Compounds for isolating undesirable antibodies in patients

Abstract

The present invention provides compounds for the sequestration of unwanted antibodies (such as those associated with autoimmune diseases) in patients. The compounds comprise an inert biopolymer scaffold and at least one antibody having the general formula P(-SP) (n-1) and a first peptide n-mer of the general formula P(-SP) (n-1) wherein each P is independently a peptide having a sequence length of 2 to 13 amino acids, and S is a non-peptide spacer, and n is an integer greater than or equal to 1, and each of the peptide n-mers is attached to the biopolymer scaffold. Also provided are pharmaceutical compositions comprising the compound, as well as methods for sequestering one or more antibodies present in an individual and for inhibiting an immune response to treatment with an active agent.

Description

[Technical Field]

[0001] The field of this invention relates to compounds for sequestrating undesirable antibodies within an organism, such as antibodies involved in autoimmune diseases. [Background technology]

[0002] Generally, antibodies are an important component of the humoral immune system, providing protection against infection by foreign organisms such as bacteria, viruses, fungi, or parasites. However, in certain situations, such as autoimmune diseases, organ transplants, blood transfusions, or the administration of biomolecular drugs or gene delivery vectors, antibodies can target the patient's own body (or foreign tissues or cells, or the biomolecular drug or vector immediately after administration), becoming harmful or disease-causing. Some antibodies may also interfere with probes used for diagnostic imaging. Hereinafter, such antibodies will be collectively referred to as "undesirable antibodies" or "unwanted antibodies."

[0003] With few exceptions, selective removal of unwanted antibodies has not reached clinical practice. Currently, indications are extremely limited. One known (but not widely established) technique for selective antibody removal is immunoapheresis. In contrast to immunoapheresis (which removes immunoglobulins), selective immunoapheresis involves filtering plasma through an extracorporeal selective antibody adsorption cartridge that depletes unwanted antibodies by selective binding to their antigen-binding sites. Selective immunoapheresis has been used, for example, to remove anti-A or anti-B antibodies from blood prior to ABO-incompatible transplantation, or for indications in transfusion medicine (Teschner et al). Selective apheresis has also been experimentally applied to other indications such as neuroimmunological indications (Tetala et al) or myasthenia gravis (Lazaridis et al), but it has not yet been established as a clinical routine. One reason why selective immunoapheresis is only applied passively is that it is a costly and cumbersome treatment intervention requiring specialized medical care. Furthermore, conventional techniques do not know how to rapidly and efficiently deplete unwanted antibodies.

[0004] Independent of apheresis, Morimoto et al. disclose dextran as a multivalent scaffold generally applicable for improving the immunoglobulin binding affinity of peptides and peptide-mimicking ligands such as FLAG peptides. International Publication 2011 / 130324 relates to a compound for the prevention of cytotoxicity. European Patent Application Publication 3059244 relates to a C-met protein agonist.

[0005] As mentioned above, apheresis is applied in vitro. On the other hand, several conventional approaches have been proposed to deplete undesirable antibodies in the body, and these are mostly related to certain autoimmune diseases involving autoantibodies or anti-drug antibodies.

[0006] Lorentz et al. have disclosed a technique to charge erythrocytes with a tolerogenic payload in situ to induce depletion of antigen-specific T cells. This is thought to ultimately reduce undesirable humoral responses to model antigens. A similar approach has been proposed by Pishesha et al., in which peptide antigen constructs are covalently loaded onto the surface of erythrocytes ex vivo and then reinjected into animal models for general immune tolerance induction.

[0007] International Publication No. 92 / 13558 relates to a conjugate of a stable, non-immunogenic polymer and an immunogen analog, the conjugate having specific B-cell binding ability to the immunogen and inducing humoral anergy to the immunogen upon introduction into an organism. These conjugates are therefore disclosed to be useful for treating antibody-mediated symptoms caused by exogenous or autoimmunogens. In connection with this, see also European Patent Application Publication No. 0498658.

[0008] Taddeo et al. have disclosed that using an anti-CD138 antibody derivative fused with an ovalbumin model antigen, they selectively induce receptor crosslinking and cell suicide in vitro in antibody-producing plasma cells expressing antibodies against the model antigen, thereby selectively depleting those cells.

[0009] Apitope International NV (Belgium) is currently developing soluble toxicogenic T cell epitope peptides that can suppress antibody responses by inducing low levels of co-stimulatory molecules from tolerance-inducing antigen-presenting cells (see, e.g., Jansson et al). These products are currently undergoing preclinical and early clinical evaluation for multiple sclerosis, Graves' disease, intermediate uveitis, and other autoimmune conditions, as well as factor VIII intolerance.

[0010] Similarly, Selecta Biosciences, Inc. (USA) is currently researching tolerance induction strategies using so-called synthetic vaccine particles (SVPs). SVP rapamycin is thought to induce tolerance by selectively inducing regulatory T cells, thereby preventing the production of undesirable antibodies (see Mazor et al.).

[0011] Mingozzi et al. have disclosed a decoy adenovirus (AAV) capsid that adsorbs antibodies but cannot enter target cells.

[0012] International Publication No. 2015 / 136027 discloses a carbohydrate ligand that presents the minimal human natural killer 1 (HNK-1) epitope that binds to anti-MAG (myelin-associated glycoprotein) IgM antibodies, and its use for the diagnosis and treatment of anti-MAG neuropathy. International Publication No. 2017 / 046172 further discloses carbohydrate ligands and moieties that mimic carbohydrate epitopes containing sphingoglycolipids of the nervous system to which anti-glycan antibodies associated with neurological diseases bind. This document further relates to the use of these carbohydrate ligands / moieties in the diagnosis and treatment of neurological diseases associated with anti-glycan antibodies.

[0013] U.S. Patent Application Publication No. 2004 / 0258683 discloses a method for treating systemic lupus erythematosus (SLE), including renal SLE; a method for reducing the risk of renal flare in an individual with SLE; and a method for monitoring such treatment. One of the disclosed methods for treating SLE, including renal SLE, and reducing the risk of renal flare in an individual with SLE involves administering to the individual an effective amount of a drug to reduce the concentration of anti-double-stranded DNA (dsDNA) antibodies, such as a dsDNA epitope in the form of an epitope-presenting carrier or epitope-presenting valency platform molecule.

[0014] U.S. Patent No. 5,637,454 relates to assays and treatments for autoimmune diseases. The agents used for treatment may include peptides homologous to identified antigenic molecular mimic sequences. These peptides may be delivered to a patient to reduce the amount of circulating antibodies having specific specificity, as disclosed.

[0015] U.S. Patent Application Publication 2007 / 0026396 relates to a peptide targeting an antibody that causes cold intolerance, and its use. It is taught that by using the disclosed peptide, it is possible to neutralize unwanted autoantibodies in vivo or ex vivo. Similar approaches are disclosed in International Publication 1992 / 014150 or International Publication 1998 / 030586.

[0016] International Publication No. 2018 / 102668 discloses a fusion protein for the selective degradation of disease-causing or undesirable antibodies. This fusion protein (named "Seldeg") comprises a targeting component that specifically binds to a cell surface receptor or other cell surface molecule at a near-neutral pH, and an antigen component that is directly or indirectly fused to the targeting component. Also disclosed is a method for depleting a patient's target antigen-specific antibody by administering Seldeg, which has an antigen component configured to specifically bind to the target antigen-specific antibody, to that patient.

[0017] International Publication No. 2015 / 181393 relates to peptides grafted onto sunflower trypsin inhibitor (SFTI)-based scaffolds and cyclotide-based scaffolds. These peptides are disclosed to be effective against autoimmune diseases. For example, a citrullinated fibrinogen sequence grafted onto the SFTI scaffold has been shown to block autoantibodies in rheumatoid arthritis and suppress inflammation and pain. These scaffolds are disclosed to be non-immunogenic.

[0018] Erlandsson et al. have disclosed the removal of idiotype antibodies in vivo using anti-idiotype antibodies and their derivatives.

[0019] Berlin Cures Holding AG (Germany) proposed an intravenous broad-spectrum neutralizer DNA aptamer (see, e.g., International Publication No. 2016 / 020377 and International Publication No. 2012 / 000889) for the treatment of dilated cardiomyopathy and other GPCR-autoantibody-related diseases, believing that high doses would block autoantibodies by competitively binding to their antigen-binding domain. In general, aptamers have not made significant progress to date and are still in the preliminary stages of clinical development. Biostability and bioavailability, as well as limitations such as nuclease sensitivity, toxicity, small size, and renal clearance, remain major challenges. A particular problem with their use as selective antibody antagonists is their tendency to stimulate the innate immune response.

[0020] International Publication No. 00 / 33887 discloses methods for reducing the circulating concentration of antibodies, particularly disease-related antibodies. These methods require administering an effective amount of epitope-presenting carrier to the individual. Furthermore, ex vivo methods using epitope-presenting carriers for reducing the circulating concentration of antibodies are also disclosed.

[0021] U.S. Patent No. 6,022,544 relates to a method for reducing an undesirable antibody response in a mammal by administering the mammal a non-immunogenic construct that does not contain high molecular weight immunostimulatory molecules. The construct is disclosed to contain at least two copies of a B-cell membrane immunoglobulin receptor epitope bound to a pharmaceutically acceptable non-immunogenic carrier.

[0022] However, conventional approaches to depleting undesirable antibodies in the body have many drawbacks. In particular, none of them are approved for routine clinical use. [Overview of the Initiative] [Problems that the invention aims to solve]

[0023] Accordingly, an object of the present invention is to provide improved compounds and methods for the depletion (or isolation) of undesirable antibodies within an individual (such as antibodies associated with autoimmune diseases), particularly for use in the treatment or prevention of diseases or conditions associated with such undesirable antibodies (such as autoimmune diseases). [Means for solving the problem]

[0024] The present invention • Biomolecular scaffolds, and at least • The first peptide n-mer of the following general formula: P(-SP) (n-1) and • The second peptide n-mer of the following general formula: P(-SP) (n-1) The present invention provides compounds containing the above.

[0025] Each P is independently a peptide having a sequence length of 2 to 13 amino acids, preferably 3 to 11 amino acids, more preferably 4 to 9 amino acids, and especially particularly 5 to 8 amino acids, and S is a non-peptide spacer. For each of the peptide n-mers independently, n is an integer of at least 1, preferably at least 2, more preferably at least 3, even more preferably at least 4, and especially at least 5. Each of the peptide n-mers is preferably bound to the biopolymer scaffold via a linker.

[0026] Preferably, at least one P is P a and / or at least one P is P b P ais a defined peptide having a sequence length of 2 to 13 amino acids, preferably 3 to 11 amino acids, more preferably 4 to 9 amino acids, particularly 5 to 8 amino acids (i.e., a peptide having a defined sequence). P b is a defined peptide having a sequence length of 2 to 13 amino acids, preferably 3 to 11 amino acids, more preferably 4 to 9 amino acids, particularly 5 to 8 amino acids (i.e., a peptide having a defined sequence).

[0027] The present invention also relates to · a biopolymer scaffold, and at least · a first peptide n-mer which is a peptide dimer of the formula P a -S-P a or P a -S-P b and includes where P P a is a defined peptide having a sequence length of 2 to 13 amino acids, preferably 3 to 11 amino acids, more preferably 4 to 9 amino acids, particularly 5 to 8 amino acids (i.e., a peptide having a defined sequence), P b is a defined peptide having a sequence length of 2 to 13 amino acids, preferably 3 to 11 amino acids, more preferably 4 to 9 amino acids, particularly 5 to 8 amino acids (i.e., a peptide having a defined sequence), S is a non-peptide spacer, and the first peptide n-mer is bound to the biopolymer scaffold, preferably via a linker. The present invention also provides a compound.

[0028] This compound preferably includes a second peptide n-mer which is a peptide dimer of the formula P b -S-P b or P a -S-P b and the second peptide n-mer is bound to the biopolymer scaffold, preferably via a linker.

[0029] The present invention also relates to compounds for the sequestration (or depletion) of compounds present in a human organism, preferably anti-human muscle nicotinic acetylcholine receptor (AChR) antibodies, anti-human muscle-specific receptor tyrosine kinase antibodies, and / or anti-human low-density lipoprotein receptor-associated protein 4 antibodies, wherein the compound comprises a biomolecular scaffold and at least two peptides having a sequence length of 7 to 13 amino acids, each of which independently comprises an AChR subunit alpha sequence identified by UniProt accession number P02708 (optionally, 5 or fewer sequence fragments, preferably 4 or fewer, more preferably 3 or fewer, even more preferably 2 or fewer, particularly 1) (for example, so that a mimotope is formed). The present invention provides a compound comprising a 7-13 amino acid sequence fragment of a muscle-specific receptor tyrosine kinase sequence identified by UniProt accession number O15146, or a low-density lipoprotein receptor-related protein 4 sequence identified by UniProt accession number O75096 (optionally, the sequence fragment below includes 5 or fewer amino acid substitutions (e.g., so that a mimotope is formed), wherein the peptide is covalently bonded to the biopolymer scaffold, preferably via a linker, and the biopolymer scaffold is selected from the group consisting of human globulin and human albumin.

[0030] The present invention also relates to a compound for the isolation (or depletion) of a compound, preferably an anti-Epstein-Barr virus nuclear antigen 1 (EBNA-1) antibody, an anti-human melatonin-related receptor (GPR50) antibody, and / or an anti-human angiotensin II receptor 1 (AT1AR) antibody present in a human organism, wherein the compound comprises a biomolecular scaffold and at least two peptides having a sequence length of 7 to 13 amino acids, each of which peptides is independently identified by UniProt accession number Q1HVF7 or P03211. The present invention provides a compound comprising a sequence fragment of 7 to 13 amino acids, comprising an A1 sequence, or a GPR50 sequence identified by UniProt accession number Q13585, or a type 1 angiotensin II receptor (AT1AR) sequence identified by UniProt accession number P30556, wherein the peptide is covalently bonded to the biopolymer scaffold, preferably via a linker, and the biopolymer scaffold is selected from the group consisting of human globulin, preferably from the group consisting of human immunoglobulin, human haptoglobin, and human albumin.

[0031] Furthermore, the present invention provides a pharmaceutical composition comprising the aforementioned compound and at least one pharmaceutically acceptable excipient. Preferably, this pharmaceutical composition is for use in the treatment of any one of the diseases or conditions described herein.

[0032] In other aspects, the present invention is a method for isolating (or depleting) one or more antibodies present in an organism, comprising obtaining a pharmaceutical composition as defined herein, and administering the pharmaceutical composition to the organism, wherein the composition is non-immunogenic in the organism, and the one or more antibodies present in the organism are at least one P, or peptide P a and / or peptide P b This provides a method that is specific to the target.

[0033] In other aspects, the present invention relates to a pharmaceutical composition comprising a compound as defined herein, further comprising an active agent, and optionally at least one pharmaceutically acceptable pharmaceutical additive. The active agent comprises a peptide fragment having a sequence length of 2 to 13 amino acids, preferably 3 to 11 amino acids, more preferably 4 to 9 amino acids, and especially particularly 5 to 8 amino acids. At least one peptide P of the compound, or peptide P a and / or peptide P b The sequence is at least 70% identical, preferably at least 75%, more preferably at least 80%, even more preferably at least 85%, even more preferably at least 90%, even more preferably at least 95%, and especially completely identical to the sequence of the peptide fragment. Preferably, this pharmaceutical composition is for use in blocking or inhibiting the immune response to the active agent.

[0034] In another aspect, the present invention provides a method for inhibiting an immune response to an active agent treatment in an individual requiring such treatment, comprising obtaining a pharmaceutical composition comprising the compound and the active agent, and administering the pharmaceutical composition to the individual, wherein the compound in the pharmaceutical composition is non-immunogenic in the individual.

[0035] In another aspect, the present invention provides a method for providing the compound of the present invention, comprising the steps of: identifying at least one individual having an undesirable antibody against an antigen; screening a peptide library to identify a peptide mimotope that is specific to the undesirable antibody; and providing the compound, wherein at least one P of the compound comprises the entire sequence of the peptide mimotope. [Effects of the Invention]

[0036] In the course of this invention, it was surprisingly found that the compounds of the present invention are highly effective in reducing the titer of undesirable antibodies in organisms. In particular, the compounds achieved remarkably good results in in vivo models with respect to selectivity, duration of titer reduction, and / or degree of titer reduction (see experimental examples).

[0037] The present invention will be further illustrated with reference to the following drawings and embodiments, but the present invention is not limited thereto.

[0038] In relation to the following drawings and examples, the compounds of the present invention are also referred to as "Selective Antibody Depletion Compounds" (SADCs). [Brief explanation of the drawing]

[0039] [Figure 1A] Figure 1: The compounds of the present invention can reduce the titer of undesirable antibodies. Each of the compounds of the present invention was administered by intraperitoneal injection at time 0 to Balb / c mice pre-immunized by peptide immunization against a defined antigen. The upper figure shows the anti-peptide titer (0.5 × serial dilution; x axis shows log(X) dilution) against the OD value (y axis) obtained by standard ELISA for detecting the corresponding antibody. The lower figure shows the pre-injection titer LogIC50 (y axis) of each compound of the present invention (i.e., titer at -48 hours and -24 hours) and the same titer after application of each compound of the present invention (i.e., titer at +24 hours, +48 hours, and +72 hours after injection; shown on the x axis). (Figure 1A) A compound having albumin as a biomolecular scaffold that binds to an antibody against EBNA1 (associated with pre-eclampsia). The mice were pre-immunized with a peptide vaccine having the EBNA-1 model epitope. [Figure 1B]A compound having albumin as a biomolecular scaffold that binds to an antibody against a peptide derived from the human AChR protein MIR (associated with myasthenia gravis). The mice were pre-immunized with a peptide vaccine having the AChR MIR model epitope. [Figure 1C] A compound having immunoglobulin as a biomolecular scaffold that binds to an antibody against EBNA1 (associated with pre-eclampsia). The mice were pre-immunized with a peptide vaccine having the EBNA-1 model epitope. [Figure 1D] A compound having haptoglobin as a biomolecular scaffold that binds to an antibody against EBNA1 (associated with pre-eclampsia). The mice were pre-immunized with a peptide vaccine containing the EBNA-1 model epitope. [Figure 1E] The selectivity was demonstrated using the same immunoglobulin-based compound of the invention that binds to an antibody against EBNA1, as used in the experiment shown in Panel C. The mice were pre-immunized with an unrelated amino acid sequence. No decrease in titer occurred, demonstrating the selectivity of the compound.

[0040] [Figure 2] The compounds of the present invention are non-immunogenic and do not induce antibody formation after repeated injection into mice. Animals C1-C4 and C5-C8 were intraperitoneally treated with two different compounds of the present invention. Control animal C was vaccinated with a KLH-peptide derived from the human AChR protein MIR. BSA-conjugated peptide probes T3-1, T9-1, and E005 (gray bars in the graph) were used at a 1:100 dilution for antibody titer detection by standard ELISA and compared with the vaccinated control animal C. This showed that antibody induction was not observed in animals treated with the compounds of the present invention (y-axis, OD450nm).

[0041] [Figure 3]It is possible to deplete antibodies in vitro using SADCs that have multiple copies of monovalent or divalent peptides. SADCs having monovalent or divalent peptides are extremely suitable for adsorbing antibodies and, therefore, for depleting them. "Monovalent" means that a peptide monomer is bound to the biopolymer scaffold (i.e., n=1), and "divalent" means that a peptide dimer is bound to the biopolymer scaffold (i.e., n=2). In this case, the divalent peptide is "homodivalent". That is, the peptide n-mer of the SADC is E006-spacer-E006.

[0042] [Figure 4] Rapid and selective antibody depletion in mice using various SADC biomolecular scaffolds. The treatment groups (especially SADC-TF) showed a rapid and significant decrease in antibodies at 24 hours compared to the mock-treated control group, SADC-CTL (containing unrelated peptides). SADCs with albumin scaffolds are SADC-ALB; SADCs with immunoglobulin scaffolds are SADC-IG; SADCs with haptoglobin scaffolds are SADC-HP; and SADCs with transferrin scaffolds are SADC-TF.

[0043] [Figure 5] Detection of SADC in plasma 24 hours after SADC injection via the peptide portion of SADC. Both haptoglobin scaffold-based SADCs (SADC-HP and SADC-CTL) showed relatively short plasma half-lives. This is superior to SADCs with other biomolecular scaffolds such as SADC-ALB, SADC-IG, or SADC-TF. SADC with an albumin scaffold is SADC-ALB; SADC with an immunoglobulin scaffold is SADC-IG; SADC with a haptoglobin scaffold is SADC-HP; and SADC with a transferrin scaffold is SADC-TF.

[0044] [Figure 6]Detection of SADC-IgG complexes in plasma 24 hours after SADC injection. Compared to SADCs with other biomolecular scaffolds, haptoglobin-based SADCs were rapidly eliminated. SADCs with an albumin scaffold are SADC-ALB; SADCs with an immunoglobulin scaffold are SADC-IG; SADCs with a haptoglobin scaffold are SADC-HP; and SADCs with a transferrin scaffold are SADC-TF.

[0045] [Figure 7] In vitro analysis of SADC-IgG complex formation. SADC-TF and SADC-ALB animals showed significant immune complex formation and binding to C1q. This is reflected in the strong signal and, in the case of 1000 ng / ml SADC-TF, the rapid decrease in signal due to the transition from antigen-antibody equilibrium to antigen excess. On the other hand, in vitro immune complex formation with SADC-HP or SADC-IG was significantly less efficient when measured in this assay. These findings support the finding that haptoglobin scaffolds are advantageous over other SADC biomolecular scaffolds because they tend to activate the complement system less. SADCs with albumin scaffolds are SADC-ALB; SADCs with immunoglobulin scaffolds are SADC-IG; SADCs with haptoglobin scaffolds are SADC-HP; and SADCs with transferrin scaffolds are SADC-TF.

[0046] [Figure 8] Measurement of IgG capture by SADC in vitro. SADC-HP showed significantly lower antibody binding ability in vitro compared to SADC-TF or SADC-ALB. SADC with an albumin scaffold is SADC-ALB; SADC with an immunoglobulin scaffold is SADC-IG; SADC with a haptoglobin scaffold is SADC-HP; and SADC with a transferrin scaffold is SADC-TF. [Modes for carrying out the invention]

[0047] The following detailed description relates to all of the above aspects of the present invention, unless expressly excluded.

[0048] The depletion of undesirable antibodies in the body (as achieved by the present invention) is advantageous, for example, in autoimmune diseases, organ / cell transplantation, or blood transfusion, or against antibodies to biological agents, replacement therapies, or viral gene delivery vectors (such as AAV), as well as in diagnostic imaging and emergency interventions after antibody treatment or active vaccination. In particular, regarding autoimmune diseases, hundreds of autoimmune conditions are associated with autoantibodies that bind to defined self-epitopes or neoepitopes present in the body. The organs or tissues that may be affected by disease-causing autoantibodies appear to be virtually limitless. Table 1 shows some examples to illustrate the diversity of indications in which selectively targeting undesirable antibodies is beneficial.

[0049] [Table 1]

[0050] For example, in transplant medicine, undesirable alloantibodies can be produced. Alloantibodies are antibodies against foreign tissue antigens and can contribute to accelerating graft rejection after transplantation (Garces et al, 2017). During tissue, bone marrow, and stem cell transplantation, foreign tissue antigens are recognized by T cells and B cells that produce antibodies against major and minor histocompatibility antigens. There is an inverse correlation between graft survival and alloantibody concentration, which supports the pathogenic role of alloantibodies. Furthermore, it has been shown that depleting undesirable blood group antibodies before and after ABO-incompatible organ transplantation is beneficial for graft survival (Rummler et al, 2016).

[0051] Antidrug antibodies (ADAs), sometimes called neutralizing antibodies (nABs), are classified as undesirable antibodies. Their existence became apparent with the emergence of biological agents that possess epitopes that induce an antidrug antibody response upon recognition as "foreign." This immune response can induce neutralizing antibodies (acting by depleting or blocking the drug, or by forming immune complexes). This phenomenon correlates with the amount of the "foreign" sequence in the drug, the drug's inherent immunogenicity, and, importantly, the drug's tendency to aggregate and form complexes once present in plasma (Moussa et al, 2016). Examples of drugs that induce ADAs include certain antibodies such as anti-TNF-alpha antibodies, replacement therapies such as hemophilia factor VIII, enzymes used in enzyme replacement therapy for conditions like Fabry disease, uricase for the treatment of refractory gout, and other types of biological agents such as erythropoietin or interferon.

[0052] Similar to the situation with ADAs, existing or induced undesirable antibodies against gene therapy vectors have become a new problem in the field of gene therapy (see, for example, Mingozzi & High, 2017). Gene therapy is advancing rapidly, showing promising preclinical and clinical outcomes not only for adeno-associated virus (AAV) but also for other viral vector gene delivery vectors. This is particularly important for hematological disorders such as hemophilia, or for several other genetic diseases involving Gaucher disease, porphyria, hemochromatosis, or enzyme deficiencies. Much effort has been put into optimizing AAV vectors, but the problem of existing or newly induced antibodies against these vectors, as well as their T-cell immunogenicity, remains unresolved. Several strategies have been proposed to overcome B-cell and T-cell immunity, including, for example, serological pre-selection of eligible target patients for AAV treatment, high-dose vector administration, capsid decoys that pre-adsorb or deplete existing or newly induced AAV antibodies, co-administration of decoy T-cell receptors, or more non-selective approaches such as concomitant immunosuppression. More practical approaches have included AAV serotype switching, plasmapheresis, selective immunoapheresis, or topical application of AAV vectors. Essentially, immunological strategies involve either immunosuppression or tolerance induction. However, none of these strategies have been able to satisfactorily solve the problem of existing neutralizing anti-AAV antibodies (see, for example, Majowicz et al.). The main drawback of the capsid decoy strategy was that empty capsids were processed by target cells in the same way as intact AAV particles, promoting antigen presentation by MHC I and T-cell stimulation, ultimately providing an immunostimulatory effect.

[0053] In recent years, more than 2,000 clinical trials for gene therapy (mostly Phase I or Phase II) have been conducted. Monogenetic diseases still constitute a significant portion of the typical indications for gene-based therapy. These include a wide variety of indications, such as primary immunodeficiency, hereditary neurological disorders, cystic fibrosis, eye diseases, abnormal hemoglobin disorders, hemophilia, alpha-1 antitrypsin deficiency, lipoprotein lipase deficiency, enzyme deficiencies, and many others. Other forms of gene therapy-based strategies, such as chimeric antigen receptor T cells (CAR T cells), are rapidly advancing, but still carry the risk of humoral responses to functional components of the system, such as switches, suicide gene products, or other non-self and modified protein components, or to novel antigens resulting from uncontrolled gene insertions into viral gene delivery components or protein-coding sequences. Mechanisms of gene therapy include gene repair strategies, genome editing technologies, and stable or transient gene expression strategies. As mentioned above, a common challenge remains: patients may possess pre-existing neutralizing antibodies against viral gene therapy vectors, which can reduce their effectiveness. Importantly, viral gene therapy vectors often induce T cell responses, as well as neutralizing antibodies against viral proteins and their products. Furthermore, antibody or T cell responses can be induced against the gene product itself, or against introduced DNA editing mechanisms, such as CRISPR / Cas9 components containing naturally occurring or artificially modified endonucleases (e.g., prototype Cas9) that can be applied to therapeutic genome editing. Therefore, neutralizing antibodies that affect the effectiveness of gene therapy remain a major challenge in the development of viral gene therapy vectors, especially when AAV, lentiviruses, or retroviruses are used.

[0054] Finally, in terms of safety interventions in active immunization trials (i.e., therapeutic vaccination) or passive treatment with antibodies or antibody-like compounds, there is a need for interventional drugs to rapidly and selectively remove antibodies, such as therapeutic antibodies or antibody-like biotherapeutic compounds that cause complications, under emergency conditions. In these situations, there is a particular lack of rapid and effective selective antibody reduction strategies.

[0055] The present invention provides a particularly suitable solution to the lack of adequate therapeutic strategies for rapidly and safely removing unwanted antibodies in cases such as myasthenic crisis in myasthenia gravis, before administration of replacement therapy drugs, before application of gene targeting vectors, and in cases of adverse events caused by therapeutic antibodies or any antibody-like biological compounds. The present invention is a platform for flexible and, as desired, personalized biotherapeutic agents that can be adapted to any type of unwanted or harmful polyclonal or monoclonal antibody. In particular, these biotherapeutic agents are suitable for emergency interventions because they can rapidly remove unwanted antibodies.

