WO2017129763A1 - Méthodes et compositions pharmaceutiques pour le traitement du cancer de l'estomac à cellules en bague à chaton - Google Patents
Méthodes et compositions pharmaceutiques pour le traitement du cancer de l'estomac à cellules en bague à chaton Download PDFInfo
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- WO2017129763A1 WO2017129763A1 PCT/EP2017/051805 EP2017051805W WO2017129763A1 WO 2017129763 A1 WO2017129763 A1 WO 2017129763A1 EP 2017051805 W EP2017051805 W EP 2017051805W WO 2017129763 A1 WO2017129763 A1 WO 2017129763A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
- A61K39/39558—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- 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
- C07K16/2827—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 B7 molecules, e.g. CD80, CD86
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2863—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for growth factors, growth regulators
Definitions
- the present invention relates to methods and pharmaceutical compositions for the treatment of signet ring cell gastric cancer.
- Signet Ring Cell (SRC) carcinoma of the stomach is defined by a predominant component (> 50%) of independent cells.
- the incidence of SRC carcinoma of the stomach is increasing (1,2).
- G Gastric Adenocarcinoma
- perioperative chemotherapies failed to provide any survival benefits in patients diagnosed with SRC (5, 6, 7), either resulting in the involvement of chemoresistance mechanisms, or in the patient's general status.
- IGFIR insulin Growth Factor-like 1
- IGF-2 Insulin Growth Factor-like 2
- IGF-1 and 2 IGF-2
- IGFIR might be involved in SRC cancerogenesis through activation of PI3K (14, 15), and might explain chemoresistance in SRC.
- a preclinical study showed that xenograft transfection with an inactive IGFIR increases apoptosis induced by cytotoxic chemotherapy (16).
- tumours hyperexpressing IGFIR were more likely to relapse after chemotherapy (17).
- PD-1 Programmed Cell Death 1
- PD-1 is part of a complex mechanism known as immunitory inhibitory checkpoint.
- PD-1 is expressed on activated T lymphocytes. Binding of PD-1 to its ligands PD-L1 and PD-L2 shapes tumour micro-environment in increasing T-Cell Regulators (Tregs) infiltrates and in decreasing activated T-Cells infiltrates (20). These mechanisms lead to immune escape.
- Tregs T-Cell Regulators
- PI3K pathway activated downstream of IGF1R, is related to the expression of PD-L1, resulting in immune evasion that could be reversed with blockade of PI3K in glioblastoma (21).
- PD-L1 In gastric cancer, PD-L1 is expressed in 42% (22), and a first clinical trial, evaluating efficiency of an immunotherapy targeting PD-1 (Pembrolizumab) displayed a response rate of 31% (23). Though, the exact role of this inhibitory checkpoint in SRC remains to be elucidated.
- the present invention relates to methods and pharmaceutical compositions for the treatment of signet ring cell gastric cancer.
- the present invention is defined by the claims.
- the aim of the inventors was to investigate the role of IGF1R pathway and PD-1 immunitory checkpoint in SRC, in order to propose a new therapeutic strategy in SRC: the combination of an anti-IGFIR therapy with an immunotherapy targeting PD-1.
- the inventors performed a RT-qPCR on 11 SRC and 11 GA gastrectomy samples to assess the expression of IGF1R pathway and PD-L1/PD-L2 genes. They also analysed protein expression of IGF1R pathway, PD-1 immune checkpoint, and immune infiltrates (CD4+, CD8+, FoxP3+) using immuno-histochemistry (IHC) on a TMA including 17 SRC and 12 GA.
- every tumour sample of the study expressed PD-L1 as well as PD-L2.
- IGF1R pathway in SRC.
- tumours display predictive factors for anti- IGF1R therapy success.
- Our results also show that PD-L1 is expressed in SRC as well as in GA, and that its expression shapes tumour microenvironment.
- a first object of the present invention relates to a method of treating signet ring cell gastric carcinoma in a subject in need thereof comprising administering to the subject a therapeutically effective amount of at least one PD-1 inhibitor or at least one IGF1R inhibitor.
- treatment refers to both prophylactic or preventive treatment as well as curative or disease modifying treatment, including treatment of patient at risk of contracting the disease or suspected to have contracted the disease as well as patients who are ill or have been diagnosed as suffering from a disease or medical condition, and includes suppression of clinical relapse.
- the treatment may be administered to a subject having a medical disorder or who ultimately may acquire the disorder, in order to prevent, cure, delay the onset of, reduce the severity of, or ameliorate one or more symptoms of a disorder or recurring disorder, or in order to prolong the survival of a subject beyond that expected in the absence of such treatment.
- therapeutic regimen is meant the pattern of treatment of an illness, e.g., the pattern of dosing used during therapy.
- a therapeutic regimen may include an induction regimen and a maintenance regimen.
- the phrase “induction regimen” or “induction period” refers to a therapeutic regimen (or the portion of a therapeutic regimen) that is used for the initial treatment of a disease.
- the general goal of an induction regimen is to provide a high level of drug to a patient during the initial period of a treatment regimen.
- An induction regimen may employ (in part or in whole) a "loading regimen", which may include administering a greater dose of the drug than a physician would employ during a maintenance regimen, administering a drug more frequently than a physician would administer the drug during a maintenance regimen, or both.
- maintenance regimen refers to a therapeutic regimen (or the portion of a therapeutic regimen) that is used for the maintenance of a patient during treatment of an illness, e.g., to keep the patient in remission for long periods of time (months or years).
- a maintenance regimen may employ continuous therapy (e.g., administering a drug at a regular intervals, e.g., weekly, monthly, yearly, etc.) or intermittent therapy (e.g., interrupted treatment, intermittent treatment, treatment at relapse, or treatment upon achievement of a particular predetermined criteria [e.g., pain, disease manifestation, etc.]).
- PD-1 has its general meaning in the art and refers to programmed cell death protein 1 (also known as CD279). PD-1 acts as an immune checkpoint, which upon binding of one of its ligands, PD-L1 or PD-L2, inhibits the activation of T cells.
- PD-1 inhibitor refers to a compound, substance or composition that can inhibit the function of PD-1. For example, the inhibitor can inhibit the expression or activity of PD-1, modulate or block the PD-1 signaling pathway and/or block the binding of PD-1 to PD-L1 or PD-L2.
- PD-1 inhibitor means any molecule that attenuates inhibitory signal transduction mediated by PD-1, found on the surface of T cells, B cells, natural killer (NK) cells, monocytes, DC, and macrophages.
- a PD-1 inhibitor is a molecule that inhibits, reduces, abolishes or otherwise reduces inhibitory signal transduction through the PD-1 receptor signaling pathway.
- the PD-1 inhibitor of the invention binds to a PD-1 receptor without triggering signal transduction, to reduce or block inhibitory signal transduction; (ii) the PD-1 inhibitor binds to a ligand (e.g.
- a PD-1 inhibitor of the invention is a molecule that effects a decrease in PD-1 inhibitory signal transduction, thereby increasing T cell response to one or more antigens.
- PD-1 antagonists are well known in the art and typically include antibodies or fragments thereof having specificity for PD-1 or its ligands (i.e. PD-L1 or PD-L2).
- PD-1 inhibitors are described in US Patent Nos. 7,488,802; 7,943,743; 8,008,449; 8,168,757; 8,217,149, and PCT Published Patent Application Nos: WO03042402, WO2008156712, WO2010089411, WO2010036959, WO2011066342, WO2011159877, WO2011082400, and WO2011161699.
- the PD-1 inhibitor is an anti-PD-1 antibody.
- the anti-PD-1 antibody is selected from the group consisting of MDX-1106, Merck 3475 and CT-011.
- Nivolumab MDX 1106, BMS 936558, ONO 4538
- a fully human IgG4 antibody that binds to and blocks the activation of PD-1 by its ligands PD-L1 and PD-L2 ant that is described in WO2006/121168.
