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WO2025248097A2 - Humanized anti-human her3 antibodies and uses thereof - Google Patents

Humanized anti-human her3 antibodies and uses thereof

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Publication number
WO2025248097A2
WO2025248097A2 PCT/EP2025/065004 EP2025065004W WO2025248097A2 WO 2025248097 A2 WO2025248097 A2 WO 2025248097A2 EP 2025065004 W EP2025065004 W EP 2025065004W WO 2025248097 A2 WO2025248097 A2 WO 2025248097A2
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WIPO (PCT)
Prior art keywords
seq
antibody
acid sequence
amino acid
variable domain
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Pending
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PCT/EP2025/065004
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French (fr)
Other versions
WO2025248097A3 (en
Inventor
Thierry Hercend
Olivier Dubreuil
Jean-Marc Barret
Jean-François Prost
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Gamamabs Pharma SA
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Gamamabs Pharma SA
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Publication of WO2025248097A2 publication Critical patent/WO2025248097A2/en
Publication of WO2025248097A3 publication Critical patent/WO2025248097A3/en
Pending legal-status Critical Current
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2863—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for growth factors, growth regulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • C07K16/32—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against translation products of oncogenes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/55—Fab or Fab'
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
    • 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
    • C07K2317/77—Internalization into the cell
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/94—Stability, e.g. half-life, pH, temperature or enzyme-resistance

Definitions

  • the present invention relates to humanized anti-human-HER3 antibodies and uses thereof in diagnostic and therapeutic applications.
  • the human epidermal growth factor receptor ErbB/HER family of receptor tyrosine kinases includes four members: EGFR (ErbB1/HER1), HER2 (c-Neu, HER2), HER3 (ErbB3/HER3) and HER4 (ErbB4/HER4).
  • the HER receptors comprise an extracellular glycosylated domain consisting of four structural domains, marked 1 to 4, followed by a transmembrane domain and an intracellular C-terminal part containing a kinase domain for coupling to signalling pathways. Except for HER3, the intracellular region contains a tyrosine kinase activity. Signalling is mediated through ligand-induced receptor dimerization and subsequent phosphorylation that leads to the activation of cytoplasmic signalling pathways, especially PI3K/AKT and MAP kinase pathways (Campbell et al., Clin. Cancer Res., 16: 1373- 1383 (2010)). HER2 has no specific ligand because it is naturally under an "active” conformation.
  • the other HER receptors exist as inactive monomers with the molecules folded in such a way to prevent dimerization. Ligand binding to domains 1 and 3 induces major conformational changes ultimately exposing the dimerization loop in domain 2 of the receptor. This exposure of the dimerization loop allows for receptor dimerization (Zhang et al., Cell, 66: 1025-1052 (2006)).
  • the HER3 receptor that has been first described in 1990 (Plowman et al., Proc. Natl. Acad. Sci. USA, 87: 4905-4909 (1990)), is the only HER family member receptor that shows low kinase activity and of which downstream signalling is achieved through heterodimerization.
  • the HER3 receptor as a monomer, is called “non-self” and cannot form homodimers. Binding of the ligand neuregulin (NRG) to HER3 receptor triggers the heterodimerization of HER3 with the others HER family receptors (HER2 preferentially) (Tzahar et al., Mol. Cell Biol., 16: 5276-5287 (1996)). Within the heterodimer, the HER3 kinase domain acts as an allosteric activator of its HER family partner (Baselga and Swain, Nat. Rev. Cancer, 9: 463-475 (2009)).
  • HER3 is implicated in tumorigenesis of various cancers including breast and ovarian cancer (Lee-Hoeflich et al., Cancer Res., 15: 5878-5887 (2008); McIntyre et al., Breast Cancer Res. Treat., 122: 105-110 (2010); Tanner et al., J Clin. Oncol., 24: 4317-4323 (2006)).
  • HER3 is accordingly overexpressed in over 40% of solid malignant tumors, among others in cervical and ovarian cancers, colorectal, gastric, breast, head and neck, and prostate cancer.
  • tumors with low HER2 expression which are not eligible to Herceptin treatment, are often “programmed” to strongly express HER3 (Smith et al. Br. J. Cancer, 91: 1190-1194 (2004)).
  • HER2+++ tumors which become resistant to Herceptin after prolonged treatment, are “re-programmed” to strongly express HER3 (Narayan et al., Cancer Res., 69: 2191-2194 (2009)).
  • Cetuximab resistance was also associated with HER3 over-expression in lung cancer (Wheeler et al., Oncogene, 27: 3944-3956 (2008)) and colorectal carcinomas (Lu et al., Cancer Res., 67: 8240- 8247 (2007)), together with dysregulation of EGFR internalization/degradation. Recently, HER3 over-expression was significantly associated with reduced metastasis-free survival in colorectal carcinoma (Ho-Pun-Cheung et al., Int. J. Cancer, 128: 2938-2946 (2011)).
  • HER3 over-expression and compensatory signalling through activation of the PI3K/AKT pathway are implicated in the development of resistance to treatment with HER-targeted therapies (antibodies and TKI) (Wheeler et al., Oncogene, 27: 3944-3956 (2008); Lu et al., Cancer Res., 67: 8240-8247 (2007); Narayan et al., Cancer Res., 69: 2191-2194 (2009)) but also to treatment with IGFR-targeted therapies (Desbois-Mouthon et al., Clin. Cancer Res., 15: 5445-5456 (2009)) and with chemotherapeutic agents (Kruser and Wheeler, Exp.
  • NRG1 ⁇ and ⁇ and NRG2 ⁇ and ⁇ The physiological ligand of HER3, NRG, exists in 4 forms: NRG1 ⁇ and ⁇ and NRG2 ⁇ and ⁇ . These 4 ligands share an EGF-like domain which binds to the extracellular domain of HER3 and induces receptor dimerization initiating a cascade of phosphorylations, in particular that of AKT and MAP-kinase, resulting in cellular growth and differentiation (Nagasaka and Ou, Trends Cancer, 8: 242-258 (2022)). As its receptor HER3, NRG is widely expressed in solid tumors.
  • NRG1 is expressed more particularly in lung, head and neck and breast cancers while NRG2 is preferentially expressed in renal and breast cancers, in melanoma and glioma.
  • Numerous studies using immuno-chemistry methods (or RNA scope) have described the expression of NRG in multiple solid tumors: in particular in ovarian cancer (Gilmour et al., Clin.
  • NRG1 expression was associated with aggressive features of the disease and poor prognosis.
  • Expression of NRG in solid tumors has been also reviewed by Ocana in 2016 (Ocana et al., Oncotarget, 7: 45042-45051 (2016)).
  • HER3 alterations occur in ⁇ 10% of tumours (especially bladder cancer and colorectal cancer) which could be present de novo or acquired during targeted therapy, and induce therapeutic resistance (Kilroy et al., Cancers, 14: 6174-6196 (2022)).
  • the present invention relates to a humanized neuregulin positively dependent, in particular non-competitive, anti-human-HER3 antibody comprising: (i) a heavy chain wherein the variable domain has at least 90% or 95% identity with the amino acid sequence set forth as SEQ ID NO: 1: X1VQLX2X3SGX4X5LX6X7PGX8SX9X10X11SCX12ASGFTFSSYX13MSWVRQA PGX14GLEWVAYISDX15GGVTYYX16DX17X18KGRFX19ISRDNSX20X21TLYLQMX22SL X 23 AEDTAVYYCARDRYGLFX 24 YWGQGTLVTVSS (SEQ ID NO: 1) wherein: X1 represents E or Q, in particular E; X2 represents V or L, in particular L; X 3 represents E or Q, in particular E; X4 represents G or S, in particular G;
  • the antibody according to the invention may in particular be such that: (i) the heavy chain comprises: - a H-CDR1 having a sequence selected from the group consisting of SEQ ID NO: 3 and SEQ ID NO: 4; and - a H-CDR2 having a sequence selected from the group consisting of SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10 and SEQ ID NO: 11; and - a H-CDR3 having a sequence selected from the group consisting of SEQ ID NO: 12 and SEQ ID NO: 13; and, (ii) the light chain comprises: - a L-CDR1 having a sequence selected from the group consisting of SEQ ID NO: 14 and SEQ ID NO: 15; and - a L-CDR2 having the sequence set forth as SEQ ID NO: 16; and - a L-CDR3 having a sequence selected from the group consisting of SEQ ID NO: 17 and SEQ ID
  • variable domain of the heavy chain comprises, and in particular consists in, an amino acid sequence selected from the group consisting of SEQ ID NO: 20, SEQ ID NO: 22, SEQ ID NO: 19, SEQ ID NO: 21, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26 and SEQ ID NO: 27.
  • the antibody according to the invention may be characterized in that the variable domain of the light chain comprises, and in particular consists in, an amino acid sequence selected from the group consisting of SEQ ID NO: 29, SEQ ID NO: 28, SEQ ID NO: 30, SEQ ID NO: 31 and SEQ ID NO: 32.
  • the antibody according to the invention may be selected from the group consisting of antibodies wherein: - the variable domain of the heavy chain of said antibody comprises, and in particular consists in, the amino acid sequence set forth as SEQ ID NO: 20 and/or, in particular and, the variable domain of the light chain comprises, and in particular consists in, an amino acid sequence selected from the group consisting of SEQ ID NO: 28, 29, 30, 31 and 32; or - the variable domain of the heavy chain of said antibody comprises, and in particular consists in, the amino acid sequence set forth as SEQ ID NO: 22 and the variable domain of the light chain comprises, and in particular consists in, the amino acid sequence set forth as SEQ ID NO: 29; or - the variable domain of the heavy chain of said antibody comprises, and in particular consists in, the amino acid sequence set forth as SEQ ID NO: 19 and the variable domain of the light chain comprises, and in particular consists in, an amino acid sequence selected from the group consisting of SEQ ID NO: 28, 29, 31 and 32; or - the variable domain of the heavy chain of said
  • the antibody according to the invention may be such that: - the variable domain of the heavy chain of said antibody comprises, and in particular consists in, an amino acid sequence selected from the group consisting of SEQ ID NO: 20, 22, 19, 21, 23, 24 and 25; and - the variable domain of the light chain of said antibody comprises, and in particular consists in, an amino acid sequence selected from the group consisting of SEQ ID NO: 29, 28 and 30.
  • the antibody of the invention may be characterized in that: - the variable domain of the heavy chain of said antibody comprises, and in particular consists in, an amino acid sequence selected from the group consisting of SEQ ID NO: 20, 22, 24 and 25; and - the variable domain of the light chain of said antibody comprises, and in particular consists in, an amino acid sequence selected from the group consisting of SEQ ID NO: 29 and 30.
  • the antibody according to the invention may be selected from the group consisting of antibodies wherein: - the variable domain of the heavy chain of said antibody comprises, and in particular consists in, the amino acid sequence set forth as SEQ ID NO: 20 and the variable domain of the light chain comprises, and in particular consists in, the amino acid sequence set forth as SEQ ID NO: 29; or - the variable domain of the heavy chain of said antibody comprises, and in particular consists in, the amino acid sequence set forth as SEQ ID NO: 22 and the variable domain of the light chain comprises, and in particular consists in, the amino acid sequence set forth as SEQ ID NO: 29; or - the variable domain of the heavy chain of said antibody comprises, and in particular consists in, the amino acid sequence set forth as SEQ ID NO: 24 and the variable domain of the light chain comprises, and in particular consists in, the amino acid sequence set forth as SEQ ID NO: 30; or - the variable domain of the heavy chain of said antibody comprises, and in particular consists in, the amino acid sequence set forth as SEQ ID NO: 25 and
  • Another object of the present invention is an immunoconjugate comprising the antibody according to the invention linked to a therapeutic agent.
  • a further object of the present invention is a fragment of an antibody according to the invention comprising the variable domain of the heavy chain and the variable domain of the light chain.
  • the fragment of the invention may be selected from the group consisting of Fv, Fab, F(ab’)2, Fab’, dsFv, scFv, sc(Fv)2 and diabodies.
  • Another object of the present invention is a nucleic acid sequence encoding an antibody according to the invention or a fragment of the invention.
  • a further object of the invention is a vector comprising a nucleic acid sequence according to the invention.
  • Another object of the invention is a host cell, in particular a procaryotic or eucaryotic host cell, comprising a nucleic acid sequence according to the invention or a vector according to the invention.
  • a further object of the invention is a pharmaceutical composition comprising an antibody according to the invention, an immunoconjugate according to the invention, or a fragment according to the invention, in a pharmaceutically acceptable carrier.
  • Another object of the invention is an antibody according to the invention, an immunoconjugate according to the invention, or a fragment according to the invention, for use as a drug.
  • a further object of the invention is an antibody according to the invention, an immunoconjugate according to the invention, a fragment according to the invention or a pharmaceutical composition according to the invention for use in the treatment of a HER3- expressing cancer, in particular of a HER3-expressing cancer wherein neuregulin is present, in an individual in need thereof.
  • the HER3-expressing cancer may in particular be a NRG-dependent cancer, and in particular a NRG-fusion protein driven cancer.
  • the neuregulin in particular neuregulin 1 or neuregulin 2, more particularly neuregulin 1 ⁇ , 1 ⁇ or 2, and more particularly neuregulin 1 ⁇ , present may be secreted by the cancer and/or by tissues and/or organs, in particular by tissues and/or organs in the cancer and/or surrounding the cancer.
  • the neuregulin, and in particular neuregulin 1 ⁇ , presence may also be due to its administration to the subject before, after, or at the same time as the antibody and/or the immunoconjugate.
  • a well-known method of immunohistochemistry can be applied as described in Gilmour et al., Clin.
  • the cancers or tumor cells associated with the expression of HER3 considered in the present invention may be chosen from the group consisting of head and neck cancers, squamous cell cancer, esophagus cancer, non-small cell lung cancer, cutaneous squamous cancers, cervical cancer, vulval cancer and anal cancer, gastric cancer, pancreatic cancer, glial cell tumors, ovarian cancer, bladder cancer, breast cancer, melanoma, colorectal cancer in particular colon cancer, endometrial carcinoma, salivary gland carcinoma, renal cell carcinoma, prostate cancer, thyroid cancer and hepatic cell carcinoma.
  • FIGURES Figure 1 shows the evaluation of binding of Fab-Yeast for recombinant human HER3- ECD Fc fusion by FACS for Gama-2 to Gama-13 humanized variants antibodies compared to 9F7-F11.
  • the 9F7-F11 and humanized variants antibodies in Fab format were expressed on the surface of Yeast.
  • the expression of the construct as well the binding of the recombinant HER3 to the Fab-Yeast were revealed respectively by an anti-Light chain Kappa (APC) and by an anti-human Fc conjugated antibody (PE).
  • the fluorescence ratio PE/APC reveals the binding to recombinant HER3 (8nM) normalized with the level of Fab expression on the surface of the Yeast.
  • Figure 2 shows the evaluation of binding of Fab-Yeast for recombinant human HER3- ECD Fc fusion by FACS for Gama-21, -23, -24, -25, -26, -27, -29, -31 and -33 humanized variants antibodies compared to Gama-7.
  • the humanized variants antibodies in Fab format were expressed on the surface of Yeast.
  • the expression of the construct as well the binding of the recombinant HER3 to the Fab-Yeast were revealed respectively by an anti-Light chain Kappa (APC) and by an anti-human Fc conjugated antibody (PE).
  • APC anti-Light chain Kappa
  • PE anti-human Fc conjugated antibody
  • the fluorescence ratio PE/APC reveals the binding to recombinant HER3 (200pM) normalized with the level of Fab expression on the surface of the Yeast.
  • Figure 3 illustrates the binding of the humanized antibodies to the HER3 receptor expressed at the surface membrane of SKBR3 breast cancer cell line. Binding curves of antibodies at 50 ⁇ g/ml were determined by FACS analysis with different concentrations of NRG1 (A, C and E) or in absence of NRG1 (B, D and F). Comparison of binding of Gama-5 and Gama-7 humanized antibodies with Patritumab in presence of NRG1 (A) or in absence of NRG1 (B).
  • Binding curves of antibodies at different concentration were determined by FACS analysis in presence of NRG1 at 50nM or in absence.
  • Dotted line indicates MFI background value (control).
  • Abscissa Concentration of Antibody in ⁇ g/mL. Performed using a Fortessa Flow cytometer (BD Bioscience) (PE-A setting).
  • Figure 5 illustrates the binding of the humanized antibody Gama-23A to the HER3 receptor expressed at the surface membrane of SKBR3 breast cell line in presence of different HER3 ligands.
  • FIG. 6 illustrates the thermal stabilization of the humanized variants as compared to the 9F7-F11 parental chimeric antibody by DSC (Differential Scanning calorimetry). Representations of analyzed DSC data after baseline substraction and curve fitting of (A) 9F7- F11 and (B) Gama-23A. In A) and B) the thick line represents the thermogram after baseline subtraction. The dashed lines are the deconvoluted peaks of each domain transition (Fab, CH2, CH3).
  • the thermal transition temperature (melting temperature; Tm) of the Fab of the antibody tested correspond to the highest pic on the thermogram.
  • Tm and ⁇ H for 9F7-F11 (Fab) are 75.6 °C and 543 kcal/mol respectively.
  • Tm and ⁇ H for Gama-23A (Fab) are 79.4°C and 602 kcal/mol respectively.
  • Abscissa temperature in degree Celsius.
  • Ordinate Heat capacity Cp (kcal/Mol/°C).
  • Figure 7 shows the effect of the humanized variants Gama-23A, Gama-7, Gama-23 and Patritumab on Akt (7A) and HER3 phosphorylation (7B) in T47D breast cancer cell lines in presence of NRG1 at 25nM and antibodies concentrations range from 0.05 ⁇ g/mL to 50 ⁇ g/mL.
  • HTRF ration corresponds to the TR-FRET signal corresponds to the 665 nm/620 nm emission ratio.
  • certain humanized antibodies but not others comprising several modifications compared to the chimeric antibody from which they originate, sometimes even in at least one of the CDRs, are able to preferably bind to tissues expressing HER3 wherein NRG1 is present (such as cancers, in particular cancers as defined in the present herein) compared to tissues expressing HER3 wherein NRG1 is less present or even not present (in particular healthy tissues), and at least in the same measure, or better, than the original chimeric antibody.
  • tumor-selectivity is highly interesting as it enlarges the therapeutic index of a pharmaceutical composition containing such an antibody, whilst preserving healthy HER3 + tissues, which generally contain low levels of NRG.
  • the term “neuregulin” has its general meaning in the art and is often used interchangeably with the term “heregulin”.
  • the heregulin family includes alpha, beta and gamma heregulins (Holmes et al., Science, 256: 1205-1210 (1992); U.S. Patent No. 5,641,869; and Schaefer et al.
  • NDFs neu differentiation factors
  • GGFs glial growth factors
  • ARIA acetylcholine receptor inducing activity
  • SMDF sensory and motor neuron derived factor
  • Neuregulin also referred to as NRG in the present text, may be selected from Neuregulin 1 (NRG1) or Neuregulin 2 (NRG2), more particularly be selected from Neuregulin 1 ⁇ (NRG1 ⁇ ), Neuregulin 1 ⁇ (NRG1 ⁇ ) or Neuregulin 2 (NRG2).
  • HER3 refers to the human HER3 receptor as described in Plowman et al., Proc. Natl. Acad. Sci. USA, 87: 4905-4909 (1990); see, also, Kani et al., Biochemistry, 44: 15842-857 (2005), Cho and Leahy, Science, 297: 1330-1333 (2002)).
  • antibody refers to an antibody directed against human HER3.
  • antibody or “immunoglobulin” have the same meaning, and will be used equally in the present invention.
  • antibody refers to immunoglobulin molecules and immunologically active portions of immunoglobulin molecules, i.e., molecules that contain an antigen binding site that immunochemically binds an antigen.
  • the term antibody encompasses not only whole antibody molecules, but also variants (including derivatives) of antibodies.
  • two heavy chains are linked to each other by disulfide bonds and each heavy chain is linked to a light chain by a disulfide bond.
  • the light chain includes two domains, a variable domain (VL) and a constant domain (CL).
  • the heavy chain includes four domains, a variable domain (VH) and three constant domains (CH1, CH2 and CH3, collectively referred to as CH).
  • the variable regions of both light (VL) and heavy (VH) chains determine binding recognition and specificity to the antigen.
  • the constant region domains of the light (CL) and heavy (CH) chains confer important biological properties such as antibody chain association, secretion, trans-placental mobility, complement binding, and binding to Fc receptors (FcR).
  • the Fv fragment is the N-terminal part of the Fab fragment of an immunoglobulin and consists of the variable portions of one light chain and one heavy chain.
  • the specificity of the antibody resides in the structural complementarity between the antibody combining site and the antigenic determinant.
  • Antibody combining sites are made up of residues that are primarily from the hypervariable or complementarity determining regions (CDRs). Occasionally, residues from non-hypervariable or framework regions (FR) influence the overall domain structure and hence the combining site.
  • Complementarity Determining Regions or CDRs refer to amino acid sequences which together define the binding affinity and specificity of the natural Fv region of a native immunoglobulin binding site.
  • the light and heavy chains of an immunoglobulin each have three CDRs, designated L-CDR1, L-CDR2, L-CDR3 and H-CDR1, H-CDR2, H-CDR3, respectively.
  • An antigen-binding site therefore, includes six CDRs, comprising the CDR set from each of a heavy and a light chain V region.
  • Framework Regions (FRs) refer to amino acid sequences interposed between CDRs.
  • the well-known Kabat numbering system is used in the present text for defining antibodies according to the invention, and in particular to define their CDRs.
  • antibody is used in the broadest sense and includes fully assembled antibodies, monoclonal antibodies, polyclonal antibodies, multi-specific antibodies (e.g., bispecific antibodies), antibody fragments that can bind HER3, and recombinant peptides comprising the forgoing as long as they exhibit the desired biological activity defined herein.
  • chimeric antibody refers to an antibody which comprises a VH domain and a VL domain of an antibody which are derived from one species and the constant domain which is derived from another species, for example an antibody in which the variable region sequences are derived from a mouse antibody and the constant region sequences are derived from a human antibody.
  • the term “humanized antibody” refers to an antibody having variable region framework and constant regions from a human antibody but which retains the mouse sequence origin of the CDRs of the variable V regions.
  • the terms “monoclonal antibody” or “monoclonal antibody composition” as used herein refer to a preparation of antibody molecules of single molecular composition. A monoclonal antibody composition displays a single binding specificity and affinity for a particular epitope.
  • the terms “neuregulin non-competitive” defining an antibody are used herein to indicate an antibody with a binding site not shared (even partially) with that of neuregulin, in particular with that of NRG1, and therefore an antibody that does not compete with NRG1 for its binding, in particular to human HER3.
  • a “neuregulin positively dependent” anti-HER3 antibody is used herein to indicate an antibody who’s binding to HER3 increases with the increase of the quantity of neuregulin present within the immediate vicinity of the targeted HER3. In simpler terms, this antibody's affinity for HER3 enhances as the amount of neuregulin in close proximity to the specific HER3 molecule becomes greater.
  • treatment refers to administering an active agent with the purpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve, or affect a condition (e.g., a disease), the symptoms of the condition, or to prevent or delay the onset of the symptoms, complications, biochemical indicia of a disease, or otherwise arrest or inhibit further development of the disease, condition, or disorder in a statistically significant manner.
  • a condition e.g., a disease
  • the terms “patient”, “individual”, “patient in need thereof” or “individual in need thereof” are equivalent and are intended for a human or non- human mammal affected or likely to be affected with cancer associated with the expression of human HER3, in particular of a HER3-expressing cancer wherein neuregulin is present in an individual in need thereof.
  • Said individual is preferably a human being.
  • An antibody according to the invention, an immunoconjugate according to the invention or a fragment according to the invention is implemented according to the present invention in a therapeutically effective amount.
  • a “therapeutically effective amount” of the antibody, immunoconjugate or fragment of the invention is meant a sufficient amount of antibody, immunoconjugate or fragment to treat said cancer, at a reasonable benefit/risk ratio applicable to any medical treatment. It will be understood, however, that the total daily usage of the antibody, immunoconjugate or fragment and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment.
  • the specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific antibody employed; the specific composition employed, the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific antibody employed; the duration of the treatment; drugs used in combination or coincidental with the specific antibody employed; and like factors well known in the medical arts. For example, it is well known within the skill of the art to start doses of the compound at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. For each or the amino acid sequences of interest, reference sequences are described herein. The present description also encompasses amino acid sequences (e.g.
  • enzyme amino acid sequences having specific percentages of amino acid identity with a reference amino acid sequence.
  • a specific nucleic acid sequence or a specific amino acid sequence which complies with, respectively, the considered nucleotide or amino acid identity should further lead to obtaining a protein (or enzyme) which displays the desired biological activity.
  • the "percentage of identity" between two nucleic acid sequences or between two amino acid sequences is determined by comparing both optimally aligned sequences through a comparison window.
  • the portion of the nucleotide or amino-acid sequence in the comparison window may thus include additions or deletions (for example "gaps") as compared to the reference sequence (which does not include these additions or these deletions) so as to obtain an optimal alignment between both sequences.
  • sequence homology or “sequence identity” or “homology” or “identity” are used interchangeably herein.
  • sequences are aligned for optimal comparison purposes. In order to optimize the alignment between the two sequences gaps may be introduced in any of the two sequences that are compared.
  • sequence identity is the percentage of identical matches between the two sequences over the reported aligned region.
  • a comparison of sequences and determination of percentage of sequence identity between two sequences can be accomplished using a mathematical algorithm. The skilled person will be aware of the fact that several different computer programs are available to align two sequences and determine the identity between two sequences (Kruskal, J. B. (1983) An overview of sequence comparison In D. Sankoff and J. B. Kruskal, (ed.), Time warps, string edits and macromolecules: the theory and practice of sequence comparison, pp.
  • the percent sequence identity between two amino acid sequences or between two nucleotide sequences may be determined using the Needleman and Wunsch algorithm for the alignment of two sequences. (Needleman and Wunsch, J. Mol. Biol., 48: 443-453 (1970)). Both amino acid sequences and nucleotide sequences can be aligned by the algorithm.
  • the Needleman-Wunsch algorithm has been implemented in the computer program NEEDLE.
  • the NEEDLE program from the EMBOSS package was used (version 2.8.0 or higher, EMBOSS: The European Molecular Biology Open Software Suite (2000) Rice, P. Longden J. and Bleasby, A.
  • the percentage of sequence identity between a query sequence and a sequence of the invention is calculated as follows: Number of corresponding positions in the alignment showing an identical amino acid or identical nucleotide in both sequences divided by the total length of the alignment after subtraction of the total number of gaps in the alignment.
  • the identity defined as herein can be obtained from NEEDLE by using the NOBRIEF option and is labeled in the output of the program as "longest-identity".
  • the similarity of nucleotide and amino acid sequences, i.e. the percentage of sequence identity can be determined via sequence alignments using several other art-known algorithms, preferably with the mathematical algorithm of Karlin and Altschul (Karlin and Altschul, Proc. Natl. Acad. Sci.
  • HMMER package http://hmmer.org/
  • CLUSTAL algorithm Thimpson et al., Nucleic Acids Res., 22: 4673-80 (1994)
  • GAP program mathematical algorithm of the University of Iowa
  • Myers and Miller (1989 - Cabios 4: 11-17) or Clone Manager 9.
  • Preferred parameters used are the default parameters as they are set on https://www.ebi.ac.uk/Tools/msa/clustalo/.
  • sequence matching may be calculated using e.g. BLAST, BLAT or BlastZ (or BlastX).
  • BLASTN and BLASTP programs of Altschul et al., J. Mol. Biol., 215: 403-410 (1990).
  • Gapped BLAST is utilized as described in Altschul et al., Nucleic Acids Res., 25: 3389-3402 (1997).
  • Sequence matching analysis may be supplemented by established homology mapping techniques like Shuffle-LAGAN (Brudno, Bioinformatics, 19 Suppl 1: 154-162 (2003)) or Markov random fields.
  • Shuffle-LAGAN Brudno, Bioinformatics, 19 Suppl 1: 154-162 (2003)
  • Markov random fields Markov random fields.
  • amino acids are represented in the sequences on the basis of the commonly recognized and known single-letter code which is reminded hereafter: Alanine: A; Arginine: R; Asparagine: N; Aspartic Acid: D; Cysteine: C; Glutamic Acid: E; Glutamine: Q; Glycine: G; Histidine: H; Isoleucine: I; Leucine: L; Lysine: K; Methionine: M; Phenylalanine: F; Proline: P; Serine: S; Threonine: T; Tryptophan: W; Tyrosine: Y and Valine: V.
  • the present invention provides for neuregulin (NRG)-positively dependent, in particular non-competitive, anti-HER3 antibodies, preferably in a purified form or in an isolated form, said antibodies comprising (i) a heavy chain wherein the variable domain has at least 90% or 95% identity with the amino acid sequence set forth as SEQ ID NO: 1 and (ii) a light chain wherein the variable domain has at least 90% or 95% identity with the amino acid sequence set forth as SEQ ID NO: 2.
  • NSG neuregulin
  • an antibody comprising (i) a heavy chain wherein the variable domain has at least 90% identity with the amino acid sequence set forth as SEQ ID NO: 1 and (ii) a light chain wherein the variable domain has at least 90% identity with the amino acid sequence set forth as SEQ ID NO: 2 accordingly designates an antibody comprising (i) a heavy chain wherein the variable domain has at least 90% identity with the amino acid sequence set forth as SEQ ID NO: 1 and (ii) a light chain wherein the variable domain has at least 90% identity with the amino acid sequence set forth as SEQ ID NO: 2 and having a biological activity of the same nature as an antibody having the amino acid sequences SEQ ID NO: 1 and SEQ ID NO: 2.
  • a biological activity of the same nature for an antibody herein means an antibody which is anti-HER3, in particular anti-human HER3, and which has the ability to have a significantly increased binding to HER3 in the presence of NRG1 compared to when NRG1 is absent.
  • an amino acid sequence having at least 90% identity with a reference amino acid sequence encompasses amino acid sequences having at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% and 99% nucleotide identity with the said reference amino acid sequence, and also a biological activity of the same nature as the said reference amino acid sequence.
  • an amino acid sequence having at least 95% identity with a reference amino acid sequence encompasses amino acid sequences having at least 96%, 97%, 98% and 99% nucleotide identity with the said reference amino acid sequence, and also a biological activity of the same nature as the said reference amino acid sequence.
  • An antibody according to the invention may in particular comprise a heavy chain comprising: - a H-CDR1 having a sequence selected from the group consisting of SEQ ID NO: 3 and SEQ ID NO: 4; and - a H-CDR2 having a sequence selected from the group consisting of SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10 and SEQ ID NO: 11; and - a H-CDR3 having a sequence selected from the group consisting of SEQ ID NO: 12 and SEQ ID NO: 13.
  • An antibody according to the invention may in particular comprise a light chain comprising: - a L-CDR1 having a sequence selected from the group consisting of SEQ ID NO: 14 and SEQ ID NO: 15; and - a L-CDR2 having the sequence set forth as SEQ ID NO: 16; and - a L-CDR3 having a sequence selected from the group consisting of SEQ ID NO: 17 and SEQ ID NO: 18.
  • an antibody according to the invention may comprise: (i) a heavy chain comprising: - a H-CDR1 having a sequence selected from the group consisting of SEQ ID NO: 3 and SEQ ID NO: 4; and - a H-CDR2 having a sequence selected from the group consisting of SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10 and SEQ ID NO: 11; and - a H-CDR3 having a sequence selected from the group consisting of SEQ ID NO: 12 and SEQ ID NO: 13, and more particularly a H-CDR3 having the sequence set forth as SEQ ID NO: 12; and (ii) a light chain comprising: - a L-CDR1 having a sequence selected from the group consisting of SEQ ID NO: 14 and SEQ ID NO: 15; and - a L-CDR2 having the sequence set forth as SEQ ID NO: 16; and - a L-C
  • variable domain of the heavy chain of an antibody according to the invention may comprise, and in particular may consist in, an amino acid sequence selected from the group consisting of SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26 and SEQ ID NO: 27.
  • variable domain of the heavy chain of an antibody according to the invention may comprise, and in particular may consist in, an amino acid sequence selected from the group consisting of SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24 and SEQ ID NO: 25, more particularly from the group consisting of SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 24 and SEQ ID NO: 25, and in particular from the group consisting of SEQ ID NO: 20, SEQ ID NO: 22, SEQ ID NO: 24 and SEQ ID NO: 25.
  • variable domain of the light chain of an antibody according to the invention may comprise, and in particular may consist in, an amino acid sequence selected from the group consisting of SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31 and SEQ ID NO: 32.
  • the variable domain of the light chain of an antibody according to the invention may comprise, and in particular may consist in, an amino acid sequence selected from the group consisting of SEQ ID NO: 28, SEQ ID NO: 29 and SEQ ID NO: 30 and in particular from the group consisting of SEQ ID NO: 29 and SEQ ID NO: 30.
  • an antibody according to the invention may comprise: (i) a variable domain of the heavy chain comprising, and in particular consisting in, an amino acid sequence selected from the group consisting of SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26 and SEQ ID NO: 27, in particular selected from the group consisting of SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24 and SEQ ID NO: 25, more particularly from the group consisting of SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 24 and SEQ ID NO: 25, and in particular from the group consisting of SEQ ID NO: 20, SEQ ID NO: 22, SEQ ID NO: 24 and SEQ ID NO: 25; and (ii) a variable domain of the light chain comprising, and in particular consisting in, an amino acid
  • An antibody according to the invention may be selected from the group consisting of antibodies wherein: - the variable domain of the heavy chain of said antibody comprises, and in particular consists in, the amino acid sequence set forth as SEQ ID NO: 19 and the variable domain of the light chain comprises, and in particular consists in, an amino acid sequence selected from the group consisting of SEQ ID NO: 28, 29, 31 and 32; or - the variable domain of the heavy chain of said antibody comprises, and in particular consists in, the amino acid sequence set forth as SEQ ID NO: 20 and the variable domain of the light chain comprises, and in particular consists in, an amino acid sequence selected from the group consisting of SEQ ID NO: 28, 29, 30, 31 and 32; or - the variable domain of the heavy chain of said antibody comprises, and in particular consists in, the amino acid sequence set forth as SEQ ID NO: 26 and the variable domain of the light chain comprises, and in particular consists in, an amino acid sequence selected from the group consisting of SEQ ID NO: 28, 29, 31 and 32; or - the variable domain of the heavy chain of said antibody
  • an antibody according to the invention may comprise: - a variable domain of the heavy chain comprising, and in particular consisting in, an amino acid sequence selected from the group consisting of SEQ ID NO: 19, 20, 21, 22, 23, 24 and 25; and - a variable domain of the light chain comprising, and in particular consisting in, an amino acid sequence selected from the group consisting of SEQ ID NO: 28, 29 and 30.
  • an antibody according to the invention may comprise: - a variable domain of the heavy chain comprising, and in particular consisting in, an amino acid sequence selected from the group consisting of SEQ ID NO: 19, 20, 21, 22, 24 and 25; and - a variable domain of the light chain comprising, and in particular consisting in, an amino acid sequence selected from the group consisting of SEQ ID NO: 28, 29 and 30.
  • an antibody according to the invention may comprise: - a variable domain of the heavy chain comprising, and in particular consisting in, an amino acid sequence selected from the group consisting of SEQ ID NO: 20, 22, 24 and 25; and - a variable domain of the light chain comprising, and in particular consisting in, an amino acid sequence selected from the group consisting of SEQ ID NO: 29 and 30.
  • An antibody according to the invention may be selected from the group consisting of antibodies wherein: - the variable domain of the heavy chain of said antibody comprises, and in particular consists in, the amino acid sequence set forth as SEQ ID NO: 20 and the variable domain of the light chain comprises, and in particular consists in, the amino acid sequence set forth as SEQ ID NO: 29; or - the variable domain of the heavy chain of said antibody comprises, and in particular consists in, the amino acid sequence set forth as SEQ ID NO: 22 and the variable domain of the light chain comprises, and in particular consists in, the amino acid sequence set forth as SEQ ID NO: 29; or - the variable domain of the heavy chain of said antibody comprises, and in particular consists in, the amino acid sequence set forth as SEQ ID NO: 24 and the variable domain of the light chain comprises, and in particular consists in, the amino acid sequence set forth as SEQ ID NO: 30; or - the variable domain of the heavy chain of said antibody comprises, and in particular consists in, the amino acid sequence set forth as SEQ ID NO: 25 and the variable
  • Antibodies according to the invention can be defined as being allosteric antibodies, i.e. the antibody/HER3 affinity of the antibodies of the invention is allosterically increased when neuregulin is present in the environment of HER3-positive cells.
  • the present invention also relates to fragments of an antibody according to the invention.
  • a “fragment of an antibody” herein refers to a fragment of an intact antibody that retain the ability to specifically binds to a given antigen/ligand.
  • fragment of an antibody examples include a Fab fragment, a monovalent fragment consisting of the VL, VH, CL and CH1 domains; a Fab’ fragment, a monovalent fragment consisting of the VL, VH, CL, CH1 domains and hinge region; a F(ab’) 2 fragment, a bivalent fragment comprising two Fab’ fragments linked by a disulfide bridge at the hinge region; an Fd fragment consisting of VH-CH1 domains of a single arm of an antibody, in particular of a heavy chain of an antibody; a single domain antibody (sdAb) fragment (Ward et al., 1989 Nature 341:544-546), which consists of a VH domain or a VL domain; and an isolated complementary determining region (CDR).
