurrent with cytokine treatment. Both antibodies tested showed neutralization capabilities and a single dose of Antibody 80 at 5mg/kg was sufficient to reduce serum IFN- ⁇ to baseline detectable levels (FIGURE 29) .
- Humanized antibodies against IL-12 and IL-23 can be used as diagnostic reagents for the detection of IL-12 and IL-23 in biological samples.
- An ELISA was developed to detect recombinant human IL-23.
- an anti-human pl9 antibody was used as the capture antibody and Antibody 80 was used as the detection antibody.
- Antibody 80 was able to detect recombinant human IL-23 in this sandwich ELISA format (FIGURE 30A).
- IL-12p40 was used as given in SEQ ID NO: 64.
- the only region to show a significant perturbation in the rate of H/D exchange was between amino acids 253 to 286 which corresponds to the sequence
- VQVQGKSKREKKDRVFTDKTSATVICRKNASISV (SEQ ID NO: 65) as shown in TABLE 9.
- human IL-12p40 VQVQGKSKREK KDRVFTDKTSATVICRKNASISV murine p40 . RI . R. KEKM. ETEEGCNQ . GAFLVE ... TE . Q .-. GGNVC .
- F268A (SEQ ID NO: 78) A T269A(SEQ ID NO: 79) A D270A(SEQ ID NO: 80) A
- D265A and R266A were further analysed in an ELISA in which Antibody 80, Antibody 202.1 or IL-12R ⁇ l and IL-23R was coated on the plate and transfection supernatants containing IL-23 wild-type (IL-23WT), D265A and R266A were titrated across the plate.
- the mutant, D265A displayed background levels of binding to Antibody 80 (FIGURE 31), thus identifying D265 as an important residue on IL-12p40 to which Antibody 80 binds.
- the mutant R266A displayed low levels of binding to IL-12R ⁇ l, IL-23R, Antibody 80 and Antibody 202.1 indicating that mis-folding of the mutant protein had occurred (FIGURE 31).
- mice were immunized with human IL- 12 (Peprotech) in Complete Freund's adjuvant each, followed by a boost of human IL- 12 in Incomplete Freund's adjuvant on day 14, 35 and 70.
- human IL- 12 Peprotech
- Incomplete Freund's adjuvant On day 14, 35 and 70, mouse spleens were harvested and mouse splenocytes obtained. A fusion was performed between these cells and myeloma cell line SP2/0 Ag- 14 and cells were deposited in 96-well tissue culture plates.
- Anti-IL-12, Anti-IL-12p40 and Anti-IL-23 ELISAs were performed on the supernatant for each well of the 96 well plates.
- Primers from the Novagen Murine IgG Primer Set for heavy-chain and for light-chain respectively were mixed together with cDNA and Pfu II Mastermix® (Stratagene®) then run in a Thermocyler (Eppendorf Mastercycler®) according to the following conditions:
- the PCR product was gel purified with the DNA Gel Extraction Kit (QIAgen®), A-tagged [dATPs and Taq-polymerase (InvitrogenTM) at 72°C for 15 minutes adds an A-overhang to the PCR-product], ligated into pGEM-T- Vector System (Promega®) and transformed into TOPlO competent cells (InvitrogenTM). Clones were screened for a 500 bp insert. From positive clones the plasmids were isolated (Miniprep, QIAgen®) and sequenced at a conventional sequencing facility. The nucleotide sequence was then translated into primary amino acid sequence.
- VH domains determined via DNA sequencing from the hybridoma cells, PMA202 and PMA204 were expressed with a human constant region (human IgGl heavy chain CHl, hinge, CH2 & CH3 domains). This was achieved by back translation of amino acid sequences into DNA sequences which were optimized for mammalian cell expression using GeneOptimizer technology and synthesized de novo by assembly of synthetic oligonucleotides (Gene Art, Germany). Following gene synthesis the whole sequence was subcloned into the multiple cloning site of the pTT5 heavy chain vector (Durocher et al. 2002 Nucleic Acids Res 30 E9).
- the resulting PMA202 murine-human chimeric antibody was designated Antibody 202.1.
- the resulting PMA204 murine-human chimeric antibody was designated Antibody 1. All antibodies were produced using this methodology with the candidate protein sequence being back-translated into DNA sequence, optimized and synthesis de novo by assembly of synthetic oligonucleotides. All antibodies contained a human heavy chain Fc region and a human light chain kappa constant region. All genes encoding antibody varible regions were then cloned into the pTT5 vector for expression.
- HEK293E cells were cultured in complete cell growth media (1 L of F 17 medium (InvitrogenTM), 9 mL of Pluronic F68 (InvitrogenTM), 2mM Glutamine containing 20% (w/v) Tryptone NI (Organotechnie®) with Geneticin (50 mg/mL, InvitrogenTM) at 50 ⁇ l/100 mL culture).
- F 17 medium InvitrogenTM
- Pluronic F68 InvitrogenTM
- 2mM Glutamine containing 20% w/v
- Tryptone NI Organotechnie®
- Geneticin 50 mg/mL, InvitrogenTM
- the cells were harvested by centrifugation and resuspended in fresh media (without Geneticin).
- the next day heavy and light chain DNA was mixed with FuGENE® (Roche) transfection reagent and the DNA transfection mix added to the culture drop-wise.
- the culture was incubated overnight at 37°C, 5% CO 2 and 120rpm without Geneticin. The next day 12.5 mL of Tryptone was added along with 250 ⁇ l of Geneticin per 500 mL culture. The culture was incubated at 37°C, 5% CO 2 and 120rpm. After 7 days the supernatant was harvested by centrifugation, ready for purification.
- IL- 12 (Peprotech), IL-23 (EbioscienceTM), IL-12p40 (Ebio scienceTM) or IL-12p80(Peprotech), was diluted to 1 ⁇ g/mL in carbonate coating buffer (35mM sodium carbonate, 15 rnM sodium hydrogen carbonate pH 9.6) and coated onto a 96 well plate (NuncTM, MaxisorpTM) overnight at 4 0 C. The plate was then washed three times with wash buffer (0.01M PBS pH 7.2, 0.05% Tween-20) and then three times with 0.01M PBS pH 7.2.
- carbonate coating buffer 35mM sodium carbonate, 15 rnM sodium hydrogen carbonate pH 9.6
- carbonate coating buffer 35mM sodium carbonate, 15 rnM sodium hydrogen carbonate pH 9.6
- the plate was then washed three times with wash buffer (0.01M PBS pH 7.2, 0.05% Tween-20) and then three times with 0.01M PBS pH 7.2.
- the wells were then blocked by adding 200 ⁇ l of blocking buffer (1% w/v BSA in 0.01 M PBS pH 7.2) to each well and incubating the plate at 25 0 C for 1 hour.
- the antibody was diluted in antibody diluent (1% w/v BSA, 0.05% Tween-20 in 0.01M PBS pH 7.2) sufficient to generate a titration curve.
- the wells were incubated with the antibody for 1 hour at 25 0 C.
- the plate was then washed as previously described.
- Goat anti-human immunoglobulin G (H+L) antibody HRP conjugate (Zymed®) at 1:2000 in antibody diluent was used to detect bound primary antibody.
- Goat anti-murine immunoglobulin antibody HRP conjugate (Dako) at 1:2000 in antibody diluent was used to detect bound murine antibody. After incubation at 25 0 C for 1 hour the plate was washed again as previously described. TMB substrate solution (Zymed®) was added to each well and the colour allowed to develop; the reaction was terminated by adding IM HCl to the wells. The absorbance of each well was determined at 450 nm (ref. 620 nm).
- IL-12R ⁇ l/Fc Chimera (R&D Systems®) was diluted to 1 ⁇ g/mL in carbonate coating buffer and added to each well of a 96 well plate and incubated at 4 0 C overnight. The plate was then washed three times with wash buffer and then three times with 0.0 IM PBS pH 7.2. The wells were then blocked by adding 200 ⁇ l of blocking buffer to each well and incubating the plate at 25 0 C for 1 hour. The antibody was diluted in antibody diluent sufficient to generate a titration curve. IL- 12 (Peprotech) was diluted to 300 ng/mL in antibody diluent.
