Compounds for increasing the efficacy of oncolytic viruses - Patents.com

Abstract

The present invention provides compounds for the sequestration of unwanted neutralizing antibodies against oncolytic viruses in patients. The compounds comprise an inert biopolymer scaffold and at least one compound 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 6-13 amino acids, and S is a non-peptide spacer, and independently for each said peptide n-mer, n is an integer equal to or greater than 1, and each said peptide n-mer is attached to said biopolymer scaffold. Each P independently has an amino acid sequence that includes a sequence fragment of an oncolytic virus protein sequence having a length of at least 6 amino acids. Also provided are pharmaceutical compositions comprising the compounds, as well as methods for sequestering one or more antibodies present in an individual and for inhibiting an undesirable immune response to treatment with an oncolytic virus.

Description

[Technical field]

[0001] The field of the invention relates to compounds for increasing the effectiveness of oncolytic viruses. [Background technology]

[0002] Oncolytic viruses, such as those based on adenoviruses (AdV), adeno-associated viruses (AAV), measles viruses, herpes simplex viruses (HSV), poxviruses, reoviruses, Newcastle disease viruses (NVD), rhabdoviruses, coxsackieviruses, lentiviruses, alphaviruses or flaviviruses, are suitable for cancer therapy. Some of them are used in their naturally occurring form, some of them are used "armed" with engineered (transgenic) payloads to improve their efficacy (reviewed by Cristi et al., 2022). Numerous studies in tumor models have demonstrated substantial tumor regression and extended survival rates (Lundstrom, 2018). Several clinical trials have confirmed the good safety profile and therapeutic efficacy of oncolytic viruses. Gendicine, based on oncolytic AdV, has been approved in China for use in the treatment of head and neck squamous cell carcinoma (Zhang et al., 2018). More recently, an oncolytic HSV-1 has been approved for the treatment of melanoma in the United States and Europe under the name talimogene laherparepvec, or "T-Vec" (Conry et al., 2018).

[0003] The emerging field of virus-mediated cancer therapy has been extensively reviewed by Kontermann et al., 2021. A wide variety of oncolytic viruses for local or systemic application routes are available today (see review in Cook et al., 2021). Further viral vector platforms include vesicular stomatitis virus (VSS), myxoma virus (MYXV), mengovirus, bovine viral diarrhea virus (BVDV), or chimeric constructs. An extensive overview of oncolytic vectors is provided by Apolonio et al., 2021.

[0004] The oncotoxic effect of oncolytic viruses can be increased by inserting various classes of functional genes (as payloads) into the viral genome to enhance its oncolytic function. This includes, for example, inserting sequences encoding antibodies, bispecific T cell engagers (BiTEs), bispecific adapter proteins, or various forms of fusion proteins, and may be combined with chimeric antigen receptor (CAR)-T cell therapy. These strategies can deliver immune checkpoint inhibitors, antiangiogenic antibodies, or other functional entities, such as cytotoxic fusion proteins, to tumors or hematological neoplasms.

[0005] However, oncolytic virotherapy encounters resistance mechanisms resulting from the host's humoral or cellular immune responses to the oncolytic viral vector. Bhatt et al., 2021, review various different types of resistance mechanisms, ranging from interferon signaling to epigenetic- or hypoxia-mediated mechanisms.

[0006] In addition to the innate immune response against oncolytic viral vectors (including natural killer cell or interferon responses), the presence of neutralizing antibodies (nAbs) against oncolytic vectors can also result in inhibition and (early) clearance of the vector. Various strategies have been proposed to remove or avoid the effect of such nAbs, including PEGylation, encapsulation, or polymers to block and shield viral vectors, as reviewed, for example, by de Matos et al., 2020, or Engeland & Ungerechts, 2021.

[0007] Despite these efforts, new strategies to improve the efficacy of oncolytic viruses remain needed. Summary of the Invention [Problem to be solved by the invention]

[0008] It is therefore an object of the present invention to provide compounds and methods that inhibit oncolytic virus neutralization, thereby typically increasing the efficacy of oncolytic viruses in cancer (or, more generally, anti-neoplastic) therapy. [Means for solving the problem]

[0009] The present invention relates to Biopolymer scaffolds, as well as at least a first peptide n-mer of the following general formula: P(-SP) (n-1) and a second peptide n-mer of the general formula: P(-SP) (n-1) The present invention provides a compound comprising:

[0010] Each P is independently a peptide having a sequence length of 6 to 13 amino acids, and S is a non-peptide spacer. Independently for each peptide n-mer, n is an integer of 1 or more, preferably an integer of 2 or more, more preferably an integer of 3 or more, and particularly an integer of 4 or more. Each peptide n-mer is preferably linked to the biopolymer scaffold via a respective linker. Further, each P independently represents a protein sequence (preferably a capsid protein sequence, a nucleocapsid protein sequence, a structural protein sequence, a viral envelope associated protein sequence or a receptor binding protein sequence, a tegument protein sequence, a viral enzyme sequence, a nuclear matrix protein sequence, a DNA- or RNA-binding protein sequence, a viral packaging protein sequence or a viral polymerase sequence, more preferably a capsid protein sequence, a nucleocapsid protein sequence, a structural protein sequence, a viral envelope associated protein sequence or a receptor binding protein sequence, or a tegument protein sequence, in particular a (non-pathogenic) capsid protein sequence) of an oncolytic virus (such as, for example, AAV or AdV or measles virus), in particular a capsid protein sequence of the AdV hexon protein sequence, AdV fiber protein sequence, AdV penton protein sequence, AdV IIIa protein sequence, AdV VI protein sequence, AdV VIII protein sequence or AdV IX protein sequence, any one of the capsid protein sequences identified in Figures 4 and 5 or the capsid protein sequences described in Cearley et al., 2008, or any one of the capsid protein sequences listed in UniProt P03525, P03526, P03527, P03528, P03529, P0CK31, P11078, P11079, P12418, P12419, P15024, P21270, A1Z0P5, O09800, P03170, P04288, P04289, P04291, P0 4486, P06477, P06484, P06487, P06491, P08314, P08392, P08543, P10185, P10 190, P10191, P10192, P10193, P10200, P10202, P10204, P10205, P10210, P1021 6, P10218, P10219, P10220, P10225, P10227, P10228, P10229, P10231, P10234, P32888, P68333, P08362, P35971, Q89933, P35974, P35976, P69358, P12576, Q9EMA9 and P03522. Up to 3, preferably up to 2, most preferably one or more amino acids of said sequence fragment may be independently replaced by any other amino acid.

[0011] Preferably, at least one of P is P a , and / or at least one of P is P b It is. a is a defined peptide (i.e., a peptide of defined sequence) having a sequence length of 6 to 13 amino acids, preferably 7 to 11 amino acids, and more preferably 7 to 9 amino acids. b is a defined peptide having a sequence length of 6 to 13 amino acids, preferably 7 to 11 amino acids, and more preferably 7 to 9 amino acids (ie, a peptide of a defined sequence).

[0012] The present invention relates to Biopolymer scaffolds, as well as at least ·General formula P a -SP a Or P a -SP b a first peptide n-mer which is a peptide dimer of a is a defined peptide (i.e., a peptide of a defined sequence) having a sequence length of 6 to 13 amino acids, preferably 7 to 11 amino acids, and more preferably 7 to 9 amino acids; b Also provided is a compound comprising a first peptide n-mer, wherein P is a defined peptide (i.e., a peptide of defined sequence) having a sequence length of 6-13 amino acids, preferably 7-11 amino acids, more preferably 7-9 amino acids, S is a non-peptide spacer, and the first peptide n-mer is attached to the biopolymer scaffold, preferably via a linker. ais selected from a protein sequence (preferably a capsid protein sequence, a nucleocapsid protein sequence, a structural protein sequence, a viral envelope associated protein sequence or a receptor binding protein sequence, a tegument protein sequence, a viral enzyme sequence, a nuclear matrix protein sequence, a DNA- or RNA-binding protein sequence, a viral packaging protein sequence or a viral polymerase sequence, more preferably a capsid protein sequence, a nucleocapsid protein sequence, a structural protein sequence, a viral envelope associated protein sequence or a receptor binding protein sequence, or a tegument protein sequence) of a (non-pathogenic) oncolytic virus, in particular a capsid protein sequence, in particular a capsid protein sequence of the AdV hexon protein sequence, the AdV fiber protein sequence, the AdV penton protein sequence, the AdV IIIa protein sequence, the AdV VI protein sequence, the AdV VIII protein sequence or the AdV IX protein sequence, any one of the capsid protein sequences specified in FIG. 4 and FIG. 5 or the capsid protein sequences described in Cearley et al., 2008, or any one of the capsid protein sequences listed in UniProt P03525, P03526, P03527, P03528, P03529, P0CK31, P11078, P11079, P12418, P12419, P15024, P21270, A1Z0P5, O09800, P03170, P04288, P04289, P04291, P0 4486, P06477, P06484, P06487, P06491, P08314, P08392, P08543, P10185, P10 190, P10191, P10192, P10193, P10200, P10202, P10204, P10205, P10210, P1021 6, P10218, P10219, P10220, P10225, P10227, P10228, P10229, P10231, P10234, P32888, P68333, P08362, P35971, Q89933, P35974, P35976, P69358, P12576, Q9EMA9 and P03522. Up to 3, preferably up to 2, most preferably one or more amino acids of said sequence fragment may be independently replaced by any other amino acid.

[0013] The compound preferably has the formula P b -SP b Or P a -SP b and a second peptide n-mer, which is a peptide dimer of the formula: P, wherein the second peptide n-mer is attached to the biopolymer scaffold, preferably via a linker. bis selected from a protein sequence (preferably a capsid protein sequence, a nucleocapsid protein sequence, a structural protein sequence, a viral envelope associated protein sequence or a receptor binding protein sequence, a tegument protein sequence, a viral enzyme sequence, a nuclear matrix protein sequence, a DNA- or RNA-binding protein sequence, a viral packaging protein sequence or a viral polymerase sequence, more preferably a capsid protein sequence, a nucleocapsid protein sequence, a structural protein sequence, a viral envelope associated protein sequence or a receptor binding protein sequence, or a tegument protein sequence), in particular a capsid protein sequence), in particular a capsid protein sequence of an AdV hexon protein sequence, an AdV fiber protein sequence, an AdV penton protein sequence, an AdV IIIa protein sequence, an AdV VI protein sequence, an AdV VIII protein sequence or an AdV IX protein sequence, or any one of the capsid protein sequences identified in Figures 4 and 5 or Cearley et al., 2008, or any one of the capsid protein sequences listed in UniProt P03525, P03526, P03527, P03528, P03529, P0CK31, P11078, P11079, P12418, P12419, P15024, P21270, A1Z0P5, O09800, P03170, P04288, P04289, P04291, P0 4486, P06477, P06484, P06487, P06491, P08314, P08392, P08543, P10185, P10 190, P10191, P10192, P10193, P10200, P10202, P10204, P10205, P10210, P1021 6, P10218, P10219, P10220, P10225, P10227, P10228, P10229, P10231, P10234, P32888, P68333, P08362, P35971, Q89933, P35974, P35976, P69358, P12576, Q9EMA9 and P03522. Up to 3, preferably up to 2, most preferably one or more amino acids of said sequence fragment may be independently replaced by any other amino acid.

[0014] The present invention further provides a pharmaceutical composition comprising any one of the aforementioned compounds and at least one pharma- ceutically acceptable excipient, preferably for use in therapy, preferably for use in the treatment of a neoplasm, such as a benign, in situ neoplasm or a malignant neoplasm, in particular for use in the treatment of a solid tumor or a hematological malignancy.

[0015] In another aspect, the present invention relates to a method for (temporarily) sequestering (or depleting) one or more antibodies present in an individual, comprising obtaining a pharmaceutical composition as defined herein and administering said pharmaceutical composition to said individual, wherein said composition is non-immunogenic in said individual and said one or more antibodies present in said individual are directed against at least one P or to a peptide P. a and / or peptide P b The present invention provides a method which is specific for

[0016] In yet another aspect, the present invention relates to a pharmaceutical composition (i.e. antineoplastic composition) comprising said compound as defined herein and optionally further comprising said oncolytic virus or oncolytic virus-like particle (VLP) and at least one pharma- ceutical acceptable formulation additive. Said oncolytic virus usually comprises a peptide fragment having a sequence length of at least 6, preferably at least 7, more preferably at least 8, in particular at least 9 amino acids. Said compound peptide P or peptide P a and / or peptide P b at least one sequence of has at least 70% identity with the sequence of said peptide fragment, preferably at least 75% identity, more preferably at least 80% identity, even more preferably at least 85% identity, even more preferably at least 90% identity, even more preferably at least 95% identity, in particular completely identical. Preferably, the pharmaceutical composition is for use in therapy, preferably for the treatment of neoplasms such as benign, intraepithelial or malignant neoplasms, in particular for use in the treatment of solid tumors or hematological malignancies, and / or for use in preventing or inhibiting an unwanted (humoral) immune response against the oncolytic virus (or VLP).

[0017] In yet another aspect, the present invention provides a method for inhibiting inhibition of an (undesirable) - in particular a humoral - immune response to treatment with an anti-neoplastic composition in an individual in need of treatment with said anti-neoplastic composition, or for inhibiting neutralization of an oncolytic virus in an anti-neoplastic composition for an individual in need of treatment with said anti-neoplastic composition, comprising obtaining said anti-neoplastic composition and administering said anti-neoplastic composition to said individual (preferably systemically or locally, in particular systemically), wherein said anti-neoplastic composition is non-immunogenic in said individual.

[0018] Neutralizing and inhibitory antibodies against oncolytic viruses also increase immune stimulatory antitumor activity. Thus, existing antibodies against oncolytic vectors, which are both inhibitory and beneficial at the same time, are a double-edged sword.

[0019] In other words, on the one hand, the immunostimulatory functions of oncolytic viruses support their beneficial effects on cancer cells, whereas at the same time, the immunostimulatory functions may inhibit oncolytic vector delivery, thereby reducing target access and therapeutic efficacy.

[0020] The present invention is suitable to provide a solution in the face of these conflicting goals. In the first step, nABs are selectively removed by administering the compounds of the present invention. This allows efficient delivery of oncolytic virus vectors to target tissues upon virus administration (especially when oncolytic viruses or oncolytic VLPs are administered systemically - a scenario in which the present invention is particularly effective). As the compounds of the present invention are eventually removed from circulation, nAb titers are restored after a time frame of, for example, several days. The nAbs then contribute to the immunostimulatory function of oncolytic viruses, which is required.

[0021] It has been found that the present invention provides a very suitable temporal window for oncolytic virus administration (see, for example, Example 1 and Figures 1 and 2). This window typically decreases as anti-oncolytic antibody titers recover. Thus, the selective antibody depletion compounds (SADCs, based on the concept generally first disclosed in WO2020 / 193486A1) of the present invention are well suited to enhance the effect of locally or systemically applied oncolytic viruses or oncolytic virus-like particles (VLPs) for targeting solid tumors as well as hematological malignancies.

[0022] In addition to their functional utility, multivalent peptide-based SADCs with non-immunogenic peptides bound to non-immunogenic "self" scaffold proteins have another general immune safety advantage over similar biological therapeutic constructs carrying, for example, DNA or RNA aptamers to sequester undesirable or harmful antibodies. Although it is certainly possible to produce such constructs with therapeutic effects, in contrast to the present invention, DNAA or RNA aptamer-based constructs have an inherent risk of acting like pathogen-associated molecular patterns (PAMPs), especially when they are bound to scaffold proteins in a multivalent form. DNA or RNA aptamer molecules bound to protein carriers (e.g., human albumin or human transferrin) have an inherent risk of triggering innate immune responses through Toll-like receptors (TLRs) and inducing excessive cytokine production with harmful side effects, as reviewed in Bruno, 2018. [Brief description of the drawings]

[0023] [Figure 1] Schematic diagram of the oncolytic regimen of the present invention. The antibody reducing effect of SADC allows a temporary therapeutic window for oncolytic virus administration in organisms with pre-existing immunity. OV: oncolytic virus. [Diagram 2]Transient selective reduction in pre-existing antibody titers. A rapid reduction in antibody titers was observed 24 and 48 hours after intravenous SADC administration. Titer recovery began 48 hours after SADC administration. [Diagram 3] Blood clearance of anti-CD163 antibody-based biopolymer scaffolds. In a mouse model, mAb E10B10 (specific for mouse CD163) was cleared from the circulation much more rapidly than mAb Mac2-158 (specific for human but not mouse CD163, and therefore serves as a negative control in this experiment). [Figure 4-1] AdV capsid protein sequences for use in the present invention. Database accession numbers (particularly UniProt or GenBank accession numbers) are listed. [Figure 4-2] Same as above. [Figure 5-1] AAV capsid protein sequences for use in the present invention, see database accession numbers (listing specifically UniProt or GenBank accession numbers), as well as sequences in patent publications. [Figure 5-2] Same as above. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0024] The following detailed description relates to all of the above aspects of the invention, except where expressly excluded.

[0025] In general, antibodies are important components 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 administration of biomolecular drugs or gene delivery vectors, antibodies can target the patient's own body (or foreign tissues or cells, or biomolecular drugs or vectors immediately after administration) and become harmful or disease-causing. Some antibodies may also interfere with diagnostic imaging probes. Hereinafter, such antibodies are generally referred to as "undesirable antibodies" or "undesirable antibodies." (As explained above, whether a given antibody is "undesirable" may depend on the context; in the case of oncolytic viruses, only temporary antibody depletion is generally preferred, allowing efficient delivery of the virus to the target.)

[0026] With few exceptions, selective removal of undesired antibodies has not yet reached clinical utility. At present, the indications are quite 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 undesired 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 applied experimentally in other indications, such as neuroimmunological indications (Tetala et al) or myasthenia gravis (Lazaridis et al), but has not yet been established in clinical routine. One of the reasons for the limited application of selective immunoapheresis is the fact that it is a costly and complicated therapeutic intervention requiring specialized medical care, and in the prior art it is not known how to rapidly and efficiently deplete undesirable antibodies.

[0027] Unrelated to apheresis, Morimoto et al. disclose dextran as a generally applicable multivalent scaffold for improving immunoglobulin binding affinity of peptides and peptidomimetic ligands such as FLAG peptide. WO 2011 / 130324 relates to compounds for the prevention of cytotoxicity. EP 3059244 relates to C-met protein agonists.

[0028] As mentioned above, apheresis is applied ex vivo, whereas several approaches for depleting unwanted antibodies in vivo have been proposed in the prior art, mostly related to some autoimmune diseases involving autoantibodies or anti-drug antibodies.

[0029] Lorentz et al. describe a technique to charge erythrocytes in situ with a tolerogenic payload and drive the depletion of antigen-specific T cells, which would ultimately reduce unwanted humoral responses to model antigens. A similar approach is proposed in Pishesha et al., in which peptide antigen constructs are covalently loaded onto the surface of erythrocytes ex vivo and reinjected into an animal model for general immune tolerance induction.

[0030] WO 92 / 13558 relates to conjugates of stable non-immunogenic polymers and analogues of immunogens, which have the specific B-cell binding capacity of said immunogens and induce humoral anergy to said immunogens when introduced into an individual. These conjugates are therefore disclosed as being useful for treating antibody-mediated conditions caused by foreign or autoimmunogens. See also EP 0 498 658 in this connection.

[0031] Taddeo et al. disclose the use of an anti-CD138 antibody derivative fused to an ovalbumin model antigen to selectively induce receptor crosslinking and cell suicide in vitro in antibody-producing plasma cells expressing antibodies against the model antigen, resulting in the selective depletion of these cells.

[0032] Apitope International NV (Belgium) is currently developing soluble tolerogenic T cell epitope peptides that can suppress antibody responses by resulting in low-level expression of costimulatory molecules from tolerance-inducing antigen-presenting cells (see, for example, Jansson et al.). These products are currently in preclinical and early clinical evaluation for multiple sclerosis, Graves' disease, intermediate uveitis, and other autoimmune conditions, as well as factor VIII intolerance.

[0033] Similarly, Selecta Biosciences, Inc. (USA) is currently investigating strategies to induce tolerance with so-called Synthetic Vaccine Particles (SVPs). The SVP rapamycin is thought to induce tolerance by selective induction of regulatory T cells, thereby blocking the production of unwanted antibodies (see Mazor et al.).

[0034] Mingozzi et al. disclose a decoy adeno-associated virus (AAV) capsid that adsorbs antibodies but is unable to enter target cells.

[0035] WO 2015 / 136027(A1) discloses carbohydrate ligands presenting minimal human natural killer 1 (HNK-1) epitopes that bind to anti-MAG (myelin associated glycoprotein) IgM antibodies and their use for the diagnosis and treatment of anti-MAG neuropathies. WO 2017 / 046172 further discloses carbohydrate ligands and moieties, respectively, that mimic glycoepitopes comprising nervous system glycosphingolipids bound by anti-glycan antibodies associated with nervous system diseases. This document further relates to the use of these carbohydrate ligands / moieties in the diagnosis and treatment of nervous system diseases associated with anti-glycan antibodies.

[0036] US Patent Application Publication No. 2004 / 0258683(A1) discloses methods for treating systemic lupus erythematosus (SLE), including renal SLE, methods for reducing the risk of renal flare in individuals with SLE, and methods for monitoring such treatment. One of the disclosed methods for treating SLE, including renal SLE, and reducing the risk of renal flare in individuals with SLE involves administering to the individual an effective amount of an agent for reducing anti-double stranded DNA (dsDNA) antibody concentrations, such as a dsDNA epitope in the form of an epitope-presenting carrier or epitope-presenting valency platform molecule.

[0037] US Patent No. 5,637,454 relates to assays and treatments for autoimmune diseases. Drugs used for treatment may include peptides that are homologous to identified antigenic molecular mimicking sequences. It is disclosed that these peptides may be delivered to patients to reduce the amount of circulating antibodies with a particular specificity.

[0038] US Patent Publication No. 2007 / 0026396(A1) relates to peptides targeted to antibodies causing cold intolerance and their uses. It is taught that the disclosed peptides can be used to neutralize unwanted autoantibodies in vivo or ex vivo. Similar approaches are disclosed in WO 1992 / 014150 or WO 1998 / 030586.

[0039] WO 2018 / 102668 A1 discloses a fusion protein for selective degradation of disease-causing or undesirable antibodies. The fusion protein (named "Seldeg") comprises a targeting moiety that specifically binds to a cell surface receptor or other cell surface molecule at near-neutral pH, and an antigen moiety fused directly or indirectly to the targeting moiety. Also disclosed is a method of depleting a target antigen-specific antibody from a patient by administering to the patient Seldeg having an antigen moiety configured to specifically bind to the target antigen-specific antibody.

[0040] WO 2015 / 181393(A1) 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, citrullinated fibrinogen sequences grafted onto the SFTI scaffolds have been shown to block autoantibodies and suppress inflammation and pain in rheumatoid arthritis. These scaffolds are disclosed to be non-immunogenic.

[0041] Erlandsson et al. disclose the in vivo removal of idiotypic antibodies by anti-idiotypic antibodies and their derivatives.

[0042] Berlin Cures Holding AG (Germany) proposed an intravenous broad spectrum neutralizer DNA aptamer (see, for example, WO 2016 / 020377(A1) and WO 2012 / 000889(A1)) for the treatment of dilated cardiomyopathy and other GPCR-autoantibody-associated diseases, with the idea that high doses of it would block autoantibodies by competitively binding to their antigen-binding regions. In general, aptamers have not made much progress so far and are still in the preliminary stages of clinical development. Biostability and bioavailability, as well as limitations such as nuclease susceptibility, toxicity, small size, and renal clearance, remain major challenges. A particular problem with their use as selective antibody antagonists is their propensity to stimulate innate immune responses.

[0043] WO 00 / 33887(A2) discloses methods for reducing the circulating concentration of antibodies, particularly disease-associated antibodies. These methods require administering an effective amount of an epitope-presenting carrier to an individual. In addition, an ex vivo method for reducing the circulating concentration of antibodies using an epitope-presenting carrier is also disclosed.

[0044] US Patent No. 6,022,544(A) relates to a method for reducing unwanted antibody responses in a mammal by administering to said mammal a non-immunogenic construct that does not contain high molecular weight immunostimulatory molecules, said construct being disclosed to comprise at least two copies of a B cell membrane immunoglobulin receptor epitope bound to a pharma- ceutically acceptable non-immunogenic carrier.

[0045] WO 2020 / 193486(A1) relates to compounds for the sequestration of unwanted antibodies in patients. However, this document does not mention oncolysis.

[0046] The biopolymer scaffold used in the present invention may be a mammalian biopolymer, such as a human biopolymer, a non-human primate biopolymer, an ovine biopolymer, a porcine biopolymer, a canine biopolymer or a rodent biopolymer. In particular, said biopolymer scaffold is a protein, in particular a plasma protein (unmodified or unmodified with respect to its amino acid sequence). Preferably, said biopolymer scaffold is a mammalian protein, such as a human protein, a non-human primate protein, an ovine protein, a porcine protein, a canine protein or a rodent protein. Typically, said biopolymer scaffold is a non-immunogenic and / or non-toxic protein that preferably circulates in the plasma of a healthy (human) individual and can be efficiently removed or recycled by scavenger receptors present, for example, on myeloid cells or on liver sinusoidal endothelial cells (reviewed by Sorensen et al. 2015).

[0047] WO 2020 / 193486(A1), in particular Examples 1 to 10 thereof, demonstrate that the SADC scaffold, also used in the present invention, is suitable for antibody depletion in a more general context.

[0048] In particular, said biopolymer scaffold is a (preferably human) globulin, preferably selected from the group consisting of immunoglobulins, alpha1-globulins, alpha2-globulins, and beta-globulins, in particular immunoglobulin G, haptoglobin, and transferrin.

[0049] The biopolymer scaffold may be (preferably human) albumin, hemopexin, alpha-1-antitrypsin, C1 esterase inhibitor, lactoferrin; or non-immunogenic (i.e., non-immunogenic in the treated individual) fragments of any of the above proteins, including globulins.

[0050] In another preferred example, the biopolymer scaffold is an anti-CD163 antibody (ie, an antibody specific for the CD163 protein) or a CD163-binding fragment thereof.

[0051] Human CD163 (cluster of differentiation 163) is a 130 kDa membrane glycoprotein (formerly M130) and a prototype class I scavenger receptor with an extracellular portion consisting of 9 scavenger receptor cysteine-rich (SRCR) domains involved in ligand binding. CD163 is an endocytic receptor present on macrophages and monocytes, where it removes hemoglobin / haptoglobin complexes from the blood, but also plays a role in anti-inflammatory processes and wound healing. The highest expression levels of CD163 are found on tissue macrophages (e.g., Kupffer cells in the liver) and on certain macrophages in the spleen and bone marrow. Because of its tissue- and cell-specific expression, and entirely independent of undesired antibody depletion, CD163 is considered as a macrophage target for drug delivery, for example, of immunotoxins, liposomes or other classes of therapeutic compounds (Skytthe et al., 2020).

[0052] Monoclonal anti-CD163 antibodies and the SRCR domains to which they bind have been disclosed, for example, in Madsen et al., 2004, in particular in FIG. 7. Further anti-CD163 antibodies and fragments thereof have been disclosed, for example, in WO 2002 / 032941 (A2) or WO 2011 / 039510 (A2). At least two structurally distinct binding sites for the ligand have been mapped, for example, by the use of domain-specific antibodies, such as the monoclonal antibody (mAb) EDhu1 (see Madsen et al., 2004). This antibody binds to the third SRCR of CD163 and competes with hemoglobin / haptoglobin binding to CD163. Numerous other antibodies against different domains of CD163 have been previously described in the literature, including Mac2-158, KiM8, GHI / 61 and RM3 / 1, which target SRCR domains 1, 3, 7 and 9, respectively. In addition, conserved bacteria-binding sites have been mapped and certain antibodies have been demonstrated to be either bacteria-binding but not hemoglobin / haptoglobin complex-binding or vice versa, indicating distinct mechanisms of CD163 binding and ligand interaction (Fabriek et al., 2009; see also references therein).

[0053] Completely unrelated to undesirable antibody depletion, CD163 has been proposed as a target for cell-specific drug delivery due to its physiological characteristics. Tumor-associated macrophages are one of the main targets where the possible effects of CD163 targeting are currently being explored. Of note, a number of tumors and malignant lesions have been found to correlate with CD163 expression levels, supporting the use of this target in tumor therapy. Other proposed applications include CD163 targeting by anti-drug conjugates (ADCs) in chronic inflammation and neuroinflammation (reviewed in Skytthe et al., 2020). Thus, CD163 targeting by ADCs, especially those containing dexamethasone or stealth liposome complexes, is a therapeutic principle currently being investigated (Graversen et al., 2012; Etzerodt et al., 2012).