  • Fab fragment a monovalent fragment consisting of the VL, VH, CL and CH1 domains
  • a Fab’ fragment a monovalent fragment consisting of the VL, VH, CL, CH1 domains and hinge region
  • the two domains of the Fv fragment, VL and VH are coded for by separate genes, they can be joined, using recombinant methods, by an artificial peptide linker that enables them to be made as a single protein chain in which the VL and VH regions pair to form monovalent molecules (known as single chain Fv (scFv); see, e.g., Bird et al., 1989 Science 242:423-426; and Huston et al., 1988 proc. Natl. Acad. Sci. 85:5879-5883).
  • sFv is a VH::VL heterodimer stabilized by a disulfide bond.
  • Divalent and multivalent antibody fragments can form either spontaneously by association of monovalent scFvs or can be generated by coupling monovalent scFvs by a peptide linker, such as divalent sc(Fv)2.
  • Such single chain antibodies include one or more antigen-binding portions or fragments of an antibody. These antibody fragments are obtained using conventional techniques known to those skilled in the art, and the fragments are screened for utility in the same manner as are intact antibodies.
  • a unibody is another type of antibody fragment lacking the hinge region of IgG4 antibodies. The deletion of the hinge region results in a molecule that is essentially half the size of traditional IgG4 antibodies and has a univalent binding region rather than the bivalent binding region of IgG4 antibodies.
  • UniBodies may be obtained by reference to WO 2007/059782, which is incorporated by reference in its entirety. Fragments of antibodies can be incorporated into single domain antibodies, SMIP, maxibodies, minibodies, intrabodies, diabodies, triabodies and tetrabodies (see, e.g., Hollinger and Hudson, 2005, Nature Biotechnology, 23, 9, 1126-1136).
  • diabodies tribodies or tetrabodies” refers to small antibody fragments with multivalent antigen-binding sites (2, 3 or four), which fragments comprise a heavy-chain variable domain (VH) connected to a light-chain variable domain (VL) in the same polypeptide chain (VH-VL).
  • Antigen binding fragments can be incorporated into single chain molecules comprising a pair of tandem Fd segments (VH-CH1-VH-CH1) which, together with complementary light chain polypeptides, form a pair of antigen binding regions (Zapata et al., 1995 Protein Eng.8(10); 1057- 1062 and U.S. Pat. No.5,641,870).
  • Fab fragments can be obtained by treating an antibody with a protease, papain.
  • the Fab can be produced by inserting DNA encoding Fab of the antibody into a vector for prokaryotic expression system, or for eukaryotic expression system, and introducing the vector into a procaryote or eucaryote (as appropriate) to express the Fab.
  • F(ab’)2 can be obtained by treating an antibody with a protease, pepsin. Also, the F(ab’)2 can be produced by binding Fab’ described below via a thioether bond or a disulphide bond. Fab’ can be obtained by treating F(ab’)2 with a reducing agent, dithiothreitol. Also, the Fab’ can be produced by inserting DNA encoding Fab’ fragment of the antibody into an expression vector for prokaryote, or an expression vector for eukaryote, and introducing the vector into a prokaryote or eukaryote (as appropriate) to perform its expression.
  • An antigen-binding fragment may be variable heavy chain of a single domain antibody (VHH).
  • VHHs may also be known as Nanobodies.
  • Camelid single domain antibody (sdAb) is one of the smallest known antigen-binding antibody fragments (see, e.g., Hassanzadeh- Ghassabeh et al., Nanomedicine (Lond), 8:1013-26 (2013)).
  • a basic VHH has the following structure from the N-terminus to the C-terminus: FR1-CDR1-FR2-CDR2-FR3- CDR3-FR4, in which FR1 to FR4 refer to framework regions 1 to 4, respectively, and in which CDR1 to CDR3 refer to the complementarity determining regions (CDR) 1 to 3.
  • Antibody fragments according to the invention may in particular be selected from the group consisting of Fv, Fab, F(ab')2, Fab', dsFv, scFv, sc(Fv)2 and diabodies. They may be produced by recombinant DNA techniques or by enzymatic or chemical cleavage of intact antibodies, according to methods well known to the man skilled in the art. As previously mentioned, an antibody according to the invention may be a multi- specific antibody. A “multi-specific antibody” refers to monoclonal antibody that has binding specificities for at least two different epitopes of one antigen or for at least two distinct antigens. In the present application, at least one of the antigens is HER3 as mentioned above.
  • a multi-specific antibody may be a bispecific antibody; a trispecific antibody; a tetraspecific antibody; a pentaspecific antibody; or a hexaspecific antibody, in particular a bispecific antibody.
  • the expression “bispecific antibody” refers to a molecule which combines the antigen- binding sites of two antibodies within a single molecule.
  • a bispecific antibody is able to bind two different antigens or to two distinct epitopes of a same antigen, simultaneously.
  • the distinct epitope may be overlapping epitopes or non-overlapping epitopes.
  • this at least one antigen may in particular be selected from the group comprising, and in particular consisting, of known targets for antibodies used for treating solid tumors such as those selected from the group comprising, and in particular consisting of, EGFR, HER2, MET, PD-L1, PD1, TROP2, Transferrin, Nectin-4, MUC-1, CEACAM-5, PTK7, Claudin 18.2, FolR1, NCAM-1, Siglec-2 Siglec -3, HGFR, IGF1R, PSMA, ROR-1, CD133, CD30, 5T4, Napi2b, DLL3 and LIV-1.
  • Multi-specific or bispecific antibodies can be prepared as full-length antibodies or antibody fragments as previously defined.
  • the multi-specific or bispecific antibody described herein may comprise a combination of antibodies as described herein.
  • the multi-specific or bispecific antibody may be an isolated or a recombinant bispecific antibody.
  • a multi-specific or a bispecific antibody may comprise at least a first antibody, or an antigen-binding fragment thereof, and at least a second antibody, or an antigen-binding fragment thereof, joined to each other, wherein said first and second antibodies may be selected among the antibodies of groups (i) to (vii) described herein.
  • multi-specific antibodies are described in US20090232811, US9382323, US9890204 or US8796424.
  • An antibody of the multi-specific or a bispecific antibody can be linked to or co- expressed with another antibody by any known techniques in the art.
  • an antibody or fragment thereof can be functionally linked, e.g., by chemical coupling, genetic fusion, noncovalent association or otherwise, to one or more other antibody or antibody fragment to produce a bispecific or a multi-specific antibody.
  • bispecific formats that can be used include, without limitation, e.g., scFv-based or diabody bispecific formats, IgG- scFv fusions, dual variable domain (DVD)-Ig, Quadroma, knobs-into-holes, common light chain (e.g., common light chain with knobs-into-holes, etc.), CrossMab, CrossFab, (SEED)body, leucine zipper, Duobody, IgG1/IgG2, dual acting Fab (DAF)-IgG, and Mab2 bispecific formats.
  • scFv-based or diabody bispecific formats IgG- scFv fusions, dual variable domain (DVD)-Ig, Quadroma, knobs-into-holes, common light chain (e.g., common light chain with knobs-into-holes, etc.), CrossMab, CrossFab, (SEED)body, leucine zipper, Duobody, IgG1/Ig
  • a bispecific antibody, or fragment thereof, according to the invention may be in the form of a bi-specific T-cell engager (BiTEs) (e.g., not having an Fc) or an anti-CD3 bi-specific antibody (e.g., having an Fc), and thus in the form of a bispecific antibody binding both HER3 and CD3.
  • BiTEs bi-specific T-cell engager
  • anti-CD3 bi-specific antibody e.g., having an Fc
  • a bi- or tri-specific antibody, or fragment thereof, according to the invention may be in the form of a bi-specific NK-cell engager (BiKE) or a tri-specific NK-cell engager (TriKE), having or not having an Fc, against an NK cell activating receptor, e.g., CD16A, C-type lectin receptors (CD94/NKG2C, NKG2D, NKG2E/H and NKG2F), natural cytotoxicity receptors (NKp30, NKp44 and NKp46), killer cell C-type lectin-like receptor (NKp65, NKp80), Fc receptor Fc ⁇ R (which mediates antibody-dependent cell cytotoxicity), SLAM family receptors (e.g., 2B4, SLAM6 and SLAM7), killer cell immunoglobulin-like receptors (KIR) (KIR-2DS and KIR-3DS), DNAM-1 and CD137 (41BB).
  • NK cell activating receptor e.g., CD16A
  • IgG-like molecules can be roughly divided into two categories: immunoglobulin G (IgG)-like molecules and non-IgG-like molecules.
  • IgG-like bsAbs retain Fc-mediated effector functions such as antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and antibody-dependent cellular phagocytosis (ADCP) (Spiess et al., Mol Immunol., 67 : 95–106 (2015)).
  • ADCC antibody-dependent cell-mediated cytotoxicity
  • CDC complement-dependent cytotoxicity
  • ADCP antibody-dependent cellular phagocytosis
  • Anti-human-HER3 antibodies of the invention may be produced by any technique known in the art, such as, without limitation, any chemical, biological, genetic or enzymatic technique, either alone or in combination.
  • antibodies of the invention can be synthesized by standard techniques for production of polypeptides. For instance, they can be synthesized using well-known solid phase method, preferably using a commercially available peptide synthesis apparatus (such as that made by Applied Biosystems, Foster City, California) and following the manufacturer’s instructions.
  • antibodies of the invention can be synthesized by recombinant DNA techniques well-known in the art.
  • antibodies can be obtained as DNA expression products after incorporation of DNA sequences encoding the antibodies into expression vectors and introduction of such vectors into suitable eukaryotic or prokaryotic hosts that will express the desired antibodies, from which they can be later isolated using well-known techniques.
  • nucleic acid sequence encoding an antibody according to the invention.
  • said nucleic acid is a DNA or RNA molecule, which may be included in any suitable vector, such as a plasmid, cosmid, episome, artificial chromosome, phage or a viral vector.
  • vectors The terms “vector”, “cloning vector” and “expression vector” mean the vehicle by which a DNA or RNA sequence (e.g. a foreign gene) can be introduced into a host cell, so as to transform the host and promote expression (e.g. transcription and translation) of the introduced sequence.
  • a further object of the invention relates to a vector comprising a nucleic acid of the invention.
  • Such vectors may comprise regulatory elements, such as a promoter, enhancer, terminator and the like, to cause or direct expression of said antibody upon administration to a subject.
  • promoters and enhancers used in the expression vector for animal cell include early promoter and enhancer of SV40 (Mizukami et al., J. Biol. Chem., 10: 1307-1310 (1987)), LTR promoter and enhancer of Moloney mouse leukemia virus (Kuwana Y et al.
  • any expression vector for animal cell can be used, so long as a gene encoding the human antibody C region can be inserted and expressed.
  • suitable vectors include pAGE107 (Miyaji H et al., Cytotechnology, 3: 133-140 (1990)), pAGE103 (Mizukami et al., J. Biol.
  • plasmids include replicating plasmids comprising an origin of replication, or integrative plasmids, such as for instance pUC, pcDNA, pBR, and the like.
  • viral vector examples include adenoviral, retroviral, herpes virus and AAV vectors.
  • recombinant viruses may be produced by techniques known in the art, such as by transfecting packaging cells or by transient transfection with helper plasmids or viruses.
  • virus packaging cells include PA317 cells, PsiCRIP cells, GPenv+ cells, 293 cells, etc.
  • Detailed protocols for producing such replication-defective recombinant viruses may be found for instance in WO 95/14785, WO 96/22378, US 5,882,877, US 6,013,516, US 4,861,719, US 5,278,056 and WO 94/19478.
  • a further object of the present invention relates to a host cell which has been transfected, infected or transformed by a nucleic acid and/or a vector according to the invention.
  • transformation means the introduction of a “foreign” (i.e. extrinsic or extracellular) gene, DNA or RNA sequence to a host cell, so that the host cell will express the introduced gene or sequence to produce a desired substance, typically a protein or enzyme coded by the introduced gene or sequence.
  • a host cell that receives and expresses introduced DNA or RNA bas been “transformed”.
  • the nucleic acids of the invention may be used to produce an antibody of the invention in a suitable expression system.
  • expression system means a host cell and compatible vector under suitable conditions, e.g. for the expression of a protein coded for by foreign DNA carried by the vector and introduced to the host cell.
  • Common expression systems include E. coli host cells and plasmid vectors, insect host cells and Baculovirus vectors, and mammalian host cells and vectors.
  • Other examples of host cells include, without limitation, prokaryotic cells (such as bacteria) and eukaryotic cells (such as yeast cells, mammalian cells, insect cells, plant cells, etc.).
  • a host according to the invention may in particular be a prokaryotic or eukaryotic cell.
  • E.coli Escherreocoli
  • Kluyveromyces or Saccharomyces yeasts mammalian cell lines (e.g., Vero cells, CHO cells, 3T3 cells, COS cells, etc.) as well as primary or established mammalian cell cultures (e.g., produced from lymphoblasts, fibroblasts, embryonic cells, epithelial cells, nervous cells, adipocytes, etc.).
  • mammalian cell lines e.g., Vero cells, CHO cells, 3T3 cells, COS cells, etc.
  • primary or established mammalian cell cultures e.g., produced from lymphoblasts, fibroblasts, embryonic cells, epithelial cells, nervous cells, adipocytes, etc.
  • Examples also include mouse SP2/0-Ag14 cell (ATCC CRL1581), mouse P3X63-Ag8.653 cell (ATCC CRL1580), CHO cell in which a dihydrofolate reductase gene (hereinafter referred to as “DHFR gene”) is defective (Urlaub G et al; 1980), rat YB2/3HL.P2.G11.16Ag.20 cell (ATCC CRL1662, hereinafter referred to as “YB2/0 cell”), and the like.
  • DHFR gene dihydrofolate reductase gene
  • ATCC CRL1662 rat YB2/3HL.P2.G11.16Ag.20 cell
  • YB2/0 cell Antibody assays All these antibodies may be assayed for specific binding by any method known in the art. Many different competitive binding assay format(s) can be used for epitope binding.
  • the immunoassays which can be used include, but are not limited to, competitive assay systems using techniques such western blots, radio-immunoassays, ELISA, “sandwich” immunoassays, immunoprecipitation assays, precipitin assays, gel diffusion precipitin assays, immunoradiometric assays, fluorescent immunoassays, protein A immunoassays, and complement-fixation assays.
  • Such assays are routine and well known in the art (see, e.g., Ausubel et al., eds, 1994 Current Protocols in Molecular Biology, Vol.1, John Wiley & sons, Inc., New York).
  • the BIACORE® (GE Healthcare, Piscaataway, NJ) is one of a variety of surface plasmon resonance assay formats that are routinely used to epitope binning panels of monoclonal antibodies. Additionally, routine cross-blocking assays such as those described in Antibodies, A Laboratory Manual, Cold Spring Harbor Laboratory, Ed Harlow and David Lane, 1988, can be performed.
  • Immunoconjugates Detectable label An antibody of the invention can be conjugated with a detectable label to form an anti-HER3 immunoconjugate. Suitable detectable labels include, for example, a radioisotope, a fluorescent label, a chemiluminescent label, an enzyme label, a bioluminescent label or colloidal gold.
  • the detectable label can be a radioisotope that is detected by autoradiography.
  • Isotopes that are particularly useful for the purpose of the present invention are 3 H, 125 I, 131 I, 35 S and 14 C.
  • Anti-HER3 immunoconjugates of the invention can also be labeled with a fluorescent compound. The presence of a fluorescently labeled antibody is determined by exposing the immunoconjugate to light of the proper wavelength and detecting the resultant fluorescence.
  • Fluorescent labeling compounds include fluorescein isothiocyanate, rhodamine, phycoerytherin, phycocyanin, allophycocyanin, o-phthalaldehyde and fluorescamine.
  • anti-HER3 immunoconjugates of the invention can be detectably labeled by coupling an antibody to a chemiluminescent compound. The presence of the chemiluminescent tagged immunoconjugate is determined by detecting the presence of luminescence that arises during the course of a chemical reaction.
  • chemiluminescent labeling compounds include luminol, isoluminol, an aromatic acridinium ester, an imidazole, an acridinium salt and an oxalate ester.
  • a bioluminescent compound can be used to label anti-HER3 immunoconjugates of the present invention.
  • Bioluminescence is a type of chemiluminescence found in biological systems in which a catalytic protein increases the efficiency of the chemiluminescent reaction. The presence of a bioluminescent protein is determined by detecting the presence of luminescence.
  • Bioluminescent compounds that are useful for labeling include luciferin, luciferase and aequorin.
  • anti-HER3 immunoconjugates can be detectably labeled by linking an anti-human-HER3 monoclonal antibody to an enzyme.
  • the enzyme moiety reacts with the substrate to produce a chemical moiety which can be detected, for example, by spectrophotometric, fluorometric or visual means.
  • enzymes that can be used to detectably label poly-specific immunoconjugates include ⁇ -galactosidase, glucose oxidase, peroxidase and alkaline phosphatase.
  • the binding of marker moieties to anti-human-HER3 monoclonal antibodies can be accomplished using standard techniques known to the art. Typical methodology in this regard is for example described by Kennedy et al., Clin. Chim. Acta, 70: 1-31 (1976) and Stein et al., Cancer Res. 50: 13301336 (1990). Moreover, the convenience and versatility of immunochemical detection can be enhanced by using anti-human-HER3 monoclonal antibodies that have for example been conjugated with avidin, streptavidin, and biotin (See, e.g., Wilchek et al. (eds.), “Avidin-Biotin Technology,” Methods In Enzymology (Vol.
  • ADC Antibody-drug conjugates
  • the present invention provides an anti-human-HER3 monoclonal antibody-drug conjugate.
  • An ADC of the present invention comprises a payload.
  • the term "payload” refers to a chemical moiety that is conjugated to an antibody, or fragment thereof, of the invention as part of an antibody-drug conjugate.
  • the payload is linked to the antibody component by covalent binding through a linker.
  • the payload in the ADC of the present invention is in particular a therapeutic agent.
  • the payload can fulfill its function at the target site.
  • the payload since the antibody or antibody fragment is specific for HER3, a tumor antigen, the payload is advantageously a cytotoxic agent that kills tumor cells.
  • Such cytotoxic agent may for example be selected from the group comprising a maytansinoid, such as Ravtansine (DM4) ; duocarmycin; Exatecan or Monomethyl auristatin E.
  • the payload can be introduced into an ADC of the invention at different stages of preparation.
  • a linker-payload construct i.e., a construct in which the payload is covalently linked to the linker
  • this linker-payload construct is conjugated to the antibody or antibody fragment thereof.
  • the antibody or antibody fragment thereof, linker and payload can also be prepared and conjugated in different order (e.g., the linker is conjugated to the antibody or antibody fragment thereof and subsequently the payload attached to the linker).
  • Different payloads, their preparation, conjugation and use in antibody-drug conjugates are well known in the art and are described e.g., in Nicolaou et al., Accounts of Chemical Research (2019), vol. 52(1), p. 127-139; Madema et al., Molecular Pharmaceutics (2015), vol.12(6), p.1798-1812; Gromek et al., Current Topics in Medicinal Chemistry (2014), vol. 14(24), p. 2822-2834.
  • An ADC according to the present invention may comprise only one type of payload (i.e. one ADC molecule is linked to only one kind of payload, e.g. Monomethyl auristatin E, wherein one or more copies of the payload (in this example Monomethyl auristatin E) may be linked to the ADC molecule) or several types of payloads (i.e. one ADC molecule is linked to two or more kinds of payload, e.g. Monomethyl auristatin E and DM4, wherein one or more copies of each payload (in this example one or more copies of auristatin E and one or more copies of DM4) may be linked to the ADC molecule).
  • one ADC molecule is linked to only one kind of payload, e.g. Monomethyl auristatin E, wherein one or more copies of the payload (in this example Monomethyl auristatin E) may be linked to the ADC molecule) or several types of payloads (i.e. one ADC molecule is
  • an antibody-drug conjugate according to the present invention may comprise only one kind of payload.
  • the copy number payloads linked to one ADC molecule i.e., in the first example above the number of Monomethyl auristatin E molecules linked to one ADC molecule, and in the second example above the number of Monomethyl auristatin E molecules plus the number of DM4 molecules linked to one ADC molecule
  • the "drug-antibody ratio" (or "DAR") of an ADC is the (average) number of payloads per ADC molecule divided by the number of antibodies or antibody fragments per ADC molecule.
  • the DAR of an ADC can for example be determined by identifying the molecular components of an ADC molecule by mass spectrometry and subsequently dividing the number of payload molecules in an ADC molecule to the number of antibodies or antibody fragments thereof in the ADC molecule (the ADC according to the present invention preferably containing one antibody or antibody fragment thereof per ADC molecule).
  • the DAR values of the embodiments defined below are preferably determined by this approach, i.e., calculated from structural information obtained by mass spectrometry.
  • ADCs with different DAR can be prepared by linking different numbers of payloads to the ADC molecule.
  • a linker-payload construct including one payload copy per linker can be prepared, and subsequently multiple copies of this linker-payload construct are linked to each antibody or antibody fragment thereof.
  • the number of linker-payload constructs that are linked per antibody or antibody fragment thereof can be influenced by the reaction conditions (e.g., the concentrations of the antibody or antibody fragment thereof, degree of activation of components, duration of conjugation reaction etc.), as known to a skilled person.
  • the drug-antibody ratio (DAR) of an antibody-drug conjugate according to the present invention may be in the range of from 1 to 100, in particular from 1 to 90, in particular from 1 to 80, in particular from 1 to 70, in particular from 1 to 60, in particular from 1 to 50, in particular from 1 to 40, in particular from 1 to 30, in particular from 1 to 20, more particularly in the range of from 1 to 10, more particularly in the range of from 1 to 8, even more particularly from 1 to 4 or 4 to 8, more particularly from 2 to 4.
  • an elevated DAR in particular DARs superior to 8
  • the payload of an ADC of the present invention is in particular a therapeutic agent.
  • a "therapeutic agent”, as used herein, is an agent that exerts an effect that is linked to a therapeutic benefit if administered to a patient (for example by killing a tumor cells, reducing an undesired inflammation, stimulating the activity of the immune system, or by suppressing the immune response).
  • Therapeutic agents useful in accordance with the present disclosure include, but are not limited to, cytotoxic agents, anti-inflammatory agents, immunostimulatory agents, immunosuppressive agents and proteolysis targeting chimera (PROTACs) agents.
  • the therapeutic agent is a cytotoxic agent, anti-inflammatory agent, anti-oncogenic agent, immunostimulatory agent or immunosuppressive agent.
  • the therapeutic agent is a cytotoxic agent.
  • a "cytotoxic agent” is a substance that is toxic to cells (i.e., causes cell death or destruction).
  • a cytotoxic agent in an ADC according to the present invention may typically be a small molecule chemical compound, peptide, or nucleic acid molecule.
  • cytotoxic agents that can be used in ADCs are known to the skilled person (Nicolaou et al., Accounts of Chemical Research (2019), vol. 52(1), p. 127-139; Madema et al., Molecular Pharmaceutics (2015), vol. 12(6), p. 1798-1812; Gromek et al., Current Topics in Medicinal Chemistry (2014), vol. 14(24), p. 2822-2834; Garcia- Echeverria, Journal of Medicinal Chemistry (2014), vol. 57(19), p. 7888-7889).
  • cytotoxic agents include, but are not limited to, auristatins (e.g.
  • auristatin E MMAE (monomethyl auristatin E), MMAF (monomethyl auristatin F), dolastatin 10, dolastatin 15
  • maytansinoids e.g. maytansin, DM1, DM2, DM3, DM4; since maytansinoids are derived from maytansin, they are sometimes referred to herein also as “maytansins"
  • tubulysin exatecan, camptothecin, SN38, Dxd, duocarmycin, CBI dimer (Cyclopropanebenz[e]indoline dimer, also referred to herein as "CBI")
  • doxorubicin or diazepines e.g.
  • the cytotoxic agent according to the present disclosure is a chemotherapeutic agent or a radioactive isotope, preferably a chemotherapeutic agent.
  • the therapeutic agent of an ADC may be an Eg5 inhibitor, a V-ATPase inhibitor, a HSP90 inhibitor, an IAP inhibitor, an mTor inhibitor, a microtubule stabilizer, a microtubule destabilizer, an auristatin, a dolastatin, a MetAP (methionine aminopeptidase), an inhibitor of nuclear export of proteins CRM1, a DPPIV inhibitor, an inhibitor of phosphoryl transfer reactions in mitochondria, a protein synthesis inhibitor, a kinase inhibitor, a CDK2 inhibitor, a CDK9 inhibitor, a proteasome inhibitor, a kinesin inhibitor, an HD AC inhibitor, a DNA damaging agent, a DNA alkylating agent, a DNA intercalator, a DNA minor groove binder, an RNA polymerase inhibitor, a topoisomerase inhibitor and a DHFR inhibitor.
  • a chemotherapeutic agent may for example be a maytansinoid (such as DM1, DM2, DM3, or DM4), an anti-metabolite (e.g., methotrexate, 6-mercaptopurine, 6-thioguanine, cytarabine, 5 -fluorouracil decarbazine), an ablating agent (e.g., mechlorethamine, thiotepa chlorambucil, meiphalan, carmustine (BSNU), lomustine (CCNU), cyclophosphamide, busulfan, dibromomannitol, streptozotocin, mitomycin C, cis-dichlorodiamine platinum (II) (DDP) cisplatin, anthracycline (e.g., daunorubicin (formerly daunomycin), doxorubicin), an antibiotic (e.g., dactinomycin (formerly actinomycin), bleomycin
  • a pyrrolobenzodiazepine or indolinobenzodiazepines a taxoid, CC-1065, CC- 1065 analog, duocarmycin, duocarmycin analog, enediyne (such as calicheamicin), a dolastatin or dolastatin analog (e.g.
  • auristatin a tomaymycin derivative, a leptomycin derivative, adriamicin, cisplatin, carboplatin, etoposide, melphalan, chlorambucil, calicheamicin, taxanes, DNA-alkylating agents (e.g., CC-1065 or a CC-1065 analog), anthracyclines, tubulysin analogs, cytochalasin B, gramicidin D, ethidium bromide, emetine (including derivatives thereof).
  • DNA-alkylating agents e.g., CC-1065 or a CC-1065 analog
  • anthracyclines e.g., tubulysin analogs
  • cytochalasin B gramicidin D
  • ethidium bromide emetine
  • cytotoxic payloads for ADCs can for example be found in Cytotoxic Payloads for Antibody-Drug Conjugates (Drug Discovery, Band 71), 1st edition (2019), editors Thurston and Jackson, Royal Society of Chemistry (U.K.).
  • Examples for cytotoxic agents that are radioactive isotopes are At 211 , 1 131 , 1 125 , Y 90 , Re 186 , Re 188 , Sm 153 , Bi 212 , P 32 , P 212 , Zr 89 and radioactive isotopes of Lu 176 .
  • the cytotoxic agents mentioned above may achieve cell killing by different mechanisms and thus may be divided into different classes according to their mechanism of action (Nicolaou et al., Accounts of Chemical Research (2019), vol. 52(1), p. 127-139).
  • the cytotoxic agent included in the ADC of the present disclosure may thus be selected from the group consisting of an inhibitor of microtubule formation, an EG5 inhibitor and a DNA damaging agent (e.g., Anderl et al., Methods in Molecular Biology (2013), vol. 1045, p. 51- 70).
  • An "inhibitor of microtubule formation” is an inhibitor that acts by inhibiting tubulin polymerization or microtubule assembly, and thus has anti- proliferative/toxic effects on cells.
  • said inhibitor of microtubule formation is selected from the group consisting of an auristatin (preferably auristatin E, MMAE or MMAF), a maytansinoid (preferably maytansin, DM1, DM2, DM3 or DM4) and tubulysin.
  • An "EG5 inhibitor” is an inhibitor that inhibits the protein EG5, and thus is toxic to cells.
  • EG5 refers to member 11 of the human kinesin family, which is also known as KIF11, HKSP, KNSL1 or TRIP5.
  • EG5 inhibitors are for example those described in Celli et al., Molecules (2019), vol.24(21), p. 3948.
  • said EG5 inhibitor may be selected from the group consisting of structures described in ispenisib, filanesib, litronesib and K858 (Chen et al., ACS Chem Biol. (2017), vol. 12(4), p. 1038-1046).
  • a "DNA damaging agent” is an agent that acts to damage cellular DNA, e.g., by inducing double-strand breaks, cross-linking specific sites of DNA or intercalating between DNA base pairs.
  • said DNA damaging agent is selected from the group consisting of a topoisomerase I inhibitor, a topoisomerase II inhibitor and a DNA alkylating agent.
  • said cytotoxic agent is a topoisomerase I inhibitor. In some embodiments, said cytotoxic agent is a topoisomerase II inhibitor. In some embodiments, said cytotoxic agent is a DNA alkylating agent.
  • Said topoisomerase I inhibitor may be selected from the group consisting of exatecan, camptothecin, SN38, Dxd and variants thereof, wherein in particular said topoisomerase I inhibitor is exatecan, SN38 or Dxd.
  • Said topoisomerase II inhibitor may be doxorubicin or a variant thereof, preferably doxorubicin.
  • Said DNA alkylating agent may be selected from the group consisting of duocarmycin, a CBI dimer, a pyrrolobenzodiazepine and variants thereof, wherein said DNA alkylating agent may be selected from the group consisting of duocarmycin, a CBI dimer and a diazepine (preferably a pyrrolobenzodiazepine or indolinobenzodiazepine).
  • the therapeutic agent may be selected from the group consisting of auristatin, MMAE (monomethyl auristatin E), duocarmycin, CBI (Cyclopropanebenz[e]indoline) dimer, maytansin, pyrrolobenzodiazepine and indolinobenzodiazepine.
  • the therapeutic agent may be selected from the group consisting of an auristatin, a duocarmycin, a CBI (Cyclopropanebenz[e]indoline) dimer and a maytansinoid.
  • the therapeutic agent may be selected from the group consisting of MMAE (monomethyl auristatin E), duocarmycin, CBI (Cyclopropanebenz[e]indoline) dimer and maytansinoid DM4.
  • MMAE monomethyl auristatin E
  • duocarmycin duocarmycin
  • CBI Cyclopropanebenz[e]indoline dimer
  • maytansinoid DM4 may be selected from the group consisting of MMAE (monomethyl auristatin E), duocarmycin, CBI (Cyclopropanebenz[e]indoline) dimer and maytansinoid DM4.
  • the therapeutic agent may be selected from the group consisting of a dolastatin, an auristatin, MMAE, MMAF, amberstatin 269, auristatin 101, auristatin f, auristatin w, CEN-106, CM1, DGN462, DGN549, DM1, DM2, DM4, doxorubicin, duocarmycin, exatecan, OX-4235, PNU-159682, rapamycin, SG3199, SGI 882, SN-38, tubulysin, amanitin, aminopterin, anthracy cline, calicheamicin, camptothecin, fujimycin, hemiasterlin, a maytansinoid, PBD, rapamycin or vinblastine.
  • a dolastatin an auristatin, MMAE, MMAF, amberstatin 269, auristatin 101, auristatin f, a
  • the therapeutic agent is an immunostimulatory agent.
  • an "immunostimulatory agent” is a substance that enhances the development or maintenance of an immunologic response.
  • the immunostimulatory agent may be an agonist of an immunostimulatory molecule or an antagonists of a molecule inhibiting an immunologic response.
  • the immunostimulatory agent comprises an agonist of an immunostimulatory molecule, such as an agonist of a costimulatory molecule found on immune cells such (as T cells) or an agonist of a costimulatory molecule found on cells involved in innate immunity (such as NK cells).
  • the immunostimulatory agent comprises an antagonist of an immunosuppressive molecule, e.g., an antagonist of a cosuppressive molecule found on cells involved in innate immunity (such as NK cells).
  • Administration of an ADC with an immunostimulatory agent as payload preferably results in an improvement of a desired immune response.
  • administration of an ADC with an immunostimulatory agent as payload results in an improved anti-tumor response in a patient, or in an animal cancer model, such as a xenograft model, as compared to the administration of a control molecule that does not include said immunostimulatory agent.
  • the immunostimulatory agent may be or may comprise an antagonist of an inhibitor of T cell activation.
  • the immunostimulatory agent is or comprises an agonists of a stimulant of T cell activation.
  • the immunostimulatory agent is or comprises an agent that antagonizes or prevents cytokines that inhibit T cell activation, such as IL-6, IL- 10, TGFP, VEGF.
  • the at least one immunostimulatory agent comprises an antagonist of a chemokine such as CXCR2, CXCR4, CCR2 or CCR4.
  • the immunostimulatory agent is or comprises an agonist of a cytokine that stimulates T cell activation, such as IL-2, IL-7, IL-12, IL-15, IL-21 and IFN ⁇ .
  • the immunostimulatory agent may in particular be selected from the group consisting of a Toll-like Receptors (TLR) including TLR3 agonist, TLR7 agonist, a TLR8 agonist, a TLR7 antagonist, a TLR8 antagonist, TLR9 agonist, a Sting inhibitor, a TGF beta inhibitor, an a2A inhibitor and an a2B inhibitor.
  • TLR Toll-like Receptors
  • the therapeutic agent is an immunosuppressive agent.
  • an "immunosuppressive agent” is an agent that inhibits the development or maintenance of an immunologic response.
  • Such inhibition by an immunosuppressive agent can be effected by, for example, elimination of immune cells (e.g., T or B lymphocytes); induction or generation of immune cells that can modulate (e.g., down- regulate) the functional capacity of other cells; induction of an unresponsive state in immune cells (e.g., anergy); or increasing, decreasing or changing the activity or function of immune cells, including, for example, altering the pattern of proteins expressed by these cells (e.g., altered production and/or secretion of certain classes of molecules such as cytokines, chemokines, growth factors, transcription factors, kinases, costimulatory molecules or other cell surface receptors, and the like).
  • immune cells e.g., T or B lymphocytes
  • induction or generation of immune cells that can modulate (e.g., down- regulate) the functional capacity of other cells e.g., an unresponsive state in immune cells (e.g., anergy); or increasing, decreasing or changing the activity or function of immune cells
  • an immunosuppressive agent has a cytotoxic or cytostatic effect on an immune cell that promotes an immune response.
  • said immunosuppressive agent results in the reduction of an undesired immune response as compared to the administration of a control molecule that does not include said immunosuppressive agent.
  • the immunosuppressive agent may be selected from the group consisting of an IMDH (inosine monophosphate dehydrogenase) inhibitor, an mTor (mechanistic target of rapamycin) inhibitor, a SYK (spleen tyrosine kinase) inhibitor, a JAK (janus kinase) inhibitor and a calcineurin inhibitor.
  • the therapeutic agent is a PROTAC (or also referred to herein as PROTAC moiety).
  • a proteolysis targeting chimera (PROTAC) is a two-headed molecule capable of removing unwanted proteins by inducing selective intracellular proteolysis.
  • PROTACs consist of two protein binding moieties, one for binding an E3 ubiquitin ligase and the other for binding a target protein. By binding both proteins, PROTAC brings the target protein to E3 ligase, resulting in the tagging (i.e., ubiquitination) of the target protein for subsequent degradation by the proteasome.
  • Ubiquitination involves three main steps: activation, conjugation, and ligation, performed by ubiquitin-activating enzymes (Els), ubiquitin-conjugating enzymes (E2s), and ubiquitin ligases (E3s), respectively.
  • Els ubiquitin-activating enzymes
  • E2s ubiquitin-conjugating enzymes
  • E3s ubiquitin ligases
  • the result of this sequential cascade is to covalently bind ubiquitin to the target protein.
  • the ubiquitinated proteins eventually get degraded by proteasome.
  • the PROTAC technology was first described in 2001 (Sakamoto et al.,“Protacs: chimeric molecules that target proteins to the Skpl-Cullin-F box complex for ubiquitination and degradation,” Proceedings of the National Academy of Sciences of the United States of America. 98 (15): 8554-9).
  • ADC comprising as therapeutic agent a PROTAC are also called Antibody-PROTAC conjugates (APCs).
  • ADC comprising as therapeutic agent a PROTAC are also called Antibody-PROTAC conjugates (APCs).
  • ADCs Antibody-PROTAC conjugates
  • the target protein binder in the PROTAC portion finds the target protein and brings it to E3 ubiquitin ligase for ubiquitination.
  • the ubiquitinated target protein is marked for degradation by proteasomes.
  • PROTAC according to the present invention are for example described in WO2019/140003 and in Zhijia Wang et al. Acta Pharm Sin B. 2023 Oct;13(10):4025-4059.
  • the therapeutic agent is a pro-drug converting enzyme.
  • the pro-drug converting enzyme can be recombinantly fused to the antibody or fragment thereof or chemically conjugated thereto using known methods.
  • Exemplary pro-drug converting enzymes are carboxypeptidase G2, ⁇ -glucuronidase, penicillin-V-amidase, penicillin-G-amidase, ⁇ -lactamase, ⁇ -glucosidase, nitroreductase and carboxypeptidase A.
  • the present invention specifically relates to an “anti-human- HER3 monoclonal antibody-drug conjugate”.
  • an antibody-drug conjugate (ADC) according to the invention comprises an antibody according to the invention wherein the variable domain of the heavy chain of said antibody comprises, and in particular consists in, the amino acid sequence set forth as SEQ ID NO: 20 and/or the variable domain of the light chain comprises, and in particular consists in, the amino acid sequence set forth as SEQ ID NO: 29.