[0056] The biopolymer scaffold used in the present invention may be a mammalian biopolymer such as a human biopolymer, a non-human primate biopolymer, a sheep biopolymer, a pig biopolymer, a canine biopolymer, or a rodent biopolymer. In particular, the biopolymer scaffold is a protein, especially a plasma protein (unmodified or unmodified in terms of its amino acid sequence). Preferably, the biopolymer scaffold is a mammalian protein such as a human protein, a non-human primate protein, a sheep protein, a pig protein, a canine protein, or a rodent protein. Typically, the biopolymer scaffold is preferably a non-immunogenic and / or non-toxic protein circulating in the plasma of a healthy (human) individual, which can be efficiently removed or recycled by scavenger receptors present, for example, on myeloid cells or hepatic sinusoidal capillary endothelial cells (review by Sorensen et al 2015).

[0057] In particular, the biopolymer scaffold is (preferably human) globulin, preferably selected from the group consisting of immunoglobulin, alpha-1-globulin, alpha-2-globulin, and beta-globulin, and especially immunoglobulin G, haptoglobin, and transferrin. Haptoglobin, in particular, has several advantageous properties, especially a favorable safety profile, as shown in Examples 5-9.

[0058] The biomolecular scaffold may be non-immunogenic (i.e., non-immunogenic in the treated individual) fragments of any of the aforementioned proteins, including (preferably) human albumin, hemopexin, alpha-1-antitrypsin, C1 esterase inhibitor, lactoferrin, or globulin.

[0059] The peptide (i.e., peptide n-mer) is preferably covalently bonded (i.e., covalently bonded) to the biomolecular scaffold via a linker known in the art (non-immunogenic), such as an amine sulfurhydryl linker, a bifunctional NHS-PEG-maleimide linker, or other linkers known in the art. Alternatively, the peptide (i.e., peptide n-mer) can be bonded to the epitope carrier scaffold, for example, by the formation of a disulfide bond (also referred to herein as a "linker") between the protein and the peptide, or by using non-covalent assembly techniques, spontaneous isopeptide bond formation, or non-natural amino acids for bio-orthogonal chemistry by genetic code extension techniques (review by Howarth et al 2018 and Lim et al 2016).

[0060] The compounds of the present invention may contain at least two copies, preferably three to forty copies, of one or more different peptides (which may exist as different forms of peptide n-mers as disclosed herein). The compounds may contain one type of epitope peptide (in other words, an antibody-conjugated peptide or a paratope-conjugated peptide), but the diversity of epitope peptides bound to a single biomolecular scaffold molecule may be, for example, a mixture of eight or fewer different epitope peptides.

[0061] Typically, the peptides present in the compounds of the present invention bind specifically to selected undesirable antibodies; therefore, their sequences are usually chosen and optimized to provide specific binding so as to ensure selectivity for the depletion of undesirable antibodies from the blood. For this purpose, the peptide sequence of the peptide typically corresponds to the whole epitope sequence or a portion of the epitope of the undesirable antibody. The peptides used in the present invention may be further optimized by replacing one, two, or up to four amino acid sites to allow for, for example, adjustment of the binding affinity to the undesirable antibody that needs to be depleted. Such single or multiple amino acid substitution strategies known in the art that can provide a “mimotope” with enhanced binding affinity have been previously developed using phage display strategies or peptide microarrays (see, for example, Application Note, 'T PEPperMAP® - Full Substitution Scan of HA and M13 Epitopes', by PEPperPRINT GmbH, Heidelberg, Germany). In other words, the peptide used in the present invention does not need to be exactly identical to the natural epitope sequence of the undesirable antibody.

[0062] Typically, the peptides used in the compounds of the present invention (e.g., peptides P, P) a , P b , P 1、P2) consists of one or more of the 20 amino acids commonly found in mammalian proteins. Furthermore, the repertoire of amino acids used in the peptide may be extended to post-translation modified amino acids, such as those resulting from post-translational modifications that affect the antigenicity of the protein, particularly oxidative post-translational modifications (see, e.g., Ryan 2014) or modifications to the peptide backbone (see, e.g., Muller 2018), or to non-natural amino acids (see, e.g., Meister et al 2018). These modifications may also be used in the peptide to adapt the binding interaction and specificity between the peptide and the variable region of an undesirable antibody. In particular, the epitope (and therefore the peptide used in the compound of the present invention) may include, for example, citrulline in the case of autoimmune diseases. Furthermore, by introducing modifications to the peptide sequence, the tendency to bind to HLA molecules may be reduced, stability and physicochemical characteristics may be improved, and affinity for the undesirable antibody may be increased.

[0063] In many cases, the undesirable antibodies to be depleted are oligoclonal or polyclonal (e.g., autoantibodies, ADA, or alloantibodies are typically polyclonal or oligoclonal), meaning that the undesirable (polyclonal) antibody covers a larger epitope region of the target molecule. To address this situation, the compounds of the present invention may contain a mixture of two or more epitope peptides (in other words, antibody-conjugated peptides or paratope-conjugated peptides), thereby enabling adaptation to the polyclonal or oligoclonal nature of the undesirable antibody.

[0064] Such polyepitope compounds of the present invention can effectively deplete unwanted antibodies, and are often more effective than monoepitope compounds when the epitopes of the unwanted antibodies extend over a larger range of amino acid sequences.

[0065] It is advantageous that the peptide used in the invention compound be designed to specifically recognize the variable region of the undesirable antibody to be depleted. The peptide sequence used in the present invention may be selected, for example, by applying fine epitope mapping techniques (i.e., epitope walks, peptide deletion mapping, amino acid substitution scanning using peptide arrays as described in Carter et al 2004 and Hansen et al 2013) to the undesirable antibody.

[0066] Preferably, the peptide used in the compound of the present invention (for example, P or P) a or P b ) comprises an epitope or epitope moiety (e.g., at least two, preferably at least three, more preferably at least four, even more preferably at least five, even more preferably at least six, especially at least seven, and even more preferably at least eight amino acids) in one of the following antigens (involved in autoimmune diseases) identified by a UniProt accession number.

[0067] P01023, A8K2U0, P49588, Q5JTZ9, O95477, Q8IZY2, P08183, P33527, O15438, Q96IU4, P00519, P42684, Q9BYF1, P22303, Q99798, P68133, P60709, P63261, P12814, O43707, P61158, Q13705, P37023, O75077, Q9UKQ2, Q76LX8, Q6ZMM2, P35611, P07327, P00325, P35348, P25100, P08588, P07550, P25098, P35626, P30566, P43652, P02771, Q5U5Z8, Q15109, P35573, Q9UL18, Q9UKV8, O00468, P01019, P30556, Q09666, P02765, O43918, Q9Y6K8, Q02952, P14550, P15121, O95154, P02768, P00352, P49189, Q9UM73, P09923, P05187, P03971, P49418, P03950, Q9BY76, Q15327, P15144, P04083, P50995, P07355, Q3ZCQ2, P12429, P09525, P08758, P08133, O76027, Q13367, P27695, Q9BZZ5, P02647, P04114, P02749, P05067, P29972, P55087, Q8N726, P05089, Q9UNA1, P52566, Q99819, Q15052, P07306, P04424, P08243, Q9BXN1, P15336, P13637, P05026, P98194, P20648, P51164, P06576, P48047, P54252, Q8WXX7, P01185, P25311, Q9H6S1, P61769, Q13072, O75531, Q99728, P10415, P41182, P11274, O14503, Q93088, O00499, O15392, P35226, P12643, P18075, Q8N8U9, Q13873, P17213,Q9NP55, Q96DR5, Q8TDL5, P15056, Q7Z569, P38398, P51587, Q58F21, Q8IWQ3, Q8NE79, Q9Y224, Q13901, P02745, P01024, P00915, P00918, P07451, O00555, Q00975, Q9NY47, Q9Y698, Q8TC20, Q05682, P27482, P27797, P27824, P04632, P52907, P42574, Q14790, P31415, P41180, P20810, O15446, P04040, Q9NTU7, Q5M9N0, Q3V6T2, P10147, P13501, P20248, P14635, P24385, Q8ND76, P51681, P49368, P48643, P50990, Q9NZQ7, P28906, P16671, P04234, P15529, P08174, P13987, P01732, P21926, P30305, P12830, P55291, P22223, P55283, P06493, P42771, P51861, Q01850, Q9H211, P13688, P06731, Q9UNI1, P49450, P07199, Q03188, Q02224, P49454, Q9H3R5, Q92674, Q6IPU0, Q7L2Z9, A8MT69, Q5JTW2, P00751, P08603, Q03591, P36980, Q02985, Q9P2M7, O95992, Q14839, P10645, P36222, Q15782, Q9UKJ5, Q9Y259, P11229, P08172, P20309, P08173, P08912, P02708, Q9UGM1, P11230, Q8NCH0, Q99828, O75339, Q14011, Q07065, P12277, Q96MX0, P06732, A8K7I4, O95832, O75508, P30622, Q96KN2, Q12860, Q02246, Q8IWV2, O94779, Q9UQ52, P78357, Q9UHC6, Q7Z7A1, P38432, Q5TAT6,Q9UMD9, P02452, Q01955, P29400, Q14031, P12111, Q02388, Q9Y215, P49747, Q14019, P00450, P16870, Q8TCG5, P17927, Q9NS37, Q9UJA2, P02741, P02511, P53674, O95825, O75390, Q9Y600, P04141, P09919, P0DML2, Q14406, Q6UVK1, Q01459, Q9GZU7, P16410, P35222, P53634, P07339, P08311, Q14247, O60494, Q14999, Q86UP6, P61073, P05108, P05093, P04798, P05177, P08686, P11509, P20813, P33261, P11712, P10635, P05181, P08684, Q8N907, P09172, P43146, P07585, P20711, Q16832, Q9NR30, O00571, Q86XP3, Q9NY93, O75398, P35659, P17661, Q96SL1, O94907, P10515, P09622, P36957, P24855, Q8NFT8, O00429, Q8N608, P27487, P42658, Q14195, Q9BPU6, P21728, P14416, Q08554, Q02487, Q14574, Q02413, Q14126, P32926, Q86SJ6, P15924, Q03001, Q9NRD8, Q05923, O75923, O95905, Q9NTX5, Q16610, O43854, P25101, Q15075, P68104, O00418, O95967, P01133, P00533, P20042, P38919, Q04637, P08246, Q12926, Q14576, P26378, P15502, P19622, P06733, P09104, P22413, O43768, P11171, P16422, P07099, P34913, P01588, P11678, P58107, P04626, Q96RT1, Q8IUD2,Q14264, P10768, P03372, Q9Y603, Q92817, Q9Y3B2, Q01780, Q13868, Q9NQT5, Q9NPD3, Q9NQT4, Q5RKV6, Q15024, Q96B26, Q06265, P15311, P00488, P08709, P00451, P00740, P15090, Q14320, P48023, P49327, Q8TES7, P22087, P35555, Q75N90, P09467, P12319, O75015, O75636, Q7L513, P02675, P11362, P62942, Q9UIM3, P20930, Q14315, O75955, Q14254, O43155, P35916, P02751, Q04609, P01225, Q12841, O95954, P02794, P02792, P09958, P35637, P51114, Q9UM11, P35575, O95166, P60520, Q9UBS5, O75899, Q99259, Q05329, Q13065, P22466, Q14376, P04406, P41250, P01350, P15976, P50440, P02774, P01275, Q8N6F7, P23434, P55107, P50395, P56159, Q9UJY5, P01241, P01286, Q9UBU3, P09681, O14908, P29033, Q9NS71, Q6ZMI3, P23415, P15104, Q6IB77, P49915, Q13823, P01148, P30968, Q92805, Q08379, Q08378, Q13439, A6NI86, A8MQT2, Q14789, P07359, P55259, P40197, Q9HCN6, P14770, Q9NQX3, P06744, Q13098, P24298, P18283, P42261, P42262, P42263, P48058, O43424, P39086, Q13002, Q16478, Q05586, Q12879, Q13224, Q4V328, Q13255, P41594, P28799, P07492,P08263, P21266, P78417, P09211, Q00403, P35269, P25092, P08236, P02724, P07305, P16104, O75367, P84243, P12081, Q96D42, P68871, Q13547, Q92769, O15379, P56524, Q9UQL6, P19113, Q9UBI9, P51858, Q00341, Q9NRV9, O00291, O75146, P54198, P16402, P58876, P62805, P19367, P09429, P26583, P04035, Q01581, P54868, P05114, P05204, Q14541, P09651, P22626, Q99729, Q14103, P52597, P31943, P31942, P61978, P14866, Q8WVV9, Q9NSC5, Q99714, Q7Z5P4, P14060, P08238, P14625, P0DMV8, P0DMV9, P34932, P11021, P11142, P04792, Q12988, P10809, Q92598, P08908, Q13639, Q9Y4L1, P10997, Q05084, Q9UMF0, O75874, Q5TF58, Q16666, Q9BYX4, P01563, P01574, P01579, Q9NWB7, P05019, P08069, P01344, Q9NZI8, Q9Y6M1, O00425, P11717, P18065, P17936, P01876, P01877, P01854, P01857, P01859, P01860, P01861, A6NGN9, Q8N6C5, P22301, Q13651, Q08334, Q14005, Q16552, Q96PD4, Q14116, P01583, P01584, P14778, P60568, Q9GZX6, P08700, P05112, P05231, P40189, Q96LU5, Q9NV31, P29218, O14732, P12268, Q9NQS7, P01308, Q96T92, P06213, P46940, Q14653,Q13568, P35568, P17301, P08514, P23229, P20701, P11215, P05107, P05106, P16144, Q14643, Q9Y6Y0, O60674, P17275, Q15046, P16389, P22459, Q9UK17, Q9NZI2, Q9NS61, P78508, P48050, P51787, O43525, Q8N5I3, Q6PI47, P35968, Q9Y4F3, Q96Q89, P43626, P43628, Q5JT82, Q53G59, Q8IXQ5, Q9UKR3, P03952, P26715, P26717, Q13241, P13645, P02533, P19012, P08779, Q04695, P05783, P08727, P12035, Q8N1N4, P05787, Q9NSB2, O15230, P11047, P13473, Q14739, P31025, P13796, P07195, P01130, Q9Y2U8, P09382, P05162, P17931, Q08380, Q3ZCW2, O95970, Q5TDP6, P22888, P49917, P07098, P02545, P20700, Q03252, P61968, P29536, P08519, Q07954, P98164, O75096, Q8TF66, Q32MZ4, Q8ND56, Q9Y4Z0, P02788, Q17RY6, P20645, Q8NHW3, P20916, P43358, O15479, O60732, Q9H0U3, P46821, P11137, Q16584, O43318, P45984, Q16644, P21941, O00339, P56270, P02144, Q9UIS9, P11226, P02686, Q01726, P32245, Q8IVS2, Q99705, Q969V1, Q8TDD5, Q8NE86, P40925, Q00987, O00255, P50579, P46013, Q16655, P03956, P45452, P08253, P09237, P14780, Q13201, Q13875, Q16653,Q13724, Q14149, Q9UBU8, O00566, Q99547, P40238, P05164, Q00013, Q9NZW5, P25189, P22897, Q9Y605, P82909, P43246, P52701, Q13421, P26038, Q9UJ68, P26927, Q13043, Q04912, Q9NZJ7, Q86UE4, P15941, Q8WXI7, O15146, Q9UIF7, P10242, P01106, Q99417, P12524, Q8N699, P12882, P35580, P35749, Q9UKX3, Q7Z406, Q9Y2K3, Q9UKX2, P11055, Q9Y623, P13533, P12883, A7E2Y1, P13535, P35579, B0I1T2, P54296, Q14CX7, E9PAV3, Q13765, Q8WY41, Q96I59, Q9UBB6, Q9UHB4, Q00604, P28331, P20929, P07196, P07197, Q8NG66, Q8TD19, O60524, O94856, P01138, Q8N4C6, P30414, P59047, Q8N427, Q13253, Q15155, P29475, P51513, Q9UNW9, P55786, O60500, P06748, P01160, P17342, P01303, Q9Y5X4, Q8IXM6, Q9ULB1, Q9HDB5, Q9Y4C0, Q9NXX6, P04629, Q16620, Q16288, Q02818, P80303, Q14980, P49790, Q8TEM1, O15504, Q14990, Q5BJF6, Q9ULJ1, Q6UX06, P78380, P41143, P35372, Q9P0S3, Q92791, Q9UQ80, Q13310, Q9UM07, Q7Z2X7, Q5JRK9, Q96GU1, Q13177, Q99497, P09874, P40424, Q15154, P12004, P29120, Q8WUM4, O95263, O76083, P16234, P09619, O00330, P30101, Q8N165,O00151, Q5T2W1, P16284, P02776, P10720, P35080, P18669, P00558, O95394, P35232, Q99623, Q9BVI0, Q92576, O43175, P11309, O75364, Q9Y446, P04054, Q13018, P16885, Q15149, Q9H7P9, P40967, P29590, Q01453, Q9NR77, P54277, P16233, P54317, Q8ND90, Q9UL42, P00491, Q9H9Y6, O14802, Q99575, P16435, Q15063, Q01851, Q12837, Q15181, P62937, O60437, P35813, P01298, Q9HAZ2, P32119, Q13162, P30041, P13727, Q92954, P17612, P17252, P01236, P04553, P04554, O60678, P04070, Q9UNN8, P54821, Q99811, P07477, P24158, Q9BXM0, O43653, O75475, P20618, P40306, P49721, P28074, P28062, P28065, P61289, Q6PGN9, P26599, Q8WV60, P01270, P06454, Q06124, Q9Y2R2, P08575, Q12913, Q16849, Q92932, Q86Y79, Q9UHX1, P20472, Q9BRP8, P51153, Q9UI14, Q15276, P63244, Q92878, Q06609, P04049, Q15311, Q9UKM9, Q14498, P38159, P10745, Q06330, P53805, O95199, Q9P258, P35243, P46063, P05451, Q8IX06, P57771, P08100, P12271, O60930, O00584, Q9ULK6, Q99942, Q9UBF6, P13489, O75116, Q01973, P15927, Q9Y2J0, Q9UNE2, Q02878, P05388, P05386, P05387,Q9BUL9, P78346, P78345, P62277, P60866, O75676, O43159, Q15404, O00442, Q92541, Q9NQC3, Q9Y265, Q9Y230, P48443, P21817, Q92736, P31151, P04271, P0DJI8, P0DJI9, P10523, P49591, O43290, Q99590, Q8WTV0, Q14108, P13521, P05408, Q14524, Q9BWW7, P34741, Q86SQ7, Q9UDX4, Q13228, P16109, P04279, Q9HC62, P49908, Q9HD40, P01009, P05543, P30740, P29508, P48594, P35237, P05121, P07093, P05155, Q9BYW2, Q7Z333, Q8N474, Q9BWM7, Q99961, O15266, O60902, Q9NYZ4, Q9Y336, Q9H0K1, Q14190, Q13239, Q14493, Q9H0C2, P12235, P05141, Q9H2B4, O43511, P11168, Q8IWU4, O00400, P08195, Q8IWA5, P48751, Q9Y6R1, Q9BRV3, Q92911, P37840, O76070, P08621, P09012, P14678, P09234, P62314, P62316, P62318, P62304, P62306, P62308, P63162, O14512, P00441, P04179, Q9BQB4, O00570, P56693, P35716, O15370, O60248, Q9UN79, O95416, Q9H6I2, P35713, P48431, Q9Y651, P41225, O94993, Q06945, P35711, P35712, Q9BT81, P57073, P48436, P08047, P23497, Q13342, Q9H930, Q15506, Q8N0X2, P00995, P16150, O43791, P10451, Q8TCT8, Q8TCT7, Q8TCT6, Q13813,Q13501, P10124, P61011, O76094, Q05066, P05455, O43805, P61278, Q13586, Q9P246, P31948, P49842, P16949, Q7Z7C7, Q13033, O75558, P61266, Q13190, Q8IWZ8, Q9Y2Z0, Q8IWU6, P63165, P61956, P17600, P08247, P21579, P37837, Q15633, Q13148, P26639, Q9NYW0, P20226, O60806, P24557, P17987, O60522, O14746, P02787, P05549, Q92734, P10646, P02786, P01266, P01137, P21980, Q08188, P49221, P07204, P40225, P10827, P10828, Q9UPZ6, P31483, P29401, Q9Y490, O60602, Q8TDI7, P17152, P42167, P42166, P01375, O00300, P43489, P19237, P48788, P19429, P13805, P45379, P45378, P09430, Q8NDV7, P11387, Q969P6, P11388, Q13472, O95985, P04637, Q9H3D4, O15350, P60174, P09493, P07202, P12270, P56180, O43280, Q92519, Q96RU7, P19474, O15164, Q9UPN9, Q6AZZ1, P10155, P48995, Q13507, Q7Z4N2, Q7Z2W7, Q9HBA0, Q9BZW7, P01222, P16473, Q9H2G4, Q14166, Q8WZ42, P02766, P07437, O00294, Q15672, Q9P2K2, Q86VQ3, Q6A555, P14679, Q9BZF9, Q13404, Q14139, O95155, P11441, Q9UMX0, P17480, P09936, P15374, Q9Y3C8, P19224, P16662, P07911, Q8TCY9,Q9Y6N9, Q13107, P63027, Q15836, P18206, P55072, P21796, P08670, P04275, O75083, Q14191, P98170, Q13426, P13010, P12956, P67809, Q9Y2T7, O43829, Q13105, Q15915, O95409, Q8N9L1, Q9UDV7, Q9Y3S2, Q9UL40, Q14966, Q9H0M5, Q9Y5V0, Q96C28, Q9H5H4.,

[0068] More preferably, the peptide used in the compound of the present invention (for example, P or P) a or P b ) comprises an epitope or epitope moiety (e.g., at least two, preferably at least three, more preferably at least four, even more preferably at least five, even more preferably at least six, especially at least seven, and even more preferably at least eight amino acids) in one of the following histocompatibility antigens identified by a UniProt accession number.

[0069] P04233, O15523, O14602, Q30201, P01891, P01892, P04439, P05534, P10314, P10316, P13746, P16188, P16189, P16190, P18462, P30443, P30447, P30450, P30453, P30455, P30456, P30457, P30459, P30512, Q09160, P01889, P03989, P10319, P18463, P18464, P18465, P30460, P30461, P30462, P30464, P30466, P30475, P30479, P30480, P30481, P30483, P30484, P30485, P30486, P30487, P30488, P30490, P30491, P30492, P30493, P30495, P30498, P30685, Q04826, Q29718, Q29836, Q29940, Q31610, Q31612, Q95365, P04222, P10321, P30499, P30501, P30504, P30505, P30508, P30510, Q07000, Q29865, Q29960, Q29963, Q95604, Q9TNN7, P28067, P28068, P06340, P13765, P20036, P04440, P01909, P01906, P01920, P05538, P01903, P01911, P01912, P04229, P13760, P13761, P20039, Q29974, Q30134, Q30167, Q5Y7A7, Q95IE3, Q9GIY3, Q9TQE0, P79483, P13762, Q30154, P13747, P30511, P17693, Q9BY66, Q29983, Q29980, P22090, Q03519, O14607, P08048.

[0070] Other preferred examples include the peptide used in the compound of the present invention (e.g., peptide P or P). a or P b) refers to the following antigens in AAV antigens (such as AAV capsid proteins; see Example 10, for example), particularly when the AAV is one of AAV-8, AAV-9, AAV-6, AAV-2, and AAV-5, or identified by the UniProt accession number of the gene delivery vector: A9RAI0, B5SUY7, O41855, O56137, O56139, P03135, P04133, P04882, P08362, P10269, P12538, P69353, Q5Y9B2, Q5Y9B4, Q65311, Q6JC40, Q6VGT5, Q8JQF8, Q8JQG0, Q98654, Q9WBP8, Q9YIJ1; The peptide comprises an epitope or epitope moiety (for example, at least two, preferably at least three, more preferably at least four, even more preferably at least five, even more preferably at least six, particularly at least seven, and even more preferably at least eight amino acids) in one of the proteins, wherein the peptide preferably comprises the AAV-8 capsid protein sequence LQQQNT (SEQ ID NO: 18), TTTGQNNNS (SEQ ID NO: 19), or GTANTQ (SEQ ID NO: 20).

[0071] Further preferred examples include the peptide used in the compound of the present invention (e.g., peptide P or P). a or P b ) refers to the following antigens in AAV antigens (such as AAV capsid proteins; see Example 10, for example), particularly when the AAV is one of AAV-8, AAV-9, AAV-6, AAV-2, and AAV-5, or identified by the UniProt accession number of the gene delivery vector: A9RAI0, B5SUY7, O41855, O56137, O56139, P03135, P04133, P04882, P08362, P10269, P12538, P69353, Q5Y9B2, Q5Y9B4, Q65311, Q6JC40, Q6VGT5, Q8JQF8, Q8JQG0, Q98654, Q9WBP8, Q9YIJ1; The peptide comprises an epitope or epitope moiety (for example, at least two, preferably at least three, more preferably at least four, even more preferably at least five, even more preferably at least six, particularly at least seven, and even more preferably at least eight amino acids) in one of the proteins, wherein the peptide preferably comprises the AAV-8 capsid protein sequence LQQQNT (SEQ ID NO: 18), TTTGQNNNS (SEQ ID NO: 19), or GTANTQ (SEQ ID NO: 20).

[0072] Further preferred examples include the peptide used in the compound of the present invention (e.g., peptide P or P). a or P b ) comprises an epitope or epitope moiety (e.g., at least two, preferably at least three, more preferably at least four, even more preferably at least five, even more preferably at least six, especially at least seven, and even more preferably at least eight amino acids) in one of the antigens of the following drugs / active agents identified in Table 2.

[0073] [Table 2-1]

[0074] [Table 2-2]

[0075] [Table 2-3]

[0076] DrugBank (https: / / www.drugbank.ca / ); KEGG: Kyoto Encyclopedia of Genes and Genomes (https: / / www.genome.jp / kegg / ).

[0077] The respective DrugBank and KEGG database accession numbers are shown in Table 3 below (the versions of the DrugBank and KEGG databases are as of March 20, 2019).

[0078] [Table 3-1]

[0079] [Table 3-2]

[0080] [Table 3-3]

[0081] [Table 3-4]

[0082] Drugs / active agents to which the present invention can be applied (i.e., drugs / active agents that produce undesirable antibodies that may be depleted by the compounds of the present invention) are also disclosed in Spiess et al 2015 and Runcie et al 2018. These may be scFv, Fab2, Fab3, Bis-scFv, divalent minibodies, diabodies, triabodies, or tetrabodies. Furthermore, such drugs / active agents may be affibody molecules (Protein Data Bank: 1LP1), affimers (Protein Data Bank: 1NB5), affitin molecules (Protein Data Bank: 4CJ2), anticalin molecules (Protein Data Bank: 4GH7), atrimers (Protein Data Bank: 1TN3), fynomers (Protein Data Bank: 1M27), armadillo repeat proteins (Protein Data Bank: 4DB9), Kunitz domain inhibitors (Protein Data Bank: 1ZR0), knottin molecules (Protein Data Bank: 2IT7), or designed ankyrin repeat proteins (Protein Data Bank: 2Q4J); the Protein Databank (PDB) version is as of March 20, 2019. Further suitable drugs / active agents are disclosed, for example, in International Publication No. 2017 / 220569, International Publication No. 2017 / 087589, U.S. Patent No. 82100547, and European Patent Application Publication No. 1697421 (particularly its Sequence ID No. 1). As described above, the peptides used in the compounds of the present invention (e.g., peptide P or P) a or P b) may contain an epitope or epitope moiety (for example, at least two, preferably at least three, more preferably at least four, even more preferably at least five, even more preferably at least six, particularly at least seven, and even more preferably at least eight amino acids) in any one amino acid sequence of the drug / active agent disclosed in the above source.

[0083] Furthermore, it is highly preferable that the peptides used in the compounds of the present invention do not bind to any HLA class I or HLA class II molecules (i.e., in the individual being treated, e.g., a human) in order to prevent presentation and stimulation via T cell receptors in vivo and induce an immune response. Generally, in contrast to antigen-specific immune tolerance approaches, suppressive (or stimulating) T cell responses are undesirable. Therefore, in order to avoid T cell epitope activity as much as possible, the peptides of the compounds of the present invention (e.g., peptides P, P) are not bound to any HLA class I or HLA class II molecules. a , P b , P 1、 Alternatively, P2) preferably satisfies one or more of the following characteristics:

[0084] • In order to reduce the possibility that the peptides used in the compounds of the present invention bind to HLA class II or class I molecules, the peptides (e.g., peptides P, P) a , P b , P 1、 Alternatively, P2) has a preferred length of 4 to 8 amino acids. However, slight variations in length are acceptable.

