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Sci Transl Med. 2019 Jun 12;11(496). pii: eaav5989. doi: 10.1126/scitranslmed.aav5989.

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

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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 Basel, pRED, Grenzacherstrasse 124, 4070 Basel, Switzerland.
University of Basel, Center for Cellular Imaging and NanoAnalytics (C-CINA), Biozentrum, Klingelbergstrasse 70, 4056 Basel, Switzerland.
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.
Roche Innovation Center New York, pRED, 430 E 29th St, New York, NY 10016, USA.
Roche Innovation Center Munich, pRED, Nonnenwald 2, 82377 Penzberg, Germany.
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.


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.

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