An Open-Label, Multicenter, Phase Ib Study to Evaluate Safety and Therapeutic Activity of RO6874281, an Immunocytokine, Consisting of Interleukin-2 Variant (IL-2v) Targeting Fibroblast Activation Protein-Α (FAP), in Combination with Pembrolizumab (Anti-PD-1), in Participants with Advanced or Metastatic Melanoma

This is an open-label, multicenter, Phase Ib study to evaluate the safety and therapeutic activity of RO6874281 in combination with pembrolizumab. The study will consist of 3 parts: a safety run-in (Part I: Cohorts 1.1. and 1.2) and two expansion parts (Parts II and III). Part II will start once all participants in Cohort 1.1 have completed the observation period. Part III will start once all participants in Cohorts 1.1 and 1.2 have completed the observation period.

Start Date24 Jun 2019

Sponsor / Collaborator

Hoffmann-La Roche, Inc.

100 Clinical Results associated with FAP x IL-2Rβγ

100 Translational Medicine associated with FAP x IL-2Rβγ

0 Patents (Medical) associated with FAP x IL-2Rβγ

Literatures (Medical) associated with FAP x IL-2Rβγ

01 Jan 2021·mAbsQ2 · MEDICINE

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

Q2 · MEDICINE

Article

Author: Gonzalez-Nicolini, Valeria ; Bacac, Marina ; Evers, Stefan ; Van Puijenbroek, Erwin ; Umaña, Pablo ; Fahrni, Linda ; Sam, Johannes ; Bommer, Esther ; Cline, J. Mark ; Dugan, Gregory ; Teichgräber, Volker ; Gerrits, Danny ; Colombetti, Sara ; Cavallo, Federica ; Freimoser-Grundschober, Anne ; Steinhart, Virginie ; Waldhauer, Inja ; Charo, Jehad ; Nayak, Tapan K ; Moessner, Ekkehard ; Husar, Elisabeth ; Garg, Pradeep K. ; Hosse, Ralf J. ; Klein, Christian ; Acuna, Gonzalo ; Neubauer, Markus ; Boerman, Otto C. ; Lang, Sabine ; Geven, Edwin J. W.

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.

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