  • an antibody-drug conjugate (ADC) comprises: - an antibody according to the invention wherein the variable domain of the heavy chain of said antibody comprises, and in particular consists in, the amino acid sequence set forth as SEQ ID NO: 20 and/or the variable domain of the light chain comprises, and in particular consists in, the amino acid sequence set forth as SEQ ID NO: 29; and - two or more, in particular two, types of payloads (i.e. one antibody molecule is linked to two or more kinds of payload, e.g.
  • an antibody-drug conjugate (ADC) comprises a linker.
  • the linker is a molecular group that covalently links the payload and the antibody or antibody fragment thereof of the ADC.
  • a variety of linkers that can be used for the ADC of the present invention and related methods are known from the art, such as in WO2004/010957.
  • linker there will be one linker per payload i.e., one linker molecule for each individual occurrence of a payload in an ADC; this means that, if two copies of a payload are present in an ADC, there will be two linkers, wherein the first linker covalently links the first payload to the antibody component, and the second linker covalently links the second payload to the antibody component.
  • one linker links more than one payload moiety to the antibody component of the ADC.
  • Covalent linking of the antibody or antibody fragment thereof and the payload via a linker can for example be achieved by a linker having two reactive functional groups (i.e., a linker that is bivalent in a reactive sense).
  • Bivalent linker reagents which are useful to attach two or more functional or biologically active components are known to the skilled person (see e.g., Hermanson, Bioconjugate Techniques (1996), Academic Press (New York), p 234-242)).
  • a linker-payload construct comprising payload(s) covalently attached to a linker may be prepared by methods of organic synthesis.
  • linker-payload construct can then be conjugated to the antibody component by methods known to the skilled person (see e.g Dickgiesser et al., in: Methods in Molecular Biology: Enzyme-Mediated Ligation Methods (2019), editors Nuijens and Schmidt, vol. 2012, p. 135- 149 or Dickgiesser et al., Bioconjugate Chem. (2020), vol.31(4), p. 1070-1076)).
  • a linker in an ADC of the present invention may preferably be stable extracellularly (i.e., outside of the cell, e.g., in plasma).
  • the ADC before transport or delivery into a cell, the ADC is preferably stable and remains intact, i.e., the antibody remains linked to the payload.
  • An effective linker will: (i) maintain the specific binding properties of the antibody or fragment thereof; (ii) allow intracellular delivery of the payload; (iii) remain stable and intact, i.e., not cleaved, until the conjugate has been delivered or transported to its targeted site; and (iv) maintain the therapeutic efficacy of the payload (e.g., the cytotoxic, cell-killing effect of the payload).
  • Whether a linker is stable in the extracellular environment can for example be determined by incubating independently with plasma both (a) the ADC (the “ADC sample”) and (b) an equal molar amount of unconjugated antibody or therapeutic agent (the “control sample”) for a predetermined time period (e.g. 8 hours) and then comparing the amount of unconjugated antibody or therapeutic agent present in the ADC sample with that present in the control sample, as measured, for example, by high performance liquid chromatography.
  • a linker that is stable outside of the target cell may be cleaved at some efficacious rate inside the target cell.
  • the linker that is cleavable under intracellular conditions is cleavable by a cleaving agent that is present in the intracellular environment (e.g., within a lysosome or endosome or caveolea).
  • the linker can for example be a peptidyl linker that is cleaved by an intracellular peptidase or protease enzyme, including, but not limited to, a lysosomal or endosomal protease.
  • the peptidyl linker is at least two amino acids long or at least three amino acids long.
  • Cleaving agents can include cathepsins B and D and plasmin, all of which are known to hydrolyze dipeptide drug derivatives resulting in the release of active drug inside target cells (see e.g., Dubowchik and Walker, Pharm. Therapeutics (1999), vol.83, p. 67-123).
  • a peptidyl linker that is cleavable by the thiol-dependent protease cathepsin B which is highly expressed in cancerous tissue, can be used (e.g., a Phe- Leu or a Gly-Phe-Leu-Gly linker (SEQ ID NO: 3)).
  • Other such linkers are for example described in US6214345.
  • the peptidyl linker cleavable by an intracellular protease is a Val-Cit linker or a Phe-Lys linker (see for example US 6214345, which describes the synthesis of doxorubicin with the Val-Cit linker).
  • One advantage of using intracellular proteolytic release of a therapeutic agent is that the agent is typically attenuated when conjugated and the serum stabilities of the conjugates are typically high.
  • the cleavable linker is pH-sensitive, i.e., sensitive to hydrolysis at certain pH values. Typically, the pH-sensitive linker is hydrolyzable under acidic conditions.
  • an acid-labile linker that is hydrolyzable in the lysosome e.g., a hydrazone, semi carb azone, thiosemicarbazone, cis-aconitic amide, orthoester, acetal, ketal, or the like
  • a hydrolyzable linker is a thioether linker (such as a thioether attached to the therapeutic agent via an acylhydrazone bond, see for example US5622929).
  • the linker is cleavable under reducing conditions (for example a disulfide linker).
  • a disulfide linker for example a disulfide linker.
  • disulfide linkers are known in the art, including, for example, those that can be formed using SATA (N-succinimidyl-5- acetylthioacetate), SPDP (N-succinimidyl-3-(2-pyridyldithio)propionate), SPDB (N- succinimidyl-3-(2- pyridyldithio)butyrate) and SMPT (N-succinimidyl-oxycarbonyl- alpha-methyl-alpha-(2- pyridyl-dithio)toluene), SPDB and SMPT (see e.g.
  • the linker is not cleavable inside the target cell, but the payload is released, for example, by antibody degradation.
  • the linker is a malonate linker (Johnson et al., Anticancer Res. (1995), vol.15, p.1387-1393), a maleimidobenzoyl linker (Lau et al., Bioorg- Med-Chem. (1995), vol.3(10), p.1299-1304), or a 3'-N-amide analog (Lau et al., Bioorg-Med- Chem.
  • the linker may be cleavable under intracellular conditions (as described above) or not cleavable under intracellular conditions. In some embodiments, the linker is not cleavable under intracellular conditions. In other embodiments, the linker is cleavable under intracellular conditions. Such a linker is particularly preferred if the payload is a therapeutic agent. Preferably, the linker is cleavable under intracellular conditions, such that cleavage of the linker releases the payload from the antibody component in the intracellular environment.
  • linker of an ADC may be examined by exposing the ADC to the conditions to be tested and then verifying the integrity of the linker in the treated sample and an untreated control sample by standard analytical techniques such as mass spectroscopy, HPLC, and the separation/analysis technique LC/MS.
  • said linker is stable in the extracellular environment.
  • the designation that a linker is "stable in the extracellular environment" preferably means that said linker is stable in human serum.
  • a linker is "stable in human serum” if in an assay in which ADC molecules including the linker are exposed to human serum, after an incubation of 48 h at 37 °C at least 50%, preferably at least 75% of the linkers in the ADCs have been neither cleaved nor degraded.
  • said linker is/said linkers are stable in the intracellular environment.
  • a linker that is "stable in the intracellular environment” may be a linker that has such a structure that if ADC molecules including the linker are taken up by cells (i.e., enter into the intracellular environment of the cells), after an incubation of 24 h at 37 °C at least 50%, preferably at least 75% of the linkers in the ADC molecules have been neither cleaved nor degraded.
  • said linker is cleaved upon exposure to the intracellular environment.
  • a linker that is "cleaved upon exposure to the intracellular environment” is a linker that has such a structure that if ADC molecules including the linker are taken up by cells (i.e., enter into the intracellular environment of the cells), the linkers in the ADC molecules are cleaved efficiently (preferably at least 90% of the linkers are cleaved within 24 h, more preferably within 12 h). As the skilled person understands, this allows for release of the payload into the target cells.
  • said linker is stable in the extracellular environment, but cleaved upon exposure to the intracellular environment.
  • a linker that is "stable in the extracellular environment, but cleaved upon exposure to the intracellular environment” is preferably a linker that is stable in human serum, but has such a structure that if ADC molecules including the linker are taken up by cells (i.e., enter into the intracellular environment of the cells), the linkers in the ADC molecules are cleaved efficiently (preferably at least 90% of the linkers are cleaved within 24 h, more preferably within 12 h). As the skilled person understands, this allows for release of the payload into the target cells.
  • said linker is cleavable by enzymatic or chemical cleavage.
  • a linker that is "cleavable by enzymatic cleavage” is a linker that is cleaved in the presence of a certain enzyme, but stable in the absence of this enzyme.
  • this enzyme will typically be an enzyme that the ADC is not exposed to in the extracellular environment but exposed to upon uptake of the ADC into the target cell, resulting in a linker that is extracellularly stable, but cleaved upon entry into the target cell.
  • a linker that is "cleavable by chemical cleavage” is a linker that is cleaved by a non-enzymatic reaction that results in the breakage of a covalent chemical bond.
  • linkers that are pH-sensitive or cleavable under reducing conditions (see above).
  • said linker is cleavable by enzymatic cleavage.
  • said enzymatic cleavage is cleavage by exposure to a glycosidase, protease or esterase.
  • a glycosidase is an enzyme of E.C. (Enzyme classification) 3.2.1 that catalyzes the hydrolysis of glycosidic bonds in complex sugars.
  • a protease is an enzyme of E.C. 3.4 that catalyzes the cleavage of peptide bonds.
  • An esterase is an enzyme of E.C.3.1 that catalyzes the cleavage of ester bonds.
  • said glycosidase is a glucuronidase.
  • a glucuronidase is an enzyme of E.C. 3.2.1.31 that catalyzes the cleavage of P-Glucuronides.
  • said protease is a cathepsin (most preferably cathepsin B).
  • Cathepsins are a group of proteases within E.C.3.4 that catalyze the proteolytic cleavage of peptide bonds.
  • the use of a lysosomal, endoproteolytic cathepsin is particularly advantageous, since these become activated at low pH (as in lysosomes) and cleave within a peptide sequence.
  • Cathepsin B is a cathepsin classified as E.C. 3.4.22.1.
  • said enzymatic cleavage is by exposure to a tumor-specific enzyme, preferably a tumor-specific protease or esterase.
  • a "tumor-specific" enzyme is an enzyme that is present in a certain tumor (i.e., there is enzymatic activity of said enzyme in the tumor), whereas the enzyme is substantially absent from other cells and tissues (i.e., outside of said tumor substantially no, preferably no, enzymatic activity of said enzyme).
  • said linker includes a protease cleavage site, preferably a cathepsin B cleavage site.
  • said linker includes a glucuronide (which is a molecular group that can be cleaved by glucuronidase). In some embodiments, said linker is cleavable by chemical cleavage. In some embodiments, said linker that is cleavable by chemical cleavage is a pH-sensitive linker. Preferably, said linker includes a hydrazone. In some embodiments, the linker that is cleavable by chemical cleavage is cleavable under reducing conditions. Preferably, said linker includes a disulfide linkage.
  • said linker comprises a cathepsin B cleavage site, a glucuronide or a disulfide linkage.
  • An ADC according to the present invention may comprise a solubility tag.
  • a "solubility tag" is a molecular group linked to a molecule of interest that has the purpose of increasing the solubility of the molecule of interest in aqueous environment, compared to the same molecule of interest without the solubility tag. Thus, it is intended that the molecule with the solubility tag linked to it has a higher solubility in aqueous environment than the same molecule without the solubility tag linked to it.
  • the solubility tag of the present disclosure is based on an oligosaccharide. As shown in the examples of the present disclosure, inclusion of such a solubility tag in an ADC results in various advantageous effects.
  • the ADC according to the present invention may comprise one or more than one solubility tag per ADC molecule. Typically, the solubility tag(s) will be covalently attached to the antibody-drug conjugate.
  • the solubility tag may be linked to the ADC of the present disclosure by a covalent bond between the solubility tag and the linker.
  • the solubility tag can also be linked to the ADC by a covalent bond between the solubility tag and a component of the ADC other than the linker.
  • An antibody-drug conjugate according to the present invention may comprise one or more solubility tags.
  • an ADC of the invention comprises only one solubility tag.
  • an ADC of the invention comprises at least one, preferably at least 2, more preferably at least 3, more preferably at least 4 solubility tags.
  • an ADC of the invention comprises up to 10, preferably up to 8, more preferably up to 6, more preferably up to 4, more preferably up to 2 solubility tags, more preferably only one solubility tag.
  • an ADC of the invention comprises at least 1 and up to 4 solubility tags.
  • an ADC of the invention comprises at least 3 and up to 10 solubility tags.
  • At least one solubility tag is covalently linked to an ADC of the invention.
  • at least 2, preferably at least 3, more preferably at least 4 solubility tags are covalently linked to an ADC of the invention.
  • up to 10, preferably up to 6, more preferably up to 4, more preferably up to 2 solubility tags are covalently linked to an ADC of the invention, more preferably only 1 solubility tag is covalently linked to an ADC of the invention.
  • at least 1 and up to 4 solubility tags are covalently linked to an ADC of the invention.
  • at least 3 and up to 10 solubility tags are covalently linked to an ADC of the invention.
  • the number of solubility tags covalently linked to an ADC of the invention is an average number (which is determined over a population of said ADC).
  • said population is a homogeneous population.
  • only one kind of solubility tag is covalently attached to the antibody-drug conjugate. This means that all solubility tags covalently attached to the antibody-drug conjugate are identical (they are of the same kind with regard to their molecular structure). In some embodiments, more than one kind of solubility tag is covalently attached to said antibody-drug conjugate.
  • solubility tags covalently attached to an ADC of the invention are of more than one kind with regard to their molecular structure.
  • up to two kinds of solubility tags are covalently attached to said antibody-drug conjugate.
  • the solubility tag of an ADC of the invention will include monosaccharide units that are linked by covalent bonds.
  • said solubility tag comprises monosaccharide units.
  • said solubility tag consists of monosaccharide units.
  • a "monosaccharide” is a sugar that is not decomposable into simpler sugars by hydrolysis, is classed as either an aldose or ketose, and contains one or more hydroxyl groups (-OH) per molecule.
  • monosaccharides include glucose (dextrose), fructose (levulose), and galactose.
  • Monosaccharides are the building blocks of disaccharides (such as sucrose and lactose), oligosaccharides, and polysaccharides (such as cellulose and starch).
  • the present disclosure uses the term "monosaccharide” or “monosaccharide unit” to refer to a single monosaccharide residue in an oligosaccharide.
  • an monosaccharide unit is a monosaccharide that is linked to another monosaccharide via covalent bond formed by a hydroxyl group of said monosaccharide (e.g. a glycosidic bond).
  • oligosaccharide refers to a compound containing two or more monosaccharide units.
  • oligosaccharide refers to a compound containing 2-12 monosaccharide units connected by glycosidic bonds.
  • oligosaccharides are depicted herein with a non-reducing end on the left and a reducing end on the right.
  • Monosaccharides and oligosaccharides can be chemically synthesized by standard methods of carbohydrate chemistry (see for example CRC Handbook of Oligosaccharides (1990), Vol. I-III, (published 2019), editors: Liptak et al., CHR Press, Inc.).
  • oligosaccharides can be prepared by biotechnological methods (see e.g., Meyer et al., Biotechnological Production of Oligosaccharides - Applications in the Food Industry, Food Production and Industry (2015)).
  • the oligosaccharide can be purified by standard methods of organic chemistry, including e.g.
  • Monosaccharides and oligosaccharides can be characterized by standard methods known to a person of skill in the art (see e.g., Carbohydrate Chemistry (1988), editor El Khadem, Academic Press (San Diego)).
  • said solubility tag comprises an oligosaccharide consisting of monosaccharide units. In some embodiments, said solubility tag consists of an oligosaccharide consisting of monosaccharide units.
  • the solubility tag comprises up to 25, preferably up to 20, more preferably up to 15, more preferably up to 12, more preferably up to 10, more preferably up to 9, more preferably up to 8, more preferably up to 7, more preferably up to 6, more preferably up to 5 monosaccharide units.
  • the solubility tag comprises at least 2, preferably at least 3, more preferably at least 4, more preferably at least 5 monosaccharide units.
  • the monosaccharide units of which said solubility tag consists are linked by covalent bonds, forming an oligosaccharide.
  • the solubility tag of the antibody-drug conjugate according to the present invention may comprise or consist of a chito- oligosaccharide.
  • chito-oligosaccharide refers to oligosaccharides obtained upon hydrolysis of (not deacetylated, partially deacetylated or fully deacetylated) chitin with diluted aqueous mineral acid.
  • chito-oligosaccharides that can be further separated into different chito-oligosaccharide species e.g., by ultrafiltration, gel permeation chromatography, cation exchange chromatography and capillary electrophoresis.
  • the preparation of chito-oligosaccharides by this approach is for example described in Schmitz et al., Marine Drugs (2019), vol. 17(8), p. 452.
  • Chito-oligosaccharides may alternatively be obtained by chemical synthesis (Bohe and Crich, in: Comprehensive Organic Synthesis, 2nd edition (2014), vol. 6, editors Knochel and Molander, Elsevier Ltd.).
  • chito-oligosaccharides may be obtained by a biotechnological approach (see for example Samain et al., Carbohydrate Research (1997), vol.302, p.35-42; Samain et al., Biotechnol. (1999), vol.72, p.33-47). Chito- oligosaccharides may then be further purified and characterized as described above for oligosaccharides in general.
  • chito-oligosaccharides are composed of D-glucosamine (GlcN) and/or N-acetyl-D-glucosamine (GlcNAc), resulting in the general formula (GlcNAc)m(GlcN)n., wherein m and n are integer numbers.
  • the monosaccharide units in chito-oligosacharides are typically linked by P-(l,4)-glycosidic linkages.
  • N-acetyl-D-glucosamine also referred to as “N- acetylglucosamine” and abbreviated as “GlcNAc”
  • N- acetylglucosamine 2-acetylamino-2-deoxy- D- glucose (also termed 2-acetamido-2-deoxy-D-glucose).
  • Glucose is abbreviated herein as “Glc”.
  • D-glucosamine also referred to as “glucosamine” and abbreviated as “GlcN” is 2-amino-2-deoxy-D-glucose.
  • the monosaccharide units of the solubility tag according to the present invention are independently selected from the group consisting of aldoses, ketoses and chemically modified forms of said aldoses or ketoses.
  • said solubility tag comprises no monosaccharide units other than monosaccharide units selected from the group consisting of glucose, chemically modified forms of glucose, galactose and chemically modified forms of galactose.
  • said solubility tag comprises no monosaccharide units other than monosaccharides selected from glucosamine (GlcN), N-acetyl-glucosamine (GlcNAc), fucose (Fuc) and 6-methyl-fucose.
  • said solubility tag comprises only monosaccharides selected from glucosamine (GlcN) and N-acetyl- glucosamine (GlcNAc) as monosaccharide units.
  • said solubility tag comprises only N-acetyl-glucosamine (GlcNAc) as monosaccharide units.
  • the solubility of an ADC can be assessed by measuring the formation of aggregates under different ADC concentrations in appropriate buffers during formulation development (Duerr and Friess, European Journal of Pharmaceutics and Biopharmaceutics (2019), vol. 139, p. 168-176). This approach allows to compare the solubility of an ADC with and without a certain solubility tag.
  • Therapeutic uses Antibodies, fragments thereof or immunoconjugates, in particular antibody-drug conjugate, of the invention are useful for treating any HER3-expressing cancer.
  • the antibodies, fragments thereof or immunoconjugates of the invention may be used alone or in combination with any suitable agent.
  • HER3-expressing cancers may in particular be derived from squamous cells, i.e.
  • HER3-expressing squamous cell cancers include but are not limited to, carcinoma, including squamous, epidermoid and adenocarcinoma, lymphoma, blastoma, sarcoma, and leukemia.
  • cancers include head and neck cancers, squamous cell cancer, esophagus cancer, non-small cell lung cancer, cutaneous squamous cancers, cervical cancer, vulval cancer and anal cancer, gastric cancer, pancreatic cancer, glial cell tumors, ovarian cancer, bladder cancer, breast cancer, melanoma, colorectal cancer in particular colon cancer, endometrial carcinoma, salivary gland carcinoma, renal cell carcinoma, prostate cancer, thyroid cancer, hepatic cell carcinoma.
  • They are preferably chosen among breast cancer, ovarian cancer, small-cell lung cancer, non-small cell lung cancer, melanoma, pancreatic cancer and colorectal cancer, and more particularly among breast cancer, ovarian cancer and pancreatic cancer.
  • a cancer treated using the methods of the present invention is breast cancer or ovarian cancer.
  • a cancer treated using the methods of the present invention is selected from the group consisting of head and neck cancer, gastro-esophageal cancers, non-small-cell lung cancer, mucinous adenocarcinoma of the lung, pancreas and pancreatic ductal cancer, breast cancer and colon cancer.
  • the present invention discloses a method for treating a HER3-expressing cancer comprising administering a subject in need thereof a therapeutically effective amount of an antibody, a fragment thereof, or an immunoconjugate of the invention, in particular in the form of a composition according to the invention.
  • the antibodies, fragments thereof, and immunoconjugates of the invention are more particularly effective for treating a HER3-expressing cancer associated wherein neuregulin is present, in particular neuregulin 1 or 2, more particularly neuregulin 1 ⁇ , 1 ⁇ or 2, and more particularly neuregulin 1 ⁇ .
  • an object of the present invention is an antibody, and/or an immunoconjugate, according to the invention for its use in the treatment of a HER3-expressing cancer wherein neuregulin is present in an individual in need thereof.
  • the antibodies, fragments thereof and immunoconjugates of the invention are particularly suitable for the treatment of NRG-fusion protein driven cancers (see in particular Odintsovet al., Clin.
  • cancer wherein neuregulin is present it is meant a cancer wherein neuregulin, in particular neuregulin 1 or 2, more particularly neuregulin 1 ⁇ , 1 ⁇ or 2, and more particularly neuregulin 1 ⁇ , (i) is secreted by the cancer and/or by tissues and/or organs, in particular by tissues and/or organs in the cancer and/or surrounding the cancer, or (ii) is present due to its administration to the subject before, after, or at the same time as the antibody and/or the immunoconjugate.
  • the antibodies of the invention are particularly suitable for the treatment of autocrine, juxtacrine or paracrine ligand-dependent tumors (due to their allosteric effect). Accordingly, in an embodiment of the invention, the neuregulin present is secreted by the tumor and/or by the tissues and/or organs in the tumor and/or surrounding the tumor.
  • the antibodies, fragments thereof and immunoconjugates of the invention are particularly suitable for the treatment of cancers that are resistant to the treatment with antibodies, tyrosine kinase inhibitors (TKI), chemotherapeutic agents or anti- hormone agents.
  • TKI tyrosine kinase inhibitors
  • the antibodies of the invention are particularly suitable for the treatment of cancers selected from the group consisting of triple-negative breast cancer, mucinous adenocarcinoma of the lung, pancreatic cancer, pancreatic ductal cancer and renal cell carcinomas, in particular consisting of triple-negative breast cancer, pancreatic cancer, and renal cell carcinomas.
  • the antibodies of the invention are particularly suitable for the treatment of cancers selected from the group consisting of pancreatic cancer, head and neck cancer, gastro-esophageal cancer, non-small-cell lung cancer, breast cancer, colon cancer and renal cell carcinomas.
  • an anti-human-HER3 antibody, a fragment thereof, or an immunoconjugate, in particular an antibody-drug conjugate, according to the invention is used in combination with a second agent for treatment of a disease or disorder.
  • an anti-human-HER3 antibody, a fragment thereof or an immunoconjugate, in particular an ADC may be used in combination with conventional cancer therapies such as, e.g., surgery, radiotherapy, chemotherapy, or combinations thereof.
  • other therapeutic agents useful for combination cancer therapy with an anti-HER3 antibody or antibody-drug conjugate in accordance with the present invention include anti-angiogenic agents.
  • an antibody or antibody-drug conjugate in accordance with the present invention is co-administered with a cytokine (e.g., a cytokine that stimulates an immune response against a tumor).
  • a cytokine e.g., a cytokine that stimulates an immune response against a tumor
  • other therapeutic agents useful for combination therapy include an antagonist of certain factors that are involved in tumor growth such as, for example, EGFR, HER2, or HER4.
  • an anti-human-HER3 monoclonal antibody, a fragment thereof, or immunoconjugate, in particular antibody-drug conjugate, of the present invention is used in combination with an anti-human-HER2 monoclonal antibody, such as Trastuzumab or Pertuzumab, or other antibodies that interact with HER3 heterodimer-partners such as anti-human-EGFR monoclonal antibody such as Cetuximab.
  • an anti-HER3 antibody, a fragment thereof, or an immunoconjugate, in particular antibody-drug conjugate, of the invention is used in combination with a tyrosine kinase inhibitor (TKI).
  • TKI tyrosine kinase inhibitor
  • TKIs include, but are not limited to: Imatinib mesylate (Gleevec®, Novartis); Gefitinib (Iressa®, AstraZeneca); Erlotinib hydrochloride (Tarceva®, Genentech); Vandetanib (Zactima®, AstraZeneca), Tipifarnib (Zarnestra®, Janssen-Cilag); Dasatinib (Sprycel®, Bristol Myers Squibb); Lonafarnib (Sarasar®, Schering Plough); Vatalanib succinate (Novartis, Schering AG); Lapatinib (Tykerb®, GlaxoSmithKline); Nilotinib (Novartis); Lestaurtinib (Cephalon); Pazo
  • an anti-HER3 antibody, a fragment thereof, or an immunoconjugate, in particular antibody-drug conjugate, of the invention is used in combination with a checkpoint inhibitor, such as PD-1 antagonist, Pembrolizumab (Keytruda®, Merck), Nivolumab (Opdivo®, BMS), PD-L1 antagonist Atezolizumab (Tecentriq®, Roche) and/or Avelumab (Bavencio®, Merck), or such as OX40 agonists and LAG3 antagonists.
  • a checkpoint inhibitor such as PD-1 antagonist, Pembrolizumab (Keytruda®, Merck), Nivolumab (Opdivo®, BMS), PD-L1 antagonist Atezolizumab (Tecentriq®, Roche) and/or Avelumab (Bavencio®, Merck), or such as OX40 agonists and LAG3 antagonists.
  • An anti-HER3 antibody, fragment thereof, or immunoconjugate, in particular antibody-drug conjugate, of the invention may more generally be combined with one or more additional therapeutic agents, e.g., an inhibitory immune checkpoint blocker or inhibitor, a stimulatory immune checkpoint stimulator, agonist or activator, a chemotherapeutic agent, an anti-cancer agent, a radiotherapeutic agent, an anti-neoplastic agent, an anti-proliferation agent, an anti-angiogenic agent, an anti-inflammatory agent, an immunotherapeutic agent, a therapeutic antigen-binding molecule (mono- and multi-specific antibodies and fragments thereof in any format (e.g., including without limitation DARTs®, Duobodies®, BiTEs®, BiKEs, TriKEs, XmAbs®, TandAbs®, scFvs, Fabs, Fab derivatives), bi-specific antibodies, non-immunoglobulin antibody mimetics (e.g., including without limitation adnectin
  • the present invention further relates to the use of an antibody of the invention, or a fragment thereof, in the engineering of CAR-T cells for the treatment of cancer, as well as to such CAR-T cells themselves.
  • the invention concerns the genetic modification of T cells, in particular of T cells from a patient according to the invention, to express an antibody, or a fragment thereof, according to the invention at their surface, thereby conferring upon said CAR-T cells the ability to recognize and engage with cancer cells expressing the target antigen in the patient.
  • the invention accordingly also concerns a T cell genetically modified to express an antibody, or a fragment thereof, according to the invention at its surface, and in particular concerns a T cell from a patient of the invention, the cell being genetically modified to express at its surface an antibody, or a fragment thereof, according to the invention.
  • the CAR-T cell is engineered to express a full-length antibody according to the invention, wherein the antibody comprises a variable region that specifically binds to the target antigen and a constant region that mediates effector functions.
  • the CAR-T cell express a fragment of the antibody as previously defined, in particular a single-chain variable fragment (scFv) or a Fab fragment, which retains the antigen-binding specificity.
  • a CAR-T cell of the present invention may be generated using any suitable gene transfer technique known in the art, including but not limited to viral transduction, non-viral transfection, or genome editing methods such as CRISPR/Cas9. Following engineering, the CAR-T cell may be ex vivo expanded and administered to a patient in need thereof for the treatment of cancer.
  • a CAR-T cell according to the invention may be of any generation of CAR-T cells. Indeed, the intracellular regions of different generations of CAR-T are different. The earliest first generation of CAR-T only has the intracellular region of CD3 molecule.
  • the intracellular region of the second generation of CAR-T is a co-stimulatory molecule CD28+ CD3zeta or 4- 1BB + CD3 zeta and can transmit two signals of T cell activation.
  • Two co-stimulatory molecules, CD28 and 4-1BB molecule, are added in the third generation CART.
  • the fourth generation of CAR-T cells are based on second-generation constructs, the latest being additionally modified with a constitutive or inducible expression cassette containing a transgenic protein such as a cytokine. They are also known as TRUCK CAR-T cells.
  • a fifth generation has moreover recently been developed, differing from the previous one in that the CAR-T cells integrate an additional membrane receptor compared to the TRUCK CAR-T cells.
  • the invention further encompasses pharmaceutical compositions comprising a CAR-T cells described herein, as well as methods for their use in the treatment of cancer. These methods may involve the administration of the CAR-T cells alone or in combination with other therapeutic agents, such as chemotherapy, radiation therapy, or immune checkpoint inhibitors, as described herein.
  • these modified T cells are activated by coming into contact with their target antigen, which leads to the induction of the secondary transgene, subsequent transcription, and secretion into the extracellular fluid.
  • the secreted signal not only stimulates CAR-T cells to remain active and form memory T cells but also reactivates the immune system to respond to restimulation.
  • compositions for administration the anti-human-HER3 monoclonal antibody, fragment(s) thereof or antibody-drug conjugate of the invention is formulated as a pharmaceutical composition.
  • a pharmaceutical composition comprising an anti-human-HER3 monoclonal antibody, a fragment thereof, or an antibody-drug conjugate according to the invention can be formulated according to known methods to prepare pharmaceutically useful compositions, whereby the therapeutic molecule is combined in a mixture with a pharmaceutically acceptable carrier.
  • a composition is said to be a “pharmaceutically acceptable carrier” if its administration can be tolerated by a recipient patient.
  • Sterile phosphate-buffered saline is one example of a pharmaceutically acceptable carrier.
  • Other suitable carriers are well-known to those in the art. (See, e.g., Gennaro (ed.), Remington's Pharmaceutical Sciences (Mack Publishing Company, 19th ed. 1995).) Formulations may further include one or more excipients, preservatives, solubilizers, buffering agents, albumin to prevent protein loss on vial surfaces, etc.
  • the form of the pharmaceutical compositions, the route of administration, the dosage and the regimen naturally depend upon the condition to be treated, the severity of the illness, the age, weight, and sex of the patient, etc.
  • the pharmaceutical compositions of the invention can be formulated for a topical, oral, parenteral, intranasal, intravenous, intramuscular, subcutaneous or intraocular administration and the like, and more particularly can be formulated for parenteral, intravenous or intraocular administration and the like.
  • the pharmaceutical compositions contain vehicle(s)/carrier(s) which is/are pharmaceutically acceptable for a formulation capable of being injected.
  • saline solutions monosodium or disodium phosphate, sodium, potassium, calcium or magnesium chloride and the like or mixtures of such salts
  • dry, especially freeze-dried compositions which upon addition, depending on the case, of sterilized water or physiological saline, permit the constitution of injectable solutions.
  • the doses used for the administration can be adapted as a function of various parameters, and in particular as a function of the mode of administration used, of the relevant pathology, or alternatively of the desired duration of treatment.
  • an effective amount of the antibody may be dissolved or dispersed in a pharmaceutically acceptable carrier or aqueous medium.
  • the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions; formulations including sesame oil, peanut oil or aqueous propylene glycol; and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
  • the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi.
  • Solutions of the active compounds as free base or pharmacologically acceptable salts can be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • Carriers An antibody of the invention can be formulated into a composition in a neutral or salt form.
  • Pharmaceutically acceptable salts include the acid addition salts (formed with the free amino groups of the protein) and which are formed with inorganic acids such as, for example, hydrochloric or phosphoric acids, or such organic acids as acetic, oxalic, tartaric, mandelic, and the like.
  • Salts formed with the free carboxyl groups can also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, histidine, procaine and the like.
  • the carrier can also be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetables oils.
  • the proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • the prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminium monostearate and gelatin. Sterile injectable solutions are prepared by incorporating the active compounds in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
  • a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
  • the preferred methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • the preparation of more, or highly concentrated solutions for direct injection is also contemplated, where the use of DMSO as solvent is envisioned to result in extremely rapid penetration, delivering high concentrations of the active agents to a small tumor area.
  • solutions will be administered in a manner compatible with the dosage formulation and in such amount as is therapeutically effective.
  • the formulations are easily administered in a variety of dosage forms, such as the type of injectable solutions described above, but drug release capsules and the like can also be employed.
  • parenteral administration in an aqueous solution for example, the solution should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose.
  • aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration.
  • sterile aqueous media which can be employed will be known to those of skill in the art in light of the present disclosure.
  • one dosage could be dissolved in 1 ml of isotonic NaCl solution and either added to 1000 ml of hypodermoclysis fluid or injected at the proposed site of infusion, (see for example, “Remington's Pharmaceutical Sciences” 15th Edition, pages 1035-1038 and 1570-1580). Some variation in dosage will necessarily occur depending on the condition of the subject being treated. The person responsible for administration will, in any event, determine the appropriate dose for the individual subject.
  • the antibodies of the invention may be formulated within a therapeutic mixture to comprise about 0.0001 to 1.0 milligrams, or about 0.001 to 0.1 milligrams, or about 0.1 to 1.0 or even about 10 milligrams per dose or so. Multiple doses can also be administered.
  • liposomes and/or nanoparticles are contemplated for the introduction of antibodies into host cells.
  • the formation and use of liposomes and/or nanoparticles are known to those of skill in the art.
  • Nanocapsules can generally entrap compounds in a stable and reproducible way. To avoid side effects due to intracellular polymeric overloading, such ultrafine particles (sized around 0.1 ⁇ m) are generally designed using polymers able to be degraded in vivo.
  • Biodegradable polyalkyl-cyanoacrylate nanoparticles that meet these requirements are contemplated for use in the present invention, and such particles may be easily made.
  • Liposomes are formed from phospholipids that are dispersed in an aqueous medium and spontaneously form multilamellar concentric bilayer vesicles (also termed multilamellar vesicles (MLVs)).
  • MLVs generally have diameters of from 25 nm to 4 ⁇ m. Sonication of MLVs results in the formation of small unilamellar vesicles (SUVs) with diameters in the range of 200 to 500 ⁇ , containing an aqueous solution in the core.
  • SUVs small unilamellar vesicles
  • Antibodies can be humanized using a variety of techniques known in the art including, for example, CDR-grafting (EP 239,400; WO91/09967; US5,225,539; US5,530,101 or US5,585,089), veneering or resurfacing (EP592,106; EP519,596; Padlan and Kabat, Methods Enzymol., 203:3-21 (1991); Studnicka et al., Protein Eng., 7: 805-814 (1994); Roguska et al., Proc Natl Acad Sci USA., 91: 969-973 (1994)), and chain shuffling (US5,565,332).
  • CDR-grafting EP 239,400; WO91/09967; US5,225,539; US5,530,101 or US5,585,089)
  • veneering or resurfacing EP592,106; EP519,596; Padlan and Kabat, Methods Enzymol., 203:3-21 (1991); Studnicka et al
  • variable domain of the heavy chain consists in the amino acid sequence set forth as SEQ ID NO: 19 and the variable domain of the light chain consists in the amino acid sequence set forth as SEQ ID NO: 31.
  • Gama-3 is an antibody according to the invention wherein the variable domain of the heavy chain consists in the amino acid sequence set forth as SEQ ID NO: 19 and the variable domain of the light chain consists in the amino acid sequence set forth as SEQ ID NO: 29.
  • Gama-4 is an antibody according to the invention wherein the variable domain of the heavy chain consists in the amino acid sequence set forth as SEQ ID NO: 19 and the variable domain of the light chain consists in the amino acid sequence set forth as SEQ ID NO: 32.
  • Gama-5 is an antibody according to the invention wherein the variable domain of the heavy chain consists in the amino acid sequence set forth as SEQ ID NO: 19 and the variable domain of the light chain consists in the amino acid sequence set forth as SEQ ID NO: 28.
  • Gama-6 is an antibody according to the invention wherein the variable domain of the heavy chain consists in the amino acid sequence set forth as SEQ ID NO: 20 and the variable domain of the light chain consists in the amino acid sequence set forth as SEQ ID NO: 31.
  • Gama-7 is an antibody according to the invention wherein the variable domain of the heavy chain consists in the amino acid sequence set forth as SEQ ID NO: 20 and the variable domain of the light chain consists in the amino acid sequence set forth as SEQ ID NO: 29.
  • Gama-8 is an antibody according to the invention wherein the variable domain of the heavy chain consists in the amino acid sequence set forth as SEQ ID NO: 20 and the variable domain of the light chain consists in the amino acid sequence set forth as SEQ ID NO: 32.
  • Gama-9 is an antibody according to the invention wherein the variable domain of the heavy chain consists in the amino acid sequence set forth as SEQ ID NO: 20 and the variable domain of the light chain consists in the amino acid sequence set forth as SEQ ID NO: 28.
  • Gama-10 is an antibody according to the invention wherein the variable domain of the heavy chain consists in the amino acid sequence set forth as SEQ ID NO: 26 and the variable domain of the light chain consists in the amino acid sequence set forth as SEQ ID NO: 31.
