Persistent t-cell engagers targeting FSHR and methods of use in cancer therapeutics

Abstract

Disclosed herein are compositions comprising persistent bispecific anti-FSHR T cell engagers and a persistent multivalent anti-FSHR T cell engagers, fragments thereof, variants thereof, combinations thereof, and recombinant nucleic acid sequences encoding the same, fragments thereof, variants thereof, combinations thereof, and methods of use thereof.

Description

PERSISTENT T-CELL ENGAGERS TARGETING FSHR AND METHODS OF USE IN CANCER THERAPEUTICSCROSS REFERENCE TO RELATED APPLICATION

[0001] This application claims priority to U.S. Provisional Application No. 63 / 652,849, filed May 29, 2024. and U.S. Provisional Application No. 63 / 655,925. filed June 04, 2024, each of which is hereby incorporated by reference herein in its entirety.STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

[0002] This invention was made with government support under CAO 10815. awarded by the National Institutes of Health. The government has certain rights in the invention.REFERENCE TO A “SEQUENCE LISTING7’ SUBMITTED AS AN XML FILE

[0003] The Sequence Listing written in the xml file: “206193-0139-00WO_Sequence Listing.xml”; created on May 23, 2025, and 235,142 bytes in size, is hereby incorporated by reference herein in its entirety.BACKGROUND OF THE INVENTION

[0004] Ovarian cancer (OC) represents the deadliest gynecologic malignancy. It stands as the fifth major driver of deaths from cancer among women accounting for the highest number of deaths for cancer of the female reproductive system. As per the American Cancer Society, it is estimated that there were 21,410 women with a new ovarian cancer diagnosis and 13,770 deaths due to OC in 2021 (Kunit et al., 2021, Obstet Gynecol.2021 ; 137(1): 108-21 ; Key Statistics for Ovarian Cancer. Accessed Nov 22, 2021. cancer.org). OC is a highly heterogeneous cancer where 90% of tumors are of epithelial origin. The most prevalent subtype of epithelial ovarian cancer (EOC) is high-grade serous cancer constituting around 70-80% of cases, whereas low-grade serous (<5%), endometrioid (10%), clear cell(10%) and mucinous (3%) represent less predominant subtypes (Barnes et al., 2021, Genome Med. 13(1): 140).

[0005] Surgery and chemotherapy are the primary treatments for OC (Y ang et al., 2020, Front Immunol. 11 :577869). These approaches are partially successful with many patients developing chemoresistance within a few years after their initial treatment who are next faced with disease recurrence (Y ang et al., 2020, Front Immunol. 11:577869). OC high mortality is also linked to low rates of early detection often due to the lack of subjective symptoms as well as marginally invasive techniques for primary detection. Therefore OC remains a critical need area for novel therapeutic approaches (Banno et al., 2014, Biomed Res Int, 2014:232817). There is a close interaction between the ovarian tumor cells and the tumor microenvironment, development of treatment approaches which not only target the tumor cells but also can maintain their anti-tumor function in this microenvironment is of particular importance (CSSOCR. Ovarian Cancers: Evolving Paradigms in Research and Care. Washington (DC): National Academies Press (US); 2016). A growing area of study are immune based therapies for OC. Such studies include immune checkpoint inhibitors (ICIs), chimeric antigen receptor (CAR)- and T cell receptor (TCR)- engineered T cells (Yang et al., 2020, Front Immunol. 11 :577869). Notably, a prime obstacle in the development of CAR therapies is to find targets w ith specific expression confined to the surface of tumor cells, but not on healthy tissues (Perales-Puchalt et al., 2017, Clin Cancer Res, 23(2):441- 500). The follicle-stimulating hormone receptor (FSHR) is one important target reported to have selective expression in ovarian granulosa cells versus low levels of expression in the normal ovarian endothelium. FSHR is expressed in 50-70% of serous ovarian carcinoma cases providing an important potential target for immune therapies (Perales-Puchalt et al., 2017, Clin Cancer Res. 23(2):441- 500).

[0006] Monoclonal antibody therapy has been a game-changer in cancers therapeutics, however, this treatment has several limitations including requirement for repeated administration, more limited stability and cost.

[0007] Bispecific T cell engagers (BTEs) are a powerful, antibody-based immunotherapy designed to simultaneously bind immune and cancer cells to trigger cancer’s selective destruction. To accomplish this, they are equipped with multiple binding domains that recognize distinct epitopes or antigens, with most research directed at binding to the CD3 complex of T cells alongside a relevant TAA (Nie et al., Antibody Therapeutics, 2020. 3(1): p. 18-62). The dual specificity forces a proximal relationship between target and T cells, withthe goal of engaging the T cell-mediated cellular cytotoxicity (CMC) of cancer cells through the formation of artificial, MHC-independent synapses. While clinically successful, first- generation BTEs given their simplified, dual single-chain variable fragment (scFv) design suffer a short half-life of ~2 hours (hrs) owing to the absence of an Fc region that would otherwise facilitate an extended circulation time from a higher molecular weight (MW) and neonatal Fc receptor (FcRn)-mediated recycling (Einsele, H., et al., Cancer, 2020. 126(14): p. 3192-3201).

[0008] Dramatic improvements to circulation time have been made by numerous second-generation formats that reintroduce an Fc domain, such as the Persistent BTE (PBTE) that is equipped with a single-chain Fc domain (scFc) linked to the conventional BTE molecule (Wei et al.. Frontiers in Immunology, 2022. 13). However, no new generation bispecific or multivalent t-cell engagers that target FSHR have been developed.

[0009] Thus there is need in the art for longer-lived, simpler production, antibodybased products for targreting FSHR in cancer immunotherapy. The current invention satisfies this need.SUMMARY

[0010] In some embodiments, the invention relates to a synthetic binding molecule, or a binding fragment thereof, or a nucleic acid molecule encoding one or more synthetic binding molecule, or a binding fragment thereof, wherein the one or more synthetic binding molecule comprises at least one antigen binding domain specific for binding to follicle stimulating hormone receptor (FSHR), and at least one immune cell engaging domain.

[0011] In some embodiments, the immune cell engaging domain targets a T cell, an antigen presenting cell, a natural killer (NK) cell, a neutrophil or a macrophage.

[0012] In some embodiments, the immune cell engaging domain targets at least one T cell specific receptor molecule selected from the group of CD3, the T cell receptor (TCR), CD28, CD16, NKG2D, 0x40, 4-1BB, CD2, CD5, CD40, FcgRs, FceRs, FcaRs and CD95. In some embodiments, the immune cell engaging domain targets CD3.

[0013] In some embodiments, the synthetic binding molecule comprises: a FSHR heavy chain amino acid sequence of SEQ ID NO: 1, or a fragment thereof comprising at least the CDRs; a FSHR light chain amino acid sequence of SEQ ID NO: 2, or a fragment thereof comprising at least the CDRs; a CD3 heavy chain amino acid sequence of SEQ ID NO: 3, ora fragment thereof comprising at least the CDRs; and a CD3 light chain amino acid sequence of SEQ ID NO: 4, or a fragment thereof comprising at least the CDRs.

[0014] In some embodiments, the synthetic binding molecule further comprises: an Fc domain comprising SEQ ID NO:5, or a fragment or variant thereof.

[0015] In some embodiments, the synthetic binding molecule further comprises: a second FSHR heavy chain amino acid sequence of SEQ ID NO: 1, or a fragment thereof comprising at least the CDRs; and a second FSHR light chain amino acid sequence of SEQ ID NO: 2, or a fragment thereof comprising at least the CDRs.

[0016] In some embodiments, the synthetic binding molecule comprises SEQ ID NO:6 or SEQ ID NO:7.

[0017] In some embodiments, the synthetic binding molecule comprises an amino acid sequence selected from the group consisting of SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17. SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO:20, SEQ ID NO:21. SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO 24, SEQ ID NO:25, SEQ ID NO:26. SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO 35, SEQ ID NO:36, and SEQ ID NO:37.

[0018] In some embodiments, the invention relates to a nucleic acid molecule encoding one or more synthetic binding molecule, or a binding fragment thereof, wherein the one or more synthetic binding molecule comprises at least one antigen binding domain specific for binding to follicle stimulating hormone receptor (FSHR), and at least one immune cell engaging domain.

[0019] In some embodiments, the nucleic acid molecule is selected from the group consisting of an RNA molecule and a DNA molecule.

[0020] In some embodiments, the nucleic acid molecule comprises a nucleotide sequence selected from the group consisting of SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:40. SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO 43, SEQ ID NO:44, SEQ ID NO:45. SEQ ID NO:46, SEQ ID NO:47. SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50. SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO 53, SEQ ID NO 54, SEQ ID NO:55, SEQ ID NO:56, SEQ ID NO:57, SEQ ID NO:58, SEQ ID NO:59, SEQ ID NO:60, SEQ ID NO:61, SEQ ID NO:62, SEQ ID NO:63, SEQ ID NO:64, SEQ ID NO 65, SEQ ID NO:66, SEQ ID NO:67. SEQ ID NO:68, SEQ ID NO:69. SEQ ID NO:70, and SEQ ID NO:71.

[0021] In some embodiments, the nucleic acid molecule comprises an expression vector.

[0022] In some embodiments, the invention relates to a composition comprising the the invention relates to a synthetic binding molecule, or a binding fragment thereof, or a nucleic acid molecule encoding one or more synthetic binding molecule, or a binding fragment thereof, wherein the one or more synthetic binding molecule comprises at least one antigen binding domain specific for binding to follicle stimulating hormone receptor (FSHR), and at least one immune cell engaging domain.

[0023] In some embodiments, the composition further comprises a pharmaceutically acceptable excipient.

[0024] In some embodiments, the composition further comprises at least one immune checkpoint inhibitor.

[0025] In some embodiments, the composition further comprises at least one nucleic acid molecule encoding at least one immune checkpoint inhibitor.

[0026] In some embodiments, the immune checkpoint inhibitor is selected from the group consisting of an inhibitor of PD-1, an inhibitor of PD-L-1, an inhibitor of cytotoxic T- lymphocyte antigen-4 (CTLA-4), an inhibitor of mucin-domain containing-3 (TIM-3), and an inhibitor of Lymphocyte Activating 3 (LAG3).

[0027] In some embodiments, the composition comprises a lipid nanoparticle comprising the synthetic binding molecule, or a binding fragment thereof, or a nucleic acid molecule encoding one or more synthetic binding molecule, or a binding fragment thereof, wherein the one or more synthetic binding molecule comprises at least one antigen binding domain specific for binding to follicle stimulating hormone receptor (FSHR), and at least one immune cell engaging domain.

[0028] In some embodiments, the invention relates to a method of preventing or treating a disease or disorder associated with FSHR expression in a subject, the method comprising administering to the subject the synthetic binding molecule, or a binding fragment thereof, or a nucleic acid molecule encoding one or more synthetic binding molecule, or a binding fragment thereof, wherein the one or more synthetic binding molecule comprises at least one antigen binding domain specific for binding to follicle stimulating hormone receptor (FSHR), and at least one immune cell engaging domain, or the composition comprising the at least one synthetic binding molecule, or a binding fragment thereof, or a nucleic acid molecule encoding one or more synthetic binding molecule, or a binding fragment thereof.

[0029] In some embodiments, the disease is a benign tumor, cancer or a cancer- associated disease.

[0030] In some embodiments, the disease is ovarian cancer, breast cancer, prostate cancer, renal cancer, colo-rectal cancer, stomach cancer, lung cancer, testicular cancer, endometrial cancer, or thyroid cancer.BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Figure 1 depicts in vitro and in vivo expression of anti-FSHR and anti-CD3 PBTE and PMTEs.

[0032] Figure 2A through 2E depict the results of example experiments demonstrating FSHR-targeted BTEs follow similar formatting trends for binding and potency in vitro. Figure 2A shows anti-FSHR scFvs in BTE. PBTE. and PMTE formats. Anti-CD3 scFvs were unchanged. Figure 2B depicts flow cytometry binding curves to OVCAR3-FSHR and T cells. An irrelevant IgGl was used as negative control. Data are presented as mean + / - SEM. Figure 2C depicts the concentration-dependent degree of OVCAR3-FSHR cytotoxicity is expressed as the percent of healthy cell control after 5 days. An irrelevant BTE was used as negative control. Data are presented as mean of duplicates. Figure 2D depicts KD values from flow cytometry binding analyses for OVCAR-FSHR and T cells. Figure 2E depicts EC50 calculations from the OVCAR-FSHR killing assay.DETAILED DESCRIPTION

[0033] The present invention relates to compositions comprising FSHR-specific binding molecules including a persistent bispecific T cell engaging antibody (PBTE) and a persistent multivalent T cell engaging (PMTE) antibody, an scFv antibody fragment and CAR molelcules, fragments thereof, variants thereof, combinations thereof and nucleic acid molecules encoding the same.

[0034] In one embodiment, the PBTE or PMTE comprisies at least one antigen binding domain, and at least one immune cell engaging domain. In one embodiment, the immune cell engaging domain is specific for an antigen expressed on the surface of an immune cell. Immune cells include, but are not limited to, T cells, antigen presenting cells, NK. cells, neutrophils and macrophages.

[0035] In various embodiments, the immune cell engaging domain comprises a nucleotide sequence encoding an antibody, a fragment thereof, or a variant thereof specificfor binding to a immune cell specific receptor molecule. In one embodiment, the immune cell specific receptor molecule is a T cell surface antigen. In one embodiment, the T cell specific receptor molecule is one of CD3, TCR, CD28, CD16, NKG2D, 0x40, 4-1BB, CD2, CD5, CD40, FcgRs, FceRs, FcaRs and CD95.

[0036] In various embodiments, the antigen binding domain comprises a nucleotide sequence encoding an antibody, a fragment thereof, or a variant thereof specific for binding to an antigen. In one embodiment, the antibody or fragment thereof is a DNA encoded monoclonal antibody (DMAb) or a fragment or variant thereof. In one embodiment, the antibody or fragment thereof is an mRNA encoded monoclonal antibody or a fragment or variant thereof.

[0037] In one embodiment, the antigen binding domain of the PBTE or PMTE is specific for binding a target antigen, and recruiting a T cell to the target antigen. In one embodiment, the target antigen is a tumor antigen. In one embodiment, the antigen follicle stimulating hormone receptor (FSHR). Therefore, in one embodiment, the invention provides compositions comprising one or more PBTE or PMTE and methods for use in treating or preventing cancer or a disease or disorder associated with cancer in a subject.Definitions

[0038] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In case of conflict, the present document, including definitions, will control. Preferred methods and materials are described below, although methods and materials similar or equivalent to those described herein can be used in practice or testing of the present invention. All publications, patent applications, patents and other references mentioned herein are incorporated by reference in their entirety. The materials, methods, and examples disclosed herein are illustrative only and not intended to be limiting.

[0039] The terms “comprise(s),” “include(s),” “having,” “has,” “can,” “contain(s),” and variants thereof, as used herein, are intended to be open-ended transitional phrases, terms, or words that do not preclude the possibility of additional acts or structures. The singular forms “a,” “and” and “the” include plural references unless the context clearly dictates otherwise. The present disclosure also contemplates other embodiments “comprising,” “consisting of’ and “consisting essentially of,” the embodiments or elements presented herein, whether explicitly set forth or not.

[0040] “Antibody’' may mean an antibody of classes IgG, IgM, IgA, IgD or IgE, or fragments, fragments or derivatives thereof, including Fab, F(ab')2. Fd. and single chain antibodies, and derivatives thereof. The antibody may be an antibody isolated from the serum sample of mammal, a polyclonal antibody, affinity purified antibody, or mixtures thereof which exhibits sufficient binding specificity to a desired epitope or a sequence derived therefrom.

[0041] “Antibody fragment” or “fragment of an antibody” as used interchangeably herein refers to a portion of an intact antibody comprising the antigen-binding site or variable region. The portion does not include the constant heavy chain domains (i.e. CH2, CH3, or CH4, depending on the antibody isotype) of the Fc region of the intact antibody. Examples of antibody fragments include, but are not limited to, Fab fragments, Fab' fragments. Fab'-SH fragments, F(ab')2 fragments, Fd fragments, Fv fragments, diabodies, single-chain Fv (scFv) molecules, single-chain polypeptides containing only one light chain variable domain, singlechain polypeptides containing the three CDRs of the light-chain variable domain, singlechain polypeptides containing only one heavy chain variable region, single-chain polypeptides containing the three CDRs of the heavy chain variable region, nanobodies, or long CDR3Fv.

[0042] “Antigen” refers to proteins that have the ability to generate an immune response in a host. An antigen may be recognized and bound by an antibody. An antigen may originate from within the body or from the external environment.

[0043] “Coding sequence” or “encoding nucleic acid” as used herein may mean refers to the nucleic acid (RNA or DNA molecule) that comprise a nucleotide sequence which encodes an antibody as set forth herein. The coding sequence may further include initiation and termination signals operably linked to regulatory elements including a promoter and polyadenylation signal capable of directing expression in the cells of an individual or mammal to whom the nucleic acid is administered. The coding sequence may further include sequences that encode signal peptides.

[0044] “Complement” or “complementary” as used herein may mean a nucleic acid may mean Watson-Crick (e.g.. A-T / U and C-G) or Hoogsteen base pairing between nucleotides or nucleotide analogs of nucleic acid molecules.

[0045] “Endogenous antibody” as used herein may refer to an antibody that is generated in a subject that is administered an effective dose of an antigen for induction of a humoral immune response.

[0046] “Fragment’' may mean a polypeptide fragment of an antibody that is function, i.e., can bind to desired target and have the same intended effect as a full length antibody. A fragment of an antibody may be 100% identical to the full length except missing at least one amino acid from the N and / or C terminal, in each case with or without signal peptides and / or a methionine at position 1. Fragments may comprise 20% or more, 25% or more, 30% or more, 35% or more, 40% or more, 45% or more, 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more. 80% or more, 85% or more. 90% or more, 91% or more, 92% or more, 93% or more, 94% or more, 95% or more, 96% or more, 97% or more, 98% or more, 99% or more percent of the length of the particular full length antibody, excluding any heterologous signal peptide added. The fragment may comprise a fragment of a polypeptide that is 95% or more. 96% or more, 97% or more, 98% or more or 99% or more identical to the antibody and additionally comprise an N terminal methionine or heterologous signal peptide which is not included when calculating percent identity. Fragments may further comprise an N terminal methionine and / or a signal peptide such as an immunoglobulin signal peptide, for example an IgE or IgG signal peptide. The N terminal methionine and / or signal peptide may be linked to a fragment of an antibody.

[0047] A fragment of a nucleic acid sequence that encodes an antibody may be 100% identical to the full length except missing at least one nucleotide from the 5’ and / or 3' end, in each case with or without sequences encoding signal peptides and / or a methionine at position 1. Fragments may comprise 20% or more, 25% or more, 30% or more. 35% or more, 40% or more, 45% or more, 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 91% or more, 92% or more, 93% or more, 94% or more, 95% or more, 96% or more, 97% or more, 98% or more. 99% or more percent of the length of the particular full length coding sequence, excluding any heterologous signal peptide added. The fragment may comprise a fragment that encode a polypeptide that is 95% or more, 96% or more, 97% or more, 98% or more or 99% or more identical to the antibody and additionally optionally comprise sequence encoding an N terminal methionine or heterologous signal peptide which is not included when calculating percent identity. Fragments may further comprise coding sequences for an N terminal methionine and / or a signal peptide such as an immunoglobulin signal peptide, for example an IgE or IgG signal peptide. The coding sequence encoding the N terminal methionine and / or signal peptide may be linked to a fragment of coding sequence.

[0048] “Genetic construct'’ as used herein refers to the DNA or RNA molecules that comprise a nucleotide sequence which encodes a protein, such as an antibody. The coding sequence includes initiation and termination signals operably linked to regulator}' elements including a promoter and polyadenylation signal capable of directing expression in the cells of the individual to whom the nucleic acid molecule is administered. As used herein, the term "expressible form" refers to gene constructs that contain the necessary regulatory elements operable linked to a coding sequence that encodes a protein such that when present in the cell of the individual, the coding sequence will be expressed.

[0049] “Identical” or “identity” as used herein in the context of two or more nucleic acids or polypeptide sequences, may mean that the sequences have a specified percentage of residues that are the same over a specified region. The percentage may be calculated by optimally aligning the two sequences, comparing the two sequences over the specified region, determining the number of positions at which the identical residue occurs in both sequences to yield the number of matched positions, dividing the number of matched positions by the total number of positions in the specified region, and multiplying the result by 100 to yield the percentage of sequence identity. In cases where the two sequences are of different lengths or the alignment produces one or more staggered ends and the specified region of comparison includes only a single sequence, the residues of single sequence are included in the denominator but not the numerator of the calculation. When comparing DNA and RNA, thymine (T) and uracil (U) may be considered equivalent. Identity may be performed manually or by using a computer sequence algorithm such as BLAST or BLAST 2.0.

[0050] “Immune response” as used herein may mean the activation of a host’s immune system, e.g., that of a mammal, in response to the introduction of one or more nucleic acids and / or peptides. The immune response can be in the form of a cellular or humoral response, or both.

[0051] “Nucleic acid” or “oligonucleotide” or “polynucleotide” as used herein may mean at least two nucleotides covalently linked together. The depiction of a single strand also defines the sequence of the complementary strand. Thus, a nucleic acid also encompasses the complementary strand of a depicted single strand. Manx- variants of a nucleic acid may be used for the same purpose as a given nucleic acid. Thus, a nucleic acid also encompasses substantially identical nucleic acids and complements thereof. A single strand provides a probe that may hybridize to a target sequence under stringent hybridization conditions. Thus,a nucleic acid also encompasses a probe that hybridizes under stringent hybridization conditions.

[0052] Nucleic acids may be single stranded or double stranded, or may contain portions of both double stranded and single stranded sequence. The nucleic acid may be DNA, both genomic and cDNA, RNA, or a hybrid, where the nucleic acid may contain combinations of deoxyribo- and ribo-nucleotides, and combinations of bases including uracil, adenine, thymine, cytosine, guanine, inosine, xanthine hypoxanthine, isocytosine and isoguanine. Nucleic acids may be obtained by chemical synthesis methods or by recombinant methods.

[0053] “Operably linked” as used herein may mean that expression of a gene is under the control of a promoter with which it is spatially connected. A promoter may be positioned 5' (upstream) or 3' (downstream) of a gene under its control. The distance between the promoter and a gene may be approximately the same as the distance between that promoter and the gene it controls in the gene from which the promoter is derived. As is known in the art, variation in this distance may be accommodated without loss of promoter function.

[0054] A “peptide,” “protein,” or “polypeptide” as used herein can mean a linked sequence of amino acids and can be natural, synthetic, or a modification or combination of natural and synthetic.

[0055] “Promoter” as used herein may mean a synthetic or naturally-derived molecule which is capable of conferring, activating or enhancing expression of a nucleic acid in a cell. A promoter may comprise one or more specific transcriptional regulatory sequences to further enhance expression and / or to alter the spatial expression and / or temporal expression of same. A promoter may also comprise distal enhancer or repressor elements, which can be located as much as several thousand base pairs from the start site of transcription. A promoter may be derived from sources including viral, bacterial, fungal, plants, insects, and animals. A promoter may regulate the expression of a gene component constitutively, or differentially with respect to cell, the tissue or organ in which expression occurs or, with respect to the developmental stage at which expression occurs, or in response to external stimuli such as physiological stresses, pathogens, metal ions, or inducing agents. Representative examples of promoters include the bacteriophage T7 promoter, bacteriophage T3 promoter, SP6 promoter, lac operator-promoter, tac promoter, SV40 late promoter, SV40 early promoter, RSV-LTR promoter, CMV IE promoter, SV40 early promoter or SV 40 late promoter and the CMV IE promoter.

[0056] “Signal peptide” and “leader sequence” are used interchangeably herein and refer to an amino acid sequence that can be linked at the amino terminus of a protein set forth herein. Signal peptides / leader sequences typically direct localization of a protein. Signal peptides / leader sequences used herein preferably facilitate secretion of the protein from the cell in which it is produced. Signal peptides / leader sequences are often cleaved from the remainder of the protein, often referred to as the mature protein, upon secretion from the cell. Signal peptides / leader sequences are linked at the N terminus of the protein.

[0057] “Stringent hybridization conditions” as used herein may mean conditions under which a first nucleic acid sequence (e.g., probe) will hybridize to a second nucleic acid sequence (e.g., target), such as in a complex mixture of nucleic acids. Stringent conditions are sequence dependent and will be different in different circumstances. Stringent conditions may be selected to be about 5-10°C lower than the thermal melting point (Tm) for the specific sequence at a defined ionic strength pH. The Tm may be the temperature (under defined ionic strength, pH, and nucleic concentration) at which 50% of the probes complementary to the target hybridize to the target sequence at equilibrium (as the target sequences are present in excess, at Tm, 50% of the probes are occupied at equilibrium). Stringent conditions may be those in which the salt concentration is less than about 1.0 M sodium ion, such as about 0.01- 1.0 M sodium ion concentration (or other salts) at pH 7.0 to 8.3 and the temperature is at least about 30°C for short probes (e g., about 10-50 nucleotides) and at least about 60°C for long probes (e.g., greater than about 50 nucleotides). Stringent conditions may also be achieved with the addition of destabilizing agents such as formamide. For selective or specific hybridization, a positive signal may be at least 2 to 10 times background hybridization. Exemplary stringent hybridization conditions include the following: 50% formamide, 5x SSC, and 1% SDS. incubating at 42°C, or, 5x SSC, 1% SDS, incubating at 65°C. with wash in 0.2x SSC, and 0.1% SDS at 65°C.

[0058] “Subject” and “patient” as used herein interchangeably refers to any vertebrate, including, but not limited to, a mammal (e.g., cow, pig, camel, llama, horse, goat, rabbit, sheep, hamsters, guinea pig, cat, dog, rat, and mouse, a non-human primate (for example, a monkey, such as a cynomolgous or rhesus monkey, chimpanzee, etc) and a human). In some embodiments, the subject may be a human or a non-human. The subject or patient may be undergoing other forms of treatment.

[0059] “Substantially complementary” as used herein may mean that a first sequence is at least 60%. 65%. 70%. 75%. 80%. 81%. 82%. 83%. 84%, 85%, 86%, 87%, 88%, 89%,90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the complement of a second sequence over a region of 8, 9. 10. 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23. 24, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100 or more nucleotides or amino acids, or that the two sequences hybridize under stringent hybridization conditions.

[0060] “Substantially identical” as used herein may mean that a first and second sequence are at least 60%, 65%, 70%, 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%. 89%. 90%. 91%. 92%. 93%. 94%. 95%. 96%. 97%. 98%.or 99% over a region of 1, 2. 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100 or more nucleotides or amino acids, or with respect to nucleic acids, if the first sequence is substantially complementary to the complement of the second sequence.

[0061] “Synthetic antibody” as used herein refers to an antibody that is encoded by the recombinant nucleic acid sequence described herein and is generated in a subject.

[0062] “Treatment” or “treating,” as used herein can mean protecting of a subject from a disease through means of preventing, suppressing, repressing, or completely eliminating the disease. Preventing the disease involves administering an antibody of the present invention to a subject prior to onset of the disease. Suppressing the disease involves administering a antibody of the present invention to a subject after induction of the disease but before its clinical appearance. Repressing the disease involves administering an antibody of the present invention to a subject after clinical appearance of the disease.

[0063] “Variant” used herein with respect to a nucleic acid may mean (i) a portion or fragment of a referenced nucleotide sequence; (ii) the complement of a referenced nucleotide sequence or portion thereof; (iii) a nucleic acid that is substantially identical to a referenced nucleic acid or the complement thereof; or (iv) a nucleic acid that hybridizes under stringent conditions to the referenced nucleic acid, complement thereof, or a sequences substantially identical thereto.

[0064] “Variant” with respect to a peptide or polypeptide that differs in amino acid sequence by the insertion, deletion, or conservative substitution of amino acids, but retain at least one biological activity. Variant may also mean a protein with an amino acid sequence that is substantially identical to a referenced protein with an amino acid sequence that retains at least one biological activity. A conservative substitution of an amino acid, i.e., replacing an amino acid with a different amino acid of similar properties (e.g., hydrophilicity, degree and distribution of charged regions) is recognized in the art as typically involving a minor change.These minor changes can be identified, in part, by considering the hydropathic index of amino acids, as understood in the art. Kyte et al., J. Mol. Biol. 157: 105-132 (1982). The hydropathic index of an amino acid is based on a consideration of its hydrophobicity and charge. It is known in the art that amino acids of similar hydropathic indexes can be substituted and still retain protein function. In one aspect, amino acids having hydropathic indexes of ±2 are substituted. The hydrophilicity of amino acids can also be used to reveal substitutions that would result in proteins retaining biological function. A consideration of the hydrophilicity of amino acids in the context of a peptide permits calculation of the greatest local average hydrophilicity of that peptide, a useful measure that has been reported to correlate well with antigenicity and immunogenicity. U.S. Patent No. 4,554,101, incorporated fully herein by reference. Substitution of amino acids having similar hydrophilicity values can result in peptides retaining biological activity, for example immunogenicity, as is understood in the art. Substitutions may be performed with amino acids having hydrophilicity values within ±2 of each other. Both the hyrophobicity index and the hydrophilicity value of amino acids are influenced by the particular side chain of that amino acid. Consistent with that observation, amino acid substitutions that are compatible with biological function are understood to depend on the relative similarity of the amino acids, and particularly the side chains of those amino acids, as revealed by the hydrophobicity, hydrophilicity, charge, size, and other properties.

[0065] A variant may be a nucleic acid sequence that is substantially identical over the full length of the full gene sequence or a fragment thereof. The nucleic acid sequence may be 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical over the full length of the gene sequence or a fragment thereof. A variant may be an amino acid sequence that is substantially identical over the full length of the amino acid sequence or fragment thereof. The amino acid sequence may be 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical over the full length of the amino acid sequence or a fragment thereof.

[0066] "Vector" as used herein may mean a nucleic acid sequence containing an origin of replication. A vector may be a plasmid, bacteriophage, bacterial artificial chromosome or yeast artificial chromosome. A vector may be a DNA or RNA vector. A vector may be either a self-replicating extrachromosomal vector or a vector which integrates into a host genome.

[0067] For the recitation of numeric ranges herein, each intervening number there between with the same degree of precision is explicitly contemplated. For example, for the range of 6-9, the numbers 7 and 8 are contemplated in addition to 6 and 9, and for the range 6.0-7.0, the number 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, and 7.0 are explicitly contemplated.Compositions

[0068] In one embodiment, the present invention relates to compositions comprising a persistent bispecific T cell engager (or PBTE) or persistent multivalent T cell engager (or PMTE), a fragment thereof, a variant thereof, or a combination thereof. The compositions, when administered to a subject in need thereof, can result in the generation of a synthetic bispecific or multivalent T cell engager in the subject. In some embodiments, the PBTE or PMTE of the invention is encoded by a nucleic acid molecue (e.g., DNA or mRNA). Therefore, in some embodiments, the invention relates to nucleic acid molecules encoding a PBTE or PMTE.Synthetic Binding Molecules

[0069] In some embodiments, the invention relates to synthetic binding molecules (e.g., PBTE or PMTE), or a combination thereof. In some embodiments, the synthetic binding molecule of the invention comprisies at least one antigen binding domain, and at least one immune cell engaging domain. In one embodiment, the immune cell engaging domain is specific for an antigen expressed on the surface of an immune cell. Immune cells include, but are not limited to, T cells, antigen presenting cells, NK cells, neutrophils and macrophages.

[0070] In various embodiments, the antigen binding domain comprises at least one antibody, a fragment thereof, or a variant thereof specific for binding to an antigen (e.g., scFv, nanobody, or long CDR3Fv). In one embodiment, the antigen is a tumor antigen. In one embodiment, the antigen is follicle stimulating hormone receptor (FSHR).

[0071] In some embodiments, the synthetic binding molecules may comprise at least one heavy chain and at least one light chain complementarity determining region (“CDR ’) set, respectively interposed between at least one heavy chain and at least one light chain framework ("FR") set which provide support to the CDRs and define the spatial relationship of the CDRs relative to each other. The CDR set may contain three hypervariable regions ofa heavy or light chain V region. Proceeding from the N-terminus of a heavy or light chain, these regions are denoted as “CDR1,” “CDR2,” and CDR3. " respectively. An antigenbinding site, therefore, may include six CDRs, comprising the CDR set from each of a hea\ y and a light chain V region.Heavy Chain Polypeptide

[0072] The binding molecule of the invention can include a heavy chain polypeptide, a fragment thereof, a variant thereof, or a combination thereof. The heavy chain polypeptide can include a variable heavy chain (VH) region and / or at least one constant heavy chain (CH) region. The at least one constant heavy chain region can include a constant heavy chain region 1 (CHI), a constant heavy chain region 2 (CH2). and a constant heavy chain region 3 (CH3). and / or a hinge region.Light Chain Polypeptide

[0073] The binding molecule of the invention can include a light chain polypeptide, a fragment thereof, a variant thereof, or a combination thereof. The light chain polypeptide can include a variable light chain (VL) region and / or a constant light chain (CL) region.

[0074] The light chain polypeptide can include a complementarity determining region (“CDR”) set. The CDR set can contain three hypervariable regions of the VL region. Proceeding from N-terminus of the light chain polypeptide, these CDRs are denoted “CDR1,” “CDR2,” and “CDR3,” respectively. CDR1, CDR2, and CDR3 of the light chain polypeptide can contribute to binding or recognition of the antigen.Linker Sequence

[0075] The binding molecule of the invention of the invention can include one or more linker sequences. The linker sequence can spatially separate or link the one or more components described herein. In other embodiments, the linker sequence can comprise an amino acid sequence that spatially separates or links two or more polypeptides. In one embodiment, the linker sequence is a G4S linker sequence.Leader Sequence

[0076] The binding molecule of the invention of the invention can include one or more leader sequences. In one embodiment, the leader sequence is a signal peptide. Thesignal peptide can be an immunoglobulin (Ig) signal peptide, for example, but not limited to. an IgG signal peptide and a IgE signal peptide.Antigen Binding Domain

[0077] In one embodiment, the binding molecule is directed to an antigen or fragment or variant thereof. The antigen can be a nucleic acid sequence, an amino acid sequence, a polysaccharide or a combination thereof. The nucleic acid sequence can be DNA, RNA. cDNA, a variant thereof, a fragment thereof, or a combination thereof. The amino acid sequence can be a protein, a peptide, a variant thereof, a fragment thereof, or a combination thereof. The polysaccharide can be a nucleic acid encoded polysaccharide.

[0078] The antigen can be a tumor antigen. The antigen can be associated with increased risk of cancer development or progression. In one embodiment, the antigen can be FSHR.

[0079] In one embodiment, a synthetic bispecific immune cell engager (PBTE or PMTE) of the invention targets two or more antigen binding domains. In one embodiment, each of the antigen binding domains is specific for binding to a tumor antigen. In one embodiment, the antigen can be FSHR.

[0080] Aspects of the present invention include compositions for enhancing an immune response against FSHR in a subject in need thereof, comprising administering a synthetic binding molecule capable of recruiting an immune cell to an FSHR expressing cell in the subject. In some embodiments, the synthetic antibody of this invention is a PBTE or PMTE comprising at least one scFv targeting FSHR.Immune Cell Binding Domain

[0081] In some embodiments, one of the binding sites of an antibody molecule according to the invention is able to bind a T-cell specific receptor molecule and / or a natural killer cell (NK cell) specific receptor molecule. A T-cell specific receptor is the so called "T- cell receptor" (TCRs), which allows a T cell to bind to and, if additional signals are present, to be activated by and respond to an epitope / antigen presented by another cell called the antigen-presenting cell or APC. The T cell receptor is known to resemble a Fab fragment of a naturally occurring immunoglobulin. It is generally monovalent, encompassing alpha.- and .beta. -chains, in some embodiments, it encompasses .gamma. -chains and .delta. -chains (supra). Accordingly, in some embodiments, the TCR is TCR (alpha / beta) and in someembodiments, it is TCR (gamma / delta). The T cell receptor forms a complex with the CD3 T- Cell co-receptor. CD3 is a protein complex and is composed of four distinct chains. In mammals, the complex contains a CD3y chain, a CD36 chain, and two CD3E chains. These chains associate with a molecule known as the T cell receptor (TCR) and the fychain to generate an activation signal in T lymphocytes. Hence, in some embodiments, a T-cell specific receptor is the CD3 T-Cell co-receptor. In some embodiments, a T-cell specific receptor is CD28, a protein that is also expressed on T cells. CD28 can provide costimulatory signals, which are required for T cell activation. CD28 plays important roles in T- cell proliferation and survival, cytokine production, and T-helper type-2 development. Yet a further example of a T-cell specific receptor is CD134, also termed 0x40. CD134 / OX40 is being expressed after 24 to 72 hours following activation and can be taken to define a secondary costimulatory molecule. Another example of a T-cell receptor is 4-1 BB capable of binding to 4-1 BB-Ligand on antigen presenting cells (APCs), whereby a costimulatory signal for the T cell is generated. Another example of a receptor predominantly found on T- cells is CD5, which is also found on B cells at low levels. A further example of a receptor modifying T cell functions is CD95, also known as the Fas receptor, which mediates apoptotic signaling by Fas-ligand expressed on the surface of other cells. CD95 has been reported to modulate TCR / CD3-driven signaling pathways in resting T lymphocytes.

[0082] An example of a NK cell specific receptor molecule is CD16, a low affinity Fc receptor and NKG2D. An example of a receptor molecule that is present on the surface of both T cells and natural killer (NK) cells is CD2 and further members of the CD2- superfamily. CD2 is able to act as a co-stimulatory molecule on T and NK cells.

[0083] In some embodiments, the synthetic binding molecule comprisies at least one binding site of the synthetic binding molecule binds a tumor antigen and at least one binding site that binds a T cell specific receptor molecule and / or a natural killer (NK) cell specific receptor molecule.

[0084] In some embodiments, at least one binding site of the synthetic binding molecule binds FSHR, and at least one binding site of the synthetic binding molecule binds a T cell specific receptor molecule and / or a natural killer (NK) cell specific receptor molecule. In some embodiments, the first binding site of the antibody molecule binds FSHR and the second binding site binds one of CD3, TCR, CD28, CD16, NKG2D, 0x40, 4-1BB, CD2, CD5, CD40, FcgRs, FceRs, FcaRs and CD95. In some embodiments, at least one bindingsite of the synthetic binding molecule binds FSHR and at least one binding site of the synthetic binding molecule binds CD3.

[0085] In some embodiments, at least one binding site of the synthetic binding molecule binds a T cell specific receptor molecule and / or a natural killer (NK) cell specific receptor molecule and two or more bindings sites of the synthetic binding molecule a tumor antigen. In some embodiments, at least one binding site of the synthetic binding molecule binds a T cell specific receptor molecule and / or a natural killer (NK) cell specific receptor molecule and two or more bindings sites of the synthetic binding molecule bind FSHR. In some embodiments, at least one binding site of the synthetic binding molecule binds one of CD3, TCR, CD28, CD16, NKG2D, 0x40, 4-1BB, CD2, CD5, CD40, FcgRs. FceRs, FcaRs and CD95, and the second binding site binds FSHR. In some embodiments, at least one binding site of the synthetic binding molecule binds CD3, and two or more bindings sites of the synthetic binding molecule bind FSHR.Arrangements

[0086] In one embodiment the synthetic binding molecule of the invention comprises a PBTE or PMTE, comprising an antibody Fc domain linked to one or more tandem scFv antibody fragments, thereby allowing the PBTE or PMTE to bind or react with the desired target molecules.

[0087] In one embodiment the PBTE or PMTE comprises at least one scFv specific for binding to a target disease-specific antigen linked to at least one scFv specific for binding to a T cell specific receptor molecule. The linkage may place the tandem scFv domains in any order, for example, in one embodiment, the scFv specific for binding to a target diseasespecific antigen is oriented C-terminal to a scFv specific for binding to a T cell specific receptor molecule. In another embodiment, scFv specific for binding to a target diseasespecific antigen is oriented N-terminal to a scFv specific for binding to a T cell specific receptor molecule. In some embodiments, each scFv has a heavy chain and a light chain. In some embodiments, the heavy chain of the disease-specific scFv is C-terminal to the light chain of the disease-specific scFv. In some embodiments, heavy chain of the disease-specific scFv is N-terminal to the light chain of the disease-specific scFv. In some embodiments, the heavy chain of the T cell specific receptor molecule scFV is C-terminal to the light chain of the T cell specific receptor molecule scFV. In some embodiments, the heavy chain of the Tcell specific receptor molecule scFv is N-terminal to the light chain of the T cell specific receptor molecule scFv.

[0088] In one embodiment the PBTE or PMTE comprises at least one scFv specific for binding to a target disease-specific antigen linked to at least one scFv specific for binding to a T cell specific receptor molecule and an Fc domain. In one embodiment, the Fc domain is oriented C-terminal to the scFv domains. In another embodiment, the Fc domain is oriented N-terminal to the scFv domains. In various embodiments, the immune cell engaging domain comprises a nucleotide sequence encoding an antibody, a fragment thereof, or a variant thereof specific for binding to a immune cell specific receptor molecule. In one embodiment, the immune cell specific receptor molecule is a T cell surface antigen. In one embodiment, the T cell specific receptor molecule is one of CD3. TCR. CD28, CD 16, NKG2D, 0x40. 4- 1BB, CD2, CD5, CD40, FcgRs, FceRs, FcaRs and CD95.Persistent Bispecific T cell Engager

[0089] In some embodiments, the binding molecule of the invention can be a persistent bispecific T cell engager (PBTE). a fragment thereof, a variant thereof, or a combination thereof.

[0090] In one embodiment, the PBTE comprises an antibody Fc domain linked to an antigen binding domain linked to an immune cell engaging domain. In some embodiments, the Fc domain comprises SEQ ID NO:72. In some embodiments, the Fc domain further comprises at least one stabilization motif. In some embodiments, the Fc domain comprises at least two copies of SEQ ID NO:72, connected by a linker. In some embodiments, the PBTE comprises the Fc domain of SEQ ID NO: 5. In some embodiments, the PBTE comprises an antibody Fc domain linked to an FSHR scFv comprising a heavy chain and light chain specific for binding to FSHR operably linked to a CD3 scFv comprising a heavy chain and light chain specific for binding to CD3. In some embodiments, the FSHR heavy chain comprises SEQ ID NO: 1 and the FSHR light chain comprises SEQ ID NO:2. In some embodiments, the CD3 heavy chain comprises SEQ ID NO: 3 and the CD3 light chain comprises SEQ ID NO:4. In some embodiments, the PBTE comprises an Fc domain operably linked to an anti-FSHR scFv comprising SEQ ID NO: 1 and SEQ ID NO:2 and further operably linked to an anti-CD3 scFv comprising SEQ ID NO:3 and SEQ ID NO:4. In some embodiments, the anti-FSHR scFv is between the Fc domain and the anti-CD3 scFv. In some embodiments, the anti-CD3 scFv is between the Fc domain and the anti-FSHR scFv. In someembodiments, the anti-FSHR heavy chain is C-terminal to the anti-FSHR light chain. In some embodiments, the anti-FSHR heavy chain is N-terminal to the anti-FSHR light chain. In some embodiments, the anti-CD3 heavy chain is C-terminal to the anti-CD3 light chain. In some embodiments, the anti-CD3 heavy chain is N-terminal to the anti-CD3 light chain.

[0091] In some embodiments, the PBTE comprises the amino acid sequence of SEQ ID NO:6 or 7, or a fragment of variant thereof.Persistent Multispecific T cell Engager

[0092] In some embodiments, the binding molecule of the invention can be a persistent multispecific T cell engager (PMTE), a fragment thereof, a variant thereof, or a combination thereof.

[0093] In one embodiment, the PMTE comprises an antibody Fc domain linked to a first antigen binding domain linked to an immune cell engaging domain linked to a second antigen binding domain. In some embodiments, the Fc domain comprises SEQ ID NO:72. In some embodiments, the the Fc domain further comprises at least one stabilization motif. In some embodiments, the Fc domain comprises at least two copies of SEQ ID NO:72, connected by a linker. In some embodiments, the PMTE comprises the Fc domain of SEQ ID NO:5. In some embodiments, the first and second antigen binding domain are both specific for binding to FSHR. In some embodiments, the PMTE comprises an antibody Fc domain linked to a first FSHR scFv comprising a heavy chain and light chain specific for binding to FSHR operably linked to a CD3 scFv comprising a heavy chain and light chain specific for binding to CD3 linked to a second FSHR scFv comprising a heavy chain and light chain specific for binding to FSHR. In some embodiments, the first FSHR heavy chain comprises SEQ ID NO: 1 and the first FSHR light chain comprises SEQ ID NO:2. In some embodiments, the CD3 heavy chain comprises SEQ ID NO: 3 and the CD3 light chain comprises SEQ ID NO:4. In some embodiments, the second FSHR heavy chain comprises SEQ ID NO:1 and the second FSHR light chain comprises SEQ ID NO:2. In some embodiments, the PBTE comprises an Fc domain operably linked to a first anti-FSHR scFv comprising SEQ ID NO: 1 and SEQ ID NO:2, operably linked to an anti-CD3 scFv comprising SEQ ID NO:3 and SEQ ID NON, operably linked to a second anti-FSHR scFv comprising SEQ ID NO:1 and SEQ ID NO:2. In some embodiments, the anti-CD3 scFv is between the first and second anti-FSHR scFv. In some embodiments, the heavy chain of the first anti-FSHR scFv is C-terminal to the light chain. In some embodiments, the heavy chainof the first anti-FSHR scFv is N-terminal to the light chain. In some embodiments, the anti- CD3 heavy chain is C-terminal to the anti-CD3 light chain. In some embodiments, the anti- CD3 heavy chain is N-terminal to the anti-CD3 light chain. In some embodiments, the heavy chain of the second anti-FSHR scFv is C-terminal to the light chain. In some embodiments, the heavy chain of the second anti-FSHR scFv is N-terminal to the light chain.

[0094] In one embodiment, the PMTE comprises the amino acid sequence of SEQ ID NO: 8-37, or a fragment or variant thereof.Multivalent Antibody

[0095] The persistent multivalent T cell engager of the invention can be a multivalent antibody, a fragment thereof, a variant thereof, or a combination thereof. The multivalent antibody can bind or react with at least three target molecules, for example, an immune cell and at least two different antigens. The multivalent antibody can be comprised of at least three tandem linked scFvs, thereby allowing the multivalent antibody to bind or react with at least three desired target molecules.

[0096] The invention provides novel multivalent antibodies comprising a first antigen-binding site that specifically binds to a first target and a second antigen-binding site that specifically binds to a second target, and a third antigen-binding site that specifically binds to a third target, with particularly advantageous properties such as producibility. stability, binding affinity, biological activity, specific targeting of certain T cells, targeting efficiency and reduced toxicity. In some instances, there are multivalent antibodies, wherein the multivalent antibody binds to each target with different affinity. In some instances, there are multivalent antibodies, wherein the multivalent antibody binds to each target with the same affinity.

[0097] A multispecific binding molecule according to the invention may have at least three binding sites of any desired specificity. In some embodiments, one of the binding sites is capable of binding a tumor antigen. In some embodiments, the binding site included in the single chain Fv fragment is a binding site specific for a FSHR tumor antigen.

[0098] In one embodiment the multispecific binding molecule, comprises a first scFv specific for binding to a target disease-specific antigen linked to a scFv specific for binding to a T cell specific receptor molecule linked to a second scFv specific for binding to a target disease-specific antigen. The linkage may place the first and second domains in any order, for example, in one embodiment, an scFv specific for binding to a target disease-specific antigenis oriented C-Terminal to a scFv specific for binding to a T cell specific receptor molecule. In another embodiment, a nucleotide sequence encoding a scFv specific for binding to a target disease-specific antigen is oriented N-Terminal to a nucleotide sequence encoding a scFv specific for binding to a T cell specific receptor molecule.Extension of Antibody Half-Life

[0099] The synthetic antibody (e.g., PBTE or PMTE) may be modified to extend or shorten the half-life of the antibody in the subject. The modification may extend or shorten the half-life of the antibody in the serum of the subject.

[0100] The modification may be present in a constant region of the antibody. The modification may be one or more amino acid substitutions in a constant region of the antibody that extend the half-life of the antibody as compared to a half-life of an antibody not containing the one or more amino acid substitutions. The modification may be one or more amino acid substitutions in the CH2 domain of the antibody that extend the half-life of the antibody as compared to a half-life of an antibody not containing the one or more amino acid substitutions.

[0101] In some embodiments, the one or more amino acid substitutions in the constant region may include replacing a methionine residue in the constant region with a ty rosine residue, a serine residue in the constant region with a threonine residue, a threonine residue in the constant region with a glutamate residue, or any combination thereof, thereby extending the half-life of the antibody.

[0102] In other embodiments, the one or more amino acid substitutions in the constant region may include replacing a methionine residue in the CH2 domain with a tyrosine residue, a serine residue in the CH2 domain with a threonine residue, a threonine residue in the CH2 domain with a glutamate residue, or any combination thereof, thereby extending the half-life of the antibody.Substrates

[0103] In one embodiment, the present invention provides a scaffold, substrate, or device comprising a bispecific immune cell engager (e.g.. PBTE or PMTE), fragment thereof, or nucleic acid molecule encoding the same. For example, in some embodiments, the present invention provides a tissue engineering scaffold, including but not limited to, a hydrogel, electrospun scaffold, polymeric matrix, or the like, comprising the modulator. In certainembodiments, a bispecific immune cell engager, fragment thereof, or nucleic acid molecule encoding the same, may be coated along the surface of the scaffold, substrate, or device. In certain embodiments, the bispecific immune cell engager, fragment thereof, or nucleic acid molecule encoding the same is encapsulated within the scaffold, substrate, or device.Recombinant Nucleic Acid Sequence

[0104] In some embodiments, the invention provides a recombinant nucleic acid sequence encoding a synthetic binding molecule as described above. The recombinant nucleic acid sequence can encode the bispecific immune cell engager (e.g.. PBTE or PMTE), a fragment thereof, a variant thereof, or a combination thereof.

[0105] The recombinant nucleic acid sequence can be a heterologous nucleic acid sequence. The recombinant nucleic acid sequence can include at least one heterologous nucleic acid sequence or one or more heterologous nucleic acid sequences.

[0106] Exemplary nucleotide sequences encoding a PBTE capable of binding FSHR include, but are not limited to, the nucleotide sequences set forth in SEQ ID NO:38 or SEQ ID NO:39, or a fragment or variant thereof.

[0107] Exemplary nucleotide sequences encoding a PMTE capable of binding FSHR include, but are not limited to, the nucleotide sequences set forth in SEQ ID NO:40-71 or a fragment or variant thereof.

[0108] The recombinant nucleic acid sequence can be an optimized nucleic acid sequence. Such optimization can increase or alter the immunogenicity of the antibody. Optimization can also improve transcription and / or translation. Optimization can include one or more of the following: low GC content leader sequence to increase transcription; mRNA stabili ty and codon optimization; addition of a kozak sequence (e.g., GCC ACC) for increased translation; addition of an immunoglobulin (Ig) leader sequence encoding a signal peptide; and eliminating to the extent possible cis-acting sequence motifs (i.e., internal TATA boxes).

[0109] The recombinant nucleic acid sequence can include one or more recombinant nucleic acid sequence constructs. The recombinant nucleic acid sequence construct can include one or more components, which are described in more detail below.

[0110] The recombinant nucleic acid sequence construct can include a heterologous nucleic acid sequence that encodes a heavy chain polypeptide, a fragment thereof, a variant thereof, or a combination thereof. The recombinant nucleic acid sequence construct caninclude a heterologous nucleic acid sequence that encodes a light chain polypeptide, a fragment thereof, a variant thereof, or a combination thereof. The recombinant nucleic acid sequence construct can also include a heterologous nucleic acid sequence that encodes a protease or peptidase cleavage site. The recombinant nucleic acid sequence construct can also include a heterologous nucleic acid sequence that encodes an internal ribosome entry site (IRES). An IRES may be either a viral IRES or an eukaryotic IRES. The recombinant nucleic acid sequence construct can include one or more leader sequences, in which each leader sequence encodes a signal peptide. The recombinant nucleic acid sequence construct can include one or more promoters, one or more introns, one or more transcription termination regions, one or more initiation codons, one or more termination or stop codons, and / or one or more polyadenylation signals. The recombinant nucleic acid sequence construct can also include one or more linker or tag sequences. The tag sequence can encode a histadine tag (6xHis tag).Nucleotide Sequence Encoding Bispecific T Cell Engager

[0111] In some embodiments, the nucleic acid molecule encodes a bispecific T cell engager (BTE), a fragment thereof, a variant thereof, or a combination thereof.

[0112] In one embodiment, the BTE comprises linked scFv binding molecules comprising an antigen binding domain linked to an immune cell engaging domain. In some embodiments, the BTE comprises a FSHR scFv comprising a heavy chain and light chain specific for binding to FSHR operably linked to a CD3 scFv comprising a heavy chain and light chain specific for binding to CD3. In some embodiments, the FSHR heavy chain comprises SEQ ID NO: 1 and the FSHR light chain comprises SEQ ID NO:2. In some embodiments, the CD3 heavy chain comprises SEQ ID NO: 3 and the CD3 light chain comprises SEQ ID NO:4. In some embodiments, the anti-FSHR heavy chain is C-terminal to the anti-FSHR light chain. In some embodiments, the anti-FSHR heavy chain is N-terminal to the anti-FSHR light chain. In some embodiments, the anti-CD3 heavy chain is C-terminal to the anti-CD3 light chain. In some embodiments, the anti-CD3 heavy chain is N-terminal to the anti-CD3 light chain.

[0113] In some embodiments, the nucleotide sequence encoding the anti-FSHR heavy chain is 3’ to the nucleotide sequence encoding the anti-FSHR light chain. In some embodiments, the nucleotide sequence encoding the anti-FSHR heavy chain is 5’ to the nucleotide sequence encoding the anti-FSHR light chain. In some embodiments, thenucleotide sequence encoding the anti-CD3 heavy chain is 5’ to the nucleotide sequence encoding the anti-CD3 light chain. In some embodiments, the nucleotide sequence encoding the anti-CD3 heavy chain is 3’ to the nucleotide sequence encoding the anti-CD3 light chain.Nucleotide Sequence Encoding Persistent Bispecific T Cell Engager

[0114] In some embodiments, the nucleic acid molecule encodes a persistent bispecific T cell engager (PBTE), a fragment thereof, a variant thereof, or a combination thereof.

[0115] In one embodiment, the PBTE comprises an antibody Fc domain linked to an antigen binding domain linked to an immune cell engaging domain. In some embodiments, the Fc domain comprises SEQ ID NO:72. In some embodiments, the the Fc domain further comprises at least one stabilization motif. In some embodiments, the Fc domain comprises at least two copies of SEQ ID NO:72, connected by a linker. In some embodiments, the PBTE comprises the Fc domain of SEQ ID NO: 5. In some embodiments, the PBTE comprises an antibody Fc domain linked to a FSHR scFv comprising a heavy chain and light chain specific for binding to FSHR operably linked to a CD3 scFv comprising a heavy chain and light chain specific for binding to CD3. In some embodiments, the FSHR heavy chain comprises SEQ ID NO: 1 and the FSHR light chain comprises SEQ ID NO:2. In some embodiments, the CD3 heavy chain comprises SEQ ID NO:3 and the CD3 light chain comprises SEQ ID NO:4. In some embodiments, the PBTE comprises an Fc domain operably linked to an anti-FSHR scFv comprising SEQ ID NO: 1 and SEQ ID NO:2 and further operably linked to an anti-CD3 scFv comprising SEQ ID NO:3 and SEQ ID NO:4. In some embodiments, the anti-FSHR scFv is between the Fc domain and the anti-CD3 scFv. In some embodiments, the anti-CD3 scFv is between the Fc domain and the anti-FSHR scFv. In some embodiments, the anti-FSHR heavy chain is C-terminal to the anti-FSHR light chain. In some embodiments, the anti-FSHR heavy chain is N-terminal to the anti-FSHR light chain. In some embodiments, the anti-CD3 heavy chain is C-terminal to the anti-CD3 light chain. In some embodiments, the anti-CD3 heavy chain is N-terminal to the anti-CD3 light chain.

