WO2016170039A1 - Polythérapie d'anticorps se liant à l'angiopoïétine 2 avec un anticorps se liant au polypeptide de mort programmée 1 - Google Patents

Polythérapie d'anticorps se liant à l'angiopoïétine 2 avec un anticorps se liant au polypeptide de mort programmée 1 Download PDF

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WO2016170039A1
WO2016170039A1 PCT/EP2016/058869 EP2016058869W WO2016170039A1 WO 2016170039 A1 WO2016170039 A1 WO 2016170039A1 EP 2016058869 W EP2016058869 W EP 2016058869W WO 2016170039 A1 WO2016170039 A1 WO 2016170039A1
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antibody
binds
ang
vegf
seq
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PCT/EP2016/058869
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Frank Herting
Hans-Joachim Mueller
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F. Hoffmann-La Roche Ag
Hoffmann-La Roche Inc.
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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
    • C07K16/22—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against growth factors ; against growth regulators
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A61K2039/507—Comprising a combination of two or more separate antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/31—Immunoglobulins specific features characterized by aspects of specificity or valency multispecific
    • 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
    • C07K2317/33—Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Definitions

  • the present invention relates to a combination therapy of an antibody specifically binding to angiopoietin 2 (ANG-2) with an antibody specifically binding to programmed death 1 polypeptide (PD-1).
  • ANG-2 angiopoietin 2
  • PD-1 programmed death 1 polypeptide
  • Angiopoietins which play a key role in angiogenesis and blood vessel remodeling, are part of the pro-angiogenic armamentarium of growing tumors. Importantly they are one of the major factors leading to secondary resistance during anti-VEGF therapy (Saharinen, P., et al, Trends Mol Med 17 (2011) 347-362).
  • ANG-1 angiopoietin- 1
  • ANG-2 angiopoietin-2
  • ANG-1 tends to stabilize and matures blood vessel (Yancopoulos, G. D., et al, Nature 407 (2000) 242-248)
  • ANG-2 promotes tumor angiogenesis and growth by destabilizing blood vessels.
  • ANG-2 thereby opposes ANG-1 in its function (Cascone, T. et al, J Clin Oncol 30 (2012) 441-444).
  • blocking ANG-2 but not ANG-1 normalizes tumor blood vessels (Falcon, B. L., H.
  • WO 2010/069532 relates to ANG-2 antibodies.
  • ANG-2 antibodies for treatment of cancer is also disclosed, e.g. in WO 2010/069532.
  • VEGF/VEGF-A Human vascular endothelial growth factor
  • VEGF/VEGF-A Human vascular endothelial growth factor
  • VEGF is involved in the regulation of normal and abnormal angiogenesis and neovascularization associated with tumors and intraocular disorders (Ferrara, N., et al, Endocr. Rev. 18 (1997) 4-25; Berkman, R.A., et al, J. Clin. Invest.
  • VEGF is a homodimeric glycoprotein that has been isolated from several sources. VEGF shows highly specific mitogenic activity for endothelial cells. VEGF has important regulatory functions in the formation of new blood vessels during embryonic vasculogenesis and in angiogenesis during adult life (Carmeliet, P., et al, Nature, 380 (1996) 435-439; Ferrara, N., et al, Nature, 380 (1996) 439-442; reviewed in Ferrara, N., et al., Endocr. Rev. 18 (1997) 4-25.
  • Anti-VEGF neutralizing antibodies suppress the growth of a variety of human tumor cell lines in mice (Kim, K.J., et al, Nature 362 (1993) 841-844; Warren, S.R., et al, J. Clin. Invest. 95 (1995) 1789-1797; Borgstrom, P., et al, Cancer Res. 56 (1996) 4032-4039; and Melnyk,
  • WO 94/10202, WO 98/45332, WO 2005/00900 and WO 00/35956 refer to antibodies against VEGF.
  • Humanized monoclonal antibody bevacizumab (sold under the trade name Avastin®) is an anti-VEGF antibody used in tumor therapy WO 98/45331).
  • WO 2010/040508 A9 and WO 2011/117329 relate to bispecific anti- VEGF/anti-ANG-2 antibodies and a therapeutic use thereof, e.g. for the treatment of cancer.
  • WO 2009/080253 and WO 2011/117330 relate to bispecific bivalent antibody formats.
  • Co-stimulation or the provision of two distinct signals to T-cells is a widely accepted model of lymphocyte activation of resting T lymphocytes by antigen- presenting cells (APCs) (Lafferty et al, Aust. J. Exp. Biol. Med. Sci. 53: 27-42 (1975)).
  • APCs antigen- presenting cells
  • This model further provides for the discrimination of self from non-self and immune tolerance (Bretscher et al., Science 169: 1042-1049 (1970); Bretscher, P.A., P.N.A.S. USA 96: 185-190 (1999); Jenkins et al, J. Exp. Med. 165: 302-319 (1987)).
  • the primary signal, or antigen specific signal is transduced through the T- cell receptor (TCR) following recognition of foreign antigen peptide presented in the context of the major histocompatibility-complex (MHC).
  • TCR T- cell receptor
  • the second or co- stimulatory signal is delivered to T-cells by co-stimulatory molecules expressed on antigen-presenting cells (APCs), and induces T-cells to promote clonal expansion, cytokine secretion and effector function (Lenschow et al., Ann. Rev. Immunol. 14:233 (1996)).
  • APCs antigen-presenting cells
  • T-cells can become refractory to antigen stimulation, do not mount an effective immune response, and further may result in exhaustion or tolerance to foreign antigens.
  • the simple two-signal model can be an oversimplification because the strength of the TCR signal actually has a quantitative influence on T-cell activation and differentiation (Viola et al., Science 273: 104-106 (1996); Sloan-Lancaster, Nature 363: 156-159 (1993)). Moreover, T-cell activation can occur even in the absence of co-stimulatory signals if the TCR signal strength is high. More importantly, T-cells receive both positive and negative secondary co-stimulatory signals. The regulation of such positive and negative signals is critical to maximize the host's protective immune responses, while maintaining immune tolerance and preventing autoimmunity.
  • Negative secondary signals seem necessary for induction of T-cell tolerance, while positive signals promote T-cell activation. While the simple two- signal model still provides a valid explanation for naive lymphocytes, a host's immune response is a dynamic process, and co-stimulatory signals can also be provided to antigen-exposed T-cells.
  • the mechanism of co-stimulation is of therapeutic interest because the manipulation of co-stimulatory signals has shown to provide a means to either enhance or terminate cell-based immune response.
  • T cell dysfunction or anergy occurs concurrently with an induced and sustained expression of the inhibitory receptor, programmed death 1 polypeptide (PD-1).
  • PD-1 programmed death 1 polypeptide
  • an antibody that binds to ANG2 enhances the efficacy of an antibody that binds to PD-1 in the treatment of cancers, in delaying progression of a tumor, or with respect to the survival of a patient afflicted with cancer, e.g. with a solid tumor.
  • the delay of cancer progression, and the longer overall survival represent a major benefit for patients.
  • the present invention relates to an antibody that binds to angiopoietin 2 (ANG-2), wherein the antibody is administered in a combination therapy with an antibody that binds to programmed death 1 polypeptide (PD-1), for use in a) treating cancer,
  • ANG-2 angiopoietin 2
  • PD-1 programmed death 1 polypeptide
  • the antibody that binds to ANG-2 for use according to the invention is administered in combination therapy with an antibody that binds to vascular endothelial growth factor (VEGF) and with an antibody that binds to PD-1.
  • VEGF vascular endothelial growth factor
  • the antibody that binds to ANG-2 for use according to the invention binds to ANG-2 and to VEGF. In one embodiment, such antibody is a bispecific antibody.
  • the invention relates to an antibody that binds to PD-1, wherein the antibody is administered in a combination therapy with an antibody that binds to ANG-2, for use in
  • the antibody that binds to PD-1 for use according to the invention is administered in a combination therapy with an antibody that binds to VEGF and with an antibody that binds to ANG-2. In one embodiment, the antibody that binds to PD-1 for use according to the invention is administered in a combination therapy with an antibody that binds to ANG-2 and to VEGF. In one embodiment, such antibody binding to ANG-2 and VEGF is a bispecific antibody.
  • the invention relates to an antibody that binds to VEGF, wherein the antibody is administered in a combination therapy with an antibody that binds to ANG-2 and with an antibody that binds to PD-1, for use in
  • the antibody that binds to VEGF for use according to the invention binds to VEGF and to ANG-2. In one embodiment, such antibody is a bispecific antibody. In certain embodiments, the antibodies for use according to the invention are for use in
  • Further aspects of the invention relate to methods of treatment, uses of the antibodies for the manufacture of a medicament, pharmaceutical compositions comprising the antibodies, methods for the manufacture of a pharmaceutical composition comprising the antibodies, and articles of manufacture suitable for application in a combination therapy according to the invention.
  • Figure 1 In vivo anti-tumor efficacy of a combination therapy according to the invention (results of the experiment described in example 2). Indicated is the tumor growth inhibition (median +/- inter quartile range) until day 31.
  • Figure 2 In vivo anti-tumor efficacy of a combination therapy according to the invention (results of the experiment described in example 2). Indicated is the tumor growth inhibition of the individuals of the groups treated with anti-PD-1 monotherapy (Fig. 2A, 2 tumor free / 2 living individuals at day 89), and combination therapies with anti-VEGF/anti-PD-1 (Fig. 2B, 0 tumor free / 0 living individuals at day 89), anti-ANG-2/anti-PD-l (Fig. 2C, 2 tumor free / 2 living individuals at day 89), and anti- ⁇ ANG-2/VEGF>/anti-PD-l (Fig. 2D, 4 tumor free / 5 living individuals at day 89) until the end of the experiment at day 89.
  • Fig. 2A 2 tumor free / 2 living individuals at day 89
  • combination therapies with anti-VEGF/anti-PD-1 Fig. 2B, 0 tumor free / 0 living individuals at day 89
  • anti-ANG-2/anti-PD-l Fig
  • Figure 3 In vivo anti-tumor efficacy of a combination therapy according to the invention (results of the experiment described in example 2). Indicated is the survival of the treated individuals.
  • antibody herein is used in the broadest sense and encompasses various antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments so long as they exhibit the desired antigen-binding activity.
  • monoclonal antibody or “monoclonal antibody composition” as used herein refer to a preparation of antibody molecules of a single amino acid composition.
  • a “recombinant antibody” is an antibody which has been produced by a recombinantly engineered host cell. It is optionally isolated or purified.
  • a "human antibody” is one which possesses an amino acid sequence which corresponds to that of an antibody produced by a human or a human cell or derived from a non-human source that utilizes human antibody repertoires or other human antibody-encoding sequences. This definition of a human antibody specifically excludes a humanized antibody comprising non-human antigen-binding residues.
  • the term "recombinant human antibody”, as used herein, is intended to include all human antibodies that are prepared, expressed, created or isolated by recombinant means, such as antibodies isolated from a host cell such as a NSO or CHO cell or from an animal (e.g.
  • a mouse that is transgenic for human immunoglobulin genes or antibodies expressed using a recombinant expression vector transfected into a host cell.
  • Such recombinant human antibodies have variable and constant regions in a rearranged form.
  • the recombinant human antibodies according to the invention have been subjected to in vivo somatic hypermutation.
  • the amino acid sequences of the VH and VL regions of the recombinant antibodies are sequences that, while derived from and related to human germ line VH and VL sequences, may not naturally exist within the human antibody germ line repertoire in vivo.
  • a “humanized” antibody refers to a chimeric antibody comprising amino acid residues from non-human HVRs and amino acid residues from human FRs.
  • a humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the HVRs (e.g., CDRs) correspond to those of a non-human antibody, and all or substantially the entire FRs correspond to those of a human antibody.
  • a humanized antibody optionally may comprise at least a portion of an antibody constant region derived from a human antibody.
  • a "humanized form" of an antibody, e.g., a non- human antibody refers to an antibody that has undergone humanization.
  • Specificity refers to selective recognition of a particular epitope of an antigen by the antigen binding moiety, e.g. an antibody. Natural antibodies, for example, are monospecific.
  • the term "monospecific antibody” as used herein denotes an antibody that has one or more binding sites each of which bind to the same epitope of the same antigen.
  • Multispecific antibodies bind two or more different epitopes (for example, two, three, four, or more different epitopes). The epitopes may be on the same or different antigens.
  • An example of a multispecific antibody is a "bispecific antibody” which binds two different epitopes. When an antibody possesses more than one specificity, the recognized epitopes may be associated with a single antigen or with more than one antigen.
  • epitope is a region of an antigen that is bound by an antibody or antigen binding moiety.
  • epitope includes any polypeptide determinant capable of specific binding to an antibody or antigen binding moiety.
  • epitope determinants include chemically active surface groupings of molecules such as amino acids, glycan side chains, phosphoryl, or sulfonyl, and, in certain embodiments, may have specific three dimensional structural characteristics, and/or specific charge characteristics. Conformational and nonconformational epitopes are distinguished in that the binding to the former but not the latter is lost in the presence of denaturing solvents.
  • binding and “specific binding” refer to the binding of the antibody or antigen binding moiety to an epitope of the antigen in an in vitro assay, preferably in a plasmon resonance assay (BIAcore®, GE-Healthcare Uppsala, Sweden) with purified wild-type antigen.
  • binding or that/which specifically binds to means a binding affinity (K D ) of 10 "8 mo 1/1 or less, in one embodiment 10 "8 M to 10 "13 mol/1.
  • an multispecific antibody according to the invention specifically binds to each antigen for which it is specific with a binding affinity (K D ) of 10 "8 mol/1 or less, e.g. with a binding affinity (K D ) of
  • variable domains or “variable region” as used herein denotes each of the pair of light and heavy chains which is involved directly in binding the antibody to the antigen.
  • the variable domain of a light chain is abbreviated as "VL” and the variable domain of a heavy chain is abbreviated as "VH”.
  • the variable light and heavy chain domains have the same general structure and each domain comprises four framework (FR) regions whose sequences are widely conserved, connected by three "hypervariable regions” (or complementary determining regions, CDRs).
  • the framework regions adopt a beta-sheet conformation and the CDRs may form loops connecting the beta- sheet structure.
  • the CDRs in each chain are held in their three-dimensional structure by the framework regions and form together with the CDRs from the other chain the antigen binding site.
  • the antibody's heavy and light chain CDR3 regions play a particularly important role in the binding specificity/affinity of the antibodies according to the invention and therefore provide a further object of the invention.
  • the term "antigen-binding portion of an antibody” when used herein refer to the amino acid residues of an antibody which are responsible for antigen- binding.
  • the antigen-binding portion of an antibody comprises amino acid residues from the "complementary determining regions" or "CDRs".
  • “Framework” or “FR” regions are those variable domain regions other than the hypervariable region residues as herein defined. Therefore, the light and heavy chain variable domains of an antibody comprise from N- to C-terminus the domains FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. Especially, CDR3 of the heavy chain is the region which contributes most to antigen binding and defines the antibody's properties. CDR and FR regions are determined according to the standard definition of Kabat et al, Sequences of Proteins of Immunological Interest, 5th ed., Public Health
  • constant domains or “constant region” as used within the current application denotes the sum of the domains of an antibody other than the variable region.
  • the constant region is not directly involved in binding of an antigen, but exhibits various effector functions.
  • antibodies are divided in the "classes": IgA, IgD, IgE, IgG and IgM, and several of these may are further divided into subclasses, such as IgGl, IgG2, IgG3, and IgG4, IgAl and IgA2.
  • the heavy chain constant regions that correspond to the different classes of antibodies are called ⁇ , ⁇ , ⁇ , ⁇ and ⁇ , respectively.
  • the light chain constant regions (CL) which can be found in all five antibody classes are called ⁇ (kappa) and ⁇ (lambda).
  • constant domains as used in the antibodies disclosed herein are preferably from human origin, which is from a constant heavy chain region of a human antibody of the subclass IgGl, IgG2, IgG3, or IgG4 and/or a constant light chain kappa or lambda region.
  • Such constant domains and regions are well known in the state of the art and e.g. described by Kabat, et al, Sequences of Proteins of Immunological Interest, 5th ed., Public Health Service, National Institutes of Health, Bethesda, MD (1991).
  • the "Fc part” of an antibody is not involved directly in binding of an antibody to an antigen, but exhibit various effector functions.
  • a “Fc part of an antibody” is a term well known to the skilled artisan and defined on the basis of papain cleavage of antibodies.
  • antibodies or immunoglobulins are divided in the classes: IgA, IgD, IgE, IgG and IgM, and several of these may be further divided into subclasses (isotypes), e.g. IgGl, IgG2, IgG3, and IgG4, IgAl, and IgA2.
  • the different classes of immunoglobulins are called ⁇ , ⁇ , ⁇ , ⁇ , and ⁇ , respectively.
  • the Fc part of an antibody is directly involved in ADCC (antibody-dependent cell-mediated cytotoxicity) and CDC (complement-dependent cytotoxicity) based on complement activation, Clq binding and Fc receptor binding.
  • ADCC antibody-dependent cell-mediated cytotoxicity
  • CDC complement-dependent cytotoxicity
  • Complement activation is initiated by binding of complement factor Clq to the Fc part of most IgG antibody subclasses. While the influence of an antibody on the complement system is dependent on certain conditions, binding to Clq is caused by defined binding sites in the Fc part. Such binding sites are known in the state of the art and described e.g.
  • binding sites are e.g. L234, L235, D270, N297, E318, K320, K322, P331 and P329 (numbering according to EU index of Kabat, E.A., see below).
  • Antibodies of subclass IgGl, IgG2 and IgG3 usually show complement activation and Clq and C3 binding, whereas IgG4 do not activate the complement system and do not bind Clq and C3.
  • ANG-2 Human angiopoietin-2 (ANG-2) (alternatively abbreviated with ANGPT2 or ANG2) (SEQ ID No: 1) is described in Maisonpierre, P.C., et al, Science 277 (1997) 55-60 and Cheung, A.H., et al, Genomics 48 (1998) 389-91.
  • the angiopoietins-1 and -2 (ANG-1 and ANG-2) were discovered as ligands for the Ties, a family of tyrosine kinases that is selectively expressed within the vascular endothelium (Yancopoulos, G.D., et al, Nature 407 (2000) 242-48). There are now four definitive members of the angiopoietin family.
  • Angiopoietin-3 and -4 may represent widely diverged counterparts of the same gene locus in mouse and man (Kim, I., et al, FEBS Let, 443 (1999) 353-56; Kim, I., et al, J Biol Chem 274 (1999) 26523-28).
  • ANG-1 and ANG-2 were originally identified in tissue culture experiments as agonist and antagonist, respectively (see for ANG-1 : Davies, S., et al, Cell, 87 (1996) 1161-1169; and for ANG-2: Maisonpierre, P.C., et al, Science 277 (1997) 55-60).
  • ANG-1 was shown to support EC survival and to promote endothelium integrity (Davis, S., et al, Cell, 87 (1996) 1161-1169; Kwak, H.J., et al, FEBS Lett 448 (1999) 249-53; Suri, C, et al, Science 282 (1998) 468-71; Thurston, G., et al, Science 286 (1999) 2511-14; Thurston, G., et al, Nat. Med.
