Antibody drug conjugates (ADC) containing saponin

Abstract

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Description

2026226426   02 Sep 2026 Drug Name Indication Target Last Development Stage SGN-CD70A Diffuse Large B-Cell Lymphoma; Follicular Lymphoma; Mantle Cell Lymphoma; Metastatic Renal Cell Carcinoma; Non-Hodgkin Lymphoma Cells Expressing CD70 Antigen (CD27 Ligand or Tumor Necrosis Factor Ligand Superfamily Member 7 or CD70) Phase I RG-7636 Metastatic Melanoma Endothelin B Receptor (Endothelin Receptor Non Selective Type or EDNRB) Phase I SC-006 Metastatic Colorectal Cancer Phase I MM-310 Breast Cancer; Endome-trial Cancer; Esophageal Cancer; Gastric Cancer; Gastroeso-phageal (GE) Junction Carcino-mas; Head And Neck Cancer Squamous Cell Carcinoma; Non-Small Cell Lung Cancer; Ovarian Cancer; Pancreatic Ductal Adenocar-cinoma; Prostate Cancer; Small-Cell Lung Cancer; Soft Tissue Sarcoma; Solid Tumor; Transitional Cell Carcinoma (Urothelial Cell Carcinoma) Ephrin Type A Receptor 2 (Epithelial Cell Kinase or Tyrosine Protein Kinase Receptor ECK or EPHA2 or EC 2.7.10.1) Phase I PF-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 (M6P1 or 5T4 Oncofetal Antigen or 5T4 Oncofetal Trophoblast Glycoprotein or Wnt Activated Inhibitory Factor 1 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 XMT-1522 Breast Cancer; Gastric Cancer; NonSmall Cell Lung Cancer Receptor Tyrosine Protein Kinase ERBB 2 (Metastatic Lymph Node Gene 19 Protein or Proto Oncogene Neu or Proto Oncogene C ErbB 2 or Tyrosine Kinase Type Cell Surface Receptor HER2 or p185erbB2 or HER2 or CD340 or ERBB2 or EC 2.7.10.1); Tubulin Phase I AMG-595 Anaplastic Astrocyto-ma; Recurrent Glioblasto-ma Multiforme (GBM) Cells Expressing Epidermal Growth Factor Receptor (Proto Oncogene c ErbB 1 or Receptor Tyrosine Protein Kinase erbB 1 or HER1 or ERBB1 orEGFRorEC 2.7.10.1) Phase I pinatuzumab vedotin Chronic Lymphocytic Leukemia (CLL) Cells Expressing B Cell Receptor CD22 (B Lymphocyte Cell Adhesion Molecule or Sialic Acid Binding Ig Like Lectin 2 or T Cell Surface Antigen Leu 14 or CD22) Phase I cantuzumab ravtansine Colorectal Cancer; Non-Small Cell Lung Cancer; Pancreatic Cancer; Solid Tumor Phase I 2026226426   02 Sep 2026 Last Drug Name    Indication                      Target                            Development AVE-9633 Acute Myelocytic Leukemia (AML, Acute Myeloblas-tic Leukemia) Cells Expressing Myeloid Cell Surface Antigen CD33 (Sialic Acid Binding Ig Like Lectin 3 or gp67 or CD33) Phase I BIWI-101 Breast     Cancer;     Carcino-mas; Esophageal Cancer; Head And Neck Cancer Squamous Cell Carcinoma Cells Expressing CD44 Antigen (CDw44 or Epican or Extracellular Matrix Receptor III or GP90 Lymphocyte Homing / Adhesion Receptor or HUTCH I or Heparan Sulfate Proteoglycan or Hermes Antigen or Hyaluronate Receptor 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 Related Tumor Marker CA125 or Ovarian Carcinoma Antigen CA125 or MUC16) Phase I ASG-5ME Adenocar-cinoma;          Hormone Refractory (Castration Resistant, Androgen-lndepen-dent)     Prostate Cancer; Metastatic Adenocar-cinoma of The Pancreas Cells Expressing Choline Transporter Like Protein 4 (Solute Carrier Family 44 Member 4 or SLC44A4) Phase I DCDS-0780A B-Cell Non-Hodgkin Lymphoma Phase I SC-004 Endome-trial Cancer; Epithelial Ovarian Cancer; Fallopian Tube Cancer; Peritoneal Cancer Phase I RG-7600 Ovarian Cancer; Pancreatic Ductal Adenocar-cinoma Phase I sofituzumab vedotin Epithelial Ovarian Cancer; Fallopian Tube Cancer; Ovarian Cancer; Pancreatic Cancer; Peritoneal Cancer Cells Expressing Mucin 16 (Ovarian Cancer Related Tumor Marker CA125 or Ovarian Carcinoma Antigen CA125 or MUC16) Phase I IMGN-289 Breast Cancer; Esophageal Cancer; Gastric Cancer; Head And Neck Cancer Squamous Cell Carcinoma; Non-Small Cell Lung Cancer; Solid Tumor Cells Expressing Epidermal Growth Factor Receptor (Proto Oncogene c ErbB 1 or Receptor Tyrosine Protein Kinase erbB 1 or HER1 or ERBB1 orEGFRorEC 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 (CD107 Antigen Like Family Member A or CD107a or LAMP1) Phase I SGNCD-19B B-Cell Non-Hodgkin Lymphoma; 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 orCD19) Phase I SGNCD-123A Refractory Acute Myeloid Leukemia; Relapsed Acute Myeloid Leukemia Cells Expressing Interleukin 3 Receptor Subunit Alpha (CD123 orlL3RA) Phase I 2026226426   02 Sep 2026 Last Drug Name    Indication                      Target                            Development SGNCD-352A Refractory Multiple Myeloma; Relapsed Multiple Myeloma Cells Expressing SLAM Family Member 6 (Activating 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 Gene E Protein or Stem Cell Antigen 2 or Thymic Shared Antigen 1 or LY6E) Phase I IMGN-388 Solid Tumor Cells Expressing Integrin Alpha V (Vitronectin Receptor Subunit Alpha or CD51 or ITGAV) Phase I lorvotuzumab mertansine Refractory Multiple Myeloma; Relapsed Multiple Myeloma Cells Expressing Neural Cell Adhesion Molecule 1 (Antigen Recognized By Monoclonal Antibody 5.1 H11 or CD56 or NCAM1) Phase I lorvotuzumab mertansine Neuroendo-crine         Carcinoma; Neuroendo-crine Tumors; Non-Small Cell Lung Cancer; Ovarian Cancer; Skin Cancer Cells Expressing Neural Cell Adhesion Molecule 1 (Antigen Recognized By Monoclonal Antibody 5.1 H11 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 orCA9 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 B Lymphocyte Antigen CD19 (B Lymphocyte Surface Antigen B4 or Differentiation Antigen CD19 or T Cell Surface Antigen Leu 12 orCD19) Phase I ADCT-502'11 Bladder Cancer; Breast Cancer; Esophageal Cancer; Gastric Cancer; Non-Small Cell Lung Cancer Cells Expressing Receptor Tyrosine Protein Kinase ERBB 2 (Metastatic Lymph Node Gene 19 Protein or Proto Oncogene Neu or Proto Oncogene C ErbB 2 or Tyrosine Kinase Type Cell Surface Receptor HER2 or p185erbB2 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 Tumor Necrosis Factor Ligand Superfamily Member 7 or CD70) Phase I lmmuRAIT-LL2 B-Cell Non-Hodgkin Lymphoma Cells Expressing B Cell Receptor CD22 (B Lymphocyte Cell Adhesion Molecule or Sialic Acid Binding Ig Like Lectin 2 or T Cell Surface Antigen Leu 14 or CD22) Phase l / ll indusatumab vedotin Adenocar-cinoma Of The Gastroesophageal Junction; Gastric Cancer Cells Expressing Heat Stable Enterotoxin Receptor (Guanylyl Cyclase C or or Phase l / ll 2026226426   02 Sep 2026 Last Drug Name    Indication                      Target                            Development Intestinal Guanylate Cyclase or GUCY2C or EC 4.6.1.2) clivatuzumab tetraxetan Pancreatic Cancer Cells Expressing Mucin 1 (Breast Carcinoma Associated Antigen DF3 or Episialin 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 Tumor Associated Mucin or CD227 orMUCI) Phase l / ll depatuxizumab 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 l / ll CDX-014 Metastatic Renal Cell Carcinoma; Papillary Renal Cell Carcinoma Cells Expressing Hepatitis A Virus Cellular Receptor 1 (Kidney Injury Molecule 1 or T Cell Immunoglobulin And Mucin Domain Containing Protein 1 or T-Cell Immunoglobulin Mucin Receptor 1 orT Cell Membrane Protein 1 or CD365 or HAVCR1) Phase l / ll vadastuximab talirine111 Refractory Acute Myeloid Leukemia; Relapsed Acute Myeloid Leukemia Cells Expressing Myeloid Cell Surface Antigen CD33 (Sialic Acid Binding Ig Like Lectin 3 or gp67 or CD33) Phase l / ll vadastuximab talirine Myelodys-plastic Syndrome Cells Expressing Myeloid Cell Surface Antigen CD33 (Sialic Acid Binding Ig Like Lectin 3 or gp67 or CD33) Phase l / ll MLN-2704 Metastatic Hormone    Refractory (Castration Resistant, Androgen-Indepen-dent) Prostate Cancer Cells       Expressing       Glutamate Carboxypeptidase 2 (Folate Hydrolase 1 or Prostate Specific Membrane Antigen or PSMA or Pteroylpoly Gamma Glutamate Carboxypeptidase or Cell Growth Inhibiting Gene 27 Protein or FOLH1 or EC 3.4.17.21) Phase l / ll Oncolysin B AIDS - Related Lymphoma Cells Expressing B Lymphocyte Antigen CD19 (B Lymphocyte Surface Antigen B4 or Differentiation Antigen CD19 or T Cell Surface Antigen Leu 12 orCD19) Phase l / ll coltuximab ravtansine Diffuse Large B-Cell Lymphoma Cells Expressing B Lymphocyte Antigen CD19 (B Lymphocyte Surface Antigen B4 or Differentiation Antigen CD19 or T Cell Surface Antigen Leu 12 orCD19) Phase II coltuximab ravtansine Acute Lymphocy-tic Leukemia (ALL, Acute Lympho-blastic Leukemia) Cells Expressing B Lymphocyte Antigen CD19 (B Lymphocyte Surface Antigen B4 Phase II 2026226426   02 Sep 2026 Drug Name Indication Target Last Development Stage or Differentiation Antigen CD19 or T Cell Surface Antigen Leu 12 orCD19) coltuximab ravtansine Diffuse Large B-Cell Lymphoma Cells Expressing B Lymphocyte Antigen CD19 (B Lymphocyte Surface Antigen B4 or Differentiation Antigen CD19 or T Cell Surface Antigen Leu 12 orCD19) Phase II indusatumab vedotin121 Adenocar-cinoma Of The Gastroesophageal Junction; Gastric Cancer; Metastatic Adenocar-cinoma of The Pancreas Cells Expressing Heat Stable Enterotoxin Receptor (Guanylyl Cyclase C or or Intestinal Guanylate Cyclase or GUCY2C or EC 4.6.1.2) Phase II depatuxizumab mafodotin Squamous 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 depatuxizumab mafodotin121 Anaplastic Astrocyto-ma; Anaplastic Oligoastro-cytoma;      Gliosar-coma; High-Grade Glioma; 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 Sodium Dependent Phosphate Transport Protein 2B (Sodium Phosphate Transport Protein 2B or NaPi3b or Sodium / Phosphate Cotransporter 2B or NaPi 2b or Solute Carrier Family 34 Member 2 or SLC34A2) Phase II lifastuzumab vedotin Ovarian Cancer Sodium Dependent Phosphate Transport Protein 2B (Sodium Phosphate Transport Protein 2B or NaPi3b or Sodium / Phosphate Cotransporter 2B or NaPi 2b or Solute Carrier Family 34 Member 2 or SLC34A2) Phase II Bismab-A Acute Myelocytic Leukemia (AML, Acute Myeloblas-tic Leukemia) Cells Expressing Myeloid Cell Surface Antigen CD33 (Sialic Acid Binding Ig Like 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 orCD19) Phase II Avicidin01 Colorectal Cancer; Prostate Cancer Cells Expressing Epithelial Cell Adhesion Molecule (Adenocarcinoma Associated Antigen or Cell Surface Glycoprotein Trap 1 or Epithelial Cell Surface Antigen or Epithelial Glycoprotein 314 or KS 1 / 4 Antigen or KSA or Tumor Associated Calcium Signal Transducer 1 or CD326 or EPCAM) Phase II 2026226426   02 Sep 2026 Drug Name Indication Target Last Development Stage pinatuzumab vedotin Diffuse Large B-Cell Lymphoma; Follicular Lymphoma Cells Expressing B Cell Receptor CD22 (B Lymphocyte Cell Adhesion Molecule or Sialic Acid Binding Ig Like Lectin 2 or T Cell Surface Antigen Leu 14 or CD22) Phase II SGN-15 Metastatic Breast Cancer; Non-Small Cell Lung Cancer; Ovarian Cancer; Prostate Cancer Cells Expressing Lewis Y Antigen (CD174) Phase II cantuzumab ravtansine Gastric Cancer; Gastroe-sophageal (GE) Junction Carcino-mas Phase II ASP-6183 Ovarian Cancer Phase II SAR-566658 Metastatic Breast Cancer Cells Expressing Sialoglycotope CA6 Antigen Phase II Oncolysin S 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 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 glembatumumab vedotin Metastatic Melanoma; Metastatic Uveal Melanoma;          Osteosar-coma; Squamous Non-Small Cell Lung Cancer Cells Expressing    Transmembrane Glycoprotein NMB   (Transmembrane Glycoprotein HGFIN orGPNMB) Phase II MM-302 Metastatic Breast Cancer Cells Expressing Receptor Tyrosine Protein Kinase ERBB 2 (Metastatic Lymph Node Gene 19 Protein or Proto Oncogene Neu or Proto Oncogene C ErbB 2 or Tyrosine Kinase Type Cell Surface Receptor HER2 or p185erbB2 or HER2 or CD340 or ERBB2 or EC 2.7.10.1) Phase ll / lll Neuradiab Brain     Cancer;      Glioblasto-ma Multiforme (GBM) Cells Expressing Tenascin (Cytotactin or GMEM or GP 150-225 or Glioma Associated Extracellular Matrix Antigen or Hexabrachion or JI or Myotendinous Antigen or Neuronectin or Tenascin C or TNC) Phase III clivatuzumab tetraxetan Metastatic Adenocar-cinoma of The Pancreas Cells Expressing Mucin 1 (Breast Carcinoma Associated Antigen DF3 or Episialin 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 Tumor Associated Mucin or CD227 orMUCI) Phase III 2026226426   02 Sep 2026 Last Drug Name    Indication                      Target                            Development depatuxizumab mafodotin(2) Glioblasto-ma 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 III vadastuximab talirine111 Acute Myelocytic Leukemia (AML, Acute Myeloblas-tic Leukemia) Cells Expressing Myeloid Cell Surface Antigen CD33 (Sialic Acid Binding Ig Like Lectin 3 or gp67 or CD33) Phase III glembatumuma b vedotin(2) Metastatic Breast Cancer Cells Expressing    Transmembrane Glycoprotein NMB   (Transmembrane Glycoprotein HGFIN orGPNMB) Phase III Oncolysin B B-Cell Leukemia; Lymphoma Cells Expressing B Lymphocyte Antigen CD19 (B Lymphocyte Surface Antigen B4 or Differentiation Antigen CD19 or T Cell Surface Antigen Leu 12 orCD19) Phase III lmmuRAIT-LL2 B-Cell Leukemia Cells Expressing B Cell Receptor CD22 (B Lymphocyte Cell Adhesion Molecule or Sialic Acid Binding Ig Like Lectin 2 or T Cell Surface Antigen Leu 14 or CD22) Preclinical indusatumab vedotin Metastatic Colorectal Cancer Cells Expressing Heat Stable Enterotoxin Receptor (Guanylyl Cyclase C or 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 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 HER1 or ERBB1 or EGFR or EC 2.7.10.1) Preclinical ZW-33 Gastric Cancer; Metastatic Breast Cancer Cells Expressing Receptor Tyrosine Protein Kinase ERBB 2 (Metastatic Lymph Node Gene 19 Protein or Proto Oncogene Neu or Proto Oncogene C ErbB 2 or Tyrosine Kinase Type Cell Surface Receptor HER2 or p185erbB2 or HER2 or CD340 or ERBB2 or EC 2.7.10.1) Preclinical ZW-33 Ovarian Cancer Cells Expressing Receptor Tyrosine Protein Kinase ERBB 2 (Metastatic Lymph Node Gene 19 Protein or Proto Oncogene Neu or Proto Oncogene C ErbB 2 or Tyrosine Kinase Type Cell Surface Receptor HER2 or p185erbB2 or HER2 or CD340 or ERBB2 or EC 2.7.10.1) Preclinical SGNCD-352A Non-Hodgkin Lymphoma Cells Expressing SLAM Family Member 6 (Activating NK Receptor or NK T B Antigen or CD352 or SLAMF6) Preclinical 2026226426   02 Sep 2026 Drug Name Indication Target Last Development Stage HuMax-CD74- ADC Oncology Cells Expressing HLA Class II Histocompatibility Antigen Gamma Chain (HLA DR Antigens Associated Invariant Chain or la Antigen Associated Invariant Chain or p33 or CD74) Preclinical sacituzumab govitecan Pancreatic Ductal Adenocar-cinoma 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 GA733-1 orTACSTD2) sacituzumab govitecan Adenocar-cinoma; Cervical Cancer; Colorectal Cancer; Endome-trial Cancer; Epithelial Ovarian Cancer; Esophageal Cancer; Follicular Thyroid Cancer; Gastric Cancer; Glioblasto-ma Multiforme (GBM); Head And Neck Cancer Squamous Cell Carcinoma; Hepato-cellular Carcinoma; Kidney Cancer (Renal Cell Cancer); Metastatic Hormone Refractory (Castration Resistant, Androgen-lndepen-dent) Prostate      Cancer;      Metastatic Transitional (Urothelial) Tract 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 GA733-1 orTACSTD2) sacituzumab govitecan Hepato-cellular 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 GA733-1 orTACSTD2) 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 GA733-1 or TACSTD2) sacituzumab govitecan Non-Small Cell Lung Cancer; SmallCell Lung 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 GA733-1 orTACSTD2) 2026226426   02 Sep 2026 Drug Name Indication Target Last Development Stage sacituzumab govitecan Metastatic Breast 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 GA733-1 orTACSTD2) (1) Discontinued due to adverse events (2) Discontinued due to lack of efficacy TABLE A3 - ADCs that reached phase III clinical development Drug Name Indication Development Stage Last Development Stage Reason for Discontinuation trastuzumab emtansine Gastric Cancer Marketed Phase ll / lll Unspecified MM-302 Metastatic Breast Cancer Discontinued Phase ll / lll Business / Strategic Decision trastuzumab emtansine Metastatic Breast Cancer Marketed Phase III Unspecified trastuzumab emtansine Gastric Cancer Marketed Phase III Unspecified ibritumomab tiuxetan Diffuse Large B- Cell Lymphoma Marketed Phase III inotuzumab ozogamicin Follicular Lymphoma Marketed Phase III inotuzumab ozogamicin Diffuse Large B-Cell Lymphoma; Non-Hodgkin Lymphoma Marketed Phase III Lack of Efficacy rovalpituzumab tesirine Small-Cell Lung Cancer Phase III Phase III rovalpituzumab tesirine Small-Cell Lung Cancer Phase III Phase III Neuradiab Brain Cancer; Glioblastoma Multiforme (GBM) Inactive Phase III Unspecified clivatuzumab tetraxetan Metastatic Adenocarcinoma of The Pancreas Inactive Phase III Unspecified depatuxizumab mafodotin Glioblastoma Multiforme (GBM) Inactive Phase III Lack of Efficacy vadastuximab talirine Acute Myelocytic Leukemia (AML, Acute Myeloblastic Leukemia) Discontinued Phase III Adverse Events 2026226426   02 Sep 2026 glembatumumab vedotin Metastatic Breast Cancer Discontinued Phase III Lack of Efficacy Oncolysin B B-Cell Leukemia; Lymphoma Discontinued Phase III Business / Strategic Decision TABLE A4. Tumor-specific cell-surface receptor targets which can be targeted by any of the antibodycomprising conjugates of the invention, immunoglobulins according to the invention, and antibodies that can be used for the ADCs and the antibodies provided with a saponin, and the ADCs provided with a saponin, of the present invention (not presented as a limitation; further immunoglobulins are equally suitable for the invention) Target       cell surface receptor Example monoclonal antibodies HER2 anti-HER2 monoclonal antibody such as trastuzumab and pertuzumab CD20 anti-CD20 monoclonal antibody such as rituximab, ofatumumab, tositumomab and ibritumomab CA125 anti-CA125 monoclonal antibody such as oregovomab EpCAM (17-1 A) anti-EpCAM (17-1 A) monoclonal antibody such as edrecolomab EGFR anti-EGFR monoclonal antibody such as cetuximab, panitumumab and nimotuzumab CD30 anti-CD30 monoclonal antibody such brentuximab CD33 anti-CD33 monoclonal antibody such as gemtuzumab and huMy9-6 vascular integrin alpha-v beta-3 anti-vascular integrin alpha-v beta-3 monoclonal antibody such as etaracizumab CD52 anti-CD52 monoclonal antibody such as alemtuzumab CD22 anti-CD22 monoclonal antibody such as epratuzumab CEA anti-CEA monoclonal antibody 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 huN901 CD38 anti-CD38 monoclonal antibody such as daratumumab CA6 anti-CA6 monoclonal antibody such as DS6 IGF-IR anti-IGF-IR monoclonal antibody such as cixutumumab and 3B7 integrin anti-integrin monoclonal antibody such as ONTO 95 syndecan-1 anti-syndecan-1 monoclonal antibody such as B-B4 Table A5: RIPs from plants* Plant Family Plant Species Proteins Classification Adoxaceae Sambucus ebulus L. Ebulitin a, Ebulitin p: Ebulitin y RIP 1 2026226426   02 Sep 2026 Ebulin f, Ebulin I, Ebulin r1, Ebulin r2, SEA RIP 2 SEAII, SELfd, SELId, SELIm lectin Sambucus nigra L. a-Nigritin, P-Nigritin, y-Nigritin, Nigritin f1, Nigritin f2 RIP 1 basic Nigrin b, Nigrin b = SNA-V, Nigrin f = SNA-Vf, Nigrin 11, Nigrin I2, Nigrin s, SNA-I, SNA-I’, SNA-lf, SNAflu-l, SNLRP1, SNLRP2 RIP 2 SNA-ld, SNA-lm, SNA-II, SNA-Ill, SNA-IV = SNA-IVf, SNA-IVI, SNApol-l, SNApol-ll, TrSNA-l, TrSNA-lf lectin Sambucus racemosa L. basic racemosin b, SRA RIP 2 SRLbm = SRAbm lectin Sambucus     sieboldiana (Miq.) Blume ex Graebn. SSA = SSA-b-1, Sieboldin-b = SSA-b-2 RIP 2 SSA-b-3, SSA-b-4 lectin Aizoaceae Mesembryanthe-mum crystallinum L. RIP1 RIP 1 Amara nthaceae Amaranthus caudatus L. Amaranthin = ACA lectin Amaranthus cruentus L. ACL lectin Amaranthus hypochondriacus L. [Syn.: Amaranthus leucocarpus S. Watson] A. leucocarpus lectin lectin Amaranthus mangostanus L. Amaramangin RIP 1 Amaranthus tricolor L. AAP-27 RIP 1 Amaranthus viridis L. Amaranthin RIP 1 Beta vulgaris L. Beetin-27 = BE27, Beetin-29 = BE29, Betavulgin 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. Aralin RIP 2 Panax ginseng C.A.Mey Panaxagin peculiar RIP 1 candidate / RNase Panax quinquefolius L. Quinqueginsin peculiar RIP 1 candidate / RNase Asparagaceae Asparagus officinalis L. Asparin 1, Asparin 2 RIP 1 Drimia maritima (L.) Stearn [Syn.: Charybdis maritima (L.) Speta] Charybdin RIP 1 Muscari       armeniacum Leichtlin ex Baker Musarmin 1, Musarmin 2, Musarmin 3, Musarmin 4 RIP 1 Polygonatum multiflorum (L.) All. PMRIPm, PMRIPt RIP 2 Yucca gloriosa var. tristis Carriere [Syn.: Yucca recurvifolia Salisb ] Yucca leaf protein = YLP RIP 1 Basellaceae Basella rubra L. Basella RIP 2a, Basella RIP 2b, Basella RIP 3 RIP 1 Caryophyllaceae Agrostemma githago L. Agrostin 2, Agrostin 5, Agrostin 6, Agrostin RIP 1 2026226426   02 Sep 2026 Dianthus barbatus L. Dianthin 29 RIP 1 Dianthus caryophyllus L. Dianthin 30, Dianthin 32 RIP 1 Dianthus chinensis L. [Syn.: Dianthus sinensis Link] D. sinensis RIP RIP 1 Gypsophila elegans M.Bieb. Gypsophilin RIP 1 Silene chalcedonica (L.) E.H.L.Krause [Syn.: Lychnis chalcedonica L.] Lychnin RIP 1 Silene glaucifolia Lag. [Syn.: Petrocoptis glaucifolia (Lag.) Boiss] Petroglaucin 1, Petroglaucin 2 RIP 1 Silene laxipruinosa Mayol & Rossello [Syn.: Petrocoptis grandiflora Rothm] Petrograndin RIP 1 Saponaria ocymoides L. Ocymoidin RIP 1 Saponaria officinalis L. Saporin-L1 = SO-L1, Saporin-L2 = SO-L2, Saporin-L3 = SO-L3, Saporin-I = SO-I = SO-4, Saporin-R1 = SO-R1, Saporin-R2 = SO-R2, Saporin-R3 = SO-R3, SO3a, SO3b, Saporin-S5 = Saporin 5 = SO-S5, Saporin-S6 = Saporin 6 = SO-6 = SO-S6, Saporin-S8 = SO-S8, Saporin-S9 = Saporin 9 = SO-S9, SAP-C, SAP-S RIP 1 Myosoton aquaticum (L.) Moench [Syn.: Stellaria aquatica (L.) Scop.] Stellarin RIP 1 Stellaria media (L.) Vill. RIPQ3 RIP 1 Vaccaria hispanica (Mill.) Rauschert [Syn.: Vaccaria pyramidata Medik ] Pyramidatin RIP 1 Cucurbitaceae Benincasa hispida (Thunb.) Cogn. Hispin RIP 1 a-benincasin, p-benincasin sRIP 1 Bryonia cretica subsp. dioica (Jacq.) Tutin. [Syn.: Bryonia dioica L.] Bryodin 1 = BD1, Bryodin 2, Bryodin-L, Bryodin-R RIP 1 BDA lectin / RIP 2 like Citrullus colocynthis (L.) Schrad. Colocin 1, Colocin 2 RIP 1 Cucurbita foetidissima Kunth Foetidissimin peculiar RIP 2 Foetidissimin II RIP 2 Cucumis ficifolius A.Rich. [Syn.: Cucumis figarei Delile ex Naudin] Cucumis figarei RIP = CF-RIP RIP 1 candidate Cucurbita         maxima Duchesne Cucurmoschin sRIP 1 candidate Cucurbita        moschata Duchesne [Syn.: Cucurbita moschata (Duchesne ex Lam.) Duchesne ex Poir ] Cucurmosin, Cucurmosin 2, C. moschata RIP, Moschatin, PRIP 1, PRIP 2 RIP 1 a-moschin, p-moschin sRIP 1 candidate Cucurbita pepo L. Pepocin RIP 1 Cucurbita pepo var. texana (Scheele) D.S.Decker [Syn.: Texanin RIP 1 2026226426   02 Sep 2026 Cucurbita texana (Scheele) A. Gray] Gynostemma pentaphyllum (Thunb.) Makino Gynostemmin RIP 1 Lagenaria siceraria (Molina) Standi. Lagenin RIP 1 candidate Luffa acutangula (L.) Roxb. Luffaculin-1, Luffaculin-2 RIP 1 Luffangulin sRIP 1 Luffa acutangula fruit lectin lectin Luffa cylindrica (L.) M.Roem [Syn.: Luffa aegyptiaca Mill ] Luffin, Luffin-a, Luffin-b, a-luffin, p-luffin, LRIP RIP 1 Luffacylin, Luffin P1 sRIP 1 Luffin-S, LuffinS(1), LuffinS(2) = luffin S2, LuffinS(3) sRIP 1 candidate Marah oreganus (Torr. & A. Gray) Howell MOR-I, MOR-II RIP 1 Momordica balsamina L. Balsamin, MbRIP-1, Momordin II RIP 1 Momordica charantia L. MAP 30, a-momorcharin = a-MC = a-MMC, p-momorcharin = P-MC = P-MMC, b-momorcharin = 6-MMC, Momordin, Momordin = Momordica charantia inhibitor, Momordin II, Momordin-a, Momordin-b RIP 1 y-momorcharin = y-MMC, Charantin sRIP 1 RIP 1 candidate RIP 1 candidate MCL = M. charantia lectin, anti-H Lectin, Momordica agglutinin, Momordin, protein fraction 1, protein fraction 2 lectin MCL = Momordica charantia seed lectin = Momordica charantia lectin, MCL1 RIP 2 Momordica cochinchinensis Spreng. Cochinin B, Momorcochin, Momorcochin-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 Sechium edule fruit lectin lectin Trichosanthes anguina L. Trichoanguin RIP 1 SGSL lectin / RIP 2 like Trichosanthes cordata Roxb. TCA-I, TCA-II lectin Trichosanthes cucumerina L. TCSL lectin / RIP 2 candidate Trichosanthes cucumeroides (Ser.) Maxim. P-trichosanthin = P-TCS RIP 1 Trichosanthes       kirilowii Maxim. a-kirilowin, p-kirilowin, TAP 29, TK-35, Trichobitacin, Trichokirin, Trichomislin = TCM, Trichosanthin = Trichosanthes antiviral protein = TAP = TCS = a-trichosanthin = a-TCS = GLQ223, Trichosanthin, p-trichosanthin = P-TCS, y-trichosanthin = y-TCS RIP 1 2026226426   02 Sep 2026 Trichokirin S1, S-Trichokirin, Trichosanthrip sRIP 1 TKL-1 = Trichosanthes kirilowii lectin-1 lectin / RIP 2 candidate TK-I, TK-II, TK-III, Trichosanthes kirilowii lectin lectin Trichosanthes       kirilowii Maximovicz var. japonica (Miquel) Kitamura Karasurin-A, Karasurin-B, Karasurin-C RIP 1 Trichosanthes lepiniate Trichomaglin RIP 1 Trichosanthes dioica Roxb. TDSL lectin / RIP 2 candidate Trichosanthes sp. Bac Kan 8-98 Trichobakin RIP 1 Cupressaceae Thuja occidentalis L. Arborvitae RIP RIP candidate Euphorbiaceae Croton tiglium L. Crotin I RIP 1 candidate Crotin 2 RIP 1 Euphorbia characias L. E. characias lectin lectin Suregada         multiflora (A.Juss.) Baill. [Syn.: Gelonium       multiflorum A.Juss.] Gelonin = GAP 31 RIP 1 Hura Crepitans L. Hura crepitans RIP, Hura crepitans RIP-5 RIP 1 Hura crepitans latex lectin RIP 2 Crepitin, Hurin, Hura crepitans seed lectin lectin Jatropha curcas L. Curcin, Curcin 2, Curcin-L, Jc-SCRIP RIP 1 Manihot palmata Mull. Arg. Mapalmin RIP 1 Manihot esculenta Crantz. [Syn.: Manihot utilissima Pohl] Manutin 1, Manutin 2 RIP 1 Ricinus communis L. Ricin = crystalline Ricin = Ricin D, Ricin E, RCA = Ricinus communis agglutinin = RCAI = RCA120 = R. communis hemagglutinin = RCB-PHA I, RCAII = RCA60 = RCB-PHA II RIP 2 Ricinus communis, USA Ricin 1, Ricin 2, Ricin 3 RIP 2 Ricinus communis, India Ricin I, Ricin II, Ricin III RIP 2 Ricinus sanguienus, France Ricinn, Riciniz, Ricinz RIP 2 Fabaceae Abrus precatorius L. Abrin, Abrin-a = Abrin C = Abrin-lll, Abrin-b, Abrin-c = Abrin A = Abrin-I, Abrin-d, Abrin-ll, APA = Abrus precatorius agglutinin = Abrus lectin = AAG, APA-I, APA-II RIP 2 Abrus pulchellus Thwaites Pulchellin, Pulchellin PI, Pulchellin Pll, Pulchellin Pill RIP 2 Pisum sativum subsp. sativum L. [Syn.: Pisum sativum var. arvense (L.) Poir] a-pisavin, p-pisavin RIP 1 Pisum sativum     var. macrocarpon Sativin RIP 1 candidate Iridaceae IrisRIP = IRIP, IrisRIP.AI, lrisRIP.A2, lrisRIP.A3 RIP 1 2026226426   02 Sep 2026 Iris hollandica var. Professor Blaauw IRA, IRAb, IRAr RIP 2 Lamiaceae Clerodendrum aculeatum (L.) Schltdl. CA-SRI RIP 1 candidate Clerodendrum inerme (L.) Gaertn. CIP-29 RIP 1 CIP-34 RIP 1 candidate Leonurus japonicus Houtt. Leonurin RIP candidate Lauraceae Cinnamomum bodinieri H. Lev. Bodinierin RIP 2 Cinnamomum camphora (L.) J.PresI Camphorin RIP 1 Cinnamomin, Cinnamomin 1, Cinnamomin 2, Cinnamomin 3 RIP 2 Cinphorin sRIP 2 Cinnamomum parthen oxy Ion (Jack) Meisn. [Syn.:       Cinnamomum porrectum (Roxb.) Kosterm] Porrectin RIP 2 Malvaceae Abelmoschus esculentus (L.) Moench Abelesculin RIP 1 Nyctaginaceae Boerhaavia diffusa L. Boerhaavia inhibitor RIP 1 candidate Bougainvillea spectabilis Willd. BAP I, Bouganin = Bougainvillea RIP I 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.) Standi. ME1, ME2 RIP 1 Mirabilis jalapa L. MAP, MAP-2, MAP-3, MAP-4, MAP-S RIP 1 Olacaceae Malania oleifera Chun & S. K. Lee Malanin lectin / RIP 2 candidate Ximenia americana L. Riproximin = Rpx, Rpx-I, Rpx-ll RIP 2 Passifloraceae Adenia digitata (Harv.) Engl. Modeccin = Modeccin 4B, Modeccin 6B RIP 2 Adenia ellenbeckii Harms A. ellenbeckii lectin RIP 2 candidate Adenia fruticosa Burtt Davy A. fruticosa lectin lectin Adenia glauca Schinz A. glauca lectin RIP 2 candidate Adenia goetzei Harms (unresolved name) A. goetzei lectin RIP 2 Adenia keramanthus Harms A. keramanthus lectin RIP 2 candidate Adenia lanceolata Engl. Lanceolin RIP 2 Adenia racemosa W. J. de Wilde 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 Volkensin RIP 2 2026226426   02 Sep 2026 Phytolaccaceae Phytolacca americana L. a-PAP, PAP = Phytolacca americana protein = pokeweed antiviral protein, PAP-I, PAP-II, PAP-III, PAP-C, PAP-H, PAP-R, PAP-S, PAP-S1, PAP-S2 RIP 1 Phytolacca dioica L. Diocin 1, Diocin 2, PD-L1, PD-L2, PD-L3, PD-L4, PD- S1, PD-S2, PD-S3 RIP 1 Phytolacca     dodecandra L’Her. Dodecandrin, Dodecandrin C RIP 1 Phytolacca heterotepala H. Walter Heterotepalin 4, Heterotepalin 5b RIP 1 Phytolacca insularis Nakai Insularin = PIP = Phytolacca insularis antiviral protein, PIP2 = P. insularis antiviral protein 2 RIP 1 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 Tritico m a estiva m 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 Eranthis hyemalis (L.) Salisb. EHL RIP 2 Santalaceae Phoradendron californicum Nutt. PCL RIP 2 Viscum album L. (Himalayan mistletoe) HmRip, HmRip 1, HmRip 2, HmRip 3, HmRip 4 RIP 2 Viscum album L. (European mistletoe) ML-I = Mistletoe lectin I = Viscumin = Eu-ML = EML-1 = VAA-I, ML-II = Mistletoe lectin II = VAA-II, ML-III = Mistletoe lectin III = VAA-III RIP 2 Viscum articulatum Burm. f. Articulatin-D RIP 2 Viscum coloratum (Korn.) Nakai [Syn.: Viscum album subsp. coloratum Korn ] KML, KML-C, KML-IIL, KML-IIU, VCA RIP 2 Solanaceae Nicotiana tabacum L. CIP31 RIP-like protein TRIP RIP 1 candidate Thymelaeaceae Phaleria        macrocarpa (Scheff.) Boerl. P. macrocarpa RIP RIP candidate * Schrot J, Weng A, Melzig MF, et al. Ribosome-inactivating and related proteins. Toxins (Basel). 2015 May 8;7(5):1556-615. An aspect of the invention relates to a conjugate comprising or consisting of an antibody and an antisense oligonucleotide such as an antisense BNA, covalently linked together. In Figure 1-5, the genesilencing activity of such a conjugate is depicted (in vivo test in an animal tumor model). Reference is 5 also made to the Examples section. An aspect of the invention relates to a combination of a first composition comprising a conjugate comprising or consisting of an antibody and an antisense oligonucleotide such as an antisense BNA, 2026226426   02 Sep 2026 covalently linked together, and a second composition comprising free saponin of the invention (see Table A1, Scheme I). In Figure 1-7A and in Figure 1-7C, the gene-silencing activity of such a conjugate is depicted (in vitro cell-based bioassay with human tumor cells). Reference is also made to the Examples section. 5           An aspect of the invention relates to a pharmaceutical combination comprising or consisting of a first composition comprising a first conjugate comprising or consisting of an antibody and an antisense oligonucleotide such as an antisense BNA, and a second composition comprising a first conjugate comprising or consisting of the same antibody and at least one saponin of the invention. In Figure 1-5, the gene-silencing activity of such a conjugate is depicted (in vivo test in an animal tumor model). In 0 Figure 8-5, the gene-silencing activity of such a conjugate is depicted (in vitro cell-based bioassay with human tumor cells). Reference is also made to the Examples section. An aspect of the invention relates to a pharmaceutical combination comprising or consisting of a fourth composition comprising a fourth conjugate comprising or consisting of an antibody and an antisense oligonucleotide such as an antisense BNA, and a fifth composition comprising a first conjugate 15 comprising or consisting of a different antibody and at least one saponin of the invention. In Figure 10-6A and in Figure 10-6C, the gene-silencing activity of such a conjugate is depicted (in vitro cell-based bioassay with human tumor cells). Reference is also made to the Examples section. An aspect of the invention relates to a conjugate comprising or consisting of an antisense oligonucleotide such as an antisense BNA, covalently linked to at least one saponin of the invention. In 20 Figure 1-3, the gene-silencing activity of such a conjugate is depicted (in vitro cell-based bioassay with human tumor cells). Reference is also made to the Examples section. An aspect of the invention relates to a conjugate comprising or consisting of an antisense oligonucleotide such as an antisense BNA, covalently coupled to a polymeric scaffold such as a dendron such as a G4-dendron, wherein the polymeric scaffold is covalently conjugated with one or more saponin 25 molecules of the invention, such as four saponin molecules. In Figure 1-3, the gene-silencing activity of such a conjugate is depicted (in vitro cell-based bioassay with human tumor cells). Reference is also made to the Examples section. An aspect of the invention relates to a conjugate comprising or consisting of an antibody such as a monoclonal antibody with specificity for a tumor marker or tumor-cell receptor, covalently linked to 30 at least one antisense oligonucleotide molecule such as antisense BNA, and covalently linked to at least one saponin molecule of the invention. In Figure 2-4, the gene-silencing activity of such a conjugate is depicted (in vivo test in an animal tumor model). Reference is also made to the Examples section. An aspect of the invention relates to a conjugate comprising or consisting of an antibody such as a monoclonal antibody with specificity for a tumor marker or tumor-cell receptor, covalently linked to 35 at least one antisense oligonucleotide molecule such as antisense BNA via a tri-functional linker such as the linker of Scheme II, and covalently linked to at least one saponin molecule of the invention via the same tri-functional linker. In Figure 1-1, the gene-silencing activity of such a conjugate is depicted (in vivo test in an animal tumor model). Reference is also made to the Examples section. An aspect of the invention relates to a therapeutic combination consisting or comprising of a 40 eighth composition comprising a conjugate comprising or consisting of an antibody, preferably a 2026226426   02 Sep 2026 monoclonal antibody with specificity for a tumor marker or tumor-cell receptor, covalently linked to at least one saponin molecule of the invention, preferably via at least one linker, preferably at least one cleavable linker, cleavable under physiological acidic conditions, and further comprising a ninth composition comprising an antisense oligonucleotide such as an antisense BNA molecule. In Figure 65    2, the gene-silencing activity of such a conjugate is depicted (in vivo test in an animal tumor model). In Figure 5-2A and Figure 5-2C, the gene-silencing activity of such a conjugate is depicted (in vitro cellbased bioassay with human tumor cells). Reference is also made to the Examples section. An aspect of the invention relates to any of the aforementioned conjugates or compositions or therapeutical combinations, for use as a medicament. 0           An aspect of the invention relates to any of the aforementioned conjugates or compositions or therapeutical combinations, for use in the treatment or prophylaxis of a cancer. Of course, as said before, any and all of a, b, c, d, e, f, g, h, I, j, k, m, n, p, q, r, s, t, u, v, w and / or x have the value in accordance with each individual embodiment and aspect of the invention for any and all of 15 the aforementioned aspects and embodiments according to the invention. In addition, (tri-functional) linkers L1, L2, L4, L5, L6, L8, L9 and / or L10, if present in a molecule or conjugate or moiety of the invention, are the (tri-functional) linkers as indicated for each and any of the aforementioned aspects and embodiments of the invention, as is readily appreciated by the skilled person. The oligomeric or polymeric scaffolds L3 and / or L7, if present in a molecule or conjugate or moiety of the invention, are 20 the oligomeric or polymeric scaffolds as indicated for each and any of the aforementioned aspects and embodiments of the invention, as is also readily appreciated by the skilled person. Furthermore, the first ligand A1 and the first effector moiety B1, if present, and the second ligand A2 and the second effector moiety B2, if present, and the first effector moiety A1 and the first ligand B1, if present, and the second effector moiety A2 and the second ligand B2, if present, are the selected and indicated ligands and 25 effector moieties, as disclosed for the first, second, third, fourth, fifth, and sixth series of embodiment and aspects of the invention, and all further embodiments and aspects of the invention, outlined here above. Saponin C is any one or more of the saponins referred to and listed in any of the aforementioned aspects and embodiments of the invention, in particular one or more saponins selected from Scheme I and / or Table A1. 30 The invention is further illustrated by the following examples, which should not be interpreted as limiting the present invention in any way. EXAMPLES 35 EXAMPLE A - TREATING A MAMMALIAN TUMOR-BEARING ANIMAL WITH A CONJUGATE OF THE INVENTION IN COMBINATION WITH AN ADC RESULTS IN SURVIVAL AND TUMOR REGRESSION Female Balb / c nude mice were injected subcutaneously with a suspension of human A431 tumor cells. 40 Under the skin of the mice, a human epidermal carcinoma developed in the xenograft animal tumor 2026226426   02 Sep 2026 model. After injection of the tumor cells, the xenograft tumor was allowed to develop to a size of approximately 170-180 mm3. The A431 tumor cells have the following characteristics: high EGFR expressors, medium CD71 expressors, low HER2 expressors. In Table A, the results of the treatment of control mice and tumor-bearing mice are presented. 5 Tumor-bearing mice were treated with the indicated antibodies directed to either human Her2 / neu, human EGFR, or human CD71, which are cell-surface receptors on the xenograft tumor. Cetuximab was covalently conjugated with saponin SO1861. The SO1861 was first provided with the linker EMCH (N-s-maleimidocaproic acid hydrazide), which EMCH is a maleimide-and-hydrazide crosslinker for covalently conjugating sulfhydryls (reduced cysteines of the antibody)) to carbonyls (aldehyde or 0 ketones; here the carbonyl of the aldehyde at position C-23 of the saponin). The saponin-EMCH was covalently coupled to reduced cysteines of the Cetuximab, forming a covalent thio-ether bond between the EMCH and the cysteine side chain. The ADCs trastuzumab-saporin (covalent conjugate) and anti-CD71 mAb (OKT-9, IgG) - saporin (covalent conjugate) were tested for their tumor-attacking efficacy in the mice, measured as tumor volume in time after start of the treatment with the ADCs. The dose of the 15 ADCs was sub-optimal in the tumor model. That is to say, from previous experiments, it was established at which sub-optimal dose of the ADCs no tumor-regression or arrest of tumor growth would be observable. TABLE A: RESULTS OF TREATING A MAMMALIAN TUMOR-BEARING ANIMAL WITH A CONJUGATE OF THE INVENTION IN COMBINATION WITH AN ADC RESULTS IN SURVIVAL AND TUMOR REGRESSION Treatment group Patient / healthy animal treatment tumor size (volume in mm3 or'+’ for growth, for regression, and ‘stable’ for growth nor regression) 1 xenograft vehicle 2000 mm3(death / euthanasia) 2 xenograft T rastuzumab-saporin 2000 mm3(death / euthanasia) 3 xenograft Anti-CD71 mAb OKT-9 -saporin           (covalent conjugate) 2000 mm3(death / euthanasia) 4 xenograft Cetuximab-SO1861 (covalent conjugate) 2000 mm3(death / euthanasia) 5 xenograft Cetuximab > 170 mm3, but < 2000 mm3 (death / euthanasia) 6 xenograft Trastuzumab-saporin (covalent conjugate) + Tumor regression from 180 mm3 at the start of treatment back to 80 mm3 (survival) Cetuximab-SO1861 (covalent conjugate) 7 xenograft Anti-CD71 mAb OKT-9 -saporin          (covalent conjugate) + Cetuximab-801861         (covalent conjugate) Tumor regression from 180 mm3 at the start of treatment back to 40 mm3 (survival) 2026226426   02 Sep 2026 These results demonstrate that the combination therapy of an ADC at a dose which is ineffective when treatment of tumor-bearing mice with the ADC alone is considered (tumor growths, death of the mice is not prevented (euthanasia)), with a conjugate of the invention consisting of a tumor-cell specific receptor 5 targeting antibody covalently bound to a saponin, i.e. SO1861, the covalent conjugate administered to the mice suffering from cancer, at a non-effective dose when administered alone (tumor growths, death of the mice is not prevented (euthanasia)), provides an efficient and efficacious treatment regimen, expressed as tumors in regression and prolonged survival of the treated animals (beyond the duration of the experiment). The sub-optimal dose of ADC combined with a covalently bound saponin-comprising 10 conjugate of the invention which has no anti-tumor activity when administered alone, thus provide for an effective treatment option for cancer patients, wherein a relative low dose of the ADC is efficacious. A lower dose of ADC bears the promise of less risk for adverse events, or even no side effects at all. In addition, the stimulatory effect of the saponin-bearing conjugate of the invention when the efficacy of the ADC is considered, shows that ADCs which previously have proven to lack efficacy when tumor 15 patient treatment is concerned, may gain renewed attention and value, since ADC efficacy is improved in combination therapy setting, as the current example demonstrated. Reference is made to Table A2 and Table A3, summarizing ADCs which were previously investigated in the human clinical setting, but then were for some ADCs retracted from further clinical investigation. Especially the ADCs for which clinical development was terminated due to observed lack of efficacy and / or due to occurrence of 20 unacceptable adverse event are ADCs which may gain renewed value for cancer patients when combined with a covalently bound saponin-comprising conjugate of the invention, such as the cetuximab-saponin tested. EXAMPLE B - saponins mixture of Quillaja saponaria comprising QS-21, with 25 endosomal / lysosomal escape enhancing activity Scheme I displays the common molecular structure of a series of QS-21 saponins (in part adapted from: Conrado Pedebos, Laercio Pol-Fachin, Ramon 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, Item No. 6857; 30 InvivoGen, product ‘Quil-A’) may be applied in the endosomal / lysosomal escape enhancing conjugate, composition, combination ofthe 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 ofthe saponins comprised by the mixture, such as QS-21 and QS-7. 2026226426   02 Sep 2026 The inventors demonstrated that the mixture of saponins from Quillaja saponaria at 2,5 microgram / ml dose was capable of enhancing endosomal escape of dianthin, as tested with mammalian tumor cells in a cell-based bioassay. The effector moiety exposed to the cells was dianthin covalently coupled to the ligand EGF: EGF-dianthin. Cells tested were tumor cell lines HeLa for free saponins, and 5   A431, MDA-MB-468, CaSki and A2058 fortesting the saponins when covalently coupled to cetuximab. Example 1 A trifunctional linker scaffold was designed and produced with specific chemical end groups (DBCO, TCO) for conjugation (labile, (L) conjugation) with on one arm an SO1861 molecule and on the other 0 arm an antisense HSP27BNA oligo nucleotide (targeting and inducing degradation of the onco-target hsp27 mRNA in cancer cells) to produce SO1861-L-trifunctional linker-L-HSP27BNA (Figure 16-1). SO1861-L-trifunctional linker-L-HSP27BNA was conjugated with its the third arm (maleimide) to the cysteine residues (Cys) anti-EGFR antibody, cetuximab (cetuximab-Cys-(SO1861-L-trifunctional linker-L-HSP27BNA)4). 15           This scaffold comprising conjugate was tested in a A431 xenograph ‘nude’ mouse tumor model for EGFR-mediated tumor targeted gene silencing activity. Dosings started at day 12 when tumors reached ~170mm3 in size and tumor samples were collected at 72h after the first dosing and analysed for HSP27 gene expression compared to cellular control mRNA expression (reference genes). This revealed that 1 dosing of 25mg / kg cetuximab-Cys-(SO1861-L-trifunctional linker-L-HSP27BNA)3’7 20 resulted in a 40% reduction in HSP27 gene expression in the tumors compared to single dosing of cetuximab-(Cys-L-SO1861)3’8 or cetuximab-(Lys-L-HSP27BNA)4 mono therapies (Figure 1-1). Compared to the vehicle control tumors a reduction of 25% gene silencing was observed. This shows and enables that conjugated SO1861 efficiently can induce targeted delivery of therapeutic oligo nucleotides in tumors, in vivo. 25 To further strengthen this, cetuximab-Cys-(SO1861-L-trifunctional linker-L-HSP27BNA DAR4)4 was tested for enhanced HSP27 gene silencing in EGFR expressing (A431), in vitro as illustrated in Figure 2-1. Cetuximab-Cys-(SO1861-L-trifunctional linker-L-HSP27BNA)3’7 efficiently induces HSP27 gene silencing in A431 cells (IC50=...) compared to Cetuximab-(Lys-L-HSP27BNA)4 or Cetuximab-(Cys-L-SO1861)3'8 alone (Figure 2-1). 30 Example 2 1 target 2-components system is the combination treatment of mAb1-(dendron(SO1861)n)n and mAb1-effector as illustrated in Figure 11-1 and whereas the 2 target 2-component system is the combination of mAb1-(dendron(SO1861)n)n + mAb2-effector as illustrated in Figure 12-1. 