WO2013112801A1 - Targeting interferon-lambda with antibodies potently enhances anti-tumor and anti-viral activities - Google Patents
Targeting interferon-lambda with antibodies potently enhances anti-tumor and anti-viral activities Download PDFInfo
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- WO2013112801A1 WO2013112801A1 PCT/US2013/023093 US2013023093W WO2013112801A1 WO 2013112801 A1 WO2013112801 A1 WO 2013112801A1 US 2013023093 W US2013023093 W US 2013023093W WO 2013112801 A1 WO2013112801 A1 WO 2013112801A1
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Definitions
- the present invention relates to compositions and methods of therapeutic use of DOCK- AND-LOCKTM (DNLTM) complexes comprising interferon-lambda (IFN- ⁇ ), more preferably IFN- ⁇ , attached to an antibody or antigen-binding antibody fragment.
- DOCK- AND-LOCKTM DOCK- AND-LOCKTM
- IFN- ⁇ interferon-lambda
- IFN- ⁇ interferon-lambda
- the antibody may be an anti-TROP-2, anti-CEACAM5, anti-CEACAM6, anti- HLA-DR, anti-mucin, anti-CD 19, anti-CD20, anti-CD74, anti-AFP, or anti-CD22 antibody.
- the skilled artisan will realize that the invention is not so limited and more broadly covers antibody-interferon complexes.
- the DNLTM complexes are made using compositions and techniques as exemplified in U.S. Patent Nos. 7,521,056; 7,527,787;
- the antibody-conjugated interferons retain in vitro activity and show substantially enhanced in vivo efficacy and increased serum half-life. Additional advantages of the DNLTM products may also include lower immunogenicity, decreased dosing frequency, increased solubility, enhanced stability, and reduced renal clearance.
- Interferon-a has been reported to have anti-tumor activity in both animal models of cancer (Ferrantini et al., 1994, J Immunol 153:4604-15) and human cancer patients
- IFNa can exert a variety of direct antitumor effects, including down-regulation of oncogenes, up-regulation of tumor suppressors, enhancement of immune recognition via increased expression of tumor surface MHC class I proteins, potentiation of apoptosis, and sensitization to chemotherapeutic agents (Gutterman et al., 1994, PNAS USA 91 :1198-205; Matarrese et al., 2002, Am J Pathol 160: 1507-20; Mecchia et al., 2000, Gene Ther 7: 167-79; Sabaawy et al., 1999, Int J Oncol 14: 1143-51 ; Takaoka et al, 2003, Nature 424:516-23).
- IFNa can have a direct and potent antiproliferative effect through activation of STAT1 (Grimley et al., 1998 Blood
- IFNa can inhibit angiogenesis (Sidky and Borden, 1987, Cancer Res 47:5155- 61) and stimulate host immune cells, which may be vital to the overall antitumor response but has been largely under-appreciated (Belardelli et al., 1996, Immunol Today 17:369-72).
- IFNa has a pleiotropic influence on immune responses through effects on myeloid cells (Raefsky et al, 1985, J Immunol 135:2507-12; Luft et al, 1998, J Immunol 161 :1947-53), T-cells (Carrero et al, 2006, J Exp Med 203:933-40; Pilling et al., 1999, Eur J Immunol 29:1041-50), and B-cells (Le et al, 2001, Immunity 14:461-70).
- IFNa induces the rapid differentiation and activation of dendritic cells (Belardelli et al, 2004, Cancer Res 64:6827-30; Paquette et al., 1998, J Leukoc Biol 64:358-67; Santini et al., 2000, J Exp med 191 :1777-88) and enhances the cytotoxicity, migration, cytokine production and antibody- dependent cellular cytotoxicity (ADCC) of N cells (Biron et al., 1999, Annu Rev Immunol 17:189-220; Brunda et al. 1984, Cancer Res 44:597-601).
- ADCC antibody- dependent cellular cytotoxicity
- IFN- a2 for treating hairy cell leukemia, chronic myelogenous leukemia, malignant melanoma, follicular lymphoma, condylomata acuminata, AIDs-related Kaposi sarcoma, and chronic hepatitis B and C; IFN- ⁇ for treating multiple sclerosis; and IFN- ⁇ for treating chronic granulomatous disease and malignant osteopetrosis.
- IFN- ⁇ for treating multiple sclerosis
- IFN- ⁇ for treating chronic granulomatous disease and malignant osteopetrosis.
- Interferons are critical role players in the antitumor and antimicrobial host defense, and have been extensively explored as therapeutic agents for cancer and infectious disease (Billiau et al., 2006, Cytokine Growth Factor Rev 17:381-409; Pestka et al., 2004, Immunol Rev 202:8-32).
- type I and II interferons IFN- ⁇ / ⁇ and ⁇
- their use in clinic settings have been limited because of the short circulation half-life, systemic toxicity, and suboptimal responses in patients (Pestka et al., 2004, Immunol Rev 202:8-32; Miller et al., 2009, Ann N Y Acad Sci 1182:69-79).
- IFN- s designated as type III interferons, are a newly described group of cytokines that consist of IFN- ⁇ , 2, 3 (also referred to as interleukin-29, 28A, and 28B, respectively), that are genetically encoded by three different genes located on chromosome 19 (Kotenko et al., 2003, Nat Immunol 4:69-77; Sheppard et al., 2003, Nat Immunol 4:63-8).
- ⁇ - ⁇ 2 and - ⁇ 3 are is highly homologous, with 96% amino acid identity, while IFN- ⁇ shares approximately 81% homology with WN- 2 and - ⁇ 3 (Sheppard et al., 2003, Nat Immunol 4:63-8).
- IFN- s activate signal transduction via the JAK/STAT pathway similar to that induced by type I IFN, including the activation of JAKl and TYK2 kinases, the phosphorylation of STAT proteins, and the activation of the transcription complex of IFN-stimulated gene factor 3 (ISGF3) (Witte et al., 2010, Cytokine Growth Factor Rev 21 :237-51 ; Zhou et al., 2007, J Virol 81 :7749-58).
- IGF3 IFN-stimulated gene factor 3
- IFN- ⁇ / ⁇ signals through two extensively expressed type I interferon receptors, and the resulting systemic toxicity associated with IFN- ⁇ ⁇ administration has limited their use as therapeutic agents (Pestka et al., 2007, J Biol Chem 282:20047-51).
- IFN- s signal through a heterodimeric receptor complex consisting of unique IFN- ⁇ receptor 1 (IFN ⁇ Rl) and IL-10 receptor 2 (IL-10R2).
- IFN- Rl has a very restricted expression pattern with the highest levels in epithelial cells, melanocytes, and hepatocytes, and the lowest level in primary central nervous system (CNS) cells.
- CNS central nervous system
- Blood immune system cells express high levels of a short IFN- ⁇ receptor splice variant (sIFN- Rl) that inhibits IFN- ⁇ action.
- sIFN- Rl short IFN- ⁇ receptor splice variant
- IFN-a and IFN- ⁇ induce expression of a common set of ISGs (interferon- stimulated genes) in hepatocytes, unlike IFN-a, administration of IFN- ⁇ did not induce STAT activation or ISG expression in purified lymphocytes or monocytes (Dickensheets et al., 2013, J Leukoc Biol. 93, published online 12/20/12). It was suggested that IFN- ⁇ may be superior to IFN-a for treatment of chronic HCV infection, as it is less likely to induce leukopenias that are often associated with IFN-a therapy (Dickensheets et al., 2013).
- IFN- s display structural features similar to IL- 10- related cytokines, but functionally possess type I IFN-like anti-viral and anti-proliferative activity (Witte et al., 2009, Genes Immun 10:702-14; Ank et al., 2006, J Virol 80:4501-9; Robek et al., 2005, J Virol 79:3851-4).
- IFN- ⁇ and - 2 have been demonstrated to reduce viral replication or the cytopathic effect of various viruses, including DNA viruses (hepatitis B virus (Robek et al., 2005, J Virol 79:3851-4, Doyle et al., 2006, 44:896-906) and herpes simplex virus 2 (Ank et al., 2008, J Immunol 180:2474-85)), ss (+) RNA viruses (E CV; Sheppard et al., 2003, Nat Immunol 4:63-8) and hepatitis C viras (Robek et al., 2005, J Virol 79:3851-4, Doyle et al., 2006, 44:896-906; Marcello et al., 2006, Gastroenterol 131:1887-98; Pagliaccetti et al., 2008, J Biol Chem 283:30079-89), ss (-) RNA viruses (vesicular stomatitis virus
- IFN- 3 has been identified from genetic studies as a key cytokine in HCV infection (Ge et al., 2009, Nature 461 :399-401 ), and has also shown potent activity against EMCV (Dellgren et al., 2009, Genes Immun 10: 125-31). A deficiency of rhinovirus-induced IFN- ⁇ production was reported to be highly correlated with the severity of rhinovirus-induced asthma exacerbation (Contoli et al., 2006, Nature Med
- IFN- ⁇ therapy has been suggested as a new approach for treatment of allergic asthma (Edwards and Johnston, 201 1 , EM BO Mol Med 3:306-8; Koltsida et al., 201 1 , EMBO Mol Med 3:348-61).
- IFN- s The anti-proliferative activity of IFN- s has been established in several human cancer cell lines, including neuroendocrine carcinoma BONl (Zitzmann et al., 2006, 344: 1334-41 ), glioblastoma LN319 (Meager et al., 2005, Cytokine 31:109-18), immortalized keratinocyte HaCaT (Maher et al., 2008, Cancer Biol Ther 7:1109-15), melanoma F01 (Guenterberg et al., 2010, Mol Cancer Ther 9:510-20), and esophageal carcinoma TE-11 (Li et al., 2010, Eur J Cancer 46:180-90).
- neuroendocrine carcinoma BONl Zitzmann et al., 2006, 344: 1334-41
- glioblastoma LN319 Meager et al., 2005, Cytokine 31:109-18
- IFN- s induce both tumor apoptosis and destruction through innate and adaptive immune responses, suggesting that local delivery of IFN- ⁇ might be a useful adjunctive strategy in the treatment of human malignancies (Numasaki et al., 2007, J Immunol 178:5086-98).
- PEGylated IFN- ⁇ (PEG-IFN- ⁇ ) has been provisionally used for patients with chronic hepatitis C virus infection.
- PEG-IFN- ⁇ has been provisionally used for patients with chronic hepatitis C virus infection.
- antiviral activity was observed at all dose levels (0.5-3.0 ⁇ g kg), and viral load reduced 2.3 to 4.0 logs when PEG- IFN- ⁇ was administrated to genotype 1 HCV patients who relapsed after IFN-a therapy (Muir et al., 2010, Hepatology 52:822-32).
- compositions and methods comprising interferon-lambda- antibody complexes, which retain the bioactivity of the unmodified interferon, but exhibit improved in vivo efficacy, decreased toxicity and/or superior pharmacokinetic properties.
- the present invention discloses methods and compositions for producing DNLTM complexes comprising an interferon, preferably interferon- ⁇ , more preferably IFN- ⁇ , attached to an antibody or antigen-binding antibody fragment.
- the interferon moiety may be conjugated to a dimerization and docking domain (DDD) moiety from human protein kinase A (PKA) regulatory subunit RIa, Rip, Rlla or RIip or alternatively to an anchor domain (AD) moiety from an A-kinase anchoring protein (AKAP).
- DDD dimerization and docking domain
- PKA human protein kinase A
- AD anchor domain
- AKAP A-kinase anchoring protein
- the antibody or antibody fragment moiety is conjugated to a complementary AD or DDD moiety.
- a DNLTM complex may be assembled from effectors, such as an interferon, an antibody or an antibody fragment, each of which is attached to a DDD moiety or an AD moiety.
- the DNLTM complex preferably contains one, two, or four copies of the interferon moiety attached to the antibody or fragment.
- the skilled artisan will realize that other types of DNLTM complexes with different structures and different ratios of interferon to antibody may be constructed and used within the scope of the claimed methods and compositions, such as those disclosed in U.S. Patent Nos. 7,521,056; 7,527,787; 7,534,866; 7,550,143 and 7,666,400.
- the DNLTM complex may be covalently stabilized by introduction of cysteine residues at appropriate locations in the DDD and AD sequences, to form disulfide bonds that stabilize the complex.
- the DNLTM complex comprising an interferon- conjugated antibody shows a rate of clearance from serum that is at least an order of magnitude slower than the unconjugated interferon.
- Exemplary agents include MIF, HMGB-1 (high mobility group box protein 1), TNF-ot, IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-15, IL-16, IL-17, IL-18, IL-19, IL-21, IL-23, IL-24, CCL19, CCL21, IL-8, MCP-1, RANTES, MDMA, MIP-1 B, ENA-78, MCP-1, lP-10, Gro- ⁇ , Eotaxin, interferon-a, interferon- ⁇ , interferon- ⁇ , interferon- ⁇ , G-CSF, GM-CSF, SCF, PDGF, MSF, Flt-3 ligand, erythropoietin, thrombopoietin, hGH, CNTF, leptin, oncostatin M, VE
- Antibodies that may be of use for targeted therapy of cancer within the scope of the claimed methods and compositions include, but are not limited to, LL1 (anti-CD74), LL2 and RFB4 (anti-CD22), RS7 (anti-epithelial glycoprotein- 1 (EGP-1)), PAM4 and KC4 (both anti- mucin), MN-14 (anti-carcinoembryonic antigen (CEA, also known as CD66e), MN-15 (anti- CEACAM6), Mu-9 (anti-colon-specific antigen-p), Immu-31 (an anti-alpha-fetoprotein), anti- TAG-72 (e.g., CC49), anti-Tn, J591 or HuJ591 (anti-PSMA (prostate-specific membrane antigen)), AB-PG1-XG 1-026 (anti-PSMA dimer), D2/B (anti-PSMA), G250 (anti-carbonic anhydrase IX), hL243 (anti-HLA
- panitumumab (anti-EGFR); rituximab (anti-CD20); tositumomab (anti-CD20); GA101 (anti- CD20); and trastuzumab (anti-ErbB2).
- Such antibodies are known in the art (e.g., U.S. Patent Nos. 5,686,072; 5,874,540; 6,107,090; 6,183,744; 6,306,393; 6,653,104; 6,730.300; 6,899,864; 6,926,893; 6,962,702; 7,074,403; 7,230,084; 7,238,785; 7,238,786; 7,256,004; 7,282,567;
- Anti-TNF-a antibodies are known in the art and may be of use to treat immune diseases, such as asthma (see, e.g., Erin et al., 2006, Am J Respir Crit Care Med 174:753-62).
- Known antibodies against TNF-a include the human antibody CDP571 (Ofei et al., 2011, Diabetes 45:881-85); murine antibodies MTNFAI, M2TNFAI, M3TNFAI, M3TNFABI, M302B and M303 (Thermo Scientific, Rockford, IL); infliximab (Centocor, Malvern, PA); certolizumab pegol (UCB, Brussels, Belgium); and adalimumab (Abbott, Abbott Park, IL).
- anti-B-cell antibodies such as veltuzumab, epratuzumab, milatuzumab or hL243; tocilizumab (anti-IL-6 receptor); basiliximab (anti-CD25); daclizumab (anti-CD25); efalizumab (anti-CDl la); muromonab-CD3 (anti-CD3 receptor); anti- CD40L (UCB, Brussels, Belgium); natalizumab (anti-a4 integrin) and omalizumab (anti-IgE).
- anti-B-cell antibodies such as veltuzumab, epratuzumab, milatuzumab or hL243; tocilizumab (anti-IL-6 receptor); basiliximab (anti-CD25); daclizumab (anti-CD25); efalizumab (anti-CDl la); muromonab-CD3 (anti-CD3 receptor); anti- CD40L (UCB,
- Macrophage migration inhibitory factor is an important regulator of innate and adaptive immunity and apoptosis. It has been reported that CD74 is the endogenous receptor for MIF (Leng et al., 2003, J Exp Med 197:1467-76).
- the therapeutic effect of antagonistic anti- CD74 antibodies on MIF-mediated intracellular pathways may be of use for treatment of a broad range of disease states, such as cancers of the bladder, prostate, breast, lung, colon and chronic lymphocytic leukemia (e.g., Meyer-Siegler et al., 2004, BMC Cancer 12:34; Shachar & Haran, 2011 , Leuk Lymphoma 52:1446-54);; kidney diseases such as renal allograft rejection (Lan, 2008, Nephron Exp Nephrol.
- the pharmaceutical composition of the present invention may be used to treat a subject having a neurodegenerative disease, such as Alzheimer's disease.
- Bapineuzumab is in clinical trials for Alzheimer's disease therapy.
- Other antibodies proposed for therapy of Alzheimer's disease include Alz 50 (Ksiezak-Reding et al., 1987, J Biol Chem 263:7943-47), gantenerumab, and solanezumab.
- Infliximab an anti-TNF-a antibody, has been reported to reduce amyloid plaques and improve cognition.
- CD74 may be a target for peptide or antibody therapy, or for targeting a therapeutic, to these areas of the brain of Alzheimer patients.
- HIV-1 human immunodeficiency virus 1
- Known anti-HIV antibodies include the anti-envelope antibody described by Johansson et al. (AIDS.
