ENHANCED CELL-TARGETED BINDING MOLECULE

Abstract

A first protein molecule, characterized in that it comprises a first binding site for binding to a first epitope of a first cell surface molecule, the first protein molecule being provided with at least one saponin covalently linked via at least one linker and / or via an oligomeric or polymeric scaffold to an amino acid residue of said first protein molecule, or covalently linked directly to an amino acid residue of said first protein molecule, wherein the at least one saponin is a triterpenoid saponin and / or a bisdesmosidic triterpene saponin belonging to the type of a 12,13-dehydrooleanane with an aldehyde function at the C-23 position, and wherein the first binding site comprises or consists of an immunoglobulin, or at least an immunoglobulin binding domain and / or at least an immunoglobulin binding fragment, such as an antibody, an IgG,a molecule comprising or consisting of a Vhh domain or Vh domain, a Fab, a scFv, an Fv, an sdAb, an F(ab)2, an Fcab fragment.,

Description

IMPROVED CELL TARGETED BINDING MOLECULE technical field The invention relates to a first protein molecule comprising a first binding site for binding to a first epitope of a first cell surface molecule, the first protein molecule provided with at least one saponin covalently linked through at least one linker and / or through an oligomeric or polymeric scaffold to an amino acid residue of said first protein molecule, or covalently linked directly to an amino acid residue of said first protein molecule. The invention also refers to a therapeutic combination, in which the therapeutic combination comprises the first pharmaceutical composition comprising the first protein molecule of the invention and a second pharmaceutical composition comprising a second protein molecule different from the first protein molecule, the second protein molecule comprises a second binding site for binding to a second epitope on a second cell surface molecule different from the first cell surface molecule, and comprises an effector moiety, wherein the second epitope is different from the first epitope. Additionally, the invention relates to a therapeutic combination, wherein the therapeutic combination comprises (a) the first pharmaceutical composition of the invention comprising the first protein molecule according to the invention and comprising the first binding site for binding to the first epitope on the first cell surface molecule; and (b) a third pharmaceutical composition comprising a third protein molecule, the third protein molecule comprising the first binding site for binding to the first epitope on the cell surface molecule of (a) and an effector moiety, wherein the first binding site of the first protein molecule and the first binding site of the third protein molecule are the same, and wherein the first cell surface molecule and the first epitope on the first cell surface molecule, to which it can bind the first protein molecule, and the first cell surface molecule and the first epitope on the first cell surface molecule, to which the third protein molecule can bind, are the same. One aspect of the invention is a composition comprising the first protein molecule of the invention and the second protein molecule of the invention. One aspect of the invention relates to a composition comprising the first protein molecule of the invention and the third protein molecule of the invention. The invention also relates to a composition comprising the first protein molecule of the invention and any one or more of an oligonucleotide, an acid M A / I / UO / JOS nucleic acid and a xenonucleic acid, preferably selected from at least one of a vector, a gene, a transgene that induces cell suicide, deoxyribonucleic acid (DNA), ribonucleic acid (RNA), antisense oligonucleotide (ASO, AON), small interfering RNA (siRNA), microRNA (miRNA), DNA aptamer, RNA aptamer, mRNA, mini-circle DNA, peptide nucleic acid (PNA), morpholino phosphoramidate oligomer (PMO), locked nucleic acid (LNA), bridged nucleic acid (BNA), 2'-deoxy¡-2'fluoroarabin nucleic acid (PANA), 2'-O-methoxyethyl-RNA (MOE), 2'-0,4'-aminoethylene bridged nucleic acid , 3'-fluorohexitol nucleic acid (FHNA), a plasmid, glycol nucleic acid (GNA) and threose nucleic acid (TNA), or a derivative thereof. The invention also relates to an antibody-drug conjugate or a ligand-drug conjugate comprising the first protein molecule of the invention and an effector moiety. One aspect of the invention relates to a pharmaceutical composition comprising the composition of the invention or the antibody-drug conjugate of the invention or the ligand-drug conjugate of the invention, and optionally further comprising a pharmaceutically acceptable excipient. The invention also relates to the therapeutic combination of the invention or the composition of the invention or the antibody-drug conjugate or ligand-drug conjugate of the invention or the pharmaceutical composition of the invention, for use as a medicament. Background On many occasions, molecules with therapeutic biological activity are, in theory, suitable for application as an effective therapeutic drug for the treatment of a disease such as cancer in human patients in need thereof. A typical example is biologically active fractions of small molecules. However, many, if not all, potential drug-like therapeutics and molecules currently in use in the clinic suffer from at least one of a plethora of shortcomings and drawbacks. When administered to a human body, therapeutically active molecules can exert off-target effects in addition to biological activity directed at an underlying aspect of a disease or health problem to be treated. Said off-target effects are undesired and carry a risk of inducing side effects of the administered molecule that endanger health or even life. It is the occurrence of such adverse events that causes many drug-like compounds and therapeutic fractions to fail in phase III clinical trials or even phase IV clinical trials (post-market follow-up). MA / t / ZUZ I / UO / JOS Therefore, there is a strong desire to provide drug molecules such as small molecule therapeutics, where the therapeutic effect of the drug molecule must, for example, (1) be highly specific for a biological factor or biological process. that drives the disease, (2) be safe enough, (3) be effective enough, (4) be sufficiently targeted to the diseased cell with little or no off-target activity in non-diseased cells, (5) have a mode of sufficiently timely action (for example, the administered drug molecule must reach the target site in the human patient within a certain period of time and must remain at the target site for a certain period of time), and / or (6) have a sufficiently long-lasting therapeutic activity in the patient's body, among others. Unfortunately, to date, 'ideal' therapeutics with many or even all of the beneficial features described herein above are not available to patients, despite long-term and intensive research and impressive advances. achieved in various areas of the difficulties and drawbacks encountered addressed individually. Chemotherapy is one of the most important therapeutic options for the treatment of cancer. However, it is often associated with a low therapeutic window because it has no specificity towards cancer cells over dividing cells in healthy tissue. The invention of monoclonal antibodies offered the possibility of exploiting their specific binding properties as a mechanism for the targeted delivery of cytotoxic agents to cancer cells, while sparing normal cells. This can be accomplished by chemically conjugating cytotoxic effectors (also known as payloads or warheads) with antibodies, to create antibody-drug conjugates (ADCs). Typically, very potent payloads such as emtansine (DM1) that have a limited therapeutic index (a ratio comparing toxic dose to effective dose) are used in their unconjugated forms. Conjugation of DM1 with trastuzumab (adotrastuzumab emtansine), also known as Kadcycla, increases the tolerable dose of DM1 by at least two-fold in monkeys. Tremendous efforts and investments have been made in recent decades to develop therapeutic ADCs. However, it remains a challenge to bring ADCs to the clinic, despite promising preclinical data. The first ADC approved for clinical use was gemtuzumab ozogamicin (Mylotarg, targeting CD33, Pfizer / Wyeth) for relapsed acute myelogenous leukemia (AML) in 2000. However, Mylotarg was withdrawn from the market at the request of the Drug Administration and food ΜΛ / I / UO / JOS (FDA) due to a number of concerns, including its safety profile. Patients treated with Mylotarg died more frequently than patients treated with conventional chemotherapy. Mylotarg was re-entered the market in 2017 with a lower recommended dose, a different regimen in combination with chemotherapy or alone, and a new patient population. To date, only five ADCs have been approved for clinical use, and approximately fifty-five ADCs have been halted in clinical development in the meantime. However, interest remains high and approximately eighty ADCs are still in clinical development in nearly six hundred clinical trials today. Despite the possibility of using toxic payloads that are not normally tolerated by patients, a low therapeutic index (a ratio of toxic dose to effective dose) is a major problem explaining the disruption of many ADCs in development. clinical, which can be caused by several mechanisms such as off-target toxicity on normal cells, the development of resistance against cytotoxic agents and the premature release of drugs into the circulation. An FDA systematic review of ADCs found that the toxicity profiles of most ADCs could be categorized according to the payload used, but not the antibody used, suggesting that toxicity is primarily determined by release. premature payload. Of the approximately fifty-five ADCs that were discontinued, it is estimated that at least twenty-three were due to a poor therapeutic index. For example, development of a conjugate of trastuzumab tesirine (ADCT-502, targeting HER-2, ADC Therapeutics) was recently discontinued due to a narrow therapeutic index, possibly due to an in-target and out-of-tissue effect on the tissue. lung that expresses considerable levels of HER2. Additionally, several ADCs in phase 3 trials have been discontinued due to the lack of a primary endpoint. For example, Phase 3 trials of a depatuxizumab mafodotin conjugate (ABT-414, targeting EGFR, AbbVie) tested in patients with newly diagnosed glioblastoma, and a mirvetuximab soravtansin conjugate (IMGN853, targeting folate receptor alpha (FRa ), ImmunoGen) tested in patients with platinum-resistant ovarian cancer, were recently stopped and showed no survival benefit. It is important to note that the clinically used dose of some ADCs may not be sufficient for their full anticancer activity. For example, adotrastuzumab emtansine has an MTD of 3.6 mg / kg in humans. In preclinical models of M A / IZ / ΖυΖΊ / UO / JOS breast cancer, ado-trastuzumab emtansine induced tumor regression at dose levels at or above 3 mg / kg, but more potent efficacy was observed at 15 mg / kg. This suggests that at the clinically administered dose, ado-trastuzumab emtansine may not exert its maximum potential antitumor effect. ADCs are mainly composed of an antibody, a cytotoxic moiety as a payload, and a linker. Various novel strategies in the design and development of new ADCs have been proposed and carried out to overcome the existing problems, which address each of the components of ADCs. For example, by identifying and validating suitable antigenic targets for the antibody component, by selecting for antigens that have high levels of expression in the tumor and little or no expression in normal tissues, antigens that are present on the cell surface that are accessible to circulating ADCs, and antigens that allow internalization of ADCs into the cell after binding; and alternative mechanisms of activity; designing and optimizing linkers that improve the solubility and drug / antibody ratio (DAR) of ADCs and overcome protein-induced resistance that can transport the chemotherapeutic agent out of cells; improve the DAR ratio by including more payloads, select and optimize antibodies to improve the homogeneity and developability of the antibodies. In addition to the technological development of ADCs, new clinical and translational strategies are also being implemented to maximize the therapeutic index, such as changing dosing schedules through fractionated dosing; perform biodistribution studies; include biomarkers to optimize patient selection, capture response signals early and monitor duration and depth of response, and report combination studies. An example of ADCs with clinical potential are those ADCs such as brentuximab vedotin, inotuzumab ozogamicin, moxetumomab pasudotox, and polatuzumab vedotin, which are being evaluated as a treatment option for lymphoid malignancies and multiple myeloma. Polatuzumab vedotin, which binds to CD79b on (malignant) B cells, and pinatuzumab vedotin, which binds to CD22, are tested in clinical trials in which ADCs were combined with co-administered rituximab, a monoclonal antibody that binds to CD20 and it is not provided with a payload [B. Yu and D. Liu, Antibody-drug conjugales in clinical trials for lymphoid malignancies and multiple myeloma; Journal of Hematology & Oncology (2019) 12:94]. Combinations of monoclonal antibodies such as these examples are still a further approach and attempt to arrive at the 'magic bullet' that combines many or even all of the aforementioned desired features of ADCs. Meanwhile, in recent decades, nucleic acid-based therapeutics are being developed. Therapeutic nucleic acids can be based on deoxyribonucleic acid (DNA) or ribonucleic acid (RNA), antisense oligonucleotides (ASO, AON) and small interfering RNA (siRNA), microRNA and DNA and RNA aptamers, for approaches such as therapy gene, RNA interference (RNAi). Many of them share the same fundamental basis of action by inhibiting the expression of DNA or RNA, thus preventing the expression of abnormal proteins related to the disease. The largest number of clinical trials are taking place in the field of gene therapy, with nearly 2,600 clinical trials ongoing or completed worldwide, but only about 4% entering phase 3. This is followed by clinical trials with ASO. Similar to ADCs, despite the large number of techniques being explored, therapeutic nucleic acids share two main problems during clinical development: delivery to cells and off-target effects. For example, ASOs such as peptide nucleic acid (PNA), morpholino phosphoramidate oligomer (PMO), locked nucleic acid (LNA), and bridged nucleic acid (BNA), are being investigated as an attractive strategy to specifically inhibit target genes. and especially those genes that are difficult to target with small molecule inhibitors or neutralizing antibodies. Currently, the efficacy of different ASOs is being studied in many neurodegenerative diseases such as Huntington's disease, Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis and also in various stages of cancer. The application of ASOs as potential therapeutic agents requires safe and effective procedures for their delivery to the cytoplasm and / or nucleus of target cells and tissues. Although the clinical relevance of ASOs has been demonstrated, ineffective cellular uptake, both in vitro and in vivo, limits the efficacy of ASOs and has been a barrier to therapeutic development. Cellular uptake may be < 2% of the dose, resulting in too low an ASO concentration at the active site for a sustained effective result. Consequently, this requires an increase in the administered dose that induces off-target effects. The most common side effects are activation of the complement cascade, inhibition of M A / t / ZUZ I / UO / JOS the coagulation cascade and toll-like receptor-mediated stimulation of the immune system. Chemotherapeutics are most commonly small molecules, however their efficacy is hampered by secondary off-target toxicity, as well as poor solubility, rapid clearance, and limited tumor exposure. Small molecule scaffold-drug conjugates, such as polymer-drug conjugates (PDCs) are pharmacologically active macromolecular constructs, comprising one or more molecules of a small molecule drug attached to a carrier scaffold (for example, polyethylene glycol (PEG)). Such a conjugate principle has attracted much attention and has been under investigation for several decades. Most small molecule drug conjugates under preclinical or clinical development are for oncology indications. However, only one non-cancer drug (Movantik, a PEG conjugate oligomer of the opioid antagonist naloxone, AstraZeneca) has been approved to date for opioid-induced constipation in chronic pain patients in 2014, which is a non-cancer indication. oncology. The translation of the application of drug-scaffold conjugates into the treatment of human subjects has provided little clinical success so far. For example, PK1 (N-(2-hydroxypropyl)methacrylamide (HPMA) doxorubicin copolymer; developed by Pharmacia, Pfizer) showed strong anticancer activity in both solid tumors and leukemia in murine models. , and was under clinical investigation for oncological indications. Although it demonstrated a significant reduction in non-specific toxicity and improved pharmacokinetics in man, the improvements in efficacy against cancer were found to be marginal in patients and further development of PK1 was discontinued as a consequence. The failure of small molecule scaffold-drug conjugates is attributed, at least in part, to their poor accumulation at the tumor site. For example, while in murine models PK1 showed 45- to 250-fold greater accumulation in tumor than in healthy tissues (liver, kidney, lung, spleen, and heart), accumulation in tumor was only seen in a small subset. of patients in the clinical trial. One possible solution to the aforementioned problems is the application of nanoparticle drug delivery systems, such as liposomes. Liposomes are sphere-shaped vesicles consisting of one or more phospholipid bilayers, which form spontaneously when phospholipids are dispersed in water. ΜΛ / I / UO / JOS The amphiphilicity characteristics of phospholipids provide them with self-assembling, emulsifying and wetting properties, and these properties can be used in the design of new drugs and new drug delivery systems. Drug encapsulated in a liposomal delivery system can provide several advantages over direct drug delivery, such as improvement and control over pharmacokinetics and pharmacodynamics, tissue-targeting property, decreased toxicity, and improved drug activity. One example of such success is the liposome-encapsulated form of a small-molecule chemotherapy agent, doxorubicin (Doxil: a pegylated liposome-encapsulated form of doxorubicin; Myocet: a non-pegylated liposomal doxorubicin), which have been approved for clinical use. . Therefore, a solution still needs to be found that allows drug therapies such as anti-tumor therapies, applicable for non-systemic use when desired, where the drug has, for example, an acceptable safety profile, little off-label activity target, sufficient efficacy, sufficiently low clearance rate from the patient's body, etc. For an embodiment of the present invention, it is a first objective to provide an improved biologically active compound or composition comprising said improved biologically active compound. It is one of several objectives of embodiments of the present invention to provide a solution to the problem of non-specificity encountered when small molecule therapeutically active compounds are administered to a human patient in need thereof. One of several objectives of embodiments of the present invention is to provide a solution to the problem of drugs with suboptimal specificity for a biological factor or biological process that causes disease. It is one of the various objectives of the embodiments of the present invention to provide a solution to the problem of insufficient safety features of current drugs, when administered to human patients in need thereof. It is one of several objectives of embodiments of the present invention to provide a solution to the problem that current drugs are less effective than desired, when administered to human patients in need thereof. It is one of several objectives of embodiments of the present invention to provide a solution to the problem that current drugs do not sufficiently target the cell. Diseased ΜΛ / I / UO / JOS with little or no off-target activity on non-diseased cells, when administered to human patients in need thereof. It is one of several objectives of embodiments of the present invention to provide a solution to the problem that current drugs do not have a sufficiently timely mode of action (for example, the administered drug molecule must reach the target site in the human patient within of a certain period of time and must remain at the target site for a certain period of time), when administered to human patients in need thereof. It is one of the various objectives of the embodiments of the present invention to provide a solution to the problem that current drugs do not have sufficiently long-lasting therapeutic activity in the patient's body, when administered to human patients in need thereof. At least one of the above objectives of embodiments of the invention is achieved by providing a first protein molecule of the invention, comprising a cell-targeting moiety and at least one saponin, the first protein molecule also being suitable for use. use as a medicament or suitable for involvement in a pharmaceutical combination according to the invention, and suitable for use as a semi-finished product in the manufacture of an ADC or an antibody-oligonucleotide conjugate (AOC) of the invention, according to the invention. The therapeutic combination comprises the first protein molecule comprising covalently bound saponin and comprises a second protein molecule comprising an effector molecule, also referred to as an effector moiety, wherein the first and second protein molecules comprise a different binding site for a different epitope displayed on a different cell surface molecule of a target cell, wherein the different cell surface molecules are expressed by the same target cell and displayed on the surface of the same target cell. The present invention will be described with respect to particular embodiments, but the invention is not limited thereto, but only by the claims. The embodiments of the invention described herein may operate in combination and cooperation, unless otherwise specified. One aspect of the invention relates to a first protein molecule comprising a first binding site for binding to a first epitope of a first cell surface molecule, the first protein molecule provided with at least one saponin covalently attached through at least one connector and / or through scaffolding M A / t / ZUZ I / UO / JOS oligomeric or polymeric to an amino acid residue of said first protein molecule, or covalently linked directly to an amino acid residue of said first protein molecule. According to the invention, the first protein molecule is a finished product for application in, for example, a therapeutic combination comprising a first pharmaceutical composition comprising the first protein molecule with saponin covalently attached to it (first conjugate comprising the first protein molecule protein with covalently coupled saponins). Second, the first covalently coupled saponin protein molecule is also a semi-finished product. The first protein molecule can be linked to for example at least one effector moiety such as an enzyme, toxin such as a protein toxin, oligonucleotide such as a BNA, providing an ADC or AOC according to the invention, the ADC or AOC is provided with one or more covalently linked saponins, optionally via a linker and / or an oligomeric or polymeric scaffold. Therefore, one aspect of the invention relates to a conjugate comprising or consisting of the first protein molecule comprising a first binding site for binding to a first epitope of a first cell surface molecule, with at least one saponin. covalently linked through at least one linker to the first protein molecule and / or with at least one saponin covalently linked through an oligomeric or polymeric scaffold to an amino acid residue of said first protein molecule, or otherwise linked forms covalently directly to an amino acid residue of said first protein molecule. One embodiment is the first protein molecule of the invention, wherein the first binding site comprises or consists of an immunoglobulin, or at least one immunoglobulin binding domain and / or at least one immunoglobulin binding fragment. One embodiment is the first protein molecule of the invention, wherein at least one saponin is a triterpenoid saponin and / or a bisdesmosidic triterpene saponin belonging to the type of a 12,13-dehydrooleanane with an aldehyde function at the C-position. 23 and optionally comprising a glucuronic acid function on a carbohydrate substituent in the C-3beta-OH group of the saponin, and / or a saponin isolated from a Gypsophila species and / or a Saponaria species and / or an Agrostemma species and / or a Quillaja species such as Quillaja saponaria. One embodiment is the first protein molecule of the invention, wherein the first epitope of the first cell surface molecule to which the first protein binding site binds ΜΛ / t / ZUZ I / UO f JOS the first protein molecule is a first tumor cell-specific epitope of the tumor cell-specific receptor preferably selected from CD71, CA125, EpCAM(171A), CD52, CEA, CD44v6, FAP, EGF- IR, integrin, syndecan-1, vascular alpha-V beta-3 integrin, HER2, EGFR, CD20, CD22, Folate receptor 1, CD146, CD56, CD19, CD138, CD27L receptor, PSMA, CanAg, integrin-alphaV, CA6, CD33, mesothelin, Cripto, CD3, CD30, CD239, CD70, CD123, CD352, DLL3, CD25, ephrinA4, MUC1, Trop2, CEACAM5, CEACAM6, HER3, CD74, PTK7, Notch3, FGF2, C4.4A, FLT3, CD38, FGFR3, CD7, PD-L1, CTLA4, CD52, PDGFRA, VEGFR1, VEGFR2, more preferably selected from CD71, EGFR, HER2. One embodiment is the first protein molecule of the invention, wherein the first tumor cell-specific epitope, first tumor cell surface molecule, or first tumor cell-specific receptor is a first epitope or a first molecule or a first receptor that are internalized by the tumor cell after binding of the first protein molecule of the invention to the first epitope or first molecule or first receptor, and wherein preferably the first protein molecule undergoes tumor cell receptor-mediated internalization, for example via endocytosis, or tumor cell surface molecule-mediated internalization, for example via endocytosis, when binding to the cell surface molecule comprising the first epitope, the tumor cell surface molecule or the specific receptor for tumor cell. One aspect of the invention relates to a therapeutic combination, wherein the therapeutic combination comprises: (a) a first pharmaceutical composition comprising the first protein molecule of the invention and optionally a pharmaceutically acceptable excipient; and (b) a second pharmaceutical composition comprising a second protein molecule different from the first protein molecule, the second protein molecule comprising a second binding site for binding to a second epitope on a second cell surface molecule different from the first molecule. cell surface, and comprising an effector moiety, the second pharmaceutical composition optionally further comprises a pharmaceutically acceptable excipient, wherein the second epitope is different from the first epitope. One aspect of the invention relates to a therapeutic combination, wherein the therapeutic combination comprises: (a) the first pharmaceutical composition of the invention comprising the first protein molecule according to the invention and comprising MA / E / ZUZ I / UO / JOS the first binding site for binding to the first epitope on the first cell surface molecule, the first pharmaceutical composition optionally further comprising a pharmaceutically acceptable excipient; and (b) a third pharmaceutical composition comprising a third protein molecule, the third protein molecule comprising the first binding site for binding to the first epitope on the cell surface molecule of (a) and an effector moiety, the third pharmaceutical composition optionally further comprising a pharmaceutically acceptable excipient, wherein the first binding site of the first protein molecule and the first binding site of the third protein molecule are the same, and wherein the first cell surface molecule and the first epitope on the first cell surface molecule, to which the first protein molecule can bind, and the first cell surface molecule and the first epitope on the first cell surface molecule, to which the third protein molecule can bind, are the same. One embodiment is the first protein molecule and / or the second protein molecule of the invention, which is a semi-finished product for the manufacture of an ADC conjugated to at least one saponin, or which is a semi-finished product for the manufacture of an AOC conjugated to at least one saponin, at least one saponin coupled to the ADC or AOC through covalent bonds, preferably through at least one linker, and preferably through an oligomeric or polymeric scaffold to which at least one is covalently coupled saponin, preferably through a linker (Figure 91, 92). One embodiment is the first protein molecule of the invention, and / or therapeutic combination of the invention, in which the first binding site and / or the second binding site is / are or comprise(s) a monoclonal antibody or at least a fragment and / or cell surface molecule binding domain thereof, and preferably comprise or consist of any one of cetuximab, daratumumab, gemtuzumab, trastuzumab, panitumumab, brentuximab, inotuzumab, moxetumomab, polatuzumab, obinutuzumab, monoclonal anti- CD71 OKT-9 type IgG, pertuzumab, rituximab, ofatumumab, Herceptin, alemtuzumab, pinatuzumab, anti-CD38 monoclonal antibody OKT-10, and an antibody from Table A4, preferably cetuximab or trastuzumab or OKT-9, or at least one fragment or cell surface molecule binding domain thereof, with the proviso that the first binding site of the first protein molecule is different from the second binding site of the second protein molecule. One embodiment is the therapeutic combination of the invention, in which the effector moiety that is composed of the second protein molecule and / or the third protein molecule comprises or consists of any one or more of an oligonucleotide, a nucleic acid, a xenonucleic. One embodiment is the therapeutic combination of the invention, in which the effector moiety that is composed of the second protein molecule and / or the third protein molecule comprises or consists of at least one protein molecule, preferably selected from any one or more of a peptide, a protein, an enzyme such as urease and Cre-recombinase, a ribosome-inactivating protein, a protein toxin. One embodiment is the therapeutic combination of the invention, in which the effector moiety composed of the second protein molecule and / or the third protein molecule comprises or consists of at least one payload, preferably selected from any one or more than one toxin. one that targets ribosomes, a toxin that targets elongation factors, a toxin that targets tubulin, a toxin that targets DNA, and a toxin that targets RNA. One embodiment is the therapeutic combination of the invention, in which the first protein molecule comprises more than one saponin, preferably 2, 3, 4, 5, 6, 8, 10, 16, 32, 64 or 1-100 saponins, or any number of saponins among these, such as 7, 9, 12 saponins, covalently attached directly to an amino acid residue of the first protein molecule, preferably to a cysteine ​​and / or to a Physin, and / or covalently attached to through at least one linker and / or through at least one cleavable linker and / or through at least one polymeric or oligomeric scaffold, preferably 1-8 of said scaffolds or 2-4 of said scaffolds, in which at least one scaffold optionally based on a dendron, in which 1-32 saponins such as 2, 3, 4, 5, 6, 8, 10, 16, 32 saponins, or any number of saponins in between, such as 7, 9, 12 saponins, bind covalently to at least one scaffold. One aspect of the invention relates to a composition comprising the first protein molecule of the invention and the second protein molecule of the invention. One aspect of the invention relates to a composition comprising the first protein molecule of the invention and the third protein molecule of the invention. One embodiment is the composition of the invention, comprising either the second or the third protein molecule, together with the first protein molecule, wherein the effector moiety that is composed of either the second protein molecule or the third protein molecule is a any of the effector moieties according to the invention and is preferably a BNA. M A / Ε / ΖυΖΊ / UO / JOS One embodiment is the composition comprising the first protein molecule of the invention and any one or more of an oligonucleotide, a nucleic acid and a xenonucleic acid, preferably selected from at least one of a vector, a gene, a transgene that induces cell suicide , deoxyribonucleic acid (DNA), ribonucleic acid (RNA), antisense oligonucleotide (ASO, AON), small interfering RNA (siRNA), microRNA (miRNA), DNA aptamer, RNA aptamer, mRNA, mini circle DNA, acid peptide nucleic acid (PNA), morpholino phosphoramidate oligomer (PMO), locked nucleic acid (LNA), bridged nucleic acid (BNA), 2'-deoxy-2'-fluoroarabino nucleic acid (FANA), 2'-O- methoxyethyl-RNA (MOE), 2'-O,4'-aminoethylene bridged nucleic acid, 3'fluorohexitol nucleic acid (FHNA), a plasmid, glycol nucleic acid (GNA) and threose nucleic acid (TNA), or a derivative thereof, more preferably a BNA, for example a BNA to silence HSP27 protein expression. One aspect of the invention relates to an antibody-drug conjugate or a ligand-drug conjugate comprising the first protein molecule of the invention and an effector moiety. One embodiment is the antibody-drug conjugate or ligand-drug conjugate of the invention, wherein the antibody can bind to any one of CD71, CA125, EpCAM(17-1A), CD52, CEA, CD44v6, FAP, EGF -IR, integrin, syndecan-1, vascular beta-3 alpha-V integrin, HER2, EGFR, CD20, CD22, Folate receptor 1, CD146, CD56, CD19, CD138, CD27L receptor, PSMA, CanAg, integrin-alphaV , CA6, CD33, mesothelin, Cripto, CD3, CD30, CD239, CD70, CD123, CD352, DLL3, CD25, ephrinA4, MUC1, Trop2, CEACAM5, CEACAM6, HER3, CD74, PTK7, Notch3, FGF2, C4.4A, FLT3 , CD38, FGFR3, CD7, PD-L1, CTLA4, CD52, PDGFRA, VEGFR1, VEGFR2, preferably CD71, HER2, EGFR, and / or wherein the antibody is or comprises any one of cetuximab, daratumumab, gemtuzumab, trastuzumab, panitumumab, brentuximab, notuzumab, moxetumomab, polatuzumab, obinutuzumab, anti-CD71 OKT-9 IgG monoclonal antibody, pertuzumab, rituximab, ofatumumab, Herceptin, alemtuzumab, pinatuzumab, anti-CD38 OKT-10 monoclonal antibody, an antibody to the Table A2 or Table A3 or Table A4, preferably cetuximab or trastuzumab or OKT-9, or at least one tumor cell receptor-binding fragment thereof and / or at least one tumor cell receptor-binding domain thereof, and / or wherein the antibody-drug conjugate comprises any one of Gemtuzumab ozogamicin, Brentuximab vedotin, Trastuzumab emtansine, Inotuzumab ozogamicin, Moxetumomab pasudotox and Polatuzumab vedotin and a conjugate M A / t / ZUZ I / UO / JOS of the antibody-drug of Table A2 and Table A3, or wherein the ligand-drug conjugate comprises at least one ligand for binding to a cell surface molecule such as EGF or a cytokine. One embodiment is the antibody-drug conjugate or ligand-drug conjugate of the invention, wherein the effector moiety is any one or more of the effector moieties according to the invention. One aspect of the invention relates to a pharmaceutical composition comprising the composition of the invention or the antibody-drug conjugate of the invention or the ligand-drug conjugate of the invention, and optionally further comprising a pharmaceutically acceptable excipient. One embodiment is the therapeutic combination of the invention or the composition of the invention or the antibody-drug conjugate or ligand-drug conjugate of the invention or the pharmaceutical composition of the invention, for use as a medicament. One aspect of the invention relates to any of the following ADCs and AOCs, and their semi-finished conjugates, comprising the first protein molecule of the invention and / or the second protein molecule of the invention and / or the third protein molecule of the invention and comprising either at least one effector molecule of the invention or comprising at least one saponin of the invention, or both: Anti-EGFR-Saponin Antibody; Anti-EGFR Antibody - triterpenoid saponin and / or a bisdesmosidic triterpene saponin belonging to the type of a 12,13-dehydrooleanan with an aldehyde function at position C-23 and optionally comprising a glucuronic acid function on a carbohydrate substituent in the C-3beta-OH group of the saponin; Anti-EGFR Antibody - SO1861; Anti-EGFR Antibody - GE1741; Anti-EGFR Antibody - SA1641; Anti-EGFR Antibody - Quil-A; Anti-EGFR Antibody - QS-21; Anti-EGFR antibody - saponins in water-soluble saponin fraction of Quillaja saponaria; Cetuximab - saponin; Cetuximab - triterpenoid saponin and / or a bisdesmosidic triterpene saponin belonging to the type of a 12,13-dehydrooleanane with an aldehyde function at position M A / I / UO / JOS C-23 and optionally comprising a glucuronic acid function on a carbohydrate substituent on the C-3beta-OH group of the saponin; Cetuximab-SO1861; Cetuximab-GE1741; Cetuximab-SA1641; Cetuximab-Quil-A; Cetuximab-QS-21; Cetuximab - saponins in water soluble saponin fraction from Quillaja saponaria; Anti-HER2 antibody - saponin; Anti-HER2 antibody - triterpenoid saponin and / or a bisdesmosidic triterpene saponin belonging to the type of a 12,13-dehydrooleanane with an aldehyde function at position C-23 and optionally comprising a glucuronic acid function on a carbohydrate substituent in the C-3beta-OH group of the saponin; Anti-HER2 Antibody - SO1861; Anti-HER2 Antibody - GE1741; Anti-HER2 Antibody - SA1641; Anti-HER2 Antibody - Quil-A; Anti-HER2 Antibody - QS-21; Anti-HER2 antibody - saponins in water-soluble saponin fraction of Quillaja saponaria; Trastuzumab - saponin; Trastuzumab - triterpenoid saponin and / or a bisdesmosidic triterpene saponin belonging to the type of a 12,13-dehydrooleanane with an aldehyde function at position C-23 and optionally comprising a glucuronic acid function on a carbohydrate substituent in the group C-3beta-OH from saponin; Trastuzumab-SO1861; Trastuzumab-GE1741; Trastuzumab-SA1641; Trastuzumab-Quil-A; Trastuzumab-QS-21; Trastuzumab - saponins in water soluble saponin fraction from Quillaja saponaria; Anti-CD71 antibody - saponin; M A / t / ZUZ I / UO / JOS Anti-CD71 antibody - triterpenoid saponin and / or a bisdesmosidic triterpene saponin belonging to the type of a 12,13-dehydrooleanane with an aldehyde function at position C-23 and optionally comprising a glucuronic acid function on a carbohydrate substituent in the C-3beta-OH group of the saponin; Anti-CD71-SO1861 Antibody; Anti-CD71 Antibody -GE1741; Anti-CD71 Antibody - SA1641; Anti-CD71 Antibody - Quil-A; Anti-CD71 Antibody - QS-21; Anti-CD71 antibody - saponins in water-soluble saponin fraction of Quillaja saponaria; OKT-9 - saponin; OKT-9 - triterpenoid saponin and / or a bisdesmosidic triterpene saponin belonging to the type of a 12,13-dehydrooleanane with an aldehyde function at position C-23 and optionally comprising a glucuronic acid function on a carbohydrate substituent at the C-3beta-OH group of saponin; OKT-9-SO1861; OKT-9-GE1741; OKT-9-SA1641; OKT-9-Quil-A; OKT-9-QS-21; OKT-9 - saponins in water-soluble saponin fraction from Quillaja saponaria; Anti-EGFR antibody - oligonucleotide; Anti-EGFR Antibody - antisense oligonucleotide; Anti-EGFR Antibody - siRNA; Anti-EGFR Antisense-BNA Antibody; Anti-EGFR Antisense-BNA Antibody (HSP27); Anti-EGFR antibody - protein toxin; Anti-EGFR antibody - protein that inactivates the ribosome; Anti-EGFR antibody - diantin; Anti-EGFR antibody - saporin; Cetuximab - oligonucleotide; Cetuximab - antisense oligonucleotide; ΜΛ / I / UO / JOS Cetuximab-siRNA; Cetuximab - antisense BNA; Cetuximab - antisense BNA (HSP27); Cetuximab - protein toxin; Cetuximab - protein that inactivates the ribosome; Cetuximab - diantine; Cetuximab - saporin; Anti-HER2 antibody - oligonucleotide; Anti-HER2 antibody - antisense oligonucleotide; Anti-HER2 Antibody - siRNA; Anti-HER2 Antibody - Antisense BNA; Anti-HER2 Antibody - Antisense BNA (HSP27); Anti-HER2 antibody - protein toxin; Anti-HER2 antibody - protein that inactivates the ribosome; Anti-HER2 antibody - diantine; Anti-HER2 antibody - saporin; Trastuzumab - oligonucleotide; Trastuzumab - antisense oligonucleotide; Trastuzumab-siRNA; Trastuzumab - antisense BNA; Trastuzumab - antisense BNA (HSP27); Trastuzumab - protein toxin; Trastuzumab - protein that inactivates the ribosome; Trastuzumab - diantine; Trastuzumab - saporin; Anti-CD71 antibody - oligonucleotide; Anti-CD71 antibody - antisense oligonucleotide; Anti-CD71 Antibody - siRNA; Anti-CD71 Antibody - Antisense BNA; Anti-CD71 Antibody - Antisense BNA (HSP27); Anti-CD71 antibody - protein toxin; Anti-CD71 antibody - protein that inactivates the ribosome; Anti-CD71 antibody - diantine; ΜΛ / t / ZUZ I / UO / JOS Anti-CD71 antibody - saporin; OKT-9 - oligonucleotide; OKT-9 - antisense oligonucleotide; OKT-9-siRNA; OKT-9 - antisense BNA; OKT-9 - antisense BNA (HSP27); OKT-9 - protein toxin; OKT-9 - protein that inactivates the ribosome; OKT-9 - diantine; OKT-9 - saporin; Anti-EGFR (-oligonucleotide)(-saponin) antibody, wherein the oligonucleotide is any one or more of antisense oligonucleotide, siRNA, antisense NAB, and antisense NAB (HSP27), and wherein the saponin is any one or more of a triterpenoid saponin and / or a bisdesmosidic triterpene saponin belonging to the type of a 12,13-dehydrooleanane with an aldehyde function at the C-23 position and optionally comprising a glucuronic acid function in a carbohydrate substituent in the C- group 3beta-OH of the saponins, SO1861, GE1741, SA1641, Quil-A, QS-21, and saponins in water-soluble saponin fraction from Quillaja saponaria, wherein the anti-EGFR antibody is preferably cetuximab; Anti-EGFR (- protein