Methods of treating influenza infections

Abstract

Provided herein are methods for inhibiting, reducing, or shortening influenza virus replication or infection in a human subject, and methods for treating influenza infection or related conditions in a human subject in need thereof. The method comprises administering a zanamivir-Fc conjugate having a structure of formula (I) at a dose of 10 mg to 900 mg.

Description

Background Technology

[0001] The need for novel antiviral treatments for influenza is significant and particularly critical in the medical field. The influenza virus, the pathogen of influenza, causes three to five million severe cases each year, resulting in approximately half a million deaths globally. While most people fully recover from influenza within one to two weeks, others develop life-threatening complications such as pneumonia. Therefore, influenza can be fatal, especially for young people, the elderly, or those with chronic illnesses. People with weakened or compromised immune systems, such as those with advanced HIV infection or transplant recipients (whose immune systems are suppressed for medical reasons to prevent organ rejection), are more susceptible to influenza complications. Pregnant women and young children are also at high risk of complications.

[0002] Developing treatments against influenza viruses remains an ongoing challenge. Several antiviral drugs have been approved for clinical use, playing a crucial role in modulating disease severity and controlling pandemics during vaccine development. However, resistant strains have emerged for the most commonly used inhibitors.

[0003] Antiviral drugs primarily target proteins on the surface of influenza virus particles. The influenza virus envelope contains two immunodominant glycoproteins, hemagglutinin and neuraminidase, which play crucial roles in viral infection and transmission. Hemagglutinin initiates viral entry by interacting with surface sialic acid, allowing the virus to attach to host cells. Neuraminidase is an exoglycosidase that cleaves sialic acid (terminal neuraminidase residues) from the glycan structure on the surface of infected host cells, releasing progeny viruses and allowing the virus to spread from host cells to uninfected surrounding cells. Therefore, inhibiting neuraminidase can serve as a pharmacological target for antiviral drugs. Viral neuraminidase inhibitors have been identified for reducing viral transmission, including oseltamivir (Tamiflu™), zanamivir (Relenza™), and peramivir (Rapivab™).

[0004] Influenza in transplant recipients still exhibits prolonged viral shedding, increasing the likelihood of drug-resistant strains developing. New and more effective treatments for influenza are needed. Summary of the Invention

[0005] In a first aspect, this disclosure provides a method for inhibiting, reducing, or shortening influenza virus replication or infection in a human subject. The method comprises or consists of administering, subcutaneously or intramuscularly, a conjugate of formula (I) to a human subject at a dose of 10 mg to 900 mg (e.g., 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 150 mg, 300 mg, 450 mg, or 900 mg), wherein the conjugate of formula (I) has the following structure: Formula I Each E is a single entity of the Fc structural domain; n is 2; T is an integer from 3 to 6; and The wavy line represents a nitrogen atom of lysine or a sulfur atom of cysteine ​​in E that is covalently attached to the solvent.

[0006] In another aspect, this disclosure provides a method for treating human subjects suffering from or at risk of influenza infection. The method comprises or consists of administering, subcutaneously or intramuscularly, a conjugate of formula (I) to the human subject at a dose of 10 mg to 900 mg.

[0007] On the other hand, this disclosure provides methods for reducing the area under the curve (VL-AUC) of influenza viral load in human subjects (e.g., human subjects with influenza infection), reducing the time to peak influenza viral load, reducing the time to a negative influenza test, reducing the total clinical symptom score (TSS-AUC), lowering the peak TSS, or shortening the time to symptom resolution. These methods include or consist of administering 10 mg to 900 mg of the conjugate of formula (I) subcutaneously or intramuscularly to human subjects.

[0008] On the other hand, this disclosure provides a method for inhibiting, reducing, or shortening influenza virus replication or infection in human subjects, wherein the method comprises or consists of maintaining a minimum plasma concentration of the conjugate of formula (I) at at least 300 ng / mL for four to six months. In some embodiments, the method comprises or consists of maintaining a minimum plasma concentration of the conjugate at at least 1 μg / mL. In some embodiments, the minimum plasma concentration of the conjugate in the subject is maintained at at least 300 ng / mL for six months. In some embodiments, the minimum plasma concentration of the conjugate in the subject is maintained at at least 300 ng / mL for four months. In some embodiments, the minimum plasma concentration of the conjugate in the subject is maintained at at least 1 μg / mL for six months. In some embodiments, the minimum plasma concentration of the conjugate in the subject is maintained at at least 1 μg / mL for four months.

[0009] In some embodiments of any of the above methods, the method comprises: a single administration of the conjugate to a human subject. In some embodiments, a single dose of the conjugate of 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 150 mg, 300 mg, 450 mg, or 900 mg is administered to a human subject.

[0010] In some embodiments of any of the above methods, the method includes or comprises administering the conjugate to a human subject two or more times (e.g., three or four times). In some embodiments, the method includes or comprises administering the conjugate to a human subject twice, wherein the two administrations are spaced 60 to 120 days apart (e.g., 75 to 105 days apart).

[0011] In some embodiments, a single dose of the conjugate is administered, comprising 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 150 mg, 300 mg, 450 mg, or 900 mg.

[0012] In some embodiments of any of the methods described above, the conjugate is conjugate A, which has the structure provided herein.

[0013] In another aspect, this disclosure provides unit dosage forms of pharmaceutical compositions, wherein the pharmaceutical composition comprises 10 mg to 900 mg of a conjugate of formula (I) (e.g., conjugate A). In some embodiments, the pharmaceutical composition comprises 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 150 mg, 300 mg, 450 mg, or 900 mg of the conjugate.

[0014] In another respect, this disclosure provides a kit comprising the above-described pharmaceutical composition and instructions for use for any of the methods described herein.

[0015] In some embodiments of any of the foregoing aspects, the conjugate comprises an Fc domain comprising a protein having an amino acid sequence having at least 95% identity with the sequence of any one of SEQ ID NO:62, SEQ ID NO:63, SEQ ID NO:64, SEQ ID NO:67, SEQ ID NO:68, SEQ ID NO:72, SEQ ID NO:73, SEQ ID NO:76, SEQ ID NO:77, SEQ ID NO:80, SEQ ID NO:81, SEQ ID NO:82, SEQ ID NO:85, SEQ ID NO:86, SEQ ID NO:90, SEQ ID NO:91, SEQ ID NO:94, or SEQ ID NO:95. In some embodiments, the conjugate comprises an Fc domain comprising a protein having an amino acid sequence having any one of SEQ ID NO:63, SEQ ID NO:64, SEQ ID NO:67, SEQ ID NO:68, SEQ ID NO:72, SEQ ID NO:73, SEQ ID NO:76 or SEQ ID NO:77.

[0016] In some implementations, the influenza virus is influenza A virus. In some implementations, the influenza virus is influenza B virus. In some implementations, the influenza virus is influenza C virus.

[0017] definition To facilitate understanding of this invention, several terms are defined below. The terms defined herein have meanings commonly understood by one of ordinary skill in the art related to this invention. Terms such as “an,” “a,” and “the” are not intended to refer to a single entity, but rather to encompass general categories that can be illustrated using specific examples. The terms used herein are for describing specific embodiments of the invention, but their use does not limit the invention except as outlined in the claims.

[0018] "Influenza infection" refers to the pathogenic growth of the influenza virus in a host organism (e.g., a human subject). Influenza infection can be any situation in which a swarm of influenza viruses causes damage to the host. Therefore, a subject is "infected" with influenza virus infection when an excessive swarm of influenza virus is present in or on the subject's body, or when the presence of the viral swarm damages the subject's cells or other tissues.

[0019] As used herein, the term "Fc domain monomer" refers to a monomer that contains at least a hinge domain as well as second and third antibody constant domains (C). H 2 and C H3) or a polypeptide chain of a functional fragment thereof (e.g., a fragment capable of: (i) dimerizing with another Fc domain monomer to form an Fc domain, and (ii) binding to an Fc receptor). The Fc domain monomer can be any immunoglobulin antibody isotype, including IgG, IgE, IgM, IgA, or IgD (e.g., IgG). Additionally, the Fc domain monomer can be an IgG subtype (e.g., IgG1, IgG2a, IgG2b, IgG3, or IgG4) (e.g., IgG1). The Fc domain monomer does not contain any portion of an immunoglobulin capable of serving as an antigen recognition region, such as a variable domain or complementarity-determining region (CDR). The Fc domain monomer in the conjugates described herein may contain one or more variations (e.g., 1-10, 1-8, 1-6, 1-4 amino acid substitutions, additions, or deletions) relative to the wild-type Fc domain monomer sequence, which alter the interaction between the Fc domain and the Fc receptor. Examples of suitable variations are known in the art. In some embodiments, the human Fc domain monomer (e.g., the IgG heavy chain, such as IgG1) includes a region extending from any of Asn208, Glu216, Asp221, Lys222, or Cys226 to the C-terminus Lys447 of the heavy chain. The C-terminal Lys447 of the Fc region may be present or absent without affecting the structure or stability of the Fc region. The C-terminal Lys447 can be cleaved by proteolytic hydrolysis after peptide expression. In some embodiments of any Fc domain monomer described herein, the C-terminal Lys447 may optionally be present or absent. This disclosure specifically contemplates SEQ ID NOs: 1-4, 11, 16, 19, 20, 32-37, 48-53, and 60-68 that do not contain a C-terminal Lys corresponding to Lys447. The N-terminal N (Asn) of the Fc region (e.g., any of SEQ ID NO: 60-77) may or may not be present without affecting the structure or stability of the Fc region. The N-terminal Asn may be deamidated during peptide expression. In some embodiments of any Fc domain monomer described herein, the N-terminal Asn may optionally be present or absent. This disclosure specifically contemplates any of SEQ ID NO: 60-77 that does not contain an N-terminal Asn. Unless otherwise stated herein, the amino acid residues in the IgG or Fc domain monomer are numbered according to the antibody EU numbering system (also known as the Kabat EU index), such as, for example, Kabat et al. Sequences of Proteins of Immunological Interest As described in the 5th edition, Public Health Service, National Institutes of Health, Bethesda, MD, 1991.

[0020] As used herein, the term "Fc domain" refers to a dimer of two Fc domain monomers capable of binding to the Fc receptor. In the wild-type Fc domain, the two Fc domain monomers bind through two C-terminals. H 3. The interaction between the constant structural domains of the antibody dimerizes, and in some embodiments, one or more disulfide bonds are formed between the hinge domains of the two dimerized Fc domain monomers.

[0021] As used herein, "surface-exposed amino acid" or "solvent-exposed amino acid," such as surface-exposed cysteine ​​or surface-exposed lysine, refers to an amino acid that is solvent-accessible to a protein. Surface-exposed amino acids can be naturally occurring or engineered variants of the protein (e.g., substituted or inserted). In some embodiments, surface-exposed amino acids are those that, when substituted, do not substantially alter the three-dimensional structure of the protein.

[0022] As used herein, the term "treatment" means the administration of a pharmaceutical composition for preventive and / or therapeutic purposes. "Prevention of disease" means the preventive treatment of a subject who is not yet ill but is susceptible to or at risk of contracting a disease. "Treatment" of a human subject with influenza infection means treating a subject who already has influenza infection to improve or stabilize the subject's condition. Therefore, in the claims and embodiments, treatment is the administration of the medication to a subject for therapeutic or preventive purposes.

[0023] As used herein, the term "T" refers to the number of dimers of the neuraminidase inhibitor conjugated to the Fc domain within a population of conjugates. In some embodiments, the average number of dimers of the neuraminidase inhibitor conjugated to the Fc domain monomer within a population of conjugates (i.e., the average value of T) can be from 1 to 20 (e.g., an average value of T of 3 to 6 or 3.5 to 5.5). In some embodiments, the average value of T is 4.5.

[0024] As used herein, the term "pharmaceutical composition" refers to a pharmaceutical or pharmaceutical preparation containing a conjugate of formula (I) and one or more excipients and diluents to suit the active ingredient for a method of administration. The pharmaceutical compositions disclosed herein comprise pharmaceutically acceptable components compatible with the conjugate of formula (I).

[0025] As used herein, the term "pharmaceuticalally acceptable carrier" refers to an excipient or diluent in a pharmaceutical composition. For example, a pharmaceutically acceptable carrier can be a medium capable of suspending or dissolving the (I) conjugate. A pharmaceutically acceptable carrier must be compatible with the other components of the formulation and harmless to the recipient. In this disclosure, a pharmaceutically acceptable carrier must provide sufficient pharmaceutical stability for the conjugate described herein.

[0026] As used herein, the term "pharmaceutically acceptable salt" refers to a salt of a conjugate of formula (I) that, to the extent of reasonable medical judgment, is suitable for use as described herein without undue toxicity, irritation, and / or anaphylactic response. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in the following literature: Pharmaceutical Salts: Properties, Selection, and Use (Edited by PH Stahl and CG Wermuth), Wiley-VCH, 2008. The salt can be prepared in situ during the final separation and purification of the conjugates described herein, or prepared separately by reacting the free base group with a suitable organic acid.

[0027] The term “drug-to-antibody ratio” or “DAR” refers to the average number of small molecule drug moieties conjugated to an Fc domain (e.g., the average number of small molecule drug monomers or dimers). In some embodiments described herein, DAR is represented by “T” (e.g., in formula (I)). As used herein, each dimer moieties conjugated to an Fc domain corresponds to a DAR value of 1.0 (e.g., “T” is 1.0). For example, the DAR of an Fc domain conjugated to four zanamivir dimers is 4.0 (e.g., “T” is 4.0). DAR can also be calculated as the average DAR of a population of molecules (e.g., a population of Fc domains). DAR values ​​can affect the efficacy, potency, pharmacokinetics, or toxicity of a drug.