  • ANG-2 had the opposite effect and promoted blood vessel destabilization and regression in the absence of the survival factors VEGF or basic fibroblast growth factor (Maisonpierre, P.C., et al, Science 277 (1997) 55-60).
  • VEGF vascular endothelial growth factor
  • ANG-2 might be a complex regulator of vascular remodeling that plays a role in both vessel sprouting and vessel regression.
  • ANG-2 specifically binds to the same endothelial-specific receptor, Tie-2, which is activated by ANG- 1, but has context-dependent effects on its activation (Maisonpierre, P.C., et al, Science 277 (1997) 55-60).
  • Antibodies that bind to ANG-2, which are useful for the combination treatment as described herein are, e.g., disclosed in detail in WO2010/069532 (e.g. antibodies ⁇ ANG-2>Ang2i_LC06, ⁇ ANG-2>Ang2i_LC07, or ⁇ ANG-
  • WO2011/014469 e.g. antibody HI H685P
  • US2011/150895 e.g. antibodies SAIT-Ang-2-5, SAIT-Ang-2-6, or their humanized versions
  • WO2009/097325 e.g. antibody MEDI 1/5 characterized by the VL of SEQ ID NO:3 and the VH of SEQ ID NO:7, both SEQ ID NOs as numbered in WO2009/097325
  • WO2009/105269 in WO 2006/068953 or in WO 03/030833.
  • a particularly useful antibody that binds to human ANG-2 is antibody ⁇ ANG-
  • Bispecific antibodies that bind to ANG-2 and to VEGF, which are useful for the combination treatment as described herein are, e.g., disclosed in detail in WO2010/040508, WO 2011/117329 or WO2012/131078.
  • binding sites e.g. VH and VL domains
  • the binding sites as disclosed in WO2010/040508, WO 2011/117329 or WO2012/131078 may be used.
  • ANG-2 refers to the human protein angiopoietin 2 (SEQ ID NO: 1).
  • an antibody “binding to human ANG-2”, “specifically binding to human ANG-2”, “that binds to human ANG-2” or “anti-ANG-2 antibody” refers to an antibody specifically binding to the human ANG-2 antigen with a binding affinity of a K D -value of 1.0 x 10 "8 mo 1/1 or lower, in one embodiment of a K D -value of
  • VEGF vascular endothelial growth factor
  • an antibody “binding to human VEGF”, “specifically binding to human VEGF”, “that binds to human VEGF” or “anti- VEGF antibody” refers to an antibody specifically binding to the human VEGF antigen with a binding affinity of a K D -value of 1.0 x 10 "8 mol/1 or lower, in one embodiment of a K D -value of 1.0 x 10 ⁇ 9 mol/1 or lower, in one embodiment of a
  • PD-1 or "human PD-1” refers to the human protein PD-1 (SEQ ID NO: 3).
  • an antibody “binding to human PD- 1", “specifically binding to human PD-1”, “that binds to human PD-1” or “anti- PD-1 antibody” refers to an antibody specifically binding to the human PD-1 antigen with a binding affinity of a K D -value of 1.0 x 10 ⁇ 8 mo 1/1 or lower, in one embodiment of a K D -value of 1.0 x 10 ⁇ 9 mo 1/1 or lower, in one embodiment of a K D - value of 1.0 x 10 "9 mol/l to 1.0 x 10 "13 mol/1.
  • the binding affinity is determined with a standard binding assay, such as surface plasmon resonance technique (BIAcore®, GE -Healthcare Uppsala, Sweden).
  • administered in combination with refers to the administration of the anti-ANG2 antibody as described herein, and the anti-PD-1 antibody as well as - in certain embodiments - the anti- VEGF antibody as described herein, e.g. as separate formulations/applications or as one single formulation/application.
  • the anti-ANG2 antibody and the anti-PD-1 antibody are administered as separate formulatios and in different application schemes.
  • the co-administration can be simultaneous or sequential in either order, wherein preferably there is a time period while both (or all) active agents (i.e.
  • Said anti-ANG2 antibody and said anti-PD-1 antibody (and, in certain embodiments, the anti-VEGF antibody) are co-administered either simultaneously or sequentially (e.g. intravenous through a continuous infusion).
  • the therapeutic agents i.e. the antibodies
  • the antibodies are co-administered sequentially the dose is administered either on the same day in separate administrations, or one of the agents is administered on day 1 and the further agent(s) is/are coadministered within the next 7 days (preferably at day 2 to 4).
  • the term “sequentially” means within 7 days after the dose of the first component, preferably within 4 days after the dose of the first component; and the term “simultaneously” means at the same time.
  • co-administration with respect to the maintenance doses of anti-ANG2 antibody, and/or anti-PD-1 antibody- and/or in certain embodiments the anti-VEGF antibody mean that the maintenance doses can be either co-administered simultaneously, if the treatment cycle is appropriate for all of the antibodies s, e.g. every week. Or the further agent(s) are e.g. administered e.g. every first to third day and said antibody is administered every week. Or the maintenance doses are co-administered sequentially, either within one or within several days.
  • the amount of co-administration and the timing of co-administration will depend on the type (species, gender, age, weight, etc.) and condition of the patient being treated and the severity of the disease or condition being treated. Said anti-
  • ANG2 antibody and further agent are suitably co-administered to the patient at one time or over a series of treatments e.g. on the same day or on the day after.
  • the antibodies are administered to the patient in a "therapeutically effective amount” (or simply “effective amount") which is the amount of the respective compound or combination that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician.
  • a “therapeutically effective amount” or simply “effective amount” which is the amount of the respective compound or combination that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician.
  • 0.1 mg /kg to 50 mg/kg is an initial candidate dosage for co-administration of said drugs to the patient.
  • the term "patient”, “subject” or “individual” preferably refers to a human in need of treatment of cancer, or a precancerous condition or lesion.
  • the term “patient”, “subject” or “individual” may also refer to non-human animals, e.g. mammals such as mice, dogs, cats, horses, cows, pigs, sheep and non-human primates, among others, that are in need of treatment.
  • chemotherapeutic agents include, but are not limited to, anti-neoplastic agents including alkylating agents including: nitrogen mustards, such as mechlorethamine, cyclophosphamide, ifosfamide, melphalan and chlorambucil; nitrosoureas, such as carmustine (BCNU), lomustine (CCNU), and semustine (methyl-CCNU); Temodal(TM) (temozolamide), ethylenimines/methylmelamine such as thriethylenemelamine (TEM), triethylene, thiophosphoramide (thiotepa), hexamethylmelamine (HMM, altretamine); alkyl sulfonates such as busulfan; triazines such as dacarbazine (DTIC); antimetabolites including folic acid analogs such as methotrexate and trimetrexate, pyrimidine analog
  • the chemotherapeutic agent is selected from the group consisting of taxanes (like e.g. paclitaxel (Taxol), docetaxel (Taxotere), modified paclitaxel (e.g., Abraxane and Opaxio), doxorubicin, sunitinib (Sutent), sorafenib (Nexavar), and other multikinase inhibitors, oxaliplatin, cisplatin and carboplatin, etoposide, gemcitabine, and vinblastine.
  • the chemotherapeutic agent is selected from the group consisting of taxanes (like e.g.
  • the additional chemotherapeutic agent is selected from 5-fluorouracil (5-FU), leucovorin, irinotecan, or oxaliplatin.
  • the chemotherapeutic agent is 5-fluorouracil, leucovorin and irinotecan (FOLFIRI).
  • the chemotherapeutic agent is 5- fluorouracil, and oxaliplatin (FOLFOX).
  • combination therapies with additional chemotherapeutic agents include, for instance, taxanes (e.g., docetaxel or paclitaxel), a modified paclitaxel (e.g., Abraxane or Opaxio), doxorubicin, capecitabine and/or bevacizumab (Avastin) for the treatment of breast cancer; therapies with carboplatin, oxaliplatin, cisplatin, paclitaxel, doxorubicin, modified doxorubicin (Caelyx or Doxil), or topotecan (Hycamtin) for ovarian cancer, the therapies with a multi-kinase inhibitor MKI (Sutent, Nexavar, or 706) and/or doxorubicin for treatment of kidney cancer; therapies with oxaliplatin, cisplatin and/or radiation for the treatment of squamous cell carcinoma; therapies with taxol and/or carboplatin for the treatment of lung cancer.
  • the additional chemotherapeutic agent is selected from the group of taxanes (docetaxel or paclitaxel), a modified paclitaxel (Abraxane or Opaxio), doxorubicin, capecitabine and/or bevacizumab for the treatment of breast cancer.
  • the combination therapy disclosed herein may be co-administered with a therapeutic agent targeting epigenetic mechanism.
  • agents include, but are not limited to, histone deacetylase inhibitors, demethylating agents (e.g., Vidaza) and release of transcriptional repression (ATRA) therapies can also be combined with the antigen binding proteins.
  • the combination therapy disclosed herein may be co-administered with a radiation therapy.
  • the antibodies used in a combination therapy as disclosed herein are preferably produced by recombinant methods. Such methods are widely known in the state of the art and comprise protein expression in prokaryotic and eukaryotic cells with subsequent isolation of the antibody polypeptide and usually purification to a pharmaceutically acceptable purity.
  • nucleic acids encoding light and heavy chains or fragments thereof are inserted into expression vectors by standard methods. Expression is performed in appropriate prokaryotic or eukaryotic host cells, such as CHO cells, NS0 cells, SP2/0 cells, HEK293 cells, COS cells, yeast, or E. coli cells, and the antibody is recovered from the cells (from the supernatant or after cells lysis).
  • the antibodies may be present in whole cells, in a cell lysate, or in a partially purified, or substantially pure form. Purification is performed in order to eliminate other cellular components or other contaminants, e.g. other cellular nucleic acids or proteins, by standard techniques, including alkaline/SDS treatment, CsCl banding, column chromatography, agarose gel electrophoresis, and others well known in the art (see Ausubel, F., et al, ed. Current Protocols in Molecular Biology, Greene Publishing and Wiley Interscience, New York (1987)).
  • the heavy and light chain variable domains of the specific antibodies indicated herein that may be used in a combination therapy according to the invention are combined with sequences of promoter, translation initiation, constant region, 3' untranslated region, polyadenylation, and transcription termination to form expression vector constructs.
  • the heavy and light chain expression constructs can be combined into a single vector, co-transfected, serially transfected, or separately transfected into host cells which are then fused to form a single host cell expressing both chains.
  • the control sequences that are suitable for prokaryotes include a promoter, optionally an operator sequence, and a ribosome binding site.
  • Eukaryotic cells are known to utilize promoters, enhancers and polyadenylation signals.
  • composition refers to a preparation which is in such form as to permit the biological activity of an active ingredient contained therein to be effective, and which contains no additional components which are unacceptably toxic to a subject to which the composition would be administered.
  • a pharmaceutical composition of the present invention can be administered by a variety of methods known in the art. As will be appreciated by the skilled artisan, the route and/or mode of administration will vary depending upon the desired results. Regardless of the route of administration selected, the antibodies used in a combination therapy of the present invention, which may be used in a suitable hydrated form, and/or the pharmaceutical compositions of the present invention, are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those of skill in the art.
  • Actual dosage levels of the active ingredients in the pharmaceutical compositions of the present invention may be varied so as to obtain an amount of the active ingredient (i.e. the antibody) which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient (effective amount).
  • the selected dosage level will depend upon a variety of pharmacokinetic factors including the activity of the particular compositions of the present invention employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion of the particular compound being employed, other drugs, compounds and/or materials used in combination with the particular compositions employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
  • pharmaceutically acceptable carrier includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption/resorption delaying agents, and the like that are physiologically compatible.
  • the carrier is suitable for injection or infusion.
  • Pharmaceutically acceptable carriers include sterile aqueous solutions or dispersions and sterile powders for the preparation of sterile injectable solutions or dispersion. The use of such media and agents for pharmaceutically active substances is known in the art.
  • the carrier can be, for example, an isotonic buffered saline solution.
  • compositions according to the invention may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of presence of microorganisms may be ensured both by sterilization procedures, supra, and by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.
  • treatment refers to clinical intervention in an attempt to alter the natural course of the individual being treated, and can be performed either for prophylaxis or during the course of clinical pathology.
  • Desirable effects of treatment include, but are not limited to, preventing occurrence or recurrence of disease, alleviation of symptoms, diminishment of any direct or indirect pathological consequences of the disease, preventing metastasis, decreasing the rate of disease progression, amelioration or palliation of the disease state, and remission or improved prognosis.
  • Specific effects desired for the combination therapy of the present invention are specified below.
  • a method of treating when applied to, for example, cancer refers to a procedure or course of action that is designed to reduce or eliminate the number of cancer cells in a patient, or to alleviate the symptoms of a cancer.
  • a method of treating does not necessarily mean that the cancer cells or other disorder will, in fact, be eliminated, that the number of cells or disorder will, in fact, be reduced, or that the symptoms of a cancer or other disorder will, in fact, be alleviated.
  • a method of treating cancer will be performed even with a low likelihood of success, but which, given the medical history and estimated survival expectancy of a patient, is nevertheless deemed to induce an overall beneficial course of action.
  • the invention relates to a combination therapy, encompassing the coadministration of an antibody that binds to ANG-2 with an antibody that binds to PD-1.
  • the combination therapy is applicable in
  • a cell mediated immune response particularly stimulating cytotoxic T-lymphocytes, or stimulating macrophage activity.
  • the stimulation of the cell mediated immune response occurs during the treatment of cancer.
  • stimulating the cell mediated immune response as indicated under d) encompasses stimulating the activity of cytotoxic T-lymphocytes, or stimulating the activity of macrophages. It has been shown that applying said combination therapy was potent to improve ANG-2 based cancer therapy in treated individuals suffering from cancer.
  • anti-ANG2 antibodies enhance the efficacy of anti-PD-1 antibodies to treat cancers, delay progression of a tumor, or prolonging the survival of a patient afflicted with cancer e.g. with a solid tumor.
  • the delay of cancer progression, as well as the longer overall survival represent a major benefit for patients.
  • the combination therapy of the invention may further encompass administration of an antibody that binds to VEGF.
  • the aforementioned beneficial effects, particularly the delay of cancer progression and a longer overall survival of individuals suffering from cancer could be further improved by adding an anti- VEGF antibody to the combination therapy according to the invention.
  • One aspect of the invention relates to an antibody that binds to ANG-2, or an antibody that binds to PD-1 for use in a combination therapy according to the invention.
  • the invention relates to an antibody that binds to angiopoietin 2 (ANG-2), wherein the antibody is administered in a combination therapy with an antibody that binds to PD-1, for use in
  • the invention relates to an antibody that binds to ANG-2, wherein the antibody is administered in a combination therapy with an antibody that binds to PD-1, for use in
  • the invention relates to an antibody that binds to ANG-2, wherein the antibody is administered in a combination therapy with an antibody that binds to PD-1, for use in treating cancer. In one embodiment the invention relates to an antibody that binds to ANG-2, wherein the antibody is administered in a combination therapy with an antibody that binds to PD-1, for use in prolonging the survival of a patient suffering from cancer.
  • the invention relates to an antibody that binds to ANG-2, wherein the antibody is administered in combination therapy with an antibody that binds to VEGF and with an antibody that binds to PD-1, for use in a) treating cancer,
  • the antibody that binds to ANG-2 and the antibody that binds to VEGF may be provided as separate antibodies or may be provided in a form of a single antibody that binds to ANG-2 as well as to VEGF.
  • the invention relates to an antibody that binds to ANG-2, wherein the antibody is administered in combination therapy with an antibody that binds to VEGF and with an antibody that binds to PD-1, for use in a) treating cancer,
  • the invention relates to an antibody that binds to ANG-2, wherein the antibody is administered in combination with an antibody that binds to VEGF, and wherein the antibody is administered in combination with an antibody that binds to PD-1 , for use in treating cancer.
  • the invention relates to an antibody that binds to ANG-2, wherein the antibody is administered in combination with an antibody that binds to VEGF, and wherein the antibody is administered in combination with an antibody that binds to PD-1, for use in prolonging the survival of a patient suffering from cancer.
  • the invention relates to an antibody that binds to ANG-2 and VEGF, wherein the antibody is administered in a combination therapy with an antibody that binds to PD-1, for use in
  • the antibody that binds to ANG-2 and the antibody that binds to VEGF is provided in a form of a single antibody that binds to ANG-2 as well as to VEGF.
  • said antibody that binds to ANG-2 and VEGF is a bispecific antibody.
  • the invention relates to an antibody, in one embodiment a bispecific antibody, that binds to ANG-2 and VEGF, wherein the antibody is administered in a combination therapy with an antibody that binds to PD-1, for use in
  • the invention relates to an antibody, in one embodiment a bispecific antibody, that binds to ANG-2 and VEGF, wherein the antibody is administered in a combination therapy with an antibody that binds to PD-1, for use in treating cancer.
  • the invention relates to an antibody, in one embodiment a bispecific antibody, that binds to ANG-2 and VEGF, wherein the antibody is administered in a combination therapy with an antibody that binds to PD-1, for use in prolonging the survival of a patient suffering from cancer. anti-PD-1 antibody for use
  • the invention relates to an antibody that binds to PD-1, wherein the antibody is administered in a combination therapy with an antibody that binds to ANG-2, for use in
  • the invention relates to an antibody that binds to PD-1, wherein the antibody is administered in a combination therapy with an antibody that binds to ANG-2, for use in
  • the invention relates to an antibody that binds to PD-1, wherein the antibody is administered in a combination therapy with an antibody that binds to ANG-2, for use in treating cancer.
  • the invention relates to an antibody that binds to PD-1, wherein the antibody is administered in a combination therapy with an antibody that binds to ANG-2, for use in prolonging the survival of a patient suffering from cancer.
  • the invention relates to an antibody that binds to PD-1, wherein the antibody is administered in a combination therapy with an antibody that binds to ANG-2 and an with antibody that binds to VEGF, for use in
  • the antibody that binds to ANG-2 and the antibody that binds to VEGF may be provided as separate antibodies or may be provided in a form of a single antibody that binds to ANG-2 as well as to VEGF.
  • the invention relates to an antibody that binds to PD-1, wherein the antibody is administered in combination therapy with an antibody that binds to ANG-2 and with an antibody that binds to VEGF, for use in
  • the invention relates to an antibody that binds to PD-1, wherein the antibody is administered in combination therapy with an antibody that binds to ANG-2 and with an antibody that binds to VEGF, for use in treating cancer.
  • the invention relates to an antibody that binds to PD-1, wherein the antibody is administered in combination therapy with an antibody that binds to ANG-2 and with an antibody that binds to VEGF, for use in prolonging the survival of a patient suffering from cancer.
  • the invention relates to an antibody that binds to PD-1, wherein the antibody is administered in a combination therapy with an antibody that binds to ANG-2 and VEGF, for use in
  • the antibody that binds to ANG-2 and the antibody that binds to VEGF is provided in a form of a single antibody that binds to ANG-2 as well as to VEGF.
  • said antibody that binds to ANG-2 and VEGF is a bispecific antibody.
  • the invention relates to an antibody that binds to PD-1, wherein the antibody is administered in a combination therapy with an antibody, in one embodiment a bispecific antibody, that binds to ANG-2 and VEGF, for use in a) treating cancer,
  • the invention relates to an antibody that binds to PD-1, wherein the antibody is administered in a combination therapy with an antibody, in one embodiment a bispecific antibody, that binds to ANG-2 and VEGF, for use in treating cancer.
