Fibroblast Activation Protein α-Targeted CD40 Agonism Abrogates Systemic Toxicity and Enables Administration of High Doses to Induce Effective Antitumor Immunity.

Autor:	Sum E; Roche Innovation Center Zurich (RICZ), Roche Pharmaceutical Research and Early Development (pRED), Schlieren, Switzerland., Rapp M; Roche Innovation Center Munich (RICM), pRED, Penzberg, Germany., Fröbel P; Roche Innovation Center Zurich (RICZ), Roche Pharmaceutical Research and Early Development (pRED), Schlieren, Switzerland., Le Clech M; Roche Innovation Center Zurich (RICZ), Roche Pharmaceutical Research and Early Development (pRED), Schlieren, Switzerland., Dürr H; Roche Innovation Center Munich (RICM), pRED, Penzberg, Germany., Giusti AM; Roche Innovation Center Zurich (RICZ), Roche Pharmaceutical Research and Early Development (pRED), Schlieren, Switzerland., Perro M; Roche Innovation Center Zurich (RICZ), Roche Pharmaceutical Research and Early Development (pRED), Schlieren, Switzerland., Speziale D; Roche Innovation Center Zurich (RICZ), Roche Pharmaceutical Research and Early Development (pRED), Schlieren, Switzerland., Kunz L; Roche Innovation Center Zurich (RICZ), Roche Pharmaceutical Research and Early Development (pRED), Schlieren, Switzerland., Menietti E; Roche Innovation Center Zurich (RICZ), Roche Pharmaceutical Research and Early Development (pRED), Schlieren, Switzerland., Brünker P; Roche Innovation Center Zurich (RICZ), Roche Pharmaceutical Research and Early Development (pRED), Schlieren, Switzerland., Hopfer U; Roche Innovation Center Basel (RICB), pRED, Basel, Switzerland., Lechmann M; Roche Innovation Center Munich (RICM), pRED, Penzberg, Germany., Sobieniecki A; Roche Innovation Center Zurich (RICZ), Roche Pharmaceutical Research and Early Development (pRED), Schlieren, Switzerland., Appelt B; Roche Innovation Center Zurich (RICZ), Roche Pharmaceutical Research and Early Development (pRED), Schlieren, Switzerland., Adelfio R; Roche Innovation Center Zurich (RICZ), Roche Pharmaceutical Research and Early Development (pRED), Schlieren, Switzerland., Nicolini V; Roche Innovation Center Zurich (RICZ), Roche Pharmaceutical Research and Early Development (pRED), Schlieren, Switzerland., Freimoser-Grundschober A; Roche Innovation Center Zurich (RICZ), Roche Pharmaceutical Research and Early Development (pRED), Schlieren, Switzerland., Jordaan W; Roche Innovation Center Zurich (RICZ), Roche Pharmaceutical Research and Early Development (pRED), Schlieren, Switzerland., Labiano S; Department of Fundamental Oncology, University of Lausanne, Epalinges, Switzerland., Weber F; Roche Innovation Center Basel (RICB), pRED, Basel, Switzerland., Emrich T; Roche Innovation Center Munich (RICM), pRED, Penzberg, Germany., Christen F; Roche Innovation Center Basel (RICB), pRED, Basel, Switzerland., Essig B; Roche Innovation Center Munich (RICM), pRED, Penzberg, Germany., Romero P; Department of Fundamental Oncology, University of Lausanne, Epalinges, Switzerland., Trumpfheller C; Roche Innovation Center Zurich (RICZ), Roche Pharmaceutical Research and Early Development (pRED), Schlieren, Switzerland. pablo.umana@roche.com christine.trumpfheller@roche.com., Umaña P; Roche Innovation Center Zurich (RICZ), Roche Pharmaceutical Research and Early Development (pRED), Schlieren, Switzerland. pablo.umana@roche.com christine.trumpfheller@roche.com.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2021 Jul 15; Vol. 27 (14), pp. 4036-4053. Date of Electronic Publication: 2021 Mar 26.
DOI:	10.1158/1078-0432.CCR-20-4001
Abstrakt:	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 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 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. Conclusions: 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. (©2021 American Association for Cancer Research.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu