WO2017165742A1 - Procédés de traitement d'événements indésirables liés à l'immunité gastro-intestinale dans des polythérapies anti-ctla4 et anti-pd-1 - Google Patents
Procédés de traitement d'événements indésirables liés à l'immunité gastro-intestinale dans des polythérapies anti-ctla4 et anti-pd-1 Download PDFInfo
- Publication number
- WO2017165742A1 WO2017165742A1 PCT/US2017/023981 US2017023981W WO2017165742A1 WO 2017165742 A1 WO2017165742 A1 WO 2017165742A1 US 2017023981 W US2017023981 W US 2017023981W WO 2017165742 A1 WO2017165742 A1 WO 2017165742A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- antibody
- dose
- administered
- polypeptide
- integrin
- Prior art date
Links
Classifications
-
- 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
- C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- 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
- C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
- C07K16/2818—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152
-
- 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
- C07K16/2839—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the integrin superfamily
-
- 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
- A61K2039/507—Comprising a combination of two or more separate antibodies
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
Definitions
- the present invention relates to methods of ameliorating gastrointestinal immune- related adverse events (gi-irAEs) in subjects undergoing an immune oncology treatment.
- gi-irAEs include colitis and diarrhea
- immune oncology treatment can include single agent and combination treatment with anti-CTLA4 and anti-PD-1 antibodies.
- Immune oncology is a growing and promising field in the fight against cancer.
- immune oncology provides efficacious treatments without many of the negative side effects of systemic chemotherapy or radiotherapy.
- immune oncology can produce significant gi-irAEs, including colitis and diarrhea.
- 40%, or more, of subjects undergoing immune oncology treatment with anti- CTLA4 and anti-PD- 1 antibodies may experience treatment interruption or treatment discontinuation, thus abrogating much of the benefit of the immune oncology treatment. Accordingly, a need exists for methods of reducing gi-irAEs, such as colitis and diarrhea, in subjects undergoing an immune treatment, such as an immune oncology treatment.
- the invention provides, inter alia, methods of reducing gi-irAEs, such as colitis and diarrhea, in subjects undergoing an immune treatment, such as an immune oncology treatment.
- the invention is based, at least in part, on Applicant' s discovery that a polypeptide that inhibits MAdCAM- ⁇ 4 ⁇ 7 integrin binding, such as an anti-a4 7 integrin antibody, can advantageously reduce gi-irAEs in a subject undergoing an immune oncology treatment.
- polypeptides that inhibit MAdCAM- ⁇ 4 ⁇ 7 integrin binding can reduce gi-irAEs with no significant reduction in efficacy of the immune therapy and with a better safety profile.
- gi-irAEs are acute conditions that stand in contrast to spontaneous and/or chronic autoimmune disease such as inflammatory bowel disease (IBD), and are not known to be mediated by common mechanisms of action. Accordingly, it would not necessarily be expected that a treatment for a spontaneous autoimmune IBD would work for a gi-irAE.
- IBD inflammatory bowel disease
- the effectiveness of corticosteroids or infliximab in the management of gi-irAEs has not been confirmed in randomized clinical trials.
- infliximab is registered as a treatment for IBD it also has a broader therapeutic spectrum that includes rheumatoid arthritis, psoriatic arthritis, plaque psoriasis, and ankylosing spondylitis.
- the invention provides methods of treating a
- gastrointestinal immune-related adverse event in a mammalian subject (or treating a subject with cancer) undergoing a treatment with a PD- 1 antagonist, such as an anti-PD-1 antibody; a CTLA4 antagonist, such as an anti-CTLA4 antibody; or both a PD- 1 antagonist and a CTLA4 antagonist.
- a PD- 1 antagonist such as an anti-PD-1 antibody
- a CTLA4 antagonist such as an anti-CTLA4 antibody
- both a PD- 1 antagonist and a CTLA4 antagonist both a PD- 1 antagonist and a CTLA4 antagonist.
- second medical uses e.g. , as medicaments
- targeted uses of a polypeptide that inhibits MAdCAM- ⁇ 4 ⁇ 7 integrin binding corresponding to the methods provided by the invention are encompassed as well.
- the polypeptide that inhibits MAdCAM- ⁇ 4 ⁇ 7 integrin binding is an anti-o ⁇ 7 integrin antibody, such as an anti-o ⁇ 7 integrin antibody that competes with vedolizumab for binding ⁇ 4 ⁇ 7 integrin, more particularly, where the antibody has the epitopic specificity of vedolizumab, more particularly where the antibody comprises the complementarity determining regions (CDRs) of vedolizumab, still more particularly where the antibody is vedolizumab.
- the anti-o ⁇ 7 integrin antibody is administered at a dose of between about: 1.25 to 8.0 mg/kg.
- the anti-o ⁇ 7 integrin antibody is administered at a dose of between about: 1.25 to 4.25 mg/kg, 1.75 to 3.75 mg/kg, 2.25 to 3.25 mg/kg, e.g. , about 2.86 mg/kg, e.g., about 2.8 mg/kg or about 2.9 mg/kg.
- the anti-o ⁇ 7 integrin antibody is administered at a dose of between about: 5.0 to 8.0 mg/kg, 5.5 to 7.5 mg/kg, 6.0 to 7.0 mg/kg, e.g. , about 6.43 mg/kg, e.g., about 6.4 mg/kg or about 6.5 mg/kg .
- the anti-o ⁇ 7 integrin antibody is administered at a unit dose of about: 108, 150, 165, 200, 216, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750 mg, or more, to a human subject.
- the anti-o ⁇ 7 integrin antibody can be administered at any of the foregoing doses on a variety of schedules, such as once every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 weeks, or more, for, e.g. , 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more administrations, e.g. , including use without a predetermined end point.
- schedules such as once every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 weeks, or more, for, e.g. , 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more administrations, e.g. , including use without a predetermined end point.
- the administrations may be at the same doses, or different doses, e.g., escalated, for example, with a first dose unit dose of 200 mg, with subsequent doses of 450 mg.
- the anti-o ⁇ 7 integrin antibody is administered to achieve a serum concentration (e.g. , a serum trough concentration) of about: 10 ⁇ g/ml, or more, e.g., about: 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 93, or 100 ⁇ g/ml, e.g. , for a period of at least 20 weeks.
- the anti-o ⁇ 7 integrin antibody is administered to achieve a serum trough concentration above 15 ⁇ g/ml for at least 20 weeks.
- the polypeptide that inhibits MAdCAM- ⁇ 4 ⁇ 7 integrin binding is administered at least once before a PD- 1 antagonist, a CTLA4 antagonist, or both a PD- 1 antagonist and a CTLA4 antagonist.
- the polypeptide that inhibits MAdCAM- ⁇ 4 ⁇ 7 integrin binding is administered at least four times, where the second dose is administered about two weeks after the first administration, the third dose is administered about four weeks after the first administration, and the fourth dose is administered about 12 weeks after the first administration.
- the polypeptide that inhibits MAdCAM- ⁇ 4 ⁇ 7 integrin binding is administered as primary prophylaxis to a patient to be treated with immunotherapy, before emergence of one or more symptoms of gi-irAEs.
- the polypeptide that inhibits MAdCAM- ⁇ 4 ⁇ 7 integrin binding is administered in a treatment setting, in response to one or more symptoms of gi-irAEs.
- the subject is undergoing treatment with (or, in certain particular embodiments, is administered) an anti-PD-1 antibody, such as an anti-PD-1 antibody that competes with nivolumab for binding PD-1, or more particularly, where the antibody has the epitopic specificity of nivolumab, or more particularly where the antibody comprises the complementarity determining regions (CDRs) of nivolumab, or still more particularly where the antibody is nivolumab.
- the anti-PD-1 antibody treatment is at a dose of about: 0.5-6.0 mg/kg.
- the dose is between about: 0.5 to 2.0 mg/kg, 0.5 to 1.5 mg/kg, 0.75 to 1.25 mg/kg, e.g., about 1.0 mg/kg. In other particular embodiments, the dose is between about: 1.5 to 6.0 mg/kg, 2.0 to 5.0 mg/kg, 2.0 to 4.0 mg/kg, 2.5 to 3.5 mg/kg, e.g., about 3.0 mg/kg.
- the anti-PD-1 antibody treatment is a flat dose, e.g., about 200 mg, 220 mg, 240 mg, 250 mg, 260 mg, or 280mg.
- the anti-PD- 1 antibody can be administered at any of the foregoing doses on a variety of schedules, such as once every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 weeks, or more, for, e.g. , 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 administrations, or more, e.g. , including use without a predetermined end point.
- the anti-PD-1 antibody is administered at a dose of about 1 mg/kg once every two weeks or once every three weeks.
- the anti-PD-1 antibody is administered at a dose of about 3 mg/kg once every two weeks.
- the subject is undergoing treatment with (or, in certain particular embodiments, is administered) an anti- CTLA4 antibody, such as an anti-CTLA4 antibody that competes with ipilimumab for binding CTLA4, or more particularly, an antibody that has the epitopic specificity of ipilimumab, still more particularly where the antibody comprises the complementarity determining regions (CDRs) of ipilimumab, and still more particularly where the antibody is ipilimumab.
- an anti- CTLA4 antibody such as an anti-CTLA4 antibody that competes with ipilimumab for binding CTLA4, or more particularly, an antibody that has the epitopic specificity of ipilimumab, still more particularly where the antibody comprises the complementarity determining regions (CDRs) of ipilimumab, and still more particularly where the antibody is ipilimumab.
- the anti- CTLA4 antibody is administered at a dose of about: 1.5 to 10.0 mg/kg (e.g., up to about 10 mg/kg), 2.0 to 5.0 mg/kg, 2.0 to 4.0 mg/kg, 2.5 to 3.5 mg/kg, or about 3.0 mg/kg.
- the anti- CTLA4 antibody can be administered at any of the foregoing doses on a variety of schedules, such as once every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 weeks, or more, for, e.g. , 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 administrations, or more, e.g. , use without a predetermined end point.
- the anti-CTLA4 antibody is administered at a dose of about 1 mg/kg once every three weeks, once every six weeks, or once every 12 weeks.
- the subject being treated by the methods provided by the invention is a human, such as an adult human.
- the subject being treated by the methods provided by the invention has a cancer selected from: melanoma (including unresectable or metastatic melanoma), non-small cell lung cancer (both squamous and non- squamous), renal cell carcinoma, head and neck cancer, bladder cancer, small cell lung cancer, colorectal cancer (including metastatic), Hodgkin lymphoma, non-Hodgkin lymphoma, myeloma, and prostate cancer (including metastatic hormone-refractory prostate cancer).
- melanoma including unresectable or metastatic melanoma
- non-small cell lung cancer both squamous and non- squamous
- renal cell carcinoma head and neck cancer
- bladder cancer small cell lung cancer
- colorectal cancer including metastatic
- Hodgkin lymphoma non-Hodgkin lymphoma
- myeloma myeloma
- prostate cancer including metastatic hormone-refractory prostate cancer
- the subject being treated by the methods provided by the invention has a cancer selected from: melanoma (including unresectable or metastatic melanoma), non-small cell lung cancer (both squamous and non-squamous), renal cell carcinoma, head and neck cancer, bladder cancer, small cell lung cancer, Hodgkin lymphoma, non-Hodgkin lymphoma, myeloma, and prostate cancer (including metastatic hormone-refractory prostate cancer).
- the subject has melanoma or non-small cell lung cancer.
- the subject has melanoma, including unresectable or metastatic melanoma.
- the subject has non-small cell lung cancer, including both squamous and non-squamous non-small cell lung cancer.
- the subject following at least one administration of the polypeptide that inhibits MAdCAM- ⁇ 4 ⁇ 7 integrin binding, the subject is undergoing treatment with a PD-1 antagonist, such as an anti-PD-1 antibody, which is administered every two weeks, e.g., at a dose of about 3 mg/kg.
- a PD-1 antagonist such as an anti-PD-1 antibody
- the subject following at least one administration of the polypeptide that inhibits MAdCAM- ⁇ 4 ⁇ 7 integrin binding, the subject is undergoing treatment with a CTLA4 antagonist, such as an anti-CTLA4 antibody, and is administered every three weeks, e.g., at a dose of about 3 mg/kg, concurrently with a PD-1 antagonist, e.g. , at a dose of about 1 mg/kg.
- the subject is undergoing treatment with a CTLA4 antagonist, such as an anti-CTLA4 antibody, which is administered every three weeks, e.g., at a dose of about 3 mg/kg, concurrently with a PD-1 antagonist (such as an anti-PD-1 antibody, e.g. , at a dose of about 1 mg/kg), where, following four administrations of the CTLA4 antagonist, no further CTLA4 antagonist is administered and the PD-1 antagonist, such as an anti-PD-1 antibody, is administered every two weeks (e.g., at a dose of about 3 mg/kg).
