POLYPEPTIDE Fc FRAGMENT OF IMMUNOGLOBULIN FOR THE PRODUCTION OF THERAPEUTIC POLYPEPTIDE FUSIONS AND CONJUGATES

Abstract

The invention relates to the field of biotechnology, specifically to Fc-fragment polypeptides of immunoglobulins, and is suitable for use in medical applications. The revealed Fc-fragment polypeptides of immunoglobulins exhibit high binding capacity to FcRn and low binding capacity to FcRγ, and can be used for the production of fusion polypeptides and conjugates with therapeutic activity.

Description

[0001]Fc FRAGMENT POLYPEPTIDE FOR PRODUCING THERAPEUTICALLY ACTIVE FUSION POLYPEPTIDES AND CONJUGATES FIELD OF THE INVENTION It has been discovered that the binding of an Fc fragment polypeptide-based antibody or fusion construct to FcRn and FcgRs can be modified by changing amino acid residues in the Fc fragment polypeptide. The conjugates and fusion constructs based on the Fc region polypeptides disclosed herein can be used, for example, for treating diseases that require retention times specifically selected for systemic administration. BACKGROUND OF THE INVENTION Immunoglobulin Fc domain receptors (FcRs) are divided into two major classes: those involved in effector functions, such as FcRs for IgG (FcgRI, II and III), IgE (FceRI), and IgA (FcαRI), and ones that are responsible for transporting immunoglobulins across epithelial surfaces, namely the polymeric IgA receptor (pIgR) and FcRn, the neonatal IgG transporter. The neonatal Fc receptor (FcRn) is important for the metabolic pathway of the IgGantibodies in vivo. The FcRn function is to rescue wild-type IgG from the process oflysosomal degradation, resulting in reduced clearance and increased half-life of the immunoglobulin. The neonatal Fc receptor is a heterodimeric protein consisting of two polypeptides: a 50 kDa major histocompatibility complex class I-like protein (α-FcRn), and a 15 kDa β2-microglobulin (β2m). FcRn binds with high affinity to the CH2-CH3 portion of the IgG antibody Fc region. The interaction between an IgG-class antibody and FcRn ispH-dependent and occurs in a stoichiometric ratio of 1:2, i.e. one IgG antibody moleculecan interact with two FcRn molecules via its two heavy chain Fc region polypeptides (see, e.g., HUBER A. H. et al., Crystallization and stoichiometry of binding of a complex between a rat intestinal Fc receptor and Fc, Journal of molecular biology, 1993, V.230, N.3, p.1077-1083). Thus, binding properties / characteristics of the IgG molecules in relation to FcRn invitro are indicative of its in vivo pharmacokinetics in blood.The antibody Fc fragment also interacts with various Fc receptors and ligands that mediate effector functions of the immune cells. This family of receptors includes Fc-gamma RI (CD64), including isoforms: Fc-gamma RIa, Fc-gamma RIb, and Fc-gamma RIc; Fc-gamma RII (CD32), including isoforms: Fc-gamma RIIa, Fc-gamma RIIb (including Fc-gamma RIIb-1 and Fc-gamma RIIb-2), and Fc-gamma RIIc; and Fc-gamma RIII (CD16), including isoforms Fc- gamma RIIIa and Fc-gamma RIIIb (see NAGELKERKE S. Q., KUIJPERS T. W., Immunomodulation by IVIg and the role of Fc-gamma receptors: classic mechanisms of action after all?, Frontiers in immunology, 2015, V.5, p.674). Fc-gamma receptors are known to have the extracellular domain mediating interaction with Fc, the membrane-bound region, and the intracellular domain that can mediate some signaling events within a cell. These receptors are expressed on a variety of immune cells including monocytes, macrophages, neutrophils, dendritic cells, eosinophils, mast cells, platelets, B cells, large granular lymphocytes, Langerhans cells, natural killer (NK) cells, and T cells. Formation of the Fc / Fc-gamma-R complex mediates interactions of these effector cells with antigens, which typically results in cellular signaling and important downstream immune responses such as release of the inflammatory mediators, B-cells activation, endocytosis, phagocytosis, and antibody-dependent cellular cytotoxicity. The ability to mediate phagotoxic effector function is a potential mechanism for exerting the antibodies' anti-infective defense (seeNAGELKERKE S. Q., KUIJPERS T. W., Immunomodulation by IVIg and the role of Fc-gamma receptors: classic mechanisms of action after all?, Frontiers in immunology, 2015, V. 5, p.674). The interaction between FcRn and the IgG antibody Fc region involves various amino acid residues of the heavy chain CH2 and CH3 domains. The amino acid residues involved in interaction with FcRn are localized starting from about position 243 according to EU numbering to position 261 according to EU numbering, from about position 275 according to EU numbering to position 293 according to EU numbering, from about position 302 according to EU numbering to position 319 according to EU numbering, from about position 336 according to EU numbering to position 348 according to EU numbering, at position 408 according to EU numbering, and from about position 424 according to EU numbering to position 440 according to EU numbering. More specifically, the following amino acid residues according to EU numbering of Kabat are involved in the Fc region and FcRn interaction: F243, P244, P245 P, K246, P247, K248, D249, T250, L251, M252, I253, S254, R255, T256, P257, E258, V259, T260, C261, F275, N276, W277, Y278, V279, D280, V282, E283, V284, H285, N286, A287, K288, T289, K290, P291, R292, E293, V302, V303, S304, V305, L306, T307, V308, L309, H310, Q311, D312, W313, L314, N315, G316, K317, E318, Y319, I336, S337, K338, A339, K340, G341, Q342, P343, R344, E345, P346, Q347, V348, C367, V369, F372, Y373, P374, S375, D376, I377, A378, V379, E380, W381, E382, S383, N384, G385, Q386, P387, E388, N389, Y391, T393, S408, S424, C425, S426, V427, M428, H429, E430, A431, L432, H433, N434, H435, Y436, T437, Q438, K439, and S440. Research using site-directed mutagenesis showed that the critical sites for binding to FcRn within the IgG Fc region are histidine 310, histidine 435 and isoleucine 253; and, to alesser extent, histidine 433 and tyrosine 436 (see, e.g., KIM J. K. et al., Mapping the site onhuman IgG for binding of the MHC class I-related receptor, FcRn, European journal ofimmunology, 1999, V. 29, N. 9, p.2819-2825; RAGHAVAN M. et al., Analysis of the pH dependence of the neonatal Fc receptor / immunoglobulin G interaction using antibody and receptor variants, Biochemistry, 1995, V. 34, N. 45, p.14649-14657; MEDESAN C. et al., Delineation of the amino acid residues involved in transcytosis and catabolism of mouse IgG1, The Journal of Immunology, 1997, V.158, N.5, p.2211-2217). Methods are known for enhancing the IgG binding to FcRn that have been accomplished through mutating various amino acid residues within IgG: threonine 250, methionine 252, serine 254, threonine 256, threonine 307, glutamic acid 380, methionine428, histidine 433, and asparagine 434 (see, e.g., KUO T. T. et al., Neonatal Fc receptor: fromimmunity to therapeutics, Journal of clinical immunology, 2010, V.30, N.6, p.777-789). Studies of interactions between immunoglobulins and FcgRs revealed that binding sites for C1q and FcgR are located within the IgG CH2 domain. A mutagenesis analysis of IgG2b mAb identified glutamic acid, lysine and lysine residues at positions 318, 320 and 322, respectively, as key binding motif for C1q. Furthermore, the amino acid residues at positions 234–238 are involved in the high-affinity interaction of mouse IgG2a with FcgRI. In addition, the substitution of aspartic acid with alanine at position 265 (D265A) has been shown to eliminate interaction of mouse IgG1 with the low-affinity FcgRIIb and FcgRIII (BAUDINO L. et al., Crucial role of aspartic acid at position 265 in the CH2 domain for murine IgG2a and IgG2b Fc-associated effector functions, The Journal of Immunology, 2008, V.181, N. 9, p.6664-6669). Thus, for some therapeutic applications, it is better to avoid the activation of complement and FcgRs. For example, it is undesirable to stimulate complement whenadministering therapeutically active polypeptides fused to Fc fragments of antibodies (see, e.g.,CAPON D. J. et al., Designing CD4 immunoadhesins for AIDS therapy, Nature, 1989, V. 337, N.6207, p.525-531). Further, due to relatively lower affinity of human IgG2 and IgG4 for FcgRsand complement receptors (BRUHNS P. et al., Specificity and affinity of human Fcγ receptorsand their polymorphic variants for human IgG subclasses, Blood, The Journal of the American Society of Hematology, 2009, V. 113, N. 16, p.3716-3725) these two subclasses are used in development of therapeutic monoclonal antibodies (mAbs) (e.g., denosumab, natalizumab, panitumumab, and eculizumab), in cases where their minimal effector potential is required. So, for example, glucagon-like peptide 1 (GLP-1) was fused to human IgG2 to avoid unwanted immunogenicity, and was shown to have superior therapeutic and pharmacologicalproperties compared to native GLP-1 in a mouse model of type I diabetes (WANG Q. et al.,Novel GLP-1 fusion chimera as potent long acting GLP-1 receptor agonist, PloS one, 2010, V.5, N. 9, p.e12734). However, it is also possible to cause a decreased effector function of oneeffector system by simultaneously activating another effector system. In particular, it wasobserved that the mast cell activation by FceR can be suppressed by the simultaneous activation of the inhibitory FcgRIIb (DAËRON M. et al., The same tyrosine-based inhibition motif, in the intra-cytoplasmic domain of FcγRIIB, regulates negatively BCR-, TCR-, and FcR-dependent cell activation, Immunity, 1995, V.3, N.5, p.635-646), which has stimulated development of several Fc fusion proteins that inhibit inflammation and are useful in the treatment of allergic asthma. In summary, it can be assumed that introducing certain modifications into the Fc fragment to which a biologically active partner is fused or conjugated can enhance the binding ability of the fusion protein to FcRn and reduce its binding ability to effector FcgRs, which can significantly improve pharmacokinetic properties of the fusion protein. The present invention is directed to the generation of immunoglobulin Fc fragment polypeptides having a high binding ability to FcRn and a low binding ability to FcgRs, for use in the creation of therapeutically active fusion polypeptides and conjugates. SUMMARY OF THE INVENTION All terms and abbreviations used in this application have the same meanings as those generally accepted in the art, and are evident to the skilled persons. The term "alteration" means a mutation (substitution), insertion (addition) or deletion of one or more amino acid residues in a parent antibody or fusion polypeptide, e.g., a fusion polypeptide comprising at least one FcRn-binding portion of an Fc region, said alteration(s) resulting in production of a modified antibody or fusion polypeptide. The term "mutation" means that a certain amino acid residue is replaced by another amino acid residue. For example, the L234A mutation means that the lysine amino acid residue at position 234 in the antibody Fc region (polypeptide) is substituted by the alanine amino acid residue (lysine to alanine substitution) (numbering corresponds to the EU index). The term "amino acid mutation" means substitution of at least one existing aminoacid residue with another different amino acid residue (i.e., a substituting amino acid residue). The substituting amino acid residue may be a "natural amino acid residue" selected from the group consisting of alanine (three-letter code: ala, one-letter code: A), arginine (arg, R), asparagine (asn, N), aspartic acid (asp, D), cysteine (cys, C), glutamine (gln, Q), glutamic acid (glu, E), glycine (gly, G), histidine (his, H), isoleucine (ile, I), leucine (leu, L), lysine (lys, K), methionine (met, M), phenylalanine (phe, F), proline (pro, P), serine (ser, S), threonine (thr, T), tryptophan (trp, W), tyrosine (tyr, Y), and valine (val, V). The substituting amino acid residue may be a "non-natural amino acid residue", including, but not limited to, a D-stereoisomer of a "natural amino acid residue". The term "amino acid insertion" means the (additional) insertion of at least one amino acid residue at a predetermined position in an amino acid sequence. In oneembodiment of the present invention, an "insertion" is the insertion of one, two, three, ormore amino acid residues. The inserted amino acid residues may be any natural or non-natural amino acid residues, or a combination thereof. The term "amino acid deletion" means the removal of at least one amino acid residue from a predetermined position in an amino acid sequence. The term "CH2 domain" means the portion of an antibody heavy chain polypeptide spanning from about position 231 according to EU numbering to position 340 according to EU numbering (EU numbering system of