WO2017102789A1 - Polythérapie à base d'anticorps anti-her3 et d'anticorps anti-her2 - Google Patents

Polythérapie à base d'anticorps anti-her3 et d'anticorps anti-her2 Download PDF

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WO2017102789A1
WO2017102789A1 PCT/EP2016/080890 EP2016080890W WO2017102789A1 WO 2017102789 A1 WO2017102789 A1 WO 2017102789A1 EP 2016080890 W EP2016080890 W EP 2016080890W WO 2017102789 A1 WO2017102789 A1 WO 2017102789A1
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antibody
her2
her3
human
seq
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PCT/EP2016/080890
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Birgit Bossenmaier
Maurizio CEPPI
Max Hasmann
Martin Weisser
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F. Hoffmann-La Roche Ag
Hoffmann-La Roche Inc.
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Definitions

  • the present invention relates to the combination therapy of anti-HER3 antibodies and anti-HER2 antibodies, in patients suffering from a HER2 low, HER3 positive and hormone receptor (HR) positive breast cancer including dose schedules and additional therapies.
  • HR hormone receptor
  • Human HER3 encodes a member of the epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases which also includes HER1 (also known as EGFR), HER2, and HER4 (Kraus, M.H. et al, PNAS 86 (1989) 9193-9197; Plowman, G.D. et al, PNAS 87 (1990) 4905-4909; Kraus, M.H. et al,
  • the transmembrane receptor HER3 consists of an extracellular ligand- binding domain (ECD), a dimerization domain within the ECD, a transmembrane domain, an intracellular protein tyrosine kinase domain (TKD) and a C-terminal phosphorylation domain.
  • ECD extracellular ligand- binding domain
  • TKD transmembrane domain
  • HER3 has a heregulin (HRG) binding domain within the extracellular domain but its kinase domain is inactive. Therefore, when activated by binding of its ligand, HER3 can form heterodimers with other HER family members, but cannot transphosphorylate the partner protein.
  • HRG heregulin
  • heterodimerization of HER3 leads to the activation of the receptor-mediated signaling pathway through transphosphorylation of its intracellular domain by the dimerization partner. Dimer formation between HER family members expands the signaling potential of HER3 and is a means not only for signal diversification but also signal amplification.
  • the HER2/HER3 heterodimer induces one of the most important mitogenic signals via the PI3K and AKT pathway among HER family members (Sliwkowski M.X., et al, J. Biol. Chem. 269 (1994) 14661-14665;
  • WO 97/35885 relates to HER3 antibodies.
  • WO 2003/013602 relates to inhibitors of HER activity, including HER antibodies.
  • WO2012022814, WO2012031198, WO2012044612, WO2012052230, WO2012059858 relate to HER3 antibodies.
  • Human HER2 refers to 185-kDa growth factor receptor also referred to as neu and c-erbB-2 (Slamon, et al, Science 235 (1987) 177-182; Swiss-Prot P04626) whose function is related to neoplastic transformation in human breast cancer cells.
  • Overexpression of this protein has been identified in 20-30% of breast cancer patients where it correlates with regionally advanced disease, increased probability of tumor recurrence, and reduced patient survival. As many as 30-40% of patients having gastric, endometrial, salivary gland, non-small cell lung, pancreatic, ovarian, peritoneal, prostate, or colorectal cancers may also exhibit overexpression of this protein.
  • HER2 comprises four domains, Domain I (amino acid residues from about 1-195), Domain II (amino acid residues from about 196-320), Domain III (amino acid residues from about 321 488), and Domain IV (amino acid residues from about 489-632) (residue numbering without signal peptide).
  • Domain I amino acid residues from about 1-195
  • Domain II amino acid residues from about 196-320
  • Domain III amino acid residues from about 321 488
  • Domain IV amino acid residues from about 489-632
  • Trastuzumab (e.g. Herceptin®) is a recombinant humanized anti-HER2 monoclonal antibody used for the treatment of HER2 over-expressed/HER2 gene amplified metastatic breast cancer. Trastuzumab binds specifically to the same epitope of HER2 as the murine anti-HER2 antibody 4D5 described in Hudziak, et al., Mol. Cell. BioL 9 (1989) 1165-1172.
  • Trastuzumab is a recombinant humanized version of the murine anti-HER2 antibody 4D5, referred to as rhuMAb 4D5 or trastuzumab) and has been clinically active in patients with HER2-overexpressing metastatic breast cancers that had received extensive prior anticancer therapy. (Baselga, et al, J. Clin. Oncol. 14 (1996) 737-744). Trastuzumab and its method of preparation are described in US 5,821,337.
  • Pertuzumab is a recombinant humanized version of the murine anti- HER2 antibody 2C4 (referred to as rhuMAb 2C4 or pertuzumab) and it is described together with the respective method of preparation in WO 01/00245 and
  • epitope 2C4 is the region in the extracellular domain of HER2 to which the antibody 2C4 binds.
  • a routine cross-blocking assay such as that described in "Ed. Harlow and David Lane, Antibodies, A Laboratory Manual, Cold Spring Harbor Laboratory,
  • epitope mapping can be performed to assess whether the antibody binds to the 2C4 epitope of HER2 (e.g. any one or more residues in the region from about residue 22 to about residue 584 of HER2, inclusive).
  • Epitope 2C4 comprises residues from domain II in the extracellular domain of HER2.
  • 2C4 and pertuzumab bind to sub-domain II of the extracellular domain of HER2 near the junction of domains I, II and III. See also Franklin, et al., Cancer Cell 5 (2004) 317-328.
  • the invention relates to an antibody which binds to human HER3 for use in the treatment of breast cancer in combination with an antibody binding to human HER2 and inhibiting dimerization of HER2 , wherein the breast cancer is HER2 low, HER3 positive and HR (hormone receptor) positive.
  • the breast cancer is HER2 low, HER3 positive and ER (estrogen receptor) positive. embodiment additionally either
  • an anti-hormonal agent is co-administered , wherein the anti-hormonal agent is selected from the group of: a) a selective estrogen receptor degrader (SERD), like e.g. fulvestrant, or b) a selective estrogen receptor modulator (SERM); and such as
  • SESD selective estrogen receptor degrader
  • SERM selective estrogen receptor modulator
  • aromatase inhibitor is letrozole, anastrozole or exemestane
  • chemotherapeutic agent is selected from the group of: a) a taxane or taxane derivative b) cyclophosphamide, c) cisplatin or carboplatin d) mitomycin C, e) methotrexate, f) 5-fluorouracil or capecitabine, g) doxorubicin or its liposomal formulation, or daunorubicin or its liposomal formulation, h) gemcitabine, i) mitoxantrone, j) vinorelbine, k) eribulin, and 1) ixabepilone.
  • the combination is administered as a first-line treatment.
  • the antibody which binds to human HER3 is characterized in that the heavy chain variable domain comprises a CDR3H region of SEQ ID NO: 1, a CDR2H region of SEQ ID NO: 2, and a CDRIH region of SEQ ID NO:3, and the light chain variable domain comprises a CDR3L region of SEQ ID NO: 4, a CDR2L region of SEQ ID NO:5, and a CDR1L region of SEQ ID NO:6 or a CDR1L region of SEQ ID NO:7.
  • the light chain variable domain comprises a CDR3L region of SEQ ID NO: 4, a CDR2L region of SEQ ID NO:5, and a CDR1L region of SEQ ID NO:7.
  • the antibody which binds to human HER3 is characterized in that the heavy chain variable domain VH is SEQ ID NO:8; and the light chain variable domain VL is SEQ ID NO: 10.
  • the antibody which binds to human HER3 described above is further characterized in that the antibody is of IgGl subclass and is glycosylated with a sugar chain at Asn297 whereby the amount of fucose within said sugar chain is 65 % or lower.
  • the antibody binding to human HER2 and inhibiting dimerization of HER2 is pertuzumab.
  • the antibody which binds to human HER3 is administered at a dose of 400-600 mg every 3 weeks and the antibody which binds to human HER2 is administered at a dose of 300-500 mg every 3 weeks.
  • Another aspect of the invention is an antibody binding to human HER2 and inhibiting dimerization of HER2 for use in the treatment of breast cancer in combination with an antibody which binds to human HER3, wherein the breast cancer is HER2 low, HER3 positive and HR (hormone receptor) positive.
  • the breast cancer is HER2 low, HER3 positive and ER (estrogen receptor) positive.
  • Another aspect of the invention is the use of an antibody which binds to human HER3 for the manufacture of a medicament for the treatment of breast cancer wherein the breast cancer is HER2 low, HER3 positive and HR (hormone receptor) positive and wherein the treatment is in combination with an antibody binding to human HER2 and inhibiting dimerization of HER2.
  • the breast cancer is HER2 low, HER3 positive and ER (estrogen receptor) positive.
  • Another aspect of the invention is the use of an antibody binding to human HER2 and inhibiting dimerization of HER2 for the manufacture of a medicament for the treatment of breast cancer wherein the breast cancer is HER2 low, HER3 positive and HR (hormone receptor) positive and wherein the treatment is in combination with an antibody which binds to human HER3.
  • the breast cancer is HER2 low, HER3 positive and ER (estrogen receptor) positive.
  • Another aspect of the invention is a method of treating a patient suffering from of breast cancer wherein the breast cancer is HER2 low, HER3 positive and HR (hormone receptor) positive, the method comprising the administration of (an effective amount of ) an antibody which binds to human HER3 and the coadministration of (an effective amount of) an antibody binding to human HER2 and inhibiting dimerization of HER2 .
  • the breast cancer is HER2 low, HER3 positive and ER (estrogen receptor) positive.
  • an anti-HER3 antibody described above with an antibody which binds to human HER2 and which inhibits dimerization of HER2 showed strong tumor growth inhibition of HER2 low, HER3 positive and HR (hormone receptor) positive (e.g. ER positive) breast cancers, even in tumors where the antibody which binds to human HER2 and which inhibits dimerization of HER2, only showed low to medium tumor growth inhibition when administered alone.
  • HR hormone receptor
  • MCF7 cells by anti-HER3 antibodies in different concentrations are produced by anti-HER3 antibodies in different concentrations.
  • Figure 3A,B and C Western blot after immune precipitation (IP)-HER2 and blotting against ER or pER ERa from HEK 293 cells expressing HER2 and ER.
  • 3B shows Immunoprecipitation with ant-ER and blotting against HER2 in the same cells.
  • Figure 4A,B and C Western blot after immune precipitation (IP) f ER or HER3 expressing HEK 293 cells with anti HER3 blotted against ER (4A) and pER (4B).
