Synergistic combination of IL-4, interferon gamma, and interferon alpha in treating ovarian cancer
Inventors
Puri, Raj K. • Zoon, Kathryn C. • Husain, Syed R. • Green, Daniel S.
Assignees
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Publication Number
US-10849960-B2
Publication Date
2020-12-01
Expiration Date
2038-09-07
Abstract
Methods and compositions are disclosed for treating a subject with a cancer. The compositions can include a chimeric molecule comprising an agent that specifically binds the interleukin 4 receptor (IL-4R) and a toxic moiety, an interferon alpha (IFNα), and an interferon gamma (IFNγ). In some non-liming embodiments, the compositions can also include monocytes. The methods disclosed herein include administering a therapeutically effective amount of the compositions taught herein to a subject with cancer, thereby treating the cancer in the subject, wherein cells in the cancer express IL-4R. In some non-liming embodiments, the methods can also include administering monocytes.
Core Innovation
Methods and compositions are disclosed for treating subjects with cancers where the cancer cells express the interleukin 4 receptor (IL-4R). The compositions include a chimeric molecule comprising an agent that specifically binds IL-4R and a toxic moiety; an interferon alpha (IFNα) polypeptide or its variants; and an interferon gamma (IFNγ) polypeptide or its variants. These compositions are administered in therapeutically effective amounts to treat cancers expressing IL-4R, such as ovarian cancer.
The invention addresses the significant problem of ovarian cancer treatment, particularly in advanced stages where metastasis is common and current treatments fail to prevent relapse in about 80% of patients after first-line chemotherapy. Most patients are diagnosed at an advanced stage with few therapeutic options and high mortality. There is a critical need for new agents and combination treatments that can overcome chemoresistance and improve patient outcomes.
The disclosed combination therapy targets multiple pathways simultaneously by combining IFNα, IFNγ, and the IL-4R-binding chimeric molecule (such as IL4-PE) to produce synergistic antitumor effects. This combination enhances ovarian cancer cell death beyond the effects of each individual agent, inducing apoptosis and inhibiting tumor cell proliferation. The approach also includes potential co-administration with other therapies, such as immunotherapy via monocytes, chemotherapy, surgery, or vaccines, to improve efficacy.
Claims Coverage
The patent contains one independent claim addressing a method of treating ovarian cancer by administering a combination of agents. The main inventive features relate to the combination of a chimeric molecule with IL-4 polypeptide and a toxic moiety, together with IFNα and IFNγ polypeptides, and related administration aspects.
Combination therapy comprising a chimeric molecule with IL-4 polypeptide and a toxic moiety, IFNα polypeptide, and IFNγ polypeptide for treating ovarian cancer
A method of treating a subject with ovarian cancer involving administration of a therapeutically effective amount of: (a) a chimeric molecule comprising an interleukin 4 polypeptide and a toxic moiety; (b) an interferon alpha (IFNα) polypeptide; and (c) an interferon gamma (IFNγ) polypeptide, where the cells in the ovarian cancer express IL-4R.
Use of circularly permuted IL-4 polypeptide in the chimeric molecule
The IL-4 polypeptide in the chimeric molecule can be circularly permuted.
Specification of IL-4 polypeptide sequence identity
The IL-4 polypeptide can comprise an amino acid sequence at least 95% identical to SEQ ID NO: 1 or the exact sequence of SEQ ID NO: 1.
Toxic moiety options in chimeric molecule
The toxic moiety can consist of Pseudomonas exotoxin (PE), ricin A, abrin, ribotoxin, ribonuclease, saporin, calicheamycin, Diphtheria toxin, botulinum toxin, pokeweed antiviral toxin, bryodin 1, Clostridium perfringens enterotoxin, Cholera toxin, BAD protein, ribosome-inactivating toxins, or their cytotoxic fragments.
Preferred PE variants as toxic moiety
The toxic moiety can specifically comprise a PE polypeptide or cytotoxic fragment thereof, including PE, PE38, or PE40 variants.
Chimeric molecule comprising circularly permuted IL-4 and PE
The chimeric molecule can include circularly permuted IL-4 fused to PE or a cytotoxic fragment of PE.
Use of chemotherapeutic agent as toxic moiety
The toxic moiety can alternatively be a chemotherapeutic agent such as taxane, carboplatin, cyclophosphamide, and/or doxorubicin.
Human interferon polypeptides
The IFNα and IFNγ polypeptides administered can be human.
Human IL-4 polypeptide
The IL-4 polypeptide in the chimeric molecule can be human.
Combination with additional therapies
The treatment method can further comprise administering surgery, chemotherapy, hormone therapy, radiation therapy, immunotherapy, and/or a vaccine, wherein immunotherapy can include adoptive cell therapy using monocytes.
Modes of administration
The agents—chimeric molecule, IFNα, and IFNγ polypeptides—can be administered systemically or locally to the ovarian cancer.
Subject to be treated
The subject treated by the method is a human.
The claims cover a method of treating ovarian cancer using a synergistic combination of a chimeric IL-4R-binding molecule with a toxic moiety, IFNα, and IFNγ polypeptides. The claims specify IL-4 polypeptide characterizations, toxic moiety options including PE and chemotherapeutics, human interferon usage, combination with other therapies including immunotherapy with monocytes, and administration routes, focusing on improved ovarian cancer treatment targeting IL-4R expressing cancer cells.
Stated Advantages
The combination therapy results in synergistic antitumor effects, increasing ovarian cancer cell death beyond individual agents.
The combination decreases tumor cell proliferation and induces apoptosis effectively.
The therapy provides prolonged overall survival and complete response in an aggressive ovarian cancer model despite suboptimal dosing.
The combination shows reduced toxicity, with no histological damage to vital organs and stable animal health metrics.
Intraperitoneal administration targets the site of disease with higher local concentration and reduced systemic toxicity.
Documented Applications
Treatment of ovarian cancer, including advanced and metastatic disease, especially where cancer cells express IL-4R.
Treatment of other cancers expressing IL-4R, including lung cancer, liver cancer, melanoma, osteosarcoma, and brain cancer.
Use in combination with immunotherapy, particularly adoptive cell transfer using monocytes.
Combination with standard therapies such as surgery, chemotherapy, hormone therapy, radiation therapy, and vaccines.
Intraperitoneal administration for localized treatment of ovarian cancer.
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