Fc variant and preparation thereof

Field of the invention

The present invention relates to Fc variant protein and preparation thereof. Said Fc variant has altered binding affinity towards FcRn. Fc variant prepared according to the current invention can be used for making FcRn antagonist composition or can be used for making an Fc variant containing drug or molecule with altered effector function.

Background of the invention

Neonatal Fc receptor (FcRn) is structurally homologous to the Major Histocompatibility Complex (MHC) Class I heterodimer molecule consisting of a type I transmembrane heavy chain that non- covalently associates with the soluble light chain, β2-microglobulin ( β2m), β2m is essential for the proper folding, transport, and function of FcRn, as well as other MHC Class I homologs. The FcRn heavy chain contains three soluble extracellular domains (α1, α2, and α3), a single transmembrane helix, and a cytoplasmic tail. Unlike MHC Class I molecules, FcRn does not directly present antigens to T-cells due to point mutations on the top face of FcRn that disrupt peptide binding. The ability of FcRn to protect IgG from intracellular catabolism is the result of a specific, pH-dependent interaction with the Fc portion of IgG. IgG binds FcRn in a strictly pH-dependent manner at acidic (< 6.5) but not neutral pH (> 7) mediated by electrostatics between titratable histidine residues in the CH2-CH3 domains of IgG Fc and acidic residues on the α2-domain of FcRn. Binding is further stabilized by a series of hydrophobic interactions and hydrogen bonds between Fc and residues within the FcRn α2-domain and the β2m light chain N-terminus. One IgG molecule can simultaneously bind two FcRn molecules due to the homodimeric nature of IgG resulting in a high affinity interaction between FcRn and IgG at pH 6 due to increased avidity of interaction. The 2:1 interaction between FcRn and IgG is critical for their efficient binding, recycling, and transcytosis in the FcRn expressing cells ultimately leading to the preservation of the long serum persistence of IgG such that protective antibody molecules do not have to be repeatedly produced by B cells thereby providing efficient immunity against infections. Unfortunately this same interaction also contributes to the pathogenicity of those IgG molecules that are reactive toward a self-antigen leading to numerous autoimmune disorders. Mice deficient in FcRn are protected against IgG-mediated autoimmune diseases indicating

that FcRn contributes, at least in part, to autoimmunity by maintaining the pathogenic IgGs in circulation longer. Because FcRn contributes to the serum persistence of IgG, therapeutics that block the IgG-FcRn interaction represent a potential treatment modality for IgG-mediated autoimmunity. In fact, high dose intravenous immunoglobulin (IVIg) therapy is FDA-approved for the treatment of IgG-mediated autoimmune diseases where it provides a therapeutic benefit in part by saturation of FcRn receptors, thereby increasing the catabolism of pathogenic IgG. However, IVIg therapy suffers from multiple problems. For example being a blood-derived product, it is susceptible to being contaminated with human pathogens such as HIV, HBV, HCV etc. and thus making the treatment of chronic disorders such as autoimmune diseases highly risky for the recipient patients. It is also expensive, since it requires IgG extraction from the plasma of many blood donors. Also, there is a concern of scalability because it is a human donor dependent product. Thus, novel recombinant approaches are the need of the hour to provide alternative safe, scalable and cost effective treatment options.

Monoclonal antibody based antagonists have been developed to inhibit the endogenous IgG-FcRn interaction. One approach is the use of monoclonal antibodies directed against FcRn working via the classical antibody: antigen binding mechanism. Examples of such antibodies are M281 and UCB7665 which bind human FcRn to inhibit IgG binding to FcRn and thereby accelerate the clearance of endogenous IgG. A mean reduction of endogenous IgG ranging between 25-80 % was observed with M281 in a dose dependent manner. Moreover, single doses of M281 at 30 mg / kg or 60 mg / kg maintained serum IgG at 50 % of baseline or below for 18 and 27 days, respectively (1). In healthy subjects, IgG concentrations in the serum were reduced by up to 50 % at a single IV dose of 7 mg / kg of UCB7665. The observed reductions in serum IgG concentrations in the current study persisted for weeks, with maximal reductions achieved by days 7 to 10 and thereafter gradually returning to baseline by day 57 (2).