- Antibodies against malaria parasites can be directed against the sporozoite, merozoite, schizont and gametocyte stages. Monoclonal antibodies have been generated against sporozoites (cirumsporozoite antigen), and have been shown to neutralize sporozoites in vitro and in rodents (N. Yoshida et al., Science 207:71-73, 1980). Several groups have developed antibodies to T. gondii, the protozoan parasite involved in toxoplasmosis (Kasper et al., J. Immunol. 129:1694- 1699, 1982; Id., 30:2407-2412, 1983).
- Antibodies have been developed against schistosomular surface antigens and have been found to act against schistosomulae in vivo or in vitro (Simpson et al., Parasitology, 83:163-177, 1981; Smith et al., Parasitology, 84:83-91, 1982: Gryzch et al., J. Immunol., 129:2739-2743, 1982; Zodda et al., J. Immunol. 129:2326-2328, 1982; Dissous et al., J. Immunol., 129:2232-2234, 1982)
- Trypanosoma cruzi is the causative agent of Chagas' disease, and is transmitted by bloodsucking reduviid insects.
- An antibody has been generated that specifically inhibits the differentiation of one form of the parasite to another (epimastigote to trypomastigote stage) in vitro, and which reacts with a cell-surface glycoprotein; however, this antigen is absent from the mammalian (bloodstream) forms of the parasite (Sher et al., Nature, 300:639-640, 1982).
- Anti-fungal antibodies are known in the art, such as anti-Sclerotinia antibody (U.S. Patent 7,910,702); antiglucuronoxylomannan antibody (Zhong and Priofski, 1998, Clin Diag Lab Immunol 5:58-64); anti-Candida antibodies (Matthews and Burnie, 2001, 2:472-76); and anti- glycosphingolipid antibodies (Toledo et al., 2010, BMC Microbiol 10:47).
- Suitable antibodies have been developed against most of the microorganism (bacteria, viruses, protozoa, fungi, other parasites) responsible for the majority of infections in humans, and many have been used previously for in vitro diagnostic purposes.
- Commercially available antibodies against a wide variety of pathogens are known and may be utilized.
- Exemplary anti- pathogen antibodies from Millipore (Billerica, MA) include anti-E.
- anti-pathogen antibodies from Santa Cruz Biotechnology include anti-Dengue virus (sc- 325018), anti- Vaccinia virus (sc-69949), anti-Polyoma virus (sc065925), anti-Rubella virus (scl01364), anti-Ebola virus (sc-51872), anti-EBV (sc-17500), anti-Measles (sc-58167), anti- Mumps (sc-57918), anti-Hantavirus (sc -57755) and anti-Mycoplasma hominis (sc-58171).
- Exemplary anti-pathogen antibodies from ProSci Inc. include anti- Aspergillus (35- 595), anti-Candida albicans (35-121) and anti-Saccharomyces cerevisiae (35-361).
- Exemplary anti-pathogen antibodies from KPL include anti-Staphylococcus aureus (01- 90-05), anti-Borrelia burgdorferi (01-97-91), anti-Helicobacter pylori (01-93-94), anti-Legionella spp. (01-90-03) and anti- Yersinia spp. (01-90-04).
- the DNLTM complexes are suitable for use in a wide variety of therapeutic and diagnostic applications.
- Methods of use of DNLTM complexes may include detection, diagnosis and/or treatment of a disease or other medical condition.
- Such conditions may include, but are not limited to, cancer, hyperplasia, asthma, multiple sclerosis, infectious diseases, chronic viral hepatitis, herpes virus infection, chronic infection with hepatitus B or C virus, chronic granulomatous disease, malignant osteopetrosis, Karposi's sarcoma, human papilloma virus infection, influenza, chronic myelogenous leukemia, hairy cell leukemia, cutaneous T-cell lymphoma, follicular lymphoma, metastatic renal cell carcinoma, haemangioma, hematologic malignancies, condylomata acuminata and malignant melanoma.
- Exemplary types of tumors that may be treated include acute lymphoblastic leukemia, acute myelogenous leukemia, biliary cancer, breast cancer, cervical cancer, chronic lymphocytic leukemia, chronic myelogenous leukemia, colorectal cancer, endometrial cancer, esophageal, gastric, head and neck cancer, Hodgkin's lymphoma, lung cancer, medullary thyroid cancer, non- Hodgkin's lymphoma, multiple myeloma, renal cancer, ovarian cancer, pancreatic cancer, glioma, melanoma, liver cancer, prostate cancer, and urinary bladder cancer.
- HIV immunodeficiency virus
- herpes virus herpes virus
- herpes simplex virus herpes simplex virus
- vaccinia virus herpes simplex virus
- cytomegalovirus rabies virus, influenza virus, rhinovirus, hepatitis B virus, hepatitis C virus, Sendai virus, feline leukemia virus, Reo virus, polio virus, human serum parvo-like virus, simian virus 40, respiratory syncytial virus, mouse mammary tumor virus, Varicella-Zoster virus, Dengue virus, rubella virus, measles virus, adenovirus, human T-cell leukemia viruses, Epstein- Barr virus, murine leukemia virus, mumps virus, vesicular stomatitis virus, Sindbis virus, lymphocytic choriomeningitis virus, wart virus and blue tongue virus; or the bacterium is selected from the group consisting of Streptococcus agalactiae, Legionella pneumophila, Streptococcus pyogenes, Escherichia coli, Neisseria gonorrhoeae, Neisseria men
- FIG. 1 is a cartoon drawing depicting the gene structures (A and B) for expression of Cytokine-DDD2 (C), and IgG-AD2 (D) DNL modules. The modules are combined to form DNL structures consisting of four cytokines fused to an IgG (E).
- FIG. 2 shows in vitro IFN activity in a cytokine-MAb DNL construct compared to PEGylated or native IFNa. Specific activities (IU/pmol) measured as described in the Examples. The activity of known concentrations of each test article was extrapolated from a rhIFNoc2b standard curve. Cultures were grown in the presence of increasing concentrations of 20-2b ( ⁇ ), 734-2b ( ⁇ ), v-mab (O), v-mab + 734-2b ( ⁇ ), PEGASYS (T), PEG-Intron (A) or lR-2b (V) and the relative viable cell densities were measured with MTS. The % of the signal obtained from untreated cells was plotted vs. the log of the molar concentration. Dose-response curves and EC5 0 values were generated using Prism software. Error bars, SD.
- FIG. 2(C) In vitro lymphoma proliferation assays using Daudi cells.
- FIG. 2(D) In vitro lymphoma proliferation assays using Jeko-1 cells.
- FIG. 3 shows the results of pharmacokinetic analyses in Swiss-Webster mice. Mice were administered 20-2b, oc2b-413, PEGINTRON or PEGASYS and serum samples were analyzed for
- IFNoc2b concentration by ELISA over 96 hours Serum elimination curves are shown. Serum half-life (T] /2 ) elimination rates and mean residence times (MRT) are summarized in the inserted table.
- FIG. 4(A) illustrates ADCC effector functions of 20-2b. Daudi or Raji cells were incubated with 20-2b, 22-2b, v-mab, epratuzumab (e-mab), or b.734 at 5 ⁇ g/ml in the presence of freshly isolated PBMCs for 4 h before quantification of cell lysis.
- FIG. 4(B) shows CDC effector functions of 20-2B. Daudi cells were incubated with serial dilutions of 20- 2b ( ⁇ ), 734-2b ( ⁇ ) or v-mab (O) in the presence of human complement. The % complement control (number of viable cells in the test sample compared to cells treated with complement only) was plotted vs. the log of the nM concentration. Error bars, SD.
- FIG. 5 shows enhanced depletion of NHL cells from whole blood by 20-2b.
- Fresh heparinized human blood was mixed with either Daudi or Ramos and incubated with 20- 2b ( ⁇ ), v-mab (O), 734-2b ( ⁇ ) or v-mab + 734-2b ( ⁇ ) at 0.01, 0.1 or 1 nM for two days.
- the effect of the indicated treatments on lymphoma and peripheral blood lymphocytes was evaluated using flow cytometry. Error bars, SD.
- FIG. 6(A) illustrates survival curves showing therapeutic efficacy of 20-2b in a disseminated Burkitt's lymphoma (Daudi) xenograft model.
- Female C.B. 17 SCID mice were administered Daudi cells i.v. on day 0.
- Treatments consisted of 20-2b ( ⁇ ), 734- 2b ( ⁇ ), v-mab (O), PEGASYS ( ⁇ ) or saline (X) given as a single s.c. doses. Days of treatment are indicated with arrows. Survival curves were analyzed using Prism software.
- In an Early Daudi model Groups of 10 mice were given a single dose of 0.7 pmol (solid line) or 0.07 pmol (dashed line) on day 1.
- FIG. 6(B) shows a similar study to FIG. 6(A), but in an Advanced Daudi model. Groups of 10 mice were given a single dose of 0.7 pmol (solid line), 7 pmol (dashed line) or 70 pmol (gray line) on day 7.
- FIG. 7(A) presents survival curves showing therapeutic efficacy of 20-2b in disseminated Burkitt's lymphoma (Raji and NAMALWA) xenograft models.
- Female C.B. 17 SCID mice were administered NHL cells i.v. on day 0.
- Treatments consisted of 20-2b ( ⁇ ), 734-2b ( ⁇ ), v-mab (O) or saline (X) given as s.c. doses. Days of treatment are indicated with arrows. Survival curves were analyzed using Prism software.
- groups of 10 received 250 pmol doses on days 5, 7, 9, 12, 14 and 16.
- FIG. 7(B) shows a similar study to FIG. 7(A), but in an Early NAMALWA model.
- Groups of 6 received 250 pmol doses of 20-2b or 734-2b on days 1, 3, 5, 8, 10 and 12 or 3.5 nmol doses of v-mab on days 1, 5, 9, 13, 17, 21 and 25.
- FIG. 8 (A) Schematic illustration of AD2-IFN- 1 expression module. Figure discloses SEQ ID NOS 99-100, respectively, in order of appearance. (B) Schematic diagram showing construction of interferon-antibody DNLTM module.
- FIG. 9 Cell surface expression of antigens in various cell lines.
- FIG. 10 Enhanced binding activity of (A) ( ⁇ )- ⁇ to ME-180 cells (B) (15)- ⁇ 1 to HepG2 cells and (C) (C2)- 1 to A375 cells compared to ⁇ 2- ⁇ 1 module.
- FIG. 11 Cytotoxic effect of (El )- ⁇ 1 on ME- 180 cells.
- FIG. 12 Cytotoxic effect of (15)- ⁇ 1 on ME-180 cells.
- FIG. 13 Anti-viral effects.
- A Enhanced anti-HCV potency of (c225)- l in Huh-7 cells.
- a Huh-7 stable cell line with HCV genotype lb Conl replicon expressing firefly luciferase was treated with indicated concentrations of (c225)- l, (C2)- 1, or rhIFN- ⁇ agents. After 3 days, luciferase activity was measured and antiviral effects were determined by percent activity reduction relative to untreated cells. Data were analyzed by Graph Pad Prism using a sigmoidal fit (variable slope). Samples were run twice independently in duplicate.
- B Enhanced anti- EMCV potency of (15)- ⁇ 1 in A549 cells.
- A549 cells were incubated with serial dilutions of (15)- ⁇ , (C2)-l ⁇ , rhIFN- ⁇ , or hMN 15-Fab-DDD2 before being challenged with EMCV.
- a visual cytopathic effect (CPE) determination was performed, and the data were analyzed by GraphPad Prism using a sigmoidal fit (variable slope). Samples were run twice independently in duplicate.
- a "therapeutic agent” is an atom, molecule, or compound that is useful in the treatment of a disease.
- therapeutic agents include antibodies, antibody fragments, peptides, drugs, toxins, enzymes, nucleases, hormones, immunomodulators, antisense oligonucleotides, small interfering RNA (siRNA), chelators, boron compounds, photoactive agents, dyes, and radioisotopes.
- a "diagnostic agent” is an atom, molecule, or compound that is useful in diagnosing a disease.
- useful diagnostic agents include, but are not limited to, radioisotopes, dyes (such as with the biotin-streptavidin complex), contrast agents, fluorescent compounds or molecules, and enhancing agents (e.g., paramagnetic ions) for magnetic resonance imaging (MRI).
- an "antibody” as used herein refers to a full-length (i.e., naturally occurring or formed by normal immunoglobulin gene fragment recombinatorial processes) immunoglobulin molecule (e.g., an IgG antibody) or an immunologically active (i.e., specifically binding) portion of an immunoglobulin molecule, like an antibody fragment.
- An “antibody” includes monoclonal, polyclonal, bispecific, multispecific, murine, chimeric, humanized and human antibodies.
- a "naked antibody” is an antibody or antigen binding fragment thereof that is not attached to a therapeutic or diagnostic agent.
- the Fc portion of an intact naked antibody can provide effector functions, such as complement fixation and ADCC (see, e.g., Markrides, Pharmacol Rev 50:59-87, 1998).
- Other mechanisms by which naked antibodies induce cell death may include apoptosis. (Vaswani and Hamilton, Ann Allergy Asthma Immunol 81 : 105- 119, 1998.)
- an "antibody fragment” is a portion of an intact antibody such as F(ab') 2 , F(ab) 2 , Fab', Fab, Fv, sFv, scFv, dAb and the like. Regardless of structure, an antibody fragment binds with the same antigen that is recognized by the full-length antibody.
- antibody fragments include isolated fragments consisting of the variable regions, such as the "Fv” fragments consisting of the variable regions of the heavy and light chains or recombinant single chain polypeptide molecules in which light and heavy variable regions are connected by a peptide linker ("scFv proteins").
- Single-chain antibodies often abbreviated as “scFv” consist of a polypeptide chain that comprises both a V H and a V L domain which interact to form an antigen- binding site.
- the V H and V L domains are usually linked by a peptide of 1 to 25 amino acid residues.
- Antibody fragments also include diabodies, triabodies and single domain antibodies (dAb).
- An antibody or immunoconjugate preparation, or a composition described herein is said to be administered in a "therapeutically effective amount" if the amount administered is physiologically significant.
- An agent is physiologically significant if its presence results in a detectable change in the physiology of a recipient subject.
- an antibody preparation is physiologically significant if its presence invokes an antitumor response or mitigates the signs and symptoms of a disease state.
- a physiologically significant effect could also be the evocation of a humoral and/or cellular immune response in the recipient subject leading to growth inhibition or death of target cells.
- an interferon-antibody complex is formed as a DOCK-AND- LOCKTM (DNLTM) complex (see, e.g., U.S. Patent Nos. 7,521,056; 7,527,787; 7,534,866;
- the technique takes advantage of the specific and high-affinity binding interactions that occur between a dimerization and docking domain (DDD) sequence of the regulatory (R) subunits of cAMP-dependent protein kinase (PKA) and an anchor domain (AD) sequence derived from any of a variety of AKAP proteins (Baillie et ah, FEBS Letters. 2005; 579: 3264. Wong and Scott, Nat. Rev. Mol. Cell Biol. 2004; 5: 959).
- DDD and AD peptides may be attached to any protein, peptide or other molecule. Because the DDD sequences spontaneously dimerize and bind to the AD sequence, the technique allows the formation of complexes between any selected molecules that may be attached to DDD or AD sequences.
- the standard DNLTM complex comprises a trimer with two DDD-linked molecules attached to one AD-linked molecule
- variations in complex structure allow the formation of dimers, trimers, tetramers, pentamers, hexamers and other multimers.
- the DNLTM complex may comprise two or more antibodies, antibody fragments or fusion proteins which bind to the same antigenic determinant or to two or more different antigens.
- the DNLTM complex may also comprise one or more other effectors, such as proteins, peptides, immunomodulators, cytokines, interleukins, interferons, binding proteins, peptide ligands, carrier proteins, toxins, ribonucleases such as onconase, inhibitory oligonucleotides such as siRNA, antigens or xenoantigens, polymers such as PEG, enzymes, therapeutic agents, hormones, cytotoxic agents, anti-angiogenic agents, pro-apoptotic agents or any other molecule or aggregate.
- effectors such as proteins, peptides, immunomodulators, cytokines, interleukins, interferons, binding proteins, peptide ligands, carrier proteins, toxins, ribonucleases such as onconase, inhibitory oligonucleotides such as siRNA, antigens or xenoantigens, polymers such as PEG, enzymes, therapeutic agents, hormones,
- PKA which plays a central role in one of the best studied signal transduction pathways triggered by the binding of the second messenger cAMP to the R subunits, was first isolated from rabbit skeletal muscle in 1968 (Walsh et al, J. Biol. Chem. 1968;243:3763).
- the structure of the holoenzyme consists of two catalytic subunits held in an inactive form by the R subunits (Taylor, J. Biol. Chem. 1989;264:8443).
- Isozymes of PKA are found with two types of R subunits (RI and RII), and each type has a and ⁇ isoforms (Scott, Pharmacol. Ther.
- the four isoforms of PKA regulatory subunits are Rice, Ri , Rlla and RIip.
- the R subunits have been isolated only as stable dimers and the dimerization domain has been shown to consist of the first 44 amino-terminal residues of Rlla (Newlon et al, Nat. Struct. Biol. 1999; 6:222).
