Aptamers, pharmaceutical compositions thereof, and methods for preventing or treating BCMA-related diseases or disorders

Abstract

Provided herein, in certain embodiments, are compositions, recombinant nucleotides, kits, and methods that target or are specific for BCMA that are useful for the prevention or treatment of BCMA-related diseases, such as chronic inflammatory skin diseases or conditions. In some embodiments, an aptamer is provided that includes a nucleotide sequence having at least about 80%, 85%, 90%, 95%, or 100% sequence identity to any of SEQ ID NO.1-18, or a variant or fragment thereof. Other example embodiments are described herein. In certain embodiments, the provided compositions, recombinant nucleotides, kits and methods are extremely effective in the treatment of chronic inflammatory skin diseases, are easy to manufacture and store, and are safer to use.

Description

Cross - Reference to Related Applications

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 604,153, filed on November 29, 2023, under 35 U.S.C.§119(e), the entire content of which is hereby incorporated by reference herein. Reference to Sequence Listing

[0002] This application contains a sequence listing that has been submitted electronically in accordance with 37 C.F.R.§1.821(e) and is hereby incorporated by reference in its entirety. The copy of the 37 C.F.R.§1.821(e) compliant sequence listing created on October 31, 2024, is named "A069.0000.001.PATCN.xml" and is 26 kilobytes in size. Technical Field

[0003] This application relates to compositions, recombinant nucleotides, kits, and methods for preventing or treating BCMA - related diseases or disorders (such as chronic inflammatory skin diseases or disorders). Specifically, this application relates to compositions, recombinant nucleotides, kits, and methods for preventing or treating BCMA - related diseases or disorders (such as chronic inflammatory skin diseases or disorders). Background Art

[0004] Chronic inflammatory skin diseases remain a heavy burden on patients due to their impact on quality of life, and it is estimated that 20% - 25% of the world's population is affected by these diseases. Although there are many chronic inflammatory skin diseases, the two most common are eczema (atopic dermatitis) and psoriasis. Eczema mainly occurs in children and is less prevalent in the elderly population. There are also cases of adult - onset eczema, but the incidence is low. In contrast, psoriasis is mainly seen in adults. Both of these diseases are caused by inflammation resulting from immune dysfunction. Genotypic and environmental stimuli such as infections, allergens, stress, drugs, and trauma are considered potential causes of these diseases. These stimuli cause the expression of chemokines and cytokines, leading to the infiltration of immune cells. The infiltration of immune cells, followed by exposure to an inflammatory environment, causes these new immune cells to activate and further leads to inflammatory events. This, in turn, results in the spread of an inflammatory feedback loop and severely affects the quality of life of patients.

[0005] Multiple therapies can be used to attempt to treat or prevent eczema and psoriasis, and the therapies act by targeting various aspects of the diseases. The first-line therapies for both diseases involve corticosteroids. Broadly speaking, corticosteroids affect gene transcription through various mechanisms and with different clinical benefits. Both methotrexate and acitretin can inhibit skin thickening associated with eczema and psoriasis. Cyclosporine blocks the production of cytokines to reduce T-cell activation, which is a key driver of the inflammatory cascade. Dexamethasone inhibits the migration of immune cells, thereby reducing the number of cells involved in inflammation. Another corticosteroid, desonide, blocks gene transcription to reduce the expression of inflammatory proteins.

[0006] Small molecule inhibitors are another class of drugs that are used in combination with existing first-line therapies or as second-line therapies. Small molecule inhibitors (SMIs) target proteins associated with the inflammatory cell signaling cascade. By binding to the protein and inhibiting its activity, the downstream signaling pathways are dysregulated, and subsequently, the gene expression profile is altered. SMIs are easy to administer in oral form, but due to the drug circulating systemically, systemic side effects are a concern.

[0007] Another therapeutic option is monoclonal antibodies. These treatment regimens rely on modulating the immune system by using monoclonal antibodies. Monoclonal antibodies have high binding specificity for cytokine receptors, thereby blocking receptor-ligand interactions or inflammatory cytokines. In both cases, the inflammatory activity of the cytokine is inhibited. Although the remission rate of monoclonal antibody treatment is extremely high, long-term treatment carries the risk of infusion reactions or an increased risk of infection.

[0008] Currently, much of the drug development for chronic skin inflammation focuses on inhibiting specific targets in the inflammatory signaling cascade. This can be achieved by inhibiting specific enzymes involved in cell signaling or by targeting cytokines. All available treatment methods have limitations, mainly due to side effects that occur with long-term use. Therefore, there is an urgent need to use different methods to target the target aspects of the inflammatory cascade.

[0009] Chronic inflammatory skin diseases are characterized by feedback loops involving cytokines. These cytokines attract immune cells to the area and then induce the expression of inflammatory cytokines, thereby attracting additional immune cells. Inflammation leads to the development of skin lesions. Due to the feedback loops, there are many therapeutic targets in this background environment.

[0010] Targeting the inflammatory cascade can occur in different ways. One current approach is the use of monoclonal antibodies. Antibodies are proteins with high binding specificity and affinity for ligands. The ligand can be a cytokine that prevents signal transduction between cells, or it can be a receptor that blocks the cell's response to cytokine stimulation. There are two additional mechanisms for binding to a receptor: inhibiting the receptor's ability to interact with its ligand or inducing internalization of the receptor so that it cannot bind to the ligand.

[0011] One of the problems with available therapies is the emergence of side effects after long-term use. Long-term topical application of corticosteroids can lead to epidermal thinning, increased capillary permeability, ulcer formation, and other visible side effects. For all treatment options, one of the concerns is bacterial or viral infection. The immune response to infection or injury is the cause of inflammation. Systemic drugs (e.g., oral small molecule inhibitors or monoclonal antibodies) target the inflammatory cascade and attenuate the response to infection. Additionally, infusion reactions can occur during the administration of monoclonal antibodies. Due to these problems, there is a need for an alternative treatment strategy that can be used long-term with minimal potential side effects. SUMMARY OF THE INVENTION

[0012] Disclosed herein are novel compositions, recombinant nucleotides, their sense and antisense strands and their sequences, kits, and methods that target BCMA or are specific for BCMA and can be used to prevent or treat BCMA-related diseases, such as chronic inflammatory skin diseases or disorders.