[0054] In this context, there are references showing that anti-CD163 antibodies can be rapidly internalized by endocytosis when applied in vivo. This has been shown, for example, for the monoclonal antibody (mAb) Ed-2 (Dijkstra et al., 1985; Graversen et al., 2012) or the mAb Mac2-158 / KN2 / NRY (Granfeldt et al., 2013). Based on these observations in combination with the observations made in the course of the present invention (see in particular the Examples section), it has been found that anti-CD163 antibodies and CD163 binding are highly suitable biopolymer scaffolds for the depletion / sequestration of unwanted antibodies.

[0055] A large number of anti-CD163 antibodies and CD163-binding fragments thereof are known in the art (see, for example, above). These are suitable for use as biopolymer scaffolds for the present invention. For example, any of the anti-CD163 antibodies and fragments thereof described herein or in WO2011 / 039510(A2) (hereby incorporated by reference) may be used as biopolymer scaffolds in the present invention. Preferably, the biopolymer scaffold of the compound of the present invention is the antibody Mac2-48, Mac2-158, 5C6-FAT, BerMac3, or E10B10 disclosed in WO2011 / 039510, in particular the humanized Mac2-48 or Mac2-158 disclosed in WO2011 / 039510(A2).

[0056] In a preferred embodiment, the anti-CD163 antibody or its CD163-binding fragment comprises a heavy chain variable (VH) region comprising one or more complementarity determining region (CDR) sequences selected from the group consisting of SEQ ID NOs: 11 to 13 of WO 2011 / 039510(A2).

[0057] Additionally or alternatively, in a preferred embodiment, the anti-CD163 antibody or CD163-binding fragment thereof comprises a light chain variable (VL) region comprising one or more CDR sequences selected from the group consisting of SEQ ID NOs: 14 to 16 disclosed in WO 2011 / 039510(A2) or selected from the group consisting of SEQ ID NOs: 17 to 19 in WO 2011 / 039510(A2).

[0058] In a further preferred embodiment, the anti-CD163 antibody or CD163-binding fragment thereof comprises a heavy chain variable (VV) domain comprising or consisting of the amino acid sequence of SEQ ID NO: 20 of WO 2011 / 039510(A2). H ) area.

[0059] Additionally or alternatively, in a preferred embodiment, the anti-CD163 antibody or CD163-binding fragment thereof comprises a light chain variable (VV) comprising or consisting of the amino acid sequence of SEQ ID NO: 21 of WO 2011 / 039510(A2). L ) area.

[0060] In a further preferred embodiment, the anti-CD163 antibody or CD163-binding fragment thereof comprises a heavy chain variable (VV) domain comprising or consisting of the amino acid sequence of SEQ ID NO: 22 of WO 2011 / 039510(A2). H ) area.

[0061] Additionally or alternatively, in a preferred embodiment, the anti-CD163 antibody or CD163-binding fragment thereof comprises a light chain variable (VV) domain comprising or consisting of the amino acid sequence of SEQ ID NO: 23 of WO 2011 / 039510(A2). L ) area.

[0062] In a further preferred embodiment, the anti-CD163 antibody or CD163-binding fragment thereof comprises a heavy chain variable (VV) domain comprising or consisting of the amino acid sequence of SEQ ID NO: 24 of WO 2011 / 039510(A2). H ) area.

[0063] Additionally or alternatively, in a preferred embodiment, the anti-CD163 antibody or CD163-binding fragment thereof comprises a light chain variable (VV) comprising or consisting of the amino acid sequence of SEQ ID NO: 25 of WO 2011 / 039510(A2). L ) area.

[0064] In the context of the present invention, the anti-CD163 antibody may be a mammalian antibody, such as a humanized or human antibody, a non-human primate antibody, an ovine antibody, a porcine antibody, a canine antibody or a rodent antibody. In embodiments, the anti-CD163 antibody may be monoclonal.

[0065] In a preferred embodiment, the anti-CD163 antibody is selected from IgG, IgA, IgD, IgE and IgM.

[0066] In a further preferred embodiment, the CD163 binding fragment is selected from a Fab, a Fab', a F(ab)2, an Fv, a single chain antibody, a nanobody and an antigen-binding domain.

[0067] The CD163 amino acid sequence is disclosed, for example, in WO 2011 / 039510(A2), which is incorporated herein by reference. In the context of the present invention, the anti-CD163 antibody or CD163-binding fragment thereof is preferably specific for human CD163, in particular for human CD163 having the amino acid sequence of any one of SEQ ID NOs: 28 to 31 of WO 2011 / 039510(A2).

[0068] In a further preferred embodiment, the anti-CD163 antibody or CD163-binding fragment thereof is an antibody that binds to an extracellular region of CD163 (e.g., amino acids 42 to 1050 of human CD163: UniProt Q86VB7, sequence version 2), preferably an SRCR domain of CD163, more preferably any one of SRCR domains 1 to 9 of CD163 (e.g., amino acids 51 to 152, 159 to 259, 266 to 366, 373 to 473, 478 to 578, 583 to 683, 719 to 819, 824 to 926 and 929 to 1029, respectively, of human CD163: UniProt Q86VB7, sequence version 2), or further any one of SRCR domains 1 to 3 of CD163 (e.g., amino acids 51 to 152, 159 to 259, 266 to 366, 373 to 473, 478 to 578, 583 to 683, 719 to 819, 824 to 926 and 929 to 1029, respectively, of human CD163: UniProt Q86VB7, sequence version 2). Q86VB7, amino acids 51 to 152, 159 to 259, 266 to 366, and 373 to 473 of sequence version 2, respectively), in particular specific for SRCR domain 1 of CD163 (in particular any one of the amino acid sequences of SEQ ID NOs: 1 to 8 of WO 2011 / 039510(A2), in particular SEQ ID NO: 1 of WO 2011 / 039510(A2).

[0069] In certain preferred examples, the anti-CD163 antibody or CD163-binding fragment thereof may compete with the (preferably human) hemoglobin / haptoglobin complex for binding to (preferably human) CD163 (eg, in an ELISA).

[0070] In another particularly preferred example, the anti-CD163 antibody or CD163-binding fragment thereof may compete for binding to human CD163 with any of the anti-human CD163 mAbs disclosed herein, in particular Mac2-48 or Mac2-158 disclosed in WO 2011 / 039510(A2).

[0071] In yet another particularly preferred example, the anti-CD163 antibody or CD163-binding fragment thereof may compete (e.g., in an ELISA) for binding to human CD163 with an antibody having a heavy chain variable (VH) region consisting of the amino acid sequence: DVQLQESGPGLVKPSQSLSLTCTVTGYSITSDYAWNWIRQFPGNKLEWMGYITYSGITNYNPSLKSQISITRDTSKNQFFLQLNSVTTEDTATYYCVSGTYYFDYWGQGTTLTVSS (SEQ ID NO: 1), and a light chain variable (VL) region consisting of the amino acid sequence: SVVMTQTPKSLLISIGDRVTITCKASQSVSSDVAWFQQKPGQSPKPLIYYASNRYTGVPDRFTGSGYGTDFTFTISSVQAEDLAVYFCGQDYTSPRTFGGGTKLEIKRA (SEQ ID NO: 2).

[0072] Details of competitive binding experiments are known to the person skilled in the art (eg based on ELISA) and are disclosed, for example, in WO 2011 / 039510(A2), which is incorporated herein by reference.

[0073] The epitopes of the antibodies E10B10 and Mac2-158 disclosed in WO 2011 / 039510 have been mapped (see the Examples section), and these epitopes are particularly suitable for binding of the anti-CD163 antibodies (or CD163-binding fragments thereof) of the compounds of the invention.

[0074] Thus, in a particularly preferred embodiment, the anti-CD163 antibody or CD163-binding fragment thereof is specific for a peptide consisting of 7 to 25, preferably 8 to 20, even more preferably 9 to 15, in particular 10 to 13 amino acids, said peptide comprising the amino acid sequence CSGRVEVKVQEEWGTVCNNGWSMEA (SEQ ID NO: 3) or a 7 to 24 amino acid fragment thereof. Preferably, this peptide comprises the amino acid sequence GRVEVKVQEEW (SEQ ID NO: 4), WGTVCNNGWS (SEQ ID NO: 5) or WGTVCNNGW (SEQ ID NO: 6). More preferably, said peptide comprises an amino acid sequence selected from EWGTVCNNGWSME (SEQ ID NO: 7), QEEWGTVCNNGWS (SEQ ID NO: 8), WGTVCNNGWSMEA (SEQ ID NO: 9), EEWGTVCNNGWSM (SEQ ID NO: 10), VQEEWGTVCNNGW (SEQ ID NO: 11), EWGTVCNNGW (SEQ ID NO: 12) and WGTVCNNGWS (SEQ ID NO: 5). Even more preferably, the peptide consists of an amino acid sequence selected from EWGTVCNNGWSME (SEQ ID NO: 7), QEEWGTVCNNGWS (SEQ ID NO: 8), WGTVCNNGWSMEA (SEQ ID NO: 9), EEWGTVCNNGWSM (SEQ ID NO: 10), VQEEWGTVCNNGW (SEQ ID NO: 11), EWGTVCNNGW (SEQ ID NO: 12) and WGTVCNNGWS (SEQ ID NO: 5), optionally having an N-terminal and / or C-terminal cysteine ​​residue.

[0075] Thus, in another preferred embodiment, the anti-CD163 antibody or CD163-binding fragment thereof is specific for a peptide consisting of 7 to 25, preferably 8 to 20, even more preferably 9 to 15, in particular 10 to 13 amino acids, said peptide comprising the amino acid sequence DHVSCRGNESALWDCKHDGWG (SEQ ID NO: 13) or a 7 to 20 amino acid fragment thereof. Preferably, this peptide comprises the amino acid sequence ESALW (SEQ ID NO: 14) or ALW. More preferably, said peptide comprises an amino acid sequence selected from ESALWDC (SEQ ID NO: 15), RGNESALWDC (SEQ ID NO: 16), SCRGNESALW (SEQ ID NO: 17), VSCRGNESALWDC (SEQ ID NO: 18), ALWDCKHDGW (SEQ ID NO: 19), DHVSCRGNESALW (SEQ ID NO: 20), CRGNESALWD (SEQ ID NO: 21), NESALWDCKHDGW (SEQ ID NO: 22) and ESALWDCKHDGWG (SEQ ID NO: 23). Even more preferably, the peptide consists of an amino acid sequence selected from ESALWDC (SEQ ID NO: 15), RGNESALWDC (SEQ ID NO: 16), SCRGNESALW (SEQ ID NO: 17), VSCRGNESALWDC (SEQ ID NO: 18), ALWDCKHDGW (SEQ ID NO: 19), DHVSCRGNESALW (SEQ ID NO: 20), CRGNESALWD (SEQ ID NO: 21), NESALWDCKHDGW (SEQ ID NO: 22) and ESALWDCKHDGWG (SEQ ID NO: 23), optionally having an N-terminal and / or C-terminal cysteine ​​residue.

[0076] Thus, in another particularly preferred embodiment, the anti-CD163 antibody or CD163-binding fragment thereof is specific for a peptide consisting of 7 to 25, preferably 8 to 20, even more preferably 9 to 15, in particular 10 to 13 amino acids, said peptide comprising the amino acid sequence SSLGGTDKELRLVDGENKCS (SEQ ID NO: 24) or a 7 to 19 amino acid fragment thereof. Preferably, this peptide comprises the amino acid sequence SSLGGTDKELR (SEQ ID NO: 25) or SSLGG (SEQ ID NO: 26). More preferably, said peptide comprises an amino acid sequence selected from SSLGGTDKELR (SEQ ID NO: 25), SSLGGTDKEL (SEQ ID NO: 27), SSLGGTDKE (SEQ ID NO: 28), SSLGGTDK (SEQ ID NO: 29), SSLGGTD (SEQ ID NO: 30), SSLGGT (SEQ ID NO: 31) and SSLGG (SEQ ID NO: 26). Even more preferably, the peptide consists of an amino acid sequence selected from SSLGGTDKELR (SEQ ID NO: 25), SSLGGTDKEL (SEQ ID NO: 27), SSLGGTDKE (SEQ ID NO: 28), SSLGGTDK (SEQ ID NO: 29), SSLGGTD (SEQ ID NO: 30), SSLGGT (SEQ ID NO: 31) and SSLGG (SEQ ID NO: 26), optionally having an N-terminal and / or C-terminal cysteine ​​residue.

[0077] The peptides (i.e., peptide n-mers) are preferably covalently attached (i.e., covalently bonded) to the biopolymer scaffold via (non-immunogenic) linkers known in the art, such as amine-sulfhydryl linkers, bifunctional NHS-PEG-maleimide linkers, or other linkers known in the art. Alternatively, the peptides (i.e., peptide n-mers) can be attached to the epitope carrier scaffold, for example, by formation of a disulfide bond (also referred to herein as a "linker") between the protein and the peptide, or by using unnatural amino acids for bio-orthogonal chemistry via non-covalent assembly techniques, spontaneous isopeptide bond formation, or genetic code expansion techniques (reviewed by Howarth et al. 2018 and Lim et al. 2016). Covalent or non-covalent bioconjugation reaction strategies suitable for the present invention are also discussed in Sunasee et al., 2014.

[0078] The compound of the present invention may contain at least two copies, preferably 3 to 40 copies, of one or several different peptides (which may exist as different forms of peptide n-mers as disclosed herein). The compound may contain one type of epitope peptide (in other words, an antibody-binding peptide or a paratope-binding peptide), but the diversity of epitope peptides bound to one biopolymer scaffold molecule may be, for example, a mixture of up to eight different epitope peptides.

[0079] Typically, the peptides present in the compounds of the invention bind specifically to the selected undesired antibodies, and their sequences are usually selected and optimized to provide specific binding to ensure selectivity of depletion of the undesired antibodies from the blood. For this purpose, the peptide sequence of the peptide typically corresponds to the entire epitope sequence or a portion of the epitope of the undesired antibody. The peptides used in the present invention may be further optimized by exchanging one, two or up to four amino acid sites, for example to allow for adjusting the binding affinity to the undesired antibody that needs to be depleted. Such single or multiple amino acid substitution strategies known in the art, which can provide "mimotopes" with increased binding affinity, have been previously developed using phage display strategies or peptide microarrays. In other words, the peptides used in the present invention do not need to be completely identical to the natural epitope sequence of the undesired antibody.

[0080] Typically, the peptides used in the compounds of the invention (e.g., peptides P, P a , or P b) consists of one or more of the 20 amino acids commonly present in mammalian proteins. Furthermore, the repertoire of amino acids used in the peptides may be extended to post-translationally modified amino acids, such as by post-translational modifications, such as those affecting the antigenicity of the protein, in particular by oxidative post-translational modifications (see, for example, Ryan 2014) or modifications to the peptide backbone (see, for example, Muller 2018), or even to unnatural amino acids (see, for example, Meister et al. 2018). These modifications may also be used in the peptides, such as to match the binding interactions and specificity between the peptide and the variable regions of undesired antibodies. In particular, epitopes (and thus also peptides used in the compounds of the invention) may contain citrulline, for example in autoimmune diseases. Furthermore, modifications introduced into the peptide sequence may reduce the tendency to bind to HLA molecules, improve stability and physicochemical characteristics, or increase affinity for the undesired antibodies.

[0081] In many cases, the unwanted antibodies to be depleted are oligo- or polyclonal (e.g. autoantibodies, ADA or alloantibodies are typically poly- or oligoclonal), meaning that the unwanted (polyclonal) antibodies cover a larger epitopic region of the target molecule. To accommodate this situation, the compounds of the invention may contain a mixture of two or several epitope peptides (in other words antibody-binding peptides or paratope-binding peptides), thereby allowing adaptation to the polyclonal or oligoclonal nature of the unwanted antibodies.

[0082] Such polyepitopic compounds of the invention can effectively deplete undesired antibodies and are often more effective than monoepitopic compounds when the epitopes of the undesired antibodies are spread over a larger amino acid sequence.

[0083] Advantageously, the peptides used in the inventive compounds are designed to be specifically recognized by the variable regions of the unwanted antibodies to be depleted. The sequences of the peptides 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 unwanted antibodies.

[0084] The present invention is suitable for (temporarily) depleting antibodies against all oncolytic viruses, such as those discussed in Zeng et al. 2021. Thus, the oncolytic virus can be selected from, for example, any of those discussed in Zeng et al., 2021.

[0085] Wild-type AAVs are typically non-pathogenic and can only replicate in the presence of a helper virus. One major advantage of this class of viral vectors is that they maintain long-term, persistent gene expression in host cells, making them ideal for oncolytic gene delivery. A large number of natural subtypes have been isolated that display in vivo and in vitro serological differences and unique tropisms. AAV vectors are well suited to target different cell types. Importantly, AAV vectors do not typically integrate into the genome of the host cell (Colella et al., 2017).

[0086] AAVs have been extensively studied for oncolytic approaches. For example, Feiner et al., 2020, discloses tumor targeting by presenting EGFR-binding peptides in the AAV capsid. Kuklik et al., 2021, relates to the development of a bispecific antibody-based platform for retargeting capsid-modified AAV vectors. Table I in Lundstrom, 2018, contains preclinical examples of antitumor therapy using oncolytic AAVs, among other oncolytic viruses.

[0087] To date, many different serotypes and variants have been well studied, including AAV2, AAV5, or AAV8. Li (Li et al., 2020) provides an extensive overview on AAV vectors. New concepts of improving gene expression, tissue specificity, and genome stability in combination with capsid engineering can be found in Domenger (Domenger et al., 2019).

[0088] Much effort has been expended on engineering modified AAV capsid variants to alter their biological properties, including tropism and safety. However, susceptibility to antibody neutralization by preexisting antibodies in patients remains a major challenge, see, e.g., Costa Verdera et al., 2020.

[0089] Kruzik et al., 2019 investigated the prevalence of neutralizing antibodies against various AAV serotypes in different patient cohorts. For example, neutralizing antibodies against AAV2 were found to be most prevalent at levels up to 74% of the population. Antibodies against AAV8, for example, were found to be up to 63%. Natural antibodies against AAV5 (up to 59%) and AAV1 (27%) were less common. Interestingly, most populations tested showed antibodies against more than one serotype. A review was published by Ronzitti et al., 2020.

[0090] Tseng et al., 2014, reviewed the epitopes of anti-AAV antibodies found in human sera and monoclonal antibodies. The interactions of existing or induced anti-AAV antibodies with viral capsid proteins have been primarily investigated by mutational analysis, peptide insertion or peptide scanning, and several approaches have been attempted to develop AAV variants that modify tropism and evade humoral immune responses. These strategies include directed evolution, structure-based approaches, engineering chimeric AAV vectors (e.g., Bennett et al., 2020) or displaying peptides on the surface of AAV vectors (Borner et al., 2020). Other proposed strategies to circumvent the adverse effects of neutralizing antibodies include modifying the route of administration (Mimuro et al., 2013), discovering new serotypes and variants (Salganik et al., 2015), reducing immunogenicity through PEGylation or polymeric techniques (Balakrishnan et al., 2019) or using internal (Mingozzi et al., 2013) or external (Bertin et al., 2020) capsid decoys. Immunogenic mechanisms and their clinical impact have been extensively reviewed by Monahan et al., 2021.

[0091] US Patent Publication No. 2013 / 0259885(A1) relates to immunomodulation using peptides containing epitopes recognized by CD4+ natural killer T cells. This is taught to be suitable for increasing the efficacy of gene therapy. WO 2005 / 023848(A2) discloses administering peptides to patients to increase the efficacy of adenoviral vectors.

[0092] WO 2019 / 018439(A1) relates to removing AAV neutralizing antibodies from a subject by apheresis prior to administering recombinant AAV containing a heterologous polynucleotide to the subject. Bertin et al., 2020 discloses a similar apheresis approach. Further along a similar line, WO 00 / 20041(A2) relates to a method of increasing the efficacy of a therapeutic viral agent by extracorporeal removal of anti-AdV antibodies using affinity columns based on AdV subunits (i.e., selective apheresis).

[0093] Neutralizing antibodies are not only problematic for AAV-based vectors. To date, adenovirus (AdV) serotype 5 (Ad5) has been tested in over 400 clinical trials as the prototype adenovirus vector. Gendicine, an approved oncolytic virus-based product, is also based on Ad5 (Zhang et al., 2018). Notably, up to 80% of the population carries neutralizing antibodies against Ad5 that negatively impact efficacy.

[0094] Neutralizing antibodies and epitopes against all types of AdV and other viral vectors for therapy have been previously described, for example, in Tian et al., 2018; Wang et al., 2019; Fausther-Bovendo et al., 2014; and Mok et al., 2020. For AAV vectors, much effort has been spent on circumventing pre-existing anti-vector immunity by engineering and fine mapping of epitopes of adenoviral vectors (Roberts et al., 2006).

[0095] In a preferred embodiment, the oncolytic virus is an AdV or AAV vector, preferably one that is specific for a human host.

[0096] In another preferred embodiment, the oncolytic virus is a measles virus, herpes simplex virus (HSV), a poxvirus such as vaccinia virus, a reovirus, a Newcastle disease virus (NVD), a rhabdovirus, a coxsackievirus, a lentivirus, an alphavirus such as Semliki Forest virus, a vesicular stomatitis virus (VSS), a myxoma virus (MYXV), a mengovirus, a bovine viral diarrhea virus (BVDV), a chimeric oncolytic virus, a parvovirus, a picornavirus or a flavivirus, preferably specific for a human host.

[0097] In another preferred embodiment, the sequence fragment as used herein is a sequence fragment of an AdV protein (preferably a capsid protein sequence, a nucleocapsid protein sequence, a structural protein sequence, a viral envelope-associated protein sequence or a receptor-associated protein sequence, a tegument protein sequence, a viral enzyme sequence, a nuclear matrix protein sequence, a DNA- or RNA-binding protein sequence, a viral packaging protein sequence or a viral polymerase sequence, more preferably a capsid protein sequence, a nucleocapsid protein sequence, a structural protein sequence, a viral envelope-associated protein sequence or a receptor-associated protein sequence, or a tegument protein sequence, in particular a capsid protein sequence), or an AAV capsid protein (preferably a capsid protein sequence, a nucleocapsid protein sequence, a structural protein sequence, a viral envelope-associated protein sequence or a receptor-associated protein sequence, or a tegument protein sequence, in particular a capsid protein sequence). and / or a viral protein sequence, a structural protein sequence, a viral envelope associated protein sequence or a receptor binding protein sequence, a tegument protein sequence, a viral enzyme sequence, a nuclear matrix protein sequence, a DNA- or RNA-binding protein sequence, a viral packaging protein sequence or a viral polymerase sequence, more preferably a capsid protein sequence, a nucleocapsid protein sequence, a structural protein sequence, a viral envelope associated protein sequence or a receptor binding protein sequence, or a tegument protein sequence, in particular a capsid protein sequence) (see also the Examples), particularly in which the AAV is one of AAV-8, AAV-9, AAV-6, AAV-2, and AAV-5, or in the following viral proteins identified by UniProt accession numbers: A9RAI0, B5SUY7, O41855, O56137, O56139, P03135, P04133, P04882, P08362, P10269, P12538, P69353, Q5Y9B2, Q5Y9B4, Q65311, Q6JC40, Q6VGT5, Q8JQF8, Q8JQG0, Q98654, Q9WBP8, Q9YIJ1, or the capsid protein sequence of the AdV hexon protein sequence, the AdV fiber protein sequence, the AdV penton protein sequence, the AdV IIIa protein sequence, the AdV VI protein sequence, the AdV VIII protein sequence, or the AdV IX protein sequence, or any one of the capsid protein sequences identified in Figures 4 and 5, or any one of the capsid protein sequences listed in Cearley et al., 2008, or any one of the capsid protein sequences listed in the UniProt P03525, P03526, P03527, P03528, P03529, P0CK31, P11078, P11079, P12418, P12419, P15024, P21270, A1Z0P5, O09800, P031 70, P04288, P04289, P04291, P04486, P06477, P06484, P06487, P06491, P08314, P08392, P08543, P10185, P10190, P10191, P Any one of 10192, P10193, P10200, P10202, P10204, P10205, P10210, P10216, P10218, P10219, P10220, P10225, P10227, P10228, P10229, P10231, P10234, P32888, P68333, P08362, P35971, Q89933, P35974, P35976, P69358, P12576, Q9EMA9 and P03522, Preferably, the epitope or epitope portion (eg, at least 6, particularly at least 7, even more preferably at least 8 amino acids) of

[0098] Particularly suitable epitopes for depleting neutralizing antibodies (against AAV and AdV) have been found in epitope screens and human serum screens (see also the Examples). Thus, in a preferred embodiment, a sequence fragment as used herein comprises a sequence of at least 4 or at least 5, or at least 6, preferably at least 7, more preferably at least 8, even more preferably at least 9, even more preferably at least 10 consecutive amino acids selected from the following: Group of AdV sequences ETGPPTVPFLTPPF (SEQ ID NO: 32), HDSKLSIATQGPL (SEQ ID NO: 33), LNLRLGQGPLFINSAHNLDINY (SEQ ID NO: 34), VDPMDEPTLLYVLFEVFDVV (SEQ ID NO: 35), MKRARPSEDTFNPVYPYD (SEQ ID NO: 36), ISGTVQSAHLIIRFD (SEQ ID NO: 37), LGQGPLFINSAHNLDINYNKGLYLF (SEQ ID NO: 38), SYPFDAQNQLNLRLGQGPLFIN (SEQ ID NO: 39), GDTTPSAYSMSFSWDWSGHNYIN (SEQ ID NO: 40), VLLNNSFLDPEYWNFRN (SEQ ID NO: 41), HNYINEIFATSSYTFSYIA (SEQ ID NO: 42), DEAATALEINLEEEDDDNEDEVDEQAEQQKTH (SEQ ID NO: 43), INLEEDDDNEDEVDEQAEQ (SEQ ID NO: 44), DNEDEVDEQAEQQKTHVF (SEQ ID NO: 45), EWDEAATALEINLEE (SEQ ID NO: 46), PKVVLYSEDVDIETPDTHISYMP (SEQ ID NO: 47), YIPESYKDRMYSFFRNF (SEQ ID NO: 48), DSIGDRTRYFSMW (SEQ ID NO: 49), SYKDRMYSFFRNF (SEQ ID NO: 50), and FLVQMLANYNIGYQGFY (SEQ ID NO: 51), or AAV sequence group: WQNRDVYLQGPIWAKIP (SEQ ID NO: 52), DNTYFGYSTPWGYFDFNRFHC (SEQ ID NO: 53), MANQAKNWLPGPCY (SEQ ID NO: 54), LPYVLGSAHQGCLPPFP (SEQ ID NO: 55), NGSQAVGRSSFYCLEYF (SEQ ID NO: 56), PLIDQYLYYL (SEQ ID NO: 57), EERFFPSNGILIF (SEQ ID NO: 58), ADGVGSSSGNWHC (SEQ ID NO: 59), SEQ ID NOs: 383 to 1891 (see Table 1), preferably Group III in Table 1, more preferably Group II in Table 1, particularly preferably Group I in Table 1; SEQ ID NOs: 1892 to 2063 (see Table 2), preferably Group I in Table 2; A sequence of Group II or Group III of Table 3 (see in particular SEQ ID NOs: 2064 to 2103), more preferably a sequence of Group I of Table 3, The group of sequences in Table 4, in particular the group of sequences identified in SEQ ID NOs: 2104 to 2190, or Group of sequences in Table 5.