[0085] • To further reduce the likelihood of such peptides binding to HLA class II or class I molecules, it is preferable to test candidate peptide sequences using HLA binding prediction algorithms such as NetMHCII-2.3 (review by Jensen et al 2018). Preferably, the peptides used in the compound of the present invention (e.g., peptides P, P) a , P bFor P1, or P2, the (predicted) HLA binding (IC50) is at least 500 nM. More preferably, the HLA binding (IC50) is higher than 1000 nM, and especially higher than 2000 nM (see, e.g., Peters et al 2006). To reduce the likelihood of HLA class I binding, NetMHCpan 4.0 may be applied for prediction (Jurtz et al 2017).

[0086] • To further reduce the likelihood of such peptides binding to HLA class I molecules, the NetMHCpan Rank percentile threshold may be set to a 10% background level, according to Kosaloglu Yalcin et al 2018 (PMID:30377561). Preferably, the peptides used in the compound of the present invention (e.g., peptides P, P) a , P b P1, or P2, therefore, has a % rank value greater than 3, preferably greater than 5, and more preferably greater than 10, according to the NetMHCpan algorithm.

[0087] To further reduce the likelihood of such peptides binding to HLA class II molecules, it is beneficial to perform in vitro HLA binding assays commonly used in this field, such as refolding assays, iTopia, peptide rescue assays, or array-based peptide binding assays. Alternatively, or in addition to these, analysis using LC-MS, such as in the review by Gfeller et al. 2016, may be utilized.

[0088] To more potently reduce the titer of the aforementioned undesirable antibody, it is preferable to cyclize the peptide used in the present invention (see also Example 4). Thus, in a preferred embodiment, at least one P is a circularized peptide. Preferably, at least 10% of all P are circularized peptides, more preferably at least 25% of all P are circularized peptides, even more preferably at least 50% of all P are circularized peptides, even more preferably at least 75% of all P are circularized peptides, even more preferably at least 90% of all P are circularized peptides, even more preferably at least 95% of all P are circularized peptides, and especially preferably all P are circularized peptides. Several common techniques can be used for cyclizing peptides. See Ong et al 2017, etc. Needless to say, as used herein, “cyclic peptide” should be understood as a peptide that is itself cyclized, as disclosed, for example, in Ong et al. (and not, for example, grafted onto a cyclic scaffold with a sequence length longer than 13 amino acids). Such peptides may also be referred to as cyclopeptides in this specification.

[0089] Furthermore, in order to more strongly reduce the titer of the undesirable antibody compared to the amount of scaffold used, in one embodiment of the compound of the present invention, independently for each of the peptide n-mers, n is at least 2, more preferably at least 3, and particularly at least 4. Typically, to avoid complexity in the manufacturing process, independently for each of the peptide n-mers, n is less than 10, preferably less than 9, more preferably less than 8, even more preferably less than 7, even more preferably less than 6, and particularly less than 5. In order to benefit from the higher affinity due to the divalent binding of the undesirable antibody, it is extremely preferable that n is 2 for each of the peptide n-mers.

[0090] Due to the undesirable polyvalent binding of antibodies, it is advantageous that the peptide dimer or n-mer be separated by a hydrophilic, structurally flexible, immunologically inactive, non-toxic, clinically approved spacer, such as a (hetero)bifunctional and trifunctional polyethylene glycol (PEG) spacer (e.g., NHS-PEG-maleimide) (various PEG chains are available, and PEG is FDA approved). Immunologically inactive and non-toxic synthetic polymers or glycans are also suitable alternatives to the PEG linker. Therefore, in connection with the present invention, the spacer (e.g., spacer S) is preferably selected from PEG molecules or glycan molecules. For example, the spacer, such as PEG, may be introduced during peptide synthesis. Such a spacer (e.g., PEG spacer) may have a molecular weight of, for example, 10,000 daltons. Clearly, in connection with the present invention, the covalent bonding of the peptide n-mer to the biopolymer scaffold via a linker may be achieved, for example, by directly bonding the linker to the spacer of the peptide n-mer (for example, not to the peptide of the peptide n-mer).

[0091] Preferably, each peptide n-mer is covalently bonded to the biopolymer scaffold via a linker.

[0092] The linker used herein may be selected from, for example, disulfide crosslinks and PEG molecules.

[0093] According to a more preferred embodiment of the compounds of the present invention, P is independently P a or P b That is the case.

[0094] Furthermore, in the first peptide n-mer, each P is P a And in the second peptide n-mer, each P is P b It is preferable that P a and / or P b It is circularized.

[0095] To reduce antibody titer, a bivalent bond is particularly suitable. Therefore, in one preferred embodiment, The first peptide n-mer is P a -SP a , and the second peptide n-mer is P a -SP a Is it, The first peptide n-mer is P a -SP a , and the second peptide n-mer is P b -SP b Is it, The first peptide n-mer is P b -SP b , and the second peptide n-mer is P b -SP b Is it, The first peptide n-mer is P a -SP b , and the second peptide n-mer is P a -SP b Is it, The first peptide n-mer is P a -SP b , and the second peptide n-mer is P a -SP a is, or The first peptide n-mer is P a -SP b , and the second peptide n-mer is P b -SP b That is the case.

[0096] To enhance efficacy, particularly in autoimmune diseases (which are usually caused by polyclonal antibodies; see above), in a preferred embodiment, the first peptide n-mer is different from the second peptide n-mer. For similar reasons, preferably, the peptide P a The peptide P b It is different from the peptide P a and the peptide P bThese are two different epitopes of the same antigen, or two different epitope regions of the same epitope.

[0097] In particular, to better target polyclonal antibodies, the peptide P a and the peptide P b It is advantageous that the molecules contain the same amino acid sequence fragment, and that the amino acid sequence fragment has a length of at least 2 amino acids, preferably at least 3 amino acids, more preferably at least 4 amino acids, even more preferably at least 5 amino acids, even more preferably at least 6 amino acids, even more preferably at least 7 amino acids, particularly at least 8 amino acids, and even more preferably at least 9 amino acids.

[0098] Furthermore, in order to more strongly reduce the titer of the undesirable antibody compared to the amount of scaffold used, the compound comprises a plurality of the first peptide n-mers (e.g., up to 10, 20, or 30) and / or a plurality of the second peptide n-mers (e.g., up to 10, 20, or 30).

[0099] In order to more strongly reduce the titer of the undesirable antibody compared to the amount of scaffold used, the compound is at least The third peptide n-mer of the following general formula: P(-SP) (n-1) [P is a peptide having a sequence length of 2 to 13 amino acids, preferably 3 to 11 amino acids, more preferably 4 to 9 amino acids, and especially particularly 5 to 8 amino acids, and S is a non-peptide spacer, Preferably, P is independently P c And P c It is a peptide having a sequence length of 2 to 13 amino acids, preferably 3 to 11 amino acids, more preferably 4 to 9 amino acids, and especially particularly 5 to 8 amino acids. More preferably, P c It is circularized. The fourth peptide n-mer of the following general formula: P(-SP) (n-1) [Each P is independently a peptide having a sequence length of 2 to 13 amino acids, preferably 3 to 11 amino acids, more preferably 4 to 9 amino acids, particularly preferably 5 to 8 amino acids, S is a non-peptide spacer, Preferably, each P is independently P d wherein P d is a peptide having a sequence length of 2 to 13 amino acids, preferably 3 to 11 amino acids, more preferably 4 to 9 amino acids, particularly preferably 5 to 8 amino acids, More preferably, P d is cyclized]; The 5th peptide n-mer of the following general formula: P(-S-P) (n-1) [Each P is independently a peptide having a sequence length of 2 to 13 amino acids, preferably 3 to 11 amino acids, more preferably 4 to 9 amino acids, particularly preferably 5 to 8 amino acids, S is a non-peptide spacer, Preferably, each P is independently P​​​​​​​​​​​​​​​​​​​​​​​​​​​ P(-SP) (n-1) [P is a peptide having a sequence length of 2 to 13 amino acids, preferably 3 to 11 amino acids, more preferably 4 to 9 amino acids, and especially particularly 5 to 8 amino acids, and S is a non-peptide spacer, Preferably, P is independently P g And P g It is a peptide having a sequence length of 2 to 13 amino acids, preferably 3 to 11 amino acids, more preferably 4 to 9 amino acids, and especially particularly 5 to 8 amino acids. More preferably, P g It is circularized. The n-mer of the eighth peptide in the following general formula: P(-SP) (n-1) [P is a peptide having a sequence length of 2 to 13 amino acids, preferably 3 to 11 amino acids, more preferably 4 to 9 amino acids, and especially particularly 5 to 8 amino acids, and S is a non-peptide spacer, Preferably, P is independently P h And P h It is a peptide having a sequence length of 2 to 13 amino acids, preferably 3 to 11 amino acids, more preferably 4 to 9 amino acids, and especially particularly 5 to 8 amino acids. More preferably, P h It is circularized. The 9th peptide n-mer of the following general formula: P(-SP) (n-1) [P is a peptide having a sequence length of 2 to 13 amino acids, preferably 3 to 11 amino acids, more preferably 4 to 9 amino acids, and especially particularly 5 to 8 amino acids, and S is a non-peptide spacer, Preferably, P is independently P i And P i It is a peptide having a sequence length of 2 to 13 amino acids, preferably 3 to 11 amino acids, more preferably 4 to 9 amino acids, and especially particularly 5 to 8 amino acids. More preferably, P i It is circularized. The tenth peptide n-mer of the following general formula: P(-SP) (n-1) [P is a peptide having a sequence length of 2 to 13 amino acids, preferably 3 to 11 amino acids, more preferably 4 to 9 amino acids, and especially particularly 5 to 8 amino acids, and S is a non-peptide spacer, Preferably, P is independently P j And P j It is a peptide having a sequence length of 2 to 13 amino acids, preferably 3 to 11 amino acids, more preferably 4 to 9 amino acids, and especially particularly 5 to 8 amino acids. More preferably, P j It is circularized. It may also include that.

[0100] Peptide P c ~P j In this specification, peptide P a and P b It may have one or more of the same features (e.g., sequences) as those disclosed to [the relevant entity].

[0101] As explained above, it is highly preferable that the compounds of the present invention are non-immunogenic in mammals, preferably in humans, non-human primates, sheep, pigs, dogs, or rodents.

[0102] In relation to the present invention, non-immunogenic compounds are preferably compounds in which the biomolecular scaffold (if it is a protein) and / or the peptide (in the form of a peptide n-mer) have an IC50 higher than 100 nM, preferably higher than 500 nM, more preferably higher than 1000 nM, and particularly higher than 2000 nM, with respect to the IC50 for HLA-DRB1_0101 predicted by the NetMHCII-2.3 algorithm. The NetMHCII-2.3 algorithm is described in detail by Jensen et al, which is incorporated herein by reference. The algorithm is available at http: / / www.cbs.dtu.dk / services / NetMHCII-2.3 / . More preferably, the non-immunogenic compound (or pharmaceutical composition) does not bind in vivo to any HLA and / or MHC molecules (for example, in mammals, preferably in humans, in non-human primates, in sheep, in pigs, in dogs, or in rodents, or in the individual being treated).

[0103] More preferably, the compound is for the internal isolation (or depletion) of at least one antibody within an organism, preferably in the bloodstream of the organism, and / or for the reduction of the titer of at least one antibody within an organism, preferably in the bloodstream of the organism.

[0104] In another preferred embodiment, the overall sequence of at least one peptide P, preferably at least 10% of all P, more preferably at least 25% of all P, even more preferably at least 50% of all P, even more preferably at least 75% of all P, even more preferably at least 90% of all P, even more preferably at least 95% of all P, and especially all P, optionally excluding the N-terminal and / or C-terminal cysteine, is identical to a sequence fragment of a protein, the protein being identified by one of the UniProt accession numbers disclosed herein, and optionally the sequence fragment containing 5 or fewer, preferably 4 or fewer, more preferably 3 or fewer, even more preferably 2 or fewer, and especially 1 or fewer amino acid substitutions (for the purposes described above, such as mimotope formation).

[0105] In another preferred embodiment, peptide P a The overall sequence, optionally excluding the N-terminal and / or C-terminal cysteine, is identical to the protein sequence fragment, the protein being identified by one of the UniProt accession numbers disclosed herein, and optionally the sequence fragment containing 5 or fewer, preferably 4 or fewer, more preferably 3 or fewer, even more preferably 2 or fewer, and particularly 1 or fewer amino acid substitutions (for the purposes described above, such as mimotope formation).

[0106] In another preferred embodiment, peptide P b The overall sequence, optionally excluding the N-terminal and / or C-terminal cysteine, is identical to the protein sequence fragment, the protein being identified by one of the UniProt accession numbers disclosed herein, and optionally the sequence fragment containing 5 or fewer, preferably 4 or fewer, more preferably 3 or fewer, even more preferably 2 or fewer, and particularly 1 or fewer amino acid substitutions (for the purposes described above, such as mimotope formation).

[0107] In another preferred embodiment, peptide P aThe entire sequence, with the N-terminal and / or C-terminal cysteine ​​arbitrarily removed, is identical to the sequence fragment of the protein, and peptide P b The whole sequence, optionally excluding the N-terminal and / or C-terminal cysteine, is identical to the same or another, preferably another, sequence fragment of the same protein, the protein being identified by one of the UniProt accession numbers listed herein, and optionally, the sequence fragment and / or the other sequence fragment contains five or fewer, preferably four or fewer, more preferably three or fewer, even more preferably two or fewer, and particularly one or fewer amino acid substitutions (for the purposes described above, such as mimotope formation).

[0108] Myasthenia gravis is an autoimmune neuromuscular disorder mediated by autoantibodies that causes a wide range of clinical symptoms, from mild muscle weakness to life-threatening myasthenic crisis with respiratory distress. Approximately 80% of myasthenic patients produce anti-nicotinic acetylcholine receptor (AChR) antibodies that cause postsynaptic complement-mediated dysfunction (Howard 2018), direct AChR blocking, or receptor endocytosis. These disease-causing autoantibodies are primarily against defined immunogenic regions of AChR or MuSK (Ruff 2018). These are representative examples of disease-causing autoantibodies that have been functionally well-characterized. While general immunosuppressive or B-cell targeting strategies exist, there is a need for strategies to rapidly inactivate or deplete only the disease-causing antibodies (not all antibodies, which are mostly protective antibodies), particularly in myasthenic crisis. This is because conventional immunosuppressive treatments such as corticosteroids, IVIG, thymectomy, or plasmapheresis are all unsatisfactory. Until now, there has been no convenient therapeutic intervention in myasthenia gravis that can rapidly and selectively deplete or neutralize the antibodies that cause the disease.

[0109] Rey et al. describe the characterization of human anti-acetylcholine receptor monoclonal autoantibodies derived from peripheral blood of myasthenia gravis patients using a combinatorial library.

[0110] European Patent Application Publication No. 2698386 relates to a fusion protein that claims to specifically suppress autoantibodies, such as autoantibodies involved in myasthenia gravis. The fusion protein comprises an autoantibody binding site and a fragment of the antibody heavy chain constant region that exhibits antibody-dependent cytotoxicity.

[0111] Non-selective B-cell targeting or immunotherapy approaches have not yet become established treatment options for myasthenia gravis. Furthermore, only a few in vivo and in vitro selective antibody depletion or B-cell suppression strategies targeting disease-causing antibodies in myasthenia gravis have been proposed, using indirect or direct targeting approaches to these antibodies (see, e.g., Homma 2017 and Lazaridis 2017). In addition, AChR-specific immunosuppressive therapy using adjuvant AChR vaccines has been proposed (Luo 2015). However, there remains an urgent need for a relatively effective, safe, and rapidly acting selective antibody depletion therapy.

[0112] Accordingly, as outlined, the present invention relates to a compound (for use in the prevention or treatment of myasthenia gravis, particularly in myasthenic crisis), preferably a compound for the isolation (or depletion) of anti-human muscle nicotinic acetylcholine receptor (AChR) antibodies, anti-human muscle-specific receptor tyrosine kinase antibodies, and / or anti-human low-density lipoprotein receptor-associated protein 4 antibodies present in a human organism, wherein the compound comprises a biomolecular scaffold and at least two peptides having a sequence length of 7 to 13 amino acids, each of which independently comprises an AChR subunit alpha sequence identified by UniProt accession number P02708 (optionally, the following sequence fragments may be 5 or fewer, preferably 4 or fewer, more preferably (so that a mimotope is formed) The present invention also relates to a compound comprising a 7-13 amino acid sequence fragment of a muscle-specific receptor tyrosine kinase sequence identified by UniProt accession number O15146, or a low-density lipoprotein receptor-related protein 4 sequence identified by Prot accession number O75096 (optionally, the sequence fragment below includes 5 or fewer amino acid substitutions (preferably 4 or fewer, more preferably 3 or fewer, even more preferably 2 or fewer, particularly 1 or fewer) (for example, so that a mimotope is formed), wherein the peptide is covalently bonded to the biopolymer scaffold, preferably via linkers, and the biopolymer scaffold is selected from the group consisting of human globulin and human albumin.

[0113] In particular, in order to more strongly reduce the titer of the undesirable antibody compared to the amount of scaffold used, the at least two peptides comprise peptide P1 and peptide P2, wherein peptide P1 and peptide P2 comprise identical 7-13 amino acid sequence fragments of AChR subunit alpha (optionally comprising 5 or fewer, preferably 4 or fewer, more preferably 3 or fewer, even more preferably 2 or fewer, particularly 1 or fewer amino acid substitutions (e.g., so as to form a mimotope)) or identical 7-13 amino acid sequence fragments of muscle-specific receptor tyrosine kinase sequence or low-density lipoprotein receptor-associated protein 4 (optionally comprising 5 or fewer, preferably 4 or fewer, more preferably 3 or fewer, even more preferably 2 or fewer, particularly 1 or fewer amino acid substitutions (e.g., so as to form a mimotope)), and P1 and P2 exist in the form of a peptide dimer P1-S-P2, where S is a non-peptide spacer, and the peptide dimer is covalently bonded to the biopolymer scaffold, preferably via a linker.

[0114] Preferably, the sequence fragment of amino acids 7-13 of the AChR subunit alpha is a sequence fragment consisting of amino acids 21-255 of the AChR subunit alpha sequence identified by UniProt accession number P02708 (optionally, the sequence fragment may contain 5 or fewer, preferably 4 or fewer, more preferably 3 or fewer, even more preferably 2 or fewer, and especially 1 or fewer amino acid substitutions (for example, so that a mimotope is formed)).

[0115] In a more preferred embodiment, the sequence fragment of the 7-13 amino acids of the AChR subunit alpha is a fragment of the sequence LKWNPDDYGGVKKIHIPSEK (SEQ ID NO: 1), preferably the sequence WNPDDYGGVK (SEQ ID NO: 2) or VKKIHIPSEK (SEQ ID NO: 3) (optionally, the sequence fragment may contain 5 or fewer, preferably 4 or fewer, more preferably 3 or fewer, even more preferably 2 or fewer, and particularly 1 or fewer amino acid substitutions (for example, so that a mimotope is formed)).

[0116] In a further preferred embodiment, the peptide has a sequence length of 8 to 13 amino acids, preferably 9 to 12 amino acids, more preferably 10 to 12 amino acids, and in particular the peptide consists of the sequence VKKIHIPSEKG (SEQ ID NO: 4) which optionally has an N-terminal and / or C-terminal cysteine ​​residue, and / or optionally the sequence fragment contains 5 or fewer, preferably 4 or fewer, more preferably 3 or fewer, even more preferably 2 or fewer, and particularly 1 or fewer amino acid substitutions (for example, so that a mimotope is formed).

[0117] In a more preferred embodiment, the compound further comprises at least one peptide having a sequence length of 7 to 13 amino acids, wherein the at least one peptide comprises a sequence fragment of 7 to 13 amino acids of a muscle-specific receptor tyrosine kinase sequence identified by UniProt accession number O15146, or a low-density lipoprotein receptor-associated protein 4 sequence identified by UniProt accession number O75096, and the at least one peptide is covalently bonded to the biomolecular scaffold, preferably via a linker.

[0118] Furthermore, in its use in the prevention or treatment of myasthenia gravis (particularly in myasthenic crisis), in one preferred embodiment of the compound of the present invention, at least one P is P a And at least one P is P b And, P a It is a peptide having a sequence length of 5 to 13, preferably 7 to 13 amino acids. P b It is a peptide having a sequence length of 5 to 13, preferably 7 to 13 amino acids. Peptide P aThe entire sequence, with the N-terminal and / or C-terminal cysteine ​​optionally removed, is identical to the protein sequence fragment, the protein being identified by UniProt accession numbers P02708, O15146, or O75096, and optionally the sequence fragment containing 5 or fewer, preferably 4 or fewer, more preferably 3 or fewer, even more preferably 2 or fewer, and particularly 1 or fewer amino acid substitutions. Peptide P b The overall sequence, with the N-terminal and / or C-terminal cysteine ​​optionally removed, is identical to the sequence fragment of the protein, which is identified by UniProt accession numbers P02708, O15146, or O75096, and optionally the sequence fragment contains 5 or fewer, preferably 4 or fewer, more preferably 3 or fewer, even more preferably 2 or fewer, and particularly 1 or fewer amino acid substitutions.

[0119] In some embodiments, P a and / or P b Regarding the above, the sequence fragment of the protein is a sequence fragment consisting of amino acids 21-255 of the AChR subunit alpha sequence identified by UniProt accession number P02708 (optionally the sequence fragment may include 5 or fewer, preferably 4 or fewer, more preferably 3 or fewer, even more preferably 2 or fewer, and especially 1 or fewer amino acid substitutions (e.g., so that a mimotope is formed)). In some further embodiments, particularly with respect to Pa and / or Pb, the sequence fragment of the protein is a fragment of the sequence LKWNPDDYGGVKKIHIPSEK (SEQ ID NO: 1), preferably the sequence WNPDDYGGVK (SEQ ID NO: 2) or VKKIHIPSEK (SEQ ID NO: 3). In particular, peptide Pa and / or peptide Pb consist of the sequence VKKIHIPSEKG (SEQ ID NO: 4), which optionally has N-terminal and / or C-terminal cysteine ​​residues.

[0120] Furthermore, in order to more strongly reduce the titer of the undesirable antibody associated with myasthenia gravis, in one preferred embodiment, the first peptide n-mer is P a -SP b The second peptide n-mer is Pa -SP b That is the case.

[0121] Pre-eclampsia is a pregnancy disorder that affects not only the placenta but the entire body. It occurs in 3-5% of all pregnancies, mainly in teenage and over 40 pregnant women, and typically in late pregnancy, remaining a major cause of neonatal morbidity and mortality. Characteristic features of this condition include the onset of hypertension in women with no prior history of hypertension, elevated liver enzymes and proteinuria, renal failure, thrombocytopenia (HELLP syndrome), and seizure-associated cerebral edema. There is no known specific treatment, and the exact cause of pre-eclampsia appears to be complex. Generally, treatment options are extremely limited.

[0122] The etiology of pre-eclampsia involves placental implantation abnormalities, placental hypoxia associated with the release of circulating factors, changes in endothelial cell function, and the involvement of angiogenic factors and inflammatory cytokines. Furthermore, the renin-angiotensin-aldosterone system (RAAS) plays a crucial role in pre-eclampsia. This is supported by the discovery that autoantibodies against the angiotensin II type 1 receptor (AT1-AA) contribute to the underlying pathological mechanism (Wallukat 1999).

[0123] The specificity of pre-eclampsia-associated autoantibodies has recently expanded to include, for example, anti-alpha-1 adrenergic receptors, prothrombin, and anti-cardiolipin, and more recently, GRP50 (Elliott 2016). Elliott and collaborators discovered an antigenic mimicry mechanism: patients with pre-eclampsia showed antibody titers against a peptide epitope within Epstein-Barr virus nuclear antigen 1 (EBNA-1) that cross-reacts with the placental GPR50 membrane protein expressed in placental tissue. Antibodies against the EBNA-1 antigen have also been associated with several other autoimmune diseases, including systemic lupus erythematosus, multiple sclerosis, and myalgic encephalitis / chronic fatigue syndrome.

[0124] Accordingly, as outlined above, the present invention also relates to compounds for the isolation (or depletion) of compounds present in a human organism, preferably anti-Epstein-Barr virus nuclear antigen 1 (EBNA-1) antibody, anti-human melatonin-related receptor (GPR50) antibody, and / or anti-human angiotensin II receptor 1 (AT1AR) antibody, wherein the compound comprises a biomolecular scaffold and at least two peptides having a sequence length of 7 to 13 amino acids. Each of these peptides independently comprises a 7-13 amino acid sequence fragment of an EBNA1 sequence identified by UniProt accession number Q1HVF7 or P03211, a GPR50 sequence identified by UniProt accession number Q13585, or a type 1 angiotensin II receptor (AT1AR) sequence identified by UniProt accession number P30556, wherein the peptides are covalently bound to the biomolecular scaffold. The biopolymer scaffold is selected from the group consisting of human globulin, preferably from the group consisting of human immunoglobulin, human haptoglobin, and human albumin. Regarding compounds.

[0125] The aforementioned compound can selectively reduce the concentration of undesirable antibodies that cross-react with viral antigens (such as EBNA-1) and intrinsic membrane receptor proteins (such as GRP50).

[0126] In particular, in order to more strongly reduce the titer of the undesirable antibody compared to the amount of scaffold used, the at least two peptides comprise peptide P1 and peptide P2, wherein peptides P1 and P2 comprise the same 7-13 amino acid sequence fragment of the EBNA1 sequence, the GPR50 sequence, or the AT1AR sequence, and P1 and P2 exist in the form of a peptide dimer P1-S-P2, where S is a non-peptide spacer, and the peptide dimer is covalently bonded to the biopolymer scaffold, preferably via a linker.

[0127] Preferably, the sequence fragment of 7 to 13 amino acids is a fragment of the sequence RPQKRPSCIGCKGTH (SEQ ID NO: 5) or RPQKRPSCIGCKGAH (SEQ ID NO: 6), preferably the sequence KRPSCIGCK (SEQ ID NO: 7).

[0128] In a more preferred embodiment, the sequence fragment of 7 to 13 amino acids is a fragment of any one of the sequences MILNSSTEDGIKRIQDDCPKAGRHNYI (SEQ ID NO: 8), TAMEYRWPFGNYLCK (SEQ ID NO: 9), AIIHRNVFFIENTNITVCAFHYESQNSTLP (SEQ ID NO: 10), and DVLIQLGIIRDCR (SEQ ID NO: 11), more preferably the sequence AFHYESQ (SEQ ID NO: 12).

[0129] In a further preferred embodiment, the peptide has a sequence length of 8 to 13 amino acids, preferably 9 to 12 amino acids, more preferably 10 to 12 amino acids, and in particular, at least one of the at least two peptides, preferably each of the peptides, consists of the sequence GRPQKRPSCIG (SEQ ID NO: 13) which optionally has an N-terminal and / or C-terminal cysteine ​​residue.

[0130] In a more preferred embodiment, the compound further comprises at least one peptide having a sequence length of 7 to 13 amino acids, wherein the at least one peptide comprises a 7 to 13 amino acid sequence fragment of a type 1 angiotensin II receptor (AT1AR) sequence identified by UniProt accession number P30556, preferably one of the sequences MILNSSTEDGIKRIQDDCPKAGRHNYI (SEQ ID NO: 8), TAMEYRWPFGNYLCK (SEQ ID NO: 9), AIIHRNVFFIENTNITVCAFHYESQNSTLP (SEQ ID NO: 10), and DVLIQLGIIRDCR (SEQ ID NO: 11), more preferably sequence AFHYESQ (SEQ ID NO: 12), and the at least one peptide is covalently bonded to the biomolecular scaffold, preferably via a linker.