[0013] In some embodiments, provided herein are compositions and methods for highly selective delivery of nucleic acid sequences for alleviating skin inflammation. More specifically, in some embodiments, provided herein are single-stranded DNA aptamers that include nucleic acid sequences targeting B cell maturation antigen (BCMA, CD269, TNFRSF17) expressed on the cell surface. By targeting cell surface BCMA, the aptamer can inhibit inflammation associated with chronic skin inflammation. In some embodiments, an aptamer is provided that includes a nucleotide sequence having at least 80% sequence identity to any one of SEQ ID NOs.: 1-18 or a fragment thereof.

[0014] The present invention has many advantages. In some embodiments, the provided aptamers are extremely stable as they can be stored for long periods in a lyophilized state. Since aptamers are chemically synthesized, it is easy to scale up any production process while maintaining a lower manufacturing cost compared to antibodies. When it comes to therapeutic use, the size of the provided aptamers provides a major benefit as it results in a much smaller injection volume due to their high solubility. In terms of safety, the provided aptamers show lower toxicity in vitro.

[0015] This invention describes a single-stranded DNA (ssDNA) molecule for treating chronic skin inflammation. Specifically, the molecule consists of an aptamer that targets cells of interest in vivo. This invention also provides a method for treating chronic skin inflammation by targeting BCMA-expressing cells.

[0016] In another embodiment, the present invention inhibits or attenuates gene expression of desired cells by an aptamer DNA molecule, wherein the molecule has a high affinity for cells expressing a unique cell surface marker and expresses a cell product associated with inflammation. The desired cells can range from keratinocytes, dendritic cells, macrophages, T cells, etc. The cell product can include gene or protein targets, such as one of the following: TSLP, IL-1β, IL-6, IL-19, IL-36a, IL-36b, IL-22, GM-CSF, TNF-α, IL-4, IL-33, IL-13, IL-23A, IL-17A, IL-17C, IL-17F, LCN2, CD31, VEGF-A, Ang-1, Ang-2, S100A8, S100A9, MCL-1.

[0017] In another embodiment, a method of administering a therapeutic dose of an ssDNA aptamer, wherein the aptamer has a high binding affinity, is specific for BCMA, and can bind to BCMA expressed on the cell surface. Cells expressing BCMA can include skin tissue-related cells of the following subtypes: keratinocytes, dendritic cells, plasma cells, and macrophages.

[0018] In another embodiment, a therapeutic dose of a BCMA-targeting aptamer inhibits the expression of various inflammatory cytokines expressed in skin tissue during inflammation. Examples of these cytokines can be one of the following: TSLP, IL-1β, IL-6, IL-19, IL-36a, IL-36b, IL-22, GM-CSF, TNF-α, IL-4, IL-33, IL-13, IL-23A, IL-17A, IL-17C, and IL-17F.

[0019] In one aspect, the aptamer can target BCMA and is specific for cells expressing BCMA. The ssDNA aptamer has sequences SEQ ID NO.: 1 to SEQ ID NO.: 18. Aptamer candidates are identified by bead-based SELEX and screened to select sequences with the best BCMA binding activity. When binding to BCMA, the aptamer can inhibit the BCMA ligand signaling pathway or induce internalization of the aptamer-BCMA complex.

[0020] In one aspect, the BCMA-targeting aptamer can have various nucleotide substitutions and one or more modifications to the sugar-phosphate backbone to confer nuclease resistance. Nucleoside substitutions can include at least one of the following or a combination thereof: uracil, inverted dT, purine, xanthine, 2,6-diaminopurine, 8-oxo-N6-methyladenine, 7-deazaxanthine, 7-deazaguanine, N4,N4-ethanocytosine, N6,N6-ethano-2,6-diaminopurine, 5-methylcytosine, 5-(C3-C6)-alkynylcytosine, 5-fluorouracil, 5-bromouracil, pseudoisocytosine, 2-hydroxy-5-methyl-4-triazolopyridine, isocytosine, isoguanine, inosine, non-naturally occurring nucleobases, their variants, mutants, and analogs. Preferably, the sugar-phosphate backbone modifications include 2'-O-methylation, locked nucleic acid (LNA), peptide nucleic acid (PNA), phosphorothioate, boranophosphate ester, methylphosphonate, 2'-fluoro, 2'-O-methoxyethyl, or 4'-thio.

[0021] To increase serum half-life, cellular internalization, or inhibit nuclease activity, the BCMA-targeting aptamer can be linked to one or more chemical structures. Preferably, the additional chemical structures include at least one of the following: cholesterol, cholesteryl, inverted dT, phosphatidylcholine, phosphatidylethanolamine, spermine, sialic acid, histidyl poly(lysine), palmitoyl-D-glucuronide, polyethylene glycol, polyrotaxane, chlorogenic acid chitosan, listeriolysin O, or tributylphenolol. Preferably, the additional one or more chemical structures are conjugated through one or more of the following spacers or linkers: C12 spacer, C9 spacer, C6 spacer, C3 spacer, spacer 18 (hexaethylene glycol), spacer 9, d spacer (dSpacer), r spacer (rSpacer), amino linker, carboxyl linker, or thiol linker. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 Showing the results of an enzyme-linked oligonucleotide assay (ELONA) in which the BCMA binding specificity of aptamer candidates was tested.

[0023] Figure 2 Is a set of curves generated by ELONA that show the binding affinities of three selected exemplary aptamers: SEQ ID NO.: 1–3.

[0024] Figure 3 Is a pair of images of a denaturing polyacrylamide gel that shows the stability of an exemplary aptamer (SEQ ID NO.: 3) after incubation in mouse serum or medium + 10% FBS for a specified time.

[0025] Figure 4A set of images of denatured polyacrylamide that compares the stability of unmodified and modified versions of an exemplary aptamer based on SEQ ID NO.: 6 (the exemplary modified aptamer is represented by SEQ ID NO.: 16) after incubation in fetal bovine serum for an incubation period.

[0026] Figure 5 A graph determined by ELONA that shows the binding affinity curve of the modified exemplary aptamer SEQ ID NO.: 16.

[0027] Figure 6 A graph depicting the gene expression levels of macrophage markers selected when the exemplary aptamers of SEQ ID NO.: 2 - 3 are used to inhibit the immunostimulatory effect of LPS.

[0028] Figure 7 A graph depicting the Psoriasis Area and Severity Index (PASI) in an IMQ - induced psoriasis mouse model after subcutaneous treatment with a modified exemplary aptamer based on SEQ ID NO.: 3 (the modified exemplary aptamer is represented by SEQ ID NO.: 17) or SEQ ID NO.: 6 (the modified exemplary aptamer is represented by SEQ ID NO.: 18).

[0029] Figure 8 A graph depicting the change in skin thickness of mouse skin in an IMQ - induced psoriasis mouse model after subcutaneous treatment with the modified exemplary aptamers SEQ ID NO.: 17 or SEQ ID NO.: 18.

[0030] Figure 9 A series of representative photographs of the dorsal skin of mice. A vehicle or the modified exemplary aptamers of SEQ ID NO.: 17 or SEQ ID NO.: 18 were administered subcutaneously to an IMQ - induced psoriasis mouse model.

[0031] Figure 10 Is a graph depicting DNFB The eczema area and severity index in a DNFB - induced eczema mouse model. The exemplary aptamers of SEQ ID NO.: 17 and SEQ ID NO.: 18 were administered as subcutaneous treatment options.

[0032] Figure 11 A series of representative images in a DNFB - induced eczema mouse model. A vehicle or the modified exemplary aptamer SEQ ID NO.: 17 or SEQ ID NO.: 18 was administered subcutaneously to DNFB - induced mice.

[0033] Figures 12A - 12BA series of graphs showing the frequency and duration of the itch response in a DNFB-induced eczema mouse model. Two groups of mice were administered the modified exemplary aptamers SEQ ID NO.:17 and SEQ ID NO.:18 as a subcutaneous treatment option.

[0034] Figure 13 Graphs showing the mRNA expression of IL-1b, TNFα, and IL-33 in a DNFB-induced eczema model when the exemplary aptamers SEQ ID NO.:17 and SEQ ID NO.:18 are administered as a subcutaneous treatment option.

[0035] Figure 14 Graphs showing the relative number of mast cells counted in tissue sections of a DNFB-induced eczema model when the exemplary aptamers SEQ ID NO.:17 and SEQ ID NO.:18 are administered as a treatment option. Detailed Description

[0036] As used herein and in the claims, the term "comprising" (or any related form such as "comprise / comprises"), "including" (or any related form such as "include / includes"), "containing" (or any related form such as "contain / contains") means including the following elements but not excluding other elements. It should be understood that for each embodiment in which the term "comprising" (or any related form such as "comprise / comprises"), "including" (or any related form such as "include / includes"), or "containing" (or any related form such as "contain / contains") is used, this disclosure / application also includes alternative embodiments in which the term "comprising", "including", or "containing" is replaced with "consisting essentially of" or "consisting of". These alternative embodiments using "consisting of" or "consisting essentially of" are understood to be smaller scope embodiments of the "comprising", "including", or "containing" embodiments.

[0037] For example, alternative embodiments of "a composition comprising A, B, and C" would be "a composition consisting of A, B, and C" and "a composition consisting essentially of A, B, and C". Even if the latter two embodiments are not explicitly written out, this disclosure / application includes those embodiments. Further, it should be understood that the scopes of the three embodiments listed above are different.

[0038] For clarity, "comprising", "including", "containing" and any related forms are open terms that allow additional elements or features in addition to the specified essential elements, while "consisting of" is a closed term that is limited to the elements recited in the claim and does not include any elements, steps or components not specified in the claim.

[0039] For clarity, "characterized by" or "characterized in that" (along with their related forms as described above) do not limit or change whether the list of terms that follow is open or closed in nature.

[0040] As used herein, the singular forms "a / an" and "the" are also intended to include the plural forms unless the context clearly indicates otherwise. When ranges are recited in the specification, the ranges are understood to include each discrete point within the recited range. For example, 1 to 7 means 1, 2, 3, 4, 5, 6, and 7.

[0041] As used herein, the term "about" is understood to be within the normal tolerances in the art and not more than ±10% of the stated value. By way of example only, about 50 means from 45 to 55, including all values in between. As used herein, the phrase "about" a particular value also includes the particular value, e.g., about 50 includes 50.

[0042] As used herein and in the claims, "effective amount" is an amount that effectively achieves the desired effect of at least a measurable amount. For example, the amount can effectively induce cell death. For example, the amount can effectively induce an immune response, and / or it can effectively induce a protective response against a pathogen carrying the polypeptide of interest. In some embodiments, the amount can effectively induce an immune response against cancer or a tumor.

[0043] As used herein and in the claims, "subject" refers to an animal such as a mammal, including but not limited to primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, etc. In some instances, the subject refers to a mouse or a human.

[0044] As used herein, the terms "treat", "treating", or "treatment" refer to a method that, prophylactically and / or therapeutically, alleviates, eliminates, or ameliorates the symptoms of a disease or disorder, prevents additional symptoms, ameliorates or prevents the underlying metabolic cause of the symptoms, inhibits the disease or disorder, arrests the development of the disease or disorder, reduces the disease or disorder, causes regression of the disease or disorder, alleviates the condition caused by the disease or disorder, or terminates the symptoms of the disease or disorder.

[0045] As used herein and in the claims, the terms "prevent", "preventing", "preventive / preventative", or "prevention" refer to a method of reducing the risk of onset, recurrence, or spread of a disease or disorder or one or more of its symptoms.

[0046] As used herein, the term "pharmaceutical composition" or "composition" refers to a formulation containing one or more active pharmaceutical ingredients.

[0047] As used herein, the term "variant sequence" refers to a nucleic acid or polypeptide sequence that exhibits a degree of identity (e.g., at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) with a reference or wild-type nucleic acid or polypeptide sequence. For example, a variant sequence has one or more additions, deletions, insertions, and / or substitutions or other modifications compared to the reference sequence.

[0048] As used herein and in the claims, the term "pharmaceutically acceptable carrier" or "carrier" refers to a molecule or substance (e.g., a protein or nucleotide) used as an agent or medium to deliver a drug or active ingredient in a pharmaceutical formulation. In some instances, a pharmaceutically acceptable carrier is conjugated to one or more active ingredients (e.g., a polypeptide).

[0049] As used herein and in the claims, the term "one or more aptamers" refers to one or more oligonucleotides that exhibit high affinity for a target molecule, such as single-stranded deoxyribonucleic acid (ssDNA), ribonucleic acid (RNA), xeno nucleic acid (XNA), or a peptide that binds a specific target molecule or family of target molecules (e.g., a protein, peptide, and small molecule). In some instances, the aptamer is an ssDNA that specifically binds or targets BCMA.