[0028] "Formula (I) conjugate" refers to a conjugate having the following structure: Formula I Each E contains an Fc domain monomer; n is 2; T is an integer from 3 to 6; the wavy line represents a nitrogen atom of a lysine exposed to the solvent in E or a sulfur atom of a cysteine ​​exposed to the solvent. In the conjugate, the zanamivir dimer is conjugated to each solvent-exposed lysine on the Fc domain monomer.

[0029] "Conjugate A" refers to conjugate of formula (I), wherein the average value of T is approximately 4.5, and each E has the sequence of SEQ ID NO:76. Attached Figure Description

[0030] Figure 1A It is a summary of the clinical trial research protocol. Figure 1B This is a summary of the handling of clinical trials.

[0031] Figure 2 It is a summary of demographic data of human subjects in clinical trials.

[0032] Figure 3This is a box plot of viral load-time area under the curve (VL-AUC) data for placebo and conjugate A.

[0033] Figure 4 This is a graph showing the average viral load over eight days for placebo and conjugate A, as measured by qRT-PCR.

[0034] Figure 5 This is a box plot of peak viral load data for placebo and conjugate A.

[0035] Figure 6 This is a graph showing the time from placebo and conjugate A to a negative influenza test, as determined by qRT-PCR.

[0036] Figure 7 This is a box plot of the area under the curve of the total clinical symptom score (TSS-AUC) over time for placebo and conjugate A.

[0037] Figure 8 This is a graph showing the change in mean total clinical symptom score (TSS) over time for placebo and conjugate A.

[0038] Figure 9 This is a box plot of the peak total clinical symptom score (TSS) for placebo and conjugate A.

[0039] Figure 10 This is a graph showing the time to symptom resolution for placebo and conjugate A.

[0040] Figure 11 This is a graph showing the relationship between the average plasma concentration of conjugate A per single dose, administered via intramuscular or subcutaneous injection, and time.

[0041] Figure 12 This is a graph showing the relationship between the average plasma concentration of conjugate A per single dose, administered via intramuscular or subcutaneous injection, and time.

[0042] Figure 13 This is a graph showing the relationship between the average plasma concentration of conjugate A after a single dose of 50 mg or 150 mg administered via intramuscular or subcutaneous injection and time, expressed on a semi-logarithmic scale.

[0043] Figure 14 This is a graph showing the relationship between the average plasma concentration of conjugate A per single dose, administered via intramuscular or subcutaneous injection of 50 mg, 150 mg, or 450 mg, and time, expressed on a semi-logarithmic scale.

[0044] Figure 15 This is a graph showing the average AUC of conjugate A as a function of the dose (mg) of conjugate A when administered intramuscularly and subcutaneously.

[0045] Figure 16 It shows the relationship relative to individual C. max The plot shows the predicted median concentration of conjugate A (line) and the 10th and 90th percentage points (grey shaded areas). Day 5 is shown as the dashed vertical line. The gray rectangles represent the hospitalization observation period of participants in the human challenge study.

[0046] Figure 17 This is a graph showing the model prediction of plasma concentrations for conjugate A, given a dose of 150 mg once, 300 mg once, or 150 mg twice. Detailed Implementation

[0047] influenza The conjugates and pharmaceutical compositions described herein can be used to treat influenza infections, such as influenza A, B, or C.

[0048] Influenza viruses are associated with serious human illness and cause annual epidemics during the fall and winter. While most people recover from seasonal influenza on their own within one to two weeks without medical attention, millions are hospitalized globally each year, and approximately 650,000 die from influenza, particularly infants, the elderly, and those with chronic illnesses. In the United States, during the 2018-2019 flu season, an estimated 37.4 million to 42.9 million cases of symptomatic influenza-related illness, 17.3 million to 20.1 million influenza-related medical visits, 531,000 to 647,000 influenza-related hospitalizations, and 63,400 to 61,200 deaths were reported. European countries reported similar mortality and morbidity rates. These numbers remain high year after year because there are currently no effective drugs to prevent influenza. Currently, influenza A viruses H1N1 and H3N2 are circulating in humans, along with influenza B viruses. The H3N2 virus dominates for most seasons, causing more deaths and hospitalizations than H1N1 and influenza B viruses.

[0049] Progress in developing drugs that can prevent multiple influenza virus strains and provide long-lasting protection (also known as "universal vaccines") has been disappointing. Monoclonal antibody therapies developed to date have limited scope and commercialization due to high dosage requirements and / or the need for mixtures of multiple antibodies to achieve the desired range and efficacy. Therefore, there is a significant unmet need for long-acting universal protectants.

[0050] Establishing human influenza challenge models not only helps in understanding influenza disease and transmission but also allows for the evaluation of the efficacy of antiviral drugs, immunomodulators, and vaccines. To date, most studies have used the influenza H3N2 A / Perth / 16 / 2009 challenge strain. Studies have shown that the challenge virus induces measurable disease characteristics distinct from those in uninfected participants, with approximately 60% to 75% of study participants becoming infected after vaccination. Typical influenza disease characteristics include sudden onset of rhinitis, nasal congestion, fever, malaise, myalgia (muscle pain), and sore throat. In healthy adults, this illness usually resolves without treatment, with symptoms subsiding spontaneously within 3 to 5 days. The disease characteristics of the challenge agent are consistent with the expected mild to moderate disease characteristics of the wild-type challenge virus in healthy adult participants. In conclusion, the influenza H3N2 A / Perth / 16 / 2009 challenge virus is considered safe, well-tolerated, and induces appropriate disease pathogenesis, making it an effective viral challenge agent in human viral challenge (HVC) research.

[0051] Conjugate A – Long-lasting antiviral Fc conjugate Conjugate A is a crystallizable fragment (Fc) conjugate of zanamivir. Zanamivir is a small-molecule antiviral neuraminidase inhibitor. The small-molecule targeting group selectively binds to a small, conserved pocket on the surface of the virus, which is impossible with monoclonal antibodies.

[0052] Conjugate A differs from traditional antibody-drug conjugates in the following ways: In traditional antibody-drug conjugates, the drug binds to full-length human IgG (Fc plus antigen-binding fragment); conversely, the zanamivir dimer of conjugate A is conjugated to the Fc fragment of human IgG1 (instead of full-length IgG1). In the conjugate, the conjugation of the zanamivir dimer occurs at different solvent-exposed lysine residues on each Fc domain monomer. In some embodiments, the zanamivir dimer is conjugated to one or more solvent-exposed lysine residues, such as Lys205, Lys213, Lys218, Lys246, Lys317, Lys326, Lys334, Lys392, or combinations thereof.

[0053] In traditional antibody-drug conjugates, the drug is conjugated to human IgG via a protease-cleavable linker, allowing the drug to be released into the target cell; however, the linker between zanamivir and the Fc in conjugate A is not a substrate of the protease, and it exerts its antiviral activity in the extracellular space.

[0054] Traditional antibody-drug conjugates treat cancer by rapidly releasing cytotoxic payloads into target cells; conjugate A aims to treat and prevent infectious diseases by forming long-lasting, stable conjugates with a non-cytotoxic small molecule and the Fc fragment of IgG1.

[0055] The method for preparing conjugate A is described in U.S. Patent No. 11,510,992, the entire contents of which are incorporated herein by reference.

[0056] Fc structural domain Fc domains are dimers of two Fc domain monomers; these domains typically include hinge domains, C... H 2 Antibody constant structural domain and C H 3. Antibody constant domain. The Fc domain monomer can be an immunoglobulin antibody isotype IgG, IgE, IgM, IgA, or IgD. The Fc domain monomer can be any immunoglobulin antibody isotype (e.g., IgG1, IgG2a, IgG2b, IgG3, or IgG4). The Fc domain monomer can be any immunoglobulin antibody isotype (e.g., IGHG1*01 (i.e., G1m(za)), IGHG1*07 (i.e., G1m(zax)), IGHG1*04 (i.e., G1m(zav)), IGHG1*03 (G1m(f)), IGHG1*08). (i.e., G1m(fa)), IGHG2*01, IGHG2*06, IGHG2*02, IGHG3*01, IGHG3*05, IGHG3*10, IGHG3*04, IGHG3*09, IGHG3*11, IGHG3*12, IGHG3*06, IGHG3*0 7. IGHG3*08, IGHG3*13, IGHG3*03, IGHG3*14, IGHG3*15, IGHG3*16, IGHG3*17, IGHG3*18, IGHG3*19, IGHG2*04, IGHG4*01, IGHG4*03 or IGHG4*02) (For example, Vidarsson et al. IgG subclasses and allotypes: from structure to effector function. Frontiers in Immunology (As described in . 5(520):1-17(2014)). The Fc domain monomer can also be of any species, such as human, mouse, or rat. The dimer of the Fc domain monomer (i.e., the Fc domain) can bind to the Fc receptor, which is a receptor located on the surface of leukocytes.

[0057] In some embodiments, the Fc domain monomer in the conjugates described herein contains one or more amino acid substitutions, additions, and / or deletions relative to the Fc domain monomer having the sequence of any of SEQ ID NO: 1-138. In some embodiments, Asn in the Fc domain monomer of the conjugates described herein may be substituted with Ala to prevent N-linked glycosylation (see, for example, SEQ ID NO: 12-15, where the Asn-to-Ala substitution is marked with *). In some embodiments, the Fc domain monomer in the conjugates described herein may also contain additional Cys addition (see, for example, SEQ ID NO: 9, 10, and 11, where the Cys addition is marked with *).

[0058] In some embodiments, the Fc domain monomer in the conjugate described herein includes an additional moiety, such as an albumin-binding peptide, a purified peptide (e.g., a hexahistine peptide (HHHHHH (SEQ ID NO: 146)) or a signal sequence (e.g., the IL2 signal sequence MYRMQLLSCIALSLALVTNS (SEQ ID NO: 147)), which is linked to the N- or C-terminus of the Fc domain monomer. In some embodiments, the Fc domain monomer in the conjugate does not contain any type of antibody variable region, such as V H V L Complementary Determinant Region (CDR) or High Variable Region (HVR).

[0059] In some embodiments, the Fc domain monomer in the conjugate described herein may have a sequence having at least 95% identity (e.g., 97%, 99%, or 99.5% identity) with any of the sequences shown in SEQ ID NO: 1-138 below. In some embodiments, the Fc domain monomer in the conjugate described herein may have a sequence shown in any of SEQ ID NO: 1-138 below.

