Treatment of IgE-mediated disorders

Abstract

The present invention relates to the treatment of IgE-mediated diseases using anti-IgE antibodies. In particular, anti-IgE antibodies are multifunctional antibodies against IgE that neutralize IgE and inhibit IgE synthesis. Specifically, the treatment of the present invention is effective in providing rapid and / or sustained suppression of disease symptoms.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No. 63 / 254,729, filed October 12, 2021, the contents of which are incorporated herein by reference in their entirety. [Technical field]

[0002] The present invention relates to the treatment of IgE-mediated diseases using anti-IgE antibodies. In particular, anti-IgE antibodies are multifunctional antibodies against IgE that neutralize IgE and inhibit IgE synthesis. Specifically, the treatment of the present invention is effective in rapid and / or sustained suppression of disease symptoms. [Background technology]

[0003] Unmet medical needs for various allergic diseases remain, and the prevalence of these diseases has increased significantly to more than 25% of the world's population, posing a global health threat and increasing economic burden. 1,2 Allergic (atopic) diseases such as food allergies, atopic dermatitis, asthma, and allergic rhinitis may be interrelated and are sometimes called the "allergic (atopic) march." 3-5 The disease may begin in childhood and is primarily an IgE-mediated disease. Non-allergic diseases may also be IgE-related diseases that do not involve an immune response to foreign antigens, particularly inflammatory skin diseases including chronic spontaneous urticaria (CSU).

[0004] The function of IgE is determined by the interaction of its Fc region (Cε2-Cε4) with two major receptors 8-11 The receptor is the high affinity FcεRI (K D , about 10 -10 ~10 -11 M) 6, as well as the low-affinity monomeric CD23 (FcεRII) (K D , about 10 -6 ~10 -7 M) 7 CD23 on the cell surface generally exists as a homotrimer. IgE binding affinity to free trimeric CD23 or interaction with CD23 in the form of IgE-immune complexes (IgE-IC) has an avidity strength (K D , 10 -9 -10 -10 M) 12 .

[0005] IgE has been reported to have beneficial protective effects against parasites and cancer. 13,14 Due to their deleterious effector functions in allergic conditions, they are generally recognized as not physiologically necessary and as suitable and safe targets for drug development. Omalizumab is the only anti-IgE antibody approved to date and is used in a small number of IgE-related diseases, but its use is restricted to third-line add-on treatment for moderate-to-severe persistent allergic asthma (2003), chronic idiopathic urticaria (CSU, 2014) and nasal polyps (2020). 15 New anti-IgE biologics are needed preclinically and clinically. 16,17 However, although other IgE-targeting antibodies (anti-Cε) have been investigated, only ligelizumab (QGE031) has been viable in late-stage clinical trials. 18,19 .

[0006] Standard first-line treatments for CSU typically involve small molecule drugs (e.g., antihistamines) or cyclic peptide drugs (e.g., cyclosporine) administered frequently. However, taking tablets or capsules every day for weeks can lead to non-compliance and make disease control difficult. If first-line treatments are ineffective, patients may need to turn to biologics (i.e., the only approved ones are omalizumab or ligelizumab; which were tested in pivotal phase 3 clinical trials but ultimately failed in development). However, these two anti-IgE monoclonal antibodies are administered every 4 weeks.

[0007] There remains a need in the art for effective and improved anti-IgE antibodies for treating IgE-mediated diseases. Summary of the Invention

[0008] SUMMARY OF THEINVENTION The present invention is based at least on the discovery that multifunctional anti-IgE antibodies that neutralize IgE and inhibit IgE synthesis provide effective and improved treatment of IgE-mediated diseases. In particular, the anti-IgE antibodies inhibit or block CD23-mediated downregulation of IgE production. In particular, treatment with such multifunctional anti-IgE antibodies provides rapid and / or sustained symptom relief and requires less frequent administration, improving patient comfort and convenience.

[0009] In one aspect, the present invention provides a method for treating an IgE-mediated disease, the method comprising administering to a subject in need of treatment an anti-IgE antibody, the antibody being a multifunctional antibody that neutralizes IgE and inhibits IgE synthesis. Specifically, the method of the present invention provides rapid and / or sustained symptomatic relief in the subject.

[0010] In some embodiments, the antibody binds to free IgE, membrane-bound IgE on B lymphocytes and / or IgE bound to CD23, but not to IgE bound to FcεRI on mast cells.

[0011] In some embodiments, the antibody binds to CD23-bound IgE in its free form and to CD23 in its IgE-complexed form.

[0012] In some embodiments, the antibody is an antigen-binding fragment thereof.

[0013] In some embodiments, the antibody is humanized.

[0014] In some embodiments, the antibody or antigen-binding fragment comprises: (a) a heavy chain variable region (V) comprising a heavy chain complementarity determining region 1 (HC CDR1) comprising the amino acid sequence of SEQ ID NO:2, a heavy chain complementarity determining region 2 (HC CDR2) comprising the amino acid sequence of SEQ ID NO:4, and a heavy chain complementarity determining region 3 (HC CDR3) comprising the amino acid sequence of SEQ ID NO:6; H ); and (b) a light chain variable region (V CDR1) comprising a light chain complementarity determining region 1 (LC CDR1) having the amino acid sequence of SEQ ID NO: 9, a light chain complementarity determining region 2 (LC CDR2) having the amino acid sequence of SEQ ID NO: 11, and a light chain complementarity determining region 3 (LC CDR3) having the amino acid sequence of SEQ ID NO: 13; L ), Includes.

[0015] In some embodiments, V H comprises the amino acid sequence of SEQ ID NO:15.

[0016] In some embodiments, V L comprises the amino acid sequence of SEQ ID NO:16.

[0017] In some embodiments, symptom relief includes reduced IgE, reduced itching, and / or reduced number of wheals.

[0018] In some embodiments, relief of symptoms persists for 2 to 14 weeks or more following administration.

[0019] In some embodiments, relief of symptoms occurs within one week or sooner after administration.

[0020] In some embodiments, the antibody is administered every 2 to 14 weeks or less frequently.

[0021] In some embodiments, the antibody is administered every four weeks or less frequently.

[0022] In some embodiments, the antibody is administered every 12 to 24 weeks.

[0023] In some embodiments, the antibody is administered at a dosage of 0.1-10 mg / kg of the subject's body weight.

[0024] In some embodiments, the antibody is included in a composition in a full dose and is administered to the subject in a single dose.

[0025] In some embodiments, the antibody is administered by either intravenous or subcutaneous injection.

[0026] In some embodiments, the IgE-mediated disease is allergic asthma, allergic rhinitis, atopic dermatitis, food allergy, chronic idiopathic urticaria, chronic sinusitis, systemic mastocytosis, cutaneous mastocytosis, allergic bronchopulmonary aspergillosis, recurrent idiopathic angioedema, or eosinophil-associated gastrointestinal disorder.

[0027] The invention also provides an anti-IgE antibody as described herein, or a pharmaceutical composition comprising same, for use in treating an anti-IgE mediated disease. Further disclosed is the use of an anti-IgE antibody as described herein for the manufacture of a medicament for treating an anti-IgE mediated disease.

[0028] The details of one or more embodiments of the invention are set forth in the following description. Other features or advantages of the invention will be apparent from the following detailed description of several embodiments and from the appended claims. [Brief description of the drawings]

[0029] BRIEF DESCRIPTION OF THE DRAWINGS The foregoing summary and the following detailed description of the invention will be better understood when read in conjunction with the accompanying drawings. For the purpose of illustrating the invention, there are shown in the drawings preferred embodiments. It is to be understood, however, that the invention is not limited to the precise arrangements and equipment shown. The drawings are described below.

