المؤلفون: Jakob Vowinckel, Martin Soste, David Satijn, Gemma Rigter, Yuehan Feng, Yu Wah Au, Miriam Guillén Navarro, Rianne Van der Windt, Jantine Bakema, Joost Neijssen, Martin Mehnert, Amaury Lachaud, Helene Bon

المصدر: Journal for ImmunoTherapy of Cancer, Vol 11, Iss Suppl 1 (2023)

مصطلحات موضوعية: Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

وصف الملف: electronic resource

Relation: https://doaj.org/toc/2051-1426

URL الوصول: https://doaj.org/article/e0f1be7fcd7742769ae5dce5097bb22d

المؤلفون: Ida H. Hiemstra, Kim C.M. Santegoets, Maarten L. Janmaat, Bart E.C.G. De Goeij, Wessel Ten Hagen, Sanne van Dooremalen, Peter Boross, Jeroen van den Brakel, Sieto Bosgra, Grietje Andringa, Berris van Kessel-Welmers, Dennis Verzijl, Richard G. Hibbert, Kristine A. Frerichs, Tuna Mutis, Niels W.C.J. van de Donk, Tahamtan Ahmadi, David Satijn, A. Kate Sasser, Esther C.W. Breij

المصدر: EBioMedicine, Vol 93, Iss , Pp 104663- (2023)

مصطلحات موضوعية: Antibody, CD38, Complement-dependent cytotoxicity, Hematologic neoplasms, Daratumumab, Multiple myeloma, Medicine, Medicine (General), R5-920

الوصف: Summary: Background: HexaBody®-CD38 (GEN3014) is a hexamerization-enhanced human IgG1 that binds CD38 with high affinity. The E430G mutation in its Fc domain facilitates the natural process of antibody hexamer formation upon binding to the cell surface, resulting in increased binding of C1q and potentiated complement-dependent cytotoxicity (CDC). Methods: Co-crystallization studies were performed to identify the binding interface of HexaBody-CD38 and CD38. HexaBody-CD38-induced CDC, antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), trogocytosis, and apoptosis were assessed using flow cytometry assays using tumour cell lines, and MM patient samples (CDC). CD38 enzymatic activity was measured using fluorescence spectroscopy. Anti-tumour activity of HexaBody-CD38 was assessed in patient-derived xenograft mouse models in vivo. Findings: HexaBody-CD38 binds a unique epitope on CD38 and induced potent CDC in multiple myeloma (MM), acute myeloid leukaemia (AML), and B-cell non-Hodgkin lymphoma (B-NHL) cells. Anti-tumour activity was confirmed in patient-derived xenograft models in vivo. Sensitivity to HexaBody-CD38 correlated with CD38 expression level and was inversely correlated with expression of complement regulatory proteins. Compared to daratumumab, HexaBody-CD38 showed enhanced CDC in cell lines with lower levels of CD38 expression, without increasing lysis of healthy leukocytes. More effective CDC was also confirmed in primary MM cells. Furthermore, HexaBody-CD38 efficiently induced ADCC, ADCP, trogocytosis, and apoptosis after Fc-crosslinking. Moreover, HexaBody-CD38 strongly inhibited CD38 cyclase activity, which is hypothesized to relieve immune suppression in the tumour microenvironment. Interpretation: Based on these preclinical studies, a clinical trial was initiated to assess the clinical safety of HexaBody-CD38 in patients with MM. Funding: Genmab.

وصف الملف: electronic resource

Relation: http://www.sciencedirect.com/science/article/pii/S2352396423002281; https://doaj.org/toc/2352-3964

URL الوصول: https://doaj.org/article/f33bd39a5fdd41bc885381f56bdbe832

المؤلفون: Kate Sasser, Kristel Kemper, Ellis Gielen, Mischa Houtkamp, Peter Boross, Stefanie De Poot, Patrick Engelberts, Bart de Goeij, David Satijn

المصدر: Journal for ImmunoTherapy of Cancer, Vol 8, Iss Suppl 3 (2020)