  • the invention relates to an antibody that binds to PD-1, wherein the antibody is administered in a combination therapy with an antibody, in one embodiment a bispecific antibody, that binds to ANG-2 and VEGF, for use in prolonging the survival of a patient suffering from cancer.
  • anti-VEGF antibody for use
  • One embodiment of the invention further encompasses the co-administration of an antibody that binds to VEGF in addition to the co-adminstration of an antibody that binds to ANG-2 and an antibody that binds to PD-1.
  • the invention relates to an antibody that binds to VEGF, wherein the antibody is administered in a combination therapy with an antibody that binds to ANG-2 and with an antibody that binds to PD-1, for use in
  • the antibody that binds to ANG-2 and the antibody that binds to VEGF may be provided as separate antibodies or may be provided in a form of a single antibody that binds to ANG-2 as well as to VEGF.
  • the invention relates to an antibody that binds to VEGF, wherein the antibody is administered in combination therapy with an antibody that binds to ANG-2 and with an antibody that binds to PD-1, for use in
  • the invention relates to an antibody that binds to VEGF, wherein the antibody is administered in combination therapy with an antibody that binds to ANG-2 and with an antibody that binds to PD-1, for use in treating cancer.
  • the invention relates to an antibody that binds to VEGF, wherein the antibody is administered in combination therapy with an antibody that binds to ANG-2 and with an antibody that binds to PD-1, for use in prolonging the survival of a patient suffering from cancer.
  • the method comprises the step of administering an effective amount of an antibody that binds to ANG-2 and an effective amount of an antibody that binds to PD-1 to a patient in need thereof.
  • the method comprises the step of administering an effective amount of an antibody that binds to ANG-2 and an effective amount of an antibody that binds to PD-1 to a patient in need thereof.
  • the invention relates to a method for treating cancer, wherein the method comprises the step of administering an effective amount of an antibody that binds to ANG-2 and an effective amount of an antibody that binds to PD-1 to a patient in need thereof.
  • the invention relates to a method for prolonging the survival of a patient suffering from cancer, wherein the method comprises the step of administering an effective amount of an antibody that binds to ANG-2 and an effective amount of an antibody that binds to PD-1 to a patient in need thereof.
  • the method comprises the step of administering an effective amount of an antibody that binds to ANG-2, an effective amount of an antibody that binds to VEGF; and an effective amount of an antibody that binds to PD-1 to a patient in need thereof.
  • the antibody that binds to ANG-2 and the antibody that binds to VEGF may be provided as separate antibodies or may be provided in a form of a single antibody that binds to ANG-2 as well as to VEGF.
  • the method comprises the step of administering an effective amount of an antibody that binds to ANG-2, an effective amount of an antibody that binds to VEGF; and an effective amount of an antibody that binds to PD-1 to a patient in need thereof.
  • the invention relates to a method for treating cancer, wherein the method comprises the step of administering an effective amount of an antibody that binds to ANG-2, an effective amount of an antibody that binds to VEGF; and an effective amount of an antibody that binds to PD-1 to a patient in need thereof.
  • the invention relates to a method for prolonging the survival of a patient suffering from cancer, wherein the method comprises the step of administering an effective amount of an antibody that binds to ANG-2, an effective amount of an antibody that binds to VEGF; and an effective amount of an antibody that binds to PD-1 to a patient in need thereof.
  • the invention relates to a method for a) treating cancer,
  • the method comprises the step of administering an effective amount of an antibody that binds to ANG-2 and to VEGF; and an effective amount of an antibody that binds to PD-1 to a patient in need thereof.
  • the antibody that binds to ANG-2 and the antibody that binds to VEGF is provided in a form of a single antibody that binds to ANG-2 as well as to VEGF.
  • said antibody that binds to ANG-2 and VEGF is a bispecific antibody.
  • the method comprises the step of administering an effective amount of an antibody, in one embodiment a bispecific antibody, that binds to ANG-2 and to VEGF; and an effective amount of an antibody that binds to PD-1 to a patient in need thereof.
  • an antibody in one embodiment a bispecific antibody, that binds to ANG-2 and to VEGF; and an effective amount of an antibody that binds to PD-1 to a patient in need thereof.
  • the invention relates to a method for treating cancer, wherein the method comprises the step of administering an effective amount of an antibody, in one embodiment a bispecific antibody, that binds to ANG-2 and to VEGF; and an effective amount of an antibody that binds to PD-1 to a patient in need thereof.
  • the invention relates to a method for prolonging the survival of a patient suffering from cancer, wherein the method comprises the step of administering an effective amount of an antibody, in one embodiment a bispecific antibody, that binds to ANG-2 and to VEGF; and an effective amount of an antibody that binds to PD-1 to a patient in need thereof.
  • One aspect of the invention relates to an antibody that binds to ANG-2, or an antibody that binds to PD-1 for use in the manufacture of a medicament for the use in a combination therapy according to the invention.
  • the invention relates to the use of an antibody that binds to ANG-2 for the manufacture of a medicament for a) treating cancer,
  • the antibody is for administration in a combination therapy with an antibody that binds to PD-1.
  • the invention relates to the use of an antibody that binds to ANG-2 for the manufacture of a medicament for
  • the antibody is for administration in a combination therapy with an antibody that binds to PD-1.
  • the invention relates to the use of an antibody that binds to ANG-2 for the manufacture of a medicament for treating cancer, wherein the antibody is for administration in a combination therapy with an antibody that binds to PD-1. In one embodiment the invention relates to the use of an antibody that binds to ANG-2 for the manufacture of a medicament for prolonging the survival of a patient suffering from cancer, wherein the antibody is for administration in a combination therapy with an antibody that binds to PD-1.
  • the invention relates to the use of an antibody that binds to ANG-2 for the manufacture of a medicament for
  • the antibody is for administration in a combination therapy with an antibody that binds to VEGF and an antibody that binds to PD-1.
  • the antibody that binds to ANG-2 and the antibody that binds to VEGF may be provided as separate antibodies or may be provided in a form of a single antibody that binds to ANG-2 as well as to VEGF.
  • the invention relates to the use of an antibody that binds to ANG-2 for the manufacture of a medicament for
  • the antibody is for administration in a combination therapy with an antibody that binds to VEGF and an antibody that binds to PD-1.
  • the invention relates to the use of an antibody that binds to ANG-2 for the manufacture of a medicament for treating cancer, wherein the antibody is for administration in a combination therapy with an antibody that binds to VEGF and an antibody that binds to PD-1.
  • the invention relates to the use of an antibody that binds to ANG-2 for the manufacture of a medicament for prolonging the survival of a patient suffering from cancer, wherein the antibody is for administration in a combination therapy with an antibody that binds to VEGF and an antibody that binds to PD-1.
  • the invention relates to the use of an antibody that binds to ANG-2 and VEGF for the manufacture of a medicament for
  • the antibody is for administration in a combination therapy with an antibody that binds to VEGF and an antibody that binds to PD-1.
  • the antibody that binds to ANG-2 and the antibody that binds to VEGF is provided in a form of a single antibody that binds to ANG-2 as well as to VEGF.
  • said antibody that binds to ANG-2 and VEGF is a bispecific antibody.
  • the invention relates to the use of an antibody that binds to ANG-2 and VEGF, in one embodiment a bispecific antibody, for the manufacture of a medicament for
  • the antibody is for administration in a combination therapy with an antibody that binds to PD-1.
  • the invention relates to the use of an antibody that binds to ANG-2 and VEGF, in one embodiment a bispecific antibody, for the manufacture of a medicament for treating cancer, wherein the antibody is for administration in a combination therapy with an antibody that binds to PD-1.
  • the invention relates to the use of an antibody that binds to ANG-2 and VEGF, in one embodiment a bispecific antibody, for the manufacture of a medicament for prolonging the survival of a patient suffering from cancer, wherein the antibody is for administration in a combination therapy with an antibody that binds to PD-1.
  • the invention relates to the use of an antibody that binds to PD-1 for the manufacture of a medicament for
  • the antibody is for administration in a combination therapy with an antibody that binds to ANG-2.
  • the invention relates to the use of an antibody that binds to PD-1 for the manufacture of a medicament for
  • the invention relates to the use of an antibody that binds to PD-1 for the manufacture of a medicament for treating cancer, wherein the antibody is for administration in a combination therapy with an antibody that binds to ANG-2. In one embodiment the invention relates to the use of an antibody that binds to PD-1 for the manufacture of a medicament for prolonging the survival of a patient suffering from cancer, wherein the antibody is for administration in a combination therapy with an antibody that binds to ANG-2.
  • the invention relates to the use of an antibody that binds to PD-1 for the manufacture of a medicament for
  • the antibody is for administration in a combination therapy with an antibody that binds to ANG-2 and an antibody that binds to VEGF.
  • the antibody that binds to ANG-2 and the antibody that binds to VEGF may be provided as separate antibodies or may be provided in a form of a single antibody that binds to ANG-2 as well as to VEGF.
  • the invention relates to the use of an antibody that binds to PD-1 for the manufacture of a medicament for
  • the antibody is for administration in a combination therapy with an antibody that binds to ANG-2 and an antibody that binds to VEGF.
  • the invention relates to the use of an antibody that binds to PD-1 for the manufacture of a medicament for treating cancer, wherein the antibody is for administration in a combination therapy with an antibody that binds to ANG-2 and an antibody that binds to VEGF.
  • the invention relates to the use of an antibody that binds to PD-1 for the manufacture of a medicament for prolonging the survival of a patient suffering from cancer, wherein the antibody is for administration in a combination therapy with an antibody that binds to ANG-2 and an antibody that binds to VEGF.
  • the invention relates to the use of an antibody that binds to PD-1 for the manufacture of a medicament for
  • the antibody that binds to ANG-2 and the antibody that binds to VEGF is provided in a form of a single antibody that binds to ANG-2 as well as to VEGF.
  • said antibody that binds to ANG-2 and VEGF is a bispecific antibody.
  • the invention relates to the use of an antibody that binds to PD-1 for the manufacture of a medicament for
  • the antibody is for administration in a combination therapy with an antibody, in one embodiment a bispecific antibody, that binds to ANG-2 and VEGF.
  • the invention relates to the use of an antibody that binds to PD-1 for the manufacture of a medicament for treating cancer, wherein the antibody is for administration in a combination therapy with an antibody, in one embodiment a bispecific antibody, that binds to ANG-2 and VEGF.
  • the invention relates to the use of an antibody that binds to PD-1 for the manufacture of a medicament for prolonging the survival of a patient suffering from cancer, wherein the antibody is for administration in a combination therapy with an antibody, in one embodiment a bispecific antibody, that binds to ANG-2 and VEGF.
  • One embodiment of the invention further encompasses the coadministration of an antibody that binds to VEGF in addition to the co- adminstration of an antibody that binds to ANG-2 and an antibody that binds to PD-1.
  • the invention relates to the use of an antibody that binds to VEGF for the manufacture of a medicament for
  • the antibody is for administration in a combination therapy with an antibody that binds to ANG-2 and an antibody that binds to PD-1.
  • the antibody that binds to ANG-2 and the antibody that binds to VEGF may be provided as separate antibodies or may be provided in a form of a single antibody that binds to ANG-2 as well as to VEGF.
  • the antibody is for administration in a combination therapy with an antibody that binds to ANG-2 and an antibody that binds to PD-1.
  • the invention relates to the use of an antibody that binds to VEGF for the manufacture of a medicament for treating cancer, wherein the antibody is for administration in a combination therapy with an antibody that binds to ANG-2 and an antibody that binds to PD-1.
  • the invention relates to the use of an antibody that binds to VEGF for the manufacture of a medicament for prolonging the survival of a patient suffering from cancer, wherein the antibody is for administration in a combination therapy with an antibody that binds to ANG-2 and an antibody that binds to PD-1.
  • the invention relates to the use of an antibody that binds to ANG-2 and an antibody that binds to PD-1 for the manufacture of a medicament for
  • the invention relates to the use of an antibody that binds to ANG-2 and an antibody that binds to PD-1 for the manufacture of a medicament for
  • the invention relates to the use of an antibody that binds to ANG-2 and an antibody that binds to PD-1 for the manufacture of a medicament for treating cancer, wherein the antibody is for administration in a combination therapy with an antibody that binds to PD-1.
  • the invention relates to the use of an antibody that binds to ANG-2 and an antibody that binds to PD-1 for the manufacture of a medicament for prolonging the survival of a patient suffering from cancer, wherein the antibody is for administration in a combination therapy with an antibody that binds to PD-1.
  • the invention relates to the use of an antibody that binds to ANG-2 and an antibody that binds to VEGF for the manufacture of a medicament for
  • the antibodies are for administration in a combination therapy with an antibody that binds to PD-1.
  • the invention relates to the use of an antibody that binds to ANG-2 and an antibody that binds to VEGF for the manufacture of a medicament for
  • the invention relates to the use of an antibody that binds to ANG-2 and an antibody that binds to VEGF for the manufacture of a medicament for treating cancer, wherein the antibodies are for administration in a combination therapy with an antibody that binds to PD-1.
  • the invention relates to the use of an antibody that binds to ANG-2 and an antibody that binds to VEGF for the manufacture of a medicament for prolonging the survival of a patient suffering from cancer, wherein the antibodies are for administration in a combination therapy with an antibody that binds to PD-1.
  • the invention relates to the use of an antibody that binds to ANG-2, an antibody that binds to VEGF, and an antibody that binds to PD-1 for the manufacture of a medicament for
  • the antibody that binds to ANG-2 and the antibody that binds to VEGF may be provided as separate antibodies or may be provided in a form of a single antibody that binds to ANG-2 as well as to VEGF.
  • the invention relates to the use of an antibody that binds to ANG-2, an antibody that binds to VEGF, and an antibody that binds to PD-1 for the manufacture of a medicament for
  • the invention relates to the use of an antibody that binds to ANG-2, an antibody that binds to VEGF, and an antibody that binds to PD-1 for the manufacture of a medicament for treating cancer.
  • the invention relates to the use of an antibody that binds to ANG-2, an antibody that binds to VEGF, and an antibody that binds to PD-1 for the manufacture of a medicament for prolonging the survival of a patient suffering from cancer.
  • the invention relates to the use of an antibody that binds to ANG-2 and VEGF, and an antibody that binds to PD-1 for the manufacture of a medicament for
  • the antibody that binds to ANG-2 and the antibody that binds to VEGF is provided in a form of a single antibody that binds to ANG-2 as well as to VEGF.
  • said antibody that binds to ANG-2 and VEGF is a bispecific antibody.
  • the invention relates to the use of an antibody that binds to ANG-2 and VEGF, and an antibody that binds to PD-1 for the manufacture of a medicament for
  • the invention relates to the use of an antibody that binds to ANG-2 and VEGF, and an antibody that binds to PD-1 for the manufacture of a medicament for treating cancer. In one embodiment the invention relates to the use of an antibody that binds to ANG-2 and VEGF, and an antibody that binds to PD-1 for the manufacture of a medicament for prolonging the survival of a patient suffering from cancer.
  • One aspect of the invention relates to an article of manufacture comprising a container, a composition within the container comprising an antibody that binds to ANG-2, or an antibody that binds to PD-1, and a package insert instructing the user of the composition to administer the respective antibody in a a combination therapy according to the invention.
  • Article of manufacture comprising an anti- ANG-2 antibody
  • the invention relates to an article of manufacture comprising (a) a container, a composition within the container comprising an antibody that binds to ANG-2, and (b) a package insert instructing the user of the composition to administer the antibody that binds to ANG-2 to a patient
  • the invention relates to an article of manufacture comprising (a) a container, a composition within the container comprising an antibody that binds to ANG-2, and (b) a package insert instructing the user of the composition to administer the antibody that binds to ANG-2 to a patient
  • the invention relates to an article of manufacture comprising (a) a container, a composition within the container comprising an antibody that binds to ANG-2, and (b) a package insert instructing the user of the composition to administer the antibody that binds to ANG-2 to a patient in the treatment of cancer, wherein the administration of the antibody that binds to ANG- 2 is in a combination therapy with an antibody that binds to PD-1.
  • the invention relates to an article of manufacture comprising (a) a container, a composition within the container comprising an antibody that binds to
  • the invention relates to an article of manufacture comprising (a) a container, a composition within the container comprising an antibody that binds to ANG-2, and (b) a package insert instructing the user of the composition to administer the antibody that binds to ANG-2 to a patient
  • the administration of the antibody that binds to ANG-2 is in a combination therapy with an antibody that binds to VEGF and an antibody that binds to PD-1.
  • the invention relates to an article of manufacture comprising (a) a container, a composition within the container comprising an antibody that binds to ANG-2, and (b) a package insert instructing the user of the composition to administer the antibody that binds to ANG-2 to a patient
  • the invention relates to an article of manufacture comprising (a) a container, a composition within the container comprising an antibody that binds to ANG-2, and (b) a package insert instructing the user of the composition to administer the antibody that binds to ANG-2 to a patient in the treatment of cancer, wherein the administration of the antibody that binds to ANG- 2 is in a combination therapy with an antibody that binds to VEGF and an antibody that binds to PD-1.
  • the invention relates to an article of manufacture comprising (a) a container, a composition within the container comprising an antibody that binds to ANG-2, and (b) a package insert instructing the user of the composition to administer the antibody that binds to ANG-2 to a patient to prolong the survival of a patient suffering from cancer, wherein the administration of the antibody that binds to ANG-2 is in a combination therapy with an antibody that binds to VEGF and an antibody that binds to PD-1.
  • Article of manufacture comprising an anti-PD-1 antibody
  • the invention relates to an article of manufacture comprising (a) a container, a composition within the container comprising an antibody that binds to PD-1, and (b) a package insert instructing the user of the composition to administer the antibody that binds to PD-1 to a patient
  • the invention relates to an article of manufacture comprising (a) a container, a composition within the container comprising an antibody that binds to PD-1, and (b) a package insert instructing the user of the composition to administer the antibody that binds to PD-1 to a patient
  • the invention relates to an article of manufacture comprising (a) a container, a composition within the container comprising an antibody that binds to PD-1, and (b) a package insert instructing the user of the composition to administer the antibody that binds to PD-1 to a patient in the treatment of cancer, wherein the administration of the antibody that binds to PD-1 is in a combination therapy with an antibody that binds to ANG-2.
  • the invention relates to an article of manufacture comprising (a) a container, a composition within the container comprising an antibody that binds to PD-1, and (b) a package insert instructing the user of the composition to administer the antibody that binds to PD-1 to a patient to prolong the survival of a patient suffering from cancer, wherein the administration of the antibody that binds to
  • PD-1 is in a combination therapy with an antibody that binds to ANG-2.
  • the invention relates to an article of manufacture comprising (a) a container, a composition within the container comprising an antibody that binds to PD-1, and (b) a package insert instructing the user of the composition to administer the antibody that binds to PD-1 to a patient
  • the invention relates to an article of manufacture comprising (a) a container, a composition within the container comprising an antibody that binds to PD-1, and (b) a package insert instructing the user of the composition to administer the antibody that binds to PD-1 to a patient
  • the invention relates to an article of manufacture comprising (a) a container, a composition within the container comprising an antibody that binds to PD-1, and (b) a package insert instructing the user of the composition to administer the antibody that binds to PD-1 to a patient in the treatment of cancer, wherein the administration of the antibody that binds to PD-1 is in a combination therapy with an antibody that binds to ANG-2 and an antibody that binds to VEGF.
