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

Claus, ChristinaFerrara, ClaudiaXu, WeiSam, JohannesLang, SabineUhlenbrock, FranziskaAlbrecht, RosmarieHerter, SylviaSchlenker, RamonaHusser, TamaraDiggelmann, SarahChallier, JohnMossner, EkkehardHosse, Ralf J.Hofer, ThomasBrunker, PeterJoseph, CatherineBenz, JorgRingler, PhilippeStahlberg, HenningLauer, MatthiasPerro, MarioChen, StanfordKuttel, ChristineMohan, Preethi L. BhavaniNicolini, ValeriaBirk, Martina CarolaOngaro, AmandinePrince, ChristopheGianotti, RetoDugan, GregoryWhitlow, Christopher T.Kumar, KiranSai, SolingapuramCaudell, David L.Burgos-Rodriguez, Armando G.Cline, J. MarkHettich, MichaelCeppi, MaurizioGiusti, Anna MariaCrameri, FlavioDriessen, WouterMorcos, Peter N.Freimoser-Grundschober, AnneLevitsky, VictorAmann, MariaGrau-Richards, Sandravon Hirschheydt, ThomasTournaviti, StellaMolhoj, MichaelFauti, TanjaHeinzelmann-Schwarz, ViolaTeichgraber, VolkerColombetti, SaraBacac, MarinaZippelius, AlfredKlein, ChristianUmana, Pablo2020-02-132020-02-132020-02-132019-06-1210.1126/scitranslmed.aav5989https://infoscience.epfl.ch/handle/20.500.14299/165482Endogenous 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 Fc gamma 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 Fc gamma R 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-gamma 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.Tumor-targeted 4-1BB agonists for combination with T cell bispecific antibodies as off-the-shelf therapytext::journal::journal article::research article