WO2019072566A1 - Combinaison d'anticorps anti-il10 et anti-pd1 pour le traitement du cancer - Google Patents

Combinaison d'anticorps anti-il10 et anti-pd1 pour le traitement du cancer Download PDF

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WO2019072566A1
WO2019072566A1 PCT/EP2018/076114 EP2018076114W WO2019072566A1 WO 2019072566 A1 WO2019072566 A1 WO 2019072566A1 EP 2018076114 W EP2018076114 W EP 2018076114W WO 2019072566 A1 WO2019072566 A1 WO 2019072566A1
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body weight
antibody
neutralizing antibody
dosage
melanoma
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PCT/EP2018/076114
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Christoph Uherek
Martin Koenig
Sylvia LEMKE
Christian HUEBER
Peter Herbener
Alexandra WOLLERSHEIM
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Biotest Ag
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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
    • C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
    • C07K16/244—Interleukins [IL]
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/34—Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/55—Fab or Fab'
    • 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 disclosure relates to the field of oncology, more particularly to immune oncology combination therapies for use in the treatment of malignant melanoma.
  • Malignant melanoma is the most aggressive type of skin cancer and currently accounts for more than 160,000 new cancer cases worldwide every year. Incidence of malignant melanoma is rapidly increasing - with a doubling rate of 10-20 years and a death rate of 1 1 %. However, the molecular mechanisms underlying melanoma progression are largely unknown, and there remains a need for target-specific therapies.
  • PD-1 Programmed cell death protein 1
  • CD279 is a type I membrane protein with a length of 268 amino acid residues, belongs to the extended CD28/CTLA-4 family, and is expressed on the surface of activated T cells, B cells, and macrophages.
  • PD-1 is an immune checkpoint and guards against autoimmunity through a dual mechanism of promoting apoptosis in antigen specific T cells while simultaneously reducing apoptosis in regulatory T cells.
  • the intracellular tail contains an immunoreceptor tyrosine-based inhibitory motif (ITIM), and an immunoreceptor tyrosine-based switch motif, suggesting that PD-1 negatively regulates T-cell receptor signals.
  • ITIM immunoreceptor tyrosine-based inhibitory motif
  • SHP-1 and SHP-2 were found to bind to the cytoplasmic tail of PD-1 .
  • Pembrolizumab (formerly MK-3475), marketed by Merck MSD under the tradename Keytruda, is a humanized lgG4-K immunoglobulin with a molecular weight of about 149 kDa, which targets the PD-1 receptor and inhibits binding of the PD-1 receptor ligands PD-L1 and PD-L2.
  • Pembrolizumab has been approved for the treatment of metastatic melanoma and metastatic non-small cell lung cancer (NSCLC), and is further investigated for the treatment of head and neck squamous cell carcinoma (HNSCC), and for the treatment of adult and pediatric patients with refractory classic Hodgkin's lymphoma (cHL).
  • Nivolumab Another drug targeting PD-1 receptors is Nivolumab (marketed under the tradename Opdivo, Bristol-Myers Squibb; CAS Registry Number: 946414-94-4) .
  • Nivolumab is a fully human lgG4-K monoclonal antibody. Alternative designations for nivolumab include MDX-1 106, MDX-1 106-04, ONO-4538, or BMS-936558.
  • Nivolumab (clone 5C4) and other human monoclonal antibodies that specifically bind to PD-1 are disclosed in US 8,008,449 and WO 2006/121 168.
  • Nivolumab is approved for the treatment of melanoma, lung cancer, kidney cancer, and Hodgkin's lymphoma.
  • BMS-936559 (Bristol-Myers Squibb), Atezolizumab (MPDL3280A, Roche) and Avelumab (Merck KGaA & Pfizer) target PD-L1 .
  • PD-L1 Programmed death ligand 1
  • Inhibitors of PD-L1 will only inhibit binding of PD- L1 to PD-1 , while inhibitors of PD-1 may inhibit interaction with both PD-L1 and PD- L2. It is believed that tumor cell expression of PD-L1 is used as a mechanism to evade recognition/destruction by the immune system.
  • PD-L1 expression of PD-L1 in tumors is associated with poor outcome for patients with certain epithelial cancers.
  • Expression of the other ligand for PD-1 , PD-L2 is restricted only to macrophages and dendritic cells and is also upregulated upon activation.
  • Human IL- 10 is a homodimer with a molecular mass of 37 kDa. Each monomer consists of 160 amino acids and has a molecular mass of 18.5 kDa.
  • the IL-10 dimer interacts with the IL-10 receptor alpha (IL-Rct or IL-10R1 ) and subsequently recruits IL-10 receptor beta (IL-10R or IL-10R2) into the complex.
  • the receptor is expressed on a variety of cells, in particular immune cells including most hematopoietic cells such as monocytes, macrophages, and T- and B -lymphocytes, but is also expressed on non-hemopoietic cells, such as epidermal cells or keratinocytes.
  • IL-10 receptor alpha The binding of IL-10 receptor alpha by IL-10 and the recruitment of IL-10 receptor beta leads to signal transduction via Jak1 and Tyk2 tyrosine kinases and subsequently to activation of transcription factors of the STAT family.
  • Various cellular sources of IL- 10 are known, such as T helper cells, regulatory T cells, monocytes, macrophages, B cells, eosinophils, mast cells, keratinocytes, dendritic cells and even cancer cells.
  • IL- 10 functions on B cells range from prevention of apoptosis, enhancement of proliferation, class switching events and differentiation into plasma cells (Asadullah et al., Pharmacol. Rev. 2003 Jun;55(2):241 -69) and inhibition of inflammation.
  • the small molecule compound ammonium trichloro(dioxoethylene-o,o')tellurate may inhibit IL-10 expression at the transcriptional level, and was suggested to have clinical potential in the treatment of sepsis.
  • WO 201 1/064398 and WO 201 1/064399 disclose the IL-10 neutralizing antibody BT- 063, methods for producing same, and describe the use of BT-063 in the treatment of systemic lupus erythematosus.
  • Clinical Trial NCT02521870 is a currently ongoing phase 1 b/2, open-label, multicenter, dose-escalation and expansion trial for use of intratumoral SD-101 (a TLR9 agonist) in combination with pembrolizumab in patients with metastatic melanoma or recurrent or metastatic head and neck squamous cell carcinoma.
  • TLR9 Tolllike receptor 9
  • TLR9 is unrelated to PD-1 and immune checkpoint inhibitors.
  • Kalli et al. Journal of Translational Medicine 2013, 1 1 : 120 describes a combination therapy of anti-IL-10 and a cancer vaccine in a melanoma mouse model.
  • TLR7 agonist appears to be a promising therapy for the treatment of breast cancer.
  • CTLA-4 and anti-PD-L1 with aCD40/chemotherapy in the treatment of pancreatic carcinoma are provided.
  • the present invention relates to an interleukin 10 (IL-10) neutralizing antibody or fragment thereof for use in combination with a PD-1 inhibitor in the treatment of melanoma, preferably metastatic melanoma, in a mammal, in particular in a human. Further provided is an interleukin 10 (IL-10) neutralizing antibody or fragment thereof for use in the treatment of melanoma in a mammal which is undergoing treatment with a PD-1 inhibitor.
  • IL-10 interleukin 10
  • the present disclosure further relates to a PD-1 inhibitor for use in combination with an interleukin 10 (!L-10) neutralizing antibody or fragment thereof in the treatment of melanoma in a mammal.
  • a PD-1 inhibitor for use in combination with an interleukin 10 (!L-10) neutralizing antibody or fragment thereof in the treatment of melanoma in a mammal.
  • a PD-1 inhibitor for use in the treatment of melanoma in a mammal who is undergoing treatment with an interleukin 10 (IL-10) neutralizing antibody or fragment thereof.
  • IL-10 interleukin 10
  • the IL-10 neutralizing antibody or fragment thereof comprises the heavy chain CDRs 1 -3 as shown in SEQ ID NO: 1 -3, and the light chain CDRs 1 -3 as shown in SEQ ID NO: 4-6; and/or a variable domain of the heavy chain with at least 80% sequence identity over the full length of SEQ ID NO: 7, and a variable domain of the light chain with at least 80% sequence identity over the full length of SEQ ID NO: 8.
  • a prime example of such an antibody is the fully humanized full-length antibody (BT-063).
  • the PD-1 inhibitor is pembrolizumab or nivolumab, more preferably pembrolizumab.
  • the present invention relates to an interleukin 10 (IL-10) neutralizing antibody or fragment thereof for use in combination with a PD-1 inhibitor in the treatment of melanoma in a mammal.
  • the present disclosure provides a method of treating melanoma in a mammal, comprising the step of administering an interleukin 10 (IL-10) neutralizing antibody or fragment thereof in combination with a PD-1 inhibitor, in particular a PD-1 inhibitor selected from pembrolizumab and nivolumab, more preferably pembrolizumab.
  • an interleukin 10 (IL- 10) neutralizing antibody or fragment thereof in the preparation of a medicament for the treatment of melanoma in a mammal, wherein the medicament is to be administered thereof in combination with a PD-1 inhibitor, in particular a PD-1 inhibitor selected from pembrolizumab and nivolumab, more preferably pembrolizumab.
