Expand­ing CAR Tar­gets to Non Pro­tein Antigens

Accu­rate iden­ti­fi­ca­tion of tumor‑specific mark­ers is essen­tial for advanc­ing CAR‑based ther­a­pies, espe­cial­ly in sol­id tumors where pro­tein anti­gens rarely offer suf­fi­cient speci­fici­ty. Post‑translational mod­i­fi­ca­tions, par­tic­u­lar­ly gly­co­sy­la­tion, pro­vide an alter­na­tive class of tar­gets with improved selec­tiv­i­ty. Among these, the sialyl‑Tn (STn) anti­gen is wide­ly expressed across epithe­lial can­cers but large­ly absent in healthy tissues. 

We present AM-series of mon­o­clon­al anti­bod­ies with unprece­dent­ed speci­fici­ty for the STn and no detectable reac­tiv­i­ty toward nor­mal tis­sues. Incor­po­ra­tion of the AM52.1 scFv into a second‑generation CAR design yield­ed AM52.1CAR T cells that selec­tive­ly killed STn‑expressing can­cer cell lines and patient‑derived organoids while spar­ing STn‑negative con­trols. In mul­ti­ple pre­clin­i­cal mod­els — includ­ing gas­tric, tubo‑ovarian, and col­orec­tal muci­nous peri­toneal metas­tases — AM52.1CAR T cells demon­strat­ed robust anti­tu­mor activ­i­ty. These results high­light the promise of tar­get­ing non‑protein anti­gens to expand CAR T‑cell ther­a­py into com­plex sol­id tumors.