- similar portions of the amino acid sequences of other regulatory subunits are involved in dimerization and docking, each located near the N-terminal end of the regulatory subunit.
- Binding of cAMP to the R subunits leads to the release of active catalytic subunits for a broad spectrum of serine/threonine kinase activities, which are oriented toward selected substrates through the compartmentalization of PKA via its docking with AKAPs (Scott et al, J. Biol. Chem. 1990;265;21561)
- AKAP microtubule-associated protein-2
- the amino acid sequences of the AD are quite varied among individual AKAPs, with the binding affinities reported for RII dimers ranging from 2 to 90 nM (Alto et al, Proc. Natl. Acad. Sci. USA. 2003; 100:4445). AKAPs will only bind to dimeric R subunits.
- the AD binds to a hydrophobic surface formed by the 23 amino-terminal residues (Colledge and Scott, Trends Cell Biol. 1999; 6:216).
- the dimerization domain and AKAP binding domain of human Rlla are both located within the same N-terminal 44 amino acid sequence (Newlon et al, Nat. Struct. Biol.
- Entity B is constructed by linking an AD sequence to a precursor of B, resulting in a second component hereafter referred to as b.
- the dimeric motif of DDD contained in a 2 will create a docking site for binding to the AD sequence contained in b, thus facilitating a ready association of a 2 and b to form a binary, trimeric complex composed of a 2 b.
- This binding event is made irreversible with a subsequent reaction to covalently secure the two entities via disulfide bridges, which occurs very efficiently based on the principle of effective local concentration because the initial binding interactions should bring the reactive thiol groups placed onto both the DDD and AD into proximity (Chmura et al., Proc. Natl. Acad. Sci. USA. 2001;98:8480) to ligate site- specifically.
- linkers, adaptor modules and precursors a wide variety of DNLTM constructs of different stoichiometry may be produced and used (see, e.g., U.S. Nos. 7,550,143; 7,521,056; 7,534,866; 7,527,787 and 7,666,400.)
- fusion proteins A variety of methods are known for making fusion proteins, including nucleic acid synthesis, hybridization and/or amplification to produce a synthetic double-stranded nucleic acid encoding a fusion protein of interest.
- double-stranded nucleic acids may be inserted into expression vectors for fusion protein production by standard molecular biology techniques (see, e.g. Sambrook et al., Molecular Cloning, A laboratory manual, 2" Ed, 1989).
- the AD and/or DDD moiety may be attached to either the N-terminal or C-terminal end of an effector protein or peptide.
- site of attachment of an AD or DDD moiety to an effector moiety may vary, depending on the chemical nature of the effector moiety and the part(s) of the effector moiety involved in its physiological activity.
- Site-specific attachment of a variety of effector moieties may be performed using techniques known in the art, such as the use of bivalent cross-linking reagents and/or other chemical conjugation techniques.
- AD or DDD sequences may be utilized. Exemplary DDD and AD sequences are provided below.
- DDDl and DDD2 are based on the DDD sequence of the human RIIoc isoform of protein kinase A.
- the DDD and AD moieties may be based on the DDD sequence of the human RIa form of protein kinase A and a corresponding A AP sequence, as exemplified in DDD3, DDD3C and AD3 below.
- AD and/or DDD moieties may be utilized in construction of the DNLTM complexes.
- Rlla DDD sequence is the basis of DDD1 and DDD2 disclosed above.
- the four human PKA DDD sequences are shown below.
- the DDD sequence represents residues 1- 44 of Rlla, 1-44 of RIip, 12-61 of RIa and 13-66 of Rip. (Note that the sequence of DDD1 is modified slightly from the human PKA Rlla DDD moiety.)
- DDD moiety sequences are shown in SEQ ID NO: 12 to SEQ ID NO:31 below.
- the skilled artisan will realize that an almost unlimited number of alternative species within the genus of DDD moieties can be constructed by standard techniques, for example using a commercial peptide synthesizer or well known site-directed mutagenesis techniques.
- the effect of the amino acid substitutions on AD moiety binding may also be readily determined by standard binding assays, for example as disclosed in Alto et al. (2003, Proc Natl Acad Sci USA 100:4445-50).
- Alto et al. performed a bioinformatic analysis of the AD sequence of various AKAP proteins to design an RII selective AD sequence called AKAP-IS (SEQ ID NO:3), with a binding constant for DDD of 0.4 nM.
- the AKAP-IS sequence was designed as a peptide antagonist of AKAP binding to PKA. Residues in the AKAP-IS sequence where substitutions tended to decrease binding to DDD are underlined in SEQ ID NO:3 below.
- QIEYLAKQIVDQAIQQA (SEQ ID NO:44)
- QIEYLAKQIVDNAINQA (SEQ ID NO:45)
- the SuperAKAP-IS sequence may be substituted for the AKAP-IS AD moiety sequence to prepare DNLTM constructs.
- Other alternative sequences that might be substituted for the AKAP-IS AD sequence are shown in SEQ ID NO:51-53. Substitutions relative to the AKAP-IS sequence are underlined. It is anticipated that, as with the AD2 sequence shown in SEQ ID NO:4, the AD moiety may also include the additional N-terminal residues cysteine and glycine and C-terminal residues glycine and cysteine.
- Figure 2 of Gold et al. disclosed additional DDD-binding sequences from a variety of AKAP proteins, shown below.
- FEELAWKIAKMIWSDVFQQC (SEQ ID NO:66) [076] Hundsrucker et al. (2006, Biochem J 396:297-306) developed still other peptide competitors for AKAP binding to PKA, with a binding constant as low as 0.4 nM to the DDD of the RII form of PKA.
- the sequences of various AKAP antagonistic peptides are provided in Table 1 of Hundsrucker et al., reproduced in Table 3 below.
- AKAPIS represents a synthetic RII subunit-binding peptide. All other peptides are derived from the RH-binding domains of the indicated AKAPs.
- AKAP1 -pep EEGLDRNEEIKRAAFQIISQVISEA (SEQ ID NO:76)
- AKAP10-pep NTDEAQEELAWKIAKMIVSDIMQQA (SEQ ID NO:80)
- AKAP11 -pep VNLDKKAVLAEKIVAEABEKAEREL (SEQ ID NO:81 )
- AKAP12-pep NGILELETKSSKLVQNIIQTAVDQF (SEQ ID NO:82)
- the effector moiety is an immunomodulator.
- An immunomodulator is an agent that when present, alters, suppresses or stimulates the body's immune system.
- Immunomodulators of use may include a cytokine, a stem cell growth factor, a lymphotoxin, a hematopoietic factor, a colony stimulating factor (CSF), an interferon (IFN), erythropoietin, thrombopoietin and a combination thereof.
- lymphotoxins such as tumor necrosis factor (TNF), hematopoietic factors, such as interleukin (IL), colony stimulating factor, such as granulocyte-colony stimulating factor (G-CSF) or granulocyte macrophage-colony stimulating factor (GM-CSF), interferon, such as interferon-oc, interferon- ⁇ , interferon- ⁇ or interferon- ⁇ , and stem cell growth factor, such as that designated "SI factor”.
- TNF tumor necrosis factor
- IL interleukin
- colony stimulating factor such as granulocyte-colony stimulating factor (G-CSF) or granulocyte macrophage-colony stimulating factor (GM-CSF)
- interferon such as interferon-oc, interferon- ⁇ , interferon- ⁇ or interferon- ⁇
- SI factor stem cell growth factor
- the effector moieties are cytokines, such as
- lymphokines monokines, growth factors and traditional polypeptide hormones. Included among the cytokines are growth hormones such as human growth hormone, N-methionyl human growth hormone, and bovine growth hormone; parathyroid hormone; thyroxine; insulin; proinsulin; relaxin; prorelaxin; glycoprotein hormones such as follicle stimulating hormone (FSH), thyroid stimulating hormone (TSH), and luteinizing hormone (LH); placenta growth factor (P1GF), hepatic growth factor; prostaglandin, fibroblast growth factor; prolactin; placental lactogen, OB protein; tumor necrosis factor-a and - ⁇ ; mullerian-inhibiting substance; mouse gonadotropin- associated peptide; inhibin; activin; vascular endothelial growth factor; integrin; thrombopoietin (TPO); nerve growth factors such as NGF- ⁇ ; platelet-growth factor; transforming growth factors (TGFs) such as TGF-
- the NCBI database contains both protein and encoding nucleic acid sequences for a large number of cytokines and immunomodulators, such as erythropoietin (GenBank NM 000799), IL-1 beta (GenPept AAH08678), GM-CSF (GenPept AAA52578), TNF-a (GenPept CAA26669), interferon-alpha (GenPept AAA52716.1), interferon-alpha 2b (GenPept AAP20099.1), interferon-lambda (GenPept 30G6_B; 3HHC_A; 3HHCJB; 3HHC .C; 3HHC_D; EAW56870.1; EAW56869.1; AAI40873.1) and virtually any of the peptide or protein immunomodulators listed above.
- cytokines and immunomodulators such as erythropoietin (GenBank NM 000799), IL-1 beta (GenPept AAH08678), GM-C
- cytokines are also available and may be used, such as the full-length human IFN-oc2b cDNA clone (Invitrogen Ultimate ORF human clone cat# HORFOlClone ID IOH35221).
- an antibody or antigen binding fragment thereof may be incorporated into a DNLTM construct, such as by attachment of an antibody or fragment to an interferon or other cytokine for targeted delivery of the cytokine. Any known antibody or antigen-binding fragment thereof may be incorporated into a DNLTM construct.
- the complex is of use for cancer therapy and the antibody binds to a tumor associated antigen (TAA).
- TAA tumor associated antigen
- tumor-associated antigens are known in the art, including but not limited to carbonic anhydrase IX, CCCL19, CCCL21, CSAp, CD1, CDla, CD2, CD3, CD4, CD5, CD8, CD11A, CD14, CD15, CD16, CD18, CD19, IGF-IR, CD20, CD21, CD22, CD23, CD25, CD29, CD30, CD32b, CD33, CD37, CD38, CD40, CD40L, CD45, CD46, CD52, CD54, CD55, CD59, CD64, CD66a-e, CD67, CD70, CD74, CD79a, CD80, CD83, CD95, CD126, CD133, CD138, CD147, CD154, AFP, PSMA, CEACAM5, CEACAM6, B7, ED-B of fibronectin, Factor H, FHL-1, Flt-3, folate receptor, GROB, HMGB-1, hypoxia inducible factor (HIF), HM1.24, insulin
- anti-cancer antibodies that may be utilized in DNLTM constructs include, but are not limited to, hRl (anti-IGF-l R, U.S. Provisional Patent Application Serial No. 61/145,896, filed 1/20/09) hPAM4 (anti-MUCl, U.S. Patent No. 7,282,567), hA20 (anti-CD20, U.S. Patent No. 7,251,164), hA19 (anti-CD19, U.S. Patent No. 7,109,304), hIMMU-31 (anti-AFP, U.S. Patent No. 7,300,655), hLLl (anti-CD74, U.S. Patent No.
- Antigen-binding antibody fragments are well known in the art, such as F(ab') 2 , F(ab) 2 , Fab', Fab, Fv, scFv and the like, and any such known fragment may be used.
- an antigen-binding antibody fragment refers to any fragment of an antibody that binds with the same antigen that is recognized by the intact or parent antibody. Techniques for preparing AD and/or DDD conjugates of virtually any antibody or fragment of interest are known (e.g., U.S. Patent No. 7,527,787).
- antibodies or fragment thereof may be used which is not conjugated to a therapeutic agent is referred to as a "naked" antibody or fragment thereof.
- antibodies or fragments may be conjugated to one or more therapeutic and/or diagnostic agents.
- therapeutic and diagnostic agents are known in the art, as discussed in more detail below, and any such known therapeutic or diagnostic agent may be used.
- monoclonal antibodies can be obtained by injecting mice with a composition comprising an antigen, removing the spleen to obtain B-lymphocytes, fusing the B-lymphocytes with myeloma cells to produce hybridomas, cloning the hybridomas, selecting positive clones which produce antibodies to the antigen, culturing the clones that produce antibodies to the antigen, and isolating the antibodies from the hybridoma cultures.
- MAbs can be isolated and purified from hybridoma cultures by a variety of well-established techniques. Such isolation techniques include affinity chromatography with Protein- A Sepharose, size-exclusion chromatography, and ion-exchange chromatography. See, for example, Coligan at pages 2.7.1-2.7.12 and pages 2.9.1-2.9.3. Also, see Baines et al,
- the antibodies can be sequenced and subsequently prepared by recombinant techniques. Humanization and chimerization of murine antibodies and antibody fragments are well known to those skilled in the art. The use of antibody components derived from humanized, chimeric or human antibodies obviates potential problems associated with the immunogenicity of murine constant regions.
- a chimeric antibody is a recombinant protein in which the variable regions of a human antibody have been replaced by the variable regions of, for example, a mouse antibody, including the complementarity-determining regions (CDRs) of the mouse antibody.
- Chimeric antibodies exhibit decreased immunogenicity and increased stability when administered to a subject.
- CDRs complementarity-determining regions
- a chimeric or murine monoclonal antibody may be humanized by transferring the mouse CDRs from the heavy and light variable chains of the mouse immunoglobulin into the corresponding variable domains of a human antibody.
- the mouse framework regions (FR) in the chimeric monoclonal antibody are also replaced with human FR sequences.
- additional modification might be required in order to restore the original affinity of the murine antibody. This can be accomplished by the replacement of one or more human residues in the FR regions with their murine counterparts to obtain an antibody that possesses good binding affinity to its epitope.
- the phage display technique may be used to generate human antibodies ⁇ e.g., Dantas-Barbosa et al., 2005, Genet. Mol. Res. 4: 126-40).
- Human antibodies may be generated from normal humans or from humans that exhibit a particular disease state, such as cancer (Dantas-Barbosa et al., 2005).
- the advantage to constructing human antibodies from a diseased individual is that the circulating antibody repertoire may be biased towards antibodies against disease-associated antigens.
- Fab fragment antigen binding protein
- RNAs were converted to cDNAs and used to make Fab cDNA libraries using specific primers against the heavy and light chain immunoglobulin sequences (Marks et al., 1991, J. Mol. Biol. 222:581-97).
- Library construction was performed according to Andris-Widhopf et al. (2000, In: Phage Display Laboratory Manual, Barbas et al. (eds), 1 st edition, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY pp. 9.1 to 9.22).
- Fab fragments were digested with restriction endonucleases and inserted into the bacteriophage genome to make the phage display library.
- libraries may be screened by standard phage display methods, as known in the art (see, e.g., Pasqualini and Ruoslahti, 1996, Nature 380:364-366; Pasqualini, 1999, The Quart. J. Nucl. Med. 43:159-162).
- Phage display can be performed in a variety of formats, for their review, see e.g. Johnson and Chiswell, Current Opinion in Structural Biology 3:5564-571 (1993).
- Human antibodies may also be generated by in vitro activated B-cells. See U.S. Patent Nos. 5,567,610 and 5,229,275, incorporated herein by reference in their entirety. The skilled artisan will realize that these techniques are exemplary and any known method for making and screening human antibodies or antibody fragments may be utilized.
- transgenic animals that have been genetically engineered to produce human antibodies may be used to generate antibodies against essentially any immunogenic target, using standard immunization protocols.
- Methods for obtaining human antibodies from transgenic mice are disclosed by Green et al., Nature Genet. 7:13 (1994), Lonberg et al., Nature 368:856 (1994), and Taylor et al., Int. Immun. 6:579 (1994).
- a non- limiting example of such a system is the XenoMouse® (e.g., Green et al., 1999, J. Immunol. Methods 231 :11 -23) from Abgenix (Fremont, CA).
- the mouse antibody genes have been inactivated and replaced by functional human antibody genes, while the remainder of the mouse immune system remains intact.
- the XenoMouse® was transformed with germline-configured YACs (yeast artificial chromosomes) that contained portions of the human IgH and Igkappa loci, including the majority of the variable region sequences, along accessory genes and regulatory sequences.
- the human variable region repertoire may be used to generate antibody producing B-cells, which may be processed into hybridomas by known techniques.
- a XenoMouse® immunized with a target antigen will produce human antibodies by the normal immune response, which may be harvested and/or produced by standard techniques discussed above.
- a variety of strains of XenoMouse® are available, each of which is capable of producing a different class of antibody.
- Transgenically produced human antibodies have been shown to have therapeutic potential, while retaining the pharmacokinetic properties of normal human antibodies (Green et al., 1999). The skilled artisan will realize that the claimed compositions and methods are not limited to use of the
- XenoMouse® system may utilize any transgenic animal that has been genetically engineered to produce human antibodies.
- Antibody fragments which recognize specific epitopes can be generated by known techniques.
- Antibody fragments are antigen binding portions of an antibody, such as F(ab') 2 , Fab', F(ab) 2 , Fab, Fv, sFv and the like.
- F(ab') 2 fragments can be produced by pepsin digestion of the antibody molecule and Fab' fragments can be generated by reducing disulfide bridges of the F(ab') 2 fragments.
- Fab' expression libraries can be constructed (Huse et al., 1989, Science, 246:1274-1281) to allow rapid and easy identification of monoclonal Fab' fragments with the desired specificity.