  • IP immune precipitation
  • Fig.5B after 91 days (with end of treatment on day 61).
  • Fig.5C ex vivo analyse of MAPK at day 91
  • Fig.5D ex vivo analyse of AKT at day 91.
  • Figure 6 In vivo antitumor efficacy of anti-HER3 -antibody
  • HER3-antibody Mab205.10.2 in combination with pertuzumab in only first line (1L) HER2 low, ER+, HER3 + metastatic breast cancer patients. All patients are HER2 low, ER+, HER3 +.
  • SD Stable Disease
  • PR Partial Response
  • CR Complete Response
  • PD Progressive Disease
  • ORR Overall Response Rate, DCR Disease Control rate. The best overall RECIST responses and the line of treatment are indicated.
  • the invention relates to an antibody which binds to human HER3 for use in the treatment of, or the manufacture of a medicament for the treatment of, or a method of treatment of,
  • breast cancer in combination with an antibody which binds to human HER3, wherein the breast cancer is HER2 low, HER3 positive and HR (hormone receptor) positive.
  • the breast cancer is HER2 low, HER3 positive and ER (estrogen receptor) positive .
  • the invention comprises an antibody which binds to human HER3, characterized in that the heavy chain variable domain comprises a CDR3H region of SEQ ID NO: 1
  • the invention further comprises an antibody which binds to human HER3 according to the invention characterized in that the heavy chain variable domain VH is SEQ ID NO:8; and the light chain variable domain VL is SEQ ID NO:9, or the light chain variable domain VL is SEQ ID NO: 10, or the light chain variable domain VL is SEQ ID NO: 11; or a humanized version thereof for use in the combination therapies described herein.
  • the antibody which binds to human HER3 according to the invention is characterized in comprising as heavy chain variable domain a CDR3H region of SEQ ID NO: 1, a CDR2H region of SEQ ID NO: 2, and a CDRIH region of SEQ ID NO:3, and the light chain variable domain comprises a CDR3L region of SEQ ID NO: 4, a CDR2L region of SEQ ID NO:5, and a CDR1L region of SEQ ID NO: 6 for use in the combination therapies described herein.
  • the antibody which binds to human HER3 according to the invention is characterized in comprising as heavy chain variable domain a CDR3H region of SEQ ID NO: 1, a CDR2H region of SEQ ID NO: 2, and a CDRIH region of SEQ ID NO:3, and the light chain variable domain comprises a CDR3L region of SEQ ID NO: 4, a CDR2L region of SEQ ID NO:5, and a CDR1L region of SEQ ID NO: 7 for use in the combination therapies described herein.
  • Such “chimeric” antibodies are also referred to as "class-switched antibodies.”
  • Methods for producing chimeric antibodies involve conventional recombinant DNA and gene transfection techniques now well known in the art. See, e.g., Morrison, S.L., et al, Proc. Natl. Acad Sci. USA 81 (1984) 6851-6855; US 5,202,238 and US 5,204,244.
  • humanized antibody or “humanized version of an antibody” refers to antibodies in which the framework or "complementarity determining regions"
  • the framework region can be modified by further mutations.
  • Particularly preferred CDRs correspond to those representing sequences recognizing the antigens noted above for chimeric antibodies.
  • Preferably such humanized version is chimerized with a human constant region (see e.g. Sequences SEQ ID NO: 12-16).
  • human antibody is intended to include antibodies having variable and constant regions derived from human germ line immunoglobulin sequences. Human antibodies are well-known in the state of the art (van Dijk, M.A., and van de Winkel, J.G., Curr. Opin. Chem. Biol. 5 (2001)
  • Human antibodies can also be produced in transgenic animals (e.g., mice) that are capable, upon immunization, of producing a full repertoire or a selection of human antibodies in the absence of endogenous immunoglobulin production. Transfer of the human germ-line immunoglobulin gene array in such germ-line mutant mice will result in the production of human antibodies upon antigen challenge (see, e.g., Jakobovits, A., et al, Proc. Natl. Acad. Sci. USA 90 (1993) 2551-2555; Jakobovits, A., et al, Nature 362 (1993) 255-258; Brueggemann, M.D., et al., Year Immunol.
  • human antibody as used herein also comprises such antibodies which are modified in the constant region to generate the properties according to the invention, especially in regard to Clq binding and/or FcR binding, e.g. by "class switching” i.e. change or mutation of Fc parts (e.g. from IgGl to IgG4 and/or IgGl/IgG4 mutation).
  • class switching i.e. change or mutation of Fc parts (e.g. from IgGl to IgG4 and/or IgGl/IgG4 mutation).
  • an "antibody which binds to human HER3" as used herein refers to an antibody specifically which binds to the human HER3 antigen with a binding affinity of KD 1.0 x 10 "8 mol/1 or lower (in one embodiment of KD 1.0 x 10 "8 mol/1 - 1.0 x 10 "13 mol/1) at 25°C.
  • binding to human HER2 As used herein, the terms "binding to human HER2”, “specifically binding to human HER2”, “which binds to human HER2”, “which specifically binds to human HER2”, or “ anti-HER2 antibody” are interchangeable and refer to an antibody which specifically binds to the human HER2 antigen with a binding affinity of KD- value of 1.0 x 10 "8 mol/1 or lower at 25°C, in one embodiment of a KD-value of 1.0 xlO "9 mol/1 or lower at 25°C.
  • the binding affinity is determined with a standard binding assay at 25°C, such as surface plasmon resonance technique (BIAcore®, GE-Healthcare Uppsala, Sweden).
  • an "antibody which binds to human HER2" as used herein refers to an antibody specifically which binds to the human HER2 antigen with a binding affinity of KD 1.0 x 10 "8 mol/1 or lower (in one embodiment of KD 1.0 x 10 "8 mol/1 - 1.0 x 10 "13 mol/1) at 25°C.
  • MAPK Mitogen-activated protein kinase
  • PI3K Phosphoinositide 3-kinase
  • an antibody which binding to human HER2 and inhibiting dimerization of HER2 refer to an anti-HER2 antibody which specifically binds to the human HER2 antigen and which inhibits/blocks ligand-dependent HER2 homodimerization and HER2 heterodimerization with HER1, HER3, and HER4, and especially inhibits HER2/HER3 dimerization (see e.g. Perjeta® Prescribing Information. Genentech, Inc. June 2012. Baselga J, et al; N Engl J Med. 2012;366: 109-119; Baselga J, et al Nat Rev Cancer. 2009;9:463-475; Hynes NE, et al Nat Rev Cancer. 2005;5:341-
  • Human HER3 encodes a member of the epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases which also includes FIERI (also known as EGFR), HER2, and HER4 (Kraus, M.H. et al, PNAS 86 (1989), 9193-9197; Plowman, G.D. et al, PNAS 87 (1990), 4905-4909;
  • EGFR epidermal growth factor receptor
  • the transmembrane receptor HER3 consists of an extracellular ligand-binding domain (ECD), a dimerization domain within the ECD, a transmembrane domain, an intracellular protein tyrosine kinase domain (TKD) and a C-terminal phosphorylation domain.
  • ECD extracellular ligand-binding domain
  • TKD transmembrane domain
  • This membrane-bound protein has HER3 a Heregulin (HRG) binding domain within the extracellular domain but not an active kinase domain. It therefore can bind this ligand but not convey the signal into the cell through protein phosphorylation.
  • HRG Heregulin
  • heterodimers with other HER family members which do have kinase activity. Heterodimerization leads to the activation of the receptor-mediated signaling pathway and transphosphorylation of its intracellular domain. Dimer formation between HER family members expands the signaling potential of HER3 and is a means not only for signal diversification but also signal amplification. For example the HER2/HER3 heterodimer induces one of the most important mitogenic signals via the PI3K and AKT pathway among HER family members (Sliwkowski, M.X., et al, J. Biol. Chem.
  • Anti-HER3 antibodies Mab205.10.1, Mab205.10.2, and Mab205.10.3 showed a competitive binding with the ligand Heregulin (HRG) to HER3. Expression of HER3 gene and/or expression of its protein have been reported in numerous cancers, including prostate, bladder, and breast tumors.
  • Alternate transcriptional splice variants encoding different isoforms have been characterized.
  • One isoform lacks the intermembrane region and is secreted outside the cell. This form acts to modulate the activity of the membrane-bound form. Additional splice variants have also been reported, but they have not been thoroughly characterized.
  • the HER receptor will generally comprise an extracellular domain, which may bind an HER ligand; a lipophilic transmembrane domain, a conserved intracellular tyrosine kinase domain, and a carboxyl-terminal signaling domain harboring several tyrosine residues which can be phosphorylated.
  • the extracellular domain of HER2 comprises four domains, Domain I (amino acid residues from about 1-195),
  • Domain II amino acid residues from about 196-320
  • Domain III amino acid residues from about 321 488
  • Domain IV amino acid residues from about 489-632
  • Pertuzumab (e.g. Perjeta®) is a recombinant humanized anti-HER2 monoclonal antibody used for the treatment of HER2 positive cancers. Pertuzumab binds specifically to the 2C4 epitope, a different epitope on the extracellular domain of HER2 than trastuzumab. Pertuzumab is the first in a new class of HER dimerization inhibitors (HDIs).
  • HDIs HER dimerization inhibitors
  • pertuzumab Through its binding to the HER2 extracellular domain, pertuzumab inhibits dimerization of HER2 (especially ligand-activated heterodimerization with other HER family members), thereby inhibiting downstream signaling pathways and cellular processes associated with tumor growth and progression (Franklin, M.C., et al. Cancer Cell 5 (2004) 317-328 and
  • Pertuzumab is a recombinant humanized version of the murine anti-HER2 antibody 2C4 (referred to as rhuMAb 2C4 or pertuzumab) and it is described together with the respective method of preparation in WO 01/00245 and WO 2006/007398.
  • rhuMAb 2C4 refers to an antibody that binds to the 2C4 epitope and preferably comprising the variable light and variable heavy amino acid sequences disclosed in WO 2006/044908, more particularly the humanized 2C4 version 574 disclosed in Fig. 2 of WO 2006/044908.
  • Pertuzumab encompasses all corresponding anti-HER2 antibodies that fulfill the requirements necessary for obtaining a marketing authorization as an identical or biosimilar product in a country or territory selected from the group of countries consisting of the USA, Europe and Japan.
  • the "epitope 2C4" is the region in the extracellular domain of HER2 to which the antibody 2C4 binds.
