WO2017087843A1 - Procédés de traitement de maladies prolifératives à l'aide de molécules de fusion d'anticorps et d'interféron obtenues par génie génétique - Google Patents

Procédés de traitement de maladies prolifératives à l'aide de molécules de fusion d'anticorps et d'interféron obtenues par génie génétique Download PDF

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Publication number
WO2017087843A1
WO2017087843A1 PCT/US2016/062845 US2016062845W WO2017087843A1 WO 2017087843 A1 WO2017087843 A1 WO 2017087843A1 US 2016062845 W US2016062845 W US 2016062845W WO 2017087843 A1 WO2017087843 A1 WO 2017087843A1
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nhl
cell
lymphoma
treatment
patient
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PCT/US2016/062845
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English (en)
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Michael Gresser
Kristopher STEWARD
Sanjay Khare
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Immungene, Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/52—Cytokines; Lymphokines; Interferons
    • C07K14/555—Interferons [IFN]
    • C07K14/56—IFN-alpha
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2887—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against CD20
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/54—Medicinal preparations containing antigens or antibodies characterised by the route of administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide

Definitions

  • Non-Hodgkin's lymphoma is a cancer of the lymphatic system and is the most commonly occurring hematologic malignancy in adults, representing 4.3% of all new cancer cases in the United States (US).
  • NDL Non-Hodgkin's lymphoma
  • US United States
  • NHL represents a diverse array of lymphoid malignancies derived from cell types within the B-cell and T-cell lineages, with B-cell subtypes comprising 85-90% of all NHL cases (Shankland et al, Lancet, 380(9884) :848-57, 2012).
  • the most common form of NHL is diffuse large B-cell lymphoma (DLBCL), representing approximately 30% of cases, and the second most common subtype is follicular lymphoma, corresponding to 25-30% of cases (Maloney, New Engl J Med, 366(21 ):2008-16, 2012).
  • DLBCL diffuse large B-cell lymphoma
  • follicular lymphoma corresponding to 25-30% of cases
  • first-line treatment for NHL typically includes chemotherapy, and such chemotherapy will often entail the administration of a "cocktail" of compounds, e.g., the formulation CHOP, which includes cyclophosphamide, doxorubicin, vincristine, and prednisone.
  • certain first-line NHL treatments may also include other forms of therapy, such as surgery, stem cell transplantation, radiation therapy, and immunotherapy-targeted drug therapy.
  • Mantle cell lymphoma another indolent form of NHL, is associated with a poor prognosis, and most patients relapse and develop refractory disease (Shankland et al, Lancet, 380(9884) :848-57, 2012; Skarbrink and Goy, Clin Adv Hematol Oncol., 13(1 ):44-55, 2015).
  • Interferon is an important cytokine which has multiple effects on the immune response (Theofilopoulos et al., Annu. Rev. Immunol., 23:307-336, 2005). Interferons include type 1 interferons (e.g., interferon-alpha (IFN-oc) and interferon-beta (IFN- ⁇ )) and type 2 interferons (e.g., interferon-gamma (IFN- ⁇ )). All type 1 IFNs are recognized by a shared receptor (IFN-ocR) composed of two transmembrane proteins, IFN-ocR1 and IFN-ocR2.
  • IFN-ocR shared receptor
  • IFN-a's are known to inhibit angiogenesis (Sidky YA and EC Borden, Cancer Res., 47:5155, 1987), mediate stimulation and differentiation of dendritic cells (Santini et al., J Exp Med, 191 :1777, 2000), and are important in in vivo proliferation, expansion and long-term survival of antigen specific CD8+ T cells (Tough DF et al., Science, 272:1947, 1996).
  • IFN-a's Although first described for their ability to inhibit viral replication, IFN-a's have multiple properties exhibiting anti-proliferative effects, induction of apoptosis (Rodriguez-Villanueva J and TJ McDonnell, Int J Cancer, 61 :1 10, 1995) and induction of the tumor suppressor gene, P53, in tumor cells (Takaoka A et al., Nature, 424:516, 2003).
  • IFN-a's were the first recombinant proteins used for the treatment of various cancers.
  • Human interferon-alpha 2b (hlFN-a2b) is a member of the Type I interferon family of cytokines that signal through a heterodimeric receptor complex and transduce signals through the Jak-STAT signaling pathway.
  • hlFN-a2b is a highly potent cytokine with the properties of an agonist, requiring very low picomolar (pM) concentrations for activity. Receptor binding results in activation of transcription factors and induction of expression of many
  • IFN-stimulated genes with antiviral, anti-proliferative and immunomodulatory properties have demonstrated efficacy as monotherapy against NHL (Horning et al, Cancer, 56:1305-10, 1985; Rohatiner et al., J Clin Oncol., 23:2215-23, 2005; Armitage et al., Bone Marrow Transplantation, 38:701 -2, 2006) and in combination with rituximab against NHL (Davis et al., Clinical Cancer Research, 6:2644-52, 2000; Kimby et al., Leuk Lymphoma, 49(1 ):102-1 12, 2008).
  • Immunotherapy is the name given to cancer treatments that use the immune system to attack cancers.
  • Systemic immunotherapy refers to immunotherapy that is used to treat the whole body and is more commonly used than local immunotherapy which is used to treat one "localized" part of the body, particularly when a cancer has spread.
  • cancer cells are less immunogenic than pathogens, the immune system is clearly capable of recognizing and eliminating tumor cells, and cancer immunotherapy attempts to harness the extraordinar power and specificity of the immune system for treatment of malignancy.
  • the challenge for immunotherapy is to use advances in cellular and molecular immunology to develop strategies which manipulate the local tumor environment to promote a pro-inflammatory environment, promote dendritic cell activation, and effectively and safely augment anti-tumor responses.
  • HERCEPTIN® anti-Her2/neu mAb
  • the present invention relates to methods of treating a proliferative disease, comprising administering to a patient an effective amount of a non-naturally occurring fusion molecule comprising a tumor-associated antigen antibody ("TAA Ab") attached to an interferon (IFN) molecule (hereinafter "TAA Ab-IFN fusion molecule”) wherein the TAA Ab-IFN fusion molecule is administered to the patient at a dosage of about 0.0001 mg/kg to about 0.9 mg/kg.
  • TAA Ab tumor-associated antigen antibody
  • IFN interferon
  • the TAA Ab-IFN fusion molecule is administered to the patient at a weekly dosage included in any of the following ranges: about 0.0001 to about 0.0003 mg/kg, about 0.0003 to about 0.001 mg/kg, about 0.001 to about 0.003 mg/kg, about 0.003 to about 0.01 mg/kg, about 0.01 to about 0.02 mg/kg, about 0.02 to about 0.03 mg/kg, about 0.03 to about 0.04 mg/kg, about 0.04 to about 0.05 mg/kg, about 0.05 to about 0.06 mg/kg, about 0.06 to about 0.07 mg/kg, about 0.07 to about 0.08 mg/kg, about 0.08 to about 0.09 mg/kg, about 0.09 to about 0.1 mg/kg, about 0.1 to about 0.2 mg/kg, about 0.2 to about 0.3 mg/kg, about 0.3 to about 0.4 mg/kg, about 0.4 to about 0.5 mg/kg, about 0.5 to about 0.6 mg/kg, about 0.6 to about 0.7 mg/kg, about 0.7 to
  • the TAA Ab-IFN fusion molecule is administered to the patient at a weekly dosage selected from the group consisting of .0001 mg/kg, .0003 mg/kg, .001 mg/kg, .003 mg/kg, .01 mg/kg, .02 mg/kg, .03 mg/kg, .04 mg/kg, .05 mg/kg, .06 mg/kg, .07 mg/kg, .08 mg/kg, .09 mg/kg, 0.1 mg/kg, 0.2 mg/kg, 0.3 mg/kg, 0.4 mg/kg, 0.5 mg/kg, 0.6 mg/kg, 0.7 mg/kg, 0.8 mg/kg, and 0.9 mg/kg.
  • the TAA Ab-IFN fusion molecule is administered to the patient at a weekly dosage of no greater than about any of: .0001 mg/kg, .0003 mg/kg, .001 mg/kg, .003 mg/kg, .01 mg/kg, .02 mg/kg, .03 mg/kg, .04 mg/kg, .05 mg/kg, .06 mg/kg, .07 mg/kg, .08 mg/kg, .09 mg/kg, 0.1 mg/kg, 0.2 mg/kg, 0.3 mg/kg, 0.4 mg/kg, 0.5 mg/kg, 0.6 mg/kg, 0.7 mg/kg, 0.8 mg/kg, and 0.9 mg/kg.
  • the proliferative disease is a cancer selected from the group consisting of a B cell lymphoma, a lung cancer, a bronchus cancer, a colorectal cancer, a prostate cancer, a breast cancer, a pancreas cancer, a stomach cancer, an ovarian cancer, a urinary bladder cancer, a peripheral nervous system cancer, an esophageal cancer, a cervical cancer, a melanoma, a uterine or endometrial cancer, a cancer of the oral cavity or pharynx, a liver cancer, a kidney cancer, a biliary tract cancer, a small bowel or appendix cancer, a salivary gland cancer, a thyroid gland cancer, a adrenal gland cancer, an osteosarcoma, a
  • a cancer selected from the group consisting of a B cell lymphoma, a lung cancer, a bronchus cancer, a colorectal cancer, a prostate cancer, a breast cancer, a pancreas
  • chondrosarcoma a liposarcoma, a testes cancer, and a malignant fibrous histiocytoma, a skin cancer, a head and neck cancer, lymphomas, sarcomas, multiple myeloma and leukemias.
  • a recurrent proliferative disease a recurrent proliferative disease
  • the patient has resistant or refractory cancer.
  • the cancer is refractory to immunotherapy treatment.
  • the cancer is refractory to treatment with a chemotherapeutic agent.
  • the cancer is refractory to targeted treatment with a tumor antigen-specific, depleting antibody.
  • the cancer is refractory to targeted treatment with an
  • the cancer is refractory to targeted treatment with a small molecule kinase inhibitor.
  • the cancer is refractory to combination therapy involving, for example, two or more of: immunotherapy treatment, treatment with a chemotherapeutic agent, treatment with a tumor antigen-specific, depleting antibody, treatment with a immunoconjugate, ADC, or fusion molecule comprising a TAA Ab and a cytotoxic agent, targeted treatment with a small molecule kinase inhibitor, treatment using surgery, treatment using stem cell transplantation, and treatment using radiation.
  • the fusion molecules comprise an antibody that binds to the tumor associated antigen with a dissociation constant (K D ) of at least about 1 x10 ⁇ 3 M, at least about 1 x10 4 M, at least about 1 x10 -5 M, at least about 1 x10 -6 M, at least about 1 x10 7 M, at least about 1 x10 8 M, at least about 1 x10 9 M, at least about 1 x10 10 M, at least about 1 x10 11 M, or at least about 1 x10 12 M.
  • K D dissociation constant
  • the fusion molecules comprise an antibody selected from a fully human antibody, a humanized antibody, a chimeric antibody, a monoclonal antibody, a polyclonal antibody, a recombinant antibody, an antigen-binding antibody fragment, a Fab, a Fab', a Fab 2 , a Fab' 2 , a IgG, a IgM, a IgA, a IgE, a scFv, a dsFv, a dAb, a nanobody, a unibody, or a diabody.
  • the antibody is a chimeric antibody.
  • the antibody is a humanized monoclonal antibody.
  • the antibody is a fully human monoclonal antibody.
  • the fusion molecule comprises a type 1 interferon molecule. In various embodiments, the fusion molecule comprises a type 1 interferon mutant molecule. In various embodiments, the fusion molecule comprises an interferon alpha (IFN- ) molecule. In various embodiments, the fusion molecule comprises a human IFN-a2b molecule having the amino acid sequence of SEQ ID NO: 9. [017] In various embodiments, the fusion molecules comprise an interferon molecule that is directly attached to the tumor associated antigen antibody.
  • the fusion molecules comprise an IFN molecule that is attached to the TAA Ab via a peptide linker.
  • the peptide linker is fewer than 20 amino acids in length.
  • the peptide linker has the sequence set forth in SEQ ID NO: 10.