[0116] In one embodiment, the nucleic acid molecule encoding the PBTE comprises a nucleotide sequence encoding the FSHR heavy chain, and a nucleotide sequence encoding the FSHR light chain. In some embodiments, the nucleic acid molecule encoding the PBTE comprises a nucleotide sequence encoding the CD3 heavy chain, and a nucleotide sequence encoding the CD3 light chain. In some embodiments, the nucleotide sequence encoding theanti-CD3 heavy chain is 5' to the nucleotide sequence encoding the anti-CD3 light chain. In some embodiments, the nucleotide sequence encoding the anti-CD3 heavy chain is 3?to the nucleotide sequence encoding the anti-CD3 light chain. In some embodiments, the nucleotide sequence encoding the PBTE comprises the nucleotide sequence encoding the Fc domain operably linked to a nucleotide sequences encoding the an anti-FSHR scFv and further operably linked to nucleotide sequences encoding the an anti-CD3 scFv. In some embodiments, the nucleotide sequence encoding the anti-FSHR scFv is between the nucleotide sequence encoding the Fc domain and the nucleotide sequence encoding the anti- CD3 scFv. In some embodiments, the nucleotide sequence encoding the anti-CD3 scFv is between the nucleotide sequence encoding the Fc domain and the nucleotide sequence encoding the anti-FSHR scFv.

[0117] In some embodiments, the nucleotide sequence encoding the PBTE encodies SEQ ID NO:6 or SEQ ID NO:7. In some embodiments, the nucleotide sequence encoding the PBTE comprises SEQ ID NO:38 or SEQ ID NO:39.Nucleotide Sequence Encoding Persistent Multispecific T Cell Engager

[0118] In some embodiments, the nucleic acid molecule encodes a persistent multispecific T cell engager (PMTE), a fragment thereof, a variant thereof, or a combination thereof.

[0119] In one embodiment, the PMTE comprises an antibody Fc domain linked to a first antigen binding domain linked to an immune cell engaging domain linked to a second antigen binding domain. In some embodiments, the Fc domain comprises SEQ ID NO:72. In some embodiments, the the Fc domain further comprises at least one stabilization motif. In some embodiments, the Fc domain comprises at least two copies of SEQ ID NO:72, connected by a linker. In some embodiments, the PMTE comprises the Fc domain of SEQ ID NO:5. In some embodiments, the first and second antigen binding domain are both specific for binding to FSHR. In some embodiments, the PMTE comprises an antibody Fc domain linked to a first FSHR scFv comprising a heavy chain and light chain specific for binding to FSHR operably linked to a CD3 scFv comprising a heavy chain and light chain specific for binding to CD3 linked to a second FSHR scFv comprising a heavy chain and light chain specific for binding to FSHR. In some embodiments, the first FSHR heavy chain comprises SEQ ID NO: 1 and the first FSHR light chain comprises SEQ ID NO:2. In some embodiments, the CD3 heavy chain comprises SEQ ID NO: 3 and the CD3 light chaincomprises SEQ ID NO:4. In some embodiments, the second FSHR heavy chain comprises SEQ ID NO: 1 and the second FSHR light chain comprises SEQ ID NO:2. In some embodiments, the PMTE comprises an Fc domain operably linked to a first anti-FSHR scFv comprising SEQ ID NO:1 and SEQ ID NO:2, operably linked to an anti-CD3 scFv comprising SEQ ID NO:3 and SEQ ID NON, operably linked to a second anti-FSHR scFv comprising SEQ ID NO: 1 and SEQ ID NO:2. In some embodiments, the anti-CD3 scFv is between the first and second anti-FSHR scFv. In some embodiments, the heavy chain of the first anti-FSHR scFv is C-terminal to the light chain. In some embodiments, the heavy chain of the first anti-FSHR scFv is N-terminal to the light chain. In some embodiments, the anti- CD3 heavy chain is C-terminal to the anti-CD3 light chain. In some embodiments, the anti- CD3 heavy chain is N-terminal to the anti-CD3 light chain. In some embodiments, the heavy chain of the second anti-FSHR scFv is C-terminal to the light chain. In some embodiments, the heavy chain of the second anti-FSHR scFv is N-terminal to the light chain.

[0120] In one embodiment, the nucleic acid molecule encoding the PMTE comprises a nucleotide sequence encoding the FSHR heavy chain, and a nucleotide sequence encoding the FSHR light chain. In some embodiments, the nucleic acid molecule encoding the PMTE comprises a nucleotide sequence encoding the CD3 heavy chain, and a nucleotide sequence encoding the CD3 light chain. In one embodiment, the nucleic acid molecule encoding the PMTE comprises a nucleotide sequence encoding the second FSHR heavy chain, and a nucleotide sequence encoding the second FSHR light chain. In some embodiments, the nucleotide sequence encoding the anti-FSHR heavy chain is 3’ to the nucleotide sequence encoding the anti-FSHR light chain. In some embodiments, the nucleotide sequence encoding the anti-FSHR heavy chain is 5’ to the nucleotide sequence encoding the anti-FSHR light chain. In some embodiments, the nucleotide sequence encoding the anti-CD3 heavy chain is 5’ to the nucleotide sequence encoding the anti-CD3 light chain. In some embodiments, the nucleotide sequence encoding the anti-CD3 heavy chain is 3’ to the nucleotide sequence encoding the anti-CD3 light chain. In some embodiments, the nucleotide sequence encoding the PMTE comprises the nucleotide sequence encoding the Fc domain operably linked to a nucleotide sequences encoding a first anti-FSHR scFv and further operably linked to nucleotide sequences encoding the an anti-CD3 scFv, and further operably linked to nucleotide sequences encoding a second anti-FSHR scFv. In some embodiments, the nucleotide sequences encoding the first anti-FSHR scFv are between the nucleotide sequence encoding the Fc domain and the nucleotide sequences encoding the anti-CD3 scFv, and thenucleotide sequences encoding the anti-CD3 scFv are between the nucleotide sequences encoding the first and second anti-FSHR scFv.

[0121] In some embodiments, the nucleic acid molecule encoding the PMTE encodes an amino acid sequence of SEQ ID NO:8-SEQ ID NO:37. In some embodiments, the nucleic acid molecule encoding the PMTE comprises a nucleic acid sequence of SEQ ID NO:40-71.Promoter

[0122] The recombinant nucleic acid sequence construct can include one or more promoters. The one or more promoters may be any promoter that is capable of driving gene expression and regulating gene expression. Such a promoter is a cis-acting sequence element required for transcription via a DNA dependent RNA polymerase. Selection of the promoter used to direct gene expression depends on the particular application. The promoter may be positioned about the same distance from the transcription start in the recombinant nucleic acid sequence construct as it is from the transcription start site in its natural setting. However, variation in this distance may be accommodated without loss of promoter function.

[0123] The promoter may be operably linked to the heterologous nucleic acid sequence encoding the heavy chain polypeptide and / or light chain polypeptide. The promoter may be a promoter shown effective for expression in eukaryotic cells. The promoter operably linked to the coding sequence may be a CMV promoter, a promoter from simian virus 40 (SV40), such as SV40 early promoter and SV40 later promoter, a mouse mammary tumor virus (MMTV) promoter, a human immunodeficiency virus (HIV) promoter such as the bovine immunodeficiency virus (BIV) long terminal repeat (LTR) promoter, a Moloney virus promoter, an avian leukosis virus (ALV) promoter, a cytomegalovirus (CMV) promoter such as the CMV immediate early promoter, Epstein Barr virus (EBV) promoter, or a Rous sarcoma virus (RSV) promoter. The promoter may also be a promoter from a human gene such as human actin, human myosin, human hemoglobin, human muscle creatine, human polyhedrin, or human metalothionein.

[0124] The promoter can be a constitutive promoter or an inducible promoter, which initiates transcription only when the host cell is exposed to some particular external stimulus. In the case of a multicellular organism, the promoter can also be specific to a particular tissue or organ or stage of development. The promoter may also be a tissue specific promoter, such as a muscle or skin specific promoter, natural or synthetic. Examples of such promoters aredescribed in US patent application publication no. US20040175727, the contents of which are incorporated herein in its entirety.

[0125] The promoter can be associated with an enhancer. The enhancer can be located upstream of the coding sequence. The enhancer may be human actin, human myosin, human hemoglobin, human muscle creatine or a viral enhancer such as one from CMV, FMDV, RSV or EBV. Polynucleotide function enhances are described in U.S. Patent Nos. 5,593,972, 5.962,428, and W094 / 016737. the contents of each are fully incorporated by reference.Transcription Termination Region

[0126] The recombinant nucleic acid sequence construct can include one or more transcription termination regions. The transcription termination region can be downstream of the coding sequence to provide for efficient termination. The transcription termination region can be obtained from the same gene as the promoter described above or can be obtained from one or more different genes.Initiation Codon

[0127] The recombinant nucleic acid sequence construct can include one or more initiation codons. The initiation codon can be located upstream of the coding sequence. The initiation codon can be in frame with the coding sequence. The initiation codon can be associated with one or more signals required for efficient translation initiation, for example, but not limited to, a ribosome binding site.Termination Codon

[0128] The recombinant nucleic acid sequence construct can include one or more termination or stop codons. The termination codon can be downstream of the coding sequence. The termination codon can be in frame with the coding sequence. The termination codon can be associated with one or more signals required for efficient translation termination.Polyadenylation Signal

[0129] The recombinant nucleic acid sequence construct can include one or more polyadenylation signals. The polyadenylation signal can include one or more signalsrequired for efficient poly adenylation of the transcript. The poly adenylation signal can be positioned downstream of the coding sequence. The polyadenylation signal may be a SV40 polyadenylation signal, LTR polyadenylation signal, bovine grow th hormone (bGH) polyadenylation signal, human growth hormone (hGH) polyadenylation signal, or human fl- globin polyadenylation signal. The SV40 polyadenylation signal may be a polyadenylation signal from a pCEP4 plasmid (Invitrogen, San Diego, CA).Protease Cleavage Site

[0130] The recombinant nucleic acid sequence construct can include the heterologous nucleic acid sequence encoding the protease cleavage site. The protease cleavage site can be recognized by a protease or peptidase. The protease can be an endopeptidase or endoprotease, for example, but not limited to, furin, elastase, HtrA, calpain, trypsin, chymotiy psin, trypsin, and pepsin. The protease can be furin. In other embodiments, the protease can be a serine protease, a threonine protease, cysteine protease, aspartate protease, metalloprotease, glutamic acid protease, or any protease that cleaves an internal peptide bond (i. e. , does not cleave the N-terminal or C-terminal peptide bond).

[0131] The protease cleavage site can include one or more amino acid sequences that promote or increase the efficiency of cleavage. The one or more amino acid sequences can promote or increase the efficiency of forming or generating discrete polypeptides. The one or more amino acids sequences can include a 2A peptide sequence.Vector

[0132] The recombinant nucleic acid sequence construct described above can be placed in one or more vectors. The one or more vectors can contain an origin of replication. The one or more vectors can be a plasmid, bacteriophage, bacterial artificial chromosome or yeast artificial chromosome. The one or more vectors can be either a self-replication extra chromosomal vector, or a vector which integrates into a host genome.

[0133] The one or more vectors can be a heterologous expression construct, which is generally a plasmid that is used to introduce a specific gene into a target cell. Once the expression vector is inside the cell, the heavy chain polypeptide and / or light chain polypeptide that are encoded by the recombinant nucleic acid sequence construct is produced by the cellular-transcription and translation machinery ribosomal complexes. The one or more vectors can express large amounts of stable messenger RNA, and therefore proteins.Expression Vector

[0134] The one or more vectors can be a circular plasmid or a linear nucleic acid. The circular plasmid and linear nucleic acid are capable of directing expression of a particular nucleotide sequence in an appropriate subject cell. The one or more vectors comprising the recombinant nucleic acid sequence construct may be chimeric, meaning that at least one of its components is heterologous with respect to at least one of its other components.Plasmid

[0135] The one or more vectors can be a plasmid. The plasmid may be useful for transfecting cells with the recombinant nucleic acid sequence construct. The plasmid may be useful for introducing the recombinant nucleic acid sequence construct into the subject. The plasmid may also comprise a regulatory sequence, which may be well suited for gene expression in a cell into which the plasmid is administered.

[0136] The plasmid may also comprise a mammalian origin of replication in order to maintain the plasmid extrachromosomally and produce multiple copies of the plasmid in a cell. The plasmid may be pVAXl, pCEP4 or pREP4 from Invitrogen (San Diego, CA), which may comprise the Epstein Barr virus origin of replication and nuclear antigen EBNA-1 coding region, which may produce high copy episomal replication without integration. The backbone of the plasmid may be pAV0242. The plasmid may be a replication defective adenovirus type 5 (Ad5) plasmid.

[0137] The plasmid may be pSE420 (Invitrogen, San Diego, Calif), which may be used for protein production in Escherichia coli (E.coli). The plasmid may also be p YES2 (Invitrogen, San Diego, Calif.), which may be used for protein production in Saccharomyces cerevisiae strains of yeast. The plasmid may also be of the MAXBAC™ complete baculovirus expression system (Invitrogen, San Diego, Calif), which may be used for protein production in insect cells. The plasmid may also be pcDNAI or pcDNA3 (Invitrogen, San Diego, Calif), which may be used for protein production in mammalian cells such as Chinese hamster ovary (CHO) cells.RNA

[0138] In one embodiment, the nucleic acid is an RNA molecule. In one embodiment, the RNA molecule is transcribed from a DNA sequence. Accordingly, in one embodiment.the invention provides an RNA molecule encoding one or more of the synthetic antibodies of the invention. The RNA may be plus-stranded. Accordingly, in some embodiments, the RNA molecule can be translated by cells without needing any intervening replication steps such as reverse transcription. A RNA molecule useful with the invention may have a 5' cap (e.g. a 7- methylguanosine). This cap can enhance in vivo translation of the RNA. The 5' nucleotide of a RNA molecule useful with the invention may have a 5' triphosphate group. In a capped RNA this may be linked to a 7-methylguanosine via a 5'-to-5' bridge. A RNA molecule may have a 3' poly-A tail. It may also include a poly-A polymerase recognition sequence (e.g. AAUAAA) near its 3' end. A RNA molecule useful with the invention may be singlestranded. A RNA molecule useful with the invention may comprise synthetic RNA. In some embodiments, the RNA molecule is a naked RNA molecule. In one embodiment, the RNA molecule is comprised within a vector.

[0139] In one embodiment, the RNA has 5' and 3' UTRs. In one embodiment, the 5' UTR is between zero and 3000 nucleotides in length. The length of 5' and 3' UTR sequences to be added to the coding region can be altered by different methods, including, but not limited to, designing primers for PCR that anneal to different regions of the UTRs. Using this approach, one of ordinary skill in the art can modify the 5' and 3' UTR lengths required to achieve optimal translation efficiency following transfection of the transcribed RNA.

[0140] The 5' and 3' UTRs can be the naturally occurring, endogenous 5' and 3' UTRs for the gene of interest. Alternatively, UTR sequences that are not endogenous to the gene of interest can be added by incorporating the UTR sequences into the forward and reverse primers or by any other modifications of the template. The use of UTR sequences that are not endogenous to the gene of interest can be useful for modifying the stability and / or translation efficiency of the RNA. For example, it is known that AU-rich elements in 3' UTR sequences can decrease the stabil ity of RNA. Therefore, 3' UTRs can be selected or designed to increase the stability of the transcribed RNA based on properties of UTRs that are well known in the art.

[0141] In one embodiment, the 5' UTR can contain the Kozak sequence of the endogenous gene. Alternatively, when a 5' UTR that is not endogenous to the gene of interest is being added by PCR as described above, a consensus Kozak sequence can be redesigned by adding the 5' UTR sequence. Kozak sequences can increase the efficiency of translation of some RNA transcripts, but does not appear to be required for all RNAs to enable efficient translation. The requirement for Kozak sequences for many RNAs is known in the art. Inother embodiments, the 5' UTR can be derived from an RNA virus whose RNA genome is stable in cells. In other embodiments, various nucleotide analogues can be used in the 3' or 5' UTR to impede exonuclease degradation of the RNA.

[0142] In one embodiment, the RNA has both a cap on the 5' end and a 3' poly(A) tail which determine ribosome binding, initiation of translation and stability' of RNA in the cell.

[0143] In one embodiment, the RNA is a nucleoside-modified RNA. Nucleoside- modified RNA have particular advantages over non-modified RNA, including for example, increased stability, low or absent innate immunogenicity, and enhanced translation.Circular and Linear Vector

[0144] The one or more vectors may be circular plasmid, which may transform a target cell by integration into the cellular genome or exist extrachromosomally (e.g., autonomous replicating plasmid with an origin of replication). The vector can be pVAX, pcDNA3.0, or provax, or any other expression vector capable of expressing the heavy chain polypeptide and / or light chain polypeptide encoded by the recombinant nucleic acid sequence construct.

[0145] Also provided herein is a linear nucleic acid, or linear expression cassette (“LEC”), that is capable of being efficiently delivered to a subject and expressing the heavy chain polypeptide and / or light chain polypeptide encoded by the recombinant nucleic acid sequence construct. The LEC may be any linear DNA devoid of any phosphate backbone. The LEC may not contain any antibiotic resistance genes and / or a phosphate backbone. The LEC may not contain other nucleic acid sequences unrelated to the desired gene expression.

[0146] The LEC may be derived from any plasmid capable of being linearized. The plasmid may be capable of expressing the heavy chain polypeptide and / or light chain polypeptide encoded by the recombinant nucleic acid sequence construct. The plasmid can be pNP (Puerto Rico / 34) or pM2 (New Caledonia / 99). The plasmid may be WLV009, pVAX, pcDNA3.0, or provax, or any other expression vector capable of expressing the heavy chain polypeptide and / or light chain polypeptide encoded by the recombinant nucleic acid sequence construct.

[0147] The LEC can be pcrM2. The LEC can be pcrNP. pcrNP and pcrMR can be derived from pNP (Puerto Rico / 34) and pM2 (New Caledonia / 99), respectively.Expression from the Recombinant Nucleic Acid Sequence Construct

[0148] As described above, the recombinant nucleic acid sequence construct can include, amongst the one or more components, the nucleic acid sequence encoding the PBTE or PMTE. Accordingly, the recombinant nucleic acid sequence construct can facilitate expression of the PBTE or PMTE.

[0149] Upon expression, for example, but not limited to, in a cell, organism, or mammal, the heavy chain polypeptides and the light chain polypeptides can assemble into the synthetic antibody (e.g., PBTE or PMTE). In particular, the heavy chain polypeptides and the light chain polypeptides can interact with one another such that assembly results in the synthetic antibody (e.g., PBTE or PMTE) being capable of binding the target antigen(s).Pharmaceutical Compositions

[0150] In some embodiments, the invention provides compositions comprising the PBTE or PMTE, or fragments to variants thereof. In certain embodiments, the composition can treat, prevent, and or / protect against a disease or disorder associated with FSHR expression. In certain embodiments, the composition can treat, prevent, and or / protect against cancer associated with FSHR expression.

[0151] The synthetic antibody (e.g., PBTE, or PMTE) can treat, prevent, and / or protect against disease in the subject administered the composition. The synthetic antibody (e.g., PBTE, or PMTE) of the invention can promote survival of the disease in the subject administered the composition. The synthetic antibody (e.g., PBTE or PMTE) can provide at least about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% survival of the disease in the subject administered the composition. In other embodiments, the synthetic antibody (e.g., PBTE, or PMTE) can provide at least about 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%. 79%. or 80% survival of the disease in the subject administered the composition.

[0152] The composition can result in the persistence of the synthetic antibody (e.g., PBTE or PMTE) in the subject within at least about 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 20 hours, 25 hours, 30 hours, 35 hours. 40 hours. 45 hours, 50 hours, or 60 hours of administration of the composition to the subject. The composition can result in persistence of the synthetic antibody (e.g., PBTE or PMTE) in the subject within at least about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, or 10 days of administration of the composition to the subject. The composition can result in persistence of the syntheticantibody (e.g., PBTE or PMTE) in the subject within about 1 hour to about 6 days, about 1 hour to about 5 days, about 1 hour to about 4 days, about 1 hour to about 3 days, about 1 hour to about 2 days, about 1 hour to about 1 day, about 1 hour to about 72 hours, about 1 hour to about 60 hours, about 1 hour to about 48 hours, about 1 hour to about 36 hours, about 1 hour to about 24 hours, about 1 hour to about 12 hours, or about 1 hour to about 6 hours of administration of the composition to the subject.

[0153] The composition, when administered to the subject in need thereof, can result in persistence of the synthetic antibody (e.g., PBTE or PMTE) in the subject for longer than an endogenous antibody in a subject who is administered an antigen to induce a humoral immune response.

[0154] The composition of the present invention can have features required of effective compositions such as being safe so that the composition does not cause illness or death; being protective against illness; and providing ease of administration, few side effects, biological stability and low cost per dose.

[0155] The composition dose can be between 1 pg to 10 mg active component / kg body weight / time, and can be 20 pg to 10 mg component / kg body weight / time. The composition can be administered every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or 31 days. The number of composition doses for effective treatment can be 1, 2, 3, 4, 5. 6, 7, 8, 9, or 10.Delivery Vehicles

[0156] In one embodiment, the present invention provides a composition comprising a delivery' vehicle comprising an anti-FSHR PBTE or PMTE, or nucleic acid molecule encoding the same, as described herein. In one embodiment, the nucleic acid molecule encoding the anti-FSHR immune cell engaging antibody comprises an mRNA molecule.

[0157] Exemplary deliver} vehicles include, but are not limited to, microspheres, microparticles, nanoparticles, polymerosomes, liposomes, and micelles. For example, in some embodiments, the delivery vehicle is a lipid nanoparticle loaded with a nucleic acid molecule encoding a PBTE or PMTE of the invention. In one embodiment, the nucleic acid molecule encoding the PBTE or PMTE comprises an mRNA molecule. In one embodiment, the mRNA encoding the PBTE corresponds to, or is transcribed from, the DNA sequence set forth in SEQ ID NO:38 or SEQ ID NO: 39. In one embodiment, the mRNA encoding thePMTE corresponds to, or is transcribed from, a DNA sequence as set forth in SEQ ID NO:40- 71.

[0158] In some embodiments, the delivery vehicle provides for controlled release, delayed release, or continual release of its loaded cargo. In some embodiments, the delivery vehicle comprises a targeting moiety that targets the delivery7vehicle to a treatment site.

[0159] In certain instances, expressing a protein by delivering the encoding mRNA has many benefits over methods that use protein, plasmid DNA or viral vectors. During mRNA transfection, the coding sequence of the desired protein is the only substance delivered to cells, thus avoiding all the side effects associated with plasmid backbones, viral genes, and viral proteins. More importantly, unlike DNA- and viral-based vectors, the mRNA does not carry the risk of being incorporated into the genome and protein production starts immediately after mRNA delivery. For example, high levels of circulating proteins have been measured within 15 to 30 min of in vivo injection of the encoding mRNA. In certain embodiments, using mRNA rather than the protein also has many advantages. Half-lives of proteins in the circulation are often short, thus protein treatment would need frequent dosing, while mRNA provides a template for continuous protein production for several days. Purification of proteins is problematic and they can contain aggregates and other impurities that cause adverse effects (Kromminga and Schellekens, 2005, Ann NY Acad Sci 1050:257- 265).

[0160] In order to confirm the presence of the mRNA sequence in the host cell, a variety of assays may be performed. Such assays include, for example, '‘molecular biological” assays well know n to those of skill in the art, such as Northern blotting and RT- PCR; “biochemical” assays, such as detecting the presence or absence of a particular peptide, e.g., by immunogenic means (ELISAs and Western blots) or by assays described herein to identity7agents falling within the scope of the invention.Excipients and Other Components of the Composition

[0161] The composition may further comprise a pharmaceutically acceptable excipient. The pharmaceutically acceptable excipient can be functional molecules such as vehicles, carriers, or diluents. The pharmaceutically acceptable excipient can be a transfection facilitating agent, which can include surface active agents, such as immune- stimulating complexes (ISCOMS), Freunds incomplete adjuvant, LPS analog including monophosphoryl lipid A, muramyl peptides, quinone analogs, vesicles such as squalene andsqualene, hyaluronic acid, lipids, liposomes, calcium ions, viral proteins, polyanions, poly cations, or nanoparticles, or other known transfection facilitating agents.

[0162] The transfection facilitating agent is a polyanion, poly cation, including poly- L-glutamate (LGS), or lipid. The transfection facilitating agent is poly-L-glutamate, and the poly-L-glutamate may be present in the composition at a concentration less than 6 mg / ml. The transfection facilitating agent may also include surface active agents such as immune- stimulating complexes (ISCOMS), Freunds incomplete adjuvant. LPS analog including monophosphoryl lipid A, muramyl peptides, quinone analogs and vesicles such as squalene and squalene, and hyaluronic acid may also be used administered in conjunction with the composition. The composition may also include a transfection facilitating agent such as lipids, liposomes, including lecithin liposomes or other liposomes known in the art, as a DNA-liposome mixture (see for example W09324640), calcium ions, viral proteins, polyanions, polycations, or nanoparticles, or other known transfection facilitating agents. The transfection facilitating agent is a poly anion, poly cation, including poly-L-glutamate (LGS), or lipid. Concentration of the transfection agent in the composition is less than 4 mg / ml, less than 2 mg / ml, less than 1 mg / ml, less than 0.750 mg / ml, less than 0.500 mg / ml, less than 0.250 mg / ml, less than 0.100 mg / ml, less than 0.050 mg / ml, or less than 0.010 mg / ml.

[0163] The composition can be formulated according to the mode of administration to be used. An injectable pharmaceutical composition can be sterile, pyrogen free and particulate free. An isotonic formulation or solution can be used. Additives for isotonicity can include sodium chloride, dextrose, mannitol, sorbitol, and lactose. The composition can comprise a vasoconstriction agent. The isotonic solutions can include phosphate buffered saline. The composition can further comprise stabilizers including gelatin and albumin. The stabilizers can allow the formulation to be stable at room or ambient temperature for extended periods of time, including LGS or poly cations or polyanions.Methods of Delivery of the Composition

[0164] The present invention also relates to a method of delivering the composition to the subject in need thereof. The method of delivery can include, administering the composition to the subject. In some embodiments, the present invention relates to administration of a PBTE or PMTE antibody of the invention, or a nucleic acid molecule encoding a PBTE or PMTE antibody of the invention. In some embodiments, the nucleic acidmolecule is a DNA molecule. In some embodiments, the nucleic acid molecule is an RNA molecule. In some embodiments, the nucleic acid molecule is an mRNA molecule.

[0165] Administration can include, but is not limited to, intravenous delivery of an antibody, DNA injection, liposome mediated delivery, and nanoparticle facilitated delivery.

[0166] The mammal receiving deliver}7of the composition may be human, primate, non-human primate, cow, cattle, sheep, goat, antelope, bison, water buffalo, bison, bovids, deer, hedgehogs, elephants, llama, alpaca, mice, rats, and chicken.

[0167] The composition may be administered by different routes including orally, parenterally, sublingually, transdermally, rectally, transmucosally, topically, via inhalation, via buccal administration, intrapleurally, intravenous, intraarterial, intraperitoneal, subcutaneous, intramuscular, intranasal intrathecal, and intraarticular or combinations thereof. For veterinary use, the composition may be administered as a suitably acceptable formulation in accordance with normal veterinary practice. The veterinarian can readily determine the dosing regimen and route of administration that is most appropriate for a particular animal. The composition may be administered by traditional syringes, needleless injection devices, "microprojectile bombardment gone guns", or other physical methods such as electroporation (“EP”), “hydrodynamic method”, or ultrasound.Method of Treatment

[0168] Also provided herein is a method of treating, protecting against, and / or preventing disease in a subject in need thereof by administration of a PBTE or PMTE antibody of the invention, or a nucleic acid molecule encoding a PBTE or PMTE antibody of the invention to the subject. The method can include administering a composition comprising a PBTE or PMTE antibody of the invention, or a nucleic acid molecule encoding a PBTE or PMTE antibody of the invention to the subject. Administration of the composition to the subject can be done using the method of delivery described above.

[0169] In certain embodiments, the invention provides a method of treating protecting against, and / or preventing cancer. In one embodiment, the method treats, protects against, and / or prevents tumor growth. In one embodiment, the method treats, protects against, and / or prevents cancer progression. In one embodiment, the method treats, protects against, and / or prevents cancer metastasis.

[0170] In one embodiment, the invention provides methods for preventing grow th of benign tumors, such as, but not limited to. uterine fibroids. The methods compriseadministering an effective amount of one or more of the compositions of the invention to a subject diagnosed with a benign tumor.

[0171] Upon administration of the PBTE or PTME, the PBTE or PMTE can bind to or react with the antigen. Such binding can neutralize the antigen, block recognition of the antigen by another molecule, for example, a protein or nucleic acid, and elicit or induce an immune response to the antigen, thereby treating, protecting against, and / or preventing the disease associated with the antigen in the subject.

[0172] The composition dose can be between 1 pg to 10 mg active component / kg body weight / time, and can be 20 pg to 10 mg component / kg body weight / time. The composition can be administered every' 1, 2, 3, 4, 5, 6, 7, 8, 9. 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30. or 31 days. The number of composition doses for effective treatment can be 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.Cancer Therapy

[0173] The invention provides methods of treating or preventing cancer, or of treating and preventing growth or metastasis of tumors. Related aspects of the invention provide methods of preventing, aiding in the prevention, and / or reducing metastasis of hyperplastic or tumor cells in an individual.

[0174] One aspect of the invention provides a method of inhibiting metastasis in an individual in need thereof, the method comprising administering to the individual an effective amount of a composition of the invention. The invention further provides a method of inhibiting metastasis in an individual in need thereof, the method comprising administering to the individual an effective metastasis-inhibiting amount of any one of the compositions described herein.

[0175] In some embodiments of treating or preventing cancer, or of treating and preventing metastasis of tumors in an individual in need thereof, a second agent is administered to the individual, such as an antineoplastic agent. In some embodiments, the second agent comprises a second metastasis-inhibiting agent, such as a plasminogen antagonist, or an adenosine deaminase antagonist. In other embodiments, the second agent is an angiogenesis inhibiting agent.

[0176] The compositions of the invention can be used to prevent, abate, minimize, control, and / or lessen cancer in humans and animals. The compositions of the invention can also be used to slow the rate of primary tumor growth. The compositions of the inventionwhen administered to a subject in need of treatment can be used to stop the spread of cancer cells. As such, the compositions of the invention can be administered as part of a combination therapy with one or more drugs or other pharmaceutical agents. When used as part of the combination therapy, the decrease in metastasis and reduction in primary tumor growth afforded by the compositions of the invention allows for a more effective and efficient use of any pharmaceutical or drug therapy being used to treat the patient. In addition, control of metastasis by the compositions of the invention affords the subject a greater ability to concentrate the disease in one location.

[0177] In one embodiment, the invention provides methods for preventing metastasis of malignant tumors or other cancerous cells as well as to reduce the rate of tumor growth. The methods comprise administering an effective amount of one or more of the compositions of the invention to a subject diagnosed with a malignant tumor or cancerous cells or to a subject having a tumor or cancerous cells.

[0178] The following are non-limiting examples of cancers that can be treated by the methods and compositions of the invention: ovarian cancer, breast cancer, prostate cancer, renal cancer, colo-rectal cancer, stomach cancer, lung cancer, testicular cancer, endometrial cancer, and thyroid cancer.

[0179] In one embodiment, the invention provides a method to treat cancer metastasis comprising treating the subject prior to, concurrently with, or subsequently to the treatment with a composition of the invention, with a complementary therapy for the cancer, such as surgery, chemotherapy, chemotherapeutic agent, radiation therapy, or hormonal therapy or a combination thereof.

[0180] Chemotherapeutic agents include cytotoxic agents (e.g., 5 -fluorouracil, cisplatin, carboplatin, methotrexate, daunorubicin, doxorubicin, vincristine, vinblastine, oxorubicin, carmustine (BCNU), lomustine (CCNU), cytarabine USP, cyclophosphamide, estramucine phosphate sodium, altretamine, hydroxyurea, ifosfamide, procarbazine, mitomycin, busulfan, cyclophosphamide, mitoxantrone, carboplatin, cisplatin, interferon alfa- 2a recombinant, paclitaxel, teniposide, and strep tozoci). cytotoxic alkylating agents (e.g., busulfan. chlorambucil, cyclophosphamide, melphalan. or ethylesulfonic acid), alkylating agents (e.g., asaley, AZQ, BCNU, busulfan, bisulphan, carboxyphthalatoplatinum, CBDCA, CCNU, CHIP, chlorambucil, chlorozotocin, cis-platinum, clomesone, cyanomorpholinodoxorubicin, cyclodisone, cyclophosphamide, dianhydrogalactitol, fluorodopan, hepsulfam. hy canthone, iphosphamide, melphalan, methyl CCNU, mitomycinC, mitozolamide, nitrogen mustard, PCNU, piperazine, piperazinedione, pipobroman, porfiromycin, spirohydantoin mustard, streptozotocin, teroxirone, tetraplatin. thiotepa, triethylenemelamine, uracil nitrogen mustard, and Yoshi-864), antimitotic agents (e.g., allocolchicine, Halichondrin M, colchicine, colchicine derivatives, dolastatin 10, maytansine, rhizoxin, paclitaxel derivatives, paclitaxel, thiocolchicine, trity l cysteine, vinblastine sulfate, and vincristine sulfate), plant alkaloids (e.g., actinomycin D, bleomycin, L-asparaginase. idarubicin. vinblastine sulfate, vincristine sulfate, mitramycin, mitomycin, daunorubicin. VP- 16-213, VM-26, navelbine and taxotere), biologicals (e.g., alpha interferon, BCG, G-CSF, GM-CSF, and interleukin-2), topoisomerase I inhibitors (e.g., camptothecin, camptothecin derivatives, and morpholinodoxorubicin), topoisomerase II inhibitors (e.g., mitoxantron, amonafide. m-AMSA, anthrapyrazole derivatives, pyrazoloacridine, bisantrene HCL, daunorubicin, deoxydoxorubicin, menogaril, N,N-dibenzyl daunomycin, oxanthrazole, rubidazone, VM-26 and VP-16), and synthetics (e.g., hydroxyurea, procarbazine, o,p'-DDD, dacarbazine, CCNU, BCNU, cis-diamminedichloroplatimun, mitoxantrone, CBDCA, levamisole, hexamethylmelamine, all-trans retinoic acid, gliadel and porfimer sodium).

[0181] Antiproliferative agents are compounds that decrease the proliferation of cells. Antiproliferative agents include alky lating agents, antimetabolites, enzymes, biological response modifiers, miscellaneous agents, hormones and antagonists, androgen inhibitors (e.g., flutamide and leuprolide acetate), antiestrogens (e.g., tamoxifen citrate and analogs thereof, toremifene, droloxifene and roloxifene), Additional examples of specific antiproliferative agents include, but are not limited to levamisole, gallium nitrate, granisetron, sargramostim strontium-89 chloride, filgrastim, pilocarpine, dexrazoxane, and ondansetron.

[0182] The compounds of the invention can be administered alone or in combination with other anti-tumor agents, including cytotoxic / antineoplastic agents and anti-angiogenic agents. Cytotoxic / anti-neoplastic agents are defined as agents which attack and kill cancer cells. Some cytotoxic / anti-neoplastic agents are alkylating agents, which alky late the genetic material in tumor cells, e.g., cis-platin, cyclophosphamide, nitrogen mustard, trimethylene thiophosphoramide, carmustine, busulfan, chlorambucil, belustine, uracil mustard, chlomaphazin. and dacabazine. Other cytotoxic / anti-neoplastic agents are antimetabolites for tumor cells, e.g., cytosine arabinoside, fluorouracil, methotrexate, mercaptopuirine, azathioprime, and procarbazine. Other cytotoxic / anti-neoplastic agents are antibiotics, e.g., doxorubicin, bleomycin, dactinomycin, daunorubicin, mithramycin, mitomycin, mytomycin C, and daunomycin. There are numerous liposomal formulations commercially available forthese compounds. Still other cytotoxic / anti -neoplastic agents are mitotic inhibitors (vinca alkaloids). These include vincristine, vinblastine and etoposide. Miscellaneous cytotoxic / anti- neoplastic agents include taxol and its derivatives, L-asparaginase, anti-tumor antibodies, dacarbazine, azacytidine, amsacrine, melphalan, VM-26, ifosfamide, mitoxantrone, and vindesine.

[0183] Anti-angiogenic agents are well known to those of skill in the art. Suitable anti-angiogemc agents for use in the methods and compositions of the invention include anti- VEGF antibodies, including humanized and chimeric antibodies, anti-VEGF aptamers and antisense oligonucleotides. Other know n inhibitors of angiogenesis include angiostatin, endostatin, interferons, interleukin 1 (including alpha and beta) interleukin 12, retinoic acid, and tissue inhibitors of metalloproteinase- 1 and -2. (TIMP-1 and -2). Small molecules, including topoisomerases such as razoxane, a topoisomerase II inhibitor with anti-angiogenic activity, can also be used.

[0184] Other anti-cancer agents that can be used in combination with the compositions of the invention include, but are not limited to: acivicin; aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine; ambomycin; ametantrone acetate; aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan; cactinomycin; calusterone; caracemide; carbetimer; carboplatin; carmustine; carubicin hydrochloride; carzelesin; cedefingol; chlorambucil; cirolemycin; cisplatin; cladribine; crisnatol mesylate; cyclophosphamide; cytarabine; dacarbazine; dactinomycin; daunorubicin hydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguanine mesylate; diaziquone; docetaxel; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate; dromostanolone propionate; duazomycin; edatrexate; eflomithine hydrochloride; elsamitrucin; enloplatin; enpromate; epipropidine; epirubicin hydrochloride; erbulozole; esorubicin hydrochloride; estramustine; estramustine phosphate sodium; etanidazole; etoposide; etoposide phosphate; etoprine; fadrozole hydrochloride; fazarabine; fenretinide; floxuridine; fludarabine phosphate; fluorouracil; fluorocitabine; fosquidone; fostriecin sodium; gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide; ilmofosine; interleukin II (including recombinant interleukin II, or rIL2). interferon alfa-2a; interferon alfa-2b; interferon alfa-nl; interferon alfa-n3; interferon beta-I a; interferon gamma-I b; iproplatin; irinotecan hydrochloride;lanreotide acetate; letrozole; leuprolide acetate; liarozole hydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride; masoprocol; maytansine; mechlorethamine hydrochloride; megestrol acetate; melengestrol acetate; melphalan; menogaril; mercaptopurine; methotrexate; methotrexate sodium; metoprine; meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazole; nogalamycin; ormaplatin; oxisuran; paclitaxel; pegaspargase; peliomycin; pentamustine; peplomycin sulfate; perfosfamide; pipobroman; piposulfan; piroxantrone hydrochloride; plicamycin; plomestane; porfimer sodium; porfiromycin; prednimustine; procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazofurin; riboprine; rogletimide; safingol; safmgol hydrochloride; semustine; simtrazene; sparfosate sodium; sparsomycin; spirogermanium hydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin; sulofenur; talisomycin; tecogalan sodium; tegafur; teloxantrone hydrochloride; temoporfm; teniposide; teroxirone; testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin; tirapazamine; toremifene citrate; trestolone acetate; triciribine phosphate; trimetrexate; trimetrexate glucuronate; triptorelin; tubulozole hydrochloride; uracil mustard; uredepa; vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate; vinglycinate sulfate; vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate; vinzolidine sulfate; vorozole; zeniplatin; zinostatin; zorubicin hydrochloride. Other anti-cancer drugs include, but are not limited to: 20-epi-l,25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix: anti-dorsalizing morphogenetic protein- 1; antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine; baccatin III derivatives; balanol; batimastat; BCR / ABL antagonists; benzochlorins; benzoylstaurosporine; beta lactam derivatives; beta-al ethine; betaclamycin B; betulinic acid; bFGF inhibitor; bicalutamide; bisantrene; bisaziridinylspermine; bisnafide; bistratene A; bizelesin; breflate; bropirimine; budotitane; buthionine sulfoximine; calcipotriol; calphostin C; camptothecin derivatives; canarypox IL-2; capecitabine; carboxamide-amino-triazole; carboxyamidotriazole; CaRest M3; CARN 700;cartilage derived inhibitor; carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropin B; cetrorelix; chlorins; chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine; clomifene analogues; clotrimazole; collismycin A; collismycin B; combretastatin A4; combretastatin analogue; conagenin; crambescidin 816; crisnatol; cryptophycin 8; cryptophycin A derivatives; curacin A; cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorehn; dexamethasone; dexifosfamide; dexrazoxane; dexverapamil; diaziquone; didemnin B; didox; diethylnorspermine; dihydro-5-azacytidine; dihydrotaxol, 9-; dioxamycin; diphenyl spiromustine; docetaxel; docosanol; dolasetron; doxifluridine; droloxifene; dronabinol; duocarmycin SA; ebselen; ecomustine; edelfosine; edrecolomab; eflomithine; elemene; emitefur; epirubicin; epristeride; estramustine analogue; estrogen agonists; estrogen antagonists; etanidazole; etoposide phosphate; exemestane; fadrozole; fazarabine; fenretinide; filgrastim; finasteride; flavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunorunicin hydrochloride; forfenimex; formestane; fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix; gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam; heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene; idramantone; ilmofosine; ilomastat; imidazoacridones; imiquimod; immunostimulant peptides; insulin-like growth factor- 1 receptor inhibitor; interferon agonists; interferons; interleukins; iobenguane; iododoxorubicin; ipomeanol, 4-; iroplact; irsogladine; isobengazole; isohomohalicondrin B; itasetron; jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide; leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemia inhibiting factor; leukocyte alpha interferon; leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole; linear polyamine analogue; lipophilic disaccharide peptide; lipophilic platinum compounds; lissoclinamide 7; lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine; lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides; maitansine; mannostatin A; marimastat; masoprocol; maspin; matrilysin inhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone; meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone; miltefosine; mirimostim; mismatched double stranded RNA; mitoguazone; mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast growth factor-saporin; mitoxantrone; mofarotene; molgramostim; monoclonal antibody, human chorionic gonadotrophin; monophosphoryl lipid A+myobacterium cell wall sk; mopidamol; multiple drug resistance gene inhibitor; multiple tumor suppressor 1-basedtherapy; mustard anticancer agent; mycaperoxide B; mycobacterial cell wall extract; myriaporone; N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip; naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin; nemorubicin; neridronic acid; neutral endopeptidase; nilutamide; nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn; O6-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone; ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin; osaterone: oxaliplatin: oxaunomycin; paclitaxel; paclitaxel analogues; paclitaxel derivatives; palauamine; palmitoylrhizoxin; pamidronic acid; panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase; peldesine; pentosan polysulfate sodium; pentostatin; pentrozole; perflubron; perfosfamide; perillyl alcohol: phenazinomycin; phenylacetate: phosphatase inhibitors; picibanil; pilocarpine hydrochloride; pirarubicin: piritrexim; placetin A; placetin B; plasminogen activator inhibitor; platinum complex; platinum compounds; platinumtriamine complex; porfimer sodium; porfiromycin; prednisone; propyl bis-acridone; prostaglandin J2; proteasome inhibitors; protein A-based immune modulator; protein kinase C inhibitor; protein kinase C inhibitors, microalgal; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine; pyridoxylated hemoglobin polyoxyethylene conjugate; raf antagonists; raltitrexed; ramosetron; ras famesyl protein transferase inhibitors; ras inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin; ribozymes; RII retinamide; rogletimide; rohitukine; romurtide; roquinimex; rubiginone Bl; ruboxyl: safingol; saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics; semustine; senescence derived inhibitor 1 ; sense oligonucleotides; signal transduction inhibitors; signal transduction modulators; single chain antigen binding protein; sizofuran: sobuzoxane; sodium borocaptate; sodium phenylacetate; solverol; somatomedin binding protein; sonermin: sparfosic acid; spicamycin D; spiromustine; splenopentin; spongistatin 1; squalamine; stem cell inhibitor; stem-cell division inhibitors; stipiamide; stromelysin inhibitors; sulfmosine; superactive vasoactive intestinal peptide antagonist; suradista; suramin; swainsonine; synthetic glycosaminoglycans; tallimustine; tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium; tegafur; tellurapyrylium; telomerase inhibitors; temoporfin; temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine; thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetic; thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroid stimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocene bichloride; topsentin; toremifene; totipotent stem cell factor; translation inhibitors; tretinoin; triacetyluridine:triciribine; trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenital sinus-derived grow th inhibitory factor; urokinase receptor antagonists; vapreotide; variolin B; vector system, erythrocyte gene therapy; velaresol; veramine; verdins; verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; and zinostatin stimalamer. In one embodiment, the anticancer drug is 5 -fluorouracil, taxol, or leucovorin.Agents that improve T cell response

[0185] In some aspects, the PBTE or PMTE is administered in combination with at least one agent that improves T cell response. In some embodiments, at least one agent that improves T cell response is an immune checkpoint inhibitor. In some aspects, the immune check point inhibitor used in any one of the methods disclosed herein is an antibody that binds to, and / or reduces or blocks the function of a protein involved in an immune checkpoint pathway.

[0186] In some aspects, the immune checkpoint inhibitor targets cytotoxic T- lymphocyte antigen-4 (CTLA-4). In some aspects, the immune checkpoint inhibitor that targets CTLA-4 is Ipilimumab or tremelimumab (ticilimumab, CP-675,206). In some aspects, the immune checkpoint inhibitor targets PD-1. In some aspects, the immune checkpoint inhibitor that targets PD-1 is nivolumab (ONO-4538 / BMS-936558, MDX1106, OPDIVO®), pembrolizumab (MK-3475, KEYTRUDA®), pidilizumab (CT-011), atezolizumab (MPDL328OA), cemiplimab (LIBTAYOTM), Spartalizumab (PDR001), Camrelizumab (SHR1210), Sintilimab (IBI308), Tislelizumab (BGB-A317), Toripalimab (JS 001), AMP-224, AMP-514 or Spartalizumab (PDR001). In some aspects, the immune checkpoint inhibitor targets PD-L-1. In some aspects, the immune checkpoint inhibitor that targets PD-L-1 is Avelumab, Atezolizumab. Durvalumab. KN035, CK-301, AUNP12. CA- 170, or BMS-986189. In some aspects, the immune checkpoint inhibitor targets T cell immunoglobulin and mucin-domain containing-3 (TIM-3) and / or Lymphocyte Activating 3 (LAG3) proteins. In some aspects, the immune checkpoint inhibitor targeting TIM3 is MBG453; TSR-022; or LY3321367. In some aspects, the immune checkpoint inhibitor targeting LAG3 is IMP321 (Eftilagimod alpha), BMS-986016 (Relatlimab), LAG525 (anti- LAG-3 mAh), REGN3767 (anti-LAG-3 mAh), TSR-033 (anti-LAG-3 mAb), MGD013 (a PD-l / LAG-3 bispecific DART® protein), or FS118 (a LAG-3 / PD-L1 bispecific antibody).

[0187] In some aspects, the immune checkpoint inhibitor targets indoleamine 2,3- dioxygenase-1 (IDO1). some aspects, the immune checkpoint inhibitor that targets IDO1 is Indoximod (D-1MT; NLG-8189), Navoximod (NLG-919), Epacadostat (INCB024360), BMS-986205, PF-06840003, IOM2983, or RG-70099.

[0188] In some aspects, the immune checkpoint inhibitor targets V-domain Ig suppressor of T cell activation (VISTA).

[0189] In some aspects, the at least one agent that improves T cell response is a cytokine, such as an inflammatory cytokine. In some aspects, the cytokine is type I IFN or IL-12. In some aspects, the cytokine is a cytokine that shares the common gamma chain receptor. Non-limiting examples of a cytokine that shares the common gamma chain receptor include IL-2. IL-7. IL- 15, and IL-21. In some aspects, the at least one agent that improves T cell response is IL-2.

[0190] In some aspects, the at least one agent that improves T cell response targets Treg cells. In some aspects, the agent that target Treg cells is an anti-CCR4 antibody, an neuropilin-1 (Nrp-1) inhibitor, or a semaphoring-4a (Sema4a) inhibitor. In some aspects, the at least one agent that improves T cell response is an mTOR inhibitor. Non-limiting examples of an mTOR inhibitor include rapamycin, temsirolimus (CCI-779), everolimus (RAD001), ndaforolimus (AP-23573), sirohmus, dactolisib, BGT226, SF1126, PKI-587, sapanisertib, AZD8055, and AZD2014.

[0191] The mode of administration of the immune checkpoint inhibitor is not limited, and may be any mode that is recommended for, or known to be suitable for, the immune checkpoint inhibitor, as described in the art. The mode of administration may vary' depending on the particular immune checkpoint inhibitor that is used. In some aspects, the immune checkpoint inhibitor disclosed herein may be administered via a systemic route, such as for example, parenteral routes of administration; a mucosal route; a transdermal route; or directly into a specific tissue. In some aspects, the immune checkpoint inhibitor is administered to a subject in need thereof at a therapeutically effective dose. The therapeutically effective dose depends on factors such as the type of cancer being treated, the age, weight and health of the subject, and route of administration.

[0192] The amount of immune checkpoint inhibitor administered to the subject is not limited, and may be any amount as determined by the physician and / or as described or known in the art. In some aspects, the amount of immune checkpoint inhibitor administered to the subject is in the range of about 1 pg / kg to about 50 mg / kg, such as. for example, 5 pg / kg, 10pg / kg, 50 pg / kg, 100 g / kg. 500 pg / kg. 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg. 25 mg / kg, 30 mg / kg. 35 mg / kg, 40 mg / kg, 45 mg / kg, or 50 mg / kg, including all values and subranges that lie therebetween. In some aspects, the dose may be administered in a volume of about 0.1 mL to about 1.5 mL, for example, about 0.2 mL, about 0.4 mL, 0.5 mL, about 0.6 mL, about 0.8 mL, about 1 mL, or about 1.2 mL, including all values and subranges that he therebetween.

[0193] In some aspects, the immune checkpoint inhibitor is administered concurrently with the PBTE or PMTE disclosed herein. In some aspects, the immune checkpoint inhibitor is administered PBTE or PMTE disclosed herein. In some aspects, the immune checkpoint inhibitor is administered after a PBTE or PMTE disclosed herein.Generation of Synthetic Antibodies In Vitro and Ex Vivo

[0194] In one embodiment, the PBTE or PMTE is generated in vitro or ex vivo. For example, in one embodiment, a nucleic acid encoding a PBTE or PMTE can be introduced and expressed in an in vitro or ex vivo cell. Methods of introducing and expressing genes into a cell are known in the art. In the context of an expression vector, the vector can be readily introduced into a host cell, e g., mammalian, bacterial, yeast, or insect cell by any method in the art. For example, the expression vector can be transferred into a host cell by physical, chemical, or biological means.

[0195] Physical methods for introducing a polynucleotide into a host cell include calcium phosphate precipitation, lipofection, particle bombardment, microinjection, electroporation, and the like. Methods for producing cells comprising vectors and / or exogenous nucleic acids are well-known in the art. See, for example, Sambrook et al. (2012, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory, New York). A preferred method for the introduction of a polynucleotide into a host cell is calcium phosphate transfection.

[0196] Biological methods for introducing a polynucleotide of interest into a host cell include the use of DNA and RNA vectors. Viral vectors, and especially retroviral vectors, have become the most widely used method for inserting genes into mammalian, e.g.. human cells. Other viral vectors can be derived from lentivirus, poxviruses, herpes simplex virus I, adenoviruses and adeno-associated viruses, and the like. See, for example, U.S. Pat. Nos. 5,350,674 and 5,585.362.

[0197] Chemical means for introducing a polynucleotide into a host cell include colloidal dispersion systems, such as macromolecule complexes, nanocapsules, microspheres, beads, and lipid-based systems including oil-in-water emulsions, micelles, mixed micelles, and liposomes. An exemplary colloidal system for use as a delivery vehicle in vitro and in vivo is a liposome (e.g., an artificial membrane vesicle).

[0198] In the case where a non-viral delivery system is utilized, an exemplary’ delivery vehicle is a liposome. The use of lipid formulations is contemplated for the introduction of the nucleic acids into a host cell (in vitro, ex vivo or in vivo). In another aspect, the nucleic acid may be associated with a lipid. The nucleic acid associated with a lipid may be encapsulated in the aqueous interior of a liposome, interspersed within the lipid bilayer of a liposome, attached to a liposome via a linking molecule that is associated with both the liposome and the oligonucleotide, entrapped in a liposome, complexed with a liposome, dispersed in a solution containing a lipid, mixed with a lipid, combined with a lipid, contained as a suspension in a lipid, contained or complexed with a micelle, or otherwise associated with a lipid. Lipid, lipid / DNA or lipid / expression vector associated compositions are not limited to any particular structure in solution. For example, they may be present in a bilayer structure, as micelles, or with a “collapsed” structure. They' may also simply be interspersed in a solution, possibly forming aggregates that are not uniform in size or shape. Lipids are fatty substances which may be naturally occurring or synthetic lipids. For example, lipids include the fatty droplets that naturally occur in the cytoplasm as well as the class of compounds which contain long-chain aliphatic hydrocarbons and their derivatives, such as fatty' acids, alcohols, amines, amino alcohols, and aldehydes.EXAMPLES

[0199] The present invention is further illustrated in the following Examples. It should be understood that these Examples, while indicating preferred embodiments of the invention, are given by way of illustration only. From the above discussion and these Examples, one skilled in the art can ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions. Thus, various modifications of the invention in addition to those show n and described herein will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims.Example 1: anti-FSHR and ovCAR3 PBTE and PMTE

[0200] Here presented are two molecules, the first of which is a PBTE while the second, referred to as a Persistent Multivalent T Cell Engager (PMTE), builds off the PBTE with an additional binding domain to generate a multivalent format, providing FSHR bivalency in this iteration.

[0201] FSHR-targeted PBTE and PMTE display similar formatting effects on binding and potency in vitro.

[0202] A prominent reduction on cancer cell affinity was observed from PBTE reformatting, tested by flow cytometry using FSHR-transduced OVCAR3. This was visualized by its 2-log right-shifted MFI curve compared to the BTE and quantified by a >120-fold increase in KT). Effects on T cell affinity were also observed, by measure of a 4.5- fold higher KD compared to the BTE (Figure 2A, 2D). This PBTE was then linked with a second anti-FSHR scFv to form the PMTE, which to OVCAR3-FSHR led to an 11-fold recovery in binding strength with the PMTE compared to the PBTE.

[0203] PMTE formatting also affected T cell binding kinetics, where a 3-fold recovery in KD was observed compared to the PBTE. This left the PMTE with a minimal, 1.6-fold higher T cell KD than the BTE, while the PBTE’s was higher by >4-fold. (Figure 2A. 2D).

[0204] The combined effects of these binding alterations on cytotoxic potency were subsequently tested upon the monitored co-incubation of treated OVCAR3-FSHR and T cells. After a 5-day incubation, the PBTE displayed a sizeable, 150-fold reduction in potency compared to its predecessor format.