  • a routine cross-blocking assay such as that described in Antibodies, A Laboratory Manual, Cold Spring Harbor Laboratory, Ed Harlow and David Lane (1988), can be performed.
  • epitope mapping can be performed to assess whether the antibody binds to the 2C4 epitope of HER2.
  • Epitope 2C4 comprises residues from domain II in the extracellular domain of HER2.
  • 2C4 and Pertuzumab bind to the extracellular domain of HER2 at the junction of domains I, II and III (Franklin et al. Cancer Cell 5:317-328 (2004)).
  • epitope includes any polypeptide determinant capable of specific binding to an antibody.
  • epitope determinant include chemically active surface groupings of molecules such as amino acids, sugar side chains, phosphoryl, or sulfonyl, and, in certain embodiments, may have specific three dimensional structural characteristics, and or specific charge characteristics.
  • An epitope is a region of an antigen that is bound by an antibody.
  • variable domain of an antibody according to the invention denotes each of the pair of light and heavy chain domains which are involved directly in binding the antibody to the antigen.
  • 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 ⁇ -sheet conformation and the CDRs may form loops connecting the ⁇ -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".
  • the term "antigen-binding portion" of an antibody of the invention contains six complementarity determining regions (CDRs) which contribute in varying degrees to the affinity of the binding site for antigen.
  • CDRH1 denotes the CDR1 region of the heavy chain variable region calculated according to Kabat.
  • CDRL2 and CDRL3 mean the respective regions from the heavy (H) or light(L) chain.
  • the extent of CDR and framework regions (FRs) is determined by comparison to a compiled database of amino acid sequences in which those regions have been defined according to variability among the sequences according to Kabat et al, Sequences of Proteins of Immunological Interest, 5th Ed. Public Health
  • 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 a, ⁇ , ⁇ , ⁇ , 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.
  • the term "complement-dependent cytotoxicity (CDC)” denotes a process initiated by binding of complement factor Clq to the Fc part of most IgG antibody subclasses. Binding of Clq to an antibody is caused by defined protein- protein interactions at the so called binding site. 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.
  • the antibody according to the invention comprises a Fc part derived from human origin and preferably all other parts of the human constant regions.
  • Fc part derived from human origin denotes a Fc part which is either a Fc part of a human antibody of the subclass IgGl, IgG2, IgG3 or IgG4, e.g. a Fc part from human IgGl subclass, a mutated Fc part from human IgGl subclass (preferably with a mutation on L234A + L235A), a Fc part from human IgG4 subclass or a mutated Fc part from human IgG4 subclass (preferably with a mutation on S228P).
  • the anti-HER3 according to the invention is of human IgGl subclass. In one embodiment the anti-HER2 according to the invention is of human IgGl subclass. In one embodiment the anti-HER3 and the anti-HER2 antibody according to the invention are both of human IgGl subclass. In one embodiment the anti-HER3 and the anti-HER2 antibody according to the invention are both characterized in that the constant chains are of human origin. Such constant chains are well known in the state of the art and e.g. described by Kabat, E.A., (see e.g. Johnson, G. and Wu, T.T., Nucleic Acids Res. 28 (2000) 214-218). For example, a useful human heavy chain constant region comprises an amino acid sequence of SEQ ID NO: 13. For example, a useful human light chain constant region comprises an amino acid sequence of a kappa-light chain constant region of SEQ ID NO: 12.
  • amino acid denotes the group of naturally occurring carboxy a-amino acids comprising alanine (three letter code: ala, one letter code: A), arginine (arg, R), asparagine (asn, N), aspartic acid (asp,
  • nucleic acid or "nucleic acid molecule”, as used herein, are intended to include DNA molecules and R A molecules.
  • a nucleic acid molecule may be single-stranded or double-stranded, but preferably is double-stranded DNA.
  • a nucleic acid is "operably linked" when it is placed into a functional relationship with another nucleic acid.
  • DNA for a presequence or secretory leader is operable linked to DNA for a polypeptide if it is expressed as a preprotein that participates in the secretion of the polypeptide;
  • a promoter or enhancer is operable linked to a coding sequence if it affects the transcription of the sequence; or a ribosome binding site is operable linked to a coding sequence if it is positioned so as to facilitate translation.
  • operable linked means that the DNA sequences being linked are colinear, and, in the case of a secretory leader, contiguous and in reading frame. However, enhancers do not have to be contiguous. Linking is accomplished by ligation at convenient restriction sites. If such sites do not exist, synthetic oligonucleotide adaptors or linkers are used in accordance with conventional practice.
  • the expressions "cell”, “cell line”, and “cell culture” are used interchangeably and all such designations include progeny.
  • the words “transformants” and “transformed cells” include the primary subject cell and cultures derived there from without regard for the number of transfers. It is also understood that all progeny may not be precisely identical in DNA content, due to deliberate or inadvertent mutations. Variant progeny that have the same function or biological activity as screened for in the originally transformed cell are included.
  • the anti-HER3 antibody described herein is preferably characterized in that the constant chains are of human origin.
  • Such constant chains are well known in the state of the art and described, e.g., by Kabat et al, Sequences of Proteins of Immunological Interest, 5th ed., Public Health Service, National Institutes of Health, Bethesda, MD (1991).
  • a useful human light chain constant region comprises an amino acid sequence of a kappa-light chain constant region of SEQ ID NO: 12.
  • useful human heavy chain constant region comprises SEQ ID NO: 13 to 16.
  • an anti-HER3 antibody for the respective combination therapy comprising a VH as in any of the embodiments provided above, and a VL as in any of the embodiments provided above.
  • the antibody comprises the VH and VL sequences in SEQ ID NO: 8 and SEQ ID NO: 10, respectively,; and having one or more of the following properties (determined in assays as described in Example 3 and 2): the anti-HER3 antibody inhibits the HER3 phosphorylation in tumor cells such as MCF7 cells, FaDu cells or Mel-Juso cell (in one embodiment the anti-HER3 antibody shows an inhibition of the HER3 phosphorylation in MCF7 cells of at least 80% (in one embodiment at least 90%) at a concentration of 1.0 ⁇ / ⁇ 1 ; in one embodiment the anti-HER3 antibody shows an inhibition of the HER3 phosphorylation in FaDu cells of at least 80% (in one embodiment at least 90%) at a concentration of 0.1 ⁇ / ⁇ 1 ; in one embodiment the anti-
  • the anti-HER3 antibody inhibits the proliferation of MDA-MB-175 cells with an IC50 value of less than 10 ⁇ g/ml
  • the anti-HER3 antibody binds to HER3 with a KD value of less than 5.0x lO ⁇ 9 M, in one embodiment with a KD value of less than 3. Ox 10 ⁇ 9 M.
  • an anti-HER3 antibody for the respective combination therapy is a bispecific anti-HER3/anti-HERl antibody as described in US 2010/0255010.
  • the bispecific anti-HER3/anti-HERl antibody is characterized comprising by the characteristic amino acid sequences disclosed in US 2010/0255010, i.e. A) (a) HVR-Hl comprising the amino acid sequence of
  • HVR-H2 comprising the amino acid sequence of VGEISAAGGYTD
  • HVR-H3 comprising the amino acid sequence of ARESRVSFEAAMDY
  • HVR-Ll comprising the amino acid sequence of NIATDVA
  • HVR-L2 comprising the amino acid sequence of SASF
  • HVR-L3 comprising the amino acid sequence of SEPEPYT
  • B) (a) a heavy chain variable domain with the amino acid sequence of SEQ ID NO: 30 as disclosed in US2010/0255010; (b) a light chain variable domain with the amino acid sequence of SEQ ID NO: 29 as disclosed in US2010/0255010.
  • ADCC antibody-dependent cellular cytotoxicity
  • IgGl type antibodies the most commonly used therapeutic antibodies, are glycoproteins that have a conserved N-linked glycosylation site at Asn297 in each CH2 domain.
  • ADCC antibody dependent cellular cytotoxicity
  • the antibody according to the invention is afucosylated which means the antibody is glycosylated (if it comprises an Fc part of IgGl subclass) with a sugar chain at Asn297 whereby the amount of fucose within said sugar chain is 80% or lower (Numbering according to Kabat), e.g. between 80% and 1 %. In another embodiment is the amount of fucose within said sugar chain is 65 % or lower, in one embodiment between 5% and 65%, in one embodiment from 0% to 65%, and in one embodiment the amount of fucose within said sugar chain is 0%.
  • Such antibodies are referred to in the following as
  • afucosylated antibodies or “non-fucosylated antibodies”. Such afucosylated antibodies show enhanced ADCC whereas other antibody properties remain substantially unaffected.
  • the amount of N-glycolylneuraminic acid (NGNA) is 1% or less and/or the amount of N-terminal alpha-l,3-galactose is 1% or less within said sugar chain.
  • the sugar chain show preferably the characteristics of N-linked glycans attached to Asn297 of an antibody recombinantly expressed in a CHO cell.
  • Asn297 according to the invention means amino acid asparagine located at about position 297 in the Fc region. Based on minor sequence variations of antibodies, Asn297 can also be located some amino acids (usually not more than +3 amino acids) upstream or downstream of position 297, i.e. between position 294 and 300.
  • the sugar chains show characteristics of N-linked glycans attached to Asn297 of an antibody recombinantly expressed in a CHO cell
  • NGNA glycosylation of human IgGl occurs at Asn297 as core fucosylated biantennary complex oligosaccharide glycosylation terminated with up to two Gal residues.
  • Human constant heavy chain regions of the IgGl subclass are reported in detail by Kabat, E., A., et al, Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD. (1991), and by Brueggemann, M., et al, J. Exp. Med.
  • the modified oligosaccharides of the full length parent antibody may be hybrid or complex.
  • the bisected, reduced/not- fucosylated oligosaccharides are hybrid.
  • the bisected, reduced/not-fucosylated oligosaccharides are complex.
  • amount of fucose means the amount of said sugar within the sugar chain at Asn297, related to the sum of all glycostructures attached to Asn297 (e.g. complex, hybrid and high mannose structures) measured by
  • the relative amount of fucose is the percentage of fucose-containing structures related to all glycostructures identified in an N-Glycosidase F treated sample (e.g. complex, hybrid and oligo- and high- mannose structures, resp.) by MALDI-TOF.
  • the antibodies according to the invention are preferably produced by recombinant means. 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.
  • Transient expression is described by, e.g., Durocher, Y., et al, Nucl. Acids. Res. 30 (2002) E9. Cloning of variable domains is described by Orlandi, R., et al, Proc. Natl. Acad. Sci. USA 86 (1989) 3833- 3837; Carter, P., et al, Proc. Natl. Acad. Sci. USA 89 (1992) 4285-4289; Norderhaug, L., et al, J. Immunol. Methods 204 (1997) 77-87.