[0099] In another preferred embodiment, P a and / or P bOr, P is each independently selected from GPPTVPFLTP (SEQ ID NO: 60), ETGPPTVPFLTPP (SEQ ID NO: 61), TGPPTVPFLT (SEQ ID NO: 62), PTVPFLTPPF (SEQ ID NO: 63), HDSKLSIATQGPL (SEQ ID NO: 64), SIATQGP (SEQ ID NO: 65), NLRLGQGPLF (SEQ ID NO: 66), QGPLFINSAH (SEQ ID NO: 67), PLFINSAHNLD (SEQ ID NO: 68), LGQGPLF (SEQ ID NO: 69), LNLRLGQGPL (SEQ ID NO: 70), GQGPLFI (SEQ ID NO: 71), NLRLGQGPL FINS (SEQ ID NO: 72), LFINSAHNLDINY (SEQ ID NO: 73), FINSAHNLDI (SEQ ID NO: 74), LRLGQGPLFI (SEQ ID NO: 75), GPLFINSAHN (SEQ ID NO: 76), DEPTLLYVLFEVF (SEQ ID NO: 77), TLLYVLFEVF (SEQ ID NO: 78), DEPTLLYVLF (SEQ ID NO: 79), TLLYVLFEVFDVV (SEQ ID NO: 80), TLLYVLF (SEQ ID NO: 81), MDEPTLLYVLFEV (SEQ ID NO: 82), EPTLLYVLFE (SEQ ID NO: 83), DPMDEPTLLYVLF (SEQ ID NO: 84), 84), LLYVLFEVFD (SEQ ID NO: 85), YVLFEVFDVV (SEQ ID NO: 86), PTLLYVLFEV (SEQ ID NO: 87), PTLLYVLFEVFDV (SEQ ID NO: 88), LYVLFEVFDV (SEQ ID NO: 89), EPTLLYVLFEVFD (SEQ ID NO: 90), LYVLFEV (SEQ ID NO: 91), PMDEPTLLYVLFE (SEQ ID NO: 92), LLYVLFE (SEQ ID NO: 93), VDPMDEPTLLYVL (SEQ ID NO: 94), YVLFEVF (SEQ ID NO: 95), PTLLYVL (SEQ ID NO: 96), MKRARPSEDTF (SEQ ID NO: 97), 7), KRARPSEDTF (SEQ ID NO: 98), MKRARPSEDT (SEQ ID NO: 99), MKRARPSEDTFN (SEQ ID NO: 100), ARPSEDTFNP (SEQ ID NO: 101), RARPSEDTFN (SEQ ID NO: 102), RPSEDTF (SEQ ID NO: 103), MKRARPSEDTFNP (SEQ ID NO: 104), RARPSEDTFNPVY (SEQ ID NO: 105), ARPSEDT (SEQ ID NO: 106), EDTFNPVYPY (SEQ ID NO: 107), RPSEDTFNPVYPY (SEQ ID NO: 108), KRARPSEDTFNPV (SEQ ID NO: 109),DTFNPVY (SEQ ID NO: 110), RPSEDTFNPV (SEQ ID NO: 111), PSEDTFNPVY (SEQ ID NO: 112), DTFNPVYPYD (SEQ ID NO: 113), VQSAHLIIRF (SEQ ID NO: 114), AHLIIRF (SEQ ID NO: 115), SGTVQSAHLIIRF (SEQ ID NO: 116), TVQSAHLIIR (SEQ ID NO: 117), HLIIRFD (SEQ ID NO: 118), SAHLIIR (SEQ ID NO: 119), QSAHLIIRFD (SEQ ID NO: 120), ISGTVQSAHLIIR (SEQ ID NO: 121), GTVQSAHLII (SEQ ID NO: 122), GTVQSAHLIIRFD (SEQ ID NO: 123), QSAHLII (SEQ ID NO: 124), HNLDINY (SEQ ID NO: 125), LFINSAHNLDINY (SEQ ID NO: 126), NLDINYNKGLYLF (SEQ ID NO: 127), FVSPNG (SEQ ID NO: 128), NYINEIF (SEQ ID NO: 129), NKGLYLF (SEQ ID NO: 130), INYNKGLYLF (SEQ ID NO: 131), NSAHNLDINY (SEQ ID NO: 132), WDWSGHNYINEIF (SEQ ID NO: 133), SGHNYINEIF (SEQ ID NO: 134), LGTGLSF (SEQ ID NO: 135), Column number 135), PFLTPPF (SEQ ID NO: 136), LGQGPLF (SEQ ID NO: 137), NLRLGQGPLF (SEQ ID NO: 138), NQLNLRLGQGPLF (SEQ ID NO: 139), GQGPLFI (SEQ ID NO: 140), QLNLRLGQGPLFI (SEQ ID NO: 141), SYPFDAQNQLNLR (SEQ ID NO: 142), YPFDAQNQLNLRL (SEQ ID NO: 143), LRLGQGPLFI (SEQ ID NO: 144), NQLNLRL (SEQ ID NO: 145), FDAQNQLNLR (SEQ ID NO: 146), QNQLNLR (SEQ ID NO: 147), QGPL FIN (SEQ ID NO: 148), PFDAQNQLNLRLG (SEQ ID NO: 149), DAQNQLNLRL (SEQ ID NO: 150), RLGQGPLFIN (SEQ ID NO: 151), QLNLRLG (SEQ ID NO: 152), FDAQNQLNLRLGQ (SEQ ID NO: 153), LNLRLGQGPLFIN (SEQ ID NO: 154), AQNQLNLRLG (SEQ ID NO: 155), AQNQLNL (SEQ ID NO: 156), LNLRLGQ (SEQ ID NO: 157), SYPFDAQNQL (SEQ ID NO: 158), PFDAQNQLNL (SEQ ID NO: 159), YSMSFSW (SEQ ID NO: 160),TPSAYSMSFSWDW (SEQ ID NO: 161), MSFSWDW (SEQ ID NO: 162), PSAYSMSFSW (SEQ ID NO: 163), DTTPSAYSMSFSW (SEQ ID NO: 164), TTPSAYSMSF (SEQ ID NO: 165), YSMSFSWDWS (SEQ ID NO: 166), TGDTTPSAYSMSF (SEQ ID NO: 167), FSWDWSGHNY (SEQ ID NO: 168), SFSWDWS (SEQ ID NO: 169), SAYSMSF (SEQ ID NO: 170), SFSWDWSGHN (SEQ ID NO: 171), SAYSMSFSWD (SEQ ID NO: 172), SMSFSWD (SEQ ID NO: 173), SWDWSGHNYI (SEQ ID NO: 174), AYSMSFS (SEQ ID NO: 175), SMSFSWDWSGHNY (SEQ ID NO: 176), FSWDWSG (SEQ ID NO: 177), SWDWSGH (SEQ ID NO: 178), FLDPEYWNFR (SEQ ID NO: 179), SFLDPEYWNF (SEQ ID NO: 180), PEYWNFR (SEQ ID NO: 181), LNNSFLDPEYWNF (SEQ ID NO: 182), NNSFLDPEYWNFR (SEQ ID NO: 183), FLDPEYW (SEQ ID NO: 184), DPEYWNF (SEQ ID NO: 185), NNSFLDP EYW (SEQ ID NO: 186), VLLNNSFLDPEYW (SEQ ID NO: 187), EYWNFRN (SEQ ID NO: 188), LNNSFLDPEY (SEQ ID NO: 189), LDPEYWNFRN (SEQ ID NO: 190), LNNSFLD (SEQ ID NO: 191), NSFLDPEYWN (SEQ ID NO: 192), SSYTFSY (SEQ ID NO: 193), FATSSYTFSY (SEQ ID NO: 194), YINEIFATSSYTF (SEQ ID NO: 195), SYTFSYI (SEQ ID NO: 196), ATSSYTF (SEQ ID NO: 197), EIFATSSYTF (SEQ ID NO: 198), NEIF ATSSYTFSY (SEQ ID NO: 199), ATSSYTFSYI (SEQ ID NO: 200), HNYINEIFATSSY (SEQ ID NO: 201), IFATSSY (SEQ ID NO: 202), INEIFATSSY (SEQ ID NO: 203), NYINEIFATSSYT (SEQ ID NO: 204), YINEIFA (SEQ ID NO: 205), YTFSYIA (SEQ ID NO: 206), EIFATSSYTFSYI (SEQ ID NO: 207), ALEINLEEEDDDN (SEQ ID NO: 208), ATALEINLEEEDD (SEQ ID NO: 209), EAATALEINLEEE (SEQ ID NO: 210),LEINLEE (SEQ ID NO:211), TALEINLEEEDDD (SEQ ID NO:212), EINLEEE (SEQ ID NO:213), ALEINLEEED (SEQ ID NO:214), LEINLEEEDD (SEQ ID NO:215), TALEINLEEE (SEQ ID NO:216), DEAATALEINLEE (SEQ ID NO:217), LEINLEEEDDDNE (SEQ ID NO:218), AATALEINLEEED (SEQ ID NO:219), EINLEEEDDD (SEQ ID NO:220), ATALEINLEE (SEQ ID NO:221), INLEEEDDDN (SEQ ID NO:222), NLEE EDDDNE (SEQ ID NO: 223), DEVDEQA (SEQ ID NO: 224), EDDDNEDEVDEQA (SEQ ID NO: 225), DDNEDEVDEQAEQ (SEQ ID NO: 226), EVDEQAE (SEQ ID NO: 227), DNEDEVDEQA (SEQ ID NO: 228), VDEQAEQ (SEQ ID NO: 229), EDEVDEQAEQQKT (SEQ ID NO: 230), EDEVDEQAEQ (SEQ ID NO: 231), DEVDEQAEQQKTH (SEQ ID NO: 232), NEDEVDEQAEQQK (SEQ ID NO: 233), DEVDEQAEQQ (SEQ ID NO: 234), EINLEEED DDNED (SEQ ID NO: 235), NLEEEDDDNEDEV (SEQ ID NO: 236), INLEEED (SEQ ID NO: 237), LEEEDDDNED (SEQ ID NO: 238), INLEEEDDDNEDE (SEQ ID NO: 239), DDDNEDEVDEQAE (SEQ ID NO: 240), LEEEDDDNEDEVD (SEQ ID NO: 241), DDNEDEVDEQ (SEQ ID NO: 242), EDDDNED (SEQ ID NO: 243), NLEEEDD (SEQ ID NO: 244), DDNEDEV (SEQ ID NO: 245), DDDNEDEVDE (SEQ ID NO: 246), DDDNEDE (SEQ ID NO: 247) ), EEEDDDNEDE (SEQ ID NO: 248), EEDDDNE (SEQ ID NO: 249), EDDDNEDEVD (SEQ ID NO: 250), EDEVDEQ (SEQ ID NO: 251), EEDDDNEDEVDEQ (SEQ ID NO: 252), EEDDDNEDEV (SEQ ID NO: 253), EEEDDDNEDEVDE (SEQ ID NO: 254), EVDEQAEQQK (SEQ ID NO: 255), DNEDEVDEQAEQQ (SEQ ID NO: 256), VDEQAEQQKT (SEQ ID NO: 257), EVDEQAEQQKTHV (SEQ ID NO: 258), VDEQAEQQKTHVF (SEQ ID NO: 259),ALEINLE (SEQ ID NO: 260), WDEATALEINLE (SEQ ID NO: 261), AATALEINLE (SEQ ID NO: 262), EWDEAATALEINL (SEQ ID NO: 263), EAATALEINL (SEQ ID NO: 264), LYSEDVDIET (SEQ ID NO: 265), LYSEDVDIETPDT (SEQ ID NO: 266), KVVLYSEDVDIET (SEQ ID NO: 267), IETPDTH (SEQ ID NO: 268), VDIETPDTHI (SEQ ID NO: 269), VLYSEDVDIE (SEQ ID NO: 270), DVDIETPDTHISY (SEQ ID NO: 271) , VVLYSEDVDIETP (SEQ ID NO: 272), SEDVDIETPDTHI (SEQ ID NO: 273), ETPDTHI (SEQ ID NO: 274), VLYSEDVDIETPD (SEQ ID NO: 275), DVDIETPDTH (SEQ ID NO: 276), DIETPDTHIS (SEQ ID NO: 277), EDVDIETPDTHIS (SEQ ID NO: 278), IETPDTHIS (SEQ ID NO: 279), YSEDVDIETPDTH (SEQ ID NO: 280), VDIETPDTHISYM (SEQ ID NO: 281), PKVVLYSEDVDIE (SEQ ID NO: 282), DIETPDT (SEQ ID NO: 283), Column number 283), DIETPDTHISYMP (SEQ ID NO: 284), EDVDIETPDT (SEQ ID NO: 285), ETPDTHISYM (SEQ ID NO: 286), IETPDTHISYMP (SEQ ID NO: 287), DRMYSFFRNF (SEQ ID NO: 288), DRMYSFF (SEQ ID NO: 289), YSFFRNF (SEQ ID NO: 290), IPESYKDRMYSFF (SEQ ID NO: 291), SYKDRMYSFF (SEQ ID NO: 292), ESYKDRMYSF (SEQ ID NO: 293), KDRMYSF (SEQ ID NO: 294), YIPESYKDRMYSF (SEQ ID NO: 295) ), PESYKDRMYSFFR (SEQ ID NO: 296), YKDRMYSFFR (SEQ ID NO: 297), TRYFSMW (SEQ ID NO: 298), GDRTRYF (SEQ ID NO: 299), DSIGDRTRYF (SEQ ID NO: 300), DSIGDRTRYFSMW (SEQ ID NO: 301), GDRTRYFSMW (SEQ ID NO: 302), DRMYSFFRNF (SEQ ID NO: 303), SYKDRMYSFFRNF (SEQ ID NO: 304), NYNIGYQGFY (SEQ ID NO: 305), ANYNIGYQGF (SEQ ID NO: 306), MLANYNIGYQGFY (SEQ ID NO: 307),a 6 amino acid fragment, preferably 7 amino acids, selected from the group consisting of IGYQGFY (SEQ ID NO: 308), FLVQMLANYNIGY (SEQ ID NO: 309), NIGYQGF (SEQ ID NO: 310) and QMLANYNIGYQGF (SEQ ID NO: 311); Fragments, more preferably an 8 amino acid fragment, even more preferably a 9 amino acid fragment, even more preferably a 10 amino acid fragment, and especially the entire sequence, wherein no more than 3, preferably no more than 2, and most preferably one or more amino acids may be independently replaced by any other amino acid.

[0100] In another preferred embodiment, P a and / or P b Alternatively, each P independently comprises a 6 amino acid fragment, preferably a 7 amino acid fragment, more preferably an 8 amino acid fragment, even more preferably a 9 amino acid fragment, even more preferably a 10 amino acid fragment, or an 11 amino acid fragment, or even alternatively a 12 amino acid fragment, and particularly a 13 amino acid fragment selected from the sequences of SEQ ID NOs: 383 to 1891 (see Table 1) - preferably Group III of Table 1, more preferably Group II of Table 1, and particularly Group I of Table 1 - and SEQ ID NOs: 1892 to 2063 (see Table 2) - preferably Group I of Table 2, and the sequences of Group II or III of Table 3 (particularly SEQ ID NOs: 2064 to 2103), more preferably Group I of Table 3, wherein 3 or less, preferably 2 or less, and most preferably 1 or more amino acids may be independently replaced by any other amino acid.

[0101] In another preferred embodiment, P a and / or P bAlternatively, each P independently comprises a 6 amino acid fragment selected from the group of sequences in Table 4, in particular the group of sequences identified by SEQ ID NOs: 2104 to 2190, preferably a 7 amino acid fragment, more preferably an 8 amino acid fragment, even more preferably a 9 amino acid fragment, even more preferably a 10 amino acid fragment, or alternatively an 11 amino acid fragment, or even alternatively a 12 amino acid fragment, in particular a 13 amino acid fragment, wherein up to 3 amino acids, preferably up to 2 amino acid fragment, and most preferably one or more amino acids may be independently replaced by any other amino acid.

[0102] In another preferred embodiment, P a and / or P b Alternatively, each P independently comprises a 6 amino acid fragment selected from the group consisting of the sequences of Table 5, preferably a 7 amino acid fragment, more preferably an 8 amino acid fragment, even more preferably a 9 amino acid fragment, even more preferably a 10 amino acid fragment, or even more preferably an 11 amino acid fragment, or even more preferably a 12 amino acid fragment, and particularly preferably a 13 amino acid fragment, wherein no more than 3, preferably no more than 2, and most preferably one or more amino acids may be independently replaced by any other amino acid.

[0103] In another preferred embodiment, P a and / or P bor P is each independently selected from the group consisting of YLQGPIW (SEQ ID NO: 312), VYLQGPI (SEQ ID NO: 313), WQNRDVY (SEQ ID NO: 314), DVYLQGP (SEQ ID NO: 315), QNRDVYL (SEQ ID NO: 316), LQGPIWA (SEQ ID NO: 317), RDVYLQG (SEQ ID NO: 318), NRDVYLQ (SEQ ID NO: 319), YFGYSTPWGYFDF (SEQ ID NO: 320), FGYSTPWGYF (SEQ ID NO: 321), GYSTPWGYFD (SEQ ID NO: 322), YSTPWGYFDF (SEQ ID NO: 323), NTYFGYSTPWGYF (SEQ ID NO: 324), No. 324), TPWGYFDFNRFHC (SEQ ID NO: 325), TYFGYSTPWGYFD (SEQ ID NO: 326), DNTYFGYSTPWGY (SEQ ID NO: 327), YFGYSTPWGY (SEQ ID NO: 328), FGYSTPWGYFDFN (SEQ ID NO: 329), NWLPGPC (SEQ ID NO: 330), WLPGPCY (SEQ ID NO: 331), QAKNWLPGPC (SEQ ID NO: 332), AKNWLPGPCY (SEQ ID NO: 333), MANQAKNWLPGPC (SEQ ID NO: 334), QGCLPPF (SEQ ID NO: 335), GCLPPFP (SEQ ID NO: 336) , VLGSAHQGCLPPF (SEQ ID NO: 337), LPYVLGSAHQGCL (SEQ ID NO: 338), YVLGSAHQGC (SEQ ID NO: 339), CLPPFPA (SEQ ID NO: 340), SAHQGCLPPF (SEQ ID NO: 341), VLGSAHQGCL (SEQ ID NO: 342), PYVLGSAHQGCLP (SEQ ID NO: 343), GRSSFYC (SEQ ID NO: 344), AVGRSSFYCLEYF (SEQ ID NO: 345), AVGRSSFYCL (SEQ ID NO: 346), QAVGRSSFYCLEY (SEQ ID NO: 347), NGSQAVGRSSFYC (SEQ ID NO: FFPSNGILIF (SEQ ID NO: 352), EERFFPSNGILIF (SEQ ID NO: 353), VGSSSGNWHC (SEQ ID NO: 354), and ADGVGSSSGNWHC (SEQ ID NO: 355), and particularly a 6 amino acid fragment, preferably a 7 amino acid fragment, more preferably an 8 amino acid fragment, even more preferably a 9 amino acid fragment, even more preferably a 10 amino acid fragment, particularly an entire sequence, selected from the group consisting of:Preferably, no more than two, and most preferably one or more, amino acids may be independently replaced by any other amino acid.

[0104] In a further preferred embodiment, P a and / or P b or each P independently consists of a 6 amino acid fragment, preferably a 7 amino acid fragment, more preferably an 8 amino acid fragment, even more preferably a 9 amino acid fragment, even more preferably a 10 amino acid fragment, in particular the entire sequence selected from the group consisting of any of the sequences set out in the four paragraphs above right, wherein no more than 3, preferably no more than 2, most preferably one or more amino acids are independently replaced by any other amino acid, optionally with an N-terminal and / or C-terminal cysteine ​​residue.

[0105] In the context of the present invention, peptides, e.g. a and / or P b or P (each independently) comprises a fragment of at least 4 consecutive amino acids selected from the sequences listed in any one of the rows of Tables 1-5 (see Examples section below), which fragment is preferably extended (N-terminally or C-terminally) such that the peptide comprises a longer fragment (e.g., at least 6, or at least 7, or at least 8, or at least 9, or at least 10, or at least 11, or at least 12, or 13 amino acids in length) of the source protein shown in the same row of the table. In other words, the peptide preferably comprises a portion of at least 5, or at least 6, or at least 7, or at least 8, or at least 9, or at least 10, or at least 11, or at least 12, or 13 consecutive amino acids of the viral source protein of the fragment sequence (shown in Tables 1-5).

[0106] Further suitable oncolytic viruses (i.e., viruses from which the peptide sequences of the present invention may be derived) are disclosed, for example, by Rahman & McFadden 2021, Hromic-Jahjefendic & Lundstrom 2020, and Lawler et al. 2017. There is provided a list of oncolytic viruses suitable for the present invention, e.g. DNA viruses such as AdV, herpesviruses (HSV-1, HSV-2), parvoviruses (B19PV, H1PV), poxviruses (VACV, MYXV), vaccinia virus (VACV), as well as RNA viruses such as alphaviruses (Semliki Forest virus (SFV), Sindbis virus (SINV), M1), flaviviruses (Zika virus), paramyxoviruses (measles virus, Newcastle disease virus (NDV)), picornaviruses (Coxsackievirus A21, poliovirus, Seneca Valley virus (SVV), reovirus, ECHO-7), rhabdoviruses (VSV, Maraba virus MG1). Other suitable oncolytic viruses or VLPs are disclosed, for example, in Gao et al., 2021, Jin et al., 2021, Romanenko et al., 2021, Thuenemann et al., 2021, and Kuklik et al., 2021.

[0107] Examples of suitable reovirus sequences include UniProt P03525, P03526, P03527, P03528, P03529, P0CK31, P11078, P11079, P12418, P12419, P15024, and P21270 (reviewed by Muller et al. 2020). In other words, a sequence fragment as used herein may comprise an epitope or epitope portion (e.g., at least 6, particularly at least 7 or even at least 8 amino acids) of said sequence.

[0108] Examples of suitable HSV-1 sequences include the UniProt sequences A1Z0P5, O09800, P03170, P04288, P04289, P04291, P04486, P06477, P06484, P06487, P06491, P08314, P08392, P08392, P08543, P10185, P10190, P 10191, P10192, P10193, P10200, P10202, P10204, P10205, P10210, P10216, P10218, P10219, P10220, P10225, P10227, P10228, P10229, P10231, P10234, P32888, and P68333. In other words, a sequence fragment as used herein may comprise an epitope or epitope portion (e.g., at least 6, particularly at least 7 or even at least 8 amino acids) of said sequence.

[0109] Further examples of suitable measles virus sequences include hemagglutinin H (P08362, P35971), nucleoprotein N (Q89933), phosphoprotein P (P35974), matrix protein M (P35976), fusion protein F (P69358), large protein L (P12576), or nonstructural protein V (Q9EMA9). In other words, a sequence fragment as used herein may comprise an epitope or epitope portion (e.g., at least 6, particularly at least 7 or even at least 8 amino acids) of said sequence.

[0110] An example of a suitable Coxsackievirus sequence is the protein sequence from the Coxsackievirus group B (CVB3) polyprotein (see, e.g., Liu & Luo, 2021), UniProt sequence A8UMV1. In other words, a sequence fragment as used herein may comprise an epitope or epitope portion (e.g., at least 6, in particular at least 7 or even at least 8 amino acids) of said sequence.

[0111] An example of a suitable VSV sequence is the VSV glycoprotein G (UniProt P03522; see review by Munis (Munis et al., 2020)). In other words, a sequence fragment as used herein may comprise an epitope or epitope portion (e.g., at least 6, particularly at least 7 or even at least 8 amino acids) of said sequence.

[0112] Examples of suitable oncolytic poxvirus capsid sequences are disclosed in Torres-Dominguez et al., 2019, and Forop et al., 2019. In other words, a sequence fragment as used herein may comprise an epitope or epitope portion (e.g., at least 6, particularly at least 7 or even at least 8 amino acids) of the sequence referenced or disclosed therein.

[0113] Examples of suitable vaccinia proteins from which peptides may be derived are disclosed by Resch et al., 2007 and Condit et al., 2006. In other words, a sequence fragment as used herein may comprise an epitope or epitopic portion (e.g., at least 6, particularly at least 7 or even at least 8 amino acids) of the sequence referenced or disclosed therein.

[0114] It is highly preferred that the peptides used in the compounds of the invention do not bind to any HLA class I or HLA class II molecules (in the individual to be treated, e.g., human) in order to prevent their presentation and stimulation via the T cell receptor in vivo, and thus the induction of an immune response. In contrast to antigen-specific immune tolerization approaches, it is generally undesirable to involve suppressive (or stimulatory) T cell responses. Therefore, in order to avoid T cell epitope activity as much as possible, the peptides of the compounds of the invention (e.g., peptides P, P a , or P b ) preferably satisfies one or more of the following characteristics:

[0115] 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 , or P b ) has a preferred length of 4 to 8 amino acids, although some length is acceptable.

[0116] To further reduce the likelihood that such peptides will bind to HLA class II or class I molecules, it is preferred to test candidate peptide sequences with HLA binding prediction algorithms such as NetMHCII-2.3 (reviewed by Jensen et al. 2018). Preferably, the peptides used in the compounds of the invention (e.g., P, P a , or P b ) have a (predicted) HLA binding (IC50) of at least 500 nM. More preferably, the HLA binding (IC50) is higher than 1000 nM, especially higher than 2000 nM (see, for example, Peters et al. 2006). To reduce the possibility of HLA class I binding, NetMHCpan 4.0 may be applied for prediction (Jurtz et al. 2017).

[0117] To further reduce the possibility that such peptides bind to HLA class I molecules, the NetMHC pan Rank percentile threshold may be set at a background level of 10% according to Kosaloglu Yalcin et al 2018. Preferably, the peptides used in the compounds of the present invention (e.g., peptides P, P a , or P b ) therefore have a % rank value according to the NetMHCpan algorithm of greater than 3, preferably greater than 5, and more preferably greater than 10.

[0118] To further reduce the possibility of such peptides binding to HLA class II molecules, it may be beneficial to perform in vitro HLA binding assays commonly used in the art, such as refolding assays, iTopia, peptide rescuing assays, or array-based peptide binding assays. Alternatively or additionally, LC-MS-based analysis may be used, e.g. as reviewed in Gfeller et al. 2016.

[0119] In order to more strongly reduce the titer of the undesired antibodies, it is preferred to cyclize the peptides 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 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 in particular all P are cyclic peptides. Several general techniques are available for cyclization of peptides. See, for example, Ong et al. 2017. Needless to say, a "cyclic peptide" as used herein should be understood to refer to a peptide that is itself cyclized, for example as disclosed 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 herein as cyclopeptides.

[0120] Furthermore, in order to obtain a stronger reduction in the titer of the undesired antibodies compared to the amount of scaffold used, in one embodiment of the compound of the invention, for each said peptide n-mer independently, n is at least 2, more preferably at least 3, in particular at least 4. Usually, to avoid manufacturing process complications, for each said peptide n-mer independently, 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, in particular less than 5. To benefit from the higher affinity due to bivalent binding of the undesired antibodies, it is highly preferred that n is 2 for each said peptide n-mer.

[0121] Due to the undesired multivalent binding of antibodies, the peptide dimers or n-mers are advantageously separated by hydrophilic, structurally flexible, immunologically inert, non-toxic, clinically approved spacers, such as (heter)bifunctional and trifunctional polyethylene glycol (PEG) spacers (such as NHS-PEG-maleimide) (a variety of PEG chains are available and PEG is FDA approved). As an alternative to PEG linkers, immunologically inert and non-toxic synthetic polymers or glycans are also suitable. Thus, in the context of the present invention, the spacer (such as 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 (such as PEG spacer) may have, for example, a molecular weight of 10,000 Daltons. Obviously, in the context of the present invention, the covalent attachment of said peptide n-mer to said biopolymer scaffold via a linker may respectively be achieved, for example, by attaching said linker directly to the spacer of said peptide n-mer (e.g. not to the peptide of said peptide n-mer).

[0122] Each peptide n-mer is preferably covalently attached to said biopolymer scaffold, preferably via a respective linker.

[0123] Said linker as used herein may, for example, be selected from a disulfide bridge and a PEG molecule.

[0124] According to a further preferred embodiment of the compound of the present invention, each P is independently P a Or P b It is.

[0125] Furthermore, in the first peptide n-mer, each P is P a and in the second peptide n-mer, each P is P b Alternatively or additionally, P a and / or P b is circularized.

[0126] Bivalent binding is particularly suitable for reducing antibody titers. Thus, in a preferred embodiment: The first peptide n-mer is P a -SP a and the second peptide n-mer is P a -SP a or The first peptide n-mer is P a -SP a and the second peptide n-mer is P b -SP b or The first peptide n-mer is P b -SP b and the second peptide n-mer is P b -SP b or The first peptide n-mer is P a -SP b and the second peptide n-mer is P a -SP b or The first peptide n-mer is P a -SP b and the second peptide n-mer is P a -SP a or The first peptide n-mer is Pa -SP b and the second peptide n-mer is P b -SP b It is.

[0127] To enhance efficacy, in a preferred embodiment, the first peptide n-mer is different from the second peptide n-mer. For similar reasons, it is preferred that the peptide P a is the peptide P b and preferably said peptide P a and the peptide P b are two different epitopes of the same antigen, or two different epitopic portions of the same epitope.

[0128] In particular, in order to better target polyclonal antibodies, the peptide P a and the peptide P b comprises identical amino acid sequence fragments, said amino acid sequence fragments having 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, in particular at least 8 amino acids, and even more preferably at least 9 amino acids.

[0129] Furthermore, in order to more potently reduce the titer of the undesired antibodies 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).