- F(ab) 2 fragments may be generated by papain digestion of an antibody and Fab fragments obtained by disulfide reduction.
- a single chain Fv molecule comprises a VL domain and a VH domain.
- the VL and VH domains associate to form a target binding site.
- These two domains are further covalently linked by a peptide linker (L).
- L peptide linker
- Methods for making scFv molecules and designing suitable peptide linkers are described in US Patent No. 4,704,692, US Patent No. 4,946,778, R. Raag and M. Whitlow, "Single Chain Fvs.” FASEB Vol 9:73-80 (1995) and R.E. Bird and B.W. Walker, "Single Chain Antibody Variable Regions," TIBTECH, Vol 9: 132-137 (1991).
- DABs single domain antibodies
- An antibody fragment can be prepared by proteolytic hydrolysis of the full length antibody or by expression in E. coli or another host of the DNA coding for the fragment.
- An antibody fragment can be obtained by pepsin or papain digestion of full length antibodies by conventional methods. These methods are described, for example, by Goldenberg, U.S. Patent Nos. 4,036,945 and 4,331,647 and references contained therein. Also, see Nisonoff et al, Arch Biochem. Biophys. 89: 230 (1960); Porter, Biochem. J. 73: 119 (1 59), Edelman et al, in METHODS IN ENZYMOLOGY VOL. 1, page 422 (Academic Press 1967), and Coligan at pages 2.8.1-2.8.10 and 2.10.-2.10.4.
- Antibodies of use may be commercially obtained from a wide variety of known sources.
- a variety of antibody secreting hybridoma lines are available from the American Type Culture Collection (ATCC, Manassas, VA).
- a large number of antibodies against various disease targets, including but not limited to tumor-associated antigens, have been deposited at the ATCC and/or have published variable region sequences and are available for use in the claimed methods and compositions. See, e.g., U.S. Patent Nos. 7,312,318; 7,282,567; 7,151,164;
- antibody sequences or antibody-secreting hybridomas against almost any disease- associated antigen may be obtained by a simple search of the ATCC, NCBI and/or USPTO databases for antibodies against a selected disease-associated target of interest.
- the antigen binding domains of the cloned antibodies may be amplified, excised, ligated into an expression vector, transfected into an adapted host cell and used for protein production, using standard techniques well known in the art.
- antibodies that may be of use for therapy of cancer within the scope of the claimed methods and compositions include, but are not limited to, LL1 (anti-CD74), epratuzumab (LL2) and RFB4 (anti-CD22), RS7 (anti-epithelial glycoprotein- 1 (EGP-1) or anti- TROP-2), PAM4 and KC4 (both anti-mucin), MN-14 (anti-carcinoembryonic antigen
- CEACAM5 also known as CD66e
- Mu-9 anti-colon-specific antigen-p
- Immu-31 an anti- alpha-fetoprotein
- anti-TAG-72 e.g., CC49
- anti-Tn J591 or HuJ591
- anti-PSMA prostate- specific membrane antigen
- AB-PGl-XGl-026 anti-PSMA dimer
- D2/B anti-PSMA
- G250 anti-carbonic anhydrase IX
- hL243 anti-HLA-DR
- alemtuzumab anti-CD52
- bevacizumab anti-VEGF
- cetuximab anti-EGFR
- gemtuzumab anti-CD33
- ibritumomab tiuxetan anti- CD20
- panitumumab anti-EGFR
- rituximab anti-CD20
- tositumomab anti-CD20
- GA101
- hPAM4 U.S. Patent No. 7,282,567
- hA20 U.S. Patent No. 7,251,164
- hA19 U.S. Patent No. 7,109,304
- hlMMlDl U.S. Patent No. 7,300,655
- hLLl U.S. Patent No. 7,312,318,
- hLL2 U.S. Patent No. 7,074,403
- hMu-9 U.S. Patent No.
- Anti-TNF-a antibodies are known in the art and may be of use to treat immune diseases, such as asthma.
- Known antibodies against TNF-a include the human antibody CDP571 (Ofei et al, 2011, Diabetes 45:881-85); murine antibodies MTNFAI, M2TNFAI, M3TNFAI,
- M3TNFABI, M302B and M303 Thermo Scientific, Rockford, IL
- infliximab Centocor, Malvern, PA
- certolizumab pegol UB, Brussels, Belgium
- adalimumab Abbott, Abbott Park, IL
- anti-B-cell antibodies such as veltuzumab, epratuzumab, milatuzumab or hL243; tocilizumab (anti-IL-6 receptor); basiliximab (anti-CD25); daclizumab (anti-CD25); efalizumab (anti-CDl la);
- muromonab-CD3 anti-CD3 receptor
- anti-CD40L UMB, Brussels, Belgium
- natalizumab anti- ⁇ x4 integrin
- omalizumab anti-IgE
- Macrophage migration inhibitory factor is an important regulator of innate and adaptive immunity and apoptosis. It has been reported that CD74 is the endogenous receptor for MIF (Leng et al., 2003, J Exp Med 197:1467-76).
- the therapeutic effect of antagonistic anti- CD74 antibodies on MIF-mediated intracellular pathways may be of use for treatment of a broad range of disease states, such as cancers of the bladder, prostate, breast, lung, colon and chronic lymphocytic leukemia (e.g., Meyer-Siegler et al., 2004, BMC Cancer 12:34; Shachar & Haran, 201 1, Leuk Lymphoma 52: 1446-54); kidney diseases such as renal allograft rejection (Lan, 2008, Nephron Exp Nephrol.
- the pharmaceutical composition of the present invention may be used to treat a subject having a neurodegenerative disease, such as Alzheimer's disease.
- Bapineuzumab is in clinical trials for Alzheimer's disease therapy.
- HIV-1 human immunodeficiency virus 1
- HIV-1 antibodies against the gpl20 glycoprotein antigen of human immunodeficiency virus I
- Known anti-HIV antibodies include the anti-envelope antibody described by Johansson et al. (AIDS.
- Antibodies against malaria parasites can be directed against the sporozoite, merozoite, schizont and gametocyte stages. Monoclonal antibodies have been generated against sporozoites (cirumsporozoite antigen), and have been shown to neutralize sporozoites in vitro and in rodents (N. Yoshida et al., Science 207:71-73, 1980). Several groups have developed antibodies to T. gondii, the protozoan parasite involved in toxoplasmosis (Kasper et al., J. Immunol. 129:1694- 1699, 1982; Id., 30:2407-2412, 1983).
- Antibodies have been developed against schistosomular surface antigens and have been found to act against schistosomulae in vivo or in vitro (Simpson et al., Parasitology, 83:163-177, 1981; Smith et al., Parasitology, 84:83-91, 1982: Gryzch et al., J. Immunol., 129:2739-2743, 1982; Zodda et al., J. Immunol. 129:2326-2328, 1982; Dissous et al, J.
- Trypanosoma crazi is the causative agent of Chagas' disease, and is transmitted by bloodsucking reduviid insects.
- An antibody has been generated that specifically inhibits the differentiation of one form of the parasite to another (epimastigote to trypomastigote stage) in vitro, and which reacts with a cell-surface glycoprotein; however, this antigen is absent from the mammalian (bloodstream) forms of the parasite (Sher et al., Nature, 300:639-640, 1982).
- Anti-fungal antibodies are known in the art, such as anti-Sclerotinia antibody (U.S. Patent 7,910,702); antiglucuronoxylomannan antibody (Zhong and Priofski, 1998, Clin Diag Lab Immunol 5:58-64); anti-Candida antibodies (Matthews and Burnie, 2001, 2:472-76); and anti- glycosphingolipid antibodies (Toledo et al., 2010, BMC Microbiol 10:47).
- Suitable antibodies have been developed against most of the microorganism (bacteria, viruses, protozoa, fungi, other parasites) responsible for the majority of infections in humans, and many have been used previously for in vitro diagnostic purposes. These antibodies, and newer antibodies that can be generated by conventional methods, are appropriate for use in the present invention.
- Immunogenicity of therapeutic antibodies is associated with increased risk of infusion reactions and decreased duration of therapeutic response (Baert et al., 2003, N Engl J Med 348:602- 08).
- the extent to which therapeutic antibodies induce an immune response in the host may be determined in part by the allotype of the antibody (Stickler et al., 2011, Genes and Immunity 12:213-21).
- Antibody allotype is related to amino acid sequence variations at specific locations in the constant region sequences of the antibody.
- the allotypes of IgG antibodies containing a heavy chain ⁇ -type constant region are designated as Gm allotypes (1976, J Immunol 117: 1056-59).
- Glml For the common IgGl human antibodies, the most prevalent allotype is Glml (Stickler et al., 201 1 , Genes and Immunity 12:213-21). However, the Gl m3 allotype also occurs frequendy in Caucasians (Id.). It has been reported that Glml antibodies contain allotypic sequences that tend to induce an immune response when administered to non-Glml (nGlml) recipients, such as Glm3 patients (Id). Non-Glml allotype antibodies are not as immunogenic when administered to Glml patients (Id.).
- the human Gl ml allotype comprises the amino acids aspartic acid at Kabat position 356 and leucine at Kabat position 358 in the CH3 sequence of the heavy chain IgGl .
- the nGlml allotype comprises the amino acids glutamic acid at Kabat position 356 and methionine at Kabat position 358.
- Both Glml and nGlml allotypes comprise a glutamic acid residue at Kabat position 357 and the allotypes are sometimes referred to as DEL and EEM allotypes.
- a non-limiting example of the heavy chain constant region sequences for Glml and nGlml allotype antibodies is shown for the exemplary antibodies rituximab (SEQ ID NO:85) and veltuzumab (SEQ ID NO:86).
- Veltuzumab heavy chain variable region (SEQ ID NO: 86
- nGlml, 2 allotype was characterized by glutamic acid at Kabat position 356, methionine at Kabat position 358 and alanine at Kabat position 431.
- the Glml, 2 allotype was characterized by aspartic acid at Kabat position 356, leucine at Kabat position 358 and glycine at Kabat position 431.
- veltuzumab and rituximab are, respectively, humanized and chimeric IgGl antibodies against CD20, of use for therapy of a wide variety of hematological malignancies.
- Table 5 compares the allotype sequences of rituximab vs. veltuzumab.
- rituximab (Glml7,l) is a DEL allotype IgGl, with an additional sequence variation at Kabat position 214 (heavy chain CHI) of lysine in rituximab vs. arginine in veltuzumab.
- veltuzumab is less immunogenic in subjects than rituximab (see, e.g., Morchhauser et al., 2009, J Clin Oncol 27:3346-53; Goldenberg et al, 2009, Blood 113:1062-70; Robak & Robak, 2011, BioDrugs 25:13-25), an effect that has been attributed to the difference between humanized and chimeric antibodies.
- the difference in allotypes between the EEM and DEL allotypes likely also accounts for the lower immunogenicity of veltuzumab.
- the allotype of the antibody In order to reduce the immunogenicity of therapeutic antibodies in individuals of nGlml genotype, it is desirable to select the allotype of the antibody to correspond to the Glm3 allotype, characterized by arginine at Kabat 214, and the nGlml,2 null-allotype, characterized by glutamic acid at Kabat position 356, methionine at Kabat position 358 and alanine at Kabat position 431. Surprisingly, it was found that repeated subcutaneous administration of Glm3 antibodies over a long period of time did not result in a significant immune response.
- the human IgG4 heavy chain in common with the Glm3 allotype has arginine at Kabat 214, glutamic acid at Kabat 356, methionine at Kabat 359 and alanine at Kabat 431. Since immunogenicity appears to relate at least in part to the residues at those locations, use of the human IgG4 heavy chain constant region sequence for therapeutic antibodies is also a preferred embodiment. Combinations of Glm3 IgGl antibodies with IgG4 antibodies may also be of use for therapeutic administration.
- the disclosed methods and compositions may involve production and use of proteins or peptides with one or more substituted amino acid residues.
- the DDD and/or AD sequences used to make the DNLTM constructs may be further optimized, for example to increase the DDD- AD binding affinity.
- amino acid substitutions typically involve the replacement of an amino acid with another amino acid of relatively similar properties (i.e., conservative amino acid substitutions). The properties of the various amino acids and effect of amino acid substitution on protein structure and function have been the subject of extensive study and knowledge in the art.
- the hydropathic index of amino acids may be considered (Kyte & Doolittle, 1982, J. Mol. Biol., 157:105-132).
- the relative hydropathic character of the amino acid contributes to the secondary structure of the resultant protein, which in turn defines the interaction of the protein with other molecules.
- Each amino acid has been assigned a
- glutamine (-3.5); aspartate (-3.5); asparagine (-3.5); lysine (-3.9); and arginine (-4.5).
- amino acids whose hydropathic indices are within ⁇ 2 is preferred, within ⁇ 1 are more preferred, and within ⁇ 0.5 are even more preferred.
- Amino acid substitution may also take into account the hydrophilicity of the amino acid residue (e.g., U.S. Pat. No. 4,554,101). Hydrophilicity values have been assigned to amino acid residues: arginine (+3.0); lysine (+3.0); aspartate (+3.0); glutamate (+3.0); serine (+0.3);
- amino acid side chain For example, it would generally not be preferred to replace an amino acid with a compact side chain, such as glycine or serine, with an amino acid with a bulky side chain, e.g., tryptophan or tyrosine.
- a compact side chain such as glycine or serine
- an amino acid with a bulky side chain e.g., tryptophan or tyrosine.
- the effect of various amino acid residues on protein secondary structure is also a consideration. Through empirical study, the effect of different amino acid residues on the tendency of protein domains to adopt an alpha-helical, beta-sheet or reverse turn secondary structure has been determined and is known in the art (see, e.g., Chou & Fasman, 1974, Biochemistry, 13:222-245; 1978, Ann. Rev. Biochem., 47: 251-276; 1979, Biophys.
- amino acid substitutions include whether or not the residue is located in the interior of a protein or is solvent exposed.
- conservative substitutions would include: Asp and Asn; Ser and Thr; Ser and Ala; Thr and Ala; Ala and Gly; Ile and Val; Val and Leu; Leu and lie; Leu and Met; Phe and Tyr; Tyr and Trp.
- conservative substitutions would include: Asp and Asn; Asp and Glu; Glu and Gin; Glu and Ala; Gly and Asn; Ala and Pro; Ala and Gly; Ala and Ser; Ala and Lys; Ser and Thr; Lys and Arg; Val and Leu; Leu and Ile; Ile and Val; Phe and Tyr.
- amino acid substitutions In determining amino acid substitutions, one may also consider the existence of intermolecular or intramolecular bonds, such as formation of ionic bonds (salt bridges) between positively charged residues (e.g., His, Arg, Lys) and negatively charged residues (e.g., Asp, Glu) or disulfide bonds between nearby cysteine residues.
- ionic bonds salt bridges
- positively charged residues e.g., His, Arg, Lys
- negatively charged residues e.g., Asp, Glu
- disulfide bonds between nearby cysteine residues.
- a targeting moiety of use may be an aptamer.
- Methods of constructing and determining the binding characteristics of aptamers are well known in the art. For example, such techniques are described in U.S. Patent Nos. 5,582,981, 5,595,877 and 5,637,459, the Examples section of each incorporated herein by reference. Methods for preparation and screening of aptamers that bind to particular targets of interest are well known, for example U.S. Pat. No. 5,475,096 and U.S. Pat. No. 5,270,163, the Examples section of each incorporated herein by reference.
- Aptamers may be prepared by any known method, including synthetic, recombinant, and purification methods, and may be used alone or in combination with other ligands specific for the same target. In general, a minimum of approximately 3 nucleotides, preferably at least 5 nucleotides, are necessary to effect specific binding. Aptamers of sequences shorter than 10 bases may be feasible, although aptamers of 10, 20, 30 or 40 nucleotides may be preferred.
- Aptamers may be isolated, sequenced, and/or amplified or synthesized as conventional DNA or RNA molecules.
- aptamers of interest may comprise modified oligomers. Any of the hydroxyl groups ordinarily present in aptamers may be replaced by phosphonate groups, phosphate groups, protected by a standard protecting group, or activated to prepare additional linkages to other nucleotides, or may be conjugated to solid supports.
- One or more phosphodiester linkages may be replaced by alternative linking groups, such as P(0)0 replaced by P(0)S, P(0)NR 2 , P(0)R, P(0)OR', CO, or CNR 2 , wherein R is H or alkyl (1-20C) and R' is alkyl (1-20C); in addition, this group may be attached to adjacent nucleotides through O or S. Not all linkages in an oligomer need to be identical.
- Affibodies are commercially available from Affibody AB (Solna, Sweden). Affibodies are small proteins that function as antibody mimetics and are of use in binding target molecules. Affibodies were developed by combinatorial engineering on an alpha helical protein scaffold (Nord et al., 1995, Protein Eng 8:601-8; Nord et al., 1997, Nat Biotechnol 15:772-77). The affibody design is based on a three helix bundle structure comprising the IgG binding domain of protein A (Nord et al., 1995; 1997). Affibodies with a wide range of binding affinities may be produced by
- the PGR amplified library was cloned into a phagemid vector for screening by phage display of the mutant proteins.