  • a preferred transient expression system (HEK 293) is described by Schlaeger, E.-J.
  • Monoclonal antibodies are suitably separated from the culture medium by conventional immunoglobulin purification procedures such as, for example, protein A-Sepharose, hydroxylapatite chromatography, gel electrophoresis, dialysis, or affinity chromatography.
  • DNA and RNA encoding the monoclonal antibodies is readily isolated and sequenced using conventional procedures.
  • the hybridoma cells can serve as a source of such DNA and RNA.
  • the DNA may be inserted into expression vectors, which are then transfected into host cells, such as HEK 293 cells, CHO cells, or myeloma cells that do not otherwise produce immunoglobulin protein, to obtain the synthesis of recombinant monoclonal antibodies in the host cells.
  • host cells such as HEK 293 cells, CHO cells, or myeloma cells that do not otherwise produce immunoglobulin protein.
  • Antibodies obtainable from said cell lines are preferred embodiments of the invention.
  • Afucosylated antibodies are preferably prepared via glycoengineering as described above.
  • the heavy and light chain variable domains 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-trans fected, serially transfected, or separately transfected into host cells which are then fused to form a single host cell expressing both chains.
  • the antibodies of the combination are administered as a pharmaceutical composition comprising the respective antibody.
  • the present invention provides a composition, e.g. a pharmaceutical composition, containing an antibody according to the present invention, formulated together with a pharmaceutical carrier.
  • pharmaceutical carrier includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible.
  • the carrier is suitable for intravenous, intramuscular, subcutaneous, parenteral, spinal or epidermal administration (e.g. by injection or infusion).
  • a 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. To administer a compound of the invention by certain routes of administration, it may be necessary to coat the compound with, or co-administer the compound with, a material to prevent its inactivation.
  • the compound may be administered to a subject in an appropriate carrier, for example, liposomes, or a diluent.
  • Pharmaceutically acceptable diluents include saline and aqueous buffer solutions.
  • Pharmaceutical carriers include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion.
  • parenteral administration and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intra-arterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intra-articular, subcapsular, subarachnoid, intraspinal, epidural and intrasternal injection and infusion.
  • breast cancer as used herein including any metastatic or refractory versions.
  • Another aspect of the invention is an anti-HER3 -antibody according to the invention for the treatment of cancer in combination with an antibody which binds to human HER2 and which inhibits dimerization of HER2, wherein the cancer is a HER2 low, HER3 positive and HR (hormone receptor) positive (e.g. ER positive) breast cancer.
  • Another aspect of the invention is the use of an antibody which binds to human HER3 for the manufacture of a medicament for the treatment of breast cancer in combination with an antibody which binds to human HER2 and which inhibits dimerization of HER2, wherein the cancer is a is HER2 low, HER3 positive and HR (hormone receptor) positive (e.g. ER positive) cancer.
  • Another aspect of the invention is a method of treatment of a patient suffering from breast cancer by administering an anti-HER3 -antibody antibody according to the invention to said patient in the need of such treatment in combination with an antibody which binds to human HER2 and which inhibits dimerization of HER2, wherein the cancer is a HER2 low, HER3 positive and HR (hormone receptor) positive (e.g. ER positive) cancer.
  • an anti-HER3 -antibody antibody according to the invention to said patient in the need of such treatment in combination with an antibody which binds to human HER2 and which inhibits dimerization of HER2, wherein the cancer is a HER2 low, HER3 positive and HR (hormone receptor) positive (e.g. ER positive) cancer.
  • HR hormone receptor
  • the anti-HER3 antibody used in this combination is characterized in comprising as VH an amino acid sequence of SEQ ID NO: 8 and an as VL an amino acid sequence of SEQ ID NO: 10, b) the anti-HER2 antibody used in this combination is pertuzumab, and c) the cancer is HER2 low, HER3 positive and HR (hormone receptor) positive (e.g. ER positive) breast cancer.
  • HER3 positive refers to a breast cancer or tumorous tissue which comprises cells which are characterized by HER3 protein expression and/or gene amplification. This means that the respective breast cancer samples show a detectable level of the HER3 protein expression and/or gene amplification.
  • the expression level of HER3 may be detected by an immunohistochemical method, whereas said HER3 gene amplification status can be measured with in situ hybridization methods, like fluorescence in situ hybridization techniques (FISH).
  • FISH fluorescence in situ hybridization techniques
  • HER3 can, inter alia, be detected by an immunohistochemical method.
  • immunohistochemical methods are well known in the art (see e.g. analogous methods and test for HER2 expression levels below or e.g. WO 2015/049355).
  • Other methods like qRT-PCR might be used to detect levels of HER3 gene amplification.
  • HER3 positive refers to the HER3 protein expression detected by an immunohistochemical method, which means the respective breast cancer samples show a detectable level of the HER3 protein in an corresponding immunohistochemistry (IHC) assay.
  • IHC immunohistochemistry
  • HER2 low cancer In the context of the combination therapy of an anti-HER3 antibody with an anti- HER2 antibody, wherein the anti-HER2 antibodies inhibits HER2 dimerization, the term "HER2 low” cancer also referred to as “HER2 low cancer” as used herein refers to a cancer or tumorous tissue which comprises cells which express low levels of HER2. Thus, HER2 low cancer cells do not overexpress HER2 (as defined for HER2 -positive cancer) and are not negative for HER2 expression.
  • HER2 low cancer is a cancer with an immunohistochemistry (IHC) score of 2+ and an in situ hybridization (ISH) amplification ratio ⁇ 2.0 (i.e.
  • HER2 low cancer is present if a low (IHC 1+) or moderate (IHC 2+) HER2 (protein) expression level detected e.g.
  • HER2 low cancer is defined as an immunohistochemistry (IHC) score of HER2(2+) and ISH negative or immunohistochemistry (IHC) score of HER2(1+) and ISH negative (IHC l+/ISH-negative or IHC 2+/ISH-negative).
  • the expression level of HER2 may be detected by an immunohistochemical method, whereas said HER2 gene amplification status can be measured with in situ hybridization methods, like fluorescence in situ hybridization techniques (FISH).
  • FISH fluorescence in situ hybridization techniques
  • the expression level of HER2 can, inter alia, be detected by an immunohistochemical method. Such methods are well known in the art and corresponding commercial kits are available. Exemplary kits which may be used in accordance with the present invention are, inter alia, HerceptTestTM produced and distributed by the company Dako or the test called Ventana PathwayTM. The level of HER2 protein expression may be assessed by using the reagents provided with and following the protocol of the HercepTestTM. A skilled person will be aware of further means and methods for determining the expression level of HER2 by immunohistochemical methods; see for example WO 2005/117553. Therefore, the expression level of HER2 can be easily and reproducibly determined by a person skilled in the art without undue burden. However, to ensure accurate and reproducible results, the testing must be performed in a specialized laboratory, which can ensure validation of the testing procedures.
  • the expression level of HER2 can be classified in a low expression level, an intermediate expression level and a high expression level.
  • HER2 low disease is defined by a low or weak expression level of HER2 (e.g. HER2(1+ or 2+) by IHC) and a negative ISH result, for example determined in a sample of a cancer patient. Therefore parallel testing using immunohistochemistry and in situ hybridisation is preferred.
  • HER2(0), HER2(+), HER2(++) and HER2(+++) is as follows:
  • HER2(+), HER2(++) and HER2(+++) used herein are equivalent to the terms HER2(1+), HER2(2+) and HER2(3+).
  • a "low HER2 protein expression level" used in context of this invention corresponds to a 1+ score ("negative assessment” according to the table shown herein above), and a 2+ score "weakly positive". As described herein above in detail, the evaluation of the protein expression level (i.e. the scoring system as shown in the table) is based on results obtained by immunohistochemical methods.
  • the HER2 status is, accordingly, performed by immunohistochemistry with one of two FDA-approved commercial kits available; namely the Dako HerceptestTM and the Ventana PathwayTM. These are semi-quantitative assays which stratify expression levels into 0 ( ⁇ 20,000 receptors per cell, no expression visible by IHC staining), 1+ (-100,000 receptors per cell, partial membrane staining, ⁇ 10% of cells overexpressing HER2), 2+ (-500,000 receptors per cell, light to moderate complete membrane staining, > 10%> of cells overexpressing HER2), and 3+ (-2,000,000 receptors per cell, strong complete membrane staining, > 10% of cells overexpressing HER2).
  • HER2 low disease is defined by a low or weak expression level of HER2 (e.g. HER2(1+ or 2+) by IHC) and a negative ISH result.
  • the sample to be assessed can be (obtained) from a patient with HER2 low cancer as defined above.
  • the sample may be obtained from a tumorous tissue, (a) tumor(s) and, accordingly, is (a) tumor cell(s) or (a) tumor tissue(s) suspected of being HER2 expressing tumour, like a breast tumor.
  • a person skilled in the art is in the position to identify such tumors and/or individuals/patients suffering from corresponding cancer using standard techniques known in the art and methods disclosed herein.
  • said tumor cell or cancer cell may be obtained from any biological source/organism, particularly any biological source/organism, suffering from the above-mentioned cancer.
  • particular useful cells are, preferably, human cells.
  • the tumor/cancer/tumor cell/cancer cell is a solid tumor/ cancer/tumor cell/cancer cell.
  • the cancer/tumor cell may be a breast cancer/tumor cell or said sample comprises a cancer/tumor cell, such as a breast cancer/tumor cell.
  • said tumor/cancer may be a breast tumor/cancer.
  • Hormone receptor (HR) positive or HR+ refers to Estrogen Receptor (ER) positive and/or Progesterone Receptor (PgR)-positive cancer/tumouros tissue, such as Breast Cancer.
  • ER Estrogen Receptor
  • PgR Progesterone Receptor
  • Breast Cancer are considered negative for ER or PgR if it is detected that ⁇ 1% of tumor cell nuclei are immunoreactive in the presence of evidence that the sample can express ER or PgR (positive intrinsic controls can be detected), as determined by IHC.
  • Breast Cancer are considered uninterpretable for ER or PgR if it is detected that no tumor nuclei are immunoreactive and that internal epithelial elements present in the sample or separately submitted from the same sample lack any nuclear staining, as determined by IHC.
  • the breast cancer is estrogen receptor (ER) positive (ER+).