Kabat). The term "CH3 domain" means the portion of an antibody heavy chain polypeptide spanning from about position 341 according to EU numbering to position 446 according to EU numbering. The "class" of an antibody relates to the type of its heavy chain constant domain orconstant region. There are five major antibody classes: IgA, IgD, IgE, IgG, and IgM, andsome of them can be further subdivided into subclasses (isotypes), e.g., IgG1, IgG2, IgG3,IgG4, IgA1, and IgA2. The heavy chain constant domains corresponding to the different immunoglobulin classes are called α, δ, ε, γ, and μ, respectively. The term "derived from" means that an amino acid sequence is produced from a parent amino acid sequence by introducing changes at least at one position. Such altered amino acid sequence differs from the corresponding parental amino acid sequence at least at one corresponding position (numbering scheme for Fc regions of antibodies is according to the Kabat EU index numbering system). In one of the embodiments, the amino acid sequence derived from a parent amino acid sequence differs in one or more amino acid residues at corresponding positions. Similarly, the altered amino acid sequence has high amino acid sequence identity with the parent amino acid sequence. In one of the embodiments, the amino acid sequence derived from a parent amino acid sequence has amino acid sequence identity of 90% or more. In one of the embodiments, the amino acid sequence derived from a parent amino acid sequence has amino acid sequence identity of 95% or more. A "human antibody" is an antibody that has an amino acid sequence corresponding to the sequence of an antibody produced by a human or human cell, or originating from a non-human source that utilizes human antibody repertoires or other human antibody encoding sequences. This definition of a "human antibody" specifically excludes a humanized antibody that contains antigen-binding residues not found in a human antibody. The term "a human-derived Fc fragment" means the C-terminal region of a human- derived immunoglobulin heavy chain, which comprises at least a portion of the hingeregion, the CH2- and CH3-domains. In one of the embodiments, the Fc region of thehuman IgG heavy chain spans from approximately Cys226 or Pro230 to the carboxyl terminus of the heavy chain. The C-terminal lysine residue (Lys447) of the Fc region may or may not be present. Unless otherwise indicated herein, the numbering of amino acid residues in the Fc region or constant region follows the EU numbering scheme, also referred to as the EU index, as described in KABAT E. A., Sequences of proteins of immunological interest, US Department of Health and Human Services, Public Health Service, National Institutes of Health, 1991, N. 91. The Fc region consists of two heavy chain Fc region polypeptides that can be covalently linked to each other through the hinge region cysteines that participate in disulfide bond formation between the polypeptides. The term "FcRn" means a human neonatal Fc receptor. FcRn function is to rescue IgG from the lysosomal degradation pathway, resulting in reduced clearance and increased half-life. FcRn is a heterodimeric protein consisting of two polypeptides: a 50 kDa major histocompatibility complex class I-like protein (α-FcRn), and a 15 kDa β2-microglobulin (β2m). FcRn binds with high affinity to the CH2-CH3 portion of the IgG Fc region. The interaction between IgG and FcRn is strictly pH-dependent and occurs in a stoichiometric ratio of 1:2, where one IgG molecule binds two FcRn molecules via its two heavy chains(HUBER A. H. et al., Crystallization and stoichiometry of binding of a complex between a ratintestinal Fc receptor and Fc, Journal of molecular biology, 1993, V. 230, N. 3, p.1077-1083). FcRn binding occurs in the endosome at acidic pH (pH < 6.5), and IgG is released on the cell surface at neutral pH (pH ~7.4). The pH dependent nature of this interaction facilitates FcRn-mediated protection of IgG molecules entering cells via pinocytosis from intracellular degradation through binding to the receptor under acidic conditions within endosomes. Furthermore, FcRn promotes the return of IgG back to the cell surface and subsequent release into the bloodstream following exposure of the FcRn-IgG complex to a neutral pH environment outside the cell. The term "FcRn-binding portion of the Fc region" means a portion of an antibody heavy chain polypeptide, which spans starting from about position 243 according to EU numbering to position 261 according to EU numbering, and from about position 275 according to EU numbering to position 293 according to EU numbering, and from about position 302 according to EU numbering to position 319 according to EU numbering, and from about position 336 according to EU numbering to position 348 according to EU numbering, and from about position 367 according to EU numbering to position 393 according to EU numbering and position 408 according to EU numbering, and from about position 424 according to EU numbering to position 440 according to EU numbering. In one of the embodiments, one or more of the following amino acid residues according to EU numbering numbering of Kabat, are changed: F243, P244, P245 P, K246, P247, K248, D249, T250, L251, M252, I253, S254, R255, T256, P257, E258, V259, T260, C261, F275, N276, W277, Y278, V279, D280, V282, E283, V284, H285, N286, A287, K288, T289, K290, P291, R292, E293, V302, V303, S304, V305, L306, T307, V308, L309, H310, Q311, D312, W313, L314, N315, G316, K317, E318, Y319, I336, S337, K338, A339, K340, G341, Q342, P343, R344, E345, P346, Q347, V348, C367, V369, F372, Y373, P374, S375, D376, I377, A378, V379, E380, W381, E382, S383, N384, G385, Q386, P387, E388, N389, Y391, T393, S408, S424, C425, S426, V427, M428, H429, E430, A431, L432, H433, N434, H435, Y436, T437, Q438, K439 and S440 (EU numbering). The term “a human IgG Fc fragment polypeptide” relates to an amino acid sequence resulting from at least one amino acid alteration within a native Fc region polypeptide of a human IgG, or Fc region polypeptide of a wild-type human IgG. The terms "heterodimer" or "heterodimeric" mean a molecule comprising twopolypeptide chains (e.g. having comparable lengths), wherein the two polypeptide chainshave amino acid sequences differing in at least one amino acid residue at matching positions, wherein the matching position is defined according to the EU index of Kabat. The terms "homodimer" and "homodimeric" mean a molecule comprising two polypeptide chains of comparable lengths, wherein the two polypeptide chains have amino acid sequences which are identical at matching positions, wherein the matching positions are defined according to the EU index of Kabat. An "individual" or a "subject" is a mammal. Mammals include, but are not limited to domesticated animals (e.g., bovine, sheep, cats, dogs and horses), primates (e.g., humansand non-human primates such as monkeys), rabbits and rodents (e.g., mice and rats). Insome embodiments, the individual or subject is a human. An "isolated" nucleic acid relates to a nucleic acid molecule that is separated from the components of its natural environment. The "isolated nucleic acid" includes a nucleic acid molecule comprised in cells that normally contain a nucleic acid molecule, but thenucleic acid molecule exists outside of a chromosome, or at a location on a chromosomethat is different from its natural location on the chromosome. According to the present invention, a “nucleic acid” or a “nucleic acid molecule” should be understood as a polynucleotide molecule, which may be of the DNA or RNA type, preferably of the DNA type, and, in particular, may be double-stranded. It can be of natural or synthetic origin. Synthetic nucleic acids are generated in vitro. Examples of such synthetic nucleic acids are those wherein the codons that encode a polypeptide(s), in particular, the Fc fragment polypeptide of the invention, have been optimized in accordance with the host organism where it is to be expressed (for example, by replacing the codons with more or most preferred codons based on the codon usage frequency tablesfor a similar host organism, or for the group to which the similar host organism belongs,compared to the original host). Codon optimization methods are well known to those skilled in the art. For the purposes of the present invention, the terms "nucleic acid" and "polynucleotide" are used in the same meaning and are synonymous. For example, the phrase "coding nucleic acid" is identical to the phrase "coding polynucleotide". A DNA, a polypeptide or protein "comprising" or "containing" a particular sequence 'X', as used throughout the text, relates to the DNA or protein comprising or containing at least the sequence 'X', thus, other nucleotide or amino acid sequences may be included atthe 5'-(or N-terminal) and / or 3'-(or C-terminal) end, e.g., a selectable marker, and / or a 5'-leader sequence or a 3'-trailer sequence. Similarly, the use of the term “comprise,” “comprising,” or “comprises” throughout this specification or appended claims is intended to include the specified number or step, or group of numbers or steps, but does not exclude any other number or step, or group of numbers or steps. The term "vector" as used herein relates to a nucleic acid molecule that is able to reproduce another nucleic acid to which it is linked. The term includes a vector as a self- replicating nucleic acid structure, including a "cloning vector", as well as a vector integrated into the genome of the host cell into which it is introduced. Some vectors are capable of directing expression of nucleic acids to which they are operably linked. Such vectors are referred to herein as "expression vectors." The terms "host cell", "host cell line", and "host cell culture" are used interchangeably and refer to the cells into which an exogenous nucleic acid has been introduced, including the progeny of such cells. Host cells include "transformants" and "transfected cells", which include the primary transfected cell and progeny cells thereof, regardless of the number of passages. The progeny may not be completely identical to the parent cell in terms of nucleic acid composition, and may comprise mutations. Mutant progeny having the same function or biological activity the original transfected cell is screened or selected for, is encompassed by the present invention. “Percent of (%) amino acid sequence identity” with respect to a reference polypeptide sequence is defined as the percentage of amino acid residues in a candidate sequence that are identical to amino acid residues in the reference polypeptide sequence after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and excluding any conservative substitutions as part of the sequence identity. In the context of this document, "percent identity" between two amino acid sequences means the percentage of identical amino acids between the two sequences to be compared, obtained by optimal alignment of said sequences, wherein said percentage is purely statistical and the differences between the two sequences are distributed randomly across the amino acid sequences. In the context of this document, "best alignment" or "optimal alignment" means that a specified percent identity (see below) is the highest for said alignment. Sequence comparisons between two amino acid sequences are typically performed by comparing the previously optimally-aligned sequences; this comparison is performed over comparison sites to identify and compare local regions of sequence similarity. In addition to the manual method, the most optimal alignment for the sequences to be compared can be achieved by virtue of the local homology and general homology search algorithm, using software that implements suchalgorithms (GAP, BESTFIT, BLAST Р, BLAST N, FASTA, T FAST А), and using MUSCLEmultiple sequence alignment algorithms (EDGAR R. C., MUSCLE: multiple sequence alignment with high accuracy and high throughput, Nucleic acids research, 2004, V.32, N.5, p.1792-1797).For the best alignment, it may be preferable to use BLAST software with the BLOSUM 62matrix. Percent identity between two amino acid sequences is determined by comparing the two given optimally-aligned sequences, wherein the amino acid sequences may comprise additionsand deletions relative to the reference sequence to achieve the optimal alignment between thetwo given sequences. Percent identity is calculated by determining the number of identical positions between the two given sequences, dividing this number by the total number of the positions compared, and multiplying the result by 100 to obtain the percent identity between the two given sequences. The term "peptide linker" as used herein means a peptide with different amino acid sequences that, in one of the embodiments, is