An alternative antibody engineering approach to reduce IgG levels in serum is to engineer the Fc-domain of IgG such that it has high affinity for FcRn at both pH 6 and pH 7.4. Such a molecule developed using the ‘Abdegs’ (i.e., antibodies that enhance IgG degradation) technology has been found to be effective in treating a murine model of arthritis at 25 to 50 fold lower dose than IVIg indicating that such IgG Fc-based potent antagonists of the IgG-FcRn interaction are an alternative therapeutic intervention in autoimmunity. This molecule, Efgartigimod, is in clinical development by the Netherlands-based biotech company, arGEN-X.

More recently, synthetic peptides that compete with IgG for binding to FcRn were identified from a phage library. A chemically optimized peptide dimer (SYN1436) that bound FcRn with sub nanomolar affinity at pH 6 and pH 7.4 was effective at increasing the clearance of exogenous IgG in mice as well as endogenous IgG in monkeys, but has not been evaluated in a therapeutic model of IgG-mediated autoimmunity. Alternatively, additional molecules that bind instead to Fc itself, at the CH2-CH3 domain interface to block the IgG-FcRn interaction, include a 13-amino acid cyclic peptide (FcIII) selected by phage display, a computationally designed IgG-Fc binding protein (FcBP6.1), and an endogenous Fc receptor, TRIM21. (3) Thus, the present invention provides an FcRn binder that solves various unmet needs such as, downregulation of the FcRn activity, increasing the circulating half-life of a variety of drugs, targeting of drugs and / or vaccines to specific cell types etc. The FcRn binder of the present invention can be used in treating a wide variety of diseases.

There is another class of molecules which targets immune-complex (IC) formation and immune- complex mediated FcγR mediated activation. This class of molecules are recombinant Fc multimers such as Pf-06755347 (GL-2045) and CSL730 (M230). These molecules are complex in terms of structure and may result into highly heterogenous population. These molecules are being developed for the treatment of autoimmune disease. Therefore, molecules targeting different mechanisms are under early clinical trial that are being developed as a replacement of intravenous immunoglobulin (IVIg) and subcutaneous immunoglobulin (SCIg) to avoid the dependence on the supply of human plasma and the large doses of product of up to 2 g/kg body weight needed for therapy. In this situation, it would be advantageous to get single drug that has combined effects of multiple mechanism of actions such as FcRn blockade, inhibition of FcγR activation and / or inhibition of full complement activation.

In one of the aspects, the current invention provides Fc variant molecule which is FcRn binder as well as FcγRs binders and may solve various needs together such as downregulation of the FcRn activity, increasing the circulating half-life of a variety of drugs, IC inhibition, inhibition of cytokine release mediated by IC formation, inhibition of phagocytosis mediated by FcγR activation. Preferably, the Fc variant molecule prepared according to the current invention provides one or more of the above said desired effects at a lesser dose as compared to the dose of IVIg.

Summary of the invention

The current invention provides novel Fc variant with altered binding affinity towards FcRn, preferably higher binding affinity towards FcRn. In one of the aspects, the Fc variant of the current invention has altered binding affinity towards FcγRs, preferably higher binding affinity towards FcγRs. Preferably, the said Fc variant can be used to develop drug compositions with FcRn antagonist function or increased circulating half-life, or for targeting to specific cells and / or tissues. The present invention also provides method of making novel Fc variant. The Fc variant according to the present invention is further used in the preparation of a drug either for treating diseases where activity of FcRn is detrimental or for increasing the circulating half-life of a drug or for targeting the drug to certain cells or tissues.

Brief description of figures

Figure 1: It depicts map of the vector used in library generation to make Fc variants of the present invention.

Figure 2: It depicts map of the vector used for the generation of Fc monomer and Fc dimer of the present invention.

Figure 3: It depicts map of the vector used for the generation of monoclonal antibody containing Fc monomer of the present invention.

Figure 4: It depicts the results of experiment to determine the effect of Fc variant (Fc dimer) and IVIg on total IgG serum levels in wild-type mice.

Figure 5: It depicts the results of experiment to determine the effect of Fc variant (Fc dimer) and IVIg on serum albumin levels in wild-type mice.

Figure 6: It depicts results of experiment to determine the effect of Fc variant on ADCC activity.