[0030] [Figure 1] FIG. 1 shows the kinetic analysis of IgE binding to the anti-IgE monoclonal antibody UB-221 vs. omalizumab performed by surface plasmon resonance (SPR). [Diagram 2] FIG. 2 shows the kinetic analysis of IgE binding to anti-IgE monoclonal antibodies UB-221 vs. ligelizumab vs. omalizumab performed by surface plasmon resonance (SPR). [Diagram 3] FIG. 3 shows competitive neutralization of IgE binding by UB-221 vs. omalizumab (top panel) and inhibition of IgE-specific ovalbumin (OVA)-induced degranulation of basophil FcεRI-expressing RBX SX-38 (bottom panel). [Figure 4] FIG. 4 shows the reduction in serum humanized IgE in hIGHE-knockin mice treated with one single intravenous (IV) dose of UB-221 vs. omalizumab. [Diagram 5]Figures 5A-5C show ex vivo neutralization of high-level IgE in the serum of patients with atopic dermatitis by UB-221 vs. ligelizumab vs. omalizumab, including low-level IgE (<4,800 ng / mL, Figure 5A), medium-level IgE (4,800-24,000 ng / mL, Figure 5B), and high-level IgE (>24,000 ng / mL, Figure 5C). [Figure 6] FIG. 6 shows the binding of UB-221 vs. ligelizumab vs. omalizumab to CD23-bound IgE in free form (top panel) and to CD23 in the form of a mAb:IgE complex (bottom panel). [Figure 7] Figures 7A and 7B show the effect of UB-221 vs. ligelizumab vs. omalizumab on de novo IgE synthesis in human PBMCs, including data at doses of 1, 3, and 10 μg / mL (Figure 7A) and at doses of 10, 20, and 80 μg / mL (Figure 7B). [Figure 8] Figures 8A-8D show that UB-221 can bind to IgE and CD23-bound IgE in cynomolgus monkeys and induce a rapid and significant reduction in serum IgE after a single IV administration; the data show that UB-221 can bind to cIgE (Figure 8A), that UB-221 can engage cCD23-bound cIgE in a dose-dependent manner (Figure 8B), show the pharmacokinetics (PK) of UB-221 after 5 mg / kg IV administration (Figure 8C), and show that UB-221 can induce a rapid and significant reduction in serum free form cIgE (Figure 8D). [Figure 9] FIG. 9 shows the design of a Phase 1 clinical trial to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of UB-221 administered IV in a single dose at 0.2, 0.6, 2, 6, and 10 mg / kg in 15 patients with chronic idiopathic urticaria. [Figure 10] FIG. 10 shows that UB-221 concentrations decayed with a dose-dependent half-life by 22 days in serum of patients with chronic idiopathic urticaria after treatment with a single IV dose of UB-221. [Figure 11]Figures 11A-11C show that a single IV dose of UB-221 is effective in treating chronic idiopathic urticaria, as demonstrated by the rapid reduction in UAS7 disease scores, individual (Figure 11A) and average (Figure 11B), and the diurnal variation in UAS disease scores (Figure 11C). [Figure 12] Figures 12A and 12B show that a single IV dose of UB-221 is effective in treating chronic idiopathic urticaria, as demonstrated by the rapid reduction in individual (Figure 12A) and mean (Figure 12B) HSS7 scores. [Figure 13] FIG. 13 shows individual free IgE concentrations in serum of patients with chronic idiopathic urticaria after treatment with a single IV dose of UB-221. [Figure 14] FIG. 14 shows mean serum UB-221, free IgE concentrations and UAS7 scores in patients with chronic idiopathic urticaria who received a single IV dose of UB-221. [Figure 15] 15 shows the amino acid sequences of the heavy chain variable region (VH) and light chain variable region (VL) of UB-221. The complementarity determining regions (CDRs) are underlined and include GYTFNGYWMH (HC CDR1; SEQ ID NO:2), YINPTTGHTEYNQKFKD (HC CDR2; SEQ ID NO:4), ARQEYRHSWFAY (HC CDR3; SEQ ID NO:6), QSVDYDGDTYM (LC CDR1; SEQ ID NO:9), AASNLDS (LC CDR2; SEQ ID NO:11), and QQTNEDPWT (LC CDR3; SEQ ID NO:13). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0031] The following description is merely for the purpose of illustrating various embodiments of the present invention. As such, the specific embodiments or modifications discussed herein should not be construed as limitations on the scope of the present invention. It will be apparent to those skilled in the art that various modifications or equivalents can be made without departing from the scope of the present invention.

[0032] I. Definition In order to provide a clear and ready understanding of the present invention, certain terms are first defined. Additional definitions are set forth throughout the detailed description. 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 to which this invention belongs.

[0033] As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to a "component" includes a plurality of that component and equivalents thereof known to those skilled in the art.

[0034] The terms "comprise" or "comprising" are generally used in the sense of "containing / comprising", meaning to permit the presence of one or more features, ingredients or components. The terms "comprise" or "comprising" encompass the terms "containing" or "consisting of".

[0035] As used herein, the term "polypeptide" refers to a polymer of amino acid residues linked together through peptide bonds. The term "protein" typically refers to a relatively large polypeptide. The term "peptide" typically refers to a relatively short polypeptide (e.g., containing up to 100, 90, 70, 50, 30, 20, or 10 amino acid residues).

[0036] As used herein, the term "approximately" or "about" refers to an acceptable degree of deviation that would be understood by one of ordinary skill in the art, which may vary to some extent depending on the context in which it is used. Specifically, "approximately" or "about" may mean a numerical value having a range of ±10% or ±5% or ±3% around the cited value.

[0037] As used herein, the term "substantially identical" refers to two sequences that have a homology of 80% or more, preferably 85% or more, more preferably 90% or more, or even more preferably 95% or more.

[0038] As used herein, the term "antibody" (the plural antibodies may be used interchangeably) refers to an immunoglobulin molecule capable of specifically binding to a particular target antigen molecule. As used herein, the term "antibody" encompasses intact (i.e., full-length) antibody molecules as well as antigen-binding fragments thereof that retain antigen-binding ability, such as Fab, Fab', F(ab')2 and Fv. The fragments are also well known in the art and are frequently used both in vitro and in vivo. The term "antibody" also includes chimeric antibodies, humanized antibodies, human antibodies, diabodies, linear antibodies, single-chain antibodies, multispecific antibodies (e.g., bispecific antibodies) and other modified structures of immunoglobulin molecules that contain an antigen recognition site of the required specificity, such as amino acid sequence variants of antibodies, glycosylation variants of antibodies and covalently modified antibodies.

[0039] An intact or complete antibody contains two heavy chains and two light chains. Each heavy chain contains a variable region (V H ), and the first, second and third constant regions (C H 1. C H 2. C H 3); and each light chain comprises a variable region (V L ) and the constant region (C L). Antibodies are in the shape of a "Y", the stem of which consists of the second and third constant regions of two heavy chains bound together via disulfide bonds. Each arm of the Y contains the variable and first constant regions of one heavy chain combined with the variable and constant region of one light chain. The light chain variable region and the heavy chain variable region are responsible for antigen binding. The variable regions in both chains are generally responsible for antigen binding, and each of these regions contains three hypervariable regions, so-called complementarity determining regions: the heavy chain (H) CDR contains HC CDR1, HC CDR2 and HC CDR3; and the light chain (L) CDR contains LC CDR1, LC CDR2 and LC CDR3. The three CDRs are flanked by framework regions (FR1, FR2, FR3 and FR4), which are more highly conserved than the CDRs and form a scaffold supporting the hypervariable regions. The constant regions of the heavy and light chains are not involved in antigen binding, but are involved in various effector functions. Depending on the antibody amino acid sequence of the constant domain of the heavy chain, immunoglobulins can be classified into different classes. There are five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM. The heavy chain constant domains corresponding to each class of immunoglobulin are called α, δ, ε, γ, and μ, respectively.

[0040] As used herein, the term "antigen-binding fragment" or "antigen-binding domain" refers to a portion or region of an intact antibody molecule that is involved in antigen binding. An antigen-binding fragment can bind to the same antigen as that bound by the parent antibody. Examples of antigen-binding fragments include, but are not limited to, the following: (i) V H -C H -1 and V L -C L (ii) a F(ab')2 fragment, which may be a bivalent fragment containing two Fab fragments linked by a disulfide bridge at the hinge region; (iii) a V chain of an antibody molecule bound together by a non-covalent bond. H Domains and V L(iv) an Fv fragment comprising a V domain via a peptide linker; H Domains and V L (v) a single-chain Fv (scFv), which can be a single polypeptide chain containing two V domains linked via a peptide linker; H domain and two V H Two Vs bound to the domain L It may contain the domain (scFv)2.

[0041] As used herein, the term "chimeric antibody" refers to an antibody that comprises polypeptides obtained from different origins, e.g., different species. In some embodiments, in a chimeric antibody, the variable regions of both the light and heavy chains may mimic the variable regions of an antibody obtained from a certain mammal (e.g., a non-human mammal such as mouse, rabbit, and rat), while the constant regions may be homologous to sequences of an antibody obtained from another mammal, such as a human.

[0042] As used herein, the term "humanized antibody" refers to an antibody that contains a framework region derived from a human antibody and one or more CDRs derived from a non-human (usually mouse or rat) immunoglobulin.

[0043] As used herein, the term "human antibody" refers to an antibody in which the entire sequence of the light and heavy chain sequences, including the complementarity determining regions (CDRs), are essentially derived from human genes. In some circumstances, a human antibody may contain one or more amino acid residues not encoded in human germline immunoglobulin sequences, e.g., one or more mutations in one or more of the CDRs or one or more mutations in the FRs, for example, to reduce potential immunogenicity, to increase affinity, or to remove cysteines that may cause undesired folding.

[0044] As used herein, the term "specifically binds" or "specific binding" refers to a non-random binding reaction between two molecules, e.g., the binding of an antibody to an epitope of a target antigen. An antibody that "specifically binds" to a target antigen or epitope is a term well understood in the art, and methods for determining such specific binding are well known in the art. An antibody "specifically binds" to a target antigen if it binds with higher affinity / strength, more readily, and / or for a longer period of time than it binds to other substances. In other words, by reading this definition, it can be understood that, for example, an antibody that specifically binds to a first target antigen may or may not specifically or preferentially bind to a second target antigen. Thus, "specific binding" or "preferential binding" does not necessarily require (although it may include) exclusive binding. Generally, the affinity of binding is measured by the dissociation constant (K D ) Generally, when used with respect to antibodies, specifically binding can be defined as D The value is about 10 -8 M or less, e.g., about 10 -9 M or less, about 10 -10 M or less, about 10 -11 M or less or about 10 -12 Specifically bind (recognize) a target with an affinity of at least M or less, and at least 10-fold lower, e.g., at least 100-fold lower (e.g., at least 1,000-fold lower, or at least 10,000-fold lower) than the affinity for binding to a nonspecific antigen (e.g., BSA or casein). D It refers to an antibody that binds to a specific target with an affinity equivalent to

[0045] As used herein, the term "nucleic acid" or "polynucleotide" can refer to a polymer containing nucleotide units. Polynucleotides encompass naturally occurring nucleic acids, such as deoxyribonucleic acid ("DNA") and ribonucleic acid ("RNA"), as well as nucleic acid analogs, including nucleic acids with non-naturally occurring nucleotides. Polynucleotides can be synthesized, for example, using an automated DNA synthesizer. When a nucleotide sequence is represented as a DNA sequence (i.e., A, T, G, C), it will be understood that an RNA sequence (i.e., A, U, G, C) in which "U" is substituted for "T" is also included. "cDNA" refers to a DNA that is complementary or identical to an mRNA in single-stranded or double-stranded form.

[0046] As used herein, the term "complementary" refers to the topological compatibility or compatibility of the interacting surfaces of two polynucleotides.If the nucleotide sequence of the first polynucleotide is identical to the nucleotide sequence of the polynucleotide binding partner of the second polynucleotide, the first polynucleotide is complementary to the second polynucleotide.Thus, the polynucleotide whose sequence is 5'-ATATC-3' is complementary to the polynucleotide whose sequence is 5'-GATAT-3'.

[0047] As used herein, the term "encode" refers to the natural property of, and the biological properties resulting from, a particular sequence of nucleotides in a polynucleotide (e.g., gene, cDNA, or mRNA) that serves as a template for the synthesis of other polymers and macromolecules in biological processes having either a predetermined sequence of RNA transcripts (i.e., rRNA, tRNA, and mRNA) or a predetermined sequence of amino acids. Thus, a gene encodes a protein when transcription and translation of the mRNA produced by that gene produces a protein in a cell or another biological system. As a result of the degeneracy of the genetic code, it is understood by those skilled in the art that many different polynucleotides and nucleic acids can encode the same polypeptide. It is also understood by those skilled in the art that, using routine techniques, nucleotide substitutions that do not affect the polypeptide sequence encoded by the polynucleotides described therein may be made to reflect the codon usage of the particular host organism in which the polypeptide is expressed. Thus, unless otherwise specified, a "nucleotide sequence encoding an amino acid sequence" includes all nucleotide sequences that are degenerate versions of each other and encode the same amino acid sequence.

[0048] As used herein, the term "recombinant nucleic acid" refers to a polynucleotide or nucleic acid having a sequence that is not naturally associated with it. A recombinant nucleic acid may be in the form of a vector. A "vector" may include a desired nucleotide sequence and a regulatory sequence. A vector may be used to express a desired nucleotide sequence (expression vector) or to ensure the replication, recombination, or transfer of a desired nucleotide sequence between different locations (e.g., between different organisms). A vector may be introduced into a suitable host cell for the above purposes. A "recombinant cell" refers to a host cell into which a recombinant nucleic acid has been introduced. A "transformed cell" refers to a cell into which a DNA molecule encoding a protein of interest has been introduced by recombinant DNA techniques.

[0049] Vectors may be of various types, including plasmids, cosmids, episomes, fosmids, artificial chromosomes, phages, viral vectors, and the like. Usually, in a vector, a given nucleotide sequence is operably linked to a regulatory sequence, such that when the vector is introduced into a host cell, the given nucleotide sequence can be expressed in the host cell under the control of the regulatory sequence. The regulatory sequence may include, for example, but is not limited to, a promoter sequence (e.g., cytomegalovirus (CMV) promoter, simian virus 40 (SV40) early promoter, T7 promoter, and alcohol oxidase gene (AOX1) promoter), an initiation codon, an origin of replication, an enhancer, a secretion signal sequence (e.g., α-mating factor signal), a stop codon, and other regulatory sequences (e.g., Shine-Dalgarno sequence and a termination sequence). Preferably, the vector may further include a marker sequence (e.g., an antibiotic resistance marker sequence) for subsequent screening / selection steps. For the purpose of protein production, in the vector, a nucleotide sequence of interest may be linked to another nucleotide sequence other than the above-mentioned regulatory sequences, so that a fusion polypeptide is produced, which is useful for the subsequent purification step. The fusion polypeptide may include a tag for purification, such as a His tag.

[0050] As used herein, the term "treatment" refers to the application or administration of one or more active agents to a patient affected by a disorder, a sign or symptom of a disorder, or the progression of a disorder, for the purpose of ameliorating, curing, mitigating, alleviating, altering, treating, ameliorating, ameliorating, or affecting said disorder, a sign or symptom of a disorder, or the progression of a disorder.

[0051] II. Antibodies to IgE According to the present invention, an anti-IgE antibody, as used herein, is a polyfunctional anti-IgE antibody that neutralizes IgE and inhibits IgE synthesis.

[0052] As described herein, neutralizing anti-IgE antibodies can partially or completely inhibit IgE binding to FcεRI on mast cells and basophils, and can cause any substantial inhibition or blockage of IgE signaling via FcεRI, which is involved in allergic hypersensitivity and inflammation. Neutralization can be measured by any suitable method. In one embodiment, neutralization of IgE refers to the ability of a neutralizing antibody to inhibit degranulation induced by IgE-mediated antigen stimulation by at least about 30%, preferably at least about 40%, at least about 50%, at least about 60%, at least about 75% or more (e.g., about 25-100%), compared to the amount of degranulation that normally occurs under substantially identical conditions in the absence of a neutralizing antibody.

[0053] As described herein, IgE synthesis includes de novo IgE production. IgE levels and inhibition of IgE synthesis can be measured by any suitable method. In one embodiment, an inhibitory antibody that substantially inhibits IgE synthesis can reduce the IgE level of cells treated with the inhibitory antibody by 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or more compared to the IgE level of cells under substantially identical conditions in the absence of the inhibitory antibody. Specifically, an inhibitory antibody that inhibits IgE synthesis involves interaction with CD23 in free or IgE complexed form, or both. More specifically, an inhibitory antibody inhibits IgE synthesis through interaction with CD23 in both free and IgE complexed forms, thereby substantially inhibiting or blocking CD23-mediated downregulation of IgE production.

[0054] In some embodiments, the anti-IgE antibody described herein is an anti-IgE monoclonal antibody, i.e., UB-221 mAb. The heavy chain variable region (V H ) and the light chain variable region (V L), and the amino acid sequences of their complementarity determining regions (HC CDR1, HC CDR2 and HC CDR3) (LC CDR1, LC CDR2 and LC CDR3) are shown below in Table 1. The anti-IgE antibodies of the present invention include UB-221 mAb and functional variants thereof.

[0055] [Table 1]

[0056] In some embodiments, the anti-IgE antibody of the invention comprises (a) a V CDR1 comprising an HC CDR1 of SEQ ID NO:2, an HC CDR2 of SEQ ID NO:4, and an HC CDR3 of SEQ ID NO:6. H and (b) a V comprising an LC CDR1 of SEQ ID NO:9, an LC CDR2 of SEQ ID NO:11, and an HC CDR3 of SEQ ID NO:13. L or an antigen-binding fragment thereof.

[0057] In some embodiments, the anti-IgE antibody of the invention comprises (a) a V CDR1 comprising an HC CDR1 of SEQ ID NO:2, an HC CDR2 of SEQ ID NO:4, and an HC CDR3 of SEQ ID NO:6. H and (b) a V comprising an LC CDR1 of SEQ ID NO:9, an LC CDR2 of SEQ ID NO:11, and an LC CDR3 of SEQ ID NO:13. L and the antibody has a V sequence comprising SEQ ID NO: 15 or an amino acid sequence substantially identical thereto. H and V comprising an amino acid sequence of SEQ ID NO:16 or substantially identical thereto. L Specifically, the anti-IgE antibody of the present invention may comprise a V that comprises an amino acid sequence having at least 80% (e.g., 82%, 84%, 85%, 86%, 88%, 90%, 92%, 94%, 95%, 96%, 98% or 99%) identity to SEQ ID NO: 15. Hand V comprising an amino acid sequence having at least 80% (e.g., 82%, 84%, 85%, 86%, 88%, 90%, 92%, 94%, 95%, 96%, 98% or 99%) identity to SEQ ID NO:16. L The anti-IgE antibodies of the present invention include those of the related V H or V L Also included are recombinantly produced (genetically engineered) antibodies that are encoded by a polynucleotide sequence that codes for an amino acid sequence.

[0058] U.S. Pat. No. 10,047,166 describes an example of an anti-IgE antibody of the present invention, the relevant disclosures of which are incorporated herein by reference for any purpose or subject matter mentioned herein.

[0059] The term "substantially identical" refers to the relevant amino acid sequence (e.g., FR, CDR, V H or V L) slightly different from the reference antibody, but the variant has substantially similar binding activity (e.g., affinity, specificity, or both) and biological activity as the reference antibody. Such variants may contain minor amino acid changes. It is understood that a polypeptide may have a limited number of changes or modifications that can be made within a portion of the polypeptide that are not related to activity or function, and still result in a variant with an acceptable level of equivalent or similar biological activity or function. In some examples, the change in the amino acid residue is a conservative amino acid substitution, which refers to an amino acid residue with a similar chemical structure to another amino acid residue, and has little or no effect on the function, activity, or other biological properties of the polypeptide. In general, as opposed to the CDR region, relatively more substitutions can be made in the FR region (e.g., reducing the binding affinity by 50% or more compared to the original antibody) as long as it does not adversely affect the binding function or biological activity of the antibody. In some embodiments, sequence identity may be about 80%, 82%, 84%, 85%, 86%, 88%, 90%, 92%, 94%, 95%, 96%, 98% or 99% or more between the reference antibody and the variant. Variants can be made according to methods for modifying polypeptide sequences known to those skilled in the art, for example, in references that summarize such methods, such as Molecular Cloning: A Laboratory Manual, J. Sambrook, et al., eds., Second Edition, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, 1989. For example, conservative substitutions of amino acids include substitutions made between amino acids in the following groups: (i) A, G; (ii) S, T; (iii) Q, N; (iv) E, D; (v) M, I, L, V; (vi) F, Y, W; and (vii) K, R, H.

[0060] The antibodies described herein may be animal antibodies (e.g., mouse-derived antibodies), chimeric antibodies (e.g., mouse-human chimeric antibodies), humanized antibodies, or human antibodies. The antibodies described herein may also include antigen-binding fragments thereof, such as Fab fragments, F(ab')2 fragments, Fv fragments, single chain Fv (scFv) and (scFv)2. Antibodies or antigen-binding fragments thereof may be produced by methods known in the art.