  • the invention relates to an article of manufacture comprising (a) a container, a composition within the container comprising an antibody that binds to PD-1, and (b) a package insert instructing the user of the composition to administer the antibody that binds to PD-1 to a patient to prolong the survival of a patient suffering from cancer, wherein the administration of the antibody that binds to PD-1 is in a combination therapy with an antibody that binds to ANG-2 and an antibody that binds to VEGF.
  • Article of manufacture comprising an anti-VEGF antibody
  • One embodiment of the invention further encompasses the coadministration of an antibody that binds to VEGF in addition to the co- adminstration of an antibody that binds to ANG-2 and an antibody that binds to
  • the invention relates to an article of manufacture comprising (a) a container, a composition within the container comprising an antibody that binds to VEGF, and (b) a package insert instructing the user of the composition to administer the antibody that binds to VEGF to a patient
  • the administration of the antibody that binds to VEGF is in a combination therapy with an antibody that binds to ANG-2 and an antibody that binds to PD-1.
  • the invention relates to an article of manufacture comprising (a) a container, a composition within the container comprising an antibody that binds to VEGF, and (b) a package insert instructing the user of the composition to administer the antibody that binds to VEGF to a patient
  • the invention relates to an article of manufacture comprising (a) a container, a composition within the container comprising an antibody that binds to VEGF, and (b) a package insert instructing the user of the composition to administer the antibody that binds to VEGF to a patient in the treatment of cancer, wherein the administration of the antibody that binds to VEGF is in a combination therapy with an antibody that binds to ANG-2 and an antibody that binds to PD-1.
  • the invention relates to an article of manufacture comprising (a) a container, a composition within the container comprising an antibody that binds to VEGF, and (b) a package insert instructing the user of the composition to administer the antibody that binds to VEGF to a patient to prolong the survival of a patient suffering from cancer, wherein the administration of the antibody that binds to VEGF is in a combination therapy with an antibody that binds to ANG-2 and an antibody that binds to PD-1.
  • Article of manufacture comprising an an ti- ANG-2 antibody and an anti-PD-1 antibody
  • the invention relates to an article of manufacture comprising (a) a container, a composition within the container comprising an antibody that binds to ANG-2, and (b) a container, a composition within the container comprising an antibody that binds to PD-1, and (c) a package insert instructing the user of the composition to administer the antibody that binds to ANG-2 and the antibody that binds to PD-1 to a patient
  • the invention relates to an article of manufacture comprising (a) a container, a composition within the container comprising an antibody that binds to ANG-2, and (b) a container, a composition within the container comprising an antibody that binds to VEGF, and (c) a package insert instructing the user of the composition to administer the antibody that binds to ANG-2 and the antibody that binds to VEGF to a patient
  • the invention relates to an article of manufacture comprising (a) a container, a composition within the container comprising an antibody that binds to ANG-2, and (b) a container, a composition within the container comprising an antibody that binds to VEGF, and (c) a package insert instructing the user of the composition to administer the antibody that binds to ANG-2 and the antibody that binds to VEGF to a patient in the treatment of cancer.
  • the invention relates to an article of manufacture comprising (a) a container, a composition within the container comprising an antibody that binds to ANG-2, and (b) a container, a composition within the container comprising an antibody that binds to VEGF, and (c) a package insert instructing the user of the composition to administer the antibody that binds to ANG-2 and the antibody that binds to VEGF to a patient to prolong the survival of a patient suffering from cancer.
  • the invention relates to an article of manufacture comprising (a) a container, a composition within the container comprising an antibody that binds to ANG-2, and (b) a container, a composition within the container comprising an antibody that binds to PD-1, and (c) a package insert instructing the user of the composition to administer the antibody that binds to
  • the invention relates to an article of manufacture comprising (a) a container, a composition within the container comprising an antibody that binds to ANG-2, and (b) a container, a composition within the container comprising an antibody that binds to VEGF, and (c) a package insert instructing the user of the composition to administer the antibody that binds to ANG-2 and the antibody that binds to VEGF to a patient
  • the invention relates to an article of manufacture comprising (a) a container, a composition within the container comprising an antibody that binds to ANG-2, and (b) a container, a composition within the container comprising an antibody that binds to VEGF, and (c) a package insert instructing the user of the composition to administer the antibody that binds to
  • ANG-2 and the antibody that binds to VEGF to a patient in the treatment of cancer, wherein the administration of the antibody that binds to ANG-2 and the antibody that binds to PD-1 is in a combination therapy with an antibody that binds to VEGF.
  • the invention relates to an article of manufacture comprising (a) a container, a composition within the container comprising an antibody that binds to ANG-2, and (b) a container, a composition within the container comprising an antibody that binds to VEGF, and (c) a package insert instructing the user of the composition to administer the antibody that binds to ANG-2 and the antibody that binds to VEGF to a patient to prolong the survival of a patient suffering from cancer, wherein the administration of the antibody that binds to ANG-2 and the antibody that binds to PD-1 is in a combination therapy with an antibody that binds to VEGF.
  • Article of manufacture comprising an anti-ANG-2 antibody and an anti- VEGF antibody
  • the invention relates to an article of manufacture comprising (a) a container, a composition within the container comprising an antibody that binds to ANG-2, and (b) a container, a composition within the container comprising an antibody that binds to VEGF, and (c) a package insert instructing the user of the composition to administer the antibody that binds to ANG-2 and the antibody that binds to VEGF to a patient
  • the article of manufacture comprises a container, a composition within said container comprising the antibody that binds to ANG-2 and the antibody that binds to VEGF.
  • said container comprises the antibody that binds to ANG-2 and the antibody that binds to VEGF in the form of an antibody that binds to ANG-2 and to VEGF.
  • said container comprises the antibody that binds to ANG-2 and the antibody that binds to VEGF in the form of a bispecific antibody that binds to ANG-2 and to VEGF.
  • the invention relates to an article of manufacture comprising (a) a container, a composition within the container comprising an antibody that binds to ANG-2, and (b) a container, a composition within the container comprising an antibody that binds to VEGF
  • the article of manufacture comprises one container, a composition within said container comprising the antibody that binds to ANG-2 and the antibody that binds to VEGF
  • the article of manufacture comprises one container, a composition within said container comprising the antibody that binds to ANG-2 and the antibody that binds to VEGF in the form of an antibody that binds to ANG-2 and to VEGF
  • the article of manufacture comprises one container, a composition within said container comprising the antibody that binds to ANG-2 and the antibody that binds to VEGF in the form of a bispecific antibody that binds to ANG-2 and to VEGF), and (c) a package insert instructing the user of the composition to administer the antibody that binds to VEGF
  • ANG-2 and the antibody that binds to VEGF to a patient
  • the invention relates to an article of manufacture comprising (a) a container, a composition within the container comprising an antibody that binds to ANG-2, and (b) a container, a composition within the container comprising an antibody that binds to VEGF
  • the article of manufacture comprises one container, a composition within said container comprising the antibody that binds to ANG-2 and the antibody that binds to VEGF
  • the article of manufacture comprises one container, a composition within said container comprising the antibody that binds to ANG-2 and the antibody that binds to VEGF in the form of an antibody that binds to ANG-2 and to VEGF
  • the article of manufacture comprises one container, a composition within said container comprising the antibody that binds to ANG-2 and the antibody that binds to VEGF in the form of a bispecific antibody that binds to ANG-2 and to VEGF), and (c) a package insert instructing the user of the composition to administer the antibody that binds to VEGF
  • the invention relates to an article of manufacture comprising (a) a container, a composition within the container comprising an antibody that binds to ANG-2, and (b) a container, a composition within the container comprising an antibody that binds to VEGF
  • the article of manufacture comprises one container, a composition within said container comprising the antibody that binds to ANG-2 and the antibody that binds to VEGF
  • the article of manufacture comprises one container, a composition within said container comprising the antibody that binds to ANG-2 and the antibody that binds to VEGF in the form of an antibody that binds to ANG-2 and to VEGF
  • the article of manufacture comprises one container, a composition within said container comprising the antibody that binds to ANG-2 and the antibody that binds to VEGF in the form of a bispecific antibody that binds to ANG-2 and to VEGF), and (c) a package insert instructing the user of the composition to administer the antibody that binds to VEGF
  • Article of manufacture comprising an anti-ANG-2 antibody, an anti-VEGF antibody and an anti-PD-1 antibody
  • the invention relates to an article of manufacture comprising (a) a container, a composition within the container comprising an antibody that binds to ANG-2, and (b) a container, a composition within the container comprising an antibody that binds to VEGF, and (c) a container, a composition within the container comprising an antibody that binds to PD-1, and (d) a package insert instructing the user of the composition to administer the antibodies that bind to ANG-2, VEGF, and PD-1, respectively, in a combination therapy to a patient
  • the article of manufacture comprises a container, a composition within said container comprising the antibody that binds to ANG-2 and the antibody that binds to VEGF.
  • said container comprises the antibody that binds to ANG-2 and the antibody that binds to VEGF in the form of an antibody that binds to ANG-2 and to VEGF.
  • said container comprises the antibody that binds to ANG-2 and the antibody that binds to VEGF in the form of a bispecific antibody that binds to
  • the invention relates to an article of manufacture comprising (a) a container, a composition within the container comprising an antibody that binds to ANG-2, and (b) container, a composition within the container comprising an antibody that binds to VEGF
  • the article of manufacture comprises one container, a composition within said container comprising the antibody that binds to ANG-2 and the antibody that binds to VEGF
  • the article of manufacture comprises one container, a composition within said container comprising the antibody that binds to ANG-2 and the antibody that binds to VEGF in the form of an antibody that binds to ANG-2 and to VEGF
  • the article of manufacture comprises one container, a composition within said container comprising the antibody that binds to ANG-2 and the antibody that binds to VEGF in the form of a bispecific antibody that binds to ANG-2 and to VEGF)
  • a container a composition within the container comprising an antibody that binds to PD-1
  • the invention relates to an article of manufacture comprising (a) a container, a composition within the container comprising an antibody that binds to ANG-2, and (b) container, a composition within the container comprising an antibody that binds to VEGF
  • the article of manufacture comprises one container, a composition within said container comprising the antibody that binds to ANG-2 and the antibody that binds to VEGF
  • the article of manufacture comprises one container, a composition within said container comprising the antibody that binds to ANG-2 and the antibody that binds to VEGF in the form of an antibody that binds to ANG-2 and to VEGF
  • the article of manufacture comprises one container, a composition within said container comprising the antibody that binds to ANG-2 and the antibody that binds to VEGF in the form of a bispecific antibody that binds to ANG-2 and to VEGF)
  • a container a composition within the container comprising an antibody that binds to PD-1
  • the invention relates to an article of manufacture comprising (a) a container, a composition within the container comprising an antibody that binds to ANG-2, and (b) container, a composition within the container comprising an antibody that binds to VEGF
  • the article of manufacture comprises one container, a composition within said container comprising the antibody that binds to ANG-2 and the antibody that binds to VEGF
  • the article of manufacture comprises one container, a composition within said container comprising the antibody that binds to ANG-2 and the antibody that binds to VEGF in the form of an antibody that binds to ANG-2 and to VEGF
  • the article of manufacture comprises one container, a composition within said container comprising the antibody that binds to ANG-2 and the antibody that binds to VEGF in the form of a bispecific antibody that binds to ANG-2 and to VEGF)
  • a container a composition within the container comprising an antibody that binds to PD-1
  • the invention relates to a pharmaceutical composition, comprising an antibody that binds to ANG-2, and an antibody that binds to PD-1, wherein each antibody is formulated together with a pharmaceutically acceptable carrier.
  • the antibody that binds to ANG-2 and the antibody that binds to PD-1 are formulated separately.
  • the antibody that binds to ANG-2 and the antibody that binds to PD-1 are formulated together.
  • the invention relates to a pharmaceutical composition, comprising an antibody that binds to ANG-2, an antibody that binds to VEGF, and an antibody that binds to PD-1, wherein each antibody is formulated together with a pharmaceutically acceptable carrier.
  • said pharmaceutical composition comprising an antibody that binds to ANG-2, an antibody that binds to VEGF, and an antibody that binds to PD-1
  • the antibody that binds to ANG-2 and the antibody that binds to VEGF are comprised in the form of one antibody that binds to ANG-2 and to VEGF.
  • the antibody that binds to ANG-2 and to VEGF is bispecific.
  • said pharmaceutical composition comprising an antibody that binds to ANG-2 and VEGF, and an antibody that binds to PD-1, the antibody that binds to ANG-2 and VEGF, and the antibody that binds to PD-1 are formulated separately.
  • said pharmaceutical composition comprising an antibody that binds to ANG-2 and VEGF, and an antibody that binds to PD-1, the antibody that binds to ANG-2 and VEGF, and the antibody that binds to PD-1 are formulated together.
  • composition comprising an antibody that binds to ANG-2, an antibody that binds to VEGF, and an antibody that binds to PD-1, the antibody that binds to ANG-2, the antibody that binds to VEGF, and the antibody that binds to PD-1 are formulated separately.
  • composition comprising an antibody that binds to ANG-2, an antibody that binds to VEGF, and an antibody that binds to PD-1, the antibody that binds to ANG-2, the antibody that binds to VEGF, and the antibody that binds to PD-1 are formulated together.
  • composition comprising an antibody that binds to ANG-2 and VEGF, and an antibody that binds to PD-1, the antibody that binds to ANG-2 and VEGF, and the antibody that binds to PD-1 are formulated separately.
  • the invention relates to a method for the manufacture of a pharmaceutical composition, comprising (a) formulating an antibody that binds to ANG-2 with a pharmaceutically acceptable carrier, and (b) formulating separately an antibody that binds to PD-1 with a pharmaceutically acceptable carrier.
  • the invention relates to a method for the manufacture of a pharmaceutical composition, comprising formulating an antibody that binds to ANG-2 together with an antibody that binds to PD-1 in combination with a pharmaceutically acceptable carrier.
  • the invention relates to a method for the manufacture of a pharmaceutical composition, comprising (a) formulating an antibody that binds to ANG-2 with a pharmaceutically acceptable carrier, (b) formulating separately an antibody that binds to VEGF with a pharmaceutically acceptable carrier and (c) formulating separately an antibody that binds to PD-1 with a pharmaceutically acceptable carrier.
  • the invention relates to a method for the manufacture of a pharmaceutical composition, comprising (a) formulating an antibody that binds to ANG-2 together with an antibody that binds to VEGF in combination with a pharmaceutically acceptable carrier, and (b) formulating separately an antibody that binds to PD-1 with a pharmaceutically acceptable carrier.
  • the invention relates to a method for the manufacture of a pharmaceutical composition, comprising formulating an antibody that binds to ANG-2 together with an antibody that binds to VEGF and together with an antibody that binds to PD-1 in combination with a pharmaceutically acceptable carrier.
  • the invention relates to a method for the manufacture of a pharmaceutical composition, comprising (a) formulating an antibody that binds to ANG-2 and VEGF with a pharmaceutically acceptable carrier, and (b) formulating separately an antibody that binds to PD-1 with a pharmaceutically acceptable carrier.
  • the invention relates to a method for the manufacture of a pharmaceutical composition, comprising formulating an antibody that binds to ANG-2 and VEGF together with an antibody that binds to PD-1 in combination with a pharmaceutically acceptable carrier.
  • the antibody that binds to ANG-2 that is used in a combination therapy according to the invention binds to human ANG-2.
  • the antibody that binds to ANG-2 that is used in a combination therapy according to the invention comprises the following variable domain amino acid sequences: variable heavy chain domain VH of SEQ ID NO: 4, and variable light chain domain VL of SEQ ID NO: 5 (corresponding to the VH and VL domains of ⁇ ANG-2> LC06 as disclosed herein).
  • the antibody that binds to ANG-2 that is used in a combination therapy according to the invention comprises the following variable domain amino acid sequences: variable heavy chain domain VH of SEQ ID NO: 16, and variable light chain domain VL of SEQ ID NO: 5 (corresponding to the VH and VL domains of ⁇ ANG-2> E6Q as disclosed herein).
  • the antibody that binds to PD-1 that is used in a combination therapy according to the invention binds to human PD-1.
  • the antibody that binds to PD-1 that is used in a combination therapy according to the invention comprises the following variable domain amino acid sequences: variable heavy chain domain VH of SEQ ID NO: 12, and variable light chain domain VL of SEQ ID NO: 13 (corresponding to the VH and VL domains of ⁇ PD-1> nivolumab as disclosed herein).
  • the antibody that binds to PD-1 that is used in a combination therapy according to the invention comprises the following variable domain amino acid sequences: variable heavy chain domain VH of SEQ ID NO: 14, and variable light chain domain VL of SEQ ID NO: 15 (corresponding to the VH and VL domains of ⁇ PD-1> pembrolizumab as disclosed herein).
  • the antibody that binds to PD-1 that is used in a combination therapy according to the invention comprises the following variable domain amino acid sequences: variable heavy chain domain VH of SEQ ID NO: 10, and variable light chain domain VL of SEQ ID NO: 11 (corresponding to the VH and VL domains of ⁇ PD-1> "iTME-0006-0002" as disclosed herein).
  • the antibody that binds to VEGF that is used in a combination therapy according to the invention binds to human VEGF.
  • the antibody that binds to VEGF that is used in a combination therapy comprises the following variable domain amino acid sequences: variable heavy chain domain VH of SEQ ID NO: 8, and variable light chain domain VL of SEQ ID NO: 9 (corresponding to the VH and VL domains of ⁇ VEGF> bevacizumab as disclosed herein).
  • the antibody that binds to VEGF that is used in a combination therapy comprises the following variable domain amino acid sequences: variable heavy chain domain VH of SEQ ID NO: 6, and variable light chain domain VL of SEQ ID NO: 7 (corresponding to the VH and VL domains of ⁇ VEGF> B20.4.1 as disclosed herein).
  • the combination therapy of the present invention uses the antibody that binds to ANG-2 comprising the variable heavy chain domain VH of SEQ ID NO:4, and the variable light chain domain VL of SEQ ID NO: 5 (corresponding to the VH and VL domains of ⁇ ANG-2> LC06 as disclosed herein); and the antibody that binds to VEGF comprising the variable heavy chain domain VH of SEQ ID NO: 8, and the variable light chain domain VL of SEQ ID NO: 9 (corresponding to the VH and VL domains of ⁇ VEGF> bevacizumab as disclosed herein).
  • the combination therapy of the present invention uses the antibody that binds to ANG-2 comprising the variable heavy chain domain VH of SEQ ID NO:4, and the variable light chain domain VL of
  • SEQ ID NO: 5 (corresponding to the VH and VL domains of ⁇ ANG-2> LC06 as disclosed herein); and the antibody that binds to VEGF comprising the variable heavy chain domain VH of SEQ ID NO: 6, and the variable light chain domain VL of SEQ ID NO: 7 (corresponding to the VH and VL domains of ⁇ VEGF> B20.4.1 as disclosed herein).
