Antigen-induced chimeric antigen receptor multimerization amplifies on-tumor cytotoxicity

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.

The development prospection of HDAC inhibitors as a potential therapeutic direction in Alzheimer’s disease

Alzheimer’s disease(AD)is a chronic neurodegenerative disease,which is associated with learning and memory impairment in the elderly.Recent studies have found that treating AD in the way of chromatin remodeling via histone acetylation is a promising therapeutic regimen.In a number of recent studies,inhibitors of histone deacetylase(HDACs)have been found to be a novel promising therapeutic agents for neurological disorders,particularly for AD and other neurodegenerative diseases.Although HDAC inhibitors have the ability to ameliorate cognitive impairment,successful treatments in the classic AD animal model are rarely translated into clinical trials.As for the reduction of unwanted side effects,the development of HDAC inhibitors with increased isoform selectivity or seeking other directions is a key issue that needs to be addressed.The review focused on literatures on epigenetic mechanisms in recent years,especially on histone acetylation in terms of the enhancement of specificity,efficacy and avoiding side effects for treating AD.

Ni–Al composite hydroxides fabricated by cation–anion double hydrolysis method for high-performance supercapacitor

Chemical doping of nickel hydroxide with other cations（e.g. Al^（3＋）） is an efficient way to enhance its electrochemical capacitive performances. Herein, a simple cation–anion（Ni^（2＋）and AlO_2） double hydrolysis method was developed toward the synthesis of nickel–aluminum（Ni–Al） composite hydroxides. The obtained composite hydroxides possesses a porous structure, large surface area（121 m^2/g） and homogeneous element distribution. The electrochemical test shows that the obtained composite hydroxides exhibits a superior supercapacitive performances（specific capacitance of 1670F/g and rate capability of 87% from 0.5 A/g to 20 A/g） to doping-free nickel hydroxide（specific capacitance of 1227 F/g and rate capability of 47% from 0.5 A/g to 20 A/g）. Moreover, the galvanostatic charge/discharge test displays that after 2000 cycles at large current density of 10 A/g, the composite hydroxides achieves a high capacitance retention of 98%, indicative of an excellent electrochemical cycleability.