مصطلحات موضوعية: Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

وصف الملف: electronic resource

Relation: https://doaj.org/toc/2051-1426

URL الوصول: https://doaj.org/article/cba5dcfc8a634b10bc5ba77b06d69ba0

المؤلفون: Ignacio Melero, Maria Jure-Kunkel, Uğur Şahin, Tahamtan Ahmadi, Ulf Forssmann, Özlem Türeci, Kate Sasser, Eleni Lagkadinou, Gaurav Bajaj, Esther C.W. Breij, Sebastian Kreiter, David Satijn, Mustafa Diken, Mark Fereshteh, Edward N. van den Brink, Aras Toker, Theo S. Plantinga, Juliane Quinkhardt, Angelica Sette, Fulvia Vascotto, Dennis Verzijl, Eliana Stanganello, Saskia M. Burm, Theodora W. Salcedo, Bianca Sänger, Jordan M. Blum, Kristina B. Schoedel, Maria E. Rodriguez-Ruiz, Guzman Alonso, Patricia M. LoRusso, Emiliano Calvo, Corinne Maurice-Dror, Eytan Ben-Ami, Ravit Geva, Friederike Gieseke, Isil Altintas, Elena Garralda, Alexander Muik

الوصف: Checkpoint inhibitors (CPI) have revolutionized the treatment paradigm for advanced solid tumors; however, there remains an opportunity to improve response rates and outcomes. In preclinical models, 4-1BB costimulation synergizes with CPIs targeting the programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) axis by activating cytotoxic T-cell–mediated antitumor immunity. DuoBody-PD-L1×4-1BB (GEN1046) is an investigational, first-in-class bispecific immunotherapy agent designed to act on both pathways by combining simultaneous and complementary PD-L1 blockade and conditional 4-1BB stimulation in one molecule. GEN1046 induced T-cell proliferation, cytokine production, and antigen-specific T-cell–mediated cytotoxicity superior to clinically approved PD-(L)1 antibodies in human T-cell cultures and exerted potent antitumor activity in transplantable mouse tumor models. In dose escalation of the ongoing first-in-human study in heavily pretreated patients with advanced refractory solid tumors (NCT03917381), GEN1046 demonstrated pharmacodynamic immune effects in peripheral blood consistent with its mechanism of action, manageable safety, and early clinical activity [disease control rate: 65.6% (40/61)], including patients resistant to prior PD-(L)1 immunotherapy.Significance:DuoBody-PD-L1×4-1BB (GEN1046) is a first-in-class bispecific immunotherapy with a manageable safety profile and encouraging preclinical and early clinical activity. With its ability to confer clinical benefit in tumors typically less sensitive to CPIs, GEN1046 may fill a clinical gap in CPI-relapsed or refractory disease or as a combination therapy with CPIs.See related commentary by Li et al., p. 1184.This article is highlighted in the In This Issue feature, p. 1171

URL الوصول: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::77571654a67b8230111048825587e8ec
https://doi.org/10.1158/2159-8290.c.6549569

المؤلفون: Ignacio Melero, Maria Jure-Kunkel, Uğur Şahin, Tahamtan Ahmadi, Ulf Forssmann, Özlem Türeci, Kate Sasser, Eleni Lagkadinou, Gaurav Bajaj, Esther C.W. Breij, Sebastian Kreiter, David Satijn, Mustafa Diken, Mark Fereshteh, Edward N. van den Brink, Aras Toker, Theo S. Plantinga, Juliane Quinkhardt, Angelica Sette, Fulvia Vascotto, Dennis Verzijl, Eliana Stanganello, Saskia M. Burm, Theodora W. Salcedo, Bianca Sänger, Jordan M. Blum, Kristina B. Schoedel, Maria E. Rodriguez-Ruiz, Guzman Alonso, Patricia M. LoRusso, Emiliano Calvo, Corinne Maurice-Dror, Eytan Ben-Ami, Ravit Geva, Friederike Gieseke, Isil Altintas, Elena Garralda, Alexander Muik

الوصف: Supplementary Figure from Preclinical Characterization and Phase I Trial Results of a Bispecific Antibody Targeting PD-L1 and 4-1BB (GEN1046) in Patients with Advanced Refractory Solid Tumors

URL الوصول: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::9e568b16421048c1e79b8dfceca7e687
https://doi.org/10.1158/2159-8290.22541198.v1

المؤلفون: Paul W.H.I. Parren, Patrick H.C. van Berkel, David Miao, Gary Chen, Tong Zhu, Alisher Khasanov, Wim K. Bleeker, Richard Wubbolts, Claudia M. Freitag, David Satijn, Bart E.C.G. de Goeij

الوصف: Supplementary Method S1: Quantitative determination of cell surface antigens. Supplementary Method S2: Synthesis of Duostatin-3. Supplementary Table S1: Apparent antibody affinities. Supplementary Figure S1: Distribution of HER2, EGFR and TF in unstimulated HCC1954 cells. Supplementary Figure S2: Endosomal and lysosomal colocalisation of TF, EGFR and HER2 in tumor cells after treatment with target-specific antibodies. Supplementary Figure S3: Flow cytometry analysis of SK-OV-3 cells after ADC-treatment.