  • the combination therapy of the present invention uses the antibody that binds to ANG-2 comprising the variable heavy chain domain VH of SEQ ID NO: 16, and the variable light chain domain VL of SEQ ID NO: 5 (corresponding to the VH and VL domains of ⁇ ANG-2> E6Q as disclosed herein); and the antibody that binds to VEGF comprising the variable heavy chain domain VH of SEQ ID NO: 8, and the variable light chain domain VL of SEQ ID NO: 9 (corresponding to the VH and VL domains of ⁇ VEGF> bevacizumab as disclosed herein).
  • the combination therapy of the present invention uses the antibody that binds to ANG-2 comprising the variable heavy chain domain VH of SEQ ID NO: 16, and the variable light chain domain VL of SEQ ID NO: 5 (corresponding to the VH and VL domains of ⁇ ANG-2> E6Q as disclosed herein); and the antibody that binds to VEGF comprising the variable heavy chain domain VH of SEQ ID NO: 6, and the variable light chain domain VL of SEQ ID NO: 7 (corresponding to the VH and VL domains of ⁇ VEGF> B20.4.1 as disclosed herein).
  • the combination therapy of the present invention uses the antibody that binds to ANG-2 comprising the variable heavy chain domain VH of SEQ ID NO:4, and the variable light chain domain VL of
  • SEQ ID NO: 5 (corresponding to the VH and VL domains of ⁇ ANG-2> LC06 as disclosed herein); and the antibody that binds to PD-1 comprising the variable heavy chain domain VH of SEQ ID NO: 12, and the variable light chain domain VL of SEQ ID NO: 13 (corresponding to the VH and VL domains of ⁇ PD-1> nivolumab as disclosed herein).
  • the combination therapy of the present invention uses the antibody that binds to ANG-2 comprising the variable heavy chain domain VH of SEQ ID NO:4, and the variable light chain domain VL of SEQ ID NO: 5 (corresponding to the VH and VL domains of ⁇ ANG-2> LC06 as disclosed herein); and the antibody that binds to PD-1 comprising the variable heavy chain domain VH of SEQ ID NO: 14, and the variable light chain domain VL of SEQ ID NO: 15 (corresponding to the VH and VL domains of ⁇ PD-1> pembrolizumab as disclosed herein).
  • the combination therapy of the present invention uses the antibody that binds to ANG-2 comprising the variable heavy chain domain VH of SEQ ID NO:4, and the variable light chain domain VL of SEQ ID NO: 5 (corresponding to the VH and VL domains of ⁇ ANG-2> LC06 as disclosed herein); and the antibody that binds to PD-1 comprising the variable heavy chain domain VH of SEQ ID NO: 10, and the variable light chain domain VL of SEQ ID NO: 11 (corresponding to the VH and VL domains of ⁇ PD-1> "iTME-0006-0002" as disclosed herein).
  • the combination therapy of the present invention uses the antibody that binds to ANG-2 comprising the variable heavy chain domain VH of SEQ ID NO: 16, and the variable light chain domain VL of
  • SEQ ID NO: 5 (corresponding to the VH and VL domains of ⁇ ANG-2> E6Q as disclosed herein); and the antibody that binds to PD-1 comprising the variable heavy chain domain VH of SEQ ID NO: 12, and the variable light chain domain VL of SEQ ID NO: 13 (corresponding to the VH and VL domains of ⁇ PD-1> nivolumab as disclosed herein).
  • the combination therapy of the present invention uses the antibody that binds to ANG-2 comprising the variable heavy chain domain VH of SEQ ID NO: 16, and the variable light chain domain VL of SEQ ID NO: 5 (corresponding to the VH and VL domains of ⁇ ANG-2> E6Q as disclosed herein); and the antibody that binds to PD-1 comprising the variable heavy chain domain VH of SEQ ID NO: 14, and the variable light chain domain VL of SEQ ID NO: 15 (corresponding to the VH and VL domains of ⁇ PD-1> pembrolizumab as disclosed herein).
  • the combination therapy of the present invention uses the antibody that binds to ANG-2 comprising the variable heavy chain domain VH of SEQ ID NO: 16, and the variable light chain domain VL of SEQ ID NO: 5 (corresponding to the VH and VL domains of ⁇ ANG-2> E6Q as disclosed herein); and the antibody that binds to PD-1 comprising the variable heavy chain domain VH of SEQ ID NO: 10, and the variable light chain domain VL of SEQ ID NO: 11 (corresponding to the VH and VL domains of ⁇ PD-1>
  • the combination therapy of the present invention uses an antibody that binds to ANG-2 and VEGF, the antibody comprising at least one binding site that binds to ANG-2 comprising the variable heavy chain domain VH of SEQ ID NO: 16, and the variable light chain domain
  • VL of SEQ ID NO: 5 (corresponding to the VH and VL domains of ⁇ ANG-2> E6Q as disclosed herein); and at least one binding site that binds to VEGF comprising the variable heavy chain domain VH of SEQ ID NO: 8, and the variable light chain domain VL of SEQ ID NO: 9 (corresponding to the VH and VL domains of ⁇ VEGF> bevacizumab as disclosed herein).
  • said antibody that binds to ANG-2 and VEGF is a bispecific antibody.
  • the combination therapy of the present invention uses an antibody that binds to ANG-2 and VEGF, the antibody comprising at least one binding site that binds to ANG-2 comprising the variable heavy chain domain VH of SEQ ID NO: 16, and the variable light chain domain VL of SEQ ID NO: 5 (corresponding to the VH and VL domains of ⁇ ANG-2> E6Q as disclosed herein); and at least one binding site that binds to VEGF comprising the variable heavy chain domain VH of SEQ ID NO: 6, and the variable light chain domain VL of SEQ ID NO: 7 (corresponding to the VH and VL domains of
  • said antibody that binds to ANG-2 and VEGF is a bispecific antibody.
  • the combination therapy of the present invention uses a bispecific antibody that binds to ANG-2 and VEGF, the antibody comprising: a heavy chain comprising SEQ ID NO: 17 (corresponding to the ANG-
  • the combination therapy of the present invention uses a bispecific antibody that binds to ANG-2 and VEGF, the antibody comprising: a heavy chain comprising SEQ ID NO: 17 (corresponding to the ANG-
  • the combination therapy of the present invention uses an antibody that binds to ANG-2 and VEGF, the antibody comprising at least one binding site that binds to ANG-2 comprising the variable heavy chain domain VH of SEQ ID NO: 16, and the variable light chain domain VL of SEQ ID NO: 5 (corresponding to the VH and VL domains of ⁇ ANG-2> E6Q as disclosed herein); and at least one binding site that binds to VEGF comprising the variable heavy chain domain VH of SEQ ID NO: 8, and the variable light chain domain VL of SEQ ID NO: 9 (corresponding to the VH and VL domains of ⁇ VEGF> bevacizumab as disclosed herein); and the antibody that binds to PD-1 comprising the variable heavy chain domain VH of SEQ ID NO: 12, and the variable light chain domain VL of SEQ ID NO: 13 (corresponding to the VH and VL domains of ⁇ PD-1> nivolumab as disclosed herein).
  • said antibody that binds to PD-1 comprising
  • the combination therapy of the present invention uses an antibody that binds to ANG-2 and VEGF, the antibody comprising at least one binding site that binds to ANG-2 comprising the variable heavy chain domain VH of SEQ ID NO: 16, and the variable light chain domain
  • VL of SEQ ID NO: 5 (corresponding to the VH and VL domains of ⁇ ANG-2> E6Q as disclosed herein); and at least one binding site that binds to VEGF comprising the variable heavy chain domain VH of SEQ ID NO: 8, and the variable light chain domain VL of SEQ ID NO: 9 (corresponding to the VH and VL domains of ⁇ VEGF> bevacizumab as disclosed herein); and the antibody that binds to PD-1 comprising the variable heavy chain domain VH of SEQ ID NO: 14, and variable light chain domain VL of SEQ ID NO: 15 (corresponding to the VH and VL domains of ⁇ PD-1> pembrolizumab as disclosed herein).
  • said antibody that binds to ANG-2 and VEGF is a bispecific antibody.
  • the combination therapy of the present invention uses an antibody that binds to ANG-2 and VEGF, the antibody comprising at least one binding site that binds to ANG-2 comprising the variable heavy chain domain VH of SEQ ID NO: 16, and the variable light chain domain VL of SEQ ID NO: 5 (corresponding to the VH and VL domains of ⁇ ANG-2> E6Q as disclosed herein); and at least one binding site that binds to VEGF comprising the variable heavy chain domain VH of SEQ ID NO: 8, and the variable light chain domain VL of SEQ ID NO: 9 (corresponding to the VH and VL domains of ⁇ VEGF> bevacizumab as disclosed herein); and the antibody that binds to PD-1 comprising the variable heavy chain domain VH of SEQ ID NO: 10, and the variable light chain domain VL of SEQ ID NO: 11 (corresponding to the VH and
  • said antibody that binds to ANG-2 and VEGF is a bispecific antibody.
  • the combination therapy of the present invention uses an antibody that binds to ANG-2 and VEGF, the antibody comprising at least one binding site that binds to ANG-2 comprising the variable heavy chain domain VH of SEQ ID NO: 16, and the variable light chain domain VL of SEQ ID NO: 5 (corresponding to the VH and VL domains of ⁇ ANG-2> E6Q as disclosed herein); and at least one binding site that binds to VEGF comprising the variable heavy chain domain VH of SEQ ID NO: 6, and the variable light chain domain VL of SEQ ID NO: 7 (corresponding to the VH and VL domains of
  • ⁇ VEGF> B20.4.1 as disclosed herein
  • the antibody that binds to PD-1 comprising the variable heavy chain domain VH of SEQ ID NO: 12, and the variable light chain domain VL of SEQ ID NO: 13 (corresponding to the VH and VL domains of ⁇ PD-1> nivolumab as disclosed herein).
  • said antibody that binds to ANG-2 and VEGF is a bispecific antibody.
  • the combination therapy of the present invention uses an antibody that binds to ANG-2 and VEGF, the antibody comprising at least one binding site that binds to ANG-2 comprising the variable heavy chain domain VH of SEQ ID NO: 16, and the variable light chain domain VL of SEQ ID NO: 5 (corresponding to the VH and VL domains of ⁇ ANG-2> E6Q as disclosed herein); and at least one binding site that binds to VEGF comprising the variable heavy chain domain VH of SEQ ID NO: 6, and the variable light chain domain VL of SEQ ID NO: 7 (corresponding to the VH and VL domains of ⁇ VEGF> B20.4.1 as disclosed herein); and the antibody that binds to PD-1 comprising the variable heavy chain domain VH of SEQ ID NO: 14, and the variable light chain domain VL of SEQ ID NO: 15 (corresponding to the VH and VL domains of ⁇ PD-1> pembrolizumab as disclosed herein).
  • said antibody that binds to PD-1 comprising the variable heavy
  • the combination therapy of the present invention uses an antibody that binds to ANG-2 and VEGF, the antibody comprising at least one binding site that binds to ANG-2 comprising variable heavy chain domain VH of SEQ ID NO: 16, and the variable light chain domain VL of SEQ ID NO: 5 (corresponding to the VH and VL domains of ⁇ ANG-2> E6Q as disclosed herein); and at least one binding site that binds to VEGF comprising the variable heavy chain domain VH of SEQ ID NO: 6, and the variable light chain domain VL of SEQ ID NO: 7 (corresponding to the VH and VL domains of ⁇ VEGF> B20.4.1 as disclosed herein); and the antibody that binds to PD-1 comprising the variable heavy chain domain VH of SEQ ID NO: 10, and the variable light chain domain VL of SEQ ID NO: 11 (corresponding to the VH and VL domains of ⁇ PD-1> "iTME-0006-0002" as disclosed herein).
  • said antibody that binds to PD-1 comprising
  • the combination therapy of the present invention uses a bispecific antibody that binds to ANG-2 and VEGF, the antibody comprising: a heavy chain comprising SEQ ID NO: 17 (corresponding to the ANG-
  • the combination therapy of the present invention uses a bispecific antibody that binds to ANG-2 and VEGF, the antibody comprising: a heavy chain comprising SEQ ID NO: 17 (corresponding to the ANG- 2 heavy chain of ⁇ ANG-2/VEGF> E6Q/bevacizumab as disclosed herein), a light chain comprising SEQ ID NO: 18 (corresponding to the ANG-2 light chain of
  • ⁇ ANG-2/VEGF> E6Q/bevacizumab as disclosed herein a heavy chain comprising SEQ ID NO: 21 (corresponding to the VEGF heavy chain of E6Q/bevacizumab as disclosed herein), and a light chain comprising SEQ ID NO: 22 (corresponding to the VEGF light chain of ⁇ ANG-2/VEGF> E6Q/bevacizumab as disclosed herein); and the antibody that binds to PD-1 comprising the variable heavy chain domain VH of SEQ ID NO: 14, and the variable light chain domain VL of SEQ ID NO: 15 (corresponding to the VH and VL domains of ⁇ PD-1> pembrolizumab as disclosed herein).
  • the combination therapy of the present invention uses a bispecific antibody that binds to ANG-2 and VEGF, the antibody comprising: a heavy chain comprising SEQ ID NO: 17 (corresponding to the ANG- 2 heavy chain of ⁇ ANG-2/VEGF> E6Q/bevacizumab as disclosed herein), a light chain comprising SEQ ID NO: 18 (corresponding to the ANG-2 light chain of ⁇ ANG-2/VEGF> E6Q/bevacizumab as disclosed herein), a heavy chain comprising SEQ ID NO: 21 (corresponding to the VEGF heavy chain of
  • E6Q/bevacizumab as disclosed herein
  • a light chain comprising SEQ ID NO: 22 (corresponding to the VEGF light chain of ⁇ ANG-2/VEGF> E6Q/bevacizumab as disclosed herein); and the antibody that binds to PD-1 comprising the variable heavy chain domain VH of SEQ ID NO: 10, and the variable light chain domain VL of SEQ ID NO: 11 (corresponding to the VH and VL domains of ⁇ PD-1> "iTME-0006-0002" as disclosed herein).
  • the combination therapy of the present invention uses a bispecific antibody that binds to ANG-2 and VEGF, the antibody comprising: a heavy chain comprising SEQ ID NO: 17 (corresponding to the ANG- 2 heavy chain of ⁇ ANG-2/VEGF> E6Q/B20.4.1 as disclosed herein), a light chain comprising SEQ ID NO: 18 (corresponding to the ANG-2 light chain of ⁇ ANG- 2/VEGF> E6Q/B20.4.1 as disclosed herein), a heavy chain comprising SEQ ID NO: 19 (corresponding to the VEGF heavy chain of ⁇ ANG-2 /VEGF> E6Q/B20.4.1 as disclosed herein), and a light chain comprising SEQ ID NO: 20 (corresponding to the VEGF light chain of ⁇ ANG-2/VEGF> E6Q/B20.4.1 as disclosed herein); and the antibody that binds to PD-1 comprising the variable heavy chain domain VH of SEQ ID NO: 12, and the variable light chain domain VL of SEQ ID NO
  • the combination therapy of the present invention uses a bispecific antibody that binds to ANG-2 and VEGF, the antibody comprising: a heavy chain comprising SEQ ID NO: 17 (corresponding to the ANG- 2 heavy chain of ⁇ ANG-2/VEGF> E6Q/B20.4.1 as disclosed herein), a light chain comprising SEQ ID NO: 18 (corresponding to the ANG-2 light chain of ⁇ ANG- 2/VEGF> E6Q/B20.4.1 as disclosed herein), a heavy chain comprising SEQ ID NO:
  • the combination therapy of the present invention uses a bispecific antibody that binds to ANG-2 and VEGF, the antibody comprising: a heavy chain comprising SEQ ID NO: 17 (corresponding to the ANG-
  • the antibody that binds to ANG-2 that is used in a combination therapy according to the invention is a human antibody or a humanized antibody.
  • the antibody that binds to ANG-2 that is used in a combination therapy according to the invention is of IgG isotype. In one embodiment of the invention, the antibody that binds to ANG-2 that is used in a combination therapy according to the invention is of IgGl, IgG2, IgG3 or IgG4 isotype. In one preferred embodiment of the invention, the antibody that binds to ANG-2 that is used in a combination therapy according to the invention is of human IgGl or of human IgG4 isotype. In one preferred embodiment of the invention, the antibody that binds to ANG-2 that is used in a combination therapy according to the invention is of human IgGl isotype.
  • the antibody that binds to ANG-2 that is used in a combination therapy according to the invention is of human IgGl isotype with a mutation at positions L234A and L235A. In another preferred embodiment of the invention, the antibody that binds to ANG-2 that is used in a combination therapy according to the invention is of human IgG4 isotype. In one preferred embodiment of the invention, the antibody that binds to ANG-2 that is used in a combination therapy according to the invention is of human IgG4 isotype with a mutation at position S228P. In one embodiment of the invention, the antibody that binds to ANG-2 that is used in a combination therapy according to the invention
  • the antibody that binds to ANG-2 that is used in a combination therapy according to the invention specifically binds to human ANG-2 with a K D value of less than 1.0 x 10 "8 mo 1/1, as determined by surface plasmon resonance.
  • the antibody that binds to ANG-2 that is used in a combination therapy according to the invention inhibits the interaction of human ANG-2 with TIE2 receptor with an IC50 of 15 nM or less.
  • the antibody that binds to PD-1 that is used in a combination therapy according to the invention is a human antibody or a humanized antibody.
  • the antibody that binds to PD-1 that is used in a combination therapy according to the invention is of IgG isotype. In one embodiment of the invention, the antibody that binds to PD-1 that is used in a combination therapy according to the invention is of IgG 1, IgG2, IgG3 or IgG4 isotype. In one preferred embodiment of the invention, the antibody that binds to PD-1 that is used in a combination therapy according to the invention is of human IgGl or of human IgG4 isotype. In one preferred embodiment of the invention, the antibody that binds to PD-1 that is used in a combination therapy according to the invention is of human IgGl isotype.
  • the antibody that binds to PD-1 that is used in a combination therapy according to the invention is of human IgGl isotype with a mutation at positions L234A and L235A. In another preferred embodiment of the invention, the antibody that binds to PD-1 that is used in a combination therapy according to the invention is of human IgG4 isotype. In one preferred embodiment of the invention, the antibody that binds to PD-1 that is used in a combination therapy according to the invention is of human IgG4 isotype with a mutation at position S228P.
  • the antibody that binds to PD-1 that is used in a combination therapy according to the invention specifically binds to human PD-1 with a K D value of less than 1.0 x 10 "8 mo 1/1, as determined by surface plasmon resonance.
  • the antibody that binds to VEGF that is used in a combination therapy according to one embodiment of the invention is a human antibody or a humanized antibody.
  • the antibody that binds to VEGF that is used in a combination therapy is of
  • the antibody that binds to VEGF that is used in a combination therapy according to the invention is of IgGl, IgG2, IgG3 or IgG4 isotype. In one preferred embodiment of the invention, the antibody that binds to VEGF that is used in a combination therapy according to the invention is of human IgGl or of human IgG4 isotype. In one preferred embodiment of the invention, the antibody that binds to VEGF that is used in a combination therapy according to the invention is of human IgGl isotype.