[0050] As used herein and in the claims, the term "substitution / substitute" refers to the process of replacing one or more nucleotides (e.g., adenine, guanine, cytosine, or thymine / uracil) with different nucleotides within an aptamer sequence, e.g., to improve the binding affinity, stability, or other desired properties of the aptamer.

[0051] As used herein and in the claims, the term "modification / modify" refers to the process of altering (e.g., adding, deleting, substituting) a chemical group or molecule to one or more nucleotides within an aptamer sequence. In some instances, these modifications can enhance the properties of the aptamer without changing the core sequence, such as improving stability, target binding, or detection capabilities.

[0052] As used herein and in the claims, the term "disease or disorder" refers to the state of survival or health condition of a patient or subject that can be treated with the compounds, pharmaceutical compositions, or methods provided herein. In some instances, the disease or disorder refers to BCMA-related diseases or disorders, such as chronic inflammatory skin diseases, disorders, or conditions.

[0053] As used herein and in the claims, in the context of two or more nucleic acid or polypeptide sequences, the term "identical" or "identity" percentage refers to the extent to which two or more sequences or subsequences are the same or have a specified percentage of identical amino acid residues or nucleotides (e.g., when compared and aligned for maximum correspondence in a comparison window or specified region, the identity in the specified region is about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or higher).

[0054] By way of example, the provided aptamers or compositions described herein are administered by any suitable route of administration. The route of administration can refer to any method of administration known in the art, including but not limited to aerosol, enteral, intranasal, intraocular, oral, parenteral, rectal, transdermal (e.g., topical creams or ointments, patches), or vaginal administration. Transdermal administration can be accomplished using topical creams or ointments or via transdermal patches. Parenteral administration refers to the routes of administration typically associated with injection, including suborbital, infusion, intraarterial, intracapsular, intracardiac, intradermal, intramuscular, intraperitoneal, intralung, intraspinal, intrasternal, intrathecal, intrauterine, intravenous, subarachnoid, subcapsular, subcutaneous, transmucosal, or transtracheal administration. In some embodiments, the provided aptamers or compositions described herein are administered by intravenous injection or intraperitoneal injection.

[0055] As used herein and in the claims, the B cell maturation cell surface marker (BCMA, CD269 or TNFRSF17) is a member of the tumor necrosis factor superfamily. It is a non-glycosylated integral membrane receptor for the ligands B cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL).

[0056] Although the description refers to specific embodiments, the disclosure should not be construed as limited to the embodiments set forth herein.

[0057] The present invention relates to compositions and methods for delivering BCMA-targeting aptamers to BCMA-expressing cells to inhibit specific aspects of inflammation. The present invention provides an agent comprising a BCMA-specific aptamer.

[0058] In one embodiment, the present invention describes aptamers. Aptamers are nucleic acid molecules that have high binding affinity and specificity for a target molecule of interest. They are identified by SELEX (systematic evolution of ligands by exponential enrichment). The SELEX process involves multiple rounds of binding, selection, and amplification of a library of oligonucleotides to identify oligonucleotides that bind with high specificity to the desired target. Although highly specific oligonucleotides may have been identified, there is no guarantee of the desired binding affinity or the same profile in a cell-rich environment. In the embodiments described herein, SELEX selection is used to identify aptamers that have high binding affinity and specificity for BCMA.

[0059] In some embodiments, previously identified aptamers have undergone truncation, backbone modification, or glycosylation modification. These modifications to the aptamers have been shown to improve binding specificity. According to the prior art, these modifications provide the additional benefit of increasing the exo / endonuclease resistance of the aptamer. These modifications increase the half-life of the aptamer and extend the duration of the therapeutic effect.

[0060] According to the embodiments described herein, the aptamer specific for BCMA can bind to BCMA-expressing cells, which are cell surface receptors. The main ligand of BCMA is a proliferation-inducing ligand (APRIL), which then initiates a signaling cascade in MM cells. This signaling cascade leads to proliferation, differentiation, and survival through canonical and non-canonical NFkB2 activation (Kleber 2021). Although BCMA is expressed by mature B lymphocytes and plasma cells, BCMA expression has also been identified in skin lesions of patients with psoriasis and eczema (Alexaki 2012, Carpenter 2013, Tai 2014, Leyva-Castillo 2020).

[0061] In some embodiments, the interaction between the aptamer and BCMA can inhibit the induction of the BCMA signaling pathway. This can occur by blocking the interaction between APRIL and BCMA, or by inducing the internalization of BCMA. Other aptamers have been shown to interact with BCMA, leading to the rapid internalization of cell surface proteins (Catuogno 2019). Through internalization, the reduction of BCMA present on the cell surface reduces the stimulation by its ligands.

[0062] In some embodiments, the binding of the aptamer to BCMA inhibits the activity of NFκB. NFκB plays an important role in the inflammatory response and is used as a transcription factor for various inflammatory cytokines. These cytokines trigger the response of other innate immune cells, which then act on adaptive immune cells. The creation of an inflammatory environment causes a positive feedback loop, where the spread of inflammation can pose problems for the patient.

[0063] In some embodiments, the aptamer reduces the inflammation present in skin lesions.

[0064] Numbered embodiments

[0065] Group 1

[0066] Example 1. An aptamer, wherein the aptamer comprises a nucleotide sequence having at least 80% sequence identity with any one of SEQ ID NO.: 1-18 or a fragment thereof.

[0067] Example 2. The aptamer according to Example 1, wherein the nucleotide sequence comprises or consists of: SEQ ID NO.: 3, SEQ ID NO.: 6, SEQ ID NO.: 16, SEQ ID NO.: 17, or SEQ ID No.: 18.

[0068] Example 3. The aptamer according to any one of the preceding examples, wherein the nucleotide sequence comprises one or more of the following nucleoside substitutions: uracil, reverse dT, purine, xanthine, 2,6-diaminopurine, 8-oxo-N6-methyladenine, 7-deazaxanthine, 7-deazaguanine, N4,N4-ethanocytosine, N6,N6-ethano-2,6-diaminopurine, 5-methylcytosine, 5-(C3-C6)-alkynylcytosine, 5-fluorouracil, 5-bromouracil, pseudoisocytosine, 2-hydroxy-5-methyl-4-triazolopyridine, isocytosine, isoguanine, inosine, non-naturally occurring nucleobases, variants, mutants, or analogs thereof.