[0131] Furthermore, in its use in the prevention or treatment of preeclampsia, in one preferred embodiment of the compound of the present invention, at least one P is P a And at least one P is P b And, P a It is a peptide having a sequence length of 5 to 13, preferably 7 to 13 amino acids. P b It is a peptide having a sequence length of 5 to 13, preferably 7 to 13 amino acids. Peptide P a The entire sequence, with the N-terminal and / or C-terminal cysteine ​​optionally removed, is identical to the protein sequence fragment, the protein being identified by UniProt accession numbers Q1HVF7, P03211, Q13585, or P30556, and optionally the sequence fragment containing 5 or fewer, preferably 4 or fewer, more preferably 3 or fewer, even more preferably 2 or fewer, and particularly 1 or fewer amino acid substitutions. Peptide P b The overall sequence, with the N-terminal and / or C-terminal cysteine ​​optionally removed, is identical to the protein sequence fragment, the protein being identified by UniProt accession numbers Q1HVF7, P03211, Q13585, or P30556, and optionally the sequence fragment containing 5 or fewer, preferably 4 or fewer, more preferably 3 or fewer, even more preferably 2 or fewer, and particularly 1 or fewer amino acid substitutions.

[0132] In some embodiments, P a and / or P b Regarding the above, the sequence fragment of the protein is a fragment of the sequence RPQKRPSCIGCKGTH (SEQ ID NO: 5) or RPQKRPSCIGCKGAH (SEQ ID NO: 6), preferably the sequence KRPSCIGCK (SEQ ID NO: 7). In some further embodiments, in particular P a and / or P bRegarding the above, the sequence fragment of the protein is a fragment of any one of the sequences MILNSSTEDGIKRIQDDCPKAGRHNYI (SEQ ID NO: 8), TAMEYRWPFGNYLCK (SEQ ID NO: 9), AIIHRNVFFIENTNITVCAFHYESQNSTLP (SEQ ID NO: 10), and DVLIQLGIIRDCR (SEQ ID NO: 11), more preferably the sequence AFHYESQ (SEQ ID NO: 12). In particular, peptide P a and / or peptide P b This consists of the sequence GRPQKRPSCIG (SEQ ID NO: 13), which optionally has an N-terminal and / or C-terminal cysteine ​​residue.

[0133] Furthermore, in order to more strongly reduce the titer of the undesirable antibody associated with pre-eclampsia, in one preferred embodiment, the first peptide n-mer is P a -SP b The second peptide n-mer is P a -SP b That is the case.

[0134] In particular, in relation to the undesirable depletion of anti-drug antibodies, in yet another preferred embodiment of the present invention, the whole sequence of at least one P, preferably at least 10% of all P, more preferably at least 25% of all P, even more preferably at least 50% of all P, even more preferably at least 75% of all P, even more preferably at least 90% of all P, even more preferably at least 95% of all P, and especially all P, with the N-terminal and / or C-terminal cysteine ​​optionally removed, is an alpha-1-protease inhibitor, alglucerase, taliglucerase alpha, pegademer Ze, agalsidase beta, alglucosidase alpha, laronidase, idursulfase, erosulfase alpha, galsulfase, seberipase alpha, cerliponase alpha, seberipase alpha, asfotase alpha, elapegademase, olipudase alpha, vermanase alpha, N(4)-(beta-N-acetylglucosaminyl)-L-asparaginase, rasburicase, pegroticase, human antithrombin III, plasma protease C1 inhibitor, turoctocog alpha, drolecogin alpha, emicizumab, recombinant human coagulation factor VIIa, recombinant human antihemophilia factor, human Von Willebrand factor, susoctocog alfa, recombinant human antihemophilia factor, antihemophilia factor, human recombinant, oprelbequin, aldesleukin, lilonacept, anakinra, denileukin difutitox, erythropoietin, interferon beta-1a, interferon alpha, interferon alpha-2b, interferon alphacon-1, interferon gamma-1b, recombinant interferon alpha-2b, growth hormone (UniProt P01241), insulin (UniProt P01308), IGF1 (UniProt P05019), PTH (UniProt P01270), thyrotropin alpha, chorionic gonadotropin alpha, folitropin, lutropin alpha, somatotropin, albiglutide, metreleptin, corifolitropin alpha, filgrastim, FGF2 (UniProt P09038), NGF (UniProt P01138), GDNF (UniProtP39905), BDNF (UniProt P23560), Mecasermin, Palifermin, GCSF (UniProt P09919), IGF2 (UniProt P01344), Becaprelmin, Palifermin, Tasonelmin, Aflibercept, Rilonacept, Romiprostim, Tagraxofusp, Efmoloctocog alfa, Eftrenonacog alfa, Rilonacept, Veratacept, Atacicept, Albutrepenonacog alfa, Dulaglutide, Etanercept, Asfotase alfa, Natalizumab, Rituximab, Adalimumab, Ipilimumab, Trastuzumab, Bevacizumab, Evolocumab, Ixekizumab, Omalizumab, Teprotumumab, Idarucizumab, Cetuximab, Oportuzumab Monatox The sequence fragment is identical to the amino acid sequence of monatox), ibritumomab / tiuxetan, absiximab, rituximab, ofatumumab, erenumab, emicizumab, or atezolizumab, and optionally the sequence fragment contains 5 or fewer amino acid substitutions, preferably 4 or fewer, more preferably 3 or fewer, even more preferably 2 or fewer, and particularly 1 or fewer.

[0135] In particular, in a similar context, in another preferred embodiment, peptide P a and / or peptide P bThe entire sequence, with the N-terminal and / or C-terminal cysteine ​​optionally removed, is: alpha-1-protease inhibitor, alglucerase, taliglucerase alpha, pegademase, agalsidase beta, alglucosidase alpha, laronidase, idursulfase, erosulfase alpha, galsulfase, seberipase alpha, cerliponase alpha, seberipase alpha, asfotase alpha, elapegademase, olipudase alpha, vermanase alpha, N(4)-(beta-N-acetylglucosaminyl)-L-asparaginase, rasburicase, pegroticase, human antithrombin III, plasma protease C1 inhibitor, turoctocog alpha, drolecogin alpha, emicizumab, recombinant human coagulation factor VIIa, recombinant human antihemophilia factor, human Von Willebrand factor, susoctocog alfa, recombinant human antihemophilia factor, antihemophilia factor, human recombinant, oprelbequin, aldesleukin, lilonacept, anakinra, denileukin difutitox, erythropoietin, interferon beta-1a, interferon alpha, interferon alpha-2b, interferon alphacon-1, interferon gamma-1b, recombinant interferon alpha-2b, growth hormone (UniProt P01241), insulin (UniProt P01308), IGF1 (UniProt P05019), PTH (UniProt P01270), thyrotropin alpha, chorionic gonadotropin alpha, folitropin, lutropin alpha, somatotropin, albiglutide, metreleptin, corifolitropin alpha, filgrastim, FGF2 (UniProt P09038), NGF (UniProt P01138), GDNF (UniProt P39905), BDNF (UniProt P23560), Mecasermin, Palifermin, GCSF (UniProt P09919), IGF2 (UniProtP01344), Becaprelmin, Palifermin, Tasonelmin, Aflibercept, Rilonacept, Romiprostim, Tagraxofusp, Efmoloctocog alfa, Eftrenonacog alfa, Rilonacept, Veratacept, Atacicept, Albutrepenonacog alfa, Dulaglutide, Etanercept, Asfotase alfa, Natalizumab, Rituximab, Adalimumab, Ipilimumab, Trastuzumab, Bevacizumab, Evolocumab, Ixekizumab, Omalizumab, Teprotumumab, Idarucizumab, Cetuximab, Oportuzumab Monatox The sequence fragment is identical to the amino acid sequence of monatox), ibritumomab / tiuxetan, absiximab, rituximab, ofatumumab, erenumab, emicizumab, or atezolizumab, and optionally the sequence fragment contains 5 or fewer amino acid substitutions, preferably 4 or fewer, more preferably 3 or fewer, even more preferably 2 or fewer, and particularly 1 or fewer.

[0136] In particular, in a similar relationship with anti-drug antibodies, in another preferred embodiment, peptide P a The entire sequence, with the N-terminal and / or C-terminal cysteine ​​arbitrarily removed, is identical to the sequence fragment of the amino acid sequence, and peptide P bThe overall sequence, with the N-terminal and / or C-terminal cysteine ​​optionally removed, is identical to the same or a different, preferably different, sequence fragment of the same amino acid sequence, and the amino acid sequence is alpha-1-protease inhibitor, alglucerase, taliglucerase alpha, pegademase, agalsidase beta, alglucosidase alpha, laronidase, idursulfase, erosulfase alpha, galsulfase, seberipase alpha, cerliponase alpha, seberipase alpha, asfotase alpha, elapegademase, olipudase alpha, vermanase alpha, N(4)-(beta-N-acetylglucosaminyl)-L-asparaginase, rasburicase, pegroticase, human antithrombin III, plasma protease C1 inhibitor, turoctocog alpha, drolecogin alpha, emicizumab, recombinant human coagulation factor VIIa, recombinant human antihemophilia factor, human Von Willebrand factor, susoctocog alfa, recombinant human antihemophilia factor, antihemophilia factor, human recombinant, oprelbequin, aldesleukin, lilonacept, anakinra, denileukin difutitox, erythropoietin, interferon beta-1a, interferon alpha, interferon alpha-2b, interferon alphacon-1, interferon gamma-1b, recombinant interferon alpha-2b, growth hormone (UniProt P01241), insulin (UniProt P01308), IGF1 (UniProt P05019), PTH (UniProt P01270), thyrotropin alpha, chorionic gonadotropin alpha, folitropin, lutropin alpha, somatotropin, albiglutide, metreleptin, corifolitropin alpha, filgrastim, FGF2 (UniProt P09038), NGF (UniProt P01138), GDNF (UniProt P39905), BDNF (UniProt P23560), Mecasermin, Palifermin, GCSF (UniProt P09919), IGF2 (UniProtP01344), Becaprelmin, Palifermin, Tasonelmin, Aflibercept, Rilonacept, Romiprostim, Tagraxofusp, Efmoloctocog alfa, Eftrenonacog alfa, Rilonacept, Veratacept, Atacicept, Albutrepenonacog alfa, Dulaglutide, Etanercept, Asfotase alfa, Natalizumab, Rituximab, Adalimumab, Ipilimumab, Trastuzumab, Bevacizumab, Evolocumab, Ixekizumab, Omalizumab, Teprotumumab, Idarucizumab, Cetuximab, Oportuzumab Monatox The amino acid sequences are those of monatox), ibritumomab / tiuxetan, absiximab, rituximab, ofatumumab, erenumab, emicizumab, or atezolizumab, and optionally the sequence fragment and / or the other sequence fragment contain 5 or fewer, preferably 4 or fewer, more preferably 3 or fewer, even more preferably 2 or fewer, and particularly 1 or fewer amino acid substitutions.

[0137] In one aspect, the present invention relates to a pharmaceutical composition comprising the invention and at least one pharmaceutically acceptable pharmaceutical additive.

[0138] In some embodiments, the composition is prepared for intraperitoneal, subcutaneous, intramuscular, and / or intravenous administration. In particular, the composition is intended for repeated administration (since the composition is typically non-immunogenic).

[0139] Preferably, peptide P or P in the composition. a or P b The molar ratio of the biopolymer scaffold is 2:1 to 100:1, preferably 3:1 to 90:1, more preferably 4:1 to 80:1, even more preferably 5:1 to 70:1, even more preferably 6:1 to 60:1, particularly 7:1 to 50:1, and even more preferably 8:10 to 40:1.

[0140] In other respects, the compounds of the present invention are intended for therapeutic use.

[0141] Preferably, the compound is intended for use in the prevention or treatment of autoimmune diseases in individuals who have or are at risk of developing autoimmune diseases. These autoimmune diseases include neuromyelitis optica, serogenetic neuromyelitis optica spectrum disorder, autoimmune encephalitis, multiple sclerosis, amyotrophic lateral sclerosis, systemic lupus erythematosus dementia, myasthenia gravis, especially transient myasthenia gravis of the newborn, dilated cardiomyopathy, pulmonary hypertension, Sjögren's syndrome, celiac disease, Graves' disease, Goodpasture disease, pre-eclampsia, Behçet's disease, systemic sclerosis, hypertension, type 1 diabetes, type 2 diabetes, systemic lupus erythematosus, anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, antiphospholipid syndrome, membranous nephropathy, primary biliary cholangitis, amyotrophic lateral sclerosis, Chagas disease cardiomyopathy, immune thrombocytopenic purpura, pemphigus vulgaris, bullous pemphigoid, acquired epidermolysis bullosa, and bullous systemic lupus erythematosus.

[0142] The compounds of the present invention are also useful for preventing or treating graft rejection in individuals that have or are eligible for grafts.

[0143] In another embodiment, the compound is intended for use in individuals receiving or eligible for treatment with an anti-drug antibody or an anti-gene delivery vector antibody, particularly an anti-AAV antibody, in the prevention or treatment of adverse reactions based on such an antibody, or in individuals receiving or eligible for gene therapy.

[0144] Preferably, the drug is a peptide or protein selected from the group consisting of peptides or proteins, particularly enzymes, enzyme inhibitors, antibodies, antibody fragments, antibody mimetics, antibody-drug conjugates, hormones, growth factors, coagulation factors, and cytokines, and preferably at least one peptide P, or peptide P a and / or peptide P bThe overall sequence, with the N-terminal and / or C-terminal cysteine ​​optionally removed, is identical to the sequence fragment of the amino acid sequence of the peptide or protein, and optionally, the sequence fragment contains 5 or fewer, preferably 4 or fewer, more preferably 3 or fewer, even more preferably 2 or fewer, and particularly 1 or fewer amino acid substitutions. The drug may be, for example, any one of the drugs disclosed herein.

[0145] In some embodiments, one or more antibodies present in the individual are at least one peptide P, or peptide P a and / or peptide P b The antibody is specific to the disease, and preferably the antibody is associated with the disease.

[0146] It is highly preferable that the composition is non-immunogenic within the organism (for example, the composition does not contain adjuvants or immunostimulants that stimulate the innate or adaptive immune system, such as adjuvants or T cell epitopes).

[0147] The composition of the present invention may be administered in doses of 1 to 1000 mg, preferably 2 to 500 mg, more preferably 3 to 250 mg, even more preferably 4 to 100 mg, and especially 5 to 50 mg per kg of body weight of the individual, preferably the composition is administered repeatedly. Such administration may be intraperitoneal, subcutaneous, intramuscular, or intravenous.

[0148] In one aspect, the present invention relates to a method for isolating (or depleting) one or more antibodies present in an individual, To obtain a pharmaceutical composition as defined herein, and Administering the pharmaceutical composition to the individual (in particular, repeatedly administering it, for example, at least twice, preferably at least three times, and more preferably at least five times). Includes, The composition is non-immunogenic within the organism, and the one or more antibodies present within the organism are for at least one P, or peptide P a and / or peptide Pb is specific for relates to a method.

[0149] In the context of the present invention, the subject (to be treated) may be a non-human animal, preferably a non-human primate, sheep, pig, dog, or rodent, particularly a mouse.

[0150] Preferably, the biopolymer scaffold is autologous to the subject, and preferably the biopolymer scaffold is a self-protein (i.e., mouse albumin is used if the subject is a mouse).

[0151] In some embodiments, the subject is administered a heterologous protein, preferably a heterologous antibody such as a nanobody, and the one or more antibodies present in the subject are specific for the heterologous protein, and preferably the administration of the heterologous protein is performed before, simultaneously with, and / or subsequent to the administration of the pharmaceutical composition.

[0152] The heterologous protein (particularly a human or humanized antibody) may be for, for example, the treatment of a malignant tumor or cancer (particularly immunotherapy). In some embodiments, the subject may have the malignant tumor or cancer and may be a subject to be treated, being treated, or selected for treatment with the heterologous protein such as the antibody.

[0153] Preferably, the subject is a non-human animal and the heterologous protein is a human or humanized protein, such as a human or humanized antibody (e.g., for preclinical testing of human or humanized biologics such as monoclonal antibodies).

[0154] More preferably, the subject is administered a drug, and the one or more antibodies present in the subject are specific for the drug, and preferably the administration of the drug is performed before, simultaneously with, and / or subsequent to the administration of the pharmaceutical composition.

[0155] The aforementioned drug may be any of the drugs disclosed herein.

[0156] In some embodiments, the individual is healthy.

[0157] In another aspect, the present invention comprises a compound of the present invention, further comprising an active agent such as a protein or peptide, and optionally at least one pharmaceutically acceptable pharmaceutical additive, wherein the active agent comprises a peptide fragment having a sequence length of 2 to 13 amino acids, preferably 3 to 11 amino acids, more preferably 4 to 9 amino acids, and particularly particularly 5 to 8 amino acids, and at least one peptide P of the compound, or peptide P a and / or peptide P b The present invention relates to a pharmaceutical composition in which the sequence of is at least 70% identical, preferably at least 75%, more preferably at least 80%, even more preferably at least 85%, even more preferably at least 90%, even more preferably at least 95%, and especially most preferably completely identical to the sequence of the peptide fragment.

[0158] The active agent may be an enzyme, preferably a human enzyme; an antibody, preferably a human or humanized antibody; a hormone; a growth factor; a coagulation factor; a cytokine; or a gene delivery vector (such as AAV), as particularly disclosed herein.

[0159] This composition is preferably intended for use in inhibiting an immune response to the active agent, preferably an antibody-mediated immune response.

[0160] This composition is more preferably non-immunogenic within the organism.

[0161] In another aspect, the present invention relates to a method for inhibiting an immune response to an active agent treatment in an individual requiring such treatment, comprising obtaining a pharmaceutical composition as defined above, and administering the pharmaceutical composition to the individual (preferably by repeated administration), wherein the compound of the pharmaceutical composition is non-immunogenic in the individual.

[0162] In another aspect, the present invention provides a method for providing the compound of the present invention, comprising the steps of: identifying at least one individual having an undesirable antibody against an antigen; screening a peptide library to identify a peptide mimotope that is specific to the undesirable antibody; and providing the compound, wherein at least one P of the compound comprises the entire sequence of the peptide mimotope. In this aspect, the compound can be considered a mimotope-based compound, as described above. See also Example 4. In general, the screening of peptide mimotopes is known in the art; see, for example, Shanmugam et al.

[0163] The mimotope-based compounds of the present invention have two advantages over compounds using wild-type epitopes. First, the mimotope-based compounds have a higher removal efficiency because the undesirable antibodies generally have a higher affinity for the mimotopes found in the peptide library screening. Second, even when the wild-type epitope sequence induces T cell epitope activity, the mimotope (as described above herein) allows for avoidance of such T cell epitope activity as much as possible.

[0164] Preferably, at least 10% of all P in the compound comprises the entire sequence of the peptide mimotope; more preferably, at least 25% of all P comprises the entire sequence of the peptide mimotope; even more preferably, at least 50% of all P comprises the entire sequence of the peptide mimotope; even more preferably, at least 75% of all P comprises the entire sequence of the peptide mimotope; even more preferably, at least 90% of all P comprises the entire sequence of the peptide mimotope; even more preferably, at least 95% of all P comprises the entire sequence of the peptide mimotope; and in particular, all P comprises the entire sequence of the peptide mimotope.

[0165] In some embodiments, the antigen may be a peptide or protein, and the sequence of the peptide or protein does not include the entire sequence of the peptide mimotope. In other words, the sequences of the peptide mimotope and the wild-type epitope (found on the peptide or protein) differ by at least one amino acid.

[0166] In one particularly preferred embodiment, the peptide library includes circular peptides, which typically have a higher affinity for the undesirable antibody (see Example 4). The peptide library may be, for example, a phage display library, a peptide microarray library, or a soluble peptide library.

[0167] In a more preferred embodiment, the screening of the peptide library is performed using serum obtained from at least one individual, the serum containing the undesirable antibody. For a method of screening mimotopes using serum, see, for example, Gazarian et al. or Leung et al.

[0168] In some embodiments, the compound is preferably non-immunogenic in at least one individual.

[0169] In still further embodiments, at least one of the individuals is a non-human animal, preferably a non-human primate, sheep, pig, dog, or rodent, particularly a mouse. At least one of the individuals may be a human.

[0170] In another further preferred embodiment, the biopolymer scaffold is derived from at least one of the individuals, preferably the biopolymer scaffold is a self-protein.

[0171] In some embodiments, at least one of the individuals is an individual administered with a heterologous protein, preferably a heterologous antibody such as a nanobody, and the antigen is the heterologous protein.

[0172] In another embodiment, at least one of the individuals is a non-human animal, and the heterologous protein is a human or humanized protein, for example, an antibody in the process of developing a human or humanized antibody.

[0173] More preferably, the individual is an individual administered with a drug, and the drug is the antigen. The drug may be, for example, an enzyme, preferably a human enzyme; an antibody, preferably a human or humanized antibody; a hormone; a growth factor; a coagulation factor; a cytokine; or a gene delivery vector such as AAV, as defined herein. For example, the drugs include alpha-1-protease inhibitors, alglucerase, taliglucerase alpha, pegademase, agalsidase beta, alglucosidase alpha, laronidase, idursulfase, elosulfase alpha, galsulfase, seberipase alpha, cerliponase alpha, seberipase alpha, asfotase alpha, elapegademase, olipudase alpha, vermanase alpha, N(4)-(beta-N-acetylglucosaminyl)-L-asparaginase, rasburicase, pegroticase, human antithrombin III, plasma protease C1 inhibitors, turoctocog alpha, drolecogin alpha, emicizumab, recombinant human coagulation factor VIIa, recombinant human antihemophilia factor, human Von Willebrand factor, susoctocog alfa, recombinant human antihemophilia factor, antihemophilia factor, human recombinant, oprelbequin, aldesleukin, lilonacept, anakinra, denileukin difutitox, erythropoietin, interferon beta-1a, interferon alpha, interferon alpha-2b, interferon alphacon-1, interferon gamma-1b, recombinant interferon alpha-2b, growth hormone (UniProt P01241), insulin (UniProt P01308), IGF1 (UniProt P05019), PTH (UniProt P01270), thyrotropin alpha, chorionic gonadotropin alpha, folitropin, lutropin alpha, somatotropin, albiglutide, metreleptin, corifolitropin alpha, filgrastim, FGF2 (UniProt P09038), NGF (UniProt P01138), GDNF (UniProt P39905), BDNF (UniProt P23560), Mecasermin, Palifermin, GCSF (UniProt P09919), IGF2 (UniProtP01344), Becaprelmin, Palifermin, Tasonelmin, Aflibercept, Rilonacept, Romiprostim, Tagraxofusp, Efmoloctocog alfa, Eftrenonacog alfa, Rilonacept, Veratacept, Atacicept, Albutrepenonacog alfa, Dulaglutide, Etanercept, Asfotase alfa, Natalizumab, Rituximab, Adalimumab, Ipilimumab, Trastuzumab, Bevacizumab, Evolocumab, Ixekizumab, Omalizumab, Teprotumumab, Idarucizumab, Cetuximab, Oportuzumab Monatox It may be monatox), ibritumomab / tiuxetan, absiximab, rituximab, ofatumumab, erenumab, emicizumab, or atezolizumab.

[0174] In some embodiments, the individual may be healthy.

[0175] In a more preferred embodiment, the undesirable antibody may be an autoantibody of at least one individual.

[0176] In relation to the present invention, in order to improve bioavailability, it is preferable that the compound of the present invention has a solubility in water at 25°C of at least 0.1 μg / ml, preferably at least 1 μg / ml, more preferably at least 10 μg / ml, even more preferably at least 100 μg / ml, and particularly at least 1000 μg / ml.

[0177] As used herein, the terms “prevention” or “prevention” mean to completely, almost completely, or at least to some extent (preferably significantly) prevent a disease or condition from occurring in a patient or subject, in particular to prevent such a patient, subject, or individual from occurring if there is a high risk of such a disease or condition occurring.

[0178] The pharmaceutical compositions of the present invention are preferably provided as (typically aqueous) solutions, (typically aqueous) suspensions, or (typically aqueous) emulsions. Suitable formulation additives for the pharmaceutical compositions of the present invention are known to those skilled in the art after reading this specification and include, for example, water (especially water for injection), physiological saline, Ringer's solution, glucose solution, buffer, Hanks' solution, vesicle-forming compounds (such as lipids), fixing oils, ethyl oleate, 5% glucose-added physiological saline, substances that enhance isotonicity and chemical stability, buffers, and preservatives. Other suitable formulation additives include any compounds that do not themselves induce the production of antibodies harmful to the patient (or individual) in the patient (or individual). Examples include sufficiently tolerable proteins, polysaccharides, polylactic acid, polyglycolic acid, polymerized amino acids, and amino acid copolymers. The pharmaceutical composition may be administered (as a drug) to a patient or individual in need (i.e., a patient or individual having or at risk of developing the diseases or conditions described herein) by a suitable procedure known to those skilled in the art (after reading this specification). The preferred route of administration of the pharmaceutical composition is parenteral administration, particularly via intraperitoneal, subcutaneous, intramuscular, and / or intravenous administration. For parenteral administration, the pharmaceutical composition of the present invention is preferably provided in injectable unit dosage forms, such as solutions (typically aqueous solutions), suspensions, or emulsions, formulated in combination with pharmaceutically acceptable pharmaceutical excipients as defined above. The dosage and method of administration, however, depend on the individual patient or individual being treated. The pharmaceutical composition may be administered in any suitable dose known from other biological administration regimens or specifically estimated and optimized for a given individual. For example, the active agent may be present in the pharmaceutical composition in an amount of 1 mg to 10 g, preferably 50 mg to 2 g, and particularly 100 mg to 1 g. The usual dose may also be determined based on the patient's kg body weight, for example, a preferred dose of 0.1 mg to 100 mg / kg body weight, particularly 1 to 10 mg / kg body weight (per administration session). The above-mentioned administration may be performed once a day, once every other day, once a week, or once every two weeks.Since the preferred mode of administration of the pharmaceutical composition of the present invention is parenteral administration, the pharmaceutical composition of the present invention is preferably in liquid form or in a state that can be dissolved in a liquid such as sterile, deionized, or distilled water, or sterile isotonic phosphate-buffered saline (PBS). Preferably, 1000 μg (dry weight) of such a composition comprises or consists of 0.1 to 990 μg, preferably 1 to 900 μg, more preferably 10 to 200 μg of a compound, and optionally 1 to 500 μg, preferably 1 to 100 μg, more preferably 5 to 15 μg of a (buffer) salt (preferably so as to be an isotonic buffer in final volume), and optionally 0.1 to 999.9 μg, preferably 100 to 999.9 μg, more preferably 200 to 999 μg of other pharmaceutical additives. Preferably, 100 mg (dry weight) of such dry composition is dissolved in sterile, deionized / distilled water or sterile isotonic phosphate-buffered saline (PBS) to a final volume of 0.1 to 100 ml, preferably 0.5 to 20 ml, more preferably 1 to 10 ml.

[0179] It will be obvious to those skilled in the art that the active agents and drugs described herein may be administered in the form of salts (i.e., as pharmaceutically acceptable salts of the active agents). Accordingly, whenever an active agent is mentioned herein, it shall also include any pharmaceutically acceptable salt form thereof.

[0180] Methods for the chemical synthesis of peptides used in the compounds of the present invention are well known in the art. Naturally, the peptides can also be produced using recombinant methods. The peptides can be produced in microorganisms such as bacteria, yeasts, or fungi, in eukaryotic cells such as mammalian or insect cells, or in recombinant viral vectors such as adenoviruses, poxviruses, herpesviruses, Semryki forest virus, baculoviruses, bateriophages, Sindbis virus, or Sendai virus. Suitable bacteria for producing the peptides include E. coli, B. subtilis, or any other bacteria capable of expressing such peptides. Suitable yeast cells for expressing the peptides of the present invention include Saccharomyces cerevisiae, Schizosaccharomyces pombe, Candida, Pichiapastoris, or any other yeast capable of expressing peptides. Corresponding means and methods are well known in the art. Methods for isolating and purifying peptides produced by recombinant methods are also well known in the art, including gel filtration, affinity chromatography, and ion exchange chromatography.

[0181] To facilitate binding to the biopolymer scaffold, it is particularly advantageous to add cysteine ​​residues to the N and / or C-terminus of the peptide.

[0182] To facilitate the isolation of the peptide, a fusion polypeptide may be created in which the peptide is fused (covalently bonded) at the translation stage to a heterologous polypeptide that enables isolation by affinity chromatography. Typical heterologous polypeptides include His tags (e.g., His6; six histidine residues) and GST tags (glutathione-S-transferase). The fusion polypeptide not only facilitates the purification of the peptide but also prevents its degradation during the purification stage. If it is desired to remove the heterologous polypeptide after purification, the fusion polypeptide may contain a cleavage site at the junction between the peptide and the heterologous polypeptide. The cleavage site may consist of an amino acid sequence that is cleaved by an enzyme (e.g., a protease) specific to the amino acid sequence at that site.