[0060] SEQ ID NO: 1: Mouse Fc-IgG2a (bolded) with an N-terminal IL2 signal sequence. MYRMQLLSCIALSLALVTNSPRGPTIKPCPPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVDVSEDDPDVQISWFVNNVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMSGKEFKC KVNNKDLPAPIERTISKPKGSVRAPQVYVLPPPEEEMTKKQVTLTCMVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPGK SEQ ID NO: 2: Mature mouse Fc-IgG2a PRGPTIKPCPPCKCPAPNLLGGPSVFIFPPPKIKDVLMISLSPIVTCVVVDVSEDDPDVQISWFVNNVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAP IERTISKPKGSVRAPQVYVLPPPEEMTKKQVTLTCMVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPGK SEQ ID NO: 3: Human Fc-IgG1 with an N-terminal IL2 signal sequence (bolded) and an N-terminal MVRS amino acid residue (underlined). MYRMQLLSCIALSLALVTNS MVRS DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIE KTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 4: Mature human Fc-IgG1 with N-terminal MVRS amino acid residues (underlined) added. MVRSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIE KTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 5: Mouse Fc-IgG2a with an IL2 signal sequence (bold) at the N-terminus and a hexahistine peptide (italicized) at the C-terminus. MYRMQLLSCIALSLALVTNSPRGPTIKPCPPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVDVSEDDPDVQISWFVNNVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMSGKEFKC KVNNKDLPAPIERTISKPKGSVRAPQVYVLPPPEEEMTKKQVTLTCMVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPGK HHHHHH SEQ ID NO: 6: Mature mouse Fc-IgG2a with a hexahistine peptide (italicized) at the C-terminus PRGPTIKPCPPCKCPAPNLLGGPSVFIFPPPKIKDVLMISLSPIVTCVVVDVSEDDPDVQISWFVNNVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAP IERTISKPKGSVRAPQVYVLPPPEEMTKKQVTLTCMVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPGK HHHHHH SEQ ID NO: 7: Human Fc-IgG1 with an IL2 signal sequence (bold) at the N-terminus, an added N-terminal MVRS amino acid residue (underlined), and a hexahistine peptide (italicized) at the C-terminus. MYRMQLLSCIALSLALVTNS MVRS DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIE KTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK HHHHHH SEQ ID NO: 8: Mature human Fc-IgG1 with a C-terminal hexahistine peptide (italicized) and an N-terminal MVRS amino acid residue (underlined). MVRS DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIE KTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK HHHHHH SEQ ID NO: 9: Human Fc-IgG1 with an N-terminal IL2 signal sequence (bold), an added N-terminal MVRS amino acid residue (underlined), two extra cysteine ​​residues (*) in the hinge region, and a hexahistine peptide (italicized) at the C-terminus. MYRMQLLSCIALSLALVTNS MVRSDKTHTCPPCPPC*KC*PAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK HHHHHH SEQ ID NO: 10: Mature human Fc-IgG1 with the addition of an N-terminal MVRS amino acid residue (underlined), two extra cysteine ​​residues (*) in the hinge region, and a six-histidine peptide (italicized) at the C-terminus. MVRS DKTHTCPPCPPC*KC*PAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK HHHHHH SEQ ID NO: 11: Mature human Fc-IgG1 with the addition of N-terminal MVRS amino acid residues (underlined) and two extra cysteine ​​residues (*) in the hinge region. MVRS DKTHTCPPCPPC*KC*PAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 12: Mouse Fc-IgG2a with an IL2 signal sequence (bolded) at the N-terminus, substitutions from Asn to Ala (*) and a hexahistine peptide (italicized) at the C-terminus. MYRMQLLSCIALSLALVTNSPRGPTIKPCPPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVDVSEDDPDVQISWFVNNVEVHTAQTQTHREDYA*STLRVVSALPIQHQDWMSGKEFK CKVNNKDLPAPIERTISKPKGSVRAPQVYVLPPPEEEMTKKQVTLTCMVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPGK HHHHHH SEQ ID NO: 13: Mature mouse Fc-IgG2a with Asn to Ala substitutions (*) and a hexahistine peptide (italicized) at the C-terminus. PRGPTIKPCPPCKCPAPNLLGGPSVFIFPPPKIKDVLMISLSPIVTCVVVDVSEDDPDVQISWFVNNVEVHTAQTQTHREDYA*STLRVVSALPIQHQDWMSGKEFKCKVNNKDLPA PIERTISKPKGSVRAPQVYVLPPPEEMTKKQVTLTCMVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPGK HHHHHH SEQ ID NO: 14: Human Fc-IgG1 with an N-terminal IL2 signal sequence (bold), an added N-terminal MVRS amino acid residue (underlined), substitutions from Asn to Ala (*), and a hexahistine peptide (italicized) at the C-terminus. MYRMQLLSCIALSLALVTNS MVRSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYA*STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIE KTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK HHHHHH SEQ ID NO: 15: Mature human Fc-IgG1 with substitutions from Asn to Ala (*), the addition of N-terminal MVRS amino acid residues (underlined), and a hexahistine peptide (italicized) at the C-terminus. MVRS DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYA*STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIE KTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK HHHHHH SEQ ID NO: 16: Human IgG1 Fc with the human serum albumin signal sequence (bold) at the N-terminus and the addition of N-terminal ISAMVRS amino acid residues (underlined). MKWVTFISLLFLFSSAYS ISAMVRS DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIE KTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 17: Human IgG1 Fc with the human serum albumin signal sequence (bold) at the N-terminus, the addition of N-terminal ISAMVRS amino acid residues (underlined), and the presence of a C-terminal G4S linker (italicized) and a C-terminal c-Myc tag (underlined, italicized). MKWVTFISLLFLFSSAYS ISAMVRS DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIE KTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG GGG G S EQKLISEEDL SEQ ID NO: 18: Mature human IgG1 Fc with N-terminal ISAMVRS amino acid residues (underlined) and a C-terminal G4S linker (italicized) and a C-terminal c-Myc tag (underlined, italicized) added. ISAMVRS DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIE KTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG GGG G S EQKLISEEDL SEQ ID NO: 19: Human IgG1 Fc with the human serum albumin signal sequence (bolded), N-terminal ISAMVRS amino acid residues added (underlined), and lysine to serine modification (*) to prevent lysine conjugation at this site. MKWVTFISLLFLFSSAYS ISAMVRSDKTHTCPPCPAPELLGGPSVFLFPPKPS*DTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIE KTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 20: Mature human IgG1 Fc with added N-terminal ISAMVRS amino acid residues (underlined) and lysine-to-serine modification (*) to prevent lysine conjugation at this site. ISAMVRS DKTHTCPPCPAPELLGGPSVFLFPPKPS*DTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIE KTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 21: Human IgG1 Fc with the human serum albumin signal sequence (bold) at the N-terminus, N-terminal ISAMVRS amino acid residues (underlined), lysine to serine modification (*) to prevent lysine conjugation at this site, and a C-terminal G4S linker (italicized) and a C-terminal C-Myc tag (underlined, italicized). MKWVTFISLLFLFSSAYS ISAMVRS DKTHTCPPCPAPELLGGPSVFLFPPKPS(*)DTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAP IEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG GGGGS EQKLISEEDL SEQ ID NO: 22: Mature human IgG1 Fc with N-terminal ISAMVRS amino acid residues (underlined), lysine-to-serine modification (*) to prevent lysine conjugation at this site, and a C-terminal G4S linker (italicized) and a C-terminal C-Myc tag (underlined, italicized). ISAMVRS DKTHTCPPCPAPELLGGPSVFLFPPKPS(*)DTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAP IEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG GGGGS EQKLISEEDL SEQ ID NO: 23: Human IgG1 Fc with the human serum albumin signal sequence (bold) at the N-terminus, the addition of N-terminal ISAMVRS amino acid residues (underlined), substitutions from Asn to Ala (*), and a C-terminal G4S linker (italicized) and a C-terminal C-myc tag (underlined, italicized). MKWVTFISLLFLFSSAYS ISAMVRS DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYA(*)STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAP IEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG GGGGS EQKLISEEDL SEQ ID NO: 24: Mature human IgG1 Fc with N-terminal ISAMVRS amino acid residues (underlined), substitutions from Asn to Ala (*), and a C-terminal G4S linker (italicized) and a C-terminal C-myc tag (underlined, italicized). ISAMVRS DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYA(*)STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAP IEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG GGGGS EQKLISEEDL SEQ ID NO: 25: Human IgG1 Fc with the human serum albumin signal sequence (bold) at the N-terminus, the addition of N-terminal ISAMVRS amino acid residues (underlined), the presence of H310A(*) and H435A(*) mutations that inhibit FcRn binding, and the presence of C-terminal G4S (italicized) and C-terminal C-myc tags (underlined, italicized). MKWVTFISLLFLFSSAYS ISAMVRS DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLA(*)QDWLNGKEYKCKVSNKALPAPIE KTISKA(*)KGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNAYTQKSLSLSPG GGGGS EQKLISEED L SEQ ID NO: 26: Mature human IgG1 Fc with the human serum albumin signal sequence (bold) at the N-terminus, the addition of N-terminal ISAMVRS amino acid residues (underlined), the presence of H310A(*) and H435A(*) mutations that inhibit FcRn binding, and the presence of C-terminal G4S (italicized) and C-terminal C-myc tags (underlined, italicized). ISAMVRSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLA(*)QDWLNGKEYKCKVSNKALPAPIE KTISKA(*)KGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNAYTQKSLSLSPG GGGGS EQKLISEEDL SEQ ID NO: 27: Human IgG1 Fc with the human serum albumin signal sequence (bold) at the N-terminus, the addition of N-terminal ISAMVRS amino acid residues (underlined), and the presence of a C-terminal G4S linker (italicized) and a C-terminal mutated (lysine to phenylalanine, bolded) C-myc tag (underlined, italicized). MKWVTFISLLFLFSSAYS ISAMVRS DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIE KTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG GGGGS EQFLISEEDL SEQ ID NO: 28: Mature human IgG1 Fc with N-terminal ISAMVRS amino acid residues (underlined) and a C-terminal G4S linker (italicized) and a C-terminal mutated (lysine to phenylalanine, bolded) C-myc tag (underlined, italicized). ISAMVRSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIE KTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG GGG G S EQFLISEEDL SEQ ID NO: 29: Human IgG1 Fc with the human serum albumin signal sequence (bold) at the N-terminus, the addition of N-terminal ISAMVRS amino acid residues (underlined), substitutions from Asn to Ala (*), and a C-terminal G4S linker (italicized) and a C-terminal mutated (lysine to phenylalanine, bolded) C-myc tag (underlined, italicized). MKWVTFISLLFLFSSAYS ISAMVRS DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYA(*)STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAP IEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG GGG G S EQFLISEEDL SEQ ID NO: 30: Mature human IgG1 Fc with N-terminal MVRS amino acid residues (underlined), substitutions (*) from Asn to Ala, a C-terminal G4S linker (italicized), and a C-terminal mutated (lysine to phenylalanine, bolded) C-myc tag (underlined, italicized). ISAMVRSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYA(*)STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAP IEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG GGG G S EQFLISEEDL SEQ ID NO: 31: Human IgG1 Fc with a human serum albumin signal sequence (bold) at the N-terminus, an allotype G1m(fa) (bold italic), a C-terminal G4S linker (italic), and a C-terminal mutated (lysine to phenylalanine, bold) C-myc tag (underlined). MKWVTFISLLFLFSSAYSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR D E L TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG GGGGS EQFLISEEDL SEQ ID NO: 32: Human IgG1 Fc with a human serum albumin signal sequence (bold) at the N-terminus and possessing the allotype G1m(fa) (bold italic). MKWVTFISLLFLFSSAYSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR D E LTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 33: Mature human IgG1 Fc with YTE triple mutation (bold and underlined) and the addition of N-terminal MVRS amino acid residues (underlined). MVRS DKTHTCPPCPAPELLGGPSVFLFPPKPKDTL Y I T R E PEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTL PPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 34: Human IgG1 Fc with the human serum albumin signal sequence (bold) at the N-terminus, containing the residue EPKSS (underlined) of the complete hinge region at the N-terminus including mature human IgG1 Fc, and having Cys to Ser substitutions (#) and allotype G1m(fa) (bold italic). MKWVTFISLLFLFSSAYS EPKSS (#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR D E L TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 35: Human IgG1Fc with a mouse IgG signal sequence (bold) at the N-terminus, having the EPKSSD hinge residue removed from the N-terminus of mature human IgG1 Fc and possessing an allotype G1m(fa) (bold italic). MGWSCIILFLVATATGVHSKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR D E L TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 36: Mature human IgG1 Fc with YTE triple mutation (bold and underlined), removal of EPKSSD hinge residues from the N-terminus of mature human IgG1 Fc, and possessing allotype G1m(fa) (bold italic). KTHTCPPCPAPELLGGPSVFLFPPKPKDTL Y I T R E PEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR D E L TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 37: Mature human IgG1 Fc with LS double mutation (bold and underlined), removal of EPKSSD hinge residues from the N-terminus of mature human IgG1 Fc, and possessing allotype G1m(fa) (bold italic). KTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR D E LTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSV L HEALH S HYTQKSLSLSPGK SEQ ID NO: 38: Mature human IgG1 Fc with a human serum albumin signal sequence (bold) at the N-terminus, a YTE triple mutation (bold and underlined), an allotype G1m(fa) (bold italic), and a C-terminal G4S linker (italic) and a C-terminal C-myc tag (underlined). MKWVTFISLLFLFSSAYSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTL Y I T R E PEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR D E L TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG GGGGS EQKLISEEDL SEQ ID NO: 39: Mature human Fc IgG1, wherein X1 is Met or Tyr, X2 is Ser or Thr, X3 is Thr or Glu, X4 is Asp or Glu, X5 is Leu or Met, X6 is Met or Leu, and X7 is Asn or Ser DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLX1IX2RX3PEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIE KTISKAKGQPREPQVYTLPPSRX4EX5TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVX6HEALHX7HYTQKSLSLSPG SEQ ID NO: 40: Mature human Fc IgG1, wherein X4 is Asp or Glu, and X5 is Leu or Met. DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEK TISKAKGQPREPQVYTLPPSRX4EX5TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG SEQ ID NO: 41: Mature human Fc IgG1 with a YTE triple mutation (bold and underlined), wherein X4 is Asp or Glu, and X5 is Leu or Met. DKTHTCPPCPAPELLGGPSVFLFPPKPKDTL Y I T R E PEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLP PSRX4EX5TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG SEQ ID NO: 42: Mature human Fc IgG1 with YTE triple mutation (bold and underlined) and allotype G1m(fa) (bold italic). DKTHTCPPCPAPELLGGPSVFLFPPKPKDTL Y I T R E PEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR D E LTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG SEQ ID NO: 43: Mature human Fc IgG1 with YTE triple mutation (bold and underlined) and allotype G1m(f) (bold italic). DKTHTCPPCPAPELLGGPSVFLFPPKPKDTL Y I T R E PEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR E E M TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG SEQ ID NO: 44: Mature human Fc IgG1 with LS double mutation (bold and underlined), wherein X4 is Asp or Glu and X5 is Leu or Met. DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVS NKALPAPIEKTISKAKGQPREPQVYTLPPSRX4EX5TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSV L HEALH S HYTQKSLSLSPG SEQ ID NO: 45: Mature human Fc IgG1 with LS double mutation (bold and underlined) and allotype G1m(fa) (bold italic). DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR D E L TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSV L HEALH S HYTQKSLSLSPG SEQ ID NO: 46: Mature human Fc IgG1 with LS double mutation (bold and underlined) and allotype G1m(f) (bold italic). DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR E E M TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSV L HEALH S HYTQKSLSLSPG SEQ ID NO: 47: Mature human Fc IgG1 with a mouse heavy chain MIgG Vh signal sequence (bolded) and Cys to Ser substitutions (#), wherein X1 is Met or Tyr, X2 is Ser or Thr, X3 is Thr or Glu, X4 is Asp or Glu, X5 is Leu or Met, X6 is Met or Leu, and X7 is Asn or Ser MGWSCIILFLVATATGVHSNVNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKDTLX1IX2RX3PEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQD WLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRX4EX5TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVX6HEALHX7HYTQKSLSLSPG SEQ ID NO: 48: Mature human IgG1 Fc with mouse heavy chain MIgG Vh signal sequence (bold), Cys to Ser substitution (#) and allotype G1m(fa) (bold italic). MGWSCIILFLVATATGVHSNVNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR D E L TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 49: Mature human IgG1 Fc with mouse heavy chain MIgG Vh signal sequence (bold), Cys to Ser substitution (#) and allotype G1m(f) (bold italic). MGWSCIILFLVATATGVHSNVNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR E E MTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 50: Mature human IgG1 Fc with mouse heavy chain MIgG Vh signal sequence (bold), Cys to Ser substitution (#), M428L, N434S mutations (bold / underlined) and allotype G1m(fa) (bold italic). MGWSCIILFLVATATGVHSNVNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR D E L TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSV L HEALH S HYTQKSLSLSPGK SEQ ID NO: 51: Mature human IgG1 Fc with mouse heavy chain MIgG Vh signal sequence (bold), Cys to Ser substitution (#), M428L, N434S mutations (bold / underlined) and allotype G1m(f) (bold italic). MGWSCIILFLVATATGVHSNVNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR E E M TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSV L HEALH S HYTQKSLSLSPGK SEQ ID NO: 52: Mature human IgG1 Fc with mouse heavy chain MIgG Vh signal sequence (bold), Cys to Ser substitution (#), YTE triple mutation (bold and underlined) and allotype G1m(fa) (bold italic). MGWSCIILFLVATATGVHSNVNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTL Y I T R E PEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR D E L TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 53: Mature human IgG1 Fc with mouse heavy chain MIgG Vh signal sequence (bold), Cys to Ser substitution (#), YTE triple mutation (bold and underlined), and allotype G1m(f) (bold italic). MGWSCIILFLVATATGVHSNVNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTL Y I T R E PEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR E E M TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 54: Mature human IgG1 Fc containing the mouse heavy chain MIgG Vh signal sequence (bold), with added N-terminal ISAMVRS amino acid residues (italic), M428L and N434S mutations (bold / underlined), a G4S linker (italic), a C-terminal C-myc tag (underlined), and an allotype G1m(f) (bold italic). MGWSCIILFLVATATGVHS ISAMVRS DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR E E M TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSV L HEALH S HYTQKSLSLSPG GGGGS EQKLISEEDL SEQ ID NO: 55: Mature human IgG1 Fc containing the mouse heavy chain MIgG Vh signal sequence (bold), with the addition of N-terminal ISAMVRS amino acid residues (italic), M428L and N434S mutations (bold / underlined), G4S linker (italic), C-terminal C-myc tag (underlined), and allotype G1m(fa) (bold italic). MGWSCIILFLVATATGVHS ISAMVRS DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR D E L TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSV L HEALH S HYTQKSLSLSPG GGGGS EQKLISEEDL SEQ ID NO: 56: Mature human IgG1 Fc containing the mouse heavy chain MIgG Vh signal sequence (bold), with the addition of N-terminal ISAMVRS amino acid residues (italic), YTE triple mutation (bold / underlined), G4S linker (italic), and C-terminal C-myc tag (underlined), and allotype G1m(f) (bold italic). MGWSCIILFLVATATGVHS ISAMVRS DKTHTCPPCPAPELLGGPSVFLFPPKPKDTL Y I T R E PEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR E E M TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG GGGGS EQKLISEEDL SEQ ID NO: 57: Mature human IgG1 Fc with mouse heavy chain MIgG Vh signal sequence (bold), N-terminal ISAMVRS amino acid residues added (italic), YTE triple mutation (bold / underlined), G4S linker (italic), C-terminal C-myc tag (underlined), and allotype G1m(fa) (bold italic). MGWSCIILFLVATATGVHS ISAMVRS DKTHTCPPCPAPELLGGPSVFLFPPKPKDTL Y I T R E PEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR D E L TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG GGGGS EQKLISEEDL SEQ ID NO: 58: Mature human IgG1 with mouse heavy chain MIgG1 signal sequence (bold), Cys to Ser substitution (#), C-terminal G4S (italic) and C-terminal IgA peptide (underlined), and allotype G1m(fa) (bold italic). MGWSCIILFLVATATGVHSEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR D E L TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG GGGGS QRNPRLRLIRRHPTLRIPPI SEQ ID NO: 59: Mature human IgG1 with mouse heavy chain MIgG1 signal sequence (bold), Cys to Ser substitution (#), M428L and N434S mutations (bold / underlined), C-terminal G4S (italic) and C-terminal IgA peptide (underlined), and allotype G1m(fa) (bold italic). MGWSCIILFLVATATGVHSEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR D E L TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSV L HEALH S HYTQKSLSLSPG GGGGS QRNPRLRLIRRHPTLRIPPI SEQ ID NO: 60: Mature human Fc IgG1, Z1 is Cys or Ser, and X1 is Met or Tyr, X2 is Ser or Thr, X3 is Thr or Glu, X4 is Asp or Glu, X5 is Leu or Met, X6 is Met or Leu, and X7 is Asn or Ser NVNHKPSNTKVDKKVEPKSZ1DKTHTCPPCPAPELLGGPSVFLFPPKDTLX1IX2RX3PEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKV SNKALPAPIEKTISKAKGQPREPQVYTLPPSRX4EX5TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVX6HEALHX7HYTQKSLSLSPGK SEQ ID NO: 61: Mature human Fc IgG1, Cys to Ser substitution (#), wherein X1 is Met or Tyr, X2 is Ser or Thr, X3 is Thr or Glu, X4 is Asp or Glu, X5 is Leu or Met, X6 is Met or Leu, and X7 is Asn or Ser. NVNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSSVFLFPPKPKDTLX1IX2RX3PEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCK VSNKALPAPIEKTISKAKGQPREPQVYTLPPSRX4EX5TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVX6HEALHX7HYTQKSLSLSPGK SEQ ID NO: 62: Mature human IgG1 Fc, Cys to Ser substitution (#), X4 is Asp or Glu, and X5 is Leu or Met NVNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRX4EX5TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 63: Mature human IgG1 Fc, Cys-to-Ser substitution (#), allotype G1m(f) (bold italic) NVNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR E E M TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 64: Mature human IgG1 Fc, Cys-to-Ser substitution (#), allotype G1m(fa) (bold italic) NVNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR D E L TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 65: Mature human IgG1 Fc, Cys to Ser substitution (#), M428L, N434S mutation (bold / underlined), allotype G1m(fa) (bold italic) NVNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR D E L TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSV L HEALH S HYTQKSLSLSPGK SEQ ID NO: 66: Mature human IgG1 Fc, Cys to Ser substitution (#), M428L, N434S mutations (bold / underlined), allotype G1m(f) (bold italic) NVNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR E E M TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSV L HEALH S HYTQKSLSLSPGK SEQ ID NO: 67: Mature human IgG1 Fc, Cys to Ser substitution (#), YTE triple mutation (bold and underlined), allotype G1m(fa) (bold italic) NVNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTL Y I T R EPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR D E L TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 68: Mature human IgG1 Fc, Cys to Ser substitution (#), YTE triple mutation (bold and underlined), allotype G1m(f) (bold