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Supplementary Figures 1-6 from Fibroblast Activation Protein α-Targeted CD40 Agonism Abrogates Systemic Toxicity and Enables Administration of High Doses to Induce Effective Antitumor Immunity

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posted on 2023-03-31, 22:40 authored by Eva Sum, Moritz Rapp, Philipp Fröbel, Marine Le Clech, Harald Dürr, Anna Maria Giusti, Mario Perro, Dario Speziale, Leo Kunz, Elena Menietti, Peter Brünker, Ulrike Hopfer, Martin Lechmann, Andrzej Sobieniecki, Birte Appelt, Roberto Adelfio, Valeria Nicolini, Anne Freimoser-Grundschober, Whitney Jordaan, Sara Labiano, Felix Weber, Thomas Emrich, François Christen, Birgit Essig, Pedro Romero, Christine Trumpfheller, Pablo Umaña

Supplementary Figure 1 shows more details on the mode of action and design of the used antibodies. Supplementary Figure 2 displays additional APC activation data of the human and murine FAP-CD40 molecules. Supplementary Figure 3 shows additional data for FRC in vitro assays and the OVA vaccination study. Supplementary Figure 4 shows additional data on the in vivo study comparing FAP-huCD40 and SGN40 moIgG1. Supplementary Figure 5 displays additional data on the in vivo comparison of selicrelumab and FAP-huCD40. Supplementary Figure 6 shows the data of a FAP-huCD40 dose escalation study in cynomolgus monkeys.

Funding

Swiss Cancer League

the Swiss National Science Foundation

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ARTICLE ABSTRACT

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. 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 MC38-FAP and KPC-4662-huCEA murine tumor models. 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 nontargeted 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 nontargeted 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 nontargeted CD40 agonists displayed strong systemic but limited intratumoral effects. FAP-CD40 abrogates the systemic toxicity associated with nontargeted CD40 agonists. This enables administration of high doses, essential for overcoming CD40 sink effects and inducing antitumor immunity. Consequently, FAP-targeted CD40 agonism represents a promising strategy to exploit the full potential of CD40 signaling for CIT.

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    Clinical Cancer Research

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    ImmunologyDendritic cellsImmunomodulationImmunotherapyAgonist antibodies

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