- Lambrolizumab (MK-3475 or SCH 900475) is a humanized monoclonal IgG4 antibody against PD-1.
- the PD-1 inhibitor is anti-PD-Ll antibody.
- the anti-PD-Ll binding antagonist is selected from the group consisting of YW243.55.S70, MPDL3280A and MDX-1105.
- MDX-1105 also known as BMS-936559, is an anti-PD-Ll antibody described in WO2007/005874.
- Antibody YW243.55.S70 is an anti- PD-Ll described in WO2010/077634.
- the PD-1 inhibitor is an immunoadhesin (e.g., an immunoadhesin comprising an extracellular or PD-1 binding portion of PD-L1 or PD-L2 fused to a constant region of an immuglobulin (e.g., an Fc region of an immunoglobulin sequence).
- the PD-1 inhibitor is AMP-224.
- AMP-224 also known as B7-DCIg, is a PD-L2-Fc fusion soluble receptor described in WO2010/027827 and WO2011/066342.
- the IGFIR inhibitor is an inhibitor of PD-1 expression.
- IGFIR Insulin- like growth factor 1 receptor
- IGFIR inhibitor refers to any substance that inhibits or decreases the expression, ligand binding (e.g., binding to IGF-1 and/or IGF-2), kinase activity (e.g., autophosphorylation activity) or any other biological activity of IGFIR (e.g., mediation of anchorage-independent cellular growth).
- IGFIR inhibitors include any agent that can block IGFIR activation or any of the downstream biological effects of IGFIR activation.
- IGFIR inhibitors are well known in the art. Non- limiting examples of inhibitors can be found in, for example, U.S. Pat. No. 7,329,734, U.S. Pat. No. 7,173,005, U.S. Pat. No. 7,071,300, U.S. Pat. No. 7,020,563, U.S. Pat. No. 6,875,741; US Pat. App. Pub. No. US2007/0299010, US2007/0265189, US2007/0135340, US2007/0129399, US2007/0004634, US2005/0282761, US2005/0054638, US2004/0023887, US2003/0236190, US2003/0195147; PCT Pub. No.
- IGFIR inhibitors may include, for example, imidazopyrazine IGFIR inhibitors, quinazoline IGFIR inhibitors, pyrido-pyrimidine IGFIR inhibitors, pyrimido-pyrimidine IGFIR inhibitors, pyrrolo-pyrimidine IGF inhibitors, pyrazolo- pyrimidine IGFIR inhibitors, phenylamino-pyrimidine IGFIR inhibitors, oxindole IGFIR inhibitors, indolocarbazole IGFIR inhibitors, phthalazine IGFIR inhibitors, isoflavone IGFIR inhibitors, quinalone IGFIR inhibitors, and tyrphostin IGFIR inhibitors, and all pharmaceutically acceptable salts and solvates of such IGFIR inhibitors, imidazopyrazine IGFIR inhibitors, pyrimidine-based IGF-1R inhibitors, cyclolignans, cyclolignans, pyrrolopyrimidines, pyrrolo
- OSI-906 OSI Pharmaceuticals, Melvilee, N.Y.
- BMS 536924 Wittman et al, 2005, J Med Chem. 48:5639-43; Bristol Myers Squibb, New York, N.Y.
- XL228 Exelexis, South San Francisco, Calif
- INSM-18 NDGA
- rhIGFBP-3 Insmed, Inc., Richmond, Va.; Breuhahn et al, 2002006, Curr Cancer Ther Rev. 2: 157-67; Youngren et al, 2005, Breast Cancer Res Treatment 94:37-46; U.S. Pat. No. 6,608,108
- IGFIR inhibitors include h7C10 (Centre de für Pierre Fabre), an IGF-1 antagonist; EM- 164 (ImmunoGen Inc.), an IGFIR modulator; CP-751871 (Pfizer Inc.), an IGF-1 antagonist; lanreotide (Ipsen), an IGF-1 antagonist; IGFIR oligonucleotides (Lynx Therapeutics Inc.); IGF-1 oligonucleotides (National Cancer Institute); IGFIR protein-tyrosine kinase inhibitors in development by Novartis (e.g., NVP-AEW541, Garcia-Echeverria, C. et al.
- the IGF1R inhibitor is an antibody or antibody fragment that can partially or completely block IGF1R activation by its natural ligand.
- Antibody-based IGF1R inhibitors also include any anti-IGF-1 antibody or antibody fragment that can partially or completely block IGF1R activation.
- Non- limiting examples of antibody-based IGF1R inhibitors include those described in Larsson, O. et al (2005) Brit. J. Cancer 92:2097-2101 and (2004), Y. H. and Yee, D. (2005) Clin. Cancer Res.
- Imclone e.g., IMC-A12
- ganitumab an anti-IGFIR antibody (Amgen)
- Amgen an anti-IGFIR antibody
- AVE- 1642 an anti-IGFIR antibody (Immunogen/Sanofi- Aventis)
- MK 0646 or h7C10 an anti-IGFIR antibody (Merck); or antibodies being develop by Schering-Plough Research Institute (e.g., SCH 717454 or 19D12; or as described in US Patent Application Publication Nos.
- the IGF1R inhibitor can be a monoclonal antibody, or an antibody or antibody fragment having the binding specificity thereof.
- the IGF1R inhibitor is an antibody that binds specifically to the human IGF1R. More preferably, the antibody is ganitumab.
- the IGF1R inhibitor is an inhibitor of IGF1R expression.
- antibody is thus used to refer to any antibody-like molecule that has an antigen binding region, and this term includes antibody fragments that comprise an antigen binding domain such as Fab', Fab, F(ab')2, single domain antibodies (DABs), TandAbs dimer, Fv, scFv (single chain Fv), dsFv, ds-scFv, Fd, linear antibodies, minibodies, diabodies, bispecific antibody fragments, bibody, tribody (scFv-Fab fusions, bispecific or trispecific, respectively); sc-diabody; kappa(lamda) bodies (scFv-CL fusions); BiTE (Bispecific T-cell Engager, scFv-scFv tandems to attract T cells); DVD-Ig (dual variable domain antibody, bispecific format); SIP (small immunoprotein,
- Antibodies can be fragmented using conventional techniques. For example, F(ab')2 fragments can be generated by treating the antibody with pepsin. The resulting F(ab')2 fragment can be treated to reduce disulfide bridges to produce Fab' fragments. Papain digestion can lead to the formation of Fab fragments.
- Fab, Fab' and F(ab')2, scFv, Fv, dsFv, Fd, dAbs, TandAbs, ds-scFv, dimers, minibodies, diabodies, bispecific antibody fragments and other fragments can also be synthesized by recombinant techniques or can be chemically synthesized. Techniques for producing antibody fragments are well known and described in the art. For example, each of Beckman et al, 2006; Holliger & Hudson, 2005; Le Gall et al, 2004; Reff & Heard, 2001 ; Reiter et al, 1996; and Young et al, 1995 further describe and enable the production of effective antibody fragments.
- the antibody of the present invention is a single chain antibody.
- single domain antibody has its general meaning in the art and refers to the single heavy chain variable domain of antibodies of the type that can be found in Camelid mammals which are naturally devoid of light chains. Such single domain antibody are also "nanobody®".
- single domain antibody are also "nanobody®”.
- (single) domain antibodies reference is also made to the prior art cited above, as well as to EP 0 368 684, Ward et al. (Nature 1989 Oct 12; 341 (6242): 544-6), Holt et al, Trends Biotechnol, 2003, 21(l l):484-490; and WO06/030220, WO06/003388.
- the antibody is a humanized antibody.
- humanized describes antibodies wherein some, most or all of the amino acids outside the CDR regions are replaced with corresponding amino acids derived from human immunoglobulin molecules. Methods of humanization include, but are not limited to, those described in U.S. Pat. Nos. 4,816,567, 5,225,539, 5,585,089, 5,693,761, 5,693,762 and 5,859,205, which are hereby incorporated by reference.