[0183] In connection with the present invention, the linking / binding chemistry used to link the peptide / peptide n-marmer to the biopolymer scaffold (e.g., via heterobifunctional compounds such as GMBS or, of course, others described in "Bioconjugate Techniques" by Greg T. Hermanson), or to link the spacer to the peptide, can also be selected from reactions known to those skilled in the art. The biopolymer scaffold itself may be produced by recombinant DNA or obtained from natural sources.

[0184] In this specification, the term “specific to ~” means, when used as in “molecule A specific to molecule B,” that in the body of a given individual, molecule A preferentially binds to molecule B over other molecules. Typically, this requires that the dissociation constant (also called “affinity”) of molecule A (e.g., an antibody) for molecule B (e.g., the antigen, particularly its binding epitope) is less than 1000 nM (i.e., strong), preferably less than 100 nM, more preferably less than 50 nM, even more preferably less than 10 nM, and especially less than 5 nM.

[0185] In this specification, "UniProt" refers to the Universal Protein Resource. UniProt is a comprehensive resource for protein sequence and annotation data. UniProt is a collaborative project between the European Bioinformatics Institute (EMBL-EBI), the Swiss Bioinformatics Institute (SIB), and the Protein Information Resource (PIR). Across these three institutes, more than 100 people are involved in various tasks, including database curation, software development, and support. Website: http: / / www.uniprot.org /

[0186] Entries in the UniProt database are identified by their accession numbers (referred to herein, for example, as "UniProt accession number" or simply "UniProt" followed by the accession number), which are typically six-character alphanumeric codes (e.g., "Q1HVF7"). Unless otherwise specified, accession numbers used herein refer to entries in the UniProt Protein Knowledgebase (UniProtKB). Unless otherwise specified, all UniProt database entries referenced herein are from the UniProt / UniProtKB Release 2019_02, dated February 13, 2019.

[0187] In relation to this application, when referring to entries in the UniProt database, sequence variants (referred to as "natural variants" in UniProt) are explicitly included.

[0188] "Percent (%) amino acid sequence identity" or "X% identical" (e.g., "70% identical") to a reference polypeptide or protein sequence is defined as the percentage of amino acid residues in a candidate sequence that are identical to those in the reference polypeptide sequence, after the sequences have been aligned, gaps introduced as necessary to achieve maximum percent sequence identity, and no conservative substitutions have been considered as part of the sequence identity. Alignment for the purpose of determining percent amino acid sequence identity can be achieved using various methods known in the art, such as publicly available computer software, including BLAST, BLAST-2, ALIGN, ALIGN-2, Megalign (DNASTAR), or the "needle" pairwise sequence alignment application in the EMBOSS software package. Those skilled in the art can determine suitable parameters for sequence alignment, including any algorithm necessary to achieve maximal alignment over the entire length of the comparison sequence. For the purposes of this specification, however, the % amino acid sequence identity value is calculated using the sequence alignment of the computer program "needle" from the EMBOSS software package (published by European Molecular Biology Laboratory; Rice et al., EMBOSS: the European Molecular Biology Open Software Suite, Trends Genet. 2000 Jun;16(6):276-7, PMID:10827456).

[0189] The aforementioned needle program can be accessed from the website http: / / www.ebi.ac.uk / Tools / psa / emboss_needle, or downloaded from http: / / emboss.sourceforge.net / as part of the EMBOSS package for local installation. The program can run on many widely used UNIX operating systems, including Linux.

[0190] For the alignment of two protein sequences, the needle program is preferably executed using the following parameters. Commandline: needle -auto -stdout -asequence SEQUENCE_FILE_A -bsequence SEQUENCE_FILE_B -datafile EBLOSUM62 -gapopen 10.0 -gapextend 0.5 -endopen 10.0 -endextend 0.5 -aformat3 pair -sprotein1 -sprotein2 (Align_format: pair Report_file: stdout)

[0191] The percentage amino acid sequence identity of a specific amino acid sequence A to, with, or relative to a specific amino acid sequence B (or, it can be expressed as a specific amino acid sequence A having or containing a specific percentage amino acid sequence identity to, with, or relative to a specific amino acid sequence B) is calculated as follows: 100 times the ratio X / Y In the formula, X is the number of amino acid residues scored as identical matches by the sequence alignment program needle in the alignment of A and B performed by that program, and Y is the total number of amino acid residues in B. If the length of amino acid sequence A is not equal to the length of amino acid sequence B, then the % amino acid sequence identity of A to B is not equal to the % amino acid sequence identity of B to A. If "the sequence of A is more than N% identical to the entire sequence of B", then Y is the full length of the sequence of B (i.e., the total number of amino acid residues in B). Unless otherwise specified, all % amino acid sequence identity values ​​used herein are obtained using the needle computer program, as described in the preceding paragraph.

[0192] The present invention further relates to the following embodiments.

[0193] Embodiment 1 • Biomolecular scaffolds, and at least • The first peptide n-mer of the following general formula: P(-SP) (n-1) and • The second peptide n-mer of the following general formula: P(-SP) (n-1) Includes, Each P is an independent peptide having a sequence length of 2 to 13 amino acids, preferably 3 to 11 amino acids, more preferably 4 to 9 amino acids, and especially particularly 5 to 8 amino acids, and S is a non-peptide spacer. For each of the peptide n-mers, independently, n is an integer of at least 1, preferably at least 2, more preferably at least 3, and particularly at least 4. Each peptide n-mer is preferably bound to the biopolymer scaffold via a linker. compound.

[0194] Embodiment 2 The compound of Embodiment 1, wherein at least one P is a cyclic peptide, preferably at least 10% of all P are cyclic peptides, more preferably at least 25% of all P are cyclic peptides, even more preferably at least 50% of all P are cyclic peptides, even more preferably at least 75% of all P are cyclic peptides, even more preferably at least 90% of all P are cyclic peptides, even more preferably at least 95% of all P are cyclic peptides, and particularly all P are cyclic peptides.

[0195] Embodiment 3 The compound of Embodiment 1 or Embodiment 2, wherein, independently for each of the peptide n-mers, n is at least 2, more preferably at least 3, and particularly at least 4.

[0196] Embodiment 4 For each of the peptide n-mers, independently, one compound from any one of Embodiments 1 to 3, wherein n is less than 10, preferably less than 9, more preferably less than 8, even more preferably less than 7, even more preferably less than 6, and particularly less than 5.

[0197] Embodiment 5 For each of the aforementioned peptide n-mers, one compound from any of Embodiments 1 to 4, wherein n is 2.

[0198] Embodiment 6 At least one P is P a and / or at least one P is P b And, P a The peptide has a sequence length of 2 to 13 amino acids, preferably 3 to 11 amino acids, more preferably 4 to 9 amino acids, and especially particularly 5 to 8 amino acids. P b The peptide has a sequence length of 2 to 13 amino acids, preferably 3 to 11 amino acids, more preferably 4 to 9 amino acids, and especially particularly 5 to 8 amino acids. A compound from any one of Embodiments 1 to 5.

[0199] Embodiment 7 Each P is independent, a or P b A compound which is any one of Embodiments 1 to 6.

[0200] Embodiment 8 In the first peptide n-mer, each P is P a And in the second peptide n-mer, each P is P b A compound which is any one of Embodiments 1 to 7.

[0201] Embodiment 9 The first peptide n-mer is P a -SP a , and the second peptide n-mer is P a -SP a Is it, The first peptide n-mer is P a -SP a , and the second peptide n-mer is P b -SP b Is it, The first peptide n-mer is P b -SP b , and the second peptide n-mer is P b -SP b Is it, The first peptide n-mer is P a -SP b , and the second peptide n-mer is P a -SP b Is it, The first peptide n-mer is P a -SP b , and the second peptide n-mer is P a -SP a is, or The first peptide n-mer is P a -SP b , and the second peptide n-mer is P b -SP b That is, A compound from any one of Embodiments 1 to 8.

[0202] Embodiment 10 • Biomolecular scaffolds, and at least ·Formula P a -SP a or P a -SP b The first peptide n-mer is a peptide dimer of the first peptide. Includes, P a P is a peptide having a sequence length of 2 to 13 amino acids, preferably 3 to 11 amino acids, more preferably 4 to 9 amino acids, and especially particularly 5 to 8 amino acids. b The peptide has a sequence length of 2 to 13 amino acids, preferably 3 to 11 amino acids, more preferably 4 to 9 amino acids, and especially particularly 5 to 8 amino acids, and S is a non-peptide spacer. The first peptide n-mer is preferably bound to the biopolymer scaffold via a linker. compound.

[0203] Embodiment 11 formula P b -SP b or P a -SP b It further contains a second peptide n-mer, which is a peptide dimer of the first peptide. The second peptide n-mer is preferably bound to the biopolymer scaffold via a linker. Compound of Embodiment 10.

[0204] Embodiment 12 A compound from any one of Embodiments 1 to 9 and Embodiment 11, wherein the first peptide n-mer is different from the second peptide n-mer.

[0205] Embodiment 13 The peptide P a The peptide P b Unlike the above, preferably the peptide P a and the peptide P b A compound from any one of Embodiments 6 to 12, wherein is either two different epitopes of the same antigen, or two different epitope portions of the same epitope.

[0206] Embodiment 14 The peptide P a and the peptide P b A compound from any one of Embodiments 6 to 13, wherein the compound comprises the same amino acid sequence fragment, and the amino acid sequence fragment has a length of at least 2 amino acids, preferably at least 3 amino acids, more preferably at least 4 amino acids, even more preferably at least 5 amino acids, even more preferably at least 6 amino acids, even more preferably at least 7 amino acids, particularly at least 8 amino acids, and even more preferably at least 9 amino acids.

[0207] Embodiment 15 Pa and / or P b A compound from any one of Embodiments 6 to 14, wherein the compound is cyclically formed.

[0208] Embodiment 16 A compound according to any one of Embodiments 1 to 15, wherein the compound comprises a plurality of the first peptide n-mers and / or a plurality of the second peptide n-mers.

[0209] Embodiment 17 A compound from any one of Embodiments 1 to 16, wherein the biopolymer scaffold is a protein, preferably a mammalian protein such as a human protein, a non-human primate protein, a sheep protein, a pig protein, a dog protein, or a rodent protein.

[0210] Embodiment 18 The compound of Embodiment 17, wherein the biopolymer scaffold is globulin.

[0211] Embodiment 19: The compound of Embodiment 18, wherein the biopolymer scaffold is selected from the group consisting of immunoglobulin, alpha-1-globulin, alpha-2-globulin, and beta-globulin.

[0212] Embodiment 20 The compound of Embodiment 19, wherein the biopolymer scaffold is selected from the group consisting of immunoglobulin G, haptoglobin, and transferrin.

[0213] Embodiment 21 The compound of Embodiment 20, wherein the biopolymer scaffold is haptoglobin.

[0214] Embodiment 22 The compound of Embodiment 17, wherein the biomolecular scaffold is albumin.

[0215] Embodiment 23 A compound from any one of Embodiments 1 to 22, wherein the compound is non-immunogenic in mammals, preferably in humans, non-human primates, sheep, pigs, dogs, or rodents.

[0216] Embodiment 24 A compound from any one of Embodiments 1 to 23, wherein the compound is for the intracellular isolation (or intracellular depletion) of at least one antibody within an organism, preferably in the bloodstream of the organism, and / or for the reduction of the titer of at least one antibody within an organism, preferably in the bloodstream of the organism.

[0217] Embodiment 25 The compound further comprises at least The third peptide n-mer of the following general formula: P(-SP) (n-1) [P is a peptide having a sequence length of 2 to 13 amino acids, preferably 3 to 11 amino acids, more preferably 4 to 9 amino acids, and especially particularly 5 to 8 amino acids, and S is a non-peptide spacer, Preferably, P is independently P c And P c It is a peptide having a sequence length of 2 to 13 amino acids, preferably 3 to 11 amino acids, more preferably 4 to 9 amino acids, and especially particularly 5 to 8 amino acids. More preferably, P c It is circularized. The fourth peptide n-mer of the following general formula: P(-SP) (n-1) [P is a peptide having a sequence length of 2 to 13 amino acids, preferably 3 to 11 amino acids, more preferably 4 to 9 amino acids, and especially particularly 5 to 8 amino acids, and S is a non-peptide spacer, Preferably, P is independently P d And P dIt is a peptide having a sequence length of 2 to 13 amino acids, preferably 3 to 11 amino acids, more preferably 4 to 9 amino acids, and especially particularly 5 to 8 amino acids. More preferably, P d It is circularized. The fifth peptide n-mer of the following general formula: P(-SP) (n-1) [P is a peptide having a sequence length of 2 to 13 amino acids, preferably 3 to 11 amino acids, more preferably 4 to 9 amino acids, and especially particularly 5 to 8 amino acids, and S is a non-peptide spacer, Preferably, P is independently P e And P e It is a peptide having a sequence length of 2 to 13 amino acids, preferably 3 to 11 amino acids, more preferably 4 to 9 amino acids, and especially particularly 5 to 8 amino acids. More preferably, P e It is circularized. The sixth peptide n-mer of the following general formula: P(-SP) (n-1) [P is a peptide having a sequence length of 2 to 13 amino acids, preferably 3 to 11 amino acids, more preferably 4 to 9 amino acids, and especially particularly 5 to 8 amino acids, and S is a non-peptide spacer, Preferably, P is independently P f And P f It is a peptide having a sequence length of 2 to 13 amino acids, preferably 3 to 11 amino acids, more preferably 4 to 9 amino acids, and especially particularly 5 to 8 amino acids. More preferably, P f It is circularized. The n-mer of the seventh peptide in the following general formula: P(-SP) (n-1) [P is a peptide having a sequence length of 2 to 13 amino acids, preferably 3 to 11 amino acids, more preferably 4 to 9 amino acids, and especially particularly 5 to 8 amino acids, and S is a non-peptide spacer, Preferably, P is independently Pg And P g It is a peptide having a sequence length of 2 to 13 amino acids, preferably 3 to 11 amino acids, more preferably 4 to 9 amino acids, and especially particularly 5 to 8 amino acids. More preferably, P g It is circularized. The n-mer of the eighth peptide in the following general formula: P(-SP) (n-1) [P is a peptide having a sequence length of 2 to 13 amino acids, preferably 3 to 11 amino acids, more preferably 4 to 9 amino acids, and especially particularly 5 to 8 amino acids, and S is a non-peptide spacer, Preferably, P is independently P h And P h It is a peptide having a sequence length of 2 to 13 amino acids, preferably 3 to 11 amino acids, more preferably 4 to 9 amino acids, and especially particularly 5 to 8 amino acids. More preferably, P h It is circularized. The 9th peptide n-mer of the following general formula: P(-SP) (n-1) [P is a peptide having a sequence length of 2 to 13 amino acids, preferably 3 to 11 amino acids, more preferably 4 to 9 amino acids, and especially particularly 5 to 8 amino acids, and S is a non-peptide spacer, Preferably, P is independently P i And P i It is a peptide having a sequence length of 2 to 13 amino acids, preferably 3 to 11 amino acids, more preferably 4 to 9 amino acids, and especially particularly 5 to 8 amino acids. More preferably, P i It is circularized. The tenth peptide n-mer of the following general formula: P(-SP) (n-1) [P is a peptide having a sequence length of 2 to 13 amino acids, preferably 3 to 11 amino acids, more preferably 4 to 9 amino acids, and especially particularly 5 to 8 amino acids, and S is a non-peptide spacer, Preferably, P is independently P j And P j It is a peptide having a sequence length of 2 to 13 amino acids, preferably 3 to 11 amino acids, more preferably 4 to 9 amino acids, and especially particularly 5 to 8 amino acids. More preferably, P j It is circularized. A compound comprising any one of Embodiments 1 to 24.

[0218] Embodiment 26 The overall sequence of at least one peptide P, preferably at least 10% of all P, more preferably at least 25% of all P, even more preferably at least 50% of all P, even more preferably at least 75% of all P, even more preferably at least 90% of all P, even more preferably at least 95% of all P, and especially all P, with the optional N-terminal and / or C-terminal cysteine ​​removed, is identical to that of a protein sequence fragment, and the protein has the following UniProt accession number: P01023, A8K2U0, P49588, Q5JTZ9, O95477, Q8IZY2, P08183, P33527, O15438, Q96IU4, P00519, P42684, Q9BYF1, P22303, Q99798, P68133, P60709, P63261, P12814, O43707, P61158, Q13705, P37023, O75077, Q9UKQ2, Q76LX8, Q6ZMM2, P35611, P07327, P00325, P35348, P25100, P08588, P07550, P25098, P35626, P30566, P43652, P02771, Q5U5Z8, Q15109, P35573, Q9UL18, Q9UKV8, O00468, P01019, P30556, Q09666, P02765, O43918, Q9Y6K8, Q02952, P14550, P15121, O95154, P02768, P00352, P49189, Q9UM73, P09923, P05187, P03971, P49418, P03950, Q9BY76, Q15327, P15144, P04083, P50995, P07355, Q3ZCQ2, P12429, P09525, P08758, P08133, O76027, Q13367, P27695, Q9BZZ5, P02647, P04114, P02749, P05067, P29972, P55087, Q8N726, P05089, Q9UNA1, P52566, Q99819, Q15052, P07306, P04424, P08243, Q9BXN1, P15336, P13637, P05026, P98194, P20648, P51164, P06576, P48047, P54252, Q8WXX7, P01185, P25311, Q9H6S1, P61769, Q13072, O75531, Q99728, P10415, P41182, P11274, O14503, Q93088, O00499, O15392, P35226, P12643, P18075, Q8N8U9, Q13873, P17213,Q9NP55, Q96DR5, Q8TDL5, P15056, Q7Z569, P38398, P51587, Q58F21, Q8IWQ3, Q8NE79, Q9Y224, Q13901, P02745, P01024, P00915, P00918, P07451, O00555, Q00975, Q9NY47, Q9Y698, Q8TC20, Q05682, P27482, P27797, P27824, P04632, P52907, P42574, Q14790, P31415, P41180, P20810, O15446, P04040, Q9NTU7, Q5M9N0, Q3V6T2, P10147, P13501, P20248, P14635, P24385, Q8ND76, P51681, P49368, P48643, P50990, Q9NZQ7, P28906, P16671, P04234, P15529, P08174, P13987, P01732, P21926, P30305, P12830, P55291, P22223, P55283, P06493, P42771, P51861, Q01850, Q9H211, P13688, P06731, Q9UNI1, P49450, P07199, Q03188, Q02224, P49454, Q9H3R5, Q92674, Q6IPU0, Q7L2Z9, A8MT69, Q5JTW2, P00751, P08603, Q03591, P36980, Q02985, Q9P2M7, O95992, Q14839, P10645, P36222, Q15782, Q9UKJ5, Q9Y259, P11229, P08172, P20309, P08173, P08912, P02708, Q9UGM1, P11230, Q8NCH0, Q99828, O75339, Q14011, Q07065, P12277, Q96MX0, P06732, A8K7I4, O95832, O75508, P30622, Q96KN2, Q12860, Q02246, Q8IWV2, O94779, Q9UQ52, P78357, Q9UHC6, Q7Z7A1, P38432, Q5TAT6,Q9UMD9, P02452, Q01955, P29400, Q14031, P12111, Q02388, Q9Y215, P49747, Q14019, P00450, P16870, Q8TCG5, P17927, Q9NS37, Q9UJA2, P02741, P02511, P53674, O95825, O75390, Q9Y600, P04141, P09919, P0DML2, Q14406, Q6UVK1, Q01459, Q9GZU7, P16410, P35222, P53634, P07339, P08311, Q14247, O60494, Q14999, Q86UP6, P61073, P05108, P05093, P04798, P05177, P08686, P11509, P20813, P33261, P11712, P10635, P05181, P08684, Q8N907, P09172, P43146, P07585, P20711, Q16832, Q9NR30, O00571, Q86XP3, Q9NY93, O75398, P35659, P17661, Q96SL1, O94907, P10515, P09622, P36957, P24855, Q8NFT8, O00429, Q8N608, P27487, P42658, Q14195, Q9BPU6, P21728, P14416, Q08554, Q02487, Q14574, Q02413, Q14126, P32926, Q86SJ6, P15924, Q03001, Q9NRD8, Q05923, O75923, O95905, Q9NTX5, Q16610, O43854, P25101, Q15075, P68104, O00418, O95967, P01133, P00533, P20042, P38919, Q04637, P08246, Q12926, Q14576, P26378, P15502, P19622, P06733, P09104, P22413, O43768, P11171, P16422, P07099, P34913, P01588, P11678, P58107, P04626, Q96RT1, Q8IUD2,Q14264, P10768, P03372, Q9Y603, Q92817, Q9Y3B2, Q01780, Q13868, Q9NQT5, Q9NPD3, Q9NQT4, Q5RKV6, Q15024, Q96B26, Q06265, P15311, P00488, P08709, P00451, P00740, P15090, Q14320, P48023, P49327, Q8TES7, P22087, P35555, Q75N90, P09467, P12319, O75015, O75636, Q7L513, P02675, P11362, P62942, Q9UIM3, P20930, Q14315, O75955, Q14254, O43155, P35916, P02751, Q04609, P01225, Q12841, O95954, P02794, P02792, P09958, P35637, P51114, Q9UM11, P35575, O95166, P60520, Q9UBS5, O75899, Q99259, Q05329, Q13065, P22466, Q14376, P04406, P41250, P01350, P15976, P50440, P02774, P01275, Q8N6F7, P23434, P55107, P50395, P56159, Q9UJY5, P01241, P01286, Q9UBU3, P09681, O14908, P29033, Q9NS71, Q6ZMI3, P23415, P15104, Q6IB77, P49915, Q13823, P01148, P30968, Q92805, Q08379, Q08378, Q13439, A6NI86, A8MQT2, Q14789, P07359, P55259, P40197, Q9HCN6, P14770, Q9NQX3, P06744, Q13098, P24298, P18283, P42261, P42262, P42263, P48058, O43424, P39086, Q13002, Q16478, Q05586, Q12879, Q13224, Q4V328, Q13255, P41594, P28799, P07492,P08263, P21266, P78417, P09211, Q00403, P35269, P25092, P08236, P02724, P07305, P16104, O75367, P84243, P12081, Q96D42, P68871, Q13547, Q92769, O15379, P56524, Q9UQL6, P19113, Q9UBI9, P51858, Q00341, Q9NRV9, O00291, O75146, P54198, P16402, P58876, P62805, P19367, P09429, P26583, P04035, Q01581, P54868, P05114, P05204, Q14541, P09651, P22626, Q99729, Q14103, P52597, P31943, P31942, P61978, P14866, Q8WVV9, Q9NSC5, Q99714, Q7Z5P4, P14060, P08238, P14625, P0DMV8, P0DMV9, P34932, P11021, P11142, P04792, Q12988, P10809, Q92598, P08908, Q13639, Q9Y4L1, P10997, Q05084, Q9UMF0, O75874, Q5TF58, Q16666, Q9BYX4, P01563, P01574, P01579, Q9NWB7, P05019, P08069, P01344, Q9NZI8, Q9Y6M1, O00425, P11717, P18065, P17936, P01876, P01877, P01854, P01857, P01859, P01860, P01861, A6NGN9, Q8N6C5, P22301, Q13651, Q08334, Q14005, Q16552, Q96PD4, Q14116, P01583, P01584, P14778, P60568, Q9GZX6, P08700, P05112, P05231, P40189, Q96LU5, Q9NV31, P29218, O14732, P12268, Q9NQS7, P01308, Q96T92, P06213, P46940, Q14653,Q13568, P35568, P17301, P08514, P23229, P20701, P11215, P05107, P05106, P16144, Q14643, Q9Y6Y0, O60674, P17275, Q15046, P16389, P22459, Q9UK17, Q9NZI2, Q9NS61, P78508, P48050, P51787, O43525, Q8N5I3, Q6PI47, P35968, Q9Y4F3, Q96Q89, P43626, P43628, Q5JT82, Q53G59, Q8IXQ5, Q9UKR3, P03952, P26715, P26717, Q13241, P13645, P02533, P19012, P08779, Q04695, P05783, P08727, P12035, Q8N1N4, P05787, Q9NSB2, O15230, P11047, P13473, Q14739, P31025, P13796, P07195, P01130, Q9Y2U8, P09382, P05162, P17931, Q08380, Q3ZCW2, O95970, Q5TDP6, P22888, P49917, P07098, P02545, P20700, Q03252, P61968, P29536, P08519, Q07954, P98164, O75096, Q8TF66, Q32MZ4, Q8ND56, Q9Y4Z0, P02788, Q17RY6, P20645, Q8NHW3, P20916, P43358, O15479, O60732, Q9H0U3, P46821, P11137, Q16584, O43318, P45984, Q16644, P21941, O00339, P56270, P02144, Q9UIS9, P11226, P02686, Q01726, P32245, Q8IVS2, Q99705, Q969V1, Q8TDD5, Q8NE86, P40925, Q00987, O00255, P50579, P46013, Q16655, P03956, P45452, P08253, P09237, P14780, Q13201, Q13875, Q16653,Q13724, Q14149, Q9UBU8, O00566, Q99547, P40238, P05164, Q00013, Q9NZW5, P25189, P22897, Q9Y605, P82909, P43246, P52701, Q13421, P26038, Q9UJ68, P26927, Q13043, Q04912, Q9NZJ7, Q86UE4, P15941, Q8WXI7, O15146, Q9UIF7, P10242, P01106, Q99417, P12524, Q8N699, P12882, P35580, P35749, Q9UKX3, Q7Z406, Q9Y2K3, Q9UKX2, P11055, Q9Y623, P13533, P12883, A7E2Y1, P13535, P35579, B0I1T2, P54296, Q14CX7, E9PAV3, Q13765, Q8WY41, Q96I59, Q9UBB6, Q9UHB4, Q00604, P28331, P20929, P07196, P07197, Q8NG66, Q8TD19, O60524, O94856, P01138, Q8N4C6, P30414, P59047, Q8N427, Q13253, Q15155, P29475, P51513, Q9UNW9, P55786, O60500, P06748, P01160, P17342, P01303, Q9Y5X4, Q8IXM6, Q9ULB1, Q9HDB5, Q9Y4C0, Q9NXX6, P04629, Q16620, Q16288, Q02818, P80303, Q14980, P49790, Q8TEM1, O15504, Q14990, Q5BJF6, Q9ULJ1, Q6UX06, P78380, P41143, P35372, Q9P0S3, Q92791, Q9UQ80, Q13310, Q9UM07, Q7Z2X7, Q5JRK9, Q96GU1, Q13177, Q99497, P09874, P40424, Q15154, P12004, P29120, Q8WUM4, O95263, O76083, P16234, P09619, O00330, P30101, Q8N165,O00151, Q5T2W1, P16284, P02776, P10720, P35080, P18669, P00558, O95394, P35232, Q99623, Q9BVI0, Q92576, O43175, P11309, O75364, Q9Y446, P04054, Q13018, P16885, Q15149, Q9H7P9, P40967, P29590, Q01453, Q9NR77, P54277, P16233, P54317, Q8ND90, Q9UL42, P00491, Q9H9Y6, O14802, Q99575, P16435, Q15063, Q01851, Q12837, Q15181, P62937, O60437, P35813, P01298, Q9HAZ2, P32119, Q13162, P30041, P13727, Q92954, P17612, P17252, P01236, P04553, P04554, O60678, P04070, Q9UNN8, P54821, Q99811, P07477, P24158, Q9BXM0, O43653, O75475, P20618, P40306, P49721, P28074, P28062, P28065, P61289, Q6PGN9, P26599, Q8WV60, P01270, P06454, Q06124, Q9Y2R2, P08575, Q12913, Q16849, Q92932, Q86Y79, Q9UHX1, P20472, Q9BRP8, P51153, Q9UI14, Q15276, P63244, Q92878, Q06609, P04049, Q15311, Q9UKM9, Q14498, P38159, P10745, Q06330, P53805, O95199, Q9P258, P35243, P46063, P05451, Q8IX06, P57771, P08100, P12271, O60930, O00584, Q9ULK6, Q99942, Q9UBF6, P13489, O75116, Q01973, P15927, Q9Y2J0, Q9UNE2, Q02878, P05388, P05386, P05387,Q9BUL9, P78346, P78345, P62277, P60866, O75676, O43159, Q15404, O00442, Q92541, Q9NQC3, Q9Y265, Q9Y230, P48443, P21817, Q92736, P31151, P04271, P0DJI8, P0DJI9, P10523, P49591, O43290, Q99590, Q8WTV0, Q14108, P13521, P05408, Q14524, Q9BWW7, P34741, Q86SQ7, Q9UDX4, Q13228, P16109, P04279, Q9HC62, P49908, Q9HD40, P01009, P05543, P30740, P29508, P48594, P35237, P05121, P07093, P05155, Q9BYW2, Q7Z333, Q8N474, Q9BWM7, Q99961, O15266, O60902, Q9NYZ4, Q9Y336, Q9H0K1, Q14190, Q13239, Q14493, Q9H0C2, P12235, P05141, Q9H2B4, O43511, P11168, Q8IWU4, O00400, P08195, Q8IWA5, P48751, Q9Y6R1, Q9BRV3, Q92911, P37840, O76070, P08621, P09012, P14678, P09234, P62314, P62316, P62318, P62304, P62306, P62308, P63162, O14512, P00441, P04179, Q9BQB4, O00570, P56693, P35716, O15370, O60248, Q9UN79, O95416, Q9H6I2, P35713, P48431, Q9Y651, P41225, O94993, Q06945, P35711, P35712, Q9BT81, P57073, P48436, P08047, P23497, Q13342, Q9H930, Q15506, Q8N0X2, P00995, P16150, O43791, P10451, Q8TCT8, Q8TCT7, Q8TCT6, Q13813,Q13501, P10124, P61011, O76094, Q05066, P05455, O43805, P61278, Q13586, Q9P246, P31948, P49842, P16949, Q7Z7C7, Q13033, O75558, P61266, Q13190, Q8IWZ8, Q9Y2Z0, Q8IWU6, P63165, P61956, P17600, P08247, P21579, P37837, Q15633, Q13148, P26639, Q9NYW0, P20226, O60806, P24557, P17987, O60522, O14746, P02787, P05549, Q92734, P10646, P02786, P01266, P01137, P21980, Q08188, P49221, P07204, P40225, P10827, P10828, Q9UPZ6, P31483, P29401, Q9Y490, O60602, Q8TDI7, P17152, P42167, P42166, P01375, O00300, P43489, P19237, P48788, P19429, P13805, P45379, P45378, P09430, Q8NDV7, P11387, Q969P6, P11388, Q13472, O95985, P04637, Q9H3D4, O15350, P60174, P09493, P07202, P12270, P56180, O43280, Q92519, Q96RU7, P19474, O15164, Q9UPN9, Q6AZZ1, P10155, P48995, Q13507, Q7Z4N2, Q7Z2W7, Q9HBA0, Q9BZW7, P01222, P16473, Q9H2G4, Q14166, Q8WZ42, P02766, P07437, O00294, Q15672, Q9P2K2, Q86VQ3, Q6A555, P14679, Q9BZF9, Q13404, Q14139, O95155, P11441, Q9UMX0, P17480, P09936, P15374, Q9Y3C8, P19224, P16662, P07911, Q8TCY9,Q9Y6N9, Q13107, P63027, Q15836, P18206, P55072, P21796, P08670, P04275, O75083, Q14191, P98170, Q13426, P13010, P12956, P67809, Q9Y2T7, O43829, Q13105, Q15915, O95409, Q8N9L1, Q9UDV7, Q9Y3S2, Q9UL40, Q14966, Q9H0M5, Q9Y5V0, Q96C28, Q9H5H4, A9RAI0, B5SUY7, O41855, O56137, O56139, P03135, P04133, P04882, P08362, P10269, P12538, P69353, Q5Y9B2, Q5Y9B4, Q65311, Q6JC40, Q6VGT5, Q8JQF8, Q8JQG0, Q98654, Q9WBP8, Q9YIJ1, Q1HVF7, P03211, Q13585, P04233, O15523, O14602, Q30201, P01891, P01892, P04439, P05534, P10314, P10316, P13746, P16188, P16189, P16190, P18462, P30443, P30447, P30450, P30453, P30455, P30456, P30457, P30459, P30512, Q09160, P01889, P03989, P10319, P18463, P18464, P18465, P30460, P30461, P30462, P30464, P30466, P30475, P30479, P30480, P30481, P30483, P30484, P30485, P30486, P30487, P30488, P30490, P30491, P30492, P30493, P30495, P30498, P30685, Q04826, Q29718, Q29836, Q29940, Q31610, Q31612, Q95365, P04222, P10321, P30499, P30501, P30504, P30505, P30508, P30510, Q07000, Q29865, Q29960, Q29963, Q95604, Q9TNN7, P28067, P28068, P06340, P13765, P20036, P04440, P01909, P01906, P01920, P05538, P01903, P01911, P01912, P04229, P13760, P13761, P20039, Q29974, Q30134, Q30167, Q5Y7A7, Q95IE3, Q9GIY3, Q9TQE0, P79483, P13762,Q30154, P13747, P30511, P17693, Q9BY66, Q29983, Q29980, P22090, Q03519, O14607, P08048, Identified by one of the following: In particular, the sequence fragment contains or consists of the AAV-8 capsid protein sequence LQQQNT (SEQ ID NO: 18), TTTGQNNNS (SEQ ID NO: 19), or GTANTQ (SEQ ID NO: 20). If desired, the sequence fragment may contain 5 or fewer amino acid substitutions, preferably 4 or fewer, more preferably 3 or fewer, even more preferably 2 or fewer, and particularly 1 or fewer. A compound from any one of Embodiments 1 to 25.

