Simlukafusp alfa (FAP-IL2v) immunocytokine is a versatile combination partner for cancer immunotherapy

• Published in: mAbs Vol. 13; no. 1; p. 1913791
• Main 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
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis 01.01.2021; Taylor & Francis Group
• Subjects: Animals; Antibodies, Monoclonal - pharmacology; Antineoplastic Agents - pharmacology; Cytokines - pharmacology; Endopeptidases; FAP-il2v; fibroblast activation protein; Humans; immunocytokine; Immunotherapy - methods; interleukin-2; Lymphocyte Activation - drug effects; Macaca mulatta; Membrane Proteins - antagonists & inhibitors; Mice; Neoplasms, Experimental - pathology; Recombinant Fusion Proteins - pharmacology; rg7461; Xenograft Model Antitumor Assays; rg7461; FAP-il2v; interleukin-2; fibroblast activation protein; immunocytokine
• ISSN: 1942-0862; 1942-0870
• DOI: 10.1080/19420862.2021.1913791

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 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 and 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.