35 Dendron(-L-SO1861)4 was conjugated to the anti-EGFR antibody, cetuximab via cysteine residues (Cys) conjugation with a DAR3,9, cetuximab-Cys-(dendron(-L-SO1861)4)3’9 and tested for enhanced cell killing activity in combination with an anti-EGFR antibody-protein toxin conjugate (cetuximab-saporin) in EGFR expressing cells (MDA-MB-468). Cetuximab-Cys-(dendron(-L-SO1861)4)3’9 + 10 pM cetuximabsaporin efficiently induces toxin-mediated cell killing in high EGFR expressing cells (IC50=...), whereas 40 this was not induced by Cetuximab-Cys-(dendron(-L-SO1861)4)3’9 or cetuximab (equivalent) + 10pM 2026226426   02 Sep 2026 cetuximab-saporin or cetuximab (Figure 3-1A). Similar experiments in cells that express low levels of EGFR (HeLa) revealed no activity of Cetuximab-Cys-(dendron(-L-SO1861)4)3’9 (Figure 3-1C) indicating that in the absence of sufficient EGFR receptor expression, effective intracellular SO1861 concentrations are not reached (threshold) to induce endosomal protein toxin escape and toxin-5 mediated cell killing. Next, dendron(-L-SO1861)4 was conjugated to the anti-HER2 antibody, trastuzumab via cysteine conjugation (Cys) with a DAR4, trastuzumab-Cys-(dendron(-L-SO1861)4)4 and tested for enhanced cell killing activity in combination with an anti-HER2 antibody-protein toxin conjugate (trastuzumab-saporin) in HER2 expressing cells (SK-BR-3). trastuzumab-Cys-(dendron(-L-SO1861)4)4 + 50 pM trastuzumab-0 saporin efficiently induce toxin-mediated cell killing (IC50 =...), whereas this was not induced by trastuzumab-Cys-(dendron(-L-SO1861)4)4 or trastuzumab (equivalent) + 50nM trastuzumab-saporin or trastuzumab (Figure 3-1B). Similar experiments in cells that express low levels of HER2 (JIMT-1) revealed no activity of Trastuzumab-Cys-(dendron(-L-SO1861)4)4 (Figure 3-1D) indicating that in the absence of sufficient HER2 receptor expression, effective intracellular SO1861 concentrations are not 15 reached (threshold) to induce endosomal protein toxin escape and toxin-mediated cell killing. Next, Cetuximab-Cys-(dendron(-L-SO1861)4)3’9 or Cetuximab-Lys-(dendron(-L-SO1861)4)4’4 (Lys=dendron(-L-SO1861)4 conjugated to lysines of antibody) was tested in combination with 10 pM CD71mab-saporin in a 2 target 2 components system in EGFR++ / CD71+ cells (MDA-MB-468). This showed for both conjugates a strong enhancement of the cell killing activity (IC50=.. IC50=.. resp.), 20 whereas this was not induced by Cetuximab-Cys-(dendron(-L-SO1861)4)3’9 or Cetuximab-Lys-(dendron(-L-SO1861)4)414 or cetuximab (equivalent) + 10 pM CD71mab-saporin or cetuximab (Figure 4-1A). Similar experiments in cells that express lower levels of EGFR (CaSKi, EGFR+ / CD71+) revealed reduced activity for both cetuximab-Cys-(dendron(-L-SO1861)4)3’9 or cetuximab-Lys-(dendron(-L-SO1861)4)4’4 (Figure 4-1C ) compared to the activity in high expressors (Figure 4-1 A) indicating that in 25 cells with lower EGFR receptor expression levels, the effective intracellular SO1861 concentrations is lower resulting in reduced toxin-mediated cell killing activity. Same experiment was performed with trastuzumab-Cys-(dendron(-L-SO1861)4)4 or trastuzumab-Lys-(dendron(-L-SO1861)4)4’7 in combination with CD71mab-saporin on HER2++ / CD71+ (SK-BR-3) cell lines revealing strong cell killing activity compared to the controls (Figure 4-1B). When trastuzumab-Cys-30   (dendron(-L-SO1861)4)4 or trastuzumab-Lys-(dendron(-L-SO1861)4)4’7 was tested on HER2+ / 7CD71 + (JIMT-1) in combination with 10 pM CD71mab-saporin no cell killing activity could be observed indicating that in the absence of sufficient HER2 receptor expression, effective intracellular SO1861 concentrations are not reached (threshold) to induce endosomal protein toxin escape and toxin-mediated cell killing. 35 Next, trastuzumab-Cys-(dendron(-L-SO1861)4)4 + trastuzumab-emtansine (T-DM1, antibody-small molecule toxin conjugate) was tested for enhanced cell killing activity in HER2 expressing cells (SK-BR-3). No enhanced cell killing was observed with this combination, compared to T-DM1 alone orT-DM1 + equivalent trastuzumab, since the endosomal membrane forms no barrier for small molecules to reach the cytoplasm. (Figure 5-1). 40 2026226426   02 Sep 2026 Example 3 Materials and methods dendron(SO1861)4-BNA oligo synthesis (Figure 17-1) HSP27BNA oligo disulfide (1.1 mg, 0.187 pmol) was dissolved in 20 mM NH4HCO3with 1.0 mM 5 TCEP (500 pL) and the mixture was shaken for 1 min and left standing at room temperature. After 1 hour the reaction mixture was filtered by using a centrifugal filter with a molecular weight cut-off of 3000 Da (14000 x g for 30 min). The residue solution was diluted with 20 mM NH4HCO3with 1.0 mM TCEP (500 pL) and the resulting mixture was filtered again under the same conditions described above. The residue solution was diluted with 20 mM NH4HCO3 / acetonitrile (3:1, v / v, 1.0 mL) and the resulting 0 mixture was added to dendron(SO1861)4-maleimide1 (3.54 mg, 0.375 pmol) (Figure 17-1) .The reaction mixture was shaken for 1 min and left standing at room temperature. After 10 min the reaction mixture was subjected to preparative LC-MS.4A Fractions corresponding to the product were immediately pooled together, frozen and lyophilized overnight to give the title compound (1.25 mg, 85%) as a white fluffy solid. Purity based on LC-MS 94% 15            LRMS (m / z): 1896 [M-8]8', 2167 [M-7]7' LC-MS r.t. (min): 3.776B results HSP27BNA oligo, (antisense BNA oligo targeting the mRNA transcript of the cancer target, heat shock protein 27 (HSP27BNA)) was conjugated to a dendron(-L-SO1861)4 (HSP27BNA-dendron(-L-20    SO1861)4, Figure 17-1) and co-administrated to A431 cancer cells. As readout, gene silencing of HSP27 mRNA in A431 cells was determined. This revealed that HSP27BNA-dendron(-L-SO1861)4 treatment resulted in an improvement of HSP27 gene silencing activity compared to the HSP27BNA alone (Figure 6-1). 25 Example 4 Methods SO1861 releasing assay To dendron(SO1861)4-Cbz (0.05 mg) (Figure 7-1) was added 50 pL of solution containing water / acetonitrile / TFA (1.00 mL / 1.00 mL / 4 drops). The reaction mixture was shaken for 1 30 min and left standing at room temperature. The SO1861 release was followed overtime by using UPLC- MS.4 Results The release efficiency of the SO1861 molecules from the dendron(-L-SO1861)4 under acid conditions has been determined (Figure 7-1). 35 Next, dendron(-L-SO1861)4 was tested for enhanced delivery of a targeted toxin, EGFdianthin on EGFR expressing cells (A431 and HeLa). This shows that dendron(L-SO1861)4 + 10 pM EGFdianthin can induce enhanced toxin-mediated cell killing (IC50 ....nM), whereas the ‘naked’ dendron (Dendron(NEM)4) or dendron(-L-SO1861)4 or Dendron(NEM)4 + 10 pM EGFdianthin is not showing enhanced cell killing at these concentrations (Figure 8-1 A, 8-1B). 40 2026226426   02 Sep 2026 Example 5 Materials and methods In our current work, we investigated a model scaffold consisting of four molecular arms for saponin binding via a Schiff base (imine) and one arm for click chemistry. The polymeric structure (Figure 19-1) 5 is a pentavalent polyethylene glycol-based dendrimer of the first generation (i.e. number of repeated branching cycles) that was purchased from Iris Biotech GmbH (Marktredwitz, Germany). The saponin (in this example SA1641) was purified from a saponin composite raw extract from Gypsophila species called Saponinum album obtained from Merck (Darmstadt, Germany). The powdered raw extract (2.5 g) was hydrolyzed in water (100 mL) with sodium hydroxide (0.2 g). The solution was stirred for 20 h at 0    40 °C and then supplemented with glacial acetic acid until pH 5.0 was reached. To remove tannins, the solution was shaken in a separatory funnel with 30 mL butanol. The aqueous phase was recaptured and butanol extraction repeated two times. The butanol phases were supplemented with anhydrous sodium sulfate, filtered and pooled. Butanol was evaporated and the remaining saponin powder resolved in 20% methanol to a final concentration of 30 mg / mL. After short sonication, different saponins were separated 15 by high performance liquid chromatography (HPLC). Tubes (excluding column) were rinsed with warm water (40 °C) at a flow of 1.5 mL / min and then including Eurospher RP-C18-column (5 pm, 250 x 8 mm) with isopropanol (100%). Saponins were applied to the column and eluted with a methanol gradient (20% methanol to 70% methanol within 30 min at 1.5 mL / min in water supplemented with 0.01% trifluoroacetic acid followed by 70% methanol for further 60 min) (Sama et al, 2018). Aliquots of the 20 fractions were analyzed for their SA1641 content by electrospray ionization mass spectrometry (ESIMS). Fractions containing pure SA1641 were pooled and methanol evaporated. The aqueous solution was frozen as a thin film in a rotating round-bottom flask by use of dry ice. After storage for 16 h at -80 °C, the sample was lyophilized. To produce the scaffold as defined in the invention, the polymeric structure (0.2 mM) and SA1641 (3.2 mM) were solved in water (approx. pH 8) and equal volumes mixed 25 and shaken for 24 h at 26 °C. Then sodium cyanoborohydride (NaCNBHs; 0,1 M) was added in 4-fold molar excess referred to SA1641 and the sample incubated for further 24 h. The structure was then verified by ultra performance liquid chromatography (UPLC) / ESI-MS. The samples were applied to a RP-C4-column and eluted with a methanol gradient (25% methanol to 80% methanol within 15 min in water supplemented with 0.01% trifluoroacetic acid followed by 80% methanol for further 10 min). The 30 fractions were analyzed by use of LockSpray™ that is an ion source designed specifically for exact mass measurement with electrospray ionization using LC-time-of-flight (LC-TOF) mass spectrometers from Waters Corporation. Example 6 35 Materials and methods As an example for a pharmaceutical active substance, we used the targeted toxin dianthin-Epidermal Growth Factor (dianthin-EGF). The plasmid His-dianthin-EGF-pET11d (Weng et al, 2009) (100 ng) was added to 20 pL Escherichia coli Rosetta™ 2 (DE3) pLysS Competent Cells (Novagen, San Diego, CA, USA). Cells were transformed by a heat-shock (30 min on ice, 90 s at 42 °C and 1 min on ice). 40 Thereafter, 300 pL lysogeny broth (LB) was added and the suspension incubated for 1 h at 37 °C while 2026226426   02 Sep 2026 shaking at 200 rpm. A preheated lysogeny broth agar plate with 50 pg / mL ampicillin was inoculated with 100 pl bacteria suspension and the plate incubated overnight at 37 °C. Lysogeny broth (3 mL) with 50 pg / mL ampicillin was inoculated with a colony from the plate and the bacteria were incubated for 8 h at 37 °C and 200 rpm. The suspension (50 pL) was added to 500 mL of lysogeny broth with 50 pg / mL 5 ampicillin and incubated overnight at 37 °C and 200 rpm. Subsequently, the volume was scaled-up to 2.0 L and bacteria grew under the same conditions until an optical density at wavelength 600 nm of 0.9 was reached. Thereafter, protein expression was induced by the addition of isopropyl p-D-1-thiogalactopyranoside (IPTG) at a final concentration of 1 mM. Protein expression lasted for 3 h at 37 °C and 200 rpm. Finally, the bacterial suspension was centrifuged at 5,000 x g and 4 °C for 5 min, 0 resuspended in 20 mL PBS (137 mM NaCI, 2.7 mM KCI, 8.1 mM Na2HPO4, 1.47 mM KH2PO4) and stored at -20 °C until use. For purification, bacterial suspensions were thawed and lysed by sonication. Lysates were centrifuged (15,800 x g, 4 °C, 30 min) and imidazole added to a final concentration of 20 mM. The supernatant was incubated with 2 mL of Ni-nitrilotriacetic acid agarose under continuous shaking for 30 min at 4 °C in the presence of 20 mM imidazole. Subsequently, the material was poured 15 into a 20-mL-column and washed three times with 10 mL wash buffer (50 mM NaH2PO4, 300 mM NaCI, 20 mM imidazole) and dianthin-EGF eluted by 10-mL-portions of increasing concentrations of imidazole (31,65,125 and 250 mM) in wash buffer. Eluate fractions (2 mL) were dialyzed overnight at 4 °C against 2.0 L PBS. Desalted dianthin-EGF was concentrated by an Amicon® Ultra-15 (10 kDa) and the protein concentration quantified. 20 To introduce a suitable click chemistry group into dianthin-EGF, alkyne-PEGs-N-hydroxysuccinimidyl ester in 8-fold molar excess referred to dianthin-EGF was solved in dimethyl sulfoxide and added to 9 volumes of dianthin-EGF (1 mg in 0.2 M NaH2PO4 / Na2HPO4, pH 8). After incubation at room temperature for 4 h, non-bound alkyne was separated by use of a PD10 column (GE-Healthcare, Freiburg, Germany). Click chemistry with the polymeric structure was conducted by copper(l)-catalyzed 25 alkyne-azide cycloaddition. Alkyne-dianthin-EGF (0.02 mM), dendrimer (0.05 mM), CuSO4 (0.1 mM), tris(3-hydroxypropyltriazolylmethyl)amine (0.5 mM) and sodium ascorbate (5 mM) were incubated under gentle agitation for 1 h at room temperature in 0.1 M NaH2PO4 / Na2HPO4, pH 8. Low molecular mass substances were then separated using a PD10 column. To test the efficacy of the invention, we conducted a viability assay with HERM cells. These cells are 30 fibroblasts stably transfected with the human epidermal growth factor receptor and therefore target cells for the targeted toxin dianthin-EGF. HERM cells (2,000 cells / 100 pL / well) were seeded into wells of 96-well-cell culture plates and incubated for 24 h in DMEM medium supplemented with 10% fetal calf serum and 1% penicillin / streptomycin at 37 °C, 5% CO2 and 98% humidity. The different test substances (see results and Figure 21-1) were then added in triplicates in a volume of 25 pL and supplemented with 35 further 25 pL of medium. After an incubation of 72 h, 30 pL 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (0.5 mg / mL in water) was added per well and incubated for 2 h. Thereafter, the medium was carefully removed and replaced by an aqueous solution containing 10% (v / v) isopropanol, 5% (w / v) sodium dodecyl sulfate and 400 mM HCI, and incubated for 5 min. Solubilized formazan was photometrically quantitated at 570 nM in a microplate reader (Spectra MAX 340 PC, 2026226426   02 Sep 2026 Molecular Devices, Sunnyvale, CA, USA). Untreated cells were normalized to 1 and all samples referred to the untreated control. Significance was determined by unpaired two-sample t-tests. Results The polymeric structure, in the example a pentameric dendrimer (pentrimer), does not have any 5 cytotoxic effect on the target cells, neither in absence nor in presence of SA1641 (Figure 21-1, column 2 and 3). In the absence of the scaffold, the targeted toxin (dianthin-EGF) shows half maximal toxicity at a concentration of 0.1 nM (column 4). In the presence of SA1641 the same concentration results in death of all cells indicating the general ability of SA1641 to act as an enhancer of the endosomal escape (column 5). The presence of the polymeric structure does not affect the toxicity of dianthin-EGF neither 0 in the presence nor in the absence of SA1641 (columns 6 and 7), indicating that the scaffold does not affect the toxicity of dianthin-EGF. To couple the model polymeric structure via click chemistry to the example pharmaceutically active substance of dianthin-EGF, the substance had to be coupled with an alkyne group before. . A manufacturer of a pharmaceutically active substance can introduce the click position during synthesis directly into the substance at a position of his choice where the activity of the 15 substance remains unaffected. There was no additional loss of activity when clicking the alkyne-modified pharmaceutically active substance to the polymeric structure indicating that the polymeric structure itself was not toxic. Example 7 20 Considering available chemical groups for conjugation reactions to the SO1861 molecule, four chemical groups have been identified. The alcohols and diols of the sugar residues, the aldehyde group on the triterpenoid backbone, the carboxylic acid on one of the sugar residues (glucuronic acid), and the alkene group on the triterpenoid backbone as highlighted in Figure 19-1. In view of the pros and cons of each identified chemical group (Table 1), the aldehyde and 25 alcohol groups are best suitable for reversible conjugation reactions, while the alkene and the carboxylic acid (glucuronic acid) are the groups best suitable for irreversible I stable conjugation reactions. The aldehyde group within the molecule structure of SO1861, however, is the most suitable for reversible conjugation reactions over the alcohols. On the one hand, because there is only one aldehyde present in the structure that allows chemoselective reactions. On the other hand, because the aldehyde can 30 perform reversible conjugation reactions with a variety of chemical groups such as amines, hydrazides, and hydroxylamines forming acid-cleavable moieties like imines, hydrazones, and oximes. This factor enables a freedom of choice over the chemical group for the desired reversible conjugation reaction. Contrary, the alcohols are good candidates for reversible conjugation reaction via the formation of acetals and ketals as well, but lack in chemoselectivity since they are present in a large quantity on the 35 glycosidic structure. For the formation of an irreversible and stable bond the carboxylic acid is the most suitable since it can form amides and esters with the common tools used in peptide chemistry (e.g. reaction with amines via carbodiimide mediated amide formation). 40 Table 1. Functional groups that are available for saponin conjugation reactions 2026226426   02 Sep 2026 Functional Group Pros Cons Alcohol (Diols) - Suitable for reversible acetal / ketal formation - Suitable for ester formations with activated carboxylic acids - Acetal / ketal formation without chemoselectivity - Ester      formation      without chemoselectivity Aldehyde - Suitable for chemoselective reversible hydrazone formation with hydrazides -   Suitable    for    chemoselective reversible  imine  formation with amines -   Suitable    for    chemoselective reversible oxime formation with hydroxylamines - Not suitable for acetal formation in the presence of unprotected saponin sugar diols Alkene - Suitable for chemoselective irreversible radical reactions - Not suitable for reversible conjugation reactions - Not suitable for reactions involving a hydrogenation step Carboxylic acid - Suitable for chemoselective amide / ester formation with amines and alcohols after activation - Not suitable for reversible conjugation reactions under mild conditions Regarding an ideal EMCH spacer length for conjugation to a polymeric structure, computer simulation (PerkinElmer, ChemBio3D, Ver. 13.0.0.3015) shows that the maleimide group on SO1861-EMCH is located at the periphery of the molecule and thus should be accessible for thiol bearing polymeric 5 structures (Figure 27-1). As a polymeric structure, a G4-dendron (PFd-G4-Azide-NH-BOC, Polymer Factory) with 16 functional amino end groups and an azido group at the focal point was utilized for the conjugation to SO1861 (Figure 24-1). The advantage of using a dendron over a dendrimer is the focal point that the dendron structure is exhibiting. 10           Another approach for the development of a SO1861 scaffold among the discussed polymer, and protein approach is the poly(SO1861) approach. The idea of this approach is to generate a polymer that consists of SO1861 molecules only, with pH sensitive cleavable bonds that release the SO1861. In addition, the poly(SO1861) should be able to perform conjugation reactions to toxins and biopolymers. The main goal with this approach is to keep it as simple and cost effective as possible. Since a protocol 15 for the generation of acid cleavable SO1861 has been developed already (SO1861-EMCH approach) it would be interesting to see if it is possible to polymerize the SO1861-EMCH through simple addition of 2026226426   02 Sep 2026 a polymerization initiator without further modifying the SO1861 or identifying other conjugation sites on the SO1861 molecule. In the past, several papers have discussed the polymerization of maleimide groups by using radical initiators which attack the double bond of the maleimide group and thus initiate a radical polymerization along the double bonds of the maleimides. Since SO1861-EMCH reveals a 5 maleimide group in its structure this group could potentially be explored for radical polymerization reactions to yield a poly(SO1861) with acid cleavable function. If the polymerization reaction has a reasonable reaction time the generated SO1861 polymers could be quenched with a radical quencher that not only quenches the reaction but also generates a functional group for toxin or biopolymer conjugation. Here, the system of ammonium persulfate (APS) and tetramethylethylenediamine 0 (TMEDA) is indicated in an exemplary way as radical generator and aminopropanethiol serves as a model radical quencher. Using aminopropanethiol as a quencher exemplary, the generated amine group could be specifically further modified to a click-able group or being used to directly conjugate the poly(SO1861) to a toxin. Another approach for the development of a SO1861 scaffold is the DNA approach. The idea of 15 this approach is to utilize the concept of the so-called DNA-origami (Kolb et al, 2004; Bird et al, 1988). DNA-origami as the polymeric or assembled polymeric structure to conjugate saponins to it, can offer several inherent advantages including stability, scalability, and precise control of the final size and shape of the resulting DNA-saponin scaffold. Since these DNA nanocarriers are comprised of natural DNA, they are biocompatible and do not show toxicity to living cells, and can ease the release of cargo from 20 internal cellular compartments. The multivalency of such a structure can further allow fine-tuning targeting capabilities and high capacity for a variety of payloads such as fluorophores and toxins. Thus, in this approach DNA strands are identified that offer chemical functional groups on the 3’ and 5’ endings respectively, and that are able to hybridize only in certain wanted areas of the sequence that allow a control over the final shape of the construct. The chemical groups should be utilized to couple saponins, 25 for instance though a thiol-ene reaction between the already developed SO1861-EMCH and a thiol group on one of the 3’ and 5’ DNA strands. The complementary DNA strand can offer a click function group that can be used for coupling to a targeted toxin. The concept is illustrated in Figure 23-1. A similar approach is imaginable by using a specific peptide sequence instead of DNA strands that is able to bind and release saponins and that can be polymerized forming a large poly(peptide)-like 30 structure. In this approach, a peptide sequence has been identified and purchased that has a length fitting the calculated size of a SO1861-EMCH molecule, that offers a cysteine residue in the middle of the sequence, and that obtains an amine group at both the N-terminus and C-terminus. The cysteine residue can be utilized to conjugate SO1861-EMCH via a thiol-ene reaction of the maleimide group of SO1861-EMCH and the thiol group of the cysteine residue. The two amine groups can be utilized to 35 polymerize the peptide-SO1861 conjugate with a suitable crosslinker. Example 8 SO1861-BNA oligo conjugation HSP27 BNA oligo disulfide (1.10 mg, 0.187 pmol) was dissolved in 20 mM NH4HCO3with 1.0 mM 40 TCEP (500 pL) and the mixture was shaken for 1 min and left standing at room temperature. After 1 2026226426   02 Sep 2026 hour the reaction mixture was filtered by using a centrifugal filter with a molecular weight cut-off of 3000 Da (14000 x g for 30 min). The residue solution was diluted with 20 mM NH4HCO3with 1.0 mM TCEP (500 pL) and the resulting mixture was filtered again under the same conditions described above. The residue solution was diluted with 20 mM NH4HCO3 / acetonitrile (3:1, v / v, 1.00 mL) and the resulting 5 mixture was added to SO1861-EMCH (3.54 mg, 0.375 pmol). The reaction mixture was shaken for 1 min and left standing at room temperature. After 10 min the reaction mixture was subjected to preparative LC-MS.4A Fractions corresponding to the product were immediately pooled together, frozen and lyophilized overnight to give the title compound (1.25 mg, 85%) as a white fluffy solid. Purity based on LC-MS 100%. 