of synthetic origin. In one of the embodiments, the peptide linker is a peptide having an amino acid sequence of at least 30 amino acids in length, in one of the embodiments, having an amino acid sequence of atleast 32-50 amino acids in length. In one of the embodiments, the peptide linker is apeptide having an amino acid sequence of 32-40 amino acids in length. In one of the embodiments, the peptide linker is (GxS)n, where G means glycine, S means serine (x is 3, n is 8, 9, or 10; or x is 4, and n is 6, 7, or 8), In one of the embodiments, x is 4, n is 6 or 7, In one of the embodiments, x is 4, n is 7. In one of the embodiments, the peptide linker is (G4S)6G2. The term "physiologically active molecule" means a molecule having any kind ofphysiological activity in vivo, functioning to regulate genetic expression and physiologicalfunction, and to correct abnormal conditions caused by deficiency or excess secretion of asubstance participating in the regulation of in vivo functions.The term "physiologically active polypeptide" as used herein refers collectively to polypeptides having any kind of physiological activity in vivo, typically having a polypeptide structure, and having different physiological activities. Physiologically active polypeptides include polypeptides that function to regulate genetic expression and physiological function, and to correct abnormal conditions caused by deficiency or excess secretion of a substance that participates in the regulation of in vivo functions. Physiologically active polypeptides may include conventional protein therapeutic agents. The physiologically active polypeptide may be selected from the group consisting of, inter alia, the following: glucagon-like peptide-1 (GLP-1), granulocyte colony-stimulating factor (G-CSF), human growth hormone (hGH), erythropoietin (EPO), glucagon, oxyntomodulin, insulin, growth hormone-releasing hormone, growth hormone-releasing peptide, interferons, interferon receptors, G protein-coupled receptor, interleukins, interleukin receptors, enzymes, interleukin binding proteins, cytokine binding proteins, macrophage activating factor, macrophage peptide, B-cell factor, T-cell factor, protein A, allergy inhibitor, cell necrosis glycoproteins, immunotoxin, lymphotoxin, tumor necrosis factor, tumor suppressors, metastatic growth factor, alpha-1 antitrypsin, albumin, α-lactalbumin, apolipoprotein-E, highly glycosylated erythropoietin, angiopoietins, hemoglobin, thrombin, thrombin receptor-activating peptide,thrombomodulin, blood factors VII, VIIa, VIII, IX, and XIII, and XIII, plasminogen activatingfactor, fibrin binding peptide, urokinase, streptokinase, hirudin, protein C, C-reactive protein, renin inhibitor, collagenase inhibitor, superoxide dismutase, leptin, platelet-derived growth factor, epithelial growth factor, epidermal growth factor, angiostatin, angiotensin, bone growth factor, bone growth stimulating protein, calcitonin, atriopeptin, cartilage growth inducing factor, elcatonin, connective tissue activating factor, tissue factor pathway inhibitor, follicle-stimulating hormone, luteinizing hormone, luliberin, nerve growth factors, parathyroid hormone, relaxin, secretin, somatomedin, insulin-like growth factor, adrenal cortex hormone, cholecystokinin, pancreatic polypeptide, gastrin-releasing peptide, corticotropin-releasing hormone, thyrotropin, autotaxin, lactoferrin, myostatin, cell surface antigens, vaccine antigens of viral origin, monoclonal antibodies, polyclonal antibodies and antibody fragments. Preferably, the physiologically active polypeptide can be selected from the group consisting of the following: glucagon-like peptide-1 (GLP-1), granulocyte colony-stimulating factor (G-CSF), human growth hormone (hGH), erythropoietin (EPO), glucagon, oxyntomodulin, insulin, insulin analogs and derivatives thereof. The term "insulin" for the purposes of the present invention means the human insulin hormone. Human insulin consists of two polypeptide chains: the A chain and B chain. The A chain is a 21-amino acid peptide, and the B chain is a 30-amino acid peptide, and the two chains are linked together by disulfide bridges: the first bridge is formed between the cysteine at position 7 in the A chain and the cysteine at position 7 in the B chain, and the second bridge is between the cysteine at position 20 in the A chain and the cysteine at position 19 in the B chain. The third bridge is between the cysteines at positions 6 and 11 in the A chain. The term "insulin analog" for the purposes of the present invention means a modified insulin with one or more amino acid residues of insulin replaced by other amino acid residues, and / or one or more amino acid residues removed from the insulin, and / or one or more amino acid residues added and / or inserted into the insulin. Preferred insulinanalogs of the invention include, without limitations, e.g., aspart (i.e., human insulinAspB28) and insulin lispro (i.e., human insulin LysB28, ProB29), and insulin glulisine (LysB3, GluB29 human insulin), among others. Furthermore, the term "physiologically active polypeptide" as used herein is intended to include not only naturally occurring physiologically active polypeptides, but also the agonists, precursors, derivatives, fragments or variants of each of the polypeptides. The term "non-peptide linker" as used herein relates to a biocompatible polymer comprised of two or more repeating units linked together, wherein the repeating units are linked together by any non-peptide covalent bond. This non-peptide linker may have two ends or three ends. For the purposes of the present invention, the term "drug" relates to a substance or mixture of substances of synthetic or natural origin, presented in a dosage form, including, butnot limited to the form of a tablet, capsule, solution, ointment, aerosol, etc., used for theprevention, diagnostics, and treatment of diseases. The term "pharmaceutical composition" relates to a preparation in a form that facilitates effective execution of the biological activity of the active ingredient contained therein, and does not comprise any additional components that are unacceptably toxic to a subject to which the composition is to be administered. A "pharmaceutically acceptable carrier" relates to an ingredient in a pharmaceutical composition that is different from the active ingredient and is nontoxic to a subject. A pharmaceutically acceptable carrier includes, but is not limited to a buffer, excipient, stabilizer, or preservative. As used herein, the term "treatment" (or a "therapy") relates to the clinicalintervention in an attempt to change the natural course of a disease in an individual being treated, and it may be carried out either for the purpose of prevention, or during the course of treatment of a clinical condition. Desirable effects of treatment include, but are notlimited to, preventing occurrence or recurrence of disease, alleviation of symptoms,minimizing any direct or indirect pathological consequences of the disease, preventing metastasis, decreasing the rate of disease progression, amelioration of symptoms or palliation of the disease state, and remission or improved prognosis. The term "instructions for use" is used to refer to the instructions typically included in commercial packages of therapeutic products that contain information on the indications, usage, dosages, administration, combination therapy, contraindications and / or warnings concerning the use of such therapeutic products. Embodiments of the invention The present invention provides Fc fragment polypeptides that have modified properties in relation to binding with human Fc receptors compared to the corresponding wild-type Fc fragment. Said Fc fragment polypeptides comprise specific amino acid mutations in their CH2 and / or CH3 domains. These mutations were found to allowproducing Fc fragment polypeptide variants with tailored in vivo half-lives.In one embodiment of the present invention, an Fc fragment polypeptide is the Fc fragment of the human IgG class. In one embodiment of the present invention, the Fc fragment polypeptide is the Fc fragment of the human IgG1 class. In one embodiment of the present invention, the Fc fragment polypeptide is the Fc fragment of the human IgG2 class. In one embodiment of the present invention, the Fc fragment polypeptide is the Fc fragment of the human IgG3 class. In one embodiment of the present invention, the Fc fragment polypeptide is the Fc fragment of the human IgG4 class. In one embodiment of the present invention, a pair of two Fc fragment polypeptides can form a functional dimer. In one embodiment of the present invention, a human Fc receptor is selected fromthe human neonatal Fc receptor and human Fcγ receptor. In one embodiment of the present invention, the human Fcγ receptor is selected from the human FcgRI receptor, human FcgRII receptor, and human FcgRIII receptor. In one embodiment of the present invention, the Fc fragment polypeptide differs from a wild-type Fc fragment polypeptide by 1 amino acid residue, or 2, or 3, or 4, or 5, or 6, or 7, or 8, or 9, or 10, or 11, or 12 amino acid residues at the corresponding position(s) according to the Kabat EU index numbering system. In one embodiment of the present invention, the Fc fragment polypeptide comprises one or more mutations at positions corresponding to positions 222, 223, 224, 225, 226-238, 226, 234, 235, 236, 237, 239, 250, 252, 252, 254, 256, 262, 264, 264, 264, 268, 272, 274, 283, 285, 286, 288, 294, 296, 297, 300, 302, 303, 308, 308, 309, 309, 312, 315, 327, 328, 330, 330, 331, 339, 355, 356, 358, 378, 397, 409, 419, 427, 428, 434, 434, 445, and 444-446, according to the Kabat EU index numbering system. In one embodiment of the present invention, the Fc fragment polypeptide comprises one or more of the following mutations or combinations of mutations: K222D, C223K, C224T, V225H, E226-P238del, E226W, P234E, 234insF235, V235L, A236G, G237M, S239E, T250Q, M252Y, M252W, S254T, T256E, V262W, V264del, V264D, V264E, H268Q, E272Q, Q274K, E283Q, H285E, N286E, K288M, E294Q, F296Y, N297D, F300Y, V302W, V303del, V308W, V308F, V309del, V309L, D312N, N315D, G327A, L328G, A330S, A330F, P331S, T339A, R355Q, D356E, L358M, S378A, M397V, K409R, Q419E, V427L, M428L, N434Y, N434W, P445L, and S444-G446del, according to the Kabat EU index numbering system. In one preferred embodiment of the present invention, the Fc fragment polypeptide comprises the combination of mutations corresponding to the mutations V262W, V264del, V302W, V303del, V308W, V309del, and S378A, according to the Kabat EU index numbering system. In one preferred embodiment of the present invention, the Fc fragment polypeptide comprises the combination of mutations corresponding to the mutations M252Y, S254T, T256E, and S378A, according to the Kabat EU index numbering system. In one preferred embodiment of the present invention, the Fc fragment polypeptide comprises the combination of mutations corresponding to the mutations T250Q, M428L, and S378A, according to the Kabat EU index numbering system. In one preferred embodiment of the present invention, the Fc fragment polypeptide comprises the combination of mutations corresponding to the mutations M252Y, T256E, V264D, N297D, V308F, S378A, and N434Y, according to the Kabat EU index numbering system. In one preferred embodiment of the present invention, the Fc fragment polypeptide comprises the combination of mutations corresponding to the mutations P234E, 234insF235, V235L, A236G, T256E, V264D, H268Q, H285E, N286E, N297D, F300Y, V309L, A330S, P331S, R355Q, S378A, M397V, K409R, Q419E, M428L, and P445L, according to the Kabat EU index numbering system. In one preferred embodiment of the present invention, the Fc fragment polypeptide comprises the combination of mutations corresponding to the mutations M252W, T256E, S378A, M428L, and N434Y, according to the Kabat EU index numbering system. In one preferred embodiment of the present invention, the Fc fragment polypeptide comprises the combination of mutations corresponding to the mutations S239E, T256E, V264E, A330F, S378A, and N434Y, according to the Kabat EU index numbering system. In one preferred embodiment of the present invention, the Fc fragment polypeptide comprises the combination of mutations corresponding to the mutations ins221D, V222K, ins223T, E224H, ins225W, G237M, T250Q, M252Y, and V264D, according to the Kabat EU index numbering system. In one preferred embodiment of the present invention, the Fc fragment polypeptide comprises the combination of mutations corresponding to the mutations M252Y, T256E, V264E, N297D, V308F, A330F, S378A, and N434W, according to the Kabat EU index numbering system. In one preferred embodiment of the present invention, the Fc fragment polypeptide comprises the combination of