- the phage display library may be screened against any known antigen, using standard phage display screening techniques (e.g., Pasqualini and Ruoslahti, 1996, Nature 380:364-366; Pasqualini, 1999, Quart. J. Nucl. Med. 43:159-162), in order to identify one or more affibodies against the target antigen.
- Fynomers can also bind to target antigens with a similar affinity and specificity to antibodies.
- Fynomers are based on the human Fyn SH3 domain as a scaffold for assembly of binding molecules.
- the Fyn SH3 domain is a fully human, 63 amino acid protein that can be produced in bacteria with high yields.
- Fynomers may be linked together to yield a multispecific binding protein with affinities for two or more different antigen targets.
- Fynomers are commercially available from COVAGEN AG (Zurich, Switzerland).
- Bispecific antibodies are useful in a number of biomedical applications. For instance, a bispecific antibody with binding sites for a tumor cell surface antigen and for a T-cell surface receptor can direct the lysis of specific tumor cells by T cells. Bispecific antibodies recognizing gliomas and the CD3 epitope on T cells have been successfully used in treating brain tumors in human patients (Nitta, et al. Lancet. 1990; 355:368-371). In certain embodiments, the techniques and compositions for therapeutic agent conjugation disclosed herein may be used with bispecific or multispecific antibodies as the targeting moieties.
- Bispecific antibodies can be produced by the quadroma method, which involves the fusion of two different hybridomas, each producing a monoclonal antibody recognizing a different antigenic site (Milstein and Cuello, Nature, 1983; 305:537-540).
- bispecific antibodies uses heterobifunctional cross-linkers to chemically tether two different monoclonal antibodies (Staerz, et al. Nature. 1985; 314:628- 631; Perez, et al. Nature. 1985; 316:354-356). Bispecific antibodies can also be produced by reduction of each of two parental monoclonal antibodies to the respective half molecules, which are then mixed and allowed to reoxidize to obtain the hybrid structure (Staerz and Bevan. Proc Natl Acad Sci U S A. 1986; 83:1453-1457). Another alternative involves chemically cross- linking two or three separately purified Fab' fragments using appropriate linkers. (See, e.g., European Patent Application 0453082).
- Other methods include improving the efficiency of generating hybrid hybridomas by gene transfer of distinct selectable markers via retrovirus-derived shuttle vectors into respective parental hybridomas, which are fused subsequently (DeMonte, et al. Proc Natl Acad Sci U S A. 1990, 87:2941-2945); or transfection of a hybridoma cell line with expression plasmids containing the heavy and light chain genes of a different antibody.
- Cognate VH and V L domains can be joined with a peptide linker of appropriate composition and length (usually consisting of more than 12 amino acid residues) to form a single-chain Fv (scFv) with binding activity.
- a peptide linker of appropriate composition and length usually consisting of more than 12 amino acid residues
- Methods of manufacturing scFvs are disclosed in U.S. Pat. No. 4,946,778 and U.S. Pat. No. 5,132,405, the Examples section of each of which is incorporated herein by reference. Reduction of the peptide linker length to less than 12 amino acid residues prevents pairing of V H and V L domains on the same chain and forces pairing of VH and VL domains with complementary domains on other chains, resulting in the formation of functional multimers.
- Polypeptide chains of V H and V L domains that are joined with linkers between 3 and 12 amino acid residues form predominantly dimers (termed diabodies). With linkers between 0 and 2 amino acid residues, trimers (termed triabody) and tetramers (termed tetrabody) are favored, but the exact patterns of oligomerization appear to depend on the composition as well as the orientation of V-domains (VH-linker-VL or V L -linker-VH), in addition to the linker length.
- the technique utilizes complementary protein binding domains, referred to as anchoring domains (AD) and dimerization and docking domains (DDD), which bind to each other and allow the assembly of complex structures, ranging from dimers, trimers, tetramers, quintamers and hexamers. These form stable complexes in high yield without requirement for extensive purification.
- DNL technique allows the assembly of monospecific, bispecific or multispecific antibodies. Any of the techniques known in the art for making bispecific or multispecific antibodies may be utilized in the practice of the presently claimed methods.
- Bispecific or multispecific antibodies may be utilized in pre- targeting techniques.
- Pre- targeting is a multistep process originally developed to resolve the slow blood clearance of directly targeting antibodies, which contributes to undesirable toxicity to normal tissues such as bone marrow.
- a radionuclide or other therapeutic agent is attached to a small delivery molecule (targetable construct) that is cleared within minutes from the blood.
- a pre- targeting bispecific or multispecific antibody, which has binding sites for the targetable construct as well as a target antigen, is administered first, free antibody is allowed to clear from circulation and then the targetable construct is administered.
- a pre-targeting method of treating or diagnosing a disease or disorder in a subject may be provided by: (1) administering to the subject a bispecific antibody or antibody fragment; (2) optionally administering to the subject a clearing composition, and allowing the composition to clear the antibody from circulation; and (3) administering to the subject the targetable construct, containing one or more chelated or chemically bound therapeutic or diagnostic agents, such as interferon- ⁇ .
- targetable construct peptides labeled with one or more therapeutic or diagnostic agents for use in pre-targeting may be selected to bind to a bispecific antibody with one or more binding sites for a targetable construct peptide and one or more binding sites for a target antigen associated with a disease or condition.
- Bispecific antibodies may be used in a pretargeting technique wherein the antibody may be administered first to a subject. Sufficient time may be allowed for the bispecific antibody to bind to a target antigen and for unbound antibody to clear from circulation. Then a targetable construct, such as a labeled peptide, may be administered to the subject and allowed to bind to the bispecific antibody and localize at the diseased cell or tissue.
- targetable constructs can be of diverse structure and are selected not only for the availability of an antibody or fragment that binds with high affinity to the targetable construct, but also for rapid in vivo clearance when used within the pre-targeting method and bispecific antibodies (bsAb) or multispecific antibodies.
- Hydrophobic agents are best at eliciting strong immune responses, whereas hydrophilic agents are preferred for rapid in vivo clearance. Thus, a balance between hydrophobic and hydrophilic character is established. This may be
- sub-units of the targetable construct may be chosen which have opposite solution properties, for example, peptides, which contain amino acids, some of which are hydrophobic and some of which are hydrophilic.
- Peptides having as few as two amino acid residues, preferably two to ten residues, may be used and may also be coupled to other moieties, such as chelating agents.
- the linker should be a low molecular weight conjugate, preferably having a molecular weight of less than 50,000 daltons, and advantageously less than about 20,000 daltons, 10,000 daltons or 5,000 daltons.
- the targetable construct peptide will have four or more residues, such as the peptide DOTA-Phe-Lys(HSG)-Tyr-Lys(HSG)-NH 2 (SEQ ID NO:98), wherein DOTA is 1,4,7, 10-tetraazacyclododecanel,4,7,10-tetraacetic acid and HSG is the histamine succinyl glycyl group.
- DOTA may be replaced by NOTA (1,4,7-triaza-cyclononane- 1,4,7- tri acetic acid), TETA (p-bromoacetamido-benzyl-tetraethylaminetetraacetic acid), NETA ([2- (4,7-biscarboxymethyl[l,4,7]triazacyclononan-l-yl-ethyl]-2-carbonylmethyl-amino]acetic acid) or other known chelating moieties.
- Chelating moieties may be used, for example, to bind to a therapeutic and or diagnostic radionuclide, paramagnetic ion or contrast agent.
- the targetable construct may also comprise unnatural amino acids, e.g., D-amino acids, in the backbone structure to increase the stability of the peptide in vivo.
- unnatural amino acids e.g., D-amino acids
- other backbone structures such as those constructed from non-natural amino acids or peptoids may be used.
- the peptides used as targetable constructs are conveniently synthesized on an automated peptide synthesizer using a solid-phase support and standard techniques of repetitive orthogonal deprotection and coupling. Free amino groups in the peptide, that are to be used later for conjugation of chelating moieties or other agents, are advantageously blocked with standard protecting groups such as a Boc group, while N-terminal residues may be acetylated to increase serum stability.
- protecting groups are well known to the skilled artisan. See Greene and Wuts Protective Groups in Organic Synthesis, 1999 (John Wiley and Sons, N.Y.).
- the peptides are prepared for later use within the bispecific antibody system, they are advantageously cleaved from the resins to generate the corresponding C-terminal amides, in order to inhibit in vivo carboxypeptidase activity.
- Exemplary methods of peptide synthesis are disclosed in the Examples below.
- the antibody will contain a first binding site for an antigen produced by or associated with a target tissue and a second binding site for a hapten on the targetable construct.
- haptens include, but are not limited to, HSG and In-DTPA.
- Antibodies raised to the HSG hapten are known (e.g. 679 antibody) and can be easily incorporated into the appropriate bispecific antibody (see, e.g., U.S. Patent Nos.
- therapeutic agents such as cytotoxic agents, anti-angiogenic agents, pro-apoptotic agents, antibiotics, hormones, hormone antagonists, chemokines, drugs, prodrugs, toxins, enzymes or other agents may be used as adjunct therapies to the interferon- antibody DNLTM constructs described herein.
- Drugs of use may possess a pharmaceutical property selected from the group consisting of antimitotic, antikinase, alkylating, antimetabolite, antibiotic, alkaloid, anti-angiogenic, pro-apoptotic agents and combinations thereof.
- Exemplary drugs of use may include 5-fluorouracil, aplidin, azaribine, anastrozole, anthracyclines, bendamustine, bleomycin, bortezomib, bryostatin-1, busulfan, calicheamycin, camptothecin, carboplatin, 10-hydroxycamptothecin, carmustine, celebrex, chlorambucil, cisplatin (CDDP), Cox-2 inhibitors, irinotecan (CPT-11), SN-38, carboplatin, cladribine, clofarabine, cytosine arabinoside, camptothecans, cyclophosphamide, cytarabine, dacarbazine, docetaxel, dactinomycin, daunorubicin, doxorubicin, 2-pyrrolinodoxorubicine (2P-DOX), cyano- morpholino doxorubicin, doxorubicin
- Tyrosine kinase inhibitors of use may include LFM-A13, dasatinib, imatinib or nilotinib.
- Toxins of use may include ricin, abrin, alpha toxin, saporin, ribonuclease (RNase), e.g., onconase, DNase I, Staphylococcal enterotoxin-A, pokeweed antiviral protein, gelonin, diphtheria toxin, Pseudomonas exotoxin, and Pseudomonas endotoxin.
- RNase ribonuclease
- Chemokines of use may include RANTES, MCAF, MlPl-alpha, MIPl-Beta and IP-10.
- anti-angiogenic agents such as angiostatin, baculostatin, canstatin, maspin, anti-VEGF antibodies, anti-PlGF peptides and antibodies, anti-vascular growth factor antibodies, anti-Flk-1 antibodies, anti-Fit- 1 antibodies and peptides, anti-Kras antibodies, anti-cMET antibodies, anti-MIF (macrophage migration-inhibitory factor) antibodies, laminin peptides, fibronectin peptides, plasminogen activator inhibitors, tissue metalloproteinase inhibitors, interferons, interleukin-12, IP- 10, Gro- ⁇ , thrombospondin, 2-methoxyoestradiol, proliferin-related protein, carboxiamidotriazole, CM 101, Marimastat, pentosan poly sulphate, angiopoietin-2, interferon-alpha, herbimycin A, PNU145156E, 16 proliferin-related protein, carboxi
- oligonucleotides especially antisense oligonucleotides that preferably are directed against oncogenes and oncogene products, such as bcl-2 or p53.
- a preferred form of therapeutic oligonucleotide is siRNA.
- Diagnostic agents are preferably selected from the group consisting of a radionuclide, a radiological contrast agent, a paramagnetic ion, a metal, a fluorescent label, a chemiluminescent label, an ultrasound contrast agent and a photoactive agent. Such diagnostic agents are well known and any such known diagnostic agent may be used.
- Non-limiting examples of diagnostic agents may include a radionuclide such as 110 In, l u In, 177 Lu, 18 F, 19 F, 52 Fe, 62 Cu, 64 Cu, 67 Cu, 67 Ga, 68 Ga, 86 Y, 90 Y, 89 Zr, 94m Tc, 94 Tc, " m Tc, 120 1, 123 1, 1 4 1, 1 5 1, 131 1, 154 - 158 Gd, 32 P, U C, 13 N, 15 0, 186 Re, 188 Re, 51 Mn, 52m Mn, 55 Co, 7 As, 75 Br, 76 Br, 8 m Rb, 83 Sr, or other gamma-, beta-, or positron-emitters.
- a radionuclide such as 110 In, l u In, 177 Lu, 18 F, 19 F, 52 Fe, 62 Cu, 64 Cu, 67 Cu, 67 Ga, 68 Ga, 86 Y, 90 Y, 89 Zr, 94m
- Paramagnetic ions of use may include chromium (III), manganese (II), iron (III), iron (II), cobalt (II), nickel (II), copper (II), neodymium (III), samarium (III), ytterbium (III), gadolinium (III), vanadium (II), terbium (III), dysprosium (III), holmium (III) or erbium (III).
- Metal contrast agents may include lanthanum (III), gold (III), lead (II) or bismuth (III).
- Ultrasound contrast agents may comprise liposomes, such as gas filled liposomes.
- Radiopaque diagnostic agents may be selected from compounds, barium compounds, gallium compounds, and thallium compounds.
- fluorescent labels are known in the art, including but not limited to fluorescein isothiocyanate, rhodamine, phycoerytherin, phycocyanin,
- Chemiluminescent labels of use may include luminol, isoluminol, an aromatic acridinium ester, an imidazole, an acridinium salt or an oxalate ester.
- the DNLTM construct may be conjugated to one or more therapeutic or diagnostic agents.
- 13 l l can be incorporated into a tyrosine of a protein or peptide, or a drug attached to an epsilon amino group of a lysine residue.
- Therapeutic and diagnostic agents also can be attached, for example to reduced SH groups.
- Many methods for making covalent or non-covalent conjugates of therapeutic or diagnostic agents with proteins or peptides are known in the art and any such known method may be utilized.
- a therapeutic or diagnostic agent can be attached using a heterobifunctional cross-linker, such as N-succinyl 3-(2-pyridyldithio)propionate (SPDP). Yu et al, Int. J. Cancer 56: 244 (1994). General techniques for such conjugation are well-known in the art. See, for example, Wong, CHEMISTRY OF PROTEIN CONJUGATION AND CROSS-LINKING (CRC Press 1991); Upeslacis et al, "Modification of Antibodies by Chemical Methods," in
- MONOCLONAL ANTIBODIES PRINCIPLES AND APPLICATIONS, Birch et al (eds.), pages 187-230 (Wiley-Liss, Inc. 1995); Price, "Production and Characterization of Synthetic Peptide-Derived Antibodies," in MONOCLONAL ANTIBODIES: PRODUCTION,
- a chelating agent may be attached to a protein or peptide and used to chelate a therapeutic or diagnostic agent, such as a radionuclide.
- exemplary chelators include but are not limited to DTPA (such as Mx-DTPA), DOTA, TETA, NETA or NOTA.
- Methods of conjugation and use of chelating agents to attach metals or other ligands to proteins or peptides are well known in the art (see, e.g., U.S. Patent No. 7,563,433, the Examples section of which is incorporated herein by reference).
- Particularly useful metal-chelate combinations include 2- benzyl-DTPA and its monomethyl and cyclohexyl analogs, used with diagnostic isotopes in the general energy range of 60 to 4,000 keV, such as 125 I, 13I I, 123 1, 124 I, 62 Cu, 64 Cu, 18 F, n i In, 67 Ga, 68 Ga, 99m Tc, 94m Tc, n C, 13 N, 15 0 or 76 Br for radioimaging.
- the same chelates, when complexed with non-radioactive metals, such as manganese, iron and gadolinium are useful for MRI.
- Macrocyclic chelates such as NOTA, DOTA, and TETA are of use with a variety of metals and radiometals, most particularly with radionuclides of gallium, yttrium and copper, respectively. Such metal-chelate complexes can be made very stable by tailoring the ring size to the metal of interest.
- Other ring-type chelates such as macrocyclic polyethers, which are of interest for stably binding nuclides, such as 223 Ra for RAIT are encompassed.
- methods of F-labeling of use in PET scanning techniques have been disclosed, for example by reaction of F-18 with a metal or other atom, such as aluminum.
- the 1 8 F-A1 conjugate may be complexed with chelating groups, such as DOTA, NOTA or NETA that are attached directly to antibodies or used to label targetable constructs in pre-targeting methods.
- chelating groups such as DOTA, NOTA or NETA
- Such F-18 labeling techniques are disclosed in U.S. Patent No. 7,563,433.
- Various embodiments concern methods of treating a cancer in a subject, such as a mammal, including humans, domestic or companion pets, such as dogs and cats, comprising administering to the subject a therapeutically effective amount of a interferon-antibody DNLTM construct.
- the administration of interferon-antibody DNLTM construct can be supplemented by administering concurrently or sequentially a therapeutically effective amount of an antibody that binds to or is reactive with an antigen on the surface of the target cell.