- IL- 12 was preincubated with the antibody in a deep well container for 2 hours. Then the plate was washed as previously described and wells were incubated with the antibody/IL-12 solution for 1 hour at 25 0 C. The plate was then washed as previously described and 100 ⁇ l of biotinylated anti-human IL- 12 antibody (Peprotech) at 0.5 ⁇ g/mL in antibody diluent was used to detect bound antibody for 1 hour at 25 0 C. The plate was washed as previously described. 100 ⁇ l of Streptavidin HRP (Zymed®) at 1:1000 in antibody diluent was used to detect bound biotinylated antibody.
- IL-12p80/IL-12R ⁇ l Neutralization Assay This assay was performed as described above for the IL-12/IL-12R ⁇ l neutralization assay but with the following alterations:
- IL- 12 was replaced with IL- 12p80 (Peprotech)
- IL-12R ⁇ l/Fc Chimera was replaced with IL-12R ⁇ 2/Fc Chimera (R&D Sytsems®) and was diluted to 5ug/ml instead of lug/ml.
- IL-23/Fc Chimera (R&D Systems®) was diluted to 1 ⁇ g/mL in carbonate coating buffer and added to each well of a 96 well plate and incubated at 4 0 C overnight. The plate was then washed three times with wash buffer and then three times with 0.01M PBS pH 7.2. The wells were then blocked by adding 200 ⁇ l of blocking buffer to each well and incubating the plate at 25 0 C for 1 hour. The antibody was diluted in antibody diluent sufficient to generate a titration curve. IL-23 (Ebio scienceTM) was diluted to 300 ng/mL in antibody diluent. IL-23 was preincubated with the antibody in a deep well container for 2 hours.
- the plate was washed as previously described and wells were incubated with the antibody/IL-23 solution for 1 hour at 25 0 C.
- the plate was then washed as previously described and 100 ⁇ l of biotinylated anti-human IL-12 antibody (Peprotech) at 0.5 ⁇ g/mL in antibody diluent was used to detect bound antibody for 1 hour at 25 0 C.
- the plate was washed as previously described.
- 100 ⁇ l of Strepdavidin HRP (Zymed®) at 1:1000 in antibody diluent was used to detect bound biotinylated antibody. After incubation at 25 0 C for 1 hour the plate was washed again as previously described.
- IL-23/IL-23R neutralization assay was also performed as described above for the IL-23/IL-23R neutralization assay but with the following alterations: IL-23/Fc Chimera (R&D Systems®) was replaced with internal produced IL-23R-HIS, dervied from HEK-293E cells and purified using affinity chromatography. The plate was washed three times with wash buffer without extra PBS washes. IL-23 (Ebio scienceTM) was replaced by biotinylated IL-23 (Ebio scienceTM). IL-23 was diluted to 50ng/ml instead of 300ng/ml in antibody diluent. The wells with antibody/IL-23 solution were incubated for 2 hours at 25 0 C.
- PMA204 or PMA202 was diluted to 1 ⁇ g/mL in carbonate coating buffer (35mM sodium carbonate, 15 mM sodium hydrogen carbonate pH 9.6) and coated onto a 96 well plate (NuncTM, MaxisorpTM) overnight at 4 0 C. The plate was then washed three times with wash buffer (0.01M PBS pH 7.2, 0.05% Tween-20) and then three times with 0.01M PBS pH 7.2. The wells were then blocked by adding 200 ⁇ l of blocking buffer (1% w/v BSA in 0.01 M PBS pH 7.2) to each well and incubating the plate at 25 0 C for 1 hour.
- carbonate coating buffer 35mM sodium carbonate, 15 mM sodium hydrogen carbonate pH 9.6
- wash buffer (0.01M PBS pH 7.2, 0.05% Tween-20
- 0.01M PBS pH 7.2 0.01M PBS pH 7.2
- IL-12 (Peprotech) or IL-12 (EbioscienceTM) was diluted to 0.5 ⁇ g/ml in antibody diluent (1% w/v BSA, 0.05% Tween-20 in 0.01M PBS pH 7.2) and lOO ⁇ l added to each well followed by incubation for 1 hour at 25 0 C. The plate was then washed as previously described. Serial half log dilutions of the competition antibodies were performed and lOO ⁇ l added to each well. Final protein concentrations were sufficient to generate a titration curve. The plates were incubated for 1 hour at 25 0 C and then washed as described previously.
- Protein A was immobilized onto a CM5 sensor chip using a BIAcore 3000.
- Chimeric or humanized antibody at 5 ug/mL in HBS-P was then injected for lmin at a flow rate of 20 ul/min.
- IL-12 or IL-23 was then injected over the surface at 5 ug/mL in HBS-P for lmin at a flow rate of 20 ul/min.
- Murine antibody was then injected at 5 ug/mL in HBS-P for 1 min at a flow rate of 20 ul/min.
- Controls in which IL-12 or IL-23 was replaced with HBS-P, and in which the murine antibody was replaced with HBS-P were also performed. All data was substrated from a control run in which IL-12 or IL-23 or the murine antibody was tested for background binding to the Protein A surface.
- IL-12R ⁇ l The amino acid sequence of IL-12R ⁇ l was back translated into DNA sequences which were optimized for mammalian cell expression using GeneOptimizer technology and synthesized de novo by assembly of synthetic oligonucleotides (GeneArt, Germany).
- the DNA sequence encoding IL-12R ⁇ l was subcloned into pcDNADEST-40 and then transformed into Top- 10 chemically competent E. coli cells. Plasmid DNA was recovered from cell culture using a HiSpeed Plasmid Maxi Kit (QIAgen®), and linearized by restriction enzyme digest with Seal (Promega®). Plasmids were transfected into Jurkat 6E cells (ATCC) and surface expression determined by staining with anti-receptor chain antibodies to IL- 12R ⁇ l (R&D Systems®)
- FLAG-tagged IL-12 or HIS-tagged IL-23 or IL-12p40 was co-incubated with IL- 12- R ⁇ l -expressing cells (10 6 /ml) at concentrations ranging from 1000 to .01 ng/ml by serial half log dilution for 2hours at 37 0 C. Binding of cytokine to cells was detected with phycoerythrin- conjugated mouse anti-6xHIS tag antibody (Abeam®) or FITC-conjugated anti-FLAG (Sigma-Aldrich®). Sample data were acquired on a Beckman-Coulter Quanta®.
- FLAG-tagged IL-12 or HIS-tagged IL-23 or IL-12p40 at a concentration of 250ng/ml was co-incubated with antibody at concentrations ranging from 10 to .01 ⁇ g/ml by serial half- log dilution for one hour at 37 0 C, then IL- 12R ⁇ l -expressing cells as described above were added at 10 6 /ml and incubated for a further hour.
- Cells were washed thoroughly in PBS/10% FBS and cell-bound cytokine was detected with phycoerythrin-conjugated mouse anti-6xHIS tag antibody (Abeam®) or FITC-conjugated anti-FLAG antibody (Sigma- Aldrich®). Sample data were acquired on a Beckman-Coulter Quanta.
- Detection of antibody - cytokine complexes on the surface of an IL-12R ⁇ l expressing cell line [0336] FLAG-tagged IL- 12 or HIS-tagged IL-23 or IL- 12p40 was co-incubated with IL- 12R ⁇ l-expressing cells as described above at a concentration of 250ng/ml. After 2 hours incubation, antibody was added at concentrations ranging from 10 to .Ol ⁇ g/ml by serial half- log dilution and incubated for a further hour. Cells were washed thoroughly in PBS/10% FBS and antibody bound to cell-bound cytokine was detected with FITC-conjugated Rabbit anti- human IgG (Dako). Sample data were acquired on a Beckman-Coulter Quanta®.
- a single-chain antibody fragment was derived from antibody 80 by designing a polypeptide that comprised the variable domain of the heavy chain (V L ) joined to the variable domain of the light chain (V L ) by a 15 amino acid linker of the sequence (Gly 4 Ser) 3 (scFv-80, SEQ ID NO: 27).