mutations corresponding to the mutations T250Q, M252Y, T256E, V264E, V308F, A330F, S378A, and N434W, according to the Kabat EU index numbering system. In one embodiment of the present invention, the Fc fragment polypeptide has an amino acid sequence that is at least 90% identical to the amino acid sequence of the human IgG2 Fc fragment. In one embodiment of the present invention, the Fc fragment polypeptide has an amino acid sequence that is at least 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99% identical to the amino acid sequence of SEQ ID NO:1. In one preferred embodiment of the present invention, the Fc fragment polypeptide comprises the amino acid sequence X1X2X3X4X5CPPCPAPX13X14X15X16X17PX19VFLFPPKPKDX30LX32IX34RX36PEVTCVVX44D VSX48EDPEVQFNWYVDGVEVX65X66AKTKPREEQFX77STX80RVVSVLTX88X89HQDWLN GKEYKCKVSNKGLPX110X111IEKTISKX119KGQPREPQVYTLPPSX135EEMTKNQVSLTCL VKGFYPSDIAVEWESNGQPENNYKTTPPX177LDSDGSFFLYSX189LTVDKSRWQX199GNV FSCSVX208HEALHX214HYTQKSLSLSX225G set forth in SEQ ID NO:2, wherein X1 is E or D, X2is K or absent, X3is T or absent, X4is H or absent, X5is W or absent, X13is P or E, X14is F or absent, X15is V or L, X16is A or G, X17is G or M, X19is S or E, X30is T or Q, X32is M, Y, or W, X34is S or T, X36is T or E, X44is V, E, or D, X48is H or Q, X65is H or E, X66is N or E, X77is N or D, X80is F or Y, X88is V or F, X89is V or L, X110is A, F, or S, X111 is P or S, X119is T or A, X135is R or Q, X177is M or V, X189 is K or R, X199is Q or E, X208is M or L, X214is N, Y, or W, and X225is P or L. In one embodiment of the present invention, the Fc fragment polypeptide comprises the amino acid sequence X1X2X3X4X5CPPCPAPX13X14X15X16X17PX19VFLFPPKPKDX30LX32IX34RX36PEVTCVVX44D VSX48EDPEVQFNWYVDGVEVX65X66AKTKPREEQFX77STX80RVVSVLTX88X89HQDWLN GKEYKCKVSNKGLPX110X111IEKTISKX119KGQPREPQVYTLPPSX135EEMTKNQVSLTCL VKGFYPSDIAVEWESNGQPENNYKTTPPX177LDSDGSFFLYSX189LTVDKSRWQX199GNV FSCSVX208HEALHX214HYTQKSLSLSX225G set forth in SEQ ID NO:2, wherein X1is E, X2is absent, X3is absent, X4is absent, X5is absent, X13is P, X14is absent, X15is V, X16is A, X17is G, X19is S, X30is T, X32is Y, X34is T, X36is E, X44is V, X48is H, X65is H, X66is N, X77is N, X80is F, X88is V, X89is V, X110is A, X111is P, X119is T, X135is R, X177is M, X189is K, X199is Q, X208 is M, X214 is N, and X225 is P. In one embodiment of the present invention, the Fc fragment polypeptide comprises the amino acid sequence X1X2X3X4X5CPPCPAPX13X14X15X16X17PX19VFLFPPKPKDX30LX32IX34RX36PEVTCVVX44D VSX48EDPEVQFNWYVDGVEVX65X66AKTKPREEQFX77STX80RVVSVLTX88X89HQDWLN GKEYKCKVSNKGLPX110X111IEKTISKX119KGQPREPQVYTLPPSX135EEMTKNQVSLTCL VKGFYPSDIAVEWESNGQPENNYKTTPPX177LDSDGSFFLYSX189LTVDKSRWQX199GNV FSCSVX208HEALHX214HYTQKSLSLSX225G set forth in SEQ ID NO:2, wherein X1is E, X2is absent, X3is absent, X4is absent, X5is absent, X13is P, X14is absent, X15is V, X16is A, X17is G, X19is S, X30is Q, X32is M, X34is S, X36is T, X44is V, X48is H, X65is H, X66is N, X77is N, X80is F, X88is V, X89is V, X110is A, X111is P, X119is T, X135is R, X177is M, X189is K, X199is Q, X208is L, X214is N, and X225is P. In one embodiment of the present invention, the Fc fragment polypeptide comprises the amino acid sequence X1X2X3X4X5CPPCPAPX13X14X15X16X17PX19VFLFPPKPKDX30LX32IX34RX36PEVTCVVX44D VSX48EDPEVQFNWYVDGVEVX65X66AKTKPREEQFX77STX80RVVSVLTX88X89HQDWLN GKEYKCKVSNKGLPX110X111IEKTISKX119KGQPREPQVYTLPPSX135EEMTKNQVSLTCL VKGFYPSDIAVEWESNGQPENNYKTTPPX177LDSDGSFFLYSX189LTVDKSRWQX199GNV FSCSVX208HEALHX214HYTQKSLSLSX225G set forth in SEQ ID NO:2, wherein X1is E, X2is absent, X3is absent, X4is absent, X5is absent, X13is P, X14is absent, X15is V, X16is A, X17is G, X19is S, X30is T, X32is Y, X34is S, X36is E, X44is D, X48is H, X65is H, X66is N, X77is D, X80is F, X88is F, X89is V, X110is A, X111is P, X119is T, X135is R, X177is M, X189is K, X199is Q, X208is M, X214is Y, and X225is P. In one embodiment of the present invention, the Fc fragment polypeptide comprises the amino acid sequence X1X2X3X4X5CPPCPAPX13X14X15X16X17PX19VFLFPPKPKDX30LX32IX34RX36PEVTCVVX44D VSX48EDPEVQFNWYVDGVEVX65X66AKTKPREEQFX77STX80RVVSVLTX88X89HQDWLN GKEYKCKVSNKGLPX110X111IEKTISKX119KGQPREPQVYTLPPSX135EEMTKNQVSLTCL VKGFYPSDIAVEWESNGQPENNYKTTPPX177LDSDGSFFLYSX189LTVDKSRWQX199GNV FSCSVX208HEALHX214HYTQKSLSLSX225G set forth in SEQ ID NO:2, wherein X1is E, X2is absent, X3is absent, X4is absent, X5is absent, X13is E, X14is F, X15is L, X16is G, X17is G, X19is S, X30is T, X32is M, X34is S, X36is E, X44is D, X48is Q, X65is E, X66is E, X77is D, X80is Y, X88is V, X89is L, X110is S, X111is S, X119is A, X135is Q, X177is V, X189is R, X199is E, X208is L, X214 is N, and X225 is L. In one embodiment of the present invention, the Fc fragment polypeptide comprises the amino acid sequence X1X2X3X4X5CPPCPAPX13X14X15X16X17PX19VFLFPPKPKDX30LX32IX34RX36PEVTCVVX44D VSX48EDPEVQFNWYVDGVEVX65X66AKTKPREEQFX77STX80RVVSVLTX88X89HQDWLN GKEYKCKVSNKGLPX110X111IEKTISKX119KGQPREPQVYTLPPSX135EEMTKNQVSLTCL VKGFYPSDIAVEWESNGQPENNYKTTPPX177LDSDGSFFLYSX189LTVDKSRWQX199GNV FSCSVX208HEALHX214HYTQKSLSLSX225G set forth in SEQ ID NO:2, wherein X1is E, X2is absent, X3is absent, X4is absent, X5is absent, X13is P, X14is absent, X15is V, X16is A, X17is G, X19is S, X30is T, X32is W, X34is S, X36is E, X44is V, X48is H, X65is H, X66is N, X77is N, X80is F, X88is V, X89is V, X110is A, X111is P, X119is T, X135is R, X177is M, X189is K, X199is Q, X208is L, X214is Y, and X225is P. In one embodiment of the present invention, the Fc fragment polypeptide comprises the amino acid sequence X1X2X3X4X5CPPCPAPX13X14X15X16X17PX19VFLFPPKPKDX30LX32IX34RX36PEVTCVVX44D VSX48EDPEVQFNWYVDGVEVX65X66AKTKPREEQFX77STX80RVVSVLTX88X89HQDWLN GKEYKCKVSNKGLPX110X111IEKTISKX119KGQPREPQVYTLPPSX135EEMTKNQVSLTCL VKGFYPSDIAVEWESNGQPENNYKTTPPX177LDSDGSFFLYSX189LTVDKSRWQX199GNV FSCSVX208HEALHX214HYTQKSLSLSX225G set forth in SEQ ID NO:2, wherein X1is E, X2is absent, X3is absent, X4is absent, X5is absent, X13is P, X14is absent, X15is V, X16is A, X17is G, X19is E, X30is T, X32is M, X34is S, X36is E, X44is E, X48is H, X65is H, X66is N, X77is N, X80is F, X88is V, X89is V, X110is F, X111is P, X119is T, X135is R, X177is M, X189is K, X199is Q, X208is M, X214is Y, and X225is P. In one embodiment of the present invention, the Fc fragment polypeptide comprises the amino acid sequence X1X2X3X4X5CPPCPAPX13X14X15X16X17PX19VFLFPPKPKDX30LX32IX34RX36PEVTCVVX44D VSX48EDPEVQFNWYVDGVEVX65X66AKTKPREEQFX77STX80RVVSVLTX88X89HQDWLN GKEYKCKVSNKGLPX110X111IEKTISKX119KGQPREPQVYTLPPSX135EEMTKNQVSLTCL VKGFYPSDIAVEWESNGQPENNYKTTPPX177LDSDGSFFLYSX189LTVDKSRWQX199GNV FSCSVX208HEALHX214HYTQKSLSLSX225G set forth in SEQ ID NO:2, wherein X1is D, X2is K, X3is T, X4is H, X5is W, X13is P, X14is absent, X15is V, X16is A, X17is M, X19is S, X30is Q, X32is Y, X34is S, X36is T, X44is D, X48is H, X65is H, X66is N, X77is N, X80is F, X88is V, X89is V, X110is A, X111is P, X119is T, X135is R, X177is M, X189is K, X199is Q, X208is M, X214is N, and X225 is P. In one embodiment of the present invention, the Fc fragment polypeptide comprises the amino acid sequence X1X2X3X4X5CPPCPAPX13X14X15X16X17PX19VFLFPPKPKDX30LX32IX34RX36PEVTCVVX44D VSX48EDPEVQFNWYVDGVEVX65X66AKTKPREEQFX77STX80RVVSVLTX88X89HQDWLN GKEYKCKVSNKGLPX110X111IEKTISKX119KGQPREPQVYTLPPSX135EEMTKNQVSLTCL VKGFYPSDIAVEWESNGQPENNYKTTPPX177LDSDGSFFLYSX189LTVDKSRWQX199GNV FSCSVX208HEALHX214HYTQKSLSLSX225G set forth in SEQ ID NO:2, wherein X1is E, X2is absent, X3is absent, X4is absent, X5is absent, X13is P, X14is absent, X15is V, X16is A, X17is G, X19is S, X30is T, X32is Y, X34is S, X36is E, X44is E, X48is H, X65is H, X66is N, X77is D, X80is F, X88is F, X89is V, X110is F, X111is P, X119is T, X135is R, X177is M, X189is K, X199is Q, X208is M, X214is W, and X225is P. In one embodiment of the present invention, the Fc fragment polypeptide comprises the amino acid sequence X1X2X3X4X5CPPCPAPX13X14X15X16X17PX19VFLFPPKPKDX30LX32IX34RX36PEVTCVVX44D VSX48EDPEVQFNWYVDGVEVX65X66AKTKPREEQFX77STX80RVVSVLTX88X89HQDWLN GKEYKCKVSNKGLPX110X111IEKTISKX119KGQPREPQVYTLPPSX135EEMTKNQVSLTCL VKGFYPSDIAVEWESNGQPENNYKTTPPX177LDSDGSFFLYSX189LTVDKSRWQX199GNV FSCSVX208HEALHX214HYTQKSLSLSX225G set forth in SEQ ID NO:2, wherein X1is E, X2is absent, X3is absent, X4is absent, X5is absent, X13is P, X14is absent, X15is V, X16is A, X17is G, X19is S, X30is Q, X32is Y, X34is S, X36is E, X44is E, X48is H, X65is H, X66is N, X77is N, X80is F, X88is F, X89is V, X110is F, X111is P, X119is T, X135is R, X177is M, X189is K, X199is Q, X208is M, X214is W, and X225is P. In one embodiment of the present invention, the Fc fragment polypeptide has an amino acid sequence that is at least 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99% identical to the amino acid sequence of SEQ ID NO:3. In one embodiment of the present invention, the Fc fragment polypeptide has an amino acid sequence that is at least 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99% identical to the amino acid sequence of SEQ ID NO:4. In one embodiment of the present invention, the Fc fragment polypeptide has an amino acid sequence that is at least 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99% identical to the amino acid sequence of SEQ ID NO:5. In one embodiment of the present invention, the Fc fragment polypeptide has an amino acid sequence that is at least 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99% identical to the amino acid sequence of SEQ ID NO:6. In one embodiment of the present invention, the Fc fragment polypeptide has an amino acid sequence that is at least 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99% identical to the amino acid sequence of SEQ ID NO:7. In one embodiment of the present invention, the Fc fragment polypeptide has an amino acid sequence that is at least 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99% identical to the amino acid sequence of SEQ ID NO:8. In one embodiment of the present invention, the Fc fragment polypeptide has an amino acid sequence that is at least 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99% identical to the amino acid sequence of SEQ ID NO:9. In one embodiment of the present invention, the Fc fragment polypeptide has an amino acid sequence that is at least 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99% identical to the amino acid sequence of SEQ ID NO:10. In one embodiment of the present invention, the Fc fragment polypeptide has an amino acid sequence that is at least 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99% identical to the amino acid sequence of SEQ ID NO:11. In one preferred embodiment of the present invention, the Fc fragment polypeptide has the amino acid sequence of SEQ ID NO:3. In one preferred embodiment of the present invention, the Fc fragment polypeptide has the amino acid sequence of SEQ ID NO:4. In one preferred embodiment of the present invention, the Fc fragment polypeptide has the amino acid sequence of SEQ ID NO:5. In one preferred embodiment of the present invention, the Fc fragment polypeptide has the amino acid sequence of SEQ ID NO:6. In one preferred embodiment of the present invention, the Fc fragment polypeptide has the amino acid sequence of SEQ ID NO:7. In one preferred embodiment of the present invention, the Fc fragment polypeptide has the amino acid sequence of SEQ ID NO:8. In one preferred embodiment of the present invention, the Fc fragment polypeptide has the amino acid sequence of SEQ ID NO:9. In one preferred embodiment of the present invention, the Fc fragment polypeptide has the amino acid sequence of SEQ ID NO:10. In one preferred embodiment of the present invention, the Fc fragment polypeptide has the amino acid sequence of SEQ ID NO:11. Binding to Fc receptors can be determined, e.g., by ELISA or surface plasmon resonance(SPR) using standard equipment such as the BIAcore device (GE Healthcare), and using Fc receptors that can be produced by recombinant expression. Alternatively, the binding affinity of the Fc domains or Fc domain-containing antibodies to the Fc receptors can be assessed using cell lines known to express specific Fc receptors, such as, among others, human NK cells expressing the FcγIIIa receptor. Binding to the Fc receptors can also be determined, e.g., by the label-free biolayerinterferometry (BLI) technology using ForteBio Octet system (see, e.g., TOBIAS R., MA W.,Analysis of FcRn-Antibody Interactions on the Octet Platform, ForteBio Appl Note 17, 2019,p.1-13; BAJARDI-TACCIOLI A. et al., Biolayer Interferometry-based FcγRIIa binding assay for a therapeutic antibody with strong effector function, Analytical biochemistry, 2020, V. 611, p.113842). The effector function of an Fc domain or an Fc domain-comprising antibody can be assessed by methods known in the art, e.g., by assessing the ADCC activity of the molecule of interest (CLYNES R. et al., Fc receptors are required in passive and active immunity to melanoma, Proceedings of the National