toxin) / - saponin) antibody, wherein the protein toxin is any one or more of a ribosome-inactivating protein, diantin and saporin, and wherein the saponin is any one or more than one triterpenoid saponin and / or a bisdesmosidic triterpene saponin belonging to the type of a 12,13-dehydrooleanane with an aldehyde function at the C-23 position and optionally comprising a glucuronic acid function in a carbohydrate substituent in the C- group 3beta-OH of the saponins, SO1861, GE1741, SA1641, Quil-A, QS-21, and saponins in water-soluble saponin fraction from Quillaja saponaria, wherein the anti-EGFR antibody is preferably cetuximab; Anti-HER2 antibody (-oligonucleotide) / -saponin), wherein the oligonucleotide is any one or more of antisense oligonucleotide, siRNA, antisense NAB, and antisense NAB (HSP27), and wherein the saponin is any one or more of a triterpenoid saponin and / or a bisdesmosidic triterpene saponin belonging to the type of a 12,13-dehydrooleanan with an aldehyde function at position C-23 and comprising M A / t / ZUZ I / UO / JOS optionally a glucuronic acid function on a carbohydrate substituent on the C-3beta-OH group of saponins, SO1861, GE1741, SA1641, Quil-A, QS-21, and saponins in water soluble saponin fraction from Quillaja saponaria, in which the anti-HER2 antibody is preferentially trastuzumab; Anti-HER2 (- protein toxin)(- saponin) antibody, wherein the protein toxin is any one or more of a ribosome-inactivating protein, diantin and saporin, and wherein the saponin is any one or more than one triterpenoid saponin and / or a bisdesmosidic triterpene saponin belonging to the type of a 12,13-dehydrooleanane with an aldehyde function at the C-23 position and optionally comprising a glucuronic acid function on a carbohydrate substituent in the C- group 3beta-OH of the saponins, SO1861, GE1741, SA1641, Quil-A, QS-21, and saponins in the water-soluble saponin fraction of Quillaja saponaria, in which the anti-HER2 antibody is preferentially trastuzumab; Anti-CD71 (-oligonucleotide)(-saponin) antibody, wherein the oligonucleotide is any one or more of antisense oligonucleotide, siRNA, antisense NAB, and antisense NAB (HSP27), and wherein the saponin is any one or more of a triterpenoid saponin and / or a bisdesmosidic triterpene saponin belonging to the type of a 12,13-dehydrooleanane with an aldehyde function at the C-23 position and optionally comprising a glucuronic acid function on a carbohydrate substituent in the C- group 3beta-OH of the saponins, SO1861, GE1741, SA1641, Quil-A, QS-21, and saponins in water-soluble saponin fraction from Quillaja saponaria, wherein the anti-CD71 antibody is preferably OKT-9; and Anti-CD71 (-protein toxin)(-saponin) antibody, wherein the protein toxin is any one or more of a ribosome-inactivating protein, diantin and saporin, and wherein the saponin is any one or more than one triterpenoid saponin and / or a bisdesmosidic triterpene saponin belonging to the type of a 12,13-dehydrooleanane with an aldehyde function at the C-23 position and optionally comprising a glucuronic acid function on a carbohydrate substituent in the C- group 3beta-OH of the saponins, SO1861, GE1741, SA1641, Quil-A, QS-21, and saponins in the water-soluble saponin fraction of Quillaja saponaria, wherein the anti-CD71 antibody is preferably OKT-9. One embodiment is the first protein molecule of the invention, the semi-finished conjugate of the invention, or the conjugate of the invention, in which the first binding site is selected from cetuximab, trastuzumab, OKT-9, and / or in which the effector molecule M A / t / ZUZ I / UO / JOS selects from diantin, saporin, and antisense BNA (HSP27), and / or wherein the saponin is selected from SO1861, GE1741, SA1641, Quil-A, QS-21, and saponins in fraction of water soluble saponin from Quillaja saponaria. One embodiment is the conjugate according to the invention, in which the first protein molecule is selected from cetuximab, trastuzumab, OKT-9, and / or in which the effector molecule is selected from diantin, saporin and antisense BNA (HSP27). , and / or wherein the saponin is selected from SO1861, GE1741, SA1641, Quil-A, QS-21, and saponins in the Quillaja saponaria water-soluble saponin fraction. One aspect of the invention relates to an ADC or a COC or a semi-finished ADC conjugate or a semi-finished COC conjugate comprising the first protein molecule of the invention and comprising at least one effector molecule of the invention and / or comprising at least one saponin of the invention, of Structure C: A (-S)b (-E)c Structure C, in which A is the first binding site; S is the saponin; E is the effector molecule; b = 0 - 64, preferably 0, 1, 2, 3, 4, 8, 16, 32, 64 or any integer or fraction in between; c = 0 - 8, preferably 0,1,2, 3, 4, 6, 8 or any integer or fraction in between, where S is coupled to A and / or Ε, E is coupled to A and / or S, preferably S couples to A and E couples to A. One embodiment is Structure C of the invention, wherein A is an Anti-EGFR antibody such as cetuximab, an Anti-HER2 antibody such as trastuzumab, an Anti-CD71 antibody such as OKT-9, and / or wherein S is any one or more than one saponin, a triterpenoid saponin and / or a bisdesmosidic triterpene saponin belonging to the type of a 12,13-dehydrooleanan with an aldehyde function at position C-23 and optionally comprising a glucuronic acid function at a carbohydrate substituent on the C-3beta-OH group of the saponin, SO1861, GE1741, SA1641, Quil-A, QS-21, and saponins in the water-soluble saponin fraction of Quillaja saponaria, and / or in which E is any one or more of an oligonucleotide, an antisense oligonucleotide, a siRNA, an antisense NAB, and an antisense NAB (HSP27), and / or any one or more of a protein toxin, a ribosome-inactivating protein, diantin, and saporin . M A / IZ / ZUZI / UO f JOS One embodiment is Structure C of the invention, the conjugate of the invention or the semi-finished conjugate of the invention or the first protein molecule of the invention, in which the saponin, if present, and / or the effector molecule, if present. present, is covalently coupled through at least one linker, such as a cleavage linker, and / or through at least one oligomeric or polymeric scaffold, such as a Ν-ε-maleimidocaproic acid hydrazide-based linker ( EMCH) succinimidyl 3-(2-pyridyldithio)propionate or 3-(2-Pyridyldithio)propionic acid N-hydroxysuccinimide ester (SPDP), and 1[Bis(dimethylam¡no)methylene hexafluorophosphate ]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide (HATU), and such as a dendron-based scaffold such as a G4 dendron or a trifunctional linker such as the linker of Scheme II, and / or wherein at least one lysine literal chain and / or cysteine ​​literal chain of the first binding site of the first protein molecule, preferably a monoclonal antibody or fragments or domains thereof, is involved in the covalent bond with the saponin and / or the effector molecule and / or the linker and / or the linker cleaves it and / or the scaffold, in which the saponin and / or the effector molecule is preferably covalently linked to the first site binding agent of the first protein molecule, preferably an antibody, wherein the covalent linker comprises or consists of an amide bond, a hydrazone bond, a disulfide bond. One aspect of the invention relates to the use of any of the above-mentioned conjugates of the invention or the semi-coated conjugates of the invention or the first protein molecule of the invention, as a medicament. One aspect of the invention relates to the use of any of the conjugates of the invention or the hemiacinated conjugate of the invention or the first protein molecule of the invention, for use in the treatment or prophylaxis of cancer or autoimmune disease. Figure 91 and Figure 92 show examples of the ADCs of the invention with covalently coupled saponins and the OACs of the invention with covalently coupled saponins. Definitions The term "linker" has its usual scientific meaning, and as used herein refers to a chemical moiety or linear stretch of amino acid residues complexed through peptide bonds, that attaches one molecule or atom to another molecule, e.g. example, to a ligand or to an effector molecule or to a scaffold. Typically, the linker comprises a chain of atoms connected by chemical bonds. Any linker molecule or linker technology known in the art can be used in the present disclosure. Where indicated, the linker is a linker for the covalent attachment of molecules via a chemical group on said molecule suitable for forming a covalent bond or bond with the linker. The linker may be a non-cleaved linker, eg, the linker is stable under physiological conditions. The linker may be a cleavable linker, for example, a linker that is cleaved, in the presence of an enzyme or at a particular pH value or range, or under physiological conditions such as intracellular conditions in endosomes such as late endosomes and endosomes. lysosomes from mammalian cells such as human cells. Exemplary linkers that may be used in the context of the present disclosure include, but are not limited to, Ν-ε-maleimidocaproic acid hydrazide (EMCH), succinimidyl 3-(2-pyridyldithio)propionate, or succinimidyl N-hydroxysuccinimide ester. 3-(2Pyridild¡th¡o)propionic acid (SPDP), and 1[B¡s(d¡methylam¡no)m¡leno]-1H-1,2,3tñazolo[4,5-ó]p¡ hexafluorophosphate r¡din¡o 3-oxide (HATU). The term "trifunctional linker" has its usual scientific meaning, and as used herein refers to a linker that attaches three molecules through a chemical group on each of the three molecules. The person skilled in the art can design such trifunctional connectors, based on the present disclosure and common general knowledge. Such a trifunctional linker may display, for example, a maleimido group which can be used for conjugation with targeting ligands displaying thiol groups to perform a thiol-ene reaction. Furthermore, the trifunctional linker could exhibit a dibenzocyclooctin (DBCO) group to perform the so-called strain-promoted alkyne azide cycloaddition (SPAAC, click chemistry) with an azido-carrying saponin. Finally, the trifunctional linker could obtain a third functional group such as a trans-cyclooctene (TCO) group to perform the so-called inverse electron demand Diels-Alder (IEDDA) reaction with a tetrazine (Tz)-bearing effector molecule. One skilled in the art will appreciate that the chemical groups of the trifunctional linker may be all three of the same or different, or the linker may comprise two of the same chemical groups to connect a molecule to the trifunctional linker. The bonds formed between the trifunctional linker can be covalent or non-covalent, and covalent bonds are preferred. The bonds formed between the trifunctional linker and one or two or three molecules linked through the respective chemical groups can be cleavage (labile) bonds, M A / t / ZUZ I / UO / JOS such as cleaved under acidic conditions within cells such as endosomes and lysosomes of mammalian cells such as human cells or may be non-cleavable. Of course, the trifunctional linker can span one or two chemical groups to form covalent bonds while the other two or a chemical group(s), respectively, is / are to form a non-covalent bond. Of course, the trifunctional linker can span one or two chemical groups to form cleavable bonds while the other two or a chemical group(s), respectively, is / are to form a non-cleavable bond. The term "cleaved" as used in the term "cleaved linker" or "cleaved linker" has its usual scientific meaning, and as used herein refers to cleavage under acidic conditions, reducing conditions, enzymatic conditions or light-induced conditions. For example, a cleaved linker may be cleaved under acidic conditions, preferably said cleaved linker is cleaved in vivo under acidic conditions that are present in endosomes and / or lysosomes of mammalian cells, preferably human cells, preferably at pH 4.0 - 6.5, and more preferably at pH < 5.5. As another example, a cleaved linker may be cleaved by an enzyme, eg, by cathepsin. Additionally, an example of a covalent bond cleaved under reducing conditions is a disulfide bond. The terms "oligomer" and "polymer" in the context of an oligomeric or polymeric scaffold have their usual scientific meaning. A polymer as used herein refers to a substance having a molecular structure built primarily or entirely from a large number of the same or similar units linked together; an oligomer as used herein refers to a polymer whose molecules consist of relatively few repeating units. For example, a structure comprising 5-10 or fewer identical or similar units can be called an oligomeric structure, while a structure comprising 10-50 or more monomeric units can be called a polymeric structure, while a structure of 10 monomeric units it may be referred to as oligomeric or polymeric. The term "binding site" has its usual scientific meaning, and as used herein refers to a region or epitope on a molecule, eg, a protein, DNA or RNA, to which another molecule can bind. ΜΛ / t / ZUZ I / UO / JOS The term "scaffold" has its usual scientific meaning, and as used herein refers to an oligomeric or polymeric template or a carrier or a base (base molecule or base structure), to which one or more molecules, for example , ligand molecule, effector molecule, can be covalently attached, either directly or through a linker, such as a cleavable linker. A scaffold can have a structurally ordered formation, such as a polymer, oligomer, dendrimer, dendronized polymer, or dendronized oligomer, or have an assembled polymeric structure, such as a hydrogel, microgel, nanogel, stabilized polymeric micelle, or liposome, but excludes structures that they are composed of noncovalent assemblies of monomers such as cholesterol / phospholipid mixtures. A scaffold may comprise a polymeric or oligomeric structure, such as poly or oligo(amines), eg, polyethyleneimine and poly(amidoamine); or structures such as polyethylene glycol, poly or oligo(esters), such as poly(lactides), poly(lactams), polylactide-co-glycolide copolymers; or poly(dextrin), poly or oligosaccharides, such as cyclodextrin or polydextrose; or structures such as natural and / or artificial poly- or oligo-amino acids such as poly-lysine or a peptide or a protein, DNA oligo or polymers, stabilized RNA polymers or PNA (peptide nucleic acid) polymers. Preferably, the polymeric or oligomeric structures are biocompatible, where biocompatible means that the polymeric or oligomeric structure does not exhibit substantial acute or chronic toxicity in organisms and can be excreted as is or completely degraded to excretable and / or physiological compounds by metabolism. of the body. The term "ligand" has its usual scientific meaning, and as used herein refers to any molecule or molecules that can selectively bind to a target cell surface molecule or a target cell surface receptor expressed on target cells, for example, target cancer cells or target autoimmune cells. The ligand can bind to an epitope composed of receptors or other antigens on target cells. Preferably, the cell binding ligands are antibodies. The term "antibody" as used herein is used in the broadest sense, which can refer to an immunoglobulin (Ig) defined as a protein belonging to the IgG, IgM, IgE, IgA, or IgD class (or any subclass thereof), or a functional binding fragment or binding domain of an immunoglobulin. In the context of the present invention, a "binding fragment" or "binding domain" of an immunoglobulin is defined as an antigen-binding or other fragment or domain derived from a parent immunoglobulin that essentially maintains binding activity to MA / Ε / ΖυΖΊ / UO / JOS antigen of said original immunoglobulin. Functional fragments and functional domains are antibodies within the meaning of the present invention even if their affinity for the antigen is less than that of the original immunoglobulin. "Fragments and functional domains" according to the invention include, but are not limited to, F(ab')2 fragments, Fab' fragments, Fab fragments, scFv, dsFv, single domain antibody (sdAb), monovalent IgG, scFv-Fc, reduced IgG (rlgG), minibodies, diabodies, triabodies, tetrabodies, Fe fusion proteins, nanobodies, variable V domains such as VHH, Vh and other types of antigen-recognizing immunoglobulin domains and fragments. Fragments and domains can be engineered to minimize or completely eliminate intermolecular disulfide interactions that occur between the CH1 and CL domains. Functional fragments and -domains offer the advantage of greater tumor penetration due to their smaller size. Furthermore, the functional fragment or domain can be more evenly distributed throughout the tumor mass compared to whole immunoglobulin. The antibodies (immunoglobulins) of the present invention can be bi or multifunctional. For example, a bifunctional antibody has one arm that is specific for one receptor or antigen, while the other arm recognizes a different receptor or antigen. Alternatively, each arm of the bifunctional antibody may have specificity for a different epitope on the same receptor or target cell antigen. The antibodies (immunoglobulins) of the present invention can be, but are not limited to, polyclonal antibodies, monoclonal antibodies, human antibodies, humanized antibodies, chimeric antibodies, resurgent antibodies, anti-idiotypic antibodies, mouse antibodies, rat antibodies, hybrid antibodies of rat / mouse, llama antibodies, llama heavy chain only antibodies, heavy chain only antibodies, and veterinary antibodies. Preferably, the antibody (immunoglobulin) of the present invention is a monoclonal antibody. Resurrected, chimeric, humanized, and fully human antibodies are also more preferred because they are less likely to cause immunogenicity in humans. The ADC antibodies of the present invention preferentially bind specifically to an antigen expressed on the surface of a cancer cell, autoimmune cell, diseased cell, or aberrant cell, while leaving any healthy cell essentially unaffected (eg, by not binding to said normal cell, or by binding to a lesser degree in number and / or affinity to said healthy cell). Specific antibodies that can be used for the ADCs of the present invention include, but are not limited to, anti-HER2 monoclonal antibody such as trastuzumab and pertuzumab, anti-CD20 monoclonal antibody such as rituximab, ofatumumab, tositumomab, and ibritumomab, monoclonal antibody anti-CA125 such as oregovomab, anti-EpCAM (17 -1 A) monoclonal antibody such as edrecolomab, anti-EGFR monoclonal antibody such as cetuximab, panitumumab and nimotuzumab, anti-CD30 monoclonal antibody such as brentuximab, anti-CD33 monoclonal antibody such such as gemtuzumab and huMy9-6, anti-vascular alpha-V beta-3 integrin monoclonal antibody such as etaracizumab, anti-CD52 monoclonal antibody such as alemtuzumab, anti-CD22 monoclonal antibody such as epratuzumab, anti-CEA monoclonal antibody such as labetuzumab, anti-CD44v6 monoclonal antibody such as bivatuzumab, anti-FAP monoclonal antibody such as sibrotuzumab, anti-CD19 monoclonal antibody such as huB4, anti-CanAg monoclonal antibody such as huC242, anti-CD56 monoclonal antibody such as huN901, anti-CD38 monoclonal antibody such as daratumumab, anti-CA6 monoclonal antibody such as DS6, anti-IGF-IR monoclonal antibody such as cixutumumab and 3B7, anti-integrin monoclonal antibody such as CNTO 95, and anti-syndecan-1 monoclonal antibody such as B-B4. Molecules other than antibodies that bind to a cellular receptor or antigen on a target cell can also be used as cell binding ligands for the ligand-drug conjugates of the present invention and the provided covalently bound saponin ligands of according to the invention. These ligands include, but are not limited to, proteins, polypeptides, peptides, small molecules. Examples of these non-antibody ligands are interferons (for example, IFN-α, IFN-β, and IFN-γ), transferins, lectins, epidermal growth factors (EGF) and EGF-like domains, gastrin-releasing peptides (GRPs). ), platelet-derived growth factors (PDGFs), transforming growth factors (TGFs), vaccinia growth factor (VGF), insulin, and insulin-like growth factors (IGFs, e.g., IGF-1 and IGF- 2), other appropriate hormones such as thyrotropin-releasing hormones (TRH), melanocyte-stimulating hormones (MSH), steroid hormones (eg, estrogens and androgens), somatostatin, lymphokines (eg, IL-2, IL-3 , IL-4, and IL-6), colony-stimulating factors (CSF, eg, G-CSF, M-CSF, and GM-CSF), bombesin, gastrin, Arg-Gly-Asp, or RGD, aptamers (eg, AS-141 1, GBI-10, RNA aptamers against HIV glycoprotein), small molecules (for example folate, ΜΛ / I / UO / JOS anisamide phenylboronic acid), vitamins (for example, vitamin D), carbohydrates (for example, hyaluronic acid, galactose). An "effector molecule" or "effector moiety" or "payload" has its regular scientific meaning and in the context of this invention is any substance that affects the metabolism of a cell by interaction with a target intracellular effector molecule, in which this target effector molecule is any molecule or structure within cells that excludes the lumen of the compartments and vesicles of the endocytic and recycling pathway, but includes the membranes of these compartments and vesicles. Such structures within cells therefore include the nucleus, mitochondria, chloroplasts, the endoplasmic reticulum, the Golgi apparatus, other transport vesicles, the inner part of the plasma membrane, and the cytosol. The effector molecule or moiety is a pharmaceutically active substance, such as a toxin such as a protein toxin, a drug, a polypeptide or a polynucleotide. A pharmaceutically active substance in this invention is an effector molecule or moiety that is used to achieve a beneficial result in an organism, preferably a vertebrate, more preferably a mammal such as non-human subjects or a human / subject. Benefits include diagnosis, prognosis, treatment, cure, and prevention (prophylaxis) of disease and / or symptoms and / or health problems. The pharmaceutically active substance can also cause unwanted and sometimes even harmful side effects (adverse events such as those seen during clinical trials). In this case, the advantages and cons must be weighed in order to decide whether the pharmaceutically active substance is suitable in the particular case. If the effect of the pharmaceutically active substance within a cell is predominantly beneficial to the organism as a whole, the cell is called a target cell. If the effect within a cell is predominantly harmful to the organism as a whole, the cell is called an off-target cell. In artificial systems such as cell cultures and bioreactors, target cells and off-target cells are purpose-dependent and user-defined. Examples of effector molecules and moieties are a drug, a toxin, a polypeptide (such as an enzyme), a polynucleotide (including polypeptides and polynucleotides comprising unnatural amino acids or nucleic acids), and any combination thereof. An effector molecule or effector moiety that is a drug may include, but is not limited to, anticancer agents, anti-inflammatory agents, and anti-infective agents (eg, MA / E / ZUZ I / UO / JOS example, antifungal, antibacterial, antiparasitic, antiviral). Preferably, the drug molecule of the present invention is an anticancer agent or an anti-autoimmune agent. Suitable anticancer agents include, but are not limited to, alkylating agents, antimetabolites, spindle alkaloids, cytotoxic / antitumor antibiotics, topoisomerase inhibitors, photosensitizers, and kinase inhibitors. Also included in the definition of "anti-cancer agent" are: for example, (i) anti-hormonal agents that act to regulate or inhibit hormonal action on tumors such as antiestrogens and selective estrogen receptor modulators; (ii) aromatase inhibitors that inhibit the aromatase enzyme, which regulates estrogen production in the adrenal glands; (iii) anti-androgens; (i.v.) protein kinase inhibitors; (v) lipid kinase inhibitors; (vi) antisense oligonucleotides, particularly those that inhibit the expression of genes in signaling pathways involved in aberrant cell proliferation; (vii) ribozymes such as inhibitors of VEGF expression and inhibitors of HER2 expression; (viii) vaccines such as gene therapy vaccines; topoisomerase 1 inhibitors; (ix) anti-angiogenic agents; and pharmaceutically acceptable salts, acids, solvates and derivatives of any of the foregoing. An effector molecule or moiety that is a toxin can include, but is not limited to, protein toxins (eg, bacterial-derived toxins and plant-derived toxins), toxins that target tubulin filaments, toxins that target the DNA, toxins that target RNA. Examples of protein toxins are saporin, dianthin, ricin, modecin, abrin, volkensin, viscumin, shiga toxin, shiga-like toxin, pseudomonas exotoxin (PE, also known as exotoxin A), diphtheria toxin (DT), and cholera toxin. Examples of toxins targeting tubulin filaments are maytansinoids (eg DM1 and DM4), auristatins (eg monomethyl auristatin E (MMAE) and monomethyl auristatin F (MMAF)), toxoids, tubulisins, cryptophycins, rhizoxin. Examples of toxins that target DNA are the calicheamicins: N-acetyl-Y-calicheamicin, CC-1065 analogues, duocarmycins, doxorubicin, methotrexate, benzodiazepines, camptothecin analogues, and anthracyclines. Examples of toxins that target DNA are amanitins, spliceostatins, and thailanstatins. A toxin, as used in this invention, is defined as a pharmaceutically active substance that can kill or inactivate a cell. Preferably, a target toxin is a toxin that is only, or at least predominantly, toxic to target cells but not to non-target cells. The net effect of the target toxin is preferably beneficial to the organism as a whole. An effector molecule or moiety that is a polypeptide can be, for example, a polypeptide that restores a lost function, such as, for example, enzyme replacement, gene regulation functions, or a toxin. Examples of polypeptides as effector molecules are, for example, Cas9; toxins (for example, saporin, diantin, gelonin, (de)bouganin, agrostin, ricin (toxin A chain); pokeweed antiviral protein, apoptin, diphtheria toxin, pseudomonas exotoxin) metabolic enzymes (for example, argininosuccinate lyase, argininosuccinato synthetase), enzymes of the coagulation cascade, repair enzymes; enzymes for cell signaling; cell cycle regulatory factors; gene regulatory factors (transcription factors such as NF-κΒ or gene repressors such as the methionine repressor). An effector molecule or effector moiety that is a polynucleotide can be, for example, a polynucleotide that comprises coding information, such as a gene or an open reading frame that encodes a protein. It may also comprise regulatory information, for example, binding regions of promoter or regulatory elements, or microRNA coding sequences. Said polynucleotide can comprise natural and artificial nucleic acids. Artificial nucleic acids include, for example, peptide nucleic acid (PNA), morpholino, and locked nucleic acid (LNA), as well as glycol nucleic acid (GNA) and threose nucleic acid (TNA). Each of these is distinguished from naturally occurring DNA or RNA by changes in the backbone structure of the molecule. Examples of nucleotides as effector molecules are, but are not limited to, for example, DNA: single-stranded DNA (eg, DNA for adenine phosphoribosyltransferase); double-stranded linear DNA (eg, coagulation factor IX gene); circular double-stranded DNA (eg, plasmids); RNA: mRNA (eg, TAL effector molecule nucleases), tRNA, rRNA, siRNA, miRNA, antisense RNA; antisense oligonucleotides (ASO, AON, eg, PNA, PMO, LNA and BNA). The term "protein", used, for example, in "protein molecule" and "protein toxin", are molecules and toxins that comprise at least one chain of amino acid residues that can be obtained as an expression product from a single mRNA. Said molecule or toxin may further comprise any post-translational modification, a carbohydrate such as an N- or O-linked carbohydrate, disulfide bonds, phosphorylations, sulfation, etc., as a result of any post-translational modification, and / or may M A / Ε / ΖυΖΊ / UO / JOS further encompasses any other modifications, such as those resulting from chemical modifications (for example, attachment of effector moieties, saponin, scaffolds, ligands, etc., either directly, for example, to a amino acid side chain or via at least one linker attached (covalently) to the molecule to chemically modify the protein molecule, and chemically attached (covalently) to the protein molecule). The term "protein" also encompasses and includes assemblies of such molecules, for example, homodimers, heterotrimers, heterohexamers, or complex assemblies such as ribosomes. The terms "specific" and "specifically", in the context of, for example, "specific binding" and "receptor or molecular target specifically present or expressed on the surface of a tumor cell" and the like, have their normal scientific meaning known in the art, and as used herein refers, for example, to a binding interaction of a first molecule with a second molecule that occurs with a higher affinity than any putative binding of the first molecule to an additional molecule other than the second molecule, or, for example, to expression or expression to a greater degree when, for example, considering the number of receptors or molecular targets, of a cell surface receptor or molecular target on the surface of a first cell type , such as a tumor cell, autoimmune cell, diseased cell, aberrant cell, to the degree of expression of the same receptor or molecular target in a second type of cell, such as a healthy cell, etc., in which expression in the second cell type may be completely absent or very low, relative to any degree of expression on the tumor cell, etc. Additionally, the term "specific", eg, in "specific binding", has its normal scientific meaning known in the art, and as used herein has the meaning of indicating a molecule that can have an interaction with another molecule with higher affinity. binding than the background interactions between molecules. Similarly, the term "specificity" refers to an interaction, for example, between two molecules or between a cell and a molecule, that has a higher binding affinity than background interactions between molecules. Binding molecules, such as immunoglobulins, bind via their binding site, such as the immunoglobulin variable regions of the immunoglobulin, to binding sites on the molecules, such as epitopes, cell surface receptors, etc. ., with a higher binding affinity than the background interactions between molecules. In the context of the invention, background interactions are typically interactions with an affinity less than a Kd of 10E-4 M. From M A / t / ZUZ I / UO / JOS Similarly, "specific binding domains" are domains that preferentially bind to binding sites on molecules, such as epitopes, cell surface receptors, etc., with a higher affinity than binding than the background interactions between molecules. In the context of the invention, "background interactions" are typically interactions with an affinity less than a Kd of about 10E-4 M. Preferably, specific binding domains bind with an affinity greater than a Kd of about 10E-5 m. The term "binding" is defined as interactions between molecules that can be distinguished from background interactions. Throughout the specification, the term "fragment" refers to an amino acid sequence that is part of a protein domain or that constitutes an intact protein domain. Binding fragments according to the invention should have binding specificity for the respective target, such as a cell surface receptor, eg on the surface of a diseased cell, such as a tumor cell. The term "ADC" or "antibody-drug conjugate" has its usual scientific meaning known to those skilled in the art, and as used herein refers to a class of biopharmaceutical drugs designed as a targeted therapy to treat, for example, cancer. Unlike chemotherapy, ADCs are intended to attack and destroy tumor cells without affecting healthy cells. ADCs are composed of an antibody linked to a biologically active cytotoxic (anti-cancer) drug or payload. ADCs combine the targeting capabilities of monoclonal antibodies with the cancer-killing ability of cytotoxic drugs. They are designed with the intention of discriminating between healthy cells and diseased tissue, such as tumor cells in a tumor. The term "Saponinum album" has its normal meaning and herein refers to a mixture of saponins produced by Merck KGaA (Darmstadt, Germany) containing saponins from Gypsophila paniculata and Gypsophila arostii, containing SA1657 and mainly SA1641. The term "Quillajasaponin" has its normal meaning and as used herein refers to the saponin fraction of Quillaja saponaria and thus the source of all other QS saponins, mainly containing QS-18 and QS-21. M A / I / UO / JOS “QS-21” or “QS21” has its usual scientific meaning and as used herein refers to a mixture of QS-21 A-celery (-63%), QS-21 A-xyl (-32%), QS-21 B-celery (-3.3%), and QS-21 B-xyl (-1.7%). Similarly, "QS-21 A" has its usual scientific meaning and as used herein refers to a mixture of QS-21 A-celery (-65%) and QS-21 A-xyl (-35%). Similarly, "QS-21 B" has its usual scientific meaning and as used herein refers to a mixture of QS-21 B-celery (-65%) and QS-21 B-xyl (-35%). The term "Quil-A" refers to a commercially available semi-purified extract of Quillaja saponaria and contains variable amounts of more than 50 different saponins, many of which incorporate the triterpene-trisaccharide substructure Gal-(1^2)-[Xyl (1^3)]-GlcA- in the C-3beta-OH group found in QS-7, QS-17, QS18 and QS-21. The saponins found in Quil-A are listed in van Setten (1995), Table 2 [Dirk C. van Setten, Gerrit van de Werken, Gijsbert Zomer and Gideon F. A. Kersten, Glycosyl Compositions and Structural Characteristics of the Potential Immuno-adjuvant Active Saponins in the Quillaja saponaria Molina Extract Quil A, RAPID COMMUNICATIONS IN MASS SPECTROMETRY, VOL 9, 660-666 (1995)]. Quil-A and also Quillajasaponin are saponin fractions from Quillaja saponaria and both contain a large variety of different saponins with largely overlapping content. The two fractions differ in their specific composition since the two fractions are obtained by different purification procedures. The term “QS1861” and the term “QS1862” refer to QS-7 and QS-7 api. QS1861 has a molecular mass of 1861 Daltons, QS1862 has a molecular mass of 1862 Daltons. QS1862 is described in Fleck et al. (2019) in Table 1, row No. 28 [Juliane Deise Fleck, Andresa Heemann Betti, Francini Pereira da Silva, Eduardo Artur Troian, Cristina Olivaro, Fernando Ferreira and Simone Gasparin Verza, Saponins from Quillaja saponaria and Quillaja brasiliensis: Particular Chemical Characteristics and Biological Activities, Molecules 2019, 24, 171; c¡:10.3390 / molecules24010171]. The described structure is the QS1862 apivariant of QS-7. The molecular mass is 1862 Dalton since this mass is the formal mass that includes the proton in glucuronic acid. At neutral pH, the molecule is deprotonated. When measuring in mass spectrometry in negative ion mode, the measured mass is 1861 Daltons. The terms first, second, third and similar in the description and in the claims are used to distinguish between similar elements and not necessarily M A / t / ZUZ I / UO íÓOO to describe a sequential or chronological order. The terms are interchangeable under appropriate circumstances. Embodiments of the invention may operate in sequences other than those described or illustrated herein. Additionally, the various embodiments, although referred to as "preferred" or "e.g. eg.” or "for example" or "in particular", are to be construed as exemplary ways in which the invention may be implemented rather than limiting the scope of the invention. The term "comprising", used in the claims, should not be construed as being restricted to the elements or steps listed below; it does not exclude other elements or stages. It is to be interpreted as specifying the presence of the indicated features, integers, steps or components to which reference is made, but does not preclude the presence or addition of one or more features, integers, steps or components or groups thereof. Therefore, the scope of the term "a pharmaceutical composition comprising A and B" should not be limited to a pharmaceutical composition consisting solely of components A and B, but with respect to the present invention, the only listed components of the pharmaceutical composition are A and B, and additionally, the claim is to be construed as including equivalents of those components. Similarly, the scope of the expression "a process comprising step A and step B" should not be limited to a process consisting only of steps A and B, but with respect to the present invention, the only enumerated process steps are A and B, and furthermore, the claim is to be construed as including equivalents of those steps. In addition, the reference to a characteristic in the indefinite article "a" or "an" does not exclude the possibility that more than one of the characteristics are present, such as for example a component, excipient, saponin, etc., unless the context clearly requires that there be one and only one of the characteristics. Therefore, the indefinite article "un" or "una" normally means "at least one". Brief description of the drawings Figure 1. In vivo study of antibody-protein toxin + SO1861 unconjugated. BT474 tumor-bearing mice treated with various concentrations of Trastuzumab-saporin (i.v.) + 1.5 mg / kg unconjugated SO1861 (subQ injection 1 hour before trastuzumab-saporin treatment). Figure 2. Unconjugated saponin-mediated endosomal escape and enhancement of target cell killing. A) Cell viability analysis of HeLa cells (EGFR+) ΜΛ / t / ZUZ I / UO f ¿00 treated with SO1861, S01832, S01862 (SO1861 isomer) or SO1904 with or without 1.5 pM EGFdiantin B) Cell viability analysis of HeLa cells (EGFR+) treated with EGFdiantin and concentrations SO1861, S01832, S01862 (isomer of SO1861) or SO1904. The axes and legends of A) and B) are the same. C) Cell viability analysis of HeLa cells (EGFR+) treated with SO1861 or GE1741 with or without 1.5 pM EGFdiantin. D) Cell viability analysis of HeLa cells (EGFR+) treated with various QSmix (mixture of Quillaia Saponaria saponins) with or without 1.5 pM EGFdiantin. The Y axes of C) and D) are the same. Figure 3. Activity of unconjugated SO1861 against SO1861-EMCH. EGFR-targeted antisense oligo BNA delivery and gene silencing in cancer cells, according to the invention. A, B, C) Cell viability analysis of A431 (EGFR++), HeLa (EGFR+) or A2058 (EGFR) cells treated with SO1861 or SO1861-EMCH with or without 1.5 pM diantin EG. D, E) Cell viability analysis of A431 (EGFR++) or HeLa (EGFR+) cells treated with SO1861 or SO1861-N3 with or without 1.5 pM EGFdiantin. The axes and legends of A), B), C), D) and E) are the same. That is, the legend of Figures 3A-C is shown next to Figure 30; the legend for Figure 3D and 3E is shown next to Figure 3E. Figure 4. SO1861 unconjugated vs. SO1861-EMCH (labile) vs. SO1861-S (stable). Cell viability analysis of HeLa cells (EGFR+) treated with SO1861, SO1861-S (S = HATU, stable linker) and SO1861-EMCH (labile linker) with or without EGFdiantin. Figure 5. Delivery of antisense BNA oligonucleotides targeting EGFR and gene silencing. Analysis of HSP27 mRNA expression from A431 (EGFR++) and A2058 (EGFR) cells treated with 100 nM cetuximab-(Cys-L-SO1861)3'9 or cetuximab-(Cys-L-SO1861)3'9+ HSP27BNA. The axes and legend for A) and B) are the same, and the legend is shown next to Figure 5B. The Y axis of C) and D) is the same. Figure 6. Antisense BNA oligonucleotide delivery and gene silencing in tumor-bearing mice. Mice treated with HSP27BNA + cetuximab-(Cys-LSO1861)3,9 in A431 tumor-bearing mice reveal effective tumor-directed gene silencing, compared to controls. Figure 7. In vivo activity of 1T2C. The 1T2C combination of 50 mg / kg cetuximab-(Cys-L-SO1861)4+ 25 mg / kg cetuximab-(-L-HSP27BNA)4 in A431 tumor-bearing mice reveals strong tumor-directed gene silencing, compared with those controls. Figure 8. In vivo activity of 1T2C. The 1T2C combination of 40 mg / kg trastuzumab-(Cys-L-SO1861)4+ 0.02 / 0.03 mg / kg trastuzumab-saporin in a PDX tumor mouse model (HER2 high expression) shows a effective inhibition of tumor growth. Figure 9. 2 components 1 target. EGFR-targeted cell killing in A431 (EGFR++) cells (A, C) and CaSKi (EGFR+) cells (B, D) by a therapeutic combination according to the invention. A, B) titration of Cetuximab-(Cys-L-SO1861)3'7+ fixed concentration of 10 pM cetuximab-saporin and controls on A431 (A) and CaSKi (B) cells. C, D) Titration of cetuximab-saporin + fixed concentration of cetuximab-(Cys-LSO1861)3·775 nM and controls on A431 (C) and CaSKi (D) cells. Figure 10. 2 components 1 target. EGFR-targeted cell killing in HeLa cells (EGFR+ / j (A, C) and A2058 (EGFR) cells (B, D) by a therapeutic combination according to the invention. A, B) Cetuximab-(Cys-L) titration -SO1861)3'7+ fixed concentration of 10 pM cetuximab-saporin and controls on HeLa (A) and CaSKi (B) cells. C, D) Titration of cetuximab-saporin + fixed concentration of cetuximab-(Cys-LSO1861)3·775 nM and controls on Hela (C) and A2058 (D) cells. Figure 11: 2 components 1 target. HER2-targeted cell killing in SKBR3 (HER2++) cells (A, B) by a therapeutic combination according to the invention. A) Titration of trastuzumab-(Cys-L-SO1861)4+ fixed concentration of trastuzumab-50 pM saporin and controls on SKBR3 cells. B) Titration of trastuzumab-saporin + fixed concentration of trastuzumab-(Cys-L-SO1861) 42.5 nM and controls on SKBR3 cells. Figure 12. 