  • the peptide linker has the sequence set forth in SEQ ID NO: 1 1 .
  • the peptide linker is a G/S rich linker.
  • the peptide linker is an a-helical linker.
  • the fusion molecule is a recombinantly expressed fusion molecule.
  • the present invention relates to methods of treating
  • CD20-positive Non-Hodgkin's lymphoma in a patient, comprising administering to a patient an effective amount of a non-naturally occurring anti-CD20 antibody (Ab)-IFN-a fusion molecule.
  • the fusion molecule comprises the chimeric lgG1 anti-CD20 antibody, rituximab, attached to human IFN-a2b molecules, optionally, via a peptide linker.
  • the antibody is an anti-CD20 antibody comprising a heavy chain having the amino acid sequence of SEQ ID NO: 1 and a light chain having the amino acid sequence of SEQ ID NO: 2.
  • the antibody is an anti-CD20 antibody comprising the heavy chain CDR1 of SEQ ID NO: 3, the heavy chain CDR2 of SEQ ID NO: 4, and the heavy chain CDR3 of SEQ ID NO: 5.
  • the anti-CD20 antibody further comprises the light chain CDR1 of SEQ ID NO: 6, the light chain CDR2 of SEQ ID NO: 7, and the light chain CDR3 of SEQ ID NO: 8.
  • the anti-CD20 antibody has a heavy chain having the amino acid sequence of SEQ ID NO: 1 and a light chain having the amino acid sequence of SEQ ID NO: 2, the human IFN-a2b has the amino acid sequence of SEQ ID NO: 9, and the peptide linker has the amino acid sequence of SEQ ID NO: 10 (this fusion molecule also referred to hereinafter as "IGN002").
  • the anti-CD20 antibody has a heavy chain having the amino acid sequence of SEQ ID NO: 1 and a light chain having the amino acid sequence of SEQ ID NO: 2, the human IFN-a2b has the amino acid sequence of SEQ ID NO: 9, and the peptide linker has the amino acid sequence of SEQ ID NO: 1 1 .
  • the anti-CD20 Ab-IFN fusion molecule is administered to the patient at a weekly dosage included in any of the following ranges: about 0.0001 to about 0.0003 mg/kg, about 0.0003 to about 0.001 mg/kg, about 0.001 to about 0.003 mg/kg, about 0.003 to about 0.01 mg/kg, about 0.01 to about 0.02 mg/kg, about 0.02 to about 0.03 mg/kg, about 0.03 to about 0.04 mg/kg, about 0.04 to about 0.05 mg/kg, about 0.05 to about 0.06 mg/kg, about 0.06 to about 0.07 mg/kg, about 0.07 to about 0.08 mg/kg, about 0.08 to about 0.09 mg/kg, about 0.09 to about 0.1 mg/kg, about 0.1 to about 0.2 mg/kg, about 0.2 to about 0.3 mg/kg, about 0.3 to about 0.4 mg/kg, about 0.4 to about 0.5 mg/kg, about 0.5 to about 0.6 mg/kg, about 0.6 to about 0.7 mg/
  • the TAA Ab-IFN fusion molecule is administered to the patient at a weekly dosage selected from the group consisting of .0001 mg/kg, .0003 mg/kg, .001 mg/kg, .003 mg/kg, .01 mg/kg, .02 mg/kg, .03 mg/kg, .04 mg/kg, .05 mg/kg, .06 mg/kg, .07 mg/kg, .08 mg/kg, .09 mg/kg, 0.1 mg/kg, 0.2 mg/kg, 0.3 mg/kg, 0.4 mg/kg, 0.5 mg/kg, 0.6 mg/kg, 0.7 mg/kg, 0.8 mg/kg, and 0.9 mg/kg.
  • the TAA Ab-IFN fusion molecule is administered to the patient at a weekly dosage of no greater than about any of: .0001 mg/kg, .0003 mg/kg, .001 mg/kg, .003 mg/kg, .01 mg/kg, .02 mg/kg, .03 mg/kg, .04 mg/kg, .05 mg/kg, .06 mg/kg, .07 mg/kg, .08 mg/kg, .09 mg/kg, 0.1 mg/kg, 0.2 mg/kg, 0.3 mg/kg, 0.4 mg/kg, 0.5 mg/kg, 0.6 mg/kg, 0.7 mg/kg, 0.8 mg/kg, and 0.9 mg/kg.
  • the patient has Stage 1 CD20-positive B-cell NHL. In various embodiments, the patient has Stage 2 CD20-positive B-cell NHL. In various embodiments, the patient has Stage 1 CD20-positive B-cell NHL.
  • the patient has Stage 3 CD20-positive B-cell NHL. In various embodiments, the patient has Stage 4 CD20-positive B-cell NHL.
  • the patient has a CD20-positive B-cell NHL selected from the group consisting of: front line low grade NHL, Stage lll/IV NHL, precursor B
  • lymphoblastic leukemia and/or lymphoma small lymphocytic lymphoma, B cell chronic lymphocytic leukemia and/or prolymphocytic leukemia and/or small lymphocytic lymphoma, B- cell prolymphocytic lymphoma, immunocytoma and/or lymphoplasmacytic lymphoma, lymphoplasmacytic lymphoma, marginal zone B cell lymphoma, splenic marginal zone lymphoma, extranodal marginal zone-MALT lymphoma, nodal marginal zone lymphoma, hairy cell leukemia, plasmacytoma and/or plasma cell myeloma, low grade/follicular lymphoma, intermediate grade/follicular NHL, mantle cell lymphoma, follicle center lymphoma (follicular), intermediate grade diffuse NHL, diffuse large B-cell lymphoma, aggressive NHL (including aggressive front-line NHL and aggressive relapsed NHL), primary mediastinal large B-cell
  • lymphoblastic NHL high grade small non-cleaved cell NHL, bulky disease NHL, Burkitt's lymphoma, precursor (peripheral) large granular lymphocytic leukemia, mycosis fungoides and/or Sezary syndrome, skin (cutaneous) lymphomas, anaplastic large cell lymphoma, and angiocentric lymphoma.
  • the patient has refractory CD20-positive B-cell NHL.
  • the NHL is refractory to immunotherapy treatment.
  • the CD20-positive B-cell NHL is refractory to treatment with a chemotherapeutic agent. In various embodiments, the CD20-positive B-cell NHL is refractory to targeted treatment with a tumor antigen-specific, depleting antibody. In various embodiments, the CD20-positive B- cell NHL is refractory to targeted treatment with an anti-CD20 antibody. In various embodiments,
  • the CD20-positive B-cell NHL is refractory to treatment with rituximab. In various embodiments, the CD20-positive B-cell NHL is refractory to targeted treatment with an immunoconjugate, ADC, or fusion molecule comprising an anti-CD20 antibody and a cytotoxic agent. In various embodiments, the CD20-positive B-cell NHL is refractory to targeted treatment with a small molecule kinase inhibitor.
  • the CD20-positive B-cell NHL is refractory to combination therapy involving, for example, two or more of: immunotherapy treatment, treatment with a chemotherapeutic agent, treatment with a tumor antigen-specific, depleting antibody, treatment with an anti-CD20 antibody, treatment with rituximab, treatment with an immunoconjugate, ADC, or fusion molecule comprising an anti-CD20 antibody and a cytotoxic agent, treatment with a small molecule inhibitor of a kinase, treatment using surgery, treatment using stem cell transplantation, and treatment using radiation.
  • immunotherapy treatment treatment with a chemotherapeutic agent
  • treatment with a tumor antigen-specific, depleting antibody treatment with an anti-CD20 antibody
  • treatment with rituximab treatment with an immunoconjugate, ADC, or fusion molecule comprising an anti-CD20 antibody and a cytotoxic agent
  • treatment with a small molecule inhibitor of a kinase treatment using surgery, treatment using stem cell transplantation, and treatment
  • a method of treating refractory NHL for example rituximab-refractory NHL, in a subject, comprising administering to the subject an effective amount of an anti-CD20-IFN-alpha fusion molecule, wherein the fusion molecule is administered to the patient at a dosage of about 0.001 to about 0.1 mg/kg, including for example, about 0.001 to about 0.002 mg/kg, about 0.002 to about 0.003 mg/kg, about 0.003 to about 0.004 mg/kg, about 0.004 to about 0.005 mg/kg, about 0.005 to about 0.006 mg/kg, about 0.006 to about 0.007 mg/kg, about 0.007 to about 0.008 mg.kg, about 0.008 to about 0.009 mg/kg, about 0.009 to about 0.01 mg/kg, about 0.01 to about 0.02 mg/kg, about 0.02 to about 0.03 mg/kg, about 0.03 to about 0.04 mg/kg, about 0.04
  • the anti-CD20-IFN-alpha fusion molecule is administered intravenously. In various embodiments, the anti-CD-20-IFN-alpha fusion molecule is administered weekly. In various embodiments, the NHL is CD20-positive B-cell NHL. In various embodiments, the fusion molecule is administered over a minimum of 1 hour at a maximum infusion rate of about 25 mg/hr.
  • the patient has recurrent CD20-positive B-cell NHL.
  • the methods comprise one or more additional therapies selected from the group consisting of immunotherapy, chemotherapy, targeted treatment with a tumor antigen-specific, depleting antibody, targeted treatment with an immunoconjugate, ADC, or fusion molecule comprising a TAA Ab and a cytotoxic agent, small molecule kinase inhibitor targeted therapy, surgery, radiation therapy, and stem cell transplantation.
  • additional therapies selected from the group consisting of immunotherapy, chemotherapy, targeted treatment with a tumor antigen-specific, depleting antibody, targeted treatment with an immunoconjugate, ADC, or fusion molecule comprising a TAA Ab and a cytotoxic agent, small molecule kinase inhibitor targeted therapy, surgery, radiation therapy, and stem cell transplantation.
  • the methods of the present invention provide a method of inhibiting cell proliferation (such as tumor growth) in a patient.
  • cell proliferation such as tumor growth
  • at least about 10% including for example at least about any of 20%, 30%, 40%, 60%, 70%, 80%, 90%, or 100%
  • cell proliferation is inhibited.
  • the methods of the present invention provide a method of reducing tumor size in a patient.
  • the tumor size is reduced by at least about 10% (including for example at least about any of 20%, 30%, 40%, 60%, 70%, 80%, 90%, or 100%).
  • the methods of the present invention provide a method of inhibiting tumor metastasis in a patient.
  • at least about 10% including for example at least about any of 20%, 30%, 40%, 60%, 70%, 80%, 90%, or 100%
  • tumor metastasis is inhibited.
  • the methods of the present invention provide a method for stabilizing disease progression of a proliferative disease in a patient.
  • the methods stabilize the disease by at least about 1 month (including for example at least about any of 6 months, 1 year, 2 years, 3 years, 4 years, 5 years, 10 years, 20 years, 30 years, 40 years, 50 years, or the normal life expectancy of the treated patient).
  • the methods of the present invention provide a method for slowing of disease progression of a proliferative disease in a patient.
  • the methods slow the disease progression by at least about 1 month (including for example at least about any of 6 months, 1 year, 2 years, 3 years, 4 years, 5 years, 10 years, 20 years, 30 years, 40 years, 50 years, or the normal life expectancy of the treated patient).
  • the methods of the present invention provide a method for improving the quality of life of a patient having a proliferative disease.
  • the quality of life of the patient is improved by reduced nausea, reduced fatigue, reduced joint stiffness, reduced pain, and reduced need for medications to address any such issue.
  • the methods improve the quality of life for a period of at least about 1 month (including for example at least about any of 6 months, 1 year, 2 years, 3 years, 4 years, 5 years, 10 years, 20 years, 30 years, 40 years, 50 years, or the normal life expectancy of the treated patient).
  • the methods of the present invention provide a method for prolonging the survival of a patient having a proliferative disease.
  • the methods may prolong survival by at least about 1 month (including for example at least about any of 6 months, 1 year, 2 years, 3 years, 4 years, 5 years, 10 years, 20 years, 30 years, 40 years, 50 years, or the normal life expectancy of the treated patient).
  • the present invention provides a pharmaceutical composition which comprises a TAA Ab-IFN fusion molecule as an active ingredient, in a pharmaceutically acceptable excipient or carrier.
  • the pharmaceutical composition is formulated for administration via a route selected from the group consisting of subcutaneous injection, intraperitoneal injection, intramuscular injection, intrasternal injection, intravenous injection, intraarterial injection, intrathecal injection, intraventricular injection, intraurethral injection, intracranial injection, intrasynovial injection or via infusions.
  • the pharmaceutical composition is formulated for intravenous infusion.
  • the present invention is based on the inventors' surprising finding that the TAA
  • Ab-IFN fusion molecules and methods described herein can be used to effectively treat cancers, including recurrent, resistant, or refractory cancers, at surprisingly low doses.
  • the TAA Ab-IFN fusion molecules and methods described herein appear to be optimal for leveraging IFN's multiple properties, thus providing for new effective therapies to treat patients with proliferative diseases, and in particular, patients with recurrent, resistant or refractory proliferative diseases.
  • TAA tumor associated antigen
  • the number of amino acid residues to be inserted, deleted, or substituted can be, for example, at least 1 , at least 2, at least 3, at least 4, at least 5, at least 10, at least 25, at least 50, at least 75, at least 100, at least 125, at least 150, at least 175, at least 200, at least 225, at least 250, at least 275, at least 300, at least 350, at least 400, at least 450 or at least 500 amino acids in length.
  • a "proliferative disease” includes tumor disease (including benign or cancerous) and/or any metastases.
  • a proliferative disease may include
  • hyperproliferative conditions such as hyperplasias, fibrosis (especially pulmonary, but also other types of fibrosis, such as renal fibrosis), angiogenesis, psoriasis, atherosclerosis and smooth muscle proliferation in the blood vessels, such as stenosis or restenosis following angioplasty.
  • the proliferative disease is cancer.
  • the proliferative disease is a non-cancerous disease.
  • the proliferative disease is a benign or malignant tumor.
  • beneficial or desired clinical results include, but are not limited to, any one or more of: alleviation of one or more symptoms; diminishment of extent of disease; preventing or delaying spread (e.g., metastasis, for example metastasis to the lung or to the lymph node) of disease; preventing or delaying recurrence of disease; stabilizing, delaying or slowing of disease progression; amelioration of the disease state; remission
  • treatment is a reduction of pathological consequence of a proliferative disease.
  • the methods of the invention contemplate any one or more of these aspects of treatment.
  • the term "immunotherapy” refers to cancer treatments which include, but are not limited to, treatment using agonistic, antagonistic, or blocking antibodies to co-stimulatory or co-inhibitory molecules (immune checkpoints) such as CTLA-4, PD-1 , OX-40, CD137, IDO, LAG 3, TIM-3, and VISTA, bispecific antibodies, bispecific T cell engaging antibodies such as blinatumomab, administration of cytokines such as IL-2, IL-12, IL-21 , GM- CSF and IFN-oc, cancer vaccines such as sipuleucel-T, dendritic cell vaccines, and tumor antigen peptide vaccines, chimeric antigen receptor (CAR)-T cells, CAR-NK cells, tumor infiltrating lymphocytes (TILs), adoptively transferred anti-tumor T cells (ex vivo expanded and/or TCR transgenic), and other immunostimulatory agents such as Toll-like receptor (IL), CAR checkpoints)
  • ⁇ ективное amount refers to an amount of a compound or composition sufficient to treat a specified disorder, condition or disease such as ameliorate, palliate, lessen, and/or delay one or more of its symptoms.
  • an effective amount comprises an amount sufficient to: (i) reduce the number of cancer cells; (ii) reduce tumor size; (iii) inhibit, retard, slow to some extent and preferably stop cancer cell infiltration into peripheral organs; (iv) inhibit (i.e., slow to some extent and preferably stop) tumor metastasis; (v) inhibit tumor growth; (vi) prevent or delay occurrence and/or recurrence of tumor; and/or (vii) relieve to some extent one or more of the symptoms associated with the cancer.
  • An effective amount can be administered in one or more administrations.
  • Adjuvant setting refers to a clinical setting in which an individual has had a history of a proliferative disease, particularly cancer, and generally (but not necessarily) been responsive to therapy, which includes, but is not limited to, surgery (such as surgical resection), radiotherapy, and chemotherapy. However, because of their history of the proliferative disease (such as cancer), these individuals are considered at risk of development of the disease.
  • Treatment or administration in the "adjuvant setting” refers to a subsequent mode of treatment.
  • the degree of risk i.e., when an individual in the adjuvant setting is considered as “high risk” or “low risk” depends upon several factors, most usually the extent of disease when first treated.
  • co-administration As used herein, the terms “co-administration”, “co-administered” and “in combination with”, referring to the fusion molecules of the invention and one or more other therapeutic agents, is intended to mean, and does refer to and include the following:
  • therapeutic protein refers to proteins, polypeptides, antibodies, peptides or fragments or variants thereof, having one or more therapeutic and/or biological activities.
  • Therapeutic proteins encompassed by the invention include but are not limited to, proteins, polypeptides, peptides, antibodies, and biologies (the terms peptides, proteins, and polypeptides are used interchangeably herein). It is specifically contemplated that the term “therapeutic protein” encompasses the fusion molecules of the present invention.
  • patient may be used interchangeably and refer to a mammal, preferably a human or a non-human primate, but also domesticated mammals ⁇ e.g., canine or feline), laboratory mammals ⁇ e.g., mouse, rat, rabbit, hamster, guinea pig), and agricultural mammals ⁇ e.g., equine, bovine, porcine, ovine).
  • domesticated mammals e.g., canine or feline
  • laboratory mammals e.g., mouse, rat, rabbit, hamster, guinea pig
  • agricultural mammals e.g., equine, bovine, porcine, ovine.
  • the patient can be a human ⁇ e.g., adult male, adult female, adolescent male, adolescent female, male child, female child) under the care of a physician or other health worker in a hospital, psychiatric care facility, as an outpatient, or other clinical context.
  • the patient may be an immunocompromised patient or a patient with a weakened immune system including, but not limited to patients having primary immune deficiency, AIDS; cancer and transplant patients who are taking certain immunosuppressive drugs; and those with inherited diseases that affect the immune system (e.g., congenital agammaglobulinemia, congenital IgA deficiency).
  • the patient has an immunogenic cancer, including, but not limited to bladder cancer, lung cancer, melanoma, and other cancers reported to have a high rate of mutations (Lawrence et al., Nature, 499(7457): 214-218, 2013).
  • an immunogenic cancer including, but not limited to bladder cancer, lung cancer, melanoma, and other cancers reported to have a high rate of mutations (Lawrence et al., Nature, 499(7457): 214-218, 2013).
  • “Pharmaceutical composition” refers to a composition suitable for pharmaceutical use in a human.
  • a pharmaceutical composition comprises a pharmacologically effective amount of an active agent and a pharmaceutically acceptable carrier.
  • “Pharmacologically effective amount” refers to that amount of an agent effective to produce the intended pharmacological result.
  • “Pharmaceutically acceptable carrier” refers to any of the standard pharmaceutical carriers, vehicles, buffers, and excipients, such as a phosphate buffered saline solution, 5% aqueous solution of dextrose, and emulsions, such as an oil/water or water/oil emulsion, and various types of wetting agents and/or adjuvants.
  • a "pharmaceutically acceptable salt” is a salt that can be formulated into a compound for pharmaceutical use including, e.g., metal salts (sodium, potassium,
  • administering refers to the actions taken by a medical professional ⁇ e.g., a physician), or a person controlling medical care of a patient, that control and/or permit the administration of the agent(s)/compound(s) at issue to the patient.
  • Causing to be administered can involve diagnosis and/or determination of an appropriate therapeutic regimen, and/or prescribing particular agent(s)/compounds for a patient.
  • Such prescribing can include, for example, drafting a prescription form, annotating a medical record, and the like. Where administration is described herein, "causing to be administered” is also contemplated.
  • Resistant or refractory cancer refers to tumor cells or cancer that do not respond to previous anti-cancer therapy including, e.g., chemotherapy, surgery, radiation therapy, stem cell transplantation, and immunotherapy.
  • Tumor cells can be resistant or refractory at the beginning of treatment, or they may become resistant or refractory during treatment.
  • Refractory tumor cells include tumors that do not respond at the onset of treatment or respond initially for a short period but fail to respond to treatment.
  • Refractory tumor cells also include tumors that respond to treatment with anticancer therapy but fail to respond to subsequent rounds of therapies.
  • refractory tumor cells also encompass tumors that appear to be inhibited by treatment with anticancer therapy but recur up to five years, sometimes up to ten years or longer after treatment is discontinued.
  • the anticancer therapy can employ chemotherapeutic agents alone, radiation alone, targeted therapy alone, surgery alone, or combinations thereof.
  • chemotherapeutic agents alone, radiation alone, targeted therapy alone, surgery alone, or combinations thereof.
  • the refractory tumor cells are interchangeable with resistant tumor cells.
  • engineered fusion molecules comprising at least one tumor antigen associated antibody, or antigen-binding fragment thereof, attached to at least one interferon, or interferon mutant molecule.
  • TAA Ab- IFN fusion molecules used in the methods of the present invention may comprise an antibody, or antigen binding antibody fragment, specific to any of the tumor associated antigens described in the art.
  • the TAA can be any peptide, polypeptide, protein, nucleic acid, lipid, carbohydrate, or small organic molecule, or any combination thereof, against which the skilled artisan wishes to induce an immune response.
  • Interferons which include type I interferons (e.g., IFN-a, IFN- ⁇ ) as well as type II interferons (e.g., IFN- ⁇ ) have been extensively described in the literature and are well known to one of ordinary skill in the art (see, e.g., Pestka, Immunological Reviews, 202(1 ):8-32, 2004).
  • FDA-approved interferons include, e.g., ROFERON®-A (Roche), INTRON® A (Schering), INFERGEN® (InterMune, Inc), AVONEX® (Biogen, Inc.), BETASERON® (Chiron Corporation) and REBIF® (EMD Serono and Pfizer).
  • the TAA Ab-IFN fusion molecules used in the methods of the present invention may comprise any such IFN described in the art, including any biosimilar, biogeneric, follow-on biologic, or follow-on protein version of a currently contemplated IFNs.
  • TAA Ab-IFN fusion molecules used in the methods of the present invention may comprise any such IFN mutant described in the art, including any biosimilar, biogeneric, follow-on biologic, or follow-on protein version of a currently contemplated mutant IFNs.
  • the TAA antibody-IFN fusion molecules comprise an interferon or a modified interferon that possesses, e.g., at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 100%, of the endogenous activity of the wild-type interferon having the same amino acid sequence but not attached to an antibody.
  • the TAA antibody-IFN fusion molecules will comprise an interferon or a modified interferon that possesses, e.g., less than 10%, less than 20%, less than 30%, less than 40%, less than 50%, less than 55%, less than 60%, less than 65%, less than 70%, less than 75%, less than 80%, less than 85%, less than 90%, less than 95%, less than 96%, less than 97%, less than 98%, less than 99%, less than 100%, of the endogenous activity of the wild-type interferon having the same amino acid sequence but not attached to an antibody.
  • an interferon or a modified interferon that possesses, e.g., less than 10%, less than 20%, less than 30%, less than 40%, less than 50%, less than 55%, less than 60%, less than 65%, less than 70%, less than 75%, less than 80%, less than 85%, less than 90%, less than 95%, less than 96%, less than 97%, less than 98%, less than 99%, less than 100%
  • the TAA antibody-IFN fusion molecules will comprise an interferon or a modified interferon that possesses, e.g., more than 5 times, more than 10 times, more than 15 times, more than 20 times, more than 25 times, more than 30 times, more than 35 times, more than 40 times, more than 50 times, more than 60 times, more than 70 times, more than 80 times, more than 90 times, more than 100 times, more than 125 times, more than 150 times, more than 175 times, more than 200 times, more than 250 times, more than 300 times, more than 400 times, more than 500 times, more than 750 times, and more than 1000 times, the endogenous activity of the wild-type interferon having the same amino acid sequence but not attached to an antibody.
  • an interferon or a modified interferon that possesses, e.g., more than 5 times, more than 10 times, more than 15 times, more than 20 times, more than 25 times, more than 30 times, more than 35 times, more than 40 times, more than 50 times, more than 60
  • the TAA antibody-IFN fusion molecules will show at least 10, at least 100, at least 1000, or at least 10,000-fold selectivity toward cells that express the TAA to which the antibody binds over cells that do not express the TAA, when compared to interferon having the same amino acid sequence not attached to an antibody.
  • TAA Ab-IFN fusion molecule can be joined together in any order.
  • the interferon molecule(s) can be joined to either the amino or carboxy terminal of the antibody.
  • the antibody can be joined to either the amino or carboxy terminal of the interferon molecule.
  • the antibody and interferon molecule are linked directly to each other without an intervening peptide linker sequence and synthesized using recombinant DNA methodology.
  • linked we mean that the first and second sequences are associated such that the second sequence is able to be transported by the first sequence to a target cell, i.e., fusion molecules in which the antibody is linked to a IFN- molecule via their polypeptide backbones through genetic expression of a DNA molecule encoding these proteins, directly synthesized proteins, and coupled proteins in which pre-formed sequences are associated by a cross-linking agent.
  • the antibody portion is chemically conjugated to the interferon molecule.
  • Means of chemically conjugating molecules are well known to those of skill. The procedure for conjugating two molecules varies according to the chemical structure of the agent. Polypeptides typically contain variety of functional groups; e.g., carboxylic acid (COOH) or free amine (-NH 2 ) groups, that are available for reaction with a suitable functional group on the other peptide, or on a linker to join the molecules thereto.
  • the antibody and/or the interferon can be derivatized to expose or attach additional reactive functional groups. The derivatization can involve attachment of any of a number of linker molecules such as those available from Pierce Chemical Company, Rockford III. A bifunctional linker having one functional group reactive with a group on the antibody and another group reactive on the interferon, can be used to form the desired conjugate.
  • derivatization can involve chemical treatment of the antibody portion.
  • Procedures for generation of, for example, free sulfhydryl groups on polypeptides, such as antibodies or antibody fragments, are known (See U.S. Pat. No. 4,659,839).
  • the two molecules can be separated by a peptide linker consisting of one or more amino acids.
  • the linker will have no specific biological activity other than to join the proteins or to preserve some minimum distance or other spatial relationship between them.
  • the constituent amino acids of the linker can be selected to influence some property of the molecule such as the folding, net charge, or hydrophobicity.
  • the fusion molecule is a recombinantly expressed fusion molecule and will comprise an interferon molecule attached to the antibody via a peptide linker.
  • Suitable linkers are well known to those of skill in the art and include, but are not limited to, straight or branched-chain carbon linkers, heterocyclic carbon linkers, or peptide linkers.
  • Linker length contemplated for use can vary from about 5 to 200 amino acids.
  • the linker may be a proteolysis-resistant linker of 1 to 20 amino acids in length (see, e.g., U.S. Pat. No. 8,258,263 (Morrison et al.), hereby incorporated by reference in its entirety for the proteolysis-resistant linkers and sequences provided therein).
  • the linker is rich in G/S content (e.g., at least about 60%, 70%, 80%, 90%, or more of the amino acids in the linker are G or S. In various embodiments, the linker is rich in G/C content and is less than about any of 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, or 30 amino acid long. In various embodiments, the linker is an a-helical linker and is less than about any of 7, 8, 9, 10, 15, 20, 25, or 30 amino acid long. In various embodiments, the linker comprises
  • the linker comprises
  • the preparation of the TAA Ab-IFN fusion molecules of the present invention can be generally described as follows: the heavy chain of the TAA Ab is recombinantly engineered with an interferon, or mutant thereof, at the carboxy-terminus using a peptide linker. After verifying that the fusion protein containing vector has the correct nucleotide sequence, it is transfected, along with the vector containing the light chain into, e.g., CHO cells. Transfectants are screened by ELISA for the production of the complete fusion molecule. The clone giving the highest signal is expanded and following sub-cloning is grown in roller bottles.
  • the fusion molecule of the present invention comprises an anti-CD20 antibody attached to human IFN-a molecules via a peptide linker.
  • anti- CD20 antibodies or antigen binding antibody fragments thereof, have been described in art and are well known to one of ordinary skill in the art including, but not limited to, rituximab, obinutuzumab, ibritumomab, tositumomab, ofatumumab, ocrelizumab, and veltuzumab, or antibody fragments thereof.
  • the TAA Ab-IFN fusion molecules used in the methods of the present invention may comprise any such anti-CD20 Ab described in the art.
  • the TAA Ab-IFN fusion molecule comprises the chimeric lgG1 anti-CD20 antibody, rituximab, attached to human IFN-a2b molecules via a peptide linker, wherein the anti-CD20 antibody comprises a heavy chain having the amino acid sequence set forth in SEQ ID NO: 1 :
  • the human IFN-a2b molecule has the amino acid sequence set forth in SEQ ID NO: 9:
  • IGN002 selectively bound to CD20-positive cells and exhibited potent anti-proliferative activity in vitro against CD20-positive NHL cell lines (EC 5 o values of 0.1 -2.1 pM) relative to each of the fusion partners alone. IGN002 also demonstrated enhanced cytokine-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC) activity against NHL cells, compared to rituximab, and exhibited potent pro- apoptotic activity against NHL cell lines (EC 5 o values of 1 .9 pM - 2.7 nM).
  • CDC cytokine-dependent cytotoxicity
  • ADCC antibody-dependent cell-mediated cytotoxicity
  • antiviral activity was reduced by 270-fold for IGN002, compared to non-fused IFN-a, suggesting the potential for a higher therapeutic index for IGN002 due to attenuation of systemic adverse effects (AEs) compared to molar equivalent levels of non-fused IFNa.
  • AEs systemic adverse effects
  • IGN002 treatment of OCI-Ly19 DLBCL xenograft tumor-bearing mice resulted in significantly longer survival than rituximab treatment (median survival of 96.5 versus 58 days, respectively, p ⁇ 0.0001 ).
  • the importance of CD20-targeted delivery of IFN-a was also demonstrated, as IGN002 treatment exhibited superior anti-tumor activity with a more pronounced delay in OCI- Ly19 tumor progression and a significantly longer median survival of 96.5 days, compared to 59 days for a non-targeted control mAb-IFN-a fusion molecule at the same dose (p ⁇ 0.0001 ).
  • This body of evidence supports the effect of IGN002 in patients with CD20- positive B-cell NHL, and more specifically, in patients with refractory CD20-positive B-cell NHL.
  • the fusion molecules provided herein can be formulated by a variety of methods apparent to those of skill in the art of pharmaceutical formulation. Such methods may be found, for example, in Remington's Pharmaceutical Sciences, 19th Edition (Mack Publishing Company, 1995).
  • the pharmaceutical compositions are generally formulated as sterile, substantially isotonic and in full compliance with all GMP regulations of the U.S. Food and Drug
  • fusion molecules of the invention are suitable to be administered as a formulation in association with one or more pharmaceutically acceptable excipient(s), or carriers.
  • pharmaceutically acceptable excipients and carriers are well known and understood by those of ordinary skill and have been extensively described (see, e.g., Remington's Pharmaceutical Sciences, 18th Edition, A. R. Gennaro, ed., Mack Publishing Company, 1990).
  • the pharmaceutically acceptable carriers may be included for purposes of modifying, maintaining or preserving, for example, the pH, osmolarity, viscosity, clarity, color, isotonicity, odor, sterility, stability, rate of dissolution or release, adsorption or penetration of the composition.
  • Suitable pharmaceutically acceptable carriers include, but are not limited to, amino acids (such as glycine, glutamine, asparagine, arginine or lysine); antimicrobials; antioxidants (such as ascorbic acid, sodium sulfite or sodium hydrogen-sulfite); buffers (such as borate, bicarbonate, Tris-HCI, citrates, phosphates, other organic acids); bulking agents (such as mannitol or glycine), chelating agents (such as ethylenediamine tetraacetic acid (EDTA)); complexing agents (such as caffeine, polyvinylpyrrolidone, beta-cyclodextrin or hydroxypropyl-beta-cyclodextrin); fillers;
  • amino acids such as glycine, glutamine, asparagine, arginine or lysine
  • antimicrobials such as ascorbic acid, sodium sulfite or sodium hydrogen-sulfite
  • buffers such as borate
  • the primary vehicle or carrier in a pharmaceutical composition may be either aqueous or non-aqueous in nature.
  • a suitable vehicle or carrier may be water for injection, physiological saline solution or artificial cerebrospinal fluid, possibly supplemented with other materials common in compositions for parenteral administration.
  • Neutral buffered saline or saline mixed with serum albumin are further exemplary vehicles.
  • Other exemplary pharmaceutical compositions comprise Tris buffer of about pH 7.0-8.5, or acetate buffer of about pH 4.0-5.5, which may further include sorbitol or a suitable substitute thereof.
  • compositions may be prepared for storage by mixing the selected composition having the desired degree of purity with optional formulation agents (Remington's Pharmaceutical Sciences, supra) in the form of a lyophilized cake or an aqueous solution. Further, the therapeutic composition may be formulated as a lyophilizate using appropriate excipients such as sucrose.
  • the optimal pharmaceutical composition will be determined by one of ordinary skill in the art depending upon, for example, the intended route of administration, delivery format, and desired dosage.
  • parenteral administration of a pharmaceutical composition includes any route of administration characterized by physical breaching of a tissue of a patient and administration of the pharmaceutical composition through the breach in the tissue, thus generally resulting in the direct administration into the blood stream, into muscle, or into an internal organ. Parenteral administration thus includes, but is not limited to,
  • the pharmaceutical composition is formulated for parenteral administration via a route selected from, e.g., subcutaneous injection, intraperitoneal injection, intramuscular injection, intrasternal injection, intravenous injection, intraarterial injection, intrathecal injection, intraventricular injection, intraurethral injection, intracranial injection, intrasynovial injection or via infusions.
  • the therapeutic pharmaceutical compositions may be in the form of a pyrogen-free, parenterally acceptable aqueous solution comprising the desired fusion molecule in a pharmaceutically acceptable vehicle.
  • a particularly suitable vehicle for parenteral injection is sterile distilled water in which a polypeptide is formulated as a sterile, isotonic solution, properly preserved.
  • pharmaceutical formulations suitable for injectable administration may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hanks' solution, Ringer's solution, or physiologically buffered saline.
  • Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Optionally, the suspension may also contain suitable stabilizers or agents to increase the solubility of the compounds and allow for the preparation of highly concentrated solutions. Injectable formulations may be prepared, packaged, or sold in unit dosage form, such as in ampoules or in multi-dose containers containing a preservative. Other parentally-administrable formulations which are useful include those which comprise the active ingredient in microcrystalline form, or in a liposomal preparation. Formulations for parenteral administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • the IGN002 of the present invention is supplied as a liquid in single-use, sterile vials and each vial contains a 3.1 mL fill of 10 mg/mL IGN002 formulated with 25 mM sodium phosphate, 150 mM sodium chloride, 0.1 M sucrose at pH 7.4.
  • IGN002 will be admixed with polysorbate 80 to a final concentration of 0.01 % polysorbate 80.
  • the methods of the present invention are useful in treating certain cellular proliferative diseases.