  • a PD-1 inhibitor selected from pembrolizumab and nivolumab, more preferably pembrolizumab.
  • the melanoma is metastatic melanoma.
  • the melanoma or metastatic melanoma expresses PD-L1 and/or PD-L2, and secretes IL- 10.
  • Suitable companion diagnostic tests are known in the art.
  • PD-L1 testing may be performed for PD-1 inhibitor therapy.
  • the mammal is a human subject.
  • the mammal, in particular the human is undergoing treatment with pembrolizumab.
  • an interleukin 10 (IL-10) neutralizing antibody or fragment thereof for use in the treatment of melanoma in a mammal who is undergoing treatment with a PD-1 inhibitor, in particular a PD-1 inhibitor selected from pembrolizumab and nivolumab, more preferably pembrolizumab.
  • a method of treating melanoma in a mammal comprising the step of administering an interleukin 10 (IL-10) neutralizing antibody or fragment thereof to said mammal, wherein said mammal is undergoing treatment with a PD-1 inhibitor, in particular a PD-1 inhibitor selected from pembrolizumab and nivolumab, more preferably pembrolizumab.
  • an interleukin 10 (IL-10) neutralizing antibody or fragment thereof in the preparation of a medicament for the treatment of melanoma in a mammal, wherein said mammal is undergoing treatment with a PD-1 inhibitor, in particular a PD-1 inhibitor selected from pembrolizumab and nivolumab, more preferably pembrolizumab.
  • a PD-1 inhibitor selected from pembrolizumab and nivolumab, more preferably pembrolizumab.
  • Antibodies are also referred to as immunoglobulins, and generally consist in their natural form of two heavy chains and two light chains linked by disulfide bonds.
  • Five mammalian Ig heavy chains are known: ⁇ , ⁇ , ⁇ , ⁇ , and ⁇ , wherein the heavy chain defines the isotype of the antibody, which are IgA, IgD, IgE, IgG, and IgM.
  • the heavy chain contains a constant region and a variable region. The constant region shares high homology in all naturally occurring antibodies of the same isotype within the same species.
  • a light chain also consists of a constant domain and a variable domain. In mammals there are two types of immunoglobulin light chain, lambda ( ⁇ ) and kappa ( ⁇ ).
  • variable (V) regions in particular by three variable loops in each the light (V L ) and the heavy (V H ) chain.
  • V L variable light
  • V H heavy chain
  • antibody is intended to refer to any antibody that has a typical overall domain structure of a naturally occurring antibody (i.e. comprising a heavy chain of three or four constant domains and a light chain of one constant domain as well as the respective variable domains). Nevertheless, each domain may comprise further modifications, such as mutations, deletions, or insertions, which do not change the overall domain structure.
  • the antibody may be an IgA, IgD, IgE, IgG, or IgM antibody, including any subclass of these isotypes.
  • the heavy chains are, however, preferably from the same species.
  • the term antibody "fragment” refers to a fragment or a derivative of an antibody that still retains the desired biological activity.
  • the fragment will generally comprise the antigen binding region of the antibody and, in particular, the Fab, Fab', F(ab)2, Fv and scFv fragments, as well as multivalent antibody derivatives, in particular diabodies or tandem diabodies.
  • the fragment preferably is at least 25, more preferably 50 and still more preferably 200 to 500 amino acids.
  • the fragments can be defined as those having of size of between 30 kDa and 150 kDa.
  • the antibody fragments may involve two or more peptide/polypeptide chains. For example a Fab fragment comprising two chains of between 200 and 300 amino acids in length each or TandAbs ® (tetravalent bispecific antibody formats) comprising two chains of between 400 and 500 amino acids in length each.
  • Fab fragments may be generated from an immunoglobulin by using the enzyme papain.
  • F(ab) 2 fragments are formed by using the enzyme pepsin, which cleaves below the hinge region and, thus, below the disulfide bonds.
  • the variable regions of the heavy and light chains can be fused together to form a single chain variable fragment (scFv).
  • Divalent or bivalent single-chain variable fragments consist of two scFvs in a single peptide chain, which are linked in a manner allowing the two variable regions to fold together, thereby yielding tandem scFvs. If the linkers are shortened to about five amino acids, the scFvs are forced to dimerize, thereby forming diabodies. Diabodies have a much higher affinity to their target than corresponding scFvs, and can therefore be dosed much lower than other therapeutic antibodies. Shorter linkers of one or two amino acids even lead to the formation of trimers, so-called triabodies or tribodies, and tetrabodies have also been produced. They exhibit an even higher affinity to their targets than diabodies.
  • the antibody may also be a humanized or CDR-grafted antibody, as well as a genetically/recombinantly engineered antibody, or a fully human antibody.
  • CDR-grafting is well-known in the art.
  • the antibody is a humanized or a fully-human antibody.
  • One variable region of the antibody may also be combined with another variable region, which binds to another epitope, thereby generating bivalent or polyvalent antibody constructs.
  • the antibody for use of the present disclosure is an interleukin 10 (IL-10) neutralizing antibody.
  • IL-10 interleukin 10
  • Antibodies capable of neutralizing the effects of IL-10 can operate via a number of mechanisms. They may bind to IL-10 and prevent the binding of IL-10 to IL-10Ra via steric hindrance. In particular, since functionally active IL-10 is a homodimer, two antibody molecules may bind to the same IL-10 dimer. Alternatively it is possible that a neutralizing antibody binds to a region of IL-10 not overlapping with the IL-10Ra binding site and antagonizes the IL-10Ra binding by induced conformational changes in IL-10 (Josephson et al.
  • the antibodies may bind to a region of IL-10 which prevents interaction between IL-10 and IL-10R . Further, it is also possible that an antibody binds to a site of IL-10 that is still exposed after binding of the cytokine to the high affinity receptor chain and induces a conformational change the hampers the recruitment of the second receptor chain necessary for signalling.
  • the IL-10 neutralizing antibody or fragment thereof inhibits the interaction of IL-10 with IL-10Ra by binding to the same region of IL-10 as IL- 10Ra. Accordingly, the antibodies for use of the present disclosure prevent any binding between IL-10 and IL-10Ra. As a consequence, suboptimal signaling events referred to above may be avoided. Accordingly, preferably the IL-10 neutralizing antibody or fragment thereof is a fully human, humanized, or chimeric antibody, or a - -
  • IL-10 interleukin-10
  • IL-10 neutralizing antibody or fragment thereof binds to residues between 19 and 42 and between 138 and 158 in the IL-10 dimer. Accordingly, the IL-10 neutralizing antibody or fragment of the present disclosure preferably binds to at least one residue within both of these regions so as to effectively block IL-10Ra binding.
  • the phrase "when IL-10 is bound to the IL-10 receptor” refers to the situation where IL-10 is bound with both sides, i.e. via both monomers, to the IL-10 receptor.
  • the IL-10 neutralizing antibody or fragment thereof does not bind to the same region of IL- 10 as the IL-10 receptor ⁇ (IL-1 OR ).
  • IL-10R is a low affinity shared receptor that participates in receptor complexes with other class 2 cytokine family members.
  • the IL-10 neutralizing antibody or fragment of the present disclosure preferably only blocks IL- 10Ra binding.
  • the IL-10 neutralizing antibody or fragment thereof may be defined as being capable of preventing IL-10 signalling through the IL-10Ra receptor, or as not being capable of binding to IL-1 OR expressing cells (i.e. via bound IL-10).
  • the capability of neutralizing IL-10 can be tested for by determining the capability of neutralizing the activity of IL-10 to inhibit IL-6 secretion in peripheral blood mononuclear cells (PBMCs).
  • PBMCs release lnterleukin-6 (IL-6) upon stimulation with Lipopolysaccharide (LPS).
  • LPS Lipopolysaccharide
  • a physiological activity of Interleukin-10 (IL-10) is the inhibition of secretion of cytokines, e.g. IL-6.
  • IL-10 is bound and thus not able to bind to the receptor on the cell surface.
  • the inhibitory effect of IL-10 is compensated and IL-6 secretion is restored, leading to IL-6 in the medium.
  • human PBMC are freshly prepared from different healthy volunteers by Ficoll gradient.
  • blood samples are diluted 1 : 1 with Hanks buffered solution and 20 ml Ficoll is slowly overlaid with 20 ml of this solution in a sterile 50 ml tube.
  • the tubes are centrifuged at room temperature for 25 mins at 1200xg without brake.
  • an antibody may be characterized as an IL-10 neutralizing antibody, if incubation of the cells with 40 pg/mL of said antibody (in case of an antibody of another isotype or in case of a fragment incubation with the molar equivalent) leads to a reconstitution of IL-6 secretion of at least 50% as compared to the reconstitution of IL-6 secretion by 40 pg/mL BT-063, preferably to a reconstitution of IL-6 secretion of at least 60%, more preferably to a reconstitution of IL-6 secretion of at least 70%, more preferably to a reconstitution of IL-6 secretion of at least 80%, more preferably to a reconstitution of IL-6 secretion of at least 90%, and most preferably to a reconstitution of IL-6 secretion of about 100% as compared to the reconstitution of IL-6 secretion by 40 pg/mL BT-063.