- the antibody is a fully human antibody. Fully human monoclonal antibodies also can be prepared by immunizing mice transgenic for large portions of human immunoglobulin heavy and light chain loci. See, e.g., U.S. Pat. Nos.
- mice have been genetically modified such that there is a functional deletion in the production of endogenous (e.g., murine) antibodies.
- the animals are further modified to contain all or a portion of the human germ- line immunoglobulin gene locus such that immunization of these animals will result in the production of fully human antibodies to the antigen of interest.
- monoclonal antibodies can be prepared according to standard hybridoma technology.
- the antibody of the present invention is a single chain antibody.
- single domain antibody has its general meaning in the art and refers to the single heavy chain variable domain of antibodies of the type that can be found in Camelid mammals which are naturally devoid of light chains. Such single domain antibody are also "nanobody®".
- single domain antibody are also "nanobody®”.
- (single) domain antibodies reference is also made to the prior art cited above, as well as to EP 0 368 684, Ward et al. (Nature 1989 Oct 12; 341 (6242): 544-6), Holt et al, Trends Biotechnol, 2003, 21(11):484-490; and WO06/030220, WO06/003388.
- the antibody comprises human heavy chain constant regions sequences but will not induce antibody dependent cellular cytotoxicity (ADCC). Accordingly, in some embodiments, the antibody of the present invention does not comprise an Fc domain capable of substantially binding to a FcgRIIIA (CD 16) polypeptide.
- Fc domain Fc portion
- Fc region refer to a C-terminal fragment of an antibody heavy chain, e.g., from about amino acid (aa) 230 to about aa 450 of human gamma heavy chain or its counterpart sequence in other types of antibody heavy chains (e.g., ⁇ , ⁇ , ⁇ and ⁇ for human antibodies), or a naturally occurring allotype thereof.
- the antibody lacks an Fc domain (e.g. lacks a CH2 and/or CH3 domain) or comprises an Fc domain of IgG2 or IgG4 isotype.
- the antibody consists of or comprises a Fab, Fab', Fab'-SH, F (ab') 2, Fv, a diabody, single-chain antibody fragment, or a multispecific antibody comprising multiple different antibody fragments.
- the antibody is not linked to a toxic moiety.
- one or more amino acids selected from amino acid residues can be replaced with a different amino acid residue such that the antibody has altered C2q binding and/or reduced or abolished complement dependent cytotoxicity (CDC).
- CDC complement dependent cytotoxicity
- anti-sense oligonucleotides including anti-sense RNA molecules and anti-sense DNA molecules, would act to directly block the translation of the targeted mRNA (e.g. IGF1R or PD-1) by binding thereto and thus preventing protein translation or increasing mRNA degradation, thus decreasing the level of the protein (e.g. IGF1R or PD-1), and thus activity, in a cell.
- antisense oligonucleotides of at least about 15 bases and complementary to unique regions of the mRNA transcript sequence can be synthesized, e.g., by conventional phosphodiester techniques. Methods for using antisense techniques for specifically inhibiting gene expression of genes whose sequence is known are well known in the art (e.g.
- RNAs small inhibitory RNAs
- TIM-3 or PD-1 gene expression can be reduced by contacting a subject or cell with a small double stranded RNA (dsRNA), or a vector or construct causing the production of a small double stranded RNA, such that TIM-3 or PD-1 gene expression is specifically inhibited (i.e. RNA interference or RNAi).
- dsRNA small double stranded RNA
- RNAi RNA interference
- Antisense oligonucleotides, siRNAs, shRNAs and ribozymes of the invention may be delivered in vivo alone or in association with a vector.
- a "vector" is any vehicle capable of facilitating the transfer of the antisense oligonucleotide, siRNA, shRNA or ribozyme nucleic acid to the cells and typically cells expressing the targeted protein (e.g. IGF1R or PD-1).
- the vector transports the nucleic acid to cells with reduced degradation relative to the extent of degradation that would result in the absence of the vector.
- the vectors useful in the invention include, but are not limited to, plasmids, phagemids, viruses, other vehicles derived from viral or bacterial sources that have been manipulated by the insertion or incorporation of the antisense oligonucleotide, siR A, shRNA or ribozyme nucleic acid sequences.
- Viral vectors are a preferred type of vector and include, but are not limited to nucleic acid sequences from the following viruses: retrovirus, such as moloney murine leukemia virus, harvey murine sarcoma virus, murine mammary tumor virus, and rous sarcoma virus; adenovirus, adeno-associated virus; SV40-type viruses; polyoma viruses; Epstein-Barr viruses; papilloma viruses; herpes virus; vaccinia virus; polio virus; and RNA virus such as a retrovirus.
- retrovirus such as moloney murine leukemia virus, harvey murine sarcoma virus, murine mammary tumor virus, and rous sarcoma virus
- adenovirus adeno-associated virus
- SV40-type viruses polyoma viruses
- Epstein-Barr viruses Epstein-Barr viruses
- papilloma viruses herpes virus
- vaccinia virus
- the method of the present invention comprises coadministering the PD-1 inhbitor and the IGF1R inhibitor to the subjet.
- co-administering means a process whereby the combination of the IGF1R inhibitor and the PD-1 inhibitor, is administered to the same subject.
- the IGF1R inhibitor and the PD-1 inhibitor may be administered simultaneously, at essentially the same time, or sequentially.
- the IGF1R inhibitor and the PD-1 inhibitor need not be administered by means of the same vehicle.
- the IGF1R inhibitor and the PD-1 inhibitor may be administered one or more times and the number of administrations of each component of the combination may be the same or different.
- the IGF1R inhibitor and the PD-1 inhibitor need not be administered at the same site.
- the term "therapeutically effective amount” as used herein refers to an amount or dose of the IGF1R inhibitor or dose of the PD-1 inhibitor that is sufficient to treat the SRC.
- the “therapeutically effective amount” is determined using procedures routinely employed by those of skill in the art such that an “improved therapeutic outcome” results. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment.
- the specific therapeutically effective dose level for any particular subject will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed, the age, body weight, general health, sex and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidential with the specific polypeptide employed; and like factors well known in the medical arts.
- the daily dosage of the products may be varied over a wide range from 0.01 to 1,000 mg per adult per day.
- the compositions contain 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 250 and 500 mg of the active ingredient for the symptomatic adjustment of the dosage to the subject to be treated.
- a medicament typically contains from about 0.01 mg to about 500 mg of the active ingredient, preferably from 1 mg to about 100 mg of the active ingredient.
- An effective amount of the drug is ordinarily supplied at a dosage level from 0.0002 mg/kg to about 20 mg/kg of body weight per day, especially from about 0.001 mg/kg to 7 mg/kg of body weight per day.
- the PD-1 inhibitor and/or the IGF1R inhibitor is(are) administered to the subject in combination with a chemo therapeutic agent.
- chemotherapeutic agent refers to chemical compounds that are effective in inhibiting tumor growth.
- examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, trietylenephosphoramide, triethylenethiophosphaoramide and trimethylolomelamine; acetogenins (especially bullatacin and bullatacinone); a carnptothecin (including the synthetic analogue topotecan); bryostatin; callystatin; cally
- calicheamicin especially calicheamicin (11 and calicheamicin 211, see, e.g., Agnew Chem Intl. Ed. Engl. 33: 183-186 (1994); dynemicin, including dynemicin A; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antiobiotic chromomophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, canninomycin, carzinophilin, chromomycins, dactinomycin, daunorubicin, detorubicin, 6- diazo-5-oxo-L-norleucine, doxorubicin (including morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino
- paclitaxel (TAXOL®, Bristol-Myers Squibb Oncology, Princeton, N.].) and doxetaxel (TAXOTERE®, Rhone-Poulenc Rorer, Antony, France); chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; platinum; etoposide (VP- 16); ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine; navelbine; novantrone; teniposide; daunomycin; aminopterin; xeloda; ibandronate; CPT-1 1 ; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoic acid; capecitabine; and phannaceutically acceptable salts, acids or derivatives of any of the above.
- antihormonal agents that act to regulate or inhibit honnone action on tumors
- anti- estrogens including for example tamoxifen, raloxifene, aromatase inhibiting 4(5)-imidazoles, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and toremifene (Fareston); and anti-androgens such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; and phannaceutically acceptable salts, acids or derivatives of any of the above.
- the IGF1R inhibitor and the PD-1 inhibitor are administered to the subject in the form of a pharmaceutical composition.
- the IGF1R inhibitor and the PD-1 inhibitor may be combined with pharmaceutically acceptable excipients, and optionally sustained-release matrices, such as biodegradable polymers, to form therapeutic compositions.
- pharmaceutically acceptable excipients such as biodegradable polymers
- pharmaceutically acceptable carrier or excipient refers to a non-toxic solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.
- the active principle in the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, transdermal, local or rectal administration, can be administered in a unit administration form, as a mixture with conventional pharmaceutical supports, to animals and human beings.
- Suitable unit administration forms comprise oral-route forms such as tablets, gel capsules, powders, granules and oral suspensions or solutions, sublingual and buccal administration forms, aerosols, implants, subcutaneous, transdermal, topical, intraperitoneal, intramuscular, intravenous, subdermal, transdermal, intrathecal and intranasal administration forms and rectal administration forms.
- the pharmaceutical compositions contain vehicles which are pharmaceutically acceptable for a formulation capable of being injected.
- vehicles which are pharmaceutically acceptable for a formulation capable of being injected.
- These may be in particular isotonic, sterile, saline solutions (monosodium or disodium phosphate, sodium, potassium, calcium or magnesium chloride and the like or mixtures of such salts), or dry, especially freeze-dried compositions which upon addition, depending on the case, of sterilized water or physiological saline, permit the constitution of injectable solutions.
- the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions; formulations including sesame oil, peanut oil or aqueous propylene glycol; and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
- the form In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi.
- Solutions comprising compounds of the invention as free base or pharmacologically acceptable salts can be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
- the IGFIR inhibitor and the PD-1 inhibitor can be formulated into a composition in a neutral or salt form.
- Pharmaceutically acceptable salts include the acid addition salts (formed with the free amino groups of the protein) and which are formed with inorganic acids such as, for example, hydrochloric or phosphoric acids, or such organic acids as acetic, oxalic, tartaric, mandelic, and the like. Salts formed with the free carboxyl groups can also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, histidine, procaine and the like.
- inorganic acids such as, for example, hydrochloric or phosphoric acids, or such organic acids as acetic, oxalic, tartaric, mandelic, and the like.
- Salts formed with the free carboxyl groups can also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine,
- the carrier can also be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetables oils.
- the proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
- the prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
- isotonic agents for example, sugars or sodium chloride.
- Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminium monostearate and gelatin.
- Sterile injectable solutions are prepared by incorporating the active compounds in the required amount in the appropriate solvent with several of the other ingredients enumerated above, as required, followed by filtered sterilization.
- dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
- sterile powders for the preparation of sterile injectable solutions the typical methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile- filtered solution thereof.
- the preparation of more, or highly concentrated solutions for direct injection is also contemplated, where the use of DMSO as solvent is envisioned to result in extremely rapid penetration, delivering high concentrations of the active agents to a small tumor area.
- solutions Upon formulation, solutions will be administered in a manner compatible with the dosage formulation and in such amount as is therapeutically effective.
- the formulations are easily administered in a variety of dosage forms, such as the type of injectable solutions described above, but drug release capsules and the like can also be employed.
- aqueous solutions For parenteral administration in an aqueous solution, for example, the solution should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose.
- aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration.
- sterile aqueous media which can be employed will be known to those of skill in the art in light of the present disclosure. Some variation in dosage will necessarily occur depending on the condition of the subject being treated. The person responsible for administration will, in any event, determine the appropriate dose for the individual subject.
- FIGURES
- FIG. 1 mRNA levels of IGF-1 (A) and IGF-2 (B)
- FIG. 1 mRNA levels of IGF1R (A) and IR (B)
- Figure 3 mRNA levels of A and B insulin isoforms in cancer tissue (A) and ANCT (B)
- FIG. 4 mRNA levels of IGFBP-3 (A) and IGF2R (B)
- Figure 5 mRNA levels of PD-L1 (A) and PD-L2 (B)
- Gastric cancer samples Frozen cancer tissues obtained from the resection of primary gastric cancer were retrieved in 13 SRC and 12 GA. Adjacent non-cancerous tissues (ANCT) were available in 13 SRC and 9 GA. We performed 50 ⁇ sections, immediately put in liquid nitrogen, then stored at -80°C until RNA extraction. Before and after each sample, we performed a 10 ⁇ section, which was stained (hematoxylin/eosin) and reviewed by a pathologist to assess the presence of tumoral cells.
- ANCT Adjacent non-cancerous tissues
- RNA Extraction Total RNA was extracted using RNeasy mini kit (Qiagen, USA). Quality and concentration of RNA samples was assessed using NanoVue (GE Healthcare Life Sciences, USA). Integrity was assessed on a RNA chip (Affymetrix, USA) to determine RNA Integrity Number (RIN). As previously described (25), a RIN > 5 was considered suitable for qPCR analysis. Cancer tissues were suitable for qPCR in 11 SRC and 11 GA. ANCT were suitable for qPCR in 7 SRC and 8 GA.
- Reverse transcription was performed using QuantiTect Reverse Transcription kit (Qiagen, USA) according to the manufacturer's instructions. cDNA was stored at -20°C until use.
- qPCR was performed to quantify the levels of IGFIR pathway's genes and PD-
- Real-time RT-PCRs were carried out using the Real-Time System with SYBR Green according to the manufacturer's instructions. Briefly, after cDNA denaturation (95°C, 5 minutes), amplification and quantification was carried out for 40 cycles (95°C, 15 seconds, followed by 20 seconds at hybridization temperature, and 15 seconds at 72°C), and a melting curved was performed (range from 60 to 99°C with a 0,5°C/sec increase). The content of each gene's transcripts was normalized to the content of the housekeeping gene Beta-Actin. The normalized quantity of the target gene was calculated as 2 " ⁇ . AACt was obtained by subtracting Ct for the target gene from Ct for the Beta-Actin gene. The final result was expressed as 2 ⁇ . All PCR assays were carried out in triplicates for each sample, and the values were averaged.
- TMA construction Every sample used in our study were derived from formalin- fixed, paraffin-embedded tissue samples obtained from the the resection of primary gastric cancer. Hematoxylin-eosin stained sections from the tissue blocks were reviewed by a pathologist, who marked representative tumor areas for the construction of the TMA blocks. Each tumour was represented by 4 cancerous spots, 1 mm in diameter. Each TMA block also contained 1 ANCT spot per patient, serving as controls. Cancer tissues were available in 17 SRC and 12 GA. ANCT were available in 13 SRC and 12 GA.
- Immunohistochemistry 4 ⁇ sections were cut on TMA blocks and mounted on slides. The immunohistochemical labelling was performed at the laboratory of pathology of Lariboisiere hospital, using BenchMark ULTRA staining module (Ventana Medical Systems). The sections were incubated with primary antibodies for 28 min at 36°C. Primary antibodies were used at optimized dilutions previously determined on control tissues.
- IHC results Sections were read by a pathologist blinded to the patient's data.
- IGFIR we used a semi-quantitative approach previously described (32) : The percentage of positive cells per core (0-100%) was multiplied by the dominant intensity pattern of staining, 1 being considered as negative or trace, 2 weak, 3 moderate, 4 strong, giving a modified H-score ranging from 0 to 400 .