2 components 1 target. HER2-targeted cell killing in JIMT-1(HER2+ / j cells (A, C) and MDA-MB-468 (HER2) cells (B, D) by a therapeutic combination according to the invention. A, B) Titration of trastuzumab-(Cys-L-SO1861)4+ fixed concentration of 50 pM trastuzumab-saporin and controls on JIMT-1(A) and MDA-MB-468 (B) cells. C, D) Titration of trastuzumab-saporin + fixed concentration of trastuzumab-(Cys-L-SO1861) 42.5 nM and controls on JIMT-1(C) and MDA-MB-468 (D) cells. Figure 13: Chloroquine inhibits 1 component 2 targets. Destruction of cells directed at HER2 and EGFR in SK-BR-3 (HER2++) and A431 (EGFR++) cells, by means of a therapeutic combination according to the invention + chloroquine. A) Degree of ΜΛ / t / ¿U¿ I / UO / JOS trastuzumab-saporin + fixed concentration of trastuzumab-(Cys-L-SO1861)45 nM + chloroquine 0.5 μΜ and control on SK-BR-3 cells. B) Titration of cetuximab-saporin + fixed concentration of cetuximab-(Cys-L-SO1861) 385 nM + chloroquine 0.5 μΜ and control on A431 cells. Figure 14: 2 components 1 target. EGFR-targeted gene silencing in A431 cells (EGFR++) and A2058 cells (EGFR) by means of a therapeutic combination according to the invention. A, B) Titration of cetuximab-(Cys-L-SO1861)3.8+ fixed concentration of Cetuximab-(Lys-L-HSP27BNA)4100 nM and control on A431 cells (A) and A2058 cells (B). C, D) Titration of cetuximab-(Lys-L-HSP27BNA)4+ fixed concentration of Cetuximab-(Cys-L-SO1861)3877 nM and control on A431 cells (C) and A2058 cells (D). Figure 15: 2 components 2 targets. A) EGFR and HER2 targeted cell killing in MDA-MB-468 cells (EGFR++) and HeLa cells (EGFR+ / ) and HER2 targeted cell killing in SK-BR-3 cells (HER2++) and JIMT-1(HER2+ / ) cells ) by means of a therapeutic combination according to the invention. A) Titration of cetuximab-Cys-(dendron(-LSO1861)4)3'9+ fixed concentration of 10pM cetuximab-saporin and controls on MDA-MB-468 cells (A) and HeLa cells (B). C, D) Titration of trastuzumab-(Cys-(dendron(-LSO1861)4)4+ fixed concentration of 50 pM trastuzumab-saporin and controls on SK-BR-3 cells (C) and JIMT-1 cells (D). Figure 16. 1 component 2 targets. SK-BR-3 (HER2+ / ) cells can be effectively killed with the therapeutic combination according to the invention, Tratuzumab-saporin + trastuzumab-(Cys-L-SO1861)42.5 nM, however, the T titer -DM1 + ​​trastuzumab-(Cys-L-SO1861)42.5 nM is not effective at such low toxin concentrations. T-DM1 is Trastuzumab-emtansine (Kadcyla®), which carries ~3.5 emtansine toxin (DM1) molecules per antibody (DAR3.5). Figure 17. 2 components 1 target. EGFR-targeted cell killing in A431 (EGFR++) cells (A) and CaSKi (EGFR+) cells (B) and A2058 (EGFR) cells by a therapeutic combination according to the invention. A, B, C) Titration of cetuximab-(CysL-QSmix)4'1+ fixed concentration of 10 pM cetuximab-saporin or 10 pM cetuximab-diantine and controls in A431 cells (A), CaSKi cells (B) and A2058 cells (C). QSmix is ​​a mixture of saponins from an extract of Quillaja Saponaria. Figure 18: Concept of 2 components 1 target: mAb1-SO1861 + mAb1 protein toxin. SO1861 and the toxin (ribosomal inactivating protein) are each independently conjugated to an antibody (mAb1) for delivery and internalization into target cells. 1) mAb1-SO1861 and the mAb1 protein toxin bind to the cell surface receptor, 2) receptor-mediated endocytosis of both conjugates occurs, 3) at low endolysosomal pH and appropriate concentration, SO1861 is activated to allow endolysosomal escape, 4) release of toxin into the cytoplasm occurs and 5) the toxin induces cell death Figure 19: Target 2 component concept 1: mAb1-SO1861 + oligo mAb2-BNA. SO1861 and the BNA antisense oligonucleotide are each independently conjugated to an antibody (mAb1) for delivery and internalization into target cells. 1) mAb1SO1861 and oligo mAb1-BNA bind to the cell surface receptor, 2) receptor-mediated endocytosis of both conjugates occurs, 3) at low endolysosomal pH and appropriate concentration, SO1861 is activated to allow endolysosomal escape, 4) it is produces oligo BNA release into the cytoplasm and 5) targeted gene silencing. Figure 20: Concept of 2-component target: mAb1-(scaffold(-SO1861)n)n+ mAb1 protein toxin. Dendron(-SO1861)n and the protein toxin (ribosomal inactivating protein) are each independently conjugated to an antibody (mAb1) for delivery and internalization into target cells. 1) mAb1-dendron(-SO1861)4 and the mAb1 protein toxin bind to the cell surface receptor, 2) receptor-mediated endocytosis of both conjugates occurs, 3) at low endolysosomal pH and appropriate concentration, SO1861 is activated to allow endolisosomal escape, 4) release of the toxin into the cytoplasm occurs, and 5) the toxin induces cell death Figure 21: Antibody-(-L-SO1861)4 vs. Antibody-(-L-SO1861)2. HER2 and EGFR targeted cell killing in A431 (EGFR++) and SK-BR-3 (HER2++) cells, by therapeutic combination according to the invention A) cetuximab-(-L-SO1861)4+ cetuximab-saporin 10pM compared to 10pM cetuximab-(-L-SO1861)2+ cetuximabsaporin in A431 cells. B) Trastuzumab-(-L-SO1861)4+ trastuzumab-saporin 50 pM compared to trastuzumab-(-L-SO1861)2+ trastuzumab-saporin 50 pM in SK-BR-3 cells. Figure 22: Antibody-(-L-SO1861)4 vs. Antibody-(-S-SO1861)4. HER2-targeted cell destruction in SK-BR-3 (HER2++), by means of a therapeutic combination according to the invention. B) Trastuzumab-(-L-SO1861)4+ trastuzumab-saporin 50 pM compared to trastuzumab-(-S-SO1861)4+ trastuzumab-saporin 50 pM in SKBR-3 cells. M A / t / ZUZ I / UO í JOS Figure 23. The 2T2 component system tested in the A431 tumor-bearing mouse model reveals tumor regression. Figure 24. The 2T2 component system tested in the A431 tumor-bearing mouse model reveals tumor regression and eradication. Figure 25: 2 components 2 targets. EGFR / HER2 targeted cell killing in A431 cells (EGFR++ / HER2+ / ) (A, C) and CaSKi cells (EGFR++7HER2+ / j (B, D) by a therapeutic combination according to the invention. A, B) Titration of cetuximab(Cys-L-SO1861)3'7+ fixed concentration of 50 pM trastuzumab-saporin and controls on A431 cells. C, D) Titration of trastuzumab-saporin + fixed concentration of cetuximab(Cys-L-SO1861) 3.775 nM and controls on Caski cells. The axes and legends are the same for A) and B), and C) and D). That is, the legend of Figures 25A and B is shown next to Figure 25B; the legend for Figure 25C and 25D is shown next to Figure 25D. Figure 26. 2 components 2 targets. EGFR / HER2 targeted cell killing in HeLa cells (EGFR+ / 7HER2+ / j (A, C) and A2058 (EGFR77HER2+ / ) cells (B, D) by a therapeutic combination according to the invention. A, B) Cetuximab titration (Cys-L-SO1861)3+ fixed concentration of 50 pM trastuzumab-saporin and controls on HeLa cells. C, D) Trastuzumab-saporin titration + fixed concentration of cetuximab(Cys-L-SO1861) 3.775 nM and controls on A2058 cells. The axes and legends are the same for A) and B). That is, the legend of Figures 26A and B is shown next to Figure 26B. Figure 27: 2 components 2 targets. HER2 / EGFR targeted cell killing in SKBR3 (HER2++ / EGFR+ / ) cells (A, B) by a therapeutic combination according to the invention. A Trastuzumab-(Cys-L-SO1861)4 titration + fixed concentration of 1.5 pM EGFdiantin and controls on SKBR3 cells. B) EGFdiantin titration + fixed concentration of trastuzumab-(Cys-L-SO1861) 42.5 nM and controls on SKBR3 cells. Figure 28. 2 components 2 targets. HER2 / EGFR targeted cell killing in JIMT-1 (HER2+ / EGFR+ / j cells (A, C) and MDA-MB-468 (HER27EGFR++) cells (B, D) by a therapeutic combination according to the invention. A, B) Titration of trastuzumab-(Cys-L-SO1861)4+ fixed concentration of 1.5 pM EGFdiantin and controls on JIMT-1 cells. C, D) EGFdiantin titration + fixed concentration of trastuzumab-(Cys-LSO1861) 42.5 nM and controls on MDA-MB-468 cells. The axes and legends are the same for A) and B), and C) and D). That is, the legend of Figures 28A and B is shown next to Figure 28B; the legend for Figures 28C and 28D is shown next to Figure 28D. MA / E / ZUZ I / UO f JOS Figure 29: 2 components 2 targets. HER2 / EGFR targeted cell killing in SKBR3 cells (HER2++ / EGFR+ / j (A, B) by a therapeutic combination according to the invention. A) Trastuzumab-(Cys-L-SO1861)4+ titration fixed concentration of cetuximab -10pM saporin and controls on SKBR3 cells. B) Titration of cetuximabsaporin + fixed concentration of trastuzumab-(Cys-L-SO1861) 42.5 nM and controls on SKBR3 cells. Figure 30. 2 components 2 targets. HER2 / EGFR targeted cell killing in JIMT-1(HER2+ / EGFR+) cells (A, C) and MDA-MB-468 (HER27EGFR++) cells (B, D) by a therapeutic combination according to the invention. A, B) Titration of trastuzumab-(Cys-L-SO1861)4+ fixed concentration of 10 pM cetuximab-saporin and controls on JIMT-1 cells. C, D) Titration of cetuximab-saporin + fixed concentration of trastuzumab-(Cys-L-SO1861) 42.5 nM and controls on MDA-MB-468 cells. The axes and legends are the same for A) and B), and C) and D). That is, the legend of Figures 30A and B is shown next to Figure 30B; the legend for Figure 30C and 30D is shown next to Figure 30D. Figure 31: Chloroquine inhibits the 2 components 2 targets. Cell killing targeting EGFR / HER2, EGFR / CD71 or HER2 / CD71 in A431 (EGFR++ / HER2+ / _ / 7CD71+) cells (A, B), MDA-MB-468 (EGFR++ / HER27CD71+) (C) or SK- cells BR-3 (HER2++ / EGFR+ / CD71+) (D) by means of a therapeutic combination according to the invention + chloroquine. A) Trastuzumab-diantin or trastuzumab-saporin titration + fixed concentration of cetuximab-(Cys-L-SO1861)3.975 nM + 800 nM chloroquine and controls on A431 cells. B) Titration of CD71mab-saporin + fixed concentration of cetuximab(Cys-L-SO1861) 3910.5 nM + 500 nM chloroquine and control on A431 cells. C) Titration of CD71mab-saporin + fixed concentration of cetuximab-(Cys-L-SO1861) 3910.5 nM + 500 nM chloroquine and control on MDA-MB-468 cells. D) Titration of CD71 mab-saporin + fixed concentration of trastuzumab-(Cys-L-SO1861)3.95 nM + 500 nM chloroquine and control on SK-BR-3 cells. Figure 32: 2 components 2 targets. Gene silencing directed at EGFR / HER2 in A431 cells (EGFR++ / HER2+ / j (A) and A2058 cells (EGFR7HER2+ / j (B) by means of a therapeutic combination according to the invention. A) Cetuximab-(Cys-LSO1861) titration 3'9+ fixed concentration of trastuzumab-(Lys-L-HSP27BNA)4'4100 nM and control on A431 cells (A) and A2058 cells (B) C, D) Titration of trastuzumab-(Lys-L-HSP27BNA) 44+ fixed concentration of cetuximab-(Cys-L-SO1861)3'977 nM and controls on A431 cells ΜΛ / t / ¿U¿ I / UO / JOS (A) and A2058 cells (B). The axes and legends are the same for A) and B), and C) and D). That is, the legend of Figures 32A and B is shown next to Figure 32B; the legend for Figure 32C and 32D is shown next to Figure 32D. Figure 33: 2 components 2 targets. A) EGFR / CD71 or HER2 / CD71 targeted cell killing in MDA-MB-468 cells (EGFR++ / CD71+) (A) HeLa cells (EGFR+ / 7CD71+), SK-BR-3 cells (HER2++ / CD71+) (B) and JIMT-1 cells (HER2+ / 7CD71+) by means of a therapeutic combination according to the invention. A) Titration of cetuximab-Cys(dendron(-L-SO1861)4)3'9+ fixed concentration of CD71 mab-saporin of 10 pM and controls on MDA-MB-468 cells. B) A) Titration of cetuximab-Cys-(dendron(-L-SO1861)4)3'9+ fixed concentration of CD71 mab-saporin 10 pM and controls on HeLa cells. C) Titration of trastuzumab-Cys-(dendron(-L-SO1861)4)4+ fixed concentration of CD71 mab-saporin 10pM and controls on SK-BR-3 cells. D) Titration of trastuzumab-Cys-(dendron(-LSO1861)4)4+ fixed concentration of CD71 mab-saporin 10pM and controls on JIMT-1 cells. Figure 34. 2 components 2 targets against T-DM1. A431 (EGFR++ / HER2+A) cells can be effectively killed with the therapeutic combination according to the invention, Tratuzumab-saporin + cetux¡mab-(Cys-L-SO1861)3 975 nM, however the T titer -DM1 + ​​cetuximab-(Cys-L-SO1861)3'975 nM is not effective at such low toxin concentrations. T-DM1 is trastuzumab-emtansine (Kadcyla®), which carries ~3.5 emtansine toxin (DM1) molecules per antibody. Figure 35: Control treatments in all cell lines. A-D) Cell viability when trastuzumab (A), cetuximab (B), T-DM1, (C) are free of toxins: saporin and dianthine (D) or saporin coupled to an IgG that does not bind to the cell (D) is treated with the indicated cell lines SK-BR-3, JIMT-1, MDA-MB-468, A431, CaSki, HeLa, A2058, BT474. Figure 36. 2 components 2 targets. EGFR / CD71 and EGFR / HER2 targeted cell killing in A431 cells (EGFR+++ / HER2+ / ) (A) and CaSKi cells (EGFR++ / HER2+ / j (B) and A2058 cells (EGFR7HER2+ / j) by combination therapy according to the A, B, C) Titration of cetuximab-(Cys-L-QSmix)4'1+ fixed concentration of 10 pM trastuzumab-saporin or 10 pM CD71 mab-saporin and controls on A431 cells (A).CaSKi cells ( B) and A2058 cells (C) QSmix is ​​a mixture of saponins from an extract of Quillaja Saponaria The legend to Figures 36A and 36B is shown next to Figure 36B. ΜΛ / t / ZUZ I / UO f JOS Figure 37: Concept of 2 components 2 targets: mAb1-SO1861 + mAb2 protein toxin. SO1861 and the toxin (ribosomal inactivating protein) are each separately conjugated to an antibody (mAb) for delivery and internalization into target cells. 1) mAb1-SO1861 and the mAb2 protein toxin bind to their corresponding cell surface receptor, 2) receptor-mediated endocytosis of both conjugates occurs, 3) at low endolisosomal pH and appropriate concentration, SO1861 is activated to allow escape endolisosomal, 4) release of toxin into the cytoplasm occurs, and 5) the toxin induces cell death. Figure 38: Concept of 2 components 2 targets·. mAb1-SO1861 + oligo mAb2BNA. SO1861 and the BNA antisense oligonucleotide are each separately conjugated to an antibody (mAb) for delivery and internalization into target cells. 1) mAb1-SO1861 and oligo mAb2-BNA bind to their corresponding cell surface receptor, 2) receptor-mediated endocytosis of both conjugates occurs, 3) at low endolysosomal pH and appropriate concentration, SO1861 is reactivated to allow the endolisosomal escape, 4) release of oligo BNA into the cytoplasm occurs, and 5) targeted gene silencing. Figure 39: Concept of 2 components 2 targets: mAb1 -(scaffold(-SO1861)n)n+ mAb2 protein toxin. Dendron(-SO1861)n and the protein toxin (ribosomal inactivating protein) are each separately conjugated to an antibody (mAb) for delivery and internalization into target cells. 1) mAb1-(dendron(-SO1861)4)1) and mAb2 protein toxin bind to their corresponding cell surface receptor, 2) receptor-mediated endocytosis of both conjugates occurs, 3) at low endolysomal pH and concentration appropriately, SO1861 becomes active to allow endolisosomal escape, 4) release of toxin into the cytoplasm occurs, and 5) the toxin induces cell death. Figure 40. Tumor-targeted protein toxin delivery results in reduction of tumor volume and inhibition of tumor growth, in tumor-bearing mice. A) Increasing doses (intraperitoneal, i.p.) of cetuximab-(Cys-LSO1861)3'9(Lys-S-diantine)2 in A431 tumor-bearing mice reveals reduced tumor volume, compared to control. B, C) Increasing the dose (intraperitoneal, i.p. (B) or intravenous i.v. (C)) of cetuximab-(Cys-L-SO1861)3'9(Lys-Ldiantina)2 in A431 tumor-bearing mice reveals a reduction in the tumor growth, compared to controls. M A / IZ / ΖυΖΊ / UO f JOS Figure 41. Delivery of tumor-targeted antisense BNA oligonucleotides and gene silencing in tumor-bearing mice. 30 mg / kg of cetuximab-(Cys-LSO1861)3'9(Lys-L-HSP27BNA)1'8 in A431 tumor-bearing mice reveals effective tumor-induced gene silencing, compared to controls. Figure 42. Tumor-targeted antisense BNA oligonucleotide delivery and gene silencing in tumor-bearing mice. 30 mg / kg of cetuximab-Cys(SO1861-L-trifunctional linker-L-HSP27BNA)3'7 in A431 tumor-bearing mice reveals efficient tumor-induced gene silencing, compared to controls. Figure 43: HER2- or EGFR-targeted protein toxin delivery and cell killing in cancer cells, according to the invention. A, B) Treatment of trastuzumab-(Cys-L-SO1861 )3'8(Lys-L-diantine)1'7o Trastuzumab-(Cys-L-SO1861 )38(Lys-Sdiantine)1'7 and controls on SK cells -BR-3 (HER2++) and MDA-MB-468 cells (HER2j. C, D) Treatment of cetux¡mab-(Cys-L-SO1861)3'8(Lys-L-d¡ant¡na)1'7o Cetuximab -(Cys-LSO1861)3'8(Lys-S-diantine)1'7y controls on A431 (EGFR++) cells and A2058 (EGFR) cells. Figures 43A and B have the same legend, described next to Figure 43B. Figure 43C and D have the same legend, which is described next to Figure 43D. Figure 44: EGFR-targeted antisense oligo BNA delivery and gene silencing in cancer cells, according to the invention. A, B) Treatment of cetuximab(Cys-L-SO1861)3'8(Lys-L-HSP27BNA)1'7y controls on A431 cells (EGFR++) and A2058 cells (EGFR). Figures 44A and B have the same legend, described next to Figure 44B. Figure 45: HER2-targeted antisense oligo BNA delivery and gene silencing in cancer cells, according to the invention. Trastuzumab(Cys-L-SO1861)3'8(Lys-L-HSP27BNA)3'5 treatment and controls on SK-BR-3 (HER2++) cells. Figure 46: EGFR-targeted antisense oligo BNA delivery and gene silencing in cancer cells, according to the invention. A, B) Treatment with cetuximab-Cys-(S01861-L-trifunctional linker-L-HSP27BNA)3'7 and controls on A431 cells (EGFR++) and A2058 cells (EGFR). Figure 47: Concept (S)n-(L)(E): mAb-(SO1861)n(protein protein toxin) / Both, SO1861 in cisternae (Cys) residues and protein toxin (ribosomal inactivating protein) in Usin residues are conjugated to the same antibody (mAb) for delivery and internalization into target cells. 1) mAb-(Cys-L-SO1861)4Lys)2 protein toxin binds to its corresponding cell surface receptor, 2) mediated endocytosis occurs M A / t / ¿U¿ I / UO f ¿OO by receptor of both conjugates, 3) at low endolysosomal pH and appropriate concentration, SO1861 is activated to allow endolysosomal escape, 4) toxin release occurs in the cytoplasm and 5) the toxin induces cell destruction Figure 48: Concept (S)n-(L)(E): mAb-(SO1861 )n(antisense BNA oligo)n. Both SO1861, at cysteine ​​(Cys) residues and the antisense BNA oligonucleotide, at lysine residues are conjugated to the same antibody (mAb) for delivery and internalization into target cells. 1) mAb-(Cys-SO1861)4(oligoLys-BNA)2 binds to its corresponding cell surface receptor, 2) receptor-mediated endocytosis of both conjugates occurs, 3) at low endolisosomal pH and appropriate concentration, SO1861 is activated to allow endolysosomal escape, 4) release of oligo BNA into the cytoplasm occurs, and 5) targeted gene silencing is induced. Figure 49: Concept (S)n-(L)(E): mAb-(SO1861-scaffold-oligo BNA antisense)n. The (SO1861-trifunctional linker-oligo BNA)n is conjugated to an antibody (mAb) for delivery and internalization into target cells. 1) mAb-(SO1861 - trifunctional connect-oligo BNA)4 binds to its corresponding cell surface receptor, 2) receptor-mediated endocytosis of both conjugates occurs, 3) at low endolisosomal pH and appropriate concentration, SO1861 is reactivated to allow endolisosomal escape, 4) release of oligo BNA into the cytoplasm occurs, and 5) targeted gene silencing is induced. Figure 50. Antibody-SO1861 conjugation procedure. The coupling reaction of the connection of four fractions of a saponin SO1861 of vegetable origin to the four cisternae in the light chain of an antibody is shown. First, disulfide bonds in IgG are broken under the influence of exposure to TCEP (Tris(2carboxyethyl)phosphine); second, saponin SO1861 comprising a chemical linker attached thereto is added together with trifluoroacetic acid, and four fractions of saponin are bound to IgG. To produce 'ready to conjugate' cleaved saponins, the aldehyde group of SO1861 was reacted with an EMCH (ε-maleimidocaproic acid hydrazide) linker. The hydrazide group of EMCH forms an acid-cleavable hydrazone bond with the aldehyde of SO1861. At the same time, the EMCH connect presents a maleimide group that is thiol-reactive (sulfhydryl group) and can therefore be conjugated to IgG thiols, ie the ligand moiety. With this, a conjugate of the invention is provided that enhances endosomal escape and / or a first binding molecule of the invention is provided. M A / t / ZUZ I / UO f JOS Figure 51. Synthesis of SO1861-EMCH Figure 52 Synthesis of Dendron-(-L-SO1861)4 Figure 53. Synthesis of Dendron-(-L-SO1861)8 Figure 54. Synthesis of S0181- L-trifunctional-L-HSP27BNA connector Figure 55. Synthesis of HSP27BNA-dendron-(-L-SO1861)4 Figure 56. Synthesis of Dendron(NEM)4 Figure 57: Scaffold precursor with four amino groups for saponin linkage and one azide group for click chemistry. Figure 58: Evidence for the coupling of saponins to the model scaffold. The inset shows the theoretically expected peaks and intensity distribution for the coupled saponins. Experimental data obtained by LC-MS / ESI-MS show almost exactly the same peaks at m / z 758-760 Da providing for successful saponin coupling. Figure 59: Cytotoxicity assays using diantine-targeted toxin Epidermal Growth Factor (diantine-EGF). Untreated cells were normalized to 1. The polymeric structure (Pentrimer) has no influence on cell viability neither in the presence nor in the absence of Dianthin-EGF and saponin (SA1641), indicating that there is no intrinsic cytotoxicity of the polymeric structure. . The clickable targeting toxin (Dianthin-EGF-Alkyne) has markedly reduced activity, which is a result of toxin modification but completely unrelated to the scaffold. The functionalized polymeric structure has the same activity as the non-clickable target toxin, indicating that functionalization of the scaffold does not alter the activity of the effector molecule. The effect of the saponins is identical in the presence and absence of the polymeric structure, which shows that the polymeric structure does not alter the efficacy of the saponins in the two-component system. Figure 60: H-NMR spectrum of (A) SO1861 and (B) SO1861-EMCH (EMCH = Ν-ε-maleimidocaproic acid hydrazide). (A) The peak at 9.43 ppm (Ha) corresponds to the aldehyde proton of SO1861. (B) The peak at 6.79 ppm (Hc) corresponds to the maleimide protons of SO1861-EMCH, while the peak at 7.68 ppm (Hb) corresponds to the hydrazone proton. The absence of the signal at 9.43 ppm indicates a quantitative conversion of the aldehyde group. Figure 61: (A) MALDI-TOF-MS spectrum of SO1861-EMCH and (B) SO1861-EMCH mercaptoethanol. (A) RP mode: m / z 2124 Da([M+K]+, saponin-EMCH), m / z 2109 Da([M+K]+, M A / Ε / ΖυΖΊ / UO í JOS SO1861-EMCH), m / z 2094 Da ([M+Na]+, SO1861-EMCH). (B) RP mode: m / z 2193 Da ([M+K]+, saponin-EMCH-mercaptoethanol), m / z 2185 Da ([M+K]+, SO1861-EMCHmercaptoethanol), m / z 2170 Da ( [M+Na]+, SO1861-EMCH-mercaptoethanol). Figure 62: Structure SO1861 with chemical groups highlighted for the conjugation of saponins that enhance endosomal escape to a polymeric structure. The highlighted groups are aldehyde (black circle), carboxylic acid (dotted circle), alkene (dotted pentagon), and alcohol (dotted box). The aldehyde group (arrow) is the most suitable group for chemoselective and reversible conjugation reactions. Figure 63: Strategy to produce (A) stable endosomal escape-enhancing saponins and (B) ready-to-conjugate cleavable saponins. Figure 64: Hydrolysis of the hydrazone bond of SO1861-EMCH under acidic conditions. Figure 65: Structure SO1861-EMCH. (A) Standard molecular structure and (B) 3D model. The maleimide group is circled. Figure 66: (A) SO1861-EMCH synthesis scheme. (B) MALDI-TOF-MS spectra of SO1861 (m / z 1861 Da) and (C) SO1861-EMCH (m / z 2068 Da) in negative reflector mode. TFA: trifluoroacetic acid, T.amb.: room temperature, h: hours and PM: molecular weight. Figure 67: MALDI-TOF-MS spectra of SO1861-EMCH (A) before and (B) after hydrolysis in HCI solution at pH 3. Figure 68: Reaction scheme of the SO1861-EMCH conjugation with any amine-bearing polymeric structure. Figure 69: MALDI-TOF-MS spectra of (A) BSA-SO1861 (m / z 70.0 kDa, 72.1 kDa, 74.2 kDa) and (B) BSA (m / z 66.6 kDa). Figure 70: Reaction scheme of (A) SO1861-EMCH and (B) Conjugation of SO1861-HATU (HATU = 1-[Bis(dimethyllamno)methylene]-1H-1,2 hexafluorophosphate, 3-triazolo[4,5-b]pyridinium 3-oxide) to a G5 dendrimer of polyamidoamine (PAMAM) labeled with cyanine 3 dye. Figure 71: MALDI-TOF-MS spectra of (A) Cy3-PAMAM, (BD) Cy3-PAMAMSO1861 with charge equivalents of SO1861-EMCH increasing from (B) to bottom (D). (B) corresponds to Cy3-PAMAM-SO1861 with 5 SO1861 attached by PAMAM, (C) corresponds to Cy3-PAMAM-SO1861 with 13 SO1861 attached by PAMAM, and (D) corresponds to Cy3-PAMAM-SO1861 with 51 SO1861 attached by PAMAM. ΜΛ / t / ZUZ I / UO f ¿OO Figure 72: MALDI-TOF-MS spectra of (A) Cy3-PAMAM-SO1861 with 5 SO1861-EMCH charge equivalents and (B) Cy3-PAMAM-SO1861 with 30 SO1861-EMCH charge equivalents. Figure 73: MALDI-TOF-MS spectra of Cy3-PAMAM-N0-SO1861 (NC = stable ("non-cleavable") binding. Figure 74: (A) Reaction scheme and MALDI-TOF-MS spectra of (B) Cy3 PAMAM-NC-SO1861-Dibenzocyclooctin (DBCO), (C) Cy3-PAMAM-(SO1861 )s-DBCO and (D ) Cy3-PAMAM-(SO1861)27-DBCO. Figure 75: Reaction scheme of (A) diantin-EGF-Alexa488 and (B) diantin-EGFAlexa488-SS-PEG-N3. MALDI-TOF-MS spectra of (C) diantine-EGF, (D) diantine-EGFAlexa488 and (E) diantine-EGF-Alexa488-SS-PEG-N3; Alexa488: Alexa Fluor 488 tint. Figure 76: Reaction scheme of (A) diantin-Alexa488 and (B) diantin-Alexa488SS-PEG-N3. MALDI-TOF-MS spectra of (C) diantine, (D) diantine-Alexa488 and (E) diantineAlexa488-SS-PEG-N3; Alexa488: Alexa Fluor 488 tint. Figure 77: Fluorescence images of the SDS-PAGE gel performed on a VersaDoc imaging system. M = marker, P = Cy3-PAMAM-(SO1861)27-DBCO, D = diantine-EGF-Alexa488-SS-PEG-N3, C1 = Cy3-PAMAM-(SO1861)5-Dianthine-EGFAlexa488, C2 = Cy3-PAMAM-N0-SO1861-Dianthine-EGF-Alexa488 and C3 = Cy3-PAMAM(SO1861)27-Diantine-EGF-Alexa488. Figure 78: (A) Synthesis scheme of Cy3-PAMAM-N0-SO1861 through reductive amination. (B and C) Respective MALDI-TOF-MS spectra. Figure 79: Reaction scheme for the generation of poly(SO1861) using SO1861 -EMCH as monomer, the APS / TMEDA system as polymerization initiator and aminopropanethiol as radical scavenger. Figure 80: MALDI-TOF-MS spectra of poly(SO1861) reaction batches. (A) SO1861-EMCH at 60 °C, (B) SO1861-EMCH + 1T3 APS equivalent at 60 °C, (C) SO1861EMCH + 1Γ3 APS / TMEDA equivalent at 60 °C. Figure 81: DNA approach. Use of the DNA-origami principle to generate a DNA-based scaffold that is capable of conjugating and releasing glycoside molecules. In addition, one of the DNA strands gains a click chemistry moiety that can be used for conjugation with a target toxin to form a functionalized scaffold. bp: base pair. M A / t / ZUZ I / UO / OOO Figure 82: Poly(peptide-SO1861) approach. Use of a peptide sequence that can conjugate and release glycoside molecules and can react with itself to form a poly(peptide-SO1861) construct. The poly(peptide) chain ends can be further modified with click chemistry moieties (eg, BCN-NHS linker) that can be used for conjugation with a toxin. Figure 83. MALDI-TOF-MS spectra of (A) native peptide, (B) peptide-S01861 conjugate. Figure 84. Molecular structure of G4 dendron with protected amino groups. Figure 85. Synthesis scheme for the generation of scaffolds based on dendrons and functional scaffolds. Figure 86. (A) Reaction scheme for partial dye labeling and deprotection of the G4 dendron. (B) MALDI-TOF-MS spectrum of the deprotected and partially dye-labeled G4 dendron. Figure 87. MALDI-TOF-MS spectra of G4-SO1861 dendron scaffolds with (A) 22 charge equivalents of SO1861-EMCH, (B) 10 charge equivalents of SO1861EMCH, and (C) 3 charge equivalents of SO1861-EMCH . Figure 88. Cell viability curves of HeLa cells treated with (A) Cell surface expression of EGFR determined by FACS analysis of HeLa cells (B, see Table 19), cell viability of HeLa cells treated with SO1861 + diantin-EGF (DiaEGF ), SO1861 + diantine-EGF + chloroquine 500 nM, SO1861 + diantine-EGF + PAMAM500 nM, SO1861 + diantine-EGF + dendron 667 nM (C) cell viability of HeLa cells treated with SO1861 + diantine-EGF, SO1861 + diantine- 500 nM EGF + chloroquine, SO1861 + diantin-EGF + 500 nM PAMAM, SO1861 + diantin-EGF + 500 nM PAMAM-(SH)i6, SO1861 + diantine-EGF + 500 nM PAMAM-(SH)85, SO1861 + diantine- 500 nM EGF + PAMAM-(SH)io8 (D) cell viability of HeLa cells treated with SO1861 + diantine-EGF, SO1861 + diantine-EGF + 500 nM chloroquine, SO1861 + diantine-EGF + 500 nM PAMAM, SO1861 + diantine- EGF + PAMAM-(mPEG)3500 nM, SO1861 + diantinEGF + PAMAM-(mPEG)8500 nM, SO1861 + diantin-EGF + PAMAM-(mPEG)i8500 nM. Figure 89. (A) PAMAM thiolation reaction scheme using the 2-iminothiolane thiolation reagent. MALDI-TOF-MS spectra of (B) native PAMAM, (C) thiolated PAMAM(SH)65, (D) thiolated PAMAM-(SH)65, and (E) thiolated PAMAM-(SH)65. Figure 90. (A) PAMAM PEGylation reaction scheme using the mPEG2k-NHS PEGylation reagent. MALDI-TOF-MS spectra of (B) native PAMAM, (C) PAMAM(mPEG2k)3PEGylated, (D) PAMAM-(mPEG2k)8PEGylated, and (E) PAMAM-(mPEG2k)i8PEGylated. Figure 91: Basic scaffold with click chemistry function to link any desired effector molecule. The user determines the position of the click chemistry position on the effector molecule and all additional properties of the effector molecule, eg, the choice and position of an optional ligand. Figure 92: Functionalized scaffold with pre-attached effector molecule and click chemistry to attach any desired ligand. Optionally, a pH sensitive binding can be provided to release the effector molecule from the scaffold after reaching the endosomes. Detailed description In order for a bioactive molecule to function, the molecule must be capable of binding to its target, eg, in the blood serum, on the exterior of a cell surface, or within a cell or organelle. The active fraction of nearly all protein-based targeting toxins, for example, must enter the cytosol of the target cell to mediate their targeting modulatory effect. In many constellations, the toxin remains ineffective because (1) the targeted moiety is poorly internalized and remains bound to the outside of cells, (2) is recycled back to the cell surface after internalization, or (3) is transported to endolysosomes where it is degraded. Although these fundamental issues have been known for decades and more than 500 targeted toxins have been investigated in recent decades, the issues remain unresolved and only one antibody-targeted protein toxin, moxetumomab pasudotox-tdfk (LUMOXITI®, AstraZeneca Pharmaceuticals LP), has been approved by the FDA for relapsed or refractory hairy cell leukemia to date. To overcome these problems, many strategies have been described including approaches to redirect toxins to the endogenous cell membrane transport complexes of the biosynthetic pathway in the endoplasmic reticulum and techniques to disrupt or weaken the membrane integrity of endosomes, that is, the endocytic pathway compartments in a cell, thus facilitating endosomal escape. This comprises the use of lysosomotropic amines, carboxylic ionophores, calcium channel antagonists, various cell-penetrating peptides of viral, bacterial, plant, animal, human, and synthetic origin, other organic molecules, and light-induced techniques. MA / Ε / ΖυΖΊ / UO / JOS Although the efficacy of targeted toxins is typically increased in cell culture by a hundred to a thousand-fold, in rare cases more than a million-fold, the requirement to co-administer endosomal escape enhancers with other substances harbors new problems including additional side effects, loss of of target specificity, difficulties in determining the therapeutic window, and cell type-dependent variations. All strategies, including physicochemical techniques, require enhancer molecules that interact more or less directly with membranes and essentially comprise small chemical molecules, secondary metabolites, peptides, and proteins. A common feature of all these substances is that they are not by themselves specific to the target cell and are distributed with kinetics other than targeting toxins. This is one of the main drawbacks of current approaches. The present invention will be described with respect to particular embodiments, but the invention is not limited thereto, but only by the claims. The embodiments of the invention described in this document can work in combination and cooperation, unless otherwise specified. While the invention has been described in terms of various embodiments, it is contemplated that alternatives, modifications, permutations, and equivalents thereof will be apparent to one skilled in the art upon reading the specification and studying the drawings and graphics. The invention is in no way limited to the illustrated embodiments. Changes may be made without departing from the scope that is defined in the appended claims. One aspect of the invention relates to a first protein molecule comprising a first binding site for binding to a first epitope of a first cell surface molecule, the first protein molecule provided with at least one saponin covalently attached through at least one linker and / or through an oligochemical or polymeric scaffold to an amino acid residue of said first protein molecule, or covalently linked directly to an amino acid residue of said first protein molecule. Therefore, the invention relates to the provision of a conjugate, the conjugate comprising or consisting of the first protein molecule comprising a first binding site for binding to a first epitope on a first cell surface molecule, wherein at at least one saponin is covalently attached via at least one linker to the first protein molecule and / or is attached via an oligomechanical scaffold or ΜΛ / t / ¿U¿ I / UO / JOS polymeric to an amino acid residue of said first protein molecule, or covalently linked directly to an amino acid residue of said first protein molecule. One embodiment is the first protein molecule of the invention, wherein the first binding site comprises or consists of an immunoglobulin, or at least one immunoglobulin binding domain and / or at least one immunoglobulin binding fragment, such such as an antibody, an IgG, a molecule comprising or consisting of a Vhh domain or Vh domain, a Fab, a scFv, an Fv, a dAb, an F(ab)2, Fcab fragment, and / or comprising or consisting of on at least one ligand for binding to a cell surface molecule such as EGF or a cytokine. One embodiment is the first protein molecule of the invention, wherein the first epitope of the first cell surface molecule is a first tumor cell specific epitope of a first tumor cell surface molecule, more preferably a first cell specific epitope. tumor of a first tumor cell surface receptor specifically present on a tumor cell. One embodiment is the first protein molecule of the invention, wherein at least one saponin is a triterpenoid saponin and / or a bisdesmosidic triterpene saponin belonging to the type of a 12,13-dehydrooleanane with an aldehyde function at the C-position. 23 and optionally comprising a glucuronic acid function on a carbohydrate substituent on the C-3beta-OH group of the saponin, and / or a saponin isolated from a Gypsophila species and / or a Saponaria species and / or an Agrostemma species and / or a Quillaja species such as Quillaja saponaria. One embodiment is the first protein molecule of the invention, wherein at least one saponin is a single specific saponin or is a mixture of two or more different saponins, such as one or more of the saponins in Table A1 or Scheme I, SO1861, SA1657, GE1741, SA1641, QS-21, QS-21A, QS-21 A-api, QS-21 A-xyl, QS-21 B, QS-21 Bapi, QS-21 B-xyl, QS-7 -xyl, QS-7-ap¡, QS-17-ap¡, QS-17-xyl, QS1861, QS1862, Quillajasaponina, Saponinum album, QS-18, Quil-A, Gyp1, gipsoside A, AG1, AG2, S01542 , S01584, S01658, S01674, S01832, or any of their stereomers and / or any combination thereof, preferably the saponin is SO1861 and / or GE1741 and / or SA1641 and / or QS-21 and / or saponin with a core of quilaic acid aglycone, a Gal-(1—>2)-[Xyl-(1^3)]-GlcA carbohydrate substituent on the C-3beta-OH group and a Glc-(1^3)- carbohydrate substituent Xyl-(1—>4)-Rha-(1^2)-[Xyl-(1—>3)-4-ΟΑο-Ουί-(1—>4)]-Fuc in the group M A / t / ZUZ I / UO f ¿00 C-28-OH, and / or is 3-0-beta-D-galactopyranosyl-(1^2)-[beta-D-x¡lop¡ranos¡l-(1^3)]-betaD-glucuronopyranosyl quillaic acid 28 -O-beta-D-glucopyranosyl-(1 ->3)-beta-D-xylopyranos¡l-(1 ->4)alpha-L-rhamnopyranos¡l-(1^2)-[beta-D-x¡lop ¡ranos¡l-(1^3)-40Ac-beta-D-qu¡novop¡ranosil(1—>4)]-beta-D-fucopyranos¡de, more preferably the saponin is SO1861 and / or QS-21 . One embodiment is the first protein molecule of the invention, wherein at least one saponin is a bisdesmosidic saponin having a molecular mass of at least 1,500 Daltons and comprising an olean-type triterpene containing an aldehyde group at the C- position. 23 and optionally a hydroxyl group at position C-16, with a first branched carbohydrate side chain at position C-3 which first branched carbohydrate side chain optionally contains glucuronic acid, wherein the saponin contains an ester group with a second branched carbohydrate side chain at position C-28 which second branched carbohydrate chain preferably comprises at least four carbohydrate units, optionally containing at least one acetyl residue such as two acetyl residues and / or optionally comprising deoxy carbohydrates and / or optionally comprising quinovose and / or optionally comprising glucose and / or optionally comprising 4-methoxycinnamic acid and / or optionally comprising 5-O-[5-O-Ara / Api-3,5-d¡ acid hidrox¡-6-methyl-octano¡l]-3,5dihydroxy-6-methyl-octanoic acid and / or optionally comprising 5O-[5-O-Rha-(1>2)Ara / Ap¡ acid -3,5-dihidroxy¡-6-methyl-octano¡l]-3,5-d¡h¡drox¡-6-methyl-octano¡co linked to a carbohydrate through an ester bond, or in which at least one saponin is QS-21 or any one or more of QS-21 A, QS-21 A-api, QS-21 A-xyl, QS-21 B, QS-21 B-ap¡, QS-21 B-xyl, QS-7-xyl, QS-7-ap¡, QS-17-ap¡, QS-17-xyl, QS-18, QS1861, protonated QS1861 (QS1862), Quil-A. One embodiment is the first protein molecule of the invention, wherein at least one saponin is a bisdesmosidic triterpene saponin belonging to the type of a 12,13-dehydrooleanan with an aldehyde function at position C-23, wherein at least one saponin is covalently coupled to the amino acid residue of the first protein molecule through an aldehyde function on the saponin, preferably said aldehyde function at position C-23, preferably through at least one linker, more preferably via at least one cleaved linker, wherein the amino acid residue is preferably selected from cysteine ​​and lysine. One embodiment is the first protein molecule of the invention, wherein at least one saponin is a bisdesmosidic triterpene saponin belonging to the type of a 12,13-dehydrooleanan with an aldehyde function at position C-23 and comprising ΜΛ / t / ¿U¿ I / UO / JOS a glucuronic acid function on a carbohydrate substituent on the C-3beta-OH group of saponin, where at least one saponin is covalently coupled to the amino acid residue of the first protein molecule via the glucuronic acid function on the carbohydrate substituent on the C-3beta-OH group of the saponin, preferably via at least one linker, wherein the amino acid residue is preferably selected from cysteine ​​and usin. One embodiment is the first protein molecule of the invention, wherein the aldehyde function at position C-23 of at least one saponin is covalently coupled to the Ν-ε-maleimidocaproic acid hydrazide linker, which linker is coupled covalently. forms covalently through a thio-ether bond to a sulfhydryl group on the first protein molecule, such as a sulfhydryl group on a cysteine. One embodiment is the first protein molecule of the invention, wherein the glucuronic acid function on the carbohydrate substituent on the C-3beta-OH group of at least one saponin is covalently coupled by linking 1[B¡ hexafluorophosphate s(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridino 3-oxide, the linker of which is covalently coupled via an amide bond to an amine group on the first protein molecule, such as an amine group of a lysine or an N-terminus of the first protein molecule. One embodiment is the first protein molecule of the invention, wherein the first epitope of the first cell surface molecule to which the first binding site of the first protein molecule binds is a first tumor cell specific epitope of the receptor specific for tumor cell preferably selected from CD71, CA125, EpCAM(171A), CD52, CEA, CD44v6, FAP, EGF-IR, integrin, syndecan-1, vascular alpha-V beta-3 integrin, HER2, EGFR, CD20, CD22, receptor Folate 1, CD146, CD56, CD19, CD138, CD27L receptor, PSMA, CanAg, integrin-alphaV, CA6, CD33, mesothelin, Crypt, CD3, CD30, CD239, CD70, CD123, CD352, DLL3, CD25, ephrinA4, MUC1, Trop2, CEACAM5, CEACAM6, HER3, CD74, PTK7, Notch3, FGF2, C4.4A, FLT3, CD38, FGFR3, CD7, PD-L1, CTLA4, CD52, PDGFRA, VEGFR1, VEGFR2, most preferably selected from CD71, EGFR, HER2. One embodiment is the first protein molecule of the invention, wherein the first tumor cell-specific epitope, first tumor cell surface molecule, or first tumor cell-specific receptor is a first epitope or a first molecule or a first receptor that are internalized by the tumor cell after binding of the M A / t / ZUZ I / UO / JOS first protein molecule of any one of claims 1 to 11 to the first epitope or first molecule or first receptor, and wherein preferably the first protein molecule undergoes receptor-mediated internalization of the cell tumor, for example through endocytosis, or tumor cell surface molecule-mediated internalization, for example through endocytosis, when binding to the cell surface molecule comprising the first epitope, the tumor cell surface molecule or the tumor cell specific receptor. One embodiment is the first protein molecule of the invention, wherein the first binding site of the first protein molecule comprises or consists of any one of cetuximab, daratumumab, gemtuzumab, trastuzumab, panitumumab, brentuximab, inotuzumab, moxetumomab, polatuzumab, obinutuzumab , anti-CD71 OKT-9 IgG monoclonal antibody, pertuzumab, rituximab, ofatumumab, Herceptin, alemtuzumab, pinatuzumab, anti-CD38 OKT-10 monoclonal antibody, an antibody from Table A2 or Table A3 or Table A4, preferably cetuximab or trastuzumab or OKT-9, or at least one tumor cell receptor binding fragment thereof and / or at least one tumor cell receptor binding domain thereof, preferably at least one tumor cell specific receptor binding fragment thereof and / or at least one tumor cell specific receptor binding domain thereof. One aspect of the invention relates to a therapeutic combination, wherein the therapeutic combination comprises: (a) a first pharmaceutical composition comprising the first protein molecule of the invention and optionally a pharmaceutically acceptable excipient; and (b) a second pharmaceutical composition comprising a second protein molecule different from the first protein molecule, the second protein molecule comprising a second binding site for binding to a second epitope on a second cell surface molecule different from the first molecule. cell surface, and comprising an effector moiety, the second pharmaceutical composition optionally further comprises a pharmaceutically acceptable excipient, wherein the second epitope is different from the first epitope. One embodiment is the therapeutic combination of the invention, wherein the therapeutic combination comprises: (a) the first pharmaceutical composition of the invention comprising the first protein molecule of the invention, wherein the first epitope on the first surface molecule cellular is a first tumor cell-specific epitope on a first tumor cell-specific surface molecule, preferably