  • the capability of neutralizing IL-10 of a given anti-IL-10 antibody can be tested for by determining the incapability of binding to IL-10R expressing cells via bound IL-10.
  • human peripheral blood mononuclear cells PBMC
  • the binding of the antibody to be tested on human PBMC was determined by FACS analysis using the Zenon labeling Kit (Invitrogen).
  • the antibodies are labelled using the anti-human IgG AlexaFluor488-Zenon kit according to manufacturer's instructions.
  • the reagents in the kit label the antibody to be tested via binding of fluorescently labeled Fab-fragments without affecting its antigen recognition properties.
  • a human lgG1 anti-CD4 Antibody e.g., BT061 , Biotest
  • Non-binding of an anti-IL-10 antibody to PBMC in this assay indicates that said antibody only binds to the receptor binding site of the soluble IL-10, i.e. has neutralizing activity.
  • the IL-10 neutralizing antibody or fragment thereof binds to a discontinuous epitope comprising residues of one of the IL-10 homodimer's monomers and residues of the second monomer of the IL-10 homodimer, i.e. the antibody or fragment thereof binds to a discontinuous epitope comprising residues of the first monomer and residues of the second monomer, wherein the first monomer and the second monomer make up the homodimer.
  • homodimeric form refers to functionally active IL-10 represented by a symmetric homodimer composed of two alpha helical domains (domain A and domain B) oriented at 90 degrees to one another. The structural integrity of each domain is dependent on the intertwining of alpha helices from each peptide chain such that the first four helices of one chain associate with the last two helices of the other.
  • a single IL-10 monomer is not able to bind to the IL-10 receptor, since parts of both chains are required in order to build the interface. Accordingly, an ideal IL-10 neutralizing antibody should bind to an epitope which is formed by the homodimer and not by a monomer.
  • the IL-10 neutralizing antibody or fragment thereof preferably exhibits concomitant interaction with both monomers of the wild type IL-10 dimer.
  • it binds to a "discontinuous epitope" i.e. an epitope in which amino acids are in close proximity in the folded protein, but distant when unfolded.
  • the epitope is represented by amino acids present on both chains of the IL-10 dimer.
  • the antibody or fragment thereof binds to the functionally active IL-10 with much greater affinity than to the IL-10 monomers, on which only a part of the discontinuous epitope is present.
  • the IL- 0 neutralizing antibody or fragment thereof binds to a discontinuous epitope comprising residues of helix A of one IL-10 monomer (i.e. the first monomer) and residues of helix P of the other IL-10 monomer (i.e. the second monomer).
  • the IL-10 neutralizing antibody or fragment thereof binds to a discontinuous epitope formed by the first 55 amino acids of one IL-10 monomer, more preferably to a discontinuous epitope formed by amino acids 20 to 55 and by the last 20 amino acids of the second monomer, and vice versa.
  • the IL-10 referred to herein is human IL-10, the amino acid sequence of which can be represented as:
  • anti-IL-10 antibodies can have the desired activity by known peptide screening techniques or by size exclusion chromatography.
  • Peptide screening techniques can consist of screening possible binders to IL-10, all or a fragment of which can be immobilized onto a membrane or on an adequate surface.
  • the IL-10 or IL-10 fragment can be synthesized synthetically or the encoding nucleotide sequence can be overexpressed in an adequate host such as e.g. E.coli or insect cells.
  • the regions of IL-10 identified herein as forming the epitope for the antibody of the present invention can be used.
  • Anti-IL 10 (neutralizing) antibodies can be identified using e.g. phage or ribosomal display (or mRNA display, polysomal display, yeast display) technology. With these technologies one can identify also binders recognizing discontinuous epitopes. Either the protein or the ligand (i.e. the antibody which will be selected) can be immobilized and incubated with the potential binding partner. Unbound proteins are removed and the bound ligands are eluted. Several rounds of selection will be carried out to identify high affinity binders. - -
  • the IL-10 neutralizing antibody or fragment thereof is derived from the murine B-N10 antibody or from BT-063 as disclosed in WO 201 1/064399.
  • the IL-10 neutralizing antibody or fragment thereof comprises the heavy chain CDRs 1 -3 as shown in SEQ ID NO: 1 -3, and the light chain CDRs 1 -3 as shown in SEQ ID NO: 4-6.
  • the CDR sequences of BT-063 are:
  • VH CDR1 ASGFSFATYG (SEQ ID No: 1 )
  • VH CDR3 QAYGHYMD (SEQ ID No: 3)
  • VL CDR1 SSQNIVHSNGNTY (SEQ ID No: 4)
  • VL CDR2 KVSNRFSGVPDR (SEQ ID No: 5)
  • VL CDR3 GSHVPW (SEQ ID No: 6)
  • the IL-10 neutralizing antibody or fragment can comprise variations in these sequences which do not substantially alter the affinity and/or and do not alter the specificity of the antibody or fragment thereof.
  • the variations in the sequence do not reduce the affinity or specificity of the antibody or fragment for IL-10 as compared to that of an antibody or fragment comprising the CDRs of BT-063 antibody.
  • such an antibody or fragment thereof will comprise CDRs having at most four amino acid exchanges, preferably at most three amino acid exchanges, more preferably at most two amino acid exchanges, and most preferably at most one amino acid exchange as compared to the amino acid sequence of CDR 1 , CDR 2 and CDR3 of the BT-063 variable light chain as shown in SEQ ID NO: 4-6 and/or comprises CDRs having at most four amino acid exchanges, preferably at most three amino acid exchanges, more preferably at most two amino acid exchanges, and most preferably at most one amino acid exchange as compared to the amino acid sequence of CDR 1 , CDR 2 and CDR3 of the BT-063 variable heavy chain as shown in SEQ ID NO: 1 -3.
  • said CDRs are in the same order and substantially in the same position as in BT-063.
  • the heavy chain variable region further comprises Asn73 and Ser74.
  • the IL-10 neutralizing antibody or fragment thereof can also be defined as a humanized or chimeric antibody or fragment thereof capable of binding to IL-10, wherein said antibody or fragment thereof comprises a variable region comprising CDR1 and CDR2 of BT-063 light chain and/or a variable region comprising CDR1 , CDR2 and CDR3 of BT-063 heavy chain optionally with amino acid substitutions in the sequences of the CDRs provided:
  • the light chain CDR1 comprises: Ser32, Asn33, Asn35, Tyr37
  • the light chain CDR2 comprises: Lys55
  • the heavy chain CDR1 comprises: Phe27, Ser28, Ala30, Thr31 , Tyr32
  • the heavy chain CDR2 comprises: Trp52, Arg53, Gly54, Ser56
  • the heavy chain CDR3 comprises: Tyrl OOO, Gly101 , Tyr103.
  • the heavy chain variable region further comprises Asn73 and Ser74.
  • residue type and number has been done for the purpose of clearly identifying the amino acid residue of the BT-063 CDR which is being referred to.
  • the number of the residue is not intended to limit the residue to being in that position in the candidate antibody or fragment being screened in the method.
  • Ser32 may be at position 31 within a light chain CDR1 if a non-essential amino acid residue has been deleted from the section 1 to 30 of the light chain.
  • the IL-10 neutralizing antibody or fragment may be derived from BT-063, and comprises variations in the variable heavy chain and/or variable light chain, the sequences of which are shown below:
  • the IL-10 neutralizing antibody comprises a variable domain of the heavy chain with at least 80%, preferably at least 81 %, more preferably 82%, more preferably 83%, more preferably 84%, more preferably 85%, more preferably 86%, more preferably 87%, more preferably 88%, more preferably 89%, more preferably 90%, more preferably 91 %, more preferably 92%, more preferably 93%, more preferably 94%, more preferably 95%, more preferably 96%, more preferably 97%, more preferably 98%, and most preferably 99% sequence identity over the full length of SEQ ID NO: 7, and/or a variable domain of the light chain with at least 80%, preferably at least 81 %, more preferably 82%, more preferably 83%, more preferably 84%, more preferably 85%, more preferably 86%, more preferably 87%, more preferably 88%, more preferably 89%, more preferably 90%, more preferably 91 %, more preferably 92%, more preferably 83%, more
  • an amino acid sequence has "at least x % identity" with another amino acid sequence, when the sequence identity between those to aligned sequences is at least x % over the full length of said other amino acid sequence.
  • alignments can be performed using for example publicly available computer homology programs such as the "EMBOSS" program provided at the EMBL homepage at http://www.ebi.ac.uk/Tools/psa/emboss_needle/, using the default settings provided therein (MATRIX: BLOSUM 62; GAP OPEN 10; GAP EXTEND 0.5; OUTPUT FORMAT: pair; END GAP PENALTY: false; END GAP OPEN: 10; ENDGAP EXTEND: 0.5). Further methods of calculating sequence identity or sequence similarity / sequence homology percentages of sets of amino acid sequences are known in the art.
  • the IL-10 neutralizing antibody comprises variable domains with the sequence of SEQ ID NO: 7, and SEQ ID NO: 8.
  • the IL-10 neutralizing antibody is the fully humanized full- length antibody (BT-063).
  • the IL-10 neutralizing antibody may be comprised in a pharmaceutical composition, preferably in a stable pharmaceutical composition.