[0069] Example 4. An aptamer as described in any of the preceding examples, wherein the nucleotide sequence comprises one or more of the following sugar-phosphate backbone modifications: 2'-O-methylation, locked nucleic acid (LNA), peptide nucleic acid (PNA), phosphorothioate, boranophosphate, methylphosphonate, 2'-fluoro, 2'-O-methoxyethyl, or 4'-thio.

[0070] Example 5. An aptamer as described in any of the preceding examples, wherein the nucleotide sequence is conjugated to one or more of the following chemical structures: cholesterol, cholesteryl, inverted dT, phosphatidylcholine, phosphatidylethanolamine, spermine, sialic acid, histidyl poly(L-lysine), palmitoyl-D-glucuronide, polyethylene glycol, polyrotaxane, chlorogenic acid chitosan, listeriolysin O, or butylphenol aldehyde.

[0071] Example 6. An aptamer as described in Example 6, wherein the nucleotide sequence is conjugated to the one or more chemical structures through one or more of the following spacers or linkers: C12 spacer, C9 spacer, C6 spacer, C3 spacer, spacer 18 (hexaethylene glycol), spacer 9, d-spacer (dSpacer), r-spacer (rSpacer), amino linker, carboxyl linker, or thiol linker.

[0072] Example 7. A pharmaceutical composition, the pharmaceutical composition comprising: an aptamer as described in any of the preceding examples; and optionally a pharmaceutically acceptable carrier.

[0073] Example 8. A method of preventing or treating a chronic inflammatory skin disease, disorder, or condition, the method comprising: administering to a subject in need thereof an effective amount of an aptamer as described in any of Examples 1-6 or a composition as described in Example 7.

[0074] Example 9. The method as described in Example 8, wherein the chronic inflammatory skin disease, disorder, or condition is selected from the group consisting of eczema and psoriasis.

[0075] Group 2

[0076] Example 1. An aptamer, wherein the aptamer comprises a nucleotide sequence having at least about 80%, 85%, 90%, 95%, or 100% sequence identity to any one of SEQ ID NOs.: 1-18, or a variant or fragment thereof.

[0077] Example 2. The aptamer as described in Example 1, wherein the nucleotide sequence comprises or consists of: SEQ ID NO.: 3, SEQ ID NO.: 6, SEQ ID NO.: 16, SEQ ID NO.: 17, or SEQ ID No.: 18.

[0078] Example 3. The aptamer according to any one of the foregoing examples, wherein the nucleotide sequence comprises one or more of the following nucleoside substitutions: uracil, inverted dT, purine, xanthine, 2,6-diaminopurine, 8-oxo-N6-methyladenine, 7-deazaxanthine, 7-deazaguanine, N4,N4-ethanocytosine, N6,N6-ethano-2,6-diaminopurine, 5-methylcytosine, 5-(C3-C6)-alkynylcytosine, 5-fluorouracil, 5-bromouracil, pseudoisocytosine, 2-hydroxy-5-methyl-4-triazolopyridine, isocytosine, isoguanine, inosine, non-naturally occurring nucleobases, variants, mutants or analogs thereof.

[0079] Example 4. The aptamer according to any one of the foregoing examples, wherein the nucleotide sequence comprises one or more of the following sugar-phosphate backbone modifications: 2'-O-methylation, locked nucleic acid (LNA), peptide nucleic acid (PNA), phosphorothioate, boranophosphate, methylphosphonate, 2'-fluoro, 2'-O-methoxyethyl or 4'-thio.

[0080] Example 5. The aptamer according to any one of the foregoing examples, wherein the nucleotide sequence is conjugated to one or more of the following chemical structures: cholesterol, cholesteryl, inverted dT, phosphatidylcholine, phosphatidylethanolamine, spermine, sialic acid, histidyl-poly(L-lysine), palmitoyl-D-glucuronide, polyethylene glycol, polyrotaxane, chlorogenic acid chitosan, listeriolysin O or tributylphenolol.

[0081] Example 6. The aptamer according to Example 1, wherein the nucleotide sequence is conjugated to the one or more chemical structures through one or more of the following spacers or linkers: C12 spacer, C9 spacer, C6 spacer, C3 spacer, spacer 18 (hexaethylene glycol), spacer 9, d spacer (dSpacer), r spacer (rSpacer), amino linker, carboxyl linker or thiol linker.

[0082] Example 7. The aptamer according to any one of the foregoing examples, wherein the nucleotide sequence comprises the following modifications: replacing cytosine with 2'-O-methylation and adding inverted dT at the 3' end.

[0083] Example 8. The aptamer according to any one of the foregoing examples, wherein the nucleotide sequence comprises the following modification: the cholesterol at the 5' end is conjugated by substitution through spacer C9 and inverted dT at the 3' end.

[0084] Example 9. A pharmaceutical composition, the pharmaceutical composition comprising: the aptamer according to any one of Examples 1-8; and optionally a pharmaceutically acceptable carrier.

[0085] Example 10. A method for preventing or treating BCMA-related diseases or disorders, the method comprising: administering to a subject in need thereof an effective amount of an aptamer or a composition thereof, wherein the aptamer comprises a nucleotide sequence having at least about 80%, 85%, 90%, 95% or 100% sequence identity to any one of SEQ ID NO.: 1-18, or a variant or fragment thereof.

[0086] Example 11. The method according to Example 10, wherein the nucleotide sequence comprises or consists of: SEQ ID NO.: 3, SEQ ID NO.: 6, SEQ ID NO.: 16, SEQ ID NO.: 17 or SEQ ID NO.: 18.

[0087] Example 12. The method according to Example 10 or 11, wherein the composition comprises a pharmaceutically acceptable carrier.

[0088] Example 13. The method according to any one of Examples 10 to 12, wherein the BCMA-related disease or disorder is a chronic inflammatory skin disease, disorder or condition.

[0089] Example 14. The method according to any one of Examples 10 to 13, wherein the chronic inflammatory skin disease, disorder or condition is selected from the group consisting of eczema and psoriasis.

[0090] Example 15. The method according to any one of Examples 10 to 14, wherein the aptamer or the composition thereof is administered by subcutaneous injection.

[0091] Example 16. The method according to any one of Examples 10 to 15, the method further comprising the step of: after the step of administering the effective amount of the aptamer or the composition thereof, topically administering an effective dose of imiquimod (IMQ).

[0092] Example 17. Use of an aptamer or a composition thereof in the manufacture of a medicament for preventing or treating BCMA-related diseases or disorders in a subject, wherein the aptamer comprises a nucleotide sequence having at least about 80%, 85%, 90%, 95% or 100% sequence identity to any one of SEQ ID NO.: 1-18, or a variant or fragment thereof.