Academy of Sciences, 1998, V. 95, N. 2, p.652-656). Alternatively, methods based on non-radioactive analysis can be used. Suitable effector cells for such assays include peripheral blood mononuclear cells (PBMCs) and natural killer (NK) cells. The skilled person will also know methods for analyzing FcRn binding and determiningin vivo clearance or half-life (PETKOVA S. B. et al., Enhanced half-life of geneticallyengineered human IgG1 antibodies in a humanized FcRn mouse model: potential application in humorally mediated autoimmune disease, International immunology, 2006, V.18, N.12, p.1759- 1769). According to one aspect, provided herein is a nucleic acid (polynucleotide) encoding a human IgG Fc fragment polypeptide as described herein. In some of the embodiments, the isolated nucleic acid (polynucleotide) encodes the full- length Fc region polypeptide of the invention as described herein. In other embodiments, the isolated nucleic acid (polynucleotide) encodes a polypeptide comprised in the Fc region polypeptide of the invention as described herein. In some embodiments, the polynucleotide or nucleic acid is DNA. In other embodiments, the polynucleotide of the present invention is RNA, e.g., in the form of a messenger RNA (mRNA). The RNA of the present invention can be single-stranded or double-stranded. The Fc fragment polypeptide variants of the invention can be produced by solid-phase peptide synthesis (e.g., Merrifield solid-phase synthesis) or by recombination. For recombinantproduction, one or more polynucleotides encoding the Fc fragment polypeptide, e.g., thepolypeptide described above, are isolated and inserted into one or more vectors for subsequent cloning and / or expression in a host cell. Said polynucleotide can be easily isolated and sequenced using conventional procedures. One of the subjects of the invention is a vector, preferably an expression vector, comprising one or more polynucleotides according to the invention. Methods well known to those skilled in the art can be used for constructing expression vectors comprising the Fc fragment polypeptide coding sequence along with suitabletranscriptional / translational control signals. These methods include in vitro recombinant DNAtechnologies, in vivo synthesis, and genetic recombination methods (see, e.g., THOMASON L.C. et al., Recombineering: genetic engineering in bacteria using homologous recombination, Current protocols in molecular biology, 2014, V. 106, N. 1, U.1.16). The expression vector may be part of a plasmid, a virus, or may be a nucleic acid fragment. The expression vector comprises an expression cassette in which a polynucleotide encoding an Fc fragment polypeptide (i.e., the coding region) is cloned in a way to provide its functional linkage with a promoter and / or other transcriptional or translational control elements. As used herein, a "coding region" is a nucleic acid portion consisting of codons that are translated into amino acids. Even though a "stop codon" (TAG, TGA, or TAA) is not translated into any amino acid, it can, if present, be considered part of the coding region, however anyflanking sequences, e.g., promoters, ribosome binding sites, transcription terminators, introns, 5'-and 3'-untranslated regions, etc., are not parts of the coding region. Two or more coding regionsmay be present in an individual polynucleotide construct, such as an individual vector, or inseparate polynucleotide constructs, e.g., in separate (different) vectors. Also, any vector maycomprise one or more coding regions, e.g., a vector of the present invention may encode one ormore polypeptides that are separated post- or co-translationally into final proteins by proteolytic cleavage. In one embodiment of the present invention, a vector, a polynucleotide or a nucleic acid of the present invention may encode heterologous coding regions, either fused or unfused with a polynucleotide encoding an Fc fragment polypeptide of the present invention, or variants or derivatives thereof. Heterologous coding regions include, but are not limited to, specializedelements or motifs such as a secretory signal peptide or a heterologous functional domain. Afunctional linkage is present when the coding region of a gene product, e.g., a polypeptide, is associated with one or more regulatory sequences such that expression of the gene product is under the influence or control of the regulatory sequence(s). Two DNA fragments (such as a polypeptide coding region and associated promoter) are “functionally linked”, or “operably linked” if induction of the promoter function results in transcription of mRNA encoding the desired gene product, and if the nature of the linkage between the two DNA fragments does not interfere with the ability of the expression control sequences to direct expression of the geneproduct, and does not interfere with the ability of the DNA template to be transcribed. Thus, apromoter region must be functionally linked to a nucleic acid encoding a polypeptide if the promoter is capable of transcribing the nucleic acid. The promoter may be a cell-specific promoter that supports significant levels of DNA transcription only in pre-selected cells. Othertranscriptional control elements other than promoters, e.g., enhancers, operators, repressors, andtranscription termination signals, can be operably linked to a polynucleotide to mediate cell- specific transcription. Suitable promoters and other transcriptional control regions are describedherein. A wide variety of transcriptional control regions are known to those skilled in the art.These include, but are not limited to, transcriptional control regions that function in vertebrate cells, such as, without limitation, segments of promoters and enhancers from cytomegaloviruses (e.g., the immediate early promoter in combination with intron A), simian virus 40 (e.g., the early promoter), and retroviruses (such as Rous sarcoma virus). Other transcriptional control regions include those derived from vertebrate genes such as actin, heat shock protein, bovine growth hormone, and rabbit β-globin, as well as other sequences that can control gene expression in eukaryotic cells. Further suitable transcriptional control regions include tissue-specific promoters and enhancers, and inducible promoters (e.g., tetracycline-inducible promoters). Similarly, a wide variety of translational control elements are known to those of ordinary skill in the art. These include, but are not limited to, ribosome binding sites, translation initiation and termination codons, and elements derived from viral systems (in particular, the internal ribosome entry site, or IRES, also referred to as the CITE sequence). The expression cassette may also include other specific structures such as an origin of replication and / or chromosomally integrated elements such as the long terminal repeats (LTRs) of retroviruses, or the inverted terminal repeats (ITRs) of adeno-associated virus (AAV).. In one embodiment of the present invention, the expression cassette may also include DNA or RNA encoding a short protein sequence that can be used to facilitate further purification (e.g., a histidine tag), or is intended to label the fusion protein, may be included within or at the ends of the polynucleotide encoding the Fc fragment polypeptide. In one embodiment of the present invention, the vector may further comprise, independently of each other, the following structural elements: a gene that confers tetracycline resistance to bacterial cells; a replication initiation site (ori); the ROP gene that regulates plasmid copy number; a transcription promoter (e.g., Tac-T7); a transcription terminator (e.g., rrnB1 B2 T1 txn); a LacI gene encoding a repressor of the Tac promoter. Also provided in the invention is a host cell comprising one or more polynucleotides of the invention. A host cell comprising one or more vectors of the invention is within the scope of the invention. The polynucleotides and vectors may have any of the features disclosed herein,individually or in combination. In one embodiment of the present invention, the host cellcomprises a vector (e.g., is transformed or transfected with the vector) comprising a polynucleotide that encodes an Fc fragment polypeptide of the invention. In the context of thepresent specification, the term "host cell" relates to any type of cellular system that can beengineered to produce the Fc fragment polypeptide of the invention, or fragments thereof. Host cells suitable for replication and maintaining expression of Fc fragment polypeptides are well known in the art. Such cells can be transfected or transduced as appropriate with a specific expression vector, and larger numbers of the vector-containing cells can be grown for seeding large-scale fermenters for producing the Fc fragment polypeptide in quantities sufficient for clinical use. Host cells that are useful include prokaryotic microorganisms such as E. coli, or various eukaryotic cells such as Chinese hamster ovary (CHO) cells, insect cells, or the like. For example, polypeptides can be produced in bacteria, particularly when there is no need for glycosylation. After expression, the polypeptide can be isolated from the bacterial cell paste into a soluble fraction, and can be further purified. In one embodiment of the present invention, eukaryotic organisms, such as filamentous fungi or yeast, can be used as hosts for the cloning or expression vectors that encode the polypeptide, including those fungal and yeast strains whose glycosylation pathways have been "humanized", thus allowing the production of a polypeptide with a partially or fully humanglycosylation pattern. (see GERNGROSS T. U., Advances in the production of humantherapeutic proteins in yeasts and filamentous fungi, Nature biotechnology, 2004, T. 22, N. 11, p.1409-1414; and LI H. et al., Optimization of humanized IgGs in glycoengineered Pichia pastoris, Nature biotechnology, 2006, V. 24, N. 2, p.210-215). Host cells useful for expressing (glycosylated) polypeptides can also be obtained from multicellular organisms (invertebrates and vertebrates). Exemplary invertebrate cells include insect cells; plant cells can also be used. Numerous baculovirus strains and corresponding insect cells suitable as their hosts, in particular, for Spodoptera frugiperda cells transfection, have been identified. Plant cell cultures can also be used as hosts. In one embodiment of the present invention, vertebrate cells can also be used as hosts. For example, mammalian cell lines adapted for suspension culture can be used. Other examples of suitable mammalian host cell lines include the SV40-transformed monkey kidney cell lineCV1 (COS-7); human embryonic kidney cell line, e.g., HEK293 (GRAHAM F. L. et al.,Characteristics of a human cell line transformed by DNA from human adenovirus type 5, Journal of general virology, 1977, V. 36, N. 1, p.59-72); baby hamster kidney cells (BHK); mouse Sertoli cells; monkey kidney cells (CV1); African green monkey kidney cells (VERO-76,); Human cervical carcinoma cells (HELA); canine kidney cells (MDCK); Buffalo rat liver cells (BRL 3A); human lung cells (W138); human liver cells (Hep G2); mouse mammary tumor cells(MMT 060562); TRI cells (see, e.g., MATHER J. P. et al., Culture of testicular cells in hormone-supplemented serum-free medium, Annals of the New York Academy of Sciences, 1982, V.383, p.44-68); MRC 5 cells and FS4 cells. In one embodiment of the present invention, mammalian host cell lines may be represented by Chinese hamster ovary (CHO) cells including dhfr-CHO cells (URLAUB G. et al., Isolation of Chinese hamster cell mutants deficient in dihydrofolate reductase activity, Proceedings of the National Academy of Sciences, 1980, V. 77, N. 7, p.4216-4220); andmyeloma cell lines such as Sp2 / 0, NS0, Р3Х63, Y0 (see, e.g., STEINITZ M. et al. (ed.)