[0061] III. Antibody Production There are many methods available for obtaining antibodies or antigen-binding fragments thereof that are conventional in the art.

[0062] In some embodiments, the antibodies provided herein may be produced by conventional hybridoma technology. In general, a target antigen appropriately conjugated to a carrier protein and / or mixed with an adjuvant may be used to immunize a host animal to produce an antibody that binds to the antigen. Lymphocytes secreting monoclonal antibodies are collected and fused with myeloma cells to produce hybridomas. Hybridoma clones thus formed are screened to identify and select those secreting the desired monoclonal antibodies.

[0063] In some embodiments, the antibodies provided herein may be produced using recombinant techniques. In related aspects, isolated nucleic acids encoding the disclosed amino acid sequences are also provided, along with vectors containing such nucleic acids, and host cells transformed or transfected with the nucleic acids.

[0064] For example, a nucleic acid comprising a nucleotide sequence encoding the heavy and light chain variable regions of such an antibody can be cloned into an expression vector (e.g., a bacterial vector such as an E. coli vector, a yeast vector, a viral vector, or a mammalian vector) by conventional techniques, and any of the vectors can be introduced into appropriate cells (e.g., bacterial cells, yeast cells, plant cells, or mammalian cells) for expression of the antibody. Examples of mammalian host cell lines include human embryonic kidney line (293 cells), baby hamster kidney cells (BHK cells), Chinese hamster ovary cells (CHO cells), African green monkey kidney cells (VERO cells), and human liver cells (Hep G2 cells). Recombinant vectors for expressing the antibodies described herein usually contain a nucleic acid encoding the antibody amino acid sequence operably linked to a constitutive or inducible promoter. Exemplary vectors include transcription and translation terminators, initiation sequences, and promoters useful for regulating expression of the nucleic acid encoding the antibody. The vector may optionally contain both prokaryotic and eukaryotic selectable markers. In some examples, both the heavy and light chain coding sequences are included in the same expression vector. In another example, each of the heavy and light chains of an antibody can be cloned into individual vectors and produced separately, which are incubated under appropriate conditions for assembly of the antibody.

[0065] Recombinant vectors for expressing the antibodies described herein usually contain a nucleic acid encoding an antibody amino acid sequence operably linked to a constitutive or inducible promoter. Recombinant antibodies can be produced in prokaryotic or eukaryotic expression systems, such as bacteria, yeast, insect, and mammalian cells. Typical vectors contain transcription and translation terminators, initiation sequences, and promoters useful for regulating the expression of the nucleic acid encoding the antibody. Vectors may optionally contain both prokaryotic and eukaryotic selectable markers. The produced antibody protein can be further isolated or purified to obtain a substantially homogeneous preparation for further assays and applications. For example, fractionation on an immunoaffinity column or ion exchange column, ethanol precipitation, sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), high performance liquid chromatography (HPLC), ammonium sulfate precipitation, and gel filtration.

[0066] If a full-length antibody is desired, the V H Chain and V L The coding sequence for either chain can be linked to the coding sequence for the Fc region of an immunoglobulin, and the resulting genes encoding the full-length antibody heavy and light chains can be expressed and assembled in a suitable host cell, such as a plant cell, a mammalian cell, a yeast cell or an insect cell.

[0067] Antigen-binding fragments can be produced by conventional methods. For example, F(ab')2 fragments can be produced by pepsin digestion of full-length antibody molecules, and Fab fragments can be produced by reducing disulfide bonds of F(ab')2 fragments. Alternatively, such fragments can be produced by recombinant techniques by expressing heavy and light chain fragments in suitable host cells and assembling them to form the desired antigen-binding fragment in vivo or in vitro. Single-chain antibodies can be produced using recombinant techniques by linking a nucleotide sequence encoding a heavy chain variable region and a nucleotide sequence encoding a light chain variable region. Preferably, a flexible linker is incorporated between the two variable regions.

[0068] IV. Composition In accordance with the present invention, the anti-IgE antibodies may be formulated with a pharma- ceutically acceptable carrier into a composition for delivery and absorption.

[0069] As used herein, the term "pharmaceutical acceptable" means that the carrier is compatible with the active ingredient in the composition, preferably capable of stabilizing the active ingredient, and is safe for the individual to whom it is administered. The carrier may be a diluent, vehicle, excipient, or matrix for the active ingredient. Typically, the composition comprising the anti-IgE antibody described herein as an active ingredient can be in the form of an aqueous solution, such as physiological saline, or can be provided in the form of a powder. The composition can further contain pharma-ceutically acceptable auxiliary substances necessary to approximate physiological conditions, such as pH adjusters and buffers, such as sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate, etc. The form of the composition includes suspensions, lotions, solutions, sterile injection solutions, and individually packaged powders. The composition of the present invention can be delivered via any physiologically acceptable route, such as parenterally (intramuscular, intravenous, subcutaneous, and intraperitoneal, etc.) and intranasally. In certain embodiments, the composition of the present invention is administered as a liquid injection form, which can be provided as a ready-to-use dosage form or as a dissolvable stable powder.

[0070] V. Treatment The present invention provides methods of treating IgE-mediated diseases by administering the multifunctional anti-IgE antibodies described herein. The methods of the invention are effective in providing rapid and / or sustained relief of symptoms and require less frequent administration, thereby improving patient comfort and convenience.

[0071] As used herein, the term "alleviation of symptoms" may refer to an active agent that reduces or eliminates one or more perceived symptoms of a disease or other abnormal condition. The severity level of a disease symptom may be determined by any suitable index or score known in the art. Generally, a higher level of the index or a higher score indicates a higher severity of the disease. In some embodiments, alleviation of symptoms may include a 5%, 10%, 15%, 20%, 25%, 30%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or more reduction in the level of said index or score, for example, compared to the disease level of the index or disease score that a person skilled in the art and / or a medical professional, e.g., a physician, would expect to have in an affected individual or population with similar physical characteristics and medical history. In some embodiments, alleviation of symptoms may refer to one or more perceived symptoms of a disease or other abnormal condition being alleviated to normal.

[0072] In some embodiments, the alleviation of symptoms described herein may include a reduction in IgE to CSU, alleviation of pruritus, and / or a reduction in wheal count. Specifically, the signs and symptoms of CSU were scored using two scoring systems: 1) UAS7 (Urticaria Activity Score), based on a daily score of wheal count and pruritus intensity on a scale of 0 to 3 for 7 days; and 2) HSS7 (Wheal Severity Score), based on a daily score of wheal count on a scale of 0 to 3 for 7 days. The UAS7 score is classified into five score bands: (i) no wheal, 0 points; (ii) good wheal control, 1 to 6 points; (iii) mild, 7 to 15 points; (iv) moderate, 16 to 27 points; and (v) severe, 28 to 42 points. The HSS7 score is classified into four score bands: (i) none, score 0; (ii) mild (1-6 wheals / 12 hours); (iii) moderate (7-12 wheals / 12 hours); and (iv) severe (>12 wheals / 12 hours). In certain instances, "alleviation of symptoms" as described herein can mean that a patient's condition is improved from severe to moderate, mild, or asymptomatic.

[0073] As used herein, the term "rapid relief" can mean that relief of disease symptoms occurs within one week or sooner (e.g., within 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day, i.e., within 24 hours) after administration of the active agent. "Sustained relief" refers to relief of disease symptoms that persists for 2 weeks or more (e.g., 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks) after administration of the active agent. Specifically, the term "rapid and sustained relief" refers to immediate relief that begins within 1 week or sooner (e.g., within 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day, i.e., within 24 hours) after administration of the active agent and continues for at least 2 weeks or more (e.g., 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks or more), particularly at least 3 weeks or more (e.g., 3-14 weeks or more). ), at least 4 weeks or more (e.g., 4 to 14 weeks or more), at least 5 weeks or more (e.g., 5 to 14 weeks or more), at least 6 weeks or more (e.g., 6 to 14 weeks or more), at least 7 weeks or more (e.g., 7 to 14 weeks or more), at least 8 weeks or more (e.g., 8 to 14 weeks or more), at least 9 weeks or more (e.g., 9 to 14 weeks or more), at least 10 weeks or more (e.g., 10 to 14 weeks or more), It can mean constant and stable for at least 11 weeks or more (e.g., 11-14 weeks or more), at least 12 weeks or more (e.g., 12-14 weeks or more), at least 13 weeks or more (e.g., 13-14 weeks or more), or at least 14 weeks or more. In some embodiments, relief can last for at least 8-24 weeks (2-6 months), at least 12-24 weeks (3-6 months), at least 16-24 weeks (4-6 months), at least 20-24 weeks (5-6 months), or at least 24 weeks (6 months).

[0074] As used herein, the terms "infrequent" or "infrequently" with respect to administration can mean that an active agent for treating a disease (e.g., UB-221) is administered every 2-14 weeks or less, for example, every 3 weeks, every 4 weeks, every 5 weeks, every 6 weeks, every 7 weeks, every 8 weeks, every 9 weeks, every 10 weeks, every 11 weeks, every 12 weeks, every 13 weeks or every 14 weeks or less. In some embodiments, the active agent (e.g., UB-221) is administered every 3-14 weeks or less, every 4-14 weeks or less, every 5-14 weeks or less, every 6-14 weeks or less, every 7-14 weeks or less, every 8-14 weeks or less, every 9-14 weeks or less, every 10-14 weeks or less, every 11-14 weeks or less, every 12-14 weeks or less, every 13-14 weeks or less, or every 14 weeks or less. In some embodiments, the active agent (e.g., UB-221) is administered every 8-24 weeks (every 2-6 months), every 12-24 weeks (every 3-6 months), every 16-24 weeks (every 4-6 months), every 20-24 weeks (every 5-6 months), or every 24 weeks (every 6 months).