Figure 7: It depicts results of experiment to determine the effect of Fc variant on platelet count in a mouse model of acute immune thrombocytopenia (ITP).

Definitions

The term “afucosylated” as used herein refers to a glycosylated protein with an N-linked glycan which lacks a core fucose molecule as described in US8067232, the contents of which is incorporated by reference herein in its entirety.

The term “amino acid modification” as used herein is an amino acid substitution, insertion, and / or deletion in a polypeptide sequence.

The term “amino acid substitution” or “substitution” as used herein is the replacement of an amino acid at a particular position in a parent polypeptide sequence with another amino acid. For example, the substitution T307N refers to a variant polypeptide, in this case an Fc variant, in which the threonine at position 307 is replaced with asparagine.

The term “antigen-binding molecule” according to the current invention refers to a protein that can bind to target antigen and comprising an “FcRn binding domain”. FcRn Binding domain according to the current invention is present in Fc protein, preferably, present in Fc variant of the current invention. Preferred “antigen-binding molecule” according to the present invention may include antibody or peptibody or fusion proteins comprising Fc variant of the present invention.

The term “antibody” as used herein includes whole antibodies and any antigen- binding fragments (i.e., “antigen-binding portion”). An “antibody” refers to a glycoprotein comprising at least two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds, or an antigen-binding portion thereof. Each heavy chain is comprised of a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region (Fc). The heavy chain constant region is comprised of three domains, CH1, CH2 and CH3. Each light chain is comprised of a light chain variable region (abbreviated herein as VL) and a light chain constant region. The light chain constant region is comprised of one domain, CL- The VH and VL regions can be further subdivided into regions of hyper variability, termed complementarity determining regions (CDR), interspersed with regions that are more conserved, termed framework regions (FR). Each VH and VL is composed of three CDRs and four FRs, arranged from amino -terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The variable regions of the heavy and light chains contain a binding domain that interacts with an antigen. The constant regions of the antibodies may mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (e.g., effector cells such as, NK cells, T cells, macrophages and dendritic cells etc.) and the first component (C1q) of the classical complement system.

The term “operatively linked” is intended to mean that a gene is ligated into a vector such that transcriptional and translational control sequences within the vector serve their intended function of regulating the transcription and translation of such gene.

The term “Ka” is the association rate of interaction between two molecules, whereas the term “Kd” is the dissociation rate of the interaction between two molecules. The term “KD” is an affinity rate constant, which is obtained from the ratio of Kd to Ka. It can be measured by using surface plasma resonance method which is well known in the art.

The terms “monoclonal antibody” or “monoclonal antibody composition” as used herein refer to a preparation of antibody molecules of single molecular composition. A monoclonal antibody composition displays a single binding specificity and affinity for a particular epitope.

The term “bispecific antibody” refers to a homogeneous antibody population involved in the highly specific recognition and binding of a two different antigenic determinants, or epitopes. The term “recombinant antibody”, as used herein, includes all antibodies that are prepared, expressed, created or isolated by recombinant means. In certain embodiments, however, such recombinant antibodies can be obtained by in vitro mutagenesis and thus the amino acid sequences of the VH and VL regions of the recombinant antibodies as described herein are sequences that may not naturally exist within the human antibody germline repertoire in vivo. The term “effector function” as used herein is a biochemical event that results from the interaction of an antibody Fc region with an Fc receptor or ligand. Effector functions include but are not limited to ADCC, ADCP, and CDC. The term also represents a physiological event such as circulating half-life of a drug or targeting of a drug to a particular cell or tissue type.

The term “ADCC” or “antibody dependent cell-mediated cytotoxicity” as used herein is the cell-mediated reaction wherein nonspecific cytotoxic cells that express FcγRs recognize bound antibody on a target cell and subsequently cause lysis of the target cell.

The term “ADCP” or “antibody dependent cell-mediated phagocytosis” as used herein is the cell-mediated reaction wherein nonspecific cytotoxic cells that express FcγRs recognize bound antibody on a target cell and subsequently cause phagocytosis of the target cell.

The term “effector cell” as used herein is a cell that expresses one or more Fc receptors and mediates one or more effector functions. Effector cells include but are not limited to monocytes, macrophages, neutrophils, dendritic cells, eosinophils, mast cells, platelets, B cells, large granular lymphocytes, Langerhans' cells, natural killer (NK ) cells, and γδT cells, and may be from any organism including but not limited to humans, mice, rats, rabbits, and monkeys.