0            LRMS (m / z): 1561 [M-5]5; 1951 [M-4]4' LC-MS r.t. (min): 2.466B dendron(SO1861 )4-BNA oligo conjugation HSP27 BNA oligo disulfide (1.1 mg, 0.187 pmol) was dissolved in 20 mM NH4HCO3with 1.0 mM TCEP (500 pL) and the mixture was shaken for 1 min and left standing at room temperature. After 1 15 hour the reaction mixture was filtered by using a centrifugal filter with a molecular weight cut-off of 3000 Da (14000 x g for 30 min). The residue solution was diluted with 20 mM NH4HCO3with 1.0 mM TCEP (500 pL) and the resulting mixture was filtered again under the same conditions described above. The residue solution was diluted with 20 mM NH4HCO3 / acetonitrile (3:1, v / v, 1.0 mL) and the resulting mixture was added to dendron(SO1861)4-maleimide1 (3.54 mg, 0.375 pmol). The reaction mixture was 20 shaken for 1 min and left standing at room temperature. After 10 min the reaction mixture was subjected to preparative LC-MS.4A Fractions corresponding to the product were immediately pooled together, frozen and lyophilized overnight to give the title compound (1.25 mg, 85%) as a white fluffy solid. Purity based on LC-MS 94% LRMS (m / z): 1896 [M-8]8', 2167 [M-7]7' 25            LC-MS r.t. (min): 3.776B Cell culture Cells were seeded in DMEM (PAN-Biotech GmbH) supplemented with 10% fetal bovine serum (PANBiotech GmbH) and 1% penicillin / streptomycin (PAN-Biotech GmbH), in a 96 well plate at 5,000 c / w in 100 pL / well and incubated overnight at 37 °C and 5% CO2. The next day samples were prepared in 30 DMEM and cells were treated. Gene silencing RNA isolation and Qpcr analysis was performed according to standard procedures and protocols. HSP27 primers: F: R: HSP27BNA oligo 35 HSP27BNA(-thiol) oligos (sequence 5’-GGCacagccagtgGCG-3’) (Zhang et al., 2011) were ordered at Bio-synthesis Inc. (Lewisville, Texas) Results BNAoligo, antisense BNA oligo targeting the mRNA transcript of the cancertarget (upregulated in cancer cells), heat shock protein 27 (HSP27BNA) was conjugated to SO1861-EMCH (HSP27BNA-L-SO1861) 40 or dendron(-L-SO1861)4 (HSP27BNA-dendron(-L-SO1861)4) and co-administrated to an A431 cancer 2026226426   02 Sep 2026 cell line, according to the invention. As readout, gene silencing of HSP27 mRNA in A431 cells was determined. This revealed that HSP27BNA-L-SO1861 treatment resulted in an improvement of HSP27 gene silencing activity compared to the HSP27BNA alone, whereas the activity of HSP27BNA-dendron(-L-SO1861)4 (4 SO1861 molecules / BNA) is even stronger (3-fold) compared to the gene silencing activity 5 of HSP27BNA alone (Figure 1 -3). This shows that conjugation of 1 or more SO1861 molecules improves the gene silencing activity of the therapeutic BNA oligo nucleotide due to the enhancement of SO1861-mediated endosomal escape and cytoplasmic delivery of the antisense BNA. Example 9 0    SO1861 was conjugated (labile) via cysteine residues (Cys) and dianthin (protein toxin) was conjugated (stable) via lysine residues (Lys) to cetuximab (monoclonal antibody recognizing and binding human EGFR), resulting in the production of: Cetuximab-(Cys-L-SO1861)3’9(Lys-S-dianthin)2. The conjugate was tested in a A431 (EGFR++) xenograph mouse tumor model for EGFR tumor targeted cell killing as illustrated in Figure 9-4. Dosings started at day 12 when tumors reached ~150mm3 in size and tumor 15 volume was determined after every dosing. Mice (n=3) were treated (intraperitoneal; i.p.; dose escalation) at day 12: 0.5 mg / kg; day15: 1 mg / kg and day24: 1.5 mg / kg with cetuximab-(Cys-L-SO1861 )3i9(Lys-S-dianthin)2 or cetuximab-(Lys-S-dianthin)1’6. At day 26, compared to the control group, tumor volume reduction could be observed in the tumor bearing mice treated with cetuximab-(Cys-L-SO1861)3i9(Lys-S-dianthin)2 (Figure 1-4A). This shows that labile conjugation of SO1861 to an antibody-20 protein toxin (stable) conjugate can enhance the targeted therapeutic efficacy of the tumor targeted antibody-protein toxin, thereby inducing a more effective tumor targeted therapy. Next, SO1861 was conjugated (labile) via cysteine residues (Cys) and dianthin (protein toxin) was conjugated (labile) via lysine residues (Lys) to cetuximab (monoclonal antibody recognizing and binding human EGFR), resulting in the production of: Cetuximab-(Cys-L-SO1861)3’9(Lys-L-dianthin)2. The 25 conjugate was tested in a A431 (EGFR++) xenograph mouse tumor model for EGFR tumor targeted cell killing as illustrated in Figure 9-4. Dosings started at day 12 when tumors reached ~150mm3 in size and tumor volume was determined after every dosing. Mice (n=3) were treated (intraperitoneal; i.p.; dose escalation) at day 12: 0.5 mg / kg; day15: 1 mg / kg, day24: 1.5 mg / kg with cetuximab-(Cys-L-SO1861 )3 9(Lys-L-dianthin)2 or cetuximab-(Lys-L-dianthin)1’6. This revealed that after 35 days compared 30 to the control, tumor bearing mice treated with cetuximab-(Cys-L-SO1861)3’9(Lys-L-dianthin)2 showed tumor growth inhibition (Figure 1-4B). When mice (n=3; were treated (intravenous, i.v.; dose escalation) day 12: 0.5 mg / kg; day15: 1 mg / kg, day18: 2 mg / kg, day24: 2.5 mg / kg with the cetuximab-(Cys-L-SO1861)3i9(Lys-L-dianthin)2 according to the invention also tumor growth inhibition could be observed compared to the control (data represents 1 mice, since 2 mice died during the treatments). This shows 35 that labile conjugation of SO1861 to an antibody-protein toxin (labile) conjugate can enhance the targeted therapeutic efficacy of the tumor targeted antibody-protein toxin, thereby inducing a more effective tumor targeted therapy. Next, SO1861-EMCH was conjugated via cysteine residues (Cys) to cetuximab (monoclonal antibody recognizing and binding human EGFR), with a DAR 3,9 and the antisense HSP27BNA oligo nucleotide 40 (targeting and inducing degradation of the onco-target hsp27 mRNA (gene silencing) in cancer cells) 2026226426   02 Sep 2026 via a labile (L) linker to the lysine residues (Lys) of the antibody, with a DAR 1,8 resulting in the production of cetuximab-(Cys-L-SO1861)3’9(Lys-L-HSP27BNA)1’8. Cetuximab-(Cys-L-SO1861)3’9(Lys-L-HSP27BNA)1’8was tested in a A431 xenograph ‘nude’ mouse tumor model for EGFR-mediated tumor targeted HSP27 gene silencing, according to the invention as illustrated in Figure 10-4. Dosing started 5 at day 12 when tumors reached ~150mm3 in size and HSP27 mRNA expression was determined. For this, tumor samples were collected at 72h after the first dosing and analysed for HSP27 gene expression levels compared to cellular control mRNA expression levels (reference genes). Tumor bearing mice (n=3) treated (intraperitoneal; i.p.) with 30 mg / kg cetuximab-(Cys-L-SO1861)3’9(Lys-L-HSP27BNA)1’8 showed after 1 dosing 40% reduction in HSP27 mRNA expression in the tumors compared to single 0 dosing of cetuximab-(Cys-L-SO1861)38 or cetuximab-(Lys-L-HSP27BNA)1’5 (Figure 2-4). Compared to the tumor of the vehicle control a reduction of 25% HSP27 gene expression was observed. This shows and enables that conjugation of SO1861 and HSP27BNA to the same targeting antibody, according to the invention, efficiently induces SO1861-mediated enhanced cytoplasmic delivery of a therapeutic antisense oligo nucleotide in solid tumors of tumor bearing mice, inducing tumortargeted gene silencing. 15 In another example, a trifunctional linker scaffold was designed and produced with 3 specific chemical end groups for conjugation with SO1861 on one arm and the HSP27BNA on the other arm to produce SO1861-L-trifunctional linker-L-HSP27BNA. Next, SO1861-L-trifunctional linker-L-HSP27BNA was conjugated with its third arm to cysteine residues (Cys) of the anti-EGFR antibody, cetuximab (cetuximab-Cys-(SO1861-L-trifunctional linker-L-HSP27BNA)3’7) and tested in a A431 xenograph ‘nude’ 20 mouse tumor model for EGFR-mediated tumor targeted gene silencing activity, according to the invention as illustrated in Figure 11-4. Dosings started at day 12 when tumors reached ~150mm3 in size and HSP27 mRNA expression was determined. For this, tumor samples were collected at 72h after the first dosing and analysed for HSP27 gene expression levels compared to cellular control mRNA expression levels (reference genes). This revealed that 1 dosing of 30 mg / kg cetuximab-Cys-(SO1861- 25 L-trifunctional linker-L-HSP27BNA)3’7 resulted in a 40% reduction in HSP27 gene expression in the tumors compared to single dosing of 25 mg / kg cetuximab-(Cys-L-SO1861)3’8 or 25 mg / kg cetuximab-(Lys-L-HSP27BNA)4 mono therapies (Figure 3-4). Compared to the vehicle control tumors, a reduction of 25% HSP27 gene expression was observed in tumor bearing mice treated with 1 dosing of cetuximab-Cys-(SO1861-L-trifunctional linker-L-HSP27BNA)3’7. This shows and enables that cetuximab-Cys- 30 (SO1861-L-trifunctional linker-L-HSP27BNA)3’7 efficiently induces SO1861-mediated enhanced cytoplasmic delivery of a therapeutic antisense oligo nucleotide in a solid tumor of tumor bearing mice, inducing targeted gene silencing, in vivo. Example 10 35 In another example according to the invention, SO1861 (labile) and the protein toxin, dianthin (labile or stable) were conjugated to the HER2 targeting antibody, trastuzumab. Trastuzumab-(Cys-L-SO1861 )38(Lys-L-dianthin)17 ortrastuzumab-(Cys-L-SO1861)3’8(Lys-S-dianthin)1’7, were produced and tested for enhanced cell killing in SK-BR-3 (HER2++) and MDA-MB-468 (HER2 ) cells as illustrated in Figure 9-4. Both, trastuzumab-(Cys-L-SO1861)3’8(Lys-L-dianthin)1’7 (IC50= 0,8 nM) and trastuzumab- 40 (Cys-L-SO1861)3i8(Lys-S-dianthin)1’7 (IC50= 0,8 nM) efficiently induces cell killing of SK-BR-3 cells 2026226426   02 Sep 2026 (HER2++) (Figure 4-4A). This was not observed in SK-BR-3 cells treated with trastuzumab, trastuzumab-(Lys-L-dianthin)1’7, trastuzumab-(Lys-S-dianthin)1’7 or trastuzumab-(L-SO1861)3’8 alone (Figure 4-4A). In MDA-MB-468 cells (HER2 ) no cell killing activity can be observed for any of the conjugates, according to the invention (Figure 4-4B). This shows that conjugation of SO1861 to an HER targeting antibody-5 protein toxin conjugate, efficiently induces SO1861-mediated enhanced cytoplasmic delivery of the protein toxin in the target cell resulting in target cell death. In another example according to the invention, SO1861 (labile) and the protein toxin, dianthin (labile or stable) were conjugated to the EGFR targeting antibody, cetuximab. Cetuximab-(Cys-L-SO1861)3’9(Lys-L-dianthin)2 or cetuximab-(Cys-L-SO1861)3’9(Lys-S-dianthin)2, was tested for enhanced cell killing in 0   A431 cells (EGFR++) and A2058 cells (EGFR) as illustrated in Figure 9-4. Both, cetuximab-(Cys-L- SO1861)3'9(Lys-L-dianthin)2 (IC50= 0,3 nM) and cetuximab-(Cys-L-SO1861)3'8(Lys-S-dianthin)1'7(IC50= 0,3 nM) showed enhanced cell killing in A431 cells (EGFR++) compared to cetuximab-(Lys-L-dianthin)1’6 (IC50= 2pM), cetuximab-(Lys-S-dianthin)1’6 (IC5= 2pM) alone (Figure 4-4C). In A2058 cells (EGFR ) the combination according to the invention did not show any cell killing activity (IC50> 200nM; Figure 4-4D). 15 This shows that conjugation of SO1861 to an EGFR targeting antibody-protein toxin conjugate, efficiently enhances SO1861-mediated cytoplasmic delivery of the protein toxin in the target cell resulting in enhanced target cell death. Example 11 20 In another example according to the invention, SO1861 (labile) and the HSP27BNA oligo (labile) were conjugated to the EGFR targeting antibody, cetuximab. Cetuximab-(Cys-L-SO1861)3’8(Lys-L-HSP27BNA)38 was tested for enhanced HSP27 gene silencing in A431 cells (EGFR++) and A2058 (EGFR) cells, according to the invention as illustrated in Figure 10-4. Cetuximab-(Cys-L-SO1861)3,8(Lys-L-HSP27BNA)3’8 efficiently induces HSP27 gene silencing in A431 cells (IC50= 3nM) 25 compared to cetuximab, cetuximab-(Lys-L-HSP27BNA)3’9 or cetuximab-(Cys-L-SO1861)3’8 alone (Figure 5-4A). In A2058 cells (EGFR ) no gene silencing activity can be observed with cetuximab-(Cys-L-SO1861)3,8(Lys-L-HSP27BNA)3’8 (IC50> 100nM; Figure 5-4B). This shows and enables that conjugation of SO1861 and HSP27BNA to the same targeting antibody, according to the invention, efficiently induces SO1861-mediated enhanced cytoplasmic delivery of a therapeutic antisense oligo 30 nucleotide in the target cells, inducing targeted gene silencing. In another example according to the invention, SO1861 (labile) and the HSP27BNA oligo (labile) were conjugated to the HER2 targeting antibody, trastuzumab. Trastuzumab-(Cys-L-SO1861)3’8(Lys-L-HSP27BNA)3’5 was tested for enhanced HSP27 gene silencing in SK-BR-3 cells (HER2++) cells, according to the invention as illustrated in Figure 10-4. Trastuzumab-(Cys-L-SO1861)3’8(Lys-L-35 HSP27BNA)35 efficiently induces HSP27 gene silencing in SK-BR-3 cells (IC50= 9 nM) compared to trastuzumab-(Lys-L-HSP27BNA)4’4 alone (Figure 6-4). This shows and enables that conjugation of SO1861 and HSP27BNA to an HER2 targeting antibody, according to the invention, efficiently induces SO1861-mediated enhanced cytoplasmic delivery of a therapeutic antisense oligo nucleotide in the target cells, inducing targeted gene silencing. 2026226426   02 Sep 2026 In another example, cetuximab-Cys-(SO1861-L-trifunctional linker-L-HSP27BNA)3’7 was tested for enhanced HSP27 gene silencing in A431 (EGFR++) and A2058 (EGFR) cells according to the invention as illustrated in Figure 11-4. Cetuximab-Cys-(SO1861-L-trifunctional linker-L-HSP27BNA)3’7 efficiently induces HSP27 gene silencing in A431 cells (IC50= 2nM) compared to Cetuximab-(Lys-L-HSP27BNA)4 5 or Cetuximab-(Cys-L-SO1861)3’7 alone (Figure 7-4A). In A2058 cells (EGFR) gene silencing activity was only observed at high (> 80nM) concentrations of Cetuximab-Cys-(SO1861-L-trifunctional linker-L-HSP27BNA)3’7 (IC50=1 OOnM; Figure 7-4B). This shows and enables that in high EGFR expressing cells cetuximab-Cys-(SO1861-L-trifunctional linker-L-HSP27BNA)3’7 efficiently induces SO1861-mediated enhanced cytoplasmic delivery of a therapeutic antisense oligo nucleotide in the target cells, inducing 0 targeted gene silencing. Example 12 Figure 8-4A-D displays the relative cell viability when trastuzumab (Figure 8-4A), cetuximab (Figure 84B) orT-DM1 (Figure 8-4C), unconjugated protein toxins, saporin, dianthin and saporin conjugated to a 15 (non-cell binding) IgG antibody (Figure 8-4D) are administered to various cancer cell lines SK-BR-3, JIMT-1, MDA-MB-468, A431, CaSki, HeLa, A2058. Trastuzumab and cetuximab do not or hardly influence cell viability when exposed to most of the cell lines, with some effect on cell growth inhibition via blocking the function of the HER2 growth factor receptor when trastuzumab is exposed to SK-BR-3 cells at relatively high dose and with some 20 effect on cell growth inhibition via blocking the function of the EGFR growth factor receptor when cetuximab is exposed to MDA-MB-468 cells at relatively high dose. TDM-1, or ado-trastuzumab emtansine, is a targeted therapy approved by the U.S. Food and Drug Administration to treat: HER2-positive metastatic breast cancer that has previously been treated with Herceptin (chemical name: trastuzumab) and taxane chemotherapy; early-stage HER2-positive 25 breast cancer after surgery if residual disease was found after neoadjuvant (before surgery) treatment with Herceptin and taxane chemotherapy. The TDM-1 is a combination of Herceptin (Trastuzumab) and the chemotherapy medicine emtansine. Figure 8-4C shows that the TDM-1 results in decreased cell viability for all cell lines tested at >1000 pM concentrations The free toxins saporin and dianthin and the toxin saporin coupled to a control IgG with no 30 affinity for any of the cell surface molecules on the cell lines tested, do not or hardly have any influence on cell viability over a wide range of concentrations toxin tested, up to 100.000 pM (Figure 8-4D). Example 13 (Example 1 invention 5) The 1 target 2-components system (1T2C) is the combination treatment of mAb1-protein toxin and 35   mAb1-SO1861, as illustrated in Figure 13-5. SO1861-EMCH was conjugated via cysteine residues (Cys) and HSP27BNA oligo was conjugated via lysine residues to cetuximab (monoclonal antibody recognizing and binding 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 administration, (i.p.)) and cetuximab-(Lys-L-HSP27BNA)4 (intravenous 40 administration, (i.v.)) was tested in a A431 xenograph ‘mouse tumor model for EGFR tumor targeted 2026226426   02 Sep 2026 gene silencing activity. Dosings started at day 12 when tumors reached ~150mm3 in size and tumor samples were collected at 72h after the first dosing and analysed for HSP27 gene expression compared to control gene mRNA expression levels (reference genes). This revealed that 1 dosing of 50 mg / kg cetuximab-(Cys-L-SO1861)4+ 25 mg / kg cetuximab-(Lys-L-HSP27BNA)4 resulted in a 50% reduction in 5 HSP27 gene expression in the A431 tumors compared to single dosing of cetuximab-(Cys-L-SO1861)4 or cetuximab-(Lys-L-HSP27BNA)4 mono therapies (Figure 1-5). Compared to the vehicle control tumors, a reduction of 40% HSP27 gene silencing was observed. This shows and enables that the combination of cetuximab-conjugated SO1861 + cetuximab-conjugated HSP27BNA oligo, according to the 1T2C invention, induces efficient targeted delivery of a therapeutic antisense oligo nucleotide in the cytoplasm 0 of solid tumor cells, thereby inducing tumor targeted gene silencing, in vivo. Next, SO1861-EMCH was conjugated via cysteine residues (Cys) to trastuzumab (monoclonal antibody recognizing and binding human HER2), with a DAR 4 resulting in the production of trastuzumab-(Cys-L-SO1861)4. The combination of trastuzumab-(Cys-L-SO1861)4 and trastuzumab-saporin (trastuzumab protein toxin conjugate) was tested in a mouse tumor model (patient derived xenograph tumor model, 15 PDX) with high HER2 expression levels and resistant for trastuzumab mono therapy. The combination, according to the 1T2C invention of 40 mg / kg trastuzumab-(Cys-L-SO1861)4 (intraperitoneal administration, (i.p.)) + 0.03 (Day1, 8) / 0.02 (Day 15, 22, 30, 36,43) mg / kg trastuzumab-saporin (intravenous administration, (i.v.)) revealed strong tumor growth inhibition compared to the vehicle control and the 40 mg / kg trastuzumab-(Cys-L-SO1861)4 or 0.03 / 0.02 mg / kg trastuzumab-saporin mono 20 therapies (Figure 2-5). Besides, in tumor bearing mice that were treated with a lower dosing combination (40 mg / kg trastuzumab-(Cys-L-SO1861)4+ 0.01 mg / kg trastuzumab-saporin) no tumor growth inhibiting activity was observed (Figure 2-5). This shows and enables that the 1T2C combination of trastuzumab conjugated SO1861 + trastuzumab conjugated protein toxin induces efficient targeted delivery of a therapeutic protein toxin in the cytoplasm of solid tumor cells, thereby inducing tumor cell death and 25 tumor growth inhibition, in vivo. Example 14 The 1 target 2-components system (1T2C) is the combination treatment of mAb1-SO1861 and mAb1-protein toxin (Figure 13-5) 30           SO1861-EMCH was conjugated via cysteine residues (Cys) to cetuximab (monoclonal antibody recognizing and binding human EGFR), with a DAR 3,7 (cetuximab-(Cys-L-SO1861)3’7). Cetuximab-(Cys-L-SO1861)3’7 was titrated on a fixed concentration of 10 pM cetuximab-saporin (cetuximab, conjugated to the protein toxin, saporin) and targeted protein toxin mediated cell killing on EGFR expressing cells (A431, EGFR++; CaSKi, EGFR+) was determined. This revealed strong cell killing at 35 low concentrations of cetuximab-(Cys-L-SO1861)3 7 (A431: IC50= 0,6 nM and Caski IC50= 1 nM; Figure 5A, 3-5B) whereas cetuximab, cetuximab-(Cys-L-SO1861)3’7 or cetuximab + 10 pM cetuximab-saporin could not induce any cell killing activity in EGFR expressing cells. This shows that cetuximab conjugated SO1861 efficiently enhances endosomal escape of the cetuximab conjugated protein toxin (at noneffective concentrations), thereby inducing cell killing of EGFR expressing cells. The cell killing activity 40 in A431 is more effective compared to CaSki correlating with EGFR expression levels in these cell lines. 2026226426   02 Sep 2026 EGFR receptor binding competition between both conjugates within the 1T2C is also observed when cetuximab-(Cys-L-SO1861)3’7 concentrations increase, cell killing activity declines due to outcompeting receptor binding and internalization of cetuximab-saporin (Figure 3-5A, 3-5B). Next, cetuximab-saporin was titrated on a fixed concentration of 75 nM cetuximab-(Cys-L-5    SO1861)3’7 and targeted protein toxin mediated cell killing on EGFR expressing cells was determined. This revealed that 75nM cetuximab-(Cys-L-SO1861)3’7 in combination with low concentrations cetuximab-saporin induced already efficient cell killing in EGFR expressing cells (A431: IC50= 0.4 pM; and CaSKi: (IC50= 2 pM; Figure 3-5C and 3-5D), whereas cetuximab-saporin alone or cetuximabsaporin + 75 nM cetuximab showed cell killing only at high concentrations cetuximab-saporin (IC50= 40 0 pM, IC50= 1000 pM, resp.) in both cell lines (Figure 3-5C, 3-5D). All this shows that relatively low concentrations of cetuximab-saporin can be effective and induce cell killing only in combination with low cetuximab-SO1861 concentrations in high EGFR expressing cells. The receptor competition between both conjugates within the 1T2C system is also observed in the cetuximab-toxin titration treatments when the cell killing activity of cetuximab-saporin with and without 75 nM cetuximab was compared 15 (Figure 3-5C, 3-5D). Next, cetuximab-(Cys-L-SO1861)3’7 was titrated on a fixed concentration of 10 pM cetuximabsaporin and targeted protein toxin mediated cell killing on low EGFR expressing cells or cells without EGFR expression (HeLa, EGFR+ / _; A2058, EGFR ) was determined. Cells with low (HeLa) or no (A2058) EGFR expression were not sensitive at all for any combination of cetuximab-(Cys-L-SO1861)3’7+ 10 pM 20 cetuximab-saporin (HeLa: IC50> 1000 nM; A2058: IC50> 1000 nM; Figure 4-5A, 4-5B). This shows that in the absence of sufficient EGFR receptor expression, effective intracellular delivered SO1861 concentrations are not optimal (threshold) to induce endosomal protein toxin escape and toxin-mediated cell killing. Next, cetuximab-saporin was titrated on a fixed concentration of 75 nM cetuximab-(Cys-L-SO1861)3’7 and targeted protein toxin mediated cell killing on low (HeLa) or no (A2058) EGFR 25 expressing cells was determined. Low EGFR expressing cells (HeLa) showed cell killing only at high cetuximab-saporin concentrations in combination with 75 nM cetuximab-(Cys-L-SO1861)3’7 (HeLa: IC50= 60 pM), Figure 4-5C), whereas A2058 cells (EGFR) are not sensitive at any of the tested concentrations (A2058: IC50> 10.000 pM; Figure 4-5D). All this shows that cells with low or no EGFR receptor expression are not susceptible for the combination of cetuximab-(Cys-L-SO1861)3’7 + 30 cetuximab-saporin, due to a lack of sufficient EGFR receptor that facilitates the antibody-mediated delivery of sufficient SO1861 within the endolysosomal compartments, to facilitate the escape of the protein toxin. Next, SO1861-EMCH was conjugated via cysteine residues (Cys) to trastuzumab (monoclonal antibody recognizing and binding human HER2, with a DAR 4, (trastuzumab-(Cys-L-SO1861)4). 