  • diseases include, but are not limited to, the following: a) proliferative diseases of the breast, which include, but are not limited to, invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma, lobular carcinoma in situ and metastatic breast cancer; b) proliferative diseases of lymphocytic cells, which include, but are not limited to, various T cell and B cell lymphomas, non-Hodgkins lymphoma, cutaneous T cell lymphoma, Hodgkins disease, and lymphoma of the central nervous system; (c) multiple myeloma, chronic neutrophilic leukemia, chronic eosinophilic leukemia/hypereosinophilic syndrome, chronic idiopathic myelofibrosis, polycythemia vera, essential thrombocythemia, chronic
  • myelomonocytic leukemia myelomonocytic leukemia, atypical chronic myelogenous leukemia, juvenile myelomonocytic leukemia, refractory anemia with ringed sideroblasts and without ringed sideroblasts, refractory cytopenia (myelodysplastic syndrome) with multilineage dysplasia, refractory anemia
  • myelodysplastic syndrome with excess blasts, 5q-syndrome, myelodysplastic syndrome with t(9;12)(q22;p12), and myelogenous leukemia (e.g., Philadelphia chromosome positive
  • proliferative diseases of the skin which include, but are not limited to, basal cell carcinoma, squamous cell carcinoma, malignant melanoma and Kaposi's sarcoma; e) leukemias, which include, but are not limited to, acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, and hairy cell leukemia, f) proliferative diseases of the digestive tract, which include, but are not limited to, anal, colon, colorectal, esophageal, gallbladder, stomach (gastric), pancreatic cancer, pancreatic cancer-Islet cell, rectal, small-intestine and salivary gland cancers; g) proliferative diseases of the liver, which include, but are not limited to, hepatocellular carcinoma, cholangiocarcinoma, mixed hepatocellular chol
  • proliferative diseases of the eye which include, but are not limited to, intraocular melanoma, retinoblastoma, and rhabdomyosarcoma
  • proliferative diseases of the head and neck which include, but are not limited to, laryngeal, hypopharyngeal,
  • nasopharyngeal, oropharyngeal cancers, and lip and oral cancer squamous neck cancer, metastatic paranasal sinus cancer
  • proliferative diseases of the thyroid include, but are not limited to, thyroid cancer, thymoma, malignant thymoma, medullary thyroid carcinomas, papillary thyroid carcinomas, multiple endocrine neoplasia type 2A (MEN2A),
  • pheochromocytoma parathyroid adenomas, multiple endocrine neoplasia type 2B (MEN2B), familial medullary thyroid carcinoma (FMTC) and carcinoids
  • o) proliferative diseases of the urinary tract which include, but are not limited to, bladder cancer
  • sarcomas which include, but are not limited to, sarcoma of the soft tissue, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma
  • q) proliferative diseases of the kidneys which include, but are not limited to, renal cell carcinoma, clear cell carcinoma of the kidney; and renal cell adenocarcinoma
  • r) precursor B-lymphoblastic leukemia/lymphoma precursor B-cell acute lymphoblastic leukemia), B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma
  • the methods of the present invention provide a method of inhibiting cell proliferation (such as tumor growth) in a patient.
  • cell proliferation such as tumor growth
  • at least about 10% including for example at least about any of 20%, 30%, 40%, 60%, 70%, 80%, 90%, or 100%
  • cell proliferation is inhibited.
  • the methods of the present invention provide a method of reducing tumor size in a patient.
  • the tumor size is reduced by at least about 10% (including for example at least about any of 20%, 30%, 40%, 60%, 70%, 80%, 90%, or 100%).
  • the methods of the present invention provide a method of inhibiting tumor metastasis in a patient.
  • at least about 10% including for example at least about any of 20%, 30%, 40%, 60%, 70%, 80%, 90%, or 100%
  • tumor metastasis is inhibited.
  • the methods of the present invention provide a method for stabilizing disease progression of a proliferative disease in a patient.
  • the methods stabilize the disease by at least about 1 month (including for example at least about any of 6 months, 1 year, 2 years, 3 years, 4 years, 5 years, 10 years, 20 years, 30 years, 40 years, 50 years, or the normal life expectancy of the treated patient).
  • the methods of the present invention provide a method for slowing of disease progression of a proliferative disease in a patient.
  • the methods slow the disease progression by at least about 1 month (including for example at least about any of 6 months, 1 year, 2 years, 3 years, 4 years, 5 years, 10 years, 20 years, 30 years, 40 years, 50 years, or the normal life expectancy of the treated patient).
  • the methods of the present invention provide a method for improving the quality of life of a patient having a proliferative disease.
  • the quality of life of the patient is improved by reduced nausea, reduced fatigue, reduced joint stiffness, reduced pain, and reduced need for medications to address any such issue.
  • the methods improve the quality of life for a period of at least about 1 month (including for example at least about any of 6 months, 1 year, 2 years, 3 years, 4 years, 5 years, 10 years, 20 years, 30 years, 40 years, 50 years, or the normal life expectancy of the treated patient).
  • the methods of the present invention provide a method for prolonging the survival of a patient having a proliferative disease.
  • the methods may prolong survival by at least about 1 month (including for example at least about any of 6 months, 1 year, 2 years, 3 years, 4 years, 5 years, 10 years, 20 years, 30 years, 40 years, 50 years, or the normal life expectancy of the treated patient).
  • Non-Hodgkin's lymphoma is a cancer of the lymphatic system and is the most commonly occurring hematologic malignancy in adults, representing 4.3% of all new cancer cases in the United States (US).
  • NDL Non-Hodgkin's lymphoma
  • US United States
  • NHL represents a diverse array of lymphoid malignancies derived from cell types within the B cell and T-cell lineages, with B-cell subtypes comprising 85-90% of all NHL cases (Shankland et al, Lancet, 380(9884) :848-57, 2012).
  • NHL There are more than 30 distinct types of NHL, which can be divided into aggressive (fast-growing or high grade) or indolent (slow-growing or low grade) types. NHL is further divided according to the cell type involved. There are two main types of lymphocytes: B- lymphocytes (or B cells) and T-lymphocytes (or T cells). Most types of non-Hodgkin lymphomas develop from B cells.
  • NHL examples include: front line low grade NHL, Stage lll/IV NHL, precursor B lymphoblastic leukemia and/or lymphoma, small lymphocytic lymphoma, B cell chronic lymphocytic leukemia and/or prolymphocytic leukemia and/or small lymphocytic lymphoma, B-cell prolymphocytic lymphoma, immunocytoma and/or lymphoplasmacytic lymphoma, lymphoplasmacytic lymphoma, marginal zone B cell lymphoma, splenic marginal zone lymphoma, extranodal marginal zone-MALT lymphoma, nodal marginal zone lymphoma, hairy cell leukemia, plasmacytoma and/or plasma cell myeloma, low grade/follicular lymphoma, intermediate grade/follicular NHL, mantle cell lymphoma, follicle center lymphoma (follicular), intermediate grade diffuse NHL, diffuse large B-cell lymphoma, aggressive NHL (including aggressive
  • lymphoblastic NHL high grade small non-cleaved cell NHL, bulky disease NHL, Burkitt's lymphoma, precursor (peripheral) large granular lymphocytic leukemia, mycosis fungoides and/or Sezary syndrome, skin (cutaneous) lymphomas, anaplastic large cell lymphoma, and angiocentric lymphoma.
  • the most common form of NHL is diffuse large B-cell lymphoma (DLBCL), representing approximately 30% of cases, and the second most common subtype is follicular lymphoma, corresponding to 25-30% of cases (Maloney, New Engl J Med,
  • the stage of NHL is one of the most important factors in evaluating treatment options.
  • NHL staging is the process of identifying the location of the tumor, the size of the tumor and whether the disease has spread from the original site to other parts of the body.
  • the Cotswold system (formerly the Ann Arbor Staging System) characterizes the stages of non- Hodgkin lymphoma by the number of lymph nodes involved and the regions affected by the cancer. In earlier stages of NHL, the lymph nodes affected are all on one side of the diaphragm (the breathing muscle beneath the lungs). In contiguous lymphoma, the cancerous lymph nodes are next to each other.
  • the cancerous lymph nodes are not next to each other, but are on the same side of the diaphragm. In more advanced stages of non- Hodgkin lymphoma, the disease may be on both sides of the diaphragm.
  • NHL can be staged as follows:
  • Stage II - In stage II NHL the cancer is found in two or more lymph node regions on the same side of the diaphragm, either above or below it.
  • Stage IV - In stage IV NHL the cancer has spread to one or more tissues or organs outside the lymph system (e.g., liver, lungs, bones) and may be in lymph nodes near or far away from those organs.
  • Recurrent - In recurrent NHL the cancer has returned in the lymph system or to other parts of the body after treatment.
  • the present invention relates to methods of treating CD20-positive
  • Non-Hodgkin's lymphoma comprising administering to a patient an effective amount of an isolated, non-naturally-occurring fusion molecule comprising an anti-CD20 monoclonal antibody attached via a peptide linker to human interferon-alpha molecules.
  • the fusion molecule comprises the chimeric lgG1 anti-CD20 antibody, rituximab, attached to human IFN-a2b molecules via a peptide linker.
  • the patient has Stage 1 NHL. In various embodiments, the patient has Stage 2 NHL. In various embodiments, the patient has Stage 3 NHL. In various embodiments, the patient has Stage 4 NHL. In various embodiments, the patient previously responded to treatment with an anti-cancer therapy, but, upon cessation of therapy, suffered relapse (hereinafter "recurrent NHL"). In various embodiments, the NHL is refractory NHL.
  • the NHL is refractory to immunotherapy treatment.
  • the NHL is refractory to treatment with a chemotherapeutic agent.
  • the NHL is refractory to targeted treatment with a tumor antigen-specific, depleting antibody.
  • the NHL is refractory to targeted treatment with anti-CD20 antibody.
  • the NHL is refractory to targeted treatment with rituximab.
  • the NHL is refractory to targeted treatment with an immunoconjugate, ADC, or fusion molecule comprising an anti-CD20 antibody and a cytotoxic agent.
  • the NHL is refractory to targeted treatment with a small molecule inhibitor of a kinase.
  • the NHL is refractory to combination therapy involving, e.g, immunotherapy treatment, treatment with a chemotherapeutic agent, treatment with a tumor antigen-specific, depleting antibody, treatment with an anti-CD20 antibody, treatment with rituximab, treatment with an immunoconjugate, ADC, or fusion molecule comprising an anti-CD20 antibody and a cytotoxic agent, treatment with a small molecule inhibitor of a kinase, treatment using surgery, treatment using stem cell
  • the present invention relates to methods of treating
  • Stage 1 CD20-positive B cell NHL comprising administering to a patient an effective amount of IGN002.
  • the present invention relates to methods of treating
  • Stage 2 CD20-positive B cell NHL comprising administering to a patient an effective amount of IGN002.
  • the present invention relates to methods of treating
  • Stage 3 CD20-positive B cell NHL comprising administering to a patient an effective amount of IGN002.
  • the present invention relates to methods of treating
  • Stage CD20-positive B cell 4 NHL comprising administering to a patient an effective amount of IGN002.
  • the present invention relates to methods of treating recurrent CD20-positive B cell NHL, comprising administering to a patient an effective amount of IGN002.
  • the present invention relates to methods of treating refractory CD20-positive B cell NHL, comprising administering to a patient an effective amount of IGN002.
  • the present invention relates to methods of treating
  • CD20-positive B cell NHL comprising administering to a patient an effective amount of IGN002; wherein the CD20-positive B-cell NHL selected from the group consisting of: front line low grade NHL, Stage lll/IV NHL, precursor B lymphoblastic leukemia and/or lymphoma, small lymphocytic lymphoma, B cell chronic lymphocytic leukemia and/or prolymphocytic leukemia and/or small lymphocytic lymphoma, B-cell prolymphocytic lymphoma, immunocytoma and/or
  • lymphoplasmacytic lymphoma lymphoplasmacytic lymphoma, lymphoplasmacytic lymphoma, marginal zone B cell lymphoma, splenic marginal zone lymphoma, extranodal marginal zone-MALT lymphoma, nodal marginal zone lymphoma, hairy cell leukemia, plasmacytoma and/or plasma cell myeloma, low
  • the present disclosure provides for methods of inhibiting the growth or proliferation of tumor cells in a CD20-positive B cell NHL patient, comprising administering an effective amount of IGN002 to the patient.
  • Dosage regimens are adjusted to provide the optimum desired response (e.g., a therapeutic response). For example, a single bolus may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is especially advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage.
  • dosage unit form refers to physically discrete units suited as unitary dosages for the subjects to be treated; each unit contains a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • fusion molecule to be employed in the methods of the present disclosure will depend on the route of administration, and the seriousness of the disease or disorder, and should be decided according to the judgment of the practitioner and each subject's circumstances. It is to be noted that dosage values may include single or multiple doses, and that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that dosage ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed
  • compositions of this disclosure may be based on a variety of factors, including the type of disease, the age, weight, sex, medical condition of the subject, the severity of the condition, the route of administration, and the particular antibody employed. Thus, the dosage regimen can vary widely, but can be
  • doses may be adjusted based on pharmacokinetic or pharmacodynamic parameters, which may include clinical effects such as toxic effects and/or laboratory values.
  • present disclosure encompasses intra-subject dose-escalation as determined by the skilled artisan. Determining appropriate dosages and regimens are well-known in the relevant art and would be understood to be encompassed by the skilled artisan once provided the teachings disclosed herein.
  • the total monthly dose of the fusion molecules of the invention can be in the range of 0.002-500 mg per patient, 0.002-400 mg per patient, 0.002-300 mg per patient, 0.002-200 mg per patient, 0.002-100 mg per patient, 0.002- 50 mg per patient, 0.006-500 mg per patient, 0.006-400 mg per patient, 0.006-300 mg per patient, 0.006-200 mg per patient, 0.006-100 mg per patient, 0.006-50 mg per patient, 0.02-500 mg per patient, 0.02-400 mg per patient, 0.02-300 mg per patient, 0.02-200 mg per patient, 0.02-100 mg per patient, 0.02-50 mg per patient, 0.06-500 mg per patient, 0.06-400 mg per patient, 0.06-300 mg per patient, 0.06-200 mg per patient, 0.06-100 mg per patient, 0.06-50 mg per patient, 0.2-500 mg per patient, 0.2-400 mg per patient, 0.2-300 mg per patient, 0.2-200 mg per patient, 0.2-
  • An exemplary, non-limiting weekly dosing range for a therapeutically effective amount of the fusion molecules of the invention can be about 0.0001 to about 0.0003 mg/kg, about 0.0003 to about 0.001 mg/kg, about 0.001 to about 0.003 mg/kg, about 0.003 to about 0.01 mg/kg, about 0.01 to about 0.02 mg/kg, about 0.02 to about 0.03 mg/kg, about 0.03 to about 0.04 mg/kg, about 0.04 to about 0.05 mg/kg, about 0.05 to about 0.06 mg/kg, about 0.06 to about 0.07 mg/kg, about 0.07 to about 0.08 mg/kg, about 0.08 to about 0.09 mg/kg, about 0.09 to about 0.1 mg/kg, about 0.1 to about 0.2 mg/kg, about 0.2 to about 0.3 mg/kg, about 0.3 to about 0.4 mg/kg, about 0.4 to about 0.5 mg/kg, about 0.5 to about 0.6 mg/kg, about 0.6 to about 0.7 mg/kg, about 0.7 to about
  • the TAA Ab-IFN fusion molecule is administered to the patient at a weekly dosage selected from the group consisting of .0001 mg/kg, .0003 mg/kg, .001 mg/kg, .003 mg/kg, .01 mg/kg, .02 mg/kg, .03 mg/kg, .04 mg/kg, .05 mg/kg, .06 mg/kg, .07 mg/kg, .08 mg/kg, .09 mg/kg, 0.1 mg/kg, 0.2 mg/kg, 0.3 mg/kg, 0.4 mg/kg, 0.5 mg/kg, 0.6 mg/kg, 0.7 mg/kg, 0.8 mg/kg, and 0.9 mg/kg.
  • the TAA Ab-IFN fusion molecule is administered to the patient at a weekly dosage of no greater than about any of: .0001 mg/kg, .0003 mg/kg, .001 mg/kg, .003 mg/kg, .01 mg/kg, .02 mg/kg, .03 mg/kg, .04 mg/kg, .05 mg/kg, .06 mg/kg, .07 mg/kg, .08 mg/kg, .09 mg/kg, 0.1 mg/kg, 0.2 mg/kg, 0.3 mg/kg, 0.4 mg/kg, 0.5 mg/kg, 0.6 mg/kg, 0.7 mg/kg, 0.8 mg/kg, and 0.9 mg/kg.
  • the weekly dose for a therapeutically effective amount of a fusion molecule of the invention will be 0.0001 mg/kg body weight. In various embodiments, the weekly dose for a therapeutically effective amount of a fusion molecule of the invention will be 0.0003 mg/kg body weight. In various embodiments, the weekly dose for a therapeutically effective amount of a fusion molecule of the invention will be 0.001 mg/kg body weight. In various embodiments, the weekly dose for a therapeutically effective amount of a fusion molecule of the invention will be 0.003 mg/kg body weight. In various embodiments, the weekly dose for a therapeutically effective amount of a fusion molecule of the invention will be 0.01 mg/kg body weight.
  • the weekly dose for a therapeutically effective amount of a fusion molecule of the invention will be 0.03 mg/kg body weight. In various embodiments, the weekly dose for a therapeutically effective amount of a fusion molecule of the invention will be 0.1 mg/kg body weight. In various embodiments, the weekly dose for a therapeutically effective amount of a fusion molecule of the invention will be 0.3 mg/kg body weight. In various embodiments the fusion molecules will be administered via intravenous (IV) infusion for up to three cycles of eight once weekly doses.
  • IV intravenous
  • a method of treating refractory NHL for example rituximab-refractory NHL, in a subject, comprising administering to the subject an effective amount of an anti-CD20-IFN-alpha fusion molecule, wherein the fusion molecule is administered to the patient at a dosage of about 0.001 to about 0.1 mg/kg, including for example about 0.001 to about 0.002 mg/kg, about 0.002 to about 0.003 mg/kg, about 0.003 to about 0.004 mg/kg, about 0.004 to about 0.005 mg/kg, about 0.005 to about 0.006 mg/kg, about 0.006 to about 0.007 mg/kg, about 0.007 to about 0.008 mg.kg, about 0.008 to about 0.009 mg/kg, about 0.009 to about 0.01 mg/kg, about 0.01 to about 0.02 mg/kg, about 0.02 to about 0.03 mg/kg, about 0.03 to about 0.04 mg/kg, about 0.04 to
  • the NHL is CD20-positive B-cell NHL.
  • the fusion molecule is administered over a minimum of 1 hour at a maximum infusion rate of about 25 mg/hr.
  • compositions are administered depending on the dosage and frequency as required and tolerated by the patient.
  • the composition should provide a sufficient quantity of at least one of the fusion molecules disclosed herein to effectively treat the patient.
  • the dosage can be administered once but may be applied periodically until either a therapeutic result is achieved or until side effects warrant discontinuation of therapy.
  • the dosing frequency of the administration of the fusion molecule pharmaceutical composition depends on the nature of the therapy and the particular disease being treated.
  • the patient can be treated at regular intervals, such as weekly or monthly, until a desired therapeutic result is achieved.
  • Exemplary dosing frequencies include, but are not limited to: once weekly without break; once weekly, every other week; once every 2 weeks; once every 3 weeks;
  • the methods comprise one or more additional therapies selected from the group consisting of immunotherapy, chemotherapy, targeted treatment with a tumor antigen-specific, depleting antibody, targeted treatment with an immunoconjugate, ADC, or fusion molecule comprising a TAA Ab and a cytotoxic agent, small molecule kinase inhibitor targeted therapy, surgery, radiation therapy, and stem cell transplantation.
  • additional therapies selected from the group consisting of immunotherapy, chemotherapy, targeted treatment with a tumor antigen-specific, depleting antibody, targeted treatment with an immunoconjugate, ADC, or fusion molecule comprising a TAA Ab and a cytotoxic agent, small molecule kinase inhibitor targeted therapy, surgery, radiation therapy, and stem cell transplantation.
  • a second anti-cancer agent such as a sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite
  • chemotherapeutic agent will be administered to the patient.
  • the list of exemplary chemotherapeutic agent will be administered to the patient.
  • chemotherapeutic agent includes, but is not limited to, daunorubicin, dactinomycin, doxorubicin, bleomycin, mitomycin, nitrogen mustard, chlorambucil, melphalan, cyclophosphamide, 6- mercaptopurine, 6-thioguanine, bendamustine, cytarabine (CA), 5-fluorouracil (5-FU), floxuridine (5-FUdR), methotrexate (MTX), colchicine, vincristine, vinblastine, etoposide, teniposide, cisplatin, carboplatin, oxaliplatin, pentostatin, cladribine, cytarabine, gemcitabine, pralatrexate, mitoxantrone, diethylstilbestrol (DES), fluradabine, ifosfamide, hydroxyureataxanes (such as paclitaxel and doxetaxel) and/or anthr
  • the dosages of such chemotherapeutic agents include, but is not limited to, about any of 10 mg/m 2 , 20 mg/m 2 , 30 mg/m 2 , 40 mg/m 2 , 50 mg/m 2 , 60 mg/m 2 , 75 mg/m 2 , 80 mg/m 2 , 90 mg/m 2 , 100 mg/m 2 , 120 mg/m 2 , 150 mg/m 2 , 175 mg/m 2 , 200 mg/m 2 , 210 mg/m 2 , 220 mg/m 2 , 230 mg/m 2 , 240 mg/m 2 , 250 mg/m 2 , 260 mg/m 2 , and 300 mg/m 2 .
  • Non-limiting examples of standard regimens of chemotherapy for Non-Hodgkin's lymphoma/B-cell cancers include CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone), FCM (fludarabine, cyclophosphamide, mitoxantrone), CVP (cyclophosphamide, vincristine and prednisone), MCP (mitoxantrone, chlorambucil, and prednisolone), R-CHOP (rituximab plus CHOP), R-FCM (rituximab plus FCM), R-CVP (rituximab plus CVP), and R-MCP (R-MCP).
  • CHOP cyclophosphamide, doxorubicin, vincristine, prednisone
  • FCM fludarabine, cyclophosphamide, mitoxantrone
  • CVP cyclophosphamide, vincri
  • a second targeted therapeutic agent will be
  • the second targeted therapeutic agent is a TAA Ab.
  • the TAA Ab is an anti-CD20 antibody such as rituximab, obinutuzumab, ibritumomab, tositumomab, ofatumumab, ocrelizumab, and veltuzumab, or antibody fragments thereof.
  • the second targeted therapeutic agent is an immunoconjugate, ADC, or fusion molecule comprising a TAA Ab, or antibody fragment, and a cytotoxic agent.
  • the second targeted therapeutic agent is an immunoconjugate, ADC, or fusion molecule comprising an anti-CD20 antibody, or antibody fragment, and a cytotoxic agent.
  • unconjugated monoclonal antibodies for Non-Hodgkin's lymphoma/B-cell cancers include rituximab, alemtuzumab, human or humanized anti-CD20 antibodies, lumiliximab, anti-TRAIL, bevacizumab, galiximab, epratuzumab, SGN-40, and anti-CD 74.
  • Non-limiting examples of experimental antibody agents used in treatment of Non-Hodgkin's lymphoma/B-cell cancers include ofatumumab, ha20, PR0131921 , alemtuzumab, galiximab, SGN-40, CHIR-12.12, epratuzumab, lumiliximab, apolizumab, milatuzumab, and bevacizumab. Any of the monoclonal antibodies can be combined with rituximab, fludarabine, or a chemotherapy agent/regimen.
  • the TAA Ab-IFN fusion molecule of present invention is administered with a group of agents selected from the group consisting of: a) R-CHOP
  • R-CHOP R-hyperCVAD
  • R-FCM Rituximab, fludarabine, cyclophosphamide, mitoxantrone
  • bortezomib and rituximab e) temsirolimus and rituximab
  • g) R-CVP rituximab-CVP
  • rituximab-ICE rituximab-ICE
  • FCR fludarabine, cyclophosphamide, rituximab
  • FR fludarabine, rituximab
  • the second targeted therapeutic agent is a small molecule kinase inhibitor selected from the group consisting of Bruton's tyrosine kinase (BTK) inhibitor, phosphatidylinositol-3-kinase (PI3K) inhibitor, SYK inhibitor (e.g., entospletinib), AKT inhibitor, mTOR inhibitor, Src inhibitor, JAK/STAT inhibitor, Ras/Raf/MEK/ERK inhibitor, and Aurora inhibitor (see, D'Cruz et al, Expert Opin Pharmacother, 14(6): 707-21 , 2013).