- an anti-PD-1 antibody and an anti-CTLA4 antibody are both administered at a dose of about 1 mg/kg once every three weeks.
- the anti-PD-1 antibody is administered at a dose of about 1 mg/kg once every two weeks and the anti-CTLA4 antibody is administered at a dose of about 1 mg/kg once every six weeks. In other particular embodiments, the anti-PD-1 antibody is administered at a dose of about 3 mg/kg once every two weeks and the anti-CTLA4 antibody is administered at a dose of about 1 mg/kg once every 12 weeks. In still other particular embodiments, the anti-PD-1 antibody is administered at a dose of about 3 mg/kg once every two weeks and the anti-CTLA4 antibody is administered at a dose of about 1 mg/kg once every six weeks.
- an anti-CTLA4 antibody such as ipilimumab
- an adjuvant dose e.g. , about 10 mg/kg, e.g. , every three weeks, e.g. , for four doses.
- an anti-PD-1 antibody, an anti-CTLA4 antibody, or both an anti-PD-1 antibody and an anti-CTLA4 antibody may be administered on the same day as the polypeptide that inhibits MAdCAM- ⁇ 4 ⁇ 7 integrin binding is administered.
- a subject receiving a polypeptide that inhibits MAdCAM- ⁇ 4 ⁇ 7 integrin binding, relative to a suitable control undergoing an immune oncology treatment with a PD-1 antagonist, a CTLA4 antagonist, or both a PD-1 antagonist and an CTLA4 antagonist, but not the polypeptide that inhibits MAdCAM- ⁇ 4 ⁇ 7 integrin binding exhibits one or more of: increased compliance (e.g. , reduced incidence of treatment interruption, discontinuation, or dose reduction; higher rate of treatment completion, longer treatment duration); such as at least: 5, 10, 15, 20, 25, 30, 35, 40, 45, 50%, or more, increased compliance; no significant reduction of efficacy of the immune oncology treatment (e.g.
- gi-irAE e.g. , a reduced average grade of at least 1, 2, 3, 4 or 5 grades, or reduced frequencies of a given grade, where grades are determined by NCI CTCAE 4.03
- reduced duration of gi-irAE e.g.
- At least: 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50% reduced duration e.g., reduced by 1, 2, 3, 4, 5, or 6 weeks; 1, 2, 3, 4, 5, or 6 months, or longer
- delayed onset of gi-irAE delayed by 1, 2, 3, 4, 5, or 6 weeks; 1, 2, 3, 4, 5, or 6 months, or longer
- corticosteroids oral or systemic
- antibiotics oral or parenteral
- non-corticosteroid immunosuppressive medication e.g. , anti-TNF-a agents
- lower endoscopy hospitalizations, or a combination thereof; (e.g. , at least: 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 95, or 99% reduced); or a combination thereof.
- kits useful for performing any of the methods provided by the invention comprising containers containing an effective amount of a polypeptide that inhibits MAdCAM- ⁇ 4 ⁇ 7 integrin binding along with instructions for using the polypeptide to treat or prevent a gi-irAE (e.g. , in a cancer subject, e.g. , a subject undergoing an immune oncology treatment with an anti-PD-1 antagonist and/or an anti-CTLA4 antagonist).
- the kits may further comprise the components of an immune oncology treatment described herein, such as, for example, an anti-PD-1 antibody and/or an anti-CTLA4 antibody.
- FIGURE 1 is a graphic depiction of a dosing schedule of a treatment consonant with the methods provided by the invention. Depicted are administrations of an anti-a4 7 antibody (vedolizumab) together with an anti-CTLA4 antibody (ipilimumab) anti-PD- 1 antibody (nivolumab) combination treatment.
- an anti-a4 7 antibody vedolizumab
- an anti-CTLA4 antibody ipilimumab
- nivolumab anti-PD- 1 antibody
- FIGURE 2 is a graphic deptiction of an alternative dosing schedule of a treatment consonant with the methods provided by the invention. Depicted are administration of an anti-a4 7 antibody (vedolizumab) together with an anti-CTLA4 antibody (ipilimumab) anti- PD- 1 antibody (nivolumab) combination treatment.
- an anti-a4 7 antibody vedolizumab
- an anti-CTLA4 antibody ipilimumab
- PD- 1 antibody nivolumab
- the invention provides, inter alia, treatments for gastrointestinal immune-related adverse events (gi-irAE), such as colitis and diarrhea in a mammalian subject undergoing a treatment with a PD-1 antagonist, a CTLA4 antagonist, or both a PD-1 antagonist and a CTLA4 antagonist.
- gi-irAE gastrointestinal immune-related adverse events
- These treatments encompass administering a therapeutically effective amount of a polypeptide that inhibits MAdCAM- ⁇ 4 ⁇ 7 integrin binding to the subject.
- Treatment refers to both therapeutic treatment, i.e. for those already with gi-irAE, as well as preventative treatment, when a polypeptide that inhibits MAdCAM- ⁇ 4 ⁇ 7 integrin binding is administered to the subject before the emergence of a gi-irAE. Both therapeutic and preventative treatments can result in gi-irAE “prevention,” which refers to a treatment that results in the absence or reduction in the severity of an adverse event.
- the population includes subjects for which a gi-irAE is prevented.
- An "immune-related adverse event” is an undesirable disorder induced, or exacerbated, by the on-target effect of an immune treatment, such as an immune oncology treatment.
- exemplary irAEs include colitis, diarrhea, dermatitis, hepatitis, endocrinopathies, uveitis, nephritis, and combinations thereof. IrAEs can be severe, resulting in treatment delays, interruptions, or discontinuations.
- an immune-related adverse event is a "gastrointestinal immune -related adverse event" (gi-irAE), which is an irAE of the gastrointestinal system, i.e., an undesirable acute disorder of gastrointestinal system induced, or exacerbated, by the on-target effect of an immune treatment, such as an immune oncology treatment.
- a gi-irAE is contrasted to a gastrointestinal disorder caused by an infectious agent (e.g., virus, bacteria, fungus, or protist), or a spontaneous and/or chronic autoimmune disease, e.g., inflammatory bowel disease, such as ulcerative colitis or Crohn's disease.
- infectious agent e.g., virus, bacteria, fungus, or protist
- a spontaneous and/or chronic autoimmune disease e.g., inflammatory bowel disease, such as ulcerative colitis or Crohn's disease.
- Particular gi-irAEs include colitis, ileitis, and diarrhea.
- an existing infectious agent or spontaneous autoimmune disease or IBD e.g. , ulcerative colitis or Crohn's disease will be significantly exacerbated by an immune oncology treatment and, in these embodiments, are gi-irAEs.
- a gi- irAE is induced by an immune oncology treatment, such as the combination of a PD-1 antagonist and a CTLA4 antagonist.
- Immune treatment(s) are therapeutic interventions that activate the immune system to ameliorate a condition, e.g., with one or more biologies (including antibodies, therapeutic proteins, or cells, such as modified cells, e.g. , chimeric antigen receptor (CAR)-T cells), one or more small molecules, or a combination thereof.
- Immune treatments include agonizing immune system activators (positive regulators of the immune system), antagonizing immune system suppressors (e.g. , checkpoint inhibitors), or agonizing immune system activators and antagonizing immune system suppressors.
- an “immune oncology treatment” is an anticancer immune treatment that activates the immune system, e.g., to counteract the immune- suppressive tumor microenvironment that can lead to tumors evading the immune system.
- exemplary immune oncology treatments include treatment with: a PD- 1 (OMIM 600244, human genelD 5133, Homologene 3681) antagonist, such as an anti-PD-1 antibody; a CTLA4 (OMIM 123890; human genelD 1493, Homologene 3820) antagonist, such as an anti-CTLA4 antibody; or both a PD-1 antagonist and a CTLA4 antagonist.
- Other immune oncology treatments include CCR2 antagonists (e.g.
- anti-CCR2 antibodies such as plozalizumab and related antibodies
- pan-RAF kinase inhibitors i.e. , a kinase inhibitor that inhibits more than just the BRAF (wt) and/or BRAFV600 isoforms, see e.g., WO
- immune oncology treatments can be combined with other anti-cancer treatments, such as surgery, chemotherapy, and radiation.
- a "polypeptide that inhibits MAdCAM- ⁇ 4 ⁇ 7 integrin binding” inhibits the interaction between ⁇ 4 ⁇ 7 integrin and MAdCAM (OMIM102670; human GenelD 8174).
- These polypeptides include antibodies that bind an integrin protein complex comprising an ⁇ 4 integrin (OMIM 192975, human GenelD 3676, Homologene 37364), a ⁇ 7 integrin (OMIM 147559; human GenelD 3695, Homologene 20247), or an ⁇ 4 ⁇ 7 integrin complex.
- a polypeptide that inhibits MAdCAM- ⁇ 4 ⁇ 7 integrin binding is '3 ⁇ 4 ⁇ - ⁇ 4 ⁇ 7 integrin therapy.
- a polypeptide that inhibits MAdCAM- ⁇ 4 ⁇ 7 integrin binding is an anti-o ⁇ 7 integrin antibody, such as an antibody that will only bind a4 or ⁇ 7 in the presence of the other, such as vedolizumab or a related antibody, or an antigen-binding fragment thereof.
- the anti-o ⁇ 7 integrin antibody is AMG181 (specific for ⁇ 4 ⁇ 7, see, e.g. , U.S. Patent No.
- polypeptides that inhibit MAdCAM- ⁇ 4 ⁇ 7 integrin binding and can be used consonant with the invention include: anti-MAdCAM antibodies (see, e.g., U.S. Patent No. 8,277,808, PF-00547659 or antibodies described in WO2005/067620); soluble integrin subunits (e.g., complexes comprising a4 and/or ⁇ 7, which lack a transmembrane domain or lack a transmembrane and intracellular domains) such as soluble a4 integrin, soluble ⁇ 7 integrin, or soluble ⁇ 4 ⁇ 7 integrin complex, including fusion proteins, such as Fc fusions, comprising soluble integrin subunits; and soluble MAdCAM (e.g., lacking a transmembrane domain or lacking a transmembrane and intracellular domains), including fusion proteins comprising MAdCAM, such as MAdCAM-Fc chimera, as described in
- Antibody refers to an immunoglobulin or a part thereof, and encompasses any polypeptide comprising an antigen-binding site regardless of the source, species of origin, method of production, and characteristics.
- the term “antibody” includes human, orangutan, mouse, rat, rabbit, goat, sheep, and chicken antibodies. The term includes but is not limited to polyclonal, monoclonal, monospecific, polyspecific, non-specific, humanized, camelized, single-chain, chimeric, synthetic, recombinant, hybrid, mutated, and CDR-grafted antibodies.
- antibody fragments such as Fab, F(ab')2, Fv, scFv, Fd, dAb, VHH (also referred to as nanobodies), and other antibody fragments that retain the antigen-binding function.
- antigen-binding domain refers to the part of an antibody that comprises the area specifically binding to or complementary to a part or all of an antigen. Where an antigen is large, an antibody may only bind to a particular part of the antigen.
- epipe or “antigenic determinant” is a portion of an antigen molecule that is responsible for specific interactions with the antigen-binding domain of an antibody.
- An antigen-binding domain may be provided by one or more antibody variable domains (e.g., a so-called Fd antibody fragment consisting of a VH domain).
- An antigen-binding domain can comprise an antibody light chain variable region (VL) and an antibody heavy chain variable region (VH).
- Antibody variable regions comprise complementary determining regions (CDRs), which together determine the specificity of the antibody.
- Antibodies from camels and llamas include a unique kind of antibody, which is formed by heavy chains only and is devoid of light chains.
- the antigen-binding site of such antibodies is one single domain, referred to as VHH.
- antibodies raised, or engineered, to have this topology have been termed “camelized antibodies” or “nanobodies”. See, e.g., U.S. Patent Nos. 5,800,988 and 6,005,079 and International Application Publication Nos. WO 94/04678 and WO 94/25591, which are incorporated by reference.
- antibodies for use in the methods provided by the invention are human, humanized, or chimeric.
- Antibodies for use in the methods provided by the invention can use different framework regions in different embodiments, including human: IgGl, IgG2, IgG3, or IgG4, including chimera thereof.
- an antibody that is a "related antibody” (which encompasses a “related antigen-binding fragment") of a reference antibody encompasses antibodies (and antigen-binding fragments thereof) that: compete with the reference antibody for binding the target antigen (e.g.