  • Suitable carriers and their formulations are described in more detail in Remington's Pharmaceutical Sciences, 17th ed., 1985, Mack Publishing Co. Therefore, the present invention also relates to uses of such pharmaceutical compositions.
  • a "pharmaceutical composition” as described herein may comprise the respective antibody or a fragment thereof as described herein and a pharmaceutically acceptable carrier, excipient and/or diluent.
  • the choice of carrier may depend upon route of administration and concentration of the active agent(s).
  • the pharmaceutical composition may be in the form of a lyophilised composition, or an aqueous solution.
  • the carrier include but are not limited to phosphate buffered saline, Ringer's solution, dextrose solution, water, emulsions, such as oil/water emulsions, various types of wetting agents, sterile solutions, etc.
  • the composition may further comprise an appropriate amount of a pharmaceutically acceptable salt to render the composition isotonic.
  • acceptable excipients, carriers, or stabilisers are non-toxic at the dosages and concentrations employed. They include buffers such as citrate, phosphate, and other organic acids; salt-forming counter-ions, e.g. sodium and potassium; low molecular weight polypeptides (> 10 amino acid residues); proteins, e.g. serum albumin, or gelatine; hydrophilic polymers, e.g.
  • polyvinylpyrrolidone amino acids such as histidine, glutamine, lysine, asparagine, arginine, or glycine
  • carbohydrates such as glucose, mannose, or dextrins; monosaccharides; disaccharides; other sugars such as sucrose, mannitol, trehalose or sorbitol; chelating agents such as EDTA; non-ionic surfactants such as Tween, Pluronics or polyethylene glycol; antioxidants including methionine, ascorbic acid and tocopherol; and/or preservatives, e.g.
  • octadecyldimethylbenzyl ammonium chloride hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens, e.g. methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol).
  • PD-1 inhibitor refers to any agent, including antibodies and small organic compounds, which specifically binds to PD-1 , and blocks binding of PD-L1 to PD-1 , as measured using the method described in Example 12 of WO 2016/137850. Briefly, the biological activity of the PD-1 inhibitor can be tested in a competitive binding ELISA, which measures the ability of the PD1 -inhibitor to outcompete PD-L1 and bind to PD-1 receptor molecules immobilized on an ELISA plate. Dose response curves are generated using serial dilutions of the PD-1 inhibitor - -
  • EC50 value the concentration of the PD-1 inhibitor which exhibits 50% of the maximal binding, is determined for the PD-1 inhibitor using a four-parameter logistic curve fitting analysis program. Relative potency is calculated by applying Parallel Line Analysis of dose- response curves in SoftMax® Pro 6 software (Molecular Devices, Sunnyvale, CA).
  • An agent is found to qualify as a PD-1 inhibitor, if the agent blocks binding of PD-L1 to PD-1 by at least 50%, preferably by at least 60%, more preferably by at least 70%, more preferably by at least 80%, more preferably by at least 90%, more preferably by at least 95%, and most preferably by 100% or more as compared to a control, wherein the control is selected from the anti-PD-1 antibody pembrolizumab or the anti-PD-1 antibody nivolumab, preferably wherein the control is the anti-PD-1 antibody pembrolizumab.
  • the inhibitor of PD-1 is a therapeutic antibody or fragment thereof, which blocks binding of PD-L1 and/or PD-L2, preferably binding of PD-L1 , more preferably binding of PD-L1 and PD-L2 to PD-1 .
  • the inhibitor of PD-1 is a therapeutic antibody of the lgG 4 isotype.
  • Particular examples of such a therapeutic antibody are pembrolizumab and nivolumab.
  • Pembrolizumab marketed by Merck MSD under the tradename Keytruda, is a humanized lgG4-K immunoglobulin which targets the PD-1 receptor and inhibits binding of its cognate ligands.
  • the crystal structure of pembrolizumab is provided in WO 2016/137850; including its CDRs which are shown as SEQ ID Nos: 1 -6 therein, and the sequence of the heavy and the light chain, shown as SEQ ID NO: 7-8 therein (cf. Figures 1-3 of WO 2016/137850).
  • “Pembrolizumab” as used herein refers to an antibody as defined in paragraph [0073] of WO 2016/137850: As used herein, “pembrolizumab” means (a) the lgG 4 monoclonal antibody with the structure described in WHO Drug Information, Vol. 27, No. 2, pages 161 - 62 (2013) and which is manufactured by, or on behalf of, Merck Sharp & Dohme Corp. (MSD), a company that controls or is controlled by MSD, or a successor in interest thereof (individual and collectively, “MSD”).
  • MSD Merck Sharp & Dohme Corp.
  • Each light chain of pembrolizumab comprises the three CDR sequences RASKGVSTSGYSYLH (SEQ ID No: 10, CDRL1 ), LASYLES (SEQ ID No: 1 1 , CDRL2), and QHSRDLPLT (SEQ ID No: 12, CDRL3); and each heavy chain of pembrolizumab comprises the CDR sequences NYYMY (SEQ ID No: 13, CDRH1 ), GINPSNGGTNFNEKFKN (SEQ ID No: 14, CDRH2), and RDYRFDMGFDYW (SEQ ID No: 15, CDRH3).
  • pembrolizumab The full length heavy and light chains of pembrolizumab comprise the heavy and light chain sequences shown in Figure 3 (SEQ ID No: 16 and SEQ ID No: 17, respectively).
  • pembrolizumab as used herein is also intended to include “pembrolizumab biosimilars” or “pembrolizumab variants”.
  • a pembrolizumab biosimilar means a biological product manufactured by an entity other than MSD having the same amino acid sequence as pembrolizumab, more preferably substantially the same secondary modifications and substantially the same pharmacokinetic and pharmacodynamic properties as pembrolizumab (Keytruda (TM) ) as approved in the European Union or the United States of America.
  • a pembrolizumab biosimilar means a biological product manufactured by an entity other than MSD and which is approved by a regulatory agency in any country, particularly by a regulatory agency responsible for approval in the European Union or the United States of America, for marketing as a pembrolizumab biosimilar of the reference product pembrolizumab (Keytruda (TM) ).
  • a “pembrolizumab variant” means a monoclonal antibody which comprises heavy chain and light chain sequences that are identical to those in pembrolizumab (SEQ ID NO:16 and 17 herein, respectively), except for having up to three, up to two or up to one conservative amino acid substitutions at positions that are located outside of the light chain CDRs and up to six, up to five, up to four, up to three, up to two or up to one conservative amino acid substitutions that are located outside of the heavy chain CDRs, e.g., the variant positions are located in the framework regions or the constant region.
  • pembrolizumab and a pembrolizumab variant comprise identical CDR sequences, but may differ from each other due to having a conservative amino acid substitution at no more than three or six other positions in their full length light and heavy chain sequences, respectively.
  • a pembrolizumab variant is substantially the same as pembrolizumab with respect to the following properties: binding affinity to PD-1 and ability to block the binding of each of PD-L1 and PD-L2 to PD-1 .
  • the recommended dose of pembrolizumab is 2 mg/kg IV over 30 min every 3 weeks. - -
  • Nivolumab marketed by Bristol-Myers Squibb under the tradename Opdivo (CAS Registry Number: 946414-94-4), is a humanized lgG4-K immunoglobulin which targets the PD-1 receptor and inhibits binding of its cognate ligands.
  • Alternative designations for nivolumab include MDX-1 106, MDX-1 106-04, ONO-4538, or BMS- 936558.
  • Nivolumab is approved for the treatment of melanoma, lung cancer, kidney cancer, and Hodgkin's lymphoma.
  • Nevolumab refers to an antibody as disclosed as clone 5C4 in US 8,008,449 and WO 2006/121 168.
  • Each light chain of nivolumab comprises the three r.nR connonroc ⁇ . ⁇ . ⁇ /. ⁇ ⁇ . ⁇ in ⁇ 1 « r.nm -n nA.qMRAT ⁇ FO in Mn-
  • each heavy chain of nivolumab comprises the CDR sequences NSGMH (SEQ ID No: 21 , CDRH1 ), VIWYDGSKRYYADSVKG (SEQ ID No: 22, CDRH2), and NDDY (SEQ ID No: 23, CDRH3).
  • the full length heavy and light chains of pembrolizumab comprise the heavy and light chain sequences shown in SEQ ID NO: 24 and 25 herein, respectively.
  • nivolumab as used herein is also intended to include “nivolumab biosimilars” or " nivolumab variants".
  • a nivolumab biosimilar means a biological product manufactured by an entity other than Bristol-Myers Squibb having the same amino acid sequence as nivolumab, more preferably substantially the same secondary modifications and substantially the same pharmacokinetic and pharmacodynamic properties as nivolumab (Opdivo (TM) ) as approved in the European Union or the United States of America.
  • a nivolumab biosimilar means a biological product manufactured by an entity other than Bristol-Myers Squibb and which is approved by a regulatory agency in any country, particularly by a regulatory agency responsible for approval in the European Union or the United States of America, for marketing as a nivolumab biosimilar of the reference product nivolumab (Opdivo (TM) ).