a first tumor cell-specific epitope on a first cell surface receptor specifically present on a tumor cell; and (b) the second pharmaceutical composition of the invention, wherein the second cell surface molecule is a second tumor cell-specific surface molecule different from the first tumor cell-specific surface molecule, preferably a second cell surface receptor. specifically present on a tumor cell other than the first cell surface receptor specifically present on said tumor cell, and wherein the second epitope is a second tumor cell-specific epitope. One aspect of the invention relates to a therapeutic combination of the invention, wherein the therapeutic combination comprises: (a) the first pharmaceutical composition of the invention comprising the first protein molecule according to the invention and comprising the first binding site for binding to the first epitope on the first cell surface molecule, the first pharmaceutical composition optionally further comprises a pharmaceutically acceptable excipient; and (b) a third pharmaceutical composition comprising a third protein molecule, the third protein molecule comprising the first binding site for binding to the first epitope on the cell surface molecule of (a) and an effector moiety, the third pharmaceutical composition optionally further comprising a pharmaceutically acceptable excipient, wherein the first binding site of the first protein molecule and the first binding site of the third protein molecule are the same, and wherein the first cell surface molecule and the first epitope on the first cell surface molecule, to which the first protein molecule can bind, and the first cell surface molecule and the first epitope on the first cell surface molecule, to which the third protein molecule can bind, are the same. One embodiment is the therapeutic combination of the invention, wherein the therapeutic combination comprises: (a) the first pharmaceutical composition of the invention; and (b) the third pharmaceutical composition of the invention, wherein the first cell surface molecule is expressed on a tumor cell surface, and preferably the first cell surface molecule is a tumor cell specific surface molecule, and in wherein preferably the first epitope is a tumor cell-specific first epitope. One embodiment is the first protein molecule of the invention or therapeutic combination of the invention, wherein the first binding site for binding to the first epitope ΜΛ / t / ¿U¿ I / UO / JOS on the first cell surface molecule is a binding site for a first tumor cell-specific epitope on a first cell surface receptor specifically present on a tumor cell. The inventors established that the therapeutic window of an antibody-drug conjugate, such as the second and third protein molecules in the second or third pharmaceutical composition of the invention, respectively, increases when administered to a tumor-bearing mammal (mouse) to which the first pharmaceutical composition is also administered. The first protein protein has at least one glycoside such as a saponin attached to it, preferably covalently, more preferably via a cleavage linker. Saponin increases the therapeutic efficacy of the effector moiety bound to the second and third protein molecules, probably by enhancing the endosomal escape of the effector moiety into the cytosol where effector moiety activity is desired. In this way, already at a dose lower than the conventional dose of ADC, that is, the second or third protein molecule, the therapeutic effect is established under the influence of the presence of the first protein molecule that comprises the saponin near, in and / or or within the target cell. The target cell is for example a diseased cell such as a tumor cell or an autoimmune cell or a B cell related to B cell disease, etc. The effector moiety is for example a toxin as part of an ADC or an oligonucleotide such as a BNA as part of a COC according to the invention. One embodiment is the therapeutic combination of the invention, in which the second binding site of the second protein molecule and / or the first binding site of the third protein molecule comprises or consists of an immunoglooulin, at least one binding domain of an immunoglooulin and / or at least one binding fragment of an immunoglooulin, such as an antibody, an IgG, a molecule comprising or consisting of a Vhh domain or Vh domain, an Faó, a scFv, an Fv, a dAó, an F(aó)2, Fcaó fragment, and / or comprises or consists of at least one ligand for binding to a cell surface molecule such as EGF or a cytokine. One embodiment is the therapeutic combination of the invention comprising the second pharmaceutical composition, wherein the second binding site of the second protein molecule for binding to the second epitope is a second binding site for a second tumor cell-specific epitope over a second surface receiver Cellular M A / Ε / ΖυΖΊ / UO / JOS specifically present in the tumor cell, in which the second binding site is different from the first binding site. By targeting (two) different cell surface molecules with the first and second protein molecules, delivery of the saponin and effector molecule to and within the cytosol of the same target cell is enhanced, which exposes different cell surface molecules on the surface. cell, and more specific, as compared to exposing such cells to only the second protein molecule such as an ADC or AOC, without the presence of the cell-directed saponin (first protein molecule). An aberrant cell selected to be targeted separately by the binding site of the first protein molecule and by the binding site of the second protein molecule, in which the binding sites are different and in which the epitope to which they bind the first and second protein molecules are different and located in / on a different class and type of cell surface molecule such as two different receptors, ideally carrying the first epitope and second epitope on the first cell surface molecule and the second molecule cell surface molecules respectively, to a high degree (i.e. relatively higher expression of the two distinct and different cell surface molecules on the target cell, such as a tumor cell or an autoimmune cell, than expression on a non-cell surface cell). target such as, for example, a healthy cell) and / or exposes the first and second cell surface molecules specifically, when considering healthy (neighboring) cells in a patient. Preferably, both cell surface molecules targeted by the first and second second binding sites are expressed relatively high and / or specifically on the target cell (disease, tumor) compared to healthy cells. One embodiment is the pharmaceutical combination, in which at least one of the first and second binding sites, and therefore at least one of the first and second cell surface molecules, such as a first and second tumor cell receptor, it is expressed specifically or relatively to a higher degree compared to the expression of the first cell surface molecule and / or the second cell surface molecule on the surface of a healthy (neighboring) cell. Thus, either the first epitope or the second epitope, preferably both the first epitope and the second epitope, on the target cell surface molecule is / are ideally unique to the target diseased cells, and is / are at least specifically present and exposed in the surface of the target cells. Binding of the first and second protein molecules to their respective first and second epitopes on a target cell is followed by endocytosis of the first and second protein molecule complexes. MA / Ε / ΖυΖΊ / UO / JOS first target cell surface molecule and the second protein molecule and the second target cell surface molecule. Since the first and second protein molecules have to enter the same target cell through binding interaction with two different cell surface molecules, both expressed to a sufficient degree or uniquely on the target cell compared to the other In healthy cells that should not be targeted, accumulation of a therapeutically active amount of the first and second protein molecules within the target cells is only possible and occurs if the expression levels of the two distinct target cell surface molecules are both above of a certain minimum expression threshold. At the same time, the fact that the effector moiety bound to the second protein molecule is only capable of exerting its intracellular activity (for example, cytotoxic or gene silencing) in the presence of the first protein molecule carrying the covalently bound saponin , when both the first and second protein molecules were able to enter the target cell in sufficient quantities by binding to the sufficiently exposed and expressed first and second cell surface molecules, also provides protection against the negative and unwanted side effects of the effector moiety towards, for example, healthy cells and healthy tissue that are not intended to be targeted or affected by the effector moiety, when the expression of at least one of the first and second cell surface molecules is sufficiently low in the healthy cells and preferably when the expression of both the first and second target cell surface molecules is sufficiently low in healthy cells. That is, sufficiently low expression or even absence of the exposed first and second cell surface molecules with respect to the first and second cell surface molecules, and at least the first cell surface molecule or the second cell surface molecule, bound by the first and second binding sites of the first and second protein molecules, respectively, ideally does not allow entry into healthy (untargeted) cells of the first and second protein molecules at amounts that together would result in endosomal escape of the fraction effector under the influence of the saponin bound to the first protein molecule. Since ADC or COC can be used at lower doses compared to when the first protein molecule was not added to the therapeutic regimen, entry of ADC or COC into healthy cells to a low degree already carries a lower risk of side effects. unwanted side effects when, for example, considering the M A / t / ZUZ I / UO / JOS targeting and killing diseased target cells such as tumor cells and autoimmune cells. One embodiment is the first protein molecule of the invention or the therapeutic combination of the invention comprising the second pharmaceutical composition, wherein said first and second protein molecules comprise the first and second binding sites respectively for binding to a first and second tumor cell specific epitope on a first and second tumor cell specific receptor respectively, the receptors are different and present on the same tumor cell, where the first and second binding sites are different and the first and second specific epitopes tumor cell are different. One embodiment is the first protein molecule of the invention or the therapeutic combination of the invention comprising the third pharmaceutical composition, wherein said first and third protein molecules comprise the same first binding site for binding to a first tumor cell specific epitope. on a first tumor cell-specific receptor. One embodiment is the first protein molecule of the invention or the therapeutic combination of the invention comprising the second pharmaceutical composition, in which the first receptor and / or the second receptor are selected from CD71, CA125, EpCAM(17-1 A) , CD52, CEA, CD44v6, FAP, EGF-IR, integrin, syndecan-1, vascular alpha-V beta-3 integrin, HER2, EGFR, CD20, CD22, Folate receptor 1, CD146, CD56, CD19, CD138, receptor CD27L, PSMA, CanAg, integrin-alphaV, CA6, CD33, mesothelin, Cripto, CD3, CD30, CD239, CD70, CD123, CD352, DLL3, CD25, ephrinA4, MUC1, Trop2, CEACAM5, CEACAM6, HER3, CD74, PTK7 , Notch3, FGF2, C4.4A, FLT3, CD38, FGFR3, CD7, PD-L1, CTLA4, CD52, PDGFRA, VEGFR1, VEGFR2, preferably selected from CD71, EGFR and HER2. One embodiment is the first protein molecule of the invention or the therapeutic combination of the invention comprising the second pharmaceutical composition, wherein the first and second tumor cell-specific receptors are internalized by the tumor cell after binding to the first molecule. protein of the invention and / or the second protein molecule of the invention when the therapeutic combination comprises the second pharmaceutical composition, and in which preferably the binding of the first protein molecule and / or the second protein molecule to the first and second specific receptors of tumor cell respectively, results in receptor-mediated internalization of the tumor cell, eg via endocytosis, of a complex of the M A / t / ZUZ I / UO / JOS first protein molecule and the first tumor cell specific receptor and of a complex of the second protein molecule and the second tumor cell specific receptor. One embodiment is the therapeutic combination comprising the third pharmaceutical composition of the invention or the first pharmaceutical composition according to the invention, in which the first tumor cell receptor, preferably the first tumor cell-specific receptor, is internalized by the cell. tumor after binding to the first protein molecule of the invention and / or after binding to the third protein molecule of the invention, and wherein preferably the binding of the first protein molecule and / or the third protein molecule to the first tumor cell receptor, such as the first tumor cell-specific receptor, is followed by receptor-mediated internalization of the tumor cell, for example through endocytosis, of a complex of the first protein molecule and the first tumor cell receptor and of a complex of the third protein molecule and the first tumor cell receptor. Timing is the missing link between a successful delivery strategy for mice and its application in humans. In fact, the inventors established in a series of in vivo mouse tumor models that the separate administration to the mice of a dose of free saponin and a dose of ADC (second or third protein molecule according to the invention) did not give as a result no desired antitumor activity, such as delayed tumor growth, tumor regression, decreased and slower tumor growth, compared to control animals not treated with ADC and free saponin. Free saponin was administered using various routes of administration and using various time points of free saponin administration compared to the time of ADC administration (administer free saponin before, during, and after ADC administration). The ADC tested in in vivo tumor models was cetuximab-diantine (with free SO1861) or trastuzumab-saporin (with free SO1861). Varying the dose of free saponin did not provide effective antitumor activity. The mentioned ADCs were administered at a dose which itself did not inflict any beneficial antitumor effect on the tumor-bearing animals. Surprisingly, the inventors have now established that beneficial antitumor activity can be achieved in various mammalian cell-based bioassays in vitro and / or in various animal tumor models in vivo by treating the animals with conjugates according to the invention, which optionally comprise a scaffold according to the invention, i.e. combinations of first and second or first and third protein molecules of the ΜΛ / t / ZUZ I / UO / JOS invention. The scaffold, for example, is a trifunctional linker with a covalently bound saponin (eg SO1861, QS-21) through a cleaved or non-cleavable bond, and / or with a covalently bound effector moiety (eg example, diantine, silencing of BNA (HSP27) through a non-cleavable bond or a cleaved bond, and / or with a covalently linked monoclonal antibody such as cetuxima, trastuzuma, OKT-9, or the scaffold is a dendron, such as a dendron to which, for example, four moieties such as four saponin molecules can bind, or a dendron to bind, for example, two saponins and two effector molecules, the dendron comprises a chemical group for (covalent) coupling to a ligand or an antibody or fragment or domain thereof Reference is made to the Examples section, which exemplifies several of these scaffolds according to the invention, showing anti-tumor cell activity in vivo and / or in vitro when consider cellular toxicity exerted, for example, by a protein toxin or when considering gene silencing in the tumor cell. Without wishing to be bound by theory, in view of the failures observed when considering treatment of tumor-bearing animals with an ADC together with free saponin, it is preferable to synchronize the presence of both at least one saponin and the effector moiety, preferably a toxin or an oligonucleotide, in compartments or vesicles of the endocytic pathway of the target cell, eg, a tumor cell or an autoimmune cell. With ADC and free saponin, synchronizing the presence of the molecules in the late endosomes, in order to obtain the synergistic effects in vivo, could not be beneficially obtained in accordance with the inventors' attempts. In one aspect, the invention preferably solves at least the following problem with respect to the combination of the effector moiety made up of the second protein molecule and the saponins made up of the first protein molecule: Without wishing to be limited to any theory, the only reasonable chemical group within, for example, the saponins that can be used for (covalent) coupling, in particular, unique and cleavable retainable coupling for endosomal escape activity. Known restrictions are most likely the reason that saponins have not been used in combination with pharmaceutically active substances in clinical investigations other than the application of saponins in vaccination regimens where the use of an immunoenhancing adjuvant was implied. , although the striking endosomal escape-enhancing effect of, for example, the saponins listed in Table A1 and the MA / E / ZUZ I / UO f JOS Scheme I has been known for more than 10 years. For example, providing a first protein molecule of the invention with a covalently conjugated scaffold overcomes these difficulties, at least in part. Surprisingly, saponins previously applied for their immunoenhancing activity in the vaccination context involving saponins as an adjuvant component are now also suitable for (covalent) coupling to the first protein molecule of the invention, for antitumor activity in vitro and e.g. in vivo. An effector moiety useful in the present invention preferentially relies on late endosomal escape to exert its effect. Some effectors, such as, for example, a pseudomonas exotoxin, are redirected to other organelles prior to the "late endosomal stage" and therefore would not normally benefit from coupling to the second protein molecule according to the present invention. However, such a toxin can be adapted for use with the present invention, for example, by eliminating the rerouting responsible for the signal peptide. In particular, toxins that are highly toxic and would require only one molecule to escape endosomes to kill a cell can be modified to be less potent. It is preferred to use a toxin that kills a cell if at least 2, more preferably at least 5, more preferably at least 10, more preferably at least 20, more preferably at least 50, still more preferably at least 100 toxin molecules escape the endosome. . It is further preferred that a second protein molecule of the invention comprises a covalently conjugated functionalized scaffold, i.e. a scaffold comprising the covalently bound effector moiety(s) to target the scaffold. comprising the effector moiety(s) bound to a target cell such as a tumor cell or an autoimmune cell. Additionally, in order to reduce off-target toxicity, non-cell membrane permeable small molecule toxins are preferred effector molecules over cell membrane permeable toxins. The term "ligand" as used in the present invention has its ordinary meaning and preferably means a molecule or structure that is capable of binding to another molecule or structure on the cell surface of a target cell, wherein said molecule or structure on the cell surface can be endocytosed and is preferably absent or less prominent in off-target cells. Preferably, said molecule or structure on the cell surface is constitutively endocytosed. More preferably, a ligand in the present invention induces endocytosis of said M A / t / ZUZ I / UO / JOS molecule or structure on the cell surface of target cells after binding to said molecule or structure. This is, for example, the case with the Epidermal Growth Factor Receptor (EGFR), present on the surface of a variety of cancer cells. Examples of molecules or structures on the cell surface of target cells that are constitutively endocytosed are, for example, Claudin-1 or major histocompatibility complex class II glycoproteins. A ligand can be, for example, an antibody, a growth factor or a cytokine. Combining a toxin with a ligand in a carrier molecule is one possibility to create a targeted toxin. A toxin that is only toxic to a target cell because it interferes with processes that occur only in target cells can also be viewed as a target toxin (since non-target cells cannot exert their toxic action, e.g. apoptin). . Preferably, a target toxin is a toxin that is combined with a ligand or, for example, a monoclonal antibody to be active in target cells and not in non-target cells (since it is only bound to and endocytosed by target cells). In a functionalized scaffold comprising a carrier molecule comprising a ligand and an effector moiety (ie, a second or third protein molecule), the ligand or monoclonal antibody guides the effector moiety and scaffold to target cells. After internalization, the at least one glycoside, preferably a saponin composed of the conjugate of the first protein molecule and the saponin, mediates endosomal escape of the effector moiety. The saponin is typically a saponin listed in Table A1 and Scheme I, and preferably the saponin is SO1861 and / or QS-21, and / or SA1641 and / or GE1741. Preferably, the effector moiety bound to the second or third protein molecule, the effect of which is enhanced by saponins bound to the first protein molecule, is separated from the second or third protein molecule, eg an antibody, when endocytosed. This can be accomplished by a cleaved bond that is cleaved, for example, under acidic, reducing, enzymatic, or light-induced conditions. One embodiment is the first protein molecule of the invention, and / or therapeutic combination of the invention comprising the second pharmaceutical composition, wherein the first binding site and / or second binding site is / are or comprise(s) a monoclonal antibody or at least a fragment and / or cell surface molecule binding domain thereof, and preferably comprise or consist of any one of cetuximab, daratumumab, gemtuzumab, trastuzumab, panitumumab, brentuximab, inotuzumab, moxetumomab, polatuzumab, obinutuzumab, anti-CD71 monoclonal antibody IgG-type OKT-9, pertuzumab, rituximab, ofatumumab, Herceptin, alemtuzumab, pinatuzumab, anti-CD38 monoclonal antibody OKT-10, and an antibody from Table A4, preferably cetuximab or trastuzumab or OKT-9, or at least a fragment or cell surface molecule binding domain thereof, with the proviso that the first binding site of the first protein molecule is different from the second binding site of the second protein molecule. One embodiment is the therapeutic combination comprising the third pharmaceutical composition of the invention or the first pharmaceutical composition according to the invention when composed of the therapeutic combination comprising the third pharmaceutical composition, in which the first binding site of the first molecule and the third protein molecule comprise a monoclonal antibody or at least one of a cell surface molecule binding domain and / or fragment thereof, and preferably comprise or consist of any one of cetuximab, daratumumab, gemtuzumab, trastuzumab, panitumumab , brentuximab, inotuzumab, moxetumomab, polatuzumab, obinutuzumab, OKT-9 anti-CD? 1 monoclonal antibody of the IgG type, pertuzumab, rituximab, ofatumumab, Herceptin, alemtuzumab, pinatuzumab, anti-CD38 OKT-10 monoclonal antibody, an antibody from Table A2 or Table A3 or Table A4, preferably cetuximab or trastuzumab or OKT-9, or at least a fragment and / or cell surface molecule binding domain thereof, with the proviso that the first binding site of the first protein molecule is the same as the first binding site of the third protein molecule. One embodiment is the therapeutic combination comprising the second or third pharmaceutical composition of the invention, in which the second binding site of the second protein molecule and / or the first binding site of the third protein molecule is or comprises an antibody. monoclonal or at least one cell surface molecule binding fragment or domain thereof, and preferably comprises or consists of any one of Gemtuzumab ozogamicin, Brentuximab vedotin, Trastuzumab emtansine, Inotuzumab ozogamicin, Moxetumomab pasudotox and Polatuzumab vedotin and an antibody conjugate -drug from Table A2 and Table A3. The inventors established that said immunoglobulins, domains thereof, ligands, etc., are particularly suitable for application as the first binding site of the first protein molecule (and the same binding site of the third protein molecule) comprising the first binding site. Similarly, the inventors established that ΜΛ / t / ¿U¿ I / UO / JOS said immunoglobulins, domains thereof, ligands, etc., are particularly suitable for application as the second binding site of the second protein molecule comprising the second binding site. For example, antibodies and antibody binding domains are suitable for directing an epitope onto the exposed surface of a selected cell surface molecule, resulting in the first and third (and separately the second) protein molecule being target cells expressing the cell surface molecule targeted by the first and third protein molecule and / or also target cells expressing the second cell surface molecule targeted by the second protein molecule, these cells also express the first and third molecule cell surface molecule (which is the cell surface molecule itself), and having said cell surface molecules on its cell surface. Similarly, ligands such as EGF, which target EGFR on target cells, are suitable for application as the binding site on the first and third protein molecules, or as the second binding site on the second protein molecule with the proviso that the second binding site is different from both the first and third binding sites, which first and third binding sites are the same. Preferred binding sites for the first and third epitope or for the second epitope, which are specific for the binding of the first and third protein molecules to the first cell surface molecule and / or for the binding of the second protein molecule to the second cell surface molecule, the first and second cell surface molecules exposed on the same target cell. The binding sites are based on antibodies or binding domains or fragments thereof, e.g. provide said desired specificity for a selected first, second, third epitope on a selected first or second cell surface molecule of a selected cell to target. such as a diseased cell, a tumor cell, an autoimmune cell, etc. Therefore, first, second and third antibody-based binding sites or binding molecules (fragments, domains) for the first and second and third protein molecules are preferred. By targeting the same cell surface molecule with the first and third protein molecules, delivery of the saponin and effector moiety into and within the cytosol of the same target cell is improved and more specific. An aberrant cell selected for targeting by the first and third protein molecule binding site ideally carries the cell surface molecule to a high degree and / or specifically, when considering healthy (neighboring) cells in a patient. Thus, the epitope of the target cell surface molecule is ideally unique to the target disease cells, and is at least specifically present and exposed on the surface of the target cells. The binding of the first and third protein molecules is followed by endocytosis of the complexes of the first protein molecule and the target cell surface molecule and the third protein molecule and the target cell surface molecule. Since the first and third protein molecules have to enter the same target cell through binding interaction with the same cell surface molecules, the accumulation of a therapeutically active amount of the first and third protein molecules within the cells targeting is only possible and occurs if the expression levels of the target cell surface molecule is above a certain minimum expression threshold. At the same time, the fact that the effector moiety bound to the third protein molecule is only capable of exerting its intracellular activity (for example Cytotoxic or gene silencing) in the presence of the first protein molecule that carries the covalently bound saponin, when both the first and third protein molecules were able to enter the target cell in sufficient quantities by binding to a sufficiently exposed and expressed cell surface molecule, it also provides protection against unwanted and negative side effects of the effector moiety towards, for example, healthy cells and healthy tissue not intended to be targeted and affected by the effector moiety, when the expression of the target cell surface molecule is sufficiently low in the healthy cells. That is, the low expression of the cell surface molecule bound by the binding site of the first and third protein molecules, does not allow entry of both the first and third protein molecules at amounts that, together, would result in a endosomal escape of the effector moiety under the influence of saponin bound to the first protein molecule. Since ADC or COC can be used at lower doses compared to when the first protein molecule was not added to the therapeutic regimen, entry of ADC or COC into healthy cells to a low degree already carries a lower risk of side effects. unwanted side effects when, for example, targeting and killing diseased target cells such as tumor cells and autoimmune cells are considered. Throughout the description and claims (the entire application), the terms "first" and "third" have the same meaning when considering the first and third epitope, the first and third binding site, the first and third cell surface molecule. That is, for the first and third protein molecules, the target epitope is the same, ΜΛ / t / ZUZ I / UO / ¿00 the binding site is the same, the target cell surface molecule, such as a tumor cell (specific) receptor, is the same. Tables A2, A3 and A4 list preferred examples of the first cell surface molecule comprising the first epitope for the first binding site of the first and third protein molecules. In addition, Tables A2, A3 and A4 also list preferred examples of the second cell surface molecule comprising the second epitope for the second binding site of the second protein molecule. When the first and / or second cell surface molecule is specifically expressed on the target cell, preferably both the first and second cell surface molecule, and when the first and second epitopes on the first and second cell surface molecule, respectively, to which the first binding site and / or second binding site respectively can bind, is specifically present on the first and / or second cell surface molecule, the specific targeting of the first, third and / or second protein molecule to the same desired target cell, such as a tumor cell that exposes the first and second tumor cell surface molecules, is facilitated, whereas other cells, such as healthy cells, that do not express the first and / or second second cell surface molecule or expressing the first and / or second cell surface molecule to a lesser degree, preferably not expressing the first and second cell surface molecule or expressing the first and second cell surface molecule to a lesser degree in compared to the expression of the surface molecule(s) on the target cell (aberrant) are not driven by the first, third and second protein molecule or are driven to a lesser degree. One embodiment is the therapeutic combination comprising the second or third pharmaceutical composition of the invention, wherein the effector moiety that is composed of the second protein molecule and / or the third protein molecule comprises or consists of any one or more of an oligonucleotide, a nucleic acid, a xenonucleic acid, preferably selected from any one or more than one vector, a gene, a transgene that induces cell suicide, deoxyribonucleic acid (DNA), ribonucleic acid (RNA), antisense oligonucleotide (ASO, AON ), small interfering RNA (siRNA), microRNA (miRNA), DNA aptamer, RNA aptamer, mRNA, mini-circle DNA, peptide nucleic acid (PNA), morpholino phosphoramidate oligomer (PMO), locked nucleic acid ( LNA), bridged nucleic acid (BNA), 2'-deoxy-2'-fluoroarabin nucleic acid (FANA), 2'-O-methoxyethyl-RNA (MOE), 2'-O,4'-aminoethylene bridged nucleic acid, 3'-fluoro acid M A / t / ZUZ I / UO / JOS nucleic hexitol (FHNA), a plasmid, glycol nucleic acid (GNA) and threose nucleic acid (TNA), or a derivative thereof, more preferably a BNA, for example a BNA to silence the expression of the HSP27 protein. One embodiment is the therapeutic combination that comprises the second or third pharmaceutical composition of the invention, in which the effector moiety that is composed of the second protein molecule and / or the third protein molecule comprises or consists of at least one protein molecule. , preferably selected from any one or more than one peptide, a protein, an enzyme such as urease and Cre-recombinase, a ribosome-inactivating protein, a protein toxin, more preferably selected from any one or more than one selected protein toxin from Table A5 and / or a viral toxin such as apoptin; a bacterial toxin such as Shiga toxin, Shiga-like toxin, Pseudomonas aeruginosa (PE) exotoxin or PE exotoxin A, full-length or truncated (DT) diphtheria toxin, cholera toxin; a fungal toxin such as alpha-sarcin; a plant toxin including ribosome-inactivating proteins and type 2 ribosome-inactivating protein A chain such as diantin eg diantin-30 or diantin-32, saporin eg saporin-S3 or saporin-S6, bouganin or deimmunized derivative Bouganin debouganin, Shiga-like toxin A, pokeweed antiviral protein, ricin, ricin A chain, modeccin, modeccin A chain, abrin, abrin A chain, volkensin, volkensin A chain, viscumin, viscumin; or an animal or human toxin such as frog RNase, or human granzyme B or angiogenin, or any fragment or derivative thereof; preferably the protein toxin is diantin and / or saporin. One embodiment is the therapeutic combination comprising the second or third pharmaceutical composition of the invention, in which the effector moiety composed of the second protein molecule and / or the third protein molecule comprises or consists of at least one payload, preferably selected from any one or more of a ribosome-targeting toxin, an elongation factor-targeting toxin, a tubulin-targeting toxin, a DNA-targeting toxin, and an RNA-targeting toxin, plus preferably any one or more of emtansine, pasudotox, maytansinoid DM1 derivative, maytansinoid DM4 derivative, monomethyl auristatin E (MMAE, vedotin), monomethyl auristatin F (MMAF, mafodotin), a calicheamicin, N-Acetyl-ycalicheamicin, a pyrrolobenzodiazepine dimer (PBD), a benzodiazepine, a CC-1065 analogue, a duocarmycin, Doxorubicin, paclitaxel, docetaxel, cisplatin, M A / t / ZUZ I / UO / ¿00 cyclophosphamide, etoposide, docetaxel, 5-fluorouracil (5-FU), mitoxantrone, a tubulisin, an indolinobenzodiazepine, AZ13599185, a cryptophycin, rhizoxin, methotrexate, an anthracycline, a camptothecin analog , SN-38, DX-8951Í, exatecan mesylate, truncated form of Pseudomonas aeruginosa exotoxin (PE38), a Duocarmycin derivative, an amanitin, a-amanitin, a spliceostatin, a thailanstatin, ozogamicin, tesirin, Amberstatin269, and soravtansin, or a derivative thereof. A pharmaceutically active substance in the present invention is an effector moiety that is used to achieve a beneficial result in an organism, preferably a vertebrate, more preferably a human, such as a cancer patient or an autoimmune patient. The benefit includes diagnosis, prognosis, treatment, cure and / or prevention of diseases and / or symptoms. The pharmaceutically active substance can also cause unwanted harmful side effects. In this case, the advantages and cons must be weighed in order to decide whether the pharmaceutically active substance is suitable in the particular case. If the effect of the pharmaceutically active substance within a cell is predominantly beneficial to the whole organism, the cell is called a target cell. If the effect within a cell is predominantly harmful to the whole organism, the cell is called an off-target cell. In artificial systems such as cell cultures and bioreactors, target cells and off-target cells are purpose-dependent and user-defined. An effector moiety that is a polypeptide can be, for example, a polypeptide that restores a lost function, such as, for example, enzyme replacement, gene regulation functions, or a toxin. One embodiment is the first protein molecule of the invention, wherein the first protein molecule comprises more than one saponin, preferably 2, 3, 4, 5, 6, 8, 10, 16, 32, 64 or 1-100 saponins, or any number of saponins in between, such as 7, 9, 12 saponins, covalently attached directly to an amino acid residue of the first protein molecule, preferably to a cysteine ​​and / or lysine, and / or covalently attached through at least one linker and / or through at least one cleavable linker and / or through at least one polymeric or oligomeric scaffold, preferably 1-8 of said scaffolds or 2-4 of said scaffolds, in which at least a scaffold is optionally based on a dendron, in which 1-32 saponins such as 2, 3, 4, 5, 6, 8, 10, 16, 32 saponins, or any number of saponins in between, such as 7, 9 , 12 saponins, bind covalently to at least one scaffold. Table A1 and Scheme I and the above embodiments summarize a series of saponins that have been identified for their endosomal escape-enhancing activity when contacted with mammalian cells, in particular human tumor cells, in free form together with a second molecule (eg, an effector moiety or effector molecule, such as a toxin, an oligonucleotide). In fact, in cell-based bioassays using human tumor cells it was established for the saponins tabulated in Table A1 and those in Scheme I and in the various embodiments of the invention described herein, that under the influence of these saponins , when bound to the first protein molecule, a second molecule (effector moiety) such as a nucleic acid and / or a toxin such as a protein toxin (eg, one or more of the protein toxins listed in Table A5), bound to the second or third protein molecule in the cytosol with greater efficiency and / or efficacy, presumably through intracellular release from (late) endosomes and lysosomes. That is, the endosomal and / or lysosomal escape of said second molecules (effector moieties bound to a second or third protein molecule of the invention), for example, nucleic acids and / or toxins, is less efficient in the absence of the saponin. Surprisingly, the inventors now demonstrate that a water-soluble saponin fraction from Quillaja saponaria, comprising QS-21 and its family members QS-21 A, QS-21 A-api, QS-21 A-xyl, QS- 21 B, QS-21 B-api, QS-21 B-xyl, QS-7-xyl, QS-7api, QS-17-ap¡, QS-17-xyl, QS1861, QS1862, QS-18 and Quil- A, also exhibits the ability to enhance an in vitro biological effect of, for example, a monoclonal antibody-bound nucleic acid or a monoclonal antibody-bound protein toxin (examples of a second and / or third protein molecule of the invention that comprises a covalently linked oligonucleotide or payload as a toxin (protein)), when administered to tumor cells of a mammalian species (human) in the form of a covalent conjugate comprising a monoclonal antibody (first protein molecule of the invention), together with the second and / or third protein molecule comprising the effector moiety (the aforementioned second and / or third protein molecule) and at least one glycoside such as QS-21 and its family member saponins encompassed by said preparation QS-21 (eg, water-soluble fraction of Quillaja saponaria), composed of the first protein molecule as a covalent conjugate, in which the effector molecule and glycoside, eg, the saponin fraction of Quillaja saponaria, QS- 21, SO1861, SA1641, GE1741, bind covalently to, for example, the M A / t / ZUZ I / UO / ¿00 protein molecules directly or through a linker or through a polymeric or oligomeric scaffold, either directly or through at least one linker. Without wishing to be limited to any theory, the observed stimulation or potentiation of, for example, antisense BNA-mediated reduction of HSP27 expression in tumor cells (HSP27 gene silencing) in the presence of Quillaja saponaria-derived saponins in vitro may ( also) be related to activation of the inflammasome in the tumor cell by saponins, eg resulting in pyroptosis of the tumor cell. The inventors established that the second and third protein molecules conjugated with, for example, antisense BNA or diantin or saporin, exerted any antitumor cell activity in vitro at all or enhanced antitumor cell activity when contacted with cells in cell assays. biologically based, when they were in the presence of the first protein molecule of the invention, comprising saponin, and targeted to the same (tumor) cells as the cell surface molecule targeted by the second and / or third protein molecule, while that in the absence of the first protein molecule and therefore in the absence of saponin, said activity towards the tumor cell was not observed. QS-21, and also the fraction of water-soluble saponins comprising QS-21 from Quillaja saponaria has already been known for a long time and is intensively previously applied for its immunoenhancing abilities, e.g. as an adjuvant in e.g. subunit vaccines. For example, QS-21 is applied in two phase III clinical trials with human patients, who were vaccinated with an adjuvanted mixed subunit vaccine comprising QS-21 (Glaxo-Smith-Kline, MAGRIT trial, DERMA study), wherein the subunit was the MAGE-A3 protein, which is specifically expressed and presented in tumor cells. Antitumor vaccines, boosted with QS-21, were aimed at extending disease-free survival of cancer patients (melanoma; non-small cell lung cancer). In addition, QS-21 has been tested as an adjuvant in clinical trials for the development of cancer vaccine treatments, for vaccines for HIV-1 infection, in the development of a hepatitis B vaccine, and for vaccine development. against malaria using QS-21 