- competition for the same, overlapping, or adjacent epitopes have the epitopic specificity of the reference antibody, comprise the complementarity determining regions (CDRs) of the reference antibody (in some embodiments, there may be up to 1, 2, 3, 4, or 5 conservative amino acid substitutions in the whole of the CDRs, or up to 1 or 2 conservative substitutions in each CDR), or comprise the variable heavy and variable light domains of the reference antibody (or may have at least 80, 85, 90, 95, 96, 97, 98, 99%, or more amino acid identity to the variable domains, where any amino acid changes are in the framework region and may be conservative or non-conservative).
- CDRs complementarity determining regions
- conservative substitutions are determined by BLASTp's default parameters, while, in other embodiments, conservative mutations are within class substitutions, where the classes are aliphatic (glycine, alanine, valine, leucine, isoleucine), hydroxyl or sulphur/selenium-containing (serine, cysteine, selenocysteine, threonine, methionine), cyclic (proline), armotaic (phenylalanine, tyrosine, tryptophan), basic (histidine, lysine, arginine), and acidic and amides (aspartate, glutamate, asparagine, glutamine).
- classes are aliphatic (glycine, alanine, valine, leucine, isoleucine), hydroxyl or sulphur/selenium-containing (serine, cysteine, selenocysteine, threonine, methionine), cyclic (
- a vedolizumab related antibody in different embodiments may, for example, compete with vedolizumab for binding ⁇ 4 ⁇ 7 integrin, have the epitopic specificity of vedolizumab, comprise the complementarity determining regions (CDRs) of vedolizumab, or comprise the variable heavy and variable light domains of vedolizumab.
- CDRs complementarity determining regions
- an antibody can be replaced with an antigen-binding molecule based on a scaffold other than an
- non-immunoglobulin scaffolds known in the art include small modular immunopharmaceuticals (see, e.g., U.S. Patent Application Publication Nos. 20080181892 and 20080227958), tetranectins, fibronectin domains (e.g., AdNectins, see U.S. Patent Application Publication No. 2007/0082365, published April 12, 2007), protein A, lipocalins (see, e.g., U.S. Patent No. 7,118,915), ankyrin repeats, and thioredoxin.
- small modular immunopharmaceuticals see, e.g., U.S. Patent Application Publication Nos. 20080181892 and 20080227958
- tetranectins e.g., AdNectins, see U.S. Patent Application Publication No. 2007/0082365, published April 12, 2007
- protein A e.g., lipocalins (see, e.
- Molecules based on non-immunoglobulin scaffolds are generally produced by in vitro selection of libraries by phage display (see, e.g., Hoogenboom, Method Mol. Biol. 178: 1-37 (2002)), ribosome display (see, e.g., Hanes et al., FEBS Lett. 450: 105-110 (1999) and He and Taussig, /. Immunol. Methods 297:73-82 (2005)), or other techniques known in the art (see also Binz et al., Nat. Biotech. 23: 1257-68 (2005); Rothe et al., FASEB J. 20: 1599-1610 (2006); and U.S. Patent Nos. 7,270,950; 6,518,018; and 6,281,344) to identify high-affinity binding sequences.
- PD-1 Programmed Death 1 protein
- PD-1 is recognized as an important player in immune regulation and the maintenance of peripheral tolerance.
- PD-1 is moderately expressed on naive T, B and NKT cells and up-regulated by T/B cell receptor signaling on lymphocytes, monocytes and myeloid cells (Sharpe, A.H, et al. (2007) Nature Immunology; 8:239-245).
- PD-1 antagonist means any chemical compound or biological molecule that regulates (in particular embodiments, block or inhibit) the interaction with PD-1 and its cognate ligands (e.g.
- PD-L1 and/or PD-L2 expressed on the surface of interacting cell types such as T cells, cancer cells, macrophages and antigen presenting cells (APCs).
- PD-1 human GenelD 29126
- Alternative names or synonyms for PD-1 (human GenelD 29126) and its ligands include: PDCD1, PD1, CD279 and SLEB2 for PD-1 ; PDCD1L1, PD-L1, B7H1, B7-4, CD274 and B7-H for PD-L1; and PDCD1L2, PDL2, B7-DC, Btdc and CD273 for PD-L2.
- the PD-1 antagonist inhibits or blocks binding of human PD-L1 to human PD-1, and preferably inhibits or blocks binding of both human PD-L1 and PD-L2 to human PD-1.
- Human PD-1 amino acid sequences can be found in NCBI Locus No.: NP 005009.
- Human PD-L1 and PD- L2 amino acid sequences can be found in NCBI Locus No.: NP_054862 and NP_079515, respectively.
- PD-1 antagonists useful in any of the treatment methods, medicaments and uses of the present invention include a monoclonal antibody (mAb), or antigen binding fragment thereof, which specifically binds to PD-1 or PD-L1, and preferably specifically binds to human PD-1 or human PD-L1.
- the mAb may be a human antibody, a humanized antibody or a chimeric antibody, and may include a human constant region.
- the human constant region is selected from the group consisting of IgGl, IgG2, IgG3 and IgG4 constant regions, and in some embodiments, the human constant region is an IgGl or IgG4 constant region.
- the antigen binding fragment is selected from the group consisting of Fab, Fab'-SH, F(ab')2, scFv and Fv fragments.
- Administering a PD-1 antagonist to inhibit PD-1 activity is an "anti-PD-1 treatment.”
- mAbs that bind to human PD-1 are described in US7521051, US8779105, US8008449, US8900587, US8952136, US8354509, US8735553, US9102728, US8993731, US9102727, US9181342, US8927697, US8945561, US748802, US7322582, US7524498 and US9205148.
- Specific anti-human PD-1 mAbs useful as the PD-1 antagonist in the treatment methods, medicaments and uses of the present invention include, but are not limited to: pembrolizumab (formerly MK-3475 and lambrolizumab; see CAS: 1374853-91-4, KEGG: D10574), marketed in the USA under the tradename KEYTRUDA ® , a humanized IgG4 mAb with the structure described in WHO Drug Information, Vol. 27, No.
- nivolumab (formerly ONO-4538, MDX1106 or BMS- 936558; see CAS: 946414-94-4, KEGG: D10316, PubChem: 163312346), marketed in the USA under the tradename OPDIVO , a human IgG4 mAb with the structure described in WHO Drug Information, Vol. 27, No. 1, pages 68-69 (2013), or a related antibody;
- pidilizumab also known as CT-011, hBAT or hBAT-1 ; see CAS: 1036730-42-3, PubChem: 172232483, KEGG: D10390
- a human IgGl mAb with the structure described in WHO Drug Information, Vol. 26, No. 4, page 434 (2012), or a related antibody
- the humanized antibodies h409Al 1, h409A16 and h409A17 which are described in WO2008/156712, or related antibodies
- PDR-100 SHR-1210; REGN-2810; MEDI-0680; BGB-108; and PF- 06801591.
- Specific anti-human PD-L1 mAbs useful as the PD-1 antagonist in the treatment methods, medicaments and uses of the present invention include, but are not limited to atezolizumab (MPDL3280A), BMS-936559, durvalumab (MEDI4736), avelumab (MSB0010718C) and an antibody which comprises the heavy chain and light chain variable regions of SEQ ID NO:24 and SEQ ID NO:21, respectively, of WO2013/019906, or comprise the CDRs of these variable domains.
- immunoadhesion molecules that specifically bind to PD-1 are described in WO2010/027827 and WO2011/066342.
- AMP- 224 also known as B7- DCIg
- B7- DCIg a PD-L2-FC fusion protein and binds to human PD-1.
- the PD-1 antagonist is selected from nivolumab,
- pembrolizumab PDR-001, SHR-1210, AMP-224, REGN-2810, MEDI-0680, BGB-108, PF- 06801591, atezolizumab, durvalumab, and BMS-936559, and AMP-224.
- the PD-1 antagonist is selected from nivolumab,
- pembrolizumab PDR-001, SHR-1210, AMP-224, REGN-2810, MEDI-0680, BGB-108, and PF-06801591, and AMP-224.
- the PD-1 antagonist is selected from pembrolizumab and nivolumab.
- the PD-1 antagonist is nivolumab. [0038] In some embodiments, the PD-1 antagonist is pembrolizumab.
- the PD-1 antagonist is selected from atezolizumab, durvalumab, and BMS-936559.
- the PD- 1 antagonist is a monoclonal antibody, or antigen binding fragment thereof, which comprises an antigen binding fragment of nivolumab.
- the PD- 1 antagonist is a monoclonal antibody, or antigen binding fragment thereof, which comprises an antigen binding fragment of pembrolizumab.
- the PD- 1 antagonist is a monoclonal antibody, or antigen binding fragment thereof, which specifically binds to human PD-1 and comprises (a) a heavy chain variable region of an antibody described herein or a variant thereof, and (b) a light chain variable region of an antibody described herein or a variant thereof.
- a variant of a heavy chain variable region sequence is identical to the reference sequence except having up to seventeen conservative amino acid substitutions in the framework region (i.e., outside of the CDRs), and preferably has less than ten, nine, eight, seven, six or five conservative amino acid substitutions in the framework region.
- a variant of a light chain variable region sequence is identical to the reference sequence except having up to five conservative amino acid substitutions in the framework region (i.e., outside of the CDRs), and preferably has less than four, three, or two conservative amino acid substitutions in the framework region.
- Human CTLA4 (CYTOTOXIC T LYMPHOCYTE- ASSOCIATED 4, a.k.a. CD 152) is an immunoglobulin superfamily protein expressed on activated T cells. Human versions of the CTLA4 gene were cloned in the late 1980' s and early 1990' s. Sequences and homologs for CTLA4 are known and readily available. See, for example, OMIM 123890; human genelD 1493, Homologene 3820 for reference sequences, which are incorporated by reference.
- Soluble CTLA4 acts, at least in part, to block CD28-mediated T-cell activation, thus inhibiting CTLA4 can, inter alia, de-repress T-cell activation and activate the immune system, which, in turn, can then attack cancer cells.
- One way to inhibit CTLA4 is with anti- CTLA4 antibodies or antigen binding fragments thereof.
- Use of CTLA4 antagonists for inhibiting CTLA4 activity is an "anti-CTLA4 therapy."
- CTLA4 antagonists include anti- CTLA4 antibodies.
- an anti-CTLA4 antibody for use in the methods provided by the invention is ipilimumab (sold under the trade name YERVOY ®, registered by Bristol-Myers Squibb Company) or a related antibody or antigen-binding fragment thereof.
- U.S. Patent Nos. 6,984,720 and 7,605,238 provide sequences for ipilimumab, and are incorporated by reference. See also CAS 477202-00-9, PubChem 47206447, and Kegg D04603.
- U.S. Patent No. 9,084,776 which is incorporated by reference, describes combination methods using anti-PD-1 antibodies in conjunction with CTLA4 antibodies for cancer treatment that can be adapted for use consonant with the present invention, i.e., administering one or more polypeptides that inhibit MAdCAM-a4 7 integrin binding to ameliorate gi- irAEs from the anti-PD-1 therapy/anti-CTLA4 therapy combination.
- 8,685,394 may also be adapted for use in the present invention, e.g., by administering one or more polypeptides that inhibit MAdCAM-a4 7 integrin binding to ameliorate gi- irAEs from the anti-CTLA4 treatment combination, which may, optionally, also be included with, for example, an anti-PD- 1 treatment.
- a light- activated therapy can be combined with anti-CTLA4 treatment and/or anti-PD- 1 treatment, and one or more polypeptides that inhibit MAdCAM-a4 7 integrin binding are provided to ameliorate gi-irAEs.
- U.S. Patent Application Publication No. 20100330093 describes combinations of various CTLA4 antibodies with thymosin peptides and these antibodies, and related antibodies, can be used alone, or in combination with thymosin peptides consonant with the invention.
- the combination anti-CTLA4 antibodies with anti-CD 137 (agonist) therapy in described in U.S. Patent No.
- 8,475,790 can also be enhanced by the methods provided by the invention, e.g., by administering one or more polypeptides that inhibit MAdCAM-a4 7 integrin binding to ameliorate gi-irAEs from the combination.
- Additional anti-CTLA4 treatment combination therapies that may benefit from the methods provided by the invention, e.g., by administering one or more polypeptides that inhibit MAdCAM-a4 7 integrin binding to ameliorate gi-irAEs, are described in: US20130156768A1 (describing combination treatments with anti-CTLA4 treatment and BRAF inhibitors),
- WO2013019620A2 (describing combinations treatments with anti-CTLA4 treatment, BRAF inhibitors, and MEK inhibitors), US20150283234A1 (anti-CTLA4 treatment and anti-KIR treatment combinations), US20140323533A1 (anti-CTLA4 in combination with tubulin modulators), WO2015058048A1 (which describes combinations with VEGF antagonists), US20150328311 (describing combinations with MEDI4736), WO2015125159A1 (describing combinations with IL-2RP agonists, optionally with anti-PD-1 treatment).