35 Trastuzumab-(Cys-L-SO1861)4 was titrated on a fixed concentration of 50 pM trastuzumab-saporin (trastuzumab, conjugated to the protein toxin, saporin) and targeted protein toxin mediated cell killing on HER2 expressing cells (SK-BR-3, HER2++) was determined. This revealed strong cell killing at low concentrations of trastuzumab-(Cys-L-SO1861)4 (SK-BR-3: IC50= 0,8 nM; Figure 5-5A) whereas equivalent concentrations trastuzumab, trastuzumab-(Cys-L-SO1861)4 or trastuzumab + 50 pM 40 trastuzumab-saporin could not induce any cell killing activity in HER2 expressing cells. This shows that 2026226426   02 Sep 2026 trastuzumab conjugated SO1861 efficiently enhances endosomal escape of the trastuzumab conjugated protein toxin (at non-effective concentrations), thereby inducing cell killing of HER2 expressing cells. The receptor competition between both conjugates within the 1T2C is also observed when trastuzumab-(Cys-L-SO1861)4 concentrations increase, cell killing activity declines due to 5 outcompeting receptor binding and internalization of trastuzumab-saporin (Figure 5-5A). Next, trastuzumab-saporin was titrated on a fixed concentration of 2,5 nM trastuzumab-(Cys-L-SO1861)4, according to the invention and targeted protein toxin mediated cell killing on HER2 expressing cells was determined. This revealed that 2,5 nM trastuzumab-(Cys-L-SO1861)4 in combination with low concentrations trastuzumab-saporin induced already efficient cell killing in HER2 0 expressing cells (SK-BR-3: IC50= 2 pM; Figure 5-5B), whereas trastuzumab-saporin alone or trastuzumab-saporin + 2,5 nM trastuzumab showed cell killing only at high concentrations trastuzumabsaporin (Figure 5-5B). All this shows that relatively low concentrations of trastuzumab-saporin can be effective and induce cell killing only in combination with low trastuzumab-(Cys-L-SO1861)4 concentrations in high HER2 expressing cells. 15           Next, trastuzumab-(Cys-L-SO1861)4 was titrated on a fixed concentration of 50 pM trastuzumab-saporin, according to the invention and targeted protein toxin mediated cell killing on low HER2 expressing cells (A431 HER2+ / ) or cells without HER2 expression (JIMT-1: HER2+; MDA-MB-468: HER2 ) was determined. Cells with low or no HER2 expression were not sensitive at all for any combination of trastuzumab-(Cys-L-SO1861)4+ 50 pM trastuzumab-saporin (JIMT-1: IC50> 1000 nM; 20   MDA-MB-468: IC50> 1000 nM; Figure 6-5A, 6-5B). This shows that in the absence of sufficient HER2 receptor expression, effective intracellular delivered SO1861 concentrations are not optimal (threshold) to induce endosomal protein toxin escape and toxin-mediated cell killing. Next, trastuzumab-saporin was titrated on a fixed concentration of 2,5 nM trastuzumab-(Cys-L-SO1861)4 and targeted protein toxin mediated cell killing on low or no HER2 expressing cells was determined. Low HER2 expressing cells 25 (JIMT-1) showed cell killing only at high trastuzumab-saporin concentrations in combination with 2,5 nM trastuzumab-(Cys-L-SO1861)4 (JIMT-1: IC50> 10.000 pM; Figure 6-5C), whereas MDA-MB-468 cells (HER2 ) are not sensitive at any of the tested concentrations (MDA-MB-468: IC50> 10.000 pM; Figure 6-5D). All this shows that cells with low or no HER2 receptor expression are not susceptible for the 30   combination of trastuzumab-(Cys-L-SO1861)3’7+ trastuzumab-saporin, due to a lack of sufficient HER2 receptor that facilitates the antibody-mediated delivery of sufficient SO1861 within the endolysosomal compartments, to facilitate the escape of the protein toxin. Example 15 35 In order to show that the activity of the 1T2C system is driven by the acidification of the endolysosomal compartments, the 1T2C system , according to the invention was tested in combination with an endosomal acidification inhibitor, chloroquine. Trastuzumab-saporin was titrated in combination with 5 nM trastuzumab-(Cys-L-SO1861)4in combination with or without chloroquine. Trastuzumab-saporin + 5 nM trastuzumab-(Cys-L-SO1861)4 showed a strong cell killing activity in high HER2 expressing cells 40   (SK-BR-3, HER2++; IC50= 0.2 pM;), however, trastuzumab-saporin + 5 nM trastuzumab-(Cys-L- 2026226426   02 Sep 2026 SO1861)4+ 0.5 pM chloroquine resulted in strong inhibition of the 1T2C cell killing activity in SK-BR-3 (HER2++) cells (IC50= 40pM). This shows that activity of the antibody conjugated SO1861 is reduced / blocked when acidification of endoslysomes is prohibited (Figure 7-5A). Same results were derived with the 1T2C combination, according to the invention of cetuximab-saporin + 5 nM cetuximab-5   (Cys-L-SO1861)3’8 (IC50= 1 pM) compared with cetuximab-saporin + 5 nM cetuximab-(Cys-L- SO1861)3i8+ 0.5 pM chloroquine (IC50= 200 pM) in EGFR expressing cells (A431, EGFR++; Figure 75B). Example 16 0 The 1 target 2-components system (1T2C) can also be the combination treatment of mAb1-SO1861 and mAb1 -antisense BNA oligo nucleotide as illustrated in Figure 14-5. For this we used an antisense BNA oligonucleotide against the mRNA of a cancer specific target gene (upregulated in cancer cells), heat shock protein 27 (HSP27). Upon release into the cytoplasm the antisense BNA recognizes and binds the mRNA encoding for HSP27, targeting the mRNA for destruction thereby depleting the HSP27 mRNA 15 expression within the cancer cell. HSP27BNA was conjugated to cetuximab with a DAR4 (Cetuximab-(Lys-L-HSP27BNA)4) and tested in combination with cetuximab-(Cys-L-SO1861)3’8for enhanced HSP27 gene silencing activity in EGFR expressing cells (A431, EGFR++) and non-expressing cells (A2058, EGFR), according to the invention (Figure 14-5). Cetuximab-(Cys-L-SO1861)3’8+ 100 nM cetuximab-(Lys-L-HSP27BNA)4 showed strong HSP27 gene silencing in EGFR expressing cells (A431: IC50= nM, 20 Figure 8-5A), whereas cetuximab-(Cys-L-SO1861)3 8 alone did not show any gene silencing activity. In A2058 cells (EGFR) no gene silencing activity was observed in the 1T2C combination (Figure 8-5B). Next, cetuximab-(Lys-L-HSP27BNA)4 + 76.9 nM Cetuximab-(Cys-L-SO1861)3 8 show strong HSP27 gene silencing activity in EGFR expressing cells (A431: IC50= 4 nM, Figure 8-5C), whereas cetuximab-(Lys-L-HSP27BNA)4 or cetuximab-(Cys-L-SO1861)3’8 or the combination of Cetuximab-(Lys-L-25 HSP27BNA)4+ 77 nM cetuximab did not reveal any significant gene silencing activity (IC50> 100nM). When the experiment was performed in EGFR non-expressing cells (A2058) no gene silencing activity was observed in the 1T2C combination (IC50>100 nM; Figure 8-5D). All this shows that the 1T2C system efficiently delivers an antisense BNA oligo to the cytoplasm of high EGFR expressing cells, thereby inducing mRNA degradation of the BNA target mRNA resulting in target gene silencing. 30 Example 17 The 1 target 2-components system (1T2C) can also be the combination treatment of mAb1-(scaffold(-SO1861)n)n and mAbl-protein toxin as illustrated in Figure 15-5. Dendron(-L-SO1861)4 was conjugated to cetuximab via cysteine residues (Cys) conjugation with a DAR3,9 and cetuximab-Cys-(dendron(-L-35    SO1861)4)39 was tested for enhanced cell killing activity in combination with an anti-EGFR antibody protein toxin conjugate (cetuximab-saporin) in EGFR expressing cells (MDA-MB-468). Cetuximab-Cys-(dendron(-L-SO1861)4)319 + 10 pM cetuximab-saporin efficiently induces toxin-mediated cell killing in high EGFR expressing cells (IC50= 0.4 nM; Figure 9-5A), whereas this was not induced by cetuximab-Cys-(dendron(-L-SO1861)4)319 or cetuximab + 10 pM cetuximab-saporin or cetuximab (Figure 9-5A). 40 This shows that according to the 1T2C invention, cetuximab conjugated dendron(-L-SO1861)4 efficiently 2026226426   02 Sep 2026 enhances endosomal escape of the cetuximab conjugated protein toxin (at non-effective concentrations), thereby inducing cell killing of high HER2 expressing cells.Similar 1T2C experiments were performed in cells that express low levels of EGFR (HeLa, EGFR+ / ) and this revealed no cell killing activity when the 1T2C combination, according otthe invention was used (IC50> 100pM; Figure 9-5B) 5 indicating that in the absence of sufficient EGFR receptor expression, effective intracellular SO1861 concentrations are not optimal (threshold) to induce cytoplasmic delivery of the protein toxin that results in toxin-mediated cell killing. Next, dendron(-L-SO1861)4 was conjugated to the anti-HER2 antibody, trastuzumab via cysteine conjugation (Cys) with a DAR4, trastuzumab-Cys-(dendron(-L-SO1861)4)4 and tested for enhanced cell 0 killing activity in combination with an anti-HER2 antibody-protein toxin conjugate (trastuzumab-saporin) in HER2 expressing cells (SK-BR-3, HER2++). Trastuzumab-Cys-(dendron(-L-SO1861)4)4 + 50 pM trastuzumab-saporin efficiently induces toxin-mediated cell killing (IC50= 2 nM, Figure 9-5C), whereas this was not induced by trastuzumab-Cys-(dendron(-L-SO1861)4)4 ortrastuzumab + 50nM trastuzumabsaporin or trastuzumab (Figure 9-5C). This shows that trastuzumab conjugated dendron(-L-SO1861)4 15 efficiently enhances endosomal escape of the trastuzumab conjugated protein toxin (at non-effective concentrations), thereby inducing cell killing of high HER2 expressing cells. Similar experiments in cells that express low levels of HER2 (JIMT-1, HER2+ / ) revealed no activity of Trastuzumab-Cys-(dendron(-L-SO1861)4)4 + 50 pM trastuzumab-saporin (IC50> 200 nM; Figure 9-5D) indicating that in the absence of sufficient HER2 receptor expression, effective intracellular SO1861 concentrations are not optimal 20 (threshold) to induce endosomal protein toxin escape and toxin-mediated cell killing. Example 18 The clinical approved ADC, trastuzuzmab-emtansine (T-DM1) is a conjugate of the anti-Her2 antibody, trastuzumab and the small molecule toxin emtansine (DAR3.5). T-DM1 was titrated in 25 combination with trastuzumab-(Cys-L-SO1861)4 and compared with the antibody protein toxin conjugate, trastuzumab-saporin + Trastuzumab-(Cys-L-SO1861)4, according to the invention. Whereas trastuzumab-saporin + 2.5 nM trastuzumab-(Cys-L-SO1861)4 showed enhanced activity compared to Trastuzumab-saporin + 2.5 nM trastuzumab or trastuzumab-saporin alone (IC50= 2 pM, Figure 10-5), T-DM1 + 25.6 nM trastuzumab-(Cys-L-SO1861)4 showed no enhanced cell killing activity (IC50> 100 30 pM; Figure 10-5). This shows that the 1T2C system, according to the invention, cannot enhance the delivery of an antibody small molecule conjugate, since small molecules can already passively cross (endolysosomal) membranes. Example 19 35 Figure 11-5A-D displays the relative cell viability when trastuzumab (Figure 11-5A), cetuximab (Figure 11-5B) orT-DM1 (Figure 11-5C), unconjugated protein toxins, saporin, dianthin and saporin conjugated to a (non-cell binding) IgG antibody (Figure 11-5D) are administrated to various cancer cell lines SK-BR-3, JIMT-1, MDA-MB-468, A431, CaSki, HeLa, A2058. Trastuzumab and cetuximab do not or hardly influence cell viability when exposed to most of 40 the cell lines, with some effect on cell growth inhibition via blocking the function of the HER2 growth 2026226426   02 Sep 2026 factor receptor when trastuzumab is exposed to SK-BR-3 cells at relatively high dose and with some effect on cell growth inhibition via blocking the function of the EGFR growth factor receptor when cetuximab is exposed to MDA-MB-468 cells at relatively high dose. TDM-1, or ado-trastuzumab emtansine, is a targeted therapy approved by the U.S. Food and 5 Drug Administration to treat: HER2-positive metastatic breast cancer that has previously been treated with Herceptin (chemical name: trastuzumab) and taxane chemotherapy; early-stage HER2-positive breast cancer after surgery if residual disease was found after neoadjuvant (before surgery) treatment with Herceptin and taxane chemotherapy. The TDM-1 is a combination of Herceptin (Trastuzumab) and the chemotherapy medicine emtansine. Figure 11-5C shows that the TDM-1 results in decreased cell 0 viability for all cell lines tested at >1000 pM concentrations The free toxins saporin and dianthin and the toxin saporin coupled to a control IgG with no affinity for any of the cell surface molecules on the cell lines tested, do not or hardly have any influence on cell viability over a wide range of concentrations toxin tested, up to 100.000 pM (Figure 11-5D). 15 Example 20 The 1 target 2-components system (1T2C) can also be the combination treatment of mAb1-QSmix (mixture of saponins from Quillaja Saponaria) and mAb1-protein toxin. QSmix-EMCH was conjugated via cysteine residues (Cys) to cetuximab (monoclonal antibody recognizing and binding human EGFR), with a DAR 4.1 (cetuximab-(Cys-L-QSmix)4’1). Cetuximab-(Cys-20 L-QSmix)4’1 was titrated on a fixed concentration of 10 pM cetuximab-saporin or 10pM cetuximab-dianthin and targeted protein toxin mediated cell killing on A431 (EGFR++), CaSKi (EGFR+) and A2058 (EGFR) cells was determined. This revealed strong cell killing at low concentrations of cetuximab-(Cys-L-QSmix)41 + 10 pM cetuximab-saporin or 10pM cetuximab-dianthin in A431 (EGFR++) and CaSKi (EGFR+) cells (A431: IC50= 3 nM, Figure 12-5A; CaSKi: IC50= 1nM, Figure 12-5B) whereas all control 25 treatments could not induce any cell killing in EGFR expressing cells. In cells that do not express EGFR (A2058; EGFR) no HSP27 gene silencing is observed with the combination, according to the invention (IC50> 1000 nM; Figure 12-5C). This shows that cetuximab conjugated QS21mix efficiently enhances endosomal escape of the cetuximab conjugated protein toxin (at non-effective concentrations), thereby inducing cell killing only in EGFR expressing cells. 30 Example 21 2 target 2-component system (in vivo) The 2 target 2-components system (2T2C) is the combination treatment of mAb1-SO1861 and mAb2-protein toxin, (Figure 15-6; 16-6; 17-6). SO1861-EMCH was conjugated via cysteine residues (Cys) to cetuximab (monoclonal antibody recognizing and binding human EGFR), with a DAR 4 resulting in the 35 production of: cetuximab-(Cys-L-SO1861)4. The combination of cetuximab-(Cys-L-SO1861)4 and trastuzumab-saporin or CD71mab-saporin was tested in a A431 (EGFR++ / HER2+ / 7CD71+) xenograph ‘nude’ mouse tumor model for EGFR tumor targeted cell killing as illustrated in Figure 1 -6 and Figure 26. Dose escalation was performed to determine the therapeutic efficacy (Day 9: 0.3 mg / kg trastuzumabsaporin or 0.1 mg / kg CD71mab-saporin + 5 mg / kg cetuximab-(Cys-L-SO1861)4; Day 14, 18: 0.1 mg / kg 40 trastuzumab-saporin or 0.05 mg / kg CD71mab-saporin + 5 mg / kg cetuximab-(Cys-L-SO1861)4; Day 21: 2026226426   02 Sep 2026 0.05 mg / kg trastuzumab-saporin or 0.05 mg / kg CD71 mab-saporin + 15 mg / kg cetuximab-(Cys-L-SO1861)4; Day 28: 0.02 mg / kg trastuzumab-saporin or 0.02 mg / kg CD71 mab-saporin + 15 mg / kg cetuximab-(Cys-L-SO1861)4 trastuzumab-saporin / cetuximab-SO1861. Controls were on the same dosing scheme respectively, only cetuximab (i.v.) was given 25 mg / kg every treatment day). At day 32 5 (dashed line), 35 and 39 we started the combination, according to the 2T2C invention of 25 mg / kg cetuximab-(Cys-L-SO1861)4 (intraperitoneal injection (i.p.) + 0.02 mg / kg trastuzumab-saporin or 0.02 CD71mab-saporin (intravenous administration, (i.v.)) and this revealed strong tumor regression for both 2T2C combination groups compared to the vehicle control, 25 mg / kg cetuximab-(Cys-L-SO1861)4 or 0.02 mg / kg trastuzumab-saporin / CD71 mab-saporin mono therapies (Figure 1-6, 2-6). The 2T2C system 0 even outcompetes cetuximab, the clinically used monoclonal antibody against EGFR. Next we performed the same experiment but then we started with 25 mg / kg cetuximab-(Cys-L-SO1861)4 (intraperitoneal injection (i.p.) + 0.03 mg / kg trastuzumab-saporin or 0.03 CD71 mab-saporin (intravenous administration, (i.v.)) treatment with a dosing at day 9 and 14 and thereafter 1 dosing per week. The 2T2C system according to the invention showed tumor regression in all mice and even in 1 mice in both 15 2T2C groups, complete tumor eradication (tumor volume= 0 mm3) (Figure 2-6). Also here the controls showed a strong increased in tumor volume whereas the positive control for this A431 mice model, cetuximab showed only tumor growth inhibition, but no regression (Figure 2-6). This shows and enables the 2T2C system approach, according to the invention, of cetuximab conjugated SO1861 + trastuzumab conjugated protein toxin orCD71mab conjugated protein toxin inducing highly efficient targeted delivery 20 of a therapeutic protein toxin in the cytoplasm of solid tumors of tumor bearing mice, in vivo, thereby inducing even full tumor eradication in some mice and strong tumor regression in others even in large size tumors (2000 mm3). Example 22 2 target 2-component system (in vitro) 25 Results The 2 target 2-components system (2T2C) is the combination treatment of mAb1-SO1861 and mAb2-protein toxin, (see also Figure 1-6, 2-6, 15-6, 16-6, 17-6). SO1861-EMCH was conjugated via cysteine residues (Cys) to cetuximab (monoclonal antibody recognizing and binding human EGFR), with a DAR 30    3,7 (cetuximab-(Cys-L-SO1861)3’7). Cetuximab-(Cys-L-SO1861)3 7 was titrated on a fixed concentration of 50 pM trastuzumab-saporin (trastuzumab, conjugated to the protein toxin, saporin) and targeted protein toxin mediated cell killing on EGFR / HER2 expressing cells (A431, EGFR++ / HER2+ / _; CaSKi, EGFR+ / HER2+ / ) was determined as illustrated in Figure 3-6. This revealed strong cell killing at low concentrations of cetuximab-(Cys-L-SO1861)3’7 (A431: IC50= 3 nM and CaSKi IC50= 10 nM; Figure 335   6A, 3-6B) whereas equivalent concentrations cetuximab, cetuximab-(Cys-L-SO1861)3 7 or cetuximab + 50 pM trastuzumab -saporin could not induce any cell killing activity in EGFR / HER2 expressing cells. This shows that relatively low concentrations of cetuximab-SO1861 conjugate efficiently enhances endosomal escape of the trastuzumab conjugated protein toxin (at non-effective concentrations), thereby inducing efficient cell killing of high EGFR / low HER2 expressing cells. 2026226426   02 Sep 2026 Next, trastuzumab-saporin was titrated on a fixed concentration of 75 nM cetuximab-(Cys-L-SO1861)3’7 and targeted protein toxin mediated cell killing on EGFR / HER2 expressing cells was determined. This revealed that 75 nM cetuximab-(Cys-L-SO1861)3’7 in combination with low concentrations trastuzumabsaporin induced already efficient cell killing in EGFR / HER2 expressing cells (A431: IC50= 5 pM; and 5 CaSKi: IC50= 1 pM; Figure 3-6C and 3-6D), whereas trastuzumab-saporin alone or trastuzumab-saporin + 75 nM cetuximab did not show significant cell killing activity (IC50> 10.000 pM) in both cell lines (Figure 3-6C, 3-6D). All this shows that relatively low concentrations of trastuzumab-saporin can be effective and induce cell killing in combination with low cetuximab-SO1861 conjugate concentrations in high EGFR / low HER2 expressing cells. 0 Next, cetuximab-(Cys-L-SO1861)37 was titrated on a fixed concentration of 50 pM trastuzumab-saporin and targeted protein toxin-mediated cell killing on HeLa (EGFR+ / 7HER2+ / ) or A2058 (EGFR7HER2+ / ) was determined as illustrated in Figure 4-6, 15-6 - 17-6. Both HeLa (EGFR+ / 7HER2+ / ) and A2058 (EGFR7HER2+ / ) cells do not show cell killing at low concentrations of cetuximab-(Cys-L-SO1861)3’7 + 50 pM trastuzumab-saporin (HeLa: IC50= 400 nM; A2058: IC50> 400 nM; Figure 4-6A, 4-6B). This 15 shows that in the absence of sufficient receptor expression, effective intracellular delivered SO1861 concentrations are not reached (threshold) to induce endosomal escape and cytoplasmic delivery of the protein toxin. Next, trastuzumab-saporin was titrated on a fixed concentration of 75 nM cetuximab-(Cys-L-SO1861)3’7 and targeted protein toxin mediated cell killing on HeLa (EGFR+ / 7HER2+ / ) or A2058 (EGFR7HER2+ / ) was determined. Both HeLa (EGFR+ / 7HER2+ / ) and A2058 (EGFR7HER2+ / ) cells 20 showed no cell killing activity (HeLa: IC50> 10.000 pM; A2058: IC50> 10.000 pM; Figure 4-6C, 4-6D). All this shows that cells with low or no EGFR receptor expression are not susceptible for the combination of cetuximab-(Cys-L-SO1861)37 + trastuzumab-saporin, due to a lack of sufficient EGFR receptor that facilitates the antibody-mediated delivery of sufficient SO1861 (threshold) to ensure endosomal escape of the toxin within the cytoplasm of the cell. 25          Next, SO1861-EMCH was conjugated via cysteine residues (Cys) to trastuzumab (monoclonal antibody recognizing and binding human HER2), with a DAR 4 (trastuzumab-(Cys-L-SO1861)4). Trastuzumab-(Cys-L-SO1861)4 was titrated on a fixed concentration of 1.5 pM EGFdianthin (EGFR targeted ligand toxin fusion protein) and targeted protein toxin mediated cell killing on HER2 / EGFR expressing cells (SK-BR-3: HER2++ / EGFR+ / ) was determined. This revealed strong cell killing at low 30 concentrations of trastuzumab-(Cys-L-SO1861)4 + 1.5 pM EGFdianthin (SK-BR-3: IC50= 1 nM; Figure 5-6A) whereas equivalent concentrations trastuzumab, trastuzumab-(Cys-L-SO1861)4 or trastuzumab + 1.5 pM EGFdianthin could not induce any cell killing activity in HER2++ / EGFR+ / _ expressing cells. This shows that trastuzumab conjugated SO1861 efficiently enhances endosomal escape of the EGF fusion protein toxin (at non-effective concentrations), thereby inducing cell killing of high HER2 / low EGFR 35 expressing cells. Next, EGFdianthin was titrated on a fixed concentration of 2.5 nM trastuzumab-(Cys-L-SO1861)4 and targeted protein toxin mediated cell killing on SK-BR-3 (HER2++ / EGFR+ / ) expressing cells was determined. This revealed that 2.5 nM trastuzumab-(Cys-L-SO1861)4 in combination with low concentrations EGFdianthin induced already efficient cell killing in HER2 / EGFR expressing cells (SK-40   BR-3: IC50= 1 pM) (Figure 5-6B), whereas EGFdianthin alone or EGFdianthin + 2.5 nM trastuzumab 2026226426   02 Sep 2026 showed no cell killing activity (IC50>10.000 pM) (Figure 5-6B). All this shows that relatively low concentrations of EGFdianthin can be effective and induce cell killing only in combination with low trastuzumab-(Cys-L-SO1861)4 concentrations in high HER2Zlow EGFR expressing cells. Next, trastuzumab-(Cys-L-SO1861)4 was titrated on a fixed concentration of 1.5 pM EGFdianthin and 5 targeted protein toxin mediated cell killing on JIMT-1 (HER2+ / 7EGFR+ / ) or MDA-MB-468: HER2- ZEGFR++) was determined. Both cell lines were not sensitive for any combination of trastuzumab-(Cys-L-SO1861)4 + 1.5 pM EGFdianthin (JIMT-1: IC50> 1000 nM; MDA-MB-468: IC50> 1000 nM; Figure 6-6A, 6-6B). This shows that in the absence of sufficient HER2 receptor expression, effective intracellular delivered SO1861 concentrations are not reached (threshold) to induce endosomal escape and 0 cytoplasmic delivery of the protein toxin. Next, EGFdianthin was titrated on a fixed concentration of 2.5 nM trastuzumab-(Cys-L-SO1861)4 and targeted protein toxin mediated cell killing on JIMT-1 (HER2+ / 7EGFR+ / ) or MDA-MB-468 (HER2-ZEGFR++) was determined. Both cell lines showed cell killing at high EGFdianthin concentrations with or without 2,5 nM trastuzumab-(Cys-L-SO1861)4 (JIMT-1: IC50= 10.000 pM; MDA-MB-468: IC50= 200 pM 15 Figure 6-6C, 6-6D). All this shows that cells with low or no HER2 receptor expression are not susceptible for the combination of trastuzumab-(Cys-L-SO1861)3’7+ 1.5 pM EGFdianthin, due to a lack of sufficient HER2 receptorthat facilitates the antibody-mediated delivery of sufficient SO1861 (threshold) to ensure endosomal escape of the toxin within the cytoplasm of the cell. 20          Next, SO1861-EMCH was conjugated via cysteine residues (Cys) to trastuzumab (monoclonal antibody recognizing and binding human HER2), with a DAR 4, (trastuzumab-(Cys-L-SO1861)4). Trastuzumab-(Cys-L-SO1861)4 was titrated on a fixed concentration of 5 pM cetuximab-saporin (EGFR targeting antibody-protein toxin conjugate) and targeted protein toxin mediated cell killing on HER2ZEGFR expressing cells (SK-BR-3: HER2++ZEGFR+ / ) was determined as illustrated in Figure 15-6 25   - 17-6. This revealed strong cell killing at low concentrations of trastuzumab-(Cys-L-SO1861)4 + 5 pM cetuximab-saporin (SK-BR-3: IC50= 1 nM; Figure 7-6A) whereas equivalent concentrations trastuzumab, trastuzumab-(Cys-L-SO1861)4 ortrastuzumab + 5 pM cetuximab-saporin could not induce any cell killing activity in HER2++ZEGFR+ / _ expressing cells. This shows that trastuzumab conjugated SO1861 efficiently enhances endosomal escape of the cetuximab conjugated protein toxin (at non-30 effective concentrations), thereby inducing cell killing of HER2++ZEGFR+ / _ expressing cells. Next, cetuximab-saporin was titrated on a fixed concentration of 2.5 nM trastuzumab-(Cys-L-SO1861)4 and 75 nM trastuzumab-(Cys-L-SO1861)4 and targeted protein toxin mediated cell killing on HER2ZEGFR expressing cells (SK-BR-3: HER2++ZEGFR+ / ) was determined. This revealed that 2.5 nM trastuzumab-(Cys-L-SO1861)4 in combination with low concentrations cetuximab-saporin induced 35 already efficient cell killing in SK-BR-3 cells (SK-BR-3: IC50= 1 pM; Figure 7-6B), whereas cetuximabsaporin alone or cetuximab-saporin + 2.5 nM trastuzumab showed cell killing only at high concentrations trastuzumab-saporin (SK-BR-3: IC50> 4000 pM; Figure 7-6B). All this shows that relatively low concentrations of cetuximab-saporin can be effective and induce cell killing only in combination with low trastuzumab-(Cys-L-SO1861)4 concentrations in HER2++ZEGFR+ / _ expressing cells. 