- Preferred additional MAbs comprise at least one humanized, chimeric or human MAb selected from the group consisting of a MAb reactive with CD4, CD5, CD8, CD14, CD15, CD16, CD19, IGF-1 R, CD20, CD21, CD22, CD23, CD25, CD30, CD32b, CD33, CD37, CD38, CD40, CD40L, CD45, CD46, CD52, CD54, CD70, CD74, CD79a, CD80, CD95, CD126, CD133, CD138, CD154, CEACAM5, CEACAM6, B7, AFP, PSMA, EGP-1, EGP-2, carbonic anhydrase IX, PAM4 antigen, MUC1, MUC2, MUC3, MUC4, MUC5ac, la, MIF, HM1.24, HLA-DR, tenascin, Flt-3, VEGFR, P1GF, ILGF, IL-6, IL-25, tenascin, TRAIL-R1, TRAIL
- the interferon-antibody DNLTM construct therapy can be further supplemented with the administration, either concurrendy or sequentially, of at least one therapeutic agent.
- "CVB” 1.5 g/m 2 cyclophosphamide, 200-400 mg/m 2 etoposide, and 150-200 mg/m 2 carmustine
- CVB is a regimen used to treat non-Hodgkin's lymphoma. Patti et ai, Eur. J. Haematol. 5/: 18 (1993).
- Other suitable combination chemotherapeutic regimens are well-known to those of skill in the art.
- first generation chemotherapeutic regimens for treatment of intermediate-grade non-Hodgkin's lymphoma include C-MOPP (cyclophosphamide, vincristine, procarbazine and prednisone) and CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone).
- a useful second generation chemotherapeutic regimen is m- BACOD (methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, dexamethasone and leucovorin), while a suitable third generation regimen is MACOP-B (methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone, bleomycin and leucovorin).
- Additional useful drugs include phenyl butyrate, bendamustine, and bryostatin-1.
- the interferon-antibody DNLTM construct can be formulated according to known methods to prepare pharmaceutically useful compositions, whereby the interferon-antibody DNLTM construct is combined in a mixture with a pharmaceutically suitable excipient.
- a pharmaceutically suitable excipient Sterile phosphate- buffered saline is one example of a pharmaceutically suitable excipient.
- Other suitable excipients are well-known to those in the art. See, for example, Ansel et al,
- the interferon-antibody DNLTM construct can be formulated for intravenous
- interferon- antibody DNLTM construct is infused over a period of less than about 4 hours, and more preferably, over a period of less than about 3 hours.
- the first 25-50 mg could be infused within 30 minutes, preferably even 15 min, and the remainder infused over the next 2-3 hrs.
- Formulations for injection can be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
- the compositions can take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
- the active ingredient can be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen- free water, before use.
- Control release preparations can be prepared through the use of polymers to complex or adsorb the interferon-antibody DNLTM construct.
- biocompatible polymers include matrices of poly(ethylene-co- vinyl acetate) and matrices of a polyanhydride copolymer of a stearic acid dimer and sebacic acid. Sherwood et al, Bio/T chnology 10: 1446 (1992).
- the rate of release from such a matrix depends upon the molecular weight of the interferon-antibody DNLTM construct, the amount of interferon-antibody DNLTM construct within the matrix, and the size of dispersed particles. Saltzman et al, Biophys. J. 55: 163 (1989); Sherwood et al, supra. Other solid dosage forms are described in Ansel et al, PHARMACEUTICAL DOSAGE FORMS AND DRUG DELIVERY SYSTEMS, 5th Edition (Lea & Febiger 1990), and Gennaro (ed.), REMINGTON'S PHARMACEUTICAL SCIENCES, 18th Edition (Mack Publishing Company 1990), and revised editions thereof.
- the interferon-antibody DNLTM construct may also be administered to a mammal subcutaneously or even by other parenteral routes.
- the construct is infused over a period of less than about 4 hours, and more preferably, over a period of less than about 3 hours.
- the dosage of an administered interferon-antibody DNLTM construct for humans will vary depending upon such factors as the patient's age, weight, height, sex, general medical condition and previous medical history.
- the dosage may be 10 ⁇ g, 20 ⁇ ⁇ , 50 ⁇ g, 75 ⁇ 3 ⁇ 4 , 100 ⁇ & 150 ⁇ ⁇ , 200 ⁇ & 250 ⁇ & 300 ⁇ ⁇ , 400 ⁇ & 500 ⁇ ⁇ , 750 ⁇ ⁇ , 1 mg, 1.5 mg, 2 mg, 2.5 mg, 5 mg, 10 mg, 20 mg, 50 mg, 75 mg or 100 mg.
- the skilled artisan will realize that the dosage may be decreased or treatment terminated if signs of toxicity are observed.
- the dosage may be repeated as needed, for example, twice per week for 4-10 weeks, once per week for 4-10 weeks, once per week for 8 weeks, or once per week for 4 weeks. It may also be given less frequently, such as every other week for several months, or monthly or quarterly for many months, as needed in a maintenance therapy.
- a interferon- antibody DNLTM construct may be administered as one dosage every 2 or 3 weeks, repeated for a total of at least 3 dosages.
- the construct may be administered twice per week for 4-6 weeks.
- the dosing schedule can optionally be repeated at other intervals and dosage may be given through various parenteral routes, with appropriate adjustment of the dose and schedule.
- the interferon-antibody DNLTM constructs are of use for therapy of cancer.
- cancers include, but are not limited to, carcinoma, lymphoma, glioblastoma, melanoma, sarcoma, and leukemia, myeloma, or lymphoid malignancies.
- squamous cell cancer e.g., epithelial squamous cell cancer
- Ewing sarcoma e.g., Ewing sarcoma
- Wilms tumor astrocytomas
- lung cancer including small-cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung and squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer including gastrointestinal cancer, pancreatic cancer, glioblastoma multiforme, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, hepatocellular carcinoma, neuroendocrine tumors, medullary thyroid cancer, differentiated thyroid carcinoma, breast cancer, ovarian cancer, colon cancer, rectal cancer, endometrial cancer or uterine carcinoma, salivary gland carcinoma, kidney or renal cancer, prostate cancer, vulvar cancer, anal carcinoma, penile carcinoma, as well as head-and-neck cancer.
- cancer includes primary malignant cells or tumors (e.g., those whose cells have not migrated to sites in the subject's body other than the site of the original malignancy or tumor) and secondary malignant cells or tumors (e.g., those arising from metastasis, the migration of malignant cells or tumor cells to secondary sites that are different from the site of the original tumor).
- primary malignant cells or tumors e.g., those whose cells have not migrated to sites in the subject's body other than the site of the original malignancy or tumor
- secondary malignant cells or tumors e.g., those arising from metastasis, the migration of malignant cells or tumor cells to secondary sites that are different from the site of the original tumor.
- cancers or malignancies include, but are not limited to: Acute
- Lymphoblastic Leukemia Childhood Acute Myeloid Leukemia, Childhood Brain Stem Glioma, Childhood Cerebellar Astrocytoma, Childhood Cerebral Astrocytoma, Childhood Extracranial Germ Cell Tumors, Childhood Hodgkin's Disease, Childhood Hodgkin's Lymphoma, Childhood Hypothalamic and Visual Pathway Glioma, Childhood Lymphoblastic Leukemia, Childhood Medulloblastoma, Childhood Non-Hodgkin's Lymphoma, Childhood Pineal and Supratentorial Primitive Neuroectodermal Tumors, Childhood Primary Liver Cancer, Childhood
- Endometrial Cancer Ependymoma, Epithelial Cancer, Esophageal Cancer, Ewing's Sarcoma and Related Tumors, Exocrine Pancreatic Cancer, Extracranial Germ Cell Tumor, Extragonadal Germ Cell Tumor, Extrahepatic Bile Duct Cancer, Eye Cancer, Female Breast Cancer, Gaucher's Disease, Gallbladder Cancer, Gastric Cancer, Gastrointestinal Carcinoid Tumor, Gastrointestinal Tumors, Germ Cell Tumors, Gestational Trophoblastic Tumor, Hairy Cell Leukemia, Head and Neck Cancer, Hepatocellular Cancer, Hodgkin's Lymphoma, Hypergammaglobulinemia, Hypopharyngeal Cancer, Intestinal Cancers, Intraocular Melanoma, Islet Cell Carcinoma, Islet Cell Pancreatic Cancer, Kaposi's Sarcoma, Kidney Cancer, Laryngeal Cancer, Lip and Oral Cavity Cancer, Liver Cancer, Lung Cancer, Lymphoprolifer
- compositions described and claimed herein may be used to treat malignant or premalignant conditions and to prevent progression to a neoplastic or malignant state, including but not limited to those disorders described above.
- Such uses are indicated in conditions known or suspected of preceding progression to neoplasia or cancer, in particular, where non-neoplastic cell growth consisting of hyperplasia, metaplasia, or most particularly, dysplasia has occurred (for review of such abnormal growth conditions, see Robbins and Angell, Basic Pathology, 2d Ed., W. B. Saunders Co., Philadelphia, pp. 68-79 (1976)).
- Dysplasia is frequently a forerunner of cancer, and is found mainly in the epithelia. It is the most disorderly form of non-neoplastic cell growth, involving a loss in individual cell uniformity and in the architectural orientation of cells. Dysplasia characteristically occurs where there exists chronic irritation or inflammation.
- Dysplastic disorders which can be treated include, but are not limited to, anhidrotic ectodermal dysplasia, anterofacial dysplasia, asphyxiating thoracic dysplasia, atriodigital dysplasia, bronchopulmonary dysplasia, cerebral dysplasia, cervical dysplasia, ch ondroectodermal dysplasia, cleidocranial dysplasia, congenital ectodermal dysplasia, craniodiaphysial dysplasia, craniocarpo tarsal dysplasia, craniometaphysial dysplasia, dentin dysplasia, diaphysial dysplasia, ectodermal dysplasia, enamel dysplasia, encephalo- ophthalmic dysplasia, dysplasia epiphysialis hemimelia, dysplasia epiphysialis multiplex, dysplasia epiphysialis
- Additional pre-neoplastic disorders which can be treated include, but are not limited to, benign dysproliferative disorders (e.g., benign tumors, fibrocystic conditions, tissue hypertrophy, intestinal polyps or adenomas, and esophageal dysplasia), leukoplakia, keratoses, Bowen's disease, Farmer's Skin, solar cheilitis, and solar keratosis.
- benign dysproliferative disorders e.g., benign tumors, fibrocystic conditions, tissue hypertrophy, intestinal polyps or adenomas, and esophageal dysplasia
- leukoplakia keratoses
- Bowen's disease keratoses
- Farmer's Skin Farmer's Skin
- solar cheilitis solar keratosis
- the method of the invention is used to inhibit growth, progression, and/or metastasis of cancers, in particular those listed above.
- Additional hyperproliferative diseases, disorders, and/or conditions include, but are not limited to, progression, and/or metastases of malignancies and related disorders such as leukemia (including acute leukemias (e.g., acute lymphocytic leukemia, acute myelocytic leukemia (including myeloblastic, promyelocytic, myelomonocytic, monocytic, and erythroleukemia)) and chronic leukemias (e.g., chronic myelocytic (granulocytic) leukemia and chronic lymphocytic leukemia)), polycythemia vera, lymphomas (e.g., Hodgkin's disease and non-Hodgkin's disease), multiple myeloma, Waldenstrom's macroglobulinemia, heavy chain disease, and
- endotheliosarcoma lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilm's tumor, cervical cancer, testicular tumor, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma,
- medulloblastoma craniopharyngioma, ependymoma, pinealoma, emangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, and retinoblastoma.
- the PEGylated DNLTM complexes may be of use to treat subjects infected with pathogenic organisms, such as bacteria, viruses or fungi.
- pathogenic organisms such as bacteria, viruses or fungi.
- fungi include Microsporum, Trichophyton, Epidermophyton, Sporothrix schenckii, Cryptococcus neoformans, Coccidioides immitis, Histoplasma capsulatum, Blastomyces dermatitidis or Candida albicans.
- viruses include human immunodeficiency virus (HIV), herpes virus, cytomegalovirus, rabies virus, influenza virus, human papilloma virus, hepatitis B virus, hepatitis C virus, Sendai virus, feline leukemia virus, Reo virus, polio virus, human serum parvo-like virus, simian virus 40, respiratory syncytial virus, mouse mammary tumor virus, Varicella-Zoster virus, Dengue virus, rubella virus, measles virus, adenovirus, human T-cell leukemia viruses, Epstein-Barr virus, murine leukemia virus, mumps virus, vesicular stomatitis virus, Sindbis virus, lymphocytic choriomeningitis virus or blue tongue virus.
- HCV human immunodeficiency virus
- herpes virus cytomegalovirus
- rabies virus influenza virus
- human papilloma virus hepatitis B virus
- Exemplary bacteria include Bacillus anthracis, Streptococcus agalactiae, Legionella pneumophila, Streptococcus pyogenes, Escherichia coli, Neisseria gonorrhoeae, Neisseria meningitidis, Pneumococcus spp., Hemophilus influenzae B, Treponema pallidum, Lyme disease spirochetes, Pseudomonas aeruginosa, Mycobacterium leprae, Brucella abortus, Mycobacterium tuberculosis or a Mycoplasma.
- kits containing components suitable for treating diseased tissue in a patient.
- Exemplary kits may contain at least one or more interferon-antibody constructs as described herein.
- a device capable of delivering the kit components through some other route may be included.
- One type of device, for applications such as parenteral delivery, is a syringe that is used to inject the composition into the body of a subject. Inhalation devices may also be used.
- a therapeutic agent may be provided in the form of a prefilled syringe or autoinjection pen containing a sterile, liquid formulation or lyophilized preparation.
- the kit components may be packaged together or separated into two or more containers.
- the containers may be vials that contain sterile, lyophilized formulations of a composition that are suitable for reconstitution.
- a kit may also contain one or more buffers suitable for reconstitution and/or dilution of other reagents.
- Other containers that may be used include, but are not limited to, a pouch, tray, box, tube, or the like.
- Kit components may be packaged and maintained sterilely within the containers. Another component that can be included is instructions to a person using a kit for its use.
- the pdHL2 mammalian expression vector has been used for the expression of recombinant IgGs (Qu et al., Methods 2005, 36:84-95).
- a plasmid shuttle vector was produced to facilitate the conversion of any IgG-pdHL2 vector into a C H -AD2-IgG-pdHL2 vector.
- the gene for the Fc (CH_ and CH 3 domains) was amplified by PCR using the pdHL2 vector as a template and the following oligonucleotide primers: Fc BgUILeft
- the amplimer was cloned in the pGemT PCR cloning vector (Promega).
- the Fc insert fragment was excised from pGemT with Xba I and Bam HI and ligated with AD2-pdHL2 vector that was prepared by digesting h679-Fab-AD2-pdHL2 (Rossi et al., Proc Natl Acad Sci USA 2006, 103:6841-6) with Xba I and Bam HI, to generate the shuttle vector Fc-AD2-pdHL2.
- CH 3 -AD2-IgG- pdHL2 vectors (30 ⁇ g) were linearized by digestion with Sal I restriction endonuclease and transfected into Sp2/0-Agl4 (2.8 x 10 6 cells) by electroporation (450 volts, 25 ⁇ ).
- the pdHL2 vector contains the gene for dihydrofolate reductase allowing clonal selection as well as gene amplification with methotrexate (MTX).
- transgenic clones were selected in media containing 0.2 ⁇ MTX.
- Clones were screened for Cn3-AD2-IgG productivity by a sandwich ELISA using 96-well microtitre plates coated with specific anti-idiotype MAbs.
- Conditioned media from the putative clones were transferred to the micro-plate wells and detection of the fusion protein was accomplished with horseradish peroxidase-conjugated goat anti-human IgG F(ab') 2 (Jackson ImmunoResearch Laboratories, West Grove, PA). Wells giving the highest signal were expanded and ultimately used for production.
- roller bottle cultures were seeded at 2 x 10 5 cells/ml and incubated in a roller bottle incubator at 37°C under 5% C0 2 until the cell viability dropped below 25% (-10 days).
- Culture broth was clarified by centrifugation, filtered, and concentrated up to 50-fold by ultrafiltration.
- concentrated supernatant fluid was loaded onto a Protein-A (MAB Select) affinity column. The column was washed to baseline with PBS and the fusion proteins were eluted with 0.1 M Glycine, pH 2.5.
- the IgG and Fab fusion proteins shown in Table 6 were constructed and incorporated into DNL constructs.
- the fusion proteins retained the antigen-binding characteristics of the parent antibodies and the DNL constructs exhibited the antigen-binding activities of the incorporated antibodies or antibody fragments.
- the cDNA sequence for IFN-a2b was amplified by PCR resulting in sequences comprising the following features, in which Xbal and BamHI are restriction sites, the signal peptide is native to IFN-a2b, and 6 His is a hexahistidine tag: Xbal— Signal peptide— IFNcc2b - —6 His— BamHI (6 His disclosed as SEQ ID NO: 92).
- the resulting secreted protein consisted of IFN-oc2b fused at its C- terminus to a polypeptide of the following sequence:
- PCR amplification was accomplished using a full length human IFNa2b cDNA clone (Invitrogen Ultimate ORF human clone cat# HORFOl Clone ID IOH35221 ) as a template and the following oligonucleotides as primers:
- the PCR amplimer was cloned into the pGemT vector.