  • Estrogen receptor (ER) positive or ER+ refers to breast cancer which is considered positive for ER if finding of > 1% of tumor cell nuclei are immunoreactive, as determined by Immunohistochemistry
  • the compounds 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.
  • composition must be sterile and fluid to the extent that the composition is deliverable by syringe.
  • carrier preferably is an isotonic buffered saline solution.
  • 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 an overall beneficial course of action.
  • both antibodies When both antibodies are administered simultaneously the dose is administered on the same day in one administration, e.g. during one continuous infusion.
  • both antibodies When both antibodies are administered sequentially the dose is administered either on the same day in two separate administrations, e.g. two separate continuous infusions, or one of the antibodies is administered on day 1 and the second antibody is administered on day 2 to day 7, preferably on day 2 to 4.
  • the terms "co-administration” or “coadministering" with respect to the maintenance doses of the first antibody and the second antibody mean that the maintenance doses can be either administered simultaneously, e.g. during one continuous infusion, if the treatment cycle is appropriate for both antibodies.
  • the maintenance doses are administered sequentially, either within one or several days, e.g. the maintenance dose of the first antibody is administered every 3 weeks, and the maintenance dose of the second is administered every 2 weeks.
  • other treatment cycles /usually from 1 to 4 weeks, preferably from 2 to 3 weeks, may be used for both antibodies.
  • paclitaxel derivatives like nab-paclitaxel (protein-bound paclitaxel) (e.g. Abraxane®) or docosahexaenoic acid (DHA) -paclitaxel, (e.g. Taxoprexin®)), or docetaxel (e.g. Taxotere®), b) cyclophosphamide (CTX) (e.g. Cytoxan®), c) cisplatin (e.g. Platinol®) or carboplatin (e.g. Paraplatin® and
  • Paraplatin-AQ® d) mitomycin C (e.g. Mutamycin®), e) methotrexate (MTX) (e.g. Trexall®), f) 5-fluorouracil (5-FU) (e.g. Adrucil®) or capecitabine (e.g.
  • ixabepilone e.g. Ixempra ®
  • additional an anti-hormonal agents may be used in combination treatment of the present invention.
  • agents include, for example: a) a selective estrogen receptor degrader (SERD) like e.g. fulvestrant, or b) a selective estrogen receptor modulators (SERM), such as tamoxifen, raloxifene, toremifene or lasofoxifene, or c) an aromatase inhibitor like e.g. letrozole, anastrozole or exemestane).
  • SESD selective estrogen receptor degrader
  • SERM selective estrogen receptor modulators
  • AC-Taxol AC given 3 -weekly for 4 cycles followed by paclitaxel given either 3- weekly for 4 cycles or weekly (at a smaller dose) for 12 weeks
  • TAC Taxotere (docetaxel), Adriamycin (doxorubicin), and cyclophosphamide given 3 -weekly for 4-6 cycles
  • FEC 5-fluorouracil, epirubicin and cyclophosphamide given 3 -weekly for 6 cycles
  • FEC FEC given 3 -weekly for 3 cycles followed by docetaxel given 3 -weekly for
  • TC Taxotere (docetaxel) and cyclophosphamide given 3 -weekly for 4 or 6 cycles
  • Fulvestrant exemestane alone or in combination with everolimus, anastrozole, letrozole, tamoxifene. Recently the palbociclib has been approved in combination with letrozole and fulvestrant.
  • Radioactive atoms for use in the context of this invention can be selected from the group including, but not limited to, radium, cesium- 137, iridium- 192, americium- 241, gold-198, cobalt-57, copper-67, technetium-99, iodine-123, iodine-131, and indium- 111.
  • the combination treatment of the present invention is used without such additional ionizing radiation.
  • a typical course of treatment for a patient undergoing radiation therapy will be a treatment schedule over a 1 to 6 week period, with a total dose of between 10 and 80 Gy administered to the patient in a single daily fraction of about 1.8 to 2.0 Gy, 5 days a week.
  • a preferred embodiment of this invention there is synergy when tumors in human patients are treated with the combination treatment of the invention and radiation.
  • the antibodies are administered to a patient according to known methods, by intravenous administration as a bolus or by continuous infusion over a period of time, by intramuscular, intraperitoneal, intracerobrospinal, subcutaneous, intraarticular, intrasynovial, or intrathecal routes. Intravenous or subcutaneous administration of the antibodies is preferred.
  • treating means reversing, alleviating, inhibiting the progress of, or preventing, either partially or completely, the growth of tumors, tumor metastases, or other cancer-causing or neoplastic cells in a patient.
  • treatment refers to the act of treating.
  • a method of treating or its equivalent, 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.
  • first-line treatment refers to the first type of drug therapy given for the treatment of cancer or metastasis. This can be an adjuvant or neoadjuvant or palliative chemotherapy or immunotherapy offered initially following diagnosis and/or surgery or following diagnosis of metastatic disease.
  • the first-line treatment refers to the first cancer treatment using e.g. chemical or biochemical substances, like cytotoxic drugs, targeted therapies with antibodies, or enzyme inhibitors/antagonist/or modulators.
  • the present invention further provides an article of manufacture comprising a container, a composition within the container comprising an anti-HER3 antibody and a package insert instructing the user of the composition to administer said anti-
  • HER3 antibody to a patient suffering from HER2 low, HER3 positive and HR (hormone receptor) positive (e.g. ER positive) breast cancer in combination with an anti-HER2 antibody which inhibits the dimerization of HER2.
  • HR hormone receptor
  • the article of manufacture containers may further include a pharmaceutically acceptable carrier.
  • the article of manufacture may further include a sterile diluent, which is preferably stored in a separate additional container.
  • an anti-hormonal agent is co-administered, wherein the anti-hormonal agent is selected from the group of: a) a selective estrogen receptor degrader (SERD), (in one embodiment the estrogen receptor inhibitor is fulvestrant), b) a selective estrogen receptor modulator (SERM), (in one embodiment the selective estrogen receptor modulator is tamoxifen, raloxifene, toremifene or lasofoxifene), and c) an aromatase inhibitor; (in embodiment the aromatase inhibitor is letrozole, anastrozole or exemestane);
  • SESD selective estrogen receptor degrader
  • SERM selective estrogen receptor modulator
  • an aromatase inhibitor in embodiment the aromatase inhibitor is letrozole, anastrozole or exemestane
  • chemotherapeutic agent is selected from the group of: a) a taxane or taxane derivative (like paclitaxel and paclitaxel derivatives, or docetaxel), b) cyclophosphamide (CTX), c) cisplatin or carboplatin, d) mitomycin C, e) methotrexate (MTX), f) 5-fluorouracil (5-FU) or capecitabine, g) doxorubicin (DXR) or its liposomal formulation (doxorubicin lipo), or daunorubicin or its liposomal formulation (daunorubicin lipo), h) gemcitabine, i) mitoxantrone, j) vinorelbine, k) eribulin, and 1) ixabepilone.
  • CX cyclophosphamide
  • CX cyclophosphamide
  • an anti-hormonal agent is co-administered, and wherein the anti- hormonal agent is selected from the group of: a) a selective estrogen receptor degrader (SERD), b) a selective estrogen receptor modulator (SERM); and c) an aromatase inhibitor.
  • SELD selective estrogen receptor degrader
  • SERM selective estrogen receptor modulator
  • a chemotherapeutic agent is co-administered, and wherein the chemotherapeutic agent is selected from the group of: a) a taxane or taxane derivative (like paclitaxel and paclitaxel derivatives, or docetaxel), b) cyclophosphamide (CTX), c) cisplatin or carboplatin, d) mitomycin C, e) methotrexate (MTX), f) 5-fluorouracil (5-FU) or capecitabine, g) doxorubicin (DXR) or its liposomal formulation (doxorubicin lipo), or daunorubicin or its liposomal formulation (daunorubicin lipo), h) gemcitabine, i) mitoxantrone, j) vinorelbine, k) eribulin, and 1) ixabepilone.
  • CTX cyclophosphamide
  • the chemotherapeutic agent is a taxanes or taxane derivative selected from the group of paclitaxel, nab-paclitaxel, docetaxel ( in one embodiment the chemotherapeutic agent is paclitaxel, nab-paclitaxel, in one embodiment the chemotherapeutic agent is paclitaxel).
  • the antibody according to any one of embodiments 1 to 8, wherein the combination is administered as a first-line treatment.
  • an anti-hormonal agent is co-administered, wherein the anti-hormonal agent is selected from the group of: a) a selective estrogen receptor degrader (SERD), (in one embodiment the selective estrogen receptor degrader (SERD) is fulvestrant), b) a selective estrogen receptor modulator (SERM), (in one embodiment the selective estrogen receptor modulator is tamoxifen, raloxifene, toremifene or lasofoxifene), and c) an aromatase inhibitor; (in embodiment the aromatase inhibitor is letrozole, anastrozole or exemestane);
  • SEMD selective estrogen receptor degrader
  • SERM selective estrogen receptor modulator
  • an aromatase inhibitor in embodiment the aromatase inhibitor is letrozole, anastrozole or exemestane
  • the antibody which binds to human HER3 is characterized in that the heavy chain variable domain VH is SEQ ID NO: 8; and the light chain variable domain VL is SEQ ID NO: 10. 12.
  • the antibody according to any one of embodiments 1 to 12, wherein the antibody binding to human HER2 and inhibiting dimerization of HER2 is pertuzumab.
  • the use according to embodiment 1, wherein the breast cancer is HER2 low HER3, and positive ER (estrogen receptor) positive is .
  • the use according to any one of embodiments 1 to 2 wherein
  • an anti-hormonal agent is co-administered, wherein the anti-hormonal agent is selected from the group of: a) a selective estrogen receptor degrader (SERD), (in one embodiment the selective estrogen receptor degrader (SERD) is fulvestrant), b) a selective estrogen receptor modulator (SERM), (in one
  • a chemotherapeutic agent is co-administered, and wherein the chemotherapeutic agent is selected from the group of: a) a taxane or taxane derivative (like paclitaxel and paclitaxel derivatives, or docetaxel), b) cyclophosphamide (CTX), c) cisplatin or carboplatin, d) mitomycin C, e) methotrexate (MTX), f) 5-fluorouracil (5-FU) or capecitabine, g) doxorubicin (DXR) or its liposomal formulation (doxorubicin lipo), or daunorubicin or its liposomal formulation (daunorubicin lipo), h) gemcitabine, i) mitoxantrone, j) vinorelbine, k) eribulin, and
  • breast cancer is HER2 low HER3, and positive ER (estrogen receptor) positive .