  • Gama-11 is an antibody according to the invention wherein the variable domain of the heavy chain consists in the amino acid sequence set forth as SEQ ID NO: 26 and the variable domain of the light chain consists in the amino acid sequence set forth as SEQ ID NO: 29.
  • Gama-12 is an antibody according to the invention wherein the variable domain of the heavy chain consists in the amino acid sequence set forth as SEQ ID NO: 26 and the variable domain of the light chain consists in the amino acid sequence set forth as SEQ ID NO: 32.
  • Gama-13 is an antibody according to the invention wherein the variable domain of the heavy chain consists in the amino acid sequence set forth as SEQ ID NO: 26 and the variable domain of the light chain consists in the amino acid sequence set forth as SEQ ID NO: 28.
  • Gama-21 is an antibody according to the invention wherein the variable domain of the heavy chain consists in the amino acid sequence set forth as SEQ ID NO: 20 and the variable domain of the light chain consists in the amino acid sequence set forth as SEQ ID NO: 30.
  • Gama-23 is an antibody according to the invention wherein the variable domain of the heavy chain consists in the amino acid sequence set forth as SEQ ID NO: 21 and the variable domain of the light chain consists in the amino acid sequence set forth as SEQ ID NO: 29.
  • Gama-23A is an antibody according to the invention wherein the variable domain of the heavy chain consists in the amino acid sequence set forth as SEQ ID NO: 22 and the variable domain of the light chain consists in the amino acid sequence set forth as SEQ ID NO: 29.
  • Gama-23Q is an antibody according to the invention wherein the variable domain of the heavy chain consists in the amino acid sequence set forth as SEQ ID NO: 23 and the variable domain of the light chain consists in the amino acid sequence set forth as SEQ ID NO: 29.
  • Gama-24 is an antibody according to the invention wherein the variable domain of the heavy chain consists in the amino acid sequence set forth as SEQ ID NO: 24 and the variable domain of the light chain consists in the amino acid sequence set forth as SEQ ID NO: 29.
  • Gama-25 is an antibody according to the invention wherein the variable domain of the heavy chain consists in the amino acid sequence set forth as SEQ ID NO: 25 and the variable domain of the light chain consists in the amino acid sequence set forth as SEQ ID NO: 29.
  • Gama-26 is an antibody according to the invention wherein the variable domain of the heavy chain consists in the amino acid sequence set forth as SEQ ID NO: 27 and the variable domain of the light chain consists in the amino acid sequence set forth as SEQ ID NO: 29.
  • Gama-27 is an antibody according to the invention wherein the variable domain of the heavy chain consists in the amino acid sequence set forth as SEQ ID NO: 21 and the variable domain of the light chain consists in the amino acid sequence set forth as SEQ ID NO: 30.
  • Gama-29 is an antibody according to the invention wherein the variable domain of the heavy chain consists in the amino acid sequence set forth as SEQ ID NO: 24 and the variable domain of the light chain consists in the amino acid sequence set forth as SEQ ID NO: 30.
  • Gama-31 is an antibody according to the invention wherein the variable domain of the heavy chain consists in the amino acid sequence set forth as SEQ ID NO: 25 and the variable domain of the light chain consists in the amino acid sequence set forth as SEQ ID NO: 30.
  • Gama-33 is an antibody according to the invention wherein the variable domain of the heavy chain consists in the amino acid sequence set forth as SEQ ID NO: 27 and the variable domain of the light chain consists in the amino acid sequence set forth as SEQ ID NO: 30.
  • EXAMPLE 1 SCREENING OF HUMANIZED VARIANT ANTIBODIES IN FAB-YEAST The genes corresponding to the different humanized Fab sequences were synthetized and cloned into a plasmid allowing expression on the surface of galactose-inducible yeast. The expression plasmid is then transformed into the yeast strain S. cerevisiae EBY100 as described in Sierocki et al. (2021, PLoS Neglect Trop Dis).
  • Induction of transformed yeast in SG-CAA induction medium [6.7 g/L yeast nitrogen base without casamino acids, 20 g/L glucose, 5 g/L casamino acids, 100 mM sodium phosphate, pH 6.0] allows the expression of the Fab on the yeast surface.
  • SG-CAA induction medium 6.7 g/L yeast nitrogen base without casamino acids, 20 g/L glucose, 5 g/L casamino acids, 100 mM sodium phosphate, pH 6.0
  • PBSF PBS, 0.1% BSA
  • the cells are then resuspended in a solution containing the recombinant HER3 extracellular domain (recombinant human HER3 ECD Fc fusion, ref 348- RB, R&D Systems) with or without NRG1- ⁇ (recombinant human NRG1- ⁇ ECD domain, ref 377-HB, R&D Systems).
  • the results obtained are represented in Figures 1 and 2.
  • recombinant HER3 was used at 8nM and NGR1 at 50nM.
  • recombinant HER3 was used at 2nM and 200pM respectively and NGR1 at 50nM.
  • concentration of recombinant HER3 varied in the range of 64pM to 200nM and NRG1 was used at 200nM.
  • concentration of recombinant HER3 varied in the range of 64pM to 200nM and NRG1 was used at 200nM.
  • the cells are washed with 1 mL of ice-cold PBSF to avoid dissociation of the complex Fab-antigen.
  • the cells are then incubated with the appropriate fluorescent reporters on ice for 15 min.
  • the cells are then analyzed/sorted on a BD FACSAriaTMIII cytometer using the BD FACSdivaTM Diva software.
  • the fluorescent reporters used are: anti-human Ckappa Light chain APC- conjugated (ref MA1-10385, Invitrogen) for detection of correct expression of Fab on the surface of the yeast and anti-human Fc PE-conjugated (ref H10104, Thermo Fischer) for detection of bound recombinant HER3 to the Fab-yeast.
  • the results firstly show in Figures 1A and 1B that humanized antibodies of the invention, Gama-2 to Gama-13, have a significantly increased binding to HER3 in the presence of NRG1 compared to when NRG1 is absent.
  • Gama 2 and Gama 6 have an affinity to HER3 similar to the parental 9F7-F11 chimeric antibody in the presence and in the absence of NRG1, and accordingly were able to maintain the property of interest of 9F7F11 (original chimeric antibody) despite the numerous modifications introduced in the sequences, even in the HCDR2 for Gama-6.
  • Gama 3, 4, 5, 7, 8 and 9 have an enhanced binding activity compared to the parental antibody both in the presence and in the absence of NRG1, with a significant increase of their binding to HER3 in the presence of NRG1.
  • Figures 2A and 2B show the results obtained with another set of humanized antibodies according to the invention, i.e.
  • Cells were grown at 37°C in a humidified atmosphere with 5% CO2 and medium was replaced twice a week. Cells were detached with trypsin, counted by an automatic cell count (Cellometer ® Auto1000), washed with cold PBS and diluted with cold saturation buffer (PBS 1x, BSA 2%) to a concentration of 3x10 6 viable cells/mL. All culture media and supplements were purchased from Life Technologies, Inc. (Gibco).
  • FACS Fluorescent-activated cell sorting
  • the antibodies were added at the proper concentration in 45 ⁇ L, cells were then deposited at a concentration of 1x10 5 cells / 45 ⁇ L well, in the plate already containing the diluted NRG1 (recombinant human NRG1- ⁇ ECD domain, ref 377-HB, Biotechne) and antibodies were diluted and then incubated 2 hours on ice.
  • NRG1 synthetic human NRG1- ⁇ ECD domain, ref 377-HB, Biotechne
  • FACS Fluorescent-activated cell sorting
  • Figure 3 shows the results of binding of humanized antibodies at 50 ⁇ g/mL with or without various concentrations (range 0.01nM-100nM) of NRG1 on SKBR-3 breast cancer cells.
  • the binding profile of humanized variants Gama-7 and Gama-5 (Fig 3A and 3B), Gama- 29 and Gama-31 (Fig 3C and 3D) and Gama-23 and Gama-23A (Fig 3F and 3E) indicate an allosteric enhanced binding mediated by NRG1.
  • the binding of these humanized variants increased in the presence of growing NRG1 concentrations while Patritumab’s (human anti-HER3 antibody - comparative outside of the invention) decreased under the same conditions (Fig 3A).
  • Figure 4 shows the binding profiles of humanized variant antibodies at growing concentration in absence or in the presence of 50nM NRG1.
  • the binding curves are higher in the presence of 50 nM of NRG1 than in the absence of NRG1.
  • the opposite is observed with Patritumab ( Figure 4F) for which the binding to SKBR-3 is abolished in presence of NRG1.
  • Gama-23 and Gama-29 show higher binding to SKBR-3 at low NRG1 concentrations as compared to Gama-23A and Gama-31 and are thus less prone to enhanced binding in the presence of NRG.
  • Gama-23 and Gama-23A have a very similar binding profile with low level of binding at low NRG1 concentrations.
  • EXAMPLE 3 LIGANDS BINDING ASSAY
  • the cancer cell lines SKBR-3 breast cancer cells was maintained in RPMI1640 supplemented with 10% FBS, penicillin- streptomycin and L-Glutamine. Cells were grown at 37°C in a humidified atmosphere with 5% CO2 and medium was replaced twice a week. Cells were detached with trypsin, counted by an automatic cell counter (Cellometer® Auto1000), washed with cold PBS and diluted with cold saturation buffer (PBS 1x, BSA 2%) to a concentration of 3x10 6 viable cells/ml.
  • FACS Fluorescent-activated cell sorting
  • Bound antibodies were detected by Goat anti- human IgG Fc secondary PE-conjugated (ref 12-4998-82, Life Technologies) diluted at 1/400 th with saturation buffer for 45 min at 4°C. The plate was centrifuged at 300g 5 min at room temperature and washed thrice with 200 ⁇ L of PBS. Cells were resuspended with 300 ⁇ l of PBS and data were acquired with a Fortessa Cytometer (BD). Data were analysed using GraphPad Prism 9 software and statistics p values were determined using the ordinary one-way ANOVA followed by Bonferroni’s multiple comparisons test in case of significant effect.
  • Figure 5A shows that binding of Gama-23A increases in the presence of NRG2 in the same order of magnitude as that observed for NRG1 ⁇ and NRG1 ⁇ .
  • Figure 5B shows the binding profile of Gama-23A humanized antibody according to the invention in the presence of EGF, NRG1 ⁇ and a combination of NRG1 ⁇ /EGF.
  • the binding of Gama-23A is, at least, not impacted by the presence of EGF at 0.1 and 100nM.
  • the binding of Gama-23A increases in the presence of NRG1 ⁇ , NRG1 ⁇ , and the combination of NRG1 ⁇ /EGF at 100nM.
  • EXAMPLE 4 THERMAL DENATURATION DSC analysis in PBS buffer were performed using on a MicroCal PEAQ DSC (Malvern Panalytical). Thermograms were acquired from 20°C to 100°C with a scanning rate of 60 °C/hour (1°C /min). A buffer scan (PBS 1x) was performed and used as reference. Samples were diluted to 1 mg/mL prior their analyses that were performed using PEAQ-DSC software. Raw DSC data were corrected for the instrumental baseline by subtraction of the Buffer (PBS) reference scan.
  • PBS Buffer
  • the structural stability of the Fab domain makes the significant contribution of the structure stability of the whole antibody IgG format.
  • the table below shows the DSC results of thermal transition temperature (melting point, Tm) and the enthalpy of this melting point ( ⁇ H) of the variable domain Fab for parental 9F7-F11 chimeric antibody and the humanized variants Gama-7, Gama-23 and Gama-23A according to the invention.
  • Table 1 Figures 6 shows the thermogram curves obtained by DSC scan for 9F7-F11 and Gama-23A.
  • Gama-23A according to the invention showed improved thermal stability as compared to the parental chimeric 9F7-F11 with a significant gain of 3.8-4.4 °C of Tm and 40- 80 kcal/mol of enthalpy depending on the variant considered.
  • Heat resistance is also a proxy for long-term aggregation propensity of antibodies and is indicative of long-term stability at storage temperature (Boulet-Audet et al., Anal. Chem., 86: 9786-9793 (2014)). Similar results were obtained with antibodies Gama-7 and Gama-23 according to the invention.
  • EXAMPLE 5 EFFECTS OF ANTI-HER3 HUMANIZED ANTIBODIES ACCORDING TO THE INVENTION ON HER3 AND AKT PHOSPHORYLATION.
  • Phosphorylated AKT (pAKT) and phosphorylated HER3 (pHER3) levels were quantified using the HTRF Kit from CisBio Bioassay: Phospho-HER3 (Tyr 1289) cellular kit (64HR3PEG), Total HER3 cellular kit (64NR3PEG), Phospho-AKT1/2/3 (Ser473) cellular kit (64AKSPEG), Total AKT cellular kit (64NKTPEG).
  • the T47D cancer breast cancer cells (5 x 10 4 cells/well) will be seeded in sterile 96-well flat-bottom tissue culture-treated plates (100 ⁇ L of complete medium) and cultured overnight in RPMI/1% FCS supplemented with 10% FCS and penicillin 100U/mL /streptomycin at 100 ⁇ g/mL for 18h. After 2 washes (200 ⁇ L of culture medium without serum), the cells will be incubated in culture medium/1% FCS for 18 hours for starvation.
  • NRG1- ⁇ recombinant human NRG1- ⁇ ECD domain, ref 377-HB, R&D Systems
  • 25nM of NRG1- ⁇ recombinant human NRG1- ⁇ ECD domain, ref 377-HB, R&D Systems
  • ten-fold dilutions of anti-HER3 antibodies range 50 ⁇ g/ml-0.05 ⁇ g/ml, for another 25min at 37°C.
  • NRG1- ⁇ and the antibodies were removed, and cells were lysed in the supplemented lysis buffer (Cisbio Bioassay). Plates were incubated at room temperature with shaking for 30min to lyse cells.
  • Lysates were transferred to white 384-well plates and anti- phospho HER3 (Tyr1289)-cryptate /anti-HER3-d2 or anti-phospho AKT (Ser473)- cryptate/anti-AKT-d2 antibody pairs were added to each well and left in the dark at room temperature for 4h.
  • the TR-FRET signal (665 nm/620 nm emission ratio) was measured on a HTRF reader.
  • Negative control wells contained unstimulated/non-treated cells whereas maximum of phosphorylation was obtained by stimulating cancer cells with NRG1 without antibody treatment. Data were analysed using GraphPad Prism 9 software and statistics p values were determined using the ordinary one-way ANOVA followed by Bonferroni’s multiple comparisons test in case of significant effect.
  • the cancer cell lines SKBR-3 breast cancer cells were maintained in RPMI1640 supplemented with 10% FBS, 1% penicillin- streptomycin and 1% L-Glutamine. Cells were grown at 37°C in a humidified atmosphere with 5% CO2 and medium was replaced twice a week. Cells were detached with trypsin, counted by an automatic cell count (Cellometer ® Auto1000), washed with cold PBS and diluted with cold saturation buffer (PBS 1x, BSA 2%) to a concentration of 3x10 6 viable cells/mL. All culture media and supplements were purchased from Life Technologies, Inc. (Gibco).
  • FACS Fluorescent-activated cell sorting
  • Tubes were then centrifuged at 300 g 5 min at 4°C and washed with 500 ⁇ L of cold saturation buffer (BSA 2%, PBS 1x).
  • BSA 2%, PBS 1x cold saturation buffer
  • 500 ⁇ L of pre-heated RPMI media was added and tubes were incubated at 37°C for the 1h and 2h.
  • 500 ⁇ L of cold RPMI media was added and tubes were incubated at 4°C for 1h and 2h.
  • tubes were centrifuged at 300 g 5 min at 4°C and washed twice, once with 500 ⁇ L of cold saturation buffer (BSA 2%, PBS 1x) and once with cold PBS.
  • Bound antibodies were detected by Goat anti-human IgG Fc secondary PE- conjugated (ref 12-4998-82, Life Technologies) diluted at 1/400 th with saturation buffer for 45 min at 4°C. Tubes were centrifuged at 300g 5 min at 4°C and washed twice, once with 500 ⁇ L of cold saturation buffer (BSA 2%, PBS 1x) and once with cold PBS. Cells were resuspended with 300 ⁇ l of PBS and data were acquired with a Fortessa Cytometer (BD). Binding data were represented using GraphPad Prism 8. As can be seen in Figures 8, the internalization of antibodies according to the invention is high.
  • SEQ ID NO: 1 heavy chain variable domain X 1 VQLX 2 X 3 SGX 4 X 5 LX 6 X 7 PGX 8 SX 9 X 10 X 11 SCX 12 ASGFTFSSYX 13 MSWVRQAPG X14GLEWVAYISDX15GGVTYYX16DX17X18KGRFX19ISRDNSX20X21TLYLQMX22SLX23A EDTAVYYCARDRYGLFX24YWGQGTLVTVSS SEQ ID NO: 2: light chain variable domain X25IX26X27TQSPX28X29LSX30SX31GX32RX33TX34X35CX36ASQX37VGIX38X39AWY QQKPGX40APX41LLIYSASNRYTGX42PX43RFX44GSGSGTX45FTLTISSLX46X47EDX48A X 49 YX 50 CQQYSX 51 YPYTFGQGTKLEI

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Abstract

The present invention relates to neuregulin positively dependent anti-human-HER3 antibodies comprising (i) a heavy chain wherein the variable domain has at least 90% or 95% identity with the amino acid sequence set forth as SEQ ID NO: 1 and (ii) a light chain wherein the variable domain has at least 90% or 95% identity with the amino acid sequence set forth as SEQ ID NO: 2. An immunoconjugate comprising an antibody of the invention or a fragment thereof, a nucleic acid sequence encoding an antibody of the invention or a fragment thereof, a vector as well as a host cell, a pharmaceutical composition comprising it, as well as their pharmaceutical use, are also considered.

Description

HUMANIZED ANTI-HUMAN HER3 ANTIBODIES AND USES THEREOF FIELD OF THE INVENTION The present invention relates to humanized anti-human-HER3 antibodies and uses thereof in diagnostic and therapeutic applications. BACKGROUND OF THE INVENTION The human epidermal growth factor receptor ErbB/HER family of receptor tyrosine kinases (RTK) includes four members: EGFR (ErbB1/HER1), HER2 (c-Neu, HER2), HER3 (ErbB3/HER3) and HER4 (ErbB4/HER4). The HER receptors comprise an extracellular glycosylated domain consisting of four structural domains, marked 1 to 4, followed by a transmembrane domain and an intracellular C-terminal part containing a kinase domain for coupling to signalling pathways. Except for HER3, the intracellular region contains a tyrosine kinase activity. Signalling is mediated through ligand-induced receptor dimerization and subsequent phosphorylation that leads to the activation of cytoplasmic signalling pathways, especially PI3K/AKT and MAP kinase pathways (Campbell et al., Clin. Cancer Res., 16: 1373- 1383 (2010)). HER2 has no specific ligand because it is naturally under an "active” conformation. The other HER receptors exist as inactive monomers with the molecules folded in such a way to prevent dimerization. Ligand binding to domains 1 and 3 induces major conformational changes ultimately exposing the dimerization loop in domain 2 of the receptor. This exposure of the dimerization loop allows for receptor dimerization (Zhang et al., Cell, 66: 1025-1052 (2006)). The HER3 receptor, that has been first described in 1990 (Plowman et al., Proc. Natl. Acad. Sci. USA, 87: 4905-4909 (1990)), is the only HER family member receptor that shows low kinase activity and of which downstream signalling is achieved through heterodimerization. Thus, the HER3 receptor, as a monomer, is called “non-self” and cannot form homodimers. Binding of the ligand neuregulin (NRG) to HER3 receptor triggers the heterodimerization of HER3 with the others HER family receptors (HER2 preferentially) (Tzahar et al., Mol. Cell Biol., 16: 5276-5287 (1996)). Within the heterodimer, the HER3 kinase domain acts as an allosteric activator of its HER family partner (Baselga and Swain, Nat. Rev. Cancer, 9: 463-475 (2009)). HER3 is implicated in tumorigenesis of various cancers including breast and ovarian cancer (Lee-Hoeflich et al., Cancer Res., 15: 5878-5887 (2008); McIntyre et al., Breast Cancer Res. Treat., 122: 105-110 (2010); Tanner et al., J Clin. Oncol., 24: 4317-4323 (2006)). HER3 is accordingly overexpressed in over 40% of solid malignant tumors, among others in cervical and ovarian cancers, colorectal, gastric, breast, head and neck, and prostate cancer. In a more recent meta-analysis of 25 studies on 2964 patients HER3 expression was found in those numerous solid tumors and correlates with higher death risk (HR=1.6, p<0,001) (Li et al., Oncotarget, 8: 67140-67151 (2017)). Importantly, in breast cancer, tumors with low HER2 expression, which are not eligible to Herceptin treatment, are often “programmed” to strongly express HER3 (Smith et al. Br. J. Cancer, 91: 1190-1194 (2004)). Moreover, HER2+++ tumors, which become resistant to Herceptin after prolonged treatment, are “re-programmed” to strongly express HER3 (Narayan et al., Cancer Res., 69: 2191-2194 (2009)). Cetuximab resistance was also associated with HER3 over-expression in lung cancer (Wheeler et al., Oncogene, 27: 3944-3956 (2008)) and colorectal carcinomas (Lu et al., Cancer Res., 67: 8240- 8247 (2007)), together with dysregulation of EGFR internalization/degradation. Recently, HER3 over-expression was significantly associated with reduced metastasis-free survival in colorectal carcinoma (Ho-Pun-Cheung et al., Int. J. Cancer, 128: 2938-2946 (2011)). Thus, HER3 over-expression and compensatory signalling through activation of the PI3K/AKT pathway are implicated in the development of resistance to treatment with HER-targeted therapies (antibodies and TKI) (Wheeler et al., Oncogene, 27: 3944-3956 (2008); Lu et al., Cancer Res., 67: 8240-8247 (2007); Narayan et al., Cancer Res., 69: 2191-2194 (2009)) but also to treatment with IGFR-targeted therapies (Desbois-Mouthon et al., Clin. Cancer Res., 15: 5445-5456 (2009)) and with chemotherapeutic agents (Kruser and Wheeler, Exp. Cell Res.316: 1083-110 (2010)). The physiological ligand of HER3, NRG, exists in 4 forms: NRG1 α and β and NRG2 α and β. These 4 ligands share an EGF-like domain which binds to the extracellular domain of HER3 and induces receptor dimerization initiating a cascade of phosphorylations, in particular that of AKT and MAP-kinase, resulting in cellular growth and differentiation (Nagasaka and Ou, Trends Cancer, 8: 242-258 (2022)). As its receptor HER3, NRG is widely expressed in solid tumors. According to transcriptomic data published in Human Protein Atlas, NRG1 is expressed more particularly in lung, head and neck and breast cancers while NRG2 is preferentially expressed in renal and breast cancers, in melanoma and glioma. Numerous studies using immuno-chemistry methods (or RNA scope) have described the expression of NRG in multiple solid tumors: in particular in ovarian cancer (Gilmour et al., Clin. Cancer Res., 8: 3933-3942 (2002)), head and neck cancer (Qian et al., Cancer, 121: 3600-3611 (2015)), colorectal cancer (Stahler et al., Anticancer Drugs, 28: 717- 722 (2017)), breast cancer (Seoane et al., Oncogene, 35: 2756-2765 (2016)), prostate cancer (Zhang et al., Cancer Cell, 38: 279-296 (2020)) and non-small-cell lung cancer (Fang et al., J. Environ. Pathol. Toxicol. Oncol., 40: 61-72 (2021)). In the studies where clinical data were documented NRG1 expression was associated with aggressive features of the disease and poor prognosis. Expression of NRG in solid tumors has been also reviewed by Ocana in 2016 (Ocana et al., Oncotarget, 7: 45042-45051 (2016)). Moreover, HER3 alterations (mutations) occur in ≈10% of tumours (especially bladder cancer and colorectal cancer) which could be present de novo or acquired during targeted therapy, and induce therapeutic resistance (Kilroy et al., Cancers, 14: 6174-6196 (2022)). All these findings suggest that HER3-targeting agents, and in particular antibodies susceptible to efficiently antagonize NRG effects, might help to further understand the role of HER3 signalling in cancers and may especially be used as efficient immunotherapeutics for HER3 expressing cancers. Because of the pertinence of the pathophysiological role of the target, a large number of anti-HER3 antibodies have been developed during the last 15 years. According to the last reviews of Haikala and Jänne (Clin. Cancer Res., 27: 3528-3539 (2021)) and Gandullo- Sanchez et al. (J. Exp. Clin. Cancer Res., 41: 310-336 (2022)), more than 15 antibodies (10 mono, 5 bispecific antibodies) have initiated clinical development with more than 16 Phase I clinical trials and more than 36 Phase II clinical trials in most pertinent indications (mainly squamous cell cancer of head and neck, non-small cell lung cancer, metastatic breast cancer, gastric cancer) as a single agent or in combination with targeted agents (cetuximab, erlotinib, trastuzumab) or chemotherapy (paclitaxel-carboplatin). However, despite these large development efforts no clinically meaningful activity was demonstrated. Only 2 products were carried out up to Phase III, patritumab (in NSCLC with erlotinib, HERALD study, Paz-Arez et al., J. Thorac. Oncol. 12: S1214-S1215 (2017)), or to controlled Phase II, seribantumab (in NSCLC with docetaxel, SHERLOC trial (Sequist et al., Oncologist. 24: 1095-1102 (2019)). Those studies were considered insufficiently promising for further development despite the fact the patients were prospectively selected according to NRG status. An additional factor that has negatively influenced the development of those antibodies is a poor digestive tolerability which can be related to the fact that these antibodies bind to healthy tissues expressing HER3, especially the digestive epitheliums which are physiologically rich in this receptor but lack significant NRG expression (The Human Protein Atlas, https://www.proteinatlas.org/ENSG00000065361-ERBB3/tissue). This poor tolerability was observed especially in combination with chemotherapy, and for instance has led to the discontinuation of clinical development of lumretuzumab (Schneeweiss et al., Invest. New Drugs, 36: 848-859 (2018)). Quite originally Lazrek et al. (Neoplasia, 15: 335-347 (2013)) have discovered a new mechanism of interaction between a monoclonal antibody and HER3 receptor, describing a NRG-dependent increase of antibody binding to HER3 (i.e. a positive dependency of this anti- HER3 antibody on NRG1). The molecular mechanisms by which NRG increases the binding of Lazrek’s antibodies to its epitope have not yet been elucidated. Accordingly, there remains a need in the art for availability of humanized anti- HER3 antibodies being able to have a significantly increased binding to HER3 in the presence of NRG as compared to the absence of NRG. There also remains a need in the art for availability of humanized anti-HER3 antibodies aimed at treating HER3 positive cancers, including anti-HER3 antibodies having high anti-tumor activity against NRG-fusion protein driven cancers. Moreover, there remains a need in the art for humanized anti-HER3 antibodies aimed at treating HER3 positive cancers with a minimal risk of binding to healthy tissues in an individual in need thereof, and in particular with a reduced ability to bind off-target tissues in an individual in need thereof, i.e. healthy tissues typically in a low 'NRG' environment. SUMMARY OF THE INVENTION According to a first object, the present invention relates to a humanized neuregulin positively dependent, in particular non-competitive, anti-human-HER3 antibody comprising: (i) a heavy chain wherein the variable domain has at least 90% or 95% identity with the amino acid sequence set forth as SEQ ID NO: 1: X1VQLX2X3SGX4X5LX6X7PGX8SX9X10X11SCX12ASGFTFSSYX13MSWVRQA PGX14GLEWVAYISDX15GGVTYYX16DX17X18KGRFX19ISRDNSX20X21TLYLQMX22SL X23AEDTAVYYCARDRYGLFX24YWGQGTLVTVSS (SEQ ID NO: 1) wherein: X1 represents E or Q, in particular E; X2 represents V or L, in particular L; X3 represents E or Q, in particular E; X4 represents G or S, in particular G; X5 represents G or E, in particular G; X6 represents V or K, in particular V; X7 represents Q or K, in particular Q; X8 represents G or A, in particular G; X9 represents L or V, in particular L; X10 represents R or K, in particular R; X11 represents L or V, in particular L; X12 represents A or K, in particular A; X13 represents T or A ; X14 represents K or Q, in particular K; X15 represents G, K, A or Q, in particular G, K or A, and more particularly G or K; X16 represents P or A; X17 represents T or S; X18 represents I, V or F, in particular V; X19 represents T or V ; X20 represents K or V, in particular K; X21 represents N or S, in particular N; X22 represents N or S, in particular N; X23 represents R or K, in particular R; and X24 represents A or V, in particular A; and (ii) a light chain wherein the variable domain has at least 90% or 95% identity with the amino acid sequence set forth as SEQ ID NO: 2: X25IX26X27TQSPX28X29LSX30SX31GX32RX33TX34X35CX36ASQX37VGIX38X39A WYQQKPGX40APX41LLIYSASNRYTGX42PX43RFX44GSGSGTX45FTLTISSLX46X47EDX4 8AX49YX50CQQYSX51YPYTFGQGTKLEIK (SEQ ID NO: 2) wherein: X25 represents E, D or A, in particular E; X26 represents V or Q, in particular V; X27 represents M or L; X28 represents A or S, in particular A; X29 represents T or S, in particular T; X30 represents V, L or A, in particular L; X31 represents P or V, in particular P; X32 represents E or D, in particular E; X33 represents A or V, in particular A; X34 represents L or I, in particular L; X35 represents S or T, in particular S; X36 represents K or R; X37 represents N or S; X38 represents A or Y; X39 represents V or L; X40 represents Q or K, in particular Q; X41 represents R or K, in particular R; X42 represents I or V, in particular I; X43 represents A or S, in particular A; X44 represents S or T, in particular S; X45 represents E or D, in particular E; X46 represents Q or E, in particular E; X47 represents S or P, in particular P; X48 represents F or I, in particular F; X49 represents V or T, in particular V; X50 represents Y or F, in particular Y; and X51 represents N or G. The antibody according to the invention may in particular be such that: (i) the heavy chain comprises: - a H-CDR1 having a sequence selected from the group consisting of SEQ ID NO: 3 and SEQ ID NO: 4; and - a H-CDR2 having a sequence selected from the group consisting of SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10 and SEQ ID NO: 11; and - a H-CDR3 having a sequence selected from the group consisting of SEQ ID NO: 12 and SEQ ID NO: 13; and, (ii) the light chain comprises: - a L-CDR1 having a sequence selected from the group consisting of SEQ ID NO: 14 and SEQ ID NO: 15; and - a L-CDR2 having the sequence set forth as SEQ ID NO: 16; and - a L-CDR3 having a sequence selected from the group consisting of SEQ ID NO: 17 and SEQ ID NO: 18. The antibody according to the invention may in particular be such that the variable domain of the heavy chain comprises, and in particular consists in, an amino acid sequence selected from the group consisting of SEQ ID NO: 20, SEQ ID NO: 22, SEQ ID NO: 19, SEQ ID NO: 21, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26 and SEQ ID NO: 27. In particular, the antibody according to the invention may be characterized in that the variable domain of the light chain comprises, and in particular consists in, an amino acid sequence selected from the group consisting of SEQ ID NO: 29, SEQ ID NO: 28, SEQ ID NO: 30, SEQ ID NO: 31 and SEQ ID NO: 32. More particularly, the antibody according to the invention may be selected from the group consisting of antibodies wherein: - the variable domain of the heavy chain of said antibody comprises, and in particular consists in, the amino acid sequence set forth as SEQ ID NO: 20 and/or, in particular and, the variable domain of the light chain comprises, and in particular consists in, an amino acid sequence selected from the group consisting of SEQ ID NO: 28, 29, 30, 31 and 32; or - the variable domain of the heavy chain of said antibody comprises, and in particular consists in, the amino acid sequence set forth as SEQ ID NO: 22 and the variable domain of the light chain comprises, and in particular consists in, the amino acid sequence set forth as SEQ ID NO: 29; or - the variable domain of the heavy chain of said antibody comprises, and in particular consists in, the amino acid sequence set forth as SEQ ID NO: 19 and the variable domain of the light chain comprises, and in particular consists in, an amino acid sequence selected from the group consisting of SEQ ID NO: 28, 29, 31 and 32; or - the variable domain of the heavy chain of said antibody comprises, and in particular consists in, the amino acid sequence set forth as SEQ ID NO: 26 and the variable domain of the light chain comprises, and in particular consists in, an amino acid sequence selected from the group consisting of SEQ ID NO: 28, 29, 31, and 32; or - the variable domain of the heavy chain of said antibody comprises, and in particular consists in, the amino acid sequence set forth as SEQ ID NO: 21 and the variable domain of the light chain comprises, and in particular consists in, an amino acid sequence selected from the group consisting of SEQ ID NO: 29 and 30; or - the variable domain of the heavy chain of said antibody comprises, and in particular consists in, the amino acid sequence set forth as SEQ ID NO: 23 and the variable domain of the light chain comprises, and in particular consists in, the amino acid sequence set forth as SEQ ID NO: 29; or - the variable domain of the heavy chain of said antibody comprises, and in particular consists in, the amino acid sequence set forth as SEQ ID NO: 24 and the variable domain of the light chain comprises, and in particular consists in, an amino acid sequence selected from the group consisting of SEQ ID NO: 29 and 30; or - the variable domain of the heavy chain of said antibody comprises, and in particular consists in, the amino acid sequence set forth as SEQ ID NO: 25 and the variable domain of the light chain comprises, and in particular consists in, an amino acid sequence selected from the group consisting of SEQ ID NO: 29 and 30; or - the variable domain of the heavy chain of said antibody comprises, and in particular consists in, the amino acid sequence set forth as SEQ ID NO: 27 and the variable domain of the light chain comprises, and in particular consists in, an amino acid sequence selected from the group consisting of SEQ ID NO: 29 and 30. In particular, the antibody according to the invention may be such that: - the variable domain of the heavy chain of said antibody comprises, and in particular consists in, an amino acid sequence selected from the group consisting of SEQ ID NO: 20, 22, 19, 21, 23, 24 and 25; and - the variable domain of the light chain of said antibody comprises, and in particular consists in, an amino acid sequence selected from the group consisting of SEQ ID NO: 29, 28 and 30. More particularly, the antibody of the invention may be characterized in that: - the variable domain of the heavy chain of said antibody comprises, and in particular consists in, an amino acid sequence selected from the group consisting of SEQ ID NO: 20, 22, 24 and 25; and - the variable domain of the light chain of said antibody comprises, and in particular consists in, an amino acid sequence selected from the group consisting of SEQ ID NO: 29 and 30. In particular, the antibody according to the invention may be selected from the group consisting of antibodies wherein: - the variable domain of the heavy chain of said antibody comprises, and in particular consists in, the amino acid sequence set forth as SEQ ID NO: 20 and the variable domain of the light chain comprises, and in particular consists in, the amino acid sequence set forth as SEQ ID NO: 29; or - the variable domain of the heavy chain of said antibody comprises, and in particular consists in, the amino acid sequence set forth as SEQ ID NO: 22 and the variable domain of the light chain comprises, and in particular consists in, the amino acid sequence set forth as SEQ ID NO: 29; or - the variable domain of the heavy chain of said antibody comprises, and in particular consists in, the amino acid sequence set forth as SEQ ID NO: 24 and the variable domain of the light chain comprises, and in particular consists in, the amino acid sequence set forth as SEQ ID NO: 30; or - the variable domain of the heavy chain of said antibody comprises, and in particular consists in, the amino acid sequence set forth as SEQ ID NO: 25 and the variable domain of the light chain comprises, and in particular consists in, the amino acid sequence set forth as SEQ ID NO: 30. Another object of the present invention is an immunoconjugate comprising the antibody according to the invention linked to a therapeutic agent. A further object of the present invention is a fragment of an antibody according to the invention comprising the variable domain of the heavy chain and the variable domain of the light chain. The fragment of the invention may be selected from the group consisting of Fv, Fab, F(ab’)2, Fab’, dsFv, scFv, sc(Fv)2 and diabodies. Another object of the present invention is a nucleic acid sequence encoding an antibody according to the invention or a fragment of the invention. A further object of the invention is a vector comprising a nucleic acid sequence according to the invention. Another object of the invention is a host cell, in particular a procaryotic or eucaryotic host cell, comprising a nucleic acid sequence according to the invention or a vector according to the invention. A further object of the invention is a pharmaceutical composition comprising an antibody according to the invention, an immunoconjugate according to the invention, or a fragment according to the invention, in a pharmaceutically acceptable carrier. Another object of the invention is an antibody according to the invention, an immunoconjugate according to the invention, or a fragment according to the invention, for use as a drug. A further object of the invention is an antibody according to the invention, an immunoconjugate according to the invention, a fragment according to the invention or a pharmaceutical composition according to the invention for use in the treatment of a HER3- expressing cancer, in particular of a HER3-expressing cancer wherein neuregulin is present, in an individual in need thereof. The HER3-expressing cancer may in particular be a NRG-dependent cancer, and in particular a NRG-fusion protein driven cancer. The neuregulin, in particular neuregulin 1 or neuregulin 2, more particularly neuregulin 1α, 1β or 2, and more particularly neuregulin 1β, present may be secreted by the cancer and/or by tissues and/or organs, in particular by tissues and/or organs in the cancer and/or surrounding the cancer. The neuregulin, and in particular neuregulin 1β, presence may also be due to its administration to the subject before, after, or at the same time as the antibody and/or the immunoconjugate. In order to determine if NRG, and for example NRG1α or NRG1β or NRG2, is present according to the invention, a well-known method of immunohistochemistry can be applied as described in Gilmour et al., Clin. Cancer Res., 8: 3933-3942 (2002). The cancers or tumor cells associated with the expression of HER3 considered in the present invention may be chosen from the group consisting of head and neck cancers, squamous cell cancer, esophagus cancer, non-small cell lung cancer, cutaneous squamous cancers, cervical cancer, vulval cancer and anal cancer, gastric cancer, pancreatic cancer, glial cell tumors, ovarian cancer, bladder cancer, breast cancer, melanoma, colorectal cancer in particular colon cancer, endometrial carcinoma, salivary gland carcinoma, renal cell carcinoma, prostate cancer, thyroid cancer and hepatic cell carcinoma. They are preferably chosen among breast cancer, ovarian cancer, small-cell lung cancer, non-small cell lung cancer, melanoma, pancreatic cancer, head & neck and colorectal cancer, and more particularly among breast cancer, ovarian cancer and pancreatic cancer. BRIEF DESCRIPTION OF THE FIGURES Figure 1 shows the evaluation of binding of Fab-Yeast for recombinant human HER3- ECD Fc fusion by FACS for Gama-2 to Gama-13 humanized variants antibodies compared to 9F7-F11. The 9F7-F11 and humanized variants antibodies in Fab format were expressed on the surface of Yeast. The expression of the construct as well the binding of the recombinant HER3 to the Fab-Yeast were revealed respectively by an anti-Light chain Kappa (APC) and by an anti-human Fc conjugated antibody (PE). The fluorescence ratio PE/APC reveals the binding to recombinant HER3 (8nM) normalized with the level of Fab expression on the surface of the Yeast. A) Evaluation of binding without neuregulin, here NRG1. B) Evaluation of binding with 50nM of NRG1. Figure 2 shows the evaluation of binding of Fab-Yeast for recombinant human HER3- ECD Fc fusion by FACS for Gama-21, -23, -24, -25, -26, -27, -29, -31 and -33 humanized variants antibodies compared to Gama-7. The humanized variants antibodies in Fab format were expressed on the surface of Yeast. The expression of the construct as well