[0130] As explained above, it is highly preferred that the compounds of the invention are non-immunogenic in mammals, preferably in humans, non-human primates, sheep, pigs, dogs, or rodents.

[0131] In the context of the present invention, a non-immunogenic compound is preferably a compound in which the biopolymer scaffold (if it is a protein) and / or the peptide (of a peptide n-mer) has an IC50 for HLA-DRB1_0101 predicted by the NetMHCII-2.3 algorithm of more than 100 nM, preferably more than 500 nM, more preferably more than 1000 nM, in particular more than 2000 nM. The NetMHCII-2.3 algorithm is described in detail in Jensen et al., which is incorporated herein by reference. The algorithm is publicly available at http: / / www.cbs.dtu.dk / services / NetMHCII-2.3 / . More preferably, the non-immunogenic compound (or pharmaceutical composition) does not bind to any HLA and / or MHC molecules in vivo (e.g. in a mammal, preferably in a human, in a non-human primate, in a sheep, in a pig, in a dog or in a rodent, or in the individual to be treated).

[0132] Further preferably, said compound is for the (temporary) endosequestration (or (temporary) endodepletion) of at least one antibody (anti-oncolytic virus antibody or oncolytic virus neutralizing antibody) in an individual, preferably in the bloodstream of said individual, and / or for the (temporary) reduction of the titer of at least one antibody (anti-oncolytic virus antibody or oncolytic virus neutralizing antibody) in said individual, preferably in the bloodstream of said individual.

[0133] In another preferred embodiment, the entire 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, in particular all P, optionally excluding the N-terminal and / or C-terminal cysteines, is identical to a sequence fragment of a protein, said protein being identified by one of the UniProt accession numbers disclosed herein, said sequence fragment optionally comprising 5 or less, preferably 4 or less, more preferably 3 or less, even more preferably 2 or less, in particular 1 or less amino acid substitutions (e.g. for the purposes mentioned above, such as mimotope generation).

[0134] In another preferred embodiment, the peptide P a The entire sequence of, optionally excluding N-terminal and / or C-terminal cysteines, is identical to a sequence fragment of a protein identified by one of the UniProt accession numbers disclosed herein, and said sequence fragment may contain up to 5, preferably up to 4, more preferably up to 3, even more preferably up to 2 and in particular up to 1 amino acid substitutions (e.g. for the purposes mentioned above, such as mimotope generation).

[0135] In another preferred embodiment, the peptide P b The entire sequence of, optionally excluding N-terminal and / or C-terminal cysteines, is identical to a sequence fragment of a protein identified by one of the UniProt accession numbers disclosed herein, and said sequence fragment may contain up to 5, preferably up to 4, more preferably up to 3, even more preferably up to 2 and in particular up to 1 amino acid substitutions (e.g. for the purposes mentioned above, such as mimotope generation).

[0136] In another preferred embodiment, the peptide P aThe entire sequence of the peptide P, optionally excluding the N-terminal and / or C-terminal cysteines, is identical to a sequence fragment of the protein, b The entire sequence of, optionally excluding the N-terminal and / or C-terminal cysteines, is identical to the same or to another, preferably another, sequence fragment of the same protein, said protein being identified by one of the UniProt accession numbers listed herein, said sequence fragment and / or said another sequence fragment may contain not more than 5, preferably not more than 4, more preferably not more than 3, even more preferably not more than 2 and in particular not more than 1 amino acid substitution (e.g. for the purposes mentioned above, such as mimotope generation).

[0137] In one aspect, the invention relates to a pharmaceutical composition comprising the invention and at least one pharma- ceutically acceptable formulation excipient.

[0138] In some embodiments, the compositions are prepared for intraperitoneal, subcutaneous, intramuscular, and / or intravenous administration, particularly for repeated administration (as the compositions are typically non-immunogenic).

[0139] Preferably, the peptide P or P in the composition a Or P b 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.

[0140] In another aspect, the compounds of the present invention are for use in therapy, preferably for use in the treatment of neoplasms such as benign, intraepithelial or malignant neoplasms, in particular for use in the treatment of solid tumors or hematological malignancies. The malignant neoplasm may in particular be any solid tumor selected from the group of (metastatic) tumors such as brain cancer (e.g. glioma, glioblastoma, cerebellar tumor as reviewed in Sostoa et al., 2020), breast cancer, colon and colorectal cancer, esophageal cancer, prostate cancer, bladder cancer, kidney cancer, endometrial cancer, thyroid cancer, gastric cancer, liver cancer, lung cancer, uterine cancer, tracheal cancer, testicular cancer, cervical cancer, head and neck cancer, skin cancer, bone cancer, pancreatic cancer and ovarian cancer. Alternatively, the malignant neoplasm may be a hematological malignancy, in particular selected from the group of leukemias, lymphomas and multiple myelomas as listed in the reviews of Innao et al., 2020 and Yang et al., 2021. Throughout the context of the present invention, solid tumors may be metastatic. Typically, solid tumors are malignant.

[0141] The individual (preferably human) to be treated typically has a neoplasm, such as a benign, intraepithelial or malignant neoplasm. The malignant neoplasm may be any solid tumor, in particular as defined in the paragraph above. Alternatively, the malignant neoplasm may be a hematological malignancy, in particular as defined in the paragraph above.

[0142] In the course of the present invention, it has been found that the compounds of the present invention provide a very suitable temporal therapeutic window for oncolytic virus administration (see, for example, Example 1 and Figures 1 and 2). Particularly preferably, administration of the compound (or a pharmaceutical composition comprising the compound) is followed by administration (systemic or local, in particular systemic) of an oncolytic virus or oncolytic VLP (based on oncolytic virus) within 96 hours, preferably within 72 hours or even within 60 hours, more preferably within 48 hours, even more preferably within 36 hours, even more preferably within 24 hours, in particular within 12 hours; preferably administration (systemic or local, in particular systemic) of an oncolytic virus or oncolytic VLP is performed 6 hours or more, preferably 12 hours or more, more preferably 24 hours or more after administration of the pharmaceutical composition. In other words, the time frame for administration (systemically or locally, especially systemically) of an oncolytic virus or oncolytic VLP is preferably 0 to 96 hours, more preferably 6 to 72 hours, even more preferably 12 to 60 hours, even more preferably 24 to 48 hours after administration of said compound (or a pharmaceutical composition comprising said compound).

[0143] During the course of the present invention, it has further been found that the in vivo rate at which undesired antibodies are reduced by the compounds of the present invention is usually very fast, but that undesired antibodies may then rebound moderately.It is therefore particularly preferred if the compound (or a pharmaceutical composition comprising the compound) is administered at least twice within a 96-hour window, preferably within a 72-hour window, more preferably within a 48-hour window, even more preferably within a 36-hour window, even more preferably within a 24-hour window, in particular within an 18-hour window or even within a 12-hour window; and it is particularly preferred if the anti-neoplastic composition described herein is administered within 96 hours, more preferably within 48 hours, even more preferably within 36 hours, even more preferably within 24 hours, in particular within 12 hours after this window;It is preferred that the administration (systemic or local, in particular systemic) of the oncolytic virus or oncolytic VLP is carried out 6 hours or more, preferably 12 hours or more, more preferably 24 hours or more after the administration of the pharmaceutical composition. For example, the pharmaceutical composition may be administered (systemically or locally, especially systemically) 24 hours and 12 hours prior to administration of the anti-neoplastic composition (oncolytic virus or oncolytic VLP based on oncolytic virus) at time 0.

[0144] In a particular preferred embodiment, the compounds of the invention are for use in increasing the efficacy of an oncolytic virus (specified herein) or an oncolytic VLP based on an oncolytic virus in an individual, preferably the pharmaceutical composition is administered to the individual before (systemically or locally, in particular systemically) administration of the oncolytic virus or an oncolytic VLP based on an oncolytic virus or simultaneously with (systemically or locally, in particular systemically) administration of the oncolytic virus or an oncolytic VLP based on an oncolytic virus. Alternatively or additionally, the titer of the antibody specific for the oncolytic virus or oncolytic VLP (and preferably also for the compound) is preferably determined after administration of the pharmaceutical composition and before administration of the virus or VLP, in particular the virus or VLP is administered only if the titer is below a threshold value. Otherwise, the administration of the composition may be repeated to further reduce the titer.

[0145] In some embodiments, the one or more antibodies present in the individual are capable of binding to at least one peptide P, or peptide P. a and / or peptide P b and said antibody is preferably a neutralizing antibody that neutralizes said oncolytic virus.

[0146] It is highly preferred that the composition is non-immunogenic in the individual (e.g. the composition does not include an adjuvant or an immunostimulant that stimulates the innate or adaptive immune system, such as a T-cell epitope).

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

[0148] In one aspect, the invention relates to a method for (temporarily) sequestering (or depleting) one or more antibodies present in an individual, preferably neutralizing antibodies that neutralize said oncolytic virus, comprising the steps of: Obtaining a pharmaceutical composition as defined herein; and administering said pharmaceutical composition to said individual (particularly repeatedly, e.g., at least twice, preferably at least three times, more preferably at least five times); Including, The composition is non-immunogenic in the individual, and the one or more antibodies present in the individual are directed against at least one P or a peptide P a and / or peptide P b Specific for It concerns the method.

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

[0150] Preferably, said biopolymer scaffold is autologous to said individual, and preferably said biopolymer scaffold is an autologous protein (ie when said individual is a mouse, mouse albumin is used).

[0151] In yet another aspect, the present invention relates to a pharmaceutical composition (i.e. antineoplastic composition) comprising a compound as defined herein, further comprising an oncolytic virus and, optionally, at least one pharma- ceutically acceptable formulation additive. The oncolytic virus typically comprises a peptide fragment having a sequence length of at least 6 amino acids, preferably at least 7 amino acids, more preferably at least 8 amino acids, in particular at least 9 amino acids. At least one peptide P of the compound or peptide P a and / or peptide P bis 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, in particular completely identical to the sequence of said peptide fragment. Preferably, the pharmaceutical composition is for use in the treatment of a neoplasm and / or for use in preventing or inhibiting an unwanted immune response against an oncolytic virus.

[0152] Furthermore, the composition is preferably non-immunogenic in the individual.

[0153] In yet another aspect, the present invention provides a method for inhibiting an (undesirable) - in particular a humoral - immune response to treatment with an anti-neoplastic composition as defined above in an individual in need of treatment with an anti-neoplastic composition as defined above, or for inhibiting neutralization of an oncolytic virus in an anti-neoplastic composition for an individual in need of treatment with an anti-neoplastic composition, comprising obtaining said anti-neoplastic composition, said anti-neoplastic composition being non-immunogenic in said individual; and administering (systemically or locally) said anti-neoplastic composition to said individual, preferably repeatedly.

[0154] In general, screening of peptide mimotopes is known per se in the art, see for example Shanmugam et al. The mimotope-based compounds of the invention have two advantages over compounds using wild-type epitopes: first, the undesired antibodies generally have a higher affinity for the mimotopes found in the screening of peptide libraries, so that the mimotope-based compounds have a higher removal efficiency; second, even in cases where the wild-type epitope sequence induces T-cell epitope activity, the mimotope makes it possible to avoid such T-cell epitope activity as much as possible (as described herein above).

[0155] In a further aspect, the present invention relates to a peptide, said peptide comprising the compound of the present invention, P, P a , or P b wherein any one of at least two of the peptides is defined as disclosed herein.

[0156] In certain embodiments, such peptides may be used as probes for diagnostic typing and analysis of circulating oncolytic virus neutralizing antibodies, e.g., as part of diagnostic vector neutralizing antibody typing or screening devices or kits or procedures for patient stratification or monitoring of vector neutralizing antibody levels before, during and / or after antineoplastic therapy (with oncolytic viruses) as companion diagnostics.

[0157] In a further aspect, the present invention provides a method for detecting and / or quantifying oncolytic virus-neutralizing antibodies in a biological sample, comprising the steps of: - The sample is subjected to a step of analyzing peptides defined as disclosed herein (e.g., P, P a , or P b or any of the compounds disclosed herein), and - detecting the presence and / or concentration of said antibody in said sample The present invention relates to a method comprising the steps of:

[0158] The skilled artisan is familiar with methods for the detection and / or quantification of antibodies in a biological sample, which may for example be a sandwich assay, preferably an enzyme-linked immunosorbent assay (ELISA), or a surface plasmon resonance (SPR) assay.

[0159] In a preferred embodiment, the peptides (particularly at least 10, more preferably at least 100, even more preferably at least 1000, especially at least 10000 different peptides of the invention) or said compounds are immobilized on a solid support, preferably an ELISA plate or an SPR chip or a biosensor-based diagnostic device comprising an electrochemical, fluorescent, magnetic, electronic, gravimetric or optical biotransducer. Alternatively or in addition, the peptides (particularly at least 10, more preferably at least 100, even more preferably at least 1000, especially at least 10000 different peptides of the invention) may be bound to a reporter or reporter fragment, such as a reporter fragment suitable for protein fragment complementation assay (PCA); see, for example, Li et al., 2019, or Kainulainen et al., 2021.

[0160] Preferably, said sample is obtained from a mammal, preferably a human. Preferably, said sample is a blood sample, preferably a whole blood, serum or plasma sample.

[0161] According to a preferred embodiment, the mammal (human) has a neoplasm, more preferably the neoplasm is an intraepithelial or malignant neoplasm, even more preferably a solid tumor or a hematological malignancy, and in particular the mammal has a solid tumor, preferably selected from the group of brain cancer, breast cancer, colon cancer, esophageal cancer, prostate cancer, bladder cancer, kidney cancer, endometrial cancer, thyroid cancer, gastric cancer, liver cancer, lung cancer, pancreatic cancer, uterine cancer, tracheal cancer, testicular cancer, cervical cancer, head and neck cancer, skin cancer, bone cancer, pancreatic cancer and ovarian cancer, or a hematological malignancy, preferably selected from the group of leukemia, lymphoma and multiple myeloma, and in particular the mammal (human) has been selected to be treated with an oncolytic virus or oncolytic VLP or has been treated with an oncolytic virus or oncolytic VLP.

[0162] The present invention relates to the use of peptides as defined herein (e.g., P, P) in diagnostic assays as disclosed herein above, preferably ELISA. a , or P b ) for further use.

[0163] A further aspect of the invention is a peptide as defined herein (e.g., P, P), preferably immobilized on a solid support. a , or P b In a preferred embodiment, the solid support is an ELISA plate or a surface plasmon resonance chip. In another preferred embodiment, the diagnostic device is a biosensor-based diagnostic device comprising an electrochemical, fluorescent, magnetic, electronic, gravimetric or optical biotransducer.

[0164] In another preferred embodiment, the diagnostic device is a lateral flow assay.

[0165] The present invention relates to peptides defined as disclosed herein (e.g., P, P a , or P b ). Preferably, said diagnostic kit further comprises one or more selected from the group consisting of: buffers, reagents, instructions. Preferably, said diagnostic kit is an ELISA kit.

[0166] Further embodiments include peptides defined as disclosed herein (e.g., P, P a , or P b Preferably, the peptides are immobilized on a solid support. The apheresis device is configured to immobilize at least two, preferably at least three, more preferably at least four different peptides (e.g., P, P) as defined herein. a , or P bIn a preferred embodiment, the solid support comprises a compound of the invention.

[0167] Preferably, said solid support is capable of contacting a blood or plasma stream. Preferably, said solid support is a column which is sterile and pyrogen-free.

[0168] In the context of the present invention, in order to improve bioavailability, it is preferred that the compounds of the present invention have a solubility in water at 25°C of 0.1 μg / ml or more, preferably 1 μg / ml or more, more preferably 10 μg / ml or more, even more preferably 100 μg / ml or more, especially 1000 μg / ml or more.

[0169] The term "preventing" or "prevention" as used herein means to completely, nearly completely, or at least to some extent (preferably to a large extent) inhibit the occurrence of a disease state or condition in a patient or subject, particularly when said patient, subject, or individual is at increased risk of developing such disease state or condition.

[0170] The pharmaceutical composition of the invention is preferably provided as a (typically aqueous) solution, a (typically aqueous) suspension, or a (typically aqueous) emulsion. Suitable formulation additives for the pharmaceutical composition of the invention will be known to the skilled artisan after reading this specification, and include, for example, water (particularly water for injection), saline, Ringer's solution, glucose solution, buffers, Hank's solution, vesicle-forming compounds (such as lipids), fixed oils, ethyl oleate, saline with 5% dextrose, substances that enhance isotonicity and chemical stability, buffers, and preservatives. Other suitable formulation additives include any compound that does not itself induce in said patient (or individual) the production of antibodies harmful to said patient (or individual). Examples include well-tolerated proteins, polysaccharides, polylactic acids, polyglycolic acids, polymeric amino acids, and amino acid copolymers. The pharmaceutical composition (as a drug) may be administered to a patient or individual in need thereof (i.e., a patient or individual having or at risk of developing a disease or condition described herein) by suitable procedures known to the skilled artisan after reading this specification. The preferred route of administration of the pharmaceutical composition is via parenteral administration, in particular intraperitoneal, subcutaneous, intramuscular, and / or intravenous administration. For parenteral administration, the pharmaceutical composition of the invention is preferably provided as an injectable unit dosage form, such as a solution (typically an aqueous solution), suspension, or emulsion, formulated together with pharma- ceutical acceptable formulation additives as defined above. The dose and method of administration, however, will depend on the individual patient or individual to be treated. The pharmaceutical composition may be administered in any suitable dose, as known in other biological administration regimes, 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, in particular 100 mg to 1 g. The usual dose may also be determined based on the kg body weight of the patient, for example, a preferred dose is 0.1 mg to 100 mg / kg body weight, in particular 1 to 10 mg / kg body weight (per administration session). The administration may be once daily, once every other day, once a week, once every two weeks, or the like.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 liquid 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 0.1-990 μg, preferably 1-900 μg, more preferably 10-200 μg of compound, and optionally 1-500 μg, preferably 1-100 μg, more preferably 5-15 μg of (buffer) salt (preferably to provide an isotonic buffer in the final volume), and optionally 0.1-999.9 μg, preferably 100-999.9 μg, more preferably 200-999 μg of other formulation additives. Preferably, 100 mg (dry weight) of such a dry composition is dissolved in sterile, deionized / distilled water or sterile isotonic phosphate buffered saline (PBS) to a final volume of 0.1-100 ml, preferably 0.5-20 ml, more preferably 1-10 ml.

[0171] It will be apparent to those skilled in the art that the active agents and drugs described herein may be administered in salt form (i.e., as a pharma- ceutically acceptable salt of the active agent). Thus, any reference herein to an active agent is intended to include any pharma- ceutically acceptable salt form thereof.

[0172] Methods for chemical synthesis of peptides used in the compounds of the invention are well known in the art. Of course, the peptides can also be produced using recombinant methods. The peptides can be produced in microorganisms such as bacteria, yeast, or fungi, in eukaryotic cells such as mammalian or insect cells, or in recombinant viral vectors such as adenovirus, poxvirus, herpesvirus, Semliki Forest virus, baculovirus, bateriophage, 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 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 recombinantly produced peptides are also well known in the art, and include, for example, gel filtration, affinity chromatography, and ion exchange chromatography.

[0173] It is particularly advantageous to add cysteine ​​residues to the N- and / or C-terminus of the peptide to facilitate conjugation to the biopolymer scaffold.

[0174] To facilitate the isolation of the peptide, a fusion polypeptide may be created, in which the peptide is translationally fused (covalently linked) to a heterologous polypeptide that allows isolation by affinity chromatography. Exemplary heterologous polypeptides include His-tags (e.g. His6; 6 histidine residues) and GST-tags (glutathione-S-transferase). The fusion polypeptides can facilitate the purification of the peptide, but also prevent the peptide from being decomposed during the purification step. 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 for the amino acid sequence at this site.

[0175] In the context of the present invention, the linking / binding chemistry used to link the peptide / peptide n-mer to the biopolymer scaffold (e.g. via heterobifunctional compounds such as GMBS or, of course, others described in "Bioconjugate Techniques", Greg T. Hermanson) or to bond the spacer to the peptide can also be selected from reactions known to those skilled in the art. The biopolymer scaffold itself can be recombinantly produced or obtained from natural sources.

[0176] As used herein, the term "specific for", as in "molecule A specific for molecule B", means that molecule A preferentially binds to molecule B over other molecules in the body of an individual. 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 lower (i.e., strong) than 1000 nM, preferably lower than 100 nM, more preferably lower than 50 nM, even more preferably lower than 10 nM, and especially lower than 5 nM.

[0177] As used herein, "UniProt" refers to the Universal Protein Resource. UniProt is a comprehensive resource for protein sequence and annotation data. UniProt is a collaboration between the European Bioinformatics Institute (EMBL-EBI), the SIB Swiss Bioinformatics Institute, and the Protein Information Resource (PIR). Over 100 people across the three institutes are involved in different tasks including database curation, software development, and support. Website: http: / / www.uniprot.org /

[0178] Entries in the UniProt database are identified by their accession numbers (referred to herein, e.g., as "UniProt accession numbers" or "UniProt" for short, followed by the accession number), which are typically six-letter alphanumeric codes (e.g., "Q1HVF7"). Unless otherwise noted, accession numbers used herein refer to entries in UniProt's Protein Knowledgebase (UniProtKB). Unless otherwise noted, the UniProt database for all entries referenced herein is as of September 23, 2020 (UniProt / UniProtKB Release 2020_04).

[0179] In the context of this application, when referring to entries in the UniProt database, sequence variants (denoted "natural variants" in UniProt) are explicitly included.

[0180] "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 the amino acid residues in the reference polypeptide sequence when the sequences are aligned, gaps are introduced, if necessary, to achieve the maximum percent sequence identity, and any conservative substitutions are not considered as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be accomplished using a variety of methods known in the art, such as publicly available computer software, such as BLAST, BLAST-2, ALIGN, ALIGN-2, Megalign (DNASTAR), or the "needle" pairwise sequence alignment application of the EMBOSS software package. Those skilled in the art can determine suitable parameters for aligning sequences, including any algorithms required to achieve maximal alignment over the full length of the sequences being compared. For purposes herein, however, % amino acid sequence identity values ​​are calculated using sequence alignment with the computer program "needle" from the EMBOSS software package (published by the European Molecular Biology Laboratory; Rice et al., 2000).

[0181] The needle program can be accessed from the website http: / / www.ebi.ac.uk / Tools / psa / emboss_needle or downloaded for local installation as part of the EMBOSS package from http: / / emboss.sourceforge.net / . The program can run on many popular UNIX operating systems, including Linux.

[0182] For alignment of two protein sequences, the needle program is preferably run with 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)

[0183] The % amino acid sequence identity of a particular amino acid sequence A to, with, or relative to a particular amino acid sequence B (alternatively, it can be expressed as a particular amino acid sequence A having or containing a particular % amino acid sequence identity to, with, or relative to a particular amino acid sequence B) is calculated as follows: 100 times the ratio X / Y where X is the number of amino acid residues scored as identical matches by the sequence alignment program needle in its alignment of A and B, and Y is the total number of amino acid residues in B. It is understood that 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 will not be 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 entire sequence of B (i.e., the total number of amino acid residues in B). Unless otherwise noted, all % amino acid sequence identity values ​​used herein are obtained using the needle computer program, as described in the immediately preceding paragraph.

[0184] The present invention further relates to the following embodiments:

[0185] EMBODIMENT 1 Biopolymer scaffolds, as well as at least a first peptide n-mer of the following general formula: P(-SP) (n-1) and a second peptide n-mer of the general formula: P(-SP) (n-1) Including, P is independently a peptide having a sequence length of 6 to 13 amino acids, and S is a non-peptide spacer; independently for each said peptide n-mer, n is an integer that is 1 or greater, preferably an integer that is 2 or greater, more preferably an integer that is 3 or greater, particularly an integer that is 4 or greater; each of said peptide n-mers is attached to said biopolymer scaffold, preferably via a respective linker; P each independently represents a protein sequence (preferably a capsid protein sequence, a nucleocapsid protein sequence, a structural protein sequence, a viral envelope associated protein sequence or a receptor binding protein sequence, a tegument protein sequence, a viral enzyme sequence, a nuclear matrix protein sequence, a DNA binding protein sequence or an RNA binding protein sequence, a viral packaging protein sequence or a viral polymerase sequence, more preferably a capsid protein sequence, a nucleocapsid protein sequence, a structural protein sequence, a viral envelope associated protein sequence or a receptor binding protein sequence, or a tegument protein sequence), in particular a capsid protein sequence), in particular a capsid protein sequence of an AdV hexon protein sequence, an AdV fiber protein sequence, an AdV penton protein sequence, an AdV IIIa protein sequence, an AdV VI protein sequence, an AdV VIII protein sequence or an AdV IX protein sequence, or any one of the capsid protein sequences identified in FIG. 5 or any one of the capsid protein sequences identified in Cearley et al., 2008, or the capsid protein sequences listed in UniProt P03525, P03526, P03527, P03528, P03529, P0CK31, P11078, P11079, P12418, P12419, P15024, P21270, A1Z0P5, O09800, P03170, P04288, P04289, P04291, P04486, P06477, P06484, P06487, P06491, P08314, P08392, P08543, P10185, P10190, P10191, P10192, P10193, P10200, P10202, P10204, P10205, P10210, and having an amino acid sequence comprising a sequence fragment having a length of at least 6 (preferably at least 7, more preferably at least 8, especially at least 9 amino acids) of any one of the capsid protein sequences identified by any one of P10216, P10218, P10219, P10220, P10225, P10227, P10228, P10229, P10231, P10234, P32888, P68333, P08362, P35971, Q89933, P35974, P35976, P69358, P12576, Q9EMA9 and P03522. up to 3, preferably up to 2, most preferably 1 or more amino acids of said sequence fragment may be independently replaced by any other amino acid; compound.

[0186] 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, in particular all P are cyclic peptides; or at least one P is a linear peptide, preferably at least 10% of all P are linear peptides, more preferably at least 25% of all P are linear peptides, even more preferably at least 50% of all P are linear peptides, even more preferably at least 75% of all P are linear peptides, even more preferably at least 90% of all P are linear peptides, even more preferably at least 95% of all P are linear peptides, in particular all P are linear peptides.

[0187] EMBODIMENT 3 The compound of embodiment 1 or embodiment 2, wherein, independently for each said peptide n-mer, n is at least 2, more preferably at least 3, especially at least 4.

[0188] EMBODIMENT 4 The compound of any one of embodiments 1 to 3, wherein, independently for each said peptide n-mer, 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 especially less than 5.

[0189] EMBODIMENT 5 The compound of any one of embodiments 1 to 4, wherein for each of said peptide n-mers, n is 2.

[0190] EMBODIMENT 6 At least one P is P aand / or at least one P is P b and P a is a peptide having a sequence length of 2 to 13 amino acids, preferably 3 to 11 amino acids, and more preferably 4 to 9 amino acids, P b is a peptide having a sequence length of 2 to 13 amino acids, preferably 3 to 11 amino acids, and more preferably 4 to 9 amino acids, Preferably, P a and / or P b comprises a protein sequence of an epitope sequence of an oncolytic virus or a mimotope thereof (preferably a capsid protein sequence, a nucleocapsid protein sequence, a structural protein sequence, a viral envelope binding protein sequence or a receptor binding protein sequence, a tegument protein sequence, a viral enzyme sequence, a nuclear matrix protein sequence, a DNA binding protein sequence or an RNA binding protein sequence, a viral packaging protein sequence or a viral polymerase sequence, more preferably a capsid protein sequence, a nucleocapsid protein sequence, a structural protein sequence, a viral envelope binding protein sequence or a receptor binding protein sequence, or a tegument protein sequence), in particular a capsid protein sequence), The compound of any one of embodiments 1 to 5.

[0191] EMBODIMENT 7 P is independently a Or P b The compound of any one of embodiments 1 to 6, wherein

[0192] EMBODIMENT 8 In the first peptide n-mer, each P is P a and in said second peptide n-mer each P is P b The compound of any one of embodiments 1 to 7, wherein

[0193] EMBODIMENT 9 The first peptide n-mer is P a -SPa and the second peptide n-mer is P a -SP a or The first peptide n-mer is P a -SP a and the second peptide n-mer is P b -SP b or The first peptide n-mer is P b -SP b and the second peptide n-mer is P b -SP b or The first peptide n-mer is P a -SP b and the second peptide n-mer is P a -SP b or The first peptide n-mer is P a -SP b and the second peptide n-mer is P a -SP a 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 compound of any one of embodiments 1 to 8.