The term “Fc” fragment, whose name reflects its ability to crystallize readily. The crystal structure of the human IgG Fc region has been determined (4). In human IgG molecules, the Fc region is generated by papain cleavage N-terminal to Cys 226. The Fc region is central to the effector functions of antibodies.

The term “Fc protein” as used herein refers to the portion of a single immunoglobulin heavy chain beginning in the hinge region just upstream of the papain cleavage site and ending at the C-terminus of the antibody. Accordingly, a complete Fc domain comprises at least a portion of a hinge (e.g., upper, middle, and / or lower hinge region) domain, a CH2 domain, and a CH3 domain.

The term “Fc variant containing protein” as used herein refers to any molecule that comprises an Fc variant of the current invention. Preferably, Fc variant containing protein includes antibody, fusion protein and peptibody. Antibody, fusion protein and peptibody as referred herein include any approved or under clinical trial or under pre-clinical trial antibody, fusion protein and peptibody.

The term “Fc variant containing molecule” as used herein refers to any molecule that comprises an Fc variant of the current invention. It can be fusion product where Fc variant of the current invention is linked or conjugated to a drug, wherein drug can be small peptide or receptor or toxin or any chemical molecule.

The term “Fc variant protein” or “Fc protein variant” or “Fc variant” as used herein is a Fc protein that differs from that of a wild type Fc protein by virtue of at least one amino acid modification. Fc variant may refer to the Fc variant itself, a composition comprising the Fc variant, or the amino acid sequence that encodes it. Preferably, the Fc variant has at least one amino acid modification compared to the parent protein, e.g. from about one to about ten amino acid modifications, and preferably from about one to about five amino acid modifications compared to the parent.

The term “EU position” as used herein refers to the amino acid position in the EU numbering convention for the Fc region described in reference 5.

The term “CH1 domain” as used herein refers to the first (most amino terminal) constant region domain of an immunoglobulin heavy chain that extends from about EU positions 118-215. The CH1 domain is adjacent to the VH domain and amino terminal to the hinge region of an immunoglobulin heavy chain molecule, and does not form a part of the Fc region of an immunoglobulin heavy chain.
We claim

1. An Fc variant comprising combination of substituting amino acids at specific EU position in wild-type Fc protein wherein said Fc variant comprising amino acid sequence selected from SEQ ID NO. 1, SEQ ID NO. 2, SEQ ID NO. 3, SEQ ID NO. 4, SEQ ID NO. 5, SEQ ID NO. 7, SEQ ID NO. 9, SEQ ID NO. 11, SEQ ID NO. 14, SEQ ID NO. 15, SEQ ID NO. 18, SEQ ID NO. 20, SEQ ID NO. 21, SEQ ID NO. 22, SEQ ID NO. 23, SEQ ID NO.

24, SEQ ID NO. 25, SEQ ID NO. 26, SEQ ID NO. 27, SEQ ID NO. 29, SEQ ID NO. 30, SEQ ID NO. 31, SEQ ID NO. 32, SEQ ID NO. 34, SEQ ID NO. 35, SEQ ID NO. 36, SEQ ID NO. 38, SEQ ID NO. 39, SEQ ID NO. 40, SEQ ID NO. 41, SEQ ID NO. 42, SEQ ID NO. 43, SEQ ID NO. 44, SEQ ID NO. 45, SEQ ID NO. 46, SEQ ID NO. 47, SEQ ID NO. 48, SEQ ID NO. 49, SEQ ID NO. 50, SEQ ID NO. 51, SEQ ID NO. 52, SEQ ID NO. 53, SEQ ID NO. 54, SEQ ID NO. 55, SEQ ID NO. 56, SEQ ID NO. 57, SEQ ID NO. 58, SEQ ID NO. 59, SEQ ID NO. 60, SEQ ID NO. 61, SEQ ID NO. 62, SEQ ID NO. 63, SEQ ID NO. 64, SEQ ID NO. 65, SEQ ID NO. 66, SEQ ID NO. 67, SEQ ID NO. 68, SEQ ID NO. 69, SEQ ID NO. 70, SEQ ID NO. 71, SEQ ID NO. 72, SEQ ID NO. 73, SEQ ID NO. 74, SEQ ID NO. 75, SEQ ID NO. 76, SEQ ID NO. 77, SEQ ID NO. 78, SEQ ID NO. 79, SEQ ID NO. 80, SEQ ID NO. 81, SEQ ID NO. 82, SEQ ID NO. 83, SEQ ID NO. 84, SEQ ID NO. 85, SEQ ID NO. 86, SEQ ID NO. 87, SEQ ID NO. 88, SEQ ID NO. 89, SEQ ID NO. 90, SEQ ID NO. 91, SEQ ID NO. 92, SEQ ID NO. 93, SEQ ID NO. 94, SEQ ID NO. 95, SEQ ID NO. 96, SEQ ID NO. 97, SEQ ID NO. 98, SEQ ID NO. 99, SEQ ID NO. 100, SEQ ID NO. 101, SEQ ID NO. 102, SEQ ID NO. 103, SEQ ID NO. 104, SEQ ID NO. 105, SEQ ID NO. 106, SEQ ID NO.

