给免疫治疗减毒增效的“辅助药物”（十）---输白蛋白
与ICB疗效的相关的PNI、CAR指标，都涉及到白蛋白，且白蛋白值高为宜。血清白蛋白高低除反映肝损、全身炎症程度、全身营养状况等问题外，《Serum albumin: a pharmacokinetic marker for optimizing treatment outcome of immune checkpoint blockade》这篇论文，则从药代动力学的角度，阐释说明了为什么血清白蛋白高ICB免疫疗效好。
ICB药物是IgG抗体药物。白蛋白和IgG是血浆中第一和第二丰富的血清蛋白，因为它们独特的长半衰期依赖于新生儿Fc受体(FcRn)的相同稳态调节途径。FcRn受体从细胞内降解中拯救白蛋白和IgG，并将其再循环到细胞外液中。白蛋白和IgG共享相同的FcRn回收途径，血清白蛋白水平可以反映直接影响IgG抗体清除的IgG分解代谢率。血清白蛋白水平较低的患者清除IgG抗体更快；白蛋白高清除IgG抗体速度就慢。清除速度慢，药物在体内发挥作用的时间就长，治疗获益的概率就大。
这篇论文还纳入了1479名各癌种用icb免疫治疗的患者进行了荟萃研究，认为血清白蛋白水平升高和icb疗效的改善是呈剂量依赖性的。这不仅仅体现在白蛋白水平达标和不达标的患者之间的差异；也体现在即便是白蛋白水平达标以后，也是呈剂量依赖性的。
“As we look forward to the bright future of immune checkpoint blockade (ICB) therapy, there is still lacking a pharmacokinetic marker to understand the inter-individual differences in ICB response. ICB therapy is based on IgG antibodies that share the same homeostatic pathway with serum albumin. Therefore, serum albumin level could reflect IgG catabolic rate that directly impacts the clearance of therapeutic IgG antibodies. Through interrogating a large, clinically representative pan-cancer cohort of 1,479 ICB-treated patients, this study found that higher baseline albumin levels were significantly associated with stepwise improvements in overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) (p<0.001), with the variability and reproducibility confirmed in 1,000 bootstrap-resampled cohorts. Furthermore, these findings were also confirmed in most subgroups defined by patient demographics, baseline characteristics, treatments, and cancer types, even in those with low ICB-responsive cancer types and low tumor mutation burden (TMB) (TMB≤10 mut/Mb) that most of which have not been approved by the US Food and Drug Administration (FDA) for ICB therapy. In summary, this study highlights the importance of pretreatment pharmacokinetic modeling for predicting ICB treatment outcomes. Based on serum albumin-an inexpensive, non-invasive, and easily accessible biomarker of IgG pharmacokinetics, we could take a step further towards optimizing ICB therapy.”
“Albumin and IgG are the first and second most abundant serum proteins in plasma, because both of their uniquely long half-lives depend on the same homeostatic regulation pathway by neonatal Fc receptor (FcRn). FcRn receptor salvages albumin and IgG from intracellular degradation and recycles them into extracellular fluid.Since albumin and IgG share the same FcRn salvaging pathway, serum albumin level could reflect the IgG catabolic rate that directly impacts the clearance of IgG antibodies.Indeed, it is well acknowledged that the clearance of IgG antibodies is faster in patients with lower serum albumin levels.Therefore, there is a strong rationale for using serum albumin as a mechanism-based biomarker to present the pharmacokinetics of therapeutic IgG antibodies. This study sought to propose serum albumin as a potential pharmacokinetic marker in ICB therapy, while conducting an in-depth investigation of the dose-dependent relationship of serum-albumin-based pharmacokinetics with patient survival, disease progression, and treatment response under the therapeutic context of ICB drugs.”
从这点出发，用ICB免疫治疗的前后几天输白蛋白，是一种可以考虑的减毒增效的办法。
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