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Tumor-targeted 4-1BB agonists for combination with T cell bispecific antibodies as off-the-shelf therapy.
Sci Transl Med. 2019 06 12; 11(496)ST

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.

Authors+Show Affiliations

Roche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development (pRED), Wagistrasse 10, 8952 Schlieren, Switzerland.Roche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development (pRED), Wagistrasse 10, 8952 Schlieren, Switzerland.Roche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development (pRED), Wagistrasse 10, 8952 Schlieren, Switzerland.Roche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development (pRED), Wagistrasse 10, 8952 Schlieren, Switzerland.Roche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development (pRED), Wagistrasse 10, 8952 Schlieren, Switzerland.University of Basel, Department of Biomedicine, Hebelstrasse 20, 4031 Basel, Switzerland.Roche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development (pRED), Wagistrasse 10, 8952 Schlieren, Switzerland.Roche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development (pRED), Wagistrasse 10, 8952 Schlieren, Switzerland.Roche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development (pRED), Wagistrasse 10, 8952 Schlieren, Switzerland.Roche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development (pRED), Wagistrasse 10, 8952 Schlieren, Switzerland.Roche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development (pRED), Wagistrasse 10, 8952 Schlieren, Switzerland.Roche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development (pRED), Wagistrasse 10, 8952 Schlieren, Switzerland.Roche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development (pRED), Wagistrasse 10, 8952 Schlieren, Switzerland.Roche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development (pRED), Wagistrasse 10, 8952 Schlieren, Switzerland.Roche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development (pRED), Wagistrasse 10, 8952 Schlieren, Switzerland.Roche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development (pRED), Wagistrasse 10, 8952 Schlieren, Switzerland.Roche Innovation Center Basel, pRED, Grenzacherstrasse 124, 4070 Basel, Switzerland.Roche Innovation Center Basel, pRED, Grenzacherstrasse 124, 4070 Basel, Switzerland.University of Basel, Center for Cellular Imaging and NanoAnalytics (C-CINA), Biozentrum, Klingelbergstrasse 70, 4056 Basel, Switzerland.University of Basel, Center for Cellular Imaging and NanoAnalytics (C-CINA), Biozentrum, Klingelbergstrasse 70, 4056 Basel, Switzerland.Roche Innovation Center Basel, pRED, Grenzacherstrasse 124, 4070 Basel, Switzerland.Roche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development (pRED), Wagistrasse 10, 8952 Schlieren, Switzerland.Roche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development (pRED), Wagistrasse 10, 8952 Schlieren, Switzerland.Roche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development (pRED), Wagistrasse 10, 8952 Schlieren, Switzerland.Roche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development (pRED), Wagistrasse 10, 8952 Schlieren, Switzerland.Roche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development (pRED), Wagistrasse 10, 8952 Schlieren, Switzerland.Roche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development (pRED), Wagistrasse 10, 8952 Schlieren, Switzerland.Roche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development (pRED), Wagistrasse 10, 8952 Schlieren, Switzerland.Roche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development (pRED), Wagistrasse 10, 8952 Schlieren, Switzerland.Roche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development (pRED), Wagistrasse 10, 8952 Schlieren, Switzerland.Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA.Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA.Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA.Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA.Caribbean Primate Research Center, PO Box 1053, Sabana Seca, Puerto Rico 00952, USA.Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA.Roche Innovation Center Basel, pRED, Grenzacherstrasse 124, 4070 Basel, Switzerland.Roche Innovation Center Basel, pRED, Grenzacherstrasse 124, 4070 Basel, Switzerland.Roche Innovation Center Basel, pRED, Grenzacherstrasse 124, 4070 Basel, Switzerland.Roche Innovation Center Basel, pRED, Grenzacherstrasse 124, 4070 Basel, Switzerland.Roche Innovation Center Basel, pRED, Grenzacherstrasse 124, 4070 Basel, Switzerland.Roche Innovation Center New York, pRED, 430 E 29th St, New York, NY 10016, USA.Roche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development (pRED), Wagistrasse 10, 8952 Schlieren, Switzerland.Roche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development (pRED), Wagistrasse 10, 8952 Schlieren, Switzerland.Roche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development (pRED), Wagistrasse 10, 8952 Schlieren, Switzerland.Roche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development (pRED), Wagistrasse 10, 8952 Schlieren, Switzerland.Roche Innovation Center Munich, pRED, Nonnenwald 2, 82377 Penzberg, Germany.Roche Innovation Center Munich, pRED, Nonnenwald 2, 82377 Penzberg, Germany.Roche Innovation Center Munich, pRED, Nonnenwald 2, 82377 Penzberg, Germany.Roche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development (pRED), Wagistrasse 10, 8952 Schlieren, Switzerland.University Hospital Basel, Gynecological Oncology, Spitalstrasse 21, 4031 Basel, Switzerland.Roche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development (pRED), Wagistrasse 10, 8952 Schlieren, Switzerland.Roche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development (pRED), Wagistrasse 10, 8952 Schlieren, Switzerland.Roche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development (pRED), Wagistrasse 10, 8952 Schlieren, Switzerland.University of Basel, Department of Biomedicine, Hebelstrasse 20, 4031 Basel, Switzerland.Roche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development (pRED), Wagistrasse 10, 8952 Schlieren, Switzerland.Roche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development (pRED), Wagistrasse 10, 8952 Schlieren, Switzerland. pablo.umana@roche.com.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