comprising Glaxo-Smith-Kline adjuvants AS01 and AS02. Previous studies revealed an elicited immune response against MAGE-A3 peptides presented on the cancer cell surface, under the influence of the adjuvant comprising saponin QS-21 (AS15; GSK). To the surprise of the inventors, the fraction of M A / Ε / ΖυΖΊ / UO / JOS saponin from Quillaja saponaria and therefore probably QS-21 (as part of the water-soluble saponin fraction from Quillaja saponaria) enhances the cellular antitumor activity of, for example, a payload such as a protein toxin (diantin), linked to the second protein molecule (eg, the EGF ligand). The inventors show that a monoclonal antibody directed to tumor cells provided with covalently coupled antisense BNA such as BNA(HSP27), and which was contacted with tumor cells together with a first protein molecule of the invention with covalently coupled saponin covalently (eg, SO1861, QS-21), both BNA and saponin coupled to the respective antibody (eg, cetuximab) of the first and third protein molecules through a cleavage bond is capable of silencing HSP27 in vivo in tumors , compared to control and compared to COC (third protein molecule) only, without the presence of the first saponin-coupled protein molecule. Co-administration of an ADC or an antibody-oligonucleotide (AOC) conjugate, such as an antibody-BNA conjugate, with a first protein molecule containing a saponin confers on the ADC or AOC cellular antitumor activity that is not seen with ADC alone or alone. the COC at the same dose. Of note, COC (second or third protein molecule) and covalently coupled saponin monoclonal antibody (first protein molecule) increase HSP27 expression in tumor cells, when administered to tumor-bearing mice separately in groups separated from mice, compared to a control group (vehicle only is administered). Only the co-administration of the COC comprising the effector moiety of the invention (second or third protein molecule) and the first protein molecule with covalently coupled saponin, shows reduced HSP27 expression compared to controls. Antisense BNA (HSP27) was BNA with oligonucleic acid sequence 5'GGCacagccagtgGCG-3' according to Zhang et al. (2011) [Y Zhang, ZQu, S Kim, 1 / Shi, B Liaol, P Kraft, R Bandaru, Y Wu, LM Greenberger and ID Horak, Down-modulation of cancer targets using locked nucleic acid (LNA)-based antisense oligonucleotides without transfection, Gene Therapy (2011) 18, 326-333]. It should be noted that, to the best of the inventors' knowledge, BNA is designed for application as free nucleic acid. The inventors are now the first to show that antisense BNA can be covalently coupled via a (non-)cleavable linker to a ligand or antibody, such that gene silencing activity is retained in vitro and thus more importantly, in vivo in tumor cells from a tumor-bearing animal. This ΜΛ / t / ¿U¿ I / UO / JOS approach of providing BNA-based COCs opens up new ways of delivering BNA targeted to human (cancer) patients in need thereof. The inventors describe herein that the covalent coupling of saponins such as saponins in the water-soluble fraction of Quillaja saponaria, QS5 21, SA1641, SO1861, Table A1, Scheme I, to a first protein molecule, such as via a trifunctional linker, for example, the trifunctional linker of Scheme II and Structure B, or via an oligomeric or polymeric scaffold comprising covalently linked saponins, results in enhanced cellular toxicity exerted by the effector moiety such as a toxin, composed of the second and / or third protein molecule, under the influence of the saponin covalently coupled to the first protein molecule. One embodiment is the first protein molecule of the invention comprising a saponin comprising one or more or all of the indicated structural features of the Structure A saponin in Scheme I, the Structure A saponin designated the saponin with an 'ideal' structure when endosomal escape enhances activity towards an effector moiety present in the endosome of a cell in contact with the first protein molecule, and / or a saponin selected from one or more of the additional saponins in Scheme I: MA / Ε / ΖυΖΊ / UO / JOS SCHEME I M A / t / ZUZ I / UO / JOS EITHER SCHEME I (continued) ΜΛ / t / ZUZ! / UO / JOS SCHEME I (continued) M A / t / ZUZ I / UO / JOS SCHEME I (continued) SCHEME I (continued) According to the invention, a glycoside, such as a saponin according to the invention, bound to the first protein molecule of the invention, having the 'ideal' structure for the purpose of enhancing endosomal escape of an effector molecule bound to the second or third protein molecule of the invention is a bisdesmosidic saponin according to Structure A of Scheme I, having a molecular mass of at least 1,500 Daltons and comprising an olean-type triterpene containing an aldehyde group at the C- position 23 and optionally a hydroxyl group at position C-16, with a first branched carbohydrate side chain at position C-3 which first branched carbohydrate side chain optionally contains glucuronic acid, wherein the saponin contains an ester group with a second branched carbohydrate side chain at position C-28 which second branched carbohydrate chain preferably comprises at least four carbohydrate units, optionally containing at least one acetyl residue such as two acetyl residues and / or optionally comprising deoxy carbohydrates and / or optionally comprising quinovose and / or optionally comprising glucose and / or optionally comprising 4-methoxycinnamic acid and / or optionally comprising 5-0-[5-0-Ara / Api-3,5-d¡ acid hydroxy-6-methyl-octanoyl]-3,5dihydroxy-6-methyl-octanoic acid and / or optionally comprising 5-O-[5-O-Rha-(1^2)Ara / Ap¡- 3,5-dihidrox¡-6-methyl-octano¡l]-3,5-d¡h¡drox¡-6-methyl-octano¡co linked to a carbohydrate through an ester bond. SO1861 differs from the "ideal structure" shown in Scheme I, Structure A, only in that it has only one acetyl residue in the quinovose and has an additional xylose. The "ideal structure" of a saponin for enhancing endosomal escape of an effector molecule or effector moiety is a saponin that preferably has Structure A of Scheme I, and saponins that exhibit endosomal escape-enhancing activity have one or more of the structural features shown in Structure A of Scheme I. Without wishing to be bound by any theory, the inventors believe that Structure A of Scheme I represents an "ideal saponin" (and not a minimum saponin requirement) for activity that enhances the endosomal escape, which means that not all structures (chemical groups) can or should be present in every saponin with at least enough activity that enhances endosomal escape to promote accumulation of the effector moiety in the cytosol, and which means that some saponins may have other structural elements such as acyl chains, and / or for other saponins that show endosomal escape-enhancing activity, the sugars may be different than the sugars shown in Scheme I. For example, saponin QS-21 and some of the saponins in the water-soluble fraction of Quillaja saponaria (Quillaja saponins; Quil-A) differ in the carbohydrate modification at C-28 when considering the ideal structure of Structure A in Scheme I: eg, presence of an acyl chain in QS-21. In the water soluble fraction of Quillaja saponaria, saponins such as QS-7, QS1862, are similar to the ideal Structure A and are similar to SO1861. One embodiment is the first protein molecule of the invention, wherein at least one linker is a non-cleavable linker or a cleaved linker, wherein the cleaved linker is eg subjected to cleavage under acidic conditions, reducing conditions, enzymatic conditions, or light-induced conditions, and preferably the cleaved linker comprises a hydrazone bond or a hydrazide bond subject to cleavage under acidic conditions when bound to saponin, and / or comprises a bond susceptible to proteolysis, for example proteolysis by Cathepsin B, and / o is a bond susceptible to cleavage under reducing conditions such as a disulfide bond, when bound to saponin. One embodiment is the first protein molecule of the invention, in which the cleaved linker is cleaved in vivo under acidic conditions that are present in endosomes and / or lysosomes of mammalian cells, preferably human cells, preferably at pH 4, 0-6.5, and more preferably at pH < 5.5, when the cleaved linker binds a saponin. One embodiment is the first protein molecule of the invention, wherein the oligomeric or polymeric scaffold comprises a polymeric or oligomeric backbone and comprises a chemical group, the chemical group for covalent coupling of the scaffold to the amino acid residue of said first protein molecule. According to the invention, the saponin is typically a saponin listed in Table A1, Scheme I. It has been shown to be beneficial for saponin activity, for example, the activity of enhancing endosomal escape within cells when Entry into the cell and accumulation within the cytosol of an effector moiety covalently coupled to the second or third protein molecule is considered, when the saponin is covalently coupled to the first protein molecule involving a hydrazone bond and / or a hydrazide bond and / or a disulfide bond. Such types of bonds are readily cleaved under acidic conditions within (late) endosomes and lysosomes. MA / E / ZUZ I / UO f JOS from mammalian cells, eg, human cells, and / or under reducing conditions. Alternatively, the inventors also demonstrate that covalent coupling of saponin to the first protein molecule via a bond that cannot be easily cleaved under physiological conditions within cells, eg (late) endosomes, lysosomes, cytosol, it is also beneficial for the enhancing activity of saponin on the biological effect of, for example, an effector moiety such as a nucleic acid (eg BNA that silences HSP27) and a protein toxin such as saporin. Throughout the application, which includes the claims, the term "cleavable linker", "cleavable link", etc., is also referred to as "labile linker" ("L") and "labile link", for example, in the context of the cleavage of said linker or linker in the (late) endosome and / or lysosome when a conjugate of the invention, for example, a first protein molecule optionally comprising a scaffold with saponins coupled to the first protein molecule through a connector and / or through the scaffold via hydrazone bonds or disulfide bonds. For example, Figures 6 and 7 show the silencing of the HSP27 gene in vivo in human tumors in mice. Tumor-bearing mice were treated with a first protein molecule consisting of a monoclonal antibody with saponin attached to it via a labile linker (hydrazone linker) according to the invention, while the third protein molecule comprised antisense BNA attached to silence the gene. HSP27 on tumor cells, covalently coupled to the monoclonal antibody (of the same type as the first monoclonal antibody) via a disulfide bond. That is, without wishing to be bound by theory, the hydrazone bond and the disulfide bond are cleaved in the (late) endosomes and / or lysosomes of the target tumor cells expressing the epitope on the target cell surface molecule, herein the EGFR, on the cell surface, once the therapeutic combination of the invention is internalized, for example, by endocytosis. Linkage cleavage likely contributes to endosomal escape by enhancing saponin activity when BNA entry from the endosome and / or lysosome into the cytosol is considered, although such cleavage is not a necessity to observe the gene silencing effect of the combination of the cetuximabSO1861 conjugate and the cetuximab-BNA conjugate of the invention. One skilled in the art will appreciate that a trifunctional linker is a suitable inventive scaffold for covalently coupling one to two or three saponin moieties. For the trifunctional connector, covalent coupling of one or ΜΛ / t / ZUZ I / UO / JOS two saponin fractions. The second and / or third binding site is suitable, for example, for the covalent coupling of a protein ligand such as the first protein molecule. Typical protein ligands are EGF for targeting (tumor) cells expressing EGFR on the cell surface, and cytokines for targeting tumor cells or autoimmune cells. Furthermore, the second or third binding site of the trifunctional linker is suitable for covalent coupling of an immunoglobulin such as a monoclonal antibody, i.e. the first protein molecule to bind to a cell surface molecule such as a cell surface molecule. tumor cell, preferably a tumor cell-specific molecule, more preferably a tumor cell receptor that is specifically expressed (overexpressed) on the surface of the tumor cell. Similarly, immunoglobulin, or any fragment(s) and / or domain(s) thereof encompassing the binding specificity of immunoglobulin, is suitable for binding to a cell surface molecule, such as a receptor, expressed on the surface of an autoimmune cell. Thus, in one embodiment, the first protein molecule comprises the trifunctional linker, said linker comprising or consisting of a covalently linked saponin, eg, QS-21, SO1861, and the covalently linked binding site such as a cell-targeting moiety such as a ligand or antibody for (specific) binding to a tumor cell, autoimmune cell, diseased cell, aberrant cell, unhealthy cell, B-cell disease. One embodiment is the first protein molecule of the invention, comprising the oligomeric trifunctional linker as the scaffold core structure, according to Scheme II: ΜΛ / t / ZUZ I / UO / ¿00 SCHEME II, wherein the saponins are covalently attached to the trifunctional linker scaffold via labile and cleavable (acid sensitive) hydrazone linkers and / or via a maleimide-comprising linkage, while attachment of the scaffold to the site A binding site, such as an antibody, is established by labile and cleavable (acid sensitive) hydrazone linkers and / or by a linker comprising maleimide with cysteines at the binding site such as 1, 2, 3 or 4 cysteines, forming in this way Structure B: M A / t / ZUZ I / UO / JOS Structure B, such that 1-4 scaffolds are covalently attached to a single, eg, antibody such as a monoclonal antibody. One embodiment is the first protein molecule of the invention in which the glycoside molecule is a saponin and the bond between the saponin and the first protein molecule occurs preferentially via an acid labile bond that is stable at pH 7.4. and, preferably releases the saponin below pH 6.5, more preferably between pH 6.5 and 5.0. This is done, for example, through an imine formed by an amino group of a linker that joins the saponin and the first protein molecule and the aldehyde group of the saponin. Other chemical bonds that meet the pH condition for aldehyde coupling can also be used, for example, particular hydrazones or acetals, which require hydrazide and hydroxyl groups as the linker functional group, respectively. If the bond is a cleaved bond, a saponin preferentially adheres to the polymeric or oligomeric structure of a scaffold via an aldehyde function or via one of the carboxyl groups on the saponin, more preferably via the aldehyde function, preferably an aldehyde function. at position 23. Alternatively, a saponin preferentially attaches to the first protein molecule via the scaffold polymeric or oligomeric structure via a linker connecting the scaffold polymeric or oligomeric structure, either through the aldehyde function or through the carboxylic acid function of the glycoside molecule, that is, the saponin. One embodiment is the first protein molecule of the invention, wherein at least one saponin is attached to the first protein molecule through a stable bond. In a more preferred embodiment, the stable link between the first saponin protein molecule preferably occurs through amide coupling or amine formation. This is accomplished, for example, through carbodiimide-mediated amide bond formation via an amino group of a polymeric or oligomeric scaffold structure linking the saponin and the first protein molecule, and the activated glucuronic acid group of the saponin. Chemical bonds that meet the definition of a stable bond can also be used for aldehyde coupling, for example, particular amines derived after reductive amination, which require primary amino groups as a functional group of a polymeric or oligomeric backbone of a scaffold or a connector. If the bond is a stable bond, the saponin preferentially adheres to a linker or scaffold through one of the carboxyl groups of the saponin, the linker or scaffold further connected to the first protein molecule. One embodiment is the first protein molecule of the invention in which saponin is coupled to the binding site via a scaffold according to the invention, wherein the chemical group for covalent coupling of the scaffold to the binding site is a click chemistry group. One embodiment is the first protein molecule of the invention in which the saponin is coupled to the binding site via a scaffold according to the invention, in which the click chemistry group is a tetrazine, an azide, an alkene or an alkyne, or a cyclic derivative of any of these groups, preferably an azide. A click chemistry group is a functional chemical group suitable for click chemistry, which is defined as a reaction that is modular, wide ranging, gives very high yields, generates only harmless by-products, offers high selectivity, and high tolerance over different functional groups and is stereospecific. Required features of the procedure include simple reaction conditions, readily available starting materials and reagents, no use of solvent or a solvent that is benign (such as water) or can be removed ΜΛ / t / ZUZ I / UO / JOS easily, and simple isolation of the product. The click chemistry group for coupling the saponin to the binding site on the first protein molecule optionally via a scaffold or linker, is preferably a tetrazine, azide, alkene, or alkyne, or reactive derivatives thereof such as methyl -tetrazine or maleimide (alkene), more preferably an alkyne, or a cyclic derivative of these groups, such as cyclooctin (eg aza-dibenzocyclooctin, difluorocyclooctin, bicyclo[6.10]non-4-yne, dibenzocyclooctin). Therefore, a first protein molecule according to the invention comprises at least one saponin. By "at least one" in this context it is meant that the first protein molecule comprises a saponin molecule, but it can also comprise a pair (eg two, three or four) of saponins or a multitude (eg 10, 20 or 100) of saponins. Depending on the application, the first protein molecule may comprise a covalently bound scaffold with covalently bound saponins, wherein the scaffold may be designed to comprise a defined number of saponins. Preferably, a first protein molecule according to the invention comprises a defined number or range of saponins, rather than a random number. This is especially advantageous for drug development in connection with marketing authorization. A defined number in this regard means that a first protein molecule preferably comprises a predefined number of saponins. This is achieved, for example, by designing a scaffold comprising a polymeric backbone with a number of possible moieties for the saponins to attach to. Under ideal circumstances, all of these fractions are coupled to a saponin and the scaffold comprises the previously defined number of saponins. It is envisioned to offer a standard assembly of scaffolds, comprising, for example, two, four, eight, sixteen, thirty-two, sixty-four, etc., of saponins so that the user can easily test the optimum number according to your needs. One embodiment is the first protein molecule of the invention comprising the scaffold of the invention, wherein saponin is present in a defined range such as, for example, under non-ideal circumstances, not all moieties present in a polymer backbone bind to a saponin. Said ranges can be, for example, 2-4 saponin molecules per scaffold, 3-6 saponin molecules per scaffold, 4-8 saponin molecules per scaffold, 6-8 saponin molecules per scaffold, 6-12 saponin molecules per scaffold. saponin by scaffold and so on. In such a case, a first protein molecule comprising a scaffold of ΜΛ / t / ¿U¿ I / UO / JOS according to the invention therefore comprises 2, 3 or 4 saponins if the interval is defined as 2-4. The scaffold is essentially independent of the type of saponin covalently attached to the scaffold, the scaffold subsequently (in sequential order) being covalently coupled to the first protein molecule. Thus, the first protein molecule comprising the scaffold is the base product for a new platform technology. Since the at least one covalently bound saponin mediates the intracellular delivery of the effector moiety bound to the second protein molecule, the scaffold technology according to the invention is the first known system that mediates controlled intracellular effector moiety delivery. for the saponins. The scaffold provides an optimized and functionally active unit that can be linked to the saponin(s) and to the binding site comprised of the first protein molecule, eg, a ligand, an antibody, etc., at a unique position. and defined. One embodiment is the first protein molecule comprising a scaffold according to the invention, in which the number of monomers of the polymeric or oligomeric structure is an exactly defined number or range. Preferably, the polymeric or oligomeric structure comprises structures such as poly(amines), for example polyethyleneimine and poly(amidoamine), or structures such as polyethylene glycol, poly(esters), such as poly(lactides), poly(lactams) , polylactide. - co-glycolide, poly(dextrin) or peptide or protein copolymers, or structures such as natural and / or artificial polyamino acids, for example polylysine, DNA polymers, stabilized RNA polymers or PNA (nucleic acid) polymers. peptide), which occurs as either a linear, branched, or cyclic polymer, oligomer, dendrimer, dendron, dendronized polymer, dendronized oligomer, or assemblies of these structures, whether pure or mixed. Preferably, the polymeric or oligomeric structures are biocompatible, where biocompatible means that the polymeric or oligomeric structure does not exhibit substantial acute or chronic toxicity in organisms and can be either excreted as is or completely degraded to excretable and / or physiological compounds by the metabolism of the body. Assemblies can be built by covalent crosslinking or non-covalent bonding and / or attraction. Therefore, they can also form nanogels, microgels or hydrogels, or can be attached to carriers such as inorganic nanoparticles, colloids, liposomes, micelles or particle-like structures comprising cholesterol and / or phospholipids. Said polymeric or oligomeric structures preferably carry a precisely defined number or range of coupling moieties for the coupling of glycoside molecules (and / or effector molecules and / or carrier molecules such as a ligand, monoclonal antibody or a fragment thereof). Preferably at least 50%, more preferably at least 75%, more preferably at least 85%, more preferably at least 90%, more preferably at least 95%, more preferably at least 98%, more preferably at least 99%, even more preferably 100% of the exactly defined number or range of coupling moieties in the polymeric or oligomeric backbone is occupied by one glycoside molecule in a scaffold according to the invention. Preferably, a dendron is a clearly defined, branched, tree-like polymer with a single chemically addressable group at the origin of the tree, called a focal point. A dendrimer is a connection of two or more dendrons at their focal point. A dendronized polymer is a focal point connection of one or more dendrons to a polymer. In a preferred embodiment, a scaffold according to the invention is provided, wherein the polymeric or oligomeric structure comprises a linear, branched or cyclic polymer, oligomer, dendrimer, dendron, dendronized polymer, dendronized oligomer or sets of these structures, whether either pure or mixed, where assemblies can be built by covalent crosslinking or non-covalent attraction and can form nanogels, microgels or hydrogels, and where, preferably, the polymer is a derivative of a poly(amine), e.g. polyethyleneimine and poly(amidoamine), and structures such as polyethylene glycol, poly(esters), such as poly(lactides), poly(lactams), polylactide-co-glycolide and poly(dextrin) copolymers, and structures such as natural polyamino acids and / or artificial such as polylysine, or a peptide or protein or DNA polymers, stabilized RNA polymers or PNA (peptide nucleic acid) polymers. Preferably, the polymeric or oligomeric structures are biocompatible. One embodiment is the therapeutic combination of the invention or the therapeutic combination for use according to the invention, wherein the first protein molecule comprises more than one covalently bound saponin, preferably 2, 3, 4, 5, 6, 8, 10, 16, 32, 64, 128 or 1-100 saponins, or any number of saponins in between, such as 7, 9, 12 saponins. One embodiment is the first protein molecule of the invention, in which at least one saponin is covalently attached to the polymeric or oligomeric structure of the M A / t / ZUZ I / UO / JOS oligomeric or polymeric scaffold through at least one cleaved linker according to the invention. One embodiment is the first protein molecule of the invention, wherein the chemical moiety of the oligomeric or polymeric scaffold, for covalent coupling of the oligomeric or polymeric scaffold to the amino acid residue of said first protein molecule, is a click chemistry moiety, preferably selected from a tetrazine, an azide, an alkene or an alkyne, or a cyclic derivative of these groups, more preferably said chemical group is an azide. One embodiment is the first protein molecule of the invention, wherein the polymeric or oligomeric structure of the oligomeric or polymeric scaffold comprises a linear, branched, and / or cyclic polymer, oligomer, dendrimer, dendron, dendronized polymer, dendronized oligomer, a DNA, a polypeptide, poly-lysine, a polyethylene glycol, or an assembly of these polymeric or oligomeric structures, the assembly of which is preferably constructed by covalent crosslinking. The inventors established that covalent coupling, preferably through cleavage bonds or linkers, of saponin to the first protein molecule, in accordance with any of the above embodiments herein, provides efficient, cell-directed potentiation of activity of an effector moiety bound to the second and third protein molecules, wherein the first and third protein molecules comprise the same first binding site and wherein the first and second protein molecules comprise a first and second binding site that They are different. Coupling the saponin to a cysteine ​​side chain or a lysine side chain of the first protein molecule, such as a monoclonal antibody, directly or through a linker, has been shown to be a beneficial way of delivering specific and efficient enhancing activity. of effector fraction within the target cell, when also the effector fraction is delivered in the same target cell when using the second and / or third protein molecule comprising the same first binding site as the first protein molecule when considering the third molecule proteinaceous and comprising different first and second binding sites respectively when considering the first and second proteinaceous molecules. In order to explain the invention in more detail, the process of cellular adsorption of substances was described (although the inventors do not wish to be bound by any theory) and the terminology used in the present invention. The adsorption of extracellular substances on MA / Ε / ΖυΖΊ / UO / JOS one cell per bud of vesicles is called endocytosis. Such vesicle sprouting can be characterized by (1) receptor-dependent ligand uptake mediated by the cytosolic protein clathrin, (2) lipid raft uptake mediated by the cholesterol-binding protein caveolin, (3) nonspecific fluid uptake (pinocytosis). ), or (4) nonspecific particle uptake (phagocytosis). All types of endocytosis are encountered with the following cellular procedures of vesicle transport and substance sorting called endocytic pathways. Endocytic pathways are complex and not fully understood. Without wishing to be bound by any theory, organelles can form de novo and mature into the next organelle along the endocytic pathway. However, it is now hypothesized that endocytic pathways involve stable compartments that are connected by vesicular trafficking. A compartment is a complex, multifunctional membrane organelle that is specialized for a particular set of essential cell functions. Vesicles are considered transient organelles, of simpler composition, and are defined as membrane-enclosed containers that form de novo by budding from a pre-existing compartment. Unlike compartments, vesicles can undergo maturation, which is a physiologically irreversible series of biochemical changes. Early and late endosomes represent stable compartments in the endocytic pathway, while primary endocytic vesicles, phagosomes, multivesicular bodies (also called endosome-bearing vesicles), secretory granules, and even lysosomes represent vesicles. The endocytic vesicle, which arises on the plasma membrane mainly from clathrin-coated pits, first fuses with the early endosome, which is a major sorting compartment of approximately pH 6.5. A large part of the cargo and internalized membranes are recycled back to the plasma membrane via recycling vesicles (recycling pathway). Components to be degraded are transported to the acidic late endosome (pH less than 6) via multivesicular bodies. Lysosomes are vesicles that can store mature lysosomal enzymes and deliver them to a late endosomal compartment when needed. The resulting organelle is called a hybrid organelle or endolysosome. Lysosomes sprout from the hybrid organelle in a process called lysosome reformation. Late endosomes, lysosomes, and hybrid organelles are extremely dynamic organelles, and distinguishing between them is often difficult. The degradation of an endocytosed molecule occurs within an endolysosome or lysosome. Endosomal escape is the active or passive release of a substance from the ΜΛ / t / ¿U¿ I / UO / JOS internal lumen of any type of compartment or vesicle of the endocytic pathway, preferably of the clathrin-mediated endocytosis, or recycling pathway to the cytosol. Thus, endosomal escape includes, but is not limited to, the release of endosomes, endolysosomes, or lysosomes, including their intermediate and hybrid organelles. Unless specifically stated otherwise and in particular when referring to the endosomal escape mechanism of the glycoside molecule such as the saponin of the invention, whenever the word "endosome" or "endosomal escape" is used herein , also includes endolysosome and lysosome, and endolysosome and lysosome escape, respectively. After entering the cytosol, said substance could be transferred to other cell units such as the nucleus. In formal terms, a glycoside is any molecule in which one sugar group is linked through its anomeric carbon to another group through a glycosidic bond. Glycoside molecules, such as saponins, in the context of the invention are such molecules that can further enhance the effect of an effector moiety, without wishing to be bound by any theory, in particular by facilitating endosomal escape of the effector moiety. Without wishing to be bound by any theory, glycoside molecules (saponins, such as those listed in Table A1) interact with the compartment membranes and vesicles of the endocytic and recycling pathway and make them leaky for said effector moieties. , resulting in increased endosomal escape. With the term "the scaffold can increase the endosomal escape of the effector moiety" it is understood that at least one saponin (glycoside molecule), which is coupled to the polymeric or oligomeric structure of the scaffold, is capable of improving the endosomal escape of a effector moiety when both molecules are within an endosome, eg, a late endosome, optionally and preferably after at least one glycoside, such as a saponin, is released from the first protein molecule, such as from a linker or polymeric backbone or oligomeric compound composed of said first protein molecule, for example, by cleavage of a cleaved bond between at least one glycoside (saponin) and the first protein molecule (for example, through a polymeric or oligomeric structure of a scaffold and / or through of a connector). Although a link between at least one glycoside such as a saponin according to the invention and the first protein molecule, optionally via a linker or a scaffold, may be a "stable link", this does not mean that such a link cannot be made. cleaved in endosomes by, for example, enzymes. For example, the glycoside or saponin, optionally M A / t / ZUZ I / UO / ¿00 together with a linker or a part of the oligomeric or polymeric structure of a scaffold, can be cleaved from the remaining linker fragment or the oligomeric or polymeric structure. It could be, for example, that a protease cuts a (protein) linker or a protein polymer structure, eg albumin, thus releasing at least one glycoside, saponin. However, it is preferred that the glycoside molecule (preferably saponin) is released in an active form, preferably in the original form it had before it was (ready to be) coupled to the first protein molecule optionally via a y / linker. or an oligomeric or polymeric scaffold; therefore, the glycoside (saponin) has its natural structure after said cleavage or the glycoside (saponin) has (part of) a chemical group or linker attached to it, after said cleavage, whereas the biological activity of the glycoside (activity saponin), e.g. endosomal / lysosomal escape-enhancing activity towards an effector moiety present in the same endosome or lysosome, is maintained or restored after said cleavage of the bond between the glycoside (saponin) and the carrier molecule, i.e. , the first protein molecule optionally comprising a linker and / or a scaffold of the invention. With respect to the present invention, the term "stable" with respect to the links between, for example, saponins and amino acid residues of the first protein molecule, a linker, polymeric or oligomeric structures (of the scaffold), ligands, immunoglobulins (monoclonal ) or binding domains or fragments thereof, and / or effectors (effector moieties, effector molecules), means that the bond is not easily broken or at least not designed to be easily broken by, for example, pH differences, concentrations salt or UV light, reducing conditions. With respect to the present invention, the term "cleavable" with respect to the links between, for example, saponins and the first protein molecule, linkers, amino acid residues, polymeric or oligomeric structures of the scaffold, ligands, antibodies and / or effectors, means that the bond is designed to be easily broken, for example, by differences in pH, salt concentrations, under reducing conditions, and the like. Those skilled in the art are well aware of these cleavable links and how to prepare them. Before the present invention, one of the main obstacles to the introduction of ADCs and COCs on the market was the small therapeutic window: a therapeutically effective dose of an ADC or COC is accompanied by (unacceptable) side effects that hinder the development and involvement in the treatment of patients with ADCs. By applying the first protein molecule of the invention, now M A / t / ZUZ I / UO / ¿00 it is possible to guide one or multiple glycoside (saponin) molecules into a cell (target), together with the ADC carrying a payload or together with a (monoclonal) antibody conjugated to a oligonucleotide such as a BNA according to the invention (ie, a particular second or third protein molecule of the invention). In particular, it was previously not possible to specifically guide an effector moiety of a second or third protein molecule and a particular (predefined, controllable) number or interval of glycoside molecules (saponins) per effector moiety at the same time to the cytosol of cells, such such as through the endocytic pathway of a cell. A solution provided by the invention comprises the covalent attachment of at least one saponin to the first protein molecule. A further solution provided by the invention comprises (first) polymerizing the glycoside (saponin) molecules using an oligomeric or polymeric scaffold, and providing the first protein molecule with a pool of covalently linked saponins, allowing one or more to be re-monomerized. more saponins. At the intracellular site where the saponin mode of action is desired, for example, after endocytosis. "Polymerizes" in this context means the reversible and / or irreversible multiple conjugation of saponin molecules to the first protein molecule, either through a linker or directly or through a polymeric or oligomeric backbone to form a scaffold or multiple conjugation reversible and / or irreversible release of (modified) saponins thereby forming a polymeric or oligomeric structure to form a scaffold. "Re-monomerization" in this context means the cleavage of the saponins from the first protein molecule, from the linker connecting the saponin(s) to the first protein molecule or to the scaffold, for example, after endocytosis, and recovering the (native) chemical state of the unbound saponins, which unbound saponins may or may not comprise additional chemical groups such as a chemical group for linking the saponin to a linker, an amino acid residue of the first protein molecule or to the scaffold, and / or a (chemical) linker attached to a chemical group of the saponin such as an aldehyde group or a carboxylic acid group. Due to the complex chemistry of saponins, eg 'polymerisation' of saponins on a scaffold or other linker and their 're-monomerisation' at a desired location, such as intracellularly, eg after endocytosis It was a challenging task. In particular, the chemical reactions used to provide the linkers and the scaffold comprising covalently linked glycosides for covalent attachment to the first protein molecule, eg, triterpenoid saponins (glycoside polymerization), occur M A / t / ZUZ I / UO / JOS normally in water-free organic solvents, but saponins and for Example biocompatible polymers applied as a scaffold to carry attached saponins, are water-soluble molecules. The chemical properties of the unmodified saponin further prohibited polymerization by itself, and another possible solution, to attach multiple saponins (directly) to the effector molecule, was deemed not very promising, as an effector molecule (drug, toxin, polypeptide or polynucleotide) does not normally provide sufficient binding sites and because the coupling product would become quite heterogeneous and / or the coupling of biologically active molecules, such as a saponin and, for example, a peptide, toxin, nucleic acid , together carries the risk of influencing and hindering the activity of one or even both molecules bound together in said saponin-comprising conjugate. Additionally, there was a considerable risk that the effector moiety composed of the second or third protein molecule would lose its function after the coupling of a saponin to, for example, ADC or antibody-oligonucleotide conjugate (AOC). The embodiments of the present invention solve at least one of these drawbacks. One aspect of the invention relates to a composition comprising the first protein molecule of the invention and the second protein molecule of the invention. One aspect of the invention relates to a composition comprising the first protein molecule of the invention and the third protein molecule of the invention. One embodiment is the composition comprising the first protein molecule of the invention and the second protein molecule of the invention, or is the composition comprising the first protein molecule of the invention and the third protein molecule of the invention, wherein the fraction The effector moiety that is composed of the second protein molecule or the third protein molecule is any one of the effector moieties according to the invention, preferably a BNA. One aspect of the invention refers to a composition comprising the first protein molecule of the invention and any one or more of an oligonucleotide, a nucleic acid and a xenonucleic acid, preferably selected from at least one of a vector, a gene, a cell suicide transgene, deoxyribonucleic acid (DNA), ribonucleic acid (RNA), antisense oligonucleotide (ASO, AON), small interfering RNA (siRNA), microRNA (miRNA), DNA aptamer, RNA aptamer, mRNA, DNA Mini Circle Acid, Peptide Nucleic Acid (PNA), Phosphoramidate Morpholino Oligomer (PMO), Locked Nucleic Acid (LNA), Bridged Nucleic Acid (BNA), 2'-Deoxy¡-2' Fluoroarabino Nucleic Acid (FANA), 2'-O-methoxyethyl-RNA (MOE), 2'-0,4'-aminoethylene bridged nucleic acid, 3'-fluorohexitol nucleic acid (FHNA), a plasmid, glycol nucleic acid (GNA), and threose nucleic acid (TNA), or a derivative thereof, more preferably a BNA, for example a BNA to silence the expression of the HSP27 protein (antisense BNA (HSP27)). An effector molecule, or effector moiety, in the context of the present invention is any substance that affects the metabolism of a cell through interaction with an intracellular effector molecule target, wherein this effector molecule target is any molecule or structure within cells that exclude the lumen of the compartments and vesicles of the endocytic and recycling pathway, but include the membranes of these compartments and vesicles. Such structures within cells therefore include the nucleus, mitochondria, chloroplasts, endoplasmic reticulum, Golgi apparatus, other transport vesicles, the inner part of the plasma membrane, and the cytosol. Cytosolic delivery of an effector moiety in the context of the invention preferably means that the effector moiety is capable of endosome (and / or lysosome) escape, which, as defined above, also includes endolysosome and lysosome escape, and preferably is capable of targeting the effector moiety as described herein. The invention also encompasses a new type of molecule, termed a scaffold, which serves to carry both an effector moiety and at least one glycoside molecule, such as a saponin of the invention, into an endosome at the same time in a predefined ratio, when the effector moiety is made up of the second or third protein molecule of the invention and the saponin is made up of the first protein molecule. Within the context of the present invention, the polymeric or oligomeric structure of the scaffold is a structurally ordered formation, such as a polymer, oligomer, dendrimer, dendronized polymer or dendronized oligomer, or is an assembled polymeric structure such as a hydrogel, microgel, nanogel. , stabilized polymeric micelle or