Currently, antibody or antibody-like protein drugs related to tumor immunotherapy are still in full swing. Here, we describe an antibody-fusion protein drug IMAB362-mIL-21 with mouse IL-21(mIL-21) fused into the C-terminal domain of IMAB362(a clinical antibody drug against Claudin18.2), expecting that the drug can achieve tumor targeting and activate local anti-tumor immune response more effectively, while reducing the systemic side effects of individual cytokines. To sum up, in vitro assays, compare to IMAB362 and mIL-21, the fusion protein IMAB362-mIL-21 was able to recognize its cognate antigen Claudin 18.2 and natural receptor mIL-21R at a similar binding affinity, and it could further mediate equivalent ADCC activity and activate IL-21R-mediated downstream signal pathway. Mostly, in vivo assays, IMAB362-mIL-21 could produce stronger anti-tumor effect compared with IMAB362 or mIL-21 and even their combination at equimolar concentrations. Moreover, according to the blood routine indicators, the mIL-21-Fc and combined treatment group had significant decreases (P<0.01) in red blood cells (RBC), hemoglobin (HGB) and hematocrit (HCT), while the IMAB362-mIL-21 group had not. The above results have shown that IMAB362-mIL-21 can produce better anti-tumor effect without obvious hematological toxicity, which is sufficient to show that this kind of antibody-cytokine protein has better application value than IMAB362, IL-21 as single drug or even combination. Therefore, this type of bifunctional molecule combined tumor-targeting and immune activation effectively and has a good application prospect.
The northern Xinjiang of China is a composite orogenic belt in the south central part of the Altaids formed by subduction‐accretion mainly during the Paleozoic. Geochronologic and geochemical data from the Paleozoic ophiolites and associated assemblages are reported here to place constrains on the tectonic evolution of this region and to reconstruct its history, using a model of subduction‐accretion plus large‐scale map‐view strike‐slip faulting. Geologic and geochronologic review indicates that the Paleozoic ophiolites and associated assemblages of the western and eastern Junggar regions are tectonically related, occurring as a pattern with the early Paleozoic Tangbale‐Mayile‐Hongguleleng‐Aermantai complexes in the center, the late Paleozoic Darbut‐Karamaili and the northern Tianshan complexes in the south, and the late Paleozoic Kekesentao‐Qiaoxiahala‐Kuerti complexes in the north. Available geochemical data suggest that the Paleozoic ophiolites of the northern Xinjiang are mainly oceanic fragments of these three types: mid‐ocean ridge basalt, oceanic island basalts, and island arc basalts. The Paleozoic subduction‐accretion complexes grew mainly along different segments of the Kipchak arc, and in associated with migration of magmatic arc. The Paleozoic ophiolite‐associated sedimentary sequences and subduction‐related volcanic rocks exhibit an evolution history from intraoceanic (early Paleozoic) to marginal settings (late Paleozoic), implying coeval strike‐slip stacking with subduction‐accretion processes, and by which to transport the respective complexes together and further to amalgamate with neighboring units of the Altaids. Subduction‐accretion processes terminated in the mid‐Carboniferous in this region. In the late Permian‐early Triassic, a counterclockwise rotation of fault blocks in a giant sinistral strike‐slip and extension domain between Altay and Tianshan, lastly generated present configuration of the Paleozoic subduction‐accretion complexes in the northern Xinjiang.
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