WO2001097844A1 - Bispecific fusion protein and method of use for enhancing effector cell killing of target cells - Google Patents
Bispecific fusion protein and method of use for enhancing effector cell killing of target cells Download PDFInfo
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- WO2001097844A1 WO2001097844A1 PCT/US2001/040835 US0140835W WO0197844A1 WO 2001097844 A1 WO2001097844 A1 WO 2001097844A1 US 0140835 W US0140835 W US 0140835W WO 0197844 A1 WO0197844 A1 WO 0197844A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2887—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against CD20
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
- A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
- A61K47/6811—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a protein or peptide, e.g. transferrin or bleomycin
- A61K47/6813—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a protein or peptide, e.g. transferrin or bleomycin the drug being a peptidic cytokine, e.g. an interleukin or interferon
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/52—Cytokines; Lymphokines; Interferons
- C07K14/555—Interferons [IFN]
- C07K14/56—IFN-alpha
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07K2319/00—Fusion polypeptide
Definitions
- This invention relates to a fusion protein comprising all or a biologically active portion of an interferon alpha (IFN- ⁇ ) linked to an immunoglobulin protein or polypeptide fragment thereof, which recognizes a cell surface protein expressed by a malignant cell.
- the fusion protein when bound to a malignant cell, or a target cell, would bind via IFN- ⁇ to the IFN- ⁇ receptor expressed on an effector cell (e.g., natural killer (NK) cells, polymo ⁇ honuclear (PMNs) cells and macrophages/monocytes).
- an effector cell e.g., natural killer (NK) cells, polymo ⁇ honuclear (PMNs) cells and macrophages/monocytes.
- IFN- ⁇ fusion protein The binding of IFN- ⁇ fusion protein to its receptor on effector cells enhances and potentiates extracellular (e.g., antibody-dependent cell-mediated cytotoxicity or ADCC-type), intracellular (phagocytic) and/or direct killing of the bound target cell.
- cytokines interleukin-2 (IL-2) and IFN- ⁇
- NK natural killer cells
- IFN- ⁇ interleukin-2
- NK natural killer cells
- IFN- ⁇ can regulate NK cells and lymphokine-activated killer (LAK) cells and can act in synergy with IL-2 to augment NK activity (Chikkala et al, Cancer Res. 50: 1176-82 (1990)).
- LAK lymphokine-activated killer
- systemically administered IFN- ⁇ has exhibited a limited anti-tumor effect in lymphomas, leukemia, Kaposi's sarcoma, renal cell carcinoma, melanoma, multiple melanoma, glioma and ovarian cancer. See Sell et al, IMMUNOLOGY, IMMUNOPATHOLOGY & IMMUNITY 951-2 (1996).
- IFN- ⁇ or IL-2 can cause less important severe life-threatening toxicity, which limits their administration at higher doses leading to reduced efficacy and discourages their therapeutic use (Meseri-Delwail et al, Biotechnol Ther. 5: 47-57 (1994); and Sosman et al, Semin. Oncol. 17: 22-30, 38-41 (1990)).
- Use of IFN- ⁇ is further complicated as multiple species of IFN- ⁇ exist that differ dramatically in activity, which is explained in part by different binding affinities (Webb et al, Cell Immunol 124: 158-7 (1989); and U.S. Patent 4,780,530 (1988)).
- systemic activation of NK cells and monocytes is less effective than activation at the tumor site since activated cells may not home to the tumor. This is particularly applicable to solid tumors including carcinomas.
- ADCC Antibody dependent cellular cytotoxicity
- mAb monoclonal antibodies
- ADCC can be enhanced by the cytokines IL-2 and IFN- ⁇ (Nuist et al, Cancer Immunol. Immunother. 36: 163-70 (1993)).
- Monoclonal antibodies have been designed to target specific cells or antigens. Monoclonal antibodies therefore, have been designed to act as vectors or delivery vehicles for targeting foreign antigens to cells. See for general description EP Patent No. 553,244 (1993).
- Anti-CD19 Antibodies have been raised which recognize CD19, a signal transduction molecule restricted to the B-cell lineage.
- Examples of monoclonal anti-CD19 antibodies include anti-B4 (Goulet et al, Blood 90: 2364-75 (1997)), B43 and B43 single-chain Fv (FNS191; Li et al, Cancer Immunol. Immunother. 47: 121- 130 (1998)).
- Myers et al Leuk. Lymphoma 29: 329-38 (1998) reported conjugating the murine monoclonal B43 to the tyrosine kinase inhibitor (see also U.S. Patent No.
- Rituximab and other Anti-CD20 Antibodies The FDA approved anti-CD20 antibody, Rituximab (IDEC C2B8; RITUXANO; ATCC No. HB 11388) has also been used to treat humans. Ibritumomab, is the murine counte ⁇ art to Rituximab (Wiseman et al, Clin. Cancer Res. 5: 3281s-6s (1999)).
- Other reported anti-CD20 antibodies include the anti-human CD20 mAb 1F5 (Shan et al, J Immunol.
- CD22 is a cell surface antigen expressed on normal human B cells and some neoplastic B cells.
- monoclonal anti-CD22 antibodies have been created, including HD6, RFB4, UV22-2, Tol5, 4KB 128, a humanized anti- CD22 antibody (hLL2), and a bispecific F(ab') 2 antibody linked to saporin (Li et al, Cell Immunol 111: 85-99 (1989); Mason et al, Blood 69: 836-40 (1987); Behr et al, Clin. Cancer Res. 5: 3304s-14s (1999); and Bonardi et al, Cancer Res. 53: 3015-21 (1993)).
- CD33 is a glycoprotein expressed on early myeloid progenitor and myeloid leukemic (e.g., acute myelogenous leukemia, AML) cells, but not on stem cells.
- mice An IgGi monoclonal antibody was prepared in mice (Ml 95) and also in a humanized form (HuM195), that reportedly has antibody-dependent cellular cytotoxicity (Kossma et ⁇ /., Clin. Cancer Res. 5: 2748-55 (1999)).
- HuM195 humanized form
- HuMl 95 had only modest ADCC capability against HL60 cells.
