Riillo Caterina, Caracciolo Daniele, Grillone Katia, Polerà Nicoletta, Tuccillo Franca Maria, Bonelli Patrizia, Juli Giada, Ascrizzi Serena, Scionti Francesca, Arbitrio Mariamena, Lopreiato Mariangela, Siciliano Maria Anna, Sestito Simona, Talarico Gabriella, Galea Eulalia, Galati Maria Concetta, Pensabene Licia, Loprete Giovanni, Rossi Marco, Ballerini Andrea, Gentile Massimo, Britti Domenico, Di Martino Maria Teresa, Tagliaferri Pierosandro, Tassone Pierfrancesco
Department of Experimental and Clinical Medicine, Magna Græcia University, 88100 Catanzaro, Italy.
Istituto Nazionale Tumori IRCCS-Fondazione G. Pascale, 80131 Napoli, Italy.
Cancers (Basel). 2022 Jun 11;14(12):2886. doi: 10.3390/cancers14122886.
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy burdened by poor prognosis. While huge progress of immunotherapy has recently improved the outcome of B-cell malignancies, the lack of tumor-restricted T-cell antigens still hampers its progress in T-ALL. Therefore, innovative immunotherapeutic agents are eagerly awaited. To this end, we generated a novel asymmetric (2 + 1) bispecific T-cell engager (BTCE) targeting CD1a and CD3ε (CD1a x CD3ε) starting from the development of a novel mAb named UMG2. UMG2 mAb reacts against CD1a, a glycoprotein highly expressed by cortical T-ALL cells. Importantly, no UMG2 binding was found on normal T-cells. CD1a x CD3ε induced high T-cell mediated cytotoxicity against CD1a+ T-ALL cells in vitro, as demonstrated by the concentration-dependent increase of T-cell proliferation, degranulation, induction of cell surface activation markers, and secretion of pro-inflammatory cytokines. Most importantly, in a PBMC-reconstituted NGS mouse model bearing human T-ALL, CD1a x CD3ε significantly inhibited the growth of human T-ALL xenografts, translating into a significant survival advantage of treated animals. In conclusion, CD1a x CD3ε is a novel BTCE highly active against CD1a-expressing cortical-derived T-ALL cells suitable for clinical development as an effective therapeutic option for this rare and aggressive disease.
T细胞急性淋巴细胞白血病（T-ALL）是一种侵袭性恶性肿瘤，预后较差。尽管免疫疗法最近取得了巨大进展，改善了B细胞恶性肿瘤的治疗结果，但缺乏肿瘤限制性T细胞抗原仍然阻碍了其在T-ALL治疗中的进展。因此，人们急切期待创新的免疫治疗药物。为此，我们从一种名为UMG2的新型单克隆抗体（mAb）的研发入手，构建了一种新型的不对称（2 + 1）双特异性T细胞衔接器（BTCE），靶向CD1a和CD3ε（CD1a x CD3ε）。UMG2单克隆抗体可与CD1a发生反应，CD1a是一种在皮质T-ALL细胞中高度表达的糖蛋白。重要的是，在正常T细胞上未发现UMG2的结合。体外实验表明，CD1a x CD3ε可诱导T细胞对CD1a+ T-ALL细胞产生高度的细胞毒性，表现为T细胞增殖、脱颗粒、细胞表面活化标志物的诱导以及促炎细胞因子分泌的浓度依赖性增加。最重要的是，在携带人T-ALL的PBMC重建的NGS小鼠模型中，CD1a x CD3ε显著抑制了人T-ALL异种移植物的生长，使治疗动物具有显著的生存优势。总之，CD1a x CD3ε是一种新型的BTCE，对表达CD1a的皮质来源T-ALL细胞具有高度活性，适合作为这种罕见且侵袭性疾病的有效治疗选择进行临床开发。