[0205] However, with an ~11 nM EC50 compared to the PBTE’s 710 nM, the PMTE format generated an almost-full recovery of cytotoxic potency (Figure 2C, 2E). The end result is an FSHR-targeted molecule that can benefit from half-life extension without sacrificing potency.Example 2: SequencesAnti-FSHR heavy chain (SEQ ID NO: 1)DIQMTQSPSSLSASVGDRVTISCRASESVDNYGISFLNWFQQKPGKAPKLLIYAASNQRSGVPSRFSGSG SGTDFTLTISSLQPEDFATYFCQQSKEVPWTFGQGTKVEIKRAnti-FSHR light chain (SEQ ID NO:2)E VQL VESGGGL VQPGG SLRL SC SFSGF SL ST SGMG VGWIRQAPGKGLEWV AHI WWDDDKRYNPALK SRFTLSVDRSKNTLYLQMNSLRAEDTATYYCVQINYGNYRFDNWGHGTLVTVSSAnti-CD3 heavy chain (SEQ ID N0:3)EVQLVESGGGLVQPGGSLRLSCAASGYSFTGYTMNWVRQAPGKGLEWVALINPYKGVSTYNQKFKDRFTISVDKSKNTAYLQMNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQGTLVTVSSAnti-CD3 light chain (SEQ ID N0:4)DIQMTQSPSSLSASVGDRVTITCRASQDIRNYLNWYQQKPGKAPKLLIYYTSRLESGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCQQGNTLPWTFGQGTKVEIKSSFc Domain (SEQ ID NO: 5)DKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEAPEVKFNWYVDGVEVHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS VMHEALHNH YTQKSLSL SPGKGGGG SGGGG SGGGG SGGGG SGGGGSGGGG SDKTHTCPPCP APE AAGGPSVFTTPPKPKDTT^MISRTPEVTCVVVDVSHEAPEVKFNWYVDGVEVHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKFSHR PBTE (SEQ ID NO: 6)MDWTWILFLVAAATRVHSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEA PEVKFNWYVDGVEVHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFL YSKLT VDKSRWQQGNVF SC S VMHEALHNH YTQKSL SL SPGKGGGG SGGGG SGGGGSGGGG SGGGG S GGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEAPEVKFNWYVDGVEVHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTL PPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKGGGGSGGGGSDIQMTQSPSSLSASVGDRVTISCRASESVD NYGISFLNWFQQKPGKAPKLLIYAASNQRSGVPSRFSGSGSGTDFTLTISSLQPEDFATYFCQQSKEVPW TFGQGTKVEIKRGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCSFSGFSLSTSGMGVGWIRQAPGKGLEWVAHIWWDDDKRYNPALKSRFTLSVDRSKNTLYLQMNSLRAEDTATYYCVQINYGNYRF DNWGHGTLVTVSSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGYSFTGYTMNWVRQAPGKGLEWVALINPYKGVSTYNQKFKDRFTISVDKSKNTAYLQMNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQ GTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQDIRNYLNWYQQKPGKAPKLLIYYTSRLESGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCQQGNTLPWTFGQGTKVEIKSSFSHR PBTE-His (SEQ ID NO:7)MDWTWILFLVAAATRVHSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEA PEVKFNWYVDGVEVHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFL YSKLT VDKSRWQQGNVF SC S VMHEALHNH YTQKSL SL SPGKGGGG SGGGG SGGGGSGGGG SGGGG S GGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEAPEVKFNWYVDGVEVHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTL PPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQ GNVFSCSVMHEALHNHYTQKSLSLSPGKGGGGSGGGGSDIQMTQSPSSLSASVGDRVTISCRASESVD NYGISFLNWFQQKPGKAPKLLIYAASNQRSGVPSRFSGSGSGTDFTLTISSLQPEDFATYFCQQSKEVPWTFGQGTKVEIKRGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCSFSGFSLSTSGMGVGWTRQAPGKGLEWVAHIWWDDDKRYNPALKSRFTLSVDRSKNTLYLQMNSLRAEDTATYYCVQINYGNYRF DNWGHGTLVTVSSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGYSFTGYTMNWVRQAPGKGLEWVALINPYKGVSTYNQKFKDRFTISVDKSKNTAYLQMNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQDIRNYLNWYQQKPGKAPKLLIYYTSRLESGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCQQGNTLPWTFGQGTKVEIKSSHHHHHHFSHR PMTE (Fc-HLHLHL) (SEQ ID NO: 8)MDWTWILFLVAAATRVHSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEAPEVKFNWYVDGVEVHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFL YSKLT VDKSRWQQGNVF SC S VMHEALHNH YTQKSL SL SPGKGGGG SGGGG SGGGGSGGGG SGGGG SGGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEAPEVKFNWYVDGVEVHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKGGGGSGGGGSDIQMTQSPSSLSASVGDRVTISCRASESVDNYGISFLNWFQQKPGKAPKLLIYAASNQRSGVPSRFSGSGSGTDFTLTISSLQPEDFATYFCQQSKEVPW TFGQGTKVEIKRGGGG SGGGG SGGGGSEVQLVESGGGLVQPGGSLRLSCSFSGFSLSTSGMGVGWIRQAPGKGLEWVAHIWWDDDKRYNPALKSRFTLSVDRSKNTLYLQMNSLRAEDTATYYCVQINYGNYRFDNWGHGTLVTVSSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGYSFTGYTMNWVRQAPGKGLEWVALINPYKGVSTYNQKFKDRFTISVDKSKNTAYLQMNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQDIRNYLNWYQQKPGKAPKLLIYYTSRLESGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCQQGNTLPWTFGQGTKVEIKSSGGGGSDIQMTQSPSSLSASVGDRVTISCRASESVDNYGISFLNWFQQKPGKAPKLLIYAASNQRSGVPSRFSGSGSGTDFTLTISSLQPEDFATYFCQQSKEVPWTFGQGTKVEIKRGGGGSGGGGSGGGGSEVQLVESGGGLVQ PGGSLRLSCSFSGFSLSTSGMGVGWIRQAPGKGLEWVAHIWWDDDKRYNPALKSRFTLSVDRSKNTLYLQMNSLRAEDTATYYCVQINYGNYRFDNWGHGTLVTVSSFSHR PMTE-His (Fc-HLHLHL) (SEQ ID NO: 9)MDWTWILFLVAAATRVHSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEAPEVKFNWYVDGVEVHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFL YSKLT VDKSRWQQGNVF SC S VMHEALHNH YTQK SL SL SPGKGGGG SGGGG SGGGGSGGGG SGGGG SGGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEAPEVKFNWYVDGVEVHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD1AVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKGGGGSGGGGSDIQMTQSPSSLSASVGDRVTISCRASESVDNYGISFLNWFQQKPGKAPKLLIYAASNQRSGVPSRFSGSGSGTDFTLTISSLQPEDFATYFCQQSKEVPWTFGQGTKVEIKRGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCSFSGFSLSTSGMGVGWIRQAPGKGLEWVAHIWWDDDKRYNPALKSRFTLSVDRSKNTLYLQMNSLRAEDTATYYCVQINYGNYRFDNWGHGTLVTVSSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGYSFTGYTMNWVRQAPGKGLEWVALINPYKGVSTYNQKFKDRFTISVDKSKNTAYLQMNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQDIRNYLNWYQQKPGKAPKLLIYYTSRLESGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCQQGNTLPWTFGQGTKVEIKSSGGGGSDIQMTQSPSSLSASVGDRVTISCRASESVDNYGISFLNWFQQKPGKAPKLLIYAASNQRSGVPSRFSGSGSGTDFTLTISSLQPEDFATYFCQQSKEVPWTFGQGTKVEIKRGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCSFSGFSLSTSGMGVGWIRQAPGKGLEWVAHIWWDDDKRYNPALKSRFTLSVDRSKNTL YLQMNSLRAEDTATYYCVQINYGNYRFDNWGHGTLVTVSSHHHHHHFSHR PMTE (Fc-LHLHHL) (SEQ ID NOTO)MDWTW1LFLVAAATRVHSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLM1SRTPEVTCVVVDVSHEAPEVKFNWYVDGVEVHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTIS KAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKGGGGSGGGGSGGGGSGGGGSGGGGS GGGG SDKTHTCPPCPAPEAAGGPS VFLFPPKPKDTLMI SRTPE VTC V V VD V SHEAPEVKFNW YVDGVE VHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCSFSGFSLSTSGMGVGWIRQAPGKGLEWVAHIWWDDDKRYNPALKSRFTLSVDRSKNTLYLQMNSLRAEDTATYYCVQINYGNYRFDNWGHGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTISCRASESVDNYGISFLNWFQQKPGKAPKLLIYAASNQRSGVPSRFSGSGSGTDFTLTISSLQPEDFATYFCQQSKEVPWTFGQGTKVEIKRGGGGSDIQMTQSPSSLSASVGDRVTITCRASQDIRNYLNWYQQKPGKAPKLLIYYTSRLESGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCQQGNTLPWTFGQGTKVEIKSSGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGYSFTGYTMNWVRQAPGKGLEWVALINPYKGVSTYNQKFKDRFTISVDKSKNTAYLQMNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQGTLVTVSSGGGGSDIQMTQSPSSLSASVGDRVTISCRASESVDNYGISFLNWFQQKPGKAPKLLIYAASNQRSGVPSRFSGSGSGTDFTLTISSLQPEDFATYFCQQSKEVPWTFGQGTKVEIKRGGGGSGGGGSGGGGSEVQLVESGGGLVQPGG SLRL SC SF SGFSL ST SGMG VGWIRQAPGKGLEWV AHI WWDDDKRYNPALKSRFTL S VDRSKNTLYLQMNSLRAEDTATYYCVQINYGNYRFDNWGHGTLVTVSSFSHR PMTE-His (Fc-LHLHHL) (SEQ ID NO: 11)MDWTWILFI^VAAATRVHSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHFAPEVKFNWYVDGVEVHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTIS KAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFL YSKLT VDKSRWQQGNVF SC S VMHEALHNH YTQKSL SL SPGKGGGG SGGGG SGGGGSGGGG SGGGG S GGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEAPEVKFNWYVDGVE VHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTL PPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQ GNVFSCSVMHEALHNHYTQKSLSLSPGKGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCSFSGFSLS TSGMGVGWIRQAPGKGLEWVAHIWWDDDKRYNPALKSRFTLSVDRSKNTLYLQMNSLRAEDTATYY CVQINYGNYRFDNWGHGTLVTVSSGGGGSGGGG SGGGG SDIQMTQSPSSLSASVGDRVTISCRASESV DNYGISFLNWFQQKPGKAPKLLIYAASNQRSGVPSRFSGSGSGTDFTLTISSLQPEDFATYFCQQSKEVP WTFGQGTKVEIKRGGGGSDIQMTQSPSSLSASVGDRVTITCRASQDIRNYLNWYQQKPGKAPKLLIYY TSRLESGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCQQGNTLPWTFGQGTKVEIKSSGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGYSFTGYTMNWVRQAPGKGLEWVALINPYKGVSTYNQKFKDRFTISVDKSKNTAYLQMNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQGTLVTVSSGGGGS DIQMTQSPSSLSASVGDRVTISCRASESVDNYGISFLNWFQQKPGKAPKLLIYAASNQRSGVPSRFSGSG SGTDFTLTISSLQPEDFATYFCQQSKEVPWTFGQGTKVEIKRGGGGSGGGGSGGGGSEVQLVESGGGL VQPGG SLRL SC SF SGFSL ST SGMG VGWIRQ APGKGLE WV AHI WWDDDKRYNPALKSRFTL S VDRSKN TLYLQMNSLRAEDTATYYCVQINYGNYRFDNWGHGTLVTVSSHHHHHHFSHR PMTE (Fc-LHLHLH) (SEQ ID NO: 12)MDWTWILFLVAAATRVHSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEA PEVKFNWYVDGVEVHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTIS KAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFL YSKLT VDKSRWQQGNVF SC S VMHEALHNH YTQKSL SL SPGKGGGG SGGGG SGGGGSGGGG SGGGG S GGGGSDKTIITCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSIIEAPEVKFNWYVDGVE VHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTL PPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQ GNVFSCSVMHEALHNHYTQKSLSLSPGKGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCSFSGFSLS TSGMGVGWIRQAPGKGLEWVAHIWWDDDKRYNPALKSRFTLSVDRSKNTLYLQMNSLRAEDTATYY CVQINYGNYRFDNWGHGTLVTVSSGGGGSGGGG SGGGG SDIQMTQSPSSLSASVGDRVTISCRASESV DN YGI SFLN WFQQKPGKAPKLLI YAASNQRSG VPSRF SG SG SGTDFTLTI SSLQPEDF AT YFCQQSKEVP WTFGQGTKVEIKRGGGGSDIQMTQSPSSLSASVGDRVTITCRASQDIRNYLNWYQQKPGKAPKLLIYY TSRLESGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCQQGNTLPWTFGQGTKVEIKSSGGGGSGGGGS GGGGSEVQLVESGGGLVQPGGSLRLSCAASGYSFTGYTMNWVRQAPGKGLEWVALINPYKGVSTYN QKFKDRFTISVDKSKNTAYLQMNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQGTLVTVSSGGGGS EVQLVESGGGL VQPGG SLRL SCSFSGFSLSTSGMGVGWIRQAPGKGLEWV AHI WWDDDKRYNPALKS RFTLSVDRSKNTLYLQMNSLRAEDTATYYCVQINYGNYRFDNWGHGTLVTVSSGGGGSGGGGSGGG GSDIQMTQSPSSLSASVGDRVTISCRASESVDNYGISFLNWFQQKPGKAPKLLIYAASNQRSGVPSRFSG SG SGT DFT'LTI SSLQPEDF AT YFCQQ SKE VP WTFGQG TK VE1KRFSHR PMTE-His (Fc-LHLHLH) (SEQ ID NO: 13)MDWTWILFLVAAATRVHSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEA PEVKFNWYVDGVEVHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTIS KAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFL YSKLT VDKSRWQQGNVF SC S VMHE ALHNH YTQKSL SL SPGKGGGG SGGGG SGGGGSGGGG SGGGG S GGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEAPEVKFNWYVDGVE VHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTL PPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQ GNVFSCSVMHEALHNHYTQKSLSLSPGKGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCSFSGFSLS TSGMGVGWIRQAPGKGLEWVAHIWWDDDKRYNPALKSRFTLSVDRSKNTLYLQMNSLRAEDTATYY CVQINYGNYRFDNWGHGTLVTVSSGGGGSGGGG SGGGG SDIQMTQSPSSLSASVGDRVTISCRASESV DN YGI SFLN WFQQKPGKAPKLLI YAASNQRSG VPSRF SG SG SGTDFTLTI SSLQPEDF AT YFCQQSKEVP WTFGQGTKVEIKRGGGGSDIQMTQSPSSLSASVGDRVTITCRASQDIRNYLNWYQQKPGKAPKLLIYY TSRLESGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCQQGNTLPWTFGQGTKVEIKSSGGGGSGGGGS GGGGSEVQLVESGGGLVQPGGSLRLSCAASGYSFTGYTMNWVRQAPGKGLEWVALINPYKGVSTYN QKFKDRFTISVDKSKNTAYLQMNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQGTLVTVSSGGGGS EVQLVESGGGLVQPGGSLRLSCSFSGFSLSTSGMGVGWIRQAPGKGLEWVAHIWWDDDKRYNPALKS RFTLSVDRSKNTLYLQMNSLRAEDTATYYCVQINYGNYRFDNWGHGTLVTVSSGGGGSGGGGSGGG GSDIQMTQSPSSLSASVGDRVTISCRASESVDNYGISFLNWFQQKPGKAPKLLIYAASNQRSGVPSRFSG SGSGTDFTLTISSLQPEDFATYFCQQSKEVPWTFGQGTKVEIKRHHHHHHFSHR PMTE (Fc-HLLHHL) (SEQ ID NO: 14)MDWTWILFLVAAATRVHSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEA PEVKFNWYVDGVEVHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFL YSKLT VDKSRWQQGNVF SC SVMHEALHNH YTQKSL SL SPGKGGGG SGGGG SGGGGSGGGG SGGGG S GGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEAPEVKFNWYVDGVE VHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTL PPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQ GNVFSCSVMHEALHNHYTQKSLSLSPGKGGGGSGGGGSDIQMTQSPSSLSASVGDRVTISCRASESVDNYG1SFLNWFQQKPGKAPKLLIYAASNQRSGVPSRFSGSGSGTDFTLT1SSLQPEDFATYFCQQSKEVPWTFGQGTKVEIKRGGGG SGGGG SGGGGSEVQLVESGGGLVQPGGSLRLSCSFSGFSLSTSGMGVGWIRQ APGKGLEWVAHIWWDDDKRYNPALKSRFTLSVDRSKNTLYLQMNSLRAEDTATYYCVQINYGNYRF DNWGHGTLVTVSSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQDIRNYLNWYQQKPGKAPKLLIYY TSRLESGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCQQGNTLPWTFGQGTKVEIKSSGGGGSGGGGS GGGGSEVQLVESGGGLVQPGGSLRLSCAASGYSFTGYTMNWVRQAPGKGLEWVALINPYKGVSTYN QKFKDRFTISVDKSKNTAYLQMNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQGTLVTVSSGGGGS DIQMTQSPSSLSASVGDRVTISCRASESVDNYGISFLNWFQQKPGKAPKLLIYAASNQRSGVPSRFSGSGSGTDFTLTISSLQPEDFATYFCQQSKEVPWTFGQGTKVEIKRGGGGSGGGGSGGGGSEVQLVESGGGL VQPGGSLRL SC SF SGFSL ST SGMG VG WIRQ APGKGLE WV AHI WWDDDKRYNPALKSRFTL S VDRSKN TLYLQMNSLRAEDTATYYCVQINYGNYRFDNWGHGTLVTVSSFSHR PMTE-His (Fc-HLLHHL) (SEQ ID NO: 15)MDWTWILFLVAAATRVHSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEA PEVKFNWYVDGVEVHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTIS K AKGQPREPQ V YTLPPSREEMTKNQ V SLTCL VKGF YPSDI A VE WE SNGQPENN YKTTPP VLDSDG SFFL YSKLT VDKSRWQQGNVF SC SVMHEALHNH YTQKSL SL SPGKGGGG SGGGG SGGGGSGGGG SGGGG S GGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEAPEVKFNWYVDGVE VHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTL PPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQ GNVFSCSVMHE ALHNH YTQKSLSLSPGKGGGGSGGGGSDIQMTQSPSSLSASVGDRVTISCRASESVD NYGISFLNWFQQKPGKAPKLLIYAASNQRSGVPSRFSGSGSGTDFTLTISSLQPEDFATYFCQQSKEVPW TFGQGTKVEIKRGGGG SGGGG SGGGGSEVQLVESGGGLVQPGGSLRLSCSFSGFSLSTSGMGVGWIRQ APGKGLEWVAHIWWDDDKRYNPALKSRFTLSVDRSKNTLYLQMNSLRAEDTATYYCVQINYGNYRFDNWGHGTLVTVSSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQDIRNYLNWYQQKPGKAPKLLIYYTSRLESGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCQQGNTLPWTFGQGTKVEIKSSGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGYSFTGYTMNWVRQAPGKGLEWVALINPYKGVSTYNQKFKDRFTISVDKSKNTAYLQMNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQGTLVTVSSGGGGSDIQMTQSPSSLSASVGDRVTISCRASESVDNYGISFLNWFQQKPGKAPKLLIYAASNQRSGVPSRFSGSGSGTDFTLTISSLQPEDFATYFCQQSKEVPWTFGQGTKVEIKRGGGGSGGGGSGGGGSEVQLVESGGGL VQPGG SLRL SC SF SGFSL ST SGMG VGWIRQAPGKGLE W VAHI WWDDDKRYNPALKSRFTL S VDRSKN TLYLQMNSLRAEDTATYYCVQINYGNYRFDNWGHGTLVTVSSHHHHHHFSHR PMTE (Fc-HLLHLH) (SEQ ID NO: 16)MDWTWILFLVAAATRVHSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEA PEVKFNWYVDGVEVHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTIS KAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFL YSKLT VDKSRWQQGNVF SC S VMHEALHNH YTQKSL SL SPGKGGGG SGGGG SGGGGSGGGG SGGGG S GGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEAPEVKFNWYVDGVE VHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTL PPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQ GNVFSCSVMHEALHNHYTQKSLSLSPGKGGGGSGGGGSDIQMTQSPSSLSASVGDRVTISCRASESVD NYGISFLNWFQQKPGKAPKLLIYAASNQRSGVPSRFSGSGSGTDFTLTISSLQPEDFATYFCQQSKEVPW TFGQGTKVEIKRGGGG SGGGG SGGGGSEVQLVESGGGLVQPGGSLRLSCSFSGFSLSTSGMGVGWIRQ APGKGLEWVAHIWWDDDKRYNPALKSRFTLSVDRSKNTLYLQMNSLRAEDTATYYCVQINYGNYRF DNWGHGTLVTVSSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQDIRNYLNWYQQKPGKAPKLLIYY TSRLESGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCQQGNTLPWTFGQGTKVEIKSSGGGGSGGGGS GGGGSEVQLVESGGGLVQPGGSLRLSCAASGYSFTGYTMNWVRQAPGKGLEWVALINPYKGVSTYN QKFKDRFTISVDKSKNTAYLQMNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQGTLVTVSSGGGGS EVQLVESGGGLVQPGGSLRLSCSFSGFSLSTSGMGVGWIRQAPGKGLEWVAHIWWDDDKRYNPALKS RFTLSVDRSKNTLYLQMNSLRAEDTATYYCVQINYGNYRFDNWGHGTLVTVSSGGGGSGGGGSGGG GSDIQMTQSPSSLSASVGDRVTISCRASESVDNYGISFLNWFQQKPGKAPKLLIYAASNQRSGVPSRFSG SG SGTDFTLTI SSLQPEDFAT YFCQQ SKE VPWTFGQGTK VEIKRFSHR PMTE-His (Fc-HLLHLH) (SEQ ID NO: 17)MDWTWILFLVAAATRVHSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEAPEVKFNWYVDGVEVHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD1AVEWESNGQPENNYK1TPPVLDSDGSFFLYSKLT VDKSRWQQGNVF SC S VMHEALHNH YTQKSL SL SPGKGGGG SGGGG SGGGGSGGGG SGGGG S GGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEAPEVKFNWYVDGVEVHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKGGGGSGGGGSDIQMTQSPSSLSASVGDRVTISCRASESVDNYGISFLNWFQQKPGKAPKLLIYAASNQRSGVPSRFSGSGSGTDFTLTISSLQPEDFATYFCQQSKEVPWTFGQGTKVEIKRGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCSFSGFSLSTSGMGVGWIRQAPGKGLEWVAHIWWDDDKRYNPALKSRFTLSVDRSKNTLYLQMNSLRAEDTATYYCVQINYGNYRF DNWGHGTLVTVSSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQDIRNYLNWYQQKPGKAPKLLIYY TSRLESGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCQQGNTLPWTFGQGTKVEIKSSGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGYSFTGYTMNWVRQAPGKGLEWVALINPYKGVSTYNQKFKDRFTISVDKSKNTAYLQMNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQGTLVTVSSGGGGSEVQLVESGGGLVQPGGSLRLSCSFSGFSLSTSGMGVGWIRQAPGKGLEWVAHIWWDDDKRYNPALKSRFTLSVDRSKNTLYLQMNSLRAEDTATYYCVQINYGNYRFDNWGHGTLVTVSSGGGGSGGGGSGGG GSDIQMTQSPSSLSASVGDRVTISCRASESVDNYGISFLNWFQQKPGKAPKLLIYAASNQRSGVPSRFSG SGSGTDFTLTISSLQPEDFATYFCQQSKEVPWTFGQGTKVEIKRHHHHHHFSHR PMTE (Fc-HLHLLH) (SEQ ID NO: 18)MDWTWILFLVAAATRVHSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEAPEVKFNWYVDGVEVHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLT VDKSRWQQGNVF SC S VMHE ALHNH YTQKSL SL SPGKGGGG SGGGG SGGGG SGGGG SGGGG S GGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEAPEVKFNWYVDGVE VHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTL PPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQ GNVFSCSVMHEALHNHYTQKSLSLSPGKGGGGSGGGGSDIQMTQSPSSLSASVGDRVTISCRASESVD NYGISFLNWFQQKPGKAPKLLIYAASNQRSGVPSRFSGSGSGTDFTLTISSLQPEDFATYFCQQSKEVPW TFGQGTK VEIKRGGGG SGGGG SGGGGSEVQL VESGGGL VQPGGSLRLSC SF SGF SLST SGMG VG WIRQ APGKGLEWVAHIWWDDDKRYNPALKSRFTLSVDRSKNTLYLQMNSLRAEDTATYYCVQINYGNYRF DNWGHGTLVTVSSGGGGSEVQL VESGGGL VQPGGSLRLSC AASGYSFTGYTMNWVRQAPGKGLEWV ALINPYKGVSTYNQKFKDRFTISVDKSKNTAYLQMNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQ GTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQDIRNYLNWYQQKPGKAPK LLIYYTSRLESGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCQQGNTLPWTFGQGTKVEIKSSGGGGSE VQL VESGGGL VQPGGSLRLSCSFSGFSLSTSGMGVGWIRQAPGKGLEWV AHI WWDDDKRYNPALKSR FTLSVDRSKNTLYLQMNSLRAEDTATYYCVQINYGNYRFDNWGHGTLVTVSSGGGGSGGGGSGGGG SDIQMTQSPSSLSASVGDRVTISCRASESVDNYGISFLNWFQQKPGKAPKLLIYAASNQRSGVPSRFSGS GSGTDFTLTI S SLQPEDFAT YFCQQ SKE VPWTFGQGTK VEIKRFSHR PMTE-His (Fc-HLHLLH) (SEQ ID NO: 19)MDWTWILFLVAAATRVHSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEA PEVKFNWYVDGVEVHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTIS KAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFL YSKLT VDKSRWQQGNVF SC S VMHE ALHNH YTQKSL SL SPGKGGGG SGGGG SGGGG SGGGG SGGGG S GGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEAPEVKFNWYVDGVE VHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTL PPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQ GNVFSCSVMHEALHNHYTQKSLSLSPGKGGGGSGGGGSDIQMTQSPSSLSASVGDRVTISCRASESVD NYGISFLNWFQQKPGKAPKLLIYAASNQRSGVPSRFSGSGSGTDFTLTISSLQPEDFATYFCQQSKEVPW TFGQGTKVEIKRGGGG SGGGG SGGGGSEVQL VESGGGL VQPGGSLRLSCSFSGFSLSTSGMGVGWIRQ APGKGLEWVAHIWWDDDKRYNPALKSRFTLSVDRSKNTLYLQMNSLRAEDTATYYCVQINYGNYRF DNWGHGTLVTVSSGGGGSEVQL VESGGGL VQPGGSLRLSCAASGYSFTGYTMNWVRQAPGKGLEWV ALINPYKGVSTYNQKFKDRFTISVDKSKNTAYLQMNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQ GTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQDIRNYLNWYQQKPGKAPK LLIYYTSRLESGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCQQGNTLPWTFGQGTKVEIKSSGGGGSE VQL VESGGGL VQPGGSLRLSCSFSGFSLSTSGMGVGWIRQAPGKGLEWV AHI WWDDDKRYNPALKSR FTLSVDRSKNTLYLQMNSLRAEDTATYYCVQINYGNYRFDNWGHGTLVTVSSGGGGSGGGGSGGGG SDIQMTQSPSSLSASVGDRVTISCRASESVDNYGISFLNWFQQKPGKAPKLLIYAASNQRSGVPSRFSGS GSGTDFTLTISSLQPEDFATYFCQQSKEVPWTFGQGTKVEIKRHHHHHHFSHR PMTE (Fc-LHHLLH) (SEQ ID NO:20)MD WT WILFL V AAATR VI ISDKTI ITCPPCPAPEAAG GPS VFLFPPKPKDTLMI SRTPE VTC V V VD VSI IEA PEVKFNWYVDGVEVHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTIS KAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFL YSKLT VDKSRWQQGNVF SC S VMHE ALHNH YTQK SL SL SPGKGGGG SGGGG SGGGG SGGGG SGGGG S GGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEAPEVKFNWYVDGVE VHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTL PPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQ GNVFSCSVMHEALHNHYTQKSLSLSPGKGGGGSGGGGSEVQL VESGGGL VQPGGSLRLSCSFSGFSLS TSGMGVGWIRQAPGKGLEWVAHIWWDDDKRYNPALKSRFTLSVDRSKNTLYLQMNSLRAEDTATYY CVQINYGNYRFDNWGHGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTISCRASESV DN YGI SFLN WFQQKPGKAPKLLI YAASNQRSG VPSRF SG SG SGTDFTLTI SSLQPEDF AT YFCQQSKEVP WTFGQGTKVEIKRGGGGSEVQL VESGGGL VQPGGSLRLSC AASGYSFTGYTMNWVRQAPGKGLEWV ALINPYKGVSTYNQKFKDRFTISVDKSKNTAYLQMNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQ GTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQDIRNYLNWYQQKPGKAPK LL1YYTSRLESGVPSRFSGSGSGTDYTLT1SSLQPEDFATYYCQQGNTLPWTFGQGTKVE1KSSGGGGSE VQL VESGGGL VQPGGSLRLSCSFSGFSLSTSGMGVGWIRQAPGKGLEWV AHI WWDDDKRYNPALKSR FTLSVDRSKNTLYLQMNSLRAEDTATYYCVQINYGNYRFDNWGHGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTISCRASESVDNYGISFLNWFQQKPGKAPKLLIYAASNQRSGVPSRFSGSGSGTDFTLTISSLQPEDFATYFCQQSKE VPWTFGQGTK VEIKRFSHR PMTE-His (Fc-LHHLLH) (SEQ ID N0:21)MDWTWILFLVAAATRVHSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEA PEVKFNWYVDGVEVHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTIS KAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFL YSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKGGGGSGGGGSGGGGSGGGGSGGGGS GGGG SDKTHTCPPCPAPEAAGGPS VFLFPPKPKDTLMI SRTPE VTC V V VD V SHEAPE VKFNW YVDG VE VHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTL PPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQ GNVFSCSVMHEALHNHYTQKSLSLSPGKGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCSFSGFSLS TSGMGVGWIRQAPGKGLEWVAHIWWDDDKRYNPALKSRFTLSVDRSKNTLYLQMNSLRAEDTATYY CVQINYGNYRFDNWGHGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTISCRASESV DNYGISFLNWFQQKPGKAPKLLIYAASNQRSGVPSRFSGSGSGTDFTLTISSLQPEDFATYFCQQSKEVP WTFGQGTKVEIKRGGGGSEVQLVESGGGLVQPGGSLRLSCAASGYSFTGYTMNWVRQAPGKGLEWV ALINPYKGVSTYNQKFKDRFTISVDKSKNTAYLQMNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQ GTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQDIRNYLNWYQQKPGKAPK LLIYYTSRLESGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCQQGNTLPWTFGQGTKVEIKSSGGGGSE VQLVESGGGLVQPGGSLRLSCSFSGFSLSTSGMGVGWIRQAPGKGLEWVAHIWWDDDKRYNPALKSR FTLSVDRSKNTLYLQMNSLRAEDTATYYCVQINYGNYRFDNWGHGTLVTVSSGGGGSGGGGSGGGG SDIQMTQSPSSLSASVGDRVTISCRASESVDNYGISFLNWFQQKPGKAPKLLIYAASNQRSGVPSRFSGS GSGTDFTLTI S SLQPEDFAT YFCQQ SKE VPWTFGQGTK VEIKRHHHHHHFSHR PMTE (HLHLHL-Fc) (SEQ ID NO: 22)ME) WT WILFL V AAATRVHSDIQMTQ SPS SL SAS VGDR VTI SCRASE S VDN YGISFLNWFQQKPGK APKL LIYAASNQRSGVPSRFSGSGSGTDFTLTISSLQPEDFATYFCQQSKEVPWTFGQGTKVEIKRGGGGSGGG GSGGGGSEVQLVESGGGLVQPGGSLRLSCSFSGFSLSTSGMGVGWIRQAPGKGLEWVAHIWWDDDKR YNPALKSRFTLSVDRSKNTLYLQMNSLRAEDTATYYCVQINYGNYRFDNWGHGTLVTVSSGGGGSEV QLVESGGGLVQPGGSLRLSCAASGYSFTGYTMNWVRQAPGKGLEWVALINPYKGVSTYNQKFKDRFT ISVDKSKNTAYLQMNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQGTLVTVSSGGGGSGGGGSGG GGSDIQMTQSPSSLSASVGDRVTITCRASQDIRNYLNWYQQKPGKAPKLLIYYTSRLESGVPSRFSGSGS GlDYrLTISSLQPEDFATYYCQQGNTLPWTFGQGrKVEIKSSGGGGSDlQMTQSPSSLSASVGDRVriSC RASESVDNYGISFLNWFQQKPGKAPKLLIYAASNQRSGVPSRFSGSGSGTDFTLTISSLQPEDFATYFCQ QSKE VPWTFGQGTK VEIKRGGGG SGGGGSGGGGSE VQL VE SGGGL VQPGGSLRL SC SF SGF SL STSGM GVGWIRQAPGKGLEWVAHIWWDDDKRYNPALKSRFTLSVDRSKNTLYLQMNSLRAEDTATYYCVQI NYGNYRFDNWGHGTLVTVSSGGGGSGGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPE VTCVVVDVSHEAPEVKFNWYVDGVEVHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCAV SNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYK TTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMIIEALIINIIYTQKSLSLSPGKGGGGSGGGGSGG GGSGGGGSGGGGSGGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEAPEVKFNWYVDGVEVHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISK AKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY SKLT VDK SRWQQGN VF SC S VMHE ALHNH YTQKSL SL SPGKFSHR PMTE-His (HLHLHL-Fc) (SEQ ID NO: 23)MDWT WILFL VAAATRVHSDIQMTQSPSSLSASVGDRVTISCRASESVDNYGISFLNWFQQKPGKAPKLLIYAASNQRSGVPSRFSGSGSGTDFTLTISSLQPEDFATYFCQQSKEVPWTFGQGTKVE1KRGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCSFSGFSLSTSGMGVGWTRQAPGKGLEWVAHIWWDDDKRYNPALKSRFTLSVDRSKNTLYLQMNSLRAEDTATYYCVQINYGNYRFDNWGHGTLVTVSSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGYSFTGYTMNWVRQAPGKGLEWVALINPYKGVSTYNQKFKDRFTISVDKSKNTAYLQMNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQDIRNYLNWYQQKPGKAPKLLIYYTSRLESGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCQQGNTLPWTFGQGTKVEIKSSGGGGSDIQMTQSPSSLSASVGDRVTISCRASESVDNYGISFLNWFQQKPGKAPKLLIYAASNQRSGVPSRFSGSGSGTDFTLTISSLQPEDFATYFCQ QSKE VP WTFGQGTKVEIKRGGGGSGGGGSGGGGSEVQL VESGGGL VQPGGSLRLSCSFSGFSLSTSGM GVGWIRQAPGKGLEWVAHIWWDDDKRYNPALKSRFTLSVDRSKNTLYLQMNSLRAEDTATYYCVQI N YGN YRFDN WGHGTL VT V S SGGGG SGGGG SDKTHTCPPCP APE A AGGPSVFLFPPKPKDTLMI SRTPE VTCVVVDVSHEAPEVKFNWYVDGVEVHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCAV SNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYK TTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKGGGG SGGGG SGG GGSGGGGSGGGG SGGGG SDKTHTCPPCP APEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEAP EVKFNWYVDGVEVHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISK AKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY SKLT VDK SRWQQGN VF SC SVMHEALHNH YTQKSL SL SPGKHHHHHHFSHR PMTE (LHHLHL-Fc) (SEQ ID NO:24)MD WT WILFL V AAATRVH SE VQL VESGGGL VQPGG SLRL SC SF SGF SL STSGMG VGWIRQ APGKGLEW VAHTWWDDDKRYNPALKSRFTLSVDRSKNTI,YT,QMNSLRAEDTATYYCVQINYGNYRFDNWCTHGTL VTVSSGGGGSGGGG SGGGG SDIQMTQSPSSLSASVGDRVTISCRASESVDNYGISFLNWFQQKPGKAPK LLIYAASNQRSGVPSRFSGSGSGTDFTLTISSLQPEDFATYFCQQSKEVPWTFGQGTKVEIKRGGGGSEV QL VESGGGL VQPGGSLRLSCAASGYSFTGYTMNWVRQAPGKGLEWVALINPYKGVSTYNQKFKDRFT ISVDKSKNTAYLQMNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQGTLVTVSSGGGGSGGGGSGG GGSDIQMTQSPSSLSASVGDRVTITCRASQDIRNYLNWYQQKPGKAPKLLIYYTSRLESGVPSRFSGSGS GTDYTLTISSLQPEDFATYYCQQGNTLPWTFGQGTKVEIKSSGGGGSDIQMTQSPSSLSASVGDRVTISC RASES VDNYGI SFLNWFQQKPGKAPKLLI YAASNQRSG VPSRF SG SGSGTDFTLTI S SLQPEDF AT YFCQ QSKEVPWTFGQGTKVEIKRGGGGSGGGGSGGGGSEVQLVESGGGL VQPGGSLRLSCSFSGFSLSTSGM GVGWIRQAPGKGLEWVAHIWWDDDKRYNPALKSRFTLSVDRSKNTLYLQMNSLRAEDTATYYCVQI NYGNYRFDNWGIIGTLVTVSSGGGGSGGGGSDKTIITCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPE VTCVVVDVSHEAPEVKFNWYVDGVEVHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCAV SNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYK TTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKGGGG SGGGG SGG GGSGGGGSGGGGSGGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEAP EVKFNW Y VDG VE VHNAKTKPCEEQ YGST YRC V S VLT VLHQDWLNGKE YKC A V SNK ALPAPIEKTI SKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY SKLT VDK SRWQQGN VF SC S VMHE ALHNH YTQK SL SL SPGKFSHR PMTE-His (LHHLHL-Fc) (SEQ ID NO:25)MD WT WILFL V AAATRVH SE VQL VE SGGGL VQPGG SLRL SC SF SGF SL STSGMG VGWIRQ APGKGLEW VAHIWWDDDKRYNPALKSRFTLSVDRSKNTLYLQMNSLRAEDTATYYCVQINYGNYRFDNWGHGTL VTVSSGGGGSGGGG SGGGG SDIQMTQSPSSLSASVGDRVTISCRASESVDNYGISFLNWFQQKPGKAPK LLIYAASNQRSGVPSRFSGSGSGTDFTLTISSLQPEDFATYFCQQSKEVPWTFGQGTKVEIKRGGGGSEV QL VESGGGL VQPGGSLRLSCAASGYSFTGYTMNWVRQAPGKGLEWVALINPYKGVSTYNQKFKDRFT ISVDKSKNTAYLQMNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQGTLVTVSSGGGGSGGGGSGG GGSDIQMTQSPSSLSASVGDRVTITCRASQDIRNYLNWYQQKPGKAPKLLIYYTSRLESGVPSRFSGSGS GTD YTLTI S SLQPEDF AT Y YCQQGNTLPWTFGQGTK VEIK SSGGGGSDIQMTQ SPS SL SAS VGDRVTI SC RASESVDNYGISFLNWFQQKPGKAPKLLIYAASNQRSG VPSRF SGSGSGTDFTLTISSLQPEDFATYFCQ QSKE VP WTFGQGTKVEIKRGGGGSGGGGSGGGGSEVQLVESGGGL VQPGGSLRLSCSFSGFSLSTSGM GVGWIRQAPGKGLEWVAHIWWDDDKRYNPALKSRFTLSVDRSKNTLYLQMNSLRAEDTATYYCVQI NYGNYRFDNWGHGTLVTVSSGGGGSGGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPE VTCVVVDVSHEAPEVKFNWYVDGVEVHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCAV SNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYK TTPP VLDSDGSFFL YSKLT VDKSRWQQGN VF SC SVMHEALHNH YTQKSL SL SPGKGGGG SGGGG SGG GGSGGGGSGGGGSGGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEAP EVKFNWYVDGVEVHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISK AKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY SKLT VDK SRWQQGN VF SC SVMHEALHNH YTQKSL SL SPGKHHHHHHFSHR PMTE (LHLHHL-Fc) (SEQ ID NO: 26)MD WT WILFL V AAATRVHSE VQL VE SGGGL VQPGG SLRL SC SF SGF SL STSGMG VGWIRQ APGKGLEW VAHIWWDDDKRYNPALKSRFTLSVDRSKNTLYLQMNSLRAEDTATYYCVQINYGNYRFDNWGHGTL VTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTISCRASESVDNYGISFLNWFQQKPGKAPK LLIYAASNQRSGVPSRFSGSGSGTDFTLTISSLQPEDFATYFCQQSKEVPWTFGQGTKVEIKRGGGGSDI QMTQSPSSLSASVGDRVTITCRASQDIRNYLNWYQQKPGKAPKLLIYYTSRLESGVPSRFSGSGSGTDY TLTISSLQPEDFATYYCQQGNTLPWTFGQGTKVEIKSSGGGGSGGGGSGGGGSEVQL VESGGGL VQPG GSLRL SC AASGYSFTG YTMNWVRQ APGKGLEW VALINPYKGV ST YNQKFKDRFTI S VDK SKNT A YLQ MNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQGTLVTVSSGGGGSDIQMTQSPSSLSASVGDRVTIS CRASESVDNYGISFLNWFQQKPGKAPKLLIYAASNQRSGVPSRFSGSGSGTDFTLTISSLQPEDFATYFC QQSKE VP WTFGQGTK VEIKRGGGG SGGGGSGGGGSE VQL VESGGGL VQPGG SLRL SC SF SGF SL ST SG MGVGWIRQAPGKGLEWVAHIWWDDDKRYNPALKSRFTLSVDRSKNTLYLQMNSLRAEDTATYYCV QINYGNYRFDNWGHGTLVTVSSGGGGSGGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTP EVTCVVVDVSHEAPEVKFNWYVDGVEVHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCA VSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNY KTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKGGGGSGGGGSG GGGSGGGGSGGGGSGGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHE APEVKFNWYVDGVEVHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTI SKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFF L Y SKLT VDK SR WQQGNVF SC S VMHEALHNH YTQKSL SL SPGKFSHR PMTE-His (LHLHHL-Fc) (SEQ ID NO:27)MDWT WILFL VAAATRVH SE VQL VESGGGL VQPGG SLRL SC SF SGF SL STSGMG VGWIRQ APGKGLEW VAHIWWDDDKRYNPALKSRFTLSVDRSKNTLYLQMNSLRAEDTATYYCVQINYGNYRFDNWGHGTL VTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTISCRASESVDNYGISFLNWFQQKPGKAPK LLIYAASNQRSGVPSRFSGSGSGTDFTLTISSLQPEDFATYFCQQSKEVPWTFGQGTKVEIKRGGGGSDI QMTQSPSSLSASVGDRVTITCRASQDIRNYLNWYQQKPGKAPKLLIYYTSRLESGVPSRFSGSGSGTDY TLTISSLQPEDFATYYCQQGNTLPWTFGQGTKVEIKSSGGGGSGGGGSGGGGSEVQL VESGGGL VQPG GSLRL SC AASGYSFTGYTMNWVRQAPGKGLEWVALINPYKGVSTYNQKFKDRFTISVDKSKNTAYLQ MNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQGTLVTVSSGGGGSDIQMTQSPSSLSASVGDRVTIS CRASES VDN YGI SFLN WFQQKPGKAPKLL1 Y AASN QRSG VPSRFSG SG SGTDFTLTI SSLQPEDFAT YFC QQSKE VPWTFGQGTKVEIKRGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCSFSGFSLSTSG MGVGWIRQAPGKGLEWVAHIWWDDDKRYNPALKSRFTLSVDRSKNTLYLQMNSLRAEDTATYYCV QINYGNYRFDNWGHGTLVTVSSGGGGSGGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTP EVTCVVVDVSHEAPEVKFNWYVDGVEVHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCA VSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNY KTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKGGGGSGGGGSG GGGSGGGGSGGGGSGGGGSDKTIITCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSIIE APEVKFNWYVDGVEVHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTI SKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKHHHHHHFSHR PMTE (LHLHLH-Fc) (SEQ ID NO:28)MDWT WILFL V AAATRVHSE VQL VE SGGGL VQPGG SLRL SC SF SGF SL STSGMG VGWIRQ APGKGLEW VAHIWWDDDKRYNPALKSRFTLSVDRSKNTLYLQMNSLRAEDTATYYCVQINYGNYRFDNWGHGTL VTVSSGGGGSGGGGSGGGGSD1QMTQSPSSLSASVGDRVT1SCRASESVDNYGISFLNWFQQKPGKAPK LLI YAASNQRSG VPSRF SG SG SGTDFTLTI SSLQPEDFAT YFCQQ SKEVPWTFGQGTK VEIKRGGGG SDI QMTQSPSSLSASVGDRVTITCRASQDIRNYLNWYQQKPGKAPKLLIYYTSRLESGVPSRFSGSGSGTDY TLTISSLQPEDFATYYCQQGNTLPWTFGQGTKVEIKSSGGGGSGGGGSGGGGSEVQL VESGGGL VQPG GSLRL SC AASG Y SFTG YTMNWVRQ APGKGLEW VALINPYKGV ST YNQKFKDRFTI S VDK SKNT A YLQ MNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQGTLVTVSSGGGGSEVQLVESGGGLVQPGGSLRLS CSFSGFSLSTSGMGVGWIRQAPGKGLEWVAHIWWDDDKRYNPALKSRFTLSVDRSKNTLYLQMNSLR AEDTATYYCVQINYGNYRFDNWGHGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVT ISCRASESVDNYGISFLNWFQQKPGKAPKLLIYAASNQRSGVPSRFSGSGSGTDFTLTISSLQPEDFATYF CQQSKEVPWTFGQGTKVEIKRGGGGSGGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEAPEVKFNWYVDGVE VHN AKTKPCEEQ YGSTYRCVSVLTVLHQDWLNGKEYKCAV SNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYK TTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKGGGGSGGGGSGG GGSGGGGSGGGGSGGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEAP EVKFNWYVDGVE VHN AKTKPCEEQ YGSTYRCVSVLTVLHQDWLNGKEYKCAVSNK ALP APIEKTISK AKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY SKLT VDK SRWQQGN VF SC SVMHEALHNH YTQKSL SL SPGKFSHR PMTE-His (LHLHLH-Fc) (SEQ ID NO:29)MD WT WILFL V AAATRVH SE VQL VESGGGL VQPGG SLRL SC SF SGF SL STSGMG VGWIRQ APGKGLEW VAHIWWDDDKRYNPALKSRFTLSVDRSKNTLYLQMNSLRAEDTATYYCVQINYGNYRFDNWGHGTL VTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTISCRASESVDNYGISFLNWFQQKPGKAPK LLIYAASNQRSGVPSRFSGSGSGTDFTLTISSLQPEDFATYFCQQSKEVPWTFGQGTKVEIKRGGGGSDI QMTQSPSSLSASVGDRVTITCRASQDIRNYLNWYQQKPGKAPKLLIYYTSRLESGVPSRFSGSGSGTDY TLTISSLQPEDFATYYCQQGNTLPWTFGQGTKVEIKSSGGGGSGGGGSGGGGSEVQL VESGGGL VQPG GSLRLSCAASGYSFTGYTMNWVRQAPGKGLEWVALINPYKGVSTYNQKFKDRFTISVDKSKNTAYLQ MNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQGTLVTVSSGGGGSEVQLVESGGGLVQPGGSLRLS CSFSGFSLSTSGMGVGWIRQAPGKGLEWVAHIWWDDDKRYNPALKSRFTLSVDRSKNTLYLQMNSLR AEDTATYYCVQINYGNYRFDNWGHGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVT ISCRASESVDNYGISFLNWFQQKPGKAPKLLIYAASNQRSGVPSRFSGSGSGTDFTLTISSLQPEDFATYF CQQSKEVPWTFGQGTKVEIKRGGGGSGGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPE VTCVVVDVSHEAPEVKFNWYVDGVEVHN AKTKPCEEQ YGSTYRCVSVLTVLHQDWLNGKEYKCAV SNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYK TTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKGGGGSGGGGSGG GGSGGGGSGGGGSGGGGSDKTIITCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSIIEAP EVKFNWYVDGVE VHN AKTKPCEEQ YGST YRC V S VLT VLHQDWLNGKE YKC A V SNK ALPAPIEKTI SK AKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY SKLT VDK SRWQQGN VF SC S VMHE ALHNH YTQK SL SL SPGKHHHHHHFSHR PMTE (HLLHHL-Fc) SEQ ID NO: 30)MDWT WILFL V AAATRVH SDIQMTQ SPS SL SAS VGDR VTI SCRASE S VDN YGISFLNWFQQKPGKAPKL LIYAASNQRSGVPSRFSGSGSGTDFTLTISSLQPEDFATYFCQQSKEVPWTFGQGTKVEIKRGGGGSGGG GSGGGGSEVQL VESGGGL VQPGGSLRLSCSFSGFSLSTSGMGVGWIRQAPGKGLEWVAHIWWDDDKR YNPALKSRFTLSVDRSKNTLYLQMNSLRAEDTATYYCVQINYGNYRFDNWGHGTLVTVSSGGGGSDI QMTQSPSSLSASVGDRVTITCRASQDIRNYLNWYQQKPGKAPKLLIYYTSRLESGVPSRFSGSGSGTDY TLTISSLQPEDFATYYCQQGNTLPWTFGQGTKVEIKSSGGGGSGGGGSGGGGSEVQL VESGGGL VQPG GSLRL SC AASG Y SFTG YTMNWVRQ APGKGLEW VALINPYKGV ST YNQKFKDRFTI S VDK SKNT A YLQ MNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQGTLVTVSSGGGGSDIQMTQSPSSLSASVGDRVTIS CRASE S VDN YGI SFLNWFQQKPGK APKLLI YAASNQRSG VPSRFSG SG SGTDFTLTI SSLQPEDFAT YFC QQSKEVPWTFGQGTKVEIKRGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCSFSGFSLSTSG MGVGWIRQAPGKGLEWVAHIWWDDDKRYNPALKSRFTLSVDRSKNTLYLQMNSLRAEDTATYYCV QINYGNYRFDNWGHGTLVTVSSGGGGSGGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTP EVTCVVVDVSHEAPEVKFNWYVDGVE VHN AKTKPCEEQ YGSTYRCVSVLTVLHQDWLNGKEYKCA VSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNY KTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKGGGGSGGGGSG GGGSGGGGSGGGGSGGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHE APEVKFNWYVDGVE VHN AKTKPCEEQ YGSTYRCVSVLTVLHQDWLNGKEYKCAVSNK ALPAPIEKTI SKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFF L YSKLT VDK SRWQQGNVF SC SVMHEALHNH YTQKSL SL SPGKFSHR PMTE-His (HLLHHL-Fc) SEQ ID NO:31)MDWTWILFLVAAATRVHSDIQMTQSPSSLSASVGDRVTISCRASESVDNYGISFLNWFQQKPGKAPKLLIYAASNQRSGVPSRFSGSGSGTDFTLTISSLQPEDFATYFCQQSKEVPWTFGQGTKVEIKRGGGGSGGGGSGGGGSEVQL VESGGGL VQPGGSLRLSCSFSGFSLSTSGMGVGWIRQAPGKGLEWVAHIWWDDDKRYNPALKSRFTLSVDRSKNTLYLQMNSLRAEDTATYYCVQINYGNYRFDNWGHGTLVTVSSGGGGSDI QMTQSPSSLSASVGDRVTITCRASQDIRNYLNWYQQKPGKAPKLLIYYTSRLESGVPSRFSGSGSGTDY TLTISSLQPEDFATYYCQQGNTLPWTFGQGTKVEIKSSGGGGSGGGGSGGGGSEVQL VESGGGL VQPG GSLRLSCAASGYSFTGYTMNWVRQAPGKGLEWV ALINP YKGVSTYNQKFKDRFTISVDKSKNTAYLQ MNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQGTLVTVSSGGGGSDIQMTQSPSSLSASVGDRVTIS CRASESVDNYGISFLNWFQQKPGKAPKLLIYAASNQRSGVPSRFSGSGSGTDFTLTISSLQPEDFATYFC QQSKE VP WTFGQGTK VEIKRGGGG SGGGGSGGGGSE VQL VESGGGL VQPGGSLRL SC SF SGF SL ST SG MGVGWIRQAPGKGLEWVAHIWWDDDKRYNPALKSRFTLSVDRSKNTLYLQMNSLRAEDTATYYCV QINYGNYRFDNWGHGTLVTVSSGGGGSGGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTP EVTCVVVDVSHEAPEVKFNWYVDGVEVHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCA VSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNY KTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKGGGGSGGGGSG GGG SGGGGSGGGG SGGGG SDKTHTCPPCP APE AAGGPS VFLFPPKPKDTLMI SRTPE VTC V V VD V SHE APEVKFNWYVDGVEVHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTI SKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFF L YSKLT VDK SR WQQGN VF SC S VMHEALHNH YTQKSL SL SPGKHHHHHHFSHR PMTE (HLLHLH-Fc) (SEQ ID NO: 32)MD WT WILFL V AAATRVH SDIQMTQ SPS SL SAS VGDR VTI SCRASES VDN YGISFLNWFQQKPGK APKL LIYAASNQRSGVPSRFSGSGSGTDFTLTISSLQPEDFATYFCQQSKEVPWTFGQGTKVEIKRGGGGSGGG GSGGGGSEVQL VESGGGL VQPGGSLRLSCSFSGFSLSTSGMGVGWIRQAPGKGLEWVAHIWWDDDKR YNPALKSRFTLSVDRSKNTLYLQMNSLRAEDTATYYCVQINYGNYRFDNWGHGTLVTVSSGGGGSDI QMTQSPSSLSASVGDRVTITCRASQDIRNYLNWYQQKPGKAPKLLIYYTSRLESGVPSRFSGSGSGTDY TLTISSLQPEDFATYYCQQGNTLPWTFGQGTKVEIKSSGGGGSGGGGSGGGGSEVQL VESGGGL VQPG G SLRL SC AASG YSFTG YTMNWVRQAPG KGLEWV ALINP YKG VST YNQKFKDRFTI S VDK SKNT A YLQ MNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQGTLVTVSSGGGGSEVQLVESGGGLVQPGGSLRLS CSFSGFSLSTSGMGVGWIRQAPGKGLEWVAHIWWDDDKRYNPALKSRFTLSVDRSKNTLYLQMNSLR AEDTATYYCVQINYGNYRFDNWGHGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVT ISCRASESVDNYGISFLNWFQQKPGKAPKLLIYAASNQRSGVPSRFSGSGSGTDFTLTISSLQPEDFATYF CQQ SKE VP WTFGQGTK VEIKRGGGG SGGGG SDKTHTCPPCPAPEAAGGPS VFLFPPKPKDTLMI SRTPE VTCVVVDVSHEAPEVKFNWYVDGVEVHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCAV SNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYK TTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKGGGG SGGGG SGG GGSGGGGSGGGGSGGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEAP EVKFNWYVDGVEVHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISK AKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY SKLT VDK SRWQQGN VF SC S VMHEALHNH YTQK SL SL SPGKFSHR PMTE-His (HLLHLH-Fc) (SEQ ID NO: 33)MDWT WILFL VAAATRVIISDIQMTQSPSSLSASVGDRVTISCRASESVDNYGISFLNWFQQKPGKAPKL LIYAASNQRSGVPSRFSGSGSGTDFTLTISSLQPEDFATYFCQQSKEVPWTFGQGTKVEIKRGGGGSGGG GSGGGGSEVQL VESGGGL VQPGGSLRLSCSFSGFSLSTSGMGVGWIRQAPGKGLEWVAHIWWDDDKR YNPALKSRFTLSVDRSKNTLYLQMNSLRAEDTATYYCVQINYGNYRFDNWGHGTLVTVSSGGGGSDI QMTQSPSSLSASVGDRVTITCRASQDIRNYLNWYQQKPGKAPKLLIYYTSRLESGVPSRFSGSGSGTDY TLTISSLQPEDFATYYCQQGNTLPWTFGQGTKVEIKSSGGGGSGGGGSGGGGSEVQL VESGGGL VQPG GSLRL SC AASG YSFTG YTMNWVRQAPGKGLEW V ALINP YKG V ST YNQKFKDRFTI S VDK SKNT A YLQ MNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQGTLVTVSSGGGGSEVQL VESGGGL VQPGGSLRLS CSFSGFSLSTSGMGVGWIRQAPGKGLEWVAHIWWDDDKRYNPALKSRFTLSVDRSKNTLYLQMNSLR AEDTATYYCVQINYGNYRFDNWGHGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVT ISCRASESVDNYGISFLNWFQQKPGKAPKLLIYAASNQRSGVPSRFSGSGSGTDFTLTISSLQPEDFATYF CQQSKEVPWTFGQGTKVEIKRGGGGSGGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPE VTCVVVDVSHEAPEVKFNWYVDGVEVHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCAV SNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYK TTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKGGGG SGGGG SGG GGSGGGGSGGGGSGGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEAP EVKFNWYVDGVEVHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY SKLT VDK SRWQQGN VF SC SVMHEALHNH YTQKSL SL SPGKHHHHHHFSHR PMTE (HLHLLH-Fc) (SEQ ID NO:34)MDWTWILFLVAAATRVHSDIQMTQSPSSLSASVGDRVTISCRASESVDNYGISFLNWFQQKPGKAPKL LIYAASNQRSGVPSRFSGSGSGTDFTLTISSLQPEDFATYFCQQSKEVPWTFGQGTKVEIKRGGGGSGGG GSGGGGSEVQLVESGGGLVQPGGSLRLSCSFSGFSLSTSGMGVGWIRQAPGKGLEWVAHIWWDDDKR YNPALKSRFTLSVDRSKNTLYLQMNSLRAEDTATYYCVQINYGNYRFDNWGHGTLVTVSSGGGGSEV QLVESGGGLVQPGGSLRLSCAASGYSFTGYTMNWVRQAPGKGLEWVALINPYKGVSTYNQKFKDRFT ISVDKSKNTAYLQMNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQGTLVTVSSGGGGSGGGGSGG GGSDIQMTQSPSSLSASVGDRVTITCRASQDIRNYLNWYQQKPGKAPKLLIYYTSRLESGVPSRFSGSGS GTDYTLTISSLQPEDFATYYCQQGNTLPWTFGQGTKVEIKSSGGGGSEVQLVESGGGLVQPGGSLRLSC SFSGFSLSTSGMGVGWIRQAPGKGLEWVAHIWWDDDKRYNPALKSRFTLSVDRSKNTLYLQMNSLRA EDTATYYCVQINYGNYRFDNWGHGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTIS CRASES VDN YGI SFLNWFQQKPGK APKLLI YAASNQRSG VPSRFSG SG SGTDFTLTI SSLQPEDFAT YFC QQSKEVPWTFGQGTKVEIKRGGGGSGGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEV TCVVVDVSHEAPEVKFNWYVDGVEVHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCAVS NKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT TPP VLD SDGSFFL YSKLT VDK SRWQQGNVF SC SVMHEALHNH YTQKSL SL SPGKGGGG SGGGG SGGGGSGGGGSGGGGSGGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEAPE VKFNWYVDGVEVHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKA KGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYS KLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKFSHR PMTE-His (HLHLLH-Fc) (SEQ ID NO:35)MD WT WILFL V AAATRVHSDIQMTQ SPS SL SAS VGDR VTI SCRASE S VDN YGI SFLNWFQQKPGK APKL LIYAASNQRSGVPSRFSGSGSGTDFTLTISSLQPEDFATYFCQQSKEVPWTFGQGTKVEIKRGGGGSGGG GSGGGGSEVQLVESGGGLVQPGGSLRLSCSFSGFSLSTSGMGVGWIRQAPGKGLEWVAHIWWDDDKR YNPALKSRFTLSVDRSKNTLYLQMNSLRAEDTATYYCVQINYGNYRFDNWGHGTLVTVSSGGGGSEV QLVESGGGLVQPGGSLRLSCAASGYSFTGYTMNWVRQAPGKGLEWVALINPYKGVSTYNQKFKDRFT ISVDKSKNTAYLQMNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQGTLVTVSSGGGGSGGGGSGG GGSDIQMTQSPSSLSASVGDRVTITCRASQDIRNYLNWYQQKPGKAPKLLIYYTSRLESGVPSRFSGSGS GTDYTLTISSLQPEDFATYYCQQGNTLPWTFGQGTKVEIKSSGGGGSEVQLVESGGGLVQPGGSLRLSC SFSGFSLSTSGMGVGWIRQAPGKGLEWVAHIWWDDDKRYNPALKSRFTLSVDRSKNTLYLQMNSLRA EDTATYYCVQINYGNYRFDNWGHGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTIS CRASESVDNYGISFLNWFQQKPGKAPKLLIYAASNQRSGVPSRFSGSGSGTDFTLTISSLQPEDFATYFC QQSKEVPWTFGQGTKVEIKRGGGGSGGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEV TCVVVDVSHEAPEVKFNWYVDGVEVHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCAVS NKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT TPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMIIEALIINIIYTQKSLSLSPGKGGGGSGGGGSGGG GSGGGGSGGGGSGGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEAPE VKFNWYVDGVEVHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKA KGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYS KLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKHHHHHHFSHR PMTE (LHHLLH-Fc) (SEQ ID NO: 36)MD WT WILFL VAAATRVHSEVQLVESGGGLVQPGG SLRL SC SF SGF SL STSGMG VGWIRQ APGKGLEW VAH1WWDDDKRYNPALKSRFTLSVDRSKNTLYLQMNSLRAEDTATYYCVQ1NYGNYRFDNWGHGTL VTVSSGGGGSGGGG SGGGG SDIQMTQSPSSLSASVGDRVTISCRASESVDNYGISFLNWFQQKPGKAPK LLIYAASNQRSGVPSRFSGSGSGTDFTLTISSLQPEDFATYFCQQSKEVPWTFGQGTKVEIKRGGGGSEV QLVESGGGLVQPGGSLRLSCAASGYSFTGYTMNWVRQAPGKGLEWVALINPYKGVSTYNQKFKDRFT ISVDKSKNTAYLQMNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQGTLVTVSSGGGGSGGGGSGG GGSDIQMTQSPSSLSASVGDRVTITCRASQDIRNYLNWYQQKPGKAPKLLIYYTSRLESGVPSRFSGSGS GTDYTLTISSLQPEDFATYYCQQGNTLPWTFGQGTKVEIKSSGGGGSEVQLVESGGGLVQPGGSLRLSCSF SGF SL ST SGMG VGWIRQ APGKGLEWV AHI WWDDDKR YNP ALKSRFTL S VDRSKNTL YLQMNSLRA EDTATYYCVQINYGNYRFDNWGHGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTIS CRASES VDN YGI SFLNWFQQKPGKAPKLLI Y AASNQRSG VPSRFSG SG SGTDFTLTI SSLQPEDFAT YFC QQSKEVPWTFGQGTKVEIKRGGGGSGGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEV TCVVVDVSHEAPEVKFNWYVDGVEVHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCAVS NKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT TPP VLD SDGSFFL Y SKLT VDK SRWQQGNVF SC S VMHEALHNH YTQKSL SL SPGKGGGG SGGGG SGGG GSGGGGSGGGGSGGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEAPE VKFNWYVDGVEVHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKA KGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYS KLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKFSHR PMTE-His (LHHLLH-Fc) (SEQ ID NO:37)MD WT WILFL V AAATRVH SE VQL VESGGGL VQPGG SLRL SC SF SGF SL STSGMG VGWIRQ APGKGLEW VAHTWWDDDKRYNPALKSRFTLSVDRSKNTI,YT,QMNST,RAEDTATYYCVQINYGNYRFDNWGHGTL VTVSSGGGGSGGGG SGGGG SDIQMTQSPSSLSASVGDRVTISCRASESVDNYGISFLNWFQQKPGKAPK LLIYAASNQRSGVPSRFSGSGSGTDFTLTISSLQPEDFATYFCQQSKEVPWTFGQGTKVEIKRGGGGSEV QL VESGGGL VQPGGSLRLSCAASGYSFTGYTMNWVRQAPGKGLEWVALINPYKGVSTYNQKFKDRFT ISVDKSKNTAYLQMNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQGTLVTVSSGGGGSGGGGSGG GGSDIQMTQSPSSLSASVGDRVTITCRASQDIRNYLNWYQQKPGKAPKLLIYYTSRLESGVPSRFSGSGS GTDYTLTISSLQPEDFATYYCQQGNTLPWTFGQGTKVEIKSSGGGGSEVQL VESGGGL VQPGGSLRLSC SF SGF SL ST SGMG VGWIRQ APGKGLEWV AHI WWDDDKR YNP ALKSRFTLSVDRSKNTL YLQMNSLRA EDTATYYCVQINYGNYRFDNWGHGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTIS CRASE S VDN YGI SFLNWFQQKPGK APKLLI YAASNQRSG VPSRFSG SG SGTDFTLTI SSLQPEDFAT YFC QQSKEVPWTFGQGTKVEIKRGGGGSGGGGSDKTIITCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEV TCVVVDVSHEAPEVKFNWYVDGVEVHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCAVS NKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT TPP VLD SDGSFFL YSKLT VDK SRWQQGNVF SC S VMHEALHNH YTQKSL SL SPGKGGGG SGGGG SGGG GSGGGGSGGGGSGGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEAPE VKFNWYVDGVEVHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKA KGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYS KLT VDK SRWQQGNVF SC S VMHEALHNH YTQKSL SLSPGKHHHHHHFSHR PBTE Plasmid (SEQ ID NO:38)GCTGCTTCGCGATGTACGGGCCAGATATACGCGTTGACATTGATTATTGACTAGTTATTAATAGTAATCAATTACGGGGTCATTAGTTCATAGCCCATATATGGAGTTCCGCGTTACATAACTTACGGTAAATGGCCCGCCTGGCTGACCGCCCAACGACCCCCGCCCATTGACGTCAATAATGACGTATGTTCCCATAGTAACGCCAATAGGGACTTTCCATTGACGTCAATGGGTGGAGTATTTACGGTAAACTGCCCACTTGGCAGTACATCAAGTGTATCATATGCCAAGTACGCCCCCTATTGACGTCAATGACGGTAAATGGCCCGCCTGGCATTATGCCCAGTACATGACCTTATGGGACTTTCCTACTTGGCAGTACATCTACGTATTAGTCATCGCTATTACCATGGTGATGCGGTTTTGGCAGTACATCAATGGGCGTGGATAGCGGTTTGACTCACGGGGATTTCCAAGTCTCCACCCCATTGACGTCAATGGGAGTTTGTTTTGGCACCAAAATCAACGGGACTTTCCAAAATGTCGTAACAACTCCGCCCCATTGACGCAAATGGGCGGTAGGCGTGTACGGTGGGAGGTCTATATAAGCAGAGCTCTCTGGCTAACTAGAGAACCCACTGCTTACTGGCTTATCGAAATTAATACGACTCACTATAGGGAGACCCAAGCTGGCTAGCGTTTAAACTTAAGCTTGGTACCGAGCTCGGATCCACTAGTCCAGTGTGGTGGAATTCGCCGCCACCATGGACTGGACCTGGATCCTGTTCCTGGTGGCTGCCGCCACCAGGGTGCACAGCGACAAGACCCACACATGCCCTCCATGTCCAGCACCAGAGGCAGCCGGCGGACCTAGCGTGTTCCTGTTTCCCCCTAAGCCAAAGGATACCCTGATGATCTCTCGGACCCCTGAGGTGACATGCGTGGTGGTGGACGTGAGCCACGAGGCACCAGAGGTGAAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCACAATGCCAAGACAAAGCCTTGCGAGGAGCAGTACGGCTCCACCTATCGCTGCGTGAGCGTGCTGACAGTGCTGCACCAGGACTGGCTGAACGGCAAGGAGTATAAGTGCGCCGTGTCCAATAAGGCCCTGCCTGCCCCAATCGAGAAGACCATCTCTAAGGCCAAGGGCCAGCCTAGGGAGCCACAGGTGTACACACTGCCACCCTCCAGAGAGGAGATGACCAAGAACCAGGTGTCTCTGACATGTCTGGTGAAGGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGTCCAATGGCCAGCCTGAGAACAATTACAAGACCACACCTCCAGTGCTGGACTCTGATGGCAGCTTCTTTCTGTATTCTAAGCTGACCGTGGATAAGAGCCGGTGGCAGCAGGGCAACGTGTTTAGCTGCTCCGTGATGCACGAGGCCCTGCACAATCACTACACACAGAAGTCTCTGAGCCTGTCCCCAGGCAAGGGCGGCGGCGGCAGCGGCGGCGGCGGCAGCGGCGGCGGCGGCAGCGGCGGCGGCGGCAGCGGCGGCGGCGGCAGCGGCGGCGGCGGCTCGGATAAAACCCACACATGCCCTCCCTGTCCAGCACCTGAGGCAGCCGGCGGACCAAGCGTGTTCCTGTTTCCACCCAAGCCTAAAGACACCCTGATGATCAGCAGGACCCCCGAAGTCACCTGCGTGGTCGTGGACGTGTCCCACGAGGCACCTGAAGTCAAGTTCAACTGGTACGTGGACGGAGTCGAAGTCCATAACGCCAAGACAAAGCCCTGTGAAGAGCAGTACGGCAGCACCTATAGATGCGTGAGCGTGCTGACAGTGCTGCATCAGGATTGGCTGAATGGCAAGGAATACAAGTGCGCCGTGTCTAATAAGGCCCTGCCAGCCCCCATCGAGAAGACCATCTCCAAGGCAAAGGGACAGCCAAGGGAGCCTCAGGTGTACACACTGCCTCCAAGCCGCGAAGAAATGACTAAAAACCAGGTGTCCCTGACCTGCCTGGTCAAAGGCTTCTATCCATCTGATATTGCCGTGGAGTGGGAGAGCAATGGCCAGCCCGAAAATAATTACAAGACCACACCCCCTGTGCTGGACTCCGATGGCTCTTTCTTTCTGTATTCCAAACTGACTGTGGATAAGTCTCGCTGGCAGCAGGGAAACGTGTTTTCTTGTAGCGTGATGCATGAGGCCCTGCATAACCACTACACACAGAAGTCCCTGTCTCTGAGCCCTGGCAAGGGCGGCGGCGGCAGCGGCGGCGGCGGCTCTGACATCCAGATGACCCAGTCCCCAAGCTCCCTGAGCGCCTCCGTGGGCGATAGGGTGACAATCTCTTGCAGAGCCTCTGAGAGCGTGGACAACTACGGCATCAGCTTCCTGAATTGGTTTCAGCAGAAGCCCGGCAAGGCCCCTAAGCTGCTGATCTATGCAGCATCCAACCAGCGGTCTGGAGTGCCTAGCCGCTTCTCCGGATCTGGAAGCGGAACCGACTTCACCCTGACAATCTCTAGCCTGCAGCCAGAGGACTTCGCCACATACTTTTGCCAGCAGAGCAAGGAGGTGCCATGGACCTTCGGCCAGGGAACAAAGGTGGAGATCAAGAGGGGCGGCGGCGGCAGCGGCGGCGGCGGCAGCGGCGGCGGCGGCTCTGAGGTGCAGCTGGTGGAGAGCGGCGGCGGCCTGGTGCAGCCTGGCGGCTCCCTGAGGCTGTCCTGTTCTTTCAGCGGCTTTTCCCTGTCTACCAGCGGAATGGGAGTGGGATGGATCAGGCAGGCACCTGGCAAGGGACTGGAGTGGGTGGCCCACATCTGGTGGGACGATGACAAGAGATACAACCCAGCCCTGAAGTCCAGGTTCACCCTGTCCGTGGATAGATCTAAGAACACACTGTATCTGCAGATGAACAGCCTGAGGGCAGAGGACACCGCAACATACTATTGCGTGCAGATCAACTACGGCAATTATCGCTTTGATAATTGGGGCCACGGCACCCTGGTGACAGTGTCCAGCGGCGGCGGCGGCTCGGAGGTGCAGCTGGTGGAGAGCGGCGGCGGCCTGGTGCAGCCAGGCGGCAGCCTGAGGCTGTCCTGTGCAGCAAGCGGATACTCCTTCACCGGCTATACAATGAATTGGGTGAGGCAGGCCCCTGGCAAGGGCCTGGAATGGGTGGCCCTGATCAACCCCTACAAGGGCGTGTCCACCTATAATCAGAAGTTCAAGGACCGCTTTACCATCTCTGTGGATAAGAGCAAGAACACAGCCTACCTGCAGATGAATAGCCTGAGAGCCGAGGACACAGCCGTGTACTATTGCGCACGGAGCGGATACTATGGCGACTCCGATTGGTATTTTGACGTGTGGGGCCAGGGCACCCTGGTGACAGTGAGCAGCGGCGGCGGCGGCAGCGGCGGCGGCGGCAGCGGCGGCGGCGGCTCTGACATCCAGATGACCCAGTCCCCATCTAGCCTGTCTGCCAGCGTCGGCGACAGGGTGACCATCACATGTCGCGCCTCTCAGGATATCAGGAACTACCTGAATTGGTATCAGCAGAAGCCCGGCAAGGCCCCTAAGCTGCTGATCTACTATACATCCAGGCTGGAGTCTGGAGTGCCAAGCAGGTTCTCCGGATCTGGAAGCGGAACCGACTACACCCTGACAATCTCCTCTCTGCAGCCCGAGGATTTCGCCACATACTATTGTCAGCAGGGCAATACCCTGCCTTGGACATTTGGCCAGGGCACCAAGGTGGAGATCAAGAGCTCCCACCACCACCACCACCACTGATAAGCGGCCGCTCGAGTCTAGAGGGCCCGTTTAAACCCGCTGATCAGCCTCGACTGTGCCTTCTAGTTGCCAGCCATCTGTTGTTTGCCCCTCCCCCGTGCCTTCCTTGACCCTGGAAGGTGCCACTCCCACTGTCCTTTCCTAATAAAATGAGGAAATTGCATCGCATTGTCTGAGTAGGTGTCATTCTATTCTGGGGGGTGGGGTGGGGCAGGACAGCAAGGGGGAGGATTGGGAAGACAATAGCAGGCATGCTGGGGATGCGGTGGGCTCTATGGCTTCTACTGGGCGGTTTTATGGACAGCAAGCGAACCGGAATTGCCAGCTGGGGCGCCCTCTGGTAAGGTTGGGAAGCCCTGCAAAGTAAACTGGATGGCTTTCTTGCCGCCAAGGATCTGATGGCGCAGGGGATCAAGCTCTGATCAAGAGACAGGATGAGGATCGTTTCGCATGATTGAACAAGATGGATTGCACGCAGGTTCTCCGGCCGCTTGGGTGGAGAGGCTAn'CGGCTATGACTGGGCACAACAGACAATCGGCTGCTCTGATGCCGCCGTGTrCCGGCTGTCAGCGCAGGGGCGCCCGGTTCTTTTTGTCAAGACCGACCTGTCCGGTGCCCTGAATGAACTGCAAGACGAGGCAGCGCGGCTATCGTGGCTGGCCACGACGGGCGTTCCTTGCGCAGCTGTGCTCGACGTTGTCACTGAAGCGGGAAGGGACTGGCTGCTATTGGGCGAAGTGCCGGGGCAGGATCTCCTGTCATCTCACCTTGCTCCTGCCGAGAAAGTATCCATCATGGCTGATGCAATGCGGCGGCTGCATACGCTTGATCCGGCTACCTGCCCATTCGACCACCAAGCGAAACATCGCATCGAGCGAGCACGTACTCGGATGGAAGCCGGTCTTGTCGATCAGGATGATCTGGACGAAGAGCATCAGGGGCTCGCGCCAGCCGAACTGTTCGCCAGGCTCAAGGCGAGCATGCCCGACGGCGAGGATCTCGTCGTGACCCATGGCGATGCCTGCTTGCCGAATATCATGGTGGAAAATGGCCGCTTTTCTGGATTCATCGACTGTGGCCGGCTGGGTGTGGCGGACCGCTATCAGGACATAGCGTTGGCTACCCGTGATATTGCTGAAGAGCTTGGCGGCGAATGGGCTGACCGCTTCCTCGTGCTTTACGGTATCGCCGCTCCCGATTCGCAGCGCATCGCCTTCTATCGCCTTCTTGACGAGTTCTTCTGAATTATTAACGCTTACAATTTCCTGATGCGGTATTTTCTCCTTACGCATCTGTGCGGTATTTCACACCGCATCAGGTGGCACTTTTCGGGGAAATGTGCGCGGAACCCCTATTTGTTTATTTTTCTAAATACATTCAAATATGTATCCGCTCATGAGACAATAACCCTGATAAATGCTTCAATAATAGCACGTGCTAAAACTTCATTTTTAATTTAAAAGGATCTAGGTGAAGATCCTTTTTGATAATCTCATGACCAAAATCCCTTAACGTGAGTTTTCGTTCCACTGAGCGTCAGACCCCGTAGAAAAGATCAAAGGATCTTCTTGAGATCCTTTTTTTCTGCGCGTAATCTGCTGCTTGCAAACAAAAAAACCACCGCTACCAGCGGTGGTTTGTTTGCCGGATCAAGAGCTACCAACTCTTTTTCCGAAGGTAACTGGCTTCAGCAGAGCGCAGATACCAAATACTGTTCTTCTAGTGTAGCCGTAGTTAGGCCACCACTTCAAGAACTCTGTAGCACCGCCTACATACCTCGCTCTGCTAATCCTGTTACCAGTGGCTGCTGCCAGTGGCGATAAGTCGTGTCTTACCGGGTTGGACTCAAGACGATAGTTACCGGATAAGGCGCAGCGGTCGGGCTGAACGGGGGGTTCGTGCACACAGCCCAGCTTGGAGCGAACGACCTACACCGAACTGAGATACCTACAGCGTGAGCTATGAGAAAGCGCCACGCTTCCCGAAGGGAGAAAGGCGGACAGGTATCCGGTAAGCGGCAGGGTCGGAACAGGAGAGCGCACGAGGGAGCTTCCAGGGGGAAACGCCTGGTATCTTTATAGTCCTGTCGGGTTTCGCCACCTCTGACTTGAGCGTCGATTTTTGTGATGCTCGTCAGGGGGGCGGAGCCTATGGAAAAACGCCAGCAACGCGGCCTTTTTACGGTTCCTGGCCTTTTGCTGGCCTTTTGCTCACATGTTCTTFSHR PBTE coding sequence (SEQ ID NO: 39)ATGGACTGGACCTGGATCCTGTTCCTGGTGGCTGCCGCCACCAGGGTGCACAGCGACAAGACCCACACATGCCCTCCATGTCCAGCACCAGAGGCAGCCGGCGGACCTAGCGTGTTCCTGTTTCCCCCTAAGCCAAAGGATACCCTGATGATCTCTCGGACCCCTGAGGTGACATGCGTGGTGGTGGACGTGAGCCACGAGGCACCAGAGGTGAAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCACAATGCCAAGACAAAGCCTTGCGAGGAGCAGTACGGCTCCACCTATCGCTGCGTGAGCGTGCTGACAGTGCTGCACCAGGACTGGCTGAACGGCAAGGAGTATAAGTGCGCCGTGTCCAATAAGGCCCTGCCTGCCCCAATCGAGAAGACCATCTCTAAGGCCAAGGGCCAGCCTAGGGAGCCACAGGTGTACACACTGCCACCCTCCAGAGAGGAGATGACCAAGAACCAGGTGTCTCTGACATGTCTGGTGAAGGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGTCCAATGGCCAGCCTGAGAACAATTACAAGACCACACCTCCAGTGCTGGACTCTGATGGCAGCTTCTTTCTGTATTCTAAGCTGACCGTGGATAAGAGCCGGTGGCAGCAGGGCAACGTGTTTAGCTGCTCCGTGATGCACGAGGCCCTGCACAATCACTACACACAGAAGTCTCTGAGCCTGTCCCCAGGCAAGGGCGGCGGCGGCAGCGGCGGCGGCGGCAGCGGCGGCGGCGGCAGCGGCGGCGGCGGCAGCGGCGGCGGCGGCAGCGGCGGCGGCGGCTCGGATAAAACCCACACATGCCCTCCCTGTCCAGCACCTGAGGCAGCCGGCGGACCAAGCGTGTTCCTGTTTCCACCCAAGCCTAAAGACACCCTGATGATCAGCAGGACCCCCGAAGTCACCTGCGTGGTCGTGGACGTGTCCCACGAGGCACCTGAAGTCAAGTTCAACTGGTACGTGGACGGAGTCGAAGTCCATAACGCCAAGACAAAGCCCTGTGAAGAGCAGTACGGCAGCACCTATAGATGCGTGAGCGTGCTGACAGTGCTGCATCAGGATTGGCTGAATGGCAAGGAATACAAGTGCGCCGTGTCTAATAAGGCCCTGCCAGCCCCCATCGAGAAGACCATCTCCAAGGCAAAGGGACAGCCAAGGGAGCCTCAGGTGTACACACTGCCTCCAAGCCGCGAAGAAATGACTAAAAACCAGGTGTCCCTGACCTGCCTGGTCAAAGGCTTCTATCCATCTGATATTGCCGTGGAGTGGGAGAGCAATGGCCAGCCCGAAAATAATTACAAGACCACACCCCCTGTGCTGGACTCCGATGGCTCTTTCTTTCTGTATTCCAAACTGACTGTGGATAAGTCTCGCTGGCAGCAGGGAAACGTGTTTTCTTGTAGCGTGATGCATGAGGCCCTGCATAACCACTACACACAGAAGTCCCTGTCTCTGAGCCCTGGCAAGGGCGGCGGCGGCAGCGGCGGCGGCGGCTCTGACATCCAGATGACCCAGTCCCCAAGCTCCCTGAGCGCCTCCGTGGGCGATAGGGTGACAATCTCTTGCAGAGCCTCTGAGAGCGTGGACAACTACGGCATCAGCrrCCrGAAn'GGrnCAGCAGAAGCCCGGCAAGGCCCCrAAGCTGCrGA CT rGCAGCATCCAACCAGCGGTCTGGAGTGCCTAGCCGCTTCTCCGGATCTGGAAGCGGAACCGACTTCACCCTGACAATCTCTAGCCTGCAGCCAGAGGACTTCGCCACATACTTTTGCCAGCAGAGCAAGGAGGTGCCATGGACCTTCGGCCAGGGAACAAAGGTGGAGATCAAGAGGGGCGGCGGCGGCAGCGGCGGCGGCGGCAGCGGCGGCGGCGGCTCTGAGGTGCAGCTGGTGGAGAGCGGCGGCGGCCTGGTGCAGCCTGGCGGCTCCCTGAGGCTGTCCTGTTCTTTCAGCGGCTTTTCCCTGTCTACCAGCGGAATGGGAGTGGGATGGATCAGGCAGGCACCTGGCAAGGGACTGGAGTGGGTGGCCCACATCTGGTGGGACGATGACAAGAGATACAACCCAGCCCTGAAGTCCAGGTTCACCCTGTCCGTGGATAGATCTAAGAACACACTGTATCTGCAGATGAACAGCCTGAGGGCAGAGGACACCGCAACATACTATTGCGTGCAGATCAACTACGGCAATTATCGCTTTGATAATTGGGGCCACGGCACCCTGGTGACAGTGTCCAGCGGCGGCGGCGGCTCGGAGGTGCAGCTGGTGGAGAGCGGCGGCGGCCTGGTGCAGCCAGGCGGCAGCCTGAGGCTGTCCTGTGCAGCAAGCGGATACTCCTTCACCGGCTATACAATGAATTGGGTGAGGCAGGCCCCTGGCAAGGGCCTGGAATGGGTGGCCCTGATCAACCCCTACAAGGGCGTGTCCACCTATAATCAGAAGTTCAAGGACCGCTTTACCATCTCTGTGGATAAGAGCAAGAACACAGCCTACCTGCAGATGAATAGCCTGAGAGCCGAGGACACAGCCGTGTACTATTGCGCACGGAGCGGATACTATGGCGACTCCGATTGGTATTTTGACGTGTGGGGCCAGGGCACCCTGGTGACAGTGAGCAGCGGCGGCGGCGGCAGCGGCGGCGGCGGCAGCGGCGGCGGCGGCTCTGACATCCAGATGACCCAGTCCCCATCTAGCCTGTCTGCCAGCGTCGGCGACAGGGTGACCATCACATGTCGCGCCTCTCAGGATATCAGGAACTACCTGAATTGGTATCAGCAGAAGCCCGGCAAGGCCCCTAAGCTGCTGATCTACTATACATCCAGGCTGGAGTCTGGAGTGCCAAGCAGGTTCTCCGGATCTGGAAGCGGAACCGACTACACCCTGACAATCTCCTCTCTGCAGCCCGAGGATTTCGCCACATACTATTGTCAGCAGGGCAATACCCTGCCTTGGACATTTGGCCAGGGCACCAAGGTGGAGATCAAGAGCTCCFSHR PMTE Plasmid (SEQ ID NO:40)GCTGCTTCGCGATGTACGGGCCAGATATACGCGTTGACATTGATTATTGACTAGTTATTAATAGTAATCAATTACGGGGTCATTAGTTCATAGCCCATATATGGAGTTCCGCGTTACATAACTTACGGTAAATGGCCCGCCTGGCTGACCGCCCAACGACCCCCGCCCATTGACGTCAATAATGACGTATGTTCCCATAGTAACGCCAATAGGGACTTTCCATTGACGTCAATGGGTGGAGTATTTACGGTAAACTGCCCACTTGGCAGTACATCAAGTGTATCATATGCCAAGTACGCCCCCTATTGACGTCAATGACGGTAAATGGCCCGCCTGGCATTATGCCCAGTACATGACCTTATGGGACTTTCCTACTTGGCAGTACATCTACGTATTAGTCATCGCTATTACCATGGTGATGCGGTTTTGGCAGTACATCAATGGGCGTGGATAGCGGTTTGACTCACGGGGATTTCCAAGTCTCCACCCCATTGACGTCAATGGGAGTTTGTTTTGGCACCAAAATCAACGGGACTTTCCAAAATGTCGTAACAACTCCGCCCCATTGACGCAAATGGGCGGTAGGCGTGTACGGTGGGAGGTCTATATAAGCAGAGCTCTCTGGCTAACTAGAGAACCCACTGCTTACTGGCTTATCGAAATTAATACGACTCACTATAGGGAGACCCAAGCTGGCTAGCGTTTAAACTTAAGCTTGGTACCGAGCTCGGATCCACTAGTCCAGTGTGGTGGAATTCGCCGCCACCATGGACTGGACCTGGATCCTGTTCCTGGTGGCTGCCGCCACCAGGGTGCACAGCGACAAGACCCACACATGCCCTCCATGTCCAGCACCAGAGGCAGCCGGCGGACCTAGCGTGTTCCTGTTTCCCCCTAAGCCAAAGGATACCCTGATGATCTCTCGGACCCCTGAGGTGACATGCGTGGTGGTGGACGTGAGCCACGAGGCACCAGAGGTGAAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCACAATGCCAAGACAAAGCCTTGCGAGGAGCAGTACGGCTCCACCTATCGCTGCGTGAGCGTGCTGACAGTGCTGCACCAGGACTGGCTGAACGGCAAGGAGTATAAGTGCGCCGTGTCCAATAAGGCCCTGCCTGCCCCAATCGAGAAGACCATCTCTAAGGCCAAGGGCCAGCCTAGGGAGCCACAGGTGTACACACTGCCACCCTCCAGAGAGGAGATGACCAAGAACCAGGTGTCTCTGACATGTCTGGTGAAGGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGTCCAATGGCCAGCCTGAGAACAATTACAAGACCACACCTCCAGTGCTGGACTCTGATGGCAGCTTCTTTCTGTATTCTAAGCTGACCGTGGATAAGAGCCGGTGGCAGCAGGGCAACGTGTTTAGCTGCTCCGTGATGCACGAGGCCCTGCACAATCACTACACACAGAAGTCTCTGAGCCTGTCCCCAGGCAAGGGCGGCGGCGGCAGCGGCGGCGGCGGCAGCGGCGGCGGCGGCAGCGGCGGCGGCGGCAGCGGCGGCGGCGGCAGCGGCGGCGGCGGCTCGGATAAAACCCACACATGCCCTCCCTGTCCAGCACCTGAGGCAGCCGGCGGACCAAGCGTGTTCCTGTTTCCACCCAAGCCTAAAGACACCCTGATGATCAGCAGGACCCCCGAAGTCACCTGCGTGGTCGTGGACGTGTCCCACGAGGCACCTGAAGTCAAGTTCAACTGGTACGTGGACGGAGTCGAAGTCCATAACGCCAAGACAAAGCCCTGTGAAGAGCAGTACGGCAGCACCTATAGATGCGTGAGCGTGCTGACAGTGCTGCATCAGGATTGGCTGAATGGCAAGGAATACAAGTGCGCCGTGTCTAATAAGGCCCTGCCAGCCCCCATCGAGAAGACCATCTCCAAGGCAAAGGGACAGCCAAGGGAGCCTCAGGTGTACACACTGCCTCCAAGCCGCGAAGAAATGACTAAAAACCAGGTGTCCCTGACCTGCCTGGTCAAAGGCTTCTATCCATCTGATATTGCCGTGGAGTGGGAGAGCAATGGCCAGCCCGAAAATAATTACAAGACCACACCCCCTGTGCTGGACTCCGATGGCTCTTTCTTTCTGTATTCCAAACTGACTGTGGATAAGTCTCGCTGGCAGCAGGGAAACGTGTTTTCTTGTAGCGTGATGCATGAGGCCCTGCArAACCACrACACACAGAAGrCCCTGTCTCrGAGCCCrGGCAAGGGCGGCGGCGGCAGCGGCGGCGGCGGCTCTGACATCCAGATGACCCAGTCCCCAAGCTCCCTGAGCGCCTCCGTGGGCGATAGGGTGACAATCTCTTGCAGAGCCTCTGAGAGCGTGGACAACTACGGCATCAGCTTCCTGAATTGGTTTCAGCAGAAGCCCGGCAAGGCCCCTAAGCTGCTGATCTATGCAGCATCCAACCAGCGGTCTGGAGTGCCTAGCCGCTTCTCCGGATCTGGAAGCGGAACCGACTTCACCCTGACAATCTCTAGCCTGCAGCCAGAGGACTTCGCCACATACTTTTGCCAGCAGAGCAAGGAGGTGCCATGGACCTTCGGCCAGGGAACAAAGGTGGAGATCAAGAGGGGCGGCGGCGGCAGCGGCGGCGGCGGCAGCGGCGGCGGCGGCTCTGAGGTGCAGCTGGTGGAGAGCGGCGGCGGCCTGGTGCAGCCTGGCGGCTCCCTGAGGCTGTCCTGTTCTTTCAGCGGCTTTTCCCTGTCTACCAGCGGAATGGGAGTGGGATGGATCAGGCAGGCACCTGGCAAGGGACTGGAGTGGGTGGCCCACATCTGGTGGGACGATGACAAGAGATACAACCCAGCCCTGAAGTCCAGGTTCACCCTGTCCGTGGATAGATCTAAGAACACACTGTATCTGCAGATGAACAGCCTGAGGGCAGAGGACACCGCAACATACTATTGCGTGCAGATCAACTACGGCAATTATCGCTTTGATAATTGGGGCCACGGCACCCTGGTGACAGTGTCCAGCGGCGGCGGCGGCTCGGAGGTGCAGCTGGTGGAGAGCGGCGGCGGCCTGGTGCAGCCAGGCGGCAGCCTGAGGCTGTCCTGTGCAGCAAGCGGATACTCCTTCACCGGCTATACAATGAATTGGGTGAGGCAGGCCCCTGGCAAGGGCCTGGAATGGGTGGCCCTGATCAACCCCTACAAGGGCGTGTCCACCTATAATCAGAAGTTCAAGGACCGCTTTACCATCTCTGTGGATAAGAGCAAGAACACAGCCTACCTGCAGATGAATAGCCTGAGAGCCGAGGACACAGCCGTGTACTATTGCGCACGGAGCGGATACTATGGCGACTCCGATTGGTATTTTGACGTGTGGGGCCAGGGCACCCTGGTGACAGTGAGCAGCGGCGGCGGCGGCAGCGGCGGCGGCGGCAGCGGCGGCGGCGGCTCTGACATCCAGATGACCCAGTCCCCATCTAGCCTGTCTGCCAGCGTCGGCGACAGGGTGACCATCACATGTCGCGCCTCTCAGGATATCAGGAACTACCTGAATTGGTATCAGCAGAAGCCCGGCAAGGCC CCTAAGCTGCTGATCTACTATACATCCAGGCTGGAGTCTGGAGTGCCAAGCAGGTTCTCCGGATCT GGAAGCGGAACCGACTACACCCTGACAATCTCCTCTCTGCAGCCCGAGGATTTCGCCACATACTAT TGTCAGCAGGGCAATACCCTGCCTTGGACATTTGGCCAGGGCACCAAGGTGGAGATCAAGAGCTC CGGCGGCGGCGGAAGCGACATCCAGATGACCCAGTCCCCAAGCTCCCTGAGCGCCTCCGTGGGCG ATAGGGTGACAATCTCCTGCAGAGCCTCTGAGAGCGTGGACAACTACGGCATCTCTTTCCTGAATT GGTTTCAGCAGAAGCCCGGCAAGGCCCCTAAGCTGCTGATCTATGCAGCATCCAACCAGCGGTCT GGAGTGCCTAGCCGCTTCTCCGGATCTGGAAGCGGAACCGACTTCACCCTGACAATCTCTAGCCTG CAGCCAGAGGACTTCGCCACATACTTTTGCCAGCAGTCCAAGGAGGTGCCATGGACCTTCGGCCA GGGAACAAAGGTGGAGATCAAGAGGGGCGGCGGCGGCAGCGGCGGCGGCGGCAGCGGCGGCGG CGGCTCTGAGGTGCAGCTGGTGGAGAGCGGCGGCGGCCTGGTGCAGCCTGGCGGCAGCCTGAGGC TGTCCTGTTCTTTCAGCGGCTTTTCCCTGTCTACCAGCGGAATGGGAGTGGGATGGATCAGGCAGG CACCTGGCAAGGGACTGGAGTGGGTGGCCCACATCTGGTGGGACGATGACAAGAGATACAACCCA GCCCTGAAGTCCAGGTTCACCCTGTCCGTGGATAGATCTAAGAACACACTGTATCTGCAGATGAAT AGCCTGCGGGCCGAGGACACCGCCACATACTATTGCGTGCAGATCAACTACGGCAATTATCGCTTT GATAATTGGGGCCACGGCACCCTGGTGACAGTGTCCTCTCACCACCACCACCACCACTGATAAGCG GCCGCTCGAGTCTAGAGGGCCCGTTTAAACCCGCTGATCAGCCTCGACTGTGCCTTCTAGTTGCCA GCCATCTGTTGTTTGCCCCTCCCCCGTGCCTTCCTTGACCCTGGAAGGTGCCACTCCCACTGTCCTT TCCTAATAAAATGAGGAAATTGCATCGCATTGTCTGAGTAGGTGTCATTCTATTCTGGGGGGTGGG GTGGGGCAGGACAGCAAGGGGGAGGATTGGGAAGACAATAGCAGGCATGCTGGGGATGCGGTGG GCTCTATGGCTTCTACTGGGCGGTTTTATGGACAGCAAGCGAACCGGAATTGCCAGCTGGGGCGCC CTCTGGTAAGGTTGGGAAGCCCTGCAAAGTAAACTGGATGGCTTTCTTGCCGCCAAGGATCTGATG GCGCAGGGGATCAAGCTCTGATCAAGAGACAGGATGAGGATCGTTTCGCATGATTGAACAAGATG GATTGCACGCAGGTTCTCCGGCCGCTTGGGTGGAGAGGCTATTCGGCTATGACTGGGCACAACAG ACAATCGGCTGCTCTGATGCCGCCGTGTTCCGGCTGTCAGCGCAGGGGCGCCCGGTTCTTTTTGTC AAGACCGACCTGTCCGGTGCCCTGAATGAACTGCAAGACGAGGCAGCGCGGCTATCGTGGCTGGC CACGACGGGCGTTCCTTGCGCAGCTGTGCTCGACGTTGTCACTGAAGCGGGAAGGGACTGGCTGCT ATTGGGCGAAGTGCCGGGGCAGGATCTCCTGTCATCTCACCTTGCTCCTGCCGAGAAAGTATCCAT CATGGCTGATGCAATGCGGCGGCTGCATACGCTTGATCCGGCTACCTGCCCATTCGACCACCAAGC GAAACATCGCATCGAGCGAGCACGTACTCGGATGGAAGCCGGTCTTGTCGATCAGGATGATCTGG ACGAAGAGCATCAGGGGCTCGCGCCAGCCGAACTGTTCGCCAGGCTCAAGGCGAGCATGCCCGAC GGCGAGGATCTCGTCGTGACCCATGGCGATGCCTGCTTGCCGAATATCATGGTGGAAAATGGCCG CTTTTCTGGATTCATCGACTGTGGCCGGCTGGGTGTGGCGGACCGCTATCAGGACATAGCGTTGGC TACCCGTGATATTGCTGAAGAGCTTGGCGGCGAATGGGCTGACCGCTTCCTCGTGCTTTACGGTAT CGCCGCTCCCGATTCGCAGCGCATCGCCTTCTATCGCCTTCTTGACGAGTTCTTCTGAATTATTAAC GCTTACAATTTCCTGATGCGGTATTTTCTCCTTACGCATCTGTGCGGTATTTCACACCGCATCAGGT GGCACTTTTCGGGGAAATGTGCGCGGAACCCCTATTTGTTTATTTTTCTAAATACATTCAAATATGT ATCCGCTCATGAGACAATAACCCTGATAAATGCTTCAATAATAGCACGTGCTAAAACTTCATTTTT AATTTAAAAGGATCTAGGTGAAGATCCTTTTTGATAATCTCATGACCAAAATCCCTTAACGTGAGT TTTCGTTCCACTGAGCGTCAGACCCCGTAGAAAAGATCAAAGGATCTTCTTGAGATCCTTTTTTTCT GCGCGTAATCTGCTGCTTGCAAACAAAAAAACCACCGCTACCAGCGGTGGTTTGTTTGCCGGATCA AGAGCTACCAACTCTTTTTCCGAAGGTAACTGGCTTCAGCAGAGCGCAGATACCAAATACTGTTCT TCTAGTGTAGCCGTAGTTAGGCCACCACTTCAAGAACTCTGTAGCACCGCCTACATACCTCGCTCT GCTAATCCTGTTACCAGTGGCTGCTGCCAGTGGCGATAAGTCGTGTCTTACCGGGTTGGACTCAAGACGATAGITACCGGATAAGGCGCAGCGGrCGGGCTGAACGGGGGGI TCGTGCACACAGCCCAGCT TGGAGCGAACGACCTACACCGAACTGAGATACCTACAGCGTGAGCTATGAGAAAGCGCCACGCTT CCCGAAGGGAGAAAGGCGGACAGGTATCCGGTAAGCGGCAGGGTCGGAACAGGAGAGCGCACGA GGGAGCTTCCAGGGGGAAACGCCTGGTATCTTTATAGTCCTGTCGGGTTTCGCCACCTCTGACTTG AGCGTCGATTTTTGTGATGCTCGTCAGGGGGGCGGAGCCTATGGAAAAACGCCAGCAACGCGGCC TTTTTACGGTTCCTGGCCTTTTGCTGGCCTTTTGCTCACATGTTCTTFSHR PMTE coding Sequence (SEQ ID N0:41)ATGGACTGGACCTGGATCCTGTTCCTGGTGGCTGCCGCCACCAGGGTGCACAGCGACAAGACCCACACATGCCCTCCATGTCCAGCACCAGAGGCAGCCGGCGGACCTAGCGTGTTCCTGTTTCCCCCTAAGCCAAAGGATACCCTGATGATCTCTCGGACCCCTGAGGTGACATGCGTGGTGGTGGACGTGAGCCACGAGGCACCAGAGGTGAAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCACAATGCCAAGACAAAGCCTTGCGAGGAGCAGTACGGCTCCACCTATCGCTGCGTGAGCGTGCTGACAGTGCTGCACCAGGACTGGCTGAACGGCAAGGAGTATAAGTGCGCCGTGTCCAATAAGGCCCTGCCTGCCCCAATCGAGAAGACCATCTCTAAGGCCAAGGGCCAGCCTAGGGAGCCACAGGTGTACACACTGCCACCCTCCAGAGAGGAGATGACCAAGAACCAGGTGTCTCTGACATGTCTGGTGAAGGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGTCCAATGGCCAGCCTGAGAACAATTACAAGACCACACCTCCAGTGCTGGACTCTGATGGCAGCTTCTTTCTGTATTCTAAGCTGACCGTGGATAAGAGCCGGTGGCAGCAGGGCAACGTGTTTAGCTGCTCCGTGATGCACGAGGCCCTGCACAATCACTACACACAGAAGTCTCTGAGCCTGTCCCCAGGCAAGGGCGGCGGCGGCAGCGGCGGCGGCGGCAGCGGCGGCGGCGGCAGCGGCGGCGGCGGCAGCGGCGGCGGCGGCAGCGGCGGCGGCGGCTCGGATAAAACCCACACATGCCCTCCCTGTCCAGCACCTGAGGCAGCCGGCGGACCAAGCGTGTTCCTGTTTCCACCCAAGCCTAAAGACACCCTGATGATCAGCAGGACCCCCGAAGTCACCTGCGTGGTCGTGGACGTGTCCCACGAGGCACCTGAAGTCAAGTTCAACTGGTACGTGGACGGAGTCGAAGTCCATAACGCCAAGACAAAGCCCTGTGAAGAGCAGTACGGCAGCACCTATAGATGCGTGAGCGTGCTGACAGTGCTGCATCAGGATTGGCTGAATGGCAAGGAATACAAGTGCGCCGTGTCTAATAAGGCCCTGCCAGCCCCCATCGAGAAGACCATCTCCAAGGCAAAGGGACAGCCAAGGGAGCCTCAGGTGTACACACTGCCTCCAAGCCGCGAAGAAATGACTAAAAACCAGGTGTCCCTGACCTGCCTGGTCAAAGGCTTCTATCCATCTGATATTGCCGTGGAGTGGGAGAGCAATGGCCAGCCCGAAAATAATTACAAGACCACACCCCCTGTGCTGGACTCCGATGGCTCTTTCTTTCTGTATTCCAAACTGACTGTGGATAAGTCTCGCTGGCAGCAGGGAAACGTGTTTTCTTGTAGCGTGATGCATGAGGCCCTGCATAACCACTACACACAGAAGTCCCTGTCTCTGAGCCCTGGCAAGGGCGGCGGCGGCAGCGGCGGCGGCGGCTCTGACATCCAGATGACCCAGTCCCCAAGCTCCCTGAGCGCCTCCGTGGGCGATAGGGTGACAATCTCTTGCAGAGCCTCTGAGAGCGTGGACAACTACGGCATCAGCTTCCTGAATTGGTTTCAGCAGAAGCCCGGCAAGGCCCCTAAGCTGCTGATCTATG CAGCATCCAACCAGCGGTCTGGAGTGCCTAGCCGCTTCTCCGGATCTGGAAGCGGAACCGACTTCA CCCTGACAATCTCTAGCCTGCAGCCAGAGGACTTCGCCACATACTTTTGCCAGCAGAGCAAGGAG GTGCCATGGACCTTCGGCCAGGGAACAAAGGTGGAGATCAAGAGGGGCGGCGGCGGCAGCGGCGGCGGCGGCAGCGGCGGCGGCGGCTCTGAGGTGCAGCTGGTGGAGAGCGGCGGCGGCCTGGTGCA GCCTGGCGGCTCCCTGAGGCTGTCCTGTTCTTTCAGCGGCTTTTCCCTGTCTACCAGCGGAATGGGA GTGGGATGGATCAGGCAGGCACCTGGCAAGGGACTGGAGTGGGTGGCCCACATCTGGTGGGACGA TGACAAGAGATACAACCCAGCCCTGAAGTCCAGGTTCACCCTGTCCGTGGATAGATCTAAGAACACACTGTATCTGCAGATGAACAGCCTGAGGGCAGAGGACACCGCAACATACTATTGCGTGCAGATC AACTACGGCAATTATCGCTTTGATAATTGGGGCCACGGCACCCTGGTGACAGTGTCCAGCGGCGGC GGCGGCTCGGAGGTGCAGCTGGTGGAGAGCGGCGGCGGCCTGGTGCAGCCAGGCGGCAGCCTGAGGCTGTCCTGTGCAGCAAGCGGATACTCCTTCACCGGCTATACAATGAATTGGGTGAGGCAGGCCCCTGGCAAGGGCCTGGAATGGGTGGCCCTGATCAACCCCTACAAGGGCGTGTCCACCTATAATCAGAAGTTCAAGGACCGCTTTACCATCTCTGTGGATAAGAGCAAGAACACAGCCTACCTGCAGATGAATAGCCTGAGAGCCGAGGACACAGCCGTGTACTATTGCGCACGGAGCGGATACTATGGCGACTCCGATTGGTATTTTGACGTGTGGGGCCAGGGCACCCTGGTGACAGTGAGCAGCGGCGGCGGCGGCAGCGGCGGCGGCGGCAGCGGCGGCGGCGGCTCTGACATCCAGATGACCCAGTCCCCATCTAGCCTGTCTGCCAGCGTCGGCGACAGGGTGACCATCACATGTCGCGCCTCTCAGGATATCAGGAACTACCTGAATTGGTATCAGCAGAAGCCCGGCAAGGCCCCTAAGCTGCTGATCTACTATACATCCAGGCTGGAGTCTGGAGTGCCAAGCAGGTTCTCCGGATCTGGAAGCGGAACCGACTACACCCTGACAATCTCCTCTCTGCAGCCCGAGGATTTCGCCACATACTATTGTCAGCAGGGCAATACCCTGCCTTGGACATTTGGCCAGGGCACCAAGGTGGAGATCAAGAGCTCCGGCGGCGGCGGAAGCGACATCCAGATGACCCAGTCCCCAAGCTCCCTGAGCGCCTCCGTGGGCGATAGGGTGACAATCTCCTGCAGAGCCTCTGAGAGCGT GGACAACTACGGCATCTCTTTCCTGAATTGGTTTCAGCAGAAGCCCGGCAAGGCCCCTAAGCTGCT GATCTATGCAGCATCCAACCAGCGGTCTGGAGTGCCTAGCCGCTTCTCCGGATCTGGAAGCGGAACCGACn'CACCCrGACAATCTCrAGCCTGCAGCCAGAGGACrrCGCCACATACn riGCCAGCAGl'CCAAGGAGGTGCCATGGACCTTCGGCCAGGGAACAAAGGTGGAGATCAAGAGGGGCGGCGGCGGCAGCGGCGGCGGCGGCAGCGGCGGCGGCGGCTCTGAGGTGCAGCTGGTGGAGAGCGGCGGCGGCCTGGTGCAGCCTGGCGGCAGCCTGAGGCTGTCCTGTTCTTTCAGCGGCTTTTCCCTGTCTACCAGCGGAATGGGAGTGGGATGGATCAGGCAGGCACCTGGCAAGGGACTGGAGTGGGTGGCCCACATCTGGTGGGACGATGACAAGAGATACAACCCAGCCCTGAAGTCCAGGTTCACCCTGTCCGTGGATAGATCTAAGAACACACTGTATCTGCAGATGAATAGCCTGCGGGCCGAGGACACCGCCACATACTATTGCGT GCAGATCAACTACGGCAATTATCGCTTTGATAATTGGGGCCACGGCACCCTGGTGACAGTGTCCTC TFSHR PMTE (Fc-LHHLHL) construct (SEQ ID NO:42)GACAAGACCCACACCTGCCCCCCATGCCCCGCCCCTGAGGCCGCCGGAGGTCCTAGCGTGTTTCTGTTCCCCCCCAAGCCTAAGGACACCCTGATGATCTCTAGAACACCCGAGGTGACATGCGTGGTGGTGGACGTGAGCCACGAGGCCCCTGAAGTTAAGTTCAATTGGTATGTGGACGGCGTGGAAGTGCACAACGCCAAGACAAAGCCTTGTGAAGAACAGTACGGCAGCACATATCGGTGCGTGTCCGTGCTGACCGTTCTCCACCAGGATTGGCTGAATGGCAAGGAATACAAGTGCGCCGTTAGCAACAAGGCCCTGCCTGCCCCCATCGAGAAGACAATCTCGAAGGCTAAAGGACAACCTAGAGAGCCCCAAGTCTACACACTGCCTCCTAGCAGGGAGGAAATGACCAAGAACCAGGTCTCACTGACCTGCCTGGTGAAGGGCTTTTACCCTTCCGATATCGCCGTGGAGTGGGAAAGCAATGGCCAGCCGGAGAACAACTACAAGACAACCCCTCCGGTGCTGGACAGCGACGGTTCTTTCTTTCTGTACAGCAAGCTGACGGTGGACAAGAGCAGATGGCAGCAGGGCAACGTGTTCAGCTGCAGCGTGATGCACGAGGCTCTGCACAACCACTACACCCAGAAAAGCCTGTCTTTGTCCCCTGGCAAGGGCGGAGGCGGCTCCGGCGGCGGCGGGAGCGGCGGCGGCGGAAGCGGCGGTGGAGGAAGCGGCGGCGGCGGTTCTGGTGGCGGCGGCAGTGACAAGACACACACCTGTCCTCCTTGCCCTGCCCCTGAGGCCGCCGGCGGCCCTTCTGTGTTCCTGTTCCCTCCAAAGCCTAAAGATACACTCATGATCAGCAGAACCCCTGAGGTGACCTGCGTCGTGGTGGACGTGAGCCACGAGGCGCCTGAGGTAAAGTTCAATTGGTACGTGGACGGCGTGGAAGTGCACAACGCCAAGACCAAACCATGTGAAGAGCAGTACGGCTCTACATATAGATGCGTCTCGGTGCTGACCGTGCTCCATCAGGACTGGCTGAACGGCAAGGAATACAAGTGCGCCGTGAGCAACAAGGCCCTGCCTGCCCCCATCGAGAAAACCATTAGCAAGGCTAAGGGCCAGCCCCGGGAGCCTCAGGTGTACACCCTGCCTCCCAGCCGGGAAGAGATGACCAAGAACCAGGTGAGCCTAACATGTCTGGTCAAGGGCTTCTACCCCTCTGATATCGCCGTGGAATGGGAGTCTAATGGCCAGCCCGAAAACAATTACAAGACGACACCTCCAGTGCTGGATAGTGACGGCAGCTTCTTCCTGTACTCCAAGCTGACAGTGGACAAGTCCAGATGGCAGCAGGGAAACGTGTTCTCTTGCAGCGTGATGCACGAGGCTCTGCACAATCACTACACCCAGAAGTCCCTGAGCCTGTCCCCAGGCAAGGGCGGCGGCGGCTCAGGCGGCGGAGGCAGCGAGGTCCAGCTGGTGGAATCGGGAGGCGGCCTGGTGCAACCTGGAGGCAGCCTGCGCCTGAGCTGTAGCTTTAGCGGCTTCTCTCTGTCCACCAGCGGCATGGGCGTCGGCTGGATCCGGCAGGCTCCTGGAAAAGGCCTGGAATGGGTTGCACACATCTGGTGGGACGATGACAAAAGATACAACCCCGCCCTGAAGAGTAGATTTACACTAAGCGTGGACAGATCCAAGAACACCCTGTACCTGCAAATGAACTCCCTTAGAGCCGAGGACACCGCTACCTACTACTGCGTTCAGATCAACTACGGCAACTACAGATTCGATAACTGGGGACATGGCACACTGGTGACAGTTAGCAGCGGGGGAGGCGGCTCAGGCGGAGGCGGCTCAGGTGGCGGCGGATCTGACATCCAGATGACACAGTCTCCCAGCAGCCTGAGCGCTAGCGTGGGCGACAGAGTGACAATCAGCTGCAGAGCCTCCGAGAGCGTGGATAACTACGGGATCTCTTTTCTGAACTGGTTCCAGCAGAAACCCGGCAAAGCGCCCAAGCTGCTGATCTATGCCGCCAGTAACCAGAGAAGCGGCGTGCCCAGCAGATTCAGCGGCTCTGGAAGCGGCACAGACTTCACACTGACAATATCCAGCCTTCAACCAGAGGACTTCGCTACCTACTTCTGCCAACAGTCTAAGGAGGTGCCTTGGACCTTCGGACAGGGCACAAAGGTGGAAATCAAAAGAGGCGGCGGCGGCTCAGAGGTGCAGCTGGTGGAGAGCGGCGGCGGCCTGGTGCAGCCCGGAGGCTCCCTGAGACTGTCTTGCGCCGCCTCTGGATACAGCTTCACAGGCTACACAATGAACTGGGTGCGGCAGGCTCCTGGAAAGGGACTGGAGTGGGTGGCCCTGATCAACCCTTACAAGGGCGTGAGCACCTACAACCAAAAGTTTAAGGACCGCTTCACCATCTCCGTGGATAAGTCCAAAAACACCGCCTACCTGCAGATGAACAGCCTGCGGGCCGAGGATACCGCCGTGTACTACTGCGCCAGAAGCGGATACTACGGCGATTCCGACTGGTACTTCGACGTGTGGGGCCAGGGCACCCTAGTGACCGTGAGCAGCGGTGGCGGCGGCTCCGGCGGTGGAGGTTCCGGCGGCGGAGGCAGCGACATTCAGATGACCCAGTCCCCCTCTTCTCTGAGCGCCTCAGTCGGCGATAGAGTGACCATCACCTGTCGGGCCAGCCAGGACATTAGAAACTACCTGAACTGGTACCAGCAAAAGCCCGGCAAAGCCCCTAAGCTGCTGATCTACTACACCAGCCGGCTGGAAAGCGGGGTGCCAAGCCGGTTCAGCGGCTCGGGCAGCGGAACAGACTACACCCTGACCATCTCAAGCCTGCAGCCAGAGGACTTTGCTACTTATTATTGCCAGCAGGGCAACACACTGCCCTGGACCTTCGGCCAGGGAACCAAAGTGGAAATCAAGTCGAGCGGTGGCGGCGGCAGCGACATCCAGATGACCCAGTCGCCTTCTTCCCTGTCGGCCAGCG CGGAGACCGGGTGACCATCAGCTGTAGAGCCAGTGAAAGCGTGGACAACTACGGCATCAGCTTCCTGAACTGGTTCCAGCAGAAACCTGGCAAGGCCCCTAAGCTGCTGATCTACGCCGCCTCCAATCAAAGAAGCGGCGTGCCCAGCCGGTTCTCCGGCTCTGGCTCCGGTACCGATTTCACCCTGACCATCAGCTCTCTGCAGCCAGAAGATTTTGCTACCTATTTCTGCCAGCAATCCAAGGAAGTGCCCTGGACATTCGGCCAGGGCACAAAGGTGGAAATCAAGCGTGGAGGCGGTGGCAGCGGAGGCGGCGGGAGCGGCGGCGGCGGCTCCGAGGTCCAGCTGGTGGAGAGCGGTGGGGGCCTGGTGCAACCTGGCGGATCTCTGCGGCTGAGCTGCAGCTTTAGCGGCTTCAGCCTGAGCACGAGCGGCATGGGCGTGGGCTGGATCAGACAGGCCCCAGGCAAGGGACTCGAGTGGGTCGCTCACATCTGGTGGGATGACGACAAGAGATACAATCCTGCCCTGAAGTCAAGATTCACCCTGAGCGTTGACCGGAGCAAAAACACTCTGTACCTGCAGATGAACAGCCTGAGAGCTGAAGATACCGCCACCTACTACTGTGTGCAAATCAACTACGGCAATTACCGGTTCGACAATTGGGGCCACGGCACCCTGGTGA