- An anti-CD33 immunoconjugate consisting of a humanized anti-CD33 antibody linked to the antitumor antibiotic calicheamicin reportedly demonstrated selective ablation of malignant hematopoiesis in some AML patients (Sievers et al, Blood 93: 3678-84 (1999). Pagliaro et al, Clin. Cancer Res. 4: 1971-6 (1998) described a HuM195-gelonin immunoconjugate, comprising an anti-CD33 mAb conjugated to the single-chain plant toxin gelonin.
- CD38 is an antigen expressed during early stages of differentiation in normal and leukemic myeloid cells, including myeloma cells. Ellis et al, J. Immunol 155: 925-37 (1995) reported a high affinity mAb (AT13/5) against CD38 which efficiently directed antibody-dependent cellular cytotoxicity (ADCC) against CD38 + cell lines, but which activated complement poorly and did not down- regulate CD38 expression. Flavell et al, Hematol Oncol.
- Anti-EGF-R Antibodies Epidermal growth factor-receptor (EGF-R) binds to EGF, a mito genie peptide.
- Anti-EGF-R antibodies and methods of preparing them can be performed as described in U.S. Patent Nos. 5,844,093; 5,558,864.
- European Patent No. 706,799A pu ⁇ ortedly describes an immunoconjugate comprising an anti- EGF-R mAb fused to a C-X-C chemokine, especially IL-8.
- U.S. 5,824,782 describes an immunoconjugate comprising an anti-EGFR antibody fused to IL-8, which lacks at least the first amino acid of IL-8.
- HM1.24 is a type II membrane glycoprotein is overexpressed in multiple myeloma (MM) and Waldenstrom's macroglobulinemia (Ohtomo et al, Biochem. Biophys. Res. Commun. 258: 583-91 (1999); and Goto et al, Blood 84: 1922-30 (1994)).
- a mouse monoclonal anti-HMl.24 IgG 2a / ⁇ antibody has been demonstrated to bind to HM1.24 on MM cells and reportedly induces ADCC (Ono et al, Mol Immuno. 36: 387-95 (1999)).
- a humanized anti-HM1.24 IgG ⁇ / ⁇ antibody also was shown to induce ADCC against human myeloma KPMM2 and ARH77 cells (Ono et al, Mol Immuno. 36: 387-95 (1999)).
- the ergB 2 gene is an oncogene encoding a transmembrane receptor.
- trastuzumab e.g., HERCEPTIN®; Former et al, Oncology (Huntingt) 13: 647-58 (1999)
- TAB-250 Rosenblum et al, Clin. Cancer Res. 5: 865-74 (1999)
- BACH-250 Id.
- TA1 Maier et al, Cancer Res. 51: 5361-9 (1991)
- MUC-1 is a carcinoma associated mucin.
- the anti- MUC-1 monoclonal antibody, Mc5 was reportedly administered to mice carrying transplanted breast tumors and pu ⁇ ortedly suppressed tumor growth (Peterson et al , Cancer Res. 57: 1103-8 (1997)). Mc5 was chemically linked in a non-cleavable fashion to a natural IFN- ⁇ (nIFN- ⁇ ) and reportedly inhibited growth of injected tumors in mice (Ozzello et al, Breast Cancer Res. Treat. 25: 265-76 (1993)).
- An IgG 4 anti- MUC-1 mAb, hCTMOl has been suggested as a suitable carrier for cytotoxic agents in ovarian carcinomas (Van Hof et al, Cancer Res. 56: 5179-85).
- Anti-phosphatidyl-serine antigen Antibodies Phosphatidyl-serine is a phospholipid. Antibodies have been reported which bind to phosphatidyl-serine and not other phospholipids (e.g., Yron et al, Clin. Exp. Immol. 97: 187-92) (1994)). However, anti-phospholipid antibodies appear more typically associated with anti- phospholipid syndrome and its diagnosis, than for use in the treatment or diagnosis of cancer.
- TAG-72 is a tumor-associated antigen (TAG).
- TAG-72 is a tumor-associated antigen (TAG).
- TAG-72 epitope Pavlinkova et ⁇ /., Clin. Cancer Res. 5: 2613-9 (1999)
- Additional anti- TAG-72 antibodies include B72.3 (Divgi et al, Nucl. Med. Biol. 21 : 9-15 (1994)) and those disclosed in U.S. Patent No. 5,976,531.
- Administration of recombinant IFN- ⁇ reportedly increased the amount of TAG-72 expressed on tumors (Macey et al, Clin. Cancer Res. 3: 1547-55 (1997)).
- the CC49 antibody also has reportedly been chemically conjugated to doxorubicin (Johnson et al, Anticancer Res. 15: 1387-93 (1995)) and streptavidin (Ngai et al, Nucl Med. Biol. 22: 77-86 (1995)).
- TAG-72 has also been chemically conjugated to human interleukin-2 (IL-2) (LeBerthon et al, Cancer Res. 51: 2694-8 (1991).
- IL-2 human interleukin-2
- U.S. Patent No. 5,976,531 claimed a human anti- Tag-72 antibody conjugated to an interferon but no evidence was presented indicating its efficiency in mammals. Interferon-a Immunoconjugates.
- Monoclonal antibodies raised against tumor cell lines have been covalently coupled with purified human lymphoblastoid IFN- ⁇ .
- Administration of this coupled form of IFN- ⁇ reportedly augmented killing of the tumor cells and other tumor targets by peripheral blood NK cells (Flannery et al, Eur. J Cancer Clin. Oncol. 20: 791-8 (1984)).
- CD22, CD33, CD38 and CD40 See, e.g., U.S. Patent No. 5,637,481 (1997) and EP Patent No. 610,046 (1994).
- Fusion proteins comprising the cytokine IL-15 and anti- CD20 (International PCT Application 98/16254), and fusion proteins comprising other lymphokines (e.g., T -2 and IL-3) and an immunoglobulin fragment capable of binding to a tumor antigen have been described (U.S. Patent Nos. 5,645,835 (1997) and 5,314,995 (1994); Lode et al, Blood 91: 1706-1715 (1998); Hassan et al, Leuk. Lymphoma 20: 1-15 (1995)).
