Ligand-induced receptor dimerization or oligomerization is a widespread mechanism for ensuring communication specificity,safeguarding receptor activation,and facilitating amplification of signal transduction across th...Ligand-induced receptor dimerization or oligomerization is a widespread mechanism for ensuring communication specificity,safeguarding receptor activation,and facilitating amplification of signal transduction across the cellular membrane.However,cell-surface antigeninduced multimerization(dubbed AIM herein)has not yet been consciously leveraged in chimeric antigen receptor(CAR)engineering for enriching T cell-based therapies.We co-developed ciltacabtagene autoleucel(cilta-cel),whose CAR incorporates two B-cell maturation antigen(BCMA)-targeted nanobodies in tandem,for treating multiple myeloma.Here we elucidated a structural and functional model in which BCMA-induced cilta-cel CAR multimerization amplifies myeloma-targeted T cell-mediated cytotoxicity.Crystallographic analysis of BCMA–nanobody complexes revealed atomic details of antigen–antibody hetero-multimerization whilst analytical ultracentrifugation and small-angle X-ray scattering characterized interdependent BCMA apposition and CAR juxtaposition in solution.BCMA-induced nanobody CAR multimerization enhanced cytotoxicity,alongside elevated immune synapse formation and cytotoxicity-mediating cytokine release,towards myeloma-derived cells.Our results provide a framework for contemplating the AIM approach in designing next-generation CARs.展开更多
Geobelt deformation is of significance when making prejudgments on potential failure planes in reinforced structures.A failure plane results from two geobelt failure modes,tensile failure and pullout.In order to inves...Geobelt deformation is of significance when making prejudgments on potential failure planes in reinforced structures.A failure plane results from two geobelt failure modes,tensile failure and pullout.In order to investigate the deformation characteristics of geobelts in two failure modes,results from pullout tests on sensor-enabled geobelts(SEGBs)with various lengths in sand are reported here across a range of normal pressures.Self-measurements of SEGB can provide data during the tests regarding distributions of strain,stress,and displacement.Data collected during pullout tests reveal the effects of normal pressures and specimen lengths on failure mode.A critical line considering normal pressure and specimen length is derived to describe the transition between two failure modes,an approach which can be utilized for preliminary predictions of failure mode in pullout tests.Warning criteria established based on critical line and data from the self-measurements of SEGB are proposed for failure mode prediction which can contribute to prejudgments of potential failure plane in geosynthetically reinforced soil structures.展开更多
基金supported by grants from the Double First-Class Project from the Ministry of Education(grant code:WF510162602)Innovative Research Team of High-Level Local Universities in Shanghai,Shanghai Collaborative Innovation Program on Regenerative Medicine and Stem Cell Research(grant code:2019CXJQ01)+4 种基金Overseas Expertise Introduction Project for Discipline Innovation(111 Projectgrant code:B17029)National Natural Science Foundation of China(grant numbers:82230006 and 81900206)Shanghai Shenkang Hospital Development Center(grant code:SHDC2020CR5002)Shanghai Frontiers Science Center for Biomacromolecules and Precision Medicine-ShanghaiTech University,Shanghai Pilot Program for Basic Research-Shanghai Jiao Tong University(grant code:21TQ1400226).
文摘Ligand-induced receptor dimerization or oligomerization is a widespread mechanism for ensuring communication specificity,safeguarding receptor activation,and facilitating amplification of signal transduction across the cellular membrane.However,cell-surface antigeninduced multimerization(dubbed AIM herein)has not yet been consciously leveraged in chimeric antigen receptor(CAR)engineering for enriching T cell-based therapies.We co-developed ciltacabtagene autoleucel(cilta-cel),whose CAR incorporates two B-cell maturation antigen(BCMA)-targeted nanobodies in tandem,for treating multiple myeloma.Here we elucidated a structural and functional model in which BCMA-induced cilta-cel CAR multimerization amplifies myeloma-targeted T cell-mediated cytotoxicity.Crystallographic analysis of BCMA–nanobody complexes revealed atomic details of antigen–antibody hetero-multimerization whilst analytical ultracentrifugation and small-angle X-ray scattering characterized interdependent BCMA apposition and CAR juxtaposition in solution.BCMA-induced nanobody CAR multimerization enhanced cytotoxicity,alongside elevated immune synapse formation and cytotoxicity-mediating cytokine release,towards myeloma-derived cells.Our results provide a framework for contemplating the AIM approach in designing next-generation CARs.
基金Project supported by the National Key Research and Development Program of China(No.2018YFB1600100)the National Natural Science Foundation of China(Nos.51778346 , 51608461)。
文摘Geobelt deformation is of significance when making prejudgments on potential failure planes in reinforced structures.A failure plane results from two geobelt failure modes,tensile failure and pullout.In order to investigate the deformation characteristics of geobelts in two failure modes,results from pullout tests on sensor-enabled geobelts(SEGBs)with various lengths in sand are reported here across a range of normal pressures.Self-measurements of SEGB can provide data during the tests regarding distributions of strain,stress,and displacement.Data collected during pullout tests reveal the effects of normal pressures and specimen lengths on failure mode.A critical line considering normal pressure and specimen length is derived to describe the transition between two failure modes,an approach which can be utilized for preliminary predictions of failure mode in pullout tests.Warning criteria established based on critical line and data from the self-measurements of SEGB are proposed for failure mode prediction which can contribute to prejudgments of potential failure plane in geosynthetically reinforced soil structures.
