1. Tumor-targeted 4-1BB agonists for combination with T cell bispecific antibodies as off-the-shelf therapy
- Author
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Nicolini Valeria G, Amandine Ongaro, Armando G. Burgos-Rodriguez, Christopher T. Whitlow, Wei Xu, Peter N. Morcos, Peter Brünker, Sara Colombetti, Martina Carola Birk, Michael Hettich, Sabine Lang, Christine Küttel, Stella Tournaviti, Tanja Fauti, Pablo Umana, Preethi Latha Bhavani Mohan, Sylvia Herter, Thomas von Hirschheydt, Alfred Zippelius, Johannes Sam, Christina Claus, Marina Bacac, J. Mark Cline, Tamara Hüsser, Mario Perro, Reto Gianotti, Kiran Kumar Solingapuram Sai, Viola Heinzelmann-Schwarz, Matthias E. Lauer, Maurizio Ceppi, Christian Klein, Anna Maria Giusti, Anne Freimoser-Grundschober, Hofer Thomas U, Ralf Hosse, Stanford Chen, Maria Amann, Volker Teichgräber, Rosmarie Albrecht, John Challier, Christophe Prince, Ekkehard Mössner, Jörg Benz, Claudia Ferrara, David L. Caudell, Philippe Ringler, Franziska Uhlenbrock, Sandra Grau-Richards, Henning Stahlberg, Victor Levitsky, Michael Molhoj, Catherine Joseph, Wouter H. P. Driessen, Gregory O. Dugan, Sarah Diggelmann, Ramona Schlenker, and Flavio Crameri
- Subjects
medicine.medical_treatment ,T cell ,T-Lymphocytes ,CD8-Positive T-Lymphocytes ,Article ,Cell Line ,03 medical and health sciences ,0302 clinical medicine ,Cancer immunotherapy ,Neoplasms ,Antibodies, Bispecific ,medicine ,Humans ,Cell Proliferation ,030304 developmental biology ,0303 health sciences ,Chemistry ,CD137 ,T-cell receptor ,General Medicine ,Immunotherapy ,Tumor antigen ,3. Good health ,Granzyme B ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Cancer research ,Lymph Nodes ,Colorectal Neoplasms ,CD8 - 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.
- Published
- 2019