- Chang et al, U.S. Patent 5,723,125 describes a hybrid molecule comprising an interferon, preferably IFN- ⁇ -2a or IFN- ⁇ -2b, which are joined at the carboxy terminus via a peptide to the amino terminus of a first gamma immunoglobulin Fc fragment as a means of increasing the blood half-life of the cytokine.
- Chimeric immunoglobulin proteins comprising a cytokine (e.g., TL-2, tumor necrosis factor ⁇ , etc.) and the heavy chain of an antibody for treating viral infections and cancer are described in International PCT Application 92/08495, as well as a fusion protein of IFN- ⁇ /M-CSF.
- a fusion protein of RM4/IFN-tau has demonstrated antitumor activity in mice (Qi et al, Hum. Antibodies Hybridomas 7: 21-6 (1996); and Xiang et al, Hum. Antibodies Hybridomas 7: 2-10 (1996)).
- IFN- ⁇ -2b was reported to be conjugated with ME31.3 and anti-carcinoembryonic antigen (CEA) and pu ⁇ ortedly may improve diagnostic and therapeutic potential of monoclonal antibodies making them worthy of further study (Thakur et al, J. Immunother. 20: 194-201 (1997)).
- CEA anti-carcinoembryonic antigen
- compositions comprising an immunoconjugate that comprises an antibody or immunogenic fragment thereof that binds to an antigen expressed by a target cell that is to be eradicated, wherein said antibody or immunogenic fragment thereof possesses human effector function, which antibody or immunogenic fragment thereof is fused at its carboxy terminus to a cytokine that binds a receptor expressed on the surface of a natural killer cell and/or macrophage, thereby resulting in an immunoconjugate that facilitates extracellular (ADCC-type) and intracellular (phagocytic) killing of a target cell, when said immunoconjugate is administered to a host.
- the cytokine is a interferon.
- the interferon is an ⁇ -interferon, especially one which has been FDA approved (e.g., IFN- ⁇ -2a, IFN- ⁇ -2b and IFN- ⁇ -nl).
- the target cells to which these immunoconjugates are directed may include malignant cells selected from the group consisting of a breast carcinoma cell, an ovarian carcinoma cell, a prostate carcinoma cell, a lung carcinoma cell, a leukemic T-cell, a leukemic B-cell, a multiple myeloma cell and a B-cell lymphoma cell. It is another object of the invention to provide a combination therapy to treat a malignancy in a subject comprising an immunoconjugate as described above and at least one chemotherapeutic agent or chemotherapeutic cocktail.
- the present invention relates to IFN- ⁇ fusion proteins, specifically immunoconjugates, and the use thereof as therapeutic agents that have the ability to target malignant cells and enhance the killing activity of effector cells through the binding of an IFN- ⁇ to its receptor on the effector cell and without systemic administration of IFN- ⁇ and its associated toxicity.
- immunoconjugates will have enhanced ADCC and phagocytic activity.
- IFN- ⁇ -2a Rostyrene- ⁇ -2a
- IFN- ⁇ -2b Interleukin- ⁇ -2b
- IFN- ⁇ -nl Lymphoblastoid interferon called Wellferon and produced by Wellcome Foundation Ltd - Wellcome Research Laboratories
- IFN- ⁇ -2a and consensus IFN
- fusion protein means a hybrid protein produced recombinantly including a synthetic or heterologous amino acid sequence.
- a fusion protein can be produced from a hybrid gene containing operatively linked heterologous gene sequences.
- bispecific fusion protein is meant any immunologically reactive molecule which specifically recognizes and binds two different targets at alternate times or at the same time.
- it will refer to an IFN- ⁇ antibody fusion protein, wherein the IFN is attached to an antibody, preferably anti-tumor antibody, at the carboxy terminus of the antibody, h a preferred embodiment, the antibody portion may recognize and bind to a target antigen expressed on a targeted cell.
- the antigen-binding, Fc receptor binding, Cl q and C activation, and the ability of interferon to bind to its receptor and activate effector cells and macrophages are substantially maintained activities of the immunoconjugate. This is preferably effected by attachment of the interferon directly or indirectly to the antibody hinge, CHI, CH2 or CH3 domain carboxy-terminus.
- effector cell and "effector function” as used herein means a cell which expresses an IFN- ⁇ receptor and can thereby bind to an IFN- ⁇ fusion protein. Effector cells can include natural killer (NK) cells, LAK cells, monocytes, macrophages and polymo ⁇ honuclear (PMNs) cells.
- Preferred effector cells include NK cells and macrophages.
- An "expression vector” means a nucleic acid molecule comprising (1) a promoter and other sequences (e.g., leader sequences) necessary to direct expression of a desired gene or DNA sequence, and (2) the desired gene or DNA sequence.
- the nucleic acid molecule may comprise a poly A signal sequence to enhance the stability of the gene transcript and/or to increase gene transcription and expression.
- binding domain means a binding site which recognizes and binds the entire binding area of a target or any portion thereof.
- antibodies or immunoglobulin fragments include: (1) single variable region of an antibody V L or V H ; (2) two or more variable regions (e.g., V L and N H , V and N L ; or N H and N ⁇ ) or the complementary determining region (CDR) thereof; (3) antibody fragments such as Fabi, Fab 2 , SFV, single chain antibodies, domain-deleted antibodies and minibodies; or (4) an IF ⁇ - ⁇ or a segment of IF ⁇ - ⁇ which binds to an IF ⁇ - ⁇ receptor on an effector cell.
- minibody an antigen binding protein which includes N and N H domains of a native antibody fused to the hinge region and CH3 domain of an immunoglobulin or which encodes in a single chain comprising the essential elements of a whole antibody.
- the single chain comprises the antigen binding region, CH3 domain to permit assembly into a bivalent molecule, and the antibody hinge to accommodate dimerization by disulfide linkages.
- antibody is intended to refer broadly to any immunologic binding agent such as IgG (including IgGi, IgG 2 , IgG 3 , and IgG 4 ), IgM, IgA, IgD, IgE, as well as antibody fragments.
- Antibodies in the broadest sense covers intact monoclonal antibodies, polyclonal antibodies, as well as biologically active fragments of such antibodies such as those discussed above, hi particular, domain-deleted antibodies are included within the scope of the present invention, such as CH 2 domain-deleted antibodies.