107, SEQ ID NO. 108, SEQ ID NO. 109, SEQ ID NO. 110, SEQ ID NO. Ill, SEQ ID NO. 112, SEQ ID NO. 113, SEQ ID NO. 114, SEQ ID NO. 115, SEQ ID NO. 116, SEQ ID NO. 117, SEQ ID NO. 118, SEQ ID NO. 119, SEQ ID NO. 120, SEQ ID NO. 121, SEQ ID NO. 122, SEQ ID NO. 123, SEQ ID NO. 124, SEQ ID NO. 125, SEQ ID NO.

126, SEQ ID NO. 127, SEQ ID NO. 128, SEQ ID NO. 129, SEQ ID NO. 130, SEQ ID NO. 131, SEQ ID NO. 132, SEQ ID NO. 133, SEQ ID NO. 134, SEQ ID NO. 135, SEQ ID NO. 136, SEQ ID NO. 137, SEQ ID NO. 138, SEQ ID NO. 139, SEQ ID NO. 140, SEQ ID NO. 141, SEQ ID NO. 142, SEQ ID NO. 143, SEQ ID NO. 144, SEQ ID NO.

145, SEQ ID NO. 146, SEQ ID NO. 147, SEQ ID NO. 148, SEQ ID NO. 149, SEQ ID NO. 150, SEQ ID NO. 151, SEQ ID NO. 152, SEQ ID NO. 153, SEQ ID NO. 154, SEQ ID NO. 155, SEQ ID NO. 156, SEQ ID NO. 157, SEQ ID NO. 158, SEQ ID NO. 159, SEQ ID NO. 160, SEQ ID NO. 161, SEQ ID NO. 162, SEQ ID NO. 163, SEQ ID NO.

164, SEQ ID NO. 165, SEQ ID NO. 166, SEQ ID NO. 167, SEQ ID NO. 168, SEQ ID NO. 169, SEQ ID NO. 170, SEQ ID NO. 171, SEQ ID NO. 172, SEQ ID NO. 173, SEQ ID NO. 174, SEQ ID NO. 175, SEQ ID NO. 176, SEQ ID NO. 177, SEQ ID NO. 178, SEQ ID NO. 179, SEQ ID NO. 180, SEQ ID NO. 181, SEQ ID NO. 182, SEQ ID NO.

183, SEQ ID NO. 184, SEQ ID NO. 185, SEQ ID NO. 186, SEQ ID NO. 187, SEQ ID

NO. 188, SEQ ID NO. 189, SEQ ID NO. 190, SEQ ID NO. 191, SEQ ID NO. 192, SEQ ID NO. 193, SEQ ID NO. 194, SEQ ID NO. 195, SEQ ID NO. 196, SEQ ID NO. 197, SEQ ID NO. 198, SEQ ID NO. 199, SEQ ID NO. 200, SEQ ID NO. 201, SEQ ID NO.

202, SEQ ID NO. 203, SEQ ID NO. 204, SEQ ID NO. 205, SEQ ID NO. 206, SEQ ID NO. 207, SEQ ID NO. 208, SEQ ID NO. 209, SEQ ID NO. 210, SEQ ID NO. 211, SEQ ID NO. 212, SEQ ID NO. 213, SEQ ID NO. 214, SEQ ID NO. 215, SEQ ID NO. 216, SEQ ID NO. 217, SEQ ID NO. 218, SEQ ID NO. 219, SEQ ID NO. 220, SEQ ID NO.