[0075] In some embodiments, the use of multifunctional anti-IgE antibodies as described herein as active agents for treating IgE-mediated diseases provides sustained symptom relief that lasts longer and requires less frequent administration than when subjects receive other treatments, such as small molecule drugs, cyclic peptide drugs, or other biologics. Small molecule drugs (e.g., antihistamines) and cyclic peptide drugs (e.g., cyclosporine) are usually administered frequently, such as daily tablet or capsule dosing, for extended periods of time. Other examples of biologics, such as omalizumab and ligelizumab (anti-IgE antibodies), are administered every 2 or 4 weeks. Said anti-IgE antibodies are considered as monofunctional anti-IgE antibodies (or simply called IgE neutralizers) that are capable of neutralizing IgE but fail to provide substantial inhibition of de novo IgE production (e.g., causing a 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or greater reduction in IgE levels). Specifically, such monofunctional anti-IgE antibodies have limited reactivity against CD23 or remain inactive, and therefore do not substantially inhibit CD23-mediated downregulation of IgE production.

[0076] The method of the present invention is effective for treating IgE-mediated diseases, including allergic or non-allergic diseases.The examples of IgE-mediated diseases described herein include, but are not limited to, allergic asthma, allergic rhinitis, atopic dermatitis, food allergy, chronic idiopathic urticaria, chronic sinusitis, systemic mastocytosis, cutaneous mastocytosis, allergic bronchopulmonary aspergillosis, recurrent idiopathic angioedema or eosinophil-associated gastrointestinal disorders.

[0077] The term "effective amount" as used herein refers to the amount of active ingredient to give the desired biological effect in treated subjects or cells. For example, the effective amount may be the amount of a multifunctional anti-IgE antibody as an active agent that can provide substantial inhibition of de novo IgE production and lead to rapid / or sustained symptomatic relief for IgE-mediated diseases, as described herein. The effective amount can be changed depending on various reasons, such as the route and frequency of administration, the weight and species of the individual to whom the medicament is administered, and the purpose of administration. Those skilled in the art can determine the dosage in each case based on the disclosure herein, established methods, and their own experience.

[0078] In some embodiments, the multifunctional anti-IgE antibodies described herein are administered in a dose range of 0.1-10 mg / kg, preferably 0.3-10 mg / kg, more preferably 0.5-10 mg / kg, even more preferably 1-10 mg / kg, and even more preferably 2-10 mg / kg, 3-10 mg / kg, 4-10 mg / kg, 5-10 mg / kg, 6-10 mg / kg, 7-10 mg / kg, 8-10 mg / kg, or 10 mg / kg.

[0079] In some embodiments, the antibody is contained in a composition in a full dose and is administered to the subject in a single dose.

[0080] The subject treated by the therapeutic method described herein may be a mammal, more preferably a human. Mammals include, but are not limited to, livestock, sport animals, pets, primates, horses, dogs, cats, mice and rats. A human subject in need of treatment may be a human patient who has, is at risk for, or is suspected of having a target disease / disorder. A subject suspected of having any of the target diseases / disorders may exhibit one or more symptoms of the disease / disorder. A subject at risk of a disease / disorder may be a subject who has one or more risk factors for the disease / disorder.

[0081] The present invention is further illustrated by the following examples, which are provided for purposes of illustration and not limitation. Those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention. EXAMPLES

[0082] Example 1: Determination of IgE-binding affinity of UB-221 versus Omalizumab in surface plasmon resonance (SPR) analysis Kinetic analysis of IgE binding to anti-IgE monoclonal antibodies UB-221 (UBP product from parent CHO-S clone) and omalizumab (Novartis, Xolair® CA-075) was carried out by surface plasmon resonance (SPR) technique using a Biacore X100 instrument (GE Healthcare). First, anti-human IgG Fc fragment antibody (BR-1008-39, GE) was immobilized on the surface of a CM5 gold sensor chip by amino coupling, and anti-IgE antibody diluted to 1 μg / mL was captured thereon. 0.312-50 nM Expi293-expressed human full-length IgE sample diluted in HBS-EP buffer was injected for 120 s, and dissociation was measured for 720 s under constant buffer flow. Dissociation rate constant (Kd), association rate constant (Ka) and equilibrium dissociation rate constant (K D ) was calculated using a 1:1 Langmuir curve fitting model. As a result, UB-221 was found to be more potent than omalizumab (K D , 8.98 x 10 -11 Approximately 8 times higher affinity (K D , 1.15 x 10 -11 It was demonstrated that the antibody binds to IgE at the cytoplasmic level (M). The kinetic sensorgram and binding affinity values ​​are shown in FIG. 1.

[0083] Example 2: Determination of IgE-binding affinity of UB-221 vs. Ligelizumab vs. Omalizumab in surface plasmon resonance (SPR) analysis Kinetic analysis of IgE binding to anti-IgE monoclonal antibody UB-221 (UBP product obtained from stable CHO-S clone), surrogate antibody (SA) of ligelizumab (Creative Biolabs, CB190513) and omalizumab (Novartis, Xolair® CA-075) was carried out by surface plasmon resonance (SPR) technique using Biacore X100 instrument (GE Healthcare). First, anti-human IgG Fc fragment antibody (BR-1008-39, GE) was immobilized on the surface of CM5 gold sensor chip by amino coupling and anti-IgE antibody diluted to 1 μg / mL was captured on the chip. 0.312-50 nM Expi293-expressed human full-length IgE sample diluted in HBS-EP buffer was injected for 120 s and dissociation was measured for 720 s under constant buffer flow. Dissociation rate constant (Kd), association rate constant (Ka) and equilibrium dissociation rate constant (K D ) was calculated using a 1:1 Langmuir curve fitting model. As a result, ligelizumab had the highest affinity (K D , 1.61 x 10 -11 M) binds to IgE and UB-221 (K D , 5.85 x 10 -11 M) and approximately 14 times higher than Omalizumab. Kinetic sensorgrams and binding affinity values ​​are shown in Figure 2.

[0084] Example 3: Competitive inhibition of IgE:FcεRI interactions and basophil degranulation 3.1. Inhibition of IgE binding to FcεRI-expressing RBL SX-38 cells 1×10 5RBL SX-38 cells were mixed with 400 ng / mL recombinant human IgE for 1 h on ice. After washing three times with 1% BSA / PBS, UB-221 and omalizumab were added to the cells at concentrations of 25,000 to 6 ng / mL and incubated on ice for 1 h. Finally, the cells were washed three times with 1% BSA / PBS and incubated with 0.75 μg / mL PE-labeled anti-human IgE (eBioscience, CN. 12-6986, Lot. E11877-1636) for 30 min on ice. The stained cells were analyzed on a FACS Verse cytometer after washing three times. As shown in Figure 3 (top), UB-221 inhibited omalizumab (IC) in competitive inhibition (mean ± SD, n=3) of IgE binding to FcεRI-expressing RBL SX-38. 50 It inhibited IgE binding with a three-fold advantage over naphthalene (0.035 vs. 0.106 mg / mL).

[0085] 3.2. RBL SX-38 degranulation assay β-hexosaminidase is a lysosomal enzyme released after stimulation and correlates well with histamine release, so it can be used to measure degranulation. RBL SX-38 cells (rat basophil cells expressing human FcεRI) were co-cultured with 1 μg / mL OVA-specific hIgE (AllerMAbs, CN:OVA8G9-02) and 0.002–15 μg / mL anti-IgE antibodies (UB-221 or omalizumab) for 2 h at 37°C. Afterwards, cells were washed twice with culture medium and degranulation was induced with OVA / Triton X-100 (10 μg / ml OVA in 1% Triton X-100) for 30 min. β-hexosaminidase in the cell supernatant was collected and reacted with 4-MUG in citric acid (4-methylumbelliferyl-N-acetyl-β-D-glucosaminide, Sigma-Aldrich, CN:M2133) for 1 hour. The resulting fluorescence (excitation 355 nm; emission 460 nm) was measured with a fluorescence reader. The percentage of degranulation was expressed as %β-hexosaminidase release. As shown in Figure 3 (lower panel), UB-221 was more potent than omalizumab (IC) in inhibiting degranulation of RBL SX-38 induced by IgE-specific ovalbumin (OVA)-IgE complex (mean ± SD, n=6). 50 The inhibitor showed a 7-fold inhibitory advantage over 0.14 vs 0.94 mg / mL.

[0086] Example 4: Reduction of serum humanized IgE in hIGHE-knockin mice treated with a single IV dose of UB-221 and omalizumab In human IgE knock-in C57BL / 6 mice, in which the genomic Cg1 and Ck constant regions were replaced by human Ce and Ck constant regions, the IgE-secreting B cells could produce much higher levels of humanized IgE than mouse IgE. In hIGHE knock-in mice (n=6) treated with a single ip dose of UB-221 or omalizumab at 0.3 or 3.0 mg / kg, it was observed that UB-221 induced a rapid reduction of serum free IgE by more than 90% at a low dose of 0.3 mg / kg, as shown in Figure 4, whereas a 10-fold higher dose (3.0 mg / kg) of omalizumab would be required to achieve this level of IgE reduction. Data are presented as mean ± SEM. *P < 0.05 indicates statistical significance.