31189721

Citation

Claus, Christina, et al. "Tumor-targeted 4-1BB Agonists for Combination With T Cell Bispecific Antibodies as Off-the-shelf Therapy." Science Translational Medicine, vol. 11, no. 496, 2019.
Claus C, Ferrara C, Xu W, et al. Tumor-targeted 4-1BB agonists for combination with T cell bispecific antibodies as off-the-shelf therapy. Sci Transl Med. 2019;11(496).
Claus, C., Ferrara, C., Xu, W., Sam, J., Lang, S., Uhlenbrock, F., Albrecht, R., Herter, S., Schlenker, R., Hüsser, T., Diggelmann, S., Challier, J., Mössner, E., Hosse, R. J., Hofer, T., Brünker, P., Joseph, C., Benz, J., Ringler, P., ... Umaña, P. (2019). Tumor-targeted 4-1BB agonists for combination with T cell bispecific antibodies as off-the-shelf therapy. Science Translational Medicine, 11(496). https://doi.org/10.1126/scitranslmed.aav5989
Claus C, et al. Tumor-targeted 4-1BB Agonists for Combination With T Cell Bispecific Antibodies as Off-the-shelf Therapy. Sci Transl Med. 2019 06 12;11(496) PubMed PMID: 31189721.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Tumor-targeted 4-1BB agonists for combination with T cell bispecific antibodies as off-the-shelf therapy. AU - Claus,Christina, AU - Ferrara,Claudia, AU - Xu,Wei, AU - Sam,Johannes, AU - Lang,Sabine, AU - Uhlenbrock,Franziska, AU - Albrecht,Rosmarie, AU - Herter,Sylvia, AU - Schlenker,Ramona, AU - Hüsser,Tamara, AU - Diggelmann,Sarah, AU - Challier,John, AU - Mössner,Ekkehard, AU - Hosse,Ralf J, AU - Hofer,Thomas, AU - Brünker,Peter, AU - Joseph,Catherine, AU - Benz,Jörg, AU - Ringler,Philippe, AU - Stahlberg,Henning, AU - Lauer,Matthias, AU - Perro,Mario, AU - Chen,Stanford, AU - Küttel,Christine, AU - Bhavani Mohan,Preethi L, AU - Nicolini,Valeria, AU - Birk,Martina Carola, AU - Ongaro,Amandine, AU - Prince,Christophe, AU - Gianotti,Reto, AU - Dugan,Gregory, AU - Whitlow,Christopher T, AU - Solingapuram Sai,Kiran Kumar, AU - Caudell,David L, AU - Burgos-Rodriguez,Armando G, AU - Cline,J Mark, AU - Hettich,Michael, AU - Ceppi,Maurizio, AU - Giusti,Anna Maria, AU - Crameri,Flavio, AU - Driessen,Wouter, AU - Morcos,Peter N, AU - Freimoser-Grundschober,Anne, AU - Levitsky,Victor, AU - Amann,Maria, AU - Grau-Richards,Sandra, AU - von Hirschheydt,Thomas, AU - Tournaviti,Stella, AU - Mølhøj,Michael, AU - Fauti,Tanja, AU - Heinzelmann-Schwarz,Viola, AU - Teichgräber,Volker, AU - Colombetti,Sara, AU - Bacac,Marina, AU - Zippelius,Alfred, AU - Klein,Christian, AU - Umaña,Pablo, PY - 2018/10/08/received PY - 2019/05/16/accepted PY - 2019/6/14/entrez PY - 2019/6/14/pubmed PY - 2020/7/1/medline JF - Science translational medicine JO - Sci Transl Med VL - 11 IS - 496 N2 - 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. SN - 1946-6242 UR - https://www.unboundmedicine.com/medline/citation/31189721/Tumor_targeted_4_1BB_agonists_for_combination_with_T_cell_bispecific_antibodies_as_off_the_shelf_therapy_ L2 - http://stm.sciencemag.org/cgi/pmidlookup?view=short&pmid=31189721 DB - PRIME DP - Unbound Medicine ER -