Tumor-restricted activation of Vγ9Vδ2 T cells via bispecific Evobodies: a novel strategy for safe and potent immunotherapy in ovarian cancer.

Introduction: Vγ9Vδ2 T cells have been clinically evaluated-both Material & Methods: We have developed bispecific biologics in an IgG-extended format that bind both to Folate Receptor alpha (FOLR1), which is highly expressed in the majority of ovarian cancers, and to the activating butyrophilin (BTN)3A. By reducing the affinity of the BTN3A agonist and leveraging the increased avidity of the tetravalent, bispecific antibody, activation of BTN3A is restricted to FOLR1-positive tumors, thereby avoiding off-target activation of non-tumor cells. Results: Using RTCA co-culture assays with Vγ9Vδ2 T cells and tumor cell lines, we identified "Evobodies" that exhibit a strong therapeutic window and high potency against FOLR1-positive cells, while sparing healthy, FOLR1-negative tissue. Moreover, the lead molecule demonstrates high efficacy in a human autologous, patient-derived Discussion: Thus, Evobodies represent a novel, first-in class of biologics for solid tumor treatment and are well-suited for further clinical development.