  • BTK Bruton's tyrosine kinase
  • PI3K phosphatidylinositol-3-kinase
  • SYK inhibitor e.g., entospletinib
  • AKT inhibitor e.g., entospletinib
  • mTOR inhibitor e.g.,
  • the method of the present invention may further comprise immunotherapy.
  • the method of the present invention may further comprise radioimmunotherapy.
  • Non-limiting examples of radioimmunotherapy for Non- Hodgkin's lymphoma/B-cell cancers include yttrium-90-labeled ibritumomab tiuxetan, and iodine-131 -labeled tositumomab. These therapeutic agents are approved for use in subjects with relapsed or refractory follicular or low-grade lymphoma.
  • the present invention provides a method of treating a proliferative disease, comprising administering to a patient an effective amount of a non- naturally occurring fusion molecule comprising a tumor-associated antigen antibody ("TAA Ab") attached to an interferon (IFN) molecule (hereinafter "TAA Ab-IFN fusion molecule").
  • TAA Ab tumor-associated antigen antibody
  • IFN interferon
  • the TAA Ab-IFN fusion molecule is administered to the patient at a dosage of about 0.0001 mg/kg to about 0.9 mg/kg.
  • the TAA Ab and the human IFN molecule are attached via a peptide linker having the amino acid sequence of SEQ ID NO: 10.
  • the TAA Ab and the human IFN molecule are attached via a peptide linker having the amino acid sequence of SEQ ID NO: 1 1 .
  • the proliferative disease is refractory to immunotherapy treatment.
  • the proliferative disease is refractory to treatment with a chemotherapeutic agent.
  • the proliferative disease is refractory to targeted treatment with a TAA Ab.
  • the proliferative disease is refractory to treatment with an immunoconjugate comprising a TAA Ab and a cytotoxic agent.
  • the proliferative disease is refractory to treatment with a small molecule kinase inhibitor.
  • the proliferative disease is refractory to treatment using surgery.
  • the proliferative disease is refractory to treatment using stem cell transplantation.
  • the proliferative disease is refractory to treatment using radiation.
  • the proliferative disease is refractory to combination therapy comprising two or more treatments selected from the group consisting of:
  • immunotherapy treatment treatment with a TAA Ab
  • treatment with a chemotherapeutic agent treatment with an immunoconjugate comprising a TAA Ab and a cytotoxic agent
  • treatment with a small molecule kinase inhibitor treatment using surgery, treatment using stem cell transplantation, and treatment using radiation.
  • the proliferative disease is recurrent proliferative disease.
  • the TAA Ab-IFN fusion molecule is administered to the patient at a dosage selected from the group consisting of: about 0.0001 to about 0.0003 mg/kg, about 0.0003 to about 0.001 mg/kg, about 0.001 to about 0.003 mg/kg, about 0.003 to about 0.01 mg/kg, about 0.01 to about 0.02 mg/kg, about 0.02 to about 0.03 mg/kg, about 0.03 to about 0.04 mg/kg, about 0.04 to about 0.05 mg/kg, about 0.05 to about 0.06 mg/kg, about 0.06 to about 0.07 mg/kg, about 0.07 to about 0.08 mg/kg, about 0.08 to about 0.09 mg/kg, about 0.09 to about 0.1 mg/kg, about 0.1 to about 0.2 mg/kg, about 0.2 to about 0.3 mg/kg, about 0.3 to about 0.4 mg/kg, about 0.4 to about 0.5 mg/kg, about 0.5 to about 0.6 mg/kg, about 0.6 to about 0.7 mg/kg, about
  • the present invention provides a method of treating
  • CD20-positive B-cell Non-Hodgkin's lymphoma comprising administering to a patient an effective amount of a non-naturally-occurring fusion molecule comprising an anti-CD20 antibody attached to a human IFN-a molecule.
  • the anti-CD20 antibody- human IFN-a fusion molecule is administered to the patient at a dosage selected from the group consisting of: about 0.0001 to about 0.0003 mg/kg, about 0.0003 to about 0.001 mg/kg, about 0.001 to about 0.003 mg/kg, about 0.003 to about 0.01 mg/kg, about 0.01 to about 0.02 mg/kg, about 0.02 to about 0.03 mg/kg, about 0.03 to about 0.04 mg/kg, about 0.04 to about 0.05 mg/kg, about 0.05 to about 0.06 mg/kg, about 0.06 to about 0.07 mg/kg, about 0.07 to about 0.08 mg/kg, about 0.08 to about 0.09 mg/kg, about 0.09 to about 0.1 mg/kg, about 0.1 to about 0.2 mg/kg, about 0.2 to about 0.3 mg/kg, about 0.3 to about 0.4 mg/kg, about 0.4 to about 0.5 mg/kg, about 0.5 to about 0.6 mg/kg, about 0.6
  • the anti-CD20 antibody comprises a heavy chain having the amino acid sequence of SEQ ID NO: 1 and a light chain having the amino acid sequence of
  • SEQ ID NO: 2 the human IFN-a molecule having the amino acid sequence of SEQ ID NO: 9.
  • the anti-CD20 antibody and the human IFN-a molecule are attached via a peptide linker having the amino acid sequence of SEQ ID NO: 1 0.
  • the anti-CD20 antibody and the human IFN-a molecule are attached via a peptide linker having the amino acid sequence of SEQ ID NO: 1 1 .
  • the CD20-positive B-cell NHL is selected from the group consisting of Stage 1 CD20-positive B-cell NHL, Stage 2 CD20-positive B-cell NHL, Stage 3
  • CD20-positive B-cell NHL and Stage 4 CD20-positive B-cell NHL.
  • the CD20-positive B-cell NHL is selected from the group consisting of front line low grade NHL, Stage l ll/IV NHL, precursor B lymphoblastic leukemia and/or lymphoma, small lymphocytic lymphoma, B cell chronic lymphocytic leukemia and/or prolymphocytic leukemia and/or small lymphocytic lymphoma, B-cell prolymphocytic lymphoma, immunocytoma and/or lymphoplasmacytic lymphoma, lymphoplasmacytic lymphoma, marginal zone B cell lymphoma, splenic marginal zone lymphoma, extranodal marginal zone-MALT lymphoma, nodal marginal zone lymphoma, hairy cell leukemia, plasmacytoma and/or plasma cell myeloma, low grade/follicular lymphoma, intermediate grade/follicular NHL, mantle cell lymphoma, follicle center lymphoma (f
  • the CD20-positive B-cell NHL is refractory to immunotherapy treatment.
  • the CD20-positive B-cell NHL is refractory to treatment with a chemotherapeutic agent.
  • the CD20-positive B-cell NHL is refractory to treatment with an agent selected from the group consisting of: CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone); FCM (fludarabine, cyclophosphamide, mitoxantrone) ; CVP (cyclophosphamide, vincristine and prednisone); MCP (mitoxantrone, chlorambucil, and prednisolone); R-CHOP (rituximab plus CHOP); R-FCM (rituximab plus FCM); R-CVP (rituximab plus CVP), and R-MCP (R-MCP); R-hyperCVAD (rituximab-hyperCVAD); bortezomib and rituximab; temsirolimus and rituximab; lodine-131 tositum
  • CHOP cyclophos
  • the CD20-positive B-cell NHL is refractory to targeted treatment with a TAA antibody. In a further embodiment, the CD20-positive B-cell NHL is refractory to treatment with rituximab.
  • the CD20-positive B-cell NHL is refractory to treatment with an immunoconjugate comprising a TAA antibody and a cytotoxic agent.
  • the CD20-positive B-cell NHL is refractory to treatment with a small molecule kinase inhibitor.
  • the CD20-positive B-cell NHL is refractory to treatment using surgery.
  • the CD20-positive B-cell NHL is refractory to treatment using stem cell transplantation.
  • the CD20-positive B-cell NHL is refractory to treatment using radiation.
  • the NHL is refractory to combination therapy comprising two or more treatments selected from the group consisting of: immunotherapy treatment, treatment with a TAA Ab, treatment with an anti-CD20 antibody, treatment with a
  • chemotherapeutic agent treatment with an immunoconjugate comprising a TAA antibody and a cytotoxic agent, treatment with an immunoconjugate comprising an anti-CD20 antibody and a cytotoxic agent, treatment with a small molecule kinase inhibitor, treatment using surgery, treatment using stem cell transplantation, and treatment using radiation.
  • the CD20-positive B-cell NHL is recurrent NHL.
  • composition is administered weekly.
  • composition is administered intravenously.
  • the patient is a human patient.
  • a method of treating refractory NHL for example rituximab-refractory NHL, in a subject, comprising administering to the subject an effective amount of an anti-CD20-IFN-alpha fusion molecule, wherein the fusion molecule is administered to the patient at a dosage of about 0.001 to about 0.1 mg/kg, including for example about 0.001 to about 0.002 mg/kg, about 0.002 to about 0.003 mg/kg, about 0.003 to about 0.004 mg/kg, about 0.004 to about 0.005 mg/kg, about 0.005 to about 0.006 mg/kg, about 0.006 to about 0.007 mg/kg, about 0.007 to about 0.008 mg.kg, about 0.008 to about 0.009 mg/kg, about 0.009 to about 0.01 mg/kg, about 0.01 to about 0.02 mg/kg, about 0.02 to about 0.03 mg/kg, about 0.03 to about 0.04 mg/kg, about 0.04
  • the NHL is CD20-positive B-cell NHL.
  • the fusion molecule is administered over a minimum of 1 hour at a maximum infusion rate of about 25 mg/hr.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a TAA Ab-IFN fusion molecule and an acceptable carrier or excipient.
  • the methods comprise one or more additional therapies selected from the group consisting of immunotherapy, chemotherapy, targeted treatment with a tumor antigen-specific, depleting antibody, targeted treatment with an immunoconjugate, ADC, or fusion molecule comprising a TAA Ab and a cytotoxic agent, small molecule kinase inhibitor targeted therapy, surgery, radiation therapy, and stem cell transplantation.
  • additional therapies selected from the group consisting of immunotherapy, chemotherapy, targeted treatment with a tumor antigen-specific, depleting antibody, targeted treatment with an immunoconjugate, ADC, or fusion molecule comprising a TAA Ab and a cytotoxic agent, small molecule kinase inhibitor targeted therapy, surgery, radiation therapy, and stem cell transplantation.
  • the TAA Ab-IFN fusion molecule of present invention is administered with a group of agents selected from the group consisting of: CHOP
  • R-CHOP rituximab plus CHOP
  • R-FCM rituximab plus FCM
  • R-CVP rituximab plus CVP
  • R-MCP R-MCP
  • R-hyperCVAD rituximab- hyperCVAD
  • tositumomab (Bexxar@) and CHOP; R-ICE (rituximab-ICE); FCR (fludarabine,
  • cyclophosphamide rituximab
  • FR fludarabine, rituximab
  • the combination methods comprise administering the
  • TAA Ab-IFN fusion molecule and performing the additional therapy simultaneously.
  • the TAA Ab-IFN fusion molecule administration and additional therapy are performed sequentially, i.e., the TAA Ab-IFN fusion molecule is administered either prior to or after performing the additional therapy.
  • subsequentially administered means that the TAA Ab-IFN fusion molecule and the additional therapy are performed with a time separation of more than about 15 minutes, such as more than about any of 20, 30, 40, 50, 60 or more minutes.
  • the administration period of the TAA Ab-IFN fusion molecule and the performance of the additional therapy are concurrent, i.e., the administration period of the TAA Ab-IFN fusion molecule and the performance of the additional therapy overlap with each other.
  • the present invention provides a method of inhibiting cell proliferation (such as tumor growth) in a patient, comprising administering to a patient an effective amount of a non-naturally occurring fusion molecule comprising a tumor-associated antigen antibody ("TAA Ab") attached to an interferon (I FN) molecule (hereinafter "TAA Ab-IFN fusion molecule") wherein the TAA Ab-IFN fusion molecule is administered to the patient at a dosage of about 0.0001 mg/kg to about 0.9 mg/kg.
