Off-the-shelf T-cell-redirecting bispecific antibodies targeting BCMA, GPRC5D, and FcRH5 have high activity in multiple myeloma with a manageable toxicity profile. However, not all patients respond to bispecific antibodies and patients can develop bispecific antibody resistance after an initial response. Mechanisms that contribute to bispecific antibody resistance are multifactorial and include tumour-related factors, such as high tumour burden, expression of T-cell inhibitory ligands, and antigen loss. Resistance due to antigen escape can be prevented by simultaneously targeting two tumour-associated antigens with a trispecific antibody or a combination of two bispecific antibodies. There is also increasing evidence that primary resistance to bispecific antibodies is associated with impaired baseline T-cell function. Long-term exposure to bispecific antibodies with chronic T-cell stimulation further aggravates T-cell dysfunction, which could contribute to failure of disease control. Therapeutic interference with T-cell exhaustion by targeting inhibitory or costimulatory pathways could improve bispecific antibody-mediated antitumour activity. The immunosuppressive microenvironment also contributes to bispecific antibody resistance. CD38-targeting antibodies hold promise as combination partners for bispecific antibodies because of their potential to eliminate CD38 immune suppressor cells. In conclusion, a better understanding of the mechanisms underlying the absence of disease response has provided novel insights to optimise T-cell activity and bispecific antibody efficacy in multiple myeloma.

中文翻译：

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多发性骨髓瘤中 T 细胞参与双特异性抗体的耐药机制：对新治疗策略的影响


现成的针对 BCMA、GPRC5D 和 FcRH5 的 T 细胞重定向双特异性抗体在多发性骨髓瘤中具有高活性，且毒性特征可控。然而，并非所有患者都对双特异性抗体有反应，患者在初次反应后可能会出现双特异性抗体耐药性。导致双特异性抗体耐药的机制是多因素的，包括肿瘤相关因素，例如高肿瘤负荷、T 细胞抑制性配体的表达和抗原丢失。通过使用三特异性抗体或两种双特异性抗体的组合同时靶向两种肿瘤相关抗原，可以防止由于抗原逃逸而产生的耐药性。还有越来越多的证据表明，对双特异性抗体的原发性耐药与基线 T 细胞功能受损有关。长期接触双特异性抗体并慢性刺激 T 细胞会进一步加剧 T 细胞功能障碍，这可能导致疾病控制失败。通过靶向抑制或共刺激途径来干扰 T 细胞耗竭，可以改善双特异性抗体介导的抗肿瘤活性。免疫抑制微环境也有助于双特异性抗体耐药性。 CD38 靶向抗体有望成为双特异性抗体的组合伙伴，因为它们具有消除 CD38 免疫抑制细胞的潜力。总之，更好地了解缺乏疾病反应的机制为优化多发性骨髓瘤中的 T 细胞活性和双特异性抗体功效提供了新的见解。