- a DDD2-pdHL2 mammalian expression vector was prepared for ligation with IFN-cc2b as follows.
- the C H i-DDD2-Fab-hMN- 14-pdHL2 (Rossi et al., Proc Natl Acad Sci USA 2006, 103:6841-6) vector was digested with Xba I and Bam HI, which removes all of the Fab gene sequences but leaves the DDD2 coding sequence.
- the IFN-oc2b amplimer was excised from pGemT with Xba I and Bam HI and ligated into the DDD2-pdHL2 vector to generate the expression vector IFN-a2b-DDD2-pdHL2.
- IFN-a2b-DDD2-pdHL2 was linearized by digestion with Sal I and stably transfected by electroporation into Sp/ESF myeloma cells (see U.S. Patent Application 11/877,728, the
- Clone 95-5 was expanded to 34 roller bottles containing a total of 20 L of serum-free Hybridoma SFM with 0.8 ⁇ MTX and allowed to reach terminal culture.
- the culture broth was processed and IFN- 2b-DDD2 was purified by immobilized metal affinity chromatography (IMAC) as follows.
- the supernatant fluid was clarified by centrifugation, 0.2 ⁇ filtered, diafiltered into IX Binding buffer (10 mM imidazole, 0.5 M NaCl, 50 mM NaH 2 P0 4 , pH 7.5), concentrated to 310 mL, added Tween 20 to a final concentration of 0.1%, and loaded onto a 30- mL Ni-NTA column.
- the column was washed with 500 mL of 0.02% Tween 20 in IX binding buffer and then 290 mL of 30 mM imidazole, 0.02% Tween 20, 0.5 M NaCl, 50 mM NaH 2 P0 4 , pH 7.5.
- the product was eluted with 1 10 mL of 250 mM imidazole, 0.02% Tween 20, 150 mM NaCl, 50 mM NaH 2 P0 4 , pH 7.5. Approximately 6 mg of IFNa2b- DDD2 was purified.
- IFN-a2b-DDD2 was also expressed by microbial fermentation as a soluble protein in E. coli.
- the coding sequence was amplified by PCR using IFN-a2b-DDD2-pdHL2 DNA as a template.
- the amplimer was cloned into the pET26b E. coli expression vector using Nde I and Xho I restriction sites. Protein was expressed intracellularly in BL21pLysS host cells by induction of LB shake flasks with 100 ⁇ IPTG at 18°C for 12 hours. Soluble IFN-cc2b-DDD2 was purified from cell lysates by IMAC as described above.
- Example 5 Generation of a DNL conjugate comprising four IFN-a2b-DDD2 moieties linked to C H 3-AD2-IgG
- a DNL complex comprising four IFN-cc2b-DDD2 moieties linked to C H3 -AD2-IgG
- FIG. 1 was made as follows. Briefly, a select C H 3-AD2-IgG was combined with approximately two mole-equivalents of IFN-oc2b-DDD2 and the mixture was reduced under mild conditions overnight at room temperature after adding 1 mM EDTA and 2 mM reduced glutathione (GSH). Oxidized glutathione was added to 2 mM and the mixture was held at room temperature for an additional 12-24 hours. The DNL conjugate was purified over a Protein A affinity column.
- IFN-cc2b-DDD2 each showed a major peak having a retention time consistent with a covalent complex composed of an IgG and 4 IFN-a2b groups (not shown). Similar SE-HPLC profiles were observed for the other three IFN-IgG conjugates.
- Example 6 In vitro activity of the IFN-IgG conjugates.
- the in vitro IFNa biological activity of 20-2b was compared to that of commercial PEGylated IFNa2 agents, PEGASYS and PEG-lntron, using cell-based reporter, viral protection, and lymphoma proliferation assays. Specific activities were determined using a cell-based kit, which utilizes a transgenic human pro-monocyte cell line carrying a reporter gene fused to an interferon- stimulated response element (FIG. 2A-2D). The specific activity of 20-2b (5300 IU/pmol) was greater than both PEGASYS (170 IU/pmol) and PEG-Intron (3400 IU/pmol) (FIG. 2A).
- EFNa2b can have a direct anti-proliferative or cytotoxic effect on some tumor lines.
- the activity of 20-2b was measured in an in vitro proliferation assay with a Burkitt lymphoma cell line (Daudi) that is highly sensitive to IFNa (FIG. 2C).
- Daudi Burkitt lymphoma cell line
- the parent anti-CD20 MAb of 20-2b has anti-proliferative activity in vitro on many lymphoma cell lines, including Daudi (Rossi et al., 2008, Cancer Res 68:8384-92), at considerably greater concentrations (EC 50 >10nM).
- the in vitro activity of 20-2b was also assessed using Jeko-1, which is a mantle cell lymphoma line that has lower sensitivity to both IFNa and anti-CD20 (FIG. 2D).
- Jeko-1 is only modestly sensitive to the parent anti-CD20 MAb, having 10% maximal inhibition (I max ) with an EC 50 near 1 nM.
- I max 1 nM
- I max 43%
- IFNa can potentiate ADCC activity, which is a fundamental mechanism of action (MOA) for anti-CD20 immunotherapy, by activating NK cells and macrophages.
- MOA fundamental mechanism of action
- PBMCs peripheral blood mononuclear cells
- CDC is thought to be an important MOA for Type-I anti-CD20 MAbs (including v-mab and rituximab). However, this function is lacking in the Type-II MAbs, represented by tositumomab (Cardarelli et al., 2002, Cancer Immunol Immunother 51 : 15-24), which nonetheless has anti-lymphoma activity. Unlike v-mab, 20- 2b does not show CDC activity in vitro (FIG. 4B).
- PK pharmacokinetic
- 20-2b were evaluated in male Swiss- Webster mice and compared to those of PEGASYS, PEG-INTRON and oc2b-413 (Pegylated JFN made by DNL, see U.S. Patent Application Serial No. 11/925,408).
- Concentrations of IFN-a in the serum samples at various times were determined by ELISA following the manufacturer's instructions. Briefly, the serum samples were diluted appropriately according to the human IFN-a standard provided in the kit. An antibody bound to the microtiter plate wells captures interferon.
- FIG. 3 presents the results of the PK analysis, which showed significantly slower elimination and longer serum residence of 20-2b compared to the other agents.
- 20-2b was stable in human sera (>10 days) or whole blood (>6 days) at 37°C (not shown). Concentration of 20- 2b complex was determined using a bispecific ELISA assay. There was essentially no detectable change in serum 20-2b levels in either whole blood or serum over the time period of the assay.
- the IFNa2b groups of 20-2b and 734-2b can act directly on tumor cells, augment the ADCC activity of v-mab, and possibly have some immunostimulatory effects.
- the full spectrum of IFNa- mediated activation of the innate and adaptive immune systems that might occur in vivo is not realized in this two-day ex vivo assay.
- a limitation of the mouse model is the very low sensitivity of murine cells to human IFNa2b.
- the overall therapeutic advantage of 20-2b that might be achieved in humans can involve the enhancement of both innate and adaptive immunity.
- v-mab (veltuzumab) or 734-2b at 0.7 pmol (170 ng) resulted in significant improvement in survival when compared to saline for v-mab (P ⁇ 0.0001), but not for the irrelevant MAb-IFNa control, 734-2b (FIG. 6A).
- MST median survival time
- At the highest dose tested (70 pmol) improved the MST to >105 days with 100% LTS (FIG. 6B).
- v-mab can increase survival of Daudi-bearing mice at relatively low doses (3.5 pmol) while higher doses result in LTS.
- MAb-IFNa made by chemical conjugation that revealed some of the potential clinical benefits of such constructs (Pelham et al., 1983, Cancer Immunol Immunother 15:210-16; Ozzello et al., 1998, Breast Cancer Res Treat 48:135-47).
- a recombinant MAb-IFNa comprising murine IFNa and an anti-HER2/neu MAb exhibited potent inhibition of a transgenic (HER2/neu) murine B- cell lymphoma in immunocompetent mice and was also capable of inducing a protective adaptive immune response with immunologic memory (Huang et al., 2007, J Immunol 179:6881 - 88).
- murine cells are exceedingly less sensitive ( ⁇ 4 logs) than human cells to human IFNa2b (Kramer et al., 1983, J Interferon Res 3:425-35; Week et al., 1981, J Gen Virol 57:233- 37). Therefore, very little, if any, of the anti-lymphoma activity of 20-2b in the mouse model in vivo studies described above can be attributed to IFNa2b activation of the mouse immune response. Rather, killing is due primarily to the direct action of IFNoc2b on the lymphoma cells.
- lymphoma models that are relatively insensitive to the direct action of IFNa (Raji/NAMALWA) or are resistant to anti-CD20 immunotherapy (NAMALWA), 20-2b showed superior efficacy to either v-mab or non-targeted MAb-IFNa.
- 20-2b showed activity at a 25-fold lower concentration compared to non-targeting MAb-IFNa, either alone or when combined with v-mab.
- the ex vivo setting allows the involvement of all three of the anti-CD20 MOA.
- 20-2b was more effective at depleting lymphoma from blood than IFNa or v-mab, either alone or in combination, demonstrating the significance of targeting.
- the influence of MAb targeting in the in vitro/ex vivo studies is somewhat surprising, because the MAbs, effector, and target cells are all confined throughout the experiments. We expect that 20-2b will have a substantially greater impact in vivo in human patients.
- the IFNa2b and v-mab components of 20-2b can apparently act additively or synergistically, to contribute to its enhanced potency.
- the in vitro proliferation assays suggest at least an additive effect, which was substantiated with the results of the ex vivo studies where the combination of v-mab and 734-2b was superior to either agent alone. This may be accomplished ex vivo via increased ADCC activity of v-mab as part of 20-2b or when combined with 734-2b, yet ADCC is not functional in the in vitro proliferation assays, suggesting additional
- the signal transduced by v-mab-bound CD20 may potentiate the IFNa signal, resulting in enhanced potency.
- the binding of v-mab which is a slowly internalizing MAb, may prevent the internalization/down-regulation of the Type-I IFN receptors, resulting in a more prolonged and effective IFNa-induced signal.
- Interferon lambda 1 is a type III interferon recently described as a member of the class II cytokine family, with therapeutic potential for antivirus and antitumor activity and immune system regulation.
- IFN- s like the type I IFNs, which comprise both IFN-a and IFN- ⁇ , trigger signal transduction via the JAK/STAT pathway, including the activation of JAK1 and TYK2 kinases, the phosphorylation of STAT proteins, and the activation of the transcription complex of IFN-stimulated gene factor 3 (Witte et al., 2010, Cytokine Growth Factor Rev 21:237-51; Zhou et al., 2007, J Virol 81 :7749-58).
- IFN- ⁇ / ⁇ signals through two widely expressed type I interferon receptors, which is at least partially responsible for the systemic toxicity associated with IFN- ⁇ / ⁇ therapy (Pestka, 2007, J Biol Chem 282:20047-51).
- IFN- s signal through a heterodimeric receptor complex comprising the IFN- ⁇ receptor 1 (IFN-AJRl) and the IL-10 receptor 2 (IL- 10R2).
- IFN- R 1 has a highly restricted expression pattern, with the highest levels in epithelial cells, melanocytes, and hepatocytes, and the lowest level in primary central nervous system cells (Wolk et al., 2005, Genes Immun 6:8-18). Although blood immune cells express IFN- R 1 , they exhibit impaired response to IFN- s due to the secretion of a short spliced variant of IFN- Rl that inhibits the effect of IFN- ⁇ (Witte et al., 2009, Genes Immun 10:702- 14). The limited responsiveness of neuronal cells and immune cells also contributes to the reduced toxicity of IFN-Xs, compared to type I IFN (Witte et al., 2009, Genes Immun 10:702-14).
- IFN- s display structural features similar to IL-10-related cytokines, but exhibit type I IFN-like antiviral and anti-proliferative activity (Witte et al, 2010, Cytokine Growth Factor Rev 21:237-51; Ank et al, 2006, J Virol 80:4501-9; Robek et al., 2005, J Virol 79:3851-54).
- IFN- ⁇ and IFN- 2 can reduce viral replication or the cytopathic effect of various viruses, including DNA viruses, such as hepatitis B virus (Robek et al., 2005, J Virol 79:3851-54; Doyle et al, 2006, Hepatology 44:896-906) and herpes simplex virus 2 (Ank et al., 2006, J Virol 80:4501-9); positive-sense, single-stranded RNA viruses, such as encephalomyocarditis virus (EMCV) (Sheppard et al., 2003, Nat Immunol 4:63-68) and hepatitis C virus (HCV) (Robek et al., 2005, J Virol 79:3851-54; Doyle et al, 2006, Hepatology 44:896-906); negative-sense, single-stranded RNA viruses, such as vesicular stomatitis virus (Kotenko e
- ⁇ - ⁇ 3 was identified from genetic, studies as a key cytokine in HCV infection (Ge et al., 2009, Nature 461 :399-401), and has the most potent activity against EMCV (Dellgren et al., 2009, Genes Immun 10:125-31).
- IFN- s The anti-proliferative activity of IFN- s has also been established in several human cancer cell lines, including neuroendocrine carcinoma BON1 (Zitzmann et al., 2006, BBRC 344:1334-41), glioblastoma LN319 (Meager et al., 2005, Cytokine 31:109-18), immortalized keratinocyte HaCaT (Maher et al., 2008, Cancer Biol Ther 7:1109-15), melanoma F01
- IFN- s induce tumor apoptosis and elimination through both innate and adaptive immune responses, suggesting that local delivery of IFN- ⁇ might be a useful strategy for the treatment of human malignancies (Numasaki et al., 2007, J Immunol 178:5086-98; Sato et al., 2006, J Immunol 176:7686-94).
- Fab-DDD2 modules derived from the humanized antibodies hRS7 (anti-Trop2), hMN15 (anti-CEACAM6), hL243 (anti-HLA-DR) or c225 (chimeric anti-EGFT), were dimerized and linked with AD2-IFN- 1 to produce the immunocytokines ( ⁇ )- ⁇ , (15)- ⁇ 1, (C2)-X1 and (c225)- ⁇ , respectively.
- the person of ordinary skill will realize that the invention is not limited to the exemplary antibodies, but could be performed with any known antibody.
- the bioactivities of the interferon-antibody constructs were evaluated and compared with recombinant human IFN- ⁇ (rhIFN- ⁇ ) in targeted and non-targeted cell lines.
- rhIFN- ⁇ recombinant human IFN- ⁇
- IFN- ⁇ -mediated growth suppression was remarkably enhanced by the hMN15 Fab dimer ( ⁇ 100-fold) in CEACAM6-positive ME-180 cells (EC 50 ⁇ 1 pM) and TE- 11 cells, but not in CEACAM6-negative SK-MES-1 cells.
- DNLTM complexes comprising targeting antibodies or antibody fragments attached to IFN- ⁇ can be exploited as therapeutic agents for treatment of cancer, infectious disease, asthma or multiple sclerosis.
- Antibodies and reagents - Humanized antibodies hA20-IgG (anti-CD20), hRS7-IgG (anti- Trop-2), hMN15-IgG (anti-CEACAM6) and hL243 (anti-HLA-DR) were from Immunomedics, Inc. Recombinant human IFN- ⁇ , mouse mAb against human IFN- ⁇ , and mouse FITC-IgGlk against human HLA-ABC were purchased from R&D Systems Inc. The amino acid sequences of fusion proteins comprising an AD2 moiety and poly-His sequence attached to mutant (C 17 IS) or wild-type IFNXl are shown below. Rabbit antibodies against STAT1, STAT3, pY-STATl and pY-STAT3 were purchased from Cell Signaling Technology Inc. STAT2 antibody was from Santa Cruz Biotechnology. pY-STAT2 antibody was from Millipore Corporation.
- IPTG IPTG was added to 0.5 mM and protein expression was induced at 30 °C for 4 hours.
- the cells were harvested by centrifugation and frozen at -80°C overnight.
- the pellets were thawed and homogenized in lysis buffer (2% Triton-X 100, 5mM MgS0 4 , 10 units/ml benzonase (Novagen), 100 ⁇ AEBSF, 20mM Tris-HCl, pH 8.0).
- the homogenate was centrifuged at 18,000 RPM for 30 minutes and the pellet was re-homogenized in PBS/1% Triton X-100 and then re-pelleted.
- the pellet was solubilized in 20 ml of 6 M guanidine-HCl, lOOmM Na- phosphate, pH 8.0 and loaded onto a His-Select affinity column (GE-Healthcare), which was subsequently washed with 6 M guanidine, 50 mM Na-phosphate, pH 8.0.
- the protein was eluted in 4 M guanidine-HCL 100 mM NaH 2 P04, pH 4.5, and neutralized by the addition of 200 ⁇ . of 3 M Tris-HCl, pH 8.6, DTE was added to 60 mM and the solution was held at room temperature overnight.