[0219] Embodiment 27 Peptide P a The entire sequence, with the N-terminal and / or C-terminal cysteine ​​optionally removed, is identical to the sequence fragment of the protein, and the protein is identified by one of the UniProt accession numbers listed in Embodiment 26. If desired, the sequence fragment may contain 5 or fewer amino acid substitutions, preferably 4 or fewer, more preferably 3 or fewer, even more preferably 2 or fewer, and particularly 1 or fewer. A compound from any one of Embodiments 1 to 26.

[0220] Embodiment 28 Peptide P b The entire sequence, with the N-terminal and / or C-terminal cysteine ​​optionally removed, is identical to the sequence fragment of the protein, and the protein is identified by one of the UniProt accession numbers listed in Embodiment 26. If desired, the sequence fragment may contain 5 or fewer amino acid substitutions, preferably 4 or fewer, more preferably 3 or fewer, even more preferably 2 or fewer, and particularly 1 or fewer. A compound from any one of Embodiments 1 to 27.

[0221] Embodiment 29 Peptide P aThe entire sequence, with the N-terminal and / or C-terminal cysteine ​​arbitrarily removed, is identical to the sequence fragment of the protein, and peptide P b The entire sequence, with the N-terminal and / or C-terminal cysteine ​​optionally removed, is identical to the same or another, preferably another, sequence fragment of the same protein, and the protein is identified by one of the UniProt accession numbers listed in Embodiment 26. If desired, the sequence fragment and / or the other sequence fragment may contain 5 or fewer, preferably 4 or fewer, more preferably 3 or fewer, even more preferably 2 or fewer, and particularly 1 or fewer amino acid substitutions. A compound from any one of Embodiments 1 to 28.

[0222] Embodiment 30 The whole sequence of at least one P, preferably at least 10% of all P, more preferably at least 25% of all P, even more preferably at least 50% of all P, even more preferably at least 75% of all P, even more preferably at least 90% of all P, even more preferably at least 95% of all P, and especially all P, with the N-terminal and / or C-terminal cysteine ​​optionally removed, is an alpha-1-protease inhibitor, alglucosidase, taliglucosidase alpha, pegademase, agalsidase beta, alglucosidase Alpha, laronidase, idursulfase, elosulfase alpha, galsulfase, seberipase alpha, cerliponase alpha, seberipase alpha, asfotase alpha, elapegademase, olipudase alpha, vermanase alpha, N(4)-(beta-N-acetylglucosaminyl)-L-asparaginase, rasburicase, pegroticase, human antithrombin III, plasma protease C1 inhibitor, turoctocog alpha, drolecogin alpha, emicizumab, recombinant human coagulation factor VIIa, recombinant human antihemophilia factor, human Von Willebrand factor, susoctocog alfa, recombinant human antihemophilia factor, antihemophilia factor, human recombinant, oprelbequin, aldesleukin, lilonacept, anakinra, denileukin difutitox, erythropoietin, interferon beta-1a, interferon alpha, interferon alpha-2b, interferon alphacon-1, interferon gamma-1b, recombinant interferon alpha-2b, growth hormone (UniProt P01241), insulin (UniProt P01308), IGF1 (UniProt P05019), PTH (UniProt P01270), thyrotropin alpha, chorionic gonadotropin alpha, folitropin, lutropin alpha, somatotropin, albiglutide, metreleptin, corifolitropin alpha, filgrastim, FGF2 (UniProt P09038), NGF (UniProt P01138), GDNF (UniProt P39905), BDNF (UniProtP23560), Mecasermin, Palifermin, GCSF (UniProt P09919), IGF2 (UniProt P01344), Becaprelmin, Palifermin, Tasonelmin, Aflibercept, Rilonacept, Romiprostim, Tagraxofusp, Efmoloctocog alfa, Eftrenonacog alfa, Rilonacept, Veratacept, Atacicept, Albutrepenonacog alfa, Dulaglutide, Etanercept, Asfotase alfa, Natalizumab, Rituximab, Adalimumab, Ipilimumab, Trastuzumab, Bevacizumab, Evolocumab, Ixekizumab, Omalizumab, Teprotumumab, Idarucizumab, Cetuximab, Oportuzumab Monatox It is identical to the amino acid sequence fragment of monatox), ibritumomab / tiuxetan, absiximab, rituximab, ofatumumab, erenumab, emicizumab, or atezolizumab. The sequence fragment may optionally contain 5 or fewer amino acid substitutions, preferably 4 or fewer, more preferably 3 or fewer, even more preferably 2 or fewer, and particularly 1 or fewer. A compound from any one of Embodiments 1 to 29.

[0223] Embodiment 31 Peptide P aThe entire sequence, with the N-terminal and / or C-terminal cysteine ​​optionally removed, is: alpha-1-protease inhibitor, alglucerase, taliglucerase alpha, pegademase, agalsidase beta, alglucosidase alpha, laronidase, idursulfase, erosulfase alpha, galsulfase, seberipase alpha, cerliponase alpha, seberipase alpha, asfotase alpha, elapegademase, olipudase alpha, vermanase alpha, N(4)-(beta-N-acetylglucosaminyl)-L-asparaginase, rasburicase, pegroticase, human antithrombin III, plasma protease C1 inhibitor, turoctocog alpha, drolecogin alpha, emicizumab, recombinant human coagulation factor VIIa, recombinant human antihemophilia factor, human Von Willebrand factor, susoctocog alfa, recombinant human antihemophilia factor, antihemophilia factor, human recombinant, oprelbequin, aldesleukin, lilonacept, anakinra, denileukin difutitox, erythropoietin, interferon beta-1a, interferon alpha, interferon alpha-2b, interferon alphacon-1, interferon gamma-1b, recombinant interferon alpha-2b, growth hormone (UniProt P01241), insulin (UniProt P01308), IGF1 (UniProt P05019), PTH (UniProt P01270), thyrotropin alpha, chorionic gonadotropin alpha, folitropin, lutropin alpha, somatotropin, albiglutide, metreleptin, corifolitropin alpha, filgrastim, FGF2 (UniProt P09038), NGF (UniProt P01138), GDNF (UniProt P39905), BDNF (UniProt P23560), Mecasermin, Palifermin, GCSF (UniProt P09919), IGF2 (UniProtP01344), Becaprelmin, Palifermin, Tasonelmin, Aflibercept, Rilonacept, Romiprostim, Tagraxofusp, Efmoloctocog alfa, Eftrenonacog alfa, Rilonacept, Veratacept, Atacicept, Albutrepenonacog alfa, Dulaglutide, Etanercept, Asfotase alfa, Natalizumab, Rituximab, Adalimumab, Ipilimumab, Trastuzumab, Bevacizumab, Evolocumab, Ixekizumab, Omalizumab, Teprotumumab, Idarucizumab, Cetuximab, Oportuzumab Monatox It is identical to the amino acid sequence fragment of monatox), ibritumomab / tiuxetan, absiximab, rituximab, ofatumumab, erenumab, emicizumab, or atezolizumab. The sequence fragment may optionally contain 5 or fewer amino acid substitutions, preferably 4 or fewer, more preferably 3 or fewer, even more preferably 2 or fewer, and particularly 1 or fewer. A compound from any one of Embodiments 1 to 30.

[0224] Embodiment 32 Peptide P bThe entire sequence, with the N-terminal and / or C-terminal cysteine ​​optionally removed, is: alpha-1-protease inhibitor, alglucerase, taliglucerase alpha, pegademase, agalsidase beta, alglucosidase alpha, laronidase, idursulfase, erosulfase alpha, galsulfase, seberipase alpha, cerliponase alpha, seberipase alpha, asfotase alpha, elapegademase, olipudase alpha, vermanase alpha, N(4)-(beta-N-acetylglucosaminyl)-L-asparaginase, rasburicase, pegroticase, human antithrombin III, plasma protease C1 inhibitor, turoctocog alpha, drolecogin alpha, emicizumab, recombinant human coagulation factor VIIa, recombinant human antihemophilia factor, human Von Willebrand factor, susoctocog alfa, recombinant human antihemophilia factor, antihemophilia factor, human recombinant, oprelbequin, aldesleukin, lilonacept, anakinra, denileukin difutitox, erythropoietin, interferon beta-1a, interferon alpha, interferon alpha-2b, interferon alphacon-1, interferon gamma-1b, recombinant interferon alpha-2b, growth hormone (UniProt P01241), insulin (UniProt P01308), IGF1 (UniProt P05019), PTH (UniProt P01270), thyrotropin alpha, chorionic gonadotropin alpha, folitropin, lutropin alpha, somatotropin, albiglutide, metreleptin, corifolitropin alpha, filgrastim, FGF2 (UniProt P09038), NGF (UniProt P01138), GDNF (UniProt P39905), BDNF (UniProt P23560), Mecasermin, Palifermin, GCSF (UniProt P09919), IGF2 (UniProtP01344), Becaprelmin, Palifermin, Tasonelmin, Aflibercept, Rilonacept, Romiprostim, Tagraxofusp, Efmoloctocog alfa, Eftrenonacog alfa, Rilonacept, Veratacept, Atacicept, Albutrepenonacog alfa, Dulaglutide, Etanercept, Asfotase alfa, Natalizumab, Rituximab, Adalimumab, Ipilimumab, Trastuzumab, Bevacizumab, Evolocumab, Ixekizumab, Omalizumab, Teprotumumab, Idarucizumab, Cetuximab, Oportuzumab Monatox It is identical to the amino acid sequence fragment of monatox), ibritumomab / tiuxetan, absiximab, rituximab, ofatumumab, erenumab, emicizumab, or atezolizumab. The sequence fragment may optionally contain 5 or fewer amino acid substitutions, preferably 4 or fewer, more preferably 3 or fewer, even more preferably 2 or fewer, and particularly 1 or fewer. A compound from any one of Embodiments 1 to 31.

[0225] Embodiment 33 Peptide P a The entire sequence, with the N-terminal and / or C-terminal cysteine ​​arbitrarily removed, is identical to the sequence fragment of the amino acid sequence, and peptide P bThe entire sequence, with the N-terminal and / or C-terminal cysteine ​​optionally removed, is identical to the same or a different, preferably different, sequence fragment of the same amino acid sequence, and the amino acid sequence is alpha-1-protease inhibitor, alglucerase, taliglucerase alpha, pegademase, agalsidase beta, alglucosidase alpha, laronidase, idursulfase, erosulfase alpha, galsulfase, seberipase alpha, cerliponase alpha, seberipase alpha, asfotase alpha, elapegademase, olipudase alpha, vermanase alpha, N(4)-(beta-N-acetylglucosaminyl)-L-asparaginase, rasburicase, pegroticase, human antithrombin III, plasma protease C1 inhibitor, turoctocog alpha, drolecogin alpha, emicizumab, recombinant human coagulation factor VIIa, recombinant human antihemophilia factor, human Von Willebrand factor, susoctocog alfa, recombinant human antihemophilia factor, antihemophilia factor, human recombinant, oprelbequin, aldesleukin, lilonacept, anakinra, denileukin difutitox, erythropoietin, interferon beta-1a, interferon alpha, interferon alpha-2b, interferon alphacon-1, interferon gamma-1b, recombinant interferon alpha-2b, growth hormone (UniProt P01241), insulin (UniProt P01308), IGF1 (UniProt P05019), PTH (UniProt P01270), thyrotropin alpha, chorionic gonadotropin alpha, folitropin, lutropin alpha, somatotropin, albiglutide, metreleptin, corifolitropin alpha, filgrastim, FGF2 (UniProt P09038), NGF (UniProt P01138), GDNF (UniProt P39905), BDNF (UniProt P23560), Mecasermin, Palifermin, GCSF (UniProt P09919), IGF2 (UniProtP01344), Becaprelmin, Palifermin, Tasonelmin, Aflibercept, Rilonacept, Romiprostim, Tagraxofusp, Efmoloctocog alfa, Eftrenonacog alfa, Rilonacept, Veratacept, Atacicept, Albutrepenonacog alfa, Dulaglutide, Etanercept, Asfotase alfa, Natalizumab, Rituximab, Adalimumab, Ipilimumab, Trastuzumab, Bevacizumab, Evolocumab, Ixekizumab, Omalizumab, Teprotumumab, Idarucizumab, Cetuximab, Oportuzumab Monatox The amino acid sequences are those of monatox), ibritumomab / tiuxetan, absiximab, rituximab, ofatumumab, erenumab, emicizumab, or atezolizumab. The sequence fragment and / or the other sequence fragment may optionally contain 5 or fewer, preferably 4 or fewer, more preferably 3 or fewer, even more preferably 2 or fewer, and particularly 1 or fewer amino acid substitutions. A compound from any one of Embodiments 1 to 32.

[0226] Embodiment 34 A compound from any one of Embodiments 1 to 33, wherein each peptide n-mer is preferably covalently bonded to the biopolymer scaffold via a linker.

[0227] Embodiment 35 A compound from any one of Embodiments 1 to 34, wherein at least one of the linkers is selected from a disulfide bridge and a PEG molecule.

[0228] Embodiment 36 A compound from any one of Embodiments 1 to 35, wherein at least one of the spacer S is selected from a PEG molecule and a glycan.

[0229] Embodiment 37 At least one P is P a And at least one P is P b And, P aThe peptide has a sequence length of 5 to 13, preferably 7 to 13 amino acids. P b The peptide has a sequence length of 5 to 13, preferably 7 to 13 amino acids. Peptide P a The entire sequence, with the N-terminal and / or C-terminal cysteine ​​optionally removed, is identical to that of the protein sequence fragment, and the protein is identified by UniProt accession numbers P02708, O15146, or O75096, and optionally the sequence fragment contains 5 or fewer, preferably 4 or fewer, more preferably 3 or fewer, even more preferably 2 or fewer, and particularly 1 or fewer amino acid substitutions. Peptide P b The entire sequence, with the N-terminal and / or C-terminal cysteine ​​optionally removed, is identical to that of the protein sequence fragment, and the protein is identified by UniProt accession numbers P02708, O15146, or O75096, and optionally the sequence fragment contains 5 or fewer, preferably 4 or fewer, more preferably 3 or fewer, even more preferably 2 or fewer, and particularly 1 or fewer amino acid substitutions. A compound from any one of Embodiments 1 to 36.

[0230] Embodiment 38 Especially P a and / or P b The present invention relates to any one of the compounds from Embodiments 14 to 37, wherein the sequence fragment of the protein is a sequence fragment consisting of amino acids 21 to 255 of the AChR subunit alpha sequence identified by UniProt accession number P02708 (optionally, the sequence fragment may include 5 or fewer, preferably 4 or fewer, more preferably 3 or fewer, even more preferably 2 or fewer, and particularly 1 or fewer amino acid substitutions (for example, so that a mimotope is formed).

[0231] Embodiment 39 Especially P a and / or P bRegarding the above, one of the compounds from Embodiments 14 to 38, wherein the sequence fragment of the protein is a fragment of the sequence LKWNPDDYGGVKKIHIPSEK (SEQ ID NO: 1), preferably the sequence WNPDDYGGVK (SEQ ID NO: 2) or VKKIHIPSEK (SEQ ID NO: 3).

[0232] Embodiment 40 Peptide P a and / or peptide P b However, one of the compounds from Embodiments 6 to 39, comprising the sequence VKKIHIPSEKG (SEQ ID NO: 4) which optionally has an N-terminal and / or C-terminal cysteine ​​residue.

[0233] Embodiment 41 The first peptide n-mer is P a -SP b The second peptide n-mer is P a -SP b The compound is one of any 6 to 40 embodiments.

[0234] Embodiment 42 The peptide P a and the peptide P b A compound from any one of Embodiments 6 to 40, wherein the compound comprises the same amino acid sequence fragment, and the amino acid sequence fragment has a length of at least 5 amino acids, more preferably at least 6 amino acids, even more preferably at least 7 amino acids, particularly at least 8 amino acids, and even more preferably at least 9 amino acids.

[0235] Embodiment 43 At least one P is P a And at least one P is P b And, P a The peptide has a sequence length of 5 to 13, preferably 7 to 13 amino acids. P b The peptide has a sequence length of 5 to 13, preferably 7 to 13 amino acids. Peptide P aThe entire sequence, with the N-terminal and / or C-terminal cysteine ​​optionally removed, is identical to the protein sequence fragment, and the protein is identified by UniProt accession numbers Q1HVF7, P03211, Q13585, or P30556, and optionally the sequence fragment contains 5 or fewer, preferably 4 or fewer, more preferably 3 or fewer, even more preferably 2 or fewer, and particularly 1 or fewer amino acid substitutions. Peptide P b The entire sequence, with the N-terminal and / or C-terminal cysteine ​​optionally removed, is identical to that of the protein sequence fragment, and the protein is identified by UniProt accession numbers Q1HVF7, P03211, Q13585, or P30556, and optionally the sequence fragment contains 5 or fewer, preferably 4 or fewer, more preferably 3 or fewer, even more preferably 2 or fewer, and particularly 1 or fewer amino acid substitutions. A compound from any one of Embodiments 1 to 36.

[0236] Embodiment 44 Especially P a and / or P b Regarding the above, one compound from Embodiments 14 to 36 and Embodiment 43, wherein the sequence fragment of the protein is a fragment of the sequence RPQKRPSCIGCKGTH (SEQ ID NO: 5) or RPQKRPSCIGCKGAH (SEQ ID NO: 6), preferably the sequence KRPSCIGCK (SEQ ID NO: 7).

[0237] Embodiment 45 Especially P a and / or P b Regarding the above, one compound from any one of Embodiments 14 to 36 and Embodiments 43 to 44, wherein the sequence fragment of the protein is a fragment of any one of the sequences MILNSSTEDGIKRIQDDCPKAGRHNYI (SEQ ID NO: 8), TAMEYRWPFGNYLCK (SEQ ID NO: 9), AIIHRNVFFIENTNITVCAFHYESQNSTLP (SEQ ID NO: 10), and DVLIQLGIIRDCR (SEQ ID NO: 11), more preferably the sequence AFHYESQ (SEQ ID NO: 12).

[0238] Embodiment 46 Peptide P a and / or peptide P b However, one of any two compounds from Embodiments 6 to 36 and Embodiments 43 to 45, comprising the sequence GRPQKRPSCIG (SEQ ID NO: 13) which optionally has an N-terminal and / or C-terminal cysteine ​​residue.

[0239] Embodiment 47 The first peptide n-mer is P a -SP b The second peptide n-mer is P a -SP b The compound is one of any two embodiments from Embodiments 6 to 36 and Embodiments 43 to 46.

[0240] Embodiment 48 The peptide P a and the peptide P b A compound from any one of Embodiments 6 to 36 and Embodiments 43 to 47, wherein the compound comprises the same amino acid sequence fragment, and the amino acid sequence fragment has a length of at least 5 amino acids, more preferably at least 6 amino acids, even more preferably at least 7 amino acids, particularly at least 8 amino acids, and even more preferably at least 9 amino acids.

[0241] Embodiment 49 Preferably, a compound for sequestering (or depleting) anti-human muscle nicotinic acetylcholine receptor (AChR) antibodies, anti-human muscle-specific receptor tyrosine kinase antibodies, and / or anti-human low-density lipoprotein receptor-associated protein 4 antibodies present in a human organism, wherein the compound comprises a biomolecular scaffold and at least two peptides having a sequence length of 7 to 13 amino acids, each of which is independently an AChR subunit alpha sequence identified by UniProt accession number P02708 (optionally including 5 or fewer, preferably 4 or fewer, more preferably 3 or fewer, even more preferably 2 or fewer, particularly 1 or fewer amino acid substitutions (e.g., so that a mimotope is formed) or UniProt accession number O15146 A compound comprising a 7-13 amino acid sequence fragment of a muscle-specific receptor tyrosine kinase sequence identified (optionally, the sequence fragment below includes 5 or fewer, preferably 4 or fewer, more preferably 3 or fewer, even more preferably 2 or fewer, and particularly 1 or fewer amino acid substitutions (e.g., so that a mimotope is formed)) or a low-density lipoprotein receptor-related protein 4 sequence identified by UniProt accession number O75096 (optionally, the sequence fragment below includes 5 or fewer, preferably 4 or fewer, more preferably 3 or fewer, even more preferably 2 or fewer, and particularly 1 or fewer amino acid substitutions (e.g., so that a mimotope is formed)), wherein the peptide is covalently bound to the biopolymer scaffold, and the biopolymer scaffold is selected from the group consisting of human globulin and human albumin.

[0242] Embodiment 50 The compound of Embodiment 49, wherein the at least two peptides comprise peptide P1 and peptide P2, where P1 and P2 comprise the same 7-13 amino acid sequence fragment of the AChR subunit alpha, and P1 and P2 exist in the form of a peptide dimer P1-S-P2, where S is a non-peptide spacer, and the peptide dimer is covalently bonded to the biopolymer scaffold, preferably via a linker.

[0243] Embodiment 51 The sequence fragment of amino acids 7-13 of AChR subunit alpha is a sequence fragment consisting of amino acids 21-255 of the AChR subunit alpha sequence identified by UniProt accession number P02708 (optionally the sequence fragment includes 5 or fewer, preferably 4 or fewer, more preferably 3 or fewer, even more preferably 2 or fewer, and particularly 1 or fewer amino acid substitutions (e.g., so that a mimotope is formed)), a compound of Embodiment 49 or Embodiment 50.

[0244] Embodiment 52 The sequence fragment of the 7-13 amino acids of the AChR subunit alpha is a fragment of the sequence LKWNPDDYGGVKKIHIPSEK (SEQ ID NO: 1), preferably the sequence WNPDDYGGVK (SEQ ID NO: 2) or VKKIHIPSEK (SEQ ID NO: 3), and optionally the sequence fragment contains 5 or fewer, preferably 4 or fewer, more preferably 3 or fewer, even more preferably 2 or fewer, and particularly 1 or fewer amino acid substitutions (for example, so that a mimotope is formed), wherein any one of the compounds from Embodiments 49 to 51.

[0245] Embodiment 53 A compound from any one of Embodiments 49 to 52, wherein the peptide has a sequence length of 8 to 13 amino acids, preferably 9 to 12 amino acids, more preferably 10 to 12 amino acids, and in particular, the peptide comprises the sequence VKKIHIPSEKG (SEQ ID NO: 4) having an optional N-terminal and / or C-terminal cysteine ​​residue.

[0246] Embodiment 54 A compound according to any one of Embodiments 1 to 53, wherein the compound further comprises at least one peptide having a sequence length of 7 to 13 amino acids, the at least one peptide comprising a sequence fragment of 7 to 13 amino acids of a muscle-specific receptor tyrosine kinase sequence identified by UniProt accession number O15146, or a low-density lipoprotein receptor-associated protein 4 sequence identified by UniProt accession number O75096, and the at least one peptide is covalently bonded to the biomolecular scaffold, preferably via a linker.

