2. Academic Validation
  3. Simlukafusp alfa (FAP-IL2v) immunocytokine is a versatile combination partner for cancer immunotherapy

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

  • MAbs. 2021 Jan-Dec;13(1):1913791. doi: 10.1080/19420862.2021.1913791.
Inja Waldhauer 1,  Valeria Gonzalez-Nicolini 1,  Anne Freimoser-Grundschober 1,  Tapan K Nayak 2,  Linda Fahrni 1,  Ralf J Hosse 1,  Danny Gerrits 3,  Edwin J W Geven 3,  Johannes Sam 1,  Sabine Lang 1,  Esther Bommer 1,  Virginie Steinhart 1,  Elisabeth Husar 2,  Sara Colombetti 1,  Erwin Van Puijenbroek 1,  Markus Neubauer 4,  J Mark Cline 5,  Pradeep K Garg 5,  Gregory Dugan 5,  Federica Cavallo 6,  Gonzalo Acuna 1,  Jehad Charo 1,  Volker Teichgräber 2,  Stefan Evers 2,  Otto C Boerman 3,  Marina Bacac 1,  Ekkehard Moessner 1,  Pablo Umaña 1,  Christian Klein 1
Affiliations

Affiliations

  • 1 Roche Innovation Center Zurich, Zurich, Switzerland.
  • 2 Roche Innovation Center Basel, Basel, Switzerland.
  • 3 Department of Radiology and Nuclear Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
  • 4 Roche Innovation Center Munich, Penzberg, Germany.
  • 5 Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA.
  • 6 Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Turin, Italy.
PMID: 33974508 DOI: 10.1080/19420862.2021.1913791
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.

Keywords

FAP-il2v; fibroblast activation protein; immunocytokine; interleukin-2; rg7461.

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