- PD-Ll we used a qualitative approach as described by (33). FoxP3 positivity was defined as positive nuclear staining in more than 10 lymphocytes on 3 fields at a 200 magnification (33).
- RNA-expressions and modified H-scores are expressed as means ⁇ SD. Mann Whitney non parametric test was used to compare means. Percentage comparisons were carried out using a Fisher's exact test. Statistical analysis was performed using GraphPad Prism 5 software (GraphPad Software, San Diego, CA). A p ⁇ 0,05 was considered statistically significant.
- Figure 1 shows IGF-1 and IGF-2 relative expressions for SRC and GA groups.
- There was no difference in IGF-2 expression between cancer tissue and ANCT in SRC group (figure IB).
- Figure 5 shows mRNA levels of PD-Ll and PD-L2 in SRC and GA groups.
- mRNA levels of PD-Ll and PD-L2 were detected in both cancer tissue and ANCT, in SRC as well as in GA. There were no statistical differences in mRNA levels of PD-Ll and PD-L2 in cancer tissue between SRC and GA.
- IGF1R Insulin-like growth factor receptor 1
- OX40, OX40L, PD-1, PD-Ll, or PD-L2 and acute rejection of human renal allografts.
- IGF-1R Insulin-like growth factor receptor-1
Abstract
La présente invention concerne des méthodes et compositions pharmaceutiques pour le traitement du cancer de l'estomac à cellules en bague à chaton. La présente invention concerne également une méthode de traitement du carcinome gastrique à cellules en bague à chaton chez le patient le nécessitant, comprenant l'administration au patient d'une quantité thérapeutiquement efficace d'au moins un inhibiteur de PD-1 ou d'au moins un inhibiteur de l'IGF1R.
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10323091B2 (en) | 2015-09-01 | 2019-06-18 | Agenus Inc. | Anti-PD-1 antibodies and methods of use thereof |
US10441654B2 (en) | 2014-01-24 | 2019-10-15 | Children's Hospital Of Eastern Ontario Research Institute Inc. | SMC combination therapy for the treatment of cancer |
Citations (73)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4816567A (en) | 1983-04-08 | 1989-03-28 | Genentech, Inc. | Recombinant immunoglobin preparations |
EP0368684A1 (fr) | 1988-11-11 | 1990-05-16 | Medical Research Council | Clonage de séquences d'immunoglobulines de domaines variables. |
EP0404097A2 (fr) | 1989-06-22 | 1990-12-27 | BEHRINGWERKE Aktiengesellschaft | Récepteurs mono- et oligovalents, bispécifiques et oligospécifiques, ainsi que leur production et application |
WO1993011161A1 (fr) | 1991-11-25 | 1993-06-10 | Enzon, Inc. | Proteines multivalentes de fixation aux antigenes |
US5225539A (en) | 1986-03-27 | 1993-07-06 | Medical Research Council | Recombinant altered antibodies and methods of making altered antibodies |
US5229275A (en) | 1990-04-26 | 1993-07-20 | Akzo N.V. | In-vitro method for producing antigen-specific human monoclonal antibodies |
US5545807A (en) | 1988-10-12 | 1996-08-13 | The Babraham Institute | Production of antibodies from transgenic animals |
US5545806A (en) | 1990-08-29 | 1996-08-13 | Genpharm International, Inc. | Ransgenic non-human animals for producing heterologous antibodies |
US5565332A (en) | 1991-09-23 | 1996-10-15 | Medical Research Council | Production of chimeric antibodies - a combinatorial approach |
US5567610A (en) | 1986-09-04 | 1996-10-22 | Bioinvent International Ab | Method of producing human monoclonal antibodies and kit therefor |
US5573905A (en) | 1992-03-30 | 1996-11-12 | The Scripps Research Institute | Encoded combinatorial chemical libraries |
US5585089A (en) | 1988-12-28 | 1996-12-17 | Protein Design Labs, Inc. | Humanized immunoglobulins |
US5591669A (en) | 1988-12-05 | 1997-01-07 | Genpharm International, Inc. | Transgenic mice depleted in a mature lymphocytic cell-type |
US5598369A (en) | 1994-06-28 | 1997-01-28 | Advanced Micro Devices, Inc. | Flash EEPROM array with floating substrate erase operation |
US5859205A (en) | 1989-12-21 | 1999-01-12 | Celltech Limited | Humanised antibodies |
WO1999028347A1 (fr) | 1997-11-27 | 1999-06-10 | Commonwealth Scientific And Industrial Research Organisation | Procede de conception d'angonistes et d'antagonistes du recepteur de l'igf |
US5981732A (en) | 1998-12-04 | 1999-11-09 | Isis Pharmaceuticals Inc. | Antisense modulation of G-alpha-13 expression |
US6046321A (en) | 1999-04-09 | 2000-04-04 | Isis Pharmaceuticals Inc. | Antisense modulation of G-alpha-i1 expression |
US6107091A (en) | 1998-12-03 | 2000-08-22 | Isis Pharmaceuticals Inc. | Antisense inhibition of G-alpha-16 expression |
US6150584A (en) | 1990-01-12 | 2000-11-21 | Abgenix, Inc. | Human antibodies derived from immunized xenomice |
US6194551B1 (en) | 1998-04-02 | 2001-02-27 | Genentech, Inc. | Polypeptide variants |
US6365354B1 (en) | 2000-07-31 | 2002-04-02 | Isis Pharmaceuticals, Inc. | Antisense modulation of lysophospholipase I expression |
US6410323B1 (en) | 1999-08-31 | 2002-06-25 | Isis Pharmaceuticals, Inc. | Antisense modulation of human Rho family gene expression |
US6566131B1 (en) | 2000-10-04 | 2003-05-20 | Isis Pharmaceuticals, Inc. | Antisense modulation of Smad6 expression |
US6566135B1 (en) | 2000-10-04 | 2003-05-20 | Isis Pharmaceuticals, Inc. | Antisense modulation of caspase 6 expression |
WO2003042402A2 (fr) | 2001-11-13 | 2003-05-22 | Dana-Farber Cancer Institute, Inc. | Agents modulant l'activite de cellules immunes et procedes d'utilisation associes |
US6608108B2 (en) | 1999-10-15 | 2003-08-19 | Johns Hopkins University | Method for treatment of tumors using nordihydroguaiaretic acid derivatives |
WO2003070911A2 (fr) | 2002-02-20 | 2003-08-28 | Ribozyme Pharmaceuticals, Inc | Inhibition mediee par interference arn d une expression genique de recepteur de facteur de croissance de type insuline de type 1 (igf-1r) faisant appel a des acides nucleiques interferants courts (sina) |
US20030195147A1 (en) | 1998-09-02 | 2003-10-16 | Renuka Pillutla | Insulin and IGF-1 receptor agonists and antagonists |
US20030236190A1 (en) | 1998-09-02 | 2003-12-25 | Renuka Pillutla | Isulin and IGF-1 receptor agonists and antagonists |
US20040018191A1 (en) | 2002-05-24 | 2004-01-29 | Schering Corporation | Neutralizing human anti-IGFR antibody |
US20040023887A1 (en) | 1998-09-02 | 2004-02-05 | Renuka Pillutla | Insulin and IGF-1 receptor agonists and antagonists |
