Hock Barry D, Goddard Liping, Dobson Lachlan J, MacPherson Sean A, O'Donnell John L, McKenzie Judith L, McLellan Alexander D
Haematology Research Group, Department of Pathology and Biomedical Science, University of Otago, Christchurch, New Zealand.
Haematology Department, Christchurch Hospital, Christchurch, New Zealand.
Cancer Immunol Immunother. 2025 May 24;74(7):216. doi: 10.1007/s00262-025-04078-0.
The efficacy of blocking antibodies against programmed death-1 (PD-1) and its ligand (PD-L1) is modulated by signalling through their Fc regions. The Fc region of anti-PD-1/PD-L1 antibodies, when cell-bound, represents a potential target for recognition by circulating rheumatoid factor (RF) autoantibodies. The resultant cell-associated immune complex may then provide different Fc signals to that of the PD-1/PD-L1 antibodies alone. However, little is known regarding the interaction of RF and therapeutic PD-1/PD-L1 antibodies. We report that PD-1 (pembrolizumab, nivolumab) and PD-L1 (avelumab) antibodies, when bound to their cellular targets, are recognised by both IgM-RF and IgA-RF components of RF patient serum. We further demonstrate that the presence of RF provides PD-1 antibodies with the ability to induce complement-dependent cytotoxicity (CDC) of a PD-1 target cell line in the presence of human complement. Although RF provided avelumab with the ability to induce CDC in assays using rabbit complement, no CDC was observed in the presence of human complement. The presence of RF did not modulate the level of Fc receptor-triggered cellular cytotoxicity or neutrophil activation that was induced by PD-1/PD-L1 antibodies alone. This study demonstrates that RF has the potential to modulate the Fc-associated signals generated following binding of PD-1/PD-L1 antibodies. The impact of RF on their efficacy therefore merits further investigation.
抗程序性死亡蛋白1（PD-1）及其配体（PD-L1）的阻断抗体的疗效通过其Fc区域的信号传导进行调节。抗PD-1/PD-L1抗体的Fc区域在与细胞结合时，是循环类风湿因子（RF）自身抗体识别的潜在靶点。由此产生的细胞相关免疫复合物可能会提供与单独的PD-1/PD-L1抗体不同的Fc信号。然而，关于RF与治疗性PD-1/PD-L1抗体之间的相互作用知之甚少。我们报告称，PD-1（帕博利珠单抗、纳武单抗）和PD-L1（阿维鲁单抗）抗体在与细胞靶点结合时，可被RF患者血清中的IgM-RF和IgA-RF成分识别。我们进一步证明，在存在人补体的情况下，RF的存在使PD-1抗体具有诱导PD-1靶细胞系补体依赖性细胞毒性（CDC）的能力。尽管在使用兔补体的试验中RF使阿维鲁单抗具有诱导CDC的能力，但在存在人补体的情况下未观察到CDC。RF的存在并未调节单独由PD-1/PD-L1抗体诱导的Fc受体触发的细胞毒性或中性粒细胞活化水平。这项研究表明，RF有可能调节PD-1/PD-L1抗体结合后产生的Fc相关信号。因此，RF对其疗效的影响值得进一步研究。