  • the antibody that binds to VEGF that is used in a combination therapy according to the invention is of human IgGl isotype with a mutation at positions L234A and L235A. In another preferred embodiment of the invention, the antibody that binds to VEGF that is used in a combination therapy according to the invention is of human IgG4 isotype. In one preferred embodiment of the invention, the antibody that binds to VEGF that is used in a combination therapy according to the invention is of human IgG4 isotype with a mutation at position S228P.
  • the antibody that binds to VEGF that is used in a combination therapy according to the invention specifically binds to human VEGF with a K D value of less than 1.0 x 10 "8 mo 1/1, as determined by surface plasmon resonance.
  • the antibodies that bind to ANG-2 and to PD-1 that are used in a combination therapy according to the invention are both human antibody or a humanized antibodies.
  • the antibodies that bind to ANG-2 and to PD-1 that are used in a combination therapy according to the invention are both of IgG isotype. In one embodiment of the invention, the antibodies that bind to ANG-2 and to PD-1 that are used in a combination therapy according to the invention both bind to their respective targets, i.e. human ANG-2 and human PD-1, with a K D value of less than 1.0 x 10 "8 mol/1, as determined by surface plasmon resonance. In one embodiment of the invention, the antibodies that bind to ANG-2, to PD-1 and to VEGF that are used in a combination therapy according to the invention are human antibodies or humanized antibodies, respectively.
  • the antibodies that bind to ANG-2, to PD-1 and to VEGF that are used in a combination therapy according to the invention are of IgG isotype.
  • the antibodies that bind to ANG-2, to PD-1 and to VEGF that are used in a combination therapy according to the invention bind to their respective targets, i.e. human ANG-2, human PD-1 and human VEGF, with a K D value of less than 1.0 x 10 "8 mo 1/1, as determined by surface plasmon resonance.
  • the cancer is selected from the group of lung cancer, non small cell lung (NSCL) cancer, bronchioloalviolar cell lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, gastric cancer, colon cancer, breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer
  • the combination therapy is used for treating cancer, delaying progression of cancer, or prolonging the survival of a patient suffering from cancer
  • the cancer is a solid tumor.
  • the combination therapy is used for a) treating a solid tumor
  • the combination therapy of the antibody that binds to ANG-2 and the antibody that binds to PD-1 is co-administered with a chemotherapeutic agent.
  • the combination therapy of the antibody that binds to ANG-2, the antibody that binds to VEGF and the antibody that binds to PD-1 is co-administered with a chemotherapeutic agent.
  • said chemotherapeutic agent is selected from the group of: anti-neoplastic agents including nitrogen mustards (in one embodiment mechlorethamine, cyclophosphamide, ifosfamide, melphalan, or chlorambucil); nitrosoureas (in one embodiment carmustine (BCNU), lomustine (CCNU), or semustine (methyl-CCNU)); TemodalTM (temozolamide), ethylenimines/methylmelamine (in one embodiment thriethylenemelamine (TEM), triethylene, thiophosphoramide (thiotepa), or hexamethylmelamine (HMM, altretamine)); alkyl sulfonates (in one embodiment busulfan); triazines (in one embodiment dacarbazine (DTIC)); antimetabolites including folic acid analogs (in one embodiment methotrexate or trimetrexate), pyrimidine analogs (in one embodiment 5-fluorouracil (5FU), fluor
  • T-deoxycoformycin pentostatin
  • EHNA erythrohydroxynonyladenine
  • fludarabine phosphate or 2- chlorodeoxyadenosine
  • natural products including antimitotic drugs (in one embodiment paclitaxel, vinca alkaloids including vinblastine (VLB), vincristine, vinorelbine, taxotere, estramustine, or estramustine phosphate); pipodophylotoxins (in one embodiment etoposide or teniposide); antibiotics (in one embodiment actinomycin D, daunomycin (rubidomycin), doxorubicin, mitoxantrone, idarubicin, bleomycins, plicamycin (mithramycin), mitomycin C, and actinomycin); enzymes (in one embodiment L-asparaginase); biological response modifiers (in one embodiment interferon- alpha, IL-2, G-CSF or GM-
  • the combination therapy of the antibody that binds to ANG-2 and the antibody that binds to PD-1 is administered in a therapeutic treatment, wherein no additional chemotherapeutic agent is administered.
  • the combination therapy of the antibody that binds to ANG-2, the antibody that binds to VEGF and the antibody that binds to PD-1 is administered in a therapeutic treatment, wherein no additional chemotherapeutic agent is administered.
  • the combination therapy of the antibody that binds to ANG-2 and the antibody that binds to PD-1 is co-administered with a radiation therapy.
  • an antibody that binds to angiopoietin 2 (ANG-2), wherein the antibody is administered in a combination therapy with an antibody that binds to PD-1, for use in
  • An antibody that binds to ANG-2 wherein the antibody is administered in combination therapy with an antibody that binds to VEGF and with an antibody that binds to PD-1, for use in
  • An antibody that binds to PD-1 wherein the antibody is administered in a combination therapy with an antibody that binds to ANG-2 and an with antibody that binds to VEGF, for use in
  • An antibody that binds to VEGF wherein the antibody is administered in a combination therapy with an antibody that binds to ANG-2 and with an antibody that binds to PD-1, for use in
  • variable domain amino acid sequences (a) variable heavy chain domain VH of SEQ ID NO: (a) variable heavy chain domain VH of SEQ ID NO: (a) variable heavy chain domain VH of SEQ ID NO: (a) variable heavy chain domain VH of SEQ ID NO: (a) variable heavy chain domain VH of SEQ ID NO: (a) variable heavy chain domain VH of SEQ ID NO: (a) variable heavy chain domain VH of SEQ ID NO: (a) variable heavy chain domain VH of SEQ ID
  • variable light chain domain VL of SEQ ID NO: 12 and variable light chain domain VL of SEQ ID NO: 13 (corresponding to the VH and VL domains of ⁇ PD-1> nivolumab), or (b) variable heavy chain domain VH of SEQ ID NO: 14, and variable light chain domain VL of SEQ ID NO: 15 (corresponding to the VH and VL domains of ⁇ PD-1> pembrolizumab).
  • variable domain amino acid sequences variable heavy chain domain VH of SEQ ID NO: 8, and variable light chain domain VL of SEQ ID NO: 9 (corresponding to the VH and VL domains of ⁇ VEGF> bevacizumab).
  • the binding site or binding sites binding to ANG-2 comprise a variable heavy chain domain VH of SEQ ID NO: 16, and a variable light chain domain VL of SEQ ID NO: 5;
  • the binding site or binding sites binding to VEGF comprise a variable heavy chain domain VH of SEQ ID NO: 8, and a variable light chain domain VL of SEQ ID NO: 9 (corresponding to the VH and VL domains of ⁇ VEGF> bevacizumab).
  • the binding site or binding sites binding to ANG-2 comprise a variable heavy chain domain VH of SEQ ID NO: 16, and a variable light chain domain VL of SEQ ID NO: 5;
  • the binding site or binding sites binding to VEGF comprise a variable heavy chain domain VH of SEQ ID NO: 8, and variable light chain domain VL of SEQ ID NO: 9 (corresponding to the VH and VL domains of ⁇ VEGF> bevacizumab); and
  • variable domain amino acid sequences (a) variable heavy chain domain VH of SEQ ID NO:
  • variable light chain domain VL of SEQ ID NO: 12 and variable light chain domain VL of SEQ ID NO: 13 (corresponding to the VH and VL domains of ⁇ PD-1> nivolumab), or (b) variable heavy chain domain VH of SEQ ID NO: 14, and variable light chain domain VL of SEQ ID NO: 15 (corresponding to the VH and VL domains of ⁇ PD-1> pembrolizumab).
  • the antibody that binds to VEGF for use according to any one of embodiments 17 to 21, and 22 to 26, and 30 to 31; wherein the antibody that binds to ANG-2 and VEGF comprises the following variable domain amino acid sequences:
  • the binding site or binding sites binding to ANG-2 comprise a variable heavy chain domain VH of SEQ ID NO: 16, and a variable light chain domain VL of SEQ ID NO: 5;
  • the binding site or binding sites binding to VEGF comprise a variable heavy chain domain VH of SEQ ID NO: 6, and a variable light chain domain VL of SEQ ID NO: 7 (corresponding to the VH and VL domains of ⁇ VEGF> B20.4.1).
  • the antibody that binds to VEGF for use according to any one of embodiments 17 to 21, and 22 to 26, and 31 to 32; wherein the antibody that binds to ANG-2 and VEGF comprises the following variable domain amino acid sequences:
  • the binding site or binding sites binding to ANG-2 comprise a variable heavy chain domain VH of SEQ ID NO: 16, and a variable light chain domain VL of SEQ ID NO: 5;
  • the binding site or binding sites binding to VEGF comprise a variable heavy chain domain VH of SEQ ID NO: 6, and a variable light chain domain VL of SEQ ID NO: 7 (corresponding to the VH and VL domains of ⁇ VEGF> B20.4.1); and
  • variable domain amino acid sequences (a) variable heavy chain domain VH of SEQ ID NO: 12, and variable light chain domain VL of SEQ ID NO: 13 (corresponding to the VH and VL domains of ⁇ PD-1> nivolumab), or (b) variable heavy chain domain VH of SEQ ID NO: 14, and variable light chain domain VL of SEQ ID NO: 15 (corresponding to the VH and VL domains of ⁇ PD-1> pembrolizumab) .
  • the binding site or binding sites binding to ANG-2 comprise a variable heavy chain domain VH of SEQ ID NO: 16, and a variable light chain domain VL of SEQ ID NO : 5 ;
  • the binding site or binding sites binding to VEGF comprise a variable heavy chain domain VH of SEQ ID NO: 6, and a variable light chain domain VL of SEQ ID NO: 7 (corresponding to the VH and VL domains of ⁇ VEGF> B20.4.1); and
  • variable domain amino acid sequences variable heavy chain domain VH of SEQ ID NO: 10, and variable light chain domain VL of SEQ ID NO: 11 (corresponding to the VH and VL domains of ⁇ PD-1> "iTME-0006-0002").
  • the method comprises the step of administering an effective amount of an antibody that binds to ANG-2 and an effective amount of an antibody that binds to PD-1 to a patient in need thereof.
  • the method comprises the step of administering an effective amount of an antibody that binds to ANG-2, an effective amount of an antibody that binds to VEGF; and an effective amount of an antibody that binds to PD-1 to a patient in need thereof.
  • the method comprises the step of administering an effective amount of an antibody that binds to ANG-2 and to VEGF; and an effective amount of an antibody that binds to PD-1 to a patient in need thereof. 38. The method of embodiment 37, wherein the antibody that binds to ANG-2 and
  • VEGF is bispecific.
  • the cancer is selected from the group of lung cancer, non small cell lung (NSCL) cancer, bronchioloalviolar cell lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, gastric cancer, colon cancer, breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma
  • variable domain amino acid sequences variable heavy chain domain VH of SEQ ID NO:4, and variable light chain domain VL of SEQ ID NO: 5 (corresponding to the VH and VL domains of ⁇ ANG-2> LC06).
  • variable domain amino acid sequences variable heavy chain domain VH of SEQ ID NO: 16, and the variable light chain domain VL of SEQ ID NO: 5 (corresponding to the VH and VL domains of ⁇ ANG-2> E6Q).
  • variable domain amino acid sequences (a) variable heavy chain domain VH of SEQ ID NO: 12, and variable light chain domain VL of SEQ ID NO: 13 (corresponding to the VH and VL domains of ⁇ PD-1> nivolumab), or (b) variable heavy chain domain VH of SEQ ID NO: 14, and variable light chain domain VL of SEQ ID NO: 15
  • variable domain amino acid sequences variable heavy chain domain VH of SEQ ID NO: 8, and variable light chain domain VL of SEQ ID NO: 9 (corresponding to the VH and VL domains of ⁇ VEGF> bevacizumab).
  • the binding site or binding sites binding to ANG-2 comprise a variable heavy chain domain VH of SEQ ID NO: 16, and a variable light chain domain VL of SEQ ID NO: 5;
  • the binding site or binding sites binding to VEGF comprise a variable heavy chain domain VH of SEQ ID NO: 8, and a variable light chain domain VL of SEQ ID NO: 9 (corresponding to the VH and VL domains of ⁇ VEGF> bevacizumab).
  • the binding site or binding sites binding to ANG-2 comprise a variable heavy chain domain VH of SEQ ID NO: 16, and a variable light chain domain VL of SEQ ID NO: 5;
  • the binding site or binding sites binding to VEGF comprise a variable heavy chain domain VH of SEQ ID NO: 8, and variable light chain domain VL of SEQ ID NO: 9 (corresponding to the VH and VL domains of ⁇ VEGF> bevacizumab); and
  • variable domain amino acid sequences (a) variable heavy chain domain VH of SEQ ID NO: 12, and variable light chain domain VL of SEQ ID NO: 13 (corresponding to the VH and VL domains of ⁇ PD-1> nivolumab), or (b) variable heavy chain domain VH of SEQ ID NO: 14, and variable light chain domain VL of SEQ ID NO:
  • variable domain amino acid sequences variable heavy chain domain VH of SEQ ID NO: 10, and variable light chain domain VL of SEQ ID NO: 11 (corresponding to the VH and VL domains of ⁇ PD-1> "iTME-0006-0002").
  • variable heavy chain domain VH of SEQ ID NO: 6 variable light chain domain VL of SEQ ID NO: 7 (corresponding to the VH and VL domains of ⁇ VEGF> B20.4.1).
  • the binding site or binding sites binding to ANG-2 comprise a variable heavy chain domain VH of SEQ ID NO: 16, and a variable light chain domain VL of SEQ ID NO: 5;
  • the binding site or binding sites binding to VEGF comprise a variable heavy chain domain VH of SEQ ID NO: 6, and a variable light chain domain VL of SEQ ID NO: 7 (corresponding to the VH and VL domains of ⁇ VEGF> B20.4.1).
  • the binding site or binding sites binding to ANG-2 comprise a variable heavy chain domain VH of SEQ ID NO: 16, and a variable light chain domain VL of SEQ ID NO: 5;
  • the binding site or binding sites binding to VEGF comprise a variable heavy chain domain VH of SEQ ID NO: 6, and a variable light chain domain VL of SEQ ID NO: 7 (corresponding to the VH and VL domains of ⁇ VEGF> B20.4.1); and
  • variable domain amino acid sequences (a) variable heavy chain domain VH of SEQ ID NO:
  • variable light chain domain VL of SEQ ID NO: 12 and variable light chain domain VL of SEQ ID NO: 13 (corresponding to the VH and VL domains of ⁇ PD-1> nivolumab), or (b) variable heavy chain domain VH of SEQ ID NO: 14, and variable light chain domain VL of SEQ ID NO: 15 (corresponding to the VH and VL domains of ⁇ PD-1> pembrolizumab).
  • variable heavy chain domain VH of SEQ ID NO: 14 and variable light chain domain VL of SEQ ID NO: 15 corresponding to the VH and VL domains of ⁇ PD-1> pembrolizumab.
  • the binding site or binding sites binding to ANG-2 comprise a variable heavy chain domain VH of SEQ ID NO: 16, and a variable light chain domain VL of SEQ ID NO: 5;
  • the binding site or binding sites binding to VEGF comprise a variable heavy chain domain VH of SEQ ID NO: 6, and a variable light chain domain VL of SEQ ID NO: 7 (corresponding to the VH and VL domains of ⁇ VEGF> B20.4.1); and
  • variable domain amino acid sequences variable heavy chain domain VH of SEQ ID NO: 10, and variable light chain domain VL of SEQ ID NO: 11 (corresponding to the VH and VL domains of ⁇ PD-1> "iTME-0006-0002").
  • the antibody is for administration in a combination therapy with an antibody that binds to PD- 1.
  • the antibody is for administration in a combination therapy with an antibody that binds to VEGF and an antibody that binds to PD-1.
  • the antibody is for administration in a combination therapy with an antibody that binds to VEGF and an antibody that binds to PD-1. 55. Use according to embodiment 54, wherein the antibody that binds to ANG-2 and VEGF is bispecific.
  • the antibody is for administration in a combination therapy with an antibody that binds to ANG-2.
  • the antibody is for administration in a combination therapy with an antibody that binds to ANG-2 and an antibody that binds to VEGF. 58.
  • the antibody is for administration in a combination therapy with an antibody that binds to ANG-2 and VEGF.
  • the antibody is for administration in a combination therapy with an antibody that binds to ANG-2 and an antibody that binds to PD-1.
  • the cancer is selected from the group of lung cancer, non small cell lung (NSCL) cancer, bronchioloalviolar cell lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, gastric cancer, colon cancer, breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer
  • variable domain amino acid sequences variable heavy chain domain VH of SEQ ID NO:4, and variable light chain domain VL of SEQ ID NO: 5 (corresponding to the VH and VL domains of ⁇ ANG-2> LC06).
  • variable domain amino acid sequences variable heavy chain domain VH of SEQ ID NO: 16, and the variable light chain domain VL of SEQ ID NO: 5 (corresponding to the VH and VL domains of ⁇ ANG-2> E6Q).
  • variable domain amino acid sequences (a) variable heavy chain domain VH of SEQ ID NO: 12, and variable light chain domain VL of SEQ ID NO: 13 (corresponding to the VH and VL domains of ⁇ PD-1> nivolumab), or (b) variable heavy chain domain VH of SEQ ID NO: 14, and variable light chain domain VL of SEQ ID NO: 15 (corresponding to the VH and VL domains of ⁇ PD-1> pembrolizumab).
  • variable domain amino acid sequences variable heavy chain domain VH of SEQ ID NO: 8, and variable light chain domain VL of SEQ ID NO: 9 (corresponding to the VH and VL domains of ⁇ VEGF> bevacizumab).
  • variable heavy chain domain VH of SEQ ID NO: 8 variable heavy chain domain
  • VL of SEQ ID NO: 9 variable light chain domain
  • variable domain amino acid sequences variable heavy chain domain amino acid sequences:
  • the binding site or binding sites binding to ANG-2 comprise a variable heavy chain domain VH of SEQ ID NO: 16, and a variable light chain domain VL of SEQ ID NO: 5;
  • the binding site or binding sites binding to VEGF comprise a variable heavy chain domain VH of SEQ ID NO: 8, and a variable light chain domain VL of SEQ ID NO: 9 (corresponding to the VH and VL domains of ⁇ VEGF> bevacizumab).
  • VH variable heavy chain domain
  • VL variable light chain domain
  • the antibody that binds to ANG-2 and VEGF comprises the following variable domain amino acid sequences:
  • the binding site or binding sites binding to ANG-2 comprise a variable heavy chain domain VH of SEQ ID NO: 16, and a variable light chain domain VL of SEQ ID NO: 5;
  • the binding site or binding sites binding to VEGF comprise a variable heavy chain domain VH of SEQ ID NO: 8, and variable light chain domain VL of SEQ ID NO: 9 (corresponding to the VH and VL domains of ⁇ VEGF> bevacizumab); and
  • variable domain amino acid sequences (a) variable heavy chain domain VH of SEQ ID NO: 12, and variable light chain domain VL of SEQ ID NO: 13 (corresponding to the VH and VL domains of ⁇ PD-1> nivolumab), or (b) variable heavy chain domain VH of SEQ ID NO: 14, and variable light chain domain VL of SEQ ID NO: 15 (corresponding to the VH and VL domains of ⁇ PD-1> pembrolizumab) .