[0247] Embodiment 55 Preferably, a compound for sequestering (or depleting) anti-Epstein-Barr virus nuclear antigen 1 (EBNA-1) antibody, anti-human melatonin-related receptor (GPR50) antibody, and / or anti-human angiotensin II receptor 1 (AT1AR) antibody present in a human organism, wherein the compound comprises a biomolecular scaffold and at least two peptides having a sequence length of 7 to 13 amino acids. Each of these peptides independently comprises a 7-13 amino acid sequence fragment of an EBNA1 sequence identified by UniProt accession number Q1HVF7 or P03211, a GPR50 sequence identified by UniProt accession number Q13585, or a type 1 angiotensin II receptor (AT1AR) sequence identified by UniProt accession number P30556, wherein the peptides are covalently bound to the biomolecular scaffold. The biopolymer scaffold is selected from the group consisting of human globulin, preferably from the group consisting of human immunoglobulin, human haptoglobin, and human albumin. compound.

[0248] Embodiment 56 The compound of Embodiment 55, wherein at least two of the peptides comprise peptide P1 and peptide P2, each peptide comprising the same 7-13 amino acid sequence fragment of the EBNA1 sequence or the GPR50 sequence, and P1 and P2 exist in the form of a peptide dimer P1-S-P2, where S is a non-peptide spacer, and the peptide dimer is covalently bonded to the biopolymer scaffold, preferably via a linker.

[0249] Embodiment 57 The compound of Embodiment 55 or Embodiment 56, wherein the sequence fragment of 7 to 13 amino acids is a fragment of the sequence RPQKRPSCIGCKGTH (SEQ ID NO: 5) or RPQKRPSCIGCKGAH (SEQ ID NO: 6), preferably the sequence KRPSCIGCK (SEQ ID NO: 7); and / or the peptide has a sequence length of 8 to 13 amino acids, preferably 9 to 12 amino acids, more preferably 10 to 12 amino acids, and in particular at least one of the at least two peptides, preferably each of the peptides, comprises the sequence GRPQKRPSCIG (SEQ ID NO: 13) which optionally has an N-terminal and / or C-terminal cysteine ​​residue.

[0250] Embodiment 58 A compound according to any one of Embodiments 55 to 57, wherein the sequence fragment of 7 to 13 amino acids is a fragment of any one of the sequences MILNSSTEDGIKRIQDDCPKAGRHNYI (SEQ ID NO: 8), TAMEYRWPFGNYLCK (SEQ ID NO: 9), AIIHRNVFFIENTNITVCAFHYESQNSTLP (SEQ ID NO: 10), and DVLIQLGIIRDCR (SEQ ID NO: 11), more preferably a fragment of the sequence AFHYESQ (SEQ ID NO: 12).

[0251] Embodiment 59 The compound further comprises at least one peptide having a sequence length of 7 to 13 amino acids, wherein the at least one peptide comprises a sequence fragment of 7 to 13 amino acids of a type 1 angiotensin II receptor (AT1AR) sequence identified by UniProt accession number P30556, preferably one of the sequences MILNSSTEDGIKRIQDDCPKAGRHNYI (SEQ ID NO: 8), TAMEYRWPFGNYLCK (SEQ ID NO: 9), AIIHRNVFFIENTNITVCAFHYESQNSTLP (SEQ ID NO: 10), and DVLIQLGIIRDCR (SEQ ID NO: 11), more preferably the sequence AFHYESQ (SEQ ID NO: 12); and the at least one peptide is covalently bonded to the biomolecular scaffold, preferably via a linker, the compound of any one of Embodiments 1 to 58.

[0252] Embodiment 60 A compound from any one of Embodiments 1 to 59, wherein each of the peptides is covalently bonded to the biomolecular scaffold via a linker.

[0253] Embodiment 61 A compound from any one of Embodiments 1 to 60, wherein the biopolymer scaffold is selected from human immunoglobulin and human haptoglobin.

[0254] Embodiment 62 A compound from any one of Embodiments 1 to 61, wherein the biopolymer scaffold is human haptoglobin.

[0255] Embodiment 63 A compound from any one of Embodiments 49 to 62, wherein at least one of the two peptides described above is cyclized.

[0256] Embodiment 64 A compound from any one of Embodiments 1 to 63, wherein the compound is non-immunogenic in humans.

[0257] Embodiment 65 A pharmaceutical composition comprising one compound from any one of Embodiments 1 to 64 and at least one pharmaceutically acceptable pharmaceutical additive.

[0258] Embodiment 66 The pharmaceutical composition of Embodiment 65, wherein the composition is prepared for intraperitoneal, subcutaneous, intramuscular, and / or intravenous administration, and the composition is for repeated administration.

[0259] Embodiment 67 A pharmaceutical composition according to any one of Embodiments 1 to 66, wherein the molar ratio of peptide P in the composition to the biopolymer scaffold is 2:1 to 100:1, preferably 3:1 to 90:1, more preferably 4:1 to 80:1, even more preferably 5:1 to 70:1, even more preferably 6:1 to 60:1, particularly 7:1 to 50:1, and even more preferably 8:10 to 40:1.

[0260] Embodiment 68 Peptide P in the aforementioned composition a A pharmaceutical composition according to any one of Embodiments 6 to 67, wherein the molar ratio of to the biopolymer scaffold is 2:1 to 100:1, preferably 3:1 to 90:1, more preferably 4:1 to 80:1, even more preferably 5:1 to 70:1, even more preferably 6:1 to 60:1, particularly 7:1 to 50:1, and even more preferably 8:10 to 40:1.

[0261] Embodiment 69 Peptide P in the aforementioned composition b A pharmaceutical composition according to any one of Embodiments 6 to 68, wherein the molar ratio of to the biopolymer scaffold is 2:1 to 100:1, preferably 3:1 to 90:1, more preferably 4:1 to 80:1, even more preferably 5:1 to 70:1, even more preferably 6:1 to 60:1, particularly 7:1 to 50:1, and even more preferably 8:10 to 40:1.

[0262] Embodiment 70 A pharmaceutical composition according to any one of embodiments 65 to 69 for use in treatment.

[0263] Embodiment 71 The pharmaceutical composition according to Embodiment 70 for use in the prevention or treatment of an autoimmune disease in an individual having an autoimmune disease or being at risk of developing such a disease.

[0264] Embodiment 72 The pharmaceutical composition according to Embodiment 71, wherein the autoimmune disease is selected from the group consisting of neuromyelitis optica, serogenetic neuromyelitis optica spectrum disorder, autoimmune encephalitis, multiple sclerosis, amyotrophic lateral sclerosis, systemic lupus erythematosus dementia, myasthenia gravis, particularly transient myasthenia gravis of the newborn, dilated cardiomyopathy, pulmonary hypertension, Sjögren's syndrome, celiac disease, Graves' disease, Goodpasture disease, pre-eclampsia, Behçet's disease, systemic sclerosis, hypertension, type 1 diabetes, type 2 diabetes, systemic lupus erythematosus, anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, antiphospholipid syndrome, membranous nephropathy, primary biliary cholangitis, amyotrophic lateral sclerosis, Chagas disease cardiomyopathy, immune thrombocytopenic purpura, pemphigus vulgaris, bullous pemphigoid, acquired epidermolysis bullosa, and bullous systemic lupus erythematosus.

[0265] Embodiment 73 The pharmaceutical composition according to Embodiment 70 for use in the prevention or treatment of graft rejection in individuals having or being eligible for grafts.

[0266] Embodiment 74 A pharmaceutical composition according to Embodiment 70 for use in individuals receiving or eligible for treatment with an anti-drug antibody or an anti-gene delivery vector antibody, such as an anti-AAV antibody, in the prevention or treatment of adverse reactions based on the said drug, or in individuals receiving or eligible for gene therapy, Preferably, the drug is a peptide or protein selected from the group consisting of peptides or proteins, particularly enzymes, enzyme inhibitors, antibodies, antibody fragments, antibody mimetics, antibody-drug conjugates, hormones, growth factors, coagulation factors, and cytokines, and preferably at least one peptide P, or peptide P a and / or peptide P b The overall sequence, with the N-terminal and / or C-terminal cysteine ​​optionally removed, is identical to the sequence fragment of the amino acid sequence of the peptide or protein, and optionally the sequence fragment contains 5 or fewer, preferably 4 or fewer, more preferably 3 or fewer, even more preferably 2 or fewer, and particularly 1 or fewer amino acid substitutions. Pharmaceutical composition.

[0267] Embodiment 75 The aforementioned drugs include alpha-1 protease inhibitors, alglucerase, taliglucerase alfa, pegademase, agalsidase beta, alglucosidase alfa, laronidase, idursulfase, erosulfase alfa, galsulfase, seberipase alfa, cerliponase alfa, seberipase alfa, asfotase alfa, elapegademase, olipudase alfa, vermanase alfa, N(4)-(beta-N-acetylglucosaminyl)-L-asparaginase, rasburicase, pegroticase, human antithrombin III, plasma protease C1 inhibitors, turoctocog alfa, drolecogin alfa, emicizumab, recombinant human coagulation factor VIIa, recombinant human antihemophilia factor, and human Von Willebrand factor, susoctocog alfa, recombinant human antihemophilia factor, antihemophilia factor, human recombinant, oprelbequin, aldesleukin, lilonacept, anakinra, denileukin difutitox, erythropoietin, interferon beta-1a, interferon alpha, interferon alpha-2b, interferon alphacon-1, interferon gamma-1b, recombinant interferon alpha-2b, growth hormone (UniProt P01241), insulin (UniProt P01308), IGF1 (UniProt P05019), PTH (UniProt P01270), thyrotropin alpha, chorionic gonadotropin alpha, folitropin, lutropin alpha, somatotropin, albiglutide, metreleptin, corifolitropin alpha, filgrastim, FGF2 (UniProt P09038), NGF (UniProt P01138), GDNF (UniProt P39905), BDNF (UniProt P23560), Mecasermin, Palifermin, GCSF (UniProt P09919), IGF2 (UniProtP01344), Becaprelmin, Palifermin, Tasonelmin, Aflibercept, Rilonacept, Romiprostim, Tagraxofusp, Efmoloctocog alfa, Eftrenonacog alfa, Rilonacept, Veratacept, Atacicept, Albutrepenonacog alfa, Dulaglutide, Etanercept, Asfotase alfa, Natalizumab, Rituximab, Adalimumab, Ipilimumab, Trastuzumab, Bevacizumab, Evolocumab, Ixekizumab, Omalizumab, Teprotumumab, Idarucizumab, Cetuximab, Oportuzumab Monatox Monatox), ibritumomab / tiuxetan, absiximab, rituximab, ofatumumab, erenumab, emicizumab, or atezolizumab. At least one peptide P, or peptide P a and / or peptide P b The overall sequence, with the N-terminal and / or C-terminal cysteine ​​optionally removed, is identical to the sequence fragment of the amino acid sequence of the drug, and preferably the sequence fragment contains 5 or fewer, preferably 4 or fewer, more preferably 3 or fewer, even more preferably 2 or fewer, and especially 1 or fewer amino acid substitutions. The pharmaceutical composition according to Embodiment 74.

[0268] Embodiment 76 One or more antibodies present in the individual are at least one peptide P, or peptide P a and / or peptide P b A pharmaceutical composition according to any one of Embodiments 70 to 75, wherein the antibody is specific to the disease and preferably associated with the disease.

[0269] Embodiment 77 The pharmaceutical composition according to any one of Embodiments 70 to 76, wherein the composition is non-immunogenic in the organism.

[0270] Embodiment 78 The pharmaceutical composition according to any one of Embodiments 70 to 77, wherein the composition is administered in a dose of 1 to 1000 mg, preferably 2 to 500 mg, more preferably 3 to 250 mg, even more preferably 4 to 100 mg, and particularly 5 to 50 mg, as a compound per 1 kg of body weight of the individual.

[0271] Embodiment 79 The pharmaceutical composition according to any one of Embodiments 70 to 78, wherein the composition is administered intraperitoneally, subcutaneously, intramuscularly, or intravenously.

[0272] Embodiment 80 A method for isolating (or depleting) one or more antibodies present within an individual, To obtain a pharmaceutical composition defined in any one of Embodiments 65 to 69, and Administering the pharmaceutical composition to the individual. Includes, The composition is non-immunogenic in the organism, and the one or more antibodies present in the organism are effective against at least one P, or against peptide P. a and / or peptide P b It is specific to, method.

[0273] Embodiment 81 The method of Embodiment 80, wherein the individual is a non-human animal, preferably a non-human primate, sheep, pig, dog, or rodent, particularly a mouse.

[0274] Embodiment 82 The method of Embodiment 80 or Embodiment 81, wherein the biopolymer scaffold is of the same origin as the individual, and preferably the biopolymer scaffold is a self-protein.

[0275] Embodiment 83 The individual is administered a heterologous antibody, preferably a heterologous antibody such as a nanobody, and the one or more antibodies present in the individual are specific to the heterologous protein, and preferably the administration of the heterologous protein is performed before, simultaneously with, and / or following the administration of the pharmaceutical composition, in any one of the methods of Embodiments 80 to 82.

[0276] Embodiment 84 A method from any one of Embodiments 80 to 83, wherein the individual is a non-human animal and the heterologous protein is human or a humanized protein.

[0277] Embodiment 85 The individual is administered a drug, and the one or more antibodies present in the individual are specific to the drug, preferably the administration of the drug is performed before, simultaneously with, and / or following, the administration of the pharmaceutical composition, in any one of the methods of Embodiments 80 to 82.

[0278] Embodiment 86 The aforementioned drugs include alpha-1 protease inhibitors, alglucerase, taliglucerase alfa, pegademase, agalsidase beta, alglucosidase alfa, laronidase, idursulfase, erosulfase alfa, galsulfase, seberipase alfa, cerliponase alfa, seberipase alfa, asfotase alfa, elapegademase, olipudase alfa, vermanase alfa, N(4)-(beta-N-acetylglucosaminyl)-L-asparaginase, rasburicase, pegroticase, human antithrombin III, plasma protease C1 inhibitors, turoctocog alfa, drolecogin alfa, emicizumab, recombinant human coagulation factor VIIa, recombinant human antihemophilia factor, and human Von Willebrand factor, susoctocog alfa, recombinant human antihemophilia factor, antihemophilia factor, human recombinant, oprelbequin, aldesleukin, lilonacept, anakinra, denileukin difutitox, erythropoietin, interferon beta-1a, interferon alpha, interferon alpha-2b, interferon alphacon-1, interferon gamma-1b, recombinant interferon alpha-2b, growth hormone (UniProt P01241), insulin (UniProt P01308), IGF1 (UniProt P05019), PTH (UniProt P01270), thyrotropin alpha, chorionic gonadotropin alpha, folitropin, lutropin alpha, somatotropin, albiglutide, metreleptin, corifolitropin alpha, filgrastim, FGF2 (UniProt P09038), NGF (UniProt P01138), GDNF (UniProt P39905), BDNF (UniProt P23560), Mecasermin, Palifermin, GCSF (UniProt P09919), IGF2 (UniProtP01344), Becaprelmin, Palifermin, Tasonelmin, Aflibercept, Rilonacept, Romiprostim, Tagraxofusp, Efmoloctocog alfa, Eftrenonacog alfa, Rilonacept, Veratacept, Atacicept, Albutrepenonacog alfa, Dulaglutide, Etanercept, Asfotase alfa, Natalizumab, Rituximab, Adalimumab, Ipilimumab, Trastuzumab, Bevacizumab, Evolocumab, Ixekizumab, Omalizumab, Teprotumumab, Idarucizumab, Cetuximab, Oportuzumab Monatox The method of Embodiment 85, wherein the bronco is monatox, ibritumomab tiuxetan, absiximab, rituximab, ofatumumab, erenumab, emicizumab, or atezolizumab.

[0279] Embodiment 87 The method is one of Embodiments 80 to 86, wherein the individual is healthy.

[0280] Embodiment 88 A method according to any one of Embodiments 80 to 87, wherein the composition is administered intraperitoneally, subcutaneously, intramuscularly, or intravenously.

[0281] Embodiment 89 The present invention comprises one compound from any one of Embodiments 1 to 64, further comprising an active agent such as a protein or peptide, and optionally at least one pharmaceutically acceptable formulation additive. The active agent comprises a peptide fragment having a sequence length of 2 to 13 amino acids, preferably 3 to 11 amino acids, more preferably 4 to 9 amino acids, and especially particularly 5 to 8 amino acids. At least one peptide P of the aforementioned compound, or peptide P a and / or peptide P b The sequence of is at least 70% identical, preferably at least 75% identical, more preferably at least 80% identical, even more preferably at least 85% identical, even more preferably at least 90% identical, even more preferably at least 95% identical, and especially completely identical. Pharmaceutical composition.

[0282] Embodiment 90 The pharmaceutical composition of Embodiment 89, wherein the active agent is an enzyme, preferably a human enzyme; an antibody, preferably a human or humanized antibody; a hormone; a growth factor; a coagulation factor; a cytokine; or a gene delivery vector such as AAV.

[0283] Embodiment 91 The aforementioned active agents include alpha-1 protease inhibitors, alglucerase, taliglucerase alfa, pegademase, agalsidase beta, alglucosidase alfa, laronidase, idursulfase, erosulfase alfa, galsulfase, seberipase alfa, cerliponase alfa, seberipase alfa, asfotase alfa, elapegademase, olipudase alfa, vermanase alfa, N(4)-(beta-N-acetylglucosaminyl)-L-asparaginase, rasburicase, pegroticase, human antithrombin III, plasma protease C1 inhibitors, turoctocog alfa, drolecogin alfa, emicizumab, recombinant human coagulation factor VIIa, recombinant human antihemophilia factor, and human Von Willebrand factor, susoctocog alfa, recombinant human antihemophilia factor, antihemophilia factor, human recombinant, oprelbequin, aldesleukin, lilonacept, anakinra, denileukin difutitox, erythropoietin, interferon beta-1a, interferon alpha, interferon alpha-2b, interferon alphacon-1, interferon gamma-1b, recombinant interferon alpha-2b, growth hormone (UniProt P01241), insulin (UniProt P01308), IGF1 (UniProt P05019), PTH (UniProt P01270), thyrotropin alpha, chorionic gonadotropin alpha, folitropin, lutropin alpha, somatotropin, albiglutide, metreleptin, corifolitropin alpha, filgrastim, FGF2 (UniProt P09038), NGF (UniProt P01138), GDNF (UniProt P39905), BDNF (UniProt P23560), Mecasermin, Palifermin, GCSF (UniProt P09919), IGF2 (UniProtP01344), Becaprelmin, Palifermin, Tasonelmin, Aflibercept, Rilonacept, Romiprostim, Tagraxofusp, Efmoloctocog alfa, Eftrenonacog alfa, Rilonacept, Veratacept, Atacicept, Albutrepenonacog alfa, Dulaglutide, Etanercept, Asfotase alfa, Natalizumab, Rituximab, Adalimumab, Ipilimumab, Trastuzumab, Bevacizumab, Evolocumab, Ixekizumab, Omalizumab, Teprotumumab, Idarucizumab, Cetuximab, Oportuzumab Monatox A pharmaceutical composition of Embodiment 89 or Embodiment 90, which is monatox), ibritumomab / tiuxetan, absiximab, rituximab, ofatumumab, erenumab, emicizumab, or atezolizumab.

[0284] Embodiment 92 A pharmaceutical composition according to any one of Embodiments 89 to 91, wherein the composition is prepared for intravenous administration.

[0285] Embodiment 93 A pharmaceutical composition according to any one of Embodiments 89 to 92, wherein the composition is an aqueous solution.

[0286] Embodiment 94 A pharmaceutical composition according to any one of Embodiments 89 to 93 for use in inhibiting an immune response, preferably an antibody-mediated immune response, to the aforementioned active agent.

[0287] Embodiment 95 The pharmaceutical composition according to Embodiment 94, wherein the composition is non-immunogenic in the organism.

[0288] Embodiment 96 A method for inhibiting the immune response to treatment with an active agent in an individual requiring treatment with said active agent, To obtain a pharmaceutical composition defined in any one of Embodiments 89 to 95, and Administering the aforementioned pharmaceutical composition to the individual, Includes, The compound of the pharmaceutical composition is non-immunogenic in the organism. method.

[0289] Embodiment 97 The method of Embodiment 96, wherein the individual is a human.

[0290] Embodiment 98 The method of Embodiment 96 or Embodiment 97, wherein the biopolymer scaffold is of the same origin as the individual, and preferably the biopolymer scaffold is a self-protein.

[0291] Embodiment 99 A method according to any one of Embodiments 96 to 98, wherein the composition is administered intraperitoneally, subcutaneously, intramuscularly, or intravenously.

[0292] Embodiment 100 A method for providing a compound according to any one of Embodiments 1 to 64, A step of identifying at least one individual that has an undesirable antibody against an antigen. A step of screening a peptide library to identify peptide mimotopes that are specific to the undesirable antibody, and A step of providing the compound, Includes, At least one P of the compound comprises the entire sequence of the peptide mimotope. method.

[0293] Embodiment 101 The method of Embodiment 100, wherein the antigen is a peptide or protein, and the sequence of the peptide or protein does not include the entire sequence of the peptide mimotope.

[0294] Embodiment 102 The method of Embodiment 100 or Embodiment 101, wherein at least 10% of all Ps comprise the entire sequence of the peptide mimotope, more preferably at least 25% of all Ps comprise the entire sequence of the peptide mimotope, even more preferably at least 50% of all Ps comprise the entire sequence of the peptide mimotope, even more preferably at least 75% of all Ps comprise the entire sequence of the peptide mimotope, even more preferably at least 90% of all Ps comprise the entire sequence of the peptide mimotope, even more preferably at least 95% of all Ps comprise the entire sequence of the peptide mimotope, and in particular all Ps comprise the entire sequence of the peptide mimotope.

[0295] Embodiment 103 A method according to any one of Embodiments 100 to 102, wherein the peptide library comprises circular peptides.

[0296] Embodiment 104 The method according to any one of Embodiments 100 to 103, wherein the peptide library is a phage display library, a peptide microarray library, or a soluble peptide library.

[0297] Embodiment 105 The screening of the peptide library is performed using serum obtained from at least one individual, wherein the serum contains the undesirable antibody, according to any one of Embodiments 100 to 104.

[0298] Embodiment 106 A method according to any one of Embodiments 100 to 105, wherein the compound is non-immunogenic in at least one individual.

[0299] Embodiment 107 The method according to any one of Embodiments 100 to 106, wherein at least one of the individuals is a non-human animal, preferably a non-human primate, sheep, pig, dog, or rodent, particularly a mouse.

[0300] Embodiment 108 Any one of Embodiments 100 to 106, wherein at least one of the individuals is human.

[0301] Embodiment 109 A method according to any one of Embodiments 100 to 108, wherein the biopolymer scaffold is self-derived from at least one individual, and preferably the biopolymer scaffold is a self-protein.

[0302] Embodiment 110 The method according to any one of Embodiments 100 to 109, wherein at least one of the individuals is administered a heterologous protein, preferably a heterologous antibody such as a nanobody, and the antigen is the heterologous protein.

[0303] Embodiment 111 A method according to any one of Embodiments 100 to 110, wherein at least one of the individuals is a non-human animal and the heterologous protein is human or a humanized protein.

[0304] Embodiment 112 The method according to any one of Embodiments 100 to 111, wherein the individual is an individual administered with a drug, and the drug is the antigen.

[0305] Embodiment 113 The method of Embodiment 112, wherein the drug is an enzyme, preferably a human enzyme; an antibody, preferably a human or humanized antibody; a hormone; a growth factor; a coagulation factor; a cytokine; or a gene delivery vector such as AAV.

[0306] Embodiment 114 The aforementioned drugs include alpha-1 protease inhibitors, alglucerase, taliglucerase alfa, pegademase, agalsidase beta, alglucosidase alfa, laronidase, idursulfase, erosulfase alfa, galsulfase, seberipase alfa, cerliponase alfa, seberipase alfa, asfotase alfa, elapegademase, olipudase alfa, vermanase alfa, N(4)-(beta-N-acetylglucosaminyl)-L-asparaginase, rasburicase, pegroticase, human antithrombin III, plasma protease C1 inhibitors, turoctocog alfa, drolecogin alfa, emicizumab, recombinant human coagulation factor VIIa, recombinant human antihemophilia factor, and human Von Willebrand factor, susoctocog alfa, recombinant human antihemophilia factor, antihemophilia factor, human recombinant, oprelbequin, aldesleukin, lilonacept, anakinra, denileukin difutitox, erythropoietin, interferon beta-1a, interferon alpha, interferon alpha-2b, interferon alphacon-1, interferon gamma-1b, recombinant interferon alpha-2b, growth hormone (UniProt P01241), insulin (UniProt P01308), IGF1 (UniProt P05019), PTH (UniProt P01270), thyrotropin alpha, chorionic gonadotropin alpha, folitropin, lutropin alpha, somatotropin, albiglutide, metreleptin, corifolitropin alpha, filgrastim, FGF2 (UniProt P09038), NGF (UniProt P01138), GDNF (UniProt P39905), BDNF (UniProt P23560), Mecasermin, Palifermin, GCSF (UniProt P09919), IGF2 (UniProtP01344), Becaprelmin, Palifermin, Tasonelmin, Aflibercept, Rilonacept, Romiprostim, Tagraxofusp, Efmoloctocog alfa, Eftrenonacog alfa, Rilonacept, Veratacept, Atacicept, Albutrepenonacog alfa, Dulaglutide, Etanercept, Asfotase alfa, Natalizumab, Rituximab, Adalimumab, Ipilimumab, Trastuzumab, Bevacizumab, Evolocumab, Ixekizumab, Omalizumab, Teprotumumab, Idarucizumab, Cetuximab, Oportuzumab Monatox The method of Embodiment 112, wherein the bronco is monatox, ibritumomab tiuxetan, absiximab, rituximab, ofatumumab, erenumab, emicizumab, or atezolizumab.

[0307] Embodiment 115 The method according to any one of Embodiments 100 to 114, wherein the individual is healthy.

[0308] Embodiment 116 The method according to any one of Embodiments 100 to 115, wherein the undesirable antibody is an autoantibody of at least one individual. [Examples]

[0309] Example 1: The compound of the present invention effectively reduces the titer of an undesirable antibody. Animal Model: To provide an in vivo model with measurable titers of undesirable prototype antibodies in human indications, BALB / c mice were immunized using standard experimental vaccination with KLH-conjugated peptide vaccines derived from established human autoantigens or anti-drug antibodies. After titer evaluation by standard peptide ELISA, immunized animals were treated with the corresponding SADC test to demonstrate selective antibody reduction by SADC treatment. All experiments were conducted in accordance with the guidelines of the corresponding animal ethics authorities.

[0310] Mice were immunized using a model antigen: Female BALB / c mice (8-10 weeks old) supplied from Janvier, France, were housed under a 12-hour light / 12-hour dark cycle and given free access to food and water. Immunization was performed by subcutaneous injection of a KLH carrier-conjugated peptide vaccine every other week for three doses. The KLH complex was generated using the viral antigen (EBNA-1) and peptide T3-2 (SEQ ID NO: 14: CGRPQKRPSCIGCKG), an example of molecular mimicry of the endogenous human receptor antigen, namely the placental GPR50 protein (Elliott et al.), which has been shown to be associated with pre-eclampsia. To confirm the generality of this approach, mice were immunized using a larger antigen peptide derived from myasthenia gravis, an autoimmune condition, with a human autoepitope. Similar to the case of peptide T3-2, animals were immunized with peptide T1-1 (SEQ ID NO: 15: LKWNPDDYGGVKKIHIPSEKGC), derived from the MIR (major immunogenicity region) of the human AChR protein, which plays a crucial role in the pathogenesis of the aforementioned disease (Luo et al.). Mice were immunized using the T1-1 peptide as a surrogate partial model epitope of the human AChR autoantigen. Control mice were immunized with peptide T8-1 (SEQ ID NO: 16: DHTLYTPYHTHPG) to provide a control titer to demonstrate the selectivity of the system. For the preparation of the vaccine conjugate, a KLH carrier (Sigma) was activated with sulfoGMBS (catalog no. 22324 Thermo) according to the attached protocol, and N- or C-terminally cysteine-modified peptides T3-2 and T1-1 were added, followed by the addition of Alhydrogel®. Subsequently, the conjugate was injected into the flank of the animals. The doses of vaccines T3-2 and T1-1 were 15 μg of the complex per 100 μl of injection, each dose containing a final concentration of 1% Alhydrogel (InvivoGen VAC-Alu-250).