US20050054638A1 (en) | 2001-12-07 | 2005-03-10 | Astrazeneca Ab | Pyrimidine derivatives as modulators of insulin-like growth factor-1 receptor (igf-i) |
WO2005037836A2 (fr) | 2003-10-15 | 2005-04-28 | Osi Pharmaceuticals, Inc. | Imidazopyrazines utilisees comme inhibiteurs de la tyrosine kinase |
US20050136063A1 (en) | 2003-11-21 | 2005-06-23 | Schering Corporation | Anti-IGFR antibody therapeutic combinations |
WO2005082415A2 (fr) | 2004-02-25 | 2005-09-09 | Dana Farber Cancer Institute, Inc. | Procedes d'inhibition de croissance de cellules tumorales |
WO2005097800A1 (fr) | 2004-04-02 | 2005-10-20 | Osi Pharmaceuticals, Inc. | Inhibiteurs de la proteine kinase heterobicycliques a substitution de noyau bicyclique 6,6 |
US20050282761A1 (en) | 2003-02-28 | 2005-12-22 | George Tachas | Modulation of growth hormone receptor expression and insulin-like growth factor expression |
WO2006003388A2 (fr) | 2004-06-30 | 2006-01-12 | Domantis Limited | Compositions et procedes pour le traitement de troubles inflammatoires |
WO2006009962A2 (fr) | 2004-06-21 | 2006-01-26 | Exelixis, Inc. | Acacs utilises comme genes modificateurs de la voie igf et leurs procedes d'utilisation |
WO2006012422A1 (fr) | 2004-07-20 | 2006-02-02 | Osi Pharmaceuticals, Inc. | Imidazotriazines comme inhibiteurs de la tyrosine kinase |
WO2006017443A2 (fr) | 2004-08-02 | 2006-02-16 | Osi Pharmaceuticals, Inc. | Composes a base de pyrrolopyrimidine a substitution arylamine inhibiteurs de kinases multiples |
WO2006030220A1 (fr) | 2004-09-17 | 2006-03-23 | Domantis Limited | Compositions monovalentes pour la liaison au cd40l et procedes d'utilisation |
WO2006069202A2 (fr) | 2004-12-22 | 2006-06-29 | Amgen Inc. | Compositions et procedes impliquant des anticorps diriges contre le recepteur igf-1r |
US7071300B2 (en) | 2001-03-14 | 2006-07-04 | Genentech, Inc. | IGF antagonist peptides |
WO2006074057A2 (fr) | 2004-12-30 | 2006-07-13 | Exelixis, Inc. | Modulateurs de kinase et procedes d'utilisation |
WO2006121168A1 (fr) | 2005-05-09 | 2006-11-16 | Ono Pharmaceutical Co., Ltd. | Anticorps monoclonaux humains pour mort programmee 1 (mp-1) et procedes pour traiter le cancer en utilisant des anticorps anti-mp-1 seuls ou associes a d’autres immunotherapies |
WO2007004060A2 (fr) | 2005-05-05 | 2007-01-11 | Valorisation Hsj, Societe En Commandite | Modulateurs du recepteur de la cytokine et leurs utilisations |
WO2007005874A2 (fr) | 2005-07-01 | 2007-01-11 | Medarex, Inc. | Anticorps monoclonaux humains diriges contre un ligand de mort programmee de type 1(pd-l1) |
WO2007029107A1 (fr) | 2005-09-09 | 2007-03-15 | Analytecon Sa | Derives d'isoquinolines utilises en tant qu'inhibiteurs d'igf-1r |
WO2007029106A1 (fr) | 2005-09-09 | 2007-03-15 | Analytecon Sa | Isoquinolines utilises en tant qu'inhibiteurs d'igf-1r |
WO2007031745A1 (fr) | 2005-09-16 | 2007-03-22 | Astrazeneca Ab | Dérivés de la pyrimidine utilisés pour inhiber l’activité de la tyrosine kinase igf-ir |
US20070129399A1 (en) | 2004-03-12 | 2007-06-07 | Jan Gunzinger | Tetrahydroisoquinoline-and tetrahydrobenzazepine derivatives as igf-1r inhibitors |
US20070135340A1 (en) | 2004-11-29 | 2007-06-14 | Nadia Rosenthal | IGF-1 novel peptides |
WO2007099166A1 (fr) | 2006-03-03 | 2007-09-07 | Nerviano Medical Sciences S.R.L. | Dérives de pyrazolo-pyridine actifs en tant qu'inhibiteurs de la kinase |
WO2007099171A2 (fr) | 2006-03-03 | 2007-09-07 | Nerviano Medical Sciences S.R.L. | Bicyclopyrazoles actifs comme inhibiteurs de la kinase |
EP0737248B1 (fr) | 1993-12-29 | 2007-11-14 | Centre National De La Recherche Scientifique (Cnrs) | Controle de l'expression du gene de l'igf-i |
US20070299010A1 (en) | 2006-02-10 | 2007-12-27 | Elly Nedivi | CPG15 and CPG15-2 compounds and inhibitors as insulin receptor and insulin-like growth factor receptor agonists and antagonists |
US7329734B2 (en) | 1998-12-03 | 2008-02-12 | Hoffmann-La Roche Inc. | IGF-1 receptor interacting proteins |
WO2008156712A1 (fr) | 2007-06-18 | 2008-12-24 | N. V. Organon | Anticorps dirigés contre le récepteur humain de mort programmée pd-1 |
US7488802B2 (en) | 2002-12-23 | 2009-02-10 | Wyeth | Antibodies against PD-1 |
WO2009101611A1 (fr) | 2008-02-11 | 2009-08-20 | Curetech Ltd. | Anticorps monoclonaux pour le traitement de tumeurs |
WO2010027827A2 (fr) | 2008-08-25 | 2010-03-11 | Amplimmune, Inc. | Polypeptides co-stimulateurs ciblés et leurs procédés d'utilisation dans le traitement du cancer |
WO2010036959A2 (fr) | 2008-09-26 | 2010-04-01 | Dana-Farber Cancer Institute | Anticorps anti-pd-1, pd-l1, et pd-l2 humains et leurs utilisations |
WO2010077634A1 (fr) | 2008-12-09 | 2010-07-08 | Genentech, Inc. | Anticorps anti-pd-l1 et leur utilisation pour améliorer la fonction des lymphocytes t |
WO2010089411A2 (fr) | 2009-02-09 | 2010-08-12 | Universite De La Mediterranee | Anticorps pd-1 et anticorps pd-l1 et leurs utilisations |
WO2011066342A2 (fr) | 2009-11-24 | 2011-06-03 | Amplimmune, Inc. | Inhibition simultanée de pd-l1/pd-l2 |
WO2011082400A2 (fr) | 2010-01-04 | 2011-07-07 | President And Fellows Of Harvard College | Modulateurs du récepteur immunosuppresseur pd-1 et procédés d'utilisation de ceux-ci |
WO2011159877A2 (fr) | 2010-06-18 | 2011-12-22 | The Brigham And Women's Hospital, Inc. | Anticorps di-spécifiques anti-tim-3 et pd-1 pour immunothérapie dans des états pathologiques immuns chroniques |
WO2011161699A2 (fr) | 2010-06-25 | 2011-12-29 | Aurigene Discovery Technologies Limited | Composés modulateurs de l'immunosuppression |
US8168757B2 (en) | 2008-03-12 | 2012-05-01 | Merck Sharp & Dohme Corp. | PD-1 binding proteins |
WO2014039983A1 (fr) * | 2012-09-07 | 2014-03-13 | The Trustees Of Dartmouth College | Modulateurs vista de diagnostic et de traitement de cancer |
WO2015061752A1 (fr) * | 2013-10-25 | 2015-04-30 | Pharmacyclics, Inc. | Traitement à l'aide d'inhibiteurs de la tyrosine kinase de bruton et de l'immunothérapie |
-
2017
- 2017-01-27 WO PCT/EP2017/051805 patent/WO2017129763A1/fr active Application Filing
Patent Citations (89)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4816567A (en) | 1983-04-08 | 1989-03-28 | Genentech, Inc. | Recombinant immunoglobin preparations |
US5225539A (en) | 1986-03-27 | 1993-07-06 | Medical Research Council | Recombinant altered antibodies and methods of making altered antibodies |