  • chemotherapeutic agent is selected from the group of: a) a taxane or taxane derivative (like paclitaxel and paclitaxel derivatives, or docetaxel), b) cyclophosphamide (CTX), c) cisplatin or carboplatin, d) mitomycin C, e) methotrexate (MTX), f) 5-fluorouracil (5-FU) or capecitabine, g) doxorubicin (DXR) or its liposomal formulation (doxorubicin lipo), or daunorubicin or its liposomal formulation (daunorubicin lipo), h) gemcitabine, i) mitoxantrone, j) vinorelbine, k) eribulin, and 1) ixabepilone.
  • CTX cyclophosphamide
  • CX c) cisplatin or carboplatin
  • mitomycin C e
  • an aromatase inhibitor c) an aromatase inhibitor.
  • the anti-hormonal agent is selected from the group of: a) fulvestrant, b) tamoxifen, raloxifene, toremifene or lasofoxifene; and
  • the chemotherapeutic agent is a taxanes or taxane derivative selected from the group of paclitaxel, nab-paclitaxel, docetaxel ( in one embodiment the chemotherapeutic agent is paclitaxel, nab-paclitaxel, in one embodiment the chemotherapeutic agent is paclitaxel).
  • combination is administered as a first-line treatment.
  • the antibody which binds to human HER3 is characterized in comprising as heavy chain variable domain a CDR3H region of SEQ ID NO: 1, a CDR2H region of SEQ ID NO: 2, and a CDR1H region of SEQ ID NO:3, and the light chain variable domain comprises a CDR3L region of SEQ ID NO: 4, a CDR2L region of SEQ ID NO:5, and a CDR1L region of SEQ ID NO:7.
  • the selective estrogen receptor modulator is tamoxifen, raloxifene, toremifene or lasofoxifene), and c) an aromatase inhibitor; (in embodiment the aromatase inhibitor is letrozole, anastrozole or exemestane);
  • chemotherapeutic agent is selected from the group of: a) a taxane or taxane derivative (like paclitaxel and paclitaxel derivatives, or docetaxel), b) cyclophosphamide (CTX), c) cisplatin or carboplatin, d) mitomycin C, e) methotrexate (MTX), f) 5-fluorouracil (5-FU) or capecitabine, g) doxorubicin (DXR) or its liposomal formulation (doxorubicin lipo), or daunorubicin or its liposomal formulation (daunorubicin lipo), h) gemcitabine, i) mitoxantrone, j) vinorelbine, k) eribulin, and 1) ixabepilone.
  • CX cyclophosphamide
  • CX cyclophosphamide
  • an anti-hormonal agent is co-administered, and wherein the anti- hormonal agent is selected from the group of: a) a selective estrogen receptor degrader (SERD), b) a selective estrogen receptor modulator (SERM); and
  • anti-hormonal agent is selected from the group of: a) fulvestrant, b) tamoxifen, raloxifene, toremifene or lasofoxifene; and
  • a chemotherapeutic agent is co-administered, and wherein the chemotherapeutic agent is selected from the group of: a) a taxane or taxane derivative (like paclitaxel and paclitaxel derivatives, or docetaxel), b) cyclophosphamide (CTX), c) cisplatin or carboplatin, d) mitomycin C, e) methotrexate (MTX), f) 5-fluorouracil (5-FU) or capecitabine, g) doxorubicin (DXR) or its liposomal formulation (doxorubicin lipo), or daunorubicin or its liposomal formulation (daunorubicin lipo), h) gemcitabine, i) mitoxantrone, j) vinorelbine, k) eribulin, and 1) ixabepilone.
  • CTX cyclophosphamide
  • the chemotherapeutic agent is a taxanes or taxane derivative selected from the group of paclitaxel, nab-paclitaxel, docetaxel ( in one embodiment the chemotherapeutic agent is paclitaxel, nab-paclitaxel, in one embodiment the chemotherapeutic agent is paclitaxel).
  • paclitaxel nab-paclitaxel
  • docetaxel in one embodiment the chemotherapeutic agent is paclitaxel, nab-paclitaxel, in one embodiment the chemotherapeutic agent is paclitaxel.
  • the antibody which binds to human HER3 is characterized in comprising as heavy chain variable domain a CDR3H region of SEQ ID NO: 1, a CDR2H region of SEQ ID NO: 2, and a CDR1H region of SEQ ID NO:3, and the light chain variable domain comprises a CDR3L region of SEQ ID NO: 4, a CDR2L region of SEQ ID NO:5, and a CDR1L region of SEQ ID NO:7.
  • an anti-hormonal agent is co-administered, wherein the anti-hormonal agent is selected from the group of: a) a selective estrogen receptor degrader (SERD), (in one embodiment the selective estrogen receptor degrader (SERD) is fulvestrant), b) a selective estrogen receptor modulator (SERM), (in one embodiment the selective estrogen receptor modulator is tamoxifen, raloxifene, toremifene or lasofoxifene), and c) an aromatase inhibitor; (in embodiment the aromatase inhibitor is letrozole, anastrozole or exemestane);
  • SEMD selective estrogen receptor degrader
  • SERM selective estrogen receptor modulator
  • an aromatase inhibitor in embodiment the aromatase inhibitor is letrozole, anastrozole or exemestane
  • chemotherapeutic agent is selected from the group of: a) a taxane or taxane derivative (like paclitaxel and paclitaxel derivatives, or docetaxel), b) cyclophosphamide (CTX), c) cisplatin or carboplatin, d) mitomycin C, e) methotrexate (MTX), f) 5-fluorouracil (5-FU) or capecitabine, g) doxorubicin (DXR) or its liposomal formulation (doxorubicin lipo), or daunorubicin or its liposomal formulation (daunorubicin lipo), h) gemcitabine, i) mitoxantrone, j) vinorelbine, k) eribulin, and 1) ixabepilone.
  • CTX cyclophosphamide
  • CX c) cisplatin or carboplatin
  • mitomycin C e
  • an anti-hormonal agent is co-administered, and wherein the anti- hormonal agent is selected from the group of: a) a selective estrogen receptor degrader (SERD), b) a selective estrogen receptor modulator (SERM); and
  • an aromatase inhibitor c) an aromatase inhibitor.
  • the anti-hormonal agent is selected from the group of: a) fulvestrant, b) tamoxifen, raloxifene, toremifene or lasofoxifene; and
  • a chemotherapeutic agent is co-administered, and wherein the chemotherapeutic agent is selected from the group of: a) a taxane or taxane derivative (like paclitaxel and paclitaxel derivatives, or docetaxel), b) cyclophosphamide (CTX), c) cisplatin or carboplatin, d) mitomycin C, e) methotrexate (MTX), f) 5-fluorouracil (5-FU) or capecitabine, g) doxorubicin (DXR) or its liposomal formulation (doxorubicin lipo), or daunorubicin or its liposomal formulation (daunorubicin lipo), h) gemcitabine, i) mitoxantrone, j) vinorelbine, k) eribulin, and 1) ixabepilone.
  • CTX cyclophosphamide
  • the chemotherapeutic agent is a taxanes or taxane derivative selected from the group of paclitaxel, nab-paclitaxel, docetaxel ( in one embodiment the chemotherapeutic agent is paclitaxel, nab-paclitaxel, in one embodiment the chemotherapeutic agent is paclitaxel).
  • paclitaxel nab-paclitaxel
  • docetaxel in one embodiment the chemotherapeutic agent is paclitaxel, nab-paclitaxel, in one embodiment the chemotherapeutic agent is paclitaxel.
  • the antibody which binds to human HER3 is characterized in comprising as heavy chain variable domain a CDR3H region of SEQ ID NO: 1, a CDR2H region of SEQ ID NO: 2, and a CDR1H region of SEQ ID NO:3, and the light chain variable domain comprises a CDR3L region of SEQ ID NO: 4, a CDR2L region of SEQ ID NO:5, and a CDR1L region of SEQ ID NO:7.
  • an anti-hormonal agent is co-administered, wherein the anti-hormonal agent is selected from the group of: a) a selective estrogen receptor degrader (SERD), (in one embodiment the selective estrogen receptor degrader (SERD) is fulvestrant), b) a selective estrogen receptor modulator (SERM), (in one
  • the selective estrogen receptor modulator is tamoxifen, raloxifene, toremifene or lasofoxifene), and c) an aromatase inhibitor; (in embodiment the aromatase inhibitor is letrozole, anastrozole or exemestane);
  • chemotherapeutic agent is selected from the group of: a) a taxane or taxane derivative (like paclitaxel and paclitaxel derivatives, or docetaxel), b) cyclophosphamide (CTX), c) cisplatin or carboplatin, d) mitomycin C, e) methotrexate (MTX), f) 5-fluorouracil (5-FU) or capecitabine, g) doxorubicin (DXR) or its liposomal formulation (doxorubicin lipo), or daunorubicin or its liposomal formulation (daunorubicin lipo), h) gemcitabine, i) mitoxantrone, j) vinorelbine, k) eribulin, and 1) ixabepilone.
  • CX cyclophosphamide
  • CX cyclophosphamide
  • an anti-hormonal agent is co-administered, and wherein the anti- hormonal agent is selected from the group of: a) a selective estrogen receptor degrader (SERD), b) a selective estrogen receptor modulator (SERM); and
  • the anti-hormonal agent is selected from the group of: a) fulvestrant, b) tamoxifen, raloxifene, toremifene or lasofoxifene; and
  • a chemotherapeutic agent is co-administered, and wherein the chemotherapeutic agent is selected from the group of: a) a taxane or taxane derivative (like paclitaxel and paclitaxel derivatives, or docetaxel), b) cyclophosphamide (CTX), c) cisplatin or carboplatin, d) mitomycin C, e) methotrexate (MTX), f) 5-fluorouracil (5-FU) or capecitabine, g) doxorubicin (DXR) or its liposomal formulation (doxorubicin lipo), or daunorubicin or its liposomal formulation (daunorubicin lipo), h) gemcitabine, i) mitoxantrone, j) vinorelbine, k) eribulin, and 1) ixabepilone.
  • CTX cyclophosphamide
  • the chemotherapeutic agent is a taxanes or taxane derivative selected from the group of paclitaxel, nab-paclitaxel, docetaxel ( in one embodiment the chemotherapeutic agent is paclitaxel, nab-paclitaxel, in one embodiment the chemotherapeutic agent is paclitaxel).
  • antibody which binds to human HER3 is characterized in comprising as heavy chain variable domain a CDR3H region of SEQ ID NO: 1, a CDR2H region of SEQ ID NO: 2, and a CDR1H region of SEQ ID NO:3, and the light chain variable domain comprises a CDR3L region of SEQ ID NO: 4, a CDR2L region of SEQ ID NO:5, and a CDR1L region of SEQ ID NO:7.
