Belantamab Mafodotin Triggers Immune Invigoration in Multiple Myeloma Via Inflammatory and Immunogenic Cell Death

Belantamab mafodotin, an antibody-drug conjugate targeting B-cell maturation antigen, has demonstrated significant clinical efficacy in combination therapies for relapsed or refractory multiple myeloma. Belantamab mafodotin exerts therapeutic effects through the cytotoxic action of its payload, monomethyl auristatin F, along with its ability to mediate antibody-induced cell death. Significant long-term clinical responses were previously observed in monotherapy treatment - even in patients undergoing dose holds - suggesting involvement of the adaptive immune system. Here, we show that belantamab mafodotin induces markers of immunogenic and inflammatory cell death in vitro and ex vivo. Belantamab mafodotin monotherapy treatment results in an acute inflammatory response that is detectable in patient serum within 24 hours, with increases in granzyme B, CXCL9, CCL3, and CCL4 linked to response depth. High expression of receptors LRP1 and TLR2 that mediate immunogenic cell death on patients monocytoid i.e. monocyte-macrophage cells suggests an important function of the monocytoid lineage to mediate the observed inflammation and immunogenic cell death cascades. Inflammation is followed by remodeling of the innate and adaptive immune system, with a reduction in immune inhibitory signaling alongside the emergence of a CD4 granzyme B-expressing cell population in patients who are in remission vs those that relapse. The ability of belantamab mafodotin to promote adaptive immune responses in addition to its cytotoxic activity may help explain the durable responses observed in treated patients with relapsed-refractory multiple myeloma, despite dose and schedule modifications.

贝兰他单抗莫福汀（Belantamab mafodotin）是一款靶向B细胞成熟抗原（B-cell maturation antigen, BCMA）的抗体药物偶联物（antibody-drug conjugate, ADC），在复发难治性多发性骨髓瘤（relapsed or refractory multiple myeloma, RRMM）的联合治疗方案中已展现出显著临床疗效。贝兰他单抗莫福汀通过其载荷分子单甲基澳瑞他汀F（monomethyl auristatin F, MMAF）的细胞毒作用，以及介导抗体诱导细胞死亡的能力发挥治疗效应。既往研究已在单药治疗中观察到显著的长期临床应答——即使在曾接受剂量暂停的患者群体中亦是如此，这提示适应性免疫系统参与了治疗过程。本研究证实，贝兰他单抗莫福汀可在体外及离体实验中诱导免疫原性细胞死亡与炎症性细胞死亡的标志物表达。贝兰他单抗莫福汀单药治疗可引发急性炎症应答，该应答可在给药后24小时内于患者血清中被检测到，且颗粒酶B（granzyme B）、CXCL9、CCL3及CCL4的水平升高与临床应答深度相关。患者单核细胞样（monocytoid）即单核巨噬细胞（monocyte-macrophage）表面，介导免疫原性细胞死亡的受体LRP1与TLR2呈现高表达状态，这提示单核细胞谱系在介导上述炎症反应与免疫原性细胞死亡级联反应中发挥了重要功能。炎症应答之后，机体固有免疫与适应性免疫系统发生重塑：免疫抑制信号通路活性降低，且在获得临床缓解的患者体内可检测到表达颗粒酶B的CD4阳性细胞群，而复发患者体内则未出现该细胞群。贝兰他单抗莫福汀除具备细胞毒活性外，还可促进适应性免疫应答，这或可解释尽管存在剂量与给药方案调整，复发难治性多发性骨髓瘤患者仍能获得持久临床应答的现象。