Since the turn of the century, cancer therapy has undergone a transformation in terms of new treatment modalities and renewed optimism in achieving long-lived tumor control and even cure. This is, in large part, thanks to the widespread incorporation of monoclonal antibodies (mAbs) into standard treatment regimens. These new therapies have, across many settings, significantly contributed to improved clinical responses, patient quality of life and survival. Moreover, the flexibility of the antibody platform has led to the development of a wide range of innovative and combinatorial therapies that continue to augment the clinician’s armory. Despite these successes, there is a growing awareness that in many cases mAb therapy remains suboptimal, primarily due to inherent limitations imposed by the immune system’s own homeostatic controls and the immunosuppressive tumor microenvironment. Here, we discuss the principal barriers that act to constrain the tumor-killing activity of antibody-based therapeutics, particularly those involving antibody glycans, using illustrative examples from both pre-clinical and market approved mAbs. We also discuss strategies that have been, or are in development to overcome these obstacles. Finally, we outline how the growing understanding of the biological terrain in which mAbs function is shaping innovation and regulation in cancer therapeutics.

中文翻译：

---

穿越障碍：克服基于抗体的有效癌症治疗的障碍


自世纪之交以来，癌症治疗在新的治疗方式和实现长期肿瘤控制甚至治愈方面重新焕发乐观情绪方面经历了转变。这在很大程度上要归功于单克隆抗体 (mAb) 广泛纳入标准治疗方案。这些新疗法在许多情况下都显着改善了临床反应、患者的生活质量和生存率。此外，抗体平台的灵活性导致了广泛的创新和组合疗法的开发，这些疗法不断丰富临床医生的武器库。尽管取得了这些成功，人们越来越认识到，在许多情况下，单克隆抗体疗法仍然不够理想，这主要是由于免疫系统自身稳态控制和免疫抑制肿瘤微环境所施加的固有限制。在这里，我们使用临床前和市场批准的单克隆抗体的说明性例子，讨论限制基于抗体的疗法的肿瘤杀伤活性的主要障碍，特别是涉及抗体聚糖的疗法。我们还讨论了已经或正在制定的克服这些障碍的策略。最后，我们概述了对单克隆抗体功能的生物领域的日益深入的了解如何影响癌症治疗的创新和监管。