italic) NVNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTL Y I T R E PEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR E E M TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 69: Mature human Fc IgG1, Z1 is Cys or Ser, and X1 is Met or Tyr, X2 is Ser or Thr, X3 is Thr or Glu, X4 is Asp or Glu, X5 is Leu or Met, X6 is Met or Leu, and X7 is Asn or Ser NVNHKPSNTKVDKKVEPKSZ1DKTHTCPPCPAPELLGGPSVFLFPPKDTLX1IX2RX3PEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKV SNKALPAPIEKTISKAKGQPREPQVYTLPPSRX4EX5TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVX6HEALHX7HYTQKSLSLSPG SEQ ID NO: 70: Mature human Fc IgG1, Cys to Ser substitution (#), wherein X1 is Met or Tyr, X2 is Ser or Thr, X3 is Thr or Glu, X4 is Asp or Glu, X5 is Leu or Met, X6 is Met or Leu, and X7 is Asn or Ser. NVNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSSVFLFPPKPKDTLX1IX2RX3PEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCK VSNKALPAPIEKTISKAKGQPREPQVYTLPPSRX4EX5TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVX6HEALHX7HYTQKSLSLSPG SEQ ID NO: 71: Mature human IgG1 Fc, Cys to Ser substitution (#), X4 is Asp or Glu, and X5 is Leu or Met NVNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCK VSNKALPAPIEKTISKAKGQPREPQVYTLPPSRX4EX5TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG SEQ ID NO: 72: Mature human IgG1 Fc, Cys to Ser substitution (#), allotype G1m (f) (bold italic) NVNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR E E M TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG SEQ ID NO: 73: Mature human IgG1 Fc, Cys to Ser substitution (#), allotype G1m (fa) (bold italic text) NVNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR D E L TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG SEQ ID NO: 74: Mature human IgG1 Fc, Cys to Ser substitution (#), M428L, N434S mutation (bold / underlined), allotype G1m(fa) (bold italic) NVNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR D E LTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSV L HEALH S HYTQKSLSLSPG SEQ ID NO: 75: Mature human IgG1 Fc, Cys to Ser substitution (#), M428L, N434S mutations (bold / underlined), allotype G1m(f) (bold italic) NVNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR E E M TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSV L HEALH S HYTQKSLSLSPG SEQ ID NO: 76: Mature human IgG1 Fc, Cys to Ser substitution (#), YTE triple mutation (bold and underlined), allotype G1m(fa) (bold italic) NVNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTL Y I T R E PEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR D E L TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG SEQ ID NO: 77: Mature human IgG1 Fc, Cys to Ser substitution (#), YTE triple mutation (bold and underlined), allotype G1m(f) (bold italic) NVNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTL Y I T R E PEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR E E M TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG SEQ ID NO: 78: Mature human Fc IgG1, Z1 is Cys or Ser, and X1 is Met or Tyr, X2 is Ser or Thr, X3 is Thr or Glu, X4 is Asp or Glu, X5 is Leu or Met, X6 is Met or Leu, and X7 is Asn or Ser VNHKPSNTKVDKKVEPKSZ1DKTHTCPPCPAPELLGGPSVFLFPPKDTLX1IX2RX3PEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVS NKALPAPIEKTISKAKGQPREPQVYTLPPSRX4EX5TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVX6HEALHX7HYTQKSLSLSPGK SEQ ID NO: 79: Mature human Fc IgG1, Cys to Ser substitution (#), wherein X1 is Met or Tyr, X2 is Ser or Thr, X3 is Thr or Glu, X4 is Asp or Glu, X5 is Leu or Met, X6 is Met or Leu, and X7 is Asn or Ser. VNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLX1IX2RX3PEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRX4EX5TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVX6HEALHX7HYTQKSLSLSPGK SEQ ID NO: 80: Mature human IgG1 Fc, Cys-to-Ser substitution (#), X4 is Asp or Glu, and X5 is Leu or Met VNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRX4EX5TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 81: Mature human IgG1 Fc, Cys-to-Ser substitution (#), allotype G1m(f) (bold italic) VNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR E E M TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 82: Mature human IgG1 Fc, Cys to Ser substitution (#), allotype G1m (fa) (bold italic text) VNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR D E L TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 83: Mature human IgG1 Fc, Cys to Ser substitution (#), M428L, N434S mutation (bold / underlined), allotype G1m(fa) (bold italic) VNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR D E L TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSV L HEALH S HYTQKSLSLSPGK SEQ ID NO: 84: Mature human IgG1 Fc, Cys to Ser substitution (#), M428L, N434S mutation (bold / underlined), allotype G1m(f) (bold italic) VNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR E E M TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSV L HEALH S HYTQKSLSLSPGK SEQ ID NO: 85: Mature human IgG1 Fc, Cys to Ser substitution (#), YTE triple mutation (bold and underlined), allotype G1m(fa) (bold italic) VNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTL Y I T R E PEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR D E L TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 86: Mature human IgG1 Fc, Cys to Ser substitution (#), YTE triple mutation (bold and underlined), allotype G1m(f) (bold italic) VNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTL Y I T R E PEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRE E M TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 87: Mature human Fc IgG1, Z1 is Cys or Ser, and X1 is Met or Tyr, X2 is Ser or Thr, X3 is Thr or Glu, X4 is Asp or Glu, X5 is Leu or Met, X6 is Met or Leu, and X7 is Asn or Ser VNHKPSNTKVDKKVEPKSZ1DKTHTCPPCPAPELLGGPSVFLFPPKDTLX1IX2RX3PEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKV SNKALPAPIEKTISKAKGQPREPQVYTLPPSRX4EX5TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVX6HEALHX7HYTQKSLSLSPG SEQ ID NO: 88: Mature human Fc IgG1, Cys to Ser substitution (#), wherein X1 is Met or Tyr, X2 is Ser or Thr, X3 is Thr or Glu, X4 is Asp or Glu, X5 is Leu or Met, X6 is Met or Leu, and X7 is Asn or Ser. VNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKDTLX1IX2RX3PEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCK VSNKALPAPIEKTISKAKGQPREPQVYTLPPSRX4EX5TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVX6HEALHX7HYTQKSLSLSPG SEQ ID NO: 89: Mature human IgG1 Fc, Cys to Ser substitution (#), X4 is Asp or Glu, and X5 is Leu or Met VNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRX4EX5TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG SEQ ID NO: 90: Mature human IgG1 Fc, Cys-to-Ser substitution (#), allotype G1m(f) (bold italic) VNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR E E M TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG SEQ ID NO: 91: Mature human IgG1 Fc, Cys-to-Ser substitution (#), allotype G1m(fa) (bold italic) VNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR D E L TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG SEQ ID NO: 92: Mature human IgG1 Fc, Cys to Ser substitution (#), M428L, N434S mutation (bold / underlined), allotype G1m(fa) (bold italic) VNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR D E L TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSV L HEALH S HYTQKSLSLSPG SEQ ID NO: 93: Mature human IgG1 Fc, Cys to Ser substitution (#), M428L, N434S mutation (bold / underlined), allotype G1m(f) (bold italic) VNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR E E M TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSV L HEALH S HYTQKSLSLSPG SEQ ID NO: 94: Mature human IgG1 Fc, Cys to Ser substitution (#), YTE triple mutation (bold and underlined), allotype G1m(fa) (bold italic) VNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTL Y I T R EPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR D E L TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG SEQ ID NO: 95: Mature human IgG1 Fc, Cys to Ser substitution (#), YTE triple mutation (bold and underlined), allotype G1m(f) (bold italic) VNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTL Y I T R E PEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR E E M TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG SEQ ID NO: 96: Mature human Fc IgG1, J1 is Asn or absent, J2 is Lys or absent, Z1 is Cys or Ser, and wherein X1 is Met or Tyr, X2 is Ser or Thr, X3 is Thr or Glu, X4 is Asn or Ala, X5 is Leu or Asp, X6 is Gln or His, X7 is Asp or Glu, and X8 is Leu or Met, X9 is Met or Leu, and X... 10 For Asn or Ser J1VNHKPSNTKVDKKVEPKSZ1DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLX1IX2RX3PEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYX4STYRVVSVLTVX5HX6DWL NGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRX7EX8TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVX9HEALHX 10 HYTQKSLSLSPGJ2 SEQ ID NO: 97: Mature human Fc IgG1, Cys to Ser substitution (#), J1 is Asn or absent, J2 is Lys or absent, and wherein X4 is Asn or Ala, X5 is Leu or Asp, X6 is Gln or His, X7 is Asp or Glu, and X8 is Leu or Met, and X 10 For Asn or Ser J1VNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYX4STYRVVSVLTVX5HX6DWL NGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRX7EX8TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHX 10 HYTQKSLSLSPGJ2 SEQ ID NO: 98: Mature human Fc IgG1, Cys to Ser substitution (#), DHS triple mutation (bold and underlined), J1 is Asn or absent, J2 is Lys or absent, X4 is Asn or Ala, X7 is Asp or Glu, and X8 is Leu or Met. J1VNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYX4STYRVVSVLTV D H HDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRX7EX8TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALH S HYTQKSLSLSPGJ2 SEQ ID NO: 99: Mature human Fc IgG1, Cys to Ser substitution (#), DHS triple mutation (bold and underlined), where X4 is Asn or Ala, X7 is Asp or Glu, and X8 is Leu or Met. NVNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYX4STYRVVSVLTV D H H DWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRX7EX8TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALH S HYTQKSLSLSPGK SEQ ID NO: 100: Mature human Fc IgG1, Cys to Ser substitution (#), DHS triple mutation (bold and underlined), where X7 is Asp or Glu and X8 is Leu or Met. NVNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTV D H H DWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRX7EX8TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALH S HYTQKSLSLSPGK SEQ ID NO: 101: Mature human Fc IgG1, Cys to Ser substitution (#), DHS triple mutation (bold and underlined), allotype G1m(fa) (bold italic) NVNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTV D H H DWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR D E L TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALH S HYTQKSLSLSPGK SEQ ID NO: 102: Mature human Fc IgG1, Cys to Ser substitution (#), DHS triple mutation (bold and underlined), allotype G1m(f) (bold italic) NVNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTV D H H DWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR E E M TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALH S HYTQKSLSLSPGK SEQ ID NO: 103: Mature human Fc IgG1, Cys to Ser substitution (#), DHS triple mutation (bold and underlined), allotype G1m(fa) (bold italic) VNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTV D H H DWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR D E L TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALH S HYTQKSLSLSPGK SEQ ID NO: 104: Mature human Fc IgG1, Cys to Ser substitution (#), DHS triple mutation (bold and underlined), allotype G1m(f) (bold italic) VNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTV D H H DWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR E E M TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALH S HYTQKSLSLSPGK SEQ ID NO: 105: Mature human Fc IgG1, Cys to Ser substitution (#), DHS triple mutation (bold and underlined), allotype G1m(fa) (bold italic) NVNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTV D H H DWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRD E L TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALH S HYTQKSLSLSPGK SEQ ID NO: 106: Mature human Fc IgG1, Cys to Ser substitution (#), DHS triple mutation (bold and underlined), allotype G1m(f) (bold italic) NVNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTV D H H DWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR E E M TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALH S HYTQKSLSLSPGK SEQ ID NO: 107: Mature human Fc IgG1, Cys to Ser substitution (#), DHS triple mutation (bold and underlined), allotype G1m(fa) (bold italic) VNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTV D H H DWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR D E L TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALH S HYTQKSLSLSPG SEQ ID NO: 108: Mature human Fc IgG1, Cys to Ser substitution (#), DHS triple mutation (bold and underlined), allotype G1m(f) (bold italic) VNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTV D H H DWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR E E M TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALH S HYTQKSLSLSPG SEQ ID NO: 109: Mature human Fc IgG1, Cys to Ser substitution (#), Asn to Ala substitution (*), DHS triple mutation (bold and underlined), where X7 is Asp or Glu and X8 is Leu or Met. NVNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYA(*)STYRVVSVLTV D H H DWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRX7EX8TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALH S HYTQKSLSLSPGK SEQ ID NO: 110: Mature human Fc IgG1, Cys to Ser substitution (#), Asn to Ala substitution (*), DHS triple mutation (bold and underlined), allotype G1m(fa) (bold italic) NVNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYA(*)STYRVVSVLTV D H H DWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR D E L TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALH S HYTQKSLSLSPGK SEQ ID NO: 111: Mature human Fc IgG1, Cys to Ser substitution (#), Asn to Ala substitution (*), DHS triple mutation (bold and underlined), allotype G1m(f) (bold italic) NVNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYA(*)STYRVVSVLTV D H H DWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR E E M TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALH S HYTQKSLSLSPGK SEQ ID NO: 112: Mature human Fc IgG1, Cys to Ser substitution (#), Asn to Ala substitution (*), DHS triple mutation (bold and underlined), allotype G1m (fa) (bold italic) VNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYA(*)STYRVVSVLTV D H HDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR D E L TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALH S HYTQKSLSLSPGK SEQ ID NO: 113: Mature human Fc IgG1, Cys to Ser substitution (#), Asn to Ala substitution (*), DHS triple mutation (bold and underlined), allotype G1m(f) (bold italic) VNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYA(*)STYRVVSVLTV D H H DWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR E E M TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALH S HYTQKSLSLSPGK SEQ ID NO: 114: Mature human Fc IgG1, Cys to Ser substitution (#), Asn to Ala substitution (*), DHS triple mutation (bold and underlined), allotype G1m (fa) (bold italic) NVNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYA(*)STYRVVSVLTV D H H DWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR D E L TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHS HYTQKSLSLSPGK SEQ ID NO: 115: Mature human Fc IgG1, Cys to Ser substitution (#), Asn to Ala substitution (*), DHS triple mutation (bold and underlined), allotype G1m(f) (bold italic) NVNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYA(*)STYRVVSVLTV D H H DWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR E E M TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALH S HYTQKSLSLSPGK SEQ ID NO: 116: Mature human Fc IgG1, Cys to Ser substitution (#), Asn to Ala substitution (*), DHS triple mutation (bold and underlined), allotype G1m(fa) (bold italic) VNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYA(*)STYRVVSVLTV D H H DWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR D E L TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALH S HYTQKSLSLSPG SEQ ID NO: 117: Mature human Fc IgG1, Cys to Ser substitution (#), Asn to Ala substitution (*), DHS triple mutation (bold and underlined), allotype G1m(f) (bold italic) VNHKPSNTKVDKKVEPKSS(#)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYA(*)STYRVVSVLTV D H H DWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR E E M TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALH S HYTQKSLSLSPG SEQ ID NO: 118: Mature human Fc IgG1, J1 is Asn or absent, J2 is Lys or absent, and wherein X4 is Asn or Ala, X5 is Leu or Asp, X6 is Gln or His, X7 is Asp or Glu, and X8 is Leu or Met, and X 10 For Asn or Ser J1VNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYX4STYRVVSVLTVX5HX6DWLNG KEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRX7EX8TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHX 10 HYTQKSLSLSPGJ2 SEQ ID NO: 119: Mature human Fc IgG1, DHS triple mutation (bold and underlined), J1 is Asn or absent, J2 is Lys or absent, and wherein X4 is Asn or Ala, X7 is Asp or Glu, and X8 is Leu or Met. J1VNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYX4STYRVVSVLTV D HH DWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRX7EX8TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALH S HYTQKSLSLSPGJ2 SEQ ID NO: 120: Mature human Fc IgG1, DHS triple mutation (bold and underlined), wherein X4 is Asn or Ala, X7 is Asp or Glu, and X8 is Leu or Met. NVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYX4STYRVVSVLTV D H H DWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRX7EX8TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALH S HYTQKSLSLSPGK SEQ ID NO: 121: Mature human Fc IgG1, DHS triple mutation (bold and underlined), where X7 is Asp or Glu and X8 is Leu or Met. NVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTV D H H DWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRX7EX8TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALH S HYTQKSLSLSPGK SEQ ID NO: 122: Mature human Fc IgG1, DHS triple mutation (bold and underlined), allotype G1m(fa) (bold italic) NVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTV D H H DWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR D E L TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALH S HYTQKSLSLSPGK SEQ ID NO: 123: Mature human Fc IgG1, DHS triple mutation (bold and underlined), allotype G1m(f) (bold italic) NVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTV D H H DWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR E E M TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALH S HYTQKSLSLSPGK SEQ ID NO: 124: Mature human Fc IgG1, DHS triple mutation (bold and underlined), allotype G1m(fa) (bold italic) VNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTV D H HDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR D E L TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALH S HYTQKSLSLSPGK SEQ ID NO: 125: Mature human Fc IgG1, DHS triple mutation (bold and underlined), allotype G1m(f) (bold italic) VNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTV D H H DWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR E E M TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALH S HYTQKSLSLSPGK SEQ ID NO: 126: Mature human Fc IgG1, DHS triple mutation (bold and underlined), allotype G1m(fa) (bold italic) NVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTV D H H DWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR D E L TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALH S HYTQKSLSLSPGK SEQ ID NO: 127: Mature human Fc IgG1, DHS triple mutation (bold and underlined), allotype G1m(f) (bold italic) NVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTV D H H DWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR E E M TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALH S HYTQKSLSLSPGK SEQ ID NO: 128: Mature human Fc IgG1, DHS triple mutation (bold and underlined), allotype G1m(fa) (bold italic) VNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTV D H H DWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR D E L TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALH S HYTQKSLSLSPG SEQ ID NO: 129: Mature human Fc IgG1, DHS triple mutation (bold and underlined), allotype G1m(f) (bold italic) VNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTV D H HDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR E E M TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALH S HYTQKSLSLSPG SEQ ID NO: 130: Mature human Fc IgG1, Asn to Ala substitution (*), DHS triple mutation (bold and underlined), where X7 is Asp or Glu and X8 is Leu or Met. NVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYA(*)STYRVVSVLTV D H H DWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRX7EX8TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALH S HYTQKSLSLSPGK SEQ ID NO: 131: Mature human Fc IgG1, Asn to Ala substitution (*), DHS triple mutation (bold and underlined), allotype G1m(fa) (bold italic) NVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYA(*)STYRVVSVLTV D H H DWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR D E L TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALH S HYTQKSLSLSPGK SEQ ID NO: 132: Mature human Fc IgG1, Asn to Ala substitution (*), DHS triple mutation (bold and underlined), allotype G1m(f) (bold italic) NVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYA(*)STYRVVSVLTV D H H DWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR E E M TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALH S HYTQKSLSLSPGK SEQ ID NO: 133: Mature human Fc IgG1, Asn to Ala substitution (*), DHS triple mutation (bold and underlined), allotype G1m(fa) (bold italic) VNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYA(*)STYRVVSVLTV D H H DWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR D E L TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALH S HYTQKSLSLSPGK SEQ ID NO: 134: Mature human Fc IgG1, Asn to Ala substitution (*), DHS triple mutation (bold and underlined), allotype G1m(f) (bold italic) VNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYA(*)STYRVVSVLTV D H H DWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR E E M TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALH S HYTQKSLSLSPGK SEQ ID NO: 135: Mature human Fc IgG1, Asn to Ala substitution (*), DHS triple mutation (bold and underlined), allotype G1m(fa) (bold italic) NVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYA(*)STYRVVSVLTV D H H DWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR D E L TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALH S HYTQKSLSLSPGK SEQ ID NO: 136: Mature human Fc IgG1, Asn to Ala substitution (*), DHS triple mutation (bold and underlined), allotype G1m(f) (bold italic) NVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYA(*)STYRVVSVLTV D H H DWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRE E M TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALH S HYTQKSLSLSPGK SEQ ID NO: 137: Mature human Fc IgG1, Asn to Ala substitution (*), DHS triple mutation (bold and underlined), allotype G1m(fa) (bold italic) VNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYA(*)STYRVVSVLTV D H H DWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR D E L TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALH S HYTQKSLSLSPG SEQ ID NO: 138: Mature human Fc IgG1, Asn to Ala substitution (*), DHS triple mutation (bold and underlined), allotype G1m(f) (bold italic) VNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYA(*)STYRVVSVLTV D H H DWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR E E M TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALH S HYTQKSLSLSPG As defined in this article, the Fc struct contains data obtained through C. H3. Interactions between constant antibody domains: Two dimerized Fc domain monomers, and one or more disulfide bonds formed between the hinge domains of the two dimerized Fc domain monomers. The Fc domains form the minimal structure for binding Fc receptors, such as Fc-γ receptors (i.e., Fcγ receptor (FcγR)), Fc-α receptors (i.e., Fcα receptor (FcαR)), Fc-ε receptors (i.e., Fcε receptor (FcεR)), and / or neonatal Fc receptors (FcRn). In some embodiments, the Fc domains of the present invention bind Fcγ receptors (e.g., FcγRI (CD64), FcγRIIa (CD32), FcγRIIb (CD32), FcγRIIIa (CD16a), FcγRIIIb (CD16b)) and / or FcγRIV and / or neonatal Fc receptors (FcRn).