liposome, but excludes structures that are composed of non-covalent assemblies of monomers such as cholesterol / phospholipid mixtures. The terms "polymer, oligomer, dendrimer, dendronized polymer or dendronized oligomer" have their usual meaning. In particular, a polymer is a substance that has a molecular structure built primarily or entirely from a large number of the same or similar units linked together, and an oligomer is a polymer whose molecules consist of relatively few repeating units. There is no consensus on ΜΛ / t / ZUZ I / UO / ¿00 a specific limit for "many" and "few" as used in the above definition of polymer and oligomer, respectively. However, since the scaffold may comprise a polymeric or oligomeric structure, or both, the full range of numbers of similar units attached applies to such structure, ie, from 2 monomeric units to 100 monomeric units, 1000 monomeric units and more. A structure comprising 5 or fewer, for example, may be called an oligomeric structure, while a structure comprising 50 monomeric units may be called a polymeric structure. A structure of 10 monomeric units can be called oligomeric or polymeric. A scaffold as defined herein further comprises at least one glycoside molecule such as a saponin of the invention. A scaffold preferably includes a polymeric or oligomeric structure such as poly or oligo(amines), for example, polyethyleneimine and poly(amidoamine), and biocompatible structures such as polyethylene glycol, poly(or oligo(esters)), such as poly(lactides). ), poly(lactams), copolymers of polylactide-co-glycolide and poly(dextrin), poly or oligosaccharides, such as cyclodextrin or polydextrose, and poly or oligoamino acids, such as polylysine or a peptide or protein, or Oligo or polymers of DNA. An assembled polymeric structure as defined herein comprises at least one scaffold and, optionally, other individual polymeric or oligomeric structures. Other individual polymeric or oligomeric structures of said assembly can be (a) scaffolds (thus comprising at least one glycoside molecule such as a saponin of the invention), (b) functionalized scaffolds (thus comprising at least one glycoside molecule such as a saponin, and a ligand, antibody, etc. as the first protein molecule, (c) polymeric or oligomeric structures without a glycoside molecule such as a saponin of the invention (see Table A1 for example), without a ligand, antibody, etc., as the first protein molecule A functionalized assembled polymeric structure is an assembled polymeric structure that contains (a) at least one functionalized scaffold or (b) at least one scaffold and at least one polymeric structure comprising at least one ligand, antibody, etc. as the first protein molecule Polymeric or oligomeric structures within an assembled polymeric structure that do not comprise any of the above mentioned molecules (i.e. no glycosides such as saponins, no first protein molecule such as ligands, antibodies) they are added in particular as structural components of assembled structures, which help to build up or stabilize the assembled structure ("glue-like"). Not wanting to be limited to M A / Ε / ΖυΖΊ / UO / JOS no theory, the acidic environment seems to be a prerequisite for the synergistic action between the glycoside (saponin) and the effector moiety. If a first protein molecule comprising saponins, which also comprises or not one or more linkers (cleavages) and / or optionally a scaffold, is capable of altering the acidic environment and inhibiting the endosomal escape function of at least one glycoside (saponin) it can be readily determined with an assay as described in Example 3 and as is known in the art. Inhibition is described as "increases in the amount of glycosides required to induce 50% cell destruction." It is preferred that the scaffold does not lead to an increase that is at least the increase in glycoside molecules (saponins) necessary to obtain 50% cell killing observed when Chloroquine is used as a positive control. Alternatively, and preferably, the first protein molecule comprising saponins, whether or not it additionally comprises one or more linkers (cleavages) and / or optionally a scaffold does not lead to at least a 4-fold increase in glycoside molecules to induce 50 % cell destruction, more preferably does not lead to an increase of at least 2-fold. The fold increase should be measured in an assay, essentially as described in Example 4, in which Chloroquine, as a positive control, induces a 2-fold increase in the amount of glycoside, preferably the amount of saponin in which the saponin is one or more of the saponins of the invention (see Table A1, Scheme I, previous embodiments) to observe 50% cell killing. By the term "enhance or enhance an effect of an effector moiety" it is meant that the glycoside molecule, preferably a saponin of the invention, increases the functional efficacy of that effector moiety (for example, the therapeutic index of a toxin or drug or an oligonucleotide such as a BNA; metabolic efficacy of a modifier in biotechnological procedures; gene transfection efficiency in cell culture research experiments), preferably by enabling or improving its coupling to the target. Preferably, acceleration, prolongation or enhancement of antigen-specific immune responses are not included. Therapeutic efficacy includes but is not limited to a stronger therapeutic effect, preferably at lower dosages and / or with fewer side effects. "Enhancing an effect of an effector moiety" can also mean that an effector moiety, which could not be used due to lack of effect (and was not, for example, known as an effector moiety), becomes effective when used in combination with the present invention. Any other effect, which is beneficial or ΜΛ / t / ¿U¿ I / UO / JOS may be desired and attributed to the combination of the effector moiety and the second or third protein molecule, as provided by the invention, is considered "an enhanced effect". In one embodiment, the scaffold comprising bound saponin(s) and composed of the first protein molecule enhances an effect of the effector moiety composed of the second protein molecule whose effect is intended and / or desired. In the case of a first protein molecule comprising saponin attached to a protein scaffold, the protein polymeric structure of the scaffold as such may have, for example, an effect on the colloid osmotic pressure in the bloodstream. If said effect is not the intended or desired effect of said functionalized scaffold composed of the first protein molecule, the protein structure of the scaffold is not an effector moiety as defined in the invention. Or, for example, in the case of a DNA or RNA-based scaffold that has attached saponins and is composed of the first protein molecule, parts of that DNA or RNA may have an (unintended) function, for example, by interfering with The expression. If such interference is not the intended or desired effect of the final functionalized scaffold, the DNA or RNA polymeric structure of the scaffold is not the effector moiety as defined in the invention. A number of preferred characteristics can be formulated for endosomal escape enhancers composed of the first protein molecule, i.e. a glycoside or saponin, preferably a saponin according to the invention: (1) they are preferably non-toxic and do not invoke an immune response , (2) they preferably do not mediate cytosolic uptake of the effector moiety in off-target cells, (3) their presence at the site of action is preferentially synchronized with the presence of the effector moiety, (4) they are preferentially biodegradable or excretable, and (5) preferably do not substantially interfere with biological processes in the organism unrelated to the biological activity of the effector molecule with which the endosomal escape enhancer is combined, eg, interacts with hormones. Examples of glycoside molecules such as saponins of the invention which meet the aforementioned criteria, at least to some extent, are bisdesmosidic triterpenes, preferably bisdesmosidic triterpene saponins, such as SO1861, SA1641, QS-21, GE1741 and the saponins in Table A1, Scheme I. One aspect of the invention relates to an antibody-drug conjugate or an antibody-oligonucleotide conjugate or a ligand-drug conjugate comprising the first protein molecule of the invention and an effector moiety. ΜΛ / t / ZUZ I / UO / JOS One embodiment is the antibody-drug conjugate or antibody oligonucleotide conjugate or ligand-drug conjugate of the invention, wherein the antibody can bind to any one of CD71, CA125, EpCAM(17-1A), CD52, CEA, CD44v6, FAP, EGF-IR, integrin, syndecan-1, vascular alpha-V beta-3 integrin, HER2, EGFR, CD20, CD22, Folate receptor 1, CD146, CD56, CD19, CD138, CD27L receptor, PSMA, CanAg, integrin-alphaV, CA6, CD33, mesothelin, Cripto, CD3, CD30, CD239, CD70, CD123, CD352, DLL3, CD25, ephrinA4, MUC1, Trop2, CEACAM5, CEACAM6, HER3, CD74, PTK7, Notch3, FGF2, C4.4A, FLT3, CD38, FGFR3, CD7, PD-L1, CTLA4, CD52, PDGFRA, VEGFR1, VEGFR2, preferably CD71, HER2, EGFR, and / or is or comprises any one of cetuximab, daratumumab, gemtuzumab, TRASTUZUMAB, PANITUMUMAB, Brentuximab, Inotouzumab, Moxetumomab, Polatuzumab, Obinutuzumab, Anti-CD71 OKT-9 monoclonal antibody of the IgG type, pertuzumab, rituximab, Ofatumumab, herceptin, Alemtuzumab, Pinatuzumab, anti-cd mockery antibody. uerpo of Table A2 or Table A3 or Table A4, preferably cetuximab or trastuzumab or OKT-9, or at least one tumor cell receptor-binding fragment thereof and / or at least one tumor cell receptor-binding domain thereof, and / or wherein the antibody-drug conjugate comprises any one of Gemtuzumab ozogamicin, Brentuximab vedotin, Trastuzumab emtansine, Inotuzumab ozogamicin, Moxetumomab pasudotox and Polatuzumab vedotin and an antibody-drug conjugate from Table A2 and Table A3, or wherein the ligand-drug conjugate comprises at least one ligand for binding to a cell surface molecule such as EGF or a cytokine. One embodiment is the antibody-drug conjugate or antibody oligonucleotide conjugate or ligand-drug conjugate of the invention, wherein the effector moiety is any one or more of the effector moieties according to the invention. One aspect of the invention relates to a pharmaceutical composition comprising the composition comprising the first protein molecule of the invention and the second protein molecule of the invention, or comprising the first protein molecule of the invention and the third protein molecule of the invention, or comprising the antibody-drug conjugate of the invention or comprising the antibody-oligonucleotide conjugate of the invention or comprising the ligand-drug conjugate of the invention, and optionally further comprising a pharmaceutically acceptable excipient. MA / E / ZUZ I / UO / JOS 100 One aspect of the invention refers to the therapeutic combination of the invention, which comprises either the second pharmaceutical composition or which comprises the third pharmaceutical composition, or which comprises the composition which comprises the first protein molecule of the invention and the second protein molecule. of the invention, or comprising the first protein molecule of the invention and the third protein molecule of the invention, or comprising the antibody-drug conjugate or antibody oligonucleotide conjugate or ligand-drug conjugate of the invention or pharmaceutical composition of the invention, for use as a medicament. One aspect of the invention refers to the therapeutic combination of the invention, which comprises either the second pharmaceutical composition or which comprises the third pharmaceutical composition, or which comprises the composition which comprises the first protein molecule of the invention and the second protein molecule. of the invention, or comprising the first protein molecule of the invention and the third protein molecule of the invention, or comprising the antibody-drug conjugate or antibody oligonucleotide conjugate or ligand-drug conjugate of the invention or pharmaceutical composition of the invention, for use in the treatment or prevention of cancer or autoimmune disease. As said above, at least one saponin that is composed of the first protein molecule according to the invention increases the efficacy of at least the current and new effector moieties as defined in the present invention. Potential side effects will decrease due to decreased dosage of the effector moiety composed of the second or third protein molecule, without reducing efficacy. Therefore, the invention provides a first protein molecule according to the invention for use in medicine or for use as a medicament. Therefore, one aspect of the invention relates to a first protein molecule according to the invention, the first protein molecule comprising at least one saponin, for use as a medicament. Also provided is the use of a first protein molecule according to the invention for manufacturing a medicament. Especially cancer drugs, and in particular the classic chemotherapy drugs are notorious for their side effects. Due to the targeting and synchronization in time and place of both the pharmaceutically active substance made up of the second or third protein molecule and the saponin made up of the first protein molecule, since the first and third protein molecules bear the same binding site for the same epitope on the ΜΛ / t / ¿U¿ I / UO / JOS 101 same cell surface molecule, or since the first and second protein molecules bear different binding sites for different first and second epitopes on the first and second cell surface molecules respectively, a therapeutic combination according to the invention is especially valuable for its use as a medicament, in particular for use in a cancer treatment method. The invention thus provides a therapeutic combination according to the invention or a first protein molecule of the invention for use in a method of treating cancer. The invention also provides a therapeutic combination according to the invention or a first protein molecule of the invention for use in a method of treating acquired or hereditary disorders, in particular monogenic deficiency disorders. The therapeutic combination thus comprises the first and second protein molecules and / or comprises the first and third protein molecules. Therefore, one aspect of the invention relates to a therapeutic combination according to the invention, in which the second or third protein molecule comprises a covalently bound effector moiety, for use in a method for the treatment of a cancer or an autoimmune disease. A further application of the first, second and third protein molecules of the invention in medicine is the replacement of intracellular enzymes in target cells which produce these enzymes in insufficient quantity or insufficient functionality. The resulting disease can be hereditary or acquired. In most cases, only symptomatic treatment is possible, and for a number of rare diseases, insufficient treatment options lead to a lower life expectancy of affected patients. An example of such a disease is phenylketonuria, which is an inborn error of metabolism that results in decreased metabolism of the amino acid phenylalanine. The disease is characterized by mutations in the gene for the liver enzyme phenylalanine hydroxylase. Phenylketonuria is not curable to date. The incidence is approximately 1:10,000 with the highest known incidence in Turkey at 1:2,600. A second or third protein molecule, preferably an antibody, with attached phenylalanine hydroxylase or with an attached polynucleotide encoding phenylalanine hydroxylase can be used to target liver cells using a suitable specific antibody and to replace the defective enzyme in hepatocytes. This is an example of use of the therapeutic combination of the invention that comprises a first protein molecule with a saponin attached to it and a second or third protein molecule with M A / IZ / ZUZI / UO / JOS 102 the enzyme or the oligonucleotide linked thereto according to the invention for gene replacement or therapy. In a preferred embodiment, a therapeutic combination according to the invention is provided for use in a gene therapy or replacement therapy method. The present invention also provides a method for the treatment of cancer, the method comprises administering a medicament comprising a therapeutic combination according to the invention to a patient in need thereof, preferably administering an effective dose of said medicament to a patient in need thereof, preferably a human cancer patient. Considerations regarding suitable forms for administration are known in the art and include toxic effects, solubility, route of administration, and maintenance activity. For example, drug compositions injected into the bloodstream must be soluble. Suitable dosage forms depend in part on the use or route of entry, eg, transdermal or by injection. Such dosage forms should allow the compound to reach a target cell if the target cell is present in a multicellular host. Other factors are known in the art and include considerations such as toxicity and dosage form that are delayed for the compound or composition to exert its effect. One embodiment is the combination of an endosomal escape enhancing conjugate according to the invention, comprising the first protein molecule comprising at least one covalently bound saponin, and a binding moiety, wherein the binding moiety comprises at minus an effector moiety, the binding moiety is the second or third protein molecule comprising the bound effector moiety, wherein the endosomal escape-enhancing conjugate and the binding moiety are, independently of each other, capable of specifically binding to an effector moiety. structure or target cell-specific surface molecule, thereby inducing receptor-mediated endocytosis of a complex of the endosomal escape enhancer conjugate and the target cell-specific surface molecule, and of the complex of the binding moiety and the target cell-specific surface molecule. target cell surface area, wherein the endosomal escape enhancing conjugate and the binding moiety can bind to the same target cell surface area molecule through its same binding site, or wherein the endosomal escape enhancing conjugate ndosomal escape and the binding fraction can bind to the different ΜΛ / t / ZUZ I / UO / JOS 103 target cell-specific surface molecules through their different binding sites. One embodiment is the combination according to the invention, wherein the endosomal escape-enhancing conjugate is capable of competing with the binding moiety for binding to the target cell-specific surface structure or molecule. One embodiment is the combination according to the invention, wherein the endosomal escape-enhancing conjugate and the binding moiety are, independently of each other, capable of specifically binding to the same or a different epitope. One embodiment is the combination for use in a method for the treatment of an aberration such as cancer according to the invention, wherein said endosomal escape enhancing conjugate and said binding moiety are to be administered concomitantly or sequentially. , preferably concomitant. One aspect of the invention relates to a kit comprising a first container containing an endosomal escape-enhancing conjugate according to the invention (ie the first protein molecule) and a second container containing a binding moiety according to the invention. With the invention (ie the second and / or third protein molecule), the kit further comprises instructions for using the binding molecules (ie the therapeutic combination comprising the first and second or first and third pharmaceutical compositions). M A / t / ZUZ I / UO / JOS 104 TABLE A1. Saponins showing endosomal / lysosomal (late) escape-enhancing activity, and saponins comprising a structure resembling said saponins showing endosomal / lysosomal (late) escape-enhancing activity C3beta-OH Replaces carbohydrates in the C28-OH group NP-005236 2 alpha-hydroxy oleanolic acid GlcA- Glc / Gal- AMA-1 16 alpha hydroxy oleanolic acid Glc- Rha-(1^2)[Xyl-(1^ 4)]-Rha AMR 16 alpha Hydroxyoleanolic acid Glc- Rha-(1 —>2)[Ara-(1 —>3)-Xyl-(1 —>4)]Rha alpha-Hederin Hederagenin (23hydroxy oleanolic acid) Rha -(1^2)-Ara- - NP-012672 16 alpha, 23dihydroxyoleanolic acid Ara / Xyl-(1^4)Rha / Fuc-(1^2)Glc / Gal-(1—>2)Rha / Fuc- (1—>2)-Gla Ara / Xyl- NP-017777 Gipsogenin Gal-(1—>2)-[Xyl(1^3)]-GlcA- Xyl-(1—>4)-Rha-(1— >2)-[R-(—>4)]-Fuc(R = 4E-Methoxycinnamic Acid) NP-017778 Gipsogenin Gal-(1^2)-[Xyl(1 —>3)]-GlcA- Xy|- (1 —4).Rha-(1 —»2)-[R-(—>4)]-Fuc(R = 4Z-Methoxycinnamic Acid) NP-017774 Gipsogenin Gal-(1^2)-[Xyl(1 —>3)]-GlcA- Xy l-(1 —>4)-[Gal-( 1 ^3)-Rha-(1 ^2)-4OAc-Fuc- NP-018110c, NP-017772d Gypsogenin Gal-( 1^2)-[Xyl(1 —>3)]-GlcA- Xy l-(1 —>4)-[Glc-(1 —>3)-Rha-(1—>2)3,4-di -OAc-Fuc- NP-018109 Gypsogenin Gal-(1—>2)-[Xyl(1^3)]-GlcA- Xy l-(1 —>4)-[Glc-(1 —>3)-Rha -(1 —>2)[R-(^4)]-3OAc-Fuc- (R = 4EMethoxycinnamic acid) NP-017888 Gipsogenin Gal-(1^2)-[Xyl(1 —>3)]-GlcA- Glc-(1 —>3)-Xyl-(1 —>4)-[Glc-(1 —>3)Rha-(1 ^2)-4-OAc-Fuc- NP-017889 Gypsogenin Gal-(1^ 2)-[Xyl(1^3)l-GlcA- Glc-(1 —>3)-Xyl-(1 —>4)-Rha-(1 —>2)-4OAc-Fuc- NP-018108 Gipsogenin Gal -(1—>2)-[Xyl(1^3)]-GlcA- Ara / xyl-(1 —>3)-Ara / Xyl-(1 ^4)Rha / Fuc-(1—>2)- [4-OAc-Rha / Fuc-(1^4)]-Rha / Fuc 105 SA1641% AE X55b Gypsogenin Gal-(1—2)-[Xyl- (1^3)]-GlcA- Xyl-(1 —3)-Xyl-(1 —4)-Rha-(1—2)- [ Qui-(1^4)]-Fuc- NP-017674 Quillaic acid Gal-(1 —>2)-[Xyl(1^3)]-GlcA- Ap¡-( 1 —>3)-Xyl-( 1 ^4)-[Glc-(1 ^3)]Rha-(1^2)-Fuc- NP-017810 Quillaic acid Ga)-(1 —»2)-[Xyl(1^3)]-GlcA Xyl- (1—>4)-[Gal-(1—>3)]-Rha-(12)- Fuc AG1 Quillaic acid Gal-(1^2)-[Xyl(1—>3)]-GlcA Xyl-( 1—>4)-[Gal-(1—>3)]-Rha-(12)Fuc NP-003881 Quillaic acid Gal-(1—>2)-[Xyl(1^3)]-GlcA Ara / Xyl -(1 —4)-Rha / Fuc-(1 ^4)[Glc / Gal-(1^2)]-Fuc- NP-017676 Quillaic acid Gal-(1—2)-[Xyl(1^3) ]-GlcA Ap¡-(1 —>3)-Xyl-(1 ^4)-[Glc-(1 ^3)]- Rha-(1^2)-[R-H4)]-Fuc- (R = 5-O-[5-O-Ara / Ap¡-3,5dihidrox¡-6-methyl-octano¡l]-3,5dihydroxy-6-methyl-octanoic acid) NP-017677 Gal-( quillaic acid 1—2)-[Xyl(1^3)]-GlcA Api-(1 —>3)-Xyl-(1 —4)-Rha-(1 ^2)[R-(—>4)]-Fuc - (R = 5-O-[5-OAra / Api-3,5-dihydroxy-6-methyloctanoyl]-3,5-dihidrox¡-6-methyloctanoic acid) NP-017706 Gal-(1- quillaic acid >2)-[Xyl- (1^3)]-GlcA Ap¡-(1 ^3)-Xyl-(1 ^4)-Rha-(1 ^2)[Rha-(1^3)]-4 -OAc-Fuc- NP-017705 Quillaic acid Gal-(1 —>2)-[Xyl(1^3)]-GlcA Ap¡-(1 ^3)-Xyl-(1 ^4)-[Glc-( 1 ^3)]- Rha-(1^2)-[Rha-(1^3)]-4-OAc- Fuc- NP-017773 Quillaic acid Gal-(1—>2)-[Xyl- (1^ 3)]-GlcA 6-OAc-Glc-(1 ^3)-Xyl-(1 ^4)-Rha- (1 —>2)-[3-OAc-Rha-(1 ^3)]-Fuc- NP-017775 Quillaic acid Gal-(1->2)-[Xyl(1—3)]-GlcA Glc-(1 —>3)-Xy l-( 1 ^)-Rha-(1 —>2)- [3- OAc-Rha-(1^3)]-Fuc- SA1657 Quillaic acid Gal-(1 —>2)-[Xyl(1^3)]-GlcA Xyl-(1 ^3)-Xyl-(1 ^4)-Rha-(1 ^2)- [Qui-(1^4)]-Fuc- AG2 Quillaic acid Gal-(1 —»2)-[Xyl(1^3)]-GlcA Glc-(1 ^3)-[Xyl-(1 ^4)]-Rha-(1 ^2)- [Qui-(1^4)]-Fuc- SO1861 Quillaic acid Gal-(1—>2)-[Xyl- ( 1^3)]-GlcA Glc-(1 ^3)-Xyl-(1 ^4)-Rha-(1 -^2)[Xyl-(1^3)-4-OAc-Qui-(1^4 )]-Fuc- GE1741 Quillaic acid Gal-(1 —>2)-[Xyl(1^3)]-GlcA Xyl-(1 ^3)-Xyl-(1 ^4)-Rha-(1 ^2) - [3,4-di-OAc-Qu¡-(1 ^4)]-Fuc- ΜΛΖ1 / ZUZ1 / UO l JOS 106 SO1542 Quillaic acid Gal-(1—>2)-[Xyl(1^3)]-GlcA Glc-(1—>3)-[Xyl-(1 -^4)]-Rha- (1^2)- Fuc- SO1584 Quillaic acid Gal-(1—>2)-[Xyl(1^3)]-GlcA 6-OAc-G-(1^3)-[Xyl-(1^4)]-Rha(1^ 2)-Fuc- SO1658 Gypsogenin Gal-(1 —>2)-[Xyl(1^3)]-GlcA Glc-(1—>3)-[Xyl-(1 —>3)-Xyl-(1 — >4)]- Rha-(1^2)-Fuc- SO1674 Quillaic acid Gal-(1—2)-[Xyl(1—»3)]-GlcA Glc-(1—>3)-[Xyl-( 1 —*3)-Xyl-(1 —*4)]- Rha-(1^2)-Fuc- SO1832 quillaic acid Gal-(1—>2)-[Xyl(1^3)]-GlcA Xyl- (1 ^3)-Xyl-(1 ^4)-Rha-(1 ^2)[Xyl-(1 —>3)-4OAc-Qu¡-(1 —>4)]Fuc- QS-7 (also named as QS1861) Quillaic acid Gal-(1—>2)-[Xyl- (1^3)]-GlcA Api / Xyl-(1 ^3)-Xyl-(1 -^4)-[Glc(1 ^ 3)]-Rha-(1 ^2)-[Rha-(1 ^3)]4OAc-Fuc- QS-7 api (also referred to as QS1862) Quillaic acid Gal-(1^2)-[Xyl(1^ 3)]-GlcA Api-(1^3)-Xyl-(1^4)-[Glc(1^3)]-Rha-(1 ^2)-[Rha-(1 ^3)]4OAc-Fuc - QS-17 Quillaic acid Gal-(1 —>2)-[Xyl(1—>3)]-GlcA- Api / Xyl-(1^3)-Xyl-(1^4)-[Glc(1^ 3)]-Rha-(1^2)-[R-H4)-FucR = 5-O-[5-O-Rha-(1^2)Ara / Api-3,5-dih¡drox¡- acid 6-methyloctanoyl]-3,5-dihydroxy-6-methyloctanoic) QS-18 Gal-(1—>2)-[Xyl(1^3)]-GlcA- Api / Xyl-(1^3) quillaic acid )-Xyl-(1^4)-[Glc(1^3)]-Rha-(1^2)-[R-H4)-FucR = 5-O-[5-O-Ara / Api-3 acid ,5dihydroxy¡-6-methyl-octanoyl]-3,5dihydroxy-6-methyl-octanoic) QS-21 A-Celery quillaic acid Gal-(1—>2)-[Xyl(1^3)]-GlcA - Api-(1^3)-Xyl-(1^4)-Rha(1^2)-[R-H4)-Fuc- R = 5-O-[5-O-Ara / Ap¡-3 acid ,5dihidrox¡-6-methyl-octanoyl]-3,5dihydroxy-6-methyl-octanoic) QS-21 A-xyl quillaic acid Gal-(1—>2)-[Xyl(1—>3)]- GlcA- Xyl-(1^3)-Xyl-(1^4)-Rha(1^2)-[R-H4)-Fuc- R = 5-O-[5-O-Ara / Ap¡- acid 3,5dihydroxy-6-methyl-octanoyl]-3,5dihydroxy-6-methyl-octanoic) ΜΑ / Ε / ΖυΖΊ / UO / JOS 107 QS-21 B-celery Quillaic acid Gal-(1—>2)[Xyl-(1^3)]- GlcA- Api-(1^3)-Xyl-(1^4)-Rha(1^2) -[R-(^4)]-Fuc- R = 5-O-[5-O-Ara / Ap¡-3,5dihydroxy-6-methyl-octanoyl]-3,5dihydroxy-6-methyl-octanoic acid) QS-21 B-xyl Quillaic acid Gal-(1—>2)-[Xyl- (1^3)]-GlcA- Xyl-(1—>3)-Xyl-(1—>4)-Rha- ( 1^2)-[R-H3)-Fuc- R = 5-O-[5-O-Ara / Ap¡-3,5dihydroxy-6-methyl-octanoyl]-3,5dihydroxy-6-methyl-octanoic acid ) beta-Aescin (described: Aescin la) Protoaescigenin- 21 (2-methylbut-2-enoate)-22-acetate Glc-(1—>2)-[Glc- (1^4)]-GlcA- - Saponin I from tea seed 23-Oxo-barringtogenol C-21,22-bis(2methylbut-2-enoate) Glc-(1^2)-Ara(1—>3)-[Gal(1—>2)]-GlcA - - Saponin J from tea seed 23-Oxo-barringtogenol C-21,22-bis(2methylbut-2-enoate) Xyl-(1^2)-Ara- (1^3)-[Gal- (1^2 )]GlcA- Saponin F from Assam 23-Oxo-barringtogenol C-21 (2-methylbut-2enoato)-16,22d i acetate Glc-(1—>2)-Ara(1—>3)-[Gal(1 ^2)]-GlcA Digitonin Digitogenin CO O . , -i CO (Π <5 | Φ CM 00 Tf ύ ΐ ΐ ΐ 0 CUU Acid 1 Cowslip 3, 16,28- T rihydroxyoleanan-12ene Rha-(1^2)-Gal(1—>3)-[Glc (1^2)]-GlcA- - AS64R Gipsogenic Acid - Glc-(1—>3)-[Glc-(1—>6)]-Gal- Substitutes carbohydrate in the C-23OH group AS6.2 Gal Gipsogenic Acid - Glc-(1—>3)-[Glc-(1—>6)]-Gal- a, b: Different!c, d: Different names refer to different isolates of the same structure. refer to different isolates of the same structure MA / t / ZUZ I / UO / ¿00 108 TABLE A2: ADCs that were previously investigated in the human clinical setting and subsequently withdrawn from further clinical investigation M A / t / ZUZ I / UO / JOS Drug Name Indication Target Late development stage EGFR Monoclonal Antibody Conjugate Target for oncology Oncology Cells expressing the epidermal growth factor receptor (proto-oncogene c ErbB 1 or receptor tyrosine protein kinase erbB 1 or HER1 or ERBB1 or EGFR or EC 2.7 .10.1) Discovery Affilutin Multiple Myeloma (Kahler's Disease) Discovery IMGN-779 Myelodysplastic Syndrome Cells expressing the myeloid cell surface antigen CD33 (Ig binding to sialic acid such as lectin 3 or gp67 or CD33) IND / CTA submitted Neuradlab Lymphoma Non-Hodgkin Cells expressing tenascin (cytotactin or GMEM or GP 150225 or glioma-associated extracellular matrix antigen or hexabrachion or J1 or myotendinous antigen or neuronectin or tenascin C or TNG) Phase I IMGN-779 Refractory acute myeloid leukemia; Relapsed acute myeloid leukemia Cells expressing myeloid cell surface antigen CD33 (Ig binding to sialic acid such as lectin 3 or gp67 or CD33) Phase I 109 AGS-67E Acute Myelocytic Leukemia (AML, Acute Myeloblastic Leukemia) Cells expressing the leukocyte antigen CD37 (tetraspanin 26 or CD37) Phase I AGS-67E Hairy cell leukemia; Non-Hodgkin lymphoma, refractory chronic lymphocytic leukemia (CLL); Relapsed Chronic Lymphocytic Leukemia (CLL); T-cell leukemia Cells expressing leukocyte antigen CD37 (tetraspanin 26 or CD37) Phase I ASG-15ME Metastatic transitional tract (urothelial) cancer Cells expressing SLIT and NTRK-like protein 6 (SLITRK6) Phase I vandortuzumab vedotin Cancer metastatic hormone refractory prostate (castration resistant, androgen independent) Cells expressing metaloreductase STEAPI (six prostate transmembrane epithelial antigen 1 or STEAPI or EC 1.16.1 Phase I MA / t / ZUZ I / UO / ¿00 110 Drug Name Indication Target Late development stage CDX-014 Ovarian cancer Cells expressing hepatitis A virus cellular receptor 1 (renal injury molecule 1 or T cell immunoglobulin and mucin domain containing protein 1 or receptor of T-cell immunoglobulin mucin 1 or T-cell membrane protein 1 or CD365 or HAVCRI) Phase I AGS-16M18 Liver cancer; Renal cell carcinoma Stage I vorsetuzumab mafodotin No Hodgkin lymphoma; Renal cell carcinoma Cells expressing CD70 antigen (CD27 ligand or CD70 or tumor necrosis factor ligand superfamily member 7) Phase I denintuzumab mafodotin Acute lymphocytic leukemia (ALL); B-cell non-Hodgkin lymphoma; Burkitt's lymphoma; lymphoblastic lymphoma; Mantle cell lymphoma Cells expressing the B cell antigen CD19 (B cell surface antigen B4 or differentiation antigen CD19 or T cell surface antigen Leu 12oCD19) Phase I SGN-CD70A Diffuse large B cell lymphoma; Follicular lymphoma; Mantle cell lymphoma; Metastatic renal cell carcinoma; non-Hodgkin lymphoma Cells expressing the CD70 antigen (CD27 ligand or CD70 or tumor necrosis factor ligand superfamily member 7) Phase I RG-7636 Metastatic melanoma Endothelin B receptor (endothelin receptor nonselective type or EDNRB) Phase I SC-006 Stage I metastatic colorectal cancer MM-310 Breast cancer; endometrial cancer; Esophagus cancer; Gastric cancer; Gastroesophageal junction (GE) carcinomas; Head and neck cancer squamous cell carcinoma; Non-small cell lung cancer; Ovarian cancer; Pancreatic ductal adenocarcinoma; Prostate cancer; Small cell lung cancer; Soft tissue sarcoma; Solid tumor; Transitional cell carcinoma (urothelial cell carcinoma) Ephrin Receptor 2 Type A (Epithelial cell receptor kinase or tyrosine protein kinase ECK or EPHA2 or EC 2.7.10.1) Phase I PE-06647263 Metastatic breast cancer; Ovarian cancer Cells expressing ephrin A4 (EPH-related receptor tyrosine kinase ligand 4 or EFNA4) Phase I PF-06263507 Solid tumor Cells expressing trophoblast glycoprotein (oncofetal antigen M6P1 or 5T4 or oncofetal trophoblast glycoprotein 5T4 or inhibitory factor 1 activated by Wnt or TPBG) Phase I PF-06650808 Metastatic breast cancer; Non-small cell lung cancer; Ovarian cancer Cells expressing neurogenic locus notch homolog protein 3 (NOTCH3) Phase I 111 Drug Name Indication Target Late Development Stage XMT-1522 Breast cancer; Gastric cancer; Non-small cell lung cancer Receptor tyrosine protein kinase ERBB 2 (metastatic protein of lymph node gene 19 or proto-oncogene Neu or proto-oncogene C ErbB 2 or cell surface receptor tyrosine kinase HER2 or p185erbB2 or HER2 or CD340 or ERBB2 or EC 2.7.10.1 ); Tubulin Phase I AMG-595 Anaplastic astrocytoma; Recurrent glioblastoma multiforme (GBM) Cells expressing epidermal growth factor receptor (proto-oncogene c ErbB 1 or receptor tyrosine protein kinase erbB 1 or HER1 or ERBB1 or EGFR or EC 2.7.10.1) Phase I pinatuzumab vedotin Chronic lymphocytic leukemia (CLL) Cells expressing the B-cell receptor CD22 (II-infocyte B cell adhesion molecule or sialic acid-binding Ig such as lectin 2 or Leu 14 or CD22 T-cell surface antigen) Phase I cantuzumab ravtansine Colorectal cancer; Non-small cell lung cancer; Pancreatic cancer; Solid tumor Phase I AVE-9633 Acute myelocytic leukemia (AML, acute myeloblastic leukemia) Cells expressing the myeloid cell surface antigen CD33 (sialic acid binding Ig such as lectin 3 or gp67 or CD33) Phase I MA / t / ZUZ I / UO / JOS 112 breast cancer; Carcinomas; Esophagus cancer; Squamous cell carcinoma of head and neck cancer Cells expressing CD44 antigen (CDw44 or Epican or Extracellular matrix receptor III or Lymphocyte adhesion / return receptor GP90 or HUTCH I or Heparan sulfate proteoglycan or Hermes antigen or Receptor for hyaluronate or Phagocytic Glycoprotein 1 or CD44) Phase I RG-7882 Epithelial ovarian cancer; Fallopian tube cancer; Pancreatic cancer; Peritoneal cancer Cells expressing mucin 16 (ovarian cancer-associated tumor marker CA 125 or ovarian carcinoma antigen CAI 25 or MUC16) Phase I ASG-5ME Adenocarcinoma; Hormone-resistant (castration-resistant, androgen-independent) prostate cancer; Metastatic adenocarcinoma of the pancreas Cells expressing choline transporter as protein 4 (solute transporter family 44 member 4 or SLC44A4) Phase I DCDS0780A B-cell non-Hodgkin lymphoma Phase I SC-004 Endometrial cancer; Epithelial ovarian cancer; Fallopian tube cancer; Peritoneal Cancer Phase I RG-7600 Ovarian Cancer; Pancreatic ductal adenocarcinoma Phase I sofituzumab vedotin Epithelial ovarian cancer; Fallopian tube cancer; Ovarian cancer; Pancreatic cancer; Peritoneal cancer Cells expressing mucin 16 (ovarian cancer-associated tumor marker CA125 or Ovarian carcinoma antigen CAI 25 or MUC16) Phase I 113 Drug Name Indication Target Late Development Stage IMGN-289 Breast cancer; Esophagus cancer; Gastric cancer; Head and neck cancer squamous cell carcinoma; Non-small cell lung cancer; Solid tumor Cells expressing the epidermal growth factor receptor (proto-oncogene c ErbB 1 or receptor tyrosine protein kinase erbB 1 or HER1 or ERBB1 or EGFR or EC 2.7.10.1) Phase I SAR-428926 Breast cancer; Colorectal cancer; Gastric cancer; Non-small cell lung cancer; Ovarian cancer; Prostate cancer; Solid tumor Cells expressing lysosome-associated membrane glycoprotein 1 (CD107A or CD107a or LAMPI type antigen family member) Phase I SGNCD-19B B-cell non-Hodgkin lymphoma; Diffuse large B-cell lymphoma; Follicular lymphoma Cells expressing the B cell antigen CD19 (B cell surface antigen B4 or differentiation antigen CD19 or T cell surface antigen Leu 12 or CD19) Phase I SGNCD-123A Refractory acute myeloid leukemia; Relapsed acute myeloid leukemia Cells expressing the alpha subunit of the interleukin 3 receptor (CD123 or IL3RA) Phase I SGNCD-352A Refractory multiple myeloma; Relapsed multiple myeloma Cells expressing SLAM family member 6 (activation of NK receptor or NK T B antigen or CD352 or SLAMF6) Phase I RG-7841 Breast cancer; Non-small cell lung cancer; Solid tumor Cells expressing lymphocyte antigen 6E (retinoic acid-induced E gene protein or stem cell antigen 2 or thymic shared antigen 1 or LY6E) Phase I IMGN-388 Solid tumor Cells expressing alpha V integrin (alpha receptor subunit of vitronectin or CD51 or ITGAV) Phase I MA / t / ZUZ I / UO / JOS lorvotuzumab mertansine Refractory multiple myeloma; Relapsed multiple myeloma Cells expressing neural cell adhesion molecule 1 (antigen recognized by monoclonal antibody 5.1H11 or CD56 or NCAM1) Phase I lorvotuzumab mertansine Neuroendocrine carcinoma; Neuroendocrine tumors; Non-small cell lung cancer; Ovarian cancer; Skin cancer Cells expressing neural cell adhesion molecule 1 (antigen recognized by monoclonal antibody 5.1H11 or CD56 or NCAM1) Phase I BAY-794620 Lung cancer; Solid tumor Cells expressing carbonic anhydrase 9 (carbonate dehydratase IX or pMW1 or membrane antigen MN or P54 / 58N or renal cell carcinoma-associated antigen G250 0 CA9 or EC 4.2.1.1) Phase I RG-7598 Refractory multiple myeloma; Relapsed Multiple Myeloma Phase I Oncolysin B B-Cell Leukemia; Lymphoma Cells expressing the B cell antigen CD19 (B cell surface antigen B4 or differentiation antigen CD19 or T cell surface antigen Leu 12oCD19) Phase I ΜΛ / t / ZUZ! / uo / ¿00 115 Drug Name Indication Target Late Development Stage ADCT-502(1) Bladder cancer; breast cancer; Esophagus cancer; Gastric cancer; Non-small cell lung cancer Cells expressing ERBB receptor tyrosine protein kinase 2 (metastatic protein from lymph node gene 19 or proto-oncogene Neu or proto-oncogene C ErbB 2 or cell surface receptor tyrosine kinase HER2 or p¡85erbB2 or HER2 or CD340 or ERBB2 or EC 2.7.10.1) Phase I AMG-172 Renal cell carcinoma Cells expressing CD70 antigen (CD27 ligand or CD70 or tumor necrosis factor ligand superfamily member 7) Phase I lmmuRAIT-LL2 Cell non-Hodgkin lymphoma B Cells expressing the B cell receptor CD22 (B cell adhesion molecule or sialic acid binding Ig such as lectin 2 or Leu 14 or CD22 T cell surface antigen) Phase I / ll indusatumab vedotin Adenocarcinoma of the gastroesophageal junction; Gastric cancer Cells expressing a heat-stable enterotoxin receptor (guanylyl cyclase C or intestinal guanylate cyclase or GUCY2C or EC 4.6.1.2) Phase I / ll clivatuzumab tetraxetane Pancreatic cancer Cells expressing mucin 1 (breast carcinoma-associated antigen DF3 o episialin o H23AG o Krebs Von Den Lungen 6 o PEMT o reactive peanut urinary mucin o polymorphic epithelial mucin o tumor-associated epithelial membrane antigen o tumor-associated mucin o CD227 o MUC1) Phase l / ll ΜΛ / IZ / ZUZI / UO / ΟΟΟ 116 depatuxizuma b mafodotin(2) Recurrent malignant glioma Epidermal growth factor receptor (proto-oncogene c ErbB 1 or receptor tyrosine protein kinase erbB 1 or HER1 or ERBB1 or EGFR or EC 2.7.10.1) Phase I / ll CDX-014 Metastatic cell carcinoma kidneys; Papillary renal cell carcinoma Cells expressing hepatitis A virus cellular receptor 1 (kidney lesion molecule 1 or T-cell immunoglobulin and mucin domain-containing protein 1 or T-cell immunoglobulin mucin receptor 1 or T-cell immunoglobulin protein T cell membrane 1 or CD365 or HAVCRI) Phase l / ll vadastuximab talirine(1) Refractory acute myeloid leukemia; Relapsed acute myeloid leukemia Cells expressing myeloid cell surface antigen CD33 (Ig binding to sialic acid such as lectin 3 or gp67 or CD33) Phase I / ll vadastuximab talirine Myelodysplastic syndrome Cells expressing myeloid cell surface antigen CD33 (Ig binding to sialic acid such as lectin 3 or gp67 or CD33) Phase I / II ΜΑ / Ε / ΖυΖΊ / UO / JOS Drug Name Indication Target Late Stage of Development MLN-2704 Metastatic Hormone Refractory Prostate Cancer (castration resistant, androgen independent) Cells expressing glutamate carboxypeptidase 2 (folate hydrolase 1 or prostate-specific membrane antigen or PSMA or pteroilpoly gamma glutamate carboxypeptidase or cell growth inhibitor gene 27 protein or FOLHI or EC 3.4.17.21) Phase l / ll 117 Oncolysin β AIDS-related lymphoma Cells expressing the B cell antigen CD19 (β cell surface antigen B4 or differentiation antigen CD19 or T cell surface antigen Leu 12 or CD19) Phase I / ll coltuximab ravtansine Diffuse lymphoma of large B cells Cells expressing the B cell antigen CD19 (β cell surface antigen B4 or differentiation antigen CD19 or T cell surface antigen Leu 12 or CD19) Phase II coltuximab ravtansine Acute lymphocytic leukemia (ALL, acute lymphoblastic leukemia ) Cells expressing the B cell antigen CD19 (β cell surface antigen B4 or differentiation antigen CD19 or T cell surface antigen Leu 12 or CD19) Phase II coltuximab ravtansine Diffuse large B cell lymphoma Cells expressing the antigen B cell CD19 (β cell surface antigen B4 or differentiation antigen CD19 or T cell surface antigen Leu 12 or CD19) Phase II indusatumab vedotin(2) Adenocarcinoma of the gastroesophageal junction; Gastric cancer; Metastatic adenocarcinoma of the pancreas Cells expressing a heat-stable enterotoxin receptor (guanylyl cyclase C or intestinal guanylate cyclase or GUCY2C or EC 4.6.1.2) Phase II depatuxizumab mafodotin Epidermoid non-small cell lung cancer Epidermal growth factor receptor (proto-oncogene c ErbB 1 or receptor tyrosine protein kinase erbB 1 or HER1 or ERBB1 or EGFR or EC 2.7.10.1) Phase II ΜΛ / t / ZUZ! / OU / ΟΟΟ 118 depatuxizuma b mafodotin(2) Anaplastic astrocytoma; Anaplastic oligoastrocytoma; gliosarcoma; High grade gliomas; Oligodendroglioma; Pediatric diffuse intrinsic pontine glioma; Recurrent glioblastoma multiforme (GBM) Epidermal growth factor receptor (proto-oncogene c ErbB 1 or receptor tyrosine protein kinase erbB 1 or HER1 or ERBB1 or EGFR or EC 2.7.10.1) Phase II lifastuzumab vedotin Non-small cell lung cancer Phosphate-dependent binding protein 2B (Sodium Phosphate Binding Protein 2B or NaP¡3b or Sodium / Phosphate Cotransporter 2B or NaPi 2b or Solute Transporter Family 34 Member 2 or SLC34A2) Phase II lifastuzumab vedotin Ovarian cancer Phosphate-dependent binding protein Sodium 2B (sodium phosphate transporter protein 2B or NaP¡3b or sodium / phosphate cotransporter 2B or NaPi 2b or solute carrier family 34 member 2 or SLC34A2) Phase II ΜΛ / IZ / ZUZI / UO / ΟΟΟ Drug Name Indication Target Late Stage of Development Bismab-A Acute Myeloblastic Leukemia (AML, Acute Myeloblastic Leukemia) Cells expressing the myeloid cell surface antigen CD33 (sialic acid binding Ig such as lectin 3 or gp67 or CD33) Phase II denintuzumab mafodotin Diffuse large B-cell lymphoma; Follicular lymphoma Cells Expressing B Lymphocyte Antigen CD19 (B Lymphocyte Surface Antigen B4 or Differentiation Antigen CD19 or T Cell Surface Antigen Leu 12 or CD19) Phase II Avicidin(1) Colorectal gain er; Prostate cancer Cells expressing the epithelial cell adhesion molecule (Phase II antigen 119 adenocarcinoma-associated or cell surface glycoprotein Trop 1 or epithelial cell surface antigen or epithelial glycoprotein 314 or KS antigen 1 / 4 or KSA or tumor-associated calcium signal transducer 1 or CD326 or EPCAM) pinatuzumab vedotin Diffuse B-cell lymphoma big; Follicular lymphoma Cells expressing the B cell receptor CD22 (B cell adhesion molecule or sialic acid binding Ig such as lectin 2 or T cell surface antigen Leu 14 or CD22) Phase II SGN-15 Breast cancer metastatic; Non-small cell lung cancer; Ovarian cancer; Prostate cancer Cells expressing Lewis Y antigen (GDI 74) Phase II cantuzumab ravtansine Gastric cancer; Gastroesophageal junction (GE) carcinoma Phase II ASP-6183 Ovarian cancer Phase II SAR-566658 Metastatic breast cancer Cells expressing CA6 sialoglycotope antigen Phase II Oncolysin S Small cell lung cancer Cells expressing cell adhesion molecule 1 Neural cells (antigen recognized by monoclonal antibody 5.1 H11 or CD56 or NCAM1) Phase II lorvotuzumab mertansine Small cell lung cancer Cells expressing neural cell adhesion molecule 1 (antigen recognized by monoclonal antibody 5.1 H11 or CD56 or NCAM1) Phase II 120 glembatumumab vedotin Metastatic melanoma; Metastatic uveal melanoma; Osteosarcoma; Squamous cell non-small cell lung cancer Cells expressing transmembrane glycoprotein NMB (transmembrane glycoprotein HGFIN or GPNMB) Phase II MA / E / ZUZ! / UO / JOS Drug Name Indication Target Late Development Stage MM-302 Metastatic Breast Cancer Cells expressing the ERBB receptor tyrosine protein kinase 2 (metastatic lymph node gene 19 protein or proto-oncogene Neu or proto-oncogene C ErbB 2 or cell surface receptor tyrosine-like kinase HER2 or p¡85erbB2 or HER2 or CD340 or ERBB2 or EC 2.7.10.1) Phase ll / lll Neuradiab Brain cancer; Glioblastoma multiforme (GBM) Tenascin-expressing cells (cytotactin or GMEM or GP 150-225 0 glioma-associated extracellular matrix antigen or hexabrachion or J1 or myotendinous antigen or neuronectin or tenascin C or TNG) Phase III clivatuzumab tetraxetane Metastatic adenocarcinoma