CTGTGAGTAGCCACCACCATCACCACCACFSHR PMTE (Fc-LHHLHL) coding sequence (SEQ ID NO:43)ATGATCTCTAGAACACCCGAGGTGACATGCGTGGTGGTGGACGTGAGCCACGAGGCCCCTGAAGTTAAGTTCAATTGGTATGTGGACGGCGTGGAAGTGCACAACGCCAAGACAAAGCCTTGTGAAGAACAGTACGGCAGCACATATCGGTGCGTGTCCGTGCTGACCGTTCTCCACCAGGATTGGCTGAATGGCA AGGAATACAAGTGCGCCGTTAGCAACAAGGCCCTGCCTGCCCCCATCGAGAAGACAATCTCGAAGGCTAAAGGACAACCTAGAGAGCCCCAAGTCTACACACTGCCTCCTAGCAGGGAGGAAATGACCAA GAACCAGGTCTCACTGACCTGCCTGGTGAAGGGCTTTTACCCTTCCGATATCGCCGTGGAGTGGGA AAGCAATGGCCAGCCGGAGAACAACTACAAGACAACCCCTCCGGTGCTGGACAGCGACGGTTCTT TCTTTCTGTACAGCAAGCTGACGGTGGACAAGAGCAGATGGCAGCAGGGCAACGTGTTCAGCTGC AGCGTGATGCACGAGGCTCTGCACAACCACTACACCCAGAAAAGCCTGTCTTTGTCCCCTGGCAAGGGCGGAGGCGGCTCCGGCGGCGGCGGGAGCGGCGGCGGCGGAAGCGGCGGTGGAGGAAGCGGCG GCGGCGGTTCTGGTGGCGGCGGCAGTGACAAGACACACACCTGTCCTCCTTGCCCTGCCCCTGAGG CCGCCGGCGGCCCTTCTGTGTTCCTGTTCCCTCCAAAGCCTAAAGATACACTCATGATCAGCAGAA CCCCTGAGGTGACCTGCGTCGTGGTGGACGTGAGCCACGAGGCGCCTGAGGTAAAGTTCAATTGG TACGTGGACGGCGTGGAAGTGCACAACGCCAAGACCAAACCATGTGAAGAGCAGTACGGCTCTACATATAGATGCGTCTCGGTGCTGACCGTGCTCCATCAGGACTGGCTGAACGGCAAGGAATACAAGT GCGCCGTGAGCAACAAGGCCCTGCCTGCCCCCATCGAGAAAACCATTAGCAAGGCTAAGGGCCAGCCCCGGGAGCCTCAGGTGTACACCCTGCCTCCCAGCCGGGAAGAGATGACCAAGAACCAGGTGAG CCTAACATGTCTGGTCAAGGGCTTCTACCCCTCTGATATCGCCGTGGAATGGGAGTCTAATGGCCAGCCCGAAAACAATTACAAGACGACACCTCCAGTGCTGGATAGTGACGGCAGCTTCTTCCTGTACTC CAAGCTGACAGTGGACAAGTCCAGATGGCAGCAGGGAAACGTGTTCTCTTGCAGCGTGATGCACGAGGCTCTGCACAATCACTACACCCAGAAGTCCCTGAGCCTGTCCCCAGGCAAGGGCGGCGGCGGC TCAGGCGGCGGAGGCAGCGAGGTCCAGCTGGTGGAATCGGGAGGCGGCCTGGTGCAACCTGGAGGCAGCCTGCGCCTGAGCTGTAGCTTTAGCGGCTTCTCTCTGTCCACCAGCGGCATGGGCGTCGGCT GGATCCGGCAGGCTCCTGGAAAAGGCCTGGAATGGGTTGCACACATCTGGTGGGACGATGACAAA AGATACAACCCCGCCCTGAAGAGTAGATTTACACTAAGCGTGGACAGATCCAAGAACACCCTGTACCTGCAAATGAACTCCCTTAGAGCCGAGGACACCGCTACCTACTACTGCGTTCAGATCAACTACGG CAACTACAGATTCGATAACTGGGGACATGGCACACTGGTGACAGTTAGCAGCGGGGGAGGCGGCT CAGGCGGAGGCGGCTCAGGTGGCGGCGGATCTGACATCCAGATGACACAGTCTCCCAGCAGCCTGAGCGCTAGCGTGGGCGACAGAGTGACAATCAGCTGCAGAGCCTCCGAGAGCGTGGATAACTACGG GATCTCTTTTCTGAACTGGTTCCAGCAGAAACCCGGCAAAGCGCCCAAGCTGCTGATCTATGCCGC CAGTAACCAGAGAAGCGGCGTGCCCAGCAGATTCAGCGGCTCTGGAAGCGGCACAGACTTCACACTGACAATATCCAGCCTTCAACCAGAGGACTTCGCTACCTACTTCTGCCAACAGTCTAAGGAGGTGC CTTGGACCTTCGGACAGGGCACAAAGGTGGAAATCAAAAGAGGCGGCGGCGGCTCAGAGGTGCAGCTGGTGGAGAGCGGCGGCGGCCTGGTGCAGCCCGGAGGCTCCCTGAGACTGTCTTGCGCCGCCT CTGGATACAGCTTCACAGGCTACACAATGAACTGGGTGCGGCAGGCTCCTGGAAAGGGACTGGAGTGGGTGGCCCTGATCAACCCTTACAAGGGCGTGAGCACCTACAACCAAAAGTTTAAGGACCGCTTCACCATCTCCGTGGATAAGTCCAAAAACACCGCCTACCTGCAGATGAACAGCCTGCGGGCCGAGGATACCGCCGTGTACTACTGCGCCAGAAGCGGATACTACGGCGATTCCGACTGGTACTTCGACGTGT GGGGCCAGGGCACCCTAGTGACCGTGAGCAGCGGTGGCGGCGGCTCCGGCGGTGGAGGTTCCGGC GGCGGAGGCAGCGACATTCAGATGACCCAGTCCCCCTCTTCTCTGAGCGCCTCAGTCGGCGATAGAGTGACCATCACCTGTCGGGCCAGCCAGGACATTAGAAACTACCTGAACTGGTACCAGCAAAAGCCCGGCAAAGCCCCTAAGCTGCTGATCTACTACACCAGCCGGCTGGAAAGCGGGGTGCCAAGCCGGT TCAGCGGCTCGGGCAGCGGAACAGACTACACCCTGACCATCTCAAGCCTGCAGCCAGAGGACTTTGCTACTTATTATTGCCAGCAGGGCAACACACTGCCCTGGACCTTCGGCCAGGGAACCAAAGTGGAAATCAAGTCGAGCGGTGGCGGCGGCAGCGACATCCAGATGACCCAGTCGCCTTCTTCCCTGTCGGCCAGCGTCGGAGACCGGGTGACCATCAGCTGTAGAGCCAGTGAAAGCGTGGACAACTACGGCATCA GCTTCCTGAACTGGTTCCAGCAGAAACCTGGCAAGGCCCCTAAGCTGCTGATCTACGCCGCCTCCA ATCAAAGAAGCGGCGTGCCCAGCCGGTTCTCCGGCTCTGGCTCCGGTACCGATTTCACCCTGACCA TCAGCTCTCTGCAGCCAGAAGATTTTGCTACCTATTTCTGCCAGCAATCCAAGGAAGTGCCCTGGACATTCGGCCAGGGCACAAAGGTGGAAATCAAGCGTGGAGGCGGTGGCAGCGGAGGCGGCGGGAGCGGCGGCGGCGGCTCCGAGGTCCAGCTGGTGGAGAGCGGTGGGGGCCTGGTGCAACCTGGCGGAT CTCTGCGGCTGAGCTGCAGCTTTAGCGGCTTCAGCCTGAGCACGAGCGGCATGGGCGTGGGCTGGATCAGACAGGCCCCAGGCAAGGGACTCGAGTGGGTCGCTCACATCTGGTGGGATGACGACAAGAGATACAATCCTGCCCTGAAGTCAAGATTCACCCTGAGCGTTGACCGGAGCAAAAACACTCTGTACCTGCAGATGAACAGCCTGAGAGCTGAAGATACCGCCACCTACTACTGTGTGCAAATCAACTACGGCA ATTACCGGTTCGACAATTGGGGCCACGGCACCCTGGTGACTGTGAGTAGCFSHR PMTE (Fc-LHLHHL) construct (SEQ ID NO:44)GACAAGACCCACACCTGCCCTCCTTGTCCTGCCCCTGAAGCTGCCGGCGGCCCTAGCGTGTTCCTGTTTCCTCCTAAACCTAAGGACACCCTGATGATCAGCCGGACACCCGAGGTGACCTGCGTGGTGGTGGACGTATCCCACGAGGCCCCGGAGGTCAAGTTCAACTGGTATGTGGATGGCGTGGAAGTGCACAACGCCAAAACCAAGCCTTGCGAGGAGCAGTACGGCAGTACCTACAGATGCGTGTCCGTGCTGACAGTGCTGCACCAAGACTGGCTGAACGGTAAGGAGTACAAATGCGCCGTGAGCAACAAGGCGCTGCCTGCTCCAATCGAGAAGACCATCAGCAAGGCTAAGGGCCAGCCTAGAGAGCCCCAGGTGTACACCCTGCCTCCTAGCAGAGAGGAAATGACCAAGAACCAAGTGAGTCTGACATGCCTGGTGAAGGGATTCTACCCCAGCGACATTGCCGTGGAATGGGAAAGCAACGGCCAGCCAGAGAACAATTACAAGACAACCCCTCCCGTGCTGGACTCCGATGGAAGCTTCTTCCTGTACTCCAAGCTTACTGTTGATAAGAGCAGATGGCAGCAGGGTAATGTGTTTAGCTGTAGCGTCATGCACGAAGCCCTGCACAACCACTACACCCAAAAATCTCTGAGCCTGAGCCCAGGAAAAGGCGGAGGTGGCTCTGGAGGCGGTGGATCTGGTGGTGGCGGATCAGGTGGAGGCGGGAGCGGAGGCGGCGGTAGTGGTGGAGGAGGCTCTGATAAGACCCACACCTGCCCTCCTTGCCCCGCCCCCGAGGCCGCTGGCGGACCTAGCGTCTTCCTGTTCCCCCCCAAGCCCAAGGACACCCTGATGATTAGCCGGACCCCTGAAGTAACCTGCGTGGTGGTGGACGTGTCTCACGAGGCCCCTGAGGTAAAGTTCAACTGGTACGTGGATGGCGTGGAAGTGCATAATGCCAAGACCAAGCCTTGTGAAGAACAATACGGCAGCACCTACCGCTGCGTGTCCGTTCTGACCGTGCTGCACCAGGACTGGCTGAACGGCAAGGAATACAAGTGCGCCGTGAGCAACAAGGCCCTGCCCGCCCCAATCGAGAAGACCATCAGCAAAGCCAAGGGCCAGCCTAGAGAACCCCAGGTCTACACCCTGCCTCCTAGCCGAGAGGAAATGACAAAGAACCAGGTGTCCCTGACATGCCTGGTGAAGGGCTTCTACCCTTCTGACATCGCCGTGGAGTGGGAGAGCAATGGACAGCCCGAGAACAACTACAAGACCACACCTCCTGTGCTGGATTCTGACGGATCTTTCTTCCTGTACAGCAAGCTGACCGTAGACAAGAGCCGGTGGCAGCAGGGCAACGTGTTCTCCTGTTCCGTGATGCACGAGGCCCTGCACAACCACTACACCCAGAAAAGCCTGTCCCTGAGCCCTGGCAAGGGCGGTGGTGGAAGCGGTGGCGGCGGATCTGAGGTGCAGCTCGTCGAGAGCGGCGGCGGCCTGGTGCAACCAGGAGGCTCACTGCGGCTGTCCTGCAGCTTCAGCGGCTTCTCTCTGAGCACCAGCGGCATGGGAGTCGGCTGGATCAGACAGGCCCCTGGCAAGGGCCTGGAATGGGTGGCTCACATCTGGTGGGACGATGACAAAAGATACAACCCCGCTCTGAAGAGCAGATTTACCCTGAGCGTGGATAGATCTAAAAATACACTGTACCTGCAGATGAACAGCCTGCGGGCGGAGGACACAGCCACATACTACTGCGTGCAGATCAACTACGGCAACTACCGGTTTGACAACTGGGGCCACGGCACACTGGTGACCGTATCTTCAGGCGGAGGAGGTTCAGGTGGAGGTGGATCTGGAGGTGGCGGGTCTGATATTCAGATGACGCAGAGCCCATCTAGCCTGTCTGCTTCAGTGGGCGACAGAGTGACGATCAGCTGTAGAGCCAGCGAAAGCGTGGATAATTACGGCATCAGCTTCCTGAACTGGTTCCAGCAGAAGCCTGGAAAAGCCCCCAAGCTGCTGATCTATGCGGCTAGCAACCAGAGATCCGGAGTGCCGTCCAGATTTTCTGGATCGGGATCCGGCACAGATTTTACCCTGACCATAAGCAGCCTCCAGCCCGAGGACTTCGCCACATACTTCTGCCAGCAGAGCAAGGAGGTACCTTGGACCTTCGGACAAGGAACAAAAGTGGAAATCAAGAGAGGCGGTGGCGGATCAGACATCCAGATGACCCAGAGCCCTTCATCTCTGTCTGCCTCTGTGGGCGACAGAGTGACCATCACCTGCCGGGCCAGTCAGGATATCCGGAACTACCTGAACTGGTACCAGCAGAAGCCCGGAAAGGCTCCTAAGCTGCTGATCTACTATACCAGCAGACTGGAGAGCGGCGTGCCTAGTAGATTCAGCGGCAGCGGAAGCGGCACCGATTACACACTGACCATCAGCAGCTTGCAACCTGAGGACTTTGCCACCTACTACTGCCAGCAGGGAAATACCCTCCCCTGGACATTCGGCCAGGGCACCAAAGTTGAGATCAAGTCTTCTGGAGGCGGAGGTAGTGGTGGTGGAGGGTCAGGCGGCGGTGGAAGCGAGGTGCAGCTGGTGGAGAGCGGTGGGGGCCTGGTGCAGCCCGGCGGCAGCCTGCGGCTGTCGTGTGCCGCATCTGGCTACAGCTTTACCGGCTACACAATGAATTGGGTTAGACAGGCCCCTGGCAAAGGACTGGAATGGGTGGCCCTGATCAACCCTTACAAGGGCGTGAGCACATACAACCAAAAGTTCAAGGACAGATTCACCATCTCTGTCGACAAGTCCAAGAACACGGCCTACCTGCAGATGAACAGCCTTCGGGCCGAGGATACAGCCGrGTATTACTGCGCCAGATCCGGCTACrACGGAGArAGCGATTGGTACTTTGACGTCTGGGGACAGGGCACCCTGGTGACCGTGAGCAGCGGAGGAGGCGGTTCTGATATCCAAATGACACAGTCTCCATCCTCCCTGAGCGCCAGCGTGGGAGACAGAGTGACCATCTCTTGTAGAGCTTCCGAGTCCGTGGATAACTACGGCATCTCTTTCCTGAACTGGTTCCAGCAGAAGCCAGGAAAAGCCCCTAAGCTGCTGATCTACGCCGCCTCTAATCAGCGGAGCGGCGTGCCCAGCCGCTTCAGCGGATCTGGCAGCGGCACCGACTTCACACTGACAATCTCATCTCTTCAGCCAGAGGACTTCGCCACCTACTTCTGCCAGCAGAGCAAGGAAGTGCCTTGGACCTTCGGCCAGGGCACAAAGGTGGAGATCAAAAGAGGCGGCGGAGGCAGCGGCGGCGGAGGTTCTGGCGGTGGAGGCTCCGAGGTGCAGCTCGTGGAGTCTGGAGGCGGCCTGGTGCAGCCTGGCGGCTCTCTGAGACTTAGCTGCAGCTTCAGCGGCTTCTCTCTGAGCACATCAGGCATGGGAGTTGGCTGGATCAGACAAGCTCCTGGCAAAGGCCTGGAATGGGTGGCCCACATCTGGTGGGACGACGACAAGAGATATAACCCGGCCCTGAAGAGCCGGTTCACCCTGTCTGTGGACCGGAGCAAGAACACCCTGTATCTGCAGATGAACTCCCTGAGGGCTGAAGACACCGCCACATACTATTGCGTGCAGATCAACTACGGCAACTACAGGTTCGACAACTGGGGCCATGGCACACTGGTGA CAGTGAGTTCTCACCACCATCATCACCACFSHR PMTE (Fc-LHLHHL) coding sequence (SEQ ID NO:45)ATGATCAGCCGGACACCCGAGGTGACCTGCGTGGTGGTGGACGTATCCCACGAGGCCCCGGAGGTCAAGTTCAACTGGTATGTGGATGGCGTGGAAGTGCACAACGCCAAAACCAAGCCTTGCGAGGAGCAGTACGGCAGTACCTACAGATGCGTGTCCGTGCTGACAGTGCTGCACCAAGACTGGCTGAACGGTAAGGAGTACAAATGCGCCGTGAGCAACAAGGCGCTGCCTGCTCCAATCGAGAAGACCATCAGCAAGGCTAAGGGCCAGCCTAGAGAGCCCCAGGTGTACACCCTGCCTCCTAGCAGAGAGGAAATGACCAAGAACCAAGTGAGTCTGACATGCCTGGTGAAGGGATTCTACCCCAGCGACATTGCCGTGGAATGGGAAAGCAACGGCCAGCCAGAGAACAATTACAAGACAACCCCTCCCGTGCTGGACTCCGATGGAAGCTTCTTCCTGTACTCCAAGCTTACTGTTGATAAGAGCAGATGGCAGCAGGGTAATGTGTTTAGCTGTAGCGTCATGCACGAAGCCCTGCACAACCACTACACCCAAAAATCTCTGAGCCTGAGCCCAGGAAAAGGCGGAGGTGGCTCTGGAGGCGGTGGATCTGGTGGTGGCGGATCAGGTGGAGGCGGGAGCGGAGGCGGCGGTAGTGGTGGAGGAGGCTCTGATAAGACCCACACCTGCCCTCCTTGCCCCGCCCCCGAGGCCGCTGGCGGACCTAGCGTCTTCCTGTTCCCCCCCAAGCCCAAGGACACCCTGATGATTAGCCGGACCCCTGAAGTAACCTGCGTGGTGGTGGACGTGTCTCACGAGGCCCCTGAGGTAAAGTTCAACTGGTACGTGGATGGCGTGGAAGTGCATAATGCCAAGACCAAGCCTTGTGAAGAACAATACGGCAGCACCTACCGCTGCGTGTCCGTTCTGACCGTGCTGCACCAGGACTGGCTGAACGGCAAGGAATACAAGTGCGCCGTGAGCAACAAGGCCCTGCCCGCCCCAATCGAGAAGACCATCAGCAAAGCCAAGGGCCAGCCTAGAGAACCCCAGGTCTACACCCTGCCTCCTAGCCGAGAGGAAATGACAAAGAACCAGGTGTCCCTGACATGCCTGGTGAAGGGCTTCTACCCTTCTGACATCGCCGTGGAGTGGGAGAGCAATGGACAGCCCGAGAACAACTACAAGACCACACCTCCTGTGCTGGATTCTGACGGATCTTTCTTCCTGTACAGCAAGCTGACCGTAGACAAGAGCCGGTGGCAGCAGGGCAACGTGTTCTCCTGTTCCGTGATGCACGAGGCCCTGCACAACCACTACACCCAGAAAAGCCTGTCCCTGAGCCCTGGCAAGGGCGGTGGTGGAAGCGGTGGCGGCGGATCTGAGGTGCAGCTCGTCGAGAGCGGCGGCGGCCTGGTGCAACCAGGAGGCTCACTGCGGCTGTCCTGCAGCTTCAGCGGC'l TCTCrCTGAGCACCAGCGGCATGGGAGTCGGCTGGATCAGACAGGCCCCTGGCAAGGGCCTGGAATGGGTGGCTCACATCTGGTGGGACGATGACAAAAGATACAACCCCGCTCTGAAGAGCAGATTTACCCTGAGCGTGGATAGATCTAAAAATACACTGTACCTGCAGATGAACAGCCTGCGGGCGGAGGACACAGCCACATACTACTGCGTGCAGATCAACTACGGCAACTACCGGTTTGACAACTGGGGCCACGGCACACTGGTGACCGTATCTTCAGGCGGAGGAGGTTCAGGTGGAGGTGGATCTGGAGGTGGCGGGTCTGATATTCAGATGACGCAGAGCCCATCTAGCCTGTCTGCTTCAGTGGGCGACAGAGTGACGATCAGCTGTAGAGCCAGCGAAAGCGTGGATAATTACGGCATCAGCTTCCTGAACTGGTTCCAGCAGAAGCCTGGAAAAGCCCCCAAGCTGCTGATCTATGCGGCTAGCAACCAGAGATCCGGAGTGCCGTCCAGATTTTCTGGATCGGGATCCGGCACAGATTTTACCCTGACCATAAGCAGCCTCCAGCCCGAGGACTTCGCCACATACTTCTGCCAGCAGAGCAAGGAGGTACCTTGGACCTTCGGACAAGGAACAAAAGTGGAAATCAAGAGAGGCGGTGGCGGATCAGACATCCAGATGACCCAGAGCCCTTCATCTCTGTCTGCCTCTGTGGGCGACAGAGTGACCATCACCTGCCGGGCCAGTCAGGATATCCGGAACTACCTGAACTGGTACCAGCAGAAGCCCGGAAAGGCTCCTAAGCTGCTGATCTACTATACCAGCAGACTGGAGAGCGGCGTGCCTAGTAGATTCAGCGGCAGCGGAAGCGGCACCGATTACACACTGACCATCAGCAGCTTGCAACCTGAGGACTTTGCCACCTACTACTGCCAGCAGGGAAATACCCTCCCCTGGACATTCGGCCAGGGCACCAAAGTTGAGATCAAGTCTTCTGGAGGCGGAGGTAGTGGTGGTGGAGGGTCAGGCGGCGGTGGAAGCGAGGTGCAGCTGGTGGAGAGCGGTGGGGGCCTGGTGCAGCCCGGCGGCAGCCTGCGGCTGTCGTGTGCCGCATCTGGCTACAGCTTTACCGGCTACACAATGAATTGGGTTAGACAGGCCCCTGGCAAAGGACTGGAATGGGTGGCCCTGATCAACCCTTACAAGGGCGTGAGCACATACAACCAAAAGTTCAAGGACAGATTCACCATCTCTGTCGACAAGTCCAAGAACACGGCCTACCTGCAGATGAACAGCCTTCGGGCCGAGGATACAGCCGTGTATTACTGCGCCAGATCCGGCTACTACGGAGATAGCGATTGGTACTTTGACGTCTGGGGACAGGGCACCCTGGTGACCGTGAGCAGCGGAGGAGGCGGTTCTGATATCCAAATGACACAGTCTCCATCCTCCCTGAGCGCCAGCGTGGGAGACAGAGTGACCATCTCTTGTAGAGCTTCCGAGTCCGTGGATAACTACGGCATCTCTTTCCTGAACTGGTTCCAGCAGAAGCCAGGAAAAGCCCCTAAGCTGCTGATCTACGCCGCCTCTAATCAGCGGAGCGGCGTGCCCAGCCGCTTCAGCGGATCTGGCAGCGGCACCGACTTCACACTGACAATCTCATCTCTTCAGCCAGAGGACTTCGCCACCTACTTCTGCCAGCAGAGCAAGGAAGTGCCTTGGACCTTCGGCCAGGGCACAAAGGTGGAGATCAAAAGAGGCGGCGGAGGCAGCGGCGGCGGAGGTTCTGGCGGTGGAGGCTCCGAGGTGCAGCTCGTGGAGTCTGGAGGCGGCCTGGTGCAGCCTGGCGGCTCTCTGAGACTTAGCTGCAGCTTCAGCGGCTTCTCTCTGAGCACATCAGGCATGGGAGTTGGCTGGATCAGACAAGCTCCTGGCAAAGGCCTGGAATGGGTGGCCCACATCTGGTGGGACGACGACAAGAGATATAACCCGGCCCTGAAGAGCCGGTTCACCCTGTCTGTGGACCGGAGCAAGAACACCCTGTATCTGCAGATGAACTCCCTGAGGGCTGAAGACACCGCCACATACTATTGCGTGCAGATCAACTACGGCAACTACAGGTTCGACAACTGGGGCCATGGCACACTGGTGACAGTGAGTTCTFSHR PMTE (Fc-LHLHLH) construct (SEQ ID NO:46)GATAAGACCCACACCTGTCCTCCCTGCCCCGCTCCTGAGGCCGCTGGCGGACCTAGCGTCTTCCTGTTCCCTCCAAAGCCGAAGGATACACTTATGATCTCCAGGACACCCGAGGTCACCTGTGTGGTGGTGGACGTGTCCCACGAGGCCCCTGAGGTGAAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCACAACGCCAAGACCAAGCCATGTGAAGAGCAGTACGGCTCTACATACAGATGCGTGTCCGTGCTGACCGTGCTGCACCAAGACTGGCTGAACGGCAAAGAATACAAGTGCGCCGTGTCTAACAAAGCCCTGCCCGCCCCCATTGAGAAGACCATCAGCAAGGCCAAGGGCCAGCCCAGAGAGCCTCAGGTCTACACCCTGCCCCCTTCTAGAGAAGAGATGACCAAGAACCAGGTGAGTCTGACCTGCCTGGTGAAAGGCTTTTACCCTTCTGACATCGCCGTCGAGTGGGAGAGCAACGGCCAGCCTGAGAACAACTATAAGACAACCCCTCCGGTCCTGGACAGCGACGGCTCTTTTTTCCTGTACAGCAAGCTGACAGTGGACAAGAGCCGCTGGCAGCAGGGAAACGTGTTTTCCTGTAGCGTGATGCACGAGGCCCTGCACAACCACTACACCCAGAAGAGCCTGAGCCTGTCTCCTGGCAAGGGCGGAGGTGGCTCTGGAGGCGGTGGATCTGGTGGTGGCGGATCAGGTGGAGGCGGGAGCGGAGGCGGCGGTAGTGGTGGAGGAGGCTCTGATAAGACTCACACATGCCCTCCATGCCCTGCTCCTGAGGCCGCCGGCGGTCCTTCTGTCTTCCTGTTTCCTCCCAAGCCAAAGGATACCCTGATGATCAGTCGGACCCCTGAGGTGACCTGCGTCGTGGTCGACGTGTCCCACGAGGCTCCTGAGGTGAAGTTCAACTGGTACGTTGATGGGGTGGAAGTGCACAACGCCAAGACTAAGCCCTGCGAGGAACAGTACGGCAGCACCTACAGATGTGTGTCAGTGCTGACCGTGCTCCACCAGGACTGGCTGAACGGAAAAGAGTACAAATGCGCCGTGTCTAACAAGGCTCTGCCTGCTCCCATCGAGAAAACAATCTCTAAGGCCAAAGGGCAACCTAGAGAGCCCCAGGTGTACACACTGCCTCCCTCTCGGGAAGAAATGACCAAAAACCAGGTGAGTCTTACCTGTCTGGTTAAAGGATTCTACCCCAGCGACATCGCCGTGGAATGGGAATCCAACGGCCAACCTGAAAATAACTATAAGACCACCCCTCCCGTGCTGGATTCTGATGGCAGCTTCTTCCTGTACTCTAAGCTGACAGTGGACAAGTCTAGATGGCAGCAGGGCAACGTGTTCAGCTGTTCTGTGATGCACGAAGCCCTGCACAACCACTACACCCAGAAGAGCCTCAGCCTGAGCCC GGAAAGGGCGGrGGTGGAAGCGGrGGCGGCGGATCrGAAGTCCAGCrGGTGGAGAGCGGCGGAGGCCTGGTCCAGCCTGGCGGCTCGCTGAGACTGAGCTGCAGCTTCAGCGGCTTCAGCCTGTCCACCAGCGGCATGGGCGTAGGATGGATCCGGCAGGCCCCTGGCAAGGGACTGGAATGGGTGGCCCATATCTGGTGGGACGACGACAAAAGATACAACCCCGCGCTTAAGTCTAGATTTACACTTAGCGTAGACAGATCTAAGAACACCCTGTACCTGCAGATGAACAGCCTCAGAGCAGAAGATACCGCCACCTACTACTGCGTGCAGATCAATTACGGCAACTACCGGTTCGACAACTGGGGCCACGGCACCCTGGTGACAGTCTCCAGCGGCGGAGGAGGTTCAGGTGGAGGTGGATCTGGAGGTGGCGGGTCTGACATCCAGATGACACAGTCTCCTAGCTCTCTGAGCGCCTCTGTTGGAGACCGGGTGACCATCAGCTGTAGAGCCAGCGAGAGCGTGGATAACTACGGCATCTCCTTTCTGAACTGGTTCCAGCAAAAGCCCGGCAAAGCCCCTAAGCTGCTGATCTACGCCGCCAGCAATCAAAGAAGCGGCGTGCCTAGCAGGTTCAGTGGCAGCGGCTCTGGAACAGACTTCACCCTGACTATCAGCAGCCTGCAGCCTGAAGACTTCGCTACCTACTTCTGCCAACAATCGAAGGAGGTTCCTTGGACCTTCGGCCAAGGCACAAAGGTGGAAATCAAGCGGGGCGGTGGCGGATCAGACATCCAGATGACCCAGAGTCCTAGCTCTCTGTCCGCCTCTGTGGGCGATAGAGTGACAATCACCTGCAGAGCATCTCAGGACATCCGGAACTACCTGAATTGGTACCAGCAGAAACCCGGAAAGGCCCCGAAGCTGCTGATCTACTATACCAGCCGGCTGGAATCCGGCGTCCCTTCTCGTTTCTCAGGTAGCGGCAGCGGAACCGACTACACACTCACCATTAGCAGCCTGCAGCCTGAGGATTTCGCCACATACTACTGCCAGCAGGGCAATACCCTGCCTTGGACATTTGGACAGGGCACAAAGGTGGAAATCAAGAGTAGCGGAGGCGGAGGTAGTGGTGGTGGAGGGTCAGGCGGCGGTGGAAGCGAGGTGCAACTGGTCGAAAGCGGCGGCGGACTGGTGCAGCCTGGCGGAAGCCTGAGACTGAGCTGCGCTGCTAGCGGCTATAGCTTCACCGGCTACACCATGAACTGGGTGCGGCAGGCTCCAGGAAAGGGCCTGGAATGGGTTGCCCTGATCAACCCCTACAAAGGTGTGTCAACATACAACCAGAAATTCAAGGACAGATTCACCATCAGCGTGGATAAGAGCAAGAACACCGCCTACCTGCAGATGAATAGCCTGCGCGCTGAGGACACCGCTGTCTATTACTGTGCCAGAAGCGGATACTATGGCGACAGCGATTGGTACTTCGACGTGTGGGGCCAGGGCACTCTGGTGACCGTGAGCAGCGGAGGAGGCGGTTCTGAGGTGCAGCTGGTGGAATCTGGCGGCGGCCTGGTGCAGCCCGGCGGCAGTCTGCGGCTGAGCTGCAGCTTCTCTGGCTTCAGCCTGAGCACCAGCGGCATGGGCGTGGGATGGATCAGACAGGCCCCTGGCAAGGGACTGGAATGGGTGGCCCACATCTGGTGGGATGACGACAAGCGGTACAACCCGGCCCTGAAGTCCCGGTTTACACTGTCCGTGGATAGAAGCAAGAATACCCTGTACCTGCAGATGAACAGCCTGAGAGCCGAGGATACAGCTACTTACTACTGCGTGCAGATCAACTATGGCAATTACAGATTCGACAACTGGGGACACGGCACCCTGGTGACCGTGTCTTCTGGGGGCGGCGGCTCCGGCGGCGGAGGATCCGGCGGAGGAGGCTCTGACATCCAGATGACACAGTCTCCAAGTAGCCTGAGCGCCTCTGTGGGCGATAGAGTGACAATCTCTTGCAGAGCCAGCGAGAGCGTGGACAATTACGGCATCAGCTTTCTGAACTGGTTCCAACAGAAGCCTGGAAAGGCCCCTAAACTGCTGATCTACGCGGCTTCTAATCAGAGAAGCGGAGTGCCTAGCCGGTTTAGCGGAAGTGGCAGCGGCACAGACTTCACCCTGACCATTAGCTCCTTGCAGCCCGAGGACTTTGCCACCTATTTCTGCCAGCAGAGCAAGGAAGTCCCGTGGACCTTCGGCCAGGGCACCAAGGTGGAGATCAAGAGACACCACCATCACCATCACFSHR PMTE (Fc-LHLHLH) coding sequence (SEQ ID NO:47)ArGArCTCCAGGACACCCGAGGTCACCrGTGrGGrGG GGACGTGrCCCACGAGGCCCCTGAGGlGAAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCACAACGCCAAGACCAAGCCATGTGAAGAGCAGTACGGCTCTACATACAGATGCGTGTCCGTGCTGACCGTGCTGCACCAAGACTGGCTGAACGGCAAAGAATACAAGTGCGCCGTGTCTAACAAAGCCCTGCCCGCCCCCATTGAGAAGACCATCAGCAAGGCCAAGGGCCAGCCCAGAGAGCCTCAGGTCTACACCCTGCCCCCTTCTAGAGAAGAGATGACCAAGAACCAGGTGAGTCTGACCTGCCTGGTGAAAGGCTTTTACCCTTCTGACATCGCCGTCGAGTGGGAGAGCAACGGCCAGCCTGAGAACAACTATAAGACAACCCCTCCGGTCCTGGACAGCGACGGCTCTTTTTTCCTGTACAGCAAGCTGACAGTGGACAAGAGCCGCTGGCAGCAGGGAAACGTGTTTTCCTGTAGCGTGATGCACGAGGCCCTGCACAACCACTACACCCAGAAGAGCCTGAGCCTGTCTCCTGGCAA GGGCGGAGGTGGCTCTGGAGGCGGTGGATCTGGTGGTGGCGGATCAGGTGGAGGCGGGAGCGGA GGCGGCGGTAGTGGTGGAGGAGGCTCTGATAAGACTCACACATGCCCTCCATGCCCTGCTCCTGAGGCCGCCGGCGGTCCTTCTGTCTTCCTGTTTCCTCCCAAGCCAAAGGATACCCTGATGATCAGTCGGACCCCTGAGGTGACCTGCGTCGTGGTCGACGTGTCCCACGAGGCTCCTGAGGTGAAGTTCAACTG GTACGTTGATGGGGTGGAAGTGCACAACGCCAAGACTAAGCCCTGCGAGGAACAGTACGGCAGCA CCTACAGATGTGTGTCAGTGCTGACCGTGCTCCACCAGGACTGGCTGAACGGAAAAGAGTACAAATGCGCCGTGTCTAACAAGGCTCTGCCTGCTCCCATCGAGAAAACAATCTCTAAGGCCAAAGGGCAACCTAGAGAGCCCCAGGTGTACACACTGCCTCCCTCTCGGGAAGAAATGACCAAAAACCAGGTGA GTCTTACCTGTCTGGTTAAAGGATTCTACCCCAGCGACATCGCCGTGGAATGGGAATCCAACGGCC AACCTGAAAATAACTATAAGACCACCCCTCCCGTGCTGGATTCTGATGGCAGCTTCTTCCTGTACT CTAAGCTGACAGTGGACAAGTCTAGATGGCAGCAGGGCAACGTGTTCAGCTGTTCTGTGATGCACGAAGCCCTGCACAACCACTACACCCAGAAGAGCCTCAGCCTGAGCCCTGGAAAGGGCGGTGGTGGAAGCGGTGGCGGCGGArCTGAAGTCCAGCTGGrGGAGAGCGGCGGAGGCCrGGTCCAGCCTGGCGGCTCGCTGAGACTGAGCTGCAGCTTCAGCGGCTTCAGCCTGTCCACCAGCGGCATGGGCGTAGGATGGATCCGGCAGGCCCCTGGCAAGGGACTGGAATGGGTGGCCCATATCTGGTGGGACGACGACAAAAGATACAACCCCGCGCTTAAGTCTAGATTTACACTTAGCGTAGACAGATCTAAGAACACCCTGTACCTGCAGATGAACAGCCTCAGAGCAGAAGATACCGCCACCTACTACTGCGTGCAGATCAATTACGGCAACTACCGGTTCGACAACTGGGGCCACGGCACCCTGGTGACAGTCTCCAGCGGCGGAGGAGGTTCAGGTGGAGGTGGATCTGGAGGTGGCGGGTCTGACATCCAGATGACACAGTCTCCTAGCTCTCTGAGCGCCTCTGTTGGAGACCGGGTGACCATCAGCTGTAGAGCCAGCGAGAGCGTGGATAACTACGGCATCTCCTTTCTGAACTGGTTCCAGCAAAAGCCCGGCAAAGCCCCTAAGCTGCTGATCTACGCCGCCAGCAATCAAAGAAGCGGCGTGCCTAGCAGGTTCAGTGGCAGCGGCTCTGGAACAGACTTCACCCTGACTATCAGCAGCCTGCAGCCTGAAGACTTCGCTACCTACTTCTGCCAACAATCGAAGGAGGTTCCTTGGACCTTCGGCCAAGGCACAAAGGTGGAAATCAAGCGGGGCGGTGGCGGATCAGACATCCAGATGACCCAGAGTCCTAGCTCTCTGTCCGCCTCTGTGGGCGATAGAGTGACAATCACCTGCAGAGCA TCTCAGGACATCCGGAACTACCTGAATTGGTACCAGCAGAAACCCGGAAAGGCCCCGAAGCTGCT GATCTACTATACCAGCCGGCTGGAATCCGGCGTCCCTTCTCGTTTCTCAGGTAGCGGCAGCGGAAC CGACTACACACTCACCATTAGCAGCCTGCAGCCTGAGGATTTCGCCACATACTACTGCCAGCAGGGCAATACCCTGCCTTGGACATTTGGACAGGGCACAAAGGTGGAAATCAAGAGTAGCGGAGGCGGAGGTAGTGGTGGTGGAGGGTCAGGCGGCGGTGGAAGCGAGGTGCAACTGGTCGAAAGCGGCGGCGGACTGGTGCAGCCTGGCGGAAGCCTGAGACTGAGCTGCGCTGCTAGCGGCTATAGCTTCACCGGCTACACCATGAACTGGGTGCGGCAGGCTCCAGGAAAGGGCCTGGAATGGGTTGCCCTGATCAACCCCTACAAAGGTGTGTCAACATACAACCAGAAATTCAAGGACAGATTCACCATCAGCGTGGATAAGAGCAAGAACACCGCCTACCTGCAGATGAATAGCCTGCGCGCTGAGGACACCGCTGTCTATTACTGTGCCAGAAGCGGATACTATGGCGACAGCGATTGGTACTTCGACGTGTGGGGCCAGGGCACTCTGGTGACCGTGAGCAGCGGAGGAGGCGGTTCTGAGGTGCAGCTGGTGGAATCTGGCGGCGGCCTGGTGCAGCCCGGCGGCAGTCTGCGGCTGAGCTGCAGCTTCTCTGGCTTCAGCCTGAGCACCAGCGGCATGGGCGTGGGATGGATCAGACAGGCCCCTGGCAAGGGACTGGAATGGGTGGCCCACATCTGGTGGGATGA CGACAAGCGGTACAACCCGGCCCTGAAGTCCCGGTTTACACTGTCCGTGGATAGAAGCAAGAATA CCCTGTACCTGCAGATGAACAGCCTGAGAGCCGAGGATACAGCTACTTACTACTGCGTGCAGATC AACTATGGCAATTACAGATTCGACAACTGGGGACACGGCACCCTGGTGACCGTGTCTTCTGGGGGCGGCGGCTCCGGCGGCGGAGGATCCGGCGGAGGAGGCTCTGACATCCAGATGACACAGTCTCCAAGTAGCCTGAGCGCCTCTGTGGGCGATAGAGTGACAATCTCTTGCAGAGCCAGCGAGAGCGTGGACAATTACGGCATCAGCTTTCTGAACTGGTTCCAACAGAAGCCTGGAAAGGCCCCTAAACTGCTGATC TACGCGGCTTCTAATCAGAGAAGCGGAGTGCCTAGCCGGTTTAGCGGAAGTGGCAGCGGCACAGA CTTCACCCTGACCATTAGCTCCTTGCAGCCCGAGGACTTTGCCACCTATTTCTGCCAGCAGAGCAA GGAAGTCCCGTGGACCTTCGGCCAGGGCACCAAGGTGGAGATCAAGAGAFSHR PMTE (Fc-HLLHHL) construct (SEQ ID NO:48)GACAAGACCCACACCTGCCCTCCTTGTCCTGCTCCTGAGGCTGCCGGCGGCCCTAGCGTTTTCCTCTTCCCTCCAAAGCCCAAGGATACACTGATGATCAGCAGAACCCCTGAGGTCACCTGTGTGGTCGTGGACGTAAGCCACGAGGCCCCTGAAGTGAAATTCAACTGGTACGTGGATGGAGTGGAGGTTCACAATGCCAAGACCAAGCCTTGCGAGGAACAGTACGGCTCCACA ACCGGrGCGTGAGCGrGCrGACCGlGCTGCACCAGGACTGGCTTAACGGCAAAGAGTACAAGTGTGCCGTGTCTAACAAGGCCCTGCCTGCCCCCATCGAAAAGACCATCTCCAAGGCCAAGGGCCAGCCTAGAGAGCCTCAGGTGTACACCCTGCCACCTTCTCGGGAAGAGATGACCAAAAACCAGGTGTCCCTGACATGTCTGGTGAAAGGCTTCTACCCTAGCGACATTGCCGTGGAATGGGAAAGCAACGGCCAGCCTGAGAACAACTATAAGACAACCCCTCCTGTGCTCGACAGCGACGGCTCTTTCTTCCTGTACAGCAAGCTGACAGTGGACAAGAGCAGGTGGCAACAAGGCAACGTGTTCAGCTGCAGCGTGATGCACGAGGCCCTGCACAATCACTACACACAGAAGTCTCTTAGCCTGAGCCCTGGAAAAGGCGGAGGTGGCTCTGGAGGCGGTGGATCTGGTGGTGGCGGATCAGGTGGAGGCGGGAGCGGAGGCGGCGGTAGTGGTGGAGGAGGCTCTGATAAGACACACACATGTCCTCCTTGTCCTGCTCCTGAGGCCGCCGGTGGTCCTAGCGTGTTCTTGTTCCCCCCCAAGCCAAAAGACACACTGATGATAAGCCGGACGCCTGAGGTGACGTGCGTGGTGGTGGATGTGAGCCACGAAGCTCCCGAAGTTAAGTTCAATTGGTATGTGGACGGCGTCGAAGTTCACAACGCCAAGACAAAACCGTGCGAGGAGCAGTACGGTTCTACATACAGATGCGTGTCTGTGCTGACCGTGCTGCATCAGGATTGGCTGAATGGGAAAGAGTACAAATGCGCCGTGTCTAACAAGGCCCTGCCCGCCCCAATCGAGAAGACCATCTCTAAGGCCAAGGGACAGCCAAGAGAGCCCCAGGTGTACACACTGCCTCCTAGCAGAGAAGAGATGACCAAGAATCAGGTGTCCCTGACCTGCCTGGTGAAGGGCTTCTACCCCTCTGACATCGCCGTGGAATGGGAGAGCAACGGCCAACCTGAAAACAACTACAAGACCACCCCTCCAGTGCTGGACTCTGACGGAAGTTTTTTCCTATACAGCAAGCTGACAGTCGACAAGTCCAGATGGCAGCAGGGAAATGTGTTCAGCTGCAGCGTGATGCACGAGGCCCTGCACAACCACTACACCCAGAAATCCCTGAGCCTGAGCCCAGGAAAAGGCGGTGGTGGAAGCGGTGGCGGCGGATCTGACATTCAGATGACCCAGTCTCCTTCCAGCCTGTCAGCCAGCGTGGGCGATCGCGTGACAATTAGCTGTAGAGCCTCCGAAAGTGTGGACAACTATGGCATCAGCTTCCTGAACTGGTTCCAGCAGAAACCTGGCAAGGCCCCCAAGCTGCTGATCTACGCCGCTTCCAACCAGCGGTCTGGCGTGCCTAGCAGATTTTCAGGCAGCGGAAGCGGCACAGACTTCACACTGACTATCTCTAGCCTGCAGCCCGAGGACTTTGCCACCTACTTCTGCCAACAATCCAAGGAAGTGCCCTGGACCTTCGGCCAGGGCACCAAGGTGGAAATCAAGCGGGGCGGAGGAGGTTCAGGTGGAGGTGGATCTGGAGGTGGCGGGTCTGAGGTGCAGCTGGTTGAGAGCGGAGGCGGCCTCGTCCAGCCCGGAGGCAGCCTCCGGCTGTCTTGTAGCTTCTCCGGCTTTAGCCTGAGTACCAGCGGCATGGGAGTCGGCTGGATCCGGCAGGCCCCTGGGAAGGGCCTCGAGTGGGTGGCCCACATCTGGTGGGACGACGACAAGAGATACAACCCCGCTCTTAAGTCTCGCTTCACCCTGTCTGTGGACAGATCCAAAAACACACTGTACCTGCAGATGAACAGCCTGAGAGCTGAGGATACCGCCACCTACTACTGCGTGCAGATCAACTACGGCAATTACCGGTTCGATAACTGGGGACACGGAACCCTGGTGACCGTTAGCTCCGGCGGTGGCGGATCAGACATCCAGATGACCCAGAGCCCCTCTAGCCTGAGCGCCAGCGTCGGCGATAGAGTGACAATAACATGCAGAGCTAGCCAGGACATCCGGAACTACCTGAACTGGTACCAGCAGAAGCCAGGCAAGGCCCCTAAGCTGCTGATCTACTATACCTCGCGGCTGGAATCTGGGGTGCCCAGCCGGTTCTCTGGCAGCGGCTCTGGCACCGACTACACGCTGACAATCTCTAGCCTGCAGCCCGAGGACTTCGCCACATACTATTGTCAGCAGGGTAACACCCTTCCTTGGACATTCGGACAGGGCACGAAGGTGGAAATCAAGTCGTCCGGAGGCGGAGGTAGTGGTGGTGGAGGGTCAGGCGGCGGTGGAAGCGAGGTGCAGCTGGTGGAAAGCGGAGGCGGCCTGGTGCAGCCTGGCGGATCTCTGAGACTGTCTTGCGCCGCCrCTGGCTACTCATrCACCGGCrACACCA GAATrGGGrGCGGCAGGCCCCTGGCAAAGGACrGGAATGGGTTGCGCTGATCAACCCCTACAAGGGTGTGTCTACATACAACCAGAAGTTCAAGGACAGATTTACCATCTCCGTCGATAAGAGTAAGAACACCGCCTACCTGCAAATGAACAGCCTGCGGGCGGAGGACACCGCCGTGTACTACTGCGCAAGAAGCGGCTACTACGGCGACAGCGATTGGTACTTCGACGTGTGGGGCCAGGGCACCCTCGTGACCGTGAGCTCTGGAGGAGGCGGTTCTGATATCCAGATGACACAAAGCCCCAGCTCCCTGTCTGCCAGCGTGGGAGATAGAGTGACCATCTCCTGCAGAGCCTCCGAGAGTGTGGATAACTACGGAATCAGCTTTCTGAACTGGTTCCAGCAGAAGCCCGGAAAAGCCCCTAAGCTGCTGATCTACGCCGCTAGTAATCAGAGAAGCGGTGTTCCGAGCAGGTTCAGCGGCTCCGGCTCTGGTACAGATTTCACCCTGACAATCTCTAGCCTGCAGCCTGAGGATTTCGCCACCTACTTTTGCCAGCAGTCAAAGGAAGTGCCCTGGACCTTTGGCCAAGGCACAAAGGTGGAGATCAAGAGAGGCGGCGGTGGGAGCGGCGGAGGCGGTTCCGGCGGCGGCGGCTCCGAGGTGCAACTAGTCGAAAGTGGAGGCGGACTGGTGCAGCCTGGCGGCTCTCTGAGACTGAGCTGCAGCTTCAGCGGCTTCAGCCTCAGCACCAGCGGCATGGGCGTGGGCTGGATCAGACAGGCACCAGGCAAAGGGCTGGAATGGGTCGCCCACATCTGGTGGGACGACGATAAGCGGTACAACCCTGCCTTGAAGAGCAGATTCACCCTGAGCGTGGACAGATCTAAGAATACCCTGTACCTGCAGATGAACTCACTGCGGGCCGAGGACACTGCTACCTACTACTGCGTGCAAATCAACTACGGCAATTATAGATTCGACAACTGGGGCCACGGCACCCTGGTGACCGTGTCGAGCCACCACCACCACCACCATFSHR PMTE (Fc-HLLHHL) coding sequence (SEQ ID NO:49)ATGATCAGCAGAACCCCTGAGGTCACCTGTGTGGTCGTGGACGTAAGCCACGAGGCCCCTGAAGTGAAATTCAACTGGTACGTGGATGGAGTGGAGGTTCACAATGCCAAGACCAAGCCTTGCGAGGAACAGTACGGCTCCACATACCGGTGCGTGAGCGTGCTGACCGTGCTGCACCAGGACTGGCTTAACGGCAAAGAGTACAAGTGTGCCGTGTCTAACAAGGCCCTGCCTGCCCCCATCGAAAAGACCATCTCCAAGGCCAAGGGCCAGCCTAGAGAGCCTCAGGTGTACACCCTGCCACCTTCTCGGGAAGAGATGACCAAAAACCAGGTGTCCCTGACATGTCTGGTGAAAGGCTTCTACCCTAGCGACATTGCCGTGGAATGGGAAAGCAACGGCCAGCCTGAGAACAACTATAAGACAACCCCTCCTGTGCTCGACAGCGACGGCTCTTTCTTCCTGTACAGCAAGCTGACAGTGGACAAGAGCAGGTGGCAACAAGGCAACGTGTTCAGCTGCAGCGTGATGCACGAGGCCCTGCACAATCACTACACACAGAAGTCTCTTAGCCTGAGCCCTGGAAAAGGCGGAGGTGGCTCTGGAGGCGGTGGATCTGGTGGTGGCGGATCAGGTGGAGGCGGGAGCGGAGGCGGCGGrAGrGGTGGAGGAGGCrCTGArAAGACACACACATGTCCTCCrrGrCCrGC CCTGAGGCCGCCGGTGGTCCTAGCGTGTTCTTGTTCCCCCCCAAGCCAAAAGACACACTGATGATAAGCCGGACGCCTGAGGTGACGTGCGTGGTGGTGGATGTGAGCCACGAAGCTCCCGAAGTTAAGTTCAATTGGTATGTGGACGGCGTCGAAGTTCACAACGCCAAGACAAAACCGTGCGAGGAGCAGTACGGTTCTACATACAGATGCGTGTCTGTGCTGACCGTGCTGCATCAGGATTGGCTGAATGGGAAAGAGTACAAATGCGCCGTGTCTAACAAGGCCCTGCCCGCCCCAATCGAGAAGACCATCTCTAAGGCCAAGGGACAGCCAAGAGAGCCCCAGGTGTACACACTGCCTCCTAGCAGAGAAGAGATGACCAAGAATCAGGTGTCCCTGACCTGCCTGGTGAAGGGCTTCTACCCCTCTGACATCGCCGTGGAATGGGAGAGCAACGGCCAACCTGAAAACAACTACAAGACCACCCCTCCAGTGCTGGACTCTGACGGAAGTTTTTTCCTATACAGCAAGCTGACAGTCGACAAGTCCAGATGGCAGCAGGGAAATGTGTTCAGCTGCAGCGTGATGCACGAGGCCCTGCACAACCACTACACCCAGAAATCCCTGAGCCTGAGCCCAGGAAAAGGCGGTGGTGGAAGCGGTGGCGGCGGATCTGACATTCAGATGACCCAGTCTCCTTCCAGCCTGTCAGCCAGCGTGGGCGATCGCGTGACAATTAGCTGTAGAGCCTCCGAAAGTGTGGACAACTATGGCATCAGCTTCCTGAACTGGTTCCAGCAGAAACCTGGCAAGGCCCCCAAGCTGCTGATCTACGCCGCTTCCAACCAGCGGTCTGGCGTGCCTAGCAGATTTTCAGGCAGCGGAAGCGGCACAGACTTCACACTGACTATCTCTAGCCTGCAGCCCGAGGACTTTGCCACCTACTTCTGCCAACAATCCAAGGAAGTGCCCTGGACCTTCGGCCAGGGCACCAAGGTGGAAATCAAGCGGGGCGGAGGAGGTTCAGGTGGAGGTGGATCTGGAGGTGGCGGGTCTGAGGTGCAGCTGGTTGAGAGCGGAGGCGGCCTCGTCCAGCCCGGAGGCAGCCTCCGGCTGTCTTGTAGCTTCTCCGGCTTTAGCCTGAGTACCAGCGGCATGGGAGTCGGCTGGATCCGGCAGGCCCCTGGGAAGGGCCTCGAGTGGGTGGCCCACATCTGGTGGGACGACGACAAGAGATACAACCCCGCTCTTAAGTCTCGCTTCACCCTGTCTGTGGACAGATCCAAAAACACACTGTACCTGCAGATGAACAGCCrGAGAGCTGAGGArACCGCCACCrACTACTGCGTGCAGArCAACTACGGCAAT ACCGGl TOGATAACTGGGGACACGGAACCCTGGTGACCGTTAGCTCCGGCGGTGGCGGATCAGACATCCAGATGACCCAGAGCCCCTCTAGCCTGAGCGCCAGCGTCGGCGATAGAGTGACAATAACATGCAGAGCTAGCCAGGACATCCGGAACTACCTGAACTGGTACCAGCAGAAGCCAGGCAAGGCCCCTAAGCTGCTGATCTACTATACCTCGCGGCTGGAATCTGGGGTGCCCAGCCGGTTCTCTGGCAGCGGCTCTGGCACCGACTACACGCTGACAATCTCTAGCCTGCAGCCCGAGGACTTCGCCACATACTATTGTCAGCAGGGTAACACCCTTCCTTGGACATTCGGACAGGGCACGAAGGTGGAAATCAAGTCGTCCGGAGGCGGAGGTAGTGGTGGTGGAGGGTCAGGCGGCGGTGGAAGCGAGGTGCAGCTGGTGGAAAGCGGAGGCGGCCTGGTGCAGCCTGGCGGATCTCTGAGACTGTCTTGCGCCGCCTCTGGCTACTCATTCACCGGCTACACCATGAATTGGGTGCGGCAGGCCCCTGGCAAAGGACTGGAATGGGTTGCGCTGATCAACCCCTACAAGGGTGTGTCTACATACAACCAGAAGTTCAAGGACAGATTTACCATCTCCGTCGATAAGAGTAAGAACACCGCCTACCTGCAAATGAACAGCCTGCGGGCGGAGGACACCGCCGTGTACTACTGCGCAAGAAGCGGCTACTACGGCGACAGCGATTGGTACTTCGACGTGTGGGGCCAGGGCACCCTCGTGACCGTGAGCTCTGGAGGAGGCGGTTCTGATATCCAGATGACACAAAGCCCCAGCTCCCTGTCTGCCAGCGTGGGAGATAGAGTGACCATCTCCTGCAGAGCCTCCGAGAGTGTGGATAACTACGGAATCAGCTTTCTGAACTGGTTCCAGCAGAAGCCCGGAAAAGCCCCTAAGCTGCTGATCTACGCCGCTAGTAATCAGAGAAGCGGTGTTCCGAGCAGGTTCAGCGGCTCCGGCTCTGGTACAGATTTCACCCTGACAATCTCTAGCCTGCAGCCTGAGGATTTCGCCACCTACTTTTGCCAGCAGTCAAAGGAAGTGCCCTGGACCTTTGGCCAAGGCACAAAGGTGGAGATCAAGAGAGGCGGCGGTGGGAGCGGCGGAGGCGGTTCCGGCGGCGGCGGCTCCGAGGTGCAACTAGTCGAAAGTGGAGGCGGACTGGTGCAGCCTGGCGGCTCTCTGAGACTGAGCTGCAGCTTCAGCGGCTTCAGCCTCAGCACCAGCGGCATGGGCGTGGGCTGGATCAGACAGGCACCAGGCAAAGGGCTGGAATGGGTCGCCCACATCTGGTGGGACGACGATAAGCGGTACAACCCTGCCTTGAAGAGCAGATTCACCCTGAGCGTGGACAGATCTAAGAATACCCTGTACCTGCAGATGAACTCACTGCGGGCCGAGGACACTGCTACCTACTACTGCGTGCAAATCAACTACGGCAATTATAGATTCGACAACTGGGGCCACGGCACCCTGGTGACCGTGTCGAGCFSHR PMTE (Fc-HLLHLH) construct sequence (SEQ ID NO:50)GACAAGACTCACACATGTCCCCCATGCCCCGCCCCTGAGGCTGCTGGCGGCCCTAGCGTCTTCCTGTTTCCCCCTAAGCCCAAGGACACACTGATGATCAGTAGAACACCAGAGGTGACCTGCGTTGTTGTGGACGTGTCCCACGAAGCCCCAGAAGTGAAGTTCAACTGGTACGTGGACGGCGTGGAAGTGCATAATGCCAAGACCAAGCCTTGCGAAGAACAGTACGGCTCCACCTACAGATGCGTTAGCGTGCTGACCGTGCTGCATCAGGACTGGCTGAACGGCAAGGAATACAAGTGTGCCGTGTCCAACAAGGCCCTGCCTGCTCCTATCGAGAAAACTATCTCTAAAGCCAAGGGGCAGCCCCGGGAACCCCAGGTGTACACCCTCCCACCTTCCCGTGAGGAAATGACCAAAAATCAGGTAAGCCTGACCTGCCTGGTGAAGGGATTTTACCCCAGCGACATTGCCGTGGAGTGGGAGTCTAATGGCCAGCCGGAGAATAACTACAAGACAACCCCTCCAGTGCTGGACAGCGATGGATCTTTTTTCCTGTACTCGAAGCTGACTGTGGACAAGAGCAGATGGCAGCAGGGCAATGTGTTCAGCTGTTCTGTCATGCACGAGGCCCTGCACAACCACTACACGCAGAAATCACTGTCTCTGTCACCTGGAAAAGGCGGAGGTGGCTCTGGAGGCGGTGGATCTGGTGGTGGCGGATCAGGTGGAGGCGGGAGCGGAGGCGGCGGTAGTGGTGGAGGAGGCTCTGATAAGACTCACACCTGCCCTCCTTGCCCTGCTCCCGAGGCTGCCGGCGGCCCTAGCGTGTTCCTGTTCCCCCCTAAGCCCAAAGACACACTGATGATCAGTAGAACCCCTGAAGTGACCTGCGTGGTGGTGGACGTCAGCCACGAGGCACCAGAGGTGAAATTCAACTGGTATGTGGACGGCGTCGAAGTGCACAACGCCAAGACCAAGCCCTGTGAAGAGCAGTACGGCAGCACCTACAGATGCGTGTCCGTGCTGACCGTGCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCGCCGTGTCTAACAAGGCCCTGCCTGCACCTATAGAGAAGACAATCrcrAAGGCCAAGGGACAGCCTAGAGAGCCrCAAGrGTACACACTGCCTCCCAGCCGCGAGGAAATGACAAAGAACCAGGTGAGCCTGACATGCCTGGTGAAGGGCTTCTACCCTAGCGATATTGCCGTGGAGTGGGAAAGCAACGGACAGCCTGAAAACAACTACAAGACCACACCTCCTGTGCTGGACAGCGACGGAAGCTTCTTCCTGTACAGCAAGCTGACCGTGGACAAGAGCAGATGGCAGCAAGGTAATGTGTTCAGTTGCAGCGTGATGCACGAGGCCCTCCACAACCACTACACCCAGAAGTCTTTGAGCCTGAGCCCTGGCAAGGGCGGTGGTGGAAGCGGTGGCGGCGGATCTGACATCCAGATGACCCAGTCGCCTTCTTCTCTGTCTGCTAGCGTGGGCGACAGAGTGACCATCTCTTGCAGAGCCTCCGAGAGCGTGGACAACTACGGCATCTCCTTCCTCAATTGGTTCCAGCAAAAACCCGGCAAGGCTCCTAAGCTGCTGATCTACGCCGCTAGCAACCAAAGAAGCGGCGTGCCAAGCAGATTCAGCGGCAGCGGATCAGGCACCGATTTCACATTAACCATCTCTAGTCTGCAGCCTGAGGACTTCGCCACGTACTTTTGCCAGCAGAGCAAGGAGGTGCCATGGACCTTCGGCCAAGGCACAAAGGTGGAAATCAAGCGGGGCGGAGGAGGTTCAGGTGGAGGTGGATCTGGAGGTGGCGGGTCTGAAGTGCAGCTGGTTGAAAGCGGCGGTGGCCTGGTGCAGCCTGGCGGCTCCCTGAGACTGTCTTGTAGCTTCAGCGGCTTCAGCCTGAGCACCAGCGGCATGGGCGTGGGCTGGATCCGGCAGGCCCCTGGCAAGGGCCTGGAGTGGGTTGCTCACATCTGGTGGGATGACGACAAGCGGTACAACCCTGCCCTGAAGAGCAGATTCACACTGTCCGTGGATAGAAGCAAAAACACCCTGTACCTGCAAATGAATTCCCTGCGGGCCGAGGACACCGCTACCTACTACTGCGTGCAGATCAACTACGGCAACTACCGGTTCGACAACTGGGGACACGGAACACTGGTGACAGTGTCCAGCGGCGGTGGCGGATCAGATATACAGATGACCCAGAGCCCTTCTAGCCTGAGCGCCTCAGTGGGCGACAGAGTGACCATCACCTGTCGGGCGAGCCAGGATATCAGAAACTATCTGAACTGGTACCAACAGAAGCCTGGTAAAGCCCCTAAGCTGCTGATCTACTACACCAGCCGGCTGGAAAGCGGAGTGCCTTCTAGATTCAGCGGTTCCGGCAGTGGAACCGACTACACCCTTACCATCTCCAGCCTCCAGCCAGAGGATTTCGCCACATATTACTGTCAGCAGGGCAACACCCTGCCGTGGACCTTTGGCCAGGGCACCAAAGTGGAGATCAAATCCTCTGGAGGCGGAGGTAGTGGTGGTGGAGGGTCAGGCGGCGGTGGAAGCGAGGTGCAGCTGGTGGAAAGTGGAGGCGGCCTGGTCCAGCCCGGCGGCTCTCTGAGACTGTCGTGCGCCGCCTCCGGATATAGCTTCACCGGCTACACCATGAACTGGGTGCGGCAAGCCCCTGGTAAGGGACTGGAGTGGGTGGCCCTCATTAACCCTTACAAAGGAGTCAGCACATACAATCAAAAGTTCAAGGACAGGTTCACAATCTCAGTTGACAAGTCTAAGAACACGGCCTACCTGCAGATGAACAGCTTGAGAGCTGAGGACACCGCTGTGTACTATTGCGCTAGAAGCGGCTACTACGGCGACTCTGATTGGTACTTCGATGTGTGGGGCCAGGGCACGCTGGTGACAGTGTCCTCCGGAGGAGGCGGTTCTGAAGTGCAGCTGGTGGAGAGCGGTGGCGGCCTGGTCCAGCCCGGCGGAAGCCTGAGACTAAGCTGCAGCTTCAGCGGATTCTCGCTGAGCACCAGCGGCATGGGCGTGGGATGGATCAGACAGGCCCCTGGAAAGGGCCTGGAGTGGGTGGCCCACATCTGGTGGGACGACGACAAACGGTACAACCCGGCCTTGAAGTCTCGGTTCACCCTGAGCGTGGATAGAAGCAAGAACACACTGTATCTGCAGATGAACAGCCTGAGAGCCGAGGACACCGCCACCTACTATTGTGTGCAAATCAACTATGGCAACTACAGATTCGACAACTGGGGCCACGGCACACTGGTTACAGTCTCCTCTGGCGGTGGCGGCTCTGGAGGCGGCGGCTCTGGCGGCGGTGGCTCAGATATCCAGATGACCCAGAGCCCTAGCAGCCTGAGCGCCAGCGTGGGAGATCGCGTGACCATCAGCTGCAGAGCCAGCGAGAGCGTTGATAACTACGGCATCAGCTTCCTGAACTGGTTTCAACAAAAGCCTGGCAAGGCCCCTAAGCTGCTGATCTACGCCGCCAGCAACCAGCGGTCCGGCGTGCCCAGCCGCTTTTCCGGCTCCGGCTCTGGCACAGATTTCACCCTGACTATCAGCAGCCTGCAGCCTGAGGACTTTGCCACATACTTCTGCCAGCAGAGTAAGGAAGTGCCCTGGACTTTTGGCCAGGGCACCAAAGTGGAAATCAAGCGCCACCACCACCACCATCATFSHR PMTE (Fc-HLLHLH) coding sequence (SEQ ID NO:51)ATGATCAGTAGAACACCAGAGGTGACCTGCGTTGTTGTGGACGTGTCCCACGAAGCCCCAGAAGTGAAGTTCAACTGGTACGTGGACGGCGTGGAAGTGCATAATGCCAAGACCAAGCCTTGCGAAGAACAGTACGGCTCCACCTACAGATGCGTTAGCGTGCTGACCGTGCTGCATCAGGACTGGCTGAACGGCAAGGAATACAAGTGTGCCGTGTCCAACAAGGCCCTGCCTGCTCCTATCGAGAAAACTATCTCTAAAGCCAAGGGGCAGCCCCGGGAACCCCAGGTGTACACCCTCCCACCTTCCCGTGAGGAAATGACCAAAAATCAGGTAAGCCTGACCTGCCTGGTGAAGGGATTTTACCCCAGCGACATTGCCGTGGAGTGGGAGTCTAATGGCCAGCCGGAGAATAACTACAAGACAACCCCTCCAGTGCTGGACAGCGATGGATCTTTTTTCCTGTACTCGAAGCTGACTGTGGACAAGAGCAGATGGCAGCAGGGCAATGTGTTCAGCTGTTCTGTCATGCACGAGGCCCTGCACAACCACTACACGCAGAAATCACTGTCTCTGTCACCTGGAAAAGGCGGAGGTGGCTCTGGAGGCGGTGGATCTGGTGGTGGCGGATCAGGTGGAGGCGGGAGCGGAGGCGGCGGTAGTGGTGGAGGAGGCTCTGATAAGACTCACACCTGCCCTCCTTGCCCTGCTCCCGAGGCTGCCGGCGGCCCTAGCGTGTTCCTGTTCCCCCCTAAGCCCAAAGACACACTGATGATCAGTAGAACCCCTGAAGTGACCTGCGTGGTGGTGGACGTCAGCCACGAGGCACCAGAGGTGAAATTCAACTGGTATGTGGACGGCGTCGAAGTGCACAACGCCAAGACCAAGCCCTGTGAAGAGCAGTACGGCAGCACCTACAGATGCGTGTCCGTGCTGACCGTGCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCGCCGrGrCTAACAAGGCCCrGCCTGCACCTA AGAGAAGACAATCTCrAAGGCCAAGGGACAGCCTAGAGAGCCTCAAGTGTACACACTGCCTCCCAGCCGCGAGGAAATGACAAAGAACCAGGTGAGCCTGACATGCCTGGTGAAGGGCTTCTACCCTAGCGATATTGCCGTGGAGTGGGAAAGCAACGGACAGCCTGAAAACAACTACAAGACCACACCTCCTGTGCTGGACAGCGACGGAAGCTTCTTCCTGTACAGCAAGCTGACCGTGGACAAGAGCAGATGGCAGCAAGGTAATGTGTTCAGTTGCAGCGTGATGCACGAGGCCCTCCACAACCACTACACCCAGAAGTCTTTGAGCCTGAGCCCTGGCAAGGGCGGTGGTGGAAGCGGTGGCGGCGGATCTGACATCCAGATGACCCAGTCGCCTTCTTCTCTGTCTGCTAGCGTGGGCGACAGAGTGACCATCTCTTGCAGAGCCTCCGAGAGCGTGGACAACTACGGCATCTCCTTCCTCAATTGGTTCCAGCAAAAACCCGGCAAGGCTCCTAAGCTGCTGATCTACGCCGCTAGCAACCAAAGAAGCGGCGTGCCAAGCAGATTCAGCGGCAGCGGATCAGGCACCGATTTCACATTAACCATCTCTAGTCTGCAGCCTGAGGACTTCGCCACGTACTTTTGCCAGCAGAGCAAGGAGGTGCCATGGACCTTCGGCCAAGGCACAAAGGTGGAAATCAAGCGGGGCGGAGGAGGTTCAGGTGGAGGTGGATCTGGAGGTGGCGGGTCTGAAGTGCAGCTGGTTGAAAGCGGCGGTGGCCTGGTGCAGCCTGGCGGCTCCCTGAGACTGTCTTGTAGCTTCAGCGGCTTCAGCCTGAGCACCAGCGGCATGGGCGTGGGCTGGATCCGGCAGGCCCCTGGCAAGGGCCTGGAGTGGGTTGCTCACATCTGGTGGGATGACGACAAGCGGTACAACCCTGCCCTGAAGAGCAGATTCACACTGTCCGTGGATAGAAGCAAAAACACCCTGTACCTGCAAATGAATTCCCTGCGGGCCGAGGACACCGCTACCTACTACTGCGTGCAGATCAACTACGGCAACTACCGGTTCGACAACTGGGGACACGGAACACTGGTGACAGTGTCCAGCGGCGGTGGCGGATCAGATATACAGATGACCCAGAGCCCTTCTAGCCTGAGCGCCTCAGTGGGCGACAGAGTGACCATCACCTGTCGGGCGAGCCAGGATATCAGAAACTATCTGAACTGGTACCAACAGAAGCCTGGTAAAGCCCCTAAGCTGCTGATCTACTACACCAGCCGGCTGGAAAGCGGAGTGCCTTCTAGATTCAGCGGTTCCGGCAGTGGAACCGACTACACCCTTACCATCTCCAGCCTCCAGCCAGAGGATTTCGCCACATATTACTGTCAGCAGGGCAACACCCTGCCGTGGACCTTTGGCCAGGGCACCAAAGTGGAGATCAAATCCTCTGGAGGCGGAGGTAGTGGTGGTGGAGGGTCAGGCGGCGGTGGAAGCGAGGTGCAGCTGGTGGAAAGTGGAGGCGGCCTGGTCCAGCCCGGCGGCTCTCTGAGACTGTCGTGCGCCGCCTCCGGATATAGCTTCACCGGCTACACCATGAACTGGGTGCGGCAAGCCCCTGGTAAGGGACTGGAGTGGGTGGCCCTCATTAACCCTTACAAAGGAGTCAGCACATACAATCAAAAGTTCAAGGACAGGTTCACAATCTCAGTTGACAAGTCTAAGAACACGGCCTACCTGCAGATGAACAGCTTGAGAGCTGAGGACACCGCTGTGTACTATTGCGCTAGAAGCGGCTACTACGGCGACTCTGATTGGTACTTCGATGTGTGGGGCCAGGGCACGCTGGTGACAGTGTCCTCCGGAGGAGGCGGTTCTGAAGTGCAGCTGGTGGAGAGCGGTGGCGGCCTGGTCCAGCCCGGCGGAAGCCTGAGACTAAGCTGCAGCTTCAGCGGATTCTCGCTGAGCACCAGCGGCATGGGCGTGGGATGGATCAGACAGGCCCCTGGAAAGGGCCTGGAGTGGGTGGCCCACATCTGGTGGGACGACGACAAACGGTACAACCCGGCCTTGAAGTCTCGGTTCACCCTGAGCGTGGATAGAAGCAAGAACACACTGTATCTGCAGATGAACAGCCTGAGAGCCGAGGACACCGCCACCTACTATTGTGTGCAAATCAACTATGGCAACTACAGATTCGACAACTGGGGCCACGGCACACTGGTTACAGTCTCCTCTGGCGGTGGCGGCTCTGGAGGCGGCGGCTCTGGCGGCGGTGGCTCAGATATCCAGATGACCCAGAGCCC TAGCAGCCTGAGCGCCAGCGTGGGAGATCGCGTGACCATCAGCTGCAGAGCCAGCGAGAGCGTTG ATAACTACGGCATCAGCTTCCTGAACTGGTTTCAACAAAAGCCTGGCAAGGCCCCTAAGCTGCTGA TCTACGCCGCCAGCAACCAGCGGTCCGGCGTGCCCAGCCGCTTTTCCGGCTCCGGCTCTGGCACAG ATTTCACCCTGACTATCAGCAGCCTGCAGCCTGAGGACTTTGCCACATACTTCTGCCAGCAGAGTA AGGAAGTGCCCTGGACTTTTGGCCAGGGCACCAAAGTGGAAATCAAGCGCFSHR PMTE (Fc-HLHLLH) construct sequence (SEQ ID NO:52)GATAAGACCCACACCTGCCCCCCTTGCCCCGCCCCAGAGGCTGCCGGAGGACCTAGCGTGTTTCTC TTCCCTCCTAAACCCAAGGATACACTCATGATCAGCCGGACACCTGAGGTGACCTGTGTGGTGGTT GATGTGTCTCACGAAGCCCCCGAAGTGAAGTTCAACTGGTATGTGGACGGCGTGGAGGTCCACAA CGCCAAGACAAAGCCCTGTGAAGAGCAGTACGGCAGCACATACAGATGCGTGAGCGTGCTGACAG TGCTGCACCAGGATTGGCTGAACGGCAAGGAGTACAAGTGCGCCGTGAGCAACAAGGCCCTGCCT GCTCCAATCGAGAAGACGATTAGCAAAGCTAAGGGCCAGCCTAGAGAGCCTCAGGTGTACACCCT