[0093] Example 18. An aptamer or a composition thereof for preventing or treating BCMA-related diseases or disorders in a subject, wherein the aptamer comprises a nucleotide sequence having at least about 80%, 85%, 90%, 95% or 100% sequence identity to any one of SEQ ID NO.: 1-18, or a variant or fragment thereof. Examples

[0094] This document provides examples that describe certain embodiments of this disclosure in more detail. The examples provided herein are for illustrative purposes only and are not meant to limit the scope of the invention in any way. All references given below and elsewhere in this application are hereby incorporated by reference herein.

[0095] Identification of Example 1 BCMA - specific aptamer

[0096] The initially used ssDNA library consisted of nucleotides that were 71 nucleotides (nt) in length. The middle 35-nt random region was flanked by two 18-nt linker regions. These linker regions served as primer binding sites for PCR amplification.

[0097] Selection of ssDNA aptamers by bead-binding SELEX involved multiple rounds of selection. Each round included a pre-selection step, a selection step, and a regeneration step. A total of 20 rounds of SELEX were used. In all rounds, the positive selection step involved immobilizing histidine-tagged recombinant human BCMA on Ni-NTA magnetic beads. The ssDNA pool was then incubated with the bead complex. The mixture was washed to remove unbound aptamers, and then the bound aptamers were eluted. The elution product was used for PCR, amplified using a biotinylated reverse primer, and quality checked by agarose gel electrophoresis.

[0098] To regenerate the ssDNA pool, the PCR product was incubated with streptavidin-coated magnetic beads to bind the biotinylated reverse primer. After incubation, the dsDNA PCR product was denatured by alkaline treatment. The ssDNA pool generated in the supernatant was then used for the next round of SELEX.

[0099] Starting from the 4th round, negative selection was performed before positive selection. Negative selection involved incubating the ssDNA pool with blank Ni-NTA beads or histidine-tagged non-target proteins for negative selection purposes. After incubation, the unbound ssDNA was then incubated with histidine-tagged recombinant BCMA-bound Ni-NTA beads.

[0100] According to the manufacturer's instructions, the enriched ssDNA pools from the 3rd, 6th, 9th, 12th, 15th, and 20th rounds were modified by the VAHTS Universal DNA Library Preparation Kit for V3 to ligate 5' universal adapters and 3' index DNA adapters to the ssDNA sequences. Before next-generation gene sequencing of the ssDNA pool, the concentration and size distribution of the library were measured using an Agilent 2100 Bioanalyzer and a high-sensitivity DNA kit.

[0101] The enzyme-linked oligonucleotide assay (ELONA) was used to evaluate aptamer candidates. The aptamers were synthesized by 5'-biotinylation modification. Each well of a 96-well microtiter plate was coated with 500 ng of histidine-tagged recombinant BCMA by overnight incubation at 4 °C. Non-binding sites were blocked with 1-hour BSA blocking at room temperature and then washed 4 times with DNA binding buffer for 5 minutes. 1 μM of each aptamer was added to each well and incubated for 45 minutes with gentle shaking. The wells were then washed 4 times with wash buffer, 5 minutes each time. 100 μl of streptavidin-HRP (1:10000 in PBST + 0.1% BSA) was added to each well and incubated for 30 minutes. Then 4 washes were performed with binding buffer. 50 μl of TMB was added to each well and incubated for 20 minutes. 50 μl of 2M H 2 SO 4 The reaction was stopped and then the absorbance at 450 nm was measured to determine specificity.

[0102] After multiple rounds of bead-binding SELEX, 18 aptamer candidates were identified. As observed in Figure 1 , the evaluation of binding specificity indicated that two of these aptamers did not have such strong binding specificity for the target protein. Among the candidates, only one candidate did not have binding specificity for BCMA. The nucleotide sequences of samples 1, 7, and 10 were designated as SEQ ID NO.: 1, 2, and 3, respectively. Table 1 is a list of sequence information corresponding to samples 1, 7, and 10 of Example 1.

[0103] Table 1 Sequence listing of samples (exemplary aptamers) 1, 7, and 10 of Example 1 (i.e., SEQ ID NO.: 1, 2, and 3)

[0104] Example 2 Aptamer affinity assessment

[0105] ELONA was used to evaluate the binding affinity of the aptamers. Each well of a 96-well microtiter plate was coated with 500 ng of histidine-tagged recombinant BCMA by overnight incubation at 4 °C. Non-binding sites were blocked with 1-hour BSA blocking at room temperature and then washed 4 times with DNA binding buffer for 5 minutes. Different concentrations of each aptamer were added to each well and incubated for 45 minutes with gentle shaking. The wells were then washed 4 times with wash buffer, 5 minutes each time. 100 μl of streptavidin-HRP (1:10000 in PBST + 0.1% BSA) was added to each well and incubated for 30 minutes. Then 4 washes were performed with binding buffer. 50 μl of TMB was added to each well and incubated for 20 minutes. 50 μl of 2M H 2 SO4 The reaction was stopped, and the absorbance at 450 nm was then measured.

[0106] Binding affinity evaluations were performed for all aptamers except candidate 8. Absorbance was used to plot the binding curve, and the binding affinities of samples (exemplary aptamers) 1, 7, 10 (SEQ ID NO.: 1–3) were determined from the binding curve ( Figure 2 ).

[0107] Example 3 Aptamer serum stability

[0108] To test the serum stability of the aptamers, 20 nM samples 1, 7, 10 (SEQ ID NO.: 3) were incubated at 37 °C in mouse serum or medium + 10% FBS. Samples were collected at the indicated time points and stored until evaluation ( Figure 3 ). The samples were diluted 100-fold and then amplified using Phusion High-Fidelity DNA polymerase. After amplification was complete, the samples were loaded onto a 15% denaturing polyacrylamide gel for electrophoresis. The gel was run and then stained with GelRed for imaging. Band densitometry was performed after imaging.

[0109] It was found that the half-life of sample 10 SEQ ID NO.: 3 in mouse serum was approximately 1 hour, while the half-life in medium + 10% fetal bovine serum was approximately 2 hours ( Figure 3 ).

[0110] Example 4 Aptamer truncation assessment

[0111] Twelve truncated exemplary aptamers (SEQ ID NO.: 4–15) were synthesized based on sample 10 SEQ ID NO.: 3. Table 2 shows the sequence listing of the twelve truncated aptamers (SEQ ID NO.: 4–15) from sample 10 SEQ ID NO.: 3.

