PIEZO1-mediated mechanosensing governs NK-cell killing efficiency and infiltration in three-dimensional matrices.

Natural killer (NK) cells play a vital role in eliminating tumorigenic cells. Efficient locating and killing of target cells in complex three-dimensional (3D) environments are critical for their functions under physiological conditions. However, the role of mechanosensing in regulating NK-cell killing efficiency in physiologically relevant scenarios is poorly understood. Here, we report that the responsiveness of NK cells is regulated by tumor cell stiffness. NK-cell killing efficiency in 3D is impaired against softened tumor cells, whereas it is enhanced against stiffened tumor cells. Notably, the durations required for NK-cell killing and detachment are significantly shortened for stiffened tumor cells. Furthermore, we have identified PIEZO1 as the predominantly expressed mechanosensitive ion channel among the examined candidates in NK cells. Perturbation of PIEZO1 abolishes stiffness-dependent NK-cell responsiveness, significantly impairs the killing efficiency of NK cells in 3D, and substantially reduces NK-cell infiltration into 3D collagen matrices. Conversely, PIEZO1 activation enhances NK killing efficiency as well as infiltration. In conclusion, our findings demonstrate that PIEZO1-mediated mechanosensing is crucial for NK killing functions, highlighting the role of mechanosensing in NK-cell killing efficiency under 3D physiological conditions and the influence of environmental physical cues on NK-cell functions.

Analytical similarity assessment of MYL-1402O to reference Bevacizumab.

BACKGROUND: Bevacizumab (BEV) is a recombinant humanized monoclonal immunoglobulin G1 antibody that binds to vascular endothelial growth factor (VEGF)-A and acts as an antiangiogenic agent. It is approved for treatment of many cancer indications, including metastatic colorectal cancer and nonsquamous non-small cell lung cancer. RESEARCH DESIGN AND METHODS: The analytical similarity of the BEV biosimilar MYL-1402O to reference BEV sourced from the European Union and United States was assessed using physicochemical and functional tests to support the clinical development of MYL-1402O. Assessment of physicochemical and analytical similarity showed that MYL-1402O has the same amino acid sequence and similar posttranslational modification profile as the reference BEV products. RESULTS: The functional and biologic activity of MYL-1402O assessed using inhibition of VEGF-induced cell proliferation in human umbilical vein endothelial cells, inhibition of VEGF-induced VEGF receptor 2 phosphorylation, and fragment antigen and fragment crystallizable receptor binding, was comparable to reference BEV products. CONCLUSIONS: The totality of the data assessment confirms the high degree of similarity of MYL-1402O to reference BEV with respect to physicochemical and in vitro functional properties. The product quality data presented here, along with data from phase 1 clinical studies, demonstrate the similarity of MYL-1402O to reference BEV products, supporting further clinical development of this BEV biosimilar.