[0061] In some embodiments, the Fc domain of the present invention is a non-glycosylated Fc domain (e.g., an Fc domain that retains binding to an Fc receptor (e.g., FcRn). For example, the Fc domain is a non-glycosylated IgG1 variant that retains binding to an Fc receptor (e.g., IgG1 with amino acid substitutions at N297 and / or T299 of the glycosylation motif). Exemplary non-glycosylated Fc domains and methods for preparing non-glycosylated Fc domains are known in the art, for example, as described in Sazinsky SL et al., Aglycosylated immunoglobulin G1 variants productively engage activating Fcreceptors, PNAS, 2008, 105(51):20167-20172, the entire text of which is incorporated herein by reference.

[0062] In some embodiments, the Fc domain of the present invention is engineered to enhance binding to the neonatal Fc receptor (FcRn). For example, the Fc domain may contain a triple mutation corresponding to M252Y / S254T / T256E (YTE) (e.g., IgG1, such as human or humanized IgG1 with a YTE mutation, such as SEQ ID NO:33, SEQ ID NO:36, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:52, SEQ ID NO:53, SEQ ID NO:56 or SEQ ID NO:57). The Fc domain may contain a double mutant corresponding to M428L / N434S (LS) (e.g., IgG1, such as human or humanized IgG1 with the LS mutation, e.g., SEQ ID NO: 37, SEQ ID NO: 39, SEQ ID NO: 44, SEQ ID NO: 45, SEQ ID NO: 46, SEQ ID NO: 50, SEQ ID NO: 51, SEQ ID NO: 54, SEQ ID NO: 55, or SEQ ID NO: 59). The Fc domain may contain a single mutant corresponding to N434H (e.g., IgG1, such as human or humanized IgG1 with the N434H mutation).The Fc domain may contain a single mutant corresponding to C220S (e.g., IgG1, such as human or humanized IgG1 with a C220S mutation, e.g., SEQ ID NO:34, 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:58, SEQ ID NO:59, 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:79). 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 and SEQ ID NO:95).The Fc domain may contain a quadruple mutant corresponding to C220S / L309D / Q311H / N434S (CDHS) (e.g., IgG1, such as human or humanized IgG1 with the DHS mutation, e.g., 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:111, SEQ ID NO:112, SEQ ID NO:113, SEQ ID NO:114, SEQ ID NO:115, SEQ ID NO:116 and SEQ ID NO:117). The Fc domain may contain a triple mutant corresponding to L309D / Q311H / N434S (DHS) (e.g., IgG1, such as human or humanized IgG1 with the DHS mutation, e.g., 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 and SEQ ID NO: 138). The Fc domain may include a combination of one or more of the above-described mutations that enhance binding to FcRn. Enhanced binding to FcRn can increase the half-life of the conjugate containing the Fc domain. For example, incorporating one or more amino acid mutations that enhance FcRn binding (e.g., YTE mutation, LS mutation, or N434H mutation) can increase the half-life of the conjugate by 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, 300%, 400%, 500%, or more compared to conjugates with the corresponding Fc domain but without mutations that enhance FcRn binding.Exemplary Fc domains that bind to FcRN and methods for preparing Fc domains that bind to FcRN are known in the art, for example, as described in Maeda, A. et al., Identification of human IgG1 variant with enhanced FcRn binding and without increased binding to rheumatoid factor autoantibody, MABS, 2017, 9(5):844-853, which is incorporated herein by reference.