- the cell surface molecule is a heterodimer of an c chain (CD49D, ITGA4) and a ⁇ 7 chain (ITGB7). Each chain can form a heterodimer with an alternative integrin chain, to form a ⁇ or ⁇ 3 ⁇ 4 ⁇ 7 .
- Human a 4 and ⁇ 7 genes (GenBank (National Center for Biotechnology Information, Bethesda, MD) RefSeq Accession numbers
- NM_000885 and NM_000889, respectively are expressed by B and T lymphocytes, particularly memory CD4+ lymphocytes.
- ⁇ 4 ⁇ 7 can exist in either a resting or activated state.
- Ligands for ⁇ 4 ⁇ 7 integrin include vascular cell adhesion molecule (VCAM), fibronectin, and mucosal addressin (MAdCAM (e.g., MAdCAM-1)).
- the ⁇ 4 ⁇ 7 integrin mediates lymphocyte trafficking to GI mucosa and gut-associated lymphoid tissue (GALT) through adhesive interaction with mucosal addressin cell adhesion molecule- 1 (MAdCAM- 1), which is expressed on the endothelium of mesenteric lymph nodes and GI mucosa.
- MAdCAM- 1 mucosal addressin cell adhesion molecule- 1
- a variety of polypeptides can inhibit MAdCAM- ⁇ 4 ⁇ 7 integrin binding, including: anti-o ⁇ 7 antibodies, anti-MAdCAM antibodies, soluble integrin subunits (including fusion proteins, such as Fc-fusions), and soluble MAdCAM (including fusion proteins, such as Fc-fusions).
- Use of any of these polypeptides to inhibit MAdCAM- ⁇ 4 ⁇ 7 integrin binding is an "anti-o ⁇ 7 treatment.”
- ⁇ - ⁇ 4 ⁇ 7 antibodies for use in the methods provided by the invention can, in certain embodiments, bind to an epitope on the a4 chain (e.g., humanized MAb 21.6 (Bendig et al, U.S. Pat. No. 5,840,299), on the ⁇ 7 chain (e.g., FIB504 or a humanized derivative (e.g., Fong et al, U.S. Pat. No. 7,528,236)), or to a combinatorial epitope formed by the association of the a4 chain with the ⁇ 7 chain.
- an epitope on the a4 chain e.g., humanized MAb 21.6 (Bendig et al, U.S. Pat. No. 5,840,299)
- the ⁇ 7 chain e.g., FIB504 or a humanized derivative (e.g., Fong et al, U.S. Pat. No. 7,528,236)
- the antibody is specific for the ⁇ 4 ⁇ 7 integrin complex, e.g., the antibody binds a combinatorial epitope on the ⁇ 4 ⁇ 7 complex, but does not bind an epitope on the a4 chain or the ⁇ 7 chain unless the chains are in association with each other.
- association of a4 integrin with ⁇ 7 integrin can create a combinatorial epitope for example, by bringing into proximity residues present on both chains which together comprise the epitope or by conformationally exposing on one chain, e.g., the a4 integrin chain or the ⁇ 7 integrin chain, an epitopic binding site that is inaccessible to antibody binding in the absence of the proper integrin partner or in the absence of integrin activation.
- the anti-o ⁇ 7 antibody binds both the a4 integrin chain and the ⁇ 7 integrin chain, and thus, is specific for the ⁇ 4 ⁇ 7 integrin complex.
- Such antibodies which are specific for the ⁇ 4 ⁇ 7 integrin complex, can bind ⁇ 4 ⁇ 7 but not bind ⁇ 4 ⁇ 1, and/or not bind ⁇ 3 ⁇ 4 ⁇ 7, for example.
- the anti-o ⁇ 7 antibody binds to the same or substantially the same epitope as the Act-1 antibody (Lazarovits, A. I. et al, J. Immunol, 133(A): 1857-1862 (1984), Schweighoffer et al, J. Immunol , 151(2): 717-729, 1993; Bednarczyk et al, J. Biol. Chem. , 269(11): 8348-8354, 1994).
- Murine ACT-1 Hybridoma cell line which produces the murine Act-1 monoclonal antibody, was deposited under the provisions of the Budapest Treaty on Aug. 22, 2001, on behalf of Millennium Pharmaceuticals, Inc., 40 Landsdowne Street, Cambridge, MA 02139, U.S.A., at the American Type Culture Collection, 10801 University Boulevard, Manassas, VA. 20110-2209, U.S.A., under Accession No. PTA-3663.
- the anti-o ⁇ 7 antibody is a human antibody or an ⁇ 4 ⁇ 7 binding protein using the CDRs provided in U.S. Patent Application Publication No. 2010/0254975.
- the anti-o ⁇ 7 antibody inhibits binding of ⁇ 4 ⁇ 7 to one or more of its ligands (e.g. the mucosal addressin, e.g., MAdCAM (e.g., MAdCAM- 1), fibronectin, and/or vascular addressin (VCAM)).
- MAdCAM mucosal addressin
- VCAM vascular addressin
- Primate MAdCAMs are described in the PCT publication WO 96/24673, the entire teachings of which are incorporated herein by this reference.
- the anti-a4 7 antibody inhibits binding of ⁇ 4 ⁇ 7 to MAdCAM (e.g., MAdCAM-1) and/or fibronectin without inhibiting the binding of VCAM.
- an anti-a4 7 antibody for use in the methods provided by the invention is vedolizumab (CAS Registry number 943609-66-3, American Chemical Society) or a related antibody.
- the anti-a4 7 antibodies are humanized versions of the mouse Act-1 antibody discussed supra.
- the humanized anti-a4 7 antibody will contain a heavy chain that contains the three heavy chain
- CDRs complementarity determining regions
- suitable human heavy chain framework regions CDR1, SEQ ID NO:4, CDR2, SEQ ID NO:5 and CDR3, SEQ ID NO: 6
- a light chain that contains the three light chain CDRs (CDR1, SEQ ID NO: 7, CDR2, SEQ ID NO: 8 and CDR3, SEQ ID NO: 9) of the mouse Act- 1 antibody and suitable human light chain framework regions.
- the humanized Act-1 antibody can contain any suitable human framework regions, including consensus framework regions, with or without amino acid substitutions. For example, one or more of the framework amino acids can be replaced with another amino acid, such as the amino acid at the corresponding position in the mouse Act- 1 antibody.
- the human constant region or portion thereof can be derived from the ⁇ or ⁇ light chains, and/or the ⁇ (e.g., ⁇ , j2, j3, ⁇ 4), ⁇ , a (e.g., ⁇ , ⁇ 2), ⁇ or ⁇ heavy chains of human antibodies, including allelic variants.
- ⁇ e.g., ⁇ , j2, j3, ⁇ 4
- ⁇ e.g., ⁇ , ⁇ 2
- ⁇ or ⁇ heavy chains of human antibodies including allelic variants.
- a particular constant region (e.g., IgGl), variant or portions thereof can be selected in order to tailor effector function.
- a mutated constant region can be incorporated into a fusion protein to minimize binding to Fc receptors and/or ability to fix complement (see e.g., Winter et al, GB 2,209,757 B; Morrison et al, WO 89/07142; Morgan et al., WO 94/29351, Dec. 22, 1994).
- Humanized versions of Act-1 antibody were described in PCT publications nos. WO98/06248 and WO07/61679, the entire teachings of each of which are incorporated herein by this reference.
- the anti-a4 7 humanized antibodies for use in the methods provided by the invention comprise a heavy chain variable region of vedolizumab, e.g., comprising amino acids 20 to 140 of SEQ ID NO: 1 and a light chain variable region of vedolizumab or a variant sequence, e.g. , comprising amino acids 20 to 131 of SEQ ID NO:2 or amino acids 1 to 112 of SEQ ID NO:3.
- a suitable human constant region(s) can be present.
- the humanized anti-a4 7 antibody can comprise a heavy chain that comprises amino acids 20 to 470 of SEQ ID NO: l and a light chain comprising amino acids 1 to 219 of SEQ ID NO:3.
- the humanized anti-a4 7 antibody can comprise a heavy chain that comprises amino acids 20 to 470 of SEQ ID NO: l and a light chain comprising amino acids 20 to 238 of SEQ ID NO:2.
- the humanized light chain of vedolizumab with two mouse residues switched for human residues is more human than the light chain of LDP-02 (compare SEQ ID NO: 2 to 3).
- LDP-02 has the somewhat hydrophobic, flexible alanine 114 and a hydrophilic site (Aspartate 115) that are replaced in vedolizumab with the slightly hydrophilic hydroxyl-containing threonine and hydrophobic, potentially inward facing valine residue, respectively.
- substitutions to the antibody sequence can be, for example, mutations to the heavy and light chain framework regions, such as a mutation of isoleucine to valine on residue 2 of human GM607 CL kappa light chain variable region; a mutation of methionine to valine on residue 4 of human GM607 CL kappa light chain variable region; a mutation of alanine to glycine on residue 24 of human 21/28 CL heavy chain variable region; a mutation of arginine to lysine at residue 38 of 21/28 CL heavy chain variable region; a mutation of alanine to arginine at residue 40 of 21/28 CL heavy chain variable region; a mutation of methionine to isoleucine on residue 48 of 21/28 CL heavy chain variable region; a mutation of isoleucine to leucine on residue 69 of 21/28 CL heavy chain variable region; a mutation of arginine to valine on residue 71 of 21/28 CL heavy chain variable region; a mutation of th
- the anti-a4 7 humanized antibodies for use in the methods provided by the invention comprise a heavy chain variable region that has at least about: 95%, 96%, 97%, 98%, or 99% sequence identity to amino acids 20 to 140 of SEQ ID NO: l (e.g. , are 100% identical), and a light chain variable region that has at least about: 95%, 96%, 97%, 98%, or 99% sequence identity to amino acids 20 to 131 of SEQ ID NO:2 or amino acids 1 to 112 of SEQ ID NO:3 (e.g. , are 100% identical to either of these reference sequences).
- anti-a4 7 humanized antibodies may have 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more, amino acid substitutions relative to the foregoing reference sequences.
- any amino acid substitutions are conservative substitutions.
- amino acid substitutions are non-conservative.
- amino acid substitutions are in the framework regions.
- substitutions can be in the CDRs and in these embodiments, the substitutions are preferably conservative.
- Amino acid sequence identity can be determined using a suitable sequence alignment algorithm, such as the Lasergene system (DNASTAR, Inc., Madison, WI) or BLASTp using the default parameters.
- the anti-a4 7 antibody for use in the methods provided by the invention is vedolizumab (CAS, American Chemical Society, Registry number 943609-66-3).
- Vedolizumab and related antibodies may be administered in the methods provided by the invention by any suitable method, such as by one or more of intravenous injection, subcutaneous injection, or infusion.
- suitable method such as by one or more of intravenous injection, subcutaneous injection, or infusion.
- Formulations suitable for intravenous injection which may be prepared in lyophilized form, are described in U.S. Patent Application Publication No. 20140377251, which is incorporated by reference.
- Stable liquid formulations suitable for, e.g. , subcutaneous injection are described in U.S. Patent Application Publication No. 20140341885, which is incorporated by reference.
- vedolizumab is administered at a dose of 50 mg, 100 mg, 108 mg, 165 mg, 200mg, 216 mg, 300 mg, 450 mg or 500 mg, or more.
- the vedolizumab is administered, for example subcutaneously, at a dose of 0.05 mg/kg, 0.10 mg/kg, 0.15 mg/kg, 0.2 mg/kg, 0.25 mg/kg, 0.3 mg/kg. 0.4 mg/kg, or 0.5 mg/kg, at a dose of 108 mg, 200 mg, 216 mg, 450mg, 160 mg or 165 mg.
- the vedolizumab may be administered once per day, per week, per month, or per year.
- the vedolizumab is administered at zero, two and six weeks, and then every four weeks or every eight weeks thereafter. In some embodiments, vedolizumab is administered one or more times, and then at least one month, at least six months, or at least one year later, vedolizumab is again administered one or more times. In some embodiments, 200, 300, or 450 mg vedolizumab may be administered by intravenous infusion at zero, two, and six weeks, and then at four weeks intervals or eight week intervals thereafter.
- 200, 300, or 450 mg vedolizumab may be administered by intravenous infusion at zero, two, and six weeks, and then at two, three or four week intervals, 108, 165, or 216 mg of vedolizumab may be administered subcutaneously.