[0194] EMBODIMENT 10 Biopolymer scaffolds, and at least ·Formula P a -SP a Or P a -SP b a first peptide n-mer, which is a peptide dimer of A compound comprising P a is a peptide having a sequence length of 2 to 13 amino acids, preferably 7 to 11 amino acids, more preferably 7 to 9 amino acids, bis a peptide having a sequence length of 6 to 13 amino acids, preferably 7 to 11 amino acids, and more preferably 7 to 9 amino acids, and S is a non-peptide spacer; said first peptide n-mer is attached to said biopolymer scaffold, preferably via a linker; P ais selected from the protein sequence (preferably a capsid protein sequence, a nucleocapsid protein sequence, a structural protein sequence, a viral envelope associated protein sequence or a receptor binding protein sequence, a tegument protein sequence, a viral enzyme sequence, a nuclear matrix protein sequence, a DNA- or RNA-binding protein sequence, a viral packaging protein sequence or a viral polymerase sequence, more preferably a capsid protein sequence, a nucleocapsid protein sequence, a structural protein sequence, a viral envelope associated protein sequence or a receptor binding protein sequence, or a tegument protein sequence), in particular a capsid protein sequence), in particular a capsid protein sequence of the AdV hexon protein sequence, the AdV fiber protein sequence, the AdV penton protein sequence, the AdV IIIa protein sequence, the AdV VI protein sequence, the AdV VIII protein sequence or the AdV IX protein sequence, or any one of the capsid protein sequences identified in FIG. 5 or Cearley et al., 2008, or any one of the capsid protein sequences listed in UniProt P03525, P03526, P03527, P03528, P03529, P0CK31, P11078, P11079, P12418, P12419, P15024, P21270, A1Z0P5, O09800, P03170, P04288, P04289, P04291, P04486, P06477, P06484 , P06487, P06491, P08314, P08392, P08543, P10185, P10190, P10191, P10192, P10193, P1 0200, P10202, P10204, P10205, P10210, P10216, P10218, P10219, P10220, P10225, P1022 7, P10228, P10229, P10231, P10234, P32888, P68333, P08362, P35971, Q89933, P35974, P35976, P69358, P12576, Q9EMA9 and P03522, wherein up to 3, preferably up to 2 and most preferably one or more amino acids of said sequence fragment may be independently replaced by any other amino acid. The compound.

[0195] EMBODIMENT 11 formula P b -SP b Or P a -SP b and a second peptide n-mer which is a peptide dimer of said second peptide n-mer is attached to said biopolymer scaffold, preferably via a linker; P bis selected from the protein sequence (preferably a capsid protein sequence, a nucleocapsid protein sequence, a structural protein sequence, a viral envelope associated protein sequence or a receptor binding protein sequence, a tegument protein sequence, a viral enzyme sequence, a nuclear matrix protein sequence, a DNA- or RNA-binding protein sequence, a viral packaging protein sequence or a viral polymerase sequence, more preferably a capsid protein sequence, a nucleocapsid protein sequence, a structural protein sequence, a viral envelope associated protein sequence or a receptor binding protein sequence, or a tegument protein sequence), in particular a capsid protein sequence), in particular a capsid protein sequence of the AdV hexon protein sequence, the AdV fiber protein sequence, the AdV penton protein sequence, the AdV IIIa protein sequence, the AdV VI protein sequence, the AdV VIII protein sequence or the AdV IX protein sequence, or any one of the capsid protein sequences identified in FIG. 5 or Cearley et al., 2008, or any one of the capsid protein sequences listed in UniProt P03525, P03526, P03527, P03528, P03529, P0CK31, P11078, P11079, P12418, P12419, P15024, P21270, A1Z0P5, O09800, P03170, P04288, P04289, P04291, P04486, P06477, P06484 , P06487, P06491, P08314, P08392, P08543, P10185, P10190, P10191, P10192, P10193, P1 0200, P10202, P10204, P10205, P10210, P10216, P10218, P10219, P10220, P10225, P1022 7, P10228, P10229, P10231, P10234, P32888, P68333, P08362, P35971, Q89933, P35974, P35976, P69358, P12576, Q9EMA9 and P03522, wherein up to 3, preferably up to 2 and most preferably one or more amino acids of said sequence fragment may be independently replaced by any other amino acid. The compound of embodiment 10.

[0196] EMBODIMENT 12 The compound of any one of embodiments 1 to 9 and 11, wherein said first peptide n-mer is different from said second peptide n-mer.

[0197] EMBODIMENT 13 The peptide P a is the peptide P b Preferably, said peptide P a and the peptide P bare two different epitopes of the same viral (capsid) antigen, or two different epitopic portions of the same viral (capsid) epitope.

[0198] EMBODIMENT 14 The peptide P a and the peptide P b The compound of any one of embodiments 6 to 13, wherein 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.

[0199] EMBODIMENT 15 P a and / or P b The compound of any one of embodiments 6 to 14, wherein

[0200] EMBODIMENT 16 The compound of any one of embodiments 1 to 15, wherein said compound comprises a plurality of said first peptide n-mers and / or a plurality of said second peptide n-mers.

[0201] EMBODIMENT 17 The compound of 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, an ovine protein, a porcine protein, a canine protein, or a rodent protein.

[0202] EMBODIMENT 18 The compound of embodiment 17, wherein said biopolymer scaffold is a globulin.

[0203] EMBODIMENT 19 The compound of embodiment 18, wherein said biopolymer scaffold is selected from the group consisting of immunoglobulins, alpha 1-globulins, alpha 2-globulins, and beta-globulins.

[0204] EMBODIMENT 20 The compound of embodiment 19, wherein said biopolymer scaffold is selected from the group consisting of immunoglobulin G, haptoglobin, and transferrin.

[0205] EMBODIMENT 21 The compound of embodiment 20, wherein said biopolymer scaffold is haptoglobin.

[0206] EMBODIMENT 22 The compound of embodiment 17, wherein said biopolymer scaffold is albumin.

[0207] EMBODIMENT 23 The compound of any one of embodiments 1 to 22, wherein the compound is non-immunogenic in a mammal, preferably in a human, in a non-human primate, in a sheep, in a pig, in a dog, or in a rodent.

[0208] EMBODIMENT 24 The compound of any one of embodiments 1 to 23, wherein said compound is for the (temporary) endosequestration (or endodepletion) of at least one antibody (anti-oncolytic virus antibody or oncolytic virus neutralizing antibody) in an individual, preferably in the bloodstream of said individual, and / or for the reduction of the titer of at least one antibody (anti-oncolytic virus antibody or oncolytic virus neutralizing antibody) in said individual, preferably in the bloodstream of said individual.

[0209] EMBODIMENT 25 The compound of any one of embodiments 1 to 24, wherein the oncolytic virus is an adenovirus (AdV), an adeno-associated virus (AAV), a poxvirus such as measles virus, herpes simplex virus (HSV), vaccinia virus, a reovirus, a Newcastle disease virus (NVD), a rhabdovirus, a coxsackievirus, a lentivirus, an alphavirus such as Semliki Forest virus, a vesicular stomatitis virus (VSS), a myxoma virus (MYXV), a mengovirus, a bovine viral diarrhea virus (BVDV), a chimeric oncolytic virus, a picornavirus, a parvovirus, or a flavivirus.

[0210] EMBODIMENT 26 The entire 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, in particular all P, optionally excluding the N-terminal and / or C-terminal cysteine, is identical to a sequence fragment of a protein, said protein being or any one of the AdV hexon protein, AdV fiber protein, AdV penton protein, AdV IIIa protein, AdV VI protein, AdV VIII protein or AdV IX protein, or the capsid protein sequences identified in FIG. 5 or Cearley et al., 2008, or the capsid proteins listed in UniProt P03525, P03526, P03527, P03528, P03529, P0CK31, P11078, P11079, P12418, P12419, P15024, P21270, A1Z0P5, O09800, P03170, P04288, P04289, P04291, P04486, P06477, P06484, P06487, P06491, P08314, P08392, P08543, P10185, P10190, P10191, P10192, P1019 3, a capsid protein sequence identified by any one of P10200, P10202, P10204, P10205, P10210, P10216, P10218, P10219, P10220, P10225, P10227, P10228, P10229, P10231, P10234, P32888, P68333, P08362, P35971, Q89933, P35974, P35976, P69358, P12576, Q9EMA9, and P03522. no more than 3, preferably no more than 2, most preferably no more than 1 amino acid of said sequence fragment may be independently replaced by any other amino acid; The compound of any one of embodiments 1 to 25.

[0211] EMBODIMENT 27 Peptide P a wherein the entire sequence, optionally excluding the N-terminal and / or C-terminal cysteines, is identical to a sequence fragment of a protein identified by one of the UniProt accession numbers listed in embodiment 26, The sequence fragment may contain no more than 3 amino acid substitutions, more preferably no more than 2 amino acid substitutions, particularly no more than 1 amino acid substitution. The compound of any one of embodiments 1 to 26.

[0212] EMBODIMENT 28 Peptide P bwherein the entire sequence, optionally excluding the N-terminal and / or C-terminal cysteines, is identical to a sequence fragment of a protein identified by one of the UniProt accession numbers listed in embodiment 26, The sequence fragment may contain no more than 3 amino acid substitutions, more preferably no more than 2 amino acid substitutions, particularly no more than 1 amino acid substitution. The compound of any one of embodiments 1 to 27.

[0213] EMBODIMENT 29 Peptide P a The entire sequence of the peptide P, optionally excluding the N-terminal and / or C-terminal cysteines, is identical to a sequence fragment of the protein, b is identical in its entire sequence, optionally excluding the N-terminal and / or C-terminal cysteines, to the same or another, preferably another, sequence fragment of the same protein, said protein being identified by one of the UniProt accession numbers listed in embodiment 26, The sequence fragment and / or the further sequence fragment may contain no more than 3 amino acid substitutions, more preferably no more than 2 amino acid substitutions, in particular no more than 1 amino acid substitution. The compound of any one of embodiments 1 to 28.

[0214] EMBODIMENT 30 The sequence fragment is Group of AdV sequences ETGPPTVPFLTPPF (SEQ ID NO: 32), HDSKLSIATQGPL (SEQ ID NO: 33), LNLRLGQGPLFINSAHNLDINY (SEQ ID NO: 34), VDPMDEPTLLYVLFEVFDVV (SEQ ID NO: 35), MKRARPSEDTFNPVYPYD (SEQ ID NO: 36), ISGTVQSAHLIIRFD (SEQ ID NO: 37), LGQGPLFINSAHNLDINYNKGLYLF (SEQ ID NO: 38), SYPFDAQNQLNLRLGQGPLFIN (SEQ ID NO: 39), GDTTPSAYSMSFSWDWSGHNYIN (SEQ ID NO: 40), VLLNNSFLDPEYWNFRN (SEQ ID NO: 41), HNYINEIFATSSYTFSYIA (SEQ ID NO: 42), DEAATALEINLEEEDDDNEDEVDEQAEQQKTH (SEQ ID NO: 43), INLEEDDDNEDEVDEQAEQ (SEQ ID NO: 44), DNEDEVDEQAEQQKTHVF (SEQ ID NO: 45), EWDEAATALEINLEE (SEQ ID NO: 46), PKVVLYSEDVDIETPDTHISYMP (SEQ ID NO: 47), YIPESYKDRMYSFFRNF (SEQ ID NO: 48), DSIGDRTRYFSMW (SEQ ID NO: 49), SYKDRMYSFFRNF (SEQ ID NO: 50), and FLVQMLANYNIGYQGFY (SEQ ID NO: 51), AAV sequence group: WQNRDVYLQGPIWAKIP (SEQ ID NO: 52), DNTYFGYSTPWGYFDFNRFHC (SEQ ID NO: 53), MANQAKNWLPGPCY (SEQ ID NO: 54), LPYVLGSAHQGCLPPFP (SEQ ID NO: 55), NGSQAVGRSSFYCLEYF (SEQ ID NO: 56), PLIDQYLYYL (SEQ ID NO: 57), EERFFPSNGILIF (SEQ ID NO: 58), ADGVGSSSGNWHC (SEQ ID NO: 59), SEQ ID NOs: 383 to 1891 (see Table 1), preferably Group III in Table 1, more preferably Group II in Table 1, particularly preferably Group I in Table 1; SEQ ID NOs: 1892 to 2063 (see Table 2), preferably Group I in Table 2; A sequence of Group II or Group III of Table 3 (see in particular SEQ ID NOs: 2064 to 2103), more preferably a sequence of Group I of Table 3, The group of sequences in Table 4, in particular the group of sequences identified in SEQ ID NOs: 2104 to 2190, or Group of sequences in Table 5 A sequence of at least 4 or at least 5, or at least 6, preferably at least 7, more preferably at least 8, even more preferably at least 9, and even more preferably at least 10 consecutive amino acids selected from up to 3, preferably up to 2, most preferably 1 or more amino acids of said sequence fragment may be independently replaced by any other amino acid; The compound of any one of embodiments 1 to 29.

[0215] EMBODIMENT 31 P is each independently selected from GPPTVPFLTP (SEQ ID NO: 60), ETGPPTVPFLTPP (SEQ ID NO: 61), TGPPTVPFLT (SEQ ID NO: 62), PTVPFLTPPF (SEQ ID NO: 63), HDSKLSIATQGPL (SEQ ID NO: 64), SIATQGP (SEQ ID NO: 65), NLRLGQGPLF (SEQ ID NO: 66), QGPLFINSAH (SEQ ID NO: 67), PLFINSAHNLD (SEQ ID NO: 68), LGQGPLF (SEQ ID NO: 69), LNLRLGQGPL (SEQ ID NO: 70), GQGPLFI (SEQ ID NO: 71), NLRLGQGPLFIN S (SEQ ID NO: 72), LFINSAHNLDINY (SEQ ID NO: 73), FINSAHNLDI (SEQ ID NO: 74), LRLGQGPLFI (SEQ ID NO: 75), GPLFINSAHN (SEQ ID NO: 76), DEPTLLYVLFEVF (SEQ ID NO: 77), TLLYVLFEVF (SEQ ID NO: 78), DEPTLLYVLF (SEQ ID NO: 79), TLLYVLFEVFDVV (SEQ ID NO: 80), TLLYVLF (SEQ ID NO: 81), MDEPTLLYVLFEV (SEQ ID NO: 82), EPTLLYVLFE (SEQ ID NO: 83), DPMDEPTLLYVLF (SEQ ID NO: 84) ), LLYVLFEVFD (SEQ ID NO: 85), YVLFEVFDVV (SEQ ID NO: 86), PTLLYVLFEV (SEQ ID NO: 87), PTLLYVLFEVFDV (SEQ ID NO: 88), LYVLFEVFDV (SEQ ID NO: 89), EPTLLYVLFEVFD (SEQ ID NO: 90), LYVLFEV (SEQ ID NO: 91), PMDEPTLLYVLFE (SEQ ID NO: 92), LLYVLFE (SEQ ID NO: 93), VDPMDEPTLLYVL (SEQ ID NO: 94), YVLFEVF (SEQ ID NO: 95), PTLLYVL (SEQ ID NO: 96), MKRARPSEDTF (SEQ ID NO: 97) ), KRARPSEDTF (SEQ ID NO: 98), MKRARPSEDT (SEQ ID NO: 99), MKRARPSEDTFN (SEQ ID NO: 100), ARPSEDTFNP (SEQ ID NO: 101), RARPSEDTFN (SEQ ID NO: 102), RPSEDTF (SEQ ID NO: 103), MKRARPSEDTFNP (SEQ ID NO: 104), RARPSEDTFNPVY (SEQ ID NO: 105), ARPSEDT (SEQ ID NO: 106), EDTFNPVYPY (SEQ ID NO: 107), RPSEDTFNPVYPY (SEQ ID NO: 108), KRARPSEDTFNPV (SEQ ID NO: 109),DTFNPVY (SEQ ID NO: 110), RPSEDTFNPV (SEQ ID NO: 111), PSEDTFNPVY (SEQ ID NO: 112), DTFNPVYPYD (SEQ ID NO: 113), VQSAHLIIRF (SEQ ID NO: 114), AHLIIRF (SEQ ID NO: 115), SGTVQSAHLIIRF (SEQ ID NO: 116), TVQSAHLIIR (SEQ ID NO: 117), HLIIRFD (SEQ ID NO: 118), SAHLIIR (SEQ ID NO: 119), QSAHLIIRFD (SEQ ID NO: 120), ISGTVQSAHLIIR (SEQ ID NO: 121), GTVQSAHLII (SEQ ID NO: 122), GTVQSAHLIIRFD (SEQ ID NO: 123), QSAHLII (SEQ ID NO: 124), HNLDINY (SEQ ID NO: 125), LFINSAHNLDINY (SEQ ID NO: 126), NLDINYNKGLYLF (SEQ ID NO: 127), FVSPNG (SEQ ID NO: 128), NYINEIF (SEQ ID NO: 129), NKGLYLF (SEQ ID NO: 130), INYNKGLYLF (SEQ ID NO: 131), NSAHNLDINY (SEQ ID NO: 132), WDWSGHNYINEIF (SEQ ID NO: 133), SGHNYINEIF (SEQ ID NO: 134), LGTGLSF (SEQ ID NO: 135), Column number 135), PFLTPPF (SEQ ID NO: 136), LGQGPLF (SEQ ID NO: 137), NLRLGQGPLF (SEQ ID NO: 138), NQLNLRLGQGPLF (SEQ ID NO: 139), GQGPLFI (SEQ ID NO: 140), QLNLRLGQGPLFI (SEQ ID NO: 141), SYPFDAQNQLNLR (SEQ ID NO: 142), YPFDAQNQLNLRL (SEQ ID NO: 143), LRLGQGPLFI (SEQ ID NO: 144), NQLNLRL (SEQ ID NO: 145), FDAQNQLNLR (SEQ ID NO: 146), QNQLNLR (SEQ ID NO: 147), QGPL FIN (SEQ ID NO: 148), PFDAQNQLNLRLG (SEQ ID NO: 149), DAQNQLNLRL (SEQ ID NO: 150), RLGQGPLFIN (SEQ ID NO: 151), QLNLRLG (SEQ ID NO: 152), FDAQNQLNLRLGQ (SEQ ID NO: 153), LNLRLGQGPLFIN (SEQ ID NO: 154), AQNQLNLRLG (SEQ ID NO: 155), AQNQLNL (SEQ ID NO: 156), LNLRLGQ (SEQ ID NO: 157), SYPFDAQNQL (SEQ ID NO: 158), PFDAQNQLNL (SEQ ID NO: 159), YSMSFSW (SEQ ID NO: 160),TPSAYSMSFSWDW (SEQ ID NO: 161), MSFSWDW (SEQ ID NO: 162), PSAYSMSFSW (SEQ ID NO: 163), DTTPSAYSMSFSW (SEQ ID NO: 164), TTPSAYSMSF (SEQ ID NO: 165), YSMSFSWDWS (SEQ ID NO: 166), TGDTTPSAYSMSF (SEQ ID NO: 167), FSWDWSGHNY (SEQ ID NO: 168), SFSWDWS (SEQ ID NO: 169), SAYSMSF (SEQ ID NO: 170), SFSWDWSGHN (SEQ ID NO: 171), SAYSMSFSWD (SEQ ID NO: 172), SMSFSWD (SEQ ID NO: 173), SWDWSGHNYI (SEQ ID NO: 174), AYSMSFS (SEQ ID NO: 175), SMSFSWDWSGHNY (SEQ ID NO: 176), FSWDWSG (SEQ ID NO: 177), SWDWSGH (SEQ ID NO: 178), FLDPEYWNFR (SEQ ID NO: 179), SFLDPEYWNF (SEQ ID NO: 180), PEYWNFR (SEQ ID NO: 181), LNNSFLDPEYWNF (SEQ ID NO: 182), NNSFLDPEYWNFR (SEQ ID NO: 183), FLDPEYW (SEQ ID NO: 184), DPEYWNF (SEQ ID NO: 185), NNSFLDP EYW (SEQ ID NO: 186), VLLNNSFLDPEYW (SEQ ID NO: 187), EYWNFRN (SEQ ID NO: 188), LNNSFLDPEY (SEQ ID NO: 189), LDPEYWNFRN (SEQ ID NO: 190), LNNSFLD (SEQ ID NO: 191), NSFLDPEYWN (SEQ ID NO: 192), SSYTFSY (SEQ ID NO: 193), FATSSYTFSY (SEQ ID NO: 194), YINEIFATSSYTF (SEQ ID NO: 195), SYTFSYI (SEQ ID NO: 196), ATSSYTF (SEQ ID NO: 197), EIFATSSYTF (SEQ ID NO: 198), NEIF ATSSYTFSY (SEQ ID NO: 199), ATSSYTFSYI (SEQ ID NO: 200), HNYINEIFATSSY (SEQ ID NO: 201), IFATSSY (SEQ ID NO: 202), INEIFATSSY (SEQ ID NO: 203), NYINEIFATSSYT (SEQ ID NO: 204), YINEIFA (SEQ ID NO: 205), YTFSYIA (SEQ ID NO: 206), EIFATSSYTFSYI (SEQ ID NO: 207), ALEINLEEEDDDN (SEQ ID NO: 208), ATALEINLEEEDD (SEQ ID NO: 209), EAATALEINLEEE (SEQ ID NO: 210),LEINLEE (SEQ ID NO:211), TALEINLEEEDDD (SEQ ID NO:212), EINLEEE (SEQ ID NO:213), ALEINLEEED (SEQ ID NO:214), LEINLEEEDD (SEQ ID NO:215), TALEINLEEE (SEQ ID NO:216), DEAATALEINLEE (SEQ ID NO:217), LEINLEEEDDDNE (SEQ ID NO:218), AATALEINLEEED (SEQ ID NO:219), EINLEEEDDD (SEQ ID NO:220), ATALEINLEE (SEQ ID NO:221), INLEEEDDDN (SEQ ID NO:222), NLEE EDDDNE (SEQ ID NO: 223), DEVDEQA (SEQ ID NO: 224), EDDDNEDEVDEQA (SEQ ID NO: 225), DDNEDEVDEQAEQ (SEQ ID NO: 226), EVDEQAE (SEQ ID NO: 227), DNEDEVDEQA (SEQ ID NO: 228), VDEQAEQ (SEQ ID NO: 229), EDEVDEQAEQQKT (SEQ ID NO: 230), EDEVDEQAEQ (SEQ ID NO: 231), DEVDEQAEQQKTH (SEQ ID NO: 232), NEDEVDEQAEQQK (SEQ ID NO: 233), DEVDEQAEQQ (SEQ ID NO: 234), EINLEEED DDNED (SEQ ID NO: 235), NLEEEDDDNEDEV (SEQ ID NO: 236), INLEEED (SEQ ID NO: 237), LEEEDDDNED (SEQ ID NO: 238), INLEEEDDDNEDE (SEQ ID NO: 239), DDDNEDEVDEQAE (SEQ ID NO: 240), LEEEDDDNEDEVD (SEQ ID NO: 241), DDNEDEVDEQ (SEQ ID NO: 242), EDDDNED (SEQ ID NO: 243), NLEEEDD (SEQ ID NO: 244), DDNEDEV (SEQ ID NO: 245), DDDNEDEVDE (SEQ ID NO: 246), DDDNEDE (SEQ ID NO: 247) ), EEEDDDNEDE (SEQ ID NO: 248), EEDDDNE (SEQ ID NO: 249), EDDDNEDEVD (SEQ ID NO: 250), EDEVDEQ (SEQ ID NO: 251), EEDDDNEDEVDEQ (SEQ ID NO: 252), EEDDDNEDEV (SEQ ID NO: 253), EEEDDDNEDEVDE (SEQ ID NO: 254), EVDEQAEQQK (SEQ ID NO: 255), DNEDEVDEQAEQQ (SEQ ID NO: 256), VDEQAEQQKT (SEQ ID NO: 257), EVDEQAEQQKTHV (SEQ ID NO: 258), VDEQAEQQKTHVF (SEQ ID NO: 259),ALEINLE (SEQ ID NO: 260), WDEATALEINLE (SEQ ID NO: 261), AATALEINLE (SEQ ID NO: 262), EWDEAATALEINL (SEQ ID NO: 263), EAATALEINL (SEQ ID NO: 264), LYSEDVDIET (SEQ ID NO: 265), LYSEDVDIETPDT (SEQ ID NO: 266), KVVLYSEDVDIET (SEQ ID NO: 267), IETPDTH (SEQ ID NO: 268), VDIETPDTHI (SEQ ID NO: 269), VLYSEDVDIE (SEQ ID NO: 270), DVDIETPDTHISY (SEQ ID NO: 271) , VVLYSEDVDIETP (SEQ ID NO: 272), SEDVDIETPDTHI (SEQ ID NO: 273), ETPDTHI (SEQ ID NO: 274), VLYSEDVDIETPD (SEQ ID NO: 275), DVDIETPDTH (SEQ ID NO: 276), DIETPDTHIS (SEQ ID NO: 277), EDVDIETPDTHIS (SEQ ID NO: 278), IETPDTHIS (SEQ ID NO: 279), YSEDVDIETPDTH (SEQ ID NO: 280), VDIETPDTHISYM (SEQ ID NO: 281), PKVVLYSEDVDIE (SEQ ID NO: 282), DIETPDT (SEQ ID NO: 283), Column number 283), DIETPDTHISYMP (SEQ ID NO: 284), EDVDIETPDT (SEQ ID NO: 285), ETPDTHISYM (SEQ ID NO: 286), IETPDTHISYMP (SEQ ID NO: 287), DRMYSFFRNF (SEQ ID NO: 288), DRMYSFF (SEQ ID NO: 289), YSFFRNF (SEQ ID NO: 290), IPESYKDRMYSFF (SEQ ID NO: 291), SYKDRMYSFF (SEQ ID NO: 292), ESYKDRMYSF (SEQ ID NO: 293), KDRMYSF (SEQ ID NO: 294), YIPESYKDRMYSF (SEQ ID NO: 295) ), PESYKDRMYSFFR (SEQ ID NO: 296), YKDRMYSFFR (SEQ ID NO: 297), TRYFSMW (SEQ ID NO: 298), GDRTRYF (SEQ ID NO: 299), DSIGDRTRYF (SEQ ID NO: 300), DSIGDRTRYFSMW (SEQ ID NO: 301), GDRTRYFSMW (SEQ ID NO: 302), DRMYSFFRNF (SEQ ID NO: 303), SYKDRMYSFFRNF (SEQ ID NO: 304), NYNIGYQGFY (SEQ ID NO: 305), ANYNIGYQGF (SEQ ID NO: 306), MLANYNIGYQGFY (SEQ ID NO: 307),A 6 amino acid fragment, preferably a 7 amino acid fragment, more preferably an 8 amino acid fragment, even more preferably a 9 amino acid fragment, selected from the group consisting of IGYQGFY (SEQ ID NO: 308), FLVQMLANYNIGY (SEQ ID NO: 309), NIGYQGF (SEQ ID NO: 310) and QMLANYNIGYQGF (SEQ ID NO: 311), Even more preferably, the compound according to any one of embodiments 1 to 30 comprises a 10 amino acid fragment, particularly the entire sequence, wherein no more than 3, preferably no more than 2, and most preferably one or more amino acids may be independently replaced by any other amino acid.