- monoclonal antibody an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical except for possible naturally occurring mutations that may be present in minor amounts.
- Monoclonal antibodies are highly specific, being directed against a single antigenic site.
- polyclonal antibody preparations typically include different antibodies directed against different determinants (epitopes)
- each monoclonal antibody is directed against a single determinant on the antigen.
- the monoclonal antibodies are advantageous in that they are synthesized by the hybridoma culture, uncontaminated by other immunoglobulins.
- the modifier "monoclonal” indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method.
- the monoclonal antibodies to be used in accordance with the present invention may be made by the hybridoma method first described by Kohler et al, Nature 256: 495 (1975), or may be made by recombinant DNA methods (see, e.g., U.S. Pat. No. 4,816,567).
- the “monoclonal antibodies” may also be isolated from phage antibody libraries using the techniques described in Clackson et al, Nature 352: 624-628 (1991) and Marks et al, J. Mol. Biol, 222: 581-597 (1991), for example.
- the monoclonal antibodies herein specifically include "chimeric" antibodies (immunoglobulins) in which a portion of the heavy and/or light chain is identical with or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is identical with or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they exhibit the desired therapeutic activity (U.S. Pat. No. 4,816,567; Morrison et al, Proc. Natl Acad. Sci. USA, 81: 6851-5 (1984)).
- chimeric antibodies immunoglobulins in which a portion of the heavy and/or light chain is identical with or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is identical with or homologous to corresponding sequences in antibodies
- Humanized forms of non-human (e.g., murine) antibodies are chimeric immunoglobulins, immunoglobulin chains or fragments thereof (such as Fv, Fab, Fab', F(ab') 2 or other antigen-binding subsequences of antibodies), which contain minimal sequence derived from a non-human immunoglobulin.
- humanized antibodies are human immunoglobulins (recipient antibody) in which residues from a complementarity-determining region (CDR) of the recipient are replaced by residues from a CDR of a non-human species (donor antibody) such as mouse, rat or rabbit having the desired specificity, affinity, and capacity.
- CDR complementarity-determining region
- humanized antibodies may comprise residues which are found neither in the recipient antibody nor in the imported CDR or framework sequences. These modifications are made to further refine and optimize antibody performance.
- the humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the CDR regions correspond to those of a non-human immunoglobulin and all or substantially all of the FR regions are those of a human immunoglobulin sequence.
- the humanized antibody optimally also will comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin.
- Fc immunoglobulin constant region
- target antigen is meant the antigen recognized by the antibody or immunoglobulin fragment portion of the immunoconjugate.
- Preferred target antigens include: 5E10, CD1, CD2, CD3, CDCD5, CD7, CD13, CD14, CD15, CD19, CD20, CD21, CD23, CD25, CD33, CD34, CD38, CEA, EGFR, HER-2, HLA-DR, HM 1.24, HMB 45, la, Leu-Ml, MUC1, phosphatidyl serine antigen, PMSA and TAG-72.
- nucleic acid is meant to include an oligonucleotide, nucleotide, polynucleotide and fragments and portions thereof, and a DNA or a RNA of genomic or synthetic origin, which may be single or double stranded.
- interferon ⁇ or "IFN- ⁇ ” preferably is meant to include all members of the interferon- ⁇ family of proteins. Fragments of IFN- ⁇ are also included, as long as the fragment is capable of recognizing and binding to the IFN- ⁇ receptor and thereby activating effector cells. Preferred forms of IFN- ⁇ include such FDA approved forms of IFN- ⁇ as IFN- ⁇ -2a, IFN- ⁇ -2b and IFN- ⁇ -ln.
- purified and isolated is meant, when referring to a polypeptide or nucleotide sequence, that the indicated molecule is present in the substantial absence of other biological macromolecules of the same type.
- purified as used herein preferably means at least 75% by weight, more preferably at least 85% by weight, more preferably still at least 95% by weight, and most preferably at least 98% by weight, of biological macromolecules of the same type are present.
- an "isolated nucleic acid molecule wliich encodes a particular polypeptide” refers to a nucleic acid molecule which is substantially free of other nucleic acid molecules that do not encode the subject polypeptide; however, the molecule may include some additional bases or moieties which do not deleteriously affect the basic characteristics of the composition.
- an isolated nucleic acid molecule which encodes a particular CDR polypeptide consists essentially of the nucleotide coding sequence for the subject molecular recognition unit.
- terapéuticaally effective is meant the ability of the immunoconjugate to inhibit in vitro growth of a target cell by greater than about 20%, at a concentration of about 0.1 to about 3.0 ⁇ g/ml of the immunoconjugate, wherein said target cells (e.g., tumor cells) are cultured in an appropriate culture medium and said growth inhibition is determined about 4, 5, 6, 7, 8, 9, or 10 days after exposure of the target cells to the immunoconjugate.
- target cells e.g., tumor cells
- subject is meant a living animal or human susceptible to a condition, especially cancer, h the preferred embodiments, the subject is a mammal, including human and non-human mammals.
- Non-human mammals include dogs, cats, pigs, cows, sheep, goats, horses, rats and mice.
- Nucleic acids encoding the desired fusion protein can be inserted into expression vectors for expression.
- Expression vectors useful in the invention include prokaryotic and eukaryotic expression vectors. Such expression vectors, including plasmids, cosmids, and viral vectors such as bacteriophage, baculovirus, retrovirus and DNA virus vectors, are well known in the art (see, for example, Meth. Enzymol, Vol. 185, D. V. Goeddel, ed.
- Expression vectors contain the elements necessary to achieve constitutive or inducible transcription of a nucleic acid molecule encoding an IFN- ⁇ fusion protein.
- IFN- ⁇ is described in Pitha et al, J. Immunol. 141: 3611-6 (1988).
- Preferred embodiments of the invention will utilize FDA approved forms of IFN- ⁇ .
- the recombinant nucleic acid molecules encoding an IFN- ⁇ fusion protein, an immunoglobulin polypeptide, or a specific IFN- ⁇ species or fragment thereof may be obtained by any method known in the art (.see, e.g., Maniatis et al, MOLECULAR CLONING: A LABORATORY MANUAL (Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, 1982 and 1989) or obtained from publicly available clones, such as pGL2BIFN (ATCC No. 53371) and pALCAlSIFN (ATCC No. 53369).