  • variable domain amino acid sequences variable heavy chain domain VH of SEQ ID NO: 10, and variable light chain domain VL of SEQ ID NO: 11 (corresponding to the VH and VL domains of ⁇ PD-1> "iTME-0006-0002").
  • variable heavy chain domain VH of SEQ ID NO: 6 variable light chain domain VL of SEQ ID NO: 7 (corresponding to the VH and VL domains of ⁇ VEGF> B20.4.1).
  • the binding site or binding sites binding to ANG-2 comprise a variable heavy chain domain VH of SEQ ID NO: 16, and a variable light chain domain VL of SEQ ID NO: 5;
  • the binding site or binding sites binding to VEGF comprise a variable heavy chain domain VH of SEQ ID NO: 6, and a variable light chain domain VL of SEQ ID NO: 7 (corresponding to the VH and VL domains of ⁇ VEGF> B20.4.1).
  • VH variable heavy chain domain
  • VL variable light chain domain
  • the binding site or binding sites binding to ANG-2 comprise a variable heavy chain domain VH of SEQ ID NO: 16, and a variable light chain domain VL of SEQ ID NO : 5 ;
  • the binding site or binding sites binding to VEGF comprise a variable heavy chain domain VH of SEQ ID NO: 6, and a variable light chain domain VL of SEQ ID NO: 7 (corresponding to the VH and VL domains of ⁇ VEGF> B20.4.1); and
  • variable domain amino acid sequences (a) variable heavy chain domain VH of SEQ ID NO: 12, and variable light chain domain VL of SEQ ID NO: 13 (corresponding to the VH and VL domains of ⁇ PD-1> nivolumab), or (b) variable heavy chain domain VH of SEQ ID NO: 14, and variable light chain domain VL of SEQ ID NO: 15 (corresponding to the VH and VL domains of ⁇ PD-1> pembrolizumab) .
  • the binding site or binding sites binding to ANG-2 comprise a variable heavy chain domain VH of SEQ ID NO: 16, and a variable light chain domain VL of SEQ ID NO: 5; and b) the binding site or binding sites binding to VEGF comprise a variable heavy chain domain VH of SEQ ID NO: 6, and a variable light chain domain VL of SEQ ID NO: 7 (corresponding to the VH and VL domains of ⁇ VEGF> B20.4.1); and
  • variable domain amino acid sequences variable heavy chain domain VH of SEQ ID NO: 10, and variable light chain domain VL of SEQ ID NO: 11 (corresponding to the VH and VL domains of ⁇ PD-1> "iTME-0006-0002").
  • the antibodies are for administration in a combination therapy with an antibody that binds to PD-1.
  • variable domain amino acid sequences variable heavy chain domain VH of SEQ ID NO:4, and variable light chain domain VL of SEQ ID NO: 5 (corresponding to the VH and VL domains of ⁇ ANG-2> LC06).
  • variable domain amino acid sequences variable heavy chain domain VH of SEQ ID NO: 16, and the variable light chain domain VL of SEQ ID NO: 5 (corresponding to the VH and VL domains of ⁇ ANG-2> E6Q).
  • variable domain amino acid sequences (a) variable heavy chain domain VH of SEQ ID NO: 12, and variable light chain domain VL of SEQ ID NO: 13 (corresponding to the VH and VL domains of ⁇ PD-1> nivolumab), or (b) variable heavy chain domain VH of SEQ ID NO: 14, and variable light chain domain VL of SEQ ID NO: 15 (corresponding to the VH and VL domains of ⁇ PD-1> pembrolizumab).
  • variable domain amino acid sequences variable heavy chain domain VH of SEQ ID NO: 8, and variable light chain domain VL of SEQ ID NO: 9 (corresponding to the VH and VL domains of ⁇ VEGF> bevacizumab).
  • the binding site or binding sites binding to ANG-2 comprise a variable heavy chain domain VH of SEQ ID NO: 16, and a variable light chain domain VL of SEQ ID NO: 5;
  • the binding site or binding sites binding to VEGF comprise a variable heavy chain domain VH of SEQ ID NO: 8, and a variable light chain domain VL of SEQ ID NO: 9 (corresponding to the VH and VL domains of ⁇ VEGF> bevacizumab).
  • the binding site or binding sites binding to ANG-2 comprise a variable heavy chain domain VH of SEQ ID NO: 16, and a variable light chain domain VL of SEQ ID NO: 5;
  • the binding site or binding sites binding to VEGF comprise a variable heavy chain domain VH of SEQ ID NO: 8, and variable light chain domain VL of SEQ ID NO: 9 (corresponding to the VH and VL domains of ⁇ VEGF> bevacizumab); and
  • variable domain amino acid sequences (a) variable heavy chain domain VH of SEQ ID NO: 12, and variable light chain domain VL of SEQ ID NO: 13 (corresponding to the VH and VL domains of ⁇ PD-1> nivolumab), or (b) variable heavy chain domain VH of SEQ ID NO: 14, and variable light chain domain VL of SEQ ID NO: 15 (corresponding to the VH and VL domains of ⁇ PD-1> pembrolizumab) .
  • variable domain amino acid sequences variable heavy chain domain VH of SEQ ID NO: 10, and variable light chain domain VL of SEQ ID NO: 11 (corresponding to the VH and VL domains of ⁇ PD-1> "iTME-0006-0002").
  • variable domain amino acid sequences variable heavy chain domain VH of SEQ ID NO: 6, and variable light chain domain VL of SEQ ID NO: 7 (corresponding to the VH and VL domains of ⁇ VEGF> B20.4.1).
  • the binding site or binding sites binding to ANG-2 comprise a variable heavy chain domain VH of SEQ ID NO: 16, and a variable light chain domain VL of SEQ ID NO: 5;
  • the binding site or binding sites binding to VEGF comprise a variable heavy chain domain VH of SEQ ID NO: 6, and a variable light chain domain VL of SEQ ID NO: 7 (corresponding to the VH and VL domains of ⁇ VEGF> B20.4.1).
  • the binding site or binding sites binding to ANG-2 comprise a variable heavy chain domain VH of SEQ ID NO: 16, and a variable light chain domain VL of SEQ ID NO: 5;
  • the binding site or binding sites binding to VEGF comprise a variable heavy chain domain VH of SEQ ID NO: 6, and a variable light chain domain VL of SEQ ID NO: 7 (corresponding to the VH and VL domains of ⁇ VEGF> B20.4.1); and
  • variable domain amino acid sequences (a) variable heavy chain domain VH of SEQ ID NO: 12, and variable light chain domain VL of SEQ ID NO: 13 (corresponding to the VH and VL domains of ⁇ PD-1> nivolumab), or (b) variable heavy chain domain VH of SEQ ID NO: 14, and variable light chain domain VL of SEQ ID NO: 15 (corresponding to the VH and VL domains of ⁇ PD-1> pembrolizumab) .
  • the binding site or binding sites binding to ANG-2 comprise a variable heavy chain domain VH of SEQ ID NO: 16, and a variable light chain domain VL of SEQ ID NO: 5;
  • the binding site or binding sites binding to VEGF comprise a variable heavy chain domain VH of SEQ ID NO: 6, and a variable light chain domain VL of SEQ ID NO: 7 (corresponding to the VH and VL domains of ⁇ VEGF> B20.4.1); and
  • variable domain amino acid sequences variable heavy chain domain VH of SEQ ID NO: 10, and variable light chain domain VL of SEQ ID NO: 11 (corresponding to the VH and VL domains of ⁇ PD-1> "iTME-0006-0002").
  • a pharmaceutical composition comprising an antibody that binds to ANG-2, and an antibody that binds to PD-1, wherein each antibody is formulated together with a pharmaceutically acceptable carrier.
  • a pharmaceutical composition comprising an antibody that binds to ANG-2, an antibody that binds to VEGF, and an antibody that binds to PD-1, wherein each antibody is formulated together with a pharmaceutically acceptable carrier
  • variable domain amino acid sequences variable heavy chain domain VH of SEQ ID NO:4, and variable light chain domain VL of SEQ ID NO: 5 (corresponding to the VH and VL domains of ⁇ ANG-2> LC06).
  • variable domain amino acid sequences variable heavy chain domain VH of SEQ ID NO: 16, and the variable light chain domain VL of SEQ ID NO: 5 (corresponding to the VH and VL domains of ⁇ ANG-2> E6Q).
  • variable domain amino acid sequences (a) variable heavy chain domain VH of SEQ ID NO: 12, and variable light chain domain VL of SEQ ID NO: 13 (corresponding to the VH and VL domains of ⁇ PD-1> nivolumab), or (b) variable heavy chain domain VH of SEQ ID NO: 14, and variable light chain domain VL of SEQ ID NO: 15 (corresponding to the VH and VL domains of ⁇ PD-1> pembrolizumab).
  • variable heavy chain domain VH of SEQ ID NO: 12 and variable light chain domain VL of SEQ ID NO: 13 (corresponding to the VH and VL domains of ⁇ PD-1> nivolumab)
  • variable heavy chain domain VH of SEQ ID NO: 14 and variable light chain domain VL of SEQ ID NO: 15 (corresponding to the VH and VL domains of ⁇ PD-1> pembrolizumab).
  • variable domain amino acid sequences variable heavy chain domain VH of SEQ ID NO: 8, and variable light chain domain VL of SEQ ID NO: 9
  • variable domain amino acid sequences wherein the antibody that binds to ANG-2 and VEGF comprises the following variable domain amino acid sequences:
  • the binding site or binding sites binding to ANG-2 comprise a variable heavy chain domain VH of SEQ ID NO: 16, and a variable light chain domain VL of SEQ ID NO: 5;
  • the binding site or binding sites binding to VEGF comprise a variable heavy chain domain VH of SEQ ID NO: 8, and a variable light chain domain VL of SEQ ID NO: 9 (corresponding to the VH and VL domains of ⁇ VEGF> bevacizumab).
  • composition according to any one of embodiments 91 to 105, wherein the antibody that binds to ANG-2 and VEGF comprises the following variable domain amino acid sequences:
  • the binding site or binding sites binding to ANG-2 comprise a variable heavy chain domain VH of SEQ ID NO: 16, and a variable light chain domain VL of SEQ ID NO: 5;
  • the binding site or binding sites binding to VEGF comprise a variable heavy chain domain VH of SEQ ID NO: 8, and variable light chain domain VL of SEQ ID NO: 9 (corresponding to the VH and VL domains of ⁇ VEGF> bevacizumab); and
  • variable domain amino acid sequences (a) variable heavy chain domain VH of SEQ ID NO:
  • variable light chain domain VL of SEQ ID NO: 12 and variable light chain domain VL of SEQ ID NO: 13 (corresponding to the VH and VL domains of ⁇ PD-1> nivolumab), or (b) variable heavy chain domain VH of SEQ ID NO: 14, and variable light chain domain VL of SEQ ID NO: 15 (corresponding to the VH and VL domains of ⁇ PD- 1 > pembrolizumab) .
  • variable domain amino acid sequences variable heavy chain domain VH of SEQ ID NO: 10, and variable light chain domain VL of SEQ ID NO: 11 (corresponding to the VH and VL domains of ⁇ PD-1> "iTME-0006-0002").
  • variable domain amino acid sequences variable heavy chain domain VH of SEQ ID NO: 6, and variable light chain domain VL of SEQ ID NO: 7 (corresponding to the VH and VL domains of ⁇ VEGF> B20.4.1).
  • variable domain amino acid sequences a variable domain amino acid sequence a variable domain amino acid sequence a variable domain amino acid sequence a variable domain amino acid sequence a:
  • the binding site or binding sites binding to ANG-2 comprise a variable heavy chain domain VH of SEQ ID NO: 16, and a variable light chain domain VL of SEQ ID NO : 5 ;
  • the binding site or binding sites binding to VEGF comprise a variable heavy chain domain VH of SEQ ID NO: 6, and a variable light chain domain VL of SEQ ID NO: 7 (corresponding to the VH and VL domains of ⁇ VEGF> B20.4.1).
  • composition according to any one of embodiments 91 to 102 and 108, wherein the antibody that binds to ANG-2 and VEGF comprises the following variable domain amino acid sequences:
  • the binding site or binding sites binding to ANG-2 comprise a variable heavy chain domain VH of SEQ ID NO: 16, and a variable light chain domain VL of SEQ ID NO: 5;
  • the binding site or binding sites binding to VEGF comprise a variable heavy chain domain VH of SEQ ID NO: 6, and a variable light chain domain VL of SEQ ID NO: 7 (corresponding to the VH and VL domains of ⁇ VEGF> B20.4.1); and
  • variable domain amino acid sequences (a) variable heavy chain domain VH of SEQ ID NO: 12, and variable light chain domain VL of SEQ ID NO: 13 (corresponding to the VH and VL domains of ⁇ PD-1> nivolumab), or (b) variable heavy chain domain VH of SEQ ID NO: 14, and variable light chain domain VL of SEQ ID NO: 15 (corresponding to the VH and VL domains of ⁇ PD-1> pembrolizumab).
  • the binding site or binding sites binding to ANG-2 comprise a variable heavy chain domain VH of SEQ ID NO: 16, and a variable light chain domain VL of SEQ ID NO: 5;
  • the binding site or binding sites binding to VEGF comprise a variable heavy chain domain VH of SEQ ID NO: 6, and a variable light chain domain VL of SEQ ID NO: 7 (corresponding to the VH and VL domains of ⁇ VEGF> B20.4.1); and
  • variable domain amino acid sequences variable heavy chain domain VH of SEQ ID NO: 10, and variable light chain domain VL of SEQ ID NO: 11 (corresponding to the VH and VL domains of ⁇ PD-1> "iTME-0006-0002").
  • a method for the manufacture of a pharmaceutical composition comprising (a) formulating an antibody that binds to ANG-2 with a pharmaceutically acceptable carrier, and (b) formulating separately an antibody that binds to PD-1 with a pharmaceutically acceptable carrier.
  • a method for the manufacture of a pharmaceutical composition comprising formulating an antibody that binds to ANG-2 together with an antibody that binds to PD-1 in combination with a pharmaceutically acceptable carrier.
  • a method for the manufacture of a pharmaceutical composition comprising (a) formulating an antibody that binds to ANG-2 with a pharmaceutically acceptable carrier, (b) formulating separately an antibody that binds to VEGF with a pharmaceutically acceptable carrier and (c) formulating separately an antibody that binds to PD-1 with a pharmaceutically acceptable carrier.
  • a method for the manufacture of a pharmaceutical composition comprising (a) formulating an antibody that binds to ANG-2 together with an antibody that binds to VEGF in combination with a pharmaceutically acceptable carrier, and (b) formulating separately an antibody that binds to PD-1 with a pharmaceutically acceptable carrier.
  • a method for the manufacture of a pharmaceutical composition comprising formulating an antibody that binds to ANG-2 together with an antibody that binds to VEGF and together with an antibody that binds to PD-1 in combination with a pharmaceutically acceptable carrier.
  • a method for the manufacture of a pharmaceutical composition comprising (a) formulating an antibody that binds to ANG-2 and VEGF with a pharmaceutically acceptable carrier, and (b) formulating separately an antibody that binds to PD-1 with a pharmaceutically acceptable carrier.
  • a method for the manufacture of a pharmaceutical composition comprising formulating an antibody that binds to ANG-2 and VEGF together with an antibody that binds to PD-1 in combination with a pharmaceutically acceptable carrier.
  • variable domain amino acid sequences variable heavy chain domain VH of SEQ ID NO:4, and variable light chain domain VL of SEQ ID NO: 5 (corresponding to the VH and VL domains of ⁇ ANG-2> LC06).
  • variable domain amino acid sequences variable heavy chain domain VH of SEQ ID NO: 16, and the variable light chain domain VL of SEQ ID NO: 5 (corresponding to the VH and VL domains of ⁇ ANG-2> E6Q).
  • variable domain amino acid sequences (a) variable heavy chain domain VH of SEQ ID NO: 12, and variable light chain domain VL of SEQ ID NO: 13 (corresponding to the VH and VL domains of ⁇ PD-1> nivolumab), or (b) variable heavy chain domain VH of SEQ ID NO: 14, and variable light chain domain VL of SEQ ID NO: 15 (corresponding to the VH and VL domains of ⁇ PD-1> pembrolizumab).
  • variable domain amino acid sequences variable heavy chain domain VH of SEQ ID NO: 8, and variable light chain domain VL of SEQ ID NO: 9 (corresponding to the VH and VL domains of ⁇ VEGF> bevacizumab).
  • variable heavy chain domain VH of SEQ ID NO: 8 variable heavy chain domain
  • VL of SEQ ID NO: 9 variable light chain domain
  • the binding site or binding sites binding to ANG-2 comprise a variable heavy chain domain VH of SEQ ID NO: 16, and a variable light chain domain VL of SEQ ID NO: 5;
  • the binding site or binding sites binding to VEGF comprise a variable heavy chain domain VH of SEQ ID NO: 8, and a variable light chain domain VL of SEQ ID NO: 9 (corresponding to the VH and VL domains of ⁇ VEGF> bevacizumab).
  • the binding site or binding sites binding to ANG-2 comprise a variable heavy chain domain VH of SEQ ID NO: 16, and a variable light chain domain VL of SEQ ID NO: 5;
  • the binding site or binding sites binding to VEGF comprise a variable heavy chain domain VH of SEQ ID NO: 8, and variable light chain domain VL of SEQ ID NO: 9 (corresponding to the VH and VL domains of ⁇ VEGF> bevacizumab); and
  • variable domain amino acid sequences (a) variable heavy chain domain VH of SEQ ID NO: 12, and variable light chain domain VL of SEQ ID NO: 13 (corresponding to the VH and VL domains of ⁇ PD-1> nivolumab), or (b) variable heavy chain domain VH of SEQ ID NO: 14, and variable light chain domain VL of SEQ ID NO: 15 (corresponding to the VH and VL domains of ⁇ PD-1> pembrolizumab).
  • variable domain amino acid sequences variable heavy chain domain VH of SEQ ID NO: 10, and variable light chain domain VL of SEQ ID NO: 11 (corresponding to the VH and VL domains of ⁇ PD-1> "iTME-0006-0002").
  • variable domain amino acid sequences variable heavy chain domain VH of SEQ ID NO: 6, and variable light chain domain VL of SEQ ID NO: 7 (corresponding to the VH and VL domains of ⁇ VEGF> B20.4.1).
  • the binding site or binding sites binding to ANG-2 comprise a variable heavy chain domain VH of SEQ ID NO: 16, and a variable light chain domain VL of SEQ ID NO: 5;
  • the binding site or binding sites binding to VEGF comprise a variable heavy chain domain VH of SEQ ID NO: 6, and a variable light chain domain VL of SEQ ID NO: 7 (corresponding to the VH and VL domains of ⁇ VEGF> B20.4.1).
  • the binding site or binding sites binding to ANG-2 comprise a variable heavy chain domain VH of SEQ ID NO: 16, and a variable light chain domain VL of SEQ ID NO: 5;
  • the binding site or binding sites binding to VEGF comprise a variable heavy chain domain VH of SEQ ID NO: 6, and a variable light chain domain VL of SEQ ID NO: 7 (corresponding to the VH and VL domains of ⁇ VEGF> B20.4.1); and
  • variable domain amino acid sequences (a) variable heavy chain domain VH of SEQ ID NO: 12, and variable light chain domain VL of SEQ ID NO: 13 (corresponding to the VH and VL domains of ⁇ PD-1> nivolumab), or (b) variable heavy chain domain VH of SEQ ID NO: 14, and variable light chain domain VL of SEQ ID NO: 15 (corresponding to the VH and VL domains of ⁇ PD-1> pembrolizumab).