[0216] EMBODIMENT 32 P is independently selected from YLQGPIW (SEQ ID NO: 312), VYLQGPI (SEQ ID NO: 313), WQNRDVY (SEQ ID NO: 314), DVYLQGP (SEQ ID NO: 315), QNRDVYL (SEQ ID NO: 316), LQGPIWA (SEQ ID NO: 317), RDVYLQG (SEQ ID NO: 318), NRDVYLQ (SEQ ID NO: 319), YFGYSTPWGYFDF (SEQ ID NO: 320), FGYSTPWGYF (SEQ ID NO: 321), GYSTPWGYFD (SEQ ID NO: 322), YSTPWGYFDF (SEQ ID NO: 323), NTYFGYSTPWGYF (SEQ ID NO: 324), ), TPWGYFDFNRFHC (SEQ ID NO: 325), TYFGYSTPWGYFD (SEQ ID NO: 326), DNTYFGYSTPWGY (SEQ ID NO: 327), YFGYSTPWGY (SEQ ID NO: 328), FGYSTPWGYFDFN (SEQ ID NO: 329), NWLPGPC (SEQ ID NO: 330), WLPGPCY (SEQ ID NO: 331), QAKNWLPGPC (SEQ ID NO: 332), AKNWLPGPCY (SEQ ID NO: 333), MANQAKNWLPGPC (SEQ ID NO: 334), QGCLPPF (SEQ ID NO: 335), GCLPPFP (SEQ ID NO: 336), VLGSA HQGCLPPF (SEQ ID NO: 337), LPYVLGSAHQGCL (SEQ ID NO: 338), YVLGSAHQGC (SEQ ID NO: 339), CLPPFPA (SEQ ID NO: 340), SAHQGCLPPF (SEQ ID NO: 341), VLGSAHQGCL (SEQ ID NO: 342), PYVLGSAHQGCLP (SEQ ID NO: 343), GRSSFYC (SEQ ID NO: 344), AVGRSSFYCLEYF (SEQ ID NO: 345), AVGRSSFYCL (SEQ ID NO: 346), QAVGRSSFYCLEY (SEQ ID NO: 347), NGSQAVGRSSFYC (SEQ ID NO: 348), DQY a 6 amino acid fragment, preferably a 7 amino acid fragment, more preferably an 8 amino acid fragment, even more preferably a 9 amino acid fragment, even more preferably a 10 amino acid fragment, particularly the entire sequence, selected from the group consisting of LYYL (SEQ ID NO: 349), PLIDQYLYYL (SEQ ID NO: 350), IDQYLYY (SEQ ID NO: 351), FFPSNGILIF (SEQ ID NO: 352), EERFFPSNGILIF (SEQ ID NO: 353), VGSSSGNWHC (SEQ ID NO: 354), and ADGVGSSSGNWHC (SEQ ID NO: 355), wherein no more than 3, preferably no more than 2,Most preferably, one or more amino acids may be independently replaced by any other amino acid; or P each independently comprises a 6 amino acid fragment, preferably a 7 amino acid fragment, more preferably an 8 amino acid fragment, even more preferably a 9 amino acid fragment, even more preferably a 10 amino acid fragment, alternatively an 11 amino acid fragment, or even alternatively a 12 amino acid fragment, particularly a 13 amino acid fragment selected from the group of sequences consisting of SEQ ID NOs: 383 to 1891 (see Table 1), preferably Group III of Table 1, more preferably Group II of Table 1, in particular Group I of Table 1, and SEQ ID NOs: 1892 to 2063 (see Table 2), preferably Group I of Table 2, and the group of sequences of Group II or III of Table 3 (in particular SEQ ID NOs: 2064 to 2103), more preferably Group I of Table 3, wherein up to 3, preferably up to 2, most preferably one or more amino acids may be independently replaced by any other amino acid; or The compound according to any one of embodiments 1 to 30, wherein P each independently comprises a 6 amino acid fragment, preferably a 7 amino acid fragment, more preferably an 8 amino acid fragment, even more preferably a 9 amino acid fragment, even more preferably a 10 amino acid fragment, or alternatively an 11 amino acid fragment, or even alternatively a 12 amino acid fragment, in particular a 13 amino acid fragment selected from the group of sequences consisting of the group of sequences in Table 4, in particular the group of sequences identified by SEQ ID NOs: 2104 to 2190, or the group of sequences in Table 5, wherein up to 3, preferably up to 2, most preferably one or more amino acids may be independently replaced by any other amino acid.

[0217] EMBODIMENT 33 The compound according to any one of embodiments 1 to 32, wherein P each independently consists of a 6 amino acid fragment, preferably a 7 amino acid fragment, more preferably an 8 amino acid fragment, even more preferably a 9 amino acid fragment, even more preferably a 10 amino acid fragment, in particular the entire sequence selected from the group consisting of the sequences as set forth in embodiment 31 or the group consisting of the sequences as set forth in embodiment 32, wherein no more than 3, preferably no more than 2, most preferably one or more amino acids are independently replaced by any other amino acid, optionally having an N-terminal and / or C-terminal cysteine ​​residue.

[0218] EMBODIMENT 34 The compound of any one of embodiments 1 to 33, wherein each peptide n-mer is covalently attached to said biopolymer scaffold, preferably via a respective linker.

[0219] EMBODIMENT 35 The compound of any one of embodiments 1 to 34, wherein at least one of said linkers is selected from a disulfide bridge and a PEG molecule.

[0220] EMBODIMENT 36 The compound of any one of embodiments 1 to 35, wherein at least one of the spacers S is selected from a PEG molecule and a glycan.

[0221] EMBODIMENT 37 P a but comprising a 6 amino acid fragment, preferably a 7 amino acid fragment, more preferably an 8 amino acid fragment, even more preferably a 9 amino acid fragment, even more preferably a 10 amino acid fragment, in particular the entire sequence selected from the group consisting of the sequences as set forth in embodiment 31, wherein no more than 3, preferably no more than 2, most preferably one or more amino acids may be independently replaced by any other amino acid.

[0222] EMBODIMENT 38 P bbut comprising a 6 amino acid fragment, preferably a 7 amino acid fragment, more preferably an 8 amino acid fragment, even more preferably a 9 amino acid fragment, even more preferably a 10 amino acid fragment, in particular the entire sequence selected from the group consisting of the sequences as set forth in embodiment 31, wherein no more than 3, preferably no more than 2, most preferably one or more amino acids may be independently replaced by any other amino acid.

[0223] EMBODIMENT 39 P a but comprising a 6 amino acid fragment, preferably a 7 amino acid fragment, more preferably an 8 amino acid fragment, even more preferably a 9 amino acid fragment, even more preferably a 10 amino acid fragment, in particular the entire sequence selected from the group consisting of the sequences as set forth in embodiment 31, wherein no more than 3, preferably no more than 2, most preferably one or more amino acids may be independently replaced by any other amino acid.

[0224] EMBODIMENT 40 P b but comprising a 6 amino acid fragment, preferably a 7 amino acid fragment, more preferably an 8 amino acid fragment, even more preferably a 9 amino acid fragment, even more preferably a 10 amino acid fragment, in particular the entire sequence selected from the group consisting of the sequences as set forth in embodiment 32, wherein no more than 3, preferably no more than 2, most preferably one or more amino acids may be independently replaced by any other amino acid.

[0225] EMBODIMENT 41 The first peptide n-mer is P a -SP b and said second peptide n-mer is P a -SP b The compound of any one of embodiments 6 to 40, wherein

[0226] EMBODIMENT 42 The peptide P a and the peptide P b The compound of any one of embodiments 6 to 40, wherein said 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.

[0227] EMBODIMENT 43 P a but consisting of a 6 amino acid fragment, preferably a 7 amino acid fragment, more preferably an 8 amino acid fragment, even more preferably a 9 amino acid fragment, even more preferably a 10 amino acid fragment, in particular the entire sequence selected from the group consisting of the sequences as set forth in embodiment 31, wherein no more than 3, preferably no more than 2, most preferably one or more amino acids are independently replaced by any other amino acid, optionally having an N-terminal and / or C-terminal cysteine ​​residue.

[0228] EMBODIMENT 44 P b but consisting of a 6 amino acid fragment, preferably a 7 amino acid fragment, more preferably an 8 amino acid fragment, even more preferably a 9 amino acid fragment, even more preferably a 10 amino acid fragment, in particular the entire sequence selected from the group consisting of the sequences as set forth in embodiment 31, wherein no more than 3, preferably no more than 2, most preferably one or more amino acids are independently replaced by any other amino acid, optionally having an N-terminal and / or C-terminal cysteine ​​residue.

[0229] EMBODIMENT 45 P abut consisting of a 6 amino acid fragment, preferably a 7 amino acid fragment, more preferably an 8 amino acid fragment, even more preferably a 9 amino acid fragment, even more preferably a 10 amino acid fragment, in particular the entire sequence selected from the group consisting of the sequences as set forth in embodiment 32, wherein no more than 3, preferably no more than 2, most preferably one or more amino acids are independently replaced by any other amino acid, optionally having an N-terminal and / or C-terminal cysteine ​​residue.

[0230] EMBODIMENT 46 P b but consisting of a 6 amino acid fragment, preferably a 7 amino acid fragment, more preferably an 8 amino acid fragment, even more preferably a 9 amino acid fragment, even more preferably a 10 amino acid fragment, in particular the entire sequence selected from the group consisting of the sequences as set forth in embodiment 32, wherein no more than 3, preferably no more than 2, most preferably one or more amino acids are independently replaced by any other amino acid, optionally having an N-terminal and / or C-terminal cysteine ​​residue.

[0231] EMBODIMENT 47 The first peptide n-mer is P a -SP b and said second peptide n-mer is P a -SP b The compound of any one of embodiments 1 to 46, wherein

[0232] EMBODIMENT 48 The peptide P a and the peptide P b The compound of any one of embodiments 1 to 47, wherein said 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.

[0233] EMBODIMENT 49 The compound according to any one of embodiments 1 to 48, wherein the oncolytic virus is non-pathogenic (in the individual being treated).

[0234] EMBODIMENT 50 The compound according to any one of the preceding embodiments, wherein the biopolymer scaffold is an anti-CD163 antibody (i.e., an antibody specific for the CD163 protein) or a CD163-binding fragment thereof.

[0235] EMBODIMENT 51 The compound described in embodiment 50, wherein the anti-CD163 antibody or its CD163-binding fragment is specific for human CD163 and / or for the extracellular region of CD163, preferably the SRCR domain of CD163, more preferably any one of SRCR domains 1 to 9 of CD163, even more preferably any one of SRCR domains 1 to 3 of CD163, in particular SRCR domain 1 of CD163.

[0236] EMBODIMENT 52 The compound of embodiment 50 or embodiment 51, wherein the anti-CD163 antibody or CD163-binding fragment thereof is specific for one of the following peptides: A peptide consisting of 7 to 25, preferably 8 to 20, even more preferably 9 to 15, particularly 10 to 13 amino acids, said peptide comprising the amino acid sequence CSGRVEVKVQEEWGTVCNNGWSMEA (SEQ ID NO: 3) or a 7 to 24 amino acid fragment thereof; A peptide consisting of 7 to 25, preferably 8 to 20, even more preferably 9 to 15, particularly 10 to 13 amino acids, said peptide comprising the amino acid sequence DHVSCRGNESALWDCKHDGWG (SEQ ID NO: 13) or a 7 to 20 amino acid fragment thereof; or A peptide consisting of 7 to 25, preferably 8 to 20, even more preferably 9 to 15, particularly 10 to 13 amino acids, said peptide comprising the amino acid sequence SSLGGTDKELRLVDGENKCS (SEQ ID NO: 24) or a 7 to 19 amino acid fragment thereof.

[0237] EMBODIMENT 53 The compound of embodiment 50 or embodiment 51, wherein the anti-CD163 antibody or CD163-binding fragment thereof is specific for a peptide comprising the amino acid sequence ESALW (SEQ ID NO: 14) or ALW.

[0238] EMBODIMENT 54 The compound of embodiment 50 or embodiment 51, wherein the anti-CD163 antibody or CD163-binding fragment thereof is specific for a peptide comprising the amino acid sequence GRVEVKVQEEW (SEQ ID NO: 4), WGTVCNNGWS (SEQ ID NO: 5) or WGTVCNNGW (SEQ ID NO: 6).

[0239] EMBODIMENT 55 The compound of embodiment 50 or embodiment 51, wherein the anti-CD163 antibody or CD163-binding fragment thereof is specific for a peptide comprising the amino acid sequence SSLGGTDKELR (SEQ ID NO: 25) or SSLGG (SEQ ID NO: 26).

[0240] EMBODIMENT 56 The compound of any one of embodiments 1 to 55, wherein the oncolytic virus is AAV1, AAV2, AAV3, AAV5, AAV7, or AAV8.

[0241] EMBODIMENT 57 The compound of any one of embodiments 1 to 55, wherein the oncolytic virus is AAV8.

[0242] EMBODIMENT 58 The compound according to any one of embodiments 1 to 55, wherein the oncolytic virus is Ad5.

[0243] EMBODIMENT 59 The compound of any one of embodiments 58, wherein the oncolytic virus is AdHu5.

[0244] EMBODIMENT 60 The compound according to any one of the preceding embodiments, wherein the oncolytic virus is a mammalian, particularly human, specific oncolytic virus.

[0245] EMBODIMENT 61 The compound of any one of embodiments 1 to 60, wherein the biopolymer scaffold is selected from human immunoglobulins and human transferrin.

[0246] EMBODIMENT 62 The compound of any one of embodiments 1 to 61, wherein the biopolymer scaffold is human transferrin.

[0247] EMBODIMENT 63 The compound of any one of embodiments 49 to 62, wherein at least one of said at least two peptides is cyclized.

[0248] EMBODIMENT 64 The compound of any one of embodiments 1 to 63, wherein the compound is non-immunogenic in humans.

[0249] EMBODIMENT 65 A pharmaceutical composition comprising a compound according to any one of embodiments 1 to 64 and at least one pharma- ceutically acceptable formulation excipient.

[0250] EMBODIMENT 66 The pharmaceutical composition of embodiment 65, wherein the composition is prepared for intraperitoneal, subcutaneous, intramuscular, and / or intravenous administration and / or the composition is for repeated administration.

[0251] EMBODIMENT 67 67. The pharmaceutical composition of any one of embodiments 1 to 66, wherein the molar ratio of peptide P to biopolymer scaffold in said composition is from 2:1 to 100:1, preferably from 3:1 to 90:1, more preferably from 4:1 to 80:1, even more preferably from 5:1 to 70:1, even more preferably from 6:1 to 60:1, in particular from 7:1 to 50:1, and even more preferably from 8:10 to 40:1.

[0252] EMBODIMENT 68 In the composition, the peptide P a The pharmaceutical composition of 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, in particular 7:1 to 50:1, and even more preferably 8:10 to 40:1.

[0253] EMBODIMENT 69 In the composition, the peptide P b The pharmaceutical composition of 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, in particular 7:1 to 50:1, and even more preferably 8:10 to 40:1.

[0254] EMBODIMENT 70 The pharmaceutical composition of any one of embodiments 65 to 69 for use in therapy, preferably for use in the treatment of a neoplasm, such as a benign, intraepithelial or malignant neoplasm, in particular for use in the treatment of a solid tumor or a hematological malignancy.

[0255] EMBODIMENT 71 A pharmaceutical composition for use according to embodiment 70 for use in increasing the efficacy of an oncolytic virus or oncolytic VLP in an individual, wherein preferably said pharmaceutical composition is administered to said individual before (systemic or local, preferably systemic) administration of said oncolytic virus or oncolytic VLP (based on oncolytic virus) or simultaneously with (systemic or local, preferably systemic) administration of said oncolytic virus or oncolytic VLP (based on oncolytic virus). Alternatively or additionally, the titer of antibodies specific for said oncolytic virus or oncolytic VLP (and preferably also for said compound) is preferably determined after administration of said pharmaceutical composition and before (systemic or local, preferably systemic) administration of said virus or VLP, in particular said virus or VLP is administered only if the titer is below a threshold value.

[0256] EMBODIMENT 72 The pharmaceutical composition for use according to embodiment 70 or embodiment 71, wherein administration of the pharmaceutical composition is followed by administration (systemic or local, in particular systemic) of an oncolytic virus or oncolytic VLP (based on an oncolytic virus) within 96 hours, preferably within 72 hours or even within 60 hours, more preferably within 48 hours, even more preferably within 36 hours, even more preferably within 24 hours and in particular within 12 hours; preferably administration (systemic or local, in particular systemic) of an oncolytic virus or oncolytic VLP is performed 6 hours or more, preferably 12 hours or more and more preferably 24 hours or more after administration of the pharmaceutical composition.

[0257] EMBODIMENT 73 A pharmaceutical composition for use according to embodiment 70 for use in increasing the efficacy of an oncolytic virus or oncolytic VLP (based on an oncolytic virus) in an individual, preferably wherein said pharmaceutical composition is administered to an individual prior to (systemic or local, preferably systemic) administration of said oncolytic virus or oncolytic VLP (based on an oncolytic virus) or simultaneously with (systemic or local, preferably systemic) administration of said oncolytic virus or oncolytic VLP (based on an oncolytic virus).

[0258] EMBODIMENT 74 The pharmaceutical composition for use according to embodiment 73, wherein the pharmaceutical composition is administered at least twice within a 96 hour window, preferably within a 72 hour window, more preferably within a 48 hour window, even more preferably within a 36 hour window, even more preferably within a 24 hour window, particularly within an 18 hour window or alternatively within a 12 hour window; preferably, the oncolytic virus or oncolytic VLP (based on an oncolytic virus) is administered (systemically or locally, preferably systemically) within a 96 hour window, preferably within a 72 hour window, more preferably within a 48 hour window, even more preferably within a 36 hour window, even more preferably within a 24 hour window, particularly within 12 hours thereafter.

[0259] EMBODIMENT 75 The pharmaceutical composition for use according to any one of embodiments 71 to 74, wherein the individual is a human.

[0260] EMBODIMENT 76 The one or more antibodies present in the individual are capable of binding to at least one peptide P or peptide P a and / or peptide P b The pharmaceutical composition for use according to any one of embodiments 70 to 75, wherein the antibody is specific for said oncolytic virus, and said antibody is preferably a neutralizing antibody against said oncolytic virus.

[0261] EMBODIMENT 77 The pharmaceutical composition for use according to any one of embodiments 70 to 76, wherein said composition is non-immunogenic in said individual.

[0262] EMBODIMENT 78 The pharmaceutical composition for use according to any one of embodiments 70 to 77, wherein the composition is administered at 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 preferably 5 to 50 mg of compound per kg of body weight of the individual.

[0263] EMBODIMENT 79 The pharmaceutical composition for use according to any one of embodiments 70 to 78, wherein the composition is administered intraperitoneally, subcutaneously, intramuscularly, or intravenously.

[0264] EMBODIMENT 80 1. A method for (temporarily) sequestering (or depleting) one or more antibodies present in an individual, comprising the steps of: Obtaining a pharmaceutical composition as defined in any one of embodiments 65 to 69, and administering said pharmaceutical composition to said individual. Including, the composition is non-immunogenic in the individual, and the one or more antibodies present in the individual are directed against at least one P or a peptide P a and / or peptide P b Specific for method.

[0265] Embodiment 81 The method of embodiment 80, wherein said individual is a human or a non-human animal, preferably a non-human primate, sheep, pig, dog, or rodent, in particular a mouse.

[0266] EMBODIMENT 82 The method of embodiment 80 or embodiment 81, wherein said biopolymer scaffold is autologous to said individual, preferably said biopolymer scaffold is autologous protein.

[0267] EMBODIMENT 83 The method of any one of embodiments 80 to 82, wherein the individual is administered (systemically or locally, preferably systemically) an anti-neoplastic composition comprising an oncolytic virus prior to, simultaneously with, and / or following said administration of the pharmaceutical composition.

[0268] EMBODIMENT 84 The method of any one of embodiments 80 to 83, wherein the individual is a non-human animal.

[0269] EMBODIMENT 85 The method of any one of embodiments 80 to 82, wherein the individual is administered (systemically or locally, preferably systemically) an anti-neoplastic composition comprising an oncolytic virus, and wherein the one or more antibodies present in the individual are specific for the oncolytic virus, and preferably the administration of the anti-neoplastic composition occurs prior to, simultaneously with, and / or subsequent to the administration of the pharmaceutical composition.

[0270] 86. 86. The method of embodiment 85, wherein the oncolytic virus comprises genetic material that is preferably a recombinant and / or transgenic oncolytic payload.

[0271] EMBODIMENT 87 The compound, composition or method of any one of embodiments 1 to 86, wherein said (human) individual has a neoplasm which is preferably an intraepithelial or malignant neoplasm, in particular a solid tumor or a hematological malignancy, preferably wherein said neoplasm is a benign, intraepithelial or malignant neoplasm, in particular a solid tumor or a hematological malignancy; in particular the individual has a solid tumor, preferably selected from the group of brain tumor, breast cancer, colon cancer, esophageal cancer, prostate cancer, bladder cancer, kidney cancer, endometrial cancer, thyroid cancer, gastric cancer, liver cancer, lung cancer, pancreatic cancer, uterine cancer, tracheal cancer, testicular cancer, cervical cancer, head and neck cancer, skin cancer, bone cancer, pancreatic cancer and ovarian cancer, or a hematological malignancy, preferably selected from the group of leukemia, lymphoma, and multiple myeloma.

[0272] EMBODIMENT 88 The method of any one of embodiments 80 to 87, wherein the composition is administered intraperitoneally, subcutaneously, intramuscularly, or intravenously.

[0273] EMBODIMENT 89 65. A pharmaceutical composition comprising a compound according to any one of embodiments 1 to 64, further comprising an oncolytic virus (typically said oncolytic virus comprises genetic material) or an oncolytic VLP (based on an oncolytic virus), optionally with at least one pharma- ceutical acceptable formulation additive; Preferably, the oncolytic virus comprises a peptide fragment having a sequence length of 6 to 13 amino acids, preferably 7 to 11 amino acids, more preferably 7 to 9 amino acids; At least one peptide P of said compound, or peptide P a and / or peptide P b 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, in particular completely identical, to the sequence of said peptide fragment. Anti-neoplastic composition.

[0274] EMBODIMENT 90 The anti-neoplastic composition of embodiment 89, wherein said oncolytic virus is AdV, AAV, measles virus, herpes simplex virus (HSV), poxvirus such as vaccinia virus, reovirus, Newcastle disease virus (NVD), rhabdovirus, coxsackievirus, lentivirus, alphavirus such as Semliki Forest virus, vesicular stomatitis virus (VSS), myxoma virus (MYXV), mengovirus, bovine viral diarrhea virus (BVDV), chimeric oncolytic virus, picornavirus, parvovirus, or flavivirus, or oncolytic VLPs thereof.

[0275] EMBODIMENT 91 The anti-neoplastic composition of embodiment 89 or embodiment 90, wherein the oncolytic virus is AdV, AAV, measles virus, or an oncolytic VLP thereof.

[0276] EMBODIMENT 92 The anti-neoplastic composition of any one of embodiments 89 to 90, wherein the composition is prepared for intravenous administration.

[0277] EMBODIMENT 93 The pharmaceutical composition of any one of embodiments 89 to 92, wherein the composition is an aqueous solution.

[0278] EMBODIMENT 94 The pharmaceutical composition of any one of embodiments 89 to 93, for use in inhibiting an immune response, preferably an antibody-mediated immune response, against said active agent.

[0279] EMBODIMENT 95 The pharmaceutical composition of embodiment 94, wherein the composition is non-immunogenic in the individual.

[0280] EMBODIMENT 96 1. A method for inhibiting a (humoral) immune response to treatment with an anti-neoplastic composition (comprising an oncolytic virus or an oncolytic VLP) in an individual in need of such treatment, comprising: Obtaining a pharmaceutical composition as defined in any one of embodiments 89 to 95, and administering said pharmaceutical composition to said individual; Including, said compound of said pharmaceutical composition is non-immunogenic in said individual; method.

[0281] EMBODIMENT 97 The method of embodiment 96, wherein the individual is a human.

[0282] EMBODIMENT 98 The method of embodiment 96 or embodiment 97, wherein the biopolymer scaffold is autologous to the individual, preferably wherein the biopolymer scaffold is an autologous protein.

[0283] EMBODIMENT 99 The method of any one of embodiments 96 to 98, wherein the composition is administered intraperitoneally, subcutaneously, intramuscularly, or intravenously.

[0284] EMBODIMENT 100 A peptide having a sequence length of 6 to 50 amino acids, preferably 6 to 25 amino acids, more preferably 6 to 20 amino acids, and even more preferably 6 to 13 amino acids, Group of AdV sequences ETGPPTVPFLTPPF (SEQ ID NO: 32), HDSKLSIATQGPL (SEQ ID NO: 33), LNLRLGQGPLFINSAHNLDINY (SEQ ID NO: 34), VDPMDEPTLLYVLFEVFDVV (SEQ ID NO: 35), MKRARPSEDTFNPVYPYD (SEQ ID NO: 36), ISGTVQSAHLIIRFD (SEQ ID NO: 37), LGQGPLFINSAHNLDINYNKGLYLF (SEQ ID NO: 38), SYPFDAQNQLNLRLGQGPLFIN (SEQ ID NO: 39), GDTTPSAYSMSFSWDWSGHNYIN (SEQ ID NO: 40), VLLNNSFLDPEYWNFRN (SEQ ID NO: 41), HNYINEIFATSSYTFSYIA (SEQ ID NO: 42), DEAATALEINLEEEDDDNEDEVDEQAEQQKTH (SEQ ID NO: 43), INLEEDDDNEDEVDEQAEQ (SEQ ID NO: 44), DNEDEVDEQAEQQKTHVF (SEQ ID NO: 45), EWDEAATALEINLEE (SEQ ID NO: 46), PKVVLYSEDVDIETPDTHISYMP (SEQ ID NO: 47), YIPESYKDRMYSFFRNF (SEQ ID NO: 48), DSIGDRTRYFSMW (SEQ ID NO: 49), SYKDRMYSFFRNF (SEQ ID NO: 50), and FLVQMLANYNIGYQGFY (SEQ ID NO: 51), AAV sequence group: WQNRDVYLQGPIWAKIP (SEQ ID NO: 52), DNTYFGYSTPWGYFDFNRFHC (SEQ ID NO: 53), MANQAKNWLPGPCY (SEQ ID NO: 54), LPYVLGSAHQGCLPPFP (SEQ ID NO: 55), NGSQAVGRSSFYCLEYF (SEQ ID NO: 56), PLIDQYLYYL (SEQ ID NO: 57), EERFFPSNGILIF (SEQ ID NO: 58), ADGVGSSSGNWHC (SEQ ID NO: 59), SEQ ID NOs: 383 to 1891 (see Table 1), preferably Group III in Table 1, more preferably Group II in Table 1, particularly preferably Group I in Table 1; SEQ ID NOs: 1892 to 2063 (see Table 2), preferably Group I in Table 2; A sequence of Group II or Group III of Table 3 (see in particular SEQ ID NOs: 2064 to 2103), more preferably a sequence of Group I of Table 3, The group of sequences in Table 4, in particular the group of sequences identified in SEQ ID NOs: 2104 to 2190, or Group of sequences in Table 5 A sequence of at least 4 or at least 5 or at least 6, preferably at least 7, more preferably at least 8, even more preferably at least 9, and even more preferably at least 10 consecutive amino acids selected from and a sequence up to 3, preferably up to 2, and most preferably 1 or more amino acids of said sequence may be independently replaced by any other amino acid; Preferably, the peptide is a peptide as defined in embodiment 31, embodiment 32 or embodiment 33.

[0285] EMBODIMENT 101 - contacting said sample with the peptide of embodiment 100 or the compound of any one of embodiments 1 to 64, and - detecting the presence and / or concentration of antibodies in said sample A method for detecting and / or quantifying oncolytic virus antibodies in a biological sample, comprising:

[0286] EMBODIMENT 102 The method of embodiment 101, wherein the peptide or compound is fixed to a solid support, in particular a biosensor-based diagnostic device comprising an electrochemical, fluorescent, magnetic, electronic, gravimetric or optical biotransducer, and / or the peptide or compound is bound to a reporter or reporter fragment, such as a reporter fragment suitable for PCA. EMBODIMENT 103 The method of embodiment 101 or embodiment 102, wherein the method is a sandwich assay, preferably an enzyme-linked immunosorbent assay (ELISA). EMBODIMENT 104 The method according to any one of embodiments 101 to 103, wherein the sample is obtained from a mammal, preferably a human, and wherein preferably the mammal (human) has a neoplasm, and wherein more preferably the neoplasm is a benign, intraepithelial or malignant neoplasm, and even more preferably a solid tumor or a hematological malignancy, and in particular the mammal has a solid tumor selected from the group of brain cancer, breast cancer, colon cancer, esophageal cancer, prostate cancer, bladder cancer, kidney cancer, endometrial cancer, thyroid cancer, gastric cancer, liver cancer, lung cancer, pancreatic cancer, uterine cancer, tracheal cancer, testicular cancer, cervical cancer, head and neck cancer, skin cancer, bone cancer, pancreatic cancer and ovarian cancer, or a hematological malignancy, preferably selected from the group of leukemia, lymphoma and multiple myeloma, and in particular the mammal (human) has been selected to be treated with an oncolytic virus or oncolytic VLP or has been treated with an oncolytic virus or oncolytic VLP. EMBODIMENT 105 The method of any one of embodiments 101 to 104, wherein the sample is a blood sample, preferably a whole blood, serum, or plasma sample. EMBODIMENT 106 Use of the peptide of embodiment 100 or the compound of any one of embodiments 1 to 64, preferably for a method as defined in any one of embodiments 101 to 105, in an enzyme-linked immunosorbent assay (ELISA). EMBODIMENT 107 A diagnostic device comprising the peptide of embodiment 100 or the compound of any one of embodiments 1 to 64, wherein the peptide or compound is immobilized on a solid support and / or the peptide or compound is bound to a reporter or a reporter fragment, such as a reporter fragment suitable for PCA. EMBODIMENT 108 The diagnostic device of embodiment 107, wherein said solid support is an ELISA plate or a surface plasmon resonance chip. EMBODIMENT 109 The diagnostic device of embodiment 107, wherein said diagnostic device is a lateral flow assay device or a biosensor-based diagnostic device comprising an electrochemical, fluorescent, magnetic, electronic, gravimetric or optical biotransducer. Embodiment 110 A diagnostic kit comprising the peptide of embodiment 100 or the compound of any one of embodiments 1 to 64, preferably comprising a diagnostic device of any one of embodiments 107 to 109, and preferably one or more selected from the group consisting of buffers, reagents, and instructions. EMBODIMENT 111 100. An apheresis device comprising the peptide of embodiment 100, preferably immobilized on a solid support. EMBODIMENT 112 The apheresis device of embodiment 111, wherein the solid support is capable of contacting the blood or plasma stream. EMBODIMENT 113 The apheresis device of embodiment 111 or embodiment 112, wherein the solid support comprises a compound according to any one of embodiments 1 to 64. EMBODIMENT 114 The apheresis device of any one of embodiments 111 to 113, wherein the solid support is a column that is sterile and pyrogen-free. EMBODIMENT 115 The apheresis device according to any one of embodiments 111 to 114, wherein the apheresis device comprises at least two, preferably at least three, more preferably at least four different peptides according to embodiment 100.