[0087] Example 5: Ex vivo neutralization of hyper-IgE in serum of patients with atopic dermatitis The efficacy of UB-221, ligelizumab and omalizumab in reducing high IgE in the serum of 30 patients with atopic dermatitis was compared based on competitive inhibition of IgE binding to FcεRI immobilized in an ELISA. Collected serum samples were divided into three ranges of IgE: low IgE (<4,800 ng / mL, n=9), intermediate IgE (4,800-24,000 ng / mL, n=11) and high IgE (>24,000 ng / mL, n=10). Serum samples were incubated with three concentrations of anti-IgE mAbs. Comparisons were estimated by Mann-Whitney U test (P<0.001, ns=not significant). As a result, UB-221 and ligelizumab were equally effective in neutralizing serum IgE, whereas omalizumab was less effective as shown in Figures 5A to 5C. When using the low IgE group (Figure 5A), the mAb drug concentration that achieved a 50% reduction in IgE (EC 50 , mean ± SEM) were estimated to be 450 ± 100, 419 ± 100, and 1,647 ± 317 ng / mL for UB-221, ligelizumab, and omalizumab, respectively.

[0088] Example 6: Interaction of anti-IgE mAbs with CD23 in free or IgE complexed form 5 mg / mL CD23 (100 μL) was coated onto 96-well ELISA plates and blocked with PBS-0.5% BSA. For assay of mAb binding to CD23-bound IgE, 100 ng / mL IgE / (100 μL) in PBS-0.5% BSA was added and incubated for 1 h at RT. After washing, UB-221, omalizumab and ligelizumab serially diluted from 0.0001 to 100 μg / mL were added and incubated for 1 h at RT. Binding of anti-IgE mAbs was detected using goat anti-human IgG Fc-HRP (Jackson Immuno Research, Inc.). Binding of anti-IgE mAbs to CD23 in preformed IgE complexes was examined using the same ELISA with one modification: UB-221, omalizumab and ligelizumab (1.0–200 ng / mL) were incubated at room temperature for 1 h to allow complex formation, and the mixture was added to an ELISA plate with immobilized CD23, after which anti-IgE mAbs bound to CD23 were detected with goat anti-human IgG Fc-HRP.

[0089] In ELISA using immobilized CD23 preloaded with IgE, the free form of UB-221 showed strong binding to CD23-bound IgE in a concentration-dependent manner, as shown in Figure 6 (top panel), and showed EC 50 The EC values ​​(mean ± SD) of 38.4 ± 3.6 vs. 402 ± 47.3 ng / mL were estimated to be more than 10-fold higher than those of ligelizumab, but omalizumab was inactive. Preformed UB-221:IgE complexes also showed strong binding to CD23, as shown in Figure 6 (bottom), and their EC 50 was 41.6 ± 4.6 ng / mL, which was similar to that of CD23-bound IgE, whereas ligelizumab complexed with IgE completely lost its ability to bind to CD23, and the omalizumab:IgE complex was inactive against CD23.

[0090] Example 7: Reduction of de novo synthesis of IgE in human PBMCs by UB-221, ligelizumab and omalizumab Human PBMCs from healthy donors were stimulated with human recombinant IL-4 and anti-human CD40 antibodies to synthesize de novo IgE in the presence of UB-221, omalizumab or ligelizumab. In one study using PBMCs from 14 blood donors (n=14), the effect of UB-221, in comparison with omalizumab, on IgE production on days 7 and 11 using drug doses of (a) 1 μg / mL, (b) 3 μg / mL and (c) 10 μg / mL was tested. Another study with 3-5 blood donors focused on the effect of UB-221, omalizumab and ligelizumab on IgE production on day 11 using drug doses of (d) 10 μg / mL (n=3), (e) 20 μg / mL (n=5) and (f) 80 μg / mL (n=5). Total IgE in cell culture supernatant samples was quantified by ELISA. Percentage of IgE reduction was calculated by taking the IgE level of each untreated cell as 100%. Data are presented as mean ± SEM. Different treatments were compared relative to the untreated control group using two-way ANOVA with Tukey's multiple comparisons relative to the untreated control. *p < 0.05, **p < 0.01, ***p < 0.001.

[0091] The results shown in Figure 7A indicate that UB-221 is superior to omalizumab, with UB-221 demonstrating an 87%-94% reduction in total IgE at all dose levels of 1, 3, and 10 μg / mL, while omalizumab reduced IgE at a lower rate of 7.9%-53.5%. Additional studies at doses of 10, 20, and 80 μg / mL (Figure 7B) also confirmed the superiority of UB-221 over omalizumab, with UB-221 demonstrating a higher reduction of 69%-74% versus omalizumab's lower reduction of 4.9%-31%. Ligelizumab reduced IgE overall by 16%-31%, tending to show better reduction than omalizumab, although this was not statistically significant. Thus, UB-221 was superior to ligelizumab and omalizumab in downregulating CD23-mediated IgE production, consistent with the observation that UB-221 in free form binds well to CD23-bound IgE and that UB-221 in the form of an IgE:mAb complex binds freely to CD23, whereas ligelizumab reacts only to a limited extent and omalizumab is inactive against CD23 (Figure 6).

[0092] Example 8: UB-221 can bind to IgE and CD23-binding IgE in cynomolgus monkeys and can induce a rapid and significant decrease in serum IgE after a single IV administration UB-221 was able to bind to cIgE in cynomolgus monkeys (Figure 8A) and engage cCD23-bound cIgE in a dose-dependent manner (Figure 8B), demonstrating that cynomolgus monkeys can serve as a suitable animal model for pharmacology and toxicology. In cynomolgus monkeys (n=3) administered a single IV dose of 5.0 mg / kg UB-221, the antibody was reduced in serum with a mean elimination half-life of 6.3 days (Figure 8C), and UB-221 was able to induce a rapid and significant reduction in serum free cIgE from a basal level of approximately 400 ng / mL to 90%-100% (Figure 8D). Basal IgE levels were 434, 399, and 411 ng / mL for cynomolgus monkeys No. 1, No. 2, and No. 3, respectively.

[0093] Example 9: A first-in-human Phase 1 clinical trial design demonstrated that UB-221 was safe, well tolerated, and capable of inducing long-lasting (3-6 months) disease-improving effects (UAS7 and HSS7 scores) in patients with chronic idiopathic urticaria treated with a single IV dose A phase 1 single-dose ascending study of UB-221 by IV injection as add-on therapy was conducted to evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) in subjects with chronic idiopathic urticaria (CSU) being treated with first-line H1-antihistamines. A total of 15 subjects from two study sites in Taiwan were enrolled and assigned to one of five cohorts to receive UB-221 by single IV injection at doses of 0.2 mg / kg (cohort 1), 0.6 mg / kg (cohort 2), 2.0 mg / kg (cohort 3), 6.0 mg / kg (cohort 4) and 10 mg / kg (cohort 5) (Figure 9). All 15 subjects enrolled were Asian, 8 males and 7 females, aged 21-72 years and weighing 49.0 kg-87.6 kg. Two scoring systems were used to rate signs and symptoms of CSU: 1) UAS7 (Urticaria Activity Score), which rates the number of wheals and the intensity of pruritus each day over a 7-day period, on a scale of 0 to 3; and 2) HSS7 (Wheal Severity Score), which rates the number of wheals each day over a 7-day period, on a scale of 0 to 3. Of the 15 subjects, baseline CSU was severe in 9 (UAS7 score 28-42), moderate in 4 (UAS7 score 16-27), and mild in 2 (UAS7 score 7-15).

[0094] UB-221 was safe and well tolerated. All 15 subjects completed the study. No patients discontinued treatment, discontinued, or were lost to follow-up. No dose-limiting toxicities were observed, so the 10 mg / kg dose level in Cohort 5 was determined as the maximum tolerated dose. Most of the 39 therapeutic-emergent adverse events (TEAEs) were mild or moderate and unrelated to UB-221. Doses of 2.0 mg / kg and above produced long-lasting suppression of disease symptoms for more than 2 months.

[0095] Example 10: Serum concentration curves and pharmacokinetic profiles in urticaria patients after administration of a single IV injection of UB-221 A neutralizing anti-UB-221 idiotypic monoclonal antibody capable of specifically binding to UB-221 was used as a capture antibody coated onto a plate, and serum concentrations of UB-221 after a single IV injection were measured by ELISA. Mouse anti-human IgG Fc-HRP was used as the detection antibody. The results demonstrated that the duration of UB-221 exposure was dose-dependent. The half-life of UB-221 was estimated to be in the range of 16-22 days at doses of 0.6-10 mg / kg (Figure 10).

[0096] Example 11: Efficacy score UAS in urticaria patients treated with UB-221 11.1 Urticaria Activity Score for 7 days (UAS7) Another efficacy marker of UB-221 is assessed by alleviation of disease symptoms as change in UAS7 from baseline. Individual weekly changes in disease score UAS7 in each of the five dosing cohorts over 14 weeks are shown in Figure 11A. Mean values ​​(mean ± SD) were calculated from three subjects (n = 3) in each dosing cohort (Figure 11B). Higher UAS7 scores indicate greater disease severity. The results showed that in all 13 subjects with severe to moderate CSU (UAS7 score ≥ 16) at baseline, a rapid decline in UAS7 occurred in the first week after receiving a single dose of UB-221 IV injection. In subjects with mild CSU, such as the subject in cohort 5 who had a baseline UAS7 score of 14, the response was delayed until 8 weeks after receiving a single dose of 10 mg / kg UB-221. Symptom relief to a well-controlled / disease-free stage (UAS7≦6) appeared dose-dependent and was achieved in 10 of 15 subjects (Figure 11A). Notably, all three patients in cohort 3 (2 mg / kg) and all three patients in cohort 4 (6 mg / kg) maintained a disease-free stage, i.e., complete response (UAS7=0), for 2-14 weeks of follow-up. A single dose of UB-221 retained the possibility of achieving a mean score of UAS7≦6 (disease well controlled) (Figure 11B), suggesting that a single dose of >2 mg / kg can effectively suppress the disease for a period of 3-6 months.