[0063] As used herein, an amino acid “corresponding to” a specific amino acid residue (e.g., an amino acid residue of a specific SEQ ID NO.) should be understood to include any amino acid residue that would be understood by a person skilled in the art to be aligned with a specific residue (e.g., a residue of a specific sequence). For example, any of SEQ ID Nos: 1-138 can be mutated to include YTE mutations, LS mutations, and / or N434H mutations by mutating the “corresponding residue” of the amino acid sequence.

[0064] As used herein, the sulfur atom “corresponding” to a specific cysteine ​​residue of a particular SEQ ID NO. should be understood to include the sulfur atom of any cysteine ​​residue that would be understood by a person skilled in the art to be aligned with a specific cysteine ​​of a particular sequence. The protein sequence alignments of human IgG1 (UniProtKB: P01857; SEQ ID NO: 142), human IgG2 (UniProtKB: P01859; SEQ ID NO: 143), human IgG3 (UniProtKB: P01860; SEQ ID NO: 144), and human IgG4 (UniProtKB: P01861; SEQ ID NO: 145) are shown below (aligned using Clustal Omega Multiple Pairwise Alignment). Alignments indicate cysteine ​​residues (e.g., sulfur atoms of cysteine ​​residues) that “correspond” to each other (in boxes and indicated by the • symbol). Those skilled in the art will be able to readily perform such a comparison with any IgG variant of the present invention to determine the sulfur atom of the cysteine ​​corresponding to any sulfur atom of a specific cysteine ​​in a particular SEQ ID NO. (e.g., any of SEQ ID NO: 1-138). For example, those skilled in the art can readily determine that Cys10 of SEQ ID NO: 10 (the first cysteine ​​of the conserved CPC motif in the hinge region of the Fc domain) corresponds to, for example, Cys109 of IgG1, Cys106 of IgG2, Cys156 of IgG3, Cys29 of SEQ ID NO: 1, Cys9 of SEQ ID NO: 2, Cys30 of SEQ ID NO: 3, or Cys10 of SEQ ID NO: 10.

[0065] In some embodiments, the Fc domain of the present invention has the sequence of any of SEQ ID NO: 39-138, and may further include an additional amino acid at the N-terminus (Xaa)x and / or an additional amino acid at the C-terminus (Xaa)z, wherein Xaa is any amino acid, and x and z are greater than or equal to zero, typically less than 100, preferably less than 10, and more preferably integers of 0, 1, 2, 3, 4, or 5. In some embodiments, the additional amino acid has at least 70% (e.g., 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100%) identity to the sequence of one or more consecutive amino acids in SEQ ID NO: 81. For example, the additional amino acid may be a single amino acid at the C-terminus of Lys330 corresponding to IgG1 (SEQ ID NO: 119).

[0066] As used herein, a nitrogen atom “corresponding” to a specific lysine residue of a particular SEQ ID NO. should be understood to include any nitrogen atom of a lysine residue that would be understood by a person skilled in the art to be aligned with a specific lysine of a particular sequence. The protein sequence alignments of human IgG1 (UniProtKB: P01857; SEQ ID NO: 142), human IgG2 (UniProtKB: P01859; SEQ ID NO: 143), human IgG3 (UniProtKB: P01860; SEQ ID NO: 144), and human IgG4 (UniProtKB: P01861; SEQ ID NO: 145) are shown below (aligned using Clustal Omega Multiple Pairwise Alignment). Alignments indicate lysine residues (e.g., nitrogen atoms of lysine residues) that “correspond” to each other (in boxes and indicated by an asterisk). Those skilled in the art will be able to readily perform such a comparison with any IgG variant of the present invention to determine the nitrogen atom of the lysine corresponding to any nitrogen atom of a specific lysine in a particular SEQ ID NO. (e.g., any of SEQ ID NO: 1-138). For example, those skilled in the art can readily determine that Lys35 of SEQ ID NO: 10 corresponds to, for example, Lys129 of IgG1, Lys126 of IgG2, Lys176 of IgG3, Lys51 of SEQ ID NO: 1, Lys31 of SEQ ID NO: 2, Lys50 of SEQ ID NO: 3, or Lys30 of SEQ ID NO: 10.

[0067] Protein sequence alignment of IgG1 (SEQ ID NO: 142), IgG2 (SEQ ID NO: 143), IgG3 (SEQ ID NO: 144) and IgG4 (SEQ ID NO: 145). Pharmaceutical compositions and formulations The conjugates described herein can be formulated in pharmaceutical compositions used in the methods described herein. In some embodiments, the conjugates described herein can be formulated alone in a pharmaceutical composition. In some embodiments, the conjugates described herein can be formulated in combination with an antiviral agent or an antiviral vaccine in a pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises a conjugate of formula (I) and a pharmaceutically acceptable carrier and excipients.

[0068] Acceptable carriers and excipients in a pharmaceutical composition are non-toxic to the recipient at the doses and concentrations used. Acceptable carriers and excipients may include buffers such as phosphates, citrates, HEPES, and TAEs; antioxidants such as ascorbic acid and methionine; preservatives such as hexamethyldiammonium chloride, octadecyl dimethyl benzyl ammonium chloride, resorcinol, and benzalkonium chloride; proteins such as human serum albumin, gelatin, dextran, and immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acid residues such as glycine, glutamine, histidine, and lysine; and carbohydrates such as glucose, mannose, sucrose, and sorbitol.

[0069] Other examples of excipients include, but are not limited to, anti-sticking agents, binders, coatings, compression aids, disintegrants, dyes, emollients, emulsifiers, fillers (diluents), film-forming agents or coatings, flavorings, fragrances, flow enhancers (flow enhancers), lubricants, adsorbents, suspending or dispersing agents, or sweeteners. Exemplary excipients include, but are not limited to: butylated hydroxytoluene (BHT), calcium carbonate, calcium hydrogen phosphate, calcium stearate, croscarmellose, croscarmellose, citric acid, crospovidone, cysteine, ethyl cellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methylparaben, microcrystalline cellulose, polyethylene glycol, povidone, pregelatinized starch, propylparaben, retinyl palmitate, shellac, silica, sodium carboxymethyl cellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol.

[0070] Pharmaceutical compositions may be formed in unit dosage forms as needed. The amount of active ingredient (e.g., conjugate of formula (I)) contained in a unit dosage form provides a dose in the range of 10-900 mg (e.g., 10 mg to 20 mg, 15 mg to 30 mg, 10 mg to 25 mg, 15 mg to 25 mg, 20 mg to 30 mg, 25 mg to 35 mg, 25 mg to 35 mg, 30 mg to 40 mg, 35 mg to 50 mg, 30 mg to 45 mg, 40 mg to 50 mg, 45 mg to 50 mg, 50 mg to 75 mg, 50 mg to 100 mg, 50 mg to 125 mg, 50 mg to 150 mg, 50 mg to 175 mg, 50 mg to 2...). 00mg, 50mg to 225mg, 50mg to 250mg, 60mg to 75mg, 60mg to 100mg, 60mg to 125mg, 60mg to 150mg, 60mg to 175mg, 60mg to 200mg, 60mg to 225mg, 60mg to 250mg, 70mg to 75mg, 70mg to 100mg, 70mg to 125mg, 70mg to 150mg, 70mg to 175mg, 70mg to 200mg, 70mg to 225mg, 70mg to 250mg, 80mg to 100mg, 80mg to 125mg, 80mg 150mg to 150mg, 80mg to 175mg, 80mg to 200mg, 80mg to 225mg, 80mg to 250mg, 90mg to 100mg, 90mg to 125mg, 90mg to 150mg, 90mg to 175mg, 90mg to 200mg, 90mg to 225mg, 90mg to 250mg, 100mg to 125mg, 100mg to 150mg, 100mg to 175mg, 100mg to 200mg, 100mg to 225mg, 100mg to 250mg, 150mg to 175mg, 150mg to 200mg 0mg to 225mg, 150mg to 250mg, 200mg to 225mg, 200mg to 250mg, 200mg to 275mg, 200mg to 300mg, 200mg to 325mg, 200mg to 350mg, 300mg to 325mg, 300mg to 350mg, 300mg to 375mg, 300mg to 400mg, 300mg to 425mg, 300mg to 450mg, 400mg to 425mg, 400mg to 450mg, 400mg to 475mg, 400mg to 500mg, 400mg to 525mg.400mg to 550mg, 500mg to 525mg, 500mg to 550mg, 500mg to 575mg, 500mg to 600mg, 500mg to 625mg, 500mg to 650mg, 600mg to 625mg, 600mg to 650mg, 600mg to 675mg, 600mg to 700mg, 600mg to 725mg, 600mg to 750mg, 700mg to 725mg, 700mg to 750mg, 700mg to 775mg, 700mg to 800mg, 700mg to 825mg, 700mg to 850mg, 800mg to 825mg, 800mg to 850mg, 800mg to 875mg and 800mg to 900mg). In some embodiments, the unit dosage form comprises a 150 mg formula (I) conjugate (e.g., conjugate A). In some embodiments, the unit dosage form comprises a 300 mg formula (I) conjugate (e.g., conjugate A). In some embodiments, the unit dosage form comprises a 900 mg formula (I) conjugate (e.g., conjugate A).

[0071] Route of administration and dosage In any of the methods described herein, the conjugates herein may be administered via any suitable route to treat or prevent influenza infection, or to prevent, stabilize, or inhibit the proliferation or spread of influenza virus. In some embodiments, administration includes intramuscular, intravenous (e.g., as a sterile solution in a solvent system suitable for intravenous use), or subcutaneous administration of the (I) conjugate.