[0311] Prototype SADC Production: To test the selective antibody reduction activity of SADCs in mice immunized with T3-2 and T1-1, SADCs were prepared using mouse serum albumin (MSA) or mouse immunoglobulin (mouse-Ig) as a biopolymer scaffold to provide a self-biopolymer scaffold that did not induce any immune response in mice, or using non-self human haptoglobin (which did not induce an allogeneic reaction within 72 hours after a single injection) as a biopolymer scaffold. N-terminally cysteine-modified SADC peptide E049 (SEQ ID NO: 13: GRPQKRPSCIG) and / or C-terminally cysteine-modified SADC peptide E006 (SEQ ID NO: 4: VKKIHIPSEKG) were ligated to the scaffolds using sulfoGMBS (catalog no. 22324 Thermo)-activated MSA (Sigma; catalog no. A3559), mouse Ig (Sigma, I5381), or human haptoglobin (Sigma H0138) according to the attached protocol. This provided MSA, Ig, and haptoglobin-based SADCs having a corresponding cysteine ​​peptide covalently bonded to the lysine of the corresponding biomolecular scaffold. In addition to the binding of the cysteine ​​peptide to the lysine via a bifunctional amine-sulfhydryl crosslinking agent, a portion of the added cysteine ​​SADC peptide was directly reacted with the sulfhydryl group of cysteine ​​in the albumin scaffold protein. This can be detected by treating the complex with DTT and then detecting the free peptide by mass spectrometry or any other analytical method for detecting free peptides. Finally, these SADC complexes were dialyzed against water using Pur-A-Lyzer® (Sigma) and then lyophilized. The lyophilized material was resuspended in PBS before injection into animals.

[0312] In vivo functional testing of SADC: Prototype SADC, SADC-E049, and SADC-E006 were injected intraperitoneally (ip; as an alternative to intravenous administration in humans and larger animals) into mice pre-immunized with peptide vaccine T3-2 (containing the EBNA-1 model epitope) and peptide vaccine T1-1 (containing the AChR MIR model epitope). The dose was 30 μg of SADC conjugate in 50 μl of PBS. Blood was collected by submandibular vein puncture using a capillary microhematocrit tube before (-48 hours, -24 hours) and after (+24 hours, +48 hours, +72 hours, etc.) intraperitoneal SADC injection. ELISA analysis (see below) revealed that both prototype SADCs could significantly reduce titer for at least 72 hours in this animal model. Therefore, we were able to conclude that SADC can be used to effectively reduce titer in vivo.

[0313] Titer analysis: Peptide ELISA was performed using a standard procedure with a 96-well plate (Nunc Medisorp plate; Thermofisher, catalog no. 467320) coated with BSA-conjugated peptide (30 nM, dissolved in PBS) at room temperature for 1 hour and incubated with shaking in a suitable buffer (blocking buffer: 1% BSA, 1x PBS; wash buffer: 1x PBS / 0.1% Tween; dilution buffer: 1x PBS / 0.1% BSA / 0.1% Tween). After serum incubation (dilution starting at 1:50 in PBS; typically stepwise titration to 1:3 or 1:2), conjugated antibodies were detected using Jackson Immunoresearch's horseradish peroxidase-conjugated goat anti-mouse IgG(Fc) (115-035-008). After reaction cessation, the plate was measured at 450 nm for 20 minutes using a TMB. The EC50 was calculated from the read values ​​by fitting a curve using a 4-parameter logistic regression model (GraphPad Prism) according to the manufacturer's recommended procedure. Constraining parameters for ceiling and floor values ​​were set as appropriate, and R 2 We provided curve fitting quality levels >0.98.

[0314] Figure 1A shows in vivo validation experiments in a mouse model for the selective plasma reduction activity of a prototype albumin-based SADC candidate that binds to an autoantibody against EBNA1 as a model of autoantibody and mimicry in pre-eclampsia (Elliott et al.). Mouse albumin was used in these mouse experiments to avoid any reactivity to exogenous proteins. Antibody titers were induced in 6-month-old Balb / c mice by standard peptide vaccination. The figure below shows that the titer LogIC50 (y-axis) before SADC injection (i.e., titers at -48 hours and -24 hours) was higher than the titer LogIC50 after SADC application (i.e., titers at +24 hours, +48 hours, and +72 hours after injection; shown on the x-axis).

[0315] Figure 1B shows a similar example using another example of a peptide antibody-binding moiety for a different indication. This involves the antibody-reducing activity of albumin-based SADC in a mouse model pre-immunized with a different peptide derived from the human AChR protein MIR region (Luo et al.) to mimic the situation in myasthenia gravis. The antibody titer induced against the AChR-MIR region was used as a substitute for anti-AChR-MIR autoantibodies (review by Vincent et al.) known to play a role in the cause of myasthenia gravis. A clear titer reduction was observed after SADC application.

[0316] Figures 1C and 1D illustrate the functionality of SADC variants containing different biomolecular scaffolds. Specifically, Figure 1C shows the effectiveness of using an immunoglobulin scaffold, and Figure 1D shows the use of a haptoglobin scaffold for SADC construction. Examples of both demonstrate in vivo experiments of selective antibody reduction by SADCs containing the covalently bound exemplary peptide E049.

[0317] While self-scaffolding proteins are preferred, the haptoglobin-based SADC was produced using human haptoglobin as an alternative. To avoid the formation of anti-human haptoglobin antibodies, the non-self-scaffolding haptoglobin was administered as a SADC injection only once per mouse under these experimental conditions. As predicted, no antibody reactivity was observed against this alternative haptoglobin homolog under these experimental conditions (i.e., single application).

[0318] Figure 1E shows the selectivity of the SADC system. An immunoglobulin-based SADC containing peptide E049 (i.e., the same as in Figure 1C) cannot reduce Ig titers induced by a peptide vaccine containing an unrelated, unrelated amino acid sequence (SEQ ID NO: DHTLYTPYHTHPG), which we have named T8-1. The above example demonstrates in vivo testing for the selectivity of this system. The figure above shows the anti-peptide T8-1 titer against OD values ​​(y-axis) by standard ELISA (0.5 × serial dilutions starting from 1:50 to 1:102,400; x-axis shows log(X) dilutions). After application, the T8-1 titer is not affected by the administration of SADC-Ig-E049. The figure below shows that the initial potency LogIC50 (y-axis) before SADC injection (i.e., the potency at -48 hours and -24 hours) is not affected by the administration of SADC-Ig-E049 (arrow) when compared with the potency LogIC50 after SADC application (i.e., the potency at +24 hours, +48 hours, and +72 hours; shown on the x-axis), thereby demonstrating the selectivity of the system.

[0319] Example 2: Immunogenicity of SADC To eliminate the immunogenicity of SADCs, we tested candidate prototype SADCs and investigated their tendency to induce antibodies upon repeated injection. Peptides T3-1 and T9-1 were used in this test. T3-1 is a 10-amino acid peptide obtained from the angiotensin receptor reference epitope, which forms agonist autoantibodies in pre-eclampsia animal models (Zhou et al.), and T9-1 is a 12-amino acid peptide obtained from the human IFN-gamma reference anti-drug antibody epitope (Lin et al.). These control SADC conjugates were injected intraperitoneally into untreated, unimmunized female BALB / c mice at 8-10 weeks of age, every two weeks for eight doses.

[0320] Animals C1-C4 were intraperitoneally treated with SADC T3-1 (as described in Example 1). Animals C5-C8 were intraperitoneally treated with SADC containing peptide T9-1. Plasma from control animals vaccinated three times with KLH peptide T1-1 (obtained from AChR-MIR; described in Example 1) was used as a reference signal for ELISA analysis. BSA-conjugated peptide probes T3-1, T9-1, and E005 (SEQ ID NO: 17:GGVKKIHIPSEK) were used at a 1:100 dilution each to detect antibody titers by standard ELISA, and it was shown that no antibody induction occurred in SADC-treated animals compared to vaccinated control animal C (see Figure 2). Plasma was obtained by submandibular blood collection one week after the third vaccine injection (control animal C) and after the last of eight consecutive SADC injections at two-week intervals (animals C1-C8). Thus, it was shown that SADC is non-immunogenic and does not induce antibody formation after repeated injections in mice.

[0321] Example 3: It is possible to deplete antibodies in vitro using SADCs containing multiple copies of monovalent or bivalent peptides. Plasma from mice vaccinated with E006-KLH (VKKIHIPSEKG (SEQ ID NO: 4), which has a C-terminal cysteine ​​and binds to KLH) was diluted 1:3200 with dilution buffer (PBS + 0.1% w / v BSA + 0.1% Tween20) and incubated sequentially (10 minutes / well) four times (100 μl, room temperature) on single wells of microtiter plates coated with 2.5 μg / ml (250 ng / well) SADC or 5 μg / ml (500 ng / well) albumin as a negative control.

[0322] To measure the amount of free unbound antibody present on SADC-coated wells before and after incubation, 50 μl of the diluted serum was collected before and after depletion and quantified using standard ELISA with E006-BSA-coated plates (10 nM peptide) and detection with goat anti-mouse IgG bio (Southern Biotech, 1:2000 dilution). Next, the biotinylated antibody was detected using streptavidin-HRP (Thermo Scientific, 1:5000 dilution) with TMB as the substrate. Signal generation was stopped with 0.5 M sulfuric acid.

[0323] ELISA measurements were performed at OD450nm (y-axis). The results showed that the antibody was efficiently adsorbed by either a coated monovalent or divalent SADC containing the C-terminal cysteine ​​peptide E006 (sequence VKKIHIPSEKGC, SEQ ID NO: 4) (before treatment = undepleted initiation material; monovalent and divalent correspond to the peptide presented on the SADC surface; negative control is albumin; shown on the x-axis). See Figure 3. ("Monovalent" means that a peptide monomer is bound to the biopolymer scaffold (i.e., n=1), and "divalent" means that a peptide dimer is bound to the biopolymer scaffold (i.e., n=2). In this case, the divalent peptide was "homodivalent." That is, the peptide n-mer of the SADC is E006-S-E006.)

[0324] This indicates that SADCs containing monovalent or bivalent peptides are highly suitable for adsorbing antibodies and, consequently, depleting them.

[0325] Example 4: Generation of SADC based on a mimotope Using linear and cyclic peptides derived from wild-type or modified peptide amino acid sequences, specific SADCs can be constructed to selectively remove antibodies against specific epitopes that are harmful, disease-causing, or otherwise undesirable. For specific epitopes, SADCs can be constructed using constrained peptides, such as linear or cyclopeptides, containing the epitope or a portion of its variants, which are, for example, peptides (mimotopes) in which one or more amino acids are substituted or chemically modified to improve affinity to the antibody. Peptide screening can be performed to identify peptides with optimized affinity for disease-causing autoantibodies. The flexibility of structural or chemical peptide modification provides solutions to minimize the risk of immunogenicity, particularly the risk of the peptide binding to HLA, and therefore the risk of undesirable immune stimulation.

[0326] Therefore, wild-type and modified linear and circular peptide sequences were obtained from known epitopes associated with autoimmune diseases. Peptides of various lengths and positions were systematically rearranged by amino acid substitutions and synthesized on the PEPperCHIP® peptide array Platform (PEPperPRINT GmbH, Germany). This allowed for the screening of 60,000 cyclic and linear wild-type and mimotope peptides derived from these sequences. The peptide array was incubated with autoantibodies known to be involved in autoimmune diseases. Thus, the 60,000 peptides were screened using these autoantibodies, and 100 cyclic and 100 linear peptides that hit were selected based on their relative binding strength to the autoantibodies. Of these 200 peptides, 51 sequences were identical across the cyclic and linear peptide groups. All of the best-identified peptides were considered mimotopes because they each had at least one amino acid substitution when aligned to the original sequence. Furthermore, it was found that higher binding strength could be achieved with cyclic peptides.

[0327] By preferentially using these newly identified peptides with high relative binding values, we can generate SADCs capable of removing autoantibodies against this specific epitope, or develop further mimotopes and derivatives based on their sequences.

[0328] Example 5: Rapid and selective antibody depletion in mice using various SADC biopolymer scaffolds Female Balb / c mice were intraperitoneally injected with 10 μg of mAB anti-V5 (Thermo Scientific), a model of an undesirable antibody (5 mice per treatment group; 9-11 weeks old). Subsequently, 48 hours after the initial antibody administration, 50 μg of SADC (various biomolecular scaffolds to which tagged V5 peptides are bound) was intravenously injected. Blood samples were collected from the submandibular vein at 24-hour intervals. A blood sample at hour 0 was taken immediately before SADC administration.

[0329] After SADC administration, blood samples were collected every 24 hours until 120 hours (x-axis). The decay and decrease in plasma anti-V5 IgG concentration after SADC administration was determined as shown in Figure 4 by combining anti-V5 titer readings using a standard ELISA procedure with detection using coated V5 peptide-BSA (peptide sequence IPNPLLGLDC, SEQ ID NO: 21) and goat anti-mouse IgG bio (Southern Biotech, 1:2000 dilution). Furthermore, SADC concentration (see Example 6) and immune complex formation (see Example 7) were analyzed.

[0330] The E50 [OD450] value was determined using a 4-parameter logistic curve fitting, and the relative signal decay between the initial concentration (time point 0 set to 1) and subsequent time points (x-axis) was calculated as the percentage of the EC50 value (y-axis; signal decay ratio EC50). All SADC peptides contained tags for direct detection of SADCs and immune complexes from plasma samples. The peptide sequences used were IPNPLLGLDGGSGDYKDDDDKGK(SEQ ID NO: 22)-(BiotinAca)GC for SADCs (SADC-ALB for SADCs with an albumin scaffold, SADC-IG for SADCs with an immunoglobulin scaffold, SADC-HP for SADCs with a haptoglobin scaffold, and SADC-TF for SADCs with a transferrin scaffold), and VKKIHIPSEKGGSGDYKDDDDKGK(SEQ ID NO: 23)-(BiotinAca)GC(SADC-CTR) for an unrelated peptide used as a negative control SADC.

[0331] The SADC scaffolds for the five individual organisms in each of the aforementioned treatment groups are shown in black / gray shade (see inset in Figure 4).

[0332] The treated group (especially SADC-TF) showed a rapid and significant decrease in antibody levels compared to the mock-treated control group, SADC-CTL, as early as 24 hours later. SADC-CTR was used as a reference for normal antibody decay because its peptide sequence was not recognized by the administered anti-V5 antibody and therefore lacked antibody-reducing activity. The decay of SADC-CTR is marked with a trend line to highlight the difference in antibody concentrations between treated and mock-treated animals.

[0333] To determine the effectiveness of selective antibody reduction under these experimental conditions, a two-way ANOVA was performed using Dunnett's multiple comparison test. 48 hours after SADC administration, antibody EC50 decreased significantly in all SADC groups compared to the SADC-CTR reference group (trend line) (p<0.0001). 120 hours after SADC administration, antibody reduction was significantly significant in the SADC-ALB and SADC-TF groups (both p<0.0001), significant in the SADC-HP group (p=0.0292), and the SADC-IG group showed a trend toward EC50 reduction 120 hours after SADC administration (p=0.0722). Notably, selective antibody reduction was significantly significant in the SADC-ALB and SADC-TF groups at all tested time points after SADC administration (p<0.0001).

[0334] It is concluded that all SADC biomolecular scaffolds were capable of selectively reducing antibody concentrations. The decrease in titer was most pronounced in SADC-ALB and SADC-TF, and no rebound or recycling of antibody concentrations was detected towards the end point. This suggests that undesirable antibodies were degraded as intended.

[0335] Example 6: Detection of SADC in plasma 24 hours after SADC injection Plasma concentrations of various SADC variants 24 hours after intravenous injection into Balb / c mice. Plasma concentrations (y axis) of SADC-ALB, -IG, -HP, and -TF, as well as the negative control SADC-CTR (x axis), were measured in the animal plasma described in Example 5. The injected plasma SADC concentrations were detected by standard ELISA. In this process, SADCs were captured by a combination of the biotin portion of their peptides and a streptavidin-coated plate (Thermo Scientific). The captured SADCs were detected using a mouse anti-Flag-HRP antibody (Thermo Scientific, 1:2000 dilution) that detects Flag-tagged peptides (see also Example 7).

[0336] Assuming that the theoretical amount of SADC in the blood after intravenous injection of 50 μg is approximately 25 μg / ml, the detectable amounts of SADC 24 hours after injection were in the range of 799-623 ng / ml for SADC-ALB or SADC-IG, and up to approximately 5000 ng / ml for SADC-TF. Surprisingly, however, and in contrast, SADC-HP and the control SADC-CTR (also a SADC-HP variant, but in this case having the unrelated negative control peptide E006; see previous examples) had completely disappeared from the circulatory system 24 hours after injection and were no longer detectable. See Figure 5.

[0337] This demonstrates that both haptoglobin scaffold-based SADCs (i.e., SADC-HP and SADC-CTR) tested in this embodiment exhibit relatively short plasma half-lives. Compared to SADCs such as SADC-ALB, SADC-IG, or SADC-TF, which may play a potential role in complement-dependent vascular and renal damage due to the in vivo risk of immune complex formation, both haptoglobin scaffold-based SADCs are shown to be superior. Another advantage of SADC-HP is its rapid clearance rate from the blood for undesirable target antibodies when rapid therapeutic effects are required. These results demonstrate rapid and highly effective removal of haptoglobin-based SADC scaffolds (represented by SADC-HP and SADC-CTR) from the blood, regardless of the presence or absence of SADC-binding antibodies, thereby minimizing the formation of undesirable immune complexes. SADCs such as haptoglobin-based SADC-HP in this embodiment thus offer superior therapeutic advantages over other SADC biomolecular scaffolds. This is evident, for example, from the fact that both SADC-TF and SADC-ALB remain detectable 24 hours after injection under the described conditions, in contrast to both SADC-HP and SADC-CTR being completely eliminated 24 hours after injection.

[0338] Example 7: Detection of SADC-IgG complexes in plasma 24 hours after SADC injection Following intravenous injection of 10 μg of anti-V5 IgG (Thermo Scientific) and intravenous administration of SADC-ALB, -HP, -TF, and -CTR (50 μg) 48 hours after antibody injection, plasma was collected from the submandibular vein 24 hours after SADC injection to measure the amount of IgG bound to SADC in vivo. The plasma was incubated on streptavidin plates, and SADC was captured from the plasma via its biotinylated SADC-V5 peptide [IPNPLLGLDGGSGDYKDDDDKGK (SEQ ID NO: 22) (BiotinAca)GC, or, in the case of SADC-CTR, the negative control peptide VKKIHIPSEKGGSGDYKDDDDKGK (SEQ ID NO: 23) (BiotinAca)GC]. IgG bound to the streptavidin-captured SADC was detected by ELISA using goat anti-mouse IgG HRP antibody (Jackson Immuno Research, 1:2,000 dilution) to detect the SADC-antibody complex present in plasma 24 hours after SADC injection. Background correction was performed by subtracting the OD450nm value (y-axis) obtained for negative control serum from untreated animals from the OD450nm value of the test group (x-axis).

[0339] As shown in Figure 6, a significant anti-V5 antibody signal was observed in SADC-ALB and SADC-TF injected mice (black bars represent background-corrected OD values ​​at a 1:25 dilution, the mean value of 5 mice; standard deviation error bars). On the other hand, no antibody signal was detected in plasma from SADC-HP or control SADC-CTR injected animals (SADC-CTR is a negative control with an unrelated peptide bio-FLG-E006 [VKKIHIPSEKGGSGDYKDDDDKGK (SEQ ID NO: 23) (BiotinAca)GC] that is not recognized by any anti-V5 antibody). This indicates that the SADC-HP / IgG complex is not present in detectable amounts in plasma 24 hours after intravenous administration of SADC.

[0340] Therefore, SADC-HP is eliminated more rapidly than SADC-ALB or SADC-TF in mice pre-injected with anti-V5.

[0341] Example 8: In vitro analysis of SADC-immunoglobulin complex formation To analyze SADC-antibody complex formation, 1 μg / ml human anti-V5 antibody (anti-V5 epitope tag [SV5-PK], human IgG3, Absolute Antibody) was pre-incubated at room temperature for 2 hours in PBS containing 0.1% w / v BSA and 0.1% Tween20 with SADC-ALB, -IG, -HP, -TF, and -CTR (shown on the x-axis) at increasing concentrations to form immunocomplexes in vitro. After complex formation, the samples were incubated at room temperature for 1 hour on ELISA plates pre-coated with 10 μg / ml human C1q (CompTech) to capture the immunocomplexes formed in vitro. Next, the complexes were detected by ELISA using anti-human IgG (Fab-specific) peroxidase (Sigma, 1:1000 dilution). The measurement signal at OD450nm (y-axis) reflects the antibody-SADC complex formation in vitro.

[0342] As shown in Figure 7, SADC-TF and -ALB showed significant immune complex formation and binding to C1q. This is reflected in the strong signal and the rapid decrease in signal during the transition from antigen-antibody equilibrium to antigen excess when SADC-TF was 1000 ng / ml. On the other hand, in vitro immune complex formation with SADC-HP or SADC-IG was significantly less efficient when measured in this assay.

[0343] Together with the aforementioned in vivo data (from the previous examples), these findings support the finding that haptoglobin scaffolds are advantageous over other SADC biomolecular scaffolds because they have a lower tendency to activate the complement system. On the other hand, SADC-TF or SADC-ALB show higher complexation and therefore carry a certain risk of activating the C1 complex and initiating the classical complement pathway (although this risk may be acceptable in some situations).

[0344] Example 9: Measurement of IgG capture by SADC in vitro Similar to the previous example, an immune complex was formed in vitro using a combination of 1 μg / ml mouse anti-V5 antibody (Thermo Scientific) and an increased amount of SADC (shown on the x-axis). The SADC-antibody complex was captured on a streptavidin-coated ELISA plate via biotinylated SADC-peptide (see previous example), and the bound anti-V5 was then detected using anti-mouse IgG-HRP (Jackson Immuno Research, 1:2000 dilution).

[0345] Under these assay conditions, SADC-HP exhibited significantly lower antibody-binding ability in vitro compared to SADC-TF or SADC-ALB (see Figure 8A). The calculated EC50 values ​​for IgG detection on SADC were 7.0 ng / ml, 27.9 ng / ml, and 55.5 ng / ml for SADC-TF, -ALB, and -HP, respectively (see Figure 8B).

[0346] This in vitro finding is consistent with the observation that SADC-HP has lower immune complex formation ability than SADC-TF or SADC-ALB (see previous examples). This is considered a safety advantage from the standpoint of therapeutic use for undesirable antibody depletion.

[0347] Example 10: SADC for reducing undesirable anti-AAV-8 antibodies Three SADCs are provided to reduce AAV-8 neutralizing antibodies that interfere with gene therapy (see Gurda et al. for the epitope used; also see AAV-8 capsid protein sequence UniProt Q8JQF8, sequence version 1): (a) SADC-a comprising haptoglobin as a biomolecular scaffold and at least two peptides having the sequence LQQQNT (SEQ ID NO: 18) covalently bound to the scaffold; (b) SADC-b comprising transferrin as a biomolecular scaffold and at least two peptides having the sequence TTTGQNNNS (SEQ ID NO: 19) covalently bound to the scaffold; and (c) SADC-c comprising albumin as a biomolecular scaffold and at least two peptides having the sequence GTANTQ (SEQ ID NO: 20) covalently bound to the scaffold.

[0348] By administering these SADCs to individuals undergoing gene therapy using AAV-8 as a vector, the efficiency of the gene therapy is increased.

[0349] Non-patent literature JPEG0007856286000009.jpg216159

[0350] JPEG0007856286000010.jpg226155

[0351] JPEG0007856286000011.jpg218155

[0352] JPEG0007856286000012.jpg212154

[0353] Tetala, Kishore KR, et al. "Selective depletion of neuropathy-related antibodies from human serum by monolithic affinity columns containing ganglioside mimics." Journal of medicinal chemistry 54.10 (2011): 3500-3505. Vincent, Angela, et al. "Serological and experimental studies in different forms of myasthenia gravis." Annals of the New York Academy of Sciences 1413.1 (2018): 143-153. Wallukat, Gerd, et al. "Patients with preeclampsia develop agonistic autoantibodies against the angiotensin AT 1 receptor." The Journal of clinical investigation 103.7 (1999): 945-952. Zhou, Cissy C., et al. "Angiotensin receptor agonistic autoantibodies induce pre-eclampsia in pregnant mice." Nature medicine 14.8 (2008): 855.

Claims

1. - Biomolecular scaffolds, and at least • The first peptide n-mer of the following general formula: P(-S-P) （ｎ－１） and • The second peptide n-mer of the following general formula: P(-S-P) （ｎ－１） A compound containing, P is a peptide having a sequence length of 5 to 13 amino acids, and S is a non-peptide spacer. For each of the aforementioned peptide n-mers, independently, n is an integer greater than or equal to 1. Each of the peptide n-mers is covalently bonded to the biopolymer scaffold via a linker. The aforementioned biopolymer scaffold is transferrin. The aforementioned compound.

2. The compound according to claim 1, wherein n is 1.

3. The compound according to claim 1, wherein n is 2.

4. The compound according to claim 1, wherein n is an integer of 3 or more.

5. The compound according to any one of claims 1 to 4, wherein at least one P is a cyclic peptide.

6. P is independent of P ａ or P ｂ And, P ａ This is a peptide having a sequence length of 5 to 13 amino acids. P ｂ This is a peptide having a sequence length of 5 to 13 amino acids. The first peptide n-mer is P ａ -S-P ａ and the second peptide n-mer is P ａ -S-P ａ or The first peptide nmer is P ａ -S-P ａ And the second peptide nmer is P ｂ -S-P ｂ Is it, The first peptide nmer is P ｂ -S-P ｂ And the second peptide nmer is P ｂ -S-P ｂ Is it, The first peptide nmer is P ａ -S-P ｂ And the second peptide nmer is P ａ -S-P ｂ Is it, The first peptide nmer is P ａ -S-P ｂ And the second peptide nmer is P ａ -S-P ａ is, or The first peptide nmer is P ａ -S-P ｂ And the second peptide nmer is P ｂ -S-P ｂ That is, The compound according to claim 1.

7. The compound according to claim 6, wherein at least one P is a cyclic peptide.

8. The aforementioned peptide P ａ and the peptide P ｂ The compound according to claim 6 or 7, wherein the compound is either two different epitopes of the same antigen, or two different epitope portions of the same epitope.

9. The compound according to any one of claims 1 to 8, wherein the biopolymer scaffold is human transferrin.

10. The compound according to any one of claims 1 to 9, wherein the compound is non-immunogenic in mammals.

11. The compound according to claim 10, wherein the compound is non-immunogenic in non-human primates.

12. The compound according to claim 10, wherein the compound is non-immunogenic in humans.

13. A pharmaceutical composition comprising a compound according to any one of claims 1 to 12 and at least one pharmaceutically acceptable excipient.

14. The pharmaceutical composition according to claim 13, which is non-immunogenic in humans.

15. A pharmaceutical composition according to claim 13 or claim 14 for use in therapeutic purposes.

16. A pharmaceutical composition according to claim 15, for use in the prevention or treatment of an autoimmune disease in an individual having an autoimmune disease or being at risk of developing an autoimmune disease, wherein the pharmaceutical composition is non-immunogenic in the individual.

17. A pharmaceutical composition according to claim 15, for use in the prevention or treatment of graft rejection in an individual having or being eligible for graft, wherein the pharmaceutical composition is non-immunogenic in the individual.

18. In individuals receiving or eligible for drug therapy, or in individuals receiving or eligible for gene therapy, In the prevention or treatment of adverse reactions based on anti-drug antibodies or anti-gene delivery vector antibodies, A pharmaceutical composition according to claim 15 for use, wherein the pharmaceutical composition is non-immunogenic in the organism.

19. The pharmaceutical composition according to claim 18, wherein the drug is a peptide or a protein.

20. The pharmaceutical composition according to claim 19, wherein the drug is selected from the group consisting of enzymes, enzyme inhibitors, antibodies, antibody fragments, antibody mimetics, antibody-drug conjugates, hormones, growth factors, coagulation factors, and cytokines.

21. The pharmaceutical composition according to any one of claims 18 to 20, wherein the anti-drug antibody or anti-gene delivery vector antibody is an anti-AAV antibody.

22. A pharmaceutical composition comprising a compound according to any one of claims 1 to 12, further comprising an active agent and at least one pharmaceutically acceptable excipient, The active agent comprises a peptide fragment having a sequence length of 5 to 13 amino acids. At least one peptide P of the aforementioned compound, or peptide P ａ and / or peptide P ｂ The pharmaceutical composition wherein the sequence of the peptide fragment is at least 70% identical to the sequence of the peptide fragment.

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