  • nivolumab variant means a monoclonal antibody which comprises heavy chain and light chain sequences that are identical to those in nivolumab (SEQ ID NO: 24 and 25 herein, respectively), except for having up to three, up to two or up to one conservative amino acid substitutions at positions that are located outside of the light chain CDRs and up to six, up to five, up to four, up to three, up to two or up to one conservative amino acid substitutions that are located outside of the heavy chain CDRs, e.g., the variant positions are located in the framework regions or the constant region. See, for example, Table 1 on page 34 of WO 2006/121 168.
  • nivolumab and a nivolumab variant comprise identical CDR sequences, but may differ from each other due to having a conservative amino acid substitution at no more than three or six other positions in their full length light and heavy chain sequences, respectively.
  • a nivolumab variant is substantially the same as nivolumab with respect to the following properties: binding affinity to PD-1 and ability to block the binding of each of PD-L1 and PD-L2 to PD-1 .
  • the PD-1 inhibitor may be comprised in a pharmaceutical composition, preferably in a stable pharmaceutical composition. Suitable carriers and their formulations are described in more detail in Remington's Pharmaceutical Sciences, 17th ed., 1985, Mack Publishing Co. Further guidance with regard to the pharmaceutical composition is provided above.
  • nivolumab binding of nivolumab to PD-1 likely depends on the glycosylation of PD-1 , as nivolumab bound only glycosylated PD-1 expressed in a mammalian cell but not non-glycosylated PD-1 expressed in E. coli. Possible alterations in PD-1 glycosylation patterns in tumor cells may thus affect the interaction with PD-1 targeting monoclonal antibodies, and subsequently influence the efficacy of immune checkpoint blockade therapy.
  • the recommended dose of nivolumab is 3 mg/kg IV over 60 min every 2 weeks.
  • Pembrolizumab and nivolumab are reported to show differences in their respective immunogenicity. While 1.4% of the patients treated with nivolumab developed antidrug antibodies, this was only the case in 0.3% of the patients treated with pembrolizumab.
  • Determination of the appropriate dose of an active agent of the invention or of a pharmaceutical composition comprising same for treating melanoma in a particular patient may be made by the clinician, e.g., using parameters or factors known or suspected in the art to affect treatment or predicted to affect treatment. For example, the physician may choose to initiate treatment with a dose that is somewhat less than the optimum dose or the approved dose and then increase the dose by small - -
  • the PD-1 inhibitor may be administered in a dosage of 2 mg/kg body weight to 35 mg/kg body weight, preferably 3 mg/kg body weight to 35 mg/kg body weight, such as in a dosage of 2 mg/kg body weight to 20 mg/kg body weight or 2 mg/kg body weight to 10 mg/kg body weight, preferably 5 mg/kg body weight to 35 mg/kg body weight, preferably in a dosage of 6 mg/kg body weight to 30 mg/kg body weight, more preferably in a dosage of 7 mg/kg body weight to 27.5 mg/kg body weight, mnro r »rafarahl ⁇ / in a Hnoana /oinht mnro preferably in a dosage of 9 mg/kg body weight to 22.5 mg/kg body weight, more preferably in a dosage of 10 mg/kg body weight to 20 mg/kg body weight.
  • pembrolizumab may be administered in a dosage of 2 mg/kg body weight to 35 mg/kg body weight, such as in a dosage of 2 mg/kg body weight to 20 mg/kg body weight or 2 mg/kg body weight to 10 mg/kg body weight, preferably 5 mg/kg body weight to 35 mg/kg body weight, preferably in a dosage of 6 mg/kg body weight to 30 mg/kg body weight, more preferably in a dosage of 7 mg/kg body weight to 27.5 mg/kg body weight, more preferably in a dosage of 8 mg/kg body weight to 25 mg/kg body weight, more preferably in a dosage of 9 mg/kg body weight to 22.5 mg/kg body weight, more preferably in a dosage of 10 mg/kg body weight to 20 mg/kg body weight.
  • pembrolizumab is administered weekly, biweekly, every three weeks, or monthly. In other embodiments, pembrolizumab is administered up to three times per week.
  • nivolumab may be administered in a dosage of 3 mg/kg body weight to 20 mg/kg body weight, such as in a dosage of 3 mg/kg body weight to 10 mg/kg body weight, preferably in a dosage of 5 mg/kg body weight to 17.5 mg/kg body weight, preferably in a dosage of 6 mg/kg body weight to 15 mg/kg body weight, more preferably in a dosage of 7 mg/kg body weight to 12.5 mg/kg body weight, more preferably in a dosage of 8 mg/kg body weight to 10 mg/kg body weight, more preferably in a dosage of 9 mg/kg body weight to 10 mg/kg body weight.
  • nivolumab is administered weekly, biweekly, or monthly, preferably wherein nivolumab is administered biweekly.
  • the IL-10 neutralizing antibody in particular BT-063, may be administered in a dosage of 2-25 mg/kg body weight, such as in a dosage of 2-20 mg/kg body weight or 2-10 mg/kg body weight, preferably in a dosage of 3-22.5 mg/kg body weight, preferably in a dosage of 5-20 mg/kg body weight, more preferably in a dosage of 7.5-17.5 mg/kg body weight, more preferably in a dosage of 10-15 mg/kg body weight, more preferably in a dosage of 10-12.5 mg/kg body weight, and most preferably in a dosage of 10 mg/kg body weight.
  • said antibody is administered twice weekly or once weekly.
  • pembrolizumab may, for example, be administered in a dosage of 20 mg/kg body weight
  • the IL-10 neutralizing antibody is the fully humanized full-length antibody BT-063 administered in a dosage of 10 mg/kg body weight.
  • the combined use of the IL-10 neutralizing antibody or fragment thereof and the PD- 1 inhibitor is intended to mean that both antibodies are both present in the subject to be treated in therapeutically effective amounts, e.g. in a serum concentration in which both the IL-10 neutralizing antibody or fragment thereof and the PD-1 inhibitor each exert their inhibitory effect.
  • the combined use of the IL-10 neutralizing antibody or fragment thereof and the PD- 1 inhibitor may be further combined with other agents having anti-tumor activity as deemed appropriate by the skilled person.
  • the data of the present disclosure shows that the combined use of the IL-10 neutralizing antibody or fragment thereof and the PD-1 inhibitor alone is already effective. Therefore, in one advantageous embodiment, the present disclosure provides the combined use of the IL-10 neutralizing antibody or fragment thereof and the PD-1 inhibitor without combination with further agents having anti-tumor activity.
  • agent having anti-tumor activity is understood by the skilled person.
  • the term relates to agents inhibiting the growth of a tumor or causing regression of a tumor as generally known in the art.
  • agent may either by itself inhibit the growth of a tumor or cause regression of a tumor, or it may enhance the therapeutic effect of the herein disclosed combination therapy.
  • agents are known to the skilled person and include suitable antibodies, small molecule drugs or vaccines.
  • IL-10 interleukin 10
  • PD-1 inhibitor administration of the interleukin 10 (IL-10) neutralizing antibody and the PD-1 inhibitor is either sequentially, i.e. the treatment with one agent first and then the second agent, or that administration of both agents occurs at substantially the same time, i.e. there is an overlap in performing the administration.
  • sequential administration a subject is exposed to the agents at different times so long as some amount of the first agent remains in the subject (or has a therapeutic effect) when the other agent is administered.
  • administration of both agents occurs within 3 weeks, preferably 2 weeks, more preferably within one week, and more preferably within less than one week such as within less than 6 days, such as less than 5 days, less than 4 days, e.g. less than 3 days, preferably less than 2 days, or within 1 day.
  • the treatment with both agents at the same time can be in the same dose, i.e. physically mixed, or in separate doses administered at the same time.
  • treatment means that a subject receives a therapeutically effective amount of an active agent, such as a therapeutically effective amount of an interleukin 10 (IL-10) neutralizing antibody or fragment thereof, and/or a therapeutically effective amount of the anti-PD-1 inhibitor.
  • an active agent such as a therapeutically effective amount of an interleukin 10 (IL-10) neutralizing antibody or fragment thereof, and/or a therapeutically effective amount of the anti-PD-1 inhibitor.
  • An amount is therapeutically effective if it slows down disease progression as compared to a subject who is not receiving the treatment, or if the amount of active agent stops disease progression.
  • Preferably therapeutic treatment results in a reversal of the d icopoo etdto I n fhp rpnfpv ⁇ rvf troptinn mola nnma ⁇ ⁇ nrnnrQccinn disease reversal may be monitored by tumor growth analysis, as carried out in the examples herein.
  • a subject "undergoing treatment” means that said subject receives such a theraoeuticallv effective amount.
  • the treatments according to the present invention may also be combined with other treatments deemed suitable by the skilled person.
  • Such treatments may include surgery, radiotherapy, treatments with other tumor-controlling agents, or treatments to ameliorate undesired side-effects or their symptoms.
  • the present disclosure also relates to a PD-1 inhibitor for use in combination with an interleukin 10 (IL-10) neutralizing antibody or fragment thereof in the treatment of melanoma in a mammal, in particular in combination with BT-063. Further disclosed is the use of a PD-1 inhibitor in the manufacture of a medicament for the treatment of melanoma in a mammal, wherein the medicament is to be administered in combination with an interleukin 10 (IL- 0) neutralizing antibody or fragment thereof, in particular in combination with BT-063.