- the reduced, denatured protein solution was rapidly diluted into 0.5 M arginine, 20 mM oxidized glutathione, 2 mM EDTA; 100 mM Tris, pH 8.0, then dialyzed against 5 L of renaturation buffer (0.5 M arginine, 2 mM oxidized glutathione, 0.6 mM DTE, 2 mM EDTA, 20 mM Tris, pH 8.0) and held for 72 hrs at 4 °C.
- renaturation buffer 0.5 M arginine, 2 mM oxidized glutathione, 0.6 mM DTE, 2 mM EDTA, 20 mM Tris, pH 8.0
- the solution was then dialyzed against PBS-AG-2 buffer (35.2 mM Na 2 P0 4 .7H 2 0; 0.4 M NaCl; 6.5 mM NaH 2 P04.H 2 0; 150 mM arginine; 150 mM glutamic acid, pH 8.0).
- PBS-AG-2 buffer 35.2 mM Na 2 P0 4 .7H 2 0; 0.4 M NaCl; 6.5 mM NaH 2 P04.H 2 0; 150 mM arginine; 150 mM glutamic acid, pH 8.0).
- the final product was concentrated to about 0.5 mg/ml and analyzed by SDS-PAGE.
- DNLTM constructs - The (Fab) 2 -IFN- l conjugates, including ( ⁇ )- ⁇ , (15)- ⁇ 1, and (C2)- ⁇ , were generated by the fusion of hRS7-, hMN15-, or hL243- Fab-DDD2 modules with a AD2-IFN- 1 module to form a DNLTM complex (FIG. 8B), as described previously (see, e.g., U.S. Patent Nos.
- the c225-Fab-DDD2 module was constructed according to the sequences from DrugBank (Access number: DB00002). The products were purified sequentially on Kappa-select and His-select columns and analyzed with SDS-PAGE under reducing and nonreducing conditions using 4-20% Tris-glycine gels (not shown).
- FBS FBS
- HepG2, Huh-7, and SK-MES-1 cells were grown in EMEM media (ATCC) with 10% FBS.
- A549 was grown in F12 media (Invitrogen) with 10% FBS, and T.Tn was grown in DMEM/F12 media (Invitrogen) with 10% FBS. All cell lines were cultured in a humidified atmosphere of 5% C0 2 at 37 °C.
- mice were exposed to IFN- ⁇ agents for 3 days, and their surface MHC 1 was detected by binding with FITC labeled mouse IgGlk against human HLA-ABC.
- FITC labeled non-specific mouse IgGlk was used as negative control.
- Antiviral Assays The anti-HCV activities of IFN- ⁇ and 2(Fab) ⁇ l were measured by HD Biosciences (China) Co., Ltd (Shanghai, China), using a stable Huh-7 cell line containing HCV genotype lb Conl replicon, designated as Huh-7-Conl. A firefly luciferase gene was integrated into this replicon as a reporter of viral level. Three IFN- ⁇ agents, (c225)- l, (C2)- 1 , and rhIFN- ⁇ , were included in this assay.
- (c225)- l comprises two Fabs of chimeric mAb that specifically targets EGFR on Huh-7 cell surface, while (C2)-Xl and rhIFN- ⁇ were two non-targeting controls.
- Huh-7-Conl cells were treated with three agents for 3 days, and the viral replication level was determined by measuring luciferase activity. Meanwhile, the cytotoxicity of these agents was also evaluated on parental Huh-7 cells using CellTiter Glo kit (Promega).
- the antiviral activity of (15)- ⁇ 1 was measured on A549 cells with EMCV using the cytopathic effect inhibition assay, which was performed by PBL Interferon Source (Piscataway, NJ). Included in the assay were hMN-15-Fab-DDD2 as a negative control, rhIFN- ⁇ standard (PBL Interferon Source) as a positive control, and (C2)- 1 as a non-targeting control for structural counterpart.
- PhosphoSafeTM extraction reagent EMD
- Cell lysates were resolved on SDS-PAGE, transferred onto a nitrocellulose membrane (Bio-Rad), and then blotted with rabbit antibodies against total STAT1, STAT2, or STAT3 and the phosphotyrosine-specific antibodies pY- STAT1, pY-STAT2, or pY-STAT3, detected with HRP-goat anti-rabbit antibody.
- the ⁇ -actin antibody was used for loading control.
- RT-PCR analysis HepG2 cells were treated with IFN- ⁇ agents for 24 h and total RNA was isolated using TRIzol® Reagent (Life Technologies). The mRNA expression of the myxovirus resistance A (MxA) gene was analyzed using Superscript® III One-Step RT-PCR System (Life Technologies) with forward and reverse primers at conditions: cDNA synthesis- 55°C/30 min for one cycle and PCR-94°C/15 sec, 62°C/30 sec, 68°C/30sec for 25 cycles. A 452- bp fragment of the glyceraldehyde-3-phosphate dehydrogenase (GAPDH) cDNA was amplified at similar conditions as an internal control.
- GPDH glyceraldehyde-3-phosphate dehydrogenase
- AD2-IFN- 1 module recombinant form of AD2-IFN- 1 module was produced in E. coli and purified from inclusion bodies under denaturing conditions by immobilized metal ion affinity chromatography (IMAC).
- IMAC immobilized metal ion affinity chromatography
- the protein was reduced with dithiothreitol (DTE) and then refolded in a refolding buffer containing oxidized glutathione to allow the formation of disulfide bonds.
- DTE dithiothreitol
- SDS-PAGE not shown
- the AD2-IFN- 1 protein was highly purified and existed mainly in a monomelic state. The yield of final product was about 6mg/ml E. coli cell culture.
- the (Fab) 2 -IFN ⁇ 1 conjugate was generated by combining the ⁇ 2- ⁇ - ⁇ 1 module with the Fab-DDD2 module.
- the Fab-DDD2 module of hRS7, hMN15, or hL243 was mixed with an excess molar quantity of AD2-IFN- 1, and incubated overnight with 1 mmol/L of reduced glutathione before the addition of oxidized glutathione (2 mmol/L).
- the reaction mixtures were purified on a Kappa-select column, and four conjugates ( ⁇ )- ⁇ , (15)- ⁇ 1, (C2)- 1 and (c225)- l were successfully generated.
- (15)- ⁇ 1 exhibited activity 100-fold higher than AD2-IFN- 1 or the combination of AD2-IFN- 1 and hMNl 5-IgG-AD2.
- the EC 50 of (15)- ⁇ 1 on ME-180 was about 1 pM, which is 10-fold higher than ( ⁇ )- ⁇ .
- Antiviral activity The antiviral activity of selective 2(Fab)- l constructs was measured against HCV and EMCV in Huh-7 and A549 cells, respectively.
- MHC-I MHC class I antigens
- Recombinant IFN- ⁇ has a very rapid rate of clearance in mice, showing a mean residence time of only 0.7 h.
- 2(Fab)- l demonstrates a significantly improved PK that is comparable to PEG-IFN-a [37] and PEG-IFN- ⁇ (not shown).
- IFNs type III interferons
- DOCK-AND-LOCKTM complexes comprising antibody-conjugated IFN- ⁇ to improve the anti-proliferative potency of IFN- ⁇ up to 1,000-fold in targeted cancer cell lines by tethering stabilized Fab dimers, derived from hRS7 (humanized anti-Trop-2), hMN-15 (humanized anti-CEACAM6), hL243 (humanized anti-HLA- DR), and c225 (chimeric anti-EGFR), to IFN- ⁇ site-specifically, resulting in novel
- immunocytokines designated ( ⁇ )- ⁇ , (15)- ⁇ 1, (C2)- 1, and (c225)- l, respectively.
- Trop-2 and CEACAM6 are expressed at higher levels than the receptors for IFN- ⁇ on target cells (not shown). As a result, 10-fold more molecules of IFN- ⁇ can be bound to target cells with the DNL conjugates.
- the co-ligation of Trop-2 or CEACAM6 with the heterodimeric receptors of IFN- ⁇ may also increase the binding strength of IFN- ⁇ nearly 100-fold as shown for ( ⁇ )- ⁇ in ME-180.
- the targeted delivery of immunoconjugated IFN- ⁇ provides significantly greater bioactivity for both tumor and infectious disease therapy than separately administered antibody and interferon, either alone or in combination.
- IFN- s were less effective than type I IFNs against certain cancers (Meager et al., 2005, Cytokine 31:109-18) or viruses (Ank et al., 2006, J Interferon Cytokine Res 26:373-79).
- IFN- s were less effective than type I IFNs against certain cancers (Meager et al., 2005, Cytokine 31:109-18) or viruses (Ank et al., 2006, J Interferon Cytokine Res 26:373-79).
- IFN- -based immunocytokines each comprising IFN- ⁇ conjugated site- specifically to a stabilized dimer of Fab, and demonstrated their superiority compared to the unconjugated parental modules alone or in combination. The improved effects were shown in both antitumor and antiviral assays, and are consistent with enhanced cell-surface binding and signal transduction, which are enabled by the constitutive antibody.
- ⁇ - ⁇ also induce innate and adaptive immune responses, which were not evaluated here, and in view of recent studies showing that the constitutive expression of IFN- ⁇ in several murine cancer cell lines, including B16 melanoma, BNL hepatoma, and MCA205 fibrosarcoma, despite the lack of in vitro antiproliferative activity, markedly suppressed tumor growth and metastasis in syngeneic mouse models by recruiting immune cells and related cytokines (Numasaki et al., 2007, J Immunol 178:5086-98; Abushahba et al., 2010, Cancer Immunol Immunother 59:1059-71;
- rhIFN- ⁇ was 10-fold less potent than rhIFN-a in the Huh-7/HCV system, but it is 210-fold less potent in A549 EMCV (Meager et al., 2005, Cytokine 31 : 109-18).
- recombinant IFN As a therapeutic agent, recombinant IFN is limited by its very rapid rate of clearance. Based on our previous study, recombinant IFN-a-2b, PEG-IFN-a-2a, and PEG-IFN- ⁇ x-2b exhibited a half-life of 0.7, 14.9, and 9.3 h, respectively (Rossi et al., 2009, Blood 114:3864-71). Thus, a comparable half-life of ( ⁇ )- ⁇ in mice (8.6 h) to PEG-IFN-a is promising for in vivo therapeutic use.
- AD Alzheimer's disease
- ⁇ amyloid beta peptide
- APP beta amyloid precursor protein
- ⁇ appears to have a central role in the neuropathology of Alzheimer's disease. Familial forms of the disease have been linked to mutations in APP and the presenilin genes (Tanzi et al., 1996, Neurobiol. Dis. 3:159-168; Hardy, 1996, Ann. Med. 28:255-258). Diseased-linked mutations in these genes result in increased production of the 42-amino acid form of ⁇ , the predominant form found in amyloid plaques. Immunization of transgenic mice that overexpress a disease-linked mutant form of APP with human ⁇ reduces plaque burden and associated pathologies (Schenk et al., 1999, Nature 400:173-177; WO 99/27944). Peripheral administration of antibodies directed against ⁇ also reduces plaque burden in the brain (Bard et al., 2000, Nature Medicine 6(8):916-919; WO 2004/032868; WO 00/72880).
- Antibody therapy provides a promising approach to the treatment and prevention of Alzheimer's disease.
- human clinical trials with a vaccine including ⁇ 1-42 were suspended due to meningoencephalititis in a subset of patients.
- Passive immunization with an N-terminal specific anti- ⁇ antibody resulted in a significant reduction of diffuse amyloid, but increased cerebral microhemorrhage frequency in transgenic mice.
- Pfeifer et al. Science 298:1379 (2002).
- a DNLTM complex comprising alemtuzumab attached to interferon- ⁇ is prepared according to Example 9.
- the interferon-antibody complex is administered i.v. to human patients diagnosed with Alzheimer's disease at a dosage of 2 mg, twice weekly, for 4, 8 or 12 weeks.
- Efficacy is measured by neuropsychological testing, which includes the ADAS-cog and the CERAD neuropsychological test battery.
- ADAS-cog A slight (15%) improvement in ADAS-cog is observed after 12 weeks of treatment in all patients except the lowest dosage treatment group. Similar findings are observed for the Mini- Mental State Examination (MMSE). Visual construction abilities are improved in four out of ten patients. No serious adverse effects of interferon-antibody administration are observed.
- MMSE Mini- Mental State Examination
- a DNLTM complex comprising milatuzumab (anti-CD74 humanized IgG), or its Fab fragment attached to interferon- ⁇ is prepared according to Example 9.
- This complex is administered i.v. to a 75-year-old woman with early Alzheimer's disease at twice weekly doses of 2 mg for 8 weeks. Some evidence of minor nausea and hypotension is noted after each infusion, which abates over the next 3 days.
- Efficacy is measured by cognitive skills testing (ADAS-cog) and the CERAD neuropsychological battery, at baseline and at weeks 2 and 8 post- therapy. The results indicate a 20% improvement in cognitive skills and general psychological and communicative status. The treatment is repeated 4 months later, is well-tolerated, and the patient shows maintenance of the improvement of cognitive skills, including visual construction abilities.
- a DNLTM complex comprising hL243 (anti-HLA-DR humanized IgG), or its Fab fragment attached to interferon- ⁇ is prepared according to Example 9.
- This complex is administered i.v. to a 82-year-old woman with Alzheimer's disease at twice weekly doses of 1 mg for 8 weeks. Some evidence of minor nausea and hypotension is noted after each infusion, which abates over the next 3 days.
- Efficacy is measured by cognitive skills testing (ADAS-cog) and the CERAD neuropsychological battery, at baseline and at weeks 2 and 8 post-therapy. The results indicate a 17% improvement in cognitive skills and general psychological and communicative status. The treatment is repeated 4 months later, is well-tolerated, and the patient shows maintenance of the improvement of cognitive skills, including visual construction abilities.
- Asthma is a heterogeneous family of diseases, characterized by hyper-responsiveness of the tracheobronchi to stimuli.
- asthma is manifested by the extensive narrowing of the tracheobronchi, by thick tenacious secretions, by paroxysms of dyspnea, cough, and wheezing, resulting in an increase in airway resistance, hyperinflation of the lungs and thorax, abnormal distribution of ventilation and pulmonary blood flow.
- the disease is manifested in episodic periods of acute symptoms interspersed between symptom-free periods. The acute episodes result in hypoxia, and can be fatal. Approximately 3% of the general world population suffers from the disease.
- asthma may be treated with methylxanthines (such as theophylline), beta- adrenergic agonists (such as catecholamines, resorcinols, saligenins, and ephedrine),
- glucocorticoids such as hydrocortisone
- inhibitors of mast cell degranulation i.e. chromones such as cromolyn sodium
- anticholinergics such as stropine
- MS Multiple sclerosis
- autoreactive T cells cross the blood-brain barrier and attack the myelin sheath, leading to inflammation and resulting in demyelination and axonal degeneration.
- Unpredictable episodes of neurological disability in young adults are followed by the accumulation of physical and cognitive disabilities in either discrete attacks (relapsing forms) or gradually over time.
- interferon- ⁇ therapy is now the front-line treatment for relapsing remitting multiple sclerosis, with demonstrated efficacy in terms of decreased relapse rates.
- IFN therapy is associated with significant morbidity, with side effects such as influenza-like symptoms, myelosuppression, development or exacerbation of autoimmune disease, neutropenia, thrombocytopenia and neuropsychiatric effects.
- a DNLTM complex comprising alemtuzumab attached to interferon- ⁇ is prepared as disclosed in Example 9.
- the complex is administered at 2 mg every four weeks to a 64-year-old woman with relapsing multiple sclerosis (RMS). After 12 months of treatment, there is a decrease in annualized relapse rates and a reduced risk of sustained progression of disability observed with the complex. Compared to baseline measurements, significantly fewer gadolinium-enhancing lesions per Tl -weighted MRI scan are noted. Side effects include grade- 1/2 infusion reactions, grade 1 hypotension, and some hypersensitivity, all controlled well by corticosteroids.
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JP2014554843A JP6205621B2 (en) | 2012-01-26 | 2013-01-25 | Targeting with interferon lambda with antibodies greatly enhances antitumor and antiviral activity |
CA2861335A CA2861335A1 (en) | 2012-01-26 | 2013-01-25 | Targeting interferon-lambda with antibodies potently enhances anti-tumor and anti-viral activities |
CN201380004311.9A CN104159600B (en) | 2012-01-26 | 2013-01-25 | Effectively strengthen antitumor and antiviral activity with antibody target interferon lambda |
EP13741080.9A EP2806887A4 (en) | 2012-01-26 | 2013-01-25 | Targeting interferon-lambda with antibodies potently enhances anti-tumor and anti-viral activities |
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US13/412,816 US8435540B2 (en) | 2005-04-06 | 2012-03-06 | Dimeric alpha interferon PEGylated site-specifically shows enhanced and prolonged efficacy in VIVO |
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Also Published As
Publication number | Publication date |
---|---|
EP2806887A1 (en) | 2014-12-03 |
CN104159600B (en) | 2018-04-10 |
CN104159600A (en) | 2014-11-19 |
EP2806887A4 (en) | 2015-11-04 |
CA2861335A1 (en) | 2013-08-01 |
AU2013212000A1 (en) | 2014-07-24 |
JP2015511225A (en) | 2015-04-16 |
JP6205621B2 (en) | 2017-10-04 |
AU2013212000B2 (en) | 2017-03-30 |
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