- a nucleic acid encoding an IFN- ⁇ or an antibody which recognizes a tumor-associated antigen (TAA) maybe obtained as follows.
- a population of cells known to actively express an IFN- ⁇ or a specific antibody may be obtained, and total cellular RNA harvested therefrom.
- the amino acid sequence of the IFN- ⁇ or antibody maybe used to deduce the sequence of a portion of its nucleic acid so as to design appropriate oligonucleotide primers; or, alternatively, the oligonucleotide primers may be obtained from a known nucleic acid sequence encoding an antibody or an IFN- ⁇ .
- the oligonucleotide fragment may then be used in conjunction with reverse transcriptase to produce a cDNA corresponding to the immunoglobulin and/or IFN- ⁇ encoding nucleotide sequence (Okayama et al, Methods Enzymol.
- the cDNA can then be cloned, and/or portions of the antibody or IFN- ⁇ coding region amplified from this cDNA using polymerase chain reaction (PCR) and appropriate primer sequences (Saiki et al, Science 239: 487-491 (1988)).
- PCR polymerase chain reaction
- a recombinant vector system may be created to accommodate sequences encoding IFN- ⁇ , wherein the IFN- ⁇ sequence is attached to the sequences encoding the C-terminus of an antibody or immunogenic fragment that recognizes a rumor-associated antigen.
- the resultant fusion protein will preserve the ability of the IFN- ⁇ molecule to bind to its receptor on the effector cell and enhance the effector cell's killing ability.
- the immunoconjugate will also preserve the antigen-binding Fc receptor-binding, Clq binding and C activation regions of the antibody molecule.
- Nucleic acid sequences encoding the various components of the IFN- ⁇ based fusion proteins of the invention may be joined together using any techniques known in the art, including restriction enzyme methodologies and the use of synthetic linker sequences.
- a suitable promoter/enhancer sequence may be inco ⁇ orated into the recombinant vector.
- Promoters which may be used to control the expression of the antibody-based fusion protein include, but are not limited to, the S V40 early promoter region (Bernoist et al, Nature 290: 304-310 (1981)), the promoter contained in the 3' long terminal repeat of Rous sarcoma viruses (Yamamoto et al, Cell 22: 787-797 (1980)), the he ⁇ es thymidine kinase (tk) promoter (Wagner et al, Proc. Natl. Acad. Sci.
- nucleic acids corresponding to the 3' flanking region of an immunoglobulin gene including RNA cleavage/polyadenylation sites and downstream sequences.
- a signal sequence upstream of the IFN- ⁇ fusion protein-encoding sequences may be desirable to engineer a signal sequence upstream of the IFN- ⁇ fusion protein-encoding sequences to facilitate the secretion of the fused molecule from a cell transformed with the recombinant vector.
- IFN- ⁇ containing fusion proteins can also utilize sequences encoding conservative amino acid substitutions in an IFN- ⁇ sequence, as well as substitutions in the antibody or immunoglobulin region of the fusion protein. Such changes include substituting an isoleucine, valine and leucine for any other of these hydrophobic amino acids; aspartic acid for glutamic acid and vice versa; glutamine for asparagine and vice versa; and serine for threo ine and vice versa. Other substitutions can also be considered conservative, depending on the environment of the particular amino acid and its role in the three-dimensional structure of the protein. For example, glycine for alanine can frequently be interchangeable, as well as alanine for valine due to structural and charge similarities.
- Successful inco ⁇ oration of IFN- ⁇ based fusion gene constructs may be identified by three general approaches: (a) DNA-DNA hybridization, (b) presence or absence of "marker" gene functions, and (c) expression of inserted sequences, hi the first approach, the presence of a foreign gene inserted in an expression vector can be detected by DNA-DNA hybridization using probes comprising sequences that are homologous to the inserted antibody IFN- ⁇ fusion protein DNA.
- the recombinant vector/host system can be identified and selected based upon the presence or absence of certain "marker" gene functions (e.g., thymidine kinase activity, resistance to antibiotics such as G418, transformation phenotype, occlusion body formation in baculovirus, etc.) caused by the insertion of foreign genes in the vector.
- certain "marker" gene functions e.g., thymidine kinase activity, resistance to antibiotics such as G418, transformation phenotype, occlusion body formation in baculovirus, etc.
- the recombinant expression vectors can be identified by assaying the foreign gene product expressed by the recombinant.
- the cytokine can be any cytokine or analog or fragment thereof which activates effector cells.
- the preferred cytokine is an interferon, with the preferred interferon being IFN- ⁇ , especially FDA approved forms.
- the gene encoding the cytokine can be cloned de novo, obtained from an available source, or synthesized by standard DNA synthesis from a known nucleotide sequence as discussed above.
- the heavy chain constant region for the conjugates can be selected from any of the five isotypes: alpha (IgA), delta (IgD), epsilon (IgE), gamma (IgG) or mu (IgM). Heavy chains or various subclasses (such as the IgG subclasses 1-4) can be used. The light chains can have either a kappa or lambda constant chain. DNA sequences for these immunoglobulin regions are well known in the art. (See, e.g., Gillies et al, J. Immunol Meth. 125: 191 (1989)).
- the variable region is derived from an antibody specific for the target antigen, and the constant region includes the CHI, CH2 and CH3 domains.
- the gene encoding the cytokine is joined, in frame to the 3' end of the gene encoding the constant region (e.g., CHI, CH2 or CH3 exon depending on domain-deleted form desired), either directly or through an intergenic region.
- the nucleic acid construct can include an endogenous promoter and enhancer for the variable region-encoding gene to regulate expression of the chimeric immunoglobulin chain.
- variable region encoding genes can be obtained as DNA fragments comprising the leader peptide, the VJ gene (functionally rearranged variable (V) regions with joining (J) segment) for the light chain or VDJ gene for heavy chain, and the endogenous promoter and enhancer for these genes.
- the gene coding for the variable region can be obtained apart from endogenous regulatory elements and used in an expression vector that provides these elements.