  • IL-10 interleukin 10
  • the present disclosure provides a method of treating melanoma in a mammal, comprising the step of administering a PD-1 inhibitor in combination with an interleukin 10 (IL-10) neutralizing antibody or fragment thereof, in particular in combination with BT-063.
  • IL-10 interleukin 10
  • a PD-1 inhibitor for use in the treatment of melanoma in a mammal who is undergoing treatment with an interleukin 10 (IL-10) neutralizing antibody or fragment thereof.
  • a method of treating melanoma in a mammal comprising the step of administering a PD-1 inhibitor to said mammal, wherein said mammal is undergoing treatment with an interleukin 10 (IL- 10) neutralizing antibody or fragment thereof, in particular wherein said mammal is undergoing treatment with BT-063.
  • IL-10 interleukin 10
  • a PD-1 inhibitor in the manufacture of a medicament for the treatment of melanoma in a mammal, wherein said mammal is undergoing treatment with an interleukin 10 (IL-10) neutralizing antibody or fragment thereof, in particular wherein said mammal is undergoing treatment with BT-063.
  • IL-10 interleukin 10
  • the present disclosure also relates to pembrolizumab for use in combination with an interleukin 10 (IL-10) neutralizing antibody or fragment thereof in the treatment of melanoma in a mammal, in particular in combination with BT-063. Further disclosed is the use of pembrolizumab in the manufacture of a medicament for the treatment of melanoma in a mammal, wherein the medicament is to be administered in combination with an interleukin 10 (IL-10) neutralizing antibody or fragment thereof, in particular in combination with BT-063.
  • IL-10 interleukin 10
  • the present disclosure provides a method of treating melanoma in a mammal, comprising the step of administering pembrolizumab in combination with an interleukin 10 (IL-10) neutralizing antibody or fragment thereof, in particular in combination with BT-063.
  • pembrolizumab for use in the treatment of melanoma in a mammal who is undergoing treatment with an interleukin 10 (IL-10) neutralizing antibody or fragment thereof.
  • a method of treating melanoma in a mammal comprising the step of administering pembrolizumab to said mammal, wherein said mammal is undergoing treatment with an interleukin 10 (IL- 10) neutralizing antibody or fragment thereof, in particular wherein said mammal is .
  • IL-10 interleukin 10
  • pembrolizumab in the manufacture of a medicament for the treatment of melanoma in a mammal, wherein said mammal is undergoing treatment with an interleukin 10 (IL-10) neutralizing antibody or fragment thereof, in particular wherein said mammal is undergoing treatment with BT-063.
  • IL-10 interleukin 10
  • the present disclosure also relates to nivolumab for use in combination with an interleukin 10 (IL-10) neutralizing antibody or fragment thereof in the treatment of melanoma in a mammal, in particular in combination with BT-063. Further disclosed is the use of nivolumab in the manufacture of a medicament for the treatment of melanoma in a mammal, wherein the medicament is to be administered in combination with an interleukin 10 (IL-10) neutralizing antibody or fragment thereof, in particular in combination with BT-063.
  • IL-10 interleukin 10
  • the present disclosure provides a method of treating melanoma in a mammal, comprising the step of administering nivolumab in combination with an interleukin 10 (IL-10) neutralizing antibody or fragment thereof, in particular in combination with BT-063.
  • IL-10 interleukin 10
  • nivolumab for use in the treatment of melanoma in a mammal who is undergoing treatment with an interleukin 10 (IL-10) neutralizing antibody or fragment thereof.
  • a method of treating melanoma in a mammal comprising the step of administering nivolumab to said mammal, wherein said mammal is undergoing treatment with an interleukin 10 (IL- 10) neutralizing antibody or fragment thereof, in particular wherein said mammal is undergoing treatment with BT-063.
  • IL-10 interleukin 10
  • nivolumab in the manufacture of a medicament for the treatment of melanoma in a mammal, wherein said mammal is undergoing treatment with an interleukin 10 (IL-10) neutralizing antibody or fragment thereof, in particular wherein said mammal is undergoing treatment with BT-063.
  • IL-10 interleukin 10
  • the melanoma is metastatic melanoma and/or an IL-10 expressing melanoma, and the preferably the mammal is a human subject. Further embodiments are as described above herein.
  • a package comprising an interleukin 10 (IL-10) neutralizing antibody or fragment thereof (preferably wherein the IL-10 neutralizing antibody or fragment thereof comprises the heavy chain CDRs 1-3 as shown in SEQ ID NO: 1 -3, and the light chain CDRs 1 -3 as shown in SEQ ID NO: 4-6, more preferably wherein the IL-10 neutralizing antibody comprises a variable domain of the heavy chain with at least 80% sequence identity over the full length of SEQ ID NO: 7, and a variable domain of the light chain with at least 80% sequence identity over the full length of SEQ ID NO: 8, and most preferably wherein the IL-10 neutralizing antibody is a fully humanized full -length antibody (BT-063)), a PD-1 inhibitor (preferably wherein the inhibitor of PD-1 is a therapeutic antibody blocking PD-1, more preferably a therapeutic antibody of the IgG 4 isotype, still more preferably wherein said therapeutic antibody blocking PD-1 is pembrolizumab or nivolumab, most preferably wherein said therapeutic IL
  • a package comprising an interleukin 10 (IL-10) neutralizing antibody or fragment thereof (preferably wherein the IL-10 neutralizing antibody or fragment thereof comprises the heavy chain CDRs 1 -3 as shown in SEQ ID NO: 1 -3, and the light chain CDRs 1 -3 as shown in SEQ ID NO: 4-6, more preferably wherein the IL- 10 neutralizing antibody comprises a variable domain of the heavy chain with at least 80% sequence identity over the full length of SEQ ID NO: 7, and a variable domain of the light chain with at least 80% sequence identity over the full length of SEQ ID NO: 8, and most preferably wherein the IL-10 neutralizing antibody is a fully humanized full-length antibody (BT-063)), and instructions to use same in combination with a PD-1 inhibitor (preferably wherein the inhibitor of PD-1 is a therapeutic antibody blocking PD-1, more preferably a therapeutic antibody of the IgG 4 isotype, still more preferably wherein said therapeutic antibody blocking PD-1 is pembrolizumab or nivoluma
  • the melanoma is metastatic melanoma and/or an IL-10 expressing melanoma
  • the mammal is a human subject. Further embodiments are as described above herein.
  • the present disclosure further provides a package comprising pembrolizumab, and instructions to use same in combination with an interleukin 10 (IL-10) neutralizing antibody or fragment thereof (preferably wherein the IL-10 neutralizing antibody or fragment thereof comprises the heavy chain CDRs 1 -3 as shown in SEQ ID NO: 1 -3, - -
  • IL-10 interleukin 10
  • the IL-10 neutralizing antibody comprises a variable domain of the heavy chain with at least 80% sequence identity over the full length of SEQ ID NO: 7, and a variable domain of the light chain with at least 80% sequence identity over the full length of SEQ ID NO: 8, and most preferably wherein the IL-10 neutralizing antibody is a fully humanized full-length antibody (BT-063)) in the treatment of melanoma in a mammal or in any other uses disclosed herein.
  • BT-063 fully humanized full-length antibody
  • a package comprising nivolumab, and instructions to use same in combination with
  • the IL-10 neutralizing antibody or fragment thereof comprises the heavy chain CDRs 1 -3 as shown in SEQ ID NO: 1 -3, and the light chain CDRs 1 -3 as shown in SEQ ID NO: 4-6, more preferably wherein the IL-10 neutralizing antibody comprises a variable domain of the heavy chain with at least 80% sequence identity over the full length of SEQ ID NO: 7, and a variable domain of the light chain with at least 80% sequence identity over the full length of SEQ ID NO: 8, and most preferably wherein the IL-10 neutralizing antibody is a fully humanized full-length antibody (BT-063)) in the treatment of melanoma in a mammal or in any other uses disclosed herein.
  • BT-063 fully humanized full-length antibody
  • the melanoma is metastatic melanoma and/or an IL-10 expressing melanoma
  • the mammal is a human subject. Further embodiments are as described above herein.
  • IL-10 interleukin 10
  • melanoma is an IL-10 expressing melanoma.
  • IL-10 neutralizing antibody for use of any one of the preceding embodiments, wherein the inhibitor of PD-1 is a therapeutic antibody blocking PD-1, preferably a therapeutic antibody of the IgG 4 isotype.
  • the IL-10 neutralizing antibody for use of any one of the preceding
  • pembrolizumab is to be administered in a dosage of 2 mg/kg body weight to 35 mg/kg body weight such as in a dosage of 2 mg/kg body weight to 20 mg/kg body weight or in a dosage of 2 mg/kg body weight to 10 mg/kg body weight, preferably in a dosage of 5 mg/kg body weight to 35 mg/kg body weight, preferably in a dosage of 6 mg/kg body weight to 30 mg/kg body weight, more preferably in a dosage of 7 mg/kg body weight to 27.5 mg/kg body weight, more preferably in a dosage of 8 mg/kg body weight to 25 mg/kg body weight, more preferably in a dosage of 9 mg/kg body weight to 22.5 mg/kg body weight, more preferably in a dosage of 10 mg/kg body weight to 20 mg/kg body weight.