., Humanmonoclonal antibodies: Methods and Protocols, New York : Humana Press, 2014). One of the subjects of the invention is a method for producing an Fc fragmentpolypeptide according to the invention, wherein the method comprises culturing a host cell comprising one or more polynucleotides encoding the Fc fragment polypeptide according to the invention, and optionally isolating the Fc fragment polypeptide from the host cell (or the culture medium of the host cell). In one embodiment, the present invention further provides a method for producing an Fc fragment polypeptide of the present invention by using recombinant DNA technology, including the steps of: 1) providing a nucleotide sequence encoding the Fc fragment polypeptide; 2) inserting the nucleotide sequence of (1) into a suitable expression vector to produce a recombinant expression vector; 3) introducing the recombinant expression vector of (2) into a suitable host cell; 4) culturing the transfected host cell under conditions suitable for the expression; 5) collection and purification of the expressed product. The coding sequence can be introduced into the host cell by various methods known in the art, such as, without limitation, calcium phosphate precipitation, lipofection, electroporation, microinjection, viral infection, and the alkali metal ion method. Cultivation and expression in host cells is widely known in the art (see, e.g., GRAHAM,1977; LI, 2006). Cells and debris in suspension can be removed by centrifugation, and the supernatant is collected. In one embodiment of the present invention, the product can be expressed by cells as inclusion bodies and can be further concentrated, e.g., by tangential flow filtration or diafiltration, and purified by chromatography. Methods for purifying recombinant proteins, including those comprising Fc fragments ofantibodies, are known to a person skilled in the art (see, e.g., SHI Y. et al., Advantages of CE-SDS over SDS-PAGE in mAb purity analysis, Analytical Methods, 2012, V. 4, N. 6, p. 1637- 1642). The Fc fragment polypeptide obtained as described above can be purified to substantially uniform properties, e.g., can be represented by a single band or specific bands in SDS-PAGE (sodium dodecyl sulfate polyacrylamide gel) electrophoresis. The supernatant is first concentrated. The concentrated supernatant can be further purified by gel chromatography or ion exchange chromatography, such as anion exchange chromatography or cation exchange chromatography. The gel matrix can be a matrix commonly used for protein purification, such as agarose, dextran, polyamide, etc. Finally, the purified product can be further polished by methods such as hydroxyapatite adsorption chromatography, metal chelate chromatography, hydrophobic interactionchromatography, and reversed phase high performance liquid chromatography, etc. All of theabove purification steps can be used in various combinations to ultimately obtain proteins of essentially uniform purity. The expressed Fc fragment polypeptide can be purified using an affinity chromatography column containing an antibody, a receptor or a ligand specific for the Fc fragment polypeptide. Depending on the nature of the used affinity column, the Fc fragment polypeptide bound to the affinity column can be eluted using conventional methods such as high salt buffer, pH change, etc. In one embodiment of the present invention, chromatography purification of the Fcfragment polypeptide can be optimized by using an auxiliary domain, e.g., His-tag fused with thepolypeptide N- or C-terminus (KOSOBOKOVA E. N. et al., Auxiliary domains in recombinant proteins (a review), Biochemistry, 2016, Vol.81, No.3, pp.299-314). In one embodiment of the present invention, the auxiliary domain may be a SUMOpolypeptide (see, e.g., BUTT T.R. et al., SUMO fusion technology for difficult-to-expressproteins, Protein expression and purification, 2005, V.43, N.1, p.1-9). The present invention also relates to constructs comprising the above-disclosed Fc fragment polypeptide linked to a therapeutically active molecule, including a polypeptide. In the Fc fragment polypeptide coupled to a therapeutically active molecule according to the invention, the Fc fragment polypeptide may be genetically fused to a physiologically active polypeptide, or may be chemically conjugated to a physiologically active polypeptide. A genetic fusion of the Fc region polypeptide with a physiologically active polypeptide can be designed in such a way as to fuse the sequence of the Fc region polypeptide with the polypeptide directly, or indirectly through a linker sequence. The linker composition and length can be determined using methods well known in the art, and their effectiveness can be assessed. Specific linker peptides are described herein. If desired, additional sequences, e.g., an endopeptidase recognition sequence, can also be included at the cleavage site to separate the individual fusion components. In addition, the fusion polypeptide of the invention can be chemically synthesized using polypeptide synthesis methods well known in the art (e.g., Merrifield solid-phase synthesis). The Fc fragment polypeptide of the present invention may be fused to a physiologically active polypeptide directly, or through a linker peptide comprising one or more amino acids, typically about 2-20 amino acids, to form a fusion construct. Linker peptides are known in the artand described herein. Suitable non-immunogenic linker peptides include, e.g., (G4S)n, (SG4)n,(G4S)nor G4(SG4)n, where "n" typically denotes an integer from 1 to 10, typically from 2 to 4. In one embodiment of the invention, the linker peptide consists of at least 5 amino acids, in one embodiment of the invention it consists of 5-100 amino acids, in a further embodiment of the invention it consists of 10-50 amino acids. In a specific embodiment of the invention, the linker peptide consists of 15 amino acids. In one embodiment of the invention, the linker peptide is (GxS)nor (GxS)nGm, where G denotes glycine, S denotes serine, and (х=3, n=3, 4, 5, or 6, and m=0, 1, 2, or 3), or (х=4, n=2, 3, 4, or 5, and m=0, 1, 2, or 3), in one embodiment of the invention x=4 and n=2 or 3, in another embodiment of the invention x=4 and n=3. In a specific embodiment of the invention, the linker peptide is (G4S)3(SEQ ID NO:12). In one embodiment of the invention, the linker peptide has (or consists of) the amino acid sequence SEQ ID NO:12. In one embodiment of the invention, the linker peptide has (or consists of) the amino acid sequence SEQ ID NO:13. In one embodiment of the invention, the linker peptide has (or consists of) the amino acid sequence SEQ ID NO:14. In one of the embodiments, a fusion polypeptide comprising an Fc fragment polypeptide may further comprise a leader peptide at the N-terminus. In one of the embodiments, the leader peptide is the SUMO peptide of SEQ ID NO:26. The physiologically active polypeptide may be selected from the group consisting of glucagon-like peptide-1 (GLP-1), granulocyte colony-stimulating factor (G-CSF), human growth hormone (hGH), erythropoietin (EPO), glucagon, oxyntomodulin, insulin, growth hormone- releasing hormone, growth hormone-releasing peptide, interferons, interferon receptors, G protein-coupled receptor, interleukins, interleukin receptors, enzymes, interleukin-binding proteins, cytokine-binding proteins, macrophage activating factor, macrophage peptide, B cell factor, T cell factor, protein A, allergy inhibitor, cell necrosis glycoproteins, immunotoxin, lymphotoxin, tumor necrosis factor, tumor suppressors, metastatic growth factor, alpha-1 antitrypsin, albumin, α-lactalbumin, apolipoprotein-E, highly glycosylated erythropoietin, angiopoietins, hemoglobin, thrombin, thrombin receptor activating peptide, thrombomodulin, blood factors VII, VIIa, VIII, IX, and XIII, plasminogen activating factor, fibrin binding peptide, urokinase, streptokinase, hirudin, protein C, C-reactive protein, renin inhibitor, collagenase inhibitor, superoxide dismutase, leptin, platelet-derived growth factor, epithelial growth factor, epidermal growth factor, angiostatin, angiotensin, bone growth factor, bone growth stimulating protein, calcitonin, atriopeptin, cartilage growth inducing factor, elcatonin, connective tissue activating factor, tissue factor pathway inhibitor, follicle-stimulating hormone, luteinizing hormone, luliberin, nerve growth factors, parathyroid hormone, relaxin, secretin, somatomedin, insulin-like growth factor, adrenal cortex hormone, cholecystokinin, pancreatic polypeptide, gastrin-releasing peptide, corticotropin-releasing hormone, thyrotropin, autotaxin, lactoferrin, myostatin, cell surface antigens, vaccine antigens of viral origin, monoclonal antibodies, polyclonal antibodies and antibody fragments. Preferably, the physiologically active polypeptide may be selected from the group consisting of glucagon-like peptide-1 (GLP-1), granulocyte colony-stimulating factor (G-CSF), human growth hormone (hGH), erythropoietin (EPO), glucagon, oxyntomodulin, insulin, insulin analogs and derivatives thereof, but is not limited to the above polypeptides. The term "insulin" for the purposes of the present invention means the human insulin hormone. Human insulin consists of two polypeptide chains: the A chain and B chain. The A chain is a 21-amino acid peptide, and the B chain is a 30-amino acid peptide, and the two chains are linked together by disulfide bridges: the first bridge is formed between the cysteine at position 7 in the A chain and the cysteine at position 7 in the B chain, and the second bridge is between the cysteine at position 20 in the A chain and the cysteine at position 19 in the B chain. The third bridge is between the cysteines at positions 6 and 11 in the A chain. In humans, the hormone is synthesized as a single-chain proinsulin precursor (preproinsulin), consisting of a 24-amino acid-long prepeptide followed by the 86-amino acid-long proinsulin is the following configuration: pre-peptide-B-Arg-Arg-C-Lys-Arg-A, wherein C is a 31 amino acid-long connecting peptide. Arg-Arg and Lys-Arg are the cleavage sites for cleaving the connecting peptide off the A and B chains. The term "insulin analog" for the purposes of the present invention means a modified insulin with one or more amino acid residues of insulin replaced by other amino acid residues, and / or one or more amino acid residues removed from the insulin, and / or one or more amino acid residues added and / or inserted into the insulin. Preferred insulinanalogs of the invention include, without limitations, e.g., aspart (i.e., human insulinAspB28) and insulin lispro (i.e., human insulin LysB28, ProB29), and insulin glulisine (LysB3, GluB29 human insulin), among others. Furthermore, the term "physiologically active polypeptide" as used herein is intended to include not only naturally occurring physiologically active polypeptides, but also agonists, precursors, derivatives, fragments or variants of each of the polypeptides. The Fc fragment polypeptide of the present invention can be chemically conjugated to other physiologically active molecules, e.g., physiologically active polypeptides, using well- known chemical conjugation techniques. To this end, bifunctional cross-linking reagents can be used, such as homofunctional or heterofunctional cross-linking reagents well known in the art.The type of cross-linking reagent to be used depends on the nature of the molecule to beconjugated to the Fc fragment polypeptide, and can be readily determined by those skilled in the art. In an alternative or additional embodiment, the Fc region polypeptide and / or the molecule intended to be conjugated thereto can be chemically derivatized such that both can be conjugated using a separate reaction, which is also well known in the art. The Fc fragment polypeptide of the present invention can be chemically conjugated toother physiologically active molecules, e.g., physiologically active polypeptides, via a non-peptide linker. The non-peptide linker used in the present invention may be selected from the group consisting of polyethylene glycol, polypropylene glycol, ethylene glycol-propylene glycol copolymer, polyoxyethylated polyol, polyvinyl alcohol, polysaccharide, dextran, polyvinyl ethyl ether, biodegradable polymers such as polylactic acid (PLA) and polylactic-glycolic acid (PLGA), lipid polymers, chitins, hyaluronic acid, and derivatives and / or combinations thereof, among others. Preferably, it is a polyethylene glycol. Furthermore, according to the present invention, the non-peptide linker that is linked to the Fc fragment polypeptide may be made up not only of one kind of polymer, but also a combination of different kinds of polymers. The non-peptide linker used in the present invention has reactive groups capable of binding to the Fc fragment polypeptide and a protein drug. The reactive groups at both ends of the non-peptide polymer are preferably selected from the group consisting of a reactive aldehyde group, a propionaldehyde group, a butyraldehyde group, a maleimide group, and a succinimide derivative. The succinimide derivative may be succinimidyl propionate, hydroxysuccinimidyl, succinimidyl carboxymethyl, or succinimidyl carbonate. In particular, if the non-peptide polymer has a reactive aldehyde group at both ends, the physiologically active polypeptide and the Fc fragment polypeptide bind effectively to both ends of the non-peptide linker, respectively, while non-specific reactions are minimized. The final product formed through reductive alkylation via an aldehyde bond is significantly more stable than that linked via an amide bond. The aldehyde reactive group can selectively bind tothe N-terminus at low pH, and can form a covalent bond with the lysine residue at high pH, e.g.,pH 