Tacchetti Paola, Barbato Simona, Mancuso Katia, Zamagni Elena, Cavo Michele
IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia "Seràgnoli", Bologna, Italy.
Dipartimento di Scienze Mediche e Chirurgiche, Università di Bologna, Bologna, Italy.
Cancers (Basel). 2024 Jun 26;16(13):2337. doi: 10.3390/cancers16132337.
Bispecific antibodies (BsAbs) are artificially engineered antibodies that can bind simultaneously to the CD3 subunit within the T-cell receptor complex and an antigen on tumor cells, leading to T-cell activation and tumor cell killing. BsAbs against BCMA or GPRC5D have shown impressive clinical activity in heavily pretreated patients with relapsed/refractory multiple myeloma (RRMM), with some agents having already received regulatory approval after the third (by the European Medicines Agency, EMA) or fourth (by the Food and Drug Administration, FDA) line of therapy; the results of early-phase clinical trials targeting FcRH5 are also promising. Overall, BsAbs as monotherapy correlated with an ORR that exceeded 60%, with a high CR rate ranging between 25% and 50% and a median PFS of around 1 year among patients with a median of 4-6 prior lines of therapy. The main toxicities include cytokine release syndrome, cytopenias, hypogammaglobulinemia, and infections; on-target off-tumor adverse events involving the skin, mucosa, hair, and nails may also occur with anti-GPRC5D BsAbs. Active research to increase their efficacy and improve their tolerance is still in progress, including combination therapies and application in earlier treatment lines and the development of novel agents. A better understanding of the mechanisms of resistance is a challenge and could lead to more personalized approaches.
双特异性抗体（BsAbs）是人工构建的抗体，能够同时结合T细胞受体复合物中的CD3亚基和肿瘤细胞上的一种抗原，从而导致T细胞活化并杀伤肿瘤细胞。针对BCMA或GPRC5D的双特异性抗体在复发/难治性多发性骨髓瘤（RRMM）的多次预处理患者中显示出令人印象深刻的临床活性，一些药物在第三线（由欧洲药品管理局，EMA）或第四线（由美国食品药品监督管理局，FDA）治疗后已获得监管批准；针对FcRH5的早期临床试验结果也很有前景。总体而言，双特异性抗体作为单一疗法的客观缓解率（ORR）超过60%，完全缓解（CR）率较高，在接受过中位4 - 6线先前治疗的患者中，CR率在25%至50%之间，中位无进展生存期（PFS）约为1年。主要毒性包括细胞因子释放综合征、血细胞减少、低丙种球蛋白血症和感染；抗GPRC5D双特异性抗体也可能发生涉及皮肤、黏膜、毛发和指甲的靶向非肿瘤不良事件。提高其疗效和改善耐受性的积极研究仍在进行中，包括联合疗法、在早期治疗线中的应用以及新型药物的开发。更好地理解耐药机制是一项挑战，可能会带来更个性化的治疗方法。