[0112] Their binding affinities were evaluated by ELONA. Binding curves were plotted, and the binding affinities were then calculated. Table 3 shows the Kd values of all truncated aptamer sequences (SEQ ID NO.: 4–15), where sample 10-3 SEQ ID NO.: 6 had the best Kd among all truncated aptamers, at 59 nM.

[0113] Table 3. Binding affinities of exemplary aptamers truncated from sample 10 SEQ ID NO.: 3 (SEQ ID NO.: 4–15).

[0114] Example 5 Aptamer modification

[0115] The serum stabilities of the unmodified exemplary aptamer (SEQ ID NO.:6) and the modified exemplary aptamer based on SEQ ID NO.:6 (the modified exemplary aptamer is represented by SEQ ID NO.:16) were also examined. The modifications included substituting cytosine with 2'-O-methylation and adding a reverse dT at the 3'-end.

[0116] The sequence of the modified exemplary aptamer (SEQ ID NO.:16) is shown below: mCGTAmCGGTmCGAmCGmCTAGmCTGTTGmCTGTGmCAGGAAGAATGm CAGATTmC-InvdT, where m = 2'-O-methylation; InvdT = 3'-reverse dT.

[0117] The aptamer was incubated in fetal bovine serum at 37 °C at the indicated time points ( Figure 4 ). At each time point, samples were collected and stored for later evaluation. The samples were run on a 20% denaturing polyacrylamide gel ( Figure 4 ). The gel was stained with SYBR Gold for imaging.

[0118] As can be seen in Figure 4 , the unmodified SEQ ID NO.:6 was completely degraded after 8 hours, while some of the modified SEQ ID NO.:6 was still present at 54 hours. In addition to the increased half-life, the binding affinity analysis of the modified SEQ ID NO.:6 also showed that its Kd was approximately 64.19 nM ( Figure 5 ). This was carried out by ELONA.

[0119] Example 6 Inhibition of inflammatory response

[0120] 1.5 x 10 5 RAW 264.7 murine macrophages were seeded into wells overnight. The medium was changed to DMEM with 1% FBS present. The cells were treated with 300 nM of SEQ ID NO.:2 or SEQ ID NO.:3 for 15 minutes and then the cells were exposed to 1 μg / mL of LPS for 24 hours. After 24 hours, RNA was extracted with TRIzol for qPCR. Exposure to 1 μg / mL of LPS for 24 hours stimulated the expression of iNOS, TNFα, CD163, and VEGFA mRNAs in RAW 264.7 cells.

[0121] Macrophage exposure to LPS induces an M1 response, which is beneficial for inflammation. The results showed that pretreatment with 300 nM of SEQ ID NO.:2 or 3 for 15 minutes reduced the expression of iNOS, TNFα, CD163, and VEGFA. Here, pretreatment with the BCMA-targeting aptamer sequence inhibited the induction of iNOS and TNF-α mRNA expression ( Figure 6 ). Both of these genes are associated with the M1 inflammatory response.

[0122] Example 7 IMQ psoriasis mouse model

[0123] This animal study was approved by the Hong Kong Polytechnic University Animal Subjects Ethics Review (20-21 / 274-OTHERS-R-OTHERS). This animal study was conducted at the Shenzhen Institute of Zoology, Hong Kong Polytechnic University.

[0124] On day -1, the fur on the back skin was removed. On day 0, the thickness of the shaved back skin of the mice was measured by a micrometer, and the psoriasis area severity index (PASI) score of the skin was evaluated. Then, the mice were injected subcutaneously with 100 μL of a buffer containing 600 pmol of the BCMA-targeting aptamer, or the buffer alone. After the administration of the aptamer, 62.5 mg of Aldara cream (5% IMQ) was topically applied to the shaved back skin. On days 1-3, the PASI score of the back skin was evaluated before the administration of the test article, and then IMQ was administered. On day 4, the back skin thickness was measured, and the PASI was evaluated before the animals were sacrificed. Skin samples were collected and stored in RNAlater for subsequent extraction of TRIzol RNA and qPCR. The difference was calculated by subtracting the thickness measured at the start of the experiment from the thickness at the end of the experiment.

[0125] The mice were administered modified exemplary aptamers based on SEQ ID NO.:3 (the modified exemplary aptamer is represented by SEQ ID NO.:17) or SEQ ID NO.:6 (the modified exemplary aptamer is represented by SEQ ID NO.:18). The modifications include the substitution conjugation of cholesterol at the 5'-end through spacer C9 and reverse dT at the 3'-end.

[0126] The sequences of the modified exemplary aptamers SEQ ID NO.:17-18 are shown below: (SEQ ID NO.:17) Cholesterol-SpC9-CGTACGGTCGACGCTAGCTGTTGCTGTGCAGGAAGAATGCAGATTCCCAACATGGATCCGAGCTCCACGTG-InvdT (SEQ ID NO.:18) Cholesterol-SpC9-CGTACGGTCGACGCTAGCTGTTGCTGTGCAGGAAGAATGCA GATTC-InvdT where SpC9 = spacer C9, and InvdT = 3'-inverted dT.

[0127] The aptamer was administered in combination with IMQ as a treatment option, and the aptamer sequence inhibited the development of the psoriatic phenotype ( Figure 7 ). Consistent with the differences in the psoriatic phenotype, significant differences in skin thickness changes were observed in mice treated with SEQ ID NO.:18 ( Figure 8 ). The results showed that SEQ ID NO.:18 reduced the associated increase in skin thickness.

[0128] Figure 9 A representative set of images of the skin.

[0129] The qPCR results showed a similar overall trend. IMQ treatment led to the induction of various markers (S100A8, S100A9, KRT6B, KRT16) consistent with the development of psoriasis (see Table 4). Treatment with SEQ ID NO.:17 or 18 improved the expression of these psoriasis-related markers. In addition to improving psoriasis markers, BCMA-targeted aptamer treatment also reduced the expression of multiple inflammatory cytokines such as TSLP, IL-1β, IL-6, IL-19, IL-17C, IL-17F, etc. (Table 4). All of these cytokines play a role in initiating innate or adaptive immune responses.

[0130] Table 4. Relative expression of selected psoriasis markers in the IMQ-induced psoriasis model (percentage relative to the vehicle buffer group)

[0131] The results showed that both SEQ ID NO.:17 and SEQ ID NO.:18 were able to improve the development of skin lesions.

