{"database":"GEO","file_versions":[{"headers":{"Content-Type":["application/json"]},"body":{"files":{"Other":["ftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE310nnn/GSE310399/"]},"type":"primary"},"statusCode":"OK","statusCodeValue":200}],"scores":null,"additional":{"omics_type":["Transcriptomics"],"species":["Homo sapiens"],"gds_type":[" Other","Expression profiling by high throughput sequencing"],"full_dataset_link":["https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE310399"],"repository":["GEO"],"entry_type":["GSE"],"additional_accession":[]},"is_claimable":false,"name":"Sequence and structural determinants of efficacious de novo chimeric antigen receptors","description":"Advances in generative protein design using artificial intelligence (AI) have enabled the rapid development of binders against heterogeneous targets, including tumor-associated antigens. Despite extensive biochemical characterization, these novel protein binders have had limited evaluation as agents in candidate therapeutics, including chimeric antigen receptor (CAR) T cells. Here, we synthesize variable generative protein design workflows to screen 1,487 novel protein binders targeting BCMA, CD22, and CD19 for efficacy in scalable protein binding and T cell assays. We identify three main challenges that hinder the utility of de novo protein binders as CARs, including tonic signaling, occluded epitope engagement, and off-target activity. We develop computational and experimental heuristics to overcome these limitations, including screens of sequence variants for individual parental structures, that restore on-target CAR activation while mitigating liabilities. Together, our framework accelerates the development of AI-designed proteins for future preclinical therapeutic screening, helping enable a new generation of cellular therapies.","dates":{"publication":"2026/07/06"},"accession":"GSE310399","cross_references":{"GSM":["GSM9295444","GSM9295445","GSM9295448","GSM9295449","GSM9295446","GSM9295447"],"GPL":["34295"],"GSE":["310399"],"taxon":["Homo sapiens"]}}