US5567610A (en) | 1986-09-04 | 1996-10-22 | Bioinvent International Ab | Method of producing human monoclonal antibodies and kit therefor |
US5545807A (en) | 1988-10-12 | 1996-08-13 | The Babraham Institute | Production of antibodies from transgenic animals |
EP0368684A1 (fr) | 1988-11-11 | 1990-05-16 | Medical Research Council | Clonage de séquences d'immunoglobulines de domaines variables. |
US5591669A (en) | 1988-12-05 | 1997-01-07 | Genpharm International, Inc. | Transgenic mice depleted in a mature lymphocytic cell-type |
US5693762A (en) | 1988-12-28 | 1997-12-02 | Protein Design Labs, Inc. | Humanized immunoglobulins |
US5693761A (en) | 1988-12-28 | 1997-12-02 | Protein Design Labs, Inc. | Polynucleotides encoding improved humanized immunoglobulins |
US5585089A (en) | 1988-12-28 | 1996-12-17 | Protein Design Labs, Inc. | Humanized immunoglobulins |
EP0404097A2 (fr) | 1989-06-22 | 1990-12-27 | BEHRINGWERKE Aktiengesellschaft | Récepteurs mono- et oligovalents, bispécifiques et oligospécifiques, ainsi que leur production et application |
US5859205A (en) | 1989-12-21 | 1999-01-12 | Celltech Limited | Humanised antibodies |
US6150584A (en) | 1990-01-12 | 2000-11-21 | Abgenix, Inc. | Human antibodies derived from immunized xenomice |
US5229275A (en) | 1990-04-26 | 1993-07-20 | Akzo N.V. | In-vitro method for producing antigen-specific human monoclonal antibodies |
US5545806A (en) | 1990-08-29 | 1996-08-13 | Genpharm International, Inc. | Ransgenic non-human animals for producing heterologous antibodies |
US5565332A (en) | 1991-09-23 | 1996-10-15 | Medical Research Council | Production of chimeric antibodies - a combinatorial approach |
WO1993011161A1 (fr) | 1991-11-25 | 1993-06-10 | Enzon, Inc. | Proteines multivalentes de fixation aux antigenes |
US5573905A (en) | 1992-03-30 | 1996-11-12 | The Scripps Research Institute | Encoded combinatorial chemical libraries |
EP0737248B1 (fr) | 1993-12-29 | 2007-11-14 | Centre National De La Recherche Scientifique (Cnrs) | Controle de l'expression du gene de l'igf-i |
US5598369A (en) | 1994-06-28 | 1997-01-28 | Advanced Micro Devices, Inc. | Flash EEPROM array with floating substrate erase operation |
WO1999028347A1 (fr) | 1997-11-27 | 1999-06-10 | Commonwealth Scientific And Industrial Research Organisation | Procede de conception d'angonistes et d'antagonistes du recepteur de l'igf |
US7020563B1 (en) | 1997-11-27 | 2006-03-28 | Commonwealth Scientific And Industrial Research Organisation | Method of designing agonists and antagonists to IGF receptor |
US6194551B1 (en) | 1998-04-02 | 2001-02-27 | Genentech, Inc. | Polypeptide variants |
US7173005B2 (en) | 1998-09-02 | 2007-02-06 | Antyra Inc. | Insulin and IGF-1 receptor agonists and antagonists |
US20030195147A1 (en) | 1998-09-02 | 2003-10-16 | Renuka Pillutla | Insulin and IGF-1 receptor agonists and antagonists |
US20040023887A1 (en) | 1998-09-02 | 2004-02-05 | Renuka Pillutla | Insulin and IGF-1 receptor agonists and antagonists |
US20070004634A1 (en) | 1998-09-02 | 2007-01-04 | Novo Nordisk A/S | Insulin and IGF-1 receptor agonists and antagonists |
US20070265189A1 (en) | 1998-09-02 | 2007-11-15 | Novo Nordisk A/S | Insulin and igf-1 receptor agonists and antagonists |
US6875741B2 (en) | 1998-09-02 | 2005-04-05 | Renuka Pillutla | Insulin and IGF-1 receptor agonists and antagonists |
US20030236190A1 (en) | 1998-09-02 | 2003-12-25 | Renuka Pillutla | Isulin and IGF-1 receptor agonists and antagonists |
US6107091A (en) | 1998-12-03 | 2000-08-22 | Isis Pharmaceuticals Inc. | Antisense inhibition of G-alpha-16 expression |
US7329734B2 (en) | 1998-12-03 | 2008-02-12 | Hoffmann-La Roche Inc. | IGF-1 receptor interacting proteins |
US5981732A (en) | 1998-12-04 | 1999-11-09 | Isis Pharmaceuticals Inc. | Antisense modulation of G-alpha-13 expression |
US6046321A (en) | 1999-04-09 | 2000-04-04 | Isis Pharmaceuticals Inc. | Antisense modulation of G-alpha-i1 expression |
US6410323B1 (en) | 1999-08-31 | 2002-06-25 | Isis Pharmaceuticals, Inc. | Antisense modulation of human Rho family gene expression |
US6608108B2 (en) | 1999-10-15 | 2003-08-19 | Johns Hopkins University | Method for treatment of tumors using nordihydroguaiaretic acid derivatives |
US6365354B1 (en) | 2000-07-31 | 2002-04-02 | Isis Pharmaceuticals, Inc. | Antisense modulation of lysophospholipase I expression |
US6566135B1 (en) | 2000-10-04 | 2003-05-20 | Isis Pharmaceuticals, Inc. | Antisense modulation of caspase 6 expression |
US6566131B1 (en) | 2000-10-04 | 2003-05-20 | Isis Pharmaceuticals, Inc. | Antisense modulation of Smad6 expression |
US7071300B2 (en) | 2001-03-14 | 2006-07-04 | Genentech, Inc. | IGF antagonist peptides |
EP1432433A2 (fr) | 2001-09-24 | 2004-06-30 | Novo Nordisk A/S | Antagonistes |
EP1496935A2 (fr) | 2001-09-24 | 2005-01-19 | Novo Nordisk A/S | Agonistes et antagonistes du recepteur de l'insuline et d'igf-1 |
WO2003042402A2 (fr) | 2001-11-13 | 2003-05-22 | Dana-Farber Cancer Institute, Inc. | Agents modulant l'activite de cellules immunes et procedes d'utilisation associes |
US20050054638A1 (en) | 2001-12-07 | 2005-03-10 | Astrazeneca Ab | Pyrimidine derivatives as modulators of insulin-like growth factor-1 receptor (igf-i) |
WO2003070911A2 (fr) | 2002-02-20 | 2003-08-28 | Ribozyme Pharmaceuticals, Inc | Inhibition mediee par interference arn d une expression genique de recepteur de facteur de croissance de type insuline de type 1 (igf-1r) faisant appel a des acides nucleiques interferants courts (sina) |
US20040018191A1 (en) | 2002-05-24 | 2004-01-29 | Schering Corporation | Neutralizing human anti-IGFR antibody |
US7488802B2 (en) | 2002-12-23 | 2009-02-10 | Wyeth | Antibodies against PD-1 |
US20050282761A1 (en) | 2003-02-28 | 2005-12-22 | George Tachas | Modulation of growth hormone receptor expression and insulin-like growth factor expression |
WO2005037836A2 (fr) | 2003-10-15 | 2005-04-28 | Osi Pharmaceuticals, Inc. | Imidazopyrazines utilisees comme inhibiteurs de la tyrosine kinase |
US20050136063A1 (en) | 2003-11-21 | 2005-06-23 | Schering Corporation | Anti-IGFR antibody therapeutic combinations |
WO2005082415A2 (fr) | 2004-02-25 | 2005-09-09 | Dana Farber Cancer Institute, Inc. | Procedes d'inhibition de croissance de cellules tumorales |