- Variable region genes can be obtained by standard DNA cloning procedures from cells that produce the desired antibody. Screening of the genomic library for a specific functionally rearranged variable region can be accomplished with the use of appropriate DNA probes, such as DNA segments containing the J region DNA sequence and sequences downstream. Identification and confirmation of correct clones are then achieved by DNA sequencing of the cloned genes and comparison of the sequence to the corresponding sequence of the full length, properly spliced mRNA.
- the target antigen preferably can be a cell surface antigen of a tumor cell, but also includes viral antigens or other disease associated antigens expressed on the cell surface. Genes encoding appropriate variable regions can be obtained generally from immunoglobulin producing lymphoid cells.
- hybridoma cell lines producing immunoglobulin specific for tumor associated antigens or viral antigens can be produced by standard somatic cell hybridization techniques (see, e.g., U.S. Pat. No. 4,96,265.). These immunoglobulin producing cell lines provide the source of variable region genes in functionally rearranged form.
- the variable region genes will typically be of murine origin, because the murine system lends itself to the production of a wide variety of immmioglobulins of desired specificity.
- the DNA fragment containing the functionally rearranged variable region gene is linked to a DNA fragment containing the gene encoding the desired constant region (or a portion thereof).
- Immunoglobulin constant regions can be obtained from antibody-producing cells by standard gene cloning techniques. Genes for the two classes of human light chains and the five classes of human heavy chains have been cloned, and thus, constant regions of human origin are readily available from publically available clones.
- the fused gene encoding the hybrid immunoglobulin heavy chain is assembled or inserted into expression vectors for inco ⁇ oration into a recipient cell.
- the introduction of gene construct into plasmid vectors can be accomplished by standard gene splicing procedures.
- Recipient cell lines are generally lymphoid cells.
- the preferred recipient cell is a myeloma (or hybridoma).
- Myelomas can synthesize, assemble, and secrete immunoglobulins encoded by transfected genes, and they post-translationally modify the protein.
- a particularly preferred recipient cell is the Sp2/0 myeloma which normally does not produce endogenous immunoglobulin. When transfected, the cell will produce only immunoglobulin encoded by the transfected gene constructs.
- Transfected myelomas can be grown in culture or in the peritoneum of mice where secreted immunoconjugate can be recovered from ascites fluid.
- Other lymphoid cells such as B lymphocytes, also can be used as recipient cells.
- lymphoid cells There are several methods for transfecting lymphoid cells with vectors containing the nucleic acid constructs encoding the chimeric Ig chain.
- a preferred way of introducing a vector into lymphoid cells is by spheroblast fusion, as described by Gillies et al, Biotechnol. 7: 798-804 (1989).
- Alternative methods include electroporation or calcium phosphate precipitation. See also, the methods in MANIA ⁇ S, ET AL. (1989).
- IFN- ⁇ based fusion protein produced by the host cell may be collected using any technique known in the art, including, but not limited to, affinity chromatography using target antigen or antibody specific for any portion of the fusion protein.
- the activity of the fused IFN- ⁇ or antibody e.g. , anti-CD20
- biological assays which detect or measure the activity of the lymphokine or cellular factor.
- the presence of IFN- ⁇ activity may be confirmed in assays which detect receptor binding, virus neutralization and enhanced killing ability of the effector cells.
- Preferred methods of detecting such enhanced effector cell ability can utilize receptor binding assays and virus neutralization assays. These assays are described generally below.
- Receptor binding assays such as those provided below, can be utilized to determine whether the immunoconjugate binds to the target antigen or to an IFN- ⁇ receptor.
- virus neutralization assay is one form of receptor binding assay which can be utilized to determine the efficacy of which an immunoconjugate to neutralize virus- infected cells when the antibody targets a viral antigen expressed on the cell surface.
- virus neutralizations can be determined using the method described by Ho et al, J. Virol. 65: 489-93 (1991), for fflV-1 neutralization using a ⁇ 24 assay.
- Neutralization is defined as the percent reduction in the amount of target antigen released into the culture supernatants or detected in cells from wells treated with the immunoconjugate compared with control wells not treated with the immunoconjugate.
- ADCC Assay The ability of the fusion protein to induce ADCC can be assessed using a chromium release assay. Generally, antibodies of the IgG 2a and IgG 3 subclass and occasionally of the IgGi subclass mediate ADCC. Antibodies of the IgG 3 , IgG 2a and IgM classes bind and activate serum complement. To assess the ability of the immxmoconjugates described herein to mediate ADCC and complement activation, one can use a 51 Cr-release assay. Briefly, a cell line expressing the antigen being targeted for lysis by effector cells are labeled with 100 ⁇ Ci of 51 Cr for about 1 hour prior to combining effector cells and antibodies in a U-bottom microtiter plate.
- Complement Binding Assay To assess the ability of the immunoconjugates to bind complement, the following assay can be utilized. Cells expressing the target antigen recognized by the immunoconjugate are incubated with the immunoconjugate at a concentration of 10 ⁇ g/ml. After incubating the plates containing the cells and immunoconjugate for 15 minutes at room temperature, the plates are washed three times. After the third wash, the cells are resuspended in 50 ⁇ l of a 1/10 dilution of complement (e.g., guinea pig complement from ICN) and incubated at 37°C for varying times. Then 50 ⁇ l of 0.25% (w/v) trypan blue is added and cell number and plasma integrity of the cells are estimated. Phagocytosis Assay
- the following assay can be used.
- Cells expressing the target antigen are labeled with lipophilic red fluorescent dye PKH 26.
- Buffy coat cells purified from heparinized, whole blood containing effector cells are incubated with the labeled targets at 37°C for about 6 hours in the absence or in the presence of the immunoconjugate.
- Effector cells are then stained with FITC (fluorescein isothiocyanate) labeled antibody, which binds to the effector cell at 0°C.
- FITC fluorescein isothiocyanate
- Cells are washed and analyzed using two color fluorescence by FACScan or other scanning method. Percent phagocytosis is expressed as the percent of effector cells (NK cells, monocytes, neutrophils or macrophages) that have PKH 26 stain associated with them.
- a fusion protein of the invention is administered to subjects in a biologically compatible form suitable for pharmaceutical administration in vivo.