[0132] Example 8 DNFB eczema mouse model

[0133] This animal study was approved by the Ethics Review of Laboratory Animals of The Hong Kong Polytechnic University (22-23 / 479-OTHERS-R-OTHERS). This animal study was conducted at the Institute of Shenzhen Animal Facilities of The Hong Kong Polytechnic University.

[0134] On day 0, the fur of the back skin was removed. On day 1, the skin thickness of the shaved skin was measured, and the Eczema Area and Severity Index (EASI) score was evaluated. Then the mice were administered vehicle buffer or 600 pmol of the aptamer in 100 μL. 100 μL of DNFB (0.2% v / v acetone: olive oil (4:1)) was applied to the back skin. On days 4, 6, 8, 11, and 13, the test article and DNFB solution were re-administered. On day 6, 30 minutes after DNFB administration, the mice were filmed for 15 minutes to evaluate the scratching response duration and frequency. On day 14, the back skin thickness was measured, and the EASI score of the skin was evaluated. Then the mice were sacrificed, and tissue samples were collected. The skin was fixed in 4% PFA or stored in RNA for subsequent TRIzol RNA extraction and qPCR. When SEQ ID NO.:17 or SEQ ID NO.:18 was administered to the mice as a subcutaneous treatment option in combination with the DNFB solution, the aptamer sequences inhibited the development of the atopic dermatitis phenotype ( Figure 10 ). Figure 11 Representative pictures of the back skin of mice in various treatment groups are shown. During the 15-minute observation on day 6, compared with the vehicle control, the mice treated with SEQ ID NO.:17 or 18 had fewer scratching counts and shorter scratching durations ( Figure 12A and Figure 12B ). qPCR analysis of the RNA samples collected at the end of the experiment showed that treatment with SEQ ID NO.:17 or 18 reduced the expression levels of the pro-inflammatory cytokines IL-1β, TNFα, and IL-33 ( Figure 13 ). Mast cells play a key role in the progression of eczema, so the back skin sections collected at the end of the experiment were stained with toluidine blue and examined for mast cells. Figure 14 Shows the percentage of mast cell counts relative to the vehicle buffer.

[0135] Exemplary embodiments of the present invention have thus been fully described. Although the description refers to specific embodiments, it will be apparent to those skilled in the art that the present invention can be implemented with variations of these specific details. Therefore, the present invention should not be construed as limited to the embodiments set forth herein.

Claims

1. An aptamer, wherein the aptamer comprises a nucleotide sequence having at least about 80%, 85%, 90%, 95% or 100% sequence identity to any one of SEQ ID NOs.: 1-18, or a variant or fragment thereof.

2. The aptamer according to claim 1, wherein the nucleotide sequence comprises or consists of the following: SEQ ID NO.:3, SEQ ID NO.:6, SEQ ID NO.:16, SEQ ID NO.:17 or SEQ ID No.:

18.

3. The aptamer of claim 1, wherein the nucleotide sequence comprises one or more of the following nucleoside substitutions: uracil, inverted dT, purine, xanthine, diaminopurine, 8-oxo-N6-methyladenine, 7-deazaxanthine, 7-deazaguanine, N4,N4-ethanol cytosine, N6,N6-ethanol-2,6-diaminopurine, 5-methylcytosine, 5-(C3-C6)-alkynyl cytosine, 5-fluorouracil, 5-bromouracil, pseudoisocytosine, 2-hydroxy-5-methyl-4-triazolopyridine, isocytosine, isoguanine, inosine, non-naturally occurring nucleobases, variants, mutants or analogs thereof.

4. The aptamer of claim 1, wherein the nucleotide sequence comprises one or more of the following sugar-phosphate backbone modifications: 2'-O-methylation, locked nucleic acid LNA, peptide nucleic acid PNA, phosphorothioate, boranophosphate, methyl phosphoester, 2'-fluoro, 2'-O-methoxyethyl or 4'-thio.

5. The aptamer of claim 1, wherein the nucleotide sequence is conjugated to one or more of the following chemical structures: cholesterol, cholesterol, reverse dT, phosphatidylcholine, phosphatidylethanolamine, spermine, sialic acid, histidyl poly(lysine), palmityl-D-glucuronide, polyethylene glycol, polyrotaxane, chlorogenic acid chitosan, listeriolysin O, or tylosin.

6. An aptamer as described in claim 1, wherein the nucleotide sequence is conjugated to the one or more chemical structures through one or more of the following spacers or linkers: C12 spacer, C9 spacer, C6 spacer, C3 spacer, spacer 18 (hexaethylene glycol), spacer 9, d spacer, r spacer, amino linker, carboxyl linker or thiol linker. 7 . The aptamer of claim 1 , wherein the nucleotide sequence comprises the following modifications: substitution of cytosine with 2′-O-methylation and addition of an inverted dT at the 3′ end.

8. The aptamer of claim 1, wherein the nucleotide sequence comprises the following modifications: substitution conjugation at the 5' end with cholesterol through a spacer C9 and at the 3' end with an inverted dT.

9. A pharmaceutical composition, comprising: The aptamer according to claim 1 or claim 2; and Optionally a pharmaceutically acceptable carrier.

10. A method for preventing or treating a BCMA-related disease or disorder, the method comprising: An effective amount of an aptamer or a composition thereof is administered to a subject in need thereof, wherein the aptamer comprises a nucleotide sequence having at least about 80%, 85%, 90%, 95% or 100% sequence identity to any one of SEQ ID NOs.: 1-18, or a variant or fragment thereof.

11. The method of claim 10, wherein the nucleotide sequence comprises or consists of: SEQ ID NO.:3, SEQ ID NO.:6, SEQ ID NO.:16, SEQ ID NO.:17 or SEQ ID No.:

18.

12. The method of claim 10, wherein the composition comprises a pharmaceutically acceptable carrier.

13. The method of claim 10, wherein the BCMA-associated disease or condition is a chronic inflammatory skin disease, disorder or condition.

14. The method of claim 10, wherein the chronic inflammatory skin disease, disorder or condition is selected from the group consisting of eczema and psoriasis.

15. The method of claim 10, wherein the aptamer or the composition thereof is administered by subcutaneous injection.

16. The method of claim 10, further comprising the steps of: After the step of administering an effective amount of the aptamer or the composition thereof, an effective dose of imiquimod IMQ is topically administered.

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