of the pancreas Cells expressing express mucin 1 (breast carcinoma-associated or episialin DF3 antigen or H23AG or Krebs Von Den Lungen 6 or PEMT or peanut reactive urinary mucin or polymorphic epithelial mucin or tumor-associated epithelial membrane antigen or Phase III 121 tumor-associated mucin or CD227 or MUC1) depatuxizumab mafodotin(2) Glioblastoma Multiforme (GBM) Epidermal growth factor receptor (proto-oncogene c ErbB 1 or receptor tyrosine protein kinase erbB 1 or HERI or ERBBI or EGFR or EC 2.7.10.1) Phase III vadastuximab talirine(1) Acute myelocytic leukemia (AML, acute myeloblastic leukemia) Cells expressing myeloid cell surface antigen CD33 (Ig binding to sialic acid such as lectin 3 or gp67 or CD33) Phase III glembatumuma b vedotin(2) Metastatic breast cancer Cells expressing NMB transmembrane glycoprotein (HGFIN transmembrane glycoprotein or GPNMB) Phase III Oncolysin B B-cell leukemia; Lymphoma Cells that express the B cell antigen CD19 (B cell surface antigen B4 or differentiation antigen CD19 or T cell surface antigen Leu 12 or CD19) Phase III lmmuRAIT-LL2 B cell leukemia Cells that express the receptor for B cells CD22 (B cell adhesion molecule or sialic acid binding Ig such as lectin 2 or Leu 14 or CD22 T cell surface antigen) Preclinical MA / t / ZUZ I / UO / ¿00 122 indusatumab vedotin Metastatic colorectal cancer Cells expressing a heat-stable enterotoxin receptor (guanylyl cyclase C or intestinal guanylate cyclase or GUCY2C or EC 4.6.1.2) Preclinical ASG-15ME Lung cancer Cells expressing SLIT and NTRK-like protein 6 (SLITRK6) ) preclinical ΜΛ / t / ZUZ! / OU / ΟΟΟ Drug Name Indication Target Late Development Stage HTI-1511 Bile duct cancer (cholangiocarcinoma); breast cancer; Colorectal cancer; Non-small cell lung cancer Cells expressing epidermal growth factor receptor (proto-oncogene c ErbB 1 or receptor tyrosine protein kinase erbB 1 or HERI or ERBBI or EGFR or EC 2.7.10.1) Preclinical ZW-33 Gastric cancer; Metastatic breast cancer Cells expressing ERBB receptor tyrosine protein kinase 2 (metastatic protein from lymph node gene 19 or proto-oncogene Neu or proto-oncogene C ErbB 2 or cell surface receptor tyrosine kinase HER2 or p185erbB2 or HER2 or CD340 or ERBB2 or EC 2.7.10.1) Preclinical ZW-33 Ovarian cancer Cells expressing the receptor tyrosine protein kinase ERBB 2 (metastatic protein of lymph node gene 19 or proto-oncogene Neu or proto-oncogene C ErbB 2 or cell surface receptor tyrosine kinase type HER2 or p185erbB2 or HER2 or CD340 or ERBB2 or EC 2.7.10.1) Preclinical SGNCD352A Non-Hodgkin lymphoma Cells expressing SLAM family member 6 (activation of the NK receptor or NK T B antigen or CD352 or SLAMF6) Preclinical 123 HuMax- CD74-ADC Oncology Cells expressing the gamma chain of HLA class II histocompatibility antigen (HLA DR antigen-associated invariant chain or la or p33 or CD74 antigen-associated invariant chain) Preclinical sacituzumab govitecan Pancreatic ductal adenocarcinoma Cells expressing the transducer Tumor-Associated Calcium Signal 2 (Cell Surface Glycoprotein Trop 2 or Membrane Component Chromosome 1 Surface Marker 1 or Pancreatic Carcinoma Marker Protein GA7331 or TACSTD2) sacituzumab govitecan Adenocarcinoma; Cervical cancer; colorectal cancer; endometrial cancer; Epithelial ovarian cancer; Esophagus cancer; Follicular thyroid cancer; Gastric cancer; glioblastoma multiforme (GBM); Head and neck cancer squamous cell carcinoma; Hepatocellular carcinoma; Kidney cancer (renal cell cancer); Metastatic hormone refractory prostate cancer (castration resistant, androgen independent); Transitional pathway (urothelial) metastatic cancer; Transitional cell cancer (urothelial cell cancer) Cells expressing tumor-associated calcium signal transducer 2 (Cell surface glycoprotein Trop 2 or Membrane component Chromosome 1 surface marker 1 or Pancreatic carcinoma marker protein GA7331 or TACSTD2) Name of drug Indication Target Last Stage of Development MA / t / ZUZ I / UO / JOS 124 sacituzumab govitecan Hepatocellular Carcinoma Cells expressing tumor-associated calcium signal transducer 2 (Cell Surface Glycoprotein Trop 2 or Membrane Component Chromosome 1 Surface Marker 1 or Pancreatic Carcinoma Marker Protein GA7331 or TACSTD2) sacituzumab govitecan Metastatic breast cancer ; Transitional cell cancer (urothelial cell cancer) Cells expressing tumor-associated calcium signal transducer 2 (Cell Surface Glycoprotein Trop 2 or Membrane Component Chromosome 1 Surface Marker 1 or Pancreatic Carcinoma Marker Protein GA7331 or TACSTD2 ) sacituzumab govitecan Non-small cell lung cancer; Small cell lung cancer Cells expressing tumor-associated calcium signal transducer 2 (Cell surface glycoprotein Trop 2 or Chromosome 1 membrane component Surface marker 1 or Pancreatic carcinoma marker protein GA7331 or TACSTD2) sacituzumab govitecan Metastatic breast cancer Cells expressing tumor-associated calcium signal transducer 2 (Cell Surface Glycoprotein Trop 2 or Chromosome Membrane Component 1 Surface Marker 1 or Pancreatic Carcinoma Marker Protein GA7331 or TACSTD2) (1) Discontinued due to adverse events (2 ) Suspended due to lack of effectiveness ΜΛ / Ε / ΖυΖΊ / UO / ¿00 125 TABLE A3 — ADCs Reaching Phase III Clinical Development Drug name Indication Stage of development Last stage of development Reason for discontinuation trastuzumab emtansine Gastric Cancer Marketed Phase ll / lll Unspecified MM-302 Metastatic breast cancer Suspended Phase ll / lll Business / strategic decision trastuzumab emtansine Metastatic breast cancer Marketed Phase III Unspecified trastuzumab emtansine Gastric Cancer Marketed Phase III Unspecified ibritumomab tiuxetane Diffuse large B-cell lymphoma Marketed Phase III inotuzumab ozogamicin Follicular lymphoma Marketed Phase III inotuzumab ozogamicin Diffuse large B-cell lymphoma; No Hodgkin lymphoma Marketed Phase III Lack of efficacy rovalpituzumab tesirin Small cell lung cancer Phase III Phase III rovalpituzumab tesirine Small cell lung cancer Phase III Phase III Neuradib Brain cancer; Glioblastoma multiforme (GBM) Inactive Phase III Not specified clivatuzumab tetraxetane Metastatic adenocarcinoma of the pancreas Inactive Phase III Not specified depatuxizumab mafodotin Glioblastoma Multiforme (GBM) Inactive Phase III Lack of efficacy vadastuximab talirine AML Discontinued Phase III Events adverse 126 glembatumumab vedotin Metastatic breast cancer Discontinued Phase III Lack of efficacy Oncolysin B B-cell leukemia; Suspended Lymphoma Phase III Business / strategic decision TABLE A4. Tumor-specific cell surface receptor targets that can be targeted by immunoglobulins according to the invention, and antibodies that can be used for the ADCs and saponin-provided antibodies and saponin-provided ADCs of the present invention ( not presented as a limitation; other immunoglobulins are equally suitable for the invention) Target cell surface receptor Examples of HER2 monoclonal antibodies Anti-HER2 monoclonal antibody such as trastuzumab and pertuzumab CD20 Anti-CD20 monoclonal antibody such as rituximab, ofatumumab, tositumomab and ibritumomab CA125 Antibody anti-CAI 25 monoclonal antibody such as oregovomab EpCAM (17-1 A) Anti-Epcam Monoclonal Antibody (17-1 A) As Edrecolomab EGFR Anti-EGFR monoclonal antibody such as cetuximab, panitumumab, and nimotuzumab CD30 Anti-CD30 monoclonal antibody such as brentuximab CD33 Monoclonal antibody anti-CD33 such as gemtuzumab and huMy9-6 vascular alpha-v beta-3 integrin Anti-vascular alpha-v beta-3 integrin monoclonal antibody such as etaracizumab CD52 Anti-CD52 monoclonal antibody such as alemtuzumab CD22 Anti-CD22 monoclonal antibody such as epratuzumab CEA Anti-CD52 monoclonal antibody -CEA such as labetuzumab CD44v6 Anti-CD44v6 monoclonal antibody such as bivatuzumab FAP Anti-FAP monoclonal antibody such as sibrotuzumab CD19 Anti-CD19 monoclonal antibody such as huB4 CanAg Anti-CanAg monoclonal antibody such as huC242 CD56 Anti-CD56 monoclonal antibody such as huN901 CD38 anti-monoclonal antibody CD38 as daratumumab CA6 Anti-CA6 monoclonal antibody as DS6 IGF-IR Anti-IGF-IR monoclonal antibody as cixutumumab and 3B7 Integrin Anti-integrin monoclonal antibody as CNTO 95 syndecan-1 Anti-syndecan-1 monoclonal antibody as B-B4 ΜΑ / Ε / ΖυΖΊ / UO / JOS 127 Table A5: RIP of plants Plant family Plant species Proteins Classification Adoxaceae Sambucus ebulus L. Ebulitin a, Ebulitin B, Ebulitin and RIP 1 Ebulin f, Ebulin I, Ebulin rl, Ebulin r2, SEA RIP 2 SEAN, SELfd, SELId, SELIm lectin Sambucus nigra L. α-Nigritin, β-Nigritin, yNigritin, Nigritin f1, Nigritin f2 RIP 1 Nigrin b basic, Nigrin b = SNA-V, Nigrin f = SNA-Vf, Nigrin 11, Nigrin I2, Nigrin s, SNA-I, SNA- I', SNA-lf, SNAflu-l, SNLRPI, SNLRP2 RIP 2 SNA-ld, SNA-lm, SNA-II, SNA-lll, SNA-IV = SNAIVf, SNA-IVI, SNApol-l, SNApol-ll, TrSNA-l, TrSNA-lf Sambucus racemosa lectin L. racemosin b basic, SRA RIP 2 SRLbm = SRAbm Sambucus sieboldiana lectin (Miq.) Blume ex Graebn. SSA = SSA-b-1, Sieboldin-b = SSA-b-2 RIP 2 SSA-b-3, SSA-b-4 lectin Aizoaceae Mesembryanthemum crystallinum L. RIP RIP 1 Amaranthaceae Amaranthus caudatus L. Amaranthin = ACA lectin Amaranthus cruentus L. ACL lectin Amaranthus hypochondriacus L. [Syn.: Amaranthus leucocarpus S. A. leucocarpus lectin lectin ΜΛ / t / ZUZ I / UO / JOS 128 Watson] Amaranthus mangostanus L. Amaramangina RIP 1 Amaranthus tricolor L. AAP-27 RIP 1 Amaranthus viridis L. Amarantina RIP 1 Beta vulgaris L. Beetin-27 = BE27, Beetin-29 = BE29, Betavulgina RIP 1 Celosia argentea L. [Syn .: Celosia cristata L.] CCP-25, CCP-27 RIP 1 Chenopodium album L. CAP30 RIP 1 Spinacia oleracea L. SoRIPI = BP31 RIP 1 SoRIP2 RIP 1 candidate Araliaceae Aralia elata (Miq.) Seem. Aralina Panax ginseng C.A.Mey Panaxagin Peculiar candidate RIP 1 / RNase Panax quinquefolius L. Quinqueginsine Peculiar candidate RIP 1 / RNase Asparagaceae Asparagus officinalis L. Asparin 1, Asparin 2 RIP 1 Drimia maritima (L.) Stearn [Syn.: Charybdis maritima (L. .) Speta] Charibdina RIP 1 Muscari armeniacum Leichtlin ex Baker Musarmina 1, Musarmina 2, Musarmina 3, Musarmina 4 RIP 1 Polygonatum multiflorum (L.) All. PMRIPm, PMRIPt RIP 2 Yucca gloriosa var. tristis Carrióre Cassava leaf protein = YLP RIP 1 MA / t / ZUZ I / UO / JOS 129 [Syn.: Yucca recurvifolia Salisb.] Basellaceae Basella rubra L. Basella RIP 2a, Basella RIP 2b, Basella RIP 3 RIP 1 Caryophyllacea and Agrostemma githago L. Agrostina 2, Agrostina 5, Agrostina 6, Agrostina RIP 1 Dianthus barbatus L. Diantina 29 RIP 1 Dianthus caryophyllus L. Diantina 30, Diantina 32 RIP 1 Dianthus chinensis L. [Syn.: Dianthus sinensis Link] D. sinensis RIP RIP 1 Gypsophila elegans M.Bieb. Gypsophylline RIP 1 Silene chalcedonica (L.) E.H.L.Krause [Syn.: Lychnis chalcedonica L.] Lichnina RIP 1 Silene glaucifolia Lag. [Syn.: Petrocoptis glaucifolia (Lag.) Boiss.] Petroglaucina 1, Petroglaucina 2 RIP 1 Silene laxipruinosa Mayol & Rosselló [Syn.: Petrocoptis grandiflora Rothm.] Petrograndina RIP 1 Saponaria ocimoides L. Ocimoidina RIP 1 Saponaria officinalis L. Saporina- L1 = SO-LI, Saporin-L2 = SO-L2, Saporin-L3 = SO-L3, Saporin-I = SO-I = SO-4, Saporin-R1 = SO-RI Saporin-R2 = SO-R2, Saporin -R3 = SO-R3, SO3a, SO3b, SaporinS5 = Saporin 5 = SO-S5, RIP 1 ΜΑ / Ε / ΖυΖΊ / UO / JOS 130 Saporin-S6 = Saporin 6 = SO-6 = SO-S6, Saporin-S8 = SO-S8, Saporin-S9 = Saporin 9 = SO-S9, SAP-C, SAP-S Myosoton aquaticum (L.) Moench [Syn .: Stellaria aquatica (L.) Scop.] Stellarina RIP 1 Stellaria media (L.) Vi II. RIPQ3 RIP 1 Vaccaria hispánica (Mili.) Rauschert [Syn.: Vaccaria pyramidata Medik.] Pyramidatina RIP 1 Cucurbits Benincasa hispida (Thunb.) Cogn. Hispina RIP 1 α-benincasine, βbenincasine sRIP 1 Bryonia cretica subsp. dioica (Jacq.) Tutin. [Syn.: Bryonia dioica L.] Briodin 1 = BDI, Briodin 2, Briodin -L, Briodin -R RIP 1 BDA lectin / RIP type 2 Citrullus colocynthis (L.) Schrad. Colocin 1, Colocin 2 RIP 1 Cucurbita foetidissima Kunth Foetidissimin RIP 2 peculiar Foetidissimin II RIP 2 Cucumis ficifolius A. Rich. [Syn.: Cucumis figarei Delile ex Naudin] Cucumis figarei RIP = CFRIP RIP 1 candidate Cucurbita Duchesne maxima Cucurmoschina sRIP 1 candidate Cucurbita moschata Duchesne [Syn.: Cucurmosina, Cucurmosina 2, C. moschata RIP, Moschatina, PRIP 1, RIP 1 ΜΛ / Ε / ΖυΖΊ / UO / ΟΟΟ 131 Cucurbita moschata (Duchesne ex Lam.) Duchesne ex Poir.] PRIP2. a-moschina, β-moschina SRIP 1 candidate Cucurbita pepo L. Pepocina RIP 1 Cucurbita pepo var. texana (Scheele) D.S.Decker [Syn.: Cucurbita texana (Scheele) A. Gray] Texanina RIP 1 Gynostemma pentaphyllum (Thunb.) Makino Ginostemmina RIP 1 Lagenaria siceraria (Molina) Stand I. Lagenina RIP 1 candidate Luffa acutangula (L.) Roxb. Luffaculin-1, Luffaculina2 RIP 1 Luffangulina sRIP 1 Fruit lectin luffa acutangula lectin Luffa cylindrica (L.) M. Roem [Syn.: Luffa aegyptiaca Mili.] Luffina, Luffin-α, Luffin-b, a-luffina, β- luffina, LRIP RIP 1 Luffacillin, Luffina P1 sRIP 1 Luffina-S, LuffinaS(1), LuffinaS(2) = luffina S2, LuffinaS(3) sRIP 1 candidate Marah oreganus (Torr. & A. Gray) Howell MOR-I, MOR-II RIP 1 Momordica balsamina L. Balsamina, MbRIP-1, Momordina II RIP 1 132 Momordica charantia L. MAP 30, a-momorcharin = aMMC, β-momorcharin = β-MC = β-MMC, δmomorcharin = δ-MMC, Momordina, Momordina = inhibitor Momordica charantia, Momordina II, Momordina-a, Momordina-b RIP 1 γ-momorcharin = γMMC, Charantina sRIP 1 RIP 1 candidate RIP 1 candidate MOL = M. charantia lectin, anti-H Lectin, Momordica agglutinin, Momordina, protein fraction 1, protein fraction 2 MCL lectin = Momordica seed lectin = Momordica charantia lectin, MCL1 RIP 2 Momordica cochinchinensis Spreng. Cochinin B, Momorcochina, Momorcochina-S RIP 1 Siraitia grosvenorii (Swingle) C. Jeffrey ex A.M.Lu & Zhi Y.Zhang [Syn.: Momordica grosvenorii Swingle] Momorgrosvin RIP 1 Sechium edule (Jacq.) Sw. Sechiumin RIP 1 Ricinos sanguienus , France Ricinn, Ricini2, Ricin2 RIP 2 ΜΛ / IZ / ZUZI / UO / ΟΟΟ 133 Fabaceae Abrus precatorius L. Abrina, Abrina-a = Abrina C = Abrina-lll, Abrina-b, Abrina-c = Abrina A = Abrina-I, Abrina-d, Abrina-ll, APA = Abrus precatorius agglutinin = Abrus lectin = AAG, APA-I, APA-II RIP2 Abrus pulchellus Thwaites Pulchellin, Pulchellin Pl, Pulchellin PII, Pulchellin Pili RIP2 Pisum sativum subsp. sativum L. [Syn.: Pisum sativum var. arvense (L.) Poir.] α-pisavina, 3-pisavina RIP 1 Pisumsativum var. macrocarpon Sativina RIP 1 candidate Iridaceae Iris hollandica var. Professor Blaauw IrisRIP - IRIP, IrisRIP.AI, lrisRIP.A2, lrisRIP.A3 RIP 1 IRA, IRAb, IRAr RIP 2 Lamiaceae Clerodendrum aculeatum (L.) Schltdl. CA-SRI RIP 1 candidate Clerodendrum inerme (L.) Gaenn. CIP-29 RIP 1 CIP-34 RIP 1 candidate Leonurus japonicus Houtt. Leonurina RIP candidate Lauraceae Cinnamomum bodinieri H. Lév. Bodinierin RIP 2 Cinnamomum camphora (L.) J. Presl Camforin RIP 1 Cinnamomine, Cinnamomine 3 Cinnamomine 1, Cinnamomine 2, RIP 2 MA / IZ / ZUZI / UO / JOS 134 Cynforin sRIP 2 Cinnamomum parthenoxylon (Jack) Meisn. [Syn.: Cinnamomum porrectum (Roxb.) Kosterm.] Porrectin RIP 2 Malvaceae Abelmoschus esculentus (L.) Moench Abelesculin RIP 1 Nyctaginaceae Boerhaavia diffusa L. Inhibitor Boerhaavia RIP 1 candidate Bougainvillea spectabilis Willd. BAP I, Bouganin = Bougainvillea RIP RIP 1 Bougainvillea x buttiana cv. Enid Lancester BBP-24, BBP-28 RIP 1 Bougainvillea x buttiana cv. Mahara BBAP1 RIP 1 Mirabilis expansa (Ruiz & Pav.) Stand i. ME1, ME2 RIP 1 Mirabilis jalapa L. MAP, MAP-2, MAP-3, MAP-4, MAP-S RIP 1 Olacaceae Malania oleifera Chun K. Lee Malanina lectin / RIP candidate 2 Ximenia americana L. Riproximin = Rpx, Rpx -I, Rpx-ll RIP 2 Passifloraceae Adenia digitata (Harv.) Engl. Modeccina = Modeccina 4B, Modeccina 6B RIP 2 Adenia ellenbeckii Harms A. ellenbeckii lectin RIP 2 candidate Adenia fruticosa Burtt Davy A. fruticosa lectin lectin MA / t / ZUZ! / uo / ¿00 135 Adenia glauca Schinz A. glauca lectin RIP 2 candidate Adenia goetzei Harms (name unresolved) A. goetzei lectin RIP2 Adenia keramanthus Harms A. keramanthus lectin RIP 2 candidate Adenia lanceolata Engl. Lanceolin RIP 2 Adenia racemosa W. J.deWilde A. racemosa lectin lectin Adenia spinosa Burtt Davy A. spinosa lectin RIP 2 candidate Adenia stenodactyla Harms Stenodactylin RIP 2 Adenia venenata Forssk. A. venenata lectin RIP 2 candidate Adenia volkensii Harms Volkensina RIP 2 Phytolaccaceae Phytolacca americana L. α-ΡΑΡ, PAP = American protein Phytolacca = pokeweed antiviral protein, PAP-I, PAP-II, PAP-lll, PAP-C, PAP-H, PAP-R, PAP-S, PAP-SI, PAP-S2 RIP 1 Phytolacca dioica L. Diocin 1, Diocin 2, PDLl, PD-L2, PD-L3, PD-L4, PDSI, PD-S2 , PD-S3 RIP 1 Phytolacca dodecandra L'Hér. Dodecandrin, Dodecandrine C RIP 1 Phytolacca heterotepala H. Walter Heterotepalin 4, Heterotepalin 5b RIP 1 Phytolacca insularis Nakai Insularina = PIP = antiviral protein Phytolacca insularis, PIP2 = protein RIP 1 136 antiviral P. insularis 2 Poaceae Hordeum vulgare L. Barley toxin = barley translation inhibitor = barley protein synthesis inhibitor = BPSI = RIP 30, barley toxin I = barley translation inhibitor I, barley toxin II = barley translation inhibitor II = barley protein synthesis inhibitor II = BPSI II, barley toxin III = barley translation inhibitor III, JIP60 RIP 1 Oryza sativa L. Oryza sativa RIP RIP 1 Secale cereale L. RPSI RIP 1 Triticum aestivum L. Tritin, Tritin 1, Tritin 2, Tritin 3, Tritin-S, Tritin-L RIP 1 Zea mays L. b-32 = Maize RIP = maize proRIPI Maize proRIP2 RIP 3 / peculiar RIP 1 Ranunculaceae Eranthishyemalis (L.) Salisb. EHL RIP 2 Santalaceae Phoradendron californicum Nutt. PCL RIP 2 Viscum album L. (Himalayan mistletoe) HmRip, Hr-nRip 1, HmRip 2, HmRip 3, HmRip 4 Viscum album L. (European mistletoe) ML-I = Mistletoe lectin I = Viscumin = Eu-ML = EML-I - AAV-I, ML-II = Mistletoe Lectin II = AAV-II, MLIII = Mistletoe Lectin RIP 2 MA / t / ZUZ I / UO / JOS 137 III = VAA-111 Viscum articulatum Burm. F. Articulatin-D Viscum coloratum (Kom.) Nakai [Syn.: Viscum album subsp. coloratum Kom.] KML, KML-C, KML-IIL, KML-IIU, VCA RIP 2 Solanaceae Nicotiana tabacum L. CIP31 RIP- type protein TRIP P. macrocarpa RIP RIP 1 candidate Phaleria macrocarpa (Scherff.) Boerl. *Schrot J, Weng A, Melzig MF, et al Ribosome-inactivating and related proteins. Toxins (Basel). 2015 May 8;7(5): 1556-615. It is part of the invention that the therapeutic combination, the first pharmaceutical composition, the first protein molecule, the second or third pharmaceutical composition or the second or third protein molecule of the invention is additionally combined with a covalent conjugate (complex) of a molecule or a binding moiety and a saponin, or are further combined with a pharmaceutical compound, an antibody, etc., thereby providing a composition comprising three or more enhancers, pharmaceutically active ingredients, etc., for example, a conjugate of the invention (eg, a first protein molecule and / or a second or third protein molecule) combined with a binding moiety complexed with an effector molecule, further combined with a pharmaceutical, whether or not linked to a saponin , and which is or is not coupled to a ligand such as a targeted immunoglobulin, domain or fragment thereof. Additionally, one embodiment is the therapeutic combination, first pharmaceutical composition, first protein molecule, second or third pharmaceutical composition, or second or third protein molecule of the invention, wherein the second or third protein molecule is provided with two or more effector moieties such as a toxin or immunotoxin, where the two or more effector moieties are the same or different. exemplary achievements 138 One embodiment is the endosomal escape-enhancing conjugate of the invention, wherein the saponin is a bisdesmosidic triterpene saponin belonging to the type of a 12,13-dehydrooleanan with an aldehyde function, at position 23, and wherein the saponin is preferably a saponin that can be isolated from Gypsophila or Saponaria species, more preferably the saponin is SO1861 saponin or any of its diastereomers. One embodiment is the endosomal escape-enhancing conjugate of the invention, wherein the binding site is at least one ligand, such as an immunoglobulin, with at least one effector moiety bound thereto. One embodiment is the endosomal escape-enhancing conjugate of the invention, wherein the binding site is an immunoglobulin or at least a binding domain thereof for binding to a cell surface molecule, wherein preferably the immunoglobulin molecule cell surface is selected from any of HER2, EGFR, CD20, CD22, Folate receptor 1, CD146, CD56, CD19, CD138, CD27L, PSMA, CanAg, integrin-alphaV, CA6, CD33, mesothelin, Cripto, CD3, CD30, CD33, CD239, CD70, CD123, CD352, DLL3, CD25, ephrinA4, MUC1, Trop2, CEACAM5, HER3, CD74, PTK7, Notch3, FGF2, C4.4A, FLT3, CD71. One embodiment is the endosomal escape-enhancing conjugate of the invention, wherein a linker is coupled to the glycoside via a cleavable bond, and wherein the ligand is an immunoglobulin, wherein preferably said cleavage bond is subjected to cleavage under acidic, reducing, enzymatic or light-induced conditions, and preferably the cleavable bond is a covalent bond, preferably an imine bond, a hydrazone bond, an oxime bond, a 1,3-dioxolane bond or an ester bond, wherein preferably the cleavable bond is a disulfide bond or a peptide bond. One embodiment is the endosomal escape-enhancing conjugate of the invention, wherein the saponin moiety is a terminal saponin, preferably the SO1861 saponin, the linker is a chemical linker that covalently connects the saponin to the binding site of the saponin. first protein molecule, and the first binding site of the third and first protein molecule itself is an immunoglodulin such as trastuzumad or cetuximad, the linker preferably provides a cleavable link between the terminal saponin moiety and the first binding site composed of the first and third protein molecule. One embodiment is the combination of an endosomal escape-enhancing conjugate (ie the first protein molecule) according to the invention and a M A / IZ / ΖυΖΊ / UO f JOS 139 binding moiety (i.e. the second or third protein molecule), wherein the binding moiety comprises at least one effector moiety, wherein the endosomal escape-enhancing conjugate and the binding moiety are, independently of each other , capable of specifically binding to a target cell-specific surface structure or molecule, thereby inducing receptor-mediated endocytosis of a complex of the conjugate that enhances endosomal escape and the target cell-specific surface molecule, and of the complex of the binding fraction and the target cell specific surface molecule. One embodiment is the combination according to the invention, wherein the endosomal escape-enhancing conjugate and the binding moiety are capable of specifically binding to the same target cell-specific surface structure or molecule, when the binding moiety is the third protein molecule. One embodiment is the combination according to the invention, wherein the endosomal escape-enhancing conjugate is capable of competing with the binding moiety for binding to the target cell-specific surface structure or molecule, when the binding moiety is the third protein molecule. One embodiment is the combination according to the invention, wherein the endosomal escape-enhancing conjugate and the binding moiety are, independently of each other, capable of specifically binding to the same epitope. One embodiment is the combination according to the invention, wherein the endosomal escape-enhancing conjugate is capable of specifically binding to a first epitope, which is the same as the first epitope to which the binding moiety is capable of specifically binding. , when the binding moiety is the third protein molecule. One embodiment is the combination according to the invention, wherein the endosomal escape-enhancing conjugate and the binding moiety are capable of specifically binding to different target cell-specific surface structures or molecules, when the binding moiety is the second protein molecule. One embodiment is the combination according to the invention, wherein the target cell-specific surface structure or molecule is selected from HER2, EGFR, CD20, CD22, Folate receptor 1, CD146, CD56, CD19, CD138, CD27L, PSMA, CanAg, integrin-alphaV, CA6, CD33, mesothelin, Gripto, CD3, CD30, CD33, CD239, CD70, CD123, CD352, DLL3, CD25, ephrinA4, MUC1, Trop2, CEACAM5, HER3, CD74, PTK7, Notch3, FGF2, C4.4A, FLT3, CD71. ΜΛ / t / ¿U¿ I / UO / JOS 140 One embodiment is the combination according to the invention, in which the glycoside molecule is a bisdesmosidic triterpene, preferably a saponin. One embodiment is the combination according to the invention, in which the glycoside molecule is a bisdesmosidic triterpene saponin. One embodiment is the combination according to the invention, wherein the saponin is a bisdesmosidic triterpene saponin belonging to the type of a 12,13-dehydrooleanane with an aldehyde function at position 23. One embodiment is the combination according to the invention, wherein the saponin is a saponin that can be isolated from Gypsophila or Saponaria species. One embodiment is the combination according to the invention, in which the saponin is an SO1861 or any of its diastereomers. One embodiment is the combination according to the invention, in which at least one glycoside binds to the ligand (binding site for the epitope on the cell surface molecule) through a cleavable bond, in which said bond preferably cleaved it. is subjected to cleavage under acidic, reducing, enzymatic, or light-induced conditions, and wherein the bond cleaved preferably is a disulfide bond or a peptide bond. One embodiment is the combination according to the invention, wherein the cleaved bond is a covalent bond, preferably an imine bond, a hydrazone bond, an oxime bond, a 1,3-dioxolane bond or an ester bond. One embodiment is the combination according to the invention, wherein the endosomal escape-enhancing conjugate comprises a defined number of glycosides or a defined range. One embodiment is the combination according to the invention, wherein the defined range is between 1-30 glycoside(s), preferably between 1-20, more preferably between 1-10, more preferably between 1-6, most preferably between 2-6, more preferably 2-5, more preferably 3-5, most preferably 3-4 glycosides. One embodiment is the combination according to the invention, in which the effector moiety is a pharmaceutically active substance, such as a toxin such as a protein toxin, a drug, a polypeptide or a polynucleotide. One embodiment is the combination according to the invention, wherein the target cell is a diseased cell or a disease-related cell, preferably ΜΛ / t / ¿U¿ I / UO f JOS 141 a tumor cell or a tumor-associated cell (eg, tumor vascular cell), or an immune cell (eg, a regulatory T cell), or an autoimmune cell. One embodiment is the combination according to the invention, in which at least one effector moiety is linked to the binding moiety (second or third protein molecule) through a cleaved bond, wherein preferably said cleaved bond is subjected to cleavage under acidic, reducing, enzymatic, or light-induced conditions, and / or wherein the bond cleaved is a disulfide bond or a peptide bond. One embodiment is the combination according to the invention, in which the glycoside (saponin) is capable of increasing the endosomal escape of the effector molecule. One embodiment is the composition according to the invention, for use as a medicament. One embodiment is the pharmaceutical composition comprising a combination according to the invention (previous embodiments) and a pharmaceutically acceptable excipient. One embodiment is the pharmaceutical composition according to the invention, further comprising at least one additional pharmaceutically active ingredient, such as an additional immunoglobulin. One embodiment is the combination for use according to the invention, or pharmaceutical composition according to the invention, for use in a method of treatment against cancer or autoimmune disease. One embodiment is the combination for use according to the invention, wherein the endosomal escape-enhancing conjugate (first protein molecule) and the binding moiety (second or third protein molecule) are to be administered concomitantly or sequentially, preferably concomitant. One embodiment is a method of treating cancer, the method comprising administering a combination according to the invention to a patient in need thereof. One embodiment is the method of treating cancer, the method comprises administering a pharmaceutical composition according to the invention, to a patient in need thereof. One embodiment is a kit comprising a first container containing an endosomal escape-enhancing conjugate according to the invention and a second M A / t / ZUZ! / UO / JOS 142 container containing a binding moiety according to the invention, the kit further comprises instructions for using the binding molecules. The first protein molecule is suitable for use as a semi-finished product for the manufacture of a functionalized ADC or functionalized AOC wherein the functionalized ADC or functionalized OAC comprises at least one covalently coupled saponin of the invention and at least one effector moiety of the invention. One embodiment is the first protein molecule of the invention further comprising a payload or effector moiety of the invention such as a toxin or oligonucleotide covalently linked to the first protein molecule of the invention, either directly or through a linker. of the invention, preferably a cleaved linker of the invention, and / or via an oligomeric or polymeric scaffold according to the invention. For example, said a functionalized ADC or OAC comprises 2-4 saponins covalently coupled to eg a cistern literal chain in the first protein molecule such as a ligand or an antibody (fragment), either directly or via a linker. (cleaved it), or comprises for example a dendron comprising 1-16 covalently coupled saponins attached thereto, the dendron is covalently coupled to for example a literal cysteine ​​chain and / or a literal lysine chain of the first protein molecule according to the invention. The invention is further illustrated by the following examples, which are not to be construed as limiting the present invention in any way. examples Example A - Treatment of a mammalian tumor-bearing animal with a conjugate of the invention in combination with an ADC results in survival and tumor regression Baló / c hemora nude mice were injected subcutaneously with a suspension of A431 human tumor cells. Under the skin of the mice, a human epidermal carcinoma developed in the xenograft animal tumor model. After injection of the tumor cells, the xenograft tumor was allowed to grow to a size of approximately 170-180 mm3. A431 tumor cells have the following characteristics: high EGFR expressers, medium CD71 expressers, low HER2 expressers. In Table A, the results of treatment of control mice and tumor-bearing mice are presented. Tumor-bearing mice were treated with the ΜΛ / t / ZUZ I / UO / JOS 143 indicated antibodies directed to human Her2 / neu, human EGFR or human CD71, which are cell surface receptors on the xenograft tumor. Cetuximab was covalently conjugated to the saponin SO1861. SO1861 was first provided with the EMCH (Ν-ε-maleimidocaproic acid hydrazide) linker, EMCH of which is a crosslinker of maleimide and hydrazide to covalently conjugate sulfhydryls (antibody reduced cysteines)) to carbonyls (aldehyde or ketones; in herein the carbonyl of the aldehyde at position C-23 of the saponin). The EMCH-saponin was covalently coupled to reduced cysteines from Cetuximab, forming a covalent thio-ether bond between the EMCH and the cysteine ​​side chain. Trastuzumab-saporin (covalently conjugated) and anti-CD71 mAb (OKT-9, IgG)-saporin (covalently conjugated) ADCs were tested for tumor targeting efficacy in mice, measured as tumor volume at time after initiation of treatment with the ADCs. The dose of ADCs was suboptimal in the tumor model. That is, from previous experiments, it was established at which suboptimal dose of ADCs tumor regression or tumor growth arrest would not be observed. ΜΛ / t / ZUZ I / UO / ¿00 144 TABLE A: RESULTS OF TREATMENT OF MAMMALIAN ANIMALS WITH TUMORS WITH A CONJUGATE OF THE INVENTION IN COMBINATION WITH AN ADC RESULTS IN SURVIVAL AND TUMOR REGRESSION Treatment group Patient / healthy animal treatment size of tumor (volume in mm3 or “+” for growth, for regression and stable” for growth or regression) 1 xenograft vehicle 2000 mm 3 (death / euthanasia) 2 xenograft T rastuzumab-saporin 2000 mm 3 (death / euthanasia) 3 xenograft Anti-CD71 mAb OKT-9 saporin (covalent conjugate) 2000 mm 3 (death / euthanasia) 4 Cetuximab-S01861 xenograft (covalent conjugate) 2000 mm 3 (death / euthanasia) 5 Cetuximab xenograft > 170 mm3, but < 2000 mm 3 (death / euthanasia) 6 T-rastuzumab-saporin xenograft (covalent conjugate ) + Cetuximab-S01861 (covalent conjugate) Tumor regression from 180 mm3 at the beginning of treatment to 80 mm3 (survival) 7 xenograft Anti-CD71 mAb OKT-9 saporin (covalent conjugate) + Cetuximab SO1861) (covalent conjugate) Tumor regression of 180 mm3 at the start of treatment to 40 mm3 (survival) ΜΑ / Ε / ΖυΖΊ / UO / JOS 145 These results demonstrate that combination therapy of an ADC at a dose that is ineffective when considering treatment of tumor-bearing mice with the ADC alone (tumor growth, death of mice is not prevented (euthanasia)), with a conjugate of the invention consisting of an antibody directed to the specific tumor cell receptor covalently bound to a saponin, i.e. SO1861, the covalent conjugate administered to the cancer-suffering mice, at a non-effective dose when administered alone ( tumor growths, death of mice (euthanasia) is not prevented), provides an efficient and effective treatment regimen, expressed as regressing tumors and prolonged survival of treated animals (beyond the duration of the experiment). The suboptimal dose of ADC combined with a conjugate comprising covalently linked saponin of the invention which has no antitumor activity when administered alone, thus provides an effective treatment option for cancer patients, where a relatively low dose of the ADC is effective. A lower dose of ADC holds the promise of a lower risk of adverse events, or even no side effects at all. Furthermore, the stimulatory effect of the saponin-conjugated conjugate of the invention when considering the efficacy of ADCs shows that ADCs that have previously been shown to lack efficacy when it comes to the treatment of tumor patients may gain renewed attention and value, as that the efficacy of ADC is enhanced in the combination therapy setting, as demonstrated by the current example. Reference is made to Table A2 and Table A3, which summarize ADCs that were previously investigated in the human clinical setting, but were later withdrawn from further clinical investigation for some ADCs. Especially ADCs for which clinical development was terminated due to lack of observed efficacy and / or due to the occurrence of an unacceptable adverse event are ADCs that may gain renewed value for cancer patients when combined with a conjugate. comprising covalently bound saponin of the invention, as tested by cetuximab-saponin tested. Example B - Quillaja saponaria saponin mixture comprising QS-21, with activity that enhances endosomal / lysosomal escape Scheme I shows the common molecular structure of a series of QS21 saponins (partly adapted from: Conrado Pedebos, Laercio Pol-Fachin, Ramón Pons, Cilaine V. Teixeira Hugo Verli, Atomic Model and Micelle Dynamics of QS-21 Saponin, Molecules 2014, 19, 3744-3760). A mixture of water-soluble saponins obtained from Quillaja saponaria (Sigma-Aldrich, product No. S4521; Roth, Article No. 6857; InvivoGen, product 'Quil-A') 146 can be applied in the endosomal / lysosomal escape-enhancing conjugate, composition, combination of the invention, based on endosomal / lysosomal escape-enhancing properties of at least one individual saponin present in the mixture, e.g., QS-21, or based on a combination of two or more of the saponins made up of the mixture, such as QS-21 and QS-7. The inventors demonstrated that the mixture of Quillaja saponaria saponins at a dose of 2.5 micrograms / ml was capable of enhancing endosomal escape of diantine, as tested with mammalian tumor cells in a cell-based bioassay. The effector fraction exposed to the cells was diantin covalently coupled to the EGF ligand: EGF-diantin. Cells tested were HeLa tumor cell lines for free saponins, and A431, MDA-MB-468, CaSki, and A2058 to test for saponins when covalently coupled to cetuximab. Example 1 Various concentrations of trastuzumab-saporin (HER2-targeting protein-toxin conjugate; intravenous) were tested in combination with 1.5 mg / kg SO1861 (1 hour before antibody-toxin injection; subcutaneous) to improve efficacy in a BT474 (HER2++) xenograft mouse model. Dosing began on day 13 when tumors reached a size of -150 mm3 and tumor volume was determined after each treatment. Although inhibition of tumor growth was observed in mice treated with 1 mg / kg and 0.3 mg / kg trastuzumab-saporin, no better tumor growth inhibition was observed in mice treated with the combination of trastuzumab-saporin + SO1861 . This shows that unconjugated SO1861 cannot ameliorate protein-antibody toxins within the current setup and mouse model. Example 2 Materials: QSmix(1): S4521 (Sigma Aldrich); QSmix (2): 6857.1 (Cari Roth) QSmix (3): Quil-A® adjuvant: vac-quil (InvivoGen / Brenntag). Previously, the efficacy of several saponins (SO1861, SO1642) were co-delivered as 'unconjugated free' molecules to cells in combination with a toxin-ligand fusion (eg, EGFdiantin) or antibody-protein toxin conjugate, thereby resulted in enhanced cell killing activity of target-expressing cells. Herein, three different saponin molecules (SO1861, M A / Ε / ΖυΖΊ / UO f ¿OO 147 SO1862 (isomer of SO1861), SO1832 and SO1904) isolated from a Saponaria officinalis root extract were titrated in the presence and absence of a fixed non-effective concentration of 1.5 pM EGFdiantin on HeLa cells (EGFR+). This revealed a strong enhancement of cell killing activity for all saponin variants tested (IC50 = 300 nM; Figure 2A) compared to treatments without EGFdiantin. EGFdiantin was then titrated with a fixed concentration of saponin (-1000 nM) and this revealed a strong enhancement of targeted cell killing at low pM concentrations of EGFdiantin (IC50 = 0.4 pM; Figure 2B), observed for all saponins SO1861, SO1862 (isomer of SO1861), SO1832 and SO1904. EGF-diantin alone could only induce cell killing at very high concentrations (IC50 = 10,000 pM). This shows that all of these specific types of saponins have the intrinsic ability to efficiently induce endosomal escape with only a very low amount of available target toxin. To extend this test, saponins from other sources were analyzed. A saponin purified from a root extract of Gypsophila elegans M.Bieb. (GE1741) was titrated on HeLa cells in the presence and absence of 1.5 pM EGFdiantin and compared to purified SO1861. GE1741 also enhances EGFdiantin-induced HeLa cell killing, but shows slightly lower efficacy compared to SO1861. (GE1741 IC50 = 800 nM; Figure 2C) and also shows higher overall toxicity (IC50 = 5,000 nM in the absence of EGFdiantin; Figure 1C). A similar test in which different partially purified mixtures of Quillaja saponaria saponins (QSmix 1-3) were co-administered with 1.5 pM EGFdiantin on HeLa cells and this revealed for 2 of 3 (QSmix 1 and QSmix 3) similar activity as SO1861. (IC50 QSmix / QSm¡x3 = 300 nM; Figure 1D). QSmix (2) is less effective in ameliorating cell killing induced by 1.5pM EGFdiantin (IC50 = 2000 nM; Figure 2D), however no overall toxicity is observed. This shows that also in QS extracts, specific types of saponins are available which efficiently induce endosomal escape of the EGFdiantin ligand targeting toxin. Example 3 To conjugate SO1861 molecules with antibodies, according to the invention, acid labile / sensitive linkers (-EMCH or -N3) were conjugated to SO1861 through the aldehyde group, yielding SO1861-EMCH or SO1861-N3 (Figure 60-66). . To verify the activity of SO1861-EMCH, the molecule was titrated in the presence and absence of a non-effective fixed concentration of EGFdiantin (1.5 pM) on EGFR-expressing cells. ΜΛ / t / ZUZ I / UO f ¿OO 148 (Α431, HeLa) and non-expressing cells (A2058). In all three cell lines, SO1861 alone showed a strong reduction in cell viability, whereas SO1861-EMCH as a single compound showed no toxicity up to 25,000 nM (Figure 3A-C). When SO1861-EMCH was combined with 1.5 pM EGFdiantin, a strong target-specific cell viability reduction was observed in EGFR+A431 and HeLa cells (IC50 = 3,000 nM; Figure 2A, B), while EGFR A2058 cells did not. are affected at all (Figure 3C) Similar results were obtained for SO1861-N3. SO1861-N3 co-administered with 1.5 pM EGFdiantin also shows efficient cell killing on A431 and HeLa cells (IC50 = 3,000 nM), but without EGFdiantin, overall toxicity above 10,000 nM is observed (Figure 3D, 2E). For stable conjugation of SO1861 with antibodies, according to the invention, a stable linker (HATU, Figure 70) was conjugated to SO1861 via the carboxylic acid group of SO1861 yielding SO1861-(s). To determine activity, different concentrations of SO1861-(s) were co-administered with 1.5 pM EGFdiantin and tested for cell killing activity in EGFR-expressing HeLa cells. SO1861-(s) showed similar activity to SO1861, indicating that conjugation with the carboxylic acid does not affect the endosomal escape-enhancing potency of the molecule as seen with SO1861-EMCH (Figure 4). The 2 component system 1 target (1T2C) is the protein toxin combination treatment of mAb1 and mAb1-SO1861, as illustrated in Figure 19. SO1861EMCH was conjugated via tanker residues (Cys) and the oligo HSP27BNA was conjugated through lysine residues to cetuximab (a monoclonal antibody that recognizes and binds to human EGFR), both with a DAR 4 resulting in the production of 2 conjugates: cetuximab-(Cys-L-SO1861)4 and cetuximab- (Lys-L-HSP27BNA)4. The combination of cetuximab-(Cys-L-SO1861)4(intraperitoneal, (i.p.) administration) and cetuximab-(Lys-LHSP27BNA)4(intravenous, (i.v.) administration) was tested in an A431 xenograft mouse tumor model to EGFR tumor-directed gene silencing activity. Dosing began on day 12 when tumors reached a size of -150 mm3 and tumor samples were collected 72 h after the first dose and assayed for HSP27 gene expression compared to mRNA expression levels. of the control gene (reference genes). This revealed that 1 dose of 50 mg / kg cetuximab-(Cys-L-SO1861)4 + 25 mg / kg cetuximab-(Lys-L-HSP27BN...