US20070129399A1 (en) | 2004-03-12 | 2007-06-07 | Jan Gunzinger | Tetrahydroisoquinoline-and tetrahydrobenzazepine derivatives as igf-1r inhibitors |
EP1732898B1 (fr) | 2004-03-12 | 2008-01-23 | Analytecon S.A. | Derives de tetrahydroisoquinoleino et de tetrahydrobenzazepine utilises comme inhibiteurs de l'igf-1r |
WO2005097800A1 (fr) | 2004-04-02 | 2005-10-20 | Osi Pharmaceuticals, Inc. | Inhibiteurs de la proteine kinase heterobicycliques a substitution de noyau bicyclique 6,6 |
WO2006009933A2 (fr) | 2004-06-21 | 2006-01-26 | Exelixis, Inc. | Genes cdk9 utilises comme modificateur de la voie igf et technique d'utilisation |
WO2006009950A2 (fr) | 2004-06-21 | 2006-01-26 | Exelixis, Inc. | Genes aldo utilises comme modificateurs de la voie igf et procedes d'utilisation |
WO2006009947A2 (fr) | 2004-06-21 | 2006-01-26 | Exelixis, Inc. | Migfs utiles comme modificateurs du mecanisme d'action d'igf et leurs procedes d'utilisation |
WO2006009962A2 (fr) | 2004-06-21 | 2006-01-26 | Exelixis, Inc. | Acacs utilises comme genes modificateurs de la voie igf et leurs procedes d'utilisation |
WO2006003388A2 (fr) | 2004-06-30 | 2006-01-12 | Domantis Limited | Compositions et procedes pour le traitement de troubles inflammatoires |
WO2006012422A1 (fr) | 2004-07-20 | 2006-02-02 | Osi Pharmaceuticals, Inc. | Imidazotriazines comme inhibiteurs de la tyrosine kinase |
WO2006017443A2 (fr) | 2004-08-02 | 2006-02-16 | Osi Pharmaceuticals, Inc. | Composes a base de pyrrolopyrimidine a substitution arylamine inhibiteurs de kinases multiples |
WO2006030220A1 (fr) | 2004-09-17 | 2006-03-23 | Domantis Limited | Compositions monovalentes pour la liaison au cd40l et procedes d'utilisation |
US20070135340A1 (en) | 2004-11-29 | 2007-06-14 | Nadia Rosenthal | IGF-1 novel peptides |
WO2006069202A2 (fr) | 2004-12-22 | 2006-06-29 | Amgen Inc. | Compositions et procedes impliquant des anticorps diriges contre le recepteur igf-1r |
WO2006074057A2 (fr) | 2004-12-30 | 2006-07-13 | Exelixis, Inc. | Modulateurs de kinase et procedes d'utilisation |
WO2007004060A2 (fr) | 2005-05-05 | 2007-01-11 | Valorisation Hsj, Societe En Commandite | Modulateurs du recepteur de la cytokine et leurs utilisations |
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 |
WO2006121168A1 (fr) | 2005-05-09 | 2006-11-16 | Ono Pharmaceutical Co., Ltd. | Anticorps monoclonaux humains pour mort programmee 1 (mp-1) et procedes pour traiter le cancer en utilisant des anticorps anti-mp-1 seuls ou associes a d’autres immunotherapies |
WO2007005874A2 (fr) | 2005-07-01 | 2007-01-11 | Medarex, Inc. | Anticorps monoclonaux humains diriges contre un ligand de mort programmee de type 1(pd-l1) |
US7943743B2 (en) | 2005-07-01 | 2011-05-17 | Medarex, Inc. | Human monoclonal antibodies to programmed death ligand 1 (PD-L1) |
WO2007029106A1 (fr) | 2005-09-09 | 2007-03-15 | Analytecon Sa | Isoquinolines utilises en tant qu'inhibiteurs d'igf-1r |
WO2007029107A1 (fr) | 2005-09-09 | 2007-03-15 | Analytecon Sa | Derives d'isoquinolines utilises en tant qu'inhibiteurs d'igf-1r |
WO2007031745A1 (fr) | 2005-09-16 | 2007-03-22 | Astrazeneca Ab | Dérivés de la pyrimidine utilisés pour inhiber l’activité de la tyrosine kinase igf-ir |
US20070299010A1 (en) | 2006-02-10 | 2007-12-27 | Elly Nedivi | CPG15 and CPG15-2 compounds and inhibitors as insulin receptor and insulin-like growth factor receptor agonists and antagonists |
WO2007099171A2 (fr) | 2006-03-03 | 2007-09-07 | Nerviano Medical Sciences S.R.L. | Bicyclopyrazoles actifs comme inhibiteurs de la kinase |
WO2007099166A1 (fr) | 2006-03-03 | 2007-09-07 | Nerviano Medical Sciences S.R.L. | Dérives de pyrazolo-pyridine actifs en tant qu'inhibiteurs de la kinase |
WO2008156712A1 (fr) | 2007-06-18 | 2008-12-24 | N. V. Organon | Anticorps dirigés contre le récepteur humain de mort programmée pd-1 |
WO2009101611A1 (fr) | 2008-02-11 | 2009-08-20 | Curetech Ltd. | Anticorps monoclonaux pour le traitement de tumeurs |
US8168757B2 (en) | 2008-03-12 | 2012-05-01 | Merck Sharp & Dohme Corp. | PD-1 binding proteins |
WO2010027827A2 (fr) | 2008-08-25 | 2010-03-11 | Amplimmune, Inc. | Polypeptides co-stimulateurs ciblés et leurs procédés d'utilisation dans le traitement du cancer |
WO2010036959A2 (fr) | 2008-09-26 | 2010-04-01 | Dana-Farber Cancer Institute | Anticorps anti-pd-1, pd-l1, et pd-l2 humains et leurs utilisations |
WO2010077634A1 (fr) | 2008-12-09 | 2010-07-08 | Genentech, Inc. | Anticorps anti-pd-l1 et leur utilisation pour améliorer la fonction des lymphocytes t |
US8217149B2 (en) | 2008-12-09 | 2012-07-10 | Genentech, Inc. | Anti-PD-L1 antibodies, compositions and articles of manufacture |
WO2010089411A2 (fr) | 2009-02-09 | 2010-08-12 | Universite De La Mediterranee | Anticorps pd-1 et anticorps pd-l1 et leurs utilisations |
WO2011066342A2 (fr) | 2009-11-24 | 2011-06-03 | Amplimmune, Inc. | Inhibition simultanée de pd-l1/pd-l2 |
WO2011082400A2 (fr) | 2010-01-04 | 2011-07-07 | President And Fellows Of Harvard College | Modulateurs du récepteur immunosuppresseur pd-1 et procédés d'utilisation de ceux-ci |
WO2011159877A2 (fr) | 2010-06-18 | 2011-12-22 | The Brigham And Women's Hospital, Inc. | Anticorps di-spécifiques anti-tim-3 et pd-1 pour immunothérapie dans des états pathologiques immuns chroniques |
WO2011161699A2 (fr) | 2010-06-25 | 2011-12-29 | Aurigene Discovery Technologies Limited | Composés modulateurs de l'immunosuppression |
WO2014039983A1 (fr) * | 2012-09-07 | 2014-03-13 | The Trustees Of Dartmouth College | Modulateurs vista de diagnostic et de traitement de cancer |
WO2015061752A1 (fr) * | 2013-10-25 | 2015-04-30 | Pharmacyclics, Inc. | Traitement à l'aide d'inhibiteurs de la tyrosine kinase de bruton et de l'immunothérapie |
Non-Patent Citations (48)
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10441654B2 (en) | 2014-01-24 | 2019-10-15 | Children's Hospital Of Eastern Ontario Research Institute Inc. | SMC combination therapy for the treatment of cancer |
US10323091B2 (en) | 2015-09-01 | 2019-06-18 | Agenus Inc. | Anti-PD-1 antibodies and methods of use thereof |
US10450373B2 (en) | 2015-09-01 | 2019-10-22 | Agenus Inc. | Anti-PD-1 antibodies and methods of use thereof |
US11345755B2 (en) | 2015-09-01 | 2022-05-31 | Agenus Inc. | Anti-PD-1 antibodies and methods of use thereof |
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