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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.

Author information

1
Roche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development (pRED), Wagistrasse 10, 8952 Schlieren, Switzerland.
2
University of Basel, Department of Biomedicine, Hebelstrasse 20, 4031 Basel, Switzerland.
3
Roche Innovation Center Basel, pRED, Grenzacherstrasse 124, 4070 Basel, Switzerland.
4
University of Basel, Center for Cellular Imaging and NanoAnalytics (C-CINA), Biozentrum, Klingelbergstrasse 70, 4056 Basel, Switzerland.
5
Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA.
6
Caribbean Primate Research Center, PO Box 1053, Sabana Seca, Puerto Rico 00952, USA.
7
Roche Innovation Center New York, pRED, 430 E 29th St, New York, NY 10016, USA.
8
Roche Innovation Center Munich, pRED, Nonnenwald 2, 82377 Penzberg, Germany.
9
University Hospital Basel, Gynecological Oncology, Spitalstrasse 21, 4031 Basel, Switzerland.
10
Roche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development (pRED), Wagistrasse 10, 8952 Schlieren, Switzerland. pablo.umana@roche.com.

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.

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