[0072] The dosage of the conjugates described herein is between 10 and 900 mg (e.g., 10 mg to 20 mg, 15 mg to 30 mg, 10 mg to 25 mg, 15 mg to 25 mg, 20 mg to 30 mg, 25 mg to 35 mg, 25 mg to 35 mg, 30 mg to 40 mg, 35 mg to 50 mg, 30 mg to 45 mg, 40 mg to 50 mg, 45 mg to 50 mg, 50 mg to 75 mg, 50 mg to 100 mg, 50 mg to 125 mg, 50 mg to 150 mg, 50 mg to 175 mg, 50 mg to 200 mg, 50 mg to 225 mg, 50 mg to 250 mg, 60 mg). mg to 75mg, 60mg to 100mg, 60mg to 125mg, 60mg to 150mg, 60mg to 175mg, 60mg to 200mg, 60mg to 225mg, 60mg to 250mg, 70mg to 75mg, 70mg to 100mg, 70mg to 125mg, 70mg to 150mg, 70mg to 175mg, 70mg to 200mg, 70mg to 225mg, 70mg to 250mg, 80mg to 100mg, 80mg to 125mg, 80mg to 150mg, 80mg to 175mg 80mg to 200mg, 80mg to 225mg, 80mg to 250mg, 90mg to 100mg, 90mg to 125mg, 90mg to 150mg, 90mg to 175mg, 90mg to 200mg, 90mg to 225mg, 90mg to 250mg, 100mg to 125mg, 100mg to 150mg, 100mg to 175mg, 100mg to 200mg, 100mg to 225mg, 100mg to 250mg, 150mg to 175mg, 150mg to 200mg, 150mg to 225mg 150mg to 250mg, 200mg to 225mg, 200mg to 250mg, 200mg to 275mg, 200mg to 300mg, 200mg to 325mg, 200mg to 350mg, 300mg to 325mg, 300mg to 350mg, 300mg to 375mg, 300mg to 400mg, 300mg to 425mg, 300mg to 450mg, 400mg to 425mg, 400mg to 450mg, 400mg to 475mg, 400mg to 500mg, 400mg to 525mg.400mg to 550mg, 500mg to 525mg, 500mg to 550mg, 500mg to 575mg, 500mg to 600mg, 500mg to 625mg, 500mg to 650mg, 600mg to 625mg, 600mg to 650mg, 600mg to 675mg, 600mg to 700mg, 600mg to 725mg, 600mg to 750mg, 700mg to 725mg, 700mg to 750mg, 700mg to 775mg, 700mg to 800mg, 700mg to 825mg, 700mg to 850mg, 800mg to 825mg, 800mg to 850mg, 800mg to 875mg and 800mg to 900mg). In some embodiments, the dose administered to a human subject is 150 mg of the formula (I) conjugate (e.g., conjugate A). In some embodiments, the dose administered to a human subject is 300 mg of the formula (I) conjugate (e.g., conjugate A). In some embodiments, the dose administered to a human subject is 900 mg of the formula (I) conjugate (e.g., conjugate A). The formula (I) conjugate or its pharmaceutical composition may be administered to a human subject once, for example, before flu season. Example

[0073] The following examples are provided to provide those skilled in the art with a description of how to use, prepare, and evaluate the compositions and methods described herein, and these examples are intended only as examples of the invention and not to limit the scope of what the inventors consider to be their invention.

[0074] Example 1: Clinical Trial Protocol We conducted a proof-of-concept, randomized, double-blind, placebo-controlled phase 2a study to evaluate the prophylactic antiviral activity, safety, tolerability, and pharmacokinetics of conjugate A against influenza H3N2 A / Perth / 16 / 2009 using a human viral challenge model. The DAR of conjugate A used in this study was 4.5.

[0075] To assess the preventive effect of conjugate A on reducing the viral load-time area under the curve (VL-AUC) after influenza virus challenge compared to placebo, we performed quantitative reverse transcription polymerase chain reaction (qRT-PCR) on nasal samples from day 1 (afternoon) to day 8 (morning) after viral challenge to determine the viral load-time area under the curve (VL-AUC) of the influenza challenge virus (Table 1). The study protocol is summarized in... Figure 1A middle.

[0076] A summary of the test handling procedures is as follows: Figure 1B As shown. Figure 2It displays demographic data for human volunteers. Figure 3 The box plot of the VL-AUC data in Table 1 is shown. Figure 4 The average viral load over 8 days, as measured by qRT-PCR, is shown.

[0077] Table 1. Summary of viral load-time area under curve (VL-AUC) measured by qRT-PCR.

[0078] To assess the role of conjugate A in reducing or shortening viral replication after influenza virus challenge compared to placebo, we performed quantifiable qRT-PCR measurements on nasal samples from day 1 (afternoon) to day 8 (morning) to determine peak influenza viral load as defined by maximum viral load (Table 2). Figure 5 The box plots of the viral load peaks measured by qRT-PCR in Table 2 are shown.

[0079] Table 2. Summary of peak viral loads measured by qRT-PCR.

[0080] To assess the effect of conjugate A on reducing the incidence of influenza infection induced by influenza virus challenge compared to placebo, we used qRT-PCR to detect the number of influenza infections, and the results are summarized in Table 3. A qRT-PCR-confirmed influenza infection was defined as two quantifiable (≥ lower limit of quantification [LLOQ]) qRT-PCR measurements between day 1 (afternoon) and day 8 (morning) (reported for two or more independent samples within two days). At least one positive quantifiable (≥ LLOQ) cell culture measurement was also defined as occurring between day 1 (afternoon) and day 8 (morning) in nasal samples. A qRT-PCR-confirmed symptomatic influenza infection was defined as an influenza infection confirmed by qRT-PCR between day 1 (afternoon) and day 8 (morning) (two quantifiable [≥ LLOQ] qRT-PCR measurements [reported for two or more independent samples within two days]), with ≥2 symptoms at a single time point. A moderately severe symptomatic influenza infection confirmed by qRT-PCR is defined as an influenza infection confirmed by qRT-PCR between day 1 (afternoon) and day 8 (morning) (two quantifiable [≥LLOQ] qRT-PCR measurements [reported on two or more independent samples within two days]), with ≥2 symptoms of any grade at a single time point. A laboratory-confirmed symptomatic influenza infection is defined as a culturable influenza infection confirmed by laboratory testing between day 1 (afternoon) and day 8 (morning) (one quantifiable [≥LLOQ] cell culture measurement), with ≥2 symptoms at a single time point.

[0081] Table 3. Summary of influenza infection incidence rate.

[0082] *Fisher precision test, one-sided To assess the effect of conjugate A on reducing or shortening viral shedding after influenza virus challenge compared to placebo, we used a quantifiable qRT-PCR method to test nasal samples, measuring the time (in hours) from day 1 (afternoon) until the first undetectable result after peak measurement until a negative result was confirmed. Results are summarized in Table 4 and... Figure 6 middle.

[0083] Table 4. Summary of the time from detection to negative result obtained by qRT-PCR.

[0084] To assess the effect of conjugate A compared with placebo in reducing clinical symptoms induced by influenza virus challenge, we measured the area under the curve (AUC) of the total clinical symptom score over time using a graded symptom scoring system, collecting data three times daily from day 1 (morning) to day 8 (morning). TSS-AUC data are summarized in Table 5 and... Figure 7 middle.

[0085] Table 5. Summary of the area under the curve of total clinical symptom score (TSS-AUC) over time.

[0086] To assess the effect of conjugate A on reducing clinical symptoms induced by influenza virus challenge compared to placebo, we measured the total clinical symptom score (TSS). The symptom peak diary card score consisted of the peak TSS measured using a graded symptom scoring system, collected three times daily from day 1 (morning) to day 8 (morning). The daily symptom score peak was the maximum sum of an individual's daily symptom scores from day 1 to day 8. TSS results are summarized in Table 6, with mean TSS over time as shown below. Figure 8 As shown in the box plot of the TSS data peaks. Figure 9 As shown.

[0087] Table 6. Summary of peak Total Clinical Symptom Score (TSS).

[0088] To further evaluate the effect of conjugate A compared with placebo in reducing clinical symptoms induced by influenza virus challenge, we measured the time to symptom resolution using a graded daily symptom scoring system, i.e., the time from the peak of the daily symptom score to the return to the baseline score. The time to symptom resolution data are summarized in Table 7 and... Figure 10 middle.

[0089] Table 7. Summary of time to symptom resolution.

[0090] Basic principles of research This study aimed to determine the prophylactic antiviral activity of a single subcutaneous injection of conjugate A against experimental influenza infection and to confirm its safety, tolerability, and pharmacokinetics in a healthy adult population challenged with the H3N2 A / Perth / 16 / 2009 influenza challenge strain. Given the current very low global influenza incidence, demonstrating the therapeutic or prophylactic efficacy of anti-influenza compounds in a natural infection setting is challenging. The HVC model provides a setting independent of the number of influenza cases over a specific time period. Furthermore, this model has a proven track record of safety and has demonstrated the efficacy of various antiviral compounds and vaccines in proof-of-concept studies, which have subsequently been found effective in larger-scale clinical trials in a natural infection setting. Establishing a proof-of-concept and minimum effective concentration (MPC) was crucial in this study to better design studies to determine the safety and efficacy of conjugate A.

[0091] Influenza attack strains have been used for over 20 years and have helped evaluate a variety of antiviral, immunomodulatory, and vaccine therapies.

[0092] attack factors The attack agent used in this study was influenza virus H3N2 A / Perth / 16 / 2009. The attack agent stockpile was produced under current GMP (cGMP) conditions. The attack agent stockpile underwent quality testing during manufacturing according to predetermined specifications (identity, appearance, sterility, infectivity, and contaminants), and subsequently passed extensive testing for foreign agents. The attack agent was stored safely in a -80°C freezer (normal temperature range is -60°C to -90°C).

[0093] Example 2: Single-dose pharmacokinetics of conjugate A in humans This was the first phase I, single-center, prospective, randomized, double-blind human study. The study involved escalating single-dose administration of conjugate A to healthy adult subjects via intramuscular (IM) or subcutaneous (SQ) injection, followed by a single-dose re-administration of conjugate A via the same route at 3 months or 5 effective half-lives (whichever is longer) in the intermediate- and high-dose groups (dose may be adjusted based on tolerability). The DAR of conjugate A used in this study was 4.5. Plasma concentrations of conjugate A in subjects randomly assigned to receive conjugate A were determined using a validated mixed immunoassay LC-MS method, with a lower limit of quantitation (LLOQ) of 0.1 µg / mL. The aim was to evaluate the plasma pharmacokinetics of conjugate A in humans.

[0094] The dosage levels of conjugate A followed an escalating single-dose design, with the starting dose determined based on the results of 3-month rat and monkey toxicology studies. For each route (IM and SQ), route allocation was open-label (unblinded), and subjects were randomly assigned to receive either a single dose of conjugate A injection or a saline placebo (treatment allocation was double-blinded), as detailed in Table 8.

[0095] Table 8. Design of human pharmacokinetic studies.

[0096] NA = Not applicable a Note: Prior to the second single dose administration, any dropout in the sentinel group will be randomly replaced by a subject in the main group within each dose and route, while retaining their original treatment assignment (i.e., subjects assigned to the placebo group will continue to receive placebo, and subjects assigned to conjugate A group will continue to receive conjugate A).

[0097] Each group was divided into two groups, labeled the "Sentinel" group (randomly assigned in a 1:1 ratio) and the "Main" group (randomly assigned in a 7:2 ratio): • Low-dose (50 mg) levels: Group 1A (IM) and Group 1B (SQ) — Sentinel group n=2 and main group n=9 in each pathway. • Medium dose (150 mg) levels: Group 2A (IM) and Group 2B (SQ) — Sentinel group n=2 and main group n=9 in each pathway. • High-dose (450 mg) levels: Group 3A (IM) and Group 3B (SQ) — Sentinel group n=2 and main group n=9 in each pathway. • Highest dose (900 mg) level: Group 4B (SQ) – Sentinel group n=2, Main group n=9 For each route, two subjects in either the sentinel group or the primary group (one receiving conjugate A and one receiving placebo) received the blinded study drug at one dose level and were closely monitored for safety for at least one week. After the initial sentinel group subjects completed their dose level dosing and were followed up for at least one week, the principal investigator (PI) and the sponsor reviewed the blinded safety data. Since no drug-related serious adverse events occurred, the corresponding primary group subjects were not initiated dosing until one week after the sentinel group dosing. When the dose / route of administration was determined to be safe and well-tolerated ≥14 days after dosing, the next group of subjects was recruited and randomly assigned to receive the next higher dose level of conjugate A injection or placebo.

[0098] Subjects in group 4B received a single dose of either conjugate A injection or placebo (SQ). Subjects in groups 2A and 2B, and groups 3A and 3B, received a second single dose of conjugate A or placebo after five effective half-lives following the first dose, provided the safety and tolerability of the first dose were deemed acceptable following a review of cumulative safety data. Prior to the second single dose administration, any dropouts in the sentinel group were randomly replaced by subjects in the main group at each dose and route, retaining their original treatment allocation (i.e., subjects assigned to the placebo group would continue to receive placebo, and subjects assigned to the conjugate A group would continue to receive conjugate A, which may require supervision by an unblinded researcher). After the initial sentinel group subjects completed dosing at a given dose level, the PI and sponsor reviewed the blinded safety data and followed up according to the minimum observation period (i.e., seven days) determined during the first single dose administration. Since no drug-related serious adverse events occurred, the corresponding main group subjects were not initiated dosing until one week after sentinel group dosing.

[0099] Pharmacokinetics (PK) was determined by analyzing the concentration of conjugate A in plasma samples obtained from subjects in each cohort who received conjugate A injections at different time points following the first and second single doses of the study drug. Conjugate A concentrations were analyzed in plasma samples, nasopharyngeal swabs, and nasal washes. Antidrug antibodies (ADAs) were also measured at selected time points using a validated ELISA method.