GCCCCCCTCTAGAGAGGAGATGACCAAGAATCAGGTGTCCCTGACCTGCCTGGTGAAGGGTTTTTA CCCCAGCGACATCGCCGTGGAATGGGAAAGCAACGGCCAGCCTGAGAACAACTACAAAACCACCC CACCTGTGCTGGATAGCGATGGCAGCTTTTTCCTGTACAGCAAGCTGACAGTGGACAAGTCTAGGT GGCAACAGGGCAACGTGTTCAGCTGCTCGGTCATGCACGAGGCCCTGCACAACCACTACACCCAG AAGAGCCTGTCCCTTTCTCCTGGCAAGGGCGGAGGTGGCTCTGGAGGCGGTGGATCTGGTGGTGG CGGATCAGGTGGAGGCGGGAGCGGAGGCGGCGGTAGTGGTGGAGGAGGCTCTGATAAGACACAC ACCTGCCCTCCATGCCCTGCCCCTGAGGCCGCCGGCGGCCCTAGTGTCTTCCTGTTCCCCCCGAAG CCAAAAGACACCCTTATGATCTCGAGAACCCCTGAAGTGACATGCGTAGTTGTGGACGTGTCTCAC GAGGCCCCCGAAGTGAAGTTCAACTGGTACGTAGACGGCGTGGAAGTGCACAACGCCAAGACCAA GCCCTGCGAGGAACAGTACGGCAGCACCTACAGATGTGTGAGCGTGCTGACCGTCCTGCACCAGG ACTGGCTGAATGGCAAGGAATACAAGTGCGCCGTTAGCAACAAGGCCCTGCCTGCCCCTATCGAG AAGACCATCAGCAAAGCTAAGGGACAGCCCAGAGAGCCCCAGGTGTACACCCTCCCTCCGAGCCG GGAAGAAATGACCAAGAATCAGGTGAGCCTGACCTGTCTGGTGAAGGGGTTCTACCCTAGCGACA TCGCCGTGGAGTGGGAGAGCAATGGCCAGCCTGAGAACAACTACAAAACCACCCCTCCAGTGCTG GACAGCGACGGCAGCTTCTTCCTCTACAGCAAACTGACCGTGGACAAGAGCCGGTGGCAGCAGGG CAATGTGTTCTCTTGCAGCGTGATGCACGAGGCCCTGCATAACCACTACACCCAGAAGTCTCTGAG CCTGTCACCTGGCAAGGGCGGTGGTGGAAGCGGTGGCGGCGGATCTGACATCCAGATGACGCAAT CTCCTTCTTCCCTGTCCGCCTCTGTGGGCGATAGAGTGACAATCAGCTGCAGAGCTAGCGAGTCTG TGGACAATTACGGCATCAGTTTTCTGAACTGGTTCCAACAGAAGCCTGGCAAAGCCCCTAAGCTGC TGATCTATGCCGCTTCCAATCAGCGGAGCGGCGTGCCCTCTAGATTCTCCGGTAGCGGGTCTGGCA CCGACTTCACCCTGACCATCAGCAGCCTGCAGCCTGAGGATTTTGCCACATACTTCTGCCAGCAGA GCAAGGAGGTCCCCTGGACCTTCGGACAGGGCACCAAGGTGGAGATCAAGCGGGGCGGAGGAGG TTCAGGTGGAGGTGGATCTGGAGGTGGCGGGTCTGAGGTGCAGCTGGTGGAAAGCGGCGGCGGCC TGGTGCAGCCCGGCGGCTCTCTGCGGCTGTCGTGCTCCTTCTCCGGATTCAGCCTGAGCACTTCGG GAATGGGTGTGGGATGGATCAGACAGGCCCCTGGCAAGGGCCTGGAATGGGTGGCTCACATCTGG TGGGACGACGATAAGCGGTACAACCCCGCTCTCAAGTCTAGGTTTACACTGTCAGTGGACAGATCT AAAAACACACTGTACCTGCAAATGAATAGCCTGCGGGCCGAGGACACAGCCACCTACTACTGCGT GCAGATAAACTATGGCAACTACCGGTTCGACAACTGGGGCCACGGCACACTGGTGACAGTGTCAA GCGGCGGTGGCGGATCAGAAGTACAGCTGGTGGAGAGCGGCGGCGGCCTGGTGCAGCCTGGCGG CAGCCTGAGACTGAGCrGTGCCGCTAGCGGCrACrCTrTCACAGGCTACACCArGAACrGGGriAG ACAGGCCCCTGGGAAGGGCCTCGAGTGGGTCGCCCTGATCAACCCCTACAAGGGCGTCTCTACAT ATAACCAGAAGTTCAAGGACCGGTTCACCATCAGCGTGGACAAATCTAAGAACACCGCCTACCTG CAGATGAACAGCCTGAGAGCAGAGGACACGGCCGTGTACTACTGTGCCAGAAGCGGTTATTACGG CGACAGCGACTGGTACTTCGACGTGTGGGGCCAGGGCACCCTGGTGACCGTGAGCAGTGGAGGCG GAGGTAGTGGTGGTGGAGGGTCAGGCGGCGGTGGAAGCGACATCCAGATGACCCAGTCGCCTAGC AGCCTGTCTGCTTCCGTTGGAGATAGAGTGACCATCACATGTAGAGCCTCACAGGACATCAGAAA CTACCTGAACTGGTATCAGCAGAAACCAGGAAAAGCCCCTAAGCTGCTGATCTACTATACCAGCA GACTGGAATCTGGCGTGCCCAGCCGCTTCAGTGGCAGTGGCAGCGGCACAGATTACACACTCACC ATCTCATCGCTGCAACCTGAGGACTTCGCCACATACTACTGTCAGCAGGGCAACACCTTACCTTGGACATTCGGCCAGGGCACCAAGGTGGAAATCAAGAGCAGCGGAGGAGGCGGTTCTGAAGTTCAGCT GGTGGAGTCCGGCGGAGGACTGGTGCAACCAGGCGGTAGCCTGCGGCTGTCCTGCAGCTTCAGCG GCTTCAGCCTGTCCACCAGCGGCATGGGAGTCGGGTGGATCCGACAGGCTCCCGGGAAAGGCCTG GAATGGGTGGCCCACATCTGGTGGGATGATGACAAAAGATACAACCCTGCCCTGAAAAGCCGGTT TACCCTGAGCGTGGACAGAAGCAAGAACACCCTGTACCTGCAGATGAACAGCCTGAGAGCCGAAG ACACAGCCACTTACTACTGCGTGCAAATCAATTACGGCAACTACCGCTTCGACAATTGGGGGCACGGCACCCTGGTGACCGTGTCATCCGGAGGAGGAGGCAGCGGCGGGGGCGGATCCGGAGGAGGCGGAAGCGACATTCAGATGACCCAGAGCCCTAGCTCTCTGAGCGCCTCTGTGGGCGACCGGGTCACCATCAGCTGCAGAGCCAGTGAAAGCGTGGATAACTACGGCATCTCCTTCCTGAACTGGTTTCAACAGAAGCCTGGCAAAGCCCCTAAGCTGCTAATCTATGCCGCTTCTAATCAAAGAAGCGGTGTCCCTTCTAGATTCAGCGGCTCAGGCTCTGGAACCGATTTCACTCTGACAATCAGCTCCCTGCAGCCTGAGGACTTTGCCACCTACTTTTGCCAGCAAAGCAAGGAAGTGCCTTGGACCTTCGGCCAGGGCACAAAGGTGGAAATCAAGAGACACCACCACCATCACCATFSHR PMTE (Fc-HLHLLH) coding sequence (SEQ ID NO:53)ATGATCAGCCGGACACCTGAGGTGACCTGTGTGGTGGTTGATGTGTCTCACGAAGCCCCCGAAGTGAAGTTCAACTGGTATGTGGACGGCGTGGAGGTCCACAACGCCAAGACAAAGCCCTGTGAAGAGCAGTACGGCAGCACATACAGATGCGTGAGCGTGCTGACAGTGCTGCACCAGGATTGGCTGAACGGCAAGGAGTACAAGTGCGCCGTGAGCAACAAGGCCCTGCCTGCTCCAATCGAGAAGACGATTAGCAAAGCTAAGGGCCAGCCTAGAGAGCCTCAGGTGTACACCCTGCCCCCCTCTAGAGAGGAGATGACCAAGAATCAGGTGTCCCTGACCTGCCTGGTGAAGGGTTTTTACCCCAGCGACATCGCCGTGGAATGGGAAAGCAACGGCCAGCCTGAGAACAACTACAAAACCACCCCACCTGTGCTGGATAGCGATGGCAGCTTTTTCCTGTACAGCAAGCTGACAGTGGACAAGTCTAGGTGGCAACAGGGCAACGTGTTCAGCTGCTCGGTCATGCACGAGGCCCTGCACAACCACrACACCCAGAAGAGCCTGrCCCl TrCTCCTGGCAAGGGCGGAGGTGGCTCTGGAGGCGGTGGATCTGGTGGTGGCGGATCAGGTGGAGGCGGGAGCGGAGGCGGCGGTAGTGGTGGAGGAGGCTCTGATAAGACACACACCTGCCCTCCATGCCCTGCCCCTGAGGCCGCCGGCGGCCCTAGTGTCTTCCTGTTCCCCCCGAAGCCAAAAGACACCCTTATGATCTCGAGAACCCCTGAAGTGACATGCGTAGTTGTGGACGTGTCTCACGAGGCCCCCGAAGTGAAGTTCAACTGGTACGTAGACGGCGTGGAAGTGCACAACGCCAAGACCAAGCCCTGCGAGGAACAGTACGGCAGCACCTACAGATGTGTGAGCGTGCTGACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAATACAAGTGCGCCGTTAGCAACAAGGCCCTGCCTGCCCCTATCGAGAAGACCATCAGCAAAGCTAAGGGACAGCCCAGAGAGCCCCAGGTGTACACCCTCCCTCCGAGCCGGGAAGAAATGACCAAGAATCAGGTGAGCCTGACCTGTCTGGTGAAGGGGTTCTACCCTAGCGACATCGCCGTGGAGTGGGAGAGCAATGGCCAGCCTGAGAACAACTACAAAACCACCCCTCCAGTGCTGGACAGCGACGGCAGCTTCTTCCTCTACAGCAAACTGACCGTGGACAAGAGCCGGTGGCAGCAGGGCAATGTGTTCTCTTGCAGCGTGATGCACGAGGCCCTGCATAACCACTACACCCAGAAGTCTCTGAGCCTGTCACCTGGCAAGGGCGGTGGTGGAAGCGGTGGCGGCGGATCTGACATCCAGATGACGCAATCTCCTTCTTCCCTGTCCGCCTCTGTGGGCGATAGAGTGACAATCAGCTGCAGAGCTAGCGAGTCTGTGGACAATTACGGCATCAGTTTTCTGAACTGGTTCCAACAGAAGCCTGGCAAAGCCCCTAAGCTGCTGATCTATGCCGCTTCCAATCAGCGGAGCGGCGTGCCCTCTAGATTCTCCGGTAGCGGGTCTGGCACCGACTTCACCCTGACCATCAGCAGCCTGCAGCCTGAGGATTTTGCCACATACTTCTGCCAGCAGAGCAAGGAGGTCCCCTGGACCTTCGGACAGGGCACCAAGGTGGAGATCAAGCGGGGCGGAGGAGGTTCAGGTGGAGGTGGATCTGGAGGTGGCGGGTCTGAGGTGCAGCTGGTGGAAAGCGGCGGCGGCCTGGTGCAGCCCGGCGGCTCTCTGCGGCTGTCGTGCTCCTTCTCCGGATTCAGCCTGAGCACTTCGGGAATGGGTGTGGGATGGATCAGACAGGCCCCTGGCAAGGGCCTGGAATGGGTGGCTCACATCTGGTGGGACGACGATAAGCGGTACAACCCCGCTCTCAAGTCTAGGTTTACACTGTCAGTGGACAGATCTAAAAACACACTGTACCTGCAAATGAATAGCCTGCGGGCCGAGGACACAGCCACCTACTACTGCGTGCAGATAAACTATGGCAACTACCGGTTCGACAACTGGGGCCACGGCACACTGGTGACAGTGTCAAGCGGCGGTGGCGGATCAGAAGTACAGCTGGTGGAGAGCGGCGGCGGCCTGGTGCAGCCTGGCGGCAGCCTGAGACTGAGCTGTGCCGCTAGCGGCTACTCTTTCACAGGCTACACCATGAACTGGGTTAGACAGGCCCCTGGGAAGGGCCTCGAGTGGGTCGCCCTGATCAACCCCTACAAGGGCGTCTCTACATATAACCAGAAGTTCAAGGACCGGTTCACCATCAGCGTGGACAAATCTAAGAACACCGCCTACCTGCAGATGAACAGCCTGAGAGCAGAGGACACGGCCGTGTACTACTGTGCCAGAAGCGGTTATTACGGCGACAGCGACTGGTACTTCGACGTGTGGGGCCAGGGCACCCTGGTGACCGTGAGCAGTGGAGGCGGAGGTAGTGGTGGTGGAGGGTCAGGCGGCGGTGGAAGCGACATCCAGATGACCCAGTCGCCTAGCAGCCTGTCTGCTTCCGTTGGAGATAGAGTGACCATCACATGTAGAGCCTCACAGGACATCAGAAACTACCTGAACTGGTATCAGCAGAAACCAGGAAAAGCCCCTAAGCTGCTGATCTACTATACCAGCAGACTGGAATCTGGCGTGCCCAGCCGCTTCAGTGGCAGTGGCAGCGGCACAGATTACACACTCACCATCTCATCGCTGCAACCTGAGGACTTCGCCACATACTACTGTCAGCAGGGCAACACCTTACCTTGGACATTCGGCCAGGGCACCAAGGTGGAAATCAAGAGCAGCGGAGGAGGCGGTTCTGAAGTTCAGCTGGTGGAGTCCGGCGGAGGACTGGTGCAACCAGGCGGTAGCCTGCGGCTGTCCTGCAGCTTCAGCGGCTTCAGCCTGTCCACCAGCGGCATGGGAGTCGGGTGGATCCGACAGGCTCCCGGGAAAGGCCTGGAATGGGTGGCCCACATCTGGTGGGATGATGACAAAAGATACAACCCTGCCCTGAAAAGCCGGTTTACCCTGAGCGTGGACAGAAGCAAGAACACCCTGTACCTGCAGATGAACAGCCTGAGAGCCGAAGACACAGCCACTTACTACTGCGTGCAAATCAATTACGGCAACTACCGCTTCGACAATTGGGGGCACGGCACCCTGGTGACCGTGTCATCCGGAGGAGGAGGCAGCGGCGGGGGCGGATCCGGAGGAGGCGGAAGCGACATTCAGATGACCCAGAGCCCTAGCTCTCTGAGCGCCTCTGTGGGCGACCGGGTCACCATCAGCTGCAGAGCCAGTGAAAGCGTGGATAACTACGGCATCTCCTTCCTGAACTGGTTTCAACAGAAGCCTGGCAAAGCCCCTAAGCTGCTAATCTATGCCGCTTCTAATCAAAGAAGCGGTGTCCCTTCTAGATTCAGCGGCTCAGGCTCTGGAACCGATTTCACTCTGACAATCAGCTCCCTGCAGCCTGAGGACTTTGCCACCTACTTTTGCCAGCAAAGCAAGGAAGTGCCTTGGACCTTCGGCCAGGGCACAAAGGTGGAAATCAAGAGAFSHR PMTE (Fc-LHHLLH) construct sequence (SEQ ID NO:54)GACAAGACCCACACCTGCCCTCCTTGTCCTGCTCCTGAAGCTGCTGGCGGCCCCAGCGTCTTCCTGTTCCCCCCTAAGCCCAAAGATACCCTGATGATCAGCAGAACCCCTGAGGTCACCTGCGTGGTGGTGGACGTGAGCCACGAGGCCCCCGAAGTGAAATTTAACTGGTACGTCGATGGCGTAGAAGTGCACAACGCCAAGACAAAGCCTTGTGAAGAGCAGTACGGAAGCACCTATAGATGCGTGTCCGTGCTGACAGTGCTTCACCAGGATTGGCTGAACGGAAAAGAGTACAAATGCGCCGTGAGCAACAAGGCCCTGCCAGCTCCCATCGAGAAGACCATTTCCAAAGCCAAGGGACAGCCTAGAGAGCCTCAGGTGTATACACTGCCCCCTTCCAGAGAGGAAATGACCAAAAACCAGGTGAGCCTGACTTGTCTGGTGAAGGGCTTCTACCCTTCTGATATCGCCGTGGAATGGGAGAGTAATGGACAGCCTGAAAACAATTACAAGACCACCCCTCCTGTGCTGGACAGCGATGGCAGCTTCTTCCTCTACAGCAAGCTGACAGTTGACAAGAGCAGATGGCAGCAGGGCAATGTGTTCAGCTGCTCTGTTATGCACGAGGCCCTGCACAATCACTACACCCAGAAGAGCCTGTCGCTTAGTCCCGGCAAGGGGGGAGGCGGCTCGGGCGGCGGCGGTAGCGGAGGTGGGGGATCTGGAGGCGGCGGTAGCGGCGGTGGCGGTTCCGGCGGTGGCGGTAGCGATAAGACCCACACCTGCCCTCCATGTCCTGCTCCAGAAGCTGCCGGAGGCCCTAGCGTGTTCCTGTTCCCACCTAAGCCCAAGGACACACTGArGArCAGCCGGACCCCTGAGGTGACClGCG GGlGGTGGACGrGAGCCACGAGGCACCTGAGGTGAAGTTCAACTGGTACGTGGACGGAGTGGAAGTGCACAATGCCAAGACAAAGCCCTGCGAGGAACAGTACGGCTCCACATATAGATGCGTTTCTGTGCTGACCGTGCTGCACCAGGACTGGTTGAACGGCAAAGAGTACAAATGCGCCGTGAGCAACAAAGCCCTGCCTGCTCCTATCGAGAAGACAATCTCCAAGGCTAAGGGCCAGCCGCGGGAACCCCAGGTTTACACCCTGCCCCCATCTCGGGAAGAAATGACGAAGAATCAGGTGTCACTGACTTGCCTGGTGAAAGGCTTCTACCCCTCTGACATCGCCGTGGAATGGGAGAGTAATGGCCAGCCTGAGAACAACTACAAGACCACACCCCCTGTGCTGGACAGCGACGGCTCCTTTTTCCTGTACAGCAAACTGACCGTGGACAAAAGCCGGTGGCAGCAGGGCAACGTGTTCAGCTGCAGCGTGATGCACGAAGCCCTGCATAACCACTACACCCAGAAGAGTTTAAGCCTGAGCCCTGGCAAAGGGGGCGGAGGCAGCGGTGGCGGCGGCAGCGAGGTGCAGCTGGTGGAGTCTGGCGGCGGACTGGTGCAGCCTGGCGGCTCCCTGAGACTGTCTTGCAGCTTCAGTGGCTTCAGCCTGAGCACCAGCGGCATGGGCGTGGGATGGATCCGTCAGGCCCCTGGGAAAGGCCTGGAGTGGGTGGCCCACATCTGGTGGGACGACGATAAGCGGTACAACCCCGCGCTGAAGAGCAGATTTACGTTGAGCGTGGACAGATCTAAGAACACACTTTACCTGCAGATGAACAGCCTGAGAGCCGAGGATACAGCCACCTACTACTGCGTGCAGATCAACTACGGAAACTACCGGTTCGACAACTGGGGCCATGGCACCTTAGTGACCGTCAGCAGCGGGGGGGGAGGCAGCGGCGGAGGCGGCTCCGGCGGAGGCGGCTCAGATATCCAGATGACACAGTCCCCCTCCTCCCTGAGCGCCTCTGTGGGCGACCGGGTGACCATAAGCTGCCGGGCCTCTGAGAGCGTGGACAACTACGGAATCAGCTTCCTGAATTGGTTTCAGCAAAAACCAGGCAAAGCCCCTAAGCTGCTGATCTATGCCGCCAGCAATCAGAGAAGCGGCGTGCCTAGCCGCTTTTCTGGAAGCGGCTCCGGCACCGACTTCACACTGACCATCTCCAGCCTGCAGCCCGAGGACTTCGCCACCTACTTCTGCCAGCAGTCTAAAGAAGTGCCCTGGACTTTCGGCCAGGGCACAAAGGTGGAGATCAAGCGGGGCGGCGGCGGCTCTGAGGTGCAGCTGGTCGAAAGCGGCGGAGGCCTGGTTCAGCCTGGCGGCTCTCTGAGACTGTCTTGTGCAGCCAGCGGCTACAGTTTCACCGGCTACACCATGAACTGGGTGCGGCAGGCCCCTGGCAAGGGATTGGAGTGGGTGGCCCTGATCAACCCTTACAAGGGAGTGAGCACATACAACCAAAAGTTCAAGGATAGATTCACCATCAGCGTTGACAAGAGCAAGAACACCGCCTACCTGCAAATGAATAGCCTTAGAGCCGAGGACACCGCCGTGTACTACTGCGCCAGAAGCGGATACTACGGCGACAGCGACTGGTACTTCGACGTGTGGGGACAAGGCACACTGGTGACCGTGTCTAGCGGCGGGGGAGGCTCCGGCGGGGGAGGCTCCGGAGGCGGCGGATCAGACATCCAGATGACCCAGAGCCCTAGCAGCCTGAGCGCCAGCGTGGGCGACAGGGTGACAATAACATGCCGGGCTTCTCAGGACATCAGAAACTACCTGAACTGGTATCAGCAAAAGCCTGGCAAGGCTCCAAAGCTGCTCATCTACTACACCAGCAGACTGGAATCGGGCGTGCCCTCCAGATTCAGCGGCTCCGGCAGTGGTACAGACTACACCCTGACCATCTCTTCCCTGCAGCCTGAGGACTTTGCCACATACTATTGCCAGCAGGGCAACACCCTGCCTTGGACTTTCGGCCAAGGAACGAAGGTCGAGATCAAGTCATCTGGAGGCGGCGGCAGCGAGGTGCAACTGGTGGAAAGCGGCGGAGGCCTGGTGCAACCGGGCGGTTCTCTCAGACTGAGCTGTAGCTTTAGCGGCTTCAGTCTGAGCACAAGCGGAATGGGCGTTGGCTGGATCCGACAGGCTCCTGGCAAGGGCCTGGAATGGGTCGCCCACATTTGGTGGGATGACGATAAGCGGTACAACCCCGCTCTTAAGTCGAGGTTCACTCTGTCTGTGGACAGAAGCAAGAACACCCTGTACCTGCAGATGAACAGCCTGCGGGCCGAGGATACCGCCACCTACTACTGTGTGCAGATCAACTACGGCAATTACAGATTCGATAACTGGGGCCACGGCACCCTGGTCACAGTGTCCTCCGGCGGCGGGGGCTCCGGGGGAGGCGGCAGCGGCGGGGGCGGCAGCGATATCCAGATGACCCAGTCCCCCAGCAGCCTGAGTGCCTCAGTGGGCGACAGAGTGACAATCTCCTGTAGAGCCTCTGAGTCTGTGGACAATTATGGCATCAGCTTCTTGAACTGGTTCCAGCAAAAGCCCGGCAAGGCCCCGAAGCTGCTGATCTACGCCGCTTCTAACCAGAGAAGCGGCGTTCCATCCCGGTTCAGCGGCTCTGGCTCGGGCACCGACTTCACCCTGACAATTTCCTCGCTGCAGCCTGAGGACTTCGCCACATATTTCTGCCAGCAGAGCAAGGAGGTGCCATGGACCTTTGGACAGGGAACCAAGGTGGAAATCAAAAGACACCACCATCACCACCACFSHR PMTE (Fc-LHHLLH) coding sequence (SEQ ID NO:55)ATGATCAGCAGAACCCCTGAGGTCACCTGCGTGGTGGTGGACGTGAGCCACGAGGCCCCCGAAGTGAAATTTAACTGGTACGTCGATGGCGTAGAAGTGCACAACGCCAAGACAAAGCCTTGTGAAGAGCAGTACGGAAGCACCTATAGATGCGTGTCCGTGCTGACAGTGCTTCACCAGGATTGGCTGAACGGAAAAGAGTACAAATGCGCCGTGAGCAACAAGGCCCTGCCAGCTCCCATCGAGAAGACCATTTCCAAAGCCAAGGGACAGCCTAGAGAGCCTCAGGTGTATACACTGCCCCCTTCCAGAGAGGAAATGACCA AAAACCAGGTGAGCCTGACTTGTCTGGTGAAGGGCTTCTACCCTTCTGATATCGCCGTGGAATGGG AGAGTAATGGACAGCCTGAAAACAATTACAAGACCACCCCTCCTGTGCTGGACAGCGATGGCAGC TTCTTCCTCTACAGCAAGCTGACAGTTGACAAGAGCAGATGGCAGCAGGGCAATGTGTTCAGCTGC TCTGTTATGCACGAGGCCCTGCACAATCACTACACCCAGAAGAGCCTGTCGCTTAGTCCCGGCAAG GGGGGAGGCGGCTCGGGCGGCGGCGGTAGCGGAGGTGGGGGATCTGGAGGCGGCGGTAGCGGCGGTGGCGGTTCCGGCGGTGGCGGTAGCGATAAGACCCACACCTGCCCTCCATGTCCTGCTCCAGAAG CTGCCGGAGGCCCTAGCGlGlTCCTGn'CCCACCTAAGCCCAAGGACACAClGATGArCAGCCGGACCCCTGAGGTGACCTGCGTGGTGGTGGACGTGAGCCACGAGGCACCTGAGGTGAAGTTCAACTGGTACGTGGACGGAGTGGAAGTGCACAATGCCAAGACAAAGCCCTGCGAGGAACAGTACGGCTCCAC ATATAGATGCGTTTCTGTGCTGACCGTGCTGCACCAGGACTGGTTGAACGGCAAAGAGTACAAATGCGCCGTGAGCAACAAAGCCCTGCCTGCTCCTATCGAGAAGACAATCTCCAAGGCTAAGGGCCAG CCGCGGGAACCCCAGGTTTACACCCTGCCCCCATCTCGGGAAGAAATGACGAAGAATCAGGTGTCACTGACTTGCCTGGTGAAAGGCTTCTACCCCTCTGACATCGCCGTGGAATGGGAGAGTAATGGCCA GCCTGAGAACAACTACAAGACCACACCCCCTGTGCTGGACAGCGACGGCTCCTTTTTCCTGTACAG CAAACTGACCGTGGACAAAAGCCGGTGGCAGCAGGGCAACGTGTTCAGCTGCAGCGTGATGCACGAAGCCCTGCATAACCACTACACCCAGAAGAGTTTAAGCCTGAGCCCTGGCAAAGGGGGCGGAGGCAGCGGTGGCGGCGGCAGCGAGGTGCAGCTGGTGGAGTCTGGCGGCGGACTGGTGCAGCCTGGCGG CTCCCTGAGACTGTCTTGCAGCTTCAGTGGCTTCAGCCTGAGCACCAGCGGCATGGGCGTGGGATG GATCCGTCAGGCCCCTGGGAAAGGCCTGGAGTGGGTGGCCCACATCTGGTGGGACGACGATAAGC GGTACAACCCCGCGCTGAAGAGCAGATTTACGTTGAGCGTGGACAGATCTAAGAACACACTTTAC CTGCAGATGAACAGCCTGAGAGCCGAGGATACAGCCACCTACTACTGCGTGCAGATCAACTACGGAAACTACCGGTTCGACAACTGGGGCCATGGCACCTTAGTGACCGTCAGCAGCGGGGGGGGAGGCA GCGGCGGAGGCGGCTCCGGCGGAGGCGGCTCAGATATCCAGATGACACAGTCCCCCTCCTCCCTG AGCGCCTCTGTGGGCGACCGGGTGACCATAAGCTGCCGGGCCTCTGAGAGCGTGGACAACTACGGAATCAGCTTCCTGAATTGGTTTCAGCAAAAACCAGGCAAAGCCCCTAAGCTGCTGATCTATGCCGC CAGCAATCAGAGAAGCGGCGTGCCTAGCCGCTTTTCTGGAAGCGGCTCCGGCACCGACTTCACACT GACCATCTCCAGCCTGCAGCCCGAGGACTTCGCCACCTACTTCTGCCAGCAGTCTAAAGAAGTGCCCTGGACTTTCGGCCAGGGCACAAAGGTGGAGATCAAGCGGGGCGGCGGCGGCTCTGAGGTGCAGCTGGTCGAAAGCGGCGGAGGCCTGGTTCAGCCTGGCGGCTCTCTGAGACTGTCTTGTGCAGCCAGCGGCTACAGTTTCACCGGCTACACCATGAACTGGGTGCGGCAGGCCCCTGGCAAGGGATTGGAGTGGGTGGCCCTGATCAACCCTTACAAGGGAGTGAGCACATACAACCAAAAGTTCAAGGATAGATTCAC CATCAGCGTTGACAAGAGCAAGAACACCGCCTACCTGCAAATGAATAGCCTTAGAGCCGAGGACACCGCCGTGTACTACTGCGCCAGAAGCGGATACTACGGCGACAGCGACTGGTACTTCGACGTGTGGGGACAAGGCACACTGGTGACCGTGTCTAGCGGCGGGGGAGGCTCCGGCGGGGGAGGCTCCGGAG GCGGCGGATCAGACATCCAGATGACCCAGAGCCCTAGCAGCCTGAGCGCCAGCGTGGGCGACAGG GTGACAATAACATGCCGGGCTTCTCAGGACATCAGAAACTACCTGAACTGGTATCAGCAAAAGCCTGGCAAGGCTCCAAAGCTGCTCATCTACTACACCAGCAGACTGGAATCGGGCGTGCCCTCCAGATTCAGCGGCTCCGGCAGTGGTACAGACTACACCCTGACCATCTCTTCCCTGCAGCCTGAGGACTTTGC CACATACTATTGCCAGCAGGGCAACACCCTGCCTTGGACTTTCGGCCAAGGAACGAAGGTCGAGA TCAAGTCATCTGGAGGCGGCGGCAGCGAGGTGCAACTGGTGGAAAGCGGCGGAGGCCTGGTGCAACCGGGCGGTTCTCTCAGACTGAGCTGTAGCTTTAGCGGCTTCAGTCTGAGCACAAGCGGAATGGGCGTTGGCTGGATCCGACAGGCTCCTGGCAAGGGCCTGGAATGGGTCGCCCACATTTGGTGGGATGACGATAAGCGGTACAACCCCGCTCTTAAGTCGAGGTTCACTCTGTCTGTGGACAGAAGCAAGAACACCCTGTACCTGCAGATGAACAGCCTGCGGGCCGAGGATACCGCCACCTACTACTGTGTGCAGATCAACTACGGCAATTACAGATTCGATAACTGGGGCCACGGCACCCTGGTCACAGTGTCCTCCGGCGGCGGGGGCTCCGGGGGAGGCGGCAGCGGCGGGGGCGGCAGCGATATCCAGATGACCCAGTCCCCCAGCAGCCTGAGTGCCTCAGTGGGCGACAGAGTGACAATCTCCTGTAGAGCCTCTGAGTCTGTGGACAATTATGGCATCAGCTTCTTGAACTGGTTCCAGCAAAAGCCCGGCAAGGCCCCGAAGCTGCTGATCTACGCCGCTTCTAACCAGAGAAGCGGCGTTCCATCCCGGTTCAGCGGCTCTGGCTCGGGCACCGACTTCACCCTGACAATTTCCTCGCTGCAGCCTGAGGACTTCGCCACATATTTCTGCCAGCAGAGCAAGGAGGTGCCATGGACCTTTGGACAGGGAACCAAGGTGGAAATCAAAAGAFSHR PMTE (HLHLHL-Fc) construct sequence (SEQ ID NO: 56)GACATCCAAATGACCCAAAGCCCCAGCAGCCTGTCAGCCAGCGTTGGCGACAGAGTGACCATTTCTTGTAGAGCCAGCGAGAGCGTGGACAACTACGGCATCAGCTTCCTGAACTGGTTCCAGCAGAAGCCCGGAAAAGCCCCCAAACTGCTGATCTACGCCGCTAGCAATCAGCGGAGTGGCGTTCCTAGCAGGTTCAGCGGTTCCGGCTCAGGCACAGACTTCACCCTGACAATCTCCAGTCTGCAGCCTGAGGATTTTGCCACCTACTTCTGCCAGCAGAGTAAGGAGGTGCCGTGGACCTTCGGACAGGGCACCAAAGTGGAAATTAAAAGAGGCGGAGGTGGCTCTGGAGGCGGTGGATCTGGTGGTGGCGGATCAGAGGTGCAACTGGTCGAGAGCGGCGGAGGCCTGGTCCAGCCTGGCGGCTCTCTGAGACTGAGCTGCAGCTTCAGCGGATTTAGCCTGAGCACATCCGGCATGGGCGTGGGATGGATCAGACAGGCCCCTGGCAAGGGGCTGGAGTGGGTCGCCCACATCTGGTGGGATGACGACAAGAGATACAATCCTGCTCTGAAATCTAGGTTTACGCTGAGCGTGGATAGAAGCAAGAACACCCTGTACCTGCAGATGAACAGCCTTAGAGCTGAAGACACTGCCACCTACTACTGCGTCCAGATCAACTACGGCAACTATCGGTTCGACAACTGGGGCCACGGGACCCTCGTGACAGTGAGCTCTGGfGGAGGCGGGAGCGAAGfGCAGCTGGTGGAGAGCGGCGGCGGCCTGGTTCAGCCAGGCGGCTCACTGAGACTGAGCTGTGCTGCCTCTGGCTACTCTTTCACAGGTTACACCATGAACTGGGTGAGACAGGCCCCTGGCAAGGGACTGGAATGGGTTGCTCTGATCAACCCTTACAAGGGGGTCAGCACCTACAACCAGAAATTCAAGGACAGATTCACCATCAGCGTGGACAAAAGCAAAAACACAGCCTACCTGCAGATGAATTCACTGAGAGCCGAAGATACAGCCGTGTACTATTGTGCCAGAAGCGGCTATTATGGCGACTCTGACTGGTACTTCGACGTGTGGGGACAGGGCACCCTGGTGACAGTGTCTAGCGGAGGCGGCGGTAGTGGTGGAGGAGGCTCTGGCGGTGGTGGAAGCGATATCCAGATGACCCAGTCCCCGTCTAGCCTGTCTGCCTCTGTGGGCGACAGAGTCACCATCACATGCAGAGCGAGTCAGGACATAAGAAACTACCTGAACTGGTACCAGCAGAAGCCTGGCAAGGCCCCTAAGCTGCTGATCTACTACACGAGCCGCCTGGAAAGCGGTGTGCCCTCTCGGTTCTCCGGCTCTGGATCCGGCACAGATTACACACTGACCATCTCTAGCCTGCAGCCCGAGGACTTCGCCACCTACTACTGCCAGCAGGGCAACACCCTGCCCTGGACATTCGGCCAGGGCACCAAGGTGGAAATCAAATCGTCAGGTGGCGGCGGATCTGACATCCAGATGACCCAGAGCCCTTCTTCACTAAGTGCCTCCGTGGGCGATCGCGTGACCATCTCCTGCAGAGCCTCTGAGAGCGTGGATAACTATGGCATCAGCTTCCTGAATTGGTTTCAGCAGAAGCCCGGCAAGGCCCCTAAGCTGCTGATCTACGCCGCTTCTAACCAGCGGTCTGGAGTGCCTAGCAGGTTCAGCGGCAGCGGAAGCGGCACAGACTTCACCCTGACTATCAGCAGCCTTCAGCCCGAGGATTTCGCCACATATTTCTGCCAGCAGAGCAAAGAGGTGCCTTGGACCTTCGGCCAGGGCACCAAGGTGGAGATTAAGAGAGGCGGAGGAGGTTCAGGTGGAGGTGGATCTGGAGGTGGCGGGTCTGAGGTGCAACTGGTGGAGAGCGGTGGCGGCCTGGTGCAACCTGGAGGCTCACTGCGGCTGTCATGCAGCTTCTCTGGGTTCAGCCTGAGCACAAGCGGCATGGGAGTGGGCTGGATCCGGCAAGCCCCTGGCAAGGGACTTGAGTGGGTCGCCCACATTTGGTGGGACGATGACAAGCGGTACAACCCCGCCCTGAAGAGCAGATTCACACTGAGCGTAGACAGAAGCAAGAACACACTGTACCTGCAGATGAACAGCCTGCGGGCTGAAGATACCGCCACCTACTACTGCGTTCAGATCAACTACGGCAACTACAGATTTGACAACTGGGGCCACGGAACCCTGGTGACCGTGTCTTCTGGCGGTGGCGGATCAGGAGGCGGAGGTAGTGACAAGACCCACACATGCCCTCCTTGTCCTGCTCCAGAGGCCGCCGGCGGACCTTCTGTGTTTCTGTTTCCTCCCAAGCCTAAGGACACACTGATGATCAGCCGGACACCCGAGGTGACCTGTGTGGTGGTGGACGTGAGCCATGAGGCCCCTGAAGTGAAGTTCAACTGGTACGTGGACGGCGTCGAAGTGCACAATGCCAAGACCAAGCCTTGCGAGGAACAGTACGGCAGCACCTACAGATGTGTGTCCGTCCTGACAGTGCTGCACCAGGACTGGCTGAATGGAAAGGAGTACAAATGCGCGGTATCCAACAAGGCCCTGCCTGCTCCCATCGAGAAGACCATCAGCAAGGCCAAGGGCCAGCCCAGGGAGCCTCAAGTGTACACTCTGCCACCTAGCCGGGAAGAGATGACCAAGAACCAGGTGTCTCTGACATGTCTGGTGAAGGGTTTTTACCCTTCAGACATCGCCGTGGAATGGGAGTCAAATGGCCAGCCTGAAAACAACTACAAGACCACACCTCCAGTGCTGGATTCCGACGGCTCTTTCTTCCTGTATAGCAAGCTGACCGTGGACAAGTCCAGATGGCAACAAGGAAATGTGTTCAGCTGCAGCGTGATGCACGAGGCCCTGCACAATCACTACACCCAAAA GTCGCTTTCTCTGTCTCCAGGAAAGGGTGGTGGAGGGTCAGGCGGCGGTGGAAGCGGAGGAGGCGGTTCTGGGGGAGGCGGATCTGGTGGCGGCGGTAGCGGCGGCGGCGGAAGCGACAAGACACACACCTGTCCACCCTGCCCCGCTCCTGAGGCCGCCGGCGGCCCTAGCGTGTTTCTGTTCCCCCCTAAGCCTAAAGATACCCTGATGATCTCCAGAACACCCGAGGTGACCTGTGTGGTGGTGGATGTGTCCCACGAGGCCCCAGAAGTGAAATTCAACTGGTATGTGGATGGAGTGGAGGTGCATAACGCCAAAACCAAACCTTGCGAGGAGCAGTACGGCTCTACCTACAGATGCGTGTCTGTCCTGACCGTGCTACACCAGGATTGGCTGAACGGCAAGGAATACAAGTGCGCCGTGAGCAACAAGGCCCTGCCTGCTCCAATCGAGAAAACCATCAGCAAGGCTAAGGGCCAGCCTCGGGAACCCCAGGTGTACACCCTGCCACCCTCTAGAGAAGAGATGACCAAGAACCAGGTGAGCCTGACCTGCCTGGTGAAGGGCTTTTACCCCAGCGATATCGCCGTGGAATGGGAAAGCAATGGCCAGCCTGAGAACAACTACAAAACAACCCCTCCTGTGCTGGACAGCGACGGCAGCTTCTTCCTGTACAGCAAGCTGACAGTGGACAAGAGTCGGTGGCAGCAGGGAAATGTGTTCAGTTGCTCGGTGATGCACGAAGCCCTTCACAACCACTACACCCAAAAGAGCTTATCCCTGTCCCCTGGAAAGCACCATCATCACCACCACFSHR PMTE (HLHLHL-Fc) coding sequence (SEQ ID NO: 57)ATGACCCAAAGCCCCAGCAGCCTGTCAGCCAGCGTTGGCGACAGAGTGACCATTTCTTGTAGAGCCAGCGAGAGCGTGGACAACTACGGCATCAGCTTCCTGAACTGGTTCCAGCAGAAGCCCGGAAAAGCCCCCAAACTGCTGATCTACGCCGCTAGCAATCAGCGGAGTGGCGTTCCTAGCAGGTTCAGCGGTTCCGGCTCAGGCACAGACTTCACCCTGACAATCTCCAGTCTGCAGCCTGAGGATTTTGCCACCTACTTCTGCCAGCAGAGTAAGGAGGTGCCGTGGACCTTCGGACAGGGCACCAAAGTGGAAATTAAAAGAGGCGGAGGTGGCTCTGGAGGCGGTGGATCTGGTGGTGGCGGATCAGAGGTGCAACTGGTCGAGAGCGGCGGAGGCCTGGTCCAGCCTGGCGGCTCTCTGAGACTGAGCTGCAGCTTCAGCGGATTTAGCCTGAGCACATCCGGCATGGGCGTGGGATGGATCAGACAGGCCCCTGGCAAGGGGCTGGAGTGGGTCGCCCACATCTGGTGGGATGACGACAAGAGATACAATCCTGCTCTGAAATCTAGGTTTACGCTGAGCG■rGGArAGAAGCAAGAACACCCrGTACC GCAGATGAACAGCCTrAGAGCTGAAGACAClGCCACCTACTACTGCGTCCAGATCAACTACGGCAACTATCGGTTCGACAACTGGGGCCACGGGACCCTCGTGACAGTGAGCTCTGGTGGAGGCGGGAGCGAAGTGCAGCTGGTGGAGAGCGGCGGCGGCCTGGTTCAGCCAGGCGGCTCACTGAGACTGAGCTGTGCTGCCTCTGGCTACTCTTTCACAGGTTACACCATGAACTGGGTGAGACAGGCCCCTGGCAAGGGACTGGAATGGGTTGCTCTGATCAACCCTTACAAGGGGGTCAGCACCTACAACCAGAAATTCAAGGACAGATTCACCATCAGCGTGGACAAAAGCAAAAACACAGCCTACCTGCAGATGAATTCACTGAGAGCCGAAGATACAGCCGTGTACTATTGTGCCAGAAGCGGCTATTATGGCGACTCTGACTGGTACTTCGACGTGTGGGGACAGGGCACCCTGGTGACAGTGTCTAGCGGAGGCGGCGGTAGTGGTGGAGGAGGCTCTGGCGGTGGTGGAAGCGATATCCAGATGACCCAGTCCCCGTCTAGCCTGTCTGCCTCTGTGGGCGACAGAGTCACCATCACATGCAGAGCGAGTCAGGACATAAGAAACTACCTGAACTGGTACCAGCAGAAGCCTGGCAAGGCCCCTAAGCTGCTGATCTACTACACGAGCCGCCTGGAAAGCGGTGTGCCCTCTCGGTTCTCCGGCTCTGGATCCGGCACAGATTACACACTGACCATCTCTAGCCTGCAGCCCGAGGACTTCGCCACCTACTACTGCCAGCAGGGCAACACCCTGCCCTGGACATTCGGCCAGGGCACCAAGGTGGAAATCAAATCGTCAGGTGGCGGCGGATCTGACATCCAGATGACCCAGAGCCCTTCTTCACTAAGTGCCTCCGTGGGCGATCGCGTGACCATCTCCTGCAGAGCCTCTGAGAGCGTGGATAACTATGGCATCAGCTTCCTGAATTGGTTTCAGCAGAAGCCCGGCAAGGCCCCTAAGCTGCTGATCTACGCCGCTTCTAACCAGCGGTCTGGAGTGCCTAGCAGGTTCAGCGGCAGCGGAAGCGGCACAGACTTCACCCTGACTATCAGCAGCCTTCAGCCCGAGGATTTCGCCACATATTTCTGCCAGCAGAGCAAAGAGGTGCCTTGGACCTTCGGCCAGGGCACCAAGGTGGAGATTAAGAGAGGCGGAGGAGGTTCAGGTGGAGGTGGATCTGGAGGTGGCGGGTCTGAGGTGCAACTGGTGGAGAGCGGTGGCGGCCTGGTGCAACCTGGAGGCTCACTGCGGCTGTCATGCAGCTTCTCTGGGTTCAGCCTGAGCACAAGCGGCATGGGAGTGGGCTGGATCCGGCAAGCCCCTGGCAAGGGACTTGAGTGGGTCGCCCACATTTGGTGGGACGATGACAAGCGGTACAACCCCGCCCTGAAGAGCAGATTCACACTGAGCGTAGACAGAAGCAAGAACACACTGTACCTGCAGATGAACAGCCTGCGGGCTGAAGATACCGCCACCTACTACTGCGTTCAGATCAACTACGGCAACTACAGATTTGACAACTGGGGCCACGGAACCCTGGTGACCGTGTCTTCTGGCGGTGGCGGATCAGGAGGCGGAGGTAGTGACAAGACCCACACATGCCCTCCTTGTCCTGCTCCAGAGGCCGCCGGCGGACCTTCTGTGTTTCTGTTTCCTCCCAAGCCTAAGGACACACTGATGATCAGCCGGACACCCGAGGTGACCTGTGTGGTGGTGGACGTGAGCCATGAGGCCCCTGAAGTGAAGTTCAACTGGTACGTGGACGGCGTCGAAGTGCACAATGCCAAGACCAAGCCTTGCGAGGAACAGTACGGCAGCACCTACAGATGTGTGTCCGTCCTGACAGTGCTGCACCAGGACTGGCTGAATGGAAAGGAGTACAAATGCGCGGTATCCAACAAGGCCCTGCCTGCTCCCATCGAGAAGACCATCAGCAAGGCCAAGGGCCAGCCCAGGGAGCCTCAAGTGTACACTCTGCCACCTAGCCGGGAAGAGATGACCAAGAACCAGGTGTCTCTGACATGTCTGGTGAAGGGTTTTTACCCTTCAGACATCGCCGTGGAATGGGAGTCAAATGGCCAGCCTGAAAACAACTACAAGACCACACCTCCAGTGCTGGATTC CGACGGCTCTTTCTTCCTGTATAGCAAGCTGACCGTGGACAAGTCCAGATGGCAACAAGGAAATGTGTTCAGCTGCAGCGTGATGCACGAGGCCCTGCACAATCACTACACCCAAAAGTCGCTTTCTCTGTCTCCAGGAAAGGGTGGTGGAGGGTCAGGCGGCGGTGGAAGCGGAGGAGGCGGTTCTGGGGGAGGCGGATCTGGTGGCGGCGGTAGCGGCGGCGGCGGAAGCGACAAGACACACACCTGTCCACCCTGCCCCGCTCCTGAGGCCGCCGGCGGCCCTAGCGTGTTTCTGTTCCCCCCTAAGCCTAAAGATACCCTGATGATCTCCAGAACACCCGAGGTGACCTGTGTGGTGGTGGATGTGTCCCACGAGGCCCCAGAAGTGAAATTCAACTGGTATGTGGATGGAGTGGAGGTGCATAACGCCAAAACCAAACCTTGCGAGGAGCAGTACGGCTCTACCTACAGATGCGTGTCTGTCCTGACCGTGCTACACCAGGATTGGCTGAACGGCAAGGAATACAAGTGCGCCGTGAGCAACAAGGCCCTGCCTGCTCCAATCGAGAAAACCATCAGCAAGGCTAAGGGCCAGCCTCGGGAACCCCAGGTGTACACCCTGCCACCCTCTAGAGAAGAGATGACCAAGAACCAGGTGAGCCTGACCTGCCTGGTGAAGGGCTTTTACCCCAGCGATATCGCCGTGGAATGGGAAAGCAATGGCCAGCCTGAGAACAACTACAAAACAACCCCTCCTGTGCTGGACAGCGACGGCAGCTTCTTCCTGTACAGCAAGCTGACAGTGGACAAGAGTCGGTGGCAGCAGGGAAATGTGTTCAGTTGCTCGGTGATGCACGAAGCCCTTCACAACCACTACACCCAAAAGAGCTTATCCCTGTCCCCTGGAAAGFSHR PMTE (LHHLHL-Fc) construct sequence (SEQ ID NO:58)GAGGTGCAACTGGTCGAGTCCGGGGGCGGCCTGGTCCAGCCTGGTGGCTCTTTGAGGCTGAGCTGT AGCTTCAGCGGCTTTAGCCTGAGCACCAGCGGGATGGGCGTGGGCTGGATCAGACAGGCTCCTGG AAAGGGCTTGGAATGGGTTGCCCACATCTGGTGGGATGATGACAAGAGATACAACCCTGCCCTGA AAAGCAGGTTCACCCTGAGCGTGGACAGATCTAAGAACACCCTGTATCTGCAGATGAACAGCCTT CGGGCCGAGGACACAGCGACATATTACTGCGTGCAGATCAATTATGGAAACTACAGATTTGATAA TTGGGGACACGGCACCCTGGTGACCGTGAGCAGCGGCGGAGGTGGCTCTGGAGGCGGTGGATCTG GTGGTGGCGGATCAGACATCCAAATGACCCAGAGCCCTAGCAGCCTGTCTGCCAGCGTCGGAGAT CGTGTGACCATCAGCTGTAGAGCCTCTGAGAGCGTGGACAACTACGGCATCAGTTTCCTGAACTGG 1'11CAGCAGAAGCC1GGAAAGGC1CC1AAGC1GC1GA1C1ACGCCGC1AGCAA1CAGAGAAGCGG CGTTCCTTCTAGATTCAGCGGAAGCGGTAGCGGCACCGACTTCACCCTGACCATCAGCAGTCTGCA GCCAGAGGACTTCGCCACCTACTTCTGCCAGCAGAGCAAGGAAGTGCCTTGGACCTTTGGCCAGG GCACAAAGGTGGAGATCAAGCGGGGTGGAGGCGGGAGCGAGGTGCAGCTGGTGGAAAGCGGCGG CGGCCTGGTCCAGCCTGGCGGCTCACTGCGGCTGAGCTGCGCCGCAAGCGGCTATAGCTTCACCGG CTACACCATGAATTGGGTCAGACAGGCCCCTGGCAAGGGCCTGGAATGGGTGGCCCTGATTAACC CCTACAAGGGCGTTAGCACATACAACCAGAAGTTCAAGGACAGATTCACAATAAGCGTGGATAAG TCTAAGAACACAGCCTACCTGCAGATGAACAGCCTGCGGGCTGAGGACACCGCCGTGTACTACTG TGCCAGATCCGGGTACTACGGCGATAGCGACTGGTATTTCGACGTGTGGGGCCAGGGCACCCTGG TGACAGTGTCGTCAGGAGGCGGCGGTAGTGGTGGAGGAGGCTCTGGCGGTGGTGGAAGCGACATC CAGATGACCCAGTCCCCTAGCAGCCTGAGCGCTAGTGTCGGCGATAGAGTGACCATCACATGTAG AGCCAGCCAAGACATCCGGAACTACCTGAACTGGTACCAGCAGAAACCTGGCAAAGCCCCCAAGC TGCTGATCTATTACACCAGCAGACTGGAATCCGGAGTGCCAAGTAGATTCAGCGGCAGTGGTTCCG GCACGGATTACACCCTGACAATCTCATCTCTTCAGCCTGAAGATTTCGCCACCTACTACTGCCAAC AAGGAAATACCCTGCCATGGACCTTCGGCCAAGGCACCAAGGTGGAGATCAAGAGCAGCGGTGGC GGCGGATCTGACATCCAGATGACTCAGTCCCCTTCCAGCCTGAGCGCCAGCGTAGGCGACCGGGT GACAATCTCCTGCAGAGCTAGCGAGAGCGTGGACAACTACGGCATCAGCTTCCTGAACTGGTTCC AGCAAAAGCCCGGCAAGGCCCCTAAACTGCTGATCTATGCCGCCAGCAACCAAAGATCTGGAGTT CCTTCCCGGTTTAGCGGCTCCGGATCTGGCACCGACTTCACACTGACCATCAGCTCCCTGCAGCCT GAGGATTTCGCCACATACTTTTGCCAGCAGAGCAAGGAGGTGCCTTGGACCTTCGGACAGGGCAC CAAGGTGGAGATCAAGCGGGGCGGAGGAGGTTCAGGTGGAGGTGGATCTGGAGGTGGCGGGTCT GAAGTCCAGCTCGTGGAAAGCGGCGGAGGTCTGGTGCAACCAGGCGGCAGCCTGAGACTGTCCTG TAGCTTCAGCGGCTTCAGCCTGAGCACCTCCGGCATGGGAGTAGGCTGGATCAGACAGGCCCCTG GCAAGGGTCTGGAGTGGGTGGCCCACATCTGGTGGGACGACGACAAGAGGTACAACCCCGCTCTGAAGTCCAGATTCACCCTGAGCGTGGATAGAAGCAAAAACACCCTCTACCTGCAGATGAACAGCCT GCGGGCCGAGGATACCGCCACCTACTACTGCGTGCAGATCAACTACGGCAATTACCGCTTCGACA ACTGGGGCCACGGCACACTCGTGACGGTGAGCTCTGGCGGTGGCGGATCAGGAGGCGGAGGTAGT GATAAGACCCACACCTGCCCTCCTTGTCCTGCCCCAGAGGCCGCCGGCGGCCCTTCTGTGTTCCTTT TTCCTCCTAAGCCCAAAGACACCCTGATGATCTCTCGGACCCCTGAGGTTACATGCGTGGTGGTGG ACGTGAGCCACGAGGCACCCGAGGTCAAGTTCAACTGGTACGTGGACGGCGTAGAGGTTCACAAC GCCAAAACAAAGCCCTGCGAGGAACAGTACGGATCTACCTACCGGTGCGTGAGCGTGCTGACGGT TCTGCATCAGGACTGGCTGAATGGCAAGGAATACAAGTGCGCCGTGTCTAACAAAGCTCTCCCTGC TCCTATTGAGAAGACCATCTCCAAGGCCAAGGGCCAACCTAGAGAACCCCAGGTGTACACACTGC CTCCTAGTCGTGAAGAGATGACAAAGAATCAGGTGTCCCTGACGTGTCTGGTGAAGGGCTTCTACC CCAGCGACATCGCCGTGGAATGGGAATCTAACGGCCAGCCAGAGAACAACTACAAGACAACACCCCCTGTGCTGGATAGCGACGGCTCTTTCTTCCTGTACAGCAAGCTGACAGTGGACAAGAGCAGATGGCAGCAGGGAAACGTGTTTTCCTGTTCTGTGATGCACGAGGCCCTGCACAACCACTACACTCAGAAAAGCTTATCTCTGTCACCCGGAAAAGGTGGTGGAGGGTCAGGCGGCGGTGGAAGCGGAGGAGGCGGTTCTGGCGGTGGAGGAAGTGGCGGAGGAGGCAGCGGCGGCGGAGGATCTGATAAGACACACACATGCCCCCCATGCCCCGCCCCTGAAGCCGCCGGCGGACCTTCTGTGTTCCTGTTCCCCCCAAAGCCCAAGGACACCCTGATGATTTCCCGGACACCTGAAGTGACCTGTGTGGTGGTGGACGTGTCTCACGAGGCCCCCGAAGTGAAGTTCAATTGGTACGTGGATGGAGTCGAAGTGCACAACGCCAAGACCAAGCCTTGCGAGGAGCAATACGGCTCTACCTATAGATGCGTGTCAGTGCTGACCGTGCTGCATCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCGCCGTAAGTAACAAGGCACTGCCTGCCCCCATTGAGAAAACAATCTCCAAGGCTAAGGGCCAGCCTAGAGAGCCTCAGGTGTACACACTGCCCCCCAGCCGAGAAGAAATGACCAAGAACCAGGTATCACTGACCTGCCTGGTGAAGGGGTTCTACCCCTCTGACATCGCCGTGGAATGGGAGTCTAACGGCCAACCAGAAAACAACTACAAGACCACCCCTCCAGTGCTGGATAGCGACGGCAGTTTTTTCCTGTACAGCAAACTGACCGTGGACAAGTCTCGCTGGCAGCAGGGAAACGTGTTCTCTTGCAGCGTGATGCACGAGGCCCTGCACAATCACTACACCCAGAAAAGCCTGTCCCTGAGCCCTGGCAAGCACCATCACCACCACCACFSHR PMTE (LHHLHL-Fc) coding sequence (SEQ ID NO: 59)ATGGGCGTGGGATGGATCAGACAGGCCCCCGGGAAGGGCCTGGAATGGGTTGCCCACATCTGGTGGGACGACGACAAAAGATACAATCCCGCCCTGAAGAGCCGGTTCACCCTGTCGGTTGATAGAAGCAAGAATACCTTGTACCTGCAGATGAACTCCCTGAGAGCTGAGGACACAGCCACATACTATTGTGTGCAGATCAACTATGGTAACTACAGATTCGACAACTGGGGGCACGGAACCCTGGTGACCGTGTCTTCAGGCGGAGGTGGCTCTGGAGGCGGTGGATCTGGTGGTGGCGGATCAGATATCCAAATGACCCAGTCTCCTTCAAGCCTGAGTGCCAGCGTGGGCGACCGAGTGACCATCAGCTGTCGCGCCAGCGAGAGCG■rGGACAACrACGGAATCAGCrTTCTGAACTGGITCCAGCAGAAACCrGGCAAAGCCCCTAAGCrGCTCATCTACGCCGCTTCTAATCAGCGCAGCGGCGTGCCGAGCAGATTCTCAGGCAGCGGCAGCGGAACCGATTTCACCTTAACCATCTCCAGTCTGCAGCCTGAGGACTTCGCCACATACTTCTGCCAGCAGAGTAAAGAGGTGCCTTGGACCTTTGGCCAGGGCACAAAAGTGGAGATCAAGAGAGGTGGAGGCGGGAGCGACATCCAGATGACACAATCTCCAAGCAGCCTGAGCGCCAGCGTGGGCGACAGAGTGACAATCACCTGCAGAGCCTCCCAGGACATTAGAAACTACCTGAACTGGTACCAGCAGAAGCCAGGCAAAGCTCCGAAGCTGCTGATCTACTACACCAGCCGCCTCGAGTCTGGAGTTCCTAGTAGGTTTTCCGGAAGCGGCAGCGGGACCGACTACACCCTGACAATCTCTAGCCTGCAGCCCGAAGATTTCGCCACCTACTACTGCCAGCAGGGAAACACCCTCCCTTGGACCTTCGGCCAAGGCACCAAGGTGGAAATCAAGTCTTCCGGAGGCGGCGGTAGTGGTGGAGGAGGCTCTGGCGGTGGTGGAAGCGAGGTCCAGCTGGTGGAAAGCGGTGGCGGCCTGGTGCAACCTGGCGGGAGCCTGAGACTGTCTTGTGCCGCCAGCGGCTACAGCTTCACAGGCTATACCATGAACTGGGTGCGGCAGGCCCCCGGCAAGGGTCTGGAGTGGGTAGCCCTGATCAACCCTTACAAGGGCGTGAGCACCTACAATCAGAAGTTCAAGGACCGGTTTACCATCTCAGTGGACAAGTCTAAAAACACCGCCTACCTGCAGATGAATAGCCTGCGGGCCGAGGACACTGCCGTGTACTACTGCGCCAGATCCGGTTACTACGGTGATAGCGACTGGTACTTCGACGTGTGGGGCCAGGGCACACTGGTGACCGTGAGCTCCGGTGGCGGCGGATCTGATATTCAGATGACCCAGAGCCCTAGCTCTCTCTCCGCCAGCGTGGGCGACCGGGTGACTATCAGCTGCAGAGCCTCGGAAAGCGTGGATAATTACGGCATCTCCTTTCTCAACTGGTTCCAACAGAAACCTGGTAAGGCTCCTAAGCTGCTGATTTACGCCGCCTCTAACCAGAGAAGCGGAGTGCCTTCCAGGTTCAGTGGCAGTGGCTCCGGAACGGACTTCACCCTGACCATCAGCAGCCTTCAGCCCGAGGACTTCGCCACTTACTTTTGCCAGCAAAGCAAGGAGGTGCCATGGACATTCGGCCAGGGGACCAAGGTGGAGATCAAGAGAGGCGGAGGAGGTTCAGGTGGAGGTGGATCTGGAGGTGGCGGGTCTGAGGTGCAGCTGGTCGAGAGCGGAGGAGGACTGGTGCAGCCTGGCGGCTCTCTGCGGCTGTCTTGCAGCTTCAGCGGCTTCAGCCTGTCTACCAGCGGCATGGGCGTGGGCTGGATCAGACAGGCTCCAGGCAAAGGCCTCGAGTGGGTGGCCCACATCTGGTGGGATGATGACAAGCGGTACAACCCCGCACTGAAGAGCAGATTTACCCTGAGCGTCGACCGGAGCAAGAACACACTGTACCTGCAAATGAATAGCCTGCGGGCCGAGGATACAGCCACCTACTACTGTGTGCAAATCAATTATGGCAACTACCGATTCGACAATTGGGGCCACGGCACCCTGGTGACCGTGTCCTCCGGCGGTGGCGGATCAGGAGGCGGAGGTAGTGACAAAACCCACACATGCCCTCCTTGCCCCGCTCCTGAAGCCGCTGGCGGGCCTTCTGTCTTTCTGTTTCCTCCAAAACCTAAGGACACACTGATGATCAGCAGAACACCTGAGGTGACATGCGTCGTGGTGGACGTAAGCCACGAAGCCCCTGAAGTGAAGTTCAACTGGTACGTGGACGGCGTTGAAGTGCACAACGCCAAGACAAAGCCTTGCGAGGAACAGTACGGCAGCACCTACAGATGCGTGTCCGTGCTGACCGTGCTGCACCAGGACTGGCTGAATGGGAAGGAGTACAAGTGCGCCGTGAGCAACAAGGCCCTGCCTGCCCCTATCGAGAAAACCATCTCTAAGGCCAAGGGCCAACCTCGGGAACCTCAGGTCTACACCCTGCCTCCTAGCAGAGAGGAAATGACCAAGAATCAGGTGTCGCTGACATGCCTGGTGAAGGGCTTCTACCCTAGCGACATTGCCGTGGAATGGGAATCTAATGGCCAACCTGAGAACAACTACAAGACCACCCCTCCCGTGCTGGATTCTGATGGCAGCTTTTTCCTGTACAGCAAGCTGACAGTGGATAAGAGTAGATGGCAACAGGGAAATGTGTTCAGCTGCAGCGTGATGCACGAGGCCCTGCATAACCACTACACCCAGAAGAGCCTGAGCCTGAGCCCCGGGAAGGGTGGTGGAGGGTCAGGCGGCGGTGGAAGCGGAGGAGGCGGTTCTGGGGGCGGCGGCAGCGGAGGAGGCGGCTCAGGCGGTGGCGGCAGCGACAAGACCCACACCTGCCCCCCCTGCCCTGCTCCGGAAGCTGCGGGAGGACCTAGCGTGTTCCTGTTCCCCCCCAAACCAAAGGACACCCTGATGATCAGCCGGACCCCTGAAGTAACCTGTGTAGTTGTGGATGTGTCTCACGAGGCCCCTGAGGTGAAGTTCAACTGGTATGTGGACGGCGTCGAAGTGCACAACGCCAAGACCAAGCCTTGTGAAGAGCAGTACGGCAGCACATACAGATGCGTGAGCGTGCTCACAGTGCTGCACCAGGATTGGCTGAACGGCAAAGAGTACAAGTGTGCCGTGAGCAACAAGGCCCTGCCCGCTCCCATCGAGAAGACCATCTCTAAGGCTAAGGGCCAGCCCAGAGAGCCTCAGGTGTACACCCTTCCACCAAGCCGGGAAGAGATGACCAAGAACCAGGTGAGCCTGACATGTCTGGTGAAGGGCTTCTACCCCAGCGACATCGCCGTGGAATGGGAGAGCAACGGCCAGCCGGAAAACAACTACAAGACCACACCTCCTGTGTTAGACAGCGATGGAAGCTTCTTCCTGTATAGCAAGCTGACAGTGGATAAGTCCCGGTGGCAGCAGGGCAACGTGTTCTCTTGTTCTGTTATGCATGAGGC TCTGCACAATCACTACACACAGAAGAGCCTGTCTCTGAGTCCTGGAAAGFSHR PMTE (LHLHLH-Fc) construct sequence (SEQ ID NO:60)GAAGTGCAGCTGGTTGAGTCGGGTGGAGGCCTGGTGCAACCTGGAGGGTCGCTGAGACTGTCTTG TTCTTTCAGCGGATTCAGCCTGTCCACATCCGGCATGGGCGTGGGCTGGATCAGACAAGCTCCAGGCAAGGGCCTGGAGTGGGTGGCCCACATCTGGTGGGATGATGATAAGCGGTACAACCCCGCACTTAAGTCCAGATTTACCCTGAGCGTGGATAGAAGCAAGAACACCCTGTACCTGCAGATGAACAGCCTG AGAGCCGAGGACACCGCCACA'IAClAC'l'GCGlGCAAA'l'CAAC'l'A'lGGCAAr'l ACCGG'l'lCGA'IAA CTGGGGACATGGCACCCTGGTGACAGTGAGCAGCGGCGGAGGCGGATCCGGCGGCGGAGGCTCTGGCGGCGGCGGGTCCGACATCCAGATGACCCAGAGCCCTTCTTCCCTGAGCGCCAGCGTGGGCGACAGAGTGACCATCAGCTGCAGAGCCAGCGAAAGCGTGGACAACTACGGCATTTCATTCCTGAACTG GTTTCAGCAGAAGCCTGGCAAAGCCCCCAAGCTGCTGATCTACGCCGCTTCTAATCAGAGAAGCG GAGTTCCTTCTAGATTCTCCGGTAGCGGCAGCGGCACAGATTTCACACTGACCATTAGCTCTCTGCAGCCAGAGGACTTCGCCACCTATTTTTGCCAGCAGTCTAAAGAAGTGCCTTGGACCTTCGGACAGGGAACCAAGGTGGAGATCAAGCGTGGCGGCGGGGGAAGCGACATCCAGATGACACAGAGCCCCTC TAGCCTGTCTGCCAGCGTGGGGGACAGAGTGACCATCACCTGTCGGGCCAGCCAGGATATCCGAA ACTATCTGAATTGGTATCAGCAGAAGCCCGGTAAGGCCCCAAAACTGCTGATCTACTACACCAGCC GCCTTGAGAGCGGGGTGCCTTCTCGGTTCAGCGGCTCTGGAAGCGGCACGGACTACACCCTGACAATCAGCTCACTCCAGCCCGAGGATTTCGCCACCTACTACTGTCAGCAAGGCAACACCCTGCCTTGGACCTTCGGCCAGGGCACCAAGGTTGAAATCAAGTCTAGCGGCGGCGGCGGCAGCGGCGGAGGAGGCAGCGGTGGAGGCGGCTCTGAGGTGCAACTGGTGGAGTCTGGTGGCGGATTGGTTCAGCCCGGC GGCTCCCTGCGGCTGTCTTGCGCCGCTAGCGGCTACTCCTTCACCGGCTACACAATGAACTGGGTG CGGCAGGCTCCTGGCAAAGGACTGGAATGGGTCGCGCTGATCAACCCTTACAAGGGAGTGAGCAC CTATAATCAGAAGTTCAAGGACCGGTTTACCATCAGCGTGGATAAGAGCAAAAACACCGCCTATCTGCAGATGAACAGCCTGAGAGCCGAGGACACCGCCGTGTACTACTGCGCCAGATCGGGATACTACGGCGACAGCGATTGGTACTTTGACGTGTGGGGCCAGGGTACCCTGGTCACTGTGTCCTCCGGCGGAGGGGGGAGCGAGGTGCAGCTGGTCGAGTCCGGCGGCGGCCTGGTTCAACCTGGAGGATCCCTGAGACTGAGCTGCAGCTTCAGCGGCTTCAGCCTGTCAACCAGCGGAATGGGCGTGGGCTGGATCCGGCAGGCCCCCGGGAAGGGCCTGGAGTGGGTCGCrCACArCTGGTGGGACGACGATAAGCGGrACAATCCTGCTCTGAAGAGCCGGTTTACACTGTCAGTAGACAGGTCTAAGAACACACTGTACCTGCAGATG AACAGCCTGCGGGCCGAAGACACAGCCACCTACTACTGTGTGCAGATCAATTACGGCAACTATAGATTCGACAACTGGGGCCACGGCACACTCGTGACAGTGTCCAGCGGCGGCGGCGGCAGCGGCGGCGGCGGTAGCGGGGGCGGCGGCAGCGACATCCAGATGACCCAGAGTCCTTCAAGCCTATCGGCCTCTGTTGGAGATAGAGTGACCATCTCTTGCCGGGCCTCTGAGAGCGTGGACAACTACGGAATCTCTTTCCTGAACTGGTTCCAGCAAAAGCCTGGAAAAGCCCCTAAACTGCTGATCTACGCCGCTAGCAATCAGCGGTCCGGCGTGCCTAGCAGATTCAGTGGCAGCGGTTCCGGTACCGATTTCACACTGACCATCAGCAGCCTGCAACCTGAGGATTTCGCCACCTACTTCTGCCAGCAGAGCAAGGAAGTGCCCTGGACATT CGGCCAAGGCACCAAAGTGGAGATCAAGAGAGGCGGAGGCGGTAGTGGAGGAGGCGGCTCTGAC AAGACCCACACATGTCCTCCTTGTCCTGCCCCAGAAGCTGCTGGCGGCCCCTCTGTGTTCCTCTTCCCACCTAAGCCTAAGGACACACTGATGATCTCTCGCACCCCTGAGGTGACCTGCGTGGTGGTGGACGTGAGCCACGAGGCCCCCGAAGTGAAATTTAACTGGTACGTGGACGGCGTGGAAGTCCACAATGCCAAGACCAAGCCTTGCGAAGAGCAGTACGGAAGCACCTACCGGTGCGTGAGCGTGCTGACTGTGCT GCACCAGGACTGGCTGAACGGCAAAGAGTACAAGTGCGCTGTGAGCAACAAGGCCCTGCCTGCCCCGATCGAGAAAACCATCAGCAAGGCCAAGGGCCAGCCAAGAGAACCTCAGGTGTACACCCTGCCTCCCAGCAGAGAGGAAATGACCAAGAATCAGGTGTCTCTGACATGTCTGGTGAAGGGCTTCTACCCCAGCGACATAGCCGTAGAATGGGAGAGCAACGGCCAGCCCGAAAACAACTACAAGACAACCCCACCCGTGCTGGACTCTGACGGCTCCTTCTTCCTTTATTCCAAACTGACAGTCGACAAGTCTAGATGGCAACAAGGGAACGTGTTCTCCTGCAGCGTGATGCACGAAGCCTTGCACAACCACTACACACAGAAATCCCTGTCTCTGAGCCCTGGCAAGGGCGGAGGCGGCAGTGGCGGCGGAGGCTCTGGCGGCGGCGGTAGCGGAGGAGGCGGCTCCGGCGGCGGCGGGTCTGGCGGCGGCGGCAGCGACAAGACACACACCTGTCCTCCTTGCCCCGCCCCTGAGGCCGCCGGCGGACCTAGCGTGTTTCTGTTCCCTCCCAAGCCTAAGGACACCCTGATGATTTCTAGAACCCCCGAGGTAACCTGCGTGGTGGTGGACGTGTCGCATGAGGCCCCCGAGGTGAAGTTCAACTGGTACGTGGACGGCGTGGAAGTGCATAATGCGAAGACCAAGCCTTGCGAGGAACAGTACGGCAGCACGTACAGATGCGTGTCCGTTCTGACGGTGCTGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCGCCGTGTCTAACAAAGCCCTGCCCGCCCCAATCGAGAAGACCATCTCCAAGGCCAAAGGCCAGCCTAGAGAACCCCAGGTCTACACCCTGCCTCCAAGCCGGGAAGAGATGACAAAGAACCAGGTGTCGCTCACCTGCCTGGTGAAGGGCTTCTACCCTTCTGACATCGCCGTGGAATGGGAGTCCAACGGCCAGCCTGAGAACAACTACAAAACCACCCCTCCAGTGCTGGACAGCGATGGATCTTTTTTCCTGTACAGCAAGCTGACTGTGGATAAGAGCAGGTGGCAGCAGGGCAATGTATTCAGCTGCAGCGTGATGCACGAGGCTCTGCACAACCATTACACGCAGAAAAGCCTGTCCCTGAGCCCTGGCAAGCACCACCACCACCACCACFSHR PMTE (LHLHLH-Fc) coding sequence (SEQ ID N0:61)ATGGGCGTGGGCTGGATCAGACAAGCTCCAGGCAAGGGCCTGGAGTGGGTGGCCCACATCTGGTG GGATGATGATAAGCGGTACAACCCCGCACTTAAGTCCAGATTTACCCTGAGCGTGGATAGAAGCA AGAACACCCTGTACCTGCAGATGAACAGCCTGAGAGCCGAGGACACCGCCACATACTACTGCGTG CAAATCAACTATGGCAATTACCGGTTCGATAACTGGGGACATGGCACCCTGGTGACAGTGAGCAG CGGCGGAGGCGGATCCGGCGGCGGAGGCTCTGGCGGCGGCGGGTCCGACATCCAGATGACCCAG AGCCCTTCTTCCCTGAGCGCCAGCGTGGGCGACAGAGTGACCATCAGCTGCAGAGCCAGCGAAAG CGTGGACAACTACGGCATTTCATTCCTGAACTGGTTTCAGCAGAAGCCTGGCAAAGCCCCCAAGCT GCTGATCTACGCCGCTTCTAATCAGAGAAGCGGAGTTCCTTCTAGATTCTCCGGTAGCGGCAGCGG CACAGATTTCACACTGACCATTAGCTCTCTGCAGCCAGAGGACTTCGCCACCTATTTTTGCCAGCA