Simlukafusp alfa (FAP-IL2v) immunocytokine is a versatile combination partner for cancer immunotherapy. Issue 1 (1st January 2021)

• Record Type: Journal Article
• Authors: Waldhauer, Inja; Gonzalez-Nicolini, Valeria; Freimoser-Grundschober, Anne; Nayak, Tapan K; Fahrni, Linda; Hosse, Ralf J.; Gerrits, Danny; Geven, Edwin J. W.; Sam, Johannes; Lang, Sabine; Bommer, Esther; Steinhart, Virginie; Husar, Elisabeth; Colombetti, Sara; Van Puijenbroek, Erwin; Neubauer, Markus; Cline, J. Mark; Garg, Pradeep K.; Dugan, Gregory; Cavallo, Federica; Acuna, Gonzalo; Charo, Jehad; Teichgräber, Volker; Evers, Stefan; Boerman, Otto C.; Bacac, Marina; Moessner, Ekkehard; Umaña, Pablo; Klein, Christian
• Is Part Of: MAbs. Volume 13:Issue 1(2021)
• Publication Date: 2021-01-01
• Subjects: FAP-il2v -- rg7461 -- immunocytokine -- interleukin-2 -- fibroblast activation protein; Monoclonal antibodies -- Therapeutic use -- Periodicals; Monoclonal antibodies -- Periodicals; Antibodies, Monoclonal -- Periodicals; 616.0798
• DOI: 10.1080/19420862.2021.1913791
• Languages: English
• ISSNs: 1942-0862

Abstract

ABSTRACT: Simlukafusp alfa (FAP-IL2v, RO6874281/RG7461) is an immunocytokine comprising an antibody against fibroblast activation protein α (FAP) and an IL-2 variant with a retained affinity for IL-2Rβγ > IL-2 Rβγ and abolished binding to IL-2 Rα. Here, we investigated the immunostimulatory properties of FAP-IL2v and its combination with programmed cell death protein 1 (PD-1) checkpoint inhibition, CD40 agonism, T cell bispecific and antibody-dependent cellular cytotoxicity (ADCC)-mediating antibodies. The binding and immunostimulatory properties of FAP-IL2v were investigated in vitro and compared with FAP-IL2wt. Tumor targeting was investigated in tumor-bearing mice and in a rhesus monkey. The ability of FAP-IL2v to potentiate the efficacy of different immunotherapies was investigated in different xenograft and syngeneic murine tumor models. FAP-IL2v bound IL-2 Rβγ and FAP with high affinity in vitro, inducing dose-dependent proliferation of natural killer (NK) cells and CD4+/CD8+ T cells while being significantly less potent than FAP-IL2wt in activating immunosuppressive regulatory T cells (Tregs). T cells activated by FAP-IL2v were less sensitive to Fas-mediated apoptosis than those activated by FAP-IL2wt. Imaging studies demonstrated improved tumor targeting of FAP-IL2v compared to FAP-IL2wt. Furthermore, FAP-IL2v significantly enhanced the in vitro and in vivo activity of therapeutic antibodies that mediate antibody-dependent or T cell-dependent cellular cytotoxicity (TDCC) and of programmed death-ligand 1 (PD-L1) checkpoint inhibition. The triple combination of FAP-IL2v with an anti-PD-L1 antibody and an agonistic CD40 antibody was most efficacious. These data indicate that FAP-IL2v is a potent immunocytokine that potentiates the efficacy of different T- and NK-cell-based cancer immunotherapies.