A nanobody-based tri-specific NK cell engager targeting CD5 triggers antitumor immunity

The poor prognosis of patients with recurrent or refractory T cell malignancies emphasizes the need for improved immunotherapies. CD5 is a characteristic marker of malignant T cells and is expressed on almost all normal T cells. Therefore, for treating T cell malignancies, focusing on natural killer (NK) cells lacking CD5 expression may elicit a better safety profile than that by T cell-based therapies. We generate a CD5-targeted NK cell engager (NKCE) through the specific binding of CD16a nanobody and a high-affinity anti-CD5 antibody. Its antitumor potency is demonstrated in vitro. After incorporating interleukin (IL)-15Rα/IL-15, the modified tri-NKCE exhibits stronger antitumor efficacy against CD5⁺ malignant tumor cells, with the production of more cytokines and chemokines. In vivo, tri-NKCE exhibits stronger cytotoxicity by enhancing NK cell proliferation. Compared with chimeric antigen receptor (CAR)-T cells, this tri-NKCE exhibits no toxicity to normal T cells. In conclusion, tri-NKCE offers a safer and cost-effective immunotherapy against T cell malignancies.