the binding of the recombinant HER3 to the Fab-Yeast were revealed respectively by an anti-Light chain Kappa (APC) and by an anti-human Fc conjugated antibody (PE). The fluorescence ratio PE/APC reveals the binding to recombinant HER3 (200pM) normalized with the level of Fab expression on the surface of the Yeast. A) Evaluation of binding without NRG1. B) Evaluation of binding with 50nM of NRG1. Figure 3 illustrates the binding of the humanized antibodies to the HER3 receptor expressed at the surface membrane of SKBR3 breast cancer cell line. Binding curves of antibodies at 50µg/ml were determined by FACS analysis with different concentrations of NRG1 (A, C and E) or in absence of NRG1 (B, D and F). Comparison of binding of Gama-5 and Gama-7 humanized antibodies with Patritumab in presence of NRG1 (A) or in absence of NRG1 (B). Comparison of binding between Gama-7, Gama-29 and Gama-31 humanized antibodies in presence of NRG1 (C) or in absence of NRG1 (D). Comparison of binding between Gama-7, Gama-23 and Gama-23A humanized antibodies in presence of NRG1 (E) or in absence of NRG1 (F). Dotted line indicates MFI background value (control). Ordinate: Mean Fluorescence Intensity (MFI). Abscissa (A, C and E): Concentration of NRG1 (nM). Performed using a Fortessa Flow cytometer (BD Bioscience) (PE-A setting). Figure 4 illustrates the binding of the humanized antibodies to the HER3 receptor expressed at the surface membrane of SKBR3 breast cell line. Binding curves of antibodies at different concentration were determined by FACS analysis in presence of NRG1 at 50nM or in absence. A) Gama-7, B) Gama-29, C) Gama-31 D) Gama-23, E) Gama-23A and F) Patritumab. Dotted line indicates MFI background value (control). Ordinate: Mean Fluorescence Intensity (MFI). Abscissa: Concentration of Antibody in µg/mL. Performed using a Fortessa Flow cytometer (BD Bioscience) (PE-A setting). Figure 5 illustrates the binding of the humanized antibody Gama-23A to the HER3 receptor expressed at the surface membrane of SKBR3 breast cell line in presence of different HER3 ligands. A) Binding curves of Gama-23A at different concentrations (from 0.05µg/ml to 50µg/ml) determined by FACS in absence of ligand or in presence of 50nM of NRG1α, NRG1β or NRG2. Ordinate: Mean Fluorescence Intensity (MFI). Abscissa: Concentration of ligands in nM. Performed using a Fortessa Flow cytometer (BD Bioscience) (PE-A setting). B) Binding of Gama-23A at 50µg/mL determined by FACS in presence of EGF, NRG1α, NRG1β at 100nM or a mixture of NRG1β and EGF. For the mixture, the ligands EGF and NRG1 β were used at 100nM each. P values ** = p < 0.01, *** = p < 0.001 Figure 6 illustrates the thermal stabilization of the humanized variants as compared to the 9F7-F11 parental chimeric antibody by DSC (Differential Scanning calorimetry). Representations of analyzed DSC data after baseline substraction and curve fitting of (A) 9F7- F11 and (B) Gama-23A. In A) and B) the thick line represents the thermogram after baseline subtraction. The dashed lines are the deconvoluted peaks of each domain transition (Fab, CH2, CH3). The thermal transition temperature (melting temperature; Tm) of the Fab of the antibody tested correspond to the highest pic on the thermogram. The Tm and ΔH for 9F7-F11 (Fab) are 75.6 °C and 543 kcal/mol respectively. The Tm and ΔH for Gama-23A (Fab) are 79.4°C and 602 kcal/mol respectively. Abscissa: temperature in degree Celsius. Ordinate: Heat capacity Cp (kcal/Mol/°C). Figure 7 shows the effect of the humanized variants Gama-23A, Gama-7, Gama-23 and Patritumab on Akt (7A) and HER3 phosphorylation (7B) in T47D breast cancer cell lines in presence of NRG1 at 25nM and antibodies concentrations range from 0.05µg/mL to 50µg/mL. A) Effect on Akt phosphorylation expressed in HTRF ratio (TR-FRET signal 665nm/620nM emission ratio). Phospho Akt TR-FRET signal was normalized with total Akt, B) Effect on HER3 phosphorylation expressed in HTRF ratio. HTRF ration corresponds to the TR-FRET signal corresponds to the 665 nm/620 nm emission ratio. P values b): comparison PBS (5%) + NRG1 25nM versus PBS (5%) ; c): comparison Antibody + NRG125nM versus PBS (5%) + NRG1 25nM. * = p < 0.05, ** = p < 0.01, *** = p < 0.001. Figure 8 illustrates the internalization by flow cytometry on SKBR3 breast cell line of the humanized variants Gama-7, Gama-29, Gama-23A and Patritumab (comparative) (at 50µg/mL) in the presence (Figure 8A) or in the absence (Figure 8B) of NRG1 at 50nM. The internalization was evaluated by detection of anti-HER3 antibodies binding to cell surface HER3 receptor at 37°C or 4°C at t=0h, t=1h, t=2h. Ordinate: % of internalisation. Abscissa: Time (hours). Performed using a Fortessa Flow cytometer (BD Bioscience) (PE-A setting). DETAILED DESCRIPTION OF THE INVENTION The inventors have been able to generate a plurality of humanized anti-human HER3 antibodies which unexpectedly have the ability to have a significantly increased binding to HER3 in the presence of NRG1 compared to when NRG1 is absent (i.e., humanized neuregulin positively dependent anti-human-HER3 antibodies). Surprisingly, the inventors have indeed shown that certain humanized antibodies but not others, comprising several modifications compared to the chimeric antibody from which they originate, sometimes even in at least one of the CDRs, are able to preferably bind to tissues expressing HER3 wherein NRG1 is present (such as cancers, in particular cancers as defined in the present herein) compared to tissues expressing HER3 wherein NRG1 is less present or even not present (in particular healthy tissues), and at least in the same measure, or better, than the original chimeric antibody. Taking into account the substantial changes in the overall structure of the antibody induced by the humanization process, and considering in particular the several modifications brought to the two variable regions of the chimeric antibody of reference to obtain the humanized antibodies of the invention, the man skilled in the art would expect these humanized antibodies to lose affinity to the target antigen and in particular, to lose the advantageous ability to have their binding to HER3 substantially increased in the presence of NRG1 (Admadzadeh et al., Monoclon. Antib ; Immunodiagn. Immunother., 33: 67-73 (2014); Lu et al., J. Biomed. Sci., 27: 1-302020). This unexpected outcome, following the structural changes made to the original antibody, is even more surprising for an antibody requiring a specific allosteric structure of its target HER3 which binds with a second receptor HER2 in the presence of neuregulin. Moreover, the inventors have discovered that these humanized antibodies were also facilitated in their binding to HER3 by other common isoforms of neuregulin. Unexpectedly, several of these humanized antibodies also displayed an improved stability. Furthermore, antibodies which bind the HER3 receptor and antagonize the NRG ligand-induced oncogenic phosphorylations only when NRG concentration is enhanced (versus normal tissues) in the microenvironment are especially pertinent in the context of NRG-driven tumors. More particularly, such tumor-selectivity is highly interesting as it enlarges the therapeutic index of a pharmaceutical composition containing such an antibody, whilst preserving healthy HER3+ tissues, which generally contain low levels of NRG. Definitions The term “neuregulin” has its general meaning in the art and is often used interchangeably with the term “heregulin”. The heregulin family includes alpha, beta and gamma heregulins (Holmes et al., Science, 256: 1205-1210 (1992); U.S. Patent No. 5,641,869; and Schaefer et al. Oncogene 15: 1385-1394 (1997)); neu differentiation factors (NDFs), glial growth factors (GGFs); acetylcholine receptor inducing activity (ARIA); and sensory and motor neuron derived factor (SMDF). For a review, see Groenen et al., Growth Factors, 11: 235-257 (1994); Lemke, G. Mol. Cell. Neurosci. 7: 247-262 (1996) and Lee et al. Pharm. Rev., 47: 51- 85 (1995); Falls, Exp. Cell Res. 284: 14-30 (2003). According to the invention, Neuregulin, also referred to as NRG in the present text, may be selected from Neuregulin 1 (NRG1) or Neuregulin 2 (NRG2), more particularly be selected from Neuregulin 1α (NRG1α), Neuregulin 1β (NRG1β) or Neuregulin 2 (NRG2). The term “HER3” refers to the human HER3 receptor as described in Plowman et al., Proc. Natl. Acad. Sci. USA, 87: 4905-4909 (1990); see, also, Kani et al., Biochemistry, 44: 15842-857 (2005), Cho and Leahy, Science, 297: 1330-1333 (2002)). The term “anti-human-HER3 antibody” refers to an antibody directed against human HER3. According to the present invention, “antibody” or “immunoglobulin” have the same meaning, and will be used equally in the present invention. The term “antibody” as used herein refers to immunoglobulin molecules and immunologically active portions of immunoglobulin molecules, i.e., molecules that contain an antigen binding site that immunochemically binds an antigen. As such, the term antibody encompasses not only whole antibody molecules, but also variants (including derivatives) of antibodies. In natural antibodies, two heavy chains are linked to each other by disulfide bonds and each heavy chain is linked to a light chain by a disulfide bond. There are two types of light chain, lambda (l) and kappa (k). There are five main heavy chain classes (or isotypes) which determine the functional activity of an antibody molecule: IgM, IgD, IgG, IgA and IgE. Each chain contains distinct sequence domains. The light chain includes two domains, a variable domain (VL) and a constant domain (CL). The heavy chain includes four domains, a variable domain (VH) and three constant domains (CH1, CH2 and CH3, collectively referred to as CH). The variable regions of both light (VL) and heavy (VH) chains determine binding recognition and specificity to the antigen. The constant region domains of the light (CL) and heavy (CH) chains confer important biological properties such as antibody chain association, secretion, trans-placental mobility, complement binding, and binding to Fc receptors (FcR). The Fv fragment is the N-terminal part of the Fab fragment of an immunoglobulin and consists of the variable portions of one light chain and one heavy chain. The specificity of the antibody resides in the structural complementarity between the antibody combining site and the antigenic determinant. Antibody combining sites are made up of residues that are primarily from the hypervariable or complementarity determining regions (CDRs). Occasionally, residues from non-hypervariable or framework regions (FR) influence the overall domain structure and hence the combining site. Complementarity Determining Regions or CDRs refer to amino acid sequences which together define the binding affinity and specificity of the natural Fv region of a native immunoglobulin binding site. The light and heavy chains of an immunoglobulin each have three CDRs, designated L-CDR1, L-CDR2, L-CDR3 and H-CDR1, H-CDR2, H-CDR3, respectively. An antigen-binding site, therefore, includes six CDRs, comprising the CDR set from each of a heavy and a light chain V region. Framework Regions (FRs) refer to amino acid sequences interposed between CDRs. The well-known Kabat numbering system is used in the present text for defining antibodies according to the invention, and in particular to define their CDRs. In the present text, the term “antibody” is used in the broadest sense and includes fully assembled antibodies, monoclonal antibodies, polyclonal antibodies, multi-specific antibodies (e.g., bispecific antibodies), antibody fragments that can bind HER3, and recombinant peptides comprising the forgoing as long as they exhibit the desired biological activity defined herein. The term "chimeric antibody" refers to an antibody which comprises a VH domain and a VL domain of an antibody which are derived from one species and the constant domain which is derived from another species, for example an antibody in which the variable region sequences are derived from a mouse antibody and the constant region sequences are derived from a human antibody. According to the invention, the term “humanized antibody” refers to an antibody having variable region framework and constant regions from a human antibody but which retains the mouse sequence origin of the CDRs of the variable V regions. The terms “monoclonal antibody” or “monoclonal antibody composition” as used herein refer to a preparation of antibody molecules of single molecular composition. A monoclonal antibody composition displays a single binding specificity and affinity for a particular epitope. The terms “neuregulin non-competitive” defining an antibody are used herein to indicate an antibody with a binding site not shared (even partially) with that of neuregulin, in particular with that of NRG1, and therefore an antibody that does not compete with NRG1 for its binding, in particular to human HER3. As indicated above, a “neuregulin positively dependent” anti-HER3 antibody is used herein to indicate an antibody who’s binding to HER3 increases with the increase of the quantity of neuregulin present within the immediate vicinity of the targeted HER3. In simpler terms, this antibody's affinity for HER3 enhances as the amount of neuregulin in close proximity to the specific HER3 molecule becomes greater. The term “treatment” or “therapy” refers to administering an active agent with the purpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve, or affect a condition (e.g., a disease), the symptoms of the condition, or to prevent or delay the onset of the symptoms, complications, biochemical indicia of a disease, or otherwise arrest or inhibit further development of the disease, condition, or disorder in a statistically significant manner. According to the invention, the terms “patient”, “individual”, “patient in need thereof” or “individual in need thereof” are equivalent and are intended for a human or non- human mammal affected or likely to be affected with cancer associated with the expression of human HER3, in particular of a HER3-expressing cancer wherein neuregulin is present in an individual in need thereof. Said individual is preferably a human being. An antibody according to the invention, an immunoconjugate according to the invention or a fragment according to the invention is implemented according to the present invention in a therapeutically effective amount. By a “therapeutically effective amount” of the antibody, immunoconjugate or fragment of the invention is meant a sufficient amount of antibody, immunoconjugate or fragment to treat said cancer, at a reasonable benefit/risk ratio applicable to any medical treatment. It will be understood, however, that the total daily usage of the antibody, immunoconjugate or fragment and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific antibody employed; the specific composition employed, the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific antibody employed; the duration of the treatment; drugs used in combination or coincidental with the specific antibody employed; and like factors well known in the medical arts. For example, it is well known within the skill of the art to start doses of the compound at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. For each or the amino acid sequences of interest, reference sequences are described herein. The present description also encompasses amino acid sequences (e.g. enzyme amino acid sequences), having specific percentages of amino acid identity with a reference amino acid sequence. For obvious reasons, in all the present description, a specific nucleic acid sequence or a specific amino acid sequence which complies with, respectively, the considered nucleotide or amino acid identity, should further lead to obtaining a protein (or enzyme) which displays the desired biological activity. As used herein, the "percentage of identity" between two nucleic acid sequences or between two amino acid sequences is determined by comparing both optimally aligned sequences through a comparison window. The portion of the nucleotide or amino-acid sequence in the comparison window may thus include additions or deletions (for example "gaps") as compared to the reference sequence (which does not include these additions or these deletions) so as to obtain an optimal alignment between both sequences. The terms "sequence homology" or "sequence identity" or "homology" or "identity" are used interchangeably herein. For the purpose of the invention, it is defined here that in order to determine the percentage of sequence homology or sequence identity of two amino acid sequences or of two nucleic acid sequences, the sequences are aligned for optimal comparison purposes. In order to optimize the alignment between the two sequences gaps may be introduced in any of the two sequences that are compared. Such alignment can be carried out over the full length of the sequences being compared. Alternatively, the alignment may be carried out over a shorter length, for example over about 20, about 50, about 100 or more nucleic acids/based or amino acids. The sequence identity is the percentage of identical matches between the two sequences over the reported aligned region. A comparison of sequences and determination of percentage of sequence identity between two sequences can be accomplished using a mathematical algorithm. The skilled person will be aware of the fact that several different computer programs are available to align two sequences and determine the identity between two sequences (Kruskal, J. B. (1983) An overview of sequence comparison In D. Sankoff and J. B. Kruskal, (ed.), Time warps, string edits and macromolecules: the theory and practice of sequence comparison, pp. 1-44 Addison Wesley). The percent sequence identity between two amino acid sequences or between two nucleotide sequences may be determined using the Needleman and Wunsch algorithm for the alignment of two sequences. (Needleman and Wunsch, J. Mol. Biol., 48: 443-453 (1970)). Both amino acid sequences and nucleotide sequences can be aligned by the algorithm. The Needleman-Wunsch algorithm has been implemented in the computer program NEEDLE. For the purpose of the invention, the NEEDLE program from the EMBOSS package was used (version 2.8.0 or higher, EMBOSS: The European Molecular Biology Open Software Suite (2000) Rice, P. Longden J. and Bleasby, A. Trends in Genetics 16, (6) pp276— 277, http://emboss.bioinformatics.nl/). For protein sequences EBLOSUM62 is used for the substitution matrix. For nucleotide sequence, EDNAFULL is used. The optional parameters used are a gap opening penalty of 10 and a gap extension penalty of 0.5. No end gap penalty is added. In the Output section, Yes has been indicated in response to the question “Brief identity and similarity” and “SRS pairwise” indicated as Output alignment format. After alignment by the program NEEDLE as described above the percentage of sequence identity between a query sequence and a sequence of the invention is calculated as follows: Number of corresponding positions in the alignment showing an identical amino acid or identical nucleotide in both sequences divided by the total length of the alignment after subtraction of the total number of gaps in the alignment. The identity defined as herein can be obtained from NEEDLE by using the NOBRIEF option and is labeled in the output of the program as "longest-identity". The similarity of nucleotide and amino acid sequences, i.e. the percentage of sequence identity, can be determined via sequence alignments using several other art-known algorithms, preferably with the mathematical algorithm of Karlin and Altschul (Karlin and Altschul, Proc. Natl. Acad. Sci. USA, 90: 5873-5877 (1993)), with hmmalign (HMMER package, http://hmmer.org/) or with the CLUSTAL algorithm (Thompson et al., Nucleic Acids Res., 22: 4673-80 (1994)) available e.g. on https://www.ebi.ac.uk/Tools/msa/clustalo/ or the GAP program (mathematical algorithm of the University of Iowa) or the mathematical algorithm of Myers and Miller (1989 - Cabios 4: 11-17) or Clone Manager 9. Preferred parameters used are the default parameters as they are set on https://www.ebi.ac.uk/Tools/msa/clustalo/. The grade of sequence identity (sequence matching) may be calculated using e.g. BLAST, BLAT or BlastZ (or BlastX). A similar algorithm is incorporated into the BLASTN and BLASTP programs of Altschul et al., J. Mol. Biol., 215: 403-410 (1990). BLAST polynucleotide searches are performed with the BLASTN program, score = 100, word length = 12, to obtain polynucleotide sequences that are homologous to those nucleic acids which encode the relevant protein. BLAST protein searches are performed with the BLASTP program, score = 50, word length = 3, to obtain amino acid sequences homologous to the SHC polypeptide. To obtain gapped alignments for comparative purposes, Gapped BLAST is utilized as described in Altschul et al., Nucleic Acids Res., 25: 3389-3402 (1997). When utilizing BLAST and Gapped BLAST programs, the default parameters of the respective programs are used. Sequence matching analysis may be supplemented by established homology mapping techniques like Shuffle-LAGAN (Brudno, Bioinformatics, 19 Suppl 1: 154-162 (2003)) or Markov random fields. When percentages of sequence identity are referred to in the present application, these percentages are calculated in relation to the full length of the longer sequence, if not specifically indicated otherwise. In particular embodiments, % identity between two sequences is determined using CLUSTAL O (version 1.2.4). In the present invention, amino acids are represented in the sequences on the basis of the commonly recognized and known single-letter code which is reminded hereafter: Alanine: A; Arginine: R; Asparagine: N; Aspartic Acid: D; Cysteine: C; Glutamic Acid: E; Glutamine: Q; Glycine: G; Histidine: H; Isoleucine: I; Leucine: L; Lysine: K; Methionine: M; Phenylalanine: F; Proline: P; Serine: S; Threonine: T; Tryptophan: W; Tyrosine: Y and Valine: V. Antibodies of the invention The present invention provides for neuregulin (NRG)-positively dependent, in particular non-competitive, anti-HER3 antibodies, preferably in a purified form or in an isolated form, said antibodies comprising (i) a heavy chain wherein the variable domain has at least 90% or 95% identity with the amino acid sequence set forth as SEQ ID NO: 1 and (ii) a light chain wherein the variable domain has at least 90% or 95% identity with the amino acid sequence set forth as SEQ ID NO: 2. As mentioned above, a specific amino acid sequence which complies with the considered amino acid identity should further lead to obtaining a protein which displays the desired biological activity. Herein, an antibody comprising (i) a heavy chain wherein the variable domain has at least 90% identity with the amino acid sequence set forth as SEQ ID NO: 1 and (ii) a light chain wherein the variable domain has at least 90% identity with the amino acid sequence set forth as SEQ ID NO: 2 accordingly designates an antibody comprising (i) a heavy chain wherein the variable domain has at least 90% identity with the amino acid sequence set forth as SEQ ID NO: 1 and (ii) a light chain wherein the variable domain has at least 90% identity with the amino acid sequence set forth as SEQ ID NO: 2 and having a biological activity of the same nature as an antibody having the amino acid sequences SEQ ID NO: 1 and SEQ ID NO: 2. A biological activity of the same nature for an antibody herein means an antibody which is anti-HER3, in particular anti-human HER3, and which has the ability to have a significantly increased binding to HER3 in the presence of NRG1 compared to when NRG1 is absent. As described herein, an amino acid sequence having at least 90% identity with a reference amino acid sequence encompasses amino acid sequences having at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% and 99% nucleotide identity with the said reference amino acid sequence, and also a biological activity of the same nature as the said reference amino acid sequence. As described herein, an amino acid sequence having at least 95% identity with a reference amino acid sequence encompasses amino acid sequences having at least 96%, 97%, 98% and 99% nucleotide identity with the said reference amino acid sequence, and also a biological activity of the same nature as the said reference amino acid sequence. An antibody according to the invention may in particular comprise a heavy chain comprising: - a H-CDR1 having a sequence selected from the group consisting of SEQ ID NO: 3 and SEQ ID NO: 4; and - a H-CDR2 having a sequence selected from the group consisting of SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10 and SEQ ID NO: 11; and - a H-CDR3 having a sequence selected from the group consisting of SEQ ID NO: 12 and SEQ ID NO: 13. An antibody according to the invention may in particular comprise a light chain comprising: - a L-CDR1 having a sequence selected from the group consisting of SEQ ID NO: 14 and SEQ ID NO: 15; and - a L-CDR2 having the sequence set forth as SEQ ID NO: 16; and - a L-CDR3 having a sequence selected from the group consisting of SEQ ID NO: 17 and SEQ ID NO: 18. In particular, an antibody according to the invention may comprise: (i) a heavy chain comprising: - a H-CDR1 having a sequence selected from the group consisting of SEQ ID NO: 3 and SEQ ID NO: 4; and - a H-CDR2 having a sequence selected from the group consisting of SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10 and SEQ ID NO: 11; and - a H-CDR3 having a sequence selected from the group consisting of SEQ ID NO: 12 and SEQ ID NO: 13, and more particularly a H-CDR3 having the sequence set forth as SEQ ID NO: 12; and (ii) a light chain comprising: - a L-CDR1 having a sequence selected from the group consisting of SEQ ID NO: 14 and SEQ ID NO: 15; and - a L-CDR2 having the sequence set forth as SEQ ID NO: 16; and - a L-CDR3 having a sequence selected from the group consisting of SEQ ID NO: 17 and SEQ ID NO: 18. The variable domain of the heavy chain of an antibody according to the invention may comprise, and in particular may consist in, an amino acid sequence selected from the group consisting of SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26 and SEQ ID NO: 27. In particular, the variable domain of the heavy chain of an antibody according to the invention may comprise, and in particular may consist in, an amino acid sequence selected from the group consisting of SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24 and SEQ ID NO: 25, more particularly from the group consisting of SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 24 and SEQ ID NO: 25, and in particular from the group consisting of SEQ ID NO: 20, SEQ ID NO: 22, SEQ ID NO: 24 and SEQ ID NO: 25. The variable domain of the light chain of an antibody according to the invention may comprise, and in particular may consist in, an amino acid sequence selected from the group consisting of SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31 and SEQ ID NO: 32. In particular, the variable domain of the light chain of an antibody according to the invention may comprise, and in particular may consist in, an amino acid sequence selected from the group consisting of SEQ ID NO: 28, SEQ ID NO: 29 and SEQ ID NO: 30 and in particular from the group consisting of SEQ ID NO: 29 and SEQ ID NO: 30. In particular, an antibody according to the invention may comprise: (i) a variable domain of the heavy chain comprising, and in particular consisting in, an amino acid sequence selected from the group consisting of SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26 and SEQ ID NO: 27, in particular selected from the group consisting of SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24 and SEQ ID NO: 25, more particularly from the group consisting of SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 24 and SEQ ID NO: 25, and in particular from the group consisting of SEQ ID NO: 20, SEQ ID NO: 22, SEQ ID NO: 24 and SEQ ID NO: 25; and (ii) a variable domain of the light chain comprising, and in particular consisting in, an amino acid sequence selected from the group consisting of SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31 and SEQ ID NO: 32, in particular from the group consisting of SEQ ID NO: 28, SEQ ID NO: 29 and SEQ ID NO: 30 and more particularly from the group consisting of SEQ ID NO: 29 and SEQ ID NO: 30. An antibody according to the invention may be selected from the group consisting of antibodies wherein: - the variable domain of the heavy chain of said antibody comprises, and in particular consists in, the amino acid sequence set forth as SEQ ID NO: 19 and the variable domain of the light chain comprises, and in particular consists in, an amino acid sequence selected from the group consisting of SEQ ID NO: 28, 29, 31 and 32; or - the variable domain of the heavy chain of said antibody comprises, and in particular consists in, the amino acid sequence set forth as SEQ ID NO: 20 and the variable domain of the light chain comprises, and in particular consists in, an amino acid sequence selected from the group consisting of SEQ ID NO: 28, 29, 30, 31 and 32; or - the variable domain of the heavy chain of said antibody comprises, and in particular consists in, the amino acid sequence set forth as SEQ ID NO: 26 and the variable domain of the light chain comprises, and in particular consists in, an amino acid sequence selected from the group consisting of SEQ ID NO: 28, 29, 31 and 32; or - the variable domain of the heavy chain of said antibody comprises, and in particular consists in, the amino acid sequence set forth as SEQ ID NO: 21 and the variable domain of the light chain comprises, and in particular consists in, an amino acid sequence selected from the group consisting of SEQ ID NO: 29 and 30; or - the variable domain of the heavy chain of said antibody comprises, and in particular consists in, the amino acid sequence set forth as SEQ ID NO: 22 and the variable domain of the light chain comprises, and in particular consists in, the amino acid sequence set forth as SEQ ID NO: 29; or - the variable domain of the heavy chain of said antibody comprises, and in particular consists in, the amino acid sequence set forth as SEQ ID NO: 23 and the variable domain of the light chain comprises, and in particular consists in, the amino acid sequence set forth as SEQ ID NO: 29; or - the variable domain of the heavy chain of said antibody comprises, and in particular consists in, the amino acid sequence set forth as SEQ ID NO: 24 and the variable domain of the light chain comprises, and in particular consists in, an amino acid sequence selected from the group consisting of SEQ ID NO: 29 and 30; or - the variable domain of the heavy chain of said antibody comprises, and in particular consists in, the amino acid sequence set forth as SEQ ID NO: 25 and the variable domain of the light chain comprises, and in particular consists in, an amino acid sequence selected from the group consisting of SEQ ID NO: 29 and 30; or - the variable domain of the heavy chain of said antibody comprises, and in particular consists in, the amino acid sequence set forth as SEQ ID NO: 27 and the variable domain of the light chain comprises, and in particular consists in, an amino acid sequence selected from the group consisting of SEQ ID NO: 29 and 30. In particular, an antibody according to the invention may comprise: - a variable domain of the heavy chain comprising, and in particular consisting in, an amino acid sequence selected from the group consisting of SEQ ID NO: 19, 20, 21, 22, 23, 24 and 25; and - a variable domain of the light chain comprising, and in particular consisting in, an amino acid sequence selected from the group consisting of SEQ ID NO: 28, 29 and 30. In particular, an antibody according to the invention may comprise: - a variable domain of the heavy chain comprising, and in particular consisting in, an amino acid sequence selected from the group consisting of SEQ ID NO: 19, 20, 21, 22, 24 and 25; and - a variable domain of the light chain comprising, and in particular consisting in, an amino acid sequence selected from the group consisting of SEQ ID NO: 28, 29 and 30. In particular, an antibody according to the invention may comprise: - a variable domain of the heavy chain comprising, and in particular consisting in, an amino acid sequence selected from the group consisting of SEQ ID NO: 20, 22, 24 and 25; and - a variable domain of the light chain comprising, and in particular consisting in, an amino acid sequence selected from the group consisting of SEQ ID NO: 29 and 30. An antibody according to the invention may be selected from the group consisting of antibodies wherein: - the variable domain of the heavy chain of said antibody comprises, and in particular consists in, the amino acid sequence set forth as SEQ ID NO: 20 and the variable domain of the light chain comprises, and in particular consists in, the amino acid sequence set forth as SEQ ID NO: 29; or - the variable domain of the heavy chain of said antibody comprises, and in particular consists in, the amino acid sequence set forth as SEQ ID NO: 22 and the variable domain of the light chain comprises, and in particular consists in, the amino acid sequence set forth as SEQ ID NO: 29; or - the variable domain of the heavy chain of said antibody comprises, and in particular consists in, the amino acid sequence set forth as SEQ ID NO: 24 and the variable domain of the light chain comprises, and in particular consists in, the amino acid sequence set forth as SEQ ID NO: 30; or - the variable domain of the heavy chain of said antibody comprises, and in particular consists in, the amino acid sequence set forth as SEQ ID NO: 25 and the variable domain of the light chain comprises, and in particular consists in, the amino acid sequence set forth as SEQ ID NO: 30. Antibodies according to the invention can be defined as being allosteric antibodies, i.e. the antibody/HER3 affinity of the antibodies of the invention is allosterically increased when neuregulin is present in the environment of HER3-positive cells. The present invention also relates to fragments of an antibody according to the invention. A “fragment of an antibody” herein refers to a fragment of an intact antibody that retain the ability to specifically binds to a given antigen/ligand. Examples of fragment of an antibody include a Fab fragment, a monovalent fragment consisting of the VL, VH, CL and CH1 domains; a Fab’ fragment, a monovalent fragment consisting of the VL, VH, CL, CH1 domains and hinge region; a F(ab’)2 fragment, a bivalent fragment comprising two Fab’ fragments linked by a disulfide bridge at the hinge region; an Fd fragment consisting of VH-CH1 domains of a single arm of an antibody, in particular of a heavy chain of an antibody; a single domain antibody (sdAb) fragment (Ward et al., 1989 Nature 341:544-546), which consists of a VH domain or a VL domain; and an isolated complementary determining region (CDR). Furthermore, although the two domains of the Fv fragment, VL and VH, are coded for by separate genes, they can be joined, using recombinant methods, by an artificial peptide linker that enables them to be made as a single protein chain in which the VL and VH regions pair to form monovalent molecules (known as single chain Fv (scFv); see, e.g., Bird et al., 1989 Science 242:423-426; and Huston et al., 1988 proc. Natl. Acad. Sci. 85:5879-5883). “dsFv” is a VH::VL heterodimer stabilized by a disulfide bond. Divalent and multivalent antibody fragments can form either spontaneously by association of monovalent scFvs or can be generated by coupling monovalent scFvs by a peptide linker, such as divalent sc(Fv)2. Such single chain antibodies include one or more antigen-binding portions or fragments of an antibody. These antibody fragments are obtained using conventional techniques known to those skilled in the art, and the fragments are screened for utility in the same manner as are intact antibodies. A unibody is another type of antibody fragment lacking the hinge region of IgG4 antibodies. The deletion of the hinge region results in a molecule that is essentially half the size of traditional IgG4 antibodies and has a univalent binding region rather than the bivalent binding region of IgG4 antibodies. Further details on UniBodies may be obtained by reference to WO 2007/059782, which is incorporated by reference in its entirety. Fragments of antibodies can be incorporated into single domain antibodies, SMIP, maxibodies, minibodies, intrabodies, diabodies, triabodies and tetrabodies (see, e.g., Hollinger and Hudson, 2005, Nature Biotechnology, 23, 9, 1126-1136). The term “diabodies” “tribodies” or “tetrabodies” refers to small antibody fragments with multivalent antigen-binding sites (2, 3 or four), which fragments comprise a heavy-chain variable domain (VH) connected to a light-chain variable domain (VL) in the same polypeptide chain (VH-VL). By using a linker that is too short to allow pairing between the two domains on the same chain, the domains are forced to pair with the complementary domains of another chain and create two antigen-binding sites. Further details on domain antibodies and methods of their production are found in US 6,291,158; 6,582,915; 6,593,081; 6,172,197; and 6,696,245; US 2004/0110941; EP 1433846, 0368684 and 0616640; WO 2005/035572, 2004/101790, 2004/081026, 2004/058821, 2004/003019 and 2003/002609, each of which is herein incorporated by reference in its entirety. Antigen binding fragments can be incorporated into single chain molecules comprising a pair of tandem Fd segments (VH-CH1-VH-CH1) which, together with complementary light chain polypeptides, form a pair of antigen binding regions (Zapata et al., 1995 Protein Eng.8(10); 1057- 1062 and U.S. Pat. No.5,641,870). Fab fragments can be obtained by treating an antibody with a protease, papain. Also, the Fab can be produced by inserting DNA encoding Fab of the antibody into a vector for prokaryotic expression system, or for eukaryotic expression system, and introducing the vector into a procaryote or eucaryote (as appropriate) to express the Fab. F(ab’)2 can be obtained by treating an antibody with a protease, pepsin. Also, the F(ab’)2 can be produced by binding Fab’ described below via a thioether bond or a disulphide bond. Fab’ can be obtained by treating F(ab’)2 with a reducing agent, dithiothreitol. Also, the Fab’ can be produced by inserting DNA encoding Fab’ fragment of the antibody into an expression vector for prokaryote, or an expression vector for eukaryote, and introducing the vector into a prokaryote or eukaryote (as appropriate) to perform its expression. An antigen-binding fragment may be variable heavy chain of a single domain antibody (VHH). Some VHHs may also be known as Nanobodies. Camelid single domain antibody (sdAb) is one of the smallest known antigen-binding antibody fragments (see, e.g., Hassanzadeh- Ghassabeh et al., Nanomedicine (Lond), 8:1013-26 (2013)). A basic VHH has the following structure from the N-terminus to the C-terminus: FR1-CDR1-FR2-CDR2-FR3- CDR3-FR4, in which FR1 to FR4 refer to framework regions 1 to 4, respectively, and in which CDR1 to CDR3 refer to the complementarity determining regions (CDR) 1 to 3. Antibody fragments according to the invention may in particular be selected from the group consisting of Fv, Fab, F(ab')2, Fab', dsFv, scFv, sc(Fv)2 and diabodies. They may be produced by recombinant DNA techniques or by enzymatic or chemical cleavage of intact antibodies, according to methods well known to the man skilled in the art. As previously mentioned, an antibody according to the invention may be a multi- specific antibody. A “multi-specific antibody” refers to monoclonal antibody that has binding specificities for at least two different epitopes of one antigen or for at least two distinct antigens. In the present application, at least one of the antigens is HER3 as mentioned above. In some embodiments, a multi-specific antibody may be a bispecific antibody; a trispecific antibody; a tetraspecific antibody; a pentaspecific antibody; or a hexaspecific antibody, in particular a bispecific antibody. The expression “bispecific antibody” refers to a molecule which combines the antigen- binding sites of two antibodies within a single molecule. Thus, a bispecific