[0287] The present invention is further illustrated by the following figures and examples, without however being limited thereto. EXAMPLES

[0288] Example 1: Temporary selective reduction of pre-existing antibody titers SADCs with a transferrin biopolymer scaffold conjugated to a model peptide (PAVIMGNWENHWI; SEQ ID NO: 2226) were used to test the antibody reducing effect in a mouse model (actively immunized using the peptide PAVIMGNWENHWI coupled to keyhole limpet hemocyanin (KLH) as the immunogen). Figure 2 shows the binding signal intensity (arbitrary units) for the peptide PAVIMGNWENHWI when specific IgG levels were detected by peptide array. A rapid drop in titer was observed 24 and 48 hours after intravenous SADC administration. Titer recovery begins 48 hours after SADC administration. In conclusion, the antibody reducing effect of SADC is transient in organisms with pre-existing immunity.

[0289] As explained above, antibodies against oncolytic viruses support their beneficial effects on cancer cells. However, these antibodies can simultaneously inhibit the delivery of oncolytic viruses, thereby reducing target access and therapeutic efficacy. Therefore, in light of what was observed in this example, it is particularly beneficial to administer oncolytic viruses to cancer patients in a time frame from about 12 hours after SADC administration to about 60 hours after SADC administration (particularly in larger mammals such as humans, this time frame can be extended, for example, to 96 hours after SADC administration). Typically, the titer of nAb against oncolytic viruses (or VLPs) is determined before administering oncolytic viruses (or VLPs), and oncolytic viruses (or VLPs) are administered only if the titer is below a certain threshold (e.g., less than 50%, or less than 60%, or less than 70% of the original titer). If not, administration of SADC can be repeated to further reduce the titer.

[0290] A schematic diagram of the oncolytic regimen of the present invention is also shown in FIG.

[0291] Example 2: Generation of Mimotope-Based SADCs The mAb is a murine IgG2a mAb directed against the adenovirus fiber epitope peptide (NCBI reference sequence: AP000226.1), which represents the prototype neutralizing antibody generated from UV-irradiated Ad2 virus (Kraynkh et al., 1998). Linear and circular peptides derived from wild-type or modified peptide amino acid sequences can be used to construct specific SADCs for selectively eliminating neutralizing antibodies against antiviral vectors. For certain epitopes, SADCs can be constructed using linear or constrained peptides, such as cyclopeptides, that contain parts of the epitope or its variants, e.g., peptides in which one or several amino acids have been replaced or chemically modified to improve affinity to antibodies (mimotopes). Peptide screening can be performed to identify peptides with optimized affinity to neutralizing antibodies. The flexibility of structural or chemical peptide modifications provides a solution to minimize the risk of immunogenicity, especially the risk of binding of the peptide to HLA and therefore the risk of undesired immune stimulation.

[0292] Thus, wild-type and modified linear and circular peptide sequences are obtained from epitopes of viral capsid proteins disclosed herein, for example the epitope sequence LNLRLGQGPLFINSAHNLDINY (SEQ ID NO: 34) of mAb 4D2 found according to the invention (see further below in the Examples). Peptides of various lengths and positions are systematically permuted by amino acid substitution and synthesized on a peptide array. This allows screening of 60,000 circular and linear wild-type and mimotope peptides derived from these sequences. The peptide array is incubated with mAb 4D2. The 60,000 peptides are then screened with this antibody, and 100 circular and 100 linear peptide hits are selected based on their relative binding strength to the antibody. Of these 200 peptides, 51 sequences are identical between the circular and linear peptide groups. The best peptides identified all have at least one amino acid substitution each when aligned to the original sequence and are therefore considered mimotopes, and higher binding strengths can be achieved with cyclic peptides.

[0293] These newly identified peptides with high relative binding values ​​will be preferentially used to generate SADCs to increase the efficacy of AdV-based oncolytic viruses.

[0294] Example 3: SADC temporarily reduces antibodies against measles virus For oncolytic therapy with measles virus, three SADCs are provided to reduce anti-measles virus antibodies (see also Example 15 for peptides used): (a) SADC-a having Mac2-158 (disclosed in WO 2011 / 039510(A2)) as a biopolymer scaffold and two or more peptides having the sequence SITIPYQGSG (SEQ ID NO: 2227) covalently attached to the scaffold; (b) SADC-b having human transferrin as a biopolymer scaffold and two or more peptides having the sequence PEWAPLKDNRI (SEQ ID NO: 2228) covalently attached to the scaffold; and (c) SADC-c having human albumin as a biopolymer scaffold and two or more peptides having the sequence GGHITHSGMEGMG (SEQ ID NO: 2229) covalently attached to the scaffold. These SADCs are administered intravenously to individuals with cancer who are to receive measles virus oncolytic therapy to enhance the efficiency of the oncolytic therapy, followed 24 hours after administration of the SADCs by administration of the oncolytic measles virus.

[0295] Example 4: In vivo function of anti-CD163 antibody-based SADC biopolymer scaffolds Rapid in vivo blood clearance of anti-mouse CD163 mAb E10B10 (disclosed in WO 2011 / 039510(A2)). mAb E10B10 was resynthesized using a mouse IgG2a backbone. 50 μg of mAb E10B10 and Mac2-158 (a human-specific anti-CD163 mAb disclosed in WO 2011 / 039510(A2), used as a negative control in this example as it does not bind mouse CD163) were injected intravenously into mice and blood clearance was determined by ELISA after 12, 24, 36, 48, 72 and 96 hours.

[0296] For direct comparison, both E10B10 and Mac2-158 were expressed as mouse IgG2a isotypes, but because E10B10 binds mouse CD163 whereas Mac2-158 is human specific, mAb E10B10 was cleared from the circulation much more rapidly than the control mAb Mac2-158, as shown in Figure 3 .

[0297] In conclusion, anti-CD163 antibodies are highly suitable as SADC scaffolds due to their clearance profile: SADCs bearing such scaffolds rapidly clear undesired antibodies from the circulation.

[0298] Method details: 50 μg of biotinylated monoclonal antibodies E10B10 and biotinylated Mac2-158 were injected intravenously into mice and measurements were made after 12, 24, 36, 48, 72 and 96 hours to determine clearance by ELISA: Streptavidin plates were incubated with plasma samples diluted in PBS+0.1% BSA+0.1% Tween20 for 1 hour at room temperature (50 μl / well). After washing (3 times with PBS+0.1% Tween20), bound biotinylated antibodies were detected with anti-mouse IgG+IgM-HRP antibody at 1:1000 dilution. After washing, TMB substrate was added and substrate development was stopped with TMB stop solution. Signal was read at OD450nm. EC50 values ​​were calculated by nonlinear regression using 4-parameter curve fitting with constraint curve and least squares regression. The EC50 value at time point T12 (which was the first measurement time point after antibody injection) was set as 100% and all other EC50 values ​​were compared to the value at T12.

[0299] Example 5: Epitope mapping of anti-CD163 mAb mAb E10B10 provides accelerated in vivo blood clearance mediated by CD163 in mice (see Example 11). The epitope of this antibody was fine-mapped using cyclic peptide arrays, whereby the peptides were derived from mouse CD163. As a result, the peptide cluster recognized by mAb E10B10 was identified (see Example 13).

[0300] The same epitope mapping procedure using cyclized peptides was performed with mAb Mac2-158 (as disclosed in WO 2011 / 039510(A2)). Epitope mapping for mAb Mac2-158 resulted in two peptide clusters (see Example 13) that allow further differentiation of CD163 epitope regions specifically involved in ligand internalization and antibody binding to the receptor.

[0301] Thus, these newly characterized epitopes of Mac2-158 and E10B10 revealed three preferred binding regions for anti-CD163 antibodies. Based on the fine epitope mapping studies, linear or preferably cyclic peptides will be synthesized and used for the introduction, production and selection of polyclonal or monoclonal antibodies or other CD163-binding SADC scaffolds targeting CD163.

[0302] Example 6: Epitope mapping of anti-CD163 mAb Peptides aligned to SRCR domain 1 of human CD163 were selected from the top 20 peptide hits of mAb Mac2-158 cyclic epitope mapping peptides, and the most preferred sequences were selected from two peptide alignment clusters at the N-terminus and C-terminus of SRCR-1 of human CD163. As a result, the following sequences (and motifs derived therefrom) are highly suitable epitope anti-CD163 antibodies and fragments thereof to be used as SADC biopolymer scaffolds.

[0303] [ka]

[0304] [ka]

[0305] Fine epitope mapping of mAb E10B10 was performed on Mac2-158. 1068 cyclic peptides (7, 10 and 13 amino acid sizes) derived from SRCR-1 to SRCR-3 of the mouse CD163 sequence (UniProKB Q2VLH6.2) were screened with mAb E10B10 to obtain the following top binding peptides (ranked by relative signal intensity): Human CD163 sequence was aligned to this cluster of mouse CD163 sequences revealing another highly relevant epitope.

[0306] [ka]

[0307] The human homologues of mouse peptides 01-13 from cluster 3 have the following sequence of the N-terminal part of the mature human CD163 protein (UniProtKB: Q86VB7):

[0308] [ka]

[0309] These homolog peptides are further highly suitable epitopes for anti-CD163 antibody-based biopolymer scaffolds.

[0310] Example 7: Epitope mapping of mAb 4D2 against AdV mAb 4D2 is a murine IgG2a mAb targeting the adenovirus fiber epitope peptide (NCBI reference sequence: AP 000226.1). It is a prototype neutralizing antibody generated from UV-irradiated Ad2 virus (Krasnykh et al., 1998). To obtain cyclic antibody binding peptides from the viral neutralizing epitope, mAb 4D2 was mapped against aligned cyclic peptides derived from the fiber sequence. The sequence at amino acid positions 1-581 of NCBI reference sequence AP 000226.1 was used as the starting sequence to design 7-mer, 10-mer and 13-mer cyclic peptides, which were directly synthesized and cyclicized on a peptide microarray and then incubated with various concentrations of antibody. Several binding hits obtained from the binding signal of monoclonal antibody 4D2 against the peptide were then aligned against the protein sequence and subsequently clustered. The resulting clusters were called cluster 1 (length = 14 amino acids), cluster 2 (length = 13 amino acids) and cluster 3 (length = 22 amino acids). Below is an alignment of the corresponding novel peptides that can bind to the mAb 4D2 paratope. The numbers in the peptide names correspond to the ranking of the binding signal of the antibody on the microarray (i.e., peptide 01 binds the strongest, 02 the second strongest, etc.). The top candidate binding peptides selected from the top 50 binders were aligned to the corresponding protein sequence (first line).

[0311] Cluster 1 ETGPPTVPFLTPPF (SEQ ID NO:32) 08 --GPPTVPFLTP-- (SEQ ID NO:60) 10 ETGPPTVPFLTPP- (SEQ ID NO: 61) 21 -TGPPTVPFLT--- (SEQ ID NO:62) 34 ----PTVPFLTPPF (SEQ ID NO:63)

[0312] Cluster 2 HDSKLSIATQGPL (SEQ ID NO:64) 03 HDSKLSIATQGPL (SEQ ID NO:64) 11 -----SIATQGP- (SEQ ID NO:65)

[0313] Cluster 3 LNLRLGQGPLFINSAHNLDINY (SEQ ID NO:34) 02 -NLRLGQGPLF----------- (SEQ ID NO:66) 12 ------QGPLFINSAH------ (SEQ ID NO:67) 13 --------PLFINSAHNLD--- (SEQ ID NO:68) 15 ----LGQGPLF-------------- (SEQ ID NO:69) 17 LNLRLGQGPL------------ (SEQ ID NO:70) 19 -----GQGPLFI---------- (SEQ ID NO:71) 29 -NLRLGQGPLFINS-------- (SEQ ID NO:72) 32 ---------LFINSAHNLDINY (SEQ ID NO:73) 33 ----------FINSAHNLDI-- (SEQ ID NO:74) 37 --LRLGQGPLFI---------- (SEQ ID NO:75) 39 -------GPLFINSAHN----- (SEQ ID NO:76)

[0314] The above peptides / sequences are highly suitable as peptides for SADC to reduce neutralization of AdV vectors.

[0315] Example 8: Epitope mapping of monoclonal antibody 9C12 against AdV Monoclonal antibody 9C12 (also known as mAB TC31-9C12.C9-s) was generated by immunizing mice with hexon protein (Uniprot ID: P04133, corresponding to GenBank: BAG48782.1). This neutralizing antibody is directed against the hexon protein and the neutralizing activity of this antibody has been demonstrated by Varghese (Varghese et al, 2004). Briefly, diluted antibodies were incubated with a GFP-expressing replication-deficient Ad vector and then added to HeLa cells, and the fluorescence was then read. To map the region from which paratope-binding peptides could be derived, the sequence at amino acid positions 1-952 of GenBank: BAG48782.1 was then used as the starting sequence to design cyclic 7-mer, 10-mer and 13-mer peptides that were then synthesized and directly cyclized on a peptide microarray and then incubated with various concentrations of the antibody. The binding signal of mAb 9C12 to the peptides yielded several candidates that could be aligned and clustered to the protein. A 20 amino acid epitope cluster region was identified from which paratope-binding peptides could be preferentially derived. Below is an alignment of the corresponding peptide hits from this screen. The numbers in the peptide names correspond to the ranking of the antibody's binding signal from the microarray (i.e., peptide 01 is the strongest binder, 02 is the second strongest binder, etc.). Cyclic peptides were selected from the top 50 binders in this experiment.

[0316] [ka]

[0317] The above peptides / sequences are highly suitable as peptides for SADC to reduce neutralization of AdV vectors.

[0318] Example 9: Epitope mapping of polyclonal antibody ab6982 against AdV Polyclonal antibody ab6982 (Abcam) was generated by immunization of rabbits with purified AdV. This polyclonal antibody reacts with all capsid proteins of Ad5, including hexon, fiber and penton. The antibody neutralizes Ad5 infectivity in a bioassay with 1000 particles / ml of adenovirus 5, and a 1 / 25,000 dilution of the antibody is able to inactivate the adenovirus by 50%. To identify epitope regions that may contain peptides for ab6982 paratope binding, the antibody was mapped against the sequences of fiber (NCBI reference sequence: AP 000226.1) and hexon proteins (GenBank: BAG48782.1). The fiber sequence from amino acid positions 1-581 of (NCBI reference sequence: AP 000226.1) and the hexon sequence from amino acid positions 1-952 (GenBank: BAG48782.1) were used as starting sequences to design 7-mer, 10-mer and 13-mer cyclic peptides that were synthesized on a peptide array. The binding signal of this antibody on the array yielded several peptides that were aligned and clustered to the protein sequence. The peptide clusters were named clusters 1-7 (fiber proteins) and clusters 8-16 (hexon proteins) according to the rank order of the cyclic peptide hits (i.e., cluster 1 contains the strongest binders, cluster 2 contains the second strongest binders, etc.). Below is an alignment of the corresponding peptides that bind with polyclonal antibody ab6982. The peptide name numbers correspond to the antibody binding signal rank from the microarray experiment, and the clusters 1-7 and 8-16 numbers are ranked by the content of the top binding peptides, respectively.

[0319] Cluster 1 MKRARPSEDTFNPVYPYD (SEQ ID NO:36) 001 MKRARPSEDTF------- (SEQ ID NO:97) 002 -KRARPSEDTF------- (SEQ ID NO:98) 003 MKRARPSEDT-------- (SEQ ID NO:99) 005 MKRARPSEDTFN------ (SEQ ID NO: 100) 010 ---ARPSEDTFNP----- (SEQ ID NO:101) 019 --RARPSEDTFN------ (SEQ ID NO:102) 024 ----RPSEDTF------- (SEQ ID NO:103) 035 MKRARPSEDTFNP---- (SEQ ID NO:104) 040 --RARPSEDTFNPVY--- (SEQ ID NO:105) 041 ---ARPSEDT-------- (SEQ ID NO:106) 052 -------EDTFNPVYPY- (SEQ ID NO:107) 061 ----RPSEDTFNPVYPY- (SEQ ID NO:108) 129 -KRARPSEDTFNPV---- (SEQ ID NO:109) 130 --------DTFNPVY--- (SEQ ID NO:110) 150 ----RPSEDTFNPV---- (SEQ ID NO:111) 153 -----PSEDTFNPVY--- (SEQ ID NO:112) 163 --------DTFNPVYPYD (SEQ ID NO:113)

[0320] Cluster 2 ISGTVQSAHLIIRFD (SEQ ID NO:37) 004 ----VQSAHLIIRF- (SEQ ID NO:114) 006 -------AHLIIRF- (SEQ ID NO:115) 015 -SGTVQSAHLIIRF- (SEQ ID NO: 116) 056 ---TVQSAHLIIR-- (SEQ ID NO:117) 060 --------HLIIRFD (SEQ ID NO:118) 065 ------SAHLIIR-- (SEQ ID NO:119) 076----QSAHLIIRFD (SEQ ID NO:120) 085 ISGTVQSAHLIIR-- (SEQ ID NO:121) 118 --GTVQSAHLII--- (SEQ ID NO:122) 123 --GTVQSAHLIIRFD (SEQ ID NO:123) 126 -----QSAHLII--- (SEQ ID NO:124)

[0321] Cluster 3 LGQGPLFINSAHNLDINYNKGLYLF (SEQ ID NO:38) 009 ------------HNLDINY------ (SEQ ID NO:125) 011 -----LFINSAHNLDINY------- (SEQ ID NO:126) 012------------NLDINYNKGLYLF (SEQ ID NO:127) 013 -------FVSPNG------------ (SEQ ID NO:128) 016 ----------------NYINEIF-- (SEQ ID NO:129) 020 ------------------NKGLYLF (SEQ ID NO:130) 021 ---------------INYNKGLYLF (SEQ ID NO:131) 023 --------NSAHNLDINY------ (SEQ ID NO:132) 032 ------WDWSGH----NYINEIF-- (SEQ ID NO:133) 039 ---------SGH----NYINEIF-- (SEQ ID NO:134) 044 --LGTGLSF---------------- (SEQ ID NO:135) 047 PFLTPPF------------------ (SEQ ID NO:136)

[0322] Cluster 4 SYPFDAQNQLNLRLGQGPLFIN (SEQ ID NO:39) 027 -------------LGQGPLF-- (SEQ ID NO:137) 029 ----------NLRLGQGPLF-- (SEQ ID NO:138) 030 -------NQLNLRLGQGPLF-- (SEQ ID NO:139) 058 --------------GQGPLFI- (SEQ ID NO:140) 059--------QLNLRLGQGPLFI- (SEQ ID NO:141) 062 SYPFDAQNQLNLR-------- (SEQ ID NO:142) 066 -YPFDAQNQLNLRL-------- (SEQ ID NO:143) 070 -----------LRLGQGPLFI- (SEQ ID NO:144) 072 -------NQLNLRL-------- (SEQ ID NO:145) 073 ---FDAQNQLNLR--------- (SEQ ID NO:146) 082 ------QNQLNLR-------- (SEQ ID NO:147) 093 ---------------QGPLFIN (SEQ ID NO:148) 102 --PFDAQNQLNLRLG------ (SEQ ID NO:149) 112 ----DAQNQLNLRL-------- (SEQ ID NO:150) 117 ------------RLGQGPLFIN (SEQ ID NO:151) 136 --------QLNLRLG------- (SEQ ID NO:152) 147 ---FDAQNQLNLRLGQ------ (SEQ ID NO:153) 148 ---------LNLRLGQGPLFIN (SEQ ID NO:154) 169 -----AQNQLNLRLG------ (SEQ ID NO:155) 172 -----AQNQLNL---------- (SEQ ID NO:156) 173 ---------LNLRLGQ------ (SEQ ID NO:157) 178 SYPFDAQNQL------------ (SEQ ID NO:158) 197 --PFDAQNQLNL---------- (SEQ ID NO:159)

[0323] Cluster 5 GDTTPSAYSMSFSWDWSGHNYIN (SEQ ID NO:40) 008 ---------YSMSFSW------- (SEQ ID NO: 160) 014 ----TPSAYSMSFSWDW------ (SEQ ID NO:161) 022 ----------MSFSWDW------ (SEQ ID NO:162) 028 -----PSAYSMSFSW-------- (SEQ ID NO:163) 049 --DTTPSAYSMSFSW-------- (SEQ ID NO:164) 078 ---TTPSAYSMSF---------- (SEQ ID NO:165) 079 --------YSMSFSWDWS----- (SEQ ID NO:166) 091 TGDTTPSAYSMSF--------- (SEQ ID NO:167) 095 ------------FSWDWSGHNY- (SEQ ID NO: 168) 100 ----------SFSWDWS----- (SEQ ID NO: 169) 108 -----SAYSMSF---------- (SEQ ID NO:170) 134 ----------SFSWDWSGHN-- (SEQ ID NO:171) 143 -----SAYSMSFSWD------ (SEQ ID NO:172) 144 --------SMSFSWD------- (SEQ ID NO:173) 149 ------------SWDWSGHNYI (SEQ ID NO:174) 167 ------AYSMSFS-------- (SEQ ID NO:175) 176 --------SMSFSWDWSGHNY- (SEQ ID NO: 176) 186 -----------FSWDWSG---- (SEQ ID NO:177) 193 ------------SWDWSGH--- (SEQ ID NO:178)

[0324] Cluster 6 VLLNNSFLDPEYWNFRN (SEQ ID NO:41) 017 ------FLDPEYWNFR- (SEQ ID NO:179) 018 -----SFLDPEYWNF-- (SEQ ID NO:180) 031 ---------PEYWNFR- (SEQ ID NO:181) 033 --LNNSFLDPEYWNF-- (SEQ ID NO:182) 034 ---NNSFLDPEYWNFR- (SEQ ID NO: 183) 050 ------FLDPEYW---- (SEQ ID NO:184) 053 --------DPEYWNF-- (SEQ ID NO:185) 068 ---NNSFLDPEYW---- (SEQ ID NO:186) 088 VLLNNSFLDPEYW---- (SEQ ID NO:187) 113 ----------EYWNFRN (SEQ ID NO:188) 114 --LNNSFLDPEY------ (SEQ ID NO:189) 155 -------LDPEYWNFRN (SEQ ID NO:190) 180 --LNNSFLD-------- (SEQ ID NO:191) 187 ----NSFLDPEYWN--- (SEQ ID NO:192)

[0325] Cluster 7 HNYINEIFATSSYTFSYIA (SEQ ID NO:42) 042 ----------SSYTFSY-- (SEQ ID NO:193) 043 -------FATSSYTFSY-- (SEQ ID NO:194) 055 --YINEIFATSSYTF---- (SEQ ID NO:195) 064 -----------SYTFSYI- (SEQ ID NO:196) 080 --------ATSSYTF---- (SEQ ID NO:197) 089 -----EIFATSSYTF---- (SEQ ID NO:198) 092 ----NEIFATSSYTFSY-- (SEQ ID NO:199) 097 --------ATSSYTFSYI- (SEQ ID NO:200) 099 HNYINEIFATSSY------ (SEQ ID NO:201) 104 ------IFATSSY------ (SEQ ID NO:202) 110 ---INEIFATSSY------ (SEQ ID NO:203) 119 -NYINEIFATSSYT------ (SEQ ID NO:204) 168 --YINEIFA---------- (SEQ ID NO:205) 181 ------------YTFSYIA (SEQ ID NO:206) 200 -----EIFATSSYTFSYI- (SEQ ID NO: 207)

[0326] Cluster 8 DEAATALEINLEEEDDDNEDEVDEQAEQQKTH (SEQ ID NO:43) 01 -----ALEINLEEEDDDN-------------- (SEQ ID NO: 208) 02 ---ATALEINLEEEDD---------------- (sequence number 209) 03 -EAATALEINLEEE------------------ (SEQ ID NO:210) 04 ------LEINLEE------------------- (SEQ ID NO:211) 05 ----TALEINLEEEDDD--------------- (SEQ ID NO:212) 06 -------EINLEEE------------------ (SEQ ID NO:213) 07 -----ALEINLEEED----------------- (SEQ ID NO:214) 08 ------LEINLEEEDD---------------- (SEQ ID NO:215) 09 ----TALEINLEEE------------------ (SEQ ID NO:216) 11 DEAATALEINLEE------------------- (SEQ ID NO:217) 13 ------LEINLEEEDDDNE------------- (SEQ ID NO:218) 14 --AATALEINLEEED----------------- (SEQ ID NO:219) 15 -------EINLEEEDDD--------------- (Sequence number 220) 19 ---ATALEINLEE------------------- (SEQ ID NO:221) 23 --------INLEEEDDDN-------------- (SEQ ID NO:222) 27 ---------NLEEEDDDNE------------- (SEQ ID NO:223) 10 -------------------DEVDEQA------ (SEQ ID NO:224) 12 -------------EDDDNEDEVDEQA------ (SEQ ID NO: 225) 16 ---------------DDNEDEVDEQAEQ---- (SEQ ID NO:226) 17 --------------------EVDEQAE----- (SEQ ID NO:227) 18 ----------------DNEDEVDEQA------ (SEQ ID NO:228) 20 ---------------------VDEQAEQ---- (SEQ ID NO:229) 21 ------------------EDEVDEQAEQQKT- (SEQ ID NO: 230) 22 ------------------EDEVDEQAEQ---- (SEQ ID NO: 231) 24 -------------------DEVDEQAEQQKTH (sequence number 232) 25 -----------------NEDEVDEQAEQQK-- (SEQ ID NO: 233) 26 -------------------DEVDEQAEQQ--- (SEQ ID NO: 234)

[0327] Cluster 9 INLEEEDDDNEDEVDEQAEQ (SEQ ID NO:44) 028 EINLEEEDDDNED------- (SEQ ID NO:235) 029 --NLEEEDDDNEDEV----- (SEQ ID NO:236) 032 -INLEEED------------ (SEQ ID NO:237) 034 ---LEEEDDDNED------- (SEQ ID NO:238) 035 -INLEEEDDDNEDE------ (SEQ ID NO:239) 037 -------DDDNEDEVDEQAE (SEQ ID NO:240) 053 ---LEEEDDDNEDEVD---- (SEQ ID NO:241) 057 --------DDNEDEVDEQ-- (SEQ ID NO:242) 063 ------EDDDNED------- (SEQ ID NO:243) 065 --NLEEEDD----------- (SEQ ID NO:244) 078 --------DDNEDEV----- (SEQ ID NO:245) 087 -------DDDNEDEVDE--- (SEQ ID NO:246) 096 -------DDDNEDE------ (SEQ ID NO:247) 097 ----EEEDDDNEDE------ (SEQ ID NO:248) 108 -----EEDDDNE-------- (SEQ ID NO:249) 121 ------EDDDNEDEVD----- (SEQ ID NO:250) 126 -----------EDEVDEQ--- (SEQ ID NO:251) 148 -----EEDDDNEDEVDEQ--- (SEQ ID NO:252) 185 -----EEDDDNEDEV------ (SEQ ID NO:253) 188 ----EEEDDDNEDEVDE---- (SEQ ID NO:254)

[0328] Cluster 10 DNEDEVDEQAEQQKTHVF (SEQ ID NO:45) 030 ----EVDEQAEQQK---- (SEQ ID NO:255) 031 DNEDEVDEQAEQQ---- (SEQ ID NO: 256) 036 -----VDEQAEQQKT--- (SEQ ID NO: 257) 038 ----EVDEQAEQQKTHV- (SEQ ID NO:258) 041 -----VDEQAEQQKTHVF (SEQ ID NO: 259)

[0329] Cluster 11 EWDEAATALEINLEE (SEQ ID NO:46) 033 --------ALEINLE (SEQ ID NO:260) 042 --WDEAATALEINLE (SEQ ID NO:261) 043 -----AATALEINLE (SEQ ID NO:262) 112 EWDEAATALEINL-- (SEQ ID NO:263) 124 ---EAATALEINL-- (SEQ ID NO:264)

[0330] Cluster 12 PKVVLYSEDVDIETPDTHISYMP (SEQ ID NO:47) 039 ----LYSEDVDIET--------- (SEQ ID NO:265) 040 ----LYSEDVDIETPDT------ (SEQ ID NO:266) 044 -KVVLYSEDVDIET--------- (SEQ ID NO:267) 045 -----------IETPDTH----- (SEQ ID NO:268) 046 ---------VDIETPDTHI---- (SEQ ID NO:269) 047 ---VLYSEDVDIE---------- (SEQ ID NO:270) 048 --------DVDIETPDTHISY-- (SEQ ID NO:271) 049 --VVLYSEDVDIETP-------- (SEQ ID NO:272) 050 ------SEDVDIETPDTHI---- (SEQ ID NO:273) 051 ------------ETPDTHI---- (SEQ ID NO:274) 052 ---VLYSEDVDIETPD------- (SEQ ID NO:275) 054 --------DVDIETPDTH----- (SEQ ID NO:276) 055 ----------DIETPDTHIS--- (SEQ ID NO:277) 056 -------EDVDIETPDTHIS--- (SEQ ID NO:278) 058 -----------IETPDTHISY-- (SEQ ID NO:279) 059 -----YSEDVDIETPDTH----- (SEQ ID NO:280) 060 ---------VDIETPDTHISYM- (SEQ ID NO:281) 061 PKVVLYSEDVDIE---------- (SEQ ID NO:282) 062 ----------DIETPDT------ (SEQ ID NO:283) 064 ----------DIETPDTHISYMP (SEQ ID NO:284) 070 -------EDVDIETPDT------ (SEQ ID NO:285) 071 ------------ETPDTHISYM- (SEQ ID NO:286) 159 -----------IETPDTHISYMP (SEQ ID NO:287)

[0331] Cluster 13 YIPESYKDRMYSFFRNF (SEQ ID NO:48) 072 -------DRMYSFFRNF (SEQ ID NO:288) 086 -------DRMYSFF--- (SEQ ID NO:289) 104 ----------YSFFRNF (SEQ ID NO:290) 107 -IPESYKDRMYSFF--- (SEQ ID NO:291) 120 ----SYKDRMYSFF--- (SEQ ID NO:292) 127 ---ESYKDRMYSF---- (SEQ ID NO:293) 143 ------KDRMYSF---- (SEQ ID NO:294) 152 YIPESYKDRMYSF---- (SEQ ID NO:295) 153 --PESYKDRMYSFFR-- (SEQ ID NO:296) 160 -----YKDRMYSFFR-- (SEQ ID NO:297)

[0332] Cluster 14 DSIGDRTRYFSMW (SEQ ID NO:49) 073 ------TRYFSMW (SEQ ID NO:298) 080 ---GDRTRYF--- (SEQ ID NO:299) 095 DSIGDRTRYF--- (SEQ ID NO:300) 100 DSIGDRTRYFSMW (SEQ ID NO:301) 101 ---GDRTRYFSMW (sequence number 302)

[0333] Cluster 15 SYKDRMYSFFRNF (SEQ ID NO:50) 072 ---DRMYSFFRNF (SEQ ID NO:303) 099 SYKDRMYSFFRNF (SEQ ID NO:304)

[0334] Cluster 16 FLVQMLANYNIGYQGFY (SEQ ID NO:51) 106 -------NYNIGYQGFY (SEQ ID NO:305) 122 ------ANYNIGYQGF- (SEQ ID NO:306) 123 ----MLANYNIGYQGFY (SEQ ID NO:307) 136 ----------IGYQGFY (SEQ ID NO:308) 184 FLVQMLANYNIGY---- (sequence number 309) 187 ---------NIGYQGF- (SEQ ID NO:310) 190 ---QMLANYNIGYQGF- (SEQ ID NO:311)

[0335] The above peptides / sequences are highly suitable as peptides for SADC to reduce neutralization of AdV vectors. Importantly, the binding of these peptides to the paratopes of undesired antibodies can be further improved by mutation of one, two or three amino acids to generate mimotopes with improved antibody binding properties.