- biologically compatible form suitable for administration in vivo is meant a form of the immunogonjugate to be administered in which any toxic effects are outweighed by the therapeutic effects of the protein.
- An immunogonjugate can be administered in any pharmacological form, optionally in a pharmaceutically acceptable carrier.
- Administration of a therapeutically effective amount of the immunoconjugate is defined as an amount effective, at dosages and for periods of time necessary to achieve the desired result (e.g., inhibition of the progression or proliferation of the disease being treated).
- a therapeutically active amount of an immunoconjugate may vary according to such factors as the disease stage (e.g., stage I versus stage IV), age, sex, medical complications, and weight of the individual, and the ability of the immunoconjugate to elicit a desired response in the individual.
- the dosage regimen may be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily, or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation.
- the active compound, an immunoconjugate by itself or in combination with other active agents, such as chemotherapeutic anti-cancer drugs.
- the immunoconjugate alone or in combination with other agents, may be admimstered in a convenient manner such as by injection (subcutaneous, intramuscularly, intravenous, etc), inhalation, transdermal application or rectal administration.
- the active compound may be coated with a material to protect the active compound from the action of enzymes, acids and other natural conditions which may inactivate the compound.
- a preferred route of administration is by intravenous (IN.) injection.
- an IF ⁇ - ⁇ fusion protein can be administered to an individual in an appropriate carrier or diluent, co-administered with enzyme inhibitors or in an appropriate carrier or vector, such as a liposome.
- Pharmaceutically acceptable diluents include saline and aqueous buffer solutions. Liposomes include water-in-oil-in-water emulsions, as well as conventional liposomes (Strejan et al, J. Neuroimmunol 7: 27 (1984)). Additional pharmaceutically acceptable carriers and excipients are known in the art or as described in REMINGTON'S PHARMACEUTICAL SCIENCES (18th ed. 1990).
- the active compound may also be administered parenterally or intraperitoneally.
- Dispersions of the active compound can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations may contain one or more preservatives to prevent the growth of microorganisms.
- compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions, hi all cases, the composition must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi.
- the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof.
- the proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion, and by the use of surfactants.
- a coating such as lecithin
- surfactants for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal and the like, h many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols, such as manitol, sorbitol, or sodium chloride in the composition.
- Prolonged abso ⁇ tion of the injectable compositions can be brought about by including in the composition an agent which delays abso ⁇ tion, for example, aluminum monostearate and gelatin.
- Sterile injectable solutions can be prepared by inco ⁇ orating an active compound (e.g., an IFN- ⁇ fusion protein) in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization.
- dispersions are prepared by inco ⁇ orating the active compound into a sterile vehicle, which contains a basic dispersion medium and the required other ingredients from those enumerated above.
- the preferred methods of preparation are vacuum drying and freeze-drying, which yields a powder of an active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
- the protein may be orally administered, for example, with an inert diluent or an assimilable edible carrier.
- pharmaceutically acceptable carrier includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and abso ⁇ tion delaying agents, and the like. The use of such media and agents for pharmaceutically active substances is well known in the art.
- compositions discussed above for use with an IFN- ⁇ fusion protein may also comprise supplementary active compounds in the composition. It is especially advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of a dosage.
- Dosage unit form refers to physically discrete units suited as unitary dosages for the mammalian subjects to be treated; each unit containing a predetermined quantity of active compound is calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
- the immunoconjugates described herein can be targeted to a variety of malignant cells which express a tumor-associated antigen (TAA) expressed on the surface of the cell.
- TAA tumor-associated antigen
- IFN- ⁇ fusion proteins comprising antibodies can be prepared which recognize B and T cell leukemias and lymphomas, multiple myelomas, and solid tumors (e.g., prostate carcinoma, colon carcinoma, lung carcinoma, breast carcinoma and ovarian carcinoma), preferred embodiments, the immunoglobulin portion of the IFN- ⁇ fusion protein may recognize B cell markers (e.g., CD 19, CD20, CD22), multiple myeloma antigens (e.g., CD38, HM1.24), leukemia markers (e.g., CD33), and phosphatidyl-serine antigen. Additional markers affiliated with certain malignancies and to which the immunoglobin portion of the fusion protein can include, but are not limited to, the following:
- the immunoconjugates described above can be used in combination with one or more different cancer treatment modalities, such as radiotherapy, immunotherapy, chemotherapy, and surgery.
- the combination of treatments used on any particular subject will vary depending on cancer type, stage of disease, family history, age, sex, weight and condition of the subject.
- the immunoconjugates are administered in combination with one more chemotherapeutics.
- chemotherapeutic or chemotherapeutic cocktail is administered in combination with the interferon immunoconjugate described herein, and include those listed in the table below:
- chemotherapeutic drugs and drug cocktails can be administered according to the regimens described in CANCER: PRINCIPLES & PRAC ⁇ CE OF ONCOLOGY (Vincent T. DeVita, Jr. et al. eds., 5 th ed. 1997) or as would be known to the skilled artisan.
- ChlVPP chlorambucil, vinblastine, procarbazine, prednisone
- CMVP cyclophosphamide methotrexate, 5-fluorouracil, vincristine, prenisone
- MOPP+ABVD alternating months of MOPP and ABVD
- PCVP vinblastine PCVP vinblastine, procarbazine, cyclophosphamide, prednisone
- the nucleic acid encoding an IFN- ⁇ (e.g., IFN- ⁇ -2a, IFN- ⁇ -2b or IFN- ⁇ -nl) is operably linked to the nucleic acid encoding Rituximab such that when translated the IFN- ⁇ would form the carboxy te ⁇ ninus of the fusion protein.
- the antigen-binding Fc receptor-binding, Clq binding and complement (C) activation, as well as the ability of IFN- ⁇ to bind to NK cells and macrophages are characteristics possessed by the agents.
- other nucleic acids encoding anti-CD20 antibodies can be operably attached to the nucleic acid encoding IFN- ⁇ .
- the other anti-CD20 antibodies include Ibritumomab, IF5, Bl and 1H4. EXAMPLE 2 In Vitro Testing of an Immunoconjugate
- a tumor cell line (cell expressing a target antigen) expressing Her2/neu (e.g., human breast carcinoma cells, SKBR-3) is selected to determine lysis using the immunoconjugates described herein.