221, SEQ ID NO. 222, SEQ ID NO. 223, SEQ ID NO. 224, SEQ ID NO. 225, SEQ ID NO. 226, SEQ ID NO. 227, SEQ ID NO. 228, SEQ ID NO. 229, SEQ ID NO. 230, SEQ ID NO. 231, SEQ ID NO. 232, SEQ ID NO. 233, SEQ ID NO. 234, SEQ ID NO. 235, SEQ ID NO. 236, SEQ ID NO. 237, SEQ ID NO. 238, SEQ ID NO. 239, SEQ ID NO.

240, SEQ ID NO. 241, SEQ ID NO. 242, SEQ ID NO. 243, SEQ ID NO. 244, SEQ ID NO. 245, SEQ ID NO. 246, SEQ ID NO. 247, SEQ ID NO. 248, SEQ ID NO. 249, SEQ ID NO. 250, SEQ ID NO. 251, SEQ ID NO. 252, SEQ ID NO. 253, SEQ ID NO. 254, SEQ ID NO. 255, SEQ ID NO. 256, SEQ ID NO. 257, SEQ ID NO. 258, SEQ ID NO.

259, SEQ ID NO. 260, SEQ ID NO. 261, SEQ ID NO. 262, SEQ ID NO. 263, SEQ ID NO. 264, SEQ ID NO. 265, SEQ ID NO. 266, SEQ ID NO. 267, SEQ ID NO. 268, SEQ ID NO. 269, SEQ ID NO. 270, SEQ ID NO. 271, SEQ ID NO. 272, SEQ ID NO. 273, SEQ ID NO. 274, SEQ ID NO. 275, SEQ ID NO. 276, SEQ ID NO. 277, SEQ ID NO.

278, SEQ ID NO. 279, SEQ ID NO. 280, SEQ ID NO. 281, SEQ ID NO. 282, SEQ ID

NO. 283, SEQ ID NO. 284, SEQ ID NO. 285, SEQ ID NO. 286, SEQ ID NO. 287, SEQ ID NO. 288, SEQ ID NO. 289, SEQ ID NO. 290, SEQ ID NO. 291, SEQ ID NO. 292, SEQ ID NO. 293, SEQ ID NO. 294, SEQ ID NO. 295, SEQ ID NO. 296, SEQ ID NO.

297, SEQ ID NO. 298, SEQ ID NO. 299, SEQ ID NO. 300, SEQ ID NO. 301, SEQ ID NO. 302, SEQ ID NO. 303, SEQ ID NO. 304, SEQ ID NO. 305, SEQ ID NO. 306, SEQ ID NO. 307, SEQ ID NO. 308, SEQ ID NO. 309, SEQ ID NO. 310, SEQ ID NO. 311, SEQ ID NO. 312, SEQ ID NO. 313, SEQ ID NO. 314, SEQ ID NO. 315, SEQ ID NO.

316, SEQ ID NO. 317, SEQ ID NO. 318, SEQ ID NO. 319, SEQ ID NO. 320, SEQ ID NO. 321, SEQ ID NO. 322, SEQ ID NO. 323, SEQ ID NO. 324, SEQ ID NO. 325, SEQ ID NO. 326, SEQ ID NO. 327, SEQ ID NO. 328, SEQ ID NO. 329, SEQ ID NO. 330, SEQ ID NO. 331, SEQ ID NO. 332, SEQ ID NO. 333, SEQ ID NO. 334, SEQ ID NO.

335, SEQ ID NO. 336, SEQ ID NO. 337, SEQ ID NO. 338, SEQ ID NO. 339, SEQ ID NO. 340, SEQ ID NO. 341, SEQ ID NO. 342, SEQ ID NO. 343, SEQ ID NO. 344, SEQ ID NO. 345, SEQ ID NO. 346 and SEQ ID NO. 347.

2. The Fc variant as claimed in claim 1, that binds with high affinity to human FcRn relative to the wild-type Fc protein.