- 200, 450, or 600 mg vedolizumab may be administered by intravenous infusion at zero, two, and four weeks, and then a final dose is administered at about 75, 80, 85, 90, 95, 100 days, between about 85 and about 90 days, or between about 85 to about 100 days.
- vedolizumab is administered at a dose of 200 mg, 300 mg, 400 mg, 450 mg, 500 mg, 600 mg, or more.
- the vedolizumab may be administered before, on the same day, or after administration of an anti-PD-1 antagonist and/or an anti-CTLA4 antibody.
- the vedolizumab is administered at least 30 minutes, at least 45 minutes, at least 60 minutes, or at least 90 minutes before administration of the anti-PDl-1 antibody and/or anti-CTLA4 antibody.
- 200 or 450 mg vedolizumab may be administered by intravenous infusion at zero, two, and four weeks, and then a final dose of vedolizumab may be administered at twelve weeks or thirteen weeks.
- the final dose of vedolizumab may be administered during days 84-91, days 92-99, days 84- 100, or days 92-100.
- vedolizumab is administered intravenously at four week or eight week intervals.
- vedolizumab is administered intravenously at a dose of 200 mg at week 1, day 1, week 3, day 15, week 5, day 29, and week 13, day 85; nivolumab and ipilimumab is administered intravenously at a dose of 1 mg/kg every three weeks for four doses; and nivolumab is administered intravenously at a dose of 3 mg/kg every two weeks beginning on week 13, day 85.
- vedolizumab is administered intravenously at a dose of 200 mg at week 1, day 1, week 3, day 15, week 5, day 29, and week 13, day 85; nivolumab and ipilimumab is administered intravenously at a dose of 1 mg/kg every three weeks for four doses; and nivolumab is administered intravenously at a flat dose of 240 mg every two weeks beginning on week 13, day 85.
- vedolizumab is administered intravenously at a dose of 450 mg at week 1, day 1, week 3, day 15, week 5, day 29, and week 13, day 85; nivolumab and ipilimumab is administered intravenously at a dose of 1 mg/kg every three weeks for four doses; and nivolumab is administered intravenously at a dose of 3 mg/kg every two weeks beginning on week 13, day 85.
- vedolizumab is administered intravenously at a dose of 450 mg at week 1, day 1, week 3, day 15, week 5, day 29, and week 13, day 85; nivolumab and ipilimumab is administered intravenously at a dose of 1 mg/kg every three weeks for four doses; and nivolumab is administered intravenously at a flat dose of 240 mg every two weeks beginning on week 13, day 85.
- the invention provides, inter alia, methods of treating gi-irAEs (or treating cancer, e.g., by treating gi-irAEs) in a subject by inhibiting MAdCAM-a4 7 integrin binding.
- a subject treated according to the methods provided by the invention relative to a suitable control undergoing an immune oncology treatment with a PD- 1 antagonist, a CTLA4 antagonist, or both a PD-1 antagonist and a CTLA4 antagonist, but not the polypeptide that inhibits MAdCAM- ⁇ 4 ⁇ 7 integrin binding, the subject exhibits one or more of: increased compliance (e.g., reduced incidence of treatment interruption, dose reduction, or discontinuation, higher rate of treatment completion, longer treatment duration), such as at least: 5, 10, 15, 20, 25, 30, 35, 40, 45, 50%, or more, increased compliance; no significant reduction of efficacy of the immune oncology treatment (e.g.
- gi- irAE e.g., a reduction of the average grade of at least 1, 2, 3, 4 or 5 grades; or reductions in frequency of 20, 30, 40, 50, 60, 70, 80, 90, or 100%, or more of subjects with a particular grade of a gi-irAE, such as colitis or diarrhea
- reduced duration of gi-irAE e.g.
- corticosteroids oral or systemic
- antibiotics oral or parenteral
- non-corticosteroid immunosuppressive medication lower endoscopy, hospitalizations, or a combination thereof (e.g. at least: 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 95, or 99% reduced); or a combination of any of the foregoing.
- the median time for the occurrence of Grade 2/3 colitis with ipilimumab is 6.5 weeks.
- the incidence of diarrhea was 44% with 9% Grade 3/4.
- Colitis was diagnosed in 12% of patients with 8% Grade 3/4. Enterocolitis is more frequently associated with CTLA- 4 inhibition than with PD-1 inhibitors.
- the methods provided by the invention can ameliorate these complications in whole or in part.
- An inhibitor of MAdCAM- ⁇ 4 ⁇ 7 integrin binding restricts its activity to the GI tract and gut lymph tissue and its use in the prevention of gi-irAEs will 1) have no negative impact on T-cell trafficking to tumor or T-cell subpopulations within the tumor microenvironment, and 2) reduce treatment-associated gi-irAEs resulting in clinical benefit with a better safety profile in patients with cancer, such as advanced melanoma, receiving checkpoint inhibitor combination therapy.
- subjects treated by the methods provided by the invention exhibit reduced, or in some embodiments, no grade 3 or 4 (no: Grade 3 colitis, Grade 4 (or Grade 3 that persists or worsens over 3-5 days) colitis or diarrhea), only grade 1-2 diarrhea, or if any grade 2 occurs, that the symptoms resolve, e.g., by symptomatic antidiarrheal treatment without adding prednisone or anti-TNF-a treatment; or reduced, or in some embodiments, no grade 1 or 2 symptoms.
- no, or reduced, grade 4 diarrhea is observed; more particularly, where no, or reduced, grade 3 diarrhea is observed; still more particularly, no, or reduced, grade 2 diarrhea is observed, or still more particularly, no, or reduced, grade 1 diarrhea is observed.
- grade 4 diarrhea is observed; more particularly, where no, or reduced, grade 3 diarrhea is observed; still more particularly, no, or reduced, grade 2 diarrhea is observed, or still more particularly, no, or reduced, grade 1 diarrhea is observed.
- no, or reduced, grade 4 colitis is observed; more particularly, no, or reduced, grade 3 colitis is observed; still more particularly, no, or reduced, grade 2 colitis is observed, or still more particularly, no, or reduced, grade 1 colitis is observed.
- no, or reduced, grade 4 colitis or diarrhea is observed; more particularly, where no, or reduced, grade 3 colitis or diarrhea is observed; still more particularly, no, or reduced, grade 2 colitis or diarrhea is observed, or still more particularly, no, or reduced, grade 1 colitis or diarrhea is observed.
- the methods provided by the invention reduce, or eliminate the frequency of grade 2 symptoms that persist >5 days or recur, for which 0.5 to 2 mg/kg/day prednisone equivalents is normally indicated (with a 1 month tapering of steroids once grade 1 or lower is achieved) with suggested prophylactic antibiotics for opportunistic infections; i.e. , the methods provided by the invention reduce or eliminate the need for corticosteroids and/or prophylactic antibiotics.
- the methods provided by the invention reduce or eliminate the frequency of grade 3 symptoms requiring intervention, such as treatment discontinuation, and
- corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents, and/or prophylactic antibiotics for opportunistic infections and/or lower endoscopy, and/or hospitalization; i.e. , the methods provided by the invention reduce or eliminate the need for corticosteroids, and/or prophylactic antibiotics, and/or lower endoscopy, and/or
- the methods provided by the invention reduce, or eliminate the frequency of grade 4 symptoms requiring intervention, such as treatment discontinuation, and administration of corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents, and/or prophylactic antibiotics for opportunistic infections, and/or lower endoscopy and/or non-corticosteroid immunosuppressive medication, and/or hospitalization; i.e. , the methods provided by the invention reduce or eliminate the need for corticosteroids, and/or prophylactic antibiotics, and/or lower endoscopy, and/or non- corticosteroid immunosuppressive medication, and/or hospitalization.
- grade 4 symptoms requiring intervention such as treatment discontinuation, and administration of corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents, and/or prophylactic antibiotics for opportunistic infections, and/or lower endoscopy and/or non-corticosteroid immunosuppressive medication, and/or
- the methods provided by the invention delay the onset of gi-irAEs, e.g. , the occurrence, of colitis and/or diarrhea is delayed beyond the typical 5-10 week peak occurrence (peak ⁇ week 8), e.g., the methods provided by the invention delay the onset of gi-irAEs by 2, 4, 5, 6, 8, 10 weeks or more; and more particularly, delay the onset and reduce the frequency and/or severity of gi-irAEs that do occur, e.g. , by 1, 2, 3, 4, 5, or 6 weeks; 1, 2, 3, 4, 5, or 6 months, or longer.
- Grade 1 Diarrhea ⁇ 4 stools per day over baseline; colitis: asymptomatic; clinical or diagnostic observations only
- Grade 2 diarrhea: 4-6 stools/day over base line; IV fluids indicated ⁇ 24 hours; not interfering with activities of daily living [ADL]; colitis: abdominal pain, blood in stool
- Grade 3 diarrhea: >7 stools/day over baseline; IV fluids >24 hours; interfering with activities of daily living (ADL); colitis: severe abdominal pain, medical intervention indicated, peritoneal signs); Grade 4 (colitis: life-threatening, perforation).
- grades of gi-irAEs such as colitis or diarrhea are determined by NCI CTCAE 4.03.
- a phase lb study to evaluate the safety, tolerability, and pharmacodynamics of an investigational treatment of vedolizumab in combination with standard of care immune checkpoint inhibitors in patients with advanced melanoma is undertaken. Up to about 52 subjects are enrolled. Approximately 12 subjects are assigned in dose-escalation treatments, with up to 46 subjects in an expansion. From 2-15 sites support the subjects.
- the subjects are adults, either male or female, with histologically confirmed, unresectable stage III or IV melanoma, according to the AJCC staging system, and with a ECOG performance status of 0-1.
- Subjects have adequate bone marrow reserve and renal and hepatic function.
- Subjects with active known or suspected autoimmune disease, or that are undergoing systemic treatment with either corticosteroids (>10mg prednisone or equivalents) or other immunosuppressive medications within 14 days of administration of a study drug administration are excluded, as are subjects with prior treatment with an anti-PD- 1, anti-PDL-1, anti-PDL-2, or anti-CTLA4 antibodies.
- Vedolizumab is administered by IV at a dose of 200 or 450 mg at weeks 1, 3, 5, and 13.
- Nivolumab is administered IV at a dose of 3 mg/kg Q2W, which is the standard of care. Standard of care for nivolumab together with ipilimumab is administered as follows.
- Nivolumab (1 mg/kg) and ipilimumab (3 mg/kg) are both administered IV, Q3W for 4 doses, after which nivolumab (3 mg/kg) is administered IV Q2W until disease progression or unacceptable toxicity.
- Duration of treatment is up to 50 weeks and the period of evaluation is 12 months.
- FIGURE 1 provides a graphic description of this dosing schedule.
- the primary endpoint for this study is the frequency and severity of treatment- emergent adverse events (TEAEs, e.g., colitis or diarrhea), including serious TEAEs.
- TEAEs treatment- emergent adverse events
- vedolizumab in combination with standard of care immune checkpoint inhibitors in patients with advanced melanoma is undertaken. Up to about 52 subjects are enrolled. Approximately 12 subjects are assigned in dose-escalation treatments, with up to 46 subjects in an expansion. From 2-15 sites support the subjects.
- the subjects are adults, either male or female, with histologically confirmed, unresectable stage III or IV melanoma, according to the AJCC staging system, and with a ECOG performance status of 0-1.
- Subjects have adequate bone marrow reserve and renal and hepatic function.
- Subjects with active known or suspected autoimmune disease, or that are undergoing systemic treatment with either corticosteroids (>10mg prednisone or equivalents) or other immunosuppressive medications within 14 days of administration of a study drug administration are excluded, as are subjects with prior treatment with an anti-PD- 1, anti-PDL-1, anti-PDL-2, or anti-CTLA4 antibodies.
- Vedolizumab is administered by IV at a dose of 200 or 450 mg at weeks 1, 3, 5, and 13.
- Nivolumab (1 mg/kg) and ipilimumab (1 mg/kg) are both administered IV, Q3W for 4 doses, after which nivolumab (3 mg/kg or 240 kg flat dose) is administered IV beginning on week 13, day 85 Q2W until disease progression or unacceptable toxicity.
- Duration of treatment is up to 50 weeks and the period of evaluation is 12 months.
- FIGURE 2 provides a graphic description of this dosing schedule.
- the primary endpoint for this study is the frequency and severity of treatment- emergent adverse events (TEAEs, e.g., colitis or diarrhea), including serious TEAEs.
- TEAEs treatment- emergent adverse events
- Secondary endpoints for this study are measures of disease response including objective response rate (ORR) as assessed by the investigator, duration of response (DOR), and progression- free survival (PFS) based on the investigator's assessment using the RECIST guidelines vl.l and overall survival. Changes of microbiome composition and fecal calprotectin in stool samples posttreatment are compared to pretreatment, and changes in serum levels of C-reactive protein pre- and posttreatment are measured.
- ORR objective response rate
- DOR duration of response
- PFS progression- free survival
- Bioassay entries including the annotations therein, such as structures and assays, et cetera), are hereby incorporated by reference in their entirety.
- DVVMTOSPLSLPVTPG EPASISCRSSOSLAKSYGNTYLSWYLOKPGOSPOLLIYGISN RFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCLQGTHQPYTFGQGTKVEI ⁇ RAD AAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQD SKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC*
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Immunology (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
L'invention concerne, entre autres, des procédés de réduction d'événements indésirables liés à l'immunité gastro-intestinale, tels que la colite et la diarrhée, chez des sujets subissant un traitement immunitaire, par exemple un traitement immunitaire oncologique, tel qu'une polythérapie pour un mélanome associant un anticorps anti-CTLA4 et un anticorps anti-PD-1.<i /> Sous certains aspects, les procédés comprennent l'administration d'une quantité thérapeutiquement efficace d'un polypeptide qui inhibe la liaison MAdCAM-intégrine, par exemple un anticorps contre l'intégrine α4β7 tel que le vedolizumab, ou un anticorps apparenté.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201662312826P | 2016-03-24 | 2016-03-24 | |
US62/312,826 | 2016-03-24 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2017165742A1 true WO2017165742A1 (fr) | 2017-09-28 |
Family
ID=58489429
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2017/023981 WO2017165742A1 (fr) | 2016-03-24 | 2017-03-24 | Procédés de traitement d'événements indésirables liés à l'immunité gastro-intestinale dans des polythérapies anti-ctla4 et anti-pd-1 |
Country Status (3)
Country | Link |
---|---|
AR (1) | AR107983A1 (fr) |
TW (1) | TW201735949A (fr) |
WO (1) | WO2017165742A1 (fr) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN109793891A (zh) * | 2017-11-17 | 2019-05-24 | 韩震 | 多肽化合物在制备提高治疗性抗体疗效的佐剂中的应用与组合物及其制备方法 |
WO2021213523A1 (fr) * | 2020-04-24 | 2021-10-28 | 信达生物制药(苏州)有限公司 | Utilisations d'une combinaison d'anticorps anti-pd-1 et d'anticorps anti-ctla-4 dans la prévention ou le traitement du cancer |
US11389533B2 (en) | 2016-06-12 | 2022-07-19 | Takeda Pharmaceutical Company Limited | Method of treating inflammatory bowel disease |
WO2022178557A3 (fr) * | 2021-02-22 | 2022-10-13 | Pandion Operations, Inc. | Agents thérapeutiques ciblant le pancréas et leurs utilisations |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN111944850B (zh) * | 2020-08-28 | 2023-03-31 | 澳门大学 | 表达抗cd22嵌合抗原受体和pd-l1阻断蛋白的细胞的制备方法、表达载体及应用 |
Citations (69)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US748802A (en) | 1904-01-05 | Territory | ||
WO1989007142A1 (fr) | 1988-02-05 | 1989-08-10 | Morrison Sherie L | Anticorps a region constante a modification de domaine |
GB2209757B (en) | 1987-03-18 | 1990-10-24 | Medical Res Council | Altered antibodies |
WO1994004678A1 (fr) | 1992-08-21 | 1994-03-03 | Casterman Cecile | Immunoglobulines exemptes de chaines legeres |
WO1994025591A1 (fr) | 1993-04-29 | 1994-11-10 | Unilever N.V. | PRODUCTION D'ANTICORPS OU DE FRAGMENTS FONCTIONNALISES D'ANTICORPS, DERIVES DES IMMUNOGLOBULINES A CHAINE LOURDE DE $i(CAMELIDAE) |
WO1994029351A2 (fr) | 1993-06-16 | 1994-12-22 | Celltech Limited | Anticorps |
WO1996024673A1 (fr) | 1995-02-10 | 1996-08-15 | Leukosite, Inc. | Adressines vasculaires de muqueuses et leurs utilisations |
WO1998006248A2 (fr) | 1996-08-15 | 1998-02-19 | Leukosite, Inc. | IMMUNOGLOBINE HUMANISE REAGISSANT AVEC L'INTEGRINE α4β7 |
US5840299A (en) | 1994-01-25 | 1998-11-24 | Athena Neurosciences, Inc. | Humanized antibodies against leukocyte adhesion molecule VLA-4 |
US6005079A (en) | 1992-08-21 | 1999-12-21 | Vrije Universiteit Brussels | Immunoglobulins devoid of light chains |
US6281344B1 (en) | 1997-01-21 | 2001-08-28 | The General Hospital Corporation | Nucleic acid-protein fusion molecules and libraries |
US20030086930A1 (en) | 2001-05-23 | 2003-05-08 | Mueller Eileen E. | Uses of anti-CTLA-4 antibodies |
US6682736B1 (en) | 1998-12-23 | 2004-01-27 | Abgenix, Inc. | Human monoclonal antibodies to CTLA-4 |
US20050095238A1 (en) | 2000-04-14 | 2005-05-05 | Millennium Pharmaceuticals, Inc. | Method of administering an antibody |
WO2005067620A2 (fr) | 2004-01-09 | 2005-07-28 | Pfizer Inc. | Anticorps a madcam |
US6984720B1 (en) | 1999-08-24 | 2006-01-10 | Medarex, Inc. | Human CTLA-4 antibodies |
WO2006029219A2 (fr) | 2004-09-08 | 2006-03-16 | Ohio State University Research Foundation | Anticorps monoclonaux humains anti-ctla4 dans le traitement du cancer |
US7034121B2 (en) | 2000-01-27 | 2006-04-25 | Genetics Institue, Llc | Antibodies against CTLA4 |
US7118915B2 (en) | 2001-09-27 | 2006-10-10 | Pieris Proteolab Ag | Muteins of apolipoprotein D |
US20070082365A1 (en) | 1998-12-10 | 2007-04-12 | Adnexus Therapeutics, Inc. | Protein scaffolds for antibody mimics and other binding proteins |
WO2007061679A1 (fr) | 2005-11-17 | 2007-05-31 | Millennium Pharmaceuticals, Inc. | IMMUNOGLOBULINE HUMANISEE REACTIVE AVEC L’INTEGRINE α4β7 |
US7270950B2 (en) | 1997-01-21 | 2007-09-18 | The General Hospital Corporation | Nucleic acid-protein fusions and methods of making and selecting fusions |
US7322582B2 (en) | 2003-07-17 | 2008-01-29 | Mind Wurx, Llc | Enhanced shopping cart with lowered center of gravity and frame therefor |
US20080181892A1 (en) | 2004-08-11 | 2008-07-31 | Trubion Pharmaceuticals | Binding Domain Fusion Protein |
US20080227958A1 (en) | 2006-04-14 | 2008-09-18 | Trubion Pharmaceuticals Inc. | Binding proteins comprising immunoglobulin hinge and fc regions having altered fc effector functions |
WO2008156712A1 (fr) | 2007-06-18 | 2008-12-24 | N. V. Organon | Anticorps dirigés contre le récepteur humain de mort programmée pd-1 |
WO2009006389A2 (fr) | 2007-06-29 | 2009-01-08 | Sunesis Pharmaceuticals, Inc. | Composés utiles en tant qu'inhibiteurs de la kinase raf |
US7521051B2 (en) | 2002-12-23 | 2009-04-21 | Medimmune Limited | Methods of upmodulating adaptive immune response using anti-PD-1 antibodies |
US7524498B2 (en) | 2002-05-23 | 2009-04-28 | Curetech Ltd. | Human immunomodulatory monoclonal antibodies for the treatment of cancer |
US7528236B2 (en) | 2004-09-03 | 2009-05-05 | Genentech, Inc. | Humanized anti-beta7 antagonists and uses therefor |
US7605238B2 (en) | 1999-08-24 | 2009-10-20 | Medarex, Inc. | Human CTLA-4 antibodies and their uses |
WO2010027827A2 (fr) | 2008-08-25 | 2010-03-11 | Amplimmune, Inc. | Polypeptides co-stimulateurs ciblés et leurs procédés d'utilisation dans le traitement du cancer |
WO2010064722A1 (fr) | 2008-12-02 | 2010-06-10 | Takeda Pharmaceutical Company Limited | Dérivés de benzothiazole convenant comme agents anticancéreux |
WO2010077634A1 (fr) | 2008-12-09 | 2010-07-08 | Genentech, Inc. | Anticorps anti-pd-l1 et leur utilisation pour améliorer la fonction des lymphocytes t |
US7803904B2 (en) | 1995-09-01 | 2010-09-28 | Millennium Pharmaceuticals, Inc. | Mucosal vascular addressing and uses thereof |
US20100254975A1 (en) | 2009-03-20 | 2010-10-07 | Amgen Inc. | Alpha-4 beta-7 heterodimer specific |
US20100330093A1 (en) | 2007-12-12 | 2010-12-30 | Sciclone Pharmaceuticals, Inc. | Treatment of melanoma with alpha thymosin peptides in combination with antibodies against cytotoxic t lymphocyte-associated antigen 4 (ctla4) |
WO2011066342A2 (fr) | 2009-11-24 | 2011-06-03 | Amplimmune, Inc. | Inhibition simultanée de pd-l1/pd-l2 |
US8008449B2 (en) | 2005-05-09 | 2011-08-30 | Medarex, Inc. | Human monoclonal antibodies to programmed death 1 (PD-1) and methods for treating cancer using anti-PD-1 antibodies alone or in combination with other immunotherapeutics |
US8226946B2 (en) | 2008-08-06 | 2012-07-24 | Light Sciences Oncology, Inc. | Enhancement of light activated therapy by immune augmentation using anti-CTLA-4 antibody |
US8263073B2 (en) | 2008-02-04 | 2012-09-11 | Medarex, Inc. | Anti-CTLA-4 antibodies with reduced blocking of binding of CTLA-4 to B7 and uses thereof |
WO2012151247A2 (fr) | 2011-05-02 | 2012-11-08 | Millennium Pharmaceuticals, Inc. | FORMULATION POUR UN ANTICORPS ANTI-α4β7 |
WO2012151248A2 (fr) | 2011-05-02 | 2012-11-08 | Millennium Pharmaceuticals, Inc. | FORMULATION POUR UN ANTICORPS ANTI-α4β7 |
WO2013019906A1 (fr) | 2011-08-01 | 2013-02-07 | Genentech, Inc. | Procédés de traitement du cancer à l'aide d'antagonistes se liant à l'axe pd-1 et inhibiteurs de mek |
WO2013019620A2 (fr) | 2011-07-29 | 2013-02-07 | Glaxosmithkline Llc | Méthode de traitement du cancer au moyen d'une combinaison contenant un inhibiteur de braf, un inhibiteur de mek et un anticorps anti-ctla-4 |
US8383796B2 (en) | 2005-07-01 | 2013-02-26 | Medarex, Inc. | Nucleic acids encoding monoclonal antibodies to programmed death ligand 1 (PD-L1) |
US20130156768A1 (en) | 2010-08-26 | 2013-06-20 | Bristol-Myers Squibb Company | Combination of anti-ctla4 antibody with braf inhibitors for the synergistic treatment of proliferative diseases |
US8475790B2 (en) | 2008-10-06 | 2013-07-02 | Bristol-Myers Squibb Company | Combination of CD137 antibody and CTLA-4 antibody for the treatment of proliferative diseases |
