An Engineered IFNγ-Antibody Fusion Protein with Improved Tumor-Homing Properties

Interferon-gamma (IFN gamma) is one of the central cytokines produced by the innate and adaptive immune systems. IFN gamma directly favors tumor growth control by enhancing the immunogenicity of tumor cells, induces IP-10 secretion facilitating (CXCR3+) immune cell infiltration, and can prime macrophages to an M1-like phenotype inducing proinflammatory cytokine release. We had previously reported that the targeted delivery of IFN gamma to neoplastic lesions may be limited by the trapping of IFN gamma-based products by cognate receptors found in different organs. Here we describe a novel fusion protein consisting of the L19 antibody, specific to the alternatively spliced extra-domain B of fibronectin (EDB), fused to a variant of IFN gamma with reduced affinity to its cognate receptor. The product (named L19-IFN gamma KRG) selectively localized to tumors in mice, showed favorable pharmacokinetic profiles in monkeys and regained biological activity upon antigen binding. The fusion protein was investigated in two murine models of cancer, both as monotherapy and in combination with therapeutic modalities which are frequently used for cancer therapy. L19-IFN gamma KRG induced tumor growth retardation and increased the intratumoral concentration of T cells and NK cells in combination with anti-PD-1.

Automated summary

In this study, a novel fusion protein (L19-IFN gamma KRG) is described, which selectively localizes to tumors and regains biological activity upon antigen binding. This fusion protein showed tumor growth inhibition and increased intratumoral concentration of T cells and NK cells in murine cancer models, with a better effect when used in combination with anti-PD-1 therapy.