αVEGFR2-MICA fusion antibodies enhance immunotherapy effect and synergize with PD-1 blockade.

Autor: Pan M; Antibody Engineering Laboratory, School of Life Science and Technology, China Pharmaceutical University, Nanjing, 211198, China., Wang F; Antibody Engineering Laboratory, School of Life Science and Technology, China Pharmaceutical University, Nanjing, 211198, China., Nan L; Antibody Engineering Laboratory, School of Life Science and Technology, China Pharmaceutical University, Nanjing, 211198, China., Yang S; Antibody Engineering Laboratory, School of Life Science and Technology, China Pharmaceutical University, Nanjing, 211198, China., Qi J; Antibody Engineering Laboratory, School of Life Science and Technology, China Pharmaceutical University, Nanjing, 211198, China., Xie J; Antibody Engineering Laboratory, School of Life Science and Technology, China Pharmaceutical University, Nanjing, 211198, China., Shao S; Antibody Engineering Laboratory, School of Life Science and Technology, China Pharmaceutical University, Nanjing, 211198, China., Zou H; Antibody Engineering Laboratory, School of Life Science and Technology, China Pharmaceutical University, Nanjing, 211198, China., Wang M; Antibody Engineering Laboratory, School of Life Science and Technology, China Pharmaceutical University, Nanjing, 211198, China., Sun F; Department of Internal Medicine, Myeloma Center, Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USA. fsun@uams.edu., Zhang J; Antibody Engineering Laboratory, School of Life Science and Technology, China Pharmaceutical University, Nanjing, 211198, China. zhangjuan@cpu.edu.cn.
Jazyk: angličtina
Zdroj: Cancer immunology, immunotherapy : CII [Cancer Immunol Immunother] 2023 Apr; Vol. 72 (4), pp. 969-984. Date of Electronic Publication: 2022 Oct 13.
DOI: 10.1007/s00262-022-03306-1
Abstrakt: Antiangiogenic therapy has shown significant clinical benefits in gastric cancer (GC) and non-small cell lung cancer (NSCLC). However, their effectiveness is limited by the immunosuppressive tumor microenvironment. The MHC class I chain-related molecules A and B (MICA/B) are expressed in many human cancers, enabling elimination of cancer cells by cytotoxic lymphocytes through natural killer group 2D (NKG2D) receptor activation. To improve antiangiogenic therapy and prolong its efficacy, we generated a bi-specific fusion protein (mAb04-MICA). This was comprised of an antibody targeting VEGFR2 fused to a MICA α1-α2 ectodomain. mAb04-MICA inhibited proliferation of GC and NSCLC cells through specific binding to VEGFR2 and had superior anti-tumor efficacy in both GC and NSCLC-bearing mouse models compared with ramucirumab. Further investigation revealed that the mAb04-MICA promoted NKG2D + NK cell activation and induced the tumor-associated macrophage (TAM) polarization from M2 type to M1 type both in vitro and in vivo. The polarization of TAMs upon NKG2D and MICA mediated activation has not yet been reported. Moreover, given the up-regulation of PD-L1 in tumors during anti-angiogenesis therapy, anti-PD-1 antibody enhanced the anti-tumoral activity of mAb04-MICA through stimulating infiltration and activation of NKs and CD8 + T cells in responding tumors. Our findings demonstrate that dual targeting of angiogenesis and NKG2D, or in combination with the PD-1/PD-L1 blockade, is a promising anti-tumor therapeutic strategy. This is accomplished through maintaining or reinstating tumor immunosurveillance during treatment, which expands the repertoire of anti-angiogenesis-based cancer immunotherapies.
(© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
Databáze: MEDLINE
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