US8685394B2 (en) | 2008-08-01 | 2014-04-01 | Bristol-Myers Squibb Company | Combination of anti-CTLA4 antibody with diverse therapeutic regimens for the synergistic treatment of proliferative diseases |
US8697845B2 (en) | 2009-02-26 | 2014-04-15 | The University Court Of The University Of Aberdeen | Antibodies specifically directed to a soluble form of CTLA-4 |
US20140105914A1 (en) | 2011-03-09 | 2014-04-17 | Antitope Limited | Humanised anti ctla-4 antibodies |
US8735553B1 (en) | 2013-09-13 | 2014-05-27 | Beigene, Ltd. | Anti-PD1 antibodies and their use as therapeutics and diagnostics |
US20140323533A1 (en) | 2013-04-29 | 2014-10-30 | Bristol-Myers Squibb Company | Combination of anti-ctla4 antibody with tubulin modulating agents for the treatment of proliferative diseases |
US8883984B2 (en) | 1998-12-23 | 2014-11-11 | Amgen Fremont Inc. | Human monoclonal antibodies to CTLA-4 |
US8927697B2 (en) | 2008-09-12 | 2015-01-06 | Isis Innovation Limited | PD-1 specific antibodies and uses thereof |
US8945561B2 (en) | 2004-01-09 | 2015-02-03 | Isis Innovation Limited | Receptor modulators |
US20150079100A1 (en) | 2012-03-23 | 2015-03-19 | Bristol-Myers Squibb Company | Methods of treatments using ctla-4 antibodies |
US8993731B2 (en) | 2010-03-11 | 2015-03-31 | Ucb Biopharma Sprl | PD-1 antibody |
US9062111B2 (en) | 2005-12-07 | 2015-06-23 | Medarex, L.L.C. | CTLA-4 antibody dosage escalation regimens |
US9102727B2 (en) | 2008-09-26 | 2015-08-11 | Emory University | Human anti-PD-1 antibodies and uses therefor |
US9102728B2 (en) | 2010-03-11 | 2015-08-11 | Ucb Biopharma Sprl | PD-1 antibodies |
WO2015125159A1 (fr) | 2014-02-21 | 2015-08-27 | Nektar Therapeutics (India) Pvt. Ltd. | Agonistes sélectifs d'il-2rbêta en combinaison avec un anticorps anti-ctla-4 ou un anticorps anti-pd-1 |
WO2015148828A1 (fr) | 2014-03-26 | 2015-10-01 | Millennium Pharmaceuticals, Inc. | Formulation pharmaceutique d'un inhibiteur de la kinase pan-raf, ses procédés de préparation, et procédés d'utilisation |
US20150283234A1 (en) | 2012-10-23 | 2015-10-08 | Bristol-Myers Squibb Company | Combination of anti-kir and anti-ctla-4 antibodies to treat cancer |
US9181342B2 (en) | 2008-09-12 | 2015-11-10 | Isis Innovation Limited | PD-1 specific antibodies and uses thereof |
US20150328311A1 (en) | 2014-05-13 | 2015-11-19 | Medimmune, Llc | Anti-b7-h1 and anti-ctla-4 antibodies for treating non-small cell lung cancer |
US9205148B2 (en) | 2011-04-20 | 2015-12-08 | Medimmune, Llc | Antibodies and other molecules that bind B7-H1 and PD-1 |
WO2016015675A1 (fr) | 2014-08-01 | 2016-02-04 | 中山康方生物医药有限公司 | Anticorps monoclonal anti-ctla4 ou fragment de celui-ci se liant à l'antigène, composition médicinale et son utilisation |
EP3012270A1 (fr) * | 2014-10-23 | 2016-04-27 | Institut Gustave Roussy | Produits pour moduler la composition microbienne afin d'améliorer l'efficacité d'un traitement du cancer avec un bloqueur de vérification immunitaire |
-
2017
- 2017-03-24 TW TW106110028A patent/TW201735949A/zh unknown
- 2017-03-24 WO PCT/US2017/023981 patent/WO2017165742A1/fr active Application Filing
- 2017-03-27 AR ARP170100748A patent/AR107983A1/es unknown
Patent Citations (80)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US748802A (en) | 1904-01-05 | Territory | ||
GB2209757B (en) | 1987-03-18 | 1990-10-24 | Medical Res Council | Altered antibodies |
WO1989007142A1 (fr) | 1988-02-05 | 1989-08-10 | Morrison Sherie L | Anticorps a region constante a modification de domaine |
US6005079A (en) | 1992-08-21 | 1999-12-21 | Vrije Universiteit Brussels | Immunoglobulins devoid of light chains |
WO1994004678A1 (fr) | 1992-08-21 | 1994-03-03 | Casterman Cecile | Immunoglobulines exemptes de chaines legeres |
US5800988A (en) | 1992-08-21 | 1998-09-01 | Vrije Universiteit Brussel | Immunoglobulins devoid of light chains |
WO1994025591A1 (fr) | 1993-04-29 | 1994-11-10 | Unilever N.V. | PRODUCTION D'ANTICORPS OU DE FRAGMENTS FONCTIONNALISES D'ANTICORPS, DERIVES DES IMMUNOGLOBULINES A CHAINE LOURDE DE $i(CAMELIDAE) |
WO1994029351A2 (fr) | 1993-06-16 | 1994-12-22 | Celltech Limited | Anticorps |
US5840299A (en) | 1994-01-25 | 1998-11-24 | Athena Neurosciences, Inc. | Humanized antibodies against leukocyte adhesion molecule VLA-4 |
WO1996024673A1 (fr) | 1995-02-10 | 1996-08-15 | Leukosite, Inc. | Adressines vasculaires de muqueuses et leurs utilisations |
US7803904B2 (en) | 1995-09-01 | 2010-09-28 | Millennium Pharmaceuticals, Inc. | Mucosal vascular addressing and uses thereof |
US8277808B2 (en) | 1995-09-01 | 2012-10-02 | Millennium Pharmaceuticals, Inc. | Mucosal vascular addressins and uses thereof |
WO1998006248A2 (fr) | 1996-08-15 | 1998-02-19 | Leukosite, Inc. | IMMUNOGLOBINE HUMANISE REAGISSANT AVEC L'INTEGRINE α4β7 |
US6281344B1 (en) | 1997-01-21 | 2001-08-28 | The General Hospital Corporation | Nucleic acid-protein fusion molecules and libraries |
US6518018B1 (en) | 1997-01-21 | 2003-02-11 | The General Hospital Corporation | RNA-antibody fusions and their selection |
US7270950B2 (en) | 1997-01-21 | 2007-09-18 | The General Hospital Corporation | Nucleic acid-protein fusions and methods of making and selecting fusions |
US20070082365A1 (en) | 1998-12-10 | 2007-04-12 | Adnexus Therapeutics, Inc. | Protein scaffolds for antibody mimics and other binding proteins |
US8883984B2 (en) | 1998-12-23 | 2014-11-11 | Amgen Fremont Inc. | Human monoclonal antibodies to CTLA-4 |
US6682736B1 (en) | 1998-12-23 | 2004-01-27 | Abgenix, Inc. | Human monoclonal antibodies to CTLA-4 |
US7605238B2 (en) | 1999-08-24 | 2009-10-20 | Medarex, Inc. | Human CTLA-4 antibodies and their uses |
US6984720B1 (en) | 1999-08-24 | 2006-01-10 | Medarex, Inc. | Human CTLA-4 antibodies |
US7034121B2 (en) | 2000-01-27 | 2006-04-25 | Genetics Institue, Llc | Antibodies against CTLA4 |
US20050095238A1 (en) | 2000-04-14 | 2005-05-05 | Millennium Pharmaceuticals, Inc. | Method of administering an antibody |
US20030086930A1 (en) | 2001-05-23 | 2003-05-08 | Mueller Eileen E. | Uses of anti-CTLA-4 antibodies |
US7118915B2 (en) | 2001-09-27 | 2006-10-10 | Pieris Proteolab Ag | Muteins of apolipoprotein D |
US7524498B2 (en) | 2002-05-23 | 2009-04-28 | Curetech Ltd. | Human immunomodulatory monoclonal antibodies for the treatment of cancer |
US7521051B2 (en) | 2002-12-23 | 2009-04-21 | Medimmune Limited | Methods of upmodulating adaptive immune response using anti-PD-1 antibodies |
US7322582B2 (en) | 2003-07-17 | 2008-01-29 | Mind Wurx, Llc | Enhanced shopping cart with lowered center of gravity and frame therefor |
WO2005067620A2 (fr) | 2004-01-09 | 2005-07-28 | Pfizer Inc. | Anticorps a madcam |
US8945561B2 (en) | 2004-01-09 | 2015-02-03 | Isis Innovation Limited | Receptor modulators |
US20080181892A1 (en) | 2004-08-11 | 2008-07-31 | Trubion Pharmaceuticals | Binding Domain Fusion Protein |
US7528236B2 (en) | 2004-09-03 | 2009-05-05 | Genentech, Inc. | Humanized anti-beta7 antagonists and uses therefor |
WO2006029219A2 (fr) | 2004-09-08 | 2006-03-16 | Ohio State University Research Foundation | Anticorps monoclonaux humains anti-ctla4 dans le traitement du cancer |
US8779105B2 (en) | 2005-05-09 | 2014-07-15 | Medarex, L.L.C. | Monoclonal antibodies to programmed death 1 (PD-1) |
US9084776B2 (en) | 2005-05-09 | 2015-07-21 | E.R. Squibb & Sons, L.L.C. | Methods for treating cancer using anti-PD-1 antibodies |
US8008449B2 (en) | 2005-05-09 | 2011-08-30 | Medarex, Inc. | Human monoclonal antibodies to programmed death 1 (PD-1) and methods for treating cancer using anti-PD-1 antibodies alone or in combination with other immunotherapeutics |
US8383796B2 (en) | 2005-07-01 | 2013-02-26 | Medarex, Inc. | Nucleic acids encoding monoclonal antibodies to programmed death ligand 1 (PD-L1) |
WO2007061679A1 (fr) | 2005-11-17 | 2007-05-31 | Millennium Pharmaceuticals, Inc. | IMMUNOGLOBULINE HUMANISEE REACTIVE AVEC L’INTEGRINE α4β7 |
US9062111B2 (en) | 2005-12-07 | 2015-06-23 | Medarex, L.L.C. | CTLA-4 antibody dosage escalation regimens |
US20080227958A1 (en) | 2006-04-14 | 2008-09-18 | Trubion Pharmaceuticals Inc. | Binding proteins comprising immunoglobulin hinge and fc regions having altered fc effector functions |
US8900587B2 (en) | 2007-06-18 | 2014-12-02 | Merck Sharp & Dohme Corp. | Antibodies to human programmed death receptor PD-1 |
WO2008156712A1 (fr) | 2007-06-18 | 2008-12-24 | N. V. Organon | Anticorps dirigés contre le récepteur humain de mort programmée pd-1 |
US8354509B2 (en) | 2007-06-18 | 2013-01-15 | Msd Oss B.V. | Antibodies to human programmed death receptor PD-1 |
US8952136B2 (en) | 2007-06-18 | 2015-02-10 | Merck Sharp & Dohme B.V. | Antibodies to human programmed death receptor PD-1 |
WO2009006389A2 (fr) | 2007-06-29 | 2009-01-08 | Sunesis Pharmaceuticals, Inc. | Composés utiles en tant qu'inhibiteurs de la kinase raf |
US20100330093A1 (en) | 2007-12-12 | 2010-12-30 | Sciclone Pharmaceuticals, Inc. | Treatment of melanoma with alpha thymosin peptides in combination with antibodies against cytotoxic t lymphocyte-associated antigen 4 (ctla4) |
US8263073B2 (en) | 2008-02-04 | 2012-09-11 | Medarex, Inc. | Anti-CTLA-4 antibodies with reduced blocking of binding of CTLA-4 to B7 and uses thereof |
US8685394B2 (en) | 2008-08-01 | 2014-04-01 | Bristol-Myers Squibb Company | Combination of anti-CTLA4 antibody with diverse therapeutic regimens for the synergistic treatment of proliferative diseases |
US8226946B2 (en) | 2008-08-06 | 2012-07-24 | Light Sciences Oncology, Inc. | Enhancement of light activated therapy by immune augmentation using anti-CTLA-4 antibody |
WO2010027827A2 (fr) | 2008-08-25 | 2010-03-11 | Amplimmune, Inc. | Polypeptides co-stimulateurs ciblés et leurs procédés d'utilisation dans le traitement du cancer |
US8927697B2 (en) | 2008-09-12 | 2015-01-06 | Isis Innovation Limited | PD-1 specific antibodies and uses thereof |
US9181342B2 (en) | 2008-09-12 | 2015-11-10 | Isis Innovation Limited | PD-1 specific antibodies and uses thereof |