[0336] Example 10: Epitope mapping of mAb ADK8 against AAV Monoclonal antibody ADK8 was generated by immunizing mice with AAV8 capsid. Monoclonal antibody ADK8 is directed against assembled AAV8 capsid (Sonntag et al., 2011). The neutralizing function of the antibody has been previously demonstrated (Gurda et al., 2012). Briefly, AAV8 was pre-incubated with ADK8, which resulted in a reduction in the number of viral particles present in the cytoplasm. Furthermore, after neutralization with ADK8, AAV8 binding to the nuclear membrane and nuclear translocation were inhibited. This suggests that ADK8 neutralization may prevent either cell entry and / or transport to the nucleus. ADK8 also cross-reacts with capsid proteins from other AAV serotypes, such as AAV1, AAV3, and AAV7 (Mietzsch et al., 2014), and was therefore selected as an example from which general conclusions regarding the present invention can be made.

[0337] As for other antibodies (see examples above), several clusters have been identified and regions delineated from which preferred peptides can be deduced. Most preferably, the peptides aligned below according to binding strength can be used for selective antibody depletion and detection as described above.

[0338] Cluster 1 WQNRDVYLQGPIWAKIP (SEQ ID NO:52) 01 ------YLQGPIW---- (SEQ ID NO:312) 02 -----VYLQGPI----- (SEQ ID NO:313) 03 WQNRDVY---------- (SEQ ID NO:314) 05 ----DVYLQGP------ (SEQ ID NO:315) 08 -QNRDVYL--------- (SEQ ID NO:316) 12 -------LQGPIWA--- (SEQ ID NO:317) 20 ---RDVYLQG------- (SEQ ID NO:318) 50 --NRDVYLQ-------- (SEQ ID NO:319)

[0339] Cluster 2 DNTYFGYSTPWGYFDFNRFHC (SEQ ID NO:53) 07 ---YFGYSTPWGYFDF----- (SEQ ID NO:320) 09 ----FGYSTPWGYF------- (SEQ ID NO:321) 10 -----GYSTPWGYFD------ (SEQ ID NO:322) 11 ------YSTPWGYFDF----- (SEQ ID NO:323) 17 -NTYFGYSTPWGYF------- (SEQ ID NO:324) 18 --------TPWGYFDFNRFHC (SEQ ID NO:325) 23 --TYFGYSTPWGYFD------ (SEQ ID NO:326) 26 DNTYFGYSTPWGY-------- (SEQ ID NO:327) 28 ---YFGYSTPWGY-------- (SEQ ID NO:328) 34 ----FGYSTPWGYFDFN---- (SEQ ID NO:329)

[0340] Cluster 3 MANQAKNWLPGPCY (SEQ ID NO:54) 04 ------NWLPGPC- (SEQ ID NO:330) 15 -------WLPGPCY (SEQ ID NO:331) 16 ---QAKNWLPGPC- (SEQ ID NO:332) 21 ----AKNWLPGPCY (SEQ ID NO:333) 25 MANQAKNWLPGPC- (SEQ ID NO:334)

[0341] Cluster 4 LPYVLGSAHQGCLPPFP (SEQ ID NO:55) 06 ---------QGCLPPF- (SEQ ID NO:335) 13 ----------GCLPPFP (SEQ ID NO:336) 27 ---VLGSAHQGCLPPF- (SEQ ID NO:337) 32 LPYVLGSAHQGCL---- (SEQ ID NO:338) 37 -YVLGSAHQGC------ (SEQ ID NO:339) 38 ----------CLPPFPA (SEQ ID NO:340) 39 -----SAHQGCLPPF-- (SEQ ID NO:341) 45 --VLGSAHQGCL---- (SEQ ID NO:342) 46 PYVLGSAHQGCLP---- (SEQ ID NO:343)

[0342] Cluster 5 NGSQAVGRSSFYCLEYF (SEQ ID NO:56) 14 ------GRSSFYC---- (SEQ ID NO:344) 22 ----AVGRSSFYCLEYF (SEQ ID NO:345) 24 ----AVGRSSFYCL--- (SEQ ID NO:346) 33 ---QAVGRSSFYCLEY- (SEQ ID NO:347) 35 NGSQAVGRSSFYC---- (SEQ ID NO:348)

[0343] Cluster 6 PLIDQYLYYL (SEQ ID NO:57) 19 ---DQYLYYL (SEQ ID NO:349) 29 PLIDQYLYYL (SEQ ID NO:350) 36 --IDQYLYY- (SEQ ID NO:351)

[0344] Cluster 7 EERFFPSNGILIF (SEQ ID NO:58) 31 ---FFPSNGILIF (SEQ ID NO:352) 49 EERFFPSNGILIF (SEQ ID NO:353)

[0345] Cluster 8 ADGVGSSSGNWHC (SEQ ID NO:59) 42 ---VGSSSGNWHC (SEQ ID NO:354) 48 ADGVGSSSGNWHC (SEQ ID NO:355)

[0346] Example 11: Screening for anti-AAV antibodies in human serum 2452 linear peptides were synthesized, derived from 16 different AAV sequences and with a sequence length of 15 amino acids.

[0347] Samples from human donors were screened for antibodies against these AAV-derived peptides immobilized on microarrays. For this purpose, IgG was prepared from blood obtained from human donors by protein G purification. Each IgG sample was incubated with a peptide microarray, and Ig binding signals were detected by fluorescence. The total antibody binding signals with peptides on the array were background subtracted and ranked for each sample, and a de-duplicated aggregate of each of the top 250 peptide hits (obtained from UniProt or other sources) for each donor with the original corresponding protein sequence was collected (referred to as group IV). Furthermore, a de-duplicated aggregate of each of the top 50 peptide hits for each donor was collected and referred to as group III. Further, a de-duplicated aggregate of each of the top 25 peptide hits for each donor was collected and referred to as group II. And a de-duplicated aggregate of each of the top 10 peptide hits for each donor was collected and referred to as group I.

[0348] Detailed results are shown in Table 1 below. In summary, group I contains 110 different peptide hits (assigned to the corresponding AAV vectors in Table 1), group II contains 289 different peptide hits, group III contains 428 different peptide hits, and group IV contains 1271 different peptide hits. Obviously, group I is a subset of group II, which in turn is a subset of group III, which in turn is a subset of group IV. Groups I-IV correspond to the top 4.4%, 10.5%, 17.5%, and 51.8% of all peptides screened, respectively.

[0349] Thus, all listed peptides, preferably those belonging to group III, even more preferably those belonging to group II and most preferably those belonging to group I (i.e. the top 4.4%) provide sequences from which shorter peptide sequences can be derived for antibody depletion according to the present invention. Furthermore, other peptide sequences (or fragments) from the proteins from which the peptides of Table 1 are derived (preferably from group III, but more preferably from group II, most preferably from group I) are also suitable for use for SADC according to the present invention. In addition, these peptides can also be used as probes for the diagnostic detection of anti-AAV antibodies in biological samples such as human serum.

[0350] Table 1 This table lists the detailed results of screening for linear peptides as a basis for the construction of anti-AAV antibody depletion SADCs according to the present invention. These peptides are also suitable for classifying neutralizing antibodies against AAV gene therapy vectors. Unless otherwise specified, the peptides are fragments derived from different AAV VP1 proteins. The given sources are either UniProt ID, GenBank ID, PDB ID or AAV strain name.

[0351] [Table 1-1]

[0352] [Table 1-2]

[0353] [Table 1-3]

[0354] [Table 1-4]

[0355]

Table 1-5

[0356]

Table 1-6

[0357]

Table 1-7

[0358]

Table 1-8

[0359]

Table 1-9

[0360]

Table 1-10

[0361]

Table 1-11

[0362]

Table 1-12

[0363]

Table 1-13

[0364]

Table 1-14

[0365]

Table 1-15

[0366]

Table 1-16

[0367]

Table 1-17

[0368]

Table 1-18

[0369]

Table 1-19

[0370]

Table 1-20

[0371]

Table 1-21

[0372]

Table 1-22

[0373]

Table 1-23

[0374]

Table 1-24

[0375]

Table 1-25

[0376]

Table 1-26

[0377]

Table 1-27

[0378]

Table 1-28

[0379]

Table 1-29

[0380]

Table 1-30

[0381]

Table 1-31

[0382]

Table 1-32

[0383]

Table 1-33

[0384]

Table 1-34

[0385]

Table 1-35

[0386]

Table 1-36

[0387]

Table 1-37

[0388]

Table 1-38

[0389]

Table 1-39

[0390]

Table 1-40

[0391]

Table 1-41

[0392]

Table 1-42

[0393]

Table 1-43

[0394]

Table 1-44

[0395]

Table 1-45

[0396] [Table 1-46]

[0397] Example 12: Cyclic peptide-based screening of anti-AAV antibodies in human serum More than 1200 cyclic peptides were synthesized from human and rhesus AAV sequences, as well as artificial AAV sequences with a sequence length of 14 amino acids based on Table 2.

[0398] Samples from human donors were screened for antibodies against these AAV-derived peptides immobilized on microarrays. For this purpose, IgG was prepared from blood from human donors by protein G purification. Each IgG sample was incubated with a peptide microarray and Ig binding signals were detected by fluorescence. The total antibody binding signals with peptides on the array were background subtracted and ranked for each sample, and a de-duplicated aggregate of the top 250 peptide hits for each donor (obtained from UniProt or other sources) with the original corresponding protein sequence was collected (referred to as group II). Furthermore, a de-duplicated aggregate of the top 50 peptide hits for each donor was collected and referred to as group I.

[0399] Detailed results are shown below in Table 2. In summary, group I contained 47 different peptide hits (assigned to the corresponding AAV vectors in Table 2), and group II yielded 172 different peptide hits. Clearly, group I is a subset of group II.

[0400] Thus, all listed peptides, preferably those belonging to group I, provide sequences from which shorter peptide sequences can be derived for antibody depletion according to the present invention. Furthermore, other peptide sequences (or fragments) from the proteins from which the peptides of Table 2 are derived (preferably from group I) are also suitable for use for SADCs according to the present invention. In addition, these peptides can also be used as probes for the diagnostic detection of anti-AAV antibodies in biological samples such as human serum.

[0401] Table 2 This table lists the detailed results of screening for cyclized peptides as a basis for the construction of anti-AAV antibody depletion SADCs according to the present invention. These peptides are also suitable for classifying neutralizing antibodies against AAV vectors. Unless otherwise specified, the peptides are fragments derived from different AAV VP1 proteins. The given sources are either UniProt ID, GenBank ID, PDB ID or AAV strain name.

[0402] [Table 2-1]

[0403] [Table 2-2]

[0404] [Table 2-3]

[0405] [Table 2-4]

[0406] [Table 2-5]

[0407] Example 13: Further screening of anti-AAV antibodies in human serum Using the cumulative running average signal of all sera tested for the four peptide signals aligned consecutively along the corresponding AAV sequence, 1948 linear peptides were derived from AAV vectors AAV1, AAV2, AAV5, AAV6, AAV8, AAV9 and AAVrh.10.

[0408] Detailed results are shown in Table 3 below. The top 63 candidates with the strongest signals were assigned to group I, which represents 3.2% of all AAV peptides analyzed by the moving average signal along the AAV VP1 sequence. The peptides in group I as well as 135 peptides with the second strongest signal were assigned to group II, which represents 10.1% of all AAV peptides analyzed. An additional 82 peptides (assigned to group III) were derived from the top 200 ranked peptides of this screen that were not included in groups I and II. Thus, taken together, groups I, II and III contain 280 linear peptides that are suitable for removing or detecting anti-AAV antibodies (as the basis of SADC), in particular AAV1, AAV2, AAV5, AAV6, AAV8, AAV9 and AAVrh.10 VP1 proteins.

[0409] Table 3 This table provides another compilation of suitable peptides covering the range along the VP1 sequences of commonly used AAV vectors including AAV1, AAV2, AAV5, AAV6, AAV8, AAV9 and AAVrh.10. The source given is either UniProt ID, GenBank ID, PDB ID or AAV strain name. An asterisk (*) indicates a peptide sequence that has already been assigned a SEQ ID NO in Table 1 above.

[0410] [Table 3-1]

[0411] [Table 3-2]

[0412] [Table 3-3]

[0413] [Table 3-4]

[0414] [Table 3-5]

[0415] [Table 3-6]

[0416] [Table 3-7]

[0417] [Table 3-8]

[0418] Example 14: Further screening of anti-vector antibodies in human serum Among 3285 cyclic peptides derived from Ad5 hexon protein P04133, fiber protein P11818 and penton protein P12538, and AAV VP1 sequences P03135, Q6JC40, Q8JQF8, Q9WBP8, Q9YIJ1, O56137, AAO88201.1, O41855, O56139 and Q8JQG0, the top 5% of peptides with maximum IgG signal intensity in the microarray screening were obtained, resulting in a total of 164 peptides with top signals from vector protein sequences screened. Details are shown in Table 4 below.

[0419] Table 4 This table provides another compilation of viral peptide sequences suitable as a basis for the present invention. In particular, they are suitable for use in SADC according to the present invention. The sources given are either UniProt IDs or GenBank IDs. An asterisk (*) indicates peptide sequences that have already been assigned a SEQ ID NO in Table 2 above.

[0420] [Table 4-1]

[0421] [Table 4-2]

[0422] [Table 4-3]

[0423] [Table 4-4]

[0424] [Table 4-5]

[0425] Thus, all the listed peptides, preferably those in the top 10%, provide sequences from which shorter peptide sequences can be derived for (temporary) antibody depletion using the compounds according to the invention. Furthermore, these peptides and fragments thereof can also be used as probes for the diagnostic detection of anti-AAV or anti-AdV antibodies in biological samples such as human serum.

[0426] Example 15: Identification of epitopes for temporary depletion of anti-measles virus antibodies Three regions were selected that are structurally particularly exposed regions of the measles virus hemagglutinin glycoprotein H, spanning amino acid residues 290-335, 365-416, and 571-610 (numbering based on UniProt sequence entry P08362). Based on this selection, 140 cyclic 16-mer peptides were synthesized starting from a single amino acid position in each of these three regions.

[0427] Samples from human donors were screened for antibodies against these measles virus-derived peptides immobilized on the microarray. For this purpose, IgG was prepared from blood obtained from human donors by protein G purification. Each IgG sample was incubated with the peptide microarray, and the Ig binding signal was detected by fluorescence.

[0428] The top 25% of IgG binding hits from the screened plasma samples are listed below in Table 5. Peptides falling within the top 10% hits and the corresponding starting amino acid positions within the UniProt sequence entry P08362 are specified.

[0429] [Table 5]

[0430] Thus, all peptides listed, preferably those belonging to the top 10% hits, provide sequences from which shorter peptide sequences can be derived for (temporary) antibody depletion using the compounds according to the invention. Furthermore, these peptides and their fragments can also be used as probes for the diagnostic detection of anti-measles virus antibodies in biological samples such as human serum.

[0431] Non-patent literature JPEG2025513726000071.jpg215159

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[0442] Zhu、Feng-Cai、et al. "Safety、tolerability、and immunogenicity of a recombinant adenovirus type-5 vectored COVID-19 vaccine: a dose-escalation、open-label、non-randomised、first-in-human trial." The Lancet 395.10240 (2020): 1845-1854.

Claims

1. A pharmaceutical composition for use in the treatment of neoplasms, wherein the pharmaceutical composition is for use in increasing the efficacy of oncolytic viruses or oncolytic virus-based oncolytic virus-like particles (VLPs) in individuals having neoplasms, wherein the oncolytic virus or oncolytic VLPs based on the oncolytic virus are administered within 96 hours following the administration of the pharmaceutical composition. The pharmaceutical composition comprises at least one pharmaceutically acceptable excipient, - A biopolymer scaffold, where the biopolymer scaffold is a non-immunogenic protein selected from the group consisting of globulin and albumin, 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, and here P is a peptide with a sequence length of 6 to 13 amino acids, and S is a non-peptide spacer. For each of the peptide n-mers, independently, n is an integer of 1 or more, preferably an integer of 2 or more, more preferably an integer of 3 or more, and particularly an integer of 4 or more. Each of the peptide n-mers is preferably bound to the biopolymer scaffold via a linker. Each P independently has an amino acid sequence comprising a sequence fragment of a protein sequence of an oncolytic virus having a length of at least six amino acids. Three or fewer, preferably two or fewer, and most preferably one or more amino acids in the sequence fragment may be independently replaced by any other amino acids. One or more antibodies against the oncolytic virus, which are specific to at least one peptide P, are present in the individual. A pharmaceutical composition wherein the compound temporarily reduces the titer of one or more antibodies against the oncolytic virus within the organism.

2. The pharmaceutical composition according to claim 1, wherein the oncolytic virus is a poxvirus such as measles virus, herpes simplex virus (HSV), vaccinia virus, reovirus, Newcastle disease virus (NVD), rhabdovirus, coxsackievirus, lentivirus, alphavirus such as Semryki forest virus, varicella stomatitis virus (VSS), myxoma virus (MYXV), mengovirus, bovine viral diarrhea virus (BVDV), chimeric oncolytic virus, picornavirus, parvovirus, adenovirus (AdV), adeno-associated virus (AAV), or flavivirus.

3. The aforementioned sequence fragment is The AdV sequence group includes ETGPPTVPFLTPPF (SEQ ID NO: 32), HDSKLSIAATQGPL (SEQ ID NO: 33), LNLRLGQGPLFFINSAHNLDINY (SEQ ID NO: 34), VDPMDEPTLLYVLFEVFDVV (SEQ ID NO: 35), MKRARPSEDTTFNPVYPYD (SEQ ID NO: 36), ISGTVQSAHLIIRFD (SEQ ID NO: 37), LGQGPLFFINSAHNLDINYNKGLYLF (SEQ ID NO: 38), SYPFDAQNQLNLRLGQGPLFFIN (SEQ ID NO: 39), GDTTPSAYSMSFSWDWSGHNYIN (SEQ ID NO: 40), VLLNNNSFLDPEYWNFRN (SEQ ID NO: 41), HNYINEIFATSSYTFSYIA (SEQ ID NO: 42), DEAATALEINLEEEEDDDNEDEVDEQAEQQKTH (SEQ ID NO: 43), INLEEEDDDNEDEVDEQAEQ (SEQ ID NO: 44), DNEDEVDEQAEQQKTHVF (SEQ ID NO: 45), EWDEATALEINLEE (SEQ ID NO: 46), PKVVLYSEEDVDIETPDTHISYMP (SEQ ID NO: 47), YIPESYKDRMYSFFRNF (SEQ ID NO: 48), DSIGDRTRYFSMW (SEQ ID NO: 49), SYKDRMYSFFRNF (SEQ ID NO: 50), and FLVQMLANYNIGYQGFY (SEQ ID NO: 51), or AAV sequence group WQNRDVYLQGPIWAKIP (SEQ ID NO: 52), DNTYFGYSTPWGYFDFNRFHC (SEQ ID NO: 53), MANQAKNWLPGPCY (SEQ ID NO: 54), LPYVLGSAHQGCLPPFP (SEQ ID NO: 55), NGSQAVGRSSFYCLEYF (SEQ ID NO: 56), PLIDQYLYYL (SEQ ID NO: 57), EERFFPSNGILIF (SEQ ID NO: 58), ADGVGSSSGNWHC (SEQ ID NO: 59), SEQ ID NOs: 383-1891, SEQ ID NOs: 1892-2063, and SEQ ID NOs: 2064-2103, or The group of sequences identified by sequence numbers 2104 to 2190, or Measles virus sequence group ALGELKLAALCHGEDS, LCHGEDSITIPYQGSG, GEDSITIPYQGSGKGV, EDSITIPYQGSGKGVS, DSITIPYQGSGKGVSSF, TIPYQGSGKGVSFQLV, IPYQGSGKGVSFQLVK, PYQGSGKGVSFQLVKL, YQGSGKGVSFQLVKLG, QGSGKGVSFQLVKLGV, SGKGVSFQLVKLGVWK, GKGVSFQLVKLGVWK S, AVPTTRTDKLRMETC, VPTTRTDKLRMETCF, PTTRTDDKLRMETCFQ, DDKLRMETCFQQACKG, DKLRMETCFQQACKGK, KLRMETCFQQACKGKI, LR METCFQQACKGKIQ, GKIQALCENPEWAPLK, IQALCENPEWAPLKDN, QALCENPEWAPLKDNR, ALCENPEWAPLKDNRI, LCENPEWAPLKDNRIP, CENPEW APLKDNRIPS, NPEWAPLKDNRIPSYG, PEWAPLKDNRIPSYGV, EWAPLKDNRIPSYGVL, PLKDNRIPSYGVLSVD, DQKLWCRHFCLADSE, HFCVLADSESGGHITH, LADSEESGGHITHSGME, DSEESGGHITHSGMEGM, SEESGGHITHSGMEGMG, and ESGGHITHSGMEGMGV, especially GEDSITIPYQGSGKGV, EDSITIPYQG SGKGVS, DSITIPYQGSGKGVSSF, PYQGSGKGVSFQLVKL, SGKGVSFQLVKLGVWK, GKGVSFQLVKLGVWKS, DKLRMETCFQQACKGK, KLRMETCFQQACKGKI, LCENPEWAPLKDNRIP, EWAPLKDNRIPSYGVL, PLKDNRIPSYGVLSVD, DQKLWCRHFCVLADSE, DSESGGHITHSGMEGM, and SESGGHITHSGMEGMG A pharmaceutical composition according to claim 1 or claim 2, comprising a sequence which is a sequence of at least six, preferably at least seven, more preferably at least eight, even more preferably at least nine, and even more preferably at least ten consecutive amino acids selected from.

4. The pharmaceutical composition according to claim 1 or 2, 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.

5. P is independent of P ａ or P ｂ And, P ａ However, it has an amino acid sequence comprising a first sequence fragment of a protein sequence of an oncolytic virus having a length of at least six amino acids, wherein three or fewer, preferably two or fewer, and most preferably one or more amino acids of the sequence fragment may be independently replaced by any other amino acids. P ｂ However, it has an amino acid sequence comprising a second sequence fragment of the protein sequence of an oncolytic virus having a length of at least six amino acids, wherein three or fewer, preferably two or fewer, and most preferably one or more amino acids of the sequence fragment may be independently replaced by any other 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 pharmaceutical composition according to claim 1 or claim 2.

6. The aforementioned peptide P ａ and the peptide P ｂ The pharmaceutical composition according to claim 5, wherein the two distinct epitopes are of the same viral antigen, or the two distinct epitope portions of the same viral epitope.

7. The pharmaceutical composition according to claim 1 or claim 2, wherein the biopolymer scaffold is selected from the group consisting of alpha-1-globulin, alpha-2-globulin, beta-globulin, and immunoglobulin, and in particular the biopolymer scaffold is albumin or transferrin, or the biopolymer scaffold is an antibody specific to the CD163 protein or a CD163-binding fragment thereof.

8. The pharmaceutical composition according to claim 1 or 2, wherein the compound is non-immunogenic in mammals, preferably in humans, non-human primates, sheep, pigs, dogs, or rodents.

9. The pharmaceutical composition according to claim 1 or claim 2, wherein the composition is non-immunogenic in humans.

10. A pharmaceutical composition according to claim 1 or claim 2 for use in the treatment of solid tumors or hematological malignancies.

11. The pharmaceutical composition is administered to the individual before or simultaneously with the administration of the oncolytic virus or oncolytic VLP, preferably systemically. Preferably, the neoplasm is a benign neoplasm, an intraepithelial neoplasm, or a malignant neoplasm, particularly a solid tumor or a hematological malignant tumor, according to claim 1 or claim 2.

12. A method for isolating one or more antibodies present within an individual, To obtain a pharmaceutical composition as defined in claim 1 or claim 2, 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 It is specific to; and Administering the pharmaceutical composition to the individual. The method, including the method described above.

13. An antineoplasmic composition comprising the compound specified in claim 1 or claim 2, further comprising the oncolytic virus or oncolytic VLP, and which may further comprise at least one pharmaceutically acceptable excipient.

14. A method for inhibiting the immune response to treatment with an antineoplastic composition in an individual requiring treatment with the antineoplastic composition, To obtain an antineoplastic composition as defined in claim 13, wherein the compound of the antineoplastic composition is non-immunogenic in the organism; and Administering the antineoplastic composition to the individual. The method comprising the compound, wherein the compound temporarily reduces the titer of one or more antibodies against the oncolytic virus within the organism.

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