- the V H and V L sequences were oriented at the N and C-terminal ends of the polypeptide (respectively).
- the amino acid sequence was then back- translated to a DNA sequence that was optimized for mammalian expression using GeneOptimizer technology.
- the entire gene was then synthesized de novo by assembly of synthetic oligonucleotides (Gene Art).
- the final sequence also included 5' Ncol and 3' Notl sites to facilitate further sub-cloning.
- pEGX448 The recombinant gene encoding the scFv-80 protein was sub-cloned into the Ncol and Notl sites of the pEGX448 expression vector.
- pEGX448 is designed such that any scFv sub- cloned into the Ncol and Notl sites is automatically fused a proprietary 'FLAG' affinity tag at the C-terminus.
- the scFv-80 gene was similarly sub-cloned into the pEGX412 vector for RNA production, mutagenesis and ribosome display.
- This vector was identical to pEGX253 plasmid described by Kopsidas et al. (2007), except that pEGX412 uses the gene III protein sequence to link the scFv to the ribosome instead of the C L sequence used in pEGX253.
- pEGX412-scFv80 construct described above was used to produce a pool of RNA encoding mutant variants of scFv-80.
- the plasmid was linearized with Smal and used directly as the template for single- stranded RNA (ssRNA) production using a T7 RNA polymerase kit (Promega®) as per manufacturer's instructions.
- ssRNA single- stranded RNA
- T7 RNA polymerase kit Promega®
- the resulting single- stranded RNA molecule was used as the template for error-prone replication using Q-Beta replicase (Epicentre® Biotechnologies).
- RNA was mixed with 33 mM Tris-acetate (pH 7.8), 66 mM potassium acetate, 10 mM magnesium acetate, 0.5 mM dithiothreitol (DTT), 5 mM rATP, 5 mM rUTP, 10 mM rCTP, 10 mM rGTP, 0.1 U/ ⁇ L of Q- Beta Replicase and H 2 O to a final volume of 20 ⁇ L. The reaction was incubated at 45 0 C for -16 hours.
- the Q-Beta replicase reaction generated a library of double-stranded RNA (dsRNA) molecules encoding a pool of mutants of the parental scFv-80 with 1-2 point mutations per mutant.
- the dsRNA library was converted to a pool of DNA fragments using reverse- transcriptase PCR (RT-PCR).
- RT-PCR reverse- transcriptase PCR
- the RT-PCR product was purified by agarose gel electrophoresis and gel extraction, before forming the template for a final T7 RNA polymerase reaction. The product of all reactions described above were tested by agarose gel electrophoresis.
- scFv-binders from the library of scFv-80 variants
- the scFv library described above was expressed from the pEGX412 vector to produce scFv-ribosome complexes that were then panned against IL-23 following the ribosome display protocol described by Kopsidas et al. (2007). Briefly, the scFv-ribosome complexes (which also included scFv-encoding ssRNA) were incubated with biotinylated IL-23 to a final concentration of 1 nM for 24 hrs on ice.
- ssRNA was eluted from the recovered scFv-ribosome complexes and the encoded scFv pool was amplified by RT-PCR using a Superscript III One-Step RT-PCR system (InvitrogenTM) as per manufacturer's instructions, but with 8 ⁇ L of recovered RNA as the reaction template and the scFv-specific oligonucleotide primers listed below. Note that these oligonucleotides also added 5' N col and 3' Notl sites to facilitate sub-clonin 1 gO.-
- the 200 ⁇ L expression cultures were incubated overnight at 2O 0 C and then used to produce crude bacterial lysates by adding 40 ⁇ L of lysis buffer (2 M Sucrose; 0.25M Tris pH 7; 0.2M EDTA pH 8) and agitating the plates at 900 RPM for 30 mins.
- the lysates were then cleared by centrifugation and passed through a 10 000 molecular weight cut-off filter plate (Millipore). This method was used to prepare approximately 6500 scFv samples that were screened for IL-23 binding using the high-throughput SPR protocol detailed below.
- High-throughput SPR screening was conducted using a BIAcore AlOO biosensor (GE Healthcare). Approximately 10 000 RU of the proprietary FLAG-specific capture molecule was immobilized on a CM5 Series S Sensor chip, using standard amine coupling chemistry on Spots 1 & 5 (outer spots) and 3,000RU to Spots 2 & 4 (inner spots) in each of the four flow cells of the BIAcore AlOO Biosensor.
- the running buffer used was HBS-EP+ (BIAcore) and all interactions measured at 25°C.
- ScFvs were purified from the periplasmic fraction using 1 mL column of sepharose resin conjugated to an antibody that specifically recognises the C-terminal FLAG tag.
- the affinity purified protein was concentrated to a final volume of 200 ⁇ L and subjected to gel-filtration chromatography on a Superdex 200 column (GE Healthcare) equilibrated in PBS and the peak protein fraction corresponding to monomeric scFv (-32 kDa) was collected for functional characterization (see below).
- Peak purified FLAG-tagged scFvs were diluted to 10 nM in running buffer, and captured on FC2 at a flow rate of 10 ⁇ l/min in order to capture 50 RU of scFv (typically 60 sec was sufficient to capture this level of tagged scFv).
- the target, IL- 12 or IL-23 were passed over FCl and FC2 at a flow rate of 60 ⁇ l/min at concentrations ranging from 81 nM to 0.13 nM (using a five-fold dilution of IL-12) and 81 nM to 1 nM (using a three-fold dilution of IL-23).
- the contact time for association was 180 sec and dissociation measured for 10 mins for the highest concentration and 300 sec for all other concentrations in the series.
- the sensorgram data from FC2 was subtracted from FCl and a buffer only control.
- the curves were fitted using a 1:1 Langmuir equation to generate the IQ,, k ⁇ and KD values.
- scFv-80 variants were derived by combining the mutations discovered through ribosome display and screening. It is important to note that these mutation combinations did not arise as a result of one round of ribosome display, where the mutagenesis level is intrinsically set to create one mutation (on average) per scFv sequence. These combinations were instead derived by design. Combinations were chosen by weighting each individual mutation according to TABLE 11.
- Nucleotide sequences encoding scFvs with the combinations of the highest- weighted mutations were produced by site-directed mutagenesis with scFv-80 as the template, using a Quikchange Lightning kit (Stratagene®) according to manufacturer's instructions.
- the mutagenesis primers used to add each specific mutation are listed below.
- the full range of scFvs are listed in TABLE 4X with cross-references to amino acid sequences.
- Antisense 5'-ttgggggcggactcggtatcgccgttc-3'
- Antisense 5'-aacttgggggcgtgctcggtatcgccg-3'
- Antisense 5'-tagtcggtgaaggcgtagccgctggcc-3'
- Antisense 5'-gatagtagtcggtgagggtgtagccgctggc-3' V L mutation S26P
- Antisense 5'-gctgatgctctggggggctctacaggaca-3'
- Antisense 5'-gccgctgatggactgtctggcgaagtagatc-3'
- Antisense 5'-ttgatgctgatgctccgggaggctctacagg-3' [0350] Note that no primers were designed to add heavy chain mutation Q43R or light chain mutation I55T. Instead, other mutations introduced directly into a construct that already carried R43 and T55 in the V H and V L , respectively (SEQ ID NO: 230 and SEQ ID NO: 231).
- This protocol was used to study IL- 12 and IL-23 binding of scFv-80 variants carrying mutation combinations.
- Small-scale HB2151 E. coli cultures were used to produce partially purified scFvs for medium throughput SPR analyses (see below).
- the recombinant scFvs were expressed into the periplasm and then extracted and purified using an anti-FLAG antibody-sepharose column as described above.
- the scFv samples were then buffer- exchanged into PBS using a PDlO desalting column (GE Healthcare) and concentrated to a final volume of 200 ⁇ L. This material was subjected to SPR analysis with no further purification.
- FCl was used a blank throughout the experiments.
- the experiments were run in HBS-P buffer (SPR).