  • IL-10 neutralizing antibody for use of embodiments 6 or 7, wherein pembrolizumab is to be administered up to three times per week.
  • IL-10 neutralizing antibody for use of any one of embodiments 1 -5, wherein said therapeutic antibody blocking PD-1 is nivolumab.
  • nivolumab is to be administered in a dosage of 3 mg/kg body weight to 20 mg/kg body weight such as in a dosage of 3 mg/kg body weight to 10 mg/kg body weight, preferably in a dosage of 5 mg/kg body weight to 17.5 mg/kg body weight, preferably in a dosage of 6 mg/kg body weight to 15 mg/kg body weight, more preferably in a dosage of 7 mg/kg body weight to 12.5 mg/kg body weight, more preferably in a dosage of 8 mg/kg body weight to 10 mg/kg body weight, more preferably in a dosage of 9 mg/kg body weight to 10 mg/kg body weight.
  • nivolumab is to be administered weekly, biweekly, or monthly, preferably wherein nivolumab is to be administered biweekly.
  • the IL-10 neutralizing antibody for use of any one of the preceding
  • the IL-10 neutralizing antibody or fragment thereof comprises the heavy chain CDRs 1 -3 as shown in SEQ ID NO: 1 -3, and the light chain CDRs 1 -3 as shown in SEQ ID NO: 4-6. - -
  • weight such as in a dosage of 2-20 mg/kg body weight or 2-10 mg/kg body weight, preferably in a dosage of 3-22.5 mg/kg body weight, preferably in a dosage of 5-20 mg/kg body weight, more preferably in a dosage of 7.5-17.5 mg/kg body weight, more preferably in a dosage of 10-15 mg/kg body weight, more preferably in a dosage of 10-12.5 mg/kg body weight, and most preferably in a dosage of 10 mg/kg body weight.
  • the IL-10 neutralizing antibody for use of embodiment 8, wherein said antibody is administered twice weekly.
  • the IL-10 neutralizing antibody for use of any preceding embodiment, wherein the mammal is a human.
  • the IL-10 neutralizing antibody for use of any one of the preceding
  • pembrolizumab is administered in a dosage of 20 mg/kg body weight
  • the IL-10 neutralizing antibody is the fully humanized full -length antibody BT-063 according to embodiment 7, administered in a dosage of 10 mg/kg body weight.
  • IL-10 interleukin 10
  • Pembrolizumab for use in combination with an interleukin 10 (IL-10) neutralizing antibody or fragment thereof in the treatment of melanoma in a mammal.
  • IL-10 interleukin 10
  • Pembrolizumab for use in the treatment of melanoma in a mammal who is undergoing treatment with an interleukin 10 (IL-10) neutralizing antibody or fragment thereof.
  • IL-10 interleukin 10
  • Pembrolizumab for use of embodiment 20 or 21 wherein said use is further defined as in any one of embodiments 2-8 and 12-18.
  • Nivolumab for use in combination with an interleukin 10 (IL-10) neutralizing antibody or fragment thereof in the treatment of melanoma in a mammal.
  • IL-10 interleukin 10
  • Nivolumab for use in the treatment of melanoma in a mammal who is undergoing treatment with an interleukin 10 (IL-10) neutralizing antibody or fragment thereof.
  • IL-10 interleukin 10
  • Nivolumab for use of embodiment 23 or 24, wherein said use is further defined as in any one of embodiments 2-5 and 9-17.
  • a package comprising an interleukin 10 (IL-10) neutralizing antibody or fragment thereof, a PD-1 inhibitor, and instructions to use same in the treatment of melanoma in a mammal.
  • IL-10 interleukin 10
  • PD-1 inhibitor a PD-1 inhibitor
  • a package comprising an interleukin 10 (IL-10) neutralizing antibody or fragment thereof, and instructions to use same in combination with a PD-1 inhibitor in the treatment of melanoma in a mammal.
  • IL-10 interleukin 10
  • the package of any one of embodiments 26-33, wherein the IL-10 neutralizing antibody or fragment thereof comprises the heavy chain CDRs 1 -3 as shown in SEQ ID NO: 1 -3, and the light chain CDRs 1 -3 as shown in SEQ ID NO: 4-6.
  • the package of any one of embodiments 26-34, wherein the IL-10 neutralizing antibody comprises a variable domain of the heavy chain with at least 80% sequence identity over the full length of SEQ ID NO: 7, and a variable domain - -
  • a package comprising pembrolizumab, and instructions to use same in
  • IL-10 interleukin 10
  • a package comprising nivolumab, and instructions to use same in combination with an interleukin 10 (IL-10) neutralizing antibody or fragment thereof in the treatment of melanoma in a mammal.
  • IL-10 interleukin 10
  • IL-10 neutralizing antibody comprises a variable domain of the heavy chain with at least 80% sequence identity over the full length of SEQ ID NO: 7, and a variable domain of the light chain with at least 80% sequence identity over the full length of SEQ ID NO: 8.
  • Figure 3 Schematic overview of the study design in Example 2.
  • Figure 5 hlL-10 plasmatic concentration in peripheral blood of mice. Results are expressed as mean +/- SEM.(fg/ml_). * p ⁇ 0.05 vs vehicle group, **p ⁇ 0.01 vs vehicle group. An ordinary one way ANOVA followed by a Dunnet's multiple comparison test was performed.
  • VH CDR1 ASGFSFATYG (SEQ ID No: 1 )
  • VH CDR2 IWRGGSTDYSAAFMSR (SEQ ID No: 2)
  • VH CDR3 QAYGHYMD (SEQ ID No: 3)
  • VL CDR1 SSQNIVHSNGNTY (SEQ ID No: 4)
  • VL CDR2 KVSNRFSGVPDR (SEQ ID No: 5)
  • VL CDR3 GSHVPW (SEQ ID No: 6)
  • RASKGVSTSGYSYLH (SEQ ID No: 10, CDRL1 ) LASYLES (SEQ ID No: 1 1 , CDRL2) QHSRDLPLT (SEQ ID No: 12, CDRL3) NYYMY (SEQ ID No: 13, CDRH1 ) GINPSNGGTNFNEKFKN (SEQ ID No: 14, CDRH2) RDYRFDMGFDYW (SEQ ID No: 15, CDRH3)
  • Pembrolizumab Heavy chain (SEQ ID No: 16)
  • RASQSVSSYLA SEQ ID No: 18, CDRL1
  • DASNRAT SEQ ID No: 19, CDRL2
  • QQSSNWPRT SEQ ID No: 20, CDRL3
  • NSGMH SEQ ID No: 21 , CDRH1
  • VIWYDGSKRYYADSVKG SEQ ID No: 22, CDRH2
  • NDDY SEQ ID No: 23, CDRH3
  • the aim of these examples was to assess anti-PDI (pembrolizumab, marketed as Keytruda) efficacy in combination with BT-063 (IL-10 neutralizing antibody) on A375 tumor growth in humanized NOG mice.
  • NOG NOD/Shi-scid/IL-2RYnull immunodeficient mouse strain
  • A375 (Cat n°881 13005, ECACC) melanoma cells were grown in DMEM high glucose supplemented with 10% fetal bovine serum (FBS) and penicillin / streptomycin. Under sterile conditions, A375 were detached with Phosphate Buffered saline (PBS) supplemented with EDTA 10mM and washed with PBS. The pellet was resuspended in sterile PBS to obtain a concentration of 20x10 6 tumor cells/mL. 100 ⁇ (2x10 6 tumor cells) of this solution was injected subcutaneously. DO was defined as the day of tumor cell injection (start of the experiment).
  • PBS Phosphate Buffered saline
  • the experiment was designed in order to define the optimal dose of anti-PD1 (Keytruda) for this tumor model.
  • twenty humanized mice were subcutaneously engrafted with A375 melanoma cells on each flank (right and left). Twenty days after tumor engraftment, only one tumor grew per animal whereas the other tumor was not visible.
  • CD34+ donor ID CD34+ donor ID
  • H-rate humanization rate
  • Group 1 Vehicle (injection 100 ⁇ of PBS; IP; three times per week)
  • mice were treated three times per week (a total of 7 injections were performed), tumor volumes were measured three times per week and mice were sacrificed for flow cytometry analysis on tumor and peripheral blood. A 40% tumor volume reduction could be observed in the group treated with Keytruda 20mg/kg (not significant). In addition, Keytruda treatment tends to decrease the number of T cells in the peripheral blood and the number of immune infiltrating tumor T cells.
  • Figure 1 represents tumor growth curve from the day of the randomization until the sacrifice of the mice.
  • the average volume of the tumors of the PBS- injected group was 1038 mm 3 +/- 724 vs 766 mm 3 +/- 431 for Keytruda 5 mg/kg treated group vs 898 mm 3 +/- 315 for Keytruda 10 mg/kg-treated group, vs 652 mm 3 +/- 301 for Keytruda 20 mg/kg-treated group.
  • Figure 2 represents tumor volumes on Day 34 after A375 cell engraftment. Due to the low number of mice per group, the reduction in tumor growth induced by the different doses of Keytruda was not statistically significant.
