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
  • 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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