- SPR HBS-P buffer
- IL- 12, IL-23 or IL-12p40 were passed over the surface of FCl and FC2 at concentrations ranging from 66 nM to 2 nM. Regeneration of the surface was performed using 1OmM Glycine, pH 1.0.
- the sensorgram data from FC2 was subtracted from FCl and a buffer only control.
- the curves were fitted using a 1:1 Langmuir equation to generate the kd, ka and KD values. All curves were fitted with a ⁇ 2 of less then 2.0 where possible.
- Concanavalin A and rhIL-23 was added to a final concentration of l ⁇ g/ml and 25ng/ml respectively.
- Test antibodies were titrated across samples. A typical assay had 3-5 biological replicates per test antibody, and a starting test antibody concentration of l-10 ⁇ g/ml. Each assay plate contained replicate samples that have Con A + IL-23 but no antibody and Con A alone. Plates were incubated at 37 0 C, 5% CO 2 for 3 days then supernatants were collected for IL- 17 ELISA. IL- 17 was assayed using an IL- 17 ELISA kit (R&D Systems®) as per manufacturer's instructions. Concentrations were determined by the standard curve method.
- NK92 IFN- ⁇ release assay [0355] NK92 cells (ATCC, CRL-2407) were cultured in RPMIl 640, 2mM L-Glutamine, IOOU Pen/Strep, 10% FBS and supplemented with 200U/ml of human IL-2 (Peprotech Asia) and 10ng/ml of human IL-15 (EbioscienceTM). Cells were starved from human IL-2 and human IL-15 prior to assay. The antibody was diluted in culture media sufficient to generate a titration curve. IL- 12 (Peprotech) was added to the plate and incubated at 37 0 C with 5% CO 2 for 2 hours.
- the cells were harvested and added to the wells giving a cell concentration of 1 xlO 5 cells/mL in a total volume of 200 ⁇ l/well. Cultures were incubated at 37 0 C with 5% CO 2 for 24 hours. Supernatants were harvested at the end of incubation and a Duoset ELISA human IFN- ⁇ kit (R&D Systems®) was used to detect human IFN- ⁇ produced. Human PBMC IL- 12 induced IFN- ⁇ assay
- Human PBMC were harvested from human buffy coat using lymphoprep separation and cultured at IxIO 7 cells/mL in culture media (50% DMEM, 50% RPMI, 0.045% D(+) glucose, 2mM L-Glutamine, 5% foetal bovine serum (FBS), 1OmM HEPES).
- PHA-P Sigma-Aldrich®
- Human IL-2 R&D Systems® was then added at 50 U/mL. The culture was incubated at 37 0 C with 5% CO 2 for 1 day.
- the antibody was diluted in culture media sufficient to generate a titration curve covering the ranges from lO ⁇ g/mL to O.OOl ⁇ g/mL across a 96-well plate.
- 1 ng/mL of human IL- 12 (Peprotech) was added to the plate and incubated at 37 0 C with 5% CO 2 for 2 hours.
- 1 ng/mL of hIL-2 (R&D Systems®) was added to each well.
- the cells were harvested and added to the wells giving a cell concentration of 2 xlO 5 cells/mL in a total volume of 200 ⁇ l/well. Cultures were incubated at 37 0 C with 5% CO 2 with for 2 days. Supernatants were harvested at the end of incubation and a Duoset ELISA human IFN- ⁇ kit (R&D Systems®) was used to detect human IFN- ⁇ produced.
- mice Male C57B1/6J mice were depilated on a test area of the back two days prior to the commencement of injections, then given daily intradermal injections of either PBS or rhIL-23 in two locations on the back to a total of 3 or lO ⁇ g/mouse/day. Both regimes gave some indication of inflammation but the dose of lO ⁇ g/day gave a robust response with high levels of erythema. In a later study, mice were given lO ⁇ g of rhIL-23/day for a total of 10 days to determine the full kinetics of the inflammatory response. The response was detectable from the third day of treatment, peaked at days 6-7 then started to resolve.
- Antibody testing in vivo Male C57B1/6J mice were treated with lO ⁇ g/day of rhIL-23 as described above for 6 days. One day before the start of cytokine injection they were given a single intraperitoneal injection of Antibody 80, Antibody 136 or an isotype control antibody at a dose of 10mg/kg. Mice were scored daily erythema and induration in the test area. All treatments and observations were performed blinded. At the termination of the study, skin samples were collected from each mouse and fixed for histological processing and Haematoxylin and Eosin (H&E) staining by standard protocols.
- H&E Haematoxylin and Eosin
- Chimeric IL- 12 was produced that contained human IL-12p40 and murine IL-12p35 (SEQ ID NO: 63). The protein was backtranslated into a gene sequence, optimized, synthesized and subcloned into the pTT5 vector. Chimeric IL-12 was expressed in HEK-293E cells and purified via HIS tag affinity purification columns. Responsiveness of mouse T cells to the chimeric IL-12 was tested in vitro. Mouse splenocytes (10 7 /ml) were cultured overnight in RPMI supplemented with 2mM 1-glutamine and 10% fetal bovine serum plus chimeric, recombinant mouse or recombinant human IL-12 (0-20ng/ml). Supernatants were collected and assayed for IFN- ⁇ by enzyme-linked immunosorbent assay (ELISA), using an IFN- ⁇
- ELISA enzyme-linked immunosorbent assay
- Chimeric IL-12 was capable of inducing IFN- ⁇ secretion from mouse splenocytes over a range of concentrations. Human IL-12 was inactive except at the highest concentrations tested.
- IFN- ⁇ was assayed using an IFN- ⁇ ELISA kit (R&D systems®) as per manufacturer's instructions. Concentrations were determined by the standard curve method. If the background IFN- ⁇ production (as determined from Con A-only samples) was high, this background is subtracted from the IL-12 treated sample values to give the IFN- ⁇ concentrations directly attributable to IL-12.
- mice Male C57B1/6J mice were treated with either PBS, mouse IL-12 (IL-12) at 0.03mg/kg, or chimeric IL-12 at 0.03, 0.1 or 0.3 mg/kg by intraperitoneal injection for five days. On the sixth day, terminal blood samples were collected for production of serum. IFN- ⁇ concentrations in sera were determined using a high-sensitivity IFN- ⁇ ELISA kit (EbioscienceTM) as per manufacturer's instructions.
- IFN- ⁇ was not detected in the PBS treated control mice but was detected in all groups treated with mouse or chimeric IL-12. Chimeric IL-12 treatment resulted in a robust dose- dependent induction of serum IFN- ⁇ . 0.1 mg/kg was selected as the ideal dose to measure a change in serum IFN- ⁇ response.
- mice Male C57B1/6J mice were treated with chimeric IL-12 at 0.1 mg/kg by intraperitoneal injection for five days. They were also treated with a single dose of either Antibody 80 or
- Antibody 136 5mg/kg on day 1 of cytokine injection 30 minutes before dosing with chimeric IL-12, or with three doses of Antibody 80, Antibody 136 or an isotype control on days 1, 3 and 5 of cytokine injection 30 minutes before dosing with chimeric IL-12. On the sixth day terminal blood samples were collected and serum IFN- ⁇ determined as described above.
- 96- well flat-bottom ELISA plates (Nunc Maxisorp) were coated with mouse anti- human IL-23pl9 (EbioscienceTM) at 0.5 ⁇ g/ml in PBS overnight at 4 0 C. Plates were washed (all washing is performed three times), then blocked for lhr with PBS/10% FBS. Plates were washed, then recombinant IL-23 was added at concentrations ranging between 1000 and
- PBMC peripheral blood mononuclear cells
- IL-12p40 was used at 1 mg/mL in PBS.
- Antibody 80 was used at 2.0 mg/mL in PBS.
- the antibody was coupled to POROS AL resin (Applied Biosystems) according to the manufacture's instructions.
- a mab column was packed with 600 uL of the Antibody 80 - POROS AL resin and stored at 4°C.