  • mice peripheral blood and tumors were collected for flow cytometry analysis. Analysis of the different populations of human immune cells revealed that Keytruda treatment at any concentration tends to reduce T-lymphocytes concentrations in peripheral blood. However due to the low number of mice per group, differences in T cell concentrations in peripheral blood of the HuNOG mice were not statistically different. Keytruda did not induce any variation in B, NK, monocyte and granulocyte concentration in peripheral blood. No statistical differences were observed between the mice belonging to the different treatment groups. We only observed very few granulocytes in peripheral blood of the mice.
  • the aim of this example was to find the optimal dose of anti-PD1 (Keytruda) for combination therapy in A375-tumor bearing HuNOG mice.
  • Keytruda at 20 mg/kg appear to induce the strongest anti-tumor activity on A375-tumor bearing HuNOG mice.
  • Example 2 we decided to engraft only one tumor per mouse, to increase the number of mice per group (7 mice instead of 5) and to test two different doses of Keytruda (5mg/kg and 20mg/kg) in combination with BT-063.
  • a schematic overview of the study design in Example 2 is shown in Figure 3.
  • Group 1 Vehicle (injection 100 ⁇ of PBS, IP, and 100 ⁇ of PBS, iv, three times per week)
  • mice were randomized on Day 21 , based on the tumor volume, the humanization rate and donor ID. The average volume of the tumors was 87 mm 3 at D21 and the mean H Rate was 50%. After randomization, mice were treated three times per week with Keytruda and two times per week with BT-063. A total of 9 injections for Keytruda and 6 injections for BT-063 were performed. In the groups treated with - -
  • BT-063 injection was performed one hour after Keytruda injection.
  • Figure 4 represents tumor growth curve from the day of the randomization until the sacrifice of the mouse.
  • the mouse sacrified on day 28 (from the control group) was excluded from the analysis and the mouse that succombed on day 22 (Keytruda 20mg/kg + BT-063 10 mg/kg) was also excluded from the analysis.
  • the mean tumor volume of the vehicle group was 1372 +/- 245.3 mm 3
  • the mean tumor volume was 1461 +/- 188.7 mm 3 in the group treated with Keytruda 5 mg/kg
  • the mean tumor volume was 1280 +/- 166 mm 3 in the group treated with Keytruda 20 mg/kg
  • the mean tumor volume was 1 165 +/- 120.9 mm 3 in the group treated with BT-063 10 mg/kg
  • the mean volume was 961 .4 +/- 74.18 mm 3 in the group treated with Keytruda 5 mg/kg + BT-063
  • the mean volume was 540.2 +/- 126.9 mm 3 in the group treated with Keytruda 20 mg/kg + BT-063.
  • peripheral blood and tumors were collected for flow cytometry analysis.
  • T cells T cells, CD4 and CD8 T cells and Treg
  • B cells and NK cells no difference was observed between the groups.
  • myeloid cells myeloid cells (monocytes and neutrophils)
  • Immune cell population analysis revealed that there was no statistically significant difference between the groups.
  • Keytruda treatment (5 mg/kg) tends to decrease the proportion of infiltrating T cells, including CD4+, CD8+ and T-reg cells as observed in the peripheral blood of the mice and in the first phase of the study but not in the group treated with Keytruda 20 mg/kg.
  • the proportion of immune cell infiltration was higher in the group treated with Keytruda 20 mg/kg + BT-063 (human CD45, and T cells (CD4, CD8 and T regs).
  • B cells, NK cells and monocytes By contrast, no changes was observed in the other immune cells population (B cells, NK cells and monocytes).
  • IL-10 was evaluated in the plasma of mice at sacrifice. hlL-10 concentration was measured in plasma by Flow Cytometry using Cell Bead Array (CBA) using the Enhanced Sensitivity Flex Set hlL-10 kit according to the Manufacturer's protocol. The results are visualized in Figure 5.
  • CBA Cell Bead Array
  • BT-063 is an IL-10 neutralizing antibody
  • BT-063 decreased IL-10 plasmatic concentration

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Abstract

La présente invention se rapporte au domaine de l'oncologie, plus particulièrement, des thérapies de combinaison oncologiques immunitaires destinées à être utilisées dans le traitement de mélanome malin. En particulier, la présente invention concerne un anticorps neutralisant l'interleukine 10 (IL-10) ou un fragment de celui-ci destiné à être utilisé en combinaison avec un inhibiteur de PD-1 dans le traitement d'un mélanome chez un mammifère, en particulier chez l'homme. L'invention concerne également un anticorps neutralisant l'interleukine 10 (IL-10) ou un fragment de celui-ci destiné à être utilisé dans le traitement d'un mélanome chez un mammifère soumis à un traitement avec un inhibiteur de PD-1. De manière similaire, la présente invention concerne également un inhibiteur de PD-1 destiné à être utilisé en combinaison avec un anticorps neutralisant l'interleukine 10 (IL-10) ou un fragment de celui-ci dans le traitement d'un mélanome chez un mammifère. L'invention concerne en outre un inhibiteur de PD-1 destiné à être utilisé dans le traitement d'un mélanome chez un mammifère soumis à un traitement avec un anticorps neutralisant l'interleukine 10 (IL-10) ou un fragment de celui-ci.
PCT/EP2018/076114 2017-10-10 2018-09-26 Combinaison d'anticorps anti-il10 et anti-pd1 pour le traitement du cancer WO2019072566A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN117362431A (zh) * 2023-08-25 2024-01-09 武汉爱博泰克生物科技有限公司 抗小鼠白细胞介素10的兔单克隆抗体及其应用

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
WO2011064399A1 (fr) 2009-11-30 2011-06-03 Biotest Ag Anticorps anti-il-10 humanisés destinés au traitement du lupus érythémateux disséminé (sle)
US20150297310A1 (en) * 2014-04-17 2015-10-22 Georgia Regents Research Institute, Inc. Methods for selecting a treatment for cancer
WO2016137850A1 (fr) 2015-02-27 2016-09-01 Merck Sharp & Dohme Corp. Cristaux d'anticorps monoclonaux anti-pd-1 humains

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
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
WO2011064399A1 (fr) 2009-11-30 2011-06-03 Biotest Ag Anticorps anti-il-10 humanisés destinés au traitement du lupus érythémateux disséminé (sle)
WO2011064398A1 (fr) 2009-11-30 2011-06-03 Biotest Ag Anticorps anti-il-10 humanisés destinés au traitement du lupus érythémateux disséminé (sle)
US20150297310A1 (en) * 2014-04-17 2015-10-22 Georgia Regents Research Institute, Inc. Methods for selecting a treatment for cancer
WO2016137850A1 (fr) 2015-02-27 2016-09-01 Merck Sharp & Dohme Corp. Cristaux d'anticorps monoclonaux anti-pd-1 humains

Non-Patent Citations (15)

* Cited by examiner, † Cited by third party
Title
"Remington's Pharmaceutical Sciences", 1985, MACK PUBLISHING CO
"Remington's Pharmaceutical Sciences", 1985, MACK PUBLISHING CO.
ASADULLAH ET AL., PHARMACOL. REV., vol. 55, no. 2, June 2003 (2003-06-01), pages 241 - 69
JOSEPHSON ET AL., STRUCTURE, vol. 10, 2002, pages 981 - 987
KALLI ET AL., JOURNAL OF TRANSLATIONAL MEDICINE, vol. 11, 2013, pages 120
LAMICHHANE ET AL., CLIN CANCER RES, vol. 22, 2016
LAMICHHANE ET AL., CLIN CANCER RES, vol. 22, no. 2, 2016
LU ET AL., J IMMUNOL, vol. 184, 2010, pages 5360 - 5367
PORICHIS ET AL., JOURNAL OF VIROLOGY, vol. 88, no. 5, 2014, pages 2508 - 2518
SATO ET AL., IMMUNOL RES, vol. 51, 2011, pages 170 - 182
SUN ET AL., CANCER RES, vol. 75, no. 8, 2015, pages 1635 - 1644
VICTOR ET AL., NATURE, vol. 520, no. 7547, 2015, pages 373 - 377
WHO DRUG INFORMATION, vol. 27, no. 2, 2013, pages 161 - 162
WINOGRAD ET AL., CANCER IMMUNOL RES, vol. 3, no. 4, 2015, pages 399 - 411
Z. SUN ET AL: "IL10 and PD-1 Cooperate to Limit the Activity of Tumor-Specific CD8+ T Cells", CANCER RESEARCH, vol. 75, no. 8, 26 February 2015 (2015-02-26), & 102ND ANNUAL MEETING OF THE AMERICAN-ASSOCIATION-FOR-CANCER-RESEARCH (AACR); ORLANDO, FL, USA; APRIL 02 -06, 2011, pages 1635 - 1644, XP055526100, ISSN: 0008-5472, DOI: 10.1158/0008-5472.CAN-14-3016 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN117362431A (zh) * 2023-08-25 2024-01-09 武汉爱博泰克生物科技有限公司 抗小鼠白细胞介素10的兔单克隆抗体及其应用
CN117362431B (zh) * 2023-08-25 2024-06-07 武汉爱博泰克生物科技有限公司 抗小鼠白细胞介素10的兔单克隆抗体及其应用

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