VEGFR2-targeted antibody fused with IFN mut regulates the tumor microenvironment of colorectal cancer and exhibits potent anti-tumor and anti-metastasis activity

Abstract

Although interferon α (IFN α ) and anti-angiogenesis antibodies have shown appropriate clinical benefit in the treatment of malignant cancer, they are deficient in clinical applications. Previously, we described an anti-vascular endothelial growth factor receptor 2 (VEGFR2)-IFN α fusion protein named JZA01, which showed increased in vivo half-life and reduced side effects compared with IFN α , and it was more effective than the anti-VEGFR2 antibody against tumors. However, the affinity of the IFN α component of the fusion protein for its receptor-IFNAR1 was decreased. To address this problem, an IFN α -mutant fused with anti-VEGFR2 was designed to produce anti-VEGFR2-IFN α mut, which was used to target VEGFR2 with enhanced anti-tumor and anti-metastasis efficacy. Anti-VEGFR2-IFN α mut specifically inhibited proliferation of tumor cells and promoted apoptosis. In addition, anti-VEGFR2-IFN α mut inhibited migration of colorectal cancer cells and invasion by regulating the PI3K–AKT–GSK3 β –snail signal pathway. Anti-VEGFR2-IFN α mut showed superior anti-tumor efficacy with improved tumor microenvironment (TME) by enhancing dendritic cell maturation, dendritic cell activity, and increasing tumor-infiltrating CD8 + T cells. Thus, this study provides a novel approach for the treatment of metastatic colorectal cancer, and this design may become a new approach to cancer immunotherapy.

Immunotherapies catering to the unmet medical need of cold colorectal cancer

“…However, the affinity of IFN-α2 for its receptor and its direct cytotoxicity were decreased in this combination. Thus, subsequent studies mutated IFN-α to further improve the anti-tumor efficacy and regulate TME more effectively by promoting dendritic cell maturation and enhancing CD8 + T cell infiltration ( 109 ). Although there is in vitro evidence that IFN-β inhibits tumor cell proliferation more effectively than IFN-α, no clinical trials have demonstrated its efficacy in cancer therapy ( 105 ).…”

How the Tumor Micromilieu Modulates the Recruitment and Activation of Colorectal Cancer-Infiltrating Lymphocytes

“…Moreover, VEGF-A has also been demonstrated to directly promote the proliferation of VEGFR-2-expressing regulatory T cells in colon tumor-bearing mice. Accordingly, the treatment of CRC patients with the clinically approved VEGF-A-targeting antibody Bevacizumab resulted in a significantly reduced frequency of regulatory T cells in the peripheral blood, and the in vivo administration of a fusion protein consisting of an anti-VEGFR2 antibody and IFNα successfully enhanced the accumulation of CD8 + T cells in a murine colorectal cancer xenograft model [ 145 , 146 , 147 , 148 ].…”

Biomimetic virus-like mesoporous silica nanoparticles improved cellular internalization for co-delivery of antigen and agonist to enhance Tumor immunotherapy

“…This body defense model involves a series of key steps, including the uptake and recognition of tumor-associated antigens (TAAs) by antigen-presenting cells (APCs), the presentation of the TAAs to T and B lymphocytes, and the initiation and activation of cellular and humoral immune responses. Among them, cytotoxic CD8 + T lymphocytes (CTLs) are crucial to anti-tumor efficacy through cytokine secretion and release of cytotoxic granules (Halle et al., 2017 ; Farhood et al., 2019 ; Shang et al., 2021 ). To our knowledge, the administration of TAAs, with or without adjuvants, has played an important role in tumor immunotherapy (Rosenberg et al., 2004 ).…”