9.0. The reactive groups at both ends of the non-peptide linker may be the same or different. For example, one end of the non-peptide linker may have a maleimide group, and the other end may have an aldehyde group, a propionaldehyde group, or butylaldehyde. Where a polyethylene glycol having hydroxyl reactive groups at both ends is used as a non-peptide linker, the hydroxyl groups can be activated to various reactive groups by a known chemical reaction. Alternatively, a commercially available polyethylene glycol having a modified reactive group can be used to produce the conjugate of the present invention. The present invention also relates to a method for producing a fusion construct based on the Fc fragment polypeptides described herein, wherein said method comprises culturing a host cell described herein in order to produce a fusion construct based on the Fc fragment polypeptides fused to a physiologically active polypeptide as described above. The present invention also relates to a method for producing a conjugate based on the Fc fragment polypeptides described herein, wherein said method comprises conjugating the Fc fragment polypeptide to a physiologically active polypeptide as described above.. The present invention also relates to the use of the Fc fragment of the invention for production of a drug. The present invention also relates to the use of the Fc fragment of the invention for modifying the half-life of a physiologically active polypeptide. The present invention also relates to the use of the fusion construct based on the Fc fragment polypeptide fused to the physiologically active polypeptide as described herein for production of a drug comprising said construct as an active ingredient. The present invention also relates to the use of a conjugate based on the Fc fragment polypeptide conjugated to the physiologically active polypeptide as described herein for production of a drug comprising said conjugate as an active ingredient. In one aspect of the present invention, the Fc fragment polypeptide has insulin or an agonist, precursor, derivative, fragment or variant thereof as a fusion or conjugation partner for a fusion construct or conjugate. In one aspect of the present invention, the Fc fragment polypeptide is intended for use in a method for producing a drug, wherein the use is as a fusion or conjugation partner for insulin or an agonist, precursor, derivative, fragment or variant thereof, and wherein the drug can beused in the treatment of conditions that are sensitive to insulin, e.g., type I diabetes, type IIdiabetes and hyperglycemia, and the like. In one aspect of the present invention, the Fc fragment polypeptide is intended for use in a drug preparation, as a fusion or conjugation partner for insulin, or an agonist, precursor, derivative, fragment, or a variant thereof, wherein the drug can be used in treating conditions that are sensitive to insulin, e.g., type I diabetes, type II diabetes and hyperglycemia, etc. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1. General structure of the expression plasmid for proteins fused with Fc fragment polypeptide. IMPLEMENTATION OF THE INVENTION The present invention is illustrated by the following examples, but is not limited thereto. Example 1. Generation of constructs To investigate the effect of certain modifications in the amino acid sequence of the Fcfragment polypeptide on its ability to bind to FcRn and FcgRs, the following constructs weregenerated: GP20091.01-L1-01 (SEQ ID NO:16), GP20091.01-L2-05 (SEQ ID NO:17), GP20091.01-L2-06 (SEQ ID NO:18), GP20091.01-L2-07 (SEQ ID NO:19), GP20091.01-L2-08 (SEQ ID NO:20), GP20091.01-L2-09 (SEQ ID NO:21), GP20091.01-L2-10 (SEQ ID NO:22), GP20091.01-L2-12 (SEQ ID NO:23), GP20091.01-L2-13 (SEQ ID NO:24), GP20091.01-L2-14 (SEQ ID NO:25), wherein the Fc fragment polypeptide variants were fused to the C-terminus of the single-chain insulin of SEQ ID NO:17 by the polypeptide linker of SEQ ID NO:15 or SEQ ID NO:16. To obtain said constructs, cells of Escherichia coli BL21 strain were transfected with theappropriate plasmids providing expression of GP20091.01-L1-01, GP20091.01-L2-05, GP20091.01-L2-06, GP20091.01-L2-07, GP20091.01-L2-08, GP20091.01-L2-09, GP20091.01- L2-10, GP20091.01-L2-12, GP20091.01-L2-13 and GP20091.01-L2-14 constructs fused with the SUMO leader peptide, and the ULP protease providing selective hydrolysis of the SUMO leader peptide. The coding sequences of the investigated proteins are set forth in SEQ ID NO.:27-35. The general structure of the plasmids used to produce the target proteins is shown in Fig. 1. Each plasmid comprises: 1. 1. A gene that confers tetracycline resistance to bacterial cells, a replication initiation site(ori), and the ROP gene that regulates plasmid copy number; 2. The tac / T7 transcription promoter initiating expression of the recombinant protein;3. The sequences of the gene encoding Met-SUMO-GP20091.01-L2-XX molecule and thegene encoding ULP protease, which are under control of the Tac-T7 promoter and form an operon; 4. The rrnB1 B2 T1 txn transcription terminator;5. LacI gene encoding the Tac promoter repressor;6. EcoRI and SpeI, the restriction sites where the gene is inserted;7. Pr1082 and Pr166 sequencing primers.Cell transfection was performed by electroporation. The cell biomass was isolated by centrifugation using Avanti J-HC free-standing centrifuge and JLA-8.1000 rotor according to a standard protocol (20 min, 8000 rpm). The cell pellets were packaged in the labeled polyethylene zip lock bags and stored in a freezer at temperatures not exceeding -18 °C.. For bacterial cell wall breakdown, a double sequential biomass disintegration was performed using a high-pressure homogenizer. Before cell disruption, a step of resuspending the required amount of biomass was performed. Towards this, the cell pellets were thawed at room temperature and resuspended in disintegration buffer cooled to 4 °C (20 mM Tris; 5 mM EDTA pH 8.0) using Polytron 3100D immersion homogenizer; homogenization was performed for 10 minutes until the solution was visually homogenous. Inclusion bodies were isolated by centrifugation using Avanti J-HC free-standing centrifuge and JLA-8.1000 rotor according to the standard protocol (20 min, 8000 rpm). To solubilize the constructs, a subsample of inclusion bodies was placed in a container of suitable volume, added with the required amount of the solubilization buffer solution (7 M Guanidine hydrochloride, 100 mM Tris, 15 mM DTT, pH 9.5), and stirred until the protein aggregates were completely dissolved. To produce the investigated fusion proteins in dimeric form, we used a buffer (2 M Urea, 300 mM Arg, 50 mM Tris, pH 8.25), 0.55 mM L-cysteine as a reducing agent, and 0.55 mM L-cystamine as an oxidizing agent. The refolding process was carried out for 16 hours at 2-8 ℃ anda stirring rate of 200 rpm. Purification of the resulting protein constructs Chromatography purification of the produced structures is carried out successively by affinity chromatography with protein A, hydrophobic interaction chromatography (on the Butyl Sepharose™ 4 Fast Flow sorbent), and anion exchange chromatography (using the Q sepharose 4FF sorbent). Example 2. FcRn Binding The binding of the Fc fragment polypeptide to FcRn was determined using label-free biolayer interferometry method. Binding kinetics for the prepared biotinylated neonatal Fc receptor (Immunitrack) was assessed using an Octet Red96 microplate interferometer (ForteBio) and a sensor kit (streptavidin (sa) biosensors, Sartorius), according to the manufacturer's recommendations. Rituximab from Mabxience was used as a reference. Measurements were carried out at pH 6.0. The reference subtracted binding curves were analyzed with ForteBio Acquisition Manager software according to the standard procedure using a 1:1 interaction model. The results are presented in Table 1, where R^2 is the coefficient of determination. Table 1. FcRn Binding Results The resulting Fc fragment polypeptide variants were found to have similar or improved binding to human FcRn compared to the wild-type Fc fragments. Similar results were alsoobtained at pH 7.4. Example 3. FcgRI BindingThe binding kinetics of the biotinylated FcγRI (CD64 / FCGR1A) was assessed using label-free biolayer interferometry method on the 96-well Octet Red96 microplate interferometer (Pall ForteBio). Rituximab solution (MB01, Mabxience) was used as a positive control. Streptavidin sensors (Sartorius, cat. No. 18–5019) hydrated for 10 min in 0.05% PBST solution were used in the assay. Biotinylated FcγRI receptor was used at 2.5 μg / ml. The investigated samples were diluted in 0.05% PBST solution, pH 7.4. For the rituximab positive control and GP20091.01-L2 test samples, equimolar concentrations of 1.75 nmol / mL, 0.44 nmol / mL, 0.11 nmol / mL, 0.03 nmol / mL, and 0.007 nmol / mL were assayed. The 1:1 interaction model was used in data processing. The results are presented in Table 2, wherein R^2 is the determination coefficient. Table 2. FcgRI Binding Results FcgRII Binding The binding kinetics of the biotinylated FcγRII (CD32a / FCGR2A) was assessed using label-free biolayer interferometry method on the 96-well Octet Red96 microplate interferometer (Pall ForteBio). Rituximab solution (MB01, Mabxience) was used as a positive control. Streptavidin sensors (Sartorius, cat. No. 18–5019) hydrated for 10 min in 0.05% PBST solution were used in the assay. Biotinylated FcγRII receptor was used at 2.5 µg / ml. The investigated samples were diluted in 0.05% PBST solution, pH 7.4. For the rituximab positive control and GP20091.01-L2 test samples, equimolar concentrations of 1.75 nmol / ml, 0.44 nmol / ml, 0.11 nmol / ml, 0.03 nmol / ml, and 0.007 nmol / ml were assayed. The reference subtracted binding curves were analyzed with ForteBio Acquisition Manager software according to the standard procedure using a 1:1 interaction model. The results are presented in Table 3, wherein R^2 is the coefficient of determination. FcgRIII Binding Binding kinetics to the biotinylated FcγRIII (CD16a / FCGR3A) was accessed using the label-free biolayer interferometry method in the 96-well plate-compatible interferometer Octet Red96 (Pall ForteBio). Rituximab solution was used as a positive control. (MB01, Mabxience). Streptavidin sensors (Sartorius, cat. No. 18–5019) hydrated for 10 min in 0.05% PBST solution were used in the assay. Biotinylated FcγRIII receptor was used at 2.5 μg / ml. The test samples were diluted in 0.05% PBST solution, pH 7.4. For the rituximab positive control, the following concentrations were assessed: 1.2 nmol / mL, 0.3 nmol / mL, 0.08 nmol / mL, 0.02 nmol / mL, and 0.005 nmol / mL. The GP20091.01-L2 test samples were assayed at equimolar concentrations of 25 nmol / ml, 8.3 nmol / ml, 2.8 nmol / ml, 0.93 nmol / ml, and 0.309 nmol / ml. The reference subtracted binding curves were analyzed with ForteBio Acquisition Manager software according to the standard procedure using a 1:1 interaction model. The results are presented in Table 4, where R^2 is the coefficient of determination. Table 4. FcgRIII Binding Results ddd dThe experimental results showed significantly weaker or no binding of the produced variant Fc fragment polypeptides to various human Fcg receptors as compared to the wild-type Fc fragment. Example 4. To confirm the retention of biological activity of the fusion partner, the glucose uptake induced by the resulting fusion proteins was assessed. Glucose absorption was studied using L6J1 rat myoblast cell line (Institute of Cytology, Russian Academy of Science). The working cell suspension was seeded into 96-well plates at 8000 cells / well in DMEM + 2% horse serum (HS). Cells dispersed in DMEM + 10% FBS were used as a control. After 72 hours, the medium was changed to DMEM + 2% HS in theexperimental wells and DMEM + 10% in the control wells. On the 7th day of the experiment, the cells were starved for 24 hours by adding DMEM glu 4.5 g / L, w / o phenol red, s / f, to all wells. The test sample was added to the wells at concentrations of 2 nM, 20 nM, 100 nM, 200 nM, 500 nM, 800 nM, 1600 nM, 3200 nM, and 5000 nM. Rinsulin R was added as a control at concentrations of 1 nM, 10 nM, 50 nM, 100 nM, 250 nM, 400 nM, 800 nM, 1600 nM, and 2500 nM. Cells were subsequently incubated with the test samples and controls for 72 hours. Glucose concentration was measured using the GOD-PAP glucose kit by adding culture medium to the GOD-PAP working glucose solution. Detection was carried out on a CLARIOstar multimodal microplate reader. The results are presented in Table 5. Table 5. Measurements of the induced glucose uptake All investigated fusion proteins caused a decrease in glucose levels and exhibited biological activity at the levels corresponding to the recombinant human insulin.