[0100] The PK parameters assessed in the PK analysis population at specified times using non-compartmental analysis methods and nominal protocols in Phoenix WinNonlin (Certara) include: peak plasma concentration (C0.05). max ), time to reach peak plasma concentration (T) max Terminal elimination half-life (t) ½ Apparent clearance rate (CL / F), apparent volume of distribution (V) Z / F), the area under the plasma concentration-time curve (AUC) from time 0 to the last quantifiable sample time. 0-t ), and the area under the plasma concentration-time curve extrapolated from time 0 to infinity (AUC). 0-∞ ).

[0101] The PK parameters for each group are summarized in Tables 8A-8G. Figure 11-14 The mean plasma concentration of conjugate A changes over time when it is injected intramuscularly and subcutaneously. Figure 15 The mean AUC of conjugate A was compared between intramuscular and subcutaneous injections.

[0102] Table 8A. PK parameters for group 1A (treatment 1, dose = 50 mg, IM injection).

[0103] b T 最后 = The time of the last quantifiable time point c C4320 = the predicted concentration of conjugate A on day 180. Table 8B. PK parameters for group 1B (treatment 1, dose = 50 mg, SQ injection).

[0104] Table 8C. PK parameters for group 2A (treatment 1, dose = 150 mg, IM injection).

[0105] Table 8D. PK parameters for group 2B (treatment 1, dose = 150 mg, SQ injection).

[0106] Table 8E. PK parameters for group 2B (treatment 2, dose = 150 mg, SQ injection).

[0107] Table 8F. PK parameters for group 3A (treatment 1, dose = 450 mg, IM injection).

[0108] Table 8G. PK parameters for group 3B (treatment 1, dose = 450 mg, SQ injection).

[0109] Example 3: Population pharmacokinetic model of conjugate A A Phase I Single-Augmentation-Dose (SAD) study is currently underway in healthy volunteers to evaluate the safety, tolerability, and pharmacokinetics of conjugate A at four dose levels administered subcutaneously (SQ) or intramuscularly (IM). The DAR of conjugate A used in this study is 4.5. Preliminary results from the SAD study were analyzed using a nonlinear mixed-effects model.

[0110] The pharmacokinetic analysis included a total of 66 healthy volunteers who received either placebo (3 in each group) or conjugate A (8 in each group, administered 50 mg, 150 mg, or 450 mg of conjugate A via SQ or IM, respectively).

[0111] The concentration of conjugate A was sampled in plasma and quantified using a polyclonal antibody with low cross-reactivity to human Fc alone, employing hybridization LCMS. Preliminary results were analyzed using a nonlinear mixed-effects model. The overall procedure for developing the population pharmacokinetic model of conjugate A included exploratory data analysis and basic structural model development. First-order conditional estimation methods with interactions were applied at all stages of the model development process using NONMEM version 7.3 software. The observed PK was fully described by a linear one-compartment disposition model with first-order absorption (Table 9). The half-life of conjugate A was 6 to 8 weeks.

[0112] Table 9. Parameter estimates in the final population pharmacokinetic model of conjugate A.

[0113] It is expected that all participants will reach C on day 5 after administration. max 90% Figure 16 Model-predicted plasma concentrations showed that with one or two doses of 150 mg on day 1 (i.e., 300 mg), the decline from peak to trough was slower, decreasing by approximately one log unit (1 Log) during the flu season. In contrast, administering a second 150 mg dose to subjects who had already received a 150 mg dose on day 1 during the middle of the flu season resulted in drug accumulation and reduced peak-to-trough variation (see [link to relevant documentation]). Figure 17 ).

[0114] Therefore, the half-life of conjugate A is extended to 6 to 8 weeks, and only one to two doses are needed each season to provide seasonal prevention.

[0115] Example 4: Pharmacokinetics of conjugate A over time in influenza-infected individuals In this study, human subjects were administered a single subcutaneous (SQ) dose of conjugate A, either 50 mg or 150 mg, followed by influenza virus inoculation to evaluate the time-dependent pharmacokinetics of conjugate A in influenza-infected human subjects. The DAR of conjugate A used in this study was 4.5.

[0116] Quantifiable plasma concentrations of conjugate A were observed in all human subjects at the first sampling time point after administration (Day 5 [relative to viral inoculation], 2 hours [relative to conjugate A administration]) following a single SQ dose of 50 mg and 150 mg conjugate A (Tables 10A and 10B). Human subjects were then inoculated with influenza virus on Day 0. For both 50 mg and 150 mg doses, the mean plasma concentration of conjugate A gradually increased, reaching its peak at Day 0 (relative to viral inoculation) and 120 hours (relative to conjugate A administration). Subsequently, plasma concentrations gradually decreased and fluctuated in several subjects, and additional peaks in conjugate A plasma concentrations were observed. Notably, the single SQ dose of 50 mg conjugate A maintained a mean plasma concentration of 387 ng / mL for 180 days after conjugate A administration (Table 10B). In summary, the mean plasma concentration of conjugate A at the 150 mg dose was higher than that at the 50 mg dose throughout the pharmacokinetic profile (Table 11).

[0117] Table 11. Summary of pharmacokinetics of conjugate A in human subjects following a single SQ dose of 150 mg or 50 mg.

[0118] Note: Time-related parameters are related to the dosage of conjugate A.

[0119] a Only report T max n, minimum value, median and maximum value.

[0120] b For AUC 0-∞ and t 1 / 2 n=26.

[0121] c Display T max A single value, where n=2.

[0122] Other implementation plans Although the invention has been described in conjunction with its specific embodiments, it should be understood that further modifications can be made to it, and this application is intended to cover any variations, uses, or adaptations of the invention made essentially according to the principles of the invention, including known or conventional practices that, while not part of the invention, fall within the field to which the invention pertains, and changes that fall within the essential features described above and are within the scope of the claims. All disclosures, patents, and patent applications mentioned in the foregoing specification are hereby incorporated by reference to the extent that each individual disclosure, patent, or patent application is specifically and individually incorporated by reference in its entirety.

[0123] This document provides a detailed description of one or more preferred embodiments. However, it should be understood that the invention can be embodied in various forms. Therefore, the specific details disclosed herein should not be construed as limiting, but rather serve as the basis for the claims and as a representative basis for teaching those skilled in the art to use the invention in any appropriate manner.

Claims

1. A method for inhibiting, reducing, or shortening influenza virus replication or infection in human subjects, the method comprising or consisting of: The human subject was given a subcutaneous or intramuscular dose of 50 mg to 900 mg of the conjugate of formula (I), wherein the conjugate of formula (I) has the following structure: Formula I Each E is a single entity of the Fc structural domain; n is 2; T is an integer from 3 to 6; and The waveform represents a nitrogen atom of lysine or a sulfur atom of cysteine ​​in E that is covalently attached to the solvent.

2. A method for treating a human subject, the method comprising or consisting of: A subcutaneous or intramuscular dose of 50 mg to 900 mg of a conjugate of formula (I), wherein the conjugate of formula (I) has the following structure.

3. The method of claim 2, wherein the human subject has an influenza infection.

4. A method for reducing the time to symptom resolution in human subjects, reducing the area under the curve (VL-AUC) of influenza viral load in human subjects with influenza infection, or reducing the time to peak influenza viral load in human subjects with influenza infection, said method comprising or consisting of: The (I) conjugate is administered subcutaneously or intramuscularly at doses ranging from 50 mg to 900 mg.

5. A method for reducing the time to a negative influenza test in human subjects suffering from influenza infection, the method comprising or consisting of: The (I) conjugate is administered subcutaneously or intramuscularly at doses ranging from 50 mg to 900 mg.

6. A method for reducing the total clinical symptom score (TSS-AUC) in human subjects suffering from influenza infection, said method comprising or consisting of: The (I) conjugate is administered subcutaneously or intramuscularly at doses ranging from 50 mg to 900 mg.

7. A method for reducing the peak TSS in human subjects suffering from influenza infection, the method comprising or consisting of: The (I) conjugate is administered subcutaneously or intramuscularly at doses ranging from 50 mg to 900 mg.

8. A method for inhibiting, reducing, or shortening influenza virus replication or infection in human subjects, said method comprising or consisting of: (a) Administering a first dose of the (I) conjugate, ranging from 50 mg to 900 mg, subcutaneously or intramuscularly to the human subject; and (b) administering a second dose of the (I) conjugate, ranging from 50 mg to 900 mg, subcutaneously or intramuscularly to the human subject; The interval between the administration of the first and second doses is 60 to 120 days.

9. A method for treating a human subject, said method comprising or consisting of: (a) A first dose of formula (I) conjugate, administered subcutaneously or intramuscularly, ranging from 50 mg to 900 mg; and (b) A second dose of the formula (I) conjugate, administered subcutaneously or intramuscularly, ranging from 50 mg to 900 mg; The interval between the administration of the first and second doses is 60 to 120 days.

10. The method of claim 9, wherein the human subject has an influenza infection.

11. A method for reducing the time to symptom resolution in human subjects, reducing the area under the curve (VL-AUC) of influenza viral load in human subjects with influenza infection, or reducing the time to peak influenza viral load in human subjects with influenza infection, said method comprising or consisting of: (a) A first dose of formula (I) conjugate, administered subcutaneously or intramuscularly, ranging from 50 mg to 900 mg; and (b) A second dose of the formula (I) conjugate, administered subcutaneously or intramuscularly, ranging from 50 mg to 900 mg; The interval between the administration of the first and second doses is 60 to 120 days.

12. A method for reducing the time to a negative influenza test in human subjects suffering from influenza infection, the method comprising or consisting of: (a) A first dose of formula (I) conjugate, administered subcutaneously or intramuscularly, ranging from 50 mg to 900 mg; and (b) A second dose of the formula (I) conjugate, administered subcutaneously or intramuscularly, ranging from 50 mg to 900 mg; The interval between the administration of the first and second doses is 60 to 120 days.

13. A method for reducing the total clinical symptom score (TSS-AUC) in human subjects suffering from influenza infection, said method comprising or consisting of: (a) A first dose of formula (I) conjugate, administered subcutaneously or intramuscularly, ranging from 50 mg to 900 mg; and (b) A second dose of the formula (I) conjugate, administered subcutaneously or intramuscularly, ranging from 50 mg to 900 mg; The interval between the administration of the first and second doses is 60 to 120 days.

14. A method for reducing the peak TSS in human subjects suffering from influenza infection, the method comprising or consisting of: (a) A first dose of formula (I) conjugate, administered subcutaneously or intramuscularly, ranging from 50 mg to 900 mg; and (b) A second dose of the formula (I) conjugate, administered subcutaneously or intramuscularly, ranging from 50 mg to 900 mg; The interval between the administration of the first and second doses is 60 to 120 days.

15. A method for inhibiting, reducing, or shortening influenza virus replication or infection in human subjects, said method comprising or consisting of: The minimum plasma concentration of the conjugate of formula (I) should be maintained at at least 300 ng / mL for four to six months.

16. The method of claim 15, wherein the minimum plasma concentration of the conjugate in the subject is maintained at at least 300 ng / mL over a period of six months.

17. The method of claim 15, wherein the minimum plasma concentration of the conjugate in the subject is maintained at at least 300 ng / mL over a period of four months.

18. The method of any one of claims 1-17, wherein the conjugate is conjugate A, wherein E has the sequence SEQ ID NO:

76.

19. The method of any one of claims 1-18, wherein each dose comprises 150 mg of the conjugate.

20. The method of any one of claims 1-18, wherein each dose comprises 300 mg of the conjugate.

21. The method of any one of claims 1-18, wherein each dose comprises 450 mg of the conjugate.

22. The method of any one of claims 1-18, wherein each dose comprises 900 mg of the conjugate.

23. A unit dosage form of pharmaceutical composition, wherein the pharmaceutical composition comprises 50 mg to 900 mg of a conjugate of formula (I).

24. The pharmaceutical composition of claim 23, comprising 50 mg of the conjugate.

25. The pharmaceutical composition of claim 23, comprising 150 mg of the conjugate.

26. The pharmaceutical composition of claim 23, comprising 300 mg of the conjugate.

27. The pharmaceutical composition of claim 23, comprising 450 mg of the conjugate.

28. The pharmaceutical composition of claim 23, comprising 900 mg of the conjugate.

29. The pharmaceutical composition of any one of claims 23-28, wherein the conjugate is conjugate A, wherein E has the sequence of SEQ ID NO:

76.

30. A kit comprising a pharmaceutical composition as described in any one of claims 23-29 and instructions for use for the method as described in any one of claims 1-17.

31. The method of any one of claims 1-17, the pharmaceutical composition of any one of claims 23-29, or the kit of claim 30, wherein the conjugate comprises an Fc domain, the Fc domain comprising an amino acid sequence having at least 95% identity with the sequence of any one of SEQ ID NO:62, SEQ ID NO:63, SEQ ID NO:64, SEQ ID NO:67, SEQ ID NO:68, SEQ ID NO:72, SEQ ID NO:73, SEQ ID NO:76, SEQ ID NO:77, SEQ ID NO:80, SEQ ID NO:81, SEQ ID NO:82, SEQ ID NO:85, SEQ ID NO:86, SEQ ID NO:90, SEQ ID NO:91, SEQ ID NO:94, or SEQ ID NO:

95.

32. The method of any one of claims 1-17, the pharmaceutical composition of any one of claims 23-29, or the kit of claim 30, wherein the conjugate comprises an Fc domain, the Fc domain comprising an amino acid sequence of any one of SEQ ID NO:63, SEQ ID NO:64, SEQ ID NO:67, SEQ ID NO:68, SEQ ID NO:72, SEQ ID NO:73, SEQ ID NO:76, or SEQ ID NO:77.

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