Potentiation of PD-L1 blockade with a potency-matched dual cytokine-antibody fusion protein leads to cancer eradication in BALB/c-derived tumors but not in other mouse strains.

Abstract

We have recently described a novel therapeutic antibody product (IL2-F8-TNFmut), featuring the simultaneous fusion of murine IL2 and of a TNF mutant with scFv(F8), an antibody specific to the alternatively-spliced extra domain A of fibronectin (EDA). Here, we report on the in vivo characterization of the anti-cancer activity of IL2-F8-TNFmut in four immunocompetent murine models of cancer, CT26, WEHI-164, F9 teratocarcinoma and Lewis lung carcinoma (LLC), using the product alone or in combination with a monoclonal antibody specific to murine PD-L1. All four models exhibited a strong expression of EDA-fibronectin, which was confined to vascular structures for F9 tumors, while the other three malignancies exhibited a more stromal pattern of staining. A complete and long-lasting tumor eradication of CT26 and WEHI-164 tumors was observed in BALB/c mice when IL2-F8-TNFmut was used in combination with PD-L1 blockade. The combination treatment led to improved tumor growth inhibition in 129/SvEv mice bearing murine teratocarcinoma or in C57BL/6 mice bearing murine LLC, but those cancer cures were difficult to achieve in those models. A microscopic analysis of tumor sections, obtained 24 h after pharmacological treatment, revealed that the PD-L1 antibody had homogenously reached tumor cells in vivo and that the combination of PD-L1 blockade with IL2-F8-TNFmut stimulated an influx of NK cells and of T cells into the neoplastic mass. These data indicate that potency-matched dual-cytokine fusion proteins may be ideally suited to potentiate the therapeutic activity of immune check-point inhibitors.

• Authors: Roberto De Luca, Dario Neri
• Journal: Cancer immunology, immunotherapy : CII (Cancer Immunol Immunother) Vol. 67 Issue 9 Pg. 1381-1391 (Sep 2018) ISSN: 1432-0851 [Electronic] Germany
• PMID: 29971465 (Publication Type: Journal Article)

Chemical References

• Antibodies, Monoclonal
• Antibodies, Monoclonal, Humanized
• B7-H1 Antigen
• Cd274 protein, mouse
• F8 monoclonal antibody
• Fibronectins
• Immunotoxins
• Interleukin-2
• Recombinant Fusion Proteins
• Single-Chain Antibodies
• Tumor Necrosis Factor-alpha

Topics

• Animals
• Antibodies, Monoclonal (immunology)
• Antibodies, Monoclonal, Humanized
• B7-H1 Antigen (antagonists & inhibitors, immunology)
• Female
• Fibronectins (immunology)
• Immunotoxins (genetics, immunology, pharmacology)
• Interleukin-2 (genetics, immunology, pharmacology)
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Neoplasms, Experimental (immunology, therapy)
• Recombinant Fusion Proteins (genetics, immunology, pharmacology)
• Single-Chain Antibodies (immunology)
• Tumor Necrosis Factor-alpha (genetics, immunology, pharmacology)