2026226426   02 Sep 2026 Next, trastuzumab-(Cys-L-SO1861)4 was titrated on a fixed concentration of 5 pM cetuximab-saporin and targeted protein toxin mediated cell killing on JIMT-1 (HER2+ / 7EGFR+ / ) and MDA-MB-468 (HER2-ZEGFR++) cells was determined. Both cell lines were not sensitive for the combination of trastuzumab-(Cys-L-SO1861)4 + 5 pM cetuximab-saporin (JIMT-1: IC50> 1000 nM; MDA-MB-468: IC50> 1000 nM; 5 Figure 8-6A, 8-6B). This shows that in the absence of sufficient HER2 receptor expression, effective intracellular delivered SO1861 concentrations are not reached (threshold) to induce endosomal escape and cytoplasmic delivery of the protein toxin. Next, cetuximab-saporin was titrated on a fixed concentration of 2.5 nM trastuzumab-(Cys-L-SO1861)4 and targeted protein toxin mediated cell killing on JIMT-1 (HER2+ / 7EGFR+ / ) and MDA-MB-468 (HER2-0 / EGFR++) cells was determined. Both cell lines showed cell killing at similar cetuximab-saporin concentrations with or without 2.5 nM trastuzumab-(Cys-L-SO1861)4 (JIMT-1: IC50= 80pM; MDA-MB-468: IC50= 100 pM; Figure 8-6C, 8-6D). All this shows that cells with low or no HER2 receptor expression are not susceptible for the combination of trastuzumab-(Cys-L-SO1861)4 + cetuximab-saporin, due to a lack of sufficient HER2 receptor that 15 facilitates the antibody-mediated delivery of sufficient SO1861 (threshold) to ensure endosomal escape of the toxin within the cytoplasm of the cell. Example 23 In orderto show that the activity ofthe conjugated SO1861 is driven by the acidification of the endosomal 20 compartments, the 2T2 components system, according to the invention was tested in combination with an endosomal acidification inhibitor, chloroquine. Trastuzumab-saporin + 77 nM cetuximab-(Cys-L-SO1861)3’9 or trastuzumab-dianthin + 77 nM cetuximab-(Cys-L-SO1861)3’9 showed strong cell killing activity in A431 (EGFR++ / HER2+ / ) cells, whereas this 2T2C activity, according to the invention, was inhibited when 800 nM chloroquine was co-administrated to both combinations (Figure 9-6A). Same 25 results were observed when CD71mab-saporin + 10.5 nM cetuximab-(Cys-L-SO1861)3’9 + 500 nM chloroquine was tested in A431 (EGFR++ / CD71+) and MDA-MB-468 (EGFR++ / CD71+) cells (Figure 96B, 9C) or when CD71mab-saporin + 5 nM trastuzumab-(Cys-L-SO1861)4 + 500 nM chloroquine was tested in SK-BR-3 (HER2++ / CD71+) cells (Figure 9-6D). This shows that the intracellular activity of conjugated SO1861 within the 2T2C system can be inhibited when acidification of endosomes is 30 blocked. Example 24 The 2 target 2-components system (2T2C) is also the combination treatment of mAb1-SO1861 and mAb2-antisense BNA oligo nucleotide, (Figure 16-6). Therefore, the 2T2C system was also tested in 35 combination with an antisense BNA oligonucleotide against the mRNA of a cancer specific target gene, heat shock protein 27 (HSP27). Upon release into the cytoplasm the antisense BNA recognizes and binds the mRNA encoding for HSP27, targeting the mRNA for destruction thereby depleting the HSP27 expression within the cancer cell. HSP27BNA was conjugated to trastuzumab with a DAR4.4 (trastuzumab-(Lys-L-HSP27BNA)4’4) and tested in combination with Cetuximab-(Cys-L-SO1861)3’9 for 40 enhanced HSP27 gene silencing activity in A431 (EGFR++ / HER2+ / ) cells and A2058 (EGFR7HER2+ / ) 2026226426   02 Sep 2026 cells as illustrated in Figure 16-6. Cetuximab-(Cys-L-SO1861)3 9 was titrated on a fixed concentration of 100 nM Trastuzumab-(Lys-L-HSP27BNA)4’4 and targeted HSP27BNA-mediated gene silencing activity was determined. Cetuximab-(Cys-L-SO1861)3’9 + 100 nM Trastuzumab-(Lys-L-HSP27BNA)4’4 show strong gene silencing activity in A431 cells (EGFR++ / HER2+ / ) (A431: IC50= 1 nM; Figure 10-6A), 5 compared to Cetuximab-(Cys-L-SO1861)3’9 alone. In A2058 cells (EGFR7HER2+ / ), the combination according to the invention showed no HSP27 gene silencing (A2058: IC50> 100nM; Figure 10-6B). This shows that cetuximab conjugated SO1861 efficiently enhances endosomal escape of the trastuzumab conjugated BNA oligo nucleotide (at non-effective concentrations), thereby inducing target gene silencing in EGFR++ / HER2+ / _ expressing cells. 0 Next, Trastuzumab-(Lys-L-HSP27BNA)4’4 was titrated on a fixed concentration of Cetuximab-(Cys-L-SO1861)3’9 and targeted HSP27BNA-mediated gene silencing activity was determined in A431 (EGFR++ / HER2+ / ) cells and A2058 (EGFR7HER2+ / ) cells as illustrated in Figure 16-6. Trastuzumab-(Lys-L-HSP27BNA)4’4 + 77 nM Cetuximab-(Cys-L-SO1861)3’9 show strong gene silencing activity in A431 cells (EGFR++ / HER2+ / ) (A431: IC50= 1 nM; Figure 10-60), whereas trastuzumab-(Lys-L- 15 HSP27BNA)4’4 alone or Cetuximab-(Cys-L-SO1861)3 9 alone ortrastuzumab-(Lys-L-HSP27BNA)4'4+ 77 nM cetuximab did not reveal any significant gene silencing activity (IC50>100nM). A2058 (EGFR-ZHER2+ / ) cells did not show any gene silencing activity in the combination according to the invention (A2058: IC50> 100nM; Figure 10-6D). All this shows that relatively low concentrations of trastuzumab-HSP27BNA can be effective and induce cell killing only in combination with low concentrations of 20 cetuximab-(-L-SO1861) concentrations in HER2++ / EGFR+ / _ expressing cells. Example 25 The 2 target 2-components system (2T2C) can also be the combination treatment of mAb1-(dendron(-SO1861)n)n and mAb2-protein toxin. Dendron(-L-SO1861)4 was conjugated to the anti-EGFR antibody, 25 cetuximab via cysteine residues (Cys) with a DAR3,9, (cetuximab-Cys-(dendron(-L-SO1861)4)3’9) and tested for enhanced cell killing activity in combination with an anti-CD71 antibody protein toxin conjugate (CD71mab-saporin) in MDA-MB-468 (EGFR++ / CD71+) expressing cells as illustrated in Figure 17-6. Cetuximab-Cys-(dendron(-L-SO1861)4)3’9 + 10 pM CD71mab-saporin efficiently induces toxin-mediated cell killing in MDA-MB-468 (EGFR++ / CD71+) expressing cells (IC50= 0.4 nM, Figure 11-6A), whereas 30 this could not be induced by Cetuximab-Cys-(dendron(-L-SO1861)4)3’9) or cetuximab + 10 pM CD71mab-saporin or cetuximab (Figure 11-6A). This shows that cetuximab conjugated dendron(-L-SO1861)4 efficiently enhances endosomal escape of the CD71mab-protein toxin (at non-effective concentrations), thereby inducing cell killing of EGFR++ / CD71+ expressing cells. Similar experiments were performed in HeLa cells (HER2+ / 7CD71+) cells and this revealed no activity of cetuximab-Cys-35   (dendron(-L-SO1861)4)319) + 10 pM CD71mab-saporin (IC50> 100 nM Figure 11-6B) indicating that in the absence of sufficient EGFR receptor expression, effective intracellular SO1861 concentrations are not reached (threshold) to induce endosomal escape and cytoplasmic delivery of the protein toxin. Next, dendron(-L-SO1861)4 was conjugated to the anti-HER2 antibody, trastuzumab via cysteine conjugation (Cys) with a DAR4, trastuzumab-Cys-(dendron(-L-SO1861)4)4 and tested for enhanced cell 40 killing activity in combination with an anti-CD71 antibody protein toxin conjugate (CD71mab-saporin) in 2026226426   02 Sep 2026 SK-BR-3 cells (HER2++ / CD71+) expressing cells. Trastuzumab-Cys-(dendron(-L-SO1861)4)4 + 10 pM CD71mab-saporin efficiently induces toxin-mediated cell killing in SK-BR3 cells (IC50= 3 nM, Figure 11-6C), whereas this was not induced by trastuzumab-Cys-(dendron(-L-SO1861)4)4 or trastuzumab (equivalent) + 10 pM CD71mab-saporin or trastuzumab (Figure 11-6C). This shows that trastuzumab 5 conjugated dendron(-L-SO1861 )4, according to the invention efficiently enhances endosomal escape of the CD71mab-protein toxin (at non-effective concentrations), thereby inducing cell killing of HER2++ / CD71+ expressing cells. Similar experiments were performed in JIMT-1 cells (HER2+ / 7CD71+) and this revealed no activity of trastuzumab-Cys-(dendron(-L-SO1861)4)4 + 10 pM CD71mab-saporin (IC50> 100 nM Figure 11-6C) indicating that in the absence of sufficient HER2 receptor expression, 0 effective intracellular SO1861 concentrations are not reached (threshold) to induce endosomal escape and cytoplasmic delivery of the protein toxin. Example 26 The clinical approved ADC, trastuzumab-emtansine (T-DM1) is a conjugate of the anti-Her2 antibody, 15 trastuzumab and the small molecule toxin emtansine (DAR3-4). T-DM1 was tested within the 2T2C system, according to the invention in combination with cetuximab-(Cys-L-SO1861)4. T-DM1 + 77 nM cetuximab-(Cys-L-SO1861)3’9 showed no enhanced cell killing activity compared to T-DM1 alone orT-DM1 + 77 nM cetuximab (IC50= 80.000 pM, Figure 12-6), whereas trastuzumab-saporin + 75 nM cetuximab-(Cys-L-SO1861)3’7, according to the invention showed enhanced cell killing activity compared 20 to trastuzumab-saporin + 75 nM cetuximab or trastuzumab-saporin alone (IC50=3 pM, Figure 12-6). All this shows that the 2T2C system does not enhance the delivery of antibody conjugated small molecules, that are already able to passively cross cellular (endosomal) membranes. Example 1-2 25 Various concentrations of trastuzumab-saporin (HER2 targeted protein-toxin conjugate; intravenous) were tested in combination with 1.5 mg / kg SO1861 (1 hour before antibody-toxin injection subcutaneous) for enhanced efficacy in a BT474 (HER2++) xenograph mouse model. Dosing started at day 13 when tumors reached ~150mm3 in size and tumor volume was determined after every treatment. Although tumor growth inhibition was observed in the mice treated with 1 mg / kg and 0.3 30 mg / kg trastuzumab-saporin, there was no enhanced tumor growth inhibition observed in the mice treated with the combination of trastuzumab-saporin + SO1861. This shows that unconjugated SO1861 is not able to enhance antibody-protein toxins within the current settings and mouse model. Example 2-2 35 Materials: QSmix (1): S4521 (Sigma Aldrich); QSmix (2) : 6857.1 (Carl Roth) QSmix (3): Quil-A® Adjuvant: vac-quil (InvivoGen / Brenntag). Previously, the efficacy of various saponins (SO1861, SO1642) were co administrated as ‘free’ unconjughated molecules to cells in combination with a ligand toxin fusion (e.g. EGFdianthin) or an 40 antibody-protein toxin conjugate, resulting in enhanced cell killing activity of target expressing cells. 2026226426   02 Sep 2026 Here, three different saponin molecules (SO1861, SO1862 (isomer of SO1861), SO1832 and SO1904) isolated from a root extract of Saponaria officinalis were titrated in the presence and absence of a noneffective fixed concentration of 1.5 pM EGFdianthin on HeLa (EGFR+) cells. This revealed a strong enhancement of cell killing activity for all tested saponin variants (IC50= 300 nM; Figure 2-2A) compared 5 to the treatments without EGFdianthin. Next, EGFdianthin was titrated with a fixed concentration of saponin (~1000nM) and this revealed strong targeted cell killing enhancement at low pM concentrations of EGFdianthin (IC50= 0.4 pM; Figure 2-2B), observed for all used saponins SO1861, SO1862 (isomer of SO1861), SO1832 and SO1904. EGF-dianthin alone could only induce cell killing at very high concnetrations (1050=10.000 pM). This shows that these specific types of saponins, all have the intrinsic 0 capacity to efficiently induce endosomal escape with only a very low amount of targeted toxin available. 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 EGFdianthin and compared with purified SO1861. GE1741 also enhances the EGFdianthin induced HeLa cell killing, but shows slightly less efficacy compared to SO1861. (GE1741 IC50= 800 15 nM; Figure 2-2C) and also displays a higher general toxicity (IC50= 5.000 nM in absence of EGFdianthin; Figure 2-2C). A similar test in which different partially purified mixtures of Quillaja saponaria saponins (QSmix 1-3) were co-administrated with 1.5 pM EGFdianthin on HeLa cells and this revealed for 2 out of 3 (QSmix 1 and QSmix 3) similar activity as SO1861 (IC50 QSmix / QSmix3=300nM; Figure 2-2D). QSmix (2) is less efficient in enhancing 1.5 pM EGFdianthin induced cell killing (IC50= 2000 nM; Figure 20    2-2D), however, no general toxicity is observed. This shows that also in QS extracts, specific type of saponins are available that efficiently induce endosomal escape of the targeting ligand toxin EGFdianthin. Example 3-2 25 In order to conjugate SO1861 molecules to antibodies, according to the invention, labile / acid sensitive linkers (-EMCH or-N3), was conjugated to SO1861 via the aldehyde group, producing SO1861-EMCH or SO1861-N3. To verify the activity of SO1861-EMCH the molecule was titrated in the presence and absence of a fixed non-effective (1.5 pM) EGFdianthin concentration on EGFR expressing (A431, HeLa) and non-expressing cells (A2058). In all three cell lines SO1861 alone showed a strong cell viability 30 reduction, whereas SO1861-EMCH as single compound showed no toxicity up to 25.000 nM (Figure 3-2A-C). When SO1861-EMCH was combined with 1.5 pM EGFdianthin a strong target specific cell viability reduction is observed in the EGFR+ A431 and HeLa cells (IC50= 3.000 nM; Figure 3-2A,B), while the EGFR- A2058 cells are not affected at all (Figure 3-2C). Similar results were obtained for SO1861-N3. SO1861-N3 co-administrated with 1.5 pM EGFdianthin also shows efficient cell killing on 35   A431 and HeLa cells (IC50= 3.000 nM), but without EGFdianthin a general toxicity is observed at above 10.000 nM (Figure 3-2D, 3-2E). For the stable conjugation of SO1861 to antibodies, according to the invention, a stable linker (HATU) was conjugated to SO1861 via the carboxylic acid group of SO1861 producing, SO1861-(S). To determine the activity different concentrations of SO1861-(S) were co-administrated with 1.5 pM 40 EGFdianthin and tested for cell killing activity in EGFR expressing HeLa cells. SO1861-(S) showed a 2026226426   02 Sep 2026 similar activity as SO1861, indicating that conjugation to the carboxylic acid does not affect the endosomal escape enhancing potency of the molecule as is observed with SO1861-EMCH (Figure 42). 5 Example 4-2 Labile SO1861 was conjugated via cysteine residues (Cys) to the anti-EGFR antibody cetuximab (monoclonal antibody recognizing and binding human EGFR), with DAR3.9 (cetuximab-(Cys-L-SO1861)39) and tested for its enhanced delivery of antisense BNA oligo nucleotides resulting in enhanced target gene silencing. In this study we used an antisense BNA oligonucleotide against the 0 mRNA of a cancer specific target gene, heat shock protein 27 (HSP27). Within the cytoplasm of the cell HSP27BNA bind the mRNA encoding for HSP27, target the mRNA for destruction, thereby reducing the HSP27 expression within the cancer cell. Cetuximab-(Cys-L-SO1861)39 was titrated on fixed concentration of 100 nM HSP27BNA on EGFR++ (A431) and EGFR- (A2058) cells. The combination according otthe invention showed efficient HSP27 silencing on A431 (IC50= 2 nM; Figure 5-2A), while 15 no silencing was observed for cetuximab-(Cys-L-SO1861)39 alone. Cetuximab-(Cys-L-SO1861)39 + 100nM HSP27BNA showed no gene silencing activity in EGFR-cells (A2058) (Figure 5-2B). This shows that low concentrations of antibody-conjugated SO1861 efficiently can enhance cytoplasmic delivery and endolysosomal escape of an antisense BNA oligo nucleotide, thereby inducing efficient gene silencing in target expressing cells. 20          Next the HSP27BNA was titrated on EGFR++ (A431) and EGFR- (A2058) cells combined with fixed concentration of cetuximab-(Cys-L-SO1861)3 9. This shows that HSP27BNA in combination with 28.6 nM cetuximab-(Cys-L-SO1861)3 9 or77 nM cetuximab-(Cys-L-SO1861)3 9 very efficiently enhances HSP27 gene silencing in A431 cells (IC50= 10 nM; Figure 5-2C). HSP27BNA alone or combined with a fixed equivalent of 77 nM cetuximab are less efficient (IC50= 1.000 nM; Figure 5-2C). The combination 25 treatment of HSP27BNA + 77 nM cetuximab-(Cys-L-SO1861)3 9 was also tested on EGFR- cells (A2058) and this revealed no HSP27 gene silencing enhancement (1050=1.000 nM; Figure 5-2D). This shows that cells with low or no EGFR receptor expression are not susceptible for the combination of cetuximab-(Cys-L-SO1861)3’9 + HSP27BNA, while cetuximab targeted SO1861 can enhance HSP27 gene silencing efficiently at low concentrations of non-targeted HS27BNA in high EGFR cells. 30 Next, SO1861-EMCH was conjugated via cysteine residues (Cys) to cetuximab (monoclonal antibody recognizing and binding human EGFR), with a DAR 3,8. The combination according to the invention, cetuximab-(Cys-L-SO1861)3’8 + HSP27BNA (antisense HSP27BNA oligo nucleotide targeting and inducing degradation of the onco-target hsp27 mRNA (gene silencing) in cancer cells) was tested in a A431 xenograph ‘nude’ mouse tumor model for EGFR-mediated tumor targeted HSP27 gene silencing. 35 Dosing started at day 12 when tumors reached ~150mm3 in size and HSP27 mRNA expression was determined. For this, tumor samples were collected at 72h after the first dosing and analysed for HSP27 gene expression levels compared to cellular control mRNA expression levels (reference genes). Tumor bearing mice (n=3) were treated (intraperitoneal; i.p.) at day 12: 25 mg / kg cetuximab-(Cys-L-SO1861)3’8 + 25 mg HSP27BNA and at day 15: 25 mg / kg cetuximab-(Cys-L-SO1861)3 8 + 10 mg HSP27BNA and 40 this revealed a 25% reduction in HSP27 mRNA expression in the tumors compared to vehicle control or 2026226426   02 Sep 2026 single dosing of 25 mg / kg HSP27BNA (Figure 6-2). This shows and enables that conjugation of SO1861 to a targeting antibody, according to the invention, efficiently induces SO1861-mediated enhanced cytoplasmic delivery of a therapeutic antisense oligo nucleotide in solid tumors of tumor bearing mice, inducing tumor targeted gene silencing, in vivo. 5 EXAMPLE 1-7 - targeted antisense oligonucleotide coupled to an antibody Cetuximab-(Lys-L-HSP27BNA) + saponin SO1861 An antisense BNA oligonucleotide against the mRNA of a cancer specific target gene, heat shock protein 27 (HSP27), will upon release into the cytoplasm recognize and bind the mRNA encoding for HSP27, 0 target the mRNA for destruction and thereby lower the HSP27 expression within the cancer cell. Nontargeted HSP27BNA was titrated on EGFR++ (A431) and EGFR- (A2058) cells to test for HSP27 gene silencing in combination with saponins. Data revealed efficient HS27 silencing on both A431 A2058 cells when HSP27BNA was combined with 4000 nM SO1861 -ECMH (IC50= 10 nM; Figure 1-7A, 1-7B), while no silencing was observed for single HSP27BNA treatment (IC50> 1.000 nM; Figure 1-7A, 1-7B). 15          Next, HSP27BNA was conjugated to the lysines of cetuximab with DAR1.5 and DAR3.9, resulting in cetuximab-(Lys-L-HSP27BNA)15 and cetuximab-(Lys-L-HSP27BNA)39. The conjugated cetuximab-HSP27BNA samples were again titrated on EGFR++ (A431) and EGFR- (A2058) cells to test for targeted HSP27 gene silencing in combination with saponins. These conjugates show very efficient HSP27 gene silencing in A431 (EGFR++) cells in the presence of 4000 nM SO1861-EMCH (DAR1.5 20   IC50= 0.05 nM and DAR3.9 IC50= 0.3 nM; Figure 1-7A), while the silencing of the targeted HSP27BNA samples is comparable to the non-targeted HSP27BNA in the absence of SO1861-EMCH. The silencing in A2058 (EGFR) cells is not improved compared to non-targeted HSP27BNA in general. Both in the presence and absence of SO1861 similar HSP27BNA (conjugate) amounts are required to induce silencing (Figure 1-7B). This shows that cells with high EGFR receptor expression very efficient targeted 25 HSP27 gene silencing can be achieved using targeted HSP27BNA in combination with SO1861. An antisense BNA oligonucleotide against the mRNA of a cancer specific target gene, heat shock protein 27 (HSP27), will upon release into the cytoplasm recognize and bind the mRNA encoding for HSP27, target the mRNA for destruction and thereby lower the HSP27 expression within the cancer cell. Non-targeted HSP27BNA was titrated on EGFR++ (A431) and EGFR- (A2058) cells to test for 30 HSP27 gene silencing in combination with saponins. Data revealed efficient HS27 silencing on both A431 A2058 cells when HSP27BNA was combined with 4000 nM SO1861-ECMH (IC50= 10 nM; Figure 1-7C, 1-7D), while no silencing was observed for single HSP27BNA treatment (IC50> 1.000 nM; Figure 1-7C, 1-7D). Next, HSP27BNA was conjugated to the lysines of cetuximab with DAR1.5 and DAR3.9, 35 resulting in cetuximab-(Lys-L-HSP27BNA)15 and cetuximab-(Lys-L-HSP27BNA)39. The conjugated cetuximab-HSP27BNA samples were again titrated on EGFR++ (A431) and EGFR- (A2058) cells to test for targeted HSP27 gene silencing in combination with saponins. These conjugates show very efficient HSP27 gene silencing in A431 (EGFR++) cells in the presence of 4000 nM SO1861-EMCH, requiring less HSP27BNA oligo (IC50= 0.04 nM; Figure 1-7C), while the silencing of the targeted HSP27BNA 40 samples is comparable to the non-targeted HSP27BNA in the absence of SO1861-EMCH. The silencing 2026226426   02 Sep 2026 in A2058 (EGFR) cells is not improved compared to non-targeted HSP27BNA in general. It even seems that about 10x more HSP27BNA oligo is required in the presence of SO1861, while no significant silencing is observed without SO1861 (Figure 1-7D). This shows that cells with high EGFR receptor expression very efficient targeted HSP27 gene silencing can be achieved using targeted HSP27BNA in 5 combination with SO1861. REFERENCES Weng, A.; Thakur, M.; Beceren-Braun, F.; Bachran, D.; Bachran, C.; Riese, S.B.; Jenett-Siems, K.; Gilabert-Oriol, R.; Melzig, M.F.; Fuchs, H. The toxin component oftargeted anti-tumor toxins determines 0 their efficacy increase by saponins. Molecular oncology 2012, 6, 323-332. saponinum album in a synergistic way. Journal of immunotherapy 2009, 32, 713-725. Sama, S.; Jerz, G.; Schmieder, P.; Joseph, J.F.; Melzig, M.F.; Weng, A. Plant derived triterpenes from Gypsophila elegans M.Bieb. enable non-toxic delivery of gene loaded nanoplexes. Journal of Biotechnology 2018, 284, 131-139 15           Kolb, H.C.; Finn, M.G.; Sharpless, K.B. Click Chemistry: Diverse Chemical Function from a Few Good Reactions. Angewandte Chemie 2001,40, 2004-2021. Bird, R.E.; Hardmann, K.D.; Jacobson, J.W.; Johnson, S.; Kaufman, B.M.; Lee, S.M.; Lee, T.; Pope, S.H.; Riordan, G.S.; Whitlow, M. Single-chain antigen-binding proteins. Science 1988, 242, 423426. 20          Y Zhang, Z Qu, S Kim, V 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 25