Claims

CLAIMS We claim:

1. An immunoglobulin Fc fragment polypeptide having the amino acid sequence X1X2X3X4X5CPPCPAPX13X14X15X16X17PX19VFLFPPKPKDX30LX32IX34RX36PEVTCVVX44D VSX48EDPEVQFNWYVDGVEVX65X66AKTKPREEQFX77STX80RVVSVLTX88X89HQDWLN GKEYKCKVSNKGLPX110X111IEKTISKX119KGQPREPQVYTLPPSX135EEMTKNQVSLTCL VKGFYPSDIAVEWESNGQPENNYKTTPPX177LDSDGSFFLYSX189LTVDKSRWQX199GNV FSCSVX208HEALHX214HYTQKSLSLSX225G set forth in SEQ ID NO:2, wherein X1is E or D, X2is K or absent, X3is T or absent, X4is H or absent, X5is W or absent, X13is P or E, X14is F or absent, X15is V or L, X16is A or G, X17is G or M, X19is S or E, X30is T or Q, X32is M, Y, or W, X34is S or T, X36is T or E, X44is V, E, or D, X48is H or Q, X65is H or E, X66is N or E,X77is N or D, X80is F or Y, X88is V or F, X89is V or L, X110is A, F, or S, X111is P or S, X119is T or A, X135is R or Q, X177is M or V, X189is K or R, X199is Q or E, X208is M or L, X214is N, Y, or W, and X225is P or L.

2. The polypeptide of claim 1,wherein X1is E, X2is absent, X3is absent, X4is absent, X5is absent, X13is P, X14is absent, X15is V, X16is A, X17is G, X19is S, X30is T, X32is Y, X34is T, X36is E, X44is V, X48is H, X65is H, X66is N, X77is N, X80is F, X88is V, X89is V, X110is A, X111is P, X119is T, X135is R, X177is M, X189is K, X199is Q, X208is M, X214is N, and X225is P.

3. The polypeptide of claim 1,wherein X1is E, X2is absent, X3is absent, X4is absent, X5is absent, X13is P, X14is absent, X15is V, X16is A, X17is G, X19is S, X30is Q, X32is M, X34is S, X36is T, X44is V, X48is H, X65is H, X66is N, X77is N, X80is F, X88is V, X89is V, X110is A, X111is P, X119is T, X135is R, X177is M, X189is K, X199is Q, X208is L, X214is N, and X225is P.

4. The polypeptide of claim 1,wherein X1is E, X2is absent, X3is absent, X4is absent, X5is absent, X13 is P, X14 is absent, X15 is V, X16 is A, X17 is G, X19 is S, X30 is T, X32 is Y, X34 is S, X36is E, X44is D, X48is H, X65is H, X66is N, X77is D, X80is F, X88is F, X89is V, X110is A, X111is P, X119is T, X135is R, X177is M, X189is K, X199is Q, X208is M, X214is Y, and X225is P.

5. The polypeptide of claim 1,wherein X1is E, X2is absent, X3is absent, X4is absent, X5is absent, X13is E, X14is F, X15is L, X16is G, X17is G, X19is S, X30is T, X32is M, X34is S, X36is E, X44is D, X48is Q, X65is E, X66is E, X77is D, X80is Y, X88is V, X89is L, X110is S, X111is S, X119is A, X135is Q, X177is V, X189is R, X199is E, X208is L, X214is N, and X225is L.

6. The polypeptide of claim 1,wherein X1is E, X2is absent, X3is absent, X4is absent, X5is absent, X13 is P, X14 is absent, X15 is V, X16 is A, X17 is G, X19 is S, X30 is T, X32 is W, X34 is S, X36is E, X44is V, X48is H, X65is H, X66is N, X77is N, X80is F, X88is V, X89is V, X110is A, X111is P, X119is T, X135is R, X177is M, X189is K, X199is Q, X208is L, X214is Y, and X225is P.

7. The polypeptide of claim 1,wherein X1is E, X2is absent, X3is absent, X4is absent, X5is absent, X13is P, X14is absent, X15is V, X16is A, X17is G, X19is E, X30is T, X32is M, X34is S, X36is E, X44is E, X48is H, X65is H, X66is N, X77is N, X80is F, X88is V, X89is V, X110is F, X111is P, X119is T, X135is R, X177is M, X189is K, X199is Q, X208is M, X214is Y, and X225is P.

8. The polypeptide of claim 1,wherein X1 is D, X2 is K, X3 is T, X4 is H, X5 is W, X13 is P, X14is absent, X15is V, X16is A, X17is M, X19is S, X30is Q, X32is Y, X34is S, X36is T, X44is D, X48is H, X65is H, X66is N, X77is N, X80is F, X88is V, X89is V, X110is A, X111is P, X119is T, X135is R, X177is M, X189is K, X199is Q, X208is M, X214is N, and X225is P.

9. The polypeptide of claim 1,wherein X1is E, X2is absent, X3is absent, X4is absent, X5is absent, X13is P, X14is absent, X15is V, X16is A, X17is G, X19is S, X30is T, X32is Y, X34is S, X36 is E, X44 is E, X48 is H, X65 is H, X66 is N, X77 is D, X80 is F, X88 is F, X89 is V, X110 is F, X111is P, X119is T, X135is R, X177is M, X189is K, X199is Q, X208is M, X214is W, and X225is P.

10. The polypeptide of claim 1,wherein X1is E, X2is absent, X3is absent, X4is absent, X5is absent, X13is P, X14is absent, X15is V, X16is A, X17is G, X19is S, X30is Q, X32is Y, X34is S, X36 is E, X44 is E, X48 is H, X65 is H, X66 is N, X77 is N, X80 is F, X88 is F, X89 is V, X110 is F, X111is P, X119is T, X135is R, X177is M, X189is K, X199is Q, X208is M, X214is W, and X225is P.

11. An immunoglobulin Fc fragment polypeptide having the amino acid sequence selected from SEQ ID NOs:3 to 11.

12. A nucleic acid encoding the polypeptide of any one of claims 1-11.

13. An expression cassette comprising the nucleic acid according to claim 12.

14. A vector comprising the nucleic acid of claim 12 or the expression cassette of claim 13.

15. A host cell for expressing the polypeptide according to any one of claims 1 to 11, said cell comprising the nucleic acid of claim 12, the expression cassette of claim 13, or the vector of claim 14.

16. The host cell of claim 15, wherein the cell is E. coli.

17. A method for producing the polypeptide of any one of claims 1-11, wherein the method comprises culturing the cell of claim 15 under conditions that provide expression of the polypeptide of any one of claims 1-11.

18. Use of the polypeptide of any one of claims 1-11 for producing a drug.

19. The use of claim 18, wherein the drug is the polypeptide of any one of claims 1-11, conjugated with a physiologically active molecule.

20. The use of claim 18, wherein the drug is the polypeptide of any one of claims 1-11, fused with a physiologically active polypeptide.

21. The use of claim 20, wherein the drug comprises a peptide linker by which the polypeptide of any one of claims 1-11 is fused to the physiologically active polypeptide.

22. A method for producing a drug, wherein the method comprises producing the polypeptide of any one of claims 1-11, according to the method of claim 17.

23. The method of claim 22, wherein the drug is the polypeptide of any one of claims 1- 11, conjugated with a physiologically active molecule.

24. The method of claim 22, wherein the drug is the polypeptide of any one of claims 1- 13, fused with a physiologically active polypeptide.

25. The method of claim 24, wherein the drug comprises a peptide linker by which the polypeptide of any one of claims 1-13 is fused to the physiologically active polypeptide.