URL الوصول: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::3d375554c2fbef2ec6053c3bef07e2fc
https://doi.org/10.1158/1535-7163.22502260

المؤلفون: Paul W.H.I. Parren, David Miao, Richard Wubbolts, David Satijn, Esther C.W. Breij, Hendrik ten Napel, Tom Vink, Bart E.C.G. de Goeij

الوصف: Schematic overview of the mechanism of action of bsHER2xCD63his-ADC

URL الوصول: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::55bbcdb01d2ccc5fb6b610c22894bb8f
https://doi.org/10.1158/1535-7163.22506576

المؤلفون: Paul W.H.I. Parren, David Miao, Richard Wubbolts, David Satijn, Esther C.W. Breij, Hendrik ten Napel, Tom Vink, Bart E.C.G. de Goeij

الوصف: Supplementary Figure legends for figures S1, S2 and S3

URL الوصول: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::891230aa29d0679016467a2484f66dcb
https://doi.org/10.1158/1535-7163.22506573.v1

المؤلفون: Paul W.H.I. Parren, David Miao, Richard Wubbolts, David Satijn, Esther C.W. Breij, Hendrik ten Napel, Tom Vink, Bart E.C.G. de Goeij

الوصف: Antibody–drug conjugates (ADC) are designed to be stable in circulation and to release potent cytotoxic drugs intracellularly following antigen-specific binding, uptake, and degradation in tumor cells. Efficient internalization and routing to lysosomes where proteolysis can take place is therefore essential. For many cell surface proteins and carbohydrate structures on tumor cells, however, the magnitude of these processes is insufficient to allow for an effective ADC approach. We hypothesized that we could overcome this limitation by enhancing lysosomal ADC delivery via a bispecific antibody (bsAb) approach, in which one binding domain would provide tumor specificity, whereas the other binding domain would facilitate targeting to the lysosomal compartment. We therefore designed a bsAb in which one binding arm specifically targeted CD63, a protein that is described to shuttle between the plasma membrane and intracellular compartments, and combined it in a bsAb with a HER2 binding arm, which was selected as model antigen for tumor-specific binding. The resulting bsHER2xCD63his demonstrated strong binding, internalization and lysosomal accumulation in HER2-positive tumor cells, and minimal internalization into HER2-negative cells. By conjugating bsHER2xCD63his to the microtubule-disrupting agent duostatin-3, we were able to demonstrate potent cytotoxicity of bsHER2xCD63his-ADC against HER2-positive tumors, which was not observed with monovalent HER2- and CD63-specific ADCs. Our data demonstrate, for the first time, that intracellular trafficking of ADCs can be improved using a bsAb approach that targets the lysosomal membrane protein CD63 and provide a rationale for the development of novel bsADCs that combine tumor-specific targeting with targeting of rapidly internalizing antigens. Mol Cancer Ther; 15(11); 2688–97. ©2016 AACR.

URL الوصول: https://explore.openaire.eu/search/publication?articleId=doi_________::8b52d6e2beb81895041ffd3a36f43115
https://doi.org/10.1158/1535-7163.c.6538437.v1

المؤلفون: Paul W.H.I. Parren, David Satijn, Wim K. Bleeker, Mischa Houtkamp, Vibeke Breinholt Miller, John Francis, Ali Amirkhosravi, Danita H. Schuurhuis, Sandra Verploegen, Bart E.C.G. de Goeij, Esther C.W. Breij

الوصف: PDF file - 27K, Antibody cross-competition studies; Alphascreen Assay to detect ERK phosphorylation.

URL الوصول: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::22401580ff243e444061f06e1169f5a8
https://doi.org/10.1158/0008-5472.22401593.v1