  • the heavy chain variable domain VH is SEQ ID NO: 8; and the light chain variable domain VL is SEQ ID NO: 10.
  • antibody which binds to human HER3 is of human IgGl subclass and is characterized in that the antibody is glycosylated with a sugar chain at Asn297 whereby the amount of fucose within said sugar chain is 65 % or lower.
  • antibody binding to human HER2 and inhibiting dimerization of HER2 is pertuzumab.
  • antibody which binds to human HER3 is administered at a dose of 400-600 mg every 3 weeks and the antibody which binds to human HER2 is administered at a dose of 300-500 mg every 3 weeks.
  • SEQ ID NO 12 human kappa light chain constant region
  • SEQ ID NO 13 human heavy chain constant region derived from IgGl
  • SEQ ID NO 14 human heavy chain constant region derived from IgGl mutated on L234A and L235A
  • SEQ ID NO 16 human heavy chain constant region derived from IgG4 mutated on S228P
  • SEQ ID NO 18 human HER2 (including signal peptide)
  • NMRI mice were immunized with hHER3-ECD (in-house) and boosted with hu-HER3-ECD. The immune response was monitored by testing serum samples against the HER1/2/3- ECD-ELISA. Spleen cells from mice with sufficient titers of anti-HER3 immunoglobulin were frozen for later immortalization by fusion with mouse myeloma cell line P3X63 Ag8.653. One fusion was done and hybridoma supematants screened by HER1/2/-ECD- ELISA showing no cross-reactivity, but binding to HER3-ECD and anti-HER3 selective hybridomas were selected. The relevant hybridomas were cloned by single cell FACS sorting.
  • Single cell clones from different hybridomas were cultured in vitro to produce antibody in tissue culture medium for characterization.
  • Antibodies were selected by determining their ability to inhibit HER3 phosphorylation, AKT phosphorylation and tumor cell proliferation of MDA-MB-175 cells (see Examples below). From the obtained antibodies, one was further humanized to give the following antibodies Mab 205.10.1, Mab 205.10.2 and Mab 205.10.3 with their respective VH and VL or CDRs.
  • such antibodies were prepared using constant regions of human origin e.g. SEQ ID NO: 12-13.
  • Binding assays a) Antigen specific ELISA for binding to human HER3 ECD
  • Soluble human HER3 extracellular domain fused to Streptavidin Binding Protein was captured on a streptavidine plate.
  • SBP Streptavidin Binding Protein
  • CM-5 sensor chip For affinity measurements, 30 ⁇ g/ml of anti Fey antibodies (from goat, Jackson Immuno Research) were coupled to the surface of a CM-5 sensor chip by standard amine-coupling and blocking chemistry on a SPR instrument (Biacore T100). After conjugation, anti-HER3 antibodies were injected at 25°C at a flow rate of 5 ⁇ / ⁇ , followed by a dilution series (0 nM to 1000 nM) of human HER3 ECD at 30 ⁇ / ⁇ . As running buffer for the binding experiment PBS/0.1% BSA was used. The chip was then regenerated with a 60s pulse of 10 mM glycine-
  • Mab205.10.1, Mab205.10.2, and Mab205.10.3 all showed binding to the same epitope.
  • the anti-HER3 -antibodies Ul-7, U-53 and Ul-59 described in WO 2007/077028 and Ab#6 described in WO 2008/100624 were investigated in such assay and revealed to bind to different epitopes than antibodies Mab205.10.1. Mab205.10.2, and Mab205.10.3.
  • HER3 antibodies on receptor phosphorylation in MCF7 cells is shown below and in Fig IB.
  • HER ECD in w0 2003/013602 were investigated in Mel- Juso cells. Assays in Mel- Juso cells were performed according to the aforementioned protocol for MCF7 and FaDu cells. Cell numbers and media volumes were adapted to 12-well plates Percent (%) inhibition of anti-HER3 antibodies on receptor phosphorylation in Mel- Juso cells is shown below and in Figure 1C.
  • Assays were performed in MCF7 cells according to the following protocol: Seed MCF7 cells with 30000 cells/well into Poly-D-Lysine coated 96-well plate in RPMI 1640 medium with 10% FCS and incubate for 24h. Remove medium by tapping on a clean paper towel, wash carefully with 200 ⁇ 1 serum-free medium, incubate overnight with ⁇ /well RPMI 1640 with 0.5% FCS. Remove medium as above; add antibodies in ⁇ RPMI 1640 with 0.5% FCS and incubate 1.5h. Add HRG-lb (final concentration 5ng/ml) for 10 min. Remove medium as above.
  • HER3 antibodies Mab205.10.1, Mab205.10.2, and Mab205.10.3 in a cell proliferation assay was assessed.
  • MDA-MB-175 cells VII Human Breast Carcinoma Cells, ATCC catalog no. HTB-25
  • 20,000 cells per well were seeded into sterile 96 well tissue culture plates with DMEM/F12 cell culture medium, containing 10% FCS and incubated at 37°C ⁇ 1°C with 5 % ⁇ 1% C0 2 for one day.
  • the cells are slow growing cells with a doubling time of ca. 1.5 days.
  • Anti-HER3 antibodies were added in dilution series and further incubated for 6 days. Cell viability was then assessed using the alamarBlue® readout.
  • IC50 values were calculated using means of triplicates for each antibody concentration; otherwise, if the % inhibition of cell viability at the highest concentration was below 50%, no IC50 could be calculated and it is indicated that IC 50
  • the target cells KPL4 (ADCC), breast carcinoma, cultivation in RPMI1640 + 2 mM L-alanyl-L-Glutamine + 10 % FCS ) were collected with trypsin/EDTA (Gibco # 25300-054) in exponential growth phase. After a washing step and checking cell number and viability, the aliquot needed was labeled for 30 min at
  • ⁇ calcein-stained target cells were plated in round-bottom 96-well plates, 50 ⁇ 1 diluted, afucosylated antibody (Mab205.10.1, Mab205.10.2, Mab205.10.3, preparation see below) which was added and 50 ⁇ 1 effector cells.
  • the target cells were mixed with Redimune® NF Liquid (ZLB Behring) at a concentration of 10 mg/ml Redimune.
  • the killing of target cells was assessed by measuring LDH (Lactate Dehydrogenase) release from damaged cells using the Cytotoxicity Detection kit (LDH Detection Kit, Roche # 1 644 793) according to the manufacturer's instruction. Briefly, 100 ⁇ supernatant from each well was mixed with 100 ⁇ substrate from the kit in a transparent flat bottom 96 well plate. The Vmax values of the substrate's colour reaction was determined in an ELISA reader at 490 nm for at least 10 min. Percentage of specific antibody-mediated killing was calculated as follows: (A - SR)/(MR - SR)xl00, where A is the mean of Vmax at a specific antibody concentration, SR is the mean of Vmax of the spontaneous release and
  • MR is the mean of Vmax of the maximal release.
  • the afucosylated antibody (Mab205.10.1, Mab205.10.2, Mab205.10.3) were prepared by co-transfection with four plasmids, two for antibody expression, one for a fusion GnTIII polypeptide expression (a GnT-III expression vector), and one for mannosidase II expression (a Golgi mannosidase II expression vector) at a ratio of 4:4: 1 : 1, respectively in HEK293 or CHO cells.
  • the full antibody heavy and light chain DNA sequences were subcloned into mammalian expression vectors (one for the light chain and one for the heavy chain) under the control of the MPSV promoter and upstream of a synthetic polyA site, each vector carrying an EBV OriP sequence.
  • Antibodies were produced by co- transfecting HEK293-EBNA cells or CHO cells with the antibody heavy and light chain expression vectors using a calcium phosphate-transfection approach. Exponentially growing HEK293-EBNA cells were trans fected by the calcium phosphate method.
  • the cells were co-transfected with four plasmids, two for antibody expression, one for a fusion GnTIII polypeptide expression (a GnT-III expression vector), and one for mannosidase II expression (a Golgi mannosidase II expression vector) at a ratio of 4:4: 1 : 1, respectively.
  • Cells were grown as adherent monolayer cultures in T flasks using DMEM culture medium supplemented with 10% FCS, and were transfected when they were between 50 and 80% confluent.
  • a solution of DNA, CaC12 and water was prepared by mixing 188 ⁇ g total plasmid vector DNA (four plasmids, two for antibody expression (one light chain and one heavy chain), one for a fusion GnTIII polypeptide expression (a GnT-III expression vector), and one for mannosidase II expression (a Golgi mannosidase II expression vector) at a ratio of 4:4: 1 :1, respectively), water to a final volume of 938 ⁇ and 938 ⁇ of a 1M CaC12 solution.
  • the cells were incubated at 37°C, 5%> C02 for about 17 to 20 hours, then medium was replaced with 25 ml DMEM, 10%> FCS.
  • the conditioned culture medium was harvested 7 days post-transfection by centrifugation for 15 min at 210 x g, the solution was sterile filtered (0.22 ⁇ filter) and sodium azide in a final concentration of 0.01 %> w/v was added, and kept at 4°C.
  • the secreted afucosylated antibodies were purified and the oligosaccharides attached to the Fc region of the antibodies were analysed e.g. by MALDI/TOF-MS (as described in e.g. WO 2008/077546).
  • MALDI/TOF-MS as described in e.g. WO 2008/077546.
  • oligosaccharides were enzymatically released from the antibodies by PNGaseF digestion, with the antibodies being either immobilized on a PVDF membrane or in solution.
  • the resulting digest solution containing the released oligosaccharides either prepared directly for MALDI/TOF-MS analysis or was further digested with EndoH glycosidase prior to sample preparation for MALDI/TOF-MS analysis.
  • the analyzed amount of fucose within the sugar chain at Asn297 was between 50-20%.
  • HER2/HER3 and ER estrogen receptor crosstalk (cross-signaling)
  • Cells were immunoprecipitated with and anti HER2 antibody (trastuzumab) and blotted against ERa (Cell signaling mAb # 8644) or vice versa, immunoprecipitated with an anti ERa antibody (Cell signaling mAb # 8644) and blotted against HER2 (Calbiochem Ab 3).
  • HER2 and ERa can form a complex and in this complex ERa is phosphorylated. Results are shown in Figure 3A,3B and 3C.
