Oberg Hans-Heinrich, Deseke Malte, Krohn Steffen, Winterberg Dorothee, Peipp Matthias, Bauerschlag Dirk, Künkele Klaus-Peter, Wesch Daniela, Baumann Christoph
Institute of Immunology, University Hospital Schleswig-Holstein, Kiel, Germany.
Evobright GmbH, Vienna, Austria.
Front Immunol. 2025 Jul 18;16:1628501. doi: 10.3389/fimmu.2025.1628501. eCollection 2025.
Vγ9Vδ2 T cells have been clinically evaluated-both and -for their efficacy against solid tumors over several decades. Although recent therapeutic approaches have renewed hope, significant and reproducible benefits for patients with solid tumors remains to be demonstrated.
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.
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 tumor tissue model at unaltered/physiological effector-to-target (E:T) ratios. Importantly, we show that our tumor-engaging molecules avoid premature immune cell activation, degranulation, and cytokine release in the absence of FOLR1-positive tumor cells. They likely establish a cytokine gradient from the tumor site, harnessing the full potential of the natural local anti-infection response to target cancer cells.
Thus, Evobodies represent a novel, first-in class of biologics for solid tumor treatment and are well-suited for further clinical development.
几十年来，Vγ9Vδ2 T细胞针对实体瘤的疗效已在临床上进行了评估。尽管最近的治疗方法带来了新的希望，但实体瘤患者显著且可重复的获益仍有待证实。
我们开发了一种IgG扩展形式的双特异性生物制剂，它既能与大多数卵巢癌中高表达的叶酸受体α（FOLR1）结合，又能与激活型嗜乳脂蛋白（BTN）3A结合。通过降低BTN3A激动剂的亲和力并利用四价双特异性抗体增加的亲和力，BTN3A的激活仅限于FOLR1阳性肿瘤，从而避免非肿瘤细胞的脱靶激活。
使用Vγ9Vδ2 T细胞与肿瘤细胞系的RTCA共培养试验，我们鉴定出了“进化抗体”，它们对FOLR1阳性细胞具有强大的治疗窗口和高效力，同时对健康的FOLR1阴性组织无损伤。此外，先导分子在人自体、患者来源的肿瘤组织模型中，在未改变/生理效应物与靶标（E:T）比率的情况下显示出高效性。重要的是，我们表明我们的肿瘤结合分子在没有FOLR1阳性肿瘤细胞的情况下可避免免疫细胞过早激活、脱颗粒和细胞因子释放。它们可能从肿瘤部位建立细胞因子梯度，利用天然局部抗感染反应的全部潜力来靶向癌细胞。
因此，进化抗体代表了一种用于实体瘤治疗的新型、一流的生物制剂，非常适合进一步的临床开发。