US9102727B2 (en) | 2008-09-26 | 2015-08-11 | Emory University | Human anti-PD-1 antibodies and uses therefor |
US8475790B2 (en) | 2008-10-06 | 2013-07-02 | Bristol-Myers Squibb Company | Combination of CD137 antibody and CTLA-4 antibody for the treatment of proliferative diseases |
WO2010064722A1 (fr) | 2008-12-02 | 2010-06-10 | Takeda Pharmaceutical Company Limited | Dérivés de benzothiazole convenant comme agents anticancéreux |
WO2010077634A1 (fr) | 2008-12-09 | 2010-07-08 | Genentech, Inc. | Anticorps anti-pd-l1 et leur utilisation pour améliorer la fonction des lymphocytes t |
US8697845B2 (en) | 2009-02-26 | 2014-04-15 | The University Court Of The University Of Aberdeen | Antibodies specifically directed to a soluble form of CTLA-4 |
US20100254975A1 (en) | 2009-03-20 | 2010-10-07 | Amgen Inc. | Alpha-4 beta-7 heterodimer specific |
US8444981B2 (en) | 2009-03-20 | 2013-05-21 | Amgen Inc. | Alpha-4 beta-7 heterodimer specific antagonist antibody |
WO2011066342A2 (fr) | 2009-11-24 | 2011-06-03 | Amplimmune, Inc. | Inhibition simultanée de pd-l1/pd-l2 |
US9102728B2 (en) | 2010-03-11 | 2015-08-11 | Ucb Biopharma Sprl | PD-1 antibodies |
US8993731B2 (en) | 2010-03-11 | 2015-03-31 | Ucb Biopharma Sprl | PD-1 antibody |
US20130156768A1 (en) | 2010-08-26 | 2013-06-20 | Bristol-Myers Squibb Company | Combination of anti-ctla4 antibody with braf inhibitors for the synergistic treatment of proliferative diseases |
US20140105914A1 (en) | 2011-03-09 | 2014-04-17 | Antitope Limited | Humanised anti ctla-4 antibodies |
US9205148B2 (en) | 2011-04-20 | 2015-12-08 | Medimmune, Llc | Antibodies and other molecules that bind B7-H1 and PD-1 |
US20140377251A1 (en) | 2011-05-02 | 2014-12-25 | Millennium Pharmaceuticals, Inc. | Formulation for anti-alpha4beta7 antibody |
WO2012151247A2 (fr) | 2011-05-02 | 2012-11-08 | Millennium Pharmaceuticals, Inc. | FORMULATION POUR UN ANTICORPS ANTI-α4β7 |
US20140341885A1 (en) | 2011-05-02 | 2014-11-20 | Millennium Pharmaceuticals, Inc | Formulation for anti-alpha4beta7 antibody |
WO2012151248A2 (fr) | 2011-05-02 | 2012-11-08 | Millennium Pharmaceuticals, Inc. | FORMULATION POUR UN ANTICORPS ANTI-α4β7 |
WO2013019620A2 (fr) | 2011-07-29 | 2013-02-07 | Glaxosmithkline Llc | Méthode de traitement du cancer au moyen d'une combinaison contenant un inhibiteur de braf, un inhibiteur de mek et un anticorps anti-ctla-4 |
WO2013019906A1 (fr) | 2011-08-01 | 2013-02-07 | Genentech, Inc. | Procédés de traitement du cancer à l'aide d'antagonistes se liant à l'axe pd-1 et inhibiteurs de mek |
US20150079100A1 (en) | 2012-03-23 | 2015-03-19 | Bristol-Myers Squibb Company | Methods of treatments using ctla-4 antibodies |
US20150283234A1 (en) | 2012-10-23 | 2015-10-08 | Bristol-Myers Squibb Company | Combination of anti-kir and anti-ctla-4 antibodies to treat cancer |
US20140323533A1 (en) | 2013-04-29 | 2014-10-30 | Bristol-Myers Squibb Company | Combination of anti-ctla4 antibody with tubulin modulating agents for the treatment of proliferative diseases |
US8735553B1 (en) | 2013-09-13 | 2014-05-27 | Beigene, Ltd. | Anti-PD1 antibodies and their use as therapeutics and diagnostics |
WO2015125159A1 (fr) | 2014-02-21 | 2015-08-27 | Nektar Therapeutics (India) Pvt. Ltd. | Agonistes sélectifs d'il-2rbêta en combinaison avec un anticorps anti-ctla-4 ou un anticorps anti-pd-1 |
WO2015148828A1 (fr) | 2014-03-26 | 2015-10-01 | Millennium Pharmaceuticals, Inc. | Formulation pharmaceutique d'un inhibiteur de la kinase pan-raf, ses procédés de préparation, et procédés d'utilisation |
US20150328311A1 (en) | 2014-05-13 | 2015-11-19 | Medimmune, Llc | Anti-b7-h1 and anti-ctla-4 antibodies for treating non-small cell lung cancer |
WO2016015675A1 (fr) | 2014-08-01 | 2016-02-04 | 中山康方生物医药有限公司 | Anticorps monoclonal anti-ctla4 ou fragment de celui-ci se liant à l'antigène, composition médicinale et son utilisation |
EP3012270A1 (fr) * | 2014-10-23 | 2016-04-27 | Institut Gustave Roussy | Produits pour moduler la composition microbienne afin d'améliorer l'efficacité d'un traitement du cancer avec un bloqueur de vérification immunitaire |
Non-Patent Citations (19)
Title |
---|
ALEXANDER NAVARINI ET AL: "Vedolizumab as a successful treatment of CTLA-4-associated autoimmune enterocolitis", JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, vol. 139, no. 3, 28 November 2016 (2016-11-28), AMSTERDAM, NL, pages 1043 - 1046.e5, XP055378889, ISSN: 0091-6749 * |
AMY HSIN-CHIEH HSIEH ET AL: "Vedolizumab: a novel treatment for ipilimumab-induced colitis", BMJ CASE REPORTS, 18 August 2016 (2016-08-18), XP055378883, DOI: 10.1136/bcr-2016-216641 * |
ANONYMOUS: "Study to Evaluate the Safety, Tolerability, and Pharmacodynamics of Investigational Treatments in Combination With Standard of Care Immune Checkpoint Inhibitors in Participants With Advanced Melanoma - Tabular View - ClinicalTrials.gov", 25 June 2016 (2016-06-25), XP055378673, Retrieved from the Internet <URL:https://clinicaltrials.gov/ct2/show/record/NCT02723006> [retrieved on 20170606] * |
BEDNARCZYK ET AL., J. BIOL. CHEM., vol. 269, no. 11, 1994, pages 8348 - 8354 |
BERGQVIST VIKTORIA ET AL: "Vedolizumab treatment for immune checkpoint inhibitor-induced enterocolitis", CANCER IMMUNOLOGY, IMMUNOTHERAPY, SPRINGER, BERLIN/HEIDELBERG, vol. 66, no. 5, 15 February 2017 (2017-02-15), pages 581 - 592, XP036221120, ISSN: 0340-7004, [retrieved on 20170215], DOI: 10.1007/S00262-017-1962-6 * |
BINZ ET AL., NAT. BIOTECH., vol. 23, 2005, pages 1257 - 68 |
HANES ET AL., FEBS LETT., vol. 450, 1999, pages 105 - 110 |
HE; TAUSSIG, J. IMMUNOL. METHODS, vol. 297, 2005, pages 73 - 82 |
HOOGENBOOM: "Method Mol. Biol.", vol. 178, 2002, pages: 1 - 37 |
LAZAROVITS, A. I. ET AL., J. IMMUNOL., vol. 133, no. 4, 1984, pages 1857 - 1862 |
ROTHE ET AL., FASEB J., vol. 20, 2006, pages 1599 - 1610 |
SCHWEIGHOFFER ET AL., J. IMMUNOL., vol. 151, no. 2, 1993, pages 717 - 729 |
SHARPE, A.H ET AL., NATURE IMMUNOLOGY, vol. 8, 2007, pages 239 - 245 |
SPAIN LAVINIA ET AL: "Management of toxicities of immune checkpoint inhibitors", CANCER TREATMENT REVIEWS, ELSEVIER, AMSTERDAM, NL, vol. 44, 6 February 2016 (2016-02-06), pages 51 - 60, XP029434607, ISSN: 0305-7372, DOI: 10.1016/J.CTRV.2016.02.001 * |
TIM RAINE: "Vedolizumab for inflammatory bowel disease: Changing the game, or more of the same?", UNITED EUROPEAN GASTROENTEROLOGY JOURNAL UEG WEEK 2015 ORAL PRESENTATIONS, vol. 2, no. 5, 1 October 2014 (2014-10-01), pages 333 - 344, XP055378881, ISSN: 2050-6406, DOI: 10.1177/2050640614550672 * |
WATSON ET AL.: "Molecular Biology of the Gene (4th Ed.)", 1987, BENJAMIN/CUMMINGS PUB. CO., pages: 224 |
WHO DRUG INFORMATION, vol. 26, no. 4, 2012, pages 434 |
WHO DRUG INFORMATION, vol. 27, 2013, pages 161 - 162 |
WHO DRUG INFORMATION, vol. 27, no. 1, 2013, pages 68 - 69 |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11389533B2 (en) | 2016-06-12 | 2022-07-19 | Takeda Pharmaceutical Company Limited | Method of treating inflammatory bowel disease |
CN109793891A (zh) * | 2017-11-17 | 2019-05-24 | 韩震 | 多肽化合物在制备提高治疗性抗体疗效的佐剂中的应用与组合物及其制备方法 |
WO2021213523A1 (fr) * | 2020-04-24 | 2021-10-28 | 信达生物制药(苏州)有限公司 | Utilisations d'une combinaison d'anticorps anti-pd-1 et d'anticorps anti-ctla-4 dans la prévention ou le traitement du cancer |
WO2022178557A3 (fr) * | 2021-02-22 | 2022-10-13 | Pandion Operations, Inc. | Agents thérapeutiques ciblant le pancréas et leurs utilisations |
Also Published As
Publication number | Publication date |
---|---|
TW201735949A (zh) | 2017-10-16 |
AR107983A1 (es) | 2018-07-04 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP6663493B2 (ja) | がんの処置に使用するための5−ブロモ−2,6−ジ−(1h−ピラゾール−1−イル)ピリミジン−4−アミン | |
US20240247067A1 (en) | Methods of treating gastrointestinal immune-related adverse events in immune oncology treatments | |
JP6949718B2 (ja) | 抗pd−1抗体と他の抗体の組み合わせを含む組成物 | |
WO2017165742A1 (fr) | Procédés de traitement d'événements indésirables liés à l'immunité gastro-intestinale dans des polythérapies anti-ctla4 et anti-pd-1 | |
TW201731528A (zh) | 用於癌症治療之單獨fgfr2抑制劑或與免疫刺激劑組合 | |
KR20170122810A (ko) | 암을 치료하기 위한 pd-1 길항제 및 에리불린의 조합 | |
AU2011278227B2 (en) | Superior efficacy of CD37 antibodies in CLL blood samples | |
JP2020520912A (ja) | 抗gitrアゴニスト抗体での癌の処置 | |
US20230133118A1 (en) | Compositions and methods for treating cancer | |
KR20190082782A (ko) | 요로상피암을 치료하기 위한 pd-1 길항제 및 에리불린의 조합 | |
JP2024012300A (ja) | 医薬併用 | |
KR20220137007A (ko) | Pd-1 길항제, ilt4 길항제 및 렌바티닙 또는 그의 염을 사용하는 조합 암 치료 | |
CN115087461A (zh) | 使用pd-1拮抗剂、ilt4拮抗剂和化学治疗剂的组合治疗癌症的方法 | |
CN111973739A (zh) | 抗pd-l1单克隆抗体治疗癌症的用途 | |
US20230250182A1 (en) | Methods for treating cancer or von-hippel lindau disease using a combination of a pd-1 antagonist, a hif-2 alpha inhibitor, and lenvatinib or a pharmaceutically acceptable salt thereof | |
US20230242663A1 (en) | Combination therapy comprising anti-cd137 antibodies | |
JP2024532744A (ja) | T1gitアンタゴニスト、pd-1アンタゴニスト、及び(1又は複数の)化学療法剤を含む治療的組合せ | |
JP7280387B2 (ja) | 抗原結合タンパク質 | |
WO2021160151A1 (fr) | Utilisation d'anticorps anti-pd-1 dans le traitement de tumeurs | |
CA3212604A1 (fr) | Methodes destinees a traiter le cancer avec des anticorps anti-ilt3 | |
WO2021227156A1 (fr) | Compositions et méthodes pour le traitement du cancer | |
JP2022549273A (ja) | Lag-3アンタゴニスト治療のための定量的空間プロファイリング | |
CN113365659A (zh) | 抗pd-l1抗体治疗头颈癌的用途 | |
WO2019067332A1 (fr) | Compositions et procédés de traitement du cancer par une combinaison d'anticorps anti-récepteur de mort programmée (pd-1) et d'un antagoniste de cxcr2 | |
JP6964113B2 (ja) | がんの処置に使用するための5−ブロモ−2,6−ジ−(1h−ピラゾール−1−イル)ピリミジン−4−アミン |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 17715878 Country of ref document: EP Kind code of ref document: A1 |
|
122 | Ep: pct application non-entry in european phase |
Ref document number: 17715878 Country of ref document: EP Kind code of ref document: A1 |