TY - JOUR TI - Fibroblast activation protein α-targeted CD40 agonism abrogates systemic toxicity and enables administration of high doses to induce effective anti-tumor immunity AU - Sum, Eva AU - Rapp, Moritz AU - Fröbel, Philipp AU - Clech, Marine Le AU - Dürr, Harald AU - Giusti, Anna Maria F. AU - Perro, Mario AU - Speziale, Dario AU - Kunz, Leo AU - Menietti, Elena AU - Brünker, Peter AU - Hopfer, Ulrike AU - Lechmann, Martin AU - Sobieniecki, Andrzej AU - Appelt, Birte AU - Adelfio, Roberto AU - Nicolini, Valeria G. AU - Freimoser-Grundschober, Anne AU - Jordaan, Whitney Shannon AU - Labiano, Sara AU - Weber, Felix C. AU - Emrich, Thomas AU - Christen, François AU - Essig, Birgit AU - Romero, Pedro AU - Trumpfheller, Christine AU - Umana, Pablo T2 - Clinical Cancer Research AB - Purpose: CD40 agonists hold great promise for cancer immunotherapy (CIT) as they enhance dendritic cell (DC) activation and concomitant tumor-specific T cell priming. However, the broad expression of CD40 accounts for sink and side effects, hampering the efficacy of anti-CD40 antibodies. We hypothesized that these limitations can be overcome by selectively targeting CD40 agonism to the tumor. Therefore, we developed a bispecific FAP-CD40 antibody, which induces CD40 stimulation solely in presence of fibroblast activation protein α (FAP), a protease specifically expressed in the tumor stroma. Experimental Design: FAP-CD40's in vitro activity and FAP-specificity were validated by antigen-presenting cell (APC) activation and T cell priming assays. In addition, FAP-CD40 was tested in subcutaneous (s.c.) MC38-FAP and KPC-4662-huCEA murine tumor models. Results: FAP-CD40 triggered a potent, strictly FAP-dependent CD40 stimulation in vitro. In vivo, FAP-CD40 strongly enhanced T cell inflammation and growth inhibition of KPC-4662-huCEA tumors. Unlike non-targeted CD40 agonists, FAP-CD40 mediated complete regression of MC38-FAP tumors, entailing long-term protection. A high dose of FAP-CD40 was indispensable for these effects. While non-targeted CD40 agonists induced substantial side effects, highly dosed FAP-CD40 was well tolerated. FAP-CD40 preferentially accumulated in the tumor, inducing predominantly intratumoral immune activation, whereas non-targeted CD40 agonists displayed strong systemic but limited intratumoral effects. Conclusions: FAP-CD40 abrogates the systemic toxicity associated with non-targeted CD40 agonists. This enables administration of high doses, essential for overcoming CD40 sink effects and inducing anti-tumor immunity. Consequently, FAP-targeted CD40 agonism represents a promising strategy to exploit the full potential of CD40 signaling for CIT. DA - 2021/01/01/ PY - 2021 DO - 10.1158/1078-0432.CCR-20-4001 DP - clincancerres.aacrjournals.org J2 - Clin Cancer Res LA - en SN - 1078-0432, 1557-3265 UR - https://clincancerres.aacrjournals.org/content/early/2021/03/25/1078-0432.CCR-20-4001 Y2 - 2021/03/29/17:57:49 ER -