GTCTAAAGAAGTGCCTTGGACCTTCGGACAGGGAACCAAGGTGGAGATCAAGCGTGGCGGCGGGG GAAGCGACATCCAGATGACACAGAGCCCCTCTAGCCTGTCTGCCAGCGTGGGGGACAGAGTGACC ATCACCTGTCGGGCCAGCCAGGATATCCGAAACTATCTGAATTGGTATCAGCAGAAGCCCGGTAA GGCCCCAAAACTGCTGATCTACTACACCAGCCGCCTTGAGAGCGGGGTGCCTTCTCGGTTCAGCGG CTCTGGAAGCGGCACGGACTACACCCTGACAATCAGCTCACTCCAGCCCGAGGATTTCGCCACCTA CTACTGTCAGCAAGGCAACACCCTGCCTTGGACCTTCGGCCAGGGCACCAAGGTTGAAATCAAGT CTAGCGGCGGCGGCGGCAGCGGCGGAGGAGGCAGCGGTGGAGGCGGCTCTGAGGTGCAACTGGT GGAGTCTGGTGGCGGATTGGTTCAGCCCGGCGGCTCCCTGCGGCTGTCTTGCGCCGCTAGCGGCTA CTCCTTCACCGGCTACACAATGAACTGGGTGCGGCAGGCTCCTGGCAAAGGACTGGAATGGGTCG CGCTGATCAACCCTTACAAGGGAGTGAGCACCTATAATCAGAAGTTCAAGGACCGGTTTACCATC AGCGTGGATAAGAGCAAAAACACCGCCTATCTGCAGATGAACAGCCTGAGAGCCGAGGACACCG CCGTGTACTACTGCGCCAGATCGGGATACTACGGCGACAGCGATTGGTACTTTGACGTGTGGGGCC AGGGTACCCTGGTCACTGTGTCCTCCGGCGGAGGGGGGAGCGAGGTGCAGCTGGTCGAGTCCGGC GGCGGCC GGl rCAACC'l'GGAGGATCCC'l'GAGACrGAGCTGCAGC'rrCAGCGGCl'l'CAGCCTG'rCA ACCAGCGGAATGGGCGTGGGCTGGATCCGGCAGGCCCCCGGGAAGGGCCTGGAGTGGGTCGCTCA CATCTGGTGGGACGACGATAAGCGGTACAATCCTGCTCTGAAGAGCCGGTTTACACTGTCAGTAG ACAGGTCTAAGAACACACTGTACCTGCAGATGAACAGCCTGCGGGCCGAAGACACAGCCACCTAC TACTGTGTGCAGATCAATTACGGCAACTATAGATTCGACAACTGGGGCCACGGCACACTCGTGAC AGTGTCCAGCGGCGGCGGCGGCAGCGGCGGCGGCGGTAGCGGGGGCGGCGGCAGCGACATCCAG ATGACCCAGAGTCCTTCAAGCCTATCGGCCTCTGTTGGAGATAGAGTGACCATCTCTTGCCGGGCC TCTGAGAGCGTGGACAACTACGGAATCTCTTTCCTGAACTGGTTCCAGCAAAAGCCTGGAAAAGC CCCTAAACTGCTGATCTACGCCGCTAGCAATCAGCGGTCCGGCGTGCCTAGCAGATTCAGTGGCAG CGGTTCCGGTACCGATTTCACACTGACCATCAGCAGCCTGCAACCTGAGGATTTCGCCACCTACTT CTGCCAGCAGAGCAAGGAAGTGCCCTGGACATTCGGCCAAGGCACCAAAGTGGAGATCAAGAGA GGCGGAGGCGGTAGTGGAGGAGGCGGCTCTGACAAGACCCACACATGTCCTCCTTGTCCTGCCCC AGAAGCTGCTGGCGGCCCCTCTGTGTTCCTCTTCCCACCTAAGCCTAAGGACACACTGATGATCTC TCGCACCCCTGAGGTGACCTGCGTGGTGGTGGACGTGAGCCACGAGGCCCCCGAAGTGAAATTTAACTGGTACGTGGACGGCGTGGAAGTCCACAATGCCAAGACCAAGCCTTGCGAAGAGCAGTACGGAAGCACCTACCGGTGCGTGAGCGTGCTGACTGTGCTGCACCAGGACTGGCTGAACGGCAAAGAGTACAAGTGCGCTGTGAGCAACAAGGCCCTGCCTGCCCCGATCGAGAAAACCATCAGCAAGGCCAAGGGCCAGCCAAGAGAACCTCAGGTGTACACCCTGCCTCCCAGCAGAGAGGAAATGACCAAGAATCAGGTGTCTCTGACATGTCTGGTGAAGGGCTTCTACCCCAGCGACATAGCCGTAGAATGGGAGAGCAACGGCCAGCCCGAAAACAACTACAAGACAACCCCACCCGTGCTGGACTCTGACGGCTCCTTCTTCCTTTATTCCAAACTGACAGTCGACAAGTCTAGATGGCAACAAGGGAACGTGTTCTCCTGCAGCGTGATGCACGAAGCCTTGCACAACCACTACACACAGAAATCCCTGTCTCTGAGCCCTGGCAAGGGCGGAGGCGGCAGTGGCGGCGGAGGCTCTGGCGGCGGCGGTAGCGGAGGAGGCGGCTCCGGCGGCGGCGGGTCTGGCGGCGGCGGCAGCGACAAGACACACACCTGTCCTCCTTGCCCCGCCCCTGAGGCCGCCGGCGGACCTAGCGTGTTTCTGTTCCCTCCCAAGCCTAAGGACACCCTGATGATTTCTAGAACCCCCGAGGTAACCTGCGTGGTGGTGGACGTGTCGCATGAGGCCCCCGAGGTGAAGTTCAACTGGTACGTGGACGGCGTGGAAGTGCATAATGCGAAGACCAAGCCTTGCGAGGAACAGTACGGCAGCACGTACAGATGCGTGTCCGTTCTGACGGTGCTGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCGCCGTGTCTAACAAAGCCCTGCCCGCCCCAATCGAGAAGACCATCTCCAAGGCCAAAGGCCAGCCTAGAGAACCCCAGGTCTACACCCTGCCTCCAAGCCGGGAAGAGATGACAAAGAACCAGGTGTCGCTCACCTGCCTGGTGAAGGGCTTCTACCCTTCTGACATCGCCGTGGAATGGGAGTCCAACGGCCAGCCTGAGAACAACTACAAAACCACCCCTCCAGTGCTGGACAGCGATGGATCTTTTTTCCTGTACAGCAAGCTGACTGTGGATAAGAGCAGGTGGCAGCAGGGCAATGTATTCAGCTGCAGCGTGATGCACGAGGCTCTGCACAACCATTACACGCAGAAAAGCCTGTCCCTGAGCCCTGGCAAGFSHR PMTE (HLLHHL-Fc) construct sequence (SEQ ID NO: 62)GACATCCAGATGACCCAGAGCCCTAGCAGCCTTAGTGCCAGCGTGGGCGACAGAGTGACAATCAGCTGTAGGGCCTCTGAGAGCGTGGACAACTACGGCATCAGCTTCCTGAACTGGTTCCAGCAGAAACCTGGCAAGGCTCCTAAGCTGCTGATCTATGCGGCTAGCAACCAGAGAAGCGGCGTCCCAAGCAGATTCTCCGGCAGCGGAAGCGGGACAGATTTCACCCTGACCATCAGCTCTCTGCAGCCTGAGGATTTCGCCACCTACTTCTGTCAGCAGAGCAAAGAAGTGCCCTGGACCTTCGGCCAAGGCACCAAAGTGGAGATCAAGCGGGGCGGCGGTGGCAGTGGAGGCGGCGGCAGCGGCGGAGGAGGAAGCGAGGTCCAGCTGGTCGAGTCTGGGGGCGGCCTGGTGCAGCCCGGCGGCAGCCTGCGGTTGTCTTGCTCTTTCAGCGGCTTTTCCCTCTCTACTAGCGGCATGGGCGTTGGCTGGATTAGACAGGCCCCAGGCAAGGGCCTGGAATGGGTCGCCCACATCTGGTGGGATGACGACAAGAGATACAACCCTGCTCTGAAGAGCAGATTCACACTGAGCGTGGATAGATCTAAGAATACCCTGTACCTGCAGATGAACAGCCTCAGAGCCGAAGACACTGCTACCTACTACTGCGTGCAGATCAACTACGGCAATTACCGGTTTGATAACTGGGGACATGGCACCCTGGTGACCGTCTCCAGCGGCGGGGGAGGCAGCGATATCCAAATGACCCAGAGCCCTAGCAGCCTGTCAGCCTCTGTGGGCGACAGAGTGACAATCACCTGCAGAGCCTCTCAGGACATCCGGAACTACCTGAACTGGTACCAGCAGAAGCCCGGCAAGGCCCCTAAGCTGCTGATCTACTACACCAGCCGGCTGGAGTCAGGCGTGCCAAGCCGCTTTAGCGGCAGCGGGTCCGGCACCGATTACACCCTGACAATCAGCAGCCTGCAGCCTGAAGACTTCGCGACATACTACTGCCAGCAGGGAAACACCCTGCCTTGGACCTTTGGGCAGGGCACCAAAGTGGAGATCAAGAGCTCAGGTGGCGGCGGAAGCGGGGGAGGCGGCTCCGGTGGAGGCGGCTCCGAAGTGCAGCTGGTGGAGTCTGGCGGAGGCCTGGTCCAGCCAGGCGGCAGCCTGAGACTGAGCTGCGCCGCCAGCGGCTACTCCTTTACAGGCTACACAATGAACTGGGTGCGGCAGGCGCCTGGCAAGGGACTGGAATGGGTTGCCCTGATCAACCCCTACAAGGGCGTGTCTACCTACAACCAGAAGTTCAAGGATAGATTCACCATCAGCGTGGACAAAAGCAAAAACACCGCCTACCrGCAGArGAArTCrCTGCGCGCCGAGGACACCGCrGrGTACrACTGCGCCAGATCTGGATArrACGGCGATTCTGACTGGTACTTCGACGTGTGGGGCCAGGGCACACTGGTGACCGTGTCCAGCGGTGGCGGCGGCTCTGACATCCAGATGACACAATCACCTTCCAGCCTGAGCGCCTCCGTCGGCGACAGAGTGACCATCTCTTGCAGAGCCAGCGAGAGCGTTGATAATTATGGAATTTCTTTCCTGAATTGGTTCCAGCAGAAGCCCGGCAAGGCCCCAAAGCTGCTGATCTACGCCGCCAGCAATCAGCGGAGCGGCGTGCCTAGCAGATTCAGCGGAAGCGGTAGCGGAACAGACTTCACCCTGACCATTTCCAGCCTCCAACCTGAAGACTTCGCCACCTACTTCTGTCAACAATCCAAGGAAGTGCCATGGACCTTCGGCCAGGGCACCAAGGTGGAAATCAAGCGGGGCGGAGGCGGCAGCGGCGGTGGTGGCAGCGGCGGAGGCGGCTCCGAGGTACAGCTGGTGGAGTCCGGCGGAGGTCTGGTGCAGCCTGGCGGCTCGCTGCGACTGAGCTGCTCTTTTTCTGGATTCAGCCTGTCAACAAGCGGCATGGGAGTGGGCTGGATTCGGCAGGCTCCCGGCAAGGGCCTGGAATGGGTGGCCCACATCTGGTGGGACGACGACAAGAGATACAATCCCGCTCTGAAGAGCAGATTTACCTTGAGCGTCGACCGGTCCAAGAACACCCTCTATCTGCAGATGAACAGCCTGAGAGCCGAGGACACCGCCACCTACTACTGCGTGCAAATCAACTACGGGAATTATCGGTTCGATAACTGGGGCCATGGCACACTTGTGACAGTTTCCAGCGGTGGCGGCGGCTCCGGAGGAGGTGGCTCAGATAAGACCCACACCTGTCCCCCCTGTCCTGCCCCTGAGGCCGCAGGCGGCCCTAGCGTGTTCCTTTTTCCTCCAAAGCCTAAGGACACGCTGATGATCAGCAGGACCCCTGAGGTGACATGTGTGGTGGTG GATGTGAGCCACGAGGCCCCTGAAGTCAAGTTCAACTGGTACGTGGACGGCGTCGAAGTGCACAA CGCCAAGACTAAGCCTTGTGAAGAGCAGTACGGCTCCACCTACAGATGCGTGTCCGTGCTGACCGT GCTGCACCAGGACTGGCTGAACGGCAAAGAGTACAAGTGCGCCGTGTCTAACAAGGCCCTGCCTGCTCCCATCGAGAAGACCATCTCTAAGGCCAAGGGCCAGCCTAGAGAGCCTCAGGTGTACACGCTG CCTCCTTCTCGGGAGGAAATGACAAAAAACCAGGTGTCTCTGACTTGCCTGGTGAAGGGATTTTAC CCCAGCGATATCGCCGTCGAGTGGGAATCCAATGGCCAGCCAGAAAACAACTACAAGACCACCCC TCCAGTGCTCGACAGCGACGGCTCTTTCTTCCTATACTCCAAGCTGACAGTGGATAAGAGCAGATGGCAGCAAGGAAATGTGTTCTCATGCTCCGTGATGCACGAGGCCTTGCACAATCACTACACACAGAAGTCACTGAGCCTGAGCCCAGGGAAAGGCGGCGGCGGCAGCGGAGGAGGAGGCTCAGGAGGCGG CGGCTCTGGCGGCGGAGGCAGCGGAGGCGGCGGCAGCGGCGGAGGAGGCTCCGACAAGACACATACCTGCCCTCCTTGCCCCGCTCCTGAGGCTGCCGGCGGCCCTAGCGTGTTCCTGTTCCCCCCTAAGCCTAAAGATACACTGATGATCTCAAGGACCCCTGAGGTGACATGTGTGGTCGTCGACGTGAGCCACGAGGCCCCCGAGGTGAAGTTTAACTGGTATGTGGACGGCGTGGAGGTACACAACGCCAAAACGAAGCCCTGCGAGGAGCAGTACGGGTCTACCTACCGGTGCGTGTCTGTGCTGACAGTGCTGCACCAGG ATTGGCTCAACGGCAAAGAATACAAATGCGCTGTGTCTAACAAGGCCCTGCCTGCCCCCATCGAAAAGACAATCAGCAAGGCCAAGGGCCAGCCCAGAGAGCCCCAGGTGTACACCCTGCCCCCCTCTCG GGAAGAAATGACCAAAAACCAGGTGTCTCTGACCTGTCTGGTGAAGGGCTTCTACCCTTCTGACATCGCCGTGGAATGGGAGTCCAACGGCCAGCCAGAGAACAACTACAAAACAACCCCTCCAGTGCTGG ACAGCGACGGCTCCTTCTTCCTGTATAGCAAGCTGACAGTGGATAAGTCTAGATGGCAGCAGGGC AACGTGTTCAGCTGCAGCGTGATGCACGAAGCCCTCCACAACCACTACACCCAGAAAAGCCTGAG CCTGAGCCCTGGAAAGCACCACCACCACCACCACFSHR PMTE (HLLHHL-Fc) coding sequence (SEQ ID NO:63)ATGACCCAGAGCCCTAGCAGCCTTAGTGCCAGCGTGGGCGACAGAGTGACAATCAGCTGTAGGGCCTCTGAGAGCGTGGACAACTACGGCATCAGCTTCCTGAACTGGTTCCAGCAGAAACCTGGCAAGGCTCCTAAGCTGCTGATCTATGCGGCTAGCAACCAGAGAAGCGGCGTCCCAAGCAGATTCTCCGGCAGCGGAAGCGGGACAGATTTCACCCTGACCATCAGCTCTCTGCAGCCTGAGGATTTCGCCACCTACTTCTGTCAGCAGAGCAAAGAAGTGCCCTGGACCTTCGGCCAAGGCACCAAAGTGGAGATCAAGCGGGGCGGCGGTGGCAGTGGAGGCGGCGGCAGCGGCGGAGGAGGAAGCGAGGTCCAGCTGGTCGAGTCTGGGGGCGGCCTGGTGCAGCCCGGCGGCAGCCTGCGGTTGTCTTGCTCTTTCAGCGGCTTTTCCCTCTCTACTAGCGGCATGGGCGTTGGCTGGATTAGACAGGCCCCAGGCAAGGGCCTGGAATGGGTCGCCCACATCTGGTGGGATGACGACAAGAGATACAACCCTGCTCTGAAGAGCAGATTCACACTGAGCGTGGATAGATCTAAGAATACCCTGTACCTGCAGATGAACAGCCTCAGAGCCGAAGACACTGCTACCTACTACTGCGTGCAGATCAACTACGGCAATTACCGGTTTGATAACTGGGGACATGGCACCCTGGTGACCGTCTCCAGCGGCGGGGGAGGCAGCGATATCCAAATGACCCAGAGCCCTAGCAGCCTGTCAGCCTCTGTGGGCGACAGAGTGACAATCACCTGCAGAGCCTCTCAGGACATCCGGAACTACCTGAACTGGTACCAGCAGAAGCCCGGCAAGGCCCCTAAGCTGCTGATCTACTACACCAGCCGGCTGGAGTCAGGCGTGCCAAGCCGCTTTAGCGGCAGCGGGTCCGGCACCGATTACACCCTGACAATCAGCAGCCTGCAGCCTGAAGACTTCGCGACATACTACTGCCAGCAGGGAAACACCCTGCCTTGGACCTTTGGGCAGGGCACCAAAGTGGAGATCAAGAGCTCAGGTGGCGGCGGAAGCGGGGGAGGCGGCTCCGGTGGAGGCGGCTCCGAAGTGCAGCTGGTGGAGTCTGGCGGAGGCCTGGTCCAGCCAGGCGGCAGCCTGAGACrGAGCTGCGCCGCCAGCGGCTACrCCrTTACAGGCTACACAATGAACTGGGTGCGGCAGGCGCCTGGCAAGGGACTGGAATGGGTTGCCCTGATCAACCCCTACAAGGGCGTGTCTACCTACAACCAGAAGTTCAAGGATAGATTCACCATCAGCGTGGACAAAAGCAAAAACACCGCCTACCTGCAGATGAATTCTCTGCGCGCCGAGGACACCGCTGTGTACTACTGCGCCAGATCTGGATATTACGGCGATTCTGACTGGTACTTCGACGTGTGGGGCCAGGGCACACTGGTGACCGTGTCCAGCGGTGGCGGCGGCTCTGACATCCAGATGACACAATCACCTTCCAGCCTGAGCGCCTCCGTCGGCGACAGAGTGACCATCTCTTGCAGAGCCAGCGAGAGCGTTGATAATTATGGAATTTCTTTCCTGAATTGGTTCCAGCAGAAGCCCGGCAAGGCCCCAAAGCTGCTGATCTACGCCGCCAGCAATCAGCGGAGCGGCGTGCCTAGCAGATTCAGCGGAAGCGGTAGCGGAACAGACTTCACCCTGACCATTTCCAGCCTCCAACCTGAAGACTTCGCCACCTACTTCTGTCAACAATCCAAGGAAGTGCCATGGACCTTCGGCCAGGGCACCAAGGTGGAAATCAAGCGGGGCGGAGGCGGCAGCGGCGGTGGTGGCAGCGGCGGAGGCGGCTCCGAGGTACAGCTGGTGGAGTCCGGCGGAGGTCTGGTGCAGCCTGGCGGCTCGCTGCGACTGAGCTGCTCTTTTTCTGGATTCAGCCTGTCAACAAGCGGCATGGGAGTGGGCTGGATTCGGCAGGCTCCCGGCAAGGGCCTGGAATGGGTGGCCCACATCTGGTGGGACGACGACAAGAGATACAATCCCGCTCTGAAGAGCAGATTTACCTTGAGCGTCGACCGGTCCAAGAACACCCTCTATCTGCAGATGAACAGCCTGAGAGCCGAGGACACCGCCACCTACTACTGCGTGCAAATCAACTACGGGAATTATCGGTTCGATAACTGGGGCCATGGCACACTTGTGACAGTTTCCAGCGGTGGCGGCGGCTCCGGAGGAGGTGGCTCAGATAAGACCCACACCTGTCCCCCCTGTCCTGCCCCTGAGGCCGCAGGCGGCCCTAGCGTGTTCCTTTTTCCTCCAAAGCCTAAGGACACGCTGATGATCAGCAGGACCCCTGAGGTGACATGTGTGGTGGTGGATGTGAGCCACGAGGCCCCTGAAGTCAAGTTCAACTGGTACGTGGACGGCGTCGAAGTGCACAACGCCAAGACTAAGCCTTGTGAAGAGCAGTACGGCTCCACCTACAGATGCGTGTCCGTGCTGACCGTGCTGCACCAGGACTGGCTGAACGGCAAAGAGTACAAGTGCGCCGTGTCTAACAAGGCCCTGCCTGCTCCCATCGAGAAGACCATCTCTAAGGCCAAGGGCCAGCCTAGAGAGCCTCAGGTGTACACGCTGCCTCCTTCTCGGGAGGAAATGACAAAAAACCAGGTGTCTCTGACTTGCCTGGTGAAGGGATTTTACCCCAGCGATATCGCCGTCGAGTGGGAATCCAATGGCCAGCCAGAAAACAACTACAAGACCACCCCTCCAGTGCTCGACAGCGACGGCTCTTTCTTCCTATACTCCAAGCTGACAGTGGATAAGAGCAGATGGCAGCAAGGAAATGTGTTCTCATGCTCCGTGATGCACGAGGCCTTGCACAATCACTACACACAGAAGTCACTGAGCCTGAGCCCAGGGAAAGGCGGCGGCGGCAGCGGAGGAGGAGGCTCAGGAGGCGGCGGCTCTGGCGGCGGAGGCAGCGGAGGCGGCGGCAGCGGCGGAGGAGGCTCCGACAAGACACATACCTGCCCTCCTTGCCCCGCTCCTGAGGCTGCCGGCGGCCCTAGCGTGTTCCTGTTCCCCCCTAAGCCTAAAGATACACTGATGATCTCAAGGACCCCTGAGGTGACATGTGTGGTCGTCGACGTGAGCCACGAGGCCCCCGAGGTGAAGTTTAACTGGTATGTGGACGGCGTGGAGGTACACAACGCCAAAACGAAGCCCTGCGAGGAGCAGTACGGGTCTACCTACCGGTGCGTGTCTGTGCTGACAGTGCTGCACCAGGATTGGCTCAACGGCAAAGAATACAAATGCGCTGTGTCTAACAAGGCCCTGCCTGCCCCCATCGAAAAGACAATCAGCAAGGCCAAGGGCCAGCCCAGAGAGCCCCAGGTGTACACCCTGCCCCCCTCTCGGGAAGAAATGACCAAAAACCAGGTGTCTCTGACCTGTCTGGTGAAGGGCTTCTACCCTTCTGACATCGCCGTGGAATGGGAGTCCAACGGCCAGCCAGAGAACAACTACAAAACAACCCCTCCAGTGCTGGACAGCGACGGCTCCTTCTTCCTGTATAGCAAGCTGACAGTGGATAAGTCTAGATGGCAGCAGGGCAACGTGTTCAGCTGCAGCGTGATGCACGAAGCCCTCCACAACCACTACACCCAGAAAAGCCTGAGCCTGAGCCCTGGAAAGFSHR PMTE (HLLHLH-Fc) construct sequence (SEQ ID NO:64)GACATCCAGATGACCCAGTCACCTAGCTCCCTGTCCGCCAGTGTGGGCGACCGGGTGACCATCAGCTGCAGAGCCAGCGAGAGCGTCGACAACTACGGCATTAGCTTCCTGAACTGGTTTCAACAGAAGCCCGGCAAGGCGCCCAAGCTGCTCATCTACGCCGCCTCCAATCAAAGATCTGGGGTGCCCAGCAGATTCAGCGGCAGCGGCAGCGGCACCGACTTTACACTGACCATCAGCTCTCTCCAGCCTGAGGACTTCGCCACATACTTCTGCCAACAAAGCAAAGAGGTGCCCTGGACATTCGGCCAGGGCACCAAGGTGGAGATCAAGAGAGGCGGCGGCGGCAGCGGCGGCGGCGGCAGCGGCGGCGGCGGCAGCGAGGTCCAGCTGGTGGAGAGCGGGGGCGGCCTGGTGCAGCCTGGAGGCTCCCTGAGACTGAGCTGTTCTTTCAGCGGCTTCAGCCTGTCGACATCCGGAATGGGCGTGGGATGGATCAGACAGGCCCCTGGCAAGGGCCTGGAATGGGTGGCCCACATCTGGTGGGATGATGACAAGCGGTACAACCCTGCTCTGAAGTCTAGATTCACACTGAGCGTGGACCGCTCTAAAAACACACTGTACCTGCAGATGAACAGCCTGCGGGCCGAGGACACCGCCACATACTATTGCGTGCAGATCAACTACGGCAATTACAGGTTTGACAACTGGGGCCACGGCACCCTGGTGACCGTGTCGAGCGGCGGCGGCGGAAGCGACATCCAGATGACCCAGTCTCCTAGCAGCCTGAGCGCCTCGGTCGGCGACCGAGTGACCATCACCTGTAGAGCCTCTCAGGACATCCGGAACTACCTGAACTGGTACCAGCAAAAGCCTGGCAAAGCCCCTAAGCTTCTGATCTATTATACCTCCAGACTAGAATCTGGTGTGCCTTCTAGATTCAGCGGCTCTGGCAGCGGCACCGATTACACCCTGACAATCTCATCTCTGCAGCCTGAGGATTTCGCCACCTACTACTGTCAGCAGGGCAACACCCTGCCTTGGACCTTCGGACAAGGCACCAAGGTTGAGATCAAGAGCAGCGGCGGTGGCGGTTCGGGCGGCGGCGGCTCGGGAGGAGGGGGCTCAGAGGTGCAGCTGGTCGAAAGCGGCGGCGGCCTGGTGCAGCCAGGAGGCAGCCTCCGGCTCAGCTGTGCTGCCAGCGGCTACTCTTTCACCGGCTACACCATGAACTGGGTGAGGCAAGCCCCTGGTAAAGGCCTGGAATGGGTGGCCCTGATCAACCCCTACAAGGGCGTGTCTACCTACAACCAGAAGTTCAAGGACAGATTCACCATCTCTGTGGACAAGAGCAAGAACACCGCCTACCTGCAGATGAATTCACTGAGAGCCGAAGATACAGCCGTGTACTATTGCGCCAGAAGCGGGTACTACGGCGACAGTGACTGGTATTTTGACGTGTGGGGACAAGGAACCCTGGTGACCGTGTCCTCTGGCGGAGGAGGCAGCGAGGTACAGCTGGTGGAAAGCGGCGGGGGACTGGTGCAGCCAGGTGGCTCCCTGCGGCTGTCTTGCTCGTTTAGCGGCTTCAGCCTGTCCACAAGCGGCATGGGCGTTGGTTGGATCAGACAGGCCCCAGGAAAAGGACTGGAATGGGTTGCTCATATCTGGTGGGACGATGATAAGCGCTACAACCCTGCCCTCAAAAGCCGGTTCACACTGAGCGTCGACAGATCTAAGAACACCCTGTACCTGCAGATGAACAGCCTGCGGGCCGAGGACACCGCAACCTATTACTGCGTGCAGATCAACTACGGCAACTACAGATTCGACAACTGGGGCCACGGCACCCTCGTCACAGTGAGCAGCGGTGGCGGGGGCTCCGGTGGCGGAGGCAGCGGAGGAGGCGGCAGCGACATCCAGATGACACAGAGCCCTAGTAGCCTGAGCGCCAGCGTGGGCGATAGAGTGACGATCAGCTGTAGAGCCAGCGAATCCGTGGATAATTACGGCATCAGTTTCCTGAACTGGTTTCAGCAGAAACCCGGCAAGGCCCCCAAGCTGCTGATCTACGCCGCTAGCAACCAGCGGAGCGGAGTCCCCAGCCGCTTCAGTGGCAGCGGCAGTGGAACAGACTTCACCCTTACAATCAGCAGCCTGCAGCCAGAGGATTTCGCCACCTACTTCTGCCAGCAAAGCAAGGAGGTGCCTTGGACCTTCGGCCAGGGAACCAAGGTGGAAATCAAGAGAGGCGGCGGCGGTTCCGGCGGAGGCGGC AGCGACAAGACACACACCTGCCCTCCTTGTCCTGCCCCTGAGGCCGCCGGCGGTCCTAGCGTGTTT CTGTTCCCCCCTAAGCCCAAGGATACCCTGATGATTAGCCGGACACCCGAAGTGACCTGCGTGGTGGTGGACGTGTCTCACGAGGCCCCTGAGGTGAAATTCAACTGGTATGTCGACGGCGTGGAAGTGCACAACGCCAAGACCAAGCCTTGCGAGGAGCAGTACGGAAGCACATACAGATGCGTGAGCGTGCTGACAGTGCTGCACCAGGATTGGCTGAATGGGAAGGAATACAAGTGCGCCGTGAGCAACAAGGCCCTGCCCGCCCCTATCGAGAAGACCATCAGCAAAGCTAAGGGCCAGCCCAGAGAACCCCAGGTGTACACACTGCCTCCGAGCCGAGAAGAAATGACCAAGAACCAGGTCTCTCTGACATGCCTGGTGAAGGGCTTCTACCCATCTGACATCGCTGTTGAGTGGGAATCCAATGGCCAGCCCGAGAACAACTACAAGACCACACCGCCAGTGCTGGACAGCGACGGCAGCTTTTTTCTGTATTCTAAACTGACAGTGGATAAGAGCAGATGGCAGCAGGGCAACGTGTTCTCCTGTTCCGTGATGCACGAGGCCCTGCATAACCACTATACCCAAAAAAGCCTGAGCCTGTCTCCTGGCAAAGGAGGCGGCGGAAGCGGTGGCGGAGGTTCCGGCGGCGGCGGATCTGGTGGCGGAGGCAGCGGCGGCGGAGGCAGCGGAGGCGGCGGCAGCGATAAAACCCACACATGCCCTCCATGCCCCGCCCCCGAGGCTGCTGGTGGCCCTAGTGTGTTCCTGTTTCCTCCCAAGCCTAAGGACACACTGATGATCAGCCGGACCCCTGAGGTGACCTGTGTTGTCGTGGATGTGAGCCACGAGGCACCTGAGGTCAAGTTCAACTGGTACGTGGATGGCGTCGAGGTGCACAACGCCAAGACAAAACCTTGCGAGGAACAGTATGGCAGCACCTACCGGTGCGTGAGTGTGCTGACCGTTCTGCATCAGGACTGGCTGAACGGCAAAGAGTACAAGTGCGCCGTCTCTAACAAGGCCCTGCCAGCTCCGATT GAAAAGACCATCTCCAAGGCCAAGGGCCAGCCTAGAGAGCCTCAGGTGTACACACTGCCTCCTAG CAGAGAAGAGATGACTAAGAATCAGGTGAGCCTAACCTGTCTGGTGAAGGGCTTCTACCCCAGCGATATCGCCGTGGAATGGGAGAGCAACGGCCAACCTGAAAATAACTACAAGACTACCCCTCCCGTG CTGGATTCTGATGGTTCTTTCTTCCTGTACAGCAAGCTGACAGTGGACAAATCGAGATGGCAGCAG GGCAATGTGTTCAGCTGCAGCGTGATGCACGAAGCCCTGCACAATCACTACACCCAGAAGAGCCTGTCGCTGAGCCCTGGCAAGCACCACCACCACCACCACFSHR PMTE (HLLHLH-Fc) coding sequence (SEQ ID NO:65)ATGACGCAGTCGCCCAGCAGCCTGAGTGCCAGCGTGGGCGACAGAGTGACCATTTCTTGCAGAGCCAGCGAAAGCGTTGATAACTACGGCATCTCCTTCCTGAATTGGTTTCAGCAGAAGCCTGGGAAGGCTCCTAAGCTGTTGATCTACGCCGCCTCTAATCAGAGATCGGGAGTCCCTTCCAGATTCTCTGGAAGTGGTAGCGGGACAGACTTCACCCTCACCATCTCCTCTCTGCAGCCTGAAGATTTTGCCACATACTTCTGCCAGCAGAGCAAGGAAGTGCCTTGGACCTTCGGCCAGGGGACAAAAGTGGAAATCAAGAGAGGCGGAGGTGGCTCTGGAGGCGGTGGATCTGGTGGTGGCGGATCAGAGGTGCAGCTGGTGGAAAGCGGCGGTGGACTGGTTCAGCCTGGGGGAAGCCTGAGACTGTCGTGTAGCTTCAGCGGCTTCAGCCTGAGCACCAGCGGCATGGGCGTGGGATGGATCAGACAAGCCCCCGGCAAAGGGCTGGAGTGGGTCGCCCACATCTGGTGGGATGACGACAAGAGATACAACCCTGCCCTGAAGAGCAGATTCACACTGAGCGTGGACCGGAGCAAGAACACCCTGTACCTGCAAATGAATAGCCTGAGAGCTGAAGATACAGCTACATACTACTGCGTGCAAATCAACTACGGAAACTACCGGTTCGACAACTGGGGCCACGGCACCCTGGTGACCGTGTCTAGCGGTGGAGGCGGGAGCGAAGTGCAACTGGTAGAAAGCGGCGGAGGCCTGGTGCAGCCCGGCGGAAGCCTGCGGCTTTCTTGCGCCGCCAGTGGCTACAGCTTCACAGGCTACACCATGAACTGGGTGCGGCAGGCTCCTGGAAAGGGCCTGGAGTGGGTGGCCCTGATCAATCCATACAAGGGCGTGAGCACCTACAATCAGAAGTTCAAGGACAGATTCACAATCAGCGTCGATAAATCGAAGAATACCGCCTACCTGCAGATGAACAGCCTGAGAGCCGAAGATACAGCCGTGTATTACTGTGCTAGAAGCGGATACTATGGCGATTCCGACTGGTACTTCGACGTGTGGGGCCAGGGCACACTGGTGACAGTGTCCAGCGGAGGCGGCGGTAGTGGTGGAGGAGGCTCTGGCGGTGGTGGAAGCGACATCCAGATGACTCAGTCCCCTAGCAGCCTGAGTGCCTCCGTGGGCGACCGGGTGACCATCACCTGTCGGGCTTCTCAGGACATCCGGAACTACCTGAACTGGTACCAGCAGAAGCCCGGCAAGGCTCCCAAGCTGCTCATCTACTACACCAGCCGGCTGGAATCTGGCGTCCCTTCTCGGTTCAGCGGCTCCGGATCTGGCACCGACTACACCCTCACCATCTCATCTCTGCAGCCAGAGGACTTCGCCACATACTACTGCCAGCAGGGCAACACCCTGCCATGGACCTTCGGCCAGGGTACCAAGGTGGAGATCAAAAGCTCTGGTGGCGGCGGATCTGAGGTGCAGCTGGTGGAGAGCGGCGGAGGCCTGGTGCAGCCAGGAGGTTCACTTAGACTGAGCTGCAGCTTCTCTGGATTCTCTCTGAGCACCAGCGGCATGGGAGTGGGCTGGATCCGGCAGGCTCCAGGCAAGGGACTGGAATGGGTGGCCCACATCTGGTGGGACGACGACAAGCGGTACAACCCTGCCCTGAAAAGCAGGTTTACCCTGTCTGTGGACAGATCTAAAAATACCCTGTACCTGCAAATGAACAGCCTGAGAGCCGAGGACACAGCAACATACTACTGCGTGCAGATCAACTACGGCAACTACAGATTTGACAACTGGGGGCATGGCACCCTAGTGACCGTGTCCTCTGGCGGAGGAGGTTCAGGTGGAGGTGGATCTGGAGGTGGCGGGTCTGACATCCAAATGACACAGAGCCCCTCAAGCCTGTCCGCCAGCGTTGGCGACAGAGTGACCATCAGCTGTAGAGCCTCTGAGAGCGTGGACAATTACGGCATCAGCTTTCTGAACTGGTTC CAGCAGAAGCCCGGAAAAGCCCCTAAGCTGCTGATCTACGCCGCTAGCAATCAAAGAAGCGGCGT GCCTAGCAGGTTTTCCGGCTCTGGCAGCGGCACCGACTTCACACTGACAATCAGCTCCCTGCAGCCTGAGGATTTCGCCACCTATTTTTGTCAACAGAGCAAGGAGGTGCCGTGGACCTTCGGGCAGGGCACCAAGGTGGAAATTAAGAGAGGCGGTGGCGGATCAGGAGGCGGAGGTAGTGATAAGACCCACACC TGCCCTCCTTGCCCTGCCCCCGAAGCCGCAGGAGGCCCTAGCGTGTTCCTGTTCCCACCCAAACCCAAAGACACCCTGATGATCAGCCGGACCCCTGAGGTGACATGCGTGGTGGTGGATGTGTCTCACGAGGCCCCAGAGGTGAAGTTCAACTGGTATGTGGATGGCGTGGAGGTGCACAACGCCAAAACCAAGC CTTGCGAGGAACAGTACGGCTCTACCTACAGATGCGTGAGCGTGCTGACCGTTCTGCACCAGGATT GGCTGAACGGGAAAGAGTACAAGTGCGCCGTGTCAAACAAGGCTCTGCCTGCCCCTATCGAGAAA ACCATCTCTAAGGCTAAGGGCCAGCCTAGAGAGCCTCAGGTGTATACCCTGCCTCCTAGCAGAGA GGAAATGACCAAGAACCAGGTGTCCCTGACCTGCCTGGTGAAGGGCTTCTACCCCAGCGACATCGCCGTGGAATGGGAAAGCAACGGCCAGCCAGAGAACAACTACAAGACCACCCCTCCAGTCCTGGACTCCGACGGCAGCTTTTTCCTGTATAGCAAACTGACCGTGGACAAGAGCCGGTGGCAGCAAGGGAACGTGTTCAGCTGTAGCGTTATGCACGAGGCCCTGCACAATCATTATACACAGAAGTCCCTCAGCCT GAGCCCTGGAAAGGGTGGTGGAGGGTCAGGCGGCGGTGGAAGCGGAGGAGGCGGTTCTGGCGGC GGCGGCAGCGGCGGTGGTGGCAGCGGCGGCGGGGGCAGCGATAAGACACACACATGCCCTCCTTGTCCTGCCCCTGAGGCTGCTGGCGGACCTTCTGTTTTCCTGTTCCCCCCCAAGCCCAAAGATACACTTATGATTTCTCGCACCCCTGAGGTAACATGCGTCGTGGTGGATGTGTCCCACGAGGCTCCTGAGGTGAAGTTTAACTGGTATGTGGATGGCGTCGAGGTTCACAATGCCAAGACCAAGCCCTGCGAGGAGCA GTACGGCAGCACATACAGATGCGTGTCCGTGCTGACCGTGCTCCACCAGGACTGGCTGAACGGCAAAGAATACAAGTGCGCCGTGAGCAACAAGGCCCTGCCCGCCCCGATCGAAAAAACAATTTCTAAGGCCAAGGGCCAGCCCCGGGAACCTCAGGTGTACACGCTGCCTCCTAGCAGGGAAGAAATGACCAAGAACCAGGTGAGCCTGACCTGTCTGGTGAAGGGCTTCTACCCTTCTGATATCGCCGTCGAGTGGGA GTCTAATGGACAGCCCGAGAACAACTACAAGACCACACCTCCTGTGCTGGACAGCGACGGCAGTTTCTTCCTGTACTCCAAGCTGACAGTGGACAAATCCCGGTGGCAGCAGGGAAACGTGTTTAGCTGTTCTGTCATGCACGAAGCCCTGCACAACCACTACACCCAGAAATCCCTGTCGTTGAGCCCTGGGAAGFSHR PMTE (LHHLLH-Fc) construct (SEQ ID NO:66)GAGGTGCAGCTGGTGGAGTCCGGAGGCGGCCTGGTGCAGCCTGGCGGAAGCCTGAGACTGAGCTGCAGCTTTTCTGGATTCAGCCTGTCTACTAGCGGCATGGGCGTGGGCTGGATTCGCCAGGCTCCAGGCAAGGGTCTCGAATGGGTCGCTCATATCTGGTGGGACGACGACAAGAGATACAATCCCGCCCTGAAGTCCAGGTTCACACTGAGTGTGGACAGAAGCAAAAACACCCTGTACCTGCAGATGAACAGCCTGAGAGCCGAGGATACCGCAACCTACTACTGCGTTCAAATCAACTACGGCAATTACCGGTTCGACAATTGGGGCCACGGCACACTGGTGACAGTGTCTTCTGGCGGAGGTGGCTCTGGAGGCGGTGGATCTGGTGGTGGCGGATCAGACATCCAGATGACCCAGAGCCCTTCGAGCCTGAGCGCCAGCGTGGGGGACAGAGTGACCATAAGCTGCCGCGCCTCTGAATCTGTGGACAACTACGGCATCTCTTTTCTGAATTGGTTCCAGCAGAAGCCCGGAAAGGCCCCTAAGCTGCTGATCTACGCCGCCAGCAATCAGAGGTCAGGCGTGCCATCGAGATTCAGCGGCAGCGGCAGCGGCACCGATTTCACCCTGACAATTTCTTCTCTGCAACCAGAGGACTTCGCTACATACTTCTGCCAGCAGTCTAAGGAGGTGCCTTGGACCTTCGGCCAGGGCACAAAGGTGGAAATCAAGCGCGGTGGAGGCGGGAGCGAGGTGCAGCTGGTCGAGAGCGGCGGCGGACTGGTGCAGCCCGGCGGCTCACTGCGGCTGAGCTGTGCTGCATCAGGCTACTCCTTCACCGGCTACACAATGAATTGGGTGAGACAGGCCCCTGGCAAGGGCCTGGAGTGGGTCGCCCTGATCAACCCCTACAAGGGGGTTAGCACCTACAACCAGAAATTCAAGGACAGATTCACCATCTCCGTGGACAAAAGCAAGAACACCGCCTATCTGCAGATGAACAGCCTGAGAGCCGAAGATACCGCCGTCTACTACTGCGCCAGATCCGGATATTACGGAGATAGCGACTGGTACTTCGACGTGTGGGGCCAGGGCACACTGGTGACCGTGAGTAGTGGAGGCGGCGGTAGTGGTGGAGGAGGCTCTGGCGGTGGTGGAAGCGACATCCAGATGACACAGAGCCCCAGCAGCCTGAGCGCCTCCGTGGGCGATAGAGTGACCATCACCTGCAGAGCCTCCCAGGACATCCGGAACTACCTGAACTGGTATCAGCAGAAGCCGGGGAAGGCCCCCAAACTGCTGATCTACTACACAAGCAGACTGGAAAGCGGGGTTCCCAGCAGATTTAGCGGAAGCGGCTCTGGCACAGACTACACCCTAACAATCTCCAGCCTGCAGCCAGAAGACTTCGCCACATATTACTGTCAGCAAGGCAACACCCTGCCATGGACATTCGGCCAAGGAACCAAGGTGGAGATCAAGAGCAGCGGTGGCGGCGGATCTGAGGTGCAGCTCGTGGAGAGCGGAGGCGGCCTGGTTCAGCCGGGAGGAAGTCTGAGACTGAGCTGTAGCTTTTCTGGCTTCTCACTGTCCACAAGCGGCATGGGAGTGGGCTGGATCAGACAGGCCCCTGGAAAGGGCCTGGAGTGGGTGGCCCACATCTGGTGGGATGACGATAAGCGGTACAACCCCGCCCTGAAATCTCGCTTCACGCTGAGCGTGGATAGGAGCAAGAACACACTGTACCTGCAGATGAACAGCCTGAGAGCCGAGGACACCGCCACCTACTACTGCGTGCAAATCAACTACGGCAACTACCGGTTCGACAATTGGGGCCACGGAACCCTGGTGACAGTGAGCAGCGGCGGAGGAGGTTCAGGTGGAGGTGGATCTGGAGGTGGCGGGTCTGACATCCAAATGACCCAGTCTCCTTCATCCCTTTCTGCCTCCGTCGGCGATAGAGTGACAATCAGCTGCCGGGCCTCCGAGAGCGTGGACAACTACGGCATCAGCTTCCTTAATTGGTTTCAGCAGAAGCCTGGCAAAGCCCCTAAGCTGCTGATCTACGCGGCCTCGAACCAGAGAAGTGGCGTGCCTAGCAGGTTCAGCGGTAGCGGCAGCGGCACCGATTTCACCCTGACCATCAGCAGCCTGCAACCAGAGGATTTTGCTACATATTTCTGCCAGCAGAGCAAGGAGGTGCCTTGGACCTTCGGCCAGGGAACCAAGGTGGAAATCAAGAGAGGCGGTGGCGGATCAGGAGGCGGAGGTAGTGACAAGACCCACACCTGTCCACCTTGCCCCGCCCCCGAAGCTGCCGGAGGTCCTAGCGTGTTCCTGTTCCCTCCAAAACCGAAGGACACCCTTATGATCAGTCGGACCCCTGAAGTTACCTGCGTAGTGGTGGATGTGAGCCACGAGGCTCCTGAAGTGAAGTTCAACTGGTATGTGGACGGCGTGGAGGTGCACAACGCCAAGACCAAGCCCTGCGAGGAGCAGTACGGCAGCACCTACAGATGTGTCTCTGTGCTGACTGTCCTGCACCAGGACTGGCTGAACGGAAAAGAATACAAGTGCGCCGTGAGCAACAAGGCCCTGCCCGCTCCTATCGAGAAAACCATTTCTAAGGCCAAGGGCCAACCTAGAGAACCTCAGGTGTACACGCTGCCTCCTAGCCGGGAGGAAATGACCAAGAATCAGGTGTCTCTGACATGTCTGGTCAAGGGGTTCTACCCCTCTGATATCGCCGTGGAGTGGGAAAGCAACGGCCAGCCTGAGAACAACTACAAGACCACACCTCCTGTGCTGGACAGCGACGGCTCTTTTTTCCTGTATTCTAAGCTGACCGTGGACAAGAGCCGGTGGCAGCAAGGTAACGTGTTTAGCTGCAGCGTGATGCACGAGGCCCTGCATAATCACTATACCCAGAAGAGCTTGAGCCTGAGTCCTGGCAAAGGTGGTGGAGGGTCAGGCGGCGGTGGAAGCGGAGGAGGCGGTTCTGGCGGTGGTGGCAGCGGAGGCGGCGGATCTGGCGGCGGTGGCTCTGACAAGACACACACATGTCCTCCCTGCCCTGCCCCTGAAGCCGCCGGCGGCCCTAGCGTGTTCCTGTTTCCACCTAAGCCAAAAGACACCCTTATGATCAGCAGAACCCCTGAGGTGACATGCGTAGTCGTGGACGTGTCTCACGAAGCCCCTGAAGTGAAGTTCAACTGGTACGTGGATGGCGTTGAGGTACACAACGCTAAGACCAAGCCCTGTGAAGAGCAGTACGGCAGCACGTACAGATGCGTGAGCGTGCTGACCGTGCTGCACCAAGATTGGCTGAACGGCAAGGAATACAAGTGCGCCGTGTCCAACAAGGCCCTGCCTGCTCCTATCGAGAAGACCATCTCTAAGGCCAAAGGCCAGCCAAGAGAACCCCAGGTGTACACCCTGCCCCCCAGCCGGGAAGAGATGACCAAGAACCAGGTGAGCCTGACCTGCCTGGTGAAGGGCTTCTACCCTTCTGACATCGCTGTGGAATGGGAGTCCAACGGCCAGCCTGAGAACAACTACAAAACAACCCCTCCTGTGCTGGATTCAGACGGCAGCTTCTTCCTGTACAGCAAACTGACAGTCGATAAGAGCCGGTGGCAGCAGGGCAACGTGTTTAGCTGCTCCGTGATGCACGAGGCCCTGCACAACCACTACACCCAGAAAAGTCTCTCCCTTTCTCCCGGGAAGCACCACCACCATCACCACFSHR PMTE (LHHLLH-Fc) coding sequence (SEQ ID NO:67)ATGGGCGTGGGCTGGATTCGCCAGGCTCCAGGCAAGGGTCTCGAATGGGTCGCTCATATCTGGTGGGACGACGACAAGAGATACAATCCCGCCCTGAAGTCCAGGTTCACACTGAGTGTGGACAGAAGCAAAAACACCCTGTACCTGCAGATGAACAGCCTGAGAGCCGAGGATACCGCAACCTACTACTGCGTTCAAATCAACTACGGCAATTACCGGTTCGACAATTGGGGCCACGGCACACTGGTGACAGTGTCTTCTGGCGGAGGTGGCTCTGGAGGCGGTGGATCTGGTGGTGGCGGATCAGACATCCAGATGACCCAGAGCCCTTCGAGCCTGAGCGCCAGCGTGGGGGACAGAGTGACCATAAGCTGCCGCGCCTCTGAATCTGTGGACAACTACGGCATCTCTTTTCTGAATTGGTTCCAGCAGAAGCCCGGAAAGGCCCCTAAGCTGCTGATCTACGCCGCCAGCAATCAGAGGTCAGGCGTGCCATCGAGATTCAGCGGCAGCGGCAGCGGCACCGATTTCACCCTGACAATTTCTTCTCTGCAACCAGAGGACTTCGCTACATACTTCTGCCAGCAGTCTAAGGAGGTGCCTTGGACCTTCGGCCAGGGCACAAAGGTGGAAATCAAGCGCGGTGGAGGCGGGAGCGAGGTGCAGCTGGTCGAGAGCGGCGGCGGACTGGTGCAGCCCGGCGGCTCACTGCGGCTGAGCTGTGCTGCATCAGGCTACTCCTTCACCGGCTACACAATGAATTGGGTGAGACAGGCCCCTGGCAAGGGCCTGGAGTGGGTCGCCCTGATCAACCCCTACAAGGGGGTTAGCACCTACAACCAGAAATTCAAGGACAGATTCACCATCTCCGTGGACAAAAGCAAGAACACCGCCTATCTGCAGATGAACAGCCTGAGAGCCGAAGATACCGCCGTCTACTACTGCGCCAGATCCGGATATTACGGAGATAGCGACTGGTACTTCGACGTGTGGGGCCAGGGCACACTGGTGACCGTGAGTAGTGGAGGCGGCGGTAGTGGTGGAGGAGGCTCTGGCGGTGGTGGAAGCGACATCCAGATGACACAGAGCCCCAGCAGCCTGAGCGCCTCCGTGGGCGATAGAGTGACCATCACCTGCAGAGCCTCCCAGGACATCCGGAACTACCTGAACTGGTATCAGCAGAAGCCGGGGAAGGCCCCCAAACTGCTGATCTACTACACAAGCAGACTGGAAAGCGGGGTTCCCAGCAGATTTAGCGGAAGCGGCTCTGGCACAGACTACACCCTAACAATCTCCAGCCTGCAGCCAGAAGACTTCGCCACATATTACTGTCAGCAAGGCAACACCCTGCCATGGACATTCGGCCAAGGAACCAAGGTGGAGATCAAGAGCAGCGGTGGCGGCGGATCTGAGGTGCAGCTCGTGGAGAGCGGAGGCGGCCTGGTTCAGCCGGGAGGAAGTCTGAGACTGAGCTGTAGCTTTTCTGGCTTCTCACTGTCCACAAGCGGCATGGGAGTGGGCTGGATCAGACAGGCCCCTGGAAAGGGCCTGGAGTGGGTGGCCCACATCTGGTGGGATGACGATAAGCGGTACAACCCCGCCCTGAAATCTCGCTTCACGCTGAGCGTGGATAGGAGCAAGAACACACTGTACCTGCAGATGAACAGCCTGAGAGCCGAGGACACCGCCACCTACTACTGCGTGCAAATCAACTACGGCAACTACCGGTTCGACAATTGGGGCCACGGAACCCTGGTGACAGTGAGCAGCGGCGGAGGAGGTTCAGGTGGAGGTGGATCTGGAGGTGGCGGGTCTGACATCCAAATGACCCAGTCTCCTTCATCCCTTTCTGCCTCCGTCGGCGATAGAGTGACAATCAGCTGCCGGGCCTCCGAGAGCGTGGACAACTACGGCATCAGCTTCCTTAATTGGTTTCAGCAGAAGCCTGGCAAAGCCCCTAAGCTGCTGATCTACGCGGCCTCGAACCAGAGAAGTGGCGTGCCTAGCAGGTTCAGCGGTAGCGGCAGCGGCACCGATTTCACCCTGACCATCAGCAGCCTGCAACCAGAGGATTTTGCTACATATTTCTGCCAGCAGAGCAAGGAGGTGCCTTGGACCTTCGGCCAGGGAACCAAGGTGGAAATCAAGAGAGGCGGTGGCGGATCAGGAGGCGGAGGTAGTGACAAGACCCACACCTGTCCACCTTGCCCCGCCCCCGAAGCTGCCGGAGGTCCTAGCGTGTTCCTGTTCCCTCCAAAACCGAAGGACACCCTTATGATCAGTCGGACCCCTGAAGTTACCTGCGTAGTGGTGGATGTGAGCCACGAGGCTCCTGAAGTGAAGTTCAACTGGTATGTGGACGGCGTGGAGGTGCACAACGCCAAGACCAAGCCCTGCGAGGAGCAGTACGGCAGCACCTACAGATGTGTCTCTGTGCTGACTGTCCTGCACCAGGACTGGCTGAACGGAAAAGAATACAAGTGCGCCGTGAGCAACAAGGCCCTGCCCGCTCCTATCGAGAAAACCATTTCTAAGGCCAAGGGCCAACCTAGAGAACCTCAGGTGTACACGCTGCCTCCTAGCCGGGAGGAAATGACCAAGAATCAGGTGTCTCTGACATGTCTGGTCAAGGGGTTCTACCCCTCTGATATCGCCGTGGAGTGGGAAAGCAACGGCCAGCCTGAGAACAACTACAAGACCACACCTCCTGTGCTGGACAGCGACGGCTCTTTTTTCCTGTATTCTAAGCTGACCGTGGACAAGAGCCGGTGGCAGCAAGGTAACGTGTTTAGCTGCAGCGTGATGCACGAGGCCCTGCATAATCACTATACCCAGAAGAGCTTGAGCCTGAGTCCTGGCAAAGGTGGTGGAGGGTCAGGCGGCGGTGGAAGCGGAGGAGGCGGTTCTGGCGGTGGTGGCAGCGGAGGCGGCGGATCTGGCGGCGGTGGCTCTGACAAGACACACACATGTCCTCCCTGCCCTGCCCCTGAAGCCGCCGGCGGCCCTAGCGTGTTCCTGTTTCCACCTAAGCCAAAAGACACCCTTATGATCAGCAGAACCCCTGAGGTGACATGCGTAGTCGTGGACGTGTCTCACGAAGCCCCTGAAGTGAAGTTCAACTGGTACGTGGATGGCGTTGAGGTACACAACGCTAAGACCAAGCCCTGTGAAGAGCAGTACGGCAGCACGTACAGATGCGTGAGCGTGCTGACCGTGCTGCACCAAGATTGGCTGAACGGCAAGGAATACAAGTGCGCCGTGTCCAACAAGGCCCTGCCTGCTCCTATCGAGAAGACCATCTCTAAGGCCAAAGGCCAGCCAAGAGAACCCCAGGTGTACACCCTGCCCCCCAGCCGGGAAGAGATGACCAAGAACCAGGTGAGCCTGACCTGCCTGGTGAAGGGCTTCTACCCTTCTGACATCGCTGTGGAATGGGAGTCCAACGGCCAGCCTGAGAACAACTACAAAACAACCCCTCCTGTGCTGGATTCAGACGGCAGCTTCTTCCTGTACAGCAAACTGACAGTCGATAAGAGCCGGTGGCAGCAGGGCAACGTGTTTAGCTGCTCCGTGATGCACGAGGCCCTGCACAACCACTACACCCAGAAAAGTCTCTCCCTTTCTCCCGGGAAGFSHR PMTE (LHHLLH-Fc) construct (SEQ ID NO: 68)GAGGTGCAGCTGGTGGAGAGCGGCGGAGGCCTGGTGCAACCTGGCGGATCTCTGAGACTGAGCTG CAGCTTTTCTGGCTTCTCACTGTCCACTTCTGGAATGGGCGTGGGATGGATCAGACAGGCCCCCGGGAAGGGCCTGGAATGGGTTGCCCACATCTGGTGGGACGACGACAAAAGATACAATCCCGCCCTGAAGAGCCGGTTCACCCTGTCGGTTGATAGAAGCAAGAATACCTTGTACCTGCAGATGAACTCCCTGAGAGCTGAGGACACAGCCACATACTATTGTGTGCAGATCAACTATGGTAACTACAGATTCGACAACTGGGGGCACGGAACCCTGGTGACCGTGTCTTCAGGCGGAGGTGGCTCTGGAGGCGGTGGATCTGGTGGTGGCGGATCAGATATCCAAATGACCCAGTCTCCTTCAAGCCTGAGTGCCAGCGTGGGCGACCGAGTGACCATCAGCTGTCGCGCCAGCGAGAGCGTGGACAACTACGGAATCAGCTTTCTGAACTGGTTCCAGCAGAAACCTGGCAAAGCCCCTAAGCTGCTCATCTACGCCGCTTCTAATCAGCGCAGCGGCGTGCCGAGCAGATTCTCAGGCAGCGGCAGCGGAACCGATTTCACCTTAACCATCTCCAGTCTGCAGCCTGAGGACTTCGCCACATACTTCTGCCAGCAGAGTAAAGAGGTGCCTTGGACCTTTGGCCAGGGC ACAAAAGTGGAGATCAAGAGAGGTGGAGGCGGGAGCGACATCCAGATGACACAATCTCCAAGCA GCCTGAGCGCCAGCGTGGGCGACAGAGTGACAATCACCTGCAGAGCCTCCCAGGACATTAGAAACTACCTGAACTGGTACCAGCAGAAGCCAGGCAAAGCTCCGAAGCTGCTGATCTACTACACCAGCCGCCTCGAGTCTGGAGTTCCTAGTAGGTTTTCCGGAAGCGGCAGCGGGACCGACTACACCCTGACAATCTCTAGCCTGCAGCCCGAAGATTTCGCCACCTACTACTGCCAGCAGGGAAACACCCTCCCTTGGACCTTCGGCCAAGGCACCAAGGTGGAAATCAAGTCTTCCGGAGGCGGCGGTAGTGGTGGAGGAGGCTCTGGCGGTGGTGGAAGCGAGGTCCAGCTGGTGGAAAGCGGTGGCGGCCTGGTGCAACCTGGCGGGAGCCTGAGACTGTCTTGTGCCGCCAGCGGCTACAGCTTCACAGGCTATACCATGAACTGGGTGCGGCAGGCCCCCGGCAAGGGTCTGGAGTGGGTAGCCCTGATCAACCCTTACAAGGGCGTGAGCACCTACAATCAGAAGTTCAAGGACCGGTTTACCATCTCAGTGGACAAGTCTAAAAACACCGCCTACCTGCAGATGAATAGCCTGCGGGCCGAGGACACTGCCGTGTACTACTGCGCCAGATCCGGTTACTACGGTGATAGCGACTGGTACTTCGACGTGTGGGGCCAGGGCACACTGGTGACCGTGAGCTCCGGTGGCGGCGGATCTGATATTCAGATGACCCAGAGCCCTAGCTCTCTCTCCGCCAGCGTGGGCGACCGGGTGAC TATCAGCTGCAGAGCCTCGGAAAGCGTGGATAATTACGGCATCTCCTTTCTCAACTGGTTCCAACAGAAACCTGGTAAGGCTCCTAAGCTGCTGATTTACGCCGCCTCTAACCAGAGAAGCGGAGTGCCTTCCAGGTTCAGTGGCAGTGGCTCCGGAACGGACTTCACCCTGACCATCAGCAGCCTTCAGCCCGAGGACTTCGCCACTTACTTTTGCCAGCAAAGCAAGGAGGTGCCATGGACATTCGGCCAGGGGACCAAGGTGGAGATCAAGAGAGGCGGAGGAGGTTCAGGTGGAGGTGGATCTGGAGGTGGCGGGTCTGAGGTGCAGCTGGTCGAGAGCGGAGGAGGACTGGTGCAGCCTGGCGGCTCTCTGCGGCTGTCTTGCAGCTTCAGCGGCTTCAGCCTGTCTACCAGCGGCATGGGCGTGGGCTGGATCAGACAGGCTCCAGGCAAAGGCCTCGAGTGGGTGGCCCACATCTGGTGGGATGATGACAAGCGGTACAACCCCGCACTGAAGAGCAGATTTACCCTGAGCGTCGACCGGAGCAAGAACACACTGTACCTGCAAATGAATAGCCTGCGGGCCGAGGATACAGCCACCTACTACTGTGTGCAAATCAATTATGGCAACTACCGATTCGACAATTGGGGCCACGGCACCCTGGTGACCGTGTCCTCCGGCGGTGGCGGATCAGGAGGCGGAGGTAGTGACAAAACCCACACATGCCCTCCTTGCCCCGCTCCTGAAGCCGCTGGCGGGCCTTCTGTCTTTCTGTTTCCTCCAAAACCTAAGGACACACTGATGATCAGCAGAACACCTGAGGTGACATGCGTCGTGGTGGACGTAAGCCACGAAGCCCCTGAAGTGAAGTTCAACTGGTACGTGGACGGCGTTGAAGTGCACAACGCCAAGACAAAGCCTTGCGAGGAACAGTACGGCAGCACCTACAGATGCGTGTCCGTGCTGACCGTGCTGCACCAGGACTGGCTGAATGGGAAGGAGTACAAGTGCGCCGTGAGCAACAAGGCCCTGCCTGCCCCTATCGAGAAAACCATCTCTAAGGCCAAGGGCCAACCTCGGGAACCTCAGGTCTACACCCTGCCTCCTAGCAGAGAGGAAATGACCAAGAATCAGGTGTCGCTGACATGCCTGGTGAAGGGCTTCTACCCTAGCGACATTGCCGTGGAATGGGAATCTAATGGCCAACCTGAGAACAACTACAAGACCACCCCTCCCGTGCTGGATTCTGATGGCAGCTTTTTCCTGTACAGCAAGCTGACAGTGGATAAGAGTAGATGGCAACAGGGAAATGTGTTCAGCTGCAGCGTGATGCACGAGGCCCTGCATAACCACTACACCCAGAAGAGCCTGAGCCTGAGCCCCGGGAAGGGTGGTGGAGGGTCAGGCGGCGGTGGAAGCGGAGGAGGCGGTTCTGGGGGCGGCGGCAGCGGAGGAGGCGGCTCAGGCGGTGGCGGCAGCGACAAGACCCACACCTGCCCCCCCTGCCCTGCTCCGGAAGCTGCGGGAGGACCTAGCGTGTTCCTGTTCCCCCCCAAACCAAAGGACACCCTGATGATCAGCCGGACCCCTGAAGTAACCTGTGTAGTTGTGGATGTGTCTCACGAGGCCCCTGAGGTGAAGTTCAACTGGTATGTGGACGGCGTCGAAGTGCACAACGCCAAGACCAAGCCTTGTGAAGAGCAGTACGGCAGCACATACAGATGCGTGAGCGTGCTCACAGTGCTGCACCAGGATTGGCTGAACGGCAAAGAGTACAAGTGTGCCGTGAGCAACAAGGCCCTGCCCGCTCCCATCGAGAAGACCATCTCTAAGGCTAAGGGCCAGCCCAGAGAGCCTCAGGTGTACACCCTTCCACCAAGCCGGGAAGAGATGACCAAGAACCAGGTGAGCCTGACATGTCTGGTGAAGGGCTTCTACCCCAGCGACATCGCCGTGGAATGGGAGAGCAACGGCCAGCCGGAAAACAACTACAAGACCACACCTCCTGTGTTAGACAGCGATGGAAGCTTCTTCCTGTATAGCAAGCTGACAGTGGATAAGTCCCGGTGGCAGCAGGGCAACGTGTTCTCTTGTTCTGTTATGCATGAGGCTCTGCACAATCACTACACACAGAAGAGCCTGTCTCTGA GTCCTGGAAAGCACCACCATCACCACCACFSHR PMTE (LHHLLH-Fc) coding sequence (SEQ ID NO: 69)ATGGGCGTGGGATGGATCAGACAGGCCCCCGGGAAGGGCCTGGAATGGGTTGCCCACATCTGGTGGGACGACGACAAAAGATACAATCCCGCCCTGAAGAGCCGGTTCACCCTGTCGGTTGATAGAAGCAAGAATACCTTGTACCTGCAGATGAACTCCCTGAGAGCTGAGGACACAGCCACATACTATTGTGTGCAGATCAACTATGGTAACTACAGATTCGACAACTGGGGGCACGGAACCCTGGTGACCGTGTCTTCAGGCGGAGGTGGCTCTGGAGGCGGTGGATCTGGTGGTGGCGGATCAGATATCCAAATGACCCAGTCTCCTTCAAGCCTGAGTGCCAGCGTGGGCGACCGAGTGACCATCAGCTGTCGCGCCAGCGAGAGCGTGGACAACTACGGAATCAGCTTTCTGAACTGGTTCCAGCAGAAACCTGGCAAAGCCCCTAAGCTGCTCATCTACGCCGCTTCTAATCAGCGCAGCGGCGTGCCGAGCAGATTCTCAGGCAGCGGCAGCGGAACCGATTTCACCTTAACCATCTCCAGTCTGCAGCCTGAGGACTTCGCCACATACTTCTGCCAGCAGAGTAAAGAGGTGCCTTGGACCTTTGGCCAGGGCACAAAAGTGGAGATCAAGAGAGGTGGAGGCGGGAGCGACATCCAGATGACACAATCTCCAAGCAGCCTGAGCGCCAGCGTGGGCGACAGAGTGACAATCACCTGCAGAGCCTCCCAGGACATTAGAAACTACCTGAACTGGTACCAGCAGAAGCCAGGCAAAGCTCCGAAGCTGCTGATCTACTACACCAGCCGCCTCGAGTCTGGAGTTCCTAGTAGGTTTTCCGGAAGCGGCAGCGGGACCGACTACACCCTGACAATCTCTAGCCTGCAGCCCGAAGATTTCGCCACCTACTACTGCCAGCAGGGAAACACCCTCCCTTGGACCTTCGGCCAAGGCACCAAGGTGGAAATCAAGTCTTCCGGAGGCGGCGGTAGTGGTGGAGGAGGCTCTGGCGGTGGTGGAAGCGAGGTCCAGCTGGTGGAAAGCGGTGGCGGCCTGGTGCAACCTGGCGGGAGCCTGAGACTGTCTTGTGCCGCCAGCGGCTACAGCTTCACAGGCTATACCATGAACTGGGTGCGGCAGGCCCCCGGCAAGGGTCTGGAGTGGGTAGCCCTGATCAACCCTTACAAGGGCGTGAGCACCTACAATCAGAAGTTCAAGGACCGGTTTACCATCTCAGTGGACAAGTCTAAAAACACCGCCTACCTGCAGATGAATAGCCTGCGGGCCGAGGACACTGCCGTGTACTACTGCGCCAGATCCGGTTACTACGGTGATAGCGACTGGTACTTCGACGTGTGGGGCCAGGGCACACTGGTGACCGTGAGCTCCGGTGGCGGCGGATCTGATATTCAGATGACCCAGAGCCCTAGCTCTCTCTCCGCCAGCGTGGGCGACCGGGTGACTATCAGCTGCAGAGCCTCGGAAAGCGTGGATAATTACGGCATCTCCTTTCTCAACTGGTTCCAACAGAAACCTGGTAAGGCTCCTAAGCTGCTGATTTACGCCGCCTCTAACCAGAGAAGCGGAGTGCCTTCCAGGTTCAGTGGCAGTGGCTCCGGAACGGACTTCACCCTGACCATCAGCAGCCTTCAGCCCGAGGACTTCGCCACTTACTTTTGCCAGCAAAGCAAGGAGGTGCCATGGACATTCGGCCAGGGGACCAAGGTGGAGATCAAGAGAGGCGGAGGAGGTTCAGGTGGAGGTGGATCTGGAGGTGGCGGGTCTGAGGTGCAGCTGGTCGAGAGCGGAGGAGGACTGGTGCAGCCTGGCGGCTCTCTGCGGCTGTCTTGCAGCTTCAGCGGCTTCAGCCTGTCTACCAGCGGCATGGGCGTGGGCTGGATCAGACAGGCTCCAGGCAAAGGCCTCGAGTGGGTGGCCCACATCTGGTGGGATGATGACAAGCGGTACAACCCCGCACTGAAGAGCAGATTTACCCTGAGCGTCGACCGGAGCAAGAACACACTGTACCTGCAAATGAATAGCCTGCGGGCCGAGGATACAGCCACCTACTACTGTGTGCAAATCAATTATGGCAACTACCGATTCGACAATTGGGGCCACGGCACCCTGGTGACCGTGTCCTCCGGCGGTGGCGGATCAGGAGGCGGAGGTAGTGACAAAACCCACACATGCCCTCCTTGCCCCGCTCCTGAAGCCGCTGGCGGGCCTTCTGTCTTTCTGTTTCCTCCAAAACCTAAGGACACACTGATGATCAGCAGAACACCTGAGGTGACATGCGTCGTGGTGGACGTAAGCCACGAAGCCCCTGAAGTGAAGTTCAACTGGTACGTGGACGGCGTTGAAGTGCACAACGCCAAGACAAAGCCTTGCGAGGAACAGTACGGCAGCACCTACAGATGCGTGTCCGTGCTGACCGTGCTGCACCAGGACTGGCTGAATGGGAAGGAGTACAAGTGCGCCGTGAGCAACAAGGCCCTGCCTGCCCCTATCGAGAAAACCATCTCTAAGGCCAAGGGCCAACCTCGGGAACCTCAGGTCTACACCCTGCCTCCTAGCAGAGAGGAAATGACCAAGAATCAGGTGTCGCTGACATGCCTGGTGAAGGGCTTCTACCCTAGCGACATTGCCGTGGAATGGGAATCTAATGGCCAACCTGAGAACAACTACAAGACCACCCCTCCCGTGCTGGATTCTGATGGCAGCTTTTTCCTGTACAGCAAGCTGACAGTGGATAAGAGTAGATGGCAACAGGGAAATGTGTTCAGCTGCAGCGTGATGCACGAGGCCCTGCATAACCACTACACCCAGAAGAGCCTGAGCCTGAGCCCCGGGAAGGGTGGTGGAGGGTCAGGCGGCGGTGGAAGCGGAGGAGGCGGTTCTGGGGGCGGCGGCAGCGGAGGAGGCGGCTCAGGCGGTGGCGGCAGCGACAAGACCCACACCTGCCCCCCCTGCCCTGCTCCGGAAGCTGCGGGAGGACCTAGCGTGTTCCTGTTCCCCCCCAAACCAAAGGACACCCTGATGATCAGCCGGACCCCTGAAGTAACCTGTGTAGTTGTGGATGTGTCTCACGAGGCCCCTGAGGTGAAGTTCAACTGGTATGTGGACGGCGTCGAAGTGCACAACGCCAAGACCAAGCCTTGTGAAGAGCAGTACGGCAGCACATACAGATGCGTGAGCGTGCTCACAGTGCTGCACCAGGATTGGCTGAACGGCAAAGAGTACAAGTGTGCCGTGAGCAACAAGGCCCTGCCCGCTCCCATCGAGAAGACCATCTCTAAGGCTAAGGGCCAGCCCAGAGAGCCTCAGGTGTACACCCTTCCACCAAGCCGGGAAGAGATGACCAAGAACCAGGTGAGCCTGACATGTCTGGTGAAGGGCTTCTACCCCAGCGACATCGCCGTGGAATGGGAGAGCAACGGCCAGCCGGAAAACAACTACAAGACCACACCTCCTGTGTTAGACAGCGATGGAAGCTTCTTCCTGTATAGCAAGCTGACAGTGGATAAGTCCCGGTGGCAGCAGGGCAACGTGTTCTCTTGTTCTGTTATGCATGAGGC TCTGCACAATCACTACACACAGAAGAGCCTGTCTCTGAGTCCTGGAAAGFSHR PMTE (HLHLLH-Fc) construct (SEQ ID NO: 70)GACATCCAGATGACGCAGTCGCCCAGCAGCCTGAGTGCCAGCGTGGGCGACAGAGTGACCATTTCTTGCAGAGCCAGCGAAAGCGTTGATAACTACGGCATCTCCTTCCTGAATTGGTTTCAGCAGAAGCCTGGGAAGGCTCCTAAGCTGTTGATCTACGCCGCCTCTAATCAGAGATCGGGAGTCCCTTCCAGATTCTCTGGAAGTGGTAGCGGGACAGACTTCACCCTCACCATCTCCTCTCTGCAGCCTGAAGATTTTGCCACATACTTCTGCCAGCAGAGCAAGGAAGTGCCTTGGACCTTCGGCCAGGGGACAAAAGTGGAAATCAAGAGAGGCGGAGGTGGCTCTGGAGGCGGTGGATCTGGTGGTGGCGGATCAGAGGTGCAGCTGGTGGAAAGCGGCGGTGGACTGGTTCAGCCTGGGGGAAGCCTGAGACTGTCGTGTAGCTTCAGCGGCTTCAGCCTGAGCACCAGCGGCATGGGCGTGGGATGGATCAGACAAGCCCCCGGCAAAGGGCTGGAGTGGGTCGCCCACATCTGGTGGGATGACGACAAGAGATACAACCCTGCCCTGAAGAGCAGATTCACACTGAGCGTGGACCGGAGCAAGAACACCCTGTACCTGCAAATGAATAGCCTGAGAGCTGAAGATACAGCTACATACTACTGCGTGCAAATCAACTACGGAAACTACCGGTTCGACAACTGGGGCCACGGCACCCTGGTGACCGTGTCTAGCGGTGGAGGCGGGAGCGAAGTGCAACTGGTAGAAAGCGGCGGAGGCCTGGTGCAGCCCGGCGGAAGCCTGCGGCTTTCTTGCGCCGCCAGTGGCTACAGCTTCACAGGCTACACCATGAACTGGGTGCGGCAGGCTCCTGGAAAGGGCCTGGAGTGGGTGGCCCTGATCAATCCATACAAGGGCGTGAGCACCTACAATCAGAAGTTCAAGGACAGATTCACAATCAGC...