Claims

1. A first protein molecule comprising a first binding site for attachment to a first epitope of a first cell surface molecule, the first protein molecule being provided with at least one saponin covalently linked via at least one connector and / or via an oligomeric or polymeric scaffold to an amino acid residue of said first protein molecule, or covalently linked directly to an amino acid residue of said first protein molecule.

2. The first protein molecule of claim 1, wherein the first binding site comprises or consists of an immunoglobulin, or at least an immunoglobulin binding domain and / or at least an immunoglobulin binding fragment, such as an antibody, an IgG, a molecule comprising or consisting of a Vhh domain or Vh domain, a Fab, an scFv, an Fv, a dAb, an F(ab)2, an Fcab fragment, and / or comprises or consists of at least one ligand for binding to a cell surface molecule such as EGF or a cytokine.

3. The first protein molecule of claim 1 or 2, wherein the first epitope of the first cell surface molecule is a first tumor cell-specific epitope of a first tumor cell surface molecule, more preferably a first tumor cell-specific epitope of a first tumor cell surface receptor specifically present on a tumor cell.

4. The first protein molecule of any one of claims 1 to 3, wherein the at least one saponin is a triterpenoid saponin and / or a bisdesmosidic triterpene saponin belonging to the type of a 12,13-dehydrooleanane with an aldehyde function at the C-23 position and optionally comprising a glucuronic acid function in a carbohydrate substituent at the C-3beta-OH group of the saponin, and / or a saponin isolated from a species of Gypsophila / or a species of Saponaria and / or a species of Agrostemma and / or a species of Quillaja such as Quillaja saponaria.

5. The first protein molecule of any one of claims 1 to 4, wherein the at least one saponin is a single specific saponin or is a mixture of two or more different saponins, such as one or more of the saponins in Table A1 or Scheme I, SO1861, SA1657, GE1741, SA1641, QS-21, QS-21A, QS-21 A-ap1, QS-21 A-xyl, QS-21 B, QS-21 B-ap1, QS-21 B-xyl, QS-7-xyl, QS-7-ap1, QS-17-ap1, QS-17-xyl, QS1861, QS1862, Quillajasaponin, Saponinum album, QS-18, Quil-A, Gyp1, gypsoside A, AG1, AG2, S01542, S01584, S01658, S01674, S01832, or any of their stereomers and / or any MA / E / ZυZΊ / UO f JOS 247 combination thereof, preferably the saponin being SO1861 and / or GE1741 and / or SA1641 and / or QS-21 and / or saponin with a quilaic acid aglycone core, a Gal-(1^2)-[Xyl-(1^3)]-GlcA carbohydrate substituent on the C-3beta-OH group and a Glc-(1^3)-Xyl-(1—>4)-Rha-(1^2)-[Xyl-(1—>3)-4-OAoIu-(1—4)]-Fuc carbohydrate substituent on the group C-28-OH,y / o is acid 3-0-beta-D-galactopyranosyl-(1—^-[beta-D-xylopyranosyl-U—>3)]-betaD-glucuronopyranosyl chillaic 28-O-beta-D-glucopyranosyl-(1 —>3)-beta-D-xyl-xyl-(1—>3) —>4)alpha-L-rhamnop¡ranos¡l-(1^2)-[beta-Dx¡lop¡ranos¡l-(1^3)-40Ac-beta-D-qu¡novovop¡ranos¡l(1->4)]-beta-D-fucopyranos¡l(1->4)]-beta-D-fucopyranoside, preferably the saponin Q12, and SO 6. The first protein molecule of any one of claims 1 to 5, wherein the at least one saponin is a bisdesmosidic saponin having a molecular mass of at least 1,500 Daltons and comprising an oleannan-type triterpene containing an aldehyde group at the C-23 position and optionally a hydroxyl group at the C-16 position, with a first branched carbohydrate side chain at the C-3 position, the first branched carbohydrate side chain optionally containing glucuronic acid, wherein the saponin contains an ester group with a second branched carbohydrate side chain at the C-28 position, the second branched carbohydrate chain preferably comprising at least four carbohydrate units,optionally containing at least one acetyl residue such as two acetyl residues and / or optionally comprising deoxy carbohydrates and / or optionally comprising quinovose and / or optionally comprising glucose and / or optionally comprising 4-methoxycinnamic acid and / or optionally comprising 5-O-[5-O-Ara / Ap¡-3,5-dihydroxy-6-methyl-octanyl]-3,5-dihydroxy-6-methyl-octanoic acid and / or optionally comprising 5-O-[5-O-Rha-(1^2)-Ara / Ap¡-3,5-dihydroxy-6-methyl-octanyl]-3,5-dihydroxy-6-methyl-octanoic acid linked to a carbohydrate via an ester linkage, or wherein the at least one saponin is QS-21 or any one or more of QS-21 A, QS-21 A-ap¡, QS-21 A-xyl, QS-21 B, QS-21 B-ap¡, QS-21 B-xyl, QS-7-xyl, QS-7-ap¡, QS-17-ap¡, QS-17-xyl, QS-18, QS1861, QS1861 protonated (QS1862), Quil-A., 7. The first protein molecule of any one of claims 1 to 6, wherein the at least one saponin is a bisdesmosidic triterpene saponin belonging to the 12,13-dehydrooleanane type with an aldehyde function at the C-23 position, wherein the at least one saponin is covalently coupled to the amino acid residue of the first protein molecule via an aldehyde function in the saponin, preferably said aldehyde function at the C-23 position, preferably via at least one linker, more preferably via at least one cleavable linker, wherein the amino acid residue is preferably selected from cysteine ​​and lysine.

8. The first protein molecule of any one of claims 1 to 7, wherein the at least one saponin is a bisdesmosidic triterpene saponin belonging to the 12,13-dehydrooleanane type with an aldehyde function at the C-23 position and comprising a glucuronic acid function in a carbohydrate substituent at the C-3beta-OH group of the saponin, wherein the at least one saponin is covalently coupled to the amino acid residue of the first protein molecule via the glucuronic acid function in the carbohydrate substituent at the C-3beta-OH group of the saponin, preferably via at least one linker, wherein the amino acid residue is preferably selected from cysteine ​​and lysine.

9. The first protein molecule of any one of claims 4 to 8, wherein the aldehyde function at the C-23 position of the at least one saponin is covalently coupled to the hydrazide linker of N-ε-maleimidocaproic acid, the linker being covalently coupled via a thio-ether bond to a sulfhydryl group in the first protein molecule, such as a sulfhydryl group of a cysteine.

10. The first protein molecule of any one of claims 4 to 9, wherein the glucuronic acid function in the carbohydrate substituent in the C3beta-OH group of the at least one saponin is covalently coupled to the 1-[Bis(dimethylamine)methylene]-1H-1,2,3-triazolo[4,5-b]pridinium 3-oxide hexafluorophosphate linker, the linker being covalently coupled via an amide bond to an amine group in the first protein molecule, such as an amine group of a lysine or an N-terminus of the first protein molecule.

11. The first protein molecule of any one of claims 1 to 10, wherein the first epitope of the first cell surface molecule to which the first binding site of the first protein molecule binds is a first tumor cell-specific epitope of the tumor cell-specific receptor preferably selected from CD71, CA125, EpCAM(17-1 A), CD52, CEA, CD44v6, FAP, EGF-IR, integrin, syndecan-1, vascular beta-3 integrin α-V, HER2, EGFR, CD20, CD22, folate receptor 1, CD146, CD56, CD19, CD138, CD27L receptor, PSMA, CanAg, integrin α-V, CA6, CD33, mesothelin, Crypto, CD3, CD30, CD239, CD70, CD123, CD352, DLL3, CD25, ephrinA4, MUC1, Trop2, CEACAM5, CEACAM6, HER3, CD74, PTK7, Notch3, FGF2, C4,4A, FLT3, CD38, FGFR3, MA / E / ZUZ I / UO / JOS 249 of CD71, EGFR, HER2.

12. The first protein molecule of claim 3 or 11, wherein the first tumor cell-specific epitope, first tumor cell surface molecule, or first tumor cell-specific receptor is a first epitope, first molecule, or first receptor that is internalized by the tumor cell after the first protein molecule of any one of claims 1 to 11 binds to the first epitope, first molecule, or first receptor, and wherein preferably the first protein molecule undergoes tumor cell receptor-mediated internalization, for example, via endocytosis, or tumor cell surface molecule-mediated internalization, for example, via endocytosis, when it binds to the cell surface molecule comprising the first epitope, the tumor cell surface molecule, or the tumor cell-specific receptor.

13. The first protein molecule of claim 11 or 12, wherein the first binding site of the first protein molecule comprises or consists of any one of cetuximab, daratumumab, gemtuzumab, trastuzumab, panitumumab, brentuximab, inotuzumab, moxetumomab, polatuzumab, obinutuzumab, anti-CD71 OKT-9 IgG monoclonal antibody, pertuzumab, rituximab, ofatumumab, Herceptin, alemtuzumab, pinatuzumab, anti-CD38 OKT-10 monoclonal antibody, an antibody from Table A2 or Table A3 or Table A4, preferably cetuximab or trastuzumab or OKT-9, or at least a tumor cell receptor binding fragment thereof and / or at least a tumor cell receptor binding domain thereof, preferably at least a tumor cell-specific receptor binding fragment thereof and / or at least a tumor cell-specific receptor binding domain of the same.

14. Therapeutic combination, wherein the therapeutic combination comprises: (a) a first pharmaceutical composition comprising the first protein molecule of any one of claims 1 to 13 and optionally a pharmaceutically acceptable excipient; and (b) a second pharmaceutical composition comprising a second protein molecule different from the first protein molecule, the second protein molecule comprising a second binding site for binding to a second epitope of a second cell surface molecule different from the first cell surface molecule, and comprising an effector fraction, the second pharmaceutical composition optionally further comprising a pharmaceutically acceptable excipient, wherein the second epitope is different from the first epitope.

15. Therapeutic combination of claim 14, wherein the therapeutic combination comprises: (a) the first pharmaceutical composition of claim 14 comprising the first protein molecule of any one of claims 1 to 13, wherein the first epitope on the first cell surface molecule is a first tumor cell-specific epitope on a first tumor cell-specific surface molecule, preferably a first tumor cell-specific epitope on a first cell surface receptor specifically present on a tumor cell;and (b) the second pharmaceutical composition of claim 14, wherein the second cell surface molecule is a second tumor cell-specific surface molecule different from the first tumor cell-specific surface molecule, preferably a second cell surface receptor specifically present on a tumor cell different from the first cell surface receptor specifically present on said tumor cell, and wherein the second epitope is a second tumor cell-specific epitope.

16. Therapeutic combination, wherein the therapeutic combination comprises: (a) the first pharmaceutical composition of claim 14 or 15 comprising the first protein molecule according to any one of claims 1 to 13 and comprising the first binding site for binding to the first epitope on the first cell surface molecule, the first pharmaceutical composition optionally further comprising a pharmaceutically acceptable excipient;and (b) a third pharmaceutical composition comprising a third protein molecule, the third protein molecule comprising the first binding site for binding to the first epitope on the cell surface molecule of (a) and an effector fraction, the third pharmaceutical composition optionally further comprising a pharmaceutically acceptable excipient, wherein the first binding site of the first protein molecule and the first binding site of the third protein molecule are the same, and wherein the first cell surface molecule and the first epitope on the first cell surface molecule to which the first protein molecule can bind, and the first cell surface molecule and the first epitope on the first cell surface molecule to which the third protein molecule can bind, are the same.

17. Therapeutic combination, wherein the therapeutic combination comprises: (a) the first pharmaceutical composition of claim 16; and (b) the third pharmaceutical composition of claim 16, wherein the first cell surface molecule is expressed on a tumor cell surface, and preferably the first cell surface molecule is a tumor cell-specific surface molecule, and wherein preferably the first epitope is a tumor cell-specific first epitope.

18. The first protein molecule of any one of claims 1 to 17 or the therapeutic combination of any one of claims 14 to 17, wherein the first binding site for first epitope binding on the first cell surface molecule is a binding site for a first tumor cell-specific epitope on a first cell surface receptor specifically present on a tumor cell.

19. The therapeutic combination of any one of claims 14 to 18, wherein the second binding site of the second protein molecule and / or the first binding site of the third protein molecule comprises or consists of an immunoglobulin, at least one binding domain of an immunoglobulin and / or at least one binding fragment of an immunoglobulin, such as an antibody, an IgG, a molecule comprising or consisting of a Vhh domain or Vh domain, a Fab, an scFv, an Fv, a dAb, an F(ab)2, an Fcab fragment, and / or comprises or consists of at least one ligand for binding to a cell surface molecule such as EGF or a cytokine.

20. The therapeutic combination of any one of claims 14, 15 or 18, 19 when dependent on any one of claims 14 or 15 or 18, wherein the second binding site of the second protein molecule for binding to the second epitope is a second binding site for a second tumor cell-specific epitope on a second cell surface receptor specifically present on the tumor cell, wherein the second binding site is different from the first binding site.

21. The first protein molecule of any one of claims 1 to 20 or the therapeutic combination of any one of claims 14, 15 or 18, 19, 20 when dependent on any one of claims 14 or 15 or 18 or 19, wherein said first and second protein molecules comprise the first and second binding site respectively for binding to a first and second tumor cell-specific epitope ML / t / ZUZ I / UO / JOS 252 on a first and second tumor cell-specific receptor respectively, the receptors being different and present on the same tumor cell, wherein the first and second binding site are different and the first and second tumor cell-specific epitope are different.

22. The first protein molecule of any one of claims 1 to 20 or the therapeutic combination of any one of claims 16, 17 or 18-20 when dependent on any one of claims 16 to 19, wherein said first and third protein molecules comprise the same first binding site for binding to a first tumor cell-specific epitope on a first tumor cell-specific receptor.

23. The first protein molecule or therapeutic combination of claim 21 or 22, wherein the first receptor and / or the second receptor are selected from CD71, CA125, EpCAM(17-1 A), CD52, CEA, CD44v6, FAP, EGF-IR, integrin, syndecan-1, vascular beta-3 integrin α-V, HER2, EGFR, CD20, CD22, folate receptor 1, CD146, CD56, CD19, CD138, CD27L receptor, PSMA, CanAg, integrin-αV, CA6, CD33, mesothelin, Crypto, CD3, CD30, CD239, CD70, CD123, CD352, DLL3, CD25, ephrinA4, MUC1, Trop2, CEACAM5, CEACAM6, HER3, CD74, PTK7, Notch3, FGF2, C4,4A, FLT3, CD38, FGFR3, CD7, PD-L1, CTLA4, CD52, PDGFRA, VEGFR1, VEGFR2, preferably selected from CD71, EGFR and HER2.

24. The first protein molecule of claim 21 or 23 and / or the therapeutic combination of claim 21 or 23, wherein the first and second tumor cell-specific receptors are internalized by the tumor cell after binding to the first protein molecule of any one of claims 1 to 21 or 23 and / or the second protein molecule of any one of claims 14, 15, or 18-21 or 23 when dependent on any one of claims 14, 15, or 18-21, and wherein preferably the binding of the first protein molecule and / or the second protein molecule to the first and second tumor cell-specific receptors, respectively, results in receptor-mediated internalization of the tumor cell, for example, via endocytosis,of a complex of the first protein molecule and the first tumor cell-specific receptor and of a complex of the second protein molecule and the second tumor cell-specific receptor.

25. The therapeutic combination of claim 22 or 23 or the first pharmaceutical composition according to claim 22 or 23, wherein the first tumor cell receptor, preferably the first tumor cell-specific receptor, is internalized by the tumor cell after binding to the first protein molecule of any one of claims 1 to 20, 22 or 23 and / or after binding to the third protein molecule of any one of claims 16, 17 or 18 to 20, 22 when dependent on any one of claims 16 to 20, and wherein preferably the binding of the first protein molecule and / or the third protein molecule to the first tumor cell receptor, such as the first tumor cell-specific receptor, is followed by tumor cell receptor-mediated internalization, for example via endocytosis,of a complex of the first protein molecule and the first tumor cell receptor and of a complex of the third protein molecule and the first tumor cell receptor.

26. The first protein molecule of any one of claims 1 to 15 or 18 to 21 or 24 when dependent on any one of claims 1 to 15 or 18 to 21, and / or therapeutic combination of any one of claims 14, 15, 18 to 21 or 24, wherein the first binding site and / or the second binding site is or comprises a monoclonal antibody or at least a fragment and / or binding domain of the cell surface molecule thereof, and preferably comprises or consists of any one of cetuximab, daratumumab, gemtuzumab, trastuzumab, panitumumab, brentuximab, inotuzumab, moxetumomab, polatuzumab, obinutuzumab, anti-CD71 OKT-9 monoclonal antibody of the IgG type, pertuzumab, rituximab, ofatumumab, Herceptin, alemtuzumab, pinatuzumab, anti-CD38 monoclonal antibody OKT-10, and an antibody from Table A4, preferably cetuximab or trastuzumab or OKT-9, or at least a fragment or cell surface molecule-binding domain thereof,provided that the first binding site of the first protein molecule is different from the second binding site of the second protein molecule.

27. The therapeutic combination of any one of claims 16, 17 or 18 to 20, 22 when dependent on any one of claims 16 to 20 or the first pharmaceutical composition according to any one of claims 16, 17 or 18 to 20, 22 when dependent on any one of claims 16 to 20, wherein the first binding site of the first protein molecule and the third protein molecule comprise a monoclonal antibody or at least one of a cell surface molecule binding domain and / or fragment thereof, and preferably comprise or consist of any one of cetuximab, daratumumab, gemtuzumab, trastuzumab, panitumumab, brentuximab, inotuzumab, moxetumomab, polatuzumab, obinutuzumab, anti-CD71 OKT-9 monoclonal antibody of the IgG type, pertuzumab, rituximab, ofatumumab, Herceptin, alemtuzumab, pinatuzumab, anti-CD38 OKT-10 monoclonal antibody, an antibody from Table A2 or Table A3 or Table A4,preferably cetuximab or trastuzumab or OKT-9, or at least a fragment and / or cell surface molecule binding domain thereof, provided that the first binding site of the first protein molecule is the same as the first binding site of the third protein molecule.

28. The therapeutic combination of any one of claims 14 to 27, wherein the second binding site of the second protein molecule and / or the first binding site of the third protein molecule is or comprises a monoclonal antibody or at least a cell surface molecule binding fragment or domain thereof, and preferably comprises or consists of any one of Gemtuzumab ozogamicin, Brentuximab vedotin, Trastuzumab emtansine, Inotuzumab ozogamicin, Moxetumomab pasudotox and Polatuzumab vedotin and an antibody-drug conjugate of Table A2 and Table A3.

29. The therapeutic combination of any one of claims 14 to 28, wherein the effector fraction comprising the second protein molecule and / or the third protein molecule comprises or consists of any one or more of an oligonucleotide, a nucleic acid, a xenonucleic acid, preferably selected from any one or more of a vector, a gene, a cell suicide-inducing transgene, deoxyribonucleic acid (DNA), ribonucleic acid (RNA), antisense oligonucleotide (ASO, AON), small interfering RNA (ipRNA), microRNA (miRNA), DNA aptamer, RNA aptamer, mRNA, minicircle DNA, peptide nucleic acid (PNA), morpholinophosphoamidate oligomer (PMO), blocked nucleic acid (LNA), bridged nucleic acid (BNA), 2'-deoxy-2'-fluoroarabinonucleic acid (FANA), 2'-O-methoxyethylRNA (MOE), bridged nucleic 2'-O,4'-aminoethylene, 3'-fluorohexitol nucleic acid (FHNA), a plasmid,glycol nucleic acid (GNA) and threose nucleic acid (TNA), or a derivative thereof, more preferably a BNA, for example a BNA to silence the expression of the HSP27 protein.

30. The therapeutic combination of any one of claims 14 to 29, wherein the effector fraction comprising the second protein molecule and / or the third protein molecule comprises or consists of at least one protein molecule, preferably selected from any one or more of a peptide, a protein, an enzyme such as urease and Cre-recombinase, a ribosome-inactivating protein, a protein toxin, more preferably selected from any one or more of a protein toxin selected from Table A5 and / or a viral toxin such as apoptin; a bacterial toxin such as Shiga toxin, Shiga-like toxin, Pseudomonas aeruginosa (PE) exotoxin or PE exotoxin A, full-length or truncated diphtheria toxin (DT), cholera toxin; a fungal toxin such as alpha-sarcina;a plant toxin comprising ribosome-inactivating proteins and the A chain of type 2 ribosome-inactivating proteins such as diantin, for example diantin-30 or diantin-32, saporin, for example saporin-S3 or saporin-S6, bougain or a deimmunized derivative of bougainin debouganin, Shiga-like toxin A, pokeweed antiviral protein, ricin, ricin A chain, modecin, modecin A chain, abrin, abrin A chain, volkensin, volkensin A chain, viscumin, viscumin A chain; or an animal or human toxin such as frog RNase, or human granzyme B or angiogenin, or any fragment or derivative thereof; preferably the protein toxin is diantin and / or saporin.

31. The therapeutic combination of any one of claims 14 to 30, wherein the effector fraction comprising the second protein molecule and / or the third protein molecule comprises or consists of at least one payload, preferably selected from any one or more of a ribosome-targeting toxin, an elongation-factor-targeting toxin, a tubulin-targeting toxin, a DNA-targeting toxin, and an RNA-targeting toxin, more preferably any one or more of emtansine, pasudotox, a DM1 maitansinoid derivative, a DM4 maitansinoid derivative, monomethyl auristatin E (MMAE, vedotin), monomethyl auristatin F (MMAF, mafodotin), a calicheamycin, N-acetyl-Y-caliqueamycin, a pyrrolobenzodiazepine dimer (PBD), a benzodiazepine, an analogue of CC-1065, a duocarmycin, Doxorubicin, paclitaxel, docetaxel, cisplatin, cyclophosphamide, etoposide, docetaxel, 5-fluorouracil (5-FU), mitoxantrone,a tubulisin, an indole-benzodiazepine, AZ13599185, a cryptophycin, rhizoxin, methotrexate, an anthracycline, a camptothecin analogue, SN-38, DX-8951 f, exatecan mesylate, truncated form of Pseudomonas aeruginosa exotoxin (PE38), a duocarmycin derivative, an amanitin, α-amanitin, a spliceostatin, a thailanstatin, ozogamycin, tesirin, Amberstatin269 and soravansine, or a derivative thereof.

32. The first protein molecule of any one of claims 1 to 31, wherein the first protein molecule comprises more than one saponin, preferably 2, 3, 4, 5, 6, 8, 10, 16, 32, 64 or 1-100 saponins, or any number of saponins therein, such as 7, 9, 12 saponins, covalently linked directly to an amino acid residue of the first protein molecule, preferably to a cysteine ​​and / or a lysine, and / or covalently linked via at least one linker and / or via at least one scintiphil linker and / or via at least one polymeric or oligomeric scaffold, preferably 1-8 of said scaffolds or 2-4 of said scaffolds, wherein the at least A scaffold optionally is based on a dendron, in which 1-32 saponins such as 2, 3, 4, 5, 6, 8, 10, 16, 32 saponins, or any number of saponins in it, such as 7, 9, 12 saponins, are covalently bonded to the at least one scaffold.

33. The first protein molecule of any one of claims 7 to 32, wherein the at least one linker is a non-scissile linker or a scissile linker, wherein the scissile linker, for example, is subject to cleavage under acidic conditions, reducing conditions, enzymatic conditions, or light-induced conditions, and preferably the scissile linker comprises a hydrazone bond or a hydrazide bond subject to cleavage under acidic conditions when bound to the saponin, and / or comprises a bond susceptible to proteolysis, for example, proteolysis by Cathepsin B, and / or is a bond susceptible to cleavage under reducing conditions, such as a disulfide bond, when bound to the saponin.

34. The first protein molecule of any one of claims 7 to 33, wherein the cleavage linker is subjected to in vivo cleavage under acidic conditions present in endosomes and / or lysosomes of mammalian cells, preferably human cells, preferably at pH 4.0 - 6.5, and more preferably at pH < 5.5, when the cleavage linker is attached to a saponin.

35. The first protein molecule of any one of claims 1 to 34, wherein the oligomeric or polymeric scaffold comprises a polymeric or oligomeric structure and comprises a chemical group, the chemical group for covalent coupling of the scaffold to the amino acid residue of said first protein molecule.

36. The first protein molecule of any one of claims 1 to 35, wherein the at least one saponin is covalently linked to the polymeric or oligomeric structure of the oligomeric or polymeric scaffold through at least one scissile linker according to any one of claims 32-34.

37. The first protein molecule of any one of claims 1 to 36, wherein the chemical group of the oligomeric or polymeric scaffold, for the covalent coupling MA / E / ZυZΊ / UO f ¿OO 257 of the oligomeric or polymeric scaffold to the amino acid residue of said first protein molecule, is a cyclic chemical group, preferably selected from a tetrazine, an azide, an alkene or an alkyne, or a cyclic derivative of these groups, more preferably said chemical group is an azide.

38. The first protein molecule of any one of claims 1 to 37, wherein the polymeric or oligomeric structure of the oligomeric or polymeric scaffold comprises a linear, branched and / or cyclic polymer, oligomer, dendrimer, dendron, dendronized polymer, dendronized oligomer, a DNA, a polypeptide, polylysine, a polyethylene glycol, or an assembly of these polymeric or oligomeric structures, the assembly of which is preferably constructed by covalent crosslinking.

39. A composition comprising the first protein molecule of any one of claims 1 to 38 and the second protein molecule of any one of claims 14, 15 or 18 to 38.

40. A composition comprising the first protein molecule of any one of claims 1 to 38 and the third protein molecule of any one of claims 16 to 38.

41. The composition of claim 39 or 40, wherein the effector fraction comprising the second protein molecule or the third protein molecule is any one of the effector fractions according to claim 29, preferably a BNA.

42. A composition comprising the first protein molecule of any one of claims 1 to 41 and any one or more of an oligonucleotide, a nucleic acid, and a xenonucleic acid, preferably selected from at least one of a vector, a gene, a cell suicide-inducing transgene, deoxyribonucleic acid (DNA), ribonucleic acid (RNA), antisense oligonucleotide (ASO, AON), small interfering RNA (ipRNA), microRNA (miRNA), DNA aptamer, RNA aptamer, mRNA, minicircle DNA, peptide nucleic acid (PNA), morpholinophosphoamidate oligomer (PMO), blocked nucleic acid (LNA), bridged nucleic acid (BNA), 2'-deoxy-2'-fluoroarabinonucleic acid (FANA), 2'-O-methoxyethyl-RNA (MOE), bridged 2'-O,4'-aminoethylene nucleic acid 3'-fluorohexitol nucleic acid (FHNA), a plasmid, glycol nucleic acid (GNA) and threose nucleic acid (TNA), or a derivative thereof, most preferably a BNA,For example, a BNA to silence the expression of the HSP27 protein. MA / E / ZυZΊ / UO / JOS 258, 43. Antibody-drug conjugate or ligand-drug conjugate comprising the first protein molecule of any one of claims 1 to 42 and an effector moiety.

44. Antibody-drug conjugate or ligand-drug conjugate of claim 43, wherein the antibody can be bound to any one of CD71, CA125, EpCAM(17-1 A), CD52, CEA, CD44v6, FAP, EGF-IR, integrin, syndecan-1, vascular beta-3 integrin α-V, HER2, EGFR, CD20, CD22, folate receptor 1, CD146, CD56, CD19, CD138, CD27L receptor, PSMA, CanAg, integrin-αV, CA6, CD33, mesothelin, Crypto, CD3, CD30, CD239, CD70, CD123, CD352, DLL3, CD25, ephrinA4, MUC1, Trop2, CEACAM5, CEACAM6, HER3, CD74, PTK7, Notch 3, FGF2, C4,4A, FLT3, CD38, FGFR3, CD7, PD-L1, CTLA4, CD52, PDGFRA, VEGFR1, VEGFR2, preferably CD71, HER2, EGFR, and / or is or comprises any one of cetuximab, daratumumab, gemtuzumab, trastuzumab, panitumumab, brentuximab, inotuzumab, moxetumomab, polatuzumab, obinutuzumab, anti-CD71 OKT-9 monoclonal antibody of the IgG type, pertuzumab, rituximab, ofatumumab, Herceptin, alemtuzumab, pinatuzumab, anti-CD38 OKT10 monoclonal antibody,an antibody from Table A2 or Table A3 or Table A4, preferably cetuximab or trastuzumab or OKT-9, or at least a tumor cell receptor-binding fragment thereof and / or at least a tumor cell receptor-binding domain thereof, and / or wherein the antibody-drug conjugate comprises any one of Gemtuzumab ozogamicin, Brentuximab vedotin, Trastuzumab emtansine, Inotuzumab ozogamicin, Moxetumomab pasudotox and Polatuzumab vedotin and an antibody-drug conjugate from Table A2 and Table A3, or wherein the ligand-drug conjugate comprises at least one ligand for binding to a cell surface molecule such as EGF or a cytokine.

45. Antibody-drug conjugate or ligand-drug conjugate of claim 43 or 44, wherein the effector fraction is any one or more of the effector fractions according to claims 29 to 31.

46. ​​Pharmaceutical composition comprising the composition of any one of claims 39 to 42 or the antibody-drug conjugate of any one of claims 43 to 45 or the ligand-drug conjugate of any one of claims 43 to 45, and further comprising optionally a pharmaceutically acceptable excipient.

47. The therapeutic combination of any one of claims 14 to 38 or the composition of any one of claims 39 to 42 or the antibody-drug conjugate or ligand-drug conjugate of any one of claims 43 to 45 or the pharmaceutical composition of claim 46, for use as a medicament.

48. The therapeutic combination of any one of claims 14 to 38 or the composition of any one of claims 39 to 42 or the antibody-drug conjugate or ligand-drug conjugate of any one of claims 43 to 45 or the pharmaceutical composition of claim 46, for use in the treatment or prevention of cancer or an autoimmune disease.