  • TAA Ab tumor-associated antigen antibody
  • I FN interferon FN
  • at least about 1 0% including for example at least about any of 20%, 30%, 40%, 60%, 70%, 80%, 90%, or 1 00%) cell proliferation is inhibited.
  • the present invention provides a method of reducing tumor size in a patient.
  • the tumor size is reduced by at least about 10% (including for example at least about any of 20%, 30%, 40%, 60%, 70%, 80%, 90%, or 100%).
  • the present invention provides a method of inhibiting tumor metastasis in a patient.
  • at least about 10% including for example at least about any of 20%, 30%, 40%, 60%, 70%, 80%, 90%, or 1 00%) tumor metastasis is inhibited.
  • the present invention provides a method for stabilizing disease progression of a proliferative disease in a patient.
  • the methods stabilize the disease by at least about 1 month (including for example at least about any of 6 months, 1 year, 2 years, 3 years, 4 years, 5 years, 1 0 years, 20 years, 30 years, 40 years, 50 years, or the normal life expectancy of the treated patient).
  • the present invention provides a method for slowing of disease progression of a proliferative disease in a patient.
  • the methods slow the disease progression by at least about 1 month (including for example at least about any of 6 months, 1 year, 2 years, 3 years, 4 years, 5 years, 10 years, 20 years, 30 years, 40 years, 50 years, or the normal life expectancy of the treated patient).
  • the methods of the present invention provide a method for improving the quality of life of a patient having a proliferative disease.
  • the quality of life of the patient is improved by reduced nausea, reduced fatigue, reduced joint stiffness, reduced pain, and reduced need for medications to address any such issue.
  • the methods improve the quality of life for a period of at least about 1 month (including for example at least about any of 6 months, 1 year, 2 years, 3 years, 4 years, 5 years, 10 years, 20 years, 30 years, 40 years, 50 years, or the normal life expectancy of the treated patient).
  • the present invention provides a method for prolonging the survival of a patient having a proliferative disease.
  • the methods may prolong survival by at least about 1 month (including for example at least about any of 6 months, 1 year, 2 years, 3 years, 4 years, 5 years, 10 years, 20 years, 30 years, 40 years, 50 years, or the normal life expectancy of the treated patient).
  • the example is a Phase 1 clinical trial to evaluate the safety, tolerability, and pharmacokinetics of multiple intravenous doses of IGN002 administered weekly to subjects with refractory Non-Hodgkin Lymphoma (NHL).
  • the primary objectives of the study are to evaluate the safety and tolerability of multiple doses of IGN002 administered weekly as an IV infusion to subjects with refractory NHL and to determine the maximum tolerated dose (MTD) or recommended Phase 2 dose (RP2D) of IGN002 administered weekly as an IV infusion to subjects with refractory NHL (Dose-Escalation Stage).
  • the secondary objectives of the study are to characterize the PK profile of ascending doses of IGN002 administered weekly; valuate the incidence of anti-IGN002 antibody formation; investigate the pharmacodynamic effects of IGN002 by measurement of CD19-positive B-lymphocyte counts; and assess the anti-tumor activity of IGN002 using the Lugano Classification criteria for NHL (Cheson et al., J Clin Oncol, 32(27): 3059-3068, 2014).
  • Eligible patients are 18 years and older, male or female.
  • the eligibility inclusion criteria includes: documented history of immunohistochemistry (IHC)-confirmed CD20-positive (with no subsequent history of CD20-negativity) B-cell NHL, including diffuse large B cell (DLBCL), mantle cell, marginal zone, lymphoplasmacytic, follicular, transformed follicular, or primary mediastinal B cell lymphoma; refractory disease, having failed available therapies; measurable disease; Eastern Cooperative Oncology Group (ECOG) performance status of 0-2; life expectancy > 3 months; and adequate organ function.
  • IHC immunohistochemistry
  • B-cell NHL including diffuse large B cell (DLBCL), mantle cell, marginal zone, lymphoplasmacytic, follicular, transformed follicular, or primary mediastinal B cell lymphoma
  • refractory disease having failed available therapies
  • measurable disease Eastern Cooperative Oncology Group (ECOG) performance status of 0-2; life expectancy > 3
  • the eligibility exclusion criteria includes: treatment with an approved or investigational chemotherapy drug within 28 days of Day 1 ; treatment with an approved or investigational anti-CD20 drug within 28 days of Day 1 ; treatment with an approved or investigational biologic drug that does not target CD20 within 90 days of Day 1 ; and radiation therapy within 4 weeks of Day 1 .
  • IGN002 will be administered weekly via IV infusion. Procedures for administration of IGN002 are as follows: 30 to 60 minutes prior to each dose, subjects will be premedicated with acetaminophen 650 mg PO and diphenhydramine 25-50 mg IV. IGN002 will be
  • the Dose-Escalation Stage will evaluate the safety, tolerability, PK,
  • IGN002 immunogenicity, pharmacodynamics, and anti-tumor activity of multiple doses of IGN002 administered weekly to subjects with refractory NHL.
  • the starting dose of IGN002 is 0.1 ⁇ g kg (0.0001 mg/kg). If this dose is tolerated, based upon the incidence of dose-limiting toxicity (DLT) within the 1 5-day DLT assessment period (i.e., Days 1 -1 5 of Period 1 ), the next cohort dose level will be 0.3 ⁇ g kg (0.0003 mg/kg).
  • DLT dose-limiting toxicity
  • Period 1 of the dose-escalation stage will end 8 weeks after the final patient in each cohort receives their second dose.
  • Subjects will receive a total of 2 doses of IGN002 a week apart starting on Day 1 , followed by a 6-week treatment-free interval for immunogenicity (i.e., anti-drug antibodies (ADA)) assessment.
  • the DLT assessment period will be the first 15 days of treatment (i.e., Days 1 -15) and will guide dose escalation decisions. All adverse events (AEs) will be graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03.
  • NCI National Cancer Institute
  • CCAE Common Terminology Criteria for Adverse Events
  • DLT is defined as any such AE considered related to IGN002 during the DLT assessment period with severity graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03. Dose escalation by cohort will proceed until the MTD or RP2D is identified.
  • the MTD is defined as the dose level just below the dose level with 2 or more subjects with non-IRR (infusion-related reaction) DLT or the dose level with 1 subject with IRR DLT, and is the highest dose level with 0-1 DLT-evaluable subjects with non-IRR DLT.
  • Subjects with no ADA to IGN002 during Period 1 may proceed to Period 2, where subjects will receive up to 24 additional doses of IGN002 administered weekly in three cycles of eight doses per cycle with no treatment-free interval.
  • CT or MRI
  • PD progressive disease
  • Repeat radiologic imaging will be performed after completion of the last cycle and during the 6-month follow-up period. The maximum dose level will have been reached when one of the following occurs: the MTD is exceeded, or PK futility is encountered (i.e., no increased exposure is observed with increasing dose).
  • the Expansion Stage will evaluate the safety, tolerability, PK, immunogenicity, pharmacodynamics, and anti-tumor activity of multiple doses of IGN002 administered at the MTD or RP2D. Enrollment will commence once the last subject in the Dose-Escalation Stage has begun Period 2, and the MTD or RP2D has been identified by the SRC. In the Expansion Stage, subjects will receive a maximum of 24 doses of IGN002 administered weekly at the MTD or RP2D in three cycles of 8 doses per cycle with no treatment-free interval. Based on data from the Dose-Escalation Stage, consideration may be given for inclusion of select NHL subtypes.
  • Tumor imaging will also be performed at the ADA visit during Week 6 in Period 1 of the Dose-Escalation Stage to assess tumor response, but will not serve as a basis for eligibility to proceed to Period 2. Specifically, subjects with PD during Period 1 may continue to Period 2 of the Dose-Escalation Stage.
  • IGN002 has been well tolerated, with only transient fever and infusion reactions in the patients at the two higher doses. Thus, it appears that, as had been predicted from preclinical studies of IGN002 in comparison with non-fused interferon alpha, IGN002 will be better tolerated and more efficacious than non-fused interferon.
  • amino acid sequences listed in the accompanying sequence listing are shown using standard three letter code for amino acids, as defined in 37 C.F.R. 1 .822.
  • SEQ ID NO: 1 is the amino acid sequence encoding the heavy chain of an anti-
  • SEQ ID NO: 2 is the amino acid sequence encoding the light chain of an anti-
  • SEQ ID NO: 3 is the amino acid sequence of a heavy chain CDR1 of an anti-
  • SEQ ID NO: 4 is the amino acid sequence of a heavy chain CDR2 of an anti-
  • SEQ ID NO: 5 is the amino acid sequence of a heavy chain CDR3 of an anti-
  • SEQ ID NO: 6 is the amino acid sequence of a light chain CDR1 of an anti-CD20 antibody.
  • SEQ ID NO: 7 is the amino acid sequence of a light chain CDR2 of an anti-CD20 antibody.
  • SEQ ID NO: 8 is the amino acid sequence of a light chain CDR3 of an anti-CD20 antibody.
  • SEQ ID NO: 9 is the amino acid sequence encoding a human wildtype IFN-oc2 molecule.
  • SEQ ID NO: 10 is the amino acid sequence of a peptide linker.
  • SEQ ID NO: 1 1 is the amino acid sequence of a peptide linker.
  • SEQ ID NO: 1 amino acid sequence encoding the heavy chain of an anti-CD20 antibody
  • SEQ ID NO: 2 amino acid sequence encoding the light chain of an anti-CD20 antibody
  • SEQ ID NO: 3 amino acid sequence of a heavy chain CDR1 of an anti-CD20 antibody
  • SEQ ID NO: 4 amino acid sequence of a heavy chain CDR2 of an anti-CD20 antibody GDTSYNQKFKG
  • SEQ ID NO: 5 amino acid sequence of a heavy chain CDR3 of an anti-CD20 antibody
  • STYYGGDWYFNV SEQ ID NO: 6 - amino acid sequence of a light chain CDR1 of an anti-CD20 antibody
  • SEQ ID NO: 7 amino acid sequence of a light chain CDR2 of an anti-CD20 antibody
  • SEQ ID NO: 8 amino acid sequence of a light chain CDR3 of an anti-CD20 antibody
  • SEQ ID NO: 9 the amino acid sequence encoding a human wildtype IFN-oc2 molecule

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Abstract

La présente invention concerne des procédés de traitement d'une maladie proliférative (telle que le cancer), comprenant l'administration à un patient d'une quantité efficace (soit en monothérapie, soit en polythérapie) d'une molécule de fusion d'anticorps d'antigène associé aux tumeurs ("TAA Ab") et d'interféron (IFN). En particulier, la présente invention concerne des procédés de traitement de maladies prolifératives récurrentes, résistantes ou réfractaires au moyen de doses très faibles.
PCT/US2016/062845 2015-11-20 2016-11-18 Procédés de traitement de maladies prolifératives à l'aide de molécules de fusion d'anticorps et d'interféron obtenues par génie génétique WO2017087843A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7151164B2 (en) * 2002-02-14 2006-12-19 Immunomedics, Inc. Anti-CD20 antibodies and fusion proteins thereof and methods of use
US20080089885A1 (en) * 2006-10-10 2008-04-17 Vaccinex, Inc. Anti-cd20 antibodies and methods of use
US20100196266A1 (en) * 2005-03-03 2010-08-05 Immunomedics, Inc. Humanized Anti-HLA-DR Antibodies

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7151164B2 (en) * 2002-02-14 2006-12-19 Immunomedics, Inc. Anti-CD20 antibodies and fusion proteins thereof and methods of use
US20100196266A1 (en) * 2005-03-03 2010-08-05 Immunomedics, Inc. Humanized Anti-HLA-DR Antibodies
US20080089885A1 (en) * 2006-10-10 2008-04-17 Vaccinex, Inc. Anti-cd20 antibodies and methods of use
US20090130089A9 (en) * 2006-10-10 2009-05-21 Vaccinex, Inc. Anti-cd20 antibodies and methods of use

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
XUAN ET AL.: "Targeted delivery of interferon-alpha via fusion to anti- CD 20 results in potent antitumor activity against B- cell lymphoma", BLOOD, vol. 115, no. 14, 8 April 2010 (2010-04-08), pages 2864 - 2871, XP002673645 *

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