antibody is able to bind two different antigens or to two distinct epitopes of a same antigen, simultaneously. The distinct epitope may be overlapping epitopes or non-overlapping epitopes. In the context of the present invention, in the situation where a multi-specific antibody, in particular a bi-specific antibody, or a fragment thereof, of the invention binds at least two different antigens, i.e. binds HER3 and at least one antigen different from HER3, then this at least one antigen may in particular be selected from the group comprising, and in particular consisting, of known targets for antibodies used for treating solid tumors such as those selected from the group comprising, and in particular consisting of, EGFR, HER2, MET, PD-L1, PD1, TROP2, Transferrin, Nectin-4, MUC-1, CEACAM-5, PTK7, Claudin 18.2, FolR1, NCAM-1, Siglec-2 Siglec -3, HGFR, IGF1R, PSMA, ROR-1, CD133, CD30, 5T4, Napi2b, DLL3 and LIV-1. Multi-specific or bispecific antibodies can be prepared as full-length antibodies or antibody fragments as previously defined. The multi-specific or bispecific antibody described herein may comprise a combination of antibodies as described herein. The multi-specific or bispecific antibody may be an isolated or a recombinant bispecific antibody. A multi-specific or a bispecific antibody may comprise at least a first antibody, or an antigen-binding fragment thereof, and at least a second antibody, or an antigen-binding fragment thereof, joined to each other, wherein said first and second antibodies may be selected among the antibodies of groups (i) to (vii) described herein. Illustratively, multi-specific antibodies are described in US20090232811, US9382323, US9890204 or US8796424. An antibody of the multi-specific or a bispecific antibody can be linked to or co- expressed with another antibody by any known techniques in the art. For example, an antibody or fragment thereof can be functionally linked, e.g., by chemical coupling, genetic fusion, noncovalent association or otherwise, to one or more other antibody or antibody fragment to produce a bispecific or a multi-specific antibody. Specific exemplary bispecific formats that can be used include, without limitation, e.g., scFv-based or diabody bispecific formats, IgG- scFv fusions, dual variable domain (DVD)-Ig, Quadroma, knobs-into-holes, common light chain (e.g., common light chain with knobs-into-holes, etc.), CrossMab, CrossFab, (SEED)body, leucine zipper, Duobody, IgG1/IgG2, dual acting Fab (DAF)-IgG, and Mab2 bispecific formats. A bispecific antibody, or fragment thereof, according to the invention may be in the form of a bi-specific T-cell engager (BiTEs) (e.g., not having an Fc) or an anti-CD3 bi-specific antibody (e.g., having an Fc), and thus in the form of a bispecific antibody binding both HER3 and CD3. A bi- or tri-specific antibody, or fragment thereof, according to the invention may be in the form of a bi-specific NK-cell engager (BiKE) or a tri-specific NK-cell engager (TriKE), having or not having an Fc, against an NK cell activating receptor, e.g., CD16A, C-type lectin receptors (CD94/NKG2C, NKG2D, NKG2E/H and NKG2F), natural cytotoxicity receptors (NKp30, NKp44 and NKp46), killer cell C-type lectin-like receptor (NKp65, NKp80), Fc receptor FcγR (which mediates antibody-dependent cell cytotoxicity), SLAM family receptors (e.g., 2B4, SLAM6 and SLAM7), killer cell immunoglobulin-like receptors (KIR) (KIR-2DS and KIR-3DS), DNAM-1 and CD137 (41BB). Diabodies or bi-specific antibodies can be roughly divided into two categories: immunoglobulin G (IgG)-like molecules and non-IgG-like molecules. IgG-like bsAbs retain Fc-mediated effector functions such as antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and antibody-dependent cellular phagocytosis (ADCP) (Spiess et al., Mol Immunol., 67 : 95–106 (2015)). The Fc region of bsAbs facilitates purification and improves solubility and stability. Bi-specific antibodies in IgG-like formats usually have longer serum half-lives owing to their larger size and FcRn- mediated recycling (Kontermann et al., 2015, Drug Discov. Today, 20: 838–47 (2015)). Non- IgG-like bsAbs are smaller in size, leading to enhanced tissue penetration (Kontermann et al., 2015, Drug Discov. Today, 20: 838–47 (2015)). Methods of producing antibodies of the invention Anti-human-HER3 antibodies of the invention may be produced by any technique known in the art, such as, without limitation, any chemical, biological, genetic or enzymatic technique, either alone or in combination. Knowing the amino acid sequence of the desired sequence, one skilled in the art can readily produce said antibodies, by standard techniques for production of polypeptides. For instance, they can be synthesized using well-known solid phase method, preferably using a commercially available peptide synthesis apparatus (such as that made by Applied Biosystems, Foster City, California) and following the manufacturer’s instructions. Alternatively, antibodies of the invention can be synthesized by recombinant DNA techniques well-known in the art. For example, antibodies can be obtained as DNA expression products after incorporation of DNA sequences encoding the antibodies into expression vectors and introduction of such vectors into suitable eukaryotic or prokaryotic hosts that will express the desired antibodies, from which they can be later isolated using well-known techniques. Nucleic acid sequence Accordingly, a further object of the invention relates to a nucleic acid sequence encoding an antibody according to the invention. Typically, said nucleic acid is a DNA or RNA molecule, which may be included in any suitable vector, such as a plasmid, cosmid, episome, artificial chromosome, phage or a viral vector. Vectors The terms “vector”, “cloning vector” and “expression vector” mean the vehicle by which a DNA or RNA sequence (e.g. a foreign gene) can be introduced into a host cell, so as to transform the host and promote expression (e.g. transcription and translation) of the introduced sequence. So, a further object of the invention relates to a vector comprising a nucleic acid of the invention. Such vectors may comprise regulatory elements, such as a promoter, enhancer, terminator and the like, to cause or direct expression of said antibody upon administration to a subject. Examples of promoters and enhancers used in the expression vector for animal cell include early promoter and enhancer of SV40 (Mizukami et al., J. Biol. Chem., 10: 1307-1310 (1987)), LTR promoter and enhancer of Moloney mouse leukemia virus (Kuwana Y et al. 1987), promoter (Mason et al., Cell, 41: 479-487 (1985)) and enhancer (Gillies et al., Cell, 33 : 717-728 (1983)) of immunoglobulin H chain and the like. Any expression vector for animal cell can be used, so long as a gene encoding the human antibody C region can be inserted and expressed. Examples of suitable vectors include pAGE107 (Miyaji H et al., Cytotechnology, 3: 133-140 (1990)), pAGE103 (Mizukami et al., J. Biol. Chem., 10: 1307-1310 (1987)), pHSG274 (Brady et al., Gene, 27: 223-232 (1984)), pKCR (O'Hare et al., Proc. Natl. Acad. Sci. USA, 78: 1527-1531 (1981)), pSG1 beta d2-4-(Miyaji et al., Cytotechnology, 3: 133-140 (1990)) and the like. Other examples of plasmids include replicating plasmids comprising an origin of replication, or integrative plasmids, such as for instance pUC, pcDNA, pBR, and the like. Other examples of viral vector include adenoviral, retroviral, herpes virus and AAV vectors. Such recombinant viruses may be produced by techniques known in the art, such as by transfecting packaging cells or by transient transfection with helper plasmids or viruses. Typical examples of virus packaging cells include PA317 cells, PsiCRIP cells, GPenv+ cells, 293 cells, etc. Detailed protocols for producing such replication-defective recombinant viruses may be found for instance in WO 95/14785, WO 96/22378, US 5,882,877, US 6,013,516, US 4,861,719, US 5,278,056 and WO 94/19478. Host cells A further object of the present invention relates to a host cell which has been transfected, infected or transformed by a nucleic acid and/or a vector according to the invention. The term “transformation” means the introduction of a “foreign” (i.e. extrinsic or extracellular) gene, DNA or RNA sequence to a host cell, so that the host cell will express the introduced gene or sequence to produce a desired substance, typically a protein or enzyme coded by the introduced gene or sequence. A host cell that receives and expresses introduced DNA or RNA bas been “transformed”. The nucleic acids of the invention may be used to produce an antibody of the invention in a suitable expression system. The term “expression system” means a host cell and compatible vector under suitable conditions, e.g. for the expression of a protein coded for by foreign DNA carried by the vector and introduced to the host cell. Common expression systems include E. coli host cells and plasmid vectors, insect host cells and Baculovirus vectors, and mammalian host cells and vectors. Other examples of host cells include, without limitation, prokaryotic cells (such as bacteria) and eukaryotic cells (such as yeast cells, mammalian cells, insect cells, plant cells, etc.). A host according to the invention may in particular be a prokaryotic or eukaryotic cell. Specific examples include E.coli, Kluyveromyces or Saccharomyces yeasts, mammalian cell lines (e.g., Vero cells, CHO cells, 3T3 cells, COS cells, etc.) as well as primary or established mammalian cell cultures (e.g., produced from lymphoblasts, fibroblasts, embryonic cells, epithelial cells, nervous cells, adipocytes, etc.). Examples also include mouse SP2/0-Ag14 cell (ATCC CRL1581), mouse P3X63-Ag8.653 cell (ATCC CRL1580), CHO cell in which a dihydrofolate reductase gene (hereinafter referred to as “DHFR gene”) is defective (Urlaub G et al; 1980), rat YB2/3HL.P2.G11.16Ag.20 cell (ATCC CRL1662, hereinafter referred to as “YB2/0 cell”), and the like. Antibody assays All these antibodies may be assayed for specific binding by any method known in the art. Many different competitive binding assay format(s) can be used for epitope binding. The immunoassays which can be used include, but are not limited to, competitive assay systems using techniques such western blots, radio-immunoassays, ELISA, “sandwich” immunoassays, immunoprecipitation assays, precipitin assays, gel diffusion precipitin assays, immunoradiometric assays, fluorescent immunoassays, protein A immunoassays, and complement-fixation assays. Such assays are routine and well known in the art (see, e.g., Ausubel et al., eds, 1994 Current Protocols in Molecular Biology, Vol.1, John Wiley & sons, Inc., New York). For example, the BIACORE® (GE Healthcare, Piscaataway, NJ) is one of a variety of surface plasmon resonance assay formats that are routinely used to epitope binning panels of monoclonal antibodies. Additionally, routine cross-blocking assays such as those described in Antibodies, A Laboratory Manual, Cold Spring Harbor Laboratory, Ed Harlow and David Lane, 1988, can be performed. Immunoconjugates Detectable label An antibody of the invention can be conjugated with a detectable label to form an anti-HER3 immunoconjugate. Suitable detectable labels include, for example, a radioisotope, a fluorescent label, a chemiluminescent label, an enzyme label, a bioluminescent label or colloidal gold. Methods of making and detecting such detectably labeled immunoconjugates are well-known to those of ordinary skill in the art, and are described in more detail below. The detectable label can be a radioisotope that is detected by autoradiography. Isotopes that are particularly useful for the purpose of the present invention are 3H, 125I, 131I, 35S and 14C. Anti-HER3 immunoconjugates of the invention can also be labeled with a fluorescent compound. The presence of a fluorescently labeled antibody is determined by exposing the immunoconjugate to light of the proper wavelength and detecting the resultant fluorescence. Fluorescent labeling compounds include fluorescein isothiocyanate, rhodamine, phycoerytherin, phycocyanin, allophycocyanin, o-phthalaldehyde and fluorescamine. Alternatively, anti-HER3 immunoconjugates of the invention can be detectably labeled by coupling an antibody to a chemiluminescent compound. The presence of the chemiluminescent tagged immunoconjugate is determined by detecting the presence of luminescence that arises during the course of a chemical reaction. Examples of chemiluminescent labeling compounds include luminol, isoluminol, an aromatic acridinium ester, an imidazole, an acridinium salt and an oxalate ester. Similarly, a bioluminescent compound can be used to label anti-HER3 immunoconjugates of the present invention. Bioluminescence is a type of chemiluminescence found in biological systems in which a catalytic protein increases the efficiency of the chemiluminescent reaction. The presence of a bioluminescent protein is determined by detecting the presence of luminescence. Bioluminescent compounds that are useful for labeling include luciferin, luciferase and aequorin. Alternatively, anti-HER3 immunoconjugates can be detectably labeled by linking an anti-human-HER3 monoclonal antibody to an enzyme. When the anti-HER3-enzyme conjugate is incubated in the presence of the appropriate substrate, the enzyme moiety reacts with the substrate to produce a chemical moiety which can be detected, for example, by spectrophotometric, fluorometric or visual means. Examples of enzymes that can be used to detectably label poly-specific immunoconjugates include β-galactosidase, glucose oxidase, peroxidase and alkaline phosphatase. Those of skill in the art will know of other suitable labels which can be employed in accordance with the present invention. The binding of marker moieties to anti-human-HER3 monoclonal antibodies can be accomplished using standard techniques known to the art. Typical methodology in this regard is for example described by Kennedy et al., Clin. Chim. Acta, 70: 1-31 (1976) and Stein et al., Cancer Res. 50: 13301336 (1990). Moreover, the convenience and versatility of immunochemical detection can be enhanced by using anti-human-HER3 monoclonal antibodies that have for example been conjugated with avidin, streptavidin, and biotin (See, e.g., Wilchek et al. (eds.), “Avidin-Biotin Technology,” Methods In Enzymology (Vol. 184) (Academic Press 1990); Bayer et al., “Immunochemical Applications of Avidin-Biotin Technology,” in Methods In Molecular Biology (Vol. 10) 149-162 (Manson, ed., The Humana Press, Inc. 1992). Methods for performing immunoassays are well-established. (See, e.g., Cook and Self, “Monoclonal Antibodies in Diagnostic Immunoassays,” in Monoclonal Antibodies: Production, Engineering, and Clinical Application 180-208 (Ritter and Ladyman, eds., Cambridge University Press 1995); Perry, “The Role of Monoclonal Antibodies in the Advancement of Immunoassay Technology,” in Monoclonal Antibodies: Principles and Applications 107-120 (Birch and Lennox, eds., Wiley-Liss, Inc. 1995)). Antibody-drug conjugates (ADC) In another aspect, the present invention provides an anti-human-HER3 monoclonal antibody-drug conjugate. An ADC of the present invention comprises a payload. As used herein, the term "payload" refers to a chemical moiety that is conjugated to an antibody, or fragment thereof, of the invention as part of an antibody-drug conjugate. In the antibody-drug conjugate according to the invention, the payload is linked to the antibody component by covalent binding through a linker. The payload in the ADC of the present invention is in particular a therapeutic agent. Upon recruitment of the ADC to its target site by binding of the antibody or antibody fragment to its target antigen, the payload can fulfill its function at the target site. In the context of the present invention, since the antibody or antibody fragment is specific for HER3, a tumor antigen, the payload is advantageously a cytotoxic agent that kills tumor cells. Such cytotoxic agent may for example be selected from the group comprising a maytansinoid, such as Ravtansine (DM4) ; duocarmycin; Exatecan or Monomethyl auristatin E. The payload can be introduced into an ADC of the invention at different stages of preparation. In one approach, a linker-payload construct (i.e., a construct in which the payload is covalently linked to the linker) is synthesized by standard methods of organic chemistry (as shown in the examples) and subsequently this linker-payload construct is conjugated to the antibody or antibody fragment thereof. However, the antibody or antibody fragment thereof, linker and payload can also be prepared and conjugated in different order (e.g., the linker is conjugated to the antibody or antibody fragment thereof and subsequently the payload attached to the linker). Different payloads, their preparation, conjugation and use in antibody-drug conjugates are well known in the art and are described e.g., in Nicolaou et al., Accounts of Chemical Research (2019), vol. 52(1), p. 127-139; Madema et al., Molecular Pharmaceutics (2015), vol.12(6), p.1798-1812; Gromek et al., Current Topics in Medicinal Chemistry (2014), vol. 14(24), p. 2822-2834. An ADC according to the present invention may comprise only one type of payload (i.e. one ADC molecule is linked to only one kind of payload, e.g. Monomethyl auristatin E, wherein one or more copies of the payload (in this example Monomethyl auristatin E) may be linked to the ADC molecule) or several types of payloads (i.e. one ADC molecule is linked to two or more kinds of payload, e.g. Monomethyl auristatin E and DM4, wherein one or more copies of each payload (in this example one or more copies of auristatin E and one or more copies of DM4) may be linked to the ADC molecule). In particular, an antibody-drug conjugate according to the present invention may comprise only one kind of payload. The copy number payloads linked to one ADC molecule (i.e., in the first example above the number of Monomethyl auristatin E molecules linked to one ADC molecule, and in the second example above the number of Monomethyl auristatin E molecules plus the number of DM4 molecules linked to one ADC molecule) is reflected in the drug-antibody ratio. As used herein, the "drug-antibody ratio" (or "DAR") of an ADC is the (average) number of payloads per ADC molecule divided by the number of antibodies or antibody fragments per ADC molecule. The DAR of an ADC can for example be determined by identifying the molecular components of an ADC molecule by mass spectrometry and subsequently dividing the number of payload molecules in an ADC molecule to the number of antibodies or antibody fragments thereof in the ADC molecule (the ADC according to the present invention preferably containing one antibody or antibody fragment thereof per ADC molecule). The DAR values of the embodiments defined below are preferably determined by this approach, i.e., calculated from structural information obtained by mass spectrometry. ADCs with different DAR can be prepared by linking different numbers of payloads to the ADC molecule. For example, a linker-payload construct including one payload copy per linker can be prepared, and subsequently multiple copies of this linker-payload construct are linked to each antibody or antibody fragment thereof. The number of linker-payload constructs that are linked per antibody or antibody fragment thereof can be influenced by the reaction conditions (e.g., the concentrations of the antibody or antibody fragment thereof, degree of activation of components, duration of conjugation reaction etc.), as known to a skilled person. The drug-antibody ratio (DAR) of an antibody-drug conjugate according to the present invention may be in the range of from 1 to 100, in particular from 1 to 90, in particular from 1 to 80, in particular from 1 to 70, in particular from 1 to 60, in particular from 1 to 50, in particular from 1 to 40, in particular from 1 to 30, in particular from 1 to 20, more particularly in the range of from 1 to 10, more particularly in the range of from 1 to 8, even more particularly from 1 to 4 or 4 to 8, more particularly from 2 to 4. The presence of an elevated DAR, in particular DARs superior to 8, may be facilitated through the implementation of a nanoparticle bounded to the antibody or antibody fragment thereof according to the invention (see Ashley P Wright, Cancer Res (2022) 82 (4_Supplement): P2-13-09. https://doi.org/10.1158/1538-7445.SABCS21-P2-13-09). As mentioned above, the payload of an ADC of the present invention is in particular a therapeutic agent. A "therapeutic agent", as used herein, is an agent that exerts an effect that is linked to a therapeutic benefit if administered to a patient (for example by killing a tumor cells, reducing an undesired inflammation, stimulating the activity of the immune system, or by suppressing the immune response). Therapeutic agents useful in accordance with the present disclosure include, but are not limited to, cytotoxic agents, anti-inflammatory agents, immunostimulatory agents, immunosuppressive agents and proteolysis targeting chimera (PROTACs) agents. In some embodiments, the therapeutic agent is a cytotoxic agent, anti-inflammatory agent, anti-oncogenic agent, immunostimulatory agent or immunosuppressive agent. In some preferred embodiments, the therapeutic agent is a cytotoxic agent. As used herein, a "cytotoxic agent" is a substance that is toxic to cells (i.e., causes cell death or destruction). A cytotoxic agent in an ADC according to the present invention may typically be a small molecule chemical compound, peptide, or nucleic acid molecule. Various cytotoxic agents that can be used in ADCs are known to the skilled person (Nicolaou et al., Accounts of Chemical Research (2019), vol. 52(1), p. 127-139; Madema et al., Molecular Pharmaceutics (2015), vol. 12(6), p. 1798-1812; Gromek et al., Current Topics in Medicinal Chemistry (2014), vol. 14(24), p. 2822-2834; Garcia- Echeverria, Journal of Medicinal Chemistry (2014), vol. 57(19), p. 7888-7889). Examples of cytotoxic agents include, but are not limited to, auristatins (e.g. auristatin E, MMAE (monomethyl auristatin E), MMAF (monomethyl auristatin F), dolastatin 10, dolastatin 15), maytansinoids (e.g. maytansin, DM1, DM2, DM3, DM4; since maytansinoids are derived from maytansin, they are sometimes referred to herein also as "maytansins"), tubulysin, exatecan, camptothecin, SN38, Dxd, duocarmycin, CBI dimer (Cyclopropanebenz[e]indoline dimer, also referred to herein as "CBI"), doxorubicin or diazepines (e.g. pyrrolobenzodiazepine or indolinobenzodiazepine). In some embodiments, the cytotoxic agent according to the present disclosure is a chemotherapeutic agent or a radioactive isotope, preferably a chemotherapeutic agent. The therapeutic agent of an ADC according to the invention may be an Eg5 inhibitor, a V-ATPase inhibitor, a HSP90 inhibitor, an IAP inhibitor, an mTor inhibitor, a microtubule stabilizer, a microtubule destabilizer, an auristatin, a dolastatin, a MetAP (methionine aminopeptidase), an inhibitor of nuclear export of proteins CRM1, a DPPIV inhibitor, an inhibitor of phosphoryl transfer reactions in mitochondria, a protein synthesis inhibitor, a kinase inhibitor, a CDK2 inhibitor, a CDK9 inhibitor, a proteasome inhibitor, a kinesin inhibitor, an HD AC inhibitor, a DNA damaging agent, a DNA alkylating agent, a DNA intercalator, a DNA minor groove binder, an RNA polymerase inhibitor, a topoisomerase inhibitor and a DHFR inhibitor. Methods for attaching each of these to a linker compatible with an antibody or antibody fragment of the invention are known in the art (see e.g., Singh et al., Therapeutic Antibodies: Methods and Protocols (2009), vol. 525, p 445-457). A chemotherapeutic agent may for example be a maytansinoid (such as DM1, DM2, DM3, or DM4), an anti-metabolite (e.g., methotrexate, 6-mercaptopurine, 6-thioguanine, cytarabine, 5 -fluorouracil decarbazine), an ablating agent (e.g., mechlorethamine, thiotepa chlorambucil, meiphalan, carmustine (BSNU), lomustine (CCNU), cyclophosphamide, busulfan, dibromomannitol, streptozotocin, mitomycin C, cis-dichlorodiamine platinum (II) (DDP) cisplatin, anthracycline (e.g., daunorubicin (formerly daunomycin), doxorubicin), an antibiotic (e.g., dactinomycin (formerly actinomycin), bleomycin, mithramycin, anthramycin (AMC)), and anti-mitotic agents (e.g., vincristine, vinblastine), a benzodiazepine compound (e.g. a pyrrolobenzodiazepine or indolinobenzodiazepines), a taxoid, CC-1065, CC- 1065 analog, duocarmycin, duocarmycin analog, enediyne (such as calicheamicin), a dolastatin or dolastatin analog (e.g. auristatin), a tomaymycin derivative, a leptomycin derivative, adriamicin, cisplatin, carboplatin, etoposide, melphalan, chlorambucil, calicheamicin, taxanes, DNA-alkylating agents (e.g., CC-1065 or a CC-1065 analog), anthracyclines, tubulysin analogs, cytochalasin B, gramicidin D, ethidium bromide, emetine (including derivatives thereof). Further details about cytotoxic payloads for ADCs can for example be found in Cytotoxic Payloads for Antibody-Drug Conjugates (Drug Discovery, Band 71), 1st edition (2019), editors Thurston and Jackson, Royal Society of Chemistry (U.K.). Examples for cytotoxic agents that are radioactive isotopes are At211, 1131, 1125, Y90, Re186, Re188, Sm153, Bi212, P32, P212, Zr89 and radioactive isotopes of Lu176. The cytotoxic agents mentioned above may achieve cell killing by different mechanisms and thus may be divided into different classes according to their mechanism of action (Nicolaou et al., Accounts of Chemical Research (2019), vol. 52(1), p. 127-139). The cytotoxic agent included in the ADC of the present disclosure may thus be selected from the group consisting of an inhibitor of microtubule formation, an EG5 inhibitor and a DNA damaging agent (e.g., Anderl et al., Methods in Molecular Biology (2013), vol. 1045, p. 51- 70). An "inhibitor of microtubule formation" is an inhibitor that acts by inhibiting tubulin polymerization or microtubule assembly, and thus has anti- proliferative/toxic effects on cells. In a particular embodiment, said inhibitor of microtubule formation is selected from the group consisting of an auristatin (preferably auristatin E, MMAE or MMAF), a maytansinoid (preferably maytansin, DM1, DM2, DM3 or DM4) and tubulysin. An "EG5 inhibitor" is an inhibitor that inhibits the protein EG5, and thus is toxic to cells. EG5 refers to member 11 of the human kinesin family, which is also known as KIF11, HKSP, KNSL1 or TRIP5. EG5 inhibitors are for example those described in Macroni et al., Molecules (2019), vol.24(21), p. 3948. In a particular embodiment, said EG5 inhibitor may be selected from the group consisting of structures described in ispenisib, filanesib, litronesib and K858 (Chen et al., ACS Chem Biol. (2017), vol. 12(4), p. 1038-1046). A "DNA damaging agent" is an agent that acts to damage cellular DNA, e.g., by inducing double-strand breaks, cross-linking specific sites of DNA or intercalating between DNA base pairs. In a preferred embodiment, said DNA damaging agent is selected from the group consisting of a topoisomerase I inhibitor, a topoisomerase II inhibitor and a DNA alkylating agent. In some embodiments, said cytotoxic agent is a topoisomerase I inhibitor. In some embodiments, said cytotoxic agent is a topoisomerase II inhibitor. In some embodiments, said cytotoxic agent is a DNA alkylating agent. Said topoisomerase I inhibitor may be selected from the group consisting of exatecan, camptothecin, SN38, Dxd and variants thereof, wherein in particular said topoisomerase I inhibitor is exatecan, SN38 or Dxd. Said topoisomerase II inhibitor may be doxorubicin or a variant thereof, preferably doxorubicin. Said DNA alkylating agent may be selected from the group consisting of duocarmycin, a CBI dimer, a pyrrolobenzodiazepine and variants thereof, wherein said DNA alkylating agent may be selected from the group consisting of duocarmycin, a CBI dimer and a diazepine (preferably a pyrrolobenzodiazepine or indolinobenzodiazepine). In a particular embodiment, the therapeutic agent may be selected from the group consisting of auristatin, MMAE (monomethyl auristatin E), duocarmycin, CBI (Cyclopropanebenz[e]indoline) dimer, maytansin, pyrrolobenzodiazepine and indolinobenzodiazepine. In a particular embodiment, the therapeutic agent may be selected from the group consisting of an auristatin, a duocarmycin, a CBI (Cyclopropanebenz[e]indoline) dimer and a maytansinoid. In some embodiment, the therapeutic agent may be selected from the group consisting of MMAE (monomethyl auristatin E), duocarmycin, CBI (Cyclopropanebenz[e]indoline) dimer and maytansinoid DM4. In a particular embodiment, the therapeutic agent may be selected from the group consisting of a dolastatin, an auristatin, MMAE, MMAF, amberstatin 269, auristatin 101, auristatin f, auristatin w, CEN-106, CM1, DGN462, DGN549, DM1, DM2, DM4, doxorubicin, duocarmycin, exatecan, OX-4235, PNU-159682, rapamycin, SG3199, SGI 882, SN-38, tubulysin, amanitin, aminopterin, anthracy cline, calicheamicin, camptothecin, fujimycin, hemiasterlin, a maytansinoid, PBD, rapamycin or vinblastine. In some embodiments, the therapeutic agent is an immunostimulatory agent. As used herein, an "immunostimulatory agent" is a substance that enhances the development or maintenance of an immunologic response. The immunostimulatory agent may be an agonist of an immunostimulatory molecule or an antagonists of a molecule inhibiting an immunologic response. In some embodiments, the immunostimulatory agent comprises an agonist of an immunostimulatory molecule, such as an agonist of a costimulatory molecule found on immune cells such (as T cells) or an agonist of a costimulatory molecule found on cells involved in innate immunity (such as NK cells). In some embodiments, the immunostimulatory agent comprises an antagonist of an immunosuppressive molecule, e.g., an antagonist of a cosuppressive molecule found on cells involved in innate immunity (such as NK cells). Administration of an ADC with an immunostimulatory agent as payload preferably results in an improvement of a desired immune response. In some embodiments, administration of an ADC with an immunostimulatory agent as payload results in an improved anti-tumor response in a patient, or in an animal cancer model, such as a xenograft model, as compared to the administration of a control molecule that does not include said immunostimulatory agent. The immunostimulatory agent may be or may comprise an antagonist of an inhibitor of T cell activation. In some embodiments, the immunostimulatory agent is or comprises an agonists of a stimulant of T cell activation. In some embodiments, the immunostimulatory agent is or comprises an agent that antagonizes or prevents cytokines that inhibit T cell activation, such as IL-6, IL- 10, TGFP, VEGF. In some embodiments, the at least one immunostimulatory agent comprises an antagonist of a chemokine such as CXCR2, CXCR4, CCR2 or CCR4. In some embodiments, the immunostimulatory agent is or comprises an agonist of a cytokine that stimulates T cell activation, such as IL-2, IL-7, IL-12, IL-15, IL-21 and IFNα. The immunostimulatory agent may in particular be selected from the group consisting of a Toll-like Receptors (TLR) including TLR3 agonist, TLR7 agonist, a TLR8 agonist, a TLR7 antagonist, a TLR8 antagonist, TLR9 agonist, a Sting inhibitor, a TGF beta inhibitor, an a2A inhibitor and an a2B inhibitor. In some embodiments, the therapeutic agent is an immunosuppressive agent. As used herein, an "immunosuppressive agent" is an agent that inhibits the development or maintenance of an immunologic response. Such inhibition by an immunosuppressive agent can be effected by, for example, elimination of immune cells (e.g., T or B lymphocytes); induction or generation of immune cells that can modulate (e.g., down- regulate) the functional capacity of other cells; induction of an unresponsive state in immune cells (e.g., anergy); or increasing, decreasing or changing the activity or function of immune cells, including, for example, altering the pattern of proteins expressed by these cells (e.g., altered production and/or secretion of certain classes of molecules such as cytokines, chemokines, growth factors, transcription factors, kinases, costimulatory molecules or other cell surface receptors, and the like). In typical embodiments, an immunosuppressive agent has a cytotoxic or cytostatic effect on an immune cell that promotes an immune response. In some embodiments, said immunosuppressive agent results in the reduction of an undesired immune response as compared to the administration of a control molecule that does not include said immunosuppressive agent. The immunosuppressive agent may be selected from the group consisting of an IMDH (inosine monophosphate dehydrogenase) inhibitor, an mTor (mechanistic target of rapamycin) inhibitor, a SYK (spleen tyrosine kinase) inhibitor, a JAK (janus kinase) inhibitor and a calcineurin inhibitor. In some embodiments, the therapeutic agent is a PROTAC (or also referred to herein as PROTAC moiety). A proteolysis targeting chimera (PROTAC) is a two-headed molecule capable of removing unwanted proteins by inducing selective intracellular proteolysis. PROTACs consist of two protein binding moieties, one for binding an E3 ubiquitin ligase and the other for binding a target protein. By binding both proteins, PROTAC brings the target protein to E3 ligase, resulting in the tagging (i.e., ubiquitination) of the target protein for subsequent degradation by the proteasome. Ubiquitination involves three main steps: activation, conjugation, and ligation, performed by ubiquitin-activating enzymes (Els), ubiquitin-conjugating enzymes (E2s), and ubiquitin ligases (E3s), respectively. The result of this sequential cascade is to covalently bind ubiquitin to the target protein. The ubiquitinated proteins eventually get degraded by proteasome. The PROTAC technology was first described in 2001 (Sakamoto et al.,“Protacs: chimeric molecules that target proteins to the Skpl-Cullin-F box complex for ubiquitination and degradation,” Proceedings of the National Academy of Sciences of the United States of America. 98 (15): 8554-9). Since then, this technology has been used in several drug designs such as pVHL, MDM2, beta-TrCPl, cereblon, and c-IAPl. ADC comprising as therapeutic agent a PROTAC are also called Antibody-PROTAC conjugates (APCs). Once in the cell, the target protein binder in the PROTAC portion finds the target protein and brings it to E3 ubiquitin ligase for ubiquitination. The ubiquitinated target protein is marked for degradation by proteasomes. PROTAC according to the present invention are for example described in WO2019/140003 and in Zhijia Wang et al. Acta Pharm Sin B. 2023 Oct;13(10):4025-4059. Doi: 10.1016/j.apsb.2023.06.015.). In some embodiments, the therapeutic agent is a pro-drug converting enzyme. The pro-drug converting enzyme can be recombinantly fused to the antibody or fragment thereof or chemically conjugated thereto using known methods. Exemplary pro-drug converting enzymes are carboxypeptidase G2, β-glucuronidase, penicillin-V-amidase, penicillin-G-amidase, β-lactamase, β-glucosidase, nitroreductase and carboxypeptidase A. As mentioned above, the present invention specifically relates to an “anti-human- HER3 monoclonal antibody-drug conjugate”. Such anti-human-HER3 monoclonal antibody-drug conjugates (ADC) produce clinically beneficial effects on HER3-expressing cells when administered to a subject, such as, for example, a subject with a HER3-expressing cancer, typically when administered alone but also in combination with other therapeutic agents. In a particular embodiment, an antibody-drug conjugate (ADC) according to the invention comprises an antibody according to the invention wherein the variable domain of the heavy chain of said antibody comprises, and in particular consists in, the amino acid sequence set forth as SEQ ID NO: 20 and/or the variable domain of the light chain comprises, and in particular consists in, the amino acid sequence set forth as SEQ ID NO: 29. More particularly, in a particular embodiment, an antibody-drug conjugate (ADC) according to the invention comprises: - an antibody according to the invention wherein the variable domain of the heavy chain of said antibody comprises, and in particular consists in, the amino acid sequence set forth as SEQ ID NO: 20 and/or the variable domain of the light chain comprises, and in particular consists in, the amino acid sequence set forth as SEQ ID NO: 29; and - two or more, in particular two, types of payloads (i.e. one antibody molecule is linked to two or more kinds of payload, e.g. Monomethyl auristatin E and DM4, wherein one or more copies of each payload (in this example one or more copies of auristatin E and one or more copies of DM4) are linked to the ADC molecule). Linkers As pointed out above, an antibody-drug conjugate (ADC) according to the present invention comprises a linker. The linker is a molecular group that covalently links the payload and the antibody or antibody fragment thereof of the ADC. A variety of linkers that can be used for the ADC of the present invention and related methods are known from the art, such as in WO2004/010957. Typically, there will be one linker per payload i.e., one linker molecule for each individual occurrence of a payload in an ADC; this means that, if two copies of a payload are present in an ADC, there will be two linkers, wherein the first linker covalently links the first payload to the antibody component, and the second linker covalently links the second payload to the antibody component. However, it is also possible that one linker links more than one payload moiety to the antibody component of the ADC. Depending on the number of payloads to be linked to the antibody component and on the number of payloads per linker, there may be one or more linkers in an ADC. Covalent linking of the antibody or antibody fragment thereof and the payload via a linker can for example be achieved by a linker having two reactive functional groups (i.e., a linker that is bivalent in a reactive sense). Bivalent linker reagents which are useful to attach two or more functional or biologically active components are known to the skilled person (see e.g., Hermanson, Bioconjugate Techniques (1996), Academic Press (New York), p 234-242)). Alternatively, a linker-payload construct comprising payload(s) covalently attached to a linker may be prepared by methods of organic synthesis. Subsequently, one or more copies of this linker-payload construct can then be conjugated to the antibody component by methods known to the skilled person (see e.g Dickgiesser et al., in: Methods in Molecular Biology: Enzyme-Mediated Ligation Methods (2019), editors Nuijens and Schmidt, vol. 2012, p. 135- 149 or Dickgiesser et al., Bioconjugate Chem. (2020), vol.31(4), p. 1070-1076)). A linker in an ADC of the present invention may preferably be stable extracellularly (i.e., outside of the cell, e.g., in plasma). Thus, before transport or delivery into a cell, the ADC is preferably stable and remains intact, i.e., the antibody remains linked to the payload. An effective linker will: (i) maintain the specific binding properties of the antibody or fragment thereof; (ii) allow intracellular delivery of the payload; (iii) remain stable and intact, i.e., not cleaved, until the conjugate has been delivered or transported to its targeted site; and (iv) maintain the therapeutic efficacy of the payload (e.g., the cytotoxic, cell-killing effect of the payload). Whether a linker is stable in the extracellular environment can for example be determined by incubating independently with plasma both (a) the ADC (the "ADC sample") and (b) an equal molar amount of unconjugated antibody or therapeutic agent (the "control sample") for a predetermined time period (e.g. 8 hours) and then comparing the amount of unconjugated antibody or therapeutic agent present in the ADC sample with that present in the control sample, as measured, for example, by high performance liquid chromatography. A linker that is stable outside of the target cell may be cleaved at some efficacious rate inside the target cell. In some embodiments, the linker that is cleavable under intracellular conditions is cleavable by a cleaving agent that is present in the