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Ralph Baric, Vineet Menachery and colleagues characterize a SARS-like coronavirus circulating in Chinese horseshoe bats to determine its potential to infect primary human airway epithelial cells, cause disease in mice and respond to available therapeutics. The emergence of severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome (MERS)-CoV underscores the threat of cross-species transmission events leading to outbreaks in humans. Here we examine the disease potential of a SARS-like virus, SHC014-CoV, which is currently circulating in Chinese horseshoe bat populations 1 . Using the SARS-CoV reverse genetics system 2 , we generated and characterized a chimeric virus expressing the spike of bat coronavirus SHC014 in a mouse-adapted SARS-CoV backbone. The results indicate that group 2b viruses encoding the SHC014 spike in a wild-type backbone can efficiently use multiple orthologs of the SARS receptor human angiotensin converting enzyme II (ACE2), replicate efficiently in primary human airway cells and achieve in vitro titers equivalent to epidemic strains of SARS-CoV. Additionally, in vivo experiments demonstrate replication of the chimeric virus in mouse lung with notable pathogenesis. Evaluation of available SARS-based immune-therapeutic and prophylactic modalities revealed poor efficacy; both monoclonal antibody and vaccine approaches failed to neutralize and protect from infection with CoVs using the novel spike protein. On the basis of these findings, we synthetically re-derived an infectious full-length SHC014 recombinant virus and demonstrate robust viral replication both in vitro and in vivo . Our work suggests a potential risk of SARS-CoV re-emergence from viruses currently circulating in bat populations.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Nat. Med.; doi:10.1038/nm.3985; corrected 20 November 2015 In the version of this article initially published online, the authors omitted to acknowledge a funding source, USAID-EPT-PREDICT funding from EcoHealth Alliance, to Z.-L.S. The error has been corrected for the print, PDF and HTML versions of this article.

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers, with a 5-year survival rate below 10%, largely due to late-stage diagnosis and the limited effectiveness of conventional therapies such as surgery, chemotherapy, and radiation. Claudin 18.2 (CLDN18.2)has emerged as a promising target for PDAC. While single-chain variable fragment (scFv)-based CAR-T cells targeting CLDN18.2 have demonstrated therapeutic potential, CAR-T cells engineered with variable heavy-chain-only domains (VHH) exhibit superior efficacy, highlighting the advantages of VHH-based constructs in targeting this antigen. However, the therapeutic efficacy of anti-CLDN18.2 VHH-CAR-T cells remains to be fully elucidated, as previous studies have not comprehensively characterized performance or mechanistic advantages over scFv-based counterparts. To characterize the therapeutic potential of anti-CLDN18.2 VHHs, we employed phage display technology to screen a VHH library, resulting in the identification of three positive clones. These candidates were further evaluated and ranked based on binding affinity and multi-round cytotoxicity in Chimeric antigen receptor T (CAR-T) cell models. To reduce immunogenicity, the lead VHH was humanized. VHH-CAR-T cells incorporating this humanized domain were assessed through assays measuring cytokine secretion and target cell lysis, followed by studies to evaluate antitumor efficacy in relevant xenograft models. High-affinity anti-CLDN18.2 VHHs from phage libraries and engineered CAR-T cells using HM2, a humanized VHH, as the antigen-binding domain were successfully identified. Notably, HM2-CAR-T cells demonstrated potent and sustained cytokine secretion and cytotoxic activity against CLDN18.2-expressing tumor cells . More importantly, these VHH-based CAR-T cells achieved significant antitumor efficacy , underscoring the translational potential of VHH-CAR constructs as a next-generation therapeutic platform with enhanced performance and reduced immunogenicity compared to conventional scFv-based designs. This study establishes an effective framework for developing CLDN18.2-specific VHHs and demonstrates their successful integration into CAR-T cell therapy. The humanized HM2-CAR-T cells not only maintain high antigen specificity but also exhibit strong effector functions and pronounced antitumor activity in preclinical models. These findings support the clinical promise of VHH-based CAR-T cells as a next-generation immunotherapy for CLDN18.2-expressing malignancies, particularly PDAC, where effective treatment options remain limited.