Claims

1. Therapeutic molecule with chemical structure of COMPOUND I:5                             Aim ((-L9w) ((- L1 q - B1 n)u ((- L2r - L3s) (- L4v - C)p)t))x(compound I),wherein0A1 is a first ligand if B1 is a first effector moiety, or A1 is the first effector moiety if B1 is the first ligand;C is a saponin;m = 0 or 1 if A1 is the first ligand and B1 is the first effector moiety;m = 0 - 32 if A1 is the first effector moiety and B1 is the first ligand;15 n = 0 or 1 if B1 is the first ligand and A1 is the first effector moiety, or if A1 is the first ligand and B1 is the first effector moiety;p = any of 1-128;L1 is at least one linker for covalently coupling two chemical groups;L2 is at least one linker for covalently coupling two chemical groups;20 L3 is at least one oligomeric or polymeric scaffold for covalently coupling two chemical groups;L4 is at least one linker for covalently coupling two chemical groups;L9 is a tri-functional linker for covalently coupling three chemical groups;q = 0 or 1;r = 0 or 1;25 s = 0 or 1;t = 0, 1 or 2 if s = 0, and t = any of 0-16 if s = 1;u = any of 0 - 32 if A1 is the first ligand and B1 is the first effector moiety, or u = 1 if A1 is the first effector moiety and B1 is the first ligand;v = 0 or 1;30 w = 1 or 0; andx= 1-16.

2. Therapeutic combination comprising the therapeutic molecule according to claim 1 and a second therapeutic molecule with chemical structure of COMPOUND II:35A2a ((-L10j) ((- L5d - B2b)h ((- L6e - L7f) (- L8i - C)c)g))k(compound II),40 wherein2026226426   02 Sep 2026A2 is a second ligand if B2 is a second effector moiety, or A2 is the second effector moiety if B2 is the second ligand;C is a saponin;5 a = 0 or 1 if A2 is the second ligand and B2 is the second effector moiety, or a = 0 - 32 if A2 is the second effector moiety and B2 is the second ligand;b = 0 or 1 if B2 is the second ligand and A2 is the second effector moiety, or if A2 is the second ligand and B2 is the second effector moiety;c = any of 1-128;0 L5 is at least one linker for covalently coupling two chemical groups;L6 is at least one linker for covalently coupling two chemical groups;L7 is at least one oligomeric or polymeric scaffold for covalently coupling two chemical groups;L8 is at least one linker for covalently coupling two chemical groups;L10 is a tri-functional linker for covalently coupling three chemical groups;15 d = 0or1;e = 0 or 1;f=0or1;g = 0, 1 or 2 if f = 0, and g = any of 0-16 if f = 1;h = any of 0 - 32 if A2 is the second ligand and B2 is the second effector moiety, or h = 1 if A2 is the 20 second effector moiety and B2 is the second ligand;i = 0 or 1;j = 1 or 0 and;k = 1-16.25    3. Second therapeutic molecule of claim 2, wherein g = 0,1 or 2 if f = 0 and t > 0, g = 1 or 2 if f = 0 andt = 0, g = any of 0-16 if f = 1 and t > 0, and g = any of 1-16 if f = 1 and t = 0.

4. Therapeutic molecule of any of the claims 1-3 or the second therapeutic molecule of claim 2 or 3, wherein the first ligand A1 or B1 and / or the second ligand A2 or B2 comprise(s) or consist(s) of an 30 immunoglobulin, a binding domain of an immunoglobulin or a 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, Fcab fragment, or comprise(s) or consist(s) of at least one non-proteinaceous ligand and / or at least one proteinaceous ligand, the ligand for binding to a cell-surface molecule such as EGF or a cytokine, with the proviso that the first ligand and the second ligand are the 35 same or are different.

5. Therapeutic molecule of any one of the claims 1-4 or the second therapeutic molecule of any of the claims 2-4, wherein the first ligand A1 or B1 and / or the second ligand A2 or B2 bind(s) to a tumor-cell epitope, preferably a tumor-cell specific epitope, of a tumor-cell receptor, preferably a tumor-cell specific 40 receptor, preferably selected from CD71, CA125, EpCAM(17-1A), CD52, CEA, CD44v6, FAP, EGF-IR,2026226426   02 Sep 2026integrin, syndecan-1, vascular integrin alpha-V beta-3, 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-5   L1, CTLA4, CD52, PDGFRA, VEGFR1, VEGFR2, more preferably selected from CD71, EGFR andHER2, with the proviso that the first ligand and the second ligand bind to the same or to a different tumor-cell epitope, preferably a tumor-cell specific epitope, and / or wherein the tumor-cell receptor, preferably the tumor-cell specific receptor, to which the first ligand can bind is the same as, or is different from the tumor-cell receptor, preferably the tumor-cell specific receptor, to which the second ligand can0 bind.

6. Therapeutic molecule of any one of the claims 1 -5 or the second therapeutic molecule of any one of the claims 2-5, wherein the first ligand A1 or B1 and / or the second ligand A2 or B2 comprise(s) or consist(s) of cetuximab, daratumumab, gemtuzumab, trastuzumab, panitumumab, brentuximab,15 inotuzumab, moxetumomab, polatuzumab, obinutuzumab, OKT-9 anti-CD71 monoclonal antibody ofthe IgG type, pertuzumab, rituximab, ofatumumab, Herceptin, alemtuzumab, pinatuzumab, OKT-10 anti-CD38 monoclonal antibody, an antibody of Table A2 or Table A3 or Table A4, preferably cetuximab or trastuzumab or OKT-9, or at least one tumor-cell receptor binding-domain thereof and / or at least one tumor-cell receptor binding-fragment thereof which are preferably (a) tumor-cell specific receptor 20 binding-domain(s) and / or (a) tumor-cell specific receptor binding-fragment(s), with the proviso that the first ligand is the same or different from the second ligand.