intracellular environment (e.g., within a lysosome or endosome or caveolea). The linker can for example be a peptidyl linker that is cleaved by an intracellular peptidase or protease enzyme, including, but not limited to, a lysosomal or endosomal protease. Typically, the peptidyl linker is at least two amino acids long or at least three amino acids long. Cleaving agents can include cathepsins B and D and plasmin, all of which are known to hydrolyze dipeptide drug derivatives resulting in the release of active drug inside target cells (see e.g., Dubowchik and Walker, Pharm. Therapeutics (1999), vol.83, p. 67-123). For example, a peptidyl linker that is cleavable by the thiol-dependent protease cathepsin B, which is highly expressed in cancerous tissue, can be used (e.g., a Phe- Leu or a Gly-Phe-Leu-Gly linker (SEQ ID NO: 3)). Other such linkers are for example described in US6214345. In specific embodiments, the peptidyl linker cleavable by an intracellular protease is a Val-Cit linker or a Phe-Lys linker (see for example US 6214345, which describes the synthesis of doxorubicin with the Val-Cit linker). One advantage of using intracellular proteolytic release of a therapeutic agent is that the agent is typically attenuated when conjugated and the serum stabilities of the conjugates are typically high. In other embodiments, the cleavable linker is pH-sensitive, i.e., sensitive to hydrolysis at certain pH values. Typically, the pH-sensitive linker is hydrolyzable under acidic conditions. For example, an acid-labile linker that is hydrolyzable in the lysosome (e.g., a hydrazone, semi carb azone, thiosemicarbazone, cis-aconitic amide, orthoester, acetal, ketal, or the like) can be used (see for example US5122368 or US5824805). Such linkers are relatively stable under neutral pH conditions, such as those in the blood, but are unstable at below pH 5.5 or 5.0, the approximate pH of the lysosome. In certain embodiments, the hydrolyzable linker is a thioether linker (such as a thioether attached to the therapeutic agent via an acylhydrazone bond, see for example US5622929). In yet other embodiments, the linker is cleavable under reducing conditions (for example a disulfide linker). A variety of disulfide linkers are known in the art, including, for example, those that can be formed using SATA (N-succinimidyl-5- acetylthioacetate), SPDP (N-succinimidyl-3-(2-pyridyldithio)propionate), SPDB (N- succinimidyl-3-(2- pyridyldithio)butyrate) and SMPT (N-succinimidyl-oxycarbonyl- alpha-methyl-alpha-(2- pyridyl-dithio)toluene), SPDB and SMPT (see e.g. Thorpe et al., Cancer Res. (1987), vol. 47, p. 5924-5931 or US4880935). In other embodiments, the linker is not cleavable inside the target cell, but the payload is released, for example, by antibody degradation. In yet other specific embodiments, the linker is a malonate linker (Johnson et al., Anticancer Res. (1995), vol.15, p.1387-1393), a maleimidobenzoyl linker (Lau et al., Bioorg- Med-Chem. (1995), vol.3(10), p.1299-1304), or a 3'-N-amide analog (Lau et al., Bioorg-Med- Chem. (1995), vol. 3(10), p. 1305-1312). The linker may be cleavable under intracellular conditions (as described above) or not cleavable under intracellular conditions. In some embodiments, the linker is not cleavable under intracellular conditions. In other embodiments, the linker is cleavable under intracellular conditions. Such a linker is particularly preferred if the payload is a therapeutic agent. Preferably, the linker is cleavable under intracellular conditions, such that cleavage of the linker releases the payload from the antibody component in the intracellular environment. Whether the linker of an ADC is stable or cleaved may be examined by exposing the ADC to the conditions to be tested and then verifying the integrity of the linker in the treated sample and an untreated control sample by standard analytical techniques such as mass spectroscopy, HPLC, and the separation/analysis technique LC/MS. In some embodiments, said linker is stable in the extracellular environment. The designation that a linker is "stable in the extracellular environment" preferably means that said linker is stable in human serum. A linker is "stable in human serum" if in an assay in which ADC molecules including the linker are exposed to human serum, after an incubation of 48 h at 37 °C at least 50%, preferably at least 75% of the linkers in the ADCs have been neither cleaved nor degraded. In some embodiments, said linker is/said linkers are stable in the intracellular environment. A linker that is "stable in the intracellular environment" may be a linker that has such a structure that if ADC molecules including the linker are taken up by cells (i.e., enter into the intracellular environment of the cells), after an incubation of 24 h at 37 °C at least 50%, preferably at least 75% of the linkers in the ADC molecules have been neither cleaved nor degraded. In some embodiments, said linker is cleaved upon exposure to the intracellular environment. Preferably, a linker that is "cleaved upon exposure to the intracellular environment" is a linker that has such a structure that if ADC molecules including the linker are taken up by cells (i.e., enter into the intracellular environment of the cells), the linkers in the ADC molecules are cleaved efficiently (preferably at least 90% of the linkers are cleaved within 24 h, more preferably within 12 h). As the skilled person understands, this allows for release of the payload into the target cells. In some embodiments, said linker is stable in the extracellular environment, but cleaved upon exposure to the intracellular environment. Preferably, a linker that is "stable in the extracellular environment, but cleaved upon exposure to the intracellular environment" is preferably a linker that is stable in human serum, but has such a structure that if ADC molecules including the linker are taken up by cells (i.e., enter into the intracellular environment of the cells), the linkers in the ADC molecules are cleaved efficiently (preferably at least 90% of the linkers are cleaved within 24 h, more preferably within 12 h). As the skilled person understands, this allows for release of the payload into the target cells. In some embodiments, said linker is cleavable by enzymatic or chemical cleavage. As used herein, a linker that is "cleavable by enzymatic cleavage" is a linker that is cleaved in the presence of a certain enzyme, but stable in the absence of this enzyme. For the purposes of the ADC of the present invention, this enzyme will typically be an enzyme that the ADC is not exposed to in the extracellular environment but exposed to upon uptake of the ADC into the target cell, resulting in a linker that is extracellularly stable, but cleaved upon entry into the target cell. As used herein, a linker that is "cleavable by chemical cleavage" is a linker that is cleaved by a non-enzymatic reaction that results in the breakage of a covalent chemical bond. Examples are linkers that are pH-sensitive or cleavable under reducing conditions (see above). In some embodiments, said linker is cleavable by enzymatic cleavage. In some embodiments, said enzymatic cleavage is cleavage by exposure to a glycosidase, protease or esterase. A glycosidase is an enzyme of E.C. (Enzyme classification) 3.2.1 that catalyzes the hydrolysis of glycosidic bonds in complex sugars. A protease is an enzyme of E.C. 3.4 that catalyzes the cleavage of peptide bonds. An esterase is an enzyme of E.C.3.1 that catalyzes the cleavage of ester bonds. Preferably, said glycosidase is a glucuronidase. A glucuronidase is an enzyme of E.C. 3.2.1.31 that catalyzes the cleavage of P-Glucuronides. Preferably, said protease is a cathepsin (most preferably cathepsin B). Cathepsins are a group of proteases within E.C.3.4 that catalyze the proteolytic cleavage of peptide bonds. For the purpose of the present disclosure, the use of a lysosomal, endoproteolytic cathepsin is particularly advantageous, since these become activated at low pH (as in lysosomes) and cleave within a peptide sequence. Cathepsin B is a cathepsin classified as E.C. 3.4.22.1. In some embodiments, said enzymatic cleavage is by exposure to a tumor-specific enzyme, preferably a tumor-specific protease or esterase. A "tumor-specific" enzyme is an enzyme that is present in a certain tumor (i.e., there is enzymatic activity of said enzyme in the tumor), whereas the enzyme is substantially absent from other cells and tissues (i.e., outside of said tumor substantially no, preferably no, enzymatic activity of said enzyme). In some embodiments, said linker includes a protease cleavage site, preferably a cathepsin B cleavage site. In some embodiments, said linker includes a glucuronide (which is a molecular group that can be cleaved by glucuronidase). In some embodiments, said linker is cleavable by chemical cleavage. In some embodiments, said linker that is cleavable by chemical cleavage is a pH-sensitive linker. Preferably, said linker includes a hydrazone. In some embodiments, the linker that is cleavable by chemical cleavage is cleavable under reducing conditions. Preferably, said linker includes a disulfide linkage. In some embodiments, said linker comprises a cathepsin B cleavage site, a glucuronide or a disulfide linkage. An ADC according to the present invention may comprise a solubility tag. As a skilled person understands, a "solubility tag" is a molecular group linked to a molecule of interest that has the purpose of increasing the solubility of the molecule of interest in aqueous environment, compared to the same molecule of interest without the solubility tag. Thus, it is intended that the molecule with the solubility tag linked to it has a higher solubility in aqueous environment than the same molecule without the solubility tag linked to it. The solubility tag of the present disclosure is based on an oligosaccharide. As shown in the examples of the present disclosure, inclusion of such a solubility tag in an ADC results in various advantageous effects. The ADC according to the present invention may comprise one or more than one solubility tag per ADC molecule. Typically, the solubility tag(s) will be covalently attached to the antibody-drug conjugate. In the ADC according to the present invention, the solubility tag may be linked to the ADC of the present disclosure by a covalent bond between the solubility tag and the linker. However, the solubility tag can also be linked to the ADC by a covalent bond between the solubility tag and a component of the ADC other than the linker. An antibody-drug conjugate according to the present invention may comprise one or more solubility tags. In some embodiments, an ADC of the invention comprises only one solubility tag. In some embodiments, an ADC of the invention comprises at least one, preferably at least 2, more preferably at least 3, more preferably at least 4 solubility tags. In some embodiments, an ADC of the invention comprises up to 10, preferably up to 8, more preferably up to 6, more preferably up to 4, more preferably up to 2 solubility tags, more preferably only one solubility tag. In some embodiments, an ADC of the invention comprises at least 1 and up to 4 solubility tags. In some embodiments, an ADC of the invention comprises at least 3 and up to 10 solubility tags. In some embodiments, at least one solubility tag is covalently linked to an ADC of the invention. In other embodiments, at least 2, preferably at least 3, more preferably at least 4 solubility tags are covalently linked to an ADC of the invention. In some embodiments, up to 10, preferably up to 6, more preferably up to 4, more preferably up to 2 solubility tags are covalently linked to an ADC of the invention, more preferably only 1 solubility tag is covalently linked to an ADC of the invention. In some embodiments, at least 1 and up to 4 solubility tags are covalently linked to an ADC of the invention. In some embodiments, at least 3 and up to 10 solubility tags are covalently linked to an ADC of the invention. As a skilled person will understand, the number of solubility tags covalently linked to an ADC of the invention is an average number (which is determined over a population of said ADC). Preferably, said population is a homogeneous population. In preferred embodiments, only one kind of solubility tag is covalently attached to the antibody-drug conjugate. This means that all solubility tags covalently attached to the antibody-drug conjugate are identical (they are of the same kind with regard to their molecular structure). In some embodiments, more than one kind of solubility tag is covalently attached to said antibody-drug conjugate. This means that there are at least two different types of solubility tags with different structure covalently attached to the antibody-drug conjugate (i.e., the solubility tags covalently attached to an ADC of the invention are of more than one kind with regard to their molecular structure). In some embodiments, up to two kinds of solubility tags are covalently attached to said antibody-drug conjugate. Typically, the solubility tag of an ADC of the invention will include monosaccharide units that are linked by covalent bonds. In some embodiments, said solubility tag comprises monosaccharide units. In some embodiments, said solubility tag consists of monosaccharide units. As used herein, a "monosaccharide" is a sugar that is not decomposable into simpler sugars by hydrolysis, is classed as either an aldose or ketose, and contains one or more hydroxyl groups (-OH) per molecule. Examples of monosaccharides include glucose (dextrose), fructose (levulose), and galactose. Monosaccharides are the building blocks of disaccharides (such as sucrose and lactose), oligosaccharides, and polysaccharides (such as cellulose and starch). The present disclosure uses the term "monosaccharide" or "monosaccharide unit" to refer to a single monosaccharide residue in an oligosaccharide. Within the context of an oligosaccharide, an monosaccharide unit is a monosaccharide that is linked to another monosaccharide via covalent bond formed by a hydroxyl group of said monosaccharide (e.g. a glycosidic bond). As used herein, "oligosaccharide" refers to a compound containing two or more monosaccharide units. Preferably, the term "oligosaccharide" refers to a compound containing 2-12 monosaccharide units connected by glycosidic bonds. In accordance with accepted nomenclature, oligosaccharides are depicted herein with a non-reducing end on the left and a reducing end on the right. Monosaccharides and oligosaccharides can be chemically synthesized by standard methods of carbohydrate chemistry (see for example CRC Handbook of Oligosaccharides (1990), Vol. I-III, (published 2019), editors: Liptak et al., CHR Press, Inc.). Alternatively, oligosaccharides can be prepared by biotechnological methods (see e.g., Meyer et al., Biotechnological Production of Oligosaccharides - Applications in the Food Industry, Food Production and Industry (2015)). To further increase the purity of oligosaccharides prepared by the above described approaches, the oligosaccharide can be purified by standard methods of organic chemistry, including e.g. precipitation, re-crystallization, ultrafiltration, nanofiltration, gel permeation chromatography, ion exchange chromatography, capillary electrophoresis, HPLC purification, UPLC purification, or membrane and carrier approaches as described e.g. in Pinelo et al., Separation and Purification Technology (2009), vol. 70(1), p. 1-11. Monosaccharides and oligosaccharides can be characterized by standard methods known to a person of skill in the art (see e.g., Carbohydrate Chemistry (1988), editor El Khadem, Academic Press (San Diego)). This includes, for example, LC- MS/ESI MS methods, ID and 2D NMR, gel permeation chromatography or ion mobility-mass spectrometry (Seeberger et al., Nature (2015), vol. 526(7572), p. 241- 244). In some embodiments, said solubility tag comprises an oligosaccharide consisting of monosaccharide units. In some embodiments, said solubility tag consists of an oligosaccharide consisting of monosaccharide units. In some embodiments, the solubility tag comprises up to 25, preferably up to 20, more preferably up to 15, more preferably up to 12, more preferably up to 10, more preferably up to 9, more preferably up to 8, more preferably up to 7, more preferably up to 6, more preferably up to 5 monosaccharide units. In some embodiments, the solubility tag comprises at least 2, preferably at least 3, more preferably at least 4, more preferably at least 5 monosaccharide units. In some embodiments, the monosaccharide units of which said solubility tag consists are linked by covalent bonds, forming an oligosaccharide. In a particularly preferred embodiment, the solubility tag of the antibody-drug conjugate according to the present invention may comprise or consist of a chito- oligosaccharide. As used herein, the term "chito-oligosaccharide" (abbreviated herein as "CO") refers to oligosaccharides obtained upon hydrolysis of (not deacetylated, partially deacetylated or fully deacetylated) chitin with diluted aqueous mineral acid. This results in a mixture of various chito-oligosaccharides that can be further separated into different chito-oligosaccharide species e.g., by ultrafiltration, gel permeation chromatography, cation exchange chromatography and capillary electrophoresis. The preparation of chito-oligosaccharides by this approach is for example described in Schmitz et al., Marine Drugs (2019), vol. 17(8), p. 452. Chito-oligosaccharides may alternatively be obtained by chemical synthesis (Bohe and Crich, in: Comprehensive Organic Synthesis, 2nd edition (2014), vol. 6, editors Knochel and Molander, Elsevier Ltd.). As a further alternative, chito-oligosaccharides may be obtained by a biotechnological approach (see for example Samain et al., Carbohydrate Research (1997), vol.302, p.35-42; Samain et al., Biotechnol. (1999), vol.72, p.33-47). Chito- oligosaccharides may then be further purified and characterized as described above for oligosaccharides in general. Typically, chito-oligosaccharides are composed of D-glucosamine (GlcN) and/or N-acetyl-D-glucosamine (GlcNAc), resulting in the general formula (GlcNAc)m(GlcN)n., wherein m and n are integer numbers. The monosaccharide units in chito-oligosacharides are typically linked by P-(l,4)-glycosidic linkages. As used herein, "N-acetyl-D-glucosamine", also referred to as "N- acetylglucosamine" and abbreviated as "GlcNAc", is 2-acetylamino-2-deoxy- D- glucose (also termed 2-acetamido-2-deoxy-D-glucose). Glucose is abbreviated herein as "Glc". As used herein, D-glucosamine, also referred to as "glucosamine" and abbreviated as "GlcN", is 2-amino-2-deoxy-D-glucose. In some embodiments, the monosaccharide units of the solubility tag according to the present invention (i.e., the monosaccharide units that are comprised in the solubility tag according to the present invention resp. of which the solubility tag according to the present disclosure consists) are independently selected from the group consisting of aldoses, ketoses and chemically modified forms of said aldoses or ketoses. In some embodiments, said solubility tag comprises no monosaccharide units other than monosaccharide units selected from the group consisting of glucose, chemically modified forms of glucose, galactose and chemically modified forms of galactose. In some embodiments, said solubility tag comprises no monosaccharide units other than monosaccharides selected from glucosamine (GlcN), N-acetyl-glucosamine (GlcNAc), fucose (Fuc) and 6-methyl-fucose. In some preferred embodiments, said solubility tag comprises only monosaccharides selected from glucosamine (GlcN) and N-acetyl- glucosamine (GlcNAc) as monosaccharide units. In some more preferred embodiments, said solubility tag comprises only N-acetyl-glucosamine (GlcNAc) as monosaccharide units. The solubility of an ADC can be assessed by measuring the formation of aggregates under different ADC concentrations in appropriate buffers during formulation development (Duerr and Friess, European Journal of Pharmaceutics and Biopharmaceutics (2019), vol. 139, p. 168-176). This approach allows to compare the solubility of an ADC with and without a certain solubility tag. Therapeutic uses Antibodies, fragments thereof or immunoconjugates, in particular antibody-drug conjugate, of the invention are useful for treating any HER3-expressing cancer. The antibodies, fragments thereof or immunoconjugates of the invention may be used alone or in combination with any suitable agent. HER3-expressing cancers may in particular be derived from squamous cells, i.e. HER3-expressing squamous cell cancers. Examples of HER3-expressing cancers include but are not limited to, carcinoma, including squamous, epidermoid and adenocarcinoma, lymphoma, blastoma, sarcoma, and leukemia. More particular examples of such cancers include head and neck cancers, squamous cell cancer, esophagus cancer, non-small cell lung cancer, cutaneous squamous cancers, cervical cancer, vulval cancer and anal cancer, gastric cancer, pancreatic cancer, glial cell tumors, ovarian cancer, bladder cancer, breast cancer, melanoma, colorectal cancer in particular colon cancer, endometrial carcinoma, salivary gland carcinoma, renal cell carcinoma, prostate cancer, thyroid cancer, hepatic cell carcinoma. They are preferably chosen among breast cancer, ovarian cancer, small-cell lung cancer, non-small cell lung cancer, melanoma, pancreatic cancer and colorectal cancer, and more particularly among breast cancer, ovarian cancer and pancreatic cancer. In a particular embodiment, a cancer treated using the methods of the present invention is breast cancer or ovarian cancer. In a particular embodiment, a cancer treated using the methods of the present invention is selected from the group consisting of head and neck cancer, gastro-esophageal cancers, non-small-cell lung cancer, mucinous adenocarcinoma of the lung, pancreas and pancreatic ductal cancer, breast cancer and colon cancer. The present invention discloses a method for treating a HER3-expressing cancer comprising administering a subject in need thereof a therapeutically effective amount of an antibody, a fragment thereof, or an immunoconjugate of the invention, in particular in the form of a composition according to the invention. The antibodies, fragments thereof, and immunoconjugates of the invention are more particularly effective for treating a HER3-expressing cancer associated wherein neuregulin is present, in particular neuregulin 1 or 2, more particularly neuregulin 1α, 1β or 2, and more particularly neuregulin 1β. Thus, an object of the present invention is an antibody, and/or an immunoconjugate, according to the invention for its use in the treatment of a HER3-expressing cancer wherein neuregulin is present in an individual in need thereof. In an embodiment, the antibodies, fragments thereof and immunoconjugates of the invention are particularly suitable for the treatment of NRG-fusion protein driven cancers (see in particular Odintsovet al., Clin. Cancer Res., 27: 3154-3166 (2021); Drilon et al., Cancer Discov., 8: 686-695 (2018); Schram et al., Cancer Discov., 12: 1233-1247 (2022)). By “cancer wherein neuregulin is present” it is meant a cancer wherein neuregulin, in particular neuregulin 1 or 2, more particularly neuregulin 1α, 1β or 2, and more particularly neuregulin 1β, (i) is secreted by the cancer and/or by tissues and/or organs, in particular by tissues and/or organs in the cancer and/or surrounding the cancer, or (ii) is present due to its administration to the subject before, after, or at the same time as the antibody and/or the immunoconjugate. In an embodiment, the antibodies of the invention are particularly suitable for the treatment of autocrine, juxtacrine or paracrine ligand-dependent tumors (due to their allosteric effect). Accordingly, in an embodiment of the invention, the neuregulin present is secreted by the tumor and/or by the tissues and/or organs in the tumor and/or surrounding the tumor. In some embodiment, the antibodies, fragments thereof and immunoconjugates of the invention are particularly suitable for the treatment of cancers that are resistant to the treatment with antibodies, tyrosine kinase inhibitors (TKI), chemotherapeutic agents or anti- hormone agents. In some embodiment, the antibodies of the invention are particularly suitable for the treatment of cancers selected from the group consisting of triple-negative breast cancer, mucinous adenocarcinoma of the lung, pancreatic cancer, pancreatic ductal cancer and renal cell carcinomas, in particular consisting of triple-negative breast cancer, pancreatic cancer, and renal cell carcinomas. In some embodiment, the antibodies of the invention are particularly suitable for the treatment of cancers selected from the group consisting of pancreatic cancer, head and neck cancer, gastro-esophageal cancer, non-small-cell lung cancer, breast cancer, colon cancer and renal cell carcinomas. In certain embodiments, an anti-human-HER3 antibody, a fragment thereof, or an immunoconjugate, in particular an antibody-drug conjugate, according to the invention is used in combination with a second agent for treatment of a disease or disorder. When used for treating cancer, an anti-human-HER3 antibody, a fragment thereof or an immunoconjugate, in particular an ADC, of the present invention may be used in combination with conventional cancer therapies such as, e.g., surgery, radiotherapy, chemotherapy, or combinations thereof. In certain aspects, other therapeutic agents useful for combination cancer therapy with an anti-HER3 antibody or antibody-drug conjugate in accordance with the present invention include anti-angiogenic agents. In some aspects, an antibody or antibody-drug conjugate in accordance with the present invention is co-administered with a cytokine (e.g., a cytokine that stimulates an immune response against a tumor). In some other aspects, other therapeutic agents useful for combination therapy include an antagonist of certain factors that are involved in tumor growth such as, for example, EGFR, HER2, or HER4. In one particular embodiment, an anti-human-HER3 monoclonal antibody, a fragment thereof, or immunoconjugate, in particular antibody-drug conjugate, of the present invention is used in combination with an anti-human-HER2 monoclonal antibody, such as Trastuzumab or Pertuzumab, or other antibodies that interact with HER3 heterodimer-partners such as anti-human-EGFR monoclonal antibody such as Cetuximab. In some embodiments, an anti-HER3 antibody, a fragment thereof, or an immunoconjugate, in particular antibody-drug conjugate, of the invention is used in combination with a tyrosine kinase inhibitor (TKI). BAY 43-9006 (sorafenib, Nexavar®) and SU11248 (sunitinib, Sutent®) are two such TKIs that have been approved. Other TKIs include, but are not limited to: Imatinib mesylate (Gleevec®, Novartis); Gefitinib (Iressa®, AstraZeneca); Erlotinib hydrochloride (Tarceva®, Genentech); Vandetanib (Zactima®, AstraZeneca), Tipifarnib (Zarnestra®, Janssen-Cilag); Dasatinib (Sprycel®, Bristol Myers Squibb); Lonafarnib (Sarasar®, Schering Plough); Vatalanib succinate (Novartis, Schering AG); Lapatinib (Tykerb®, GlaxoSmithKline); Nilotinib (Novartis); Lestaurtinib (Cephalon); Pazopanib hydrochloride (GlaxoSmithKline); Axitinib (Pfizer); Canertinib dihydrochloride (Pfizer); Pelitinib (National Cancer Institute, Wyeth); Tandutinib (Millennium); Bosutinib (Wyeth); Semaxanib (Sugen, Taiho); AZD-2171 (AstraZeneca); VX-680 (Merck, Vertex); EXEL-0999 (Exelixis); ARRY-142886 (Array BioPharma, AstraZeneca); PD-0325901 (Pfizer); AMG-706 (Amgen); BIBF-1120 (Boehringer Ingelheim); SU-6668 (Taiho); CP- 547632 (OSI); (AEE-788 (Novartis); BMS-582664 (Bristol-Myers Squibb); JNK-401 (Celgene); R-788 (Rigel); AZD-1152 HQPA (AstraZeneca); NM-3 (Genzyme Oncology); CP- 868596 (Pfizer); BMS-599626 (Bristol-Myers Squibb); PTC-299 (PTC Therapeutics); ABT- 869 (Abbott); EXEL-2880 (Exelixis); AG-024322 (Pfizer); XL-820 (Exelixis); OSI-930 (OSI); XL-184 (Exelixis); KRN-951 (Kirin Brewery); CP-724714 (OSI); E-7080 (Eisai); HKI-272 (Wyeth); CHIR-258 (Chiron); ZK-304709 (Schering AG); EXEL-7647 (Exelixis); BAY-57- 9352 (Bayer); BIBW-2992 (Boehringer Ingelheim); AV-412 (AVEO); YN-968D1 (Advenchen Laboratories); Midostaurin (Novartis); Perifosine (AEterna Zentaris, Keryx, National Cancer Institute); AG-024322 (Pfizer); AZD-1152 (AstraZeneca); ON-01910Na (Onconova); and AZD-0530 (AstraZeneca). In some embodiments, an anti-HER3 antibody, a fragment thereof, or an immunoconjugate, in particular antibody-drug conjugate, of the invention is used in combination with a checkpoint inhibitor, such as PD-1 antagonist, Pembrolizumab (Keytruda®, Merck), Nivolumab (Opdivo®, BMS), PD-L1 antagonist Atezolizumab (Tecentriq®, Roche) and/or Avelumab (Bavencio®, Merck), or such as OX40 agonists and LAG3 antagonists. An anti-HER3 antibody, fragment thereof, or immunoconjugate, in particular antibody-drug conjugate, of the invention may more generally be combined with one or more additional therapeutic agents, e.g., an inhibitory immune checkpoint blocker or inhibitor, a stimulatory immune checkpoint stimulator, agonist or activator, a chemotherapeutic agent, an anti-cancer agent, a radiotherapeutic agent, an anti-neoplastic agent, an anti-proliferation agent, an anti-angiogenic agent, an anti-inflammatory agent, an immunotherapeutic agent, a therapeutic antigen-binding molecule (mono- and multi-specific antibodies and fragments thereof in any format (e.g., including without limitation DARTs®, Duobodies®, BiTEs®, BiKEs, TriKEs, XmAbs®, TandAbs®, scFvs, Fabs, Fab derivatives), bi-specific antibodies, non-immunoglobulin antibody mimetics (e.g., including without limitation adnectins, affibody molecules, affilins, affimers, affitins, alphabodies, anticalins, peptide aptamers, armadillo repeat proteins (ARMs), atrimers, avimers, designed ankyrin repeat proteins (DARPins®), fynomers, knottins, Kunitz domain peptides, monobodies, and nanoCLAMPs), antibody-drug conjugates (ADC), antibody-peptide conjugate), an oncolytic virus, a gene modifier or editor, a cell comprising a chimeric antigen receptor (CAR), e.g., including a T cell immunotherapeutic agent, an NK-cell immunotherapeutic agent, or a macrophage immunotherapeutic agent, a cell comprising an engineered T-cell receptor (TCR-T), or any combination thereof. The present invention further relates to the use of an antibody of the invention, or a fragment thereof, in the engineering of CAR-T cells for the treatment of cancer, as well as to such CAR-T cells themselves. Specifically, the invention concerns the genetic modification of T cells, in particular of T cells from a patient according to the invention, to express an antibody, or a fragment thereof, according to the invention at their surface, thereby conferring upon said CAR-T cells the ability to recognize and engage with cancer cells expressing the target antigen in the patient. The invention accordingly also concerns a T cell genetically modified to express an antibody, or a fragment thereof, according to the invention at its surface, and in particular concerns a T cell from a patient of the invention, the cell being genetically modified to express at its surface an antibody, or a fragment thereof, according to the invention. In one embodiment, the CAR-T cell is engineered to express a full-length antibody according to the invention, wherein the antibody comprises a variable region that specifically binds to the target antigen and a constant region that mediates effector functions. In another embodiment, the CAR-T cell express a fragment of the antibody as previously defined, in particular a single-chain variable fragment (scFv) or a Fab fragment, which retains the antigen-binding specificity. A CAR-T cell of the present invention may be generated using any suitable gene transfer technique known in the art, including but not limited to viral transduction, non-viral transfection, or genome editing methods such as CRISPR/Cas9. Following engineering, the CAR-T cell may be ex vivo expanded and administered to a patient in need thereof for the treatment of cancer. A CAR-T cell according to the invention may be of any generation of CAR-T cells. Indeed, the intracellular regions of different generations of CAR-T are different. The earliest first generation of CAR-T only has the intracellular region of CD3 molecule. The intracellular region of the second generation of CAR-T is a co-stimulatory molecule CD28+ CD3zeta or 4- 1BB + CD3 zeta and can transmit two signals of T cell activation. Two co-stimulatory molecules, CD28 and 4-1BB molecule, are added in the third generation CART. The fourth generation of CAR-T cells are based on second-generation constructs, the latest being additionally modified with a constitutive or inducible expression cassette containing a transgenic protein such as a cytokine. They are also known as TRUCK CAR-T cells. A fifth generation has moreover recently been developed, differing from the previous one in that the CAR-T cells integrate an additional membrane receptor compared to the TRUCK CAR-T cells. The invention further encompasses pharmaceutical compositions comprising a CAR-T cells described herein, as well as methods for their use in the treatment of cancer. These methods may involve the administration of the CAR-T cells alone or in combination with other therapeutic agents, such as chemotherapy, radiation therapy, or immune checkpoint inhibitors, as described herein. In TRUCKS or fourth-generation CAR-T cells, these modified T cells are activated by coming into contact with their target antigen, which leads to the induction of the secondary transgene, subsequent transcription, and secretion into the extracellular fluid. In this approach, the secreted signal not only stimulates CAR-T cells to remain active and form memory T cells but also reactivates the immune system to respond to restimulation. CAR-T cells that use membrane receptors (fifth generation) act according to a different principle, the most one relying on the addition of IL-2 receptors that allow JAK/STAT pathway activation in an antigen-dependent manner. Pharmaceutical compositions For administration, the anti-human-HER3 monoclonal antibody, fragment(s) thereof or antibody-drug conjugate of the invention is formulated as a pharmaceutical composition. A pharmaceutical composition comprising an anti-human-HER3 monoclonal antibody, a fragment thereof, or an antibody-drug conjugate according to the invention can be formulated according to known methods to prepare pharmaceutically useful compositions, whereby the therapeutic molecule is combined in a mixture with a pharmaceutically acceptable carrier. A composition is said to be a “pharmaceutically acceptable carrier” if its administration can be tolerated by a recipient patient. Sterile phosphate-buffered saline is one example of a pharmaceutically acceptable carrier. Other suitable carriers are well-known to those in the art. (See, e.g., Gennaro (ed.), Remington's Pharmaceutical Sciences (Mack Publishing Company, 19th ed. 1995).) Formulations may further include one or more excipients, preservatives, solubilizers, buffering agents, albumin to prevent protein loss on vial surfaces, etc. Ways of administration The form of the pharmaceutical compositions, the route of administration, the dosage and the regimen naturally depend upon the condition to be treated, the severity of the illness, the age, weight, and sex of the patient, etc. The pharmaceutical compositions of the invention can be formulated for a topical, oral, parenteral, intranasal, intravenous, intramuscular, subcutaneous or intraocular administration and the like, and more particularly can be formulated for parenteral, intravenous or intraocular administration and the like. Preferably, the pharmaceutical compositions contain vehicle(s)/carrier(s) which is/are pharmaceutically acceptable for a formulation capable of being injected. These may be in particular isotonic, sterile, saline solutions (monosodium or disodium phosphate, sodium, potassium, calcium or magnesium chloride and the like or mixtures of such salts), or dry, especially freeze-dried compositions which upon addition, depending on the case, of sterilized water or physiological saline, permit the constitution of injectable solutions. The doses used for the administration can be adapted as a function of various parameters, and in particular as a function of the mode of administration used, of the relevant pathology, or alternatively of the desired duration of treatment. To prepare pharmaceutical compositions, an effective amount of the antibody may be dissolved or dispersed in a pharmaceutically acceptable carrier or aqueous medium. The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions; formulations including sesame oil, peanut oil or aqueous propylene glycol; and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi. Solutions of the active compounds as free base or pharmacologically acceptable salts can be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms. Carriers An antibody of the invention can be formulated into a composition in a neutral or salt form. Pharmaceutically acceptable salts include the acid addition salts (formed with the free amino groups of the protein) and which are formed with inorganic acids such as, for example, hydrochloric or phosphoric acids, or such organic acids as acetic, oxalic, tartaric, mandelic, and the like. Salts formed with the free carboxyl groups can also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, histidine, procaine and the like. The carrier can also be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetables oils. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminium monostearate and gelatin. Sterile injectable solutions are prepared by incorporating the active compounds in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof. The preparation of more, or highly concentrated solutions for direct injection is also contemplated, where the use of DMSO as solvent is envisioned to result in extremely rapid penetration, delivering high concentrations of the active agents to a small tumor area. Upon formulation, solutions will be administered in a manner compatible with the dosage formulation and in such amount as is therapeutically effective. The formulations are easily administered in a variety of dosage forms, such as the type of injectable solutions described above, but drug release capsules and the like can also be employed. For parenteral administration in an aqueous solution, for example, the solution should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose. These particular aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. In this connection, sterile aqueous media which can be employed will be known to those of skill in the art in light of the present disclosure. For example, one dosage could be dissolved in 1 ml of isotonic NaCl solution and either added to 1000 ml of hypodermoclysis fluid or injected at the proposed site of infusion, (see for example, “Remington's Pharmaceutical Sciences” 15th Edition, pages 1035-1038 and 1570-1580). Some variation in dosage will necessarily occur depending on the condition of the subject being treated. The person responsible for administration will, in any event, determine the appropriate dose for the individual subject. The antibodies of the invention may be formulated within a therapeutic mixture to comprise about 0.0001 to 1.0 milligrams, or about 0.001 to 0.1 milligrams, or about 0.1 to 1.0 or even about 10 milligrams per dose or so. Multiple doses can also be administered. In addition to the compounds formulated for parenteral administration, such as intravenous or intramuscular injection, other pharmaceutically acceptable forms include, e.g. tablets or other solids for oral administration; time release capsules; and any other form currently used. In certain embodiments, the use of liposomes and/or nanoparticles is contemplated for the introduction of antibodies into host cells. The formation and use of liposomes and/or nanoparticles are known to those of skill in the art. Nanocapsules can generally entrap compounds in a stable and reproducible way. To avoid side effects due to intracellular polymeric overloading, such ultrafine particles (sized around 0.1 µm) are generally designed using polymers able to be degraded in vivo. Biodegradable polyalkyl-cyanoacrylate nanoparticles that meet these requirements are contemplated for use in the present invention, and such particles may be easily made. Liposomes are formed from phospholipids that are dispersed in an aqueous medium and spontaneously form multilamellar concentric bilayer vesicles (also termed multilamellar vesicles (MLVs)). MLVs generally have diameters of from 25 nm to 4 µm. Sonication of MLVs results in the formation of small unilamellar vesicles (SUVs) with diameters in the range of 200 to 500 Å, containing an aqueous solution in the core. The physical characteristics of liposomes depend on pH, ionic strength and the presence of divalent cations. The invention will be further illustrated by the following figures and examples. However, these examples and figures should not be interpreted in any way as limiting the scope of the present invention. EXAMPLES Generation and production of the humanized anti-HER3 antibodies of the invention from chimeric antibody 9F7-F11 Methods for producing humanized antibodies based on conventional recombinant DNA and gene transfection techniques are well known in the art (See, e. g., Riechmann et al., Nature, 332: 323-327 (1988); Neuberger et al., Nature, 314: 268-270 (1985)). Antibodies can be humanized using a variety of techniques known in the art including, for example, CDR-grafting (EP 239,400; WO91/09967; US5,225,539; US5,530,101 or US5,585,089), veneering or resurfacing (EP592,106; EP519,596; Padlan and Kabat, Methods Enzymol., 203:3-21 (1991); Studnicka et al., Protein Eng., 7: 805-814 (1994); Roguska et al., Proc Natl Acad Sci USA., 91: 969-973 (1994)), and chain shuffling (US5,565,332). The general recombinant DNA technology for preparation of such antibodies is also known (see European Patent Application EP 125023, International Application WO96/02576 or Antibody Engineering Methods and Protocols, ed. Damien Nevoltris and Patrick Chames - Springer editions 2018). Illustrative antibodies according to the invention Gama-2 is an antibody according to the invention wherein the variable domain of the heavy chain consists in the amino acid sequence set forth as SEQ ID NO: 19 and the variable domain of the light chain consists in the amino acid sequence set forth as SEQ ID NO: 31. Gama-3 is an antibody according to the invention wherein the variable domain of the heavy chain consists in the amino acid sequence set forth as SEQ ID NO: 19 and the variable domain of the light chain consists in the amino acid sequence set forth as SEQ ID NO: 29. Gama-4 is an antibody according to the invention wherein the variable domain of the heavy chain consists in the amino acid sequence set forth as SEQ ID NO: 19 and the variable domain of the light chain consists in the amino acid sequence set forth as SEQ ID NO: 32. Gama-5 is an antibody according to the invention wherein the variable domain of the heavy chain consists in the amino acid sequence set forth as SEQ ID NO: 19 and the variable domain of the light chain consists in the amino acid sequence set forth as SEQ ID NO: 28. Gama-6 is an antibody according to the invention wherein the variable domain of the heavy chain consists in the amino acid sequence set forth as SEQ ID NO: 20 and the variable domain of the light chain consists in the amino acid sequence set forth as SEQ ID NO: 31. Gama-7 is an antibody according to the invention wherein the variable domain of the heavy chain consists in the amino acid sequence set forth as SEQ ID NO: 20 and the variable domain of the light chain consists in the amino acid sequence set forth as SEQ ID NO: 29. Gama-8 is an antibody according to the invention wherein the variable domain of the heavy chain consists in the amino acid sequence set forth as SEQ ID NO: 20 and the variable domain of the light chain consists in the amino acid sequence set forth as SEQ ID NO: 32. Gama-9 is an antibody according to the invention wherein the variable domain of the heavy chain consists in the amino acid sequence set forth as SEQ ID NO: 20 and the variable domain of the light chain consists in the amino acid sequence set forth as SEQ ID NO: 28. Gama-10 is an antibody according to the invention wherein the variable domain of the heavy chain consists in the amino acid sequence set forth as SEQ ID NO: 26 and the variable domain of the light chain consists in the amino acid sequence set forth as SEQ ID NO: 31. Gama-11 is an antibody according to the invention wherein the variable domain of the heavy chain consists in the amino acid sequence set forth as SEQ ID NO: 26 and the variable domain of the light chain consists in the amino acid sequence set forth as SEQ ID NO: 29. Gama-12 is an antibody according to the invention wherein the variable domain of the heavy chain consists in the amino acid sequence set forth as SEQ ID NO: 26 and the variable domain of the light chain consists in the amino acid sequence set forth as SEQ ID NO: 32. Gama-13 is an antibody according to the invention wherein the variable domain of the heavy chain consists in the amino acid sequence set forth as SEQ ID NO: 26 and the variable domain of the light chain consists in the amino acid sequence set forth as SEQ ID NO: 28. Gama-21 is an antibody according to the invention wherein the variable domain of the heavy chain consists in the amino acid sequence set forth as SEQ ID NO: 20 and the variable domain of the light chain consists in the amino acid sequence set forth as SEQ ID NO: 30. Gama-23 is an antibody according to the invention wherein the variable domain of the heavy chain consists in the amino acid sequence set forth as SEQ ID NO: 21 and the variable domain of the light chain consists in the amino acid sequence set forth as SEQ ID NO: 29. Gama-23A is an antibody according to the invention wherein the variable domain of the heavy chain consists in the amino acid sequence set forth as SEQ ID NO: 22 and the variable domain of the light chain consists in the amino acid sequence set forth as SEQ ID NO: 29. Gama-23Q is an antibody according to the invention wherein the variable domain of the heavy chain consists in the amino acid sequence set forth as SEQ ID NO: 23 and the variable domain of the light chain consists in the amino acid sequence set forth as SEQ ID NO: 29. Gama-24 is an antibody according to the invention wherein the variable domain of the heavy chain consists in the amino acid sequence set forth as SEQ ID NO: 24 and the variable domain of the light chain consists in the amino acid sequence set forth as SEQ ID NO: 29. Gama-25 is an antibody according to the invention wherein the variable domain of the heavy chain consists in the amino acid sequence set forth as SEQ ID NO: 25 and the variable domain of the light chain consists in the amino acid sequence set forth as SEQ ID NO: 29. Gama-26 is an antibody according to the invention wherein the variable domain of the heavy chain consists in the amino acid sequence set forth as SEQ ID NO: 27 and the variable domain of the light chain consists in the amino acid sequence set forth as SEQ ID NO: 29. Gama-27 is an antibody according to the invention wherein the variable domain of the heavy chain consists in the amino acid sequence set forth as SEQ ID NO: 21 and the variable domain of the light chain consists in the amino acid sequence set forth as SEQ ID NO: 30. Gama-29 is an antibody according to the invention wherein the variable domain of the heavy chain consists in the amino acid sequence set forth as SEQ ID NO: 24 and the variable domain of the light chain consists in the amino acid sequence set forth as SEQ ID NO: 30. Gama-31 is an antibody according to the invention wherein the variable domain of the heavy chain consists in the amino acid sequence set forth as SEQ ID NO: 25 and the variable domain of the light chain consists in the amino acid sequence set forth as SEQ ID NO: 30. Gama-33 is an antibody according to the invention wherein the variable domain of the heavy chain consists in the amino acid sequence set forth as SEQ ID NO: 27 and the variable domain of the light chain consists in the amino acid sequence set forth as SEQ ID NO: 30. EXAMPLE 1: SCREENING OF HUMANIZED VARIANT ANTIBODIES IN FAB-YEAST The genes corresponding to the different humanized Fab sequences were synthetized and cloned into a plasmid allowing expression on the surface of galactose-inducible yeast. The expression plasmid is then transformed into the yeast strain S. cerevisiae EBY100 as described in Sierocki et al. (2021, PLoS Neglect Trop Dis). Induction of transformed yeast in SG-CAA induction medium [6.7 g/L yeast nitrogen base without casamino acids, 20 g/L glucose, 5 g/L casamino acids, 100 mM sodium phosphate, pH 6.0] allows the expression of the Fab on the yeast surface. For cytometric analysis/sorting, between 106 and 108 induced cells are washed with 1 mL of PBSF (PBS, 0.1% BSA). The cells are then resuspended in a solution containing the recombinant HER3 extracellular domain (recombinant human HER3 ECD Fc fusion, ref 348- RB, R&D Systems) with or without NRG1-β (recombinant human NRG1-β ECD domain, ref 377-HB, R&D Systems). The results obtained are represented in Figures 1 and 2. In figures 1A and 1B, recombinant HER3 was used at 8nM and NGR1 at 50nM. For figures 2A and 2B, recombinant HER3 was used at 2nM and 200pM respectively and NGR1 at 50nM. For dose-response binding curves represented in Figures 4, concentration of recombinant HER3 varied in the range of 64pM to 200nM and NRG1 was used at 200nM. After 1h to 3h of incubation at 20°C with agitation, the cells are washed with 1 mL of ice-cold PBSF to avoid dissociation of the complex Fab-antigen. The cells are then incubated with the appropriate fluorescent reporters on ice for 15 min. The cells are then analyzed/sorted on a BD FACSAriaTMIII cytometer using the BD FACSdiva™ Diva software. The fluorescent reporters used are: anti-human Ckappa Light chain APC- conjugated (ref MA1-10385, Invitrogen) for detection of correct expression of Fab on the surface of the yeast and anti-human Fc PE-conjugated (ref H10104, Thermo Fischer) for detection of bound recombinant HER3 to the Fab-yeast. The results firstly show in Figures 1A and 1B that humanized antibodies of the invention, Gama-2 to Gama-13, have a significantly increased binding to HER3 in the presence of NRG1 compared to when NRG1 is absent. Gama 10, 11, 12 and 13, that all share the same humanized VH domain, have a very low binding capacity to HER3 in absence of NRG1, lower than the binding of 9F7-F11. Their binding to HER3 in presence of NRG1 is increased from 20 times to 40 times compared to their binding in the absence of NRG1, which is significantly superior to 9F7-F11, whose binding is increased 6 times in the presence of NRG1 compared to its binding in the absence of NRG1. Gama 2 and Gama 6 have an affinity to HER3 similar to the parental 9F7-F11 chimeric antibody in the presence and in the absence of NRG1, and accordingly were able to maintain the property of interest of 9F7F11 (original chimeric antibody) despite the numerous modifications introduced in the sequences, even in the HCDR2 for Gama-6. Gama 3, 4, 5, 7, 8 and 9 have an enhanced binding activity compared to the parental antibody both in the presence and in the absence of NRG1, with a significant increase of their binding to HER3 in the presence of NRG1. Figures 2A and 2B show the results obtained with another set of humanized antibodies according to the invention, i.e. antibodies Gama-21, -23, -24, -25, -26, -27, -29, -31 and -33, compared to Gama-7 from the first set of antibodies of the invention present in Figures 1A and 1B. It can be seen that the antibodies of the invention have a significantly increased binding to HER3 in the presence of NRG1 as compared to that in the absence of NRG1. EXAMPLE 2: BINDING OF ANTI-HER3 HUMANIZED ANTIBODIES AT THE SURFACE OF CANCER CELL LINES The cancer cell lines SKBR-3 breast cancer cells were maintained in RPMI1640 supplemented with 10% FBS, penicillin- streptomycin and L-Glutamine. Cells were grown at 37°C in a humidified atmosphere with 5% CO2 and medium was replaced twice a week. Cells were detached with trypsin, counted by an automatic cell count (Cellometer® Auto1000), washed with cold PBS and diluted with cold saturation buffer (PBS 1x, BSA 2%) to a concentration of 3x106 viable cells/mL. All culture media and supplements were purchased from Life Technologies, Inc. (Gibco). For Fluorescent-activated cell sorting (FACS) analysis shown in Figures 3 (A to F), the antibodies were added at the proper concentration in 45µL, cells were then deposited at a concentration of 1x105 cells / 45μL well, in the plate already containing the diluted NRG1 (recombinant human NRG1-β ECD domain, ref 377-HB, Biotechne) and antibodies were diluted and then incubated 2 hours on ice. For Fluorescent-activated cell sorting (FACS) analysis shown in Figures 4 (A to G), different experimental conditions were carried out. The SKBR-3 cell lines were incubated with humanized variants serially diluted starting at 100µg/mL with NRG1 at 50nM or in absence of NRG1. In each case after incubation time of antibodies in presence or in absence of NRG1, the plate was centrifuged at 300g 5 min at room temperature and washed twice with 200µL of saturation buffer. Bound antibodies were detected by Goat anti-human IgG Fc secondary PE- conjugated (ref 12-4998-82, Life Technologies) diluted at 1/400th with saturation buffer for 45 min at 4°C. The plate was centrifuged at 300g 5 min at room temperature and washed thrice with 200 µL of PBS. Cells were resuspended with 300µl of PBS and data were acquired with a Fortessa Cytometer (BD). Binding curves were analyzed using GraphPad Prism 8. Figure 3 shows the results of binding of humanized antibodies at 50µg/mL with or without various concentrations (range 0.01nM-100nM) of NRG1 on SKBR-3 breast cancer cells. The binding profile of humanized variants Gama-7 and Gama-5 (Fig 3A and 3B), Gama- 29 and Gama-31 (Fig 3C and 3D) and Gama-23 and Gama-23A (Fig 3F and 3E) indicate an allosteric enhanced binding mediated by NRG1. The binding of these humanized variants increased in the presence of growing NRG1 concentrations while Patritumab’s (human anti-HER3 antibody - comparative outside of the invention) decreased under the same conditions (Fig 3A). Figure 4 shows the binding profiles of humanized variant antibodies at growing concentration in absence or in the presence of 50nM NRG1. For the humanized variants selected (Figures 4A to 4E), the binding curves are higher in the presence of 50 nM of NRG1 than in the absence of NRG1. The opposite is observed with Patritumab (Figure 4F) for which the binding to SKBR-3 is abolished in presence of NRG1. Interestingly, Gama-23 and Gama-29 show higher binding to SKBR-3 at low NRG1 concentrations as compared to Gama-23A and Gama-31 and are thus less prone to enhanced binding in the presence of NRG. Gama-23 and Gama-23A have a very similar binding profile with low level of binding at low NRG1 concentrations. Except for Gama-31, the maximum of binding for Gama-5, Gama-7, Gama-23, Gama-23A and Gama-29 is similar. EXAMPLE 3: LIGANDS BINDING ASSAY The cancer cell lines SKBR-3 breast cancer cells was maintained in RPMI1640 supplemented with 10% FBS, penicillin- streptomycin and L-Glutamine. Cells were grown at 37°C in a humidified atmosphere with 5% CO2 and medium was replaced twice a week. Cells were detached with trypsin, counted by an automatic cell counter (Cellometer® Auto1000), washed with cold PBS and diluted with cold saturation buffer (PBS 1x, BSA 2%) to a concentration of 3x106 viable cells/ml. All culture media and supplements were purchased from Life Technologies, Inc. (Gibco). For Fluorescent-activated cell sorting (FACS) analysis described in figure 5A, cells were deposited at a concentration of 1x105 cells / 45μL well, in the plate already containing Gama-23A diluted at different concentrations (from 0.05µg/ml to 50µg/ml) in absence or in presence of NRG ligands at 50nM; NRG1α (Ref 13499-H08H, SinoBiological), NRG1β (Ref 11609-HNCH, SinoBiological) and NRG2 (Ref 21207-H08H, SinoBiological) and then incubated 2 hours on ice. For Fluorescent-activated cell sorting (FACS) analysis described in figure 5B, cells were then be deposited at a concentration of 1x105 cells / 45μL well, in the plate already containing the diluted ligands EGF (ref 236-EG-200, Biotechne), NRG1β (ref 396-HB-050, Biotechne) or a mixture NRG1β/EGF at 100nM and Gama-23A at 50µg/ml and then incubated 2 hours on ice. After incubation time, the plate was centrifuged at 300g 5 min at room temperature and washed twice with 200µL of saturation buffer. Bound antibodies were detected by Goat anti- human IgG Fc secondary PE-conjugated (ref 12-4998-82, Life Technologies) diluted at 1/400th with saturation buffer for 45 min at 4°C. The plate was centrifuged at 300g 5 min at room temperature and washed thrice with 200 µL of PBS. Cells were resuspended with 300µl of PBS and data were acquired with a Fortessa Cytometer (BD). Data were analysed using GraphPad Prism 9 software and statistics p values were determined using the ordinary one-way ANOVA followed by Bonferroni’s multiple comparisons test in case of significant effect. Figure 5A shows that binding of Gama-23A increases in the presence of NRG2 in the same order of magnitude as that observed for NRG1β and NRG1α. Figure 5B shows the binding profile of Gama-23A humanized antibody according to the invention in the presence of EGF, NRG1β and a combination of NRG1β /EGF. The binding of Gama-23A is, at least, not impacted by the presence of EGF at 0.1 and 100nM. On the opposite, the binding of Gama-23A increases in the presence of NRG1β, NRG1α, and the combination of NRG1β/EGF at 100nM. The binding of Gama-23A is interestingly not altered by the presence of EGF, which is the ligand of EGFR which interacts with HER3. EXAMPLE 4: THERMAL DENATURATION DSC analysis in PBS buffer were performed using on a MicroCal PEAQ DSC (Malvern Panalytical). Thermograms were acquired from 20°C to 100°C with a scanning rate of 60 °C/hour (1°C /min). A buffer scan (PBS 1x) was performed and used as reference. Samples were diluted to 1 mg/mL prior their analyses that were performed using PEAQ-DSC software. Raw DSC data were corrected for the instrumental baseline by subtraction of the Buffer (PBS) reference scan. The structural stability of the Fab domain makes the significant contribution of the structure stability of the whole antibody IgG format. The table below shows the DSC results of thermal transition temperature (melting point, Tm) and the enthalpy of this melting point (∆H) of the variable domain Fab for parental 9F7-F11 chimeric antibody and the humanized variants Gama-7, Gama-23 and Gama-23A according to the invention. Antibody Fab Tm (°C) ∆H (kcal/mol) 9F7-F11 75.6 543 Gama-7 79.8 634 Gama-23 80.0 622 Gama-23A 79.4 581 Table 1 Figures 6 shows the thermogram curves obtained by DSC scan for 9F7-F11 and Gama-23A. Gama-23A according to the invention showed improved thermal stability as compared to the parental chimeric 9F7-F11 with a significant gain of 3.8-4.4 °C of Tm and 40- 80 kcal/mol of enthalpy depending on the variant considered. These results indicate an unexpected better structural stability of the humanized variants which could not be predicted from the changes in the residues caused by the humanization process per se. Better stability has also been observed (data not shown). Such a better thermal stability of the antibodies of the invention could result in their improved industrial manufacturability, due in particular to an increased resistance of those antibodies to the acidic pH of viral inactivation processes. Heat resistance is also a proxy for long-term aggregation propensity of antibodies and is indicative of long-term stability at storage temperature (Boulet-Audet et al., Anal. Chem., 86: 9786-9793 (2014)). Similar results were obtained with antibodies Gama-7 and Gama-23 according to the invention. EXAMPLE 5: EFFECTS OF ANTI-HER3 HUMANIZED ANTIBODIES ACCORDING TO THE INVENTION ON HER3 AND AKT PHOSPHORYLATION. Phosphorylated AKT (pAKT) and phosphorylated HER3 (pHER3) levels were quantified using the HTRF Kit from CisBio Bioassay: Phospho-HER3 (Tyr 1289) cellular kit (64HR3PEG), Total HER3 cellular kit (64NR3PEG), Phospho-AKT1/2/3 (Ser473) cellular kit (64AKSPEG), Total AKT cellular kit (64NKTPEG). The T47D cancer breast cancer cells (5 x 104 cells/well) will be seeded in sterile 96-well flat-bottom tissue culture-treated plates (100 µL of complete medium) and cultured overnight in RPMI/1% FCS supplemented with 10% FCS and penicillin 100U/mL /streptomycin at 100µg/mL for 18h. After 2 washes (200 µL of culture medium without serum), the cells will be incubated in culture medium/1% FCS for 18 hours for starvation. After removing the medium, cells were pre-stimulated with 25nM of NRG1- β (recombinant human NRG1-β ECD domain, ref 377-HB, R&D Systems) for 5min, before adding ten-fold dilutions of anti-HER3 antibodies, range 50µg/ml-0.05µg/ml, for another 25min at 37°C. NRG1-β and the antibodies were removed, and cells were lysed in the supplemented lysis buffer (Cisbio Bioassay). Plates were incubated at room temperature with shaking for 30min to lyse cells. Lysates were transferred to white 384-well plates and anti- phospho HER3 (Tyr1289)-cryptate /anti-HER3-d2 or anti-phospho AKT (Ser473)- cryptate/anti-AKT-d2 antibody pairs were added to each well and left in the dark at room temperature for 4h. The TR-FRET signal (665 nm/620 nm emission ratio) was measured on a HTRF reader. Negative control wells contained unstimulated/non-treated cells whereas maximum of phosphorylation was obtained by stimulating cancer cells with NRG1 without antibody treatment. Data were analysed using GraphPad Prism 9 software and statistics p values were determined using the ordinary one-way ANOVA followed by Bonferroni’s multiple comparisons test in case of significant effect. As illustrated in figure 7, humanized variants Gama-23A, Gama-7 and Gama-23 inhibit phosphorylation of Akt and HER3 in a significant manner whereas Patritumab in the same conditions does not show significant inhibition of these phosphorylations. EXAMPLE 6: INTERNALISATION ASSAY Antibody mediated internalization was assessed by flow cytometry analysis. The readout of this method was the vanishing of the membrane receptor HER3 due to its internalisation. This phenomenon was shown by the diminution of signals at 37°C versus 4°C, as the internalisation process is blocked at 4°C. The cancer cell lines SKBR-3 breast cancer cells were maintained in RPMI1640 supplemented with 10% FBS, 1% penicillin- streptomycin and 1% L-Glutamine. Cells were grown at 37°C in a humidified atmosphere with 5% CO2 and medium was replaced twice a week. Cells were detached with trypsin, counted by an automatic cell count (Cellometer® Auto1000), washed with cold PBS and diluted with cold saturation buffer (PBS 1x, BSA 2%) to a concentration of 3x106 viable cells/mL. All culture media and supplements were purchased from Life Technologies, Inc. (Gibco). For Fluorescent-activated cell sorting (FACS) analysis shown in figures 8A (in the presence of NRG1) and 8B (in the absence of NRG1), the antibodies were diluted at 50µg/ml with cold saturation buffer (BSA 2%, PBS 1x) in 100 µL, as well as for NRG1-β (recombinant human NRG1-β ECD domain, ref 377-HB, R&D Systems) diluted at 50nM with cold PBS (for conditions without NRG1, 100µL of cold PBS was added). Cells were deposited at a concentration of 3x105 cells/100 μL in the tube already containing the diluted NRG1 and antibodies and incubated 30 min at 4°C. Tubes were then centrifuged at 300 g 5 min at 4°C and washed with 500 µL of cold saturation buffer (BSA 2%, PBS 1x). For kinetic conditions at 37°C, 500 µL of pre-heated RPMI media was added and tubes were incubated at 37°C for the 1h and 2h. For kinetics conditions at 4°C, 500 µL of cold RPMI media was added and tubes were incubated at 4°C for 1h and 2h. After indicated time, tubes were centrifuged at 300 g 5 min at 4°C and washed twice, once with 500 µL of cold saturation buffer (BSA 2%, PBS 1x) and once with cold PBS. Bound antibodies were detected by Goat anti-human IgG Fc secondary PE- conjugated (ref 12-4998-82, Life Technologies) diluted at 1/400th with saturation buffer for 45 min at 4°C. Tubes were centrifuged at 300g 5 min at 4°C and washed twice, once with 500 µL of cold saturation buffer (BSA 2%, PBS 1x) and once with cold PBS. Cells were resuspended with 300µl of PBS and data were acquired with a Fortessa Cytometer (BD). Binding data were represented using GraphPad Prism 8. As can be seen in Figures 8, the internalization of antibodies according to the invention is high. Moreover, while the percentage of internalization of antibodies according to the invention is high (between about 60% and about 80%) in the presence of NRG1 (Figure 8A), it significantly diminishes in the absence of NRG1 (between about 35% and about 50%). On the contrary, while the internalization of Patritumab in the presence of NRG1 remains below 20% (Figure 8A), its internalization raises above 60% in the absence of NRG1 (Figure 8B). SEQUENCES SEQ ID NO: 1: heavy chain variable domain X1VQLX2X3SGX4X5LX6X7PGX8SX9X10X11SCX12ASGFTFSSYX13MSWVRQAPG X14GLEWVAYISDX15GGVTYYX16DX17X18KGRFX19ISRDNSX20X21TLYLQMX22SLX23A EDTAVYYCARDRYGLFX24YWGQGTLVTVSS SEQ ID NO: 2: light chain variable domain X25IX26X27TQSPX28X29LSX30SX31GX32RX33TX34X35CX36ASQX37VGIX38X39AWY QQKPGX40APX41LLIYSASNRYTGX42PX43RFX44GSGSGTX45FTLTISSLX46X47EDX48A X49YX50CQQYSX51YPYTFGQGTKLEIK SEQ ID NO: 3: H-CDR1 SYTMS SEQ ID NO: 4: H-CDR1 SYAMS SEQ ID NO: 5: H-CDR2 YISDGGGVTYYPDTIKG SEQ ID NO: 6: H-CDR2 YISDGGGVTYYPDTVKG SEQ ID NO : 7 : H-CDR2 YISDGGGVTYYPDTFKG SEQ ID NO: 8: H-CDR2 YISDKGGVTYYPDTVKG SEQ ID NO: 9: H-CDR2 YISDAGGVTYYPDTVKG SEQ ID NO: 10: H-CDR2 YISDQGGVTYYPDTVKG SEQ ID NO: 11: H-CDR2 YISDKGGVTYYADSVKG SEQ ID NO: 12: H-CDR3 DRYGLFAY SEQ ID NO: 13: H-CDR3 DRYGLFVY SEQ ID NO: 14: L-CDR1 KASQNVGIAVA SEQ ID NO: 15: L-CDR1 RASQSVGIYLA SEQ ID NO: 16: L-CDR2 SASNRYT SEQ ID NO: 17: L-CDR3 QQYSNYPYT SEQ ID NO: 18: L-CDR3 QQYSGYPYT SEQ ID NO: 19: heavy variable domain of Gama-2, -3, -4 and -5 EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTMSWVRQAPGKGLEWVAYIS DGGGVTYYPDTIKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDRYGLFAYWG QGTLVTVSS SEQ ID NO: 20: heavy variable domain of Gama-6, -7, -8, -9 and -21 EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYTMSWVRQAPGKGLEWVAYIS DGGGVTYYPDTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDRYGLFAYW GQGTLVTVSS SEQ ID NO: 21: heavy variable domain of Gama-23 and -27 EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYTMSWVRQAPGKGLEWVAYIS DKGGVTYYPDTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDRYGLFAYW GQGTLVTVSS SEQ ID NO: 22: heavy variable domain of Gama-23A EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYTMSWVRQAPGKGLEWVAYIS DAGGVTYYPDTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDRYGLFAYW GQGTLVTVSS SEQ ID NO: 23: heavy variable domain of Gama-23Q EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYTMSWVRQAPGKGLEWVAYIS DQGGVTYYPDTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDRYGLFAYW GQGTLVTVSS SEQ ID NO: 24: heavy variable domain of Gama-29 and -24 EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYTMSWVRQAPGKGLEWVAYIS DKGGVTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDRYGLFAYW GQGTLVTVSS SEQ ID NO: 25: heavy variable domain of Gama-31 and -25 EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVAYIS DKGGVTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDRYGLFAYW GQGTLVTVSS SEQ ID NO: 26: heavy variable domain of Gama-10, -11, -12 and -13 QVQLVQSGSELKKPGASVKVSCKASGFTFSSYTMSWVRQAPGQGLEWVAYIS DGGGVTYYPDTFKGRFVISRDNSVSTLYLQISSLKAEDTAVYYCARDRYGLFAYWG QGTLVTVSS SEQ ID NO: 27: heavy variable domain of Gama-26, -and -33 EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVAYIS DKGGVTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDRYGLFVYW GQGTLVTVSS SEQ ID NO: 28: light variable domain of Gama-5, -9 and -13 EIVMTQSPATLSVSPGERATLSCKASQNVGIAVAWYQQKPGQAPRLLIYSASN RYTGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQYSNYPYTFGQGTKLEIK SEQ ID NO: 29: light variable domain of Gama-3, -7, -11, -23, -23A, -23Q, -24, -25 and -26 EIVMTQSPATLSLSPGERATLSCKASQNVGIAVAWYQQKPGQAPRLLIYSASN RYTGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQYSNYPYTFGQGTKLEIK SEQ ID NO: 30: light variable domain of Gama-21, -27, -29, -31 and -33 EIVLTQSPATLSLSPGERATLSCRASQSVGIYLAWYQQKPGQAPRLLIYSASNR YTGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQYSGYPYTFGQGTKLEIK SEQ ID NO: 31: light variable domain of Gama-2, -6 and -10 DIQMTQSPSSLSASVGDRVTITCKASQNVGIAVAWYQQKPGKAPKLLIYSASN RYTGVPSRFSGSGSGTDFTLTISSLQPEDIATYFCQQYSNYPYTFGQGTKLEIK SEQ ID NO: 32: light variable domain of Gama-4, -8 and -12 AIQMTQSPSSLSASVGDRVTITCKASQNVGIAVAWYQQKPGKAPKLLIYSASN RYTGVPSRFTGSGSGTDFTLTISSLQPEDFATYFCQQYSNYPYTFGQGTKLEIK

Claims

CLAIMS 1. A humanized neuregulin positively dependent anti-human-HER3 antibody comprising: (i) a heavy chain wherein the variable domain has at least 90% or 95% identity with the amino acid sequence set forth as SEQ ID NO: 1: X1VQLX2X3SGX4X5LX6X7PGX8SX9X10X11SCX12ASGFTFSSYX13MSWVRQAPGX14G LEWVAYISDX15GGVTYYX16DX17X18KGRFX19ISRDNSX20X21TLYLQMX22SLX23A EDTAVYYCARDRYGLFX24YWGQGTLVTVSS wherein: X1 represents E or Q, in particular E; X2 represents V or L, in particular L; X3 represents E or Q, in particular E; X4 represents G or S, in particular G; X5 represents G or E, in particular G; X6 represents V or K, in particular V; X7 represents Q or K, in particular Q; X8 represents G or A, in particular G; X9 represents L or V, in particular L; X10 represents R or K, in particular R; X11 represents L or V, in particular L; X12 represents A or K, in particular A; X13 represents T or A; X14 represents K or Q, in particular K; X15 represents G, K, A or Q, in particular G, K or A, and more particularly G or K; X16 represents P or A; X17 represents T or S; X18 represents I, V or F, in particular V; X19 represents T or V; X20 represents K or V, in particular K; X21 represents N or S, in particular N; X22 represents N or S, in particular N; X23 represents R or K, in particular R; and X24 represents A or V, in particular A; and (ii) a light chain wherein the variable domain has at least 90% or 95% identity with the amino acid sequence set forth as SEQ ID NO: 2: X25IX26X27TQSPX28X29LSX30SX31GX32RX33TX34X35CX36ASQX37VGIX38X39AWYQQ KPGX40APX41LLIYSASNRYTGX42PX43RFX44GSGSGTX45FTLTISSLX46X47EDX48AX 49YX50CQQYSX51YPYTFGQGTKLEIK wherein: X25 represents E, D or A, in particular E; X26 represents V or Q, in particular V; X27 represents M or L; X28 represents A or S, in particular A; X29 represents T or S, in particular T; X30 represents V, L or A, in particular L; X31 represents P or V, in particular P; X32 represents E or D, in particular E; X33 represents A or V, in particular A; X34 represents L or I, in particular L; X35 represents S or T, in particular S; X36 represents K or R; X37 represents N or S; X38 represents A or Y; X39 represents V or L; X40 represents Q or K, in particular Q; X41 represents R or K, in particular R; X42 represents I or V, in particular I; X43 represents A or S, in particular A; X44 represents S or T, in particular S; X45 represents E or D, in particular E; X46 represents Q or E, in particular E; X47 represents S or P, in particular P; X48 represents F or I, in particular F; X49 represents V or T, in particular V; X50 represents Y or F, in particular Y; and X51 represents N or G.
2. The antibody according to claim 1, wherein: (i) the heavy chain comprises: - a H-CDR1 having a sequence selected from the group consisting of SEQ ID NO: 3 and SEQ ID NO: 4; and - a H-CDR2 having a sequence selected from the group consisting of SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10 and SEQ ID NO: 11; and - a H-CDR3 having a sequence selected from the group consisting of SEQ ID NO: 12 and SEQ ID NO: 13; and, (ii) the light chain comprises: - a L-CDR1 having a sequence selected from the group consisting of SEQ ID NO: 14 and SEQ ID NO: 15; and - a L-CDR2 having the sequence set forth as SEQ ID NO: 16; and - a L-CDR3 having a sequence selected from the group consisting of SEQ ID NO: 17 and SEQ ID NO: 18.
3. The antibody according to claim 1 or 2, wherein the variable domain of the heavy chain comprises, and in particular consists in, an amino acid sequence selected from the group consisting of SEQ ID NO: 20, SEQ ID NO: 22, SEQ ID NO: 19, SEQ ID NO: 21, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26 and SEQ ID NO: 27.
4. The antibody according to any one of claims 1 to 3, wherein the variable domain of the light chain comprises, and in particular consists in, an amino acid sequence selected from the group consisting of SEQ ID NO: 29, SEQ ID NO: 28, SEQ ID NO: 30, SEQ ID NO: 31 and SEQ ID NO: 32.
5. The antibody according to any one of claims 1 to 4, wherein said antibody is selected from the group consisting of antibodies wherein: - the variable domain of the heavy chain of said antibody comprises, and in particular consists in, the amino acid sequence set forth as SEQ ID NO: 20 and/or, in particular and, the variable domain of the light chain comprises, and in particular consists in, an amino acid sequence selected from the group consisting of SEQ ID NO: 28, 29, 30, 31 and 32; or - the variable domain of the heavy chain of said antibody comprises, and in particular consists in, the amino acid sequence set forth as SEQ ID NO: 22 and the variable domain of the light chain comprises, and in particular consists in, the amino acid sequence set forth as SEQ ID NO: 29; or - the variable domain of the heavy chain of said antibody comprises, and in particular consists in, the amino acid sequence set forth as SEQ ID NO: 19 and the variable domain of the light chain comprises, and in particular consists in, an amino acid sequence selected from the group consisting of SEQ ID NO: 28, 29, 31 and 32; or - the variable domain of the heavy chain of said antibody comprises, and in particular consists in, the amino acid sequence set forth as SEQ ID NO: 26 and the variable domain of the light chain comprises, and in particular consists in, an amino acid sequence selected from the group consisting of SEQ ID NO: 28, 29, 31 and 32; or - the variable domain of the heavy chain of said antibody comprises, and in particular consists in, the amino acid sequence set forth as SEQ ID NO: 21 and the variable domain of the light chain comprises, and in particular consists in, an amino acid sequence selected from the group consisting of SEQ ID NO: 29 and 30; or - the variable domain of the heavy chain of said antibody comprises, and in particular consists in, the amino acid sequence set forth as SEQ ID NO: 23 and the variable domain of the light chain comprises, and in particular consists in, the amino acid sequence set forth as SEQ ID NO: 29; or - the variable domain of the heavy chain of said antibody comprises, and in particular consists in, the amino acid sequence set forth as SEQ ID NO: 24 and the variable domain of the light chain comprises, and in particular consists in, an amino acid sequence selected from the group consisting of SEQ ID NO: 29 and 30; or - the variable domain of the heavy chain of said antibody comprises, and in particular consists in, the amino acid sequence set forth as SEQ ID NO: 25 and the variable domain of the light chain comprises, and in particular consists in, an amino acid sequence selected from the group consisting of SEQ ID NO: 29 and 30; or - the variable domain of the heavy chain of said antibody comprises, and in particular consists in, the amino acid sequence set forth as SEQ ID NO: 27 and the variable domain of the light chain comprises, and in particular consists in, an amino acid sequence selected from the group consisting of SEQ ID NO: 29 and 30.
6. The antibody according to any one of claims 1 to 5, wherein: - the variable domain of the heavy chain of said antibody comprises, and in particular consists in, an amino acid sequence selected from the group consisting of SEQ ID NO: 20, 22, 19, 21, 23, 24 and 25; and - the variable domain of the light chain of said antibody comprises, and in particular consists in, an amino acid sequence selected from the group consisting of SEQ ID NO: 29, 28 and 30.
7. The antibody according to any one of claims 1 to 6, wherein: - the variable domain of the heavy chain of said antibody comprises, and in particular consists in, an amino acid sequence selected from the group consisting of SEQ ID NO: 20, 22, 24 and 25; and - the variable domain of the light chain of said antibody comprises, and in particular consists in, an amino acid sequence selected from the group consisting of SEQ ID NO: 29 and 30.
8. The antibody according to any one of claims 1 to 7, wherein said antibody is selected from the group consisting of antibodies wherein: - the variable domain of the heavy chain of said antibody comprises, and in particular consists in, the amino acid sequence set forth as SEQ ID NO: 20 and the variable domain of the light chain comprises, and in particular consists in, the amino acid sequence set forth as SEQ ID NO: 29; or - the variable domain of the heavy chain of said antibody comprises, and in particular consists in, the amino acid sequence set forth as SEQ ID NO: 22 and the variable domain of the light chain comprises, and in particular consists in, the amino acid sequence set forth as SEQ ID NO: 29; or - the variable domain of the heavy chain of said antibody comprises, and in particular consists in, the amino acid sequence set forth as SEQ ID NO: 24 and the variable domain of the light chain comprises, and in particular consists in, the amino acid sequence set forth as SEQ ID NO: 30; or - the variable domain of the heavy chain of said antibody comprises, and in particular consists in, the amino acid sequence set forth as SEQ ID NO: 25 and the variable domain of the light chain comprises, and in particular consists in, the amino acid sequence set forth as SEQ ID NO: 30.
9. An immunoconjugate comprising the antibody according to anyone of claims 1 to 8 linked to a therapeutic agent.
10. A fragment of an antibody according to any one of claims 1 to 8 comprising the variable domain of the heavy chain and the variable domain of the light chain.
11. The fragment of claim 10 which is selected from the group consisting of Fv, Fab, F(ab’)2, Fab’, dsFv, scFv, sc(Fv)2 and diabodies.
12. A nucleic acid sequence encoding an antibody according to any one of claims 1-8 or a fragment according to claim 10 or 11.
13. A vector comprising a nucleic acid sequence according to claim 12.
14. A host cell, in particular a procaryotic or eucaryotic host cell, comprising a nucleic acid sequence according to claim 12 or a vector according to claim 13.
15. A pharmaceutical composition comprising an antibody according to any of claims 1 to 8, an immunoconjugate according to claim 9, or a fragment according to claim 10 or 11, in a pharmaceutically acceptable carrier.
16. The antibody according to any of claims 1 to 8, an immunoconjugate according to claim 9, or a fragment according to claim 10 or 11, for use as a drug.
17. An antibody according to any of claims 1 to 8, an immunoconjugate according to claim 9, a fragment according to claim 10 or 11 or a pharmaceutical composition according to claim 15 for use in the treatment of a HER3-expressing cancer, in particular of a HER3-expressing cancer wherein neuregulin is present in an individual in need thereof.
18. The antibody, immunoconjugate, fragment or composition for use according to claim 17, wherein the HER3-expressing cancer is a NRG-dependent cancer, and in particular a NRG-fusion protein driven cancer.
19. The antibody, immunoconjugate, fragment or composition for use according to claim 17 or 18, wherein neuregulin, and in particular neuregulin 1 or neuregulin 2, more particularly neuregulin 1α, neuregulin 1β or neuregulin 2, and more particularly neuregulin 1β, (i) is secreted by the cancer and/or by tissues and/or organs, in particular by tissues and/or organs in the cancer and/or surrounding the cancer, or (ii) is present due to its administration to the subject before, after, or at the same time as the antibody and/or the immunoconjugate.
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