- the column was washed with PBS in 87.5% D 2 O. 5uL of lmg/mL IL-12p40 was mixed with 35 uL of ice chilled PBS buffer (pH 7.0) in 100% D 2 O. The IL-12p40 mixture was incubated for 500, 1500, 5000s (in separated runs) before being injected onto the antibody column. The column was washed with 200 uL of chilled PBS (with H 2 O). The column was allowed to stand at 3°C for 250, 750 or 2500s (in separate runs). 8OuL of chilled 0.8% formic acid was injected onto the column. A further 4OuL of chilled 0.8% formic acid was used to elute the antigen from the antibody column.
- This 40 uL sample was collected and to it 20 uL of chilled 2 M urea, 1 M TCEP, pH 3.0 was added. 55 uL was then injected onto a column contain pepsin to digest the protein into peptides that were separated by rpHPLC using a 13 - 40% gradient of elution buffer (95% acetonitrile, 5% water, 0.0025% TFA) over 23 mins. Eluates were analysed by mass spectroscopy in MSl: Profile and MS2: DDA modes. The SEQUEST software program (Thermo) was used to identify the sequence of the parent peptide ions.
- a gene was synthesized encoding wild-type IL-23 containing a linker between subunits and a C-terminal FLAG tag. After analysis of the X-ray crystal structures of IL-23 (e.g. 3D85) animo acids with exposed side chains were selected for mutation to an ala residue. This was performed using site-directed mutagenesis on the wild-type IL-23 gene. All genes were cloned into the pTT5 vector.
- HEK293E cells were cultured in F17 media (InvitrogenTM) with Geneticin
- IL 12R ⁇ l/Fc Chimera (R&D Systems®), IL-23/Fc Chimera (R&D Systems®), Antibody 202.1 and Antibody 80 were diluted to 1 ⁇ g/mL in carbonate coating buffer and added to each well of a 96 well plate and incubated at 4 0 C overnight. The plate was then washed three times with wash buffer. The wells were then blocked by adding 200 ⁇ l of blocking buffer to each well and incubating the plate at 25 0 C for 1 hour. The supernatant was diluted in antibody diluent sufficient to generate a titration curve and lOOul was added to wells then incubated for 1 hour at 25 0 C.
- the plate was then washed as previously described and 100 ⁇ l of Monoclonal Anti-FLAG® M2 - HRP (Sigma- Aldrich®) at 1: 1000 in antibody diluent was used to detect bound cytokine. After incubation at 25 0 C for 1 hour the plate was washed again as previously described. 100 ⁇ l TMB substrate solution (Sigma- Aldrich®) was added to each well and the colour allowed to develop for 5 minutes. 100 ⁇ l of IM HCI was added to terminate the colour development reaction and absorbance was determined at 450 nm (ref. 620 nm).
- Petkova SB Akilesh S, Sproule TJ, Hor Khabbaz H, Brown AC, Presta LG, Meng YG, Roopenian DC 2006 Int Immunol. Dec;18(12):1759-69.
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Application Number | Priority Date | Filing Date | Title |
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JP2011522351A JP5623401B2 (en) | 2008-08-14 | 2009-08-14 | Anti-IL-12 / IL-23 antibody |
CA2733642A CA2733642A1 (en) | 2008-08-14 | 2009-08-14 | Anti-il-12/il-23 antibodies |
UAA201102878A UA104297C2 (en) | 2008-08-14 | 2009-08-14 | Anti-il-12/il-23 antibody |
KR1020117005918A KR101781965B1 (en) | 2008-08-14 | 2009-08-14 | Anti-il-12/il-23 antibodies |
MX2011001409A MX2011001409A (en) | 2008-08-14 | 2009-08-14 | Anti-il-12/il-23 antibodies. |
AU2009281713A AU2009281713B9 (en) | 2008-08-14 | 2009-08-14 | Anti-IL-12/IL-23 antibodies |
US13/058,914 US8563697B2 (en) | 2008-08-14 | 2009-08-14 | Anti-IL-12/IL-23 antibodies |
NZ590816A NZ590816A (en) | 2008-08-14 | 2009-08-14 | Anti-il-12/il-23 antibodies |
EP09806241.7A EP2326668B1 (en) | 2008-08-14 | 2009-08-14 | Anti-il-12/il-23 antibodies |
KR1020167026890A KR20160116056A (en) | 2008-08-14 | 2009-08-14 | Anti-il-12/il-23 antibodies |
BRPI0917668A BRPI0917668A2 (en) | 2008-08-14 | 2009-08-14 | antibody, method for producing the antibody, nucleic acid molecule, method for treating a disease, use of an antibody, and method for producing an antigen binding domain |
EA201170323A EA026110B1 (en) | 2008-08-14 | 2009-08-14 | Anti-il-12/il-23 antibodies |
CN200980140286.0A CN102177178B (en) | 2008-08-14 | 2009-08-14 | Anti-IL-12/IL-23 antibodies |
ZA2011/00711A ZA201100711B (en) | 2008-08-14 | 2011-01-27 | Anti-il-12/il-23 antibodies |
IL210903A IL210903A (en) | 2008-08-14 | 2011-01-27 | Anti-il-12/il-23 antibodies |
TN2011000052A TN2011000052A1 (en) | 2008-08-14 | 2011-01-28 | Anti-il-12/il-23 antibodies |
MA33692A MA32629B1 (en) | 2008-08-14 | 2011-03-11 | Antibodies to EL-12 |
US14/030,147 US20140086922A1 (en) | 2008-08-14 | 2013-09-18 | Anti-il-12/il-23 antibodies |
US15/136,355 US20160264661A1 (en) | 2008-08-14 | 2016-04-22 | Anti-il-12/il-23 antibodies |
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CA (1) | CA2733642A1 (en) |
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Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004101750A2 (en) * | 2003-05-09 | 2004-11-25 | Centocor, Inc. | IL-23p40 SPECIFIC IMMUNOGLOBULIN DERIVED PROTEINS, COMPOSITIONS, METHODS AND USES |
Family Cites Families (140)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4309989A (en) | 1976-02-09 | 1982-01-12 | The Curators Of The University Of Missouri | Topical application of medication by ultrasound with coupling agent |
FR2374910A1 (en) | 1976-10-23 | 1978-07-21 | Choay Sa | PREPARATION BASED ON HEPARIN, INCLUDING LIPOSOMES, PROCESS FOR OBTAINING IT AND MEDICINAL PRODUCTS CONTAINING SUCH PREPARATIONS |
US4172124A (en) | 1978-04-28 | 1979-10-23 | The Wistar Institute | Method of producing tumor antibodies |
US5179017A (en) | 1980-02-25 | 1993-01-12 | The Trustees Of Columbia University In The City Of New York | Processes for inserting DNA into eucaryotic cells and for producing proteinaceous materials |
US4634665A (en) | 1980-02-25 | 1987-01-06 | The Trustees Of Columbia University In The City Of New York | Processes for inserting DNA into eucaryotic cells and for producing proteinaceous materials |
US4399216A (en) | 1980-02-25 | 1983-08-16 | The Trustees Of Columbia University | Processes for inserting DNA into eucaryotic cells and for producing proteinaceous materials |
US4656134A (en) | 1982-01-11 | 1987-04-07 | Board Of Trustees Of Leland Stanford Jr. University | Gene amplification in eukaryotic cells |
US5149636A (en) | 1982-03-15 | 1992-09-22 | Trustees Of Columbia University In The City Of New York | Method for introducing cloned, amplifiable genes into eucaryotic cells and for producing proteinaceous products |
US5168062A (en) | 1985-01-30 | 1992-12-01 | University Of Iowa Research Foundation | Transfer vectors and microorganisms containing human cytomegalovirus immediate-early promoter-regulatory DNA sequence |