  • the binding site or binding sites binding to ANG-2 comprise a variable heavy chain domain VH of SEQ ID NO: 16, and a variable light chain domain VL of SEQ ID NO: 5; and b) the binding site or binding sites binding to VEGF comprise a variable heavy chain domain VH of SEQ ID NO: 6, and a variable light chain domain VL of SEQ ID NO: 7 (corresponding to the VH and VL domains of ⁇ VEGF> B20.4.1); and
  • variable domain amino acid sequences variable heavy chain domain VH of SEQ ID NO: 10, and variable light chain domain VL of SEQ ID NO: 11 (corresponding to the VH and VL domains of ⁇ PD-1> "iTME-0006-0002").
  • An article of manufacture comprising (a) a container, a composition within the container comprising an antibody that binds to ANG-2, and (b) a package insert instructing the user of the composition to administer the antibody that binds to ANG-2 to a patient
  • An article of manufacture comprising (a) a container, a composition within the container comprising an antibody that binds to ANG-2, and (b) a package insert instructing the user of the composition to administer the antibody that binds to ANG-2 to a patient
  • the administration of the antibody that binds to ANG-2 is in a combination therapy with an antibody that binds to VEGF and an antibody that binds to PD-1.
  • An article of manufacture comprising (a) a container, a composition within the container comprising an antibody that binds to PD-1, and (b) a package insert instructing the user of the composition to administer the antibody that binds to PD-1 to a patient
  • An article of manufacture comprising (a) a container, a composition within the container comprising an antibody that binds to PD-1, and (b) a package insert instructing the user of the composition to administer the antibody that binds to PD-1 to a patient
  • the administration of the antibody that binds to PD-1 is in a combination therapy with an antibody that binds to ANG-2 and an antibody that binds to VEGF.
  • An article of manufacture comprising (a) a container, a composition within the container comprising an antibody that binds to VEGF, and (b) a package insert instructing the user of the composition to administer the antibody that binds to VEGF to a patient
  • the administration of the antibody that binds to VEGF is in a combination therapy with an antibody that binds to ANG-2 and an antibody that binds to PD-1.
  • An article of manufacture comprising (a) a container, a composition within the container comprising an antibody that binds to ANG-2, and (b) a container, a composition within the container comprising an antibody that binds to PD-1, and (c) a package insert instructing the user of the composition to administer the antibody that binds to ANG-2 and the antibody that binds to PD-1 to a patient
  • An article of manufacture comprising (a) a container, a composition within the container comprising an antibody that binds to ANG-2, and (b) a container, a composition within the container comprising an antibody that binds to PD-1, and (c) a package insert instructing the user of the composition to administer the antibody that binds to ANG-2 and the antibody that binds to PD-1 to a patient
  • An article of manufacture comprising (a) a container, a composition within the container comprising an antibody that binds to ANG-2, and (b) a container, a composition within the container comprising an antibody that binds to VEGF, and (c) a package insert instructing the user of the composition to administer the antibody that binds to ANG-2 and the antibody that binds to VEGF to a patient
  • the article of manufacture according to embodiment 137 comprising a container, a composition within said container comprising the antibody that binds to ANG-2 and the antibody that binds to VEGF.
  • the article of manufacture according to embodiment 137 or 138 comprising a container, a composition within said container comprising the antibody that binds to ANG-2 and the antibody that binds to VEGF in the form of an antibody that binds to ANG-2 and to VEGF.
  • 140 The article of manufacture according to embodiment 139, comprising a container, a composition within said container comprising the antibody that binds to ANG-2 and the antibody that binds to VEGF in the form of a bispecific antibody that binds to ANG-2 and to VEGF.
  • An article of manufacture comprising (a) a container, a composition within the container comprising an antibody that binds to ANG-2, and (b) container, a composition within the container comprising an antibody that binds to VEGF, and (c) a container, a composition within the container comprising an antibody that binds to PD-1, and (d) a package insert instructing the user of the composition to administer the antibodies that bind to ANG-2, VEGF, and PD-1, respectively, in a combination therapy to a patient
  • the article of manufacture according to embodiment 141 comprising a container, a composition within said container comprising the antibody that binds to ANG-2 and the antibody that binds to VEGF.
  • the article of manufacture according to embodiment 141 or 142 comprising a container, a composition within said container comprising the antibody that binds to ANG-2 and the antibody that binds to VEGF in the form of an antibody that binds to ANG-2 and to VEGF.
  • the article of manufacture according to embodiment 143 comprising a container, a composition within said container comprising the antibody that binds to ANG-2 and the antibody that binds to VEGF in the form of a bispecific antibody that binds to ANG-2 and to VEGF.
  • the cancer is selected from the group of lung cancer, non small cell lung (NSCL) cancer, bronchioloalviolar cell lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, gastric cancer, colon cancer, breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, cancer of the bladder, cancer of the kidney or ureter, renal
  • variable light chain domain VL of SEQ ID NO: 5 (corresponding to the VH and VL domains of ⁇ ANG-2> LC06).
  • variable domain amino acid sequences variable heavy chain domain VH of SEQ ID NO: 16, and the variable light chain domain VL of SEQ ID NO: 5 (corresponding to the VH and VL domains of ⁇ ANG-2> E6Q).
  • variable domain amino acid sequences (a) variable heavy chain domain VH of SEQ ID NO: 12, and variable light chain domain VL of SEQ ID NO: 13 (corresponding to the VH and VL domains of ⁇ PD-1> nivolumab), or (b) variable heavy chain domain VH of SEQ ID NO: 14, and variable light chain domain VL of SEQ ID NO: 15 (corresponding to the VH and VL domains of ⁇ PD-1> pembrolizumab).
  • variable domain amino acid sequences variable heavy chain domain VH of SEQ ID NO: 8, and variable light chain domain VL of SEQ ID NO: 9 (corresponding to the VH and VL domains of ⁇ VEGF> bevacizumab).
  • the binding site or binding sites binding to ANG-2 comprise a variable heavy chain domain VH of SEQ ID NO: 16, and a variable light chain domain VL of SEQ ID NO: 5;
  • the binding site or binding sites binding to VEGF comprise a variable heavy chain domain VH of SEQ ID NO: 8, and a variable light chain domain VL of SEQ ID NO: 9 (corresponding to the VH and VL domains of ⁇ VEGF> bevacizumab).
  • the binding site or binding sites binding to ANG-2 comprise a variable heavy chain domain VH of SEQ ID NO: 16, and a variable light chain domain VL of SEQ ID NO: 5;
  • the binding site or binding sites binding to VEGF comprise a variable heavy chain domain VH of SEQ ID NO: 8, and variable light chain domain VL of SEQ ID NO: 9 (corresponding to the VH and VL domains of ⁇ VEGF> bevacizumab); and
  • variable domain amino acid sequences (a) variable heavy chain domain VH of SEQ ID NO: 12, and variable light chain domain VL of SEQ ID NO: 13 (corresponding to the VH and VL domains of ⁇ PD-1> nivolumab), or (b) variable heavy chain domain VH of SEQ ID NO: 14, and variable light chain domain VL of SEQ ID NO: 15 (corresponding to the VH and VL domains of ⁇ PD-1> pembrolizumab).
  • variable domain amino acid sequences variable heavy chain domain VH of SEQ ID NO: 10, and variable light chain domain VL of SEQ ID NO: 11 (corresponding to the VH and VL domains of ⁇ PD-1> "iTME-0006-0002").
  • variable domain amino acid sequences variable heavy chain domain VH of SEQ ID NO: 6, and variable light chain domain VL of SEQ ID NO: 7 (corresponding to the VH and VL domains of ⁇ VEGF> B20.4.1).
  • variable heavy chain domain VH of SEQ ID NO: 6 variable heavy chain domain
  • VL of SEQ ID NO: 7 variable light chain domain
  • the binding site or binding sites binding to ANG-2 comprise a variable heavy chain domain VH of SEQ ID NO: 16, and a variable light chain domain VL of SEQ ID NO : 5 ;
  • the binding site or binding sites binding to VEGF comprise a variable heavy chain domain VH of SEQ ID NO: 6, and a variable light chain domain VL of SEQ ID NO: 7 (corresponding to the VH and VL domains of ⁇ VEGF> B20.4.1).
  • the binding site or binding sites binding to ANG-2 comprise a variable heavy chain domain VH of SEQ ID NO: 16, and a variable light chain domain VL of SEQ ID NO: 5;
  • the binding site or binding sites binding to VEGF comprise a variable heavy chain domain VH of SEQ ID NO: 6, and a variable light chain domain VL of SEQ ID NO: 7 (corresponding to the VH and VL domains of ⁇ VEGF> B20.4.1); and
  • variable domain amino acid sequences (a) variable heavy chain domain VH of SEQ ID NO: 12, and variable light chain domain VL of SEQ ID NO: 13 (corresponding to the VH and VL domains of ⁇ PD-1> nivolumab), or (b) variable heavy chain domain VH of SEQ ID NO: 14, and variable light chain domain VL of SEQ ID NO: 15 (corresponding to the VH and VL domains of ⁇ PD-1> pembrolizumab).
  • the binding site or binding sites binding to ANG-2 comprise a variable heavy chain domain VH of SEQ ID NO: 16, and a variable light chain domain VL of SEQ ID NO: 5;
  • the binding site or binding sites binding to VEGF comprise a variable heavy chain domain VH of SEQ ID NO: 6, and a variable light chain domain VL of SEQ ID NO: 7 (corresponding to the VH and VL domains of ⁇ VEGF> B20.4.1); and
  • variable domain amino acid sequences variable heavy chain domain VH of SEQ ID NO: 10, and variable light chain domain VL of SEQ ID NO: 11 (corresponding to the VH and VL domains of ⁇ PD-1> "iTME-0006-0002").
  • SEQ ID NO:2 human vascular endothelial growth factor
  • variable heavy chain domain VH of ⁇ ANG-2> E6Q which is a variant of ⁇ ANG-2> LC06 with an E6Q mutation
  • VEGF 6 VEGF: 7
  • a monospecific antibody that binds to ANG-2 was used, which is ⁇ ANG-2> LC06, of IgGl isotype, comprising the VH and VL domain amino acid sequences as indicated above.
  • a bispecific antibody that binds to ANG-2 and VEGF within the experiments, an ANG-2 binding site of ⁇ ANG-2> E6Q was used, which was derived from ⁇ ANG-2> LC06. Both binding sites (i.e. VH and VL domains) differ in only one amino acid mutation at position 6 (i.e. an E6Q substitution) in the VH domain.
  • Heavy chain and light chain amino acid sequences of the bispecific antibody binding to ANG-2 and VEGF used in this experiment are indicated in Table lb.
  • VEGF binding site of the anti-human- VEGF antibody bevacizumab is not mouse-crossreactive.
  • a mouse-crossreactive surrogate antibody herein referred to as
  • ⁇ VEGF> B20-4.1 was used for the in vivo experiments.
  • the surrogate antibody was generated by replacing only the VH and VL domains of bevacizumab by the mouse-crossreactive VEGF-binding VH and VL domains of ⁇ VEGF> B20-4.1.
  • the bispecific antibody that binds to ANG-2 and VEGF used in the experiment comprised the binding arm of ⁇ VEGF> B20-4.1 for the same reason.
  • the corresponding bispecific antibody including the VH and VL domains of bevacizumab is the antibody referred to herein as ⁇ ANG-2/VEGF> E6Q/bevacizumab (which is, e.g., disclosed in WO 2011/117329 as antibody "xMabl").
  • an anti-PD-1 mouse-crossreactive surrogate antibody was used within the experiments, which is referred to herein as ⁇ PD-1> iTME-0006-0002.
  • This heavy chain of antibody ⁇ PD-1> iTME-0006-0002 was of of SEQ ID NO: 23 and the light chain was of SEQ ID NO: 24.
  • the experiments as decribed herein use (non-humanized) Balb/c mice.
  • IC50 of antibody ⁇ ANG-2> LC06 as determined by A G-2 / Tie2 interaction ELISA
  • the interaction ELISA was performed on 384 well microtiter plates (MicroCoat, DE, Cat.No. 464718) at RT. After each incubation step plates were washed 3 times with PBST. ELISA plates were coated with 5 ⁇ g/ml Tie-2 protein for 1 hour (h). Thereafter the wells were blocked with PBS supplemented with 0.2% Tween-20 and 2% BSA (Roche Diagnostics GmbH, DE) for 1 h. Dilutions of purified bispecific Xmab antibodies in PBS were incubated together with 0.2 ⁇ g/ml huAngiopoietin-2 (R&D Systems, UK, Cat.No. 623 -AN) for 1 h at RT.
  • Test agents Indicated antibodies were generated at Roche Diagnostics GmbH, Penzberg, Germany.
  • Antibody buffer included 20 mM histidine and 140 mM sodium chloride (pH 6.0). Antibody solutions were diluted appropriately in the above mentioned buffer from stock prior to administrations.
  • Cell lines and culture conditions The murine CT26WT cell line was routinely cultured in RPMI 1640 supplemented with 10% fetal bovine serum (PAA Laboratories, Austria) and 2 mM L-glutamine at 37°C in a water-saturated atmosphere at 5% C0 2 .
  • mice Female Balb/c mice aged 6-7 weeks at arrival (purchased from Charles River, Sulzfeld, Germany) were maintained under specific-pathogen- free condition with daily cycles of 12 h light / 12 h darkness according to committed guidelines (GV-Solas; Felasa; TierschG). Experimental study protocol was reviewed and approved by local government (Reg michigan von Oberbayern; registration no. 55.2-1- 54-2531.2-32-10). After arrival animals were maintained in the animal facility for one week to get accustomed to new environment and for observation. Continuous health monitoring was carried out on regular basis. Diet food (Altromin) and water (filtered) were provided ad libitum.
  • Tumor cell inoculation The mice were s.c. injected with 1.000.000 syngeneic CT26WT tumor cells and treatment began on day 10 when tumors reached a size of about 85 mm 3 .
  • MOPC-21 antibody As a negative control, MOPC-21 antibody ("MOPC", a mouse IgGl; Bio X Cell, West Lebanon) was used. Comparative analyses included the administration of monospecific antibodies ⁇ ANG-2>LC06, ⁇ PD-1> iTME-0006-0002, ⁇ VEGF> B20.4.1, bispecific antibody ⁇ ANG-2/VEGF> E6Q/B20.4.1, and a combination therapy of antibodies ⁇ VEGF> B20.4.1 with ⁇ PD-1> iTME-0006-0002.
  • mice were euthanized according to veterinary regulations when tumors reached a size of 1200 mm 3 (endpoint). Following dosages and treatment schedules have been applied (all antibodies were applied intraperitoneally):
  • Results of tumor growth inhibition of the treated individuals are shown in Figures 1 and 2, and results showing the overall survival of the treated individuals are indicated in Figure 3.
  • the data indicate that treatment with a combination therapy of antibodies that bind to PD-1 and ANG-2 prolonged the overall survival prominently when compared to the control group, as well as the groups treated with a monotherapy of anti-ANG2, anti-VEGF or the bispecific anti-ANG2/VEGF antibody.
  • the median time-to-event i.e. when the individuals reached a tumor volume of 1200 mm 3
  • the combination therapy of anti- ANG-2 and anti-PD-1 was 43 days compared to 25 days within the control group. Both animals that survived under the combination therapy of anti-ANG-2 and anti-PD-1 were tumor free at day 89.
  • the median time-to-event in this group was >89 days, with 4 of the 5 remaining animals (day 89) being tumor free upon treatment.

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Abstract

La présente invention concerne une polythérapie d'un anticorps se liant de manière spécifique à l'angiopoïétine 2 (ANG-2) avec un anticorps se liant de manière spécifique au polypeptide de mort programmée 1 (PD-1). Selon un mode de réalisation, l'invention concerne une polythérapie d'un anticorps se liant de manière spécifique à l'angiopoïétine 2 (ANG-2), et d'un anticorps se liant de manière spécifique à VEGF avec un anticorps se liant de manière spécifique au polypeptide de mort programmée 1 (PD-1).
PCT/EP2016/058869 2015-04-23 2016-04-21 Polythérapie d'anticorps se liant à l'angiopoïétine 2 avec un anticorps se liant au polypeptide de mort programmée 1 WO2016170039A1 (fr)

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US11155610B2 (en) 2014-06-28 2021-10-26 Kodiak Sciences Inc. Dual PDGF/VEGF antagonists
US10513558B2 (en) 2015-07-13 2019-12-24 Cytomx Therapeutics, Inc. Anti-PD1 antibodies, activatable anti-PD1 antibodies, and methods of use thereof
US11066465B2 (en) 2015-12-30 2021-07-20 Kodiak Sciences Inc. Antibodies and conjugates thereof
US11498977B2 (en) 2016-09-29 2022-11-15 Beijing Hanmi Pharmaceutical Co., Ltd. Heterodimeric immunoglobulin constructs and preparation methods thereof
US11319378B2 (en) 2016-11-18 2022-05-03 Beijing Hanmi Pharmaceutical Co., Ltd. Anti-PD-1/anti-HER2 natural antibody structural heterodimeric bispecific antibody and method of preparing the same
JP2020521797A (ja) * 2017-06-02 2020-07-27 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング 抗がん剤組み合わせ治療
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CN110691790A (zh) * 2017-06-02 2020-01-14 勃林格殷格翰国际有限公司 抗癌联合治疗
CN109963592A (zh) * 2017-06-05 2019-07-02 江苏恒瑞医药股份有限公司 Pd-1抗体与vegf配体或vegf受体抑制剂联合在制备治疗肿瘤的药物中的用途
WO2019028012A3 (fr) * 2017-07-31 2019-02-28 Dana-Farber Cancer Institute, Inc. Procédés d'utilisation de pembrolizumab et de trébananib
US11753471B2 (en) 2018-02-08 2023-09-12 Beijing Hanmi Pharmaceutical Co., Ltd. Anti-PD-1/anti-HER2 natural antibody structural heterodimeric bispecific antibody and method of preparing same
WO2019154349A1 (fr) * 2018-02-11 2019-08-15 北京韩美药品有限公司 Anticorps bispécifique à forme hétérodimère de type similaire à une structure d'anticorps naturel anti-pd-1/anti-vegf et préparation associée
CN111712522A (zh) * 2018-02-11 2020-09-25 北京韩美药品有限公司 抗pd-1/抗vegf天然抗体结构样异源二聚体形式双特异抗体及其制备
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US11912784B2 (en) 2019-10-10 2024-02-27 Kodiak Sciences Inc. Methods of treating an eye disorder
WO2023042202A1 (fr) * 2021-09-14 2023-03-23 Yeda Research And Development Co. Ltd. Anticorps multispécifiques destinés à être utilisés dans le traitement de maladies
WO2023087344A1 (fr) * 2021-11-22 2023-05-25 杭州翰思生物医药有限公司 Anticorps recombinant et son utilisation

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