3. The Fc variant as claimed in claim 2, having higher binding affinity towards FcRn at pH 6.0 as compared to its said affinity at neutral pH.

4. The Fc variant as claimed in claim 2, having a KD of 10 -8 M or less, more preferably 10 - 10 M or less for FcRn.

5. The Fc variant as claimed in claim 2, that cross-reacts with FcRn from species other than human.

6. The Fc variant as claimed in claim 1 is present in Fc protein of IgG1, IgG2, IgG3, IgG4 or IgG2/G4 isotype, preferably the IgG1 isotype.

7. The Fc variant as claimed in claim 1 which is expressed in multimer form to increase half- life by increasing the molecular size and affinity through higher avidity of the Fc variant.

8. The multimeric form as claimed in claim 7 is selected from dimer, trimer, tetramer, pentamer and hexamer.

9. The Fc variant as claimed in claim 1 is present in full-length antibody form.

10. The Fc variant as claimed in claim 1 has altered affinity for an Fc gamma receptor relative to the affinity of a wild- type IgG1 Fc region for the said Fc gamma receptor.

11. The Fc variant as claimed in claim 10, has increased affinity for FcγRIIIa (CD 16a) relative to the affinity of a wild- type IgG1 Fc region for FcγRIIIa including allotypes V158 and F158.

12. The Fc variant as claimed in claim 11, comprising at least one of the following characteristic(s):

a) has an increased half-life in subject;

b) has reduced / no ADCC activity relative to wild-type Fc protein;

c) inhibits phagocytosis mediated by FcγRs and

d) inhibits cytokine release mediated by FcγRs.

13. The Fc variant as claimed in claim 1 is fused to a drug or a therapeutic peptide or polyethylene glycol or an immunogen or neutralizing antibody.

14. The Fc variant as claimed in claim 1 comprises an afucosylated N-linked glycan at EU position 297.

15. The Fc variant as claimed in claim 1 comprising an amino acid sequence selected from sequences as set forth in SEQ ID NO. 1, SEQ ID NO. 2, SEQ ID NO. 3, SEQ ID NO. 4, SEQ ID NO. 5, SEQ ID NO. 7, SEQ ID NO. 9, SEQ ID NO. 11, SEQ ID NO. 14, SEQ ID NO. 15, SEQ ID NO. 18, SEQ ID NO. 20, SEQ ID NO. 21, SEQ ID NO. 22, SEQ ID NO.

23, SEQ ID NO. 24, SEQ ID NO. 25, SEQ ID NO. 26, SEQ ID NO. 27, SEQ ID NO. 29,

SEQ ID NO. 30, SEQ ID NO. 31, SEQ ID NO. 32, SEQ ID NO. 34, SEQ ID NO. 35,

SEQ ID NO. 36, SEQ ID NO. 38, SEQ ID NO. 39, SEQ ID NO. 40, SEQ ID NO. 41,

SEQ ID NO. 42, SEQ ID NO. 43, SEQ ID NO. 44, SEQ ID NO. 45, SEQ ID NO. 46,

SEQ ID NO. 47, SEQ ID NO. 48 and SEQ ID NO. 49.

16. The Fc variant as claimed in claim 1 comprising an amino acid sequence selected from sequences as set forth in SEQ ID NO. 3, SEQ ID NO. 5, SEQ ID NO. 10, SEQ ID NO. 20 or SEQ ID NO. 22.

17. The Fc variant as claimed in claim 16, wherein SEQ ID NO. 22 comprising substitutions T307N, V308P, L309Y, H433R and N434W.

18. The Fc variant as claimed in claim 17, wherein SEQ ID NO. 22 has amino acid sequence selected from SEQ ID NO. 22a, SEQ ID NO. 22b, SEQ ID NO. 22c, SEQ ID NO. 22d SEQ ID NO. 22e and SEQ ID NO. 22f and SEQ ID NO. 22g.

19. A composition comprising Fc variant of any preceding claim and an acceptable carrier.

20. The Fc variant as claimed in any preceding claim is for use in the preparation of a drug either for treating diseases where activity of FcRn is detrimental or for increasing the circulating half-life of a drug or for targeting the drug to certain cells or tissues.

21. The Fc variant as claimed in claim 20 wherein disease is selected from infections, cancer and auto immune disorder.