US4965188A (en) | 1986-08-22 | 1990-10-23 | Cetus Corporation | Process for amplifying, detecting, and/or cloning nucleic acid sequences using a thermostable enzyme |
US4683195A (en) | 1986-01-30 | 1987-07-28 | Cetus Corporation | Process for amplifying, detecting, and/or-cloning nucleic acid sequences |
US4683202A (en) | 1985-03-28 | 1987-07-28 | Cetus Corporation | Process for amplifying nucleic acid sequences |
US6492107B1 (en) | 1986-11-20 | 2002-12-10 | Stuart Kauffman | Process for obtaining DNA, RNA, peptides, polypeptides, or protein, by recombinant DNA technique |
DE229046T1 (en) | 1985-03-30 | 1987-12-17 | Marc Genf/Geneve Ballivet | METHOD FOR OBTAINING DNA, RNS, PEPTIDES, POLYPEPTIDES OR PROTEINS BY DNA RECOMBINANT METHOD. |
SE448277B (en) | 1985-04-12 | 1987-02-09 | Draco Ab | INDICATOR DEVICE WITH A DOSAGE DEVICE FOR MEDICINAL PRODUCTS |
US4766067A (en) | 1985-05-31 | 1988-08-23 | President And Fellows Of Harvard College | Gene amplification |
US4676980A (en) | 1985-09-23 | 1987-06-30 | The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services | Target specific cross-linked heteroantibodies |
US5576195A (en) | 1985-11-01 | 1996-11-19 | Xoma Corporation | Vectors with pectate lyase signal sequence |
US5618920A (en) | 1985-11-01 | 1997-04-08 | Xoma Corporation | Modular assembly of antibody genes, antibodies prepared thereby and use |
GB8601597D0 (en) | 1986-01-23 | 1986-02-26 | Wilson R H | Nucleotide sequences |
US4800159A (en) | 1986-02-07 | 1989-01-24 | Cetus Corporation | Process for amplifying, detecting, and/or cloning nucleic acid sequences |
SE453566B (en) | 1986-03-07 | 1988-02-15 | Draco Ab | POWDER INHALATOR DEVICE |
US5225539A (en) | 1986-03-27 | 1993-07-06 | Medical Research Council | Recombinant altered antibodies and methods of making altered antibodies |
US4767402A (en) | 1986-07-08 | 1988-08-30 | Massachusetts Institute Of Technology | Ultrasound enhancement of transdermal drug delivery |
WO1988001213A1 (en) | 1986-08-18 | 1988-02-25 | Clinical Technologies Associates, Inc. | Delivery systems for pharmacological agents |
US4889818A (en) | 1986-08-22 | 1989-12-26 | Cetus Corporation | Purified thermostable enzyme |
US5260203A (en) | 1986-09-02 | 1993-11-09 | Enzon, Inc. | Single polypeptide chain binding molecules |
US4946778A (en) | 1987-09-21 | 1990-08-07 | Genex Corporation | Single polypeptide chain binding molecules |
US4704692A (en) | 1986-09-02 | 1987-11-03 | Ladner Robert C | Computer based system and method for determining and displaying possible chemical structures for converting double- or multiple-chain polypeptides to single-chain polypeptides |
US4921794A (en) | 1987-01-14 | 1990-05-01 | President And Fellows Of Harvard College | T7 DNA polymerase |
US4795699A (en) | 1987-01-14 | 1989-01-03 | President And Fellows Of Harvard College | T7 DNA polymerase |
EP0832981A1 (en) | 1987-02-17 | 1998-04-01 | Pharming B.V. | DNA sequences to target proteins to the mammary gland for efficient secretion |
DE3852304T3 (en) | 1987-03-02 | 1999-07-01 | Enzon Labs Inc., Piscataway, N.J. | Organism as carrier for "Single Chain Antibody Domain (SCAD)". |
US4873316A (en) | 1987-06-23 | 1989-10-10 | Biogen, Inc. | Isolation of exogenous recombinant proteins from the milk of transgenic mammals |
CA1341235C (en) | 1987-07-24 | 2001-05-22 | Randy R. Robinson | Modular assembly of antibody genes, antibodies prepared thereby and use |
US4939666A (en) | 1987-09-02 | 1990-07-03 | Genex Corporation | Incremental macromolecule construction methods |
JP2980626B2 (en) | 1988-01-11 | 1999-11-22 | ゾーマ・コーポレーション | Novel plasmid vector containing pectate lyase signal sequence |
US5256648A (en) | 1988-01-21 | 1993-10-26 | Yale University | Selective inhibition of gene expression by photoactivatable oligonucleotides |
US4956288A (en) | 1988-04-22 | 1990-09-11 | Biogen, Inc. | Method for producing cells containing stably integrated foreign DNA at a high copy number, the cells produced by this method, and the use of these cells to produce the polypeptides coded for by the foreign DNA |
US5130238A (en) | 1988-06-24 | 1992-07-14 | Cangene Corporation | Enhanced nucleic acid amplification process |
DE68910021T2 (en) | 1988-07-04 | 1994-05-11 | Meiji Seika Kaisha | Oxamic acid compounds and pharmaceutical compositions for use in improving damaged brain functions. |
US5223409A (en) | 1988-09-02 | 1993-06-29 | Protein Engineering Corp. | Directed evolution of novel binding proteins |
US5091310A (en) | 1988-09-23 | 1992-02-25 | Cetus Corporation | Structure-independent dna amplification by the polymerase chain reaction |
US5142033A (en) | 1988-09-23 | 1992-08-25 | Hoffmann-La Roche Inc. | Structure-independent DNA amplification by the polymerase chain reaction |
US5066584A (en) | 1988-09-23 | 1991-11-19 | Cetus Corporation | Methods for generating single stranded dna by the polymerase chain reaction |
US4987893A (en) | 1988-10-12 | 1991-01-29 | Rochal Industries, Inc. | Conformable bandage and coating material |
GB8823869D0 (en) | 1988-10-12 | 1988-11-16 | Medical Res Council | Production of antibodies |
WO1990005144A1 (en) | 1988-11-11 | 1990-05-17 | Medical Research Council | Single domain ligands, receptors comprising said ligands, methods for their production, and use of said ligands and receptors |
US5530101A (en) | 1988-12-28 | 1996-06-25 | Protein Design Labs, Inc. | Humanized immunoglobulins |
US4994370A (en) | 1989-01-03 | 1991-02-19 | The United States Of America As Represented By The Department Of Health And Human Services | DNA amplification technique |
US5266491A (en) | 1989-03-14 | 1993-11-30 | Mochida Pharmaceutical Co., Ltd. | DNA fragment and expression plasmid containing the DNA fragment |
CA2016841C (en) | 1989-05-16 | 1999-09-21 | William D. Huse | A method for producing polymers having a preselected activity |
CA2016842A1 (en) | 1989-05-16 | 1990-11-16 | Richard A. Lerner | Method for tapping the immunological repertoire |
AU652539B2 (en) | 1989-05-16 | 1994-09-01 | Medical Research Council | Co-expression of heteromeric receptors |
WO1991000360A1 (en) | 1989-06-29 | 1991-01-10 | Medarex, Inc. | Bispecific reagents for aids therapy |
KR0185192B1 (en) | 1989-10-05 | 1999-04-01 | 제임스 더블유. 데이비 | Cell-free synthesis and isolation of novel genes and polypeptides |
US5580575A (en) | 1989-12-22 | 1996-12-03 | Imarx Pharmaceutical Corp. | Therapeutic drug delivery systems |
US5681941A (en) | 1990-01-11 | 1997-10-28 | Isis Pharmaceuticals, Inc. | Substituted purines and oligonucleotide cross-linking |
DE69133566T2 (en) | 1990-01-12 | 2007-12-06 | Amgen Fremont Inc. | Formation of xenogenic antibodies |
