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

  • Sci Transl Med. 2019 Jun 12;11(496):eaav5989. doi: 10.1126/scitranslmed.aav5989.
Christina Claus  1 ,  Claudia Ferrara  1 ,  Wei Xu  1 ,  Johannes Sam  1 ,  Sabine Lang  1 ,  Franziska Uhlenbrock  2 ,  Rosmarie Albrecht  1 ,  Sylvia Herter  1 ,  Ramona Schlenker  1 ,  Tamara Hüsser  1 ,  Sarah Diggelmann  1 ,  John Challier  1 ,  Ekkehard Mössner  1 ,  Ralf J Hosse  1 ,  Thomas Hofer  1 ,  Peter Brünker  1 ,  Catherine Joseph  3 ,  Jörg Benz  3 ,  Philippe Ringler  4 ,  Henning Stahlberg  4 ,  Matthias Lauer  3 ,  Mario Perro  1 ,  Stanford Chen  1 ,  Christine Küttel  1 ,  Preethi L Bhavani Mohan  1 ,  Valeria Nicolini  1 ,  Martina Carola Birk  1 ,  Amandine Ongaro  1 ,  Christophe Prince  1 ,  Reto Gianotti  1 ,  Gregory Dugan  5 ,  Christopher T Whitlow  5 ,  Kiran Kumar Solingapuram Sai  5 ,  David L Caudell  5 ,  Armando G Burgos-Rodriguez  6 ,  J Mark Cline  5 ,  Michael Hettich  3 ,  Maurizio Ceppi  3 ,  Anna Maria Giusti  3 ,  Flavio Crameri  3 ,  Wouter Driessen  3 ,  Peter N Morcos  7 ,  Anne Freimoser-Grundschober  1 ,  Victor Levitsky  1 ,  Maria Amann  1 ,  Sandra Grau-Richards  1 ,  Thomas von Hirschheydt  8 ,  Stella Tournaviti  8 ,  Michael Mølhøj  8 ,  Tanja Fauti  1 ,  Viola Heinzelmann-Schwarz  9 ,  Volker Teichgräber  1 ,  Sara Colombetti  1 ,  Marina Bacac  1 ,  Alfred Zippelius  2 ,  Christian Klein  1 ,  Pablo Umaña  10
Affiliations
  • 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. [email protected].
PMID: 31189721 DOI: 10.1126/scitranslmed.aav5989
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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