  • ERa expressing cells were generated. Cells were starved overnight in DEMEM 0, 5% FCS. After 48h cells were stimulated with HRG (black bars) for 10 min and lysed by a Triton XI 00 lyses buffer containing Aprotinin ⁇ /mL, PMSF ⁇ /mL and Orthovanadate 2 ⁇ 1/ ⁇ 1. Cells were immunoprecipitated with and anti HER3 antibody (Ab) and blotted against ERa antibody (Cell signaling mAb # 8644) or vice versa, immunoprecipitated with an anti ERa antibody (Cell signaling mAb # 8644) and blotted against HER3 (Ab208 Roche). HER3 and ERa can form a complex in the presence and absence of HRG, but ER is strongly phosphorylated only in the presence of HRG. Results are shown in Figure 4A,4B and 4C.
  • HER3 and HER2 can form a complex with the estrogen receptor.
  • HRG activated HER2/HER3 heterodimers mediate phosphorylation of estrogen receptor.
  • - HRG is an ER regulated gene.
  • ER signaling in breast cancer induces HRG expression which in turn drives mitogenic signaling via HER2/HER3 heterodimers.
  • HER2 can activate estrogen receptor
  • the in vivo antitumor efficacy of the antibody Mab205.10.2 in combination with pertuzumab was detected in a fragment based HER2 low, ER+, HER3 + breast cancer patient-derived xenograft model (PDX) transplanted on nude mice.
  • PDX patient-derived xenograft model
  • Mab205.10.2 and pertuzumab were provided as stock solution from Roche, Penzberg, Germany.
  • Antibody buffer included histidine.
  • Antibody solution was diluted appropriately in buffer from stock prior injections. Tumor fragments
  • HBCx-19 breast cancer tumor fragments were originally obtained from a metastasis of a lobular carcinoma. Tumors of the same passage were transplanted subcutaneously onto 6-24 donor mice. When these tumors reached 1000 to 2000 mm 3 , donor mice were sacrificed and tumors excised, dissected and cut into fragments measuring of approximately 20 mm 3 . Thereafter fragments were grafted subcutaneous.
  • mice Female athymic nude mice, 6- to 9-week-old at the beginning of the experimental phase, were obtained from Harlan Laboratories (France). Animals were maintained in specific pathogen-free animal housing at the Center for Exploration and Experimental Functional Research (CERFE, Evry, France) animal facility. Animals were delivered to the laboratory 7 days before the experiments during which time they were acclimatized to laboratory conditions. Mice were housed inside individually ventilated cages (IVC) under a light-dark cycle (14-hour circadian cycle of artificial light) and controlled room temperature and humidity.
  • IVC individually ventilated cages
  • Antibody Mab205.10.2 was administered as single agent and in combination with pertuzumab at 10 mg/kg i.p. q7d once weekly until D61.
  • Pertuzumab was administered as single agent and in combination once weekly at
  • HBCx-19 breast cancer xenograft bearing mice were treated with antibody Mab205.10.2 as single agent and in combination with pertuzumab from study D26 to D61.
  • treatment with Mab205.10.2 antibody as single agent showed strong significant anti-tumor efficacy with tumors stasis until D61 and a Relative Tumor Volume (RTV) of 100%.
  • RTV Relative Tumor Volume
  • Monotherapy with pertuzumab translated into partial HBCx-19 tumor regression at 61 >.
  • superior efficacy was observed with Mab205.10.2 in combination with pertuzumab resulting in strongest tumor regression (RTV 10%).
  • the in vivo antitumor efficacy of the antibody Mab205.10.2 in combination with pertuzumab and selective estrogen receptor degrader (SERD) fulvestrant was detected in a fragment based HER2 low, ER+, HER3+ breast cancer patient- derived xenograft model (PDX) transplanted on nude mice.
  • SELD selective estrogen receptor degrader
  • Test agents Mab205.10.2 and pertuzumab were provided as stock solution from Roche,
  • Antibody buffer included histidine. Antibody solution was diluted appropriately in buffer from stock prior injections. Fulvestrant (Faslodex, Astra Zeneca) was purchased commercially.
  • Tumor fragments HBCx-19 breast cancer tumor fragments were originally obtained from a metastasis of a lobular carcinoma. Tumors of the same passage were transplanted subcutaneously onto 6-24 donor mice. When these tumors reached 1000 to 2000 mm 3 , donor mice were sacrificed and tumors excised, dissected and cut into fragments measuring of approximately 20 mm 3 . Thereafter fragments were grafted subcutaneous. Animals
  • mice Female athymic nude mice, 6- to 9-week-old at the beginning of the experimental phase, were obtained from Harlan Laboratories (France). Animals were maintained in specific pathogen-free animal housing at the Center for Exploration and Experimental Functional Research (CERFE, Evry, France) animal facility. Animals were delivered to the laboratory 7 days before the experiments during which time they were acclimatized to laboratory conditions. Mice were housed inside individually ventilated cages (IVC) under a light-dark cycle (14-hour circadian cycle of artificial light) and controlled room temperature and humidity.
  • IVC individually ventilated cages
  • Antibody Mab205.10.2 was administered at 3 mg/kg as single agent once weekly (6x) as single agent and in dual combination with pertuzumab (3 mg/kg i.p. q7dx6) or in triple combination with fulvestrant (50 mg/kg, im, q7dx6) until D57.
  • Pertuzumab was administered as single agent and in combination once weekly at 3 mg/kg and fulvestrant given im at 50 mg/kg once weekly. The corresponding vehicle was administered on the same days.
  • HBCx-19 HER2 low, ER+, HER3+ breast cancer xenograft bearing mice were treated with antibody Mab205.10.2 as single agent and in combination with pertuzumab and anti-estrogen fulvestrant from study D22 to D57.
  • the triple combination (Mab205.10.2 + pertuzumab + fulvestrant) was the most efficacious combination with tumor control of HBCx-19 BC xenografts (RTV 118%).
  • the monotherapies and dual combinations were less efficacious and HBCx-19 tumors progressed. Results are shown in Figure 6.
  • Glycoengineered Mab205.10.2 was investigated in combination with pertuzumab and paclitaxel in patients with MBC expressing HER3 and HER2 protein.
  • Anti-HER3 antibody Mab205.10.2 was administered at a dose of 500 mg on a q3w schedule (i.e., on day 1 of 3-weekly cycles).
  • Pertuzumab was administered at a loading dose of 840 mg during cycle 1 followed by 420 mg for the remaining cycles in a q3w schedule.
  • Paclitaxel was be administered at 80 mg/m 2 in a qw schedule.
  • a dose of Mab205.10.2 of 1000 mg q3w diarrhea as side effect could be detected.
  • PD Progressive Disease
  • ORR Overall Response Rate, DCR Disease Control rate. The best overall RECIST responses and the line of treatment are indicated.
  • Figure 8 In vivo antitumor efficacy (reduction of lesions) anti-HER3 -antibody Mab205.10.2 in combination with pertuzumab in only first line (1L) HER2 low,
  • Mab205.10.2 was administered at a dose of 500 mg on a q3w schedule (i.e., on day 1 of 3-weekly cycles).
  • Pertuzumab was administered at a dose of 420 mg in a q3w schedule.
  • Paclitaxel was be administered at 80 mg/m 2 in a qw schedule (data not shown).

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Abstract

La présente invention concerne la polythérapie à base d'anticorps anti-HER3 avec certains anticorps anti-HER2.
PCT/EP2016/080890 2015-12-17 2016-12-14 Polythérapie à base d'anticorps anti-her3 et d'anticorps anti-her2 WO2017102789A1 (fr)

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Citations (4)

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Publication number Priority date Publication date Assignee Title
WO2011060206A2 (fr) * 2009-11-13 2011-05-19 U3 Pharma Gmbh Matière et procédés pour traiter ou prévenir des maladies associées à her-3
WO2014036520A1 (fr) * 2012-08-30 2014-03-06 Merrimack Pharmaceuticals, Inc. Polythérapies comprenant des agents anti-erbb3
WO2014108484A2 (fr) * 2013-01-11 2014-07-17 F. Hoffmann-La Roche Ag Thérapie de combinaison avec des anticorps anti-her3
WO2014182970A1 (fr) * 2013-05-08 2014-11-13 Zymeworks Inc. Constructions de liaison aux antigènes her2 et her3 bispécifiques

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011060206A2 (fr) * 2009-11-13 2011-05-19 U3 Pharma Gmbh Matière et procédés pour traiter ou prévenir des maladies associées à her-3
WO2014036520A1 (fr) * 2012-08-30 2014-03-06 Merrimack Pharmaceuticals, Inc. Polythérapies comprenant des agents anti-erbb3
WO2014108484A2 (fr) * 2013-01-11 2014-07-17 F. Hoffmann-La Roche Ag Thérapie de combinaison avec des anticorps anti-her3
WO2014182970A1 (fr) * 2013-05-08 2014-11-13 Zymeworks Inc. Constructions de liaison aux antigènes her2 et her3 bispécifiques

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Title
ANONYMOUS: "A Study to Evaluate RO5479599 in Combination With Pertuzumab (Perjeta) and Paclitaxel in Participants With Metastatic Breast Cancer Expressing Human Epidermal Growth Factor (HER) 3 & HER2 Protein", CLINICALTRIALS.GOV ARCHIVE, 1 December 2015 (2015-12-01), pages 1 - 6, XP055267046, Retrieved from the Internet <URL:https://clinicaltrials.gov/archive/NCT01918254/2015_12_01> [retrieved on 20160420] *
CARRARO S ET AL: "Phase 1b/2 trial of the HER3 inhibitor patritumab (U3-1287) in combination with trastuzumab plus paclitaxel in newly-diagnosed patients with HER2+metastatic breast cancer (MBC)", CANCER RESEARCH, vol. 73, no. Suppl. 24, December 2013 (2013-12-01), & 36TH ANNUAL SAN ANTONIO BREAST CANCER SYMPOSIUM; SAN ANTONIO, TX, USA; DECEMBER 10 -14, 2013, pages P4 - 16, XP002756797, ISSN: 0008-5472 *
ZHANG: "Abstract 655: Combination of MM-111, an ErbB2/ErbB3 bispecific antibody, with endocrine therapies as an effective strategy for treatment of ER+/HER2+ breast cancer", CANCER RESEARCH, 2 April 2011 (2011-04-02), pages 1 - 2, XP055266204, Retrieved from the Internet <URL:http://cancerres.aacrjournals.org/content/71/8_Supplement/655.abstract?sid=afc6d588-67e3-486b-84d2-c41c76637228> [retrieved on 20160418], DOI: 10.1158/1538-7445.AM2011-655 *

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