- Effector cell samples are obtained by using heparinized whole blood or obtained from a third party.
- monocytes are cultured in Teflon containers in Macrophage Serum-Free Medium (Gibco/BRL) containing 2% human serum for 24 to 48 hours.
- Target cells are labeled with 100 ⁇ Ci of 51 Cr for one hour prior to incubation with the effector cells and immunoconjugate in a U-bottomed microtiter plate. After incubation for about 16 to 18 hours at 37°C, supernatants from each well are collected and analyzed for radioactivity. Cytotoxicity and specific lysis can be calculated as previously described.
- a mouse model can be used, hi the instance of solid tumors, about lxl 0 7 cells in culture media are injected subcutaneously into the right anterior flank of BALB/c, nu/nu or SCID mice. Approximately, fourteen days later or when the tumors have grown to about 0.8 to 1.2 cm in diameter, the mice are separated into groups of 5-10 animals and injected intravenously with 200 ⁇ l of immunoconjugate at concentrations of 1 ⁇ g to 10 mg. Pe ⁇ endicular tumor diameters are measured at regular intervals and tumor volumes can be calculated. Alternatively, animals can be euthanized and sections of tumor prepared to determine the impact on tumor progression by the immunoconjugate as compared to the control animals (untreated).
Abstract
Description
Claims
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JP2002503328A JP2003535908A (en) | 2000-06-22 | 2001-06-04 | Bispecific fusion proteins and methods of use to enhance effector cells that kill target cells |
AU6541801A AU6541801A (en) | 2000-06-22 | 2001-06-04 | Bispecific fusion protein and method of use for enhancing effector cell killing of target cells |
CA002412901A CA2412901A1 (en) | 2000-06-22 | 2001-06-04 | Bispecific fusion protein and method of use for enhancing effector cell killing of target cells |
EP01939954A EP1292334A4 (en) | 2000-06-22 | 2001-06-04 | Bispecific fusion protein and method of use for enhancing effector cell killing of target cells |
AU2001265418A AU2001265418B2 (en) | 2000-06-22 | 2001-06-04 | Bispecific fusion protein and method of use for enhancing effector cell killing of target cells |
US09/986,174 US20020193569A1 (en) | 2001-06-04 | 2001-11-07 | Bispecific fusion protein and method of use for enhancing effector cell killing of target cells |
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Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5314995A (en) * | 1990-01-22 | 1994-05-24 | Oncogen | Therapeutic interleukin-2-antibody based fusion proteins |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ZA902949B (en) * | 1989-05-05 | 1992-02-26 | Res Dev Foundation | A novel antibody delivery system for biological response modifiers |
DE122004000036I1 (en) * | 1992-11-13 | 2005-07-07 | Biogen Idec Inc | Therapeutic use of chimeric and labeled antibodies to human B lymphocyte limited differentiation antigen for the treatment of B-cell lymphoma. |
US5736137A (en) * | 1992-11-13 | 1998-04-07 | Idec Pharmaceuticals Corporation | Therapeutic application of chimeric and radiolabeled antibodies to human B lymphocyte restricted differentiation antigen for treatment of B cell lymphoma |
-
2001
- 2001-06-04 CA CA002412901A patent/CA2412901A1/en not_active Abandoned
- 2001-06-04 AU AU2001265418A patent/AU2001265418B2/en not_active Ceased
- 2001-06-04 WO PCT/US2001/040835 patent/WO2001097844A1/en active Application Filing
- 2001-06-04 AU AU6541801A patent/AU6541801A/en active Pending
- 2001-06-04 JP JP2002503328A patent/JP2003535908A/en not_active Abandoned
- 2001-06-04 EP EP01939954A patent/EP1292334A4/en not_active Withdrawn
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5314995A (en) * | 1990-01-22 | 1994-05-24 | Oncogen | Therapeutic interleukin-2-antibody based fusion proteins |
Non-Patent Citations (11)
Title |
---|
"Immunoconjugates. Antibody conjugates in radioimaging and therapy of cancer", 1987, OCFORD UNIVERSITY PRESS * |
"Immunoconjugates. Antibody conjugates in radioimaging and therapy of cancer", 1987, OXFORD UNIV. PRESS * |
BREAST CANCER RESEARCH AND TREATMENT, vol. 25, no. 3, 1993, pages 265 - 276 * |
DATABASE CANCERLIT [online] OLDHAM R.K.: "Immunoconjugates: drugs and toxins", XP002958085, accession no. STN Database accession no. 88648019 * |
DATABASE CANCERLIT [online] VOGEL C.W.: "Antibody conjugates without inherent toxicity: The targeting of Cobra venom factor and other biological response modifiers", XP002945741, accession no. Cancerlit Database accession no. 88648508 * |
DATABASE CANCERLIT [online] VOGEL C.W.: "Current approaches of immunotargeting", XP002945740, accession no. STN Database accession no. 88648500 * |
DATABASE EMBASE [online] OZZELLO ET AL.: "The use of natural interferon alpha conjugates to a monoclonal antibody anti mammary epithelial mucin (Mc5) for the treatment of human breast cancer xenografts", XP002945742, accession no. STN Database accession no. 93198745 * |
PRINCIPLES OF CANCER BIOTHERAPY, 1987 * |
QI ET AL.: "Characterization of anti-tumor immunity derived from the inoculation of myeloma cells secreting the fusion protein RM4/IFN-tan", HUM. ANTIBOD. HYBRIDOMAS, vol. 7, no. 1, 1996, pages 21 - 26, XP002945939 * |
See also references of EP1292334A4 * |
THAKUR ET AL.: "Improved antibody targeting with interferon-alpha-2beta conjugate", JOURNAL OF IMMUNOTHERAPY, vol. 20, no. 3, 1997, pages 194 - 201, XP002945738 * |
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Also Published As
Publication number | Publication date |
---|---|
EP1292334A1 (en) | 2003-03-19 |
AU6541801A (en) | 2002-01-02 |
CA2412901A1 (en) | 2001-12-27 |
AU2001265418B2 (en) | 2006-03-30 |
EP1292334A4 (en) | 2003-11-19 |
JP2003535908A (en) | 2003-12-02 |
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