Claims

CLAIMSWhat is claimed is:

1. A synthetic binding molecule, or a binding fragment thereof, or a nucleic acid molecule encoding one or more synthetic binding molecule, or a binding fragment thereof, wherein the one or more synthetic binding molecule comprises at least one antigen binding domain specific for binding to follicle stimulating hormone receptor (FSHR), and at least one immune cell engaging domain.

2. The synthetic binding molecule of claim 1, wherein the immune cell engaging domain targets a cell selected from the group consisting of a T cell, an antigen presenting cell, a natural killer (NK) cell, a neutrophil and a macrophage.

3. The synthetic binding molecule of claim 2, wherein the immune cell engaging domain targets at least one T cell specific receptor molecule selected from the group consisting of CD3. the T cell receptor (TCR), CD28, CD 16, NKG2D, 0x40, 4- IBB, CD2. CD5, CD40, FcgRs, FceRs, FcaRs and CD95.

4. The synthetic binding molecule of claim 3, wherein the immune cell engaging domain targets CD3.

5. The synthetic binding molecule of claim 1, wherein the synthetic binding molecule comprises: a) a FSHR heavy chain amino acid sequence of SEQ ID NO: 1, or a fragment thereof comprising at least the CDRs; b) a FSHR light chain amino acid sequence of SEQ ID NO: 2, or a fragment thereof comprising at least the CDRs; c) a CD3 heavy chain amino acid sequence of SEQ ID NO: 3, or a fragment thereof comprising at least the CDRs; and d) a CD3 light chain amino acid sequence of SEQ ID NO:

4. or a fragment thereof comprising at least the CDRs.

6. The synthetic binding molecule of claim 5, wherein the synthetic binding molecule further comprises: e) an Fc domain comprising SEQ ID NO: 5, or a fragment or variant thereof.

7. The synthetic binding molecule of claim 6, wherein the synthetic binding molecule further comprises: f) a second FSHR heavy chain amino acid sequence of SEQ ID NO: 1, or a fragment thereof comprising at least the CDRs; and g) a second FSHR light chain amino acid sequence of SEQ ID NO: 2, or a fragment thereof comprising at least the CDRs.

8. The synthetic binding molecule of claim 6, wherein the synthetic binding molecule comprises SEQ ID NO:6 or SEQ ID NO:7.

9. The synthetic binding molecule of claim 7, wherein the synthetic binding molecule comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 8, SEQ ID NO:9, SEQ ID NO: 10, SEQ ID NO: 1 1 , SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:

25. SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO 28, SEQ ID NO:29, SEQ ID NO:

30. SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, and SEQ ID NO:37.

10. A nucleic acid molecule encoding a synthetic binding molecule of any one of claims 1-9.

11. The nucleic acid molecule of claim 10. wherein the nucleic acid molecule is selected from the group consisting of an RNA molecule and a DNA molecule.

12. The nucleic acid molecule of claim 10, comprising a nucleotide sequence selected from the group consisting of SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:40, SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:

43. SEQ ID NO:44, SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51 , SEQ ID NO:52, SEQ ID NO:53, SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:56, SEQ ID NO:57, SEQ ID NO:58, SEQ ID NO:

59. SEQ ID NO:60, SEQ ID NO:61, SEQ ID NO:62, SEQ ID NO:

63. SEQ ID NO:64, SEQ ID NO:65, SEQ ID NO 66, SEQ ID NO:67, SEQ ID NO:

68. SEQ ID NO:69, SEQ ID NQ:70, and SEQ ID NO:71.

13. The nucleic acid molecule of any one of claims 10-12, wherein the nucleic acid molecule comprises an expression vector.

14. A composition comprising the synthetic binding molecule of any one of claims 1-9 or the nucleic acid molecule of any one of claims 10-13.

15. The composition of claim 14, further comprising a pharmaceutically acceptable excipient.

16. The composition of claim 14, further comprising at least one immune checkpoint inhibitor.

17. The composition of claim 14, further comprising at least one nucleic acid molecule encoding at least one immune checkpoint inhibitor.

18. The composition of claim 16 or 17, wherein the immune checkpoint inhibitor is selected from the group consisting of an inhibitor of PD-1, an inhibitor of PD-L-1, an inhibitor of cytotoxic T-lymphocyte antigen-4 (CTLA-4), an inhibitor of mucin-domain containing-3 (TIM-3), and an inhibitor of Lymphocyte Activating 3 (LAG3).

19. The composition of claim 14, wherein the composition comprises a lipid nanoparticle comprising the synthetic binding molecule of any one of claims 1-9 or the nucleic acid molecule of any one of claims 10-13.

20. A method of preventing or treating a disease or disorder associated with FSHR expression in a subject, the method comprising administering to the subject the synthetic binding molecule of any one of claims 1-9, the nucleic acid molecule of any one of claims 10-13 or the composition of any one of claims 14-19.

21. The method of claim 20, wherein the disease is selected from the group consisting of a benign tumor, cancer and a cancer-associated disease.

22. The method of claim 21, wherein the disease is selected from the group consisting of ovarian cancer, breast cancer, prostate cancer, renal cancer, colo-rectal cancer, stomach cancer, lung cancer, testicular cancer, endometrial cancer, and thyroid cancer.

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