[0097] 11.2 Daily changes in UAS disease scores The UAS scores of three subjects per cohort were collected daily and averaged. The average value of each day after injection was compared with the baseline value, which was the average value of the daily UAS scores from the same subjects over the 7 days before UB-221 injection. The results are shown in Table 2 and Figure 11C. [Table 2]

[0098] This profile suggested that UAS disease scores declined rapidly from day 1 onwards, and CSU patients experienced rapid symptom relief within 24 hours after UB-221 administration.

[0099] Example 12: Efficacy score HSS7 in urticaria patients treated with UB-221 One efficacy marker for UB-221 is assessed by alleviation of disease symptoms as the change from baseline in 7-day wheal severity score (HSS7). Individual weekly changes in disease score HSS7 in each of the five dose cohorts over 14 weeks are shown in Figure 12A. Mean values ​​(mean ± SD) were calculated from three subjects (n = 3) in each dose cohort (Figure 12B). Higher HSS7 scores indicate higher disease severity. As a result, in all subjects, HSS7 scores were similar to UAS7 scores (Figures 11A-11C). A rapid reduction in HSS7 scores occurred during the first week of receiving a single IV injection of UB-221. Reduction of symptoms to a well-controlled / disease-free stage (HSS7 < 6) appeared dose-dependent and was achieved in 12 of 15 subjects (Figure 12A). In particular, two patients in cohort 1 (0.2 mg / kg), two in cohort 2 (0.6 mg / kg), all three in cohort 3 (2 mg / kg), all three in cohort 4 (6 mg / kg), and two in cohort 5 (10 mg / kg) remained disease-free, i.e., in complete response (HSS7=0), for 2 to 14 weeks during follow-up. Similar to the effect on HSS7 score, a single dose of UB-221 ensured the possibility of achieving a mean score of HSS7≦6 (disease well controlled) (Figure 12B), suggesting that a single dose of >2 mg / kg can suppress the disease well for 3 to 6 months.

[0100] Example 13: Serum concentrations of free IgE in urticaria patients treated with UB-221 Single intravenous administration of UB-221 to patients with urticaria can induce a rapid and substantial decrease in serum free IgE (Figure 13). Serum free IgE was measured by ELISA using a recombinant FcεRIα-IgG.Fc fusion protein as a capture protein, followed by addition of streptavidin-poly HRP for signal enhancement after a biotinylated mouse anti-human IgE monoclonal antibody. The lower limit of quantification (LLOQ) of free IgE was 24 ng / mL. The range of free IgE concentrations at baseline before UB-221 injection was 3999 - 272 ng / mL in cohort 1 (0.2 mg / kg), < 1015 - 24 ng / mL in cohort 2 (0.6 mg / kg), 129 - 697 ng / mL in cohort 3 (2 mg / kg), 48.9 - 233 ng / mL in cohort 4 (6 mg / kg) and < 593 - 24 ng / mL in cohort 5 (10 mg / kg). For all 15 subjects, serum IgE was completely neutralized by UB-221 within 4 hours after UB-221 injection (free IgE level < LLOQ). Complete IgE neutralization persisted for 2 - 22 days in cohort 1 (0.2 mg / kg), 15 - 99 days in cohort 2 (0.6 mg / kg), 29 - 85 days in cohort 3 (2 mg / kg), > 99 days in cohort 4 (6 mg / kg) and > 85 - 99 days in cohort 5 (10 mg / kg). These data suggest that the efficacy of UB-221 is potent and long-lasting.

[0101] Example 14: Concurrent changes in serum UB-211 concentration, serum free IgE level and UAS7 disease score in patients with urticaria after single intravenous administration of UB-221 The mean serum concentration of UB-221, serum free IgE levels and UAS7 disease scores are shown simultaneously for subjects enrolled in each of the five dose cohorts over the 14-week single-dose study period. Means (mean values) with SD were calculated from three subjects (n=3) in each cohort. There is a good correlation between these three parameters, with higher serum concentrations of UB-221 resulting in more complete suppression of serum free IgE levels and a longer sustained reduction in UAS7 disease scores (Figure 14). This dose-dependent correlation suggests that in the treatment of chronic idiopathic urticaria (CSU), a disease in which serum IgE levels play an important role, UB-221 administered every 3-6 months at a single IV dose of >2.0 mg / kg can be used to treat patients with complete response (UAS7=0) or well-controlled stage (UAS7=0). < It was suggested that 6) can be achieved.

[0102] conclusion The present invention relates to the discovery that the UB-221 monoclonal antibody, a humanized anti-IgE IgG1 expressed in a CHO-S cell line, can be administered every 3-6 months to effectively treat IgE-associated chronic idiopathic urticaria. This has been demonstrated in a Phase 1 study (Example 9) of a single dose of UB-221, with supporting results (Examples 9-14). This less frequent administration regime of every 3 months (12 weeks) or 6 months (24 weeks) is in contrast to the other two anti-IgE mAbs, omalizumab, which is the only one approved, and ligelizumab, which was not developed in Phase 3 trials, which are administered every 4 weeks in the management of CSU. 24 .

[0103] The usefulness of less frequent dosing regimens is due to the unique binding and functional profile of UB-221 compared to omalizumab and ligelizumab. UB-221 binds IgE with strong affinity (Examples 1 and 2) and is superior to omalizumab in neutralizing IgE (Example 3) and reducing free IgE in treated hIGHE-knock-in mouse serum (Example 4). UB-221 and ligelizumab neutralize high serum IgE in atopic dermatitis patients with comparable potency, while omalizumab is less potent (Example 5). In cynomolgus monkeys, a single dose of UB-221 can rapidly and significantly reduce serum IgE levels (Example 8). These findings indicate that UB-221 functions as a potent IgE neutralizer.

[0104] UB-221 mAb is a novel humanized anti-IgE IgG1 antibody, which differs from omalizumab and ligelizumab in its mode of interaction with CD23. UB-221 binds to CD23-bound IgE in free form and acts on CD23 without restriction in the form of an IgE:mAb complex, whereas ligelizumab and omalizumab are restricted in both modes of indirect interaction with CD23 (Example 6). This correlates with the finding that UB-221 downregulates the maximal level of CD23-mediated de novo IgE synthesis in human PBMCs (Example 7). These findings suggest that UB-221 is a multifunctional anti-IgE antibody that functions not only as a potent IgE neutralizer but also as an effective IgE synthesis inhibitor, 1) by sweeping circulating soluble free IgE and IgE:CD23 complexes, 2) by forming UB-221:IgE complexes, and 3) by passing the UB-221:IgE complexes through the epithelial cells of the gastrointestinal lumen and bronchoalveolar epithelium, thereby removing IgE:allergen complexes and IgE:autoantibody complexes. 23 CD23 has been shown to be an efficient IgE trapper. CD23 is expressed on many types of cells. 10 On the other hand, omalizumab and ligelizumab act primarily as IgE neutralizers.

[0105] The unique properties of UB-221, which acts as a dual agent as a potent IgE neutralizer and potent IgE synthesis inhibitor, are associated with its potent IgE downregulation and long-term disease-modifying effects in the treatment of urticaria. The less frequent dosing regimen, i.e., every 3 months (12 weeks) or 6 months (24 weeks), can be applied to a variety of IgE-mediated or IgE-associated allergic and non-allergic diseases.

[0106] References 1.Awankar R. Allergic diseases and asthma: a global public health concern and a call to action. World Allergy Organ J. 2014;7:12. doi: 10.1186 / 1939-4551-7-12 2.Dierick BJH, van der Molen T, Flokstra-de Blok BMJ, Muraro A, Postma MJ, JWH Kocks, van Boven JFM. Burden and socioeconomics of asthma, allergic rhinitis, atopic dermatitis and food allergy. Expert Rev Pharmacoeconomics Outcomes Res. 2020;20:437-453. 3.Bantz SK, Zhu Z, Zheng T. The atopic march: progression from atopic dermatitis to allergic rhinitis and asthma. J Clin Cell Immunol. 2014;5:202. doi: 10.4172 / 2155-9899.1000202 4.Hill DA, Spergel JM. The atopic march-Critical evidence and clinical relevance. Ann Allergy Asthma Immunol. 2018;120: 131-137. 5.Paller Amy SAS. The atopic march and atopic multimorbidity: many trajectories, many pathways. J Allergy Clin Immunol. 2019;143:6-55. 6.Kinet J-P. The high-affinity IgE receptor (FcεRI): from physiology to pathology. Annu Rev Immunol 1999;17:931-972. 7.Conrad DH. FcεRII / CD23: the low affinity receptor for IgE. Annu Rev Immunol 1990;8:623-645. 8.Gould HJ, Sutton BJ. IgE in allergy and asthma today. Nat Rev Immunol 2008;8(3):205-217. 9.Sutton BJ, Davies AM. Structure and dynamics of IgE-receptor interaction:FcεRIand CD23 / FceRII. Immnol. Rev. 2015;268:222-235. 10.Acharya, M. et al. CD23 / FcεRII: molecular multi-tasking. Clin. Exp. Immunol. 2010;162:12-23. 11.Conrad, D. H., Ford, J. W., Sturgill, J. L. and Gibb, D. R. CD23: an overlooked regulator of allergic disease. Curr. Allergy Asthma Rep. 2007;7:331-337. 12.Kelly AE, Chen B-H, Woodward EC, Conrad DH. Production of a chimeric form of CD23 that is oligomeric and blocks IgE binding to the FcεRI. J Immunol 1998;161:6696-6704. 13.Schwartz C, Turqueti-Neves A, Hartmann S, Yu P, Nimmerjahn F, Voehringer D. Basophil-mediated protection against gastrointestinal helminths requires IgE-induced cytokine secretion. Proc Natl Acad Sci USA 2014;111:E5169-5177. 14.Ferastraoaru D, Jordakieva G, Jensen-Jarolim E. The other side of the coin: IgE deficiency, a susceptibility factor for malignancy occurrence. World Allergy Organization J. 2021;14:100505. http: / / doi.org / 10.1016 / j.waojou.2020.100505 15.Xolair FDA Approval History. Drug.com https: / / www.drugs.com / history / xolair.html 16. Guntern P, Eggel A. Past, present, and future of anti-IgE biologics. Allergy 2020;75:2491-2502. 17. Balbino B, Conde E, Marichal T, Starkl P, Reber LL. Approaches to target IgE antibodies in allergic diseases. Pharmacol. Ther. 2018;191:50-64. [ PMC free article ] [ PubMed ] [ Cross Ref ] 18. Pharmacokinetics, pharmacodynamics and safety of QGE031 (ligelizumab), a novel high-affinity anti-IgE antibody in atopic subjects. Clin Exp Allergy 2014;44:1371–1385. [ PubMed ] 19. Maurer M, Gimenez-Arnau AM, Sussman G, Metz M, Baker DR, et al. Ligelizumab for chronic spontaneous urticaria. New Engl J Med. Rev. 2019;381:1321–1 20. Gasser P, Tarchevkaya SS, Guntern P, Brigger D, Ruppli R, et al. The mechanistic and functional profile of the therapeutic anti-IgE antibody ligelizumab differs from omalizumab. Nat Communication 2020;11:165 DOI: 10.1038 / s41467-019-13815-w [ PubMed ] 21. Chen JB, Ramadani F, Pang MOY, Rebecca L. Beavil RL, et al. Structural basis for selective inhibition of immunoglobulin E-receptor interactions by an anti-IgE antibody. Sci Rep. 2018;8:11548. DOI:10.1038 / s41598-018-29664-4. 22. Shiung Y-Y, Chiang C-Y, Chen J-B, Wu PC, Hung AF-H, et al. An anti-IgE monoclonal antibody that binds to IgE on CD23 but not on high-affinity IgE.Fc receptors. Immunobiol. 2012;217:676-683. 23. Tu Y, Salim S, Bourgeois J, et al. CD23-Mediated IgE Transport Across Human Intestinal Epithelium: Inhibition by Blocking Sites of Translation or Binding", Gasgtroenterol. 2005; 129:928-940. 24. Maurer M, Eggel A, Bernstein JA, Gimenez AM, Soong W. Breakthrough in the understanding of the anti-IgE pathway in chronic spontaneous urticaria and the potential of ligelizumab. EMJ Allerg Immuno, 2020;5:20-27.