US5427908A (en) | 1990-05-01 | 1995-06-27 | Affymax Technologies N.V. | Recombinant library screening methods |
AU642273B2 (en) | 1990-05-24 | 1993-10-14 | United States of America, as represented by the Secretary, U.S. Department of Commerce, The | Bistriazenes as chemotherapeutic agents |
AU8081491A (en) | 1990-06-01 | 1991-12-31 | Cetus Corporation | Compositions and methods for identifying biologically active molecules |
US5723286A (en) | 1990-06-20 | 1998-03-03 | Affymax Technologies N.V. | Peptide library and screening systems |
KR0149181B1 (en) | 1990-06-29 | 1998-08-17 | 데이비드 알, 맥지 | Melanin production by transformed microorganisms |
GB9015198D0 (en) | 1990-07-10 | 1990-08-29 | Brien Caroline J O | Binding substance |
JPH06508511A (en) | 1990-07-10 | 1994-09-29 | ケンブリッジ アンティボディー テクノロジー リミティド | Method for producing specific binding pair members |
US5580734A (en) | 1990-07-13 | 1996-12-03 | Transkaryotic Therapies, Inc. | Method of producing a physical map contigous DNA sequences |
EP0542810A1 (en) | 1990-08-02 | 1993-05-26 | B.R. Centre Limited | Methods for the production of proteins with a desired function |
US6300129B1 (en) | 1990-08-29 | 2001-10-09 | Genpharm International | Transgenic non-human animals for producing heterologous antibodies |
US5770429A (en) | 1990-08-29 | 1998-06-23 | Genpharm International, Inc. | Transgenic non-human animals capable of producing heterologous antibodies |
WO1994025585A1 (en) | 1993-04-26 | 1994-11-10 | Genpharm International, Inc. | Transgenic non-human animals capable of producing heterologous antibodies |
US5625126A (en) | 1990-08-29 | 1997-04-29 | Genpharm International, Inc. | Transgenic non-human animals for producing heterologous antibodies |
US5633425A (en) | 1990-08-29 | 1997-05-27 | Genpharm International, Inc. | Transgenic non-human animals capable of producing heterologous antibodies |
EP0814159B1 (en) | 1990-08-29 | 2005-07-27 | GenPharm International, Inc. | Transgenic mice capable of producing heterologous antibodies |
US5789650A (en) | 1990-08-29 | 1998-08-04 | Genpharm International, Inc. | Transgenic non-human animals for producing heterologous antibodies |
US5661016A (en) | 1990-08-29 | 1997-08-26 | Genpharm International Inc. | Transgenic non-human animals capable of producing heterologous antibodies of various isotypes |
US5545806A (en) | 1990-08-29 | 1996-08-13 | Genpharm International, Inc. | Ransgenic non-human animals for producing heterologous antibodies |
WO1992005258A1 (en) | 1990-09-20 | 1992-04-02 | La Trobe University | Gene encoding barley enzyme |
IL99552A0 (en) | 1990-09-28 | 1992-08-18 | Ixsys Inc | Compositions containing procaryotic cells,a kit for the preparation of vectors useful for the coexpression of two or more dna sequences and methods for the use thereof |
GB9022648D0 (en) | 1990-10-18 | 1990-11-28 | Charing Cross Sunley Research | Polypeptide and its use |
DE69129154T2 (en) | 1990-12-03 | 1998-08-20 | Genentech, Inc., South San Francisco, Calif. | METHOD FOR ENRICHING PROTEIN VARIANTS WITH CHANGED BINDING PROPERTIES |
JPH06508022A (en) | 1991-02-21 | 1994-09-14 | ギリアド サイエンシズ,インコーポレイテッド | Biomolecule-specific aptamers and production methods |
US5404871A (en) | 1991-03-05 | 1995-04-11 | Aradigm | Delivery of aerosol medications for inspiration |
JP3693671B2 (en) | 1991-03-15 | 2005-09-07 | アムゲン インコーポレーテッド | PEGylation of polypeptides |
JP3672306B2 (en) | 1991-04-10 | 2005-07-20 | ザ スクリップス リサーチ インスティテュート | Heterodimeric receptor library using phagemids |
US5962255A (en) | 1992-03-24 | 1999-10-05 | Cambridge Antibody Technology Limited | Methods for producing recombinant vectors |
ES2141108T3 (en) | 1991-07-02 | 2000-03-16 | Inhale Inc | METHOD AND DEVICE FOR PROVIDING DRUGS IN AEROSOL. |
DE69229477T2 (en) | 1991-09-23 | 1999-12-09 | Cambridge Antibody Technology Ltd., Melbourn | Methods for the production of humanized antibodies |
US5270170A (en) | 1991-10-16 | 1993-12-14 | Affymax Technologies N.V. | Peptide library and screening method |
WO1993008829A1 (en) | 1991-11-04 | 1993-05-13 | The Regents Of The University Of California | Compositions that mediate killing of hiv-infected cells |
US5733761A (en) | 1991-11-05 | 1998-03-31 | Transkaryotic Therapies, Inc. | Protein production and protein delivery |
US5641670A (en) | 1991-11-05 | 1997-06-24 | Transkaryotic Therapies, Inc. | Protein production and protein delivery |
US5484908A (en) | 1991-11-26 | 1996-01-16 | Gilead Sciences, Inc. | Oligonucleotides containing 5-propynyl pyrimidines |
ATE408012T1 (en) | 1991-12-02 | 2008-09-15 | Medical Res Council | PRODUCTION OF AUTOANTIBODIES ON PHAGE SURFACES BASED ON ANTIBODIES SEGMENT LIBRARIES |
US5667988A (en) | 1992-01-27 | 1997-09-16 | The Scripps Research Institute | Methods for producing antibody libraries using universal or randomized immunoglobulin light chains |
US5543507A (en) | 1992-03-05 | 1996-08-06 | Isis Pharmaceuticals, Inc. | Covalently cross-linked oligonucleotides |
DE69333823T2 (en) | 1992-03-24 | 2006-05-04 | Cambridge Antibody Technology Ltd., Melbourn | METHOD FOR PRODUCING MEMBERS OF SPECIFIC BINDING SAVINGS |
WO1994006498A1 (en) | 1992-09-23 | 1994-03-31 | Fisons Plc | Inhalation device |
BR9307270A (en) | 1992-10-19 | 1999-06-01 | Dura Pharma Inc | Dry powder inhaler |
US5643252A (en) | 1992-10-28 | 1997-07-01 | Venisect, Inc. | Laser perforator |
WO1994012520A1 (en) | 1992-11-20 | 1994-06-09 | Enzon, Inc. | Linker for linked fusion polypeptides |
US5849695A (en) | 1993-01-13 | 1998-12-15 | The Regents Of The University Of California | Parathyroid hormone analogues useful for treatment of osteoporosis and disorders of calcium meatabolism in mammals |
ES2124870T3 (en) | 1993-01-19 | 1999-02-16 | Glaxo Group Ltd | AEROSOL DISTRIBUTOR AND MANUFACTURING PROCEDURE. |
PL310327A1 (en) | 1993-02-12 | 1995-12-11 | Univ Leland Stanford Junior | Adjustable transcription of target genes and other biological processes |
US5770428A (en) | 1993-02-17 | 1998-06-23 | Wisconsin Alumni Research Foundation | Chimeric retrovial expression vectors and particles containing a simple retroviral long terminal repeat, BLV or HIV coding regions and cis-acting regulatory sequences, and an RNA translational enhancer with internal ribsome entry site |
GB9313509D0 (en) | 1993-06-30 | 1993-08-11 | Medical Res Council | Chemisynthetic libraries |
US5514670A (en) | 1993-08-13 | 1996-05-07 | Pharmos Corporation | Submicron emulsions for delivery of peptides |
US5625825A (en) | 1993-10-21 | 1997-04-29 | Lsi Logic Corporation | Random number generating apparatus for an interface unit of a carrier sense with multiple access and collision detect (CSMA/CD) ethernet data network |
