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Tumor-targeted 4-1BB agonists for combination with T cell bispecific antibodies as off-the-shelf therapy

Claus, Christina and Ferrara, Claudia and Xu, Wei and Sam, Johannes and Lang, Sabine and Uhlenbrock, Franziska and Albrecht, Rosmarie and Herter, Sylvia and Schlenker, Ramona and Hüsser, Tamara and Diggelmann, Sarah and Challier, John and Mössner, Ekkehard and Hosse, Ralf J. and Hofer, Thomas and Brünker, Peter and Joseph, Catherine and Benz, Jörg and Ringler, Philippe and Stahlberg, Henning and Lauer, Matthias and Perro, Mario and Chen, Stanford and Küttel, Christine and Bhavani Mohan, Preethi L. and Nicolini, Valeria and Birk, Martina Carola and Ongaro, Amandine and Prince, Christophe and Gianotti, Reto and Dugan, Gregory and Whitlow, Christopher T. and Solingapuram Sai, Kiran Kumar and Caudell, David L. and Burgos-Rodriguez, Armando G. and Cline, J. Mark and Hettich, Michael and Ceppi, Maurizio and Giusti, Anna Maria and Crameri, Flavio and Driessen, Wouter and Morcos, Peter N. and Freimoser-Grundschober, Anne and Levitsky, Victor and Amann, Maria and Grau-Richards, Sandra and von Hirschheydt, Thomas and Tournaviti, Stella and Mølhøj, Michael and Fauti, Tanja and Heinzelmann-Schwarz, Viola and Teichgräber, Volker and Colombetti, Sara and Bacac, Marina and Zippelius, Alfred and Klein, Christian and Umaña, Pablo. (2019) Tumor-targeted 4-1BB agonists for combination with T cell bispecific antibodies as off-the-shelf therapy. Science Translational Medicine, 11 (496). eaav5989.

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Official URL: https://edoc.unibas.ch/70989/

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Abstract

Endogenous costimulatory molecules on T cells such as 4-1BB (CD137) can be leveraged for cancer immunotherapy. Systemic administration of agonistic anti-4-1BB antibodies, although effective preclinically, has not advanced to phase 3 trials because they have been hampered by both dependency on Fcγ receptor-mediated hyperclustering and hepatotoxicity. To overcome these issues, we engineered proteins simultaneously targeting 4-1BB and a tumor stroma or tumor antigen: FAP-4-1BBL (RG7826) and CD19-4-1BBL. In the presence of a T cell receptor signal, they provide potent T cell costimulation strictly dependent on tumor antigen-mediated hyperclustering without systemic activation by FcγR binding. We could show targeting of FAP-4-1BBL to FAP-expressing tumor stroma and lymph nodes in a colorectal cancer-bearing rhesus monkey. Combination of FAP-4-1BBL with tumor antigen-targeted T cell bispecific (TCB) molecules in human tumor samples led to increased IFN-γ and granzyme B secretion. Further, combination of FAP- or CD19-4-1BBL with CEA-TCB (RG7802) or CD20-TCB (RG6026), respectively, resulted in tumor remission in mouse models, accompanied by intratumoral accumulation of activated effector CD8; +; T cells. FAP- and CD19-4-1BBL thus represent an off-the-shelf combination immunotherapy without requiring genetic modification of effector cells for the treatment of solid and hematological malignancies.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Structural Biology & Biophysics > Structural Biology (Stahlberg)
UniBasel Contributors:Stahlberg, Henning
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:American Association for the Advancement of Science
ISSN:1946-6234
e-ISSN:1946-6242
Note:Publication type according to Uni Basel Research Database: Journal article
Identification Number:
Last Modified:17 Aug 2020 13:10
Deposited On:17 Aug 2020 13:10

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