Claims

1. A pharmaceutical composition for the treatment of an IgE-mediated disease, comprising an anti-IgE antibody, wherein the antibody is a multifunctional antibody against IgE that neutralizes IgE and inhibits IgE synthesis.

2. The pharmaceutical composition of claim 1, administered in an amount effective to provide rapid and / or sustained symptomatic relief of an IgE-mediated disease.

3. 2. The pharmaceutical composition of claim 1, wherein the antibody binds to free IgE, membrane-bound IgE on B lymphocytes and / or IgE bound to CD23, but does not bind to IgE bound to FcεRI on mast cells.

4. The pharmaceutical composition of claim 1 , wherein the antibody binds to CD23-bound IgE in a free form and to CD23 in an IgE-complexed form.

5. The pharmaceutical composition of claim 1 , wherein the antibody is an antigen-binding fragment thereof.

6. The pharmaceutical composition of claim 1 , wherein the antibody is humanized.

7. The antibody or antigen-binding fragment is (a) a heavy chain variable region (V) comprising a heavy chain complementarity determining region 1 (HC CDR1) comprising the amino acid sequence of SEQ ID NO: 2, a heavy chain complementarity determining region 2 (HC CDR2) comprising the amino acid sequence of SEQ ID NO: 4, and a heavy chain complementarity determining region 3 (HC CDR3) comprising the amino acid sequence of SEQ ID NO: 6; H ); and (b) a light chain variable region (V) comprising a light chain complementarity determining region 1 (LC CDR1) comprising the amino acid sequence of SEQ ID NO: 9, a light chain complementarity determining region 2 (LC CDR2) comprising the amino acid sequence of SEQ ID NO: 11, and a light chain complementarity determining region 3 (LC CDR3) comprising the amino acid sequence of SEQ ID NO: 13; L ), 2. The pharmaceutical composition of claim 1, comprising:

8. V H comprises the amino acid sequence of SEQ ID NO: 15; and / or V L The pharmaceutical composition of claim 7, wherein the amino acid sequence of SEQ ID NO: 16 is included.

9. 3. The pharmaceutical composition of claim 2, wherein the symptomatic relief includes a reduction in IgE, relief of itching, and / or a reduction in the number of wheals.

10. 3. The pharmaceutical composition of claim 2, wherein symptomatic relief persists for 2 to 14 weeks or longer after administration.

11. 3. The pharmaceutical composition of claim 2, wherein relief of symptoms occurs within one week or sooner after administration.

12. 10. The pharmaceutical composition of claim 1, wherein the antibody is administered every 2 weeks to 14 weeks or less frequently.

13. 10. The pharmaceutical composition of claim 1, wherein the antibody is administered every four weeks or less frequently.

14. The pharmaceutical composition of claim 1, wherein the antibody is administered every 12 to 24 weeks.

15. 10. The pharmaceutical composition of claim 1, wherein the antibody is administered at a dose of 0.1 to 10 mg per kg of the subject's body weight.

16. 10. The pharmaceutical composition of claim 1, wherein the antibody is contained in the composition in a total dose and is administered to the subject in a single dose.

17. 10. The pharmaceutical composition of claim 1, wherein the antibody is administered by either intravenous or subcutaneous injection.

18. 2. The pharmaceutical composition of claim 1, wherein the IgE-mediated disease is allergic asthma, allergic rhinitis, atopic dermatitis, food allergy, chronic idiopathic urticaria, chronic sinusitis, systemic mastocytosis, cutaneous mastocytosis, allergic bronchopulmonary aspergillosis, recurrent idiopathic angioedema, or eosinophil-associated gastrointestinal disorder.

19. 1. Use of an anti-IgE antibody for the manufacture of a medicament for treating an IgE-mediated disease, wherein the antibody is a polyfunctional antibody against IgE that neutralizes IgE and inhibits IgE synthesis.

20. 20. The use of claim 19, which provides rapid and / or sustained symptomatic relief in a subject.

21. the antibody binds to free IgE, membrane-bound IgE on B lymphocytes and / or IgE bound to CD23, but does not bind to IgE bound to FcεRI on mast cells; the antibody binds to CD23-bound IgE in its free form and to CD23 in its IgE-complexed form; the antibody is an antigen-binding fragment thereof; the antibody is humanized; and / or The antibody or antigen-binding fragment is (a) a heavy chain variable region (V) comprising a heavy chain complementarity determining region 1 (HC CDR1) comprising the amino acid sequence of SEQ ID NO: 2, a heavy chain complementarity determining region 2 (HC CDR2) comprising the amino acid sequence of SEQ ID NO: 4, and a heavy chain complementarity determining region 3 (HC CDR3) comprising the amino acid sequence of SEQ ID NO: 6; H ); and (b) a light chain variable region (V) comprising a light chain complementarity determining region 1 (LC CDR1) comprising the amino acid sequence of SEQ ID NO: 9, a light chain complementarity determining region 2 (LC CDR2) comprising the amino acid sequence of SEQ ID NO: 11, and a light chain complementarity determining region 3 (LC CDR3) comprising the amino acid sequence of SEQ ID NO: 13; L ), Preferably, V H comprises the amino acid sequence of SEQ ID NO: 15; and / or Preferably, V L comprises the amino acid sequence of SEQ ID NO: 16; 20. The use according to claim 19.

22. symptom relief including reduced IgE, reduced itching and / or reduced wheal count; relief of symptoms lasts for 2 to 14 weeks or more after administration; and / or Symptom relief occurs within 1 week or sooner after administration 21. The use according to claim 20.

23. the antibody is administered every 2 weeks to 14 weeks or less frequently; the antibody is administered every 4 weeks or less frequently; The antibody is administered every 12 to 24 weeks; the antibody is administered at a dose of 0.1 to 10 mg / kg of the subject's body weight; the antibody is contained in a composition in its entirety and administered to the subject in a single dose; and / or 20. The use of claim 19, wherein the antibody is administered by either intravenous or subcutaneous injection.

24. 20. The use according to claim 19, wherein the IgE-mediated disease is allergic asthma, allergic rhinitis, atopic dermatitis, food allergy, chronic idiopathic urticaria, chronic sinusitis, systemic mastocytosis, cutaneous mastocytosis, allergic bronchopulmonary aspergillosis, recurrent idiopathic angioedema or eosinophil-associated gastrointestinal disorder.

25. 1. Use of an anti-IgE antibody for the manufacture of a medicament for treating an IgE-mediated disorder and providing rapid and / or sustained symptomatic relief in a subject in need thereof, comprising: The antibody (a) a heavy chain variable region (V) comprising a heavy chain complementarity determining region 1 (HC CDR1) comprising the amino acid sequence of SEQ ID NO: 2, a heavy chain complementarity determining region 2 (HC CDR2) comprising the amino acid sequence of SEQ ID NO: 4, and a heavy chain complementarity determining region 3 (HC CDR3) comprising the amino acid sequence of SEQ ID NO: 6; H ); and (b) a light chain variable region (V) comprising a light chain complementarity determining region 1 (LC CDR1) comprising the amino acid sequence of SEQ ID NO: 9, a light chain complementarity determining region 2 (LC CDR2) comprising the amino acid sequence of SEQ ID NO: 11, and a light chain complementarity determining region 3 (LC CDR3) comprising the amino acid sequence of SEQ ID NO: 13; L ) and The use wherein the antibody is administered in a single dose every four weeks or less frequently.

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