7. Therapeutic molecule of any one of the claims 1 -6 or the second therapeutic molecule of any one of the claims 2-6, wherein the first ligand A1 or B1 is internalized by a tumor cell after binding of the first 25 ligand to its binding partner on the tumor cell, and wherein preferably binding of the first ligand to the tumor cell is followed by tumor-cell receptor-mediated internalization, e.g. via endocytosis, of a complex of the first ligand and the binding partner of the first ligand on the tumor cell.

8. Therapeutic molecule of any one of the claims 1 -7 or the second therapeutic molecule of any one of 30 the claims 2-7, wherein the second ligand A2 or B2 is internalized by a tumor cell after binding of the second ligand to its binding partner on the tumor cell, and wherein preferably binding of the second ligand to the tumor cell is followed by tumor-cell receptor-mediated internalization, e.g. via endocytosis, of a complex of the second ligand and the binding partner of the second ligand on the tumor cell.35   9. Therapeutic molecule of any one of the claims 1 -8 or the second therapeutic molecule of any one ofthe claims 2-8, wherein the first effector moiety A1 or B1 and / or the second effector moiety A2 or B2 comprise(s) or consist(s) of at least one of any one or more of an oligonucleotide, a nucleic acid and a xeno nucleic acid, preferably selected from any one or more of a vector, a gene, a cell suicide inducing transgene, deoxyribonucleic acid (DNA), ribonucleic acid (RNA), anti-sense oligonucleotide (ASO,40 AON), short interfering RNA (siRNA), microRNA (miRNA), DNA aptamer, RNA aptamer, mRNA, mini-2026226426   02 Sep 2026circle DNA, 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'-O,4'-aminoethylene bridged nucleic acid, 3’-fluoro hexitol nucleic acid (FHNA), a plasmid, glycol nucleic acid (GNA) and threose nucleic acid (TNA), or a derivative thereof, 5 more preferably a BNA, for example a BNA for silencing HSP27 protein expression, with the proviso that the first effector moiety and the second effector moiety are the same or are different.

10. Therapeutic molecule of any one of the claims 1-9 or the second therapeutic molecule of any one of the claims 2-9, wherein the first effector moiety A1 or B1 and / or the second effector moiety A2 or B2 0 comprise(s) or consist(s) of at least one proteinaceous molecule, preferably selected from any one ormore of a peptide, a protein, an enzyme such as urease and Cre-recombinase, a proteinaceous toxin, a ribosome-inactivating protein, at least one protein toxin selected from Table A5 and / or a bacterial toxin, a plant toxin, more preferably selected from any one or more of a viral toxin such as apoptin; a bacterial toxin such as Shiga toxin, Shiga-like toxin, Pseudomonas aeruginosa exotoxin (PE) or exotoxin15 A of PE, full-length or truncated diphtheria toxin (DT), cholera toxin; a fungal toxin such as alpha-sarcin;a plant toxin including ribosome-inactivating proteins and the A chain of type 2 ribosome-inactivating proteins such as dianthin e.g. dianthin-30 or dianthin-32, saporin e.g. saporin-S3 or saporin-S6, bouganin or de-immunized derivative debouganin of bouganin, shiga-like toxin A, pokeweed antiviral protein, ricin, ricin A chain, modeccin, modeccin A chain, abrin, abrin A chain, volkensin, volkensin A 20 chain, viscumin, viscumin A chain; or an animal or human toxin such as frog RNase, or granzyme B or angiogenin from humans, or any fragment or derivative thereof; preferably the protein toxin is dianthin and / or saporin, with the proviso that the first effector moiety / moieties and the second effector moiety / moieties are the same or are different.25   11. Therapeutic molecule of any one of the claims 1-10 or the second therapeutic molecule of any oneof the claims 2-10, wherein the first effector moiety A1 or B1 and / or the second effector moiety A2 or B2 comprise(s) or consist(s) of at least one payload, preferably selected from any one or more of a toxin targeting ribosomes, a toxin targeting elongation factors, a toxin targeting tubulin, a toxin targeting DNA and a toxin targeting RNA, more preferably any one or more of emtansine, pasudotox, maytansinoid30 derivative DM1, maytansinoid derivative DM4, monomethyl auristatin E (MMAE, vedotin), monomethyl auristatin F (MMAF, mafodotin), a Calicheamicin, N-Acetyl-y-calicheamicin, a pyrrolobenzodiazepine (PBD) dimer, a benzodiazepine, a CC-1065 analogue, a duocarmycin, Doxorubicin, paclitaxel, docetaxel, cisplatin, cyclophosphamide, etoposide, docetaxel, 5-fluorouracyl (5-FU), mitoxantrone, a tubulysin, an indolinobenzodiazepine, AZ13599185, a cryptophycin, rhizoxin, methotrexate, an35 anthracycline, a camptothecin analogue, SN-38, DX-8951f, exatecan mesylate, truncated form of Pseudomonas aeruginosa exotoxin (PE38), a Duocarmycin derivative, an amanitin, a-amanitin, a spliceostatin, a thailanstatin, ozogamicin, tesirine, Amberstatin269 and soravtansine, or a derivative thereof.2026226426   02 Sep 202612. Therapeutic molecule of any one of the claims 1-11 or the second therapeutic molecule of any one of the claims 2-11, wherein the therapeutic molecule and / or the second therapeutic molecule comprise(s) or consist(s) of any one of Gemtuzumab ozogamicin, Brentuximab vedotin, Trastuzumab emtansine, Inotuzumab ozogamicin, Moxetumomab pasudotox and Polatuzumab vedotin and an5 antibody-drug conjugate of Table A2 and Table A3, or at least one tumor-cell specific receptor bindingdomain thereof and / or at least one tumor-cell specific receptor binding-fragment thereof which are preferably (a) tumor-cell specific receptor binding-domain(s) and / or (a) tumor-cell specific receptor binding-fragment(s), with the proviso that the therapeutic molecule and the second therapeutic molecule are the same or are different.

013. Therapeutic molecule of any one of the claims 1 -12 or the second therapeutic molecule of any one of the claims 2-12, wherein the saponin C is a triterpenoid saponin ora bisdesmosidic triterpene saponin, belonging to the type of a 12,13-dehydrooleanane with an aldehyde function in position C-23 and optionally comprising a glucuronic acid function in a carbohydrate substituent at the C-3beta-OH group15 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.

14. Therapeutic molecule of any one of the claims 1 -13 or the second therapeutic molecule of any one of the claims 2-13, wherein the saponin C is a single specific saponin or is a mixture of two or more 20 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-21B, QS-21 B-api, QS-21 B-xyl, QS-7-xyl, QS-7-api, QS-17-api, QS-17-xyl, QS1861, QS1862, Quillajasaponin, Saponinum album, QS-18, Quil-A, Gyp1, gypsoside A, AG1, AG2, SO1542, SO1584, SO1658, SO1674, SO1832, or any of their stereomers and / or any combinations thereof, preferably the saponin is SO1861 and / or GE1741 and / or 25    SA1641 and / or QS-21 and / or saponin with a quillaic acid aglycon core, a Gal-(1->2)-[Xyl-(1->3)]-GlcA carbohydrate substituent at the C-3beta-OH group and a Glc-(1->3)-Xyl-(1->4)-Rha-(1->2)-[Xyl-(1->3)-4-OAc-Qui-(1->4)]-Fuc carbohydrate substituent at the C-28-OH group, and / or is 3-O-beta-D-galactopyranosyl-(1 ->2)-[beta-D-xylopyranosyl-(1 ->3)]-beta-D-glucuronopyranosyl quillaic acid 28-0-beta-D-glucopyranosyl-(1 ->3)-beta-D-xylopyranosyl-(1 ->4)- alpha-L-rhamnopyranosyl-(1 ->2)-[beta-D-30 xylopyranosyl-(1 ->3)-4-OAc-beta-D-quinovopyranosyl-(1 ->4)]-beta-D-fucopyranoside, more preferably the saponin is SO1861 and / or QS-21.

15. Therapeutic molecule of any one of the claims 1-14 or the second therapeutic molecule of any one of the claims 2-14, wherein the saponin C is a bisdesmosidic saponin having a molecular mass of at 35 least 1.500 Dalton and comprising an oleanan-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 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 the C-28 position which second branched carbohydrate chain preferably comprises at least four 40 carbohydrate units, optionally containing at least one acetyl residue such as two acetyl residues and / or2026226426   02 Sep 2026at least one deoxy carbohydrates and / or a quinovose and / or a glucose and / or 4-methoxycinnamic acid and / or optionally comprising 5-O-[5-O-Ara / Api-3,5-dihydroxy-6-methyl-octanoyl]-3,5-dihydroxy-6-methyl-octanoic acid and / or optionally comprising 5-O-[5-O-Rha-(1->2)-Ara / Api-3,5-dihydroxy-6-methyl-octanoyl]-3,5-dihydroxy-6-methyl-octanoic acid bound to a carbohydrate via an ester bond, or 5 wherein the 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-21B, QS-21 B-api, QS-21 B-xyl, QS-7-xyl, QS-7-api, QS-17-api, QS-17-xyl, QS-18, QS1861, protonated QS1861 (QS1862), Quil-A.

16. Therapeutic molecule of any one of the claims 1-15 or the second therapeutic molecule of any one 0 of the claims 2-15, wherein the saponin C is a bisdesmosidic triterpene saponin belonging to the type of a 12,13-dehydrooleanane with an aldehyde function in position C-23, wherein the saponin C is covalently coupled to an amino-acid residue of the first ligand A1 or B1 and / or the first effector moiety B1 or A1 and / or the second ligand A2 or B2 and / or the second effector moiety B2 or A2 via the aldehyde function in the saponin C, preferably said aldehyde function in position C-23, preferably via a linker L2,15    L4, L6, L8, L9 and / or L10, more preferably via a cleavable linker L2, L4, L6, L8, L9 and / or L10, whereinthe amino-acid residue preferably is selected from cysteine and lysine.

17. Therapeutic molecule of any one of the claims 1 -16 or the second therapeutic molecule of any one of the claims 2-16, wherein the saponin C is a bisdesmosidic triterpene saponin belonging to the type 20 of a 12,13-dehydrooleanane with an aldehyde function in position C-23, wherein the aldehyde functionin position C-23 of the at least one saponin is covalently coupled to linker N-s-maleimidocaproic acid hydrazide, which linker is covalently coupled via a thio-ether bond to a sulfhydryl group in the first ligand A1 or B1 and / or in the first effector moiety B1 or A1 and / or in the second ligand A2 or B2 and / or in the second effector moiety B2 or A2, such as a sulfhydryl group of a cysteine.2518. Therapeutic molecule of any one of the claims 1-17 or the second therapeutic molecule of any one of the claims 2-17, wherein the saponin C is a bisdesmosidic triterpene saponin belonging to the type of a 12,13-dehydrooleanane with an aldehyde function in position C-23 and comprising a glucuronic acid function in a carbohydrate substituent at the C-3beta-OH group of the saponin, wherein the saponin 30 C is covalently coupled to the amino-acid residue of the first ligand A1 or B1 and / or the first effector moiety B1 or A1 and / or the second ligand A2 or B2 and / or the second effector moiety B2 or A2 via the glucuronic acid function in the saponin C, if present, preferably via a linker L2, L4, L6, L8, L9 and / or L10, wherein the amino-acid residue preferably is selected from cysteine and lysine, more preferably the amino-acid residue is lysine.3519. Therapeutic molecule of any one of the claims 1 -18 or the second therapeutic molecule of any one of the claims 2-18, wherein the saponin C is a bisdesmosidic triterpene saponin belonging to the type of a 12,13-dehydrooleanane with an aldehyde function in position C-23 and comprising a glucuronic acid function in a carbohydrate substituent at the C-3beta-OH group of the saponin, wherein the 40 glucuronic acid function in the carbohydrate substituent at the C-3beta-OH group of the at least one2026226426   02 Sep 2026saponin is covalently coupled to linker 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate, which linker is covalently coupled via an amide bond to an amine group in the first ligand A1 or B1 and / or in the first effector moiety B1 or A1 and / or in the second ligand A2 or B2 and / or in the second effector moiety B2 or A2, such as an amine group of a lysine or an 5 N-terminus of the first ligand A1 or B1 and / or the first effector moiety B1 or A1 and / or the second ligand A2 or B2 and / or the second effector moiety B2 or A2.

20. Therapeutic molecule of any one of the claims 1-19 or the second therapeutic molecule of any one of the claims 2-19, wherein the first ligand A1 or B1 and / or the first effector moiety B1 or A1 and / or the 0 second ligand A2 or B2 and / or the second effector moiety B2 or A2 comprise(s) one or more than one covalently bound saponin C, preferably 2, 3, 4, 5, 6, 8, 10, 16, 32, 64, 128 or 1-100 saponins, or any number of saponins therein between, such as 7, 9, 12 saponins.

21. Therapeutic molecule of any one of the claims 1-20 or the second therapeutic molecule of any one15 of the claims 2-20, wherein the first ligand A1 or B1 and / or the first effector moiety B1 or A1 and / or the second ligand A2 or B2 and / or the second effector moiety B2 or A2 comprise(s) one or more than one covalently bound saponin C, wherein the saponin(s) C is / are covalently bound directly to an amino-acid residue of the first ligand A1 or B1 and / or the first effector moiety B1 or A1 and / or the second ligand A2 or B2 and / or the second effector moiety B2 or A2 when r, s, v, e, f and i are 0, preferably to a cysteine 20 and / or to a lysine, and / or is / are covalently bound via at least one linker L2, L4, L6, L8, L9 and / or L10, or via at least one cleavable linker L2, L4, L6, L8, L9 and / or L10 and / or via at least one oligomeric or polymeric scaffold L3 and / or L7, preferably 1-8 of such scaffolds or 2-4 of such scaffolds, wherein the at least one scaffold is optionally based on a dendron, wherein 1-32 saponins, preferably 2, 3, 4, 5, 6, 8, 10, 16, 32 saponins, or any number of saponins therein between, such as 7, 9, 12 saponins, are 25 covalently bound to the at least one scaffold.

22. Therapeutic molecule of claim 16 or the second therapeutic molecule of claim 16, wherein the cleavable linker L2, L4, L6, L8, L9 and / or L10 is subject to cleavage under acidic conditions, reductive conditions, enzymatic conditions or light-induced conditions, and preferably the cleavable linker 30 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, when bound to saponin, and / or the cleavable linker comprises a disulphide bond susceptible to cleavage under reductive conditions.35   23. Therapeutic molecule of any one of the claims 16-22 or the second therapeutic molecule of any oneof the claims 16-22, wherein the cleavable linker L2, L4, L6, L8, L9 and / or L10 is subject to cleavage in vivo under acidic conditions as present in endosomes and / or lysosomes of mammalian cells, preferably human cells, preferably at pH 4.0 - 6.5, and more preferably at pH < 5.5.2026226426   02 Sep 202624. Therapeutic molecule of any one of the claims 1 -23 or the second therapeutic molecule of any one of the claims 2-23, wherein the polymeric or oligomeric scaffold L3 and / or L7 comprises a polymeric or oligomeric structure and comprises a chemical group, the chemical group for covalently coupling of the polymeric or oligomeric scaffold L3 and / or L7 to the amino-acid residue of the first ligand and / or the first 5 effector moiety and / or the second ligand and / or the second effector moiety.

25. Therapeutic molecule of any one of the claims 1-24 or the second therapeutic molecule of any one of the claims 2-24, wherein the at least one saponin is covalently bound to the polymeric or oligomeric structure of the scaffold L3 and / or L7 via a cleavable linker L4 and / or L8 according to any one of the 0 claims 19-23.

26. Therapeutic molecule of any one of the claims 20-25 or the second therapeutic molecule of any one of the claims 20-25, wherein the chemical group of the polymeric or oligomeric scaffold L3 and / or L7, for covalently coupling of the scaffold to the amino-acid residue of the first ligand and / or the first effector15 moiety and / or the second ligand and / or the second effector moiety, is a click chemistry group, preferably selected from a tetrazine, an azide, an alkene or an alkyne, or a cyclic derivative of these groups, more preferably the click chemistry group is an azide.

27. Therapeutic molecule of any one of the claims 20-26 or the second therapeutic molecule of any one 20    of the claims 20-26, wherein the at least one saponin is covalently bound to the first ligand and / or to thefirst effector moiety and / or to the second ligand and / or to the second effector moiety, either directly or via at least one linker such as a bi-functional linker, for example based on N-s-maleimidocaproic acid hydrazide and / or based on 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate, or a tri-functional linker L9 when w = 1 and / or a tri-functional linker L10 when j = 25    1, such as the tri-functional linker of Scheme II.

28. Therapeutic molecule of claim 27 or the second therapeutic molecule of claim 27, wherein the trifunctional linker L9 when w = 1 and / or the tri-functional linker L10 when j = 1, comprises a second chemical group with at least one saponin covalently bound thereto, a third chemical group for covalent 30 binding to the first and / or second ligand and a first chemical group for covalent binding to at least one first and / or second effector moiety, preferably the tri-functional linker is the trifunctional linker of Scheme II.

29. Therapeutic molecule of any one of the claims 1-28 or the second therapeutic molecule of any one 35    of the claims 2-28, wherein the at least one saponin is covalently bound to the first ligand and / or to thefirst effector moiety and / or to the second ligand and / or to the second effector moiety via at least one linker comprising a tri-functional linker L9 when j = 1 and / or a tri-functional linker L10 when w = 1, to which tri-functional linker both the first ligand and the at least one first effector moiety are bound and / or to which tri-functional linker both the second ligand and the at least one second effector moiety are 40 bound, preferably the tri-functional linker is the trifunctional linker of Scheme II.2026226426   02 Sep 202630. Therapeutic molecule of any one of the claims 20-29 or the second therapeutic molecule of any one of the claims 20-29, wherein the polymeric or oligomeric structure of the scaffold L3 and / or L7 comprises a linear, branched and / or cyclic polymer, oligomer, dendrimer, dendron, dendronized polymer, 5 dendronized oligomer, a DNA, a polypeptide, poly-lysine, a poly-ethyleneglycol, or an assembly of these polymeric or oligomeric structures which assembly is preferably built up by covalent cross-linking.

31. Therapeutic molecule of any one of the claims 20-30 or the second therapeutic molecule of any one of the claims 20-30, wherein the first ligand A1 or B1 is covalently bound to the first effector moiety B1 0 or A1, respectively, via at least one linker L1, and / or wherein the second ligand A2 or B2 is covalentlybound to the second effector moiety B2 or A2, respectively, via at least one linker L5.

32. Therapeutic combination of any one of the claims 2-31, wherein the first ligand A1 is a monoclonal antibody or at least one binding fragment or-domain thereof according to any one of the claims 3-7, m15    = 1, q = 0, n = 0, u = 0, r = 0, L3 is the scaffold according to any one of the claims 20-29 and s = 1, orL3 is absent and s = 0, L4 is a linker or a cleavable linker according to any one of the claims 15-28, v = 1, p = 2-4 and t = 2-4 if s = 1 and t = 0 if s = 0, and saponin C is a saponin according to any one of the claims 12-18, preferably the saponin C is SO1861 and / or QS-21, and effector moiety A2 is an effector moiety according to claim 8, preferably a BNA, a = 1, d = 0, b = 0, h = 0, e = 0, f=0, i = 0, c = 0 and g 20    = 0.

33. Therapeutic molecule of claim 1, wherein r = 0, s = 0, v = 0, s = 0, v = 0, p = 0, t = 0, ligand A1 is a monoclonal antibody or at least one binding fragment or -domain thereof according to any one of the claims 3-7, m = 1, effector moiety B1 is an effector moiety according to claim 8, preferably a BNA, either 25 q = 0, n = 1 and u = 2-4, or q = 1, n = 2-4, u = 2-4 and linker L1 is the oligomeric or polymeric scaffoldL3 according to any one of the claims 21-30.

34. Therapeutic combination of any one of the claims 2-31, wherein the therapeutic molecule is the therapeutic molecule of claim 33, and wherein the second ligand A2 is a monoclonal antibody or at least 30 one binding fragment or-domain thereof according to any one of the claims 3-7, a = 1, d = 0, b = 0, h =0, e = 0, L7 is the scaffold according to any one of the claims 20-29 and f = 1, or L7 is absent and f = 0, L8 is a linker or a cleavable linker according to any one of the claims 15-24, i = 1, c = 2-4 and g = 2-4 if f = 1 and g = 0 iff = 0, and saponin C is a saponin according to any one of the claims 12-18, preferably the saponin C is SO1861 and / or QS-21, with the proviso that the ligand A1 and the ligand A2 are the 35 same or are different.

35. Therapeutic combination, wherein the therapeutic combination comprises:(a) a first pharmaceutical composition comprising the therapeutic molecule with chemical structure of COMPOUND I according to any one of the claims 1-34, the first pharmaceutical 40           composition optionally further comprising a pharmaceutically acceptable excipient; and2026226426   02 Sep 2026(b) a second pharmaceutical composition comprising the second therapeutic molecule with chemical structure of COMPOUND II according to any one of the claims 2-34, the second pharmaceutical composition optionally further comprising a pharmaceutically acceptable excipient.

536. The first pharmaceutical composition of claim 35 for use as a medicament.

37. Therapeutic combination for use in the treatment or prevention of cancer in a human subject, wherein the therapeutic combination comprises:0            (a) the first pharmaceutical composition of claim 35; and(b) the second pharmaceutical composition of claim 35,wherein the ligand A1 or B1 and the ligand A2 or B2 can bind to a tumor-cell epitope, preferably to a tumor-cell specific epitope, on a tumor-cell surface molecule, preferably on a tumor cell-specific surface molecule, with the proviso that the tumor-cell epitope or tumor-cell15            specific epitope to which the ligand A1 or B1 can bind is the same as, or is different from thetumor-cell epitope or the tumor-cell specific epitope to which the ligand A2 or B2 can bind.

38. The first pharmaceutical composition of any one of the claims 35-37, for use in the treatment or prophylaxis of cancer in a patient in need thereof, wherein the ligand A1 or B1 can bind to a tumor-cell 20 epitope, preferably a tumor-cell specific epitope, on a tumor-cell surface molecule, preferably a tumor cell-specific surface molecule.

39. The first pharmaceutical composition for use according to claim 36 or 38 or the therapeutic combination for use of claim 35 or 37, wherein the second pharmaceutical composition of claim 35 or 25    37 and the first pharmaceutical composition of any one of the claims 35-38 are administered to thepatient in need thereof.

40. The first pharmaceutical composition of claim 35 further comprising the second therapeutic molecule of any one of the claims 2-35.3041. The first pharmaceutical composition of claim 40, for use as a medicament.

42. The first pharmaceutical composition of claim 40, for use in the treatment or prevention of a cancer in a human subject.35

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