Ellerman Diego A
Antibody Engineering Department, Genentech Inc, South San Francisco, USA.
BioDrugs. 2025 Jan;39(1):75-102. doi: 10.1007/s40259-024-00691-0. Epub 2024 Dec 13.
After decades of gradual progress from conceptualization to early clinical trials (1960-2000), the therapeutic potential of bispecific antibodies (bisp Abs) is now being fully realized. Insights gained from both successful and unsuccessful trials are helping to identify which mechanisms of action, antibody formats, and targets prove most effective, and which may benefit from further refinement. While T-cell engagers remain the most commonly used class of bisp Abs, current efforts aim to increase their effectiveness by co-engaging costimulatory molecules, reducing escape mechanisms, and countering immunosuppression. Strategies to minimize cytokine release syndrome (CRS) are also actively under development. In addition, novel antibody formats that are selectively activated within tumors are an exciting area of research, as is the precise targeting of specific T-cell subsets. Beyond T cells, the recruitment of macrophages and dendritic cells is attracting increasing interest, with researchers exploring various macrophage receptors to promote phagocytosis or to carry out specialized functions, such as the immunologically silent clearance of amyloid-beta plaques in the brain. While bisp Abs targeting B cells are relatively limited, they are primarily aimed at inhibiting B-cell activity in autoimmune diseases. Another evolving application involves the forced interaction between proteins. Beyond the successful development of Hemlibra for hemophilia, bispecific antibodies that mimic cytokine activity are being explored. Additionally, the recruitment of cell surface ubiquitin ligases and other enzymes represents a novel and promising therapeutic strategy. In regard to antibody formats, some applications such as the combination of T-cell engagers with costimulatory molecules are driving the development of trispecific antibodies, at least in preclinical settings. However, the increasing structural complexity of multispecific antibodies often leads to more challenging development paths, and the number of multispecific antibodies in clinical trials remains low. The clinical success of certain applications and well-established production methods position this therapeutic class to expand its benefits into other therapeutic areas.
在经历了从概念化到早期临床试验的数十年逐步发展（1960年至2000年）之后，双特异性抗体（bisp Abs）的治疗潜力如今正在得到充分实现。从成功和失败的试验中获得的见解有助于确定哪些作用机制、抗体形式和靶点被证明最有效，以及哪些可能需要进一步优化才能受益。虽然T细胞衔接器仍然是最常用的双特异性抗体类别，但目前的努力旨在通过共同衔接共刺激分子、减少逃逸机制和对抗免疫抑制来提高其有效性。将细胞因子释放综合征（CRS）降至最低的策略也在积极研发中。此外，在肿瘤内被选择性激活的新型抗体形式是一个令人兴奋的研究领域，对特定T细胞亚群的精确靶向也是如此。除了T细胞，巨噬细胞和树突状细胞的募集也越来越受到关注，研究人员正在探索各种巨噬细胞受体，以促进吞噬作用或执行专门功能，例如在大脑中对β淀粉样蛋白斑块进行免疫沉默清除。虽然靶向B细胞的双特异性抗体相对有限，但它们主要旨在抑制自身免疫性疾病中的B细胞活性。另一个不断发展的应用涉及蛋白质之间的强制相互作用。除了成功开发用于治疗血友病的Hemlibra之外，正在探索模拟细胞因子活性的双特异性抗体。此外，募集细胞表面泛素连接酶和其他酶代表了一种新颖且有前景的治疗策略。关于抗体形式，一些应用，如T细胞衔接器与共刺激分子的组合，正在推动三特异性抗体的开发，至少在临床前环境中是如此。然而，多特异性抗体结构复杂性的增加往往导致更具挑战性的开发路径，并且临床试验中的多特异性抗体数量仍然很少。某些应用的临床成功和成熟的生产方法使这一治疗类别能够将其益处扩展到其他治疗领域。