US5814599A (en) | 1995-08-04 | 1998-09-29 | Massachusetts Insitiute Of Technology | Transdermal delivery of encapsulated drugs |
WO1995015388A1 (en) | 1993-12-03 | 1995-06-08 | Medical Research Council | Recombinant binding proteins and peptides |
SE9304060D0 (en) | 1993-12-06 | 1993-12-06 | Bioinvent Int Ab | Methods to select specific bacteriophages |
US5827690A (en) | 1993-12-20 | 1998-10-27 | Genzyme Transgenics Corporatiion | Transgenic production of antibodies in milk |
US6830751B1 (en) * | 1994-03-14 | 2004-12-14 | Genetics Institute, Llc | Use of IL-12 antagonists in the treatment of rheumatoid arthritis |
US5763733A (en) | 1994-10-13 | 1998-06-09 | Enzon, Inc. | Antigen-binding fusion proteins |
JP3659261B2 (en) | 1994-10-20 | 2005-06-15 | モルフォシス・アクチェンゲゼルシャフト | Targeted heterojunction of a recombinant protein to a multifunctional complex |
US5549551A (en) | 1994-12-22 | 1996-08-27 | Advanced Cardiovascular Systems, Inc. | Adjustable length balloon catheter |
US5656730A (en) | 1995-04-07 | 1997-08-12 | Enzon, Inc. | Stabilized monomeric protein compositions |
AU2466895A (en) | 1995-04-28 | 1996-11-18 | Abgenix, Inc. | Human antibodies derived from immunized xenomice |
US5730723A (en) | 1995-10-10 | 1998-03-24 | Visionary Medical Products Corporation, Inc. | Gas pressured needle-less injection device and method |
CA2229043C (en) | 1995-08-18 | 2016-06-07 | Morphosys Gesellschaft Fur Proteinoptimierung Mbh | Protein/(poly)peptide libraries |
US5853697A (en) | 1995-10-25 | 1998-12-29 | The United States Of America, As Represented By The Department Of Health & Human Services | Methods of treating established colitis using antibodies against IL-12 |
GB9526100D0 (en) | 1995-12-20 | 1996-02-21 | Intersurgical Ltd | Nebulizer |
IL125183A0 (en) | 1996-01-03 | 1999-03-12 | Glaxo Group Ltd | Inhalation device |
DE19624387C2 (en) | 1996-06-19 | 1999-08-19 | Hatz Motoren | Cold start device |
GB9712818D0 (en) | 1996-07-08 | 1997-08-20 | Cambridge Antibody Tech | Labelling and selection of specific binding molecules |
AU5702298A (en) | 1996-12-03 | 1998-06-29 | Abgenix, Inc. | Transgenic mammals having human Ig loci including plural VH and VK regions nd antibodies produced therefrom |
US5879681A (en) | 1997-02-07 | 1999-03-09 | Emisphere Technolgies Inc. | Compounds and compositions for delivering active agents |
US5921447A (en) | 1997-02-13 | 1999-07-13 | Glaxo Wellcome Inc. | Flow-through metered aerosol dispensing apparatus and method of use thereof |
US6235883B1 (en) | 1997-05-05 | 2001-05-22 | Abgenix, Inc. | Human monoclonal antibodies to epidermal growth factor receptor |
ES2284242T3 (en) | 1998-01-23 | 2007-11-01 | F. Hoffmann-La Roche Ag | ANTIBODIES AGAINST HUMAN IL-12. |
US6914128B1 (en) | 1999-03-25 | 2005-07-05 | Abbott Gmbh & Co. Kg | Human antibodies that bind human IL-12 and methods for producing |
JP3523245B1 (en) | 2000-11-30 | 2004-04-26 | メダレックス,インコーポレーテッド | Transgenic chromosome-introduced rodents for the production of human antibodies |
WO2002097048A2 (en) | 2001-05-30 | 2002-12-05 | Centocor, Inc. | ANTI-p40 IMMUNOGLOBULIN DERIVED PROTEINS, COMPOSITIONS, METHODS AND USES |
EP2298809A3 (en) | 2001-07-12 | 2012-02-15 | FOOTE, Jefferson | Super humanized antibodies |
AR051444A1 (en) * | 2004-09-24 | 2007-01-17 | Centocor Inc | PROTEINS DERIVED FROM IL-23P40 SPECIFIC IMMUNOGLOBULIN, COMPOSITIONS, EPITHOPES, METHODS AND USES |
CA2591813A1 (en) | 2004-12-21 | 2006-06-29 | Centocor, Inc. | Anti-il-12 antibodies, epitopes, compositions, methods and uses |
CN103172738A (en) | 2005-06-30 | 2013-06-26 | Abbvie公司 | IL-12/P40 binding proteins |
ME02705B (en) | 2005-08-31 | 2017-10-20 | Merck Sharp & Dohme | Engineered anti-il-23 antibodies |
US7776331B1 (en) * | 2007-01-16 | 2010-08-17 | Abbott Laboratories | Methods of treating plaque psoriasis |
EP2326668B1 (en) * | 2008-08-14 | 2018-01-17 | Teva Pharmaceuticals Australia Pty Ltd | Anti-il-12/il-23 antibodies |
-
2009
- 2009-08-14 EP EP09806241.7A patent/EP2326668B1/en not_active Not-in-force
- 2009-08-14 EA EA201170323A patent/EA026110B1/en not_active IP Right Cessation
- 2009-08-14 CA CA2733642A patent/CA2733642A1/en not_active Abandoned
- 2009-08-14 KR KR1020167026890A patent/KR20160116056A/en not_active Application Discontinuation
- 2009-08-14 AU AU2009281713A patent/AU2009281713B9/en not_active Ceased
- 2009-08-14 US US13/058,914 patent/US8563697B2/en not_active Expired - Fee Related
- 2009-08-14 WO PCT/AU2009/001047 patent/WO2010017598A1/en active Application Filing
- 2009-08-14 JP JP2011522351A patent/JP5623401B2/en not_active Expired - Fee Related
- 2009-08-14 TW TW098127368A patent/TWI501776B/en not_active IP Right Cessation
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Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004101750A2 (en) * | 2003-05-09 | 2004-11-25 | Centocor, Inc. | IL-23p40 SPECIFIC IMMUNOGLOBULIN DERIVED PROTEINS, COMPOSITIONS, METHODS AND USES |
Non-Patent Citations (3)
Title |
---|
DING, CHANGHAI. ET AL.: "ABT-874, a fully human monoclonal anti-IL-12/IL23 antibody for the potential treatment of autoimmune diseases", CURRENT OPINION IN INVESTIGATIONAL DRUGS, vol. 9, no. 5, 25 April 2008 (2008-04-25), pages 515 - 522, XP008134761 * |
REDDY, MANJULA. ET AL.: "Modulation of CLA, IL-12R, CD40L, and IL-2Ra expression and inhibition of IL-12- and IL-23-induced cytokine secretion by CNTO 1275", CELLULAR IMMUNOLOGY, vol. 247, no. 1, 2007, pages 1 - 11, XP022276469 * |
See also references of EP2326668A4 * |
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Also Published As
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US8563697B2 (en) | 2013-10-22 |
CA2733642A1 (en) | 2010-02-18 |
AU2009281713B9 (en) | 2014-05-29 |
EP2326668B1 (en) | 2018-01-17 |
MA32629B1 (en) | 2011-09-01 |
EP2326668A1 (en) | 2011-06-01 |
KR20160116056A (en) | 2016-10-06 |
AU2009281713B2 (en) | 2013-10-24 |
US20110262445A1 (en) | 2011-10-27 |
NZ590816A (en) | 2013-02-22 |
EA026110B1 (en) | 2017-03-31 |
IL210903A (en) | 2016-05-31 |
TW201010725A (en) | 2010-03-16 |
UA104297C2 (en) | 2014-01-27 |
TWI501776B (en) | 2015-10-01 |
IL210903A0 (en) | 2011-04-28 |
TN2011000052A1 (en) | 2012-09-05 |
US20140086922A1 (en) | 2014-03-27 |
JP2011530298A (en) | 2011-12-22 |
CN102177178A (en) | 2011-09-07 |
KR20110043761A (en) | 2011-04-27 |
KR101781965B1 (en) | 2017-09-27 |
MY153074A (en) | 2014-12-31 |
CN102177178B (en) | 2015-07-01 |
AU2009281713A1 (en) | 2010-02-18 |
JP5623401B2 (en) | 2014-11-12 |
EP2326668A4 (en) | 2014-01-22 |
ZA201100711B (en) | 2012-05-01 |
US20160264661A1 (en) | 2016-09-15 |
MX2011001409A (en) | 2011-03-29 |
AR073060A1 (en) | 2010-10-13 |
EA201170323A1 (en) | 2011-10-31 |
IL245547A0 (en) | 2016-06-30 |
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